Interdisciplinary Applied Mathematics

Springer Science+Business Media, LLC

Interdisciplinary Applied Mathematics
Volume 12

Editors
J.E. Marsden L. Sirovich
S. Wiggins
Mathematical Biology
L.Glass, J.D. Murray
Mechanics and Materials
S.S. Antman, R. V. Kohn
Systems and Control
S.S. Sastry, P.S. Krishnaprasad
Geophysics and Planetary Science

Problems in engineering, eomputational scienee, and the physical and biological seienees are
using inereasingly sophistieated mathematieal teehniques. Thus, the bridge between the math-
ematieal seienees and other disciplines is heavily traveled. The eorrespondingly increased
dialog between the diseiplines has led to the establishment of the series: Interdisciplinary
Applied Mathematics.

The purpose of this series is to meet the eurrent and future needs for the interaction
between varlous seienee and technology areas on the one hand and mathematies on the other.
This is done, ftrstly, by ~neouraging the ways that mathematics may be applied in traditional
areas, as weIl as point towards new and innovative areas of applieations; and, seeondly, by
eneouraging other scientifie disciplines to engage in a dialog with mathematicians outlining
their problems to both aeeess new methods and suggest innovative developments within
mathematics itself.

The series will consist of monographs and high-level texts from researehers working on the
interplay between mathematics and other fields of seienee and teehnology.
Arthur T. Winfree

The Geometry of
Biological Time
Second Edition

With 336 lllustrations

, Springer
Arthur T. Winfree
University of Arizona
Department of Ecology and Evolutionary Biology
326 Biological Sciences West
Tucson, AZ 85721
USA
art@cochise.biosci.arizona.edu

Editors
J.E. Marsden L.Sirovich
Control and Dynmnical Systems Division of Applied Mathematics
Mai! Code 107-81 Brown University
California Institute of Technology Providence, RI 02912
Pasadena, CA 91125 USA
USA
S. Wiggins
Control and DynaIDical Systems
Mai! Code 107-81
California Institute of Technology
Pasadena, CA 91125
USA

Mathematics Subject Classification (2000): 92-02, 34C35, 58Fxx, 92Bxx

Library of Congress CataIoging-in-Publication Data

Winfree, Arthur T.
The geometry of biological time I A.T. Winfree. - 2nd ed.
p. cm. - (Interdisciplinary applied mathematics ; v. 12)
IncIudes bibliographical references (p. ).

1. Biological rhythms-Mathematics. I. TItle. 11. Series.

QH527.W55 2000
57 1.7 '7--dc21 00-026155

Printed on acid-free paper.

ISBN 978-1-4419-3196-2 ISBN 978-1-4757-3484-3 (eBook)

DOI10.1007/978-1-4757-3484-3
e 2001, 1980 Springer Science+Business Media New York
OriginaIly published by Springer-Verlag New Vork, Inc. in 2001.
Softcover reprint ofthe hardcover 2nd edition 2001
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 •
I dedicate this book to my parents,
Dorothy and Van,
who first gave me tools.

And I dedicate this book

to those readers who, expecting wonders to follow so
grand a title as it flaunts, may feel cheated by its actual
content. I will be delighted if you take this beginning
as a serious challenge.

•
 . • Preface to the 2000 Edition

After any interval of fru itfu I innovation catches the spotlight there seems to be a
refractory period during which few care to further investigate whatever recently
attracted attention. The first edition of this book captured its biological topics in such a
spotlight, and the spotlight moved on. But it has recently shifted back to some of the
main topics of The Geometry
Geometl}' of Biological Time, e.g., to phase singularities in the heart,
to circadian docks, and to metabolie oscillations, in some cases correcting misimpres-
sions frozen into the 1978 writing, and in others ca ses fulfilling rash inferences largely
based on the analogy of one or another topological concept. What? Topological
concepts in real biology?! Yes, and illuminating a remarkably broad range of biological
rhythms, from the central neural mechanisms of breathing to the collective organization
f1ashing among fireflies. Three concepts pervade
of flashing parvade this diversity. You are invited here
to intimacy with the three notions that:
• "Continuous behavior can be thought of in terms of states serially connected
through a vector field, thus biological dyn..mics in time can be seen as geometry on
an unchanging timeless manifold; and
• "If cell-cell coupling enforces spatial conti~uity of states, then the state manifold of
an excitable tissue during wave circulation becomes equivalent to that of a
spontaneous oscillator; and
• "No manifold can be smoothly retracted onto its whole boundary while leaving that
boundary unmoved."
We are not talking about a mere reconceptualization of known biology, or worse,
just redescribing it in fancy language. Rather, these concepts exposed errors of fact and
pointed to unforeseen facts that no one believed on occasions when they were
encountered by accident, facts that no one would have ever considered looking for.
They present a way of thinking geometrically about biological dynamics,
dynamies, and about the
laboratory experiments implemented to check its counter-intuitive implications. This
way led to intriguing discoveries in several fields, and to questions and puzzles that still
await your attention. I have no doubt that the adventures illustrated here represent only
the crudest beginning.
Tinkering with a book written 21 years ago aga is a peculiar project, more akin to
history of science than research in biological dynamics. Actually, I am as fascinated
by the finding out - especially the processes of asking a different question, of
recognizing hallucinations for what they are, of reformulating reality - as by the
final factual answers. Johannes Kepler stated in the Preface to Astronomia Nova
(1609) that 'What matters to me is not merely to impart to the reader what I
vii
viii PREFACE TO THE 2000 EDITION

have to say, but above all to convey to him the reasons, subterfuges, .and lucky
hazards which led '" to discoveries. When Columbus, Magelhaen, and the
Portuguese relate how they went astrayon their journeys, we not only forgive
them, but would regret to miss their narration because without it the whole, grand
entertainment would be lost." In late December of 1999 at Tucson, sitting in
rebuilt remains of the black swivel chair I bought in 1977 for writing on the Isle of
Palms, I have just spent a few months flipping through my tattered copy of the
1980 printing. Its accumulated marginal notations have now been transferred and
expanded as inserts to the retyped original text. My purpose is to follow its
original topics to maturation or demise during the two intervening decades, telling
some of the unexpected twists and tums taken in the dance of experiment and
theory.
During the 21-year lifespan of today's college senior, two to three Ph.D.
dissertations per year specifically aimed at questions formulated in the old book, and
dose to 5000 new technical papers annotated in my files now inform continuing
interest in those questions. That is too much new material, even for this mostly verbal
history skipping lightly though fascinating adventures to get to the end of the
century and answer, "What is my impression today of answers to queries raised
here in 1978, mostly about the singularities of biological timing, and what are the
outstanding questions inviting answer today?" I did this update in the same way as
the original text, by first writing what I think I understand, then checking in the library
for published instances of the same material, and for counterexamples or unforeseen
discoveries. After finding and studying 300 new research reports during this
sabbatical semester and summer, I replaced by citations more draft text than I
could last time: there are about twice as many per new page, as befits matured
research areas. Two new chapters (16 and 17) constitute almost half the update. To
make room, former Chapters 16 and 17 were compressed into Examples 11 and 12
of Chapter 10, and most of their references and figures were deleted. I also deleted
some papers that appeared merely in topical lists or otherwise entered into no
specific argument. So about nine hundred works cited in the 1980 printing are still
cited, without replacement by more comprehensive reviews or corrections. The
topics of 1978 were largely those I knew from first-hand involvement in formulation
of theory and execution of experiments. Because that involvement intensified
through 1999, almost 6% of the new references are inevitably 'Winfree, 19[80.. 00]." I
apologize for the appearance of braggadocio (ameliorated here by stressing the
known errors of those publications), or worse, for echoing the stereotypical "Did I
ever tell you about my adventures in The Great War... " of a doddering old fossil. I
retain the references anyway to direct you to data that do not appear elsewhere,
without which some current interpretations might seem unsupportable. They also
direct you to seven hundred excellent papers of intermediate vintage that are not
cited again here despite their direct relevance to these topics. This update, with as
many new references entering through new text as remain in the original (see the
vintage histogram atop the bibliography) presents Nature mostly through the
achievements of multitudes of gifted experimentalists and insightful theorists, many
of whom I do not know personally, and some of whom may even be among this
update's readers. I hope you sense my admiration of the amazing fruits of your
patient ingenuity.
 PREFACE TO THE 2000 EDITION ix

5witching perspectives back and forth across so many years every day while writing
highlighted for me a feature of the sociology of science that I had not previously
appreciated: that it seems rare for any experiment to be explicitly repeated in print
either for confirmation or refutation. Repeats are expensive and time-consuming and
seldom make a welcome publication: confirmations would seem redundant, while
refutations irritate and might merely point to a need for explicitness in a Materials and
Methods section. This scarcity of checkups would be okay if the fiction could be
maintained that there is no need, every refereed publication being a permanent stone
in the Cathedral of 5cience. But in the discovery business outside of pure mathematics
both facts and the theoretical frameworks in wh ich we provisionally mount them evolve
as though in a house of mirrors, so that a decade after their publication many things are
no longer "true" in all their originally intended meanings and connotations. There is
seldom found a clear statement that something has been checked and generalized, or
that something else was amistake, or that some seemingly obvious implication in fact
should not be drawn. Many unspoken implications contradict one another, and
anomalous reports tend to be simply omitted from review papers. How can students
simultaneously believe that, once published, not much needs rechecking, and that
literature predating their high-school years has little interest or validity? Reality is so
different! The student naively entering the research library to learn new things (my role
during both writings) finds every proposition and its converse confirmed by one or
another computer model and quite a lot of ostensible contradiction and other
inconsistency in laboratory data, if not always in the words surrounding them. This
introduces a disconcerting uncertainty, particularly when we work in the mode of
mathematical biology, stressing logical consistency over statistical probabilities, and
emphasizing the decimation of models by a decisive test of their unique predictions. It
becomes hard to know what to make of the abundant ostensible counterexamples to
almost every assertion. General Douglas MacArthur is said to have remarked, "Expect
only 5% of an intelligence report to be correct. The trick of a good commander is to
isolate the 5%." With "5" considerably upgraded in application to scientific research
papers crystallized without military haste, one way to adapt to this reality it is to
maximize awareness not only of currently fashionable ways of thinking and choices of
emphasis, but also of how they got that way, and so to appreciate their vulnerability
to reappraisal. The improbable challenge to update across two decades presents a
unique opportunity to try doing just that, coloring the factual content with an interest in
the evolution of understanding. 50 I approached the task of modemizing this old
monograph for graduate students almost as a literary experiment, hopefully with some
interest outside its several narrowly technical specialties. I deliberately refrained from
hiding errors of concept and fact. Instead, lightly shaded inserts show how those now
recognized were corrected. And I draw explicit attention to confirmations or
dlsconfirmations discovered in the literature, wherever they bear directly on the
central themes of the book. The emphasis is more on what we don't understand than
on what we do. I won't know whether the experiment worked until you read it and
inform me at art@cochise.biosci.arizona.edu or the newer winfree@u.arizona.edu.
All new text is in sans-serif font and flagged by shading, except for a few one-liners
flagged only by some such phrase as "In 1999... " and for new chapters 16 and 17,
which appear in sans-serif but with shading restricted to page headers. Old phrases like
"at this writing," "not yet," "recent," "remains to be seen" are now flagged with an "in
X PREFACE TO THE 2000 EDITION

1978" or a "still so in 1999" without shading. I corrected spelling, unclear phrases, etc.
wherever my high-school English teacher would have done so, without flagging these
mutations as such; only changes of scientific content are shaded. A few figures are
improved or discarded; this forced a renumbering only in Chapter 13. These updates
are limited to developments that I perceive as gr6wth from seeds already germinating
in 1978, i.e., limited to topics in the geometry of timing, principally as it involves phase
singularities. The old text was largely about circadian and glycolytic oscillators, topics
both substantially updated here, but the more extensive change is an expansion of
Chapter 9 (Excitable Media) into updates of Chapter 13 (Chemical) and new Chapters
16 (Three-Dimensional) and 17 (Cardiac). These might also be viewed as an update of
Winfree (1987a, The Three-dimensional Dynamics of Chemical Waves and Cardiac
Arrhythmias).
Though I don't believe any of them have yet percolated into textbooks, I am pleased
to see that some of the notions proffered in the 1978 writing are now more widely
accepted. Kenneth J.W. Craik, in his 1943 book The Nature of Explanation, succinctly
captured my present feeling as to how this happened: "If lever conceive any original
idea, it will be because I have been abnormally prone to confuse ideas... and have thus
found remote analogies and relations which others have not considered! Others rarely
make these confusions, and proceed by precise analysis." Many questions requiring
precise analysis are still outstanding, and more have accumulated. Explicit questions that
seem ripe for research today are flagged in the page margins. While I was busy with the
first version of this book, Frank Hoppensteadt also invited "24 Hard Problems about the
Mathematics of 24-hour Rhythms," a chapter of puzzles to which I added a reference in
the page proofs of 1979 without remembering to cite it anywhere. Section D of Winfree
(1998a) has more. Most of those questions remain still unanswered, so I advertise them
again here.
Narrow expertise is a kind of provincialism, inducing arrogance, which, expressed
as deafness, entrenches provincialism. This is a feedback loop familiar in most human
clubs, whether composed of countryside villagers, physicists, doctors, molecular
biologists, or prelates. In attempting this book I have to draw eclectically from such
mutually isolated sources, abandoning aspiration to expertise ... but not abandoning
the will to correct my errors of fact and of perspective. I hope the reader will forgive
many blunders by instructing me to correct them. Your feedback will also be helpful in
maintaining the list of known errors and updates to this book at http://cochise.biosci.
arizona.edu/-artlY2KGBT.html.
Who knows? There might even be a third edition.

Acknowledgments

I confess that of all men I am the least able to traverse so vast a field .... I pray that
men of ability and leaming will examine my work with good will, and when they
find faults will indulgently correct them. That which I offer to the public will have
little value in the eyes of scholars ... but one should always be able to count on the
courtesy of his colleagues.
-Abd-er-Rahman ibn-Khaldun of Tunis,
Muquaddama-al-Alamat (lntroduction to the Universe), 1377
 PREFACE TO THE 2000 EDITION xi

The last exam I had the fun of working through in high school was intended to inform
students of their psychological bias toward one or another career. In my case, the retum
pointed strongly and almost exclusively to two careers: adventurer/explorer, or else
research scientist. I made the choice at the end of the Indian Ocean Expedition in 1964
by not joining a further oceanographic cruise to Antarctica. But a flavor of "The Excellent
Adventures of ATW" from college to full professorship pervades the first edition of this
book, and this update perseveres in the same style with "what happened next." Though
as narrow as any other specialty, this un-named borehole though the world of science
slants across the deep mineshafts of a wide variety of named specialties, traversing a fjeld
too vast for my solo scholarship. I thank my many correspondents and colleagues since
1978 for graciously responding to a chronic barrage of naive questions, and especially
those, e.g., Dwight Barkley, Ding Da-fu, Stephen Dillon, Ce es Diks, Igor Efimov, Paul
Fife, Leon Glass, Jaganathan Gomatam, Michael Guevara, Morris Hirsch, Raymond
Ideker, Jose Jalife, Alain Karma, James Keener, Richard Krasnow, Milos Marek, Ehud
Meron, Alexandre Panfilov, David Paydarfar, Arkady Pertsov, Eric Peterson, Theo Plesser,
Timothy Poston, Brad Roth, Jack Rogers, Steven Scott, John Tyson, Wilbert van
Meerwijk, Brian Welsh, and the late Frank Witkowski, who undertook to rectify my
confusions and find out real answers by analysis, computation, or laboratory
experiments. I am especially grateful for the opportunity to kibbitz medical experiments
(at Syracuse and at Duke until about 1990, at Edmonton until 2000), suggest new
ventures, and see the results: this humbling experience has usefully eliminated a lot of
nonsense. In my own lab, results since 1978 would have been much slower to arrive
without the dedicated technical assistance of Harold Aberman, Scott Caudle, C. C. Chen,
Gang Chen, Marc Courtemanche, Mark Gallagher, William Guilford, Chris Henze,
Wolfgang Jahnke, Patrick McGuire, Erszebet Lugosi, Pramod Nandapurkar, Victor
Reiner, Dean Schulze, William Skaggs, David Stone, Steven Strogatz, Zoltan Szilagyi,
George Twaddle, Erik Winfree, and Michael Wolfson, half of whom took the initiative to
venture into my lab as advanced undergraduates. You all went on to greater things,
followed by my gratitude for your willingness to help me out during the earliest stages of
your own adventures.
Histories of science give me the impression that the actual sources of innovative
ideas are commonly forgotten in later publications. I was taken aback to discover a
striking instance in the original version of this book: no allusion to the works of
Nicholas Rashevsky. In fact, I still find no specific place to use any particular one of his
results. But the Dover paperback of his two-volume Mathematical Biophysics seems in
long retrospect the clear source of many of my biases since that 1961 encounter,
while a sophomore in the Engineering Physics Department at Comell. In particular,
Rashevsky pointed me to reaction-diffusion systems of both chemical and electro-
physiological sorts, and to the variety of their solutions in two- and three-dimensional
geometries. I owe him at least this belated acknowledgment.
The Institute for Natural Philosophy has been the mainstay of my efforts since
1980. I thank the US National Science Foundation for persistently funding my lab
through these two additional decades, and more importantly for funding the many
younger scientists elsewhere whose efforts made this update possible and interesting.
I thank David Paydarfar and others who sent me corrections to the original text. Leon
Glass, John Guckenheimer, Dwight Barkley, and my patient editor, Ach i Dosanjh,
collectively read most of the new insertions; without their patient critique, much that
xii PREFACE TO THE 2000 EDITION

embarrassed me would still be visible. Needless to say, my sparkling wife, Ji-Yun, put
up with a lot of neglect while science magnetized her husband's attention, and
without her love it would have all come to ruin. She also read the manuscript for
comments that I need not retain, saw to it that I delete them, and made the 900 new
references presentable.

AT. Winfree
Tucson, Arizona
Winter Solstice 1999
 Preface to the 1980 Edition

As I review these pages, the last of them written in summer 1978, some thoughts
come to mind that put the whole business into better perspective for me and might
aid the prospective reader in choosing how to approach this volume.
The most conspicuous thought in my mind at present is the diversity of wholly
independent explorations that came upon phase singularities, in one guise or
another, during the past decade. My efforts to gather the published literature during
the last phases of actually writing a whole book about them were almost equally
divided between libraries of Biology, Chemistry, Engineering, Mathematics,
Medicine, and Physics.
A lot of what I call "gathering" was done somewhat in anticipation in the
form of conjecture, query, and prediction based on analogy between develop-
ments in "different fields." The consequence throughout 1979 was that our long-
suffering publisher repeatedly had to replace such material by citation of
unexpected flurries of papers giving substantive demonstration. I trust that the
authors of these many excellent reports, and especially of those I only found too
late, will forgive the brevity of allusion I feit compelled to observe in these
substitutions.
It is clear to me already that the materials I began to gather several years aga
represented only the first flickering of what turns out to be a substantial
conflagration. Accordingly, I took a liberty with the 1978 reference list. You will
notice that about 20% of its entries are not to be found in the page index of
publications cited. That is because they are not explicitly cited. Readers who like
to browse will easily find these extra papers: they lie among papers on similar
topics by much-cited authors. They lead in the directions of significant
expansion .
.. In eed they did, so t ey are less interesting today: I ave accordingly deleted them.
The new and shertened eid reference lists, each new with about 900 iterns, are
al habetized tegether. ...
And what comes next? WeIl, one never knows; that is half the fun of doing
science. But one inevitable development is especially conspicuous by its absence
here. In fact, the original 30 chapters came down to 23 by purging 7 to ripen further
into a later volume 1. You will find here almost no mention of rhythmic drlving of

L This became The Timing ofBiological Clocks Freeman. 1986 and When Time Breaks DOWn: The Three-
Dimensional namics ofElectrochemical Wayes and Cardiac Arrh>: hmi{lS, Princeto,n Univ. Press, 1987.

xiii
xiv PREFACE TO THE 1980 EDITION

biological dynamics. Plainly that must contain the essence of any practical
application, be it in honnonal gating of cell division, in cardiac or gastric
pacemaking, or in agricultural photoperiodism. Many surprises await discovery in
connection with alternative modes of entrainment, the consequences of synchro-
nization, and evolution in periodic environments. This topic is the natural successor
to the present volume on autonomous periodicity. It is now undergoing rapid
development, mainly at the hands of neurobiologists, mathematicians, and
engineers, and will be riper for harvest a few years hence. 2
A residue of loose ends (questions for research) is largely collected in the index
under "Queries."

.. Surv1vors and replacernents are instead flasged in the margins for-the Y2K Edition ....

It has been my good fortune to visit lively investigators in many laboratories.

I have been stimulated by early exposure to their discoveries (which fill out so
much of the following chapters), and their critical attention to my own seminars
has refined into presentable fonn most of what is presented here. But I have
never found an opportunity to teach on these subjects, as you can see by the
lack of problem sets in this presentation. I suspect that substantial improve-
ments of content and clarity as weIl as significant new directions would
inevitably emerge through contact with students who are eager and ready to
study living systems in a mathematical spirit. That is a hard clientele to locate; I
could use some help.
I wish you good reading and wish you to send me marginal notations to collect
on my copy. Who knows? There might even be a second edition. 3

Acknowledgments
I wrote this book but its authors live all over the world. In a broad sense the list of
authors is the bibliography. But in a more precise sense this gathering of facts and
ideas was shaped by about twenty-five individuals whose conversation and
correspondence molded every topic represented here. Many others also will
recognize in these pages the distorted reflection of their own imagination and
skepticism. Rather than belabor the apologies and disclaimers usual in books of this
sort, let me just remark that without the impact of Ralph Abraham, Arthur Brill,
Rohert DeHaan, Wolfgang Engelmann, Brian Goodwin, Hennan Gordon, Joseph
Higgins, Walter Kaufman-Bühler, Stuart Kauffman, Richard Levins, Robert
MacArthur, Graeme Mitchison, Jay Mittenthal, George Oster, Theodosios Pavlidis,
Colin Pittendrigh, John Platt, Kendall Pye, John Rinzel, Frank Rosenblatt, Otto
Rössler, Rene Thom, John Tyson, and Trisha Woollcott, my explorations into the
dynamics of evolved life would have lacked the special richness and color that I here
seek to share.

See Glass, L. and Mackey, M.C. From Clocks & Chaos: TheRhyrhms vf Li{e Princeton Uni\'. Press. 1988.
After a second printing in 1990 that fixed many typos, Ihis is it.
 PREFACE TO THE 1980 EDITION XV

Perseverance in this line of inquiry was made possible by the generous financial
support of the National Science Foundation since 1965 and of the National
Institutes of Health during 1973-1978. I am especially indebted to my department
chairmen, Jack Cowan and Henry Koffler for safe escort through the three grades of
professorship while I remained lost in the dream world here described.
Finally, I wish to acknowledge the frequent restoration of my sanity by the
turquoise waters, white sands, and blinding sunlight of the Isle of Palms, South
Carolina, where most of these pages were first drafted in 1977.

A. T. Winfree
West Lafayette, Indiana
April 1980
xvi PREFACE TO THE 1980 EDITION

•
Imagine that we are living on an intricately patterned carpet. It may or may
not extend to infinity in all directions. Some parts of the pattern appear to be
random, like an abstract expressionist painting; other parts are rigidly
geometrical. A portion of the carpet may seem totally irregular, but when the
same portion is viewed in a larger context, it becomes part of a subtle
symmetry.
The task ofdescribing the pattern is made difficult by the fact that the carpet
is protected by a thick plastic sheet with a translucence that varies {rom place
to place. In certain places we can see through the sheet and perceive the
pattern; in others the sheet is opaque. The plastic sheet also varies in
hardness. Here and there we can scrape· it down so that the pattern is more
clearly visible. In other places the sheet resists all efforts to make it less
opaque. Light passing through the sheet is often refracted in bizarre ways, so
that as more of the sheet is removed the pattern is radically transformed.
Everywhere there is a mysterious mixing of order and disorder. Faint lattices
with beautiful symmetries appear to cover the entire rug, but how far they
extend is anyone's guess. No one knows how thick the plastic sheet is. At no
place has anyone scraped deep enough to reach the carpet's surface, if there is
one.

-Martin Gardner
Scientific American
March 1976, p. 119

•
 Contents

Preface to the 2000 Edition vii

Preface to the 1980 Edition xiü
mmOOu~oo Dill

1. Circular Logic 1
A: Spaces 1
B: Mappings 4
C: Phase Singularities of Maps 24
D: Technical Details on Application to Biological Rhythms 30

2. Phase Singularities (Screwy Results of Circular Logic) 41

A: Examples 42
B: Counterexamples 75
C: The Word "Singularity" 77

3. The Rules of the Ring 80

A: Basic Principles, Paradigms, Language Conventions, and Epistemology 80
B: Dynamics on the Ring 83
C: Derivation of Phase-Resetting Curves 88
D: Historical Appendix 97

4. Ring Populations 101

A: Collective Rhythmicity in a Population of Independent
Simple Clocks 101
B: Communities of Clocks 119
C: Spatially Distributed Independent Simple Clocks 134
D: Ring Devices Interacting Locally 138

xvii
xviii Contents

5. Getting off the Ring 146

A: Enumerating Dimensions 146
B: Deducing the Topology 147
C: The Simplest Models 149
D: Mathematical Redescription 151
E: Graphical Interpretation 155
F: Summary 159

6. Attracting Cycles and Isochrons 161

A: Unperturbed Dynamics 161
B: Perturbing an Attracting-Cycle Oscillator 177
C: Unsmooth Kinetics 188

7. Measuring the 'frajectories of a Circadian Clock 198

A: Introduction 198
B: The Tune Machine Experiment 200
C: Unperturbed Dynamics 206
D: The Impact of Light 213
E: Deriving the Pinwheel Experiment 216
F: So What? 220
G: In Conclusion 228

8. Populations of Attracting-Cycle Oscillators 229

A: Collective Rhythmicity in a Population of Independent Oscillators:
How Many Oscillators? 230
B: Collective Rhythmicity in a Community of
Attracting-Cycle Oscillators 231
C: Spatially Distributed Independent Oscillators 236
D: Attracting-Cycle Oscillators Interacting Locally in
Two-Dimensional Space 250

9. Excitable Kinetics and Excitable Media 258

A: Excitability 258
B: Rotors 264
C: Three-Dimensional Rotors 291

10. The Varieties of Phaseless Experience: In which the

Geometrical Orderliness of Rhythmic Organization
Breaks Down in Diverse Ways 303
A: The Physical Nature of Diverse States of Ambiguous Phase 304
B: The Singularities of Unsmooth Cycles 333
C: Transition to Bestiary 336
 Contents xix

11. The Firefly Machine 338

A: Mechanics 338
B: Results 341
C: Historical 344

12. Energy Metabolism in Cells 347

A: Oscillators 347
B: The Dynamics of Anaerobic Sugar Metabolism 348
C: The Pasteur Effect 350
D: Goldbeter's PFK. Kinetics 351
E: Phase Control by ADP 353
F: More Phase-Resetting Experiments 354
G: Results: The TIme Crystal 355
H: A Repeat Using Divalent Cations 359
I: A Repeat Using Acetaldehyde 360
J: Phase Compromise Experiments 366

13. The Malonic Acid Reagent ("Sodium Geometrate") 368

A: Mechanism of the Reaction 371
B: Wave Phenomena 377
C: Exdtation in Nonoscillating Medium 382
D: Wave Patterns in Two- and Three-Dimensional Context 383
E: Pacemakers 406

14. Electrlcal Rhythmicity and Excitability in Cell Membranes 411

A: Rephasing Schedules of Pacemaker Neurons 413
B: Mutual Synchronization 422
C: Waves in One Dimension 428
D: Rotating Waves in Two Dimensions 432

15. The Aggregation of Slime Mold Amoebae 443

A: The Life Cycle of a Sodal Amoeba 443
B: Questions of Continuity 446
C: Ceil Chemistry and Cell-Ceil Coupling 449
D: Phase Resetting by a cAMP Pulse 451
E: Historical Note 453

16. Numerical Organizing Centers 455

A: Seroil Filaments in 1Wo Dimensions 456
B: Seroll Rings Shrink and Drift 467
C: Linked and Knotted Ring Anatomy 469
xx Contents

D: Linked and Knotted Ring Dynamies 472

E: Efforts to Analytically Derive and Numerically Confirm the
Laws of Filament Dynamies 474
F: The Discovery of Persistent Ring Configurations 483
G: For the Future 490
H: Transition to Chapter 17 About Heart Muscle 492

17. Electrical Singular Filaments in the Heart Wall 495

A: Rotors in a Field of Coupled Oscillators 498
B: The Pinwheel Experiment 505
C: Pinwheel Experiment Revisited (PER) 518
D: Two- vs. Three-dimensional Instabilities of the Singular Filament
in Heart Muscle 525
E: A Quick Summary of the April 1997 Experiments 532
F: What's Next? 533

18. Pattern Formation in the Fungi 537

A: Breadmold with a Circadian Clock 538
B: Breadmolds in 1Wo-Dimensional Growth 539
C: Pattern Polymorphism in Bourret's Nectria 540
D: Integration of Pattern 543

19. Circadian Rhythms in General 545

A: Some Characteristics of Circadian Rhythms 561
B: ClockEvolution 576
C: The Multioscillator View of Circadian Rhythms 585

20. The Circadian Clocks of Insect Eclosion 592

A: Basics of Insect Eclosion Clocks 592
B: Phase and Amplitude Resetting in Drosophila Pseudoobscura 606
C: Other Diptera 620

21. The Flower of Kalanchoe 624

A: Type 0 Resetting 624
B: Resetting Data at Many Stimulus Magnitudes 627
C: A Phase Singularity 630
D: Arrhythmicity Not an Artifact of Populations 630
E: Amplitude Resetting 631

22. The Cell Mitotic Cycle 632

A: Three Basic Concepts and Some Models 634
B: Regulation of Mitosis by the Circadian Clock 640
 Contents xxi

C: Further Developrnents in the Area of Circadian Rhythrns, Applied Back to

the Cell Cycle 642
D: Physarum Polycephalum 644

23. The Female Cycle 650

A: Wornen, Hormones, and Eggs 650
B: Statistics ("Am I Overdue?!") 653
C: Rephasing Schedules 655
D: The Question of Srnoothness 657
E: Circadian Control of Ovulation 658

Index of Author Citations and Publications 661

Index of Subjects 761
 Introduction

Ubi materia, ibi geometria.

-Johannes Kepler, 1571-1629

This is a story about dynamics: about change, flow, and rhythm, mostly in things
that are alive. My basic outlook is drawn from physical chemistry, with its state
variables and rate laws. But in living things, physical and chemical mechanisms are
mostly quite complex and confusing, if known at all. So I'm not going to deal much
in mechanisms, nor even in cause and effect. Instead I will adopt the attitude of a
naturalist-anatomist, describing morphology. The subject matter being dynamics,
we are embarked upon a study of temporalmorphology, of shapes not in space so
much as in time. But by introducing molecular diffusion as a principle of spatial
ordering, we do come upon some consequences of temporal morphology for the
more plainly visible shapes of things in space.
This is a story about dynamics, but not about all kinds of dynamics. It is mosdy
about processes that repeat themselves regularly. In living systems, as in much of
mankind's energy-handling machinery, rhythmic return through a cyele of change is
a ubiquitous principle of organization. So this book of temporal morphology is
mostly about circles, in one guise after another. The wordpwe is used (over 1,200
times in 1978) to signify position on a cirele, on a cycle of states. Phase provides us
with a banner around which to rally a weiter of diverse rhythmic (temporal) or
periodic (spatial) patterns that lie elose at hand all around us in the natural world. I
will draw your attention in particular to "phase singularities": peculiar states or
places where phase is ambiguous but plays some kind of a seminal, organizing role.
For example in a chemical solution aphase singularity may become the source of
waves that organize reactions in space and time.
This book is intended primarily for research students. Readers who come to it
seeking crystallized Truth will go away irritated. I suspect that the most satisfied
readers will be those who come with revisionist intentions, seeking the frayed ends
of new puzzles and seeking outright errors that might lead to novel perspectives. I
am confident that you will find plenty of both, since this project has ramified into
more specialty areas than I can keep abreast of, ranging from topology through
biochemistry. I've done all I can to eliminate nonsense from earlier drafts, with
indispensable help from my very critical friends, especially Herman Gordon and
xxiii
xxiv INTRODUCTION

Richard Krasnow. But the material is kaleidoscopic. As long as I work at it, the
pieces keep rearranging themselves into tantalizing new patterns. Most of these
dissolve under continued scrutiny but more remain than I can pursue. I have chosen
to lay them out in the one-dimensional way inevitable to written communication as
follows.
~ At the time of this Y2K update I am more impressed y human ability to narrate long
about visions seen from one direction only, that are often mirages. We begin to feel
that a new thing has reality only when we see it from several directions or stumble
across it along multiple paths crossing through that part of a multi-dimensional space.
So this update strives to embed each new item in several pertinent contexts. The Index
is useful for finding them all. ...

This volume has two roughly equal parts. The first half mainly develops a few
themes in an order natural to the fundamental concepts involved. The second half is
organized more like a "dramatis personae." I call it the Bestiary. It teIls about the
organisms or other experimental systems from which the conceptual themes arose.
In more detail:
Experiments with docks and maps constitute the principal theme of this book.
Phase singularities figure prominently in these experiments. Secondary themes will
be played through again and again in different contexts: the progression from
dynamics in a single unit (a cell, an organism, a volume element) to collective
dynamics in populations of independent units, then to populations of promiscu-
ously interacting units, and to populations arranged in space with interaction
restricted to immediate neighbors (as by molecular diffusion). New phenomena
emerge at each level.
Apart from those themes, the material gathered here might at first seem to have
few unifying features. I have chosen examples from a diversity of living organisms
and nonliving experimental models. Each recurs in several places, illustrating
different points. Dur trail through this jungle of exotic flowers intersects itself in
several places as these themes surlace again and again in new combinations, in new
experimental contexts.
The material is handled in three ways:
1. A single thread of text proceeds through the first half of the book under 10
chapter headings. By the following two devices this part is kept as lean as
possible to enable the reader to seoot through for perspective before choosing
where to invest more critical thought.
2. Along the way, frequent allusion is made to endosed "boxes" of finer print, each
elaborating a particular point, raising questions for exercise or research, or
offering an anecdote. These stand aside from the main thread of text like scenic
overlooks along the toll road. I think they contribute interest and perspective,
but you may want to pass over them until you locate the chapters dosest to your
particular interests.
3. The second half of the book is a Bestiary of 13 chapters about particular
experimental systems. These provide background facts about the organisms or
phenomena most frequently alluded to in the first half of the book. These
might be the most interesting chapters for readers with little use for theories
 INTRODUCTION xxv

and models and for readers unfamiliar with the experimentallaboratory. I had
to put one or the other perspective first and naturally some people think I
should have chosen the other way around. I think that only your taste should
determine whether you read the Bestiary first, or the preceding abstract
notions that inter-relate its contents.
The whole is sandwiched between a table of contents and an extensive
bibliography.
In your first glance through these pages you will notice a mathematical flavor
about some topics. Though my aim is to avoid mathematical "models" wherever
possible, some reasoning with symbols seems inevitable to this subject matter.
Mathematics enters in four ways:
1. Simply using numbers to quantify experimental data for presentation as graphs
and for comparison with quantified ideas about their meaning ("models").
2. Using digital computer languages to implement data handling and to extract
implications from numerical statements of an hypothesis. For example, we
might assume that in some useful approximation ceIls divide when some
constantly synthesized substance accumulates to a critical concentration, and
then digitally seek the implications for a compact tissue in which this substance
leaks between adjacent ceIls.
3. Using standard undergraduate mathematics to extract such implications when
conjectures can be formulated in terms tractable to geometry, elementary
differential equations, and so on. I've made a big effort to avoid mathematical
equations. This is only in part because I seldom manage to get equations right.
My deeper motivation is a feeling that numerical exactitude is alien to the
diversity of organic evolution, and pretense of exactitude often obscures the
qualitative essentials that I find more meaningful. My aim is to get those right
first. And that purpose seems better served by words and pictures supplemented
by occasional numerical simulations and lots of experimental measurements.
4. Employing a little of the language of topologists in an effort to extract from
models or from observations what seems to be the essence of their behavior,
independent of quantitative variations. Such efforts are fraught both with
technical difficulties and with the ever-present danger of extracting mathema-
tically trivial tautologies while discarding as "mere quantitative variations" all
that is of factual interest about a particular phenomenon. Nonetheless, I believe
such efforts constitute an indispensable prelude to explanation: "What is the
phenomenon to be explained, as distinct from incidentals to be glossed over?
What aspects require explanation in terms of empirical cause and effect, and
what aspects are merely mathematical consequences of fads already known?"
It is my belief that the life sciences in particular have much to gain from, and
perhaps something to contribute to, mathematical developments in the general area
of topology. I wish the reader to consider this. Thus I will dweIl on such topological
notions as I have found useful in designing experiments and in interpreting their
results. From heuristic beginnings, my own efforts seldom go far toward logical
rigor, yet I have found much satisfaction in the fruitful dialog between theory and
experiment that this approach has fostered.
xxvi INTRODUCTION

,.. A caution: the word "topological" is (mis}use in recent biomedical literature as a

synonym for "qualitative" in geometrical contexts, e.g./ about the shapes of proteins
or of cortical maps. This book stiJI uses it as in most 'prior biological literature, in
physics, in mathematics, and in chemistry, to connote certain precise features (having
three holes rather than one, being connected like-a sphere not Iike a torus, having two
dimensions rather than one) that are independent of continuous quantitative variations
of shape. <c

We turn now to the simplest abstractions about "rhythms," "cycles," and

"docks," with a few examples. Examples are merely mentioned here, pending their
fuller description in later chapters, where the context is riper.
 DIM"'äi'

Circular Logic

Philosophy is written in this great book-by which I mean the universe-which

stands always open to our view, but it cannot be understood unless one first
leams how to comprehend the language and interpret the symbols in which it is
written, and its symbols are triangles, circles, and other geometrie figures,
without which it is not humanly possible to comprehend evenone word of it;
without these one wanders in a dark labyrinth.
-Galileo Galilei, 1623

My objective for this chapter is to draw your attention to a few peculiarities inherent
in the logic of periodic functions. I find a visual approach the most fruitful for
thinking about such matters. As the pictures involved consist mainly of mappings
between circles and products of circles, I must first say a few words about the
notions of topological spaces and mappings. This chapter thus has four seetions:
A. Spaces, with emphasis on rings (Le., elosed loops. To avoid the more exact
connotations of the word circle I use ring, trusting the reader to not confuse my
meaning with algebraic rings).
B. Mappings, with emphasis on the winding number of mappings to a ring
C. Phase singularities of maps, with emphasis on the consequences of a nonzero
winding number
D. Technical details on the application of circular logic to biological rhythms
The next chapter goes on to examine experimental examples of mappings to the
ring that contain phase singularities. Discussion specifica1ly focusing on the
physical nature of phase singularities in each case is reserved to Chapter 10.

A: Spaces
As used in this book, a topological space is a collection of points connected in some
way. Spaces are distinguished by the distinctive manner in which these connections
are made, Le., by the rules that associate to any given point an immediate
neighborhood of other points. Six examples follow:
1. The real number axis, denoted by IR l , is a topological space. Each real number
lies arbitrarily elose to a slightly bigger number and a slightly sma1ler number.

A. T. Winfree, The Geometry of Biological Time 1

© Springer Science+Business Media New York 2001
2 1: CiRCULAR LOGIC

This ordering of points stretches from minus infinity to plus infinity or from
zero to infinity, as in rays from an origin. Any endless open line or curve that
does not cross itself is topologically equivalent to IR 1. The great majority of
familiar variables of concern in science and in schools are represented by real
numbers: time, chemical concentration, temperature, energy, etc. A finite
interval of 1R 1 is called 01 • Geneticists, for example, derive from breeding
experiments a number between 0 and! that teIls how far apart any two genes are
along the chromosome to which both belong. The space of genetic map
distances is thus 01 . (For interesting exceptions, see Example 4 below).
The variables of concern in this volume are of a fundamentally different sort
(Example 4).
2. The unlimited two-dimensional space of plane geometry, denoted 1R2 , is another
topological space. Its connectivity is richer in that points can be neighbors
without being greater or less than each other. There are two dimensions, a
north-south axis in addition to an east-west axis. This is the space of complex
numbers or, if you like, pairs of numbers. It is the topological product of two
independent IRvs (e.g., two perpendicular real number axes), thus the notation
1R 1 x 1R 1 = 1R2 A finite section of a two-dimensional space, a bed sheet or a
blackboard, for instance, is topologically equivalent to 01 x 01 = 02 , and is also
equivalent to the unit disk 1!}2, whose boundary is the unit cirele §1 to be
considered below.
3. In three-dimensional space the neighborhood relationship is richer still: Points
can be distinguished even when identical in respect to east-west and north-south
position. Unbounded three-dimensional space is denoted by IR 1 X IR 1 X IR 1 = 1R3 • A
cubical chunk of it is ß3 (the product of three intervals). Asolid spherical chunk
of it, a ball, is topologically equivalent to 03 (just round off the cube's corners).
4. Retuming to one-dimensional spaces, consider the isolated segment 01• By
joining together (or identifying, as topologists would say) the ends of the line
segment, one forms the circle or ring. The cirele is conventionally denoted 1R 1 for
"one-dimensional sphere," and is of paramount interest in this monograph. All
elosed one-dimensional manifolds are topologically equivalent to § 1. A manifold
is a topological space that is locally Euclidean: a figure-8, for example, is not a
manifold due to the crossing point, but a pair of disjoint cireles is; a plane with a
hole cut out is a "manifold with boundary".

Several quantities of familiar practical science take their values not on the real
number axis 1R 1 but on the ring §1: angles or compass directions, perceived hues of
colored objects, orientations of a receptive field of a ganglion cell in the retina, and
phases in a cyele, such as the time of day or the season of the year.
Shortly after Lederberg's discovery of sex in bacteria made it possible to apply
the standard techniques of genetic mapping to bacteria, geneticists encountered an
amusing dilemma that could only be resolved by abandoning the notion that genetic
maps are mappings from an observable frequency of certain genetic events to a
segment 01 of the realline. That assumption implied that there is a unique distance
between any two genetic loci. The following experiment violated that implication.
Up until about 1961 it had always been found that if three genes lie in order ABC
(Figure 1) along the genetic map and if a fourth gene D is found to lie in order ADC,
 A: SPACES 3

(0) (0)
Figure 1. Three loei on a genetic map assumed topologically
equivalent to 0'. •....- - - - - - -...- - - - 4
ABC

then it will necessarily He in segment Aß or in segment BC. But this proved not to be
true of bacteria and, later, of viruses! The genetic crosses often showed that the
genes lay in order DAß or BCD, seemingly incompatible with the view that D is
between A and C. More crosses showed that bacterial and viral genetic maps have
the connectivity of a ring. On a ring, D can He bt!tween A and C along any of three
arcs (Figure 2). The surprising topological discovery that the numerically
constructed genetic map has the connectivity of a ring of course suggested that
the genetic material is physically ring-shaped. This was eventually proved by direct
obseIVation of bacterial (Stahl, 1967) and viral (Thomas, 1967) chromosomes.

A
(0)

figura 2. Three loei on a genetic map assumed topol,ogically

equivalent to §'.

(0)

S. One two-dimensional analogue of a ring is the surface of a doughnut, alias torus,

§l x §l = T 2. (The one-dimensional torus Tl is the same as §l: a ring). This
surface can be formed by swinging a ring around in a ring perpendicular to its
plane; such a surface is the product of two rings. Each point of T2 can be
identified by giving its position on its two generating circles as two angles or
two phases. This is the natural space for representing astate given by two
independent angles, e.g., the space of physiological times, compounded of the
hour of the diurnal cycle and the season of the annual cycle.
6. The product of §l by itself is called T 2, not §2. §2 is reseIVed for the two-
dimensional surface of a sphere. The connectivity of §2 is natural for
representation of directions in three-dimensional space, e.g., the orientation
of apolar molecule floating in solution, or of aspace shuttle during maneuvers
in orbit, or the direction to a star or the position of a ship at sea.
There are many other finite-dimensional topological spaces, which in a natural
way represent the possible values of quantities of concern in experimental science.
Those Hsted above constitute a sufficient catalog for our present purposes, so we
turn now to mappings.
4 1: CiRCULAR LOGIC

B: Mappings
A "map" takes points in one space (the source space) to certain points that the map
identifies as the "corresponding points" in another space (the target space). This
could be done in a piecemeal way or it could be done continuously. By continuous, 1
mean that sufficiently nearby points in the source space remain nearby in the target

Figura 3. A map from one real number axis to another.

space. 1 Thus the mapping amounts to a distorted image of source space in the target
space. The maps we work with in this volume will always be continuous, even
smooth, except at isolated points or along a special locus. Such points or loci
constitute the main focus of all that follows. Before proceeding to examine such
irregularities, you may want to refresh your familiarity with smooth maps by
reading through the following 14 examples. A good Scientific American reference is
M. Shinbrot, 1966.
1. Rl _ Rl : Input a number, output a number. This kind of map, a function of one
variable, is most conveniently portrayed as a graph (Figure 3), depicting, for
example, the light emission as a function of time in a culture of glowing cells, or
land elevation above sea level as a function of distance along U.S. Route 90 from
Chieago.
2. R I _ 1R2 : Input a number, output a point on aplane. This kind of mäp maps the
line onto the plane (Figure 4). It could be represented as an image of the source
spaee IR l in the product spaee IR I x 1R2 = 1R3 of the source spaee and the target
space, as in the first example. Figure 4 is just this three-dimensional plot seen in
two-dimensional projeetion. (Any map can be so represented but it beeomes
visually inconvenient exeept in the very simplest eases). For example, IR l might
be time and 1R2 might be the eoneentration of two substanees in a chemical
reaction. The map then eonstitutes a "trajectory" of the ehanging ehemical
composition. (If the reaction is exaetly cyelic, so that its state in concentration
spaee moves in a eirele, then the map in IR l (time) x 1R2 (coneentrations) looks
like a eorkserew or helix). Such trajeetories will be useful in Chapter 7.

1 Continuity defined: F(X) is continuous at X '" A means that

1. F is defined at A.
2. The limitx~A F(X) exists.
3. The limit F(A) is the same when X approaches A from any and all directions.
Such a map is additionally "c I .. if the rate of change of F as X varies is also continuous, and "c;oo" or
"smooth" if this is true for partial derivatives of all orders.
 8: MAPPINGS 5

y
t
figur. 4. A map from the real number axis to the plane, geometrically
viewed in the product space 1R3 , seen in planar projection.

y v

figura 5. The xy plane is mapped into the uv plane (not intended to portray specific features
common in retinotectal maps).

3. 1R2 _ 1R2 (or n2 _ n2 if finite): Input a point on a plane, output a point on some
other plane (or on some two-dimensional surface topologically equivalent to a
plane). For example, the source space might be the retina of a frog's eye and the
target space might be the frog' s optic tectum. The map is then the retinotectal
projection of ganglion cell fibers onto their cortical targets. A convenient trick
for visualizing such a map (Figure 5) is to rule a coordinate grid on the source
space (e.g., retina) and then examine its distorted image in the target space (e.g.,
tectum), or vice versa, as is in fact the habit ofvisual electrophysiologists (Gaze,
1970; Jacobson, 1970). In Chapters 8 and 9, the source space will be a two-
dimensional disk of reacting fluid and the target space will be the state space
identifying the local chemical composition by two concentrations. The map is
the image of the disk in this state space. In this format the kinetics of reaction
interacting with molecular diffusion turns out to be more readily comprehen-
sible than in more familiar formats. We will find many occasions throughout
this book to think in terms of a two-dimensional medium's image in some state
space.
4. 1R2 _1R 1: Input a point on a plane, output a number. This is a simplified version
of the preceding map, in that instead of associating two independent numbers
with each point in the source space (the plane), we pay attention to only om
target coordinate. The contour map is a familiar convenience for representing
such a mapping. Each contour line depicts the locus of points on the plane
which all map to the same point of the real number axis. In other words, a
coordinate grid has been ruled on the target space. This "grid" in one dimension
6 1: CiRCULAR LOGIC

consists merely of equispaced tick marks. We examine its image in the source
space. The grid image in the R2 _ R2 maps considered above is just a
superposition of two contour maps, one for the east-west coordinate in the
target space, and one for the north-south coordinate. In R2 - R1, we deal with
only one of these. As an example consider the temperature distribution in a
sheet of encapsulated liquid crystals used for temperature sensing. Each
temperature corresponds to a color. The bands of color on the plastic sheet
constitute a contour map of the temperature field showing how the two-
dimensional sheet maps onto the temperature axis. Another example is the
familiar geodetic sUIVey map of any two-dimensional area, showing contours of
altitude above mean sea level.
Dimension-reducing maps such as R2 _ R1 correspond in a natural way to the
process of measurement: Some aspect of a more richly variable phenomenon is
singled out for attention by such a map, typically by reduction to a single number.
5. §2 _ §1: Input a direction in space or a point on a sphere, output a number or a
point on a line.
The principle is the same as above. Examples: the familiar weatherman's
contour map of barometrie pressure around the globe, or the amplitude of radio
reception as a function of orientation of an antenna.
The next four kinds of map involve conversions to and from the cirele or ring § 1.
Topologists call the line R1 (for one-dimensional real number) and the circle §1 (for
one-dimensional sphere) because these are very different objects. This book exploits
the differences.
Few indeed are the instruments of modem science that report back a point on
a cirele (compass, goniometer, circular counters) rather than a point on the line
(thermometers, volt meters, pH meters). The mainstream of experimental science
has always flowed along the real number axis R1 and its product spaces. It wasn't
until 1953 that anyone even went to the trouble to formalize an equivalent of
Gaussian statistics for observables on §1 (Gumbel et al., 1953; Greenwood and
Durand, 1954; Zar, 1984). Nonetheless, just as the practical mathematics of
engineering and science is mostly about numbers on the realline, so the practical
mathematics of things periodie and rhythmic is mostly about points on the cirele.
7

Figur. 6. A map from each point on the ring to its own number between
o and 1.

o
6. §1 _ 01: Input an angle or a point on a ring, output a number or a point on a line
segment. See Box A.
 B: MAPPINGS 7

Such a -map is inscribed on every compass and protractor and on the face of
every dock. Around the circular edge one finds numbers from 0° to 360 or from 0
0 ,

to 12 or 24 hours. If each point on the ring maps to a different number, there must
inevitably be a discontinuity, e.g., at the point in Figure 6 that maps to 1 or O.
Note that in this volume I adhere to the navigators and dock maker's
convention when it is necessary to label points on the ring as though they were
numbers: We go dockwise from north at the top. Mathematicians and the makers of
protractors tend to go anticlockwise from east at the right.
7. §I - 1R 1: Input a point on a circle, output a point on a line.
The tangent function of trigonometry is an example (Figure 7). It produces a
number ranging anywhere from -00 to +00 depending on the angle given. The act

o x= tan 2'/Tcp

figur. 7. A two-part map from the ring to the infinite line.

i
There is a discontinuity at ± cycle.

..'

of measuring a biological rhythm might be considered another example of this kind

of map; given a phase in the organism's daily cycle, there corresponds the numerical
value of some quantity that we find it convenient to measure, such as a diurnally
fluctuating body temperature or a rhythmically varying chemical concentration or a
rate of egg laying.
~ Humans in "tempora l isolation" in an environ ment lack ing th e usual time cues, e.9 .,
living in a subterranean cave for some weeks er months, ma intain an astonishingly
accurate circadi an rhythm, estimated in Wi nfree (1983a, 1984a, 1986a) 35 24 hours and
18 minutes :!: about 6 mi nutes, confirmed in Czeisler et al. (1999) as 24 hou rs and 11
minutes:!: about 3 minutes. Its phase at the onset of sleep (a point on §1) provides a
reliable forecast of the duration of that sleep until next spontaneaus waking (a point on
R'). As Figure 7.1 shows, this dependence contains a large d iscontin uity, a critical
phase before which the duratio n of sleep will not exceed 10 hours er so (average
a bout 7), but after which the d uration of sleep abruptly switches to at least 13 hou rs
(average about 17!). Same cla sses of dynamical model fo r the neural mechanism s
invelved are incempatib le with areal discontin uity in this map, so it was regarded as a
steep segme nt of a continuous dependence until another d ass of model made th is
interpretation more acce ptable (see Box A of Chapter 20.) The theorist has an option
here, to regard this actually as a map from §1 (sl eep onset phase) to §1 (wake Oflset
phase). As we wil! see below (item 14), discontinuities arise more natura lly, even
inevitab!y, in such maps. Could this topological fact point the way to a reinterpretation
of human sleep timing? ....
8. 1R 1 _ §l: Input a point on a line, output a point on a circle.
8 1: ClRCULAR LOGIC

2T 2T
NEXT
® WAKE
ONSET
WAKE
ONSET

.: " '. .
"~"'- "

. ..... .
r-<I~"""""~ ~ .' :.! \ • ~

o
:
"
"
. .
:"
,'.
®
~ . ..t . . . .
"" • 1,- •
~""
!.+ • ,,'
"
. ,
. ........
.' .'

: ," . T

NEXT
SLEEP SLEEP
ONSET ONSET
2T 2T

Figure 7.1. Dn the right, the observeq drcadian- phase of spolltaneolls w.aking lS double-
plotted as a funct!on Qf the priofphase of sleep onset (subject Je of Jouvet et al.. 1~7 4), The
duration of sleep is the phase difference, constant alo09 norizontaHines-in tnis plot there is a
big -discontinuity, (And on the left, that phase at ~aking is 'pl6tted 'Jgainst the n.xt sl~
onse, reveallng no fuoctional dependence,) (From Winf(ee, 1983a, Figure, 13, witf\
p'ennission. - •

An example of such a map is the visual angle between the Moon and the Sun as a
function of time. As the year advances this angle varies through one full monthly
cycle and repeats itself during the next month and the next and the next. It can be
thought of geometrically as wrapping the real line (the time axis) around and
around the cirele. As noted above, anY map can be thought of as an image of the
source space in the product of source and target spaces. In this case the product
space is a cylinder, 1R 1 x §1, and the source space's image on the cylin4er is a helix
(Figure 8).
9. ßl -t §1: Input a number between 0 and 1, output a point on a cirele or ring.
An example is the inverse of map 6, which necessarily suffers the same
discontinuity though in reverse: While nearby numbers always map to nearby points
on the ring, so do some quite different numbers near the extremes of the interval.
This underlies the necessity of an International Date Line (see Box A) and accounts
for the principal annoying feature of compasses and protractors: We have to
remember that 360 0 is the same as 00 • Figure 9 depicts this map as an image of 01 in
the product cylinder 01 x § 1• This picture is equivalent to Figure 6.

{2} Figura 8. A map from the real number axis to the ring,
geometrically viewed in the product space.
 B: MAPPINGS 9

Any map to §I can also be colorfully depicted as a contour map on its source
space using bands of different hues. It is a curious fact of human vision that we
elassify spectral distributions of light in a way that has circular connectivity: Red is
elose to orange is elose to yellow is elose to green is elose to blue is elose to indigo is
elose to violet is elose to red is elose to orange .. " So the different kinds of map from
any space to §I can be represented by the qualitatively different ways to paint that
space with different hues.
Maps to § I are a primary theme of this book.
10. §2 _ §I: Input a point on a sphere, output a point on a circie.
A weather map's depiction of worldwide wind directions is such a map. Some
''homing'' and migrating birds apparently convert the three-dimensional orientation
of the Earth's magnetic field (which can be described as a point on a sphere of
directions) to a compass heading (a point on a ring). Another instance of such maps
o 0 t ... 1

O_-_-_-_~I'li//~)
END-ON SIDE VIEW
F"l9ure 9. The map of Figure 6, geometrically viewed in the product space.

occurs in the crystallization of synthetic polypeptides and polynueleotides (artificial

analogues of biological proteins and genetic material). Such substances are fibrous,
giving to each point on the surface of a crystalline ball (§2) an orientation. The
orientation may be specified as a point on an abstract sphere (§2) or, given that the
fiber lies in the plane of the surface, on an abstract ring (§I) of compass directions.
There is no way to cany out such a map smoothly. There must be at least one point
of confused orientation. These points are elearly visible by polarized light
microscopy (see Robinson, 1966; Wilkins, 1963; Anderson et al., 1967).
11. 1R2 _ § I: Input a point on aplane or any curvy two-dimensional surface
topologically equivalent to the plane, output a point on a cirele.
Consider, for example, a sheet of cells, all of which are regularly carrying out
some rhythmic function such as cell division. Given a sufficiently elear snapshot of
such a sheet of cells, one could write labels all over it indicating at each point in the
plane what stage of the cyele the cells have reached. Such maps will playa central
role in our discussion of peculiarities in the rhythmic morphogenesis of slime molds
and of fungi, and of the periodie organization of oscillating chemical reactions in
space.
Glass (1977) calls such maps "phase maps" and uses them to interpret the
peculiar symmetries of regeneration and reduplication in the growth of embryos
and in the restoration of amputated limbs in lower animals capable of such tricks
(see Example 11 in Chapters 2 and 10). We use that name here not only for maps of
phase on real physical space, but also on state spaces (see below). The term's quite
different usage in Wever (1979) will not concern us here.
10 1: ClRCULAR LOGIC

Box A: The International Date Line

The roads by which men anive at their insights into celestial matters seem to
me almost as worthy of wonder as those matters themselves.
Johannes Kepler, Astronomia Nova (summary ofCap.45), 1609
As Example 6 (§l _ ~l) suggests, a difficulty arises in trying to reconcile the notion of
cyclic daily time (a point on a clock rim) with the notion of progressive linear time (in a
history book). When an astronaut traces the path of Pan American #2 eastward from
San Francisco back to San Francisco in qhours, flying 200 miles above the sea, he
passes through zones of local time that advance through one full day. So he must anive
back over San Francisco 1~ hours later, but in tomorrow! That is not wbat an observer
on the ground would say. Nor would the astronaut.
The 18 survivors of Magellan's expedition around the world were the first to present
this dilemma for the bewilderment of all Europe. After three years westward sailing,
they first made contact with European civilization again on Wednesday 9 July, 1522 by
ship's log. But in Europe it was already Thursday the 10th! Pigafetta writes (translated
in Stanley's The First Voyage Around The World, Hakluyt Society, vol. 52, 1874, p. 161):
In order to see whether we had kept an exact account of the days, we charged
those who went ashore to ask what day of the week it was, and they were told
by the Portuguese inhabitants of the island that it was Thursday, which was a
great cause of wondering to us, since with us it was only Wednesday. We could
not persuade ourselves that we were mistaken; and I was more surprised than
the others, since having always been in good health, I had every day, without
intermission, written down the day that was current.
Cardinal Gasparo Contarini explained the discrepancy as due to the westward
direction of the voyage-in 13th century Abu-I-Fida of Damascus knew the globe is ~ sea, .
and that circumnavigation would cost you or gain you a day, and some Arab learning bad
percolated into Europe through occupied Spain. But seeing theory confirmed in practice
still excited the humanists ofthe sixteenth century with the same sense ofwonder (Zweig,
1938) we feel about the space-time singularities that our relativity theorists impute to
black holes, perhaps more wonder inasmuch as the missing day was a direct human
observation.
As far as lamaware, the young Lewis Carroll (later to author Alice in Wonderland)
was the first to stiggest what to do about it, in a whimsical essay in The Rectory Umbrella
published about 1850 (reprinted by Dover, 1971). This was 19 years before Charles
Dowd proposed implementing the "Time Zones" originally suggested by Benjamin
Franklin, for the sake of simplifying transcontinental railroad timetables based on
myriad local city times. Carroll wrote:
Half of the world, or nearly so, is always in the light of the Sun: as the world
turns round, this hemisphere of light shifts round too, and passes over each
part of it in succession.
Supposing on Tuesday it is morning at London; in another hour it would be
Tuesday morning at the west of England; if the whole world were land we
might go on tracing2 . Tuesday Morning, Tuesday Morning all the way round,

2 The best way is to imagine yourself walking round with the Sun and asking the inhabitants as
you go "what moming is this?" if you suppose them living all the way round, and all speaking one
language, the difficulty is obvious.
 B: MAPPINGS 11

till in 24 hours we get to London again. But we know that at London 24

hours after Tuesday morning it is Wednesday moming. Where then, in its
passage round the Earth, does the day change its name? where does it lose
its identity?
Practically there is no difficulty in it, hecause a great part of its joumey is
over water, and what it does out at sea no one can tell: and besides there are so
many different languages that it would he hopeless to attempt to trace the
name of any one day all round. But is the case inconceivable that the same land
and the same language should continue all round the world? I cannot see that
it is: in that case either there would be no distinction at all between each
successive day, and so week, month &cc so that we should have to say "the
Battle of Waterloo happened to-day, about two million hours ago," or some
line would have to be fixed, where the change should take place, so that the
inhabitant of one house would wake and say "heigh hol Tuesday momingl" and
the inhabitant of the next, (over the line,) a few miles to the west would wake a
few minutes afterwards and say "heigh hol Wednesday momingl" What
hopeless confusion the people who happened to live on the line would always
be in, it is not for me to say. There would be a quarrel every morning as to what
the name of the day should be. I can imagine no third case, unless everybody
was allowed to choose for themselves, which state of things would be rather
worse than either of the other two.
Thus we have the International Date Line, established 1800 from Greenwich,
England in 1878. When an astronaut crosses that line in the mid-Pacific Ocean
moving from west to east, he pops back 24 hours into yesterday, so when he arrives
back over San Francisco it is 1~ hours later today, not tomorrow. Each new date
starts along this line as it rolls through midnight. Tomorrow has then begun. The
International Date Line leads an expanding crescent of tomorrow around the east
side of the Earth into the dawn light, around through noon and dusk and back to
midnight (see figure below). When the Date Line reaches the midnight point it starts
the next day in the same manner. Thus the citizens of Tafahi in the Tonga islands
are among the first to report back to work after each weekend. Meanwhile, their
neighbors on Savia in nearby Western Samoa, 150 miles to the east, greet the same
day as a Sunday.

.. Iii) 978 flnding out this litt e fact of ooscure geograpliy for this Box, l feit -t was exotic.
ow things ~ave clfangedl.ln 1999 an intell1et site WaS a ctioning the rights to perform
"the first k\ss, , etc .• of the.J'lJew Millennium, wlth the blessing of King Taufa'ahau Tupuo IV
öf J'onga ..Tonga is ~Iso seiling<:lomain_names *:to by ;redit card on tJie w~b. This is more
or less th.e story of! great many topics updated in the next s;x hundred pages: quite a few
-forme y obscure exotica experienced their 15 minutes of ~tne durihg the intervening 20
ears. ... '
By glib reference to this line the modem astronaut excuses hirnself from what
seemed a bewildering conundrum to Pigafetta. Yet there remains something peculiar
about this line. What kind of line is it? Evidently it is not a circle since it was
transgressed only once in a flight from San Francisco to San Francisco. So it ends
somewhere. What if I go to the end and walk around it, cross over, walk around the end
again, cross over again, and so on? Can I ratchet myself into the remote future or past, a
day at a time? Unfortunately not. The International Date Line has its endpoints at the
poles, the two phase singularities implicit in mapping the glohe onto an equatorial
circle of 24 hours [see Figure 10 (right) and Example 3, next chapter]. It gains back for
12 1: ClRCULAR LOGIC

NOON
The Earth viewed from astation above the North Pole (NP).
Monday started when the Intemational Date Une (IOL) rotated
through midnight. A satellite poised above the midnight
point can connect Sunday morning and evening with Monday
moming.

us the day lost in walking a loop around the pole. Viewed in this way, the Date Line is a
necessary consequence of the geometry of a rotating planet; but somehow its
inevitability doesn't make it any more intuitive.
~ Starting around 1980 a comparable dilemma emerged from the efectrical mapping of
circulating activation patterns on the heart surface by simultaneous pickup fram many
electrodes. Successive positions of the activatian front are conventionally plotted on one
map spal1ning the duration of one cycle without overlap. Tnen the last cantour, called tne,
"frame line," is drawn thicker to demarcate the equivalent of an IDL, and it reappears on
the next map as the first of another cycle of contours....

Phase maps will also serve us weIl in discussing circadian rhythms in flies
(Chapter 20). The source space is either a two-dimensional physical space such
as a desktop or the more abstract two-dimensional space of different stimuli
determined by two quantities at the experimenters' disposal. The target space is
the phase of a circadian rhythm reset at that place or by that stimulus. Such a
map is drawn point-by-point by simply measuring the phase in §i associated
with each point in R2 . It is convenient to run a smooth curve through all points
in R2 that correspond to the same phase. Winfree (1967a) dubbed such curves
"isochrons" ("same-times") on account of the usual association of §i with a
rhythm in time (see Chapter 6).
12. §2 ~ ~2: Input a point on a sphere, output a point on aplane.
These maps include the many projections used by geographers to map the globe,
inevitably with some distortion, onto the flat page of a book. As we all realize,
perhaps with a residual twinge of perplexity since being intimidated by a fourth
grade geography teacher's inadequate explanation, these maps never quite cut the
mustard. Unless the Earth's surface is printed as at least two disjoint regions, there
always arise points or curved paths at which the distortion is infinite (Figure 10).
 B: MAPPINGS 13

Q b
ONE SINGULARITY TWO SINGULARmES
Figur. 10. Two ways of mapping the sphere on a flat (POLAR PROlECTlON) (AXIAl. PROJECTION)
surface. Mapping onto the unbounded plane on the
left requires a singularity (at the North Pole) and
pushes it out to ~nfinity. Mapping onto a cylinder on
the right requires two singularities (one at each pole),
pushed to opposite infinities.

These are called singularities. They playaprominent role in this book, starting with
the next chapter.
13. IR? -+ §2: Input a point on a plane, output a point on a sphere.
In a microtome slice through a fibrous biological material, such as insect
cuticle, microscopic fibers at various points on the section plane can be
characterized by orientations in three-dimensional space. One geometrically
convenient way to visualize the pattern of fiber directions is to think of orientation
as a point on the sphere and to map each point of the section onto its corresponding
orientation by appropriately stretching an image of the section plane onto a
spherical surface. This map may be many-to-one if several regions (or even a one-
dimensionallocus) of the section plane have the same fiber orientation. Just such
maps provided a key to a puzzle about the ultrastructure of the insects' corneallens
(Example 12 of Chapters 2 and 10).
14. §I -+ §I: Input a point on a ring, output another point on a ring.
Maps from rings to rings resemble the simplest maps treated above (example
1, from the real line to the real line) but with a surprising new feature. The
periodicity inherent in a ring results in the kind of quantization which allows us to
classify continuous §I -+ §I maps into distinctly different types. (This is in fact
precisely the origin of quantization in the physics of hydrogen atoms around
1912). Each "type" is associated with an integer-valued "winding number." The
winding number is the net number of times the output value runs through a full
cycle around a ring, as the input value is varied once forward along its ring.
Because these topologically distinct types arise again and again in our
experimental observations, I take time here to give eight examples and to dweIl
at some length on the logic of maps among rings.
Just as the map from IR I to IR I is most conveniently displayed as a curve in the
plane 1R2 , the product of IR I and IR I , so any map from §I to §I is most conveniently
displayed as a curve on the product space §I x §I = T 2 , the surface of a doughnut.
If there is a unique output value qy' ("phi-prime") corresponding to each input value
r/J, then the curve relating r/J' to r/J is a closed ring, reaching once around the r/J axis and
necessarily retuming to the same qy' value after it is followed once around (Figure
11). But notice that such a curve can link any number of times through the hole. It
can wind any number of times around the r/J' axis during each circumnavigation of
14 1: ClRCULAR LOGIC

Figure 11. A map from § 1 to § 1, viewed geometrically in the

product space.

the <p axis. This integer winding number distinguishes qualitatively between the
kinds of § I to § I map.
Unfortunately, toroidal graph paper does not easily fit into a book. We must
map the torus onto the plane of the page. In Figure 11 I attempted this one
way but it leaves much to be desired since some regions are badly distorted and
half of the surface is hidden behind the other half. A convenient alternative is
to map §l x §I -+ 1R 1 X IR! by unrolling the two circular axes along
perpendicular linear axes. This is equivalent to cutting the torus open along two
perpendicular cireles and stretching it into a flat square, then repeating these
square unit cells in all directions (Figure 12). It would suffice to present one
unit cell since all the rest are identical, except that to do so hides the continuity
of the data from the right side of one unit cell to the left side of the next. So I
will usually present 2 x 2 unit cells or one surrounded by fragments of the
eight adjoining cells.

o
Figure 12. A ring on the torus, laid flat for convenient inspection. Repeated as 2 x 2 unit cells
on the left, and on the right as a unit cell flanked by fragments of adjacent reduplications.

In this format, the winding number of a map is revealed by the number of unit
cells through which the data elimb vertically in the space of one unit cell
horizontally. Examples follow:
Example A. Red is elose to orange is elose to yellow is elose to green is
elose to blue is elose to indigo is elose to violet is elose to red is elose to
orange: ROYGBIVRO. Thus hue (disregarding saturation and intensity) is a
psychophysical quantity with the connectivity of a ring (see Box B). In a
photograph taken under a colored light, hues appear altered. The change of hue
can be depicted as a map from the color ring to itself: §l -+ §1. Suppose for
example that a colorlul butterfly is taken indoors to be photographed by the
 B: MAPPINGS 15

Box B: The Colors of Flickering Ughts

It tums out that the purely abstract ring of hues can be put into a practically useful
correspondence with the phase ring of a rhythm in real time. If a light-dark alternation
is displayed at a frequency on the order of several cycles per second, one sees a
flickering gray. Now if a line drawing is briefly illuminated during the nondark half
cyde, its black ink seems tinged with color, and the color varies according to the phase
of its presentation in the light-dark cyde as suggested in Figure a. The eighth of over a
dozen published rediscoveries of this phenomenon, by C. E. Benham, was implemented
in 1894 as a popular toy in England, a spinning disk decorated with annular patterns of
black and white called "Benham's top" (Figure b). The "waveform" of the black-white
cyde determines a color.

RED

a) Timing of black-and-white picture presentations to

elicit various color sensations. High position indicates GREEN
picture cutoff (dark). The arrows show when to
project a black and white image in order to tinge
its black areas with the indicated color.
BLUE

b) When this disk is rotated clockwise at 300 rpm, the

innermost rings appear red and the outermost appears blue
(or vice versa if anticloekwise). The middle rings are greenish .

.. The mec anisms of this perception remain only Piilrtly aise osed. 6ut they seem to
involve- phase-sensitive lateral interactions among neurons,' both in the retina and in the
brain. The ex{;ellent revieW by von Campenhausen qnd Schramme (1995) perrnits me to
delete here a paragraph of mistaken speculations and questions of vintage 1978. But it
does not perrnit replacement by a paragra h of definitive e~lanatiQns . ...

Despite ignorance of its physiological origins, television engineers managed to parlay

Benham's Top into a scheme for broadcasting color pictures over black-and-white
transmitters and black-and-white horne receivers. The device is called the Butterfield
(1968) color encoder. Three color filters are arranged on a rapidly spinning wheel to
alternate with three consecutive opaque segments in front of the television camera. The
red-blocking filter immediately follows the opaque tcyde. Then comes a green
16 1: C1RCULAR LOGIC

blocking filter, then a blue-blocking filter. Since black lines seen early in the nonopaque
cycle appear red, and those seen in the middle appear green, and those seen at the end
appear blue, this phased presentation of the three complementary color images
reconstructs a colored picture on the black-and-white television screen.
1ts first public demonstration was a soft-drink advertisement over station KNXT in
Los Angeles. Nothing was said about color, to the constemation of thousands of viewers
who seemed suddenly to be hallucinating. 1ts last public demonstration was in
Argentina during political advertisements by Eva Peron.
Unfortunately the perceived color proved to vary from individual to individual and
depends unpredictably on the colors of its surrounding background. Moreover the effect
works best at five to ten cycles per second. The resulting flicker of the color picture was
so distasteful to television audiences that they preferred to buy the more cosdy RCA tri-
phosphor system or to forgo the color and stick to black-and-white transmissions in
which the flicker can be made so fast as to escape perception.

bluish glare of fluorescent lights. Each color on its wings is mapped to a

similar, but not identical, color on the photographic print through a
combination of the emission spectrum of the lamp and the absorption spectra
of the photographic emulsion and its dyes. If we restrict our interest to hues,
ignoring saturation, then the color map is §1 to §1. It is continuous because
similar colors similarly affect the emulsion. The map might have winding
number W = 1 if all hues still appear under the bluish light [Figure 13 (right)]
or it might have winding number W = 0 if the blue is so pure that every color
is captured as some shade near blue [Figure 13 (left)].
Example B. A rowboat in a strong current holds a compasS heading in
direction </>. It proves convenient to measure </> on a scale 0 to 1: north is 0, east is
1, south is !, west is i. The boat's actual track is a straight line in some other
direction </>'. The map from heading to track is §1 to §1. The character of this map
is determined by the speed of the boat in the water, relative to the current. Figure
14 depicts the rowboat R at a point in the stream. The stream's velocity is
indicated by the vertical arrow. Its speed is v*. If the rowboat heads in direction
RH (compass heading </» at speed v relative to the water, while the water flows
downstream at speed v*, then the rowboat's actual track is RR' relative to terra
firma. The rowboat's velocity component toward the shore, BH or AR', is v
sin(21T</». Its velocity component parallel to the shore, RA, is v COS(21T</» -v*. The
ratio of these two components is AR'IRA = tan(21T</>'), so
tan(21T</>') = v sin (21T</»/[V COS(21T</» - v*]

>
äi

~
~I----p..~~ W=1
m

~ ........
_-'-----'
ROYGBIVROYGBIV ROYGBIVROYGBIV

F"tgure 13. Two qualitatively distinct maps from the color ring to the color ring.
 B: MAPPINGS 17

NORTH

- ~ -: \
:. ~~><,' .::.:.>
, .."

Figure 14. A rowboat heads in direction r/> at

speed v while being carried south in current v". ...>.. ' . ..
ß 1 BH ~
.p'
~t·· :. :
v..·· .."
'/.'.' .
:. ". .'
Its actual track is in compass direction r/>'. . " . . ..' .

...'. . t A R' t ":'.··W·

. ::'.:~·. '.
.. .'
. ..
"

.' . .'
SOUTH

or in terms of "slowness," 5 = lIv, additionally adopting the more compact notation

sn rjJ = sin(271'rjJ), and similarly cs for cos and tn for tan:
, sn rjJ
tn rjJ = cs,+,-s
A. / *.
s

Figure 15 plots several of these heading vs. track or rjJ' vs. rjJ conversion curves
for various rowing speeds v. Note the qualitative transition at v*/v = 5/5* = 1. At this
speed the boat cannot track upstream against the current and the map's winding
number switches from 1 to O. We will see this formula again in context of circadian
rhythms.

N t---+----+~ N r--+---+--I
W W
V*<V ~ V*>V 5 W=O
E
N J---,f---t---I N 1---1---+--1

NESWN NESWN
Flgure 15. Four qualitatively distinct maps 4/ = f(ep}; the dashed curves represent the extreme
cases v" = 0, v* --> 00.

Example C. Local time varies with geographie longitude. At any moment, one
is a function of the other: a map from §l (longitude) to §l (dock phase), This map
(Figure 16) constituted the whole motivation for the design of mechanical docks
with such accuracy as we take for granted today. Who would have cared to
monitor Greenwich Mean Time (GMT) precisely in a world still free of bus, train,
and jet schedules? Maybe astronomers. But the practical impetus to develop docks
came from merchants, whose mariners could reckon a ship's longitude only by the
four-minute-per-degree discrepancy between local noon and the GMT chron-
ometer on board (see Box C). San Francisco time changes as GMT changes. The
dependence of San Francisco time on GMT is the same kind of map from §1 --->
§I (Figure 17): Both have winding number W = 1.
(Examples A, B, and C are elaborated as Examples 1, 2, and 3 in the next
chapter).
18 1: CiRCULAR LOGIC

Figure 16. Clock phase varies one-to-one with longitude.

0"--360"
PHASE OIFFERENCE

Example D. A starling is ready to migrate south, a direction it knows relative to

the Sun. A physiologist (Hoffmann, 1960) resets the phase of its circadian dock by
six hours (one-quarter cyde) and releases it. It flies off in some other direction
relative to the Sun's azimuth, specifically about 90° away (one-quarter cyde). The
map from dock phase to flight direction is §1 ~ §1. It has been measured in a few
kinds of organism. A Type 1 map (winding number W = 1) was found in the sunfish
(Figure 18). A Type 0 map (winding number W = O)was found in the pond skater
(insect) (Figure 19).
Example E. A regular oscillation goes on in all the growing cells of a fungus.
The fungus is a thin sheet, growing only along its border. The border is a ring. The
phase of the oscillation varies locally. How does phase vary with position along the
ring-like border? The answer can be represented as a map from position (along a
ring) to phase (along a ring) (Figure 20). See Chapter 4, Section C; Chapter 8,
Section C; and Chapter 18.
Example F. Microorganisms sometimes make seawater glow around a
swimmer at night. Hastings and Sweeney (1957) made the sensational discovery
that, when brought into a dark laboratory, such water glows again at 24-hour
intervals. Moreover, if exposed to light at phase <jJ of the rhythm, the suspended
animals reschedule their glow as though thephase <jJ had been some other phase <jJ'.
The map from old phase <jJ to new phase <jJ' is §1 ~ §1. This example is developed
further in Section D.
Example G. Consider an optical device, in outward appearance resembling a
telescope, in which you view a scene. As you rotate the eyepiece, the scene rotates.
The angle of eyepiece rotation <jJ is indicated against a degree scale by a fiduciary
black dot. The angle of scene rotation () can be read against the same scale by
projecting the obvious upward direction from the center of the scene (as in Figure
21). Plot () vs. <jJ must be a smooth curve of some integer winding number. By
thinking of simple experiments (such as rotating yourself, rotating the degree scale,
rotating the scene), can you show that the winding number is necessarily zero? If
so, what do you make of the accompanying mall-order catalog advertisement which
makes it appear that one rotation of the eyepiece results in two rotations of the
scene: winding number ±2? I was so perplexed by this paradox that 1 ordered one of
the optical devices advertised (in a less expensive version). When it came, 1 looked
through it at my page of notes purporting to prove that winding number ±2 is
impossible. It was impossible to read the proof! The reason for this and the reason
for the irrelevance of the "proof' turns out to be that the optical device presents a
mirror image of the scene viewed through it (see Box D).
 B: MAPPINGS 19

Box C: Clocks and Maps

In Isaac Newton's day, ships sailed east and west with no practical means for
determining longitude. The sextant sufficed for latitude, hut without the longitude, life
was too frequently tragic for navigators and their crews, drowned on unexpected reefs
while the hest commercial fruits of Europe littered the sandy bottom. Navigators wrote
books on the problem. Outlandish schemes were tried. The best, originally due to
Galileo, permitted determination of longitude at all the chief ports of call in both
hemispheres, and did so with startling precision, but was impractical on a ship's deck in
weather. This scheme used a telescopic sighting of Jupiter's four moons together with a
table of their anticipated positions as a function of Parisian local time. The Jovian
satellites provided a universal dock of unfaltering precision hy which to know Paris
time. A sextant observation determined Iocal time by determining the moment when the
Sun or some other star reached its maximum altitude. The difference, a fraction of 24
hours, is a phase point on a cirde that can be reinterpreted as the cirele of longitudes at
~o of west longitude per minute of delay (360°/(24 x 60 minutes».
It was seldom possible to observe the celestial chronometer from a rolling ship's
deck. Nonetheless, two hundred years after Magellan's extravagant experiment of 1519-
1522 (see Box A), it was dearly recognized that the Iongitude could best be acquired as
a map from one ring to another: from the face of a 24-hour chronometer to the required
coordinate on the circle of 360°. So serious was the need that the Admiralty offered a

Shown here heavily restored and working, John Harrison's first attempt at the Longitude Prize
weighed 75 pounds. Its 3-pound great grandchild (H-4) claimed the prize. Photograph Courtesy
of National Maritime Museum, London. Since 1993 all four reside in the Old Royal Observatory
at Greenwich.
20 1: ClRCULAR LOGIC

prize of 20,000 British pounds (in 1714 currency: some millions of U.S. dollars today)
for a sufficiently accurate ship chronometer. So taxing was the challenge that for 45
years "the longitude prize" was household metaphor for "the impossible" - somewhat
like "the perpetual motion machine" today.
But in 1759 John Harrison's H-4 was complete. On a stoIm-racked 81-day trip to the
West Indies it erred by only 5 seconds (1/17,000 of a cyde), corresponding to 1! miles at
equatorial latitudes, and so claimed the advertised prize in 1763. Harrison never
received it.
Those who, like myself, are stirred to transports of excitement by this sort of tale will
want to savor the marvelous essay entitled "The Longitude" by Brown in vol. 2 of The
World of Mathematics (J. R. Newman, ed., Simon and Schuster, New York, 1956) and
The nlustrated Longitude, D. Sobel and W.J.H. Andrewes, Walker and Company, N.Y.
(1998).

Figura 17. San Francisco time varies one-to-one with Greenwich time.

0_24 hr
GREENWICH MEAN TIME

..
W
,. .
5 . F1gura 18. The direction of sunfish movement VS. time of day (data

.
! i replotted from Braemer, 1960, Figure 7). Note that the left and right
edges are the same (midnight) and the top and bottom edges are the

..
E
same (north) .

N
MID- NOON MID-
NIGHT NIGHT

W .. Figura 19. Angular orientation of a water strider to an artificial sun

5 .. 'I. vs. time of day (data replotted from Birukow, 1960, Figure 2). Note
that the left and right edges are the same (midnight) and the top
and bottom edges are the same (north). Five more such appear on
E
p. 304 of The Handbook of Behavioral Neurobiology volume 4
(1981), ed. J. Aschoff.
N
MID- NOON MID-
NIGHT NIGHT
 B: MAPPINGS 21

Figura 20. Eaeh point of the frontier ring of arhythmie fungus maps to the phase of the loeal
rhythm at that point. In this example every point maps within about one-fifth of the eyde. Points
at the same north-south latitude are mapped to the same phase.

Figura 21. A eatalog advertisement for a Dove prism and

a seene viewed through a Dove prism image rotator.
,
..... _-

Example H. Consider a wave circulating around a ring, such as a nerve

impulse going around and around a ring of heart muscle or around the
circumference of a jellyfish. For our simple purposes, we might think. of each
little piece of tissue as repeatedly traversing a continuous cycle of states with
landmarks conventionally denoted "rest," "excited," "refractory," "relatively
refractory," "rest," "excited," and so on. At every instant each point on the
physical ring is somewhere in this cycle. At any instant (on a snapshot of the ring)
the map from ring to cycle is §l ~ §l. If a solitary wave revolves clockwise, the
mapping has winding number + 1. It has winding number -1 if the wave
circulates anticlockwise. Two pulses chasing each other around a ring correspond
to a map of winding number ±2, Le., weaving around a line of slope ±2, etc.
(Figure 22). If the ring beats almost homogeneously, then the map varies about
the horizontal, with mean slope 0, and so its winding number is O.
15. §l x §l ~ §1: Input two independent points on a ring (two phases, a phase and an
angle, two directions, etc.), output a point on a ring (a phase, a direction, etc.).
These maps, like the §l ~ §l maps considered above, can be classified byan
integer winding number. Maps with different winding numbers have qualitatively
22 1: ClRCULAR LOGIC

Box D: The Dove Prism Paradox

Suppose you have a deviee, something like a teleseope in outward appearanee, through
whieh you ean peer at the standard optieal objeet, an arrow (Figure a, top). We will
eonsider rotations about the eommon axis of your eye and the deviee. The arrow is
mounted perpendieularly on this axis. Suppose first that we rotate the deviee and the
arrow together, as though rigidly eonneeted, through an angle rjJ. This is equivalent to
rotating your eye (yourself) through -rjJ about the same axis. The image of the arrow on
your eye must then rotate to angle rjJ. Now rotate the deviee alone back to its former
position, through angle -rjJ. The arrows image has thus been rotated through some
additional amount (} =f( -rjJ) eharaeterizing this deviee, for a total rotation of rjJ + f{ -rjJ).
This result is the same as though you and the glass had remained fixed while you
m
watehed someone rotate the arrow to rjJ so its image must also rotate to rjJ [see below].
So we have that rjJ + f( -rjJ) =rjJ, whieh means f( rjJ) =0 eontrary to the advertised miraele of
f{rjJ) =2rjJ. Yet the deviee can be purehased and the image of the arrow does revolve fully
twiee, uniformly, as the deviee is turned through a full eirele! What's going on?

<{- - - - - - - ~
(D __ 1_\
90 0
1
I- - - - - - - -

j a
~o
EYE DEVICE ARROW

J
b
Looking at an arrow through an image rotator. The eye sees the arrow as shown in Figure 21.

When the prism arrived 1 re-read my proof of its nonexistenee, then opened the box.
Unwrapping the prism, 1 eagerly peered through it at the nearest object, the proof. It
was unreadable! No, not quite, but just mirror-imaged, besides being rotated. It turns
out that the arrow's mirror image rotates onee clockwise as the arrow turns onee
counter-clockwise. So at the (:t) above, rjJ must be replaeed by -tjJ, whereupon f(rjJ)
beeomes 2rjJ as advertised.
In fact the wondrous deviee is nothing more than a mirror with refraeting prisms to
straighten out the refleeted optical axis (Figure b, bottom).

different properties. Such maps and their winding numbers play an essential role in
much that follows. We begin with four examples:
Example A. Suppose a smooth chemical oscillation, e.g., glycolysis in yeast cells
(Chapter 12), is going on in each of two equal volumes. Ghosh et al. (1971) made the
intriguing discovery that when such volumes are abruptly combined, the hybrid
 B: MAPPINGS 23

-9
'"

RING OF TISSUE IMAGED ON CIRCLE OF STATES

U'J$distance) (9-= time)

Figur. 22. Upper left: Distance around a ring of tissue is denoted by 0 :s; rP <1. Upper right:
Each point of the ring maps to a phase 0 :s; rP <1 in the cyde of local excitation and recovery.
Given two circulating pulses, the ring's image wraps twice around the cyde of states. Lower:
The same map from rP to 9 is diagrammed in starker format.

volume continues to oscillate at some compromise phase somehow detennined

between the two "parent" phases. This compromise would be most naturally
described by a mapping from the phase cirele of parent A and the phase eirele of
parent B to the phase cirele of the combined volume: §I x §I -+ §I.
ExampleB. Suppose a motor neuron in a running insect fires at some phase in the
rhythmic cyele of locomotion as in the experimental studies of Stein (1974). Let this
phase be detennined by the timing of two impulses received in each cyele: one from
a left leg proprioceptor and one from a right leg proprioceptor or one each from fore
and aft segments. The dependence of firing phase on the input phases is most
naturallyportrayedas afunction oftwophases: ifJ' = F(ifJA, r/>a), thatis, F: §I x §I -+ §I.
Example C. An airplane's compass reads a direction, a phase on the horizon
circle. But before it can be useful, installed among the distortions of Earth's field
caused by the motor and radios, the compass must be adjusted. This is done by
moving two litde screws, each of which rotates a pair of tiny magnets geared
together beneath the compass. With the plane facing in one fixed direction, the
compass reading depends on the orientations of the two pairs of magnets: once
again a map from §I x §I -+ §I.
Example D. At the Kodak Museum in Rochester, New York, there is a device
in which two plastic wheels overlap in front of a diffuse light. Each wheel
supports around its perimeter a continuum of colored celluloids, running
through the whole color circle ROYGBIVROY. By rotating these wheels, you
can superimpose in front of the light two filters of any chosen hues and obsexve
24 1: ClRCULAR LOGIC

the resulting hue. The perceived overlap hue is detexmined by two hues: Once
again this is a map §l x §l _ §l.
Examples E+. Many other topological maps naturally organize little areas of
experience. Celestial navigation is largely about maps from the product of three
circles (input: time, season, and sextant angle) to a sphere (output: your position on
the globe). The quantum mechanics of electrons and other fexmions concems maps
to and from the three-dimensional projective plane 1R!?3, which is locally §2 x §l
Bolker (1973). This is also the topological space of fibril orientations in a wide
variety of biological polymers.

... Examples include the plant cell wall (Emons and Mulder, 1998). arthropod cuticle
(Bouligand, 1972a, 1978; Gordon and Winfree, 1978; Bouligand, 1986), the cornea of
the human eye (Gordon, 1976). Its two-dimensional version is the space of elongated
fibroblast orientations in a culture dish (Eisdale and Wasoff, 1976), offingerprint ridges
(Penrose, 1979), and of retinal line orientations processed by the visual cortex of the
brain: like fibers on a plane, lines can be oriented in any direction, and directions 180 0

apart are indistinguishable. This will give us phase singularities in Example 17 in

Chapter 2 and in Chapter 10.
The cortex can also be mapped for sensitivity topreferred directions of line motion.
This map turns out to be coupled to the orientation map, the wo angles together
describing aspace topologically equivalent to the Klein bottle, X 2 (Tanaka, 1995;
Swindale, 1996). Theonly otherinstance ofsuch an exotic map in biology, asfaras I know,
is the putative map from the sole ofthe foot to the sensory cortex mentioned in the first
edition ofthis book 0/Verner, 1970). I never heard any more aboutthat one. This one, too,
proves a little disappointing in that its projection on thetwo-dimensional cortex turns out
notto be continuous. Each ofthe two kinds of closed ring that can be traced on the Klein
bottle, when continuousJymapped to the cortex would have to encircle a discontinuity,
presumably a point of phase singularity. But in fact, the discontinuity of direction turns out
to be an extended line connecting point singularities of orientation; in crossing that line,
the direction inverts abruptly, As Sherlock Holmes remarks at the outset of A Question cf
Identity, "life is inflnitely stranger than anything that the mind of man could invent. We
would not dare to conceive thethings thatare really mere commonplaces ofexistence.
if we could ... it would make all fiction ... most stale and unprofitable." -41

Let's stop without inttoducing any more topological spaces as raw materials,
and begin to investigate some of the curious logical implications of maps among
circles: what I call "circular logic."

C: Phase Singularities of Maps

A Phase Determined by Two Phases

"But that," said Perlon, "is nonsense." "Of course it is," said Horvendile. ''That is
probably why it happens."
Jurgen (CabeIl)
 C: PHASE SINGUlARITIES OF MAPS 25

I begin with item 15 above, §1 x §1 ____ §1. Call the two input phases or parent
phases 4>A and c/Ja, and let the resultant or hybrid phase be called 4>'. As noted above,
the (4)A, 4>B) plane goes on and on periodically like wallpaper, in principle to infinity,
but we need deal with only one copy of the repeated unit cell since all the rest are the
same. In a wide variety of physical and biological situations, the following three
axioms hold:
1. For almost all inputs (4)A, c/Ja), a small change in 4>A or c/Ja results in at most a
small change of 4>'.
2. 4>A and c/Ja are interchangeable: They play equivalent roles.
3. When parent phases 4>A and 4>B are nearly the same, the hybrid phase 4>' is nearly
the same as both.
Referring to Figure 23, consider what happens to 4>' if 4>Ais increased through a
full cycle while c/Ja is held fixed (at a value that we mayas weIl call 4>B = 0). If 4>'
changes, it must change in such a way as to return to its first value as 4>A completes
its scan of the cycle. As in earlier examples, the periodic dependence of 4>' on 4>A has
an integer winding number, the number of times 4>' runs through its cycle as 4>A runs
forward through its cycle. Whatever it turns out to be, call that winding number W
and mark it on path Clß in Figure 23. Note that Cl, ß, 'Y, 0 all represent 4>A = c/Ja = 4>' =
O. Along path ClO and therefore along equivalent path ß'Y, 4>' changes through W
cycles again, since this is the same experiment with the A and B labels

Figure 23. A phase t/J varies as a function of position on the (t/JA, t/Js)
torus. Along path aß or (Yr, t/J' scans through W cycles. Along path
'Ya it scans through -1 cycle. aß,o all represent the same point on
the torus.

interchanged. Now returning to Cl along diagonal "{Cl, 4>' backs up through one cycle
according to axiom 3. Thus, from Cl to ß to "{ and back to Cl, 4>' has changed through
some nonzero integer number of cycles 2W -1. A contradiction is coming up; watch
carefully.
Let us ignore the word "almost" in axiom 1. Then a slight deformation of path
Clß, for example, cannot change the behavior of 4>' along the path enough to alter the
fact that it scans through W cycles (rather than W -1 or W + 1) from Cl to ß. Since W
cannot change except by integer jumps, and jumps are disallowed by axiom 1,
therefore W cannot change at all. We can thus deform path Clß'YCl as we please. In
particular, we can shrink it with impunity to as small a ring as we like. But around
that ring, 4>' still changes through at least one full cycle in response to arbitrarily
minute changes of 4>Aand c/Ja.
26 1: CiRCULAR LOGIC

12 Y2
o ~~~~~---+0A 0

o "2 1
Figur. 24. A relaxation oscillator's contour lines of uniform 4>' as a function 4>A and 4>s. Values
are not indicated numerically but increase along the arrow. In this case 4>' changes abruptly by
one-half cycle whenever 4>A or 4>s = O.

This is ealled aphase singularity, and it violates the edited version ofaxiom 1.
Without the "almost," in other words, axioms 1, 2, and 3 are ineompatible. One
cannot have a smooth symmetrie dependenee of phase on two other phases sueh
that 4/ runs through a full cycle with cPA and 1>B when they are equal.
What does this mean in terms of the four examples under item 15 above?
Example A. Apparently there is at least one eritieal eombination of parent
phases cPA and 1>B near whieh the resultant eompromise phase is unpredietable and
irreproducible. There might also be more than one. For example, there might be a
whole line of near-diseontinuities along cPA = 0 and along 1>B = 0 if at that phase the
oscillator changes its ehemical composition suddenly (Figure 24a), or if the one
farther past 0 dominates the compromise (Figure 24b), or (Figure 24c) the one less
advanced beyond 0 dominates. The point of Figure 23 is that even if the mechanism
is smooth, and is not such a so-called relaxation oscillator, then there still must be a
phase discontinuity. And if it is not extended along a one-dimensionalloeus, then it
must be the much more violent and eondensed kind called a "phase singularity"
(Figure 25). In the

~ In case (a) asymmetrie compromise is struck between <PA and 4>a as measured from a
nonarbitrary 0; in case (b) the later of the two phases dominates the "compromise"; in '
(c) the earlier....

simplest kinds of chemical oscillator, the phase singularity is a special

combination of parent phases whose intermingling forces the hybrid oscillation

Figur. 25. As in Figure 24, but in this case the inevitable discontinuity is
compressed to a phase singularity point in each triangular half of the
unit cel\.
 C: PHASE SINGULARITIES OF MAPS 27

to its steady state (see Chapter 5). But in case of anything more realistic, the
phase singularity is not so easy to describe in terms of mechanism. We return to
this topic in Chapter 6.
Example B. In the running insect, it might mean that when r/JA and r/JB are a half-
cycle apart, the third neuron cannot make up its mind whether to fire between A and
B or between B and A. This would be the right interpretation if the inevitable
discontinuity were a diagonallocus 4>a = r/JA + ! cycle (Figure 26). But if it were an
isolated phase singularity, then some more subtle mechanism would seem to be
called for.
Example C. Few of us have ever taken the time to play systematically with
the two adjusting screws under a correctible automobile compass. 1 did once,
and subsequently took the thing apart, while preparing an exercise for a course
in "The Art of Scientific Investigation." It tums out that the compass follows
rules 1, 2, and 3 and that the compass reading becomes extremely sensitive at
certain critical combinations of screw angles. This is because at just those
angles, the two pairs of little magnets exactly neutralize the Earth's magnetic
field, or whatever distortion of it reaches the compass inside the car. The
slightest departure from neutrality gives the compass a direction, but it can be
any direction, depending minutelyon the orientation of each magnet. r/J' tums
out to have aphase singularity (Figure 25) at a critical combination of r/JA and
4>a.
Example D. In the case of color perception, it means that on any color wheel
some combination of two hues must be exactly complementary, resulting in a
neutral gray transmission. .
These are glib interpretations, not obviously correct. The point 1 wish to make
here is only that there exists a wide variety of mechanistic possibilities underlying
the inescapable mathematical fact that there exists no smooth map of the sort
required, so we must settle for a map containing at least one isolated phase
singularity, or some more extensive kind of discontinuity (see Figures 24 a, b, and c).
That much is mathematics. The science comes in locating and making use of the
discontinuity, and discovering which of many alternative mechanisms underlie its
particular character.
My appreciation of this mathematical fact is the work of Graeme Mitchison,
who suggests a more compact statement, which 1 paraphrase as follows:
Theorem. The only continuous maps from the disk (e.g., the area inside triangle
aßTa) to the circle (the possible values of r/J') have winding number 0 around the
border of the disko If the winding number cannot be 0 (e.g., because ofaxiom 3), then
the map cannot be continuous no matter what the underlying physical or biochemical
mechanism may be. In fact no manifold can be retracted to its whole boundary while
leaving that boundary pointwise fzxed without a discontinuity appearing somewhere.
For general background and proofs of this theorem in its various guises, see
almost any textbook of homotopy theory, e.g., J. Milnor (1965) or E. H. Spanier
(1966) or Guillemin and Pollack (1974). A definition of "manifold" appears on
page 2.

... Strogatz (1984) produced the most succi nct and mathe matically accurate statement
I know of,. and supp lemented it with examp les from Winfree (1986a,1987a: the
28 1: ClRCULAR LOGIC

Figur. 26. As in Figures 24 and 25, but the inevitable discontinuity is

placed along a 45° line. Here <p' jumps by one-half cyde.
~
o
o ~ ,

~manuscript ofwhat was intended to be a single bOoK.9rganized ~röun

see",both._bqoks.for more examp!es)... • . __ <_ _ ~,_ _ _ _w....~_,

A Phase Determined by a Phase and a Magnitude

With the topological essence of the phase singularity thus extracted and crystallized,
it is convenient to turn attention back to the less symmetrie case of a phase
detennined by a single other phase, as in items 14A to H above. For example, in item
14F (page 18) the experimental system determines aphase. But the independent
variables at the experimenters disposal are now a phase <p, as above, and a stimulus
magnitude M instead of another phase. The map is §1 x 01 -+ §1. Thus the resulting
phase <P' is to be plotted over the <p by M plane rather than over the <PA by <PB plane.
Let us find a stimulus magnitude which maps <p to <P' with W = 0 and use that as the
unit M. Just as we circumnavigated a triangle in the first part of this seetion. we now
circumnavigate a square (Figure 27): Along line PQ with stimulus magnitude 0, <P' =
<p. If Q is placed one cycle beyond P, then along PQ, <p' rises through one cyde. Along
QR, <P' changes by some amount; call it x.

Figur. 27. Analogous to Figure 23 but one axis

(M) is a scalar variable rather than a phase. New
phase <p' is to be evaluated along path PQRSP.

The winding number being 0 along RS, <p' rises and falls without net progression
in either direction. Then from S to P, the change x is undone because PS at phase 0
is identical to QR at phase 1 = O. So the winding number of <P' around the box is
exactly 1 + x + 0 - x = 1. For the same topological reasons as encapsulated in the
 C: PHASE SINGULARITIES OF MAPS 29

theorem, a peculiar discontinuity must lie within the box. The most localized
possibility is an isolated point phase singularity (Figure 28).

.... re is ~ notatiOna pro lern. or e most 'part, I Os M for stimulus magnitude

roughout this' bObk, But in _some instances (partieularly when the stimulus. is a
öuratiolT In setonds) ~ used S instead, emd in others (partictJlarly. ....;he~ the stimufus is
the dose of a chemical perturbation) I used D. To add to the confusion D also ir'lcicates
dlmenslon ·of astate 'sl?aceup to ttie miqdle of Chapter 9 and beyond that it only
indicates a{diffusion coeffici~nt, as it also does once near the end of Cha ter 4.
Apologies for tlie inconsiS\enty/ but i~ is too deeply roateCi for repair in thepreserved
1978 text and .
_....-~_ -
.......
One can visualize the necessity of some such irregularity by trying to construct a
smooth surface of data points over the square, subject to the constraint that along
the boundary PQRSP it must rise up one floor like a parking garage ramp way.
Think how this is arranged in the garage: It isn't. The concrete apron never doses,
but has an inside edge everywhere. It's the same in a helical staircase or sliding
board: The central upright is there not just for structural reasons, but also to hide a
discontinuity. Architects too, not only the Creator, must design around the facts of
topology.
In some cases, the discovery of this screw-like discontinuity constitutes only a
trivial insight into the physical mechanisms involved. In some cases, it constitutes a
more profound insight, which would be difficult to anive at in any other way. And in
some cases, it has little to do with mechanism but rather points to a fundamental
limitation in the process of measurement. As noted above, measurement consists of
defining a suitably convenient observable of state and carrying out the map from a
system's state space to the space on which that observable is defined. But every
experienced scientist knows that we are not free to define observables arbitrarily.
One way the use of language in science differs from its everyday uses is that in
science one cannot simply define a new term in an intuitively convenient way,
obtain consensus on a concise definition, and proceed to use it. For terms refer to
concepts, and concepts sometimes prove to harbor latent ambiguities, irremovable
ones, e.g., "simultaneity" before relativistic physics. Physicists ran up against this
problem, for example, in the 1920s when it was discovered that no one could specify

Flgure 28. Contour lines of rj;' are added to Figure 27

as in Figures 24-26. In this example the contours are
allowed to converge to a single point.

o 1
30 1: CrRCUlAR LOGIC

simultaneously the position and velocity of an electron, although position and

velocity had seIVed as the basic independent obseIVables of mechanies since the
time Qf Newton. In the same way, if we insist upon forcing nature into a description
in terms of phases, we may encounter ambiguities, even paradoxes, implicit in the
very definition of that obseIVable because there are situations in which phase is
ambiguous or can only be defined by admitting ghastly discontinuities into the
description of our obseIVations.
This fact of topology provides us a tool for uncovering phase singularities in a
wide variety of contexts. In the next chapter we examine an assortment of such
singularities preliminary to entertaining notions in subsequent chapters about their
diverse origins in biochemical dynamies. We will then be in a position to inquire into
the physical nature of the phase singularity in each example in Chapter 10.

D: Technical Details on Application to Biological Rhythms

This chapter has mostly concemed mappings among circles. As Chapter 2 mainly
illustrates phase singularities by empirical data, it will be weIl to pause before
plunging into those examples to make sure that two much-used conventions are
clearly grasped. These are:
1. The correspondence between the ring §l and the phases of something periodie
in time
2. The format here used for portraying empirically measured maps from the phase
ring to itself

The Phase of a Rhythm

"Phase," like compass direction, is a point on a cirele, on §I.We identify directions
by a number, on 1R 1, inscribed on the rim of a compass. We teach our children to
think of time schizophrenically both as a thread (1R 1) along which we inexorably
progress from left to right, from a past lost in the mists of antiquity into a future
forever receding before our advances, and also as a cirele (§I) along which we creep
like the hour hand that creeps repeatedly around the face of a elock somewhere in
Greenwich. According to the Oxford English Dictionary, the original Old English and
Old Teutonie stern of our word "time" meant "abstract extension." There was no
connotation of recurrence in daily or seasonal cyeles such as children now appreciate
in asking, "What time is your piano lesson?" The distinctive features of rhythmic
systems seem perplexing, even paradoxieal, as long as our minds dweIl implicitly in
IR I. Let us then plant them firmly on §I in this chapter about eireular logie and phase
maps.
By "phase" I mean a point on a ring. But what point and what ring? Let's use the
unit eirele in the standard (x, y) eoordinate plane:
x = sin(211t) ( 1)
Y = cos(211t) x, y, tE IR
 D: TECHNICAl DETAILS ON ÄPPLICATION TO BIOlOGICAl RHYTHMS 31

or, in complex notation,

z = x + iy = i exp( -27rit) (z E 1R 2 ).

As t runs from 0 to 1, the phase point runs dockwise around the cirde from north to
north (see Figures 6 and 9). As in Example 6 in Section B, our convention for angles
is taken from the mariner's compass: dockwise from north, rather than antic-
lockwise from east as in the mathematician's convention.
In connection with an ongoing rhythm, phase is a function of time: It is the
fraction of aperiod elapsed since the most recent recurrence of whatever event is
c;hosen to mark <p ;: O. Thus we write:
f()
.-I.
'I' = t = (time t since marker event)
(standard period T)
d 1
mo uo 1

which makes <p ;: 1 equivalent to <p ;: O. In an undisturbed, perfectly regular

rhythm of period T, this definition implies that <p constantly increases:

df(t) = l/T.
dt
For notational convenience, we take T as our unit of time henceforth and denote d!
dt by an upper dot. Then the above expression becomes
~= 1.
Defined this way, "phase" is just a conveniently periodic measure of elapsed time.
To indicate the position of a rhythm on a time axis, we will sometimes speak of
its phase as though it were a fixed quantity, not increasing in time. This is only
shorthand. What is intended here is <p(to) at some time to which must be specified.
For example, the "old phase" of a rhythm is its phase at the moment when a stimulus
begins, and "new phase" is its altered phase at the moment when the stimulus ends.
Sometimes people use "old phase" to mean as I do here plus stimulus duration, Le.,
prestimulus phase extrapolated to the moment "new phase" is defined at stimulus
end (Kawato, 1981).
In the preceding paragraphs, we deal in rhythms without giving a thought to the
mechanism of rhythmicity. Slipping a little further from pure obselVation toward
interpretation of mechanism, phase is used to denote the state of any process that
varies only along a ring or cyde (Chapter 3). Unlike almost any rhythmic process
outside the domain of dassical mechanics, the only state variable of any
consequence in a mechanical dock is the angular position of its meshed gears, as
indicated by the position of its hour hand. For many purposes, the same is true in
good approximation for circadian docks. The models of Chapter 3 emphasize this
aspect. With such models in mind, one tends to think of the phase <p E §1 of a dock
mechanism. This is a subtle but weighty shift of meaning from the more innocent
use of "phase" above, merely to describe an obselVed rhythm. It leads to paradoxes
in certain kinds of experiments with biological docks. Thus, when pondering
mechanisms we must stick to the purely descriptive definition of phase with
fundamentalist zeal; exception is made only in Chapter 3, where the state space
consists of no more than a ring, so each state can be unambiguously associated with
32 1: ClRCULAR LOGIC

aphase of a rhythm, and vice versa. But in dealing with real organisms, phase must
be defined simply as an observable, a quantity you can wring out of a measured
rhythm, without assuming a one-to-one correspondence with the state of the
(unknown) mechanism that causes the rhythm. In terms of mechanism, phase is a
nontrivial function of state and our objective is to infer from experiments the
topological features of that function. Such features turn out to have interesting
implications.

/ Figura 29. Phase, considered as a number rather than

/
as a point on a ring, cannot steadily increase. It has to
jog back to zero at unit intervals. This notation carries
with it the misleading connotation of abrupt change.
o
t

I dislike to think of phase as a number from 00 to 3600 or from 0 to 24 hours or

from 0 to 271" radians or from 0 to 1 as in Figure 29. To do so gives the impression of a
relaxation oscillator, as though something physiologically unique must necessarily
occur sometime in the cycle, which time we single out to call 4>0 = 0 = 1. In general,
nothing of the sort is so. For instance. no one feels momentary vertigo in crossing
the International Date Line (see Box A). The mathematical artifact is the same in
both cases: lt comes of insisting that the circle should be mapped onto a line. In
fourth grade geography we leamed not to insist upon mapping the sphere onto a
plane but every map in the book nevertheless did it, with apologies. In the same way,
we do not always escape it entirely here. Just as we once leamed to think in spheres
while staring at flat pictures, so in this book the reader must try to think in circles
while inevitably handling numbers.

A Format for Plotting Empirical Maps § 1 -+ §1

We have one more task before going on to Chapter 2. If you are already familiar with
phase-resetting experiments, you may find it expeditious to skip ahead. but I urge
you at least to scan the following pages on data presentation. For the present book I
have committed myselfto redundancy in this matter (e.g., see Chapters 14 and 19)
in order to be sure that the idea comes across to every reader, but it might not work
unless you suffer through some of the redundancy.
Recall Example 14F in which a biological rhythm is rephased from an old
(prestimulus) phase to a new (poststimulus) phase. Let's develop this example in
greater detail. Experiments in this format will play a major part in chapters to
follow. This example focuses attention on the regularities of phase resetting. We
experience phase resetting when we cross meridians by jet travel. We inflict it on a
wristwatch by pulling out its stern and twisting it to adjust to the time at our landing
place. In later chapters (3, 4, 5, and 6) it will be important to deal with the process of
 D: TECHNICAL DETAILS ON ApPLICATION TO BIOLOGICAL RHYTHMS 33

rephasing. But here we deal only with results: What is the new phase arrived at given
the initial phase? The format in which phase resetting experiments are described in
this book was chosen for compatibility with one of the many formats used to depict
them in the long-published literature, viz., the one first used by Eccles and Hoff
(1934) in connection with resetting the heartbeat and by Pittendrigh and Bruce
(1957) and by Hastings and Sweeney (1958) in connection with circadian rhythms.
As this is the most direct representation in terms of experimental data and it meshes
nicely with convenient theoretical diagrams to appear in later chapters, I adopt it as
the standard format for all presentations of resetting experiments in this volume.
Data drawn from experimental papers in several different formats (e.g., see Box C of
Chapter 4) are all converted to this format.
Before going into detail about the format, a word is in order about the basic idea
of aresetting experiment. The notion is that something rhythmic is going on: Once
started by some standard procedure, some event reliably recurs at unit intervals of
time. We could just sit and watch it, fascinated by the regularity. But we are soon
seized by an impulse to poke at it and see what happens. Very complicated things
can happen depending on when in the cycle we poke. We restrict our attention here
to just one aspect. In the aftermath of a poke the system eventually reasserts its prior
rhythmicity with the event occurring at a time () (neglecting multiples of 1) after the
stimulus. The whole idea of these "hit-and-run" experiments is simply to record the
time () and how it depends on the time in the cycle when the poke is given.
Remarkably enough, something can be learned by systematic attention to this
simple observation. Moreover, it is an observation of immediate practical relevance
whenever one rhythm is to be synchronized by another, or whenever the expected
time of an event is to be changed. In order to accomplish this rescheduling we need
to know how the time () depends on the time in the cycle when we do something
about it. My objective here is merely to layout the format of such hit-and-run
experiments in a standard way that will lend itself to interpretation of real
experiments in subsequent chapters.
Since Eccles and Hoff (1934), experiments of this kind have been published in
diverse formats, using rhythms as different as the cell division cycle, pacemaker
neurons' electric rhythms, the circadian rhythms of whole-animal activity, and the
periodic ovulation of female vertebrates. It seems as though every rationally
conceivable format has been employed, and then some. But if comparisons are to be
attempted, a convenient standard format must be adopted. This turns out to be one
of those intriguing problems for which our habitual reliance on Cartesian
coordinates does not provide the optimum choice of format. Toroidal coordinates
prove most natural for visualizing the relationships of idealized rhythms. (See item
14 of Section B above). But let's work our way around to that inference gradually,
starting with the familiar Cartesian graph format.
Figure 30 presents such a format for laying out the results of hit-and-run
perturbation of rhythmic processes. In Figure 30, we see a vertical time axis. The
origin of time is at the moment when rhythmicity is started by some standard
procedure. For example, circadian rhythms can be started by transferring cells from
constant light to constant darkness. Thereafter, some conspicuous event recurs at
regular intervals. We take that naturally given interval as our unit of time. By
choosing the event to call phase 0, we determine the quantity ()o between the
34 1: ClRCULAR LOGIC

0=0
T
fl}=o

fl}=o Figur. 30. Defining quantities 80 , T, cp, M, and 8 in a hit-and-run

rephasing experiment.

e
16=0

fl}=0

~=O

TIME

standard start and the appearance of phase O. Thus, the standard procedure starts
the rhythm, by definition, at phase 1 - (Jo. Bear in mind that we have two time scales
going now. We have absolute time t measured from the start all the way down the
time axis. And we have periodic time cf; measured modulo 1 from the phase
reference events. Further down the axis I have diagrammed a stimulus. The stimulus
need not be instantaneous. It can be any procedure, for example, turning on the
lights and letting them fade gradually back into darkness, or exposing a celI to a
series of action potentials 10 milliseconds apart for as long as the stimulus lasts. The
essential point is that up to stimulus time, and after the stimulus ends, the rhythmic
system is left alone in a standard environment where it is known to function
rhythmically with unit period. As diagrammed, the stimulus begins at a time cf; in the
cycle, lasts for duration M, and then ends. After its end, normal rhythmicity is taken
up again with the marker event recurring after a time eplus multiples of 1. The main
point of this diagram is to layout the format of an experiment and to define the
quantity e which, because it is the complement of a phase, we call "cophase."
Cophase is the time (modulo 1) from the end of a stimulus to the cf; = 0 marker event.
Just as "phase" always implicitly means the phase of a process at a particular
designated time, so "cophase" means the cophase at a particular designated time.
The cophase at the end of the stimulus is (J, thus the phase at the end of the stimulus
is a fraction e of a cycle prior to cf; = 0, that is, 1 - e. Equivalently, the cophase at
any time is 1 minus the phase at that time. It is the "latency" time from end of
stimulus to the rescheduled event. This quantity has proven convenient to
 D: TECHNICAL DETAILS ON ApPLICATION TO BIOLOGICAL RHYTHMS 35

neurophysiologists «Eccles and Hoff, 1932 and 1934; Matthews,1933; Schulman,

1969; Hartline, 1976; Pinsker, 1977), to circadian physiologists (Ottesen, 1965;
Winfree, 1968 et seq.; Pavlidis, 1973; Saunders, 1976a, 1978), and to cell biologists
(Kauffrnan and Wille, 1975), although under a variety of names. Unfortunately, the
names are sometimes ambiguous. For example, Kauffman and Wille (1975) use
the symbol cf; not for the phase of a plasmodium but for the time until the next
mitosis, Le., for a cophase. Pinsker's (1977) cophase is measured from the
beginning of his stimulus (train of action potentials) rather than as originally
defined (Winfree, 1968) from its end, the beginning of free-run, and Kawato
(1981) measures "old phase" (by extrapolation) from the end rather than the
beginning of the stimulus (see Chapter 6).
Figure 31 introduces a format for comparing the effects of stimuli given at
different phases in the cycle. In Figure 31, a large number of experiments are
displayed side by side, each in the format of Figure 30. They are laid side by side
with stimulus times aligned, so the starting time is systematically advanced along
a 45° line at the top in such a way that the phase at the beginning of the stimulus
systematically increases to the right. Stimulus time scans through two full cycles
in this diagram. The quantity cf;, the phase at the beginning of the stimulus, can
therefore be measured equivalently from the last phase reference event to the
stimulus, as in Figure 30, or measured to the right as diagrammed. The quantity f)
can be measured from the end of the stimulus to the first phase reference event, or
equivalently, from any anniversary of the stimulus' end, forward in time to the
next phase reference event. The complement of f) is the new phase of the rhythm
at the anniversary of the stimulus end or, equivalently, at the end of the stimulus.
This new phase is designated cf;' in the diagram.

Figura 31. Many copies of Figure 30 (simplified), with "START" at

progressively earlier times before the stimulus. The stimulus has no
effect, so the new phase (measured from stimulus end) is simply the old e
phase (when the stimulus started) plus stimulus duration, M. This layout ~,
is from Eccles and Hoff (1934).
e
~,

In Figure 31, the stimulus has no effect: The marker event occurs rhythmically
all the way down each time axis, straight through the stimulus. New phase is just old
phase plus stimulus duration, because Figure 31 diagrams an unperturbed contral.
In Figure 32 it is' redrawn with the vertical time axes suppressed and with
36 1: CiRCULAR LOGtC

continuous diagonal lines replacing the diagonal trails of dots. In other words,
Figure 32 is intended to represent a limiting case of Figure 31 with infinitely many
experiments, separated horizontally only by arbitrarily small intervals of stimulus
phase. Figure 32 introduces coordinate frames:
1. At the upper left, the time T at which stimulus begins provides a coordinate to
the right, while the latency of the marker event after the stimulus provides a
vertical downward time coordinate B.
2. In the lower right of the figure, the old phase axis, </> from 0 to 1, stretches
horizontally to the right, aligned by the marker event at stimulus time. The new
phase axis </>' stretches from 0 to 1 upward, aligned by anniversaries of the
stimulus end.
(All this sounds dreadfully complicated in words, but it isn't. Please stare a long
time at the diagram to make it all come clear. Similar diagrams are re-described in
somewhat different context in Chapters 3, 7, 14, and 19).

Figur. 32. A redrawing of Figure 31 with trails of dots replaced by continuous

e t-r-+---r------i curves (uninterrupted 45° diagonals: Stimulus has no effect). Two equivalent
coordinate frames are indicated by ((J, 1) and (f!J', f!J).

This being an unperturbed control experiment, the data points lie along the </>' =
</> + M locus: New phase equals old phase plus stimulus duration because the
stimulus did nothing, and the new phase is evaluated at the end of the impotent
stimulus of duration M, whereas old phase is evaluated at the beginning of the
stimulus.
The new phase vs. old phase coordinate frame is mobile: It can be moved
vertically or horizontally by unit steps. We expect our data in the present
idealization to be periodic both horizontally and vertically, so that it makes no
difference which placement of the new phase vs. old phase axes is chosen. We will
come to exceptions later in the context of real experiments (e.g., see Chapters 7, 20,
21).
In Figure 33, Figure 32 is redrawn under a different assumption about the effect
of the stimulus: The stimulus is taken to restart the rhythm, no matter when in the
cycle the stimulus is presented. For example, the stimulus might force the oscillator
 D: TECHNICAL DETAILS ON ApPLICATION TO BIOLOGICAL RHYTHMS 37

to a standard state, the rhythm restarting when the stimulus ends. This stimulus
serves as a repeat of the start procedure used above along the 45° line. In this case,
the new phase is always 4;0 = 1 - 00, no matter what the old phase. Thus, the data lie
along a horizontalline.
How else might data lie on such a diagram? The essence of the diagram is its
double peri~dicity, taken together with our assumption of continuity, implicit in
replacing a trail of dots by an unbroken line. As that line is traced horizontally
through one full cycle, it must move vertically through some integer number of full
cycles, possibly 0 as in Figure 33, possibly 1 as in Figure 32, possibly some other
integer as in Figure 34. But if it doesn't get back to the same new phase at the same
old phase, then it is telling us that the system was after all only superficially
periodic, or else that a given experiment can have two or more alternative outcomes,
depending on unknown factors not specified in this diagram.

Flgure 33. As in Figure 32 except that the stimulus resets rhythms

from any prior T (or 4» to a fixed phase, i.e., (J = (Ja or 4>' = 4>a. 9. 1,
e

fI'
'1
fI.
fI

But let us assurne that the system really is periodic and weIl behaved. The
essence of its periodicity is captured more compactly by a topological trick. A
vertical sheet of wallpaper such as the bottom half of Figure 32 can be rolled up
horizontally, superimposing the repeated columns of identical unit cells. In this
form, our graph has an extended periodic 4;' axis vertically and a single circular 4;
axis in which 4; = 1 is identified explicitly with 4; = 0 by joining them. We have thus
carried out explicitly the "modulo" operation implicit in our definition of phase. We
might have done the same for the 4;' axis, rolling vertically to obtain a horizontal
cylinder. It is not too late (Figure 11). Conducted in either order, these two rolling
operations leave us with a doughnut-shaped piece of graph paper, a torus.
(Conducted in this order, the 4;' axis threads the hole). Figure 34 was just the
single toroidal surface slit open along two perpendicular circles, laid flat, and
repeated for the sake of continuity (see Example 14: §l -4 §l). Though redundant,
the planar representation is useful and we will see it again in several contexts
because real world data are not exactly periodic and the departures from exact
periodism are sometimes systematic and meaningful. They would be lost as "noise"
in a strictly periodic procrustean bed such as Figure 11. But for now, that is
38 1: CiRCULAR LOGIC

W·1

Figura 34. A mosaic of three different possible outcomes of

resetting measurements. plotted in the format of the lower parts of
Figures 32 and 33. Resetting types are classifred by an integer W:
The number of rp' cycles crossed per cycle of rp. Figure 32 is an
W=-1
extreme case (flat diagonal) of W = 1. Figure 33 is an extreme case
(flat horizontal) of W = O. W = -1 (also shown here) or any other
integer type of resetting is possible.

precisely what we want to do: We want to examine the strict implications of exact
periodicity in order to generate a rigid skeleton of ideas and expectations on which
to hang more flexible realities later.
Let us turn to the torus and inquire how a continuous trail üf data points might
lie on its surface. If we concern ourselves only with the logic of continuity and of
periodicity, then the data trails must rise through an integer number of unit cells in
Figure 34 as they advance horizontally through one unit cello In terms of Figure 11,
this means that the data form a closed ring, threading the hole in the doughnut in
one direction or the other some number of times. Such curves fall into distinct
groups, according to how many times and in which direction they loop through the
doughnut's hole. Two limiting cases will serve as examples:
1. Suppose the stimulus is so brief (M -+ 0) that it has almost no effect as in Figure 32,
so q/ ;;; ep. The data then lie in a ribbon exactly superimposed on the controls. This
curve parallels the main diagonal on our toroidal graph paper, forming a ring that
winds once through the hole in what we henceforth take to be the positive
direction (as ep increases, so does ep'). This is called Type 1 resetting, according to its
winding number. The winding number is the same as the average value of the
slope, dep'/dep. Even if ep' differed from the controls by a fixed amount independent
of ep (e.g., if the stimulus does nothing but lasts a long time so ep' - ep = M is not
negligible), the data would parallel the main diagonal and link once through the
hole. Even if q/ depended markedly on cp in certain ways (e.g., cp' = cp + 100
sin(21l'cp», the topological type of resetting would still be the same: The data ring
then passes many times through the hole, but each time except once it turns
around and comes back out again. And although the slope dcp'/dcp reaches great
extremes, it averages out to exactly 1 on account of the requirement of periodism.

2. Suppose the stimulus restarts the rhythm at phase CPo whenever delivered, so
that cp' is equal to CPo independent of cp. This curve parallels the equator of our
toroidal graph paper, maintaining a fixed verticallevel as it rounds the ep axis. It
 D: TECHNICAL DETAILS ON ApPLICATION TO BIOLOGICAL RHYTHMS 39

never loops through the hole. This is called Type 0 resetting. Even if </J' were 100
sin(27r</J), the topological type of resetting would still be 0, as the winding
number of the data through the hole remains 0 despite its passing in and out of
the hole (in opposite directions) many times. The mean slope d</J'ld</J is also O.
(For example, see Boxes B and C in Chapter 4.)

~ Type 0 resetting is sometirnes ca e "even" resetting (e.g., tHrougHout Wln ree

1986a and 1987a) because eac rjJ' Gan be reach~d from an even number of distinpt QJ
(but each phase .hift is reached frOfT! an oad nurnber of distrnct.cf>')~ It is sometimes
called :'strO,;g" resetting because in eve/y' case it requires a stronger stim~llts than
does Type 1, plias odd, alias weak resetting: In Wlnf;ee (1983b) t calleit "strong
re.dt.duling. ~f As long as no Types other than , 1 and 0 are founC4 tnese alternative
!lames remain unambiguous, but I will stick to the original integer'names tht'ougbout
this book" . -, - - . -
As l'lot~d in Chapter 1, Section$, Examp!& 14 cirele maps can äiso be desGribed in
terms of.lnteger winding number, e-qual to 0 in th 5 ease, .or to 1- in- case' oJ,Jype 1
r.esetting. In terms of a pofynomlaf rnap fr0tnthe unit ekele of the complex plaJile t
itself, the al eb"ralc de ree..of the 0 no ial s the same role. ... .

Curiously, no other resetting types than 0 and 1 have been reported from
experimental systems in which a reasonably smooth curve can be sketched
through adequately resolved data (unless Cote (1991) is correct, that Type 2
resetting was observed, without recognizing it, in Euglena). In principle, any
integer type is compatible with the requirements of continuity and of periodicity.
What further restrietion constrains naturally occurring resetting curves to Type 0
(</J' vs. </J wiggling parallel to the stimulus) and Type 1 (</J' vs. </J wiggling parallel to
the start)? This question will be more approachable later, when we have passed
beyond classifying data, into a discussion of kinds of dynamical systems. It turns
out (Chapters 4 and 8) that populations of independent oscillators of arbitrary
nature are generally expected to show only these two resetting types, unless they
are so nearly identical and stay so nearly synchronous when perturbed, that their
individual nature is exposed in the population behavior. It turns out (Chapter 6)
that some kinds of oscillator mechanism can yield only Type 1 resetting, some
kinds can yield both Type 0 and 1, and other kinds can in principle yield any
integer type. At that point, we will also have to deal with the realistic fact that in
certain experiments there are systematic deviations from periodicity along the rp
axis, or along the rp' axis, or along both. Thus, Figure 34 cannot really be strict1y
rolled up onto the doughnut coordinate system of Figure 11. Such irregularities do
not prevent our measuring phase and cophase by extrapolating the poststimulus
rhythm back to the first moment of free-run after the stimulus. These particulars
are dealt with later in connection with particular classes of mechanism, and in
Bestiary chapters about particular organisms.
A second big assumption lurks scarcely beneath the surface here: An
assumption of continuity, glossed over earlier in stating that resetting curves thread
their way smoothly from one unit cell to the next, in Figures 32 through 34. In
imagining a smooth curve threading the data points, we suppose that a small
change in the time at which stimulus is given makes only a small change in the
40 1: C1RCULAR LOGIC

resulting <p. In other words, we neglect both the possibility of a threshold phase at
which the system's physiology changes discontinuously by a jump or a jerk, and the
possibility that even while the physiology changes continuously, the phase response
can switch discontinuously. Counterexamples abound. We take up some of these
cases in connection with some kinds of neural pacemaker in Chapter 6, Seetion C, in
connection with the cell cycle in Chapter 22, and in connection with the female
cycle in Chapter 23.
m fact, a resolute pursuit of even the continuous cases with winding number W
-# 1 leads relentlessly to a discontinuity of the monstrous sort called a "phase
singularity" (Chapter 2). But we cannot appreciate the inevitability of a
discontinuity without first pursuing the narrow path of idealization, restricting
ourselves slightly to consider systems whose phase-resetting data appear to lie on
smooth curves.
 Phase Singularities
(Screwy Results of Circular Logic)

. .. beware of mathematicians and all those who make empty prophecies.

The danger already exists that the mathematicians have made a covenant
with the devil to darken the spirit and to confine man in the bonds of
Hell.
Aurelius Augustinus, Bishop of Hippo

A phase singularity is a point at whlch phase is ambiguous and near whlch

phase takes on all values. My purpose in this chapter is to give examples by
somewhat idealized description of phase singularities observed in several
experimental systems. In some cases, the phase singularity is at this writing
(viz., in 1978: see below and in Chapter 10 for 1999 updates) only inferred and
not yet demonstrated. Same cases of purely hypothetical and trivial nature are
also thrown in to help darify the principles that I take to be involved in the
more interesting biological examples. Much is glossed over here that should
disturb a thoughtful person acquainted with the physiology of any one of these
systems. These details are dealt with in Chapter 10 and in the Bestiary
(Chapters 11-23).
The seventeen examples I've chosen are organized in this chapter as
follows:
First come four that are intuitively more familiar than the rest, to make
the geomeny familiar. Examples 5-10 all concern biological time measure-
ment: They describe phase singularities of living docks. Physical space is not
essentially involved, except maybe in Example 10, which features docks in a
growing fungus. From there on, physical space plays an indispensable role.
The singularity is actually visible as the organizing center of a two-
dimensional pattern. Example 15 describes the most sensationally visible
example of all, an oscillating chemical reaction in whlch colorful red and
blue striations are organized around phase singularities in three-dimensional
space.

out laser

A. T. Winfree, The Geometry of Biological Time 41

© Springer Science+Business Media New York 2001
42 2: PHASE SINGULARITIES (SCREWY RESULTS OF ClRCULAR LOGlc)

A: Examples
Example 1. Color Vision. My first example is at the same time the most
abstract and the most compellingly graphie. It concerns an oddity of human
color vision cited in the previous chapter as Examples 14A and 15D. Normal

x,

Figure 1. The plane X1 + X2 + X3 = 1 in the three-coordinate

1 ' - - - - - ; ; . - - X3 positive Cartesian depiction of color receptor excitations.

x,

Figure 2. The locus of spectral hues (heavy); its psychophysical

closure through purples (dashed); and the uniform-hue con-
tours, all on the triangular plane of fixed intensity from Figure 1.

color vision in humans is based on three primary colors or more precisely,

color receptor cones. Each color of light falling on the retina excites the three
distinct receptor processes to different extents. (Other animals have different
numbers of separate color sensors.) The infinite variety of physical colors, each
defined by a distribution of energy across the visible part of the spectrum, is
thereby reduced in human perception to three numbers, three rates of neIVe
activity. Each color occupies a place in the three-dimensional space so defined.
This is a very simple model, ignoring as it does the effects of surrounding color
and texture. However, it is entirely adequate for pure homogeneous color
phenomena, the situation for which the colorimetric model was invented by
Isaac Newton, James Clerk Maxwell, Hermann Helmholtz, and Thomas Young
(see Sheppard, 1968).
If we neglect differences in overall brightness, Le., if we confine our interest to
equally bright stimuli (e.g., by the criterion Xl +X2+X3= 1 in Figure 1), then we need
 A: ExAMPLES 43

deal only with a two-dimensional section through this three-space (Figure 2). The
boundary of this section is a triangle, topologically equivalent to a ring. Near the
triangle's center, we find the least saturated colors, the grays assodated with
roughly equal excitation of all three receptors. On this triangular section, the
spectrally pure colors map to an open U-shaped curve that represents the
wavelength axis from about 400 nm to about 700 nm. The corners and edges of
the triangle are normally inaccessible because (outside of dreams and elever
procedures in the psychophysical laboratory) it is impossible to exdte one
receptor to the complete exelusion of others, on account of their overlapping
absorption spectra.
The peculiar fact about human color vision is that we subjectively perceive
mixtures of red and blue as a "pure" intermediate hue called indigo or purple. These
hues complete a ring between the endpoints of the spectral U locus. They complete
it without repeating the spectral hues in reverse order. Thus red is elose to orange is
~~~~~~~~~~~~~~~~~~~~~~
elose to red is elose to orange. The essence of any topological space is its
connectivity, and we have ring-like connectivity in the case of hues. The elosed U is
the "color wheel" of grammar school.
Phrased otherwise, the peculiar fact about human color perception is that we
subjectively recognize colors not by the Cartesian coordinate system 1R3 that our
three receptor excitations define, nor by any topologically equivalent coordinate
system, but rather by darkness and brightness (topologically equivalent to radial
distance from the origin), by saturation (topologically equivalent to distance from
the gray diagonal Xl = X2 = X3), and by hue (topologically equivalent to an angle
about that diagonal). That is, we employ a coordinate system that somehow maps
1R3 _ §l as far as hue alone is concerned.
What this means on the color triangle is that the Iod of uniform hue (neglecting
saturation and brightness) are curves each of which crosses the maximum
saturation ring (the color wheel, the elosed U) at one point. Inside the color wheel
these curves can only converge. The color to which they converge evidently has all
hues or no hue: It is gray. It is aphase singularity, in an abstract sense that involves
no rhythms in space or in time, but only an irregularity in mapping the triangular
disk to a ring. No such map can be canied out continuously unless the winding
number is zero along every ring that can be traced on the disko In this case, the
border ring has winding number W = 1 so that continuity is preeluded. The
inevitable discontinuity turns out to be the most localized and violent kind: aphase
singularity.

Example 2. Navigation in a Rowboat. In Example 14B of the previous chapter we

dwelt upon the relationship between the compass heading adopted by a boatman
and the actual track of his boat as altered by a steady current. Weanived at a
trigonometric formula relating track </>' to heading </> and the relative swiftness of the
current. We noted that this relation takes either of two qualitatively different forms,
depending on whether the current or the boat is swifter. This peculiarity is
associated with aphase singularity implicit in the equation when the boat heads
directly upstream (</> = 0) with the same velocity as the current (v = v*). In this
situation the boat hangs poised forever motionless in midstream, depending for
44 2: PHASE SINGULARITIES (SCREWY RESULTS OF CiRCULAR LOGlc)

movement on fluctuations in the heading, the boatman's vigor, or the current. The
slightest deviation from equilibrium gives the boat a gentle drift in some direction <pI,

NORTH

FIXED
0'
FIXED Figure 3. Taken from Figure 14 of Chapter 1 to indicate the
v* q;
combinations of cp and v that are compatible with any fixed and
v*.

Figure 4. The navigators mapping: The coordi-

nates are heading relative to the current (hor-
izontal) and velocity relative to the current
(vertical). The curves are level contours of resultant
track direction, relative to the current.

o
SWNESWNES

and all directions are equally accessible. The combinations of <p and v that result in
the same <p' are indicated geometrically in Figure 3. Figure 4 depicts this dependence
as a contour map of track direction <P' plotted on the (heading <p, velocity ratio v*/v)
plane. The contour lines of each given track direction are identified by their
intersections with the heading axis at v*/v = 0 (no current), where heading = track.
At v*/v = 1 all contours converge near a north heading (upstream). At greater
currents or lesser rowing speeds, all tracks are downstream regardless of heading.

Example 3. What Time is It? What time it is depends on where you are, doesn't it?
The docks behind the newscaster's desk say "Tokyo," "Moscow," "New York," and
"Canberra" and each reads a different time. But this madness has its method, as
noted in Example 14C of the previous chapter. If we layout a ring of docks along a
globe-girdling path-Iet's say the path ofPan American Flight #2-then we have a
big circle and along that circle, at any instant, local time advances through a full
day. This leads to a difficulty. Our ring of docks is a big circle lying on the surface of
the planet (Figure 5). Let's contract it a little. If we think of it as a necklace of 40
million pocket watches, a meter apart, we can envision taking up a meter of slack,
pushing the watches apart, and doing it again repeatedly. As the ring shrinks, we
may have to walk a bit north to keep up with it. If we take care that every watch
moves north, then each stays in its local time zone and need not be reset as it moves.
 A: ExAMPLES 45

Eventually, after all but 100 meters of wire have been rolled up, the other side of the
ring comes into sight over an ice flow, dragging its millions of pocket watches.
Gather up another 100 meters of wire. Now, what time is it? All times, no time,
summertime? Look at the Sun if the docks don't agree. When it is at its highest, in
the south, call it noon. But the Sun is circling at fixed altitude along the horizon and
every direction is south.
This place is aphase singularity.

Figura 5. A ring of pocket watches, initially on the Equator, during

its contraction toward the North Pole.

t
Figur. 6. Apolar view of the North Hemisphere on the equinox
showing boundaries of (idealized) time zones. T0 assign a time to
each place on this hemisphere, the hemisphere must be mapped
to the phase ring (below). This cannot be done smoothly.

Let's look at it more abstractly. At every instant the determination of local time
as a function of position on the globe is a map from §2 -+ §1. Along the equator the
map is quite tidy: local noon advances four minutes for every degree of east
longitude. [This simple fact was the whole reason for development of accurate
chronometers: They were indispensable for global navigation (see Box C of the
previous chapter)]. So the equator is a convenient line along which to cut the sphere
open, the better to deal with each of the hemispheres separately as a disko The two-
dimensional disk must be mapped to § 1 in such a way that winding number equals 1
along the disk's border (Figure 6). This cannot be done continuously. The most
localized form which the inevitable discontinuity could take is a phase singularity: a
46 2: PHASE SINGULARITIES (SCREWY RESULTS OF ClRCULAR LOGlc)

point at which all phases converge, a point that the map pulls apart to all phases.
This is naturally placed at the pole, being both the Earth's rotation axis and a place
where almost nobody lives. It is also worth noting that the time zones of convention
are imposed by map-makers. Except on either equinox, on an Earth whose daily
spin axis tilts 23° from its yearly revolution axis, the reality in tenns of sunrise and
sunset is a bit different, because a disk around one or the other pole is constantly in
sunlight or in darkness day after day. Contours of same time of day defined with
reference to the Sun do indeed have a phase singularity, but it is all along the rim of
that disk, not just at a point.
Because time and place are symmetrlcally measured on the Earth's two
hemispheres, there is a seeond phase singularity. Both have fascinated navigators
since the globe was first eharted beeause both represent inevitable convergenees of
meridian lines that were initially sketched to separate and to distinguish sueeessive
ares along the equator (see Box A).

Example 4. Timing the Tides.

It is even said (by foot soldiers returned from Alexander's expedition to the Arabian
Sea) that the many ebbings and risings of the sea always come round with the Moon
and upon certain fixed times.
Aristode, recipient of the first grant funding
for free scientific research (from Alexander).
Another phase singularity of the same kind is familiar to oceanographers
concerned with the predietion of Ioeal tides and with understanding the eompIex-
ities of their geographie variation along the world's shorelines. This example brings
out more clearly the involvement of rhythms in time. The tides have many harmonie
eomponents based on the Earth's period of rotation and on both the Earth's and the
Moon's periods of revolution about their primaries, and on loeal resonances
determined by shoreline geography and depth profiles. The excellent approximation
provided by linear theory allows us to deal with eaeh eomponent separately. The
amplitudes of the eomponents vary loeally, but each eomponent is independently
subjeet to the same principles. Consider for example the fundamental harmonie of
the lunar semidiurnal tide M2 , whieh happens to be dominant on the Isle of Palms
where I am writing.
In the very first approximation, the lunar tide is a rotating pair (beeause the
center of rotation of the Earth-Moon system lies deep inside the Earth) of bulges of
water above the global mean sea level. Viewed loeally, it is arhythmie rise and fall of
the water surface, or arhythmie advance and retirement of water along the sloping
shoreline. The tide cannot be globally synchronous because there is a fixed quantity
of water available. So there is a geographie pattern of phase. This is easy to measure
along the shores, and it is possible to measure at sea using sonar depth finders.
Thus, the tidal pattern on an instantaneous snapshot of the glohe could be portrayed
as a map of the sphere onto the phase eirele (§2 ~ §1). This poses no problem to
imagination. A sphere is easily mapped into a eircle, e.g., as in Figure 7. But the map
wanted here must also embody a special fact, namely, that the local rhythm's phase
seans through two full eycles along any ring girdling the Earth near its equator.
 A: ExAMPLES 47

Box A: Living Clocks at a Geographical Phase Singularity

Physiologists as weIl as navigators have been fascinated by the poles. A garage a few
hundred meters from the South Pole became the scene of a unique biological
experiment when Karl Hamner arrived by an Air Force transport with hamsters, fruit
flies, bean plants, and breadmold (Hamner et al., 1962). Perched on a counter-rotating
platform at the endpoint of the International Date Une, what time would their
biological docks think it was? Two major possibilities were envisioned:
A. x hours later than it was x hours ago, when they were elsewhere: Expected on
hypothesis 1, that the biologica1 rhythms derive from internal biochemical
oscillators that take no notice of geography.
B. No definite time because at the pole no dear physiological rhythms will persist by
which to evaluate subjective physiological timing: Expected on hypothesis 2, that
the rhythm really reflects some local consequence of the Earth's rotation, to which
the chosen species are more sensitive than are their observers' instruments.
What happened? Outcome A: The organisms continued in their physiological
rhythms just as a man's pocket watch does, not caring that it is carried across the pole.
This observation encourages belief in hypothesis 1, that circadian rhythmicity arises
from an internal physiological dock.
Unfortunately, the observation of outcome A did not really distinguish rigorously
between hypotheses 1 and 2 because organisms could have been reading Greenwich
Mean Time just as plausibly as they could have been reading other subtle concomitants
of the Earth's rotation. For example, a Greenwich Mean Time readout is available
synchronously around the globe not only from station WWV but also in the vertical
gradient of electric potential in the atmosphere. This is caused by a global maximum
rate of thunderstorm formation a certain number of hours after the major continental
land masses roll into the sunlit hemisphere at 7 P.M. in London (Feynman et. al., 1964,
vol. 2, p. 9-3). Because the ionosphere conducts so weIl, this readout is available
unattenuated at the South Pole unless experiments are conducted in a Faraday cage.
Palmer (1976) also notes that the magnetic South Pole is 1,500 miles away, near New
Zealand. Thus organisms on the cosmically stationary platform were subjected to a
rotating magnetic field with 24-hour period.
Apart from these quibbles, the idea of the experiment was ingenious: If biological
rhythms are geographically caused, then they should vanish when the organism is
placed in a geographic phase singularity. They don't. We will see in Examples 5-9 that a
similar experiment can be done too: If biological rhythms are physiologically caused,
then they should vanish when the organism is placed in a physiological phase
singularity. They do.

Since the winding number is 2, not 0, there is no such continuous map. Try to
visualize every point on a spherical rubber balloon assigned to a point on the cirele
while wrapping the equator twice around that circle as required. Figure 8 shows this
operation on the Northern Hemisphere. The balloon has to be stretched flat like a
pancake, and to finish the job, its surface must be punctured, in general at two (or
any multiple of two) points in each hemisphete. The edges of each puncture flyout
all around the equatorial circle, so each puncture is aphase singularity. This would
be the simplest possible geographie pattern of tidal phase.
48 2: PHASE SINGULARITIES (SCREWY RESULTS OF CtRCULAR LOGlc)

52 _ 5 '

Figura 7. The surface of a sphere mapped into a segment

of a circle.

It turns out that there are quite a Lot of phase singularities. Some of them
perhaps are lost inside the continentalland masses, hut there are thought to be
several in the open sea (Defant, 1961; Platzman, 1972). Oceanographers depict these
so-called amphidromic points hy drawing "cotidal contours" on the ocean map as in
Figure 9 (from Chart 1 of Defant, 1961). A cotidal contour is the geographie locus of
synchronous tides, the locus along which the tide crests simultaneously. Thus, each
cotidal contour can he assigned a unique dock time, the phase of the 12.4-hour
cycle when this locus is at full tide. These contours radiate from the amphidromic
point. At the amphidromic point, the tide is full at all times or at no time. That is,
EQUATOR

Figura 8. An attempt to map the North Hemisphere

onto a ring with the Equator wrapped twice around.
The hemisphere must be punctured at two points.

NORTHERN
HEMI5PHERE

there is HO tidal component at the period in question (M 2 in this case, which

typically carries most of the amplitude). The water surface pivots about the
amphidromic point like a rotating tilted plane (Figure 10)

... or rises and falls at the penod of some residual cO!TIponent, e.g., dlumal rather t an
semilunar. (The Earth-Sun system's center of mass being outside the Earth, we get 0 ly
one bulge at the corresponding period.) Figure 9 as substantially updated by Ernst
Schwiderski twenty years later is colored forphase on pages 1~.17 of Winfree (1 y86a),
and that that·too is superceded after another decade by direct measurements' from
Earth-orbiting sateJlites. These successive maps differ quite a Jot but all illustrate the
essential principle stressed here. William Whewell (Master of THnity College, Cam-
bridge, in the 1840s, who coined the words 'scientist' and 'p"ysicist') was the first to
conceivEi ofsuch points and IJl0tthem on an oceanographic map (Whewell, 1836); buthe
.did not extrapolat~ to larger oceans from the one ormaybe two phase slngularities in the
North Sea/English Cnannel, nor could he even prove the existence of one to the
satisfaction ?f thEr Astronomer Royal, who scoffed in mathematicaJlY more sophfsticat ~
ter.P.1s: So tne matter WqS Jar9.e1y dropped.an for otten for about 80 yaars. Only' tI1en
10 70"

30 ~~ .-J-- \I"" 1J'''r~ Ja'

JU~
~_---m.'~~8Z ~~ \
" 4 : : ' , , ")7,0'
~~
~ t9:\\\ti~.~~~5 ~tl ~;tJ ' ' l n ,~-=U/ J/'il"'~to'
30"

50'

70 10

Figur. 9. A map of the globe showing the "cotidal" loci along which the tide crests at each hour of a 12.4-hour cycle (accommodated here by ;t:>
sometimes having a "12" contour distinct from "0"). (Adapted from Defant, 1961 with permission.)

i"
rn

~
50 2: PHASE SINGULARITIES (SCREWY RESULTS OF ClRCULAR LOGlc)

CURRENTU'
ACTIVE
OOTlDAL
CONTOUR

AMl'HIllROMIC
POINT

F'l9ure 10. Tidal circulation in a large basin (exaggerated).

- TIDAL
CREST
- MEAN
DEPTH
- TIOAL
TROUGH

Example S. The Fnrltfly's Body Clock. Most living organisms have an innate
tendency to repeat their behavior and physiological activities at inteIVals of about 24
hours. This tendency is ascribed to the working of an internal physiological oscillator
called a "circa-dian" dock or pacemaker (see Chapter 19). What litde is known of its
mechanism in any species (in 1978: see Chapter 19 for recent molecular genetics)
mosdy comes from watching the timing of behavioraI rhythms that it indirecdy
drives. One of the best studied of these is a neurosecretory rhythm that ultimately
times the first appearance of butterflies, moths, flies, and wasps after metamorphosis
(see Chapter 20). Newly hatched flies appear from a heap of metamorphosing pupae
at 24-hour inteIVals. These bursts of edosion activity reveal the phase of an internal
dock that can be started, stopped, and reset in phase by exposures to light.

The Pinwheel Experiment. It was in such an experimental system, developed

primarily by Colin Pittendrigh, that 1 was first able to demonstrate aphase
singularity in a biological dock. The ideal was to conduct the following rather
inconvenient experiment:
A lawn of young pupae is spread out on a desk top under constant light (Figure
11). By slowly moving a shadow from east to west like nightfall, oscillations are
started in columns of pupae as they fall under the shadow (see Chap~er 20). If the
shadow takes three days to engulf the desktop, an east-west phase gradient spanning
three cydes of phase is established. With all pupae now steadily oscillating in the
dark, they are exposed to light, almost simultaneously, by moving the shadow
southward, exposing first the north edge of the desk, and eventually the whole desk.
lust before it withdraws from the south edge, it is suddenly moved back up to cover
the whole desktop. Thus, each row of pupae was exposed for a time proportional to
its north-south position. Those at the north edge were exposed for a long time and
those at the south edge were not exposed at all. The desk top now contains an
orderly array of combinations of phase (0 ::; 4J ::; 3, east-west) and duration of
 A: ExAMPLES 51

BIG

Figure11. A "gedanken experiment" in which a rectangular M

field of circadian docks is manipulated by light, obstructed
bya moving shadow. 0

o 2

exposure (0 ~ M ~ BIG, north-south). We wait to see where pupae simultaneously

emerge, and when. This was called the "pinwheel" experiment because the
anticipated result was a pinwheel-shaped wave of eclosion or, rather, three identical
pinwheels rotating side by side, one in each repeat of the east-west phase gradient.
Each should rotate clockwise. This forecast rested on three well-established
observations:
1. Of Kalmus (1935) and Bunning (1935): That eclosion follows the light-dark
transition by a fixed interval plus multiples of 24 hours thereafter. Thus, the
eclosion wave must move along the south edge of the desk from east to west
(point D to point A in Figure 12) in each of the three unit cells.
2. Of Pittendrigh and Bruce (1959): That early in the fruitfly's subjective night
(point B), abrief but saturating light pulse delays eclosion somewhat whereas
early in the subjective morning it (point C) somewhat advances eclosion. It was
presumed (and subsequently verified by Engelmann, 1969; Frank and
Zimmermann, 1969; Chandrashekaran and Loher, 1969b; Winfree, 1970b and
c) that a lesser exposure gives lesser delays or advances.
3. Also of Pittendrigh and Bruce (1959): That with saturating exposures, the
transition from the delay part of the cycle to the advance part (point B to point
C) is made through a region in which the delay inflicted increases by about two
hours for each hour into the subjective night. In other words, eclosion follows
later after a light pulse given later in the subjective night.
What this adds up to is that if eclosion happens first at point A in Figure 12, then
a little while later it is occurring at point B and a little while after that at point C and
a little while after that at point D and a little while after that at point A again. The
sums of these times necessarily add to 24 hours since everything in Figure 12 has a
24-hour period. In other words, the region of active eclosion circulates clockwise
around the borders of region ABCDA in each of the three unit cells of the
accompanying figure.

Figur. 12. Figure 11 is repeated after the shadow covers all

permanently, indicating the dockwise sequence of activity expected
along paths ABCDA.
o 2
52 2: PHASE SINGULARITIES (SCREWY RESULTS OF CiRCULAR LOGlc)

But if the wave of edosion rotates, then its pivot point has no definite phase. The
pupae in that region cannot be eclosing on a 24-hour schedule. This suggested
consequences that might be biologically interesting, so the experiment seemed
worthwhile not just to verify what seemed a foregone condusion but to ask in what
manner rhythmicity would break down at the pivot of the anticipated rotating wave.
So in 1967 I relocated my graduate studies from the Biophysics Department at John
Hopkins University to the Biology Department at Princeton, where Colin
Pittendrigh allowed me to carry out this attempt in the constant-temperature
darkness of a basement animal room during his tenure as Dean of the Graduate
School. The job was finished in a well-insulated basement meat locker in the
University of Chicago's Department of Theoretical Biology in 1969 and 1970.
Altogether, it required 510 separate experiments in a standard format (Recall Figure
30 of Chapter 1):
1. The rhythm was initiated in young pupae by transfer from constant light to
darkness.
2. The darkness was punctuated T hours after initiation by an exposure of duration
M seconds.
3. The times of at least three consecutive emergence peaks were observed several
days after light pulse.
The 510 separate experiments in this format may be regarded as discrete
sampies of one big experiment, the pinwheel experiment described above. There
is no difference in principle between these two descriptions because (unlike some
other insects) Drosophila pupae determine their eclosion time on the basis of
individually perceived light stimuli, without regard to neighbors' docks or
edosion time. Thus, it doesn't matter whether they are handled as separate
homogeneous populations or as areas in a continuous sheet of differently treated
pupae.
The results are idealized in Figure 13 in the form of a computer-plotted
contour map. Each contour band indicates the locus in Figures 11 and 12 along
which flies are simultaneously active evexy 24 hours. It indicates the combina-
tions of<p and M resulting in emergence peaks after the same delay. Thus after 0
+ 24n hours, eclosion is along the loci marked by a vertical curve. After 2 + 24n
hours, edosion occurs along loci one band clockwise from there, and so on
through the 12 bands representing 24 hours at each of the 3 pivot points. As
anticipated by the simplistic arguments resorted to above, activity revolves
clockwise about pivots disposed at 24-hour intervals in the direction of increasing
<p (old phase).
There is a more artistic and experimentally more direct way to present the
data summarized by Figure 13. Figure 13 is a contour map of the surface obtained
by plotting activity time (cophase) below the plane coordinated by stimulus time
(old phase) and stimulus magnitude. Why not just plot the data and draw the
surface in three-dimensional perspective, instead of resorting to a Bat contour
map? Figure 14 does this. (The cloud of data points through which I sketched the
surface is presented in stereo perspective in Chapter 20, Figure 5.) The surface
climbs upward as in a spiral staircase winding around poles along the first two
singularities.
 LOGM
M _
---li"' . . .- ..
--..::~ ~ E §
:::
-
-- -i---_.
-- - ---- ''''H'' -
5
j a=
==
M,* ---- ? l!HFI'::',;'::'l:. -::. •• i! iii i ä:::
~
i un
Im' -::-f~I;~~=
"""1.- -
~ a:...... == a
$= =::5 §
ii'r' :: .:;:~'!:. ' ::1::- -~
SE :::1
== a == -== - --
... -
1II :ESPF: \5 ,.. -~ ~
:;:: -~
a ==
sä ;:J
- ~ -=--,1 ::
M*2 - - ~l~~il~~~ ä§ §! == .:es==: #.~ . _ i
M;~ 5':::::- zIl:'~. == 5;::
l
I'mEiSE:;=,S E == ,.:f ':.1.;'\
l - --.= - 55 ae
::: == ;:;: J;r~J.ii=
i_ ::= - .,.
i~' ~ ~ m~ i ! ::= := E :; Im ==:: :: :. :: e §~j
ia ~ ~ ~ ~ i li! § ~~ !ii = ;;;: ,li =:1: i: 'I:. m. _ := =:::

T
o 12 24 36 48 60
t
1;*
t-r:* ,-:*
I 2 3

Figure13. Computer-printed level contours of new phase 4J' on the plane of exposure time T, to the right, and exposure duration or energy M,
upward. [4J is T/24 modulo 1, offset by a constant; 4J' is (emergence time 8)/24 modulo 1, offset by a constant. 4J' approaches cp at small M.] Arrows
indicate wave movement. This is a contour map of an a!gebraically-defined surface (see Chapter 20) very similar to the hand sketch in the next
figure.
~

-c
i
Gi
CII
W
54 2: PHASE SINGULARITIES (SCREWY RESULTS OF CiRCULAR LOGlc)

STIMULUS - - STIMULUS TIME (Hr •• ) ~

DURATION
o (Hr •• ) 24 48
o 72

1/

....
•-.
%
96 CI)

...
::::I
::::I
2
~
CI)
a:
tc
lI.t
~
lI.t 120 ~
CI)
oe ~
c
:z: lI.t
~ ~

~
lI.t
Z

1
144
0 1
OLD PHASE

Figura 14. Six unit cells of the fruitfly clock's time crystal. Data points are plotted larger in the
foreground, smaller in background. Stimulus duration M increases toward do
hour in the
background from 0 in the foreground. Stimulus time T spans two cycles after transition from
continuous light to continuous dark, to the right. Eclosion peak timing () is measured downward
from stimulus time. M, T, and () in hours. New phase tjJ and old phase tjJ' are measured with
respect to the control experiment (foreground) as fractions of a 24 hour cycle. See data in
stereo without the idealized surface in Figure 5 of Chapter 20.

The essential point of all this i.s that the activity monitored appears on the
stimulus plane as a rotating wave. The position of the wave at any instant is a
horizontal cross-section through this screw-shaped surface at the corresponding
vertical level. Since the surface is screw-shaped, its cross-sections, at successively
lower verticallevels, (successively later times) appear to rotate about the central
vertical axis, which serves as a pivot point for the wave (Box B). Actually there are
three distinct pivot points spaced 24 hours apart along the east-west phase axis in
Figures 11 and 12. These correspond to three repeats of the screw-shaped surface
(only two of which are drawn in Figure 14). Since the data are periodic both along
the horizontal old phase axis and also along the vertical new phase axis, we have
 A: ExAMPLES 55

Box B: Type 0 Resetting Implies a Screw Surface

This seems a good place to draw your attention to a fact more abstractly stated in the
previous chapter, Le., that the screw pattern is very nearly implicit in a much simpler
experiment, namely, the measurement of Type 0 resetting. You might reasonably ask,
'1f it is implicit then why bother to cany out the more laborious experiment?" My
answer is:
1. Its derivation is not quite a tautology. There could be more intricate kinds of
singularity, or multiple singularities, which would point to distinct physical
interpretations.
2. Behavior in other respects than phase resetting (e.g., amplitude resetting) is of
critical interest, and such observations come out of the same experiment
(Chapter 7).
3. Quantitative aspects ofthe measurement, not onlythe qualitative, topological structure
of the resetting schedule, are also of interest (Chapter 20).
How is it that Type 0 resetting betrays the presence of a screw surface within the time
crystal? The reason once again derives from the theorem of Chapter 1, Seetion C, along
with some facts and assumptions:
1. Type 0 resetting is obtained with a ''big'' stimulus.
2. Every rhythmic system exhibits Type 1 resetting in response to a sufficiently
attenuated stimulus, because in the limit of vanishing stimulus, new phase equals old
phase.
3. If the system is really rhythmic, then new phase depends on stimulus magnitude
(intensity, duration, or whatever) in the same way at phase 4> as at phase 4> + 1.
4. We suppose, until forced to recant, that the dependence is continuous: A small
change of stimulus magnitude results in at most a small change of new phase.
5. The winding number must be an integer.
We can reason about the topology of the resetting map on a box diagram in the
stimulus plane (Figure a). Let the M axis represent stimulus magnitude from 0 to some
''big'' stimulus that elicits Type 0 resetting. We need to know the winding number of new
phase around box ABCDA. From A to B, the new phase increases through one full cyde
by item 2. From B to C it changes from 0 to some X. From C to D it goes up and down
with no net change according to item 1. From D to A it goes back down from X to 0 by
item 3. Thus, the antidockwise winding number is 1. According to the theorem of
Chapter 1, Section C, there must be an internal discontinuity. This would be a screw
axis if the discontinuity is as simple and as violent as an isolated phase singularity. But

o c
(a) A rectilinear path spanning one cycle of old phase and the range of
stimulus magnitude from 0 up to big enough M to elicit Type 0
resetting.

A B 0
56 2: PHASE SINGULARITIES (SCREWY RESULTS OF CrRCULAR LOGIC)

(b) Some of the structures that can appear in a contour map of new
phase, superimposed on (a)

it could be that boundary ABCDA cannot shrink all the way to a point because the
inevitable discontinuity is more extensive. For example, it might consist of an isolated
singularity and an extra pair of counter-rotating singularities or any greater
constellation of an odd number of singularities, or even a disk whose boundary
constitutes a one-dimensional singular locus inside which phase is undefined (Figure
b). It is also not unusual in theoretical models for the singularity to be one-dimensional,
viz., a ring or an open segment of a CUIVe rather than a point, as indicated in Winfree
(1979).

In point of fact, the experimental result for this kind of fruitfly looks about as simple
as it could be: a single smooth screw surface with an isolated point singularity.
Experiments in which I attempted to improve data resolution near the screw axis
(Winfree, 1973a, Appendix) indicated no "inner structure" to the single ostensibly
simple singularity seen here at a low resolution.
Another way to look at box ADCBA brings out the connection between Type 0
resetting, a singularity, and a screw-like surface. Type 0 resetting with large stimuli
implies nonzero winding number around the whole box because with small stimuli the
resetting is necessarily Type 1, and 0 + X + 1 -X = 1. With winding number W = 1
around the box, new phase rises vertically through one full cycle around the box. This
establishes the border of the new phase surface within the box. It resembles a helix.
Only a screw surface fits within a helical border. A screw surface necessarily has an
internal singularity (or some constellation of them).

here essentially a crystal lattice of data. Each unit cell of the lattice contains one
turn of a screw-shaped surface. I have sometimes referred to this whole structure
as a "time crystal" because it resembles a crystal lattice and all three of its
coordinate axes represent time. The characteristic screw-like appearance of phase
plots near a singularity gives this chapter its subtitle, "Screwy Results," following
hard on the heels of our anticipating the phenomenon via "Circular Logic" in the
preceding chapter.
This example (the fruitfly dock) was induded:
1. To introduce the equivalence of an abstract space of stimulus parameters to
real physical space, as a setting for rotating waves.
 A: ExAMPLES 57

Box C: Singularity Trap Protocol

"The singularity trap" is a procedure for experimentally tightening a noose around the
phase singularity in a serew-like resetting surlaee.
We first draw a eoordinate plane with an old phase axis extending through exaetly
one full cyde and, 90° antidockwise from it, a stimulus magnitude axis from zero to
"big." A big stimulus is one for whieh the resetting eurve (new phase vs. old phase) has
winding number W =0, i.e., as old phase is ehanged through one eyde, new phase rises
and falls with no net change. This guarantees that the winding number of new phase
around box ABCD in Figure 15(a) is W = 1. Aeeordingly, new phase plotted above the
plane of Figure 15 deseribes a helix along path ABCDA.
How ean we most simply fill out the inside of Figure 15 with data points? The
objeetive should be to loeate the serew axis (assuming only one) from whieh the rest of
the surlaee fans out to its helical border. One way is to exeeute aseries of experiments
repeatedly biseeting the square ABCD of Figure 15(a). In the first step, the stimulus
range (or the eyde) is divided into two equal intervals by a dozen experiments
equispaeed along line EF in Figure 15(b), all at middle phase with inereasing stimulus
magnitude. This line divides square ABCD into two reetangular boxes. Depending on
how new phase varies along their eommon border EF, one box still has W = 1 and the
other has W = 0: the boundary of one box (and not of the other) is helieal. Take the
helical box. Biseet it by a dozen experiments along perpendieular line GH. Of the
resulting squares, only one is guaranteed to have a helieal border and therefore to
eontain the serew axis. Take that square and repeat the preeeding two-step
measurement. In eaeh ease retain the same number of experiments, even though they
are spaeed doser together along the shorter line segments used. In eaeh stage, new
phase rises through a full eyde around the box, so that the same number of data points
is needed to outline a smooth eurve. Three repeats of this proeedure locate the serew
axis (4)*, M*) to within one-eighth of a eyde and one-eighth of the original stimulus
magnitude range [Figure 15(e)]. This proeedure fills the box ABCD with enough data
points (automatically eoneentrated in the steeper parts) to outline the whole surlaee.

2. To introduce the equivalence of piecemeal resetting experiments to spatial

wave experiments, via the time crystal's screw-shaped data surface.
3. To illustrate again the central role of the winding number in maps of §l ~ §l:
The resetting of a rhythm's phase constitutes such a map, and if it has
winding number 0 (Type 0 resetting), then the winding number cannot be 0
around a certain ring in stimulus space. Therefore that ring must endose an
unpaired singularity (Box B).
4. To introduce a nontrivial context of application, namely, biological docks.

The next few examples have the same format and similar results as far as the
topological essentials are concemed, each using a different kind of organism.
Quantitatively, these experiments do far more than just confirm the generality of the
58 2: PHASE SINGULARITIES (SCREWY RESULTS OF CiRCULAR LOGlc)

picture first painted by D. pseudoobscura because each species has its own
surprising idiosyncratic distortions of the basic pattern. But for the sake of keeping
our exploration focused on principles in this chapter, these details are relegated to
Chapter 14 and to the Bestiary.
Example 6. A Mutant Fruitfly's Body Clock (The Singularity Trap Experi-
ment). Box C provides an algorithm for experimentally locating a singularity
by checking the winding number of phase along more and more constrlctive
rings of stimuli on the stimulus plane. Its application was demonstrated using
light pulses to rephase the eclosion rhythm of pe,s mutant Drosophila
melanogaster Winfree and Gordon (1977). Konopka (1972) had diseovered
Type 0 resetting in the pupal eclosion rhythm of this mutant, whereas only
Type 1 had been observed in the wildtype. So aeeording to Box C, a
singularity is implicit in the mutant, though not neeessarily in the wildtype. A
series of rephasing experiments around a box FBCEDGAF in the stimulus
plane of Figure 15 produced the eclosion rhythms laid out in Figure 16. Its
phase drifts through one full eycle around the box. Thus the winding number
around the box is nonzero, betraying the presenee of aphase singularity inside
that box. Dividing this box by a vertical partition (a chain FHE of experiments

o
.. 0*
........ ....c: .....--......:E
I

BIG ---,
D D E C
o 0

.............
o •
° G oH G H
M
lR-
o 0
o 0
o •
A A F B
o
o. b. c.
Figur. 15. Stimulus parameter plane: one cycle of old phase vs. stimulus magnitude. (a) The
first round of measurements is indicated by dots along loei BC and CD. In (b), experiments in
the second round of measurements are indicated by dots along loei EF and GH. In (c), after the
fourth round, the singularity at old phase = cp* and stimulus magnitude = M*, is known to be in
the innermost square.

at fixed phase in Figure 15(b), we find that the right half does not eontain a
singularity and the left half does. Subdividing the left half by a ehain GH of
experiments at fixed duration, we find that the top half does not contain a
singularity. The bottom half does (Figure 17). Thus, by repeated alternations
between applications of the theorem and execution of the corresponding
experiments, we converge on a singular light pulse of 1,700 erg/cm2 (17
seconds of standard 100 erg/cm2/sec blue light) applied five hours after the
light to dark transition (or at 24 hours, or at 43 hours, etc., sinee this mutant
has a 19-hour rhythm). This singular exposure terminates rhythmicity. This is
the phase singularity, (fjJ*, M*) ("phi-star, M-star"). Putting all the data together
in Figure 18, in exactly the format of Figure 14 for D. pseudoobscura, onee
 A: ExAMPLES 59

---------------------------------------0
TIME AFTER EXPOSURE
IN MULTIPLES OF
19.2 HOURS
2

AROUM> niE BOX, COUNTERCLOCKWISE

F BC E DGA F

Figura 16. 60 emergence rhythms in per mutant Drosophila me/anogaster populations are
plotted vertically downward from stimulus time (exposure to light). Time is measured in periods
of 19 hours. The rhythms are stacked up from left to right in order around box FBCEDGAF. The
rhythm's phase scans through one cycle in one tour around this box. You can reconstruct the
box and the data above it by photocopying this figure and folding it into a cylinder,
overlapping the terminally redundant histograms. The data then ascend helically. On boxes not
enclosing a singularity, the data form a stack of closed rings instead.

---------------------------cr
TIME AFTER EXPOSURE I 1
IN MULTIPLES OF t
19.2 HOURS
2

Figura 17. As in Figure 16 except that path FBCEDG

is replaced by shortcut FHG. The rhythm still scans a
cycle around this diminished box, so the singularity is
not in the omitted part.

AROUND THE BOX, COUNTERCLOO<WISE

F H E DG A F

again we behold a single simple screw surface. Figure 10 of Chapter 20 plots

the raw data as a stereo pair.

.~ . n the last line of Winfree an Gordon (1977); mention was made' that several
inferences would be strengtbened lfthe'sameJesults could be confirmed in indivIdual
flies. Saunders et aL (19.94) provided this confirmation using the adult activity rhythm.
See Chaeter 20. .. ......._'~ __•..._,~~ .._
60 2: PHASE SINGULARITIES (SCREWY RESULTS OF ClRCULAR LOGlc)

---T •
o 19 38
o 60
M

70 sec.

79

98 9

!
117

0'
0
136
0
{21

Figur. 18. As in Figure 14 but for the per mutant of Drosophila melanogaster used in Figures
16 and 17. Also only four cydes of new phase are plotted vertically instead of three. All data in
the first cyde of old phase are double-plotted, being repeated in the second cyde. See
unduplicated data in stereo in Figure 10 of Chapter 20. T and () in hours. r/J and r/J' in cycles of 19
hours measured from an arbitrary origin.

In starker form than any before it, this example illustrates the essential
connection between winding number and singularities of maps 1R2 -+ §1. Although
winding number 0 around a box is necessary for absence of singularities, it does not
guarantee an absence of singularities within the box. Phase singularities can be
clockwise or anticlockwise. Paired, they cancel each other's contributions to a
winding number along any ring that encloses them both. The winding number only
teIls us the net excess of clockwise or anticlockwise singularities. If that excess is
nonzero, then that many unpaired singularities must lie somewhere within the ring.
But if it is zero, there might still be any number of balanced pairs. This fact has a
curious implication for regeneration experiments in animals, namely, the
occasional production of superfluous left-right paired limbs, as we will see in
Example 11.
 A: EXAMPLES 61

---T ~

24
24N

24N+24 eI
j
0' o

24N+48
o

Figure 19. As in Figure 14 but for the fly Sarcophaga, according to Saunder's data (1978, with
permission). The published data cover only one cycle of old phase and new phase, here
repeated twice in each direction. See data in stereo in Figure 11 of Chapter 20. M, T, and e in
hours. rp and q; in cycles of 24 hours measured from an arbitrary origin.

Example 7. A Fly that is 1,000 Times Less Sensitive. David Saunders in

Edinburgh found Type 0 resetting in the pupal eclosion rhythm of the fleshfly
Sarcophaga in 1976 (Chapter 20). In this case, as in adult fruitflies (Engelmann,
personal eommunication) the light pulse must eontinue for several hours at about
the same intensity as above: Stimuli less than four hours long elicit Type 1 resetting,
and stimuli more than four hours long elicit Type 0 resetting. The several resetting
eurves of various durations are assembled to ereate Figure 19, whieh suggests onee
again a serew-like dependenee of new phase on old phase and stimulus magnitude.
Figure 11 of Chapter 20 plots in stereo perspeetive the data on whieh this guess is
based. The neighborhood of the serew axis has not yet (1978 and 1999) been
explored systematical1y.

Example 8. Resetting a Flower's Clock. Turning to eireadian rhythms in plants,

Engelmann et al. (1973), working in Tubingen, Germany, earried out measurements
in exaetly the same format using Kalanchoe blossfeldiana (Chapter 21). In this ease,
a red light pulse of some hours duration resets the rhythmic opening and closing of
Kalanchoe's little red flower. My idealization of their results is shown in Figure 20.
Onee again, we have a two-dimensional lattiee of serew-like unit eells. This is
supposed to fit the data presented as a stereo pair in Figure 5 of Chapter 21. In this
62 2: PHASE SINGULARITIES (SCREWY RESULTS OF ClRCULAR LOGlc)

--T-
23 46 69
o
M

23

46 9

!
69

~-92
o
Figura 20. A time crystal of the plant Kalanchoe according to the data of Engelmann et al.
(1973), with permission. Three cycles of old phase are plotted to the right and four cycles of
new phase are plotted vertically. The format is as in Figures 14, 18, and 19 but the first
singularity on the left lies outside the range of these data. See data in stereo in Figure 5 of
Chapter 21. T, M, and (} in hours. <p and <p' in cycles measured from an arbitrary origin.

data set, pulse durations varied only up to three hours, but the critical stimulus
magnitude M* is more than four hours at the first T*. Thus the screw axis in this
first column of unit cells is outside the field of view.
The topological structure of these results is not dependent on the specific
mechanism by which light affects the circadian dock. The same basic structure is
obtained by repeating the above experiment, but with the light pulse replaced by a
prolonged temperature pulse (Engelmann et al., 1974). Chandrashekaran (1974)
obtained similar results using prolonged temperature shocks with the D.
pseudoobscura eclosion rhythrn. However, his measurements don't go quite far
enough along the stimulus duration axis: The plot of eclosion time vs. initial phase
and exposure duration looks like the first half of Figures 14 and 18, the
measurements extending only about as far as the screw axis (or so I interpret it).

Example 9: APhase Singularity for Beer Drinkers. Energy metabolism in yeast

proceeds without oxygen by breaking sugar molecules down to alcohol. Due to a
 A: ExAMPLES 63

peculiarity in the feedback regulation of its rate, the passage of sugar through this
pathway is commonly pulsatile, and the associated biochemistry stably oscillates
with aperiod in the order of aminute. Depending on when in the cyde it is
administered, abrief exposure to oxygen induces aphase shift in this oscillation.
Reasoning from the topological notions repeatedly used above and from the Pasteur
effect (Chapter 12), I proposed in 1971 that the resetting should be Type O. My
subsequent measurements verified this (Winfree, 1972d), together with the entire
helicoidal resetting surface and its singularity (Figure 21; raw data in stereo
perspective in Figure 4 of Chapter 12). The critical dose is about 1/lmole of oxygen
per wet gram of cells, given a few seconds before the NADH maximum. Projecting
the screw-like data cloud onto the stimulus plane, we obtain a wave of NADH
fluorescence rotating about this point.

The singularities discovered through Type 0 resetting arise from an impossible

map from §l x IR l - t §l (from a cylinder to a ring, Le., from the combination of a
phase and a stimulus magnitude to a resulting phase) or, as portrayed in Figures 12
and 13, from the disk 02 -+ §l. In Chapter 1 we also deal with maps from two phases
64 2: PHASE SINGULARITIES (SCREWY RESULTS OF ClRCULAR LOGlc)

to aphase §I x §I - t §I. We saw (in context of color mixing in Example 1) that

regardless of any hypotheses about mechanisms, a certain symmetric format of
experiment induces a map of this sort that cannot possibly be continuous. It might
include aphase singularity. This fact has its corresponding expression in the
chemistry of yeast cells because oscillating glycolysis in yeast, so easily perturbed by
exogenous chemicals, can also be perturbed by contact with differently phased cells.

--T-
o 30
50 -30
M

Figura 21. Similar to Figure 20, but the data concem the
30-second NADH rhythm of yeast cells. Prestimulus data
o
I are included at the top, clarifying the relationships of this
(and previous perspective drawings) to Figures 30
e through 33 of Chapter 1. All data are double-plotted to
the right. Also this one plots M into the foreground, so
I the sense of the screw is reversed. See data in stereo in
30
+ Figure 4 of Chapter 12. T and e in seconds, ifJ and ifJ' in
cycles of 30 seconds from an arbitrary origin, and
stimulus magnitude, M, is given here in ",liters of
oxygen-saturated buffer per 160 mg aliquot of wet cells
suspended in 2 ml of buffer. M* is about 30 on this scale,
which corresponds to about 26 ",M extracellular [021.

o 0

The two methods can be distinguished as folIows: A hit-and-run attack with a

chemical stimulus (oxygen, calcium, or acetaldehyde) is only one way to probe the
reactions of an oscillator throughout its cycle. In some ways a more natural
stimulus is another batch of cells, oscillating on the same cycle, but at a different
phase. Thus, instead of testing each part of a cycle with a small to large dose of one
of its chemical substrates, we could test each phase by confrontation with each
other phase: with a variety of stimuli varying not in amount but in a quality that
varies along a cirele. In other words, two batches of cells could be combined at
different phases in the cycle. They interact to establish mutual synchrony. What is
the compromise phase?
This experiment was actually carried out (for other reasons) by Ghosh et al.
(1971). Ireplotted their data in Figure 22, dividing the cyele into 10 equal-time parts
and ruling a 10 x 10 square to represent the phases of the two "parent" volumes of
oscillating yeast cells. (The phase was observed as usual by following the sinusoidal
changes of NADH fluorescence; see Chapter 12.) The phase observed in the mutually
synchronized mixture is extrapolated back to the moment of mixing when the parent
phases were as indicated. I tabulated this resultant phase in the appropriate little
 A: EXAMPLES 65

figur. 22. Phase compromise experiments, plot-

ting hybrid phase as a function of two parent
phases: The digits represent actual hybrid phase in
one-tenth cycle intervals from the data of Ghosh et
al. (1971). The digits are placed within one-tenth
cycle by one-tenth cycle boxes; their positions
within each box are arbitrary. The contours lines
roughly link equivalent data.

square, once again in units of one-tenth of a cycle. The 47 experiments shown do not
give a clear impression but they are at least not incompatible with a continuous map
such as I have drawn on an overlay. The continuous map was designed:
1. To fit the data as weIl as any smooth pattern could. (All but four out of 47 data
i;
fall within ± cycle from the contour map.)
2. To show the resultant mixture phase equal to both parent phases in the case of
control experiments (not actually reported) in which aliquots of equal phase
were recombined.
3. To reflect, in its symmetry about the main diagonal, the arbitrariness of calling
one aliquot A and the other one B.
4. To confine the necessary discontinuity to as small an area as possible. In this
case, we end up with one isolated phase singularity in each triangle, above and
below the diagonal. (Using the nuclear division cycle in Physarum (Chapter 22),
the experiments in identical format seem to reveal a quite different sort of
discontinuity instead of a phase singularity.)
A caveat: These experiments have not been repeated (a big problem in
contemporary science, generally.) The uncommonly severe variability of results in
the pioneering study of Ghosh et al. leaves room for a radically different
interpretation, Le., that cell mixtures don't compromise at all but always
synchronize to one or the other of the parent populations. In all but two out of
the 47 trials shown, the "compromise" phase was within one-tenth cycle of one
parent's phase. It might be that uncontrolled variables such as the details of mixing
determine which parent dominates.
However that may be, the phase singularities discovered by chemical
perturbation (oxygen, calcium, acetaldehyde) are distinctly visible in those data. I
first proposed the experiments shortly after finding the phase singularity in a
circadian system. Because of the temptation to believe that the phase singularity
might reveal something unique about a universal circadian dock mechanism, it
seemed incumbent upon me to demonstrate that the topological argument is really
66 2: PHASE SINGULARITIES (SCREWY RESULTS OF ClRCULAR LOGlc)

model-independent by applying it to a chemically different dock. Glycolytic

oscillations seemed to qualify in view of their short period and acute temperature
sensitivity of rate. We know from the pioneering studies of Chance and Pye (see
Chapter 12) that yeast oscillations respond to AMP exactly as circadian systems
respond to light. Thus experiments could be carried through in identical format
using oxygen gas instead of blue light. The results were qualitatively the same.
In the remaining six examples we turn to phase singularities involving physical
space in a more substantial way than in the pinwheel experiments previously cited,
which were actually carried out piecemeal. The first example is another circadian
rhythm that, because it shows Type 0 resetting, is a strong candidate for
experimental realization of a phase singularity.

Example 10. Morphogenesis in Fungi. The creature I have in mind is the fungus
Neurospora crassa, the one Hamner took to the South Pole (see Box A).lts rhythm
is a banding pattern that marks the loci of the frontier of growth at successive 22-
hour intervals. Hyphae formed along the frontier at the same hour of each
successive circadian cyde turn out to mature into conidia, the asexual spores by
which Neurospora reproduces. Hyphae formed at intermediate phases remain
forever vegetative, without forming conidia.
Suppose the pinwheel experiment of Examples 5-9 were conducted on a
square sheet of Neurospora growing on a much larger bed of nutrient agar.
According to Figure 13, the winding number of new phase around the square
ABCD must be W = 1. Suppose phase increases steadily dockwise. That means
that as the square continues to grow at its edges, the locus of conidiation moves
around the edge, circumnavigating the edge every 24 hours at the frontier moves
out. Thus, the conidiation pattern is henceforth aspiral. Another way to visualize
this implication can be seen in Figure 23. The continuity of pinwheel experiments

Figur. 23. An idealized colony of Neurospora is shown with thirteen

- f-tt1ftt1+H+H bt-tirt-tt+tt-t-tt----"uccessive positions of its frontier. Radial contour lines indicate
successive positions of phase 0 of the circadian dock. The locus of (</>
= 0 on the frontier) is accordingly an Archimedes' spiral.

using other circadian docks suggested that in Neurospora, too, phase should vary
continuously with the timing and intensity of a light pulse, i.e., with position on
the mycelium. The usual result in Examples 5-9 is that the contour lines of
uniform phase diverge from an internal singularity after the stimulus is given. An
hour later, the phase contours are all still there, but the phase each represents is
an hour later, as with the cotidal contours of Example 4. Alternatively, one could
say that the contour of maximum conidiation-induction moves dockwise from
 A: ExAMPLES 67

one hour to the next, revolving around the singularity like a searchlight beam as
do the eclosion contours of Example 5. As it goes, it induces hyphae along the
expanding frontier to differentiate into conidia. Thus the conidia appear along a
spiral locus.
, This experiment has not yet (1978) been tried.

The pinwheel experiment is only one way to arrange a nonzero winding number
around the frontier. According to one view of the underlying physiology (Chapter 4
and Chapter 8), the fungus is liable to fall into ahabit of any small integer winding
number immediately after germination from a tiny dot of spores. In this way,
multiple spirals, both clockwise and anticlockwise, as well as concentric ring
patterns should arise spontaneously. This is in fact obseIVed (at least up to winding
numbers +3 and -3) in Nectria, in Penicillium, and in Chaetomium (see Chapter
18). At present, nothing is known about the phase singularity (or multiple phase
singularities) that must lie within spiral or multiple-spiral mycelia. According to
one theoretieal model (Winfree, 1970a), the rhythmic system of the germinating
spore begins in the phase-singular state. In D. pseudoobscura, as weIl, it seems that
laIVae reared from the egg in conditions of constant temperature and constant
darkness remain in the phase-singular state (Zimmerman, 1969; Winfree, 1970b,c,
1971a).
The next three examples are drawn from the recent (in 1978) literature of
developmental biology.

Example 11. Regeneration of Limbs. According to one view of development in

higher organisms, each organ emerges from a little two-dimensional patch of tissue
that has some kind of organizational coherence. Such patches are called
developmental fields. French et al. (1976) and Bryant et al. (1977) gathered an
impressive body of evidence under the proposition that (at least in arthropods, and
maybe in some vertebrates too) each ceIl knows its role in the developmental field
by retaining within it a quantity defined on the ring-something like a phase, or an
angle. At present no one has the slightest idea what this might mean
biochemieally. It might seem appropriate to remark, as Isaae Newton onee did
in a similar ease, that
To tell us that every Species of Thing is endowed with an occultspecifick Quality by
which it acts and produces manifest Effects, is to tell us nothing.
Opticks, 1730
68 2: PHASE SINGULARITIES (SCREWY RESULTS OF CiRCULAR LOGlc)

However, the complex mechanisms of evolved systems must be unraveled by layers.

In this case the deeper layers of molecular mechanism await another generation,
while our present concern is with the implications of the putative phase-like
quantity. French et al. (1976) argue in effect (and Glass (1977) recasts their
argument to bring out this aspect more forcefully) that the center of the field is a
phase singularity, and that if experimental manipulations so rearrange blocks of
tissue that additional phase singularities are inevitably created, then additional
organs of appropriate handedness must emerge at those sites. A number of startling
experiments are demonstrated which readily lend themselves to this (punning)
"dock-face" interpretation, as it has come to be called. This matter is dearly of
central importance in any discussion of the biological role of phase singularities.
The biological background and alternative interpretations of the data are elaborated
in Winfree (1980, 1984b) (and in Chapter 16 of the 1980 and 1990 printings of the
first edition of this book). The physiological nature of the putative singularity is
examined in Chapter 10 together with other kinds of singularity collected in this
ehapter.
This example and the next are included to play the role of "straw men." Their
apparent phase singularities are, in my view, partieularly insubstantial. Although
these two examples can be described in terms of maps among rings, I believe this
language is inappropriate and misleading. I include them beeause if I am right, the
existence of such cases alerts the reader against meehanical application of language:
We are trying to do science, not just make mathematical metaphors. I include them
also because I might be wrong, in which case they greatly enrich the catalog of
biological phase singularities.

Example 12. The Cuticle of the Arthropods. The lens of the insect eye might be
regarded as an organ, somehow assembled by a few underlying cells whose job it is
to secrete perfeetly transparent cutide in the right geometrie pattern. This pattern is
periodie on the scale of wavelengths of light. This periodism was initially ascribed to
rhythmic secretion of cutide. Electron micrographs of microtome sections through
the lens cutide consistently exhibit aphase singularity of rhythmic banding in
seetions transverse to the optic axis. A spiral of more eleetron dense cutide is plainly
seen winding in toward this center. In sections parallel to the optic axis, a periodic
banding is seen. Every verticalline penetrating into the lens parallel to the optic axis
exhibits rhythmic alternations of electron density along its length, Le., along the
time-of-deposition axis. In seetions perpendicular to the optic axis, the phase of this
rhythm is seen to advanee through one full cycle as sampies are taken at suceessive
positions around any ring concentric to the dark spiral's center. Thus, we have a
nonzero winding number of a structural rhythm (originally a temporal rhythm in
sequence of deposition) and a phase singularity continuing in depth like a screw
dislocation in a crystal. Taken together, these perpendicular sections suggest a
screw-like, helicoidal surlace of electron density within the block of sectioned
euticle that was lens. Does this have some developmental meaning? Yes, but it is not
at all what it appears to be. This mystery is investigated further as Example 11 in
Chapter 10. My objective for the present chapter is simply to present many cases of
phaSe singularities as phenomena without resolving interpretations; this is reserved
for Chapter 10 after a groundwork of theoretical concepts has been laid in
 A: ExAMPLES 69

intennediate chapters, and after the reader has acquainted hirnself with more of the
pertinent experimental details in Chapters 11-23.

Example 13. Cellular Slime Molds. A third example from the lore of develop-
mental biology concems the marvelous social amoeba Dictyostelium discoideum,
which has figured so prominently of late in the burgeoning literatures of cAMP and
of intercellular communication (Chapter 15).
It has been appreciated for a long time that the preamble to morphogenesis of
social amoebae consists of a gathering together of widely dispersed individual
cells, mediated by their periodic relaying of a chemotactic signal from a
pacemaker cello This signal guides many thousands of other cells to the
pacemaker (Shaffer, 1962). Here they contact one another and assemble a little
jelly-like slug which creeps away to find a place suitable for metamorphosis into a
fruiting body.
The organizing waves emitted by a pacemaker cell are elosed rings concentric
to their source, like ripples emanating from a rain drop in a puddle. Thus, some
interest attached to Gerisch's observation (1965) of rotating spiral waves in the
same situation with the same consequences. The essential differences are that a
spiral wave consists of one continuous locus of cell movement rather than a
series of disjoint rings of moving cells, and that it requires no special cell at its
source. Thus spiral waves commonly arise just as soon as the maturing cells
develop a capacity for signal relaying, but before any cells begin to oscillate
spontaneously.
How can a wave have no source? It would seem that each wave must first appear
somewhere, and that point is its source. But what is manifestly true of concentric
ring waves is not necessarily true of rotating spiral waves. If we trace a piece of a
spiral wavefront backward in time, we never come to a elear source. Rather, we end
up in a vague region of indetenninate periodicity or end up circulating endlessly
about a tiny cirele bounding such a region, concentric to the pivot (see Section B of
Chapter 9). The wavefront at any instant may be taken as a locus of synchronous
cells: all cells pulse periodically, at the regular intervals of spiral rotation, and the
wavefront is the locus of simultaneous pulsing. A multiple-exposure photograph
taken by opening the shutter at intervals of one-tenth cyele would presumably show
10 equispaced parallel spirals, all converging toward the pivot or its bounding cirele.
If these loci be the contours of unifonn phase, then that cirele is (or contains) a
phase singularity.

Close observations of this interesting region have just begun to appear. In the
three-dimensional slug this singularity is thought to become a one-dimensional
rotation axis (Clark and Steck, 1979).
70 2: PHASE SINGULARITIES (SCREWY RESULTS OF CiRCULAR LOGlc)

Example 14. Pathological Rotating Waves in Heart, Brain, and Eye. The
Dictyostelium cell's sudden triggerable release of cAMP in many ways resembles the
sudden triggerable inrush of sodium ions through a nerve cell's plasma membrane.
In both cases, the excited (permeable) state propagates onee triggered by a
threshold-transgressing stimulus (Chapter 14).
Thus a pinwheel wave similar to Dictyostelium's might be looked for in an
extensive planar expanse of nerve-like tissue. The obvious candidate is heart
muscle. At least since McWilliam (1888), medical physiologists have postulated
some kind of rotating wave, a "circus movement," as an explanation for high-speed
rhythmic flutter, and for the much more pemicious mode of asynchrony called
"dementia cordis" or fibrillation. Though there are probably other mechanisms
too, some kinds of flutter and fibrillation do behave, in many ways, like a
sourceless traveling excitation which rotates simply because it got started
somehow. But until 1973, the best case for its existence rested on indirect
physiological inference and on a well-developed mathematical theory (Wiener and
Rosenblueth, 1946; Krinsky, 1973). In 1973, Allessie et al. published the first clear
observation, using a piece of rabbit atrium stretched out flat to accommodate the
necessary array of 10 observing electrodes. Using a delicately timed electrical
stimulus to initiate the wave, he found instances of persistent, pernicious rotation.
Electrical activity circulates as a pinwheel wave, recurrentlyexciting every patch
of muscle to contract (Figure 24). Every point is rhythmically active except the
central patch around what would be a pivot of the pinwheel wave. In this central
patch, activity is irregular, as befits aphase singularity. The nature of fitful activity
in this region poses extremely interesting questions for neurophysiology and for
mathematics, both. The question has mathematical interest because the phenom-
enon is apparently not a consequence of the inevitable inhomogeneities and
physiological complexities of real rabbit myocardium. A similar pivoting wave and
similar irregularities near its "pivot" were observed by Gulko and Petrov (1972) in
a very simple computer simulation based on an idealized notion of excitable
 A: ExAMPLES 71

-OmV
.0
A
•
-.
I -0
B
~ ~

-.
15
i
C i
31 I'

E
-.
-5G1TIMC
1100 mV

5mm

Figur. 24. Map of the spread of activation in a piece of isolated left atrial muscle during a
period of sustained tachycardia as constructed from time measurements of the action
potentials of 94. different fibers. The impulse is continuously rotating in a clockwise direction
with a revolution time of 105 msec. At the left are shown the transmembrane potentials of five
fibers which lie along the circular pathway (A-E). The moments of depolarization, in msec, are
given together with the action potentials and the isochronic lines of the map (Allessie et al.,
1977 I Figure 1I by permission of The American Heart Association, Inc.)

membrane, a simplification of the Hodgkin-Huxley equation (see Figure 5 of

Chapter 14).
• This topic explode In t e ate 19805 with Zy OV'5 (198"6) discovery t at sei f ,
aetivity" is often simply quasiReriodic in uniform numencal media (see this editlon's
new index under "meander' 1 and in the mid-1990s that it isn't always so: "hyper
meander" is still ha dto describe. This uzzte seems r' e for mathematkal in si ht. ....
A much more slowly rotating wave of quite different pathological mechanism
occurs in the cortex of the brain and in the retina of the eye. Still another kind of
rotor, associated with seizures, has been observed in the cortex. See Chapters 9 and
14 for detail and references.

Example 15. SeH-Organizing Patterns of Chemical Reaction. 1 conclude this

section with aremarkable example of (in 1978) recent vintage from physical
chemistry. It tums out that some kinds of chemical reaction are capable of
sustained oscillation and of excitability, very much as in Dictyostelium and in nerve
membrane. Chapter 13 elaborates in detail about the most convenient of these, a
malonic acid reaction in which chemical changes reveal themselves colorfully in
water solution at room temperature on a time scale of seconds to minutes.
Consider this reaction in a three-dimensional volume of liquid. Imagine that you
could wander through it, monitoring the phase of the red-blue alternation going on
72 2: PHASE SINGULARITIES (SCREWY RESULTS OF ClRCULAR LOGlc)

everywhere. Let's start at any place P in Figure 25 and follow a closed path through
the liquid, ending up back at P. The path pp is a ring. Let's suppose we could
monitor phase instantaneously around the ring. The net change of phase along path
pp must be an integer number of cycles. Call this integer W, the winding number of
phase along ring PP. Unless W = 0, the path PP cannot be contracted to a point
without encountering a phase discontinuity. Only two possibilities present
themselves:
1. W is necessarily always O. This is simply not true, as the photograph in Figure 26
shows.
2. Locus PP loses its winding number by unit increments, necessarily abruptly as
some special loci are passed during the progressive contraction. These loci
would be phase singularities. Eventually there remains only one enclosed within

Figure 25. A closed path in three-dimensional space.

Flgure 26. A photograph of rhythmic pattems of

chemical activity in a dish of malonic acid reagent.
Twelve sources are visible. A survey of instantaneous
phase along any one of the three closed paths shown
leads thus through the indicated integer number of
complete cycles of phase. This is the number of left-
handed spiral sources minus the number of right-handed
spiral sources enclosed.

PP, so PP can be contracted to a tiny ring of winding number ± 1 around that

locus, or pulled across and contracted to homogeneous phase. This is, in fact,
how it iso Figure 26 gives an example in two dimensions, each singular locus
being just a point.
In three dimensions, the phase singularity must be at least a one-dimensional
locus, a thread or filament of ambiguous phase in the reacting liquid. This is
 A: EXAMPLES 73

necessary because each phase singularity must be encountered along any path of
contraction of PP. Such paths are surfaces bounded by PP. If every such surface

'*
Figure 27. Three (out of a continuum of) caps bounded by a closed CAP~
ring (PP)as in Figure 25. Each cap is a locus along which pp is '~I;~~
contracted to a point. Each contains a phaseless point. The locus of ,
such points (**) is thus one-dimensional. GAP
PP

encounters the singular point, then the singularity must be at least a one-
dimensionallocus (Figure 27).
This thread of ambiguity has been observed visually and I have reconstructed
several from chemically fixed serial sections of three-dimensional blocks of malonic
acid reagent. These threads typically elose in rings for reasons perhaps not evident
here but elaborated in Chapters 9 and 13.

~ ample 15 'concluded u ihls settion in 1978, bllt in 19991 append two-more here}
m.ain!y because their ongins are so physically dlstinctiVe. Other new examples, such as
therfollowihg, are distributed throughout later chapters, each in context where it best
iI~ustratesa point under discussion'
..' . .
• Jhe h~li€oidal resErtting sarface a Cl (jramatlc singujarity of daily bfoluminescence
irnrsea~ater suspension.of dfnoflagellates', e o~ed by biochemical inhibition of proteiri
syntnesis. This is in Cnapter 19, new Figure O. Delive,y ofthe singular stimulus in this"
cas~ results jn prolonged terminatio of drcadian rhyt/:lmicityJ perhaps because the
many-independent cells collectively moriitored al! recoverto normal rhythmicity but at
mdependently ~nd<;>m phases, The question has not yet been posed experimentally.
• • A simHar time; crystal remeasured in the brainstem oscil/ator tbat. regulates
breatl-)ing, ·this ohe perturbed by positive stimuli remeasured using negative stimuli.
This JS among the updates of'Chapter 14 ab out neural pacemakers. Anather was
isco\tered by electrically excitjng 't he J?acemaker ceUs of the heart also new in Chapter
14. Jn aU three ca ses tI1e singular stimulus.causes at most a brief pause, after which
coherent oscillation promptly resumes at unpredictable phase. Neural oscillators
ger:lerally have special jnterest'in that there seems not to be any one unique singular
stimulus, but Jather ,~ one-pai'ameter set of (f,S) combinations wjthin a certaln range of
sttffiulus magnitudes, S, where the resetting curve is discontinuous between Type 1 and
Type O. .
• The helicoidal resetting surface and phase singularity Cf the chemical oscil/ator
fea r"ed in Example 15, just above,. but now homogeneously oscillating in a
stirred tank reac:t0r. T,he phase-shifting stimulus is a measured injection of bromide
ions. As in the neuta exam le , th,S s stem de arts prom t1
from its> phase
74 2: PHASE SINGULARITIES (SCREWY RESULTS OF CiRCULAR LOGlc)

I expected in 1'967 that,1here rnight be a few more rnstances cf similar nature in

other circadian docks and pemaps in chemlc~1 oSciliaJors, .and tha 1978-writing.could
indeed cite several such qiscoveries;, but 1)0 !]"lore were expected. But sil)ce then 31
more published episodes ' 0(phase resetting th~t isolated a phase singularity heve·
accumlilated, In almost that manY'diverse physical, chemital, and biological systems.
,1nitialry, opeor MO appeared every<year, ,<!nd. the rate seems not tiistingliishably
different iR 1999. 50 I jllst slij:p them ihto tbe text: ~. appropria e sites' (ether than
tiresomely prolongil}g this initia~ liSt of examples, ex.cept for ~e following:
, . .
'" -.. . ~

Example 16. Coherent light. Eigure 26 could almost be a, slice tnrough a three-
dimensional field of laser light, transver~e to its propagation. The'''oscillators" are the
intrinsic 101S-Hz periodicities of visible photons, and' their linkage by diffusion is
replaced by diffraction, but f.emarka~ly, mUGh:etsetemains the same. Nothing req!;Jires
winding numbers always to be 0 on closed paths in a fjeld of sound wwes (Wright and
Berry, 1984), nol' of quantum field wC!ves (Berr:y et aL, 1980), nor of electromagnetlc
waves (Baranova' .et al., . 1983). .Jransverse sections ' through any. such fteld are
generically marked 'by phase $ingularities, 'pqints where the amplitude is O. In thre .
dimensions they, (Jre filaments "of quiet Of of r.nass-fI'ee vacu m Qr of darkness. My
expectation was that they. would occur more or l.ess. at random, subject onfy- te
continui!y constraihts, like 100se. spagbett' except 'that they ay often form closeQ
rings. BrarY)billa et al. "(1991~ nQwever, a gue thatthey t~nd to form 'phase si gtl~a
·crystalst and tI'ien ' proc.ee,d io d~monstra1e tnem in tne IIgh wlthin an Na2 laser.
5chueuer and Orenstein (1999). found compar'able optlc;al pbase ~n.gu'larity arrange.
m~nts in semicOh'ductor rnicrQcavi jes. Coullet et
al. (1989) anticipate tl1at .eacfl pbase
singutarIty would form a spira~wavefront around ltself if glven en.ougb space, which- 15
not avallable inthe·foregoing two laboratory arrangements. [n three dimensions thrs i .
a helicoidal iso-phase ?urface, .its: C!xis along the direGtion of propagatiml. The
tran sve rse "Archil'fledean spiral is only a "phase 'walle" or "pseudowave." Yu- et .al:
(1996) and Coullet et al. (1998) go further 'to argue that the ffeld within a laser
described by the Max..well-Bloch equations can constitu!e an ,xdtabl. mediuTl1.

Example 17~ Vis~al Topography 0l'! th. Brain~ ExamEfles· E+ of C~apter "s.-Section
B introduced the. projective plane to systelJlatize description ' 0 Irne. orien..tati9ns:
This topological space is in many respects equivalent to the cirde: ~ cOfJld a~sIgn
ori~ntations 0:-180° to phases Q-3600(_then cqlor thern like- the· hues ROYGB1V-
ROYGBIV of toe color wneel :' his ?epiction . of phases as ~TUes provides visual
language fqr attempts to reason about' pinwheel expe{iments and , phase
singularities without explicit symbolic' rnathematics (Winfree, 1983bl- 1986a, and
1987a).rWith orientations so presented we rnight expect to ~ee the seime Rinds of
phase singularity.: in t1ie mammalian cortex, .unless some. amazing developmental
.proscription forbids them. -S.windale (-1982) s~stematized thi's problem in the tem:t
of this.book and-adopted the. ,same rdentificatlon of phases with colors .tc> clarify the
.cortical maps:' Blasdef anq -Salama .(~ 986)' ccintinued with this colorin~ s~heme. on
the cover of Nature to illl:istrate the local .orientatio re erences of neuro so . ilie
 B: COUNTEREXAMPLES 75

m9nkey cortex. Bon oeffer al} Grinva Cl (1991) . si i arly du6becf the phase
singularities "Rinwheel 'centers"; they are also sotnetimes callec:t " vortices" and
".ha~f-rotation polRt s!ngularitieslJ 'and "1I"-periodic singularities." They 'cover striate
cortex (a,rea 17) seemingly randomly: except that nearest neighbor.s (typically
i
around rnm ap~rt) tent! ta have opposite nanded/'!ess (Obermayer and BIasdei,
1997). . . . '
Ä tUr'iOl:.l5 featu~e 6f these ' ma.ps is" the physiologlcal coupllng between 000 kinds
toat rernain' topologically djstinct , ' ,
"

•
. But b~ecause the tocat 0 ientation ~ preference tel')ds t9 stat perpendicular. to the
local' direction flreference, tbe two rhaps are .coupled, with h~ result that d~rection '
Rreference ras lts discot)tinuities -at the $CIme half-rotation phase singularities as
does orientation and along ares connecting 50ch singuraritie.s. Along these ares of
ractureI the direction shifts abruptly bY one half eyde. (Swindale et al., ':t987; ·
Weliky et al., 1996; Swrnpale. and Bauer, 1~~8), ,In other words, tbe full-rotation
pbas~ singularity: of difectio~ is strung out: ~fong a waf)dering ar.c several
millimeters long connectir;Jg orientation singularities.. ' .
The same color rnap supported Nature's com LJnication of further ihguiries into
the biological import of these neurol.ogicaf pha$e slngularjties in 1990 (DurbJI1 and
M'1chison), ~,1991 (BQ 'hoeff-er al1a atinvald}, and" in 1998 (Wolf and Giesel); a~d
also 'of; ti.rhjng relations in the he in 1998 (Gray et aL)r in which tull rotation
phase siogularlties also 'tend to ite s rung out ~Iong several-centimeter ares ot
"60ndlfctioh . block" in a medium charactetizec! by local orientation preference,
vi~+ ' the local muscle fiöer dlrection (Chapter 17). In heart musder however, the
e?$tent of discontinlJtty is flot ev.erywhere· l 'cYcle out tapers both 'waY$ to '0 from
that value in the middle- of the arc, .and the ends cf the wandeejng are of ghase
disco.irtlnuity qre not orientatlon sihgularities, except in the sense that every point
is, because in the third dimension (heart wall thickness) fiber orientation turns fuUy
around. =rom mind · tAe~ are stretcned'-out full-rotation slnglliarities. ~ ,

B: Counterexamples

That will be enough for examples of the smooth patterns of timing that lead one
to anticipate some kind of singularity at the center. A few counterexamples now
seem appropriate to forestall any impression that such patterns and their phase
singularities are topologically inevitable consequences of using a circular
measure, and therefore of no scientific interest. This inference has enough truth
to it that I have at times mistaken it for the whole truth. It comes especially elose
to being the whole truth in connection with the rowboat navigation problem. As
76 2: PHASE SINGULARITIES (SCREWY RESULTS OF ClRCULAR LOGlc)

elaborated in Chapter 10, much the same might be said of the cases of visual
cortex patterning and of limb regeneration: There I believe the apparition of a
phase singularity has more to do with logic and the peculiar but convenient
choice of a phase-like measure than it has to do with questions of dynamics, of
models, of mechanism.
It is essential in this business to attempt a segregation of issues of logic and
measure from issues of fact anti. mechanism; that comes in later chapters. For
now it will suffice to note that aphase singularity of some kind (though not
necessarily an isolated point) is a topologically generic consequence of continuity
and Type 0 resetting (Box C). However, many kinds of rhythmic systems violate
continuity or do not exhibit Type 0 resetting. For example, experiments that might
have revealed Type 0 resetting or phase singularities in the cyde of cell division still
leave those matters in doubt (Chapter 22). Resetting experiments on models of the
female cycle, and probablyon the real mechanism too, exhibit gross discontinuities,
possibly due to threshold processes assumed to underlie hormone release,
ovulation, etc. (Chapter 23). Many kinds of nerve, though rhythmic in their firing,
either in isolation or in response to specific stimuli, seem to suffer such an abrupt
alteration of membrane behavior during the action potential that resetting maps are
grossly discontinuous (though curiously, not always at action potential time)
(Chapter 14).

Turning from particular cases to more abstract categories, there are

mechanisms in which rhythmicity is secured through abrupt transition from one
state to another, eventually leading back to a prior state. Such discrete state
devices, or logical automata as they are called, have been widely employed as
metaphors for biological rhythms. But there is no place in such models for
resetting curves or surfaces or, for that matter, for considerations of topological
continuity.
The dass of models taken up in the next chapter are completely continuous and
smooth in their behavior but, for reasons to be developed there, can only support
Type 1 resetting. These too have enjoyed wide popularity as underpinnings for
experimental design and inference about biological docks, but they have no
singularity.
Another dass of mechanism employs continuous kinetics up to a point at which
a fast mechanism, previously inconspicuous, intervenes like a deus ex machina to
 C: THE WORD "SINGULARITY" 77

abruptly restart the process at its beginning. These so-called relaxation oscillators
have traditionally provided the physiologists' first recourse for explanation of
spontaneously rhythmic happenings (see Chapter 6, Section C). But on account of
the near-discontinuous jump, their resetting maps are not practically classifiable,
winding number goes undetermined, and topological arguments cannot fence in a
singularity. If one exists, it cannot be detected by examining the geometry of timing
relations elsewhere (hut see Chapter 10, Section B).
Thus, if we in fact observe aphase singularity, then we have some explaining to
do in the contingent terms of empirical science, not only by making the graceful
gestures of abstract topology.

C: The Word "Singularity"

The appearance of singularities in a physical theory suggests inconsistency and room
for improvement.
Narlikar, 1970
Before departing this chapter, I wish to return to its opening lines, in which
the word singularity was defined. Let me elaborate on that definition. As used
by mathematical physicists and as I use it here, the word singularity means a
place where slopes become infinite, where the rate of change of one variable with
anothet exceeds all bounds, and where a big change in an observable is caused
by an arbitrarily small change in something else. As James Clerk Maxwell
observed,
Every existence above a certain rank has its singular points: the higher the rank the
more of them. At these points, influences whose physical magnitude is tao small to
be taken account of by a finite being, may produce results of the greatest importance.
All great results produced by human endeavor depend on taking advantage of these
singularities when they occur.
Cited on p. 972 of Newrnan, 1956
According to the bible of theoretical physics (Morse and Feshbach, 1953) during the
years when those who taught me physics were learning it:
... singularities... are usually the most important aspects of scalar and vector fields.
The physical peculiarities of the problem at hand are usually closely related to the
sort of singularities the field has. Likewise, the mathematical properties of the
solutions and differential equations are determined by the sorts of singularities that
the equation and its solutions have. Much of our time will be spent in discussing the
physical and mathematical properties of singularities in fields.
My involvement with singularities began at a desk in the Eisenhower library in
Baltimore, to which I retired each morning in the fall of 1965 with only a pencil and
pad to discover some questions natural to an interest in physiological periodism. At
length I fumbled to an interest in maps among rings and products of rings. The
essence of that subject, according to the quote above, lies in the singularities of
those maps. That led to noticing such objects between the lines of current papers
from experimental physiologists. A singularity is a kind of discontinuity. It might or
78 2: PHASE SINGULARITIES (SCREWY RESULTS OF C1RCULAR LOGlc)

might not be interesting. Interest goes with meaningfulness. Following Fahrenheit

and Celsius, I might invent a new temperature scale called Winfree, on which the
temperature Winfree is defined as the reciprocal of temperature Fahrenheit. Thus
the temperature Winfree would have a singularity somewhat below the freezing
point of water, where temperature Fahrenheit goes through zero. But this would
have no possible physical significance. This is what is called a "mere coordinate
singularity," a mathematical artifact of choosing a peculiar coordinate system.
Other kinds of singularity cannot be removed by any reasonable change of
coordinates. In other words, they are defined in terms of variables whose physical
import is immediate. Such, for example, are the space-time singularities
associated with black holes. One of these is widely believed to be the creation
of the universe. That's interesting. On a more modest scale, the singularity of heat
capacity that ushered in the quantum mechanics of crystal lattices under the
banner of "the ultraviolet catastrophe" was a nonremovable singularity interrelat-
ing basic physical quantities. Arguments about winding numbers and the theorem
of page 27 have been deployed to establish the existence of elementary particles as
singularities in quantum-mechanical continua (Rebbi, 1979) and the existence of
Bloch points as singularities in magnetic bubbles (Slonczewski and Malozemoff,
1978).
Yet according to one cogent viewpoint, singularities happen only in models. In
reallife, the singularity is always somehow evaded. Wind velocity falls back to zero
in the core of a tornado, color mixtures vanish into grayness, and a rhythm can
simply go flat or become very wiggly with no fundamental-frequency component.
When aphase singularity results from feeding observed facts into a soundly
reasoned model, we know that something has gone wrong in this model and that we
are looking at a distillate of the logical contradictions implicit in our nations of how
the real world operates. Experiments that seem to imply a singularity signal a
contradiction borne of leaving something out. The purpose of dabbling in models
and of contriving experiments is to find out what is left out of our thinking, to see
what hidden escape hatch a real system takes in evading the demand that it achieve
the impossible.
In the case of black holes, there remains a lively debate over the reality of
singularities in the space-time "continuum." For example, during the month in
which I first wrote up Drosophila's answer to the pinwheel experiment for
publication, Fred Hoyle accosted the Royal Society with the question, "Do
singularities exist in the real world or are they only metaphysical entities?"
(Bakerian Lecture, June 1968) I suspect that what is ultimately being asked is
whether or not our cherished observables (for example, distance, time, and mass)
are in fact as fundamental as we imagined before finding that they can be involved
in singularities. Maybe they are only observables, poorly chosen in view of their
peculiar behavior near singularities, like the Winfree temperature scale. The
question then becomes: What are the proper quantities in terms of which the world
functions rationally and continuously?
My attempts to answer this question in the cases of biological and biochemical
phase singularities require additional familiarization with the experimental systems
(Chapters 11-23) and some elaboration of dynamic models (Chapters 3-9). Only in
context of the very simplest dynamic models (next chapter) does the phase
 C: THE WORD "$INGULARITY" 79

singularity acquire an ineluctably paradoxical character. Subsequent chapters

provide amendments to the simplest models whereby phase singularities become
perlectly tarne, though not uninteresting, biological phenomena. We reconvene in
Chapter 10 for a look at the physical origins of the phase singularities used as
examples above.
Because we must dabble in dynamical systems, I must issue advance warning
about a homonym. "Singularity" also means simply "a point where something
singular happens." "Something singular" need not necessarily involve a disconti-
nuity. Thus, mathematicians in speaking of the singularities of maps may mean
nothing more sensational than the point in deforming a curve at which it first
acquires an extra bump. Developmental biologists identify the sites where a hair will
emerge on an insect's cuticle as singularities. Engineers use the terms "singular
point" or "singularity" interchangeably in speaking of dynamical systems to indicate
that unique state at which all rates of change are simultaneously zero, as in a
che.mical steady state or the mechanical equilibrium position of a rocking horse.
This ambiguity contributes to the terrible confusion in many people's minds about
"catastrophe theory," which, in its presently best elaborated manifestation, concerns
the zeros of potential flows. This is a subject whose richest domain of clear
application seems to lie in engineering physics (Thompson, 1975; Thompson and
Hunt, 1977). The zeros of potential flows are the states at which all rates have
dwindled to nothing, the equilibrium states, commonly referred to as singularities in
the engineering literature. But the singularities of catastrophe theory are in a
different space altogether, the space of control parameters. They are the particular
combinations of control parameters (e.g., loads on a structure) at which the
configuration of equilibria (singularities in the engineers sense) undergoes a
change.
The distinct uses of "singularity" create an opportunity for real confusion in this
book because in certain kinds of dynamic systems, described in Chapters 5 and 6,
the state which is singular in respect to rates of change, being astate of zero
amplitude of oscillation, is also a part of the phase singularity, the locus of states
where phase does a particular something singular. In fact, in special kinds of
dynamical systems (Chapter 5), it is exactly coextensive with the phase singularity.
But in less exactingly specialized kinds, e.g., in the chemical patterns described
above, the reaction steady state is in no way related to aphase singularity (Chapters
6, 8, and 9). To help preserve this distinction, I will usually say "phase singularity"
rather than just "singularity" in this book, and in referring to the steady state of
reaction, I will say "steady state," not "singularity."
The arguments explored up to this point have not in any way involved
conjectures about dynamic systems or kinetic models. But because some of the most
intriguing phase singularities do arise from processes in time, we would like to
know what kinds of dynamic systems are at least compatible with the observed
facts and what those kinds would lead us to expect about the nature of the phaseless
state. As Sherlock Holmes was wont to enounce, "Singularity is almost invariably a
clue." Thus we pass to the next chapter, about dynamics on rings.
 The Rules of the Ring

As scientists we do not merely read the book of Nature. We write it. .. How much
more so then the biologist, who deals with reality of such elusive complexity that
only deli berate simplification can cloak it with the appearance of intelligibility.
Nevertheless, this is the way our science progresses. But we must accept our
concepts for what they are, provisional approximations that are as much fictions
of our minds as they are faithful depictions of the facts.
Christian de Duve, 1969

A: Basic Principles, Paradigms, Language Conventions, and

Epistemology

All things by immortal power

Near or far
Hiddenly
To each other linked are,
That thou canst not stir a flower
Without troubling astar.
Francis Thompson, 1860-1907

Although it may be fashionable to acknowledge that everything is connected to

everything else in principle, some things are more tightly connected to each other
than to all the rest. Such a little knot of causal interactions goes by the name of a
system. It is also fashionable to speak of one's playthings as systems, and 1 shall
adhere to this convention. It will make life easier in the long run to clarify some
conventional jargon at this point, as folIows.

The Instantaneous State

The state of a deterministic system eonsists of everything you need to know about it
right now in order to know what it will do next in response to seleet stimuli. A

A. T. Winfree, The Geometry of Biological Time 80

© Springer Science+Business Media New York 2001
 A: BASIC PRINCIPLES. PARADIGMS. LANGUAGE CONVENTIONS. AND EPISTEMOLOGY 81

system's present state is determined by a collection of variables of state. Each one

takes its values within some topological space, e.g.,
1. On the real line (e.g., temperature from -273°C to very high values, or
concentration from zero to a solubility limit), or
2. On the complex plane (e.g., the impedance of an electric circuit, or the quantum
mechanical wave function of a particle at a particular place and time), or
3. On a set of discrete points (e.g., the excited, resting, or refractory states of a
model neIVe cell, or the on or off states of switches or of genes), or
4. On a ring (e.g., the phase of an alternating current or the color of a lizard), or
5. On a sphere (the position of a navigator's boat on the globe, or the orientation of
a tlying bat)
Most systems have a lot of state variables; in principle any number if indeed
"thou canst not stir a tlower without troubling a star." But for specific interests some
few of these variables are more important than the rest. Call the state variables that
you consider important Xl (i = 1,2, ... , D). Ignore all the other state variables that
are fuvolved in principle but which have little bearing on the observables of interest.
An obseIVable is something you can monitor, measure, or otherwise interact with.
Like state variables, different kinds of obseIVables must be defined on different
topological spaces (discrete points, rings, etc.). The present value of each obseIVable
or measurement is determined by the present state of the system and so it teIls
something about the system. If it doesn't depend on the state of the system of
interest, it may still be obseIVable and measurable, but it won't be in the list. Call the
obseIVables Fr (i = 1, 2, ... , N) with the understanding that Fi = Fi(XJ, ... , X D ). In
special cases, an obseIVable may depend mainlyon just one state variable. For
example, it may be a direct readout of that state variable: Fi =Xi. Nonetheless, it is
important to preseIVe a clear mental distinction between state variables and
measures or observables that depend on the system's state. This may sound
pompous and academic, but setting up the format now will be helpfullater on.
Any measurement or obseIVation may be thought of abstractly in geometric
terms, either of two ways:
1. As a mapping or projection from the systems state space onto some lower
dimensional space such as a single-coordinate axis which defines an obseIVable.
For example, to each state of a chemical reaction in water (defined by many
concentrations) there corresponds an electrical conductivity of the solution
(defined on the positive half-line). We can think of obseIVing the conductivity as
projecting state space into the half Une or as looking into state space from such a
perspective that states of the same electrical conductivity are seen superimposed
and these sets of superimposed states are arranged along the Une in order of
increasing conductivity.
2. As a contour map defined on the state space. For example, in the above example we
could write on each point in state space its electrical conductivity and draw
contour surtaces through points of the same conductivity. All points on the same
surface go to the same point on the conductivity line.
Needless to say, we can invent any number of obseIVables. (How many
"properties" does an organism have?) But if a system has only D state variables (i.e~,
82 3: THE RULEs OF THE RING

its state space, whatever its topology may be, is D-dimensional), then the first D
independent observables (that are functions of state suffice to determine the state.
Any further observables are redundant because given the state, every function of
state is determined.

Dynamics
This book focuses on dynamical systems: systems with the interesting property of
continually spontaneously changing state. At any instant, each state variable has a
rate of change that depends only on the current state of the system.
Here we encounter a linguistic choice. Obviously, any system's behavior
depends on environmental conditions: its temperature, the voltage of its power
supply, the amount of light falling on it, the position of its knobs. We could consider
these as state variables that don't change spontaneously. Then we can say that the
rate of change of state depends only on the state. Or we could say that the state
variables are those things that change spontaneously, and that things that don't
change spontaneously are called parameters, not variables. Then the rate of change
depends on both. I choose this format. Notationally, then,
dXi/dt = ~(X,P)
where R i is the rate function for the ith state variable. Its inputs are all the state
variables (X) and all the external parameters (P). Its output is the rate of change of
Xi. As there is a rate function for each i, we might denote more compactly:
X=R(X,P)
using also the dot convention to indicate rate of change with time (. = dldt).
Having thus divided our initial collection of state variables into those that
change spontaneously and those that don't (parameters), we might back up and note
that observables also depend on both parameters and state variables:
Ei = Ei (X, P).
For example, the apparent color of a lizard may depend on its emotional state; but
the measurement is affected also by the color of the ambient light.
This frivolous example brings us to a crucial point: Not all observables are
numbers, or even combinations of numbers. Some observables, like color or
direction or the phase in a cycle, are defined not on the real number line, but on a
ring (or on more interesting topological spaces). It is usual to try to salvage the more
familiar form by representing such a measurement in terms of a number. For
example, it is conventional to map the ring onto a line by speaking of "degrees" with
the convention that 360 is equal to 0 A less clumsy device is to map the ring onto a
0 0
•

plane (which is the product of two lines), and identify a point on the ring by two
numbers, X =sin <p and Y =cos <p. This might be a natural device and it might not be.
We will look at cases of both sorts in context of rhythmic patterns in space and time,
in living systems, and in chemical reactions.
In this chapter I dwell on cases in which it is not natural to think of the ring
as embedded in aspace of more than one dimension. In these cases, the
measurement of phase (an observable) is most naturally regarded as a fairly direct
 B: DVNAMICS ON THE RING 83

mapping from the system's state space, which is in fact shaped like a ring, onto
the abstract ring on which phase is defined (Fi = Xi). The topology of rings has
some peculiar consequences for the behavior of such systems, and of our
measurements.
In Chapters 5 and 6 we dweIl on cases in which it is natural to think of a
phase measurement (defined on a ring) as being embedded in aplane or higher
dimensional space. There we take the observable "phase" as a function of state, Fi
= Fi(X., X 2 ). It is natural to ask whether any meaning attaches to the inside of the
ring. Maybe not. Maybe the very question is nonsense. For example, what is inside
the cirele of 12 hours on a elock's face? That might make a good Zen koan. But
the question does make sense in some cases. For example, what is inside the wheel
of saturated colors? Brown and gray. They are real. What's inside the sphere of
latitude and longitude coordinates? Gold, coal, and magnetic fields. They are real.
Thinking of phase measurement in terms of a continuous map in state space, we
see no place for the inside of the ring. Each point in state space has some phase
value and the surfaces of constant phase occupy state space completely. If there is
astate that has no phase, then it must correspond to some kind of disastrous
irregularity in the map: a singularity. The process of measurement being at heart a
mapping from one space to another, it seems natural that the singularities of maps
should playavital role in science. This monograph exploits one aspect of this fact
by gathering together experimental systems where phase singularities play a
conspicuous role.

B: Dynamics on the Ring

It will be seen that some cases definitely do not fit the theory. This is not surprising
since uncomplicated systems are seldom found by accident. One function of theory is
to define the properties of simple systems so that they may be recognized when
encountered.
Camphell, 1964

Hourglasses
The world abounds with processes whose states val)' in only one way, for most
practical purposes, and whose last states are the same as the first. For example:
1. Nerve cells and their analogues in the plant world can be thought of as "resting"
until "excited" beyond some "threshold," whereupon a standard sequence of
changes ensues by which the cell goes "refractory," then through stages of
decreasing "relative refractoriness," and then relaxes back to "rest" (Chapter 14).
DiagrammaticaIly, the states of such a system constitute a ring.
2. The cell cyele is sometimes thought of as an excursion, somehow triggered, from
a noncycling state called A or G, through the rest of the growth stage G1, a DNA
synthesis stage S, a second interval of growth G2, mitosis M, and back to A
(Chapter 22). At this level of abstraction, the human reproductive cyele of
ovulation, conception, gestation, delivery, and ovulation has the same form, i.e.,
84 3: THE RULES OF THE RING

a one-dimensional developmental progression that returns to its origin and is

thus a ring.
3. In the female cycle, in "reflex ovulators" such as the rabbit, hormonal events
triggered by sexual stimuli precipitate an egg into the uterus and, if it isn't
fertilized, they ripen a next egg in anticipation of next coitus (Chapter 23). This
cycle of states is a ring.
4. The circadian cycle in some organisms is thought of by analogy to an hourglass
(Chapter 19). It is "turned over" daily by some such event as sunset, then runs
through a process of standard duration, terminating with the original pre-
triggering state.
Adopting the jargon of circadian physiologists, I will refer to such a process-or
more exactly to this idealization of such a process-as an "hourglass device." It is an
especially simple kind of excitable system (see Chapter 9).

Simple Clocks
But in many systems of interest, that first and last stage is not a resting state, so that
cycle after cycle ensues without interruption, without need of an extemal stimulus
to initiate each new cycle. For example:
1. Most kinds of rotating or reciprocating machinery have a fixed cycle of changes
through which they repeatedly progress, at whatever rate the engineer chooses.
This seems to be how bacteria swim, their helical flagellae being driven by a
turbine rotor (Berg, 1974).
2. The astrophysical cyeles that give us the seasons, the tides, and the day repeat
without interruption.
3. In the human menstrual cyde and in the female cycles of other spontaneous
ovulators, each hormonal event sets the stage for the next, eventually leading
back to another ovulation (unless pregnancy intervenes).
4. The circadian "dock" of many kinds of animals and plants, according to one
useful approximation, is always somewhere in its cyele and advancing under its
own power by roughly one hour of subjective circadian time per hour of real
time.
5. The cell mitotic cyde is so often thought of in this way that Campbell (1964) was
provoked to define the term "simple clock":
We shall assume that with respect to the division cyde, the cell behaves like a simple
dock ... by simple we mean that there is a single variable on which all the interesting
properties of system depend; that any cell can be assigned a time on the dock, and
that the expected behavior of any two docks which read the same time will be the
same regardless of their histories. If we replace "time" by "phase" and acknowledge
that the cell will pause for 0 time at each of several "checkpoint" phases until other
conditions are met, we have a fair description of the nudear division cyde.

Ring Devices
What both categories (the hourglasses and the simple docks) have in common is
their restrlction to a one-dimensional ring of states (e.g., the angular position of the
 B: DYNAMICS ON THE RING 85

meshed gear works in a mechanical dock}. I will henceforth refer to hour-glasses

(which need to be turned over) and simple docks (which turn themselves over) as
"ring devices," emphasizing the essential fact that they run on a fixed cyde. The
notion of a ring of states is naive, and deliberately so. The purpose of such gross
approximation is to isolate one essential feature of one dass of phenomena. The
ring idea constitutes the skeleton, the bare bones, of a realistic analysis of its natural
analogues. Chapter 5 hangs flesh on the bones, but to see what is gained by thus
complicating the picture, it is worthwhile first to examine carefully what the
skeleton alone can do.
I begin with the observation that some systems, and perhaps most, can fall into
either category of ring device (hourglass or simple dock) according to external
conditions. For example, the cell division cyde in bacteria proceeds apace with
regularity in a nourishing medium but is arrested at a certain phase in phosphorus-
poor medium (and so it can be gated by "ticks" of injected phosphate; Goodwin,
1969). A nerve celllingers in its resting state until a stimulus induces it to fire an
action potential, but if continually biased with a tiny electrical current or placed in a
calcium-deficient solution, it fires spontaneously and rhythmically (Guttman et al.,
1980). The circadian dock in the fly Sarcophaga cydes spontaneously when warm
but arrests at a certain phase when cold (Saunders, 1978).

Rate Equations and Stimuli

Let us put this fact into more general context and make something of it. The
point is that a ring device's rate of advance through its cycle is conditioned by an
external influence, which we might denote as an influence or intensity parameter
I. For example, an alga's cell cyde duration is shorter when it is grown under
brighter light. A sensory neuron fires at shorter intervals when exposed to a
stronger smell, hotter surface, brighter light, harder touch, or whatever it is
specifically devised to sense.
In general, the effect of I may be different at different phases of the cyde, so that
we write:
cP = v( ifJ, I)
or, in words, the instantaneous rate of change of phase (the clock's angular velocity
v) is jointly determined by its instantaneous state (phase, ifJ) and by the external
influence parameter. In some standard environment I = 10 in which we initially
calibrated the cycle to define "phase," cP = 1 by definition. In other words, v( ifJ,/o} = 1
(Figure 1).
But in any other environment I :f:. 10 , the ring device's angular velocity
(expressed in the phase units of 1= lo) generally varies throughout its cycle (Figure
2). Thus, the ring device runs faster or slower, depending on its current phase ifJ(t) ,
as long as exposed to I :f:. 10 • This modulation of rate, expressed as a sensitivity
function (Winfree, 1967a) or as an angular velocity response curve (Swade, 1969;
Daan and Pittendrigh, 1976b, pp. 279-280, pp. 287-288) has been invoked to
account for several features of circadian rhythms (see Chapter 19). In neural
contexts, the same vision has been useful to Wendler (1974), Wilkens and Young
(1975), and Young & Coyer (1979).
86 3: THE RULES OF THE RING

Figur. 1. The angular velocity (vertieally) as a function of phase

o.
(horizontally), using model ~=1+1 eos 21r~, with 1= The eirele
above depict5 by the length of the eurved arrow the angular
v(~.O) velocity at eaeh phase.

o
o
-1

-
v(~.~) F"tgur.2. As in Figure 1 but I=l

o
o
-1

Flgure 3. As in Figure 1 but 1= 1~, past the bifureation at 1= 1. An

attractor-repellor pair has opened up from phase ~=~, inverting
the angular velocity within that are.

-1 0
 B: DYNAMICS ON THE RING 87

Box A: The Indecisive Stopwatch

David Saunders drew my attention to the behavior of a standard commercial stopwatch

(i.e., standard before the digital revolution). It is a ring device. Its parameter I has only
three discretely different values, chosen by punching the wind-up stern: 1=0, 1, or2.
At I = 0, iP = 1: The dock ticks forward uniformly.
At I = 1, iP = 0: The dock freezes where it is.
At I = 2, iP is very positive in the arc after 180° and very negative in the arc before
180°. As in Figure 3, iP = Oonly at ~a (0°) and at ~r (180°). If ~ is sufficiently dose to ~r
when you change from 1= 1 to I = 2, the poor thing scarcely knows whether to advance
or delay and can linger, unstably, at ~r' This corresponds to aresetting stimulus so
strong that extraordinary brevity is required to catch ~ still on the way to ~a when the
stimulus ends. (I haven't yet succeeded.)
This indecisiveness near ~r is not to be confused with the entirely different
phenomena associated with aphase singularity (Brady, 1974).

With large enough I, v may even go negative during part of the cycle (Figure 3).
Phase then "sticks" stably at the beginning of this interval, at the attracting
stagnation point Pa. Unless helped past the repelling stagnation point Pr (e.g., by
changing back to 10 for a while), it won't do the next cycle. Thus, our simple dock
has become an hourglass (see Box A). Figures 1, 2, and 3 might have been taken
from Figure 4 at levels 10 , h and h The zones of negative angular velocity are
indicated as islands in Figure 4. At any fixed I, phase will stick on the upwind shore
of any such island.

Figura 4. Arrows depict iP above the ~ axis at each

level of I. The levels of Figures 1 through 3 are
indicated on the 1axis. Within the shaded region, i! < O.
The left branch of the U is the attracting phase. The
I
1\ - - -
- - -
right branch is the repelling phase. ~ •
o ~+-~+-~+-~+-~.-~--

The shape of the function v of course depends on the 10 chosen for the initial
calibration of phase. This arbitrariness in defining phase does not affect the
qualitative property essential for what folIows, namely, whether v is positive or
negative. A different choice of 10 would only distort the horizontal scale of these
diagrams (see Daan and Pittendrigh, 1976b, Figure 10).

Is This Caricature T00 Simple-Minded?

A pause may be useful to put this ring model in perspective. We are developing the
simplest model of a repeatable continuous process. In this simplest case, we have
only one variable of state (the phase), only one observable (the same), and only
88 3: THE RULES OF THE RING

one parameter (I). More complicated models might introduce a second variable of
state. For example, in Chapter 5 we abandon the restriction to a unique cyde of
fixed amplitude and take amplitude of oscillation as a second variable of state.
Alternatively, we might find that our real experimental system responds not so
much to the physical parameters of its environment as to their rates of change.
For example, such rate-dependent stimulus transduction is important in the light
responses of the sporangiophore of Phycomyces (Delbrück and Reichardt, 1956),
in Dictyostelium's response to cAMP (Gerisch and Hess, 1974; and Chapter 15) and
in chemotaxis generally. According to our definitions, system behavior depends
only on its state and its environment, so that in such cases there must be a second
variable of state, astate of adaptation to the external stimulus. This component of
the state changes quickly, tracking the stimulus and buffering it out as long as it
doesn't change.
One way to proceed is to try the simplest interpretation first. To be sure, it will
not long remain possible to evade more realistic complexities. But only after pin-
pointing the simple interpretation's limitations can one recognize the most
economical amendment. We adhere in this way to the principle of Occam's razor,
but not because of a naive hope that evolved dynamics are simple but rather because
the plainest interpretations are the most expeditiously testable. (This is the strategy
of looking for an object lost in the dark by working outward from a lamp post while
our eyes adapt to the darkness.)

C: Derivation of Phase-Resetting Curves

Figures 1-4 are all drawn using a simple representative model:
v(4),1) = 1 +1cos27r4> (1)
with 10 = O. 1 might represent light intensity for circadian rhythms, or biasing
current or pressure for a pacemaker neuron. By setting 10 = 0, we make 1 the
departure from standard conditions. So 1 might represent deviations from
standard temperature or standard ionic composition of the medium surrounding
a heart cello Pippard (1979) describes quantum-mechanical Josephson junctions
in this way, I being the electrical current across the junction and 4> being the
wave function's phase shift across it. The simple dock range of 1 is -1 < 1 < 1.
Beyond that range, v goes negative at certain phases and we therefore have an
"hourglass."
In standard conditions, d4>/dt = v( 4>,0) == 1. If we denote the beginning phase by
cf;, stimulus duration (magnitude) by M, and the final phase by cf;', then a control
stimulus, at nonnal intensity 1 = 0, gives

rMd4> rM
cf;' = cf; + io dt dt = cf; + io dt = cf; + M. (2)

In this case, no phase shift is accumulated during interval M because the dock
advances normally.
 C: DERIVATION OF PHASE-RESETTING CURVES 89

Box B: A Parable of Three Clocks

Suppose, contrary to the principles of simple-dock resetting, that the new-phase vs. old-
phase CUIVe smoothly rises and falls back in some region of negative slope. Suppose we
take three docks in this region, old phase 1 < old phase 2 < old phase 3. Exposing all
three simultaneously to the resetting stimulus, we send them to new phases in the
opposite order, new phase I' > new phase 2' > new phase 3' (Figure a). This results in an
awkward paradox if we tIy to describe the mechanism behind the monitored rhythm as
a biological dock with some phase that is advanced or delayed at unusual but phase-
determined rates during a stimulus-as in resetting a wristwatch. To experience this
paradox take a sealed business envelope, cut off the ends with a scissors, and open it
into a cylinder. Let its circumference be aphase axis and its length be a "time during the
stimulus" axis, ranging from 0 up to stimulus duration or magnitude M. We will follow
the three docks' changes of phase during the stimulus as they advance or delay around
the cyde. Mark the dockwise direction of the phase axis, and at the left end mark initial
old phases in order 1 < 3. At the right end, mark the three final new phases in opposite
order I' > 2' > 3'. Now we draw CUIVes connecting 1 to I', 2 to 2', and 3 to 3' (Figure b).
This may sound rather arbitrary, but it doesn't much matter. The point is that we cannot
connect the numbers without some two CUIVes crossing en route. And what's wrang
with that? At the moment of crossing (some time during the stimulus) two docks with
identical phases, subject to the same stimulus, proceed to change phase at different
rates. That presents a problem if docks at the same phase are expected to function
similarly. They are expected to function similarly in all descriptions of phase contral in
terms of ring devices (Brinkmann, 1967; Winfree, 1967a,b; Pittendrigh, 1960; Swade,
1969; Kuramoto and Yamada, 1976; Fujü and Sawada, 1978), i.e., that environmental
parameters determine, in a phase-dependent way, the rate of change of phase (i.e.,
phase velocity) of the dock in its cyde. Thus the resetting CUIVes of ring devices, as
described in this chapter, cannot have negative slope anywhere.

This obsexvation is actually not so devastating as it appears at first glance because

there are two straightforward escapes from this conundrum, both by routes that most
physiologists, I think, would accept as plausible in terms of familiar experimental
findings:
1. An organism with a negative slope in its resetting CUIVes may differ from a simple
dock in that its biological dock changes amplitude as weIl as phase durlng a
resetting perturbation. Wever (1963, 1964, 1965) was the first to argue persistently
90 3: THE RULES OF THE RING

w
CI) 1'»1
0( 0(
:z:
11.
:z:
2' 11.
9 .' ~
o 3' z

_ _ TlIIII! DURINO ST1MULUS - - - - - . - - T I M E DURING STIMULUS - - - - - . .

l ' t--:f---\ 3'~~ __~------1

w W
~ 1' ..---~ ~ 2'~--~~~~~
f 3' t - - - + t - \ f l' !---++-I-"':"""'-1H
~
w ~
Z
z

123 113 456

OLDPHASE
a b OLDPHASE

Left: A new-phase vs. old-phase curve with a negative slope region, where the order of phases
is inverted. During such an inversion, phase can be followed on a cylinder whoselong axis is
time during the stimulus. Some pairs of docks must come to the same phase at the same time
in this process. Any similar diagram in which new phase goes through any number of cydes
backward (rather than none as diagrammed here) has the same problem.

in the circadian literature against describing every experiment in tenns of phase

alone, as though that were an unambiguous detemrination of the state of a circadian
dock. Phase does tell all there is to know about the state of almost every kind of
commercial dock, but it appears that when we kick a biological dock, not only do its
hands rotate, but they shrink or elongate too: even through length 0 to reappear at
positive length 1800 away. This trick makes all the difference, as we shall see in
Chapter 5.
2. An organism with a negative slope in its resetting curve may differ from a simple
dock in that it really consists of many potentially independent docks. If their
aggregate behavior is the basis of our resetting measurements, then the negative
slope of the resetting curve could be merelyan expression of incoherence. As we will
see in Chapter 4, dispersion of phase within a composite pacemaker (a "dockshop")
has the same gross consequences as change of amplitude, induding the possibility of
inversion through zero. There are good reasons to believe that many physiological
rhythms reflect the aggregate rhythmicity of many individual circadian docks, be
they simple docks or not (Chapter 19).

With I =f. 0, the algebra is a little clumsier, but without belaboring details it turns
out as follows. During the stimulus, diP/dt = v( iP,I) =f. 1. Rearranging,
 C: DERIVATION OF PHASE-RESETTING CURVES 91

Box C: Integration Formulas For a Simple-Clock Model

Let ~ = 1 + I cos 21r(p.

Then for 111 < 1,
tan mj>' = A tan(1rMF + tan- l [ta~1re/>]).

where A=JI~~~I and F=~.

And for 1= ±1,
tan G+ G- 1re/>')) = +M + tan G+ G- 1re/>) ).
And for 111 > 1,
K
tan 1r<j/ = A [--1]
- .
K+l

A + tan 1re/>]
where K= [A-tan1re/> exp(21rMF).
M, like e/>, is measured as a fraction of the unperturbed cycle duration. Portions of the
equivalent formulas, rederivecYin different notations, appear in Kuramoto and Yamada
(1976), Aizawa (1976), and Fujii and Sawada (1978). The same model can be applied to
wave-like periodism in chemical reactions. All the figures in this chapter are computed
from the above.

dqi = dt (3)
(1 + I cos 271'4»

M= 1 M
dt= ltP' 1+/~:S271'4>' (4)

This integral is a hit tricky to solve, hut it is a standard lookup. For the case -1 < I <
1 (simple dock) it takes one fonn, and for 111 > 1 (hourglass) it takes another (see
Box C). In either case, the messy algehraic result is M = f(c/>',c/>,I). This can he used to
calculate c/>' as a function of C/>, M, and I.
A simple consequence of some utility is that the rate of change of c/>' with c/> is
necessarily positive: A later final phase is reached at the end of a later starting
stimulus of given length. More exactly,

dc/>' v( c/>' , I)
dc/> = v( e/>, I) .

These two velocities necessarily have the same sign hecause the sign could only
change by going through zero; hut when velocity = 0, nothing changes. Thus
92 3: THE RULES OF THE RING

resetting cwve slope is positive for all mechanisms of perturbation based on

modulation of angular velocity, as in simple docks. This is not true of other dasses
of oscillating kinetics. This fact is used in Chapter 22, page 638. It also shows that
resetting achieved by modulation of angular velocity cannot produce Type 0
resetting cwves, which necessarily have a region of negative slope. See Box B.

Graphical Interpretation: How Phase Changes in Time

The cwves q/(<p, M) tell what final phase <P' is reached by the end of a stimulus of
duration M that began at phase <p. These dose-response cwves are plotted in
Figure 5 for the cases 1 = 0, I = !, and I = !. Phase, ~, starts at <p at t = 0 and it
increases to <P' at t = M. In the simple dock case [1 <1: Figure 5(a, b)] the period T
is indicated as the time elapsed from ~ = <p to ~ = <p + 1. It is the same for any
choice of beginning <p. The diagrams are sideways (time t plotted upward instead

o
p

o o

.\

o
Cb) Ce)
Figura 5. Parts (a), (b), (c) correspond to Figures 1 through 3. In each, the time dependence of
q, is plotted as a curve, starting from each of various initial phases. The phase axis runs
horizontally and the stimulus duration time axis runs vertically. Thus initial and final phases rP
and rP' correspond to times 0 and M on the vertical axis. The time T from any phase rP to rP + 1 is
the period I/VI - 1'.
 C: DERIVATION OF PHASE-RESmING CURVES 93

of horizontally as usual) to facilitate comparison with their source, the velocity

characteristic v( {J,I) plotted above.
A very weak stimulus (I elose to 0) has little or no effect even if prolonged. In this
case 4>' = 4> + M [Figure S(a)]. Now, let I differ significantly from 0 so that v is not
uniformly 1 as in the previous case, but varies above and below as {J varies [Figure
S(b)]. As long as 1I1 < 1, the result is that {J(t) rises along a sinuous path from each
initial4>.1t rises by one full cyde in time t = T, which was 1 at 1= 0 but exceeds 1 with
1-# O. This is because the ring device is moving around its phase circle at a rate that
varies locally. Thus it gets around quicker or takes longer according to the sum of
the times taken in each increment of phase. The phase integral of lI(this altered
local velocity) is the period. The mathematical result from Equation (4) (see Box C)
is that if 4>' -4> = 1 (Le., for completion of exactly one full cyele during M at I < 1),
then stimulus duration must be M = I/VI - 12 • This M is therefore the period T
obtained under chronic exposure to I -# O. Note that a plot of this M against I looks
like a potential weIl with its bottom at I = 0 and vertical walls at I = ± 1. It is t1at at the
bottom, connoting homeostasis of period near I = o. If v were chosen less
symmetric, or if the cyde had been calibrated at some I -# 0, or if v happened to vary
less symmetrically about 1, then this well would have its t1at part to one side of 1= 0
(cf. Daan and Pittendrigh, 1976b, p. 278 on the periods of rodents' circadian docks).
If I differs so much from 0 that the ring device almost stops at a certain phase,
then it takes a very long time to complete its cyele. Departures of velocity from 1 are
weighted more heavily on the slow side because phase dawdles longer in the slow
regions. With any further increase in I we may pass the critical value for transition to
hourglass kinetics [Figure S(c)]. The ring device then lingers forever where ,p = o. The
appearance of a range of negative velocities creates a pair of stagnation points, one
attracting ( {Ja) and one repelling ( {Jr). The ring device approaches {Ja and sticks there.
Notice that on each ofthe preceding diagrams [Figure S (a, b, c)], above any point
ip on the horizontal phase axis the CUIVes have the same slope. That is to say, ,p = v( ip,I)
is given by Equation (1) for that phase. From that phase, the subsequent behavioris the
same in every case (supposing constant 1), regardless of past history. In other words,
the {J(t) CUIVes differ only in their displacement along the vertical time axis. This is
what it means to say that in any given environment (Le., exposed to a given stimulus,
Le., given a fixed I), the instantaneous angular velocity v depends only on
instantaneous phase. This is the central fact about ring devices, as here defined. It
determines their most characteristic properties.
For example, this implies that at any fixed I the paths {J(t, I) do not cross each
other. If they did, then ,p would not be uniquely determined by {J and I at that phase.
This fact is put to work in Box B.
When the stimulus ends and I is changed back to 0, then {J carries on from
phase 4>' according to ,p = v( {J,O) = 1, Le., in free run as defined in that standard
environment 1= o.

Graphical Interpretation: Resetting Curves

Now let's back up and look at this same model from a different perspective. We ask
how the new phase of a single ring device depends not on M at fixed beginning
phase 4>, as in the preceding section, but on its beginning phase 4>, supposing fixed
94 3: THE RULES OF THE RING

M. What phase shift </>' - (</> + M) does the stimulus (I, M) inflict, depending on the
phase</> when it begins?
Mathematically, the answer is given above where we calculated a formula by
which duration M and beginning phase </> determine final phase </>'. However, it is
helpful to summarize in graphical terms. This is done in Figure 6, which plots a
whole family of so-called resetting curves. Each resetting curve shows the final
phase </>' as a function of initial phase <P for one fixed stimulus duration M. The
family of curves shows how this resetting curve changes as we use stimuli of
different durations from 0 up to infinity. The lower row of figures plots not <p' but </>'
- (</> + M) = ll</> against <p. These curves have three conspicuous properties:
1. They are continuous: If the beginning phase <p is changed a little bit, then the
final phase <p' changes by only a corresponding little bit.

0' 2

I=1~

II
.00 f6 r

80 1
ADVANC1N8 ADVANCING

/4.'0
0
0

DEI.AYING DELAYING DELAYING

-1 -1 -1

(0) (b) (e)

Figure 6. These panels go underneath the lower panels of Figure 5 to redescribe them by
plotting (upper panels) f/J' vertically against f/J horizontally, for each of several stimulus durations M,
and (lower panels) by plotting vertically the phase shift f/J' - (f/J + M). This is the height of the curve
above the corresponding curve at I = 0, corrected by subtracting the duration, M, ofthe stimulus.
Advances are plotted upward, delays downward. The M = 0 curve lies on the ßf/J == 0 axis.
2. They are periodie along the <p axis, since starting a stimulus at phase <p in one
cyde or in the next makes no difference to the results.
3. Theyare periodic along the <p' axis. The observed result is a rhythm, and saying
that its phase is <p' is the same as saying that its phase is <p' + 1 or <p' - 2 or <p' plus
or minus any number of complete cycles.
 C: DERIVATION OF PHASE·RESETIING CURVES 95

Thus, our schoolboy habit of plotting things on perpendicular Cartesian

coordinates is not the most appropriate or natural in this situation. The Cartesian
coordinate in no way represents the fact that the end of the phase axis signifies
exactly the same state as does its beginning. Actually both phase axes 4>' and 4> are
rings. This fact would be brought out more dearly if the Cartesian graph paper were
rolled up horizontally to elose the horizontal 4> axis in a ring with its endpoint
exactly superimposed on its beginning point. Or, if it were rolled in the
perpendicular direction to elose the vertical 4>' axis into a ring, bringing its endpoint
onto its beginning. If we do both operations, we have rolled the graph paper into a
torus, a doughnut-shaped space whose topology exactly captures the logical
structure of experiments on a rhythmic system. On this doughnut-shaped graph
paper, the resetting curve is a elosed ring which links once through the hole in the
doughnut. The fact that it is a ring comes from the fact that any 4> determines a
unique 4>' in this kind of experiment. The fact that it is a closed ring comes from the
continuity property, i.e., results of nearby experiments are similar. The fact that it
links once through the hole comes from the fact that as the beginning phase 4> is
scanned through one full cyde, the final phase 4>' likewise scans through a full cyele
in the same direction. In fact, not only does 4>' advance through a cyde as 4> does, but
more: 4>' never decreases as 4> increases. This is a conspicuous hallmark of ring
device kinetics.

Graphical Interpretation: The Resetting Surface

It is now time to parlay the notion of aresetting cuIVe into the notion of aresetting
surface. This extension is necessary in order to incorporate stimulus duration M as
a second stimulus parameter, supplementing the time of application 4>. Take a
family of curves in Figure 6, e.g., take 6c at 1= q. Set them up side by side on as
many vertical coordinate frames, cjl vs. M, arranged in order of the beginning phase
4>. Collectively, they outline a smooth surface 4>'(4),M) which teIls what final phase 4>'
the ring device achieves (vertical axis) at any 4> (horizontal axis perpendicular to M).
This is the resetting surface (Figure 7). It is a theoretical prototype of the
experimentally measured time crystal introduced in Examples 5 through 9 of the

Figura 7. The preceding figures are gathered into a

single three-dimensional plot of 1jJ' as a function of ljJ
and M at I = 1~. The corresponding picture at I < 1
differs only in that it has no range of phases in which 1jJ'
decreases with increasing M.

o
96 3: THE RULES OF THE RING

previous chapter. This is the time crystal of a simple dock. It differs from those
obtained experimentally in that it has no phase singularity linking the (here)
separate resetting surfaces stacked periodically along the cp' axis.
Think of it as embedded in a cube of clear plastic. The cube could be sliced up
into a stack of thin layers perpendicular to any one of its three edges:
1. We have already seen it sliced perpendicular to the cp axis. Each such slice is a
dose-response curve, showing how cp' changes during longer and longer
exposures started from a given cp (Figure 5).
2. Consider now planes of constant M, Le., cp' x cp planes, each cutting the resetting
surface at one fixed stimulus duration M. The curve along which it cuts the
surface is the resetting curve for stimuli of that duration, administered at each
beginning phase cp [Figure 6(c)]. Such curves are elaborated in experimental
context in Chapters 1, 7, 14, 19, and 20.
3. We can plot what the resetting surface tells us in one more convenient way by
sectioning along planes of fixed cp'. These planes intersect the surface in a locus of
(cp, M) combinations that guide the ring device to the same final phase cp'. A
composite figure such as Figure 8, showing the family of such curves for stepwise
increments of cp', is a contour map of the resetting surface for one fixed stimulus
intensity I. Figure 8, like Figures 5 and 6, shows the qualitative appearance at I =
0,1 = 1!, andI = 1!. In eachpanel, eachcurve is alevel contouroffinal phase cp' on
the stimulus plane of beginning phase cp x stimulus duration M.
In the pinwheel experiments encountered in the previous chapter the stimulus
plane was in real physical space. In that context each level curve of cp' may be
regarded as the instantaneous position of a wave in space. This wave is marked by
appearance of a marker event E, which signals passage through phase ip = O. This is
because all ring devices at a given final phase cp' when the stimulus ends will
encounter ip = 0 simultaneously, at a time 1 - cp' later. Those in the next lower

2
M M

(0) (b)
Figure 8. Figures 5 and 6 represent two perpendicular cross-sections through Figure 7. Here is
the third perpendicular cross-section. Initial phase increases to the right as in all preceding
graphs, and stimulus duration M increases vertically as in Figure 5. The curves are level contours
of uniform 4/.
 0: HISTORICAL ApPENDIX 97

horizontal section plane, at cf>' - 8 when the stimulus ends, will reach ifJ = 0
simultaneously at a time 8 after that. The contour map representation and the wave
representation will both play conspicuous roles in later experiments with yeast cells
(Chapter 12), malonic acid reagent (Chapter l3), flies (Chapter 20), and flowers
(Chapter 21). These contour lines do not converge to a point. It can be shown
mathematically that they cannot do so, in the case of any resetting process that
amounts to modulation of angular velocity. In such a case, a pinwheel experiment
cannot possibly evoke a rotating wave.

0: Historical Appendix
The circle is the first, the most simple, and the most perfect figure.

Lo cerchio e perfettissima figura.

Applications of the Simple-Clock Idea in Developmental Physiology

It is not unusual for developmental processes to proceed through a sequence of
stages, each of which seems to be a necessary precondition for the next. The
development of a frog from egg through tadpole to adult to egg, for example,
progresses continuously through the Pollister and Moore stages like a train passing
stations along its track. Though its speed may vary according to temperature,
hormonal supplements, and the availability of food, the stages and their ordering
are unchanged.
In the case of temperate zone animals which repeat an annual cycle within their
life cycles, Mrosovsky (1970) declared that a system "that could give rise to annual
cycles is a sequence of linked stages, each taking a given amount of time to complete
and then leading into the next, with the last stage linked to the first again... as in the
case with pregnancy... it should be possible to alter frequencies by slowing down,
speeding up, or reducing certain stages." This is the essence of a "simple dock."
The same may be said of development on the level of a single cello In this case,
there might even be a relatively simple structural analogue to a railroad track.
Halvorson et al. (1971) reviewed experimental indications that the genome (a
railroad track) is transcribed in linear sequence, resulting in a sequential ordering of
biochemical changes during the cell cyde. The following excerpts from pre-1978
research literature point to the fundamental role of simple-dock models in this area:

Edmunds (1975) writes:

The cell cycle ... comprises aseries of relatively discrete morphological and
biochemical events, although the specific elements may vary among different

Commentaxy on the first book of Euclid's Elements; on Definitions XV and XVI. Cited in Polya
(1954), p. 168.
2 Convivio 1/. XIII. 26. Cited in Polya (1954), p. 168.
98 3: THE RULES OF THE RING

systems. These developmental sequences are not necessarily linearly ordered,

however, since branching networks (and even "nested do-Ioops") may provide
several alternative pathways, some of which may operate concurrently .... In this
sense then, the cell cyde is a "dock": the specific events correspond to the numerals
on the dial ... under a different set of conditions, the cell cyde consists of the same
sequence but ... the relative time spent between such stages is different.
Hartwell et al. (1974) write:
Mitotic cell division in eukaryotes is accomplished through a higbly reproducible
temporal sequence of events that is common to almost all higher organisms .... How
are (these events) ... coordinated in the yeast cell cycle so that their sequence is
fixed? ... There may be a direct causal connection between one event and the next. In
this case it would be necessary for the earlier event in the cyde to be completed
before the later event could occur .... A second possibility ... invokes the
accumulation of a specific division protein and another atemporal sequence of
genetic transcriptions .... No event in this pathway can occur without the prior
occurrence of all preceding events.
Tyson and Kauffman (1975) write:
The periodic event with which we shall be particularly concemed is cell division.
Mitosis is an event of short duration relative to the cell cyde. The exact nature of
the system controlling its regular periodicity is not yet known for any organism ....
Some have supposed that the cyde is a cyclic sequence of discrete states, each
causing the next. Evidence in bacteria and yeast that the temporal sequence of
genes transcribed during the cycle may be related to the sequentiallinear order of
the genes on the chromosomes have prompted speculation that the cyde is
controlled by sequential transcription around circular DNA molecules in
eukaryotic chromosomes.

Applications of the Simple-Clock Idea in Circadian Physiology

A tape-reading or railroad track analogy equivalent to those conceived of in context
of the cell division cyde (see above) was explicitly proposed by Pittendrigh (1966a,
p. 305) and by Watson (1976, p. 510) as a possible basis for biological timing and
biological docks in general. Ehret and Trucco (1967) elaborated just such a
molecular model of circadian docks with the additional proviso that the genes
sequentially activated needn't be physically consecutive along the genome. Their
dock is a sequential machine composed of concentrated lumps of transcribable
DNA. Emphasizing the one-dimensional character of this mechanism, they make
analogies to the one-dimensional docks used in ancient times:
The chronon bears an interesting, though somewhat superncial, resemblance to the
calibrated candle docks of the medieval period in which the end-to-end
consumption by a flame of carefully selected lengths of rosined rope was a
standard measure of time.
They suggest that the spontaneous .periodism of the dock might even have a
structural basis in the dosure of the DNA track in a ring, as in the genomes of
viruses, bacteria, and mitochondria.
 0: HISTORICAL ApPENDIX 99

Even prior to this incamation of the simple-dock paradigm in a physical ring,

elaborate developments of the idea were propounded by experimental investigators
of circadian rhythmicity. As early as 1940, Kalmus thought of the circadian dock in
fruitflies by analogy to a rotating, repeating gramophone message or the drum of a
music box. (See Chapter 20 for biological background on fruitfly docks for the next
few pages.) Brett (1955) likewise hung his observations of fruitfly docks on a
rotating wheel model. Bunning (1956a) compared the cyde of activity in plants to
the playback of a gramophone record. Enright (1975) continued this theme of tape
recorder loop analogies, in the context of the periodic fine structure observed in the
activity records of a marine isopod on his beach at La Jolla.
So profoundly did the simple-clock metaphor pervade thinking about circadian
rhythms during the 1950s and 1960s that alternative notions seldom seemed to pose
achallenge worthy of experimental test. One gains the consistent impression from
the literature that, apart from the few writers who do their modeling explicidy by
way of equations, most folks do theirs implicidy, in terms of ring devices. The notion
thus shapes the choice of descriptive language and the design and interpretation of
the experiments. This may be sound procedure: Simpler analogies are easier to test
than complex ones and so should be tried first. The dock metaphor also has great
appeal due to the fact that time is reckoned one-dimensionally both in principle and
in almost all human contrivances for time keeping. Introduced by Hoagland (1933),
the dock metaphor was adopted in the context of 24-hour rhythms by Johnson
(1939). It was first popularized by Brown in the early 1950s in connection with his
belief that circadian rhythms are in fact one indicator of external geophysical docks.
Pittendrigh pursued the dock metaphor in the later 1950s in connection with his
belief in an internal timepiece whose evolutionary raison d'etre is to monitor the
passage of time.
The idea that a circadian dock goes through a fixed cyde more quickly or slowly
according to its phase and environmental factors, such as visible light intensity, was
first suggested by Rawson (1956) and later by DeCoursey (1959, 1960). The idea
promised an interpretation simultaneously for resetting curves and for the fact of
entrainment to a fluctuating light schedule. Brown's notion of "autophasing" (1959;
see Palmer 1976, p. 250) invokes exacdy this principle-that the rate of advance
depends only on phase and environmental conditions-to rationalize the supposed
generation of a circadian rhythm by a geophysical rhythm of different period.
The previously implicit simple-dock paradigm was first made explicit and
articulate by Campbell (1964) in the context of mitotic cydes, as noted above.
Stimulated by Campbell's analysis and by six months with a population of simple-
dock-like oscillators in Pittendrigh's Princeton laboratory (Chapter 11),1 contrived
an analysis of a simple dock's entrainment by a rhythmically fluctuating stimulus
(Winfree, 1967a). Swade (1969) applied similar principles to entrainment of rodent
activity cydes in the fluctuating light of the Arctic summer.
The simple dock interpretation of circadian rhythms was most vigorously
advanced by Pittendrigh, starting with Pittendrigh and Bruce (1957). Goodwin
(1976) reviewed:
The minimum number of variables assumed to be necessary for an oscillation in
biological system is two... however, there is an even simpler type of oscillation than
100 3: THE RULES OF THE RING

this, dimensionally speaking, and that is what has been referred to as a generalized
relaxation oscillation [see Chapter 6, Box A; read "simple dock'} This is a periodic
function of time that can have different periods, but practically no change of
amplitude. The state of such an oscillator can be defined in tenns of one variable
only, which is its phase; i.e., it is like an ordinary dock which can be set to any time
and will then run at fixed speed with the only visible indicator of state heing the
position of the hands ... from very extensive and ingenious studies of the behavior of
biological docks in response to various types of perturbation, Pittendrigh and Bruce
(1957) proposed a [two-oscillator] model in which the chronometer (A) was assumed
to be an oscillator of this relaxation type [Le., a kind of simple dock] whose phase
could be instantaneously reset by a light or other signal, but whose amplitude
remained unaffected. Any transients in the observable response to the signal were
then regarded as occurring in that process (B) which is controlled by the dock (A)
and by which its existence is made manifest. This model is widely used and has had
very considerable success.
(All bracketed insertions are mine.)
Tbis A-B two-oscillator model has had a profound influence on the development
of circadian physiology. Its genesis lies, once again, in the simple-dock paradigm.
Pittendrigh and Bruce (1959, p. 491) argue:
Any model based on a single oscillator is unable to explain the concurrence of the
three features that strongly characterize resetting in the fly: (1) ultimate detennina-
tion of phase by a signal seen three cydes previous to the new steady state, (2) the
presence of transients, and (3) the dependence of transient length on the time of the
cyde at which the signal fell. These features are, on the other hand, all explained by a
model for the system based on two coupled oscillators.
These facts really place no constraint on an oscillator model unless by
"oscillator" one implicitly means a simple dock.
The point I am tIying to make here is not that the simple dock interpretation is
wrong or an inconvenient approximation (although we will be more concerned with
its deficiencies in later chapters) but that it has been important in the development
of thought and experiments in several areas of physiology and biochemistry. It
might be added that ring devices He at the very heart of any industrial society for the
simple reason that industry consists largely of automated productive activities, and
automation goes farthest quiekest in processes that are Tepetitious. In any repetitive
fabrication, machines and their operators traverse again and again stereotyped one-
dimensional cydes of states: consider internal combustion engines, automated
knitting and weaving machines evolving to digital program loops, and the
distribution of power synchronized to the rotation of innumerable dynamos.
 Ring Populations

If thou (dear reader) art wearied with this tiresome method of computation,
have pity on me, who had to go through it seventy times at least, with an
immense expenditure of time ...
Johannes Kepler, 1609,
Astronomia Nova, Chapter 16

My intent in this chapter is to direct your attention to several idealizations of

rhythmic behavior in collections of many similar ring devices. It turns out that
some of the peculiar limitations on the behavior of simple docks do not apply to
populations of simple docks. Here we also encounter our first example in which a
phase singularity emerges from an idealized model of the structure and mechanism
of a rhythmic system. The chapter is divided into four seetions:
A. Collective rhythmicity in a population without interactions among constituent
docks. This is mainly about phase resetting by a stimulus.
B. Collective rhythmicity in a population whose individuals are all influenced by
the aggregate rhythmicity of the community. This is mainly about mutual
synchronization and opposition to it.
C. Spatially distributed simple docks without interactions. This is mostly about
patterns of phase in space.
D. Ring devices interacting locally in space. This is mostly about waves.

A: Collective Rhythmicity in a Population of Independent

Simple Clocks

Definitions
Before anything else we need a definition of coUective rhythmicity. If we were
pooling sine waves of various phases and amplitudes, all with the same period, the
result would always be another sine wave. So there would be no ambiguity about its
phase: Whatever is the measure of phase on a single dock, the same measure is used
for the aggregate (e.g., phase = fraction of a cyde past a maximum). But what if the
output of each dock is a sharp action potential as in the neural oscillators of

A. T. Winfree, The Geometry of Biological Time 101

© Springer Science+Business Media New York 2001
102 4: RING POPULATIONS

Chapter 14, or a sawtooth wave as in the neon glow tubes used in Chapter 11? Then
the sum of many bears little resemblance to the familiar waveform in terms in
which phase was defined. If we are going to ascribe some "phase" to such a
collective waveform, then we must have some additional rule. The choice is
essentiallyarbitrary, a matter of convenience, but it must be made definite. I choose
the following definition.
Any periodic waveform can be depicted as a superposition of sine waves of
suitable amplitudes and phases. This superposition ineludes one sine of each
frequency, from the fundamental on up by integer multiples. We want a number
to characterize the phase of a rhythm of unit period. (We take its period as our
unit of time.) A number at least as good as any other is the phase of the
fundamental, scaled to range from 0 to 1. Whatever the rhythm's shape this
measure changes by c (modulo 1) if the whole waveform is delayed by a time c.
This measure is unaffected by changing the overall amplitude. In nearly
synchronous populations it registers the same phase as the phase of each single
oscillator. In slightly less synchronous populations, the collective phase is the
mean of the phase distribution.
Geometrically this measure is especially convenient. If we represent the cyele of
each simple elock as a perfect circle traversed at uniform speed (letting the central
angle on this diagram be the fraction of the cyele elapsed), then a population of
docks can be depicted as so many dots moving with constant angular velocity
around this cirele (Figure 1). The cirele represents the fundamental sine wave. The
X coordinate of each dot traces in time the fundamental sinusoidal component of
that elock's rhythm. The superposition of all sinusoids contributed by the many
docks of a population is traced by the center of mass (*) of the eloud of dots on this
diagram. The phase of that aggregate rhythm is the central angle of the center of
mass. We can rule the diagram with radiallines each of which corresponds to a

y
Figure 1. The outer cirde represents unit amplitude of the first
("fundamental") harmonie of any rhythm. Dots represent docks at
.8 .2 various phases. The asterisk represents the phase and amplitude of their
collective rhythm (the average of nine sine waves). It follows the inner
cirde as long as the docks are independent and unperturbed. The radial
lines link positions of equal phase.

L - - - - - - -__ x

given phase, namely, the phase at which it intercepts the unit cirele. Any aggregate
rhythm's phase is read off by simply locating the population's center of mass on one
of these radii.
This choice of aphase measure dovetails nicely with an analysis of physiological
"transients" put forward by Mercer in 1965 and more explicitly by Kaus in 1976.
According to this interpretation, the physiological obseIVables. that we choose to
monitor in the laboratory sometimes do not happen to participate directly in the
 A: COLLECTIVE RHYTHMICITY IN A POPULATION OF INDEPENDENT SIMPLE CLOCKS 103

mechanism of the "dock." Rather, they are only indirectly driven by the dock
mechanism. In some cases, it apparently suffices to regard the driven observable as
a linear filter, selectively transmitting the fundamental frequency of the driving
dock. Its higher harmonies vary too quickly to have much influence on such a
sluggish driven system. In such a case (and the fruitfly's circadian rhythm seems to
be one of them) the observed rhythm would be determined by a population of docks
in exactly the way suggested above.
Having chosen a collective measure of phase, we now apply it to the case of two,
three, and more noninteracting simple docks.

Two Clocks: Unperturbed Kinetics

The state of a population of N docks consists of the phases (rPb rPz, ... ,rPN) of its N
members. The state space is thus §I X §I X ... X §I = T N , the N-dimensional
hypertorus. In the case of just two docks, this is § 1 X § 1 = TZ, the familiar surface of
a doughnut. We unrolI it to form a doubly periodic presentation on flat paper in
Figure 2. Let the horizontal phase coordinate be dock 1 and let the vertical phase
coordinate be dock 2. We have two things to draw on this surface:
1. Contour lines indicating the phase and amplitude of the pair (considered as a
unit) as a function of the two individual phases, and
2. The unperturbed trajectories of the pair of docks in this state space
Taking the two docks to have equal periods and equal weight, the phase of the pair
is the central angle of a point midway between them on this cirde diagram (Figure
3). This can be written trigonometrically, but after a little algebra it reduces to
something geometrically obvious: The phase of the aggregate rhythm of two equal
docks lies in the direction midway between the two, at an amplitude less than either
by an amount that increases with their phase differenee. When the two are one-half
eyde apart, amplitude of the fundamental harmonie passes through 0 and phase is

L--~
I1
I
1
I1
I
I
1
I
II
L_______ . 1. .
I I
I I
--t"~

~1

Flgure 2. The state space of a pair of simple docks, being a torus, can be depicted on flat
paper as one unit cell of a sheet of wall paper.

therefore ambiguous. If we move either oscillator's phase a little bit, the aggregate
phase switehes back and forth by one-half cyde through amplitude O. Amplitude 0
in this ease means only that the fundamental has vanished. All the even harmonies
are still there but, because of the twofold symmetry within each period, the
104 4: RING POPULATIONS

Figura 3. By the convention adopted in Figure 1, the phase of a pair

~_---lit-.... of simple docks lies midway between their individual phases. The
average amplitude of the pair is the radius of the dashed cirde.

aggregate rhythm's phase is indetenninate, Unless the two docks are exactly one-
half cyde apart, advancing both in phase by any amount advances the aggregate
rhythm in phase by the same amount.
The aggregate phase depends on CPI and CP2 symmetrically, with a discontinuity
along the 45° degree line where CPI and CP2 are one-half cyde apart, as indicated in
Figure 4. Pending fuller definition in Chapter 6, let's call any locus of unifonn phase
an isochron ("same time"). We might also indicate amplitude contours as A = COS
21l'[(cpI - cp2)/2]. The phase discontinuity is the "amplitude:::; 0" contour.
Next we need to depict this system's natural motion in its state space. If both
oscillators have the same period, then cpI = cp2 = 1 (in which an upper dot denotes the
rate of change in time). So the system's path, a trajectory from any initial (cpJ, cp2)
combination, is a 45° line. Aggregate phase thus advances uniformly and aggregate
amplitude is steady (Figure 5).
If one oscillator moves a bit faster than the other, then the path's slope T I /T2 is
no longer 1. It therefore slants at a different angle, slowly crossing amplitude
contours. It passes through the zero-amplitude discontinuity at intervals 1I(1/TI - 11
T2 ). This path on the torus depicts geometrically the familiar beat note seen or heard
by superposing nearby frequencies.

Figura 4. Contours of <p, and <P2 along which the

phase (<p, solid) or amplitude (A, dashed) of a pair of
simple docks remain the same.
y.
2

o
o
 A: COLLECTIVE RHYTHMICllY IN A POPULATION OF INDEPENDENT SIMPLE CLOCKS 105

figura 5. Motion of a pair of identical independent docks across the

(4)1, tf>2) torus in the environment I= 0 used to calibrate phase in
proportion to time. These paths are dosed rings of period T = 1.

Two Clocks: Perturbed

Thus far we have implicitly assumed undisturbed cycling of the simple clocks in
whatever standard environment was used to define phase in proportion to elapsed
time. In the notation of the previous chapter, this means I =O. Let us now consider 0
< I < 1. This is the range in which each simple dock continues to cycle, but its
positive angular velocity is greater or less at different phases. During prolonged
exposure to the constant stimulus, each dock lurches and pauses around the
common cycle. If two docks start at different phases, then the phase angle between
them constantly increases and decreases back again with the period of each
oscillator's altered traversal of the common cyde. Thus the pair's trajectories on the
(4J1r </>2) torus are no longer aseries of parallel straight lines but now comprise a set
of snaky lines (Figure 6).
If I > 1 then each dock will come to rest at 4Ja before it has traversed a full cyde.
This 4Ja is the front edge of the range of phases in which angular velocity has gone
negative (Figure 4 of Chapter 3). This behavior is shown simultaneously for both
oscillators in Figure 7.
Thus if I = 0 for a long time, but then we make I =F 0 for a while, then during
that inteIVal of exposure to the stimulus the oscillator pair is moved from its prior
45° trajectory to a new one. When I reverts to 0, the pair continues in motion along
the new 45° trajectory. At that time it will generally be on a different phase contour
than is an unperturbed control for which I remained 0 during the same interval. The
new phase reached by the time the stimulus ends depends on two things:
1. The stimulus (I and its duration)
2. The initial state (4Jl' 4J2)

figura 6. Motion of a pair of identical independent docks across the

(4)1, tf>2) torus in an altered environment I =~, which still permits cyding.
These paths are dosed rings of period T = 1jv"1-/2. This figure and
Figures 7-9, 12-14, are sketched from grainy computer print-outs and
so are not quantitatively exact.
106 4: RING POPULATIONS

Flgure 7. Motion of a pair of identical clocks across the (!/J" !/J~

torus with I = 1~o Each gravitates to an attracting phase !/Jao

0,

Note in (2) that it is not sufficient to specify just the initial phase of the
aggregate rhythm. That external observable only locates the state on a certain 4J
contour (isochron) but does not tell where the two-dock system is on that
isochron. During exposure to the stimulus, trajectories lead in various directions
through the many states on that locus of uniform aggregate phase. We have to
expect a different result from disturbing a pair of oscillators at phase 4J,
depending on whether the aggregate phase is 4J because both are at 4J or because
one is at 4J + x and the other is at 4J - x. We need to know the complete internal
state of the system. The external observable 4J is a sufficient identification of a
rhythmic system's state only in very special cases. In general, it is one convenient
measure of state but not in itself sufficient for design and interpretation of
experiments because two systems at the same phase can have quite different
subsequent behavior.
To know the complete internal state of a two-dock population, we could know
the phase of each oscillator or, equivalently, we could know which contour of
aggregate phase the population lies in and where it lies along that amplitude locus in
Figure 4. With the aggregate phase measure we have chosen, this means knowing
the mean phase of the two docks and their phase difference. In populations with
more simple docks we would in principle need to know the phase of each dock in
the population or equivalently their mean phase and enough higher moments of the
distribution to specify the distribution unambiguously. If we could assume that
dock phases are unimodally distributed around the mean, then the measures of
most importance of our purposes would be the mean phase and the range or
variance of phases.
Let us now return to the two-dock case to determine how the mean phase
of such a population depends on the timing of the stimulus. It is convenient
here and will be convenient again in other contexts to think of the stimulus as
a mapping from the plane which describes the stimulus (its duration M and the
initial phase 4J when it starts) into the (4Jt. 4J2) state plane. This can be done as
follows. Choose an initial phase difference between the two docks. The pair's
trajectory is then a diagonal that far displaced from the main diagonal, as
indicated in Figure 8. Points along this displaced diagonal are, trivially, the
states reached by applying a stimulus I :f= 0 of duration M = 0 at each initial
phase 4J. This diagonal is the 4J axis of an image of the (4J, M) plane in state
space. Now expose the population for a duration M at each 4J, marking off
 A: COLLECTIVE RHYTHMICITY IN A POPULATION OF INDEPENDENT SIMPLE CLOCKS 107

Figure 8. As in Figure 4-7 but a portion is shaded,

consisting of all states reachable from the chosen initial
unperturbed trajectory (<P2 - <P1 = x) by increasing
durations of exposure to I = 1~. The curves crossing
perturbed trajectories are loci of fixed duration M.

increments of equal duration along the trajectory followed (Figure 8) during

stimulation. Through each initial <p this establishes an M axis. Collectively these
measurements constitute a <p x M grid on the state plane. It is an image of the
(<p, M) plane on which we can immediately read off the new phase values
arrived at by reference to the overlying contour lines of Figure 4. In
imagination, stencil those contour lines onto this distorted image of the (<p,
M) plane, then pick it up and stretch it out flat and uniform and you have
Figure 9. All this can be done by trigonometrie equations; in fact, that is how
Figures 6-9 were obtained. But the qualitative principles are evident in the
graphical methods described above and are independent of quantitative details
about the chosen dynamies.

Figura 9. On the (<p, M) plane, level contours of q/, the phase

reached by maintaining I = 1~ for duration M (in units of 0.2
unperturbed cyde period), starting at phase </>, with <P2 - <P1 =
0.3 cyde initially. The dotted U locus represents amplitude A
= 0; other amplitude loci are omitted. As M -+ 00 contours
0.1
near <Pa diverge to fill the whole space. The U becomes
symmetrie about <Pr and approaches width 0.3 as M -+ 00. As
M increases across the U, <p' jumps one-half cyde.
o

As long as the phase difference was initially not 0, there is a phase range within
which a stimulus of sufficient duration carries the pair's state across the zero-
amplitude locus, where the phase changes discontinuously because the two
oscillators are one-half cycle apart. This happens only within a certain range of
initial phases. The perturbed trajectory from other initial phases never crosses the
discontinuity locus. The phase map of Figure 9 on the stimulus plane shows this
piece of discontinuity locus as a U.
108 4: RING POPULATIONS

We have spent a long time belaboring a trivial example in order to lay the
foundations for understanding situations of greater biological interest. The next
step in that direction comes by looking at a system of three simple docks. This is
as far as we will need to go with simple docks because it turns out that three do
everything that a larger population can do, as far as our present interests are
concemed.

Three Clocks: Unperturbed Kinetics

The principles are the same but the state space is three-dimensional, being §1 x §1
X §1. That could be thought of as a cube with its opposite faces identified pairwise
by analogy to the method of depicting a two-dimensional torus as a square with its
opposite faces identified pairwise. The trajectories followed by astate point (1Jb 1J2,
1J3) within the cube are much the same. The only novel feature is encountered in
trying to depict the Iod of fixed aggregate phase (the isochrons) in this state space.
In the two-dock case they were straight lines transverse to the trajectories, abutting
discontinuously along the zero-amplitude locus. In a three-dimensional state space
they must be two-dimensional surfaces, once again transverse to all the trajectories
because moving all oscillators forward by amount c must move the aggregate phase
forward by the same amount. A theorem often used before can now be invoked to
show that something peculiar must happen in the way that these isochron surfaces
come together in the three-dimensional state space. Consider Figure 10 and the
gedanken experiment indicated by the four-sided dosed path ABCDA (heavy
arrows). Along path AB the phases of all three docks increase equally and thus
advance through one full cyde of aggregate phase. Along path BC docks 2 and 3 are
held fixed while dock 1 moves through a full cyde. This causes the aggregate phase
to change somewhat and change back to its original value without scanning
through a full cyde, because the single clock affected is in the minority in a three-
dock population. This feature of the collective phase measure chosen above is more
obvious in a population of thousands of clocks, only one of which is allowed to vary
at a time; it turns out to be true for any number of identical docks down to and

Figure 10. The </>, x </>2 X </>3 hypertorus "unrolled and laid flat" as a cubical
unit cell of a three-dimensional crystal. Path ABCDA is followed in a
::onceptual experiment.

A~---..v

induding three. At point C the phases are all the same as they were at point A and
point B. Next dock 2 is varied, holding docks 1 and 3 fixed. Once again for the same
reasons the aggregate phase does not scan through a complete cyde. The same is
true along arc DA (and along any number of additional arcs of the same sort which
would be required in describing a population of many simple docks). The upshot is
that the aggregate phase has winding number 1 around the dosed path ABCDA.
 A: COLLECTIVE RHYTHMICl1Y IN A POPULATION OF INDEPENDENT SIMPLE CLOCKS 109

Now imagine any two-dimensional surface topologically equivalent to a disk

bounded only by path ABCDA. I intend to assign to each point on such a surface
some aggregate phase. Thus I propose a map from a two-dimensional disk to a
phase cirde in such a way that its boundary maps around the cirele with
winding number 1. Once again (see p. 28), this cannot be done without accepting
a discontinuity. Supposing that the aggregate phase function varies only slightly
in response to slight changes in the phases of constituent docks, then the
winding number remains 1 along any distortion of this path ABCDA. By
continuing to distort the path by shrinking it, I eventually localize the
discontinuity to a unique state. Along a very tiny path around that state, all
phases of the aggregate rhythm are realized. Thus this is astate of ambiguous
phase. I could have carried out this argument using any surface of two
dimensions, bounded by the required dosed-ring path. Each such two-dimen-
sional surface contains a point of ambiguous phase. The locus of ambiguous
phase consists of all these points, so it is one-dimensional. It is a curve along
which all the isochron surfaces converge.
In the three-dock case this is easy to understand in more mechanistic terms.
Situations of ambiguous phase will occur only when the three docks are
symmetrically disposed, so that their center of mass lies at the origin, at zero
amplitude and ambiguous angle. Figure l1(a) shows the three docks at the corners
of an equilateral triangle. Any rotation of this configuration leaves the collective
phase ambiguous. This ring of positions of the triangle corresponds to the one-
dimensional locus of phase triplets that correspond to ambiguous phase in the
aggregate rhythm. Any slight displacement of 1Jt or 1J2 or 1J3 from such a point can
radically change the aggregate rhythm's phase. At that point, not only is phase
ambiguous but, additionally, all phases are near at hand. Why? Not just because the
aggregate rhythm's amplitude is O. That was true in the two-clock case, but only a
discontinuity, not a phase singularity, was obtained. The underlying difference of
mechanism is brought out in Figure 11 (b). Figure l1(a) shows the three-clock
situation and Figure 11 (b) shows the two-clock situation. In both cases symmetry is
required to attain the situation of zero amplitude and ambiguous phase. But in the

0)

Figura 11. Symmetrie dispositions of three clocks (a) and of two

clocks (b), which may be arbitrarily rotated while keeping aggregate
phase ambiguous.

b)
110 4: RING POPULATIONS

two-dock case, minute adjustment of phases can only move the aggregate phase off
zero to the left or right. In the three-dock case, the center of mass can be displaced
from zero to any angle by minutely adjusting any two phases. This feature, of
course, also obtains with any greater number of docks in the population.

Three Clocks: Perturbed

What does this imply for the response of a three-clock population's aggregate phase
to the timing of astimulus? Preciselyas in the previous case, we can visually map the
stimulus plane (rp, M) into the (rpl,
(rpl' rp2, rp3) state space. Let's assume the same simple
dock kinetics as before for I > O. Without going through the details, the image of the
stimulus plane turns out to fall across the convergence of all the isochron surfaces.
Thus a cross-section through their convergence appears on the (rp, M) plane. Figure
12 shows the result of a computer calculation of this map using the same simple-
dock dynamics as in Figures 6-9, based on the models of Chapter 3. Figure 13 shows
the result with 50 simple docks. It is essentially the samel (see Box A).
Now I wish to draw out four aspects of this result.

1. The Role of Initial Phase Variance. In all these simulations the docks' phases
During unperturbed
were initially uniformly distributed across an arc of 0.3 cyde. Durlng
operation the trajectory of the population is therefore parallel to the main diagonal
of the state space, but displaced from it. With a narrower distribution of phases a
population's prestimulus trajectory is doser to the main diagonal rpl = rp2 = rp3.
During exposure to the stimulus (I i 0) the population is driven along trajectories
little bit of initial variance
initially diverging from that locus only very slowly. So a litde
in phase gives the population a big head start toward the discontinuity (with two
docks) or singularity (with three or more). With a narrower initial distribution of
phase, the phase singularity would occur only after a very prolonged exposure to the
stimulus. In the limit of initially perfect synchrony, the population behaves just like
a single simple dock: As we see in Chapter 3, it has no phase singularity. In fact it
can be shown analytically that the phase singularity lies at critical duration of
exposure M* that decreases in proportion to the logarithm of the initial variance of
phases.
Given a wide initial range of phase scatter in the population, M* becomes
very short. The reason is essentially as folIows. To obtain very low amplitude
of the aggregate rhythm requires that docks be distributed symmetrically

1 You might expect more fine structure in these maps, especially for small numbers of docks. It is there.
The number of docks can be counted by counting repeated features in the contour maps. But these
features are smaller the greater the number of docks so they are easily lost in the variability of data.
Although they are plainly enough revealed by mathematical analysis, very fine-grained computation is
required to map them out numerically. The maps I present in Figures 9 and 12 and in Chapter 8 are
deliberately smoothed to emphasize only their gross qualitative structure.
 A: COLLECTIVE RHYTHMICI1Y IN A POPULATION OF INDEPENDENT SIMPLE CLOCKS 111

Box A: Screwy Behavior in Schizoid Populations

A phase singularity appears in the collective behavior of a population of identical simple
docks, none of which individually exhibits such peculiar behavior. How can that be? To
be rigorous and opaque, it can be shown mathematically by taking ratios of
trigonometric functions weighted by the distribution of phases in the population as it
changes during a stimulus. But the essence can be appreciated more simply as follows.
Figure a once again depicts the fundamental harmonic of each dock's contribution to
the collective rhythm. Points around the circle are phases of the simple-dock cyde. The
radialline through each phase point connects points of the same phase on sinusoids
(cirdes) of lower amplitude. The mean of many unit-amplitude cydes in a population of
imperfectly synchronized docks follows one of those smaller circles while all docks
advance around the unit circle at unit speed.
Now suppose that during a stimulus each dock moves away from 4>r toward 4>a as
indicated by the arrows in Figure b. If the stimulus begins when the population does not
straddle 4>n then all docks together advance or delay toward 4>a during the stimulus. But
if the population does straddle 4>r when the stimulus begins, then it splits into an
advancing portion (4) > 4>r) and a delaying portion (4) < 4>r). Ifthey are about equal in size,
then their center of mass drops directly toward 4>a, deviating neither dockwise nor
antidockwise. As the population's two halves advance and delay, their aggregate rhythm
keeps about the same phase but loses amplitude until, at a critical duration M*,
amplitude reaches a minimum (Figure b). The center of mass of this population is now
dose to the center of the circle; phase is ambiguous because the sum of oppositely
phased fundamentals has very low amplitude.
Now notice that slight adjustments of timing can reposition the center of mass
arbitrarily. It can be moved up and down by adjusting the duration of the stimulus. It
can be moved left or right by adjusting the proportions of docks in the advancing and
delaying groups, Le., by starting the stimulus earlier or later, when fewer or more of its
docks have passed I/Jr. In other words, the population's collective rhythm can be
maneuvered anywhere near this convergence of phase lines by slight adjustment of I/J
near 4>* = 4>r and of M near M*. This is a phase singularity in the collective rhythm of the
population. Its physical basis is the splitting of a population at 4>ro This little acom grows
into a big tree in Tass (1999) Chapter 6.

0)

(a) As in Figure 1 but emphasizing the (radial) loci of equal phase

connecting orbits of various amplitudes. (b) The doud of docks near I/J,
is split during stimulus I > 1 into advancing and delaying subdouds.
Their center of mass passes through amplitude zero if the stimulus is
suitably timed.

b)
112 4: RING POPULATIONS

around the cycle. This is easily achieved if their phases are already dispersed,
but if they are initially dose together on the cyde, then they can be scattered
only by an exposure that catches them all dose to phase rPr. Here slightly
precocious docks are forced still further ahead by the stimulus whHe slightly
retarded ones are drawn backward (Figure 3 of Chapter 3). But in either case,
phase velocities near phase 0 are very small. Thus a very long exposure is
required.

2. Type 0 Resetting. Figure 12 and 13 show that by varying through one full cyde
the moment at which the stimulus starts, the final phase of the aggregate rhythm is
made to vary also through one full cyde, if and only if M < M*. At the end of a
stimulus of duration exceeding M* only some final phases are obtained and each is
obtained from an even number of different initial phases. In other words, we have
Type 0 resetting in the aggregate rhythm (see p. 38) even though no dock in the
population is capable of Type 0 resetting! This phenomenon was first hinted at in
the circadian rhythm literature by Johnsson et al. (1973) in connection with
populations of Kalanchoe flowers, whose petal movement rhythms are customarily
assayed. collectively in bunches of 16. The analytic basis for this startling
phenomenon is described in Winfree (1976).

Flgure 12. As in Figure 9 but with a population of three docks

instead of two, spanning 0.3 cyde. The U-shaped discontinuity
typical of dock pairs is replaced by the phase singularity typical
of all larger populations. The dotted curves show how pieces of
certain contours join up at higher M.

Figura 13. As in Figure 12 but with a 50-dock population.

 A: COLLECTIVE RHYTHMICIIY IN A POPULATION OF INDEPENDENT SIMPLE CLOCKS 113

Box B: 15 There Really Such a Thing a5 Type 0 Re5etting?

It is, of course, a trifle, but there is nothing so important as trifles.
Sherlock Holmes in "The Man with the Twisted Lip"

The existence of Type 0 resetting is a live issue in circadian physiology (in 1978 and still
in 1993 at least), where the models of Chapter 3 (which allow only Type 1 resetting)
have been deployed with excellent success, in studies of the cell cycle (Chapter 22), and
in neurophysiology (Chapter 14) where models involving a real discontinuity of
mechanism are widely used as approximations to the less intuitive Hodgkin-Huxley
formalism (Chapter 6, last section). What do the data really show?
Even without looking at data, it seems clear that Type 1 resetting exists: This is what
we get with no stimulus at all, orwith one that induces only small advances and/or delays,
or induces the same big phase shift whenever administered. Could it be that what appears
to be Type 0 resetting is really just an extreme version of the familiar Type 1 resetting or
the unheard-of Type -1 resetting, as in Figure a? Many a data set has been published
graphically as though it were (see Box C). It appears to have been tacitly assumed that if a
phase shift increases over a certain range of phases, then it must decrease, abruptly if not
gradually, during the remainder of the cycle. The fact was not appreciated that what goes
up null not come down, i.e., that there are alternatives to Type 1 resetting.
What are the essential features by which Type 0 resetting is recognized in real data?
By definition of Type 0, new phase rjJ' varies with old phase rjJ in such a way that as rjJ
increases the corresponding rjJ' changes and then reverses that change, leaving no net
change. Thus each 4>' is accessible twice, at two different 4>'s (and maybe twice again, in
general an even number of times). This situation contrasts with every other resetting
map type. Only in Type 0 need 4>' not scan across the full cycle. 1t can (see atop page 39)
but the range of rjJ' accessed can also be very narrow, as in the limiting case of Figure 33
in Chapter 1.
The reality of this pattern is harder to assess when data are presented in terms of
phase shifts. Phase shift is conventionally measured as the time difference between the
nth event in the contral rhythm and either the nth event in the perturbed rhythm or the
nearest event in the perturbed rhythm. Either way, a discontinuity develops in the curve
unless the resetting behavior is Type 1. This discontinuity in the presentation looks
superficially like a discontinuity in the experimental result. If there were really a big
change in the result due to only a small change in stimulus timing, then one might
reasonably infer a discontinuity in the underlying mechanism. But in fact the phase
shift just before the discontinuity commonly appears to differ by exactly one cycle from
the phase shift just to the right: The resulting new phase changes little if any across the
putative discontinuity (e.g., see Figure 1 of Chapter 19). Thus I find a different
interpretation appealing. When the raw data are plotted directly or when the processed
(phase shift) data are plotted on graph paper of topology natural to the experiment (the
torus), then one is no longer confronted with this topological artifact. In many cases a
plausible alternative pattern emerges in which the data are smoothly connected by a
Type 0 curve (Box C).
This is, of course, an interpretation, not an irrefutable certainty. We're asking about a
ClUVe hut the evidence consists of a set of discrete points. Any kind of curve can be
drawn through them. Should we choose the smoothest curve that hits every point? Or
the smoothest one that comes reasonably elose to most of them? Should smoothness be
adopted apriori as a criterion? If not, then the same data can be threaded on curves of
114 4: RING POPULATIONS

(al Format as in Figures 30 through 33 of Chapter 1. Phase-

TYPE 1
resetting data can in principle be threaded by curves of any
topological Type if there is no strong reason to expect
smoothness and modest slopes.
1-t1H+-tll-H-t+-t1 TYPE-I

n'PEO

any topological type (Figure a). What obseIVations enable us to select the correct type, if
such classification is appropriate at all? The question is rhetorical. The answer is to
improve data resolution (e.g., Figure b). The CUIVes commonly threaded through plotted
data often preseIVe the appearance of Type 1 resetting by means of a very steep segment
devoid of data points, and spanning exactly one cyde. If such a CUIVe rightly interprets
the data, then points can be placed in this region by suitabIy dose spacing of
measurements along the ifJ axis. In Figure b this does not happen: The 593
measurements plainly follow the Type 0 pattern.

Alternatively one could abandon preoccupation with resetting CUIVes at fixed

stimulus magnitude and instead sampie the dependence of new phase jointly on old
phase and stimulus magnitude. This produces a surface in the time crystal, as described
in Chapter 2, Exampie 5 and the end of Chapter 3. If the resetting CUIVes elicited by
strong stimuli are really nearIy discontinuous extremes of Type 1 resetting, then the data
doud should resemble a stack of separate surlaces, as in Figure 7 of Chapter 3. But if
strong stimuli evoke Type 0 resetting, then the data cloud should remain a single surlace
multiply wrapped around a singular axes.
This test was one of the chief purposes of the first pinwheel experiment, done with
the cooperation of Drosophila pseudoobscura. The result was a semi-helicoid or screw
surlace in each unit cell of the time crystal, joining smoothly onto the screws in all four
adjacent unit cells. Similar obseIVations have since been made in equivalent
experiments using per mutant Drosophila melanogaster (Winfree and Gordon, 1977),
Kalanchoe (Engelmann et al., 1978), glycolytic oscillations in yeast (Winfree, 1972d;
Greller, 1977; Aldridge and Pye, 1979), pacemakers in the heart (Sano et al., 1978), and
water regulation in oat seedlings (Johnsson, 1976).
• And in 1999 we can also look at more time crysta s, Or at least resettin9 curves orTypes
1 and 0 below and a~ove ~ of glycolysis, chemieally pe'rturl?ed (Dano,) 9,99; Dano ~tal.,
1999}, of the human c,i raadian mythm of co~e ~?dy t\9rpperature rese by light (Czeisleret
al., 1989' Jewett et al. 1 9-,1 994) ~f Gonyaulax's öi luminesc:e ce reset b dela of
<
 A: COLLECTIVE RHYTHMICIIY IN A POPULATION OF INDEPENDENT SIMPLE CLOCKS 115

o 1,0

(b) New phase vs. old phase measured by 593 edosion peaks in about 200 separate
experiments with Drosophila's edosion rhythm. The stimuli were saturating light pulses given
any time during two consecutive cydes of phase. (Adapted from Figure 12 of Winfree, 1973a.)

proteiri synt esis (Taylor et a., 1982), of Ellg ena's aily ce I ivision reset oy ig t
(Malinowski et a1., 1985), of tpe cat's breathing reset by perturbing the brainstem oscillator
(Paydarfar et a1., 1986; Paydarfar anä Eldridge, 1987; Eldridge et al., 1989; LeWis et al.,
1990, 1992; and see Figure 2.1 of Chapter 14), of cardlac pacemaking reset by electrical
shock ("!an Meerwijk et al., 1984; Guevara et al., 1986), of chemical cycles reset by chemicaf
injection in the Belousov-Zhabotinsky QsciJlator (Dolnik et al., 1984, 1986; Sorensen and
ynne, 1989; Kosek et al., 1994; and see Figure 3.1 of Chapter 14), and of myriad models.
Upto about 1980 I col1ected published data like·those ofBox Cthatcoold be seenas Type
o resetting, because thete were objections to the concept and to such data reinterpreta-
tions and these continued Into the 19905 (e.g., see Rusak, 1993, containing perceptive
debate between six prominent investfgators). Beyond the mid 80s the fashion reversed, to
noticing and repQrting as Type 0 resetting even in dubious cases, so I quit collecting.
There remain plenty of curves puncttiateo by ost~nsjble diseontinuities, so that mean
resetting sl.op~ mightnoteven be an integer, e.g., tI1e observations of Stein 'et al. (1978) on
Par!<insonian ",emor, of Kitano and Komatsu (1988) on the respiratory oscillator, and of
Dulos (1981a,b), Dulos and DeKepper (1983), and Agladze et al. (1995) on chamical
oscillator:s reset by light. Could these reflect"transients," as analyzed by Kawato (1981)7 Or
codimensioh-1 phaseless sets, as analyzed by Winfree (1979), Glass and Winfree (1984),
and MacKay (1991)? Or real molecular-level discontinuities, as suggested by Guevara e1.,al.
(1986)? Or something else? It is rare for any experiment to be repeated in print either for
confirmation or disconfirmation, so it is hard to know what to make of ostensible
counterexam les. <411
My condusion is, "Yes, Type 0 resetting is real." The next question is, "What does it
mean?" This chapter presents one possible answer, most pertinent for whole-organism
circadian docks: The dock observed is really a composite of many docks. Chapter 5
makes another suggestion.

Given Type 0 resetting in response to a sufficiently prolonged stimulus, one

can turn the logic around to derive the phase singularity by a technique used
repeatedly in earlier chapters (e.g., see Box B of Chapter 2). The empirical
basis for belief in Type 0 resetting in the real world is elaborated in Boxes B
and C.
116 4: RING POPULATIONS

Box C: Data Sources for Type 0 Resetting in 1978

The greatest number of careful measurements come from workers in circadian

physiology of protists, fungi, plants, and invertebrate animals. Several neuroelectric
rhythms have also shown Type 0 rephasing in response to appropriate stimuli. This was
expected on principle because the Hodgkin-Huxley equations for periodie nerve firing
have an attracting-cyde solution (see Chapters 6 and 14). But practically speaking, it
came as a surprise that the resetting behavior of pacemaker neurons can be sufficiently
continuous to have a Type. The action potential consists of such a violent and abrupt an
excursion of electric potential that resetting behavior immediately after such a
discharge would not generally be expected to resemble behavior immediately before
the discharge. Yet, in at least the preparations cited below, new phase varies smoothly
with old phase right through the action potential. The lower part of the following table
cites various biochemical and physiological oscillations that also show Type 0 resetting
by impulsive stimuli. Examples from the female cyde (Chapter 23) and the cell mitotic
cyde (Chapter 22) remain conspicuously absent.
-.. Tney, ar-e still-aosent in 19. 9, to the best .:=.of,-m
~~~;:;.;.:.;:==-",-

Formats for presentation of these data are diverse enough to defy dassification. In
the third column I indicate my interpretation of the published format, on which basis I
replotted ifJ' vs. ifJ to see whether a smooth periodie curve would fit the data and, if so, to
divine its topological Type. Because CUlVes appear in such diverse formats it is essential
for darity to speak of resetting Type, not curve type.

My notation: ifJ = phase ofstimulus beginning, relative to an arbitraryphase in the cyde

ifJ' = phase at end of stimulus or an integral number of cydes later
M = stimulus duration in units of one cyde
K, C = some constants

Apart from matters of conceptual convenience, the choice of format makes little
difference, as it involves only 45° shearing and choices of direction for axes. The secret
to reading data in the many formats of published papers is to find the locus of the
unperturbed control experiments then mentally flip andlor shear the whole published
diagram as required to align that controllocus as desired in the preferred format.
References Figure Format
Circadian rhythms
Hastings and Sweeney, 1958 8 ifJ'-ifJ-M vs. ifJ
Pittendrigh and Bruce, 1959 4 K-ifJ vs. C+ifJ-ifJ'
Bruce et al., 1960 1 K-ifJ vs. C+ifJ-ifJ'
Pittendrigh, 1960 14(12h ,4h) ifJ+M-ifJ'vs. ifJ
Zimmer, 1962 1,2 K-ifJ vs. C+ifJ-ifJ'
Engelmann and Honegger, 1967 3 K-ifJ vs. C+ifJ-ifJ'
Honegger, 1967 3 K-ifJ vs. C+ifJ-qJ
Halaban, 1968 2 ifJ+M-ifJ'vs. ifJ
Nayar,1968 5 K-ifJ vs. C+ifJ-ifJ'
Sweeney, 1969 3-17 ifJ+M-ifJ'vs. ifJ
Cumming, 1972 21 K-ifJ vs. C+ifJ-ifJ'

King and Cumming, 1972
Konopka, 1972
Christianson and Sweeney, 1973
Engelmann et al., 1973
Winfree, 1973
Engelmann et al., 1974
Karakashian and Schweiger, 1976
Saunders, 1976
Simon et al., 1976b
Jacket, 1977
Winfree and Gordon, 1977
Wiedenmann, 1977
Saunders and Thomson, 1977
Harris and Wilkins, 1978
Neural rhythms
Perkel et al., 1964
Walker, 1969
Taddei-Ferretti and Cordolla, 1976
Pinsker, 1977
Winfree, 1977
Hanson, 1978
Sano et al., 1978
Yamanishi et al., 1979
Biochemical rhythms
Chance et al., 1965
Winfree, 1972d
Greller, 1977
Malchow et al., 1978
Aldridge and Pye, 1979
Other physiological rhythms
Karve and Salanki, 1964
Johnsson and Israelsson, 1969
Johnsson, 1976
B: COMMUNITIES OF CLOCKS 117
5 K-cjJ vs. C+cjJ-cjJ'
5-2b cjJ' -cjJ- M vs. cjJ
m cjJ' -cjJ- M vs. cjJ
V K-cjJ vs. C+cjJ-cjJ'
5 to 17 K+cjJ' vs. cjJ
md cjJ+M-cjJ' vs. cjJ
5 cjJ' -cjJ- M vs. cjJ+ M/2
8 cjJ' -cjJ- M vs. cjJ
3 cjJ-cjJ' vs. cjJ
2 cjJ+M-cjJ' vs. cjJ+M/2
11 K+cjJ' vs. cjJ
2 cjJ+M-cjJ' vs. cjJ+M/2
2 cjJ' -cjJ- M vs. cjJ
2 cjJ-K+M/2 vs. C+cjJ-cjJ'
2b cjJ-cjJ' vs. cjJ
3 cjJ+M-cjJ' vs. cjJ
3 cjJ-cjJ' vs. cjJ
9E cjJ'+M vs. cjJ
1 cjJ'vs.cjJ
6 cjJ-cjJ' vs. cjJ
5 cjJ-cjJ' vs. cjJ
6 cjJ' vs. cjJ
4B cjJ' -cjJ vs. cjJ
7 K+cjJ' vs. cjJ
28 cjJ' vs. cjJ
5 cjJ' -cjJ- M vs. cjJ
5a cjJ' vs. cjJ
2 K-cjJ vs. C+cjJ-cjJ'
5,6 K-cjJ vs. C+cjJ-cjJ'
4 cjJ' vs. cjJ
118 4: RING POPULATIONS

NEW
PHASE

o
The eight phase transition measurements in Acetabu/aria (Kar-
NEW akashian and Schweiger, 1976, Figure 5, replotted). A Type 0
PHASE curve presurnably lies sornewhere in the shaded area, but
o alternative constructions are hard to rule out.

OLO PHASE OLD PHASE

o 10

merely swallowin,9 at I',andom times'(:juring re axed

ffset of the r~sp'irato!y rhythm afterward. ~ ~ ~

These experiments establish the reality of Type 0 resetting. Some may yet Iend
themselves to interpretation as population artifacts involving Type 1 resetting by
individual docks of an incoherent population. lt is essential in such cases to inquire
whether the individual dock is by itself capable of Type 0 resetting. In the case of
circadian rhythms, only since 1977 has Type 0 resetting even been documented directly
in an individual organism (Saunders and Thomson, 1977; Wiedenmann, 1977;
Engelmann and Mack, 1978). In no case has it been plainly exhibited in a single cello
The dosest approach to date is the Type 1 curve ofKarakashian and Schweiger (1976),
which, like many curves reported in the references above, lends itself to reinterpreta-
tion as Type 0; but there are only eight data points (see figure above.)

As far as lamaware (in 1978), all other smooth resetting curves ever measured in
living systems are Type 1. This strikes me as something worth puzzling over, as all but
the very simplest models are capable of other integer Types of resetting.

3. A Rotating Wave and a Screwy Swface. Given Type 0 resetting and a phase
singularity (Le., given a contour map like Figures 12 and 13), one can choose either
of two equivalent descriptions of the whole pattern of rephasing of a population's
aggregate rhythm:
1. Figures 12 and 13 have the same format as we found convenient to describe a
pinwheel experiment in Examples 5-9 of Chapter 2. Each contour line of new
phase (isochron) shows the locus along which <p = 0 recurs simultaneously. This
event moves from one isochron to the next, cart wheeling about the phase
singularity. This interpretation presupposes a physicallayout for the experiment
in which a phase gradient at zero stimulus duration lies transverse to a gradient
of stimulus duration.
 B: COMMUNITIES OF CLOCKS 119

2. If instead of watching waves circulate on the stimulus plane we plot event time
vertically above that plane, then each contour line lies higher than the one
before, as in interpreting the contour map of a ski slope. In this case, the surlace
thus plotted pivots around a singularity as it rises, constructing a helical sliding
board. Thus we have a screw of many turns, each turn formed by one day of data.
4. Amplitude Resetting. The most conspicuous distinguishing feature of the phase
singularity deriving from incoherence within a population of independent docks is
the amplitude resetting that goes along with rearrangement of phases. After the
perturbation each dock still follows the common cyde at the common period. The
distribution of phase does not change, apart from rotating around the cyde. Thus
the amplitude of the fundamental is permanently reset (so the waveform is changed)
without effect on the period.
It is worth noting that amplitude resetting in this context consists of dividing a
population of docks into two distinct populations, one of which advanced while the
other delayed under the stimulus. This splitting of the population provides the
dearest experimental test by which to distinguish this mechanism (see Box D).
If the periods are not all exactly equal, then phases can disperse further and the
aggregate rhythm eventually runs down. Recovery to the standard amplitude of a
single simple dock is obtained only by restoring synchrony within the population.
In the absence of an external rhythmic stimulus to synchronize all the individual
docks, this recovery can only be affected by mutually synchronizing interactions
among the docks. This is our next topic.

B: Communities of Cloeks
Mutual entrainment is a theme that recurs again and again throughout the
physiology of rhythmic systems. I've chosen to place our first encounter with it
here, in context of simple docks. By thus restricting each rhythmic system to a
one-dimensional path through its state space, we enormously simplify the
analysis, so much so indeed that it becomes tractable. A few typical phenomena
emerge that appear to have some physiological interest.

e overview, ~ee Stro9~tz ana Stewart (1993) in Scientific

Two Clocks
As in the previous section we begin with two identical simple docks, but now we let
them affect each other: The angular velocity of each now differs from 1 by an
amount that depends on its phase and on the phase of its partner.
~l = 1 + !(rPl, rP2)
120 4: RING POPULATIONS

Box 0: Optical Computation of Phase Scatter

If so much importance must be attached to scatter of phases within a population, then it
should be worthwhile to acquire convenient techniques for evaluating the impact of a
stimulus on preexisting scatter. The contour map of new phase on the stimulus plane
lends itself to this purpose in two ways:
1. Small scatter is altered in proportion to the derivatives of new phase with old phase
and perceived stimulus magnitude:
, 81· 81
dif> =DI= 8if>dif>+8MdM.

This is the directional derivative of if>' =f(if>,M). It is readily evaluated by shading a

finely drawn contour map in alternate black and white bands. Then either place a
crystal of Iceland spar on top of it, producing two images slightly displaced in the
direction (dif>, dM) of the crystal's edge, or hold a transparency over the original
displaced in direction (dif>, dM). The result in each case is a Moire pattern (Guild,
1956). The regions of interference form contours of dif>' on the (if>,M) stimulus space.
They thus show how any stimulus increases or decreases the population scatter.
Proof: The superimposed replicas form a mesh of parallelograms defined by contour
lines, each perpendicular to V'( if>,M) or V'( if> + dif>, M + dM). The Moire runs along the
short diagonals of these parallelograms, Le., along the difference vector perpendi-
cular to V'(f(if>,M) - (if> + dif>, M + dM». A curve perpendicular to a gradient is a level
contour (in this case of Df = dif>').
2. Large scatter, approaching arrhythmicity, must be handled by finite methods. The
simplest is to consider the subject stimulus as a "bloh" of width AcjJ and height AM.
This blob is transfixed by a range of isochron curves. Shade them with a yellow
highlighter pen, following the funnel of contours down to the if> axis. That range is
Aif>', the scatter after the stimulus. Note that near if>* there is a critical M* at which an
initially compact population is split into two halves about a half-cyele apart.
An experimentally determined contour map, such as Figure 13 in Chapter 2, can be
dealt with in this way in order to find out what (dif>, dM) best accounts for the
sharpeningor broadening of event timing after a stimulus. In the case of Drosophila~s
eelosion rhythm, this is the change of peak width relative to the minimal peak width in
perfectly synchronized populations. These data are tabulated in my computer alongside
the mean phase data from which the phase contour map was constructed in the first
place. It turns out that most of the scatter of if>' is attributable to amplification of an
initial scatter of if> amounting to about one hour. (Following up the Appendix in
Winfree, 1973a, this was established experimentally in several independent ways,
together with similar estimates of pupa-to-pupa variance of dock period, phase,
amplitude, and photoreceptor sensitivity, and other dock parameters and their roles in
experimental quasi-arrhythmicity. This manuscript never reached the publisher due to
a secretarial error that resulted in its destruction, with all copies and much of the data,
in a Post Office paper shredder during the summer of 1972. CuriousIy, this disaster
didn't arrest the Progress of Science.)

This can be justified also as the generic approximation for weakly-coupled

oscillators of any kind (Winfree 1967a; Rand and Holmes, 1980).
 B: COMMUNITIES OF CLOCKS 121

0)

Figura 14. As in Figure 5 except that the two identical docks affect
each others rates of change in a phase-dependent way. The result is
that one or more trajectories become attracting dosed rings at the
expense of others. (In this illustration ~rp" rp2J is chosen to be a function
of (rp, - rp2J alone so the antiphase diagonal is straight; generically,
both would be curvy).

This situation obviously has a certain symmetry, most readily brought out by
plotting the path of the pair of docks in their toroidal state space as in Figures 5-8.
In Figure 14 the unperturbed trajectories curve because each dock's rate is
influenced by the other dock. But because docks 1 and 2 are interchangeable, the
whole diagram remains symmetric about the main diagonal. The main diagonal
represents the path of perfect synchrony. Because there are mutual influences, the
synchronized docks run faster through some phases and slower through others.
They might run faster or slower on the average than either of them would by itself.
Trajectories might converge to the main diagonal, conferring on it a Ioeal stability as
in Figure 14(a). The synehronized solution thereby becomes an attracting cyde
(Chapter 6). But the trajeetories might altematively diverge as in Figure 14(b). In
this ease the synchronized solution is not stable. Due to the diagram's symmetry,
there must be another dosed path around the torus, midway between repeats of the
main diagonal in Figure 14(b). On this path the two simple docks stay one-half cyde
apart on the average, though wobbling about this position as they push and pull
each other through the entrained eyde. 2 In Figure 14(b) I drew nearby trajectories
diverging from the path of perfect synchrony and converging onto this antiphase
path of entrainment without synchrony. (By entrainment I mean a locking together
of frequencies, though not necessarily with a stable phase relationship, let alone in
synchrony. By synchrony I mean entrainment with, in addition, exact lock-step of
phase.) This analysis proceeds without major revision in the more interesting case
of unequal periods. The main change is that if the periods are too unequal or the
mutual influence is too faint, then the mutual entrainment is lost. For example, see
the exaet analytic solutions by Fujii and Sawada (1978), by Neu (1979b), and by
Rand and Holmes (1980) in connection with ehemical oscillators.
2 This is the case with two identical siphon oscillators such as are commonly assumed to imitate the
biochemical regulation of mitosis in blobs of Physarum (Scheffey, 1975, pers. comm.; see Chapter 22). In
fact it is usual for the more realistically complicated oscillators taken up in Chapters 5 and 6 (e.g .• van der
Poloscillators: Linkens. 1976. 1977) to have multiple stable modes of pairwise entrainment (Ruelle, 1972).
and usual physiologically (Block and Page, 1980). See Box F of this chapter and Box A of Chapter 8.
122 4: RING POPULATIONS

Box E: An Unexplored Kind of Singularity

A critical point mediates the transition from an incoherent mass of docks to a

synchronously pulsing unit capable of disciplining its members to strict entrainment
Cwhen discovered in Winfree (1965), dubbed "syn-talansis": "together oscillating"). This
transition resembles in some ways the phase transitions 3 of more familiar materials,
e.g., the sudden collective orientation of magnetic dipoles at the Curie temperature or
the emergence of long-range order when any liquid crystallizes. In mutual synchroniza-
tion, the long-range ordering is in time rather than in space, but its emergence is still a
critica1 phenomenon. The nature of such a singularity remains to be explored in
connection with the collective behavior of coupled oscillator populations.
~ By 1999 applied matliematicians have made aonsiderab e progress in the c;ase of one
specially symmetric.simple dock model~ see the review of Strogatz (2090) J"he tr<lnsition is
usuallx a Hopfbifurcationor som~thing simHar: amplitude ioitially ITI;:IlI, but Increasihg f<\st
while frequency hardly changes. ~uramoto (199t) re ports ~ cOl')trasting instance of $llddle-
node bifurcation: abrupt appearance at finite amplitude but frequency initially, smalL TQis
occurs in populations of a kind of Qsdllator that in ividua!Jy exhibit slich beh~vior..•
I think the quantum mechanical applications Ce.g., laser optics) have quite a different
nature from what is required in connection with living organisms. This is because the
oscillators of physics are all identical harmonie oscillators, whereas in living organisms
we confront simple docks or strongly attracting cydes (Chapter 6). Moreover, the
nonzero variance of periods in living docks plays a dominant role in their collective
behavior: With no variance, mutual entrainment can eventually arise even with
infinitesimal interaction (Zwanzig, 1976; Grattarola and Torre, 1977; Neu, 1980); with
nonzero variance, a unimodally peaked distribution of native periods is capable of
transition to mutual entrainment only above a finite second order critica1 point
(Kuramoto, 1975); a flat-topped distribution has a first order critical point (Winfree,
1967a).
• In 1967"1 "drew attention to ~ . a alogy . m p ase trans,itions il1'con enseQ-matt~r
physics, not thinking it might also work in reverse. for-discussion ofthat arialogy see John
Mackall's "Coupl~d Oscillators: The Invisible Hand.of Physi!=s"at httpi//www.SiJcom.com/
"VimackalI (Februaty 1997). ~ " ~. .;

3 Beware of a terrible pun. We have dealt with singularities implicit in "phase transitions," in the
sense of maps from cP E §I. In this box we use the thermodynamicist's term "phase transitions,"
meaning a change of collective organization, as from water to ice.

Many Clocks
Now what about populations of many simple docks, each faintly influencing all the
others in the general way considered above? One possibility is that the pooled
influence of the many on any one amounts only to faint random noise because the
docks are randomly phased around the cyde. This situation can be stable if the
mutual influence is too weak andlor the distribution of native penoels is too broad.
Another possibility is that with stronger mutual influence or a narrower distribution
of native penods, such complexity is unstable. In contrast, mutual synchronization
 B: COMMUNITIES OF CLOCKS 123

Box F: Mutual Entrainment of Simple Clocks

When a pair of identical simple docks with identical natural periods lock together, Le.,
entrain each other, they do not typically synchronize. Rather there is aphase difference,
commonly quite a substantial phase difference. To see why, imagine that in the periodic
environment provided by dock B, dock A runs a little bit faster or slower than normal,
depending on the phase difference 8 = 4>A - !/JE. Clock Bis subject to the same law at
phase difference -8. Mutual entrainment requires that the period at phase difference 8
equals the period at phase difference -8. To solve this problem in an idealized case with
8 constant throughout the cyde, we plot the period as a function of 8 and the period as a
function of -8 together on the same graph. One curve (solid) now depicts A's period and
the other (dashed) depicts B's period, in both cases as a function of 8, B's phase lag
behind A (see figure). These curves necessarily intersect at one or more pairs of points,
providing at least two solutions. One is at 8 = 0, with the two docks running
synchronously at an altered common period. Another solution is elsewhere, near 8=! in
this case. Are these solutions stable? An equilibrium is stable if and only if A's curve lies
below B's to the right of the crossing, because then if A lags B more, its period is shorter
than B's and it catches up. So the synchronous equilibrium need not be stable. If it isn't,
then mutual synchronization of large populations cannot be stable.

What is required for synchrony is that the mechanism of mutual coupling should so
delay or phase shift the influence of one dock on another that a stable equilibrium is
moved doser to 8 = O. Lacking this adjustment. a population of interacting docks not
only might fall to synchronize, but they would actually oppose entrainment by any
external rhythm; or, if started synchronously, they would disperse around the phase
circle much faster than would be expected in view of their range of natural periods. This
occurs in about half of computer simulations of simple dock populations, viz., the half
in which the influence-sensitivity loop is traversed antidockwise (Winfree, 1967a).
In addition to this phase requirement, coupling must be of sufficient magnitude, so
that each dock takes up a leading or lagging position as required to match its period to
the common period taken up by the others. Contrary to frequently repeated assurances,
this common period need not be the fastest nor the slowest nor the average in a
population of isolated individual docks. The situation can be visualized as follows.
Suppose all docks are entrained by some external rhythm. They adopt a certain phase
lead or lag depending on its frequency. Their influence rhythm is thus synchronous with
the entraining rhythm at a certain frequency. It can thus substitute for that rhythm only
at that frequency, which is wholly unrelated to the distribution of native periods. If
there is no such frequency, then mutual entrainment is actively opposed.
These requirements are formulated more precisely in Winfree (1967a), additionally
taking into account the distribution of natural periods in the population. As caricatured
in that paper, each individual dock traverses a fixed eyde at a varying rate, as in
Chapter 3. This approximation may be adequate for strongly attracting limit-cyde
oseillators (Chapter 6), such as seen in common physiological contexts. In other cases it
may not be, as we will see in Chapter 8. In such cases, the amplitude or waveform of the
124 4: RING POPULATIONS

Af A B Clock A runs faster (or slower), on the average over a cyde, by

positive (or negative) amount Llf depending on the relative
phase fj of dock B. Clock B follows the same rule with respect
L..-~"-+----lcc-7'C----I Ö to dock A in relative phase 1 - 8. At two values of 8 both
1 clocks run at the same rate.

oscillator is altered when it entrains to arhythmie extemal infiuence, e.g., the aggregate
influence emanating from its neighbors. For example, van der Poloscillators (Chapter
6) coupled in one straight-forward way (Chapter 8) can prove unahle to achieve mutual
synchronization unless initially entrained by an extemal rhythm, which changes their
amplitude. But once synchronized, their mutual infiuence suffices to maintain
synchrony, making the external entraining rhythm dispensable. If the magnitude of
coupling is then reduced sufficiently, the mutual synchronization suddenly comes apart
and cannot be restored.
.. By 1999 tnere seJ~ms to Eie no confi(TT1il'l9 report of any su pnehome'non in van oe
Pol oscilJatoYs, .no . even ~or. tlie .simple dockS ill whieh it rst ,1llmed 'up (as -faf as.l i{now)
(Win ee, 1966; 1967a,Fi Te 9 . '$'"0. is one needs acheck

could be stable because in that condition the coherent influence of the many
impinges upon each as a strong entraining rhythm, thus keeping them sufficiently
synchronous to generate a coherent influence rhythm. Unless all docks have
identical native period in a noise-free environment, this condition occurs only above
a critical point of coupling intensity (see Box E). The first docks to synchronize are
those whose native periods are so dose together that their collective rhythm has
sufficient amplitude to entrain within that narrow band of periods. With a little
increase of coupling intensity, more oscillators are captured; their periods were a
little further removed from that of the densest nucleus. This adds to the aggregate
rhythm's amplitude, so that the mutually synchronized nudeus expands a little
more, capturing a few more oscillators, and so on. This process limits itself when
the acquisition of additional oscillators requires a greater increase of collective
amplitude than their acquisition provides.
As in the two-oscillator case, treated in the first part of this section and in Box
F, a mutually entrained population can run at any period, even faster tlum. the
fastest individual in the population would in isolation, or slower t1uzn the
slowest.
Now we are in a position to appreciate the pertinence of the two-oscillator case
in thinking about the pooled influence of the mo:ny on any one dock. Consider "the
one" to be dock 1 and "the many" to be dock 2. The lone dock 1 might synchronize
to the group 2, thus contributing to the aggregate rhythm as above. But it might also
entrain at some nonzero phase angle, depending on the detailed shape of the
aggregate influence rhythm and of the simple dOCKS rhythm of sensitivity (Box F).
If dock 1 entrains without synchronizing, then it either leads or lags the many. But
this analysis pertains to every dock in the population. They can't all lead or lag the
rest. One possible outcome is a schism in which about half of the population plays
dock 1 and the residue plays dock 2. In this "twinned" mode the aggregate rhythm
 B: COMMUNITIES OF CLOCKS 125

has two peak.s per cyde one-half cyde apart on the average, as in Figure 14(b). This
is a common pattern in the activity rhythms of mammals (Chapter 19). Similar
hehavior was observed in a population of mutually coupled neon glow tuhe
oscillators (Winfree, 1965 and Chapter 11). Pavlidis (1971,1973, pp. 154-156) offers
additional analytic models of such splitting; Daan and Berde (1978) offer still more.
I obtained these phenomena by computer simulations and reduced their
quantitative analysis to a description of each simple dock by two properties: its
phase-dependent contribution to some aggregate "influence" and its phase-
dependent "sensitivity" (in terms of angular velocity) to that aggregate influence
(see Box A of Chapter 6). By plotting influence against sensitivity throughout one
cyde (Figure 15), one obtains a closed loop whose area and moment of inertia
determine the phenomena described above (Winfree, 1967a).

.. Cohen and Neu (1979), Neu (1979a,b; 1980), and Murray (1993 p. 227) explored the
consequences of simplifying oscillator interaction to a function like M'C~'!), the
dependence of influence-sensitivity area on the phase difference. These functions
need not have a single upslope and single downslope. While graduate students in the
Johns Hopkins University Biophysics Department, Jay Mitte-nthal and I derived them
algebraically from the phase-dependent dot product of the oscillator's vector field
with a perturbing vector fjeld induced by the influence of other oscillators: in general,
these could have multiple peaks per cyde. Then we didn't know what more to do with
them. Kuramoto (1981 section 3) lucidly presents an analysis in similar terms and
similarly sets its further development aside as "an interesting future problem." While
writing Winfree (1967a) I had evaded that problem by simply writing Fortran programs
in wh ich both functions are short Fourier series. These commonly produced two cr
more alternative phases of possible stable entrainment to the collective influence
rhythm. Thus a population of oscillators covering a range of native periods covers the
corresponding!jJ-ranges of M'(~'}). Those with native periods beyond the extrema of
this function are scattered at phase-dependent density over the entire circle of 'i! white
those with intermediate periods synchronize to the collective influence rhythm along
the M'{lj!) downslopes (or upslopes, in the reverse notation of Daido, 1995, 1996). The
number of oscillators surfing any slope is determined only by initial conditions. This
partitioning determines the shape of the collective rhythm, thus the shape of M'(~l
Within broad limits its shape, amplitude, and period are therefore adjustable in fine
steps by switching asciIlators fram one to the other cluster (Winfree, 1967a page 36;
Winfree 1979 Questions 8 and 24). Daido (1995, 1996) confirmed these observations
and went on to enumerate the possible states in terms of combinations of oscillator
phases on the several slopes. Near the critical coupling intensity to nucleate
synchronized clusters, he found it to vary as the } power of excess beyond critical. ...

As far as I'm aware (1978) no naturally occurring observation of mutually

synchronizing or mutually repelling docks has been analyzed in these terms.

.. In connection with a series-connected string of nonidentical Josephson junctions,

Wiesenfeld et al. (1996) provided the first physical realization of Kuramoto's model of
many simple clocks mutually synchronizing by speeding up or slowing down in
126 4: RING POPULATIONS

proportion to the sum of the sines of all pairwise phase differences between their
quantum-mechanical wave functions. The connection is all -ta-all, as we want, not
neighbor-to-neighbor as one might expect, because the "influence" is the electrical
current running through the whole series of junctions. This is still the only application I
know of.
Für the future, candidate systems might include glycolytic osciliations in yeast cell
suspensions and eircadian rhythms in suspensions of single cells. Aldridge and Pye
(1976) tried to measure a eritieal eoupling intensity for yeast cells to synchronize their
metabolism of sugar in a half-minute cycle (Chapter 12), but apparently, their answer
was two orders of magnitude tao low (cf. results of Aon et al., 1992), and the
experiment has not yet been repeated (but Dano, 1999, seems ready to). This system
presents a beautiful opportunity to assemble the first quantitative biological
demonstration of syntalansis. It would seem that cellular slime mold cells present
another, but this lilie of inquiry also has not been followed up since Malchow et al.
(1978), as far as I know. The same may be said far synchronous nudear division in the
true slime mold, last treated in these terms two decades ago (see Chapter 23), and for
suspensions of oscillati ng mitochond ria (Gooch and Packer, 1971, 197 4a, b;
Holmuhamedov, 1986). Today we have two additional opportunities, in cultured
neurons from the rodent circadian pacemaker, analogous to the liver cell suspensions
neg lected since Ha rdeland (1972, 1973) and in suspensions of fl uorescent
eya nobacte ri a individ ua II y supporting ci rcadi an rhythms (see eha pter 19). Neda et
al. (2000) introduce a fascinating new case in the synchronization of opera-hause
dapping. But with so few positive results obtained experimentally, it seems fair to say
that during its entire thirty~five-year history, understanding of mutual synchronization
in populations of dOCks or oscillators has been advanced primarily by mathematicians.
Emphasis has focused on simple docks, i.e., systems with inflexible amplitude,
characterized only by a phase. In this area almost all work has evotved from Kuramoto's
1975 formulation (see Box A of Chapter 6), reviewed in Kuramoto (1984).
As an alternative to the Kuramoto formulation, the undeveloped original still awaits
attention. To my mind, its use of a single "influence" function of phase and conjugate
single "sensitivity" function (e.g., both for acetaldehyde-coupling between yeast
cells) lends itself better to correlation with such experimental results as we may
expect from yeast, from both kinds of slime maid, and from neurons of the
suprachiasmatic nucleus (the "brain clock" of mammals). The Kuramoto model's
modulation of phase velocity by the sine of the phase difference applies beautifuily
and naturally to Josephson junctions, but seems less weil adapted for biochemistry.
It could be assembled by taking both the influence and sensitivity functions to be
strictly sinusoidal and, following page 33 of Winfree (1967a), inventing a second
agent of interaction (e.g., pyruvate) with influence and sensitivity functions identical
in ampiitude but phase advanced by 90' as noted in Box A of Chapter 6 and
Winfree (1979 page 108). On the coordinates of Figure 15c, both influence-·
sensitivit~' loops are circles traversed clockwise: Xl ((D) = sink)), Zl(0) = a co s{!;i) , X2(('~)
= cos(ö), Zl(O} = ~ a sinto). Both circumscribe area 71" times the adjustable coupling
coefficient, a, and their effects are summed in the phase velocity of the affected
oscillator. The threshold vaiue for this coupling coefficient in Winfree (1967a) is (41
(influence-sensitivity loop area))/(peak density of oscillators On the frequency axis).
In Kuramoto's model that area is twice 70, and the threshold coupling coefficient is
 B: COMMUNITIES OF CLOCKS 127

{2hr)/(peak density of osei 11 ato rs on the frequeney axis): the same, as expected. Th is
Is. a- threshold for very faint beginnings of collective oscillatlön, with contributions
coming only' fram the few -osci!!ators in the peak of the native frequency density
distribution. Ermentrout . Ü9~5) ·.found a particular case.· that lends itself to a
complete' analytical solution,. by-whieh tabulates thresholds .for fotal synchro-he
niiation, depending on distribution shape, for distributions with no oscillators
outSide· acertain range; . -' . _ -' . - .' ". ..'..' .
. . KUrar'ncito~s, symmetrized two-factor analysis makes the mathematics tractable
in '" the following . way -that '. doesn't work · out with the original single-factor
analysis. Therate equationfor any 6neosdllator~ j, iri the notation of Winfree
(1979) and as elsewhere in this book, in un its of cycles rath er than radi ans or
degrees, _is: . -

dljJj/dt "==Wj +a
.'
L sin(1;) -1jJ})
i-#j

whe:re' "a" J again, is the scalarcoupling coefficient. Then ifwe use thestandard notation
for'a,sum of sine waves,' andl for yCI to avoid confusing it with the' indices, .

....•. . " Ae N ;: L:e I6i , .

- i#-j

.
.ind' multiply it bye -t<P;,
' . ' _. " . "-.
wec·an~rite '. .
.. , ' .

': -. AeI\"'~~J) .~L eI((j>;-:r/>,} ,

. ,: .
. . ' . " i'f:j . '. .

:Thensetting aside the real. parts, we are left with .

.. , ' - ". Ashl(1/> -r/>~) '==Lsin(~i ~-<Pj), '.
.: ' . ' ;'l-j - ..
"~ .'
So'
,': .
.... · ~J·l'.dt.... '=w.J' ·+'
.,
a. ~
f;j Sin(cf>i ' ~ ,cf>'))
a~d :then we adopt apolar. coordinate frame rotating with 1jJ and call that 0:

' .,: " di/>j/dt=:,wj-~aAsin(PJ) .

::: : Th~sku~amoto's special case' tidies ur

the expressions tö be solved in a way that
rem~ined lmpossibl ein terms of Winfreeis {1967 a} single factor mediati n9 the cau pi ing
with arbiiraryperiodic waveform. Of.course, one still has to determine A, but this is just
Yfner~ Kuramoto andmany students began .the beautiful adventure in mathematics
sury,marized- by Strogatz(2000); FurthElr: surprises . come when the phase model is
ai:>andoned firstinfavor of less symmetrie simple docks, and then in favor of osdllators
cap,;Jble ofvariable amplitt.Jd~ (indudingpass.age through O),ascontinued in Cha pter 8.
-,'Almöstall.·publ ished work.,in this: areaf6cuses on models that easi Iy fall into mutua I
syoq,ronization. -This sele<:tton was- ne:ver,intended to give. thei mpression that "most
'osglla.törs imd cO\Tesp~!1.ding,-c_9upljng schemesuare like that ..
128 4: RING POPULATIONS

The phrase or mutually repelling" above refers to a surprising situation implicit

tt

in the simple-dock model. As noted above, mutual synchrony may be impossible if

the influence and sensitivity rhythms are so phased that Figure 15 has negative area.
In this case each dock interferes destructively with the entraining rhythm. So not
only does spontaneous synchronization fail, but even if it is established as an initial
condition, it fails actively. I mentioned above that there are organized alternatives
to mutual synchrony, e.g., the twinned mode with two groups of docks. But that
x a) c)

z
b

x
z b)

Figura 15. (a) One cycle in the rhythm of influence X(rp); (b) one cycle in the rhythm of
sensitivity, 2(4)); (c) X plotted against 2 is a closed ring.

doesn't have to be stable either. If each dock's rhythmic influence is very smooth, it
is nearly devoid of the harmonics that would survive superposition of symmetrically
phased subpopulations. Then the amplitude of the aggregate rhythm is quite low in
two-group or three-group modes of temporal organization. Commonly the
amplitude is too low to entrain enough docks to maintain that organization. In
such cases irregularity prevails, but not just for want of mutual coupling: it prevails
actively, "bucking" any external would-be synchronizer by developing a counter-
vailing rhythm, to the extent that any synchronization at all is imposed (Winfree,
1967a and supplementary computer simulations).
I know of no definite biological examples of such "antisyntalansis," hut Ghosh
et al. (1971) suggest that acetaldehyde may be an agent of phase-scattering mutual
influence among yeast cells (oops: by 1999 it seems clear thatthe opposite is true:
see Chapter 12.) Richter (1960, 1965) suggests a need for such mutual influence to
maintain steady-state output in the thyroid gland, which may he viewed as a
population of rhythmically secreting follides.

.. O n a giobai scale in the 1990s, th e Internet contains myriad periodic sources (e .g.,
video data) and has tra{fi c problems when the usual assumption of independent
asyn chrony is violated . Floyd and Jacobson (1994) argue that synta lansis arises
abru pt)y in the network when certain interaction thresholds are transgressed, and they
provide recommenda tions fc r preventing it.
 B: COMMUNITIES OF CLOCKS 129

Unless a time delay mediates each oscillator's effect on the others, active
scattering does not occur when oscillators interact in the special way typical of
chemical reactions coupled by diffusion. As far as this can be mimicked in terms of
a single state variable ("phase"), it implicates two influence-sensitivity pairs of equal
clockwise area on Figure 15c (Box A of Chapter 6; Winfree 1979). Thus no
possibility of antisyntalansis emerges from Kuramoto's (1975), Neu's (1979c), or
Rand and Holmes' (1980) reductions of this case to the simple-dock approximation.

Communication by Rhythmic Impulses

In some kinds of natural oscillator populations, mutual influence does not vary
smoothly in time but is episodie and pulse-like.
In the case of pulse-like influence, the individual oscillator might be
characterized by aresetting map, showing what new phase it recovers to after
receipt of an aggregate pulse from the· whole population. The analysis of
entrainment by Perkel et al. (1964) provides necessary and sufficient conditions
on the §1 _ §1 map from old phase before one such stimulus to new phase after the
stimulus. This analysis was independendy derived in context of circadian rhythms
by Pittendrigh and Minis (1964), Ottesen (1965), Keller (1967), Daan and Berde
(1978), and Kawato and Suzuki (1981), and in other contexts by Dong (1970),
Guckenheimer et al. (1977), Yamanishi et al. (1980), and doubtless many others.

Figura 16. New-phase 4>' vs. old-phase 4>, double-

plotted from data of Walker (1969) from the chorusing
~II
rhythm of crickets perturbed at various phases by the
sound of their own call. Phase 0 is the moment of
calling.

-flI-

There arises a dilemma ofinternal phase compatibility similarto that encountered

above. For mutual synchronization at the same native period the phase shift (if/ -(p)
130 4: RING POPULATIONS

~~--------~--------~

_~ IL..-_ _ _ _ _ _ _ _-X-_ _ _ _ _ _ _ _- - l

-'-2 0
--rzj--

should be changing from small advances to small delays at the phase ofpulse emission
(in general, delays increasing or advances decreasing). More exacdy, and in terms of
new phase rather than phase shift, the resetting map, 4>' vs. 4>, should cross through the
4>' = 4> diagonal at slope between + 1 and -1 at the phase of pulse emission, as in Figure
4-16. Any other resetting map would result in more complicated aggregate behavior
than simple synchrony; for example Figure 4-17 probably would. In four cases the
ingredients of such an analysis have been obtained experimentally:
1. The mutual synchronization of cAMP pulsing in suspensions of slime mold cells
mentioned above gives aresetting map of the anticipated sort (Malchow et al.,
1978; and Figure 3 of Chapter 15).
2. Mutual synchronization of chorusing in populations of tree crickets does also
(Walker, 1969; see Figure 16).
3. Electrical synchrony of cells in the pacemaker of the heart was once thought to
be mediated by a similar resetting curve (Sano et al. 1978, Figure 5). Peskin
(1975, pp. 250-278) analyzed the mutual synchronization of cells in the heart's
pacemaker in terms quite similar to those alluded to above. Exact equations
were derived for the two-oscillator case, but the population problem awaits
completion.
 B: COMMUNITIES OF CLOCKS 131

O~~~--·
......... Ol--~------.t

o o o
Flgure 18. The new phase of the f1ashing rhythm in fireflies of three spedes perturbed by the
sight of their own flash at various old phases. The flash occurs at phase 0 on this scale. Each box
is exactly one cyde by one cyde. (Replotted from Hanson, 1978 Figure 7).

4. The same behavior has been obtained from studies of mutual synchronization of
flashing in two different kinds of southeast Asian fireflies, one with Type 0
resetting and one with Type 1 resetting (Hanson, 1978; see Figure 18 left and
middle). Hanson also found that entrainment cannot always be understood
quantitatively as repeated phase-resetting a la Perkel, Le., iterating the
appropriate resetting cmve (in his case 7c) gives false results. This means that
simple-dock models fail in at least this one species. The next theoretical effort
might entail a study of impulse response and entrainment in attracting-cyde
oscillators of the sort familiar to neurophysiologists (see Chapter 14),
developing the consequences for a population whose aggregate output is itself
the entraining rhythm.
If each dock responds in a way describable neither as a jump along a fixed cyde
nor as a modulation of angular velocity along a fixed cyde (e.g., if amplitude can
vary, too), then this whole format must be abandoned. We therefore return to this
subject in Chapter 8 after developing a fuller appreciation of oscillating kinetics in
Chapters 5 and 6.
132 4: RING POPULATIONS

Collective Enhancement of Precision

A little studied question of some physiological significance concems the precision
of rhythmicity in mutually synchronized populations. It is often stated in research
papers (it is even alleged that 1 proved this in 1967, or that Norbert Wiener did,
hut as far as 1 know it remains unproved) that mutual synchronization disciplines
each oscillator to much improved regularity of oscillation at the common
frequency.
 B: COMMUNITIES OF CLOCKS 133

One argument might run as follows. Suppose mutual entrainment is stable with
deterininistic oscillators of native period Ti, each entrained to the aggregate rhythm
at period TO' Each locks to that rhythm at some phase t/J(Ti - Ta). Suppose small Ti
-TO, weak coupling, and a strongly attracting cycle, so that t/J changes slowly and
little else changes at all. Then we can write '!j;= 1fT - 1fTo + M(t/J) for some suitably-
invented function M. Entrainment requires that '!j; = 0 and M' < O. Now suppose we
have not a population of individually precise oscillators of various periods but
rather a population of oscillators of identical statistical behaviors, individually
somewhat irregular of rhythmicity. If they do achieve mutual entrainment, does the
aggregate rhythm drone on with a steadiness orders of magnitude greater than
any individual's, disciplining each individual to adhere to the collective rhythmicity?
If Ti should slowly change, then'!j; =I 0 nudges t/J toward the equilibrium typical of an
oscillator with the revised Ti' Should Ti fluctuate more rapidly within the range of
T/S characteristic of this population, then t/J will tluctuate about its stable position
for oscillators of middling Ti. Either way the situation remains qualitatively the
same. Thtis it would appear that the aggregate rhythm does discipline each
individual to enormously enhanced regularity.
Some biologists are inclined to account in this way for the uncanny accuracy of
some circadian rhythms.

But as far as lamaware, neither the physiology nor the mathematical essence of
such a collective refinement mechanism has yet been revealed. The matter awaits
the attention of a master of stochastic dynamics. Substantial beginnings are made in
Stratonovich (1967, Chapter 9), in Kuramoto (1975), and in Enright (1980a, 1980b).
A valuable contribution could be made by following them up, perhaps along the
lines of Winfree (1979).

... r analytic~1 results arlo corre~ondi/lg comput~r s~mu ations, now see amagucni
etal. (1981), Shimizuand Yamagu,cni(1982), and)'amaguchi and Shtmitu (1~84) I:Jsing
a popcdation of v fl der Pol osdllators- with ~ernal nOlse added, and snowing tne
consiste;pcy of ,their resu t with the entropy~pi"ocduction c!i~rion' of Glansdorff 'and
Prlgogrne (t971). Kuramoto (1984, Cbapter 5) ahd Tass' (19?9) furthe explore the
eifects of norse on the threshoid critelion for mutual synchr{)ni~tlon among oscillators
cf fjxed amplitude (ri~gdevices). Corresgonding biological observations may soon
same to han,d; Lil,l et al. (1997), for exarnple, usa, the phrase that heads this 'sectiol'T(
ho Efful that its sub'ect can be ex oted tlsin their e aration 0 su ra h'asmatic.-
134 4: RING POPULATIONS

Box G: Active Transport by a Row of Simple Clocks (The Wave Broom)

I am indebted for this notion to Dr. R. H. Wilhelm, who died before we could develop it
further (August 6, 1968). Wilhelm's keenest interest at the time was in rhythmic
principles that might underlie active transport in cell membranes (Wilhelm, 1966;
Wilhelm et al., 1968). After hearing him lecture on parametric pumping, it occurred to
me that even a row of simple docks, properly phased, suggests a mechanism for
transport of substances in the direction of wave propagation. Consider a line of cells
along which a periodic disturbance is propagating from left to right. Let its period be
our unit of time. Consider any substance involved in this disturbance. Let its
intracellular concentration vary periodica1ly, for whatever reason: c(t) = c(t + m), m
being any integer number of cycles. Given such periodism in cell metabollsm it would
seem unnatural not to let the permeability of the cell membrane also vary periodically:
p(t) = p(t + m). The rate of transport of substance across the cell partition is given by
Fick's law of diffusion as:

Then recalling that C2 is just a delayed version of CII and integrating over a full cyde,
the mean flux to left or right, integrated over a cyde, is:

j = f j dt = f (c(t) - c(t - 8))p(t)dt ~ 8 f p dc,

where 8 is the time delay between adjacent cells. This net flux is just 8 times the area
of the loop formed by plotting p(t) against c(t). 1t could be either positive or negative,
but it would be exacdy zero only by deliberate selection of appropriate shapes of c
and/or p. Thus material will in general be transported to left or right as the wave
passes. It is tempting to invoke some such "wave broom" to account for maintenance
of pacemaker activity, once established, in any potentially rhythmic medium, e.g., the
malonic acid reagent (Chapter 13) or the cellular sllme mold (Chapter 15). More
sophisticated wavebroom-like models have been pursued in various contexts,
supposing various mechanisms, by Hejnowicz (1970) and Goodwin (1973, 1974,
1975, 1976).

nucleus celTs and 'Golohies of bacteri a inrnvlduatly p

awalt attention f~om ·thisJj?erspective. ~ ". ___.......'--__...__~_ _~ ___

C: Spatially Distributed Independent Simple Clocks

In this section my intent is only to outline a format of deseription that receives
further development in later chapters. Our subject here is a population of simple
docks distributed in space. We are not here concemed with pooling their outputs
nor with their loeal neighbor interaetions. We are coneemed with maps again, this
time from a physical space in whieh the docks are distributed to a ring-like state
space on which each dock's phase is deseribed. Two examples will suffiee (see also
Box G).
 C: SPATIALLY DISTRIBUTED INDEPENDENT SIMPLE CLOCKS 135

The Ascomycete Frontier as a One-Dimensional Population of Simple

Clocks Without Interaction

o· b c
I I"
w., I
0 /\
/'
'
I
0

~o·
' \,/
1 - --4:1--,
'4
Io.!
v-
00 90" 180' 27r1' (1' ~
AZIMUlH
01155".~

Flgure 19. (a) An idealized sketch of a fungus colony on which spore density is rhythmic along
each radial growth path. The phase of the radial rhythm drifts through one cycle from north (00 )
to east (90°) to south (180°) to west (270°) (b). In (c) each point on the frontier ring is mapped to
its momentary phase on the cycle.

fixed velocity, its internal metabolie rhythms affeet the style of growth: The
myeelium beeomes locally thick or thin, eventually making spores or not. The
moving frontier of the colony thus leaves behind a permanent record of its
metabolie rhythm in the form of periodically alternating bands of conspicuously
different-looking tissue. Time lapse movies of a disk of such a fungus show that the
pattern is laid down at the growing edge, the circular frontier of the colony. As in the
construction of rings in deciduous trees, or deposition of the colorful decorations in
sea shells, the pattern does not change after the foundations are laid at the growing
frontier (Winfree, 1973d and corresponding time-lapse movies).
The frontier is a ring, a one-dimensional continuum eaeh point of which may be
regarded as harboring a physiological dock. The phase of this dock can be
evaluated by measuring back either in time or in spaee along the radial path of
growth to the most recent occurrence of some marker event chosen for convenience
to be called phase 0, for example, a maximum of sporulation density [(Figures
19(a), 20(a)]. As it happens, phase almost always varies continuously along the
b c
I/J w·o 0

/~bl
~o\
1 --

~
l<z
,I
i
11"
I•
\
LDCUS OF
SPORULATlON

Flgure 20. As in Figure 19 but phase meanders back and forth without net effect from north (0°)
to east (90°) to south (180 0 ) to west (270°).
136 4: RING POPULATIONS

frontier ring. (There are exceptions and some physiological interest attaches to these
exceptions as opportunities to observe the outcome of a natural experiment. See
below.)
It will be convenient to plot the observed dependence of phase on azimuth.
Azimuth is the compass direction from some internal origin to a boundary point. A
natural choice of origin is the inoculum from which the whole disk has expanded.
To help distinguish rings in physical space from the abstract phase ring, we
calibrate azimuth in degrees from 0 to 360, while phase is expressed in fractions of a
cyele from 0 to 1.
Figure 19 idealizes the phase vs. azimuth plot from the frontier ring of a
mycelium on which a single spiral intersects the boundary in three places. Figure
20(b) idealizes the phase vs. azimuth plot from the frontier of a mycelium on which
concentric rings intersect the boundary in four places. (See Chapter 18, Figures 5
and 6 for real measurements.)
It would be more natural to conduct a measurement by mapping the ring-
shaped frontier onto the elock cyele, idealized as a ring as in Figure 20 of
Chapter 1. Choosing a point on the cyele to represent phase 0 (e.g., the phase at
which sporulation is fated in newly created tissue), we plot each frontier point on
the ring according to its radial distance (its time) from phase O. This is done in
Figure 19(c) and 20(c). In Figure 19 phase increases more than it decreases as
we traverse the frontier elockwise. It increases exactly one full cyele more,
resulting in winding number W = 1. In contrast, in Figure 20 the image of the
frontier has winding number W = 0 around the phase circle. Phase increases and
decreases through more than a full cycle around the frontier, but it decreases
back again exactly as much as it increases. A completely synchronous mycelium
has W = O. Its frontier maps to a point circulating around the phase ring. In this
case sporulation patterns consist of concentric rings (65 mycelia out of 100). A
map with winding number W = ±1 corresponds to elockwise or antielockwise
spiral morphogenesis (26 mycelia out of 100). In the case of a two-armed spiral,
the map turns out to wind twice around the phase cirele (W = ±2) in a direction
(+ or -) determined by the handedness of the twin spiral (most of the remaining
cases).
The phase cirele might portray the states of a ring device functioning in each
little patch of tissue, if each frontier point harbors a simple elock. Sinee phase
advances (by definition) uniformly in time, this map is to be thought of as
rotating rigidly onee in eaeh period of the ring deviee. This is 16 hours in the
case of the Nectria fungus, whieh provided the examples deseribed above
(Winfree, 1973d).
In all the foregoing, we have paid no attention to the likely possibility that
neighboring frontier cells interact to some degree. This seems particularly
noteworthy in cases where phase changes rapidly over a short arc of frontier, Le.,
where there is a radial edge dislocation in the periodie banding of the fungal disk.
One might reasonably expect that physically nearby cells (or hyphae, to be more
exact) would compromise in phase, smoothing over the steep spatial phase gradient.
Smoothing of near-discontinuities of phase does occur, but slowly. A discontinuity
typically lasts through many cyeles before it is really smoothed out. So in this first
approximation we ignore interactions.
 C: SPATIALLY DISTRIBUTED INDEPENDENT SIMPLE CLOCKS 137

Note that this example deals only with the colony's growing frontier.
Suppose we had certain proof (as Dharmananda and Feldman, 1979 might for
the similar ascomycete Neurospora) that interior points (old frontiers) also retain
the same rhythmic activity as the present frontier more plainly exhibits. Then it
would be appropriate to map the whole disk onto the phase ring. As we have
often seen before, this cannot be done smoothly unless the frontier's winding
number is o. In the other cases, a violent phase discontinuity is implicit
somewhere inside the disko There the phase gradient is too steep to permit
neglect of interactions. In fact it is too steep for any finite accounting. This will
force us from simple-dock models to a biochemically more realistic view in
which the mapping is not a ring but a two-dimensional state space (Chapters 5
and 6). The mapping to a two-dimensional space is smooth regardless of
winding number and it permits neglect of interactions in a first approximation
even in situations with W =F o. But for the present we must confine our
attentions to the frontier.

A Liquid Chemical Oscillator Viewed as a Population of Simple Clocks

Without Interaction
Imagine a fluid in which each tiny volume element periodically executes a cyde of
changes, returning to an initial state at regular inteIVals of time. If nearby volume
elements are in nearly the same state, then (apart from concem about the stability of
this situation) we can neglect coupling through molecular diffusion because there
are no significant concentration gradients to drive enough flux of anY substance
from one volume element to the next.
The best studied example is the oscillating Belousov-Zhabotinsky reagent
(Chapter 13). Using one-dimensional coIumns of this reagent with sufficiently
shallow phase gradients, Beck and Varadi (1971, 1972), Thoenes (1973), Kopell
and Howard (1973a), Varadi and Beck (1975), and Beck, Varadi and Hauck
(1976) studied wave-like patterns of chemical activity in terms of spatial
patterns of phase. As in the Nectria fungus, disks of this reagent typically show
concentric ring patterns and spiral patterns of chemical activity, indicated by
the dye, ferroin. Its color varies between red and blue. In a ring pattern, all
points along any ring map to the same point on the phase cirde. Adjacentrings
map to adjacent phase points. The geometry is suggested by Figure 21: The
whole disk maps exactly as does each radial wedge of the disko If there are
many cycles of phase along each radius, then the map winds many times
around the phase ring.
As indicated in the case of Nectria, a two-dimensional spiral wave cannot
be mapped continuously onto the ring. Apart from the theorem about
winding numbers, the problem Can be visualized as follows. Consider the
border of the disk of reacting fluid. Having winding number W = 1, it maps
onee around the phase ring. So does the ring of fluid just interior to this
border, and so on by eoneentrie rings inward toward the pivot. An arbitrarily
small ring of liquid around the pivot also maps onee around the phase ring.
Inside that, there is either a diseontinuity in the state of the fluid or the tiny
138 4: RING POPULATIONS

PHYSICAL
SPACE PHASE
CIRCLE

Figura 21. A two-dimensional oscillating chemical medium momentarily has uniform phase
along closed rings concentric to point a. Each ring is shrunk to a point in imagination,
identifying points of equal phase. This collapsed image of the plane is mapped onto the ring of
phases.

disk at the very center covers the whole inside of the phase ring. But this
"inside" is not part of the state space and has no conceivable interpretation
in tenns of a simple-dock mechanism. To avoid this paradox, we will have to
abandon interpretation of spirals in tenns of phase in a cyde, turning to a
state space of two dimensions in order to support the required map: aspace
which gives insides to the phase ring. This is reserved to Section C of
Chapter 8.
In the one-dimensional case, each point in a column of oscillating fluid
maps to a point of the phase ring 01 -+ §1. The image of the column rotates
steadily around the ring. This picture was given more interest by contriving a
temperature gradient (Kopell and Howard, 1973a) or an acidity gradient (Beck
and Varadi, 1972; Thoenes, 1973) so that one end of the column cydes faster
than the other. In this situation the image of the column continually stretches
out along the phase ring as the leading (hot or acid) end wraps through more
and more turns than the lagging (cold or less acid) end. There are as many
cydes of wave-like activity along the column as there are windings of the
image. Eventually there are so many, and the waves are packed so dose
together, and the image is stretched so taut, that local interactions can no
longer be left out of the picture. At this point a new phenomenon first appears:
real propagating waves of chemical activity.

D: Ring Devices Interacting Locally

Linear Coupling to Neighbors
Consider a simple dock whose motion along the phase ring can be described
(vacuously) as cf> ;:;: {(cf». Suppose as in example 14H of Chapter 1 that we have a
physical ring of such docks in which the angular velocity of each is affected by its
fore and aft neighbors. To construct the simplest case, suppose there are so many
docks on a ring that neighbors are at very nearlythe same phase. Let the influence
 D: RING DEVICES INTERACTING LOCALLY 139

of each dock on its neighbor's rate then be simply proportional to the phase
difference between them:
dcjJ·
dt' = f(cjJ) + k(cjJi-l - cjJi) + k(cjJi+l - cjJi) für each cell, i = 1 tü N. (1)

In words, rate equation (1) says that each dock speeds through its cyde as it
would if alone but, additionally, it is hurried along or retarded by its two neighbors,
depending on whether they lead or lag. Each dock then tends to take up aphase
midway between its neighbors without deviating toward the interior of the ring in
state space. This set of N ordinary differential equations can be iterated in a
computer to follow the changes of each cjJi. I did this in 1973, collaborating with R.
Casten and J. Mittenthal over those aspects of the problem that could be approached
analytically. Problems of this sort have a tradition, and mathematicians know lots of
solutions, though apparently not for exactly the situations that caught our attention
then. Equation (1) could be written:

d!i = !(cjJi) + D (~) ~ (~) (2)

in which h is the physical spacing between cells, D is a diffusion coefficient, and k is

written D!h 2 • Letting h -+ 0, the interaction term is seen to be the second derivative
of cjJ along the chain of cells. So dropping subscripts, we think of cjJ as a continuous
function of time and position along the line of cells, and write (2) as a parabolic
partial differential equation:
8cjJ ff2cjJ
at = f(cjJ)+D 8()2 , (3)

where cjJ is distance along the line.

140 4: RING POPULATIONS

Equation (3) presents a familiar challenge. There exists a big and rapidly
growing literature of mathematical solutions for special forms of f(cp) (e.g., see
Murray, 1977 and 1993 and Fife, 1979), but only for cp and 9 as real-valued numbers
on the line. Surprisingly little attention has been lavished on the case in which cp is a
point on a ring rather than a point on the line (a phase rather than, let us say, a
voltage or a concentration;) and is also a point on a ring rather than on a line (Le.,
the physical medium [in which ri> = f(cp) is going on everywhere] is a closed loop
rather than an open thread). Nonetheless the qualitative features introduced by
incorporating spatial interactions are the same in any context. The main feature
introduced is wave propagation.

Waves
Two kinds of waves invite distinction as extreme cases. In the first case suppose f( cp)
> 0 for all cp so that we have a simple-clock medium, and suppose D is so small or
that cp changes so slowly with that Dd2cp/drf can be ignored in Equation (3). (In the
limit, this case would belong in Section C: noninteracting clocks). The medium can
still give the appearance of conducting waves because wherever cp varies with 9, cp =
o is reached first in one place, then a little further along, and so on. These
"pseudowaves" differ from real propagating disturbances (see Box C of Chapter 13)
 D: RING DEVICES INTERACTING LOCALLY 141

in that their wave shape and velocity are determined only by </J«(}). In fact that
apparent velocity, being lI(d</J/d(}), varies locally and can even be infinite. I speak of
this case only to provide contrast with the real waves that I call "trigger" waves. In a
trigger wave a local displacement of </J tends to travel along the () axis, eventually
shaping itself into a certain waveform moving at a fixed speed. Both simple docks
and hourglasses behave similarly in this situation: Either kind of ring device will
conduct a trigger wave. Waves of this sort are quite unlike those of dassical physics.
Unlike sound waves, light waves, and waves on water, they vanish at the ends of the
line instead of reflecting. They annihilate each other in head-on collisions instead of
passing through each other. In these respects they resemble the waves of electrical
activity typical of nerve, heart, and brain tissue (Chapter 14) and their chemical
analogues (Chapter 13).
Quite different mathematical approaches to waves in ring-device continua are
detailed in the appendix of Goodwin and Cohen (1969), in Ortoleva and Ross (1973),
and in Neu (1979a).

Mappings and Their Winding Numbers (Again)

I now return to the special case in which Equation (3) represents a continuum of
identical ring devices arranged in a physical ring, so there are no boundary
conditions to choose. As in the previous section it is helpful to visualize this
situation by mapping the physical ring onto the ring of states, </J«(}):§1 ~ §1. The
image of the physical ring necessarily winds some integer number W of times
around the phase ring. Once established, there is no way that winding number
can change without cutting the image. Cutting the image is forbidden as long as
</J«(}) is continuous: Arbitrarily nearby points on the ring cannot have finitely
different phases as long as molecular exchange continues, guaranteeing local
uniformity. The diffusion term confers coherence on the ring's image. Equation
(1) shows that diffusion is analogous to elasticity of the image of the physical
ring: Each element of length moves (on the phase ring) toward its neighbors at a
speed proportional to their separation on the phase ring (see Box D of Chapter
8). The physical ring's image then behaves much like a massless rubber band,
moving in a viscous medium which itself moves according to <fo = f(</J). Each little
piece of the ring follows this Iocal rule of angular velocity but additionally
stretches to relieve tension in locally more taut places (where phase </J in state
space changes more quickly with distance in real space). Each little piece,
traversing the same cyde as its fore and aft neighbors, is continually adjusting its
velocity to stay poised midway between them. That fact and the conservation of
winding number constitute the whole story of qualitative behavior of ring devices
with smooth kinetics interacting locally by such simple rules as Equation (1)
expresses.

Computational Experiments
Consider for exampie an hourglass ring device described by:
f(</J) = </J(l - </J)(</J - a) (4a)
142 4: RING POPULATIONS

with f= 0 at <P = a or at 0 or 1, which are identified, or

!(<p) = 1 +lcos21l"<Pi for 111> 1. (4b)
There is a repelling equilibrium <Pr [at <P = 1= 0 in (4a); elsewhere depending on I > 1 in
(4b)] and an attracting equilibrium <Pa [at <P = a in (4a); at<p = - <Pr in (4b)]. Without

o Figura 22. Kinetics on the phase ring during strong perturbation. analogous to
Figure 3 of Chapter 3.

spatial coupling, all volume elements of a ring of such a medium would follow the <P
arrow of Figure 22 to <Pa. But that would cause a rupture of continuity at <Pr. Volume
elements initially just to the left and just to the right of <Pr separate increasingly as
they approach <Pa anticlockwise and clockwise, respectively. If Iocal interaction is
allowed, that cannot happen. What does happen now depends on the winding
number of the image. If W = 0 as in Figure 23(a), then the whole image slides around
to <Pa. IfW -# 0, thatcan'thappen. IfW = 1 asinFigure 23(b), then theimage becomes
tauter near <Pr and denser near <Pa, but the anticlockwise circulation of f(<p) prevails.
The whole image then continuousIy rotates. Thus even though the Ioeal kinetics
during perturbation describes an hourglass, incapable of oscillating by itself, yet the
whole system still continuously oseillates just as it did at 1= O. Every volume element
along the physical ring is pulled around the eycle each time a wave of activity

a)

b)

Figura 23. A ring of docks (dots) mapped onto the phase ring. If W = 0 as in (a). then the ring
can homogeneously contract to tPa. If W 1= 0 as in (b). then it cannot. but instead rotates forever.
 D: RING DEVICES INTERACTING LOCALLY 143

circumnavigates the physical ring. Cardiologists call this a "reentrant circus wave." If
W = - 3, there are three such waves, rotating dockwise, and they never stop.
We observedthese behaviors for diverse choices of f(4J), using the computer to
iterate through Equation (1). It doesn't much matter whether f( 4J) describes a simple
dock, an hourglass, or something else. The velocities of wave propagation and the
wave shapes agreed weIl with analytic solutions for a single wave on the open line
when we made the physical ring large. For example, in Equation (4a) the velocity is
dose to V = v'2(t -a) and the wave shape 4J(O - vt) = 1/(1 + e Hvt - 8» as Huxley found
analytically (McKean, 1970) and as Nitzan et al., (1974) derived in a more general
context. More generally, covering cases which cannot be approximated analytically,
we found that as ring circumference is increased, velocity increases toward an upper
limit equal to the speed of a solitary pulse on the open line. As ring circumference is
decreased toward 0, wave speed decreases toward O. Without being able to make the
mathematical proof completely rigorous, Casten conjectured that the period of
circulation (circumference/velocity) should also increase with the circumference.
This was found numerically in every case. The reciprocal period appears to
approach the mean 4J as ring circumference approaches 0:

~ -+ Jf(4J)d4J.

In this limit the wave appears to flatten out to 4J(O,t) = (tIT) + 0 x (any integer), as
might be expected with molecular diffusion averaging reaction rates throughout the
whole of a very small ring. Using the above expression for T, it appears .that the
stable solutions to Equation (3) as D -+ 00 on a dosed ring are:

4J(O,t) = WO+t f f(4J)d4J

for any nonzero integer W.

1 present these fragmentary results (in 1978) because their apparently great
generality seems to invite a more elegant mathematical resolution.

From One Dimension to Two

144 4: RING POPULATIONS

Cases with W :I 0 are important for biological applications such as the ring-
shaped frontier of a fungus engaged in spiral morphogenesis in Section C. But the
really interesting cases come when we try to treat two-dimensional media. This
could be attempted by expanding the physical ring to an annulus and filling in its
central hole until it is closed and we have a disko If tP has nonzero winding number
around the edge of the disk, then there has to be a ring of discontinuity inside the
disko In the simplest case this ring is as small as can be, namely, a point phase
singularity. This is unavoidable but it is an embarrassment to models in which the
local state can vary only along a one-dimensional state space, because then all these
different phases that converge at the phase singularity represent discretely different
states. The phase singularity then represents a confrontation of distinct states in an
arbitrarily small space. This is physiologically and biochemically unrealistic. Using
Equation (4b), Kuramoto and Yamada (1976) tried to account for spiral waves in
chemical media (Chapter 13) but were frustrated by the central phase singularity
(their Sections 3.0 and 4). Thoenes (1973) had previously attempted a less
mathematical argument of the same sort, overlooking the contradiction implicit at
the pivot of a spiral wave in a medium whose state varies only in respect of phase.
 D: RING DEVICES INTERACTING LOCALLY 145

In the next chapter we begin to remedy these contradictions by widening our

view to encompass models whose internal state can vary independently in two ways.
 Getting off the Ring

To bring a quality within the grasp of exact science, we must conceive it as

depending on the values of one or more variable quantities, and the first step in
our scientific progress is to determine the number of these variables which are
necessary and suffici.ent to determine the quality.
James Clerk Maxwell

My purpose in this chapter is to start "putting flesh on the bones" of the simple
dock metaphor. Up to this point, I've tried to hold your attention on "phase" and
its rate of change by confining discussion to the simplest metaphor of smooth
cyclic dynamics, namely, the ring device. I have studiously avoided allusion to
other degrees of freedom of the "state" of any biological dock. To make the
transition to a broader perspective in an orderly way, I now wish to introduce just
one additional notion, i.e., that a rhythmic process might be adjustable not only in
phase, our exdusive preoccupation in previous chapters, but also in some measure
of its vigor, amplitude, range, or degree of variation during the cyde.
I do this by elaborating on a few strictly idealized examples, drawing out the
main features in which they differ from simple docks. These new features are
met again in more realistic models in Chapter 6 and in several sets of
measurements on biological systems examined for such features in the laboratory.

A: Enumerating Dimensions

Just as people have asked how many components there are in the sensation of
color (three) or of taste (four) so it also seems basic to ask how many
components there are to the sense of time. Here that question is restricted to the
particular sense of circadian, rhythmic time. A commonly accepted answer is
"one," by analogy to the unidirectional character of linear time. The inadequades
of linear descriptions of time have been met by recognizing that the one-
dimensional time axis, in cases of rhythmic time measurement, describes a cirde.
No significance is attached to the insides of the drele, just as we attach no
significance to places off the one-dimensional historical time axis. In preceding
chapters we adhere to this viewpoint and test its limits by mathematical

A. T. Winfree, The Geometry of Biological Time 146

© Springer Science+Business Media New York 2001
 B: DEDUCING THE TOPOLOGY 147

inference and comparison with obseIVations. The obseIVations of negative slope

in resetting curves, of Type 0 resetting, and of phase singularities present
paradoxes for this paradigm. The result is that we are forced in this chapter to
contemplate the possibility that the sensation of time has two or more
components.
There are serious conceptual problems about enumerating the degrees of
freedom of a real system. It is not obvious that there is any unique number of this
sort because every real system involves myriads of variables, some of dominant
importance, some of negligible interest. But neither is it usual for people to deal
with real systems. We deal instead with certain aspects of their behavior that we
consider "relevant." In our heads, we deal with adequate approximations,
caricatures, metaphors, models that acknowledge only the dominant variables of
real systems. For a model system I use the term "degrees of freedom" to indicate the
integer number of independently varying quantities which jointly determine its
state, in the sense that if and only if all are simultaneously known (together with any
relevant environmental parameters), then their immediate rates of change are all
unambiguously determined. This is the sense in which "degrees of freedom" is used
in thermodynamics and statistical mechanies. It is the dimension of the state space.
It is the number of oscillators only if each oscillator is a simple dock with a single
state variable (the phase). In certain other literatures usage differs. For example, in
mechanies the state variables always come in conjugate (position, momentum)
pairs, so "degrees of freedom" has come to mean the number of pairs, i.e., half the
dimension of the state space (Feynman et al., I 49-6). This is the number of
oscillators if each is a simple harmonie oscillator with two independent variables of
state. In electrical engineering "degrees of freedom" means the number of changing
quantities in an equation, not counting their rates of change as distinct degrees of
freedom. This can be a much smaller number than the dimension of the state space
(for example, see Pavlidis, 1973).
In this chapter we entertain the notion of exactly two components, but the
qualitative inferences emphasized here are also valid for any greater number of
components.

B: Deducing the Topology

As long as we envisioned only a one-dimensional set of states with the connectivity
of a ring, there was no latitude of choice in selecting astate space. All one-
dimensional dosed manifolds are topologically equivalent to a ring.
But if we are driven to recognize different flavors of each phase, then we must
choose one of many possible state spaces. The issues at stake are dimension and
connectivity. Consider some of the options for introducing just one more variable,
bringing the dimension of state space to two. We might consider involving a second
dock for the second degree of freedom. The state space would be the product of two
rings: (§l x §l), the two-dimensional torus. Without belaboring detail, this turns
out to entail some discontinuities not obseIVed in practice. But a system of three or
more simple docks would seIVe (Chapter 4, Section A). If our "system" is really a
composite of many similar simple docks, the required additional degrees of
148 5: GrnlNG OFF THE RING

freedom might lurk in the distribution of phase about the mean phase. In many
respects the narrowness of the distribution would determine an amplitude,
intensity, or vigor of aggregate rhythmicity.
Alternatively, we could supplement the "phase" description of a simple clock
with a second quantity, an "amplitude" of oscillation. Diagrammatically this
could be done by picturing the circle of phases as girdling a cylinder. The
cylinder's long axis distinguishes oscillations of different amplitudes. Dynamics in
systems with cylindrical state spaces has been systematized by Minorsky (1962,
Chapter 8) and by Andronov (1966, Chapter 7) among others. Without belaboring
detail, I also reject the cylindrical state space because its qualitative features
don't correspond to the qualitative behavior of the biological systems all this is
supposed to be about.
Our state space might alternatively be a surface of a cone or its topological
equivalent, a disko The cycles of different amplitude would be rings concentric to an
axis or point of zero amplitude. The singularity of zero amplitude might then be
regarded as adegenerate ring in which all phases are indistinguishable.
In principle there are lots of alternatives, each characterized by a topology and
corresponding idiosyncrasies of behavior. If we want astate space of two
dimensions, the state might be described by two real numbers or by two positive
real numbers (like chemical concentrations) or by a phase and areal number (the
cylindrical state space) or by two phases (a torus or a Klein bottle) or in ways that
lend themselves less readily to verbal description (as on the surface of a sphere with
17 handles, six of which are knotted together). And if more than two dimensions are
countenanced, the possibilities exceed the capacity of human imagination. How is
one to choose the state space natural to a given phenomenon? If I may quote
Ambrose Bierce (on "sleep," from The Devil's Dictionary):
It is hardly a burning question: it is not even a problem that presses for solution.
Nevertheless, to minds not incurious as to the future, it has a mild, pleasing interest,
like that of the faindy heard beating of the beIls of distant cows that will come in and
demand attention later.

For present purposes levade the whole issue by choosing IRD , in fact only its
positive part, as though the process with which we will be concerned is determined
simply by D chemical concentrations (D here stands for "dimension", though just a
few pages above I used it for a diffusion coefficient). By this choice I conjecture that
for the systems we will be concerned with there is a continuum of realizable states
between any two states and that any closed ring of states can be contracted through
realizable states to a point. (This is not true, for example, of §l nor of §l x §l, nor
of §l x IR l contemplated above.) Beyond that conjecture I make no more. For
example, we have little reason to suppose that D = 2, as though only two quantities
suffice to adequately determine the state of a biological dock. This is commonly
assumed for reasons of convenience in constructing solvable models, but rarely is
more substantial justification given. To assume D = 2 is to postulate the
nonexistence of a number of peculiarities that require a third degree of freedom,
as we will see in Chapter 6. The models in this chapter all suppose D = 2 for simplicity
but I will deal only in those properties of the models that generalize straightfor-
wardly to D > 2.
 C: THE SIMPLEST MODELS 149

C: The Simplest Models

Does this elaboration of what may seem an arbitraIy descriptive language have any
meaning in terms of hard-nosed empirical science? What is gained by abandoning
the simple traditional state space §I for some manifold of greater dimension and
different topology? What is gained in the end bolls down to the existence of a
continuum of states connecting each point of the familiar cyde to a point of
ambiguous phase, not on the usual cyde. That may not seem like much but it allows
us at least to describe consistently the observed negative resetting curve slopes, Type
oresetting, and phase singularities of biological docks, all of which seem perplexing
in terms of the geometry of a single simple dock or even of a pair.
In short, the following models emphasize only two interrelated supplements to
the simple dock idea:
1. A second dimension of internal state
2. Astate of ambiguous phase
Example 1. Consider a pendulum. It goes through a smooth cyde induding (in
order) states of:
1. Lowest position in middle, maximum momentum to the right
2. Medium height on right, medium momentum to the right
3. Highest right position, zero momentum
4. Medium height on the right, medium momentum to the left
5. Lowest position in the middle, maximum momentum to the left
6. Medium height on the left, medium momentum to the left
7. Highest left position, zero momentum
8. Medium height on the left, medium momentum to the right
9. Lowest position in the middle, maximum momentum to the right (etc.)
This is diagrammed in Figure 1. The pendulum executes its cyde with pretty
much the same period at any amplitude. The amplitude increases with the energy
we impart to the pendulum in starting it. At zero amplitude (zero energy) , the
phases are indistinguishable and the pendulum bob simply hangs straight down.

RIGHTWARO
MOMENl\JM

Figur. 1. One circular trajectory in the (position, momentum)

state space of a simple pendulum (inset upper left). L = left, R =
right, cP = phase, A = amplitude.

LEFTWARO
MOMEN1VM
150 5: GmlNG OFF THE RING

The simplest kind of perturbation of this motion is a mechanical impulse, a kick.

Such an event quickly alters the momentum without significantly changing the
position, as when you shove a child on a swing. This alters both phase and
amplitude in a coordinated way.
All the above (as long as it is restricted to low amplitudes) applies equally weIl to
any harmonic oscillator. Classical physics is built out of harmonic oscillators.
Example 2. Examples from mechanics are a bit misleading in that the two
ostensibly independent state variables, position and momentum, are secretly
related in a way that is fundamental to the whole structure of mechanies:
Momentum is proportional to the rate of change of position in time. But similar
diagrams arise in context of chemical kinetics. In these diagrams the perpendi-
cular coordinates are concentrations of two distinct chemical substances. In 1920,
A. J. Lotka proposed purely theoretically that a chemical reaction could oscillate if
two reactions could be so coupled that the rate of each depended suitably on the
other's product concentration. Diagrammatically, the state of the overall reaction
can be indicated by the concentrations Cl and C2 of two products. In the simplest
caricatures there is a steady state at Cl = C~, C2 = C;. If either concentration is
disturbed from the steady state then Cl and C2 begin to change to new values. It
transpires that change persists rhythmically as Cl and C2 bobble up and down
along a closed path in state space (Figure 2). The amplitude of this closed path is
determined by the initial displacement from steady state, just as the pendulum's
amplitude is determined by the energy of an initial mechanical displacement from
equilibrium.
In terms of chemical kinetics, the simplest imaginable perturbation would
consist of selectively adding or removing one compound, e.g., by photolysis of
substance 1, diagrammatically as in Figure 3.

.. This simple caricature ' as provkled a 9.o~d matcn~ to -circadian c10c resetting
observed in a variety of spedes sinc~ 1968. lri the CqS~ of Drosophila "substance 1" i5
now thought to be the unknown protein product)_TIM'. 'of- the- "time/ess" gene. Thi5
might not be' a univers3\1 identifiCatipn. See Chapter 195 new mptenal.. ,

A quick dialysis that removes both in proportion to their concentrations would

change the state as diagrammed in Figure 4.
Example 3. Also in 1926, Vito Volterra independently published an identical
scheme in which concentration Cl represents the population density of animal

C,

Figure 2. A pendulum-like oscillation in the state space of a chemical

reaction determined by two concentrations C, and C2 • (Note that this
caricature is unsound both thermodynamically and kinetically, due to
general peculiarities of real chemical kinetics. But it suffices for now to
introduce the notion of amplitude.)
 D: MATHEMATICAL REDESCRIPTION 151

figura 3. Figure 2 is altered to depict revised kinetics during a perturbation

that quickly destroys substance 1.

C2

//
1/____
Figura 4. Kinetics during removal of both species at a rate proportional to
their abundances.

-
;/~

species 1 and C2 represents the population density of species 2. His intent was to
abstract the essential features of ecological dynamics in fisheries. Thus he
considered the consequences of perturbations such as temporarily introducing a
harvester that selectively removes species 1 (reduces Cl, Figure 3) or unselectively
takes species 1 and 2 in proportion to their abundances (reduces Cl and C2 together,
Figure 4). The timing of rhythmic fluctuations in species abundance is govemed by
the same geometric relations as in the previous cases.

0: Mathematical Redescription
The purpose of this section is to articulate more exactly the very simplest models of
phase resetting in an oscillator characterized by an amplitude as well as by a phase.
Modulation of angular velocity, the mechanism explored in Chapter 3, is not
adequate to describe or analyze the phase control of such an oscillator. We will see
why and how that is by doing as we did in Chapter 3: We will write equations for a
few general styles of perturbation (such as Figures 3 and 4) and graphically examine
their implications. The four models to be presented here all resemble a pendulum in
that under unperturbed conditions (I = 0) trajectories are concentric circles
traversed clockwise at uniform angular velocity, the same on every circle. The radius
of the circle is the oscillation's "amplitude," and angular position along the cirele
(measured clockwise from the positive Yaxis) is the oscillation's instantaneous
phase (Figure 1).
The four models to be presented here differ in the ways they react to a
stimulus I =f O. During an interval when I =f 0, the oscillator does not behave as
152 5: GmlNG OFFTHE RING

it does when I = O. Its state changes in a different way. Our analysis proceeds by
following the state along a trajectory of unperturbed dynamics (I = 0) up to a
certain phase, then following it from there along trajectories of perturbed
dynamics (I =1= 0) during the stimulus, then reverting to unperturbed dynamics
(I = 0) after the stimulus. This is essentially what we did in Chapter 3 for
simple docks except that there the trajectories were geometrically identical, all
being limited to a common one-dimensional path. They differed only in speed
along that path. Now we admit perturbations of speed in two directions. The
perturbed path in state space thus differs geometrically. To keep the story
simple we consider only one nonzero value of I without describing how the
dynamic depends continuously on I.
This method of altemating flows has been used in diverse contexts that involve
perturbed oscillators; by Danziger and Elmergreen (1956) in connection with an
endocrine cyde and its control by hormonal stimuli; by FitzHugh (1960, 1961) to
analyze the effects of electrical stimuli on nerve membrane; by Kalmus and
Wigglesworth (1960) to describe the impact of daylight on a circadian dock; by
Campbell (1964) to analyze mitotic synchrony; by Strahm (1964), by Moshkov et al.
(1966), and by Pavlidis (1967) to rationalize resetting experiments in the fruitfly's
circadian dock.
Example 1. Let us suppose that the stimulus removes substance Cl at a constant
rate k. If this rate is large and the stimulus is brief, then as in Fig 3. we can ignore
other processes occurring during the stimulus and write:

dZ = -k,
I so C~ = Cl - kl

where the prime indicates the new, reset value of Cl after astimulus of duration t.
Let's call kt the "magnitude" M of the stimulus. (Note that usage is a litde different in
Chapters 3 and 4, where stimulus magnitude is interpreted stricdy as duration at
fixed I.)
In the case of a pendulum, Cl might be the momentum coordinate, the
stimulus being a shove; the magnitude of the stimulus is then the mechanical
impulse, the momentum change. In ecological context Cl might be deer
population density, the stimulus being the hunting season. Continuing to use
unprimed symbols to represent the state at the beginning of an interlude of
perturbed dynamics and primed symbols to represent the state at the end of that

c,
Figur. 5. An impulse changes the momentum of a pendulum or the
density of a species by amount M. The vector M from the initial state to
the final state determines the new phase and amplitude trigonome-
trically. Essentially the same diagram can be found in Mercer (1965,
Figure 12) and Winfree (1975a).

C2
 D: MATHEMATICAL REDESCRIPTION 153

interlude, Le., at the beginning of unperturbed dynamics after the stimulus, we

have (see Figures 2 and 5):
C~ = C2 = C; + A' sin 27r</>' = C~ + A sin 27r</>.
Letting the initial amplitude be our unit so that A = 1 and again adopting the
more compact notation of Example 2 in Chapter 1, sn </> = sin(27r</» and similarly cs
for the cosine and tn for the tangent, and moving the origin to (C~,C;), we have
C~ = sn</>
and
C~ = A'es </>' = es </> - M
where M is the momentum change. Thus
,;,' _ C~ _ sn</>
tn,/, - q - es</>-M

for the new, reset phase. At the same time, the amplitude is changed to A', which can
also be written in terms of </> and M if desired.
Notice the same formula, for essentially the same geometric reasons, in
Example 14B of Chapter 1 and Example 2 of Chapter 2.
Example 2. We now suppose a more complicated effect of the stimulus, more
like Fig 4. Suppose the perturbed trajectories resemble Figure 6(a), with velocities
adjusted so that after a time t any oscillator started on the unit cirele at phase</> is on
a small circle of radius R(t) and centered at D(t), at angle</> from the center of the
smaller circle [Figure 6(b)]. Suppose for example that R(t) and D(t) both decrease
with t in such a way that DIR = kt = M. The geometry says (Figure 7):
tn </>' = R sn </> - D = sn</> - M
Res</> es</>
as in model I above.

Figure 6. (a) Curvy trajectories toward an attract-

ing state during perturbation of the hypothetieal
oscillator of Example 2. (b) Geometrie eonstrue-
tion of the trajectories in (a) by defining R(t} and
D(t}, functions of duration t of perturbation.

a b

Example 3. Instead of supposing DIR = kt as in model 2, suppose that as t goes

to infinity D goes to 1 and R goes to O. Then we have a stimulus that forces the
oscillator toward a unique equilibrium on the unit cirele (Figure 8). Turning off this
stimulus releases the oscillator back into its unperturbed dynamics along the unit
154 5: GETTING OFF THE RING

Figura 7. Enlargement of a triangle in part (b) of Figure 6 to clarify

trigonometrie relations.

Figura 8. Trajectories toward an attracting state during perturbation of

E----+--.---4---\ the hypothetieal oscillator of Example 3. The circles are loci reaehed
from the initial (outer) circle after equal durations of exposure.

eirele. Sueh a stimulus imitates the suppressing effeet of visible light on the
eireadian rhythrn in fruitflies (Chapter 20) or of moleeular oxygen on the glyeolytic
rhythm in yeast cells (Chapter 12). The expression for <jJ' in terms of <jJ and M
becomes
A.' _ RSll<jJ - D _ Sll<jJ - f{M)
tll'f' - Rcs<jJ - cs<jJ ,

where f increases from 0 to 00 as M increases from 0 to 00. This case differs only
trivially from that of Figure 4, in which the stimulus wipes out both substanees 1
and 2 in proportion to their concentrations.
Example 4. AB a last example consider a different definition of phase. In all
the above we took phase in the sense of time past the maximum of Clon a
eyele of any amplitude. The Iod of uniform phase were therefore simply radii
from the center of rotation. For some purposes (examples: Pavlidis and

Figura 9. The loeus of phase <p = 0 might be the upward

erossing of a threshold level C, = € + C;. Phase is thus
undefined for oscillations of amplitude A < € (shaded).
 E: GRAPHICAL INTERPRETATION 155

Kauzmann, 1969; Kauffman and Wille, 1975) it might be more realistic to

define phase as the time after the upward crossing of a threshold as in Figure
9. In such a case the loci of uniform phase are not radii but rotational
translations of that arc of the threshold as in Figure 10. (Phase goes undefined

Flgure10. The <p = 0 locus of Figure 9 is rotated to consecutive 0-+--+-"""7"-"'\

positions one-fifth cycle apart to construet isochrons (supposing
the angular velocity of trajeetories on this diagram is everywhere
the same).

on cydes of less than threshold amplitude inside the black hole, Figure 10). In
this model the phase rjJoF of an oscillator at astate given in polar coordinates as
(rjJ, A) is (Figure 11):

Figura 11. Given threshold level fand amplitude A of oscillation, the two
altemative definitions of phase <p and <pt are geometrically related.

so
rjJ+ = rjJ + the correction cs- 1 ~,

where A is the amplitude expressed in terms of rjJ and M.

E: Graphical Interpretation
Now what does this little game get for us? It gets us equations by which to
instruct a computer to draw the anticipated consequences of experiments in
which a single harmonic oscillator is perturbed for any duration at various
times in its cyde. The behavior of such an oscillator presents a marked contrast
to that of the simple docks examined in equal detail in Chapter 3. This new
156 5: GrnlNG OFF THE RING

behavior is intuitively accessible in tenns of pushing on a pendulum, just as the

simple clock's behavior was intuitively accessible in tenns of modulating the
angular velocity of a rotating machine. In certain qualitative essentials the new
behavior found here resembles the behavior typical of a much wider and more
realistic variety of biochemical and physiological oscillators. The reason for this
resemblance will come out in the next chapter. This chapter finishes with a
display of some of the computer plots alluded to. These plots have three main
qualitative features:
1. ql = <j; in the limit of very brief stimuli, M -+ O.
2. Near phase <j; = 1 cycle, near stimulus magnitude M = 1, the new phase <j;' has
a singularity. Writing <j; as 1 + x and M as 1 - y, we have in good approximation for
small departures x and y,

Flgure 12. As in Figure 7 of Chapter 3 except that

new phase is deterrnined by old phase and
stimulus magnitude according to the equation of
Example 1 rather than according to simple-dock
kinetics.

0--0-1 o

x
tn<j;' =-
y
In other words, the new phase of the oscillator is entirely deterrnined by the
ratio of the tiny departures from <j; = 1 and M = 1. The slightest error in
approximating that stimulus timing can therefore evoke any phase, but at a very
small amplitude (in models 1,2,3; in model 4 phase is undefined at arnplitudes less
than threshold).
3. At very large M, tn <j;' -+ 0, Le., a sufficiently prolonged stimulus essentially
resets the oscillator to a unique phase regardless of the initial conditions.
The easiest way to see how <j;' jointly depends on <j; and on M is by plotting <j;' in
three dimensions above the (cp, M) plane. It is a screw surface repeated in each repeat
of <j;' along the vertical axis and in each repeat of <j; along the horizontal axis. It all
consists of one single surface wound around vertical poles at <j; =any integer, M = 1
(Figure 12 and Figure 4 of Chapter 2). The corresponding plot of new, reset
amplitude A' of oscillation would show a deep pit descending to zero at <j; = any
integer and M = 1, rising to unity (by definition) along the front wall at M = 0 and
taking other values elsewhere according to the particular dynarnics adopted.
 E: GRAPHICAL INTERPRETATION 157

Figur. 13. As in Figure 4 of Chapter 2 the (<p, M) plane is

depicted with the contour lines of fixed new phase, <p', at M
intervals of ~ cyde. In the simple dock case (Figure 8 of Chapter
3) they were parallel displacements of a common curve whereas
in this case they are various pieces of sine curves converging to a
singular point.

It is convenient to portray these surfaces as contour maps on the stimulus plane

as we did for the new reset phase of a simple dock in Chapter 3. These contours
depict the (4), M) combinations along which 4>', and therefore tn 4>', is constant. Thus
their shapes are given by a sn 4>' = es 4>' - M. These are arcs of sinusoids, all
converging to M = 1,4> = 1 and all touching the M = Oline at 4>' = 4>. Figure 13 shows
the contour map of new reset phase for Examples 1 through 3.
The new phase 4>' at the moment the stimulus ends is the complement of the
event latency, the time until phase 4>' = 0 recurs after the stimulus ends. I call this
latency the cophase because phase plus latency (cophase) is necessarily one cyde.
Thus a plot of event latency downward from the stimulus plane is identical to a plot
of new phase upward.
In some applications it has been convenient to think instead in terms of
phase shifts. This is a convenience, for example, in thinking about one model
of entrainment, according to which an oscillator of native period T keeps up

TYPE
1
"WEAK"
(M<MI')

Figura 14. The top two panels (a, b) show Type 1 resetting; on the left (a) as aresetting curve,
plotting new phase upward (or cophase downward) against old phase to the right, and on the
right (b) as a phase response curve (PRC), plotting phase advances upward and delays
downward, also against old phase to the right. The bottom two panels (c, d) do the same for
Type 0 resetting.
158 5: GETTING OFF THE RING

\ ~~\
~
M

Figura 15. As in Figure 13 except that the contours represent (cp, M) combinations resulting in
the same phase shift, ÄCP, rather than the same new phase. The phase shift is the new phase
minus the old phase minus the stimulus duration. Stimulus duration is taken to be negligible in
this figure. Contoured at intervals of one-tenth cycle as in Figure 13, using equation M = tn Äcpl
(sn cp + es cp tn ÄCP) from Example 1.

with a periodic driving stimulus of period T by doing a little phase shift ß<jJ =
T - <jJ. In tenns of old phase and new phase, the phase shift ß<jJ is <jJ' - (<jJ +
stimulus duration). Thus a plot of (J or <jJ' is readily converted to a plot of Ä<jJ
by shearing it 45° along the <jJ axis (Figure 14). A contour map of ß<jJ on the
stimulus plane is sketched in Figure 15 for Examples 1-3. Figure 16 plots the
same ß<jJ vs. <jJ for several stimulus magnitudes ranging from M = 0 to M = 2.
Note the abrupt change of topology at M = 1, where the phase singularity is
encountered at <jJ = 1. This family of phase response CUlVes (PRCs) should be

-~-
o

1
6~

Figura 16. Similar to Figure 6(c) of Chapter 3, showing phase shift (advances A, upward) vs.
phase for several stimulus magnitudes ranging from M = 0 to 00. Curves of this sort are more
commonly depicted in various experimental literatures as indicated in the lower left. The
dashed segment should not be interpreted as part of the curve, but is commonly drawn or even
drawn solid.
 F: SUMMARY 159

contrasted with the family of phase response curves following from simple
dock models, in which phase shifts accumulate by modulation of angular
velocity on the ring [Figure 6(c), Chapter 3]. In that family there is no
topological change. The simple dock's strong stimulus PRC is simply an
extreme version of its weak stimulus PRC. It indudes a very steep narrow
upslope region. Nothing of the sort is seen in the models of this chapter.
Instead, all the steepness is packed into that one critical stimulus duration M
= 1 at the phase singularity.
The reason for this qualitative difference of behavior lies in the qualitatively
different mechanisms of rephasing. The simple dock achieves its big advance or
big delay to the opposite side of the cyde by advancing or delaying through half
the cyde. Because the choice between advancing and delaying depends on
whether the initial phase was just before cjJ = 1 or just after cjJ = 1, large stimuli
applied sufficiendy dose to this phase can have extremely variable results. In
contrast, the pendulum-like oscillator achieves both big advances and delays by
a process that entails a reduction of amplitude toward zero, and through zero,
and a rebuilding of amplitude on the opposite side of the cyde. The only
sensitive stage is the passage through zero amplitude, where phase is
ambiguous.

F: Summary
In Chapter 3 we thought of a single simple dock as behaving differendy along its
cyde according to the intensity of some environmental parameter such as light
intensity. Here we see the same principle in a two-dimensional state space. In the
presence of some external modifier of the system's dynamics, its state changes
along different paths in state space. In Chapter 3 we calculated the consequences in
terms of phase-dependent phase resetting. The result was a "time crystal": a
periodie lattice of unit cells composed of old phase and new phase repeats along
two axes, with a third perpendicular axis depicting some measure of stimulus
magnitude. Within each three-dimensional unit celllies a two-dimensional surface
describing new phase as a function of stimulus magnitude and the old phase at
which that stimulus was given. This "surface" proved to be a stack of separate
surfaces repeating along both phase axes.
We redo the calculation in this chapter to see whether a topologically
different kind of dynamic model implies a qualitative difference in resetting
behavior. If so then resetting behavior might provide a useful criterion for
rejecting models that are inappropriate to given experimental system. It transpires
that there is one conspicuous qualitative difference: Resetting in this two-
dimensional state space consists of aresetting of phase and a conjugate and
equally stable resetting of amplitude. There is a peculiarity of the phase response
when the amplitude is reset to zero. A specific, exacting combination of stimulus
timing and magnitude is required to guide the system to this steady state and
leave it there. At this special old phase and magnitude, new phase is arbitrarily
sensitive to details of the stimulus. The new phase surface tilts vertically and
winds around a screw axis at that point. This phase singularity links all repeats
160 5: GrnlNG OFF THE RING

along <p and <p' directions into one single surface quite unlike the stack of separate
surfaces that characterize a simple dock. We have seen this pattern in
experimental data. Chapter 4 gives us one interpretation for it in terms of
internal incoherence among many docks. Here we have another in terms of the
dynamic steady state of a single oscillator.
In coming chapters we ask which features of Figures 1 through 4 are
essential for this result. It turns out that the behavior exhibited in Figures 12
through 15 is typical of a much broader dass of less idealized biochemical
dynamics and has little to do with the equilibrium state or with stable resetting
of amplitude. But this simplest example is convenient for introducing the result,
preliminary to perceiving it in less contrived models. (It also turns out that the
fruitfly' s circadian dock behaves remarkably like this simplest caricature:
compare Figures 13 of this chapter and Chapter 2.)
 Attracting Cycles and Isochrons

In Section A of this chapter we associate aphase with each state of an attracting

limit-cyde oscillator during dynamics in the absence of any perturbing influence. In
Section B a stimulus smoothly alters the trajectories so that phase changes in
peculiar ways, even discontinuously. This analysis is intended to apply to smooth
dynamics. Accordingly, in Section C references are compiled to models that violate
this precondition and thus do not fall within the purview of this chapter.

A: Unperturbed Dynamics

Introduction
By referring everything to the purely geometrical idea of the motion of an imaginary
fluid, I hope to attain generality and precision, and to avoid the dangers arising from
apremature theory professing to explain the cause of phenornena. If the results of
mere speculation which I have collected are found to be of any use to experimental
philosophers, in arranging and interpreting their results, they will have seIVed their
purpose, and a mature theory, in which physical facts will be physically explained,
will be formed by those who by interrogating Nature herself, can obtain the only true
solution of the questions which the mathematical theory suggests.
James Clerk Maxwell, 1856, "On Faraday's Lines of Force"
We saw in Chapter 4 that the collective amplitude of a population of simple docks
can be arbitrarily small. It is determined by the distribution of phase within the
population. But this distribution is stable only in the limiting case of complete
independence among identical simple docks contributing to an aggregate rhythm.
If any interaction is allowed andJor if the simple docks' periods differ at all, then the
phase distribution does change in time and with it the shape of the collective rhythm
changes. The collective rhythm might damp out altogether as phases gradually
randomize. Or it might approach an attracting cyde as the many simple docks
entrain one another to a common frequency in a self-stabilizing phase distribution.
Under various assurnptions about the manner of interactions there might be several
different attracting cydes.
Chapter 5 is built around the idea that a single oscillator also can have an amplitude
as well as aphase. But only in physical situations characterized by symmetry principles

A. T. Winfree, The Geometry of Biological Time 161

© Springer Science+Business Media New York 2001
162 6: AnRACTING CYCLES AND ISOCHRONS

and conservation laws is it usual that dynamic systems can oscillate persistently at
arbitrary amplitude, as in the simple idealizations exploited in Chapter 5.

Attracting Cycles
We pass from Chapter 5 to this Chapter through the idea that an oscillator can
have a preferred amplitude from which it can be perturbed and to which it
regulates back again. For example, this is how the Lotka-Volterra oscillator of
Examples 2 and 3 in Chapter 5 behaves if the underlying ecological assumptions
are made a little more realistic and generic (May, 1972). This type of behavior is
typical of oscillators that tend to a stable periodic behavior. Such an oscillator's
degrees of freedom, be they few or many, affect each other's rates of change in
such a way that all eventually settle into a regularly repeated cycle. Poincare called
this a 'limit cycle" because it is asymptotically approached in the limit of infinite
time. For application to experimental science we are concerned only with
attracting (as opposed to repeUing) limit cycles. Because we seldom await the
limit of long time, and for brevity, I often drop the word limit. Thus we embark
upon a study of attracting cycles. Geometrically, an attracting cycle is a closed
ring in state space. It may be quite irregular, even knotted, in aspace of many
dimensions, but the essential feature for our purposes is that it is a closed ring
path and that all nearby paths gradually funnel onto it. The region occupied by
paths leading onto an attracting cycle is called the cycle's attractor basin. Any
states not in the attractor basin comprise that cycle's phaseless set.

A geometrically simple example is shown in Figure 1. In polar coordinates the

system is described by instantaneous phase r/> and instantaneous amplitude R. The
angular velocity r/> depends on the instantaneous amplitude and so does the rate of
change of amplitude R:
~ = A(R)

R= B(R).
 A: UNPERTURBED DYNAMICS 163

If R= KR( 1 - R) then the amplitude R regulates to the unit cirde R = 1. It does so

quickly if K is big, or spirals more gradually toward the unit cirde if K is small
[Figure 1(a); see also Box A]. If K = 0, then R == 0, so that any amplitude is stable
forever as in Figure 1 of Chapter 5.
If ~ is constant, then the period is the same at any amplitude, as in a pendulum
or a population of simple docks. If ~ is not constant, then the period depends on the
amplitude.
Note that "radius" and "angle" change their values in a nonlinear way if either of
the (generally incommensurable) coordinate axes is rescaled, e.g., by changing from
fLmolar (fLM) to molar units, or volts to millivolts. See Box G of Chapter 6.
The attractor basin is the whole plane minus the origin. The phaseless set
eonsists onlY of the steady state at the origin, R = 0.
In all these simple examples trajeetories converge toward every are along the
attraeting eyde. But in general some ares may repel trajeetories if other ares attract
more vigorously.

Latent Phase
I draw attention to this geometrie earieature of an oseillator because it helps
introduce, in an exaet way, a generalization on the notion of phase that proves erucial
for mueh that follows. In Chapter 5 we defined phase as the fraetion of a cyde
elapsed sinee some phase marker event such as the maximum of Cl or the upward
erossing of a threshold. That definition supposed that behavior was strietly periodic
following any initial eonditions. But in attracting-cycle dynamies, behavior is not
initially periodie. It is strictly periodic only in the undisturbed system and only in the
164 6: AnRACTING CVCLES AND ISOCHRONS

Box A: Simple Clocks as Caricatures of Attracting Cycles

Before leaving this section, note that for some purposes the simple dock of Chapters 3
and 4 is a suitable approximation to either:
1. A system whose state space really is §i for structural reasons (e.g., the state is the
position of a polymerase on a ring of DNA) or
2. A dynamical system of arbitrary complexity in which trajectories flow swiftly
toward an attracting cyde under all experimental conditions considered.
In terms of the models of this section, if R= 100000 x (1 - R)R then the oscillator's
amplitude regulates very swiftly to R = 1, so that for all practical purposes the system
always runs on that unique ring, except for a brief moment after violent perturbation.
Withl =1= 0, a simple dock runs on the same cyde but at phase-dependent angularvelocity.
If I enters only into the expression ~ =AO for angularvelocity and not into the expression
R =BO for amplitude regulation then the same is true of this attracting-cyde model.
It is also true in good approximation if the stimulus (I =1= 0) adds anything to the
oscillator's kinetics that is too weak to substantially oppose the violently amplitude
regulating R = B(R). Then R is still confined dose to the unperturbed cyde and we
need deal only with alterations of its angular velocity. Thus its dynamics can be
summarized in a sensitivity function Z(t/», representing the fractional deviation of
angular velocity from its unperturbed unit rate, per unit stimulus, that is per unit
deviation from standard environmental conditions. This Z(t/» (Winfree, 1967a) is the
velocity response curve of Swade (1969), Daan and Pittendrigh (1976a,b), and
Pittendrigh and Daan (1976a,b,c). In the notation of Chapter 3, the angular velocity of
a simple dock is denoted v(t/>,l). Performing a Taylor series expansion in I gives ~ =
v(t/>,I) = 1 + (I - 10)Z(t/» + neglected terms in higher powers of (I -/0). This extreme
version of an attracting cyde has been called a generalized relaxation oscillator
(Winfree, 1967a; Swade, 1969; Kramm, 1973; Goodwin, 1976). The term originated in
the idea that relaxation oscillators (see Section C) adhere very dosely to an attracting
cyde that indudes a jump. The generalization consists in embracing smooth cydes as
weIl as nearly discontinuous cydes. See also Box A of Chapter 9.
Kuramoto (1975) takes this limit explicitly, reducing the A - W oscillator to a simple
dock in order to simplify the calculation of mutual entrainment in populations. In place
of my single influence and sensitivity, he invokes an orthogonal pair of conjugate
influence-sensitivity pairs, coupling oscillators by

~ = 1 +sint/>jCOSt/>i - cost/>jsinifJ; = 1 +sin(ifJj - ifJ;).

The symmetry of this coupling facilitates analysis as noted in Winfree (1979) and
above, pp. 126-27.
Levinson (1950), Neu (1979a,b,c) and Rand and Holmes (1980) show mathematically
just how a D-dimensional oscillator with a strongly attracting cyde can indeed be
reduced to the simple-dock approximation, as merely assumed in Winfree (1967a) with
hand-waving arguments.

limit of long time. So a more practical definition is called for. A notion that naturally
recommends itself is the latent phase: One waits until the perturbed system reverts to
regular periodism, and then extrapolates that rhythm back to the time in question to
discover its latent phase at that past moment. Equivalently, one might start a "test"
 A: UNPERTURBED DYNAMICS 165

system at time 0 in some state whose latent phase we wish to know and
simultaneously start another on the cycle at phase zero. After a long time both are
on the attracting cycle but the test system is some fraction ifJ ahead of the control.
Then ifJ is the latent phase of that initial condition. 1
This is in fact how physiological experiments are conducted. For example,
suppose a periodically firing nerve cell is electrically stimulated. During that
stimulus the cell's rhythmicity is disrupted. When the stimulus is removed the
membrane is left in some peculiar state not necessarily on the cycle. From that
initial condition, its normal rhythmicity recovers during the subsequent
unperturbed free run. The phase of that recovered rhythm is recorded. By
comparison with the control rhythm or by extrapolation back to the moment
when the stimulus ended, the latent phase reached at the end of that stimulus is
measured (Chapter 14, Section A). The same format has been used to explore
the dynamics of circadian docks (Chapters 19, 20, 21), of biochemical
oscillations (in the slime molds of Chapter 15; and in the yeast cells of Chapter
12), and of the cell cycle (Chapter 22). In these and many other cases,
attracting-cycle models have been proposed to link the observed rhythmicity to
plausible biochemical kinetics.
It is useful to develop a little bit of abstract geometry about the relationship
between latent phase and an attracting-cyde oscillator's state. The pair of
equations above gives us a way to start thinking about it. Now that we have
quit thinking of the state space as a ring, phase and state are no longer
synonymous. Now phase is some function of state.· What kind of function? The
next section defines it analytically for the special case of polar symmetric two-
variable kinetics represented by the pair of equations above. [Guckenheimer
(1975) gives a far more general, precise, and rigorous treatment for state spaces of
arbitrary finite dimension and topology. He also treats examples of the sort to
which we now turn. Also see Kawato and Suzuki (1978).]

The Isoehrons of Symmetrie Attracting Cycles

We resort once again to useful jargon: Any set of states having the same latent phase
ifJ is called an isochron, specifically"isochron ifJ" (see Box B). Suppose as above that
~ = A(R) withtheunitoftimechosensothatA(Ro) = 1
and
R= B(R) withB = oand dB/dR < 0 at some positive Ro.
This is the simplest attracting-cycle oscillator. If there is only one such R o then
Ro is a unique attracting cycle and we mayas well scale R to make R o ;:: 1.

Unknown to this biologist before 1974, existence proofs for ordinary differential equations are to be
found in Coddington and Levinson (1955, Theorem 2.2, p. 323); Haie (1963, Theorem 10.1, p. 94); Haie
(1969, Theorem 2.1, p. 217); in Hirsch and Smale (1974, Theorem 13-3 p. 284-5), in Fenichel (1974, 1977)
and, for functional differential equations, HaIe (1977, Theorem 3.1, p. 242) where it is called "asymptotic
phase."
166 6: ATTRACTING CYCLES AND ISOCHRONS

Box B: On Definitions of Isochrons

I invented isochrons in 1967 to help me think about timing relations in oscillators

perturbed off their attracting cycles. This is important in physiological applications
because biological oscillators are almost never on their attracting cycles. The term
isochron has since been used in a number of senses, some only subtly different and
some radically different. This Box provides abrief overview.
As used in the series of papers begun in 1967, an isochron is a certain set of
phase-equivalent initial conditions in the state space of any process that immediately
or eventually runs at a fixed period that we take as a unit of time. These initial
conditions are equivalent in the sense that they lead to rhythms that are
synchronous in whatever operational sense we have adopted. Thus an isochron is
the inverse image of a point in §I for a map cJ : X ...... §I from the state space X of
an oscillator to the circle of phase §I. In the simple clocks of Chapter 3, the only
admissible initial conditions are all on the cycle: X = §I. Thus no two initial
conditions Xt. X2 € X are equivalent unless they are identical. If they are not
identical, the rhythms begun from such initial conditions differ by a phase shift
cJ(X2) - cJ(XI). The notion of an isochron first acquires nontrivial interest in Chapter
5, where we consider models that run stablyon cycles of various amplitudes. In this
situation, rhythms of different amplitudes might be considered equivalent if they go
through their maxima at the same time or if they cross a threshold at the same
time. If, as in the present chapter, we are talking about a limit cycle process and
initial conditions in the attractor basin of that cycle, then initial conditions are
considered equivalent if oscillators started at those initial conditions funnel
synchronously onto the cycle. In this case trajectories from any initial conditions
on the same isochron eventually become indistinguishable, and trajectories from any
other isochron eventually differ only by a time translation equal to the latent phase
difference cJ(X2) - cJ(XI) or the cophase difference (1 - cJ(XI» - (1 - cJ(X2» between
those two isochrons.
It is helpful to visualize isochrons by thinking in terms of a stroboscopic
presentation of dynamics in the oscillator's state space, as folIows. Taking the cycle
period as I, we start an oscillator at any initial condition at time 0 and look again to
see what state it has reached at unit intervals thereafter. If we happened to start
exactly on a closed ring trajectory (the only choice for oscillators of the sort
considered in Chapters 3, 4, and 5), then at each later observation it will be back to
exactly the same state. The same will be true of an attracting-cycle system only if we
start the oscillator exactly on the attracting cycle. But more generally, at each
successive look we find the oscillator's state closer to the attracting cycle. The
sequence of states reached approaches a cluster point on the cycle. All these points lie
on the same isochron (see Figure below). I believe this is true even near a segment of
the globally attracting cycle that happens to be locally repelling.
I have used the term isochron sometimes to mean a locus in state space as above,
but sometimes also to mean a set of stimuli, i.e., a locus in the (<pM) plane or cylinder.
These are the stimuli that evoke synchronous rhythms by pushing oscillators onto a
given isochron set in state space. Thinking of the stimulus space as a map into state
space as in Figures 5-11, we see that a given isochron appears in stimulus space where
the image of stimulus space intersects that isochron in state space.
In terms of cophase, an isochron is the locus of constant cophase but the cophase
intended can refer to a function of state, or to a function of stimulus parameters that
achieve the required state."
 A: UNPERTURBED DVNAMICS 167

Points on a trajectory spiraling toward the attracting cyde are

made to emit a flash of light at unit intervals of time. The
sequence of such points converges to a fixed point on the cyde,
outlining an isochron.

Guckenheirner (1975) applies topological analysis to prove the existence and

main properties of isochrons in the attractor basin of a limit cycle 1• He inquires into
the conditions on state space topology and "genericity" of dynrunics that hedge in my
conjectures (Winfree, 1974c) about isochrons and their phaseless set. Guckenhei-
mer's paper and mine are reprinted together in Levin (1978).
Kauffman (1974) refers latent phase not to the attracting cycle but instead to the
next threshold crossing as in Example IV of Chapter 5. This may be viewed as an
experimentalist's approximation to the measurement of latent phase in real
physiological systems that take an inconveniently long time to approach their
attracting cycles. Or it might be viewed as a different definition of latent phase, in
which the isochrons have somewhat different topological properties than those
considered above. Pavlidis (1973), Pinsker (1977), and Kawato and Suzuki (1978) also
use this definition of latent phase, focusing on only the very next event and ignoring
the regular rhythmicity presumed to persist a long time after the stimulus (after any
transient irregularities have died out).
The word isochron has also been used in quite different senses not to be confused
with any of the above by
1. Bouligand (1972a), to mean the locus in physical space along which cuticle is
simultaneously deposited;
2. Moe et al. (1941), to mean the loeus of simultaneous excitation during
propagation of an electrical wave in heart muscle (Chapter 14); later cardiac
electrophysiologists mutated it to "isochrone";
168 6: ATTRACTING CYCLES AND ISOCHRONS

3. Pinsker (1977) ("isochronous") to mean "having the same period" as in Christian

Huygens' Horologium Oscillatorium (1673): "Pendula isochrona vocentur, quorum
oscillationes, per arcus similes, aequalibus temporibus pernguntur." (There is now a
1986 English version: see Index of Author Citations and Publications on p. 698.)

Since the dynamical flow has polar syrnmetry, the isochrons must also have
polar syrnmetry:
!P = g(fjJ, R) = fjJ - f(R).

Now the latent phase !P necessarily increases at unit angular velocity as the
oscillator follows its kinetic equation. Thus we write

so
df ~-1
=
dR R
This is a differential equation for f(R). We can integrate it and then obtain g(fjJ, R).
Given an antidockwise attracting cyde, the sign of d{!dR teIls whether isochrons
wind clockwise (+) or antidockwise (-) out of the origin; this may, of course,
change as R changes.
Example 1 and Figure 1. Suppose
R = 5(1- R)R Figurel(a)
~=1 Figurel(b)
then
df
dR=O

so
[(R) = constant, chosen so !P = 0 at R = 1 and fjJ = O.
so
!P =g(fjJ,R) = fjJ Figure1(c)
With A(R) constant the isochrons are radial, as noted above .
. In this case, the latent phase corresponds perfecdy with the simplest local
instantaneous definition of phase, viz., the fraction of a cyde elapsed between
extrema of x or y. This is exceptional. Isochrons are more commonly complex curves.
They usually differ from such loeal definitions of phase as one might be tempted to
invent. This is illustrated in the next example.
Example 2 and Figure 2. Suppose
R = 5(1- R)R2 Figure2(a)
~=R Figure2(b)
 A: UNPERTURBED DVNAMICS 169

R 1.5

R o
1.5

.8

(al ( bl (cl

F1gure1. (a) R= 5R(1- RI. (b) A single trajectory ofthe dynamical scheme described in the text.
The unit cirele is an attracting limit cycle. (c) Isochrons of the same dynamic, marking off
intervals of one-fifth cyele along all trajectories in the attractor basin of the cycle. Trajectories
begun on any isochron reappear on it at unit intervals of time, closer to the point R = 1.

Here the trajectories have the same geometry hut the state traverses these
trajectories at speedsR times fasterthan in Example 1. In this case the angularvelocity
~ is no longer independent of amplitude, hut rather increases in proportion to R. Thus

df R-l 1
= =
dR 5R(1- R)R - 5R2
so

1
f(R) = 5R + constant
so

. 1
if! = g(4), R) = 4> - 5R + 0.2 Figure 2(c).

Thus the isochron structure elose to the repelling focus of this two-variahle
kinetics consists of tight spirals. In contrast to the straight-in radial isochrons of
simple elocks (Chapter 3), elockshops (Chapter 4), and harmonie oscillators

R
ot"--+--I---<\.5
~o .6

(0) (bI (cl

F1gure 2. (a) R =5R(1 - RlR. (b) As in 1a except both components of velocity are multiplied bya
scalar fjeld, leaving directions unaltered. (c) The changed isochrons reflect the radial
dependence of angular velocity.
170 6: ATTRACTING CYCLES AND ISOCHRONS

Box C: Isochrons in Nonsymmetrical Kinetics

The example on display here is taken from FitzHugh (1961). FitzHugh sought a useful
simplification of the Hodgkin-Huxley equation. He found it in a second order cubic
polynomial equation constructed by hybridizing Bonhoeffer's (1948) model ofiron wire
excitability (see also Box B in Chapter 14) with van der pors (1926) model ofthe heart-
beat. This "FHN" model mimics a pacemaker neuron with a repelling steady state and
an attracting cyde. I computed its isochrons as folIows:
1. The attracting cydewas found byintegrating the rate equations numerically. Apoint
from the cyde is chosen arbitrarily to be phase o. The cyde period is taken as unit
time.
2. An arbitrary initial state was chosen and once again the rate equations were
integrated by iterating the difference equation in steps t1t until the state comes
within a smalI tolerance of phase 0 on the cyde.
The isochrons are interrupted where the calculation becomes too delicate, along the
spiral separator. Coordinates are as in Figure b but the region near the steady state is
here greatly enlarged. All trajectories (not shown) are dockwise exponential spirals out
of the steady state, cutting isochrons at unit rate. The dashed CUlVe is the lower right-
hand arc of the attracting cyde shown complete in part (b) of this figure.
3. Backing up along that trajectory, the latent phase was noted at each step as tJ.j =
-Nilt modulo 1, N being the step number.
4. This was done for many different initial states.
5. The isochrons were sketched through states of equallatent phase at intervals of
one-tenth cyde. From states on one isochron, the time to phase 0 is the same,
modulo 1. All trajectories pass from one isochron to the next at intervals of one-
tenth cyde.
The results near the steady state are shown in Figure a. For purposes of convenience
a linear transformation of variables was effected in plotting the trajectories and
isochrons. This was done in order to display trajectories near the steady state as
exponential spirals and to give the whole diagram polar symmetry. The isochrons
approach the steady state in a distinctly complicated way.
Further out, the trajectories approach their attracting cyde and the isochrons behave
as one might expect intuitively:
1. They are packed dose together near the strongly divergent trajectory, or
separator, that represents a threshold for excitation (Figure b): A slight
displacement of state where the system is in one of these states elicits a big
change of phase in its eventual rhythm.
2. A small depolarizing (excitatory) pulse advances phase during the depolarizing
phase of the action potential and delays it during the relatively refractory recovery
interval. Hyperpolarizing (inhibitory) pulses have the opposite effect.
 A: UNPERTURBED DVNAMICS 171

a
,,,
8
7

,
t

I
I 9
6

ffi

5
b -~ ... ------.......,
~- \

(a) Similar in principle to part (c) of Figures 1 through 4. The isochrons are calculated in the
linear region near the steady state of FitzHugh's FHN model of pacemaker activity in nerve
membrane:

X=C(Y+X_~3+Z)
iJ = -(x - a + by)/c
a = 0.7 b = 0.8, c = 3.0, z = -0.4

(b) Similar in principle to parts (b and c) of Figures 1 through 4. Isochrons are solid curves.
Trajectories (dashed) wind out of the repelling steady state and diverge along the spiral
separator. The picture is somewhat skewed from the conventional representation in FitzHugh's
Figure 5 [see depolarizing (0) and recovery (R) variables] by the linear transformation required
to symmetrize the spirals near the steady state. Figure (a) enlarges that region.
172 6: ATTRACTING CYCLES AND ISOCHRONS

Box D: A Measurement Problem

Does the ornate structure of isochrons near their convergence point provide an
experimental distinction between such oscillators as we considered earlier and the
attractingcycle dynrunics under consideration in this chapter? It might, but only in
principle.
In practice, isochron structure is poorly resolved near the isochrons' convergence.
The models of Chapters 4 and 5 have unusually low-amplitude rhythmicity in this
region. That implies unusual difficulty in measuring phase with adequate precision
near the region of convergence. It also means that the system is particularly susceptible
to the random perturbations that chronically afflict any real experiment, especially
biological experiments. Maybe in dealing with an attracting-cycle mechanism, as in this
chapter, one might escape that difficu1ty because the amplitude will regenerate. Why
not wait for normal amplitude to recover, then measure phase and extrapolate back to
that earlier moment when amplitude was too low? This works fine if regeneration is
swift but the longer the wait, the greater the imprecision of phase measurements.
Extrapolation is not accurate across manY cycles during which random perturbations
are always creeping into the experimental system. In every case, the mere fact that the
isochrons do converge means that high resolution is essential. Slight variability in
stimulus timing, or in the sensitivities of individual biological organisms, has a
disproportionate impact on phase measurements near a convergence of isochrons, e.g.,
see measurements of this variability in Winfree, 1974, Appendix, for the Drosophila
circadian system. In short, data variance is typically greatest in the very region where
highest resolution is needed to distinguish the isochrons. Because measurement is so
imprecise near a singularity, there is little point in deploying refined models. The screw
surfaces and pinwheel contour maps I have fitted to data have all had the simplest,
plainly radial isochron structure near the phase singularity.
 A: UNPERTURBED DYNAMICS 173

(Chapter 5), those associated with attraeting eycles typically exhibit ornate
nonmonotone strueture near their convergenee (see Box C). Only in perlect1y
symmetrie models with only two variables is this structure as simple as the
bundle of spirals derived above. And in such cases, the spirals degenerate to
radial lines as in Example 1 only if the angular velocity A is independent of
amplitude (see Box D).
Example 3 and Figure 3. Suppose
R= (1- R)R Figure 3(a)

~ = 1 +c(1- R) Figure 3(b)

so

so
f= c In R + constant
so
4i=cfJ-dnR Figure 3(c)
'this example shows that the isochron spiral can turn either way relative to
trajectories, depending on the sign of €.

~
\~
(ol
• ( bl
~)
(cl
.B

Flgure 3. {al R= R(1 - I?}. {bl As in 1{al but radially five times slower and azimuthally somewhat
dependent on radius. {cl The isochrons make exponential spirals into the origin, in contrast with
the hyperbolic spirals of Figure 2{cl.
174 6: ATTRACTING CVCLES AND ISOCHRONS

Example 4 and Figure 4. Suppose

Figure4(a)

~= 1 +c(1-R) Figure4(b)

The point here is to examine a self-sustaining oscillator that is not also self-exciting
(examples: the circadian dock models of Kalmus and Wigglesworth (1960) and of
Pavlidis and Kauzmann (1969); Teorell's (1971) mathematical model of pressure-
sensitive neural pacemakers; my own computation of isochrons for pacemaker neIVe
membrane with Best (1976, 1979) and its confirmation by Guttman et al. (1980) in
squid axons; Aldridge and Pye's (1979) theory and measurements of oscillating
glycolysis in yeast; Johnsson's (1976) and Johnsson et al.'s (1979) on oscillatory
transpiration, and Jalife and Antzelevitch's (1979) measurement of cardiac pace-
maker cells; and in 1999 there are also Kapral (1987), Anumonwo et al. (1991), and
more examples cited in Guevara and Jongsma (1992»:

df
dR= 5R(R-!)
c
=
(1R-! 1) *S'2
-R
c

For R < !, iP will go undefined. For R > !

2c R-!
f = Sln ~ + constant
so

Figure4(c)

The phase singularity in this case is not a point but the whole codimension-1 border
of a black hole. (This provides an alternative mechanistic basis for Example 4 of the
preceding chapter.)

.2

R
0+-+-+--1l.S

-1.5

( cl (bl (cl

Figure 4. (a) R= SR(1 - R)(R - ! ).

(b) The azimuthal equation is as in Figure 3(a) while the radial
equation is modified to create a repelling cycle at R =!-
Trajectories inside that radius wind into
!.
the attracting equilibrium. (c) The phaseless set is the disk R = Along its border all isochrons
converge (as they did in Figures 1(c), 2(c), and 3(c) but with R = 0).
 A: UNPERTURBED DVNAMICS 175

Phaselessness vs. Timelessness

In all the above examples, the phaseless set is an equilibrium or its attractor basin.
Ambiguous phase is achieved by timelessness in these cases: the system ceases to
change state. Do not be deceived by simple examples to imagine that this is
necessary or even usual. Even in kinetics involving only two variables as above, the
phaseless set could consist in part of quite lively states, e.g., it could be the attractor
basin of a different cyde. A phase singularity is not necessarily timeless, but only
indeterminate in respect to the phase of a rhythm of specified period.
To assume that any given physiological oscillator has exacdy two important
degrees of freedom is of course a rather special assumption. It is a common
assumption because two is the minimum number needed to describe an attractor
basin around a cyde. Two is also the maximum number of dimensions compatible
with a number of widely used analytic and graphie techniques required for exact
mathematical solution of models. However, the features that I would bring out do
not rely on this restrictive ad hoc assumption. They do not rely on the geometry of the
plane, and they do allow us to treat the more complex models which are becoming
common in the 1970s literature of physiological and biochemical control systems
(BoxE).

Oscillators of Greater Complexity

The main principle involved in generalizing from 1 to an arbitrary number of
dimensions has been encountered before (page 27). It is that a disk cannot be
mapped continuously onto the phase ring unless the winding number of phase
along the disk's rim is zero. This principle applies as follows in context of latent
phase in a D-dimensional state space. Suspend from the attracting cyde any
simply connected two-dimensional surface, i.e., a cap whose boundary is the
attracting cyde. Now ask what is the latent phase q, of each point in this cap?
Around the boundary q, = 4J: Its winding number is 1. Thus q, cannot be assigned
in a continuous way to all points in the cap. Theremust be a discontinuity. This is
true of ever)' cap that can be hung on the cyde. Thus the necessary point of
discontinuity in each cap is that cap's interseetion with a phaseless locus of at
least D-2 dimensions. That locus threads the cyde, in the sense that it penetrates
every cap.
How does this peculiarity of q,(x) relate to anything obsetvable in the phase
relations of perturbed oscillators? This is the subject of the next section, but let's
first tidy up this seetion by summarizing the essential and generalizable features of
latent phase seen in the foregoing examples:
1. Within the region of state space from which all trajectories lead to the eyde (its
attractor basin), every state has a unique latent phase q,.
2. States having the same latent phase lie in a single connected continuum of
dimension one less than the dimension of state space. I call these continua
176 6: ATIRACTING CVCLES AND ISOCHRONS

Box E: Dynamics Involving Three or More Interacting Variables

By conceptually simplifying a system to a single-variable kinetic model, we lose track of

phenomena thatare conspicuous in the laboratory. The same is often true ofsimplification
to onlytwo variables. In matters ofphysiology and biochemistryitis no mere affectation to
abjure reliance on mathematical methods that fall when a third or fourth variable comes
on stage. Anyaction involving two ormore oscillators, forexample, transpires in aspace of
at least four dimensions (except in the most emasculated approximation, that makes one
or both into a simple clock). Any action transpiring in space, in a continuum of coupled
oscillators, is properly described by a partial differential equation. This may be written in
approximation as a set of many repeats of the ordinary differential equations of kinetics,
one foreach volume element, thus multiplyingthenumberofdimensions bythenumberof
volume elements considered. Kinetics portrayed in terms ofa time delay likewise require a
partial differential equation or approximation by a high-dimensional ordinary differential
equation. You will also find in perusing the bibliography of Chapters 12 -14 that realistic
chemical kinetics seldom involve as fewas two major interacting variables. Three or four
are typically involved in the models employed to mimic oscillating glycolysis in yeast,
cAMP pulsation in slime molds, altemating oxidation and reduction in the malonic acid
reaction, and the permeability interactions in neIVe membrane.
It is not unusual for smooth dynamics involving three or more variables to exhibit
chaotic behavior. Oscillators and coupled sets of oscillators seem especially susceptible
to such departures from periodicity. See 1976-79 papers of Rössler.

isochrons, meaning same-time loci. The isochrons fill up the attractor basin of
the cycle.
3. The isochrons never intersect (except that they merge on the basin's boundary.)
4. Bach of these isochrons cuts the cycle at one and only one point, in order
around the cycle.
 B: PERTURBING AN AnRACTING-CYCLE OSCILLATOR 1n

5. ~ changes at unit rate along all trajectories in the attractor basin. Therefore, the
isochrons are transverse to trajectories everywhere inside the attractor basin.
6. Initial conditions (states) outside the cyele's attractor basin have no latent phase.
This phaseless set of states ineludes all steady states of the dynamics as wen as
the trajectories leading to such steady states (their "attracting manifolds").
7. Along the boundary of the attractor basin all isochrons typically converge in
such a way that they all become arbitrarily elose together. This boundary, the
phase singularity, has either one or two fewer dimensions than the state space: it
has codimension 1 or 2. A piece of it also threads the cyele.
8. The phase singularity has nothing necessarily to do with timelessness. It only
indicates failure to return to the standard mode of rhythmicity.
In the above models we used unperturbed dynamic equations (1 = 0 implicitly)
to determine the latent phase function of state ~ = g(x): 1R2 _ §I. Then we plotted its
contour map in state space by plotting the locus of states (the isochron)
corresponding to each ~. We did not inquire into behavior during perturbation
(I 1= 0). The next section does this and in so doing shows how to transfer the
isochrons onto aspace of experimental stimuli, which is our only window into the
state space of a system whose mechanism and state variables are still unknown.

B: Perturbing an Attracting-Cycle Oscillator

Introduction
In most of the experimental situations gathered into this book we deal with systems
that are eventually regularly rhythmic. Because we don't know what complexities of
physiological dynamics mediate between the oscillator we wish to study and our
more peripheral rhythmic observable, we cannot easily interpret any observations
preceding establishment of that standard rhythmic state. But once that condition is
achieved, aphase displacement of the observable rhythm may be taken to reflect an
equal phase displacement of the underlying oscillator. In other words, in the last
analysis our only reliable observable is the oscillator's latent phase. This function of
its state was deduced from sampie dynamic equations in Examples 1-4. The states
of equallatent phase were there plotted as isochrons. Having drawn the isochrons in
state space, we can now forget about trajectories and their equations.
But all this pertains only to the standard environmental conditions, the
unperturbed condition we denote by 1 = O.

Perturbed Trajectories
In the presence of a stimulus (by definition), the oscillator's dynamic is altered. Its
state no longer moves from one isochron to the next at unit rate. How does it move?
We must draw trajectories again as we did in Chapter 5, Figures 3, 4, 6, 8. Nothing of
those diagrams is changed in principle in this chapter about attracting cyeles. The
only new feature introduced in this chapter is that the isochrons are generally
wiggly curves instead of straight lines. The topological outcome is the same.
Whether we consider cophase (the event latency after stimulus) or latent phase ~
178 6: ÄTTRACTING CVCLES AND ISOCHRONS

(a function of the state reached at the end of the stimulus) or new phase <P' (of the
poststimulus rhythm, extrapolated back to the end of the stimulus), the graphs
above the stimulus plane (<p, M) all resemble a lattice of screw surfaces when plotted
in the three-dimensional time crystal. Recall also that we may conveniently speak of
that three-dimensional graph in terms of its contour map on the stimulus plane. The
contours being Iod of equal time of an event, latent phase resembles a pinwheel
wave when plotted as a contour map on the stimulus plane.
The purpose of this section is to put those observations in a more general
context. This seems to be called for because the qualitative features of resetting
behavior seem remarkably independent of many quantitative details of model
equations and because in real physiology we seldom have equations anyway, nor
do we know how to define the state space in which to draw the trajectories and
isochrons that such equations would describe. Can we set aside these
hypothetical constructs to deal only with what we can observe? The following
argument may provide a step in that direction, to be pursued experimentally in
Chapter 7.
We suppose a dynamical system whose state may be represented by a point in giJ.
We suppose the system tends to an attracting cyele, which is some elosed ring in RD ,
not necessarily circular, possibly even knotted. The essential feature is only that it has
the topological connectivity of § 1. We suppose also that every point x in that cyele's
attractor basin in prindple has a latent phase ~ = g(x), defined on the cirele §1.
Let us suppose that when a stimulus begins at time t = 0 the oscillator is
somewhere on the attracting cyele. In general it departs from that cyele during the
stimulus. After a time 1).t, oscillators initially on the cyele have moved to other states
as schematically indicated in Figure S. Assuming continuity and smoothness of the
dynamics, those new states at time t = 1).t also lie on a ring: a distorted version of the
ring of initial conditions along the attracting cyele. If the stimulus continues (and so
the perturbed trajectories extend to t = 21).t) then the set of states arrived at is another
ring, further displaced from the attracting cyele. We are defining a two-dimensional
surface in the state space giJ. This surface is fibered by the perturbed trajectories,
each from a different initial phase <p, and, criss-crossing that ruling, by the rings, each
for a different duration t of perturbation. The surface is an image of the stimulus
plane (<p,t) mapped into state space. Topologically it is a cylinder like a windsock
blowing from the attracting cyele. Where it intersects the isochron surfaces in state
space we have the isochrons of stimulus space, the Iod of stimulus combinations
(<p,t) that are equivalent in that they evoke synchronously reset rhythms.
Suppose some kind of rhythmicity persists under indefinite prolongation of the
stimulus, as is the case for circadian rhythms exposed to dim enough continuous
light and for pacemaker neurons biased by a small enough electrical current. Then
the rings approach a limiting ring along which the state continues to drculate at a
new period. This is the system's attracting cyele under conditions of continual
exposure to the stimulus. The set of states reached by such stimuli thus constitutes a
cylinder, as in Figure S(a).
But suppose the perturbing stimulus is such that the system is eventually brought
to rest at a unique equilibrium. This is the case for some circadian rhythms exposed to
prolonged artificial daylight, and fornerve in a voltage-clamp device and foroscillating
glycolysis suppressed by oxygen (the Pasteur effect). In geometric terms all trajectories
 B: PERTURBING AN ATTRACTING-CYClE OSClllATOR 179

o
Figure 5. (a) Points initially on the attracting cycle at time t = 0
are "blown" off it during exposure to a stimulus. The trajectory
from one initial point is shown with arrows. The ring of all initial
points progressively deforms and moves to a new attracting
cycle as t -> 00. (b) As above. but the cycle degenerates under
continued exposure: The stimulus forces the system to a
steady state regardless of its initial phase. For examples in
context of circadian rhythms, see Peterson and Jones (1979)
and Peterson (1980a).

converge to that rest state, the standard starting state from which trajectories
approach the attracting cycle again in permissive conditions. So the two-dimensional
cylindrical surface converges to a point, like a cone (Figure 5(b». Incorporating that
point, the surface is closed. It is a two-dimensional cap bounded only by the attracting
cycle (attracting under unperturbed conditions, in the absence of the stimulus). This
cap is topologically equivalent to a disk whose boundary (cf>,O) is that cycle.

Topology to the Rescue

We know a theorem about mapping such a disk to §i, as we implicitly assigning a
latent phase i/! € §I to each stimulus (cf>,t): the map cannot be continuous unless the
winding number of ip around the boundary (cf>,O) is O. But it isn't. By definition, i/!; ::
cf> around the cycle: The winding number is 1. So i/! cannot vary with stimulus
coordinates (cf>,t) in a continuous way.
What kind of discontinuity might be expected? Since there is no discontinuity
along the boundary, it must be a closed locus inside the cap. That locus could be as
small as a point at which the isochrons converge. This is our minimum phase
singularity. It does not commonly lie at the apex of the cap in Figure 5(b): If it did,
the rhythm would start at no definite phase upon reversion to permissive
conditions. So in general, the phase singularity can be reached by following some
perturbed trajectory from a particular phase, cf>* for a particular finite stimulus
duration T*. In other words, regardless of the complexity with which any number of
variables may be interacting in a rhythmic system, some point of the phaseless set
can be reached by varying stimulus parameters in only two ways.
What does a point in the phaseless set correspond to physically? It is most likely
not an equilibrium of the unperturbed dynamics. This is because for D > 2, any two-
dimensional cap oftrajectories altogether misses most points (e.g., the equilibria) in
W>. There seems little to be said about it apart from discussion of a specific dynamic
180 6: ATTRACTING CYCLES AND ISOCHRONS

Box F: Phase Compromise in Chemical Oscillators

One way to construct a cap across an attracting cycle in state space is to perturb the system
from thecycletowardafixed point. Wehave seen thatthe setofstatesso reachednecessarily
encounters aß isochrons and encounters their convergence point in the phaseless set.
There is another way, too. By mixing two chemical oscillators one creates an
oscillator of hybrid composition. Suppose the two "parents" are identical but for timing,
and both are on their common attracting cycle, and that aß their state variables are
substance concentrations that quickly reach an intermediate compromise. Then the
hybrids initiaßy occupy states on straight lines joining the two parent phases in state
space. By fixing one parent's phase and varying the other as well as the volume ratio of
the two parents, one can explore a two-dimensional set of states bounded only by the
attracting cycle: a cap (Figure below). This cap necessarily intersects the convergence of
isochrons, the phase singularity along the common boundary of the phaseless set and the
attractor basin (which are the same thing unless the phaseless set has codimension 0).

By mixing two copies of a chemical oscillator, of different volumes,

at different phases, one achieves chemical compositions inter-
mediate between those mixed. The set of all such hybrids
constitutes a cap bounded only by the attracting cycle.

Note that this can be done for any choice of the one parent's fixed phase. Thus in an
experiment varying both parent's phases at fixed one-to-one volume ratiothe singularity
is encountered twice: once as above and once under an exchange of the two parents'
phases and relative volumes. (See also Box A of Chapter 22.)
An exception arises in the special case of aplane circular cycle with a repelling steady
state at its center. Then by combining equal volumes of any twO geometricaßy opposite
phases, one creates the state at the convergence ofisochrons, viz., the central steady state.
This phase discontinuity thus appears not as two isolated points but as a one-dimensional
curve in the (<PI ,<P2) plane. Afullerpresentation ofthe relevant geometry is given in Winfree
(1974c and Chapter 7 of 1986a). It turns out that the phase singularity occurs along a one-
dimensionallocus in the three-space of <PI, <P2 and the volume ratio. In the exceptional case
mentioned, this locus is a straight line falling exactly in the equal-volume plane.
 B: PERTURBING AN ATTRACTING-CYCLE OSCILLATOR 181

Box G: The Dilemma of ''The Man Without aMetrie"

Figures 1 through 4 assume an underlying state space homeomorphic to the surface on

which they are printed. If, as must usually be the case, the actual state space has more
than the two dimensions of this paper's smooth surface, we can still get by. We just say
that the picture shows only the two-dimensional set of states encountered along
trajectories departing under the standard stimulus from the ring of different possible
initial conditions. The isochrons are then one dimensional intersections of this surface
with the higher dimensional isochron surfaces or hypersurfaces of dimension D-l, as
in Figure 11. Whatever the interpretation, we are concerned only with the relative
geometry of the perturbed trajectories and the unperturbed trajectories. That is what
deterrnines how the dock changes phase under diverse combination of stimulus timing.
So someone could come along and deform the underlying state space arbitrarily,
stretching it here, twisting it there, compressing it elsewhere. 1t doesn't matter as long as
the deformations are merely quantitative and do not violate the topological connectivity
of the space. In other words, this is rubber sheet geometry, in which scissors, pins, and
razor blades are disallowed. Also such quantities as "radius" and "angle" have no
absolute meaning because the several coordinate dimensions are not calibrated in
commensurable units. As long as the perturbed and unperturbed trajectories (and
therefore the isochrons) are deformed together, the resetting behavior is unaffected.
Thus the resetting behavior of any simple smooth kind of oscillator can be obtained from
much more complicated oscillators, even from oscillators in which things change
abruptly and trajectories shoot across great distances at lightning speed, as in relaxation
oscillators. To argue that a pattern of resetting behavior indicates a quantitative feature
of the underlying oscillator, it is necessary to know apriori how that oscillator works,
either in the presence or the absence of the chosen stimulus. 2 Resetting behavior reveals
only a companson between perturbed and unperturbed dynamics.
This simple fact seems to me to invalidate any inference from dynamics observed
experimentally to the many kinds of dynamic model or metaphor that populate the
Journal of Theoretical Biology, the Bulletin of Mathematical Biophysics, Biological
Cybernetics, the Journal of Mathematical Biology, etc. Quantitative inference works only
in the other direction, Le., from an assumed mechanism to the expected resetting
behavior. Departures from such behavior, if large enough, might be taken to exdude the
underlying hypothesis about mechanisms. But concurrence with observation proves
nothing.
On the other side of the coin, certain kinds of resetting behavior cannot occur unless
the state space has the right connectivity and enough dimensions to allow trajectories
the required elbow room in which to maneuver. Thus certain qualitative patterns of
resetting behavior (e.g., negative slope in aresetting curve) suffice to exdude certain
topological categories of mechanism (in the same example, mechanisms based on
modulation of angular velocity along a single, circular, state coordinate). And some
conspicuous structures that must occur in ~, such as a phaseless set threading the
attracting cyde, need not occur in spaces of other topology, such as the cylindrical state
spaces of rotating machinery (Andronov, et al., 1966, Chapter 7).

2 Conditions are more favorable in phase compromise experiments with chemical oscillators.
When two volumes of reaction at distinct phases are mixed, each perturbs the other in a known and
simple way, viz., taking a weighted average of concentrations. See Box F.
182 6: ATTRACTING CYCLES AND ISOCHRONS

Box H: Resetting Curves For Multiple Stimuli

Campbell (1964) initiated the practice of analyzing entrainment of biological rhythms

in terms of regular alternation between two environments, and thus between two
dynamics. (He had in mind synchronization of the mitotic cyde by rhythmic alternation
between two growth temperatures.) This technique is useful not only for his simple
dock, but also for any oscillator that quickly recovers to an attracting cyde in one of the
two environments (e.g., during absence of the stimulus). Phase control of such an
oscillator by a rhythmic stimulus can be analyzed by calculating the impact of a single
(repeated) exposure to that stimulus. This was first spelled out by Perkel et al. (1964) in
context of neural pacemakers driven by a volley of action potentials and by Pittendrigh
and Minis (1965) in context of circadian docks driven by a daily light pulse.
We are thus equipped to ask, "What is the winding number Wn of the phase resetting
curve induced by a sequence of n regularly spaced stimuli?" This resetting curve teIls
how weIl an arbitrarily phased oscillator is synchronized to the entraining rhythm after
the nth pulse. As far as the topological Type of the curve is concerned the answer is
conveniently simple: Wn = Wr. To see why, reason as folIows. As we vary rPo, the phase at
which the first stimulus encounters the oscillator, we change the phase rPo' at the end of
that first stimulus. As rPo varies through one cyele, rPo' varies through W1cyeles. The next
stimulus arrives after a fixed interval T at phase rPl' = rPo' + T. For each cyele through
which rPl is varied, rPl' and therefore rP2 varies through W1cydes. Thus rP2 varies through
W 1 x W1 cyeles per cyele of rPo. And so on.
Thus if W1 is 2 or -3, let us say, then Wn can be arbitrarlly large. In other words the
average slope of the resetting curve (to a volley of repeated stimuli) can be arbitrarily
large.
On the other hand, if W\ = 0 or 1, then W n = 0 or 1. This doesn't guarantee small
resetting curve slopes, but the guaranteed small average slope is a necessary (not
sufficient) precondition for small slopes. Interestingly, these are the only two resetting
Types thus far observed in nature, as far as I am aware (in 1978).
 B: PERTURBING AN AnRACTING-CVCLE OSCILLATOR 183

system. It is just a point in the attractor basin's boundary through which the
unperturbed trajectory, wherever it may lead, does not return to the attracting cycle.
The take-horne lesson seems to be that observing aphase singularity in the
stimulus plane (observing a helicoid in each unit cell of the time crystal or observing
a rotating wave in a pinwheel experiment) in itself suggests nothing very specific
about the underlying mechanism. It may be interesting that more complicated
phenomena are not observed, but the observation of only this much scarcely
indicates more than: (a) that the physiological dynamics tends to a unique cycle
when unperturbed; (b) that it tends to a steady state under the stimulus used; and (c)
that both these processes behave in reasonably smooth ways.
In fact it turns out that convergence to a steady state is by no means necessary:
Displacement toward a new attracting cycle as in Figure 5(a) can serve the same
purpose. The same result also emerges from an entirely different style of
perturbation (see Box F). Nor is smoothness of the dynamics really necessary
(see Section C and Box G). In fact, the same behavior has been found even in
oscillators that are not describable by finite-dimensional state spaces (Johnsson and
KarIsson, 1971).

Our interpretation of the t coordinate as stimulus duration is more

restrictive than necessary. First of all, the stimulus need not be a fixed
parameter change. If the stimulus program is a concatenation of simpler stimuli
as in Box H or a wildly time-varying schedule of influences, it still drives the
system's state along some path. The only geometric change induced by this
generalization is that such paths can now intersect each other and themselves.
That only means that the (ifJ, t) surface may be folded and may pass through
itself, but this is of no concern to our topological results. t may also therefore
be interpreted as dosage of a substance or magnitude of aperturbation
delivered all at once, which only gradually dribbles into the dynamic system. As
in Chapter 5, M here refers to stimulus magnitude, thus generalizing the usage
184 6: ATTRACTING CYCLES AND ISOCHRONS

in prior chapters where a stimulus was described as lasting for duration M,

from t = 0 to t = M.

Oscillators of Greater Complexity

Given at least three state variables to play with, one can obtain rather complex
patterns of phase response. Depicted as isochrons on the stimulus plane, these
patterns typically amount to arrangements of singularities smoothly connected
together as in Figure 6. In the M ranges indicated, the dependence of 4/ on <p can be
Type -I, 0, 1,2, etc. In the simpler models considered up to now we have seen only
Types 0 and 1. Let me explain briefly how these things can happen.
In a1l the following, we will assurne as a stimulus some fixed change in the
oscillator's dynamies. This is applied for a while then removed. During such a
stimulus the rate of change of state depends only on the state, not on how or when that
state was reached. (This is the definition of "state," not an assumption.) The
trajectories in state space therefore cannot cross through each other. We saw in
Chapter 3 that simple docks respond to such stimuli with Type 1 resetting. In
Chapters 4 and 5 we saw that by introducing a second variable of state we can also
obtain Type 0 resetting. The "Type" is the winding number of latent phase around the
ring along which all the perturbed trajectories end, starting from the attracting cycle.
. This r;I1$, rntr ace in (Winfree, 1968 '. eventu~Uy nee ea ' a . name: It -c~m
to be CaJred ' ''tne 'shifted CY.C eil n Glass and W}nf ee 1984 and Winfree- 1987a
Appendix). The shifted cycle, being a smooth distortion of the cycle (under non-self-
intersecting flow in two dimensions), either encircled the phaseless set with winding
number 1 (as at stimulus duration O) or was pushed beyond the phaseless set to
obtain winding number 0 (as in the limit of approach to equilibrium under
prolonged exposure to the stimulus) (see Figure 7).

!:! ~\@~~@ Figur. 6. Isochrons as they might appear in the (4J, M) plane
of initial phases and stimulus magnitudes. The trajectory
followed as M increases from initial phase 0 passes through a
succession of encounters with phaseless sets. At these

i :[ critical M's, the resetting Type changes by ±1. See also Box
B of Chapter 2.

1{ L......L......J....I........I.-L......L......

o
 B: PERTURBING AN ÄTTRACTING-CYCLE OSCILLATOR 185

Flgu... 7. Rings a, b, c depict states reached during flow toward point d

from the attracting cycle of an oscillator with only two independent
degrees of freedom (the two-dimensional analogue of Figure 5(b)). The
radial strokes indicate isochrons. Rings a and b wind once through the
cycle of isochrons. Ring c has winding number O. These are the only two
choices for non-self-intersecting flow in the plane.

What if there are more degrees of freedom than two? Can other resetting Types
be obtained? First, note that invoking additional degrees of freedom might be the
same as invoking a more complex pattern of perturbation: A constant stimulus such
as considered above might appear to an oscillator as a time-varying pattern of
interference in its operation if there are internal degrees of freedom that slowly
move in response to the fixed stimulus and, as they change, affect the working of the
oscillator. In physiological systems it would be quite astonishing to find only two
state variables and the corresponding elementaIy resetting behavior. Up to now only
such simple resetting behavior has been found in the several systems examined in
detail), so it seems to me timely to indicate in broad strokes some other behaviors
that undoubtedly await discovery.
To begin, recall that in a two-dimensional state space the phaseless set is at
least an attracting or repelling steady-state point and that in a three-dimensional
state space the phaseless set is at least the extension of that point into a one-
dimensional curve. This curve consists of the two trajectories leading toward or
away from the steady state. 3 This phaseless set is the convergence point for all the
isochrons, arranged in order around the cycle. It threads the cycle. Latent phase
has winding number 1 around the phaseless set along any closed path near the
attracting cycle. We will now proceed by considering how oscillators initiallyon
that cycle might be moved to new states under a stimulus. We thus consider
distortions of a ring of initial conditions assumed to coincide with the cycle at
stimulus magnitude M = O. Figure 8 suggests how a stimulus can change this
winding number from 1 to O. Viewed in projection along the phaseless locus,

3 Which must exist. supposing the trajectories point inward from infinity, as they must in all real
chemical systems (Wei, 1962).
186 6: ATTRACTING CVCLES AND ISOCHRONS

Figure 8 would look a lot like Figure 7. Figures 9 a and b suggest how a
somewhat different geometry of change during the perturbation could induce a
winding number of 2, i.e., Type 2 resetting. Alternatively, the phaseless set could
be coiled as in Figures 9(c) and (d). Figure 10 suggests another alteration of the
flow during perturbation, which would result in winding number 0 and then, with
a further prolongation of the stimulus, would result in winding number -1. In
fact any of the integer winding numbers, all of which are allowed as long as we
consider only the abstract logic of phase resetting, can also be achieved by
appropriately contrived smooth dynamical flow involving no more than three
state variables.

Figur. 8. Figure 5(b) is elaborated to include pieces of several isochrons to show how they
converge along a curve wh ich threads the attracting cyde from which the cone hangs like a
wind sock. Isochrons acquire their phase labels in the order of intersection with states along
that cyde at t = O. At any t > 0 the ring of states reached either does or does not encircle this
locus. The resetting Type is the winding number of this ring around the phaseless set.

"'y
-e
c)

~,
,., b~ d) .. , §;)
M -;.; ---1)--=
Figur. 9. During perturbed dynamics, oscillators initially on the attracting cyde at t = 0 are displaced
only slightly (mostly in region abc) to achieve W = 2. The horizontalline in a and b is supposed to be
the convergence locus of isochrons, i.e., the phaseless set. In panels a and b, perturbed dynamics are
little different from unperturbed except around phase b, where the stimulus pushes the system's state
into the background. Altematively, in c and d, states on the attracting cyde are equally perturbed
rightward, but the phaseless set is not a straight line.
 B: PERTURBING AN ÄTTRACTING-CYCLE OSCILLATOR 187

t=O-~

Figu... 10. Suppose the dynamical flow during the stimulus is a

clockwise rotation about an axis indicated by the dot, perpendi- t=1 -----~-- W=O
cular to the page. Then a ring of states initially with winding ~• ~
number W = 1 around the phaseless locus next converts to W = 0 ~
and then to W = -1.

t"2--~-W"-1

Figure 8 shows not just distortion of the initial ring of states achieved at the
end of the stimulus, but the whole continuum of progressive distortion,
comprising the cylinder of states that can be reached by stimuli of increasing
magnitude beginning at any phase on the cyde. This can be made to intersect the
phaseless set any number of times in a great variety of ways as in Figures 9 and
10. The two-dimensional surface in Figure 8 is a mapping of the stimulus plane
into state space. So isochrons on the stimulus plane (f/>,M) can in principle
converge to any number of phase singularities of either dockwise or antidockwise
orientation, as in Figure 6. No one has yet obseIVed such behavior experimentally
(in 1978 and in 1999) but I feel confident that it only awaits the investment of
labor. Almost any circadian oscillator should exhibit multiple phase singularities
in the stimulus plane for very dim light at durations comparable to the circadian
period.
In Figure 11 we switch emphasis from the phaseless set to examine how a
single isochron surlace in state space might intersect the (f/>,M) cylinder. The
geometry of three dimensions allows intersections along a dosed-ring locus with
the consequence that isochrons in the stimulus plane can present the appearance
of a bull's eye, a nest of concentric rings as in Figure 6. (e.g., Johnsson and
KarIsson, 1971; Best, 1976). This is impossible in the case of only 2 degrees of
freedom.

TUBEOF
TRAoIECTORIES
~~

Figu... 11. Similar to Figure 8, but the tube of displaced mRACT1NG

L
rings of initial conditions (the (4J,MJ surface of Figure 6) ~~
intersects some isochrons in closed rings (the ring CF S11MU us
isochrons of Figure 6). This can only happen in astate
space of at least 3 degrees of freedom.
188 6: ATTRACTING CYCLES AND ISOCHRONS

C: Unsmooth Kinetics

In deriving the existence of phase singularities from simple observations in Chapters

1 and 2, we relied on topological arguments. We have now seen that phase
singularities are also implicit in a variety of dynamical models. In both cases
smoothness (in space, in time, in state space) was an indispensable ingredient of the
argument. But in some kinds of data and in some kinds of dynamical model, things
 C: UNSMOOTH KINETICS 189

do not change so smoothly; things sometimes change quick as lightning. The theory
of discrete state automata, catastrophe theory, and the like provide an abundance of
intoxicating perspectives on processes involving abrupt change, but my purpose
here is only to examine the discontinuities implicit even in smoothness.
Accordingly, the remainder of this chapter provides no more than abrief survey
of the role played by quick changes of pace in the experimental systems most
involved in this volume.
The main points I would submit to your attention in these examples are:
1. Systems exhibiting abrupt changes have commonly been described by
discontinuous models. Most commonly, these models involve only a single
internal variable of state. They are essentially simple docks with a
discontinuity in their rate functions. Such models have no place for phase
singularities.
2. Nevertheless, the experimental systems in question commonly turn out to
exhibit one or more phase singularities.
3. A big improvement of realism in modeling is achieved by recognizing the
necessary existence of at least one other internal variable of state. This at least
makes it possible to consistently describe a dynamical mechanism without
invoking magic at the discontinuity. For examples in biophysical contexts see
van der Pol and van der Mark (1928), Fitzhugh (1960, 1961), Katchalsky and
Spangler (1968), Franck (1968), Lavenda et al. (1971), and Linkens et al. (1976).
In more general context, see Chapter 8 of Andronov et al. (1966) and Chapters 26
and 31 of Minorsky (1962).
4. Such models are topologically equivalent to their smoother relatives and their
phase behavior is qualitatively the same as that of smoother models except that
a lot of it is compressed into the very brief interval during which lightning
changes transpire.
5. Such models often exhibit phase singularities similar to those considered in prior
chapters. But sometimes no singularity is evident because it is squeezed into the
brief interval of rapid change, where data resolution is particularly poor.
Let us now turn to some examples in order of their appearance in the Bestiary.

Relaxation Oscillators
The neon glow tube used in the coupled oscillator population of Chapter 11 provides
an example of arelaxation oscillator. It works by aecumulating a voltage on a
capacitor. The voltage rises toward a limit. If the voltage exceeds a threshold, then
the tube discharges before reaehing the limit, and the eyde restarts. If the threshold
exceeds the limit, then the tube waits to fire until stimulated and then restarts its
accumulation. This caricature invokes arbitrarily rapid change in one state variable
at a certain phase in the cyde, in every cyde. In ring devices it oecurs only in
retuming toward the cyde after a disturbance (Box A). These are two different
limiting cases of a smooth attracting cyde, both of whieh eliminate all but one state
variable (corresponding to phase) by tuming the others into a seldom invoked "deus
ex machina." Such approximations usually do violence to the moders accuracy in
situations other than routine circulation along the attracting cyde.
190 6: ATTRACTING CYCLES AND ISOCHRONS

The Malonic Acid Reaction

Though the time course of any reaction is necessarily continuous, certain steps can
go very much faster than others. In the malonic acid reaction (Chapter 13) the
transition from red to blue, with all that it entails, can be (depending on acidity, etc.)
so abrupt that we mayas weIl think of it as a discontinuous change at a threshold, or
so it would seem. But cutting corners in this way leads to contradictions when we
come to consider reaction geometries in which phase has a nonzero winding
number around some ring. This is because such a ring necessarily contains aphase
discontinuity, as we have often seen. If phase is identified with some chemical
concentration, that means a concentration discontinuity. But that is impossible in a
physically continuous medium. So it is necessary to retain the more complex
description involving rapid but continuous changes in two or more mutually
regulating reactions.
The malonic acid reaction can be thought of as arelaxation oscillator whose
primary variable of state is bromide concentration. Bromide concentration falls
exponentially as bromide is consumed. At a threshold, it is recreated during a
momentary explosion of oxidative activity. But within this fraction of a second, a
second variable of state, HBr02 , increases a thousandfold. Vavilin et al. (1968) also
showed that the system can be phase-shifted without permanently altering the
reaction's parameters, using a pulse of ultraviolet light. Thus the malonic acid
reaction presents us with all we need in order to find a phaseless set: an enterprise
that makes no sense in terms of single-variable relaxation oscillator models. By
locating the singular combination of dosage and timing that puts the system in its
phaseless set, one might discover factually (not just assume by analogy with
simplified dynamical models) whether the steady state is locally an attractor or a
repellor. However, such matters have not yet (1978) been pursued in the laboratory
so we don't really know how much of the topologicallogic of resetting actually will
prove useful in an oscillator with such stiff kinetics.
 C: UNSMOOTH KINETICS 191

0.6 0.8

FJg~ ... 12. Experimental results for the new phase ,pf a Belousav-Zhabatinsky relaxiltion
oscillator reached by a~in9 th& vertfcally indicated ddsage of bromide iORS (note 10'9 scala) at
th~ old phase' indicated non ontalry. Phase 0 is tne abrupt oxidation upstroke_The C~lntoors
represent an ~ttempted best fit at the -new p'hase levels indicated beside eaGn, td actual dilta
(not given here llumerically) from each experiment indic.ated by a dot. They cjescribe -a
nfilicoidal surtace. The Wide a ea between contours at 0.3 would show a saddle. point ~e(-e
comour level 0.35 dTilwn. l.eraSecl a clo$ed'ring conrour.tlirough the four dots near the. putative
saddle. (Adaptecl from Physica D 21, Doll'ijk; M.• Scttreiber-,l, tmd ~a(elcr M, 'IDynamic regimes
ih a periodi~ally fQICed .fea~ol1.cell: wittl QscillatQry che~ic:al react\o ". pp. 7a- 92, Figure ,p,
Copyright 19S6, with pe"!'ission fio Elsevjer Science:). . ;r.

Perturbation of a "strongry relaxationat' version of the Belousov-Zhabotins1<Y'tYpe

(broino--) 'malonic acid oscillator using measuFed injectiol1' of bromide ions at 14., sQ,
140, aRd 500 J.ltM pr-oduced phase resetting <iuNes ofType 1,1,0, and 0, respectil1ely:
(Dolnik et al., 1984, "1986), more pr less as expected from e-xperience with stnoother
oscillatots: With data added from two more dosages, the resu!ts were oontoured
smoothly in the format of a pinwheel expenrnent (Figure '12) hardly different from
familiar 'Precedent in Drosopliifa; glycolysis, etc. Sexcikova et aj. (1982) ad reported
Type 0 resetting, ut because cerium liad a lastIng ~ect OÄ the öscilrator's p-eriod,
."phase shi;ft" oulct not oe. defined as strictly as w~ wdulct .ptefer (segrEigated from
"transients" rand so ·the. T e 0 inte re-tation emains a b' UOllS in this <:ase ..

Electric Rhythms in Cell Membranes

Relaxation oscillators are widely used to depict nelVe kinetics. In fact it was in
context of neural rhythms that A. V. Hill (1933) initially declared that all biological
oscillations are of this sort, aremark echoed in contemporary papers even as
sophisticated as Nelsen and Becker (1968), Sarna et al. (1971), and Linkens et al.
(1976). In the latter paper the relaxation oscillator is really continuous, following a
192 6: AnRACTING CVCLES AND ISOCHRONS

tradition instigated by van der Pol (1926), in which a periodic jump can be made as
swift as desired by choosing a parameter in a differential equation. But another
tradition makes no compromises with continuity. According to this interpretation of
pacemaker activity in neurons, the membrane voltage slowly falls as sodium leaks
in. Meanwhile the threshold for sudden increase of sodium permeability gradually
rises, recovering from a previous action potential. When the two meet, an action
potential occurs and both are discontinuously reset to widely separated values,
resuming their approach to equality. For example, see models in Perkel et al., 1964;
Rescigno et al., 1970; Knight, 1972; Fohlmeister et al., 1974; Peskin, 1975; Hartline,
1976; Pinsker, 1977; Allessie et al., 1976, 1977; and Glass and Mackey, 1979. This
kind of model of a neural oscillator resembles a leaky bucket in which a single
quantity accumulates until the bottom springs open momentarily, after which
accumulation resumes. In such models there is no place for Type 0 resetting nor for
rotation about a pivotal phase singularity.
Electrophysiological kinetics has also been caricatured in terms of the other
kind of single-variable discontinuous kinetic scheme, the ring device. The first well-
developed model came from Wiener and Rosenblueth in 1946. They envisioned the
heart cell as having an instantaneous excited state followed by a prolonged
refractOI"y period, which terminates in a resting state. With the resting state and the
excited state identified as adjacent, and the refractory state portrayed as an interval
along which state advances at a steady rate, the model resembles a ring device.
Krinsky (1968) stretched the excited state out to a finite duration to recapture some
phenomena lost in Wiener's more ascetic simplification, thus anticipating
experimental results which later induced a similar amendment of the Hodgkin-
Huxley equations for the heartbeat (McAllister, Noble, and Tsien, 1975). Those two
early papers led into substantial mathematical developments about the behavior of
ring devices in sheets, spatially coupled to admit the possibility of wave propagation
as in the heartbeat, in epileptic seizure, and in spreading depression (see Chapter
14). One upshot is that there cannot be a stably rotating wave of excitation unless
the substrate has a substantial hole in it.
The rotating wave and Type 0 resetting are both admitted only when a second
variable is admitted. It is not necessary to exclude discontinuous kinetics though.
For example, Zeeman's (1972) "cusp catastrophe" model of nerve membrane and
heart muscle, whatever its other defects, does support a rotating wave, given
suitable quantitative adjustments (Winfree, 1973c).
The fast kinetics of the threshold process is described in continuous detail by the
Hodgkin - Huxley equations using {our variables of state. Along most of the cycle
two variables are changing slowly and the other two faster variables behave almost
like instantaneous functions of the slow pair. They exhibit interesting behavior only
during the moment of the nerve's firing, which is reduced to instantaneous
discontinuity in the more compact approximations.
Eric Best in his dissertation (1976) inquired whether Type 0 resetting and a
phaseless set are implicit in the Hodgkin-Huxley equations. He computed
resetting curves for a periodically firing squid axon using the Hodgkin - Huxley
equation with parameters as measured on squid. He used a current bias to
induce oscillation, described by an attracting cyele in the four-dimensional state
space. One of the state variables is membrane voltage. At various times in the
 C: UNSMOOTH KINETICS 193

cyele, he increased or decreased this voltage by some fixed amount by charging or

discharging the membrane capacitance. He then continued the computation until
the membrane had returned elose enough to its attracting cyele so that its phase
was increasing very nearly uniformly in time. Extrapolating back to the moment of
the voltage impulse, he plotted the new phase just after the stimulus as a function of
the old phase at whieh the stimulus was given. For stimuli of middling magnitude,
either positive or negative, the resetting curves looked discontinuous. But by
enormously increasing the time resolution in the ostensibly discontinuous region,
we were able to show that the curves are in fact continuous, and that they change
topology from Type 1 to Type 0 at a critical pulse magnitude. 4

According to the Hodgkin-Huxley equation the singular depolarizing (excita-

tory) pulse and its actual discontinuity of phase are found in midcyele, between
action potentials. At nearby stimulus magnitudes the resetting curve has a region
too steep to distinguish experimentally from a discontinuity. For hyperpolarizing
(inhibitory) pulses, this lies near the end of the cyele, just before the action potential.
Suggestively similar experimental results appear in Moore et al. (1963, Figure 14),
Perkel et al. (1964, Figure 2A), Schulman (1969), Jalife and Moe (1976, Figs. S and
9), Pinsker (1977, Figure SE-1), Ayers and Selverston (1979, Figs. 5, 6, and 11), Jalife
and Antzelevitch (1979), Jalife and Moe (1979, Figure 14) and Scott (1979).
Discontinuities are not commonly associated with the action potential itself. Scott
(1979) argues that they represent encounters with the separator emanating from the
singularity (see Box C).
Best's result also illustrates the importance of using a continuous causal model
for real dynamie systems, however quick some stages of their dynamies may be.
When we settle for a threshold relaxation caricature of membrane kineties, we
invoke magie at the threshold to bring about the necessary changes. All questions
of process and of causation are obviated by collapsing that critieal interval to a
single structureless instant. After resorting to such an approximation, it seems

4 Because Best chose parameters such that the steady-state is locally an attractor competing with the
attracting cyde, the geometry was not quite so simple in detail. Resetting CUIVes too dose to the critical
pulse magnitude are not eitlrer type, because each has a zone of old phase in wbich new phase is
undefined. This happens because the system falls into the locally attracting steady-state after any such
stimulus. Only along the boundmy of tbis attractor basin does new phase behave in an honestly
singular way. See contour maps in Winfree (1983b and 1987a.) A slight adjustment of the biasing
current would presumably eliminate tbis peculiarity without affecting much else.
194 6: ATTRACTING CVCLES AND ISOCHRONS

difficult to understand the Type 0 resetting observed in pacemaker neurons, in

which the Hodgkin-Huxley cyde is evidently very much smoother than it is in
squid.

Biochemical Excitability in Slime Molds

A sheet of aggregating social amoebae behaves as an excitable medium capable
of relaying a pulse of cAMP (see Chapter 15). The triggering of cAMP synthesis
and release is abrupt. Nonetheless, pacemaker cells exhibit Type 0 resetting.
And sheets of cells support rotating waves, pivoting around a three-dimensional
phase singularity that later becomes the assembled animal (Clark and Steck,
1979).

Circadian Clocks
Relaxation oscillators have been invoked as models for the mechanisms of circadian
docks since the earliest days (e.g., Pittendrigh and Bruce, 1957, p. 84; Bunning,
1960 and 1964; and Pavlidis, 1967a). Arecent (in 1978) addition to this literature by
Rössler (1975) ties the relaxation oscillator notion to a chemical mechanism for
temperature independence. But the reasons for adopting discontinuous models
seem to me less than compelling. They are:
1. Tension discharge models are especially easy to visualize and to test
experimentally.
2. Resetting curves, when plotted in terms of phase shift, commonly suggest a
discontinuous change from one-half cyde advance to one-half cyde delay. This
"phase jump" was thought to be the "discharge" of a physiological
accumulator.
Because smooth attracting-cycle kinetics leads to the smooth screw surface
actually observed in the time crystal, I rejected the relaxation oscillator idea
(Winfree, 1970b). That was wrong too. Only the single-variable discontinuous
caricature is exduded by this observation. Nonsmooth kinetics can readily result in
smooth resetting behavior (see Box G), just as smooth kinetics can result in
nonsmooth, even strictly discontinuous, resetting behavior (e.g., Figure 9 of Chapter
4 or any case with codimension-1 phaseless set).
 C: UNSMOOTH KINETICS 195

The Cell Cycle

Extensive resetting measurements have been conducted using the 10-hour cycle of
nuclear division in the acellular slime mold (Chapter 22). These and other
experiments have led many to believe that cell division is governed by a
cytochemical oscillator which once per cycle triggers the sequence of processes
required for DNA synthesis and nuclear fission. Is the oscillator arelaxation
oscillator, constrained to a fixed cycle with an abrupt jump in it? Several
mechanisms of this sort have been proposed (e.g., Rasmussen and Zeuthen 1962;
Rusch et al., 1966; Fantes et al., 1975). Or might it be a feedback process that
functions like a smooth attracting cycle? Several models of this sort have also been
proposed (Sel'kov, 1970; Burton and Canham, 1973; Gilbert, 1974; Kauffman, 1974;
Tyson and Kauffman, 1975; and see more, up to 1999, in Chapter 22 update). These
two classes can be distinguished by examining their resetting behaviors even prior
to learning more about the physical mechanism. Tyson and Kauffman (1975) and
Kauffman and Wille (1975, 1976) have tried to put Physarum in a position to reveal
the smoothness of its cycle using such measurements. Unfortunately, Physarum
doesn't cooperate. Most experiments up to now show a sharp discontinuity in
resetting behavior less than a hour before mitosis (Sachsenmaier et al., 1972; Tyson
and Sachsenmaier, 1978; Loidl and Sachsenmaier, 1982) The particular simplicity
of the discontinuity obseIVed in Physarum strongly recommends a model in which
the concentration of a mitotic inhibitor or activator abruptly doubles or halves
when receptor sites on the DNA are doubled during replication.
More fundamentally discontinuous models have been elaborated. Kauffman
(1969), for example, envisions the cell cycle as a sequential machine not unlike a
digital computer, in which each configuration of gene activity induces a unique next
state until the whole dance has worked through to a new beginning. Nothing like a
phase singularity would be expected in such a case, either. In fact there seems to be
no compelling evidence to date (1978) that the cell cycle need be described by
anything more than the one dimension of phase.
... h 1999 the bjoc emical story as become too cemplrcateel 0 ' suc~ -simp istic
distinctiöns as seel'ned tempting in 1978. 'See Borisuk and Tyson (1998) an"d the
p'datecl first a e of Cha ter 22 ....

Rhythmic Ovulation
The female cycle (Chapter 23) has usually been described in terms of sudden
discrete changes of state (e.g., ovulation, hormone levels transgressing thresholds,
etc.) that eventually recreate a prior state. The early mathematical model of
Danziger and Elmergreen (1957) is typical in this respect. In such a case the cycle's
rephasing by exogenous hormonal stimuli would be expected to reflect these
discontinuities. This is the case in experiments on Bogumil's (1972) numerical
summary of the endocrine kinetics thought to underlie the human menstrual cycle.
Estrogen infusions of various sizes applied at various phases do reveal stark
discontinuities in the model's response (Best, 1975). If there are any phase
singularities, they are weIl hidden in these discontinuities.
196 6: ATTRACTING CVCLES AND ISOCHRONS

Box I: Alternatives to the Attrading Umit-Cycle Interpretation of

Biological Clocks
Kalmus and Wigglesworth (1960) provided one of the first applications of the
qualitative theory of ordinary differential equations to understanding the behavior of
circadian rhythms. This model invoked a pair of attracting cyeles, one attracting and
one repelling. Its architects were aware that they were instigating a conceptually
important departure from the then widespread implicit assumption of simple-elock
dynamics: "We hope that they may selVe us better than the alarm elock which our
children hear ringing from the inside of Peter Pan's crocodile, and which has misled
many of us in the past." This hope was weIl placed, as we shall continue to see in
subsequent chapters .. Nonetheless we shall also see that the attracting-cyele metaphor
falls in several important ways.
First, in the real world one never does get to the limit. What if recovery to the
attracting cyele takes much longer than the typieal intelVal between successive stlnluli?
Then the existence of the limit has no more than academic pertinence. It is therefore
important to measure the rate of recovery. This is undertaken for Drosophila's circadian
elock in the next chapter.
Second, it may not be usual to find a single isolated physiologica1 oscillator. More
commonly they come in pairs or in larger populations, interacting at least weakly. Two
mutually synchronized oscillators have at least one attracting cyele, and generally
several alternative attracting cycles in aspace of twice the single oscillator's number of
dimensions. In principle this case may still be regarded in terms of dynamics around an
attracting cyele, but that may not be too helpful in situations involving significant
departures from the cyele because then the complexities of flow in high-dimensional
space can become quite unmanageable.
Third, it is not obvious that real physiological systems commonly bave a limit cyele
at all, though they may nonetheless be attracted into a ring-like volume of states. It is
entirely possible for a system involving three or more variables to meander
aperiodieally without ever converging either to a stationary state or to a unique
attracting cyele. Laboratory examples of such irregularly periodie dynamics are just
beginning to appear in the research literature of 1977. Many of the theoretical
examples, notably due to Rössler (in 1978; see Box E), suggest that cbaotic dynamics in
strange attractors readily arises in connection with slightly perturbed oscillators and
pairs or populations of mutually interacting oscillators.
It seems partieularly ironie that most of this cbapter's contents were developed from
1966 to 1972 in an effort to account for the reaction of Drosophila's circadian elock to a
single phase-resetting stimulus. But more recent experiments (Winfree, 1973a) gave
scant support to the notion that Drosophila's eelosion dock bas an attracting cyele; if it
does, it attracts much more slowly than anyone bad imagined. More recent theoretical
models of this circadian dock (Winfree, 1975b, 1976) tend to emphasize its
resemblances to a population of oscillators whose collective behavior is not dominated
by an attracting cycle. These matters are pursued in Cbapters 7 and 8.
 C: UNSMOOTH KINETICS 197

The only complete resetting cwves presently available (1978) from living
mammals were obtained with such potent synchronizing stimuli that little can be
inferred about the smoothness or discontinuity of the cyclic mechanism (see
Chapter 23).

Conclusion
In respect to phase resetting and patterns of phase in space, there seems to be little
qualitative difference between attracting-cycle oscillators with smooth kinetics and
others that change state abruptly during the normal cyde. Resetting behavior is
really discontinuous if the state space is one-dimensional or if the attracting cyde
has certain ungeneric exact symmetries (e.g., Box F). However aphase singularity
can be caught up in an inteIVal of sudden change, where the time axes are, as it
were, very compressed. This can result in such severe distortion of the bundle of
converging isochrons that one sees only stark discontinuity. This can happen, but
need not, and apparently does not in some of the experimental systems referred to
above.
These last remarks are not just theoretical, but conjectural as wen. With a
parting reference to Box I it now seems appropriate to depart from the extremes of
theoretical abstraction approached in this chapter. We will next pursue operational
definitions and experimental methods for testing the utility of isochrons and allied
notions in connection with a particular physiological system. In the next chapter I
present such an attempt using Drosophila pseudoobscura's circadian dock.
 Measuring the Trajectories
of a Circadian Clock

If an experiment does not hold out the possibility of causing one to revise one's
views, it is hard to see why it should be done at all.
Peter B. Medawar

A: Introduction
If, in context of real laboratory experiments, we wish to seriously contemplate
models with more than one degree of freedom, then we must find two or more
independent empirical measures corresponding to the movements of the system in
its state space. We must seek to plot a trajectory in aspace of two or more
measurable quantities. If we can find a way to do this, then we can distinguish the
quickly attracting cyde of Chapter 6 from the orbitally stable kinetic schemes of
Chapters 4 and 5.
In mechanical systems such as the pendulum of Chapter 5, position in space
and its rate of change (the velocity or momentum) comprise a natural choice of
coordinates for the state space. In chemical systems, this kind of plot is much
less natural because reaction rates depend only on concentrations, not on their
rates of change. Ideally we would monitor two or more concentrations or
functions of the concentrations and plot these against each other to measure a
trajectory. Observations in this style have been collected by Ghosh and Chance
(1964), Betz and Chance (1965), Betz (1966), Degn (1969), Vavilin et al. (1970),
Betz and Becker (1975a), Blandamer and Roberts (1978), and Wegmann and
Rössler (1978).
Lacking such complete information, people have resorted to plotting any
single accessible observable against its rate of change. The hope is that both
quantities-the observable and its rate of change-are reasonably smooth,
independent functions of the state variables (concentrations). If so, then a plot of
the one function of state against the other might constitute a recognizable,
though distorted, image of a two-dimensional projection from the state space.
The least risky attempt of this sort is a plot of concentration against its rate of
change in a system believed to be weIl understood and to involve only two important
variables of state, one of which is the measured concentration.

A. T. Winfree, The Geometry of Biological Time 198

© Springer Science+Business Media New York 2001
 A: INTRODUCTION 199

A more adventuresome attempt with the same procedure might use a system
believed to importantly involve interactions among several quantities. Trajec-
tories of this kind are familiar to neurophysiologists using membrane voltage
(one of the four coordinates in Hodgkin's and Huxley's state space, essentially a
ratio of inside/outside ion concentrations) as the only direct obsetvable (e.g.,
Jenerick 1963; Gola, 1976; and Guttman et al. 1980. See Chapter 14 for
background).
More precarious is the attempt to use a conveniently obsetvable function of
state without the support of any well-tested idea of what the basic variables of
state might be or what kind of function of state the obsetvable might be. In this
category we might consider any circadian rhythm in which some quantity can
be monitored continuously. For example, the openness of Kalanchoe's flower is
such a quantity. A plot of openness against its rate of change winds 'round and
'round a center, with variations of amplitude, at reasonably uniform angular
velocity. Such plots provided the first direct measurement of "isochrons" (see
Chapter 21).
Still more perilous is the effort undertaken in this chapter to use an
obsetvable that is not even defined on the same kind of space as are the
presumed variables of state. The obsetvable most natural to our interest in things
rhythmic is the phase of a circadian rhythm. Of course that makes a rather dull
plot since phase, being defined in proportion to elapsed time, has rate of change
identically 1. But persevering in this preoccupation with phase, we might instead
take the reset phase of a rhythm as our obsetvable and plot this value against its
rate of change as we vary the time at which a stimulus is given. Those two
obsetvations presumably constitute two independent measures of the unperturbed
dock's state. To put it another way, we do as in the previous paragraph, but our
rhythmic obsetvable is "the phase to which the rhythm would be reset if
perturbed right now in some standard way." We plot that against its rate of
change. This is simply the familiar rhythm of sensitivity, the resetting map,
plotted against its slope.
The labor involved in such an effort is nearly prohibitive. Why go to the trouble?
What will be gained by it?
The result will be some kind of distorted look into a circadian oscillator's
dynamical space: the first ever obtained. In principle it might reveal any kind of
unanticipated dynamical complexity, any unforeseen pattern of organization among
attracting and repelling steady states, attracting and repelling limit cydes, thresh-
olds, and separatrices, etc.: No one had examined the dynamics of any circadian
dock for its essential, qualitative features beyond phase resetting and entrainment
behavior. In fact, as you will see, what emerges is startlingly simple and
disconcertingly unlike the relaxation oscillator model and quickly attracting limit
cyde models previously entertained.
Such an experiment requires thorough automation. The remainder of this
chapter mostly presents the results of the first such experiment, using the
circadian rhythm of edosion in populations of Drosophila pupae and my
University of Chicago "time machine." See Winfree, 1973a and Chapter 20 for
background and see the end of Seetion E below regarding several repeats using
diverse species.
200 7: MEASURING THE TRAJECTORIES OF A ClRCADIAN CLOCK

B: The Time Machine Experiment

It is a capital mistake to theorize before one has data. Insensibly one begins
to twist facts to suit theories, instead of theories to suit facts.
Sherlock Holmes, "A Scandal in Bohemia"

Background
To put the forthcoming trajectories in context of our earlier encounters with
Drosophila, let me remind you of the pinwheel experiment and its resulting time
crystal (Chapter 2, Chapter 20). The pinwheel experiment was contrived to
distinguish the dock's states by keeping it for a while in one environment
(constant dark or red light up to a time T or phase ifJ) and then for a while in
another (constant blue light for a duration M). Edosion timing then provided one
measure of the dock's state at the end of that treatment. The measured
dependence of the resulting cophase, 9, on T and M was depicted in two
equivalent ways:
1. As a lattice of screw surfaces in which a screw axis is the only conspicuous
irregularity, and
2. As a contour map or a wave rotating on the stimulus description plane, in which
the pivot corresponds to the screwaxis at T = T*, M = M*).
This 9 provides one measure of the dock's state at the end of the stimulus.
However, as we saw in Chapter 3, single-variable models proved inadequate to
account for all the facts of phase-resetting. So we need to discriminate some
additional way the dock's state can change. We thus need to figure out how to assay
the state of the dock as it follows some path possibly off its "normal" cyde. We can
then ask whether the path observed is or is not the same old usual cyde. If not, how
quickly does it return to the standard cyde? Or does it noticeably approach the
standard cyde at all? In performing this exercise I will abjure theory and stick
consistently to facts taken from a single circadian system, viz., Drosophila
pseudoobscura edosion.
It seems appropriate to start by defining observables in strict operational
terms. How can we monitor the state of a circadian dock without knowing
what a circadian dock is? We don't know the dock's biochemical state
variables, but we do have some observables that may qualify as functions of
state (Figure 1):
A. For a first measure take the time from t hours after the initializing stimulus
(T, M) until edosion in continuous red light or darkness. As long as edosion occurs
in reasonably narrow unimodal peaks, the center of mass of the peak (the daily
average edosion time) will adequately characterize the interval from t to teclosion'
That measure of the dock's state x at time t will be called 9(x (t)) = teclosion - t,
referring to edosion in the singly pulsed pupae. Because this is merely proportional
to time after the initializing stimulus, it is not an especially informative measure of
dock behavior after that stimulus.
 B: THE TIME MACHINE ExPERIMENT 201

Flgure 1. Defining 8 and 8' (8" is c/(J'/dt). The

~~_---'~~__-_ _.....(!_(t_)).....
_ _....,o....-__..... +.. .~_-"''--
horizontal time axis starts with transfer of pupae
to darkness (downstroke), then leads through a
?-
I
I
rI
24hours
:
I

~
stimulus after T hours and the assay pulse (or its T 0 - 9 (11(t)1
absence) after t more hours, then ends in a
sequence of eclosion peaks about 24 hours apart. ~t I "
o .. 9(11(0))

B. For a second measure, do as above but also give the organisms a standard
120-sec exposure at 100 erglcm2/sec :: 10-5 W/cm2 of 450-nm blue light at time t,
prior to leaving them undisturbed in red light. Because of the blue light exposure,
which we call an "assay" pulse, the time to eclosion turns out to be different. Call
that revised time (}'(X(t» :: teclosion - t, referring to eclosion in the doubly pulsed
pupae. Two details:
1. The assay pulse should be strong enough so that variations in its duration or
intensity do not cause the resulting eclosion times to vary much. In other words
the assay pulse should saturate the phase response. This will prove to be an
important technical convenience below.
2. The blue exposure maps the state x(t) to a new state x'(t), so (}'«X)t) is the same
as (}(x'(t». This relation will be useful because through it we will be able to
measure the mapping x ---+ x' imposed by blue light.
C. For a third measure evaluate the rate of change with time of the second
measure:
iJ' == d81~(t)) == d8(x ' (t)) .
t dt
(Note that I try to consistently use the upper dot rather than the prime for the time
derivative here; the prime has no such connotation in this book.) A word about the
actual operational meaning of the "time derivative": Because the measurement has
to be done with discrete aliquots of the population of flies, () and ()' cannot be
measured continuously. () is measured once and ()' is measured in replicate
populations at two-hour intervals of t. With ()' plotted against t, we put a smooth
curve through the data points by hand, digitize it at intervals of one-fifth of an hour
(Le., at 10 points between actual measurements) and define iJ' as five times the
difference between successive ()' values.
There are obviously other possible measures. For example, we could take the
time to eclosion if we sprinkle cigarette ashes on the pupae at the same time as we
give a cold pulse or we could take the fifth time derivative of that measure, etc. But
three will be quite enough and the particular three observables detailed above do
lend themselves especially nicely to manipulation. 1
Now how do we set up initial conditions at t :: 0, from which to follow (}(t),
(}'(t), and O'(t)? First of all, we need a standard starting state. Call it Xo. This is
obtained by very long continuous exposure to white light. To obtain different

In Winfree (1973a) I used a slightly different notation. M was there S (stimulus seconds), avoided
here out of deference to topological notation for the circle. t was WAIT. (j' was 82 •
202 7: MEASURING THE TRAJECTORIES OF A ClRCADIAN CLOCK

48HOURS
I . ,
o r---------------

..... w

- w

o
t ~e, i
e'X--
E E E I

L-
I _ _____ _______ __ ~,

24 HQURS

Figure 2. Treatment of one harvest of pupae to measure 9(t), 9'(t), and 9"(1) following initial
conditions established by stimulus (T, M).

initial conditions, x(O) 1= Xo, we start with this standard state Xo, wait a time T, and
then expose once again to standard light for a duration M. If M = 0 then x(t) is still
the trajectory from Xo. If M 1= 0 then x(t < T) is still the same but x(t > T + M) is a
trajectory from some new state reached at the end of M. Three measures, B, B', and
Ö', monitor this x(t > T + M). Luckily these turn out to be smooth periodic
functions and it turns out that two suffice: a third is superfluous.

Implementing the Experiment

My aim now is to fit all these results together in an understandable way. This is a
nontrivial game because we are doing not mathematics but empirical science: All
the experimental results are estimates subject to diverse sources of error and we
have to find out what aspects of the data to regard as noise so that we don't base too
sensitive a calculation on them. We need to find out how to bring out the essence of
the results graphically. I tried many ways and show here only the ones that worked.
With that overview, we proceed through the experiment in finer detail. In
Figure 2 we examine the measurement of a single trajectory, starting from whatever
state the dock reaches after the initial stimulus (T, M). In Figure 2 time increases
through about two weeks from the left to the right. Beyond the far Ieft, fertilized
eggs are laid during an interval of about four days. The maturing larvae are reared
and allowed to pupate under continuous light. At time T = 0 they are taken into red
light (equivalent to darkness). The bottom diagonalline represents the removal of a
tiny aliquot of these pupae to serve as an overall control, unperturbed by any
further exposures to light.
The rest of the pupae remain under red light until a time T when the blue light is
tumed on for a duration M. This creates the initial condition following which we
intend to monitor a trajectory. The second diagonal line to the lower right
represents removal of a small aliquot of this population to serve for measurement of
B, the time to edosion in a subsequently undisturbed population. In this aliquot and
 B: THE TIME MACHINE ExPERIMENT 203

in all of those to be described below, the new "time zero" is located at the end of a
blue light pulse.
Eclosions occur only during an observation window (dashed box) during which
the eggs fertilized 20 days previously achieve sufficient maturity to hatch as adult
flies. The eclosion peaks and their previous anniversaries (E's in Figure 2) mark the
times when (J = O. They measure observable A, the (J associated with t = 0, at the
initial conditions set up by the end of the pulse (T, M). (J at any later time is that
measured (J minus the elapsed t. This is because the time remaining until eclosion is
less by t after that much time has elapsed.
The top 24 diagonallines represent a division of the remaining population into
24 equal aliquots. In each of these an assay pulse is given at a different time in order
to measure (J' at that time. These assay pulses are given at two-hour intervals of t as
diagrammed. Thus the assay pulses scan altogether two cycles of x(t) following
establishment of initial conditions t = O. The times (J' from assay pulse until eclosion
in each of these 24 populations are measured from a new zero of time at the end of
the assay pulse. Like (J measurements, these measurements are available only
during the observation window. They are taken only after a minimum of three
cycles have elapsed since the assay pulse; earlier rescheduled eclosions are
sometimes irregular. The observed times (J' are indicated by dots on the top 24
horizontals in Figure 2. They most commonly lie along four smooth curves during
the four-day observation window. The vertical axis can be taken as the taxis,
spanning the two days scanned by the assay pulses. The t's at which (J(t) = 0 are
indicated by E's on the rjght.
Bear in mind that we have three consecutive regimes of time measurement here.
The first extends from 0 to T between the light-dark transition and the blue pulse
that establishes initial conditions. The second extends from 0 to t between the end of
that pulse and the beginning of the assay pulse. The third extends from 0 to (J' at
eclosion, starting at the end of an assay pulse and continuing under constant red
light or darkness until the flies have hatched and died, ending the experiment.
Twenty-four assay pulses are given, each two hours later than its predecessor
(except for the first, which is given sometime within two hours after the initializing
light pulse).
It is convenient now to remove the observation window and rotate it 90° as in
Figure 3(a). This lays the t axis horizontally to the right with the twenty four (J' axes
extending vertically downward in the standard format of previous chapters. (J' is
plotted downward instead of upward so that the "new phase" axis extends vertically
upward on the same diagram.
In Figure 3(b), Figure 3(a) is sheared by one hour vertically per hour
horizontally in order to bring the zeros of all 24 (J' axes into horizontal alignment.
Thus (J' is measured downward from a common zero. This shearing puts the data
into the format of Figures 31-33 of Chapter 1, in which Type 0 resetting has average
slope 0 and Type 1 resetting has average slope 1.
Figure 4 shows the results of an actual measurement in this format, using
Drosophila's eclosion rhythm. In this particular case the prior M = 0, therefore T is
arbitrary. It shows that the eclosion peaks are of uniform narrow width. (I believe
this is because the 120-second duration of· the saturating assay pulse evokes
rhythmicity of standard high amplitude in the circadian clock. I disallowed myself
204 7: MEASURING THE TRAJECTORIES OF A ClRCADIAN CLOCK

o 24

........."",1
,~
I
I

:
I

,,
r, I
I
I

i
I
I
I
I I
I I
I
, i
I J
I

I
I
i I
I
Lp-'-''"'''-'>..u...u .............,............u~
9'
l
9'

• L
o 24

(0 ) (b)

Figure 3. (a) Observation window from Figure 2, rotated 90°; (b) part (a) with the zeros of the 24
time axes aligned horizontally.

this approximation in the more rigorous exposition of Winfree (1973a) but for our
present purposes it works weIl enough). Thus we can use the centroid of each peak
(the average eclosion time) as a sufficient measure of eclosion behavior.
In Figure 5 for contrast, the assay pulse is omitted. The 24 eclosion records are
handled exactly as in Figure 4, i.e., the time when the assay pulse should have been
given is made time zero and all the zeros are aligned horizontally. The qualitative
change in the data layout shows that the assay pulse is doing something in Figure 4.
Without it, in Figure 5, the 24 aliquots are indistinguishable, except for the
systematic displacement imposed on their time axes.
In Figure 6, T = 6.2 and M = 20 seconds. The point here is to show that the prior
pulse (T, M) does set up different initial conditions by showing the different

t
0 24 48
0 HOURS

24

48

72 Figure 4. Actual experimental results with M = 0, in the

format of Figure 3(b). The shaded regions represent missing
96 data (mostly mechanical failures).

120

144

168

9'
 B: THE TIME MACHINE ExPERIMENT 205

t
0 24 48

0 HOURS
24

48

Figure 5. For contrast, an experiment identical to the one 72

shown in Figure 4, except that the assay pulse was omitted.
96

120

144

168

9'

subsequent configurations of data. The B' measurements differ systematically from

those encountered in Figure 4. Peaks are still of standard width, so the centroid
remains a sufficient numerical measure of the subsequent rhythmicity.
Figure 7 (right) simplifies the data more, focusing interest only on the
centroids. Because the centroids recur periodically along the B' axis at intervals
dose to 24 hours, it will suffice to reduce them to a single collective measurement,
viz., B' modulo 24 hours. Figure 7 (right) shows the data replotted in this way. At
each t there are now two or three dots representing the two or three successive
edosion peaks, all reduced to nearly equal B' values by removing multiples of 24
hours. These B' points He in a reasonably well-defined corridor through which I
have presumed to draw a smooth curve by hand. (In my first approach to these

t
o 24 48

o HOURS
24

48
Figura 6. As in Figure 4 but M::/= O. Specifically, a 20-second
exposure was delivered 6.2 hours after oscillation began, 72
then (J' was measured by assay pulses at two-hour intervals
for the next 48 hours, as in Figure 4. 96

120

144

168

9'
206 7: MEASURING THE TRAJECTORIES OFA ClRCADIAN CLOCK

data I tried a "hands off' method, automatically fitting a ninth degree polynomial
to the digitized data points. But these polynomials proved to fit the data no better
than the hand-sketched curve (standard error = ±0.6 hour) and they often had

-4
- . .... ... .
' '::
~

...
Er 0
.# . t

"
Figura 7. (right) As in Figure 4 but only the centroid of each peak is retained, and all centroid
times (J' are reduced modulo 24 hours. The (J' scale is given on the left to minimize dutter. (Ieft)
The vertical downw~rd axis is (J' in units of 1 hour. Each dot projected from the right is located
horizontally by its (J' (the local slope along the curve on the right). Eclosion time in the
unassayed control is marked E on the right.

unnecessary bumps and wiggles in them.) This is Figure 4 with M = o. Thus (), ()',
and the siope Ö' are being measured along the standard cycle initiated by a light-to-
dark or bIue-to-red transition. The curve is not strictly periodic along the taxis.
This is the reason why 1 use rectilinear measures T and t rather than circular
measures such as <Pt and <P2 for the times of the first and second pulses: The flies'
behavior deviates systematically from perfect periodicity and so it is inappropriate
to implicitly map our observations onto the phase circle. This can be done later as
an explicit approximation if that seems appropriate after we have looked at the raw
data without first coloring them by theory. Note the arrows marked E for eclosion:
These mark the times at which ()(t) = 0 along the taxis. This is how the () measure is
brought into this diagram. Nowall 3 observables «(), ()', and Ö') are presented in a
single plot.

C: Unperturbed Dynamics
As a matter of convenience we could eliminate the taxis, plotting ()' against Ö' in
Figure 7 (left) (redrawn in more convenient format as Figure 8). This kind of
plot necessarily gives us a clockwise rotation since ()' is increasing (downward)
when its rate of change is positive (to the right). (If it is a rotation, does it rotate
about some point? If so, that point must be on the Ö' = 0 line. 1 have drawn an
asterisk at Ö' = 0 at ()' = -3 hours: watch this spot in the subsequent diagrams.)
This clockwise rotation provides some kind of picture of the standard cycle. It
might be called a trajectory in «()',Ö') space. If ()'(x(t)) and Ö'(x(t» are functions of
the state x(t) then this diagram must be some two-dimensional projection out of
the space containing x. What kind of projection? There is no way to know in
advance. Maybe B' and Ö are such peculiar functions of x that the projection will
be twisted and folded so that trajectories appear to criss-cross. FortunateIy, this
turns out not to be so, as we will see by examining trajectories started from 30
different initial conditions.
 C: UNPERTURBED DVNAMICS 207

Note that no theory or models have been involved so far nor will they be in what
comes next.

·10

..........

. ,. . .'.:..... 'J,.
."
9'

Figur. 8. As in Figure 7 but rescaled. Letters E are placed on

the trajectory where 8(t) = 0 by observation in the unassayed ...
eontrol. At states along loeus 8' = -1, 8' + t = eonstant along
trajectories, Le., the assay pulse inflicts the same phase shift
whenever given. Note that the 8' axis is really a circle: -12 -2 2
hours is the same as +12 hours, modulo 24 hours. The inset
eoordinate arrows at the upper right show how the (01
directions are related to "new phase" fjJ'.

10

Many Trajectories
The next job is to compare trajectories from other initial conditions, that is (T, M
i= 0). These initial conditions might or might not prove to be on the standard
eyde. Let's see. Figure 9 shows about half of the 30 experiments, in the format of
Figure 7, starting from diverse initial states by using diverse initial (T, M)
exposures. Even though we cannot define a metric on (O',Ö') space, it seems dear
that x(t), as assayed by (O'(t),Ö'(t», does not follow a unique cyde. The ehanging
state of the dock cannot be regarded as a mere time displacement along one
preferred trajectory.
A big transient is seen in a few of these trajectories. In an
cases it lies entirely
within the early parts T + t < j; cyde after pupae are removed from the prior
continuous light in which they were reared. This feature does not repeat at 24
hour inteIVals. It is a one-time transient. A number of other circadian rhythms
and other biological docks by 1978 have revealed a similar transient upon release
from prior inhibition (e.g., in Kalanchoe, Chapter 21; see also Johnsson and
Israelsson, 1969 Peterson and Jones, 1979; Peterson and Saunders, 1980;
Dharmananda, 1980). The dock may be winding down from the initial state in
which it was held by whatever prolonged stimulus was used to arrest dock
motion (in this case eontinuous light). In Drosophila this feature is not due to the
photoreeeptor's dark adaptation, although that also follows prolonged exposure to
light; nor is it an indication that the assay pulse is less than wholly saturating: A
similar anomaly is obseIVed when the assay pulse exposure is easily 105 times
208 7: MEASURING THE TRAJECTORIES OFA ClRCADIAN CLOCK

T=3
'. M·30
-4
•
9' 0 t---+-t-+---I-~--~
-, 3
9'
H •••••••••• • •••••

4
E E

T=3
M=20
" .

...

1 !\
.,-_.,

.J
iJH:r

"':-
Flgure 9a.

W .
.

.'
'.

-'::':<,:.,:" .

Tz 19
Mz 80
·w
'
!
· . ,·
..
..
"

' ..
•

,.'. ",

Flgure 9b.
 C: UNPERTURBED DVNAMICS 209

r'11
M'SO

1\/\
~
r·s
M·SO

W
." .

. .

1\ 1\.
~
Figure 9c.

. ...
~ .. " ..

: ',' :.

")
pp
I .~~ I>
.' J"

Figure 9d.
210 7: MEASURING THE TRAJECTORIES OF A CiRCADIAN CLOCK

........ ,:.
• ~ ':,'. . "
11>-

•
1
PA
,"

.
~
.
. I>

T=7
M*3Q

~
1• • ". '. • t>

Figure 9•• As in Figure 7 but with diverse initial (T, MYs. T is in hours. M is in seconds'
exposure at 100 mW/m 2 blue (= 400 nEinsteins/m 2/sec; Einsteins = moles of photons). All the
labels and scale markings are as in Figure 8. To minimize clutter I have left them off all but the
first experiment in this sampie of 15. They are arranged in order of decreasing amplitude. All
trajectories and curves start 48 minutes after the 1st assay pulse. Trajectories all run clockwise.

greater (unpublished experiments, and Pittendrigh, personal communication

1972).
This 16-hour transient is 011 one would ever observe in the wild, where elocks
seldom run as long as 16 hours before daylight returns and arrests further progress
through the cycle.
At first sight this big transient looks like a winding down to a unique attracting
cycle, as in Chapter 6. Such behavior was anticipated in the mathematical
metaphors of Wever (1964, 1965) and Pavlidis (1967). However, there is no
corresponding trajectory winding outward toward the same cyele. Rather there
seems to be a continuum of parallel concentric orbits of smaller sizes that go right
down to zero. After the first 16 hours there is no conspicuous tendency inward or
outward, neither to a preferred cycle, nor to a steady state. Thus the effect of the
light pulse (T, M) is not just displacement of the rhythm in time but is also
something like aresetting of amplitude.
The tendency of each trajectory to repeat its previous path after the initial
transient is more conspicuous when all the initial parts of trajectories with T +
t < ~; cyele are omitted (Figure 10). Here we see that the trajectories sampl~d in
Figure 9 elose more or less concentrically about the point B' = -3 hours at B' = 0
(the asterisk).
 C: UNPERTURBED DYNAMICS 211

"0

Figure 10. The left-hand parts of Figure 9 are superimposed,

omitting the inward transient characteristic of the first 16 hours
after release from constant-light inhibition. These theory-free -2
observations startlingly resemble the anticipations of Goodwin
(1963).

10

It is also convenient to examine this behavior by constructing a Poincare

return map as follows. Points along the first 24 hours of each trajectory are
connected by arrows each to its corresponding point along the same trajectory
24 hours later (Figure 11). In case of perfect periodicity these two points
should be identical. In case of perfect periodicity obscured by noise the arrow
connecting the two points should have some nonzero length but random

Figure11. In the format of Figures 8 and 10, the trajectories of

the left-hand parts of Figure 9 are used to con~ruct a 24-hour
retum map. Each "nail" proceeds from a (9',9) point (at the
blunt end) to the point reached 24 hours later along the same
trajectory (at the sharp end). The Initial transient is distinctly
inward, but it is hard to see any later departure from closed
concentric orbits.

10
212 7: MEASURING THE TRAJECTORIES OFA ClRCADIAN CLOCK

direction. Figure 11 shows a distinct inward tendency of the arrows from high
amplitude. This transient in the first 16 hours is followed by essentially
random variation around periodicity at all subsequent points along the
trajectories. There seems to be no systematic dependence of the period on
the amplitude.
Orbits are concentric to the asterisk. Viewing this «()',Ö') theory-free plot of
experimental data as a projection from the dynamic space of the docks'
mechanism, we might take this as evidence that there is nothing like an
alternative attracting equilibrium or a saddle point, nor a repelling cyde between
attracting cydes anywhere within the accessible portions of the dock's state
space. In other words, its dynamics seem very smooth and simple, and more
resemble the anticipations of Goodwin (1963) than the strongly attracting limit
cyde I expected to document by these observations. However it must be
remembered that edosion timing is determined by the collective influence of
many cellular oscillators, and we do not know how well synchronized they are
within each pupa.

Isochrons
The next question we can approach through these data is, "At what states is the
dock found 24 N hours before edosion occurs?" We used the () measurement to
put a letter E on the taxis wherever ()(t) = 0 in Figure 7 (right). In Figure 8 these
were transferred to the trajectory plot as two letter E's, one on each of the two
cydes during which the trajectory was measured by assay pulses. Collecting
together the 30 trajectories, each of 2 cycles' duration starting from 30 different
initial conditions, we obtain a doud of 60 letter E's, shown as dots in Figure 12.
These constitute a ray projecting downward to the left from the singularity at the
asterisk. This shows that edosion occurs not at any fixed ()' value nor upon

·10

....
. t~;::, Figure 12. All 30 trajectories are superposed in the format of
Figure 10, but only the E's are retained (as dots). All other points
2 3
are suppressed. This ray of dots marks the states of the dock that
precede edosion by multiples of 24 hours.

10
 D: THE IMPACT OF LIGHT 213

crossing any definite Ö' threshold, but rather along a radius cutting trajectories of
all amplitudes.
This might suggest that edosion timing is not determined directly by either of
these aspects of the photosensitive clOCKS instantaneous state, but only after a time
delay by some secondary, driven process with comparable time scale, phased mainly
by the fundamental harmonie of some underlying dock's recent cycles as proposed
by Pittendrigh et al. (1958) and by Kaus (1976).

Figura 13. Figure 12 is extended to show eight isochrons by

proceeding for the appropriate number of hours along each
trajectory from E before placing a dot. Contours are eyeballed
through the dots at three-hour intervals. The dashed parts are 9
extrapolated beyond the presently available data.

More generally one can ask, 'Where was the (O~ 0') state any number of hours
before edosion, or the complementary number of hours after one of the pre-
anniversaries of edosion?" This is answered by marching along any trajectory to
that number of hours beyond the ray of E's and placing a dot, and then another one
24 hours further along. After we've done this for all 30 trajectories, each of these new
clouds of dots contains about 60 points (Figure 13). All extend radially from the
asterisk near the center of rotation of trajectories. Though uncertain now whether
the attracting cycle theory of Chapter 6 applies here, I call these sets of states
"isochrons": equivalent time loci, as far as eventual edosion time is concerned. This
is the second direct measurement of the isochrons of a circadian dock. (In the first I
used a simpler experimental technique with data from the plant Kalanchoe; see
Chapter 21.)

0: The Impad of Light

All the above was about the trajectories followed in darkness, the nominally
"unperturbed" trajectories. Now how does the individual trajectory's shape depend
on the timing and duration of the stimulus (T, M) that was used to establish its
beginning state? One can ask about the stable amplitude after the initial inward
214 7: MEASURING THE TRAJECTORIES OF A ORCADIAN CLOCK

Figura 14. As in Figure 8 but only the first 18 hours of the M = 0

_ trajectory is shown, and the axes are suppressed. The circles
mark the approximate starting places of 30 trajectories. These
starting places are successive points along perturbed (blue light)
trajectories, here connected and numbered in order of increasing
M at fixed T.

transient: Which preliminary stimuli lead to big cycles and which lead to smaller
cycles? In more detail one can ask, "How does exposure to light move the state of
the clock from the standard trajectory?" The way to ask the question is to find out at
what (O',iJ') state each trajectory starts, immediately after the initial conditions are
set up by exposure for M seconds to a light that started T hours after the oscillation
began. At each T we have several durations of M, from M ::: 0 up to the duration (120
sec) of the assay pulse. The sequence of states reached by longer and longer Misthe
clock's trajectory during the blue light exposure.
Figure 14 connects the initial points of 30 trajectories in order of duration in
blue light, at each initial T. The initial point of each red light trajectory was
obtained by extrapolating the trajectory backward from the first datum (typically
at t ::: 1 to 2 hours) to isochron 0(0). In five cases the first few points along the
trajectory were too far apart to permit confident extrapolation: Those five are
omitted from this plot. All the remaining blue light trajectories start along the M
::: 0 trajectory (which is here given six "starting points," since M ::: 0 can be
assigned to any T.) The trajectories generally shoot leftward to lower Ö' in blue
light, remaining at roughly constant 0'. This is as expected: the initial 0' is the
time to eclosion after a saturating assay pulse; if instead we give a stimulus of
duration M followed without interruption by a saturating pulse, that combination
pulse is also saturating and should therefore result in the same eclosion time ()'.
In fact what is peculiar in these data is that 0' is not quite constant as M
increases. I do not know why it is not. Maybe the assay pulse is not really as
thoroughly "saturating" as I believed from earlier measurements. In any case the
main point to notice is that the blue light trajectories are not along the cycle, and
cannot be described as bacldng up (phase delaying) or hurrying ahead (phase
advancing) along the cycle.
The predominantly leftward trajectories must end up along a special locus
that can be constructed as folIows. Saturating exposure by definition leaves the
 D: THE IMPACT OF liGHT 215

Figura 15. Intersection (J = (J' are estimated using the isochrons

measured in Figure 13. At such points (marked by circles) the
assay pulse has no effect on the clock's phase. These points lie
roughly along the vertical line at iJ' = -1.

,/
,,"
6 6

dock in astate such that its phase is not affected by further immediate exposure,
so () = ()'. The Iod of fixed () are the isochrons in Figure 13. The Iod of fixed ()'
are horizontal lines. The intersection between a given isochron and the
corresponding ()' stratum occurs along the heavy arc in Figure 15. This has to
be where all the long exposures end up. In point of fact they don't end up exactly
along this locus but Figure 14 suggests that they tend toward it as exposure
duration increases.
So much for the direction of blue light trajectories. Now what about marking off
time along them? The 30 exposures given to initiate the 30 trajectories all had

l
I
i

Figura 16. As in Figure 14 but initial states reached after

roughly the same Mare linked, regardless of T. Rows 0, 1, 2, 3, 1---
-2
4, 5 are described in the text.

,
,,
I
:

~l~
216 7: MEASURING THE TRAJECTORIES OF A CiRCADIAN CLOCK

durations 0, 20, 30, 40, 50, 60, 80, or 120 seconds. So time marks can be roughly
placed along the blue light trajectories by drawing links (Figure 16) between the M =
20-30 second experiments (row 1), another row of links between the 40 second
experiments (row 2), another row connecting the M = 50-60 second experiments
(row 3), and another connecting the M = 80 second experiments (row 4). We already
have links connecting the M = 0 second experiments (row 0) because this is the
unperturbed red light trajectory. These rows of links get closer and closer together
as M approaches saturation.

E: Deriving the Pinwheel Experiment

Now, combining the trajectories at fixed T and their cross-links at fixed M we have
a (T, M) grid. This superposition of Figures 13, 14, and 16 teIls what isochron we
get to by starting an oscillation with a light-dark transition, waiting T hours, and
then giving M seconds of blue. This experimentally determined diagram (Figure
17) tums out to be essentially identical to the one I presented as a theoretical
inference in summer of 1968 at the Federation of European Biochemical Societies'
meeting in Prague (Figure 11 of Winfree, 1968). 1t can be regarded as a contour
map of 8 above the (T, M) plane. This is made a bit clearer by straightening out the

-~l!

T-'7.0

T·7.7
__ 9' Figura 17. The isochrons on a (T, M) grid constructed by
superposing Figures 13, 14, and 16.

I
I
I
I
I

I
~l~
 E: DERIVING THE PINWHEEL ExPERIMENT 217

distorted (T, M) grid of Figure 17 to create Figure 18. We have seen this picture
before as Figure 13 of Chapters 2, 4, and 5.lt is the contour map of one unit cell of
the time crystal portrayed in Figure 14 of Chapter 2. The time crystal came from
the pinwheel experiment, which I was conducting while building the time machine

i
Flgure 18. As seen in Figure 17, Figures 14 and 16 superposed ~
constitute a curvilinear (T, M) grid. Graphically pulling Figure ~
17 into rectilinear shape, the isochrons and initial points lil
(circles) are moved to the positions here shown. (Compare :l
Figures 13 in Chapters 2, 4, and 5, and Box B of Chapter 12.) I

46810 12

- T,HOURS-

o
o HOURS

24

Figur. 19. As in Figure 6 but the prior stimulus was 40 48

seconds exposure at 6.2 hours after initiating oscillations. This
near-singular pulse resulted in almost arrhythmie eclosion. 72
There is very little time dependence of 8' in rhythmic eclosion
shown here after a second stimulus (e.g., the assay pulse). The 96
measured trajectory winds close around • (see Figure 20).
120

144

168

9'

to undertake this more elaborate measurement of trajectories. The results of that

earlier experiment (fortunately) turn out to be implicit and are independently
corroborated as shown below, in these more comprehensive results. The phase
singularity is the point, *, about which all trajectories revolve in the absence of a
perturbing stimulus.
Note the trajectory starting (at M = 0) at T = 6.2 in Figure 17. It passes very
nearly across the singularity. If blue light (at 450 nm, 10- 5 W/cm 2 standard
intensity, as used in all these experiments) is terminated after only about 40
seconds, the dock should be left in astate of uncertain phase. In fact the
218 7: MEASURING THE TRAJECTORIES OF A ClRCADIAN CLOCK

edosion "rhythm" becomes virtually aperiodic after such a stimulus (Figure 19)
and the trajectmy measured after such a stimulus has exceptionally Iow
amplitude (Figure 20). This is as much as to say that whenever light again
strikes the dock, it restores normal rhythmicity at practically the same phase,
specifically, the phase of the isochron which roughly paralleis blue light
trajectories proceeding Ieftward from the environs of the singularity. This is also
the phase of rhythm initiation in "naive" flies, suggesting that prior to some
stimulus to mark "time zero," the newly created dock in a young fruitfly lanra
lingers near the * in its state space.

-10

2 2 3
Flgure 20. As in Figure 8, replotting the data of Figure 19.

10

What about trajectories under perturbing light of a different color or

intensity? If photons get into the dock through a single chromatophore (i.e., if
the dock is color blind), then color and intensity should be interchangeable.
There seems every reason to believe the same trajectories are followed under
higher intensity illumination, but faster: The net effect of brief (<1 hour)
illumination seems determined by energy. But what of much dimmer lights? As
intensity approaches zero the trajectories must approach the concentric rotation
measured in utter darkness. This part of the story has not yet been filled in but
Peterson (1979, 1980, 1981) does a nice job using the entirely similar mosquito.
From Winfree (1974a) we know that Drosophila pseudoosbscura's dock is
arrested under prolonged illumination brighter than iö mW/m 2 , but continues to
oscillate under illumination 10 times dimmer. From Chanclrashekaran and
Engelmann (1976) we know that T* remains the same under illumination as
dirn as fö mW/m2 , even though M* has increased to 14 Murs in such dim light.
Thus it would appear that the transition from unperturbed to perturbed
geometry occurs in the range between 360 and fö mW/m 2 of blue light (for which
1 mW is about 4 nEinsteins/sec).
 E: DERIVING THE PINWHEEL ExPERIMENT 219

As noted in Chapter 2, several other circadian systems and at least one

biochemical oscillator all gave qualitatively similar results in a pinwheel experi-
ment. Do they also exhibit dosed concentric trajectories when probed with a second
pulse as here described? Engelmann et al. (1973) repeated this two-pulse
measurement using the plant Kalanchoe and obtained answers similar to
Drosophila's, but more detail was needed for an exact comparison. Kalanchoe,
unlike Drosophila, provides a continuous readout of its dock's activity (as opposed
to only one datum per cyde, at edosion time). So it should be possible to construct
complete trajectories by the methods of Chapter 21, using only the existing
experimental records from which the published phase measurements were
extracted. This remains to be attempted in detail, but Engelmann et al. (1978) do
report that the Kalanchoe dock's amplitude, once reduced by a critically timed
stimulus, usually stays reduced for at least several days.

Turning now from circadian docks to biochemical rhythms of shorter period,

we find measurements in the same format by Greller (1977) using the glycolytic
oscillation in yeast, a business further followed up by Aldridge and Pye (1979b). Up
to now (1978) the published data are too few to assemble a convincing trajectory,
but just as noted above in regard to Kalanchoe, the archived Buorometer traces
could presumably be used to plot trajectories more directly by the method of
Chapter 21 (in this case, plotting NADH Buorescence vs. its rate of change).

Similar re marks apply to Johnsson's (1973, 1976) and Johnsson et al.'s (1979)
recordings of oscillatory water transport in seedlings, perturbed for various durations
at various phases. This case is especially interesting because both the steady state and
the limit cyde locally attract trajectories. Thus a second, and repelling, eyde might be
revealed when detailed trajeetories are plotted from the existing data.
Malehow et al. (1978) inBict single-pulse perturbations on the cAMP dock of
Dictyostelium (Chapter 15) while eontinuously recording optical properties of cells
in liquid suspension. They too note that recovery to an attraeting eyde is not swift:
Effects on amplitude are conspicuous.
220 7: MEASURING THE TRAJECTORIES OF A ClRCADIAN CLOCK

F: So What?
This is the end of the data presentation for this experiment. What good are these
results? First of all they fulfill the objective I proposed at the beginning, namely, to
elicit a picture in model-free form, a picture in which Nature could reveal herself
directly prior to any attempt on our part to impose theoretical interpretations. Any
model that can draw this picture or any· consistent distortion of it gets by
unexcluded. The (Ö') plane is an arbitrary and possibly peculiarly distorted
projection from the assumed state space. The data require only a relationship
between the isochron grid, the red-light trajectories, and the bIue-light trajectories.
 F: So WHAT? 221

Any distortion of the space on which they are all drawn still leaves those
relationships intact and therefore is as valid a picture of the dynamical flows as is
any other distortion. The particular choice of coordinates employed here happily
presents an especially simple and pleasing picture of smooth round concentric red-
light trajectories, parallel blue-light trajectories, and nearly radial isochrons.
Though it is pretty, remember it is not unique.
To my mind the most noteworthy and previously unsuspected features of the
circadian dock which are brought out by these experiments are:
1. The time crystal with its helicoidal unit cell
2. The phase singularity (and its equiva1ence to the initial state of the dock in
organisms which have never been exposed to an environmental stimulus)
3. The smoothness of the concentric closed trajectories
4. The initial transient following prolonged arrest in a nonpermissive environment
(e.g., under continuous light)
5. Lability of the apparent amplitude of oscillation, with very nearly the same
period at all amplitudes
6. An effect of perturbing stimuli which to a first approximation resembles parallel
displacements of state along one state variable, as though one particularly
labile substance were destroyed by the stimulus, down to a minimum near
concentration O.

Here are three quite different dasses of mechanism that typically exhibit such
features.

A Single Nonsimple Oscillator

There are abstract dynamical models asserting (by analogy to mechanical, electrical,
or chemical kinetic equations; see Box A) that the dock has two or more state
variables that affect each other's rates of change in such a way that an oscillation is
engendered. As far as Drosophila is concerned, the most successful of these models to
date emerges from the tradition begun by Danziger and Elmergreen (1956),
developed by Strahm (1964) as a masters thesis project specifically to match
Pittendrigh's Drosophila pseudoobscura data, and further refined by Pavlidis (1967,
1973). Several specific assumptions of this model have been found awkward in the
decade since its first publications, but the basic ideas (feedback oscillations around
an equilibrium state, lateral displacement of states during perturbation) remain the
foundations of theory in this area (see Boxes A and B). Recovery or decay of
amplitude in Drosophila (as assayed by the resetting curve) proved to be so slow that
two whole days can go by without noticeable (:1::10%) change. This can be
accommodated by an ad hoc adjustment of descriptive parameters in such a model
to make its lower amplitude trajectories more nearly closed rings.
222 7: MEASURING THE TRAJECTORIES OF A ClRCADIAN CLOCK

Box A: A Tradition in Modeling Drosophila's Circadian Clock by

Mathematical Metaphors
(See also Chapter 20, Section B)
There was a time when biologists had not heard the words '1imit cyele," which
have become so popular since about 1965, though Mori (1947) had proposed in other
words the notion that circadian elocks are biochemical limit-cycle oscillators. The
next significant incursion of that idea into the world of circadian rhythmology was
through Kalmus and Wigglesworths' paper presented at the first symposium on
biological elocks at Cold Spring Harbor in 1960. That paper expounded the doctrine
of attracting cyeles and separated it from the notion of repelling equilibria but
neglected to delineate in any explicit way the dynamical interpretation of a stimulus
(e.g., an exposure to light). This might have been picked up from FitzHugh (1960,
1961) on neural oscillators, but its first explicit application to circadian experiments
(in fact, to Pittendrigh's Drosophila data) was in Strahm's (1964) unpublished masters
thesis at MIT. Borrowing from Danziger and Elmergreens' (1956) interpretation of
periodic disease, Strahm outlined in considerable detail essentially the view of elock
dynamics that prevails in today's literature, after refinement and quantification by
Pavlidis (1967 et seq.).
The Strahm-Pavlidis model involves spiral trajectories winding out from a repelling
equilibrium, but limited in amplitude by a "wall" beyond which no further decrease of
one variable is allowed (perhaps because this is concentration 0). This nonlinear cut-off
thus becomes one arc of an attracting limit cyele. Trajectories do not just approach the
attracting cyele, but actually get onto it (by hitting the wall) within a day or two from
most initial conditions. This seems to be as natural a first model of rhythmic dynamics
as the van der Poloscillator or the A-W oscillator (alias radial-isochron dock after 1982,
alias Poincare oscillator after 1988); After Danziger and EImergreens' model of
catatonic schizophrenia and the Drosophila elock model, it apparently arose again
independently in Hunters (1974) analysis of the sleep-wake cyele and in Nicolis and
Prigogine's (1977, p. 394) model of lac operon dynamics in E. eoli. In the world of
mechanics this is the classical model of a tethered block sliding on a frictional moving
belt (e.g., PipPard' 1979 page 337).
The Strahm-Pavlidis model postulates that the wall-limited quantity is photolabile:
During exposure to light it swiftly approaches the wall. Strahm even introduced the
notion of circadian modulation of a threshold of developmental readiness as the basis
for the quantization of populations into discrete eclosion peaks (Chapter 20, Box A).
Pavlidis' influential contribution to this story lay largely in directing attention
quantitatively to the implications of brief perturbation. He was the first to calculate
resetting curves quantitatively, as a function of stimulus magnitude. The first mention
of a singular combination of stimulus phase and duration is in Pavlidis (1967), where
the further conelusion is drawn from nonobservation of such a disaster that trajectories
must diverge with extraordinary haste from equilibrium toward the attracting limit
cyele. Except for this, Figures 10 and 14 look remarkably like Pavlidis' diagrams
describing the model.
However in the case of Drosophila's eelosion rhythm, the circadian rhythm most
studied by perturbations in the 1960s, there was never any evidence specifically
indicating either instability of the steady state or return toward an attracting cyele. I
think my own experiments were the first to look for such indication, and none were
found. In fact an adjustable-amplitude model more like a frictionless pendulum than an
attracting limit cyele fits the data splendidly(?!). This Winfree (1972e) model may have
 F: So WHAT? 223

seemed retrogressive from the by-then-fashionable assumption of an attracting limit

cycle. However, the adjustable-amplitude model selVed all purposes of phase re setting
equally well and additionally accounted for the newly obselVed plasticity of the resetting
CUlVes (the subject of this chapter) and the arrhythmicity of dark-reared animals. It also
successfully predicted suppression of circadian rhythmicity by incredibly dim light.
However, it too proved deficient in still further tests. See Box B.

Is it really necessary to abandon the now-widespread assumption that circadian

docks are typically rapidly recovering attracting-cyde oscillators? Such mechanisms
may still be compatible with observations 1-6 above if we admit the possibility of
many relatively independent sources of circadian rhythmicity, for example all the cells
of some rhythmic tissue. Phase dispersion may at first seem an outlandish possibility,
scarcely worth checking. But the fact is that we have precious little reason to assume
that the circadian docks in most organisms necessarily oscillate as a functional unit,
except under conditions of entrainment by an externallight-dark cycle. There exists
considerable evidence to the contrary, especially in the vertebrates and in plants (see
Chapter 19). One need not necessarily expect strong mutually synchronizing
interactions among circadian oscillators in small, nearly transparent, non-tempera-
ture-regulating organisms, since all of their circadian docks would normally be
independently entrained by the external cyde of light and dark, hot and cold. In no
experimental organism have we yet resolved even the simple question whether Type 0
resetting betrays scattering of phases within the organism as in Chapter 4 or, as in
Chapters 5 and 6, it reflects a single oscillator's dynamics.
Thus we come to the second of three dasses of mechanism:

Bilateral Symmetry in the Fruitfly

Within the practicallimits of resolution in biological phase-resetting experiments, a
smooth screw-shaped resetting surface and smooth concentric trajectories would be
expected of a population of three or more simple docks (Chapter 4). How many
independent attracting-cyde oscillators would be required to give this appearance in
the individual organism? Under the rule used in Chapter 4 to pool the outputs of
many oscillators into a single aggregate observation, the answer is "just two." Pair-
wise redundancy of the circadian mechanism has long been suspected in bilaterally
symmetric organisms and is especially dearly brought out in the experiments of Page
et al. (1977) using the cockroach and ofKoehler and Fleissner (1978) using a beetle,
and of many workers intrigued by the splitting of activity rhythms in various
vertebrates (see Chapter 19). The left-and right-brain docks of Koehler and
Fleissner's beetle apparently function independently. Similarly, let Drosophila's
two oscillators be loosely enough coupled so that they show no measurable tendency
to synchronize during the two days throughout which their composite trajectory was
monitored. It turns out that an excellent caricature of the data is given by combining
the outputs of only two independent oscillators, separately reacting to a light pulse in
the ways characteristic of the rapidly attracting oscillators explored in Chapter 6. In
fact, I have quantitatively fitted all my Drosophila data, both for the one-pulse
perturbations used in the pinwheel experiment and for the two-pulse perturbations
used in this trajectory experiment, to a very simple model ofthis sort. The root-mean-
224 7: MEASURING THE TRAJECTORIES OF A ClRCADIAN CLOCK

Box B: Are Phase and Amplitude Enough?

The adjustable-amplitude model of Winfree (1972e, Appendix) was forrnulated in
response to 3 discoveries. First of all Winfree (1968) and Zimmerrnan (1969) had found,
contrary to previous report, that the arrhythmicity of "naive" Drosophila populations
(with no experience of external time markers) could not be attributed to random
phasing of individuals: rather, each animal's dock lay stably at equilibrium. Second,
this initial state seemed the same as the "singular, phaseless" state reached by critical
perturbation of previously rhythmic Drosophila. Third, it had been found (Winfree,
1972b,e) that the Drosophila dock's relative sensitivity to light during the first day after
constant-light inhibition resembled dark adaptation in a dock-independent photo-
receptor. Peterson and Jones (1979) and Peterson & Saunders (1980) observed
something similar in Sarcophaga and Dharrnananda (1980) in Neurospora.
The principal conjecture embodied in this model is that the dock is strictly periodic
but has a second variable of state, an unchanging "amplitude" conjugate to its phase,
and that amplitude and phase together comprise a complete identification of its state.
Amplitude zero is the phaseless or naive state. The dock can oscillate along any of a
continuum of dosed concentric trajectories of constant amplitude. As shown in Chapter
5, this leads to the observed resetting behavior (two Types, a singularity, and a lattice of
screw surfaces) and to an amplitude dependence of the resetting curves such as we
observe in this chapter. Forrnulated a little differently, the behavior of this model is
entirely summarized in a family of phase-resetting curves and a family of amplitude-
resetting curves. In these families the shape of each curve depends on stimulus
magnitude or initial amplitude. This result was first foreseen by Wever (1962, 1963,
1964, 1965).
The last paragraph of Winfree (1973a) explicitly conjectures that this expansion
from one to two variables of state is complete and sufficient. But (1978 and 1999)
this has not yet been checked experimentally and there are now plenty of reasons to
doubt it. These are

1. Significant shortcomings of the perrnanently-adjustable amplitude model,

conceived of as a single oscillator:
a. Under sustained light its amplitude should decrease at a rate proportional to
the light intensity. It seems not to (Winfree, 1974a).
b. It provides no interpretation of the transient observed in the first 16 hours of
darkness.
c. Unless the "amplitude" is actually an indicator of synchrony among
independent (cellular?) oscillators of fixed amplitude, it should blow up under
entrainment by light pulses 26 hours apart. It does not.
d. It does not automatically account for the apparent constancy of the period at
all amplitudes.
2. The availability of a different dass of model, namely, a population of relatively
independent attracting-cyde oscillators. Such models typically accommodate the
facts of phase resetting and also accommodate points a-d above.

If models of dass 2 are appropriate, then the Winfree '1ast paragraph" conjecture
mentioned above should be demonstrably wrong. The reason is that there are many
ways for a population to achieve any given amplitude of oscillation by different
distributions of phase. Such different populations should phase-shift differently in
 F: So WHAT? 225

square fit is quite as good as for any other models thus far contrived, and almost as
good as the reproducibility of phase measurements allows.
~ TotIay'we Know qUite a otmore aoout t . e cellu ar· ~siology 9T circa ian G oe Sdn
the frujttty, ~t least some of them .are cell·at:lt~momous( and ttlere- arenrstindJcatio
öf t1ie l:iiocnemlcal {;hannel oftheir interaction for mutual synchronization (~enn' et.a!./
ZOOO),t may SGon becorne Rossible tQ e~ruate tbe relevance. of. such odefil19 ~o
iolo 'car reali • " •• >" ': • .

Lots of Attracting·Cycie Oscillators

Chapter 4 presented the third dass of models that mimic the trajectories of
Drosophila's dock. In these models a population of very weakly interacting or
completely independent oscillators of almost any kind individually pursue a
common cyde, be that an attracting cyde or the unique cyde of a ring device. In
such a population, phase corresponds to the mean phase of the population and
amplitude corresponds to the dispersion of phase within the population. The blue
light trajectories reflect the changing phase and amplitude of the fundamental
harmonic of such a population's aggregate rhythm during the independent changes
of phase of all of its many constituent oscillators.
In the first 16 hours after release from constant light, the clock's trajectory
winds swiftly inward before repeating along a cyde of whatever amplitude it finally
adopts. This inward transient is hard to account for in terms of simple docks. But it
could represent the collective behavior of many attracting-cyde oscillators
individually winding inward to a standard amplitude. The final dosed cyde could
be the collective behavior of those oscillators all moving on the common cyde, but
nearly synchronously.
Demonstration that the peri.od of the whole organism's rhythm depends on its
amplitude would suffice to exclude this notion of superposition of independent
cellular docks.
Besides the initial transient, there is another way in which the resetting behavior
of a population of attracting-cyde oscillators differs from that of a population of
simple docks. In simple-dock populations, the singular stimulus duration goes to
infinity as the initial dispersion of phases goes to zero. In contrast, the singular
stimulus duration in an attracting-cycle oscillator population goes to a finite limit,
namely to the singular stimulus duration of the single oscillator.
This suggests an experiment, not yet undertaken as far as I know (in 1978 and in
1999: but the means are now in hand: see Chapter 19), in which an organism would
be subjected to a particularly severe entraining rhythm prior to the phase-shifting
226 7: MEASURING THE TRAJECTORIES OF A CiRCADIAN CLOCK

experiment. The idea here is to impose the strictest attainable synchrony on

whatever oscillators might comprise the individual's dock. If this treatment
increases the singular duration, it might be "explained" by an increase of each
cellular dock's amplitude. Bit if it {ails to increase the singular duration then it
might be supposed that dispersion of circadian phases within the individual
organism plays a negligible role in determining the phase singularity. This would
indicate at least that the individual circadian oscillator does have a helicoidal
resetting surface, unlike a simple dock. It would remain to be determined whether
this dock's trajectories approach an attracting cyde slowly enough to explain
(without invoking phase dispersion) the nearly concentric trajectories found above.
A more direct resolution of the question might employ a histological assay in which
the pertinent part of the fly's brain would be microscopically examined for
synchrony of its cellular secretory rhythms. Ostensibly arrhythmic flies might show
distinct rhythmicity in their randomly phased cells or they might show arrhythmi-
city all the way down to the cellular level (Figure 21). Suppose internal homogeneity
and coherence of circadian function or nonfunction could be established by some
such assay. Then phase-resetting experiments on whole organisms could finally be
interpreted at face value, providing much stronger constraints on interpretations of

0)

Figur. 21. Contrasting two mieroseopie eauses of maeroseopie arrhythmicity: in

(a) individual eells remain normally rhythmie but are randomly phased; in (b) eaeh
eell is arrhythmie. (Experiment suggested by Bunning, 1959, p. 522 perhaps
following Eecles and Hoff, 1934.)

b)

the dock mechanism than they do at present 1978 and 1999). But suppose it were
found that the cells or tissues of a single organism can persevere in circadian
rhythmicity at arbitrary relative phases. Then phase singularities and less drastic
changes of amplitude would not tell us much about the individual dock in
multicellular organisms or in populations of single-celled organisms until a way is
found to guarantee and monitor coherence among their many docks .
.. · T~!s i . p'os~i5Je toda ,l.Jsing immurrofiLiorescence of P R aha TIM ifO e nS.-4

At least in the case of certain free-swimming unicellulars, the question lends

itself to resolution by a tidy experiment, which seems more immediately feasible
than the above. Owing to the continual sedimentation of cells suspended in water, it
is not unusual for circadian rhythms of motility, density, adhesiveness, etc., to
manifest themselves as circadian variations in the vertical density distribution of
 F: So WHAT? 227

cells. Arrhythmicity induced by diversifying phases within the population could

then be distinguished from arrhythmicity of every cell by removing sampies of
liquid from various depths into new bottles. This either will or will not isolate
observably more coherent subpopulations. The same kind of experiment could be
used to determine whether the Type 0 resetting observed in such organisms (e.g.,
Gonyaulax) represents Type 0 resetting of each cell or only a splitting into advanced
and delayed subpopulations.

All such experiments presuppose that the cells' docks do not strongly or rapidly
influence each other. Such interactions have beeij.looked for, and none have been
found (see Chapter 19).
228 7: MEASURING THE TRAJECTORIES OF A ClRCADIAN CLOCK

G: In Conclusion
No one expected the phenomena demonstrated in Drosophila in this chapter, least
of all myself. Yet in retrospect they can be derived with almost no specific
assumptions on oscillator mechanisms, without even invoking interdependence
among the individually competent docks. By the same methods Peterson (1981)
found exactly the same behavior in Culex. Going still further, Aldridge and Pavlidis
(1976) and Aldridge and Pye (1979a,b) point out that incoherence can last a long
time even with strong coupling among multitudes of docks.
The moral seems to be that it is of the greatest importance to check for
coherence (e.g., among cells) in the circadian rhythms of multicellular organisms.
This remains the crux of the dilemma stressed by Wilkins (1965):
Unfortunately, nothing is known about the amplitude of the basic oscillating system
or how it is related to the amplitude of the rhythms in the physiological or
biochemical process used to monitor the behavior of the basic system.
 CHAPTER 8

Populations of Attracting-Cycle
Oscillators

There was a door to whieh I found no key.

There was a veil past whieh I eould not see.
The Rubiyat of Omar Khayyam

Chapter 4 provides a prelimiruuy look at the phenomena to whieh we now turn:

the phenomena typical of aggregates of oscillators. Just as the oseillator
populations of physies eomprise a very special ease with very special properties
(associated with linearity, energy eonservation, ete.), so did the simple docks of
Chapter 4 comprise another very special case with very special properties
(associated with the one-dimensionality of their state space). My objective in
this chapter is to organize under the same four headings as in Chapter 4 some
discussions and examples of what I take to be the characteristic behavior of
attracting-cyde oscillators in populations and communities. Such oscillators can
have any number (:;::2) of variables mutually determining their rates of change
in nonlinear ways. Linear oscillators, conservative oscillators, and simple docks
are special limiting cases of the attracting-cycle oscillators considered in this
chapter.
The chapter is organized in four sections:
A. Collective rhythmicity in a population without interactions among constituent
oscillators. Mainly about phase resetting by a stimulus.
B. Collective rhythmicity in a community with completely promiscuous
interactions (all individuals influenced by the aggregate rhythmicity of
the population). Mainly about mutual entrainment and mutual repul-
sion.
C. Spatially distributed oscillators without interactions. Mainly about patterns of
phase in space.
D. Oscillators interacting locally in space. Mainly about smoothing of concen-
tration gradients that would become discontinuities were neighbors not
coupled.

A. T. Winfree, The Geometry of Biological Time 229

© Springer Science+Business Media New York 2001
230 8: POPULATIONS OF ATTRACTING-CYCLE OSCILLATORS

A: Collective Rhythmicity in a Population of Independent

Oscillators: How Many Oscillators?
As in the case of simple-dock populations, we can ask of a population of attracting-
cyde oscillators whether there are characteristic features of the collective phase
response by which to distinguish the kind and number of independent oscillators

r
M

Figur. 1. Ten equispaced contours of new phase on the (old

phase. stimulus magnitude) plane. calculated for a pair of
M" independent attracting-cyde oscillators similar to Example 1
of Chapter 6. The two are initially 0.3 cyde apart. At the
dashed line. new phase shifts by one-half cycJe.

involved. For this purpose I adopt the same measure of collective rhythmicity as
before: the phase and amplitude of the fundamental harmonic of the aggregate
rhythm. This aggregate rhythm is simply the sum of the rhythms f(l/Ji) of N identical
oscillators at phases <Pi on the attracting cycle. The scalar function f of phase is
arbitrary but might be one of the chemical concentrations involved in the
oscillation.
To recapitulate, we found in Chapter 3 that in a single simple dock new phase
depends on old phase and stimulus magnitude in an especially simple way: All the
contour lines of uniform new phase are parallel translations of a single monotone
curve. The behavior of a pair of simple docks is characterized by a U-shaped locus
along which new phase jumps one-half cyde. A population of three or more
simple docks dissembles as a single pendulum-like oscillator in that its phase-
resetting pattern is organized around a singularity and its amplitude is as labile as
its phase.
A single attracting-cyde oscillator also typically exhibits one or more phase
singularities, but its amplitude recovers promptly to normal. Now a pair of such
oscillators, like a pair of simple docks, tums out to exhibit a U-shaped locus of (old
phase, stimulus magnitude) combinations along which new phase shifts discon-
tinuously (if the two docks contribute exactly equally) by one-half cyde. But in this
case the locus does not go to infinity along the magnitude axis: It terminates at two
half-singularities as in Figure 1. The reason for this odd behavior is understandable.
At any time when the two oscillators straddle <P*, there is a stimulus magnitude,
roughly M*, that sets them to opposite phases (Figure 2). Here collective amplitude
is 0 and a slight change of stimulus magnitude makes it positive or negative (i.e.,
positive at either of two opposite phases). At either extremity of this range, one
oscillator can be placed on its singularity by M = M*. A suitable slight change of l/J or
 B: COLLECTIVE RHYTHMICITY IN A COMMUNITY OF ATTRACTING-CYCLE OSCILLATORS 231

-e-

FlgUfe 2. Figure 13 of Chapter 5 is repeated with

emphasis on resetting from two old phases e apart, M
straddling q,*. New phase has winding number W = 1
around path ABCDA. The phase difference along BA
at M = 0 is e. At sufficiently large M, along CBAD, it is
dose to 1. If there are no discontinuities along this
path then the phase difference must pass through ~ at
some smaller M.

M will change that oscillator's phase to any desired phase, as we saw in Chapter 6,
while negligibly altering the phase response of the other oscillator. Now suppose
that both oscillators recover to their attracting cycles, and suppose that we continue
to employ the collective phase measure introduced in Chapter 4. Then the phase of
the pair ranges through half a cycle in the near neighborhood of each of these two
points in the stimulus plane.
A more stringent test of the two-clock interpretation at the end of Chapter 7
might make use of Figure 1, in which the split singularity presents the signature of a
pair of independent oscillators. To test for this experimentally, the first thing to do is
to ensure that the putative two oscillators are well separated in phase. A way to
arrange this reliably in many replicate organisms remains to be contrived.
Three or more independent attracting-cyde oscillators behave pretty much like
one, except that unlike the single oscillator, a population's collective amplitude does
not recover from adjustment of the phase distribution. Also its apparent M* is less
than the single oscillator's by an amount that increases with the initial variance of
phases.
As noted on page 110, the finer details of resetting behavior, if they can be
resolved experimentally, do reveal the number of independent oscillators collec-
tively obsexved. However, if N > 3, such details are easily obscured, especially in data
collected from populations of individual animaIs or plants.

B: Collective Rhythmicity in a Community of Attracting-Cycle

Oscillators

From populations of independent oscillators we now turn to consider communities

of (interacting) oscillators and mutual entrainment among many docks. This part of
the . story is not much altered by exchanging the community of simple docks
considered in Chapter 4 for the community of attracting-cyde oscillators considered
here. However, owing to the additional degrees of freedom of the attracting-cyde
oscillator, there do exist additional instabilities through which such a population
can escape the mutually synchronized state to other modes of organization in time.
As far as lamaware (in 1978 and in 1999) these have not been systematically
explored.
232 8: POPULATIONS OF ATTRACTING-CYCLE OSCILLATORS

Oscillators of Identical Period

A particularly tidy mathematical study of this sort was carried through by Zwanzig
(1976) using an idealization of a mechanical dock: a piecewise linear attracting-
cyde oscillator (Minorsky, 1962 Figure 26.2). He specified the conditions under
which mutual synchronization is stable, at least for the case of identical oscillators.
Grattarola and Torre (1977) achieved the same for populations of identical van der
Poloscillators, suitably coupled. Neu (1979c) did it for chemical oscillators with a
circular attracting cyde.
I think the restriction to populations of identical oscillators is probably a
serious one. At least in simple dock communities (Winfree, 1967a), mutual
entrainment is a threshold phenomenon requiring contributions from a number of
oscillators proportional to the range of native periods they span. But in a population
of identical noise-free oscillators, that range is zero.

A Finite Range of Native Periods

Envision a two-variable dynamic flow with polar symmetry. As in Section A of
Chapter 6, suppose that phase increases at a uniform rate dependent only on the
amplitude and that amplitude also changes at a rate dependent only on the
amplitude. This is the)..-w model exploited by Kopell and Howard (1973b), the A-B
model of Ortoleva and Ross (1974), or the "radial-isochron dock" in the special case
of amplitude-independent angular velocity. In the limit of very rapid regulation of
amplitude to the attracting cyde, this is almost a simple dock (see Box A of Chapter
6). If the rate of change of phase is now made to depend instant by instant upon the
aggregate of all the oscillators' outputs ("influence" functions), then we have a dose
approximation to the situation encountered in Chapter 4. The main result there was
that, in a population with somewhat dissimilar native periods, interaction might
encourage or discourage synchrony, depending on the magnitudes and phase
relations of an influence and a sensitivity to that influence within the model
oscillator_ In the case of encouragement, synchrony arises by a collective process,
above a critical density. Some of these features carry over to populations of
attracting-cyde oscillators; for example compare Figures 6 and 7 ofWinfree (1967a)
about simple dock populations with Figures 1, 2, and 6 of Aizawa (1976) about
radial-isochron dock populations. Kuramoto (1975) successfully dealt with this
limit, in the special case of interactions similar to molecular diffusion between
chemical oscillators. Grasman and Jansen (1979) generalized the results presented
in Chapter 4 for the case of mutually coupled relaxation oscillators with at least two
degrees of freedom.
 B: COLLECTIVE RHYTHMICITY IN A COMMUNITY OF AnRACTING-CVCLE OSCILLATORS 233

Systematic Reorganization of Amplitudes

Unlike simple docks, any attracting-cyde oscillator is able to deviate from the
common cyde during rhythmic perturbation. In the simplest cases each oscillator
adjusts not only its phase but also its amplitude, which depends on the relative
phase while entrained. This not only alters each oscillator's contribution to the
aggregate rhythm but also alters its mode of response to further rhythmic influence
and, typically, its period too. One consequence is that mutual synchronization may
be stable, but only after it is initiated: If mutual coupling falls briefly, mutual
synchronization is lost and cannot again arise spontaneously from the disorganized
state (Winfree, 1966, 1967a, and further computer simulations of 1978-1979
circulated privately). Another consequence of labile amplitude is that chemical
oscillators, mutually synchronized by free exchange of reactants through molecular
diffusion, are susceptible to instabilities of a wave-like nature in space (Nicolis and
Prigogine, 1977; Ashkenazi and Othmer, 1978). Through such diffusive instabilities,
spatial gradients of phase or even discontinuities akin to shock waves can arise
(Howard and Kopell, 1974, 1977; Neu, 1979a).
Prodded by instructive conversations with J. Mittenthal in 1969, I ran extensive
computer simulations of a population of van der Poloscillators in order to explore
the range of validity of the simple dock approximation. Except in the limit of very
strong amplitude regulation (large 1-'), new modes of behavior were readily
demonstrable, all of which involve systematic dependence of the individual
oscillator's entrained amplitude on its native period. These phenomena induded
splitting of the population into two oppositely phased parts and inability of the
initially randomly phased population to approach mutual synchrony even though
synchrony was stable once achieved (by entraining the whole population to an
external rhythm). Informal circulation of these results, and discussions with
Mittenthal and Pavlidis, led to much mathematical analysis but no broad
generalizations. You may wish to consult analyses of special cases by Pavlidis
(1969, 1973), Linkens (1974), Aizawa (1976), and Aldridge (1976, p. 77). Aldridge
and Pye (1979a,b) point out that if the oscillators' attracting cyde and steady state
both attract, then perturbations may have lasting effects on collective amplitude
even when oscillators are strongly coupled: by bumping some of them into the
steady state's attractor basin.
234 8: POPULATIONS OF AnRACTING-CYCLE OSCILLATORS

Hysteresis
van der Poloscillators are typical of attracting-cycle devices in their weil -known
hahit of entraining to rhythmic input in more than one stahle way. These
alternatives give rise to hysteresis if the driving frequency is varied up and down.
They also suggest that mutual synchronization in a population may admit almost as
many waveforms as there are oscillators to choose hetween alternative modes of
entrainment. Viewed in the aggregate, a population of many such oscillators would
then appear to have a continuum of neutrally stahle waveforms and amplitudes,
rather like a Hamiltonian oscillator. We saw such behavior in populations of
coupled simple clocks in Chapter 4. And in Chapter 7 we saw it in the fruitfly's
 8: COLLECTIVE RHYTHMIClIY IN A COMMUNIIY OF ATTRACTING-CYCLE OSCILLATORS 235

circadian rhythm, which might reasonably be suspected of a composite origin in

many imperfectly synchronized cells.

~ ,In 1999 tl)ls Susplclon ec Des in t e qirect 9DseIVations 0 /il atrtz ef a. 1997~ -ana
of Hege ·et al. (1997J, However the first senten ce of tne Rreceding paragraph is
mistaken, Non-self-sustaining oscillators db inäeed·1ypically e·ntrafh stably at either
of two pmases about a half"cycle apart, one with a high amplitude ana one with a
low amplitude, but tf:üs is not typ1cally the case with self·sustalned (attracting limit
cycle) 0scillators (fiayashl, 1964; Abraham and Shaw, T982 p. 196: Ueda, 1992). The
plasticity of collective amplitude obseNed in populations of simple docks (Wlnfree
1966, 1967a, 1979; Daido 1995, 1996) has not yet been reported from experiments
withattracting-cyde populations as far as r know. Nor has "~ctive seatter," alias
"antisyntalansis," i.e., reol'"ganization of pbases'to buHer 'o ut any lmposed would-be
entrain}ng rhYthm in the same modality as the uni! !;lscillators influence Md
corresponding sensitivity. Nor l1as the bistability/hysteresis discussErd il:l Box F of
Chapter 4, in Winrree (1996 Note 2; 196?a-oFigure' 9; 1979 Quest.ion \!II}: Ir") theory,
and in one simulation l!.sing 10(1 van der Poloscillators, syntalansis can ·oe ,ah
attractor above a certai.n collective amplitude ' even though it dcas not arise
spontaneously fr9m low collective amplitude. lt is cone ivable tl1at these modes are
stable only in simple dock pop latioh$, whereas the); "are unstable among oscillators
with the additional degre~ of freedom to chang~~ amplitude. Simulations JI'f the
1960s often showed su~h po pu atiolils segregatillg jnto. two isolated clusters in the
state plane, whose outputs sum to rnake a collectjve rhythm almost· devoid of first
harmonie power:, t6 which each cluster cap accordingly entrai.n at eittler of two
alternative hases. "0lIl •

The Chemistry of Coupling

At a less abstract level of analysis, one would like to know what mediates the
interactions between biological oscillators of each kind.
The Physarum plasmodium, in which myriad nuclei synchronously fission,
seems to represent a case of very strong interaction (see Chapter 22, Section B). The
chemical nature of the coupling factor remains to be discovered (still so in 1999, I
believe). Nor does anyone yet know what substances synchronize mitotic timing in
yeast cells dividing in suspension culture (Halvorson et al., 1971) or cultured
mammalian cells (Dewey et al., 1973),
Gooch and Packer (1971 and 1974a,b) impute to the ATP-ADP ratio a
dominant role in mutual synchronization of respiratory oscillators in
suspensions of mitochondria; according to Holmuhamedov (1986), the spatial
patterns observed in a thin layer of such suspension indicates metabolic
coupling between them. Aldridge and Pavlidis (1976) and Aldridge (1976)
demonstrate that cells in a well-stirred suspension of oscillating yeast cells are
metabolically coupled in a phase-dependent way. The troublesome challenge is
to guess what molecular messenger couples the cellular oscillators. None of
the presently envisioned candidates satisfy all the presently envisioned
requirements.
236 8: POPUlATIONS OF ATTRACTING-CYCLE OSCILIATORS

The adenyl cydase oscillation in social amoebae presents a well-studied

example of attracting-cyde oscillators synchronizing through chemical coupling.
The chemical is cAMP. Gerisch et al. (1975) and Malchow et al. (1978) contrived
ways to perturb this oscillation in suspensions of single cells, with much promise
for combined experimental and theoretical investigation of mutual synchroniza-
tion.
In the case of circadian rhythms, not much is known about the channels of
communication through which the various organs stay synchronized during
prolonged residence in an arrhythmie environment (Moore-Ede et al., 1976,
Sulzman et al., 1978). Sometimes they don't stay synchronized.

C: Spatially Distributed Independent Oscillators

Oscillators Arranged in One Dimension Without Interactions
As long as they don't interact and we leave to them to their autonomous kinetics,
attracting-cyde oscillators run near a fixed cyde almost like simple docks. Qnly
their reaction to perturbation reveals their lack of constraint to the one-dimensional
world of simple docks. This section examines the spatial consequences of a
rephasing perturbation, building on the examples used in Section C of Chapter 4,
and leading to a reconsideration of wave-like patterns in space.
 C: SPATIAllY DISTRIBUTED INDEPENDENT OSClllATORS 237

Reversing a Pseudowave
The first principle at work here is, again, the principle of a "pseudowave." You
saw one of these the last time you noticed the chain of flashing strobe lamps at
the end of an airport runway. The lamps flash in quick succession, giving the
appearance of a ball of fire moving toward the runway threshold. This is not a
wave in the usual sense: It is not a propagated disturbance. It is just a spatial
gradient in the timing of strictly local oscillators. Its speed is simply - lI(d(jJ/
dZ)T, T being the period. This ball of fire can "move" at any speed, even faster
than the speed of light if the phase gradient is shallow enough. Moreover it
takes no notice of whatever ostensible barrier might be erected across its path.
That is why in my first publication on chemical oscillators and their wave
behavior, 1 distinguished this case as a pseudowave (Winfree, 1972c; see also

Figure 3. A three-dimensional diagram shows how the <p' vs. I/>

resetting curve revises a phase gradient in space (x). The resetting
stimulus reverses the gradient between points x = a and x = b.

Beck and Varadi, 1971; Thoenes, 1973; Varadi and Beck, 1975). It has since
been called a "phase wave" as weIl. In the slightly more general context of
spatially graded period (from which emerges a changing gradient of phase),
Kopell and Howard (1973a) called it a "kinematic" wave. They demonstrated the
irrelevance of an impermeable barrier inserted after the gradient was
established. 1
Now what would happen if a one-dimensional array of independent oscillators,
spatially graded in phase, were exposed to a phase-shifting disturbance, spatially
graded in magnitude? Consider, for example, exposing a dish of oscillating malonic
acid reagent to a flash of ultraviolet light. Vavilin et al. (1968) and Busse and Hess
(1973) showed that aphase shift results, though they did not systematically measure
its dependence on phase and on the energy of the flash. But let us suppose behavior
typical of an attracting-cycle oscillator. A sufficiently brief exposure would induce
only slight phase shifts and would therefore leave the geometry of preexisting

Their excellent paper in Science was delayed in publication by the referee's (my) insistence on that
experiment; meanwhile Thoene's (1973) almost identical paper appeared in Nature, but without the
critical experiment. The same experiment, in this case proving that electrical wave trains in the brain are
not pseudowaves, was performed by Petsche et al. (1970) and Petsche and Rappelsberger (1970).
238 8: POPULATIONS OF AnRACTING-CVCLE OSCILLATORS

pseudowaves qualitatively unaltered. Local phase gradients would be changed in

proportion to the ratio dtjJ'/dtjJ (from dtjJ/dx to dtjJ'/dx) resulting in aproportional
change of pseudowave speed in that region. The direction of propagation would
remain unaffected.
The story would end here were we still thinking in terms of ring devices, whose
response to a temporary disturbance consists entirely of a phase-dependent change
of rate along a fixed cycle. But in this chapter we deal in attracting-cycle oscillators.
A somewhat larger perturbation can therefore elicit aresetting cwve with a region
of negative slope dtjJ'/dtjJ < O. This inverts the local phase gradient in space and so
turns pseudowave velocity backward (Figure 3). (Note also that at the boundaries
of this region, where dtjJ'/dtjJ=O, there dtjJ'/dx=O so pseudowave speed is infinite, not
0). Figure 3 shows the old and new phases at time t = 0 at each point x. We transfer
the new tjJ'(x) cwve from Figure 3 to Figure 4 now (dropping the prime) and watch
as tjJ continues to increase everywhere. The pseudowave can be visualized by
considering how phase changes everywhere as t increases from 0: Every tjJ(x)

t>O

t·o Figura 4. The revised phase pattem <PVc> in Figure 3 changes

in time as all phases increase together. Pseudowaves appear
to emerge from point x = a and vanish at x = b.

a b

increases in register. As the tjJ(x) cwve moves up the tjJ axis its points of intersection
with any Une parallel to the x axis are found to move. The points at which tjJ=O
might be taken as wavefront markers. At unit inteIVals of time two pseudowaves
now emerge from point a, and at a later moment they annihilate each other at
point b.
Preliminary to incorporating nearest neighbor interactions into this picture, we
should note that in the preceding figure we made use of a map from the line
segment 01 to the phase eirele §1 (rolled out along linear coordinate axes). It will be
convenient to draw pietures of the Une segment mapped into the state space of the
oscillator. Let's now put that map into context by changing the target space to W',
the D-dimensional spaee of chemical concentrations (or whatever other variables
might define the oscillators' state). Such a map can be visualized as an embedding of
01 in RD • Specifically 01 maps along the attracting cyele in RD in Figure 5 as specified
 C: SPATIALLY DISTRIBUTED INDEPENDENT OSCILLATORS 239

figur. 5. The x axis of Figure 3 before perturbation is mapped onto

the attracting cycle of the local oscillation.

by cp(x). Figure 6 shows this map transfonned to cp'(x) by a stimulus. The ostensible
source point a and collision point b are indicated.

Rhythmic Fungi Again

For more practice in thinking geometrically, reconsider the case of Nectria, the
fungus that makes spores only in periodic patterns of ring or spiral topology. When
we first considered these patterns it sufficed to think. of phase maps from the
frontier ring to the ring of phases of a simple elock. The moving frontier left
rhythmic zonations in its wake. But how are we to think. of the origin of pattern in a
genninating spore or very tiny mycelium? This question will be examined more
elaborately below in context of two-dimensional media, but we ean make a
beginning here while thinking only about the one-dimensional outer border, the
frontier of the mycelium. Because it has the connectivity of a ring, its image in any
state spaee that identifies the loeal eomposition is also a ring. Reeognizing that the
ungenninated spore is donnant, we might reasonably suppose that the oseillation
eneountered in the large, mature myeelium began from some unifonn state in the
germinating spore or in the very small myeelium. Thus the frontier' s image is
initially very small, lying quite elose to the pregennination state. Suppose that state
is the repelling equilibrium state of whatever reaetion engenders rhythmicity later

Figur. 6. Figure 5 is revised in correspondence with the resetting

curve diagrammed in Figure 3. After perturbation point x = a leads
the image around the cycle, while point x = b is the last to
experience each event.
240 8: POPULATIONS OF ATTRACTING-CVCLE OSCILLATORS

Figur. 7. A ring of 15 cells, initially near equilibrium and encirding

it, diverge toward the attracting cyde in Figures 5 and 6. The
winding number of latent phase is unchanged because the
oscillators are independent.

on. The equilibrium lies within the convergence of isochron surfaces (not shown) in
state space. In fact the equilibrium state is the unique convergence point of the
isochrons if we suppose for a moment that the oscillation is engendered by
interaction .between only two variables, so that the state space is only two-
dimensional. In this simplification it is easier to see that the frontier ring necessarily
has some integer winding number around the ring of phases represented by the
converging isochrons. Each isochron indicates the latent phase of the oscillation
prior to realization of its destiny on the attracting cyde. So the winding number
realized here and now foretells exactly the winding number and therefore the
pattern type of the mature mycelium. (In contrast to Chapter 4, Seetion D, in which
we had this result for coupled simple docks, here it requires absence of coupling.)
In this two-dimensional simplification the unperturbed trajectories of Figure 5
diverge from the repelling equilibrium, so that every oscillator on the frontier is

w=o

Figure 8. Situations analogous to Figure 7 are

{J
+~~ N depicted at an early moment when all cells are near
~\ to equilibrium. A ring of cells (with north, east,
W=l +
~ l~jI south, and west points indicated) has winding
S number W = 0, 1, or - 2 about the phaseless set
E (here shown simply as an equilibrium point). At the
right we see the rhythmic pattern that will form on
an expanding mycelium whose frontier has each

-+18
_ winding number shown.
W=-2
 C: SPATIALLY DISTRIBUTED INDEPENDENT OSCILLATORS 241

independently carried out toward the attracting cyde. [In D-dimensional space,
they would diverge from the entire (D - 2)-dimensional phaseless set.] The
frontier image expands onto the attracting cyde without ever changing its
winding number (Figure 7). The winding number could only increase or
decrease through a stage in which some part of the frontier's image crosses over
the convergence of isochrons. But the local reaction flow is away from that
state.
The crucial point of this story is that because the initial conditions are
arbitrarily dose to equilibrium, their winding number is determined by initially
arbitrarily minute fluctuations about that equilibrium composition (Figure 8). In
that respect this diagram rationalizes the observed polymorphism of pattern in
mycelia grown under seemingly identical conditions from genetically identical
single spores (Winfree, 1970a and 1973d; and Chapter 18).

Oscillators Distributed Across Two-Dimensional Space Without

Interaction
As in the one-dimensional case, the new features introduced by substituting
attracting-cycle kinetics for simple-dock kinetics are (1) the attracting-cycle
oscillator's different pattern of rephasing by a stimulus and (2) the existence of a
phaseless locus in the attracting-cycle oscillator's state space, where latent phase (a
function of state) can suffer a discontinuity while the state itself still changes
continuously.
The new feature introduced by substituting two dimensions of physical space
for the single dimension to which we previously restricted our attentions is the
possibility of applying a stimulus gradient transverse to a preexisting phase
gradient. This is the format of the pinwheel experiment, by which the time crystal's
helicoid and singularity were discovered in circadian docks, in oscillating
glycolysis, and in transpiration in plants.
My purposes for this section are to describe the pinwheel experiment in terms of
a map from two-dimensional physical space into state space and to exhibit a similar
mapping derived from our consideration of Nectria's growth rhythm.

Pinwheel Experiments: Two-Dimensional Arrays of Independent

Attracting-Cycle Oscillators
Suppose an extended medium such as a two-dimensional rectangle in which every
area element is oscillating on a common attracting cyde. For example, imagine a
dish of Belousov-Zhabotinsky oscillator, as in Busse and Hess' (1973) demonstra-
tion of local phase shifting by a focused beam of ultraviolet light. Let there be an
east-west phase gradient such as might have been established by the earlier passage
of a solitary wave of excitation from east to west.

~ Sometning lik:e tt)is experiment was- irnplemeJlte in 1.983: see for example Chapter
9~s Sgure 1.5 arfd. Amemiya et aL (1996).
. ~
The: expected.. phase singularities did
~
242 8: POPULATIONS OF ATTRACTING-CYCLE OSCILLATORS

As a geometrie convenience, roll up the rectangle to superimpose any repeats

of the full cycle of phase along the east-west gradient. We now have a cylindrical
piece of oscillating medium with a cycle of phase around its circumference as
shown in Figure 9. This is only a pseudowave. It sweeps around the cylinder as
indicated by the arrow. Now suppose we apply a stimulus graded in magnitude M
along the vertical axis, transverse to the circular phase axis. At the bottom of the
cylinder let M = O. At the top let M be "big" by the criterion that Type 0 resetting is
evoked. Consider the fate of a ring-shaped element R of the cylinder, shown in
state space in Figure 10. All points on R receive the same stimulus, but these
points are at all of the old phases cp on the attracting cycle. R initially has winding
number W= 1 around the circle of latent phases because the attracting cycle does
and R maps directly onto the attracting cycle. If the stimulus acts in a way
qualitatively resembling the models of Chapter 6, then R is moved off the cycle
during the stimulus. By the time the stimulus ends, R's image in state space may
or may not still have winding number W= 1 around the convergence of isochrons.

BIG

dc

M
Figur. 9. Phase has winding number W= 1 around a cylinder of oscillating
R medium. It is exposed to a stimulus for a longer time at higher altitudes,
resulting in winding number W=Q along ring R.
ab
0
0,1

~
For big enough M, it doesn't. It can have any other integer winding number in
general, or none at all in rare cases of discontinuity or degeneracy. But let's
suppose W=O at big M.
Figure 10 shows the terminal states reached by ring R for bigger and bigger
M. It is a mapping of the (cp, M) cylinder into state space. The convergence of
the isochrons necessarily lies within the stippled area. We know this because
between the ring M = 0 and the ring M = big, W has changed from 1 to O. More
formally, if both boundaries are traversed in one sweep along path ABCDA in
Figure 11 (a), then the winding number of new phase along the composite
border of the stippled area is 1. That means that a full cycle of isochrons enter
the stippled area but do not emerge from it. It also means that the stippled area
cannot be mapped continuously onto the phase circle. There mllSt be an
internal discontinuity. That is where the missing isochrons vanish. The tidiest
way to manage it would be a single point where they all converge: aphase
singularity. The models of Chapter 6 do it that way. Figure 11 (b) shows the
isochrons in the shaded area, converging to an internal phase singularity in
agreement with Figure 10. The shaded area being an image of the cylinder of
Figure 9, these isochrons can be drawn on the cylinder. Slitting the cylinder
along vertical element and laying it flat, we have the stimulus plane of the
pinwheel experiment [Figure 11 (c)]. The isochronsmay be regarded as level
 C: SPATIALLY DISTRIBUTED INDEPENDENT OSCILLATORS 243

Figura 10. After the stimulus of Figure 9 this cylinder is mapped into a
three-variable state space. Isochrons of the dynamical flow are schema-
tically illustrated by the "paddlewheel." The attracting cyde is the heavier
ring at the bottom. Before the stimulus the whole cylinder was on the
attracting cyde (similar to Figure 8 of Chapter 6).

contours of new phase fjJ' plotted above the (fjJ, M) plane. They therefore
describe a screw surface winding up around the critical stimulus (fjJ*, M*) as
observed in the several biological oscillators tediously overworked in this
volume.
The isochrons may also be regarded as the successive positions of a wavefront,
the loci of fjJ' = 0 on the cylinder. The wavefront circulates around the base of the
cylinder, on ring M =0, at the same time as it rotates, pivoting about (fjJ*, M*). This
(fjJ*, M*) remains stationary once all oscillators have independently recovered nearly
to the common attracting cycle, because then phase advances by the same
increment everywhere in each increment of time.
We've been through this argument before, perhaps too often. In each
previous context the object of interest was the single oscillator. Here it is a
population of oscillators, specifically a two-dimensional continuum. The argu-
ment is the same because the area elements of this continuum are here assumed
not to interact.
This idealization has sometimes been adopted as a useful approximation to
the mechanism of periodic patteming in two-dimensional films of malonic acid
reagent (Chapter 13). Thoenes (1973), Smoes and Dreitlein (1973), and Smoes
(1976) even went as far as to suggest that a11 the wave phenomena, spirals
included, can be so interpreted. According to this interpretation every volume
element is at some phase on the attracting cycle. The two-dimensional wave
pattern is then a contour map showing where phase = 0 at the moment. On
account of the phase singularity implicit in every rotating wave, this description
would be tenable only if it were acceptable to suppose (as Smoes' model does)
that arbitrarily small adjacent volume elements can remain at finitely different
phases Le., that the state variables of the oscillator do not diffuse significantly
on the time scale of this reaction's kinetics, even on a tiny space scale. But they
do, and in fact diffusion of HBr02 and Br- is the driving principle behind one
kind of wave propagation in this medium (Field and Noyes, 1972; Murray,
1976a; Tyson, 1976). Such diffusion-coupled waves are typically a few
millimeters apart, or less, and travel relatively slowly, on the order of several
244 8: POPULATIONS OF ATIRACTING-CVCLE OSCILLATORS

Figur. 11. (a) The conical image of the cylinder after a graded
stimulus (from Figure 10). Locus ab-dc is the cylinder element
(bI abcd in Figure 9. (b) Part (a) is redrawn to show intersection loci of
the cone with the isochrons and their phaseless set. (c) Parts (a)
D C and (b) unrolled and straightened into the rectangular format of <p
..---------~ x M (cl. Box Band Figure 13 of Chapter 2, Figure 13 of Chapter
4, Figure 13 of Chapter 5, Figure 6 of Chapter 6, Figure 18 of
Chapter 7, Figure 2 of this chapter and Box B of Chapter 12).

(cl

millimeters per minute. These oxidative "trigger waves," first described by

Zaikin and Zhabotinsky (1970), are probably what Busse (1969) and Herschko-
witz-Kaufman (1970) mistook for stationary "dissipative structures," and what
Beck and Varadi (1971), Varadi and Beck (1975), and Beck, Varadi, and Hauck
(1976) mistook (I suspect) for pseudowaves or kinematic waves. In contrast, the
waves observed by Zhabotinsky (1968), by Thoenes (1973), and by Kopell and
Howard (1973a) were spaced apart by centimeters or more, and moved at
speeds in the order of meters per minute. 1 think these probably were the
pseudowaves or kinematic waves expected theoretically by Beck and Varadi
(1971, 1972), Winfree (1972c), Kopell and Howard (1973a), and Thoenes (1973)
Le., phase gradients in a spatially distributed oscillating medium such as
reported by Hejnowicz and Wohlfarth-Botterman (1980) in Physarum. So far
they have been examined in detail only in one-dimensional context. See Box C
of Chapter 13.
 C: SPATIALLY DISTRIBUTED INDEPENDENT OSCILLATORS 245

use an-artificia oie s as Wiener an Rosen uel (1 40 reguire to p,reverit

creation of a pha,se singularity. fpsen et al. t1 97) cOniputed the like with no
artifidalhole using 60th complex Gillzburg-Landau equation solutiQn,s for ' any
field 'of oscillators near the Hopf plrurcation and spedficaHy the Belousa.v-
,lhabotlnsky €hemical oscillatQ[. .plus diffusion. Tnese d6 ct quite fulfilf' the
forecast in Winfree (1974e) that ;such' osollatory ("pseudo-wäve," "pnas -wave")
vortices wol1ld appeaf. in this cher:nical medium when someone figures out h0W to
instigate one, "because thä demonstrations remail"l thus farc o~ly computations (er
experiments ·with an artificiat hole). The flfpr~cast') ' ma be wrang, if afte so long
no such observation "has "been (eported. Is 1«:'I'1g ' a.bsenc Qf conflrtnation
e ulvalent to refutation? '~

The Ascomycete Frontier as a Two-Dimensional Population of

Independent Attracting-Cycle Oscillators
We turn back to the fungus Nectria for an example of attracting-cycle oscillators
arranged in a two-dimensional spatial continuum. In Chapter 4, Seetion C the
colony's frontier was idealized as a ring of ring devices. You may have wondered
at the time what is to be done about the interior of the colony which, after all,
constitutes both its overwhelrning bulk and the whole of the area in which
patterning is clearly visible. We mapped the frontier continuously onto the phase
circle, confident that this was only an act of selective attention, that the frontier
map was only a restricted part of the whole disk's continuous map onto the phase
circle.

1. A Point of Ambiguous Phase. But a paradox lurked in the circurnstance that

Nectria makes not only ring-shaped fonnations but, alternatively, spirals. The
frontier map for spiral morphogenesis necessarily has nonzero winding number.
But it is impossible to continuously map a disk onto the cirde in such a way that its
boundary has nonzero winding number.
Must the map then be literally discontinuous? Very steep concentration
gradients pose no challenge to the imagination but an actual discontinuity
would be hard to accept in a fine-meshed mycelium of richly interconnected
hyphae. Moreover, there is typically no hint of phase discontinuity at any time
during the mycelium's growth, as recorded in the visible zonations left by the
moving frontier. Is this discontinuity always kept away from the frontier? Even
in the tiny young mycelium? How could a tiny web of cytoplasm, less than a
millimeter across, harbor the fierce discontinuity of phase implicit in spiral
zonations?
Rather than answer such riddles, we could abandon the single-variable
simple-dock model for a more complicated, but more realistic vision of
oscillator dynamies: an attracting cyde in astate space of two or more
variables, as in any of the last decade's reviews of biochemical oscillations
(Higgins, 1967; Hess and Boiteux, 1971; Nicolis and Portnow, 1973; Goldbeter
and Caplan, 1976). In such reviews, there is not one ring device to be found. In a
previous seetion of this chapter OUf map of the mycelium's frontier onto the
246 8: POPULATIONS OF ATTRACTING-CYCLE OSCILLATORS

phase ring was accordingly revised, becoming a map into aspace of at least two
dimensions in which phase is a function of state as in Chapter 6. We look to
this state space of at least two dimensions for the state of each tiny patch of
tissue, small enough to be considered homogeneous, but large enough to have a
steady average composition.

2. Mapping. 1R2 --+ 1R3. Now it is time to quit restricting our attention to the
one-dimensional frontier. Figure 12 depicts a snapshot of the whole two-
dimensional mycelial disk mapped into a three-variable state space. I use
three dimensions instead of two because three is the most we can easily
visualize, and restrietion to two implicitly assumes some rather special
features that the fungus has not yet exhibited. I call it a "snapshot" because
Figure 12 only depicts each cell at its instantaneous combination of chemical
concentrations, and those concentrations are all thought to be changing
rhythmically in time.
The heavy ring represents the conjectured attracting cycle, and the finer
curves show how concentrations tend to that cycle "in the limit" of long enough
time.
The chief assumption implicit in this picture is that concentrations vary
smoothly in space, Le., nearby hyphae map as neighbors in state space. The frontier
maps wholly onto the attracting cycle. If its winding number is 0, then the whole
disk can map wholly onto the cycle. But Figure 12 shows a case with winding
number W f= O. Where is the continuity problem? Instead of a discontinuity of state
and the implicit infinite concentration gradient somewhere inside the mycelium as
required by the simple-dock conjecture, we have here a perlectly smooth variation
of concentrations across the mycelium.
If we insist on assigning aphase to each point in the mycelium, there still
has to be a phase singularity. But that no longer forces us to accept a singularity
in the biochemical state of the mycelium unless we insist on adherence to the
attracting cycle everywhere. The mapping to state space can be, and presumably
is, perlectly smooth. It is the further map from state space to the ring of latent
phase values that harbors the singularity, as explained in Chapter 6. And that
poses no paradox: there is no reason to expect an arbitrarily chosen function of
state ("latent phase") to be free of pathological behavior. The fine trajectories of
Figures 5, 6, 7, and 12 show how most sets of initial conditions lead onto the
attracting cycle.

Figure 12. An image of a disk of oscillating medium in state space,

supposing its border has winding number W= 1 around an attracting
cycle.
 C: SPATIALLY DISTRIBUTED INDEPENDENT OSCILLATORS 247

The cyde's attractor basin is necessarily shaped like a doughnut surrounding the
cyde. Even if the doughnut is puffed up to endose as much of state space as
possible, a part of its boundary (what bounded the inner hole) must thread the cyde.
In the less graphic terms of topology: Any eap bounded only by a cyde must contain
at least one point (an initial state) from which trajectories never return to the cyde.
Guckenheimer (1975) furthershowed that trajectories from nearby initial states
reach the attracting cyde at every phase. This point is the phase singularity first
intimated by the simple-dock model of Chapter 4. This point is a part of the
"phaseless set," the locus of D - 1 or D - 2 dimensions (codimension 1 or 2) from
which you cannot get to the attracting cyde by spontaneous processes without help
from outside. In Figure 12, D=3, so the phaseless set is one-dimensional
(codimension 2 in this 3-space). Specifically, it consists of the two trajectories
labeled with an asterisk.

3. The Genninating Spore. A mycelium with nonzero winding number constitutes

such a cap, so somewhere inside it is a patch of tissue with ambiguous or
indeterminate phase. Following this line of argument back in time to the very young
and very small mycelium, scarcely more than a germinating spore, we infer that the
single spore from which emerged a spirally-pattemed mycelium must have been in
or very dose to the phaseless set.
In principle a spore could contain any concentrations of the relevant
substances and still not oscillate until a parameter change during germination
disinhibits their chemical interactions. In such a case, the initial concentrations
would determine the latent phase of the whole mycelium, which would
accordingly go onto the attracting cyde homogeneously. A homogeneously
oscillating mycelium makes concentric rings. This is what most rhythmic
ascomycetes do.
Therefore any fungus that spontaneously makes spirals must have had its initial
conditions near the phaseless set. That means little in terms of concrete
biochemistry until the oscillating mechanism is chemically isolated, but it does
"predict" (or more correctly, rationalize) a somatic polymorphism, as noted in the
previous section and as observed in Nectria.
So if spiral morphogenesis is observed, then genetically identical spores,
cultivated under identical conditions, must be expected to develop into mycelia
bearing rings, spirals of left and right handedness, double spirals, etc. This is just
what happens in Nectria. The other two ascomycetes known to make spirals
(Penicillium diversum, Chaetomium robusta) also make rings, but further details of
their behavior have not been reported.
Note that the pattern originates in every case from the relatively homogeneous
initial conditions required by our assumption of smoothness of concentrations in a
tiny mycelium. Such homogeneity in a simple-dock model would imply homo-
geneity of phase and therefore concentric circular zonations. But the phaseless set
of the attracting-cyde model gives us the possibility of a phase singularity without
the biologically impossible state singularity. The state is initially relatively
homogeneous, but the divergence of trajectories from the phaseless set gives us a
deviation-amplifying device that soon puts points of the frontier at widely different
states on the cyde.
248 8: POPULATIONS OF ATTRACTING-CVCLE OSCILLATORS

Box C: Untested Implications

(1) We suppose that the angular distribution of phase around the frontier of a small
mycelium is achieved by small random displacements from an initial state. If this initial
tiny ring of states cannot adopt a variety of winding numbers, then it must not be dose
to the D - 2 dimensionallocus (where the isochrons converge) about which the winding
number is defined. Being tiny, it therefore does not endose that locus, its winding
number is W = 0, and its patterning therefore consists of concentric rings. In other
words, this model requires that a fungus which routinely restricts its rhythmic
patterning to one winding number must make dosed rings, as is most common among
rhythmic fungi.
(2) A disturbance that alters the phase of a biochemical rhythm does so by
temporarily changing the rates of reactions involved in the oscillation. Only in the
exceptional case that all rates change in the same proportion is the geometry of flow in
state space unaltered. Otherwise not only rates but also directions of flow are altered.
Thus trajectories previously constituting the boundary of the phaseless set during
unperturbed oscillation are replaced during perturbation by trajectories that cross that
boundary. A ring of oscillators encircling the phaseless set is then blown across it and
ends up lying to one side, no longer encircling the phaseless set (Figure a). Its winding
number has changed to W =0, so morphogenesis thereafter changes to concentric
closed rings.
(3) The same principles allow transition from rings to spirals, but only if the
stimulus is exquisitely timed. Suppose a frontier with winding number W =0 is
exposed to the perturbation diagrammed in Figure a. Suppose the stimulus begins
when the ring of initial conditions is exactly "upwind" from the phaseless set. Let it
continue just long enough to take part of the ring through the phaseless set,
changing its winding number from zero. If the stimulus terminates at this time,
spiral morphogenesis must ensue. If the stimulus continues longer then the winding
number reverts to zero as in (2). However, if the stimulus is applied at the wrong
time or in a mycelium initially too homogeneous in phase, then the winding number
remains W =o.

Figur. a. Similar to Figure 8, but the ring-shaped image of the frontier

is moving along trajectories of the perturbed dynamic. As it moves, its
winding number changes discretely. The five radiallines are supposed
to be isochrons.
 C: SPATIALLY DISTRIBUTED INDEPENDENT OSCILLATORS 249

. p ase singQlaritles ara p aces. IN ere tne oscll ator is at its steaay
state j L~., where its tWo state varrables" isocoocentration contours' intersec;t,
and if those cantours are independe~tly random in shape, then th~ meah
number of ~uch points ~hould be near (2/!.1') e/A, I! being tneir lengths witliin
a disk of area A = 1I'Rl. rt follo~s froni the observed !rlean of OA (or from
fhe power ' series In (4») that 1. '= 0,2 (211'R): pFe~u ably a smallish smooth
closed ting arol:/fIq an intemal extrei'num, at the
til'De .d ie oscil ators start up
in the 'initial mycelium. '. . .

4. Consequences. Three predictions follow from the foregoing (see Box C):
If a fungus makes patterns of only one winding number, then that winding
number must be zero and the pattern must consist of equispaced disjoint rings.
For example, there should be no mutant that makes only clockwise two-armed
spirals.
A fungus with spiral polymorphism should go on to make only rings if shocked
during gennination. (A shock is anything that disturbs the oscillator's mechanism
by the criterion that it inflects aphase shift on a rhythmic mycelium).
A fungus that mainly exhibits rings should sometimes convert to spiral
morphogenesis following a suitably tirned shock.

3. Potential Difficulties. There exist alternatives to the central conjecture

elaborated above that each tiny patch of mycelium harbors a continuous
attracting-cyde "dock" which functions essentially independently in each patch
and whose state varies continuously across the organism.
For example, more might be made of the inevitable interactions between
nearby patches of tissue: The model elaborated above achieves its seductive
simplicity by ignoring molecular diffusion and cytoplasmic mixing. Particularly
in very young and small mycelia, spatial coupling of oscillators could dominate
the launching of morphogenesis into concentric ring patterns. In the next
section of this chapter, a beginning is made toward incorporating such
interactions.
What about the many other internally rhythmic ascomycetes that do not make
spiral zones, but only concentric rings? Why the anomalous ability of Nectria,
Penicillium, and Chaetomium to make rings and spirals? Suggestions:
1. Conceivably the others, if they harbor biochemical oscillators at all, have
"simple docks." The simple dock can only have winding number W= 0
around a very tiny mycelium, and this can initiate morphogenesis only in
rings.
2. The critical feature of the attracting-cycle model for spiral polymorphism is
that the steady state changes from attractor (in spores and old, crowded, or
damaged hyphae) to a repellor (in rapidly growing hyphae) while staying
250 8: POPULATIONS OF AnRACTING-CYCLE OSCILLATORS

fixed at the same concentrations. For if it moved in concentration space, then

all the cells previously attracted would soon find themselves to one side of
the repellor and go into oscillation synchronously. Nearly synchronous
oscillation means W = O. It might seem a bit too ad hoc to propose a model
in which the steady state changes its stability without changing its position in
state space. But this idiosyncrasy is strictly necessary to account for spiral
polymorphism in terms of an oscillator model. It might thus account for the
phylogenetic rarity of the phenomenon.
Neurospora crassa (band, csp-l), which makes only rings spontaneously,
exhibits Type 0 resetting, so (1) is exduded for Neurospora. Dharmananda and
Feldman (1979, Figure 2) report that the banding rhythm usually starts up from
germination within a predictable third of the cycle. Thus the initial steady-state lies
off to one side from the convergence of isochrons in the mature dynamies. So (2)
seems likely for Neurospora.

D: Attracting-Cycle Oscillators Interacting Locally in

Two-Dimensional Space
To ignore interaction among neighboring area elements of a reacting continuum is
to make a gross approximation. Sometimes that is exactly what we want to do in
order to abstract an essential principle out of an incidentally more complicated
context. The appropriateness of such an approximation sometimes depends on the
scale of time and space we are concerned with, in relation to the time and space
constants of reaction and of Iocal interaction. But not here. In dealing with spiral
patterns we confront a topological difficulty that cannot be resolved without
invoking some kind of dynamical interaction between adjacent patches of tissue.
Why is that? According to the hypothesis of independent kinetics, every patch of
tissue promptly moves into the attracting cycle. The only exception is that single
cubic micron that initially happens to be poised in its phaseless set. If all its
neighbors soon begin to oscillate on the cyde, then this neighborhood experiences
oscillating concentration gradients of startling intensity. Unless the tissue be divided
up into Iargish chunks by nearly impermeable membranes, there will be arhythmie
exchange of materials between differently phased neighbors, and corresponding
modulation of Iocal kinetics.

Tying the Mycelium Together

Accordingly, we now add neighbor interactions. Specifically, let each area
element not only go about its own business according to its local kinetics but
also let it tend to adopt astate midway between its immediate neighbors, as
in the last part of Chapter 4. In terms of equations this is represented by
adding V2c to the rate equation of each state variable c - for exampIe, as
mentioned above, to represent idealized chemical waves with a radial-isochron
dock plus diffusion (Winfree 1972 computation lab notes; Kopell and Howard,
1973b analytically) while Field and Noyes (1972) were doing it properly with
 D: AnRACTING-CYCLE OSCILIATORS INTERACTING LOCALLY IN Two-DIMENSIONAL SPACE 251

Box 0: The Medium's Image in Concentration Space Behaves Like an

Elastic Membrane

As noted on page 141, the parabolic partial differential equation of reaction and
diffusion has the same form as the equation describing the movements of a simple kind
of elastic membrane immersed in a viscous flow. To make this metaphor explicit
imagine the membrane as a rectangular grid work of springs connected at four-way
junctions (Figure A). I wish each spring to develop mechanical tension in direct
proportion to the vector separating its endpoints. These forces add at each junction of
four springs:

Now suppose this bedspring is immersed in a viscous medium moving with velocity
v(r) at each point r. So let each junction r be subject to an additional viscous drag force
due to its motion relative to the local flow:
F(r) = k L (rNBR - r) + p,(v(r) - r)

If both bedspring and surrounding fluid be essentially massless, then there are no
significant inertial forces, F(r), to balance the spring forces and viscous drag. Then we
can write

r = v(r) + ~p, L (rNBR - r).

Now call k/p,=D and interpret r not as r=(x, y) in physical space but as C=(Cl, C2) in
concentration space. Interpret v(r) as the reaction flow R(c). And recall that ~(CNBR -c)
is the discrete approximation to the Laplacian:
c= R(c) + D'l2 c.
I find it easiest to "intuit" the solution of such equations by thinking of them as
motions of a thin elastic membrane caught up in flowing molasses. Its flow is exactly
the phase portrait of the local kinetics. Note that this metaphor is accurate only if the
diffusion matrix is a scalar, Le., all pertinent diffusion coefficients are equal. Thus it is
252 8: POPULATIONS OF ATIRACTING-CYCLE OSCILLATORS

close-to-accurate only in reactions involving molecules of comparable mobility and in

biological systems involving random bulk transport of all reactants, as in cytoplasmic
translocation in fungi .
• In 1999 my file 'case h.olds.47 Rapers examining chemical wave propagation
numerically/theoretlcany if') excili3ble media witH-.all rGactal'1ts diffusing equally,
only half of them after T980,.only fou! after 1990. I had expected that this wouJd
have been simpler mathematj<;ally andthe riehest vein for exploration, due to its
relati~e ease of cp"neeptualization. But it seems cle,ar in retrospect th 9t the Ilvisua
intuition'" I favored for this purpose eompletely missed the "meander" instability
(see berow' and in Chapter: 13), the spiral breakup that afflicts such . models i
certain parameter raf'1g~s, t~e Turing-like spatial p'sttems possible even Wi~
equal diffusion ~oefficients' even in tne absence of. a' Turing instabi!ity of the
'u~iform steady state (Vastane et al. ~ 198n the Turing instabilities expected at
nearly equ,al diffusion coefficients (Pearson and l:iorsthemke, 1989), and 'the
r!gid\y rotating scalar waves of Dellnitz et al. (1995)-see Box D of Chapter 9. In
all cases'the reason for these oversights seems to be that we (or at leaSt/i) bave In
fact surprisingly litt/e intuition for the dynamics of a massless grid of 'spririg~
wherr it is stretcheefin peeuliar ways while .dragged by eve!'} the simplest reaqiof,l
flows!, Both -ana!ysls anc:tgeometric intuition pre helpful in. retrospect, but it ~eems
that we needed numerical experiments (ormore faith in laboratory exper,i.ment~).
to discover these dramatjc. . .events. ..- ....
..

their chemically realistic model. Physically the added Laplacian is equivalent to

introducing molecular diffusion between adjacent area elements. Geometrically
it corresponds to confening on the image of the medium in state space a
coherence or integrity which (if all diffusion coefficients are equal) for many
purposes resembles an elasticity (in state space, not in real geographical space)
(Winfree, 1973c, 1974b,f; 1978a and Box D). Viewed in any of these ways, the
essential result is that the area elements can no longer depart freely from their
neighbors in state space. Nearby points initially have, and continue to have,
nearby compositions. Composition varies smoothly because extreme concentra-
tion gradients do not long survive unless aided and abetted by an extreme
irregularity in the kinetic rate equations.
With this understanding, Figure 12 contains less to disturb the skeptical
reader. Without local exchange of reactants, the center of the mycelium's
image in state space would be stretched infinitely thin and taut as almost all
volume elements independently approach the attracting cycle. With diffusion
res training the divergence of neighboring states, the map stays smooth as
sketched. In the absence of neighbor interactions, area elements initially near
the phase singularity would independently diverge, tearing a hole in the image
of the continuum or stretching it infinitely thin. Only that infinitesimal area
element that was initially exactly on the equilibrium state would remain inside
the cycle. But the effect of molecular exchange is to preseIVe continuity. The
image stretches toward the attracting cycle and thins out in the middle, but
not forever. Beyond a certain point the concentration gradients near the phase
 D: ÄTTRACTING-CYCLE OSCILLATORS INTERACTING LOCALLY IN Two-DIMENSIONAL SPACE 253

singularity are steep enough (area elements have moved far enough apart in
state space) that molecular exchange prevents further divergence. The
oscillation remains thus attenuated near the phase singularity, as it would
not were every area element independent. The image of the medium continues
to rotate and every area element oscillates synchronously. But full amplitude
is achieved at only some distance from the phase singularity. Area elements
near the phase singularity are in dose contact by molecular diffusion with
area elements at all phases of the cyde so that they scarcely vary in
composition.

Other Possible Outcomes and Interpretations

As described in the foregoing paragraph, support for this metaphor comes mainly
from numerical computations of specific examples (Winfree, unpublished, 1973 and
1974; Yamada and Kuramoto, 1976; Emeux and Herschkowitz-Kaufman, 1977;
Cohen, Neu, and Rosales, 1978).
There are (our main alternatives to the qualitative pictures presented above. The
first is that the whole situation could be subject to instabilities of a nonintuitive sort
in which the medium's image, initially girdling the cyde, pulls across the
convergence of isochrons, defying the local kinetic trajectories. After this, all rings
have winding number W=O, the whole medium oscillates synchronously, and its
entire image contracts to a point circulating on the attracting cyde. This happens in
my numerical solutions if the physical medium is too small or (the same thing) if the
reaction is too sluggish relative to the homogenizing influence of molecular
exchange.
The mathematics of Kopell and Howard (1973b), Othmer (1977), Ashkenazi
and Othmer (1978), and Conway et al. (1978) can be invoked to show that in the
presence of molecular diffusion (and/or random cytoplasmic streaming), nonzero
winding number of phase is unstable on too small a physical ring, though it is
perfectly stable on large. The critical size depends on the ratio of the diffusion
coefficient to a quantity related to the vigor of radial divergence from the
phaseless set (see Murray, 1993, section 14.9). Given W =I 0 in such an unstable
situation, the rate at which it evolves towards a switch to winding number 0
depends on these two factors and on the frontier's circumference, which is
meanwhile increasing as the mycelium grows, and might increase enough to
restore stability before winding number changes. But if it doesn't then only
concentric rings will be obselVed.
We still lack figures to test this conjecture for Nectria. But estimating the
effective diffusion coefficient at 10- 5 cm2/sec for extracellular small ions and
assuming kinetics such that the attracting cyde would be approached with a time
constant in the order of an hour, the minimum stable size for spiral morphogenesis
should be in the neighborhood of 1 cm of circumference. In Nectria, this represents
an age of about 50 hours. So it might be that in Nectria, unlike Ascomycetes that
embark only upon ring morphogenesis, intramycelial coupling is restricted durlng
the first 50 hours; or it might be that the ip.stability doesn't develop to completion
within that time; or it might be that the dock process is not disinhibited until at
least 50 hours after germination. In fact, this region never does develop dear
254 8: POPULATIONS OF ATTRACTING-CYCLE OSCILLATORS

Box E: Chains and Sheets of Coupled Oscillators

The behavior of oscillating continua has been of vital concern for over a centwy in
connection with mechanical vibration, acoustics, and optics_ From such studies of
crystalline solids we inherit the geometrie wonders of Brlllouin zones, Fermi surfaces,
and such useful technology as laser optics and semiconductor electronics.
On a more nearly macroscopic scale than that of atomic lattices, spontaneously
rhythmic living tissue and oscillating chemical reactions have acquired new interest.
What will come of it cannot be guessed as yet, but there seems good reason to anticipate
insights of comparable scope and applicability in the area of biochemical dynamies.
 D: ATIRACTING-CYCLE OSCILLATORS INTERACTING LOCALLY IN Two-DIMENSIONAL $PACE 255

inter epen ent blrtfi: an ' ea rates .)rwo ve .' a i · sion, .ana aisco\ler
p~opagating w~ves .(Pubois, 1975; Murray., 1993 Chapters 14 'anq 2n), ~istoricar
data CI" the two-dimensional.spread ofagricultural'societles in Neolithlc times, of
the Slack Death in the {oul1eenth tentury (Noble, 1974)" of rabies n mOdem
England(MlIrr.ay ~t al., :19.86), and of Africanized bees in the Americas (Rinderer et
al., 1993) reveal solitary ffonts of abundance 'ch.ange to whlcb. a- fixe ' speed
comp~tible with such 1nterpr~t~ion seems pJausibly imputea. T~e~e ~esemb1e
the waves featur'ed in the next chapter, M~ght .such fronts, tru'ncated, also
redrculate to bring about the locally r~current but globaOy incessan'f ep,idelTl'cs:
conjectured in Winfree'· (1974e)7 Tothe best qf my knojVledge', thi~ has still not
beert tned (ntJmeJi~al[~ I hor are there any con"incingl~ suggestive fieJd äa:tcl.
Contemporary olunpncohu,gions travel rather d~fferently,' due to airlines
connectrng remote populatton €enters near-instantanee\:Jsly {and in some
instances dissem'nfiting contagion aU along the airway, as in ~e sporadic cholera
outbreaks in '~urol?e and North Africa .4nder flights frorn India: Ronqle et a)., '
~~~~~______~__________a--
1978, The to 010 has chan ed .....

banding. I personally doubt that coupling by diffusion plays any important role in
Nectria, other than ensuring reasonable smoothness of the bands. But the foregoing
possibilities remain unexcluded alternatives to interpretations based on strictly
parochial oscillation.

The second conspicuous alternative to the simple ideas about Nectria

underlying Figure 12 is that while W "# 0 is preserved, the medium's image does
continue to rotate, but not rigidly: Area elements near the phase singularity dart
this way and that irregularly, always tethered inside the attracting cycle by the
requirements of continuity, but not stably so. This makes a rotating wave whose
tip, the apparent "center," is forever meandering. Many versions of the malonic
acid reagent exhibit such meandering centers (Winfree, 1973c; Rössler, 1977,
Rössler and Kahlert, 1979).
256 8: POPULATIONS OF ATTRACTING-CYCLE OSCILLATORS

,parameters of the reaction Kineti~ varieo. Wo gang -:Jannke, tnen an a vapce ,

undergraduata student visiting for a yearirom the University of Tübingen/. v~~ifjed
simllar meander ," flowers',! in the liiboratory (Ja nke et al., 1989), thus kicking P~ n
avafanahe of such investigations Usir:lg the maloni<; acid reagent and numerical'
models of, it (see Cliapter. 13). We later leamed that Rqvinsky (1986) had already
cornputed comparabl3 )piral waves, using, a qifferent cbernical mCiiael of the
~inetics, qut his didnot, meaAder, and that Zykov (1986) had already 0bs~rved
' meander f1ow~rs rn c-omeutatiQns with an eIKtrop."ysiolog;cally motivateä model
Bef?retne mid-80s my own Cl:omputations, like Rovinsky's, by chance had 'qll use
parameters outside tlw meander domain, in what we now recognize- as:;a low-
exeitabllity- frlnge of parameter space!'""Systematic vflriation of numeric:al parameters
,driving deeper into the- meander domain soon encou['ltered "hypermeander" in t
~hemjcal . model Oahnke and Winfree, 1991a; Plesser and Müller, 1995~ and se
new Chapter 16) but such ostensible irregularity has not yet öeen repolted I
parametrically unif0f'lIl .geJ.5 in lhe. laborato .. -4 ,~_.-'~~...

Ihird, it could weIl be that only the frontier oscillates. Hyphae left behind the
frontier in crowded conditions on staled nutrient medium might not be oscillating
at all. If the pertinent metabolic parameters differ so drastically from place to place,
then it is wholly inappropriate to map all those places onto a common dynamic flow
as in the foregoing diagrams. However, at least in the case of Neurospora,
Dharmananda and Feldman (1979) succeeded in showing experimentally that the
oscillation does persist, only slightly altered in period, at points sampled weIl behind
the frontier.
My fourth conspicuous alternative occurs first to most people, i.e., that the
local kinetics (neglecting transport) does not oscillate at all, but that the growth rate
at the frontier "stutters" due to an instability of the balance between inward
diffusion of nutrients and production of "staling" by products that locally inhibit
growth. With the proviso that any such model must involve at least two such
substances in order to accommodate patterns other than concentric rings (Winfree,
1970a, 1973d), this seems to me as plausible as the '10cal docks" model. The
question simply awaits someone to explicitly formulate a plausible model, verify
that it exhibits the obsetved delicate polymorphism in two dimensions, and point to
a distinguishing obsetvation.
And here we arrive at the badly frayed end of this story. There are good
problems here for applied mathematics students (Winfree, 1979) .

... See LakiD~Troma.s (1995)'for a su~ci'l~ summary".of the- Key ~results. ~ ~~~7;;N~>:I"C.:!m

As the take-horne lesson from this chapter, I emphasize a conjecture: that the
usual mode of organization in a field of independent oscillators is a wave rotating
around a central pivot (a point in two dimensions or a curve in three dimensions);
and that this remains so if neighboring volume elements are coupled by balanced
diffusion. The main difference in that the rotating wave becomes an Archimedean
spiral. The following chapter asserts that it even remains so if we now break open
the attracting cycle so that the medium is merely excitable. There we entertain
kinetic schemes similar to the hourglass kinetics considered in Chapter 3 in which
 0: AnRACTING-CYCLE OSCILLATORS INTERACTING LOCALLY IN Two-DIMENSIONAL SPACE 257

oscillation is not spontaneous. Such media, of course, do not support pseudowaves,

but given neighbor interaction they do support real propagating waves, even
pivoting rotating waves similar to those we encountered above. Some promising
starts have been made toward identifying the properties of these waves both by
numerical experiments in digital computers and by observing biological media of
practical interest such as brain and heart muscle.
 Excitable Kinetics and Excitable Media

The beauty of life is, therefore, geometrical beauty of a type that Plato would
have much appreciated.
J. D. Bemal, The Origin of Life

Chapter 3 on ring devices is followed by Chapter 4 on populations and communities

of such single-variable units: both simple docks and the nonoscillating hourglasses.
Chapter 6 on oscillators with more than one variable of state is followed by
populations and communities in Chapter 8. What about nonoscillatory kinetics with
more than one local state variable? That case is taken up here, together with
consequences of interaction in spatially distributed communities. The upshot is a
new kind of oscillator and a new kind of phase singularity, both of which are
apparently exhibited in diverse chemical and physiological systems. Even though no
isolated piece of it may oscillate, an excitable medium can organize itself spatially in
a way that stabilizes oscillation at a characteristic period. Architecturally, this
configuration more resembles a dock than anything encountered in previous
chapters: It consists of crossed concentration gradients, any one of which might be
taken as the dock's "hand," apointer that physically rotates about a fixed pivot once
in each cyde of oscillation. At the pivot, nothing changes; the pivot is a phase
singularity and all the rest is buHt around it.

A: Excitability

Clocks and Hourglasses Again

In Chapter 3 we encountered the simplest form of smooth oscillator, the simple
dock. We saw that a tiny, local change in its rate law converts it from a
spontaneously recycling dock into an hourglass. An hourglass is a system that rests
poised at a delicate equilibrium, waiting to be helped across a shallow barrier to
complete one cyde on its own. Both simple docks and hourglasses are ring devices.
Any ring device is excitable if a tiny but finite disturbance triggers it into a big
excursion followed by spontaneous approach toward the original state. If the
recovering excitable system sticks at an attracting equilibrium, awaiting a stimulus
to trigger the next excursion from that original state, then we have an hourglass. If it

A. T. Winfree, The Geometry of Biological Time 258

© Springer Science+Business Media New York 2001
 A: ExClTABILITY 259

-
(ol

-
(bl

Figure 1. Two ways for an attracting cycle to change locally, resulting in excitable kinetics
without spontaneous oscillation. Case (a) is initially an excitable oscillator; case (b) is not initially
excitable. These are sketches, not computations.

never quite stops but just creeps on to go spontaneously into another excursion,
then we call it a simple dock.
I called both by the name "ring device" to emphasize their distinguishing feature,
that the state space is a one-dimensionalloop. Real kinetic systems, however, can
seldom be realistically approximated in terms of a single degree of freedom. So in
Chapter 6 we generalize the ring device to a dynamic system with an arbitrary
number of degrees of freedom D. In such a higher dimensional dynamic system, all
trajectories can eventually funnel onto an attracting dosed trajectory like the unique
cyde of a simple dock. The same sort of generalization is appropriate in the case of
an hourglass. In this larger world of D-dimensional state space, attracting-cyde
kinetics and hourglass kinetics can be closely related through a smalliocal change in
the directions of trajectories. It is common for model biochemical schemes or more
abstract dynamic models such as the Hodgkin-Huxley equations to exhibit either
behavior, depending only on fine adjustments of some parameter (Figure 1). Box A
gives some examples in biological and biochemical contexts.
260 9: ExCITABLE KINETICS AND EXCITABLE MEDIA

Box A: Oscillation in Excitable Kinetics

Studies of biochemical kinetics have produced spontaneous oscillators, induding the

excitable kind that readily convert to mere excitability without oscillation. For
theoretical examples see Rössler (1972b,c, 1974a,b), Hahn et al. (1974), Karlunkel
and Seelig (1975), Othmer (1975), and Sanglier and Nicolis '(1976). The cAMP kinetics
of sodal amoebae exhibits this transition in real Iife (Cohen, 1977, 1978; Goldbeter and
Segel, 1977; Goldbeter et al., 1978); and so might the phospho&uctokinase oscillator of
sugar metabolism (Goldbeter and Emeux, 1978).
A conceptual model convenient to the themes of this volume is implicit in the radially
symmetric oscillator used in Chapter 6, Section A. There an attracting cyde was
approached by two variables according to kinetics described in polar coordinates as 1> =1,
R= KR(1 - R). With large K, this is practically a simple dock as noted in Box A of Chapter
6. Adding a uniform rate ofincrease of one concentration (e.g., ofx =R cos 21r1>, dxldt =C fV

271) as in Figure 1(b), theattractingcydeisscarcelydeformed, but changesto 1 +f(C/K)sin

1> as in the perturbed ring devices of Chapter 3. Above a critical C/K, the cyde is interrupted
by an attractor and repellor just as in the single-variable models.

Another dass of conveniently simple two-variable models are piecewise linear with
the two pieces of state space separated by a threshold level of one variable. This kinetic
scheme has been used for a long time to caricature nerve membrane (Offner et al., 1940;
 A: ExCITABllI1Y 261

Cohen, 1971; Rinzel and Keller, 1973), docks (Andronov et al., 1966), and excitable
reactions (Winfree, 1974b,f; Zaikin, 1975). The computation shown in Section C used
such a kinetic equation. With slight adjustment of the threshold level, it oscillates
spontaneously. By playing about with this model and with the malonic acid reagent I
believe I have shown that the wavelike phenomena described up to now in this reagent
come from a property quite independent of its oscillation, namely its excitability alone.

Excitable Media
Consider now an extended line, surface, or volume, each point of which harbors the
excitable dynamic system. Neighboring volume elements are coupled so that each
can excite the next. Such a continuum is called an excitable medium. Just as in the
case of the excitable continuum of ring devices discussed in Chapter 4, these
dynamically more elaborate media turn out to support waves. Analytic solutions are
more challenging than when only a single rate equation is involved, but some
examples have been solved explicitly. The most thoroughly explored equations, of
course, exploit some particular simplification. The commonest are:
1. Elimination of all but one degree of &eedom (examples in Chapter 4).
2. Incorporation of all the nonlinearities into a single threshold (piecewise linear
models: Offner et al. (1940), Minorsky (1962, Chapter 31), Andronov et al.,
(1966, Chapter 8), McKean (1970), Rinzel and Keller (1973), Winfree (1974b,f),
Zaikin (1975), Zwanzig (1976). The models of Tyson (1977a, Figure 3) and of
Zaikin and Kawczynski (1977, Figure 2) and of Goldbeter et al. (1978, Figure 1)
are geometrically essentially the same as the piecewise linear models .
.: AMr191.8 pie~ewlse linear ·kinet1cs. unoet1ay e.. p1ajority of RUsSian-language
p~blications o~ pFPRaga~ion. in .~xdtab'~ media: se~ for :.e~~mple, the papers of
P~rfilov,- of Pe-itSo~ 1 of Zykov ar:lcLtheir cit :tiPns. Barfdey 1 991: ~SPIRAL)--and Dowle'
e al. 199J:~ SSGROLp provided software wlth cqnvenien~ graF>hl ~Iln!eifaces -that
make a continu§us cublc excitable mediuf')"'(-even more eomRutatror]ally efffcient than
plecewise linear mod:els. ware exp~ct~d to be. l3arkley's modet currently plays a
p'!omiMot role in ongoln _dfscoveries..

3. Segregation of smooth continuous dynamics into one or two slowly changing

variables and one other that moves much more quickly (Minorsky (1962, Chapter
26) and Andronov et al. (1966, Chapter 10». Cens are commonly coupled only
through this fast variable [Hodgkin and Huxley (1952), Zhabotinsky and Zaikin
(1973), Karfunkel and Seelig (1975), Ortoleva and Ross (1975), Yakhno (1975),
Hastings (1976), Troy (1977), Zaikin and Kawczynski (1977), Collins and Ross
(1978), Fife (1979), and Tyson and Fife (1980)]. This dass indudes catastrophe
262 9: ExCITABLE KINETICS AND EXCITABLE MEDIA

theory models of excitable media and theirwaves (Zeeman, 1972; Winfree, 1973c;
Tyson, 1976; Feinn and Ortoleva, 1977; Schmitz et al., 1977; and Rössler, 1978).
 A: ExCITABILl1Y 263

A variety of wavelike phenomena have been derived or simulated in these

approximations. Some of these waves propagate through the medium by means of
an effect of one area element on the next, like the trigger waves first encountered in
hourglass media in Chapter 4, Seetion D. A trigger wave can travel stably as a single
isolated event, tending to a standard waveform and velocity. In a trigger wave, each
volume element's local dynamical excursion is triggered by encroachment of the
wave through neighboring volume elements. The triggering event propagates like a
grassfire, behind which the grass grows back after a while, restoring readiness to
conduct another trigger wave should one come along.

Rotating Waves
In Chapter 4, Seetion 0, we saw that, given a suitable spatial distribution of activity,
nearest-neighbor interactions can gloss over the slight difference of geometry (Figure
l(a» that determines whether or not an excitable kinetics will cycle spontaneously.
The result is that a ring ofpotentially quiescent hourglass material is enabled to sustain
rhythmical activity. Looked at another way, this is not remarkable. The period is just
the circulation time of excitation propagated as a wave on a ring of excitable medium.
Something more interesting arises when we cany over the same principle to two-
dimensional media. This was impossible in Chapter 6 because a rotating wave has a
264 9: ExCITABLE KINETICS AND ExCITABLE MEDIA

nonzero winding number about an interior disk, and that implies aphase singularity
inside the disko Phase singularities are verboten in continua composed of coupled
ring devices because they require infinite gradients of chemical composition
whereby all the different phases confront one another at the singularity.

As we saw in Seetion D of Chapter 8, no such dilemma arises in continua with two

or more dynamic variables. A two-dimensional rotating wave arises in every pinwheel
experiment, and its geometry can remain much the same when the adjacent
oscillators are coupled by diffusion. It is not hard to imagine the same thing
happening in media whose isolated volume elements do not spontaneously cyde, if
excitability is the dominant principle. Imagine how Figure 12 of Chapter 8 might
change while we change the Iocal dynamics as suggested in Figure 1 of this Chapter.
The alteration affects onlya tiny domain of state space, occupied at any moment by a
small patch of the physieal medium (the wavefront, roughly speaking). Because the
medium is cohesive, adjacent patches help along the patch that is temporarily
tempted to backslide into equilibrium. It is pulled away from equilibrium and
stimulated into another cyde of excitation. Thus the whole medium perseveres in
rhythmic activity almost as though the loeal kinetics were spontaneousIy oscillatory.
At the center of this rotation is a new kind of phase singularity. It is dosely
related to the phase singularities previously described in two-dimensional continua
of attracting-cyde oscillators such as the rhythmic fungi, circadian docks in plants
and flies, and oscillating glycolysis. This new kind of phase singularity differs from
those encountered before in that it fundamentally involves coupling between
volume elements by molecular diffusion. It arises in excitable media such as the
malonic acid reagent (Chapter 13), heart musde (Chapter 14), and slime mold
(Chapter 15). I call it a "rotor."

B: Rotors

A rotor is the self-maintaining source of a rotating wave. It arises about where the
phase singularity arose in the final seetion of the previous chapter.
B: ROTORS 265
266 9: EXCITABLE KINETICS AND EXClTABLE MEDIA

Figure 1.2: This 10/25/95 snapshot of a thin layer of cyclohexanedione excitable reagent was
recorded by green paneiescent background illumination. It shows two rotors, one of which was
targeted an hour earlier for on-line continuous identification by the criterion that the vector
cross product of (visible) ferroin concentration gradient with [Invisible) bromous acid
concentration gradient exceeds a threshold magnitude. Bromous acid concentration u was
guessed qualitatively by solving the second equation of the Oregonator model with input from
ferroin v color density observations (Winfree 1992, 1993a p281, 1994d p. 48):

u(x,y) = d/dt v(x,y) + v(x,y) - D \72 v(x,y).

This d/dt was estimated from the difference of successive ferroin observations at 4-second
intervals, and the Laplacian by summing the differences between neighboring pixels at one time,
and scaling by pixel size. The superposed fine black curlicue is the path ofthe spiral tip upward and
rightward during the prior hour. Note that this figure introduces "0' as the diffusion coefficient, a
usage that continues throughout this book. Its use as the dimensionality of astate space is
terminated here. And all subsequent mentions of "dimensionality" pertain to real physical space,
not state space. (From Winfree et al., 1996, Figure 6, with permission)
 B: ROTORS 267

E
0.30 0.20 0.10 0.05 0.03

0.00
0.10
0.20
0.30
0.40 *
ß 0.50 --
0.60
0.70
-<):t.,
0.80 "r
0.90 -4.
1.00
1.10
1.20
1.30
1.40 AO
aM
aR
ap
268 9: ExClTABLE KINETICS AND EXClTABLE MEDIA
 B: ROTORS 269

Initial conditions for a rotor can be set up by executing the pinwheel experiment
on an excitable medium whether or not it happens (as in that section) to oscillate
spontaneously. This has not yet (1978) been attempted in the laboratory in the direct
and obvious way, using a graded stimulus transverse to a phase gradient or a
traveling wave.

~
ffi
t
WEilt<

~
~ t
-STRONG-------- -------

~
:::E
i=
l
WEAK

~ ~
nMING GRADIENT

A B
C 0

FIgur. 1.5: Mirror-image singl,llarities created by applying Ci spatial y graded stimulus ta a

timil)9 gtadient in a erni~Uy excitabfe tned\nT1 ...(a) Schematlc of BfI'~n~ements in tpis- 16
mm square, fro019t27j83~ab book; (b) A fewseconds ratet; then (c~f)alf aminute later a stable
pail' 5)f rotors persist (d) oeyond passa~e of C1iverse transrents. In ccmnectio with cardiac
dysrhYtf!mia, this is calfed 'tRgure,.of-elght"· reentry in E-Sherif e al. (1985): {From Figure
f2.19 of Winfree, 1985, with errnisSfOQ.} .•
270 9: ExCITABLE KINETICS AND ExCITABLE MEDIA

Let me show the alternative ways it has been done. (in 1978) and then show a
few more pietures describing rotors in state space. Then we will turn to abrief
romance about rotors in three-dimensional excitable media (which, in 1999,
expands to become Chapter 16).

The Basic Anatomy of a Rotor

What are the essential qualitative features of the situation in Figure 12 of Chapter 8?
I see two:
a. A piece of the physical medium maps smoothly across the interior of the usual
cyde realized elsewhere, and
b. (which is the same. thing) within that piece the level contours of one state
variable are not parallel to those of another state variable. At the moment
captured in Figure 2, A increases from north to south within the rotating center of
the disk's image. B increases from west to east and Cincreases from southeast to
northwest. All three gradients rotate together.
I now argue backward to this situation from:
1. The observed existence of a spiral wave (see below)
2. An experimental method of creating a rotor by abutting a wave onto another piece
of medium not containing a wave (Winfree, 1974d, in malonic acid reagent), and
3. An experimental method of creating a rotor by shearing a preexisting wave
(Winfree, 1972c, also in malonic acid reagent)
1: To show that the existence of a spiral wave implies features a and b. Suppose a
wave rotates about a hole. On each ring concentric to the hole, nearly the same
 B: ROTORS 271

Flgure 2. As in Figure 12 of Chapter 8 but geographie labels are

affixed to the image, rotating with it. Three level eontours are
also indicated: one for A, one for B, and one for C. These are
fixed in eoneentration spaee and therefore rotate in relation to - - -A
the geographie labels in physieal spaee.

sequence of states is realized in clockwise order around the ring. In other words,
each ring maps with winding number 1 onto a common ring of states in state space.
Now plug the hole with a disk of the same medium and assume that the wave
continues to rotate around the former border of the hole. Suppose this central disk,
this plug, adopts a distribution of compositions compatible with the wave. How
does the central disk map into state space in such away that its boundary

c)

Flgure 3. The disk whose image appears in Figure 2. In (a), contour

lines of A rotate clockwise. At this moment maximum A oceurs in
the southeast and minimum A oeeurs in the north. In (b), eontour
lines of B rotate synehronously with those of A. At this moment
maximum B oeeurs in the east and minimum B oeeurs in the west.
The indieated wavefront is the loeus of A maxima on eoneentrie
rings. Altematively, a wavefront eould be a eertain level of A or B,
ete.
b)

continuously joins the border of the hole? It has to map across the interior of the
cycle in state space as in Figure 2. This is feature a.
Now let's do it in terms of level contours of concentrations A and B in the
physical medium (forgetting C for simplicity). Traveling clockwise around the
border or around any inner ring concentric to it in Figure 3(a), A must fall and rise
back to its maximum. Call the maximum of A along any ring the wavefront. Contour
lines of A are indicated. There are two branches of each level contour: one branch
272 9: ExCITABLE KINETICS AND EXCITABLE MEDIA

LL
Figura 4. If to each A level there corresponds a unique B level, then the image in
concentration space of any ring, and in fact of the whole two-dimensional medium,
/ would be one-dimensional.
A

(dashed) where concentration is falling clockwise and the other (solid) where it is
rising back again. A and B do not vary together along any ring, otherwise their cycle
in state space would be flat as in Figure 4 and there would be no asymmetry to
distinguish clockwise from anticlockwise circulation of the wave. B rises and falls
around each ring, but out of phase with A. Thus the central disk is seen to contain a
concentration gradient of A pointed north-south, and a concentration gradient of B
pointed east-west. It contains crossed gradients of these two essential state
variables. This is feature b.
In contrast, a disk of medium entirely on the excitation-recovery loop (therefore
necessarily with winding number W = 0) has all its concentration gradients parallel.
This can be seen as follows. Each point necessarily has some phase on the cycle, so
that contour lines of uniform phase can be smoothly drawn without singularities on
a snapshot of the disko All concentration gradients are perpendicular to those
contours. Thus they are locally parallel.
2: To show that a method of reliably creating a rotor is compatible with features a
and b. The method I have in mind starts with a wave in a two-dimensional piece of
medium and a second piece of identical medium containing no wave. The two are
shoved together as in Figure 5. Concentrations initially its outcomes are not
surprising vary discontinuously across the dotted seam. How do these disconti-
nuities resolve themselves into a continuous gradient? We depict the level contours
of A in the upper left half of Figure 6 and of B in the lower left half. The right half
shows how the concentrations would be expected to spread into the unexcited
medium in the first instant of contact, prior to any significant degree of reaction.
Figure 7 superimposes these two right halves. Gradients A and B are seen to criss-
cross through the cycle average values of each state variable in the stippled region:
This is feature b.

Figure 5. Two rectangles of medium are pushed into contact.

The one on the left bears a wave moving from bottom to top.

Now let's look at the same manipulation in terms of the images of the two blocks
of medium in state space. The left half block maps degenerately along a one-
dimensional trajectory from near-equilibrium through excitation and back to near-
equilibrium (Figure 8). This is the locus of states realized during the traveling wave
cycle. The right half block maps even more degenerately to a single point, the
 B: ROTORS 273

I
I
I
I
I
I

====__,
... - - - - ... --01

A AVG-
MAX
.::.:_-_:;;j
--------1
- - - - - ...--1
AVG-
------,,I

I
I
I
8 AVG-
MAX-
AVG-
I

FIgur. 6. (Ieft) A and B levels at the moment of contact in Figure 5. (right) Shortly thereafter,
when initial discontinuities of concentration have been resolved: equallevels (marked "AVG")
behind and in front of maximum connect together.

.. .. - -- .. . . _
Figure 7. The right of Figure 6, combined to emphasize ~_~_:-::_""'_':"'_':"':_"', "
criss-crossing of the average levels of A and B in the ~ \
stippled region. • _-.- __ __ _ ~~,

equilibrium. When the two are joined along the seam, each pair of abutted points
becomes the center of a little composition gradient stretching in a straight line in
state space from the composition of the left block at that point along the seam to the
(uniform) composition of the right block. Thus area elements from the inner edges
of both blocks are pulled into the interior of the cyde. This is property (a). This
procedure is implemented experimentally in Winfree (1974d) and is implemented
computationally in Winfree (1978a). It seems to bear an intriguing analogy to the
regeneration of limbs on animals manipulated surgically in analogous ways. (See
Example 11 in Chapter 10.)
3: To show that the ''shearing'' method of creating a rotor in an excitable chemical
medium is also compatible with features a and b. Start a solitary wave in a thin layer
of the malonic acid reagent. The wave propagates outward as an expanding ring.
Gently tilt the dish containing this liquid reagent, shearing the upper layers of fluid
relative to those doser to the bottom of the dish as in Figure 9. The east-west
shearing has little effect at the north and south edges of the wave because there the
fluid flows parallel to the wavefront. But at east and west the tilting stretches each
cylinder of uniform composition between dosely overlying and underlying layers
with composition much closer to equilibrium. Figure 10 shows the northeast
quadrant (shaded) of the circular wave before and after the operation of Figure 9.
Along the three radial Iod the chemical state initially varies from equilibrium
through a rise of A and then of B (the wave) and back to equilibrium (before, right).
But after the spatially graded mixing is carried out, the changes along path 3 are a
274 9: ExCITABLE KINETICS AND EXCITABLE MEDIA

Figur. 8. A is plotted against B along the wave moving up

ST'EAOYIV/"_--~
the left side of the squares in Figures 6 and 7. The entire
STATE ""':--_-.1 right half of each square is initially at a steady state (called
"equilibrium" in the text). At the moment of contact each
point along the seam abuts (radial lines) a point at the
steady state. The seam then comes to adopt a midway
composition (dashed).

,..,...-- -r--
I
L
1
,...... r--. ,
\ J
\
\
1
1\ ............ /:1 \-----1 :
............. - , / ,, 1
1
1
I
1
I
1
I
I
I
I

1I1 I 1I1 i~}~

o b c

Figur. 9. (a) A cylindrical wave propagates away from the center of a shallow dish of liquid
excitable medium; (b) the dish is tilted, shearing the cylinder; (c) only the north and south sides
of the cylinder survive, while the east and west sides are thoroughly mixed with liquid at the
steady state. The result is four free endpoints of wavefronts!

lot more attenuated than along path 1. The image of the shaded region, formerly
one-dimensional on aeeount of the polar symmetry of the original wave, hasbeen
made two-dimensional by the stimulus gradient. Beeause the stimulus eonsists of a
mixing of states originally present on the wave eyde (before, right), the new image
(after, right) fi.lls the inside of that eyde.

BEFORE~_[L
Figur. 10. The circular wave of Figure 9(a) and (c) is
mapped into the concentration space of Figure 8.

AFTER
 B: ROTORS 275

The image thus shows property Ca). The preceding paragraphs have repeatedly
shown that property (h) is equivalent. The result in this experiment is a rotor in each
of the four quadrants of Figure 9(c), with appropriate mirror symmetries.
276 9: ExCITABLE KINETICS AND EXC1TABLE MEDIA

Bibliography of Examples
Experimentally, rotors in excitable media have been on record at least since 1963.
Suzuki et al. (1963) had established such waves in a two-dimensional grid of iron
 B: ROTORS 277

wires in nitric acid. This is an electrochemical system which, in its simpler one-
dimensional arrangement, has been studied as an analogue to electrical excitation
in neIVes. Unfortunately, their Japanese publication and follow-ups were never
translated to English until 1976 (Suzuki) and came to my attention only in 1978.
With the exception of Yoshizawa (below), all subsequent rediscoveries in diverse
experimental systems were apparently also made in ignorance of the Suzuki result:
Rotors in excitable media were reported by Gerisch (1965) in the social amoeba
(see Chapter 15), by Yoshizawa et al. (1971) in an electronic network, by
Zhabotinsky (1970) and Winfree (1971c) and Zhabotinsky and Zaikin (1971a,b,
1973) in the malonic acid reagent (see Chapter 13), by Allessie et al. (1973) in
rabbit heart muscle, by Petsche et al. (1974) in rabbit cortex, by Shibata and Bures
(1972, 1974) in rat cortex, and by Martins-Ferreira et al. (1974) the retina of the
eye (see Chapter 14).

Using various mathematical approximations to an excitable (but not oscillatory)

continuum, persistent spiral waves were early produced numerically, analytically,
andlor via graphical arguments by Selfridge (1948), Farleyand Clark (1961), Buerle
(1962), Lukashevitch (1963), Balakhovsky (1965), Krinsky (1968), Gulko and Petrov
(1972), Winfree (1974b and f, 1978a), and Karfunkel (1975); and by Reshodko and
Bures (1975), Greenberg and Hastings (1978), and Greenberg et al. (1978) who work
with a reticulated medium like the one introduced by Moe et al. (1964) for computer
simulations of fibrillating heart muscle. Pursuing a more mathematical analysis,
Greenberg and Hastings (1978) ingeniously exploited a discretized analogue of the
winding number that plays such a conspicuous role in association with phase
singularities of continuous media.
278 9: ExCITABLE KINETICS AND EXCITABLE MEDIA

To give only one example of a rotor, I choose my own computations (1974b)

using piecewise linear kinetics. This dynamic invokes only two variables often
supposed to represent measures of excitation and refractoriness in nerve
membrane.

Figur. 11. A specific implementation of excitability using two

T variables named A and B as in Figure 8. The fine trajectories sampie
the vector fjeld of Equation (1), which is linear above and below
threshold T, The stippled ring with electro-physiological jargon on it
is the cycle roughly followed in waves of excitation.
 B: ROTORS 279

In that applieation, adjaeent eells are eoupled by diffusion only through the
first variable (voltage). I took the same kinetics to represent the neIVe-like
behavior of the malonie acid reaetion (Chapter 13), and so eoupled adjaeent
volume elements by diffusion equally through both variables (departures of the
eoneentrations of small moleeules from an equilibrium level).
Diagrammatically, the loeal kineties (without diffusion) is as portrayed in Figure
11. In terms of numbers,

~~ = - A - B (+ 20 if and only if A > 1)

dB A
dt
= 2'
In one simulation, a 1-mm square was divided into 61 x 61 eells, eaeh harboring
this kinetics. Eaeh interior eell was eonneeted to its four neighbors by Fick's law of
diffusion, aeeording to whieh A and B tlow between adjaeent eells at a rate
proportional to the instantaneous eoneentration differenees, A - A' and B - B',
respectively. (Boundary eells have three or two neighbors only.) Figure 12 shows the
result of a prolonged eomputation in which a rotor formed and stabilized. Eaeh area
element is here mapped into (A,B) state spaee. All eontinually revolve along paths
parallel to the heavy rings. A eentral area element (darkened) holds fast, its loeal
kineties exaetly balaneed by diffusion from its neighbors.

Figur. 12. A square of excitable medium bearing a rotor is mapped onto

the dynamical portrait of Figure 11. This is a moment in the periodic
steady state of a computation using Equation (1) together with no-f1ux
boundary conditions and crossed-gradl.nt initial conditions. Area
elements in this 61 x 61 grid deviate from the trajectories of isolated
homogeneous.

(c)

a b
Figur. 13. Figure 12 is replotted in dual representation as level contours of A (left) and of B
(right) on the 61 x 61 cell grid of excitable medium. The five circles are the ring paths of
Figure 12.
280 9: ExCITABLE KINETICS AND ExCITABLE MEDIA

Box B: Spiral Waves in the Sky

In the physical sciences we are accustomed to waves of diverse sorts, emitted as

concentric closed shells from a radiating source. But where is one to find a spiral wave?
1t tums out that they are not quite so uncommon as one might have supposed. In the
simplest case, a rotating source of particles wraps itself in aspiral locus; this is
apparently the typical configuration of the solar wind, e.g., winding through several
tums as far as the orbits of the middle planets (Gosling and Hundhausen, 1977). Though
the physical principles involved are a bit more subtle, much the same geometry arises in
the magnetic field surrounding a rotating dipole. This is thought to be a prominent
feature of pulsars (Ostriker, 1971). On a still grander scale, the process of massive blue
star formation is thought to be "contagious," resulting in solitary waves of creation
within the gas that constitutes most of any galaxy's mass (Mueller and Amett, 1976).
Behind the wave of creation lies a wave of type II supernovas and behind that lies a
refractory zone that persists until gas again wanders into the relative vacuum. The
simplest models of discrete-state excitable media (Wiener and Rosenblueth, 1946)
predict involute spirals rotating about any long-lived holes in the susceptible
continuum. Later refinements (e.g., Krinsky, 1968) allow spirals without holes if
discontinuities of local parameters be allowed. But even without these effects, galaxies
develop spiral structure through the continual shearing of waves by the faster rotation
of the galactic core (Mueller and Amett, 1976; Gerola and Seiden, 1978).
~ Elaoorations on tfiis tneme apReqred'in H"ernst an ·Assousa 1979), oza ura
and Ikeuchl (1984), Söhl11man and Seiden (1986J, Nozakura and tkeucht {1988),
and Seiden and Schulman (1990), ' combining excitable reaction-diff\:Jsion or'
celrular automaton models of. wave- propagat~on with .gravitational rotation to
interp~et the observed' structtlres of galactic arms vigorously lnvolQ,ed In star-
formation, The mode1s' "percolation phase transition" is WHgtt WI# caW thEt
pa'rameter-space proeagation boundary in Figure 1.1, above. The star's life cyde
provide~ a refra~ory period In tne molecular clöod. In dwarf galaxies (like Oil[
own Magellanic Clouds, Icicking density waves and spiral arms) "se f-propagating
stochastic star formation" is currentry considered the most Jikely ' mechanism
uodetJying dramatic bUJsts of hot starlight on the seide of 1 to"20 'illion yeal"S
(Harris .and Zaritsky~ 1'999 . · -

The less illuminating but more familiar dual representation appears in Figure
13. Here we see the square covered by level cantours of concentrations A and B. This
pattern rotates anticlockwise about the central pivot cell at constant angular
velocity, as shown in Figure 14. The corners, given compass labels N, S, E, W, are
indicated by heavy dots in Figure 12.
•6

rtgure 14. The angular orientation of the 8 = 7 contour line of Figure 13,
plotted at 1-second intervals spanning fifteen 12-second rotations.

o 5 10
TlME, AR8ITRARY lHTS
 B: ROTORS 281

Box C: Pastureland a5 an Excitable Medium

A "fairy ring" is a visibly distinct locus in a pasture or on a big lawn of grass that rather
resembles a circle or fragments of a circle. It turns out to indicate where a certain
basidiomycete fungus has recently been active. Parker-Rhodes (1955) wrote:
A large grass field carrying a system of fairy rings can be visualized as like a pond
in a light shower of rain. Each ring grows outwards at a constant (or irregularly
fluctuating) rate, and new rings are added to the system with approximately
constant frequency. When rings of the same species meet, then, unlike ring
waves on water, their intersected portions are obliterated; but as between
different species either or both may survive the intersection. The important
thing is that no ring ever remains still, but only stops growing when it dies.
However, all these processes take place with extreme slowness; in the rain-drop
analogy the rings grow at a few feet per second, and new ones appear at the order
of ten per square foot per second, whereas fairy rings grow at a few feet per year
and appear less often than ten per hundred acres per year.
Ritzema Bos (1901) used the analogy of a grassfire (moment of heat incredibly brief
compared to the interval before new-grown and dried grass is again ready to burn) in
describing how fairy rings constantly advance, sweeping around obstacles, mutually
annihilating one another in collisions and leaving a swath refractory to infection by the
same species for some distance behind the advancing wave.
Parker-Rhode's description, elaborated mathematically in Stevenson and Thompson
(1976), might he taken almost word for word to describe the bull's-eyes of concentric
circular waves in the malonic acid reagent (Chapter 13), except that the source, heing
the germination of the single spore, is not periodic. But he goes on to describe the effect
of a breach in the wavefront, such as might be induced by temporarily sterilizing a few
yards of soil:
Let us suppose that by some means ... a length ofthe perimeterof a growing ring is
abolished. The subsequent growth of such a ring should ideallyproceed with two
incurving horns which, when they meet, will reconstitute the closed perimeter
and at the same time abstrict a T-shaped portion from which a new ring could
grow inside the parent. Such a secondary ring will helong to the next impingent
group afterthat of its primary; the points of origin of secondaries willlie at a more
or less definite distance within the effective perimeter of the primary.
282 9: ExCITABLE KINETICS AND EXCITABLE MEDIA

Continued propagation of an interrupted ring cannot heal the

two open endpoints. They should become centers around
which spirals form. Fusion of adjacent spiral ares makes rings.

· .2'-~

'ttIfIl!I':
~I
J'I e
• r,. • '.
1
f.: -. t
1984 1996

Spiral Waves in Two Dimensions

In the preceding biophysical contexts among others (see Boxes Band C) a rotating
source emits a wave into the surrounding medium, which conducts the disturbance
at essentially uniform velocity. The resulting wave resembles aspiral with fixed
radial spacing between its successive turns. Along any radial path out of the source
one observes aperiodie wave train. Along any closed ring around the source, eutting
 B: ROTORS 283

each radius once, the phase of this rhythm undergoes a net change of one cyele: The
winding number of phase around the ring or of the ring's image around the cirele of
phase is W = 1. (See Figure 26 of Chapter 2).
To plot the time evolution of such a wave we might stack up aseries of
snapshots taken at unit intervals of time. The whole pattern rotates about its pivot as
time advances upward, sweeping out a screw-shaped surface (Figure 15). This
surface could also be constructed by plotting vertically the recurrence times of
excitation of each point in the plane or by plotting the phase of the rhythm at each
point in the plane as in the pinwheel experiment in Chapter 2. Any horizontal cross-
section through this surface is a snapshot of the spiral wave rotating in the plane.
As far as algebraic description is concerned, Archimedes' spiral is the simplest.
This is the shape of a neatly coiled rope and of the groove in a phonograph record. In
normalized polar coordinates (0 < () < 1, unit spacing between turns) it is described by
() = r.
This is the locus of any fixed phase rPo taken to mark the wavefront. To be
more accurate, this is the locus of a stream of partieles emitted radially from a
uniformly rotating source like a garden sprinkler. Regarded as a wave, this locus
has the peculiarity that its radial velocity rather than its velocity perpendicular

TIMe

Flgure 15. Plotting wave arrival time above the plane of a wave emitted
from a rotor is equivalent to stacking up successive snapshots of the
wave. The surface so constructed resembles a screw. Its singularity is
above the pivot.

.. In stereo color, Figure 2' of Lee leiter et al. (1991) displays exa y this in ,successive
s!1~shots of calcium waves in a Xenopus oocyte. In such noisy data tbe edges of these
conical funnels stand putdramatically in projection, as later illustrated by Davidenko et
al. (1992) 'and Pertsov e~ al. (1993) in even noisier optical recordings of voltage-
moduJated flu9rescence in.heart muscle. In an almost noise-free situation, Winfree and
i.lahnke (1 ~89) found thls feature useful to locate chemical V6ltex filaments three-
dimensional! . '~ .

to the local wavefront is everywhere the same. This difference is conspicuous near
the center where the perpendicular to a wavefront is far from radial.
Another description of aspiral wave emitted by a rotating source is obtained by
strict adherence to the assumption that the wavefront locally propagates at unit
velocity perpendicular to itself. This idea is embodied in Huygens' principle for
conduction of light or sound or any other disturbance in a uniform medium with
284 9: ExCITABLE KINETICS AND EXCITABLE MEDIA

uniform propagation velocity. Taking the most symmetrie case for illustration, one
might simultaneously adopt this velocity rule and a second requirement, i.e., that
the spiral wave's advancement in time be indistinguishable from a rotation. Taken
together, these two rules imply

( dB)2
dr = 1-
1
(27lT')2'
(See Winfree, 1972c, for a derivation in context of chemical waves.) This isto be
contrasted with the previous case, which might be rewritten:

(:y = l.
The difference is conspicuous only at small r. Note the curious dilemma: Unlike
Archimedes' spiral, this curve cannot continue toward the center beyond 27!T = 1
because then dOldr turns from real to imaginary. This conundrum draws attention to
the ultimate incompatibility of our two rules: Close enough to the pivot of a rotating
wave, movement must be slower than any chosen speed unless the rotation period
decreases toward zero.
This is the "involute" wave first described by Wiener and Rosenblueth (1946)
as an approximation to waves of excitation on the surface of the living heart
(Figure 16). The involute idea was later elaborated by Stibitz and Rytand (1968) in
context of experiments on animal heart and by Durston (1973) in context of
aggregation waves in slime mold. These models implicitly assume that the
underlying kinetics has only a single variable of state as in a ring device, and they
assume an unflinchingly steadfast velocity. On both counts such models conjure
unreasonable paradoxes at the pivot. Other reasons that an involute wave cannot
be exactly right are belabored in Chapter 13 in context of chemical activity.

Figura 16. An involute of the eirele can be drawn with a pencil tethered
to spool of thread, and unwinding it. If every element of are along this
loeus moves perpendieular to itself at the same speed (arrows) then the
loeus rotates rigidly.

Greenberg (1976) made an attempt to derive a spiral wave directly from the
general equation of local reaction and molecular diffusion, not limited to a single
reactant. The calculation becomes awkward near the pivot and was left unfinished
there, but further out it is possible to calculate the coefficients of an expansion:

( dO)2 = 1-~-~2 ...

dr r r
 B: ROTORS 285

and it tums out that, unlike the involute idealization, a # O. For more on this topic
see Chapter 13, Section D.
In thls general reaction-diffusion case, the phase singularity at the pivot does
not imply an unboundedly steep gradient of concentrations there. This is because in
kinetic models involving more than one variable of state aphase is not the same as a
state on the wave cyde. That the state of reaction near the pivot varies smoothly is
shown in computations by Gulko and Petrov (1972), Karfunkel (1975), Winfree
(1974b and f, 1978a), Emeux and Herschkowitz-Kaufman (1977), Yamada and
Kuramoto (1976), and Cohen etal. (1978). The former three use nonoscillating
excitable kinetics (the topic of this chapter). The later three use nonexcitable
oscillating kinetics (the topic of the previous chapter). The hybrid case works the
same way (unpublished computations, Box A). Cohen et al. achieved for the first
time a complete analytic solution for a rotor. At this writing (1978) its stability and
physical reasonableness remain to be checked.
286 9: ExCITABLE KINETICS AND EXCITABLE MEDIA

Ring Devices Can't Make Rotors

Men are rather beholden... generally to chance, or anything else, than to logic, for the
invention of Alts and Sciences.
Franeis Bacon,
The Advancement of Learning, 1605
My own rediscovery of rotors and the spiral waves they emit came about
through an experiment that I deliberately posed to check an argument alleging that
spiral morphology violates the most basic principles of physical chemistry.
My reasoning was (too) simple. Spiral morphology corresponds to aspiral
configuration of the contour lines of uniform chemical composition. The
topological essence of aspiral locus is that it passes an odd number of times
across any closed ring encircling the spiral center (Figure 17). But chemical
concentration contours, like the altitude contours of a geodetic survey map,
necessarily cross any closed path an even number of times. This is because what
goes up must come down in order to get back to the starting altitude or
concentration after one eircuit of the ring. So spatially distributed reactions can
only produce closed ring contours, or bits and pieces of closed rings interrupted by
the container's walls, but certainly not spiral contours converging to a central point.
The reason for seeking a way to test this seemingly obvious argument was the
discovery by Bourret et al. (1969) of spiral morphogenesis in the ascomycete fungi
(Chapter 18). Stuart Kauffman had brought this paper to my attention a few months
earlier, and I had envisioned an interpretation in terms of a biochemical oscillation.
 B: ROTORS 287

Figure17. Any closed ring around the inner endpoint of any single spiral cuts the
spiral at an odd number of places.

This interpretation had to be wrong if chemical concentration contours could not

have spiral configurations.
So when my student Andre Laszlo brought to my attention the recent
publication by Zaikin and Zhabotinsky (1970), we thought we understood why
only ring-shaped waves were reported there. To check this argument, it seemed
imperative at least to prepare the Zaikin and Zhabotinsky reagent, and to try various
tricks that might induce spiral waves if the argument were somehow mistaken.

It came as a bewildering surprise, on October 10, 1970, to behold several

perfectly stable spiral waves sedately rotating in a dish of this chemical reagent. This
saved the oscillator interpretation of ascomycete morphogenesis. But what was
wrong with the topological argument? My error lay in confusing composition with
concentration in the second paragraph above.
That identification is valid if and only if chemical composition, as it affects fungus
growth or chemical wave conduction, is determined essentiaIly by some single
concentration. Figure 18 shows that if composition varies in two or more ways, a locus

Figur. 18. A locus of fixed composition, determined by at least two independent

quantities, can cut a ring just once and then vanish (as A = 1 and B = 1 diverge).
2<""B:1
A-I
9-1
288 9: ExCITABLE KINETICS AND ExCITABLE MEDIA

of fixed composition (for example A =1, B =1) can cut a ring around the pivot at an odd
number of places while the concentration contour lines A = 1 and B = 1 each cut the
ring an even number of times, as they must. Thus, spiral morphogenesis in fungus
growth or in the malonic acid reagent is a mystery only in terms of single-
concentration interpretations. (In 1999 this mystery has transformed into another:
see Box D.) The alert reader may retort, "Okay, it can cut a ring at an odd number of
places. But to salvage the topological argument above requires that it cut any ring
around the pivot an odd number of times.1t can't do that unless the contour lines join
at a sharp angle at the pivot dot, which is physically unreasonable. Moreover, only one
compositionlocus could do so, but we're implicitly asked to believe that most, ifnot all,
compositions achieved along this spiral follow spiral contours."
That's right. The topology of a spiral cannot be maintained all the way into the
pivot. In fact, the "pivot" is an idealization, like the position of an electron, which
serves a purpose only when not examined too dosely. The practical essence of the
spiral is that there are an odd number of intersections along any ring hig enough to
securely endose the pivot, but the pivot cannot be localized within a minimum area.
To think realistically and precisely about the structure of this critical disk requires
that we turn inside out our habitual way of thinking about spatial distribution of
reactions, thinking of the physical medium mapped into a concentration space
rather than concentrations mapped onto the physical medium.

AI
AI Flgure 19. A wave is bounded both fore and aft by the same A
concentration level, although the composition differs fore and aft because
B's level contours are not parallel to A's (cl. computation, Figure 13).

AZ

In terms of composition involving two or more concentrations, there is no

equivalent to the notion that what goes up must come down. lt need not, so that an
odd number of intersections is feasible. An odd number of crossings is also feasible
in models based not on concentration (topologically, a point on the real number line
~)1, but on aphase of a simple-dock oscillation (topologically, a point on the circle
§)1. However, in this case the unavoidable implication is a discontinuity (e.g., a
phase singularity) inside any such ring. This is physically unrealistic in any
continuous, simply connected medium spatially coupled by molecular diffusion. So
simple-dock models are exduded in all these phenomena, just as are single-
concentration models (but see Box D!).
Another way to resolve the dilemma posed by a dish full of spiral waves is to
recognize that although a concentration level contour may be a wavefront, the
converse is not true: A wavefront is not a concentration level contour. It is part of a
concentration level contour, the rest of which goes around behind the wavefront to
cut the boundary again, thus ensuring an even number of intersections, and
removing the paradox (Figure 19; cf. Figure 13).
 B: ROTORS 289

".. ft is fIot po~sible that a.oontinuous rate equation, duldt = IM for a single real-
v~lued guantity, u, shoül~ osCHlate; Why not? Each vallJe of U' passed during t~e '
putative cycle wou.ld have tb-be passed·twfce,. once jising and ence falling. But
the rate eql:.latiorr appoirtts.ta.each value of u a unique du/dt, not the altemation
be~een successivelipositive and negative ratesr.equir~H er an oscilla~iorr. A
se~ond .stat~ variaoie i ne ed to rnaf(e that possible.- . "I
An evasion~ a sil'lgl~ ·§1:;valueä. Eiuahtity, tu r~named mnemot'\ically to ifJ tO I
~epres'ent< ~ ph'~se .o c:;ompass direction or h~e,. can ' cYc;le, e.9'1 dipldt = 1:
Each pna$e" i.s the passed only onc~ per c..yde( witfi unique 'angular veloci!y~
~ow tJ;y R.utting-this kind :cf sofution on -a disk, with tne initial phases around
e: rirn 0 tp'e:;äisk advancing tt1rough 9ne cycle-. Thisis a rotating wClve, but it
HCjI~. tbe probrem that ~cann'ot be contilluously defined ,evel)'Whera inside the
tne
!:IfP, al1d simplest possible' dlscontinuity is 'CI phase singulClrity. Conneeting.
~d}acen PQiot; bi p~äse Biffusion fadding a ~ap.lacian.to tbe r.ate equationr.
m,aRes. p~se cJiSCOFTt'IJuftie . impossible, but it ddep not resolve' this
impossioility of ~ontfn.u01:lS· definition: it simply rnakes it impossiBle to paye
.. oozero Wjndir;Tg n ITlber alohs ,the .boundalY or any other closed .GuNe,' an'd
thus· {Tlakes. rotating' wave~: impossible. - . . '. .~ -
":'The;'e~are 1)0 other.· 5i gle'-variahle manifolds 'than toe- Iiße an~ the. circle ' So
bave "we foqnd t~a~~spjrar waves on the. disk are impossible unl~s t):1e local
state variable has a~ lea_ st twe components? Wait a mpme t~ one c0T)1binati0n
as leff uritested: lirie-valued u with diffus(on. We ound it imposs,ible -only -in
qel aöser}ce of diffusion, implidtly assuming that aClding diffusion. woul(;/ only.
make_the- challenge inore difffcl!llt. 'Delln,itz et ~I. ' (1995) found that apding
diffusior,l actually remove~ th~ impossibility (which shoutd come as no surprise:
adäing d]ffusion to an 'o~ ioary d!fferential equatior:l changes it to a partial
differentlal"- equation, acting in .an infinite-dimensional state space where the
geometrie impossibility of oscillation -on. a..line segment no longer presents a
~rtinen.t constraint.). . '. ,
Tbey· constrocted rigidly rotating wave solutions on the dlsk for real-valued
äuld(= 'f(u) + diffusion! In 'particular, they show one- and two-armed spiral
w.a~es for bistable f{u) = >.u-u3 . Amazinglyenough, they (otate. Each value of
u. js indeed rJcountered at two (or other even number of) poil)t$ along every
dosed path around the center and pivot, but the added Laplacian diffusion
.,term alleviates ihe. problem mentioned' above, that tne rate had to be the
,same ,at botb points. Jt c(oesn't have to if the numedcal value of the local
[aplacian is different. This .can evidently happeFl in such a way that the:
' soluti6ns can oScillate, after' all! lhey found that solutions seem not to he
.st-a.ble, and they da not ftt finite no-flux 60unda!y. condi~ions, but tbe' fact that
any,thingöf, the. sort can e-xist ?t all is dramatically instr:uctive aöout jumping_t<;>
Jntuitively plausible' conclusions frGrn loose reasoning. ~
. See also -a- comment Oll this. .ingenrous cotrnterexample near the end of
Ch~Eter ;{,"<I( • ~ .,' ~ •
290 9: EXCITABLE KINETICS AND ExCITABLE MEDIA

The notion that the contours of chemical composition must be rings or

pieces of rings seems to have deep intuitive roots, perhaps because we take our
cues from the simplest conjecture that composition equals the concentration of a
single important substance. This notion impeded until 1969 the recognition that
"rings" in fungi are often spirals (and there is a huge literature of rings, going
back to pre-World War I German botanists). It impeded the recognition of spiral
Liesegang (1939) rings for thirty years; in fact the cover photo of a book on these
"rings" of chemical precipitation is in actuality (Figure 20) a photo of six parallel
spirals! While studying electrical waves on the beating heart, Wiener and
Rosenblueth (1946) conceived an otherwise fruitful single-variable model of
excitation that led them to the mistaken conclusion that rotors or phase
singularities could not exist. In their model spiral waves could exist but only in
the form of a wave circulating on the rim of a big hole. Selfridge (1948) refined
the argument to show that they could exist without the hole but only unstably.
Balakhovsky (1965) and Krinsky (1966) and Kuramoto and Yamada (1976)
argued for stability, ignoring the implicit discontinuity at the spiral's source. All
these problems evaporate when we quit restricting our thoughts to single-variable
dynamics.

Figura 20. Six spirals (one highlighted for this figure) from Rothmund (1907, Figure 1), as
pointed out by the photographer Liesegang (1939).
 C: THREE-DIMENSIONAL ROTORS 291

A similar assortment of riddles present themselves in context of morphogenesis

in animals. Locke (1960), Lawrence (1970, 1971), and Lawrence et al. (1972)
perceived the wrinkle patterns on insect cutiele as contour maps of the
concentration of a single morphogenetic substance. If a morphogenetic gradient
were ever found to run in a elosed ring, a fundamental challenge would seem to be
posed for the notions that the gradient is a substance gradient and that local polarity
is its direction of dilution.
This is exactly what has occurred in the case of limb regeneration in insects.
The elockface ("elock phase") model of French et al. (1976) and of Glass (1977)
meets the challenge of an ostensibly continuous circular gradient by entertaining
the notion of a morphogenetic phase variable. A phase gradient can elose in a
ring. To my mind, a tidier and more conservative approach would be to extend
the substance gradient paradigm to encompass two substances whose concentra-
tions jointly determine the local cell type. This would eliminate the phase
singularity and any suggestion of time periodicity. In more mathematical terms,
essentially the same response independently appeared in a paper by Cummings
and Prothero (1978).

C: Three-Dimensional Rotors

Isochrons and Phaseless Sets Again

An excitable continuum inhabited and organized by a rotor is driven
periodically at the rotor's period of rotation. Every volume element can thus
be assigned a phase relative to some reference elock oscillating at the same
period. What do the loci of uniform phase look like? The wavefront is one such
locus. Its earlier positions mark other such loci. We might call these loci
isochTOns (Iod of same time) even though in present context the isolated
volume element is not an oscillator. The isochrons are thus defined only in real
physical space, not in state space. Goodwin and Cohen (1969, appendix) adopt
this descriptive convenience in using the eikonal equation2 to assign a phase to
each cell in an organism whose development is supposed to be govemed by
periodic waves.
In the case of a rotating wave in two dimensions it is clear that the
isochrons necessarily converge somewhere near its center. If the wave strictly
rotates about a pivot point, like a picture engraved on a rotating tumtable, then
the isochrons converge toward the pivot (Figure 21). Inside a central disk of
circumference ~ 1 wavelength, recognizable phases are not realized, owing to
the mixing of states through molecular diffusion. But for purposes of gross
description, I want to ignore the finite dimensions of this disk, and now pretend
that isochrons come all the way in to the pivot point. Phase can be defined
operationallyon any cirele concentric to the pivot by simply watching the
periodic fluctuations of any concentration at any point. Whenever such a

2 The eikonal equation formalizes the notion that every piece of wavefront advances parallel to itself at
constant speed. See Keller (1958).
292 9: ExCITABLE KINETICS AND ExCITABLE MEDIA

Flgure 21. A rotating wave in the malonic acid excitable

medium (Chapter 13) is almost an involute spiral. Parallel
involutes drawn 400 p.m apart by computer approximately
mark past positions of the same wave. They are thus isochrons.
They cannot be reliably followed inward past the evolute circle
but appear to be converging to the pivot.

concentration reaches its maximum, call that phase zero and measure off a full
cyele of phase hehind it around the cirele through the pivot. Concentration
fluctuations on the tiniest cirele will not amount to much, so the chemical state
realized at each phase on a tiny circle is not identical to the state at that phase
on higger cireles where the full-amplitude cycle of excitation is realized.
Nonetheless, these isochrons permit us to deal with timing relations throughout
the whole continuum. (We can do this only if concentrations vary in a strictly
periodic way. They do in computer solutions of some equations, hut not in
others, nor in malonic acid reagent. In the latter cases the periodicity
approximation gets worse closer to the pivot. I wish here to sweep such
matters under the rug (in 1978».
 C: THREE-DIMENSIONAL ROTORS 293

y{;4
2 3

1 rnm
3 2

The isochrons so defined converge to a pivot that is therefore aphase

singularity. This simply means that there is no discernible timing relation here
relative to the reference dock for the very good reason that concentrations do not
change in time at the center of a rotating pattern.
What becomes of such a point in the larger context of a three-dimensional
continuum? Like the intersection of isochrons in state space, the zero-dimensional
convergence point of isochron lines in two-dimensional physical space becomes a
one-dimensional convergence line of isochron surfaces in three-dimensional
physical space. The simplest three-dimensional extension of the spiral wave is a
scroll (Figure 22).
294 9: EXCITABLE KINETICS AND EXCITABLE MEDIA

Figura 22. Scroll-shaped waves have aspiral cross-

section perpendicular to the pivotal axis from wh ich
they emerge. In (a) the axis is a short upright line
segment. In (b) it slants from floor to ceiling. In (c) it
curves around in a U. (From Winfree (1973b and c,
1974b) Copyright 1973 by the American Association
for the Advancement of Science.)

The scroll's rotation axis is the three-dimensional equivalent of the pivot point in
two dimensions. It is a one-dimensional phase singularity. This rotation axis
threads its way through the three-dimensional continuum as a filament of
ambiguity. As far as phase relations are concerned, Clark and Steck (1979) argue
that this actually happens in the migrating stirne mold slug.
 C: THREE-DIMENSIONAL ROTORS 295

Scroll Rings
How does the scroll axis end? It might not. Apart from the possibility that the
medium itself might end (at a glass wall in the case of malonic acid reagent), the
usual behavior of the scroll axis is to elose into a ring (Figure 23b». This may seem
strange. Isn't it rather unlikely that a one-dimensional locus meandering through
three-space should exactly elose on itself? Certainly so if that were the real structure
of this situation. Were we dealing with a continuum of ring devices, that indeed
would be the case: The isochron surfaces would be arbitrarily positioned, and so
would be their convergence, so that the locus of convergence would not typically
ever intersect itself or elose into a ring. But then neither would there be a
convergence locus: A singularity is a serious matter, strictly an impossibility, for
ring devices because it implies finite differences of state between volume elements
arbitrarily elose together.
So let's go one step further toward realism. A biophysically realizable excitable
medium typically consists of interacting chemical reactions. Its state is not
determined unless at least two concentrations have been specified. The organization
of reaction in space is a mapping of the physical continuum 1R3 or 03 into astate
space such as 1R2 • A whole one-dimensional set of the three-dimensional continuum
thus maps onto each composition. In particular the pivotal composition is realized
along a one-dimensional set: a thread in the physical continuum.
Looked at another way, the pivotal composition is a particular combination
of at least two concentrations. Call them A* and B*. Let's think about that. The
locus along which A = A * is some two-dimensional surface in three-dimensional
continuum. The locus along which B = B* is some other two-dimensional
surface. If a composition (A*, B*) is realized, it is an interseetion of those two
surfaces. So it is a one-dimensional locus. Though such a locus might end at the
296 9: ExCITABLE KINETICS AND EXCITABLE MEDIA

(]

O(Q)
b c

Flgu... 23. Aseroll ring may be envisioned by joining the ends of an imaginary cylinder
eontaining aseroll wave (a). This can be done as in (b) or as in (9. . im arting a twist of 3600 (or
multiples thereof) to the cylinder before joining its ends. ,.thirtk ihat this- was 'the' frrst Rrlnt
mention pf "twist" 0 . rotor p ase along, seroll 11 amentS, . an<:! of Cl" unref"ovable totar twi
loeked. into aseroll ring. A, few years later it was realized {hat for 1ess flat rings:the qual'ltiz
eonserved quantity is actu,aUy the $Um ofthat total twist pllB '~w'rithing'" twist canexchil,og
with writhing ,jf a ring ·develops torsion out ofth~ plane, i,lS indeed [t m~ i[ knott~ Winfre
ancl.Strogatz, 1988 b,c; see numedcatsimulation in Winfree, 199Gb Figura 24, and cl chemica
instanee in Welsh et al., 1990'Figures 6-8). But thefe-ls. still ho known Iqbo(atory case of a 'seroll
t nle~ it be the' interpretafion (Reitdorf et: al.. 1997) o(~MP 'f/ayes and eons~uent cell motill~
in the annular stime meld grex as a writl1e-rree scrollJlng wltl, several.eyges Qf tWist locRed i
(s~ th.e nexf~oR!c! "Fan Rings")." _ _ _ •...i."""._ _,;:....~......-"'~~_""--.:::;.c

boundaries of the medium (e.g., a glass wall), its typical configuration is a ring as
in Figure 24.
These arguments beeome stieky when one thinks of the state spaee as involving
three or more reaetants. And the geometry of mapping 02 or 03 _ 1Il3 with a singular
loeus closed in a ring is quite diffieult to visualize. It is not easy to bring our three-
dimensional geometrie intuition to bear on problems involving five or more
dimensions.

Figura 24. If two non-self-intersecting orientable smooth surfaees

intersect in three-climensional spaee, they typieally intersect along a
ring. The ring may be knotted.

Nonetheless let's forge ahead as best we can. If the seroll's axis typically closes in
a ring, then scroll rings should be easy to demonstrate in three-dimensional
excitable media such as the malonic acid reagent. This has been done. ScroIls of 1-
mm wavelength have been found in malonic acid reagent, with the axis closed in
rings of any length exceeding about 1 mm. This was demonstrated in serial seetions
of waves ehemically fixed in a three-dimensional block of reagent (Winfree, 1974d).
 C: THREE-DIMENSIONAL ROTORS 297

Flgure 25. Aseroll ring, slieed open along diameters (similar to Figure 22(e)
but viewed from below).

The photographically enlarged sections, reconstructed on stacks of Plexiglas sheets,

resemble Figure 25.

Fancy Rings
With that much established as fact, we are encouraged to ask the next question: What
other modes of ring closure might occur? For example, could the ring be knotted? Or
could the spiral cross-section be gently twisted through 360 x N degrees along the
length of the closed ring? [Figure 23(c)]. Or combinations of both? These are all
feasible geometries as far as the surfaces of uniform concentration are concemed. At
least the once-twisted, unknotted ring can be realized in terms of concentration
gradients from source Iod without cutting or otherwise doing topological violence to
the continuum. But doing so requires creation of another ring. The trefoil knot, in
contrast, can he arranged in solitaire (unpublished 1977 sculptures). Are such
structures stable then? I think probahly yes, at least as stable as the experimentally
demonstrated spirals, scroils, and scroll rings. Any instability would have to be based
on long-range interactions, since the scroll is locally stahle.
298 9: EXCITABLE KINETICS AND ExCITABLE MEDIA

Figure 26. Circular loci of fixed phase on the surface of a doughnut.

Only half of each cirde is visible. One of these cirdes is the edge of
the wave in Figure 23(c). The others are its earlier and later positions.
Any disk plugging the hole touches these iso phase cirdes in order
along its boundary. Phase thus increases dockwise through a full
cyde around this boundary.

"Long-range" here means several millimeters. In the ease of ehemieal seroll

rings in the malonie acid reagent, the typical time scale for long-range eommu-
nieation through diffusion is in the order of L2/D, L being the strueture's nominal
diameter. For aseroll ring of diameter 2 mm, with diffusion rates typical of small
reaetants in water, this is about 30 minutes. This is mueh greater than the I-minute
rotation period of aseroll emitting the typical I-mm waves.
As far as I am aware (in 1978) no one has looked into this matter
eomputationally or experimentally.
 C: THREE-DIMENSIONAL ROTORS 299

(1984) ·slioweCi oy aAalyticaf aRpraximatioh effectively that th.e ~exact - Iaw is

~(PJD) = r-8, a constant independent of.the choke of units for space and time.
Panfilov et al. (1989) generalized -it to d(4'AhrD)fdt = -8) where qrL2/4 for a cirele is
replaced by the. area A pf any arg~ p'lan'cir til)9J ·not necessari!y~'a perfect drele, This
t
ru!e. wa~ eonfir1)1ed to abdl.Jt ~± using rough ci~eles ih' ~emi<;al experiments with
substantialJy unequal diffusiool' a d. more exactly in numerical mpdels wi~h perfectly ,
equal diffusIon (review~d InWinfree, 1995b),. Mother way to write' the same rule: each
'segment> of fitarnent moves towacä'its center ofc~rvature at speed r:tear the product of
the diffusio~ coefffcient by the local cutvatt:Jl'e, or In teUTlS of a drele 0fradius R,.dRldt
=. :.. .DiR:.S ee Chap er .1Qfor .gel;leralizati~ms3. " , -, - ' •
It is sOl,11etimes 'comvenien , to d~oose 'the spiral wavelength and.period as natural '
. nits for f1 and.t. 'Then dL 2Ldt = ":'SD becomes dL21dt = -8/Q, where Q is the rotors
dirnEmsionless quality ' fcktOff .x/fOr0' _ ncited o~ page 278~ "lius; given equal
diffUsion, !iI .non-m"'eandering ring does irffäct collapse fn as many rqtation peri9ds as
GIB time ,its. initial sqt1ared (jiameter. {Wlnfree; 1995a Figure 10 shows how
me~nder cha.nges:this.}Cori~spondingly, dRldt =. -DIR be(;;omes dR/dt = .- tI.QR in
~e-- ne .. ynits-.We ar~ -ihus emandpated ..from 'cancern about the value of the
c!iffusion cOl=!fficient" which rSilnges .over nine orders of ma9ni~ude in problems- of
'in erest. '~ . , ~-' :- •

Some peculiar topological consequences invite testing by such experiments.

For example, in the case of the once-twisted seroll, phase runs through a full
cyde along any ring around the axis perpendicular to the plane of the ring
ambiguity (Figure 26). Waves emitted from this ring therefore converge in a
spiral toward that perpendicular axis (Figure 27). Along any two-dimensional
surrace bounded by a ring interior to the phaseless ring (the scroll axis), phase
has winding number W = 1. How is phase organized along such a surface? The
answer is a map of the two-dimensional disk to the phase circle. But we know
that no continuous map exists unless W = 0 along the border. Therefore, at
least one phaseless point (or locus) lies within every such surface. Since the
three-dimensional medium is composed of a continuum of such surraees, this
argument indicates a new phaseless locus of at least one dimension threading the
previously established phaseless ring. Does this new locus typically dose in a
ring, linking the first ring? Does it emit a spiral wave? Do all twisted scroll rings
necessarily come in linked pairs?
Such questions abound in the study (not yet undertaken, as far as I know in
1978) of three-dimensional continua of oscillators. We eonfront such media in the
malonic acid re agent (Chapter 13), in cardiac muscle and in brain tissue (Chapter
14), in aggregations of Dictyostelium cells conducting pulses of cAMP (Chapter 15),
in suspensions of yeast cells rhythmically processing sugar to make ATP (Chapter
12), in suspensions of mitochondria rhythmically making ATP by oxidative

3" ,Note the resemblance ofthi law to that fur ~rved wavefrorit propagation speed, c(ewvature) =
C(O) -'D ~urvattu-e. It i!.temptin~·to use thls for ä I).euris~c. derlva~on of cUIVed ~ent s~ed. ~een'er
ami. Tyson. 1985-). But It shoilld be remembered that tbis: IS the filament law only m media Wlth equal
ai(fusion of all reactints. and the wavetrontlaw oilly for. a solitiUywaverronfl fot wave trains at rotor
~ri~ as surro~~ filament) the..coefficientof curvarure isaoout twice ~t (Wellner'et al .• 19?7}.
300 9: EXCITABLE KINETICS AND EXCITABLE MEDIA

Figura 27. The twisted scroll ring of Figure 26 is repeated to show

the progression of phase through one cycle around an equatorial
ring. Every disk bounded by that ring must therefore contain a phase
discontinuity or singularity, presumably located along the hole axis.
The spiral wavefront shown in that disk is converging toward the
center, Le., it rotates antklockwise. The isophase circles covering the
toroidal surface are moving anticlockwise and outward along the
visible half of the torus shown.

phosphorylation (Chance and Yoshioka, 1966), and in three-dimensional tissues

composed of cells rhythmically dividing (Chapter 22) or harboring circadian docks
(Chapter 19). Any investigation of the geometrie and topological constraints
characterizing waves in such media would probably encounter something new
almost immediately.

~ This did indeed prove fruitful, mostly tl"irough mat ematica ana ysis supplemente
with computation from the complex-valued Ginzburg-Landau equations (Yakushe-
vitch, 1984; Skierski et aL, 1988 and' 1989; Frisch and Rica, 1992; Aransof"l et al., 199&,
Rousseau et aL, 1998i Gabbay et al., 1998j see ~x E Cf Chapter 8). The persistent
vortex tangles of Aranson et a.L (1998) resemble those familiar' in rnodels of supe.rfluid
helium (Schwarz,. 1988) ancl pemaps those of Fenton and Kanna (1998a,b) in excitabje
media. The helical filaments of Rousseau et al. (1998) ans of Nam et aL (1"9~8)
appatently arise in oscillatlng media by the same '!sproing " in.stability as Menze et a!.
(1990) described in excitab/e media, but those of Aranson et al. (1998) have a different
origin ...

There are few true firsts in science. Questions about rotating patterns of activity,
the threads about which such patterns rotate, their dosure into rings, linkage
among the rings, and interaction among such rings (attraction, repulsion, etc.) were
addressed a century aga by Hermann Helmholtz (1867) and Sir William Thomson
(1867) (later Lord Kelvin).

Vortex Atoms
Heimholtz, Thomson, and contemporaries were concerned with the luminiferous
aether, then considered as an incompressible three-dimensional fluid, a continuum
whose motions are organized by vortex lines not unlike the axis of our scroIl waves.
The idea was entertained that atoms are indestructible vortex rings in this or one of
the other aethers. According to this vision, moleeules are assemblages of vortex
rings, linked, knotted, knitted, and otherwise bound together. Thomson even went
so far as to calculate their hydrodynamic interactions in quantitative terms and to
show that the principles so discovered lent themselves to quantitative interpreta-
tion of binding energies in reactions fashionable to the physical chemistry of his
day.
 C: THREE-DIMENSIONAL ROTORS 301

Thomson's vortex atoms died a quiet death, forgotten rather than discredited by
experiment (apart from the experiments that undermined belief in the luminiferous
aether). Meanwhile general relativity and quantum mechanics have given back to us
something very like an aether for matter and for the ostensible vacuum. And in
excitable media we may have a new context in which something like the vortex atom
theory can live again, strangely transfigured.

~ A-compara . I~' spe ation (0 modem times:i ovolves soliton'S Ifl tnree-dimenslonal
Lagrangian fields H"ädeev and Nietni" 1991). Another evokes topologkal defects in the
vacuum state of il1tergalactic SPlace, alleged to manifest as "cosmic strings" of
rncrediblefinelless ( 0-30 crn thick), lengtO: (conceivably ~s tang ~s 1020 cm), density
(like a b,lIion neutron stars, squeeze int1:) the volume of an electron), mass (>1019
IgramsJcm); and velocity _(cloSEf ta· the speed of light). The Sciences deleted air
r.eferences ~from_ my" nbn-ted)h it~1 es~ay on ihis tqpic (Winfree, 1986c): its Key
strophysicalltems . er.e Kibble (1.980) and Vilenkin (1981" 1984, 1985~ ~ 986~, to wh ich
we can add in 1999 ~Ione fbrtY~some pap,eIs in theoretical physics joumals. Str4ngs arel
suppbsed to be;exotic relics of ihe fOl1l1atkm of tHe SP?ce-tiiTle .continuum, Th~Y are
top logica"y stabl~ ·elose rir:lgs in tne vacul1lm-aether around which 1t happened, at
the time cf a Yang-MiU symmetrY breakdown" 1o' adopt such phase- values of the
Higgs field tb at ooe can trace throug~ ;.t .fu!! c:y,cle of-pbase alohg seme closed path ..
akov ZeI1~ovich"ftorrr whom I leained 0 cosmk strings in 1283, pwposed that they
were tne. initial cause of :el~ster:lng in galaxies.. WOJciech Zurek suggested . studying ,
t~etTl"bY' aAalogy,"llSit)g "orte~ filaments in .superiluid helium. (Zurek, 1985;-,Schwarz
1;985, 1988; BaueKe et al. t 19961. In my view,~infi-ee, 1987a p. 241) the vort~x ünes in
the. malonic ~cid reageFlt br corr~poocliri9 nLlmeri.ca~' mdd~ls p"rovide. another
!nteresting al1alogy, ~s . they move b>l similar rules/ only in' generafJy orthogonal
{tirectlons. -For a oontinuatipn of sudl" themes in. fluid mecbani I see Ricca (1996,
1998). ., . • . ' ~
Th'ere are today other three-:di.!Tlensronal media in which' spatiotemporal -organiza-
tioti lsdominated by §croll waves; Besldes the Pltr'ely numerical onesr • and tne old
liquid diemical media, there are J:he intermediate liquid/solid '(living) media ,
lTi'ention~d ' above '?Ind' a new' one:. tnick heart museIe (see Chapter 17). Any solids"2
es, if Y0 !f~ count the new1y dl,s covered optical vorte5< filamen.~s In I~sing
se~icor'lpuctors (Scheuer and Orenstein, '9~9.) Whatabout gas phase? Brambilla et
ar. (1991) described something similar In lasing soefium vapor. But why are there no
gas-phase chemlcalfy re·excitable media? Weil, there are, for example in the two-
dimensional pre-mixed flame~ filmed by Pearlm_an and _Ronney {1994, ' 1995).
EXcitability is there limiled. to the two-dimensI6nai extent of' a flame front, in wh ich
spiral waves of hotter bumi~g ~re seen spin at about 100 Hz. Is it possible to have fully
thi~e.:dtfnensional repeatable exdtability in gas phase? lo find out; -I tried to make-
~ en'ca gas. With .a 'Ifttle help frollJ t ord Rayleigb .(l921.} and~a Ijttle care in handling
yellow pnos!=>horus; it proved feasjbleto' contrive a gas--phase excitable medium from
Rhosphorus Y9por.andvel)' difute o~geA.in a tissue-cufture flask. With eyes [bng dark
aClapted. on~ ~an see waves of.~ farnt : gl()~ propagating at roughly 2' em/sec.
RP'~r:ellti ·only a small proporti'on of -available reactants .is c~nsumed' be{ore some
side-reaction ioduees tempora !X; reffactorLness in each sLic'~~~sive combustion front,
302 9: ExCITABLE KINETICS AND EXClTABLE MEDIA
 CHAPTER 10

The Varieties of Phaseless Experience:

In which the Geometrical Orderliness
of Rhythmic Organization Breaks Down
in Diverse Ways

A cautious man should above all be on his guard against resemblances; they are
a very slippery sort of thing.
Plato, The Sophist, translated on p. 180 of F. M. Cornford,
Plato's Theory of Knowledge, 1935

In Chapter 1 we dwelt on the notion of smooth maps from one space to another. In
Chapter 2 it emerged that certain kinds of mapping involving circles cannot be
contrived smoothly. As an application we saw that certain kinds of experimentally
observed continuity and smoothness involving measures that are periodic in space
or time inescapably imply an unobserved (but observable) discontinuity. Aphase
singularity is one way to resolve this crisis of continuity implicit in the observation
of nonzero winding number.
The six chapters 3, 4, 5, 6, 8, and 9 elaborated a variety of dynamical schemes
commonly employed in biological time keeping. Those included were chosen for
two essential features: periodicity and smoothness of mechanism. In each case it
emerged that the topological crisis encountered in Chapter 2 has a parallel in the
more concrete terms of mechanism and structure.
This feature acquires a disproportionate interest on account of the thorough-
ness with which our sciences are permeated with the idea of smooth maps. An
assumption underlying almost all science is that similar causes have similar effects.
It is this rule of thumb that we implicitly invoke in supposing that our deliberately
simple-minded "explanations" of idealized aspects of things are useful approxima-
tions to the real causes of real-world messy phenomena. Without that faith, there
would be no laboratories in which especially simple versions of phenomena are
contrived for study and there would be no explanations of phenomena conceptually
isolated from an the goings-on that surrounded them.
If science is mostly approximation and approximation means a smooth map
from "cause" to "effect" then exceptional interest inevitably attaches to those
isolated states near which the cause-to-effect mapping loses its smoothness, even its

A. T. Winfree, The Geometry of Biological Time 303

© Springer Science+Business Media New York 2001
304 10: THE VARIETIES OF PHASELESS ExPERIENCE

continuity. There is little we can do to satisfy curiosity about such things when the
discontinuity is as abrupt as an earthquake, a mutation, or amirade. But if the
discontinuity is surrounded on all sides by smoothness Ce.g., the trajectories and
phase patterns of Chapter 7) and is even implicit in that smoothness, then we can
creep up on the exceptional event gradually and know why it has to be there. This is
the beauty of Thom's catastrophe theory, of the physical theory of state transitions,
of the mathematics of singular perturbation and, I would add, of the singularities
implicit in the geometry of biological time.
We have looked at the smooth geometrie patterns of timing Cor more abstract
phase) that surround singularities, by which their existence is inferred. This we did
both abstractly in Chapters 1 and 2, and in terms of component processes in
Chapters 3, 4, 5, 6, 8 and 9. We now fix our attention steadfasdy on the organizing
center of those patterns: the singularity itself.
In doing so, Sections A and B below will again follow the outline of
mathematically oriented Chapter 2. Section A consists of four intuitively familiar
cases, followed by five cases involving biological docks not necessarily involving
physical space, then eight more critically involving spatial periodism. Section B
consists of three cases in which there may exist a physiologically important phase
singularity, but if so it cannot be inferred just from the geometry of smooth timing
relations elsewhere. I hope you will find it useful in connection with many of these
brief statements to read the corresponding chapter of experimental background in
the Bestiary.

A: The Physical Nature of Diverse States of Ambiguous Phase

Example 1. Color Vision. A short list of the most tantalizing mysteries
prominent in daily experience could hardly exdude human color vision. Even the
simplest aspect, the dassification of homogeneous colors according to hue along
a color wheel, has no parallel in psychophysics unless it be that we dassify
musical tones along a cyde by perceiving a repeat at octave intervals. This
analogy, together with the color sensations induced by suitably timed rhythms of
black and white, has prompted suggestions (1999: never yet substantiated; see
review by von Campenhausen and Schramme, 1995) that the neural coding of
color is somehow basically rhythmic, involving periodic patterns of firing by
visual neurons. Unlike disparate musical tones, two superposed colors vanish into
a new color. Implicit in this fact is a singularity of hue: a color of no hue or of
ambiguous hue. Obviously this is merely gray, obtained by mixing complemen-
tary colors.
In present context the most important fact about gray is that it is a
singularity only from the limited viewpoint of hue measurements. When one
takes account of saturation as well as hue, gray no longer seems discretely
different from nearby colors. Suppose there were mutants who perceived only
hue and intensity, but not saturation. To such a person the singularity of hue
would present a striking phenomenon. But when colors are distinguished
according to saturation no singularity is perceived. It is evaded by the
saturation going to zero at gray, making all hues indistinguishable: Grays
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 305

slightly tinged by any hue are all perceived as similar, not as disparate points
on a color cyde.

Example 2. Navigation in a Rowboat. Here again the singularity is an artifact

of an artificially restricted viewpoint. If we attend only to direction of
movement, neglecting speed, then the zero of velocity is a singularity. A boat
rowed directly upstream so as to remain at rest with respect to the shore has all
directions or no direction as you like. An arbitrarily small perturbation directs
the rowboat in any direction. It is much the same in correcting the compass
with the two little magnets attached to screws mounted in the case (Chapter 1,
Section C, Example C): At a certain setting, the Earth's magnetic field is exactly
neutralized and any further adjustment, no matter how small, can give the
needle a preferred orientation in any direction. Only the delicacy of its mounting
hides from us the fact that the magnitude of the orienting field is passing
through zero at the singularity of direction. In the same way the directional
singularity implicit in wind patterns revolving about barometric highs and lows
resolves itself simply in a calm at the center. Even in a tornado, the center is
becalmed as far as compass direction of flow is concerned. The conservation of
mass is satisfied by evoking an overlooked dimension; the wind roars straight
upward.
So it is with singularities in general. As noted in Chapter 2, Section C, the
ostensible singularity is always evaded by bringing into play a degree of freedom
that remained inconspicuous everywhere else. This comes as a surprise only if you
really didn't think there was another degree of freedom. The way in which that
evasion comes about can be most revealing, a viewpoint which fanciers of black
holes will warmly endorse, and which I also adopt in connection with biological
docks.
To return to the rowboat and its compass, nothing of much interest transpires at
these singularities except that some vector passes through a reference zero in a
perfectly smooth way. These singularities amount to little more than artifacts of the
choice of coordinate systems and consequently have no further interest.

Example 3. What Time Is It? On the scale of global time keeping, just as in the
eye of a hurricane or a tornado, a singularity is inevitable: It is a pivot, a point of
zero amplitude rotation, an axis about which the whole Earth turns. Viewed from
this axis the Sun neither rises nor sets each day but simply boxes the compass,
invoking a new degree of freedom, an "amplitude" of the day-night cyde, which is
zero if the Sun keeps constant altitude. (All this supposes our observations to be
made on the equinox, or else that we first straighten up the Earth's spin axis relative
to the plane of revolution about the Sun. Without such tidying, or on other days of
the year, the timeless place is a finite disk and the isochronal contours converge to
its edge more like Figure 10 in Chapter 5.)

Example 4. Timing the Tides. An equally smooth attenuation of amplitude with

geographical presumably explains the amphidromic points of the global tide charts
(though to be strictly correct, I don't think anybody has ever identified such a point
and monitored the sea level there).
306 10: THE VARIETIES OF PHASELESS ExPERIENCE

~ In August 1840 Captain Francis Beaufort actually did, at a plaee where the tide
eonsists mainly of just one' harmonie component. How.ever theorlsts -eould not
understand jt.so the observation was suppressed (Cartwright, 1999, page 1-14-15).
Direct observ~tion ~y satellite-based radar;.in ,the.1990s corroborates digital solutions.
of enormous systems of equatiöns'confirming the apparition of seores of.!!mphidromi 1
points throughout the world's oceans. ... .
The tidal range falls to zero at each such point, with nearby points of the ocean
surlace slightly rising and falling in sequence around the horizon. It is worth noting
that this vanishing of amplitude pertains only to one harmonie of the tide. It is not a
vanishing of fluctuation because the other harmonies generally have their
amphidromie points elsewhere. In this respect the singularities of the tidal rhythm
resemble those of attracting-cyde oscillators, though actually they are driven by the
Earth's rotation under Moon and Sun. Putting such an oscillator into its phaseless set
typieallyensures only that the subsequent trajectory, wherever else it might go, does
not lead back to the standard cyde. This phaselessness amounts to absolute
timelessness only in the special case of an oscillator with only two degrees of freedom,
whieh in the case of the tides may correspond to recognizing only a single harmonie.

~ Thls principle-- that the pliase"singularitieS'of Clistmct .incornmensurapfe frequeney

components typically appea(Ooat distinct geograp~icallo ation~ - is eVident al~o ift the
meandering of"rotors 'n exr;itable media. ... . .

Example 5. The Fruitfly's Body Clock. Does any of the foregoing provide a
useful due to the meaning of phaselessness in circadian rhythms? And what has the
fruitfly to tell us of such matters? First of all it does not seem likely that
phaselessness in the fruitfly represents phase scattering in a population of simple
docks, if only because it can be achieved in mere seconds even under dim light. It
seems unreasonable to suppose that ring devices could zip through half of a 24-hour
cyde in so short a time. However a population of docks each having two or more
variables of state, one of which is photolabile, might easily achieve the large phase
shifts required in an arbitrarily short time.

The Clock's Singularity

Setting aside the possibility that the singularity is an artifact of physiological
incoherence,the first question to ask is whether the singularity might simply be the
steady state of a biochemieal oscillation. Before we tackle that question, let's make
sure not to beg the question by perpetrating a pun. As noted on page 77, the word
singularity means one thing to mathematicians and physicists, and another to
engineers, and both, as weIl as other things, to biologists. The phase singularities
inferred on topologieal grounds throughout this book are singularities in the sense
of mathematicians and physicists. They are discontinuities at which physieally
important variables change infinitely abruptly. This is the sense of Penrose and
Hawking in their study of black holes as space-time singularities (see Misner et al.,
1973), of Guckenheimer (1975) in his study of the phase singularities of attracting
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 307

cycles, and of Rene Thom (1975) in his study of catastrophes as singularities of

maps. The "physically important variable" in present context is the phase of the
subjective daily cycle.
In contrast, the "singularity" commonly referred to in engineering literature is
the critical point, equilibrium, or steady state of a set of kinetic equations. This is the
sense of Higgins' (1967) analysis of biochemical oscillations, of Pavlidis' (1967)
analysis of circadian rhythms, and of Kauffman and Wille's (1975, p. 50) study of the
dynamics of the cell cycle.
Unfortunately for my present attempt to distinguish usages of the word, 1 used
the term singularity in both senses simultaneously in the first three papers
describing Drosophila's phase singularity. These two senses do coincide in the
limited context of two-variable models. 1 argued explicitly from experimental data
that the phase singularity is areaction steady state in astate space of dimension 2
(Winfree, 1968). That argument could have been correct and these two senses of
"singularity" could be reasonably taken to coincide, as Pittendrigh and Daan (1976c)
choose to emphasize:
[Winfree] has accomplished the delicate feat of "stopping" the D. pseudoobscura
pacemaker by driving it onto the "singularity" of its phase plane where it is,
apparently, stably motionless .... [Winfree] has done the same to oscillations in the
redox state of NAD which he generates by disturbing the steady state of yeast
glycolysis .... In all oscillating systems capable of self-sustained limit-cycle move-
ments, no matter what their physical nature, there is, as analytic necessity, a point
equilibrium or singular state on the phase plane . ... The only empirical question is
whether or not that singularity is stable-and how stable.
Unfortunately, there is not necessarily a phase plane, nor such analytic
necessity in the expected generic case of dimension exceeding 2, nor do we know
that we are working with an attracting limit cycle process. The statement quoted
is true only on the assumptions that a steady state exists, that it is accessible, and
that the only acceptable models are ordinary differential equations involving
exactly two variables. Some models proposed in the circadian rhythm literature
are of this sort but many others are not; e.g., simple clock models (Chapter 3),
independent-oscillator population models (Chapters 4 and 6), time delay models
(Johnsson and KarIsson, 1971, 1972, Karlsson and Johnsson (1972), Engelmann
et al., 1973, 1974, 1978), singularity-free discontinuous oscillators (e.g., Pavlidis,
1967a), differential equations involving three or more variables (Chapter 6 and
Cummings, 1975), and coupled oscillator models (Pavlidis, 1976). It could be that
the circadian clock has only two important state. variables (clusters of molecular
activities perhaps), in which case the data plots of Chapter 7 acquire much more
vital impact. But 1 no longer find the evidence persuasive on this point. (See the
end of Chapter 7.)

The Clock's Steady State

Following the tradition of inquiry into chemical oscillators (Chapter 12), oscillations
in sugar metabolism (Chapter 13), neural rhythms (Chapter 14), and rhythms of cell
308 10: THE VARIETIES OF PHASELESS EXPERIENCE

division (Chapter 22), almost every conceivable conjecture has been offered about
the steady state of the circadian dock:
1. It doesn't exist. The circadian cyde could be an oscillation with no steady state
and only slightly adjustable amplitude, as in Danziger and Elmergreen's (1957)
models of the female cyde applied to the circadian cyde by Strahm (1964) and
Pavlidis (1967a). Or it could be a simple dock (Swade, 1969), even a physical
ring of DNA traversed periodically by a polymerase (Ehret and Trucco, 1967), or
a physical rotor like the turbine wheel of bacterial flagellae. In such a model
perturbations only vary the rate of change of phase. Nonphase states make no
sense.
2. It does exist but is so violent a repellor that for all practical purposes it is
inaccessible, and amplitude regulates completely back to the standard cyde
from almost any subnormal amplitude within a day (Pavlidis, 1967b, 1968, 1978
quoted on p. 422).
3. It exists and repels (i.e., amplitude regulates away from 0), but not so quickly.
The near dosure of trajectories during the two days monitored after
perturbation to lower amplitude (Chapter 7) could be interpreted as lethargie
regeneration of amplitude (Pavlidis, 1976).
4. The dock has more than the two variables assumed under 2 and 3. For
example, Cummings (1975) invents a three-variable biochemical oscillator and
Pavlidis (1976) supposes an oscillator composed of two or more oscillators
coupled together, each contributing two variables. Thus, if aphase singularity
is found, it is probably not because dock kinetics was forced to a steady state,
but rather because it was tricked into some other dynamic mode (possibly
leading to the steady state) conspicuously different from the usual 24-hour
oscillation.
5. The steady state exists and attracts from nearby states (Kalmus and Wiggles-
worth, 1960; Pavlidis and Kauzmann, 1969). Starting from below a critical
amplitude, such an oscillation is unstable and degenerates to stationarity. Such
a situation could even result from coupling many oscillators whose steady states
individually repel. Below a critical amplitude of collective rhythmicity, mutual
synchronization is unattainable so that the population remains incoherent and
any slight initial collective rhythmicity degenerates (Winfree computer experi-
ments privately circulated, 1967).
6. The question cannot be answered from the observed behavior of whole animals
because multicellular docks consist of many cellular docks functioning
independently for all short-range purposes. In such a case the vigor, amplitude,
or intensity of circadian oscillation in the whole organism, being a sum over
many separate oscillators, would mainly measure the coherence of their phases.
Any stimulus that further scatters phases within the population would thereby
attenuate the collective rhythmicity, and if interaction were weak, then
coherence would not soon recover. Without an independent assay of phase
scatter among the oscillating units, little would be revealed about each unit's
amplitude.
In using a succession of models, theorists collectively have thus covered every
base.
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 309

My favorite conjecture is 6, that the circadian dock is actually a composite of

two or more independently competent oscillators and that the whole-organism
rhythm reflects some kind of average over this population. In such composite
dock models, the facts are explained by incoherence in the population. I suggested
a model involving only these essentials, not even invoking coupling among the
component docks. This simplest, though perhaps least general, interpretation
accounts for all the Drosophila data quantitatively (unpublished computations).
The quantitative fit can probably be retained even with weak synchronizing
interactions between the individual docks (Pavlidis, 1976) or even with strong
synchronizing interactions (Aldridge and Pye, 1979b). A wide variety of
conjectures might suffice to "save the data." The essential qualitative point is
that the phase singularity is interpreted in terms of incoherence in a population
rather than as a steady state of areaction. Given any such composite dock
interpretation, the phase singularity could be a steady state only if all the docks
were perturbed to their individual steady states simultaneously. The fact that a
phase singularity is obtained by adjusting only two stimulus parameters makes
this an implausible interpretation. In short, whatever evidence points toward a
composite structure of circadian docks in multicellular organisms also points
away from interpretations of the phase singularity as areaction steady state. A
few experiments are suggested at the end of Chapter 7 that might help to resolve
this ambiguity.

.. ,My in:Jpr~~sion to ay is.-t at (1) is wrong, (2) js unlikely, (3) could 5e dose to the truth l
(4) rs pre~ sure (e.g., see Leloup eta!., -1999)"despite attempts t~ mimj~.tbe· circadian
0sCilfatClr wjth just two dominant intel'acting quanti~ies, (S) rs wrong, ahd (6) is Gorre-ct
anä. ready fbr exploration in tne laboratory which:willle 9 d tö resettlng experiments on
sinle dock cells. See new te>s,t in Cha ter 19. ~

The Singularity in Development

A related question dealt with in more detail on page 612 concems the arrhythmicity
of edosion in naive pupae that have never experienced a change of lighting or
temperature by which to start or set their docks. Are they in the same state as are
"rhythmically experienced" pupae retumed to arrhythmicity by a singular stimulus?
They are by the criterion that both populations become indistinguishably rhythmic
after exposure to light or a temperature shock, though evidence from more
discriminating comparisons would be reassuring. Until such further comparisons
reveal unforeseen distinctions, it seems a plausible guess that the singular state in
Drosophila's dock is its primordial state, as assembled in the maturing egg prior to
activation by an extemal stimulus.

Example 6. A Mutant Fruitfly's Body Clock.. Drosophila melanogaster's dock

has been probed nowhere near so intensively as D. pseudoobscura's. But neither
have any conspicuous differences been detected (in 1978; and in 1999 see Saunders
et al., 1994, for finer details) to distinguish the 19-hour mutant m.elanogaster from
the wildtype pseudoobscura, apart from the 20% difference in their periods.
310 10: THE VARIETIES OF PHASELESS ExPERIENCE

Example 7. A Fly that is 1000 Times Less Sensitive. Sarcophaga has not been
examined in respect to its singularity, except to demonstrate its existence by the
screw-shaped pattern of rephasing around it and the relative arrhythmicity of
edosion near it. Saunders (1978) believes that some forms of arrhythmicity in
Sarcophaga represent incoherence among circadian rhythms within the individual
fly. But the question whether this is true of arrhythmicity elicited by a singular pulse
has not yet (1978 and 1999) been posed experimentally.

Example 8. Resetting a Flower's Clock. As noted in Chapter 21, Engelmann et

al. (1978) believe that the arrhythmicity induced by a critical stimulus in the
individual Kalanchoe flower represents a steady state of the circadian oscillator
throughout the flower, possibly because the dOCKS biochemical steady state is
locally an attractor. If this inference withstands the further tests in process in
Engelmann's laboratory (in 1999 I think it did not), it may provide a unique
opportunity to implement the following experiment proposed by Winfree (1970b)
and by Tyson et al. (1976).
On the assumption that diverse physical and chemical influences alter dock
dynamics in diverse ways, then, applied to a dock at its steady state, they should
induce rhythmicity at diverse phases. If time be allowed for relaxation to the steady
state after the critical stimulus then the dependence (on next-stimulus magnitude)
of the phase of renewed rhythmicity after a second stimulus should characterize the
site of interference in dock dynamics. Thus, suitably selective interfering agents can
be classified according to their sites of action (supposing they don't all act at
multiple sites). The sites of action can thus be enumerated. The chemical nature of
each site may be suggested by chemical properties common to those agents that
apparently act at that site. There might also be a minimum dose required to elicit
any rhythmicity, revealing that the arrhythmic state is a local attractor and thus
confirming that it is not a mere artifact of incoherence. In the case of Avena's 30-
minute transpiration rhythm, the experiments of Johnsson (1976, Figures 4 and 8)
and of Johnsson et al. (1979) gave particularly clear-cut results: The singular
stimulus kicked the seedling into a locally attracting steady state of water transport.
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 311

singl.l. arity along any on~ sudi pat woulcl there6y reveal e 'common trait oy wnich
they impact a dock part, a",d possibly thereby enutnerate the cellular rnechanism's
impörtant degr~es of freedom (2 or more). I am not.. C!.ware of attemptS.to overcome
whatever practical difficulties i ede iir)!?lementation of this scheme. ~ ___"..______.~_--

Example 9. A Phase Singularity for Beer Drinkers. The chemically well-

studied oscillation of anaerobic glycolysis in yeast cells provides a nice opportunity
to try out the foregoing method in a better understood system. A start has been
made through the experiments of Winfree (1972d), of Greller (1977), of Aldridge and
Pye (1979a,b) (and now of Dano, 1999 and Dano et al., 1999). These investigations
established that oxygen, acetaldehyde, and calcium elicit rhythmicity from
previously arrhythmic cell suspensions, respectively, at the phase of NADH
maximum, one-quarter cycle later, and one-half cycle later.
The nature of arrhythmicity in this system has not been clearly established.
However, Greller (1977) and Aldridge and Pye (1979a,b) argue cogently both
1. that the individual oscillator has an attracting steady state in addition to an
attracting cycle, and
2. that the cell population is made inhomogeneous by near-critical stimuli that
divide it into a synchronously oscillating subpopulation and another subpopu-
lation trapped within the steady state's attractor basin.

These inferences may eventually be checked by direct microfluorometry of

individual cells.
There are now six ways to drive glycolysis into its phaseless set:
1. by mixing differently phased cell populations,
2. by applying a suitably timed critical dose of oxygen,
3. or of acetaldehyde,
4. or of calcium,
5. or of EGTA (which chelates calcium; its critical phase is opposite to (4), just as
in stopping a pacemaker neuron with positive or negative voltage displacements
(Best, 1976, 1979; Guttman et al., 1980),

If glycolysis has a unique attracting steady state, then all six techniques
presumably direct cells eventually to that state, even if the six techniques enter
the phaseless set at different points. But no one has yet excluded the alternative
possibility that different arrhythmic states are reached by these six techniques.
The question could be substantially resolved by reinitiating rhythmicity with
agent i after annihilation with agent j. If the new phase depends only on i
independent of j, then the five singularities very likely have a single biochemical
basis. If this result is obtained only after an interval during which the result
depends on the time between j and i, then the points of entry into the phaseless
312 10: THE VARIETIES OF PHASELESS ExPERIENCE

set are different but a unique steady state is eventually reached. If the result
depends differentlyon i for various j's, then there are distinct alternative
attractors.

Example 10. Morphogenesis in Fungi. In the case of Nectria, phase-resetting

experiments have not yet produced quantitatively reliable results (Winfree and
Gordon, accordingly unpublished, and by 1999 there has been no more work
with pattern-formation in Nectria). However, a phaseless state within the two-
dimensional mycelium can be inferred from the nonzero winding number of
phase around the mycelium's frontier in cases marked by spiral conidiation.
Most likely the entire interior of the mycelium has ceased to oscillate due to
locally altered nutrient conditions, so the singularity is lost in the general
collapse of rhythmicity for other reasons. However, in the youngest smallest
mycelia, there is no "interior." The whole germinating mycelium must initially
be elose to the singular state to allow the observed delicate indeterminism of
winding number. Thus the singular state in Nectria is probably the biochemical
steady state of the dormant spore, somewhat as conjectured above in embryonie
Drosophila.
In the case of Neurospora crassa, Dharmananda and Feldman (1979) have
shown persistence of ostensibly normal oscillation throughout mycelia bearing
bands of conidiation. Nonzero winding number (spiral patteming of mycelia) has
not yet been contrived and apparently does not happen spontaneously. However, it
seems likely that this will be contrived in view of the following result.
Dharmananda (1980, and I confirmed it in my own lab) found Type 0 resetting
of this circadian rhythm by a light pulse, which strongly suggests the existence of
a singularity at some shorter exposure time M*. The physiological nature of the
singularity in this spatially distributed continuum of oscillators will be especially
susceptible to scrutiny by microscopy, by histological procedures, and by
biochemical tests.

Example 11. Regeneration of Limbs. The "clockface" model of pattern

formation beautifully organizes a diversity of perplexing experiments involving
regeneration of organs and parts of organs. It accounts for the striking regularities
of mirror-image reduplication in cases where regeneration fails. It enables
prediction of the appearance of unanticipated extra limbs where parts of normal
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 313

limbs are forced into unnatural contact. All this and more comes from a simple set
of roles about hypothetical phase values, invented by French et al. (1976).
Translated into mathematical language (e.g., by Glass, 1977), the phase rules
become remarks about topological index values alias winding numbers along dosed
paths, and the corresponding encirded singularities. As if that weren't enough to
suggest something periodic at the root of it all, the very diagrams of French et al.
resemble docks, even being bordered with rings of digits 1-12. These observations
understandably created a stir among theorists, whose files already bulged with
papers about "docks" and "maps" underlying normal development, e.g., Goodwin
and Cohen (1969), Bourret et al. (1969), Robertson et al. (1972), Winfree (1970a,
1973d), Goodwin (1976), Cooke and Zeeman (1976), Stern and Goodwin (1977) and
Kauffman et al. (1978) to remind of only a very few. Much of this stir inevitably
emphasized the circles in the clockface model, seeking some mechanistic
interpretation. The cap often drawn over a cyde in state space in this book even
emerged naturally as aregeneration blastema.
Such enthusiasms aside, in 1977 I had the misfortune to conceive a
reconstruction of the same experiments which makes no use of those concepts
but seems to me geometrically at least as simple as current (1978) versions of the
dockface construction. My belief at this point in the furor is that the circles,
winding numbers, and phase singularities are strictly mathematical inventions that
have no mechanistic interpretation in these particular living systems, however
convenient they may be as didactic tools.
The fundamental question for theorists in this affair is, 'What must a model do
to satisfy all the data?" My condusion is, "Not much." The data almost force us to a
continuous map 1R2 ~ 1R2 , from a two-dimensional sheet of cells to a two-coordinate
"tissue specificity space" of cell types. This map and its transformations only involve
circles if a circle is gratuitously drawn on the sheets of cells, andJor if one artificially
restriets attention to a ring-shaped subset of the tissue specificity space. If these
things are done then the 1R2 ~ 1R2 maps are restricted to §1 ~ §1 or 1R2 ~ §1 maps.
This is what French et al. do, and it represents a major conceptual advance both
over the IR l ~ IR l maps common in the "morphogenetic gradient" literature since the
time of Child (1941), and over the 1R2 ~ IR l maps so ingeniously deployed by
Lawrence (1970, 1971), Lawrence et al. (1972), and others to account for otherwise
perplexing patterns that arose when two-dimensional sheets of cells were surgically
transplanted. But my belief is that the §1 topology is only a result of artificially
restricting 1R2 and thus should be viewed only as a tantalizing way-station en route to
a broader view in which cells are located two-dimensionally by two transverse
gradients, each of which follows the rules long familiar in one-dimensional contexts.
Cummings and Prothero (1978) also came to this view. Such constructions have no
necessary place for cycles or singularities but they seem to account for the facts
quite gracefully. Viewed in this way, the apparent singularities from which limbs
emerge in the dockface outlook have no biochemical or physiological import. They
just happen to lie at the arbitrarily chosen center of a descriptively-convenient polar
coordinate grid.
There is nothing uniquely appropriate about the description of these phenomena
in terms of phase, rings, winding numbers, and phase singularities. I think these
objects arise as artifacts of a theory that tries to segregate the two dimensions of
314 10: THE VARIETIES OF PHASELESS EXPERIENCE

\
I Figure 1. A bounded divergent flow in two-space necessarily includes a
cycle (of "most-proximal" cell types encircling the "most distal" type).

\
I
tissue specificity, isolating "proximal-distal positional information" as though it
could be analyzed independently. One then has to impute the topology of a ring to the
remaining single variable of azimuthal tissue specificity, and accept the attendant
fictional discontinuities. We have seen this happen before in trying to apply simple-
elock notions to circadian rhythms in Chapters 3 and 4 (retaining the phase aspect of
an oscillator's state while ignoring amplitude as an independent problem) and in
trying to understand rotating waves in terms of ring device kinetics in Chapter 9,
pages 286-89 (once again insisting upon a single-factor description of a process
involving at least two mutually interacting factors). I am accordingly skeptical of
theories (mainly of my own invention) which take the prominently featured ring as a
cue for seeking causal answers in terms of oscillators, circulating waves, or singular
points. Needless to say, I would rejoice to find this skepticism unfounded.
I think there is one way in which my skeptical outlook could soon prove wrong.
The fact seems increasingly well established that cells do not acquire their type
specificities in a passive way by smoothly bridging the differences between their
neighbors, but are rather invested with some dynamic. Goodwin (1976) was the
first, I think, to suggest attributing to new cells a tendency to diverge from more
distal types toward more proximal types in a way that might be summarized
geometrically by a vector flow diverging from a point in state space. This divergence
must be bounded and its boundary is topologically a ring (Figure 1). This ring
presumably consists of the most proximal cell types, and the center of divergence is
the most distal cell type. Thus it is at least conceivable that there exists a meaningful
natural origin for apolar coordinate system that can be identified with the
singularities implicit in the elockface scheme. To establish this as a fact would
require monitoring the changing fate of proliferating cells.
Nothing of the sort has emerged (in 1978 and still in 1999 to my knowledge) so it
still appears to me that these experimental results reveal little more than that
developmental fields map smoothly into a suitable descriptive space, wherein the
images of newcells lie elose to the images of their progenitors. I hope by posing the
problem in this format to encourage the discovery of critical experiments that may
resolve present-day (1978) ambiguity about the topology of that space, about its
metrie, and about the dynamical flow that presumably guides cells to their final
positions in it.
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF ÄMBIGUOUS PHASE 315

Kau an 1.!789), and kautfrnan (1992, Rages 510 ff an 617 ff) have sinee c,onflrmed
its ,cdncll,Jsion that the phase sh1golarity implicit in the "c1ockface" model of two-
dimensional developmental organizing centers is a decoy, as f~r asthe themes ahhis
book are concemed. I take <:omfort in Ludwig Wittgenstein's coml'Bent that "If people
never did silly thmgs, nothing intelligent wou[d ever be done." ForrnerChapter 16 is
now replaced by the posH978 story' 'o f th ee-dimensional "otg~nizing centers" in
nonliving reaction-äiffuslon. edia. '

'. , 'EXimple 12. - e Relicokfal Cuticle ofÄrthropo s. (augmente jn 1999 by graft

fro~ deleted Chapter 17, which space. ~as now Reen giyen over to helicoidally
strucrured cardiac. museIe and itS electrical ~irals)... '. .

A case in which the singularity even more clearly turned out to harbor only a
mathematical artifact concerns the regular plywood-like laminations of skeletal
material in arthropods. The passage of a microtome knife through cutide elicits a
pattern of periodie banding that might at first (to me it did) suggest rhythmic
secretion by the cells that constructed the cuticle. The observed bands would then
be seen as markers of biological time, like archaeological strata, indicating the
horizontal distribution uf phase of those vertically secreting docks. The wonder of it
was that in many cases, most conspicuously in the lens cutide of the compound eye,
a ring could be drawn on the cutide round which the phase of this putative
"secretory rhythrn" had nonzero winding number. The implicit singularity was
plainly visible in the microscope as the inner endpoint of a spiral of relatively more
opaque cuticle. But here, for sure, my enthusiasm to find biological expressions of
phase singularities depended too much on imagination. It tumed out, thanks to a
remarkable geometrie insight by Yves Bouligand (1972), that these "rhythms" derive
from the bent-liquid-crystal ultrastructure of cuticle. Here is the story as it unfolded
in the late 1970s:
Cuticle is made of chitin fibers embedded in a protein matrix. The fibers are
aligned side by side, so such cutide polarizes light. In most arthropods, during
part of the circadian cyde new cutide is secreted in this way, and during the
complementary part of the cycle there is an additional interesting gimmick: no
one knows why, but the direction of fiber orientation continuously rotates during
this phase. The molecular architecture of such cuticle is thus helicoidal. As the
crab or insect grows, its cutide becomes laminated in repeating sheets of linear
and helicoidal chitin some microns thick. A circadian dock governs this
alternation, so in the normal light-dark cyde the distance between successive
sheets of chitin in such laminated cutide represents 24 hours' growth. In
constant conditions in the laboratory the alternation continues, hut now with
only circadian period. It is not yet dear whether this period reflects the
oscillation of some central, perhaps neurosecretory, pacemaker. It might he
under Iocal control from the separate circadian docks in each cell that secretes
cutide. Wiedenmann (1977) finds that the cutide dock is at least independent of
the brain dock that controls activity rhythrns. Zelasny and Neville (1972), Brady
(1974, Seetion 3.2.4), and Lukat (1978) suggest that insect epidermis is a two-
dimensional sheet of oscillators, each capahle of autonomous cycling (no brain
needed). But each is dynamically coupled to its immediate neighbors so local
316 10: THE VARIETIES OF PHASELESS ExPERIENCE

Box A: A Structural Phase Singularity in Museie Fibers

In iron whiskers (where it is responsible for mechanical strength), tobacco mosaic

virus, and in bacterial flagellae, a strictly structural rhythm is so arranged in space
(around a screw dislocation) that a point of ambiguous phase is implicit. In the
following case it also turns out to be biochemically unique.
The individual fibrils of vertebrate skeletal muscle show conspicuous bands a few
microns apart along their whole length of some millimeters or centimeters. This
astonishingly precise periodism reflects the muscle's underlying molecular architecture.
Myosin filaments alternate with overlapping actin filaments in repeated structural units
called sarcomeres. The sarcomeres are joined end-to-end in thousands of repeats like
the unit cells of a crystal. A muscle fiber is composed of many such fibrils lying side-by-
side with their sarcomeres exactly in register. The fiber thus gives the appearance of a
stack of flat disks, each one sarcomere long, monotonously repeated.
With this architecture in mind it comes as a surprise find several kinds of
invertebrate muscle fiber that are helically striated, like abarber pole. In such fibers
the molecular filaments of actin and myosin are still aligned parallel to the fiber's long
axis and they still repeat with exquisite periodism in this direction. But adjacent
filaments are slightly out of register in a systematic way. Proceeding once around the
fiber following the edge of a helical band, one advances along the fiber by some
integer number W of unit cells. Or girdling the fiber at a fixed level, one crosses W
helical bands. In other words the phase of the banding rhythm has winding number W
# 0 around the fiber.
So much for the visible surface of the fiber. What about its interior? In vertebrate
striated muscle (W = 0) each band visible on the surface is only the border of a disk
extending smoothly through the interior. Can a disk have a helical boundary? It cannot.
A helical boundary cannot be continued into the interior of a cylinder with creating a
singular axis along which phase must be ambiguous. Does anything of physiological
interest transpire there? In this case, it does: helicoidally striated muscle fibers have a
central cytoplasmic axis utterly devoid of actin and myosin filaments! (Lanzavecchia,
1977 Figures 16 and 21)

synchrony is maintained even when cells are not all entrained by the external
light-dark cycle. Thus insect epidennis could have organizational properties in
common with the models of local oscillation in two-dimensional fungus mycelia
considered in Chapter 18. In particular, there might be phase gradients, even
circular phase gradients enclosing aphase singularity. Whether such spectacles
occur normally and whether such phase patterns as might exist bear any
resemblance to those inferred by French et al. (1976), no one has asked or
reported. But the record of local phase is presumably there, preserved in the
insect's hardened cuticle, awaiting inquiIy.
Electron microscope pietures of seetions through arthropod eyes show these
altemating lamina (Figure 2). The part in question here, the corneal lens, is
described in textbooks available in 1978 as a secretion from underlying cells, like
other parts of the cuticle. The alternating lamina are portrayed as tiny cups, all
skewered concentrically on the optic axis of the lens. The cup-like shape of the
layers of cuticle would be determined by the curvature of underlying cell surfaces
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 317

---Lena

Figura 2. (al Schematic of the exocone eye. (bl Cross-section perpendicular to plane (al and to
(a)'s long axis. (cl Cross-section in plane (al. (From Wolken, 1971 Figure 3.13, with permission.l

and the relative phases of their secretory rhythms. 1 took a keen interest in this
stnlcture because seetions parallel to the surface showed not concentric ring-
shaped zones of black and white as required by the textbook model, but rather a
one-armed spiral. winding into the center. Figure 2 shows both views. If the
alternating black and white zones reflect alternating phases of a secretory
rhythm, then the spiral pattern betrays a phase gradient in space, which, in one
full cycle of black to white to black, winds once around a symmetry axis. That
means that the center of the spiral is a point of ambiguous phase, a phase
singularity of the sort postulated by French et al. (1976) as an organizing center
for discrete organs such as arms, legs, wings, antennae, and, in this case, perhaps
the single corneal lens.
It tums out that this growth rhythm has much shorter than circadian period.
The growth rate of lens cutide is such that the period seems minutes to an hour. So
we are not looking at Zelasny and Nevilles' sheet of long-period docks. In fact, an
entirely different interpretation comes 10 light with the realization that although in
oblique sections the dark zones appear much more widely spaced, they are really
onlya few tenths of a micron apart in three dimensions, and they correspond not to
layers but to certain directions of chitin fibers in the helicoidal ultrastnlcture. We
owe the discovery of this ultrastnlcture to physicist A. A. Michelson in aremarkable
paper written late in his dazzling career. There we read of the beede Plustiotis
resplendens, whose
318 10: THE VARIETIES OF PHASELESS ExPERIENCE

whole covering appears as if coated with an electrolytic deposit of metal, with a

luster resembling brass ...Finding that light reflected from this surface is circularly
polarized ...the effect must therefore be due to a screw structure of ultramicroscopic,
probably of molecular, dimensions.
This startling insight collected dust in libraries for the customary half-centmy
before the ridclle was solved in detail by the morphologist and geometer Yves
Bouligand. 1 Bouligand (1965) brilliantly developed the idea of Michelson (1911) and
of Schmidt (1924) that cuticle is composed of layers of parallel chitin fibrils whose
orientation turns through 180 in less than a micron, comparable to the distance
0

occupied by a wavelength of visible light (Figure 2.1). This kind of architecture is

Figure 2.1. Fibers in cholesteric liquid crystals lie parallel in planes, their
orientation progressively rotating from plane to plane.

common to the cellular fibers of the mammalian heart wall (Streeter et al., 1969;
Streeter, 1979) and to aggregates of a wide variety of elongated macromolecules
(Bouligand, 1978) including the collagen constituting the corneas of certain
vertebrate eyes (Trelstad and Coulombre, 1971; Gordon, 1976); the DNA packed
into cell nuclei (Bouligand, 1972a; Livolant et al., 1978) or into sperm heads (Sipski
and Wagner, 1977), and the cellulose deposited in the walls of growing plant cells
(H. Gordon, ms. circulated privately in 1976). As Michelson foresaw, much of the
iridescent decoration of insect cuticle derives from this helicoidal periodism in the
molecular architecture of chitin (Neville, 1975).
Bouligand (1972a) realized that the alternating dark and clear zones seen in
microtomed sections of cuticle are not different materials at all, butartifacts of
mechanical interaction between the moving microtome knife and the cuticle's
periodic fibrillar ultrastructure. He argued that the regions, as seen by the electron
microscope, arose where the chitin fibrils had a certain three-dimensional

1 !fyou love geometIy, look at Bouligand's papers on dislocations in liquid crystals (Journal de Physique,
1972-1974). Theyare full of astounding singularities, including cusps, screws, and even Möbius bands. At
least some of these have been identified in biological materials and may play essential mIes in the
mechanics of plant cell elongation and of chromosome condensation. The literature of liquid crystal
spherulites (of polypeptides; DNA, etc.) likewise is a study in singularities, since there is no way to
smoothly map a sphere's surlace to the ring of possible compass orientations for moleeules on that
surlace. See also Slonczewski and Malozemoff (1978) on orientational singularities in three dimensional
magnetic bubbles.
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 319

orientation relative to the knife's path. But this liquid crystal model of chitin
implies a certain kind of mapping from any slice of chitin (§2) to the sphere of
fibril directions (§2). According to the idea that certain fibril orientations result in
local darkening, that region of orientations can be painted dark on §2, indicating
that darkness is acquired by whatever parts of the slice (0 2 ) map onto that region.
It turns out to be implicit in the symmetries of liquid crystal architecture t;hat the
pertinent maps must be two-Iayered, in such a way that if some locus in 02
acquires darkness, then so must another, symmetrically disposed, locus. This

Figur. 3. Computer simulation supposed to represent

a cross-section similar to Figure 2(b). Each tiny dot is
the endpoint of a chitin fiber. The dots were initially
uniformly dense, then each was slightly displaced
according to local fiber orientation relative to micro-
tome knife motion. Orientations were described
mathematically according to the observed curvatures
of cuticle in the exocone lens together with Bouligand's
liquid-crystal model of chitin. The displacements create
a slngle-spi ra I locus of thickening and thinning.

model necessarily yields twin spirals. intexwoven. Figure 2 and its kin show only
one. If there is only one spiral of darkness then either the supposed liquid crystal
architecture is wrong (a repugnant notion) or (more likely) the spiral is not after
all a microtoming artifact, at least not of the exact sort Bouligand postulated. Then
might there still be something to discover in this phenomenon, something about
rhythmic secretion, phase maps of nonzero winding number, and a morphogenetic
phase singularity?
This was my hope. Unfortunately, however, Herman Gordon (then an under-
graduate) and 1 managed to contrive an alternative mechanical model by which the
single spiral of darkness does appear to be an artifact of microtoming. According to
this simple interpretation (1999 insert: as yet untested by new experiments, and
contested in Bouligand, 1986), the moving knife compacts material in certain
places by inducing relative movement between chitin fibrils and their surrounding
matrix (Gordon and Winfree, 1978). Mathematically describing the helicoidal
structure of cholesteric liquid crystals in a computer and arithmetically displacing
fibrils according to our supposed rule of movement, we obtained single-spiral
patterns of compression such as in Figure 3. These look disappointingly similar to
the patterns observed, for example, in Figure 2.
Under this interpretation, the phase singularity at the center of the dark spiral is
nothing more than the point of tangency between aplane of parallel fibrils and the
320 10: THE VARIETIES OF PHASELESS ExPERIENCE

cutting plane of the knife. Thus aphase singularity in the fonnal description of an
object does not necessarily indicate an event of singular interest. The phase of this
rhythm of banding is detennined geometrically. It becomes ambiguous where the
local screw axis of the liquid crystal is perpendicular to the plane of the cut.
Mathematically that is indeed a phase singularity, but all it represents physicaUy is
just a critical orientation relative to the knife. No rhythm of secretion, no pattern of
phases, just prosaic mechanical engineering.
"The shop seemed to be full of all manner of curious things-but the oddest part
of it was that, whenever she looked hard at any shelf, to make out exactly what it had
on it, that particular shelf was always quite empty, though the others round it were
crowded as full as they could hold."
Lewis Carroll, Alice Through the Looking Glass

Example 13. The Cellular Slime Molds. What then of the phaseless center from
which wave trains of cAMP release emerge in spiral pattern on a monolayer of
Dictyostelium cells? Is that point different in any significant way from all other
points, apart from being the locus of a mathematical phase singularity? It certainly
becomes so soon enough. All cells within reach of those ripples of cAMP move
toward the source and eventually accumulate into a multicellular organism at that
site (see Chapter 15). But was there initially any special kind of cell at the phaseless
origin of the rotating wave? I know of no reason to think so. In continuous media
dynamically similar to the cellular medium of a Dictyostelium monolayer, spiral
waves are created by temporary interruptions of continuity. A wave passing such a
gap acquires two free endpoints, each of which becomes the source of aspiral wave
if continuity is reestablished before the endpoints find one another again. In media
composed of wandering cells such temporary interruptions presumably come and
go all the time as local cell density fluctuates. In continuous media the source points
so fonned exhibit a unique interplay between reaction and diffusion by which a
state is created and maintained which never occurs anywhere else. But in media
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 321

composed of discrete cells communicating by pulses, the arguments of continuum

meehanics and of topology have no clear application. 1 see no reason to believe that
the phase singularity in Dictyostelium initially has any locally deteetable unique
properties. (Hut onee again, being the center toward which cells colleet, it soon
acquires unique properties.)

Example 14. Pathological Rotating Waves in Heart, Brain, and Eye. On a

grosser scale, waves geometrieally similar to the slime mold's temporally organize
the repetitive firing of excitable membranes in vertebrates. These patterns were
initially discovered in the early 1970s, in every case by severe artificial
stimulation. This only shows that neuromuscular tissue is capable of persistent
rotating self-excitation. The normal role of such rotors, if any, remains to be
discovered. In all eases but one the singularity is not available for examination,
being lost in a eentral patch of tissue damaged by the stimulus. (See Chapter 14
for details.) In that one ease (Allessie et al., 1973) the phaselessness of the
singularity is nothing so simple as attenuation of amplitude to zero. The pivotal
patch of membrane is not held stably at a voltage (and at ion permeabilities)
intermediate between those realized in the wave circulating around it. Instead the
rotor's central patch is irregularly invaded by sizable "wavelets," so its
phaselessness consists of irregularity rather than of timelessness. Nonetheless it
may appear as timelessness in a grosser maeroseopic deseription of the
phenomenon (see Box B).

It seems natural to interpret atrial flutter or ventricular flutter in terms of one or

more rotors. What about fibrillation, the higher frequency, less regular mode of
arrhythmia? One line of thought suggests that fibrillating tissue is possessed by
many tiny rotors, continually being created and extinguished within a two-
dimensional medium of spatially inhomogeneous refractoriness (Krinsky, 1966,
1968; Krinsky and Kholopov, 1967a,b; Krinsky et al., 1967). Hut a slightly earlier and
apparently independent literature places less stress on the "tiny rotors" idea and
more on the "many tiny" idea. These are the papers of Moe and collaborators
(Moe and Abildskov, 1959; Moe, 1962; Moe et al., 1964), which 1 suspect were
imaginative and deep beyond their time, yet remain today undeservedly
negleeted. Moe's
variant of the circus movement theory proposes that fibrillation is maintained by the
irregular wandering of numerous wavelets generated by the fractionation of a
322 10: THE VARIETIES OF PHASELESS ExPERIENCE

Box B: The Human Heartbeat's Phase Singularity (?)

The figure shows two kymograph tracings recorded in 1913 by a young physiologist
who, a few months after submitting them for publication, accidentally killed himself in
electrical experiments on his own heartbeat. These tracings were made bya rabbit's
heart whose regular oscillation was occasionally perturbed by an electrical stimulus of
suitable intensity (Mines, 1914). As you can see following each dot on the tracings, most
such stimuli induced at most a transient upset without resetting the sinoatrial
pacemaker. But stimuli delivered at a critical phase instead stopped the heartbeat for
a long time. Presumably this singular result requires not only the exact timing
determined by Mines but also suitable stimulus intensity, in that a much weaker
stimulus would have little effect and a much stronger one would resynchronize the
heart muscle and sinoatrial node altogether. But when administered at this phase, the
intensity employed induced ventricular fibrillation: microscopically supposed to be a
jumble of circulating waves, but as I believe, macroscopically a phase singularity in the
behavior of an elaborate partial differential equation oscillator.
As far as I know (in 1978: still so in 1999) this is the first recorded encounter with a
physiological phase singularity. The whole subject might have received much earlier
development had not its discoverer's enthusiasm led so promptly to stopping his own
heart.
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 323

de~th in his laboratory eg to speculatron thatlle cnight have b~en experlmentally

pecturb 'ng his eartbeat (Winfi"ee, 1963b). Inf.ormatioh abtai ned;recently wom tPe
M~GjIJ Uh'iversity P~X~iolbgy: Del?3rtmel':lt} nakes this seem iess' Ilkery." -: ,"
'f.his mfoni'iation is 'retalPe,d in a sealed vault, to be opened OA the'first.day of
2001, very short!y atter tI:Yis second edition is pubJished. What surprises ~wait us? ~
.Check m 'web site .. ....,. . ; .

wavefront passing through tissue in astate of inhomogeneity with respect to

excitability and conduction velocity. The arrhythmia is assumed to sustain itself
when the number of wavelets is so great that coalescence is improbable. The number
of wavelets which coexist in the tissue should be directly related to some function of
the mass of the tissue, and inversely related to the duration of the refractory period
and to the conduction velocity.
This sounds superficially like Krinsky et al. seven years later, but Moe's
computer simulations show very little that suggests locally regular rotation. Rather
the process more resembles the "chemical turbulence" or "diffusion-induced chaos"
long sought in the homogeneous, nonconvecting malonic acid reagent, and
numerically studied by Rössler (1978) and Rössler and Kahlert (1979), Kuramoto
(1978), and others in homogeneous media.
324 10: THE VARIETIES OF PHASELESS ExPERIENCE

As Moe described bis fibrillation, spatial inhomogeneity of parameters is the

sine qua non of fibrillation. When refractoriness was suddenly made spatially
uniform in bis model, the previously turbulent activity simplified, sometimes to
one or more rotors. My bet is that the role played by inhomogeneity of one
parameter in Moe's essentially single-variable model of bis local kinetics is
served by the second or third degree of freedom required for chaotic behavior
in partial differential equations and in ordinary differential equations,
respectively. Thus I tbink the issue of inhomogeneity is a red herring and that
the theories of chaos and turbulence arising in the late 1970s may in the end
have more to do with fibrillation than will theories about rotors and phase
singularities.
A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 325
326 10: THE VARIETIES OF PHASELESS ExPERIENCE
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 327

Example 15. Self-Organizing Patterns of Chemical Reaction. A strictly

continuous analogue of the excitable media discussed in the two preceding
examples is presented by the malonic acid reagent (Chapter 12). In this case one
might expect the volume element at the center of symmetry to be held at time-
independent average composition. This would seem a reasonahle consequence of
diffusion from volume elements only a small distance away which are at all stages of
the periodic cycle of excitation. In fact though, the center is suhject to irregular
color changes. Tracing the movements of the indistinct endpoint of the spiral wave
of oxidation, one obtains a jumhle of loops each of length ahout one wavelength, all
consistently clockwise or anticlockwise, mostly contained within a central disk of
diameter ahout one-half wavelength. (The wavelength is the spacing hetween turns
of the spiral.)

This area is certainly phaseless hut hy no means time-independent in its

activity. The cause of the irregularity has not yet been determined. As noted in
Chapter 9, some computer simulations of idealized excitable media show similar
effects, hut in others the patterns pivot rigidly about a fixed center. In each case
the amplitude of the unit period fundamental falls to zero at a central fixed point
hut what determines the amplitude pattern at other frequencies, harmonic or
otherwise?
328 10: THE VARIETIES OF PHASELESS ExPERIENCE

What about the size of the central region within which the fundamental is
substantially attenuated, whether or not other frequencies substantially increase
their amplitudes there? I call this finite disk surrounding a singularity a "rotor." In
the malonic acid reagent it is about one-third the wavelength in diameter (except for
marginally excitable recipes, in which the wavelength becomes immense while the
diffusion-controlled region around the wave tip, the "rotor" does not). In three-
dimensional experiments the rotor is a thread of about that thickness wandering
through the reagent like the core of a tornado. Rotors are unstable within confines
smaller than this dimension, or eloser than this to an impermeable barrier. It is my
impression that rotors are attracted to walls and to counter-rotating rotors that
come this elose. This also happens in computer simulations of the reaction-diffusion
equation used in Chapter 9. Whether adjacent rotors of the same handedness also
repel, and if so whether the effect varies according to their phase difference, remain
to be looked into (in 1978). Such effects could have much to do with the allowed
topological changes undergone by the rotor thread in three dimensions, such as
decay into little rings, knotting or unknotting, linkage or unlinking of rings (see
Chapter 16).

Another way to characterize the rotor bypasses consideration of phase and

amplitude and instead focuses attention on concentration gradients. In anY plane
wave, all level contours of chemical concentration are parallel to the wavefront.
Gradients are normal to the front, pointing along the direction of propagation. In its
outer parts, the spiral wave looks like aplane wave so its concentration gradients are
nearly parallel. To measure departures from this parallelism in computer
simulations, I like the magnitude of the vector cross-product of the gradients. As
one follows any gradient inward toward the wave tip, the source of rotation, this
 A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 329

vorticity inereases (Winfree 1974b,f, 1978a). It inereases slowly at first and then
quite abruptly inereases a thousandfold within a short range around the tip. The
width of this bell-shaped peak, taken between its infleetion points, is onee again
about one-third wavelength in fully excitable media (Winfree, 1978a).
In geometrie terms, the region of erossed gradients around the wave tip is
the part of the medium's image in state spaee that departs substantial1y from the
eycle, eomprising the eap or diaphragm bounded by the eycle. This is the part
that produeed time singularities in state spaee analyses of the pinwheel
experiments.
330 10: THE VARIETIES OF PHASELESS ExPERIENCE
A: THE PHYSICAL NATURE OF DIVERSE STATES OF AMBIGUOUS PHASE 331
332 10: THE VARIETIES OF PHASELESS ExPERIENCE
 B: THE SINGULARITIES OF UNSMOOTH CYCLES 333

B: The Singularities of Unsmooth Cycles

A theory has only the alternatives of being right or wrong.
A model has a third possibility: it might be right but irrelevant.
Manfred Eigen

The alert reader may have noticed something missing from discussions of the
Belousov-Zhabotinsky oscillator: There has been no mention of resetting eurves and
no use of the pinwheel experiment argument that Type 0 resetting implies rotating
waves. That is because (in 1978) no such measurements have been reported. And I
suspect that when they do appear, anything of topological interest about them will
be well hidden in practical discontinuities.

The adjective "practical" is important here. Chemical reaetions follow

eontinuous differential equations which, in the case of the malonie acid reaction,
describe an attraeting eyde. Chemical perturbations, being modifications of the
continuous dynamical equations, continuously map any state initially on the cycle
to a new latent phase, effectively mapping the cyde to itself with some integer
winding number. All the reasoning used in previous ehapters must apply... in
principle. But maybe not in a practical way. This remains to be seen.

~ Itremainea for five year-s. In September 1983 I executed the pinwhee 'exp~riment oy'
transversely.gradil')g brief. ilfumination of a pnase gradient in a sheet of photosensitive ,
malonlc acid reagent. :rh~ expecfed pair of persistent mirror-image rotors d'id em,erge'
,(Chapter 9's' Figura 1.5). .Tbe, experiment replicated successfully .in the hands of
Amemiy~ et-al. (1996). Co.mpatibly, in 1984 and 1986 Doll1i1t et al~ confirmed Type 0
phase resettihg In tl:ie B~lousov-Zhabotjnsky -o~ciUator (see Chapter q.(Fig re-12); Both
recipes- prQvrded stiffly exc.it~ble kiYletics, aso dQ neu~al pac;emakers that; perhaps
,syrprisingly, e~nibit srPooth TYR& 0 r~sett.ing. $0 ,it seams tl)atexpectatiön based oD
topo[ogl,c~ argumen~s ~ pr;öduc~.th.e sal1la 9ualitative results whether.the os~illati<?n
'is sr,noErln Elr ~as an abrupt .stage, and in .fact,even if the local kinetics js- not oscillating.
Whether it alWays"äoes so 15 !"lot known~ butt~e hopethatit w~uld do in myocar~ium
(Winfre '.10 1.983,b) was rewa~ed in practjfe. See Chapter 14 about ventricul~r.lT)yoc~es
firibg sharp action pötentials at regu ar intervats and Chapter'1} aboutvortic.es"even in
,m 0 al'diu that·othe ise oes--not §?ontaneouslY fYde. • : •
334 10: THE VARIETIES OF PHASELESS EXPERIENCE

An analogous case is seen in the stirne mold, whose cAMP oscillator also has a
very abrupt jump in its biochemical cycle. Nonetheless it is in principle continuous
and Type 0 resetting has been measured by exposing these cells to cAMP pulses. It is
not yet clear (1978 and 1999) how the singularity implicit in this observation relates
to the singularity geometrically observed at the pivot of the spiral wave in a two-
dimensionallayer of cells or in the three-dimensional grex.
Spontaneous rhythmicity in nerve membrane presents another case of this
sort. The Hodgkin-Huxley equations and their various adaptations to neural
oscillators are continuous. With most practical settings of parameters, their
solutions include jumps so abrupt that simpler discontinuous models are more
often used than the full continuous equations. Nonetheless the full continuous
equations, if not the simpler discontinuous models, have a phaseless set and in it a
dynamical steady state. Moreover, experiments on pacemaker neurons published
as long aga as 1964 show what was later interpreted as Type 0 resetting (Winfree,
1977). It follows that a phaseless set should be accessible to a sufficiently
attenuated stimulus of the same sort, suitably timed, and the prediction was there
ventured that some electrophysiological pacemakers might be at least unstably
switched off by momentary application of the critical stimulus. Best (1979)
demonstrated this computationally using the Hodgkin-Huxley equation for
rhythmically firing squid axon, current-biased to make the steady state a local
attractor, so the switch-off was in fact permanent. In this way we expanded the
phaseless set from its minimum dimension (codimension 2) to its maximum
dimension (that of its state space, Le., codimension 0), turning this least promising
of neural oscillator models into a sure-fire demonstration. As in James Thurber's
"The 13 Clocks,"
... he tampered with the docks to see if they would go, out of a strange peIVersity,
praying that they wouldn't. Tinkers and tinkerers and a few wizards who happened
hy tried to start the docks with tools or magic words, or hy shaking them and
cursing, hut nothing whirred or ticked. The docks were dead...
Guttman et al. (1980) and Jalife and Antzelevitch (1979) set out to confirm these
computational results experimentally, and succeeded. A suitably timed voltage pulse
of just the right size kicks the membrane off its attracting cycle into its phaseless set
wherein it promptly retires to the attracting steady state. This effect was also
observed by Teorell (1971) in a two-variable model of a sensory pacemaker neuron,
and by others cited in Chapter 6, Section A, Example 4.
 B: THE SINGULARITIES OF UNSMOOTH CVCLES 335

I wonder if a similar phenomenon may await discovery in other biological

docks? Section B of Chapter 2 described three counterexamples, viz., certain other
neural pacemakers, the nudear division cyde, and the endocrine oscillator that
times ovulation and menstruation. Because of their characteristic near-disconti-
nuities, these docks render only impertinent and scarcely recognizable homage to
the topological principles that supposedly govern biological docks. They might have
phaseless sets and, within them, steady states, but these are evidently such
asymmetrically violent repellors that only discontinuities are evident in such
imperfectly resolved measurements as are feasible in the laboratory.
The example of neural pacemakers raises the question whether the steady states
of the female cyde and the steady state of the mitotic cyde might not also become
local attractors in the right hormonal environments. In fact, we know they can, but
with the techniques currently in use ("the pill" and antimitotic cancer drugs) they
become global attractors, leaving no attractor basin for the cyde. As everyone
realizes, there are medical side effects connected with such severe alteration of the
normal parameters. Is it possible that the steady state can be given an adequate
but much smaller attractor basin by using far less of the medications already in
use? No one would ever have noticed a small attractor basin by accident without
looking for it. 1t might be there. The way to look for it is by a pinwheel
experiment, in the singularity trap format of Chapter 2, Example 6. While
maintaining the treatment intended to alter the steady state's stability, one varies
the two parameters (T and M) of a fleeting perturbation. After each stimulus the
resetting of the continuing rhythm is measured. Those measurements can be put
together to construct the resetting maps, isochrons, and winding numbers in such
a way as to guide the search for the singularity. When it is found it will prove
either attracting or repelling ... hopefully attracting as in Jalife's and Guttman's
experiments and in Johnsson's (1976) and Johnsson et al.'s (1979) experiments
with the oat sprout's transpiration oscillator.
In the cell cyde this would switch off proliferation, either permanently or until
another sufficient perturbation reinitiates it. In the case of unicellular organisms
that reproduce by cellular fission, this would also be arrest of the life cycle. In larger
animals, e.g., female humans, it would mean arrest of ovulation. One might switch it
back on by administering another stimulus to kick the system back out of the steady
state's attractor basin or by removing the relatively mild chronic therapy that keeps
the steady state attracting.
Obviously this is an ambitious and tedious program. But more monotonous
searches have been successfully conducted in the past. As the Robbit was once
overheard to remark, "There's nothing like looking, if you want to find something."
336 10: THE VARIETIES OF PHASELESS EXPERIENCE

This sort of phenomenon may be more common than we realize. Richter (1965)
has collected myriad examples of biological rhythms, mostly of a pathological sort
from his clinical experience, which seem to be turned on and off unexpectedly by
fleeting perturbations.
Returning from clinical speculation to a somewhat broader context, it seems to
me remarkable that in this whole catalog of examples there is not one clear case of a
smoothly cycling biological dock with a violently repelling phaseless set. This is in
striking contrast to the models most commonly elaborated by theorists. Wieden-
mann's cockroach shows promise of providing the first example of a strongly
repelling phaseless set. Attempts to locate its singularity produced unpredictable
rephasing but never a sign of arrhythmicity in the individual animal (Wiedenmann,
1977).

C: Transition to Bestiary

This ends the predominantly theoretical section of the materials I have gathered
between these covers. Probably you have already delved extensively into the more
experimental material that follows in the distressingly one-dimensional order
inevitable to books. Nonetheless, this spot marks a transition and seemed to me the
best place to articulate a few caveats explicitly. As Hermann Hesse says in The
Steppenwolf Treatise,
All attempts to make things comprehensible require the medium of theories,
mythologies, and lies; and... [an author who respects his readers] ... should not omit
at the elose of an exposition to dissipate those lies as far as may be in his power.
Some authors of a theoretical bent, in neglecting to do this, have brought down
around their necks the wrath of the Eumenides, manifest most notably of late as
Kolata (1977), Pearson and McLaren (1977), and Zahler and Sussmann (1977). I
don't think that much in the way of disclaimers will be required for this book, as no
one is likely to mistake my pictures and guesses for mathematical proofs of
anything. There is much room for proof in many of the more theoretical chapters
where remarks are made about the anticipated behavior of idealized model systems.
Such remarks are mostly "proofs by example" buttressed by geometric diagrams and
computational results. Perhaps some reader of mathematical inclination, recogniz-
ing a favorable case, will pick up one of these remarks and establish its exact domain
 C: TRANSITION TO BESTIARY 337

of validity as an exercise. For myself, the pictures are of value mainly in a heuristic
way in connection with laboratory work. I am not persuaded that much is to be
gained for empirical science by distinguishing, for example, exactly which kinds of
dynamical system give phase singularities inside a ring of nonzero winding number,
and which others give discontinuities of other sorts. I adopt this rather cavalier
attitude partly because topological notions are in principle incapable of rigorous
application to empirical science: sufficient quantitative distortion would (and does)
alter any topological structure beyond hope of practical recognition; it can make any
topological structure look like any other, as far as experiments of finite accuracy can
resolve. My aim is more nearly to discover patterns in the sense of the quote
opening the Introduction to this book, than to prove that they had to be there all
along and that it wasn't really necessary to look. I believe that I have found some,
and that pleases me profoundly. As to their meaning in terms of particular
mechanisms, I follow George P6lya's recommendation in How to Solve It (1957):
Quite often it matters little what your guess is; hut it always matters a tot how you
test your guess.
The matter preceding this page largely concerns guesses. The matter following
largely concerns testing.
 The Firefly Machine

The Glowwonns represent another shew, which settle on some Trees, like a fiery
cloud, with this surprising circumstance, that a whole swann of these Insects,
having taken possession of one tree, spread themselves over its branches,
sometimes hide their Light all at once, and a moment after make it appear again
with the utmost regularity and exactness, as if they were in perpetual Systole and
Diastole.
Kaempfer, 1727

A: Mechanics

In 1964 I buHt a machine christened "polytalanton" ("many-oscillators": Figure 1) in

which 71 flickering neon lamps were each coupled electrically to all the others
(Winfree, 1965, 1967a, 1971). (There were 71 because out of 100 constructed, 29
drifted outside the intended range of autonomous period during initial "wearing
in.") The purpose of building this machine was just to '1ook and see what would
happen," on a hunch that groups of oscillators might synchronize together in
fleeting alliances of "syntalansis" ("together-oscillation.") One hope was that by
plotting the output of this population of interacting oscillators in the same fonnat as
biologists use to plot activity rhythms of multicellular animals, enough resem-
blances might be noticed to suggest some interpretation of the tantalizingly complex
biological records.
The neon lamp operates as follows (Tuttle and Doughery, 1963). Current from a
fixed voltage power supply-V, in Figure 2-trickles into a capacitor C, steadily
raising its voltage. The capacitors voltage appears across two metal electrodes
separated by neon gas N. The gas has some slight electrical conductivity, and passes
a current from one electrode to the other. For reasons that have to do with the
kinetics of ionized atoms in electric field, this current depends in an S-shaped way
on the electric field maintained between the electrodes (Figure 3). At least, this is
how the current-voltage relationship would look under steady-state conditions.
However, conditions are not steady because the capacitor voltage rises as current
trickles into it. When it reaches E 2 , the glow discharge ignites and the current
A. T. Winfree, The Geometry of Biological Time 338
© Springer Science+Business Media New York 2001
 A: MECHANICS 339

suddenly rises to h This current short-circuits the capacitor so that E very quicldy
falls down to E 1 and the glow discharge ceases. The current drops abruptly to 11•

Figure 1. On the right, mounted in a Plexiglas frame, the "Polytal" array of 71 neon oscillators,
individually shielded in brass tubes. The silvered funnel on top swings down to expose a
photodetector to the 71 flickering lights. The oscilloscope is painting a pattem like Figures 4
through 7. Instruments on the left borrowed from the lab of Victor Bruce, Princeton, 1965.

From here E slowly increases again. The neon oscillator was originally chosen for its
simplicity and reliability and for the analogy it presents to a rhythmically flashing
firefly, a heart cell or other pacemaker neuron (see Chapter 14), the cAMP oscillator
in a slime mold cell (Chapter 15), or any other biological oscillator based on a
quantity like membrane voltage which accumulates to a threshold and then
discharges abruptly.
The several-millisecond period of the cycle can be made quite stable by "aging"
the lamps at high current for several days, cleaning the glass bulbs against
conducting films of humidity, using an individually trimmed triclde resistor, and

v
Figure 2. A single neon oscillator (Ieft)
is one of many connected through N
impedances Xl and grounded through
1----'------ - - --1El-~-I&1----
common impedance xo. The impe-
dances used were resistive or capaci-
tive.
340 11: THE FIREFLY MACHINE

~ -------------

Figura 3. The steady-state current-voltage curve of a neon glow tube. The

negative-slope branch represents unstable states, so current jumps to a stable
branch at E, and E2 .
~--i::--=--E

encapsulating the whole circuit in a grounded metal cylinder to protect against

extraneous eleetrie fields and especially against visible light. In the machine, the
distribution of periods was tuned to a standard deviation about ten percent of the
mean. The oscillators were all coupled equally to one another by connecting each to
a eommon tenninal through a small capacitor. This terminal was grounded through
a larger variable capacitor so that the magnitude of mutual influence could be
adjusted.
A signal depicting the aggregate activity of the 71 oscillators was derived
eleetronieally or through a photoelectrie monitor watehing a subset of the flickering
lamps. The signal was used to modulate the brightness of an oseilloscope display,
just as in a television receiver. The horizontal sweep was tuned to twiee the mean
period of the oscillator population, thus painting a horizontal strip of bright or dark
segments eorresponding to activity above or not above a chosen threshold
throughout two eonseeutive aetivity cycles (essentially the same as one cyele
repeated for easier visualization). The vertical sean rate was mueh slower so that
these "daily records" were painted one above the next on the oscilloscope screen,
stacked some hundred eycles deep in complianee with the custom of circadian
physiologists. Thus, if all 71 oscillators flash in synchrony, the horizontal sweep ean
be tuned to (half) that frequency and the display presents a (repeated) solid vertieal
eolumn of horizontal bright segments. If the population period lengthens, then the
fonnerly vertieal column drifts to the right as it goes down, as eaeh day's activity is a
little later than on the day before (taking .the horizontal sean period as two
eonventional "days") (see Figure 4) .

.... 1 O.8i I...

-
""'--
~
-----
~ -1 _ _
~2-3:
4 _5 Figura 4. The time axis is broken into stacked segments (slanting) of

---
r-s_ 1-
length 2T. An event repeats (dots) at intervals 0.8T in this idealized
~
example.
I--
I-
I-
~
----
~
 B: RESULTS 341

B: Results
What, in fact, happens? First of all, with no coupling all oscillators run at their own
periods. Though initially synchronous, phases spread around the whole cycle within
20 cycles after starting. During these 20 cycles, the activity bar widens from a point
and its mean level drops proportionately, eventually falling below the display
threshold. Figure 5(b) shows a population in this condition, displayed as described
above. The horizontal axis is two "days" or two cycles at the population's mean
period. Vertically the recording covers several hundred cydes. A black gap appears
in the record whenever an oscillator discharges. Vague trails of gaps slant across the
displayas little groups of oscillators gain phase (to the left) or lose phase (to the

Figura 5. (right) In the double-plotted format of Figure 4, spanning several hundred cyc/es from
top to bottom, sudden changes of voltage appear as black dots arranged in criss-cross trails.
Each trail represents a fleeting alliance of some few synchronous oscillators. (Ieft) The
corresponding voltage waveform is plotted on the same vertical time axis, increasing
downward, with collective voltage at the common node plotted to the right.

right) relative to the scan period. Mutual coupling is so weak that only the most
fleeting alliances occur. Figure 5(a) shows a simultaneous tracing of a voltage to
which all 71 oscillators contribute equally: Its amplitude is quite low and fluctuates
irreguIarlyas oscillators drift in and out of synchrony.
With resistive coupling (Cl and Co replaced by resistors), no matter how strong,
the result is about the same: random phases. Thus, it appears that simply admitting
mutual influence is not sufficient to guarantee mutual synchrony in a population of
"docks." This result goes somewhat against intuition, especially for oscillators that
342 11: THE FIREFLY MACHINE

easily lock together in pairs, given almost any kind of coupling of intensity
commensurate with the difference between their natural periods. The reason for
this failure of synchronization in groups seems to be a phase compatibility
problem, as touched upon in Chapter 4, Section B and in Chapter 14, Section B.
Near the moment of the nearly synchronous discharge, the phase adjustment
inflicted on each individual depends on that individual's exact phase in such a way
that the spread of phases in the population is increased rather than decreased. I call
this unexpected behavior antisyntalansis.
However, with capacitive coupling mutual synchrony is achieved abruptly at a
threshold intensity of mutual influence. In this situation the intrinsically slower
oscillators are imposed upon to speed up a bit, and the faster ones slow down, so all
stay in step at one common frequency. But the exact mechanism of mutual
synchronization was never determined quantitatively in this machine. Figure 6 is
analogous to Figure 5 but has its vertical time axis much expanded to reveal
individual cydes. Figure 6(a) shows the sawtooth voltage waveform to which all 71
oscillators contribute equally. As groups of sawtooth oscillators drift out of
synchrony the collective waveform develops multiple zigzags in each cyde and
decreases its peak-to-peak amplitude. Each zigzag appears as a whiter patch
(because it is traced twice, not just once) of width proportional to the number of
oscillators that discharged at that time. The phase relations among these groups are
displayed more conveniently in Figure 6(b) [(with the same vertical scale as Figure
6(a), Le., much expanded relative to Figure 5; the horizontal scale also happens to be
compressed relative to Figure 5(b)]. The scan is solidly interrupted (black gap) when
many oscillators discharge simultaneously. The discharge of smaller subpopulations
appears as a proportionally smaller interruption. When two major groups are about
one-half cyde apart the waveform in Figure 6(a) exhibits about half its maximum
amplitude.
With still stronger coupling (smaller Co) the synchronous population abruptly
splits in two, with a slight change of period (Figure 7). This spontaneous schism
doubles the frequency of the aggregate rhythm. Formally, this is a familiar
bifurcation in the behavior of coupled ordinary differential equations (as one might
view the coupled oscillators). I found its mechanism in detail in the case of smoothly
varying simple-dock oscillators (Winfree, 1967a). Pavlidis (1971, 1973) derived
similar behavior in oscillators involving two variables. Durston (1973) reports a
similar abrupt frequency doubling in the similarly pulse-like rhythmic coherence of
social amoebae (Chapter 15), though he suggests quite a different mechanism for it.
I expect to see more studies of mutual synchronization in populations of equally
coupled cells of this creature in the near future, thanks to the suspension technique
of Malchow et al. (1978). Records of circadian activity rhythm in vertebrate animals
often show such ostensibly spontaneous splitting into two components (see page
587). Splitting of an animal's activity pattern might reveal the presence of exactly
two oscillators (Pittendrigh, 1974; Daan and Berde, 1978; Block and Page 1980), but
the possibility exists that neither of the two oscillators has a distinct identity, each
being assembled at the time of splitting by aggregation of randomly gathered
individual oscillators.
It is not unusual to see small groups of neon oscillators temporarily escape
entrainment and fleetingly slant across the screen, showing up at later and later or
 B: RESULTS 343

Figure 6. Similar to Figure 5 but the vertical time scale is much expanded and the horizontal
scales are calibrated differently.

earlier and earlier times in successive cycles untU they are again absorbed into a
larger group. In these respects the population of oscillators exhibits some of the
tantalizing features of mammalian activity records which have suggested to many
observers that the whole organism's activity is govemed not by one central
pacemaker but by many committees of circadian rhythms, possibly situated in the
several centers of hormonal and neurosecretory control. (See Chapter 19, Section C
on multioscillator interpretations of multicellular circadian rhythms.)

A
Figur. 7. As in the right part of Figures 5 and 6, calibrated in d B
cycles of 1 day = 24 hours. At B the population splits into two that 8
persevere in wobbly mutual entrainment but avoid synchroniza- Y
tion. Notice that the period lengthened; it always shortens when I c
hamster circadian activity rhythms do this. (From Winfree in ,
400
Biochronometry (1971), page 151, with the permission of the
National Academy of Sciences, Washington, D.C.)

12 36

-hour ....
344 11: THE FIREFLY MACHINE

C: Historical

The neon device was originally intended to simulate a two-dimensional sheet of

cortical neurons. Spatial synchronization and wave-like activity, hopefully of
some novel variety, were to be sought as a means of discovering which features
of real neuron behavior are essential to such phenomena. This had been tried
before. Leon Harmon told me of technical difficulties with his similar population
of neon discharge tubes. His were packed elose together without shielding and
without connecting wires in hopes of achieving mutual synchronization and
waves by means of optical and electrostatic coupling. I resolved to eliminate such
unquantifiable influences from my own device and to test it first with all units
electrically coupled to a common terminal. Only after examining mutual
synchronization phenomena in this mode would coupling be rewired on a
neighborhood basis. By the time this much was accomplished (1965) it had
become elear that computer simulation offered a more controllable model and a
more flexible format for observation and output. Moreover, in this same year,
Farley (1965) published a computer simulation of spatially coupled, idealized
neurons that exhibited synchronization, waves, and even pinwheel-like rotating
waves. In the same year, Gerisch (1965) published an account of nerve-like
excitability and rotating waves in populations of social amoebae. Also in the
same year, Balakhovsky (1965) published a geometrie model of excitable media
showing wave propagation and spirals. Then came the discovery that yeast cell
suspensions are populations of mutually synchronizing oscillators (Chapter 12),
and Zaikin and Zhabotinsky's (1970) discovery of a repeatedly excitable chemical
medium (see Chapter 13). With this convenient liquid in hand, even computer
simulation seemed inconvenient as a way to investigate mutual synchronization
and the spatial activity modes characteristic of such media. So the neon device
was never wired for neighborhood interaction (such as couples cells of the heart's
pacemaker node, for example) and such behavior as had been recorded under
conditions of promiscuous interaction was never rationalized in quantitative
terms.
C: HISTORICAL 345
346 11: THE FIREFLY MACHINE
 Energy Metabolism in Cells

The want of which incomparable Artifice (microscopes) made the Ancients' ...
erre in their... observations of the smallest sort of Creatures which have been
perfunctorily described as the disregarded pieces and huslement of the
Creation.... In these pretty Engines are lodged all the perfections of the largest
animals ... and that which augments the miracle, all these in so narrow a room
neither interfere nor impede one another in their operations. Ruder heads stand
amazed at prodigious and Colossean pieces of Nature, but in these narrow
Engines there is more curious Mathematicks.
Henry Power, physician, Experimental Philosophy, 1663

A: Oscillators
Cells have three alternative means of procuring energy for digestion and
biochemical synthesis, for maintaining concentration gradients, for muscular
contractions and cell division, and for maintaining body heat:
1. Photosynthesis: The chloroplasts of green plants capture photons to convert
ADP to ATP. Water is split to reduce NADP to NADPH, releasing oxygen.
2. Respiration: The mitochondria use that oxygen and convert ADP to ATP. In the
process, NADH is oxidized to NAD and water.
3. Glycolysis: Ladung illuminated chloroplasts or lacking oxygen, cells metabo-
lize sugars by fermentation to make a little ATP from ADP. Historically, this
was probably the first way to make the high-energy pyrophosphate bond of
ATP. All cells maintain this pathway. Most cells fall back on glycolysis only
when they have no better alternative, hut it is common to have no hetter
alternative. The microorganisms of yogurt, sauerkraut, gangrene, and food
poisoning, for example, subsist wholly on glycolysis, as do facultative
anaerobes such as intertidal bivalves (e.g., oysters) and parasitic helminths
(e.g., schistosomes) and diving vertebrates (e.g., green sea turtles) during their
prolonged periods of contented ahstinence from respiration. Red blood cells
have no other energy supply. Poorly vascularized tissue such as the cornea of
the eye, compact tumors, and embryos rely heavily on glycolysis for their
energy needs. For shorter intervals, so do the aching musdes of any animal

A. T. Winfree, The Geometry of Biological Time 347

© Springer Science+Business Media New York 2001
348 12: ENERGY METABOLlSM IN CELLS

in violent exercise, especially those of diving mammals such as the porpoise

and whale .
.. Unde"r conditions of oxygen deprivation Q'Rou e
et al. (1994) found in heart cells
1OO-second , oscillations of Ca + and of cell membrane potential. These apparently
2

reflect a dramatic effect of sRontaneously osdlrating glycolysis on the. cell membrane's

electrical _behavior. ~ .

The first three biochemical oscillators discovered (all since 1955) were in these
three sources of energy: photosynthesis in chloroplasts, respiration in mitochondria,
and glycolysis in the cytoplasm of yeast cells (and later in more dilute cell-free extracts
of yeast, heart muscle, and skeletal muscle). See reviews by Hess and Boiteux (1971),
Nicolis and Portnow (1973), by Goldbeter and Caplan (1976), and by Goldbeter (1996).

B: The Dynamics of Anaerobic Sugar Metabolism

The most vigorously and successfully studied biochemical oscillator is still (1999)
oscillating glycolysis in yeast. In fact, biochemistry originated (the word "enzyme"
means "in yeast") in studies of the mechanism of glycolysis in yeast, which makes
ethanol. The chemistry is consequently weIl understood. Yet it wasn't until 1957 that
Duysens and Amesz obtained the first hint that glycolysis does not always produce
energy in a steady DC mode: it sometimes goes AC, the cells oscillating like little
dynamos with aperiod on the order of aminute (Figure 1). With this realization came
a new emphasis on the second and less well-developed aspect of biochemistry: Not
only must we understand the sequence of molecular transformations among reaction
pathways, but we must also understand the regulation of rates of transformation.
Molecular transformations are mediated by enzymes. The enzymes' catalytic rates are
govemed by the concentrations of pertinent substrates and cofactors, most of which
are themselves produced in other enzyme-catalyzed reactions of the same pathway.
The discovery that such a system can spontaneously vary its rate by factors of 10 to 100

_ü~ ~ r-t 1tJ if.IJ ~ ~ ~ 'IViNVV!

I

oe 11M GIueost
-- p.. ~ ~f
01- 0
-"'*' '!"""" DPNHf
r--

Figure 1. NADH f1uorescence in a suspension of metabolically oscillating yeast cells (from Pye
in Biochronometry (1971) page 627 with the permission of the National Academy of Sciences,
Washington, D.C.). Other variables change in a much more abrupt fashion. People committed
to describing this oscillation as "pendulum-like" or "relaxation-oscillator-like" would partition
into mutually antagonistic schools according to their choice of astate variable to watch.
 B: THE DYNAMICS OF ANAEROBIC SUGAR METABOLlSM 349

="" (PFK '\ • I

'~ ~~ ~
2PG
2 PEP
~ '7~~
PGK

2AOP=J 2N H - 2NAD
PK 0
2A~ 2
2PYR
~~~~====S:~z:===:2~CT~E
I- 2AA 2 ETHANOL

Flgure 2. A schematic of the sequence of transformations undergone by a glucose molecule

becoming ethanol (in yeast) or lactate (in muscle). At triose phosphate (TP) there is also a short
connection to glycerol. These changes are wrought by some dozen enzymes, of which only four
!
are indicated here in italics. Flux at 25-3rc. is to 1 JLmole glucose/sec per wet gram of cells.
The bold arrows indicate the immediate effect of oxygen: increasing ATP and NAD.

in a regularly repetitious way seemed at first to offer the experimental biochemist a

particularly favorable opportunity to study regulation. And it seemed to offer a
particular challenge to those who would formulate the mathematics of regulatory
kinetics. But it turns out that as far as investigations of mechanism are concerned, the
fact of oscillation in itself has provided no particular experimental opportunity. It also
has provided few constraints by which to eliminate what proved to be a plethora of
possible mechanisms. Far from requiring very special arrangements, oscillation turns
out to be a common feature of even very simple regulatory kinetics, a feature that
rapidly becomes all but unavoidable as reaction complexity increases (Goodwin,
1963; Higgins, 1967; May, 1973).
In the particular case of glycolysis, then. the problem is not to think of a possible
mechanism. but to determine by ingenious experiment which of the many
potentially oscillatory aspects of that pathway in fact assume dominant importance
under physiological conditions. This job was carried out primarlly by Higgins in
Philadelphia. working with biochemists brought together by B. Chance, and by
Sel'kov in Moscow, working with biochemists brought together by Hess in
Dortmund and by Betz in Stockheim.
350 12: ENERGY METABOLlSM IN CELLS

Glycolysis consists of a chain of a dozen enzyme-catalyzed transformations of a

six-carbon sugar (Figure 2). The sugar is twice phosphorylated, then split into two
three-carbon fragments, each of which gets phosphorylated again, gives up both
phosphates to ADP, and ends up as pyruvate (PYR in Figure 2). On the way to
pyruvate, each gets oxidized, simultaneously reducing NAD 1 to NADH. In oxygen-
starved musde a final reaction converts three-carbon pyruvate to three-carbon
lactate, a cause of general anxiety, of charley-horses, and of labor pains. In yeast, a
preliminary step deaves off carbon dioxide, making the broth fizzy and leaving two-
carbon acetaldehyde (AA) to be reduced. The result is then grain alcohol, a cause of
highway disasters for drinkers and their victims. Either way, the final reaction
oxidizes the NADH accumulated earlier back to NAD. This NADH, as it happens,
fluoresces blue-green in ultraviolet light. Following the innovation of Duysens and
Amesz (1957) one can monitor the flux of material through the pathway by
watching this glow. This works because the reactions increasing and decreasing
NADH happen to fluctuate out of phase with each other. Like the NAD-NADH
couple, an ATP-ADP couple also links remote reactions in this pathway (Figure 2).
But here the books are not kept so neatly balanced: Each triose that runs this gantlet
uses and restores one ATP but additionally converts one ADP to ATP in shedding its
final phosphate group to become pyruvate. And here we come to the crux of the
matter: Glycolysis is for making ATP, and is regulated accordingly.

C: The Pasteur Effect

The rate of glycolysis is regulated by the cells' balance of ATP and ADP. When there
is more ADP (less ATP), glycolysis runs faster, converting ADP to ATP at the expense
of glycogen or starch reserves. When there is less ADP (more ATP), e.g., when there
is enough oxygen for operation of the mitochondria, the cell's main ATP factory,
then glycolysis shuts down. This regulation is called the Pasteur effect.
How is this trick managed? It turns out that it is managed mainly by one enzyme,
the one that puts the second phosphate on the sugar. This is phosphofructokinase
(PFK). When there is enough ADP around, the concentration of AMP is also high and
some of it sticks onto a special receptor site on the PFK molecule. This changes its
shape so that it works more quickly, admitting a swift flow of sugar through
glycolysis to convert the excess ADP back to ATP. The activity of PFK in fact changes
10 to 100 fold during each eyde of oscillation (Hess et al., 1969).
But here lurks a paradox. PFK is a phosphorylating enzyme. It uses ATP,
degrading it to ADP. Thus it is aetivated by its immediate product. A potential for
instability is implicit. As sugar passes PFK, ADP aceumulates and enhanees the rate
of sugar passage and of ADP accumulation, unless that ADP is eonsumed at a
correspondingly increased rate further down the pathway. If there is any delay (and
there is) in the arrival of phosphorylated sugar further down the disassembly line,
then the pulse will grow until its front does reaeh the later reaetions. Then so much
ADP is eonverted to ATP that PFK shuts off the input altogether.

I BefOI"e 1970, NADH was called DPNH.

 D: GOLDBETER'S PFK KINETICS 351

Verbally, this is how the oscillation arises. But as Hermann Hesse obseIVes in The
Steppenwolf Treatise, "Things are not so simple in life as in our thoughts, nor so
rough and ready as in our poor idiotie language." All such verbal arguments about
cydes are specious, a realization aptly artieulated by Wojtowiez (1972, p. 65) and by
Aldridge (1976, p. 2). One knows where to make such an argument only by the
hindsight acquired through biochemical experiments and through solving kinetic
equations. The problem with verbal rationales lies in their inability to decide whether
1. The verbally artieulated mechanism can or cannot settle down to a nice
balanced rate at which ATP is produced exactly as fast as it is consumed.
2. The regularly periodic oscillation is approached spontaneously from the steady
state. However these questions have been resolved in a variety of other ways.
The dominant model sterns from the work of Goldbeter and collaborators,
whose kinetic analyses we will also meet in Chapter 15 in connection with
Dictyostelium's cAMP oscillation. Goldbeter's analysis (Goldbeter and Lefever,
1972; Boiteux, Goldbeter, and Hess, 1975; Goldbeter, 1996) derives much ofthe
obseIVed behavior from an attracting cyde of allosteric activation of PFK by
ADP. This is not to deny that other reactions are involved, but this reaction
asserts itself especially conspicuously under common operating conditions. This
understanding postdates my 1972 analysis (of 1970 experiments), which was
informed only by abstract dynamical theory and the models of Higgins (1964)
and of Sel'kov (1968a,b).

D: Goldbeter's PFK Kinetics

Though it is not glycolysis, the single enzyme oscillator built around PFK is
sufficient to account for many of the facts of oscillating glycolysis. Not only
sufficient, it may be a necessary part of the glycolytic oscillator in cell-free extracts
of glycolysis. This is revealed by the following fact. It is possible to bypass the first
steps of the pathway by starving the cell-free extract for sugar, then dripping into the
reacting extract any substrate that normally appears after the PFK step. With PFK
thus bypassed, no oscillations have been obseIVed (Hess and Boiteux, 1968).
Higgins and Chance's early recognition of the pivotal roles of PFK and of the
ATP-ADP couple also rested heavily on the fact that the many substrates of
glycolysis oscillate in essentially four groups. All those prior to PFK oscillate
synchronously. All those after PFK and before GAPDH also oscillate as a group, but
180 phase-shifted from those preceding PFK, as though PFK were the fulcrum of a
0

teeter-totter. Those from GAPDH to PK are synchronous, though somewhat delayed

relative to their precursors. And all substrates after PK are 180 opposite to that
0

phase. The two enzymes PFK and PK mainly seem to be gating the flow. Whenever
mass flow through one of these bottlenecks increases, downstream concentrations
rise and upstream concentrations fall.
An essential third clue implicating the ATP-ADP balance in controlling the
oscillation came from phase-resetting experiments. An injected pulse of ADP was
found to profoundly affect the oscillation in cell-free extract (Chance, 1965; Pye,
1969, with an even smaller dose). Not every substrate does this. In particular, Pye
352 12: ENERGY METABOLlSM IN CELLS

(1969) found that FDP has no such effect. FDP is the other product of PFK, and like
ADP it also activates PFK. The demonstration that FDP has no effect and that ADP
has a profound effect led to Goldbeter's updating of the earlier models of Higgins
(1964) and Sel'kov (1968a,b).

Caveats

Every theory of the course of events in Nature is necessarily based on some process
of simplification and is to some extent, therefore, a fairy tale.
William Napier Shaw 1854-1945
Without going into much more detail here, itseems appropriate to note that
glycolysis is really much more complicated than its simplest adequate model. In
particular:
A. Phase shifting by ADP in extracts requires about 30 times more ADP (about
12 j.tmole/g of broken cells) than would be expected for the 0.4 j.tmole/g swing of its
concentration in the oscillation. The strong phase-shifting by oxygen requires the
equivalent of about 1 j.tmole/g of ADP. Thus one might guess that the effect of O2 is
not mainly by depletion of ADP and that ADP is not a primary state variable in the
oscillation mechanism. In fact the other adenosine phosphates play weightier roles
in controlling PFK activity. All three adenosine phosphates are in equilibrium
through myokinase, so from a functional point of view, any one may be considered
the control. Sel'kov and Betz (1968) found that, under conditions allowing
oscillation, PFK is controlled almost exclusively by AMP. 2 Chance et al. (1965)
found that cyclic AMP phase shifts the oscillation about a hundredfold more
efficiently than does ADP.
B. At least two other reactions play important roles in the oscillation:
1. Pyruvate kinase (PK), another phosphorylating enzyme, is sensitive to ADP
levels and rhythmically gates the flow of material through glycolysis almost as
much as PFK does.
2. Glyceraldehyde phosphate dehydrogenase (GAPDH), regulated by fluctuating
NADH levels, likewise plays a modulating role. In fact, 3-PGK and GAPDH
alone, without PFK, seem to constitute aseparate autonomous oscillator under
some conditions (Chance et al., 1967; Dynnik and Sel'kov, 1973). The dynamics
of two interacting oscillators is much richer than that of one alone. This lower
part of glycolysis is not so thoroughly studied as is the upper tract, and may yet
contain many secrets. The effect of cyclic AMP (see A above) seems to be on an
enzyme after 3-PGK.
C. All the critical control points of glycolysis change according to the cell type
and its physiological state (determined by dietary conditions and hormone levels).

2 Today we would say "by F2,6B," discovered in the 1980s; but Richard et al. (1996b) found that [F2,6BJ
varies only insignficantly during the oscillation.
 E: PHASE CONTROL BV ADP 353

Substrate concentrations and cofactor concentrations detennine the operating

points of the enzymes and so detennine what quantities their rates react to most
sensitively. Sel'kov (1968a,b), Garfinkel et al. (1968), and Higgins et al. (1968) have
given myriads of different approximations to the complete kinetics of glycolysis,
each appropriate under different operating conditions.

D. Glycolysis can be reconstituted in glassware from crystallized enzymes,

substrates, cofactors, and an ATPase to simulate "the rest of the cell." It worles fine
and it oscillates (Hess and Boiteux, 1968). But this trick has not yet been achieved
using any less than all the enzymes from hexokinase through alcohol dehydrogenase.

/
/ TYPE'
/ RESETTlNG
/

Figur. 3. Piecing together observations of phase resetting at high dose, NEW 1

low dose, and insensitive phase, we obtain a helical boundary on the ~
surface that describes new phase as a function of old phase and dose.

OLO PHASE 11

E: Phase Control by ADP

The resetting data of Chance (1965) and of Pye (1969) are fragmentary hut they
suggestType 1 resetting in response to a 0.7 mM ADP increase and Type 0 resetting
354 12: ENERGY METAB0l15M IN CELLS

in response to a 2.5 mM ADP increase. They also indicate that an injection of ADP
during about half of the cycle has little lasting effect on the oscillation's phase.
Taking these observations at face value, they describe a helical boundary on the
three-dimensional graph of the glycolytic oscillator's new phase as a function of the
size of an ADP dose and the old phase at which it was administered (Figure 3).
Interpolation into the middle range of doses and phases in Figure 3 leads us to
anticipate a helicoidal resetting surface inside the helical boundary (see Chapter 1,
Seetion C and Box B of Chapter 2). We are driven to this surface by assuming a
smooth dependence of phase on the stimulus parameters. Yet such a surface
necessarily contains a discontinuity. The most compact discontinuity we can get
away with is a phase singularity.
If the unavoidable discontinuity manifests itself in this form, then aphase
singularity should result from perturbing glycolysis by a suitable change in the ATP-
ADP balance, neither too drastic nor too subtle, at just the right phase. What would
happen to cells so treated? Their new phase should be unpredictable and
irreproducible. We might also observe some effect on the amplitude of oscillation.
The magnitude and nature of such effects could tell us whether the glycolytic
oscillation has a smooth attracting cycle or more nearly resembles an hourglass-like
relaxation oscillation, whether it has one or more steady states, and whether they
are repellors or attractors.

F: More Phase-Resetting Experiments

I went to E. K. Pye's lab in Philadelphia to try this experiment in 1970. WitllOut his
making every service available to me, it never would have worked in the single week
I had scheduled (in which the daylight hours became unexpectedly busy because
Nixon chose that week to invade Cambodia).
As a novice, leery of cyanide-inhibited respiration and of homogenized cells, I
preferred to use intact living cells. So I chose to perturb the ATP-ADP balance
indirectly, using an oxygen pulse. This was necessary because phosphorylated
intermediates do not penetrate the cells' plasma membrane, 3 but oxygen does. Given
a tiny amount of buffered water containing dissolved oxygen, the stimulated cells'
mitochondria quickly deliver a measured burst of ATP, whereupon the correspond-
ing amount of ADP vanishes within the cells. During the few seconds required to
consume it, the oxygen concentration was well above the 0.4 J.LM concentration
required to saturate mitochondrial activity (Chance, 1965). In other words, I used
the Pasteur effect as a perturbation. Glycolysis was allowed to run in its usual
anaerobic oscillation and was then switched to aerobic metabolism. Aerobic
metabolism operates at a high steady ATP level with very slight flux through the

3 They do in Aplysia neurons, whose electrical rhythms are regulated by PFK activity (Chaplain, 1976,
and Chapter 14). Chou et al. (1992) and O'Rourke et al. (1994, 1995) have since found glycolytic
ocillations driving action potentials also in cardiac myocytes and in pancreatic beta cells. Besides oxygen,
also glycerol, acetaldehyde, and ethanol cross the cell membrane quickly by diffusion. In 1970-2, various
prior experiments (that later turned out to mislead) informed us that these do not oscillate measurably,
andlor do not affect the oscillation in return, or permanently alter its amplitude and period. So none but
oxygen seemed good candidates for testing phase responses.
 G: RESULTS: THE TIME CRYSTAL 355

pathway. But the switch to aerobic dynamics was scarcely begun when the small
pulse of oxygen ran out.

G: Results: The Time Crystal

In 88 separate experiments, I gave various doses of oxygen at various times in the
cycle, all the while monitoring the NADH fluorescence rhythm. The results appear
in Figure 21 of Chapter 2, and, in stereo without artwork, as Figure 4 of this chapter.
Each NADH maximum is plotted as a dot in three dimensions along three axes:
1. Vertically downward, the time of the maximum, measured from the time of
oxygen injection
2. Horizontally to the right, the time of the injection, measured from the time of
the prior NADH maximum
3. Horizontally in depth, the amount of oxygen given
Sure enough, the data points fill out a screw-like surface in each 30 seconds x
30 seconds unit cell of the time crystal. Its singularity lies a few seconds before the
NADH fluorescence maximum (which is also the ADP maximum) at about 20 j.tl of
oxygen-saturated buffer. These 20 j.tl contain 28 nmole of oxygen which, if
completely used by the cells' mitochondria, would deplete 170 nmole of ADP in
the 160 mg of suspended cells. So we're talking about an ADP depletion of about 1
j.tmole/g of cells. As noted above, this is at least double the whole range of
fluctuation of ADP in these cells. Thus, some doubt is raised about the simple
interpretation I use throughout this chapter in terms of the ADP-PFK mechanism
considered in isolation. The phase of the singularity seems right, though. A
coordinated increase of ATP and depletion of ADP from the ADP maximum on the
anaerobic cycle would move the oscillator toward its stationary state.
Amplitude effects were a little harder to evaluate because, being a tyro in this
business, I prepared rather poor cells. Their oscillations ran down exponentially,
each maximum being only about half the size of its predecessor after the cells start
at high amplitude upon running out of oxygen and going anaerobic. In experiments
right at the singularity of the phase surface, the cell suspension nearly quit
oscillating [Figure 5(a)], but I saw no conspicuous effects on amplitude otherwise. A
more careful reexamination of the data years later [prompted by Aldridge's (1976)
resetting experiment using Ca2 + pulses and by Greller's (1977) resetting experiments
using acetaldehyde pulses] shows that there are effects on amplitude following
nonsingular perturbations. Specifically, the damping is precociously advanced the
closer the stimulus was to the critical phase and critical dose. This is what would be
expected of the ADP-PFK mechanism. Goldbeter's equations show trajectories
winding many times around the steady state before the oscillation recovers most of
the way back to the attracting cycle, after an increment of ADP moves its state into
the inside of the cycle.
356 12: ENERGY METAB0L15M IN CELLS

Box A: How to Look at Figure 4

The stereo picture in this chapter, the three in Chapter 20, and the one in Chapter 21 are
intended for viewing with the help of a mirror. (This is my alternative to the eye-
crossing method, which requires practice, and to the red and green spectacles method,
which involves the publisher in color printing.) A first-swface mirror works best, but
ordinary silvered glass will serve if you can ignore the duplicate reflection off the glass
front surface. Mount the figure directly in front of you. Hold the mirror very steady in
the symmetry plane of your head so that it touches your nose and reflects the right
image into your right eye. Look at the left image with your left eye. Adjust the mirror to
align the two images. The graph should now snap into three-dimensional perspective.

Figure 4. Stereographic views of 342 measurements of NADH peak timing before and after an
oxygen pulse. (For viewing, see Box A.) Coordinates and perspective as in Figure 21 of Chapter
2. The two interior uprights depict the presumed singularity, a pole around which data points
climb in cork-screw fashion. The 10 dots stacked up in middle background are unperturbed
controls. All data are double-plotted to the right.
 G: RESULTS: THE TIME CRYSTAL 357

Box B: The Fluorescent Pinwheel Experiment

As in the ease of other phase-resetting experiments explored in this volume, the Pasteur-
effect rephasing by oxygen pulses applied to oseillatory energy production in yeast cells
can be described in terms of one single experiment conducted in two-dimensional space.
Imagine a thin layer of yeast cells spread out on a table top, conducting aerobic
metabolism. Now we begin to cover them with a glass sheet or some other surface
capable of excluding oxygen. Slide the shield from east to west at a constant velocity
sufficient to reach the cells furthest to the west within a minute or two. As the cells are
covered and consume a residue of dissolved oxygen, they enter upon anaerobic
metabolism and begin oscillating. By grading from east to west the times at which this
happens we establish an east-west phase gradient covering two to four cycles. Now to
administer a transversely graded stimulus, we slide the oxygen barrier northward then
return it immediately to its original position. The southemmost cells are thus exposed (at
various phases along the east-west gradient) to oxygen for a relatively long time, while
those at the northem extremity are exposed for only a moment or not at all, at the
extremity of the oxygen shield's movement. We have thus assembled in an orderly way in
two dimensions all the individual resetting experiments that can more conveniently be
carried out one by one in the fluorometer. This experiment presents in a continuum all
combinations of (phase, oxygen dose) within the chosen limits. Our 88 fluorometer
experiments constitute 88 sampies within one eyde of phase in this idealized two
dimensional experiment. The results were plotted in Figure 4 and in Figure 21 of Chapter
2 in the format of a time crystal. Each unit eell of that plot contains a screw surface
whose altitude at each point is the time of the NADH fluorescence maximum at that
particular combination of initial phase and dosage of oxygen administered at that phase.
A contour map of this surface consists of curves, each of which indicates a locus of
constant altitude on this surface (Figure a). Constant altitude means constant time of the
fluorescence maximum. Each such contour could be obtained by taking a cross-section
at fixed altitude through the time erystal. The time crystal is a stack of serial sections of
this sort or, equivalently, a set of eontour lines as sketched in the adjaeent figure. In these
contours we see the result of the phase-resetting experiment reassembled in two-
dimensional format as a pinwheel experiment. At any given moment, one of those
contour lines marks the locus of brightest blue-green fluorescence. A few seconds later
the next contour line is brightest and a few seconds after that the next, and so on. Thus

Mean loei along which NADH fluorescence peaks up at the

indicated number of seconds after an oxygen dose of D
nmoles per wet gram of cells applied T seconds after an
NADH maximum. D* ("D star") = 187 11-1 oxygen-saturated
buffer/g wet cells = 8.3 II-g or 0.26 II-mole of O 2 per gram wet
cells = 26 II-M extracellular O 2, at 1:10 cell density. Sketched
from serial sections of the data cloud in the time crystal of
Figure 4, and Figure 21 of Chapter 2.
358 12: ENERGY METAB0L15M IN CELLS

we see that the glow is a wave whieh sweeps 'round and 'round a eentral pivot at the
singularity of the serew surfaee.
This rotating wave is only a "pseudowave," in the sense elaborated in Chapter 4.
However, if the two-dimensional experiment were eondueted in a small enough
physical spaee, let's say 1 centimeter by 1 centimeter, then the moleeular interactions
whieh normally synehronize nearby yeast eells would be reaehing aeross eells of
signifieantly different phase in the eyde in times eomparable to one eyde duration or
less. Without solving the equations of kinetics and diffusion, one doesn't know what
would beeome of this situation, but similar initial eonditions in the malonie acid
reaetion (Chapter 13) and in Dictyostelium (Chapter 15) result in stable rotation of a
spiral wave around that fixed pivot. To aetually see this in yeast would require the
services of a seanning fluorometer not unlike the seanning eleetron microseope or a
television eamera.

Aecording to Goldbeter and Erneux (1978), the glycolytic oscillator can be

"excitable" in a physiologieally reasonable range of parameters, in the same sense as
the malonie acid reagent and Dictyostelium are excitable. On this basis, too, one might
reasonably anticipate metabolie wave propagation, rotors, and seroll rings in one-, two-,
and three-dimensional media eomposed of yeast eells.
 H: A REPEAT USING DIVALENT CATIONS 359
T'2eSEC
a) o• 0.28 I"""le/gram
~

Flgure 5. (a) Two NADH f1uorescence traces superimposed.

The heavy trace is an unperturbed contro!. In the thin trace, a
critical dose of oxygen was administered at the critical phase
(arrow), quenching rhythmicity (from Winfree 1972 Figure 11).
(b) As above but from Greller, 1977, Figure 29, using
acetaldehyde instead of oxygen. (The time scale is somewhat
different.) b)

~
~- -
Aldridge and Pye (1979a,b) enVlSlon a slightly more exotic mechanism of
amplitude adjustment. They propose that the steady state and the limit cycle are
bolh atlractors. A near-singular perturbation then deposits some cells inside the
steady state's atlractor basin and they stay there, contributing little or nothing to the
aggregate amplitude. It is argued from numerical studies that this situation is stahle
even in the face of the strong mutually synchronizing interaction known to be at
work in yeast cell suspensions of the density used.

H: A Repeat Using Divalent Cations

Essentially the same phase and amplitude behaviors as noted above were elicited by
Aldridge and Pye (1979a,h) using pulses of Ca2 + or Mg2 + concentration. The effect of
rem.oving ions from the extracellular medium was qualitatively the same as the
effect of adding a comparable amount a half-cycle earlier or later. The mechanism
by which these sudden changes of ion concentration affect the kinetics of glycolysis
has not been resolved. Activation of membrane-bound enzymes that process ATP,
ADP, andJor AMP seems a likely possihility.
360 12: ENERGY METAB0L15M IN CELLS

,,
I
,
I

,,
I
I

\
,
\
,

' also foun pnase singulantJes l,,~~cle apart fö?Ca~ aa

ce"_stJspens·ons. :'Ii '.' , _ .....~.........."'-.____~_

I: A Repeat Using Acetaldehyde

There are basically two good ways to deliver a sharp kick to glycolysis in intact cells.
One is to transiently kick glycolysis indirectly, by activating mitochondria with
oxygen or by afflicting the membrane with ions as above. The other is to transiently
kick glycolysis itself directly with one of the nonphosphorylated substrates that
occur late in sugar degradation. Pyruvate (PYR) and acetaldehyde (AA) are obvious
candidates, as are ethanol (ETOH) and glycerol (GLY) (Figure 2). And it turns out
that PYR and AA both cause large phase shifts at submillimolar concentrations
(Richter et al., 1975; Betz and Becker, 1975b). As with ADP, AA has been used to
measure Type 1 (weak) resetting (Betz and Becker, 1975b; Greller, 1977) and, at the
same dose, Type 0 (strong) resetting (Greller, 1977). An AA concentration of 50-60
J.LM seems to be the dividing line between weak and strong resetting. Greller's data,
like Aldridge and Pye's, once again describe a helical boundary for the surface
within each unit cell of the time crystal. Greller found the expected singularity at M*
about 50 J.LM AA, at aphase <jJ* about one-third cycle before the NADH peak [Figure
5(b)]. AA presumably (Figure 2) strikes first at lower glycolysis, in the less studied
GAPDH/3·PGK oscillator. Its immediate impact is on NADH, oxidizing it and thus
further diminishing NADH concentration. The measured <jJ* is hard to interpret on
this basis because the <jJ* is already near the minimum of NADH fluorescence. From
there, a further decrease of NADH leads outside the cycle and so cannot lead back
toward the stationary state if only two variables are importantly involved. Unless
there is somehowa delay of one~half cycle, this observation would seem to preclude
any such simple tidy interpretations as attempted above for the oxygen singularity in
terms of ADP and ATP. Greller points out that a model involving at least three
variables seems to be required. This might be a reflection of the fact that this
experiment, by striking low in glycolysis, does indeed implicate additional variables
in the disruption of the oscillator.
 I: A REPEAT USING ACETALDEHYDE 361

~ The t r~e-dlmensiol')al gr~ph on pqge 64 calibratea oxyg~natio(l magnitude, M, in

pl 'of buffer per 160 rng of wet cells, convenient units in the lab. Here I call'it dose, D,
in llnits Q ~ rT,Iole/g of wet -teils, mor-e Conv.enien1} or chemical theory. The observed
D~ for. Qxygen was 0.26 f.tmql~ of wef cells given at P a few,seconds before the
real<' of NADH .fluorescence: In Gtellers (1,977} repeat U ing AA, D* was a dose that
inltially raises eXtracel1ular cQncentratian by 50-60 pM. This is roughly in the mlddle. of
th.e! to 1 ~mole dose range that Richter et al. (197SY reported as causing "measurable
phase. shift" in 1 gram of yeast su~pended in 10ml Qf buffer, and comparable to the ·
normal range of· AA' f1l:1ctuatiol'i in cell suspensions ofthe sam.e "densityJ rep9rted by
Rkh.ard et al. (1996al. Te find~e sTnguJarity this critical dose must b& given at 1'* a
qttarter cycle earJrer thaI) wlth 9xygen, aboufi cycle after the minimum of NADH
fluorescepca (f use IJT'*" 'here In the original sense of 1968-to represent the-- critical
phase; Richard uses "P" to mean what r caUed <p +' f): se.e Figure '30 ofChapter 1).
There is no mOfe reason that 7* should be the same for' different agents than that D*
should be. But'it is interestlng that at this P extracellular AA is near its cycle maximum
in' tne later experiments of Richa~d et aL (1996a) under comp~rable conditions.
Tqough M is not'part of the twowarial3le PFK oscillator model, it is c1early pC\,rt of the
oscillator rnechanisr'n, since it is pfoduced -rhythmically and the mechanism is
rhythmical/y sensitille to ' it. In fact, any two-v~riable model necessarily has its
~ingularity in:;ide the cycle in phase space; so it ~-ould have trouble accommodating a
singutar stiml:l(us given by elevatin.g one variable above its cyclic maximum. No such
eature Is gene~ic to attractfog ' Gycles. in'thre:e or more dimensions, höwever. It seems
that we deal witb ooe s\,Jch nefe, SO)Ne must at least preferrT)ore elaborate versions.
of the PFK osci/lato moOeJ. They must involve r;nore than just two priocipally
important cotlcentrations affeding each others' rates cf change on cOfTlparable time
scales. From the fact that AA arises r,lear the end of"glycolysis,remote-trom PFK, and is
npt ~nown to pe an l,romed!ate aJlost~ric c~ntroller of,PFK, I am ed to suppose that
tne oscillator in cell suspensions rnust importantly invoJve more- or other enzymes than:
PFK.
" .
Dan~ (1999) and Dano et al. (1999) .used AA Ruises in a (roughly) pO suspension
(~ 10'0 cells/mi) of S. ce~visiae during really permanent mutual synchronization
(Figure 7) to fihd the phaseless set. The critical phase TI' turned out to be at the
i
bo~o,,! of the NADH rhythih, rnaybe cycle earlier. that Greller's, at D* = 98 pM.
(Greller's was 50 to 60 ~M in '5. carlsbergensis' grown under somewhat different
conditions). Ahother serLes of expei:il1'l~nts' showed that the pha"seless set can also be
reached from tne top ohhe NADH t:hythm by an injection of 1 mM glucose. Glucose
is interesting f-or its possible role as anotner mediUtn of mutual synchronizat!on,
particull:ldy' in nonfermentlhg ., beta cells (Iacking AA) in tRe pancreatic islets of
Lar:lgemans; collective gly.colytic oscil!atrors there see'!' connected with insulin pulses
Clrou et ~I., 1992). ..... - .: ' h

Mutual Synchronization
Another point of interest in AA as a perturbing agent is that AA has been
considered a candidate for the coupling agent diffusing between cells to keep them
synchronous. Without such an agent, a cuvetle full of yeast would not long exhibit
362 12: ENERGY METABOLlSM IN CELLS

-:r
;j
«i

0
«
~
l 1111 : 1
?l Il~ 14~ Mi! 11: I I, tls
25000 30000 35000 40000

-:r
;j
«i

0
«
~ _:
32500 33000 33500 34000 34500 t/s

-:r
;j
ni

a
«
~ _:
33400 33450 33500 33550 33600 t/s

coherent oscillation. But with a steady trieIde of sugar input, von Klitzing and
Betz (1970) kept it running for days with roughly normal periodism. As in the
yeast mitotic cycle (Halvorson et al., 1971) and in Dictyostelium's cAMP pulsations
in cell suspensions (Gerisch and Hess, 1974; Malchow et al., 1978), it is evident
that mutual synchronization is occurring. It is probably mediated by a small ion or
moleeule. AA (Pye, 1969) and PYR (Betz and Becker, 1975b) have been nominated
as candidates.

On the other hand, Ghosh et al. (1971) show that no loss of synchrony follows
addition to the extracellular medium of enzymes that tend to remove PYR and AA
and of chemicals (e.g., KCN) that tend to trap AA. This experiment might be refined,
possibly to show that neither substrate alone is the intercellular messenger. These
hints are corroborated by an implication of the following experiment (according to
my interpretation only).
The strength of the mutually synchronizing interactions was measured in a
dilution experiment by Aldridge and Pye (1976). If cells are far enough apart, their
mutual coupling should be negligible. At some point in the dilution of a cell
suspension, they will fail to synchronize their metabolic rhythms, and the collective
amplitude of the population will fall drastically. Aldridge and Pye (1976) found this
 I: A REPEAT USING ACETALDEHYDE 363

threshold4 at a dilution (cell density) of about one cell volume per 10,000
surrounding water volumes. This indicates a startling specificity of the coupling
agent. Assuming a flux of one-half ttmo1e of fructose per gram of yeast per second
(Betz, 1966), at most 1 ttmoleS of AA can be exported per second into the 10,000
grams of water. Thus its concentration couId increase by only 3 ttM per 30-second
cycle. To maintain synchrony, cells must adjust phase substantially during each
cycle. A dose of even 10 ttM produces scarcely noticeable phase shifts, even if
applied at the optimal phase (Greller, 1977). Moreover Betz and Chance (1965) find
that AA concentration
1. does not fluctuate during the cycle, but only climbs steadily, and
2. is three orders of magnitude lower than the maximum concentration estimate
given above, presumably because ADH promptly changes it all to ethanol.
Thus AA seems after all a paor candidate.
Then what about PYR? It fluctuates by 0.2 mMlg during the cycle. A substantial
portion of this amount appears extracelluIarly (Betz and Chance, 1965). In 1:10,000
suspension, this amounts to only 0.02 mM changes. Since PYR causes large phase
shifts only at 70 mM concentration, this 0.02 mM variation does not seem adequate
to maintain synchrony.

~ In. Aon et al. r 92) at cel ensitres n'ear 1:500' .b ot AA an .PYR are S own to
6scillate at only ' about T #M ana .are ~accordingfy disr:nissed 'Rs effective ·couplers.
Richard et al. 11996b', Dano. at aL (1?99)j and Daoo.(19c.?9) .äl~o .dlscard ~YR on g~ow ds
thatlt shows little; jf any, osdllation extracellulany even at;higher s.uspension densities
near <1:10 to 1:20 (only Ao ~t al., 1992, and Aidlidg~ and· Pye~ . 1976; ventUre .far
outside that range). Aon et al. i:!roff~r 'etlianol (E!OH,.osdllating at 2Q M amplittlde)
as tne wlnner. However, jus:t as aetz and Chahce, (1965) dismisseä EtQR f0f not
o!idllating, Richard (f996b) dismlsses it on grounds. that its range is ont 10% of e
meaJl eveh in steadily oscillating suspensiqns. And they- r-enominate 'AA ss
the onlyj
plsuslbte candidate (Richard et·al. 1994, 1996a,b). HQ'{'I .did- that happen after it wa
excruded apQve-.'~acc6rding to my interpretation only"? .. '.
First of aU, whereas tbe measurements of -Betz and Chance (1965) had snown no'
oscillation of M or: of EtOH in their S. car!sbergerrsis suspensions duril1g glycolyt1c
·osdllatrons that damped by about 25% per oyde, it has since tumed out tbat ÄA does'
osciflc~te when, S. cerevisiae is harvested at a diff~ent. stage, with correspondingly
different enzyme concentrationst and With pscmations not damping at all. At high
suspension ~ensities AA coricentration ranges abou 40 ttM ·o 00 ftM at the perrod of
tne NADH rh m. T IS revision of faC!s rob~bl does not stern from fue fhanae of

4 Othmer and Aldridge (1978), and Aldridge and Pye (1979b) favor an alternative interpretation, Le., that
each cell quits oscillating when too isolated from its neighbors by dilution. This possibility can be checked
by spectrophotometry of single-cell NADH rhythms (Chance et al., 1968) but definitive results have not
been reported.
364 12: ENERGY METABOLlSM IN CELLS

Aldridge and Pye also found an upper limit to cell density, at volume ratios in
the order of 1:3, above which the rhythm dies out more rapidly. Presumably the
oscillation is suppressed in every cell by excessive exposure to its own and its
neighbor's diffusible products or by depletion of the initial glucose charge.
Uncertainty about the role of cell density subverts Chance et al.'s (1968) estimation
of the range of single-cell natural frequencies in a cell suspension: Their calculation
was based on comparison of observed damping rates of single cell rhythms and
population rhythms, but the cell densities in those two cases were not the same and
were not reported.
I: A REPEAT USING ACETALDEHYDE 365
366 12: ENERGY METAB0L15M IN CELLS

J: Phase Compromise Experiments

The vigor of cell-cell interaction is shown in another series of experiments, all done at
the same cell density (1:12) as in my phase-setting measurements using O2 and in
Greller's using AA. In these experiments two equal suspensions of cells at different
phases in the cycle are poured together. They quickly establish aphase compromise,
as in Physarum (Chapter 22) and resurne normal hut now synchronous oscillation
(Pye, 1969). The design of this kind of experiment has a striking symmetry, and that
symmetry has a curious mathematical consequence (Chapter 1 Section C). The
consequence is that the experimental result (a compromise phase) cannot depend .
continuously on the phases of the two parent populations at the moment they are
poured together. This statement has nothing to do with any interpretations of the
mechanism ofrhythmicity. However, the nature of the discontinuity might reveal
something ahout the mechanism. For example, a smooth attracting-cycle mechan-
ism would localize its discontinuity as two isolated phase singularities, supposing
perfectly instantaneous mixing of all reactants and neglecting the exceptional case of
perfect symmetry (Box F of Chapter 6 and Box A of Chapter 22). On the same basis, a
discontinuous relaxation oscillator would have aphase discontinuity varying in
magnitude along a pair of perpendicular lines at the jump phase. In fact, glycolysis in
yeast shows neither pattern clearly. At first sight, it shows almost no pattern at all,
according to the experimental results of Ghosh et al. (1971). With a little imagination
(Winfree, 1974c), the data can be seen as a noisy approximation to a two-screw
 J: PHASE COMPROMISE ExPERIMENTS 367

pattern surrounding two isolated phase singularities (Chapter 2, Example 9). This is
what would be expected from such attracting-cycle models as those of Higgins (1964,
1967; et al., 1968), Sel'kov (1972), and Goldbeter and Lefever (1972).

~ T js ml~ing Ei> ase-compt9mise experiment was aso undertakel') ~ r circa ian

rhythms in ceH suspe' 5)01:15 of GonY~flltax. ~ reported in Sulmran ' et al: (1982),
Hasting~ et al. (1985), and Bro~a et al. (1 ~86), little carne of j~ because in the dominant
first approximation cells did not-compromi5e, but largeJy igqored C?ne .another: .
, I computed sych patterns by,algebraicallYlT1ixing {Wo radial-Isochton docks (1974c,
1974q pages 224-225; 1986a) the!'l in 1975 buHt a"mix-map" machine in theform of.a
Plexiglas tetrah-e ron-with three wäter"'Cooled, magnetically stlrred syrihge~' so join~d
that I could quickly mix arbltrary volume.s from any two ofthese oseillating reactprs fnto
the third, and assay the compromise phase achieved. As -an ul'ldergraduate, Jan Rybka
autbmated-;the experiments fn BASJC langl,fage. lh:\s praduced experimentai result
LI like-< the prototyping computation~ "So I renne the computation usirig a gift from
Richard Field in ,.976: the 'GeCIr integrato( forthe Freld-Körös-Noyes model of the
Belousov-Zhabotinsky osdHator. Results still dlffered wildi}' from observations.
Unfortunately, thls compmation used the mistaken "Hi tr parameter:s then favored
(sl11ce corrected to "t~'1 values by Tyson, 1985),$0 it is considered irrelevant today. A
more vital reason for tlle' mlsfit t(;1me~ out to be that I had neglected ~he importanGe of
diffusioh-coupling among volume elements in th'e ,:mix-map machine's 0.01 cm 3 of
stagnant nozzles a\"ld the Tygon "il1travenous" segmentS' connecting thern. As far as I
know, tt:lis experiment has not 'yet been redone In a way that precludes wave
propagation. Prom this debade we tum to the fascina~ing phenomenology of chemical
waves in the next cha ter ... -
 i'lti1äilCl

The Malonic Acid Reagent

("Sodium Geometrate")

The unexpected is the whole point of scientific research.

Brian Flowers

A new chemical reaction with either excitable or periodic dynamies appears every
month in the theoretical journals (in 1978). But only one has been widely studied
experimentally in ways that reveal wave-like organization in space. There are
already two entire books about it: Zhabotinsky (1974, in Russian) and Tyson (1976) .

• And ir)' 1999·thereare many more; Field an BCJr~er (e s;-) ' r985)., Ho (je et al. (~ s:
(1991), Scott{.199Z\;), ~nd Kapral and SHowalter (eds. (1995) are representative. ::rhere are
f.low.also rnany mor~ real, lab<?ratory chemicaJ oscillators, largely glJe 'roihe initiativeof
Irving Epstein (Othan,et aLJ , WS1; E'psteih et aLl 1983; Epstein) tnd Kustin, 1984). My
197.8 ahempt in thi.s chapters ~itJe to"distlnguish th~ Dr0rnate..oased ferroin/l'l1alo.nie
a<;:id nonoscillating, excitable 'medil::l rn frorn tfie original' cerrum/cittie~acid osdll~or
(Belousov, "'958) by' nartijng the exeltable medium "malonic aCid reactio'n" has sirtce
proved'inept. Jhere Was irifact al ready a chemieally very different malonie acid osclilator,
thöugh not lIsed for spatial pro.pagatien studies, in whid i peroxide anaiodate replaeeä
bromate (Briggs ,an.d Ra!Jscher, J973). And there were alreaä~ so maoy ahernative'
substrates for the Belousov-Zhabotinsky-type reaction (acetoacetat~ a'cetylaeetQne
. a li a~' F>entariedi~rle, tri-fluora--ac~tylaeetone, -cydohe~nedlone, ditnethyl malonate,
ete. , and many more.after 1978) that a bettefl;name for aH brpmine-based media of is
sort was,needed: it seems to have appropriatelysettled to"Belousov::"Zhaöotinsky," tbe
same as tbe citrate oscillator. 1ni~. booK, -howey}er €ontinues to use " Belousov~
Zhabotinsky" where stressing SPQntaneous bulK oscillatiol1, and '''malonjoacid'' where
stressing propägation in non-osc!lIatif'lg modifieatiOtis after ~ 970. ." .
I've often b~en asked why I've used the·term "reagefl~:~ slIlee'1972 in naming this
liquid. The djctionary definItion is "a ~ubstance u,s,e d iri a, chem1caI reactionto detect,
rneasure, examine, cr p'rcälJc~ other substance5,j, Actua11y only ttr~ferroin dye does 50
in the ehemi'st's·sense. What I had (n minais the whofe ~ action ,seIil1ng.to detect arid
exposethe "geomei '" covertly in~erent in ap,y sl?,afall extended reeü;tion. <4 -

This is a catalytic oxidation of an organic substrate to carbon dioxide in water

solution at room temperature. As far as that much goes, it sounds (in 1978) almost
biochemieal, especiallyas three of its possible substrates (citric acid, oxalacetic acid,

A. T. Winfree, The Geometry of Biological Time 368

© Springer Science+Business Media New York 2001
 A: MECHANISM OF THE REACTION 369

Box A: Recipes
To prepare this reagent, the following aqueous solutions are to be made from
anhydrous reagents:
To 67 ml of water, add 2 ml of concentrated sulfuric acid and 5 g of sodium bromate
(total 70 ml). To 6 ml of this in a glass vessel, add 1 ml of malonic acid solution (1 g per
10 ml). Add 0.5 ml of sodium bromide solution (1 gin 10 ml) and wait for the bromine
color to vanish. Add 1 ml of 25 mM phenanthroline ferrous sulfate and a drop of Triton
X-IOO surfactant solution (1 gin 1000 ml) to facilitate spreading. Mix well, pour into a
covered 90 ml Petri dish illuminated from below (Figure 1, top). Bubbles of carbon
dioxide can be removed every 15 minutes by stirring the liquid: It turns blue then reverts
to red and the color changes begin anew. The reagent will turn permanently blue after
about 45 minutes at 25°C. Amounts are not critical except that no more than 4 mM
chloride can be tolerated; in other words, use distilled water and keep your salty fingers
off any surfaces that will contact the liquid. Avoid using the European Merck ferroin,
which contains 75 mM chloride. I have usually found it necessary to recrystallize the
sodium bromate, even from Analytical Reagent grade stocks. Leaving out half of the
recommended sulfuric acid will suppress spontaneous oscillation, at least in thin layers
exposed to the air (Figure 1, bottom). In this condition, the blue, oxidizing phase
propagates like a grassfire when started but never occurs spontaneously.

The easiest way to watch the chemical waves is to pour a 1-mm depth of reagent into
a very clean dish resting on top of a light box. Disposable plastic tissue culture dishes
are good for this purpose. They are optically perfect and free of dirt and scratches,
which otherwise serve both as nuclei for carbonation bubbles and as pacemaker nuclei
that engender a discouraging profusion of waves. Waves may start spontaneously. If
not, a touch of a hot needle will help. Setting the dish over a second dish filled with blue
copper sulfate solution (to which a few drops of sulfuric acid are added for clarity) both
prevents the rapid destruction of waves by convection currents and greatly enhances
370 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE'1

visual contrast between the vivid blue wavefront and its orange-red background. Be
sure to cover the reagent dish: The sUghtest air current disrupts the perlection of the
wavefronts. Escaping byproducts (CO? Br2?) will give you a headache as areminder.
You must be very careful not to bump, vibrate, or tUt the dish, or liquid flow will destroy
the waves.
Two m1 of colloidal silicon dioxide can be used to gell m1 of reagent. Waves
propagate in this peanut-butter-like gel exactlyas in the unbound fluid. This makes it
easy to insert barriers to block a wave, or to shear waves in a controlled way, or to cut
out the center of a spiral or ring source, etc.
DeSimone et al. (1973) showed another way to eliminate possible complications
from hydrodynamic movements, by binding the ferroin catalyst-indicator in a thin film
of "collodion" cellulose esters. This film is then wetted by floating on a solution of all the
other ingredients of the malonic acid reagent. I find it more convenient to prepare the
complete reagent and then drop a Millipore filter disk onto the liquid's surface.
Millipore is a paper-like material made of cellulose esters or of vinyl chloride pervaded
by submicroscopic tunnels Iess than a micrometer in diameter. The reagent quickly
soaks into this ultra-sponge and is immobilized by its own viscosity. Thus the Millipore
can be handled freely without disrupting wave patterns. However, once again, beware
of salty fingertips and iron forceps: Use nylon or stainless. I have not found any other
kind of micropore filter that works weIl. Not all versions of the reagent propagate in
Millipores, but the recipe given above does when suitably protected from air to retard
evaporation and exclude oxygen. I sandwich the filter between plastic sheets or stick it
to the inside of the Ud of a closed plastic dish, or drop it in oil. Carbon mono/dioxide
passes off without forming bubbles and, in such a thin layer, reaction heat passes off
efficiently enough that all the phenomena observed can be reasonably thought of as
isothermal.
For demonstration purposes, it is sometimes convenient to have a supply of dry
Millipores that need only be wetted to start the reaction. These make excellent waves
that continue to move about for half an hour at room temperature. Prepare 1 M
ammonium malonate l in water. Mix this with an equal volume of standard 25 mM
ferrous phenanthroline. Combine this mixture with an equal volume of 4 M ammonium
bisulfate. Float a Millipore on this solution, remove surface liquid by dabbing with filter
paper, and allow it to dry on a plastic surface. Don't let it dry completely before
removing it from the plastic surface, lest it crack when removed. Stored dry in a plastic
baggie in the refrigerator, these have shown no sign of deterioration in several years. To
produce waves, wet the filter by floating it very brieflyon i M sodium bromate in water.
(0.015 mlIcm2 is the right amount per unit area of dry Millipore.) Protect the wetted
filter from oxygen and drying between two sheets of plastic. Blue dots soon appear and
grow into waves propagating at a few millimeters per minute in ring and spiral
configurations.
~. Walker{197-Sy'; FielCl anQ Wih ree (1979), a
these metnod~ after y'Jritjng this box. '4

In a previous publication (Winfree, 1978a) I gave this recipe with ammonium

bromomalonate. It tums out that this is not necessary, which is just as weIl since this is usually
a rnixture of mono-with dibrominated product in variable proportions.

and hydroxylsuccinic acid) are prominent in the Krebs cycle, one of them (citric acid)
inhibits PFK (see Chapter 12), and another (malonic acid) is a specific inhibitor of
the Krebs cycle. The catalyst can be an iron ion held in an organie ring complex
 A: MECHANISM OF THE REACTION 371

called "ferroin," not unlike the heme group of oxidative enzymes. But the
resemblance to cell metabolism ends about there. The organic must be easily
brominated and water soluble, but can be any one of many alternative substrates.
The ferroin can be replaced by ruthenium bipyridyl, cerium, manganese, or cobalt
and presumably by other transition metal ion complexes. In fact, oscillation with HO
catalyst has been reported (Kuhnert and Linde, 1977; Körös and Orban, 1978; Orban
and Körös, 1978) .

... fitte years ater I" e(jmea thatBelousov nad stumbled onto this'rel:\ction a age 57 (I)
1-951 . In fad while" t!ying to uhde,rstand catalysls in tHe ~rebs cycle! His persistel'}t
Lnvestigation of this oscillating reaction (at least until too discouraged at age 64)
exemplifies the, 'mportance"O bulldog tenadty to a flagrant anomaly. William Jar:nes .
succi ctly summarized the le~on learned by succes~ful investigators since Ärislqtle:
"Änyon~ will reno,:,ate '~his scien.ce who will steadily rook after he irregular
pnenomena:: Belousov had recognized an anomary and steadily looked after it, but
otners at that time were not so eager to revise their view. CharIes Darwjn tjad noticed a
'ce tl,Iry befote: "Nevertbe!ess, our joint productions excited very little attention, and '
the only published notice of them that I can remember was by Professor Haughton ef
Ouölin, whose verdict was !hat all that was new in them was false a d all that was true
was old. T]1is "Shows how n~cesS?ry it is that any new view should b~ explained ,at
cOrlsiderable length."But-Belousov was limited to a single' published page. For history
see Schnoll et aL (1981)( Winrree (1984c). Znabotins~y (1985), Showalter al1d Tys9n
(19.87) Zhabotinsl5Y 1991 , and Perraud 1994). ~ . . .'

The chief indispensable feature is an acid solution rieh in bromate ions. Much of
the chemistry seems to rest on peeuliarities of bromate, bromide, and more exotic
bromine-based ions. Its essence is oxidation of an organic substrate by bromate in
water at low pH. Exotic though some of the elementary reaetions may be, the
reagent is easy to prepare and it works reliably. The recipe I prefer is one I adapted
from Zaikin and Zhabotinsky's version of 1970, whieh was itself an improvement on
Zhabotinsky's 1964 recipe, in whieh the oseillations were enhanced by substituting
malonic acid for Belousov's original citrie acid. The 1970 recipe substituted the
colorlul ferroin for cerium, to serve double duty as catalyst and redox indicator
following Busse's (1969) introduction of a traee of ferroin to improve color contrast
in the cerium recipe and Vavilin's (1969) discovery that the reaction then works as
well even without cerium (see Boxes A and B).

A: Mechanism of the Reaction

The mechanism of this chemical oscillation (Tyson, 1976) has been dissected in fine
detail by many investigators, but most notably by Field, Körös, and Noyes (reviews
in Eyring and Henderson, 1978). In gross oudine, bromate is continually converted
to molecular bromine, which continually attacks malonic acid and brominates it
while inhibiting a seeond reaction. The bromate is decomposed by either of two
routes, depending on the bromide concentration. At high bromide, aseries of
oxygen atom transfers is involved, which incidentally consume bromide. When
372 13: THE MALONIC ACID REAGENT ("SüDIUM GEüMETRATE")

Box B: Chemical Oscillations, Practical Jokes, and Chaos

Men stumble over the truth from time to time, but most pick themselves up and
huny off as if nothing happened.
Winston Churchill
The first version of this reaction was encountered by Belousov (1958) in 1950 while
trying to assay citrate quantitatively in an acid mixture containing bromate, bromide,
and a standard reagent for oxidation-reduction titration, ceric sulfate. Needless to
say, the fluctuating composition of the mixture occasioned initial constemation. I
found this useful as a practical joke during recalibration of a repaired Cary
spectrophotometer. A cuvette of pale yellow malonate reagent (using the original
cerium instead of the visually more colorful ferroin) is placed in the sampie beam,
with an equivalent cuvette lacking malonate in the reference beam. Ordinary
reactions show a monotone approach to a stable optical density at each wavelength.
But with the malonic acid reagent, large irregular excursions of optical density in the
ultraviolet continue for half an hour while the visible yellow scarcely changes (Figure
a). The perplexity of an unsuspecting expert in electronics can last longer. (The
irregularity is due to carbon mono/dioxide bubbles and spatial differentiation of
phase in the unstirred oscillation.)
E. K. Pye, while a research student of biochemistry at the University of Manchester
in 1963, encountered similar vexing "instabilities" while spectrophotometrically
following sugar metabolism in yeast by NADH fluorescence. Measurements were
simply irreproducible. Every other possible source of error was proven fault-free before
testing the outrageous conjecture that NADH concentration was fluctuating with a
regular 30-second rhythm (See Chapter 12).
Many phenomena, including vital clinical measurements, in which irreproducible
readings have been tolerated as "biological variability," have been found to be
regularly periodie. For an especially nice example, see Young (1978). This fact
provides the foundations for the whole field of circadian physiology (see Chapters 19,
20, and 21).
A deterministic interpretation of irregularly variable measurements has been
found in the concept of "strange attractors." In such cases, the ostensibly chaotic
fluctuations of chemical concentration are traced, not to probabilistic causes, but
to lawful variation through known reactions. The malonic acid reagent exhibits
such behavior in an appropriate range of oxidant concentrations. (See Schmitz
et. al., 1977; Rössler and Wegmann, 1978; Wegmann and Rössler, 1978; Tyson,
1978; Yamazaki et al., 1978, 1979; Hellwell and Epstein, 1979; for other
examples of chemical chaos see Olsen and Degn, 1977; and Schmitz et al.,
1979.)
 A: MECHANISM OF THE REACTION 373

t
j ~ ~ 11

(\ (\ ~ A(\ fl [!I!
~ ~\
VV\ ~ ~ V v VV

I
3'10·68
ATW

-- TlME -

Optical density in the ultraviolet, as traced by a spectrophotometer looking through 1 cm of

cerium-catalyzed malonic acid reagent. This was in the days before Vavilin et al. (1969) noticed
that ferroin could replace the less visible cerium. The irregularities are presumably due to
spatial gradients of phase and slow fluid convection.

fi r.n 1t1 . 197~ t ai Eid to perceive it. HersCtiKow~-KadfrTian {1970f ad unrecognized

seroll waves in her beavtiful pnotographs for the French Academy of Sciences. $0 did I
in 1971 when atmost dropping into the post box for the cover: of Scierrce (Winfree,
1972c about two-dimensional spirals) tne photograph that I instead withdrew, just
~ore it sild out of reacp, and later presented in Winfree (1'973b,c about three-
dim~nsional serolls). In sbort, none of us perceived unexpected structures that seem
toda nm·stakable.:oe ~

bromide falls below a critical concentration, a free radical mechanism (the second
reaction) comes to dominate. As bromide falls below this switching threshold,
HBr0 2 appears explosively (increasing a thousandfold in less than a second) by
areaction that abruptly consumes the last vestiges of bromide. In this
transition, the red ferrous "ferroin" is oxidized to the blue ferric "ferriin"
which, in turn, will oxidize the accumulated bromomalonic acid. As it does so,
it turns back to the red form and bromide and carbon dioxide are released.
When enough bromide accumulates, control is handed back to the first
reaction.

~ I is is an archaic verbal aescription, from my 1974 Scie,nti{'c American artide. Some

rate coefficients jnvolved in. batter quantitative versions were incorrect by three orders
of magnitude in 1978, a,nd other essential reactions were complet~ly unknown. Tyson
(1985) sorted out many of the seeming cQntradictiOf1s and provided a workable "Lo"
set of parameters to repJace former values that he called "Hi." :Toe verbalizations
c an ~ accordin Iy: .....
374 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

Figure 1. (top) Circular waves emerge periodically from randomly scattered pacemaker nue/ei
in a 1.5 mm thickness of reagent. (A few pacemakers lie outside the field of view.) These blue
waves of malonic acid oxidation cancel each other where they collide. Each successive
collision occurs e/oser to the lower-frequency pacemaker until it is entrained. These four
successive snapshots by transmitted light were taken 60 sec apart. The field of view is 66 mm
in diameter. Wave velocity is about 8 mm/min. Pacemaker frequencies range from about one
to three rings per minute. The tiny eire/es are growing gas bubbles (C0 2 and maybe CO).
(bottom) Everything is as above except that the first two intervals are 90 sec and the reagent
is less acidic (to minimize pacemaker activity and to slow wave propagation to 4 mm/min).
This reagent, when conducting ring-shaped waves, was deformed by gentle tilting. (See
Chapter 9, Figure 9.) Segments of blue wave revert to red, and the surviving pieces begin to
pivot around their free ends, winding into paired involute spirals. Each spiral rotates once
each minute. Notice the widening space between the outermost waves: Waves move a little
faster into virgin territory than into reagent still recovering from the passage of a prior wave.

Silica, polyacrylamide, and agar served best as gels. As substrates (after fi tering
out a precipitate) 1,3-cyclohexanedione and ethyl acetoacetate served wen
(Winfree, 1974d page 83), independently confirmed by Salter and Sheppard,
1982, and by Ouyang et al., 1987), blJt the tri-fluoro-acetyl acetate introduced
shortly by Jessen e al. (1976) proved best. Unfortuf}ately, this also precipitates an
oily potent lachrymator, so the discovery by Kurin-Csorgei et ai. (1995-:97) that
1,4-cyclohexanedione produces only soluble ~yproducts was welcomed with
enthusiasm. .
Another way to prevent bubbles tearing though volumes of the malonic acid
reaction is to keep concentrations and temperature so low that the gases remain in
aqueous solution for an hour or so wjth slight pressurization (Welsh et al., 1983), or
10 9tmospheres (Tam et al., 1988)1 or 2 atmosp'heres (Skinner and Swinne 1991).
A: MECHANISM OF THE REACTION 375
376 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

T*

0.9.,0
(M)

Körös-Noy~~ rqec anism ".t. anti its simpli ie Oregonator mo e 's tnree-yaria e
yerSi0n,,, ' . -~ '. .
Ägla.dz~ et' al. (199.S) 'us~d light pulses ·to 'phase shift the rutheniutn-catalyzeo
BeJ<?l:Jsov-Zhabotins~ osc1lFator; they found on1y phase delays ending d,s:coDtinU-
ously a a certain phase in the, cycle. The observed dependence on rectp ,
parameters violates the widely adopted assumRtion that light'~ is mainly reJeaSi~n
Br- (Kuhnert, 1986). l'ben, in a format more like the .first such experimel'lts, using
~(itically timed applkation of the right humbef of photons to acces~ a0d
demonstrate the phaseless -set in a circadlan dock, Sorensen et al. (1.9~6) showe<:l
the usua] pllenoJl1ena ~ssociated with a pnase 'sing,ularity in t~~ ruthenium<atafyzeti
~elo\:.lsov.....Zhabotinsky o§dllator (Figur~ 1.4). F,,6~ #Je discovered values of ~T* an9
S*. they shpw again .th?t the. effect of light cannot' b~ simply the 'release- of Bli- a,s
had been supeo~ed, , . :
As relatecl i!\ Sectiol'l C pf Chapter 10, the frrst seC!c.essf~.d effQFt, in Prague, to
check the getl.erallty of phase resettjrrg prins;iples in the m~Jonit acid ! eaoion' Li,sed
injections of- Br~ qu[ina very stiff attractlng-cycle o~cillatiQnsl the "r-elaxatiorl
osemator" opposite .ease frc the quasi:.harrnonic oscillatio1;ls .~rranged for . he
Copenhageo quenenin9 eXF?e,riments. The pinwheel .experirl1,ent 0 Dolnlk et aL
(1'986) ney,Eiitheless revealed. the ü,sua) heJieo.idar time cryst'al ~(C~~p>ter 61 Figure f~),
tQis time 'with a vlolently repe Iin!;J 'pnaselesS" set at its; axjs: Sorenseri, Hynne, et ,al.
(ahoveL tameä 'th,is vid)en.ce by adjusting 'the reclpe' to ß Hopf bifurcatiort th~1) tI'I
il1evitable -smalF err<>J'- 0 r an attem ' ted sin ular . ulse led not to lmmedia
 B: WAVE PHENOMENA 3n

T*

In an unstirred volume this reaction is spatially coupled by molecular diffusion.

According to the analysis of Field et al. (1972, 1974, 1979), things would probably go
quite differently if HBr0 2 were somehow prevented from diffusing. Physical
movement of other reactants is probably less important, though for conceptual
convenience equations are commonly written as though all diffusion coefficients
are exactly equal.

B: Wave Phenomena

This chemical reagent provides very nearly what 1 aspired to create by wiring
together a lot of neon glow tubes in Chapter 11, what Franck and Mennier
(1953) created by wiring together electrochemical oscillators, and what Diamant
et al. (1970), Sarna et al. (1971), Brown et al. (1975) and Patton and Linkens
(1978) approximated by wiring together electronic oscillators (Chapter 14). It is
a continuum of mutually coupled oscillators. However, they are not all
indiscriminately coupled: Nearest neighbors are coupled most strongly. Thus
the sought-after mutual synchronization phenomena acquire spatial organiza-
tion (Figure 1). It was in thin layers of such a ferroin-malonic acid reagent that
Zaikin and Zhabotinsky (1970) discovered sharp bands of vivid blue cruising
through the motionless red liquid. (Busse (1969) had photographed them but
described them as "steady chemical waves," in stationary dissipative structures.)
The behavior of these waves has stimulated much curiosity and investigation.
378 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

Box C: Pseudowaves
As the papers of M. 1. Smoes testify (1979a,b and 1980), I have introduced some
confusion into the research literature of chemical waves along with my notion of
pseudowaves (Winfree, 1972c and this book pages 137-41, and Section C of Chapter 8).
I believe the problems stern from amistake I presented in December 1973 at the
Faraday Society meetings of the Royal Society (Winfree, 1974d).
This twofold error consists firsdy of calling something a pseudowave that was not
definitively shown to be such (and, as I now perceive, mosdy likely was not one); and
secondly in falsely equating pseudowaves with wave trains of time period equal to the
spontaneous oscillation's period in an isolated volume element.
Stricdy speaking, pseudowaves exist only in imaginary continua of completely
independent identical oscillators. The spatial integrity of such waves gradually decays,
being provided only by the initial conditions. Any real medium is a poor
approximation to that ideal, especially in that adjacent volume elements are inevitably
tighdy coupled by diffusion. However, phenomena do occur in a real oscillating
reactions, which strikingly resemble pseudowaves. These occur where the local
oscillation is not quite synchronous across a wide space. Such waves were first
reported by Zhabotinsky (1968, p. 90). They are distinguishable by their wide spacing
(wavelength at least several centimeters) and high velocity (at least a millimeter per
second). Such waves occur only as periodic wave trains. They pass each point at the
same period, indistinguishable from the period of oscillation in an isolated volume
element. Their apparent velocity thus necessarily varies locally in inverse proportion to
the local phase gradient. They are not noticeably disturbed by impermeable barriers.
This effect is documented in Kopell and Howard (1973a), whose wave is one-
dimensional and runs along a gradient of oscillation period. In this context Kopell
and Howard call it a kinematic wave. Something similar is reported in a living
organism (Physarum) by Henjnowicz and Wohlfarth-Bolterman (1980). See also Box
A of Chapter 14.
The notion of a pseudowave thus seems at present (1978: better examples have since
appeared) primarily a theoretical construction, introduced primarily as a contrast to
"trigger" waves. A trigger wave moves with spatially uniform velocity. It can occur as a
single unrepeated wavefront.
Now, what I showed at the Faraday Society meeting was an oscillating reagent in
which passage of a trigger wave train left the reagent behind it without any source of
excitation save its own spontaneous oscillation. That oscillation was phased in each
volume element by the prior passage of the last trigger wave. Every volume element
turned blue at the fixed intervals of local oscillation after passage of that trigger wave.
Thus even if every volume element were completely isolated from its neighbors, they
would still turn blue in succession as observed, and a train of pseudowaves would
follow the receding trigger wave forever at exacdy its velocity. That is what I saw and I
called it a pseudowave. But it couldn't have been.
It could not have been a pseudowave because the volume elements were not
mutually independent. Neither could the concentration gradients have been shallow
enough to ensure that diffusion had negligible impact on the course of local
reactions. On the contrary, all the diffusion gradients were as steep as in the initial
trigger wave because whenever a volume turns blue it initiates a trigger wave like
the first one. In a slighdy shallower phase gradient, volume elements would turn
blue in succession faster than the trigger wave propagates and this spontaneous
bluing would outrace true propagation. The continually triggered wave would be
 B: WAVE PHENOMENA 379

continually anticipated by the scheduled local oscillation in the volume elements

ahead. But here the steepest sustainable phase gradient was established by a
moving trigger wave, so that the pseudowave had no greater speed than a trigger
wave.
I think what I observed was in fact aseries of trigger waves, each nearly a replica
of the first one used to establish the phase gradient. Each was initiated at the extreme
point of the phase gradient, when that volume element tumed blue in its spontaneous
oscillation. But away from that point diffusion could not be ignored. The fact that the
waves passed each volume element at the period of the homogeneous oscillation does
not mean that the wave is only a phase gradient along a continuum of independent
local oscillators (a pseudowave) but only that it was triggered by the local oscillation
at the origin with that period. Had all volume elements been magically uncoupled, a
true pseudowave of much the same appearance and timing would have continued. But
the real wave was not a pseudowave because volume elements were distinctly
coupled, and diffusion was not negligible, and the phase gradient was not too shallow
to matter.
I suspect that Beck and Varadi's (1971) introduction of the same notion fell prey to a
similar error. They rightly noted that Busse's (1969) "dissipative structures" probably
were traveling waves. But they were probably not pseudowaves and probably did
critically involve diffusion, being so elose together. I think they were trigger waves .
... BewerSttoiff's '(1983) repeat ~Ila.:analysis pr a ' similar experiment seems to confinn-
thi ....

Calculations by Reusser and Field (1979) show a gradual transition from trigger-
wave-like velocity to pseudowave-like velocity over the critical range of initial phase
gradient steepness. They elearly show that the waves I contrived at the steep end of that
range were like pseudowaves only in their periodicity and that "true" pseudowaves are
revealed only in the limit of infinitely shallow gradients .
... These . istinctions a(e reviewed In Ross et al. (1988). Tlie more su tle intermediate
\;a~s {)f "phase diffusion" were taken op via the Burgers' equation, ete. as first indicated
by Louis Howard and Nancy Kopen (1974) and independently at the same time, CIS so
often happens by Yoshiki Kuramoto and students (revlewed in Kuramoto, 1984), end with
chemical experiments as weil, by John Ross and students. For references and re cent
findings see Aliev and ßiktashev (1994), Aliev (1994), Aliev \ (1996), and Aliev et al.
(1997a,b). These include logaritftmfc spiral pseudowaves rotating at the penoel of bulk
oscillations, as first anticipated by Hagan (1982) and Krinsky and Mafomed (1983). Log
spirals occur only in "nondisllersive' media, i.e.! those wjth fixed period, so "propaga-
tion" .speed is inversely proportionClI'to the phase gradient. In an other cases the spacing
between tums is a strict ~nction of the period, so spirals approacn fixed spacing like
invo\ute orArcbimedean spirals. .
Delaney'et al. (199t4) and Kleinfeld et,al. (1994) observe somethlng·like pseudowaves in .
the olfact~ pulb of the garden slug, Limax. ~

Two extremes of wave behavior warrant separate attention, though it should be

remembered that they are only extremes of a continuum and grade into each
other through intermediates (see Box C).
At one extreme, the malonic acid reagent exhibits "pseudowaves." These are
periodic patterns of color which appear to move through the liquid, not by
380 13: THE MALONIC ACID REAGENT (USODIUM GEOMETRATEU)

virtue of any physical conduction or propagation but as a natural consequence

of a parochial oscillation whose phase varies in space. In such a case, the
successive color changes of adjacent volume elements give an appearance of
motion.
At the other extreme let the spatial phase gradient be very steep. The waves will
then creep so slowly and be so elose together that molecular diffusion between
adjacent volume elements has a substantial impact on the local reaction within each
volume element. This will occur when the emigration of molecules from a volume
element proceeds faster than local synthesis can replace them and when their
immigration is correspondingly faster than local degradation can consume them.
When the waves move this slowly and come this elose together, the blue oxidizing
excitation actually propagates like a grassfire. Volume element after volume element
is triggered to a pulse of oxidative activity by the activity of its neighbor, and in turn
conducts the impulse to its neighbor on the other side. In this extreme, we have
what Zeeman (1972) called a "trigger wave." Such waves are characterized by a
reasonably uniform velocity, though it depends somewhat on wave spacing.
Pseudowaves, in contrast, are characterized by a uniform periodicity in time
(Figure 2).

TIME

Figura 2. (above) Pure pseudowaves. Only in a linear gradient of phase do such waves alt have
the same apparent speed. (Period = horizontal spacing and speed = slope on this diagram.)
(below) Real propagating waves. Only when far apart do such waves all have the same period.
Trigger waves persist when the chemical composition of the reagent is so altered that its
oscillation period becomes very long or ceases altogether, that is, when the clock-like behavior
is tumed into hourglass-like behavior (Chapter 3). This can be done either gradualty, following
the wave behavior and bulk oscillation period as the reagent ages by consuming its substrate
(Winfree, 1974d; see Box C), or discretely, by preparing areagent that doesn't oscillate even in
the beginning (Winfree, 1972c).
 B: WAVE PHENOMENA 381

are ·a most as unr'eliab e, each fo( a different t osyncratio reason (pa~ola et ,a <,
1988; Foerster et aL, 1989; Jahnke ~t al., 1989; Steinbock and, ,Müller/ 1992a;.
I(:!sselles et al., 1998)! and none (except Figure 2.1) cany the measurem~nts into
the Interestlng re9ion below the speed of aves:from a rotor. But all c-oflfirmed t~e
<

~ey result. at the speed of a flat front is not measurably deRendent Oll spacing beyond
a
1 cm,:monotonicalty decr.eases ~owaTd 'nite mini~um spaGtng, anq enqs above mm
before its tangent turns radjal 0n these coordinates. In oscillatory m'edia the
dependence 'of speed on spadng rises at the long-spadng . end toward a radial
asymptote sloped.at the period of bulk oscillations. (The asy ptote is of course veitical
orrs eed vs, perlod coord;;,;i.n. .a.;,;.t;,,;;e...s,~...:-;;.__........_

0.08

•
0.05
...
• • • I ••
. :. ...•:' : ..•..
.. •
•
•
••••• ••
. l ~I'.'
•
.
••
••• •lI•'

I
co 0,02

0.01

o
o 10 20 30 40 50 eo 70 eo 90 100
period (sec)

Figura 2.1. Propagation speed of an oxidation pulse in a capillary tube of agar-gelled excitable
medium (substrate 1A-cyclohexanedione, catalyst ferroin, as in Winfree et al., 1996) as a
function of its distance behind the prior pulse, As an undergraduate project, Scott Caudle
acquired each datum at nearly the same "age" after mixing each batch of gel. The period of the
wave train emitted by a rotor in a gel made from the same recipe, at the same temperature and
age, held two-dimensionally between glass plates, was 33 sec, weil beyond the minimum shown
here for one-dimensional wave trains, This might be the first chemical dispersion curve to show
the theoretically required segment below rotor period,

The pertinent physical quantity that deternrines which limit the system falls
into is a dimensionless ratio between a measure of diffusion flux across the
spatial scale of the wave and a measure of the reaetion rate's sensitivity to
concentrations. The measure of diffusion is the minimum diffusion eoefficient
divided by the square of the seale length. The measure of the reaetion's
sensitivity is the maximum differential rate of change of reaetion rate as loeal
eoneentration is ehanged. These conditions are specified quantitatively in
382 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

mathematical papers of Othmer (1977), Ashkenazi and Othmer (1978), and

Conway et al. (1978).

C: Excitation in Nonoscillating Medium

I contrived a nonoscillating version of the malonic acid reagent in 1970 in order
to demonstrate abolition of waves when the isolated volume element's attracting
cycle was abolished. That seemed a reasonable expectation at the time, since
oscillation and periodic wave propagation were the main features distinguishing
this reaction. However incredible this may seem today, at the time I was not
thinking in terms of "excitable media" such as nerve membrane or layers of
social amoebae, which are capable of recurrent wave propagation whether or not
they support a local oscillation. But by early 1971 my reagent bottles, facetiously
labeled "I normal solution of the wave equation" (at that time connoting
periodicity), had to be relabeled "aqueous solution of the Hodgkin-Huxley
equation" because the non oscillating reagent proved to conduct waves almost
indistinguishable from those seen earlier in oscillating reagents. Rössler and
Hoffmann (1972) were, I think, first to publicly note that the qualitative parallels
to electrophysiological· waves are quite striking. This analogy was pursued
heuristically in Winfree (1974e) and in mathematical detail by Troy (1978). Troy
and Field (1977) assembled an analysis of excitability without spontaneous
oscillation, based on the original oscillator mechanism. [Since then Goldbeter et
al. (1978) and Goldbeter and Erneux (1978) achieved the same for the oscillatory
biochemistry of Dictyostelium and of yeast glycolysis, respectively.] Tyson
(1977a) reduced the chemical equations to the mathematically typical phase
portrait of an excitable medium. In this approximation, the malonic acid
reaction's kinetics resembles the still simpler caricature I used (Winfree, 1974b,f)
to isolate the essential geometric principles of stably rotating patterns of reaction
and diffusion in this reagent.
It is my impression that the main phenomena of wave-conduction and pattern-
formation in this chemical reagent derive not from its oscillation, but from its
completely independent property of excitability.
The nonoscillating reagent presents us with a second surprise. Its quiescence
turns out to be perfectly stable in the unstirred liquid, as weIl. No diffusive
instabilities occur: as in other excitable media, the spatially uniform steady state is
stable. To initiate oxidative activity (red-to-blue color change), a perturbation is
required, and it must exceed a threshold magnitude. This fact about the malonic
acid reagent was persistently overlooked by theorists of "dissipative structures" who
saw waves in this reagent as examples of structures arising from diffusive
instabilities (Busse, 1969; Ross, 1976; Cottrell, 1978; Defay et al., 1977 p. 507,
 D: WAVE PATTERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 383

following Beck and Varadi, 1972, also mistook the waves for a surface
phenomenon, apparently by never looking at them).

0: Wave Patterns in Two-and Three-Dimensional Context

A flask of liquid malonic acid reagent, at first glance, looks like effervescent deep
purple Kool-Aid. The bubbles are carbon dioxide (and carbon monoxide:
Noszticzius, 1977; Ouyang et al., 1987; my own measurements show in these
bubbles only one of the three carbons of malonic acid appearing as carbon dioxide).
Closer inspection reveals that the color is mottled red and blue in bands a millimeter
or less apart which constantly move. Turmoil is guaranteed by the occasional ascent
of a bubble from the vessel wall to the upper surface and by the convective turnover
of the reacting liquid as it warms itself by several°C. This liquid proves to be as full of
surprises as any of the organisms I expected it to resemble. Latent in this reagent,
waiting for the right stimulus to conjure it into vivid red and blue animation, is a
three-dimensional self-regenerating pattern of activity quite unlike anything seen
before in a chemical solution.
In sufficiently thin layers of reagent, frame by frame analysis of movies reveals
this pattern in two-dimensional cross-section. It is a rotating spiral wave.
(a) Each piece of the spiral wave is propagating at fixed velocity perpendicular to
the local wavefront, as though following Huygens' principle of optics.
(b) The whole wave is also pivoting rigidly as though engraved on a rotating disko
As noted on pages 283-84, one waveform is compatible with both descriptions.
This is the involute of a cirele, i.e., the curve traced by the end of a taut string
winding around a cirele of cireumference equal to the standard wave spacing. One
property of such a curve is that perpendiculars to it are all tangent to that eentral
eircle. Figure 3 shows this eonstruetion on a typical snapshot of a spiral wave.

Figure 3. An involute spiral is plotted atop a photograph

of the inner two tums of a spiral wave in malonic acid
reagent. Its evolute is a central disk of unit circumfer-
ence. The unit is 1.85 mm. The minimum radius of
curvature along the front is about 0.15 mm, too large to
slgnHkantly MoW down propagation. The departure
from the involute model near the spiral tip is rather due
to "meander."
384 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

As Eugene Wigner (1960) noted, "Every empirical law has the disconcerting
quality that we do not know its limitations." Some of the limitations of
approximation (a) plus (b) are exposed in the following four points:
1. Experimentally, wave velocity is not quite uniform: The malonic acid reagent
conducts an excitation somewhat more slowly if it has done so in the recent
past. In consequence, the wave velocity increases somewhat with wave spacing
(and a variety of situations do admit local variations in wave spacing, e.g., the
sudden extinction of a nearby source).
2. The experimentally observed wave does not truly pivot. Its inside end more
nearly "meanders" through a central disk of circumference about equal to the
standard opening.
3. Mathematically, the involute solution terminates perpendicular to the boundary
of the (convex) central disko Inside that disk, the solution becomes imaginary,
signaling that our two descriptive approximations a and b are incompatible too
elose to the pivot.
4. According to the involute approximation (a and b together), all the contour lines
uniform reactant concentration on a snapshot would be parallel involutes. But
this is impossible, since on a trip around any ring-shaped path the concentration of
each substance must go up and back down, so we run across each concentration
an even number of times. The contour lines thus come in pairs that must join
together on the inside. They cannot all just dive into the pivot because an infinitely
steep concentration gradient would then appear at the pivot, but this is impossible
in the face of molecular diffusion. Instead, each concentration contour line
connects onto its mate as in Figures 13 and 19 of Chapter 9, violating the exact
involute description. Burton et al. (1951), Guckenheimer (1976) and Greenberg
(1976) all independently proved mathematically that concentration contours
cannot all be parallel spirals without violating the basic equation of reaction and
diffusion, because the latter entails a speed decrement in proportion to contour
convexity. This correlation between speed and curvature was also explicit in
Markstein (1951) in context of flame propagation, in DeSimone et al. (1973) in
context off malonic acid reaction, in the experiments of Foerster et al. (1988)
confirming the latter, and in Zykov and Petrov (1977) about heart musele. But far
from the core, the contours are less curved and can approximate both involute and
Archimedean spirals quite well (see Tyson, 1976, pp. 98-103) and "far" can be quite
near if the kinetics are nearly discontinuous.
 D: WAVE PATTERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 385

U et aL (199 ) ana Belrnonte et al. (~997) a,cliievecl such sta6 e arrangemeElt:S that
twentY tums could be f~tted almost perfectly. But attempts to discrlmililate between
alternative algebraic descr1ptions (Keener and Tyson, 1986; Müller et al., 1987b)
feveaf only that differences are impossibly' subtle outside the first tum of the spiral
(where tbe ass\.lmptions demandihg a 1-parameter involut~ shape seem realistic),
and inside that distance none fit particularly weil. There exist also diverse instabilities
of long-range wave train , propagation that causeadjacent pulses to bunch up
(~Iphick et al. 1990; Ouyahg et ..aL, 1996), thus defeating any rigidly rotating
. .description of time-independent spiral shape. . ". "
. Maybe more importantly a'ffecti.ng osfenslble shape of a non-meandering. shape in
the- laboratory is the wavefront/s tllt in the- 1 tQ 2 mm depth of liquid or gel with
excitability diminished' by contact with air in the top harf millimeter or so, or in the
comparable gradient of raw-materlal availability across a Vycor porous glass drsk with
half-hour diffusion time ( (0.04 cm)2/rt 10,7 cm 2/sec): see Box F):
" Fu, erfotting attemF?ts to'tidily 'rescale spiral wave~ is the fad that, whether in lab
or computer,. the tip-of the spiral cloes generally me~mder-i.e'f the curvature of the
P!3tti traced by the moving tip is modulated"":"'at a frequency generally different from
but comparable' to that of tbe overall rotation: See- also B9x D: Simple Notation, and
in new Chapter 16 see Box A: Hypermeander. •

1 • ~

The
...
Prot~acted
"'"
Discovery ~.
of TWQ:-Period "Florar
-.
fr Meanger
'

"Meander" y.'as footnoted ir" Wlnfree (1973b) as a- cp(rection to my prior paper that .
had stressed exact simple periödism in spiral wave~, At t e time i seemed likely . that
mea~der would go ·· away wnen experimental conditions .were. pelfected ,apd th_at
meanwhjle ir w~s as random as those impeTfections despite Occ9sional exceptionally
Jlretty, instances, and. in any case it was confined witnin a perimeter of about on
wavelength around the phase singularity (i,e., was an intemal d}'liamic. of the rotor
without lar9.e-scale consequences), For example, this_Is stated in Example 15 of
}:hapter 10, virttage 1978. Bll by rneticulous attention to the 'Computed illustrations in
Gul'ko and Petrov (1972), in Sbcherbunov et al. (1973), in van Capelle et al. (1980), and
in Pertsav et al. (1'984) wjth pencil and tradng paper, one can expose glimpses of a few
tums of either start-up transients' or wbat we ca!! today quasiperiodic "floral" rotor
omean8er (e.g" see Winfree 1987a page 110). The 'f irstto rec0gnize meandeiin their
own eomputC\tions may have been RQssler and. Kahlert (19791, stressing its
resetT]blance ta.chaos, and thel') Zykov (1981)/ rel')aming it "nonstationary rotation,"
Its pattern was alr~ady plain "enou.gh in my 1970 Iflovies of rotors and spiral waves in
the malonic acid reagent, yet I failed to perceive it. Only ·a decade·later were tracings
of two-pe.riod qtJasiperiodi~ m~ander transcTfced with ernpha,sis on regular looping
(Konstantjn Agladze's 19aJ thesis and Wirfree/ f9~7a r;;aga 181). In 1985 pramod
, ariadpurkar and I, ir.'l ·l.,a Jona, were plJzzJing over such iJowersf met~mQrphoses as we
varied the Fitzldugh-Nagumo model 'parameters, under the assolllption (which turned
aLt to be miStaken) thClt they vy~e a nU.,.rtierical artifa~ th.at' occurs only-when diffusion ~
~oeffkients are ,sufficieritly unequal. (ul'dike, liquid chemical meoia), ~,S"., as start-up
nsients frorn arbitrary initiaJ cpnditions. or else a~ circllfar tlp path.s .not qllite c!Qsing
, ue' on)y t ' cumu ative error in Ion . ca~tllatioris. eanwl:de VI di ir Zykov, in
386 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")
D: WAVE PATIERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 387
388 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")
 D: WAVE PATTERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 389

Eartn s onger*p'enoa rotation arouna e.Sun (!he super*addea meander cycle)? Earth
am,plitude rose al:5ruptly, maybe p<;lraboli<;:a/ly, at a critical value of chemical '
parametefS, its perro8 meanwh'le cHanging undramati(:ally (Jahnkeet al ", 1989 Figures
Sb' and Sc for the Oregonator;' Lugosi, 1989 Figure 7 for Zykov!s model), Thus arosecour
guess thflt meander' onset is ~ ' .s&Ip4Ircrifical -Hopf b~rcat[on as parameters of
excitability are slowly tnanged (those papers anQ Nandapurkar 'and Wiofree, 1989),
Merof). (1989, 1991) suggesteptha this-may be a curvature*dependEmt instab(!ity of the
wa\leftpnt" Proof.ofthe Hopfbifu cation was provfdedcQmputationally by Karma (1990)-
in the FitzHug~NagU'mo2 mode 's outward-pe~al onset and btBarkley eta!. (1990) and
Barn.ley (19.9.2) 1n a similar cobic model covering both inward*and outward*p-etal onsets,
and then in the malotlic aci_d reagent by Skinner and Swinney (1991) arid b~ Li et a :
(1996), and analyt!cafly in special ca ses by Kessler-anctKupfel'1"i1an (J 9~7) and by, Hakim
nd !{?nna (1997, ,999),. ' , _
, Wlfifree (1991 a, 1993). extrapolated r.lu,merical "experiments to fore cast that in the
limit cf large ratio cf recovery time to excitation risetime, especially near 8R, the wo
frequencies -wqulcl be ~elat-ed 2~1; Hakim änd K"Clrma (1997, 1999~ confirmed this
ana(ytically and ",by computation. - ~ ~>
-, In variqus special ta ses Karma (1992)/ Kessler et al. (1994), Mttkov et al : (1-;996),
EI j et aL (1998), and Hakim andl<arma (1997,1999) numerically and or analyrically '
confirm d the guess '9f Rössl-er and Kanlert (1979) ana Winfree (1991 a),,~ that at least
in - medi with -qnly the fast v,arJable diffüsing, mean.der inevltably ' arises as
parameters change , to increas.e the ratio' 'Cf rec~very tim~ to excitatfon risetime.
ifhis nieans that the singUlar- FierturoationJrmit (Le., extremely fast excitatlon relative '
to recovetY) must ~e us~O cautlo!Jsly in ar9urnents::that aIs6 iqeöjlize _$piral rotation '
as I:l.l1ifoJnl a,nd rigid, at' leaSt when tn~ reco el)' variabl4i1s not aHo~ed to diffuse. It
d99S not i malonic acid reagent ,witnferroin catalyst firmly bound in a sj,rrca gel, and
it -does- npt in the eteC:'!rO'physiotogicaJ case, witQ every loca~ statevar1able but the
E!!edric~l potential anchored fjrrf1ry. in the celf rnembr~me. - ~ I
The astronomica,1 metaphor was ",~hort-lived. It required us. to visualize the Earth
hqnging rnotfenless in space whlle the Moop orbits, then as, parameters cross the
bifurcqtion to meand~rr Earth adopting a tiny orbit with period_somewhat longer than _
the Moon's for outWard-petarfiowers, or somewhat shorter thanthe MoonrS'for inward-
petal f10wers" out wLth larger ard larger, even inf inite, oro't in cases of nearly equal,
perioa. ,It is hard to imagioe a metaphorica: excuse for s-Uch idiosyncrasies. Moreover,
:ouassumption that hoth comf?onents of ni'otion'are circalar proved false. Barkley et al.
(1990) e>sposed the secondary periodidty'5 closed loop, fltbe Earth'sorbit," by adopting
"the Moon,'s" FU\ating 5,:oordina'terrame:-ittums out to be not a circle but m,9re typically
ao ellipse" or less sYlJ)metric JO?R, ever.t fight at the Hopf bifurcation. So Skinner and
Swinney; (199;1) corrected OUt de~crjption of tWo.period meahder from "compound
circular 'mtrtio "to "c,ompound:totation:" AccordinglYI in Jahnke and Winfree (1991 a)
and Winfree (1991 a) we drapped thß p-r;:me~Yy metaphor for the less specific langaage
of -I'cl,Ir:yature modulatiQn," "flower petals,' etc JerminoJogy continues t0 diversify;
BeJrrronte', et al. ( 997)' u b..st!!:~te " ~Q9r'ade and retrograde. m~ander" in lace of·

2 1 use adjective ufitzHugn.. agUtno" In the se~e o( the1>apers of FitzHu&n and. agumo. In the
Russiau literature it also ~nnoreS piecewise lfueaT cari.catures of that cubickinetics, but I cäll these
"l>je€e~ li:nea~." : • ; .' " .
390 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

Figure 3.1. The dashed hypocyeloid is traced out by a point on the

larger cirele, M ("Moon," the rotor), whose center moves along the
smaller circle, T ("Earth," modulating the curvature of the Moon-
point's otherwise circular path through four maxima during an
---", ungenerically exact three rotor periods.) This would be one point
"---' on the "90 0 isogon" in Figure 1.3 of Chapter 9. Barkley et al. (1990)
discovered that the closed "Earth" orbit (the smaller one here) need
I \ not be circular. (Reprinted from Physica D 40, Lugosi, E., "Analysis of
I I
meandering in Zykov-kinetics", pp. 331-337, Figure 5, Copyright
I I
I , (1989), with permission from Elsevier Science.)
---
\ I
 D: WAVE PATTERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 391

A~~hing new in scierke tands. to~splat-Ijke fi,rst raindrops frorn a ,super'Saturatee ,

atmospher.e onto, dupJicate side~alks in qulck succession, and· to receive , as
r.rrarw names, thus,.fö~exarriple :'cycloids" (prolate/ epi- h~po-) in Russia (Zykov
1

'papers), and "Mbortl~ C\m! !IEar.th" '· epiGycle~ ',compone~ts of a compound

(O~tron in YSA (my Lab~~ pape!?)- in the late 980s, In e e,arly 19905
'. escii ' tipns of sRtral meanqel' divetsjfred ~ Iq,tn~'papers-or BarKley a~rid of"M,eron
subscripts 1 and 2 repres~nt, respec;t1vely~ tlie 'an9ular.velo~ities of t~e rotor~ and
ofc~rvature modulation arong the tlp'patt\ but irrtfiose of ~win~e~, (!)f Rotli, and
otDiks1hey repre~ent Mocn apo ~rth, whi~h in Plesser papers are instead.given
subsenpts' 0 a!1d 1 to stay cOhsistent wiTh the notations I· have stu.c . to since'
197,2. The Plesser papers ;:IIso give- opposlte signs' to, epicyde frequencies or
perlods tf the corresponding';[Gtations are 'clockwise ar:icf anticrockwise. -
The6~ drawn 0 'a phenorneoon from~ diverse directions cornes with. di-ierse'
notations that ft,jrther COnfOLlnq ihe originaL babel. eventually requiiing an :
lntemational Con9re,ss-<?~' Nomenclature to set sraneJards. With .no prete~sions
to the al:lthcirity of such an augllst body, J neverthetess propose some standards
he~1 'witl) 'a' fe.";: translations that~ may rema!n pelpf41 until lome standard is
widely adopted or' the' subJect is forgotten. , , ~
The- orIginal notatioh, 1'0 for the rotor penod cOl1tinues In use,-for example
throughout !his book. dt tS' poSlt1ve; whether t~e ,rotor turns ~tockwise or
antictdckwise. Other:s name; leiter arose, also adapting to tlle neea, for anglliar
.vetoci~, 21(iperjod, al1d freqwency/' 1/peri08: 'Tspiral,' To, ~O, . W1J 4!tip. 'fi" (,ttq,
':Moon," tQ name onl1 these rr'io'st' used. The. orfg/nal standarp subscript' 0
remind,s us'that the rotation period has tfo interaGtio.n with the' periods ef rotor-
shape instabilities arising ~y Hopf bifurcation: jt doe~ not count, for ~xample, in
tallying freq\.lencies towacd 3 föd:he 'first possibleconset of chaos. A distaflt
observation station is excited at inteNals 1'0. ,.... ' . •
, ' The. first new period introduced with biperiodic meander is' the positive
period at which the tip path's curvature is mQdulated, introduced In Jahnke
et al. (1989 Figure S)'without a name. This period i's (1-1/n} ro, where 1/n i
the central angle subtendeB by successive loops along the path, expressed
as a f(aetlon of a full cirele. The denominator n neeq hot be integer, emd it is
negative for inward-petal f1owets. In case of closed-path flowers, it is some
integer number of petals pjsRlayed over ,some integer number of circuits
around the flower: center. The . curvature modulation period has .since been
called 'f.2, its angular velocity W2: its frequency hl and f?q' ! wo,~ld downgrade
the subsqipt to 1, recalling th~t it f. the first shape il1stability afflicting rigid
,rotation thus T1. W11 f,. In tbe. case of outwarc}J-petars, the flower's center
(noUhe ~ore of-the. spirqLwave) is 'excited by a' passing wave as: 'Qften as tip
path ,curVature is .rnihlmwm (ar :naximtJm)~' thtlJ at 'the same , pertod cr
~quency as. tuiVatut ~oduJa,tion. " IA known examples 'this ' period °
fr~quency diffe.fS ' no more tha~ twofold from)he J:ot~r's, . NQ'Gne knQws
why, e~cept that tbis . perio~ c:annot b~come, shdrt~ thaI'! th -, mediUm's
hfnlmu eriQd'c' reSEo se i t.eNal.
392 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

Details aside, we do see a spiral wave in sufficiently thin layers of liquid. The
thinness required to justify a two-dimensional description is roughly the diameter of
the troublesome central disk of the involute approximation. This disk is the source
of the outer wave and is the only region in which something more interesting than
straightforward wave conduction is taking place. Experimentally, a spiral wave does
not survive in a box smaller than about the diameter of the moders central disko It is
unstable in smaller confines: The reacting liquid lapses into unifonnly red
stationarity. This critical dimension gives us a practical definition of the topological
idealizations "zero-dimensional," "one-dimensional," "two-dimensional," and
"three-dimensional."
How does the two-dimensional rotor fit into the more richly structured three-
dimensional picture? The first clue is that the period of the three-dimensional
structures is indistinguishable from the period of the two-dimensional rotors.
(There also exist structures of quite distinctive appearance with other periods, called
"pacemakers" or "leading centers." See Section E below.)
The second clue is that the two-dimensionallayer is not reaHy two-dimensional.
1t has a finite thickness and within that thickness, the spiral wave resembles a very
narrow scroll, like a watch spring. And that scroll has an axis, a short verticalline
seen in vertical projection as the pivot point. What if it were longer? What if it were
tilted over, not perpendicular to both interfaces? Figure 22 of Chapter 9 sketches
such situations. It turns out that the structures seen in somewhat thicker layers can
be interpreted in some detail in terms of such curvy tilted scrolls. There is a depth
threshold at which simple spiral patterns give way to the more complex patterns
 D: WAVE PATIERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 393

that I interpret as three-dimensional struetures seen in projeetion. This depth turns

out to be just what is required to admit a horizontal seroll axis. Beyond this depth,
the seroll axis ean meander to arbitrary distanees between the liquid's upper and
lower interfaces.
The seroll axis has some intriguing properties. Particularly notable among
them is its indecisiveness. Every other volume element in the reaeting fluid eycles
regularly through red and blue stages with a universal period. Only at the seroll
axis is such regularity impossible. It is impossible precisely because of the
regularity elsewhere. On any eross-seetion through ascroll axis, the eontour lines
of fixed phase in the red-blue eycle are all spirals eonverging to the seroll axis.
Near the seroll axis, all phase values appear in order around any tiny encircling
ring. Around this ring, phase has winding number W = 1. At the seroll axis, all
phases eonverge, making the seroll axis a point of ambiguous phase. In three
dimensions, it is a one-dimensional loeus, a filament of ambiguous phase. Here
the ehemistry neeessarily beeomes time-independent or else varies in a way that
has no eomponent at the otherwise universal period (see Chapter 2, Example 15
and Chapter 9, Seetion B).
Another peeuliarity is that the seroll axis is physieally so long and narrow, unless
eonfined in a tiny reaetion vessel. Laterally, its dimensions are in the order of tenths

Figura 4. A seron ring is cut open along a plane through its axis of
rotational symmetry. The inner wave is topologieally a disk
bounded by the seron ring. As this rotates about the seron ring,
it buds off tomato-shaped waves that beeome more nearly
spherieal as they expand.

CD
I

of a millimeter while in length it may eommonly extend many eentimeters before

running into a wall or closing in a ring.
Furthermore, exaet closure in rings is typical. This feature initially seemed
quite surprising in view of the narrow eross-seetion of this filament of ambiguity.
In retrospect, and in view of the interpretation of the spiral's eore (the rotor) given
in Chapter 9, it seems less surprising. Aceording to that view, a rotor appears
when eoneentrations of bromous acid ions and eerie ions or ferriin ions cross
through a eritical range as transverse eoneentration gradients in spaee. The seroll
axis is seen as the interseetion of two surfaees of eritical eoneentration in three-
dimensional spaee: one of bromous acid eoneentration and one of ferriin
concentration. The interseetion of two eurving surfaees in three dimensions is
typically a ring (Figure 24 in Chapter 9). Thus the typical configuration in whieh a
two-variable excitable reaction organizes itself in time and spaee is ascroll ring
(whieh appears within the eonfines of a small container as ascroll axis bounded
394 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

by wallS). At any point in the volume dominated byany such wave (exeept along a
ring-shaped phase singularity from whieh the wave emerges), excitation reeurs at
the same fixed interval of time. The volume thus dominated is bounded by
surfaees along whieh outgoing waves eollide with waves emitted by another
source. Such surfaees have fixed shape and position if the other source is also a
seroIl ring and therefore emits waves at the same period. Beeause seroil rings emit
waves all along their length, there may be eomplieated eollision surfaees even
within the domain of a single ring. Outside the smallest sphere eompletely
enclosing the simplest kind of seroil ring, the waves are topologieally equivalent to
disjoint eoneentrie spheres; inside that sphere the seroil ring wave is one single
eontlnuous surfaee (Figure 4).

Finally, in a uniform medium the seroll axis is stable, onee ereated. In this
respeet, it resembles the vortex line of classical hydrodynamies, but the seroil axis
differs from a vortex line in that the circulation period is independent of distanee
from the vortex line and an seroll axes rotate with nearly the same period. Aseroll
ring also differs from the quantized vortex ring of liquid helium in that the ring can
have any length, above a minimum required for stability.
0: WAVE PATIERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 395

()
".

!::l !::l .......

!::l N .;>- 3:
~
'-'
0
~ ~

~ ~ a

~
~
.... s:>

.-
~

0
0
e er
;;-
c«
~

3"
(I

.......
3
=r
'-'
~
N "
0
0
..."
:E

..
c

~I
u
0
0
396 13: THE MALONIC ACID REAGENT ("SüDIUM GEüMETRATE")

1
E
10 20 SO 100 200 500 1000

2 ® ~ ~ +

3 ~ ~ r .(

4 ~ ~ 'f -X

5 ~ JE.
6 ~
• ~

•
7

10

11

12
f
~~
D: WAVE PATTERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 397

...,..
cA(M)
p p
~
'"....
...10.,' ...,
..
0
'73.1

.... 71.1
....
47':'
111.0 SOU
'.,7
,.... ....
012
,l1li3 SU
§
f ,....
'0G.3

~ eo..o
,2.

i:l \"J!
,...I
:r. .42

" '7'U

,. . .. u. ... .. ,.... 100

..,~

1A
." "" . "" ..." ",..
.,
00

f
.'"

'" ." ,,'

.....
,~

HO

,...
n.l

,,,.
'"
398 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

~
CD 1.0
~

gX 0.8
~
J:
~ 0.6

0.4 simple spiral

0.2 •• • •

0.2 0.3 0.4 0.5 0.6 0.7 0.8

8
(H 2 SO.)O (M)

There remains at present (1978) a conspicuous shortage of physical insight into

the mechanism of these rotating diffusive structures that generate spiral waves in
two dimensions and generate scroll rings in three dimensions. Any chemically
realistic picture of this tiny chemical vortex must be built out of the continuity
D: WAVE PATIERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 399
400 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")
 D: WAVE PAlTERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 401

properties of reaction kinetics in time and the continuity properties of concentra-

tion patterns in space. These matters are briefly dealt with in terms of models in
Chapter 9 and in Box E.
Even more mysterious is the appearance of spontaneous pacemakers. These
may represent local violations of continuity, e.g., dust motes. See Section E
below.

Monitoring Vortex Filament Geometry in Three Dimensions

402 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")
 0: WAVE PATTERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 403

Figur. 5. A serail ' wave was created a!ong the· vertical z axis of a 2.3-mm Teflon gt!inder,
filmed durlng 180" of fotatiofl) and tomograph1cally reeonstructed. resulting In a volume
containing ferroln concentration valuas at 0.0135-mm intervals in all three directlons. One
isoconcentratlon surfaee is here displayed from a favorable viewpoint Only 0.7 mm of the z
vis is slited outfor presentatiotl here-•..so that the inner coils of the ~croll are not obstructed
from view, The outside ring is the O.4-mm-thick Teflon jacket. Just inside this jaeket lies a rind
of~nvisibilit.Y believed to be due to imperfect matching otrefractlve indices. Twocfull turns of a
2-mm seroll wave are visible insrde that (From Figure 4 of Winfree et al., 1996. with
Rermission).

Comp eta pans or ; e gizmo, its user' [l13huars, and especially the eight
th9usand lines of commented custom C code and shell scripts needed to uniquely
interpret its two-dimensional observations into three-dimensional concentration
patterns have been available on my web. site, http://cochise.biosci.arizona.edufl''Vart
since 1996. The gizmo has been replicated afla productively employed at least
by . Stock <ind Müller 1996). T . e search for stable organizing centers and

FIgur. 6. Tomo9raphic reconstruction offerrOlh eoneentration ihrovgnout a rapidfy s'pinning

CHD gel produced a 'three-dlmensional arra~ from "'(hich this 5-mm eube was t'lumerieally
at
extracted for display. ReconstrtJctiQh is ifnplemented fro"'m video tape whatever intervals are
wanted, exceeding the mechanical spin period of 1.5 sec fot a 1800 scan. The wave pattems
tool( eomplicated. so we attend instead only to their sourees in the '\~xtiigure: the curved and
twisted seroll fllaments:;;._ __
404 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

Figure 7a. Flgure 7b. Flgur.7c.

Figure 7. Rather f1attened, ribban-shaped filamentS a,re identified by finding voxels with
particularfy large ve-C1:or croSS-Rroeluct of the feiroin gradient with its value 1.5 .sec later. The
0.54 cm filament inside Figure 6 does not end perpendlcularly to the- oste~sible :walls.
because they a(e TeaUy just datq-selection cu planes. 0.49 c;m apart, not impermeable
boundaries. On panels a,b,c we see evolution at 10-{Ilil,1ute intervals. Flom a to c' (~xTO
minutes) the segmen with shortest initial radIUS of curvature, R near 0.1S cm, moved
(obliqueLy'to the plane of projection in this figura) 0.08 cm In 1200 seo, t'oughly as expected
under the rUle dRldt "" -DIR first articulated by Pa.nflloi lind Pertsov (1984}" 'given' a
diffusion coeffi~ent D = 10- 5 cmi/sec 1ypicaf of such readants ir wateT. TfllS"demonstTatiorr
was executed by undergf<!~uate physics m~jot Scatt audle ,and graduate 's tudent Ga 9
Chen [n fall of 1'997. -..' •

obsetvation , of their interna I eollision oLm aries ~otfi awal

suitable' initial conditions . ill fel1'oin-eatalyzedeyclohexanedione ag ar gel. This
excitable me<;iium proved fortuitously photosensItive (\Ninf~ee er al., 1996;
Kurin-Csorgei et aL, 1'997) ' and biStable ·in.. baten mode ,Chen, 20001. Flux
terms are essential te ·make the Oregonaior bistable (Tyson, . f977b) so Ghen
constructed a somewhat diffe~ent kinetie ' model fgr' th.e eHD reacti6n. The
gel'S ~bjstaOility results in ' s ontaneous formatiol;l of vortex lines and rin s as

Figure 8. 'One filament like those of Figure 7 is processed by a 'module of tKe custom Pascal
toolkit used ;n Nandapurkar (1988), Henz~ et al, (1990), and siflillar papers fr:om this lab. ihe
swarm of filament voxe!s guides the construction of a smOQth 'curve, renderecr by Foune
series', alon9 which torsion, twist, and curvature are anal,ytical[y evaluatei3. Using the next
such fjla"1en~, each s99ment's.[ateral motion is also 9u~ntlfied frorn time to time
 -
D: WAVE PATTERNS IN TWO-AND THREE-DIMENSIONAL CONTEXT 405

Figure 98.
"::::;?
.
I,

c • ,.
.
b

Figur. 9b.

Flgure 9c.
406 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

E: Pacemakers

As noted in Figure 4, a rotationally symmetrie scroll ring is aperiodic source of

concentric spherical waves of very short period.
There is another mechanism by which Ionger-period concentric spherical
waves are instigated. It gets short shrift in this volume because it does not
involve aphase singularity, but since it occurs in the malonic acid reagent, in
the cellular slime mold, and in heart muscle, it deserves at least passing
mention. This is the pacemaker point. (Actually, in the slime mold literature
spiral wave sources are also called pacemakers, but we will keep them verbally
distinct here.)
The term "leading center" in spontaneously oscillating reagent distinguishes
pacemaker mechanisms that involve no particle. Such a pacemaker can be
made in oscillating reagent by simply phase-shifting a spot. Busse and Hess
(1973) did this by briefly irradiating a spot in a dish of malonic acid reagent
with ultravioiet light. That spot turns blue ahead of surrounding volume
elements in the next cycle and thereafter, so that a ring of blue is seen
expanding out of that spot.
 E: PACEMAKERS 407

By another trick involving a scroll ring (Box C), a radial phase gradient can be
established. Its central extremity becomes the origin of a "bull's-eye" of spherical
pseudowaves radiating away at intervals equal to the period of oscillation in
spatially uniform reagent.
If a spontaneously oscillating medium has any slight parameme inhomo-
geneity (e.g., nonuniform temperature), then there is a point of locally
minimum period (commonly on the boundary). The phase of the oscillation
advances faster here than elsewhere, so a spatial phase gradient develops. When
the phase gradient becomes steep enough, waves from this point reach distant
points before the liquid out there spontaneously completes its own cycle. (If the
local gradient of phase is not initially that steep, it will eventually become so,
since the short-period center is constandy advancing in phase relative to its
surroundings.) The waves emanating from such a source are, of course,
concentric spheres, or segments thereof. All points within that source's domain
of influence cycle at that same period without exceptions for any locus of
ambiguous phase. As with scroll rings, the domain of influence is bounded by
impermeable barriers or by surfaces along which waves collide with those from
other sources. In the latter case, the collision surfaces are constandy changing
shape unless both sources should happen to have identical periods, a situation
guaranteed if and only if both sources are pieces of untwisted scroll rings. If the
periods differ, then the collision surface constantly moves toward the longer
period source

This happens because each collision wipes out a pair of waves. Of the two waves
next in line, the one from the short-period side will reach that prior collision point
after a short period and the one from the long-period side would reach it after a long
period. Thus, the next collision occurs after an intermediate period and closer to the
long-period source. Each pacemaker has its temporary domain of control, but
shorter period domains expand at the expense of longer period domains (see Figure
5, top).
In non oscillating media, heterogeneous nuclei seem to induce local oscillation
with much the same consequences. In the malonic acid reagent, these nuclei seem
to be dust particles andlor surface defects in the container (Rastogi et al., 1977). In
heart muscle they are called ectopie {oei, which include patches of tissue irritated
by abrasions, or by chemieals, or by local defects of blood circulation. In cellular
slime molds, they seem to be single cells that have shorter period than most others.
Tyson and Fife (1980) then Tyson (1987) undertook analysis of possible reaction-
diffusion mechanisms, raising many fascinating questions; there has been litde
follow-up (to 1999).
Numerous models have also been proposed whereby nonoscillating excitable
media may, without the help of heterogeneous nuclei, generate concentric ring
waves from sources with periods greater than the rotation period of scroll rings (see
Shcherbunov et al., 1973; Zhabotinsky and Zaikin, 1973; Yakhno, 1975; and Zaikin
408 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")

and Kawczynski, 1977). The mechanisms invoked there suggest another application
of the "wave broom" principle (Box G of Chapter 4), Le., substances can be
transported toward a source of waves. The transported substance would only have
to encourage spontaneous cycling, or shorten its period, in order to make the origin
of a first wave into a permanent pacemaker.

In no case has a pacemaker been found with aperiod less than the rotor's. The
reason for this peculiarity seems clear only in terms of relatively naive models that
involve the notion of an absolute refractory period. In such a case, the minimum
supportable period is the refractory period, and this is realized by a rotor, so no
pacemaker can do better. Unfortunately, such models imply a discontinuity of
concentration within the spiral's core. This may be acceptable in cellular media such
as heart muscle (but in 1999 I think it is not) and social amoebae, but it is definitely not
acceptable in the malonic acid reagent. When we turn to strict1y continuous models of
excitability, however, there seems a possibility for the rotor's period to exceed the
minimum stable period of plane waves. Whether it can also exceed the minimum
stable period of waves emitted from point source remains to be determined.

4 At shorter periods approaching the rotor's, the critical radius becomes about twice as long in media
allowing all reactants to diffuse equally, thus the pacemaker nucleus must control an eightfold larger
volume during each such shorter period. I have never seen a pacemaker with period short enough to
compete with rotors.
 E: PACEMAKERS 409

iffUslon coe fcientZpr.opagatioFl -spee ) for .successtUf' .nucleation of a wave? How

o en ."could such a ball repeatedly igl1iteJ ~ I. estirhate it woulct -have to remove a
ost
'eC?,ntirllJous inffux of ~ 1Q-r~-rnoIe's/sec across tl:1e critical sphere's surfa~e, but ä 1
partide contains om äpbut'1 0;1~ moles", so it has to be' a cat~lyst, not an absorber..
Whel'l it was faune that·' the.. vas ma-jorily of pacemakers, vanish after" 0:22 J.k
filtr-atlori, the natural experiment to ,probe'?those femaihing' seemed t~ be disr:uption '
.of -their dyparnics by, s!::torter-F.leriop stiln}Jlf: if ~~y.., are particles, they ~hould I
'reemerge wttrr the or.igina eriod ar:ld' in the ame pface after such pasing is o
'discontinLlecf(W~Afree, 1918 ), A:~ladz&and:, Krinsky (1984) were the first to.try it on
unfiltered !,1ort6sdllatory reage'1tnThose;.probed did behave- as expected of partides.
Btit the e'S!?e(lrneht neeqs tp e repeated 'in tiltered osciUatory media. Tyson (1987)
suggesls that.tnere may be allotne(, kind of pacemaker nudei, a kind thai: affect the
Oregonator parameter k's and are"small~noi.Jgh to- slip through. even 0.22 J.l- fllters.
Using a photosensitlve oscillatlCl9 medium, t~rget~p'attelT) centers -could oe entrained
by periodic~ Hruminatiol) t~~ ~~e whetner they ' r~el11~rge wnen. pacing ceases. If not,
they may very weil be spatJotemp.QCal structures/ the: long sought leading centers,
father ~han particulate nudel as J ave s~pposed sinte 1970. I '

A nurnber of ' provocative observations ,on pacemakers appeared in the mid-

1980s. In -1989 L vfdeoiapeq pacemakers in pscillating reagent and shoyv~d -that
their periods chat)ge systernafcally' over tIme, perhaps due their rising or falling
through a gradient of exci~bmW impd eGl by· ir. exposure" at the surface 6f the
H91i1d (Wif'lfree,. 1985),. Vidal e al. (3987) prepared histograms of pacemaker
periods. (5ut ~ithout f10ting the con;esponding ' totor pe~iod). ~Idal and Pagola
H9a9} carefull obs,erv,~d p~cemaker on the- 1i9uid urface and another floating
withir:} tbe liquid, evreently of radius !e?s than 3 JI'-. But nothing conclusive has '
?ince em~rged o. clarifY the natUr~imd ' ~ynamicS' of pacemaker nl,lclei. One of the
~ore re~~rkable hist6rical aspects- -cf, tbe cn-emical wave ' business is that thirty
y'ears, after the "dramati'c eub/ication Jn Mature showlng pacemakers of diverse
perioäs (Zaikin and ZhabotinskYf .. 1970), we still do not kflow wnat they are al}d
ho they wofk It might not be tba~ ha d to ', find out. Imagif)e, for example,
determinfng' whether ihei( ab~"dal'}ce 's .proportlonal to' volume or to sulface area .
(of air, of ' glass) I;loundlng tb,e I.i!:fuid. Or many . kinds of pure ' dust could be
collected (pollens, spor~s" diatoms, gro~nd .glass( watercolor pigmer}ts, abrasive
grits. for polishing, ~queous colloidal suspensions. of oils, metals, sLlica, etc.) to
dasslfythem by theili pacemaker actions. Da the most effective cines bind ' brornine
,. bromide, for example, or dö tt1ey ~taly.Ze the reactions that consume bromid~?
Po they all haverl)icrorr-scale 'surface ~onvolutions and cracks? Minute ftuctuations
in CI prop~rfy aring crade could 'indte spontane'ous' wave prppagation (Winfree,
19'ß5; I{ogan et a1.. t992) Qr imaginea 'l lroject' in which diverse ' malonic acid
reagents, are comRared for. absence <;>f pacemakersf ' are ·1:hey . ever seen in
cydöPexanedJo.ne ~edla? In siltca g~ls? ' in MHJipore? in ~twa:-dimensjonal 'Iiquid
,jayer.s sandwlched <'tao ·'thIA betw~en grass . plates or iQ glass tubes drawn one-
dimen ronally to, micron~scale diameters? in liquias filtereä through ' pores finer
than 100, 10, 1,+0 p,? Can, 'tf:le~ JJJ$ recovered n:om tl]e fnt~r 'paper? Can they be
pelleted or stratifted ilJ a ~~trIfuge? ~re they often associated with ga~ bubbles
becaus~ tti~ mechanism IOvolves an· inte'rfacß, 0 because tha same partide , also'
nu'cleated tFie bü b eV '.
410 13: THE MALONIC ACID REAGENT ("SODIUM GEOMETRATE")
 Electrical Rhythmicity and Excitability
in Cell Membranes

False facts are highly injurious to the progress of science, for they often endure
long; but false views, if supported by some evidence, do little harm, for everyone
takes a salutary pleasure in proving their falseness.
Charles Darwin, Chapter XXI,
The Descent of Man and Selection in Relation to Sex, 1871

Every cell has a plasma membrane. The plasma membrane is a thin film, less than
a hundred angstroms thick, which maintains a difference between inside and
outside by gate-keeping the passage of molecules and ions. Every cellular
membrane is freely permeable to some substances Ce.g., water) and essentially
impermeable to others Ce.g., proteins and certain ions). Nerve cells and some
secretory cells are distinguished from most other kinds of cell chiefly in that the
selective permeability of their plasma membranes depends sharply on an electric
field. All cells experience an electric potential difference between inside and
outside, ultimately because amino acids bear an ionic charge and, once
polymerized inside the cell, they can't get out. 1 This potential difference is typically
about one-tenth of a volt, so the thin plasma membrane is stressed by an electric
field in the order of 10 million volts/rn. In nerve cells, molecular anatomy within the
plasma membrane is believed to readjust when this field is reduced to less than a
certain threshold. With its selective permeability altered, the membrane passes
certain ions that it had formerly restrained, resulting in a further decrease in the
field maintained, and a self-catalyzing breakdown of membrane potential quickly
ensues. But things are so arranged that a recovery promptly follows in which
electrical imbalance is restored.
The kinetics of this "action potential," as it is called, has been a favorite object of
study among biophysicists. The first thorough quantitative description of the major
ionic events was given by Hodgkin and Huxley (1952) on the basis of their electrical
experiments using a squid's giant axon, the high-speed conductor for the squid's
escape reflex.

This potential difference would persist without expenditure of energy were the membrane perlectly
impenneable to select ions. But it leaks a little, so the observed voltage must also be maintained by
sodium-potassium ATPase pumping ions across the membrane.

A. T. Winfree, The Geometry of Biological Time 411

© Springer Science+Business Media New York 2001
412 14: ELECTRICAL RHYTHMICITY AND EXClTABILITY IN CELL MEMBRANES

Hodgkin and Huxley clarified the mechanisms of nerve excitability by

documenting in irrefutable detail five facts then widely accepted for the squid
axon:
1. Excitability is a membrane phenomenon. If the cytoplasm is involved, it is
involved only as a dilute solution of the several essential ions (and, in the long
term, as the biochemical support of the membrane).
2. Fast changes of membrane potential V derive from changes in selective passive
permeability to ions, notably sodium, potassium, and chloride (and calcium, in
many of the pacemaker membranes of concern in this chapter; but that is a
more recent appreciation).
3. The rates of these permeability changes are governed instantaneously by V.
4. A standard linear electrical equation describes the rate of change of V in terms
of the membrane's capacitance, its permeability to ions, and ion currents driven
by the potential difference across the membrane.
5. Active pumps in the membrane compensate for imperfections of its selective
permeability.

For at least a decade this much bad been explicitly formulated, though not
yet universally accepted (e.g., see Rashevsky, 1936 or Rushton, 1937 or Offner et
al., 1940). The achievement of 1952 lay in contriving ingenious experimental
methods to actually measure the expected functional dependencies and in
showing numericaIiy that they suffice to rationalize the familiar neuroelectric
phenomena. Hodgkin and Huxley summarized the kinetics of voltage and
permeabilities in a four-dimensional Ioeal differential equation augmented by
diffusion terms representing the spread of current in space. The best description
of the equation's behavior, in both topological and biophysical terms, is due to
FitzHugh (1960, 1961). A variety of simplifications in current use today retain the
essentials of interest in present context. So do other modifications which
introduce altered conductivity functions or a fifth variable quantity expanding
application of Hodgkin and Huxleys' paradigm to encompass myelinated nerve,
Purkinje fibers of the heart, pacemaker sensory neurons, etc. The books of eole
(1968); of Jack et al. (1975, especially Chapter 8); and of Kuffler and Nicholls
(1976) give excellent and readable accounts of experimental and theoretical
aspects of neuroelectric dynamics. Some fascinating historical background is
summarized by Harmon and Lewis (1966) and in the book of MacGregor and
Lewis (1977).

My purpose in this chapter is not to dweIl on membrane biophysics or

differential equations but to describe four classes of neuroelectric behavior that
relate to the themes of this book through their phase singularities and their
rhythmic interactions:
1. Rephasing schedules of pacemaker neurons
2. Mutual synchronization in the zero-dimensional case
 A: REPHASING SCHEDULES OF PACEMAKER NEURONS 413

3. Waves in one dimension

4. Rotating waves in two dimensions

This material is intended to provide the physiological context that readers

untrained in biology may require in order to evaluate the significance or triviality of
phase singularities described in the main text.

A: Rephasing Schedules of Pacemaker Neurons

Experimental Results
Some kinds of neIVe cells fire with impressive regularity at a rate determined by
environmental conditions. The most sensational examples 1 know of are the stretch
receptor cell in crayfish muscle (Firth, 1966), the pacemaker in the brain of the fly
Calliphora (Barneveld, 1971; Leutscher-Hazelhoff and Kuiper, 1966), the similar
neuron in the brain of the housefly Musca (Hengstenberg, 1971; Shipp and
Gunning, 1975), the pacemaker in crayfish optic neIVe (Nudelman and Glantz,
1977). Under constant conditions, firing inteIVals vary by only a couple percent of
the mean, in these cases .

.. TOcfay a more sensationaJ examp e is under study in the pacemaker nucleus of the
electric fish, Eigenmannia (Heiligenberg, 1980; Dye and Heiligenberg, 1987; WesseH,
1995; Moortgat et al., 1998, 200Oa,b). It appears that even the individual ce 11 ,
independent of interactions with other cells, has an intrinsic precision of about ro
percent, whi(:h meahs no more than.1 to 2 #Sec standard deviation in the regularity of
its periodic firing! No one has yet convincjngly proposed a f>lausible mechanism 'to
account for such Rrecis'on, roacned in no other cellular oscillator.•

Many other kinds of pacemakers also fire with sufficient regularity to suggest
description in terms of phase in a cycle. Perkel et al. (1964) and Schulman (1969)
measured the rephasing schedules (alias resetting maps) of a stretch receptor cell in
the crayfish, which seIVes as a strain gauge on the muscles: Its firing frequency is
modulated by mechanical tension. At a fixed tension its electrical cycle is regular but
it is transiently upset by arrival of impulses from a synapsing inhibitory neuron.
Upon recovery of regular firing (essentially within one cycle time), the rhythm
continues as though it has been displaced along the time axis. (For details about
systematizing such obselVations, see beiow. If you read the first half of this seetion
easily, then skip the second half.) A replotting of their data reveals Type 0 resetting
in response to one kind of stimulus and Type 1 resetting in response to others
(including, of course, "placebo" nonstimuli). Hartline (1976) automated the
procedures of stimulation, recording, and display so as to obtain a new phase vs.
old phase plot directly on an oscilloscope screen (Figure 1) in the same format as
that used by Schulman (1969) and that used throughout this volume. Similar
experiments using endogenous bursting neurons in the abdominal ganglion of
Aplysia also resulted in smooth Type 0 resetting (Pinsker, 1977). Sano et al. (1978,
Figure 5 filled circles) found Type 0 resetting in rabbit sinus node. Populations of
414 14: ELECTRICAL RHYTHMICITY AND EXClTABILlTY IN CELL MEMBRANES

KEY TO PHASE-SCAN PLOTS

'ollowln, .lfik •. r-WIfHOUf SUMlULUS
~ • rWUH ST' .... ULUS

.2 i I
t
ITIMUt..US
- DELAY

----..DELAY

DELAY

COPHASE

, CQPHASE

Flgure 1. The firing pattern of spikes (solid vertical bars) following seme triggering event (at left
margin of plot) is represented as a function of phase within the normal interspike interval. The
phase cP of the perturbation (arrow marked "stimulus") is translated into verticallevel in the plot
(cP = 0 at top). Three representative phases are shown in the figure for purposes of illustration.
The plot is triggered by the spike preceding the stimulus (spike-referenced plot) or by the
stimulus itself (stimulus-referenced plot), and the following spike pattem in time is plotted as
tics (vertical bars) to the right of the time origin. For comparison, the plot pattems for a null
stimulus (one producing no pattem perturbation) are indicated with broken bars (adapted from
Hartline, 1976).

rhythrnic neurons also exhibit smooth Type 0 resetting, as seen in the neuromus-
cular network of Hydra (Taddei-Ferretti and CordeIla, 1976), the chirp reflex in a
cricket (Walker, 1969; see Figure 16 in Chapter 4), and the finger-tapping rhythm
investigated by Yamanishi et al. (1979, 1980).
As I write (1978) the collection of resetting data from neuromuscular oscillators
is in about the same state as was the corresponding collection from circadian
rhythms in 1967 when the significance of Type 0 resetting was first seized upon. I
expect a similar development in neuroelectric measurements: measurement of the
complete helicoid2 and lattice of helicoids, investigation of the singular perturba-
tion,3 a test of two-pulse interactions (as required for the entrainment model of
Perkel et al., 1964; Pinsker, 1977, and Scott, 1979, have weIl begun this), and
measurement of oscillator trajectories during recovery from near-singular perturba-
tion by means of two-pulse experiments as in Chapter 7.

2 Added in proof(1979); data from Jallfe seem to provide this forthe first time, using sinus node ofthe
kitten.
3 Added in proof (1979); this has a1ready appeared in Guttman et al. (1980) who incidentally point out
that Teorell (1971 Appendix 3) observed a singular annihilating pulse in his 2-variable model of a sensory
pacemaker (his Figures lOe, 12h, 16c). Both these cases, as weIl as Best's computations, expedite location
of the phase singularity by adjusting parameters to make the neuroelectric steady-state locally an
attractor. Jalife and Antzelevitch (1979) using kitten sinus node also demonstrated annihilation by a
critically timed singular stimulus.
 A: REPHASING SCHEDULES OF PACEMAKER NEURONS 415

~ P-eterson an Cala r~s~ (1982) presented Typ~ 1 and Type. 0 resetting curves by
stimulating intemeLirOI1S in the pacemaker network of t/1e leech heart, sufficient to
'sketch'the nelicoid. Theyfound the stimuJus that almost reaches the phase singularity,
following which rhythmic!ty js at least confused during the next few heartbeats.
Guevara (1984) exprored such ma~ers thoroughly in aggregates. of tissue-cultured
heart cells, and Zeng el al. (1992) e)(ecuted the correspooding two-pulse experiments
jeft incom lete"Ö p·ü'Isker and b Scott see ages 219 a!1d 42~. <0( •.
Discontinuities in the resetting curve are common with inhibitory (hyperpo-
larizing) stimuli (e.g., Perkel et al., 1964 Figure 2A; Schulman, 1969 Figure 3;
Pinsker, 1977 Figure 5; Ayers and Selverston, 1977 Figure IB). Discontinuity is
required by a widely used dass of models that essentially amount to a
topologically altered, but more intuitively usable, approximation to the Hodgkin-
Huxley model (Perkel et al., 1964; Rescigno et al., 1970; Knight, 1972; Mayeri,
1973; Peskin, 1975; Hartline, 1976). The Hodgkin-Huxley model, adjusted to fire
rhythmically, does predict Type 0 resetting though it would not likely be smooth
enough to distinguish empirically from stark discontinuity (Best, 1979). Some of
the modifications recendy contrived in connection with pacemaker cells might
possibly have smoother resetting behavior, but this has not yet been looked into
(see Box C of Chapter 6).

Thus it comes as a surprise that continuous, even smooth, resetting maps are
obtained from electrically rhythmic membranes that suffer catastrophic reorganiza-
tion at the moment of the spike action potential, and that in cases where there is a
discontinuity in new phase as a function of old phase, it doesn't necessarily coincide

MEMBRANE
VOLTAGE

TIME

F1gure 2. Idealization of a typical slow wave or pacemaker potential as seen on an oscilloscope

plotting membrane potential vertically and time to the right. Where the wave transgresses a
threshold it fires action potentials at a rate that increases with the excess potential.

with the nerve's firing (e.g., Perkel et al., 1964 Figure 2; Pinsker, 1977 Figure 15). See
pages 193-94.
A possibly related peculiarity is the discovery that smooth oscillations of
membrane potential can continue even when tetrodotoxin (a puffer fish poison) is
416 14: ELECTRICAL RHYTHMICI1Y AND ExCITABILl1Y IN CELL MEMBRANES

used to inhibit the spike (e.g., Strumwasser, 1968, 1971, Mathieu and Roberge,
1971; Junge and Stevens, 1973, McDonald and Sachs, 1975; Pinsker, 1977, p. 539;
Raper 1979). These oscillations are commonly called "pacemaker oscillations" or
"slow waves." They are commonly seen in a wide variety of neuroelectric
preparations even without tetrodotoxin. They start as subthreshold rhythmicity of
membrane potential, building up until threshold is exceeded during each cycle
(Figure 2). During the interval when membrane potential exceeds threshold the
otherwise smooth potential oscillation is decorated with spikes, unless tetrodotoxin
is used to suppress them (e.g., Arvanitaki and Chalazonitis, 1968; Bortoff, 1969;
Junge and Stephens, 1973; El-Sharkaway and Daniel, 1975; Kuriyama and Suzuki,
1976). These observations suggest that oscillation along a smooth attracting cycle
triggers spikes between successive threshold crossings, but that the oscillation is not
itself drastically affected by the triggered spike. A strong suggestion of such
separation of cause and effect had first been made by Brink et al. (1946). They
observed an irregular train of spikes issuing from frog sciatic nerve but the intervals
between successive spikes were always nearly integer multiples of a least quantum,
as though a regular subthreshold oscillator continued undisturbed whether it
managed to trigger aspike or not. 4 The smoothness of the resetting curves or the
phasing of their discontinuities might derive from the properties of this oscillator,
functioning independently of the action potential.
What might be the physical nature of this underlying oscillator? How strict is
the separation of cause (the putative smooth rhythm) and effect (triggering of
membrane spikes)? An early viewpoint on these phenomena emphasized the fact
that the Hodgkin-Huxley model and certain of its simplifications are capable of
subthreshold oscillations. Their period is essentially determined by the membra-
ne's Resistance Capacitance time constant (1-1O msec) and roughly matches the
period of the highest frequency pacemaker activity. Possibly, random fluctuations
of some sort occasionally direct the membrane to recycle along the subthreshold
route. Wilson and Wachtel (1974), Gola (1976), Connor (1978), and Gulrajani and
Roberge (1978), working with pacemaker neurons in mollusks and crustacea,
trace their rhythmicity to a negative-resistance segment of the membrane's
current-voltage characteristic. Connor and Stevens (1971a,b,c), Plant and Kim
(1975, 1976), and Plant (1976, 1977), and Carpenter (1979), among many others,
also trace rhythmic modulation of firing rate to the Hodgkin-Huxley equation
with suitable modifications. This approach quite satisfactorily accounts for
electrical rephasing of pacemaker rhythms and control of their frequency (or
even suppression, leaving only the rhythmic "slow wave") by a steady biasing
current.

4 Similar measurements have emerged in the literature of the female cyde and of the cell cyde. Cycles
without ovulation seem to occur in the menstrual rhythm, without upsetting its quasi-regularity (Chapter
23). According to Kauffman and Wille (1975), the mitotic cyde in Physarum can be suppressed without
suppressing a timer that brings about the next mitosis one or two or three cydes later, roughly on
schedule. If these observations are to be taken at face value, they suggest that the action potential,
ovulation and mitosis are caused by a covert timer (see, for example, Both et al., 1976) but do not in turn
affect it unless they just happen to affect it in such a manner that the time to the next event is the same
eitherway.
 A: REPHASING SCHEDULES OF PACEMAKER NEURONS 417

It is not clear that the whole cause of rhythmically varying conductivities (etc.)
is to be sought within the membrane itself in all cases. Both et al. (1976) and
Chaplain (1976) postulate a separate metabolie oscillator whose activity affects
membrane permeabilities and potential. They emphasize the role of glycolysis and
in particular of phosphofructokinase (PFK), suggesting some relationship to the
glycolytic oscillation in yeast, as explored in Chapter 12.

Rapp and Berridge (1977) also suppose aseparate metabolic oscillator but put
more weight on observations implicating calcium ions and cAMP. They suggest a
relationship to the cAMP oscillations in the cellular slime moId, explored in Chapter
15. (Note that Goldbeter's pre-1978 kinetic model, Chapter 12, allegedly serves for
both PFK oscillations and cAMP oscillations.) Tsien and Carpenter (1978) attribute
spontaneous firing in cardiac Purkinje fibers to oscillatory release of Ca2 + from
intracellular stores. Rapp and Berridge (1977) and Pollack (1977) even go as far as to
argue that the ultimate source of rhythmicity in the heartbeat may be a Ca2+ -cAMP
oscillator, rather than an instability of the membrane potential.

Formats for Rephasing Measurements

Perhaps the single most conspicuous fact about most biological rhythms is our
present ignorance of their chemical mechanisms (for exceptions, see Chapter 12).
In many cases, we do not even know for sure whether or not our chosen
observables themselves participate in the oscillatory mechanism. In some cases, it
seems likely that they are causally "downstream" from the undiscovered source of
periodicity, being only indirectly affected by it, and not affecting it in return.
Despite extraordinary advances in biophysical measurement since 1950, the
mechanisms even of electrophysiological rhythms still challenge the most
resourceful investigators.
In this situation, workers in several areas of experimental physiology (cell
cycles, circadian rhythms, biochemical oscillations, and neural and cardiac
rhythms) have frankly accepted the challenge of indirect inference. One can ask a
question of the mechanism by probing it with discrete stimuli. One sure indicator of
impact (whether direct or indirect) on the mechanism generating a rhythm is
alteration of the rhythm's phase, period, or shape as measured under standard
conditions. Thus the imposed disturbance must be temporary, e.g., a currentpulse,
not a step up or down. If the measurement were conducted under conditions other
than those in which its prior phase was measured, then it would be hard to know
what the new phase measurement means in terms of the old phases. The
significance of the experiment would be obscured to the extent that we are ignorant
of the changes imposed by the changed conditions on the structure of the rhythm-
generating mechanism.
In the cases of concern here, ephemeral disturbances usually have little lasting
effect on a rhythm's period. But the detailed time course of the rhythm may be
418 14: ELECTRICAL RHYTHMICITY AND ExClTABILITY IN CELL MEMBRANES

altered, most conspicuously by a peImanent phase shift. The phase of an oscillator

is the main feature we can measure reliably by watching an arbitrarily chosen
rhythm without necessarily knowing anything about how the hidden oscillator
imposes its rhythmicity on this feature that we find it convenient to monitor. We
measure the phase some time after a fleeting disturbance, after transient effects on
the rhythm's shape or period have died away. One can discriminate between
alternative conjectures about an oscillator's dynamics on the basis of the distinctive
regularities in its patterns of phase adjustment in response to the timing and
magnitude of such a stimulus.
Thus biochemists have probed reaction sequences by looking for an advance or
delay in rhythmic NADH fluorescence following injection of a consumable substrate
(Chapter 12); behavioral physiologists have revealed the causes of seasonal
flowering and hibernation by examining the phase control of circadian rhythms
by suitably timed exposure to visible light (Chapters 19-21); cell physiologists have
examined the "excess delay" of cell division following some physiological shock to a
regularly dividing cell suspension (Chapter 22); and electrophysiologists have
studied motor coordination by systematically measuring how far a post-synaptic
potential resets the phase of a pacemaker neuron.
Such data are now widely available. They exhibit certain regularities that may
be diagnostic of various classes of mechanism, permitting us in some respects a
"sneak preview" of what will not be properly understood in teImS of molecular
mechanism for a very long time yet. But it is troublesome that resetting data are
available in such an imaginative array of formats. (See Box C of Chapter 4.)
My purpose here is to redescribe the fOImats in use among neurophysiologists
in relation to the founat I've chosen as a common standard for the diverse rhythmic
systems and conceptual models gathered in this book.
A physiological rhythm consists of either a discrete conspicuous event repeated
rhythmically (e.g., aspike discharge) or smoother rhythmic variations in some
quantity (e.g., membrane potential). In the latter case, a "phase reference event" is
chosen on the smooth rhythm to serve as a discrete event (e.g., a local maximum or
minimum or an upward or downward zero crossing). In the fOImer case, the system
has already chosen for us: The discrete event was presumably triggered by some
underlying smoothly vaI)'ing quantity reaching a threshold.
It is usual to plot the rhythm as a trail of dots, each marking the occurrence of
the chosen event, along a time axis extending horizontally to the right. It is usual to
stack up such lines vertically in order of the time when a stimulus of fixed quality
and duration was given. Here two choices present themselves. In depicting them, I
use the notation ofHartline (1976), who electronically automated an on-line display
of a pacemaker neuron's resetting, simultaneously in both fOImats.
Format 1: Spike-referenced or control-referenced (Figure 1). Experiments are
plotted on horizontal time axes stacked vertically with the prestimulus rhythms
aligned; hence the name "control referenced." In Hartline's cases, the data points
outlining the rhythm consist of neuroelectric spikes, hence the name "spike
referenced." On each successive line, vertically, the stimulus comes later, so that the
vertical downward axis is the old-phase axis.
In this fOImat, data points in Type 0 resetting fall along curves wriggling about a
parallel to the stimulus diagonal. Type 1 resetting data wriggle about verticallines
 A: REPHASING SCHEDULES OF PACEMAKER NEURONS 419

parallel to the controls. This format has the advantage that deviations of the
poststimulus rhythm from periodism in both horizontal and vertical dimensions are
plainly exposed, and that if one wishes to simplify, omitting those features to plot
onlya phase shift, then this is easily done by clipping out a square unit cello Rotated
90° and flipped over, this is a phase-response curve (PRC). It plots vertically the
change of phase expected if an impulse arrives at the phase plotted horizontally. I
dislike this operation because it breaks up the continuity of the data: Type 0
resetting thus spuriously acquires a full-cycle "breakpoint" which corresponds to no
comparable discontinuity in the data or in the physiology of the oscillator (e.g. see
Figure 1 of Chapter 19).
Presenting results in a format reduced to a single unit cell not only violates the
continuity of experimental data and shows only one square out of a larger pattern,
but it also commonly entails presenting the difference between a perturbed rhythm
and an unperturbed control rather than presenting the unprocessed direct
observations. This procedure might eliminate correlated sources of error, but in
my experience those are slight compared to the independent sources of deviation
from perfect rhythmicity. So, in taking the difference, data variance is increased.
Moreover, the difference must be taken between a chosen event in the perturbed
rhythm and a chosen event in the control rhythm. Which ones are chosen? There are
several different equally valid conventions in use, and if the result is to be confined to
the interval ±! cycle, then it usually requires a change of convention at that point.
However, this format is most convenient in arguments about entrainment,
which typically deal with small phase shifts repeatedly inflicted during a standard
cycle by stimuli of one standard duration. It is also convenient in arguments where
the process of phase change is of less interest than the end effect: a small advance or
delay in each cycle of the stimulator. Perkel et al. (1964), Walker (1969), Stein
(1974), Taddei-Ferretti and Cordella (1976), Pinsker (1977), Scott (1979), and Jalife
and Moe (1979) have presented their experimental results in this format.
Format 2: Stimulus-referenced (Figure 1). This is the same as spike-referenced
except that the successive horizontallines are sheared over 45° to vertically align the
previously diagonal traH of stimuli. "Cophase" or "stimulus latency" is measured to
the right from stimulus time, so that the poststimulus horizontal axis becomes the
cophase axis in all experiments. Cophase being complementary to phase, the
horizontal time axis is also the new phase axis, running from right to left. In Type 0
resetting, data points lie along a curve wriggling rhythmically about avertical,
parallel to the stimulus column. Type 1 resetting data wriggle about diagonals
parallel to the control diagonal.
If the stimulus-referenced plot is rotated 90° and flipped over, then we have the
old phase axis horizontal to the right (previously vertically down), the new phase
axis vertically up (previously horizontal to the left), and the cophase axis vertically
down. This is the format of Schulman's (1969) and Harcombe and Wyman's (1977)
presentation of pacemaker neuron resetting, and the format of all my publications,
including this book. Schulman's silent period Dis exactly my cophase, supposing
exactly normal rhythmicity follows the first poststimulus spike. This format has the
advantage of presenting all the experimental data plainly while portraying the phase
transition curve, alias resetting map, in each square unit cello This curve is
convenient for analysis of entrainment in terms of phase just before and just after
420 14: ELECTRICAL RHYTHMICITY AND ExClTABILITY IN CELL MEMBRANES

the successive entraining pulses (Perkel et al., 1964).lt also lends itself to analysis of
the process of phase resetting (during the stimulus, as its duration increases) in
terms of the phase reached, or the internal state of an oscillator at each moment.
Such analyses are more cumbersome when conducted in terms of the phase shift,
the changing difference between the phase reached and whatever the initial phase
may have been.
 A: REPHASING SCHEDULES OF PACEMAKER NEURONS 421

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A.

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Figure 2,;1. tfie ralnstel'Tl oscil ator that regu ates breatfiing in the cat is reset by weak,
~ntermediate, or strong stimuli that inhibjt ventilation (usI!'1g the superior laryngeal nerVel or
that"excite ventilation (by di~ electrification qf.t11 t'nidöraln). In two cats (top, bottom)
five magnitudes -cf e citatory stimuli (panels 1eft to nght) here evoke- resetting curves, '
progcessing from Type. 1 to Type O. A$sembled in threa dimensions, they reveal a time
crystalwen as Paydarfar Qresaw in 1983. partly by anaJogy io the pacemaker neuron
resetting experiments reinterpreted In Wiqfree (1 ?77). (From Paydarlaret al., 1987 , Figura
l witl1..E ·Ssion.)

ottsc alk et al. 1994) accept Paydartar's time crystals as a new toudistone for
~jscrimi(lating between hypotheses about central neural mechanisms, and present
a new neurological model ttiat nicefy, reproduces them.
• Paydarfar et al. (1995) show using ' human subjects 'that the mere stimulus of
voluntary swallowing •.at arious times in the cyde of breathfng not only
interrupts 'I!lreathing for a f~w seconds but also resets the phase of its
subsequent rhythmkity; Clnd in a ;ry e 0 way! If a "'partial" swallow or swallow
'·of an · object of 'appropriate . V0lume or consistency; elicits Type 1 resening,
.. then swa!lowing somethin9 in betw.e~n at the right time might so confuse the
process that bre-athing. · wOl,lld not res\Jme for a 'whlle, and then at
unpredictable phase, O( t at the normal muscufar· thythms · would become
uncootdinated, resulting 'in aspiration into, the airway, the wellknown
emergency for .wh~cn tbe Valsalva, mane ver often provides an adequate
solution. ~
~~----~--~~~~~.--------~--~.~~._---~~-----~
422 14: ELECTRICAL RHYTHMICITY AND ExClTABILITY IN CELL MEMBRANES

B: Mutual Synchronization
Mutual synchronization is an interesting problem, and one that all societies have to
solve. 1t can be solved dictatorially, every individual being entrained to an external
rhythm (a common zeitgeber in the jargon of circadian physiology) or to a unique
pacemaker individual (a "master clock"). Or it can be solved democratically, each
individual contributing equally to an aggregate signal, a virtual pacemaker that
serves the same purposes as a zeitgeber or master clock, holding all entrained in
synchrony.
In the case of nerve-like individuals, the spike discharge is presumably the most
influential part of the signal. If so, then mutual synchrony requires that whether the
spike be nominally excitatory or inhibitory, each cell should advance (or delay)
slightly if it encounters the aggregate spike slightly before (or after) its own was
scheduled to occur. 1deally the advance or delay would be exactlyequal to the phase
discrepancy. Taking the output spike to mark phase fjJ == 0, the ideal response would
consist simply of resetting the phase to 0, ie., fjJ'(fjJ) == 0 independent of <p. This is the
extreme form of Type 0 resetting. However all that is really required is that -1 <
dfjJ'/dfjJ< 1 near fjJ = O. This supposes re setting independent of the size of the input
spike, and entrainment near the native period, such as observed, for example, in the
cases of rhythmically flashing fireflies (Figure 18 of Chapter 4; Hanson et al., 1971;
Buck and Buck, 1976; Hanson, 1978) and of chorusing crickets and cicadas, phase-
shifted by hearing their own collective chirp (Walker, 1969; Figure 16 of Chapter 4).
If fjJ' =1= fjJ at fjJ = 0, then each time a population fires, it advances or delays itself. If
IdfjJ'/dfjJl exceeds 1 near fjJ = 0 (as in Winfree, 1977, Figure 1A, for example), then
entrainment is unstable (Perkel et al., 1964). Thus such patterns of response would
bring about interesting consequences, such as a general speeding up or slowing
down, or fragmentation of the population into two or more subgroups (see Buck
and Buck, 1968, on alternation synchrony in chorusing grasshoppers), or even
active resistance to mutual synchronization such as we saw in context of simple
docks in Chapter 4, Section B.
Mutual synchronization is especially important among the cells of the sinoatrial
pacemaker node of any mammal's heart (Jongsma et al., 1975; Clay and DeHaan
1979), and among all the cells of certain less differentiated hearts, e.g., in the hagfish
(Jensen, 1966). The process of mutual synchronization is directly observable in a
culture dish of individual pacemaker cells taken from the enzymatically dissociated
heart of a four-day-old chick embryo (Figure 3). The cells visibly beat as they creep
about undeIWater. They encounter one another, form electrical gap junctions, and
begin to beat synchronously (DeHaan and Sachs, 1972). Eventually large clusters of
electrically joined cells are seen to twitch rhythmically as waves of contraction
sweep repeatedly from a leading center. It was my good fortune to work under
Robert DeHaan's direction in summer 1966 while trying to measure the phase
resetting of a pacemaker cell in response to injected current pulses. I wasn't
successful, but Stephen Scott was (1979 dissertation),
 B: MUTUAL SYNCHRONIZATION 423

Figur. 3. Single cells of dissociated chick heart creeping across the floor of a tissue culture dish
in summer 1966. The rounder brighter cells are about to divide. The field of view is ~O.1 mm in
diameter.
424 14: ELECTRICAL RHYrHMICITY AND ExClTABILITY IN CELL MEMBRANES

6.0

2.1
206/
#
1.9 .;§J r:a
1.1 #'
1.5 ~"
1.3 /
1.0
o PHASE •1

Figura 3.1:;. One unit ce h;) t e tlme:try~a ac j ven u"ar ce aggre9,ate,. pe"rj:uJ
with a depolarizing current pulse of 50 msec duration. a.t'CU(l"~l)t Jevel indicated in nA on eaen
resetting curve, lne zero of .phase when t/ie stimulus was gfve,n) and of time (of the nel(f
action -potential after th"e prestimulus action potential) is the action p0teptial peak. Notice the
smooth heficoidaJ ,amp and!he elongated phase singularity'at its core. (Adapfed rrornJ. qen.
Phy,Siol. 8~f 613; van Meerwijk et aL (1984) a~ irr Winfree. 19&7a fig!Jre ~. 1 O. by copyright
Rermilision of The R kefeiJe Ul\!yersitY, Press. ~ ~.__...

.' M~anwhile G)Jevara was using on y trypsinize ventr.lcu ar cel s. e o6tajn~a simi ;;Ir
results, except that the transitien ..was made throtlgh plaihty discp tinuous resetti("lg
curves (similarto Scott's exp'erience}ovet'abou"t &wafold range-ofstimulu$ siz;e. One of
the .printipal iess-ons leam~d from these, e~ertmen~ 'i:;oric ms the @1ystery pt.lzzfed
over on pages 77, 116-1.7 1 19~ 4~ 15 .that the p!1,qse resettins eiec"t!:0physioIQgical bf
pacemakers aod chemicat oscilJators' commol:1ly~hows a hear-disconti lIity that is not
associat"ed with~hea~on potenti~1. GuevEra (1984) ancfGuevara et al. (1986; 'shown
~so in GlassandMadey, 1~88 Figare 6. tnused 1'00-.1501-' isopotel'ltial aggregates of
embryonic-9hlck ventri~uJar ~I{s to d~monstrate that t Is can be ~ real di~GontinuitY(
not just a steep -s~o~_e requirili(S finer (eso~ution of stimul~s. timin"g. "A _depotarizin
stimulys appli~d 1"42 msec after the' act!on potential .either; evokes n~ actiC!l~.·potential
and sligntlydelaysthe; subseguent rhythm, or elseevokes 0rle-and slightly-ac:tYanses the
rhythm. No ihtermediate restdts eve(occurred. ihe sama-stimulus 1 msec e~rfierOfla~el'
in{h)~6 tS-nisec pacetnake thythm cO("lsistently produces ei~erthe frrst orthe second,
discretefy ditferentr rest:Jlt. This seems understandabfe terms ofan -att~acting .~c1ein
around tHree steady stcites (Figura- 3.2a), tWo reRellihg an~d a . ~aädle.. j:>0int betWeen
tfiertl"{Winfree, 1979; E:lay et a1., 984; Glass qr:ld'Winfreei 1984, GtJß;vara et a1., 1-986;
MacKay, 1991). In _such models; ~ke ones in ..which: the single ste~dy ~te jn'stead
atfraru and is suri6unde.c! bya repelflng limit aycle" nsiae thEf a~racl~ng limit cycle,ßJ ,
plJase singularity has codimen~io[l 1, ot .cOdimension 2)FigL\re 3:2b). Tliere seems
good reason 'to entertain such odels for a var ety oftelectroRhysiofogical osefllators.ln
such cases the phasel~ss set. is a separatri~ trajecto conneCting the .two epellors
through the saddle. TYRe 1 resetting follows a- srnall stimulus, lmä ij"ype r'.esetting cr
follollfs a-big one, as i~ famjliar fOfldynamicswlth a single repe.lling s'teady state irlside
tOe attractih OIe, but ,as in severalless carefl1l1 &tudied cases. (\Ninfree-, .1982d tbe-
 B: MUTUAL SYNCHRONIZATION 425

A B 0 .1

FIgur. -n AIr attfatting Imlt" Cfc e can contain a pnaseless. set a mo e resembles ,3 Ine
th~n ~ poIOt. This happens If the r.epelling, s.teady stl!te inside
it bifvrcates into a~triplet of
steady states,.as though toe orlgi\1a pointwer~ split'and its two halves separated by an a~c of
pnaselessn~S5. Isochrons,meet tnis a(c.~ngentially. at infinite density. Any-path cuttirm this
Me thus eh ounters a Rnilse discontitluity. Frorn 91ass. ai1d Wi free 1984, witb RettnISsion.)

transiti,?n-from ype, 1 t~ ype 0 is not direct. At intermedfate stimutus Sfzes the

resetting curv~ is discQ!"tlnuous !r mid-cycle. This seems to be I:;ecause tne imaQe of.tlie
attracting cycl~,~shifted by such stimuli, intersects an extended, rather than pornt-like,
phaseless set and sq intersects lts pounda!y, the pha$e si.nguli;lrity: either. the
codjm~nsjon-1 boundary of a bl~c oie- 01' the codimension-1. curvy lihe segment
Ii~klng the saddle poiht to the WO repelling ~eady states. ln principle, more than just
two alternative new phase outcomes occur, In fact a ~nti"uum covering al\.possible
phases should occljr, But Best and I found that they ar-e packed into a picosecond t:allge
of oId phase~ unJikely to he sarnpled in just a few nundre9 near-replicate experiments at
:the ostensible discontinu.ity~' And it may weil be that thjs range existS Ol1ly in the
contiFluouS qlfferential equatiori,not in real cells with a finite number of sodium
channels. . • •
In several places througbout this 1999r. update r de1eted reference to Figure 9 of
Jalife and Moe-(1976), which in 1978 was my prize example in cardiac. c~text of the
antlcipated TYf?e.0 resetting. For that perception lt 'was necessary to ove look ci new
phase gap of 0.3 cydes between two data p'oints that are adjacent along the
coarsely sampled old phase axis. Carried away by enthusiasm to reapply to Purkinje
fibers the concepts developed for circadian docks, I' asked 1)0 queStions. Today i~
seems mOfe lil<ety (<Duevara and· Shrfer, 1987) that tliis was an early example of the
frankly discontinuous resetting curves intermediate betwHn Type 1 and Type O. In '
1978 such intermediates had no precede tin theory; Michael Guev<;lra (1984) was
the first to recognize aod interpret thern in laboratory data. · · -
. AhOther correction pertains to the time crystal of Reiner and . Antzelevitch (1985)
for phase r~settlng in an electrophysiological model of. tbe sinoatria~ node,
showcased in VYinfree (1981a). Both for hypetpolarizing and for depolarizing stimuli,
thjs . strongly resembles he first neural time crystal, calculated from the Hodg~in-'
Huxley equations (Best, 1979). except that it ostensibly contains the wanted punctate'
plaase singularity rather than the extended black hole that we· had contrive in
iml>atience to 'be done. Kowever, öuevara and Jong&rna (1990) find th~tine analogy
Was a IIttle too magnetic, qnd that while Reiner's singularities a(I\:ually do ~xrst,. they
lIe outside e range of Stim'
rus stre 9ths used i 1985. ihis olJld av~ ecome
426 14: ELECTRICAL RHYTHMICITY AND EXClTABILITY IN CELL MEMBRANES

There exists a tantalizing prospect that in some cases mutual synchronization

among nerve-like cells might not be based so much on exchange of electric spikes as
on electrotonic influences or chemical interactions among the smooth metabolie
rhythms that time the spikes or slow waves. Watanabe et al. (1967) found that
mutual synchronization among the heart cells of a large shrimp is mediated both by
spikes and by "slow waves" (oscillatory pacemaker potentials), both of which
independently affect the phasing of the slow waves in the cells they reach. Raper
(1979) shows the lobster's stomatogastric ganglion oscillation largely organized by
electrotonic interactions. I do not know whether the slow wave, like the action
potential, originates in the ionic mechanisms of the membrane or has some other
metabolie basis.
 B: MUTUAL SYNCHRONIZATION 427

negative current pulse might see m finally ta ptovide a basis or modeling collective
mutuClI synchronization f gi~en a knowledge of the cells' neighbor connectivities.
Är\ticipating that such data would esemble the like from resetting measurements in
aggregates or intact tl$sue (e.g., those of Sano et a!., 1978, or those of Ypey et al.,
1982a,bl, In J984 I assembled a linked-list nUmerical a!gotithm to do the bookkeeping
of all these resets irr a population of model cells, supposing that 'each ce!! fires a delta
function bumping all others simultaneously by some srtlall increment tpward theirfiring
threshold. The numerical results Were more complicated ~han expected, presum bly
d eta unrealistic assumptions made. One is betrayed by the following paradox. I bad
seen in DeHaan's lab that the collective pace is not set by the s~ontaneously fastest c~W
as i'equired in syntalansis mediated by impulses-:-f<;>r example, see the .analysis of
impulse coupling by Mi 0110 anc:f Strogatz (1990a). This is why my analysis.of sinoatrial
pacemaker mutual synchronization (Winfree, 1967a) does not feature iF'0pu~se phas
resetting, but rather an integral of continlfousinfluence anc:f sensiti'lity over the wnole
cycle. DeHaan and S<;lchs (1972), Sano et aJ ..(1978), Ypey etal. (1982a,b), de Bruln et a!.
.(1983), Jangsma et a\. (1983), and 'Steenstra and DeHaan (1986) argued witH increasing
certainty that the probiem' lies in the "c1assical pacemaker hypothesis" tflat calls
interact only unidil'ectionally by impulses that phase-reseuhe- recipient. Rather, cells so
c10sely coup[ed in'teract reciprocally through prolongei:f exchanges of currel)t'~uring
the entire cycle, which not only accererate slow ooes but"al54 ietard fast ones (ar
additionally accelerate' or refard all to a pac~ outsld.. the range cf indivk~uals,
dependln.g on the-area ofthejAfluence~sensitiVity loop inWinfree, 1967al. T)1is seems
to. happen in cultures~ of coupled rat heart celts, as shoWIT in.f.:igure, 1 (put not Figure 5)
.0f:JongSma' et al. (1983-). Following a q-dimensional simulatfo(l by 't-'pey et al. (1982a)
with neighbor coupfihg.only by ii'npulses, Micnaels et al. (1987, 1990) ;;imulated such
"demoGratie'! mutual synchronization qmong a few. tnOl.\5and cells wlth divers_e native
~eriods; un,iformly coupled to -immediate neighbors.. by botft .tonic and phas.i c
':elec;trotonic currents. !hey were able to mimic much of the known spatiotemporal
bebavlor 0 the sinus n:ode (Jalife and Mic aels, 1989). For example, With ihtercelTular
coupling attehuated, synchronization fatled. With- coupling "closer to normat
netgnborhoods sYrlchronized I'>arochially. And a~ lEweis tl:lought represeQtative of the
normal node, tsynchrohization be.Game grobal, with a radial 'Phase gradie'n t such as is
. normaJly observed. Calculattons of this kind have since been elaborated to inClude
m1!lions:af cells~ spatially pattemed connectivity, and the latest detarled ionicmodels on
membrane dynamics (Winslow et aL, 1993). .
, On a mucn shorter time scale, ple~ty of componentS of the.cer.ltralnervous system
are; inherently osGillatory,(Llinas, j 988). Aggregates of such cells in some cases normally
entrain one another, as in the mamma ian inferior olive (Llinas and Yarom, 1985), the
parahippocanwalsource of the rat's theta my:thm (Skaggs f 1995), the electric organ of
certain fish (Dye -and Heiligenberg, 1987; Wessell, 1995; Moortgat et al.•. 1998,
2000a,b) .and 'the olfactory bulb of certa~n invertebrates (Gelperin, 1994; Kleinferd e
a", 1994). A popular theory assodates·-aw.areness, cognition, and attent~on with 40-Hz.
syochronization between the ir.\volved parts ofthe,brain, howeverfar apartthey may be
(S.Qt:npolinsky etaL, 1990; Uinas C\nd Ribary, 1993; Singer, 1993). Other kinds of mtltuaJ
$ynchrohization are maladaptive, ·as in epileptlc seizures of the hippocampus (Tass,
1992; Jung and Milton, 2000) and Parkinsonian emor (Elble and Koller, 1990; EIÖle et
1. 1992; Tass, 1999)~.•"~,-~",;;",.""",,,,,,,~_~,,,.____-,,;,,;,,,,,,, _ .........___
428 14: ELECTRICAL RHYTHMICITY AND EXClTABILITY IN CELL MEMBRANES

Whatever its mechanism, local synchrony does not necessarily guarantee global
synchrony. One possible outcome of extension in space is propagation of a wave, as
in a row of upright dominos. Buck and Buck (1968) mention waves of synchrony in
swarming fireflies. We have seen this in layers of pulsing Dictyostelium cells
(Chapter 15) and in oscillating chemical reactions (Chapter 13). It is equally familiar
in the olfactory cortex, in chains of heart cell aggregates, and in the intact sinus
node.

C: Waves in One Dimension

Hodgkin and Huxleys' analysis of a quarter-century ago admirably fulfilled their aim
to calculate the squid's traveling action potential and to rationalize its constant
velocity in terms of local permeabilities. A similar wave sweeps across the bulging
surface of a human's fu1l atrium to squeeze the contained blood into the ventricle. A
wave propagating along the Purkinje bundle, arborizing down into the much thicker
muscle of the ventricle, initiates its almost synchronous contraction. But the wave-
like sequencing of cardiac contraction plays little functional role in either the atrium
or ventricle alone. Both in the heart and in the squid's motor neuron, things would
go even better with instantaneous transmission of each impulse within each
compartment.
Wave behavior plays a more essential functional role in vertebrate intestine
where it ushers food along the route from stomach to anus. The intestine is a long
tube enveloped by a lining of smooth muscle. There is a layer of longitudinal smooth
muscle and a layer of smooth muscle of quite different electrophysiological and
chemical properties engirdling the intestine in circular bands. Each of these rings
contracts homogeneously around its circumference like a sphincter. In an isolated
segment of intestine, these contractions are regularly rhythmic. No one knows how
the electrical signals for contraction originate, but they are apparently myogenie in
that they originate in the longitudinal muscle itself, not in the associated nerve cells.
Spontaneous rhythmicity is apparently the rule for smooth muscle in bladder,
ureter, vas deferens, oviduct, uterus, scrotum, penis, and all the veins and arteries,
as weIl as in the gastro-intestinal tract (Golenhofen, 1970).
In the latter case, the native frequency of this rhythm is highest nearest the
stornach (",20/minute) and falls off in a monotone way toward the ileum, where the
native frequency is lowest (",lO/minute). All this is most commonly observed
electrically, by way of chronically implanted electrodes (in dogs and cats). The
visible muscle contraction follows in consequence of the electrical rhythm crossing
a threshold of depolarization that elicits action potentials that in turn evoke the
mechanical response (Holaday et al., 1958).
The word wave enters this story because intestine does not normally come in
disjoint segments, but in one long continuum. Local electrical activity stimulates a
similar response in adjacent muscle membrane, which responds vigorously enough
to conduct a propagating wave. The one-dimensional gradient of native frequency is
apparently responsible for the unidirectional bias of movement in the small
intestine from stomach toward anus, a feature of considerable adaptive importance.
The waves of electrical depolarization are typically several minutes and several
 C: WAVES IN ONE DIMENSION 429

centimeters apart. By stimulating circumferential contraction, they divide the small

intestine into moving beads, each encouraging the conveyance of a bolus of digested
food, as in a peristaltic pump. (However, as in almost everything biologieal, it isn't
really that simple. Superimposed "segmentation" contractions squish food in both
directions. See Davenport, 1977, Chapter 3.)
The smooth unidirectional gradient of native period encourages unidirectional
movement of peristaltic contractions. But it does not guarantee smooth movement
because the frequency gradient covers a range of native frequencies spanning a full
octave. To a first approximation, in any intact segment of intestine, the high-
frequency end serves the functional role of a pacemaker. At any point in that
segment there are as many waves per unit time as there are pacemaker cycles.
Downstream, these periodie disturbances stimulate electrically more lethargie
membranes. At same distance, the local membrane has become too sluggish to
respond as often as waves arrive from the high-frequency pacemaker. So an
occasional wave encounters refractory membrane, is ignored, and gets deleted. This
might be looked upon in two ways:
1. A local oscillator is driven by a high-frequency stimulus. If the frequency
discrepancy is too great, then entrainment is imperfeet and an occasional pulse
is lost, or the slow oscillator simply runs at its own native period, somewhat

~r-----------------------------------------------,
MIl-OI..IXlE~, 18/MIN ~mw«M\
19
l.f'PER JE~NUM, 181MI!! ~

18"'---...... IRST ZONE CF WAXING ANO wt.NING ~

13

I,
10U0D0IUM! ILEUM
r
Figur. 4. Frequency of the basic electrical rhythm of the small intestine of the anesthetized cat.
The stepwise heavy line shows the observed frequency, 18 per min in the duodenum and upper
jejunum and descending to 12.5 per min in the terminal ileum. Segments of the electric record
from which the frequency was measured are shown. The upper slanting dashed line shows 1/
refractory period. The lower slanting dotted line shows the intrinsie frequency displayed by
short, isolated segments of the intestine. If the intestine is transected at the point labeled CUT,
the frequency distal to the cut falls to that of the intrinsic frequency at the point of transection.
[From Davenport, H. W.: Physiology of the Digestive Tract, 4th edition, 1977, Year Book
Medical Publishers, Inc., Chicago. Used by permission. (Adapted from Diamant and Bortoff,
1969. Electric records supplied by A. Bortoff.)] The rates in man are slower by about~.
430 14: ELECTRICAL RHYTHMICI1Y AND ExCITABILl1Y IN CELL MEMBRANES

Box A: A Biochemical "Analog Computer" for Intestinal Peristalsis

It might be amusing to use our model excitable medium ("aqueous solution of

Hodgkin-Huxley equations," Chapter 13) to mock up a length of intestine, or
Arshavsky's nerve (1964). 1 think this is what Diamant, Sarna, Daniel, Brown, and the
others might have done instead of running van der Pol equations in the computer for a
couple dozen discrete segments of intestine, had they access to such an analogous
continuum of excitable and rhythmical material. 1 tried it crudely. By mounting a
copper bar between hot and cold water baths I established a temperature gradient along
its length. Then I laid along the bar a strip of chromatography paper soaked in malonic
acid reagent, so that the warmer end alternates between red and blue more frequently
than the colder end. Each time the warmer end turns blue, that blue wave is added to
the train of waves propagating toward the colder ~nd. Now imagine any intermediate
point and ask, 'What is its oscillation frequency?" Is it the local oscillator frequency
corresponding to the temperature at that position? No, it turns blue more often than
that, to be exact, as often as a blue wave arrives from the hot end. As far as electrode
recording goes, you'd say it adopts the frequency of the hot end, as does every upstream
point that those waves passed.
But what becomes of these waves as they propagate into naturally slower regions?
Eventually they must get to a place where the reagent cannot respond as often as waves
arrive: Its refractory period is too long. So a wave gets deleted. From there on,
"frequency" is lower, and remains the same at every station along the chromatography
strip up to a point where a next wave is deleted. Now I can't say that this process
unfolded itself before my wondering eyes with perfect c1arity in that one first emde
attempt, but something like this was happening, rather like the plateaus of synchrony in
gut (see Figure 4). There is a region of so many waves per minute, a disorganized
transitional region, a region of fewer waves per minute, another disorganized
transitional region, and so on. And all these plateaus are rather labile, their boundaries
shifting back and forth as wave spacing varies, resulting in critical spacing and deletion

PLATEAU{ \

~{,

I-T'WARM

TIME -

A strip of oscillating medium, seen at time zero on left end of box, conducts horizontal waves
vertically from warmer end (below) toward cooler end (above). Waves are shown at front edge
of strip as time increases to right. Shorter period waves from below must be deleted as they
ascend into longer period regions. Deletion levels (dashed) mark boundaries of frequency
plateaus in Figure 4.
 C: WAVES IN ONE DIMENSION 431

of waves at different points along the full length. These phenomena pose intriguing
mathematical problems .

.. f:\ start was maae in EJTl)entrout and Kopen (1984) and Ermentrout ano Troy
(1986) using raqial-isocrron docks linked by diffusion. Something of the sort
also oecufS in ,plasmodia of the acellular slime mold attemptfng sYl1chronous
nudear divisj.on on a temeerature gradient (Hejnowicz and Wohlfarth-
Bottermann, ~ 980) and in .cylindrical chemical reactors (Tam et al. • . 1989).•
Nothing IIke a thorough understaodir'l9 has yet been ass~mbled r as far as ,
know in 1999. . "
It wilt be important to finisn. because simnar phenomena are common in the
heart. wtlere adjacent domains abut discretely, tbe abruRt change of intrinsic
refractoriness serves as a toll--gate deleting m out of n impulses arrivil"lg at
sufficiently shprt interYals. Th~s "Wenckebach block" is familiar at the edge of
the atrioventricular node, for example (Glass and Mackey. 1989): If the short
'ntervals are provided by a rotor in a 'two- or three-dimensional myocardium
ith electrical characteristics gently graded on ascale of centimeters. one may'
expect to, see boundarfes "!ithln tlte tIssue at Which the average frequency
cltanges abruptly by -s4cb interrnittent pulse deletion. Frank W~tkowski -and I
filmed such zone boundarjes withJn: a 5-cm square of dog epic*dium ·during
, tr"transition.to fibrillation, qriven, .as--we bel[eved, by vorte filaments hldden
insiae the eart wall (Win.free 'and WitKowski, 1998). We guess thafmuch of the
bste{lsible complicatedness of fibriflation may boil down to ' moving vortex
filaments (Winfree, 1994a,c) acting upon such smooth gradie.nts of intr[ns[c
parameters to create- blockS of uscle that respol'lctto it at rat,iorral fractions of
the .drive fre ~. _ _. . .,......._ _"--

What the analogy to excitable media suggests, then, is simply that a slightly
different emphasis is possible in which the crltical parameters would be not local
oscillator frequency but rather local refractory perlod. It seems to me likely that the
local capacity to oscillate is not very important in intestinal smooth muscle, except at
the most anterior end. (And perhaps elsewhere to provide a local ''backup'' pacemaker
in case waves from the anterior end should be somehow blocked, e.g., by ulceration or
by surgery.) Local rhythmicity might be important if local excitation were not so
grossly anticipated by an arriving wave; but if it is, then it hardly matters whether the
local membrane would have recycled spontaneously somewhat later or would have
lingered at resting potential until excited. In either case what matters is not native
frequency, but reciprocal refractory period. Spocht and Bortoff (1972) and Sama and
Daniel (1974) did emphasize refractory period. This change of emphasis has proven
critical for a number of phenomena (for example the rotor) in excitable films of
malonic acid reagent and of slime mold cells. One way to find out whether it is
important in smooth muscle might be to inhibit spontaneity of firing without greatly
altering the refractory period, perhaps pharmacologically ras was done chemically in
the malonic acid reagent (Winfree, 1972c)]. A direct measurement of refractory period
along the intestine should allow explicit prediction of the positions of plateau
boundaries and of the step-down in frequency from one plateau to the next by
deletion of waves rather than by mutual synchronization of local oscillators. For a
theoretical treatment of wave propagation along a gradient of refractoriness, see
Krinsky and Kholopov (1967).
432 14: ELECTRICAL RHYTHMICITY AND ExClTABILITY IN CELL MEMBRANES

perturbed by impinging electrical disturbanees. But strict entrainment is

maintained within the segment up to that critical frequency. This segment
might be looked upon as a population achieving mutual entrainment through
electrical interactions. Only a certain range of frequencies can thus cohere, so
the intestine breaks up into aseries of domains, each operating at its own
frequency. Figure 4 shows some of these frequency plateaus and the temporally
disorganized transition zones between them. Models of this situation have been
contrived and studied in relation to real intestine. These models are basically
anterior-to-posterior chains of van der Poloscillators, each coupled electrically
to its posterior (Diamant et al., 1970) and anterior (Sama et al., 1971) neighbors.
The most advanced modeling of this sort that 1 know of (in 1978) is in Brown et
al. (1975) and in Patton and Linkens (1978).
2. An excitable membrane is refractory for some time following each response to
an adequate stimulus. During this time, a bigger stimulus is required to elicit
another response, and the response may even then be only half-hearted. So if a
second wave arrives during the refractory interval, it falls to stimulate and is
blocked at that point as surely as though a gate had been lowered. Arshavsky et
al. (1964) contrived an analogous situation in a long nerve from an earthworm
by laying it on a temperature gradient. Waves initiated electrical1y at the hot end
get only so far before occasional deletions are inevitable. The surviving waves
readjust their spacing and proceed into cooler and still more slowly responding
and recovering medium, until another drops out (and so on).

1 suspect that the differences between these two approaches are in part semantic
differences and that a quantitative, rather than a verbal, biophysical model may
behave much the same under either description. However, the differences of
concept can be exposed by changing the model's parameters. 1 think so because
that's how it is in the malonic acid reagent (Chapter 13), in which the analogous
situation can be set up (see Box A) and in which models similar to those of
electrophysiology have proven useful (Rössler Hoffmann, 1972; Winfree, 1973c,
1974b,e Troy, 1977b, 1978). But a systematic study of such dynamical systems has
not yet appeared in the literature (in 1978 and 1 think still in 1999). It might be a
useful exercise.

D: Rotating Waves in Two Dimensions

The wall of the intestine is treated as a one-dimensional continuum because our

interest in it in this chapter is limited to a single layer of muscle (eliminating the
depth dimension) that acts much more nearlysynehronously around each
circumference than along its length. But if we follow the intestine anteriorly, we
discover that it abruptly flows out into a much more symmetrie bag cal1ed the
stomaeh. The smooth muscle lining of the stornach behaves much as does the
intestinal smooth muscle. The lower half of it is spontaneously rhythmie in a way
that suggests to Sama, Daniel, and Kingma (1971, 1972a,b) and Sarna and Daniel
(1973, 1974) and Kingma and Min (1975) a two-dimensional continuum or network
of electrophysiological oscillators beating several times per minute.
 D: ROTATING WAVES IN Two DIMENSIONS 433

The local coherence and larger scale wave-like organization of the stornach
activity keeps food properly churned up and eventually forces it toward the upper
bowel via the pylorus. As in the intestine, there are marked gradients of native
rrequency, the most anterior muscle having the highest rrequency. Surgical excision
of ulcerated or cancerous parts of this gradient can result in peculiar alterations of
wave behavior, by juxtaposing regions of dissimilar native rrequency. Diamant et al.
(1973) remark that the postoperative side effects of operations for peptic ulcer often
include diarrhea and anomalies of stornach movement that are usually attributed to
damaging the vagus nerve, but might really reflect altered coupling in a sheet of
distributed pacemakers. Specht and Bortoff (1972) and Sama and Daniel (1973)
explored this problem somewhat, both with dogs and with networks of van der Pol
oscillators. They believe electronic gastrointestinal pacemakers may have medical
uses comparable to the now-conventional cardiac pacemaker (see Sama and
Bowes, 1976).
Apart rrom derangements of the normal gradient, are there new geometrie
possibilities for wave conduction in the more expansive context of stornach wall?
Reshodko (1973) obtained rotating spiral waves in models of smooth-muscle sheets
implemented in a digital computer. The data of Sama et al. indicate that real
stornach is characterized by steep gradients of excitability and of native rrequency in
the spontaneously rhythmic region. I find it hard to imagine stable rotation of a
wave in such a situation, but the question remains to be studied empirically. The
situation is quite different in the excitable tissue of the heart and of the brain. In
both cases, the theoretically predicted possibility of perniciously rotating vortex-like
excitation was demonstrated experimentally during the 1970s.

.... Anä Lammers(1 if97) exper~rne 'tal y nswere ttje question tRat had for a ae.cade
.ev*e no ihterestamong'elettn?physiolog'SU! of s~ooth. muscle: he found rotors in
the myometriu{O ofthe_ pr~9Pant ute(uS' (F.igt1re 4.1). I had pror:noted watchft.tlheSS for a
rotation period ne~rtsec( r~asonesi as follows. The myometrium's passive linear spac~
.constant is ~ cm,aF;ld ,tIme constaht f:::4 ~ec; so its D migbt be ';::;:dö cm 2/sec.
propagation speed ~3 Cm/sec then-argues' for excitation nsetime 'f:::D/speed 2 ~
sec. Given Q> 611" and possibly ~10(},:the rotor perjod, ~O'risetlme, would be >0.104
sec, possibly. ~0.555 sec ... with, perimeter accordingJy ;::;0.31 to 1.66 cm. Flgure 4.1 '
i
shows about asec, fitting comfortqbly in a cm spac;e, comparable the rotors found in
he: rt muscle. Lclr:nmers calls these rotQrs_.~'a rare but;J1onnal phenornenon." .~ .

Rotors in Hearts
.. leave this section little altered in 1999. Chapter 11 has oeen guttea to mal<e 'room
01' a thorou h u. date entirely conce~ved from the erspective ·of 19.'19-...

We first examine the heart muscle, in which the demonstration is clearest. For
almost a hundred years it has been unoriginal to speculate that some forms of high-
frequency irregularity of heartbeat (e.g., atrial flutter) might represent the effect of
one or more circulating waves. Details of this hypothesis have varied and the most
ingenious evidences have been brought to bear, but the following papers comprise
the main contributions I have found to this story.
434 14: ELECTRICAL RHYTHMICITY AND EXClTABILITY IN CELL MEMBRANES

536 • 850 msec

••• 1,.;; • ..;;....;.....;....;...~

• ....;.,.

The basic idea is that an excitable medium that can fire rhythmically forever
should also be able to conduct a circulating wave, if the medium is made into a
ring and asymmetrically stimulated. This was shown in jellyfish (Mayer, 1908,
1914; Kinosita, 1937), in strips of heart muscle (Mines, 1913, 1914; Garrey, 1914),
and in earthworm nerve (Arshavsky et al., 1965). In fact, Pastelin et al. (1978)
showed that one mode of flutter is essentially one-dimensional in this sense: It
originates in pulses circulating along three loops of specialized conduction
bundles.
The equivalent experiment in a two-dimensional sheet of excitable medium
would be to punch out a hole or to inactivate a disk whose periphery may then
serve as the required ring. According to the simplest models, this would only work
if the circumference of the ring or central obstacle were adequate to
accommodate the shortest periodie wave that the material will support; or
otherwise put, if it is long enough so that the circulation time of a pulse will
exceed the material's absolute refractory period. The hole might even be the aorta
 D: ROTATING WAVES IN Two DIMENSIONS 435

or superior vena cava in a large vertebrate's heart, such as man's. Stibitz and
Rytand (1968) attempted to demonstrate such an excitation whirling around inlet
and outlet ducts of dog heart and of human heart, using the published data of
several research groups.
Balakhovsky (1965) and Krinsky (1966) argued that a hole mightnot even be
necessary. Farley and Clark (1961), Buerle (1962), Farley (1964), and Moe,
Rheinboldt, and Abildskov (1964) had observed such rotors in computer
simulations of nerve-like excitable media without holes. See Box B. In 1965,
Gerisch published a photograph of a rotating wave of excitation in an ostensibly
uniform field of Dictyostelium cells (see Chapter 15). Rosenshtraukh et al. (1970,
1989) demonstrated such a wave using the atrium (alias auricle) of a frog's heart
stretched out on a frame in Ringer's solution. Gulko and Petrov (1972) and
Shcherbunov et al. (1973) computed rotors in perfectly homogeneous tissue using
heart-like versions of the Hodgkin-Huxley equation. In 1970 in Chicago and in
Puschino, Zhabotinsky and I found stably rotating waves in a perfectly uniform
and continuous excitable medium that resembles heart muscle in several
qualitative essentials (see Chapter 13) .

• In 99 'preparations 0 fieaitpacema~er ce ls an ' tne mea~s to ol3serve em are both

suöstantialry more sophisticated than when~ as a graduate stlldent, I snapped Figura 3.
My aimat that time Was to determine pnase re setting curves (nke\y aone-by others in the
~terim, as-noted above) and tore late thern to tbe observed distribution ofnative penoa
not yet done toda1{) and to·an observed cduplin"g~level tbreshold or aen$ity threshold for
,mutual synchro"i~lon (which aim remains frustrated by the parochIal m~nner 0 i
inte~cel[u~r-coupling In Petfidishes). Twenty-three years late(some Qfthese hopes had
faded, but pthers replaced' them: maybe such preparations couLd check the idea that
uniform sheets of excitable cardiac cells (in contfastto the comple>< ar.chitecture ofthe
left atrium, where something like rotors had first been demonstrated b!Jt with aJ,

sfgnWicantty different interpretation) wou d support stqble rotors at periods and sizes
comRatible with prefibrillatory dysrhythmias in rabbit hearts (WinfrEte, 19<?0). Guevara
ncl Jongsma {1990 p. 743}'discussed tfiis suggestroo and its possible irnplementation
amt r~leyance, but much as in Dictyoste/ium, no report of deliberate rotor induction in
c;el1 cuhüre has yet appeared, nor have the .excitability and the intercellular
connectedness of such preparations' been quantified. Are they analogol)s to normal
tissue? Arf3 th-ey even elecfrlcal continua; as presupposed in comparisons with partia
Ifferential equations? .
Bub et al. (l998) first demonstrated spontaneous rotors (or phase waves around ,a
slngul<'lYlty?) in such two~jrTlensional cultures. The properties of individual ceJls and the
resistiVity and abundance pfgap junctions connecting them alt remain to be determined
~n that l>repaJation (see pra,gress in Gonzalez et ,at., '1999), Jongsma et al, (1983) showeed
that such preparatlons of rat heart cells exhibit mpre aod more f'~ular beating as they
conneGt ogeth.er. but since thrs happens over a span of days and individual ' cel1
pfoperties tnight ~Iso change while. COMectiorts are forming, it seems hard to relate
resuJts .to an art cular aoatyJcal , ma~d;;.;e_I......~_,,-,-
.. __

In sufficiently inhomogeneous media a more aggravated condition arises in

which no macroscopic periodism has been detected. This "fibrillation," as it is
436 14: ELECTRICAL RHYrHMICIIY AND ExCITABILlIY IN CELL MEMBRANES

Box B: The Iron Wire Model

William Ostwald (1900) was first to notice that iron wire in nitric acid exhibits an
electrochemical surtace phenomenon quite similar to the action potential in nerve. It was
vigorously investigated with this in mind for decades (Suzuki, 1976; MacGregor and
Lewis, 1977 for reviews). A two dimensional surlace (a ten-inch iran sphere) behaves in
many ways like a human heart, even "fibrillating" when made too excitable or stimulated
too frequently (Smith and Guyton, 1961). A grid work of iron wires also supports waves.
The first publication of this experimental system (Suzuki et al., 1963) exhibited both
circular waves radiating from a point source of excitation and spiral waves rotating
loosely about one endpoint of the wavefront (Figure a). Unfortunately for many in the
West, this remarkable and thorough study was published only in Japanese in aseries of
papers that passed almost unnoticed in English-speaking countries.

'~I~lIJliJ[Gla
lfJ.~.r510r]' 12
"~5~J~3f)~

Pencil tracings at ~ sec intervals (Ieft to right, then down a row) from 1961 movies of a 30 cm x 30
cm grid of 25 x 25 iron wires in nitric acid. After initial stimulation (prior to the first frame here)
spontaneous activity persists for a while in the form of waves irregularly pivoting about moving
endpoints. (Adapted from Suzuki et al., 1963, Figure 15)

called, was explored by Gordon Moe and collaborators in an exciting series of

experiments and computations emphasizing the role of microheterogeneity of
refractory periods. See Chapter 10, Example 14.
The most conspicuous features of flutter (and of fibrillation) that suggest a
sourceless rotating wave are the facts that
 D: ROTATING WAVES IN Two DIMENSIONS 437

1. High-frequency "tachycardia" has aperiod limited only by the refractory period

and is thus faster than any other pacemaker. This is potentially troublesome
medically because a focus throwing out waves more often than other sources is
able to expand its domain of control with each mutually annihilating collision of
two waves.
A minimum area is needed (West and Landa, 1962), as in the malonic acid
reagent. In Allessie's experiments (see below) this is about 40 mm2 . Flutter is not
stable in smaller hearts and is not observed at all in much smaller hearts. Fibrillation
is never seen in frog heart or house cat atrium. The cat's ventricle is sufficiently bigger
than its atrium to fibrillate transiently, but it still spontaneously recovers. So does dog
atrium. Dog ventricle, however, fibrillates persistently, as does human atrium .

.. ÄS RolJert Mtlrphy, my 10"ttl gra e iology tea,cher endlessly .(efterctted, we must

and just as he foretold t~e ine itabfe cg\;lnteroexarnple has'
nev~r,. say. "never"or l'all,'
9W been. faun&. rhe mouse hear;t js not ooly uniquely small among mamrnals but
also . as \l~ique electrophysiology in 'that t/:Ie familiar: plateau phase of the cardiac
as;tiorl' potential is ab'sent fts , entricular muscle fires more like. .a nerve cell. It-· is.
~cco ~illgJ~ ,capable of sugpoiting rotors atshorter R~.riod and~in a ,smaHer' space.. than
expecte , alJcf seems. capable o . oysrhythmia othelWise indistihguishable fronl the'
fibtiUatlon of rnllch !arger heartS. w~th. familiarly~lö(lg ~ction P4t~rit.ials '(Wftkowski et al.,
199]; Vaidya et al., 1999), . ' • , ~."., . ". • ... '
Ev~n j . tbe.Jl'lore "conventionar' l1'lyocardfum öf guitlea plgs, rab~its, dogst pigs,
~,peep and humans t notions of r6tor.core·area,have widely div_e~ifjed frolT) ~he original,
rough estimate as th area cireumscribed by p.ropagation during one rotor period'.
fo
':;Area" 'i~ ambiguous in. ·aniso~ropic meqia .. It wquld 00. ~\:)04~: see :x 30 ern/sec;
en:cI:IPlscribfng 1 cm2 in. al'lj~ot opie,medium, or about 2- to 3-fold less (3C1-S0 .mm 2)
consideon,g the eontractiotl ot effeetive distance measures trans'ilerse to fibers; I:.ee-et
~1. (1996a) faund roughly the. an.ticl~atea area in'1he dog ventricl~s '{25-29'7m m.2). ßut ,
measures of rotor or care areä ~re still äivers~fying: th.e area. inside the envelopl? of aU
,perpendiculars to the wavefrol1t In an i,sotropie meqiumi myocardium is nqt), the area '
in which the magnitude of the, cross product of {otal state-"Variable gradlenfs exceeds
so me thresl:Jold~ the area circu'mscrioed, by the movihg Point at which the contour of;
some threshold of flu<;?rescense cr voltage intersects its recent positi?n, etc. ,This last
depends entirely llpon the ehoice Qf threshold setting: by setting it low the area
CI cU,mscribed ean be made cis small as severa mm i or, I suppose, even ~ade to
n
..,anish. Mandapati et al. 998).present this measure in rabbit ventricIes: su~b a core
seem's no bigger than thos.e similarlY'CIssayed in the mouse, though for sur,vi)/al rotors
heed much more room iniabbit tban in mouse. The small area '0 w.hich flGctuations of
the diffUsing variable or of onaof the nondiffusjng variables are less tha~ 10% or 30%
(ete.) ..cf that observed elsewhere is sometimes called "thecenter of the core."
A~ention tO; definitions fs essential ifthe "area" wanted for applicatiohs is s.omething
more I'ke the smallest confined area in whrch periodfc rotation ca ' persistr or haltthe
le~st area that can su P.2,rt a mirror-image pair of n wly created rotqrs. <111

2. Convulsive synchronization restores control to the sinoatrial node of the heart.

I've watched this happen during open heart surgery at Johns Hopkins Hospital.
438 14: ELECTRICAL RHYTHMICITY AND ExCITABILITY IN CELL MEMBRANES

The heart starts flopping more and more irregularly, and less and less
coherently until it is all a jumble. Synchrony is restored with a pair of smooth,
flat electrodes, making the whole heart simultaneously refractory: The next
pacemaker discharge restores coherent contraction. This erasure of the
pathological wave would not work if its source were a little nucleus of irritable
membrane, because the nucleus would still be there after synchronization
destroyed the preexisting wave pattern.
3. Gulko and Petrov obtained a rotating wave in a computer by interrupting an
established wavefront with a temporarily inhibited zone, such as might be
produced by an untimely local stimulus (Figure 5). [The procedure is similar for
the malonic acid reagent's rotor and for the rotating wave of spreading depression
(see below). All three were independently discovered in formally similar excitable
media within a span of one or two years. As far as I know, no one has yet reported
attempts to deliberately induce a rotor in Dictyostelium.]

D E F

[]LJ~
l1$ _ 300_ 1liX)f1/JIC

Figura 5. Computer simulation of an action potential wave in nerve membrane. Its progress to
the southeast is obstructed by cross-hatched barrier (artificially held at resting potential), which
is later removed. The wavefront pq continues to revolve about the middle of the square. (From
Gulko and Petrov, 1972, Figure 5).

All these observations set the stage and enhanced anticipation for the
experiment of Allessie et al. (1973). They used a sheet of rabbit atrium, once again
without an anatomical obstacle, stretched on a frame perfused with an oxygen rich
solution at 37°C. To initiate tachycardia, they stimulated electrically at onepoint at
regular intervals of time. Every so often, they also stimulated just behind that wave
and then waited to see if spontaneous high-frequency excitation persisted in the
absence of further stimulation. Sometimes it did (Figure 6). The effect is not
 D: ROTATING WAVES IN Two DIMENSIONS 439

consistent nor is the mechanism of action very clear. The procedure originated from
two observations:
1. Wiener and Rosenblueth's (1946) original theoretical study of wave conduc-
tion in heart muscle argued (incorrectly: see Selfridge, 1948 and Abakumov et
al., 1970 and Durston, 1973) that it should be possible to initiate a rotor in this
way. The corrected version of that argument requires an anatomical obstacle
or inhomogeneity to wipe out one of a pair of symmetrie waves thus initiated.
Allessie et al. believe that they are taking advantage of such inhomogeneities
in the refractory zone just behind the wave initiated by the first of their two
pulses.

2. According to Katz and Pick (1962), periods of tachycardia or fibrillation in man

almost without exception are preceded by apremature beat.
In any case, once tachycardia started, Allessie et al. used an array of 10
electrodes, moving the array to as many as 30 different positions during aperiod of
persistently sustained activity in the rabbit's atrium. From those hundreds of
recordings, they were able to build up a composite two-dimensional pieture of the
rotor. For example, Allessie et al. (Figure 6) show how the time of pulse arrivallags
progressively along the perimeter of a circle of 10 electrodes around the putative
pivot. The winding number of phase of this periodie excitation is thus W = ± 1
around the ring, and so the ring must contain aphase singularity. In their Figure 5
the wavefront is shown in 17 successive positions as it pivots around this singularity.
Allessie et al. are careful to point out that this demonstration does not yet prove that
such rotors occur in living animals, nor that they are the only mechanism of flutter
even if they do. But this is the first putative mechanism that has actually been
verified physiologically.
One of its most intriguing features is of course the phase singularity. What can
be going on there, electrophysiologically? This is not even clear in Gulko and
Petrov's computations, which serve up every variable to the experimenter for precise
observation. Their wave does not exactly pivot around a fixed point but seems to
wobble, to meander, as can be seen in Figure 5 by superimposing tracings of the
successive panels. So the central patch of membrane, while not participating in the
regular rhythm expressed everywhere else, is also not electrically stationary. A
similar perplexing wobble occurs in the malonic acid reagent's rotor. Rössler (1978)
440 14: ELECTRICAL RHYTHMICITY AND ExCITABILITY IN CELL MEMBRANES

A
B
C
o
E

H
J

-
K _&--J'--'i

, ,"'-
tbulc beat t
premature beat tachycardla

J ___ ~r--C

H---1---

E
Figur. 6. Initiation of tachycardia bya premature beat. Surface electrograms recorded at 10
sites on the left atrium (A-K). The atrium was driven regularly with abasie interval of 500 msec.
The first arrow indicates the last basic stimulus, applied near A and spreading toward F. The
second arrow indicates the premature stimulus (interval 81 msec). The sketch at the bottom
shows the sites at which the electrograms were recorded; the site of stimulation is represented
by the asterisk. Note that conduction of the premature impulse failed in direction KJHG. This
area was activated from site F in a retrograde fashion. Sites A, B, C, etc., were then reexcited
from site K. This pattern persisted during the ensuing tachycardia. (Adapted from Allessie et al.,
1973, Figure 4, with permission from the American Heart Association, Inc.; see also the
idealization in Figure 24 of Chapter 2.)

and Rössler and Kahlert (1979) believe that it may be an instance of "chemical
turbulence"; in the heart we would have to call it "electrophysiological turbulence."
There is also turbulent activity, not quiescence, at the center of the rotor in rabbit
atrium. The wavefront seems to run through the center irregularly. Given many
such rotors packed elose together we might see only a writhing mass of short-lived
wave-ieles not unlike the turbulence described by Moe et al. (1964) when their
electrophysiological equivalent of a critical Reynolds number was exceeded in
computer simulations of the atrium.
 D: ROTATING WAVES IN Two DIMENSIONS 441

~ AI essie- et al. (1985) con~incingly emonstrated suc'n a s1c\te of ~ffairs in fiEriliating

atrtä, TI)os.e rotors are far from stationary, presumably more on a(:count .ot the peculiar
tnhom geneities of atrial tissue than on accouht of rotor interactiOns .....

Rotors in Brains
We are accustomed to think of neIVe membrane as an electrically excitable medium
along which a sharp impulse can propagate at a steady high velocity. There are also
lower velocity waves of collective firing in brain tissue (Verzeano, 1963; Petsehe and
Stere, 1968; Petsche et al., 1970; Verzeano; 1972). Petsche et al. (1974, Figure 6)
show that these waves can stably rotate at 10 cycles per second around little patches
of rabbit cortex a few millimeters square.
There is still another mode of electrical wave activity in masses of neIVe cells, a
mode that is insensitive to tetrodotoxin, i.e., a mode that does not at all require the
sodium-based electrical action potential. It is induced by applying any of a variety of
mild stimuli to any of a variety of cortical structures of any of a variety of different
animals. In this mode, cells depolarize and leak potassium ions from their
potassium-rich insides, thus further depolarizing themselves and their neighbors,
who therefore also leak potassium and so propagate the condition. A droplet of
potassium chloride solution is thus a reliable stimulus for starting it. After a few
minutes, metabolie potassium pumps restore normal ionic conditions and the cells
return to their usual function. There remains only a ring-shaped frontier of newly
depressed cells that will in turn soon recover. In this way the frontier moves
outward [Tuckwell and Miura (1978)]. This phenomenon, called "spreading
depression," was discovered by Leao during his Ph.O. thesis research during World
War II (Leao, 1944). Leao was studying epileptic seizure by deliberately initiating
the bulk excitation that causes it in the cortex of a rabbit. It turned out that weak
mechanical or electrical stimuli applied to the exposed cortex can also trigger a
depression of activity that Iasts locally for some minutes and spreads as an
expanding ring. In fact, this phenomenon commonly follows epileptic seizures
anyway. Ouring this depression, all neurons are turned off within a 2-mm zone as
the wave goes by. Accordingly, the EEG is Iocally attenuated. The ring's rate of
expansion is determined by the diffusion rate of potassium in the extracellular
medium, the rate of potassium leakage from depolarized neurons, and the rate at
which cells bail themselves out after ceasing to leak potassium. In the presence of
obstacles (e.g., the edge of the tissue, or a knife cut, or a bit of thermally coagulated
tissue), the wave propagates around the obstacle according to Huygens' principle
exactly as in Dictyostelium or the malonic acid reagent (page 283). It can be induced
to Totate around a big enough obstacle by blocking one of the two waves into which
the obstacle splits an oncoming wavefront. The sUIViving half-wave then circulates
for as many as 50 rotations of approximately constant period (Shibata and Bures,
1972,1974). These waves travel about 3 mm per minute, comparable to the cortical
disturbance associated with lacksonian epilepsy. [In this connection it is intriguing
to note that although spreading depression is supposedly a Iocal condition,
propagated by diffusion of potassium ions and maybe neurohormones, Leao found
that when only one hemisphere is stimulated, spreading depression arises also at the
442 14: ELECTRICAL RHYTHMICITY AND EXClTABILITY IN CELL MEMBRANES

mirror-image spot on the other hemisphere (presumably by way of the corpus

callosum.)]
The surface conduction speed of spreading depression is also similar to that of
the scintillating blind spot associated with migraine headache (Lashley: see Bures,
1959, p. 245; Richards, 1971; Martins-Ferreira et al., 1974; Bures et al., 1974;
Lauritzen, 1987, 1994; Lambert and Michalicek, 1994; Sacks, 1999). Gouras (1958)
discovered that spreading depression also occurs in the retina of the eye. In this
case, one does not need electronic machinery to observe it because there is a visible
change of light scattering in the retina itself as the wave goes by. AB in the cortex,
spreading depression can be induced to circulate around an obstacle for six to seven
hours, completing as many as 50 rotations of strikingly uniform period (Martins-
Ferreira et al., 1974).
After Shibata went back to Japan, Reshodko came from Kiev to Bures's
laboratory in Prague to undertake computer simulation of the rotating wave and of
the mechanism of its induction. Basically, his model is similar to Wiener and
Rosenblueth's (1946) and the other two-dimensional excitable media discussed in
this book. As in the latter cases, Reshodko and Bures (1975) found that the central
obstacle is not necessary. A stable spiral wave was found to pivot around a point in a
sheet of several thousand cells (in the computer). This has not yet been observed in
real nerve tissue; however, 1 see no good reason to discount the possibility that it
will be. Allessie et al. (1973, 1976, 1977) found that it is tricky to start a rotor in atrial
muscle unless there is a substantial obstacle. It can be done, but the mechanism
relies on unpredictable inhomogeneities in the excitable medium, such as might not
have been achieved in trials on cortex or retina.

~ fn the case-of heqrt mtlscle tnecnanisms {)t rotor induct10h l1l?reili ~eepil:lg wiffi>tft '
l

uniform,cohtinuitx emphasized throughout this bock have .since- been' e~aQorated'and

tested . in h~althy , myocardium: ,see- Chapter 17. In o~utal prepara~kms' n th:e
laooratory, I 'am 'not avware of mu<;:h more that relates to tr e themes o( this bookt
'apalt from the eXRlicit demonstration of a dispersion. curve for spreading depreS?iom. in
the retil')a (Gorelova and Bures, ' 1983; Brand et al., 1997) "and of rotors in ' retinal
spreading, depression: (Gorel9va and Bures, 1983; Agladze et aL, 1983, Dahlern ahd
Müller, 199~). Largo et al: (1997) present evidelJce that spre~dlng depressio'1
propagates not py extracellular diffusion of ions and neurotransmitters as formerly
suppose?, b,ut raj:her through gap Junctions co~necting , neuron~, Glia
unne <;.ess~ary, :'111 ~ •
 The Aggregation of Slime Mold
Amoebae

The main respect in which the biological picture is more complicated than the
physical one is the way time is involved in it.
C.H. Waddington,
The Strategy of the Genes, 1957

Two kinds of slime mold play central roles in this book. Later on we will meet
the "true" slime mold (Myxomycetes), an acellular jelly remarkable for the
regularity and synchrony of mitosis in its many nudeL Topologically, the true
slirne mold is one single monstrous cello But in the present chapter, our
concern is with the cellular slime molds (Acrasiales), the best studied of which
is Dictyostelium discoideum (Bonner, 1967; Gerisch, 1968). This creature is
more conventional in its cellular structure but is equally astonishing
topologically in that its cells wander independently, like the individual workers
of an ant colony. Like the ant hive, Dictyostelium is a "superorganism," a
genetically homogeneous being composed of autonomous individuals, never-
theless organized altruistically for the collective good. Some think it represents
an early stage in the evolution of multicellular organisms. The life cycle runs as
follows.

A: The Life Cyde of a Social Amoeba

Spores borne on wind and rain arrive at a substrate that encourages their
germination. Following much visible turmoil within the ovoid spore capsule,
a crack appears and a vibrantly active little blob of jelly escapes, leaving
behind the transparent shell. This 10-micrometer-diameter single cell, a
"sodal amoeba" as it is called, wanders about the substrate voradously
consuming bacteria. As they feed, the amoebae divide by fission. Eventually,
the population outruns its food supply. During the next few hours, an
internal transformation takes place by which these formerly independent cells
become more alert and responsive to their neighbors. Depending on
conditions not yet darified in detail (but see theoretical bifurcation diagrams

A. T. Winfree, The Geometry of Biological Time 443

© Springer Science+Business Media New York 2001
444 15: THE AGGREGATION OF SUME MOLD AMOEBAE

in Cohen, 1977 and Goldbeter, 1996 Chapter 7), a cell may become
spontaneously active, whereupon it emits a pulse of cAMP every five
minutes, or it may only emit a pulse of cAMP when triggered by its
neighbors. This principle of pulse relaying was discovered by Shaffer in 1957.
The fact that the substance involved in the pulse is cAMP was discovered by
Konijn et al. (1967). As in other systems of similar biochemical dynamies, a
hairline difference in membrane properties is believed to distinguish these
two modes of behavior: spontaneous activity (as in pacemaker neurons,
spontaneous ovulators, or oscillating malonate reagent) or mere excitability
(as in quiescent neurons, reflex ovulators, or the nonoscillating version of
malonate reagent). This developmental change is believed to be spontaneous,
in large measure. But it is also accelerated by exposure to cAMP, especially
if the cAMP comes in pulses (Gerisch and Hess, 1974). Darmon et al. (1975)
and Gerisch et al. (1975) also showed contact site formation to be
accelerated by cAMP pulsing.
Relaying behavior results in wave conduction if the cells are sufficiently weIl
coupled, Le., if a cell receiving the chemical impulse passes it on, amplified up to a
saturation level. If cells He elose enough together, then the amplified impulse
reaches enough unexcited cells before it is attenuated too much to trigger them.
So they relay it and a wave of cAMP release propagates across the field of cells at
2 to 3 mm per hour. The passage of a cAMP wave is made visible by the slightly
later passage through the field of cells of a geometrically identical wave of altered
refractivity (Alcantara and Monk, 1974). These waves were discovered and filmed
by A. Amdt in 1937. As in heart muscle (Chapter 14) and in malonic acid reagent
(Chapter 13), two kinds of wave occur: concentric rings emitted from a
homogeneous pacemaker, and spiral waves emitted from a quiescent center.
Figure 1 shows a photograph of a spiral wave, first published by Gerisch in 1965.
As in heart muscle and in the malonic acid reagent, these rotating waves resemble
involutes of a circle whose circumference equals the wavelength. See Figure 2; cf.
Figures 2-26, 9-15, and 13-3. The wavelength as weIl as the rotation period are
both shorter than in concentric ring waves. Apart from their sources and their
distinctive shapes, the two kinds of wave (rings and spirals) share the same
mechanism and properties.
Nonetheless, Dictyostelium is not heart muscle and Dictyostelium is not the
malonic acid reagent. There are some differences. For example, Dictyostelium's
cells move around. Shortly after it emits its reflex pulse of cAMP, each cell
elongates and moves about 1 cell diameter in the direction from which it was
triggered. In consequence of the repeated movement toward the source of the
waves, cells accumulate at the center. When enough have gathered, a "tip"
differentiates and secretes cAMP continuously, thus ending the spiral wave. The
ring of nearby excitable cells is triggered to release cAMP as often as it recovers
from the prior release, and the subsequently emitted waves form a nest of
concentric rings (if they hadn't already adopted that configuration around a
pacemaker cell).
To finish the life cycle, cells continue to accumulate until the tip is raised aloft
on a substantial column of cells, which eventually toppIes over. This little bloh of
transparent jelly, called a "grex" or "slug," is motile, perhaps due to the caterpillar-
 A: THE liFE CVCLE OF A SOCIAL AMOEBA 445

like waves of contraction rippling down its length from the tip at about five-
minute intervals. It crawls off toward whatever light and warmth may be nearby,
stops, and rights itself again. Then the tip is shoved aloft by a fountain-like
streaming of cells, in which about one-third of their number sacrifice themselves
to become a hard dead stalk. The remainder turn into spores in a tiny ball atop
this erect column. Eventually, the spore capsule ruptures and the life cycle is
complete.
• foreseen in C apier 9 near Figure 23, rotor observations have now been
extended )nto tHree-dirnehsionaf l)ictyastelicu'n-aggregations, just as in the malonic
acid ·reagent (Chapter 12) and in he art muscle (Chapter 17). An int~guing
geometry puzzle ' arises here. If we' think only of the 'Iskin" cf tbe grex, ,and
anarogize it to -the flat film of cells 'streaming towari:f aspiral source-,during 'the ,
t>rlQr aggregation phase, th~n we r~adrly suppose that jndivldua~ cells continue
mClrching towar'd that sour'Ce, which thus becomes the lei\din tip of the migrating
grex. But two problems are. ~M;~rlooked in this glib brushoff. First, cells in the skin
no longer have a fixed external supS'trate. to crawt on, but rather only more cells,
which are also movlng; Clnd second, the CAMP wave that oriehts the;r motioJ1 'fS
now a three-dimensiol1.al scroU, not a flat spiral, SO ' the wave comes froPl the
intemal long axis: of the grex, not from i1$ tip, 0Qly If the scrolr were twisted
would there be a component of mgtion ./ong the a?<ls, not fust towarq it. Cells
would then step toward the end wn~re rotors tum faster' tO' maintain 'the twist. If
the axis buckled} e.g., by the "sproing" instabilitY (Henze et al., 1990 and Box C
of Chapter 16), thel1 its endpoints wOl.\ld settle perpendicularly on ~ nearby ,pojnts
in the curved surface and the in ervening curved, ar.C of filament would shrink, so
it Is nQt dear te me that this can be a stable arrangement. Fcor recent detailed
models of cell migrafton and its contral by wave propagation from a rotor or
singular filament, see Goldbeter (1996), B(etschneider et ·al. !1997), Vasiev and
WeijEfr (1999), and the new pClragraph accornpanying Flgur~ 23 :Cf Chapter 9.
Reitdorf 'St al. (1997) go fui'ther: to argue that ring-shaped slugs contain a, 'scrolf
ring, and_roore, that its a~i~ may 19c"k- 'in one 0" more integer rotations of phase
tw~st. The ~orrespon~ingly conieal slant .of the actjvation fronts would fhu? compel
cells to mlg te not on] fcrward al n tbe rif,\9 but also tot{llard ,that interior
446 15: THE AGGREGATION OF SUME MOLD AMOEBAE

B: Questions of Continuity

Because the slime mold consists of discrete cells, it is not obvious apriori that
continuum models are appropriate vehicles for understanding iiS wave behavior.
In fact, Cohen and Robertson's (1971a,b) quantitative interpretation of
aggregation waves took a radically different approach. It was based on a
discretized approximation in which each cell is a point in a lattice (betraying
Cohen's alter ego as asolid state physicist), capable of responding to
stimulation after a fixed delay by emitting a discrete pulse of cAMP. Following
this it is completely refractory to stimulation for a fixed interval and then once
again returns to excitability. A medium of such cells might conduct waves not
smoothly but by discrete leaps at fixed intervals of time. Alcantara and Monk
(1974) observe just such leaps of 60 J.Lm every 12 seconds. Also according to this
view, the source of the rotating spiral wave is not aphase singularity but a
discontinuity. The geometrie model of Balakhovsky (1965) makes this dis-
continuity a line of length equal to half the spiral's wavelength, along which
cells at all stages of excitation and refractoriness abut. In this respect
Dictyostelium, as a collection of discrete cells like a nerve network (Chapter
14), may differ qualitatively from continuous excitable media such as the
malonic acid reagent (Chapter 13) and associated partial differential equation
models .
... Questions 0 continuity arise in every iologlca e>-tcitao meaj(J. Cons~
quences of d/scontinufty are expllcitly or implicitly ass~inecl in most cf the
literature to dominate the electrical behavior of heart musde during short-perio8
activations (but see a con-trarian view in Winfree, -1991). Keizer and Smith (1998)
and Dawson et al. (1999) analyzed t!c1e dependence of speed on parameters, with
application to calcium . yvaves of all sorts, many of which are manifestl
discontinuous in the sense that activations of contigvous cells or tntracellwlali
calcium stores hardly ovenap. Much of -such discussion woulcl seem Rertinen-t to
Dictyostelium. __ , .

The chief alternative to this supposition that adjacent cells can differ
discretely in their biochemical states is to suppose that rotors appear only where
a cAMP pulse can circulate around a physical hole in the "continuum" of cells. I
doubt that asound case can be made for this alternative. In many cases, a
distinct doughnut-shaped stream of connected cells clearly supports a circulating
impulse, and its center is empty [e.g., Gerisch, 1961; computer-simulations by
Mackay (1978) at low cell density]. But in other cases, a thick droplet of cells,
many layers deep, plainly supports a rotating wave, pivoting within the pile of
cells (Gerisch, 1971, Figure 9). Neither the original photos of Gerisch (e.g., Figure
1) nor a more recent one published editorially in Nature (12 June 1975, p. 522)
shows a hole in the field of cells near the spiral'score. Moreover the spiral waves
 B: QUESTIONS OF CONTINUITY 447

seen in early aggregation fields all have nearly the same period and wavelength.
That would seem to impose upon the hole model the awkward ad hoc
assumption that every hole must have the same circumference viz., the observed
common wavelength. Although waves can also be made to circulate around the
edge of a hole, and the source of the spiral wave can sometimes be a pulse
circulating around the hole's perimeter (Clark and Steck, 1979), my inference is
that this is not a necessary or even typical mechanism.

Whether or not biochemical continuity is commonly maintained in two-

dimensions in the film of eeIls, their discreteness and motility no doubt do make
Dictyostelium's eonnectivity at least precarious in some situations. As the pictures of
Gerisch (1961) and the simulations of MaeKay (1978) both show, eells are further
apart in some regions than in others. A sufficiently low-density region may serve
functiotudly as a hole. These inhomogeneities presumably have mueh to do with the
early appearanee of rotors and the spiral waves they emit. Rotor pairs never anse
spontaneously during wave propagation in the malonie acid reagent beeause the
chemical solution remains almost perfeetly homogeneous until a suitable Iocal
irregulanty is deliberately introduced. 1 But in a eertain Dictyostelium mutant (aggr
52) that makes no pacemaker ceIls, rotors anse in abundance (Gerisch, 1971). The
same oecurs in mutant 91A of Durston (1974a,b). The eause may be that loeal density
fluctuations ensure that the functional equivalent of holes continually appear and
vanish again. The Russian literature of excitable media is replete with mathematical
analyses of such inhomogeneous media (e.g., Krinsky, 1973, 1978). These papers are
directed toward fibrillation in eardiae muscle, but the formal results might as weIl
describe Dictyostelium. The prediction for both media is that waves of minimum
supportable period should anse and multiply. In the normal case, this would go on
only until eaeh differentiates into a pulsing "tip." However, Gerisch's mutants do not
form tips, so they support rotating waves for a very long time.
448 15: THE AGGREGATION OF SUME MOlD AMOEBAE

have -reachea -a rratufe -tage, wa"v~s are eras cf

y -a spray CAM~; ereaftet,
waves arise spontaf')eously onlY if1 concentric rings, jost as in the malonic aGid
reagent for any other COr1\Ir1UOUS: e~cjt~ble meäiuQ'I I?:unctuated. only by isola~d
pGlcemakers. Th~ reason is presumably that now cell _deosities at various stages cf
maturation are stayi,!1 liniforrn. ~ ., . i '

Gerisch (1971, Figure 9) has also seen tiny blobs of cells possessed by rotors
with two or more arms. Such multiarmed rotors seem to be unstable in
continuous uniform excitable media; this may be a difference between continuous
and discrete media.
 C: CELL CHEMISTRY AND CELL-CELL COUPLING 449

att;ifactua reS! ue 0 ß nole. 111 1982 t e oie was inexcitaole, ci ake -of chloride
pOjsoning, in 1992 jnexcitable dtJe ~to b~omfde 'p,oisol'li'hg fr91ll, the photolytic effect
of an argon ~aser, and in . ne 1-997 FitzHugn--Nagumo model it was exdtaple but
fronts avoided it due, to propagation failure induced by even a tittle front curvature
in a marginally excitable medIum None demoJ'lst(ated. a fusi9n of on,e-armed rotors
into a stable unlt with characteristically different period or a capacity for meander,
which I thinkshoald be the cntetion for recognizing a 1unctional unit. with dynamics
lik~ familiar. rotors but with ml,lltiple arms. 'Do any mwltiarmed rotors meander as a
unit? By 1999 I have seer.;!, only OAe situation ;n which .a niultiarmed rotor (that is
oistlnguishable forn .a chance a9g egation. of.- one-atm~d rotors) remains stable in
the absence of some cenUql jnhomogeneity Or an extreme -cOl1ditiol'\ of marginal
excitability: Fohlmeister et ~I. (,1995) and Kistler et al. (19YS) report preference for
three--armed otors in thelr discrete-cell computatlonal model -of cerebral cortex.
Ob ervatio . of real cör:tex at the required ;resolution in time and space is not yet
p·ossib e, but should sOOh l5e, using camera arrangemel1ts, similac to those of
Witkowski -et al, (1998 . .. ,' _ •
' . ,
' The. ostensible two-, tliree-, and fiye-arnied spiral waV9S in Dictyostelium thus
rerTjaih mysteriQj.ls, unless, as slJ9-gested Ir;) Vasie et al. (1997), they oi:ise only
when the medil{m IS onr .marginatly abte . to support rotation at alt, an<;1 then only"
sUQ orts rotation of sll htty ~urvea ' ro 15 circulating around a big excitable disko ...

C: Cell Chemistry and Cell-Cell Coupling

In regard to the single cell's biochemical dynamics, it seems worthwhile to mention
two special features of Dictyostelium's spatial coupling mechanism.
1. Although released cAMP is the only known coupling agent, it is not transported
as such inward across the receptor cell's plasma membrane. Rather, cAMP
affects membrane surface receptors, which in turn affect intracellular
reactions.
2. The influence of cAMP seems more nearly proportional to the rate of change of
extracellular concentration than to the absolute amount released.
What goes on inside the cell? For purposes of qualitative analogy we might think
of the cell as a triggerable switch that can be at rest, excited, or refractmy, as in the
discrete-state model of Cohen and Robertson (1971a,b). But suppose we want a
continuous biochemical characterization of the process of excitation and of its
spatial distribution? Goldbeter (1975) put fOIWard the first detailed quantitative
model of this kind. The model consists of three rate equations for enzyme-mediated
reactions involving cAMP synthesis and degradation.
1. Energy is provided by a constant intracellular production of ATP, which is
consumed by the following reactions.
2. At a rate enhanced by cAMP, ATP pyrophosphohydrolase degrades ATP to 5'-
AMP, which is constantly removed by a nucleotidase, and
3. At a rate enhanced by S'-AMP, adenyl cyclase tums ATP to cAMP, which is
constantly degraded to S'-AMP by a phosphodiesterase.
450 15: THE AGGREGATION OF SUME MOLO AMOEBAE

.. Needless to say, this model has Ileen substantially l:lpgraaed by 1999 For a
thorough update see Goldbeter (1996), Müller. et al. tl-998), and Halloy et al. (1998).
Goldbeter' s book is also the place to look for refinemet:lts of the scheme Clescribed in
the next paragraph; <l1li
Marcus Cohen (former student of the Morrel Cohen referred to above)
undertook a graphical and mathematical analysis of kinetic schemes of this sort,
analogous in many ways to formal models of excitability in nerve membrane and in
the malonic acid reagent (Chapter 13). Cohen's (1978) model seems to account for
the development of excitability and other aspects of social dynamies during
Dictyostelium's life cycle.
In another version of this model (Goldbeter and Segel, 1977; Goldbeter et al.,
1978) reaction 2 is ignored, and is replaced by an isomorphie expression for
extracellular cAMP transport. The same equations are saved under a renaming of
variables to replace internal5'-AMP by external cAMP [there being currently some
difficulty in confirming the Rossomando and Sussman (1973) measurement on
which the original interpretation was based (Klein, 1976; Roos and Gerisch, 1976).]
Either way, behavior strikingly like that of Dictyostelium cells is obtained when the
pertinent biochemical parameters are assigned plausible values. Depending on the
exact values, the equations either oscillate, thereby producing a cAMP spike every
several minutes, or respond with a cAMP spike only upon stimulation by
extracellular cAMP .
.. The variQus models are susceptible to ofo<i:hemical testlng, tanks to t ~
development by Ger1sch and Hess (1974) of techniques for observing synchrono s
biochemical activity in aqueous .suspensions _cf many Dictyostelium cells. At this
writing (1978), it has been found that adenyl cyclase activity fluctuates as in the
postulated kinetics, but the predicted intracellular ATR fluctuations are quite small or
_I')ot yet mea~(Jrable (Roos et aL, 1977; Geiler and Brenner, 1978). <l1li _~_ _. _ - - '
.. This seems still so in Gold eter (1996}. <l1li

Essentially the same kinetic equations were previously deployed, under another
exchange of names, to mimic the mechanism of glycolytic oscillations in yeast cells,
based on PFK inhibition (Goldbeter et al., 1978; Goldbeter and Erneux, 1978). As yeast
(both real and modeled) has been shown to support aphase singularity in the pinwheel
experiment without diffusion (Chapter 12), much the same might be expected of
Dictyostelium. Would diffusion-coupling evolve such initial conditions into a rotor?
With the help of digital and analog computers, kinetic schemes of a qualitatively
similar nature have been diffusion-coupled in two dimensions through one reactant,
as does Dictyostelium through cAMP:
1. Gulko and Petrov (1972) obtained a rotating action potential using three
equations of membrane conductivity coupled only through membrane voltage
(see Chapter 14, Figure 5).
2. Karfunkel (1975) obtained a rotating biochemical wave using enzyme kinetics
coupled only through one substrate, and
3. Winfree (1974b,f) shows the detailed anatomy of rotating waves in a
hypothetical excitable medium borrowed from nerve modeling, coupling
 E: HISTORICAL NOTE 451

volume elements through diffusion of all reactants (Chapter 9). It works nearly
indistinguishably when coupling is only through the variable that represents
cAMP or membrane voltage.
Presumably the same will be shown in this case, coupling cells by way of cAMP.
Ih January 1987 we got bacK to t is proje by first computing fotors from suitable
initial . conditions for the ,Öregonator model of the malonic acid reaction (plus
molecular diffusion) (Jahnke et aL, 1988, 1989), and then in' 1988 from the 1977
Beeler-Reuter model of heart musde (plus diffusion of electric potential) (\Ninfree,
989a; Courtemanche and Wrnfree, 1990a,b, 1991). Simultaneously, lyson et al.
(1989), Tyso and Mlirray (1989), Monk ..and Othmer (1989, 1990), found rotors in.
continuurn models of Diqyost~/jum, in both cases with substantial "exc;itable gaps",
I.e, with period longer than the shortest stable periodicity. Witn improved
biocnemical mqdels Goldbeter (1996 pp. 231-234) and (Halloy et al., 1998) confirrned
'and improved this kind of computation. These continuum rotors differ somewhat from '
Dictyostelium'sl' and it remcHns <;Fijicult for contin'uum models to theoretically match
.tne observed dispersion curve, i.e., the d~pendence of propagation speed on period
(references above, plus Siegert and Weijer, . 1989). The. ineasured dependence of
speed On curvature ' of the propagating cAMP front, In cont(ast, turned out
surprisingly nicely (Foerster et al., 1990) in relation to continuum theory. Maybe these
comparisons reveal the dominant ir)Volvement of factors other than continuous
reaction and diffusion, e.g., lack of continuity between sparsely distributed cells, cell
motility and fluctuations of local cell density, and heterogeneity of cell.developmental
stages and their corres onding teactions to cAMP ....

D: Phase Resetting by a cAMP Pulse

It is possible to rephase the spontaneous oscillation by injecting cAMP into a
cell suspension. The new phase varies according to the old phase at which
the cells are exposed to cAMP. Using a cAMP pulse much smalle~ than what
the suspended cells provide themselves every eight minutes, Malchow et al.
(1978) have found Type 0 resetting (Figure 3). Their resetting curve lingers
along the diagonal (new phase-oId phase) near the usual phase of cAMP
release. Thus a slow cell gets advanced and a fast cell gets delayed by each
collective pulse of cAMP, so that synchrony is maintained. However, there are
also effects on the amplitude of the cAMP rhythm following these pulses, so
the effects of repeated pulsing cannot be evaluated simply by repeated
application of this curve. It should be possible to compare these results with
similar experiments on the Goldbeter model and others. It is first necessary to
verify that all cells are oscillating in the cell suspension and not just a small
minority with the more numerous remainder responding after a delay.

2 By "smaller" I mean the total amount released. The cells might be more concemed about the peak
rate of release.
452 15: THE AGGREGATION OF SLiME MOLD AMOEBAE

Figur. 2. Diagram of the spiral pattem of chemotactic

signals in an early stage of cell aggregation. Top: Cells are
attracted towards their inner rieighbors (arrows) along a
curved line that forms a spiral. The zones where such aspiral
wave meets the neighboring ones become sharp bound-
aries between adjacent aggregation territories. From these
boundary zones the cells are withdrawn by chemotactic
attraction towards either side. From top to bottom the
movement of the origin of the spiral around a central area
(dotted) and the propagation of the spiral wave over the
aggregation territory is shown. The data on bottom apply to
time dense cell layers. In more dilute cell populations the speed
of wave propagation is higher (Alcantara and Monk, 1974).
(Data from Gerisch, 1965). From Figure 1 of Gerisch 1978,

1 with permission.

wave propagation
=4J}Jmxmin-1
lperiod
=5min
--
WQve length
=2JO}Jm

Y2~--------------~--------------~

1
0' o

-Y2 -l'------..--------.fC-----r-----~
-~2 0 12

- - 0 ---..
Figur. 3. The experimentally determined new phase q/ reached by rhythmically pulsing D.
discoideum cells when stimulated by a cAMP pulse at phase. The data are replotted from
Figure 5 of Malchow et al. (1978), which plots phase shlfts (advances A, delays D). The
spontaneous cAMP pulse occurs at <p == O. The second cyde of <p here is merely a duplicate of
measurements reported in the first cyde.
 E: HISTORICAL NOTE 453

E: Historical Note

Before leaving the subject of periodic wave-like activity in slime mold morphogen-
esis, I interject a point of historic comparison with other experimental systems in
this Bestiary.
1. The first quantitative analytical attack on these intriguing problems (Keller and
Segel, 1970) was based on a linearized continuum approximation. This invoked
diffusion-induced instabilities of a spatially uniform steady state. This approach
proved to be in error:
A. Experimentally, the uniform steady state is stable so the phenomenon is
intrinsically nonlinear.
B. The linear analysis produces only periodic solutions, but Dictyostelium is
capable of propagating a solitary pulse (Robertson et al., 1972).
C. The linear analysis allows arbitrary superposition of whatever eigenpatterns
have positive growth rates. But in fact only pure rings and pure standard-
pitch spirals are observed. Also of interest in this connection is Nanjundiah's
quantitative argument (1973, last page) that continuous secretion as
postulated by Keller and Segel would be much less efficient as a detectable
chemotactic signal than would be a periodic pulse of the same substance.
Pulsatile morphogenesis may have been adopted by cellular slime molds for
reasons of economy.3
2. The same thing happened in the first attempts to rationalize ring and spiral
patterns in the malonic acid reagent (e.g., DeSimone et al., 1973). Its periodic
patterns reminded theorists of the instabilities of linear kinetics coupled
spatially by sufficiently asymmetrie linear diffusion. Because the mathematics
were weIl developed, they seized the imagination, squeezing such observations
as the following out of consciousness: the same patterns arise in reagent with
a stahle uniform steady state; spirals do not arise spontaneously; colliding
waves completely vanish. To my mind such phenomena make "diffusive
instabilities" a far-fetched metaphor. Yet so tenacious is the appeal of a
beautiful idea that theorists continue to interpret the real phenomena in terms
of the instabilities of linear kinetics (Ross, 1976; Defay et al., 1977; Thompson
and Hunt, 1977).
3. The similar concentric ring and involute spiral patterns in Nectria fungi
(Chapter 18) predictably served as a conspicuous target for application of the
same models (various people's preprints, withdrawn before publication),
despite the equally conspicuous fact that no hint is ever observed of the
pattern superposition expected of linear models (unless by exquisite tuning of
parameters all wavelengths but one are given negative growth rates).

3 Although Keller and Segel's original interpretation of slirne mold aggregation seems incorrect for
Dictyostelium, practically the same equations seem to account nicely for the moving bands of chemotactic
bacteria (Keller and Segel, 1971a,b). This is not at all an unusual pattern of discovery. For exampIe,
Newton's equilibrium theory of the tides is utterly mistaken for seawater, but it seIVed beautifully for tides
in the atmosphere when they were discovered.
454 15: THE AGGREGATION OF SUME MOLO AMOEBAE

I think. it is important for research students to be aware of such trends in the

elaboration of theory, and doubly important for those whose mathematical
aptitudes make their minds susceptible to infection by whatever beautiful and
sophisticated models chance to be currently in fashion. As Sherlock Holmes once
remarked, "It is a capital mistake to theorize before you have all the evidence. It
biases the judgment" (A Study in Scarlet). My impression is that after the facts are
collected with an eye receptive to surprises, new biological phenomena almost
always suggest quite different models than whatever first came to mind.
 "If you can make a computer say it, it must be right," enthused Simplicio. But Saviati
scoffed, "That is too easy; I would rather say if you can't, it probably isn't right."
- From a dreamed version of Galileo's Dialogues

This first of two new chapters (16 and 17) for the Y2K edition tries to succinctly relate
twenty years' "experimental mathematics" about two- and three-dimensional rotors,
following up the new parts of Chapter 9's Section C. It stresses unsolved problems
that await the reader's attention. As noted in 1978's Chapter 10 (Section C: Transition
to Bestiary), Chapters 11 through 23 are less about concepts than about the specific
experimental systems by which our many-forked tree of guesswork is pruned toward
reality. This chapter combines mathematical concepts with numerlesl experiments
that test conjectures about the solutions of equations, largely by providing
counterexsmples to steer thinking away from minefields. Equations in this area do
not exactly represent physical mechanisms; to that extent they are only metaphors for
the laboratory phenomena. These metaphors are awkward analytically, so to find their
implications we do a fair amount of intuitive guessing and numerical simulating. The
numerical experiments are in some respects as effective as laboratory experiments for
disillusioning ourselves from mental mirages. In this mode we leam principally from
'silures: failures to produce a quantitatively worlcable incarnation of some
hypothesis, or failures of the quantitative incarnation to do what a simpler analytical
model does. And we leam from unexpected encounters with altemative solutions. So
this chapter is mostly about alternatives and counterexamples, in that respect not
unlike the former Chapter 16, which was a comparison and contrast of two topological
descriptions of the phenomenology of animal limb regeneration (now shriveled to
Example 11 in Chapters 2 and 10; the original also escaped intact as Chapter 5 of G.
M. Malacinski's Pattem Formation: A Prim er in Deve/opmental Bio/ogy, Macmillan
1984).
Because what little we know of three-dimensional wave behavior in excitable
media is debated in terms of numerical artifacts just as observations by electron
microscopy used to be debated in terms of fixation artifacts (see Example 12 of
Chapters 2 and 10 for an example), it seems to me appropriate to frankly recognize
the solving of these equations as an experimental subject, appropriate to this
bestiary.

A. T. Winfree, The Geometry of Biological Time 455

© Springer Science+Business Media New York 2001
456 16: NUMERICAL ORGANIZING CENTERS

The subject matter in this chapter is a completely continuous idealization of

excitable media, in every case with fairly simple dynamies, whether intended for
propagation in isothermal flames or malonic acid reagent or idealized heart muscle or
other media that seem continuous on the scale of excitation. This chapter presents as
a chronological story just the path I happened to follow with students at Purdue, at
UCSD, and at the University of Arizona. A much thicker chapter (ca lied a "book")
would be needed to interweave evetyone's paths into the full tapestry of discovery in
this area during those twenty years; the best I can do in this short space is to highlight
the spots where my one path intersects several others. Pointers to several more
comprehensive reviews appear throughout the chapter. See the next chapter for
idiosyncrasies by which heart muscle is subtier than the idealizations represented in
this chapter.

A: Seroll Filaments in Two Dimensions

What algorithms most efficiently represent excitable media? For continua such as the
malonic acid reagent (Chapter 13) or nerve membrane along a squid axon (Chapter
14) or the three-dimensional bidomain continuum of heart muscle (Chapter 17) it is the
parabolic partial differential equation of reaction and diffusion: an ordinary differential
equation for local reaction plus the Laplacian operator for neighbor diffusion. In the
linear case its solutions are analytically accessible, but how should the non linear case
be solved? Many more elaborate methods have been tried, but to this day it remains
commonly solved as in Chapter 9, by the explicit Euler method on a square or cubic
lattice with 5-point discretized Laplacian in two dimensions or 7-point in three
dimensions (or 19-point as in Dowle et al., 1997). In other words, the local reactions
are updated by incrementing or decrementing concentrations according to the rate
laws of local concentration, then adjacent cells exchange contents in proportion to
their differences, then both steps are repeated in the next small increment of time,
and so on. The choice of an ordinary differential equation was complicated by
proliferation of piecewise linear models after 1974, by the advent of Oregonator and
cubic FitzHugh-Nagumo continuous models after 1988, and in all these settings it was
complicated by the presence of a few parameters whose effects were only vaguely
appreciated.
During the 1980s two-dimensional rotor periods and wavelengths varied wildly
among published models and seemed to depend on parameters in qualitatively
different ways: every new published computation had a unique phenomenon to show.
One key problem proved to be that small €, the dimensionless ratio of excitation to
recovery time scales, in some writings multiplies the polynomial representing the slow
variable's rate of change, in others divides that of the fast variable, in yet others
appears in both places. These usages need to be distinguished by a superscript prefix
as in Winfree (1991 a) because the unit of time, of course, depends on € in different
ways according to its role in the equations. Another problem was that publications
using different models were sampling only narrow parameter ranges where
confusingly different behaviors resulted, while others were doing nearly the same
computation while giving different names for the same parameters and using different
units for the same dynamical variables. As in the early discovery stages of any new
 A: ScROlL FIlAMENTS IN Two DIMENSIONS 457

thing, strange new phenomena commanded attention. Reports proliferated and in the
absence of any expeeted pattem of outcomes, typographical errors in published
equations or parameters passed unnoticed, and the effects of overly coarse numerical
grids were not always distinguished from effects of parameter variation in the
continuous ideal. More might be leamed if we could compare one lab's result with
another's. This required algebraic translation among the major equation formats in
use (Winfree, 1991 a), and it required computing for several models a "Iandscape" or
"flower garden" of rotor behaviors coordinated in terms of two generic parameters,
viz., the ratio of time scales, E, and the excitation threshold (see new material in
Seetion B of Chapter 9).
While the first such landscapes were coming into focus there were so many ideas
about the ways in which two-dimensional rotor behavior depends on parameters that
almost whatever pattems emerged did indeed conform to some prior anticipation,
yet what would emerge next was at no stage foreseen. It was always surprising.
Figures 1-4 sampie the first several landscapes produced. Notice the common
themes:
• Figure 1, from Zykov (1986), sketches meander flowers in a model of heart
muscle, with only the voltage variable diffusing. Flowers are plucked only at the
special parameter values where the angle between successive petals is exactly
2·71/integer. The curved arrows in this pioneering figure can mislead the casual

ke,
1,5 rö fÖ

-- -----------. ....... --....

rO rO
\
ro ro
ro
\
\
----00\-...........
1,0 fi ~ ro ? '«1-
\
\

7
\

o,S ~ fk r;& f(j\(o

, ,,
""
0
0,1 0,2 0,3 e
Figur. 1. The first landscape of meander behavior against two parameters, hand-sketched
(another version in is Zykov and Morozova, 1990, Figure 4) from computations of a two-variable
piecewise linear excitable medium. The dashed lines indicate two analytical criteria for meander
onset. The curved arrows below the dashed meander boundaries indicate that the clockwise-
spinning rotor additionally moves .Ith.,. clockwise or anticlockwise (at different parameter
settings) while its tip inscribes these closed paths. (Adapted from Zykov, 1986 Figure 3).
458 . 16: NUMERICAL ORGANIZING CENTeRs

glance. All the rotors spin clockwise, and this is the meaning of the arrows on
the dosed loops above the dashed lines. Each individual loop below the
dashed lines is also traversed dockwise in one rotor period, only these loops do
not quite dose, because the rotor is moving. The arrows below the dashed lines
indicate its direction of movement. Lugosi (1989) replicated Zykov's survey in
very nearly the same format, using a finer numerical grid and recording tip
paths, periods, and wavelengths quantitatively. In general the paths do not dose
(Lugosi, Figure 1). A particularly surprising feature of both studies is the "Iinear
looping" behavior between f10wers with inward petals and those with outward
petals. See "The Protracted Discovery of Two-period "Floral" Meander" in
Chapter 13.
• Figure 2 again shows similar behavior in the two-variable Oregonator model for
the malonic acid reaction with both variables diffusing. Because these computa-
tions were so dosely meshed with chemical experiments, I introduced them first in
Box E of Chapter 13 alongside attempts to check them in the laboratory (Nagy-
Ungvarai et aL, 1993; Li et aL, 1996; Belmonte et aL, 1997). Here I overlay
bifurcation loci 8P beyond which propagation is sustained, 8R beyond which

l/E
10 20 50 100 200 500 1000

f
5

Figure 2. A survey similar to Zykov's was undertaken using a numerical excitable medium then
supposed to potentially bear comparison with laboratory experiments: the two-variable
Oregonator model of the cerium-catalyzed malonic acid reaction. Here there are no
discontinuities in the rate functions. Parameter f is similar to Zykov's, but it is hard to relate
his other parameter, k. to the Oregonator's f. Increasing f (downward) decreases excitability as
though bromide concentration increased and/or the batch reagent aged. The Hopf bifurcation
to spontaneous limit cycle oscillation occurs near f.=2.4 within the range of f shown here; it has
little effect on flower shapes. Notice the 0 0 isogon segregating only a narrow wedge of flowers
with inward petals; notice the absolute distance scale bar, "20 Oregonator space units." Unlike
all other such diagrams, rotors here tum in elther direction due to accidents of our initial
conditions. (From Jahnke and Winfree, 1991 a, with perrnission.)
 A SCROLL FilAMENTS IN TwO DIMENSIONS 459

rotors are viable, and äM beyond which two-period meander ensues. By

quantifying the rotor periods and wavelengths, this numerical experiment was
the first to corroborate Fife's scaling, according to which rotor period, wavelength,
and wave speed should vary as powers of the cube root of the "f." ratio of time
scales of excitation and recovery, in the limit of small f. (Fife 1984, 1985, 1988;
Kessler and Levine, 1989). In 1990 this seemed to many, myself included, rather
improbable. Its numerical confirmation immediately led to fruitful applications of
Fife's remarkable insight (Barkley 1992; Bemoff 1991; Karma, 1991, 1992; Kessler
et al., 1992ab; Mitkov et al., 1996; Mitkov, 1996). (It does not apply to everything,
though, for example not to myocardium, on account of the sluggishness of its
repolarization.) Like the FitzHugh-Nagumo medium in Figure 3, this Oregonator
medium shows "hypermeander" beyond the indicated bifurcation locus äC. See
Box A, placed in this chapter rather than Chapter 13 because it is still only a
computation.
• Figure 3 presents more detail from the FitzHugh-Nagumo cubic excitability model.
A pattem begins to emerge, and much of Zykov's picture can be imagined

E
0.30 0.20 0.10 0.05 0.03

0.00
0.10
0.20
0.30
0.40
ß 0.50
0.60
0.70
0.80
0.90
1.00
1.10
1.20
1.30
1.40

Figura 3. This is Figure 1.3 of Chapter 9, with the flowers added which resist description in
terms of two periods, segregated beyond fence ac in the lower right. It seems likely that
meander inevitably arises as € approaches 0; is this also true of hypermeander? New arrows also
point to the parameter combinations used for the eight stable three-dimensional organizing
centers of Henze (1993), viz., (0.3, 0.7) and forthe wildly meandering ones ofWinfree (1994b,
1995a), viz., (0.2, 0.9). Note the normalization of flower sizes by the spiral wavelength at that
parameter combination, in contrast to the absolute scale adopted in Figure 2. All rotors here
tum in the same direction. As in the Oregonator, the 0° isogon shaves off only a narrow wedge
containing inward-petal flowers. (Adapted from Winfree, 1991 a Figure 13 with permission.)
 embedded in this pattern. Mathematical understanding seems to be developing
most rapidly along certain narrow paths that traverse this diagram:
o Between the top half containing spontaneously oscillating media and the
bottom half containing non-spontaneous excitable media lies a zone around
the Hopf bifurcation to a spatially unifonn attracting cycle: for f values
approaching 1 (to the left, beyond the range of this figure), behavior nearby is
reasonably weil understood through the Ginzburg-Landau equation. For f to
the right of 0.3 this Hopf bifurcation occurs near ß-~: notice that it has little
impact on the flowers.
o All along aR is the domain of marginal excitability where the period and
wavelength are long, wavefront curvature easily aborts propagation, rotors stand
off from walls while rolling along them, and scroll rings expand. Not much is
understood about these wall effects, equivalent to interaction with a nearby
mirror-image rotor, but rigid rotation in the open has been weil described
analytically. This area is shaded, avoiding the area around (0.3, 0.7) where there
are two alternative stable rotors.
o There is still no theory of ap, so far as I know, so Ileave unshaded the area below
aR.
o The Fife domain is at the far right: the rotors period and size are observably
proportional the cube root of f, and extrapolating to the limit as f approaches 0,
they spin infinitely quickly or slowly and are microscopic or galactic in size
depending on wh ether excitation is very quick or recovery is very slow (or both),
Le., depending on the "fonnat" of the rate equations in respect to usage of "f."
Rotors evade our understanding here by exhibiting hypenneander, so I refrain
from shading this region yet.
These results were obtained with parameter "b" or ""{" of the FitzHugh-Nagumo
model set to 0.5, and diffusion of the slow variable set to O. Qualitative results
seemed little affected by increasing "{ to 1 so that the local kinetics became
bistable, or by varying the ratio of diffusion coefficients from 0 to 1.
• Figure 4 presents the schematic landscape for Barkley's related two-variable cubic
excitable medium, also with only the fast variable diffusing, at f=5~' Just as in the
FitzHugh-Nagumo equation, at smaller f hypenneander also occurs: in Fall 1992
Wade Leitner in my lab found it at Barkley's f=SÖo' a=~, b- ~, and Diks et al. (1995)
,doo.
analyzed it extensively at f=2Öo' a=!, b- See Box A.
• As noted in Section B of Chapter 13, Barkley (1995) showed that several features
of these landscapes can be expressed as continuous extensions of the
neighborhood around the intersection of the 0° isogon and aM, where they are
consequences of five necessary symmetries: two for translation invariance in the
plane, one for rotation (phase) invariance, and two for the Hopf-bifurcated
oscillation that modulates path cu rvature. Writing the simplest set of five first-
order ordinary differential equations that embody these symmetries, he showed
that its solutions trace out all the familiar meander modes in their correct
relationships on a three-parameter landscape. The features not included in this
description are ap, ac and the hypenneander domain beyond it, and any
turbulent domain. An extra feature included but not yet detected by chemical or
computational experiments is the presence of extra intemal loops in some of
Barkley's f10wer petals.
 a
0.2 0.4 0.6 0.8 1

Rgure 4. Neither parameter here is like €, a ratio of time scales that is fixed at 0.02 in this slice
through a three-parameter landscape. As in Figures 1 and 3, diffusion of the slow recovery
variable is forbidden here. The propagation boundary, aP, is not explicitly indicated but
presumably runs dose alongside aR, just inside the dashed region on the left. The 0° isogon is
dashed. (From Barkley, 1995 Figure 2, with permission.)

• The kinematic description of meander, extrapolated from a derivation valid for

marginally excitable media (Mikhailov et al., 1994; Mikhailov and Zykov, 1995;
Hakim and Karma, 1999) yields alandscape similar to Barkley's.

The gradual emergence of this landscape, in which many facts about rotors find a
place in relation to neighboring facts, is reminiscent of a geologist's enthusiasm for the
like experience:
Beginning, then, with the beginning, in a purely inductive way, I collected all the
barometrical observations of previous travelers, and fromthem calculated hundreds of
altitudes; I marked on a large scale map all geological and physical observations that had
been made by different travelers - the facts, not the hypotheses, and I tried to find out
what structural lines would answer best to the observed realities ...

There are not many joys in human life equal to the joy of the sudden birth of a
generalization, iIIuminating the mind after a long period of patient research. Wh at has
seemed for years so chaotic, so contradictory, and so problematic takes at on ce its
proper position within a harmonious whole. Out of a wild confusion of facts and from
behind the fog of guesses - contradicted almost as soon as they are bom - a stately
picture makes it appearance, like an Alpine chain suddenly emerging in all its grandeur
from the mists which concealed it the moment before, glittering under the rays of the
Sun in all its simplicity and variety, in all its mightiness and beauty. And when the
generalization is put to a test, by applying it to hundreds of separate facts that had
seemed to be hopelessly contradictory the moment before, each of them assumes its
Box A: Hypermeander Compounded of Ptolemaic Epicydes

Systematic variation of kinetic parameters while monitoring rotor behavior in various models
produced flowers resembling Zykov's and our own as described in the "Earth-Moon"
metaphor. But then a new bifurcation locus was discovered beyond which successive
petals of the flower kept changing shape. The initial impression was that a thlrd, much
longer, period had emerged and our simple "astronomy" was going to need
supplementary epicycles:
More prolonged computations using the Zykov model seem to show the flower pattem
itself slowly moving along astilI larger circle. One must wonder whether such delicate
subtleties reflect more about computational procedures than about the original
equations, but the observation might suggest that a third discrete frequency can arise,
beyond another bifurcation border in parameter space.
- From Winfree (1990a)

Since "meander," as known before, is a quasiperioclic motion compounded of

two frequencies, this "hypermeander" must consist of at least three frequencies,
and probably more. If there were only three discrete frequencies, meander could
be described as a motion on a three-torus. However, three-tori are often
structurally unstable: such systems usually exhibit extremely complex behavior,
often including chaos (Grebogi et aL 1983, 1985; Berge et aL, 1986; Linsay and
Cumming, 1989). We have not yet examined sufficiently long time-series of
hypermeander (or checked the numerous possibilities for numerical artifacts to
qualitatively alter the outcome), but in a loose sense we tentatively label this
domain "chaos" in Figure 9. This supports the early anticipation of Rossler and
Kahlert (1979).
- From Jahnke and Winfree (1991 a), about the Oregonator model.

(By way of correction, it should be noted that high-dimensional chaos can anse
directly from 2-period toroidal flows as shown in Moon, 1997. A thorough
exposition of three-oscillator dynamics appears in Baesens et aL, 1991.)

Similar behavior tumed up in FitzHugh-Nagumo media (Winfree, 1991 a). We labeled the
new "hypermeander" domain tao eagerly as "chaos" in Jahnke and Winfree (1991a),
and this guess was at first affirmed and elaborated by Zhang and Holden (1995) using
the FitzHugh-Nagumo example and by Diks et aL (1995) using Barkley's medium.
Meanwhile, I had continued those first hypermeander computations to still more
rotations, and found in Fourier spectra that quite a few (not just two or three) low
frequencies remain sharp despite the presence of a low diffuse background of uncertain
origin (Figures a, b). Plesser and Müller (1995) continued this Oregonator hypermeander
example, and obtained spectra at many other parameter combinations as weil. They
found discrete spectra (Figure c), but (discounting harmonics) no more than four clear
peaks, even in hypermeander.
If "spatiotemporal chaos" necessarily entails dynamical dimension diverging in
proportion to the area of the medium, then hypermeander of one rotor does not seem a
plausible candidate for such description. But it is an intrinsically spatial phenomenon of
considerable temporal complexity, beckoning with the promise of some unexpected insight
into dynamical systems.
 A: $CROLL FilAMENTS I Two DIt-1ENSIONS 463

12r-----~----~----~----,_----~

10

2~----~----~----~----~----~
2 8 10 12

Figure a: A short segment of meander path in the middle of a longer run generated at high
resolution for Fourier analysis, using Barkley's cubic excitable medium with 9-point Laplacian,
with only the fast excitor variable diffusing, parameter a=0.25, b=O.OO1, 1::=0.005, box side 20
space units divided into 190 grid points, time step dt=0.OO1 (about 2000 steps per rotation).

01

001

0_00'

0000 '

I~~------~--------~--------~------~
o .00 • 000 '.00 2000

F1gure b: A sam pie of the Fourier spectrum corresponding to a 400 time-unit continuation of
Figure a, showing only positive frequencies. The tall peak is at rotor spin frequency 308.64,
corresponding to 2.12 time units since the frequency unit is 25 data sampies per time unit/2 '4 .
Notice the profusion of intriguingly spaced sharp peaks and negative "Fraunhofer lines"
decorating a continuous background on this logarithmic scale. This was largely the work of C.
C. Chen in my lab in 1995.

At least three frequencies would be needed for chaos by hypertorus instability, since, as
Rand (1982) had shown in another context and Barkley et al. (1990) and Barkley (1992)
applied to rotors, the rotation period doesn't count; but even with so many in hand, spectra
remained sharp, and, at least in the Oregonator rotor hypermeandering at f .. 8, sensitive
dependence on initial conditions was completely absent. Opinion seems to have changed
back to the view that hypermeander is often merely "complex" {Plesser and Müller, 1995;
 e _ _ _ . . . . . . . . . . ... ·' '·1.40

l ",--"" .. ,."" I ""'''''',,,,,~,, '-1.79

..
~""--""----""i I ··.... .~".".r.2.26
l." .. ,,--.. --···( ! ······.. t ____ t ..
h • • , . __

".'.3.20

1. ""." ... --' ··r '.

··'t·-- ',, __ ... , f·3 .96

1...;"",,······'&/ i \···~,.",,*,
I
f.5.96

,/ 1\ ~n ~
' ,
··1'
'
··· .. --... __ ., ..
@
_
.. """ .. ·········1
' I I
~
Li I .. '.. n
'.8.20

,
,
:• 1:
I •
I •
I •

/ " !i ...

............... .. ............
... '. " " " __ • " •. , . , -8.70
25

20
:i
.;
ci 15
..
"2 10
ii
; 5
......... .. '
o~~~-.~wW~~~~~~--~

·1.0 -0.5 0.0 0.5 1.0

v II/O .l.u.

Figura c: For the Oregonator model of Jahnke and Winfree (1991 a) at € = 0.01, Plesser and
Maller (1995) recomputed the meander flowers of Chapter 16 Figure 2 and plotted their Fourier
power spectra in Oregonator space units of amplitude for circular "epicyde" components of
motion. The dominant peak to the right of zero frequency is the unmodulated rotor. The one to
the left (negative frequency = opposite sense of rotation) starting from about f=2 is the "Earth"
meander frequency, not that of tip path curvature modulation. Beyond f=6 additional
frequencies appear (plus ignorable harmonics). At each f the hyperbola through the rotors
amplitude and frequency indicates that every other Fourier component modulating the rotor
has a smaller amplitude x frequency product, and so is individually unable (in fact, they seem
COllectively unable) to arrest propagation at the speed observed in the rotor·period wave train
far from center, speed being roughly a fixed factor times that product. "O.s.u." and "1/0.t.u."
indicate Oregonator space units of 0.18 mm and reciprocal time units of 21 sec (Jahnke et al.,
1989). (From Plesser and Müller, 1995 Figure 4, with permission.)

Diks, 1996; Mitkov, 1996; Mitkov et al., 1996; Biktashev and Holden, 1998). Meanwhile, Qu
et al. (2000) exhibit hypermeander in a complex ionic model of cardiac excitability with
sensitive dependence on initial conditions and a spectrum that cannot be described in
rational combinations of two frequencies. Hanusse and Gomez-Gesteira (1996) discovered
"super-meander" and gave it a three-frequency description. Is this a special case of
hyperrneander, or something different?
 € = 0.01
.6

:; .4
.;

"- .2
ci

" 0.0
~
V.

-.2 VI

2 4 6 8 10
f
F1gure d: Where Jahnke and Winfree (1991 a) had described the hypermeander bifurcation, {}C,
Plesser and Müller (1995) found the onset of a third frequency (around f=6) and then a fourth
(around f=7), disregarding trivial harmonics, of course. Notice that they become equal near
f=9.5: do they lock together in a small range nearby? Frequency is denoted by "v" vertically,
not by "f": "f" horizontally is a chemical parameter. (From PI esser and Müller, 1995 Figure 9,
with permission.)

Barkley's (1995) one-paragraph statement 4.1.4 about our experimental knowledge of

hypermeander illustrates the rapidity of change:

(a) It had been observed in the chemical laboratory: Nagy-Ungvarai et aL (1993) offer
suggestive evidenee that today still awaits confirmation;
(b) It was not known whether numerical instances are simply three-period quasi per-
iodicity or truly chaotic states (the two guesses of Jahnke and Winfree, 1991 a): today
it seems they are neither, but rather something new and interesting;
(c) Hypermeander was known in only two numerical models from the same custom
software (Oregonator in Jahnke and Winfree, 1991 a; FitzHugh-Nagumo in Winfree,
1991a), but it had not been found elsewhere, for example in Barkley's FitzHugh-
Nagumo-like cubie model: today it has been (Diks et al., 1995, Diks, 1996), and in
other models (Mitkov et aL, 1996; Qu et aL, 2000), and the former two cases have
been extensively confirmed elsewhere.

In two-variable models it appears now that only richly multiple quasiperiodicity has been
observed numerically, and it stems from a localized source so dynamical complexity does not
inerease with the area observed. Laboratory observations have not yet decisively
distinguished hypermeander from simple two-component quasiperiodicity (see Nagy-
Ungvarai et aL, 1993, for the dosest approach to date). It might be that even num.ries'
experiments are sufficiently afflicted with discretization errors and round-off errors to blur the
coneeptual distinction between quasiperiodicity and some sort of chaos. lonic models of
cardiac muscle show rotors meandering in ways that are definitely not 2-periodic, but
whether this is "hypermeander" as in simpler models remains undetermined.
The nature of the bifurcation to hypermeander remains unclear. Maybe there are just
suceessive Hopf bifurcations to more and more frequencies, but there seems good cause to
suspect an abrupt cascade producing the observed rieh high frequency spectrum.
 Surprisingly, the example given in Figure b admits accurate description in terms of only two
frequencies, e.g., rotor frequency 308.64 and first ("Earth") meander frequency-178.21,
linearly compounded in large integer proportions. The program I wrote to find those
integers can do each of the 46 dominant frequencies (including the 13 positive lines with
greatest area in Figure b) typically in a few ways at the finite precision of available data,
with integers < 20, so this may be more invention (i.e., spurious) than discovery. Such
numerological description needs some guidance from analytical theory. Dante Chialvo
provided this in 1995 but we never clarified the details for publication.
A question about the many frequency components of hypermeander: is their putative
non-interaction an artifact of holding the curvature and twist of the filament strictly zero
by restriction to two dimensions? In three dimensions meander affects and is affected by
the filament's curvature and twist (Winfree, 1995a). Does an initially straight,
synchronously meandering filament then become asynchronously snaky? Might a filament
at hypermeander parameters exhibit fewer frequency components than in two
dimensions, its many modes interacting through curvature and twist to lock together in
rational fractions?
Do the many distinct modes in hypermeander lock together when parameters are
tuned to bring two of them near equality as in Figure d near f= 9.5? The proscription
discovered by Barkley et al. (1990) applies only to mode-Iocking with the rotor ("Moon")
fundamental, and only in two-dimensional monodomain continua, as far as I understand.
There is no implication that processes at the rotor period T 0 cannot interact with
processes at first meander period Tl to provide a variety of lower rational combination
frequencies.

due position, increasing the impressiveness of the picture, accentuating some

characteristic outline, or adding an unsuspected detail full of meaning. The general-
ization gains in strength and extent; its foundations grow in width and solidity; while in
the distance, through the far-off mist on the horizon, the eye detects the outlines of new
and still wider generalizations.

He who has once in his life experienced this joy of scientific creation will never forget
it; he will be longing to renew it; and he cannot but feel with pain that this sort of
happiness is the lot of so few of us, while so many could also live through it - on a
small or grand scale - if scientific methods and leisure were not limited to a handful
of men.
Pyotr Kropotkin, Memoirs of a Revolutionist

A similar paean cannot be sung about hypermeander or about three-dimensional

persistent organizing centers at this stage of investigation.
How generic are these two-parameter landscapes? Samplings of parameter
combinations in models used to represent heart muscle with attenuated excitability
(Efimov et al. 1995; Fenton and Karma, 1998a; Beaumont et al., 1998) show similar
behaviors. At more normal excitability the spiral wave's tip may traverse a slowly
rotating slit-like core reminiscent of Balakhovsky (1965), and/or execute something like
hypermeander. What real heart muscle does is less clear. Venturing beyond excitability
into the unexplored domain of smoother oscillation (i.e., with excitation not much faster
than recovery), Bär and Eiswirth (1993) found in addition to the domains represented
above several more, including two kinds of turbulence. Near the Hopf bifurcation to
bulk oscillation Ipsen et al. (1997) found similar turbulence in the three-variable
 B: SCR'OLL RINGS SIiRIN

Oregonator model, as did Ouyang and FIesseIles (1996) in a corresponding oscillatory

Belousov-Zhabotinsky reagent: wavefrants break and new rotor pairs emerge as
foreseen by Kuramoto (1984). In the nonoscillating malonic acid reagent Ouyang et aL
(2000) experimentally found a turbulent domain not yet found in computational models
of the same reaction.
My purpose in executing high-resolution quantitative landscapes by the same
procedures for four distinct models, each over a wide range of parameter values, was
to find out what they have in common and eventually at least qualitatively to locate
on that generie landscape any given experimental excitable medium: heart muscle
with electrical waves, slime mold with cAMP waves, frog eggs or hippocampal
astrocyte slices with calcium waves, single myocytes with calcium waves, malonic acid
or cyclohexanedione reagent with oxidation/reduction waves, platinum crystals with
carbon monoxide oxidation waves, the retina with spreading depression waves,
hotspots in flames, etc. Any medium would then be characterized by its rotor's
behavior, using the contours overlaid on the landscape to summarize the dependence
of propagation speed, rotor period, wavelength, and petal symmetry on the control
parameters. Two such measures would be needed: for example, the foregoing or any
two of the dimensionless Q = speecf. period/D, and/or the dimensionless ratio of
excitation to recovery times, and/or the dimensionless ratio of activation threshold to
amplitude of excursion might serve. (In the ca se of myocardium, it would be good to
add a "wavelength" overlay, in the special sense of that term in cardiology:
propagation speed times action potential duration, Le., the duration of lingering
depolarization.)
This has not yet been achieved even for two-dimensional malonic acid reagent, the
best-studied instance of meander in the laboratory. In fact, there is not yet even a
mapping from malonic acid recipe parameters to the two-variable Oregonator's f
parameter! A generic view might require landscapes with more than just two
parameters, e.g., in the Belousov-Zhabotinsky oscillator, three or even four as
suggested by the results of quenching experiments (Sorensen and Hynne, 1989;
Hynne et aL, 1991). Barkley's (1994, 1995) extraction of the physical symmetries
involved needs three parameters for full generality, and two-parameter slices like
Figure 4 through the three-parameter landscape of his cubic excitable medium do not
all look the same. The chemical experiments of Belmonte et aL (1997, Figure 5) suggest
a similar need for more than just two parameters.
Two-dimensional rotors can be thought of as three-dimensional scroll sources
lacking any curvature, torsion, or twist. In the next section we add curvature, then in the
next, torsion and twist.

B: Scroll Rings Shrink and Drift

The simplest extension of the rotor into three dimensions is the serail, and it
typically forms rings. As long aga as 1974 the recently discovered planar scroll ring
in malonic acid reagent was found to shrink while the scroll's rotation period stayed
fixed, finally collapsing in a time comparable to the ratio of initial ring area, L2 , to
the diffusion coefficient, D. As noted in Chapter 9, Yakushevitch (1984), then
Panfilov and Pertsov (1984), Panfilov et al. (1986), and Panfilov et al. (1989) derived
the collapse in the form dRidt = -DIR for a strictly circular ring of radius R or in
more general form as dAidt = -2nD, for planar rings of arbitrary shape and area A,
in both ca ses assuming equal diffusion of all pertinent reactants. While
demonstrating this numerically, Panfilov et al. additionally discovered that the
radius-independent coefficient differs somewhat from simple theory and can even
be negative (!) if the various reactants have different D's. And they discovered that
the ring then also drifts perpendicular to its plane at a rate proportional to a
multiplier of all the D's and to the local curvature (Panfilov and Rudenko, 1987). If
local curvature is not the same everywhere, then such a ring soon loses its
numerically prescribed initial f1atness, and the circumscribed area is no longer
unique (though it probably has a unique minimum, as in Plateau's problem about
bounded soap films).
Next, the 1974 laboratory experiments with f1at circular rings were repeated to
compare observation against the area coefficient expected in case of equal diffusion,
viz., -2n1Q in units of wavelengths and periods, or -2nD in centimeters and seconds.
The pertinent chemical D's are not exactly equal: they differ by about half in the malonic
acid reagent. Compared to equal-diffusion theory and trying to take account of
different temperatures, the shrinkage measurements seemed no more than 30% lower
(Jahnke et aL, 1988; Winfree and Jahnke, 1989) or 40% higher (Agladze et aL, 1991)
than expected with all reactants equally diffusing (see retrospective analysis in Winfree,
1995b). With unequal diffusion coefficients, numerical rings move not directly toward
their centers of curvature, but at an angle, thus "drifting" while they shrink or expand, as
noted above. Though observed profusely in numerical experiments, first by Panfilov
and Pertsov (1984), I am not sure this drift has yet been quantitatively confirmed in the
laboratory, i.e., convincingly distinguished from interaction with a boundary, or motion
in a parameter gradient, or liquid convection. I have no doubt that it will be, and the
expansion of rings in uniform media of marginal excitability, too. But I think it is
interesting to observe how abundantly phenomena anticipated from computations
have been assumed to have been actually observed or spuriously observed in chemical
experiments on account of that expectation. Instances include apparitions of Type 0
resetting, a linear dependence of propagation speed on curvature and on repetition
rate, "dissipative structures" in layers or on the surface of malonic acid reagent (see the
end of Chapter 13's Section C) or forming particle-free pacemakers, linked and knotted
scroll rings, "turbulence" or "spatiotemporal chaos," bistability, etc. Complementarily,
when a thing is not expected its absence tends be observed, even when the
unexpected reality is blatantly evident: see page 244 of Chapter 8, Section C, and Box
B of Chapter 13. The more reliable function of experiment and observation is to correct
our ideas, rather than to confirm them.
An unexpected numerical counterexample to the theory of scroll rings tumed
up in 1987: As a graduate student William Skaggs found in a range of parameters
outside the meander domain and near the domain of spontaneous oscillation of
the FitzHugh-Nagumo excitable medium that drifting vortex rings shrink symme-
trically only to a preferred stable radius. These do not spontaneously vanish, but
remain robustly stable even when deliberately perturbed (Skaggs et aL 1988;
Courtemanche et aL, 1990). The plot of dRidt vs 1/R is not the familiar radial line
with slope -D, but a parabola falling through the origin with somewhat steeper
slope, bottoming out, then rising back through dRidt = 0 at the stable (reciprocal)
 · ,

·469
'

C: LtNj«ED AND KNOmD RINGANATOMY

radius. Is this an isolated numerieal peeuliarity? The only other example I know of
tumed up in Brazhnik et al. (1987) and our attempts to repeat this eonfirming
example on a finer numerieal grid resulted in its eollapse (but it may be that results
would have been different with some adjustment of kinetic parameters). In any
ease, something like this is now theoretieally deseribed in kinematie terms for
marginally excitable media (Mikhailov et al., 1994; Mikhailov, 1995; Mikhailov and
Zykov, 1995).
This narrow range of parameters in the FitzHugh-Nagumo medium provides
another eounterexample: to the idea that the period and wavelength of the rotor are
always unique functions of whatever parameters uniquely identify the medium. In
addition to the rotor and seroll ring of period near 11 arbitrary time units, this medium
has another near period 17. Its seroll rings expand (Winfree, 199Of, 1991 b). This result is
eonfirmed in Karma (1990) and in Lee (1997), both demonstrating two alternative rotor
periods at nearly the original parameters in nearly the original equation (after suitable
substitution of variables).
Though the simplest geometrieally, the symmetrie seroll ring was not the first
diseovered eompact, stable, particle-like entity in three-dimensional excitable media.
And the others, before and after, are mueh less fussy about aeeeptable parameter
values.

C: Linked and Knotted Ring Anatomy

This part of the story (up to November 1985) appears with better illustrations and more
details in Winfree (1987a).
The question that had originally provoked interest in sueh matters is, "OK, we see
that symmetrie seroll rings shrink and vanish in the malonie acid reagent, but might
linked or knotted rings (if they can exist at all) prove robustly stable for topologica'
reasons?" With prospective graduate student Lewis Larsen I drew up a detailed flow
ehart of numerieal experiments to provide at least theoretical answers (summer of 1974).
But they proved impractieable: in summer of 1974 maehine memories were too small
and CPUs too slow. Moreover, we only hoped to figure out suitable initial eonditions;
and we had no eoneept of twist. Topologieally unremovable twist in linked and knotted
filaments was diseovered a few years later, not by eomputation or mathematies, but
simply by seulpture with red and blue waxes that melted in the summer heat just after
the last pages of Chapter 9 were illustrated. (See them used for a simpler seroll
problem, disappointingly printed only in grays in Winfree, 1973e, then reprinted in eolor
as Figure 9 of Winfree, 1984d.) More seulpture in 1979 also showed that two pairs of
toroidal ehemical isoeoneentration surfaees could fit together to make linked seroll
rings, and that intersecting two-holed isoeoneentration surfaees eould make a knotted
ring. Can sueh arrangements eontinuously transition tolfrom topologieally different
on es? I thought not, but another pound of wax in 1983 showed that rings and knots
could eome undone by smooth transformations of eoneentration fields, whieh meant
that any geometrieally eonsistent object eould also be ereated from symmetrie seroll
rings (familiar in the laboratory) by sueh events in reverse. Sueh seulpture might be
ealled "analog eomputation," of sorts, but its resemblanee to dreaming indieated a
need for mathematics or eomputation.
Box B: The Differential Geometry of Singular Filaments

A singular filament is aspace curve, r(s). Parameter s here denotes position in terms of arc
length from an arbitrary zero point along the filament, and r denotes Euclidean (x,y,z)
coordinates at that position. An additional vector is associated with each point to indicate
the rotors angular orientation. This may be chosen as the local gradient of any of the
chemical quantities defining the filament, e.g., gradients of "A" or "B" in Chapter 9.
Together with the space curve it defines a ribbon.
The space curve is conveniently described in terms of its local unit tangent vector, 7'(s),
and its local unit normal vector, N(s) pointing toward the center of curvature, 1I1I:(s) = 11
dT/ds distant. Adding abinormal vector S(s) = 1'(s) x N(s) we complete a right-handed
local rectangular coordinate frame called the Frenet "ame. It rotates to keep N in the
local osculating plane of curvature as s moves forward along the filament. This rate of
rotation is called torsion, T(S). The space curve's shape is completely described (apart
from an arbitrary translation and rotation) by the two scalar functions lI:(s) and T(s). If the
ribbon is defined economically by using N itself for the vector associated with each point
along the curve, it is called the "Frenet ribbon." But a different definition is more useful
where rotors and associated chemical gradients are involved. We use one of the
independent gradient vectors suggested above, pointing somewhere in the N,B plane at
angle r/> in the Frenet frame. The ribbon so defined twists at a rate equal to the torsion of
the curve (the twist of the Frenet ribbon, T(S)) plus dr/>/ds. This is the twist we want for
physical-chemical purposes, the absolute rotation of the chemical pattem (the rotor) along
the filament.
The confusion starts here. Do we count angles clockwise or anticlockwise? Relative to
what? Does it depend on the direction of rotation of the scroll? Which way is arc length, s,
oriented along the filament? After three years chasing minus signs, John Tyson and I,
Steven Strogatz, and Jim Keener met over beers at a Gordon Conference in Tilton to agree
to one standard consistent with the Winfree and Strogatz starters of 1983-84. In the ''TWSK
convention" of 6/16/88:

• r/> in radians increases in the direction of the rotors spin;

f11
• along any closed-ring filament, the integral of phase twist di ds is necessarily an integer;
• looking forward along the filament, the rotor spins clockwise, as usual for angular
velocity vectors;
• torsion, T(S), as usual is defined positive where B tums away from the center of
cu rvature;
• local twist, w(s), means dr/>/ds + T (radians per space unit);
• (non integer) total twist, Tw, along a ring means difw(s)ds
• the linking integer, Lk, between two oriented rings is formed by projecting the pair
onto a plane and noting whether the one on top crosses to east or west, with the
one on bottom oriented north: Lk is the number eastward minus the number
westward;
• the writhing of a ring is Wr = Lk- Tw of any ribbon based on that ring; it is zero on any
ring described on the surface of a sphere.

The convenient properties of these definitions are reviewed in Winfree and Strogatz
(1983c), Winfree (1990b), and Tyson and Strogatz (1991). They are not always used
consistently (see Appendix A of Winfree, 1990b) even by Signatories to the Convention, but
consistency still seems an ideal worth striving toward.
 c~ UNKED AND KNonEo RING ANATOW

While enJoymg the hospitality of James D. Murray at the Oxford University

Mathematieal Institute in 1982, I followed up the end of Chapter 9 by formulating the
topology of potential organizing centers in terms of linkage and twist. A visit from
Steven Strogatz, then a Prineeton undergraduate taking a year abroad at Cambridge,
provided opportunity to enlist his energetie and insightful eollaboration, eulminating in
Winfree and Strogatz (1983a,b,e and 1984a,b). Together with other invaluable insights,
Strogatz introdueed the global variable "writhing" from his prior experienee with the
geometry of DNA double-helical ribbons. Writhing is an integral of torsion (modulo a
ehangeable integer) in a closed-ring filament; it tums out to provide a buffering
reservoir for twist. The total twist loeked into a ring plus its writhing is the algebraie
number of times it "self-links" (if knotted) and/or other oriented filaments thread it (Box
B). In the late 1980s twist in the "per unit length" sense, w{s), tumed out to be not just
an inevitable part of the differential-geometrie deseription, but also a physieally
important eausal factor, as we will see below.
Before I mustered the courage to tackle three-dimensional partial-differential
equations, in 1981-82 my 13-year-old son, Erik, built a "copy of Apple" computer and
programmed it for three-dimensional cellular automata with three local states:
quiescent, excited, and refractory. "Quiescent" stays so unless excited by sufficiently
many neighbors (e.g., 1), "excited" spontaneously beeomes "refractory" in the next
time step, and then becomes "quiescent" again. Arranging topologically interesting
initial conditions by hand in 1983-84, we produced stable seroll rings with linked and
knotted filaments (Winfree et al., 1985; Winfree, 1987a pages 233-36). But then he
proved by ingenious classifieation of cases on arbitrary graphs (thus in particular on our
three-dimensional cubic lattices) that it is a peculiarity of such three-state cellular
automata that on any and every closed path the winding number cannot change onee
initiated. So these eomputations proved irrelevant to questions about stability on
continua. More sophisticated cellular automaton models of excitable media (Markus
and Hess, 1990; Markus et aL, 1991; Gerhardt et aL, 1991; Weimar et aL, 1992a,b;
Klevecz et aL, 1992; Henze and Tyson, 1996) evolved to bypass this particular difficulty
and a few others. But the doubling of silicon efficiency every two years ("Gordon
Moore's law") meanwhile had made partial differential equations more attractive.
In 1981 David Epstein, at Warwiek, then again in 1985 Timothy Poston, at UCLA,
showed me how to realize initial conditions for linked and knotted seroll rings in terms of
complex-valued polynomials (Winfree, 1987a Appendix; Poston and Winfree, 1992).
These enabled an attempt at solving three-dimensional partial differential equations for
aseroll ring with unremovable twist when Alexandre Panfilov gained aecess to a mflop 1
ES 10-30 computer at Pusehino in the USSR and invited me to prescribe interesting
initial conditions for a grid of 27,000 points. The result in 1984 was a coarsely resolved
seroll ring with one cycle of twist built in, as imagined at the end of old Chapter 9
("Faney Rings"). It immediately crashed into a wall, but illustrated feasibility and the
importanee of twist: with a unit twist locked into the closed ring, it still shrinks and drifts
as in the cylindrically symmetrie case, but at a different rate (Panfilov et al., 1985;
Panfilov and Winfree, 1985).
By 1985 premed undergraduate Victor Reiner and I were computing topologieally
exotie sero 11 rings in the piecewise-linear excitable medium first used to demonstrate
eompletely stable rotors (Winfree, 1974b,f). On the eentral computers ofthe University
of Califomia at San Diego it was impossible to do mueh more than initiate them, and
even that only on a coarse grid. Then Pramod Nandapurkar pioneered the next stage of
this assault, writing vectorized code for "supercomputers."

D: Linked and Knotted Ring Dynamics

What are the purposes of an effort to discover the laws of motion for singular
filaments in excitable or oscillatory media? The questions that most motivated my own
efforts are:

• In two-dimensional malonic acid reagent and a few biological media, rotors

seem to persist as long as the medium's excitability does, but in three
dimensions they seem generically to take the form of symmetrie seroll rings,
wh ich seH-extinguish by contraction in only as many rotation periods as the
diameter2 (in spiral wavelength units) times 0/8, where the dimensionless quality
factor Q is usually 0(100) (see page 278). Does this collapse manifest a general
principle? Are seroll rings then mere transients in simply connected volumes of
excitable medium? Krinsky (1987) argued so in relation to excitable media, and in
context of theory of the origin of life Cronhjart (1995) and Cronhjart and Nyberg
(1996) found that the resistance to parasites conferred by hypercycle rotors
(Boerlijst and Hogeweg, 1991) is lost in a three-dimensional setting. Is the
topological persistence of rotors in two-dimensional media merely an artifact of
confining an otherwise-three-dimensional reality between closely adjacent
boundaries? Looking ahead a little: Some linked and knotted configurations
seem to resist collapse, at least in numerical simulations; they have not yet been
sought in real excitable media.
• Singular filaments in excitable media have a Iocal property supplementary to the
curvature and torsion that together describe arbitrary space curves and all other
vortex filaments known to physics: as much diseussed above, they also have
"twist," the dependence of rotation phase on are length along the filament. What
role does it play in their dynamies? Looking ahead a little: It provokes straight
filaments to abruptly become helical, given more than a certain threshold of twist,
as described in Box C, and it shortens the local period of rotation, so that waves
radiating from such segments of filament eventually impact directly upon less-
twisted segments with slower rotation. Only the source segments enjoy the
shielding from wave impact that is presumed in all analytical approximations to
filament dynamics up to this writing. The impacted segments, in contrast, are
forced outward. Both may contribute to the observed resistance of linked and
knotted ring configurations ("organizing centers") against shrinkage and collapse.
This has yet to be described in analytical terms, or even to be systematically
resolved in numerical experiments.
• Given at least the form of the laws of motion, a numerieal simulation of any
configuration of rings in a given medium might reveal the missing numerieal
coefficients, and other ring configurations in the same medium should give the
same values. Using those values one might go on to analytically predict
configurations that could robustly persist (if the form of the putative rules admits
such things), and then perhaps contrive suitable initial conditions and try them out.
 ,
b: t.JI'iIKED-A~D KNOmO RINGi)yNA~ICS

Looking ahead a little: we have the persistent configurations, but at present little
idea of the form of whatever laws govem them.
• Might it tum out that the laws must be of such form that they lead
asymptotieally to rigid-body motion of the filament, and to the rotors spin rate
then being the same all along it, and require that rings simply reseale in
proportion to changing spiral wavelength as excitability parameters are varied
(while keeping Q fixed)? A wide variety of stable organizing centers seem to
have nearly these properties.

As these inquiries got underway in 1986, the topological anatomy was weil in
hand, together with existenee demonstrations of (motionless, fixed-period) linked
and knotted rings emitting rotating spiral waves in three-dimensional cellular
automata. Seulpture of isoconeentration surfaces had revealed that filament
segments coming into three-dimensional contact could reconnect and pass through
one another, thus undoing knots and links. They "could" in the sense that this
would not violate geometrieal necessities about the associated ehemical concentra-
tion fields (Winfree and Strogatz, 1984a). But to find out whether the dynamics of
moving filaments would actually favor such events, we need to seed sueh organizing
centers in the solutions of the continuous partial differential equations of excitability
and diffusion.
Three-dimensional computation of seroll rings evolved too quickly to make much
use of the landscapes developed in Section A, which in any case are still not available
for the widening diversity of excitable and oscillatory media deployed in numerical
studies of singular filament dynamics.
Software for three-dimensional studies evolved in Tucson mostly from 1986 to 1990
in the hands of William Guilford, Chris Henze, Erszebet Lugosi, Pramod Nandapurkar,
Victor Reiner, William Skaggs, Michael Wolfson, and myself. About half consists of
vectorized Fortran implemented at suecessive supercomputer centers. These codes
make three-dimensional initial conditions from complex-valued polynomials, integrate
any of a variety of excitable media from those initial conditions or from the saved results
of other integrations, then extract the singular filaments. Filaments go to a Pascal toolkit
for assaying their differential geometry in relation to the local Frenet frame and for
quantitatively correlating with their movements. Altogether these amount to some
30,000 lines of entirely eustom code debugged by proeessing synthetic "data" for
which the correct results were known exactly beforehand. Although the source code
comments, user manuals, examples, and control experiments are thorough, not many of
these tools can be used for long without adjusting source code, and it was all made in
the days before GUls and pre-fabricated 3D graphics became widely available.
So Dwight Barkley (1991) produced EZSPIRAL, a numerically efficient version of
the FitzHugh-Nagumo model in the form of exceptionally convenient C software for
two-dimensional rotor computations and graphic display. With graduate students at
Tueson (e.e. Chen, Gang Chen) I elaborated this to handle a wide variety of
excitable media and initial conditions with different boundary conditions, to do
cylindrically symmetrie scroll waves, to manually change excitability parameters and
filament curvatures while watching the computations evolve, to simultaneously plot
state-space projections of the spatial grid, intervals between suecessive excitations at
chosen grid points, etc. Barkley meanwhile evolved two-dimensional EZSPIRAL to
three-dimensional EZSCROLL, for the first time implementing the superior 19-point
Laplacian discretization (Dowle et aL, 1997). 80th are available for down load to UNIX
machines at http://www.maths.warwick.ac.ukl''-'barkley. Aigorithms for construeting
topologically diverse initial conditions remain available in Fortran for input to the old
veetorized Fortran integrator or to EZSCROLL, together with the Tucson Pascal
Toolkit for analyzing the output in terms of filament geometry and movement, at
http://cochise .biosci .arizona.edul",art.
Exploration of singular filament dynamics can be thought of in terms of two main
currents, as presented in the next two sections.

E: Efforts to Analytically Derive and Numerically Confirm the

Laws of Filament Dynamics
I segregate dynamics into two parts: filament motion and rotor period.

The Dependence of Lateral Filament Motion on Local Geometry

This effort began with attention restrieted to the isolated segment of filament with very
slight twist of spiral phase along its length, and qualitatively slighter curvature and
gradient of twist. It encompasses the first two of the three motivations bulleted above. It
began from the "Iocal geometry hypothesis" first articulated for filaments without twist
or torsion in terms of the radius of a perfeetly circular filament: it was thought to change
at a rate inversely proportional to radius (Yakushevitch, 1984; Panfilov et aL, 1986),
though later numerical experiments indicated that in some media the funetion can be
more general, even having multiple zeros. Imputation of this global rule to each short
segment along a nonuniformly curved filament was implicit; for general filaments that
stay sufficiently far from wave collision interfaces it was soon explicitly articulated
(Winfree and Guilford, 1988) and tested experimentally (Jahnke and Winfree, 1988;
Winfree and Jahnke, 1989; Agladze et al., 1989; Panfilov et aL, 1989), against the
original DIR rule with results good to perhaps ±50% or so.
The local geometry hypothesis bears an analogy to the "Iocalized induction
approximation" for vortex lines in fluids (Ricca, 1991, 1994), according to which the
motion of each segment is proportional to its local curvature, and points in the
binormal direetion, perpendicular to the plane of the locally tangent cirele. The idea
was that in media sufficiently inexcitable to evade spontaneous meander, perhaps the
positive local curvature, some funetion of the local twist and its arc length derivative
(neither of which has any role in fluids), and the local torsion and would jointly
determine

a) the local spin rate (in radianslunit time) or frequency (in cyeles per unit time) of the
rotor
and the two motion components of filament velocity in the local Frenet frame:
b) Vn , alias Rt dot N, toward the center of curvature, and
c) Vb, alias Rt dot B, perpendicular to that and to the filament, usually in the (positive)
direetion of wave propagation through the center of curvature.
 .
E; EFFORTSTOANALYTlCALLY DERIVEAND NUMERldLlY CONFIRM THE LAWS Of ACAMENT Q.YNAMICS
. 475

By summer of 1988 it seemed clear from symmetry considerations alone

(Winfree, 1990b) that candidate laws of motion could involve twist only as an even
function, and the same for the spin rate, e.g., as square of the local twist (or as its
absolute value: Mikhailov et aL, 1985), and that curvature could affect the spin rate
also only as an even function. J.P. Keener's (1988) pioneering analysis provided the
first comprehensive treatment of this problem. A first essential move was to toss
out my silly conjecture that torsion per se could be causally effective. (See Ricca,
1993, for a similar development in hydrodynamics, but using torsion in a context
where twist has no significance.) Keener derived local filament behavior in the
limit of small twist and very small cu rvature, with the conclusion that spin rate, Vn ,
and Vb should be linear combinations three measures of local geometry: local
curvature, k{s), and twist as ~(s), and dw(s)/ds. With the standardized sign
conventions of Box B, with angles measured in radians, and using adefinition of
are length s that keeps each segment of filament at rest in the local tangent
direction:

Increase of rotor spin rate plus corrections for slow rotation of the frame of
reference
=c,k+b,dwlds-a,~ {al

and the two mOfion equations,

(b)

(cl

Note that Vn in (b) is taken positive inward, toward the center of cu rvature,
consistent with Panfilov and Pertsov's (1984) rule "dRidt = -DIR." This rule suffices if
there is no twist or if its four motion eoefficients vanish, as indeed may be the ease
aeeording to Biktashev et al. (1994) or as might be guessed from the implieation of (b)
that a straight filament would otherwise have finite Vn in an indeterminate direction
(Winfree, 1990b page 20). Coefficient c, has the dimension of spaee_units/time_unit. If
it is 0 or k is, then (a) is equivalent to Burgers' equation with weil known solutions that
seem for a while to propagate but eventually become uniform along the filament.
Coefficients a" b" b2 , and C3 have spaee_units2/time_unit; and a2, a3, C2, and C4 have
spaee_units3/time_unit. These coefficients aecordingly contain as dimensional factors
appropriate powers (~, 1, ~) of the diffusion coeffici ent, D, (spaee_units2/time_unit). In
these equations the sealing of organizing centers to spiral wavelength suggested above
is guaranteed if wavelen th is ehanged only by changing D, or if c, oe J(DITo ) and a2,
a3, C2, and C4 oe (fi3 Iro ) consistent with requirements of dimensional consisteney, or
all five are identieally zero, eonsistent with Biktashev et aL (1994).
"Twist" is here defined as torsion of the Frenet frame plus the are length derivative
of phase referred to the Frenet frame (see Box B). Torsion aecordingly appears in the
equations only paired with d</>/ds to eonstitute twist. (In eontrast, Gabbay et aL, 1997
and 1998, mean by "twist" only the arc length derivative of phase referred to the Frenet
frame, without torsion.)
.416 16: NU(01ERICAL ORGANIZ/NG CENTERS

Keener's ansatz should equally weil fit excitable media or fields of oscillators such as
the complex Ginzburg-Landau equation represents, since it is founded only on having
the same reaction-diffusion pattem in all normal planes to a threading filament, with
very little change of orientation from one plane to the next. Gabbay et al. (1997, 1998)
confirm this by computation.
It should also provide an especially simple characterization of media in which all
diffusion coefficients are equal. In that case, of the nine coefficients needed in general
to express (a), (b), (c) in terms of three measures of local geometry, coefficients b, and
~ tum out to be D and all four c's tum out to be O. That leaves only the three aj to be
determined empirically and, as noted above, two of them might be 0 in any case. In
general, though, all nine must be determined by numerical experiment or more
elaborate analysis.
Further analysis by Biktashev et al. (1994) confirmed for excitab'e media in the limit
of vanishing curvature and twist that c, and all four motion coefficients involving twist
(a2, C2, a3, C4) must be 0, even without restriction to equal diffusion. So only two of the
motion coefficients remain to be measured or derived: the two multipliers of DIR
featured in Panfilov and Pertsov (1984) and Panfilov et al. (1986, 1989), similar to b 2 and
C3 above. Gabbay et al. (1997, 1998) came to the same conclusion for slightly curved
and twisted filaments in Ginzburg-Landau oscillatory fields.
If this is correct also for filaments with substantial curvature and twist (the only
kind found in compact configurations of entangled rings such as can be managed
in the computer), then it negates my conviction since Panfilov and Winfree (1985)
that the topological locking-in of unit twist markedly affects motion, and it
simplifies the general description of motion back to what was leamed about large
symmetric twist-free scroll rings in 1983-86: that the isolated vortex filament
emitting scroll waves moves in proportion to (or as some more general function of)
only its local curvature. This is tantamount to describing the filament as a curve
with elasticity, (Yakushevitch, 1984; Panfilov and Pertsov, 1984; Panfilov and
Rudenko, 1987; Krinsky, 1987; Biktashev et al., 1994). (Note that this elasticity in
physical space is not related to the elasticity in state space discussed in Box D of
Chapter 8). Very slightly curved rings shrink if their "tension" is positive (as it
always is in Ginzburg-Landau media and in excitable media with all diffusion
coefficients equal) or unstably expand into tangles if it is negative (as it can be in
excitable media with unequal diffusion coefficients).
"If this is correct. .. then" as stated, or - and this is my own guess - it shows that
(a), (b), (c), considered as the start of aseries expansion in geometric terms, at least need
supplementation by some other important terms, at least when twist is not small. This is
the approach taken in trying to account for the "sproing" instability (incompatible with
a2 being 0) in Keener and Tyson (1990, 1991, 1992). Courtemanche et al. (1990) also
reported linear dependence of rotation period on curvature, incompatible with c, being
o when k is substantial.
While twist may indeed play no important role in the analytically tractable limit of
very small twist and cu rvature, the unforeseen "sproing" instability of filaments
bearing local twist more than about a half tum per wavelength distance (Box C)
cautions us not to extrapolate to the substantial twists inevitable in numerically
manageable linked or knotted rings. During this explosion of local torsion and global
writhing, slightly curved filaments move vigorously away from the center of curvature,
 • i
Ji: EFfCm'S TO ANALYTICA~Y DERIVE ANE> NUMERIGA,LLY CONFIRM :rHE LAWS OF FIlAMENT DYNAMICS

whereas in the absence of twist they move toward it. $0 twist can be considered
irrelevant to filament motion only as long as that twist is slight, as presupposed in the
analytieal derivations.
Meander gives rise to another intriguing counterexample to the idea that
filament motion is determined only by local curvature (at least in the absence of
twist). Though this seems an accurate rule in many tested cases, at least when
averaged over the meander cycle, consider the following case. Adjust the medium's
parameters so the rotor or straight, untwisted filament meanders by looping along a
straight line of arbitrary orientation determined merely by initial conditions. This glide
speed typically exceeds that due to slight curvature of the filament. $0 it would seem
that a ring's net motion could be inward or outward or at any other angle depending
only on initial conditions. I tried this numerically, using asymmetrie scroll ring in the
FitzHugh-Nagumo medium (Winfree, 1990a). At radii comparable to a wavelength,
the glide invariably reorients parallel to the ring's axis of rotational symmetry, i.e., to
the binormal direction. Then curvature alone does indeed still dominate the ring's
shrinkage as anticipated in the absence of meander, but there is an unexpectedly
large binormal drift independent of curvature. In less curved rings the filament differs
from the uncurved (two-dimensional) case much as foreseen, though its direction of
glide gradually changes, thus the direction and rate of drift and of shrinkage or
expansion gradually change: they are not simply fixed properties of the medium.
The analytical theory of such rings, which predicts shrinkage or expansion in the
normal direction at rate DIR, is thought to become more accurate as curvature 1/R
becomes smaller, but the opposite seems more true in thi. range of excitability
parameters.
Efforts to evaluate Keener's six or Biktashev's two motion coefficients by numerical
observation of stable organizing centers have thus far yielded results inconsistent with
the idea that motion components depend separatelyon curvature, twisr, and twist
arclength derivative only through coefficients that characterize a given medium (Winfree,
1990a,b; Henze, 1993). The two coefficients of curvature, for its linear effects on motion
in the Frenet normal and bi normal directions, Vn and Vb, mostly came out in the
expected range, comparable to the diffusion coefficient and in the expected directions
(toward the center of curvature and in the direction of wave propagation through it).
Multiple linear regression for the two coefficients of the arc length derivative of twist and
the two aj coefficients of twist2 (that Biktashev et al. and Gabbay et al. required to vanish)
gave large positive and negative values that differed from one organizing center to the
next, all in the same medium (Henze, 1993). Here again it seems that curvature and twist
must be slighter and the organizing center less compact, or else the local geometry
hypothesis for excitable media needs some sort of supplementation, perhaps to take
account of a nonlocal interaction as worried in Winfree and Guilford (1988).
Another problem, first encountered when Wolfson and Winfree (unpublished) then
Henze and Winfree (1991) got our quantitative differential geometry software working
reliably for the trefoil knot, is that there;. no unique definition of the filament's position,
nor of its twist, from moment to moment! In twisted, curved filaments the gradients of
local state variables, by which phase and so twist are defined, do not tum during one
rotor period at uniform and identical rates as they do in two-dimensional rotors. They
stay mutually entrained, but lurch through the rotation asynchronously. $0 the measure
of twist depends markedly on whether you look at the gradient of A or of B, and at wh at
478

moment during the rotation cycle! And even though parameters are set to avoid
meander in two dimensions, in three dimensions no measure ofthe filament's center sits
still during each tum. The original concepts of instantaneous phase, position, and
direction can be replaced by cycle-averaged concepts defined on a moving window, but
with intraperiod variations so large, this ad hoc expedient is troublesome in practice.
Tyson and Keener (1995) summarize the descriptive successes (often supported by
terms and coefficients beyond the three mentioned above) of the local geometry
hypothesis in application to minimally curved or twisted filaments in relatively
inexcitable media not near collision interfaces. But they acknowledge that "Iocal
geometry is of little help in understanding the known stable organizing centers, which
are the most interesting objects encountered to date in excitable media ... the laws of
filament interactions... are still completely unknown." For a critique of the local
geometry hypothesis as applied to compactly entangled rings with substantial twist and
curvature, see (Winfree, 1995b).

The Dependence of Spin Rate or Rotor Period on Local Geometry

The curvature coefficient C1 of spin rate in (a) above was appraised as -0.044
space_unitltime_unit in a medium with rotor period T 0 = 11.1 time units (Courtemanche
et aL, 1990). In the absence of quantitative analytical theory, the point here was only
that the coefficient is clearly distinguishable from zero. So our attempts to numerically
evaluate the depend.ence of rotor spin rate on twist used a uniformly twisted but
uncurved filament. They progressed no further than confirming the analytical
anticipation of Mikhailov et aL (1985) that twist always shortens the rotation period
in excitable media. (For a review of algebraic attempts to quantify this, see Winfree,
1995b. In Ginzburg-Landau oscillator fields Gabbay et aL (1997, 1998) surprisingly
show that twist can lengthen the period, too.) Then a surprise ended that project.
Although it was unanticipated in motion rules of the form considered so far, in a variety
of media whenever the uniform twist exceeded a certain threshold, seldom far from ~
full rotation per wavelength distance along the filament, the twisted filament abruptly
took on a helical form. The helix expanded, in some cases to a stable radius, in other
cases until striking the boundaries. We ca lied this unexpected instability "sproing"
(Henze et aL, 1990). Beyond this we could not measure the effect of twist alone on
period because sproing converts twist to writhing, decreasing the twist and increasing
the cu rvature. See more on filament instabilities in Box C.
Margerit and Barkley (2000) provide a fresh beginning, in the form of analytical
derivation of the uncurved filament's spin rate as a function of twist. This new
analysis is not limited to small twist and does not require particularly small f by
the standards of two-dimensional calculations common today. Published three-
dimensional calculations mostly resorted to larger f for the sake of numerical
efficiency (smaller € takes proportionately longer per grid point and requires finer
grid spacing in all three dimensions), but they can be redone in today's faster
machines. The expectation is that motion rules will follow, which are not limited to
small twist or curvature, and which will quantify the "sproing" phenomenon that
seems to playa major role in preventing the collapse of organizing centers in
excitable media.
' I:; EFWRTS TO ANAlYfICAl1.Y DERIVE ~ NUMERICA\.LY CONFIRM TI-tE LAW$ OF FILAMENT DY~MICS 479

Box C: Filament instabilities based on local geometry

My assumption in the 1978 version of Chapter 9 was that seroll filaments are stable in
excitable media, exeept for the observed eontraction of symmetrie seroll rings. Maybe
they are, in sufficiently shallow, relatively inexcitable uniform layers. But several surprises
awaited:

• In typieal excitable media the rotor meanders, and so does the filament in three
dimensions. Even in the ease of simple two-period meander, synehrony 8'ong the
filament is unstable, and so the filament soon looks irregularly helieal even in the
absence of mueh twist, perhaps because filament eurvature affects the meander period
(Winfree, 1995a).
• 5tarting from Barkley's model of meander as five symmetry-based ordinary differential
equations, Aranson and Mitkov (1998) eonfirmed analytieally, then by eomputation, that
meanderlng filaments tend to go helieal spontaneously (no threshold required) even
without any initial twist, due to an influence of curvature.
• In marginally excitable media the effective "tension" of a slightly curved, isolated
filament may be negative (Panfilov and Rudenko, 1987; Krinsky, 1987; Biktashev et al.,
1994), with the result that it can behave like a rubber band with negative elasticity. So
even wlthout twist or meander, it spontaneously becomes 'onger and more
convoluted, even budding off little rings.
• A straight nonmeandering filament bearing more than a threshold amount of twist
i
(about ~ to tum per spiral wavelength distanee along the filament in the few cases thus
far examined) suddenly "sproings" into helical form, in some eases stopping at a finite
helix diameter, and in other cases expanding apparently without limit (Henze et al.,
1990).
• In the laboratory Mironov et al. (1996) sought and found this sproing instability in the
malonie acid reagent, dose to the predicted twist threshold and with the predicted pitch
(i.e., the same as oceupied by one cyde of twist). However their medium was not
uniform: there was adeliberate gradient of temperature, thus of spin rate, along the
filament.
• With twist aecumulating and wavelength shortening, the sproing threshold must be
reached unless twist unravels faster at the ends. The original (over-) estimate of a
critical filament length or medium thickness or differential spin rate for accumula-
tion suffieiently faster than unraveling (Winfree, 1994a, 1995c) contained an
arithmetic error. This was spotted by Fenton and Karma (1998a) and they
corrected the result for heart musde to somewhat less than 1 cm: about the
thickness of the dog or human heart wall. Applying the same formula to the
chemieal experiment of Mironov et al. and guessing a sproing threshold near 0.7
tum/wavelength as in our Oregonator computations, we find agreement: Mini-
mum_necessary_differential_spin_rate =spin_rate Ti- D/(speed filamenUength
sproing_threshold) =0.00167/sec 9.87 1.5 10·Scm 2/sec 1(10·3cm/sec 1cm 0.7) =
0.00036 sec. Can we find the data? Mironov et al. reported the critical temperature
difference as 2.8°C and reported spin rates near 0.00167/sec and 0.00133/sec at
the end temperatures: a differential spin rate of 0.OOO34/sec (spuriously exact,
given the roughness of all estimates involved).
• Rousseau et al. (1998) verified the sproing instability threshold in the Ginzburg-
landau field of harmonie oscillators; it arises by supercritical Hopf bifu rcati on, at a
level depending on parameters. And they find a further Hopf bifurcation to
supercoiling of these helices, which has not yet been reported in excitable media.
 , -
16: NUMERICAL ORGANIZlNG C~NTERS.
\.

Independently, Nam et al. (1998) show how the sproing threshold depends on the
two parameters of the Ginzburg-Landau oscillator, and how (in such oscillating, non-
excitable media) that threshold can be as small as zero. I do not know whether a
similar mechanism underlies sproing in exeitable media. In polar coordinates
Mikhailov et al. (1985) and in Cartesian coordinates Winfree (1990b) showed that
the dynamics of a uniformly twisted straight filament in reaction-diffusion media
differs from that of the two-dimensional rotor only by addition of some Laplacian-
like terms proportional to twisf: is it possible to determine analytically at what
magnitude of twist these terms induce the rotor to suddenly f1ee from the former
symmetry axis?
• A blossoming wiggliness of stretching vortex filaments evolves from the Ginzburg-
Landau equations of Aranson et al. (1998) in certain parameter ranges, even in the
absence of twist or meander. Since the effective tension can only be positive in
Ginzburg-Landau media (Iarge rings never expand), this mechanism differs from the one
Biktashev discovered in excitable media.

This package mayamount to generic instability, since meander is generic and

accumulation of twist is inevitable everywhere inside the boundaries of any imperfectly
uniform medium, as weil as in shrinking dosed filaments that are knotted or mutually linked
in even a perfectly uniform medium. In fact, rings topologlcally required to contain a
complete cyde of phase twist (nonzero integer-valued rotation as referred to the Frenet
frame, thus nonzero reaJ.valued physical twist if filament torsion does not add up to much
writhing-and it does not in computed organizing centers-seem to shrink only untll the
local twist approaches the sproing threshold forthat medium (Henze, 1993; Winfree, 1995a).
Something like twist accumulation might account for the comings and goings of rotors
observed on the epicardial surface of thick heart walls. "The rotor" in three dimensions is
actually an open-ended vortex filament that continually becomes more twisted if there is
any transmural gradient of rotor period. It can dissipate accumulated twist only at the
endpoints on epicardial and endocardial surfaces, so if the wall is thick enough its interior
will soon reach a threshold of twist:

• According to one scenario, wavefronts are then too dose together, resulting in patchy
conduction block and creation of new scroll rings (Winfree, 1990c).
• According to another, the sproing threshold is tim reached, as verified by Mironov et al.
(1996) in malonic acid gel, and then filaments lengthen helically, presumably break
against the surfaces, and so multiply.
• Fenton and Karma (1998a,b) found that even wlthout any parameter gradients, mere
twist of the substrate (the rotating anisotropy of thick heart musde) can also induce a
related instability, given about the same minimum thickness. If oriented perpendicularto
fibers, thus along the axis of their rotation in such a "cholesteric liquid crystal," the
filament tends to buckle into localized "twistons" that propagate along it and sometimes
break off as separate rings or transmural filaments (Figure a). This, of course, requires
that the rate of fiber rotation exceed a threshold, but not by too much, lest the medium
become effectively isotropic on the scale of the rotor. Since the total rotation is ~ to 1
1800 tum in any mammalian ventricular wall at least several millimeters thick, this means
that twistons are expected only in walls of middling thickness, around ~ to 1 cm, as is
common in big rabbits, dogs, pigs, and humans.
• In media with such cholesteric anisotropy, again in a middling range of fiber rotation
rates, filaments tend to align to the fiber direction (Berenfeld and Pertsov, 1998), so here
is yet another instability of the upright, transmural filament.
• Which one of the foregoing potential instabilities is the first to erupt may depend
delicately on quantitative parameters.
 Flg.... '" Vortex Hne, m"""ting the de"" of
"tachycardia" to "fibrillation" as conceived in terms
@~ @
of filament instability in an adequately thick heart
wall. The rectangular volume eontains anisotropie ~[l@ ~
eardiae membrane modeled on its known electrieal
eharacteristies, including the progressive rotation of
fiber direction around a vertieal axis parallel to the
initial filament extension. (From Fenton and Karma,
'99ab, with penn;",;on.) ~~ ~

Regardless of the ehoice of potential filament instabilities, nothing much can become of
them unless the medium (e.g., the heart wall) is thick enough to accommodate a rotor Iying
on its side. Only then can instabilities blossom into writhing filaments. This was my theme
song at cardiology meetings after 1988, culminating in a 1994 review in Science. Since then
a wide variety of theoretical filament instabilities have come to light, and some of them do
as foreseen when given adequate wall thickness. Whether any of them occur in thick heart
muscle remains to be seen (Chapter 17).

The all-important shortening of rotor period as some even function (e.g., the
square) of loeal twist has still not been measured numerieally in excitable media, and the
only related laboratory observation is Figure 2b of Pertsov et al. (1990). This shows a
15% shortening of period over the observed range, not of loeal twist, but of total twist
on a very nonuniformly twisted filament. But Mironov et al. (1996) improved the
experiment of Pertsov et al. (1990) in gelled malonic acid reagent under conditions that
might permit observation of sproing in sufficiently twisted filaments. They found it
(though again only in a persisting gradient of rotation period). The threshold reported
is about 0.7 rotation per wavelength distanee along the filament, as in the anticipatory
Oregonator and FitzHugh-Nagumo eomputations. Rousseau et al. (1998) found a
similar instability in Ginzburg-Landau media and argued that, like meander, it
represents a forward Hopf bifureation.
To the extent that overall shape stays the same while linked and knotted rings
shrink, a eertain total rotation of eoneentration fields is eonserved: the loeal twist (i.e.,
per unit length) inereases during eontraction. Quantitative observation (Henze and
Winfree, 1991; Henze, 1993; Winfree, 1995a) shows that eontraction stops when loeal
twist approaehes the sproing threshold. At this point twist abruptly begins to trade off
into writhing. The sproing instability shows a eritically important involvement of twist in
a eurved filament's motion, at least when twist exeeeds threshold. So either the four
motion eoefficients of twis~ and of the are length derivative of twist cannot all stay zero
as Biktashev et al. (1994) and Gabbay et al. (1997, 1998) show them to be while rings are
very large, with correspondingly slight twist, or, thinking of the laws of motion as power-
series representations as in Keener and Tyson (1990, 1991,1992,1995) and in Tyson and
5trogatz (1991), there must be more terms mixing twist and eurvature, or we need an
altemative to power-series expansions.
 In short, computation, analysis, and laboratory experiments overlap convincingly in
only two principles, so far:
• twist-free flat large vortex rings shrink like "dA/dt = -211D," and
• twisted filaments sproing into a helix when uniform twist exceeds a threshold.
Both can be stated more quantitatively in terms like (a), (b), (c) above:
• Vn and Vb are both proportional to filament curvature, with coefficients D and 0 in
case of equal diffusion, and
• Sproing can be accommodated in (a), (b), (c) by supplementing them with new
terms appropriately featuring curvature 2 and twist4 (Keener and Tyson, 1990, 1991,
1992, 1995).
Are these two oppositely directed " mechanisms" sufficient? Numerical experiments
dash this hope with yet another counterexample. The Borromean rings of Henze (1993)
and of Winfree (1994b, 1995a) are not in the classification scheme of Winfree and
Strogatz (1984a) because they are neither pairwise linked nor knotted. For the same
reason their twist, even if it were not initially uniformly zero, would promptly become so
unless something beyond the scope of present-day theory intervenes. It does. The
initially flat rings develop little writhing, some torsion, and substantial nearly equal and
opposite thus positive and negative local twist. The local twist in fact develops further
than it does in any other known object, right to the sproing threshold for this well-
characterized excitable medium. So wh at is theextra "something"? Each ring drifts in the
standard direction (the direction of waves through the interior of an isolated ring) only
until it visibly snags on the perpendicular filament of another ring, and accordingly
bends while more distant parts of the same ring drift a little farther before stopping. The
big, uniformly curved ares of each ring are now drifting badcwards, in the negative
binormal direction, opposite to wave propagation through the inside of the curve. It
proved impossible to find even a convincing ad hoc descrlption of this ring's motion in
terms of additive effects from local geometry. Moreover, after it "smushed" into a wall,
not only at its front near the plane of contact but also almost immediately at its rear, as
though parts of the organizing center interact not through diffusion but through wave
propagation. When that wall was then removed, the deformed organizing center
showed no elastic rebound to its original three-fold symmetry, but continued misshapen
through another 50 rotor periods of gliding through an enlarged box. This suggests that
solutions are not asymptotically unique (perhaps because the positions of intemal wave
collision interfaces are not).
At the moment, the principles we have seem insufficient to interpret numerically
observed filament dynamics. No analytical theory provides even a richly parame-
trized framework for the needed "something." Twist-induced sproing seems to be a
key local geometry factor contributing to the observed reluctance of such rings to
contract any further, thus preserving organizing centers from reconnection and
collapse, but motion is strongly affected by something else, too. I suspect that is
another twist-induced mechanism, a shortening of the local rotor period, which
impels wavefront collision interfaces toward less-twisted segments. With chagrin, I
feature this in Section F as no more than a speculation. In a ten-year computational
buildup that filled meters of shelf space with neatly organized three-dimensional
numerical experiments, just about everything was measured except, ironically, what I
now retrospectively imagine was the most important thing: motion of the collision
interface.

F: The Discovery of Persistent Ring Configurations

Might there be diverse alternative solutions to the reaction-diffusion equations of
a given excitable medium? Answering this question is the last of the three aims
bulleted above. This stream of inquiry had to proceed almost independently from
inferring laws of motion (known only for isolated filaments with little curvature or
twist) because stable closed rings turn out to be rather compact. They have much
greater curvature and twist and are length derivative of twist than contemplated in
analytical approximations, and they do in fact behave quite differently from
analytical expectations. But first we must find some.
The very first were scroll rings without twist, confined in a cube with numerical no-
flux boundaries like the glass walls of a square test tube. With parameters adjusted to
marginal excitability, rings expand, are repelled from walls, roll up the walls to a ceiling,
and shrink while rolling along it, but only to a stable radius. Some rings pulsate,
extending along one diagonal, then along the other (Nandapurkar and Winfree, 1989).
These solutions seemed to require support from the walls, and they arose only in the
peculiar margins of parameter space. But a very similar "bell-ringing" ellipse was also
observed in the smooth FitzHugh-Nagumo medium (Henze, 1993), not involving walls,
and not requiring marginal excitability. This inertia-like behavior would seem to
implicate changing twist distributions (measurements lacking) in directing the filament's
lateral motions, or else it subverts the very notion that motion is wholly determined by
instantaneous geometry.

Compact, Localized, Particle-like Solutions: Stable Organizing Centers

According to the last section of Chapter 9, the next thing to do after watehing scroll
rings shrink and vanish in the laboratory, and then in the computer (Section B above),
would be to compare with ascroll ring made with one fu" cycle of twist locked in.
Gomatam (1982) and Gomatam and Grindrod (1987) showed that something like this
could be a solution to linear;zed reaction-diffusion equations. Its ethereal beauty
remained unguessed until its movements were animated computationally on videotape
and illustrated in stereo color with the help of a 3D graphics computer (Winfree and
Strogatz 1983b). When it became possible to actually compute it from the nonlinear
partial differential equations of a piecewise linear excitable medium (Panfilov et al.,
1985; Panfilov and Winfree 1985) it was found to be stable, at least short-term, except
that it slowly drifted at about 1% of wave speed (Mach 0.01) until colliding with one wall
of the containing box, whereupon it vanished, leaving only the topologically required
singular filament threading the original ring. This unclosed filament quickly became a
stably persisting vortex line with ends on two opposite walls. By allowing the drifting
ring, as it exits through the ceiling, to reenter the f100r of its finite volume of medium
(periodie boundary conditions) Nandapurkar and Winfree (1987) and Nandapurkar
(1988) discovered that the ring's slow shrinkage, unlike that of the vortex ring with no
twist locked in, comes to a halt: the ring cannot shrink too tightly around the threading
singularity created by its twist. Perturbed, it springs back to the preferred diameter and
continues its steady drift. Thus we have a stable solitary ring, the first reported fully
three-dimensional stable organizing center, independent of walls.
But is it really independent of walls? Maybe not, since its threading filament needs
them, or else needs to go on forever or to elose in some big ring, but in the latter case
wouldn't we be tal king about the stability or instability of a linked pair of twisted rings,
not of a single twisted ring? Maybe this numerical experiment doesn't really count as a
fully three-dimensional stable organizing center. Or maybe it does count if the
threading filament is simply the locus of inward collisions originating from the ring, not
really a source of waves. In Winfree (1990b Figure 20) I presented it so in some detail,
but later computations showed that things can also happen otherwise. In 1987, using
FitzHugh-Nagumo cubic excitability with only the fast activator diffusing, Bill Skaggs
had discovered a parameter combination such that the radially symmetrie scroll ring
shrinks to a stable radius, as noted above. In 1991 I repeated that experiment with the
same medium and parameters but with a twisted ring (perfect cirele, one cyele of
uniform twist locked into it). This time the ring expanded rapidly while writhing out of
the plane, and the vertical threading filament became an outgoing scroll all along its
twisted and helical length. These experiments were not diversified to determine how
much this behavior owed to initial conditions (vertical filament too twisted, thus
radiating at aperiod shorter than the ring? ring too smalI, thus twisted beyond the
sproing threshold?), but they did show that the answers for a given topology do depend
on the excitability model and/or the initial conditions.
As for the linked pair of equally twisted rings (both left-twisted, or both right-
twisted), they have often proved unstable, but Henze (1993) showed one robustly
persisting in that same Skaggs-parameter version of FitzHugh-Nagumo excitability. So
let's count the twisted ring as the first stand-alone case, but footnote that it seldom lasts
long, particularly if either ring is interrupted by a wall.
The second stable organizing center also came from Nandapurkar's (1988)
computations in 1986-87. This is a trefoil knotted ring, which, like the linked twisted
pair, exists in either of two mirror-image forms. Its anatomy was exhaustively studied by
Wolfson and Winfree, then by Henze and Winfree (1991) (Figure 5). Keener (1989) was

Figura 5. A view along the symmetry rode of a stably

precessing, trefoil-knotted phase singularity. The seroll
waves radiating from it are textured in light gray. They are
interrupted along the sides by the invisible and imperme-
able walls of this eube of excitable medium. Rotors in this
medium spin rigidly without meander. The organizing
center in three dimensions is spatially smooth, quite
regularly periodic in time, and reeovers nicely from
perturbations. (From Henze and Winfree, 1991 Figure
14h of a set of 12 color photographs from various
perspectives wh ich collectively give a clearer impression
of the geometry.)
 F: THE DISCOVERY OF STABLE RING CONFIGURATIONS 485

able to show that a very large knot can be a solution to the reaction diffusion equation,
but it was not possible to specify its parameters for any particular such medium; in our
experience (numerically limited to nonlarge knots), a knot is stable only when small in
the sense that total are length is only about 8 wavelengths of the spiral, so rotors are
tangent along much of this perimeter and its average twist approaches half a tum per
wavelength.

• Is it stabilized topologically, by a reluctance of filament segments to pass through

one another as the knot shrinks? Filaments never get doser together than about ~
spiral wavelength. Because of a mutual repulsion? Or is that too far apart to evoke
substantial interaction? No effects of such proximity per se have yet been
detected.
• So is it instead stabilized by the coincidental circumstance that as it shrinks to the
size at which rotors come in contact, the locked-in twist (cumulatively about 3 full
tums along about 8 wavelengths of filament perimeter) along the three most-
twisted straight intemal segments reaches the sproing threshold? Though this twist
does not become uniform (why not?), no segment dearly exceeds the (roughly
known) sproing threshold, nor has any sudden change of shape been observed in
the last stage of shrinkage.
• So is it instead stabilized by wavefronts from faster-rotating segments slapping
outward the less-twisted outer segments of filament?

All three processes become plausible candidates at about the same size during the
knot's gradual contraction.
Meanwhile, the knot slowly precesses and glides helically along its symmetry axle.
Each big curved are of the knot is slowly drifting in the positive binormal direction like a
piece of a twist-free scroll ring. In fact, every one of the dozen or so organizing centers
known in media whose rotors don't spontaneously meander eventually moves like a
rigid wire sculpture tossed spinning through the air. Does this tell us something about
the underlying "Iaws" of filament motion? What dass of rules guarantees evolution of
shape until every segment moves as though the whole were a unified rigid body?
The trefoil knot is a stable particle-like solution to the reaction-diffusion equations
of at least the piecewise linear excitable medium used above and of the FitzHugh-
Nagumo excitable medium at various parameter combinations. It violates the rules
derived for vanishingly slight curvature and twist in that:
• 5harply curved segments of filament do not further contract toward their centers of
curvature;.
• In any stable ring configuration every segment of which looks like an outgoing
scroll wave, each scroll's rotation period must be the same all along its length. In
fact, it iso If this synchrony is established only through local geometry, through a
spin rate function of geometry like (a) above, then this subjects the triplet
(curvature, twist, are length derivative of twist) to one constraint. In this
descriptive three-space every ring in such a stable organizing center must then
lie like a necklace on a single isoperiod surface (wh ich would be a plane, in such
additive framework as (a) above), and every other kind of stable organizing
center in the same medium must lie on adjacent surfaces according to their
respective periods. Necklace plots did not bear this out for the trefoil knot in
486

the piecewise linear excitable medium of Henze and Winfree (1991); nor for
similar knots and other structures in the cubic FitzHugh-Nagumo medium of
Henze (1993).
• The distribution of twist along the filament does not become uniform. In the
limiting-case analysis of huge rings with correspondingly slight twist (Keener, 1988),
spin rate is augmented in proportion to the length derivative of local twist and the
square of local twist, from which follows Burgers' equation for the evolution of local
twist along the filament, and its Cole-Hopf transformation produces the heat
equation, under which localized peaks of twist should not long persist. But they do
in these small rings (Henze and Winfree, 1991). And since they do (and supposing
spin rate is much more sensitive to twist than to other factors), the spin rate should
vary along the filament, so if waves are outgoing all along the filament, then the
organizing center should not exhibit a uniform periodicity. But it does, presumably
because along some ares waves are in fact incoming at least from one side, spoiling
the assumptions that led to the unforced Burgers' equation. We deal rather with a
forced Burgers' equation, but it is still autonomous since the forcing comes from
some part of its solution.

The third-discovered stable organizing center might be the helix that bloomed to a
preferred radius by "sproing" when more than a critical twist was uniformly imposed on an
initially uncurved filament (Henze et al., 1990). But this one also runs on to infinity or to
supporting floor and ceiling, so it is compact and particle-like only in two of its three
dimensions. Or the third discovered might be the symmetrie scroll ring encountered by
Brazhnik et al. (1987) and Skaggs et al. (1988), as deseribed in Section B. Various published
litanies have put the several objects found in 1986-89 in various orders beeause actually
each only graduallyqualified as "stable" and as nonartifactual during the eourse of about
of year of diverse and overlapping numerieal experiments with different media,
parameters, grid refinements, boundary conditions, and initial conditions. As with
mushrooms culminating after a week of rains, their maturations overlapped during those
years of brash trials with still-evolving software.
By 1991 all differential geometry software was working reliably, and the
FitzHugh-Nagumo landscape survey (Section A) was finished. A parameter
combination was chosen in which to examine three-dimensional solutions completely
quantitatively. Skaggs's 1987 ehoice seemed ideal for speed of eomputation and
stability of the rotor (only the fast reactant diffusing, comparable rates of excitation
and recovery, no meander, no spontaneous oscillation), so Chris Henze continued
with it for his dissertation (1993). The upshot was a collection of nine: three familiar
plus six new topologically distinct particle-like linked and/or knotted organlzlng
centers. These appear to be alternative solutions to the same partial differential
equation:

• radially symmetrie circular seroll ring (as described in Section B)

• 2:3 torus knot, alias trefoil knot (as previously described using piecewise linear local
reaction laws, but with a markedly different twist distribution w(s) in this medium
with eontinuous local reaction laws)
• stable helices (Iike those found earlier using a piecewise linear local reaction and
using the Oregonator chemical model with both reactants diffusing)
 ,j:; THB D'SCOVE~ Of STABtE RING CONFJ~URA'tIONS I

• 2:5 torus knot (new)

• linked pair of twisted rings (stable, though it seemed not so when using piecewise
linear reactions)
• pair of rings each Iinked twice through the other (new)
• "Star of David" pair of rings each Iinked three times through the other (new)
• three rings each linking once through the other two (new)
• Borromean rings: three not pairwise linked but inextricably entangled (new)
These successes demonstrated the utility of complex-valued polynomials for
initial conditions (Winfree, 1987a Appendix; Poston et al., 1992), though
parameters required finicky tailoring. (The Borromean rings, moreover, because
not topologically linked, required an ad hoc method.) The resulting solutions
quantitatively exhibit the topological rules for writhing, twist, and linkage
discussed in Winfree and Strogatz (1983a,b,c), in Winfree (1990b), and in Tyson
and Strogatz (1991). Possibly because of their high curvatures and twists, they do
not reveal any one consistent set of the six (or less) motion parameters implicated
in dynamical analysis of motion in low-curvature, low-twist filaments.
All these rings shrink until skew segments of filament are about one half
wavelength apart, with the collision interface midway between them, little more than
a rotor radius from each. Each glides and precesses along a symmetry axle at rates
two orders of magnitude slower than wave propagation from the rotor. All appear to
be stable, except that the trefoil knot and the Star of David thrice-linked pair have a
tendency for one lobe to abruptly balloon out after the shape had seemed to be
converging to maturity for scores of rotor periods, and except that Borromean rings
exhibited an unexpected plastic defonnation after rebounding from a wall, as
mentioned above. I suspect that if we could see the slightly twist-accentuated spin
rates of all segments, and the correspondingly slow motions of internal collision
interfaces between sero 11 segments, then we could begin to understand the real
detenninants of shape and stability.

A Dramatically Simple Counterexample

For an simple example to compare with analytical models in their simplest ca se (equal
diffusion), I made a knot in FitzHugh-Nagumo medium with only the "excitor" variable
diffusing, as usual in "application" to electrophysiology, then gradually introduced
diffusion of the "inhibitor" reactant until the two diffusion coefficients were equal, as
usual in "application" to chemicals in solution. (See Malevanets and Kapral (1996) for a
chemical interpretation of these specific equations.) Parameters were chosen from the
equal-diffusion equivalent of Figure 3 to produce nonmeandering filaments. If theory
based on equal diffusion and local geometry with asymptotically slight curvature and
twist were pertinent even to this finite case, then twist would be irrelevant and each
segment of the knotted ring would shrink like a segment of a circle, moving directly
toward its center of curvature at speed DIR. They did indeed shrink, though even at the
outset their curvature and twist were doubtless weil beyond tolerance for at least the
str;ct interpretation of that asymptotic theory. Shrinkage continued only until the three
cycles of twist confined along the shrinking ring resulted in "sproing." Thereafter, the
knot reexpanded steadily back to its original size, exploded into helical "sproing,"
underwent a filament collision and re-connection, and expanded further as a pair of
linked rings, to the limits of the large numerical grid used (Winfree, 1995a). If it had a line
tension (Yakushevitch, 1984; Panfilov and Pertsov, 1984; Panfilov and Rudenko, 1987;
Krinsky, 1987; Biktashev et al., 1994), that tension must have been initially positive, as
required with equal diffusion, but then it apparently became persistently negative! This
dramatic violation of expectations suggests the working of a supplementary, nonlocal,
mechanism.

Turbulent Tangles: "Persistent Organizing Centers"

The question naturally arises, whether the stability of the nine known periodic
organizing centers depends critically on the peculiar choice of FitzHugh-Nagumo
parameters adopted. The first of them, the symmetrie sero 11 ring, is known to lose its
stability if those parameters are altered by more than 10% (Courtemanche et al.,
1990). And the others, with skew segments so delicately juxtaposed that their
concentration gradients seem to turn like meshed gears in a transmission,
additionally lead one to wonder wh at would happen were filaments to meander.
Perhaps the same as when an organizing center is substantially deformed
numerically: segments cross-connect or pass through one another, and we end up
with shrinking disjoint rings. Or with parameters tuned for "linear looping" meander,
segments might glide in diverse directions, tearing the organizing center apart.
Could all the organizing centers found to date be only "hothouse plants," in the
sense that they survive only under carefully selected permissive conditions? Krinsky
(1987), for example, rightly notes that no analytical solutions have been found for
such objects, and there is no evidence of them in nature, so they must at least
provisionally be regarded askance.
I accordingly created new organizing centers in bi9ger boxes and gradually
changed the medium's parameters toward maximally violent meander, as indicated
by the two arrows on Figure 3. Filaments became asynchronously wiggly, and wave
pattems grew complicated and never repeated, in stark contrast to the regular

Figura 6. Stereo view of a closed-ring singular filament (suppressing the surrounding scroll
waves radiating from from it) configured as a trefoil knot. The line segment protruding from the
center of the cube into the foreground is the original symmetry axle of initial conditions
prescribed by complex-valued polynomials. The cube is 3.6 rotor wavelengths on edge. View
with eyes crossed through a pencil point midway between eyes and page. (Reproduced from
Physica D 84, Winfree, A. T., "Persistent tangles of vortex rings in excitable media" pp. 126-47
Figure 1, Copyright (1995a), with perrnission from Elsevier Science.)
 ~ -
F; TH,E DISCOVE~_ OF STABLE RING CONFlGUAATIONS 489

Flgure 7. Stereo view of three rings eonfigured so eaeh links through the other two. All of these
Figures 6 through 9 depict objects that have persisted through scores of rotor periods without
visible indieation of seeular trends after the first dozen or so, apart from slow glide and rotation
along the original symmetry axle. Asymmetrie seroll ring of eomparable initial size in the same
medium shrunk and vanished eompletely long before these snapshots. (Reprodueed from
Physiea D 84, Winfree, A. T., "Persistent tangles of vortex rings in exeitable media" pp. 126-47
Figure 1, Copyright (1995a), with permission from Elsevier Scienee.)

Flgure 8. Stereo view of three rings inextrieably entangled without pairwise topological
linkage, initially three identieal but orthogonal ellipses. (Reprodueed from Physiea D 84,
Winfree, A. T., "Persistent tangles of vortex rings in excitable media" pp. 126-47 Figure 1,
Copyright (1995a), with permission from Elsevier Scienee.)

"'

/
~
Figur. 9. Stereo view of two rings, eaeh linking twiee through the other and (I do not know
why) maintaining symmetry through the indicated axle while they beeome otherwise ostensibly
irregular. (Reprodueed from Physica D 84, Winfree, A. T., "Persistent tangles of vortex rings in
excitable media" pp. 126-47 Figure 4, Copyright (1995a), with permission from Elsevier
Science.)
periodism and beautiful symmetries of all prior organizing centers (Figures 6 through
9). I call them "persistent turbulent tangles." Relative to the initial stable organizing
centers, these rings when induced to meander all expanded somewhat as though
thermally agitated, but they did not tear apart and they did not cross-connect or
pass through one another: surprisingly, they preserved their topological integrity
(Winfree, 1994b, 1995a). These organizing centers are robustly persistent; they are
not hothouse plants. Their robustness suggests that such things might be observable
in the laboratory.

G: For the Future

He has his own little methods which are, if he won't mind my saying so, just a little too
theoretical and fantastic, but he has the makings of a detective in him.
- said of Sherlock Holmes, in The Red-Headed League

An Unproven Alternative to Local Geometry as the Cause of Motion

All analytical work on singular filament dynamics (Keener, 1988; Winfree, 1990b;
Keener and Tyson 1990, 1991; Tyson and Strogatz, 1991; Keener and Tyson, 1992;
Biktashev et aL, 1994; Tyson and Keener, 1995; Aranson et aL, 1998; Gabbay et
aL, 1997, 1998; Margerit and Barkley, 2000) is founded on the notion that the
scroll wave everywhere along the ring is radiating outward. This screens the source
filament from the impact of waves from afar. Winfree and Guilford (1988)
anticipated possible trouble here, inasmuch as internal wavefront c:ollls;on
interfaces could be presumed to move from faster (more twisted) filament
segments until slower (Iess twisted) segments are directly slapped. Such events
have been much studied only in two dimensions (Krinsky and Agladze, 1983;
Sakaguchi, 1989; Huber, 1993, 1994; Aranson et al., 1996; Ruiz-Villarreal et aL,
1996, 1997; Steinbock, 1997; Rogers et aL, 1997; Schebesch and Engel, 1999; see
Box D). In three dimensions Henze and Winfree (1991) found symmetrically
disposed segments along the stable trefoil knot where the spiral's core was
unprotected from periodic slapping by wavefronts presumably radiated from more-
twisted, shorter-period segments elsewhere on the knot. It seems possible that this
twist-induced nonlocal interaction is a sec:ond (after sproing) source of outward
pressure by which organizing centers resist curvature-induced collapse. In fact,
every known persistent organizing center in excitable media that support meander
does reveal slapped segments (Winfree, 1994b, 1995a), and so does the non-
meandering knot of Henze and Winfree (1991).
This is proffered as a mechanism, not the mechanism. Some persistent rings seem
supported by sproing alone, without slapping. Henze (1993) reported no "slapping"
in nine topologically distinct stable organizing centers in the narrow peculiar range of
FitzHugh-Nagumo parameters that stabilizes even the perfectly uniform and
symmetric, twist-free scroll ring. Nor can it occur in the perfectly uniform slim stable
helices of Oregonator media (Henze et aL, 1990). And non-ring filaments such as we
encounter during fibrillation in heart muscle (next chapter) can last at least a long time
 G: FOR THE FUTURE 491

Box D: A Numerical Artifact

The slapping of one rotor by waves from another is a familiar enough observation in
chemical gels, particularly when the "shrinking blue lake" mechanism initiates rotors
asymmetrically and dose together. But what if they are initiated with such perfect symmetry
as can be achieved only by double-precision digital computation? Spontaneous symmetry-
breaking in the real analog world is not hard to understand: there are at least molecular
noise fluctuations, and if the system's eigenvalues have positive real part, then one of the
corresponding mirror-image asymmetrie pattems will intensify exponentially until it
becomes macroscopically conspicuous. But a digital computer manipulates discrete bits
and has no significant noise fluctuations. In floating-point ca!culations there are round-off
errors, but they happen identically in replicate computations. Replicates can be run for a
long time, saved, then differenced to the last bit: the resulting array contains not a single
bit. And initial conditions for a pair of rotors can be prescribed by writing the array's left half,
then replicating its contents in column-reversed order into the right half, with no error. Rotor
behavior then proceeds with ostensibly perfect symmetry, the two mirror-image fields
staying exactly so - but only for a while, surprisingly. Then differences in the high-precision
bits begin to show, and after an hour or so one rotor is slapping the other into a logarithmic
spiral path of retreat. Which one? The selection seems random in runs with slightly different
parameters or initial conditions, but in exact repeat runs it is always the same one. What on
Earth could be going on?
Gang Chen and I took this up as a puzzle during a few days of 1997, during his graduate
studies in Tucson. The answer surprised us both, though undergraduate majors in
philosophy, logic, or computer science could probably have told uso This provides an
entertaining diversion from reading dull books, and I recommend it here. If you want to
peek, see my web site.

if oppositely oriented filaments do not strongly attract one another and their
endpoints are on disjoint boundaries of the medium (e.g., endocardium and
epicardium).
This chapter is thus ending with the unsatisfactory conclusion that there may
be multiple mechanisms of sero 11 ring stabilization, just as there are apparently
multiple mechanisms of filament instability, and none of them are yet weil
understood. But it gives an impression of the dominant importance 01 twist on
filament motion, either through the local laws of filament motion underlying the
sproing instability, and/or through its local effect on spin rate and so on the non-
local movement of internal collision interfaces whose eventual contact with the
filament may be what preserves the twist distribution fram becoming uniform, and
so restrains filament rings from further curvature-induced contraction. How much
of this is fantasy? We still do not know the mechanism of the sproing instability.
Nor have the anatomy and motion of collision interfaces within stable organizing
centers been described in adequate detail. We made vigorous efforts to add an
interface detector to the Fortran toolkit, but not much came of it beyond Figure
15 of Henze and Winfree (1991) and the few verbal descriptions of interfaces in
Henze (1993). In 1994 I reported turbulent tangles robust enough numerically to
encourage attempts to observe them in nature, then abandoned such computa-
tions in order to design and build an instrument for optical tomography (Winfree
et al., 1996; see last section of Chapter 13) and then to collaborate with Frank
Witkowski (Archer, 2000; Corr, 2000) in experiments on living hearts (Witkowski et
al., 1998). If computations could be resumed today with machines an order of
magnitude more powerful and with the questions in better focus, their answers
might come to hand promptly.
The next adventure in computation should be to find out whether the formerly
invisible movements of intemal collision interfaces really are the missing ingredient in
this story. And then to find out what aspects of the now-familiar behavior of simple
excitable media also appear:

• in much simpler, nonexcitable media like the smooth quasi-harmonie oscillators

described by the complex Ginzburg-Landau equation. Gabbay et al. (1997,
1998), Nam et al. (1998), and Rousseau et al. (1998) provide a good start on this
in the limiting case of slight twist and slighter curvature and are length derivative
of twist. To date no stable organizing centers have been described in this
medium; or
• in media with a higher-dimensional local state space. We think of the vortex
filament as the intersection of critical isoconcentration surfaces of the two
prominent reactants in the Oregonator or FitzHugh-Nagumo models, but what if
there are three, as in a fuller Field-Körös-Noyes approximation that includes [Br-]?
What if the center manifold is not rapidly approached?
• in such arbitrarily complicated Rube-Goldberg's as we encounter in electrophysio-
logical membrane excitability, particularly in heart muscle.

H: Transition to Chapter 17 About Heart Musde

One could (and I did) start on the last question, at least in two dimensions, by going
directly to eight local state variables in the Beeler-Reuter (1977) model of the
ventricular muscle cell membrane of the mammalian heart, in hope of answering also:
• Can heart muscle be usefully treated as a continuum?
• Does a realistic ionic membrane model support rotors? Support singular filaments?
• If so, are they plausible as mechanisms of familiar electrical dysrhythmias in the
normal heart?
• Are such solutions preposterously large compared to a rabbit heart or small
compared to muscle cells?
• Is their period much longer or shorter than familiar prefibrillatory tachycardias?
• Does the cube of the period depend linearlyon the product of excitation time by
the square of recovery time, when the ratio of those times exceeds 100 or so, as in
the Fife domain of simpler models?
• Do this complex model's rotors exhibit meander of the kind familiar in simpler
media?
• Can rotors be erased in the various ways familiar in simpler media?
• Are there other modes of sustained electrical activity, unknown in simpler media?
• And a question definitely requiring supplementary variables in a more elaborate
tissue model: Once a rotor is started, does it slowly modify the rapidly paced tissue
 so as to make rotors less viable, thus curing the problem, or so as to make
propagation unstable, resulting in fragmentation of wavefronts and pernicious
multiplication of rotors?'
Answers to the first five became clear weil before 1990: yes, yes, yes, no, no.
Different answers would have stopped this development in its tracks, but instead the
foeus had by then shifted to laboratory experiments in living hearts, in large part due
to four invitations from Jose Jalife, MD, to visit and give seminars on seroll waves,
starting in 1979, and another eight visits with Ray Ideker, PhD and MD, starting in
1985 and six visits with Frank Witkowski, Bach. Electr. Eng. and MD, for experiments
on dog hearts. Their openness to engage a new paradigm starting in the early 19805
made a difference; it became possible to publish such notions in physiological and
medical media. The illuminating survey book of Zipes and Jalife (1985), for example,
still eontained nothing of this sort, but a chapter on scroll waves in fibrillation appears
in Zipes and Jalife (1990) and still more, by multiple authors, in Zipes and Jalife
(1995). The new willingness of physiologists to test this conceptual and topological
paradigm in the laboratory was timely, because attempts to quantify its inferenees by
incamating them in electrophysiologieal computations were producing fewer real
results than gratifying mirages. The 1977 Beeler-Reuter model, for example, proved
not so realistie as hoped for. Models informed by more recent electrophysiology
behave in more complicated ways. It is not yet known how the complex behavior of
rotors and waves in such models relates to that witnessed in real myocardium, nor
what aspects of either represent adaptive enhancement of heart function, and what
others are just happenstanee side effects of complexity evolving with neutral selective
value.
But it ;5 known that efforts such as reviewed in this chapter and in Chapter 13 on
chemical rotors have usefully informed at least the formulat;on of que5t;ons about
cardiac dysrhythmias. For example, six kinds of chemical experiments have exact
analogues in myocardium:
• creation of seroll rings in opaque media and interpretation of patterns of wave
eruption on their surfaces (Winfree, 1973e, 1974d; Medvinsky et aL, 1982, 1984),
and similarly for ares of scroll filament ending on internal surfaces (Winfree,
1973b and c, 1974b; Biktashev et aL, 1999; Efimov et al., 1999; Vigmond et aL,
1999);
• creation of rapidly moving J-shaped filaments that are partly transmural and
partly intramural (Jahnke et aL, 1988; Agladze et aL, 1989; Krinsky et aL,
1990);
• observation of wave trains from a rotor propagating along a gradient of material
properties, resulting in formation of discrete domains of successively lower
frequencies (Box A of Chapter 14; Figure 8 of Chapter 17);
• systematic search for a thickness threshold beyond which rotors could become
freely moving filaments (Winfree, 1973c; Kavanagh et aL, 1992);
• quantitatively controlled creation of paired phase singularities (Winfree, 1983b,
1985; Shibata et al., 1988; Frazier et al., 1989);

The most sophisticated model deployed to date indicates the latter: Chudin et al. (1999).
 • erasure of phase singularities (rotors) by momentarily extremizing a parameter of
the local reaction throughout the medium (Winfree, 1978a; electric shock
defibrillation in general).
In the next chapter we examine the recent evolution of thinking and experiments in
this area, from the limited perspective of this book's original themes: the geometry of
periodic dynamies, and in particular of phase singularities.
 CHAPTER 17

Then fell Alcathous, son of noble Aesyetes: he was son-in-Iaw to Anchises [the father
of Aeneas) ... him did Neptune lay low by the hand of Idomeneus [leader of the
contingent from Crete), blinding his bright eyes and binding his strong limbs in
fetters so that he could neither go back nor to one side, but stood stock still like
some pillar or lofty tree when Idomeneus struck him with a spear full in the middle of
his ehest. The coat of bronze mai I that had hitherto protected his body was now
broken, and rang harshly as the spear tore through it. He fell with a thud, and the
spear stuck in his heart, which still beat, and made the butt-end of the spear quiver
till dread Mars put an end to his life.
The /liad, Chapter 13,
lines 435-45 translations hybridized from
Samuel Butler, Augustus Taber Murray

Thus Homer first described agraphie recording from anormal, healthy ventricular wall,
presumably ending with fibrillation 3500 years aga during the siege of Bronze-Age Troy
by bloodthirsty heroes from Mycenaean Greece.
Since that time, Silicon-Age heroes have leamed quite a lot of cellular, molecular,
and electrical detail about the heartbeat, and about many of its electrical
dysrhythmias. A dinically important dass of them-reentrant tachycardias of extremely
short period, which catalyze the onset of fibrillation-in some respects seemed in
1978 to resemble rotors. This seemed interesting because fibrillation is the leading
cause of death among adults in the United States; one in every five of us will die this
way. Something like one in three males dying at age 20 to 64 would not have died if
fibrillation could have been prevented or promptly reversed. Although three in four of
those men had at least some prior hint of heart trouble, or autopsy revealed
unsuspected cardiac disease, the remaining "sudden cardiac deaths" by fibrillation
are hard to account for, in the sense that the heart seems to have been functioning
normally, and was not affected by lesions or infections. Yet it abruptly switched to
fibrillation. Not many cases of fibrillation are triggered by bronze spear/cardiographs
today, but something triggers them. The viewpoint of this chapter, which seems
supported at least in laboratory experiments using living hearts, is that the acute
episode starts with creation of phase singularities (rotors in two dimensions or singular
filaments in three), which somehow induce fibrillation. Like a nematode or a
bacterium, these dynamical entities can infect healthy tissue and make it malfunction
in a way that is not compatible with effective pumping. After only a few minutes of

A. T. Winfree, The Geometry of Biological Time 495

© Springer Science+Business Media New York 2001
496

ineffective pumping and correspondingly inadequate blood pressure the brain is

starved for oxygen and nutrients and becomes irreversibly damaged. The phase
singularity itself is not an instability, but just an altemative-and fatal-mode of
operation in normal tissue. Because one or another of its instabilities in the thick
ventricular wall of the heart leads promptly to fibrillation, we associate fibrillation with
the lethai global failure of blood pressure and circulation that even a single stable
rotor causes. But no one knows whether this is how it happens in sudden cardiac
deaths, and if so, what created the singularity.
50lving this problem would seem to entail identifying the stimulus that conjures
phase singularities, .understanding how singularities become rotors and so
precipitate the change from normal beating to tachycardia, understanding the
dynamics transition to fibrillation and the spatiotemporal structure of fibrillation, and
discovering a stimulus to reliably induce the reverse change without damaging the
heart. This chapter focuses on roughly the first half of this package: understanding
the creation of a phase singularity (under artificial laboratory conditions) and the
initial behavior of the rotor forming around it. Its short period alone is fatal: even if
rotors were stable, the heart would not pump blood. Practical interest in the
dynamics of rotors concems their mode of orl9'n and possible means of getting
rld of them, preferably before their instabilities further complicate matters. Theory
and experiments have successfully illuminated their ori9'n by electric shock as
described below, but little is yet understood of their origin outside the laboratory,
which rarely involves electric shock. As to getting rief of them, theorists have
graceful solutions for stable rotors, but as yet nothing better for unstably
proliferating rotors and squirming vortex filaments than the crude and undepend-
able massive electroshock that remains today still the only known therapy for
fibrillation.
This second of two completely new chapters is not about medicine and therapy. It is
about the physics and mathematics of timing in the electrical turbulence that we know
only in fibrillating hearts. My own path through this puzzle originated as ignorant
chasing of mirages in a direction I now consider embarrassing (as, perhaps I may later
be compelled to regard the visions proffered here.) But six components of that initial
vector did fortuitously align with a suddenly growing eigenfunction:

• Toward normal heart muscle, rather than diseased. Fibrillation does occur in
healthy hearts and seems substantially the same thing, or at least indistinguishable
by current crude measures. So the quantifiable consistency of normal physiology
offers a more supportive context for theoretical inference and decisive experimental
testing.
• Toward physically contlnuous and uniform mechanisms, rather than discontin-
uous and heterogeneous. Discontinuities and heterogeneities abound, especially
in diseased hearts, and they may play an essential role in defibrillation by
electric shock, but the dominant assumption that fibrillation would be utterly
different or would not exist without them seemed to me gratuitous, obstructive,
and unproven.
• Toward "reentrant" two- and especially three-dimensional mechanisms, as first
timidly ventured in Winfree (1973c), rather than toward classical preference for one-
dimensional "circus movement" rings and for zero-dimensional (point-like) "focal"
 A: ROTORS IN AFIELD OF COUPlED OSClLlATORS 497

mechanisms. The latter were preferred I think because they were familiar and could
be feasibly investigated with the tools at hand in cardiac electrophysiology before
1990; the former appealed more to me because they were familiar and could be
feasibly investigated with the tools at hand in physical chemistry and computation.
After 20 years of fantasizing these two streams merged substantively in the 1990s.
• Toward more substantial realizations of the mere notion just germinating in 1978's
Box B of Chapter 10 that ventricular fibrillation is "a phase singularity in the
behavior of an elaborate partial differential equation" (the heart).
• Toward those features in which electrical reaction-diffusion mechanisms like the
Hodgkin-Huxley cable equation differ from a variety of widely appreciated models
for propagation and reentry that collectively dominated the literature, because
even though partial differential equations may be harder to come to grips with in
more than one dimension, they are more faithful to the physically fundamental real
mechanisms.
• Toward the simplest possible ionic membrane models or caricatures, rather than
toward every refinement of detail. Because many powerful research groups sought
answers through greater realism, stressing intricate complexity and variability in this
"reaction" part while minimizing the "diffusion" part, i.e., the simple geometry, to
me thinking about geometry seemed an adventurous way to exploit a vacant
ecological niche.

A much thicker chapter (called a "book") would be needed to interweave the many
threads of interest into the tapestry of discovery in this area during 1978-98; the best I
can do in a short space is to highlight the spots where my one thread intersects several
others. Because this chapter threatened to grow too long I narrowly refocused it on the
themes of the 1978 book: nonlinear dynamics as a geometry of timing, mostly about
phase singularities in two and three dimensions. These updates are related in roughly
chronological order under several topic headings. They are here in the Bestiary rather
than in the first half of the book, because they are mostly about experiments in a
particular living system: healthy ventricular muscle of the mammalian heart. Box A
describes that system and the several ways it is prepared for examination in the
laboratory. Box B stands in place of adefinition of "fibrillation."
Note the language adopted here. Use of "arrhythmia" or "dysrhythmia" for
irregularity of heartbeat is a bit of a tossup, but since the stress here is on "arrhythmias"
that tum out to be sharply periodic at any one site on the heart, I prefer "dys-"
("unwanted-") to "a-" ("non-"). The terms "vortex," "reentry," and "reentrant circuit" in
use several decades aga developed more specific meanings in "reverberator" alias
"spiral wave" (to describe the activation front's shape as it radiates away from whatever
source mechanism), "Ieading circle" (a description of the source of reentry in the
atrium), and "rotor" (the source mechanism in reaction-diffusion or cable-equation
continua), all of which are nevertheless often used interchangeably in the literature.
After 26 years "phase singularity," "rotor," and "scroll wave" have become acceptable,
even as keywords for indexing, in the cardiological joumals. During the 1980s they were
still not allowed: referees and editors required experimentalists to expunge them in
favor of traditional concepts before a manuscript could be published. A chaos of names
befuddles the reader of primary literature during this transition. The "singular point"
was renamed "critical point." "Vortex" was already in use among cardiac electro-
physiologists since at least 1940, so it often serves for "rotor" (and for other things), and
"vortex filament" serves for "singular filament." Another synonym for "rotor" is "critical
point reentrant circuit." In this literature "phase singularity" now sometimes means
nothing more than the endpoint of a broken aetivation front, and "scroll wave" no
longer connotes the presence of a scroll-shaped wave, but merely the singular filament
that would generate one were the tissue thicker.
I hope to avoid some ambiguities by sticking to the original meanings of "phase
singularity," "rotor," and "singular filament" or "vortex filament" in this chapter. Even
though I find it personally gratifying to see "scroll wave" used so much now in
Circu/ation, Circu/ation Research, and The Journal of Cardiovascu/ar Electrophysiology,
I avoid the term here, along with its two-dimensional analogues, "reverberator" and
"spiral wave," because those rather large propagation pattems are actually seen only in
numerical models with discontinuities or spuriously weak cell-cell coupling, not in
normal hearts as small as used in this pertinent experiments. I also avoid the terms
"spiral wave theory" because it connotes such different ideas in different papers, and
"wavelength" because in the cardiologicalliterature means thickness ofthe depolarized
part of the action potential, not the spacing between fronts of a spiral (reasonably, there
being no full spirals).
This chapter also omits discussion of regular, two-period "meander" because all
attempts to observe it in myocardium have been frustrated by the ephemeral or at least
erratic character of electrical rotors. Only when excitability is sufficiently reduced in ionic
models of two-dimensional uniform ventricles do such pattems appear as expected
(Efimov et al., 1995; Fenton and Karma, 1998a). These pattems are interestingly
affected by model improvements to incorporate the unequal anisotropies of
intracellular and interstitial domains. Although the quantitative effect is generally
slight, a qualitative change occurs in the special case that rotor period and curvature
modulation period scarcely differ: they now lock together, making the meander f10wer
exactly closed and non-rotating or making it slowly drift (Roth, 1998b, 2000). Regular
meander might occur in laboratory preparations with chemically-depressed excitability
or in abnormal hearts, e.g., underlying the poorly understood dysrhythmia called
torsade de pointes, but I mostly use the term "wander" instead of "meander" below.

A: Rotors in a Field of Coupled Oscillators

We begin by backing off from preoccupation with the ventricles to consider first the
sinoatrial pacemaker node of the right atrium. This is a region of hundreds of thousands
of cells (in a largish heart such as the dog's or the reader's) each of which beats
spontaneously two to three times each second unless suppressed by acetylcholine from
the vagus nerve. As you rest at your desk, propping your head over this tiresome
monograph, your vagus nerve is quite aetive, so (unless you have been neglecting a
decent exercise schedule) your pacemaker triggers your heartbeat less than 60 times
per minute (mine did 56 times just now). Mutual synchronization among these
pacemaker cells is analyzed theoretically in Chapter 14, Section B. That is one mode for
their temporal organization. 00 rotors provide another?
A rotor in a two-dimensional continuum of coupled sinusoidal oscillators like these
pacemaker cells is not much more than an arrangement of their phases like the civil time
 A: ROTORS IN A FJELD OF COtJPl.ED OSCILLATORS 499

Box A: Essentials of Cardiac Physiology

The left ventricle of the heart resembles a cup with thick walls. The empty cavity inside
fills with blood then empties to eject its contents up the aorta when the surrounding
muscle contracts. The right ventricular free wall can be thought of as a thinner flap of
muscle attached outside to create and envelop a lesser cavity that wraps halfway around
the thick heavy cup. This is the right ventricle, serving the lungs. We ignore it in this
chapter. Closing over the top of the cup, and separated by an unexcitable rim, are the
two atrial chambers that receive the retum flow of blood from lungs and from the body
and then prime the two ventricular chambers for their forceful pumping action. The atrial
muscle, discussed somewhat in Section D of Chapter 14, has a more complicated
architecture that is functionally neither two- nor three-dimensionaL It is extremely
inhomogeneous in respect to propagation speed and spontaneity of oscillation (VVinfree,
1991c; Schuessler et aL, 1992, 1993; Winfree, 1994a p116; Gray et aL, 1996; Gray and
Jalife, 1998).
This chapter focuses on the more uniform muscular mass of the left ventride. Like
skeletal muscle, it consists of elongated cells arranged into longer fibers. Unlike skeletal
muscle, these cells and fibers are electrically connected by resistive pores in all
directions to constitute a uniform contlnuum with anisotropie resistivity and mechanical
properties (this is a viewpoint, not a fact, defended in Winfree, 1997). Here we address
only its electrical properties. This anisotropy amounts to about an order of magnitude
enhancement of electrical coupling along fibers. The fiber direction precesses
anticlockwise with increasing distance behind the visible surface, reaching 90° not far
beyond mid-wall, and continuing. Thus slices through the ventricular wall resemble slices
through insect cuticle or a cholesteric liquid crystal (Figure a). This makes for a peculiar
geometry of propagation.
Any serious physiologist will be shocked by these simplifications, and medical doctors
more so. First of all, it is not perfectly clear that ventricular myocardium is normally
electrically continuous, at least transverse to sheets of well-connected fibers (Nielsen et aL,
1991; LeGrice et al., 1995). Most writers on this subject have assumed that it is not, at least in
diseased tissue, though sometimes for reasons that may be spurious (e.g., see Roth, 2oo0b).
In the clinical context, the ventricular muscle seen Is damaged or diseased and often
extremely inhomogeneous in all respects. Many of the conditions medical doctors seek to
remedy would be inconspicuous if the muscle were as uniform as in healthy hearts. But the
condition this chapter draws your attention to does occur in healthy hearts, and has not
proven understandable in indescribably heterogeneous hearts. So we attempt to under-
stand it fim in the reproducibly quantifiable context of normal physiology, hoping that many
varieties of d'n;ca' aberration will later be more easily understood and remedied as
modifications of this basic understanding.
Fibrillation (Box B) seems an altemative mode of normal electrical dynamies: a certain
electrical shock will flip anormal heart into fibrillation, and another will flip it back. No
disease process is needed, no change of parameters. It is an altematlve attrador basin.
T0 find out what kind, hearts are studied:

• In the ambulatory human or dog or pig or rabbit by recording from surface electrodes
(electrocardiograms (ECG), Holter monitors) and by activating sterile stimulus
electrodes inserted into the heart cavities through the vaseulature; in hospital this is
called an "EP" (electro-physiologic) workup;
• In the same animals during open-ehest surgery that exposes the heart surface
for observation of the spat1al pattem of electrical activity, rather than just V(t) at
500 17: ELECTRICAL SINGUlAR FILAMENTS IN THE HEART WAU

ENDOCARDIUM EPICARDIUM

Figure a: Slices of the fully contracted dog ventricle, taken parallel to the epicardial surface at
the right, at increasing depths through the wall, to the endocardial surface at the left. Muscle
fibers lie in parallel bundles separated by gaps, their orientation progressively rotating one half
turn through the wall, anticlockwise with increasing distance away from the viewer whether
viewed from either side; here all are viewed from the epicardial side. The figure spans 4 mm of
wall thickness. Compare to Figure 2.1 in Chapter 10. (Adapted from Streeter, D. D., Spotnitz, H.
M., Patel, D. P., Ross, J., and Sonenblick, E. H. (1969) Fiber orientation in the canine left ventricle
during diastole and systole. eirc. Res. 24. 339-347).

one point or a global summation over all surfaces as in the electrocardiogram's

~V(t):
o by a two-dimensional array of metal button electrodes or
o bya three-dimensional array oftips oftiny insulated wires carried in plunge needles.
Blood circulation is sometimes maintained through plumbing from an adjacent animal's
nonfibrillating heart, or sometimes not, in which case chemical conditions change rapidly;

• In the isolated heart, removed from the chest cavity (Figure b) and supported at 37°C
while a blood-containing or blood-like fluid is pumped through it and through agas
exchanger, a temperature regulator, and a filter.

Flgure b: A mongrel dog (D0497) was rescued

from the pound, de-wormed, fed weil for the first
time in a while, groomed, treated like a queen for a
month, then put to sleep comfortably by injection
of anesthetic. The dog's head and respirator are
beneath the camera. The chest wall is held open by
white towels supported by steel retractors. The
pericardium has been slit and is held open by
suture threads at five points to expose the beating
heart. The ventricles are above, reflecting the
lamp's glare; the right atrium below shows a
reflecting edge; the left atrium and aorta are
covered in white fat. We next removed the heart
to cold saline while affixing the Langendorff
plumbing, then circulated warm support medium
through gas exchanger, filter, and beating heart.
Di-4-ANEPPS f1uorescence reveals electrical activa-
tion patterns under a 1-msec CCD camera.
 • All normally attached nerves are, of course, severed, and the intemal pacemaker is
usually disabled and replaced by an electrical pacer. Properly maintained, such a heart
will keep beating for hours, though fluid balance is poor and it eventually swells visibly
with edema, which changes its electrical behavior. The same electrode arrays can be
attached, or the surface can be observed by video camera while an injected dye
f1uoresces in proportion to local cell membrane potential; this is the technique I have
been most involved in, with my collaborator, Frank Witkowski;
• In sheets of muscle shaved from the epicardial surface like big postage stamps
maintained in a culture dish under warm, swirling blood substitute. Observation is by
dyes or electrodes as above. In this case and the next there is no fluid f10w through the
tissue, so only a surface film of cells remains viable;
• In thin confluent layers similar to the microscopic ball-like aggregates of heart cells
maintained in tissue culture after dissolving an embryonic heart into its constituent
cells, then letting them reaggregate (see Chapter 14). In these sheets the mutual
electrical coupling is seldom comparable to that of adult tissues or spherical
aggregates.

In this list notice the absence of long thin muscle fibers and of isolated cells: the
preparations listed all constitute two- or three-dlmensional tissues. The idea is that
fibrillation is a geometrical pattern of electrical activity that needs a certain amount of room
and connectivity to maintain itself dynamically.

zones of the Earth converging to a "north pole." Their mutual coupling by diffusion of
electrical potential, however, admits the possibility of propagation, too. "Propagation"
being "encouraging a neighbor to do it sooner," the activation front may radiate from
such a rotating phase gradient at aperiod somewhat shorter than the isolated cells'
oscillations.
What would a rotor look like in the state space of such smooth round attracting-
cycle models as are used for pacemaker nodal cells? It would look much as in
Chapter 8'5 Figure 12 or figures in Chapter 9's Section B. How could the tissue
have gotten that way? Just as described there: the "pinwheel experiment" of 1978,
for example, would do the trick, in this ca se with a radial gradient of phase
(concentric closed isophase contours around node center) and a radial gradient of
stimulus intensity (concentric closed contours around a stimulus electrode outside
the node) symmetrically intersecting as described in Chapter 2's Example 5.
Continuity requires rotor creation in mirror-image pairs (except at the medium's
boundary), but in a steeply graded environment they drift rapidly from the site of origin.
Let's suppose one ends up in the small area of spontaneously oscillating cells called the
sinoatrial node, while the other ends up outside that area, in the excitable but
nonspontaneous atrial muscle. Let's think first of the one nascent rotor among
sinusoidal oscillators. Can we estimate its period and its minimum size in terms of rotor
theory? My first try (Winfree 1987a, pp. 126-34) came up short of quantification, and
more sophisticated estimates (Guevara and Jongsma 1990; Winfree, 1993b and 1995c;
Mercader et al., 1995) still vary over a roughly ninefold range of rotor diameter. My own
first guess may have been threefold too high, but even so, the consensus is still that a
rotor would not fit in the small area of a rabbit's node (Kirchhof et al., 1990; Allessie et
al., 1988; Bonke et al., 1990). Mercader et al. (1995) conclude that it would, but there is
 17~" "ELECTRICAL
9. . SINGULAR i=lLAMEN'fS IN. THE HEA~"{:'WALL ';
',.
~ ~.. . _ ~

still no experimental evidence of rotors persisting even as long as two tums in any
animal's sinoatrial node.
The main problems for theorists in this case are the steep radial gradient of local
membrane properties in the node, which would lead it to slither around, and the wide
range (eightfold!) of reported estimates for the passive space constant, equivalent to
64-fold uncertainty about the diffusion coefficient, D, of electrical potential in the
sinoatrial node (or parts of it).
Then what about the mirror-image rotor that must also have been created by
whatever stimulus, now somewhere out in the sodium-channel-rich excitable muscle of
the atrium, which only propagates the periodic impulse originating in the node? Here
the argument of Chapter 9 (elaborated into a later book as Winfree, 1987a) is that
coercion or seductlon effectively substitutes for spontane/ty. Given initial
conditions resembling a rotor, nonspontaneous cells would finish the cycle and settle
into quiescence, except that cell-cell coupling keeps pulling them back into action
behind neighbors recently so excited. This is how rotors work in any other uniform
excitable medium, so why not in heart muscle?
Anyway, following some such line of thought, at Robert DeHaan's 1976 Gordon
Conference on Rhythmic Activity in Heart Muscle, unaware of Allessie et al. (1973), I
drew attention to the existence of a "vulnerable phase" in any periodically driven
excitable medium, during which a single well-timed stimulus would create pa/red
rotors. Maurits Allessie then presented the contents of his group's 1976 and 1977
papers demonstrating something like a rotor (not always paired) in rabbit atrial
muscle, evoked by stimulating twice through one and the same point electrode.
They developed a "Ieading circle" description for reentry in the atrium (Allessie et
al., 1976), with properties in some ways differing from those of the "generic rotor"
mechanism that seemed more natural to a theorist ignorant of the complexities of
atrial tissue. This novel idea, together with the technical finesse of corresponding
experiments, organized inquiry about reentry throughout the coming decades. See
Box 0 to follow this story to 1999.
And wh at about ventricular muscle, which is considerably more uniform? Naively
presuming to lecture further on this at the NIH in December 1977, I was informed by
cardiologists that the "predicted" ventricular "vulnerable phase" had been known
clinically for forty years (Wiggers and Wegria, 1939, 1940), even under the same name
(and as "vulnerable period"), and that even though this proto-theory thus tumed out to
imply something true, so did many altemative and better-developed notions, and even
if it was correct for spontaneously oscillating media in general, its relevance to heart
muscle did not follow because the oscillation there is driven, not spontaneous.
The key point here is that cells in the ventricles, though not spontaneous
oscillators, are driven to behave IIke oscillators during the normal heartbeat, so they
traverse a cycle in some state space and are shifted across it by any sharp
perturbation, and so may show spatial pattems of resetting equivalent1 to those

Equivalent in some respects but not all: the main difference is that the resetting curves of a driven
oscillator may have an abrupt jump at the moment when the driving periodicity hits it. This could be modeled
as a discontinuity, deflating all topological arguments. In fact nothing discontinuous happens in real
physiology, and the size of the abrupt place can only be discovered in the lab, where also one finds out
whether or not idealized conceptual arguments pointed the way to discovery or to confusion.
 A~ ROTORS IN A FIEtp OFCOUPl:ED OSC;ltLATORS

Box B: Ventricular Fibrillation

The word "fibrillation" has a 100-year history, in which its meanings have diversified more
than they have converged. Some cell physiologists call irregular twitching of a damaged
single myocyte "fibrillation." Clinicians mean a grosslyirregular low-amplitude noise-like
trace coming out of an electrocardiogram, whatever may be the underlying mechanism.
Early fibrillation can be sharply periodic (e.g., page 108 of Winfree, 1987a; Carlisle et al.,
1988, 1990a,b; Witkowski and Penkoske, 1990; Opthof et al., 1991; Clayton et al., 1993;
Gray et al. 1997; Taneja et al., 1997), reflecting its origin as a very fast "tachycardia" ("fast
heartbeat"). It progresses through stages over several minutes from almost sinusoidal
large-amplitude 6-12 Hz tachycardia to low-amplitude noise. So me aspects of this
progression reflect merely the failure of blood f10w through the muscle after fibrillation
starts, while others (the on es of interest here) occur also when f10w is artificially
maintained. The stage at which the label "tachycardia" is taken down and "fibrillation"
posted in its place depends on the purpose of the argument. Among bioengineers,
nonverbal criteria are required when programming the microprocessors intended to
trigger an implanted defibrillator to shock the heart back into synchrony; they tend to be
complexly algorithmic and statistical in proprietary ways.
Some people seem to mean by "fibrillation" any activity that makes an imperfectly
regular electrocardiogram at rates exceeding those typical of heavy exercise, even if almost
perfect rhythmicity is maintained at each point in the heart most of the time and activation
waves on the heart surface look relatively simple and orderly. Others mean that the spatial
pattern of activity has become very complicated, a feature seldom assayed in humans. The
same word is used for irregular behavior in the substantially three-dimensional, relatively
uniform ventricles, and in the atria, where various parts are effectively one-, two-, or three-
dimensional and conduction is more heterogeneously anisotropic. The mechanisms
underlying anything so vaguely defined may differ from case to case.
For this chapter's purposes I use the term only to refer to a pattem of electrical
propagation in normal, healthy ventricles of mammalian hearts, which
• excites every point faster than the fastest stable rhythm for that animal in vigorous
exercise,
• covers the visible surface with multiple activation fronts at every moment in a fairly
periodic way that, summed over sUrfaces, does not repeat as reliably as
"tachycardia" does, and
• maintains itself as long as blood f10w is maintained.

On this topic my favorite theory paper up to 1978 (found for the prior edition of
this book only at the last minute, and slipped into galleys in only one place) is Krinsky
(1978). It is also the first to use "Spiral Wave" in a title on this topic (though the Russian
"Reverberator" had the same import as far back as Krinsky (1966)). Since then many
candidates for the mechanism underlying fibrillation have been thoughtfully analyzed, for
example:

• A basically O-dimensional mechanism: An antiphase mutual excitation among

neighboring ventricular cells, each firing at intervals twice as long as the ostensible
period of such collective fibrillation (which was argued to be shorter than any cell's
refractory period, overlooking the need to measure it durlng fibrillation, when it tums
out to be much shorter) (Herbschieb et al., 1982; http://homepage.esoterica.ptJ
"-'johan).;
 • A basically one-dimensional mechanism: Abnormal foci like pacemakers within the
ventricles firing off circular activation fronts at critically short intervals (Bardy et aL,
1983; Ideker et aL, 1981, 1984);
• The classical "wandering wavelets" discussed in 1978 Chapter 14's Section D,
intended for the atria (Moe et aL, 1964) and nicely demonstrated there (Allessie et aL,
1985); I believe it does not apply as weil to the ventricles;
• Fragments of "spiral waves" multiplying and extinguishing along electrical disconti·
nuities pervading the muscle in a way that enables perpetuation in a smaller space and
at shorter periods than a single spiral in uniform muscle could achieve (Krinsky, 1978);
• Multiple "Ieading circle" sources for spiral waves, characterized bya period equal to
the refractory period, absence of an "excitable gap" between one activation front and
the next, a center that is not the source but is kept refractory by irregular invasions of
activation from a race-track-Iike source surround it (Allessie et aL, 1973, 1976, 1977,
1985);
• Multiple rotors, each with its own period because "pinned" on a local patch of
relatively inexcitable tissue, or moving in a gradient of electrophysiological properties
and persisting because domination by the currently fastest one is short-lived, or even a
single rotor emitting Doppler-shifted spiral waves while wandering rapidly (Gray et aL,
1995b);
• Waves from a rotor emitting activation fronts that break up remotely to create new
rotors where they pass through a narrow constriction between inexcitable zones or
pass a sharp comer (Panfilov and Pertsov, 1982; Pertsov et aL 1990; Winfree, 1990a;
Agladze and Keener, 1994; Cabo et aL, 1996), or even simply because propagation at
short periods is inherently unstable (Box C);
• Singular filaments formed withln the heart wall ("intramural") by a stimulus applied at
the critical phase during normal sinus rhythm (Winfree, 1989a, 1990d; see experimental
follow-ups in Section D below);
• Singular filaments spanning the heart wall ("transmural"), going helically unstable
because the rotor spins faster at one end (e.g., epicardial surface of the wall)than at the
other (e.g., endocardial) (Winfree, 1990c). Mironov et aL (1996) mimicked this situation
in a chemically excitable gel and, as shown in Chapter 16, observed the anticipated
"sproing" instability and the expectation that the required threshold intensity of twist
could accumulate only if the product of wall thickness by the transmural difference of
rotor periods exceeds a certain threshold;
• Singular filaments spanning the wall, going unstable via "twistons' on account of the
rotational anisotropy of muscle fibers (Fenton and Karma, 1998a,b).

There seems Iittle good reason to suppose that only one of these, if any, can be
right; they mlght even all be right under different conditions or when considered as
approximations with different purposes. Beyond the first two in this list, all require at
least two dimensions of space, and beyond the next three all involve rotors.
Most of the listed guesses are grounded in normal electrophysiology of a dynamical
mode (rotors, singular filaments) that seemed in 1978 c!oser to science fiction than to
reality, as far as real myocardium is concemed. It was not then widely accepted that there is
any conspicuous periodicity to ventricular fibrillation; in fact, the definition in many texts
includes "complete irregularity." Nor, even for healthy heart musc!e, that the cell
membrane's ionic mechanisms work normally during fibrillation, nor that propagation of
action potentials, in the usual sense, occurs at all during fibrillation; for example, maybe at
such short intervals the sodium channels or the calcium channels could be defunct, seriously
altering the rate equations and physiological performance. The first solid indication to the
 .: B: THE PINWHEEl ExPERIMENT - 505

contrary that I can recall came from Dwight Barkley's unpublished November 1991 analysis
of Frank Witkowski's data from a 7 x 11 array of monopolar electrodes 2 mm apart on
fibrillating dog epicardium. Most electrodes showed activations repeating at rough 100
msec intervals. Ostensibly focal sources radiated uniformly propagating fronts at such
!
intervals, at speeds ranging from infinity at the focus down to m/sec peripherally (rarely
less). Barkley's activations plainly showed normal propagation, and seldom anything slower.

familiar in arrays of oscillators. If so, then their tight neighbor coupling may preserve
the topology of that pattem even in the absence of further periodic input from the
sinoatrial pacemaker. Tortuous technical arguments and hand waving seemed to
suggest that this is at least worth a try in the laboratory, but until 1983 it had not yet
even been tried in a perfectly continuous chemically excitable medium.

B: The Pinwheel Experiment

The simplest way to implement the pinwheel experiment in a photosensitive chemical

solution is to start a wavefront along a line, let it propagate, then lay across it (at right
angles) a fuzzy bar of light at such energy that quiescent medium is strongly excited
along the midline, less to either side, and not at all several millimeters away. The
refractory wake elose behind the wavefront also fails to excite or propagate excitation.
So the excited rectangle has its ends on the boundaries of the medium, and its two
parallel walls begin to propagate outward, except for two little gaps in the refractory
wake. One edge of each gap meets the prior wavefront, and the other, where the new
wavefront crosses at right angles into the old one's refractory zone, is a phase singularity
for the incipient rotation. I did this in 1983 (see Figure 1.5 of Chapter 9), and Amemiya et
al. (1996) did it with much sharper cutoff of light intensity at the rectangle's edges.
Neither experiment differs much from what Wiener and Rosenblueth would have done in
1946, had they access to the malonic acid reagent. But they would have thought about
it in a different way, and the results (a pair of rotors) would have made them
reconsider their conelusion that rotors could not exist. They knew that spiral waves
could exist, and could be started by some such stimulus, but they required a hole in
the medium where the impossible rotor might have been. Worse still, the wave's
period of circulation around the hole had to exceed the refractory period and to be
proportional to hole size above that minimum. Actual rotors, in contrast, freely move
around: they are not necessarily associated with any localized peculiarity of the
medium. And they have a unique period that by definition necessarily exceeds the
"refractory period," but the latter is not an independent quantity: it turns out to
depend sharply on the interva I between successive excitations, thus on the rotor
period. So all quantitative aspects of the 1946 vision are either false or untestable.
This is why we need the cable equation (Box 0).
This "pinwheel experiment" got its name from the pinwheel-like arrangement of
isochronal contours on an abstract map of circadian rhythm phase after stimuli of
various sizes given at various times in the cyele: they converge to a point and spin
around it at the period of local oscillation. The same principles turned out to have
broader application, _for example to glycolytic oscillations in yeast cells, then to
· 506 ~
17: ELECTR1CAl SI~OULAR
.
F'LAMENTS
I:
IN THl= HEART WAll.!.

Box C: 00 Rotors Spin Too Fast for Stable Propagation?

Inherent instability of propagation at sufficiently short intervals (tagether with a source
that persists at such arate) provides anather interpretation of the onset of electrical
turbulence independent of parametric inhomogeneities. The basic idea of this altemative
is much simpler in that it involves so Iittle geometry. It grew from a conjecture of
Nolasco and Dahlen (1968), progressively developed by Guevara et al. (1981), Lewis et
al. (1987), Courtemanche et al. (1993, 1996), and Karma et al. (1994) in context of one-
dimensional propagation, and in two-dimensional context by Karma (1993, 1994) and by
Courtemanche (1993, 1996) in his dissertation at Tucson. It even seemed that "there is
little reason to think rotors are involved [in fibrillation], except as short-period sources
that provoke fibrillation" (Winfree, 1994a). The idea was that fibrillation stems from a
feature of normal and uniform heart muscle that seems not to play a crucial role in
other excitable media: a steep dependence of the duration of each action potential's
depolarized stage upon the interval of periodic activations, or more precisely, on the
interval since the prior action potential ended. This is called the "action-potential-
duration restitution curve." If, at sufficiently short intervals, the dependence on period is
tao steep (slope ~) or the equivalent dependence on diastolic interval is tao steep (slope
1), then, as Nolasco and Dahlen noted in 1968, an instability can ensue (Figure a) akin
to one in the heart that Lewis (1925) dubbed "altemans." In context of propagating

Flgure a: The duration, D, of the next cardiac action potential is longer when the tissue gets a
longer rest interval, R, after the end of the prior action potential. That monotone increasing
function D{R) is called the "restitution curve" for action potential duration. During regular pacing
at period T the succession of D's and R's can be followed by reflecting off heavy curve D{R) and
the dashed line of fixed sum D+R= T. Their intersection is the only periodic solution. It attracts if
dD/dR at the intersection is less than 1 at the chosen T, otherwise, it repels. A given initial D leads
(leftward) to the dashed line at the next R complementary to period T, which gives (down) a next
D on the curve, and so on, spiraling outward because the slope here exceeds 1. This criterion
provides only a rough guesstimate when used in context of spatial propagation.

excitations the thresholds are not exactly ~ or 1, but the same sort of altemation arises
and develops into patchy "conduction block" and spatially complicated irregularity of
activation. This scenario resembles the view almost universally held among cardiologists,
that activation fronts "break up" on localized parametric inhomogeneities,2 except that

2 Classical notions of spatially random parametric inhomogeneity as the basis of fibrillation might be
mirrored more accurately in the processes of electrical defibrillation. At this writing, real hearts and
uniform tissue models do not respond to electric shock in quantitatively comparable ways. But if
inhomogeneities of resistivity are strewn throughout the modeled tissue, it becomes more responsive,
and simulated fibrillation can be erased with shocks of reasonable energy. For a review see papers in
the March 1998 issue of Chaos.
 100
APD RESrmmON
Figur. b: During electrically induced fibrillation
in the dog heart (without DAM, but with
cytochalasin D instead, to minimize mechanical
motion) the durations of action potentials (APD,
like D in Figure a) vary widely in a way that (over
the range of interest) depends steeply on the i eo ,2 = 0.97
interval (DI, like R in Figure a) between activa- !
tion and the nominal end of the prior such c~
duration taken at a voltage-sensitive dye fluor- 40
escence threshold. These data come from three
seconds of chronic fibrillation during collabora-
tive experiments with the late Frank Witkowski,
notebook IV, item #5331. They include some
awfully short "action potentials" that we did not
discriminate from "electronic" echoes of real
action potentials nearby.
DI(mMC)

here the latter are vanishingly slight or even absent, and so ephemeral conduction
blocks appear in different places in near-replicate (numerical) experiments. In two- and
three-dimensional context, the original source of short-period excitation could be a rotor
(no altemative pacemaker has been shown capable of such short periods) and the
broken activation fronts tum into more rotors, or would if they were not slapped by
other activations before more than one rotor period elapses (as indeed they are: see
review in Winfree, 1998a).
Theory in this area has rapidly encountered a bewildering variety of subtle caveats.
Although Courtemanche found slopes as high as 2-3 in the Beeler-Reuter ionic model of
the ventricular muscle membrane, there seemed little reason to believe that this was
realistic, nor that it could be related directly to cardiac tluue (nonetheless, this is exactly
what Frank Witkowski found in the laboratory 11 years later: Figure b). Spiral wave breakup
in simpler models seemed seldom determined by such a dependence. In the more
complicated Luo-Rudy I model (wh ich, it must be remembered, needed amendment in the
channels controlling action potential duration, but the resulting Luo-Rudy 11 model (1994) is
too complicated for computation) Vigmond and Leon (2000) numerically studied three
different ways to measure these slopes in a three-dimensional block of simulated normal
and uniform myocardium affected by pharmaceutical modulation of various channels, and
two different measures of such curves that might predict breakup of waves radiated at
periods as short as the rotors. They found surprisingly little consistency or predictability.
The idea that action potential duration is a unique function of the preceding diastolic
interval, and that propagation at short intervals must be unstable if that function's slope
exceeds 1 over an adequate range, seems too loose and subject to too many
counterexamples to usefully inform attempts to predict even a moders behavior. The
lesser assertion that breakup will not occur without a wide enough adequately steep
segment of the curve might prove reliable, though it is not in simpler (noncardiac)
excitability models, because they first exhibit other mechanisms of instability.
But might real tissue behave more simply than its numerical models? My 1994c
review of published measurements using tissue paced at shortening intervals seldom
reproducibly showed slopes against diastolic interval even as high as 1: believers at
that time needed to focus their attention selectively on ostensibly favorable rare data.
And "diastolic interval" must be redefined carefully because by the usual definition,
during fibrillation there is no such interval, as shown by Opthof et al. (1991) with
intracellular electrodes and by Witkowski et al. (1994) with both unipolar extracellular
electrodes and optical recording. Moreover, Gilmour et al. (1997) experimentally
faulted the very ldea of action potential duration depending mainly on the one interval
since the prior repolarization. Then Koller et al. (1998) found another way to do these
measurements, obtaining slopes in fact as high as the numerically forecast but
discredited 2 to 3 during fibrillation, and found that drugs decreasing this measured
slope also suppress the transition from reentrant tachycardia (rotors) to fibrillation
(Riccio et al., 1999). The mechanism is presumably prevention of activation front
breakage and formation of new phase singularities (but this was not checked by
monitoring propagation geometrically).
It is peculiar that rapid pacing (e.g., by a rotor) is thought also to f1atten this curve, but
does not cause fibrillation to revert to relatively stable rotors. It remains to be seen how this
curve's shape evolves during the transition from rotor-induced or other tachycardia into
fibrillation. If it becomes shallower, why does fibrillation (and maybe tachycardia as weil)
not self-extinguish? If it steepens, why does pacing at the maximum normal heart rate
during strenuous exercise not precipitate instabilities?
This is all particularly interesting because this geometry-free interpretation provides a
possible mechanism for seemingly spontaneous ereatlon of (unstable) rotors. No one
knows exactly what physiological stimulus triggers sudden death in normal hearts, but
unlike artificially contrived electrical "pinwheel" stimulation, it probably does not start
rotors directly. More likely it provides a rapidly repeated focal excitation that stimulates
tissue more rapidly than it can stably respond, so propagating activation fronts
spontaneously break up (Swain and Valley, 1970). One such source is weak 50-60 Hz
electric current: no one argues that AC electrification directly starts rotors, but it does push
myocardium to excite at minimal intervals near the point of contact.
The conceptual problems with this idea (and maybe the practical problems, too)
could stem from its negled olgeometry. The several papers of Courtemanche (1993-
96) made a strong start on working one- and two-dimensional propagation into these
concepts. He found that propagation substantially changes the story. Phase gradients
and "slow repolarization fronts" play major roles. Their prominence was largely
confirmed in later numerical studies (Leon et al., 1994; Vinet and Roberge, 1994) but
as far as I know today, slow repolarization fronts have not yet been reported from
laboratory studies.
Apart from conceptual problems, the stark question of fact remains today still
unresolved. It concems the observation that reasonably stable rotors are observed only
in two-dimensional heart muscle, and that spontaneous transition to spatiotemporally
complicated fibrillation is observed only in three-dimensional heart muscle. Either

• the rotor period in normal heart muscle is too short for stable propagation but a wide
variety of two-dimensional preparations mislead, being abnormal in ways that make the
rotor period longer, or
• it is indeed normally longer but only in normally three-dimensional heart muscle is the
singular filament geometrically unstable, or
• thickness per se somehow shortens the period until it is too short for stable
propagation.

This riddle is considered further in Section D.

Another question to be answered is, "Why does It matter, in clinical-pharmaceutical
context, given that a rotor in the heart wall is fatal even Hit does not induce breakup
of wavefronts?" T0 answer this, one must know something of the ways in which rotors
 (or whatever they decay intol get erased during electrical defibrillation. Maybe it is
harder to get rid of themall if they are meanwhile multiplying. But this is only more
guesswork.

inorganic chemical oscillators. Would the outcome still be much the same even in
the absence of spontaneous oscillation if the cells affected are excitable and
coupled to neighbors for coercion? The period would then shorten to some apriori
unknown propagation/rotation period, rather the period of a known oscillator, but
the topology might remain the same. First explicitly intended for heart muscle in
Winfree (1978b), then critiqued and improved in cardiology seminars in Amsterdam,
one version of the experiment was given at least a numeriesl stage rehearsal in van
Capelle and Durrer (1980).
A more abstractly topological version treated the paced ventricles as an oscillator
and implied a phase singularity in their response to a critically timed stimulus of
critical strength. Neither coupling between cells nor propagation played any role. In
Winfree (1983b and 1987a) this was made explicit in spatial terms: the phase
singularity was a place on the heart surface where a circling phase gradient provided
perfect initial conditions for prompt evolution of a rotor. The idea was to arrange
transverse gradlents of two main state variables so that cells along a ring around
some area would find themselves in the successive phases of the usual cycle.
(Analogously, fluid vortices are created where the gradient of flow velocity
transversely crosses that of pressure.) One way to do this is to deploy a gradient of
stimulus magnitude transverse to a phase gradient (Chapter 8 between Figures 8 and
9). With a cycle so initiated around a phase singularity, rotation could be expected to
continue (but for more than one cycle?) even without coupling between cells. Or
with cells coup'ed to excite their neighbors (Chapter 9) it might continue beyond one
cyde, then repeat at an unknown period. Imaged in the cell membrane's state space,
this area could be seen as a map of the epicardium stretched to cover the cell's
excitation-recovery cycle, as in Chapter 9's Figures 2 or 12. Areas mapped to the
interior of that cycle constitute the rotor, and those mapped more nearly onto the
cycle constitute outward-propagating waves. Given mirror symmetry of the initial
conditions, 3 the same would be expected in the outcome: a "figure of eight" mirror-
image pair of rotors, as EI-Sherif et al. (1985) named it.
In spring of 1985 I was thrilled to receive a phone call from Dr. Raymond Ideker,
leading a lab in a position to test the proposed cardiac pinwheel experiment. This
initiated a round of cross-country visits for exchanging theory and data and manuscripts,
a particularly satisfying interval in my leaming about fibrillation, for wh ich I am very
grateful. The na'ive design of Winfree (1981 a, 1983b, 1984e) was changed, for example
to forget about innervation and to replace the sinus node by an electrical pacing
electrode in the ventricle. Arrangements would mimic the design of Wiener and
Rosenblueth (1946), of classical assays of "ventricular fibrillation threshold," and of the

3 Unless quite dose to a boundary, a localized stimulus in a continuous medium can produce only adjacent
mirror-image rotors, as stressed in Winfree (197 4f, 1978a, and 1983b about myocardium): this fact rather than
the symmetry of large-electrode initial conditions is probably the ongin of the pattern that eventually acquired
the memorable name "figure of eight."
Box 0: Taking the Nonlinear Cable Equation Seriously
The rotor concept as applied to normal ventricular myocardium evolved from visions of
reentry in the more-studied atrium. A key factor was the "excitable gap" required in waves
emitted by a rotor, but thought to be absent from myocardial reentry. (For hairsplitting
about this concept and the related "refractory period" see Winfree, 1991 a, section VII E 3).
The story unfolded something like this:

• The cable equation, so called from its origin in engineering the North Atlantic undersea
telegraph cable, describes the spread of electrical potential along a line characterized
by distributed resistance and capacitance. Add a local non linear battery and you have
the nonlinear cable equation that Rashevsky (1936) and innumerable subsequent
authors applied to action potential propagation along nerve fibers.
The next four bullets ignore the cable equation:
• Wiener and Rosenblueth (1946) thought they had proved that rotors cannot exist,
i.e., reentry can circulate only around a hol. in the medium, radiating spirals with
turn-to-tum spacing equal to the hole's perimeter, and a proportional period always
exceeding the refractory period, i.e., waves with an unmistakable excitable gap;
• Selfridge (1948) corrected some of the slip-ups in that pathfinding paper, to the extent
of showing an unstable circulation with no excitable gap around a slit-like discontinuity
(wh ich the contemporaneously developed laws of electrotonic coupling in heart
muscle could not permit);
• Balakhovsky (1965) showed that it could be stable in a sense (again, ignoring
electrotonic interactions);
• Moe et al. (1964) represented atrial fibrillation in a persuasive cellular automaton model
("ceII" meaning a cluster of tens of thousands of cytologist's cells supposed to function
as a unit) that supported spiral waves ("vortices") with no excitable gap. They were
stable unless "cells" varied randomly and sufficiently with respect to intrinsie
refractoriness, in which case "fibrillation" promptly developed;
• Zhabotinsky (1970) discovered the rotor in his reaction-diffusion chemically excitable
medium. I supposed it relevant to tachycardia because heart muscle as conceived in
the electrophysiologist's non linear cable equation is a reaction-diffusion excitable
medium, only with electrical potential replacing a chemical concentration (Winfree,
1973c);
• Gul'ko and Petrov (1972), Shcherbunov et al. (1973), and Winfree (1974b,f)
independently computed rotors from the nonlinear cable equation, i.e., from
membrane models with electrotonic interactions;
• Elaborating on Wiener and Rosenblueth and still bypassing the cable equation, the
leading circle description (Allessie et al., 1977) stressed that reentry in two-dimensional
atrial muscle is better conceived in terms of a pulse circulating on a ring of tissue. This
preferred circuit shrinks until its perimeter is the refractory period times the
propagation speed, both of which depend on the period of excitation and on
pharmaceutically controlled parameters of excitability. A disk of tissue inside the
minimal circuit plays the role ofWiener's minimum hole: it is kept refractory most of the
time by intermittent excitations propagating inward. The waves radiating outward form
aspiral with no gap of excitability between one tum and the next.
This much informed the 1978 writing of Part D of Chapter 14, and is reviewed in Winfree
(2oooa). Then:
• van Capelle and Durrer (1980) repeated reaction-diffusion eomputations like those
above, but on such a eoarse anisotropie grid that propagation was saltatory and
 the consequences of continuity were not observed. They accordingly found an
excitable gap, f1uctuating as the wave rounds comers of a rectangular hole in the
grid;
• Medvinsky et al. (1982) pointed again to the conspicuous excitable gap during vortex-
like atrial reentry; Ikeda et al. (1997), among others, confirmed it, dismissing both
isotropie and anisotropie versions of the leading circle model;
• Rotors in thinned, two-dimensional v.ntrlcular myocardium tumed out to have a
period about 20% (30 msec) longer than the ostensible refractory period. Allessie et
al. (1989,1990) interpreted this excitable gap as an effect of anisotropy, arguing that
its electrophysiological mechanism depends on propagation being markedly faster
along the fiber grain. In contrast, introduction of uniform anisotropy into the
electrophysiologist's continuous cable equation (the reaction~iffusion equation for
electrical potential) has no effect on the temporal aspect of its solutions (see page
286). Does this invalidate the leading circle description or continuum interpretations
of heart muscle?
• Zykov (1984 in Russian; translated to English in 1988) stressed the importance of
including electrotonic interactions (the Laplacian operator, diffusion of electrical
potential) in electrophysiological models (i.e., the importance of taking th.
non"n•• cable .quation serlously). He stressed that even in a continuum and
whether or not the medium is isotropie, rotors always show a substantial excitable
gap, which f1uctuates during spontaneous meander in numerical models;
• Winfree (1989a, 1990c) stressed that anisotropy cannot alter timing relations in
continuous electrophysiological models, so if there is a regularly f1uctuating gap in
normal (= continuous: Winfree, 1997, 1998b) tissue, it may point to a meandering rotor
as the mechanism of tachycardia; similarly, an irregularly f1uctuating gap would be
expected during ventricular fibrillation;
• While the prefibrillatory tachycardia, torsade de pointes, was thought to reflect the
simultaneous operation of two unrelated ventricular ectopic foci (Bardy et al. 1983;
Inoue et al., 1986), Winfree (1988, 1989a, 1990c) pointed to the altemative
interpretation of such electrocardiograms as the calling card of a meandering rotor
or singular filament (with the caveat that such hearts are abnormal, and, in particular,
human torsade periods seem longer than the dominant periods of fibrillation and/or
rotors known in normal ventricles and presumed to underlie torsade);
• Davidenko (1993), Jalife and Davidenko (1993 p. 616-17), Gray et al. (1995a) and
Starmer and Starobin (1996) confirmed this interpretation or modified it from
"meandering" to "rapidly drifting" or "wandering";
• The cellular automaton model of Moe et al. (1964) tumed out to support "fibrillation"
even in the absence of such inhomogeneities as were thought to be its indispensable
preconditions in that model and in reality (Winfree, 1995c);
• First in the atrium (Kirchhof et al., 1993), then in the ventricles (Boersma et al. 1994; Cha
et al., 1994; KenKnight et al. 1995; Kwaku and Dillon, 1996), the predicted excitable
gap was reconfirmed in stable rotors and during fibrillation;
• Gray et al. (1997) again dismissed the leading circle concept in favor of the rotor
concept, and reiterated reasons to think torsade is a meandering or wandering rotor;
• Ikeda et al. (1997) and Athill et al. (1998) assayed wandering rotors in the dog atrium to
discover that the core is not irregularly made refractory as reported by Allessie et al.
(1973, 1975, 1977) in the rabbit atrium, and as interpreted through the leading circle
model. Rather, it stays quiescently excitable as might be expected of rotors in a
medium of depressed excitability. Since regular meander would not be expected in
that case, we see once again (as in every published experiment in cardiac
 electrophysiology) that laboratory preparations and procedures are more subtle than
contemporary concepts;
• Efimov et al. (1999), in contrast, reported no evidence of fully excitable cells in the long
singular filament they found in the rabbit's left ventricle. Is this a species difference?
• Peculiarities of reported reentry in the atria prompted the guess that atria hardly
resemble their uniform and two-dimensional models (Winfree, 1991c). Investigations
by Schuessler et al. (1992, 1993) and by Gray et al. (1996) and Gray and Jalife (1998)
concluded that atrial tissue is not reasonably approximated as uniform, nor either two-
or three-dimensional, and even raised doubt that there are rotors in the atrium.

photochemical pinwheel experiment, by delivering one big shock at a site in the wake
of a passing activation front. It was anticipated that a pair of mirror-image rotors would
result, each centered at one of the two places where tissue is exposed to stimuli of local
intensity straddling a "critical stimulus" (thus within some annulus around the electrode)
while at a "critical phase" during recovery of excitability (thus along some former
position of the passing activation front). The spatiallocus of critical phases could only be
supposed to lie (for hyperpolarizing shock, not deliverable in bulk myocardium) in the
depolarized plateau of the action potential, and (for depolarizing shock, somehow
resulting from gross electrification) in the relatively refractory phase soon after local
repolarization. The critical stimulus magnitude in the latter case could only be guessed
as several times the voltage gradient (about 1 Vlcm of extracellularfield when limited to
a pulse of a few msec) known to constitute threshold for stimulation of completely
recovered tissue. At that time the rotor's period in myocardium was unforeseeable from
theory, but see Box E for the easiest estimate known today. Such theory was based on
topological ideas too crude to account for electrotonic interactions between the phase
singularities expected to arise, so it would all have to be done on a large scale, in dogs
or pigs, not in rabbits or mice, with centimeter-size electrodes and enough current to
conjure the anticipated singularities centimeters away and centimeters apart, thus
independent enough to rotate predictably as required in the original definition of
"phase singularity (see Box F)."
How could we construct a conceptual bypass to evade the uncrossable intended
future construction site of a physical theory of electric shock? Abandoning Beeler-
Reuter and other ionic membrane models for a while, and abandoning all attention to
the microscopic anatomy of myocardium, I exhumed the simplistic FitzHugh-Nagumo
caricature by which the experiments had been designed, and tried to use it to
illustrate the qualitative principles imagined to underlie experimental results in the
dog ventricle at Duke University Medical School (ldeker and Shibata, 1986). These
experiments could be thought of as testing the topological notions introduced in
Winfree (1983b, 1986d, 1987a). Seven specific expectations were tested in which
predictions differed from more familiar schemes:
(i) Two-dimensional reentry that leads to fibrillation should be evoked reliably bya
deterministic two-factor procedure, specifically by doing something to the tissue
at a particular time with a particular strength);
(ii) This should creates a phase singularity, which evolves into something like a
rotor, its reentrant activation fronts pivoting around a point or disk, not dragging
Box E: The Period of Prefibrillatory Tachycardia

The rotor's period seems characteristic of the fastest tachycardias, the ones that
promptly dissolve into fibrillation with aperiod about the same or a little shorter. It
seems about the same in any mammal's heart (except the mouse's, which has a
peculiarly short action potential to facilitate a rapid pace). It is much shorter than the
refractory period during the normal heartbeat and also shorter than the ostensible rotor
period in computations from the Beeler-Reuter model. So Winfree and Guilford (1988)
acknowledged it as an embarrassment to the 1981 notion of twin phase singularities
starting fibrillation. Then Fishier and Thakor (1991) first obtained a realistically shorter
period in computations with coarser numerical grid but improved Beeler-Reuter-like
membrane. Beaumont et al. (1998) have since iIIuminated the mechanism by which the
rotor in cardiac muscle can spin faster than its ostensible refractory period and still leave
an excitable gap: it has to do with electrotonic coupling prematurely aborting the
normally long duration of the action potential in the wave circulating around the
quiescent area neighborhood of the phase singularity.
An easy way to anticipate the rotor's period, 7 0 , is to know the rule of thumb (see page
278) that the dimensionless quality factor Q = Co27 JD cannot be less than 67T (reaching this
limit only in spontaneous oscillators, it seems), is typically about 8~ in excitable media, and
exceeds that by more than about threefold only when the parameters of excitability are so
adjusted that rotors are barely viable (near 8R). This ratio is independent of the units of
measure and independent of direction in anisotropie media such as heart muscle. The
electrotonic diffusion coefficient D is known: about 1 cm 2/sec along muscle fibers and
tenfold smaller transversely. The speed Co of along-fiber propagation into partially
refractory medium at the rotor's short period 7 0 is not known apriori but is expected to
be a bit slower than the 60 cm/sec propagation of the solitary pulse propagating into fully
recovered, quiescent tissue: say, 40 cm/sec. Taking Q = 100 for a first-guess application to
heart muscle (Winfree, 1993b), we have 7 0 = 62 msec, whereas observed values range from
about 90 -130 msec. Had we supposed 30 cm/sec as in 1993, or cheated by adopting an
idiosyncratically large Q = 200 more typical of myocardium, the results would have been
inside the observed range. Another way is to note that Dle o2 is O(risetime of activation),
thus 7 0 is around Q risetimes of about 1 msec (during short-period propagation). Another
way is to actually solve a detailed quantitative ionic model of ventricular tissue: periods
today come out in the range of observation, but this is largely a result of tinkering
imprecisely measured parameters. Quantities are imprecise in this area; with the singular
exception of the mouse, it is not even clear that rotor periods depend on mamma I species
or heart size: they all seem roughly 100 msec (Winfree, 1994a,c).
The first clean observation of the standard mammalian 1oo-msec rotor may be Figure
341 in Lewis (1925): a smooth sinusoidal electrocardiogram from a cat who fibrillated
spontaneously while exposed to chloroform (but there was no way to distinguish its
spatial structure: it was thought of as an impulse circulating on a ring).
Knowing the period and propagation speed, one has the spacing between tums of the
spiral, and the diameter of the presumptive rotor at the core of the spiral, inside a circle of
perimeter equal to that spacing. By the same reckoning this spacing would be 3.3 cm along
fibers (and about 1.1 transversely, due to the tissue's anisotropy). Dividing by 7T to get rotor
long and short diameters, we find 1.1 cm by 0.4 cm for that core. It might then be expected
that smaller hearts cannot support rotors and therefore might not be susceptible to
fibrillation, unless they are also electrophysiologically rather different. The mouse heart is
too small yet does support rotors (Morley et al., 1997; Vaidya et al., 1999); sure enough, its
 action potential is uniquely abbreviated (in time) more than twofold by absence of the
plateau phase characteristic of larger mammals, and shortened more (in space) by reduced
propagation speed near the phase singularity. In the absence of DAM (see Box G) its rotor
period is less than half the nominal 100 msec of larger mammals.

along a slit-like arc of conduction block (at least, this can sometimes happen,
and arcs in general tend to shorten toward lengths below 1 cm);
(iii) This point of phase singularity should appear near the interseetion of a locus of
critical local phase in the prestimulus cycle of excitation and recovery, with a
locus where local stimulus strength is neither too small nor too big, and
probably several times the diastolic threshold;
(iv) Experiments in which one of these gradients does not exist, or these contours
do not cross, or they cross all along their superposed lengths, should produce
no phase singularities therefore no rotors;
(v) Given the simple symmetric geometry of the planned experiment, a line (of
preexisting isochron in the wake of a prior activation front) and a circle (of
uniform stimulus intensity) should cross twice to produce mirror-image phase
singularities that tum into mirror-image rotors spinning in a direction to fire
activations back at the stimulus eleetrode along the midline between them;
(vi) They are about 15 mm in diameter as measured along fibers (and possibly
almost as long transverse to surface fibers, if fibers only a few millimeters deep
into the wall line up in that direction);
(vii) On a diagram of timing and strength of the applied stimulus, effective
combinations should cluster into a "bull's-eye" surrounded by stimuli that evoke
onlya few quick beats, surrounded by those that evoke only one or none (Figure
1). Thus the vulnerable phase should have an unexpected upper limit for
stimulus strength.
These seemed bome out in experiments reported by Ideker and Shibata (1986),
Chen et aL (1988), Shibata et aL (1988), and Frazier et al. (1989) at Duke, then confirmed
in other laboratories. For example, Figures 2-6 show results from a variety of
subsequent tests establishing the reality of item vii's "upper limit of vulnerability," Le.,
closure of the cloud of experiments resulting in fibrillation at large stimulus magnitudes.
[In 1986 Ideker found that this was not quite "unexpected": almost equivalent data had
been lost in the literature since Lesigne et aL, 1976.] Notice that the critical local
stimulus magnitude is about 5 V/cm (for an acute pulse of a few msec duration)
wherever it was carefully measured (Figure 2), and that the critical phase is in the relative
refractory period, as anticipated for depolarizing stimuli (the opposite for hyperpolariz-
ing stimuli, if they could be delivered extracellularly).
It has to be noted here that in the 1980s no one had better than an empirical idea of
what "stimulus" means in electrical terms, though more extracellular current could
probabr be taken to deliver a bigger "stimulus" to a mass of myocardium, and about 4
mAlcm seemed sufficientto activate quiescent bulk tissue. The situation is quite different
when one uses intracellular microelectrodes: then "stimulus" is a maintained voltage
displacement or current per unit area of cell membrane, and one can distinguish anodal
from cathodal, "make" from "break" excitations, etc. But current is delivered to gross
tissue from extracellular electrodes. Where does how much of it cross cell membranes? In
 Box F: In Heart Muscle "Phase Singularities" Seldom Become Rotors

Phase singularities are visible by voltage-modulated fluorescence on the ventricular surfaces

of isolated rabbit, dog, and sheep hearts during fibrillation. They appear in parity-conserving
pairs in association with particularly steep phase gradients, Le., where conduction is too slow
(Gray et al., 1995b) and they sometimes move at sprint speeds up to Mach 0.4 (40% of action
potential propagation speed). Whatever the cause of such unexpected speed (unless it be
slow drift of a singular filament almost parallel to the surface), such a situation is decisively
nonperiodic and so cannot fit the original definitions of phase and phase singularity. But
another definition of "phase" is possible, not in temporal terms but in terms of the local
state. In this definition the "phase singularity" is astate in the middle of the excitation-
recovery loop (Winfree and 5trogatz, 1983a, page 39; 1984a page 228; and Winfree, 1989a
page 358; see Chapter 9 near Figure 1.2). This definition captures wavefront endpoints
whether or not they are involved in periodic circulation. So the end of a segment of
wavefront gliding along a temporarily refractory wall could present as a "phase singularity"
moving even as fast as Mach 1. This kind certainly does not have aperiod nor centrally zero
amplitude atthat period, as required underthe original definition of phase singularity. It may
or may not become temporally periodic (a rotor) when that wall dissolves, according to
Beeler-Reuter calculations (Winfree, 1993a, 1993b p. 671 and color plate A20, described in
more detail in Winfree, 1995c). It seems to me simpler to call it a wavefront endpoint rather
than a phase singularity. But epicardial maps deploying the color wheel scheme of Winfree
(1983b and 1987a) rather than the voltage-to-color scheme previously standard in
electrophysiological mapping do look the same under either definition and so do present
phase slngularitles of color, so the name is now widely used even for ephemeral endpoints.
For this reason it is essential to be sure which of the three color schemes is in use in any given
picture. Most of Gray's points (phase-colored for the state-space definition of phase) do
indeed vanish by pairwise mutual annihilation very promptly. If they last longer than rotation
period r 0 (around 100msec) and so become roughly periodic, thus more like real phase
singularities, they are christened as "rotors." But almost none do last longer than two
rotations, in marked contrast to na'ive expectation based on twCH.Iimensional numerical and
chemical analogies, but in excellent agreement with the similar myocardial observations of
Lee et al. (1996a), Kim et al. (1998), Chen et al. (1998), and Rogers et al. (1999). For more
examples including color maps of phase geography for comparison with topological theory
in Winfree (1983b, 1987a), see the dramatic experiments and computations of Gray et al.
(1998) and Biktashev et al. (1999).
This distinction is important. In models of fibrillation involving spontaneous creation of
rotors by breakage of wavefronts, rotors behave like the phase singularities (alias
wavefront endpoints) here observed, except that such models provide no reason for
them to move rapidly unless discontinuities and steep parameter gradients pervade the
tissue. In contrast, models of fibrillation involving singular filaments (vortex filaments,
sero 11 waves) show rotor pair creation and subsequent rapid motion not by spontaneous
wavefront breakage, but rather by tangency of the moving filament to the epicardium
where activations were erupting in a focal manner at unaccountably high speed. The
latter events require no inhomogeneities: they are generic even in perfectly uniform
three-dimensional media.

the linear fjeld" no more than a few space constants from the electrode, this can be
calculated with some confidence and verified by observation. Calculations suggest
 5.16.

'"~
0..,
::l SINGLE
EXTRASYSTOLE
:.: Figura 1. Theory underlying the pinwheel experiment for
g MULTIPLE
creation of singular filaments predicted closed coneentric
:I: EXTRASYSTOLES
'" eontours (sueeessively lighter) of persistent fibrillation,
15 FIBRILLATION
ephemeral taehyeardia, a single extrasystole, or no effect, at
8-' a time when this diagram was eonsidered too im probable to
merit testing. (From a Fall 1988 seminar about fibrillation as
intramural seroll waves, published in Zipes, D.P. and Jalife, J.,
1990, page 228, Figure 26-7, adapted from Winfree, 1983b,
with permission.)

MILlISECONOS AFTER aRS

'"
~ ,S<»

~ Figura 2. Like Figure 1, but drawn from the experimental data of

LIJ
0:: Frazier et al. (1989) with open-ehest dog, and aceordingly
~ 1D:)O
ealibrated in physical units. The tiny dots are single or multiple
3
::l
extrasystoles; the enlarged ones are fibrillation. (From Winfree
:0 1990e, Figure 7, with permission.)
~ ~
-'
«
§ . ~--~----~~~----~
.. so ..
LOCAL PHASE T OF SHQCK (mse<:)

10.

Figura 3. The same principle, but drawn from the data of Shibata
et al. (1988), dogs again. The same four eategories as in Figure 1
3 0.1 are indicated by the same levels of shading. (From Winfree
::l
:0 1990e, Figure 8, with permission.)
!ii
0.01

110 130 150 170 190

STIMULUS TIMING. MSEC.
 ~ 517

10.

~
5> 8.

Figure 4. Gray-coded as in Figures 1 and 3, comparable results ffi~ 8.

in sheep ventricular epicardium, adapted from Davidenko et al.
(1991). Stimulus strength is measured by volts applied for 2 ~
msec. (From Winfree 1993a Figure 13c, with permission.) ~ 4.

2.

o.
180 200 220 240 260
STIMULUS TIMING. MSEC.

700
~
eoo
ic: 500
AOV

!
a; MlO
..lII:
300
j 200
f/I
100
140 160 180 200 220 240
Coupllng Inlarval (rntI)

Figur. 5. The isolated, perfused rabbit heart exhibits no dysrhythmia at stimulus strength,
timing combinations indicated by circles, a brief run of rotor-like impulses at squares, and
persistent fibrillation at triangles. "AOV" = "Area of Vulnerability." Stimulus strength is
measured in volts applied for 5 msec. (From Fabritz et al., 1996 Figure 2, with permission)

40 0000000000000
0000000000000
~~ 0000000000000
..,: 25 000000.000000
20 iii 000000.000000
Figur. 6. The isolated right atrium of a dog exhibits a similar 15 !f 000000.000000
pattem of response in respect to rapidly wandering vortices of ::> 10 000000 • • 00000
() 8 00000 • • • • 0000
electrical activity. As in Figures 1-5, if the stimulus (here ::> 6
CI)
0000 • • • • • • • 00
measured in mA at 5 msec duration) is too large or too smalI, ..J
::> 4 000000 • • • 0000
too early or too late, rotors are not induced. (Adapted from ~ 2 0000000000000
Ikeda et al., 1997 Figure 3A, with permission.) . 1 ti 0000000000000
1/2 0000000000000

60 90 120 150 180

STIMULUS TIMING, MSEC
 .'"
17: EL eTRlCAl SIN.GULAR FIlAMENTS IN THE HEARTWALL
. 7 - . " .......---"-"'--_""'_ _

vanishingly little transmembrane current farther away, as long as we ignore fiber rotation
and curvature and microscopic clefts between fibers. Observations (Frazier et aL, 1988;
Zhou et aL, 1995) show otherwise in that "farfield," suggestively implicating irregularities
of fiber geometry.
An unconventional way of thinking about far-field electrical shock and the
membrane's active response without having to know detailed mechanisms survived
exelusion in the experiments mentioned above. Was some altemative notion disproved
by these observations? Not really: others are likely valid in some other myocardial
context. At least the proposition was exeluded again that "theoretical biology based on
abstract topological concepts instead of specific ionic mechanisms and cell physiology
can produce no valid surprises." But what was leamed? The rotor's period was
determined in the dog's ventricular myocardium. A transmural singular filament was
exhibited for the first time. The surprising (at least to me) fact was obtained that it
promptly goes unstable, instigating fibrillation within several rotations. The main effects
of the experiments at Duke were, I think, to provide a distinct and visible target for
scoring new experimental observations (see plentiful violations of i-vii below), and to
attract the attention of more theorists to this area.
Theorists have since engaged two main questions:

1. "Exactly how were these phase singularities created, in tenns of specific

electrical mechanisms of the initiating shock and in terms of the membrane's
ionic response, and wh at other ways might there be?" This is taken up in
Section C;
2. "What kinds of instability might mediate the observed transformation of rotors to
fibrillation, in two dimensions and in three?" This is taken up in Section D.

C: Pinwheel Experiment Revisited (PER)

The physicist J. Willard Gibbs wrote (1881) that "One of the principal objects of
theoretical research in any department of knowledge is to find the point of view from
which the subject appears in its greatest simplicity." Certainly, this was done in the
pinwheel experiment design for rotor creation in myocardium. Was it overoone? Alfred
North Whitehead recommended to "seek simplicity... and then distrust it." Albert
Einstein is also said to have remarked (Reader's Digest, October 1977) that we "should
make everything as simple as possible, but not simpler." The good sense behind these
reiterated cautions is weil illustrated in recent follow-ups to the pinwheel experiment.
The decent correspondence between items i-vii above and the actual outcomes of
experimental tests was surprising. The next natural step is to recast the original
abstractions in less abstract terms more elosely related to electrophysiological concepts
and more specifically tailored to the actual experiments. Chen et aL (1988, 1993, 1997),
Shibata et aL (1988), Winfree (1989a), Kavanagh et aL (1992), Knisley et aL (1992),
Pertsov et al. (1993a), Krassowska and Kumar (1997) all achieved this in diverse testable
versions, and all encountered the same problem: none could dependably quantify the
effect of an electric shock on the state of the membrane in a tissue of connected cells,
particularly beyond a neighborhood of a few millimeters around the electrode. My
version eva des the problem by provisionally supposing that on the space scale of
interest (>5 mm) any three-dimensional block of heart wall is functionally isotropic in the
plane of the shock gradients because the rotating anisotropy gives it about equally
many fibers pointing in every such direction. The "stimulus magnitude" can then be
characterized (for sufficiently brief pulses) in V/cm or mA/cm 2 . This first-order
simplification was tested by contriving estimates from basic physics for a number of
known electrical thresholds of bulk myocardium (for pacing, for on set of fibrillation, and
for defibrillation, with various electrode arrangements); the outcome (fortuitously?)
seems to be in reasonable agreement with long-familiar laboratory values (Winfree,
1990e, 1991c). On the basis of the same assumption Min and Mehra (1998) made
detailed comparisons of the clinical effectiveness of various commercial defibrillating
catheter electrodes, and again found good agreement.
Resort to such empirical expedients for guesstimating far-field effects will no
longer be necessary when bidomain computations of the pinwheel protocol become
quantitatively reliable in application beyond a several-millimeter neighborhood
around the electrode. At the moment there is still a "missing link" (Roth and
Krassowska, 1998): an order-of-magnitude discrepancy between stimulus thresholds
calculated from cell membrane models and those observed in tissues of connected
cells. But let's turn from this dilemma now to consider theory and experiment recently
working hand in hand within the near-field context.
The concepts and particularly the quantitative models deployed in 1985 seem
crude today, particularly in one respect little appreciated then. That is the importance of
the fact that the electrical anisotropy of the conducting liquid space between cells is
much les5 than that of the cytoplasmic space, the syncytium of cells connected by
conducting gap junctions. In such bldomain media certain symmetries of equal-
anisotropy physics are broken. One result is that the polarity of stimulation now makes
a difference. Another is that the anisotropy of conduction and propagation can no
longer be removed by merely rescaling distances transverse to fibers. Maybe the most
important consequence of a" this can be visualized simply: the footprint of an electrical
point stimulus is not a set of concentric isointensity rings around it, intensity fa"ing off
radially, but instead something more like a quadrupole, a "dog-bone" or "clover-Ieaf"
containing "virtual electrodes" of opposite sign (Sepulveda et al., 1989). See Figure 7.

Figure 7. This is a black & white version of Fig. 3f from

Sepulveda et al. (1989). Fibers are horizontal in this 8x8 mm
square of simulated tissue. The white around the stimulus
electrode at the center (black rectangle), is depolarized tissue,
resembling a "dog-bone" when its extensions to north and
south are considered, The black lakes to east and west are
hyperpolarized tissue. Middle gray is near rest potential. (From
Bradley Roth, with permission.)

Still ignorant of this in July 1989, my analysis of rotor induction with bipolar
electrodes (Winfree, 1991 c, drawing on Jack et al., 1975 and Freeman, 1975 Chapter 4,
in reverse) postulates extracellular potential gradients more like those expected in a
resistive continuum such as graphite or saltwater. This was written in the year Sepulveda
reported the c1over-leaf, and it was uninformed by that landmark discovery, so it is
completely wrong. It seemed to account quantitatively for the known fibrillation
threshold, and it correctly anticipated formation of two or four mirror-image rotors,
depending on angular orientation of phase gradients and the bipole to muscle fibers,
but today these seem more like coincidences. Roth (1995, 1996, 1997) computationally
obtains shock thresholds in the same range by correct bidomain physics.
In 1989 it seemed that "the dual anisotropy of myocardium provides another
candidate answer in context of this theory of intersecting singular contours. Propagation
away from a point stimulus is anisotropic, with velocity differentials in perpendicular
directions as large as 3:1 in some situations; consequently, the isochronal contours are
3:1 ellipses. Electrical conductivity in the extracellular interstices is also anisotropic, but
not necessarily in the same ratio ... The S* singular contour may then be an ellipse of a
different shape from the P singular contour. Both being centered at the one e/ectrode,
they may intersect 2 or 4 times. ... This problem would benefit from quantitative
attention." (Winfree, 1990d), wh ich is exactly wh at it was independently already getting
from Sepulveda et al. (1989).
The follow-up was executed computationally by Roth and Saypol (1991), Saypol
and Roth (1992), Roth (1997), then in the laboratory by Un et al. (1999). This sequence
culminated in a beautiful demonstration in the ventricles of large rabbits: four mirror-
image (ephemeral) rotors are indeed created by two successive shocks from one point
electrode, whenever the interval falls in a critical range during relative refractoriness. It
had long been known that multiple stimulation at one point induces fibrillation if and
only if intervals are short enough, but the mechanism was unclear. Un's experiment
optimizes this kind of stimulus to require only the two shocks used in pinwheel
experiments, but now from a single electrode as in the original experiments of Allessie
et al. They demonstrate the mechanism in perfectly lucid terms of the bidomain
model's clover-Ieaf pattern of de- and hyperpolarized tissue near the electrode. It
should probably be noted that these rotors survive only a few tums in two-dimensional
computations before they recombine, whereas they survive only so long in the
laboratory for the different reason that they incite fibrillation.
At this point the originally more specific label "pinwheel experiment" is
expanding almost to the point of covering all two-shock protocols for initiating
rotors. But these go back at least to 1939 when Wiggers and Wegria (1939, 1940)
discovered the vulnerable phase by delivering two successive shocks, an $1 to start a
wave, then an $2 in its wake to start fibrillation. "$1-$2" protocols diversified from
that origin, together with labels "twin stimulus protocol," "crossed-gradient initial
conditions" (e.g., Chapter 9 Figure 12), "cross-field stimulus," etc. Allessie et al.
(1973), for example, deliver them both through the same point electrode in the
atrium, much as Un et al. (1999) do in the ventricles. Davidenko et al. (1991) and
Pertsov et al. (1993a) use abipole for $2 in the refractory wake, but deliver a
relatively weak shock through it, like Allessie and like Un. The distinguishing feature
of the "pinwheel experiment" was its use of such a large $2 shock (and not from the
same electrode) that tissue became depolarized centimeters away, so phase
singularities arose predictably and noninteractingly centimeters apart in relatively
smooth far-field gradients of stimulation, and tumed into stationary rotors. But there
 ~. ' ~

C: PINWHE;L ~PERIMENT REVlSlTED (P6R) 521

are also circumstances in which "phase singularities" created dose together in a

congested neighborhood will interact electrotonically to spring violently apart in the
first milliseconds while developing the shape of a rotor. This happens where stimulus
gradients are steep and curvy, for example between dose-spaced bipole electrodes
or, as Lin et al. show, even in the neighborhood of a unipole (see pages 275-76).
5ince this is a nonperiodic situation, the original definition of "phase singularity"
cannot fit it without a bit of tailoring or back-pedaling.
50 the question naturally arises, "Could the concepts of T* and S* that seemed
useful in the far-field context also be applied to near-field shocks in which the more
commonly used smaller currents create more steeply graded stimulus pattems in a
much smaller area around the electrode?" 00 the recent near-field experiments
depart from the original plan of crossing stimulus gradient and phase gradient to create
a phase singularity, or can they be conceived of as the same thing, with the medium's
dual anisotropy transforming radially symmetric electrode arrangements to transversely
crossing gradients? As late as 1994, somehow blocking Allessie et al. (1973) from
consciousness, I was still thinking of crossed gradients as "necessary and sufficient
conditions" (Winfree, 1994a). And this is roughly the approach taken in "The Pinwheel
Experiment Revisited" (PER-1) of Roth (1998a). Reverting to the context of an $2
electrode firing in the wake of a wave from an $, electrode elsewhere, Roth reanalyzes
rotor induction in terms of intersecting critical contours, but corrects the excitation
footprint from concentric ellipses to a dover-Ieaf containing disjoint ring contours or
(depending on choice of anode or cathode) elongated dog-bone contours. This covers
the case of shock during the local relatively refractory phase (Td* for local
depolarizations). It could also cover shock during the local action potential plateau
(Th * for local hyperpolarizations) by attending to intersections with the similarly-shaped
deexcitation lobes introduced with the dover-Ieaf. In either case the whole pattem is so
small that mirror-image singularities are predicted mere millimeters apart, making
"critical contour" identification impractical: a nascent rotor 1 cm across cannot be
located precisely enough to distinguish its origin on this or,that one of many contours
packed into a smaller space, especially because it moves rapidly while still coming into
being in that steep electrical environment.
But more importantly, the deep thought given these matters in the new context of
bidomain electrophysiology highlights two layers of ambiguity in contemporary
discussion of crossed gradients:

• The first ambiguity: Gradients of what? At the origin of theory involving T* and S*
they were transverse geographical gradients of local state: for convenience of
manipulation, a gradient of local T inaugurated from one electrode provided one
component, and a transverse gradient of local $ supported from another electrode,
some centimeters away, imposed another. Are transverse gradients of timing and
shock intensity merely sufficient, but not necessary to create the transverse
gradients of state required for mapping the tissue's image across its excitation-
recovery loop?
• The second ambiguity: ls it essential that this mapping be complete at the
instant the stimulus ends, or might it spontaneously evolve during the next
milliseconds from a mapping that did not yet cover the loop? This is discussed
in Chapter 9's 5ection B near Figure 10, and illustrated on my web site.
 • Combining the two ambiguities: If this second ambiguity is resolved in favor of
accepting such "spring-loaded" initial conditions for a rotor at the end of a discrete
stimulus, and the first is resolved by back-pedaling from the necessity of certain
timing and stimulus gradients to the necessity of the state gradients they can
produce, and thus to the necessity only of a gradient of timing or stimulus, then the
"theory" of rotor evocation has been reduced nearly to tautologies beyond the
reach of disproof by evidence, and is no longer "science."

This was roughly the state of affairs by 1998, when Dillon and Kwaku (1998)
presented observations of failed defibrillation by electric shock together with
interpretations inconsistent with the prior theory purporting that they fail because the
shock also creates some (1'*, 5*) intersections, some of which (depending on details of
geometry) evoke new rotors at the same time the same stimulus is erasing old ones
(Winfree 1987a, page 138; Chen et al., 1986a,b). The newer experiments show that
rotors can also arise by other means.
Meanwhile, as in the sequence of computations leading to the laboratory
demonstration by Lin et al. (1999) using a twice-fired s;ngle electrode, a numerical
model would be more credible than contour-sketching as preparation for a decisive
experiment in the original pinwheel experiment fonnat. This is provided by Lindbiom et
al. (2000) in a paper subtitled "Pinwheel Experiment Revisited" again (call it PER-2). They
examine the effects of dual anisotropy in context of the classical pinwheel experiment,
with a remote electrode called 51 launehing a wave to create a phase gradient, and local
electrode called 52 creating stimulus gradients at the right moment (i.e., at the right
place in the wake of that wave). The results differ somewhat from anticipations in PER-1,
so a few caveats should be noted before relating them. PER-1 looks into implications of
the notions of intersecting contours that I adopted as an extravagant simplification
suitable for such smooth stimulus gradients far from such a big electrode as used in the
Duke University experiments: the far-field case. The limiting spatial resolution of that
approximation is something like a 1-cm rotor diameter. The aim in PER-1 is to "test the
envelope" again as done in guesstimating electrical thresholds (Winfree, 1991 cl, this
time by applying the same notions to baroquely convoluted clover-Ieaf contours packed
into no more than several millimeters around the electrode. PER-1 made four
predictions, some of which worked out and some of which did not, when tested
numerically in PER-2. I assume that the failures reflect consequences of electrotonic
interactions on the small spatial scale of this computation (Winfree, 2000b). Anticipating
the next step (Iaboratory trial), it should be noted that the numerical test is not
quantitative for real myocardium, for two reasons:

• First, it uses a Beeler-Reuter membrane model patched by ad hoc modifications,

rather than any of that model's modem descendants. Its action potential lacks the
depolarized plateau phase characteristic of myocardium, for example.
• 5econd, and maybe more importantly, it takes myocardium to be a unifonnly
anisotropie sheet of straight parallel fibers as in linear trabeculae (Weidemann,
1951) rather than a cholesterically twisted volume of curving fibers oriented
(within a few millimeters to either side of the sheet) to all directions in the plane
of the sheet. Consequently, the shock is effective only within several space
constants (mms) around the electrode. 50 the far-field effects that dominated the
 ,c:OPINWHEEt ExPERIMENT REvISITED ~(PER) 523

Duke experiments are absent from this model. This caveat will become pertinent
only when the experiment is done and in any ca se will not affect comparison
with results near the electrode.

Meanwhile, the computations in PER-2 beautifully confirm that in this near-field

setting "the pinwheel experiment" must be expected to result in four mirror-image
phase singularities, not the two anticipated while neglecting the inequality of
anisotropies, i.e., the two observed in the 'ar-field laboratory experiment. Most
surprising and interesting is their survival despite being created so dose together.
This kind of rotor induction was first reported by Davidenko et al. (1991) and Pertsov
et al. (1993a) at Syracuse with a comparably compact and steeply structured 52 (a
narrow bipole): phase singularities "too dose together" rapidly spring apart to
become rotors. But at Syracuse there were only two (one observed and one imputed
through the symmetry of electrode arrangements). In the PER-2 eomputations there
were four, but one pair commonly vanished as "expected" by mutual annihilation or
by blockade of the activation front joining them, as also observed experimentally in
the single-electrode configuration of Lin et al. (1999).
It is not dear that these computations pertain to 'ar-field experiments with big
electrodes, such as the discussed original pinwheel experiment, but they may finally
give a precise mechanistic aecounting (alternative to the attempt do it with a
monodomain model in Winfree, 1991 c) for the original 51-52 induction of fibrillation by
Wiggers and Wegria (1939, 1940) using more eomparable arrangements.
Everything so far concerns the dassical vulnerable phase, when the tissue is
relatively refractory. The corresponding stimuli are excitatory, i.e., depolarizing.
According to Winfree (1989a,b) there should also be a vulnerable phase during the
depolarized plateau, demonstrable if it were possible to hyperpolarize any large
expanse of tissue (several millimeters across) some centimeters from an electrode.
At the time, this was thought impossible, but according to Sepulveda et al. (1989),
it is at least possible in miniature: a good portion of the dover-Ieaf footprint of a
point electrode consists of hyperpolarized tissue, whether the stimulus is anodal or
cathodal. In PER-1 and the experiments of Lin et al. (1999) no mention is made of
stimuli applied during this period. (Nor in PER-2, because there ;s no plateau in
that computational model.) But Efimov et al. (1998, 1999, 2000) produce phase
singularities, rotors, and singular filaments by an electrical shock during the
depolarized plateau phase, by a mechanism involving virtual electrodes. This would
seem to suggest that this long-expected singular phase for hyperpolarizations might
also be observable in the two-pulse experiment of Lin et al.
Efimov's experiment is even more interesting in that it might require no
preexisting phase gradient. There ;s one, of course, since the locally uniform
depolarization came by propagation from a remote pacing electrode. But Efimov et
al. ascribe the apparition of a phase singularity to a new mechanism independent of
phase gradients. Moreover, in the sequence leading to Lin et al. (1999) both stimuli
came from the same electrode, apparently in violation of the ideas underlying (i)-(vii)
above, unless one quibbles that the two domains (intraeellular, interstitial) are not
equally anisotropie, so behind the 51 wave there may be some slight criss-crossing of
T eontours with the dover-Ieaf contours of imminent 52' Struggle is necessary here,
but the struggle to understand the essen ce of the new mechanism is more interesting
524

Box G: How to Stabilize Rotors and Singular Filaments in Heart Museie

Li et aL (1985) found that 2,3-butanedione monoxime (BDM), alias diacetyl monoxime

(DAM), prevents muscular movement in heart cells without obvious impact on the
membrane's electrical behavior. Osaka et aL (1987) introduced a new preparation of heart
muscle resembling "postage stamps" cut from the epicardial surface, then maintained in a
warming dish by diffusive exchange with oxygenated salt solution. Putting them together
with CCD camera and image processor, Davidenko et aL (1990, 1991) and Baxter et aL
(1997) inaugurated a decade of observing phase singularities, rotors, and the surface
manifestations of singular filaments in the ventricular epicardium of diverse mammals.
Several laboratories have since found that DAM depresses ventricular excitability in the
mouse (Vaidya et aL, 1999), in the rabbit (Knisley and Hili, 1995), and in the dog (Riccio et
aL, 1999) to such extent that fibrillation immediately reverts to sharply regular tachycardia at
longer period and Q than normal rotors. Rabbit hearts, for example, support continuing
"torsade," interpreted as wandering rotors or intramural singular filaments, without
converting to fibrillation (Davidenko et aL, 1993; Gray et aL, 1995a). The " chronic
fibrillation" we discovered in normal dog ventricles (Witkowski et aL, 1998; Winfree and
Witkowski, 1998; Vigmond et aL, 1999) has not been reported from any preparation using
DAM. But persistent rotors and singular filaments are reported abundantly in such
preparations (Davidenko et aL 1990, 1991, 1992, 1993; Pertsov et aL, 1993a; Efimov et aL,
1998 and 1999 and 2000). My impression is that by depressing some aspect of excitability,
much as we found necessary to stabilize rotors in the first such computations using a
realistic ionic model of the cell membrane (Winfree, 1989a; Courtemanche and Winfree,
1991), DAM in otherwise normal hearts stabilizes the dynamics of rotors and singular
filaments that would normally catalyze fibrillation within several rotation times. One aspect
clearly depressed is the restitution curve slope that drives breakup of rotor-period activation
fronts (Riccio et aL, 1999; see Box C.)

than a struggle to interpret everything in terms of T* and 5*. Two key features
distinguish the new mechanism of "virtual-electrode-induced phase singularities" from
the old. First, the old concept of (excitatory) local stimulus intensity, 5, involved only
current density, but the new involves po/arity too; reversing polarity reverses the
resulting rotor's handedness. 5econdly, the old mechanism embraced only stimuli that
arrange membrane potential and refraetoriness pattems to resemble a rotor, but the
new seems not to. The problem stems from the underlying basic concept of a rotor as
a transverse crossing of two gradients: how can a single gradient or parallel
gradients provide initial conditions for an object made of transverse gradients? Is it
really no longer necessary to start by providing transverse gradients orthogonal to
intersecting T and 5 contours? One conjecture, probably equally pertinent to both
experiments if to either (Efimov, Lin), is offered in Chapter 9's 5ection B near Figure
10. Another, more substantially illustrated numerically in Roth (1999) but possibly
boiling down to a similar principle, is that the hyperpolarizing virtual electrode
deexcites such a large patch of tissue to either side of a unipolar metal electrode that
a segment of activation front can propagate in it until adjacent depolarized tissue
recovers. In PER-2 this achievement required first tailoring the Beeler-Reuter
membrane model to recover several-fold more rapidly than formerly, but with that
 0: Two· VS. IHREE·DIM5NSIONAl jNsTABIUnES OF THE SINGULAR fiLAMENT IN HEART MUSClE

done it enabled creation of two rotor pairs that survived as long as three periods in
the complete absence of any prior timing gradient. This is the clearest possible
violation of the condition required in item (iv) above. Yet short-lived rotors still
emerge, perhaps as indicated in Chapter 9.
So much for question 1, about initial conditions for a rotor in myocardium. We now
turn to question 2, about the instabilities of rotors in myocardium and so about the
transition from mere tachycardia to fibrillation.
The simplest instabilities are two-dimensional: wandering rotors of opposite
orientation find one another and mutually annihilate, while pairs are created and f1y
apart where one or another instability of front propagation at the short period of rotors
creates a temporary arc of conduction block. Thus the number of rotors could f1uctuate
around a stati sti ca I equilibrium as some pairs mutually annihilate and other pairs spring
into existence. In this case we could view fibrillation as an infection, not by living self-
replicators such as bacteria, nor even by non-living but self-replicating dynamical states
as in "mad cow disease" proteins, but by non-living self-replicating purely dynamical
entities of an electrical nature, the quintessence of Glass and Mackey's (1988) notion of
"dynamical disease." I think this is the prevalent view. There is an alternative.

D: Two- vs. Three-Dimensional Instabilities of the Singular

Filament in Heart Museie
In pinwheel experiments the phase gradient points from the pacing electrode across
the width of the ventricles, and does so at all depths into the heart wall. So one might
imagine that whatever happens on the visible epicardial surface must happen similarly
at every depth. In particular, the phase singularity at the center of rotation on the
surface seems likely to be just the visible endpoint of a singular filament transfixing the
wall. To check this conjecture ehen et al. (1988) mastered the sophisticated technology
required to insert a fine grid of electrodes to appropriate depths on plunge needles,
and demonstrated persistence of a rotor as a transmural singular filament spanning the
7-mm thickness of a dog's right ventricular outflow tract. Their "critical points" are thus
revealed as the visible endpoints of singular filaments in three dimensions. Three-
dimensional investigations have since progressed considerably in living heart muscle
(e.g., Krinsky et al., 1990; Pertsov and Jalife, 1995; Biktashev et al., 1999; Efimov et al.
1999), and they are currently familiar subjects of computer simulation (papers collected
in Panfilov and Holden, 1997, and in the March 1998 issue of Chaos, and many specific
citations below).
The spontaneous transition from simple and regular rotors to ventricular fibrillation
is not only three-dimensional in thick heart walls (how could it not be?), but mayaiso be
inherently three-dimensional in the sense that it does not happen in functionally two-
dimensional (Le., thin) normal ventricular muscle (Winfree, 1993b, 1994a,c). What does
happen in two dimensions is persistence of rotors, sometimes pinned on localized
patches of lesser excitabiI ity, sometimes rapidly gliding in (presumed) gradients of
excitability, sometimes impacting one another, but not developing the kind of spatial
complexity that the word "fibrillation" connotes. Of course, this connotation may be
dispensable: As far as clinical interest is concemed, a rotor is lethai enough, and
 .,.. • ( r.
526 17: ELECrRJCAL
.
SINGU':A~ FILAMENTS Ir\! TliE,HEAAi WAU.
'~

multiple or rapidly wandering rotors suffice to make a wiggly enough electrocardiogram

to qualify for a "code blue." And diseased or otherwis8 abnormal, functionally two-
dimensional he art muscle can develop arbitrarily complex wave patterns when
provoked initially by rotors (or perhaps by any other source, if there were one, with
comparably short period). 50 can the geometrically and electrically heterogeneous
normal atrium. But an intriguing incompatibility arises between models and
observations when we insist upon the "spatiotemporal complexity" meaning of
"fibrillation" in normal, healthy ventricles.
The problem arose from the discovery in 1987-88 that (unsurprisingly, though it
had not yet been tested or shown) the electrophysiologist's detailed ionic models do
support ephemeral rotors, and that (surprisingly, at the time) these short-period
sources induce fragmentation of activation fronts and pairwise creation of new rotors
even in perfectly uniform, continuous, isotropie two-dimensional simulations. No
parametrie inhomogeneities are needed to catalyze this breakdown. Within a few years
the same had been found in a wide variety of related excitability computations on
smoother and smoother two-dimensional grids eventually approaching continua, and
this seemed to provide adequate interpretation of fibrillation. (For examples see Box e,
Winfree, 1989a, Courtemanche and Winfree, 1991, Panfilov and Hogeweg, 1993,
Karma, 1993, Bär and Eiswirth, 1993, Winfree, 1998a 5ection B3, and the issue of Chaos
that it introduces, and Chudin et aL, 1999.) What was missing is a quantitative
comparison of such spatial patterns against those-not available at adequate resolution
before the late 1990s-in heart muscle. Both are clearly "complex," but are they
otherwise similar or are they distinctively different? Numerical models seem to be
dominated by pairwise rotor-creations and annihilations, whereas the patterns that have
caught my attention in real ventricles since 1990 are instead dominated by "focal"
sources at the period of rotors, consisting of closed-ring anisotropie propagation initially
at impossibly high speeds (Winfree, 1990c, d, g). The first good videotape of fibrillation
(shown in 1989 in connection with Witkowski et aL, 1990), for example, struck me and
Dwight Barkley as radically different from two-dimensional models in that it was
dominated by activation fronts appearing out of nowhere at rotor period. Propagation
often ended at domain boundaries about 1 cm apart where something discontinuous
happened intermittently. At that time, we did not know whether the sources were
transmural breakthroughs from three-dimensional intramural filaments-my sanguine
interpretation-or inscrutably complicated two-dimensional activation fronts somehow
originating at domain boundaries, beyond analysis at 2 mm x 10msec resolution-
Frank's cautious interpretation. Witkowski et al. (1994) noted that transmural activation
had never been confirmed during fibrillation. It was this abortive experiment that
!
initiated the design and construction of the mm x 1 msec machine for our April 1997
experiment to resolve the answers (see below).
Another question: do two-dimensional models prove too much, i.e., do they
demonstrate things that don't happen even in ventricular walls thinned to functional
two-dimensionality? In otherwise normal ventricular muscle made so thin rotors are
seldom, if ever, seen to arise from spontaneous wavefront breakage, whether in
preparations artificially thinned by endocardial infarct, or by freezing the endocardium,
or by isolating a slice of epicardium, or in unmodified thin heart walls. Rogers et aL
(2000) find that the observed spatiotemporal pattern of fibrillation in the pig's right
ventricle is simpler than in the thicker left. Could experimental arrangements for
observation have spuriously depressed excitability to simplify rotor behavior in all such
thin preparations? Box G suggests a way this could happen in some, but not all, of
these diverse preparations. If at least some are to be taken at face value as consistently
differing only in thickness from intact ventricular walls, then it seems of interest that
rotors induce electrical turbulence only in walls thicker than about 4 mm (Winfree,
1994c). This is also the nominal diameter of a rotor in that direction transverse to fibers,
and the calculated thickness threshold for twistons, and about the thickness expected to
adequately support gradient-induced accumulation of twist (see Box C of Chapter 16);
The picture emerging thus far seems consistent with avision of two-dimensional rotors
that remain stable (unlike two-dimensional rotors in numerical models of "breakup" and
in electrophysiologically abnormal slices). This produees only taehyeardia: "mono-
morphie" if the rotor is motionless, "polymorphie" if it wanders. According to this view
of the data, fibrillation in the sense of spatially and temporally complex activity arises in
normal myocardium only where thiek enough. The data are not perfectly dear, so this is
onlya viewpoint, but let's examine it. Astrophysicist Sir Arthur Eddington eommented in
another eontext in 1934 that "It is a good rule not to put too mueh confidenee in the
observational facts that are put forward until they are confirmed by theory." Is there any
plausible theory that might be associated with such a "fact"?
We begin by asking how depth perpendicular to the epieardial surfaee could
matter so dramatically. Specifieally, we ask, "What if the filament runs the other way,
parallel tO, rather than perpendieular to, the epi- and endocardial surfaces?" It cannot if
those surfaces are too dose together. However, it can do so in heart walls thieker than
the rotor's diameter of about 4 mm in that direction transverse to fibers. The most
dramatic example might be the oldest. In a c1assical method for assaying a "ventrieular
fibrillation threshold" in the "vulnerable period" of normal beating initiated by the
sinoatrial node, the initial phase gradient runs not along the heart surface as in the
experiments mentioned above, but perpendieular to that. This is because in the
unaltered heart excitation in some areas comes directly up to the epicardial surface
from the ventride's endocardiallining of Purkinje fibers. In parts of the wall that directly
overlie endoeardial areas of Purkinje ramification the phase gradients point directly
transmurally, i.e., at right angles to the gradients produeed by a pacing needle
electrode. In the dassical protoeol there is no pacing electrode, but there is a shock
electrode on the ventricular surface, so iso-stimulus surfaces around it now intersect
those iso-phase wavefront surfaees ;ntramurally, parallel to the epicardial surfaee.
Idealizing the geometry, the singular filament eould be a dosed ring inside the wall,
nowhere penetrating the surface. On the surface one would see only broad patches of
excitation appearing at the intervals typical of a rotor, but with no rotor or spiral wave in
sight, at least until/unless the singular filament so tilts as to intersect the surface.
This is at least how it tumed out in a chemical experiment for starting aseroll ring in
opaque three-dimensional media (Winfree, 1974d). The resulting pattems of activation
in 8 observed interior planes erupt at rotor period onto the surface with horseshoe-
shaped hallmark that seems hard to aecount for without an intramural dosed-ring seroll
source. As far as I am aware there was no published discussion of seroll waves as the
source of fibrillation before Winfree (1973e, Section V: Possible Applications in Biology),
nor was there any evidence until Medvinsky et al. (1982, 1984, before his dissertation of
1985) recognized this very pattem on the surface of atrial myocardium subjected to
essentially the same stimulus protocol. (For a review with both kinds of data graphics,
 ~ ~.

~ - ,
528 [.~ 7: ElECmICAL Si NGULAR FILA.M~NTS IN THE HEAAT WAU-
~'I

supplemented by idealized computer graphies, see Winfree (1984d, 1987a pages 205-
213.)
The Fall 1988 plan for a better-eontrolled and fully three-dimensional experiment in
",' the ventricu'ar wall (Winfree, 1989a, 1990d,g) has not yet been earried out, perhaps in
part due to the diffieulty of deploying so many mieroelectrodes three-dimensionally.
But using low temperature and DAM to suppress the usual degeneration of serolls to
fibrillation in rabbit ventricles, Gray et al. (1995a) interpret eontinuing 10-Hz
"polymorphie taehyeardia" of the torsade type as intramurally wandering filaments.
In electrophysiologieally normal hearts, the eritieal thiekness of one transverse rotor
diameter might not in itself promote any known instability. However, if intramural
filaments are subject to one or another kind of instability, then this eritieal thiekness
allows their elaboration into moving, growing, and breaking electrieal tomadoes.
Paraphrasing: "In this intramural ring eonfiguration, the fast axis of propagation rotates
into and out of the plane of the rotor. It is hard to envision the distortions of
propagation implicit in this arrangement. Substantial asymmetries must be expected to
develop, possibly forcing the vortex ring to eventually protrude and so to expose
mirror-image rotors on both surfaees of the myoeardium." (Winfree, 1990d). Two years
later the problem was still unsolved: "Maybe the systematic twisting of electrieal
anisotropy shortens the period of rotors in thiek preparations and/or alters their
stability... In the dog the total transmural rotation is about 120 to 1500 aeross about 8 to
12 mm in the left ventricle. Is this the aspect of three-dimensionality that aeeounts for
the observed instability of vortex filaments eonjured by a single electrieal stimulus
during the 'vulnerable phase' of the heartbeat? Filaments eome in two orientations:
aeeording to theory the filament should lie intramurally between and roughly parallel to
the surfaees if propagation before the stimulus was from endo- toward epieardium; and
it is demonstrably transmural and perpendieular to interfaces when propagation before
the stimulus is contrived at right angles to that. What is the effect of this twisting
anisotropy on such filaments in an idealized eontinuous medium? In one or the other
orientation, does it make them somehow unstable?" (Winfree, 1994d).
Attempts in 1991 to find out from a three-dimensional model used the obvious
algorithm (Roth and Guo, 1988) and ran afout of an unexplained numerical artifact
afflicting computations by the Euler method unless grid spacing be extraordinarily fine
(Winfree, 1994d). I think this was never resolved, and it remains an interesting puzzle.
Meanwhile, Panfilov and Keener (1993, 1995a,b) and Panfilov (1997) examined
qualitative consequences of rotational anisotropy using this algorithm in simulating a
transmurally discontinuous wall, and others engaged more elaborate algorithms for
three-dimensionally continuous wall models (e.g., Rogers, 1993; Entcheva et al., 1998;
Fenton and Karma, 1998a,b). As mentioned already in Box C of Chapter 16 on filament
instabilities, Fenton and Karma (1998a,b) thus clarified the transmural (upright) ease by
discovering "twistons" computationally. Using a new model of fast and slow inward
and slow outward currents that supports meandering rotors in two dimensions, they
found that transmural filaments in a cu be of idealized myocardium promptly become so
distorted that they bud off new, expanding rings. All of these fragment upon contact
with epicardium or endocardium at sites of ostensibly foca' eruption, so that within
about 1 second a wall thicker than 4 to 6 mm (threshold for the instability) is filled with
disjoint, squirming segments of filament (Figure a, Box C of Chapter 16). This
mechanism would not work in heart walls thicker than a few centimeters (since the total
fiber rotation is about the same regardless of thickness, so the twist per millimeter
would accordingly be subthreshold) nor in walls thinner than a millimeter (since so much
fiber rotation packed into a passive space constant may constitute functional isotropy
for wavefronts themselves comparably thick). To the extent that it plays a decisive role
in the multiplication of rotors, this transition from tachycardia to fibrillation should thus
occur more readily in the thinner right ventricular free wall of larger animals, and in the
thicker left ventride of smaller ones (other things being equal, and the heart not being
too smalI, of course).
Meanwhile, Berenfeld and Pertsov (1998), using the Roth-Panfilov method,
addressed the intramural (horizontal) case numerically, in an idealized uniform
cholesteric ventricular wall much thicker than the rotors 4-mm diameter transverse to
fibers, so there is little fiber rotation within the diameter. They found that filaments
tend to reorient along fibers, thus parallel to surfaces, while more slowly floating up
or down into a layer doser to their orientation. Thus oriented, each cross-section
perpendicular to the filament and to musde fibers is a rotor in an isotropic medium,
so there is no asymmetry. But every other orientation is numerically observed to
induce filament motion. They did not report twistons in the upright case, perhaps
because their rate of fiber rotation is so slight.
So much for computations. It is about time to have a look for ourselves.
While building my own computer-driven optical equipment for looking at scroll
waves three-dimensionally in chemical gels (Chapter 16), I had weekly discussions
with Frank Witkowski over his invention of related equipment for looking at voltage-
modulated f1uorescence on the epicardial surface of the fibrillating heart (Witkowski
et aL, 1998a). Experience in tomography suggested that background division and
appropriate median filtering could salvage a digitized image that might otherwise
retain only a few bits above noise level. From acquaintance with the glowing spiral
waves observed by Pearlman and Ronney (1995) in flame fronts we knew that CCD
chips could give good service even at 1000 Hz in dim reddish light such as di-4-
ANEPPS dye f1uoresces. Irradiated with a carefully regulated bright turquoise light,
about 1/10 W/cm 2 (like sunlight cooled through water), cell membranes loaded with
this purpie dye give off an orange f1uorescence, about 10 microW/cm 2 (Iike
moonlight: the intensity used for dock phase-shifting in Chapter 20), of which 1 to
2% f1uctuates linearly with local Vm • If the 100-fold greater orange background can
be filtered out, and the 10,000-fold greater turquoise with it, and two stages of
image intensification do not add too much noise, then fibrillation might be
observable for the first time at adequate resolution.
When it came time for first experiments (April 1997), we started paired rotors in
the usual way on the ventricular epicardium of an isolated Langendorff-perfused dog
heart. As a novice, leery of the unknown side-effects of excitation-contraction
uncouplers, I insisted that we do it for the first time without DAM (Box G), and
arranged Lucite blocks with suitable pressure to eliminate motion artifacts during
fibrillation. The main results (Witkowski et aL, 1998b; Winfree and Witkowski, 1998;
Vigmond et aL, 1999) are similar to those of Gray et aL (1998) in isolated rabbit and
sheep hearts, of Lin et al. (1999) in the rabbit, and of Kim et al. (1998) in various
preparations from pig, dog, and human hearts, in that rotors (i.e., intersection of
singular filaments with the surface) proved ephemeral in normally thick ventricular
walls. They move around rapidly, and might also suffer extinctions and re-creations. A
rotor seldom turns more than a few times before it is slapped by exeitation from some
shorter-period source (perhaps another rotor, Doppler-shifted by rapid approach).
Fluorescence observations (without DAM) at any point on the surface of the dog's
ventrieles reveal strikingly regular periodicity (Figure 8) at around 133-msec intervals, a
little Ion ger than is typical of rotors. Adjacent regions can have slightly different
periods because along certain loei, which become region boundaries, pulses are
sometimes deleted. We presume these "boundaries" are not anatomical disconti-
nuities, but just the places in a smooth shallow gradient of membrane parameters at
which the changing minimum stable period of response first exceeds the fixed period
of arriving excitation from a rotor or singular filament source (see Box A of Chapter
14.) They are probably the slow-moving discontinuities observed using electrodes
(therefore also without DAM) about 1 cm apart in the 7 x 11 prototype experiment of
November 1991 (on page 505). After several minutes this initial regularity still
continues, now at comparable 115-msec intervals, but the spatial pattem becomes
more complex and less regular. Spotty major eruptions of fluorescence then occur as
though transmurally propagated activation fronts encounter the epicardium here and
there. I mapped fifty-five such breakthrough "splats" in the 30 square cm featured in
Witkowski et al. (1998b) during 1200 msec of chronic fibrillation: roughly 1.5 ± 0.2
times per cm 2 per sec (Winfree and Witkowski, 1998). Looking back to earlier
literature for evidence of rotor-periodic eruptions onto the epicardium forecast in
Winfree (1990 c,d,g) during sustained fibrillation, I found Gray et al. (1995a) in rabbits,
and Janse et al. (1995) with 0.8/cm 2-sec and Huang et al. (1998) with 1.0Icm2 -sec in
pigs, both with periodicity and propagation speed elose to ours. Lee et al. (1996a) at
an earlier stage that we would distinguish as "aeute fibrillation" (characterized by
ephemeral surface rotors) showed thirtyfold less of these ostensibly focal eruptions, as
did we also at that stage. We postulated intramural singular filaments as the source.
The later "chronic" pattern of fibrillation has not yet been reported in preparations
affected by DAM nor from (otherwise normal) thinned ventricular walls; in fact, the latter
do not show fibrillation at all, in the sense of spatiotemporal complexity based on
breakup of spiral waves.
What is the meaning of the observed eruption rate, on the order of one per
cm 2 -sec during the "chronic" stage? This rate is also on the order of once per
period per unit area of visible surface, the area unit being period, 1"0' times
longitudinal propagation speed, Co, times transverse speed, co /3. If these eruptions
each start at the surface point nearest to an intramural singular filament with no
endpoints on the visible surface, then the observed rate would suggest that such
extrema (such U-shaped filaments attached to the endocardium, perhaps) lie about
one spiral wave spacing apart. This is the interval at which they are created in
chemically excitable media when some disturbance partly erases a spiral or scroll
wave. How the like could occur in myocardium, I cannot imagine.
The unproven possibility intrigues me, that transition from early aeute to later
chronie fibrillation may involve singular filaments that were initially transmural
becoming elongated intramurally. The computations of Fenton and Karma (1998a,b)
and of Berenfeld and Pertsov (1998) might provide plausible mechanisms for this
transition. A scenario of this sort could help explain the instability of rotors on the
epicardium of thick ventrieles during early fibrillation, and during later fibrillation the
frequent arrival of broad areas of excitation on that surface, apparently from within
Figur. 8. During 1200 msec (vertically) a 55-mm square of epicardium (horizontally) is colored by dF/dt,
F being the noise-filtered voltage-proportional membrane fluorescence. In this three-dimensional data
block I made transparent all but two vertical x vs. t slices. On the foremost slice you see eight intervals
defined by nine pulses propagating at about 133 msec intervals from the right (diagonallines of dF/dt
extrema) at speed = slope 32 crn/sec. Two-thirds of the way along, they cross a curve in (x,y) where one
pulse in nine is regularly deleted, presumably because membranes to the left cannot excite at that
pace, but they can at ~ that pace, i.e., in seven intervals of about 150 msec. It could be presumed that
the corresponding arc of conduction block has edges, at which opposite phase singularities necessarily
appear after every eighth interval, however we did not deterrnine the geometry of the regions bounded
by these curves. (From Dog 0497 after 7 sec of fibrillation in record VF7, analyzed 3 July, 1997. Other
aspects of this experiment are telegraphically reported in Witkowski et al., 1998b, and in the CD of data
movies that accompanied reprints. The low-resolution prototype analyzed with Dwight Barkley in 1991
revealed similar features less quantifiably.)

the wall, at roughly the period of rotors in the same medium. We do not know yet
whether there is commonly just one moving singular filament at the source of all
the complieated short-period activation pattems in fibrillating ventrides, or perhaps
severa' independent sourees. As noted in Chapter 16, topology ean stabilize
singular filaments: they ean persist if they dose in linked or knotted rings (unlikely in
heart walls no thicker than a few rotor diameters) or if their endpoints adhere to
disjoint surfaces, e.g., the endocardium and the epieardium. Unlike two-dimensional
opposite-handed rotors, oppositely-oriented filaments of arbitrary and changing
shape do not easily find one another to zip together and vanish.
It is hard to find out what is actually happening electrieally inside opaque heart
walls. But something ean be inferred from activity visible on the surfaee, partieularly
from its teIltale period, that of singular filaments. Mandapati et al. (1998) eonfirm, over
a four-fold range of periods lengthened by progressive isehemia, that the dominant
period of the electroeardiogram is indeed the period of rotors in the same
preparation. Working from epieardial evidenee Efimov et al. (1999a) report within
the 2-to-S mm-thiek left ventricular wall of the rabbit (and not within the thinner right
wall) a long intramural singular filament with anisotropie vortex eore a little f1atter than
my forecast of 10 mm x 3 mm. It persists as a taehyeardia rather than going unstable,
possibly thanks to the presenee of DAM (see Box G). Gray et al. (1995a) used DAM to
preserve singular filaments from instability in rabbit ventrides during a 10Hz
taehycardia that they interpreted in terms of wandering intramural serolls. Biktashev et
al. (1999) also used DAM in a 3x3 cm piece of sheep ventricular wall, observed by
voltage-dependent surface fluorescence during tachycardia of the sort that usually
proceeds to fibrillation. They coded the observed 10Hz eruptions of activity into
phase readings just as Gray et al. (1998) did in whole hearts (Box F). They see few
phase singularities on the inner or outer surfaces, and interpret the sources of
observed activations as intramural singular filaments. They do not observe "breakup"
of spiral waves in this three-dimensional context, but whether this is normal or an
abnormality induced by DAM (e.g., by its lengthening of the rotors period) is still
unknown.

E: A Quick Summary of the April 1997 Experiments:

• Two years went into invention of the machine and software (Witkowski et al., 1998a;
as inviter, editor, and referee, I removed my own name.)
• The experiments visibly supplemented those at Duke by creating paired rotors with
the expected positions and handedness in a pinwheel experiment, but with much
lower current.
• After 6 months writing C to analyze the CDs on my workstation, two unexpected
bonuses emerged:
• Rotors can produce excitation at multiple periods, and so produce a
fibrillation-like electrocardiogram in summation over the whole of an extended
epicardium with graded properties, by the familiar inability of sluggish regions
to respond at the same frantic pace as a rotor in some livelier region. This is
iIIustrated in Figure 8: one out of every 9 conseeutive pulses is regularly
deleted in the middle of this transect erossing from a region of average
period 133 msec into a region that accordingly averages ~ longer; and
• Excitation splats onto the epieardium as though originating from intramural
singular filaments spaced apart by roughly the distance of propagation
during one rotor period (Witkowski et al. 1998b; Winfree and Witkowski,
1998).
The "intramural singular filaments" interpretation would be proved imaginary
• if it tums out that the same surfaee "eruptions" are observed even in muscle too
thin to support intramural rotors, e.g., smooth, isotropie, two-dimensional parts of
the atrium. Or
• if electrical defibrillation during ehronic fibrillation, followed by prompt
reapplieation of the shoek that initially started rotors when applied to the
normally beating ventricles, does not reinaugurate the same progression, but
instead precipitates "ehronic" fibrillation direaly. In that case one might suppose
that the muscle's electrical properties were altered by prolonged activation at
100-msec intervals, and discount as coincidence the rotor-like periodicity of
eruptions, and consider seriously sueh ungeometrical altematives as sketched in
Box C. Or
• if it were shown that the transmural activation fronts arise from the endocardiallayer
of Purkinje fibers, which might possibly be activated by retrograde conduction from
a myocardial rotor anywhere in the ventricles, whose filament may lie in any
orientation, even directly transmural.
 533 .

Though I trust that other laboratories will follow up, there will be no more
Witkowski and Winfree papers to complete these tests, due to the death of my
elose and generous friend at age 52 just as I am sending this chapter to press, 17
Oecember 1999 (Corr, 2000). We met in summer 1988 at Or. Eugene Oownar's
Aigonquin workshop on cardiac electrophysiology, when Frank was bubbling over
with enthusiasm about recording the spatial pattem of fibrillation in the thick
ventrieles and labout three-dimensional scroll waves. Frank was an enthusiastic
inventor of incredibly refined instruments for mapping fibrillation in the hearts of
dogs and humans. His ingenuity and energy defined the cutting edge of
technological revolutions and provided his collaborators with first looks at one
after another unexpected aspect of fibrillation. I reproduce here our last publication,
an abstract and preamble to the experiments for which we spent the last three years
building hardware and tinkering image-processing software:

Tbree-Dimensional Ventricular Fibrillation?

IEEE Biomedical Engineering Society Cleveland abstract, June 1998
A.T. Winfree, Ph.D. and F.x. Witkowski, M.D. University of Arizona, EEB Oept.,
Tucson Äl. and
University of Alberta, Oept. of Cardiology, Edmonton, Alberta, Canada

Ouring canine ventricular fibrillation, voltage-dependent di-4-ANEPPS f1uorescence

was recorded (without any excitation-contraction uncoupler) on the surface of healthy
right (and part of left) ventriele during Langendorff perfusion. After an initial few
minutes of ostensibly two-dimensional, sharply periodic (130 msec) propagation,
activation pattems become more complex and less regular, while retaining roughly the
same period (115 msec), as though from a eontinuing re-entrant souree meehanism.
Spotty major eruptions of fluorescence then occur as though transmurally propagated
activation fronts encounter the epicardium here and there roughly once per period per
unit area of visible surface, our area unit being period times longitudinal propagation
speed times transverse speed. We speculate that the transition from acute to chronic
fibrillation may involve vortex filaments that were initially transmura' beeoming
e'ongated Intramurally. Altematively, Purkinje fibers may be somehow involved. The
distinction might be made by inactivating PFs and/or (if intramural fiber anatomy and
connectivity were weil known) by numerically back-extrapolating surface excitations to
their sources on intramural vortex filaments or on the endocardium.

F: What's Next?
In retrospect, the past decade seems to have been marked by abundant discovery of
geometrical electrical instabilities in theoretically approachable cases all around what
are thought to be the normal operating conditions of ventricular museIe. 00 any of
them or all of them apply to the real thing? 00 these theoretical instabilities just
interpret the familiar fact that departures from normal are fraught with peril of
dysrhythmia, or do they interpret multiple, overlapping mechanisms (alternative
attractor basins) in healthy hearts, various of which, exacerbated in case of specific
abnormalities, will eventually be distinguished as distinct types of fibrillation?
 Can anything we have leamed be applied to parametrically optimize myocardium for
resistance to rotor-creation? Winfree (1987a, pp. 152-53) comments on some
possibilities (none of which proved valid), "We still lack a thorough understanding of
the impact of drugs on wave propagation and stability... medical prescription remains
an empirical art, and some of its successes seem counterintuitive." Some actually tumed
out not to have been successes, I think largely for want of a correct theoretical
understanding of excitability, reentry, and fibrillation. Here is an example. One could
imagine that evolution should have so arranged normal myocardium that when paced at
rates beyond the norm for high-stress activities, i.e., at rates that indicate infection by a
rotor, its excitability would swiftly drop, e.g., by accumulation of K+ in the interstitial
space. If this effect could linger while rotors spin slower and slower, then extinguish, the
onset of fibrillation might be averted. Since evolution apparently did not arrange this,
should doctors intervene to compensate for its inadequacies? Such a therapeutic
intervention has long been clinical practice: this is the prescription of "Class I
antiarrhythmic medications" to patients at risk for spontaneous ventricular reentry and
fibrillation. They increase the dimensionless ratio we called € in cable-equation models,
thus pushing excitability toward äR (e.g., on Figure 1.3 of Chapter 9). But we have known
since at least the 1980s that propagation in marginally excitable media is apt to fail when
activation fronts are imposed upon to curve sharply, as in rounding the corner of an
inexcitable infarct; and then the front detaches from that boundary and forms a rotor
(Panfilov and Pertsov, 1982; Pertsov et al., 1990; Winfree, 1990a; Agladze and Keener,
1994; Cabo et al., 1996). Should advocates of drug prescription based on
unsophisticated verbal theory have yielded to the Cassandras of equally untested
mathematical modeling? Probably not. Nonetheless, when finally checked in double-
blind controlled clinical trials, Class I "antiarrhythmic" medications tumed out to be
proarrhythmic in enough cases to annually cause 40,000 more deaths in the USA alone
than would have occurred while instead taking a placebo (Moore, 1995). We still do not
know why (Buxton et al., 1999).
Starmer et al. (1991, 1993) and Starobin et al. (1994) suggested the following
mechanism related to rotor mechanics. A notion originating in Wiener and Rosenblueth
(1946) makes the duration of the vulnerable period (when a given localized excitation
will create a rotor pair) inversely proportional to the speed of propagation: their product
should be a constant. Winfree (1989a Figure 14; 1991c Figures 19.6, 19.7) illustrated
this computationally with a crude FitzHugh-Nagumo model. Starmer et al. (1993)
confirmed it both with the Beeler-Reuter model and experimentally during various
degrees of use-dependent sodium channel blockade similar to antiarrhythmic
medication (pers.comm.). 1I the slowing of propagation is the main effect of such
medication, and if it has little effect on whatever spontaneous excitations conjure rotors
in hearts at risk, then their chance of falling in the widened vulnerable period is
increased by such drugs. This is at least consistent with the disastrous effect consistently
observed after FDA approval and universal use of such drugs.
Attention to "electrical turbulence" in myocardium from the viewpoint of rotors in
reaction-diffusion systems began in the 1980s with emphasis on "generic" media as a
provocative metaphor with implications foreign to accepted understanding of cardiac
electrophysiology. Some of those implications tumed out to be valid in real
myocardium, thus attracting more critical scrutiny. See the March 1998 issue of the
American Institute of Physics joumal Chaos for clear presentations adapted to the
 F: WHATS NEXTl

perspective of mathematicians and physicists. Today attention has properly shifted

from generic media to the special idiosyncrasies of normal myocardium, such as the
following:

• Its recovery at the end of the action potential is much more sluggish than in
FitzHugh-Nagumo-like and Oregonator-like models of Chapter 16. Unlike the
depolarizing phase transition that propagates so rapidly, repolarization seems not
to propagate, even though it can be triggered by adjacent tissue (Beaumont et al.,
1998). So the cube-root rule asked about at the end of Chapter 16 seems not to
apply, at least in the range of realistic ion channel kinetics (contrary to Winfree
1994a,1995d);
• Its anisotropy and the cholesteric rotation thereof through the heart wall may play
essential roles in filament instabilities;
• The different anisotropy ratios of the microscopically interpenetrating intracellular
and interstitial volumes require the bidomain model for any analysis involving
extracellular (that is, not transmembrane) electrodes, e.g., for defibrillation;
• Its rotor, unless pinned on an inhomogeneity, wanders rapidly and unpredictably,
so it is not really a "phase singularity" in the original sense of strict temporal
periodicity, and might be more aptly named simply " wave tip"; there is seldom
seen any point-like center of rotation but more often a long arc of "conduction
block" like the line singularities of direction preference in visual areas of the cortex
(Chapter 2, Example 17). In heart muscle these lines are not commonly even
stationary, and in fact, fibrillation erupts after several cycles unless the tissue is
chemically altered or mechanically thinned;
• The unexpectedly steep dependence of local action potential duration on the
interval since the prior action potential finished seems vitally important for stability
of propagation at short periods;
• The susceptibility of cell membrane potential to resetting by extracellular electric
shock admits practical, effective implantable defibrillators, but no one knows
exactly how they work or how to optimize their performance.

In a review of idealized singular filament dynamies, Tyson and Keener (1995)

remark that "myocardium is a dlscontinuous (cellular, fibrous), inhomogeneous
(anisotropic) tissue that can be modeled by homogeneous chemical reactions only in
the fondest dreams of theoretical chemists and applied mathematicians." Together
with the notion of codimension-2 phase singularities derived from experience with
circadian rhythms, this is precisely the dream that initially oriented the mirage-chasing
thread that organizes this chapter. It also helped to orient some experimental inquiries,
whose results are now reorienting initial dreams toward reality.
Perhaps in the early 2000s the dynamics of normal tissue can be understood as a
baseline case with reference to which specific abnormalities and their consequences
can be better quantified and ameliorated. Ironically, W.H. Auden remarked that "health
is the state about which medicine has nothing to say," but unhealth is a condition that
normal physiology might hope to illuminate. When fibrillation can be understood in
healthy hearts, the attention of theorists will more usefully focus on the original subject
of interest: conspicuously heterogeneous and discontinuous diseased myocardium in
humans believed to be on that account at greater risk of sudden cardiac death.
Postscript, summer 2000:
As this went to the printer, three new papers appeared which report observations on
the ventricular epicardium and endocardium of isolated rabbit and sheep hearts. Their
results seem compatible with this chapter's inferences from high-resolution fluores-
cence observations on dog epicardium during fibrillation:

Chen et al. (2000) observed fibrillation in rabbit ventricles both with and without
DAM. Using their new definition of "phase singularity," only one in fifty survived even
one rotation (mean survival time only 15 msec). But the observations of most interest are
independent of the definition used, because they concern the nonobservation of
reentry on the epicardium: They observed in the rabbit 13 "splats" in several rabbit
hearts, like the 55 noted above in one dog, and they similarly conclude that the source
of fibrillation may be intramural singular filaments producing scroll waves within the
thickness of the ventricular wall. Zaitsev et al. (2000) came to the same conclusion.
Zaitsev et al. (2000), using sheep with DAM, argued that the puzzling boundary lines
along which we observed intermittent conduction block on dog epicardium (Figure 8)
serve in the sheep like down-shift gears to keep the great mass of heart wall activating at
periods shorterthan the rotor's in some such integer ratio as 4:5,3:4, or even 1:2. All this
activity is presumed to be driven ultimately by an invisible intramural vortex filament. The
electrocardiogram's departures from the clean periodicity expected of such sources may
thus, in fact, be due to smooth parameter gradients such as featured in Box A of Chapter
14 and Figure 8 of this chapter, but unaccountably steeper. They found that these down-
shift boundaries delimit domains of average size about 1 cm 2, comparable to the 1 cm
spacing we observed without DAM, and showed at least several on the ventricles. The
electrical activities of all these get summed into the electrocardiogram. If this
phenomenon proves universal then instabilities of the rotor or singular filament need
not be invoked to account for the complex spatial and temporal pattems of fibrillation.
In connection with Box C of this chapter, Rogers and Ideker (2000) accordingly
suggested that "recent emphasis on the breakup of rotors as the driving force of
ventricular fibrillation is misplaced."
Such plausible corroboration suggests a pretty consistency, but an unbiased
observer would remember that inferences about fairly subtle and unorthodox three-
dimensional dynamics are still based only on two-dimensional observations, and that
even multiply confirmed "observations" at the edge of perceivability are notoriously
liable to bias by preconceptions. For example, Antoniadi and then many other
observers fully confirmed Schiaparelli's 88-day orbit-synchronous rotation period for
Mercury, satisfied, as I was, with the analogy to our Moon's similar synchrony and its
explanatory theory of tidal friction; but Mercury's aaual day is ~ of that, and the
fraction's exactitude is corroborated by a more subtle theory. The challenge for
cardiac theorists is then to find three-dimensional interpretations alternative to the
scheme of Winfree (1990d; 1994a, c), Witkowski et al. (1998b), Winfree and Witkowski
(1998) and Vigmond et al. (1999) for dogs, and of these recent extensions using other
mammalian species (Chen et al., 2000; Zaitsev et al., 2000), and to show them to be
compatible with all the same two-dimensional evidence, or else to specify critical
observations or experiments that would distinguish between these alternative
interpretations. At the moment I don't know of any.
 Pattern Formation in the Fungi

Good problems and mushrooms of certain kinds have something in common:

they grow in clusters. Having found one, you should look around; there is a good
chance that there are some more quite near.
George P6lya, p. 65 of How Ta Salve It

In Chapter 12 we dwelt on a biochemical dock in an ascomycete, the yeast cello

The familiar bread molds and their relatives are also ascomycetes. They are called
colonial aseomycetes because of their habits of growth: see Box C in Chapter 8
and Chapter 9. Like animals, these fungi derive their energy by oxidizing organic
fuels. Like plants, they grow where the seed falls and feed through roots. An
ascomycete colony starts when a spore falls on a food surface. It germinates and
extends a fine web of hair-like filaments, ealled hyphae, across the food as an
expanding disko This two-dimensional disk of hyphae is called a mycelium. It is
not really a ceUular organism since the septa dividing hyphae into tiny
compartments typically have holes in them, so that cytoplasm flows freely
between the compartments.
It is not unusual to find mycelia banded with concentric rings of heavy growth
and/or sporulation. In many cases, these rings turn out to be 24 hours apart on the
expanding disko Each ring marks those regions that were in a certain range of ages
when it was daylight, or hot, or wet (or whatever) in the diel cyde, much as rings of
heavier growth mark the annual seasons of a tree.
Setting aside such cases of obvious environmental influence, there remain a vast
array of papers describing spatially periodic growth in ascomycete mycelia.
Independence of environmental rhythms can be verified in these cases by adjusting
either the growth temperature or light intensity or nutrient conditions to change the
period, or by using a transient stimulus of the same sort to inflict a permanent phase
shift in the growth rhythm.
What might cause such banding? We may be short of tested explanations, but
there is no lack of plausible conjectures and little reason to expect any one of them
to cover all Cases (see Winfree, 1973d).
By a daring leap of faith, we might for example conjecture that what is not
driven by an external rhythm of environmental conditions is driven by an internal
metabolie rhythm. Only reeently has the first experiment been reported showing

A. T. Winfree, The Geometry of Biological Time 537

© Springer Science+Business Media New York 2001
538 18: PATIERN FORMATION IN THE FUNGI

repetitious activity of any sort in patch of hyphae [Dharmananda and Feldman

(1979) in the case of Neurospora crassa].
An alternative seems equally plausible, Le., that conditions on the frontier of
growth locally determine the immediate activity mode of newly created ceIls,
which in any case soon lapse into a standard metabolic condition as the growth
frontier moves on. For example, frontier cells might be transiently disinhibited to
"high" activity if and only if the nearest high activity event was a sufficient number
of hours in the past andJor sufficient number of millimeters behind the growth
frontier. In the latter case, some mechanism of transport, such as cytoplasmic
streaming or diffusion must be invoked to separate events in space. Models of this
sort have been exploited to good advantage in connection with periodic banding of
bird feathers (Nickerson, 1944), Liesegang ring formation in inorganic gels (Stern,
1967), etc.
It seems appropriate to look at these phenomena with respect for the
diversity of nature's inventions. We first cursorily survey similar phenomena in
four ascomycetes and then stick to one for a more detailed correlation of
facts.

A: Breadmold with a Circadian Clock

Neurospora crassa, the geneticist's favorite mistress before E. coli, exhibits several
mutant varieties of circadian rhythm as weIl as banding rhythms of other periods.
These currently (1978) offer some of the best dues to a circadian dock's
biochemical mechanism (see 1999 fulfillment in Chapter 19 following). The
typical circadian rhythm properties of temperature-compensated period, suppres-
sion by dim light, phase resetting by brief exposures to blue light, and clarity of
period are best exhibited by the "band" mutant, usually grown on very long "race
tubes." In this technique, a floor of nutrient agar is poured in a U-shaped glass
tube with a wide flat bottom. The inoculum of spores or hyphae placed at one end
soon elaborates a mycelium that propagates at a uniform speed of about 1 mm
per hour across the sterile nutrient. After a weeks' growth in constant darkness at
25°C, six to eight bands are found to be placed at circadian intervals along the
tube. Within each band, spores differentiate in the mycelium's luxurious aerial
arborization (Figure 1). Abrief exposure to light increases or decreases the
interval to the next band, depending on the phase of the rhythm at exposure time
and the amount of light given. After that phase shift, the rhythm continues at
circadian intervals, but phase-shifted relative to the series of bands preceding the
stimulus. Thus resetting curves can be measured as in any other circadian rhythm.
Type 1 (weak) resetting is observed following brief enough exposures. Type 0
(strong) resetting is found after greater exposures (Dharmananda, 1980, and
replicated in my own lab).
Dharmananda and Feldman additionally tested bits of mycelium behind the
frontier for their phase. This is done by cutting them out and transplanting them
to a new race tube to observe band phasing in the renewed growth, as
Chevaugeon and van Huong (1969) had done previously with the rhythmic
ascomycete, Ascobolus immersus.
 B: BREADMOLDS IN Two-DIMENSIONAL GROWTH 539

Figura 1. Rhythmic banding in race tubes of Neuro- -4

spora "timex" (= an invertase-deficient strain of "band")
from unpublished experiments of W. Engelmann. This
stack of tubes is presented in the format of Figures 31 e
through 33 of Chapter 1, calibrated in cycles of 21
hours. Growth is vertically downward. The stimulus was
a cold shock that scarcely affected the rhythm.

However, unlike Ascobolus, it appears that each patch of Neurospora mycelium,

even many days old, continues to keep time with the same circadian rhythm. The
whole mycelium apparently remains nearlyl synchronous in phase beneath the
waves of growth and sporulation that record each patch's phase at that moment
long ago when it passed a decisive age. Demonstration of a persistent clock in a
fungus is not surprising in itself. The docks of Daldinia (Ingold and Cox, 1955) and
of Pilobolus (Bruce et al., 1960) were studied twenty years earlier, but this is the first
demonstration that a dock underlies the spatial periodicity of a fungus.

B: Breadmolds in Two-Dimensional Growth

Although much less studied, Penicillium diversum also exhibits a rough 24-hour,
temperature-compensated rhythm of growth and sporulation. In this case, however,
no sensitivity to visible light has been shown. Because its frontier moves much more
slowly, it is convenient to culturePenicillium diversum as a disk on two-dimensional
agar plates, not only along essentially one-dimensional slants. In this configuration,
Bourret et al. (1969) made a most remarkable observation: Though many mycelia
are banded in concentric cirdes 24 hours apart, many also make a single continuous
band winding round and round the inoculum as an Archimedean spiral (Figure 2).
Along any radius (equivalent to a radial race tube), zonation has a 24-hour rhythm.
But as one changes the azimuth of the chosen radius, the phase of that rhythm

More exacdy, Dharmananda and Feldman (1979) find a phase gradient of about ~ hours per day's
growth, suggesting that young hyphae right on the contemporary frontier cycle that much faster than
older hyphae Ieft behind on staled medium.
540 18: PATTERN FORMATION IN THE FUNGI

drifts, drifting through one full cycle as the imaginary race tube is rotated through
360°.

......
~
f:
~ ,
Figure 2. A spiral locus of heavier sporulation on a disk-
shaped mycelium of Penicillium diversum, from Bourret et
; al. (1969) copyright 1969 by the American Association for
: the Advancement of Science .

""i
..... ,
....~' " ;.; ...~.. ~;,./'"
I cm

Archimedean spirals of zonation, as an occasional alternative to the more

usual concentric rings, were also reported in Chaetomium robustum, another
filamentous ascomycete with a 24-hour rhythm on nutrient agar (Kraepelin and
Franck, 1973).

C: Pattern Polymorphism in Bourret' 5 Nectria

Another ascomycete, identified as Nectria cinnabarina 2 exhibits a noncircadian 16-
hour rhythm of growth and sporulation in slant tubes. It has the same habit in two
dimensions (Figure 3). Its bands are approximately 1 mm apart at 20°C. By shaving
all the surface growth off an agar plate like that of Figure 3, one obtains an agar
layer containing bands of denser and lighter growth. Running this through a
densitometer, and plotting the positions of successive density maxima along any
radius, one ohtains a distinctly periodic record. Figure 4 shows the distribution of
distances (0.9±0.2 mm) between 264 adjacent bands. This interval and its variability
showed no conspicuous differences with age or distance from the inoculum in the
10 mycelia examined.
In two-dimensional growth, Nectria 's bands appear as distinct rings nominally 1
mm apart in about two-thirds of the colonies, and as clockwise and anticlockwise
spirals in about two-thirds of the remainder. Nectria has also been caught making
distinct two-armed and three-armed spirals. In such cases, each arm winds around

2 Probably misnamed. It is not the same as the British N. cinnabarina (the "coral spot fungus") nor the
same as the N. cinnabarina that decimated N.Y. State beech trees in 1975. According to the rather
confused taxonomy of order Hypocreales , to which family Nectriaceae belongs, N.c. is the perfect stage of
a fungus whose imperfect stage (fusarium) is called Tubercularia vulgaris (Bessey, 1950, p. 287).
Hypomyces may be another name for Nectria.
 C: PATTERN POLYMORPH15M IN BOURRET'S NECTRIA 541

at a pitch of 2-mm or 3-mm (respectively) per 360°. Thus bands along any radius
occur at I-mm intervals as usual. The difference is that the phase of the radial
rhythm progresses through two or three cycles rather than one (as in one-armed
spirals) or zero (as in disjoint rings) as the chosen radius is swung through 360° of

Flgure 3. This disk-shaped mycelium of Nectria, printed at actual size, bears two spiral ridges of
spores. Note the glass cover slip inserted deep into the agar radially at 2 o'clock before the
mycelium had grown big enough to touch the glass. The mycelium does not go below it. It has
no discemible effect on the sporulation pattern. The wedge-shaped patches are colonies of
faster growing mutants. See also the cover photograph of Science for November 7,1969.

NUMBER OF BA/IDS
so

Figur. 4. This histogram classifies into 100-J.Lm intervals 264 measurements of

the distance between adjacent bands. The measurements were read by
computer from densitometer tracings of hyphal density in shaved agar along 40
radial tracks from the inocula of ten 8-cm mycelia.

azimuth. Figures 5 and 6 show digitizer tracings of R(4)), the radial distance of a
spore band from the inoculum as a function of compass angle: Figure 5 is the
two-armed spiral of Figure 3 and Figure 6 is a one-armed spiral. The spacing
between successive bands is nominally 1 mm in both cases.
542 18: PATIERN FORMATION IN THE FUNGI

This situation lends itself to several different styles of description. For

example, one might emphasize the global integration of pattern: Spores
differentiate along an integer number of distinct rings or spiral arms, each
of which either encircles the inoculum concentrically (in the case of ring
morphogenesis) or (in the case of spiral morphogenesis) winds at mean pitch
proportional to the number of arms. This point of view raises challenging
questions about the large-scale integration of pattern. How are the distinct Iod
of sporulation distinguished? At various times during growth of the disk-like

R (mm)

F'Jgure 5. Figure 3 was placed on a digitizer platen while the electronic cross-hair was moved by
hand and eye along the locus of densest sporulation. Its position was continually plotted in
millimeters from the mycelium's center (vertically) and in degrees of azimuth from north
(horizontally). The first 360 0 panel was replicated 6 times so that both spirals can be followed
through several complete tums without jumping back from 360° to 0°.

R (mm)

Figure 6. As in Figure 5 but the sporulation loeus is a single spiral of opposite handedness in a
different Petri dish. The radial spacing is about the same as in Figure 5.

mycelium, each one is interrupted by the frontier at several places, yet as the
mycelial disk expands, they grow together exactly. How do the segments of
each successive ring "know" that they belong with the other segments of that
ring and avoid joining up with segments of other rings currently under
 D: INTEGRATION OF PATTERN 543

construction elsewhere? One is led by these questions to consider possible

channels of long distance communication within the mycelium, such as the
waves postulated by Goodwin and Cohen (1969) [and in fact seen in
Dictyostelium (Chapter 15)]. But by implanting glass barriers, cutting out
pieces, etc., it can be quickly shown that pattern formation is independent of
spatial continuity (Winfree, 1973d). Integration of pattern is somehow managed
on a local basis.

D: Integration of Pattern
Another due is afforded by looking for the most predictably reproducible aspect of
the observed patterns in hopes that it may suggest the appropriate language of
description, which in turn may suggest a mechanistic basis for the terms used. For
example, is the slope dRld4> of the spiral reliably predictable? No. Neither the
distance to the frontier from a spore ridge, nor its distance from the inoculum
varies regularly with angle (Figures 5 and 6). The only sure thing is that the
average slope on a full cyde of 360 azimuth will be an integer (with exceptions as
0

noted below).
To cut a long story short, what is most reliably conserved is the nominal1-mm
periodicity along each radius (Figure 4). Even when the pitch of spirals or rings
changes by local quantitative variation or by a global qualitative change of
connectivity, still a 1-mm spacing is conspicuous in densitometer tracings made
along every radius. The standard deviation of this spacing is fully 22% of the mean
and shows no serial correlations. This makes it about half again as unreliable as the
notoriously variable menstrual period (Chapter 23). But the essential point in
present context is that the spacing is not correlated with pattern topology: It does
not double or halve in two-armed spiral patterns.
A second reliable feature is the propagation of pattern defects along the
direction of growth. It commonly happens that rings do not quite dose: There is a
mismatch as in a lock washer. Maintained during cyde after cyde of growth, this
sudden change of phase with azimuth becomes the site of a radial mismatch of
many bands, resembling a zipper or an edge dislocation in a crystal. Only after
many cydes do the adjacent hyphae synchronize well enough for bands to cross this
fault line smoothly. This feature points once again to substantiallocal autonomy,
certainly as far as interactions transverse to the mean direction of growth are
concerned.
A third reliable feature is that zonation patterns are always concentric to the
inoculum. The centers of rings and the pivots of spirals are always where the colony
started.
If we choose to emphasize these dues over others, then the natural terms of
description will feature the radial rhythm and the variation of its phase with
azimuth. The dues that suggest local autonomy lead us directly to a simple
interpretation in terms of such a local oscillation as has been widely assumed for
many years and in 1979 actually shown in Neurospora. The dues that point radially
to the inoculum suggest that we seek the origin of the topologically distinct morphs
in the initial condition of the germinating mycelium.
544 18: PATTERN FORMATION IN THE FUNGI

So my next experiment asked, "Does the shape of the inoculum determine the
choice between the several patterns of differentiation?" I found no way to dassify
the microscopically observed shapes into groups that correspond to the eventual
patterns that each develops. So my answer is "no."
Then "might the initial conditions be invisibly latent in the hereditary material?"
The required experiment is to grow a mycelium from a single spore, collect its
identical asexual spores, and plate these separatelyon agar, several to a dish. Each
dish turns out to contain mycelia of the several various morphs even though each is
started from genetically identical units and is grown under identical culture
conditions. This is so even if the spores are floated on a Millipore raft on a sea of
liquid nutrient to make culture conditions just as homogeneous as possible.
So it would seem that the difference between initial conditions is very subtle and
delicate, even though these differences do lead to qualitatively distinct patterns of
differentiation into sporulating and nonsporulating hyphae. In other words, we are
looking for some reasonable interpretation of a singularity. It turns out that the kind
indicated is just the kind found to underlie the helicoidal resetting behavior of
circadian docks. (See Chapter 4, Section C and Chapter 8, Section C.)
But what about other internally rhythmic ascomycetes that do not make several
alternative rhythmic patterns, but stick to one reliably? That one is always the
concentric ring pattern, with rings parallel to the frontier and concentric to the
inoculum. When it occurs, spiral polymorphism reveals something intriguing about
the mechanisms of differentiation and pattern formation, but why is it so rare? At
present this question can only be answered by conjecture in terms of a proposed
interpretation of Nectria's biochemistry. Such conjectures are found at the end of
Chapter 8, Seetion C.
 ilt!ii1lil

Circadian Rhythms in General

Time sleeps quite naked, Anaitis, and, though it is a delicate matter to talk about,
I notice he has met with a deplorable accident.
So that time begets nothing anymore, Jurgen, the while he brings about old
happenings over and over....
J. B. Cabell, Jurgen

One doesn't have to look at many living organisms before noticing that a lot of
behavioral physiology is temporally organized in periodic patterns. In fact, if I
had to decide what impresses me as the single most conspicuous feature of
natural ecosystems, I would say that it is the daily and seasonal periodism and
the consequent temporal organization of niche structure, food webs, and
behavior.

Of course, it would seem natural to assume that any given daily rhythm or
seasonal rhythm is a response to the environmental cycle of days and nights,
summer and winter. This is often the case. It is, for example, in the case of "deep
scattering layers." These are layers of diverse fauna in all the world's oceans that
show up very clearly on sonar. They go deeper in the daytime and rise back toward
the surface by night. My job on an Indian Ocean Expedition cruise from Woods
Hole in summer of 1964 was to study these deep scattering layers using sonar and
tow nets during their diurnal up-and-down migrations. Investigators in Cousteau's
diving saucer found that the deep scattering layer consists largely of small fish, their
swim bladders resonating at sonar frequencies. They seem to simply follow light
intensity, e.g., they come up during eclipses. Enright and Hamner (1967) later found
a substantial role of endogenous rhythmicity in the vertical diurnal migrations of
invertebrates in the scattering layers.
That opportunity to participate in field work in 1964 started me wondering
about the dynamics of physiological rhythms in general. Probably the most
pervasive physiological rhythms, phylogenetically speaking, are the ones with 24-
hour period, a subject on which Colin Pittendrigh had delivered one of his typically
enthralling lectures at Comell shortly before my summer at sea. Thus I leamed that

A. T. Winfree, The Geometry of Biological Time 545

© Springer Science+Business Media New York 2001
546 19: CiRCADIAN RHYTHMS IN GENERAL

24-hour rhythms are commonly found to continue at about the same period even
when apparently isolated from all diurnal influences. The period is often quite exact,
but seldom exactly 24 hours. In other words, organisms have endogenous rhythms:
circadian rhythrns as they are called from the Latin "circa diern" meaning "roughly
a day." The word has, unfortunately, become Americanized to cir-cä-dian, with the
result that more than once (first in 1972; most recently in 1999) I've been asked after
a lecture on "cicadian rhythms" why I never got around to the subject of the 17-year
cicada. So I pronounce it circadian.
The observed circadian rhythrns are said to reflect the functioning of a
biological dock. It is called "biological" because it is apparently generated from
within the organism, and it is called a "dock" because it measures time in a periodic
way, sometimes with surprising precision, with period dose to 24 hours. Circadian
rhythms have been found in every major group of animals and plants except the
prokaryotes, which indude Archaebacteria and Eubacteria. The latter include blue-
green algae or cyanobacteria. There exist two reports of vague circadian rhythmicity
in bacteria, but both await confirmation (Rogers and Greenbank, 1930, analyzed by
Halberg and Connor, 1961; and Sturtevant, 1973).

In protozoa and true algae we find 24-hour rhythms of capacity for

photosynthesis, of mitosis, of motility, and of bioluminescence. In some fungi
there is a daily hour of spore discharge. In plants there are diurnal rhythms of leaf
movement and of flower opening and dosing. Many kinds of insects periodically
regulate the times of egg laying, egg hatching, and emergence from the pupal case
(see next chapter). Vertebrates induding man have conspicuous circadian rhythms
of activity and sleep, of body temperature, and of hormonal activity. Menaker et al.
(1978) provide an excellent review, focused on five specific experimental systems.
 A: SOME CHARACTERISTICS OF ClRCADIAN RHYTHMS 547

pers.stent osctlations 0 ong period. e thoug taoout medlanisms of mutua

synchroni~tipn in tissues of such cell-autoClomQus docks, and proposed experi-
ments to elucidate such matters. Tflls was branded "theoretical' biology': and
dismissed ifl. ' mo~t laboratorresi except by eager graduate. students. Five years later
j w.orked in Goodwin/s ab in' Brighton, and then in Francis Crick'slSydney Brenners
in Carnbridge, coh'sidering experiments in which Drosophila brains would be phase-
shifted ·by a light flash, and then homoge ized to pour tnrcugh sephaaex Gofumns
fur comparison with controls,. . naively hoping to , isolate sRecifc oiochemical
changes. We decided that tb.e signal/noise ratio would- oe' ,too small. 1hen I
considß.l".ed mutating tne 959,-cell Dematode Caenorhabditis elega~s to determihe
whicli eerls contaln the dock; if hot an cells-. But I nevef- found any circaqian rhythm
of behavior; nothins Game cf any of this-. 1 I went back to O!Jcago to finish the
expeiments of Chapter 7 t wh]ch showed that the atttacting· li~it-cycle vision . of
D~osoph;la's clock does ~ot provide a good descriptior.l of this 'oiolo.gical elocK, but
sometfling more ' H e Goadwin' s. conser:vative cydes mtght; or else. the fly' s clo~k is
really a population of loosely cOl:Jpled, desynchronizable cell-autonomouS" attra'ct-
ipg.-cycle docks. Nothing came or that either, though.. jt has not. yet been quite
forgotteh (Lakin-Thomas e al, 1991) and I stifl think it must eventually serve
'ndispensably. . .. .,"
Biologists dismissed nudear epigenetic oscillations partly becaus of laooratory
expetiments, some of which still stand today as glaring 'cout1te examples to that
pro!?osition, Sween~y and Haxo (1961) end Schweiger. et al. (1964) had found in
Acetabufaria that circadian rhythmidty per'sists after the cell JludeuS') s removed; the
last review cf tonow-up experiments (Edmun.ds, 1988) still points mare to the
clliorop!ast than.. to- the nu deus as horne" of the doc~. A hkenazl ' et al. (1975)
reportea circadian rhythms in stored human red bloOd cells, from wf,ich the nuc1eus
long ago vanisheCl (but atternpts to replicate were unsuccessfw! at last repO/i in
Edmunds, 1988). ~or a review of the many thoElgntful arguments, againlt hour-to-
hour involvement of epigenetic mechanisn'ls in the dockworks, _read pages 295-
310 of Hastin~ and Schweiger (T976). On a yellowing preprint of ,t I find scribbles
fIT rny own hand to the effect that few of these experiments ·seemed wholly
convir;Jcing. Better experiments did fellow. Feldman (19?5} .and D.umap and
Feldman (1968} stressed tb-at heavy cycloheximide qosage of. the frq-7 mutant of
Neu(ospora stops more than 9,9% of pr~tein synthesis but has negliglble effect on"
th~ circadian ' dock. Contrary. results with hormal Neurosp0ia in Nakashima et aL
(1'981) and the anisomydrr time- crystal in ;Jaylor et a1. (19~2) (see Figure 0.1 of. this
Chapter) ·were theref0re 'taken .to stem rrom so me u'1known side effe~ of these
cbemicals, not rrom theif inhibition of-protein synthesis Pl..ltatjv~ly arudal 10 a do~k
mechan[sm. Sadakane and Nakashima'" (1995) also fOUhd in ·· Neurosp.ora that
Inhibition-of translatabre RNA synthesis öloeks. the phase-shif!ing effect of light -(i.e ,
mRN synthesis is Ileeded for signal transduction) but farls to phase-shift (i.a.,
mRNA synthesis 1s not needed for osejllation!) ' '
548 19: C1RCADIAN RHYTHMS IN GENERAL

ANISOMYCIN 1h PULSES
RESETTlNG SURFACE: NEW PHASE CONTOURS

TIME OF PULSE
(hours In constant dlm)

I don't kj10W what became of tliese. ostensib y ecisive COl.mterexamplesto· e

nation th~t the ~Iock me~hClnis1l) depends-upon /"(lRNA .trat:1sc~iptioh (!nd transla on.
Maybe in Acetabu/aria the ' dock genes ' da reside in the chloroelast, ' wnich is also.
capable of DNA-dependent mRNA transc.ription Mayba in N~vros ora not an
translation waS'st~pped, an~ the 0 'Ilafor's frq mRNA spec;:j cally 'escaped inhibitlol1,
or maybe degradation waf> a'so stopped. Today Rupft et aJ (1999aib} argt:le that a
suitably modified GOO,dwin-type model does accornmodate this seemingly cohtrary
experimental result. Howeverr La~itl-T~omas (1998b) and Lakil)-Thomas. and Brody
(2000) argue that frq is only an Input to the stIll-undiscovered dock mecbanism in
Neurospora, and that ir:') general plan ' 1 docks might nQt ~veFl i,nvolve a transcription.;..
translation feedback Ipop' analogous t o Drosophila'so -.' '
In Edmunds"198B review, the. ~cetabularia experiments still .~eemed Rersuasive, the
per product in Drosophila stiil showed no conv[ociog circadian mythm (a "fact" that
changed shortly-after, in Hardin et-?I., 1990), ~nd the conject re of ~asti~gs, Goodwin;
.and others still seemed only Orle among many guesses. But the role of experimental
evidence in empirieal scienc~ -is Gtuite ä~fferen :fr:orn its:.re1e in mathe atical re?soning:
A . single ostensible c9unterexa,mple _' oes_ hot ._suffrce t~ exclude an-" empirlca
proposition. In ge~erall it is a ptobJem for err)Rfr:ical sei nce that abnost every
p.roposition in every' ar-ea of 'inquiry s~ems to evoke publisl:led o~tensible counter-
examples, most of whi,=b a}e not a_cc~pt~,d as l:Idi or afe r ust guietl ~ rgotten ears
A: SOME CHARACTERISTICS OF CiRCADIAN RHYTHMS 549
550 19: CiRCADIAN RHYTHMS IN GENERAL
A: SOME CHARACTERISTICS OF ClRCADIAN RHYTHMS 551
552 19: CiRCADIAN RHYTHMS IN GENERAL
A: SOME CHARACTERISTICS OF ClRCADIAN RHYTHMS 553
554 19: CiRCADIAN RHYTHMS IN GENERAL
 A: SOME CHARACTERISTICS OF CiRCADIAN RHYTHMS 555

prior explö~atio./Ts of circa Jan dock dynamics in multicellular organisms, (flies

prosophila pse.u90obscura 1968, Drosophila melanogaster pe,s mutant 197-6! and
Sarcaphaga argyrostotna 1978, and plant Kalanchoe bfossfeldiana 1973). The
resetting .surlace (Rgure 0.1) is a helicoid, its cross sections at fixed dose are Type'
1, then Type 0, and perpendicular to that they splay out rNal-z and Sweeney; 1979)
in the draracleristic way fjrst reveafed tn Drosophila, and at the center of all this Js
a,,'phase, singulari~ (see Winfree 1986a pp. 114-15 and Winfree 1987a pp. 22-24)
All this suggests that GonyatJlax's dock mechanism belongs to the same dass as
the others, as far as its dynamica organization is concerned, and suggests that its
mechanism aepends on protein synthesis, The present evidence does not
necessarily irpplicate rH}tthmic protein synthesis or dock c0ntrol of mRNA
t(~nscriptii::m. , •
Little more has been discovered Ciboutthe dock mechanism in thfs specles, but, as
in Neurospora, some -doubt haS' arisen conceming t"'e cooclusion orqwn from
M Murry and Hastings (1972) that there is only one dock methanism in the cell.
Roennebetg and Morse (1993) aDd Roenneberg and Deng (199?) argue that there
are at least two ci~adlan osdllators with distinct periods, .coexisting. Roenneberg
an.a Hastings (1988), Roenneberg and Dehg (1997j and Roen eberg and ~oster
(:1997) . also offer persuasive evidence that tnere are' af:.: least two Inde~endent
photoreceptors affecting circadian rhythrn.idty, as is also common in hrghel" plants.
~or exa[llpl~, .depeilding :00 color, the dock's period -progresslvely rlengthens or,
sEiQrt~ s as they increase the inte, sity pf continu,ous tight. This a,hswers negSltLvel~
{for GonyiJlIJax} the.-question .posed. in i978 regarQing Drosophila, whether drcadian
docks are necessarily color-blind (pages 603-604. The answet for Drosophila may .
afso be O-i" il"l the I;mited sense tHat the adult activity i'hythm.i~ inflQ.enced throug~
rfiodopsiQ. whkh may. in tum affecr ~he circadian dock, Kaneko et al. (toool }llso
iinpHcate phosphoJipase. C in larval dock pnotoreception, independent of eR'? .
~
"'
,
.
I
. . .
~

_
..

,
"..

efoka~es, Specifically V~ri0US "Blue-Green Algae" (Cyanobacteria, in

the , ..
.Eub~cterta) ~

Th~ cyanobacteria arose almost 3000 l'!liihon .years ago. They ar:e thought to have
produced the stromatolite limestone deposits found at the ver:y start of the fossil
ecord, as weil as the bulk of modem petroleum deposits. The plastias of an eukaryotic
cellS der/ve from symbiotic cyanobacteria. Free-living cyanobacteria generate a large
~ortfon of tne oxygen we breathe, and ih.e .rest of it. comes trom thai! pfastid
desce'nda!}ts, the chloroplasts of green plants. Ghallenging tbe long-st~nding
generatization iliat circadian rhythms occur onl~ in eukaryotes (see -fitst-e~it!orl t~xt
on page 583: "A Critical Observation to Make'1 Mod et at. (f996) and Kondo et al.
(1997) re ' xamined cyanobac eMa _Mori et al. found'<;ell-division only during a wjndow
.cf the circadi~m cycle, and Kondo et al. found circadian rhythms continuing even while
DNA replkation ~nd ceil diVision were occurring more than tWice per circadlan cycle,
on .averag~. DNA replication seems not to interfere witb fue dock roechanism in this
rrokaryote. In 1.998 Ishiu,-a et af. cloned and sequenced a clusterof three' dock genes
In Synec'hococcus1 and .dubbeCl them kaiABCr from the Japanese word for "cycla.'" A
mutatiClm in anY"one>of them {nineteen are known, wfth periods ranging from 14 to 60
hours r.emlniscent of tun . can ramaticall aher the eire dian rh hm. ~rt from
556 19: ClRCADIAN RHYTHMS IN GENERAL
A: SOME CHARACTERISTICS OF CiRCADIAN RHYrHMS 557
558 19: ClRCADIAN RHYTHMS IN GENERAL
 A: SOME CHARACTERISTICS OF ClRCADIAN RHYTHMS 559

been private y entertain by anyone W 0 oeneveCl in the early 1980s tnat human
~ocks are probably like all ihe others known. '
Although light is the only unlversally potenrnatural rese1;ting cue for circadlan docks, it
might ultimately prove ,more convenieht to reset the dock by direct phannaceutica!
interference in the mechani~ms of PR-TIM hybridization or .degradation.
All this pertains only to resetting the Inner clock, the soure. of repetitiousness at 2~-hour
period in the absence of-extemaIJir'ning cues, Presumably, this is the best we can da, but
no one yet knows . to what e:xtent OUf various physiological rhythms have their own
dynamics of transieht response !O r~ng of beth intemal doc ano envirenmental
dOCKS, and how slU99ishly they might reen~rain tQ either. ,'" .
Added in press, summer· 2000; fterqecaäes of basically superstitious "science and
·heafth" reporting on jetlag in pt.lblic media, the Wall Street Journal of 7 April. 2000 fina~y
acknowledges that the effective ~medy is daylight applied in late lTIoming after a lang
eastbound flight, and in late aftemOQn eifter westbound (with no such ~pecWcS'as above,
ahd is was onl e first of a dozen recommeDdations on the Travel eage W16) .

Other a b
Chemleal
Variables

SUNSET Phoenix

mPER, ete. mPER, ete.

c d

SUNSET SUNSET

mPER, ete. mPER, ete.

impervious to intrusions fram circa ian pnysio ogy (H~lberg. 1977; Hrushesky, 1994),
pemaps bQth because individuals differ so much and !here is no way to calibrate
)ndlviduals t short of weeks in temporal isolation, and because the idea has such a long
history of 'llJackery; e.g." the Strasbourg Cathedral dock (1352) showed proper time of
da fo bio dlettfn each eo ra "real art of the body.Jn the area of hase-shifting
560 19: ClRCADIAN RHYTHMS IN GENERAL
 A: SOME CHARACTERISTICS OF ClRCADIAN RHYTHMS 561

Besides regulating the daily activities of organisms adapted to life on a rotating

planet, circadian rhythms have become involved in seasonal adaptations to life in
orbit around a star. Circadian docks are involved in the measurement of daily
photoperiod to govern flowering in agricultural plants; to regulate diapause in their
pest insects; and to organize migration, navigation, and reproductive seasonality in
the vertebrates.
The rest of this chapter is divided into three parts to review some general
characteristics of circadian rhythms, to speculate "without fig leaves," as Bacon
said, about their evolutionary origins, and to gather observations suggesting
multioscillator organization of "the" dock.

A: Some Characteristics of Circadian Rhythms

Circadian organization is one of the most pervasive facts of physiology and of
ecology. Since Pittendrigh (1960, page 160) conspicuously deployed the seldom-
used adjective "ubiquitous" in this context, its appearance has become de rigueur. I
think this literature could be selectively gathered by a text search for that single
word. However "the" mechanism of endogenous temporal organization probably
does not exist: instances are likely mediated by different organ systems and
562 19: C1RCADIAN RHYTHMS IN GENERAL

8tOOme

Figure O.2.-The rneasured human phase re setting rve in response to a rather complicate
dirn lig~exposure is here supposed similar to the respons.e to the iotended single, shortl
more intense exeosure: Horizohtalfyold phase, andvertical/y neV/phase< are indicated from a
o at pel'Sonal .dusk. The spadmy covers personal Aighlin öoth .directions.. Löci of Dxed,phase
shlft or langitude drang_ are diagona[ lines.-For any n~eded sh.ift, follow the correspondiog
diagonal to the CUNe ~nd notice the time at horna relapve to the Shadecf block on ;the old'
phase axis anp on the /lew phase axis time at destinatio telative to :ttle shaded block wheQ
and where tlie exposure"is taken that fesets the dock from fhat oIe:{ phase 1<;> that loeill new
phase. (The umbers illong the axes ilre in h'oursrelatlveto core bad)' temp'srqture .minimurn,
Jlot useful in this context.) Notice that ehtrainme'1t to tl')e -prior Iigl)tldark cyde (shilding} so
phase _ e dock that its hours of negligible phase shift .(along· the- 0°; diagonals) oecur
mldday On the prior envifonment 1-.e". f personal habits of daylight exposure at honte), with
modest advances Gecumng du ring personal moming ~fitst hQurs of dayHght eXp05ure).-and
balancing:delays during'personal aftemoon. The hour of ~12-hour rese).ting arrives sllghtly
after the mlddle of darkness or personal midntght at horne. NotTee tha in terms cf time at
destinatIOn, 'i.e., the time to whid~ the. dock is thus ,reset, the hours o( 'Substantial phase
4Iifting all occur in daylight, when the job can be done" weather perrnitting. Modest
advances ar.e taken in the personal moming at destination after eastward fHght, and delays
aft,er westward fTight in the personal aftemoon at destiAation, co,nverging toward- the middle
cf the pef'$Onal lightl.dark cyde in the case of the largest advance/delays. (Adapted from
Czeisler et al., 1989 Figure 5 in Sc;eJlce 244, 1328~ 13.33. copyright 1989 Am~r.lcan
Assoc;iation for, the Advaneemel1t of Science.)

biochemical pathways in men, fruittlies, paramecia, pigweeds, and bread molds (see
Section B). Yet some aspects offunction seem almost universal:
1) A spontaneous periodicity of about 24 hours (Box B).
2) Relative temperature independence of that period as long as the temperature is
constant (see pages 567-70).
3) Persistence of the rhythm even in the smallest unit of biological function, the
single cello
4) Immunity to many kinds of chemical perturbation. Exceptions include
infiltration with heavy water, exposure to some inhibitors of protein synthesis
(whether at transcriptional or translational level), and exposure to other
substances affecting membrane structure [possibly including general anes-
thetics (Bunning, 1956b; Keller, 1960)].
 A: SOME CHARACTERISTICS OF ClRCADIAN RHYTHMS 563

Box B: Is 24 Hours a Long Time?

Persons trained in chemistry, physics, and electronics often express surprise that a
biophysical object can generate aperiod as long as a day. Could such long periods be
compounded from oscillations of shorter period? For example, two oscillators of similar
short period could generate a beat note with aperiod much longer than either oscillator.
Or a counter could reset only after accumulating a thousand ticks of a milliday oscillator.
Almost all commercial docks work this way. Such analogies have often been invoked for
biological docks (Pittendrigh and Bruce, 1957, p. 94; Schmitt, 1960; Higgins, 1967; Pye,
1969; Pavlidis, 1969). 1 have never found this view very plausible because:
(1) The rephasing behavior of circadian dock mechanisms gives no hint of short-
period repetitions, and (2) most such schemes make the long period extremely sensitive
to changes in the short period (see Tyson et al., 1976).

My own belief is that ponderously slow dynamic processes are unfamiliar not
because they are in any sense rare or can only arise by compounding the more common
short-period oscillators, but only because long periods are inconvenient in the
laboratory. Until recently, environmental controls and measuring instruments were
seldom built to tight specifications for baseline drift on time scales greater than several
hours. Anyway, few souls are hold enough to found a career on one datum per day.
Chemical processes which, at least in theory, greatly expand the time scale of
familiar kinetic schemes without invoking the biochemical equivalent of a gear hox
have been advanced by many theorists since at least 1960. To me it hardly seems
necessary to struggle with familiar fast kinetics in order to contrive a slow process.
Simply because they are slow we are unfamiliar with protracted reactions, like those
involved in aging or in the female endocrine cyde or in replacement of membrane
channels and phospholipids. 1t seems to me reasonable to look to slow reactions for the
mechanism of long-period cydes rather than trying to compound a slow reaction out of
fast ones.
564 19: ClRCADIAN RHYTHMS IN GENERAL

120 .-------,-------.-------,-------,-------,-------.

100 __ ..... _._.. i .......... ~......,., .........._ ~ ..,....... ,.... ,., ..... ,.,............",." ... " ··"·,·_····1'-·····_-_····_ -_····· __ ········1········.....-......-.'. ..-.

..... " .................... .............................. ,.... ~ .......... ......................~ .... ,., .................. ,.,....~, ... _._ "
- _

60

40 ··········..····· ..

o ~----~~--
~----~
-~---=
-~--~-
=---~--~-
:-~-
~·--~---
~
o 100 200 300 400 500 600
time (min)
Figure a: On a time scale spanning 600 minutes, cell divisions of E. coli bacteria carrying the
repressilator circuit are indicated by short bars. Following each, one daughter cell was chosen
at random for plotting GFP fluorescence intensity ofthat single cell (ordinate, in arbitrary units).
From Elowitz and Leibier (2000), with permission.
 A: SOME CHARACTERISTICS OF ClR<;ADIAN RHYTHMS 565

cted suc an osdllator in E. coli, usihg its l.,ac!:

tetR (tetracycline resistance), and a ge'ne from. lambda phage. This three-gen~
"represSlato":' circuit makes th.e bacterillh'l glow dramaticalfy with green fluorescent
prote;n "t 2-~ H'our intervals (Flgure a); in the rangeGoodwin foresaw. :rhis is still an order
of magnitude shorwr than th.e qrcadian period, but It is only the _flr~t-cof many ep'~genetfc
oscillators to come. lf CI- posttran.slational binary reaction such as Drosophila's PER-TIM
dlrneriiatfon were needed to complete the' repressive feedback loop, a sl:.IbstantiaLtime
delay might bß introduced. . . t'
Simulations of the known mecbanism reveal an. acute sensiti\(ity to noise unless the
Ilumber of moleeules per cell is substantially il)creas.ed. < Barkai and 'teible! (2000)
!-presented these compulations Wlth thE! interesting sl,.lggestion that putative mechahisms
-of circadian docks, at least in unlceltular organisms, would pe plausiole only if they do not
have this property. . ' "
Leayiog outthe rans!an<?o 'step".and allowing the RNA tran sc riptto directly attath to a next
promoter site on designer DNA, Winfree (Erik, personat communication} shows a surprising
readiness of continuous, e i enetic s it ihg etworks to oscillate persistently ..

5) Sensitivity to visible light of an appropriate color (with rare exceptions: see pages
600-601). Light suppresses oscillation in some organisms even at intensities weIl
below full-moon light. Given in a brief pulse, light rephases. Given in periodic
pulses of adequate energy, light entrains the circadian rhythm if the period of the
recurrent light is not too different from the native period of the endogenous dock.

At the level of concrete mechanism in particular organisms almost nothing is known

of the biochemical basis of circadian rhythmicity even in the best studied species (as
of 1978, and in fact as of 1990 too: but then things changed as noted above). Current
guesses are that circadian rhythmicity has something to do with respiration and
mitochondria, something to do with membranes and ions, something to do with
glycolysis, and/or something to do with DNA transcription and RNA translation. All
these processes are nonnally found in circadian organisms. Circadian rhythmicity
has been modeled by borrowing Danziger and Elmergreen's (1956) model of the
menstrual cyde (Pavlidis, 1967a), by borrowing Higgins' (1964) model of oscillating
glycolysis in yeast (Pavlidis and Kauzmann, 1969), and by borrowing Goldbeter's
(1975) model of cAMP rhythms in slime maId (Cummings, 1975). Saunders (1978)
has remarked that there seem to be almost as many models as investigators. This
reminds me of Byron Goldstein's humorous obseIVation that some shortage of
equations is suggested by the reappearance of essentially the same mathematical
fonns, thinly disguised, in so many models
566 19: ORCADIAN RHYTHMS IN GENERAL

One might make sense of both quips by guessing that although mathematical
principles are universal, mechanisms are diverse. Such a guess is suggested by the
facility with which model makers, in each decade of changed emphasis in
biochemistry, have collected data from many species in support of the correspond-
ing fashion in modeling circadian rhythms. Taken collectively, this literature
amounts to a parody of reductionism. Maybe cell chemistry provides an incredibly
fertile seedbed of mechanisms for long-period oscillation (see Box B). One could
imagine that the oscillators we see today are exempted from the general tyranny of
homeostasis only because their periods easily conform themselves to a 24-hour
environment. Beyond this, one expects selection of certain functional attributes,
e.g., photosensitivity, but as far as inner workings go, the only common features
may be those common to a wide dass of ordinary differential equations.
Though the physical, biochemical, and genetic dissection of dock processes is
part of a literature mostly still unwritten (in 1978, and in fact also in 1990: but as seen
above, not in 19991), it seems likely that the mechanisms, when discovered, will
exhibit a diversity comparable to the mechanisms of homeostasis or of endocrine
contro!, rather than such conservative uniformity as is found in sugar metabolism,
protein synthesis, and oxidative phosphorylation. For the present, the most
promising experimental systems appear to be fungi mutated in fatty acid metabolism
(implicating membrane structure: Brodyand Martins, 1979), and birds whose pineal
dock is somehow involved in melatonin and serotonin metabolism (Zimmerman
and Menaker, 1975; Menaker and Zimmerman, 1976; Turek et al., 1976).
 A: SOME CHARACTERISTICS OF ClRCADIAN RHYTHMS 567

tlie most cl.lrious surprise rom molecu ar genetics toqay is that clrcadlan docKS
mechanisms discovered in ,diverse phyla keep displayi09 substantlally the same drama,
~n which the spme few actors-recognizably c0nservecl Rroteins-ffeely exchange
costumes to playaach other's rales! Apart rrom their' invplvement in episenetic elbck
meehanlsms, we da not now know wh at functions PER, TLM, CRY, etc. serveltliroughout
the organisrp. Whatever, it could be that they do'a' better joo in alternation tban in a
steady state (like processes in the menstrual cycleor ,he mitotlc cycle),and that it has
proven convenient to synchf"!)nize these 'altemations by referenee to the light/dark
eyele • .Mutua regulatIon to achieve this has appareptly e\lolved in a variety of ways
among slmilar proteins !n diverse phyle.. Why all sboll~d result in spontaneous cyeling in
the absence of light/dark eueing ..emaiI.lS1.et ahot~er mystery: All rcan thfnk.oflrl thrs
respect is.that jf for som~ reason it takes so any hoursJor up-shift regulation then so
any for down-shift that it i5 by now almost til1)e fo the usual environmental eue
(sunrise?), 't~en mutants in whom compietion" of do~n-shift redU dantly cues the start.of
up-shift (thus closing a spontaneous cycle) "Would do 00 harrn and mlght conf.er
oecasional adyantage. As 9dysseus groused 01:1 Ci reze's. island (Homer's Odyssey,
Chapter 10), "My fnends, we do not know east froT west, we clon)t khOW whete the sun
rlses to give 1ight to.all mankind or where lt goes down under the earth. Weil-, then. wh~t
are Wf:( to do? We must tT)l:tö, th'ink of sornething ~t once. F.or rny part, r..Gal1't thtn 0
in .".... ~ .

Temperature Dependence of Circadian Clocks

In the earlyyears ofinquiryinto eircadianrhythms (before they were so named) debate
and contradictory evidence obseured the temperature independenee expected of a
functional "dock." Such independence was first noted by Wahl (1932) in connection
with thetime senseofbees. Brown and Webb (1948), forexample, thought therhythm
to be independent of temperature because the dock" was in faet ultimately the
11

rotation ofthe Earth. Kalmus (1935, 1940) thought it temperature-dependent because

the first cycle of Drosophila melanogaster's eclosion after a temperature change
occurred atlengthened (if colder) or shortened (ifwarmer) intervals. Brett (1955), also
using D. melanogaster, affumed a temperature-independent period. These were the
beginnings. Pittendrigh (1954), switching to D. pseudoobscura and improving on
Kalmus' experiments, argued for temperature independence up to the final 24 hours
before edosion. Pittendrigh and Bruce (1957) distinguished between the dock and the
physiological or behavioral rhythms that the dock drives, which we happen to find
convenient to monitor. They verified relative temperature independence ofperiodonly
in the former. It proved important to distinguish clearly between "temperature
independence" and temperature independence of period. Only the period (over-
looking transient behavior, photoreceptor kinetics, amplitude, etc.) has been system-
atically explored as a function of temperature.
568 19: ClRCADIAN RHYTHMS IN GENERAL

Although many circadian docks have nearly the same period at any temperature
within a reasonable physiological range, acute sensitivity to temperature changes is
not uncommon. This sensitivity in the basic dock, as weIl as in peripheral driven
physiology, is shown by synchronization of circadian rhythms to tiny changes of
temperature on a 24-hour schedule (Hoffmann, 1969b), and by large and lasting
phase shifts in the rhythm at constant temperature, following abrief exposure to
heat or cold, in Euglena (Brinkmann, 1966), in various strains of Drosophila
(Winfree, 1972a; Maier 1973; Chandrashekaran, 1974), and in Kalanchoe (En-
gelmann et al., 1974).

Arguing as an evolutionary biologist on grounds of plausible selective

advantage, one might reasonably expect complete temperature independence of
the circadian clockworks. Yet what has been found is instead a temperature
independence of period at constant temperature, a condition that few organisms
have ever experienced. What selective advantage attaches to such temperature
compensation of period in an organism acutely sensitive to temperature changes, in
a world whose temperature never stops changing? Even when the world doesn't, the
organism changes temperature by moving from sunlight to shade or by working.
Bumblebees, honeybees, and wasps, for example, get 10°C hotter in flight (Heinrich
and Bartholomew, 1972; Heinrich and Casey, 1973). The optimum temperature for
insect flight musde is typically 30-40°C (Esch, 1976). Small homeotherms typically
abandon temperature regulation while sleeping, and thus cool off by 20°C. Such
observations suggest that something of further interest may lurk here, awaiting
discovery: something about the rate of change of temperature (e.g., see Zimmerman
et al., 1968; Pavlidis and Kauzmann, 1969).
Returning to the question of temperature compensation of period at fixed
temperature, there has been widespread speculation since about 1970 that the
mechanism lies in membrane melting and in the well-known biochemical
accommodation of melting point to ambient temperature (Njus et al. 1974; Wisnieski
and Fox, 1976; Mattem et al., 1982).1 have been an eager consumer of this literature
since coming to believe that the quite different temperature sensitivities of
Zimmerman's flies and mine (see Chapter 20) might stern from their different diets,
especially their lipid compositions. Yet in the current (1978) enthusiasm we tend to
overlook a surprising abundance of alternative mechanisms. It turns out that
temperature compensation of rates and periods is quite common in inorganic
 A: SOME CHARACTERISTICS OF CiRCADIAN RHYTHMS 569

chemistry, biochemistry, and physiology. I offer a short menu of randomly

encountered examples in chronological order:
1. Skrabal (1915) found that the temperature coefficient of the iodine dock
reaction depends on sodium sulfate concentration. The rate fuctor per 100 e can
be adjusted from 1.25 through 1 down to 0.85. This is about the range observed
in circadian docks.
2. In general, inorganic reactions may absorb heat or liberate it. In the latter case,
the reaction is fostered by cold: It has a rate fuctor less than 1. It is also common
in association reactions [2NO ~ (NO h; 21 ~ 12 ] to find an optimum temperature,
at which a compromise is struck between molecules finding each other and not
bouncing apart in the collision. On the high temperature side of an optimum,
the rate fuctor is less than 1.
3. Bullock (1955) observes that the Arrhenius rate law, such as Hoagland (1933) first
observed in his fevered wife's time estimates and such as we use to estimate the
outdoor temperature by the frequency of cricket chirps, is actually very
uncommon. Temperature independence of period is surprisingly common.
Bullock gives an impressive example in the pulsing rates of a jellyfish. The rate
seems nearly constant over a wide range of temperatures surrounding the seasonal
temperature of seawater and falls off sharply at both the high and the low ends.
Golenhofen (1970) shows temperature independence of period in the electrical
slow waves of isolated guinea pig intestine over a 15°e range. Much the same is
typically true of growth and development in poikilotherms, at least to the extent
that there is a range of optimal temperature in which rates are almost
temperature-independent, falling off to either side.
4. If molecular diffusion plays a big role, its relative independence of temperature
can dominate. Ehret and Barlow (1960), Ehret and Trucco (1967), Pavlidis and
Kauzmann (1969), and Sel'kov (1973) invoked diffusion limitations to account
for the temperature independence of overall rate in circadian rhythms.
However, even such conjectures risk proving too much because circadian dock
kinetics is not temperature independent.
~ Actua'l y, item 4" was a rea herring: The cited references invo e that prir1ciple wlthout
"data or citatio!1s. 'I t turns ,?ut that molecular diffusion. coefficien~ are typically . lesl'
ternperature-independent tlaatl is ,dock perfod. For examp'le~ see chemical data in
Kuh'; rt.eta[ (198S), Foe steretal. (·19.91}/or Lechleiter etal. (1992). Moreover, di:ffuskm
t' es vJi~!r:l ~iri9Iec~lIs ~odld barely be noticeable 00 a. drcadian tim~ scale: 5upposing
as llitle as 9,8 cm 2/sec for large or' adsorbed molecules in C}1ogel" .anö tn'tracellular
,distances even- as great as 0.005- cm, equilibration underdiffusion would tak,e no more
tbän a few'times (0.005 cf!lf/( 0·8 ·C , 2/sec)=2S00 sec, thus a few nours'at most.... .

5. At physiological substrate concentrations, the rate of enzyme reactions in

poikilotherms may be relatively independent of temperature because the
enzyme-substrate complex falls apart prematurely at higher temperatures, or
because Km increases with temperature as fast as Vm, and the overall rate
depends on their ratio (Somero and Hochachka, 1969; Newell, 1969).
6. In general, the rate of a compound reaction depends on the rates of its constituent
reactions in a complex way, often involving relatively temperature independent
570 19: ClRCADIAN RHYTHMS IN GENERAL

ratios of rate coefficients. These notions have been repeatedly invoked in

connection with circadian rhythms by Hastings and Sweeney (1957), Spangler
and Snell (1961), Goodwin (1963), Pavlidis and Kauzmann (1969), and Sel'kov
(1973). This principle is exploited in connection with chemical relaxation
oscillators as models of circadian docks in a delightful paper by Rossler (1975).

7. Mano (1975) reports that the cytoplasmic oscillator underlying cell division in
sea urchin eggs has the same period over a wide range of temperatures. Reasons
such as the above, based on hypothetical kinetics, might be advanced.
Altematively, making use of the widespread belief that the cell division cyde
is nearlya "simple dock" (Chapter 22), it seems appropriate to draw attention to
the cute example of environmental determination of period given on page 93. It
tumed out there that simple docks generally run slower to either side of an
optimum environment. Given that this optimum is normal, we have plateau
around normal, which might be looked on as a homeostatic adaptation. Daan
and Pittendrigh (1976b, p. 278) use an analysis of this sort in connection with
homeostasis of frequency in noctumal rodents. Such parabolic rate laws are not
uncommon in circadian rhythms (Hastings and Sweeney, 1957, Figure 2;
Caldarola and Pittendrigh, 1974, Figure 2).
Homeostasis of frequency thus seems to result "naturally" by a variety of simple
mechanisms. In many observed cases, there is no obvious selective pressure for such
homeostasis. In this connection, it would be of interest to examine denizens of
constant temperature environments such as the abyss and deep caves. To me, the
evolutionary question of greatest interest about temperature compensation in
circadian rhythms, is, "Why aren't they even better adapted to keep step with the
Earth's rotation in the midst of daily temperature fluctuations?" It would also be of
interest to compile a catalog of temperature-compensated and of temperature-
sensitive features of circadian docks, of their photoreceptors, and of the systems
they drive. Is anything but the period at constant temperature regulated? If so, what
adaptive significance do those features have in common?

Topological Properties
Even before knowing about mechanisms, one can ask about dynamics. To this end it
is essential at some point to find out about the topology of the state space in which
the dock process carries out its circadian routine. At the simplest level, one needs to
know whether the dock has access to only a one-dimensional continuum of states,
like a repetitive knitting machine, intemal combustion engine, or wind-up music
box. Altematively it might have access to states off the standard cyde, retuming
toward that cyde between perturbations. If so, how many dimensions are there in
the state space, and how many other attracting cycIes or equilibrium states coexist
in it? And how does the system move from one to the other? Questions of this sort
have been posed by chemical engineers and electrical and mechanical engineers
 A: SOME CHARACTERISTICS OF ClRCADIAN RHYTHMS 571

I.
.
DROSOPHILA
PSEUOOO8ScUR"
Rgure 1. The fruitfly's circadian dock shows increasing delays ~
following exposure to a light pulse at a later phase... up to the 1 ~
"breakpoint" at which the curve is conventionally dropped vertically ~
to the complementary advance. Advances then decrease. Note that 1-:~~IotI'II'~=----+--l
the slope does not change in crossing the vertical segment. From
Pittendrigh and Minis (1964, Figure 8), with permission. (Note that w
advance. are plotted upward by convention since about 1965) ~
c

concerned with the dynrunics of control systems important to industrial daily life.
They have also been posed by physiologists striving to understand respiration,
honnonal balance, tissue differentiation, and the pathologies to which each is
susceptible. In the area of circadian physiology, attempts at such system-level
description have mosdy started with the control of phase. People studied the
resetting of phase by a single stimulus, and then by two successively, and in the limit
(as in the natural outdoors) by prolonged periodic light cydes.
The study of dock dynamics has progressed most notably through investiga-
tions of the way in which stimuli inflict aphase shift on a circadian rhythm.
In talking of daily schedules, docks, and phase resetting it seems only natural to
think of phase advances and phase delays. It has long been conventional to plot phase
advances and phase delays against the phase at which aresetting stimulus is given.
This plot is called aphase-response CU1Ve (PRC) (Figure 1). It characterizes the dock's
rhythm of sensitivity to the given stimulus. It may seem to some less natural to plot,
instead of the phase shift, the new phase to which the dock is reset. Of course the two
representations are 100% equivalent, so a preference for one or the other may seem
rather a crotchety affeetation. Nonetheless the reader will have noted by now that I
have a definite preference. Let me dedare here, in context of circadian rhythms, why
I think you will find it much easier to understand the principles underlying phase
resetting if you think in tenns of phase rather than phase differences. My remarks on
this subject are collected in the next two sub-sections.

Real vs. Artifactual Discontinuities

As noted in Chapters 1 and 14, the PRC is a cut-out unit square from a more
complete description of the experiment. This cutting severs Type 0 resetting curves
in such a way that they appear discontinuous. The choice of where to locate the unit
square's cut edges is arbitrary. It is usual to place these cuts in such a way that the
smooth trail of data points is interrupted where the reset rhythm is shifted one-half
cyde from a control rhythm. Alternatively one might cut the data where a driven
rhythm changes its habit from catching up to the reset dock to falling back into the
preceding cyde (as in Zimmennan et al., 1968). Another option is to cut the data
where the reset rhythm has shifted through a JulI 3600 back into synchrony with the
control rhythm (as in Pittendrigh, 1967a). Whatever the choice, it detennines a
phase at which an ostensible jump occurs from a large delay or advance response to
something that differs by exacdy one period. This discontinuity is an artifact of
572 19: CiRCADIAN RHYTHMS IN GENERAL

description but is commonly treated as a reality. For example, when asolid curve is
put through the data points it is turned vertical at this point as though threading
(nonexistent) data points on a very steep segment. 3
Discussions of this "phase jump" (example Wiedenmann, 1977 or Francis and
Sargent, 1979) seldom make the critical distinction that it is really "phase shift
jump" from a big delay to the complementary advance. This means that it is no
phase jump at all unless one imagines that the dock reaches a given phase only by
passing through all the intermediate phases, as in a ring device (Chapter 3).
Much of the literature gives the impression that "what goes up must come
down" in the world at phase shifts: that if a system gives delays at one phase and
advances at one later phase, then at some intermediate phase the curve must rise
from delays, through zero, to advances. This is true of real numbers, i.e., points on
the realline IR I . But we are concerned with phases, i.e., points on the ring §1. On a
ring there are two arcs "between" any pair of points, not only the one that indudes
zero. Thus one can go smoothly from the delayed semicirde of phases to the
advanced semicircle of phases either through 0° or through 180°.
In the case of a simple dock (the most popular, if implicit, mental model of a
smooth physiological dock), the transition has to occur through zero. This is
because the basis for advancing and delaying in a simple dock is a phase-dependent
angular velocity which cannot go from minus to plus without passing zero unless
the mechanism itself is discontinuous. Thus the "observed" data-free jump is
sometimes interpreted (I believe incorrectly in most cases, though possibly correctly
in some particular organisms) as a physiological jerk or discontinuity in the
oscillator's mechanism or in its mechanism of response to the perturbation used.
For example:
1. It was apparently within this context that Frank and Zimmerman (1969) chose
to determine action spectra for phase shifting at phases only two hours apart: an
hour be fore and an hour after the phase jump. They sought different
photoreceptors mediating advance and delay phase shifts of the fruitfly's
circadian rhythm. This is an important experiment and a very sensitive
experimental design if one believes that the circadian dock is phase-shifted by
advancing or delaying along its cycle, or that the plotted phase jump actually
represents a physiological discontinuity. However, no difference in photosensi-
tivity was detected, as would be expected under any hypothesis about the
photoreceptor if one interprets the adjacent big advance and big delay as just
two ways of plotting essentially the same physiological process.
2. Zimmer (1962) obtained a smooth dependence of the phase of Kalanchoils
flower-opening rhythm on the timing of a rephasing stimulus (see Figure 2 in
Chapter 21). But the curve she sketches through the data (Figure 1 in Chapter
21) does not follow the smooth path: It leap across a cycle to join points in
adjacent smooth trails of rhythmic data. The resulting discontinuity is preserved

There is one instance in which data points do appear on the very steep segment of a Type 1 curve
(Pittendrigh and Bruce, 1959, Figure 8). However, the raw data (Pittendrigh and Bruce, 1959, Figure 4)
shows that these dots represent multiple recurrences of the monitored event during an interval of
transient irregularities.
 A: SOME CHARACTERISTICS OF C1RCADIAN RHYTHMS 573

as a conspicuous feature of Kalanchots circadian cyele when later writers plot

the curve without data points in phase shift format.
3. Karve and Salanki (1964) follow the same procedures in repeating Zimmer's
experiment in a different physiological context. Here a geotropic stimulus is
used to upset a two-hour bending rhythm of aplant seedling. The resulting
oscillations have their maxima at nearly the same interval after the stimulus,
but the curve threaded through them is made to jump almost a full cyele
between data points in order to preserve the appearance of Type 1
connectivity. The phase jump thus imposed on the data is reckoned to be
an important physiological event.
4. Hastings and Sweeney (1958) show smoothly vru:ying data on the rephasing of
Gonyaulax by a light pulse. But in Christianson and Sweeney (1973, Figure 3)
the plotting is switched to phase shift format and a large phase jump is assumed
in order to make the curve look like a magnified version of Type 1 resetting.
Sweeney (1974) suggests that the phase jump may refIect an abrupt change from
active to passive transport in the plasma membrane of Gonyaulax. In my
opinion the pervasive notion that there is aphase jump, which needs to be
accounted for, derives less from any data than from interpreting them within the
simple-dock paradigm. If one does so then it appears that the simple elock's
cycle is not continuous but has a sharp break in it. This is accounted for by
supposing that a "chronogen" accumulates during a prolonged tension phase up
to a threshold concentration, at which an abrupt change in cell dynamics brings
on the complimentary relaxation phase. This may be quick or protracted, but
when completed it restarts the tension phase. This idea goes back at least to
Rasmussen and Zeuthen's (1962) division protein model, to the mitogen
accumulation model of Sachsenmaier et al. (1972) for cell cyele timing and to
models of rhythmicity in pacemaker neurons in which a generator potential
accumulates toward a threshold for membrane conductivity (Hill, 1933). In
context of circadian rhythms Bunning (1960), Wagner and Cumming (1970),
Wagner et al. (1975), and Wagner (1976) associate the chronogen with energy
metabolism.

~ 5. Part of the argument for ihe ottlerwise prescient "chronon" moeel of the doCk
me.chanism and its involvement with huclear replkation (Ehretand T r\Jcco, 1967) was
that this "breakpoint" is another manifest.ation Qf the "point of no return" in the cell
division $=Ycle. •

Though I look askance on such interpretations, it must be recognized that the

sparseness of data points along the vast majority of circadian response curves
preeludes any very rigid inferences about the topological Types of resetting thus
observed. Type 1 has been widely assumed tacitly, but in only a few cases in the
earlier literature [e.g., Figure 1, the Drosophila curve of Pittendrigh and Minis,
(1964)] were the curves clearly enough resolved to make the reality of Type 0
resetting arguable. (See Box C of Chapter 4.)

.. Tnere are, of Cdurse, real discantinuitles also, at least in some kinds of continuous
model and. erhs 's in some drcadian sys!erns. 'These arise when tbe phaseless set has
574 19: C1RCADIAN RHYTHMS IN GENERAL

Figure 2. (Left) Delay and advance are opposite

D +-~---I directions along a cycle. (Right) If perturbation is not
+----=---i restricted to a one-dimensional cycle then the largest
A delays and advances can be indistinguishable.

Advance vs. Delay Ambiguity

By classifying all phase responses as advances or delays we force ourselves to
violate the topology of the phase ring as folIows. On the phase ring a small advance
and a small delay are nearly the same thing. Also any advance .<or delay) and a
slightly smaller advance (or delay) are nearly the same thing. A 90 advance is quite
0

different from a 900 delay. But a 1790 delay is not as different-as can be from a
179 advance. They are in fact virtually the same thing, as far as the end result is
0

concemed. The same is true not only of the end result but also of the process of
rephasing (except in the special case of simple docks: Chapter 3). A small
displacement of state by some amount in some direction (to the left in Figure 2) is
interpreted either as a small advance or as a small delay, depending only on the
prior phase of the oscillator. Large displacements of state that result in the biggest
advances or delays not onlY change the state in the same direction by the same
amount but also are very nearly identical in the sequence of states passed through.
These two diagrams may look like mystic symbols here, but they acquire
operational meaning in terms of the presumed multiplicity of equivalent oscillators
in multicellular organisms in Chapter 4, in terms of hypothetical underlying
biochemistry in Chapter 6, and in terms of experimental manipulations of the
fruitfly's eclosion rhythm in Chapter 7.
The language of advances and de1ays suggests that advance and de1ay are
opposites, but they are not, since a big enough delay is an advance. 1t suggests that
advancing and delaying are opposites, but they are not, except in the special case of
simple docks. Moreover, an advance or delay can be obtained without advancing or
delaying by simply freezing the oscillator for the duration of a prolonged stimulus.
The very notions of advancing or delaying are ambiguous. The following three
nonequivalent definitions are in current use:
If the perturbed rhythm leads the unperturbed control rhythm by less than one-
half cyde, then one speaks of an advance, or if it lags by less than one-half cycle, one
speaks of a delay.
A net delay can come about by accumulation of abnormally short inteIVals until
the accumulated advance exceeds one-half cycle. Zimmerman (1969, personal
 A: SOME CHARACTERISTICS OF ClRCADIAN RHYTHMS 575

communication) obtained a four-hour-delayed edosion rhythm in the fruitfly by

way of a progressive 20-hour advancing transient. In general, the resetting of a dock
that can both advance and delay might register with the extemal world by way of a
unidirectional process that can only be advanced or only delayed. See Christianson
and Sweeney (1973, p. 98) for another example.
The net effect of a stimulus changes as its duration is prolonged. If (0 + M), the
event time measured from the start of the stimulus, increases with M, the stimulus
duration, then the stimulus is delaying the rhythm, and if (0 + M) decreases with M,
then it is advancing the rhythm. Saunders (1976a) obtained both advance and delay
phase shifts by convention 1 but only delays according to this convention 3. And if
one measures the new phase at the end of the stimuli, then all of Saunders' shifts are
obtained by advancing.
For such reasons I have adhered to the conventions of full data presentation
originally fostered by Hastings and Sweeney (1958, Figure 8), Pittendrigh and Bruce
(1957, p. 95 and 1959, p. 486), and Zimmer (1962, Abb. 2). I avoid the more recent
convention of data reduction in the notation of phase shifts. Neurophysiologists in
the 1970s, encountering problems of phase control similar to those first tackled by
circadian physiologists in the 1950s, reverted to the similar practice of full
disdosure, forgotten since Ecdes and Hoff (1932, 1934) (see Chapter 14, the
second part of Section A).

Looking Behind the Adaptive Facade

If dues to dynamic organization are to be sought in behavioral experiments, it is
essential to know something of the adaptive value of that behavior, and so about the
evolutionary origin of the mechanism to be explored. Pittendrigh and Bruce (1959)
succinctly stated the essential principle that features with adaptive value must be
avoided:
Again there are difficulties here which stern from the fact that diverse physical
systems can be devised (or evolved) to behave in a fonnally similar way. In the
comparison of living dock systems for instance, we can take neither temperature
independence nor entrainability by light as evidence of a common mechanism;
selection must have demanded both these features as functional prerequisites of
dock systems and will, of course, have been indifferent to the particular physical
mechanism by which the functional end is met. If we are to test the proposition of a
common mechanism and use only fonnal properties, these must be of such a nature
that selection can reasonably be dismissed as the agent responsible for their
universal association with cellular dock systems; in short, the properties must lack
adaptive value.
Or as Pavlidis (1971) put it:
Therefore, their study can provide little insight into the structure of the system that
regulates the daily rhythmicity of organisms. On the other hand, one may expect
more from the study of features that do not seem to have any survival value and
therefore may be indicative of the structural properties of the system. This point
may be illustrated by the following example. Consider a passenger on a train who
wants to find out whether the locomotive is steam, diesel or electric. (One may
576 19: ClRCADIAN RHYTHMS IN GENERAL

assume that the engine was attached to the train after he boarded it and therefore he
did not see it). He may try to do so by obseIVing the details in the changes in velocity
while the train goes through curves or stops at stations. While it is theoretically
possible to achieve identification in this way, it is quite difficult because all
locomotives tend to show rather similar functional characteristics. On the other
hand, the identification could be quite easy by obseIVing nonfunctional features, like
smoke, noise, etc.
Rephasing experiments probably seIVe this purpose admirably, as long as the
stimuli used are quite unlike natural daylight photoperiods. For example we will see
s
in the next chapter that the phase singularity of Drosophila dock can only be
revealed by exposure to light whose energy is a million times attenuated relative to
natural photoperiods, and only if it is given just once, not repeated dailyas in nature.
But what are the evolutionary origins and purposes of circadian rhythmicity?
The next section explores this question, leading to recommended experiments and
obseIVations.

B: Clock Evolution
Who knows for certain? Who shall declare it? Whence was it born? Whence came
creation? The gods are later than this world's formation; who then can know the
origins of the world? None knows whence creation arose and whether he has or
has not made it; He who surveys it from lofty skies, only He knows '" or perhaps
He knows not.
Rig Veda X:129

I list here three alternative conjectures, all in need of development, about the
evolutionary origin of circadian dock dynamics. These three make different
assumptions about the selective pressures dominan't at the time. The first starts
with a timer selected to anticipate the dawn by degrading or accumulating a
substance during the night. The second starts with the cells' daily cycle of activities,
imposed by the daily cyde of light and dark, warmth and cold. The third starts with
the cell metabolizing steadily in a constant environment, and asks how stable this
situation might be.

First Dream: Dawn Warning

In the Archaezoic Seas. Suppose it were necessary for cells in the primordial slime,
perhaps cyanobacteria, to coordinate their biochemical activities on a diurnal
schedule. In a stimulating speculative essay, PiUendrigh (l966b) suggested
advantages that would accrue to whatever mutants could best anticipate the rising
ofthe Sun:
'" it is a reasonable speculation that the daily alternation of light and darkness was
the historical cause (selective agent) of circadian oscillations in the first place.This
line of thought derives from recalling the prerequisites for organization in a chemical
system. The principal of these is that the constituent reactions cannot proceed
spontaneously at the prevailing levels of free energy. Thermochemically, this means
 B: CLOCK EVOLUTION 577

of course that the reactions the cell employs involve energy barriers insurmountable
at prevailing temperatures; they proceed only on command that rests with enzymes
and ultimately with the nuclear store of information. Little attention seems to have
been given-in this general context-to the problem of visible radiation as an energy
source that threatens organization.Of course, the fact is that the majority of the ceIls'
constituents are colorless; and uncontrolled activation by the visible is thus excluded.
It may weIl be that in the history of the cell there has been selection for colorless
molecules, but if that is true (and it seems likely) it is a fact that for some functions,
colorless molecular devices have not been found. The flavins and cytochromes are
examples of ubiquitous fundamentally important molecules that are colored-and
where color has no detected function. No attention seems to have been given to the
consequences of illuminating these molecules whose color is without obvious
function. At any rate it is surely reasonable to consider, at least, the likelihood that
some subroutines in these cells' overall tasks are impaired by the activation of
molecular piece-parts in the flood of visible radiation to which it is subjected each
day. To that extent, the routine delegation of some chemical activity to the recurrent
darkness of each night would be an obvious escape from the photochemical threat to
organization.. , an enzyme system involved in repairing UV damage to the genetic
material absorbs in the visible ...

.. Emery et al. (1998), Miyamoto an Sancar ~1998), Kume et al. (1999), 'Freeaman et
aL ,(1999.), and Ceriani et al. (1999) have since identiHecj the flavopr,otein"
cryptochrom~ (closely related to the photolyases alfcideq .to above). as a critical part
of circadian docks in insects an~ In mammals, and it dbes ser:ve as the photoreceptor
in Droso hila (but not i the mouse). .. '

If, in keeping with the Middle Dutch origin of the word "dock" (clok, a bell), an
alarm timer is needed to anticipate the dawn, it seems reasonable to expect that the
simplest timer would be invented OOt. This would presumably be arelaxation
oscillator, the same as has been widely invoked to account for the timing of cell
division (Chapter 22) and for the timing of rhythmic contraction in nerve and in
musde and in heart musde (Chapter 14). Specifically, some byproduct would
accumulate during the dark, up to a threshold. At threshold, a conversion is
undertaken from metabolism appropriate to darkness to metabolism appropriate in
the glare of sunlight. It is to be assumed that the sunlight and/or the cells'
preparation for it turns off the accumulator and allows the product to dissipate
until next darkness. (The reciprocal version is similar, in which a product decays in
the night and is restored to a standard concentration by the end of day.) A
sophisticated accumulator might even adjust the threshold or the rate of
accumulation to improve timing tomorrow if the threshold was reached a little
too early or too late today.

Conservative Evolution of a Simple Mechanism. If cells need to invent a timer,

here is a simple beginning. Such a single-variable hourglass mechanism has
appealed to many investigators of contemporary circadian rhythms. From the
viewpoint of evolution, its most conspicuous features are its responsiveness to the
environment and its one-shot relaxation character under hypothetical conditions of
constant daylight or constant darkness.
578 19: ClRCADIAN RHYTHMS IN GENERAL

Given enough mutants, it is easy to imagine the prosperity of the cell's

descendents with the most reliable hourglass and the most cleverly engineered
attachments to general metabolism. If all this confers a selective advantage, then
woe be unto the apostate cell that attempts radical innovation or abandons
altogether this valued heirloom. Inheritance may well be conservative and we could
end up with a universal circadian clock or hourglass as faithfully replicated as the
mechanisms of glycolysis, of oxidative phosphorylation, and of protein synthesis. In
multicellular organisms, the indispensable timer might well be expressed in a
specialized tissue that serves to coordinate the whole organism.
This case is the most favorable for scientists, so they prefer it. An accumulator
mechanism with a single most important variable, marked by sudden transitions
once or twice a day, would be the easiest to pinpoint biophysically, especially if one
is free to choose the most favorable organism in which to explore each aspect of the
mechanism, and if it functions most conspicuously in a certain organ (let us say, the
brain or the pineal gland).

On the Other Hand. ... Unfortunately, I see rather little evidence to encourage
this outlook. It is by now well established that many cell types in each organism
exhibit circadian timing. Moreover, though there are exceptions (Lees, 1972), the
timer's cycle most comrnonly does spontaneously repeat at 24-hour intervals
despite the lack of obvious selective pressure for such a contrivance. A primordial
hourglass easily could have mutated to turn itself over, but given the regularity of
sunrise and sunset, no clear advantage would accrue to such cells. Saunders
(1976b) notes of the fly's clock that "only when the night is extended to more than
24 hours is the oscillatory nature of the system revealed," and that seldom happens
in nature. Remmert (1962) and Hoffrnann (1971a, p. 199; 1976) are perplexed by
the apparition of a spontaneously recycling internal timer. After all, organisms
were selected only for ability to cycle in a regularly cycling environment. Enright
(1970) in a particularly valuable essay addresses the question, 'What selective
advantages led to the evolution of internal timing mechanisms, and in particular
to an internal timing mechanism which is rhythrnic and self-sustaining rather
than to a one-cycle timer which must be reinitiated by environmental stimuli each
day.-;>"

J~ There still seems to be no very persuasive answer, just 'a~ when Charles Darwin
penned his doubts (The Power of Movement in Plafjts, 1880) that eireadtan leaf and
tendril rhythms could evoJve through natural selection. My own engagement pf these
proble"ms as 'a graduate ,student was motivated by the possiqility that dr;eadfan ,
oscillations are indispensable to the individual eukaryotie eell, being someh0w
i~volved in sequentfal nudear transtription that temporally organlzes · eellular
~etabolism. Appreciating the~ealtty of Type 0 resettil1g, then ,the topologrcally
ineseapable eonsequence that .a phase singulariw, exists and can be reaehed by a
criticallight Plllse, I imagined that if I couldactually demonstrate ft (the target date was
my 26~ birthdayr then 1 would also,witr;1ess a major derangement of metamorphosis,
even o.t r:neta6olism;.:in the. fruitfly. The singularity trap protoG:ol" converged on it' in' a.
timely way, hut there, was no c0nspicuous biologicaJ effect: the birthday' present was
~ , pooby-pnze. At least at t~e organ~~ni level the eu'pal eloe 's nase , sin .
 B: CLOCK EVOLUTION 579

provecH ' compat;!:) e wl~ norma rpetat"(lorpnosis. But maybe ,the" Inoiviaual .. cells
rerfialned rhythmic? J 9day. we kn,ow a.lso "that armythmiCi:- mutants in breaö ,molas·,
fruitfliesl a'ld ~mice -are "'all arrhY-tttmic at the celll1lar'le\(el Nejtner>aberrati?fl. seems to
cause -those ceJ1s or -o[ganisms any , dlffi:Clllt)!, iThere ,cs- still .no cur.rently believed.
quant~tatjve demonstration da c1rcaclian ~clock's,selective advamage' in any ~ukaryote­
(but-see. OuYang et ~I., ', 1998, for ' a prokaryote). : The dasest approac may bethe
obsetvation of Njus' et al. (1981) that the periods cf (noninteracting) Gonyao/ax cells in
seawater. susp~nsion consiStently differ er indivldually w9bbl~ by less thah an hour
from the23-hour mean: where are- :t.li'e ,mutaflts of ore extreme p,~riod. t"at should
accumulate unless elimina;ted by ~electior;\(
It was idely assumecj decades ago that ~t.e" circadian dock evolved as an
a'daptation in eu~arY0tes amd "jts.:! mechanlsm has remained geeply censel\led durihg
~ubseguent ev.olution. Reviews of receht lJlolecular, gene-tics stil carty'this- flavor
(punlap, 1999). kfewever, e >eYiqence nas, hot i::Jissua<iled me from the contr-arian
vjewpojnt (e.g., Win ree, '197-6b-) tnat still, colors ,tbis rev'iew 24-years lale!-. . _
. Adde;:i in pr-ess, summer 2000: A. c0'!1parab1y skeptlcat -end_be :er 'infOh"'fled, vlew of
currel1t1 unders!ood rnechanis s ha~ si1id~ ael'eared. 111 iakio-Tho aso(2000) ....

I still suspect that circadian spontaneity is not an adaptation at all, but an

accident of neutral selective value. (For a contrary opinion, see Pittendrigh and
Daan, 1976.) As such it may provide some due that the origin and mechanism of the
dock do not lie in this dass of mechanisms. Finally, reinforcing this condusion, I
know of no indications of a physiological jump in the normal cyde, as assayed by
resetting experiments.

Second Dream: Indirect Selection

Back to the Archaezoic Seas. This one starts dock evolution not with the need for
a single timer, but with a preexisting cyde of biochemical activity, driven by the
daily alternation of light and dark, of warmth and cold. With many metabolie pools
driven into reasonably predictable diurnal fluctuations, the cell could be regarded as
executing a regular cyde of activities, e.g., photosynthesis by day, heat prostration
by evening, perhaps mitosis by night, starvation by morning.
Given an alternating environment that intrudes forcibly into the cells' internal
affairs and the consequendy inevitable internal rhythms, a cell needs no additional
dock. But it could improve itself by optimizing the transfer from one
predominant metabolie activity to the next. To economize waste, to anticipate
changes and bridge them smoothly, to resist diversions during vicissitudes such as
an eclipse or the passage of a cold front, the successful cell would accumulate
modifier genes to facilitate each handoff of control during this imposed cyde.
Impelled by selection to gather more and more fail-safe backups to guarantee
efficient state transition, the cell might surprise itself to discover, 3.5 billion years
later (or 2.7 billion if prokaryotes be exduded: Brocks et al., 1999) when some
scientist first puts it into constant conditions, that it shuffles its way
spontaneously through almost the same cycle. Yet the ability to do so was never
of any use and was never selected for.
580 19: ClRCADIAN RHYTHMS IN GENERAL

A Critical Experiment. If cells can actively intemalize environmental rhythms in

the way here vaguely suggested, then it should be possible to demonstrate the effect
by bacterial selection experiments in a chemostat. By altemating the nutrient influx
from glucose without oxygen, to oxygen without glucose, to alanine and oxygen,
cells would be forced into a three-point metabolic cyde. Mutants could be sought
which prosper better in that milieu, and then tested for spontaneous cyding on
nutrient agar with suitable color indicators. By reversing the order of the driving
cyde, it should be possible also to select cells whose docks ron backwarci.

On the Other Hand.... This vision of the origin of docks seems weIl fitted to
models of dock dynamics in which there are no states accessible to the cell apart
 B: CLOCK EVOLUTION 581

from one or a few discretely different sequences of transformations. Such one-

dimensional models have enjoyed much success in connection with the cell cyde,
which in fact might have arisen in circumstances similar to those portrayed above,
the composition of cytoplasm being rhythmically changed by the recurrent
replication and phased transcription of the nudear genome (Pittendrigh, 1966b;
Ehret and Trucco, 1967). One-dimensional models have also heavily influenced the
devising of experiments and interpretations in circadian physiology (see Chapter 3).
However once again I doubt their suitability to account for circadian rephasing
behavior: Type 0 resetting does not come naturally to such mechanisms. So let's at
least think of one more dass of plausible model for dock evolution.

Third Dream: Steady-State Start

The Statistics of Stability. This one starts not with an engineering goal, nor with a
forced cyde, but with steady-state operation of cell chemistry, supposing perfect
homeostasis in a constant environment. Our outlook here may be taken from
Bunning (1973, p. 27), who cites Oatley and Goodwin (1971).
Statistical explorations of the kind of equations that describe reaction kineties
suggest a difficulty about steady-state operation (Goodwin, 1963; May, 1973). The
more complex the reactions, and the more regulatory coupling to other reactions,
the less the chance that any one steady state will be stable. Of course there may be
more steady states in a complex kinetic scheme, but probably not enough to
guarantee one being an attractor. In other words, mutants of complex regulated
pathways almost all exhibit instabilities of the homeostatic steady state. Departure
from a steady state need not lead to regular oscillations, but that is one possibility,
and mutants of this sort must be expected in vastly greater abundance than mutants
whose steady state is wen regulated.

Instability May be Desirable in ItseH, Even in a Constant Environment. Are

there intensive selective pressures against such mutations? I doubt it. There is
presumably some advantage to homeostasis, but only to keep fluctuations within
livable bounds. I see no virtue in perfect stationarity per se. In fact, several loose
arguments suggest the contrary. Chemical engineers are finding more and more
examples in which process control is improved by rhythmic'departure from average
conditions. This might be expected, in general: Deviation from monotony is one
more degree of freedom in which to search for optimization. In reactions with
sharply nonlinear rate laws, excursion to extreme conditions may "allow every dog
his day": A cyde facilitates segregation in time of conditions conducive to
incompatible reactions. cens commonly accommodate such processes by compart-
mentation in space, but another possibility is to compartmentalize in time, as for
example in cyanobacteria doing nitrogen-fixation only when photosynthesis is not
producing (toxie) oxygen.
It seems worth noting in this regard that steady pressure on a naH accomplishes
less than a rainfall of sharp hammer blows. A steady subthreshold level of sexual
tension is less conducive to mating than the familiar build-up to a sudden release.
Similarly nature has designed us to sleep and wake, but not to practice moderation
in all things by groggily intermingling the two.
582 19: CiRCADIAN RHYTHMS IN GENERAL

In short, there may be reasons why even if organisms didn't live in a fluctuating
extemal environment, they might benefit by inventing one intemally. The statistics
of ordinary differential equations suggest that much more intense selection would
be needed to avoid inventing one.
None of this specifically implies regular fluctuations, nor is regularity
necessarily to be expected of kinetic schemes involving more than the two
variables so familiar in theoretical journals (see Box B of Chapter 13). Nor is
regularity widely observed in the physiological rates of organisms except in certain
preferred selection windows along the frequency axis. But fluctuations that
happen to occur regularly, and at frequencies that dosely match dominant
regularities of the natural environment, may have special uses. Having started
dock evolution by simply not counterselecting the inevitable instabilities of
homeostasis, we now turn to the rhythmic environment for refining selective
pressures. For example, the effective value of any rhythmic environmental
parameter can be adjusted to any value within the range of daily variation by
locking the organism's experience of that parameter to a particular phase of the
cyde. If an organism ventures from its underground burrow only by night, then
daytime temperature is unimportant. This principle of phase locking has been put
to spectacular use in the laboratory by scientists from Michael Faraday (item 33 of
Experimental Researches in Electricity, to prove that voltaic and galvanic
electricities are equivalent), to Henry Cavendish (the experiment to demonstrate
gravitational attraction), to Amo Allan Penzias and Robert Wilson (detection of
the primordial fireball). It should be no surprise if organisms have exploited it
almost since the fireball cooled down.
If so, then we may expect accumulation of modifier genes to augment the
amplitude of such selected spontaneous fluctuations and to phase-lock them to the
environment through a photoreceptor or other sensor.
From this perspective, one might anticipate a diversity of circadian rhythm
mechanisms as great as the diversity of female cyde mechanisms and of
homeostatic feedback schemes in general... even within the single cell (in 1999:
as reported for Gonyaulax in Roenneberg and Morse (1993), for example, or as
considered an unexduded possible interpretation for Neurospora in Lakin-Thomas
(1998a,b». There may have been many independent evolutionary starts, and no one
had to win out. Moreover with several independently competent systems oscillating
within each cell, the dock is fail-safe, so each part is free to mutate without
imperiling the function collectively subserved. Thus, no aspect of mechanism need
be conserved during the radiation of species. On this basis, one would rather solve
the mechanism of one cell completely, than to select dues to a universal mechanism
from experiments on diverse cell types.

Conclusion
These three "dreams" are not mutually exdusive. They suggest three distinct
principles that might have contributed to the origin of circadian docks under
different conditions. Which ones would work fastest under any given conditions?
Did docks of different sorts evolve under different conditions? We don't yet know.
 B: CLOCK EVOLUTION 583

~ ' olRipg in tfle ~eceQt narvest of 'nto ation ' rom mofecular, biology yet permits u,s
Q distinguish between the foregoioo conjectures, beyond exduding a strfctly
c:onserved· evolution tram a unlque, prirnordlal echanism. One other v~ew (Kippert,
J985) held thatcircadian docks are an adaptation for temporal brgahization of severa"
,.Rrocary~tlc partiCipants attempting symbiosis" and coordinated . d~vision in wha
eventuaHy became the eUK~ryot1c cell, This mlg t seem leiss likely now thaJ: prokarydtic
.............d.;.;;.;
ian docks (presumabl r~ating' e karyotes> have been found: <4

A Critical Observation to Make. None of these three conjectures make any

distinetion between prokaryotes ('10wer" ,organisms, lacking subcellular orga-
nelles) and eukaryotes (made of one or more cells, with nudei and other
membrane-delimited organelles). Nor do they discriminate between cells with
generation times exceeding 24 hours and those that divide more frequently. But
as noted on page 546 a strong generalization among circadian physiologists has
it that circadian rhythms occur only in eukaryotes with cell divisions more than
24 hours apart (Ehret and Wille, 1970). Counterexamples have been sought
(Rogers and Greenbank, 1930; Halberg and Connor, 1961; Sturtevant, 1973) but
not convincingly followed up. An implication of the conjectures risked above is
that better counterexamples wiD be found. I would begin with a survey of the
colonial eubacteria (Actinomycetes), e.g., streptomyces or the tuberculosis germ,
mycobacterium. Other promising candidates among the prokaryotes might be the
nitrogen-fixing photosynthetic bacteria (cyanobacteria, blue-green algae). If no
circadian docks are found, then the scenarios elaborated above have overlooked
some major factor.

., As note, in 1999 revisions~bove~ Ur;s experiment Tias ooen äone ana the expecte(j'
circadlan d0'Cks wer. found. Ih this instance acaöemic folR-wisdom proved less
reliabl~ than reasored speculati~ri, butt!1is only means that the' hereticäl viewpoint of .
1978 evC!ded exdusion.oRJ:his~one graund. twen~~ne. years furtherdown the road, it
has evaded a few, more (s.g. t/le notion that hlJm~n docks are flmdam.entally
differ t), but tl'iere is stilf .no prov.n, ,q llantltativ. model of any drcadian dock's
molec~lar anti- ceHular mechanisms-,by which to strictly exelude the simple docks of
'Chapters 3 and 4, nor. in which an attractlng gyCle is confirmed (ar a' commuriity thereof
l:>eDavirtg collective~y like a ~o~seNative oscillator as in Chapter 7). rexpect it within a
very few years, but it cannotyet b~ claimed that facts have comptetely laid conjecture
~to rest in this matter... - . . '.~ _.

For example, it might be that prokaryotes typically enjoy much quicker

biochemical responsiveness to environmental changes than do eukaryotes. If so
then maybe no significant improvements of efficiency accrue to prokaryotic
mutants with long-period timers of any sort, so no single frequency band is favored
among mutations to spontaneous oscillation.

The Importance of Choosing One Case to Solve. My own initial enthusiastic

belief in a universal mechanism perished during the 1960s by counterexamples to
almost every specific proposal. Some creature physically lacks a substance or
584 19: ClRCADIAN RHYTHMS IN GENERAL

structure postulated to be essential, or can be functionally deprived of it be a

suitable poison, yet perseveres in its circadian time keeping. Like many others, I am
a true believer tumed apostate in this matter. But, disliking middle courses, I now
believe at the opposite fanatical pole, Le., that circadian mechanisms are as diverse
as species, or even as diverse as their cell types, or even as diverse as the modes of
operation in each cell in different hormonal and nutritive surroundings, or even
more diverse, if there are several independently competent circadian oscillators
within the cell's regulatory mechanisms under any given conditions.

~ In 1'999 it appears that. mechanisms in mammals ClifteT somewhat frorru ffiose in

insects, which them'selves djffer frpm one, spedes tO,die ' next and ever:\ within one;
organism's drfferel'lt tiss~es. All these are quite different fr:om mechanisms in fungi,
and those in .. cyanobacte ia are still more wil8{y aiffe(~J1t. 'Se~ the survey 19905: of
mole.cular
. enetics above,
- . ~ • ~~
"

It therefore seems to me of first importance to completely solve the mechanism

in one cell type, forsaking for the present dues gathered edectically from diverse
phyla, and then to solve it completely in another cell type, or to look for involvement
of the first found mechanism in another cell type. Thanks to Max Delbruck's
advocacy of this stratagern for virus genetics a quarter-century ago, surprisingly
rapid and cross-fertilizing progress became the hallmark of that field. Why not in
circadian physiology too?
Until a few years aga (in 1978) it was easy to indulge in speculation about the
biophysical mechanism of any particular circadian dock because almost any
particular physiological system X is involved: Either a disturbance of X disturbs the
monitored rhythm or even alters its period or permanently resets its phase (perhaps
indirectly), or disturbance of the dock alters the behavior of X. This game can be
played both physiologically and genetically. What is needed and what has been
lacking is a proof of both simultaneously: that X affects timing, and timing affects X,
so that X is implicated as a part of the timer. But even given this, there remains one
more necessary step: to show that X is an indispensable part of the timer.

__, This rel'l1alHs a -m~jo~ Issue,in 19~ . nvestiga,ttons Qf t e circaaian froc ' (OT doc;k:s!) in.
Newospora (Lakin-Tho~~st 1998a,b) nave r.es;ently ericouQtered tAis problem in acut~
-form .and engaged it 'articulately. A m~cb~ebated .
~ ,
G~rrent concept is that ~a (teore
cl6ck" of strongly rnt~racting cQ!TIponel1ts . earl ,?e äistfnguishep:.-fro~ · a ~alo ?
components less. esserttral for R1aintaining. at least some ,recognizably; cin;:a9Ian-like-
osdllations. The halo contains'peripheral' inptlts (wh ich are to some'extent affected by
the core) and physiol09i~al observables ·that the core cloc~ drives (whicry to so me
extent feed baek to reset the core). ~ L_._
'_'.._ ....
.

These feats are not beyond the capacities of modem biochemical physiology, but
they do require concerted effort focused on a single cello The day is at hand (in 1978)
when that effort will be made. From its origin in field naturalism and evolutionary
biology, and from its confusion with astrology and biorhythm fads, the exploration of
circadian rhythms has come a long way. Nowadays, even molecular biophysicists
have heard of the "dock" and believe that it might have some definite universal
 C: THE MULTIOSCILLATOR VI8N OF ClRCADIAN RHYTHMS 585

properties. As indicated above, I think that is amistake, if one means biochemical

properties. But the point is that we are now in a position to find out.

It is my belief not only that one organism should be chosen, but additionally that it
should be either a single cell or a cell population in wruch both autonomy of the
individualand synchrony among individuals can be monitored (a bigorder). Obviously
the dynamical behavior of a population of interacting oscillators can be quite different
from the behavior of one alone. This point was belabored in Chapters 4 and 8. We also
saw in those chapters that collective measures on a sufficiently incoherent population,
even of noninteracting oscillators, can be very misleading about the basic type of
dynamics underlying oscillation in each independent individual.

C: The Multioscillator View of Circadian Rhythms

Trus section is intended to gather indications that circadian rhythmicity may
typically reflect the collective circadian activity of many independently competent
sources, each oscillating at a circadian period with or without its neighbors. If this
be true, then we have two new sources of dynamic complexity to explore above and
beyond the behavior of the single oscillator:
1. The interactions among such physiological oscillators and
2. The manner in wruch their influences are pooled in a rhythm of activity, body
temperature, or what-have-you.
Moore-Ede et al. (1976) provide a useful brief statement of the problem. In
collecting the evidence, I omit two categories of information:
1. Experiments showing that single-cell unicellular organisms exhibit circadian
rhythms. Circadian rhythmicity does not require multicellular organization, but
the fact argues neither one way nor the other in the question as to whether
circadian rhythmicity is structurally and functionally composite in multicellular
organisms. Experiments with unicellular organisms might ultimately contribute
with a demonstration that behavior attributed to composite structure in
multicellular organisms is found only in multicellular organisms. (Trus would
not include "transients," because found by Dunlap et al. (1980) in unicellular
Gonyaulax.). But for the present, the most pertinent obseIVations involve
multicellular organisms and their isolated tissues.
2. Experiments showing that multicellular organisms have many rhythmic
activities that readjust toward the common new phase at diverse rates. In trus
respect a multicellular organism does comprise a population of transiently
separable rhythmic functions but such indications do not in themselves argue
for independently competent sources of rhythmicity.
I gather the evidence into two sets of experiments. The first set indicates that the
dock is structurally composite in multicellular organisms. The second set of
experiments indicates that it is functionally composite.
586 19: C1RCADIAN RHYTHMS IN GENERAL

That "The" Circadian Clock is Structurally Composite

We turn now to experiments indicating that there are separate circadian oscillators
physically distributed throughout the many organs and tissues of a multicellular
organism.
1. In mammals, the dearest demonstration comes from Andrews' (1971) discovery
that hamster adrenal glands, isolated in tissue culture, persist in distinct
circadian rhythmicity of endocrine secretion for many days in ostensibly
constant conditions. A similar effort by Tharpe and Folk (1965) to exhibit
circadian rhythmicity in rat heart and in isolated rat heart cells in tissue culture
produced only rather unconvincing evidence. Hardeland (1972, 1973) reported
dear-cut rhythmicity of enzyme activities in suspensions of isolated rat liver
ceIls, and Ashkenazi et al. (1975) have reported the like in stored human red
blood cells. No convincing results have yet (1978) come of attempts to repeat
these experiments in other laboratories .
... I found no further informätion about red bl'ood cefts, out a wide variety of
mammalian. tissue cultures now di~p'lay circa3ian rh)1hms in ce Is with nudei. ....;;
~_...-

2. Arechiga (1977) reported several experiments exhibiting circadian rhythmicity in

isolated ganglia, limbs, eye stalks, etc., of crustacea. Nishiitsutsujii-Uwo and
Pittendrigh (1968a,b), Page et al. (1977), and Page (1978) using cockroaches;
Konopka (1972) using genetically mosaic flies; Engelmann and Mack (1978) using
flies; and Koehler and Fleissner (1978) using beetles reported evidence of at least
two major circadian oscillators, physically distinct, in the individual insect.
3. Jacklet and Geronimo (1971) and Benson and Jacklet (1977) showed that each
eye of the mollusk Aplysia constitutes a self-sufficient circadian oscillation, as in
fact do isolated pieces of the retina. Besides the two eyes, at least one other
structure, the parietovisceral ganglion, has its own circadian dock (Strumwas-
ser, 1974; Lickey et al., 1976; Page and Block, 1980).
4. For a long time it has been realized that the individual leaves of plants are
capable of circadian rhythmicity independent of the rest of the plant; the same
is true of flower petals (Bunning, 1973). Simon et al. (1976a, b), exploring the
causes of the leaf moment rhythms typical of many plants, showed the
oscillation to be self-sufficient in isolated pulvini of Samanea. Wilkins and
Holowinsky (1965) reported circadian rhythms of respiration in cultured bits
of callus tissues taken from the succulent. plant Bryophyllum. Mergenhagen
and Schweiger (1975) found circadian rhythms of photosynthetic activity in
fragments of a single cell of Acetabularia.
5. Circadian rhythmicity persists in pieces of diverse fungi.

... sy 1999 such result5 ..have become commonp ace. Welsh e a. (1995), and Uu ,et l.
(1997) confirmed that individual neurons of the roeent SeN are autOrlomous docks (at
least wnen in tissue culture) arid PI~utl et al. (1997)·a(ld Hege et al. (1997) identtfied
cellular -docks (without: isolating the cells form one- ano!her) in di'(erse Drosophila
tissues,. as djd Whitmore e~ al. (2000) in the zebrafisR •.The hext interesting questions
concem dynamical in~er9ctions a ong ~any docksjn one tissu anq in p e organisrT). ~..
 C: THE MULTIOSCILLATOR VIEW OF ClRCADIAN RHYTHMS 587

That "The" Circadian Clock Is Functionally Composite

Next, we examine the most convincing cases presently available that circadian
docks are functionally composite in multicellular organisms.
1. In plants, as noted above, individualleaves and petals maintain rhythmicity on
locally altered schedules, even when not physically separated from the rest of
the plant. Mayer and Sadleder (1972) found the primary and secondary pulvini
of legumes to function with different circadian periods.
2. The several docks of Aplysia show no indication of mutual coupling, so far.
In cases 3 through 7 to follow, only two components have been observed.
3. In insects, birds, and mammals, there are numerous indications that circadian
docks originate in nerve tissue. The bilateral symmetry of these organisms
suggests two physical docks. Can they function independently? The lasting
alteration of future resetting behavior that accompanies phase resetting in flies'
edosion rhythms (Chapter 7) can be accounted for in quantitative detail in
terms of:
a. Two independent attracting-cyde oscillators, possibly located in the left and
right sides of the brain (Winfree, unpublished computations, 1974) or
b. A population of many docks, in this case not necessarily with attracting
cydes (Winfree, 1975b, 1976) or
c. Two coupled attracting-cyde oscillators of the sort envisioned by Pavlidis
(1976).
Koehler and Fleissner (1978) show functional dissociation of left-right docks in
insects. In bees, Medugorac and Lindauer (1967) and Beier et al. (1968) report
experiments suggesting bimodal dock activity, possibly originating in experimental
desynchronization of two docks. See also Block and Page (1980).
In cases 4 to 7 to follow, the two oscillators are not imagined to be equivalent as
above but are thought to have quite different properties.
4. Salisbury and Denney (1971), King (1975), and Bollig (1977) point to different
docks regulating leaf movement and flowering in three kinds of weed.
5. Engelmann and Mack (1978) report that two docks of 6% different period
oscillate simultaneously in Drosophila pupae: One govems edosion and the
other govems the rhythm of adult activity.
6. Pittendrigh (1960, Figure 12) was the first to report a peculiar splitting of
daily activity rhythms in rodents, which has since become a fruitful subject of
investigation not only in rodent species (Pittendrigh, 1967b, Figures 1-4; Daan
et al., 1975; Pittendrigh and Daan, 1976c; Rusak, 1977) but also in other
vertebrates (Hoffmann, 1969, Figure 3, 1971b, Figure 4 in the tree shrew;
Gwinner 1974 in birds; Underwood, 1977 in lizards). In the latter case, the
demonstration is particularly spectacular: Two components of the activity
rhythm run through each other without synchronizing, just as they do in
Koehler and Fleissner's beetle.
7. Wever (1975), Aschoff and Wever (1976), Sulzman et al. (1977), and Wever
(1979) argued that there are two oscillators of quite different period in man and
other primates, one predominantly affecting the activity rhythm and one
588 19: ORCADIAN RHYTHMS IN GENERAL

predominantly affecting the body temperature rhythm. The two have been
induced to scan through each other repeatedly:
the human circadian system consists of a multiplicity of oscillators that are usually
coupled to each other hut [which] may change their phase relationship depending on
conditions, and if they ever hecame desynchronized, free-running with different
frequencies ... The rhythms of activity and of temperature are both influenced hy two
different classes of self-sustaining oscillators, hut to different extents.
Aschoff and Wever, 1976
Note that the experimental physiologists cited under 6 and 7 above all surmise
that the "two" oscillators observed might each consist of many interacting
oscillators, normally well-synchronized into clusters. (See suggestive rodent activity
records in Pittendrigh and Bruce, 1959, their Figure 7; DeCoursey, 1961, her Figures
3,9; Swade and Pittendrigh, 1967, their Figure 9; Morin et al., 1977a, her Figures 2
and 3.) Stimulated by such conjectures, I looked for similar behavior in a
deliberately contrived population of electrical oscillators (Winfree, 1965, 1967a,
and Chapter 11) and in computer simulations of better characterized oscillations. It
turned out that bath the coherence of each cluster and the splitting of a population
into two clusters with somewhat different properties can be understood in terms of
similar oscillators symmetrically coupled through a metabolic pool (Winfree, 1967a;
Daido 1995, 1996). Disaggregation into three or more clusters was also observed
from time to time. It is seen in rodent activity rhythms (e.g., Pittendrigh 1960,
Figure 12 and Rusak, 1977, Figures 2 and 5). Pavlidis (1971, 1973) also constructed
models of such phenomena.
The next section summarizes to the hest of my knowledge what little information
is presently available about interaction within aggregates of circadian clocks.

Interaction Among Circadian Oscillators

Cell Populations in a Shared Nutrient Medium. It is clear that in some cases
circadian oscillators do interact to maintain mutual synchronization. For example,
Page et al. (1977) found strong interactions between the left-and right-side clocks in
the brain of the cockroach. Synchrony is normally maintained within the enormous
cell of Acetabularia despite the fact that isolated pieces of the cell are capable of
sustained circadian rhythmicity (Mergenhagen and Schweiger, 1975). What about
populations of separate individual unicellular organisms, such as Acetabularia,
Gonyaulax, Paramecium, Tetrahymena, and Euglena? Rhythmicity in collections of
Acetabularia plants promptly decays as individuals drift out of synchrony and
Gonyaulax population glow rhythms damp as though cell periods differ by abaut 2%
(Njus et al. 1981), but in the other three populations it persists without conspicuous
damping for a long time in the absence of known external synchronizers. In
Euglena, it persists for months (Brinkmann, 1966, 1967; Terry and Edmunds, 1970;
Edmunds et al., 1971).
The latter cases could be accounted for in three ways:
1. The rhythm is actually driven by a covert periodic influence; but this seems
unlikely since the period seldom exactly matches the 24-hour period of the most
plausible candidates.
 C: THE MULTIOSCILLATOR VIEW OF ClRCADIAN RHYTHMS 589

2. The members of the population all have so nearly the same period that their
initial coherence persists without need of mutually synchronizing interactions
and without need of an extemal pacemaker. Njus (1975) and Njus et al., (1981)
estimate that in order to account for the continued narrowness of Gonyaulax's
daily glow peak without invoking synchronizing interactions, one must assume
a standard deviation of period not exceeding 1 to 4% (15 minutes to an hour).
(The higher figure represents a standard deviation of the period within each
cell of a population of statistically identical individuals; the lower figure
represents the standard deviation of period between cells of a population of
perfect oscillators.) This order of precision is not implausible. The circadian
docks of individual Drosophila pupae have periods that differ by only about
this much (Winfree, 1973a, Appendix). But it is hard to account in this way for
observations of undamped rhythmic settling or phototaxis in Euglena
populations over the course of months (Brinkmann, 1971).
3. The individual cells could interact in such a way as to maintain mutual
synchronization, as elaborated in the 1999 updates to Seetions B of Chapters 4
and 8, and Chapter 11. Suspensions of yeast cells maintain synchrony of
glycolytic oscillations by metabolie interactions (Chapter 12). Southeast Asian
fireflies maintain synchrony of flashing through the phase-shifting effect of a
light flash on each individual's flashing rhythm (Buck and Buck, 1976; Hanson,
1978). Individual cells of the heart's pacemaker achieve the same electrically
(Watanabe et al., 1967; Jongsma et al., 1975; Clay and DeHaan, 1979; Jongsma
et al., 1983; Michaels et al., 1987, 1990).
Empirically, one could test for such interactions among circadian docks in
three ways:
a. As in Aldridge and Pavlidis (1976), using yeast cell suspensions, one could
dilute the suspension in seareh of a threshold at which coherence is abruptly
lost, i.e., the collective rhythm suddenly begins to decay (see Chapter 12).
Such experiments have not been reported in circadian systems.
b. As in Ghosh et al. (1971), using yeast cell suspensions once again, one could
combine two populations of cells with different phases to see whether the
combined result is simply a superposition of the two populations mixed or
something different that might indicate interactions.
Nonsuperposition would prove interaction, though not necessarily of the kind
that favors mutual synchronization. If the observed rhythms were conspicu-
ously nonsinusoidal (e.g., aspike every 24 hours) then superposition might also
prove noninteraction. But, with smooth sinusoidal observables, as in the cited
cases, superposition is indistinguishable from aresetting of amplitude, an
interpretation that can be exduded only by showing that the circadian dock in
question adheres dosely to a standard cyde. Such few circadian rhythms as
have been examined in the required detail do not seem to adhere dosely to a
standard cyde (Drosophila, Chapter 20; and KD.lanchoe, Chapter 21).
c. Altematively, one could try phase-shifting a cell suspension by adding
supematant from a differently phased population. In this way an interaction
might be discovered. It would remain to be proven that such interaction
would result in stable mutual synchronization.
590 19: ClRCADIAN RHYTHMS IN GENERAL

Experiments of types b and c have been reported: Mergenhagen and Schweiger

(1974) using Acetabularia; Hastings and Sweeney (1958) using Gonyaulax;
Brinkmann (1966, 1967) and Edmunds (1971) and Edmunds et al. (1971) using
Euglena. In these trials exact superposition was not the usual result. But neither did
the combined rhythm indicate immediate synchronization by taking up the large
amplitude typical of a coherent population. Nor did addition of supernatant from
another phase (c) cause an obvious immediate phase shift. One can also calculate
(from the known dispersion of native periods and the magnitude of phase response
to light) that interaction through the glow rhythm would be orders of magnitude too
weak. What these experiments show is that there are no violent and immediate
mutually synchronizing interactions. More systematic and prolonged mixing
experiments are required to ask about gentle and slow-acting interactions.
It may also be noteworthy that these tests have been applied not to the somatic
cells of a multicellular organism, but to populations of anarchists, possibly not
selected for cooperation. Moreover the populations studied all consist of green cells,
necessarily exposed to the diurnal light-dark cyde in nature. Even if there were
some advantage in synchrony, one would. not necessarily expect selection for
mutually synchronizing interactions, as there is no functional requirement for them.
Support for this speculation comes from the leaves and petals of flowering plants,
which are indeed capable of independently phased circadian rhythmicity: Whatever
interactions may exist, they don't quickly induce synchrony. It might be that only
the cells of noctumal animals, cave fungi, the inner tissues of large animals etc. are
sufficiently isolated from the environmental day-night cyde to experience some
selective advantage in mutual synchronization. As noted above, Page et al. (1977)
and Block and Page (1980) found strong synchronizing interactions between the
two circadian pacemakers in the brain of a noctumal animal.
~, Despite ner9fc effOrts, ne story to ay is aoout .t e s~me 'in. ~nyau ax (Sulzman e
al., 1982; Hasti~gs...et al.,1985; Broda et al., ~986, ~ummarized in Win'free, 1986a pp.
111-14). All tl\es~ stra~ghtforwatd eXp'enments should I::fe retried with susp'ensions 0
cyanooacte~a, anä with suspensions- or plated ar'rd sYnClpticaHy connected cultures of
neurons from the :su'pf6chias/!latic. nu:~leLis, .
The· ~lT9US Netit~spora might seem a favorable intermediate ca se.. for detecting
,whateve,r interactions~ccur between srgmEtn~ of a hypha, or be.tween hyphae.
However, the only ,. experiments' condu,cted to date (Winfree and Tw&ddle, 1981)
prov€d lncondusive for seemingly irreiEwant tecbnical reasons (see ' ExampIe 10 j
C.hapt-ers 2 and 10). As dtearned in Winfre'e (1986a pp. 72-73' 19aZa pp. 27-9i see
also Chapter. 10 Example 8 above), another approach mighf be taken with the belp
oi a sufficient!y br~ad plant I~af. Miliar et al. (199.5) showed t~a Arabidopsis q3 ee
engineereq to " express luciferase 'or green fl~orescent : protein in step widi the
circadian dOCK. If"a sharpl detimited area ,of.leaf sIJrface coüld be ptrase sh;fted
using bl'u e' IightJ just a.s done with the fungus, ,then the ,Poundary might move or
be.come fuzzy in a evealing way, An imposed gradient of phase mrgh OI might no
tum into a pfopagat-ir9 pu'se 01 phasft shift. If it d~s, then ~he square.. of its speed
(possibly seve~1 cm/day?) provides an estitnati! of tne ratIo of diifusjoT'l coefficient
couRling' ceUs- (pre~umably 10-5 to 10.6 crn21sec) to l~e ~actlvation time of the
e
erop,agating event in th~ circadian de, which we might pe ab to measure in the
 C: THE MULTIOSCILLATOR VIEW OF C1RCADIAN RHYTHMS 591

range of 10 secon , s. Setter yet, a pinwtreel experiment executed on one leafs

surtace woul ,develop a rotor or not, a~cording to the presence or absef\ce of
late r.a I coupling between cells Aacoroing 10 the theorx of such things, a rotors size
but not ltS period of rotation depends on the strength of coupling (unless th~t be
zero or so smaH that the rotor dces not fit w~thin tra tissue boul)daries), so ~
noncircadian periop (pJ'esl.\mably a shorter period) would ·deci~ively betray coupling.
n theory, the rotors diameter would be, its· wavelengthhr and as an 'oscillator wjth
9="~/(ToD~0. 1 -1.0cm?) ~61r tnis shi?uld be around 1 cm~ _
IR" cells. t~~t GO not us~ ct)tp10q,r?me or what~ver to see the: light/dark cycle
dlrectJY, ne .mlgb 'suPRose- so!"e neur~11 or piochemicaJ mutual coupJjng· (maybe
sOfFethins like "Iasma-bame rneJatonin, cr tne:newer "pigment dispersing factor" of.
Renn ~t al., 2000, if not directnei9hbo~ G6~pling) is necessary to mediate mutual
syn~t:lr'onization. Sut 1 some spades" environrnental temperature cydes might serve
.the sarDe purpose iCl preference to. t1!!)htldark, as for example: jl} Neurospora llu et
at. (1998) tr)a~e the iptf'igwing sugg~stion "'that tile, ,J -4°'(. rhythm of h.Um~m·~cQre
ody temperature me9iat~ systemic 'entrai~ment of all tissue- docks '"to the
n otlialamic the ostat ..

Mutual Entrainment vs. Mutual Synchronization. It seems widely assumed that

if rhythmic interactions occur between circadian oscillators, then, supposing only
that the coupling is strong enough relative to the dispersion of periods in the
population, mutual synchronization is the natural outcome. It is crucial to
distinguish here between mutual entrainrnent, which only implies phase locking
at a common frequency, and mutual synchronization, which means that,
additionally, the phases are all nearly the same. Mutual entrainrnent is commonly
achieved between two similar oscillators, given strong enough coupling. Surpris-
ingly, tbis was found not to be the case in a study of idealized oscillator populations
(of more than two) by electronic experiments, mathematical analysis, and computer
simulation (Winfree, 1967a). It was found that mutual interactions can either
contribute to mutual synchronization or oppose it, depending on phase relations
between each cell's rhythm of mutual influence and each cell's rhythm of sensitivity
to that influence (see Chapter 4, Section B; Chapter 8, Section B; and Chapter 14,
Section B). The reason is basically that although mutual entrainment is commonly
found between similar coupled oscillators, it does not usually consist of mutual
synchronization. The mutually entrained oscillators may, e.g., be 180 out of phase.
0

In a population, mutual entrainrnent is more difficult to arrange without mutual

synchronization because the entraining rhythm feit by each oscillator, being a sum
over all the others, is weaker to the extent that synchronization is imperfect (unless
there is only one other). Thus, interacting mutants might be selected both in
situations requiring mutual synchrony, and in situations such as Richter (1965)
suggests might require collective arrhythmicity of individually rhythmic units.
 The Circadian Clocks of Insect Eclosion

... indeed what reason may not go to Schoole to the wisdome of Bees, Aunts,
and Spiders? what wise hand teacheth them to doe what reason cannot teaeh
us? ruder heads stand amazed at those prodigious pieces of nature, Whales,
Elephants, Dromidaries and Camels; these I eonfesse, are the Colossus and
Majestiek pieces of her hand; hut in these narrow Engines there is more eurious
Mathematicks, and the civilitie of these littIe Citizens more neatly sets forth the
wisedome of their Maker.
Sir Thomas Browne, physician, regular correspondent of Henry Power

Understanding the circadian timing of eelosion in insects is a pretty big

undertaking. A lot of teehnical detail is essential and a lot of elose reasoning from
meticulous experiments stands in the place of direct observations on the "dock's"
unknown physiological mechanism. In that respect clockology has some of the
intelleetual delight of the earlier years of genetics. However, (as of the 1978 writing)
the whole argument has never been spelled out for publication in one plaee. This
ehapter onee again attempts only an outline of the essentials. The story presented
here seems to he generally valid for butterflies and moths, flies and mosquitoes,
wasps and bees (Le., Lepidoptera, Diptera, and Hymenoptera), hut I emphasize my
own experimental beast, the fruitfly. For a review of insect edosion systems from
the viewpoint of physiology and ecology, see Remmert (1962).

A: Basics of Insect Eclosion Clocks

The Life Cycle
An insect starts as a fertilized egg. Within the egg, development culminates in the
emergence of a larva (caterpillar, maggot, "worm"). The larva eats by burrowing
through semisolid food until it attains suitable maturity. At this point, feeding
stops and the animal sheds and hardens its outer cuticle, now called the pupal
case. Then the next miracle begins: construetion of the adult by metamorphosis.
Prior to the pervasive transformations that metamorphosis comprises, the organs
of an adult lie among the larva's organs as rudimentary hag-like sheets of
undifferentiated cells. These are called imaginal disks. Most of the larva's organs
dissolve during metamorphosis. The materials thus made available are used as
nutrients by the growing imaginal disks. Some larval organs do survive into the

A. T. Winfree, The Geometry of Biological Time 592

© Springer Science+Business Media New York 2001
 A: BASICS OF INSECT ECLOSION CLOCKS 593

adult though they undertake extensive remodeling. Examples indude the brain
and the insect's equivalent of a kidney, the Malphigian tubules. 1 It is to these few
that we must look for an understanding of the timer that schedules, well in
advance of metamorphosis, the hour at which the winged adult will emerge from
the former worm's coffin, the pupal case. This opening of the pupal case, called
edosion, happens all of a sudden at the appointed hour. This is a time of great
vulnerability and conspicuousness for the young adult, so it is all gotten over with
as quickly as possible. The wings are hardened, the cutide tanned, and the adult is
ready to go within the hour. Mating and fertilization normally follow an eight-
hour fast. The life cyde is then complete.
The gating of pupal edosion time has been used to experimentally study
circadian dock resetting in the cotton bollworm, Pectinophora (Pittendrigh and
Minis, 1971); the silkworm moths Antheraea, Hyalophora, and Cecropia (Truman,
1971, 1972); the fruitflies Drosophila pseudoobscura and melanogaster (Skopik and
Pittendrigh, 1967; and references throughout this chapter); the mosquito, Anopheles
(Reiter and Iones, 1975); the midge, Clunio (Neumann, 1978); the Queensland
fruitfly, Dacus (Bateman, 1955); and the fleshfly, Sarcophaga (Saunders, 1976b). For
a review, see Saunders (1976). Most of what follows is about flies.

Clock Physiology and Development

Every line of evidence today suggests that the insect's edosion dock is in its brain
(Saunders, 1976):
1. The dOCKS photosensitivity, in flies and in moths, is at the head end, specifically
in the brain.
2. Behavioral mutations affect the circadian rhythm of adult activity if and only if
(in genetic mosaic flies) the brain tissue has the mutant genotype.
3. In moths, transplanting the brain is equivalent to transplanting the eclosion
schedule.
The circadian dock that ultimately governs eclosion timing already exists
when the egg hatches. In fact Minis and Pittendrigh (1968) in an elegant series of
experiments showed that it exists in the egg prior to its acquiring the sensitivity
to light by which its phase is normally determined. They achieved this in the
moth Pectinophora gossypiella by using a single temperature pulse to induce
rhythmicity in otherwise arrhythmie populations reared in constant conditions.
But even so nonspecific a stimulus as a temperature pulse failed to "set the dock
in motion" in eggs fertilized less than 5! days earlier: Evidently the dock had not
594 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

yet fonned. In the fruitfly Dacus, according to Bateman (1955), there is no

arrhythmic stage: Larvae inherit the phase of their mother's dock. Brett (1955)
and later Zimmennan (1969, 1971) showed that in Drosophila the dock persists in a
regular cyde, from the youngest larvae straight through metamorphosis, once it is
started by terminating an exposure to visible light. Remarkable as it may seem, the
circadian dock appears to evade any substantial involvement in the developmental
revolutions taking place all around it, at least up to the last few days before the adult
emerges. It might have been expected that dock properties would change with
developmental age, but to an excellent first approximation this seems not the case
during larval and pupal stages in Drosophila. (In Sarcophaga photosensitivity
changes with age: Saunders 1976, 1978). It might also have been reasonably
anticipated (and it was: Harker, 1958; Skopik and Pittendrigh, 1967) that the dock
that govems the nominal termination of metamorphosis would also regulate the
timing of intennediate steps. It came as a disappointment (especially to me, having
switched universities in the middle of graduate study in order to explore
developmental regulation by circadian docks) to find that this is not the case in
Drosophila (Pittendrigh and Skopik, 1970). This circadian dock seems less a
synchronizer of developmental and epigenetic dynamics than a behavioral device
seated in the nervous system.

Behavioral Output
Pupating insects are a great convenience for laboratory investigations. The pupal
case encloses a self-contained '1ife capsule" requiring only oxygen (and not much of
that) from outside. The animals are weIl protected in their life capsules and can be
handled almost as casually as so many rice grains. They do not move around, so cages
are dispensable. They don't need food and water, and accordingly extrude no excreta.
Best of all, the life capsule contains within it all the instrumentation required to assay
the phase of the circadian dock within, covertly marking time in cycles of 24 hours .

.. It is hard to find a unique idea, extept by, avoiding i5raries: Fourteef1 years betore
this notion ratiqnalize<;l the Qbserved timing- of pupal edosion in relation "to both
developmental age' and circaqian phase r Fraps (1954) had aPf,?lied ,it to o""ulation '~n
birds... - . .
. ... -- -
I ,
""
_-

My belief is that it works like this. Each animal's developmental readiness to

emerge increases continually with its age during metamorphosis. At some point, let's
say when readiness reaches some threshold, the honnones are released which trigger
edosion. Suppose the threshold fluctuates diumally. As Figure 1 suggests, individuals
starting their dimb to maturity as fertilized eggs at different times would then acquire
threshold maturity in bunches 24 hours apart. These bunches constitute the train of
discrete packets, or edosion peaks, typically seen in populations of mixed age (Figure
2). Other things equal, the phase of this edosion rhythm is taken to indicate the phase
of this putative threshold rhythm, itself driven by the underlying photosensitive dock.
This may be indirect, but there you have it.
In contrast, with a constant threshold, each individual would acquire threshold
maturity a fixed time after fertilization, and the edosion distribution would
 A: BASICS OF INSECT ECLOSION CLOCKS 595

MATURITY
/- 24tv:-!

TlME

Figur. 1. The timing of eclosion peaks in a mixed-age population betrays the phase of an
oscillation here imagined to determine a f1uctuating threshold of developmental maturity at
whieh the f1y elects to step forth and be eounted. Pupae starting metamorphosis at various
times during the darkened interval at the left side on the time axis first eneounter threshold
along the darkened are and so eonstitute the darkened eclosion peak. Their younger and older
siblings fall into diseretely separated peaks unless the threshold rhythm's slope is everywhere
shallower than the eurve of maturation (here plotted as a straight line without 1055 of generality).

therefore exactly parallel the age distribution. This is in fact what happens in pupae
whose docks are suppressed by continuous light (Skopik and Pittendrigh, 1967) or
otherwise induced to fluctuate much less conspicuously (see Box A).

FLIES
1000 PER
HOUR

500

o 216

Figur. 2. Summation of over 100 unperturbed control experiments eollected from 1968
through 1976. Eaeh recorded the number of flies emerging hourly after pupae were taken from
prior continuous light into everlasting darkness. We are eoneemed with peak timing
(horizontally in multiples of 24 hours), not with the number of flies emerging in eaeh peak.
596 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

There are two important facts to note about this diagram in present context:
A. The size of an edosion peak is determined entirely by the age distribution. All
pupae starting in the shaded range of the time axis emerge as adults in the shaded
edosion peak. The size of an edosion peak has occasionally been confused as
some measure of the "amplitude" of the circadian oscillation. But this is quite a
different matter, as elaborated in Chapter 7. Only the timing of peaks, not their
size, is determined by the phase and amplitude of the threshold rhythm.
B. The putative threshold rhythm must not be confused with "the waveform of the
circadian oscillator," on at least two accounts:
1. The very notion of the waveform is ill defined and, 1 think, more nearly a
troublesome fiction than helpful concept.
2. The edosion peaks are not always regularly spaced along the time axis
immediately after a phase-resetting stimulus. It would appear that edosion is
determined not directly and immediately by the reset dock, but by some
physiological rhythm indirectly driven by a more nearly periodic dock, and that
this rhythm (the B oscillator of Pittendrigh and Bruce, 1957, or the threshold
rhythm of Figure 2) catches up to dock phase only after a few days of transient
irregularities.
The interpretation of transients is presently a weak link in this whole story, but
potentially a veryimportant one. After all, the organism's behavior in nature is
probably little more than a continual renewal of transients. Only in the laboratory
does physiology continue in a perfectly periodic way. The character of the transient
irregularities varies a lot from one lab to the next (Pittendrigh and Minis, 1964;
Engelmann, 1969; Chandrashekaran and Loher, 1969b; Winfree and Gordon, 1977).
Accordingly all measurements of phase reported in this volume are conducted at
least three days after the last change in the environment that might have any effect
on the circadian dock, so that transients are over, by the criterion that emergence
peaks recur at regular intervals of approximately 24 hours.

A Rhythm of Responsiveness to Stimuli

In the insect edosion systems described in this chapter, rhythmicity is initiated
by transfer from constant light into constant darkness. One's first impression is
that something periodic has been disinhibited. Further investigation reveals that
it is even more exactly periodic than it looks in that variations in peak size
merely indicate population size in successive one-day age dasses, and transient
variations in the intervals between peaks dissipate within a few days after a
disturbance.
Using this rhythm of edosion gating in a slightly more involved experiment,
one can monitor a second rhythm, a rhythm of rephasing. This is done by
interrupting the dark with a single pulse of light and then monitoring the phase
of the poststimulus train of edosion peaks relative to the prestimulus rhythrn.
This phase depends on the phase at which the light pulse was given. This
rhythm of sensitivity has been much studied. It reveals, among other things,
that the oscillation initiated by the light-to-dark transfer is less strictly periodic
than appears from watching edosion timing alone. By examining not only the
 A: BASICS OF INSECT ECLOSION CLOCKS 597

Box A: Rhythmic Gating and Arrhythmicity

Figure 1 presents one vision of how a smooth rhythm can determine the timing of a
discrete event. In a population of organisms starting development at tirnes strewn
continuously along the time axis, this vision provides a way to think about "gating" of
behavioral events. If the rhythmic variation in the threshold has sufficient amplitude,
then during part of each cyde the threshold is rising faster than developmental
readiness can catch up. The result is a complete absence of events at rhythmic intetvals.
All events occur in discrete peaks of activity with more mature animals arriving first at
each gate.
This diagram is only an art form, with little scientific substance. However, one could
play a game of taking it seriously by asking how event timing, thus understood, would
be affected by a change in the amplitude of the threshold oscillation, or of the rate of
development. Amplitude in Drosophila's circadian dock can apparendy be reset stably
by a suitably timed light pulse and perhaps by rearing in continuous dim light of
suitable intensity. And the rate of development can be increased or decreased by
adjusting the temperature without affecting the dock's period.
Suppose that development were speeded up or the dock's amplitude were so reduced
that threshold no longer rises faster than developmental readiness (Figure a). Then
events would occur at a1l times, no longer bunched into discrete packets. This abrupt
running-together of peaks as a critical amplitude or developmental rate is reached
might provide an interpretation for the arrhythmicity obsetved in edosion experiments
when the dock is in some way inhibited or suppressed.
Suppose the developmental rate were such that the rising readiness crossed
threshold several times (Figure b). Suppose edosion were temporarily inhibited during
the first crossing (e.g., by exposing pupae to ~% chloroform vapor). The diagram says
edosion would again be possible at certain times (where the readiness CUIVe remains in
the unshaded region above the threshold) but not at other times (where it is below
threshold). This implication could be tested.
Suppose one were to work with single animals of known developmental age.
According to these figures, the age of eclosion t is given as a function of the dock's
amplitude A and its phase 4> extrapolated to some standard reference age. Edosion time
would be determined by the solution of an equation qualitatively similar to
t = Asin(4) - t),
The graph of such solutions is a surface in three dimensions: a plot of age t at eclosion
above the (phase, amplitude) plane or, equivalendy, above the (T, M) plane describing
the light pulse used to set 4> and A (Figure c). The surface turns out to be built around
the infamous "cusp catastrophe" (Zeeman, 1977).
1t turns out that a considerable diversity of dynamic models for dock mechanisms
and their interactions with behavioral timing can be reduced to pictures of this sort. So
it might be worthwhile to find out whether we have here some general rules for the
qualitative behavior of rhythmically controlled events .

• This simple notion as $in.ce ounCl P er Joles to p ay in physib ogical dyriamics.

Scharstein (1979) argue that a slmllar princip1e mOst gavem the fiti"g of a pacemakE!r
neurorl'Subjected to sinusoid I input, and Petrfllo and Glass (191l4) deploy such pictureSi in
botb cases with bot" OppE!f and loWer threshalds lTlodulated . to interpret th.e
nchronization of breathin b a ecnanical re 'rator. The functional cfEjpe",dence of
598 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

(a) With hastened maturation or attenuated circadian rhythmicity of threshold (relative to Figure 1),
some pupae reach threshold at every hour. Eclosion peaks abruptly broaden and fuse at this point.
(b) With development sufficiently slowed down, each pupa crosses repeatedly above threshold
and back under. The darkened intervals might be detectable. (c) Apolar coordinate contour map
of age at eclosion (level contours of tin the equation below) as a function of the threshold rhythm's
amplitude A (relative to rate of maturation) and its phase fjJ at any chosen reference age (or age at
phase zero). Note the region around fjJ = 0 at A-1 where the surface folds into three layers,
representing the three possible intersections in Figure 1. The edges of this cups are involutes of
the unit circle. At any amplitude A > 1 the age at eclosion changes abruptly at this critical value of
"age at phase zero," cleaving a mixed-age population into discrete peaks.

rhythm of edosion after a delicate light pulse, but also the rhythm of sensitivity,
it has been found (see Chapter 7) that in the first 16 hours the dock deviates
from exact periodism quite conspicuously in a systematic way. The circadian
dock in D. pseudoobscura, released from inhibition under continuous bright
 A: BASICS OF INSECT ECLOSION CLOCKS 599

light, does not enter into strictly periodic motion from an initial state that
recurs at 24-hour inteIVals. It seems to approach a more strictly repetitious
behavior after one or two cycles in the dark, or after one or two cycles of an
entraining light cycle.
Thus we have now two independent aspects of transient deviations from
periodism (see Figure 3):
1. Periodism is irregular along the vertical time axis in each experiment for two or
three days before inteIVals between eclosion peaks revert to 24 hours. These are
the old transients, believed to reflect peripheral physiology mediating the clock's
control of eclosion (see Pittendrigh et al., 1958, and Kaus, 1976).
2. Periodism is irregular along the horizontal time axis in aseries of experiments
for about one day while the freshly started oscillator settles down to regular
cycling. These are the new transients, distinct from the above and from any
possible transient changes in photoreceptor sensitivity (because this effect is
obseIVed even with saturating exposures).
Developmental changes would constitute a third and distinct kind of transient,
distinguishable as an age-dependent changing of Figure 3. In studying experiments
that deviate systematically from repetitiousness, one must take care about inference
on the basis of the "circular logic" of Chapter 1, which is appropriate only to strictly
periodic systems.

Flgure 3. Two kinds of transients, portrayed in the

format of Figures 31 through 33 of Chapter 1. (a)
Transients in the source of rhythmicity, e.g., gradual
increase of amplitude after startup. (b) Transients in
peripheral mechanisms causally downstream from the
source of rhythmicity. Such rhythmically driven mechan-
isms commonly require a few cycles to entrain stably to
the recently started or reset source of rhythmicity.

~
(0 ) (b)

Input to the Clock: Light

So much for the output side of the dock. Since our experiments consist of varying the
light intensity, it is also necessary to dweIl brieflyon the peculiarities of the input side.
The circadian dock in birds and mammals takes its cues in part from sensory
systems that entail a lot of central neural processing, e.g., hearing, vision, and social
interactions. In "lower" organisms, we find only more primitive sensory transduc-
tion. For example, the severe impact of sudden temperature changes on dock
600 20: THE ORCADIAN CLOCKS OF INSECT ECLOSION

kinetics encountered in the fruitfly Drosophila (Winfree, 1972a) and in the

breadrnold Neurospora (Francis and Sargent, 1979) is presumably mediated by a
temperature-dependence of membranes and reactions involved. There seems no
reason to imagine a specialized thermo-receptor. Slower temperature changes are
buffered out (see Section A of Chapter 19) .
... In Uu et al. (1998) this i~ elaborated for Neurospora along the lines 0 Pe erson's
(1981) analysis of phase-re setting by step changes of dlm light resetting Drosophi/ats
dock. 'iIIII ' •

Is the response to visible light this primitive? The visual nervous system is
involved in some organisms.

But this is not usual in the invertebrates. 1 know no persuasive evidence that
dock photosensitivity in invertebrates attaches to any selectively specialized
structures or pigments, nor that the absorbing substance is involved in whatever
causalloop runs the oscillating mechanism .

... Persuasive,ev;aence is rapiClly accumUlating CryptQcnrome in rosop lIa (Emery et

al., 1998, 2000) may or may not be part of tne indispensable cJock mechanism (the
answer· possibly differing from one cell type t9 ahotner) but it appears to be a
selectlvely specialized pIgment, and in fUngi and in 'green plants the photoreceptor
probab./y is part of the c\ock's cyding m,echanism. It definltely ;s in mar'nmals
(Miyamoto anq Sancar1.1998· Kume--et al., 1999.). ..

In fact, there are some reasons to think otherwise; e.g., some circadian docks
seem to lack photosensitivity altogether (Tweedy, 1970; Saunders, 1976a) and one
doesn't know about deep sea life. Other hints in this direction come from detailed
study of dock photosensitivity in the fruitfly D. pseudoobscura:
1. It doesn't take much light to rephase. My standard light source provides 0.1 W/
m 2 (four orders of magnitude below sunlight) near 450 nm. This is 4 x 10 - 7
Einsteins/m2/s = 400 nElm2 /s (Einstein = moles of photons.) Multiplying by the
maximum conceivable absorption cross-section (2.3 x lOs Vmole-cm = 2.3 x
104 m 2/mole as in rhodopsin, chlorophyll, phytochrome) we find that 1% ofthe
molecules, at the ver)' most (and probably 1000-fold less: see item 3 just below),
absorb a photon each second (Winfree 1973e, p. 173). But in only several
seconds, far less than the minimum expected waiting time for any given
molecule to absorb a photon, the phase response saturates in dark adapted
pupae. Evidently, then, the phase response does not saturate for want of any
surviving excitable or photolabile molecules; the vast majority of them don't
even know the light is on before the phase response is saturated, and continued
exposure, though it must result in more absorptions, does little more to dock
phase in larvae.
 A: BASICS OF INSECT ECLOSION CLOCKS 601

While this obselVation might be compatible with the notion that the
photoreceptor is itself a rhythmically fluctuating component of the dock
mechanism, it is not compatible with the implication sometimes invoked, Le.,
that phase shifting is accomplished directly by substantially changing the amount
of that substance. (However, many other circadian rhythms are far less
photosensitive. )

~ In 1999 tnis means t at tne Ight~induced degradation of tiM protern must oe ;

accomplished indlrectly, perhaps b,y a photore.ceptpr organized to trigger a chemical
avalanche when only a lew percent of its CRY molecules absorbphotons. Or lt might
mean that thefa are orders of magnitude more CRY molecules thah TIM, 'so that
photoactivation of a 5ma!! percentage of CRY· molecules, it they can' retain that
act!vation during diffusion to frnd a TIM molecule, suffices to bind most of TIM (or In '
mammals, rather PER; It might even be that CRY also binds PER in Drosophila, as
h1n~ed by p~r mutation grea~y changing the fly clock's photQsensitivity: item 2
below). As merely guessed KI Wfnfree (1-986 p. 142), hard facts now il'ldici:!te that in
some spedes, ~,g., Neurospora, the photorecepto( itself is·under circadlan contr6l,.so

0'
In the sense of int.egratioo into the cause-effect loop (e~cept during dar/mess) the
pbotorecepto is a part the dock mechanism in such seecies. In the mouse SCN
and in some (but not aU) brain cells of Drosopnila the dock does not work even in the
dark without an intact photo'receptor. . ," •. "
In the mouse, the l5are threshold for phase shifting Is about 3 X 1013 photons/cm 2
and .the response satlJrates with a thoosand tinies1hat dosage (Shlgeyöshi et al., ,1 997t
For comparison, one second of the ,100. erg/cm21.sec =. 10.5 W/crn 2 blue ligh(used
throughout this book ~~j( iiliove thre$old f~I dark adapted DrosopFlfIcf pseudDobs~
ct1ra pu ae) de]ivers 2.5 X 1013 photonslcm2: and saturatiol1lies about a hund~d-fold
beyon . A single laleral neuron 5- fJ. in dlamete'r'.would be penetrated by about 5.x 106
photons. at most, and must centain :clt-least- 1Gq c'Yptpchrome mo ecüles, or more ·
Jikely a thousand times more, jn or er to secbre- a single activation. This is.at least 2.5
nM concentration, or more Hkely 2.5 fJ.M. ActuaUy, for. substantlal resetling a
substantial fradion of the cytoplasmic TIM-PER heterodimers in a substantial fraction
of dock cells must eadt encounter an activated photoreceptor, according to current
understanding"Cf the mechanisr,n, We do not know how many TIM·PER there are per
cell (thousands?), büt it might someday be estiil1ated, from qUqntitative irpmuno-"
fluorescehce- in the single cell' (not yet technical/yfeasible1 Fitlding out tbe actual
CJYP~cnrol)]e concentration might now be feasible, as' its presumably deep orange
color tnust mark its column {r.action. If CRY's abundance does not exceed TIM's by 102
to 105 then we are about to leam somethi unex/?Eicted·... ,_'__ _

2. In D. pseudoobscura (but, curiously, not in the per mutant of D. melanogaster:

Winfree and Gordon, 1977) I was surprised to discover that prolonged
illumination reduces the dock's photosensitivity during its next cyde by 10- to
20-fold. Subsequent dark adaptation takes days and is reversible by light that
sums not to affect the clock. This suggests to me bleaching of a photoreceptor
that is not necessarily apart of the oscillating mechanism. I believe this
possibility was first suggested in a mathematical model by Pavlidis (1967b) and
602 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

in context of fruitfly experiments by Chandrashekaran and Loher (1969b).

Similar "dark adaptation" has since been found in diverse species, e.g., in
Gonyaulax (Christianson and Sweeney, 1973); in Kalanchoe (Engelmann et al.,
1978); in Neurospora (Dharmananda, 1980); in Chaoborus (Bradshaw, 1972)
and in Culex (Beach and Craig, 1979; Peterson and Jones, 1979; Peterson,
1980a).

.. In Drosophila me1anogaster this eff'ect seems to e mediated y cryptocnrome,

which Emery et al. (1998, Figure 6e, bottom panel) showed to inerease dramatically in
a monotone way during the tirst day in darkness, and to substantially disappear durihg
prolonged exposure to bright Irght. Winfree and Gordon (19.77) observed that
melanogaster's per mutant does not show the dark adaptation diseovered in wildtype
Drosophila pseodoobscura pupae (Winfree, 1972b,e) but I ~ believe no one has yet
eheeked the witdtype mf!lanogaster). ..

However, in Sarcophaga (Saunders, 1978) and in Pharbitis (Bollig, 1975)

photosensitivity decreases after transition from constant light into constant
darkness. In this connection, note that Chandrashekaran and Engelmann (1973)
suggested a correction on Winfree (1972b,e). Maybe dark adaptation occurs not
smoothly but by stages at each successive T* of the dock. Another possibility is
that the dock is spiraling inward to a lower-amplitude orbit (conjecture 8 of
Winfree 1972e; Peterson and Jones 1979; Peterson, 1980a,b; Dharmananda,
1980) .

.. In 1999, f think there has been little progress towar exe uSlon"O any of these
conjectures, though Emery's discovery ofsmoothly ihcreasing qyptochrome con-
centration riifght favor the original intemretation, at least in flies ...

3. Even at the wavelength of greatest effectiveness (Frank and Zimmennan,

1969; Klemm and Ninnemann, 1976) 104 J/m 2 (J for Joule = watt-second)
is required for the "bleaching" in D. pseudoobscura (Winfree, 1972e). Given
a photoreceptor with absorption cross-section comparable to rhodopsin or
chlorophyll or phytochrome, that much light would hit each molecule
1,000 times on the average. It may be that only a rare hit pennanendy
bleaches the molecule. But if bleaching is the usual concomitant of
absorbing a single photon (as in rhodopsin, chlorophyll, and phytochrome),
then the molecule's absorption cross-section or extinction coefficient at the
optimum wavelength falls a thousandfold below that of good biological
photoreceptors, discounted by whatever attenuation factor the overlying
opaque tissues might provide. This is scarcely above the range typical of
colorless organic molecules, a fact compatible with the failure of many
attempts to see and isolate a dock pigment. This suggests to me that the
extreme sensitivity of some circadian docks to visible light is due less to
efficient photon capture per mole of photoreceptor than to the abundance
of such molecules relative to dock molecules and the extreme specificity
of impact of the rare excited photoreceptor molecule in the dock
mechanism.
 A: BASICS OF INSECT ECLOSION CLOCKS 603

4. (As of 1978) I know of no condusive studies establishing whether a circadian

dock has "a" photoreceptor pigment, Le., is color blind, having only a single
color receptor. Altematively (as in the case of temperature sensitivity), the
oscillator might be affected in different ways through a variety of not-quite-
colorless molecules. Bunning and Joerrens (1960) suggested as much about
an insect. There are stronger indications of this in plants. The action
spectrum for rephasing in some plants seems to depend on the phase at
which it is measured, i.e., the resetting curve shape depends on the color of
light used (Bunning and Moser, 1966; Halaban, 1969; Schrempf, 1975). In
other words, the clock in plants has color vision. Frank and Zimmerman
(1969) specifically tested for this possibility in D. pseudoobscura and found
no indication of a phase-dependent action spectrum. However, their test was
not delicate, comparing photoresponses at phases separated by only two
hours. Moreover, their measurements (and those of Klemm and Ninneman,
1976) used pupae whose photosensitivity would have been an order of
magnitude greater had they been exposed a day later; this increase might
reflect the appearance of a second pigment. (In this connection see Winfree,
1975c, capping Zimmerman's prior disqualification of Drosophila's rhodopsin
alone.)
Do action spectra provide an efficient inroad to the dock's molecular
mechanism if the photoreceptor only affects the dock while illuminated, but isn't
part of the mechanism in the sense of affecting and being affected even in the dark?
Or if the action spectru.m is compounded of more than one absorption spectru.m? I
think not.
The circadian dock in most insects functions differently while exposed to
sudden changes of temperature andlor to light, even quite dim light, of a suitable
color. In no case has the photoreceptor been identified.

~ ,knote, • in up~ated material abov,e, Drosophila's doc photoreceptor, or at least a

sec;ond p.potoreGeptQr lOrlg suspected to supplement, rhodopsin, has been identified:
Eme\)' et ar. (1998( 2000) and 'Star.tewsky et al. t1998), following Miyamoto and Sancar
-(19f}8)~iq the mouse, came up ~jth tf1e flavoprot.ein cfyptochromE!, a resl:llt that would
haVe gratined CoHn Pittendrigb (1966p; deceased 1996). Cryptochromein the mouse,
hO,wever., seems (lot just an input chaMel for: Ugbt effects, bot more fundarnentally
involved: in its abs~[\ce he:: dock doesn'f work: . The homologous WC-2 in
}:Jeurospora (<::rostnwAite et a\" 19.97) ~ay also be esse tiaJ; and Kuooe et al. {1999)
sugge.st tPat tne sarne may be true of CRY in DrO"sophira, but co~patible with the
inference ofWinfree {1.972b,e att1986 p. 142) from pJJpal etJosion ,experiments,
Stan~wsl<Y et al. ("'9981 show that cJt,null mutation disab[es only the majorfty Qf dock
cellSl in the adul fly brain: .soQl9: lateral neurons p~rsevere i cireadian mythrnicity.
~tho(J h recen~ wor has abundanfu: confrrp:1ed ~he. €.Q!1 rusign of tbe 19705 that
604 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

rhodopsin is not required (or dock photoreception and plays at -most only a slight
role. that does not mean that it plays no roje ($tanewsky E!t aL, 1998). For example,
rhodopsin..may dictate behavioral pctivjty in adldts (n.?t,. i;' pupae~r whi~h may -in tum
affect the circadian cloc~ (Emery et al., 2000), ahd rK'<ineko et -Cl1. (2000) found that1
the norpA gene plays a rele in normal rhodopsjn-mediated visior) and 'irr laNal
dock resetting. In the matter of dual photoreceptol'SJ Roenneberg end ' Ha~tjngs
(1988) and Roenneberg and ' Foster (1997) also found at least two independent
photoreceptors affecdng Circa..dian rhythmidty in GoilyatJlax, as is also common in
higher plarits '(Millar e~ al., 1995): their docks are h.o t color blind. -.
In no case has its impact on the dock mechanism been described (in 1978, and
it is still not quite dear in 1999), except in terms of analogies to electronic
oscillators, chemical effects on glycolytic oscillations, differential equations, and so
on. Nonetheless, the dock does function differently while illuminated, so we can use
abrief interlude of illumination to explore its state space, by starting from different
phases in the usual cyde and continuing from there to various durations before
reverting to darkness.
Under prolonged illumination, the Drosophila dock mechanism approaches a
time-independent state. The edosion distribution is then no longer gated into
discrete bursts. Prolonged illumination provides the standard initial condition for
almost all our experiments. Upon transfer to darkness, oscillating kinetics is
resumed from that initial state and the edosion rhythm's phase is determined by the
time of transfer. This trick was discovered by Bunning (1935).

Why Use Populations?

Having assembled a provisional picture of the individual physiological dock, in
context of its sensory inputs and outputs to the timing of edosion, we have
finally to contend with the fact that edosion measurements are typically
conducted in populations. In principle, populations should not be necessary.
Using cohorts of pupae collected as prepupae formed within a two-hour
interval, Skopik and Pittendrigh (1967) showed that edosions occur in a peak
less than three hours wide (measured as twice the RMS deviation of counts
about the mean). They showed that the time of the peak reveals the phase of
something (the dock) that varies periodically after transfer to darkness. In
principle, phase shifts of the dock could be assayed with adequate precision by
comparing the edosion time of a single fly against Skopik and Pittendrigh's
series of control experiments, in which the mean edosion time was measured in
cohorts after the dock was started (by transfer to darkness) at different ages.
But a technical difficulty intervenes. The control series would have to be rerun
in each experiment because as little as a ~oC difference in mean temperature
during metamorphosis is equivalent to a 5% change of developmental rate (and
almost no change in dock period). In the 200 hours of D. pseudoobscura
metamorphosis this amounts to a major fraction (~) of a 24-hour cyde.
Nutritional differences caused by crowding presumably also affect the mean rate
of development. Since edosion time is jointly determined by dock phase and
developmental readiness (Figure 1), any uncontrolled influence on develop-
 A: BASICS OF INSECT ECLOSION CLOCKS 605

mental rate spoils the single-pupa phase assay. So the usual expedient is to use
populations spanning a range of at least several days of age. This way, even if
pupae achieve adequate maturity some hours or days earlier or later than usual,
there are still some mature pupae available at any given time during the week
when edosion is monitored. Ideally, one would record the age distribution in a
separate control experiment and correct edosion peak times for the influence of
departures from flatness using an algorithm suggested by Figure 1. It was my
habit to do so, by routine computer processing of data, but it didn't make much
difference in experiments that terminated in several discrete and narrow
edosion peaks. It suffices to ignore peak shape and accept any measure of
central tendency as the phase of the dock, if one can live with the one-to two-
hour irreproducibility of that measure.
Numerous warnings about interpretation of population data have been
issued in the circadian rhythm literature since the mid-1950s (Harker, 1958;
Wever, 1963, 1965b; Skopik and Pittendrigh, 1967; Ehret, 1971; Karlsson and
Johnsson, 1972; Engelmann et al. , 1973; Johnsson et al., 1973). Most of these
prove irrelevant for insect eclosion systems producing discrete sharp peaks.
However, population inhomogeneity does become a crucial factor for inter-
pretation of experiments that produce vague or irregular rhythmicity, as
discussed below.

Recapitulation
For present purposes, the central facts to bear in mind are:
1. The eclosion dock is started by transfer from constant illumination to
everlasting darkness (perhaps punctuated by one or two light pulses weH before
eclosion time).
2. The position of the eclosion peak sequence along the time axis reveals the phase
of the underlying dock if the edosion peaks are sharp and uniformly spaced at
24-hour intervals.
3. "Phase" means the fraction of a cyde elapsed, or 1 minus the fraction remaining.
Thus two conventions must be specified.
a. The time at which phase is evaluated: 1 evaluate old phase at the beginning
of the first stimulus; 1 evaluate new phase (alias final phase) at the end of
the last stimulus, which is the beginning of the final dark free-run to
edosion.
b. A phase reference point to call phase zero on the edosion assay: Let this be
the center of mass (centroid) of the daily eclosion peak. Thus time T = 0 (the
light-to-dark transition) is phase 1- (*) = 0.2 in my strain of D. pseudoobs-
cura, because edosions follow the transition after 17 hours and thereafter at
multiples of nearly 24 hours. The phase after some stimulus is 1 - (0/24),
where 0 is the number of hours (modulo 24) from the end of the stimulus to
recurrent eclosions.
Much of the circadian rhythm literature uses a different convention, defining
"subjective circadian time" (SeT) as hours elapsed (modulo the period) since the
606 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

dark-to-light (not light-to-dark) transition in a 12 hour-light-12 hour-dark cycle.

Since eclosion in D. pseudoobscura occurs at SCT 3 under these conditions,
SCT is sometimes redefined as 3 plus the number of hours since eclosion, or 3
plus 24 minus the number of hours until next eclosion, assuming regular
periodism.

B: Phase and Amplitude Resetting in Drosophila pseudoobscura

All this is a dream. Still, examine it by a few experiments. Nothing is too wonderlul to
be true if it be consistent with the laws of nature. And in such things as these
experiment is the best test of such consistency.
Michael Faraday, 19 March 1849
Lab Book EntIy 10,040

Technology
In D. pseudoobscura the technology of eclosion monitoring centers around the fact
that the freshly emerged fly is wet, white, weak, and wingless for about i hour after
eclosion. During this time, it stands motionless, clinging to the pupal case or some
nearby object while wings inflate and other cuticle tans and hardens. So tenaciously
do they cling that Pittendrigh found it necessary to use the automated hammer
blows of a heavy-duty solenoid at frequent intervals to shake them loose into a vial
of soapy water. As a student in the lecture hall under Pittendrigh's laboratory at
Princeton, I was accustomed to solving mathematics puzzles while "the Army of
Science marched overhead," compelling the lecturer to briefly shuffle his papers in
silence. Always alert to potential improvements of technology, Pittendrigh contrived
a "superbang" machine in 1967. While optimizing the number and magnitude of
bangs, I noticed that "banging" is necessary only in the light. In the dark, flies fall
spontaneously, and if mounted over a Teflon-lined funnel (an innovation by W.
Engelmann), they fall aIl the way to whatever fate one intends for them. Thus one
can assemble a light-weight, compact fraction collector to handle as many as 100
separate pupal populations within the space of a desktop. Under an array of funnels
slowly glides a Lucite tray of chemicaIly wetted water, divided into compartments,
each of which accumulates the flies emerging during one hour from one population.
These hourly body counts underlie all the fly dock data plotted in this book. A ruby
red safe-light, also introduced by Engelmann following Brett (1955), enormously
facilitated manipulations originally conducted in absolute darkness (often with
refugees from Nishiitsutsujii-Uwo's coclcroach surgical experiments crawling up my
arm). The safe-light was eventually upgraded to the sodium doublet, improving
visibility for flies and men both, without effect on the pupal circadian dock
(Winfree, 1975c). Blue light exposures were automated by a Rube Goldberg
contraption of relays, mirrors, and solenoids caIled the "Time Machine" (Figure 4)
for its responsibility to shift pupae into the past or into the future of their otherwise
undisturbed cydes (see Materials and Methods, Winfree, 1973a). Data processing
was automated first for an IBM 7094 at Princeton (1967), then for an IBM 360/50 at
 B: PHASE AND AMPLITUDE RESETTING IN DROSOPHILA PSEUDOOBSCURA 607

Figura 4. The time machine, built of parts

scrounged from garbage cans at Princeton in
1968 in my Wyman Cottage garage called the
"Mistake Factory" (where I make mistakes.) It
finally went into production in a refrigerated-meat
storage locker at the University of Chicago's
Department of Theoretical Biology. Twelve brass
cups house as many populations of pupae
mounted to receive a measured exposure of blue
light from a central rotating mirror when a timer
activates the corresponding solenoid above each
cup.

the University of Chicago (1970), and finally for a desk-top HP 9830 at Purdue
(1973). During this system's ten years of evolving operation, I executed altogether
4,100 separate experiments (approximately one megafly), each experiment measur-
ing the phase of one population's edosion rhythm in darkness after suitably
scheduled exposure to light, by recording the edosion time of each individual to
within ±! hour. The majority were diverse control experiments, repeats on several
different mutant strains of Drosophila (all of which behaved in very nearly the same
war), repeats or disconfirmations of other people's published experiments that
played a critical role in the logic of my own, and several unpublished elaborate
boondoggles.
But the remainder proved informative and enter significantly into our
exploration of biological phase singularities:
1. The pinwheel experiment Chapter 2, Example 5; see next section, this chapter.
2. The time-machine experiment for plotting trajectories in Chapter 7.
3. Experiments exploring conditions required to induce arrhythmicity, and the
nature of that arrhythmicity (see below).
These experiments used about 1,200 populations of females of a sex-
ratio strain that I assembled in 1967 from wild D. pseudoobscura kindly
brought back from the Sonora desert of Arizona by Ronald Quinn, following
a suggestion of Pittendrigh, and cutide marker mutants (yellow, singed
bristles) kindly provided by T. Dobzhansky. I destroyed this strain in 1975 so
that I would have to escape the plateau of diminishing returns forecast by
the realization in that year that any substantial progress in dock dynamics
would have to await resolution of questions about interaction and mutual
synchronization among dock cells in the individual fly, a business better
left to labs of cell biology and molecular genetics. The flies are extinct but
every individual's dock phase at death is preserved on a long shelf of
computer-printed notebooks and magnetic tapes.

2 In 1967, I was using ethyl methane sulfonate, a gift from Seymour Benzer, to make mutants, hut
never found an interesting one. Ron Konopka (1972) produced pd and others, and kindly provided them to
me for pupal eclosion experiments.
608 20: THE CiRCADIAN CLOCKS OF INSECT ECLOSION

4. Another 600 experiments went for the singularity trap experiment (Chapter 2,
Example 6 and Box C) using both males and females of Ron Konopka's 19-hour
per dock mutant of Drosophila melanogaster (see below). All data are similarly
preserved.

The TIming of the Screw

This section describes an algebraic surface contrived to fit smoothly through the D.
pseudoobscura data points obtained by hit-and-run experiments with a single pulse.
The pulse of duration S is given T hours after the dock is started by transferring
pupae from light into darkness. We then record the edosion time (), in hours
measured from the stimulus or from stimulus anniversarles at multiples of 24 hours
after the stimulus. The results were described in Figures 13 and 14 of Chapter 2,
where a stereo plot of unadorned data was promised. Here it is (Figure 5). The
coordinate axes are three:
1. Horizontally to the right, the time or phase at which the light pulse was given, or
the east-west Iocation of a pupa on the imaginary desk top of Example 5,
Chapter 2.

.. .
..
~

...: .'.

'.

Figur. 5. Stereographie views of 879 measurements of eclosion time in Drosophila

pseudoobscura following a brief light pulse. (For viewing see Box A of Chapter 12.)
Coordinates and perspective as in Figure 14 of Chapter 2. The two interior uprights depict the
presumed singularities, poles around which data points c1imb in corkscrew fashion. The second
singularity is further in the foreground mainiy on account of dark ada tation in the clock's
photoreceptor during the first 31 ho urs of darkness.1j1is dar!:< ~daptatro(l may oe d ~ to C
recoveiy fro bleaching i,n prlc5r'su~ined bri~ht Ij~! (Eme et al, 1998,' Figure 6c, . ot:nl·

2. Horizontally in depth, the duration S or energy of the exposure. (In this range
of durations, the dock is responding to energy, no matter how quickly or
 B: PHASE AND AMPLITUDE RESETTING IN DROSOPHILA PSEUDOOBSCURA 609

slowly it is delivered (Engelmann, 1969; Chandrashekaran and Engelmann,

1973). This is also the north-south Iocation of a pupa on the imaginary desk
top. These two coordinates constitute the stimulus plane: Each point on the
desk top represents a unique combination of the two parameters that define a
stimulus. These are the independent variables of the experimental question
posed to the flies.
3. Vertically downward, the times of edosion. This is the flies' answer, the dependent
variable, aseries of times spaced 24 hours apart along the vertical axis above each
stimulus point. In this plot time is measured from the stimulus downward. This is
a simple, direct way to plot the rhythm's new reset phase upward. (See Chapter 1,
Section D. Figures 31-33 in Chapter 1 are only two-dimensional because Stakes a
single fixed value in each. Here S varies in depth.)
It would be easier to grasp the dependence of the phase resetting on the stimulus
parameters T and S if we could fit a smooth surlace {} (T, S) to the complete doud of
1,574 centroid data. I did this by hand in Figure 14 of Chapter 2. Example 1 of
Chapter 5, Seetion E, seIVes the same purpose, with a litde tinkering to incorporate
the unexpected slow dark adaptation of dock photosensitivity:
211" {} sin ( ~ [T - 7])
tan 24 ( + 1.1) =1_ e-F(l + cos(~ [T - 7J))

where times T, {}, "7", "24", "1.1" are in hours, and function F is dimensionless:

F= S
(6 + 140e-T / 8 )
with T and "8" in hours, exposure duration S, "6", and "140" in seconds. This S (for
"seconds" to remind of the units used in this rescaling formula) was more vaguely
called M (for magnitude) in several other places, e.g., Chapter 2.
F is the "subjective" exposure magnitude, proportional to physical energy or
duration S scaled by an exponential dark adaptation factor (Winfree, 1972b). 3 Note the
singularity at F = F* ("F star") = In 2, T = T* ("T star") = 7 + 24n hours.

~ In 1999, tne f'eculiar dark a aptation seems to reflect a monotone increase of

ayptochrQme concentration. inc the dark (Emery et CI!., 1998), With or without this
fancy. del}ominator, the resetting etJIves pradul=ed by this kInd of model necessarily
have ~ertain peculiarities of shape that were otherwis~ ·unexp.ected at the- time
(Wil"\free, ·1970b FlgIJres 15'-16, and1970c Eigures C3-C5). n the absence of dark-
adaptaticm, by a ;.Simple geometrie construction overlaying Figure 5 of Chapte 5
you can ,show YOlJrself that or.•mec::hanisms of this general sort, the peak-to-peak
amplitude·of any Type 1 or Type 0 resettjng curve plus the w.idth,of its steeper. half
cOl'll'.lectihSJ those extrema = one half cycle.·' 'A gathermg of tl1e 15 weU-resolved
lat9.e~ampJitude circadia~ resetting cuNes availClble for F!lan.ts and . anjmals. ether

Chandrashekaran and Engelmann (1973) suggested replacing this smooth function by a stepwise
increase in photosensitivity with steps at each T*. That would produce a tear in the resetting surface, an
edge dislocation in the time crystal. I see no such tear in my Figure 5.
610 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

than Drosophila In 1968 ' showed that they do mostly He near the co~responajng
locus. This was but a sketchy hint of future 'Utility for this 197Q version of the radial-
isochron clock. It has since seen' wide ~ervice, as speCies~ after ~species pro ed to
follow its characteristic scheme 'of phase and amplitude resetting in ~ome detaif
(Peterson 1980a,b; Peterson and.saunders 1980; Taylor etal. 1982; Lakiri-Thomas et
al.l 1991). Czeisler et al. (1989) used the same forrnula to represent their clinical data
from light-induced ~esetting of tne human core body temp~rature dock, incluäing
detection of the Type 0 resetting, amplitude r~etting, ahd l'hase sihgularity
suggested for humans In Wfnfree (1986a). (And peak-to-peäk vs. width m~asu(e­
ments of these 15 a~ditlonal ' single-pulse' resetting curvesjust,fill outthe same cloud
of dots as indicated by the first 15. $0 do, the many resetting cUJ\fes assayed wjth
both spedas of Drosophila in the interim. Remarkably, so'd6 the four of Zeng et a,1"
1992 Figures 6 and 8, from spontaneously beating heart cells rathler ~han clrcadian
docks.) ... .......
-.- ,.

The fly data stray from this sUITace by ±2 hours, on the average. Some of this
discrepancy is systematic due to my choice of a very simple fitting equation. But as
the reproducibility of aphase measurement is only ± 1.5 hours anyway, it didn't
seem worthwhile to tailor the fit more meticulously.
Plotted above the (T, S) plane, this ()(T, S) is a single suITace wound around a
series of screw axes, scarcely distinguishable from Figure 14 of Chapter 2 (where S
was called M, without change of meaning or numerical value). It resembles a
vertical corkscrew or aspiral staircase linking together tilted planes. With S rescaled
to F so the surface is periodic along both the T and () coordinates, it resembles a two-
dimensional crystal lattice. I call it a time crystal because its two periodic
dimensions both represent time in units of one day.
The suITace in Figure 14 of Chapter 2 is in the same graphic format as developed
for simple docks in Chapter 3. Notice how different its shape iso Simple-dock
resetting surfaces consisted of separate sheets, whereas here each unit cell of the
crystallattice contains one turn of a screw suITace and these all fit together into a
single periodic suITace. Let's examine one of these unit cells in detail by serial
sectioning, as though running it through a microtome for microscopy. Figure 13 of
Chapter 2 shows serial sections through three consecutive unit cells of the idealized
surface (the equation) at 12 levels of fixed edosion time (). These are successive
positions of the edosion wave on the stimulus plane (the desk top of the pinwheel
experiment of Chapter 2). In other words, a pivoting wave, plotted in terms of wave
arrival time above the plane on which it rotates, resembles a screw, a "helicoid." The
axis of the screw stands vertically above the rotor's pivot at T = T*, S = S*. Thus a
piecemeal resetting experiment, whose outcome resembles a crystallattice of screw
suITaces, is equivalent to a pinwheel experiment in which the graded stimulus
evolves a rotating wave.
Figure 13 of Chapter 2 (with S called M) shows a composite of serial sections
cut perpendicular to the () axis. If we instead cut perpendicular to the S axis we have
resetting maps, as described in Chapters 1, 3, 7, 14, and 19. As the composite in
Figure 6 shows, they are all Type 1 up to a critical stimulus magnitude S*. At S*,
Type 0 resetting abruptly emerges. The critical dose S* tums out to be remarkably
small by the standards we were accustomed to in the circadian business, viz., less
 B: PHASE AND AMPLITUDE RESETTING IN DROSOPHILA PSEUDOOBSCURA 611

than aminute of dirn light. Given at T* to elicit singular behavior, S must be within
20% of the exact value S*, and it has to be administered within! hour of T* (though
T* and S* vary from one batch of pupae to the next). It is not hard to understand
how this effect was overlooked until a theoretical model predicted the existence of a
critical combination of time and dose and prescribed a recipe for finding it.
Figure 7 re-presents Figure 6 as phase response curves: Instead of plotting the
new phase or eclosion time vertically, we plot the amount by which the stimulus
changed it, the phase shift.

-T-
o 24

Figur. 6. Using the particular formula here adopted to I

e
approximate phase-resetting in D. pseudoobscura
t
t
pupae. these are resetting curves for aseries of
stimulus magnitudes ranging from 0 to 64 seconds
exposure to 0.1 W/m 2 light at about 410 nm (about
400 f/Elm 2/sec). Each relates time T past LUDD (or old 0'
phase ep) to time (J until eclosion (or new phase ep'. I
neglecting multiples of 24 h).

-0-
o

Figura 7. Phase shift (advances upward) vs. initial phase

for aseries of stimulus durations up to 64 seconds. This
is Figure 6 sheared downward to the right by 45°
without subtracting stimulus duration. since even 64
seconds is a negligible fraction of 24 hours.
t
b.0
I

In the next seetion we examine the singular (T*, S*) after which no phase can be
assigned to the dock.

Arrhythmicity in Fruitfly Populations

Circadian rhythms are usually monitored in populations of independently
rhythmic docks, be they individual organisms or single cells of a tissue. If
612 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

they interact in unknown ways, then not much can be learned without
monitoring each individual's rhythm, at least weIl enough to establish that the
population is always coherent in phase on a common cycle. It commonly
happens that populations created and reared in constant conditions are
arrhythmic, raising the question as to whether collective arrhythmicity is just
a consequence of incoherence among normally oscillating individuals. Brett's
(1955) condusion in respect to arrhythmie edosion in populations of dark-
reared D. melanogaster was "yes." The same condusion was accepted for D.
pseudoobscura (Pittendrigh, 1954, footnote 10; Pittendrigh and Bruce, 1957;
1958, pp. 251-52; 1960, p. 102; 1961, p. 116; Bunning, 1957). All the facts
seemed consistent with this belief up through 1968, as Beck (1968, p. 62)
summarized: "It is though that the light signal has the effect of synchronizing
the rhythmic functions of all the members of the population." As Zimmerman
(1969) noted, this belief meshes weIl with
A. The general notion that the maintenance and entrainment of circadian
oscillations is essential to the normal physiology and the development of
eukaryotic organisms (Pittendrigh, 1960, 1961; Bunning, 1964) and
B. The more specific hypothesis of Ehret and Trucco (1967) that the mechanism
for circadian oscillations inheres in the physieal organization-and therefore
transcription-of the DNA in eukaryotic cells.

~ In 1999 it.seems nec~ssary to add parenthetically ffiat, whife ~~is- 967 specu ation B
never seemed sensible in my circles, Its antecedent in Hastings and Sweene~ (1959)
and Goodwfn (t963).and [>ittenprigh (1966a,b),was, and was large-Iy neglected. The
actual mechaflism of th-e cel!uJar clockworks is now·know-n to ent'ail transcription -and
translation, as reviewed in ~hapter 19. Speculation- A was also relegated to the
history' s dustbin after: tlie phase singularity was confirmed in 1968 and found to have
no conspicu0uS effect on pupal metamorphosis, and found to leave- pupae in a .state
indlstinguishable from that of norma/ly developing pupae that had never experienced
a chaQge of light or tempetature, and after tne experiments-of Piftendrigh emd SKOpik
(1970) tracked Orosophlla metamorphosis hourly under the microscope with circadian
docks arrested or running in twelve phase relations tQ the start of development, and
found developmental timi!:lg I}ot measurably affected. :..

Zimmerman goes on to note that this belief had never been seriously tested in an
animal, even after Bunning (1959, p. 522) had reported both cases in plants. Kalmus
and Wigglesworth (1960) challenged that belief via a non-simple-dock model and
Sweeney and Hastings (1960, p. 102) called for such a test, both at the first circadian
dock symposium at Cold Spring Harbor.
In August of 1968 Zimmerman, at Amherst, submitted his paper critically
testing and disproving this assumption by a trick using D. pseudoobscura's Type 1
resetting. In the same month I submitted a paper from Princeton achieving the same
result by a different trick using Type 0 resetting in the same organism (Winfree,
1968). Both unequivocally excluded the possibility of interpreting the arrhythmicity
of dark-reared populations in the customary way. This outcome, in Zimmerman's
 B: PHASE AND AMPLITUDE RESETTING IN DROSOPHILA PSEUDOOBSCURA 613

words, "considered in conjunction with the fact that most organisms can reproduce
and function normally in aperiodic environments, presents definite difficulties
for ..." notions A and B.

'. Ahd 10"1q99 we can ;:lad at while tfie flctJon of strong but asynchronous oscillation
it'l o.vertly arrnythmi<; Neurospora lasted three deeades'longef, it was finally decisively
exduded.b Crosthwaite eJ al:· (1997). .. . . ' . '_

The question is important enough to lend interest to an examination of the

evidence. What does it consist of, and how broad is its pertinence?

Zimmerman's Experiment
Zimmerman's experiment used Type 1 resetting by a temperature pulse to
implement the suggestion of Sweeney and Hastings (1960) that after a small
phase shift, a population of docks initially covering the cyde would still be
spread completely around the cyde, so edosion should still occur at all hours.
As the experiment turned out, such a pulse applied to dark-reared arrhythmie
pupae evokes sharp discrete daily bursts of edosion. Therefore these dark-reared
pupae could not have had normally running docks. Zimmerman goes further,
conduding that the docks "were inherited at rest." This inference rests on a
notion that has never been checked, Le., that the docks in dark-reared pupae
are no more temperature-sensitive than the rhythmic populations on which the
Type 1 resetting was calibrated. Even the more conservative condusion that the
docks could not have been running normally needs reinforcement at three
points:
1. It implicitly supposes that pupae do not interact, e.g., to synchronize to the
phase of a majority. They do in other species, e.g., in edosing silkworm moths
(Truman, 1972) and in another species of fly (Saunders, 1976a). Noninteraction
in Drosophila had been explicitly supposed since Kalmus (1940), but the
question had never been of real concern in Drosophila edosion experiments
because pupal rhythms had always been forced to synchrony anyway. So 1
checked it by three independent experimental tests (Winfree, 1970c appendix),
none of which reveal any conspicuous or reproducible interactions. So this
supposition seems safe.
2. My subsequent efforts to repeat Zimmerman's experiment failed because in
my control experiments with rhythmic populations, the temperature pulse he
used (28°C for 12 hours) did not give the same small phase shifts as in his
controls. Even with much briefer incubations, 1 obtained large persistent
phase shifts (Winfree, 1972a), compatible with a Type 0 curve and
incompatible with Zimmerman's argument, which was based on the phase
shifts being small.
3. Zimmerman's (1969) Figures 1 and 2 are incompatible in a way that suggests
some confusion about the time scales. 1 have not been able to reproduce the
reported timing of the edosion rhythms according to either figure.
614 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

Supplementary Experiments
All this, together with widespread difficulties in working with temperature effects,
leads me to doubt the proof while accepting the result. I accept the result because it
also emerges from experiments using light instead of temperature:
1. After learning of Zimmennan's experiment, I repeated his fonnat but used a
very brief light pulse to evoke the required Type 1 resetting. The outcome was
qualitatively the same as his (Winfree, 1970c). It is also subject to the same
quibble, that the light pulse might seem subjectively longer or brighter to dark-
reared pupae than it does to the rhythmic pupae used to assay its potency. In
fact, this now seems quite likely, in view of the subsequent discovery of 20-fold
dark adaptation in D. pseudoobscura (Winfree, 1972b and e). A pulse that much
brighter, like the more effective temperature pulse, would have qualitatively the
same synchronizing effect as is observed even if the population were indeed
composed of randomly phased, nonnally running docks.
2. My 1968 experiment had employed a different trick, using the Type 0 resetting
evoked by a light pulse of saturating intensity and duration as in Pittendrigh
and Bruce (1957). Thus questions of sensitivity are bypassed. The trouble with
this experiment is that no one seems to understand it. So let me try to explain it
in a different way this time, without belaboring quantitative details. Type 0
re setting necessarily has two ranges of old phase in which the new phase
scarcely varies. Given an initially unifonn distribution of old phase, the
distribution of new phase should therefore exhibit two peaks, with lesser
densities in between (Figure 8). Now there is a subtlety: We do not directly
observe dock phase in an emergence distribution. Even a perfectly coherent
population produces an edosion peak six hours wide at two standard
deviations, and wider at the base. (Skopik and Pittendrigh, 1967, showed that
most of this breadth is due to the population's heterogeneity in regard to
developmental age.) So what we really want to ask of the observed edosion
distribution is, "How can I represent these data as a superposition of 24
standard edosion peaks phased around the dock, each with the right number
of pupae in it to account for the observed distribution?" Resolving the observed
edosion distribution into standard peaks is valid if and only if:
a. Pupae at different phases do not interact. As noted above, this was verified.

Flgure 8. Any smooth distribution of old phase

covering the eyde, transfonned by Type 0 resetting,
becomes a distribution of new phases aecording to
the conservation law p(rjJ)d<jJ = p'{rjJ1drjJ'. Because drfl
drjJ = 0 at one or more pair of phases, the new phase
distribution has one or more pair of homs.
 B: PHASE AND AMPLITUDE RESETIING IN DROSOPHILA PSEUDOOBSCURA 615

b. Even if docks were not running nonnally prior to the Type 0 light pulse, they
are afterwards. There is no way to be sure of this but the result of the
experiment turned out to be an edosion rhythm indistinguishable from those
obtained simply by moving pupae from the light into the dark. Also Honegger
(1967) measured aresetting curve on such a population and this too looks the
same as in pupae whose docks were running nonnally after light-to-dark
transition.
c. It can be done without using negative densities at any phase, and in such a
way that the results match observations within the expected statistical
fluctuations associated with counting error.
A computer program was contrived to produce the best-fitting representations
and chi-squared estimates of the match. It worked quite reliably in a variety of
control experiments. For example, it resolved the phase distributions in popula-
tions artificially constructed by transferring batches of pupae from light to dark at
different times of day, and then counting their edosions together. It produced
excellent matches to all the experimental data, and it failed on made-up data.
Essentially the same trick (deconvolution) was then adopted by Njus (1975) and
Njus et al. (1981) to extract the distribution of cell dock phases from the
broadened glow rhythm of a Gonyaulax population. In the control experiments
with pupal populations deliberately constructed to be arrhythmic (12 aliquots
taken to dark at two-hour intervals around the dock, then exposed to the
saturating light pulse) the result was as expected: a two-peaked distribution of
phases within a few hours of the expected phase. In contrast, finally getting around
to the results sought, dark-reared populations treated in the same way produced a
phase distribution resembling a single narrow spike: a condusively different result,
condusively showing that dark-reared populations are relatively homogeneous in
their behavior.

Conclusion
In this case, it does seem legitimate to infer with Zimmennan that the pupae
inherited their docks at rest. At rest? Stuck at what phase? Dark-reared pupae react
to a temperature pulse or to a light pulse much as do pupae made phaseless by a
singular perturbation. This observation is awkward for any simple-dock model in
which arrhythmicity is interpreted as arrest at some special phase on the cyde, as in
experiments on the cell cyde. It suggests an alternative interpretation, Le., that dark-
reared docks are created near a steady state and linger there until kicked into
oscillation about the steady state.
The question as to whether ostensible arrhythmicity is only a matter of
incoherence among individuals or cells of a population must be answered yes in
order to sustain the view that lured me into this business, viz., that the circadian
dock plays a crucial organizing role in the machinery of life. But at the
population level, we have just seen that Drosophila answers no. Then what at the
cell level? If the eclosion rhythm can be regarded as an observation on the
population of pupae then it can also be regarded as an observation on a larger
population of cells. Does the inference made above carry through to the cell
616 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

level? It does not, beeause we would have to show that the eells do not interaet.
They probably do interaet. The many eells of an individual pupa's brain
somehow jointly determine the moment at whieh it takes adecision to open its
pupal ease. Here we know nothing. It eould be that arrhythmicity in the
individual pupa is only a manifestation of ineoherenee among its normally
rhythmie eells. If so, then eytological incoherenee is a major uncontrolled
variable in dock experiments, and many years of experimentation may be ripe
for a critical review of interpretations. If not then the belief that circadian
rhythmicity is an essential principle of physiological organiwion must be
abandoned, and so must be hypothetieal mechanisms whieh have no place for a
phase singularity. Since the eonsequences are interesting either way, 1 consider
this high-priority business for the laboratory.

• 80th have, i~deed, been comp!etely aban oneCl, In genera!, mere were plenty of
surprises in tl]is adventure. A~ far as I am concenied, the p~ase singularity was not one
of them, but tbe acute temperature-sensitiv ~t'y, the tenfold inerease of photösensitivity
betw.eE1n the first aNd se~ood' ~ln$ular pha~es (the.n its aesencein -perS .lT)utants) the
arrhythmicity.cf indiviqual dark:reared pupae, 'an&~he Rersistence:,pf r~set'(decniased)'
dock ~mpl~tuae _y.l~t'e.aO so ~ompleteJy', ur:lexpe~edthat'i ·was r7lu~ant to publi~h for ~
Ions tl'11e, I,.e./ unt'!.repea.,tsac~or;npan,ed by dlyerse_cdntrol l.experJme/1ts ,c~nslstently
G:onfitmeq -those outcomes. J a'm grateful that Qth~rs were willing to -cbeck out ottier
specie.s in comparatil~ expenn:ientS. Recent ?pedacular.results o. ßioclleniical 'nguiry
jnto dock mechslf"sms in di'ierse mutant$ se.em t'O have driven the last nails' ir;to the
.~offin ' of -those" ~omantic ideas that' ~ad .initial~y lured me. ln.to drcadlan doc
eXpE!riments ~ ... -' ..
---.... .........
_ -~~ --

Other Modes of Arrhythmicity

There are at least four other contexts in which edosion rhythmicity is lost. All
four challenge the notion that circadian docks are essential for temporal
coordination:
1. There are mutants in which chosen observables are arrhythmie. As in the case of
rhythmic morphogenesis in fungi (Chapter 18), this may prove to be a matter of
altered permissive conditions (some change of diet or of temperature might
disinhibit the dock or restore coupling to the few aspects of physiology that we
monitor) or it might be that an essential component of the mechanism is simply
. absent (Hastings and Schweiger, 1976, Part 5) .

• . 2.' hi 1999, irstances , o'hhe -latte" are profGsely abunäant in f'Jeurospora ana in
. Drosoppila. The arrhythmie mutants are flOW knowo to 'b e so c;ltth~ cenular level,
.,-om leting the proof. .... . . .: . .

3. Saunders (1976a) found relatively arrhythmie edosion in Sarcophaga following

exposure to light-dark cydes in which Light + Dark = 12, 36, 60, ... , hours. He
suggested that this could reflect incoherence among oscillators within each fly,
but this has not been tested as far as 1 know in 1999.
 B: PHASE AND AMPLITUDE RESETTING IN DROSOPHILA PSEUDOOBSCURA 617

4. The transition from Type 1 to Type 0 resetting is made through a phase

singularity: An exposure of this size given at a critical phase induces lasting
arrhythmicity in each pupa. There is some reason to conjecture that this state is
the same as the dark-reared state (Winfree, 1968, 1970b) but proof is stilllacking
(in 1999 as in 1978).
5. Bright continuous light inhibits circadian rhythmicity in many organisms,
induding flies. This is what Zimmerman (1969) called secondary arrhythmicity:
imposed by continued exposure to nonpermissive conditions. Pittendrigh
(1966a) produced the first really convincing demonstrations that the dock
actually stops in each pupa after 12 hours in the light. This notion is frequently
challenged (e.g., Brady, 1974, p. 18), especially since the advent of experiments
with dim continuous light (Chandrashekaran and Loher, 1969a; Winfree, 1974a;
Pittendrigh, 1976 Peterson and Jones 1979; Peterson 1980a, 1980b). However, 1
know of no observations incompatible with suitable models in which sufficiently
intense illumination does indeed stop a nonsimple dock (Pavlidis, 1978).

The Fruitfly Clock is Not a Simple Clock

The question is sometimes raised (I think first by Pittendrigh and Bruce, 1957, in
context of experimental tests) as to whether the circadian dock is affected more by
the abrupt transition from dark to light or light to dark ("differential action"4) than
by the continual impact of photons on some ultimately photochemical mechanism
("continuous action'>4). As long as these alternatives were only considered in
connection with the widespread but implicit notion that the circadian dock is a
simple dock (Chapter 3), it seemed most reasonable to adopt the differential action
outlook (Pittendrigh, 1958 and especially 1960, p. 175). Yet it remained difficult to
understand in these tenns the lasting arrhythmicity observed forever after a
transition from darkness to continuous light: Did the moment of transition
(putatively the only stimulus perceived) switch the dock into some state of
indeterminate phase? No such state exists in the cyde of a simple dock.

1. Pavlidis' Model. (See also Box A of Chapter 7.) Pavlidis (1967b) first resolved
this difficulty explicitly in context of D. pseudoobscura data by postulating a disk of
states inside the cyde of conventional phases. 5 In other words, Pavlidis adopted the
alternative inference overlooked in Pittendrigh's experiment of 1960 cited above,
Le., that the circadian dock in Drosophila is not a simple dock. Moreover,
acceptance of "continuous action" is the premise underlying Pavlidis' second model

4 In the more recent notation of Pittendrigh and Daans' five major papers of 1976, "continuous action"
equals "parametric" and means duration has a continuing conspicuous effect on the phase shift, while
"differential response" equals "nonparametric" and means that beyond a short time after abrupt light
onset duration has little further consequence.
5 As with most other innovations, one could point to earlier independent discoverers: Kalmus and
Wigglesworth (1960); Wever (1962-3-4); Moshkov et al. (1966) applied the same ideas in the same
format to circadian rhythms in general, but they failed to pin thls model explicitly to one data set. Strahm
(1964) (cited only in Pavlidis, 1967a) had all the essentials, applied specifically to D. pseudoobscura but he
neglected to publish after submitting his thesis (see Chapter 7, Box A).
618 20: THE C1RcADIAN CLOCKS OF INSECT ECLOSION

(1967b) and all the topological inferences in this volume. We owe to this paper the
critical reestablishment of continuous action as a reasonable interpretation of
Drosophila dock experiments, but now in the enlarged context of a dock whose
state can vary in two ways, not only in phase.
On this basis Pavlidis (1968) first anticipated something that makes no sense in
terms of simple-dock models: the possibility of stopping the Drosophila dock by a
delicately timed light pulse. Pavlidis seems to have mistakenly thought his inference
was in error, an exorciseable artifact of mathematical modeling:
... the model should be designed in such a way as to exclude the possihility that a
smalllight stimulus would bring the system into R. .. therefore while a strong light
stimulus would fai! to damp out the oscillation, a weak one . .. would damp it. This is
completely in contrast to the experimental findings and therefore we conclude that
the critical point should be unstable ...
[The quotation is restricted to the italicized parts in Pavlidis, 1978]
But the necessity of some such singular event could be inferred from fragments of
published data on model-independent topological grounds (Winfree, 1967b).
Shortly thereafter it was experimentally verified in D. pseudoobscura (Winfree,
1968) and then in other species (Kalanchoe: Johnsson et al., 1973; Sarcophaga:
Saunders, 1976a; D. melanogaster: Winfree and Gordon, 1977).

Acceptance of these inferences and of the experimental demonstration was

retarded by the simple-dock concept, in ways typical of assumptions long and
widely accepted, hut never explicitly articulated. For example, the model-
independent inference of a singularity rests on demonstration of Type 0 resetting
(Box B of Chapter 2 and Boxes Band C of Chapter 4) but up to that time it was
common to stretch Type 1 resetting CUlVes through Type 0 data, even if it was
necessary to run the CUlVe through more than 18 hours without a data point: only
Type 1 resetting was sensible in terms of the implicit simple-dock paradigm. Even
Pavlidis once misrepresented in this way the Type 0 resetting behavior of his
potentially revolutionary model (1968, Figure 6b; Pavlidis and Kauzmann, 1969,
Figure 7) bringing it into line with the published Type 1 representations of Type 0
experimental data. Such is the power of an idea.
As noted above, the Drosophila dock's.peculiar behavior in dim continuous light
(Winfree, 1974a; Pittendrigh, 1976) is also implicit in this dass of dock models
(Winfree, 1972e; Pavlidis, 1978) but poses paradoxical difficulties in terms of the
simple-dock assumption.

2. Amplitude Resetting Accompanies Phase Resetting. Finally, there is the

question of dock behavior after a prior rephasing stimulus. According to the simple
dock idea, implicit in the definition of phase shift for one circadian docks
symposium (Aschoff, 1965, p. xii: "Phase shift: a single displacement of an
oscillation along the time axis") the dock's reaction to a second stimulus should
exactly follow the same phase-specific schedule as before. This is the prediction of
any model in which the circadian pacemaker, whatever its concrete nature, is
limited to a cyde of fixed amplitude.
 B: PHASE AND AMPLITUDE RESmiNG IN DROSOPHILA PSEUDOOBSCURA 619

The assumption of a constant amplitude inherent in Pittendrigh's method of

dealing with two successive phase-shifting stimuli, though reasonably successful
with large stimuli eliciting small phase shifts, has been questioned and put to
experimental tests by Johnsson et al. (1973). Their experiments using Kalanchoe
(next chapter) did not give a condusive result. However, experiments carried out
simultaneously using D. pseudoobscura did (Chapter 7). I found that the answer
depends on the stimulus magnitude in the way expected of a non-simple-dock
mechanism:
1. Saturating stimuli take the oscillator from one phase to another on the cyde.
2. More delicate perturbations reveal the presence of states "inside" the standard
cyde of phases (Winfree, 1973a). These smaller stimuli, still causing phase shifts
of all sizes but not saturating the response, reveal the continuum of alternative
cydes that so distinguish the fruitfly's circadian dock from the earlier simple-
dock models. Following such a stimulus, the edosion rhythm looks entirely
normal, only being displaced along the time axis as in the definition above. But
its reaction to a stimulus offered up to two days later (i.e., the sensitivity
rhythm) is systematically different in a way that makes sense in terms of a cyde
of altered amplitude.
620 20: THE CiRCADIAN CLOCKS OF INSECT ECLOSION

e) That fly circadian docks can ce extremely

_contrary to prior certainty; al'ld .
. f) T~at circaqjan Sloc~~ ~(e not necessary to normal metabolism and d~vel9

C: Other Diptera

~ How Different Is th'e Mosquito?..

. .
In short, Peterson and JQnes (1979), Peterson (1980,a,b), 'arId Peterson (1981)
repeated the 1~pulse and 2-pwse toli>ologically motivated e~etiments that this 1~80
book reviewed in' brosophila pupal populations/ but usmg the i"divldual adult
mosquito, ' Cu/ex. !bey obtained similar. results ~d drew the ' corresponding
conclusions) exceptthat not all individuals sbowed long-lasting ampljtude iesett'.iilg.
See discussiqn.in Winfree'<~986aJ?p., 5 -54 and 103"""t06.) ...

How Different Is D. Melanogaster?

D. melanogaster, the geneticist's pet since Morgan adopted it around 1905, was
introduced into the circadian rhythm business by Kalmus in 1935, largely for
studies of the temperature dependence of the eclosion rhythm. From these
experiments, Kalmus first introduced the idea of an endogenous oscillator as
the cause of rhythmic behavior in this fly. Bunning (1935) discovered that
although continuous light suppresses rhythrnicity, rhythrnicity can be reini-
tiated by simply turning off the lights, even after 14 arrhythmic generations
have passed. Kalmus (1940) established the arrhythmicity of dark-reared
cultures, and that a single one-minute light pulse suffices to elicit persistent
24-hour rhythmicity. Brett (1955) showed that all larval and pupal stages are
susceptible to synchronization by light. Brett was also the first to use cohorts
(populations of narrowly defined age) to investigate the development of dock
properties.
Interest in D. melanogaster waned soon after Pittendrigh (1954) introduced
D. pseudoobscura, which responds to light pulses with a much larger phase shift
[though not because it is any more sensitive to light: The response of whatever
magnitude saturates at about the same energy in both species (Zimmerman and
Goldsmith, 1971; Winfree and Gordon, 1977)]. This dirninished melanogaster's
attractiveness during years of emphasis on phase control and entrainment.
However, in 1971, during a renaissance of interest in dock genetics, Konopka
and Benzer produced melanogaster mutants of 10ng and short period. The pers
R339 mutant

.. (adding perspettive fiom 1999 now) is a single'mis-sense at position 589/1220, wner

serine is replaced by asparagine. TKisOfs the worlc!'s tirst behavioral mutatl(m at.tIi,
level 01 amino-acld s.quence. Tlie ·first discovery cf any drcadian clqck 1s molecula
mecl1ani m, and all that fdllowed in cotnparab,le organisms (see Chapter 19),r steITlmed
from this an'd subs~lJent tJtati09S of D,' rrrelanogaste my.,tant R339, whiah
 C: OTHER DIPTERA 621

has the advantage that its rephasing is "disinhibited" relative to the wildtype and
is in fact scarcely distinguishable from the rephasing pattern of D. pseudoobscura
except that its period is compressed to 19 hours (see Chapter 2, Example 6, Box
C, and Figure 18). Otherwise, the most conspicuous difference is a mere
technical annoyance: freshly emerged flies, hanging by their feet in the dark, do
not fall down before their wings inflate. Having built a light-weight plastic
edosion monitor without moving parts, I had no option but to revert to banging
to dislodge them (see Section B above, first paragraph). Fortunately, it turned out
that a puff of carbon dioxide puts them to sleep without affecting the unedosed
pupae, so the edosion monitor was "air-conditioned" with carbon dioxide,
regulated for temperature and humidity, entering and being blown out at half-hour

FUES PER HOUR

HOURS

Figur. 9. Eclosion rhythms in populations of Drosophila melanogaster's 19-hour mutant, pers

R339 resemble those of Drosophila pseudoobscura (Figure 2). This superficial similarity extends
to the ways in which the timing of these rhythms depends on the timing of light pulses.

intervals. With this modification, the edosion assay works almost indistinguishably
for the two species (Figures 2 and 9). Phase-resetting results are also much the same,
as Figure 18 of Chapter 2 showed. Figure 10 presents the same data in stereo for
those who will take the trouble to locate a hand mirror. No time-dependent
distortion of the energy scale is conspicuous in this case, perhaps because D.
melanogaster's dock dark adapts very much more quickly or slowly than does D.
pseudoobscura's.

How Different Is the Flesh Fly?

The principles of edosion timing and of its regulation by a circadian dock are
quite similar in the fly Sarcophaga, whose maggot begins life not in a potato
meal mush but, as its name suggests, in decaying meat. Saunders first cultivated
this fly as a host for the parasitic wasp Nasonia during his ingenious studies of
622 20: THE ClRCADIAN CLOCKS OF INSECT ECLOSION

~:

-I' .... '.

.// ~
I \)-_'' '_1P--"7'_'_1R'
. .. :.-
.... /
~" ""

,.
",
·~'I";' . ,
. ".
. .~ . . ....
',.,..
"~
. . .. . , ....,:

· .
" r!..:.·' ". ,..". '. ".: .II!i!'
·'''1'' "
.,..;. ..., .'
:'".. ~j ,:." /1...:,. '..
~
.••. ,.~.1I
~.. "
..
:.",.:: "' .....
. :I'· ""
:

. '..-.. ..". .~
I'
:. .'~ ". :.... ~ ..:.i;;'

.
r;.~.....

.
: ~·llts.· ': ,," ',o0i.ir""

.
· !;: . • I
::

v
. '1 '"

F'lgure 10. Stereographic views of 622 measurements of eclosion time in Drosophila

melanogaster (19h pers R339 mutant) following a brief light pulse. (For viewing, see Box A
of Chapter 12.) Coordinates and perspective as in Figure 18 of Chapter 2 but without
reduplication of data points from T< 19 to T + 19. The two interior uprights depict the
presumed singularities. poles ,!!o!:lnd which data p~i.nts d~lJIb in corks<:.;ew fashion. (pata from
Winfree and Gordon. 1977).iSal,lnders et al. (19~4) repeated these experu"nents. using inst~acL
the flight aCtivity ofthe indlvia~a! a~u"it, and'obtained nearly,th~ same r~sults tha~,. äs·in exceBt
D.'pseudoobscura. the adul~ pr~~~sJeSs P-h_otos~ft~it~ve.

the wasp's seasonal diapause (hibernation). It tumed out that the flesh fly has a
circadian dock of great interest in itself, quite similar to the edosion docks of

. >.•:;:!';~:!~':f.'\':;.~::r~~ h
/ ...... . ..... ~ / .....
Flgure 11. Stereographic views of 188 measurements (courtesy of D. Saunders) of eclosion
timing in Sarcophaga after a light pulse of some hours' duration. (For viewing, see Box A of
Chapter 12.) Coordinates and perspective as in Figure 19 of Chapter 2. The two interior
uprights depict the presumed singularities. poles around which the data points climb in
corkscrewfashion. All data are double-plotted both to the right and top-to-bottom (i.e., you see
four identical copies of a unit ce").
 C: OTHER DIPTERA 623

fruitflies (see Chapter 2, Example 7). The salient differenees reported by

Saunders (1976, 1978) are:
1. Light pulses are administered only in the larval stage beeause the pupal stage is
insensitive to light; even so, three orders of magnitude more light is required to
elicit phase resetting of a magnitude similar to Drosophila's.
2. Sarcophaga edoses three weeks after experimental interventions are eompleted
and the pupae are put away to metamorphose. So transients are not observed
and do not eomplieate the data analysis.
3. Sarcophaga pupae seem to interaet to stimulate eaeh other at edosion time, as
do silkworm pupae (Truman, 1972) and quall eggs (Vinee et al., 1971). Saunders
minimizes this effeet by housing eaeh animal separately in the edosion
monitor.
4. Like the fruitfly's, the fleshfly's doek ehanges sensitivity, but apparently more
with developmental age than with time in the dark. Figure 11 here eorresponds
to Figure 19 of Chapter 2. As with the other stereo pictures, the left eye's view is
identieal in perspeetive to the picture in Chapter 2.
 The Flower of Kalanchoe

If you do not expect the unexpected you will not find it; for it is hard to be sought
out, and difficult.
Heraclitus c 500 BC

Things are seldom what they seem.

Buttercup to Captain Corcoran in HMS Pinafore

The tiny red flowers of Kalanchoe blossfeldiana open and elose at 23-hour intervals.
They do this for a week even when plucked from the plant and placed in a vial of
sugar water under constant green light, at a constant temperature. Though blind to
green, the flower's elock is sensitive to red light. By exposing the flower to red light
of intensity several watts per square meter for minutes to hours, one disrupts the
normal rhythmicity. In most cases, it recovers sufficiently within four days so that a
phase shift can be measured.

A: Type 0 Resetting
The first systematic experiments of this sort were conducted by Zimmer (1962).
Her results show what I take to be Type 0, or "strong," resetting in response to a
two-hour light pulse. The original publication draws a Type 1 curve through the
data (Figure 1) by inserting an 18-hour data-free discontinuity through the phase
measurements. This seems to me an exaggerated concession to the theoretical
prejudice that, in connection with phase shift plots, what goes up must come
down. If the data must be construed as Type 1 resetting, then there must be an
extremely steep part of the curve and one would expect more variance of the
measured phase shift near this point. As this is not observed, it seems to me that
the phase jump probably doesn't exist and that the data fit better in the pattern of
Type 0 resetting.
Phase shifts can also be measured substantially in advance of the petal rhythm's
settling down to a steady cyele (which, in fact, it never does in Figure 2). This is
because of the fortunate circumstance that, unlike many circadian rhythms such as
the eelosion rhythms of Chapter 20, Kalanchoe's petal movement rhythm can be
monitored almost continuously. Instead of having to wait for an event to signal
passage of phase 0, at every moment we have at least two measurements in hand,
namely, floweropenness and the rate of change of that measurement. Let's caIl

A. T. Winfree, The Geometry of Biological Time 624

© Springer Science+Business Media New York 2001
 A: TYPE 0 RESETTING 625

these position P and velocity V. If the mechanism of petal movement involves no

more than two important variables then by measuring any two functions of state we
should be ahle to distinguish the system's state from nearhy other states. This should
suffice to distinguish the latent phase (Chapter 6) of the rhythm while still far from
an attracting cycle.

-.:
6

10

14
\ ....
\,,,
,
A.
\

------- ~- ------lo.r -----)-------\----t-------

I'\"
"\
'
~
'lo.
\. .
.
\
'.
..,
~,

:5
I 18 ~ \ '\ \} ""~\
'i r ~l
.e l
- \
22

-
b -'.

.. __ J ....--...._._._
__ .....
I \,
I ~
.!!' 1 _
I" .----~
0 2 -----~~---- .....-
..... r • .;,

--~---
~
------"h.::'------
""\

",.",
,
r ~
'"""\
1""
I 6
t l .\.
.1 i
\

10 ,,\ ~\ \
14 -----l_______ ---- --- -- ~---_-.:\.-----
\
Light pul ••
D.rk control • 9 9

16 3 15 3 15 3 Hr

Flgure 1. An early resetting experiment using Kalanchoe's petal movement rhythm. Altemating
maxima and minima of openness are plotted to the right following a light pulse given at the
time indicated along the diagonal slash. Prior to the stimulus (Ieft), all flowers were
synchronous. After stimulus and transients, these rhythms fall into the Type 0 pattern,
paralleling the stimulus rather than the controls. Zimmers dotted curve, however, adheres to
the Type 1 pattem, progressively distorting a parallel to the controls (the prestimulus pattem).
From Zimmer 1962, Abb. 2.

To test this notion, I plotted position vs. velocity for Zimmer's (1962) 13 cyeles
of unperturhed control rhythm (her curves 1-20 up to the light pulse, and Control
curve, all in Figure 2). Much as in Chapter 7, each such plot constitutes a
trajectory winding part way around the origin, or 2~ times around in the case of
Contro!. From the common start at "light out," I proceeded fOIWard along each
winding trajectory, writing down the present phase at three-hour intervals, using
integers 1-8 repeatedly in a 24-hour cycle. (The rhythm's period is closer to 23 h ,
but 3 x 8 is elose enough for present purposes.) All these numbers turn out to
make a reasonably coherent pattern (Figure 3). For example, the region of the
(position, velocity) plane extending upward in a narrow wedge from the origin
turns out to be occupied by measurements taken from flowers at phase three-
eighths of a cyele (plus whole cyeles) after the beginning of darkness. These are
the points at which the position is almost a local maximum (flower fully open) and
626 21: THE FLOWER OF KALANCHOE:

Figure 2. The raw data from which the previous figures was derived (Zimmer,
1962, Abb. 1). The triangles and inverted triangles of Figure 1 mark the times of
maxima and minima, respectively, on these curves. Note that the stimulus
resets the amplitude of the rhythm along with its phase.

11 .3 111 3 11 1 Hr

its rate of change is near O. The region extending to the left in the narrow wedge
from the origin turns out to be occupied by measurements taken from flowers at
phases five-eighths of a cycle (plus whole cycles) after the beginning of darkness.
These are phases at which leaf position is neutral and its rate of decrease is almost
a Iocal maximum.

,,

Figure 3. As described in the text, the prestimulus P(t} data

p of Figure 2 were plotted against their own rates of change,
v(t) "" p(t + 3 hours} - P(t) at intervals of three hours.
Successive (P, V) points were numbered 1, 2, 3, ... from the

•
., .
,',
,
"".
'. ,
6

7Z ,'1
final dusk. The digits outline isochrons (dashed) by which a
phase can be assigned to any (P, V) state without waiting for
transient to subside.
,
'I
\
\. \
\

",
\
\

V
u ·..... r
""::=.""/'\..".I:.!'-I'_ _ _ _ _

By plotting position vs. velocity at any moment, one can operationally define the
phase of that flower in terms of unperturbed controls. If the (position, velocity)
 B: RESETIING DATA AT MANY STIMULUS MAGNITUDES 627

plane is some kind of distorted image of the clock's state space as argued in Chapter
7, then the numbers 1-8 must correspond to equispaced latent phases. The clouds of
numbers must be images of isochrons. So by plotting a perturbed rhythm in the
same way, we should have a measure of latent phase from each successive data
point. These numbers should increase consistently, Le., by 1 every three hours after
the stimulus. Zimmer's data permit at test of this method. She provides about 40
cycles of raw data from 20 resetting experiments, each following a two-hour red
light pulse given at a different initial phase. These were digitized and individually
used to evaluate latent phase according to the numbered regions in the (position,
velocity) plane. The first three data (the first nine hours) after each light pulse gave
inconsistent latent phase readings, suggesting that more than 2 degrees of freedom
were involved in these early transients. The remaining measurements came out
quite consistently along a Type 0 curve (Figure 4). This is nothing exceptional. A
Type 0 curve is obtained by simply following the maxima on Figure 2, which run
roughly parallel to the stimulus diagonal rather than running vertically, parallel to
the control maxima.

~I

Figur. 4. Each poststimulus datum in Figure 2 is plotted

on Figure 3 to assign it a phase and thus to estimate the DUSK 41
3 e
2

new phase some hours earlier when the stimulus ended. 2 1 5 1 2 5 22 2

2 83 • 21 e 4 72 2 8
That new phase, rf/, is here plotted (vertically) against the a 4512 a 2 7 1 e 1 a 4512
old phase, r/J, of the prestimulus rhythm, when the 814213 2
[122
1 11. 814213 2
2 a 122
stimulus began (horizontally). The digits record the DAWN
number of such measurements giving each (new phase,
old phase) pairing. Zeros are implicit where no digit
appears. The measurements fall in a Type 0 pattern.

DAWN DUSK

However by using all the laboriously collected data instead of using only the
times of maxima, it gives a clearer impression of the variability of measured phase.
This makes it plainer that there is no phase of particular variability, as would be
expected near a steep segment of the resetting curve. My inference is again that
Zimmer's measurements outline Type 0 resetting rather than Type 1 resetting with a
near-discontinuity in the curve, as it was depicted in Figure 1 and by subsequent
authors (e.g., Aschoff, 1965, pp. 98, 109, and 279).

B: Resetting Data at Many Stimulus Magnitudes

The implication of Type 0 resetting is that the complete resetting surface must
contain a discontinuity. (Having exorcised one discontinuity, we have conjured
forth another!) The most localized form it could take would be a phase singularity.
628 21: THE FLOWER OF KALANCHOt

Kalanchoits resetting surface was measured by Engelmann et al. (1973), repeating

the format of the Drosophila experiments that first revealed the complete helicoidal
resetting pattern of a circadian rhythm (Winfree, 1968). They published their data
most completely in terms of phase shifts (their Figure 3); only a small subset of their
data are given in the more direct stimulus reference format in their Figure 5. I
replotted it all in the latter format for Figure 20 of Chapter 2. How were these figures
obtained from those data points? The idea is to plot vertically the observed times of
greatest flower openness, so the first step is to reconstruct the original observations
from the reported phase shifts. The phase shift, by convention, is the difference in:
hours between the time of greatest opening in the experimental rhythm and in the
nearest such time in an undisturbed contro!. Since the latter are not explicidy
reported, it is in principle impossible to reconstruct observations from phase shifts.
However, maxima normally occur at 23-hour intervals in the control rhythm, at
about hours 20, 43, 66, etc., after transfer from light into the darkness. Thus aphase
shift reported as a seven-hour delay indicates maximum openness at hours 27, 50, or
73 (etc.) after transfer to the dark, i.e., at hour 27 - (T + M), 50 - (T + M), 73 - (T +
M) (etc.), after the end of a light pulse which began at hour T after transfer into the
dark, and lasted M hours. But which one of those times is right? Their Figure 3
collects data taken in cycles 3 and 4 after the light pulse ends. Not knowing which is
which, I plotted half the points, taken at random, in cycle 3, i.e., in hours 46 through
46 + 23 = 69 after the light pulse ends. The remaining points were plotted in cycle 4,
i.e., in hours 69 through 93. Engelmann also generously provided me with
unpublished plots of data taken in cycle 1 and in cycle 2, also in phase shift format.
These are accordingly used to reconstruct the original observations in the same way,
namely: () (hours after stimulus end) = 20 + delay (0-12 hours) or -advance (0-12
hours) - (T + M) + 23N.
N is an integer chosen to reconstruct () in the appropriate range 0-23,23-46,46-
69, or 69-92 hours after the light pulse ends.
These reconstructed data were plotted repeatedly, as seen from various
perspectives, until I could see the shape of a surface that approximates the 1,536
data points. They are shown in Figure 5 and in Figure 20 of Chapter 2 from the
viewpoint of an observer at T = 20 hours, M = -15 hours, () = 20 hours. The box
around the data consists of planes T = 0 (= transition into darkness) and T = 69
hours (= three cydes later), () = 0 (end of light pulse, beginning of undisturbed free
run), and () = 92 (= four cycles later), M = (undisturbed controls), and M = 3 hours.
Within this box the idealized surface was constructed as folIows:

1. At M =0, T + () =20 hours plus multiples of 23 hours. These are the undisturbed
controls. These loci are drawn as diagonals on the front wall in Figure 20 of
Chapter 2.
2. At T = 0, the flower has been in the light for 12 hours and the phase of its rhythm
in subsequent darkness is approximately set by the time of transfer from light to
dark: T + () = 20 hours plus multiples of 23 hours independent of M. These loci
are plotted as horizontals on the left wall.
3. If the dock is really periodic, then item 2 above is repeated at 23-hour intervals
of T. These loci are the horizontals in the remaining unit cells of this 3 x 4
lattice. [Actually, Kalanchoits dock is not quite periodic: Like D. pseudoobs-
 B: RESmlNG DATA AT MANY STIMULUS MAGNITUDES 629

.,~":, ,,<',
. " -. ." '
,

'0:r;,' :, .... rI' ;

, 1:! : ,'ö.

i ' ,,~

" ::~ ,:,: I C', ,: : : .. 'I

""
",
"

Figur. 5. Stereographic views of 1,536 measurements of the timing of Kalanchoe flower

opening after a light pulse, (For viewing, see Box A of Chapter 12,) Coordinates and perspective
as in Figure 20 of Chapter 2. The two interior uprights, and one exterior on the left, depict the
presumed singularities around which data climb in corkscrew fashion, () values in the bottom two
cycles are randomly altered by ±23 hours relative to assignments in Figure 20 of Chapter 2,

cura's, it grows more photosensitive with time in the dark. But that doesn't
matter for locating aphase at which phase (if not necessarily amplitude) is
utterly insensitive to light.]
4. The data appear to wind around two vertical screw axes. If this plant's dock
behaves like the only other circadian docks for which we presently have such
complete resetting data (the three kinds oftly, Chapter 20), then we might expect:
A. Near the screw axis T =T*, M = M*, this surface resembles a spiral staircase.
B. T* is about one-quarter cyde and M* just measures the organism's sensitivity
to the light used, which might increase as the organism dark adapts, In
Kalanchoe using red light of 2.3 watts/m2 , Engelmann et al. find T* = 7 hours
plus multiples of 23 hours. At three successive T*'s, they find M* = 4 hours, 2
hours, and 1~ hours,
C. At T*, a light of duration M < M* has little effect on phase and a light of
duration M > M* hours inverts phase. This situates the spiral staircase
vertically: Radü extend at fixed T and () to the M = 0 controls on the front
surface and to the large-M resetting curve on the back surface,
5. These features can be visualized in terms of the contour map of () above the
(T, M) plane (Figure 6). It seems that features A, B, C can be linked
smoothly by joining the contour lines as shown in dashes, The linking
surfaces are then sketched on the three-dimensional plot. This part was
630 21: THE FLOWER OF KALANCHO~

done on tracing paper over the data, trying both to follow the data and to
make the surface as smooth as possible and as nearly as possible the same
in each vertical repeat.
M

Figura 6. A sketch of text items 4A, B, C in terms of the level

contours of () (or of 4/) on the stimulus plane. The dashed
segments constitute one possible way to smoothly join the
described features. 1'* is the fully closed position of the flower, 7
hours past sunset.

C: A Phase Singularity
Figure 5 and Figure 20 of Chapter 2 show these results plotted in the three-
dimensional time crystal format used elsewhere in this book. The data doud looks
like a screw with a phase singularity near two hours exposure, beginning about I!
cydes after transfer of the flowers to constant darkness and again at 23-hour
intervals later (Engelmann et al., 1978). As in Drosophila's circadian dock,
photosensitivity increases in the dark: The helicoid in cycle 1 has its singularity
one-quarter cyde after the light-to-dark transition, but at twice the exposure
duration needed in cycle 2. There is little further change in cyde 3.
Engelmann et al. (1978) show that rhythmicity of petal movement is commonly
lost after near-singular exposure. This exposure inflicts a discontinuity on the phase
response possibly because it extinguishes the oscillation until such time as a second
stimulus reawakens it.
In some of these experiments there is a substantial dispersion of phase among the
16 individual flowers collectively monitored for rhythmicity. Engelmann et al. (1973)
note that the singular stimulus magnitude M* might be underestimated from such
population data. In fact the apparent Type 0 resetting, and so the whole helicoid,
could be artifacts of phase scatter within a small population of flowers each of which
exhibits only Type 1 resetting (Johnsson et al., 1973, p. 158; Winfree, 1976a).
However, Engelmann et al. (1978) verify Type 0 resetting on individual flowers, and
M* in individual flowers turns out to be nearly the same as in populations.
. Engelmann et al. (1974) obtained quite similar results in less extensive
experiments replacing the red light by exposure to 30°C. The point here, I think,
is that these phenomena reflect the basic dynamic structure of the circadian dock
and have little to do with the particular mode by which its functioning is disturbed.

D: Arrhythmicity Not an Artifad of Populations

What happens at the screw axis? This singular stimulus is found to annihilate
rhythmicity in each Kalanchoe flower (Engelmann et al., 1978). Does it do so by
 E: AMPLITUDE RESETTING 631

arresting rhythmicity in each cell of the flower or by merely inducing incoherent

rhythmicity in the population of cells whose collective behavior comprises the gross
movement of the petals? This latter possibility is suggested by the unlimited
steepness of the resetting surface at its singularity. The slightest variation of initial
phase or of photosensitivity would seem sufficient to cause large variations in the
new phase of a cellular dock.
In the format Zimmerman and I used for fruitfly pupae (Chapter 20, Section B),
Engelmann et al. (1978) pose the question of incoherence to the cells of a single
flower in which the petal-opening rhythm had been annihilated by singular
perturbation. l A Type 1 resetting stimulus, M*/4, was then given, which should have
only slightly synchronized cell docks if each were independently rhythmic on the
normal cyde. As in the Drosophila experiments, high-amplitude rhythmicity was
immediately evoked. If the rhythm in the whole flower is a mere superposition of
cell rhythms of turgor, then this result is more readily interpreted as displacement
from a homogeneous equilibrium state than as resynchronization from scattered
phases on the usual cyde. Bunning (1959, p. 523) was the first to discover (in a
plant) that the rhythm evoked by a single stimulus derives not from synchronization
of preexisting rhythms in single cells, but from initiating rhythmicity in each cell;
the same seems to apply to the Kalanchoe flower returned by a prior singular
stimulus to an arrhythmic condition.

E: Amplitude Resetting
The range of petal movement in Kalanchoe flowers provides a more direct measure
of amplitude than the laboriously acquired measure based on resetting CUIVes,
applied using Drosophila in Chapter 7. This range measure can be used to plot
contours of reset amplitude just as we have often plotted contours of reset phase on
the (T, M) stimulus plane. Engelmann et al. (1978) show that amplitude falls off by
concentric rings around the singularity. In this respect also, Kalanchoits pattern
resembles Drosophila's. This could be due to some mixture of phase scatter among
cells and attenuation of amplitude in some cells. All we really know about it is that
every individual cell's amplitude is severely depressed following the flower's singular
stimulus, but we do not know whether that is the same stimulus for every cell (i.e.,
how much do cells differ in their initial phase and in their photosensitivity?) nor
how attenuation depends on nearness to singularity in a cello

Referees required its removal from the final published version.

 The Cell Mitotic Cycle

Rules of Reasoning in Philosophy. Rule TI: ... We are certainly not to relinquish
the evidence of experiments for the sake of dreams and vain fictions of our own
devising; nor are we to recede from the analogy of Nature, which is wont to be
simple, and always consonant to itself.
Isaac Newton, The System of the World

In no case is the process weIl understood (in 1978) whereby the growing cell
"decides" to replicate its genome, segregate its chromosomes into two nuclei, and
wall them off from each other by cell fission.

A. T. Winfree, The Geometry of Biological Time 632

© Springer Science+Business Media New York 2001
 A: THREE BASIC CONCEPTS AND SaME MODELS 633

including Go as the phase singularity, and recognized that no known facts then exd~ded
sucn a vision, At the MRC laboratory of Molecular Biology in Cambridge in 1~70-71
Gr-aeme Mitchison and I fleshed out this idea after 5el'kov (1970 + ) had (unknown to us)
'presented sl,lch a model in Russian journals, What became ofthis vision? Thougli argued
only In seminars, itstilLsul'Vives, ostens~bly unexcluded, in the review books of Edmunds
(1'988, Chapte 3) and Goldbeter (1996, Chapter 10), buthardly as the center of attention,
Attention rightly centers on'·the newly available tacts of blochemicat 'eomplexity ane!
diveFSity, And'as far as pherlomenolog)/.goes, I still know no indisputable lostsnce of.
Type 0 resetting or 0 phase singularities manjfest in any cell type ,LJncler CUlY
r
drGLJmst~mces, though still beHev~such may await observers of syt1chr~>nous n~dear'
division cYcles 'in dipteran- and amphibian eggslembryos or ce I-free extracts thereof.
~d Haase ar..lp Reed.(1999) remind os of30-yearfamiliaritywith the budding oscHlator
trat.cGmtinues cell.divisi,?n cydesi'Vithout DNA replieat/on in infact yeastcells,' But qnly in
sucp ~pecia~situations ao~s dfvision proceed unchecked, In samatic tissues--groWth i5<
alSo ;nequirernent, and tlie tdklcydin story. is eplbellished witha growth checkpoJnt a
G,1/5 In a.dditlon to haltiog at'a G2/M"e;heckpointfor completion of DNA synthesis and
€lne at "]eta,/an.aphase for corre;t spindie assembry involving J'activatlon. pr~motirg
(;omplex,'~AP~, Novflk-and7ysqn 199~b) maJntain·tha~the.core;Qfthr cell cyc!els.more
akin 10 an excitable"Or bistable,s~em than to.a spontaneous- osdHatOr, though when
roWtfi is inc;;I\!dedi tf)e excitatlon lS rekindlecf !lt regularintervals, Galdqeter (1996}, il1
(;ontrast, sees -the eell cyde aS' €ompounded . rom' ~o cycl' ~bas.ed attractin~1:Yd.e
oscilrator:s; one ihvo".~ing C%lin.apdcdk kin ase to make'DNAceplication periodic,and the
other involllrng a srmllarpairto.make cell diviSion periodic, these two 'osciltate[s normallx
being coupled. Unlike ecentl)!.Qlsc0vered mecnanlsms-forthecircadian oscillator, oo'ii
of ~hlS imtaifS feedbacR r,epression- of nudear. trcinscription ~Of' regulatlo~ ' f mRNA
'1;rnnslation: apa~ frorn-initial synthests of the enzymes i~volve~ Jts reg\Jlc\ticin inyoJves
only·<cyt:oplasmi~ metabOJlsm:-A fcisdna-tlng evplutionary-biochemical-<lyn~mics per~
spectiVeon aH this isavaifqble in N yak e1: al (1998). .
Iteave tf:lis chaRter intad, as a museum specimen, largely because it isshort and is~ so~
abund~!)t y·alluded,to 6n oth.er'Pages·that have been preserved-intact It provi~es a.
cautionarytnstance in whicb we see Nature expressing her impatienc:;e with conceptually
beautifu. expectations based on - (my) general simple-mindedness and notions of
conti ut ... ~- . -

Such a fundamental biological process presumably has some universal aspects. Its
appeal as an object of investigation is further enhanced by the seductive belief that the
mechanism of replication is constrained to some kind of simplicity by these facts:
1. The end stat,e is elose to the initial state (namely, a freshly divided cell); and
2. The whole process repeats at fixed inteIVals of time, at least in certain kinds of
cells in optimal growth conditions.
Abrief foray into this intriguing puzzle is ineluded here for three reasons:
A. At least three influential notions about elock-like dynamics arose first in this
context and later found application in studies of circadian rhythrns (Chapters
19-21).
B. There is a elose but poorly understood causal link between circadian rhythms
and the mitotic cyele,
634 22: THE CELL MITOTIC CVCLE

C. Techniques of analysis evolved in circadian experiments later stimulated parallel

enquiries into the cell cyde, (mostly by Kauffman et al.: see below), with results
that bear upon our exploration of phase singularities (Chapters 2 and 10).
1 devote a few pages to each of these three topics. Section D goes into a little
more detail about one specific experimental system, the true slime mold Physarum.
Like the three other members of kingdom fungi celebrated in this Bestiary (yeasts in
Chapter 12, cellular slime molds in Chapter 15, colonial ascomycetes in Chapter 18),
the true slime mold is conspicuously periodic in its biochemical habits. In this case
a dock-like regularity of mitosis is most prominently featured. With this periodism
comes the by now familiar crisis of circular logic. It is resolved in this case not by a
phase singularity but by a discontinuity that appears to reveal an honest
physiological catadysm.

A: Three Basic Concepts and Some Models

A Sequence of States
The earliest inquiries into the cell cyde provide a paradigm that seems to pervade
much of the circadian literature, though only in recent years (1970s) has it become
explicit and articulate. This paradigm is best summarized graphically in the
diagrams used by peopie professionally involved in unraveling the mechanisms of
rhythmic mitosis (Figures 1 and 2). As generally envisioned, the cell cyde is a
series of discrete steps or states that a cell must execute in sequence if it is to
replicate normally. Pictured abstractly, these steps constitute a one-way cyde, a
ring device, though possibly adorned with baroque appendages. There may be
loops in the cyde, or alternate pathways here and there. There may be stopping
places at which the cell is unable to go on to the next step until some permissive
signal is given. But the central point for my purpose here is the intrinsically one-

f..""

(:J
l Gr.~"
Figure 1. Diagram of a generalized cell cycle. The four classical phases are
shown: G1 (gap 1), S (synthetic), Gz (gap 2), and M (mitotic). In addition, a
number of arbitrarily chosen points are designated by dots in order to illustrate

_
possible altemative pathways, branched network, loops, and blockage points.
Any precise resemblance to a particular cell is purely coincidental. (From
• ~/ m Edmunds, 1974, Figure 1, with permission.)
.
............
M><tO
r"'"

dimensional character of the process. The dynamics more resembles driving a car
on roadways than piloting a sailboat or airplane in continua with more degrees of
freedom.
It is this vision of the cell cyde that gave rise to the concept of a simple dock
(Campbell, 1964, and Chapter 3), and, by analogy, to much thinking about circadian
docks, and to my experimental efforts to askwhether acircadian dockis asimple dock.
 A: THREE BASIC CONCEPTS AND SOME MODELS 635

.' Sl.rl~
"
"
\
lOS
'"" BE
,.
",
~

OS )

IN~ J;'~M mNO

Figure 2. The circuitry of the yeast cell cycle. Events connected by an arrow are proposed to be related
such that the distal event is dependent for its occurrence upon the prior completion of the proximal
event. Numbers refer to cdc genes that are required for progress from one event to the next; HU and
TR refer to the DNA synthesis inhibitors hydroxyurea and trenimon, respectively; MF refers to the
mating factor, a factor. (From Hartwell et al., 1974, copyright 1974 by the American Association for the
Advancement of Science.)

Phase-Specific Arrest Within the Cycle

If the cell cycle consists of a sequence of processes, some of which are necessary and
sufficient causes of others, then the first job in preparing a "trouble shooter's manual of
the cell cycle" is to construct a flow chart ofthese cause-and-effect connections, similar
to a flow chart of metabolic pathways (Figures 1 and 2). With the normal cycle thus
verbally divided up into stages, it would be illuminating to seek mutants incapable of
each process named, just as biochemical geneticists unraveled the intricate
contingencies that constitute the manufacture of small molecules in intermediary
metabolism by finding out which subsequent events are also arrested in such a mutant.
HartweIl et al. (1974) discovered in this way that the cell cycle in yeast consists
of at least two parallel sequences of events, one of which can proceed, even
repetitiously, while the other is blocked. One involves DNA synthesis and nuclear
division, and the other involves budding and cytoplasmic division.

Rephasing as a Quantitative Test

Systematic phase-resetting experiments to probe the mechanism underlying a
physiological rhythm made their first appearance in the cell cycle literature. The
protocol was typically as folIows:
a. Synchronize mitoses by selecting cells that are a certain size or sticky in a
certain range of phases, or by synchronous release of a population from arrest
by an inhibitor, or by fusion of randomly phased plasmodia.
b. At some initial phase <p (measured as hours elapsed since mitosis), interfere with
normal operation of the cell cycle by changing the temperature, introducing a
poison, or whatever.
c. Continue the stimulus for a time M (for magnitude of disturbance) and then
return the cells to standard culture conditions.
d. Observe the setback or excess delay of mitosis time beyond what would be
expected if the cell cycle were simply paralyzed during treatment time M. Excess
delay Dis defined as the actual period P (measured in units of one normal cycle)
from the last mitosis before perturbation to the first mitosis after perturbation
636 22: THE CELL MITOTIC CYCLE

minus the usual period between mitoses (which we take for our unit of time)
minus stimulus duration M:
D = P - 1 - M = P - M(modulo 1 period).

t .4
• • ~.. /
f6-f6'
.2
.. ~
I 00 .2
•
.4 .6 .8 1.0

~ ..
F"lgure 3. Excess mitotic delays in Physarum induced by 30 - min pulses of 10 J-tg/ml
cycloheximide. (abscissa) Fraction of cell cycle completed when pulses beg in. Mitosis at 0 and
1.0. DNA synthesis ends around 0.3. (ordinate) Excess delay (delay in excess of pulse duration)
plotted as fraction of a control cell cycle. (From Scheffey and Wille, 1978, Figure 1, with
permission.)

Converting to terms used elsewhere:

1. Phase shift, with advances taken as positive, is
Ll</> = 1 - (D + M) = 1- P = -P(modulo 1 period).
2. Final phase at the end of M,
</>' =</>-D
where </> is the initial phase at which the stimulus begins.
3. Cophase at the end of the stimulus is
e= 1- </>' = D - </>.
e. Plot D against the initial </> (when the treatment began). Many such plots are
available in the literature since Thormar published the first in 1959. For example
see Figure 3. Their main uses are:
1. To indicate whether or not a given treatment affects the mechanism of the
mitotic timer, and if so during what phases, and
2. To detect any physiological discontinuity in the cells' sensitivity. There are
typically two discontinuities (Figure 4):
(i) A point of no return in the cycle, beyond which the very next mitosis
occurs on schedule, though phase shifts may be evident in subsequent
mitoses;
 A: THREE BASIC CONCEPTS AND SOME MODELS 637

PRE-STIMUWS
MITOSES

Flgure 4. Two kinds of discontinuity in the cell cycle's

phase resetting as a function of initial phase. This STIMULUS
diagram is in the format of Figure 31 through 33 of
Chapter 1. Discontinuity (i) is relatively superficial. OBSERVED
Discontinuity (ii) signals a discontinuous event in the POST-STIMULUS
mechanism of rhythmicity. The lower shaded region is MITOSES
seldom sampled for data points, but this is clearly
essential for distinguishing (i) from (ii). Does (i) normally NOT
OBSERVED
coincide with either (0) or (ii) ?

(ii) And, near mitosis time, an abrupt change in the new phase to which the
whole subsequent rhythm is reset if the stimulus is given near that time.

Testing Models
Before passing on to Section B, 1 would like to elaborate a bit on rephasing as a
quantitative test of models. Though resetting curves are available, it is not usually
possible to make rigorous use of the circular logic presented in Chapter 1 and
subsequent chapters on dynamics because:
1. These mitotic resetting curves usually leave a substantial gap surrounding
mitosis, so it is impossible to determine the topological Type of resetting.
2. Measurements usually neglect mitoses after the one that immediately follows
the stimulus, leaving us to assume that this first mitosis reflects a rephasing of
the mitotic timer for all cydes to follow. In circadian rhythms, in glycolysis in
yeast, and in neural pacemakers, this is not always asound assumption. Nor is it
in the case of mitosis in Physarum (Brewer and Rusch, 1968; Devi et al., 1968;
Sachsenmaier et al., 1970; and Kauffman and Wille, 1975, 1976).1t is sound and
requires no empirical check if and only if (as seems widely assumed) the mitotic
cyde is a simple dock and mitosis is part of its mechanism.
3. There is no complete set of measurements in which both initial phase <p and
stimulus duration M are varied.
4. It is not always dear that the population of cells observed were perfectly
synchronous to start with, nor that their mitoses were unimodally
distributed when the reset phase was later determined. Chapters 4 and 8
underscore that this is essential for interpreting the topological features of
resetting curves.
638 22: THE CELL MITOTIC CYCLE

The Simple Clock

Setting aside these caveats for amoment, it would appear that excess delay data
might nevertheless be capable of exduding the notion that the cell cyde is a
simple dock, Le., a continuum or finely spaced sequence of successive states
along which the cell moves more quickly or slowly according to environmental
conditions. If the cell cyde were a simple dock, then the slope of a final
phase versus initial phase plot could not be negative anywhere (proof in
Chapter 3, page 89-90). In other words, using the conventions of this field
together with formula d2 of Section A above, the excess delay cUIVe's slope
could not exceed 45° anywhere. In fact, it usually doesn't. (For example, see
Mitchison, 1971 pp. 204-240.) One gets the impression from looking at a lot of
these CUIVes that there is a distinct limit at 45° against which many excess
delay CUIVes press, without transgressing it. To this extent, the cell cyde is
several organisms does give an appearance of restriction to a fixed cyde,
varying only its rate of progress or of retrogression in response to external
conditions.
But there do exist counterexamples in which the slope runs as high as 2 or 3;
specifically, (1) sea urchin eggs irradiated with X rays (Rustad, 1970); (2)
Tetrahymena shocked with chemicals, heat, etc. (heat: Frankei, 1962, Figures 4
and 5; chemicals: Rasmussen and Zeuthen, 1962, Figures 9 and 11; Hamburger,
1962; and Frankei, 1969).
Unless these can be somehow explained away (e.g., on the basis of
population schism as in Chapters 4 and 8, or interpreting the apparent phase
shift as only a transient of the first cycle after treatment), then they constitute
dear violations of the simple-dock model. Thus, for example, we cannot think of
mitosis in these cells as being governed by any single "division protein" or
"mitogen" accumulating or decomposing at a rate which is merely altered,
directly or indirectly, by these stimuli, nor as governed by any complex of
chemical factors that always change in strict mutual coordination, at varying
rates, along the dosed ring of states.
The simple-dock paradigm has served so weIl that subversive observations such
as these should not be allowed to pass unchallenged.

Feedback Oscillation
Alternatives have been prepared for consideration, as we see in Chapter 5.
Goodwin (1963) finds periodic dynamics implicit in the regulation of transcription
and translation, which he suggests may have aperiod long enough to account for
the ceIlcyde or for the circadian cyde. Goodwin's principal innovation is
emphasis or feedback regulation as a source of instability in a biochemical steady
 A: THREE BASIC CONCEPTS AND SOME MODELS 639

state: quite a different notion from progress around a ring. In tbis respect, this
notion resembles
1. the cytoplasmic oscillator proposed later by Goodwin (1966) to account for the
serial ordering of enzyme activities in E. coli during its repeated fission; 1
2. the circadian oscillator which commonly gates successive rounds of mitosis;
3. the growth cyde distinguished from the DNA division sequence in Mitchison
1971, pp. 244-249;
4. the cell dock biochemical attracting cycle proposed by Sel'kov (1973);
5. the "budding" oscillator proposed by Hartwell et al. (1974) from his observa-
tions of mutant yeast;
6. the cytoplasmic oscillator observed by Mano (1975) and Yoneda et al. (1978) in
association with early divisions of sea urchin eggs and by Hara et al. (1980) and
Kirschner et al. (1981) in frog eggs;
7. the cytoplasmic attracting cyde proposed for nudear division in the acellular
slime mold by Kauffman (1974), Kauffman and Wille (1975, 1976), and Tyson
and Kauffman (1975); and
8. the attracting cyde of 4-hour period supposed by Klevecz et al. (1978) to
underlie mitosis in mammalian cells.

From these papers, it would appear that if there is anything about the cell cycle
that resembles an oscillator, it plays a role accessory to the one-dimensional
sequence of processes that constitute nuclear replication: Perhaps the oscillator
governs cytoplasmic replication and division, and initiates the next start of nudear
replication.

Apart from Goodwin's first heresy of 1963, all the investigators cited above buHt
their mitotic timers outside the actual mechanisms of nudear replication.

Note that this chapter concems mitosis in eukaryotes exclusively. The corresponding process, ca1led
"cell division" in prokatyotes, need not have similar dynamics.
640 22: THE CELL MITOTIC CVCLE

These models, and less specifically detailed suggestions toward the same ends
by Engelberg (1968), Burton (1971), Burton and Canham (1973), and Gilbert (1974),
all emphasize continuous aspects of biochemical dynamics.

Biochemical Switching Networks

At the opposite extreme, one could emphasize switch-like aspects of reaction
kinetics involving, say, allosteric enzymes andlor mechanical events (like polymer-
ase attachment) on the DNA itself. This interpretation is encouraged by the
observation of stepwise doubling of membrane transport in mammalian cells (Jung
and Rothstein, 1967; and Sander and Pardee, 1972) andofenzyme activity inB. eoli
and in yeast (see reviews by Halvorson et al., 1971 and Tyson, 1979), each enzyme
showing its increase at a characteristic phase.
This idea was pioneered in Kauffman's Boolean logic network model of the cell
(1969). According to the logical net model, everything important about the state of
the cell is known when one knows which genes are active and which are inactive.
There are no intermediate levels of activity. Each activity state results in
biochemical processes which directly or indirectly shut off some genes and induce
or derepress others. As in a switching network, the cell's state keeps changing until
some prior state recurs, completing one cycle of gene activity and of gene
replication, and thus permitting one cell division. There are many alternative
cycles, each corresponding to a different state of differentiation (liver cell, muscle
cell, etc.). According to this model, cycling persists in nondividing cells, but each
gene is transcribed without being replicated. Further exploitation of this stimulating
suggestion awaits evidence of such regularly periodic genetic activity in nondividing
cells.
A related model by Ehret and Trucco (1967) suppose a unique order of
replication of the genome, its stages separated by delays while substances diffuse
across the nuclear membrane. Each stage consists of processing one "chronon,"
tailored by natural selection to the right length for the required timing.

B: Regulation of Mitosis by the Circadian Clock

The average rate at which cells run through their cycle of division is govemed by
many factors including hormones, some of which (e.g., adrenalin) are secreted in a
daily rhythm. Adrenalin has been shown to affect the average rate of mitosis in the
epithelium of a mouse's ear (Bullough and Lawrence, 1964). The result is that while
mitosis continues at all hours of the day, the mitotic index of this tissue is very
much greater during some parts of day than during others (Moller et al., 1974; and
Taguchi and Tabachnick, 1974). Circadian regulation ofmitotic rates can even go to
the extreme of completely suppressing division during part of the circadian cycle.
Mitoses in Euglena (Edmunds, 1974a, 1975) and in Tetrahymena (Edmunds, 1974b)
and in Gonyaulax (Sweeney and Hastings, 1958), for example, occur only during
 B: REGULATION OF MITOSIS BYTHE CiRCADIAN CLOCK 641

certain phases of their circadian cyde. In these cases it is inferred that only a small
fraction of the population divides during any one daily opportunity. The same
inference follows from the extreme daily variation of mitotic index in rat cornea
(and other tissues), in which a cell divides onlyevery month or two but finally does
so at a particular time of day (Scheving and Pauly, 1973).
Complete inhibition of mitosis during certain hours of the day can be
important for therapeutic applications (Llanos and Nash, 1970). Timed admin-
istration helps cytotoxic medication to discriminate between two tissues,
selectively killing a proliferating tumor tissue while leaving the normal healthy
tissue unpoisoned.
,. See,Hai erg (1974, 19 ), Reinberg an .. SmolenskY (1983)( and Hr1,.Ishesky (1994) for
a elicatioos.•
The cell dock models of Sel'kov and Sozinov (1970), Sel'kov (1970,1973) and
Wille (1979) look on the circadian cyde and the mitotic cyde as essentially the
same biochemical process. Similarly, the chronon model of Ehret and Trucco
(1967) envisions a dose relationship between the mechanisms of the eukaryotic
cell's mitotic cyde and of its circadian cyde. In fact the "point of no return" for
inhibiting the next round of division is nearly identified with the "breakpoint" in
the circadian resetting curve, which this book interprets instead as a
numerological artifact. Admittedly not very much is known about the mechan-
isms of either cyde. Still one might take the fact that the circadian dock can run
while the cell cyde is inhibited and vice versa (Bruce, 1965; Barnett, 1966; and
Edmunds, 1975) to suggest two distinct coexisting mechanisms, each capable of
affecting the other under suitable conditions. Mitosis is sometimes gated at
circadian intervals as we saw above, and eukaryotic cells are incapable of
circadian output while mitosing at intervals shorter than 24 hours (Ehret and
Wille, 1970; Ehret, 1974; Wille, 1979).
:. 15, owe~er, iSJ10t true 0 . pro aryotes: 'at least Synec ococcus gatescell division
by multiples of a circadian' dock cycle even when dividing at inteevals averaging as
little as 10 bours {Mori et al., 1996' Kondo et al., 1997),
A dramatfc example of division g~ting by the circadian dock is the helicoidal tirr'e
crystal and pbase singularity of niitotic ,timing imposed on EugJena through its
tn
circadian dock (Malin6'(\'ski' et aJ., 1985). a .sEtnse, Type 0 resetting of t~e circadian
clQck that gates mitosis amounts to a Type 0 resetting of the mitotic cycle, but I have
ot found ~a way t9 -use"this sen$e to infer anything about the dynamics of mitosis.
Tnare IS; howev.E!r; a related conjeCfiJJe 'n-need of test In the laboratory. Just as egg-
laylng (~raps 1954),_ Drosophila edosion (Chapter 2~ and human sleep timing '
(Winfree, 198~a, 198~ar r986a, 5troga12 1986, 1987a< and- b) seem regu(ated by a
$epa~te' circadian "lock accoiding to the principles of Ch~pter 20, Figure 1 and Box
AI '~ might e, cell divisiol; ' ILtnis coula ,be es.tablished -(by the same simple
observatio[ls as irr- the: othel' three casesr, it migl:lt have- vital implicatiQns for cancer
'~.ßfl1o~herapy. C::ould gatfng princ1pJes fo,: the control of cell division timing by the.
ircadtan rhythltLOr' by, a light-dark.c:ycle be ihvestigated 'ln at least Synechococcu~,
Eugfeha, Gonyau/ax, and i Physarum when its circadian clock is:oiscovered? As fat as I
am aware, they- hay~ not yet f,?und use i.n connection with.cell division. But cell cultures
do someti ' es) sh,?w discre gates- it no calls dividing in the inteftm.. ~as in Figur~ 1
642 22: THE CELL MITOTIC CVCLE

(Edmunds, 1984, 1988; Mori et al., 1996). Figure 1 of Oiapter 20's Box A can be
modified to represent cell division as growth toward a threshold at which cells dlvide
back to half size and resume growth, while a cir<:adian rhythm smoothly modulates
some rate or threshofd involved jn this process. (If many ' independent rates and
thresholds are modulated, I do not know how complex the results may become.).
Culture conditi~ns could be such thatwith the circadian dock suppressed (~d a" rates
a!1d thresholds hetd fixed somewhere inside the llsual circadian range) the .mean
division interval isso dose to 24n/m (n,m any integers) hours that this model converges
to strict periodicity during circadian f1uctuations. But otherwise the entire darkened are
of Figure 1 ~ould be sarnpled, with testable impFcations for tbe distribution of division
times (thevertl~al projection 'n Figure 1) and fprthe 'distriö:ution of cell size at divisioR
(the horizonta} prorectron), and for a characteristic abrupt change in both when the
amptitude of threshold modulation passes the level at which tcmgency becomes
possible in Figure 1. Or every such model could be exduded by showing that there are
110 circadian rhythms in cultured cells whose division intervals anyway continUe to look
random, orthat modulat1on by anextemal mythm of nutnent availabilitY. ortemperatur.e
produces no suCh characteristic distribution shapes, or, in particular, that the di~fsion­
free gates are only a rarity that can be more readily interpretEtd as an artjfact.
To review the relatioflsbips between mitotic and drcadfan cydes in eu~aryotes, see
Edmunds and Adams (1981) anq Edmunds 1984, 1988). ~

C: Further Developments in the Area of Circadian Rhythms,

Applied Back to the Cell Cycle
A Phase Singularity?
It was in context of circadian rhythms that Type 0 resetting (see Boxes B and C of
Chapter 4) was first noticed as something qualitatively distinctive and impossible to
account for in terms of movement along a fixed cyde. This led to development of
experimental criteria for distinguishing between qualitatively different kinds of
dock mechanisms, in terms of topological features of their resetting behavior. Such
methods are capable of revealing whether the cell cycle really ought to be thought of
strictlyas a cyde (as in Figures 1 and 2). An alternative would be to endow it with
"insides," necessarily induding astate of indeterminate or ambiguous phase as in
Chapter 6. Such astate would have no dear interpretation in terms of the sequence-
of-stages interpretation of the cell cyde. During the 1970s at least seven models of
this sort were advanced in the cell biology literature. Though there are some
experimental grounds for taking this possibility seriously (see Section D), all the
results I know of seem compatible with a notion advanced in several fonns by
Rasmussen and Zeuthen (1962), Rusch et al. (1966), Zeuthen and Williams (1969),
Pritchard et al. (1969), Sachsenmaier et al. (1972), Cohen (1972), Fantes et al. (1975)
and Sudbery and Grant (1976). According to this dass of models, some single
structure (division protein) or substance (mitogen) accumulates or is diluted
steadily during the cell's growth. When enough has accumulated or when cell
volume has sufficiently increased, mitosis is triggered and the substance is made
anew or accumulation is restarted, initiating the next cycle. An appealing version
 C: FURTHER DEVELOPMENTS IN THE AREA OF ClRCADIAN RHYTHMS 643

due to Sachsenmaier is that the accumulating initiator substance combines with

nuclear receptor sites, which double stepwise at each mitosis. Mitosis is triggered as
often as all available sites are saturated. Thus the control mechanism of mitosis acts
like an hourglass or relaxation oscillator. In terms of the categories of model
mentioned above, it acts like a simple dock with a single switch. The abrupt
resetting characteristic of such models is inferred from the abrupt change typieally
observed in the plasmodium's response to fusion with another plasmodium at a
particular phase in the cyde.
This is not a necessary inference from the observations, since the same
data could indicate a phase singularity associated with a smooth cyde of a
correcdy chosen shape (Winfree, 1974c; and Kauffman, 1974). But experiments
have produced no compelling reasons to doubt the earlier interpretation (see
Section D).

Chaotic Dynamics Outside the Nucleus?

Advocates of oscillator mechanisms for mitotic timing usually place the oscillator
outside the nudeus, leaving the nudeus to initiate its chain of necessary events upon
signal from the triggering oscillator (see the list above under "Feedback Oscillation").
It seems to me likely that such a parochial "gate keeping" aspect of the cell cyde might
vary in behavior and in mechanism from one cell type to the next. In the extreme case
of very complicated or irregular (chaotic) dynamics, such a gate-keeper dynamic
might account for the great variability of intervals between mitoses typieal of
mammalian cells. Conjectures of this sort began with Engelberg (1968), who
suggested that mitosis might be triggered when the sum of many separate harmonie
oscillations in cell metabolism momentarily exceeds a threshold. Burton (1971) and
Burton and Canham (1973) elaborated on this notion. Leigh (1965), studying
superimposed predator-prey oscillations in ecological context, worked out the
statisties of such threshold crossings. But comparisons with data on mitotic variability
were never carried out. The first explicit efforts to distinguish between models on the
basis oftheir statistical behavior are due to Bums and Tannock (1970) and Smith and
Martin (1973). They suggest that the variability of mitotie intervals is almost all due to
a variable delay of unknown cause between the completion of one cyde and the
initiation ofthe next. They found that the delay can be described by a Poisson process.
Subsequent experiments bear this out: Minor and Smith (1974); Brooks (1975, 1976,
1980); Shields (1976, 1977); and Shilo et al. (1976).
Models have thus far attempted most combinations of continuity versus
discreteness of state; of involvement vs. independence of the stages of nudear
replication; of one state variable vs. two; of determinism vs. probabilism. The next
innovation will probably have to exploit the fashionable behavior of "strange
attractors" and "cusp catastrophes," by accounting for both mitotic repetitiousness
and for variability in terms of three state variables, two of which cyde smoothly
644 22: THE CELL MITOTIC CYCLE

while the third undergoes a jump at mitosis time. The raw materials for such a
model can be found in the papers of Zeeman (1977) and of Rössler (1976-78) (see
also Box B of Chapter 13). The stochastic-start models originated by Bums and
Tannock (1970) and Smith and Martin (1973) sound like natural candidates for
formalization in terms of a chaotic attractor or an attracting cycle tangent to a
homoclinic point.
It should be noted in connection with such a phylogenetically eclectic literature
that experiments on bacteria, slirne molds, yeasts, frog eggs, and mammalian cens
might not all require the same interpretation.

a·
... This field has 'seen deeade of revolutlonary progress sihc'e the iscovery Of genes
ede1 and cde2 and corresponCling cycUn.- del'endent klnases. On~ corresponding
dynamical model (Romond et al., 1999) invokes oscillatory klnetiFs ba~ed' on th~se
proteins to regulate M phase (the mitotic cyde), 'ariQ again; with 'related proteins, to
regulate 5 phase (DNA synthesis.) Depending on hQw tAe Mo ttracting cyeles arE!
coupled/ one gets regular penodicity or chaos. ,.._:~'..>o-""_ _• _ _ _"",,,,_ _ ......._ .........

D: Physarum polycephalum
Synchronous Nuclear Division
F. L. Howard discovered in 1932 that the true slime mold, Physarum polycephalum,
behaves in nuclear division much like a single gigantic cell. All its nuclei coexist in
one blob of jeIly, undivided by plasma membranes or cell walls. A similar situation
obtains in other members of the kingdom fungi, in multinucleate tumor cens, in
multinucleate frog eggs, in the malaria plasmodium, in artificially fused cells, and in
early insect eggs. In all these cases, nuclear division among the several nuclei occurs
synchronously. In Physarum, the effect is more dramatic and biochemically more
convenient for its sheer massiveness, as millions of nuclei cleave within 15 minutes
during a 9- to 12-hour cycle. Such synchrony is difficult to obtain and is ephemeral
in suspensions of independent cens.
The fact of nuclear synchronyencourages belief that division is triggered by
soluble factors equally distributed throughout the cytoplasm. The causes of the
observed synchrony are not understood, but have been subjected to much
experimental study, especially since Guttes et al. (1969) discovered the
technique for fusing two plasmodia. Though each of the two parent plasmodia
is synchronous within itself, their phases may be quite different. Fusion results
in thorough mixing of the two parents. As they now constitute one plasmodium,
nuclear fission is again synchronous. Rao and Johnson (1970) and Rao et al.
(1974) carried out fusion in the same format using mammalian ceIls, with
results much like those obtained in the more extensive experiments with
Physarum.

Phase Compromise Experiments

One question asked in such experiments is, "What will be the compromise phase?"
 D: PHYSARUM POLYCEPHALUM 645

Guttes et al. observe that the compromise phase is simply the average of the
parent phases, or a weighted average in case of unequal weights of the two parent

Figura 5. Fusion of plasmodial pieces derived from

two differently phased macroplasmodia (A) and (8) at
various time intervals. Small plasmodial pieces (",1.5
cm 2) were excised from (A) and (8) and placed on top
of each other. The horizontal projection of each point
onto the oblique line indicates the time when fusion
was started. Three examples are marked with double
arrows (a, b, cl. Fusion is complete within approxi-
mately 1 hour. Time unit: duration of one division cycle
('" 10 hours). (.) Time of mitoses in parent cultures
(telophase) ; (0) mitoses in mixed plasmodia. (shaded
areal Entire period of mitosis (8,) from prophase to
telophase. (From Sachsenmaier, 1976, Figure 1, with
perrnission .)
8, •
o .5 '.0 TIME 1.5

plasmodia. In taking this average, they consider phase as a number from zero just
after division, increasing to one just before next division. A unit discontinuity occurs
at division. In a critical series of experiments Sachsenmaier et al. (1972) took two
plasmodia one-half cycle apart, and fused sampies of each from time to time
throughout the 10-hour cycle. For the first five hours of fusion time, the fused
plasmodia eventually divided at a certain fixed compromise time (Figure 5). But
fusion after the leading parent divided resulted in eventual phase compromise five
hours shifted relative to that observed in the first half of the experiment. For the
remaining five hours of fusion time, the result stayed the same, then it shifted back
after the lagging parent divided. This all suggests a startlingly simple interpretation.
In the words of Tyson and Sachsenmaier (1978):
An unstable activator, which is synthesized at a rate proportional to cell mass, binds
reversibly to certain nuclear sites. When enough activator has accumulated to titrate
all these sites, mitosis and another round of DNA synthesis are initiated .... (or) ... an
unstable cytoplasmic inhibitor is in equilibrium with a nuclear component so that
its total amount is proportional to the number of genome equivalents in the
plasmodium. During growth, inhibitor concentration decreases until it reaches a
critical value below which nuclear divisions and DNA synthesis are no longer
suppressed.
The question of phase compromise is made even more tantalizing by the
observation (see Chapter 1, last section) that it is impossible to construct even a
hypothetical table of compromise phase as a function of parent phases without
including either a large discontinuity or aphase singularity.
I recall the excitement of Sachsenmaier's year at Princeton in 1969 and our
conversations about the prospects of someday completing the phase compromise
646 22: THE CELL MITOTIC CYCLE

measurements. The experiments we outlined would fill out the (<PA, <PB, weight ratio)
cube, plainly exposing the anatomy of the unavoidable discontinuity. When these
laborious experiments are done in such a way that fusion is prompt and synchrony
is complete, then the critical questions will be:
1. Does the dependence of compromise phase on parent phases and bulk ratios
have
a. A diagonal discontinuity plane (two-dimensional), indicating a perfecdy
circular attracting cycle with a perfectly eentered stationary state (Chapter 1,
Figure 26). Or,
b. Two perpendicular diseontinuity planes (two-dimensional) near mitosis
time, indicating a eritieal phase, as in the hourglass or sawtooth relaxation
oseillator model? (Chapter 1, Figure 24). (Note that both this case and (a)
may be viewed as extreme limiting eases of an attraeting eycle.) Or,
e. A filament-like (one-dimensional) phase singularity indieating an asym-
metrie attraeting eycle? (Chapter 1, Figure 25). Or,
d. Some other presently unforeseen shape, possibly beeause some state
variables equalize mueh more slowly than others after plasmodia are fused?
(Box A).
2. Is there any loeus of fixed <PA or <PB erossing the (<PA, <PB) unit eell at equal parent
weights along whieh no diseontinuity is eneountered (Figure 6)? This would be
awkward to aeeount for by any model involving a physiologieal jump at a
eritieal phase in the nuclear division eycle; and if not,
3. Does the compromise phase Vary along that locus with winding number W= 0,
implieating aphase singularity?

Figur. 6. The (rftA, rfta) torus, skinned and flattened as a

unit cell in a square lattice. Does the compromise phase
jump discontinuously somewhere in every band crossing
the square, e.g., the shaded zones?

This measurement would be unbelievably laborious if earried through the

seeond or third division following fusion, as a purist would require. So it is unlikely
ever to be done. However, enough data have been available in the plane of weight
 D: PHYSARUM POLYCEPHALUM 647

Box A: Phase Compromise Among Physarum Nuclei

In Section C of Chapter 1, in Example 9 of Chapter 2, and in Box F of Chapter 6, we saw

that the dependence of hybrid phase on parent phases cannot be continuous. In those
arguments we assumed that the hybrid's phase typically varies smoothly as one parent's
phase is varied through a full cyde. This was assumed because the alternative is to
assume a discontinuity at the outset, leaving nothing to prove. But that may be exactly
what Physarum offers uso It appears that there is aphase somewhat before nudear
division when Physarum's dock changes its reaction to perturbation so rapidly that no
experiment has yet succeeded in resolving the change as a process in time. For practical
purposes of measurement, it is a discontinuity.
Does this mean that attracting-cyde interpretations are exduded in favor of single-
variable relaxation oscillators? Nothing of the sort. Nor does a rapid jump in the course
of an attracting cyde necessarily imply anything about dynamics elsewhere in state
space, or about isochron geometry and singularities. It only prevents our using the
purely topological arguments of Chapters 1 and 2.
Box F of Chapter 6 took an alternative approach by supposing a particular dynamic,
interpreting the state variables as chemical concentrations, and supposing that
oscillators combine by pooling their corresponding chemicals. That particular model
could be modified to give the attracting cyde an abrupt jump of some sort at phase 0
(e.g., Tyson and Kauffman, 1975). Then the contour map of hybrid phase c/>3 would
resemble the figure below: c/>3 has a mirror-image pair of phase singularities in each unit
cell and a discontinuity along the perpendiculars c/>! = 1 and c/>2 = o. These features are
by no means mutually exdusive. Finding one does not eliminate the other.
But Physarum evades this test too, for whatever may be the nudear state variables
governing the division dock, it seems unlikely that they all mix freely when plasmodia
are fused. That means that the hybrid's state is given unambiguously only in the
product space of two oscillators: aspace of at least four dimensions in which the
geometry of isochrons and their singularities is harder to visualize. Hence category
(ld) : If there is another discontinuity besides the one associated with the jump in the
normal division cyde, it may take unforeseen forms.
No such objects have been found in any shape or form. But the data are imprecise
and much remains for eager hands to undertake.
l2l e
648 22: THE CELL MITOTIC CVCLE

ratio = 1 sinee 1972 to strongly suggest (1b) and praetieally rule out (1e): Remy,
1968; Saehsenmaier et al., 1972; Chin et al., 1972; summarized in Tyson and
Sachsenmaier, 1978). Contour lines through these measurements dearly show
perpendieular one-half eyde diseontinuities as in Chapter 1, Figure 24. The data are
sometimes irregular but there is no dear hint of aphase singularity (1 c) penetrating
the plane of weight ratio = 1.
Kauffman et al. (see below) reexamined the question with particular alertness to
evidenee of attraeting-cyde kinetics in the mitotic eyde. They pursued the two main
dasses of experiment that have beeome traditional in this field:
1. Two plasmodia at different phases are fused, resulting in aphase eompromises
as their two division rhythms synehronize to one. The results are examined for
evidenee of eritieal phases, at whieh either eell's physiology abruptly ehanges, or
for a eombination of phases such that the eompromise phase is unpredietable in
the ways anticipated from the attraeting-eyde conjecture (Chapter 6) (Kauff-
man, 1974; Tyson and Kauffrnan, 1975; Kauffman and Wille, 1975, 1976).
2. A physiological shock, such as incubation at 37°C, retards or advances the next
division. Clues are sought in the amount and direction of phase shift as a
function of the initial phase when the shock is administered (Wille et al., 1977).
Both experiments are potentially capable of revealing a phase singularity if one
exists, and both are capable of demonstrating Type 0 resetting.
However, neither phenomenon has emerged from Physarum (Tyson and
Sachsenmaier, 1978; Loidl and Sachsenmaier, 1982). In fact, those of the fusion
data from Kauffman and Wille (1975) in which thorough mixing and synchronyare
reported do fill out the 1972 pieture more thoroughly and quite consistently.
Kauffman and Wille (1975) condude that nudear division in Physarum behaves
more like arelaxation oscillator than does their model.
In this circumstance I feel compelled for the present to abide by the first of
Newton's two exhortations at the opening of this chapter, despite the attractiveness
of theoretical schemes involving phase singularities. At the same time it must be
remembered that Physarum fusion experiments can never resolve events more
dosely than the 45 minutes required for plasmodia to fuse. Any number of
singularities might lurk unresolved in the hour of ostensible discontinuity preceding
mitosis.

Who Ca res?
Knowledge of cell dynamics has obvious practical importance and obviously
involves considerations of circular logic akin to those outlined in Chapter 1. I
remember with pleasure recurrent discussions on this fact with Graeme Mitchison
in 1971, eontinuing hours after tables had been cleared in the Cambridge MRC Lab
cafeteria. We wondered whether phase singularities could reasonably be pursued in
this matter, and decided against it. But Stuart Kauffman decided on a more
aggressive approach to the question, taking it to the master, Physarum. If Kauffman
and friends accurately interpreted Physarum's answer, then nudear division is
regulated by a continuous attracting-cyde oseillation that operates independently of
nudear division itself.
 D: PHYSARUM POLYCEPHALUM 649

Such a discovery would belong in a conspicuous place in the main text of this
volume as perhaps the main fruit of the search for phase singularities. I have chosen
not to put it that much in the spotlight because I am apprehensive that Physarum's
behavior may be very much more complicated than any of the simplistic models
here entertained. But more data may come and I do recommend the matter to your
attention, as the outcome may be important.
 The Female Cycle

Depend upon it: there is nothing so unnatural as the commonplace.

Sherlock Holmes, A Case of ldentity

.. Would that"! had worcfs tliat are unknoym, .utterances an sayil1gs in resn
language; without 'that whicb has been said repeatedl)l', ra!her tha . utterance
that has growr:f stale. being wh at the ancestors have alr~ady said. .
. KhekhepRere--Sonbu of Egyptabout 2150 B.~.E'J
(translate? by Adolf Errnan in Literature of thaAncfent cgyptians, 1929)

Tl'\is short chapter rernains just as it was, not because I think it answers fundarnenta~
.questions. but because in 1999 answers to, those lt posed 'n 1978 are still nowhere to
be found. These question$ probably seem fnappropriate Horn the' viewp?int 0
endocrinologists decip ering an arnazingfy co rn pli cated mechanisrn. But.the same
appearance of Junacy cha!act~rized several other ventures/ehapters in which the
answers I?toved inteIe~in9' ... .,.

A: Women, Hormones, and Eggs

Monthly bleeding rnay have been commonplace among nuns, spinsters, and the
infertile centuries ago, but it could hardly have been common among the wornen to
whose uteri we all owe our existence. When they were not pregnant, their breast
feeding encouraged lactation, which suppressed ovarlan cycling. Short (1976)
estirnates that it rnay have been uncommon to experience three consecutive
menstrual cydes in a lifetim,e under these conditions. Accordingly, the human
female endocrine system's menstrual cycle has not been subjected to selection
pressure for its dock-like attributes. In fact, there are diverse dues that some
fraction of wornen are reflex ovulators, not spontaneous cyders at all (Clark and
Zarrow, 1971).1 In a reflex ovulator, mature follides await rupture by a surge of

Rats too (Taleisnik et al., 1966; Moss et al" 1977) .

A. T. Winfree, The Geometry of Biological Time 650

© Springer Science+Business Media New York 2001
 A: WOMEN, HORMONES, AND EGGS 651

Box A: The Mechanisms of the Normal Human Female Cycle

The chief actors in this drama are two glancls, the ovary and the anterior pituitary.
Neither alone is intrinsically cydic in its activity. Corresponding to the two glands are
two pairs of honnones.
First, there are the two glycoprotein gonadotropins, so called because they affect the
gonad (the ovary). These are luteinizing honnone (LH) and follide-stimulating
honnone (FSH). These are secreted by specific cells in the anterior pituitary in
response to honnonal releasing factors from the hypothalamus.
Then there are the two dasses of steroid sex honnones, aimed at the anterior
pituitary (by way of the hypothalamus) and at the uterus (see below). These are
estrogenic steroids (E) and progestational steroids (P), all synthesized in the gonad
(the ovary) and secreted.
The principal gland of the ovary is the follide, of which there are many, all being
matured under the stimulation of gonadotropic honnones to secrete estrogen. Some
mature as far as to release an egg then secrete mixed estrogen and progesterone. The first
step ofthe cyde, when the follides are only making estrogen, is called the follicular phase.
After one of them ovulates, it turns into a yellowish body called the corpus luteum, which,
in addition to estrogen, synthesizes and releases progesterone. This postovulatory half of
the cyde is therefore called the luteal phase. These ovarian steroid secretions in turn
control the pattern of pituitary gonadotropin release both directly and by way of the
hypothalamus, thus dosing the causal cyde. In humans, the corpus luteum has a built-in
lifetime of about 14 days, toward the end of which its progesterone and estrogen outputs
decline. This disinhibits pituitary gonadotropin release with the result that a new follide
begins its sequence of estrogen production, rupture, and combined estrogen and
progesterone secretion, while its predecessor degenerates.
Not linked in this dosed chain of cause and effect, the lining of the uterus
proliferates under the sequential stimulation first of estrogens and then of progesterone.
The luteal progesterone says, "The follide has ruptured, prepare for implantation."
When the corpus luteum begins to fade after two weeks, it no longer provides enough
progesterone to support the uterine deciduum, which thus eams its name by sloughing
off. This marker event is the onset of monthly flow, conventionally indicating day one of
the cyde. Because it is affected by, but does not affect the honnonal interactions, it is
not properly a part of the dock-like mechanism. (According to another convention of
labeling, menses start not on day 1 but on day 14, ovulation taking the preferred
position of day 1 in the cyde.)
Women differ from animals with a breeding season in that gonadotropins are
secreted all year round in amounts adequate to encourage follides to develop. In
seasonal breeders, gonadotropin levels are kept below a minimal level, thus inhibiting
cycling, except when the photoperiod is right (and the photoperiod is monitored by a
circadian dock). Most women also differ from reflex ovulators in that gonadotropin
secretion reaches a peak when the follide is mature, causing it to release its ovum. In a
reflex ovulator, in contrast, adequate LH output and rupture of the follide occurs only
upon command to the hypothalamus by stimuli associated with mating. In rodents that
cyde spontaneously this stimulus to the hypothalamus and thence to the anterior
pituitary may be provided daily by an internal circadian dock in or mediated by the
suprachiasmatic nucleus. In humans the hypothalamic stimulus seems independent of
circadian factors and independent of sexual stimulation.
The sketch provided above is obviously misleading in its oversimplification (van de
Wiele, et al., 1970; Lein, 1979). The female cyde, like many biological regulatory
652 23: THE FEMALE CVCLE

mechanisms, is characterized by redundancy, by multiple fail-safe devices. This makes

it hard to unravel any one "mechanism." It also allows great evolutionary diversifica-
tion, since many parts of the interacting machinery can mutate independently without
imperiling the main function they collectively subserve. Thus, every published
experiment on female cycle mechanisms must necessarily be flagged with a label:
"guinea pig," "hamster," "rat," "marsupial," "ungulate," "primate," or "human."

hormone that is elicited only by sexual stimulation. The ovum then starts its joumey
down the fallopian tube, and pregnancy (or, less likely, recycling) ensues.
One of the stranger byproducts of improved survival of infants and of western
sexual mores is that lactation is discouraged in industrialized societies. Consequently,
the female endocrine system nowadays commonly functions in a periodic mode. It
cycles only because after an ovum worles its way into the well-prepared uterus without
finding a sperm, there is little alternative but to start over with the next follicle.
The one baffling mystery in this glib story surrounds the fact that the next-ripest
follicles are so immature that they will take weeks to ripen, thus ensuring adefinite
minimum interval between ovulations. No one seems to have a clue as to the
mechanism that selects a single ovum out of a teeming ovary and encourages its
growth for a full month. In fact, a multiplicity of candidate follicles are initially
recruited but most of them eventually wither, yielding to the one chosen. This
competition may contribute to the notorious variability of the female cycle, most of
which is confined to the preovulatory, follicular half of the cycle. It is not even
certain that release of the egg is an essential part of the causalloop that constitutes
the female cyele at all. According to one view, it is only a peripheral process
governed by, but not importantly affecting, the female cyele. The evidence is
basically that anovulatory cyeles take about the same length of time whether
ovulation occurs or somehow fails to occur. To me, such evidence speaks rather for
two parallel alternative pathways of cyele completion, one with a follicular estrogen
spurt and subsequent progesterone manufacture by the corpus luteum, and one
without. The hormonal receptors of the female endocrine system might be
indifferent to these alternatives only in the limited sense that both paths might
happen to take about two weeks. Fuller understanding awaits clarification of the
mechanisms of competition and selection among follieles in the ovary.

Though ovulation may or may not be a peripheral, gated process, monthly

sloughing of uterine decidua definitely iso The human female cyele proceeds
normally in the absence of the uterus and there is no known hormonal or neural
 B: STATISTICS ("AM I OVERDUE?!") 653

feedback from the uterus to the endocrine glands (see Box A, outlining the normal
endocrine cycle).

B: Statistics ("Am I Overdue?!")

Oblivious to our uncertainties about mechanism, the human ova!)' in nonpregnant,
nonlactating women releases an ovum every four weeks or so. The consequence in
modem society is monthly flow. So widespread and long established is this
phenomenon that women sometimes complain of menstrual irregularities and
even prefer birth control pills that artificially induce periodic bleeding (perhaps as
reassurance that pregnancy has in fact been forestalled for another 28 days). How
regular is the female cycle? It appears that successive intervals between recurrences
of menstrual onset (the most obvious phase marker) are nearly independent
sampies from a probability distribution. The mean interval depends in a regular
way on the individual age (Treloar et al., 1967; Pochobradsky, 1972). For women
aged 20 to 40 the standard deviation is typically a few days (that is, about two-thirds
of intervals fall within a few days of the mean and about nineteen-twentieths fall
within twice that range).

figur. 1. Vertically, intervals between 189 successive 30 1----+--------l~-+--_+--I

menstrual onsets, in days, recorded by DSW. Note the I ." .. :'. ., ':: .., :." .:~.-".-:~"" .. "".:. ",
..
four long intervals caused by pregnancies. Ovulation was ro ~-~-+----II---+-~~--I
not regulated by "the pill" or other artificial synchronizers.

In the example shown in Figure 1 (data collected by my mother from age 18 to

age 33), 189 consecutive cycles (intenupted by three pregnancies and terminated
after a fourth) have a mean of 25.0 days with a standard deviation of 3.2 days,
most of which is presumably (according to Presser, 1972) in the preovulatory half
of each cycle. These statistics do not Va!)' markedly between the four segments
punctuated by pregnancies (Figure 2). Figure 3 plots each interval against the next.
If flow onset occurred sometimes early or sometimes late in a more regular
underlying cycle, or if the calendar dates were inaccurately recorded, then this
cloud of dots would be elongated along a -45 slope, since errors that lengthen
0

one interval would shorten the next by the same amount. If there were long term
variations of period (for example, longer periods in winter or when older), the
cloud would be elongated along the +45 0 slope, since long intervals would tend to
654 23: THE FEMALE CVCLE

'5

Figure 2. As in Figure 1 but the vertical scale is

t 10
cumulative days, spanning fifteen years. The mean
interval and standard deviation are indicated before
each pregnancy terminates that record. The four means
are about one standard deviation shorter than Presser's
(1972, p. 150) population mean, and exhibit about the
same variability as he found (op. cit., p. 154).

160 200

follow long intervals, etc. Neither effect stands out conspicuously in these data.
Gunn (1937) reported little positive or negative correlation between consecutive
cycles on the basis of much larger sampIes and more thorough statistical analysis.
This would seem to minimize the plausibility of lunar entrainment (Menaker and
Menaker, 1959).
If a hormonal disturbance caused a sudden phase shift, how noticeable would
it be? How many cycles N should we wait for passage of any transients before
observing the asymptotic phase shift inflicted on the central timing mechanism?
Using the same data base, Figure 4 portrays the unperturbed rhythms' probability
distribution of times of next flow onset, of the second flow onset, and of the
third, all measured from a given onset at T = O. Jf there were no correlations
between successive intervals, aphase shift of less than about twice the standard
deviation times the square root of N would be lost in the intrinsic variability of
the period. With a standard deviation of 3.2 days and allowing two cycles in case
the first period is abnormal, the minimum reliably measurable phase shift would
be (±2 x 3.2 x V2) = 9 days out of 25. Figure 4 indicates that this is indeed
approximately the observed variability in the second cycle, and it gets worse after
three or four cycles. This makes it difficult to work quantitatively with the female
cycle's resetting curves.

40

30
Flgure 3. The successive intervals of Figure 1 are plotted each
against the next (omitting the four pregnancies). The symmetry of
20 the scatter indicates no positive or negative serial correlation of
intervals.
10

°O~~IO~-2O~~3O~~4O--~~
I,.,
 C: REPHASING SCHEDULES 655

.
3D

'"

'0

O ~ _____......

o
" WEEQ

Flgure 4. On a horizontal scale of weeks, the number of intervals of each duration is plotted:
Peak 1, from one onset to the next, i.e., from i to i + 1. Peak 2, from i to i + 2. Peak 3, from i to
i + 3. Peak 4, from i to i + 4. (Data from Figure 1.)

C: Rephasing Schedules
Despite quantitative variability, at least one qualitatively essential feature should be
discemible. We should be able to detennine the female cyele's topological Types of
resetting. Does it achieve Type 0, given a sufficiently strong perturbation? If so, then
some interesting discontinuities are implicit at lower doses. The possibility even
exists that the female cycle has a phaseless set (see Chapter 6), from which it never
comes out again spontaneously, once perturbed into that range of states. Accidents
of this sort could conceivably underlie some varieties of amenorrhea. Lasting
amenorrhea, induced deliberately by a single fleeting perturbation, might have
some advantages as a contraceptive technique. Preliminary evidence comes from
limited clinical experiments, from computer simulations hopefully summarizing the
best contemporary information on the hormonal mechanisms of the human
menstrual cyele, and from more extensive experiments using the estrous cyeles and
menstrual cyeles of large mammals.
First, the clinical results: Hormonal phase shifting is possible and the first full
cyele after perturbation seems normal. The phase shift is a sufficiently reproducible
function of phase to pennit reliable entrainment to perturbations administered on a
regular schedule at periods elose to the normal cycle duration (Cseffalvay, 1966;
Boutselis et al., 1971, 1972; Yen and Tsai, 1972; Arrata and Chatterton, 1974;
Abraham et al., 1974; Dhont et al., 1974; and Shaikh and Klaiber, 1974). There are
some reports that visible light also serves this purpose (Lacey, 1975; Dewan, et al.,
1978). Large phase shifts are possible, as is required for Type 0 resetting. For
example, the large dose of estrogen commonly administered in cases of rape
promptly dumps the uterine decidua and therefore presumably resets the female
cyele to a standard phase; however, I have not seen data demonstrating that
656 23: THE FEMALE CVCLE

subsequent eydes are normal nor that the reset is nearly independent of the initial
phase in the follieular and hormonal eyde.
Seeond, the results from reasoning through the detailed meehanism of
menstrual rhythmicity: A variety of numerieal models of the endoerine
interaetions thought to underlie the female cyde have appeared in the teehnieal
literature. The deficiencies of some of these models have been eonspicuous and
their evolution has been prompt. It is by no means clear that reality is in hand
at present. However no Type 0 resetting ewves have yet been produeed from
these models. Using the model of Shaek et al. (1971) and Stetz (1971), I tried
progesterone doses of various sizes applied at various times throughout the eycle
and obtained only small phase resets (1972, unpublished). Using the mueh more
sophisticated model of Bogumil et al. (1972), graduate student Erie Best and I
tested the effeet of estrogen injeetions at various times in the eycle, looking for a

.
- 21 "r-_H...;.;E~Ä...;..;JS~--:"1

.. ...
•

..
..
. . I Figura 5. Datafrom Cooperand Rowson,1975, Figure 1, replotted
DAYS in the format of Figures 31 through 33 of Chapter 1. Dots indicate
onset of behavioral heat in heifers. The normal period length is 21
I
+
days; these experiments thus scan one cycle. Onsets occur two to
three days after the standard stimulus regardless of when in the cycle
it was administered.
O~"""'''''''''''''''''''''"''''="'''1
2
4
... ·'::·':·1 1·····.

permanent rephasing of the subsequent endoerine rhythmicity. The data

obtained (Best, 1975) showed eonspicuous diseontinuities as a funetion of the
initial phase and in many eases lapsed into strange eydes that seemed to raise
doubts about the realism of our implementation of the model of Bogumil et al.
(1972). Subsequent simulations by Bogumil examined the effeet of estrogen
infusions administered at various times in the eyde. The resulting resetting
ewve showed three glaring diseontinuities in the follieular half of the cycle and
none at ovulation or in the luteal phase (Bogumil, 1976, personal eommuniea-
tion)?

2 Note that real diseontinuities in the rephasing response do not necessarily reveal diseontinuities in
the oscillator meehanism. If they did, one might have to look askance on Bogumil's simulation beeause its
diseontinuities eorrespond to no eonspicuous physiological event. For example, a smooth kinetie scheme
whose attraeting cyele is knotted has a phaseless set of peculiar topology in the pertinent state space. This
results in surprising discontinuities of new phase over a whole range of (old phase. stimulus magnitude)
eombinations.
 D: THE QUESTION OF SMOOTHNESS 657

.'
Figure 6. As in Figure 5 but data are from Palmer and Jousset, 1975a, Tables 2 .'.'
and 3. Dots represent the beginning of high progesterone phase in mares, which
also have a 21-day cycle. In both Figures 5 and 6 many of the single dots
represent several duplicate experiments using different individual animals.

Third, the results from animal experiments: The best animal data come from
veterinary endocrinologists tIying to optimize the efficiency of artificial insemina-
tion in cattle breeding (Cooper and Rowson, 1975; Palmer and Jousset, 1975a,b ). If
discontinuities be disallowed apriori, then the problem of synchronizing a
randomly phased herd amounts to the problem of obtaining a very flat Type 0
resetting curve. Resetting curve data obtained by these investigators in response to
schedules of hormonal perturbation applied at various phases in the cycle are
replotted in Figures 5 and 6. Close synchronization is obtained. The data look
superficially like Type 0 curves. However, it must be remembered that these
obseIVations terminated with a demonstration of excellent synchrony soon after the
last of a sequence of injections. Confirmation of Type 0 topology awaits a repeat
with verification that there is no very steep segment of the (Type 1) curve as in
Chapter 3, Figure 6 (I > 1, long M), and verification that subsequent rhythmicity is
normal following injection at each phase. (Note that the estrous cycle of ungulates
differs in mechanism from the human menstrual cycle.)

... In -199<P I carr find no further peFtinent reportS. :0( .,"_.,;=.;..'-.... "',..,"'~~~-". ;"',,;K;.Jo~"""""'"~'- ... ,.,,:.

D: The Question of Smoothness

Another issue involved here is even more fundamental than ascertaining the reality
of the Type 0 resetting which is so important in theoretical constructions: Can the
female cycIe be thought of realistically in terms of smooth dynamics on a time
scale of days, or at worst, hours? Most thinking on the subject of the female cycle
employs switch-like models that neglect considerations of continuity. Like the cell
cycle (Chapter 22), the female cycle is commonly described much as people
describe the operation of an internal combustion engine: as a sequence of discrete
steps linked by thresholds and logical switches, all proceeding in a closed loop
(e.g., Danziger and EImergreen, 1957). In this view, those parts of state space not
visited along the attracting cycle are ignored as though they did not exist. But, if
they do exist, they are important when the cycle doesn't pursue its normal course.
Contemporary fertility technology ensures that states off the normal cycle will
indeed be traversed, just as cancer chemotherapy ensures it for the cell cycle.
658 23: THE FE MALE CYCLE

Nonetheless, it is possible that this language of discrete state transitions is not

only a convenient artifice during an early stage of investigation, but also an
aeeurate refleetion of the dynamies of the female eyde. If the female cyde
embodies proeesses with radically different time scales then intervals of
eontinuous dynamics may be joined in a switch-like way by means of thresholds,
with the result that on a time scale of days and hours we face more discontinuities
than the minimum assortment required .topologieally. In that case many of the
methods exploited in this book would be superfluous because they only serve to
identify a discontinuity implicit in smooth kineties.

E: Circadian Control of Ovulation

In contrast to the human menstrual cyde, the four- to five-day estrous eyde of some
rodents has a short enough period to suceumb to regulation by circadian rhythms.
This may even have seleetive value in terms of optimal phasing for eoordination of
sexual activity in the day-night eyde. The principle that mammalian physiology is
organized on a 24-hour basis manifests itself in this situation as a regular time of
day for ovulation in such rodents as the laboratory rat, the laboratory mouse and the
golden hamster. The signal that ruptures the Graffian follide is an luteinizing
hormone (LH) pulse from the pituitary, which is in turn responding to a daily signal
from the supraehiasmatie nudei (SeN) (Fitzgerald and Zucker, 1976; Moore and
Eichler, 1976; Stetson and Watson-Whitmyre, 1976; Watson-Whitmyre and Stetson,
1977; Morin et al., 1977a; Rusak, 1977). The SeN, located just in front of the
erossing of left and right optie nerves, are in turn governed by the externallight-dark
eyde by way of the retinohypothalamic projeetion. But if that nerve eable is cut, the
SeN still exhibit eircadian periodicity, now free-running at the individual's own
period near 24 hours. The estrous eyde remains entrained four-to-one or five-to-one
by a circadian LH pulse: only every fourth or fifth day does the daily pulse find a
follide mature enough to rupture and produee a corpus luteum, whose seeretory
activity ultimately starts the next eyde.
In this situation, the female cyde's phase shifts in a predictable way. In response
to hormonal perturbation, it shifts by an integer number of cireadian cydes
depending on when in the four- or five-day eyde the hormone is administered.
Because the phase shift is thus quantized, the resetting "eurve" is discontinuous.
Topological arguments thus have no pertinence. To make any finer adjustment of
phase than this, it is necessary to rephase the seN dock, e.g., by delaying or
advancing the light-dark eyde. In eonstant darkness, resetting by a single light pulse
would also work, hut results are more variable (Daan and Pittendrigh, 1976h).
Not only does the circadian dock regulate the female cyde, but also
eonversely, estradiol feeds back to the circadian dock to shorten its period (in
hamsters) and also to alter the daily timing of its activity rhythm (Morin et al.,
1977b). In birds, testosterone has been shown to "split" the circadian rhythm and
to alter its period (Gwinner, 1974). The 1970s continue to treat us to an exciting
chapter of physiological investigation as the neural, neurosecretory and humoral
interactions among the pineal gland, the SeN, and the sex glands are progressively
revealed.
 E: ClRCADIAN CONTROL OF OVULATION 659

In contrast, no substantial role of circadian fluctuations has been established in

human or other primate female cycles, despite several deliberate inquiries, e.g.
Cameron (1969) (and I believe still so in 1999.)
The circadian clock plays a dominant role also in the seasonal photoperiodic
suppression and release of ovarian activity, not only in rodents but also in many
other varieties of mammal, bird, and reptile as weil as in the invertebrate animals.
660

•
Isn't it interesting to live in our time and have such wonderful puzzles to
work on?
RP. Feynman, quoted in James Gleick, Genius p. 352

I approached Feynman after one of his Cornelliectures in 1964 for advice about
how best to move into mathematical biophysics from engineering physics as I had
planned when choosing Cornell. He cautioned against any such move, on grounds
that biology is too much a matter of tricks and accidents of evolution, and too
complex for useful mathematical representations. I believe that is correct, on
average, but the rich diversity of living nature provides many niches for peculiar
questions and aptitudes.

•
 Index of Author Citations and
Publications
100
90
80
't:I 70
Q)
:t=
(.)
60 01978
e 50 01985
8- 40 1999
l 30
20
10
0
0 LO 0 LO 0 LO 0 LO 0
co co ....... ....... co co CJ) CJ) 0
CJ) CJ) CJ) CJ) CJ) CJ) CJ) CJ) 0
T'"" T'"" T'"" T'"" T'"" T'"" T'"" T'"" C\J

Shading Legend: Vintage years for the first edition of this book, for The Three-dimensional Dynamics of
Electrochemical Waves and Cardiac Arrhythmias (1987a), and for this Y2K update.

This histogram shows the nine hundred publications from which data were drawn for the 1978
arguments of The Geometry of Bio/ogical Time and the nine hundred added in 1999 for those in the new
(shaded) text. The trough between these scarcely-overlapping sources is filled by about as many other
publications cited in my intervening papers and (the middling distribution of about four hundred)
vintage-1985 monograph. I interpret the jaggedness as JN sampling error. In all three distributions the
year of writing is the next after and beiow the peak. After the 1977 and 1984 peaks the next entries were
mainly preprints received, listed without page numbers until galley proofs. It can be presumed simiIarIy
that the fall-off after the 1998 peak does not represent The End of Science but only my own siowness to
notice new discoveries.
None of these three distributions attempt to survey the world of publication on these topics, but only
to draw upon it for essential pieces of the puzzles here snapped together. They are drawn not from
literature searches but from the two- to three hundred papers per year, steadily over thirty years, that I
have found reason to study with care, marking up the figures and in many cases outlining the text. One
third of them (eighteen hundred) appear in the following reference list index that points to their roles in
specific arguments.

In the following list of References, the pages alluding to each publication follow immediately after
the name(s) in bold type within brackets.

Abakumov, A. S., Gulyayev, A. A., and Gulyayev, G. A. [439] (1970)

Propagation of excitation in an active medium. Bio{izika 15(6), 1074-1080.
Abraham, G. B., Chakmakjian, Z. H., Buster, J. B., and Marshall, J. R. [655] (1974)
The effect of exogenous conjugated estrogen on plasma gonadotropins and
ovarian steroids during the menstrual cycle. Obstet. Gynec. 43,676-684.
661
662 INDEX OF AUTHOR ClTATIONS AND PUBLICATIONS

Abraham, R. H. and Shaw, C. D. [176, 235] (1982) Dynamies, The Geometry of

Behavior, Part Dne: Periodic Behavior. Aerial Press, Santa Cruz CA.
Abraham, R. H. and Shaw, C. D. [176] (1984) Dynamies, The Geometry of Behavior,
Part Two: Chaotic Behavior. Aerial Press, Santa Cruz CA.
Abraham, R. H. and Shaw, C. D. [176] (1985) Dynamies, The Geometry of Behavior,
Part Three: Global Behavior. Aerial Press, Santa Cruz CA.
Abraham, R. H. and Shaw, C. D. [176] (1988) Dynamics, The Geometry of Behavior,
Part Four: Bifurcation Behavior. Aerial Press, Santa Cruz CA.
Agladze, K. 1 [292, 385] (1983) Charaeteristies of two-dimensional autowave
processes in ehemical aetive media. Ph.D. dissertation, Puschino.
Agladze, K. I. and Krinsky, V. I. [448] (1982) Multi-armed vortices in an aetive
chemical medium. Nature 296, 424-426.
Agladze, K. I. and Krinsky, V. 1 [409] (1984) On the meehanism of target pattern
formation in the distributed Belousov-Zhabotinsky system. In: Seif Organization:
Autowaves and Structures Far From Equilibrium, ed. V. I. Krinsky, Springer.
Agladze, K. 1, Keener, J. P., Müller, S. C., and Panfilov, A. [447] (1994) Rotating
spiral waves created by geometry. Science 264, 1746-1748.
Agladze, K. I., Kocharyan, R. A., and Krinsky, V. I. [402, 468] (1991) Direct
observation ofvortex ring collapse in a chemically aetive medium. Physica D 49,
1-4.
Agladze, K. 1, Krinsky, V. 1, Panfilov, A. V., Linde, H., and Kuhnert, L. [402, 474,
494] (1989) Three-dimensional vortex with a spiral filament in a chemieal active
medium. Physica D 39, 38-42.
Agladze, K. 1, Obata, S., and Yoshikawa, K. [115, 376] (1995) Phase-shift as a basis
of image processing in oscillating chemical medium. Physica D 84, 238-245.
Aizawa, Y. (1975) Perturbational approach to the phenomena of mode-locking in
nonlinear systems. Phys. Lett. 54A, 485-486.
Aizawa, Y. [91, 163,233] (1976) Synergetic approach to the phenomena of mode-
locking in nonlinear systems. Prog. Theor. Phys. 56, 703-716.
Alcantara, F. and Monk., M. [444, 446, 452] (1974) Signal propagation during
aggregation in the slime mould Dictyostelium discoideum. J. Gen. Microbiol. 85,
321-334.
Aldridge, J. [233, 235, 351, 355] (1976) Short-range intereellular eommuniea-
tion, biochemie al oseillations, and circadian rhythms. In: Handbook of
Engineering in Medicine and Biology, D. Fleming, ed. CRC Press, Cleveland, Ohio,
pp. 55-147.
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Zhabotinsky, A. M. [244, 378] (1968) A study of self-oscillatory chemical reaction
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Zhabotinsky, A. M. [277, 287, 510] (1970) Investigations of homogeneous chemical
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Zhang, H. and Holden, A. V. [462] (1995) Chaotic meander of spiral waves in the
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(1995) Optical transmembrane potential measurements during defibrillation-
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Zimmerman, N. H. and Menaker, M. [566] (1975) Neural connections of sparrow
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Zimmennan, W. F. and Goldsmith, T. H. [621] (1971) Photosensitivity of the
circadian rhythm and of visual receptors in carotenoid-depleted Drosophila.
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Zykov, V. S. [265, 278, 285, 331, 511] (1984) Simulation of Wave Processes in
Excitable Media. Nauka, Moscow, 1984; also in English translation ed. A. T.
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 759

•
Even a fool, when he holdeth his peace, is counted wise; and he that shutteth his
lips is esteemed a man of understanding. - Proverbs 17:28

It's too late for me. But maybe I can yet reform ....

•
 Index of Subjects

Acetabularia, 118, 547, 548, 586, 588, 590 Antheraea pernyi, 549, 553, 593
Acetaldehyde coupling (see also Phase resetting Antiarrhythmic pharmaceuticals, 534
by stimuli), 126, 236, 375 Antisyntalansis, 123, 128, 129, 132, 235, 345,
Acetylcholine, 406 365,422
Action potential, 411-42, 455-94 Aplysia, 176,413, 586, 687
duration restitution, 325, 408, 506--08, 524 Archimedes' spiral, 254, 284, 384
Active scattering of phases (see Entrainment, Aristotle, 46, 371
mutual: active resistance to) Arp, Halton, 549
Adult activity rhythm (see Drosophila Arrhythmia (so-called), cardiac (see Heart
melanogaster; Drosophila musde)
pseudoobscura; Mosquito) Arrhythmie mutants of circadian docks, 228,
Advance vs. advancing, 574 616
Advance vs. delayambiguity, 574 Arrhythmieity (see also Annihilation by
Aether, 300 singular stimulus; Incoherence)
Africanized bees, 255 Drosophila pupae (see also Drosophila
Aggregate rhythmicity (see Collective pseudoobscura, dark-reared), 217-18,
amplitude or rhythmicity; Entrainment, 611-17,631
mutual) electrocardiogram (see Heart musde)
Agladze, Konstantin, 385-88 Kalanchoe, 310, 631
Alpha rhythm (brain), 345 Neurospora mycelia, 228, 613
Alternans, 408, 506--08 Sarcophaga, 310
Alternative attractor basins (see also Black hole; Ascobolus immersus, 539
Blue lake in cydohexanedione reagent), Ascomycete fungi (see also Ascobolus
162,193,196,212,219,233,260,311, immersus; Daldinia concentrica; Nectria
406,486,499 cinnabarina; Neurospora crassa;
Alternative flows, 178, 179, 182,213-16 Penicillium diversum; Pilobolus), 135,
Alternative rotor periods, 329, 460, 469 253,537
Amoeba, social (see Dictyostelium discoideum) Asymptotie phase (see Latent phase)
Amphidromic point, 48-50, 268, 305 Atrium (see Heart musde)
Amplitude, 219,451 Attracting cyde
aggregate or collective, 102, 109, 111, 112, defined, 162
119,219,233 Drosophila dock (none observed in), 196,
death, 234 222
of fundamental harmonie, zero, 327 infinite-dimensional, 183, 188
Amplitude resetting knotted, 173,656
chick ventricular ceWmyocyte aggregates, 219 Attracting steady state of oscillator (see Black
Dictyostelium, 219 hole, of attracting cyde oscillator)
Drosophila, 221, 224 Attractor-cyde oscillator (see Attracting cyde)
human, 182,228,610 Attractor-repellor pair (see Bifurcations, saddle-
Kalanchoe, 631 node)
model docks and oscillators, 119 Auden, W.H., 535
mosquito (Culex), 620 Augustinus, Aurelius, 41
Angles, conventions for, 7 Avenasativa, 114, 117,219,310,335
Angular velocity Azimuth,defined,136
in model docks and oscillators, 85, 86
modulation of, inadequate as a model, 151 Backfire in excitable media, 406
negative, 86, 87, 93,105 Bacon, Francis, 286, 561
Anisotropic media (see Heart muscle; Platinum Barkley, Dwight, 473, 505, 526, 531
crystals) BarkIey excitable medium, 261, 389, 460, 461,
Annihilation by singular stimulus, 118, 335, 463,467
414,426,611-17 Beeler-Reuter model, 325, 326, 492, 493,507,
762 SUBJECT INDEX
522, 524, 534
Belousov, Boris, 372
Belousov-Zhabotinsky reaction (see also
Malonic acid reaction), 57, 73, 74, 137,
180,190,241,323,333,367-411
Benham's top (or disk), 15
Benzer, Seymour, 607
Bemal, J.D., 258
Bidomain cable equation, 275-76, 456,518-25,
535
Bifurcations (see also Instabilities)
lIopL 122,254,260,266,267,375,376,389,
391,398,399,460,479,481
complexity boundary, 458-67
meander boundary, 267, 389, 398, 399, 458-
67,460
period-doubling, 173
propagation boundary, 267, 458-67
rotor bounclary, 26, 265, 399, 458-67
saddle-node, 122, 172,260,261,322
Bioluminescence (see Gonyaulax polyhedra)
Black Death, 255
Black hole, 10,78, 193
of attracting cycle oscillator, 155, 174, 188,
193,260,311,334,335,358,425
of periodically driven excitable medium (see
Rotor)
Bloch points, 78
BIue-green algae (see Cyanobacteria)
Blue Lake in cyclohexanedione reagent, 405,
406,491
Borromean rings, 482, 487
Brain
alpha rhythm, 345
breathing, 73, 336, 359,420
cortex, 24, 71,143,332
cortical map, 74
epilepsies, 71, 129, 192,345,427,441
hippocampus, 129,277,427
inferior olive, 427
insect, 547, 550, 553, 587, 588, 593, 601,
603,616
left and right clocks, 587, 590
ocular dominance columns, 332
olfactory bulb (of Limax) 244, 379, 427
Parkinsonian tremor, 129, 234, 345, 427
spreading depression, 441, 442
suprachiasmatic nucleus, 126, 133, 143,227,
234,236,366,552,557,563,586,590,658
visual (or striate) cortex, 24, 74, 143
Breakpoint (see Phase resetting "Type": illusion
of discontinuity in 1YPe 0)
Breakup of short-period waves in excitable
media,325,326,447,504,506,507,
527, 532
Breathing or respiratory oscillation, 73, 336,
359,420
Brenner, Sidney, 547
Briggs-Rauscher oscillator, 180, 190,368
Bromate, bromide, bromous acid, 73, 190, 191,
243,244,266,275,371,373-77,448,
458
Broom waves, 134,408
Browne, Thomas, 592
Bubbles (in excitable media), 373-75
Bull's eye in stimulus parameter plane, 514-17
Burgers'equation, 139, 140, 143,379,475,486
Buttercup, 624
ButterfieId color encoder, 15
Cable equation (see also Bidomain cable
equation), 510, 511
Caenorhabditis elegans, 547
Calcium waves, 277, 278, 283, 285, 348
Carbon monoxide (see also Platinum crystals),
277,278,326,370,374,375,383
Cardiac (see lIeart muscle)
Carroll,Lewis, 10,320
Catastrophe theory, 79, 189, 192,261, 304, 307,
597
Caudle, Scott, 381, 404
Cavendish, lIenry, 582
Cdc2 kinase, 98, 632, 639, 642-44, 649
Cell division or cell cycle (or in eucaryotes,
mitosis) (see also Gating of events by
rhythms), 84, 98,180, 195,335,555,
632-50
Cell wall, plant, 318
Cellular automata, 76, 139, 145,277,280,324,
471,510
Chaetomium robusta, 247, 249, 540
Chaos, 176, 196,326,372,462,643
spatiotemporal, 323, 331,462,468,526-32
spiral-defect, 323
Chemical oscillators
cyclic AMP, 443-54
Belousov-Zhabotinsky, 57, 73, 74, 137, 180,
190,241,323,333,367-411
Briggs-Rauscher, 180, 190,368
glycolysis, 347-67
Chen, C.C., 463, 473
Chen, Gang, 268,404,473,491
Chialvo, Dante, 466
Chick ventricular ceWmyocyte aggregates, 118,
131,172,183,188,219-20,336,415,
422-427,501,619
Chitin fibrils, 315-20
Chloride, 369, 412, 441, 448
Chloroplasts, 347, 555
Cholera, 255
Cholesteric (rotational) anisotropy (see Cornea;
Cuticle; lIeart muscle)

Chronon, 98, 573,612,640
Churchill, Winston, 372
Circadian rhythms and docks in species (see
species narnes: Antheraea pernyi;
Cyanobacteria; Daldinia concentrica;
Drosophila melanogaster; Drosophila
pseudoobscura; Euglena gracilis;
Gonyaulax polyhedra; Humans;
Ktllanchoe blossfeldiana; Mosquito
(Culex pipiens); Neurospora crassa;
Pectinophora gossypiella; Penicillium
diversum; Physarum polycephalum;
Pilobolus; Sarcophaga argyrostoma)
Circadian rhythms and docks, dynamical
features, 545-632
affected by temperature, 567-70
arrhythmic state (see also Drosophila
pseudoobscura, dark-reared), 611-17
bilateral symmetIy, 223
color blindness, 218, 555, 603, 604
dark adaptation, 182,207,224-35,550-51,
601~2,609,630
defined, 546
diversity of mechanisms, 549, 563, 566--67
duplicate, 555
evolution, 575, 576
general characteristics, 561
human (see Humans)
inhibition by constant light, 33, 50, 178,
211-16,577,595,599-604,617
isochrons directly measured (see also Phase
resetting map or surface), 198-228
mutual entrainment or syntalansis, 566
physiologically essential to cells?, 594, 616
selective advantage, 549, 556, 568, 576-83,
590,594,616
splitting of rhythm, 111, 112, 119, 124, 125,
233,235,342,345,422,587,588,658
trajectories in state space, measured, 196,
198--228
two-oscillator models, 90, 103~8, 119, 121,
130,106,223,224,230-31,342,566,
587,588,633,647
Circus wave (heart), 70, 143, 188,321,496
Clancy, Tom, 560
Clapping, 126, 132
Clockface model, 291, 312, 313, 314
Clockshop model, 90,224,225,585
Cloverleaf pattern of polarization in bidomain
media, 275, 276, 519-23
Coherent light, 74, 332, 333
Collagen (see Cornea)
Collective amplitude or rhythmicity, 101-145,
161,338--46
Collision interface, 394, 402, 407, 478, 482,
484,487,490
SUBJECT INDEX 763
Color blindness, 218, 555, 603, 604
Color vision or perception, 15,23,27,42,304
Color wheel, ring, or circle, 14-16,23,27,43, 74
Compass, 6-7, 27
Composite dock (see Clockshop model;
Collective amplitude or rhythmicity)
Composition vs. single concentration, 265, 287
Composition space, 265
Continuity, defined, 4
Continuous action vs. differential action, 617
Convolution and its inversion, 614-15
Cophase,defined,34,157
Core (see Rotor)
Core body temperature, 114, 580, 591, 610
Cornea (mammal), 24, 318, 347, 641
Corneal exocone lens (insect), 13,68,315-20
Cortex and cortical maps, 24, 71, 74, 143,332
Cosmic strings, 301, 332, 333
Cotidal contour, 48-50
Counterexamples, 40, 75, 115, 264, 289, 335,
386,408,437,455,468,477,482,487
Courtemanche, Mare, 507, 508
Cowan, Jack, 326
Crick, Francis H. C., 547, 549
Crickets, 129,414,422,569
Critical (minimum) coupling intensity (for
mutual entrainment), 122-32, 232, 342,
345,362-66,435,497-98,519,589
Critical (minimum) size for pattern-formation
(see Instabilities)
Critical point (see Entrainment, mutual; Phase
singularity or singular point; Singularity)
Cross product, 265, 266, 328, 404
Cryptochrome (CRY), 216, 550-53, 577, 591,
600~3,609, 619
Culex (see Mosquito)
Curvature modulation (see also Meander), 267,
268,385-387,388,390,391,399
Cutide, arthropod, 13,68, 315-20
Cyanobacteria, 126, 134, 227, 546, 555, 580,
583,584,590,641
Cyclin,98,632,638,639,642-44,649
Cydohexanedione reagent, 266, 368, 374, 381,
403,405,409
D: dimension, diffusion, or duration? 29, 82,
139,266
Daldinia concentrica, 539
Dark adaptation in circadian docks
Drosophila pseudoobscura, 182,207,224,
225,550,551,601,602,609
Ktllanchoe flowers, 630
Neurospora, 224
other insects, 224
Sarcophaga, 224
Dark-reared insects
764 SUBJECT INDEX
Drosophila pseudoobscura, 67, 218, 224,
309,611-17
other insects, 593, 594
Darwin, Charles, 371, 411, 578
DeDuve,Christian,80
DeHaan, Robert, 422, 502
Deep scattering layer, 545
Defibrillation (see Reart musde)
Degrees of freedom (see Dynarnical dimension,
more than two)
Delay vs. delaying, 574
Delbruck, Max, 584
Developmental readiness and timing, 222,309,
578,593-98,604,612,616,640
Diacetyl monoxirne, 507, 514, 524, 528-31, 536
Dictyostelium discoideum (slime mold or social
amoeba), 88,194,320,443-54
mutual entrainment, 236, 362
phase resetting, 334, 451
rotors, 451
scroll ring wave of cAMP, 69, 294-95, 445
spiral wave of cAMP, 69
Differential action vs. continuous action, 617
Differential geometry, 473, 477, 486
Diffusion and diffusion coefficients
effect in reaction-diffusion equations, 286,
330,511
electrical (see Electrotonic coupling)
equal,251,252,299,468,476,487
temperature dependence, 569
Diffusion-induced instability (see Instabilities)
Discontinuities, 27, 446
cardiac mapping, 75, 504
cortical mapping, 24, 75
kinetics (see also Piecewise linear kinetics;
Relaxation oscillator), 188-197
parameters, 496
phase compromise, 26, 646-67
phase resetting (see also Relaxation
oscillator), 73,110-15, 188, 191, 194,
230,415,420,425,502,571-73,637,
656,658
sleep timing, 7-8, 598
Discoveries overlooked, 244, 252, 292, 372-73,
468, 514
Discrete-state device or logical automata (see
Cellular automata)
Dispersion curve, 265, 380, 381, 384, 401, 442
Dispersion (see Incoherence)
Dissipative structure (see Instabilities)
Division protein or mitogen (see Cyclin)
Dobzhansky, Th., 607
Dog-bone (see Cloverleaf pattern of polarization
in bidomain media)
Doppler, 504, 530
Dove prism, 18, 20-21
Drake, Francis, 176
Drosophila melanogaster (see also
Circadian rhythms and docks,
dynarnical features)
19-hourperiodmutant, 58-60, 114,219,309,
548,550,555,607,660,620,621,622
adult activity rhythm, 59, 219, 587, 621
chemical mechanism of circadian dock, 550-
552
dock genes (dk, cyc, dbt, per, tim), 150,
180,185,216,221,548,550-54,556,
564-65,601
Malphigian tubules, 552, 593
photoreceptor, 550
singularity trap experiment, 58-60
time crystal, 60
Drosophila pseudoobscura (see also Circadian
rhythms and eIocks, dynamical features)
amplitude resetting, 221, 222, 618
attracting cyeIe of circadian eIock (none),
196,210-12
dockshop interpretations, 223, 225-26, 227
dark adaptation, 182,207,224,225,550,
551,601,602,609
dark-reared (naIve) 67, 218, 224, 309, 611-
17
developmental timing not dependent on
clock,578,594,612,616
isochrons measured, 53, 198-228
gating of edosion (see Gating of events by
rhythms)
life cyde and metamorphosis (larva, pupa,
adult),592
phase resetting curves, 115, 571
photoreceptor, 216, 218-220, 551, 555, 599-
604
pinwheelexperiment, 50-58
temperature effects on circadian dock, 567-
70,616
time crystal, 54
time machine experiments, 198-228
trajectories measured, 198-228
transients of phase resetting, 207, 220
Dynamical dimension or degrees of freedom,
more than two, 176, 185-87,224
Dynamical disease, 525
Dysrhythmia (see Heart musde)
Eckhaus instability, 447
EeIosion, 198-228,592-621
defined, 593
Ecological waves (epidemies), 254, 255
Eddington, Arthur, 527
Efimov, Igor, 275, 523
Eigen, Manfred, 333
Eikonal equation, 291, 283, 383, 441

Einstein, Albert, 518, 600
Einsteins, defined, 210
Elastie image in state space (see Image)
Electric fish, 133,413,427
Electrotonic coupling, 130, 507-13, 521, 522
Engelmann, Wolfgang, 61, 606
Entrainment, mutual (syntalansis), 119-29, 143,
231-36,498,338-46,426-28,563
active resistance to (antisyntalansis), 123,
128,129,132,235,345,365,422
analogy to physieal phase transitions, 122
chick ventricular ceWmyocyte aggregates,
422-27
circadian docks, 588
crickets, 422
critical coupling intensity. 122-32, 362-66,
435
Dictyostelium cells, 236, 362
electric fish pacemaker neurons, 427
electrical oscillators, 338-46
fireflies, 422, 589
glycolysis in yeast cells, 126,235,361-66,
435,589
Internet, 128
inferior olive of brainstem, 427
mediated by impulses, 129-132
mitochondria, 23
neon glow tubes, 338-46
neurons of suprachiasmatic nudeus (see also
Brain), 133,227,234,236, 552, 563,
590
nudear divisions in Physarum, 235, 644-48
threshold (see critical coupling intensity
under this heading)
sinus nodal cells, 131,422,426-27,589
Entrainment, nonmutual, 99, 129, 131, 157, 182,
224,233,414,419,422,426,429,554,
557-59,591,654-55
defined, vs. synchronization, 121
Epidemics, 254, 255
Epigenetic cellular oscillators, 180, 185,546,
547,556,558,564,565
Epilepsies, 71, 129, 192,345,427,441
Epstein, David, 471
Equations and models
Barkley excitable medium, 261, 389, 460,
461,463,467
Beeler-Reuter; 325, 326, 492, 493, 507, 522,
524, 534
bidomain (see also Reart musde, anisotropie
bidomain inequality; Meander,
bidomain media), 275-76, 387, 518-
25, 535
Burgers' phase diffusion, 139, 140, 143, 379,
475,486
eikonal, 283, 291, 383, 441
SUBJECT INDEX 765
Field-Koros-Noyes, 367, 492
FitzHugh-Nagumo, 262, 263, 326, 329, 389,
400,408,449,459,460,462,468,483,
484,487,492,512,534
Ginzburg-Landau, 163,254,300,327,460,
476,478,479-81,492
Hodgkin-HuxIey, 170, 192, 193,259,334,
411,415,435,497
Kuramoto's coupled docks, 127, 164
Kuramoto's phase diffusion, 140
lambda-omega, 163, 164,222,232,254
Lotka-Volterra oscillator, 150, 162,254
Luo-Rudy, 507
Martiel-Goldbeter, 295
Maxwell-Bloch,74
nonlinear cable, 510, 511
Oregonator (see also Oregonator model),
255,266,292,327,376,387,395-99,
408,458,462,464,467
radial isochron dock, 143, 163, 172,220,
222,227,232-34,254,367,431,560,
563,565,610
reaction-diffusion generically, 285, 286, 330
van der Pol, 124, 170, 192, 222, 233, 234,
235,432
Zykov excitable medium, 388, 400, 457
Equilibrium (see Steady state)
Estradiol, 652, 658
Estrous cyde, 656, 658-59
Ethyl methane sulfonate, 607
Euglena gracilis, 39, 115, 568, 588, 590, 641
Evolution
cell division cyde, 633
circadian dock, 549, 568, 570, 575-85
conservative, 553, 566, 577-78
development (social amoeba), 443
female cyde, 652
hypercyde models, 277
Excess delay, 418, 636
Excitability and excitable media, 258-302, 368-
536
defined,258-59,262-63, 265
gas- or plasma-state (see Phosphorus)
liquid-state (see Malonie acid reagent)
living (see Heart musde; Brain)
marginal or weak, 265, 278, 286, 328, 330,
331,448,449,460,461,469,470,479,
483, 534
numerical models (see also Equations and
models), 258-302, 368-411, 455-494
dimensions defined by rotor diameter, 392
solid-state, 301
three kinds, 259
Excitable gap, 331, 451, 504, 510--13
Explanation as mapping, 303
Eye (see Cornea; Corneal exocone lens; Firefly;
766 SUBJECT INDEX
Retinal headings)
Fairy ring, 281
Far field vs. near field, 515, 518-23
Faraday, Michael. 582, 606
Female cyeles, 650-663
estrous, 658-59
circadian elock and, 658
no 'tYPe 0 resetting, 657
evolution, 652
menstrual, 116, 195-97,236,335,416,650-59
ovulation, 195,594,641,652
ovaries alternating, 652
Fenton, Flavio, 481
Feynman, Richard P., 660
Fibrillation, 70, 268, 293, 497
acute, 324,326, 503, 530, 533
as attractor basin, 499, 533
atrial, 322, 324
defibrillation, 326,494,496,506,519,522,
535
foeal eruptions, "splats" on epicardium, 293,
294,496,505,508,515,524-536
three4iUnensional, 292-94, 525, 526, 533
transition to, from tachycardia, 481, 503,
508,518
two4iUnensional, 325, 326, 506, 525, 526
ventricular acute, 324, 326, 503, 530, 533
ventricular chronie, 324, 327, 507, 524, 530,
532,533
wandering wavelets model, 277, 321, 324,
440,504, 510, 511
Fibroblast, 24
Field-KOros-Noyes model, 367, 492
Fife scaling ansatz, 331, 459, 460, 492, 535
Figure-of-eight waves, 269, 509, 525
Fingerprints, 24, 76
Firefly
exocone lens of eye, 68, 317
rhythmic flashing, 130, 131
Firefly Machine, 338-46
FitzHugh-Nagumo equation, 262, 263, 326,
329,389,400,408,449,459,460,462,
468,483,484,487,492,512,534
Flames, 98,277, 301, 302, 456, 467,529
Flower (see KI11a.nchoe blossfeldiana; Meander,
floral ... )
Flower, Brian, 368
Flower garden (see Meander, parameter-
dependence; Rotor, parameter-dependence)
Football field problem, 132
Frame line, 12
Frenetframe, 470, 475
Frequency plateaus (intestine, fibrillation,
parameter gradient), 430, 432
Frequency demultiplication, 563
Frontier, defined, 135
Fruitfly (see Drosophila melanogaster;
Drosophila pseudoobscura)
Fundamental sine wave (see also Amplitude),
46,78,102,103,111,119,213,225,
227,328,466
Fungus (see Ascobulus immersus; Daldinia
concentrica; Nectria cinnabarina;
Neurospora crassa; PeniciUium
diversum; Pilobolus; Yeast)
GABA (gamma-aminobutyric acid), 227, 236
Gainsborough, Thomas, 236
Galilei, Galileo, 1, 19,455
Gap, excitable, 331, 451, 504, 510-13
Gap junctions between cells, 435, 442, 519
Gating of events by rhythms
breathing, 597
circadian eelosion in insects, 222, 593-98,
604,641
circadian mitosis (in Cyanobacteria, Euglena,
Gonyaulax, Physarum, Tetrahymena),
640-42
daily egg-Iaying of birds, 594, 641
pacemaker neurons (slow waves), 415-17
sleep, 560, 598
Gelling chemically excitable media, 373-75
Geophysieal rhythms, 99
Germination of spores, 247-49
Gibbs, Josiah Willard, 518
Ginzburg-Landau equation, 163,254,300,327,
460,476,478,479-81,492
Gizmo and gizmology, 402, 403
Glass, Leon, 270
Glycolysis, anaerobic oscillating, 22, 23, 63,
126,311,347-67,375,382,417,450,
578,589
Goldstein, Byron, 565
Gonyaulax polyedra, 18, 73, 184, 227, 367, 546,
548,554-56,565,573,579,582,585,
588-90
Goodwin, Brian C., 546, 547, 565
Gordon, Herman, 319
Gradients
circular, 291
crossed concentration or potential, 258, 269,
270-76,279,329
frequency, 430, 433, 481
morphogenetic, 291, 313, 314
parameter, 138, 378, 408, 430-32, 493, 525,
531, 536
phase, 136,238,333,379,380,407,427,
508, 514, 515, 527, 539
stimulus magnitude, 514, 521, 522
vector cross-product, 265, 266, 328, 404
Green fluorescent protein, 310,563, 564, 565,

590
Greller, Lany, 63
Guilford, William, 473
Hannon, Leon, 344
Hanison, John, 19-20
Heart muscle (see also Sinoatrial node) 270,
495-536
altemans (see Instabilities)
anisotropy
2d,276,437,499,511,522
3d cholesteric or rotating, 75, 318, 480,
481,499,500,504,519,528,535
bidomain inequality, 275-76, 387, 499,
518-25, 535
arrhythmia vs. dysrhythmia, 321, 497
atrial,322,324,441,499,510,512,517,520,
526, 527. 528
chick myocyte/ventricular cell aggregates,
118,131,172,183,188,219-20,336,
415,422-27,501,619
circus wave, 70, 143, 188, 321,496
conduction block, 75, 480
defibrillation (see fibrillation under this
heading)
dysrhythmia vs. arrhythmia, 321, 497
electrical fluorescence (di-4-ANEPPS), 499,
500,529,533
electrieal thresholds, 270
fibrillation, 70,268,293,497
acute, 324, 326,503, 530, 533
as attractor basin, 499, 533
atrial, 322, 324
defibrillation,326,494,496,506,519,
522, 535
foeal eruptions, "splats" on epicardium,
293,294,496,505,508,515,524-536
three-dimensional, 292-94, 525, 526, 533
transition to, from tachycardia, 481, 503,
508,518
two-dimensional, 325, 326, 506, 525, 526
ventricular acute, 324, 326, 503, 530, 533
ventricular chronie, 324, 327, 507, 524,
530,532,533
wandering wavelets model. 277, 321, 324,
440,504,510,511
figure-of-eight reentry (see Rotor, figure-of-
eight; rotors, ephemeral untier this
heading)
flutter(atrialorventricular), 70, 71, 321
foeal activations from singular filaments,
294,496,505,508,515,524-36
Langendorff mount, 500, 529, 533
leeeh, 118,335,415
mouse, exceptional, 437,513
quatrefoil reentry (rotors) in bidomain, 276,
519,520,525
SUBJECT INDEX 767
rotor in single cell, 277
rotors, ephemeral, 275-77, 433, 498, 512-15,
529,530
rotors stabilized by DAM, 514, 515, 524
rotors in tissue culture, 435
singular filaments (intramural) (see also
Rotors; rotors untier this heading),
293-94,326-27,493,498,504,516,
524-32, 536
singular filaments (transmural), 431, 497,
498, 518, 525-32
sudden cardiac death, 71, 167, 322, 495, 535
tachycardia, 496,503,513
leading circle description, 497, 502, 504,
511
monomorphic vs. polymorphie, 527, 528
torsatie de pointes, 498, 511, 524, 528
vortex filaments (see singular filaments
under this heading)
vortex rings, 527, 528
vulnerability, upper and lower limits, 270,
514-517
vulnerable phase (aka vulnerable period),
502,514,520,523,527,534
Wenckebach block and domains (see also
Gradients, parameter), 431, 531. 536
Helical border and helicoidal surface (see also
Phase resetting map or surface), 29, 63,
73,119,191,316,376,478
Henze, Chris, 473, 483
Heraclitus, 624
Hesse, Hermann, 336, 351
Heterogeneity (see Inhomogeneity)
Heterogeneous nudei (see Pacemaker)
Hippocampus, 129,277,427
Hit and run (see also Phase resetting "1)rpe"),
33
Hobbit, The (Tolkien), 335
Hodgkin-Huxley equations and descendants,
170,192,193,259,334,411,415,435,
497
Homer, 495, 567
Holmes, Sherlock, 24, 79, 113, 200, 454, 490,
650
Hopfbifurcations, 122,254,260,266,267,375,
376,389,391,398,399,460,478,481
Hormonal cycles (see Female cycles)
Horseshoe signature of vortex ring, 527
Hourglass model, 84, 85
Howell, Donna, 384
Hoyle, Fred, 78, 580
Humans
alpha rhythm, 345
breathing, 421
circadian dock period (sIeep, jetlag, and
phase resetting), 7, 8, 114, 182, 183,
768 SUBJECT INDEX
227,549,556-62,565,583,587-88,
591,598,620,618,641
color vision, 9, 15, 23, 42,43, 304
core body temperature rhythm, 114, 580,
591,610
cornea, 24
hewrt, 71,435, 511, 529,535
intestines, 429
menstrual cyele (see Female cyeles)
Huygens' principle and eikonal equation, 283,
383,441
Hydrodynamic vortex filaments, 297, 475, 509
Hypercyeles, 277, 472
Hypermeander, 71, 256, 293, 327, 389, 399,
459,460,462,467
Hysteresis, 234, 235
Ideker, Raymond E., 493, 509
Iliad (Homer), 495
Image (mapping to state space)
I-dimensional vs. 2-dimensional, 275
diffusion-coupling = elasticity, 141,251,476
embryonic tissues (tissue specificity space),
313,314
fungus frontier (see Nectria cinnabarina)
rotor, 271, 274, 279
Incoherence (see also Entrainment, mutual:
active resistance to)
circadian clocks, 120, 226-28, 306, 309, 579,
612,630
computation of, 120
simple elocks, 90, 106, 110
Infinite-dimensional dynamical systems, 176,
183,188,289,307
Influence function or rhythm, 126, 139, 235
Influence-sensitivity loop, 123, 125, 126,233,
345,365,427
Inhomogeneity (parametric), 321, 323, 324-26,
407,408,441,442,496,506,511,518,
526
Initial conditions
circadian elock amplitude, 207
circadian elock initiation (see also Circadian
rhythms and elocks, inhibition by
constant light), 200, 604
fungus morphogenesis, 247-49, 543
isochrons, 166
linear-looping meander direction, 331, 396,
477
linked and knotted vortex rings
(polynomials), 297,471,473,487
multistable mutual entrainment, 125
rotor, 269-76, 357-58, 451, 502, 521-24
sensitivity to (see also Chaos), 463
shifted cyele (see Shifted cyele)
singular filaments in CHD gels, 406
spring-loaded for rotor, 275, 521-24
Instabilities (see also Bifurcations)
altemans of action potential duration, 408,
506
diffusion-induced (e.g., Thring), 233, 252,
244,256,377,379,382,453,468
Eckhaus, 447
front propagation (breakup, conduction
block),325,326,385,506,525
hypertorus (3 oscillators to chaos), 462
meander (see Meander)
mirror image rotors merging, 525
mutual entrainment, 231
multiarm rotors or spirals (see Rotor)
pattern-formation, minimum size, 253, 381
singular filament (aka vortex filament), 297,
479,491,525,535,536
steady state, 222, 253, 308, 350, 580, 581,
638
sproing of singular filament, 298, 300, 445,
476-87,491,504
thickness of hewrt wall for singular filaments,
392,479-81,480,493,504,508,527,
528
twist (see sproing of singular filament under
this heading)
twiston,480,504,527,528
International date line, 8, 10, 32
Intersections of random curves, 249
Intestine, oscillations and waves, 428-32, 569
Intramural singular filaments (see Heart musele,
singular filaments)
Iridescence (see Cutiele, arthropod)
Iron wire, 287, 436
Isochron, 104, 166, 167,292
analytically solved models, 165-74
defined, 166, 176,213,291
Belousov-Zhabotinsky oscillator, 191,376,
377
Drosophila, 53, 212
FitzHugh-Nagumo oscillator, 170
GonyauIax, 548
heart musele, 71
Kalanchoe, 12, 626
properties listed, 177
yeast, 357
Isochrone, 167,212
Isogon, 267,388,390, 398-99,458-61
Jahnke, Wolfgang, 256
Jallfe, Jose, 493
James, William, 371
Jetlag, 557,562
Jones, David, 593
Josephsonjunction, 125,126
 SUBJECT INDEX 769

Kalanchoe blossfeldiana circadian dock, 310, analogy to arthropod cutide, 315

572,624-32 analogy to ventricular wall of heart, 499
amplitude resetting, 309, 631 "Local geometry hypothesis," 298, 394, 474,
coherence among flowers, 630 479,490
dark-adaptation, 630 "Localized induction approximation," 298
isochrons, 12,626 Logical automata (see Cellular automata)
time crystal and phase singularity, 61, 62, Longitude, 20
626-30 Lorenz, E., 176
transients, 207 Lotka-Volterra oscillator, 150, 162, 254
two-pulse phase resetting, 219 Luciferase, 310, 563, 590
~a,Ahrin,477,479 Lugosi, Erszebet, 386, 473
Kauffman, Stuart A., 648 Luo-Rudy model, 507
Keener, J.D., 470, 476
Kepler, Johannes, 10, 101 Magellan, Ferdinand, 10, 19
Kettunen, Petteri, 561 Magnetic bubble, 78
Khayyam, Omar, 229 Malonic acid reaction (or reagent) (see also
Khekheppere-Sonbu of Egypt, 650 Rotor, malonic acid reagents; Scroll
Kidney, 236 wave), 57, 72. 190,368-410,430-31,
Kinematic wave, 237, 244, 329, 330 467
Klein bottle, 24, 148 Malphigian tubules, 552, 593
Knotted limit cyde, 162, 172, 178 Manifolds,2, 147, 162
Knotted vortex lines (see Singular filament, Marginal or weak excitability, 265, 278, 286,
linked and knotted rings) 328,330,331,448,449,460,461,469,
Krebs cyde, 368, 371 470,479,483,534
Kropotkin, Pyotr, 466 Martiel-Goldbeter model, 295
Kuramoto's coupled docks equation, 127, 164 Maxwell-Bloch equation, 74
Kuramoto's phase diffusion equation, 140 Maxwell, James Clerk, 77, 146, 161
Meander (of rotor), 145, 252, 255, 292, 306.
Lambda-omega (A.-ro) oscillator, 163, 164,222, 325,330,331,383,384,456,457,498,
232,254 506,511
Lamprey (swimming), 139 O-degree isogon (see also linear looping
Langendorff preparation, 500, 529, 533 under this heading), 388, 390, 396-99,
Landscape (see also Meander, parameter- 458,459
dependence; Rotor; parameter- bidomain media, 387
dependence),457,460, 466 biperiodic, floral, 2-period (see floral ...
Laplacian operator for diffusion, 139,250-52, under this heading)
275,289,456,474,511 coil spring (see linear looping under this
Larsen, Lewis, 469 heading)
Laszlo, Andre, 287 curvature modulation, 267, 268, 385-91, 399
Latent phase, defined (see also Isochron, cydoids, prolate (epi-, hypo-), prograde and
properties listed), 163-165, 177 retrograde (see also floral ... under this
Leading center, 392, 406, 408 heading), 390. 391
Leechheart, 118,335,415 epicycle metaphor (Moon-Earth), 388-90,
Lens (firefly eye), 68, 317 391,462,464
Lichen, 281, 282 excitation of flower center, 267, 391
Liesegang rings, 290 floral, flower petals inward or outward, 256,
Life cyde 267,292,293,327,385-402,459
annihilation, 335 Fourierspectrum, 463,464
fly(Lhvsophila),592 hypermeander, 71, 256, 293, 327, 389, 399,
social amoeba (Dictyostelium), 443-46 459,460,462,467
Light (coherent, laser), phase singularities, 74, inevitable in singular perturbation limit, 389
332,333 isogons,267,388,390, 398-99,458-61
Limax,244,379,427 kinematic description, 461
Limit cycle (see Attracting cycle) linearlooping,328,388,488
Linear looping (see Meander) parameter-dependence (landscape), 395-98,
Liquid crystal, cholesteric, 9 457-59
770 SUBJECT INDEX
quasiperioclic (see floral ... under this
heading)
three-dimensional, 297, 387
two-period (see floral ... under this heading)
vs. wandering (see also Heart musde,
torsade de pointes), 498, 511
Medawar, Peter B., 198
Melatonin, 566, 591
Menstrual cyde, 116, 195-97,236,335,416,
650-59
Mercury (planet), 536
Metric, lack of, 181
Michelson, A.A., 317
Migraine headache and spreading depression,
442
Mines, George R. (death), 322
Mitchison, Graeme J., 633, 648
Mitochondria, 299, 347, 556
Mitogen (see Cydin)
Mitotic cyde in eukaryotes
checkpoints, 84, 639
mechanisms as understood since 19905, 632,
633,638,639,643,644
mutual synchronization, 235
no Type 0 resetting, 116
simple dock, 84, 98
MittenthaI. Jay E., 125
Moire patterns, 120
Morphogenesis (see Cutide; Dictyostelium
discoideum; Nectria cinnabarina;
Neurospora crassa; Regeneration
blastema)
Morphogenetic gradient, 291, 313, 314
Mosquito (Culex pipiens), 218, 565, 568, 600,
602,617,620
amplitude resetting, 228, 610
steady state, 179
phase singularity, rhythm annihilation,
singularity trap, 57
two-pulse phase resetting experiments, 219,
620
Mouse heart, 437, 513
mRNA transcription, 366, 546, 547, 556, 563,
565,566,580,593,612
Multi-oscillator (see Clockshop model)
Murray, James D., 471
Musde fibers, helically striated, 316
Mutual repulsion among docks (see
Entrainment, mutual: active resistance
to)
Mutual synchronization (see Entrainment, mutual)
Mycelium, 66,67, 134-37,228,239-241,537-44
Myxomycetes (see Physarum polycephalum)
Naive flies (dark-reared) (see Drosophila
pseudoobscura, dark-reared)
Nandapurkar, Pramod, 472, 473
Native period distribution, 122-25, 130-33,
232,340,427,435
Navigation, animal, 18, 561
Near field vs. far field, 515, 518-23
Nectria cinnabarina, 136, 137, 245-57, 312,
332,453,540-43
Neon glow tube, 125, 338-40, 377
Nerve impulse (see Action potential)
Neural rhythms (see Pacemaker)
Neurospora crassa, 66, 67, 137,224, 228, 245-
57,312,538,565,582,600,616
band, frq, timex, wc-2 dock genes and
mechanism, 539, 547, 548, 550, 553,
554
photoreceptor, 224, 554, 566, 601, 603
temperature dominating entrainment, 554,
568
New phase, defined, 31
Newton, Isaac, 19,67,453,632
Nitrocellulose membranes, 369-70, 401
Non-retraction theorem, 25, 27-29, 47, 55, 72,
137, 175, 179
Non-uniform dispersion of refractoriness (see
Inhomogeneity)
Nuclear division (see Cell division or cell cycle;
Physarum polycephalum)
Ocular dominance columns, 332
Odyssey (Homer), 567
Old phase, defined, 31
Olfactory bulb of Limax, 244, 379, 427
Oregonator model (see also Equations and
models)
fudge factor f, 369, 396, 398
Lo and Hi parameter sets, 373, 387
Organizing centers in excitable media (see also
Scroll rings)
shrinking, 298-99,394, 467-89,471,474-
78,482
stable, 483-87
persistent, 488-90
Orgasm, 560
Ottesen, Erik, 176
Ovulation, 195, 594,641,652
Pacemaker (chemical, in malonic acid reagent),
392,405-10
Pacemaker period always longer than rotors?,
408-10
Pancreatic beta cells, 354,365,417
Panfilo~Alexandre,471
Parable of three docks, 89
Parameter, defined, 82
Parameter gradients (see Gradients)
Parametric pumping, 134

Parkinsonian tremor, 129,234,345,427
Pasteur effect, 63, 178, 350-52, 354, 358
Pattern formation, minimum size for (see
Instabilities)
Pavlidis, T., 222
Paydarfar, David, 420
Pectinophora gossypiella, 592
Pendulum, 149-59
PeniciUium diversum, 247,249,539,540
Penzias, A.A., 582
Period gene and PER protein (see also
Drosophila melanogaster, dock genes),
180,226,550,558,564,565,601
Peristalsis, 428-32, 569
Phase
compatibility (see also Entrainment, mutual:
active resistance to), 123-24, 342
compromise, 26, 27,65,132,180,181,227,
366,367,644
defined, 268
diffusion equation
Burgers' equation, 139, 140, 143, 379,
475,486
Kuramoto's equation, 140
dispersion (see Incoherence)
distribution, two-horned, 614
gradients, 136, 238
jump (see Phase resetting "Type":
discontinuous from smooth kinetics)
latent (see Latent phase)
map, defined, 9
reference event, defined, 418, 605
rescheduling (= resetting), 33, 38, 39
response curve (PRC) (see also shift under
this heading), 157-59, 571-75
scatter (see Incoherence)
shift,419
slip,259-61
transition or critical point (condensed matter
physics), 122
turbulence, 447
velocity, 80-98, 105, 106, 119-29, 151, 164
waves (nearly uniform period), 52, 74, 140,
237,238,244,245,358,378-80
Phase resetting curves (data figures, other than
full resetting surfaces)
Acetabularia circadian dock, 118
chemical oscillators, 333
cricket chorusing, 129
data plotting formats, 32-40, 114,414,417
Dictyostelium cAMP dock, 130,452
discontinuous (see Phase resetting "1YPe")
Drosophila circadian dock, 115, 571
female cyde, 655-57
firefly flashing rhythm, 131
heart pacemaker cells, 130
SUBJECT INDEX 771
human circadian rhythm, 182,228,557,558,
562
Killanchoe circadian dock, 625
models, 85-92
negative slope, 89, 90, 147
phase (shift) response curve (PRC), 157-59,
419,571-75
Physarum nuclear division cyde, 636, 644-
48
reference list, original, 116-18
shape peculiarities quantified, 610
simple dock, 88, 91
Phase resetting map or surface ("time crystal")
algebraic description, 91, 95, 96, 146-60
Belousov-Zhabotinsky oscillator. 191, 376,
377
brainstem respiratory dock, 420, 421
chick ventricuJar cellJmyocyte aggregates,
424
defined, 56, 159
Drosophila circadian dock, 52-54, 60, 198-
228, 608
glycolytic oscillator (yeast), 62-64, 355-61
Gonyaulax circadian dock, 548
Kalanchoe circadian dock, 62, 629, 630
mosquito (Cule.x) circadian dock, 57
Sarcophaga circadian dock, 61
simple docks, 92-97
sinoatrial node, 425
yeast, 62-64, 355-61
Phase resetting by stimuli
acetaldehyde (AA), 63, 64, 311, 360
acetylcholine, 130
ADP,353
bromide, 191,373,375,376
calcium, 63, 64, 117,219,311,359,360
cerium4 +, 373, 375, 377
cAMP, 130, 452
electrical impulses (see also Heart muscle,
chick ... ), 115-18,413-28
female hormones, 655-57
fusion with another oscillator (see Phase,
compromise; Physarum polycephalum)
glucose, 311, 356, 361, 375
impulses, 117, 118, 129-32,232,413-28
light
in chemical oscillators, 190,376,377
in circadian oscillators (see species names
under Phase resetting headings)
in fireflies, 131
mechanical force (see Pendulum)
multiple successive stimuli, 182
osmotic potential, 114, 117,219,310,335
oxygen (Pasteur effect), 63, 64, 311, 354
protein synthesis inhibition, 547, 554, 562, 636
periodically repeated stimuli (see
772 SUBJECT INDEX
Entrainment, mutual: mediated by
impulses)
pyruvate, 360
repeated stimuli, 182
swallowing (brainstem respiratory oscillator),
118,421
two successive stimuli (see also Two-pulse
phase-resetting experiments), 336,415
temperature changes, 62, 554, 568, 613
Phase resetting "Type"
continuous 1YPe 0 =even =strong, defined, 39
continuous 'JYpe 1 =odd =weak, defined, 38
continuous types other than 0 and 1 absent,
39, 118, 185-87
defined, 30--32
discontinuous from smooth kinetics, 73,114,
188,191,194,230,415,420,424,425,
571-73,656
illusion of discontinuity in 1YPe 0, 113, 190,
419,571,625
"resetting type" vs. "resetting curve," 116
1YPe 0 not in simple docks, 89-92
Phase singularity or singular point (see also
Singular filament)
adjustable compass, 6-7, 27
Avena,219,310, 335
Belousov-Zhabotinsky oscillator, 191, 376,
377
brainstem respiratory oscillator, 42a-21
codimension (0, 1, or 2) (see also Phaseless
set), 162, 172, 174, 175, 177, 180, 193,
194,247,335,375,425,535,574
color vision, 43, 515
crystal (of coherentlight), 74, 332
defined,26,536
depolarizing electrical stimuli, 512, 521
at developmental origins
dark-reared Drosophila (see Drosophila
pseudoobscura)
fungus mycelia, 247-49
insects, 594
regeneration, 312-15
due to incoherence in simple dock
population, 109-12
geographical, 265, 267, 268
geometrie (in state space) vs. temporal, 265,
268,269,326,330,515
glycolytic oscillator, 64, 311, 356, 357, 359,
361,365,375
half-cyde apart for +,- stimuli, 76, 311, 359,
360,420
half-rotation (see Projective plane)
heart musde (see also Reart musde, rotor),
498,512-15
hyperpolarizing electrical stimuli, 512, 523
human circadian dock, 228, 610
Kalanchoe circadian dock, 61, 62, 626-30
malonic acid reagent (see Rotor)
microtomed cutide (see Cutide, arthropod)
mirror-image, 269, 281, 312, 333, 437, 460,
491,501,509,514,520,521,523,528,647
mitotic cyde (none unless Go)' 633
mosquito (Culex), 57
lVecUia,67,247-49
nudear division cyde (none unless Go)' 633
paired (see mirror-image under this heading)
Penicillium polymorphism, 67, 247-50
renamed "critical point," 497
vs. state singularity, 306-09
vs. steady state (zero amplitude), 79, 150--53,
159,307,308
temporal vs. geometrie (in state space) (see
geometrie ... under this heading)
tidal harmonics, 48-50, 268, 305
vs. wavefront's endpoint, 268, 269, 274, 281,
287,320,326,439,498,515,525
zero of collective amplitude of running
docks, 102, 109, 111, 112
Phaseless set (or manifold), 188, 190, 193
codimension 0, 162, 193,335
codimension 1, 115, 162, 172, 175, 177, 194,
247,335,425,574
codimension 2 (unless otherwise specified),
162,172,193,247,335,375
Phaselessness vs. timelessness, 175-77, 179,
306, 307, 327
Pheromones, 236
Phosphofructokinase (PFK), 35a-53, 417
Phosphorus (gas-phase excitable medium), 301,
302
Photoperiodism, 553, 561, 659
Photoreceptor (see Circadian rhythms and
docks, dynamical features)
Phycomyces, 8
Physarumpolycephalum, 121, 126, 180, 195,
235,244,366,636,637,644-48
Piecewise linear kinetics, 188-97,260,261,
279,387,389,456,458,471,483
Pigment-dispersing factor (and arrhythmia,
coupling agent), 227, 234
Pilobolus sphaerosporus, 539
Pineal gland, 566, 578, 658
Pinned rotor, 504, 525
Pinwheel protocol (experiment), 5a-58, 66, 114,
326,333,522,523,607
chemically excitable media, 191, 505
circadian dock tissues, 50, 116,310, SOl,
505, 591
Drosophila, 216
fluorescent, in yeast glycolysis, 63, 114,357
heart musde, 114,518,520
independent simple docks, 97
lVeurospora,66-67

simple docks, 96
stirred chemical oscillators ("quenching"),
375-77, 467
unstirred chemical oscillators, 241
Pinwheel center, 75, 332
Pittendrigh, Colin S., 213, 545, 561, 603, 606
Plague, 255
Platinum crystals, 277, 278, 326
Plato, 303
Poincare, Renri, 162
Poincare return map, 211
Polymorphlsm in fungal conidiation
(sporulation) patterns, 239, 540-43
Polynomial initial conditions, 297, 471, 473,
487,488
P6lya, George, 337, 537
Polytalanton, 338-46
Polyvinyl chloride membranes, 401
Populations (see also Dictyostelium discoideum;
Sinoatrial node; Yeast)
animal species (see Lotka-Volterra
oscillator)
attractor-cyde oscillators, 225-28, 229-57
circadian docks, generally, 585-91
fruitfly (Drosophila) pupae, 52, 547, 594-98,
604-05,611-15
Kalanchoe flowers and cells, 630, 631
relaxation oscillators or neon glow tubes,
338-46
rhythmic neurons (see also Brain; Sinoatrial
node) , 133,413-14,427,552,563
ring devices or simple docks, 101-45
syntalansis (see Entrainment, mutual)
Poston, TImothy; 471
Power, Henry, 347, 592
Precision, temporal
enhanced by mutual entrainment, 132-34, 435
isochron measurement, 172
single-cell docks, 220, 413, 589
Projective plane, 24, 74, 75
Prokaryotes, 546, 549, 555-56,579-80, 583-
84,639,641
Pseudowave (nearly uniform period), 52, 74,
140,237,238,244,245,358,378-80
Pulsar (see Star formation)
Pupal emergence (edosion) of insects, 198-228,
592-621
Purkinje fibers, 322, 412, 417, 425, 527, 533
Pye,E.Kendall,372
Pyruvate, 63,126,350,352,360,363
Quality factor "Q/ 265, 278, 285, 286, 299,
302,331,358,395,397,400,401,433,
467,472,473,513,591
Quantum mechanical waves, 74,126
SUBJECT INDEX 773
Quenching experiment, 375-77, 467
Quinn, Ronald, 607
Radial isochron dock, 143, 163, 172,220,222,
227,232-34,254,367,431,560,563,
565, 610
Recipes (for malonic acid reagent), 369
Reaction-diffusion equations generically, 285,
286, 330
Reaction-diffusion patterns
by formation of rotors or vortex filaments
(see Rotor)
by instability of uniform steady state (see
Instabilities, diffusion-induced )
minimum spatial scale (see Instabilities;
Pattern-formation, minimum size for)
Reagent,defined,368
Regeneration blastema, 273, 291, 312, 313
Reiner, Victor, 471. 473
Relaxation oscillator (see also Discontinuities,
kinetics; Discontinuities, phase
resetting), 25, 26, 77, 164, 189-94,232,
344,348,377,577,643,647
Repelling (anti-limit-) cyde, 162, 199,424
Rephasing (see Phase resetting map or surface)
Repressilator, 564, 565
Rescheduling (= resetting), 33, 38, 39
Resetting map (see Phase resetting map or
surface)
Restitution of action potential duration, 325, 506
Retinal ganglion cells, rods, and cones, 552, 600
Retinal spreading depression, 441, 442
Reverberator, 497
Rhodopsin, 550, 553, 555, 600--04, 619
Rig Veda, 576
Ring device (see also Simple dock), 85, 192
defined, 84, 259
Rotating scalar wave, 144, 252, 289
Rotating wave misnomer, 63, 118, 263, 282
Rotational (cholesteric) anisotropy (see Cornea;
Cutide; H~art musde)
Rotor
area in core of reverberator or spiral wave,
284,437
alternative stable periods, 329,460,469
anatomy, 270-76
atrial, 512
circadian dock tissues, 310
creation, 270-76
defined,264
Dictyostelium, 451
discovery in chemically excitable media, 287
figure-of-eight (mirror-image pair), 269, 509,
525
flames, 277,278, 301,529
glycolysis, 63, 277, 358
774 SUBJECT INDEX
heart cell sheet in tissue culture, 435
heart cell, single, 277
heart muscle (see Heart muscle)
hippocampus, 129,277,427
initial conditions, 269-76, 357, 358, 451,
502, 521-24
interior excitable but quiescent, 321, 444, 511
kinematic description, 329, 330, 469
malonic acid reagent, 72, 255, 273-74, 292-
93,323,327-332,368-411,448-49
meander and hypermeander (see Meander)
minimum size, 253, 381
mirror image pair, 269, 509, 512-28
multiarmed: illusory?, 331, 448, 449
ontological status, 144,287, 329
parameter-dependence (see also Meander),
266-67,385,410,457,467,476,478,
486, 511, 513
period always shorter than pacemakers'?,
408-10
period independent of diffusion coefficient,
286,330,511
period too short for stable propagation? 506
pinned, 504, 525
quality factor "Q," 265, 278, 285, 286, 299,
302,331,358,395,397,400,401,433,
467,472,473,513,591
quatrefoil (mirror-paired figures-of-eight)
(see Heart muscle)
sinoatrial,501
slapped by short-period wave train, 328, 331,
332,394,405,472,490
spontaneous generation from propagating
waves, 508
uterine smooth muscle, 277, 433, 434
ventricular, 495-536, 515
wandering,328,511,517,525
yeast ceIl-free extract, 63, 277, 358
Xenopus oocyte, 277, 283
Rowboat, 16-17,43,305
Saccharomyces and Schizosaccharomyces (see
Yeast)
Saddle-node bifurcation, 122, 172,260,261,
322
Salisbury cathedral, 281
Saltatory propagation, 510
Sarcophaga argyrostoma, 61, 85, 224, 310, 593,
594,602,621
Scatter (see Incoherence)
Scheffey, C., 121
SCN (see Suprachiasmatic nucleus)
Serew-like surface (see Helical border and
helicoidal surface; Phase resetting map
or surface)
Scroll axis (see Singular filament)
Scroll rings (see also Singular filament; Vortex
filament, line or ring), 295-300, 393,
394,445
cylindrically symmetrie, 467-69, 473, 486
drift (binormal), 468, 474-78
elliptical (bell-ringing), 483
entangled without pairwise linkage
(Borromean), 487, 489
horseshoe hallmark, 527
linked and knotted, 296-98, 332, 469-74,
480-88
persistent organizing center, 483-90
shrinking, 298-99, 394, 467-89, 471,
474-78,482
stable organizing center, 483-87
turbulent tangles, 488-90
Scroll wave, 293-302
Dictyostelium, 69, 294-95, 445
heart muscle (see also Heart muscle, singular
filaments), 293, 294, 326, 327, 331,
431,493,497,498,504,516,518,
524-32,536
malonic acid reagent, 73, 293-99, 373-74,
400,403,468,481
numerical models, 473, 485, 491
Selective advantage of circadian clocks
(putative),549,556, 568, 576-83,590,
594,616
Self-sustaining vs. self-exciting, 174
Sensitivity function or rhythm, 126, 140, 235
Shaw, William Napier, 352
Shifted cycle, 178, 184, 194, 216, 420, 574
Simple dock, 80-145, 84, 85, 164,220, 568,
570,572,617,634,638
no rotating waves if independent, 97
three,89,108-10,331
two, 103~8, 123
Type 0 phase resetting only in populations,
88-90,111-12,345
1YPe 1 phase resetting only, 88-90, 580
Singularity (see also Phase singularity or
singular point)
critical point, 122, 307, 497, 498, 525
definitions, 77-79
magnetic bubble, 78
trap (protocol), 57, 58, 193,375,578
Singular filament (see also Heart muscle,
singular filaments; Seroll wave)
acoustical, 74 -
excitable media, 72-73, 392-93
elasticity or tension, 476, 479, 488
instability (see Instabilities)
hydrodynamic,297
J-shaped, 493
linked and knotted rings, 296-98, 332, 469-
74,480-88

laws of motion, 472-85
malonic acid reagent (see Seroll wave)
optical, 74, 301, 332
quantum mechanical, 74, 301
slapped by short-period wave train, 328-32,
394,405,472,490
sproing instability (see Instabilities)
thickness threshold for instability (see
Instabilities)
transmural or intramural (see Heart musde)
twistons (see Instabilities)
Singular point or stimulus (see Phase singularity
or singular point)
Sinoatrial (or sinus) node, 118, 131,322,414,
427,498
Skaggs, VVilliam, 468, 473
Sleep onset and duration, 7-8, 560
Slime mold
cellular (see Dictyostelium discoideum)
true (see Physarum polycephalum)
Slow repolarization front, 508
Slowwaves, 415-17, 426,569
Smooth musde (see Intestine; Rotors, uterine
smooth musde)
Social amoeba (see Dictyostelium discoideum)
South Pole, circadian docks at, 47
Spirallocus (hut not spiral wave)
e1ectron density in microtomed cutide (see
Cutide, arthropod)
solar wind (see Star formation)
sporulation (conidiation) in fungi, 537-44
Spiral waves in 2d (see also Seroll wave), 280-86
Axchimedean,254,284,384
astronomical, 280
core, 284, 437
Hames, 277, 301, 529
hair style, 70
heart musde (aka cardiac), 495-536
involute approximation, 284, 292, 383, 384,
385
logarithmic,332,379
malonic acid reagent, 72, 255-56, 266, 278,
292-295,369-74,381,383-406
multiarmed, 136,251, 289, 331, 448, 449,
541
platinum crystals, 277, 278, 326
reverberator, 497
scalar, 144
tip detection, 266, 329, 437
Splay phase, 344
Splitting of rhythms in rodent activity and
oscillator populations (see Circadian
rhythms and docks. dynamical features)
Spreading depression, 441, 442
Sproing (see Instabilities)
Star formation, 176, 280
Starmer, Frank, 534
SUBJECT INDEX 775
State, defined, 80, 184
Stationary state (see Steady state)
Steady state
attracting (see Black hole, of attracting cyde
oscillator)
circadian dock, 307-09
vs. singularity, 79
Stereo illustrations, instructions, 356, 488
Stomaeh, 432
Stopper mutant (of Neurospora crassa), 67, 544
Stopwatch. 87
Strange attractors (see Chaos)
Strasbourg cathedral dock. 559
Strogatz, Steven H., 470
Strumwasser, Felix, 176
Sudden cardiac death. 71, 167, 322, 495, 535
Superfluidity, 298, 300, 301
Supernova (see Star formation)
Suprachiasmatic nudeus (SCN), 126, 133, 143,
227,234,236,366,552,557,563,586,
590. 658
Swallowing, 118.421
Swimming (see Lamprey)
Synechococcus (see Cyanobacteria)
Syntalansis, defined (see Entrainment, mutual)
Tachycardia. 496, 503. 513
leading cirde description, 497. 502, 504, 511
monomorphic vs. polymorphie, 527, 528
Television: color from black and white, 15-16
Temperature
coefficient, 285, 569
dominant entraining agent in Neurospora
crassa, 554
effect on circadian phase and period, 62, 194,
567,613,616,647,672-76,682
effect on rotor period and size, 285-86
gradients, 128, 138, 430-32, 479
Temporal isolation, 7
Tension (see Singular filament)
Testosterone, 658
TetTahymena, 588, 638, 640
Three-oscillator models, 110-12
Thompson, Francis, 80
Thresholds (see also Bifurcations; Gating of
events by rhythms; Instabilities;
Piecewise linear kinetics; Relaxation
oscillator)
bromous acid, 266. 371
bursting neurons, 415
dilution for mutual entrainment, 122-32,
362-66,435.497-98,525.589
electrical in heart muscle, 270,519,522,523
mutual entrainment, 122-33, 232, 342, 345,
364,435
phase resetting 1YPe 1 becomes
776 SUBJECT INDEX
discontinuous, 194
phase-slip, 261
restitution CUIVe slope, 325, 408, 506
separator in state space, 154, 163, 166, 170,
194
thickness (see Instabilities)
Thurber, James, 334
Thyroid follides, 128
lides, 46-50, 268, 305, 453
TIme crystal, defined (see also Phase resetting
map or surface), 56, 159, 610
TIme delay, 129, 134, 176, 188,294,307,564,580
TIme machlne (see also Two-puIse phase-
resetting experiments), 20()"'{)6, 606, 607
TImeless gene and TIM protein (see also
Drosophila melanogaster, dock genes),
150,221,601
TImelessness vs. phaselessness, 175-77, 179,
306,307,327
TIssue specificity space, 313, 314
Tomography (optical), 402, 403, 491, 529
Tonga,l1
Topology, 1-3, 181
Toroidal coordinates for maps on graph paper,
14, 33, 37, 38, 113
Torsion, 296, 298, 404, 467, 470-82
Traffic flow of chemical pulses, 262
'Ihmsients, 191,559
circadian rhythms, 102, 115, 574, 595, 597,
625-26
Drosophila circadian dock, 207, 220
in single cell, not only in metazoans, 585
phase resetting models, 172
reaction-diffusion structures, 472
respiratory rhythm, 420
Transpiration (see Avena sativa)
1Temor, Parkinsonian, 129, 234, 345, 427
nigger wave (nearly uniform speed), 141,244,
378-80
'liue slime mold (see Physarum polycephalum)
Thrbulence (see also Chaos, spatiotemporal),
145,323,326,440,527,534
Thrbulent tangles of seroll rings, 488-90
Turing patterns (see Instabilities, diffusion-
induced)
Twist of phase along a singular filament, 296,
404,470-82
Twiston, 480, 504, 527, 528
Two-oscillator models (see also Meander, floral
... ; Phase, compromise)
attracting cydes, 123-25, 196,223,342,633,
647
circadian docks, 90, 223, 224, 566, 587, 588
simple docks, 103-08, 119, 121, 123, 130,
230,231,587,588
Two-pulse phase-resetting experiments, 336, 415
chick ventricular ceWmyocyte aggregates,
183,336,415,426
Drosophila, 183, 198-228,607
human, 183
Kalanchoe, 219
mosquito (Culex), 219, 620
yeast, 219
TWSK convention, 470
'JYpe 0 phase resetting (see also Phase resetting
"'lYpe"; for data, see Phase resetting
headings)
collective or aggregate rhythm, 111-12, 345
female cyde (none), 116
impossible in a ring device, 89-90, 580
nuclear division cyde (none), 116
reality, table of examples, 113-18
rotating wave in sheet of oscillators (see
Pinwheel protocol)
'JYpe 1 phase resetting (see Phase resetting
"'JYpen )
lYson, John, 470
Ultraviolet light, 190, 269, 358, 373, 401, 406
Upper limit of vulnerability (see Heart muscle:
vulnerability, upper and lower limits)
Vagus nerve, 130
van der Poloscillator, 124, 170, 192,222,233,
234,235,432
Velocity response curve (see Angular velocity;
Phase, velocity)
Ventricularmyocytes, chick, 118, 131, 172,
183,188,219-20,336,415,422-427,
501,619
Vision (see Color headings)
Visual (or striate) cortex, 24, 74, 143
Virtual electrode in bidomain media, 519, 523
Vortex atoms, 300
Vortex (or singular) filament, line, or ring (see
Singular filament; Heart musde,
singular filaments)
Vorticity, 265, 329
Vulnerable phase or period (heart musde), 502,
514,520,523,527,534
vycorglass, 369,385, 398, 399,400,401
Waddington, C.H., 443
Wandering vs. meandering, 498
Waves (reaction-diffusion)
action potential propagation, 411-44, 495-536
broom, 134, 408
calcium, 277, 278, 283, 285, 348
cAMP, 278,320, 443-54
epidemie, 254
figure-of-eight (mirror-image rotors), 269,
509, 525
 SUBJECT INDEX 777

kinematic description, 237, 244, 329, 330 Whewell, William, 48

malonic acid reagent, 368-411
phase, 74,237,244,245,435
pseudo (nearly uniform period), 52, 74, 140,
237,238,244,245,358,378-80
quatrefoil (mirror-image figures-of-eight)
(see Heart muscle)
rotating around a hole, 290, 434-45
rotating (misnomer), 63, 118,263,282
rotating pseudowave, 244
rotating scalar wave, 144,252,289
speed correlated with curvature, 299, 384
trigger (nearly uniform speed), 141,244,
378-80
wavelength (in cardiology), 498
Wax sculpture, 469, 473
Web site, author's, 276, 282, 323, 403, 491, 561
Wenckebach block and domains in graded
excitable media, 431
Whitehead, A1fred North, 518
Wigner, Eugene, 384
WiIson, Robert, 582
Winding number
defined,13
non-zero, 25,40,47, 56,57,67,72,137,182,
239,241,299,393
Wiener, Norbert, 132
WilheIm, R.H., 134
Winfree, Erik, 471, 565
Witkowski, Frank, 410, 431, 492, 493, 505, 507,
526,529,533
Wittgenstein, Ludwig, 315
Wolfson, Michael, 473, 477
Writhing (of aspace curve), 296, 471, 481
Xenopus oocyte, 277, 283
Yeast
Saccharomyces carlsbergensis, 62, 65, 347-
67,349,364
Saccharomyces cerevisiae, 349, 364, 632
Schizosaccharomyces pombe. 632
two-pulse resetting experiments, 219
Zimmerman, William, 574, 613
Zykov excitable medium, 388, 400, 457
Zykov, VIadimir, 385
Interdisciplinary Applied Mathematics

1. Gutzwiller: Chaos in Classical and Quantum Meehanies

2. Wiggins: Chaotie Transport in Dynamieal Systems
3. JosephiRenardy: Fundamentals ofTwo-Fluid Dynamics:
Part I: Mathematieal Theory and Applieations
4. JosephiRenardy: Fundamentals ofTwo-Fluid Dynamies:
Part II: Lubrieated Transport, Drops and Miseible Liquids
5. Seydel: Praetieal Bifureation and Stability Analysis:
From Equilibrium to Chaos
6. Hornung: Homogenization and Porous Media
7. Simo/Hughes: Computational Inelastieity
8. Keener/Sneyd: Mathematieal Physiology
9. HaniReddy: Plastieity: Mathematieal Theory and Numerica1 Analysis
10. Sastry: Nonlinear Systems: Analysis, Stability, and Control
11. McCarthy: Geometrie Design ofLinkages
12. Winfree: The Geometry ofBiological Time, Second Edition
13. BleisteinlCoheniStockwell: Mathematics of Multidimensional
Seismie Imaging, Migration, and Inversion