The Human Genome Project and the Practice of Medicine in 2020
Abstract
The information gained from the Human Genome Project promises to affect the
practice of medicine in many ways. From radical new developments in our
understanding of disease pathogenesis and diagnosis to a dramatic increase in ability to
heal, harnessing the power of this new tool will be a challenge in all aspects of health
care and delivery. The staggering pace and breadth of this change will require both
physicians and patients to incorporate the effect of the HGP into their respective roles.
Yet, there will be little change at the most fundamental level of the physician-patient
relationship, the point at which the physician serves as the human-to-human contact
between the patient and the ever expanding world of medicine.
Introduction
Widely heralded as the greatest scientific discovery of the twentieth century,
completion of the Human Genome Project and subsequent “genomemania” has recently
dominated predictions about the future course of medicine. Worldwide, the media
searches for new terms by which to describe the potential of this information, from magic
bullet drugs to designer babies (1,2). And while the power of reading the “book of life”
will almost definitely usher in a new era of biology and forever alter the face of medicine,
the time-line and form of these changes is very difficult to predict. Still, the question of
how this tremendous collection of knowledge will affect our lives is far too provocative to
ignore.
This article will explore some of the changes we can expect from the Human
Genome Project’s massive accomplishment by the year 2020. From unprecedented
technological innovations in diagnosis and treatment, to advances in our understanding
of disease pathogenesis and symptoms, the utilization of information gained from the
HGP will challenge the role of the physician and his relationship with his patients. The
potential impact on the physician-patient relationship and the delivery of health care is
also considered here. In addition, the staggering pace at which these advances in
medicine are being made is at the very least matched by the huge number of ethical,
legal, and social questions surrounding every issue. While coverage of these issues,
ranging from genetic discrimination by employers and insurance companies to the fine
line between disease correction and trait enhancement, is outside the scope of this
article, responsible and diligent discussion of these issues will clearly be paramount to
guaranteeing the future success of this incredibly powerful tool (3). Ideally, with some
diligent forethought and consideration of these issues in their infancy, it will be possible
to assure that the outcome of this tremendous revolution is positive. Nevertheless, in
the words of Francis Collins, Director of the HGP, in a recent address at the Harvard
Medical School, “predictions in genetics beyond next week tend to be wrong”(4).
Changing the Face of Medicine
The awesome power of the human genome blueprint is far from being realized,
and it is likely that only many years from now will we truly appreciate the secrets it holds.
If it is indeed true that most (if not all) human illnesses have a hereditary component (5)
and that knowing the complete sequence of our genome will allow the human race to
identify every disease gene (6), then the future is promising. But not all changes are
months or years away. Even today we can see the web of the possibilities expanding,
from improved diagnosis capabilities to the elucidation of the molecular mechanisms
responsible for disease pathogenesis, rationally designed drugs, and even successful
genetic therapy.
Genetic Diagnosis
The revolution in the diagnosis of disease though genetic testing is one of the
most immediate and palpable changes brought forth by the Human Genome Project.
There are currently more that 800 available tests to determine an individual’s
predisposition for certain diseases (7) and this number is increasing at an astounding
rate; the number of genes found to be responsible for disease grows almost daily. In
1999, approximately 100 disease-linked genes had been isolated (8), and today, OMIM
(Online Mendelian Inheritance in Man) reports 1167 such genes (9). If the number of
diagnostically useful tests continues to increase, physicians’ ability to intervene in the
disease process at an earlier stage with preventative therapy or lifestyle changes will
most likely follow suit (10,11). In addition to diagnostic testing through genes, much
valuable information is contained in single base pair changes throughout the population,
also known as single-nucleotide polymorphisms (SNPs). Currently, some 1.42 million of
these SNPs have been characterized (12) and while some may be involved in disease
pathogenesis, such as sickle-cell anemia (13), the true power of these variations is as
genetic markers (14,15). Currently, nearly every human gene is marked by a
polymorphism, and the potential for their use in everything from prediction of disease
susceptibility and severity to individual reactions to treatment has only just begun to be
realized (16).
Breakthroughs in Elucidation of Pathogenesis
Many experts believe that the most promising aspect of the Human Genome
project in the near future will be in its role in elucidating the molecular mechanisms of
human disease and illness (17,18,19). Indeed, in many cases, such as single gene
disorders like Huntington’s disease and cystic fibrosis, this has already happened.
However, the true test will lie in multigenic, multifactorial diseases with a complex
etiology that is not solely genetic. Using the most basic building blocks of life, it should
be possible to analyze all disease pathways at the molecular level (20), and with time,
both enhance our understanding of the role of various factors in disease, and identify
new therapeutic targets. An excellent example of this is hypertension, a disease
previously thought to be far too complex to benefit from genetic study, but in which
genetics has recently been used to elucidate portions of the pathway through Mendelian
forms of high and low blood pressure caused by single genes (21). In addition, it is likely
that the next few years promise to shed new light on the biological basis of other
common diseases, such as diabetes and cancer (22), and even mental illness and
addiction (23), potentially changing the way we think about the sometimes blurred line
between biological and psychosocial causes.
As the number of genes increases, so does the power of categorization and
comparison of genes, allowing for prediction of similar phenotypes and disease
processes such as age of onset or mode of inheritance. The combination of these
factors will then allow for the possibility of a greater understanding of single genes
contributions to more complex disorders previously thought to have little or no genetic
basis (24).
Genomics-based Rational Drug Design and Pharmacogenomics
In addition to its self-contained virtue, increased understanding of disease
pathogenesis at the molecular level will continue to allow for incredible manipulation of
the disease pathway. Drugs created based on comprehensive understanding of the
genetic basis for disease and designed to inhibit specific elements of the molecular
pathway will shift the paradigm of pharmaceutical development and drastically reduce
side effects and drug interactions. A very popular example, STI571, has recently been
developed for the treatment of chronic myelogenous leukemia though a molecule that
specifically blocks the bcr-abl kinase protein responsible for the disease (25,26). To
illustrate the potential power of this discovery in drug design, it is worth noting that in an
analysis of drug targets in 1996, only approximately 500 such targets were subject to
intervention, whereas estimates of the number of genetic targets that will be available for
pharmaceutical pursuit may be as much as ten times that or more in the near future (27).
Such a revolution in multidisciplinary drug design, with much more focused and specific
aims, will likely increase efficiency and streamline the current model of clinical trials,
decreasing both the cost and time to market of new therapeutics (28,29).
The advantage of specificity inherent in genomics-based pharmaceuticals also
allows for prediction of variable reactions from individual patients, a developing field
known as pharmacogenomics. While some have forecasted widespread
pharmacogenomics within the next three to five years (30), obstacles to patient-specific
drugs such as questions of profit margins in pharmaceutical companies could play a role
in slowing the process (31). The relationship between specificity and market size is often
inverse, and as the prevalence of highly-specific protein target decreases, so will the
pharmaceutical interest in developing a drug for it. Nevertheless, there is great potential
for markedly increased efficacy and decreased complications through classification of
patients via responsiveness to drugs, and the balance between the bottom line and
patient care will continue to be tested. Examples include the tremendous effectiveness
of glucocorticoid treatment in certain cases of hypertension caused by a chimeric gene
in a well-defined genetic process (32). Another commonly cited example in the treatment
of Alzheimer’s is that of ApoE4 allele differences as a marker for tarcine effectiveness
(33,34,35), and these are likely to be followed by deluge of others within the next ten
years, providing physicians with an enhanced arsenal of patient-specific therapeutics.
Gene and Stem Cell Therapy
Perhaps the most controversial and, likely the most distant, new advance
resulting from the Human Genome Project will be in the area of gene and stem cell
therapy. However, the ability to change the biological paradigm of an inalterable genetic
code, while rife with ethical questions, is in some ways the ultimate solution to the
genetic basis of disease (36). Should a single polymorphism responsible for a disease
phenotype be easily corrected with somatic gene therapy, all other measures of
treatment at the more distal stages of the pathway will be obsolete. Rather than
treatment at a later stage in the pathway such as protein based drug therapy, or in some
cases, mere alleviation of symptoms through palliative care—physicians will be able to
stop the disease process at its very root.
In many cases, the utility of gene therapy will depend on the substrate cell that is
used, and here the advantage of pleuripotent stem cells may be crucial. These
undifferentiated cells that exist in every human possess the ability to become a whole
range of cell types found in the body, if given the correct instructions. Clearly it is not
difficult to see the promise of combining gene therapy with stem cells, as the physician
could potentially choose which instructions might fill this tabula rasa. Given a greater
understanding of the factors leading to cell differentiation, including the role of specific
genes and DNA sequences, physicians will be able to take advantage of this plasticity in
therapeutic solutions (37). Recently, a promising example was found with two children
cured of X-linked immunodeficiency using a retroviral vector to infect hematopoietic stem
cells (38). Although conducted ex vivo, the success suggests that while there is much
work to be done, the potential rewards are present and deserve further investigation.
However, it must be mentioned that this area of genetic progress is frought with
controversy and potential for abuse, given our limited understanding of the complexity
with which the human body is created. Multiple ethical questions surround issues such
as parents desiring to choose the exact personality traits of their children, or on a
grander scale, the elimination of a disease trait from the human race by germ-line stem
cell therapy.
Impact on the Practice of Medicine
The transformation in medicine that will be ushered in by the human genome
project will undoubtedly have a profound effect on typical “doctor visit” in the next
decade and beyond. With such incredible potential for improvements in diagnosis and
treatment on all levels, the emerging challenge at hand is one of adjustment. How will
both patients and doctors keep up with the tremendously rapid rate at which our
knowledge base is growing? As the intimate relationship between thousands of genes
and their respective diseases are determined, an even more difficult challenge will be
presented to the responsible physician who wishes to remain on the cutting edge.
Genetic specialists have thus far been an excellent resource for physicians with
complicated genetic cases, but as a prospective solution the supply of genetic
specialists is not likely to meet the demand (39,40). In addition, the questions of both
physician and patient education loom large, as does the issue of genetic determinism.
Underlying all of these challenges remains the question of how this paradigm shift in
medical care will extend to the fundamental relationship between patient and physician.
Education of the Physician
As of 1998, 71 percent of American adults said they would most likely ask their
primary care physician about a genetic disorder present in their family (41). Yet most
physicians graduated from medical school before genetics was taught, and on the whole
the medical profession is not prepared for this onslaught of new information. In 1997,
one third of physicians at Johns Hopkins University School of Medicine misinterpreted
results from a genetic test for familial adenomatous polyposis (42). Even today many
doctors are unaware of the variety of genetic tests available, and many are
uncomfortable with discussing the idea of genetics with their patients. However, there
are multiple solutions currently being evaluated in order to accomplish the task of
preparing physicians for the genetic revolution.
Perhaps the most promising strategy will come from the fusion of genetics with
another equally significant technological development: the internet. Given the massive
size and rapid development of this body of knowledge, the internet provides the perfect
medium for broad distribution of ever-changing information in an easy-to-access
manner. In the next few decades, physicians will rely increasingly on central sources of
regularly updated material in order to educate themselves, and then use this information
to educate their patients (43). A central and reliable source of genetic information will
allow physicians to stay genetically literate and up to date on the changes in the field.
One group that will likely continue to play a large role in this education of
physicians is the National Coalition for Health Professional Education in Genetics
(NHCPEG). Formed in 1997, the group is comprised of leaders from approximately 100
diverse health care professional organizations, consumer and voluntary groups,
government agencies, industry, managed care organizations, and genetics professional
organizations (44). Functioning as a clearinghouse of information for a huge variety of
sources, the NHCPEG is one of a number of groups developing comprehensive central
websites for genetic information. Other sites include Genetests (www.genetests.org),
Geneclinics (www.geneclinics.org), and OMIM (Online Mendelian Inheritance in Man,
www.ncbi.nlm.nih.gov).
Despite the essential role of the internet, traditional forms of education will
continue to be an important means by which to prepare physicians for the genetic
revolution. In the long term, genetics education in medical school and through
continuing medical education (CME) courses will set the foundation for understanding
the wide range of genetic information. It will be necessary to provide physicians with an
infrastructure of the basic concepts on which to build throughout their careers and as the
field changes. The nature and extent of this transformation of medical education will
likely be a source of great debate (45), but major medical curriculum revisions will be
necessary to prepare the physician for this change in the conceptualization of human
illness (46).
Challenges in Patient Care
Ultimately, the end goal of all medical advancement is the care of the patient. In
the coming era of genetic diagnosis and treatment, the effectiveness of medical practice
will be increasingly dependent on overcoming the imbalance between the level of
knowledge of patient and physician. Multiple obstacles exist, such as issues of
communication, integration, and the stigma associated with public misconception; and
these obstacles must be considered carefully by the physician in order to preserve the
integrity of the relationship with his patient. Yet, while it is clear that by the year 2020
the changes in medical practice will clearly translate into changes in the interaction
between physician and patient, it is less obvious if the fundamental relationship between
doctor and patient will be affected.
Communication and the Language of Genetics
Open, honest communication, while not a new concept in the successful
physician-patient relationship, will be vital to the explanation of complex genetic
concepts that allow the patient to make the best choice based on available information
(47). As an example, weighty decisions regarding the life of a newborn may need to be
made in relatively small amounts of time based solely on complex genetic information
relayed by the physician. Parents faced with these decisions will be challenged to make
informed choices, and may rely on the explanation of their physician in order to do so.
Should the ability to communicate properly with patients be threatened by the incredible
pace of development of genetic medicine, the practice of medicine may suffer. In a
recent study assessing the effectiveness of communication between health care
providers in Wisconsin and parents of children identified as heterozygote carriers for
cystic fibrosis, 29.2 percent of parents indicated they did not receive genetic counseling.
In addition, 15.4 percent of parents were unsure whether being a carrier could cause
illness and 12.4 percent of parents were unsure whether at least one of the parents was
a carrier of the CF gene (48). Evidence from another recent study suggests the
practices of genetic counseling are highly variable across the US, with a lack of
measurable indications of quality and a general lack of coordination between programs
(49). The frequency of newborn screening tests are likely to increase greatly as the
genes that underlie congenital disorders are elucidated; the infrastructure of support for
counsel of parents of affected children will be vital to the success of the medical
profession in maximizing the potential of the knowledge forthcoming from the Human
Genome Project.
The language used by physicians is also often confusing, unclear, and difficult for
patients to understand (50). Physicians will need to be careful when explaining concepts
and educating their patients, as there is tremendous potential for misunderstanding and
incorrect generalization of terms by the lay community. In some cases, explanation of a
concept may require very large amounts of background information, and patient
education seminars or computer-based educational resources may be necessary.
Consider explaining to the layperson the concept of penetrance, defined as “the
frequency, expressed as a fraction or percentage, of individuals who are phenotypically
affected, among persons of an appropriate genotype” (51) or answering the question
“what does ‘genetically predisposed’ mean?” Should such a question be answered in
terms of numerical risk, and if so, is that figure correctly and adequately understood by
the patient?
The potential also exists for a “genetic determinism,” in which patients may
believe that they have no control over the sequelae of their genes. For example, should
a patient have an extensive family history of cancer, he may be less inclined to quit
smoking or use sunblock in order to reduce risk of what he perceives as an inevitable
fate. Even with advances in the understanding of incomplete penetrance and
mulitfactorial disorders, the idea of genetic determinism that has been adopted by much
of the public (52) may prevail unless the patient population is well educated with the
correct language. If an inaccurate vernacular (53) develops, and the patient doesn’t
understand the terms involved, it will be very difficult to make the crucial distinction
between the idea of disease and genes that may be responsible. And lacking this
distinction, patients may easily be stigmatized or discriminated against on the basis of
the genetic makeup, over which they have no control, by employers, insurance
companies, or even family and friends.
Genetic Integration
The method by which genetics is integrated on the large-scale into the practice of
medicine will also be established in the next twenty years. This is no small point,
however, as there is huge variability in the clinical situations in which genetics will be
applicable. Variable penetrance of gene-linked diseases will confound the ability of a
physician to predict whether or not a patient will display the phenotype, and the
therapeutic options for treatment will vary greatly depending on the disease (54).
Increasingly the physician will be faced with issues such as the validity of predicative
testing using BRCA1 mutations, or the utility of testing for an incurable disease like
Huntington’s.
As genetics penetrates the field of medicine, the physician and the patient
together will be left to decide when genetic intervention is right and justified. The form of
this decision has always and will continue to depend on the model of the physician –
patient relationship. Using Szasz and Hollander’s classification (55) of the physicianpatient relationship, it is likely that with the combination of the internet as a resource and
the need for patients to take greater responsibility for their genetic health, the
relationship will oscillate between a guidance-cooperation model to one of mutual
participation. As patient specific health information such as family history, genetic
predisposition, and individual response to certain medications begins to play more of a
role in the practice of medicine, responsible patients will have a greater ability to become
experts in their own health. At times, the patient is likely to know more than the
physician about his/her particular illness, and the two will work together in selecting the
best course of treatment through mutual agreement and discussion. As the patient
becomes more of his own health advocate, the relationship again will shift to the mutual
participation model, in which case it may be necessary for the physician to rely on his
“capacity to persuade the patient of the value of his view” (56). However, this oscillation
between relationship models, while potentially biased by available genetic information, is
common to medicine as exemplified by a large range of chronic disorders, and may only
be another step in the evolution of medical practice.
Summary
Since the first days of medicine, the field has been constantly changing.
Throughout the history of medicine, and the progression from humors and tonics to germ
theory and antibiotics, physicians have been charged with the task of translating an
incredibly complex subject into layman’s terms. As the human link between the patient
and the ever-expanding world of medicine, the fundamental role of the physician has
remained unchanged in the face of tremendous evolution.
The Human Genome Project is an accomplishment that will alter that practice of
medicine on a scale never before seen in medicine. Through technological
breakthroughs, advances in our understanding of diagnosis and pathogenesis, and rapid
developments in our ability to treat and prevent disease, by 2020 the practice of
medicine will look very much different than it does today. These changes will also
challenge both physician and patient on the ethical, social, and moral level, begging
questions as profound as what it means to be human, and the ramifications of giving one
individual the power to permanently change another.
However, when viewed on the most fundamental scale of the human relationship
between patient and doctor, these new advances in the practice of medicine will likely
have little effect. If anything, the importance of this relationship will grow as the very
foundation of disease is elucidated at the molecular level. More than ever, the physician
will need to draw on his abilities to relate to his patients and bring a human perspective
to disease. As Francis Weld Peabody wrote in 1927, “one of the essential qualities of
the clinician is interest in humanity, for the secret of the care of the patient is in caring for
the patient” (57).