Technology Review
The Implications of the Human Genome Project for Family Practice Lori A. Whittaker, MD, PhD Houston, Texas
The Human Genome Project is an international effort to deal with the issues it will raise. The family physician, far map and sequence the human genome. The information from being merely an interested observer in this process, it will generate has been referred to by some as the “new will be responsible for the delivery o f much o f this tech anatomy,” and may play an important role in the future nology as it becomes available. As an intermediary be o f medicine. However, as with any new technological ad tween the technology and the individual patient, the phy vancement, the outcome of the Human Genome Project sician has a unique obligation to join in the thoughtful and the subsequent availability o f new technology will consideration and debate o f these issues. raise a myriad o f ethical, legal, and social concerns. The Key words. Research; ethics, medical; genetic screening; fear is that this technology will be applied in the clinical primary care; genetic intervention; genetic counseling. setting before the appropriate infrastructure is in place to / Fam Pract 1992; 35:294-301.
The Human Genome Project is a multibillion dollar, technology develops, however, its relevance to the pri international effort to map and ultimately sequence the mary care setting will expand. Genetic testing and diag entire human genome. This project and the genetic tech nosis is moving from the research laboratory to the nology that it will spawn have the potential to dramati routine clinical laboratory and will have an impact on cally change the practice o f medicine over the next dec such areas as prenatal care, newborn and childhood ade. Gene mapping has been referred to as the “new screening programs, the determination o f individual ge anatomy”1 and its impact likened to that o f Vesalius’ netic risk profiles and preventive health care, and preem textbook o f anatomy published in 1543, which formed ployment and insurance testing. As the number o f avail the cornerstone for modern medicine.2 With the infor able genetic tests grows, there will simply not be mation and technology gained from the Human Genome sufficient numbers o f genetics specialists to meet the Project, it is anticipated that we will be able to identify by demand for information. The delivery' and evaluation of genetic screening most inherited disorders, produce ge these tests is likely to become the responsibility of pri netic profiles o f individuals to predict their risk for a mary care physicians as a routine part o f medical prac variety o f diseases such as heart disease and cancer, and tice.4 reverse many genetic defects and treat diseases with gene O f the primary care specialists, family practice phy therapy. While the implications of this technology are sicians arc in a unique position to be affected by these exciting, they also generate considerable ethical, legal, changes, since family medicine encompasses all stages of and social concerns regarding a person’s right to privacy the human life cycle and thus may be influenced by the and autonomy and the possible misuse o f the informa full range o f genetic diagnostic possibilities. There is tion obtained from genetic testing.1-14 concern that physicians will be unprepared to meet the To date, family physicians have watched this advanc challenges this new technology will pose. Geller and ing technology largely from the sidelines. Most genetic Holtzman have suggested that several barriers exist that testing and therapy has been within the realm o f genet prevent primary care physicians from adopting genetic icists and specially trained genetics counselors. As the testing, including “lack o f knowledge, inability to inter pret problematic information, low tolerance for uncer tainty, negative attitudes about their responsibility for Submitted, revised, M ay 5, 1992. genetic counseling and testing, lack o f confidence in their From the Department o fFamily Medicine, Baylor College o f Medicine, Houston, Texas. clinical skills, and unfamiliarity with ethical issues raised Requests fa r reprints should be addressed to Lori A. Whittaker, MD, PhD, Inuvik Medical Clinic, Inuvik, Northwest Territories, Canada XOE 0T0. bv testing.”4 This paper is an attempt to break down
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some o f those barriers and familiarize the family physi Table 1. Some of the Diseases Mapped by Restriction cian with the Human Genome Project and its applica Fragment Length Polvmorphisms (RFLPs) tions, and to address some o f the important ethical and Acoustic neuroma, bilateral legal issues that will arise as this new technology expands Alport syndrome* into the primary care setting. Amyotrophic lateral sclerosis Aniridia Ataxia telangectasia Charcot-Marie-Tooth disease The Human Genome Project: The Craniosyntosis Cystic fibrosis* Technology Duchenne muscular dystrophy* Familial polyposis coli* There are 3 billion base pairs in the human genome, and Fragile X* an estimated 50,000 to 100,000 genes. By October Friedreich ataxia Hemochromatosis 1990, when the official initiation o f the Human Genome Huntington’s disease Project was announced, 1900 genes had already been Kallmann syndrome* mapped to specific chromosomes or chromosome re Long QT syndrome Multiple endocrine neoplasia, types I and II gions and 600 genes, or approximately 1% o f the total, Myotonic dystrophy had been cloned and sequenced.2 It is estimated that the Nail-patella syndrome genome project will take 15 years and 3 billion dollars to Neurofibromatosis* Polycystic kidney disease complete. It will be necessary to develop new genetic Retinoblastoma* technology as the project progresses if its goals arc to be Retinitis pigmentosa* von Hippel-Lindau syndrome* met within the anticipated time frame. The aim o f the Wilms’ tumor* project is not to blindly sequence DNA strands, but Wilson’s disease rather to first produce a physical map o f the genome, Wiskott-Aldrich syndrome using restriction enzymes to generate chromosome frag *Indicates diseases in which the gene has been isolated. ments and known genetic markers to identify their loca tion. Research groups in various countries will add new genes to the map as they are identified and sequenced. cystic fibrosis. A partial list o f diseases mapped by RFLPs Eventually, all o f the “gaps” in the genome will be filled is shown in Table 1. A description o f more sophisticated in. The resulting genomic sequence will serve as an means o f gene isolation is not within the scope o f this invaluable reference for future generations o f scientists, paper, but has been discussed elsewhere.2-3 geneticists, and clinicians. A variety o f methods may be used to isolate genes. The first, and simplest, is to identify the protein product, Potential Applications of Genetic determine a partial protein sequence, and work back Technology in Family Practice wards to determine the gene sequence. This method has allowed the sequencing o f those genes that encode blood Prenatal and Parental Screening group antigens, clotting factors, structural proteins, growth factors and their receptors, hormones, enzymes, The developing genetic technology will have applications and oncogenes. Alternatively, when the protein product in a variety o f settings in primary health eare. The first o f is not known, the study o f inherited genetic defects can these is in the area o f prenatal care and counseling, and yield valuable information. Family linkage studies may be involves both prenatal diagnosis o f fetuses and determi carried out to identify known genetic markers that co- nation o f the genetic status o f prospective parents. segregatc with, and arc therefore closely linked to, the Prenatal diagnosis, for the most part, requires am gene o f interest. Using restriction enzymes to generate niocentesis or chorionic villus sampling to obtain fetal DNA segments o f varying lengths and using the markers cells, both o f which are invasive procedures with their as probes, specific restriction patterns may be identified own risk o f morbidity and mortality. These procedures in affected individuals that arc not present in unaffected are now routinely done only in cases o f increased risk for family members. These restriction fragment length poly genetic abnormalities, such as advanced maternal age or morphisms (RFLPs), as they arc called, can be used in family history o f genetic disease. Even then, analysis is genetic screening, and arc useful in the eventual isolation done for only specific genetic or chromosomal aberra o f the gene. Examples o f genes originally identified by tions, as the current cost of screening for all detectable RELPs for which the sequence is now known include genetic aberrations is prohibitively high. Marfan’s syndrome, Duchcnnc muscular dystrophy, and As technology improves, the cost o f DNA analysis
The Journal of Family Practice, Vol. 35, No. 3, 1992 295 tv *
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296 The Journal of Family Practice, Vol. 35, No. 3, 1992 Genetic Research W hittaker
Neonatal and Early Childhood Testing gene associated with the Li-Fraumcni cancer syndrome Mandatory neonatal screening is already in place for and a variety’ of sporadic cancers including breast and diseases such as PKU, sickle cell anemia, congenital hy lung carcinomas, osteosarcomas, brain tumors, and leu pothyroidism, galactosemia, and congenital adrenal hy kemias22; the APC gene associated with familial polypo poplasia* because early intervention for these diseases sis23; and the extensive metabolic phenotype o f the cy can have a profound effect on outcome. As testing for a tochrome p450 enzyme CYP2D 6 associated with an variety' o f genetic disorders becomes possible and the increased risk o f lung cancer, especially in the face o f development o f individual genetic risk profiles becomes exposure to asbestos or polyaromatic hydrocarbons.24 the norm for preventive medical care, it may seem that The identification o f such predispositions could infancy is the best time to determine an individual's have far-reaching consequences for affected individuals. genetic makeup, at least for certain conditions for which Some would argue against such knowledge, saving it earl)' intervention could have an advantageous effect. It is could only have an anxiety-provoking and deleterious even conceivable that the government could legislate affect on the lives o f those with unfavorable genetic mandatory' testing o f all infants, denying parents the profiles. There has been much controversy over the iden right to refuse such testing. What effect could such in tification o f individuals with Huntington’s disease, a tervention have on child-rearing practices? If, for exam progressive neurological disorder with onset in late ple, a child is determined to have a predisposition for adulthood, for which presymptomatic genetic testing is available. As there is no treatment for Huntington’s heart disease, it may seem prudent to institute an ap proved American Heart Association diet as soon as pos disease, the usefulness o f detecting affected individuals early in life is questionable. Such knowledge would un sible in order to instill beneficial lifelong eating habits. derstandably be associated with some degree o f hopeless Could parents then be said to be negligent if they fail to ness and despair, and undoubtedly would affect many force their child to strictly adhere to this diet? premorbid life stages, such as peer and family relations, Particular genetic labels might have lasting effects on marriage, education, career choices, and so forth. Indeed, parent-child bonding, peer relationships, school perfor the only clear advantage o f early detection, and this is the mance and expectations, and in adolescence, on career main argument in its favor, would be in making repro choices and life plans. All new parents arc understandably ductive choices. hopeful that their child will be physically “perfect,” Another example o f early detection is von Hippcl- meaning that he or she has no identifiable abnormality. Lindau disease, a hereditary' syndrome characterized by With the advent o f genetic testing and the information it tumors and cysts in multiple organ systems. Recent iden will generate, the concept o f the perfect child may be tification o f tightly linked genetic markers for this syn changed forever. It is expected that a “perfect” genetic drome now permits accurate early diagnosis.25 Unlike profile will be exceedingly rare. Family physicians and Huntington’s disease, however, early intervention can pediatricians will be called on to explain and interpret the alter the course o f the disease, and thus provides strong results o f a multitude o f tests to anxious parents, and the argument for the importance of presymptomatic detec manner in which this information is presented may per tion. Likewise, early identification o f cystic fibrosis has manently affect the parents’ view o f their child. The implications for aggressive early interventions and treat importance o f the primary' care physician as genetic coun ment. These latter examples are perhaps more in line with sellor in this regard cannot be overemphasized. the development o f genetic profiles for predisposition o f disease. Individual Genetic Profiles Theoretically, premorbid intervention in the form of modification o f risk factors would be advantageous in As described above, one of the potential offshoots of the individuals predisposed to certain diseases. Individuals Human Genome Project is the development of “genetic predisposed to heart disease, for example, could attempt profiles” o f individuals. These profiles would identify to lower other risk factors by following low cholesterol predispositions to a variety o f diseases known to have a diets, exercising, not smoking, practicing stress-reduc strong genetic component, such as heart disease, stroke, tion techniques, and aggressively managing hypertension cancer, diabetes, hypertension, alcoholism, and schizo and diabetes. Although these are recommendations most phrenia. Examples o f such predisposing genes that have physicians currently make to all their patients, we are well already been identified include the p53 tumor suppressor aware of the problems of compliance. Perhaps knowl edge o f having a genetic risk for a particular disease
*These are the neonatal screening tests currently required by law in the state o f Texas. would increase a patient’s compliance in areas o f preven Each state varies with respect to the tests they require. tive health care.
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Gene Therapy other parts' led to the wrongful birth o f a genetically defective child, the contention being that if the parents One o f the most exciting and controversial aspects o f the had known o f their genetic risk, they would have chosen new genetic technology is gene therapy.26^32 It is unlikely abortion or contraception to prevent the birth of that that family physicians will be directly involved in this child. There are several examples o f cases in which a highly technical field, but they should be aware o f gene wrongful birth claim has been upheld. In Becker v therapy as a treatment option for a variety of conditions Schwartz (1978),33 the plaintiff was awarded economic and disease states. Somatic gene therapy involves the (but not emotional) damages when a physician failed to replacement o f an absent or defective gene with a normal warn a 37-year-old mother of a Down’s syndrome baby gene by targeting specific somatic cells. Clinical trials are o f the genetic risks o f her pregnane}' and to offer amnio already underway to replace the adenosine deaminase centesis. Karlsons v Guerinot (1977),34 which also in (ADA) gene in children with ADA deficiency and the volved the birth o f a child with Down’s syndrome, was resulting severe combined immunodeficiency syn one o f the few cases in which recovery o f damages for drome.26 In another study, tumor-infiltrating lympho emotional suffering by the parents was awarded. In two cytes genetically engineered to contain a neomycin resis other cases, the physician was found negligent in having tance marker were safely infused into melanoma patients failed to take an adequate familv history and identify the and successfully targeted to tumor sites.31 Plans are un risk o f genetic disease. In both Goldberg v Ruskin derway to use this technique to introduce tumor-necrosis (1984)3S and Howard v Lecher (1977),36 the physician factor, interferon alpha, or interlcukin-2 into the tumor- failed to identify and warn prospective parents o f their infiltrating lymphocytes to improve their antitumor ac risk o f having a child afflicted with Tay-Sachs disease. tivity.31-32 It is hoped that gene therapy will provide a Liability' may also be based on the physician’s failure to revolutionary new approach to diseases such as inborn diagnose, or identify as genetic, a disease in a previous errors of metabolism, specific genetic defects, cancer, and child and thus offer appropriate counseling for subse AIDS. quent pregnancies, as in Park v Chessin (1977; polycystic Much more controversial is the concept of germ line kidney disease),37 Schroeder v Perkel (1981; cystic fibro gene therapy, which involves the introduction o f foreign sis),38 or Turpin v Sortini (1982; hereditary deafness).39 DNA into germ cells, thus perpetuating a genetic change The second concept to be brought before the courts for future generations. French Anderson, whose group is is that of iwongful life. This is a cause o f action brought responsible for the ADA trials, has said that germ line- on behalf of the defective child, claiming that his birth has gene therapy “has a greater impact on society as a whole caused him undue pain and suffering, and that he would than treatment confined to a single individual. The gene- have been better off not having been born. In general, pool is a joint possession of all society. . . . [T]he deci courts have denied such claims, citing the “sanctity o f life sion to initiate germ line gene therapy demands assent and the difficulty o f comparing life in an impaired state— from more than the individual involved.”27 To date, the even a severely impaired state— to no life at all.”40 To NIH Recombinant DNA Advisory Committee has not date, only two wrongful life claims have been upheld. permitted any clinical trials o f germ line therapy, and The first o f these was Park v Chessin (1977; also argued considerable ethical debate will likely ensue before such on a wrongful birth claim)37 in which infant Lara Park trials arc allowed. recovered damages for her “conscious pain and suffering” for having been born with polycystic kidney disease. Her parents had had a previous child who died o f the condi Further Implications and Issues for the tion several hours after birth. An autopsy had been Family Physician performed on that child, and the parents informed that the chances o f having a second child born with the Legal and Malpractice Issues disease were “practically nil.” They had relied on this information when they conceived Lara, who died at the In our current litigious climate, no aspect o f the practice age o f 2 years.40 The second case was Curlender v Bio of medicine is free o f liability, and this includes the science Laboratories (1982),41 in which the defendant was applications of developing genetic technology. not a physician, but a medical testing laboratory that One o f the most contentious areas is that o f prenatal offered inaccurate information to a couple with a family diagnosis. The concepts o f wrongful birth and wrongful life history o f Tay-Sachs disease, stating that they were not at have been invoked in the courts to deal with this issue. risk for having an affected child. When their child was Wrong fid birth is an action taken on behalf o f parents born with the disease, a suit was filed on his behalf claiming that negligence on the part o f a physician or against the medical testing laboratory in which he recov-
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cred damages for pain and suffering endured during his storage o f the data generated. Once the information has lifetime. Today, only four states, California, Washington, been logged into such systems, confidentiality may not be New Jersey, and Colorado, recognize the wrongful life feasible. Indeed, insurance companies may well argue action.40 that if they are denied access to genetic information, then This discussion has focused on the liability' inherent those individuals with unfavorable profiles might buy in prenatal testing and counseling, but no application of more insurance on the basis o f that information, placing genetic technology' is immune from litigation. For exam an increased burden on the insurer.19 The concept ot ple, a physician could be held liable for failing to diag prior knowledge o f disease may then be brought to bear. nose or improperly interpreting a particular genetic risk If, on the other hand, insurance companies did have o f disease and offer appropriate preventive measures to access to the information, how might this affect the the patient; or for failing to offer gene therapy as a health care system? Might insurers offer differential rates therapeutic option to a patient who might benefit from based on genetic profiles? Would someone with a truly it. As with any other area o f medicine, physicians are unfavorable profile be denied health care coverage alto obliged to keep abreast o f current medical practice. The gether? prevailing legal opinion on this subject is summarized in It is likely that if testing becomes universal, most the following article published by the Tale Law Journal: people would be found to have some “good" genes and some “bad” genes, and that these would cancel each other Because knowledge of human genetics is expanding rapidly, out and offer no clear medical advantage or disadvantage. doctors should not be exonerated when they have failed to be reasonably current in this area. It has long been recognized Initially, however, certain predispositions might be given that physicians are bound to stay abreast of major medical priority. It is possible that governmental intervention developments. . . . In evaluating the adequacy of physicians’ will be required to determine how genetic information detection of genetic risk, courts should go beyond the limits will be used by the health insurance industry. Some have of this traditional requirement by strictly compelling doctors to be aware at least of techniques widely known within the suggested that these concerns may actually be an impetus medical community.42 to a national health care plan, stating that “the injustice ot private health care schemes will be accentuated once additional genetic information becomes available."43 Confidentiality and Access to Information Another area of concern is that of discrimination in the workplace. Genetic screening by employers could The potential misuse o f the information gathered from seriously limit an employee’s right to privacy and auton genetic screening is another area of great concern. De omy. Jeremy Rifkin voiced these concerns at a meeting ot termining who should have access to that information is the NIH Recombinant DNA Advisory Committee 2 a difficult question. Some argue that even patients should years ago, when he stated that “the major civil liberties not have foil access to their own test results, since the questions o f the coming decades are going to be the right implications o f certain results may not be clear and could o f genetic privacy . . . versus mandatory screening . . . in only result in anxiety or false conclusions on the part of order to have people be congenial to the environments the patient. This concept of withholding information the corporations or institutions want to place them in."44 from the patient, however, exemplifies the practice o f He cited as examples o f past discrimination Dupont’s beneficence, which is no longer considered acceptable in most medical circles. The argument does emphasize, screening o f black employees for sickle cell anemia, and though, the importance of proper interpretation, coun chemical companies in the 1970s requiring sterilization seling, and discussion on the part o f the physician ad o f female employees as a prerequisite to employment in ministering genetic tests and communicating the results certain high-risk areas. Following public outcry and con to the patient. gressional investigations in the early 1980s, such prac The question o f third-party access to information is tices arc rare today. A 1987-1988 survey o f 245 corpo somewhat more complex. One area of concern is that of rate executives revealed that only three companies health insurance screening. Already there is a precedent admitted to using any form o f genetic screening (the type for insurance companies to deny coverage to persons and purpose of the screening was not specified).45 who test positive for H IV. Attempts at keeping this Recent legislation has provided a legal basis for the information confidential have met with only marginal prohibition of genetic testing in the workplace. The success. It may be expected that a similar experience will Americans with Disabilities Act prohibits employers with be had with genetic information. It is likely that genetic 25 or more employees (and in 1994, 15 or more em testing and screening will require the use o f computer- ployees) from discriminating on the basis o f disability. It based information systems for analysis, processing, and also forbids the use o f medical tests to detect disabilities
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in employees, unless the testing relates to the ability to o f research laboratories or clinical geneticists, will have perform a specific job-rclatcd function.5 direct application to a variety o f primary health care Nonetheless, as an increasing number of genetic settings. Family physicians, along with pediatricians, in tests become available, employers will more than likely ternists, and obstetricians w ill be involved in the devel develop justifications for their use, ostensibly to enhance opment and administration o f prenatal diagnostics and worker or public safety, but at the same time trying to reproductive counseling programs, neonatal and child limit their own liability and health care costs. For exam hood testing, and preventive medicine protocols based ple, certain genes have been identified that may result in on individual genetic risks. increased susceptibility to cancer following environmen As with any new technology, the advances made by tal exposure to specific carcinogens.24 It may seem pru genetic research will generate difficult moral and ethical dent for those individuals who are at increased risk to issues. Such fundamental rights as procreative libertv and avoid exposure to the carcinogens if possible. Such med reproductive freedom, confidentiality and access to infor ically prudent behavior may limit their access to a given job, however, and must be weighed in the context o f that mation, insurability, employability, and individual au individual’s personal circumstances (such as financial re tonomy may be brought into question. Potential areas o f sources, number o f dependents, education and training, contention include the controversial and emotional issues job desirability, and the availability o f alternative jobs) as of a woman’s right to continue or terminate a pregnancy compared with the actual degree o f risk. based on genetic information; a parent’s right to refuse The concepts of worker autonomy and the right to testing for his or her child; the emotional and social make informed personal decisions were key factors in the impact o f genetic labels; an insurance company’s right to US Supreme Court’s landmark decision in United Auto deny coverage to certain individuals based on their ge Workers v Johnson Controls, Inc (1991), in which the netic profile; or an employer’s right to prohibit employ company’s policy o f excluding fertile women from areas ment o f those with a specific genetic trait or predisposi of lead exposure was declared unconstitutional.46 tion. Family physicians are frequently responsible for the From a medicolegal perspective, it will be imperative administration o f preemployment physical examinations for all physicians to be informed o f the technology as it and medical tests, and therefore have an obligation to be unfolds. The prevailing legal opinion is that lack of actively involved in the determination o f what constitutes knowledge o f genetic technology will be no defense for a fair and ethical employee screening. The Council on physician’s failure to offer the appropriate genetic test, Ethical and Judicial Affairs o f the American Medical counseling, or intervention. Inherent in this is the re Association has recently issued guidelines designed to quirement for a critical appraisal and understanding o f help physicians deal with this complex issue. Their opin the applications and limitations o f the tests themselves. ion reads in part: As with any diagnostic modality, we must understand its It would generally be inappropriate to exclude workers with therapeutic relevance and implications. Full interpreta genetic risks of disease from the workplace because of their tion will be possible only with applied clinical experience. risk. Genetic tests alone do not have sufficient predictive Public policies with regard to the use o f genetic value to be relied upon as a basis for excluding workers. Consequently, use of the tests would result in unfair discrim technology remain to be determined. It is important that ination against individuals who have abnormal test results.5 physicians, who are in a unique position as intermediaries between the technology and the patient, add their voice Onjv.in .vety.limiteduiioainxttnntuxs yue.Tas< wdviroeeu* lO' Move uTscicmtks, ectfacists, ibgisihtors, ana' trte Iky pational disease might develop so rapidly that monitor public in setting these policies. ing of exposure to a given toxin would not be possible, and the cost o f lowering the level o f the toxin in the workplace would be prohibitively high, would the AMA condone genetic screening o f employees. Acknowledgments The author acknowledges the contributions of Adel Youakim, PhD, Warren Holleman, PhD, and Alan Blum, MD, for their support and encouragement o f this work, their critical appraisal o f the manu Conclusions script, and, with Larry McCuilogh, PhD, for their thoughtful and insightful discussions on this subject. I also wish to thank the With the advent of the Human Genome Project, the next organizers and speakers of the conference, “Legal and Ethical Issues Raised by the Human Genome Project,” given by The Health Law decade will sec a revolution in genetic technology. Much and Policy' Institute of the University o f Houston, March 7 -9 , 1991, o f this technology, far from being restricted to the realm whose informative presentations provided the impetus for this work.
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See editorial comment on pajje 256.
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