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Human genome project: implications for medical science

Article  in  Ceylon Medical Journal · January 2000

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Eric Hamilton Karunanayake

University of Colombo


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Implications of the Human Genome Project

for Medical Science
Francis S. Collins, MD, PhD
The year 2000 marked both the start of the new millennium and the an-
Victor A. McKusick, MD
nouncement that the vast majority of the human genome had been se-

NTIL RECENTLY, MANY PHYSI- quenced. Much work remains to understand how this “instruction book for
cians and other health care human biology” carries out its multitudes of functions. But the conse-
professionals considered quences for the practice of medicine are likely to be profound. Genetic pre-
medical genetics as the prov- diction of individual risks of disease and responsiveness to drugs will reach
ince of specialists in tertiary care medi- the medical mainstream in the next decade or so. The development of de-
cal centers, who spent their time evalu-
signer drugs, based on a genomic approach to targeting molecular path-
ating unusual cases of mendelian
disorders, birth defect syndromes, or ways that are disrupted in disease, will follow soon after. Potential misuses
chromosomal anomalies. Asked whether of genetic information, such as discrimination in obtaining health insurance
genetics was a part of their everyday prac- and in the workplace, will need to be dealt with swiftly and effectively. Ge-
tice, most primary care practitioners nomic medicine holds the ultimate promise of revolutionizing the diagnosis
would say no. That is all about to change. and treatment of many illnesses.
To be sure, there are numerous medi-
cal conditions found in children and JAMA. 2001;285:540-544
adults that have a strong, indeed pre-
dominant, genetic basis. The continu- tory taking. A sea change is now under- helical structure of DNA.4 The role of
ously updated Online Mendelian In- way, and it is likely that the molecular RNA as a messenger and the genetic code
heritance in Man (OMIM) lists many basis for these hereditary influences on that allows RNA to be translated to pro-
thousands of such conditions,1 but of- common illnesses soon will be uncov- tein emerged over the next 15 years. This
fers a far too narrow view of the con- ered. Even though on average the quan- was followed by the advent of recombi-
tribution of genetics to medicine. Ex- titative contribution of heredity to the nant DNA technology in the 1970s, of-
cept for some cases of trauma, it is fair etiological characteristics of diseases like fering the ability to obtain pure prepa-
to say that virtually every human ill- diabetes mellitus or hypertension may be rations of a particular DNA segment.
ness has a hereditary component. 2 modest, uncovering the pathways in- However, sequencing of DNA was dif-
While common diseases, such as dia- volved in disease pathogenesis will have ficult until Sanger and Gilbert indepen-
betes mellitus, heart disease, cancer, and broad consequences, pointing toward dently derived methods of sequencing
the major mental illnesses, do not fol- possible environmental triggers as well. DNA in 1977.5,6 (It is remarkable in-
low mendelian inheritance patterns, The implications for diagnostics, pre- deed that the Sanger dideoxy method for
there is ample evidence from twin and ventive medicine, and therapeutics will DNA sequencing remains the basic tech-
pedigree studies over many decades be profound. nology on which the genetic revolution
showing that all of these disorders have is being built, albeit with major ad-
important hereditary influences. In fact, Genetics in the 20th Century vances in automation of the analysis that
for many common illnesses of devel- In the spring of 1900, 3 different inves- have come along in the last 15 years.)
oped countries, the strongest predic- tigators rediscovered Mendel’s laws.3
tor of risk is family history. With Garrod’s recognition of their ap-
Author Affiliations: National Human Genome Re-
The role of heredity in most diseases plication to human inborn errors of me- search Institute, National Institutes of Health, Bethesda,
is thus not in itself a new revelation. But tabolism, the science of human genet- Md (Dr Collins); Johns Hopkins University School of
Medicine, Baltimore, Md (Dr McKusick).
in the past, it was considered unlikely ics acquired a foundation. But it remained Corresponding Author and Reprints: Francis S. Col-
that much could be done with this in- for Watson and Crick half a century later lins, MD, PhD, National Human Genome Research In-
stitute, National Institutes of Health, 31 Center Dr, MSC
formation other than to guide medical to uncover the chemical basis of hered- 2152, Bldg 31 Room 4B09, Bethesda, MD 20892-
surveillance based on careful family his- ity, with their elucidation of the double 2152 (e-mail:

540 JAMA, February 7, 2001—Vol 285, No. 5 (Reprinted) ©2001 American Medical Association. All rights reserved.

The use of variable DNA markers for necessary maps of the genome in hand ing in 1990, that number grew to more
linkage analysis of human disorders was to provide a scaffold for this effort. than 100 by 1997.13
set forth in 1980.7 Mapping of disor- Under the leadership of James Wat- By 1996, the complete sequencing of
ders by linkage previously had been se- son, it was decided to focus the first 5 several bacterial species and yeast led to
verely limited by the relatively small years of the HGP on the development the conclusion that it was time to at-
number of usable protein markers, such of genetic and physical maps of the hu- tempt sequencing human DNA on a pi-
as blood groups. The notion that any man genome, which would them- lot scale. The introduction of capillary
mendelian disorder could be mapped selves be of great value to scientists sequencing instruments and the forma-
to a chromosomal region caught the hunting for disease genes. The HGP also tion of a company in the private sector
imagination of geneticists. An early and tackled mapping and sequencing of promising to sequence the human ge-
stunning success of this approach, the simpler model organisms, such as bac- nome for profitable purposes added fur-
mapping of the Huntington disease gene teria, yeast, the roundworm, and the ther momentum to the effort. By 1999,
to chromosome 4 in 1983, gave a burst fruit fly.9-12 Considerable investments confidence had gathered that acquiring
of confidence to this adventurous new were made in improving technology. the majority of the sequence of the 3 bil-
approach.8 But the difficulty of going Perhaps the most unusual feature for lion base pairs of the human genome
from a linked marker to the actual dis- a basic science enterprise, 3% to 5% of could be attempted. In June 2000, both
ease locus proved profoundly diffi- the budget was set aside from the out- the private company and the interna-
cult. Years of work were required to set for research on the ethical, legal, and tional public sequencing consortium an-
map a candidate region and search for social implications of this expected ac- nounced the completion of “working
potential candidate genes, and many in- celeration in obtaining genetic infor- drafts” of the human genome sequence.
vestigators in the 1980s longed for a mation about our species.10 In the past,
more systematic approach to the ge- ethical, legal, and social analysis of the Current Research Focus
nome. consequences of a scientific revolu- Though the working draft of the hu-
At the same time, potential ad- tion often were relegated to other man sequence represents a major mile-
vances in mapping and sequencing groups outside the scientific main- stone, a vast amount of additional work
technology led certain scientific lead- stream or lay dormant until a crisis de- remains to be done to understand its
ers, particularly in the US Department veloped. This time, the intention was function.
of Energy, to propose the possibility of to inspire a cohort of ethicists, social It is necessary to complete the se-
an organized effort to sequence the en- scientists, legal scholars, theologians, quence analysis by closing the gaps and
tire human genome. In the late 1980s and others to address the coming di- resolving ambiguities. This finishing pro-
much controversy raged about such lemmas associated with increased cess already has been accomplished for
proposals, with many in the scientific knowledge about the genome, from so- chromosomes 2114 and 2215 and will be
community deeply concerned that this cial and legal discrimination on the ba- carried out for the remainder of the ge-
was technologically impossible and sis of genetics to more philosophical is- nome during the next 2 years.
likely to consume vast amounts of fund- sues such as genetic determinism. The genomes of other organisms also
ing that might be taken away from other The HGP has been international from will need to be sequenced. Probably the
more productive hypothesis-driven re- the beginning. Although the United most powerful tool to identify the cod-
search. But with the strong support of States made the largest investment, im- ing exons, as well as the regulatory re-
a panel of the National Academy of Sci- portant contributions have been made by gions, is a comparison of the sequence
ences,9 and the enthusiasm of a few many countries, including Britain, across different genomes. For that pur-
leaders in the US Congress, the Hu- France, Germany, Japan, China, and pose, full-scale sequencing of the labo-
man Genome Project (HGP) was ini- Canada. The original plan9 called for ratory mouse genome already has been
tiated in the United States by the Na- completion of the sequence of the hu- initiated, and the sequencing of the rat
tional Institutes of Health and the man genome by the year 2005, though and zebrafish genomes will not be far
Department of Energy in 1990.10 there was limited confidence that this behind. In both the public and private
goal could be achieved. But one by one sectors, serious consideration is being
The Human Genome Project the intermediate milestones were accom- given to the sequencing of other large
From the outset, it was realized that a plished. The HGP agreed at the outset vertebrate genomes, including the pig,
detailed set of plans and milestones to release all map and sequence data into dog, cow, and chimpanzee.
would be necessary for a project of this the public domain. The availability of ge- An intense effort is under way to de-
magnitude. The technology for carry- netic and physical maps led to a consid- velop a catalog of human variation. While
ing out actual large-scale sequencing had erable acceleration in the successful iden- human DNA sequences are 99.9% iden-
not advanced to the point of being able tification of genes involved in single gene tical to each other, the 0.1% of variation
to tackle the 3 billion base pairs of the disorders; while fewer than 10 such genes is expected to provide many of the clues
human genome in 1990 nor were the had been identified by positional clon- to the genetic risk for common ill-
©2001 American Medical Association. All rights reserved. (Reprinted) JAMA, February 7, 2001—Vol 285, No. 5 541

lines for research, and education, and

Research Opportunities and Forecast: Genomics now focuses on the societal implica-
tions of increased information about
Key Research Opportunities Forecast
human variation, in both medical and
Define Complete List of All Human Genes and Thousands of New Drug Targets for Heart nonmedical situations.
Proteins Disease, Cancer, Diabetes, Asthma, etc
The 21st Century: Critical Elements
Define All Common Variants in the Genome, Individualized Preventive Medicine Based on
Determine Hereditary Factors in Virtually All Genetic Risk
of the Medical Research Agenda
Common Diseases, and Refine Technology Obtaining the sequence of the human
for Low-Cost Genotyping Pharmacogenomics to Improve Outcome of genome is the end of the beginning. As
Drug Therapy
Knoppers has said, “As the radius of
knowledge gets longer, the circumfer-
Environmental Risk Factor Assessment
Becomes Individual-Specific ence of the unknown increases even
more” (Bartha Knoppers, personal
Determine Regulatory Signals That Affect Therapies for Developmental Defects communication). For the full impact of
Expression of All Human Genes in Normal or advances in genetics to be felt in the
Abnormal State Precise Molecular Analysis of Malignancies, practice of medicine, major challenges
Guiding Choice of Therapy
must be addressed.
Information about the human genome
Determine Structures of All Human Proteins, “Designer Drugs” Based on Precise
Using a Combination of Experimental and 3-Dimensional Information About Targets sequence and its variants must be applied
Computational Methods to identify the particular genes that play
a significant role in the hereditary con-
Develop Safe and Effective Gene-Transfer Gene Therapy for Rare Single-Gene Disorders, tribution to common disease. This will
Vectors for Many Different Tissues and Some Common Ones
be a daunting challenge. For a disease
Vigorously Explore the Ethical, Legal, and Social Legal Safeguards Against Genetic Discrimination
such as diabetes mellitus, 5 to 10 (or
Implications of Genome Research and Breaches of Privacy maybe more) genes are involved, each
of which harbors a variant conferring a
Effective Oversight of Clinical Application of modest degree of increased risk. Those
Genetic Testing variants interact with each other and the
environment in complex ways, render-
Mainstreaming of Genetics into the Practice
of Medicine, With Achievement of “Genetic ing their identification orders of mag-
Literacy” Among Clinicians and Patients nitude more difficult than for single gene
defects. Nonetheless, with the combi-
nation of careful phenotyping (so that
nesses.16 A public-private partnership has The same large-scale analysis strat- different disorders are not inadvert-
formed to build this catalog of variants egies that have been applied so effec- ently lumped together) and sampling
as quickly as possible and has identified tively to DNA and RNA also are being genetic variants at high density across
more than 2 million of these single applied to proteins to characterize their the genome, it should be possible to iden-
nucleotide polymorphisms. Of particu- structures, quantity, location in the cell, tify disease gene associations for many
lar interest are those common variants posttranslational modifications, and in- common illnesses in the next 5 to 7
that influence gene function. teraction partners.19 years.2,16 One should not underesti-
A powerful set of technologies for With the advent of these very large mate, however, the degree of sophisti-
studying gene expression is being de- databases of information on sequence, cation in clinical investigation that will
veloped and explored.17 These meth- variation, and expression, the field of be necessary or the need for develop-
odologies, which allow analysis of the computational biology is emerging as ment of more efficient genotyping tech-
transcription of as many as 10000 genes critically important to the future. Ef- nology, such as the use of DNA chips or
in one experiment, make it possible to fective methods of sorting and analyz- mass spectrometry, to make this kind of
investigate the differences that occur be- ing the data will be required to glean genome-wide survey a reality.
tween various tissue types and to ex- biologically meaningful insights from An understanding of the major path-
plore the alterations in that expres- the plethora of data. ways involved in normal homeostasis
sion pattern during disease. Such The ethical, legal, and social impli- of the human organism must be devel-
analyses have already been proved ca- cations research program has already oped along with how those pathways
pable of identifying subtypes of cer- fostered awareness of needs for inter- are deranged in illness. Identification
tain malignancies that were identical by vention, particularly in the areas of pri- of each gene that harbors a high-risk
all other criteria.18 vacy, genetic discrimination, guide- variant will point toward a critical path-
542 JAMA, February 7, 2001—Vol 285, No. 5 (Reprinted) ©2001 American Medical Association. All rights reserved.

way for that illness. Many of those will shows dramatic results in early clinical of safer and more effective vectors will
come as a surprise, since the current trials on patients with far advanced ensure a significant role for gene
molecular understanding of most com- chronic myelogenous leukemia. therapy in the treatment of some dis-
mon diseases is rather limited. Along with the design of new drugs, eases. There already have been prom-
Efficient, high-volume methods will genomics also will provide opportuni- ising reports of the application of gene
need to be developed and applied to the ties to predict responsiveness to drug therapy for hemophilia B23 and severe
design of small-molecule drugs to modu- interventions, since variation in those combined immunodeficiency.24
late disease-related pathways in the de- responses is often attributable to the ge-
sired direction. The pharmaceutical in- netic endowment of the individual. Ex- Genetics in the Medical
dustry has been gearing up for this amples have been identified where com- Mainstream
opportunity, and most companies now mon variants in genes involved in drug The power of the molecular genetic ap-
expect that the majority of future drug metabolism or drug action are associ- proach for answering questions in the
development will come from the field of ated with the likelihood of a good or bad research laboratory will catalyze a simi-
genomics. With the application of meth- response. The expectation is that such lar transformation of clinical medi-
ods that systematically combine chemi- correlations will be found for many drugs cine, although this will come gradu-
cal components into drugs and of high- over the next 10 years, including agents ally over the course of the next 25 years
volume assays for efficacy, it is expected that are already on the market. This field (FIGURE).
that compounds can be efficiently iden- of pharmacogenomics promises to indi- By the year 2010, it is expected that
tified that block or stimulate a particu- vidualize prescribing practices.21 predictive genetic tests will be avail-
lar pathway. A gratifying recent ex- The field of gene therapy, having sus- able for as many as a dozen common
ample is the development of the drug tained a series of disappointments over conditions, allowing individuals who
STI-571, which was designed to block the the past few years, especially with the wish to know this information to learn
kinase activity of the bcr-abl kinase.20 death of a volunteer in a gene therapy their individual susceptibilities and to
This protein is produced as a conse- trial in the fall of 1999, has gone back take steps to reduce those risks for
quence of the translocation between to wrestling with the basic science ques- which interventions are or will be avail-
chromosomes 9 and 22, a chromosome tions of finding optimal methods for able. Such interventions could take the
rearrangement that is characteristic of gene delivery.22 While the optimism of form of medical surveillance, lifestyle
and central to the etiology of chronic my- the early 1990s about providing quick modifications, diet, or drug therapy.
elogenous leukemia. STI-571 blocks the solutions to a long list of medical prob- Identification of persons at highest risk
ability of the bcr-abl kinase to phos- lems was probably never fully justi- for colon cancer, for example, could
phorylate its unknown substrate and fied, it is likely that the development lead to targeted efforts to provide colo-

Figure. Steps Involved in a Genetic Approach to the Diagnosis and Treatment of Disease




Disease With Map Gene(s) to

Genetic Component Specific Chromosomal Identify Gene(s) Gene Therapy

Underlying Biology Targeted Drug Therapy
of Disease

The rate of progress for applying a genetic approach to the diagnosis and treatment of each disease will be different depending on the research investment and the
degree of biological complexity underlying the disease. First, the gene variants contributing increased disease risk must be identified by family studies and/or case-
control studies. Diagnostic opportunities may then come along rather quickly, but will be of greatest clinical usefulness once prevention measures are developed that
have proven benefit to those at high risk. Some gene variants will also show clinically useful associations with drug responsiveness (pharmacogenomics). In general,
full-blown therapeutic benefits from identification of gene variants will take longer to reach mainstream medicine. In some instances, the gene itself will be the drug
(gene therapy), while in others, a sophisticated knowledge of the underlying disease mechanism, built upon genetics, may allow the design of targeted and highly
effective drug therapy.

©2001 American Medical Association. All rights reserved. (Reprinted) JAMA, February 7, 2001—Vol 285, No. 5 543

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544 JAMA, February 7, 2001—Vol 285, No. 5 (Reprinted) ©2001 American Medical Association. All rights reserved.

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