You are on page 1of 3


65 ing symptoms, clarifying issues of personal

64 E S S AY S O N S C I E N C E A N D S O C I E T Y responsibility, and improving accessibility
63 to health care.
61 Defining Disease Human genome sequencing will reveal
thousands of genetic variations among in-
60 dividuals that many will assume are asso-
in the Genomics Era ciated with disease. But translating such
genotypic differences (genetic characteris-
57 Larissa K. F. Temple, Robin S. McLeod, Steven Gallinger, James G. Wright tics) into phenotypic states (visible charac-
56 teristics) is prone to pitfalls. For example,
55 he human genome sequence will dra- ue to define schizophrenia in terms of the genetic abnormalities differ in their pene-
T matically alter how we define, pre-
vent, and treat disease. As more and
more genetic variations among individuals
presence or absence of “positive” and
“negative” symptoms.
Diagnosis is the act of labeling some-
trance (that is, not everyone carrying a ge-
netic abnormality will suffer from adverse
consequences); environmental effects have
51 are discovered, there will be a rush to label one as diseased through clinical, laborato- not been taken into consideration; and
50 many of these variations as disease-associ- ry, and pathological findings, combined many diseases have complex etiologies
49 ated. We need to define the term disease so with clinical knowledge and judgment. that depend on a number of different
48 that it incorporates our expanding genetic Disease is generally considered to be an genes. There are very few diseases that are
47 knowledge, taking into account the caused by a single gene mutation. Auto-
46 possible risks and adverse conse- mated genomic sequencing is becoming
45 quences associated with certain increasingly sophisticated, but distin-
44 genetic variations, while acknowl- guishing between normal variations in

Downloaded from on July 2, 2017

43 edging that a definition of disease genes (polymorphisms) and alterations
42 cannot be based solely on one ge- that are detrimental (mutations) re-
41 netic abnormality. mains extremely difficult. This diffi-
40 Disease is a fluid concept influ- culty will have direct consequences for
39 enced by societal and cultural atti- genetic counselors, who must advise
38 tudes that change with time and in individuals about the presence of
37 response to new scientif ic and Image not genetic abnormalities, what they
36 medical discoveries. Historically, mean, and which treatment or pro-
35 doctors defined a disease accord-
available for
phylaxis to follow.
34 ing to a cluster of symptoms. As online use. Scant attention has been paid to
33 their clinical descriptions became defining disease in clinical medicine.
32 more sophisticated, they started to Heslow has argued against the need
31 classify diseases into separate groups, and for a definition of disease, stating
30 from this medical taxonomy came new in- that patients can be treated without
29 sights into disease etiology. For example, one.* However, the importance of
28 before the 20th century, schizophrenia and the term disease to patients, clini-
27 syphilitic insanity were treated as the same cians, and society cannot be disput-
26 disease. But by early 1900, it became evi- ed. Boorse def ines disease as “a
25 dent that psychoses without associated de- type of internal state which is either
24 mentia represented a separate disease for attribute of a pa- an impairment of normal functional abili-
23 which the term schizophrenia was then tient, whereas di- ty—that is, a reduction of one or more
22 coined. The definition of schizophrenia agnosis is the be- functional abilities below typical efficien-
21 continues to evolve: from the psychiatric lief that the patient has a disease, a belief cy—or a limitation on functional ability
20 disease of the 1960s to an illness with a that may or may not be true. In using a caused by environmental agents.Ӡ This
19 suspected genetic etiology. While the hunt single phrase to describe a set of clinical type of philosophical definition is imprac-
18 is still on for the genes involved, we contin- findings, important information can be ef- tical clinically and, more important, is un-
17 fectively communicated to other clinicians likely to make the interpretation of genetic
16 and care providers. Diagnoses are intended variations any simpler.

L. K. F. Temple, R. S. McLeod, and S. Gallinger are in

15 the Department of Surgery, University of Toronto, to inform patients and to tell clinicians In thinking about how clinicians use
14 Mount Sinai Hospital, Samuel Lunenfeld Research In- who and how to treat. the term disease, we think that three ele-
13 stitute, Toronto, ON, Canada M5G 1X5. J. G. Wright is Labeling someone as “diseased,” howev- ments should be considered: disease is a
12 in the Departments of Surgery, Public Health Sci- er, has enormous individual, social, finan- state that places individuals at increased
ences, and Health Policy, Management and Evalua-
11 tion, University of Toronto, The Hospital for Sick cial, and physical implications. Irrespective risk of adverse consequences. Treatment is
10 Children, Toronto, ON, Canada M5G 1X8. E-mail: of disease symptoms, the label itself may given to those with a disease to prevent or
9 lead to significant distress. Individuals with ameliorate adverse consequences. The key
8 asymptomatic conditions, including genetic element in this definition is risk: devia-
*G. Heslow, Theor. Med. 14, 1 (1993).
7 †C. Boorse, in What Is Disease? J. M. Humber, R. F. variations, may be perceived by themselves tions from normal that are not associated
6 Almeder, Eds. (Biomedical Ethics Reviews, Humana or others as having a disease. Such labeling with risk should not be considered syn-
5 Press, Totowo, NJ, 1997), pp. 7–8. has severe ramifications, affecting deci- onymous with disease. Our definition has
4 ‡J. G. Scadding, Lancet 348, 594 (1996). sions to have children or resulting in unjust three definable elements and should serve
§S. Cunningham-Burley, M. Boulton, in Handbook of
3 Social Studies in Health and Medicine, G. L. Albrecht,
treatment by life, medical, and disability in- clinicians well. Of course, its success will
2 R. Fitzpatrick, S. C. Scrimshaw, Eds. (Sage Publications surers. Sometimes, however, labeling some- depend on whether it becomes clinically
1 Ltd., London, 2000). one as diseased can be beneficial, legitimiz- useful.

807 SCIENCE VOL 293 3 AUGUST 2001
S C I E N C E ’ S C O M PA S S
65 Two schools—nominalist and essential- states that are associated with disease, the rather than on a clear specification of the
64 ist (reductionist)—have debated the clini- challenge is to describe potential adverse risk, the label may harm the patient. For
63 cal criteria used to label a patient as dis- outcomes comprehensively and explicitly. example, treating genetic variations in the
62 eased. Nominalists label symptoms with a Because an adverse consequence in one elderly may not only be unnecessary (be-
61 disease name, such as schizophrenia, and culture may not be viewed as such in anoth- cause of the low risk of an adverse out-
60 do not offer an explanation of the underly- er, this consideration must take into account come), but may actually lead to deleterious
59 ing etiology. Essentialists argue that for different ethnic and cultural beliefs. For ex- side effects.
58 every disease there is an underlying patho- ample, whereas menopause is considered a The continuing discovery of new genes,
57 logical etiology and that the disease state medical condition in North America, in oth- their sequences, and variations has led to
56 should be defined by the essential lesion. er cultures it is viewed as a normal aspect confusion among clinicians and patients.
55 With recent dramatic advances in genetics of aging. First, not all patients with genetic muta-
54 and genomics, essentialists could argue Although a few diseases are universally tions or abnormalities develop adverse out-
53 that the essential lesion defining the dis- and prematurely fatal, most diseases place comes. When a genetic mutation is initially
52 ease state is a genetic abnormality. patients at an increased but variable risk for identified, the likelihood of developing a
51 Scadding suggests that diseases de- morbidity or mortality. For example, some disease is unknown, and so the importance
50 fined according to the essentialist tradition patients with high blood pressure will be of the mutation cannot be gauged. For ex-
49 may be “precisely wrong,” whereas those asymptomatic throughout life, about 30% ample, it was originally estimated that 80%
48 defined in the nominalist traditional may will suffer adverse consequences such as of Ashkenazi women with mutations in the
47 be “roughly accurate.”‡ We would argue heart disease, and 5 to 10% will die from a breast cancer susceptibility genes BRCA1
46 that labeling the disease state according to stroke. Here, the “cutoff ” between the cat- and BRCA2 would develop breast cancer;
45 only the phenotype (symptoms) or the egories of diseased and nondiseased could subsequent studies revealed that the risk
44 genotype (genetic abnormality) is unsatis- be based on many factors, including an im- was closer to 50%. Thus, genetic mutations

Downloaded from on July 2, 2017

43 factory. The genotype or phenotype de- are not sufficient in themselves to
42 scribes a state that places individuals at lead to adverse consequences. Fur-
41 some def inable risk of adverse conse- thermore, individuals lacking an
40 quences and so either could be used as a identifiable genetic mutation are not
39 criterion for disease. For example, in the necessarily “disease-free.” For exam-
38 cancer predisposition syndrome hereditary Image not ple, among non-Ashkenazi women
37 nonpolyposis colorectal cancer (HNPCC), available for who develop breast cancer, only 5%
36 members of HNPCC families have a 50% have a BRCA1 or BRCA2 mutation.
35 risk of developing colorectal and other online use. Mutations in other genes or environ-
34 cancers at a very young age. HNPCC has mental factors may predispose these
33 been defined according to both genetic women to breast cancer, and so they
32 mutations and clinical criteria. Clinical cri- may have the same or even an in-
31 teria for HNPCC can be used to define the creased risk of adverse consequences
30 disease state and to advise patients and compared with women carrying an
29 family members about the need for cancer plicit understanding of risk and potential identified genetic mutation. Thus, a genetic
28 screening. In contrast, when considering for treatment. Criteria defining which indi- mutation is not an absolute prerequisite for
27 specific genetic or pharmacologic thera- viduals are diseased are important be- a disease and cannot be used as the sole
26 pies, the disease state may be better de- cause abnormalities, such as genetic vari- defining feature of that disease.
25 fined according to the type of genetic ab- ations or elevated blood pressure, may oc- The human genome sequence is likely
24 normality. Thus, both clinical criteria and cur in otherwise asymptomatic patients. to reveal many harmless genetic variations
23 genetic abnormalities can be used to de- Criteria for certain diseases, such as dia- that will turn out not to be associated with
22 fine a disease state, and the choice of defi- betes, have improved, owing to more ac- disease. Until we resolve questions about
21 nition will vary according to what one curate definitions of risk and better treat- polymorphisms, incomplete penetrance of
20 wishes to achieve (in this case, genetic ments. The risk of adverse consequences genetic mutations, and the contribution of
19 counseling of family members versus for some genetic abnormalities may be so environmental factors to disease etiology,
18 treating the patient). low that the state is better described as a we will not be able to assess the probability
17 To be considered a disease, the genotyp- risk factor rather than being viewed as of adverse consequences associated with a
16 ic or phenotypic state of the patient must synonymous with disease. Defining the particular gene abnormality. There is little
15 have the potential for adverse conse- level of risk is important because, given doubt that many genetic variations will
14 quences. In Gilbert’s syndrome, there is an the high societal expectations of human have no consequences and, like those in in-
13 asymptomatic elevation of liver enzymes in genetics, any trait, condition, or behavior dividuals with Gilbert’s syndrome, will be
12 response to stress, but this condition is not associated with a genetic abnormality is in interesting but inconsequential polymor-
11 considered a disease because it does not danger of being construed as disease-as- phisms. Until a mutation is shown to
10 lead to adverse consequences. The World sociated. This will not only overempha- demonstrate a defined risk of developing
9 Health Organization’s valuable classifica- size the genetic contribution to disease adverse consequences, individuals carrying
8 tion of adverse consequences includes etiology, but will also blur the difference that mutation should not be considered dis-
7 physical or psychological impairment, ac- between ameliorating disease symptoms eased. Defining adverse consequences and
6 tivity restrictions, and/or role limitations. and enhancing human attributes.§ determining the risk of myriad small genet-

5 The inclusion of role limitations is particu- Patients with a genetic variation who ic variations is a mammoth task. But it is
4 larly important because it acknowledges the are at minimal or no increased risk for ad- only with this information that clinicians
3 sociological consequences of disease in verse consequences should not be labeled can accurately define the term disease in
2 terms of shortening the quantity of life or as diseased. If the definition of disease is the genomics era, and in so doing, be able
1 disturbing its quality. When determining based solely on a genetic abnormality to advise their patients appropriately.

808 3 AUGUST 2001 VOL 293 SCIENCE

Defining Disease in the Genomics Era
Larissa K. F. Temple, Robin S. McLeod, Steven Gallinger and James G. Wright

Science 293 (5531), 807-808.

DOI: 10.1126/science.1062938


Downloaded from on July 2, 2017


Use of this article is subject to the Terms of Service

Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of
Science, 1200 New York Avenue NW, Washington, DC 20005. 2017 © The Authors, some rights reserved; exclusive licensee
American Association for the Advancement of Science. No claim to original U.S. Government Works. The title Science is a
registered trademark of AAAS.