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Collins FS, McKusick VA. Implications of the Human Genome Project for Medical Science. JAMA. 2001;285(5):540–544. doi:10.1001/jama.285.5.540
The year 2000 marked both the start of the new millennium and the announcement
that the vast majority of the human genome had been sequenced. Much work remains
to understand how this "instruction book for human biology" carries out its
multitudes of functions. But the consequences for the practice of medicine
are likely to be profound. Genetic prediction of individual risks of disease
and responsiveness to drugs will reach the medical mainstream in the next
decade or so. The development of designer drugs, based on a genomic approach
to targeting molecular pathways that are disrupted in disease, will follow
soon after. Potential misuses of genetic information, such as discrimination
in obtaining health insurance and in the workplace, will need to be dealt
with swiftly and effectively. Genomic medicine holds the ultimate promise
of revolutionizing the diagnosis and treatment of many illnesses.
Until recently, many physicians and other health care professionals
considered medical genetics as the province of specialists in tertiary care
medical centers, who spent their time evaluating unusual cases of mendelian
disorders, birth defect syndromes, or chromosomal anomalies. Asked whether
genetics was a part of their everyday practice, most primary care practitioners
would say no. That is all about to change.
To be sure, there are numerous medical conditions found in children
and adults that have a strong, indeed predominant, genetic basis. The continuously
updated Online Mendelian Inheritance in Man (OMIM) lists many thousands of
such conditions,1 but offers a far too narrow
view of the contribution of genetics to medicine. Except for some cases of
trauma, it is fair to say that virtually every human illness has a hereditary
component.2 While common diseases, such as
diabetes mellitus, heart disease, cancer, and the major mental illnesses,
do not follow mendelian inheritance patterns, there is ample evidence from
twin and pedigree studies over many decades showing that all of these disorders
have important hereditary influences. In fact, for many common illnesses of
developed countries, the strongest predictor of risk is family history.
The role of heredity in most diseases is thus not in itself a new revelation.
But in the past, it was considered unlikely that much could be done with this
information other than to guide medical surveillance based on careful family
history taking. A sea change is now underway, and it is likely that the molecular
basis for these hereditary influences on common illnesses soon will be uncovered.
Even though on average the quantitative contribution of heredity to the etiological
characteristics of diseases like diabetes mellitus or hypertension may be
modest, uncovering the pathways involved in disease pathogenesis will have
broad consequences, pointing toward possible environmental triggers as well.
The implications for diagnostics, preventive medicine, and therapeutics will
In the spring of 1900, 3 different investigators rediscovered Mendel's
laws.3 With Garrod's recognition of their application
to human inborn errors of metabolism, the science of human genetics acquired
a foundation. But it remained for Watson and Crick half a century later to
uncover the chemical basis of heredity, with their elucidation of the double
helical structure of DNA.4 The role of RNA
as a messenger and the genetic code that allows RNA to be translated to protein
emerged over the next 15 years. This was followed by the advent of recombinant
DNA technology in the 1970s, offering the ability to obtain pure preparations
of a particular DNA segment. However, sequencing of DNA was difficult until
Sanger and Gilbert independently derived methods of sequencing DNA in 1977.5,6 (It is remarkable indeed that the Sanger
dideoxy method for DNA sequencing remains the basic technology on which the
genetic revolution is being built, albeit with major advances in automation
of the analysis that have come along in the last 15 years.)
The use of variable DNA markers for linkage analysis of human disorders
was set forth in 1980.7 Mapping of disorders
by linkage previously had been severely limited by the relatively small number
of usable protein markers, such as blood groups. The notion that any mendelian
disorder could be mapped to a chromosomal region caught the imagination of
geneticists. An early and stunning success of this approach, the mapping of
the Huntington disease gene to chromosome 4 in 1983, gave a burst of confidence
to this adventurous new approach.8 But the
difficulty of going from a linked marker to the actual disease locus proved
profoundly difficult. Years of work were required to map a candidate region
and search for potential candidate genes, and many investigators in the 1980s
longed for a more systematic approach to the genome.
At the same time, potential advances in mapping and sequencing technology
led certain scientific leaders, particularly in the US Department of Energy,
to propose the possibility of an organized effort to sequence the entire human
genome. In the late 1980s much controversy raged about such proposals, with
many in the scientific community deeply concerned that this was technologically
impossible and likely to consume vast amounts of funding that might be taken
away from other more productive hypothesis-driven research. But with the strong
support of a panel of the National Academy of Sciences,9
and the enthusiasm of a few leaders in the US Congress, the Human Genome Project
(HGP) was initiated in the United States by the National Institutes of Health
and the Department of Energy in 1990.10
From the outset, it was realized that a detailed set of plans and milestones
would be necessary for a project of this magnitude. The technology for carrying
out actual large-scale sequencing had not advanced to the point of being able
to tackle the 3 billion base pairs of the human genome in 1990 nor were the
necessary maps of the genome in hand to provide a scaffold for this effort.
Under the leadership of James Watson, it was decided to focus the first
5 years of the HGP on the development of genetic and physical maps of the
human genome, which would themselves be of great value to scientists hunting
for disease genes. The HGP also tackled mapping and sequencing of simpler
model organisms, such as bacteria, yeast, the roundworm, and the fruit fly.9-12 Considerable
investments were made in improving technology. Perhaps the most unusual feature
for a basic science enterprise, 3% to 5% of the budget was set aside from
the outset for research on the ethical, legal, and social implications of
this expected acceleration in obtaining genetic information about our species.10 In the past, ethical, legal, and social analysis
of the consequences of a scientific revolution often were relegated to other
groups outside the scientific mainstream or lay dormant until a crisis developed.
This time, the intention was to inspire a cohort of ethicists, social scientists,
legal scholars, theologians, and others to address the coming dilemmas associated
with increased knowledge about the genome, from social and legal discrimination
on the basis of genetics to more philosophical issues such as genetic determinism.
The HGP has been international from the beginning. Although the United
States made the largest investment, important contributions have been made
by many countries, including Britain, France, Germany, Japan, China, and Canada.
The original plan9 called for completion of
the sequence of the human genome by the year 2005, though there was limited
confidence that this goal could be achieved. But one by one the intermediate
milestones were accomplished. The HGP agreed at the outset to release all
map and sequence data into the public domain. The availability of genetic
and physical maps led to a considerable acceleration in the successful identification
of genes involved in single gene disorders; while fewer than 10 such genes
had been identified by positional cloning in 1990, that number grew to more
than 100 by 1997.13
By 1996, the complete sequencing of several bacterial species and yeast
led to the conclusion that it was time to attempt sequencing human DNA on
a pilot scale. The introduction of capillary sequencing instruments and the
formation of a company in the private sector promising to sequence the human
genome for profitable purposes added further momentum to the effort. By 1999,
confidence had gathered that acquiring the majority of the sequence of the
3 billion base pairs of the human genome could be attempted. In June 2000,
both the private company and the international public sequencing consortium
announced the completion of "working drafts" of the human genome sequence.
Though the working draft of the human sequence represents a major milestone,
a vast amount of additional work remains to be done to understand its function.
It is necessary to complete the sequence analysis by closing the gaps
and resolving ambiguities. This finishing process already has been accomplished
for chromosomes 2114 and 2215
and will be carried out for the remainder of the genome during the next 2
The genomes of other organisms also will need to be sequenced. Probably
the most powerful tool to identify the coding exons, as well as the regulatory
regions, is a comparison of the sequence across different genomes. For that
purpose, full-scale sequencing of the laboratory mouse genome already has
been initiated, and the sequencing of the rat and zebrafish genomes will not
be far behind. In both the public and private sectors, serious consideration
is being given to the sequencing of other large vertebrate genomes, including
the pig, dog, cow, and chimpanzee.
An intense effort is under way to develop a catalog of human variation.
While human DNA sequences are 99.9% identical to each other, the 0.1% of variation
is expected to provide many of the clues to the genetic risk for common illnesses.16 A public-private partnership has formed to build
this catalog of variants as quickly as possible and has identified more than
2 million of these single nucleotide polymorphisms. Of particular interest
are those common variants that influence gene function.
A powerful set of technologies for studying gene expression is being
developed and explored.17 These methodologies,
which allow analysis of the transcription of as many as 10 000 genes
in one experiment, make it possible to investigate the differences that occur
between various tissue types and to explore the alterations in that expression
pattern during disease. Such analyses have already been proved capable of
identifying subtypes of certain malignancies that were identical by all other
The same large-scale analysis strategies that have been applied so effectively
to DNA and RNA also are being applied to proteins to characterize their structures,
quantity, location in the cell, posttranslational modifications, and interaction
With the advent of these very large databases of information on sequence,
variation, and expression, the field of computational biology is emerging
as critically important to the future. Effective methods of sorting and analyzing
the data will be required to glean biologically meaningful insights from the
plethora of data.
The ethical, legal, and social implications research program has already
fostered awareness of needs for intervention, particularly in the areas of
privacy, genetic discrimination, guidelines for research, and education, and
now focuses on the societal implications of increased information about human
variation, in both medical and nonmedical situations.
Obtaining the sequence of the human genome is the end of the beginning.
As Knoppers has said, "As the radius of knowledge gets longer, the circumference
of the unknown increases even more" (Bartha Knoppers, personal communication).
For the full impact of advances in genetics to be felt in the practice of
medicine, major challenges must be addressed.
Information about the human genome sequence and its variants must be
applied to identify the particular genes that play a significant role in the
hereditary contribution to common disease. This will be a daunting challenge.
For a disease such as diabetes mellitus, 5 to 10 (or maybe more) genes are
involved, each of which harbors a variant conferring a modest degree of increased
risk. Those variants interact with each other and the environment in complex
ways, rendering their identification orders of magnitude more difficult than
for single gene defects. Nonetheless, with the combination of careful phenotyping
(so that different disorders are not inadvertently lumped together) and sampling
genetic variants at high density across the genome, it should be possible
to identify disease gene associations for many common illnesses in the next
5 to 7 years.2,16 One should not
underestimate, however, the degree of sophistication in clinical investigation
that will be necessary or the need for development of more efficient genotyping
technology, such as the use of DNA chips or mass spectrometry, to make this
kind of genome-wide survey a reality.
An understanding of the major pathways involved in normal homeostasis
of the human organism must be developed along with how those pathways are
deranged in illness. Identification of each gene that harbors a high-risk
variant will point toward a critical pathway for that illness. Many of those
will come as a surprise, since the current molecular understanding of most
common diseases is rather limited.
Efficient, high-volume methods will need to be developed and applied
to the design of small-molecule drugs to modulate disease-related pathways
in the desired direction. The pharmaceutical industry has been gearing up
for this opportunity, and most companies now expect that the majority of future
drug development will come from the field of genomics. With the application
of methods that systematically combine chemical components into drugs and
of high-volume assays for efficacy, it is expected that compounds can be efficiently
identified that block or stimulate a particular pathway. A gratifying recent
example is the development of the drug STI-571, which was designed to block
the kinase activity of the bcr-abl kinase.20
This protein is produced as a consequence of the translocation between chromosomes
9 and 22, a chromosome rearrangement that is characteristic of and central
to the etiology of chronic myelogenous leukemia. STI-571 blocks the ability
of the bcr-abl kinase to phosphorylate its unknown substrate and shows dramatic
results in early clinical trials on patients with far advanced chronic myelogenous
Along with the design of new drugs, genomics also will provide opportunities
to predict responsiveness to drug interventions, since variation in those
responses is often attributable to the genetic endowment of the individual.
Examples have been identified where common variants in genes involved in drug
metabolism or drug action are associated with the likelihood of a good or
bad response. The expectation is that such correlations will be found for
many drugs over the next 10 years, including agents that are already on the
market. This field of pharmacogenomics promises to individualize prescribing
The field of gene therapy, having sustained a series of disappointments
over the past few years, especially with the death of a volunteer in a gene
therapy trial in the fall of 1999, has gone back to wrestling with the basic
science questions of finding optimal methods for gene delivery.22
While the optimism of the early 1990s about providing quick solutions to a
long list of medical problems was probably never fully justified, it is likely
that the development of safer and more effective vectors will ensure a significant
role for gene therapy in the treatment of some diseases. There already have
been promising reports of the application of gene therapy for hemophilia B23 and severe combined immunodeficiency.24
The power of the molecular genetic approach for answering questions
in the research laboratory will catalyze a similar transformation of clinical
medicine, although this will come gradually over the course of the next 25
By the year 2010, it is expected that predictive genetic tests will
be available for as many as a dozen common conditions, allowing individuals
who wish to know this information to learn their individual susceptibilities
and to take steps to reduce those risks for which interventions are or will
be available. Such interventions could take the form of medical surveillance,
lifestyle modifications, diet, or drug therapy. Identification of persons
at highest risk for colon cancer, for example, could lead to targeted efforts
to provide colonoscopic screening to those individuals, with the likelihood
of preventing many premature deaths.
Predictive genetic tests will become applicable first in situations
where individuals have a strong family history of a particular condition;
indeed, such testing is already available for several conditions, such as
breast and colon cancers. But with increasing genetic information about common
illnesses, this kind of risk assessment will become more generally available,
and many primary care clinicians will become practitioners of genomic medicine,
having to explain complex statistical risk information to healthy individuals
who are seeking to enhance their chances of staying well. This will require
substantial advances in the understanding of genetics by a wide range of clinicians.25 The National Coalition for Health Professional Education
in Genetics, an umbrella group of physicians, nurses, and other clinicians,
has organized to help prepare for this coming era.
Another crucial step is the passage of effective federal legislation
to outlaw the use of predictive genetic information in the workplace and in
obtaining health insurance.26,27
Numerous surveys have indicated that the public is deeply concerned about
the potential for discrimination, and some individuals have forgone acquiring
genetic information about themselves, since assurances cannot be currently
provided about discriminatory misuse of the information. Although more than
2 dozen states have taken some action in this regard, a patchwork of different
levels of protection across the United States is not satisfactory and this
vexing problem must be dealt with effectively at the federal level.
By 2020, the impact of genetics on medicine will be even more widespread.
The pharmacogenomics approach for predicting drug responsiveness will be standard
practice for quite a number of disorders and drugs. New gene-based "designer
drugs" will be introduced to the market for diabetes mellitus, hypertension,
mental illness, and many other conditions. Improved diagnosis and treatment
of cancer will likely be the most advanced of the clinical consequences of
genetics, since a vast amount of molecular information already has been collected
about the genetic basis of malignancy. By 2020, it is likely that every tumor
will have a precise molecular fingerprint determined, cataloging the genes
that have gone awry, and therapy will be individually targeted to that fingerprint.
Despite these exciting projections, certain tensions also will exist.
Access to health care, already a major problem in the United States, will
complicate these new advances, unless our medical care systems change in significant
ways. Antitechnology movements, already active in the United States and elsewhere,
are likely to gather momentum as the focus of genetics turns even more intensely
on ourselves. Though the benefits of genetic medicine will be profound, there
will be those who consider this advancement unnatural and dangerous. Efforts
at public education need to start now to explain the potential benefits and
to be honest about the risks.
In conclusion, this is a time of dramatic change in medicine. As we
cross the threshold of the new millennium, we simultaneously cross a threshold
into an era where the human genome sequence is largely known. We must commit
ourselves to exploring the application of these powerful tools to the alleviation
of human suffering, a mandate that undergirds all of medicine. At the same
time, we must be mindful of the great potential for misunderstanding in this
quickly developing field and make sure that the advancement of the social
agenda of genetics is equally as vigorous as the medical agenda.
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