ARTICLE Prions: Introducing a Complex Scientific
Controversy to a Biology Classroom
I G O R V. Z A I T S E V
It has been almost 50 years since Thomas Kuhn, in The Structure of
Scientific Revolutions, posited that science does not progress by the
steady accumulation of knowledge, but rather by a system of com-
petition among paradigms. They vie for supremacy through greater
parsimony, explanatory power, and popularity among the commu-
nity of scientists (Kuhn, 1962). The current controversy concerning
the identity of prions (PrPs) (proteins devoid of the nucleic acid) as
the infectious agents of transmissible spongiform encephalopathies
(TSE) elucidates all the issues involved in just such a debate.
While modern biology high school and university textbooks
cover many scientific controversies that have been resolved decades
and even centuries ago, they fail to cover current scientific disputes.
This article is intended to address such an omission by introduc-
ing the prion controversy in biology classes in high schools and
colleges.
In 1982, biochemist and neurologist Stanley Prusiner proposed
a hypothesis concerning infectious proteins. He identified them as
abnormal prions, proteinaceous infectious particles capable of
converting normal prions (naturally present proteins in mammals)
into an abnormal form causing a fatal disease of the central nervous
system (CNS) in both animals and humans. Heretofore, it had been
accepted that infections could be caused only by protozoans, fungi,
bacteria, rickettsia, viruses, or viroids. Only nucleic acids, informa-
tional polymers, were known to be able to duplicate themselves,
not proteins. For the discovery of prions which Prusiner posited
can cause TSE, he received a Nobel Prize in 1997.
Were Prusiner’s hypothesis correct, our understanding of the
organic world would be changed forever. However, Laura Manuelidis
(2007), one of most dedicated scientists in this field and the head
of neuropathology at the Yale School of Medicine, contends that
“prions thereby became canonized, although careful review of data
revealed many discrepancies.” Indeed, even Nobel
Prize winners can err (Allchin, 2008), includ-
ing Prusiner, and prions thus remain in the
realm of a hypothesis (Manuelidis, 2007).
TSE continues
to
Despite overwhelming opposing spread throughout the
data published in The Lancet, Science,
Virology, The Journal of Virology,
world, killing people who eat
Journal of Cellular Biochemistry, Viral the tissue of cattle infected
Immunology, Journal of NeuroVirology,
Proceedings of the National Academy with BSE, children treated
of Sciences, and many other scientific with human growth hormone,
publications, most, if not all, biology
textbooks in the U.S. present prions as patients in surgery ... herds of
the primary cause of TSE. While there sheep, cattle, deer, elk,
are scientists convinced of the ability of
abnormal prions to cause infections, there and mink.
are other scientists who, based on their obser-
THE AMERICAN BIOLOGY TEACHER
vations and experimental data, do not think that prions could
become infectious. Manuelidis suggests that prions may simply be
part of the late stage of a disease, not part of the cause (Mihailova,
2007), and PrP infectivity is questionable, and perhaps non-exis-
tent (Manuelidis, 2007).
Cannibalism & the Rise of TSE
Since students seem more engaged when instructors incorporate
examples from popular culture into classroom discussions (Pryor,
2008), one might start a consideration of prions with mention of
Kurt Vonnegut’s science fiction novel, Cat’s Cradle (1963), before
introducing Deadly Feasts (1997), a shocking nonfiction case his-
tory of the discovery and epidemiology of the fatal disease TSE.
Certainly, truth is stranger than fiction if one were to contrast
Richard Rhodes’ documented study and any of Vonnegut’s science
fiction novels. Cat’s Cradle, concluding in an apocalyptic climax,
concerns the ability of a nucleant that can turn water into ice, just
as an abnormal prion can allegedly turn its host prions into abnor-
mal forms, resulting in this fatal brain pathology. Deadly Feasts
begins with a description of a burial ceremony that the women
of the Fore tribe used to practice in New Guinea, “the last wild
place on earth.” Sixty or more native women with their babies and
small children, the family of a deceased woman, would gather to
bury her in their stomachs rather than abandon her to rot in the
ground. “Why should we throw away good meat? It is not right,”
one woman told an anthropologist (Rhodes, 1997). The mourners
would eat body parts, including “the bones, which they charred in
the open fire to soften them,” “even the feces would be eaten, mixed
with edible ferns and cooked in banana leaves” (Rhode, 1997). Fore
woman recalled that cannibalizing the corpses of their kindred
“started within the lifetime of the oldest grandmother.” “I eat you,”
was a Fore greeting (Rhode, 1997). The deceased who died of
leprosy or diarrhea were not consumed.
By 1950, a disease called kuru (KOO-roo), which
means shivering with cold or fear, had killed women
in every Fore village. One of the most pronounced
symptoms would be unprovoked laughter.
Because of this, the disease became known as
“laughing death.” The victims would lose their
ability to walk, shiver uncontrollably but not
from cold or fear; their speech would become
blurred. Finally, their ability to swallow would
be so impaired that their relatives would have
to chew food for the dying victims and force
it down their throats. Such symptoms were
considered to have been caused by bewitchment.
Nevertheless, the flesh of women killed by sorcery
was considered clean enough to be eaten by other
PRIONS 525
women. Fore men were blamed for practicing sorcery on their
women and children, and were hated and feared by natives of New
Guinea. Medical researchers who encountered Fore women’s symp-
toms at first thought they were dealing with a new form of encepha-
litis. The part of the brain of these Fore patients primarily damaged
was the cerebellum. Postmortem examinations revealed multiple
holes in this part of the brain. Surprisingly, there was no inflamma-
tion as in encephalitis. Interestingly enough, after the cessation of
cannibalism, kuru gradually disappeared (Gajdusek, 1977).
Another mysterious disease involving brain damage without
apparent inflammation was discovered in Germany in 1913 by a
young physician, Gerhard Creutzfeldt. He had a patient whose
cheerful personality had abruptly changed. No longer wanting
to eat or bathe, she began screaming that she was possessed of a
devil and that she was dead and wanted to sacrifice herself. At the
same time, the woman had sudden outbursts of laughter, distracted
speech, tic-like jerks in her arm, fluttering facial muscles, altered
reflexes, and tremors that started up whenever she
made a voluntary movement. In her last hours,
the woman’s swallowing was impaired and she
went into a deep stupor. Creutzfeldt, recognizing
Table 1. Some forms of transmissible spongiform
that this was a new disease, reported his findings encephalopathies in mammals.
in a German medical journal. Alfons Jakob read
SPECIES
Creutzfeldt’s paper and contacted him because
he too had lost patients with similar symptoms.
man
Thus, this disease was named Creutzfeldt-Jakob
disease (CJD). One of the most surprising charac- sheep
teristics of the kuru and CJD was that there was no
apparent inflammation to the damaged brain. In mink
1957, a neuropathologist at the National Institute cattle
of Health, Igor Klatzo, was the first to associate deer
kuru with CJD, in correspondence with virologist
elk
Daniel Carleton Gajdusek. Thereafter, research vet-
erinarian William Hadlow realized that scrapie, the
degenerative brain disease he had studied in sheep,
was also very similar to kuru and CJD in humans. Studying sheep
brain sections under the microscope, Hadlow identified cerebellar
holes and sponginess as also occur in the brains of kuru and CJD
victims, while it also affected the cerebral cortex in CJD, but not in Question
kuru victims.
Scrapie was first documented about 1750. Scrapie-infected
sheep symptoms involve behavioral changes such as biting at their
legs, itching, pulling wool from their sides, and abnormally react-
ing to noise. Infected animals develop tremors and incoordination
that progress to decumbency and death. It had been known since
1930 that scrapie was infectious. The most common method of
transmission is from dams to their own and other offspring. There
is no treatment for scrapie and animals die from one to six months
after the onset of symptoms.
If kuru and CJD have the same nature as scrapie, those fatal
human neurodegenerative diseases might also be infectious, and,
of course, would raise public health concerns. In Gajdusek’s lab, in
the 1960s, brain tissue from kuru victims had been homogenized
and inoculated into those of chimpanzees. Within a couple of years,
the animals showed the first signs of inactivity, shaking and trem-
bling, and uncoordinated movements, quickly followed by further
physical deterioration. The brains of the sacrificed laboratory ani-
mals were sectioned, and with further histological analysis, it was
evident that their brain pathology was indistinguishable from that
of the kuru victims. Indisputably, the disease had been shown to
be transmissible. If it could be passed on to chimpanzees, it could
be passed on to humans. The connection between kuru and can-
nibalism was no longer in question. CJD was not confined to New
526 THE AMERICAN BIOLOGY TEACHER
Guinea, but was occurring throughout the world. British cows had
a long history of having been fed protein supplements made from
scrapie-infected sheep offal and even infected dead cows. Richard
Rhodes called it an “industrial cannibalism” (Rhodes, 1997). It
should not have been surprising that those cows developed symp-
toms somewhat similar to those of infected sheep, which today is
known as “mad cow disease” or bovine spongiform encephalopathy
(BSE). Consumption of contaminated beef led to spreading deadly
infection to humans. Neither cooking, nor chemical disinfectants,
nor irradiation deactivate the infectious agent and, at the present
time, there is no treatment for TSE. Scientists are racing to identify
the precise agent of the fatal disease, as the controversy of possible
sources is still unresolved. TSE continues to spread throughout the
world, killing people who eat the tissue of cattle infected with BSE,
children treated with human growth hormones, patients in surgery
(transplants, transfusion, use of contaminated surgical instru-
ments), herds of sheep, cattle, deer, elk, and mink. (See Table 1.)
DISEASE ABBREVIATIONS
kuru –
Creutzfeldt-Jakob Disease CJD
scrapie –
transmissible mink encephalopathy TME
bovine spongiform encephalopathy BSE
chronic wasting disease CWD
Prions or Not Prions – That Is the
Primary experiments have shown that the causal agent of TSE
is capable of passing through bacterial filter. It causes no appar-
ent inflammation, raises no fever, nor indicates any other signs or
symptoms of an immune response. Moreover, this agent was highly
resistant to such insults as boiling and even autoclaving. It was
also resistant to disinfection with chloroform, carbonic acid, strong
formaldehyde, and UV light. No bacteria grew in scrapie-infected
tissue, and none was visible under the light microscope.
Could the causal agent of TSE be a virus, “a piece of bad news
wrapped in protein,” as Peter Medawar once quipped (Rhodes,
1997)? Many scientists reject this, citing its resistance to UV light,
which is known to kill microorganisms by damaging their nucleic
acids. An experiment done in the 1960s on the homogenate of
a scrapie brain with enzymes, known to damage nucleic acids,
demonstrated no reduction in infectivity while homogenates with
enzymes, known to damage proteins, reduced infectivity by more
than ninety percent. So is the infectious agent a protein? At first, a
positive answer to this question sounds like science fiction, since,
as far as we know, infections are not caused by proteins, but by
microorganisms. We know that in order for them to multiply, nucle-
ic acid is required. According to the current fundamental principles
of biology, proteins cannot replicate themselves, causing infections
as nucleic acid can. Prions lack any nucleic acid and, therefore,
violate the “universal” rule of protein synthesis. Francis Crick did
VOLUME 71, NO. 9, NOVEMBER/DECEMBER 2009
not want to overlook the possibility of an exception, noting that
discovery of an exception “will shake the whole intellectual basis
of molecular biology” (Rhodes, 1997). Even so, one must not jump
as yet to a quick conclusion. The infectious agent could be either a
virus whose genome is protected from UV light inside a sturdy coat
of protein, or a virus that is super efficient at repairing radiation
damage to its genome.
At this time, let us recall what Kurt Vonnegut’s Cat’s Cradle is
all about. In this science fiction tale, a scientist creates a nucleant
capable of turning all the water on the planet, including the water
in human cells and blood, into ice. In 1995, Byron Caughey and
Peter Lansbury borrowed Vonnegut’s scientific fantasy for the title
of a paper, “The Chemistry of Scrapie Infection: Implications of the
‘Ice 9’ Metaphor” (Lansbury & Caughey, 1995). Vonnegut’s ficti-
tious nucleant is a “seed” capable of converting nearby fluid water
to crystalline form. Gajdusek visualized a similar infective process
at work in the TSE. He proposed that a nucleant crystal of abnor-
mal PrP was the TSE infectious agent. According to his hypothesis,
the abnormal prion is capable of converting a normal prion into
the abnormal conformation. Prusiner coined the name “prion” and
enthusiastically pursued the proof of this hypothesis and, thus, was
rewarded a Nobel Prize.
The functions of prions in a healthy individual are still unclear.
Some researchers suggest that they might play a role in the cell
death and neural excitability. All mammals produce host prions
in both diseased and healthy individuals. Prions are expressed
across the entire CNS, especially in the hippocampus, striatum,
and frontal lobe. The unique sequences of amino acids in a prion
make it possible for these molecules to have two different, stable
tertiary structures. One type, called a cellular (“healthy”) prion
protein (PrPC), has functional structure folds with many α-helices.
The abnormal prion protein (PrPSc) has many β-plated sheets. They
are the same protein but just folded differently. PrPSc is amyloid
fibrils assembled in large structures. Prusiner’s team of research
scientists suggest that PrPSc converts α-helices into β-plated sheets
(Pan et al., 1993) and thus transmits TSE (Prusiner, 1998). Let us
consider some scientific data that contradicts rather than supports
Prusiner’s prion hypothesis:
1. It has been established that one of the major routes of trans-
mission of TSE is along the gastrointestinal tract in which
an infectious agent invades the mucosa and, thereby, infects
the Peyer’s patches. However, recently it has been shown
that the PrP is rapidly destroyed by alimentary track fluids
(Jeffrey et al., 2006). If so, it makes the ability of “infectious
PrP” to implant further, crossing the blood-brain barrier,
almost impossible. The viral hypothesis does not contra-
dict this new finding since we know that enteroviruses are
capable of withstanding acid and proteolytic secretions.
2. The presence of hundreds of different strains of TSE in
different species also challenges the prion hypothesis. The
presence of strains is one of the characteristic features of
an infectious agent with a nucleic acid. These strains have
been successfully passed from one species of animals to
another, and even back to the original species (e.g., sheep to
mice, then mice to sheep), preserving their singular strain
identity, despite PrP differences between sheep and mice
(reviewed in Manuelidis, 2007). The presence of different
forms of PrP in those species during infection does not
satisfy the first of Koch’s postulates that states that a patho-
gen must be invariably present, in a constant form, in every
case of the disease. Consequently, how can protein particles
behave as various strains while they display different identi-
ties in a single strain of the disease?
THE AMERICAN BIOLOGY TEACHER
3. Infectivity and PrP titer are not proportional across strains.
Many different animal models in different laboratories
show that PrP presence is a poor marker for the level of
infectivity, and the lack of PrP does not preclude infection
(reviewed in Manuelidis, 2007). Some slow CJD strains
show no detectable PrP. Baker et al. (2002) showed that
living microglia from a CJD-infected brain had no detect-
able prions, yet contained maximal levels of infectivity.
Another study shows that “PrP neither encodes nor alters
agent-specific characteristics” (Arjona et al., 2004). Blocking
the formation of prions by an antimalaria drug does not
lengthen CJD victims’ lives (Collinge, 2009). These are a
few examples from many studies that do not confirm prion
infectivity. Initial misleading data, suggesting that PrP is the
infectious agent, had been the result of technical difficulties
to purify PrP from nucleic acid present in infected animal
tissue; thus, infectious preparations often contain a large
amount of nucleic acids.
4. “The host can recognize a TSE agent and recruit its innate
immune system to respond as early as 20-30 days after
inoculation” while “PrP begins to accumulate only at 90
days post-inoculation, and is incapable of activating the
same immune pathways” (Manuelidis, 2007). Lu et al.
(2004) detected innate immune host responses before the
occurrence of PrP changes. “These host responses are con-
sistent with a foreign pathogen, but not host encoded PrP.
The epidemic outbreak of BSE also strongly implicates an
exogenous infectious agent” (Liu et al., 2008).
5. Virus-like particles in TSEs had been detected in many
experimental animal tissue samples by many different labo-
ratories (David-Ferreira et al., 1968; Bignami & Parry, 1971;
Lampert et al., 1971; Baringer & Prusiner, 1978; Sklaviadis
et al., 1992; Liberski & Brown, 2007; Manuelidis et al.,
2007). Treatment with low concentrations of SDS removed
residual PrP from these particles, but did not reduce
their infectivity. On the other hand, disruption of nucleic-
acid-protein complexes destroyed 99.5% of their infectiv-
ity (Manuelidis et al., 1995). It has been shown that cells
infected with scrapie and CJD agents produce intracellular
25-nm virus-like particles (Manuelidis et al., 2007). Their
size is similar to the size of small RNA viruses. Disruption
of these viral particles destroys infectivity.
The abundance of scientific data and arguments among an
impressive segment of scientists, contradicting and challenging
Prusiner’s hypothesis, warrants continued reconsideration. By
including current unresolved scientific controversies, such as the
hypothetical nature of prions, for the first time in biology courses,
students could be introduced to one of the most contentious unre-
solved disputes in the culture of a discipline so scrupulous that
finding the true answer can be as hard as “nibbling on granite,”
as they say in Russia. The theoretical importance of the topic of
infectious proteins might be compared to the eighteenth-century
debates on spontaneous generation, although the task of identify-
ing the nature of the infectious agent of fatal TSE has proven far
more complicated than what had been resolved by Francesco Redi
and Louis Pasteur. This mysterious agent, like a molecular ghost,
is still “invisible” to us even at the most sophisticated levels of
technology and molecular biology. The answers may be found as
research scientists devise new ways to evaluate the TSE infection.
Giving students the opportunity to think about and discuss this
topic will greatly expand their background and skills, as the scien-
tific community still searches for answers.
PRIONS 527
 Classroom Activities & Assessment
The prion controversy would be best introduced at the conclusion
of the biology course. Having covered the scientific method, char-
acteristics of living things, the structure of proteins and nucleic
acids, the immune response, the nervous system, and Koch’s
postulates, students would then have the background to engage
with the issues. Since this controversy requires the integration of
biological knowledge, as well as the skills to apply the scientific
method of inquiry, it could be used advantageously by biology
teachers either in high schools or colleges. Introduced in a case
studies format, such a scientific dispute can be considered during
an inquiry-based session. To increase classroom participation, and
at the same time review material covered during the course, I have
devised interrupted case classroom discussion on TSE consisting
of two sessions. Below is the suggested strategy in approaching
the topic.
First Session: The Mysterious Disease
Introduce the details of kin cannibalism in the Fore tribe of
New Guinea, but before divulging any specific information on TSE,
ask, “What might be another explanation for the death of the Fore
women other than sorcery?” Students should write their diagnostic
hypotheses so that afterwards, they can compare them to addition-
al information eventually provided them. Then, dividing students
into groups, ask them to share and debate their hypotheses with
one another.
After these group discussions, compare the symptoms of the
disease in Fore women with that of outbreaks of similar diseases
found in the other parts of the world. Provide the class with a list
of questions detailing the way the brains of the TSE patients dete-
riorate. (See Table 2.)
Table 2. Suggested questions for the first session.
1. In one word, what type of damage in the human body
would trigger tic-like jerks, tremors, and fluttering facial
muscles?
2. What is the function of the cerebellum?
3. What is the function of the cerebral cortex?
4. Why had Fore women lost their ability to walk, yet
remained conscious until they died?
5. Which centers in the brain are responsible for speech?
6. If, in kuru patients, only the cerebellum was damaged,
how you would explain blurred speech?
7. Does this additional information correspond to your pri-
mary hypotheses?
8. How would you explain the fact that, after the cessation
of cannibalism, kuru disappeared?
Before moving on, point out that if we are to satisfy each
of Koch’s fundamental postulates (see Table 3) in experiments
conducted with kuru and CJD, we would have proof not only
that those diseases are infectious, but we would able to identify
the infectious agent. Ask students to do some Internet research
on the causative agent of CJD, and summarize their findings in a
brief report.
THE AMERICAN BIOLOGY TEACHER
Table 3. Koch’s postulates.
1. Pathogen must be invariably present in constant form in
every case of the disease.
2. Infectious agent must be isolated from the host with the
disease and grown in pure culture or recombinant form.
3. The cultivated agent must be able to reproduce when it
is inoculated into a healthy susceptible host.
4. Pathogen must be recoverable from the experimentally-
infected host.
Second Session: The Virus versus Protein
At the beginning of this session, ask students what they know
about the common characteristics of the prokaryotic cell, while
refreshing their memory about immune responses to bacterial
infection. Point out that the spiroplasma (the thermostable, small,
helical bacteria discovered in the 1970s) was so small that it could
pass through bacterial filters. These bacteria have often been pres-
ent in cases of TSE, but not always (Alexeeva et al., 2006). This fact
does not satisfy Koch’s first postulate, thus ruling out spiroplasma
or any other bacteria as an etiologic agent.
At this point in an inquiry-based session, present conflicting
data from the two opposing groups of research scientists. In light of
such information, ask if any students want to reconsider their initial
hypotheses: “Why have these scientists come to such contradictory
conclusions? Could it be that the hypotheses regarding TSE infec-
tions ought to be reconsidered?” One may want to give a homework
assignment to research the methodology of studying TSE.
After providing the class with selected papers from lead-
ing scientific publications containing conflicting data, set up an
“Abnormal PrP Trial.” Announce that abnormal PrP pleads “not
guilty” in causing TSE. One group of students must devise a ratio-
nale for the defense of the abnormal prion, while another prepare
the prosecution’s arguments. During the session, one can draw the
students attention to topics covered earlier in the school year. (See
Table 4.)
After the “trial,” every student is expected to write an essay on
the “Tentative Nature of Science and the Studies Done on TSE.” In
assessing their work, one must pay attention to their originality, crit-
ical thinking, factual details, and integration of biological topics.
Table 4. Suggested questions for the second session.
1. How would you describe a nucleic acid?
2. How many different types of nucleic acids do you
know?
3. What can DNA and RNA do that proteins can not?
4. How would you explain the central dogma in biology,
and who defined the central dogma?
5. How would one define protein?
6. How many structures do proteins have?
7. How could proteins be folded in a tertiary structure?
8. Why do those folds occur?
9. What drives protein folding?
10. Can the same protein have more than one shape?
PRIONS 529
 I have observed a high level of student interest during such
Manuelidis, L., Sklaviadis, T., Akowitz, A. & Fritch, W. (1995). Viral particles are required
interruptive classroom discussions. The class becomes particularly
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disease. Students who were shy begin to ask questions. The class Mihailova, M. (2007). Yale M.D. makes leap in mad cow research. Yale Daily News.
as a whole begins to question the fact that its textbooks have com- Available online at: http://www.yaledailynews.com/articles/view/19788.
pletely ignored the theoretical importance of the complex scientific Pan, K.-M. et al. (1993). Conversion of α-helices into β-sheets features in the forma-
controversy. tion of the scrapie prion proteins. Proceedings of the National Academy of
Many recent studies show that case studies increase student Sciences USA, 90, 10962-10966.
participation and improve student understanding of subject mat- Prusiner S.B., Scott, M.R., DeArmond S.J. & Cohen F.E. (1998). Prion protein biology.
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time-consuming. Introducing the current controversy on TSE, a Pryor, G.S. (2008). Using pop culture to teach introductory biology. The American
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