Ethical Issues in Genetic Screening and Testing, Gene Therapy, and Scientific Conduct

Lisa S. Parker and Elizabeth Gettig

Bioethics, as an interdisciplinary field involving clinicians, lawyers, philosophers, theologians, and other humanists, was born in the early 1970s amid technological advances in medicine and growing respect for persons in society. The era was marked by the end of the Tuskegee syphilis study, the first widespread use of hemodialysis and mechanical ventilation, abortion reform, and the first human heart transplant. Technological capabilities clashed with individuals' values. In short, bioethics was born of conflict (26).

Respect for individuals' rights of self-determination came into conflict with some social values and with the medical profession's previously largely unchallenged paternalistic concern for patient welfare, as the medical profession and individual professionals—not patients—defined that well-being. In 1970, for example, Paul Ramsey published his patient-centered medical ethics treatise, The Patient as Person (31). The field of bioethics emerged in the wake of landmark legal cases, such as Karen Quinlan's parents' bid to remove her from her respirator (30) or the paralyzed Mr. Canterbury's suit claiming that he had not been fully informed of the risks of his surgery (7). Bioethics evolved to provide a legal and ethical framework within which to resolve conflicts between physician and patient and between social consensus and individual values. The individual patient's values came to trump the traditional values of medicine, and the privacy both of individuals and of the physician–patient relationship erected a boundary against the intrusion of society's interests.

Historically, the physician–patient relationship has been the primary focus of bioethics, but it is clear that the crisis of funding health care is emerging as the fundamental challenge of the 1990s (9, 22,35 ). Social policies and institutional contexts are now considered in association with, or occasionally instead of, the physician or health-care provider and patient relationship (21).

Developments in theoretical ethics, specifically feminist ethics, support bioethics' new focus. Feminist philosophers suggest that in order to provide just answers to ethical questions, ethics must pay increased attention to their social context and political dynamics, the balance of power, and the history of oppression (14, 15,33).

So it was in this intellectual and social climate that the Human Genome Project (HGP) was initiated in 1990 to support and coordinate efforts of the National Institutes of Health (NIH) and the Department of Energy (DOE) to produce a complete genetic map of all human genes. The Ethical, Legal, and Social Implications (ELSI) Program of the HGP was charged with anticipating the social consequences of the acquisition of this knowledge and developing policies to guide its use. With 5% of the genome budget supporting ELSI activities, the ELSI Program is both the first federally supported extramural research initiative in ethical issues and the largest source of public funds for bioethics (44).

However, the bioethical issues of the HGP are not unique. The topics of informed consent, justice, gender justice, privacy, confidentiality, discrimination, genetic discrimination, health-care needs, or private health insurance versus a national health service are familiar ones. Even those challenges to the premises of a private health insurance system presented by genetic screening are, for example, also presented by other predictive medical tests—for example, cholesterol screening for hypertension.

Advances in genetics may, however, place ethical concerns on a grander scale because everyone is at an increased risk for developing some disease. New genetic technologies may cause ethical concerns to arise at a different stage of life or of decision-making (e.g., prior to conception or at a presymptomatic stage of a disease).

If the conflict between paternalism and autonomy is seen to have been played out in the context of the doctor–patient relationship since the 1970s, the genetic counselor–consultand relationship of the 1980s and 1990s seems to reflect the resolution of that conflict. Prior to the 1970s, a priestly model accurately described the typical, paternalistic doctor–patient relationship. According to this model, decision-making is taken from the patient and placed in the hands of the expert professional who is charged with benefiting the patient; in the extreme, the physician's "moral authority so dominates the patient that the patient's freedom and dignity are extinguished" (39). In contrast, the physician–patient relationship model which is currently advocated is a contractual model: "The basic norms of freedom, dignity, truth-telling, promise-keeping, and justice are essential to a contractual relationship. The promise is trust and confidence even though it is recognized that there is not a full mutuality of interests. . . . With the contractual relationship there is a sharing in which the physician recognizes that the patient must maintain freedom of control over his own life and destiny when significant choices are to be made" (39).

The relationship between professional genetic counselors and their consultands reflects this shared decision-making process which guarantees to consultands the authority to make choices reflecting their own values. The Code of Ethics of the National Society of Genetic Counselors (NSGC) states that genetic counselors strive to: "respect their clients' beliefs, cultural traditions, inclinations, circumstances, and feelings . . . and refer clients to other competent professionals when they are unable to support the clients" (25). Thus, the consultand-centered, autonomy-oriented conception of the genetic counseling relationship reflects the outcome of at least two decades of bioethical discussions of patients' rights, of the therapeutic advantage of involving patients in their own care, and of value pluralism.

The nonpaternalistic, nondirective process of genetic counseling also embodies aspects of the doctrine of informed consent, the most prominent bioethical and legal doctrine to emerge in the early years of bioethics. Informed consent is the process whereby competent patients or research subjects are informed of the risks and benefits of proposed therapeutic or research protocols ("disclosure"), are asked to weigh these risks and benefits in light of their own values and desires, and are asked to give their informed, voluntary consent to undertake the therapy or participate in the research (2). Health-care professionals and researchers are obligated to (a) disclose the information in a manner so that a reasonable layperson can understand it and (b) answer the specific questions which the individual client or research subject may raise. Insofar as the professional or researcher becomes aware of a particular client's or subject's desire to have additional information disclosed, the professional or researcher incurs an obligation to make reasonable attempts to satisfy that desire ("dialogue"). The doctrine of informed consent has two justifications: first and most fundamentally, respect for persons and their autonomy; and second, protection of individuals' welfare by requiring their consent as a prerequisite to incur the risks of research or treatment (5).

The fundamental role of genetic counselors is to provide information to enable consultands to make free and informed reproductive and health care decisions. The NSGC Code of Ethics states that counselors "strive to enable their clients to make informed independent decisions, free of coercion, by providing or illuminating the necessary facts and clarifying alternatives and anticipated consequences" (25). Supplying information in an understandable manner, answering consultands' questions, helping consultands develop the understanding necessary to make their own decisions, and supporting those choices are the primary tasks of genetic counselors. Whereas these tasks, which comprise the disclosure and dialogue stages of the process of informed consent, are just one facet of other health care providers' jobs, they constitute, in broad outline, the primary tasks of genetic counselors.

Thus, in an important sense, the first two decades of bioethics not only provided background for current ethical consideration of issues arising from genetic research and the management of genetic disease, but actually laid the foundation for the process of modern genetic counseling. As the HGP progresses and genetic services become a more integral part of health care, ethical analysis of issues concerning these rapid advances in genetic technology and knowledge will continue to reflect this individual-oriented bioethical tradition.

Growing attention to more socially oriented bioethical concerns, such as allocation of health-care resources, however, also coincides with, and will be influenced by, advances in genetics. Allocation issues, for example, are no longer primarily questions of micro-allocation or triage, but instead focus on macro-allocation concerns, such as how to provide a decent minimum of health care to all of society's members, what constitutes a decent minimum, and whether certain types of health care should be available at all ("should organ transplantation research or gene therapy trials receive funding?").

Although the field of bioethics was born in an atmosphere of conflict and was initially concerned with the resolution of ethical conflicts, it is gradually beginning to address the social and institutional factors which may create or exacerbate ethical problems. Thus bioethics may be said to parallel preventive medicine (10,27). The practice of "preventive ethics," including its anticipatory stance and its attention to social and institutional factors, mirrors the practice of preventive medicine (12).

Waiting until a conflict arises makes resolving ethical quandaries more difficult, because by then medical and institutional factors may limit options or opposing parties may have become deeply entrenched and personally identified with their (conflicting) positions. The inadvertent disclosure of confidential information to family members about their risk for having or transmitting a genetic condition can result in long-term dysfunction in family dynamics which might be avoided by establishing and observing preventive ethics policies for information management. Therefore, even successfully resolved crises incur high human costs in terms of time and emotion expended in their resolution.

Furthermore, the crisis-resolution approach measures success in terms of whether a settlement to the particular crisis can be found and thus too readily accepts patterns of recurring ethical problems. In its early years, bioethics neglected the underlying causes of ethical conflicts, such as routine aspects of health care or social and institutional structures which have exacerbated or even directly caused ethical conflicts in the provision of health care (4). The traditional approach defines the scope of bioethics in terms of discrete problems; thus, it necessarily fails to attend adequately to the ethical aspects of health care in which no specific "problem" has been identified. Outside of genetic counseling, for example, even though the process of informed consent is important in defining the ethical character of every provider–patient interaction, the disclosure and dialogue inherent in informed consent are often ignored until the physician and patient disagree about the proper treatment.

In contrast, a preventive approach to bioethical issues can help overcome these limitations of early crisis-oriented bioethics by placing a greater emphasis on preventing the development of ethical conflicts (28). A preventive approach seeks to detect potential ethical conflicts at stages where "symptoms" of the conflicts are not yet present or are relatively mild. By identifying the predictable patterns of "pathophysiology" (3) and "ethical risk factors" shared by common ethical problems (e.g., institutional structures or differences in cultural or religious views), preventive ethics facilitates the development of mechanisms to avert serious conflicts or to reach ethically defensible plans more readily, thereby minimizing unnecessary personal anguish and social conflict.

Because preventive ethics correctly recognizes that the absence of ethical conflict is an inadequate measure of the ethical provision of health care or conduct of research, preventive ethics not only seeks to avoid conflicts, but also strives to create and preserve relationships of trust and understanding between health-care providers and recipients and between researchers and the public (12). It seeks to maximize opportunities for the exercise of autonomy and the provision of quality patient or consultand-centered care.

According to a preventive bioethics approach, alternative social policies should be judged not merely according to whether they will prevent open ethical conflicts, but also according to their capacity to promote ethical health care and the opportunity for society's members to pursue life plans reflecting their own values. In expanding the focus of bioethics from decisions in problematic cases to a general concern with both the routine aspects of health care and the social and institutional factors which affect health care, preventive ethics more fully integrates ethical considerations into health care and research.

By identifying recurrent problems, a preventive ethics approach enables researchers and health-care providers to develop ethics "protocols" for addressing them, particularly in advance of individual occurrences. Thus, the preventive approach (i) may avoid some individual hardship (or at least permit individuals to anticipate and prepare for future hardships), (ii) may, by identifying the problems, invite their innovative solution, and (iii) may prompt changes in existing structures and policies, if they are themselves contributing to the problems.

In genetic research, practicing preventive ethics in the presymptomatic testing of individuals at risk for Huntington's disease (HD) has led to a tentative code of conduct for genetic researchers (17). The code evolved from research on samples from families with genetic disease and from the development of new molecular tests. The proposed code of conduct intends to protect both the subject and researchers. Harper (17) admits that most problems encountered in genetic testing are a result of not paying adequate attention to the ethics of gene testing and therapy. HD protocols have been examined by review committees, often (unfortunately) with more attention given to the risks of the sampling procedure (dangers and discomfort of venipuncture) than to the social, psychological, and economic consequences of the test results (e.g., the detection of a genetic defect).

The proposed code also addresses the conflicts of interest between the patient's needs and the physician's or researcher's interests. Financial ties with industry, through research, personal investment in commercial ventures, or consulting fees, appear to be greater in genetics than in other fields of medicine due to the technology-driven nature of genetic research. Norman Fost (13) has written that "sometimes it is difficult to distinguish a conflict of interest from a congruence of interest. The scientist's desire of fame and fortune may drive him or her to the extra effort that results in a discovery that benefits others. The physician's desire for income may stimulate him or her to work long hours and provide beneficial services to others. But there is also evidence that self-interest can adversely affect clinical judgement, whether it be for suggesting elective surgery or for ordering expensive diagnostic tests."

Disclosure statements have become commonplace to minimize the possible effects of conflicts of interest; and some groups, notably a multicenter clinical trial of treatment after coronary-artery bypass-graft surgery, have moved toward prohibiting ties with industry when such ties are not necessary for the practice of medicine or the advancement of science (20).

The code of conduct proposed by Harper (13) also points to some of the difficulties that will be faced as genetic technologies developed in the research context are applied in the clinical diagnostic or therapeutic context. The code states the following:

The presymptomatic HD testing programs have attempted to create and preserve trust and understanding between researchers and test providers. Presymptomatic testing is a multistep process involving numerous visits to testing centers. The HD protocols prescribe review of the subject's family history, neurologic examination, psychiatric examination, review of medical charts of extended family members for confirmation of diagnostic information, psychological testing, pre-test counseling, and disclosure of results. Follow-up both clinically and for research purposes is a standard feature of presymptomatic testing protocols (11).

The HD model sometimes limited the subject's right to privacy because of the need for extensive review of family medical data and the need for samples for linkage analysis (prior to the recent discovery of the HD gene). The protocol was born from the traditional pre-1970s model of the physician–patient relationship. It is therefore criticized on paternalistic grounds. The protocols were neither publicly reviewed nor discussed. As individuals have "graduated" from the testing program, the protocols are being revisited. Suggestions and recommendations from participants are being sought in order to evaluate and possibly to modify the protocols. Moreover, the recent discovery of the gene responsible for HD has pushed the scientific community to reevaluate the protocols because extended family review is no longer necessary.

The HD model represents the first testing program which enables a person to choose to know with a high degree of certainty that he or she will die of a fatal, inherited, and presently untreatable disease. The psychiatric and social consequences of having such knowledge were anticipated and prompted the rigid protocol structure to preserve the most basic of ethical tenets—that is, to do no harm. Experience with the HD protocols has shown that explaining genetic risks is a complex subject and that understanding comes slowly (24).

The counseling steps of the HD protocols may be included in future genetic testing models. Testing without giving information, counseling, and support must be agreed to be unacceptable. Concern about stigmatization and discrimination in employment, insurance, and personal relationships should provoke society to monitor and regulate the availability and use of genetic testing to ensure that abuse or coercion does not occur (18). A preventive ethics approach allows for better planning and more open discussion of these ethical concerns.

The creation of the NIH's Recombinant DNA Advisory Committee (RAC) represents an attempt to anticipate and address ethical concerns pertaining to gene therapy. The RAC was responsible for what some consider one of the most important milestones in the history of medicine—namely, the approval of a human gene transfer study and human gene therapy protocols (40). The gene therapy protocols currently involve only somatic cell gene therapy. Somatic cell gene therapy refers to the insertion of new DNA into a particular tissue (such as bone marrow) of an affected individual. The reproductive system is not targeted, so the new DNA material serves the individual only and is not transmitted to progeny.

A preventive ethics approach is evident in the RAC's public review process. By serving to inform the public of perhaps the most controversial advances in genetics and permitting public comment on the use of gene therapy technology, the RAC provides a mechanism to minimize public concern and social conflict. The guidelines of the RAC evolved over a decade.

The RAC is not, however, without its critics. The RAC is a committee of the NIH, which, in turn, is the primary funding agent for biomedical research. The initial protocols were submitted by NIH scientists. The RAC has acknowledged the conflict in simultaneously promoting and regulating a single field of research.

In addition, because RAC review provides a safeguard against employment of potentially high risk gene therapy in the absence of safety and efficacy data, the 1992 decision to exempt one therapeutic protocol on a compassionate plea basis raises concern (20,36,37). By responding to the crisis of the moment and not fully addressing the precedent-setting ramifications of its departure from its peer review protocol, the NIH's departure from its preventive ethics stance invited criticism concerning the susceptibility of the NIH's peer review process to political pressure and constituted a potentially serious breach of public trust (8,19).

Still, the RAC again embraced the notion of preventive ethics by introducing for public debate the concept of germ-line gene therapy. Germ-line gene therapy means that the new DNA introduced into an individual may be passed to future generations. In 1990 Francis Collins, now director of the Human Genome Project, stated that "germ-line gene therapy ... is an approach that carries such risks of unknown damage to future generations that virtually all geneticists and lay organizations have concluded that it would not be appropriate to attempt it in humans" (16).

The very next year LeRoy Walters stated that "the time has now come to begin a formal public process for the ethical assessment of germ line genetic intervention" (40). Organizations such as the Council for Responsible Genetics oppose the use of germ-line gene modification in humans (29). RAC chairman Nelson Wivel (writing as a citizen and not in his official capacity) and Walters state that, "it would, in our view, be a useful investment of time and energy to continue and in fact intensify the public discussion of germ line gene modification for disease prevention, even though the application of this new technology to humans is not likely to be proposed in the near future" (43). The debate continues regarding gene therapy and its application to human subjects.

A national policy has yet to be developed governing population-based screening of genetic disease. The debate over population-based screening for the gene for cystic fibrosis (CF) has begun. Earlier screening programs, particularly screening for the gene for sickle cell anemia in the African-American population, failed to clearly establish program goals, failed to distinguish promotion of patient autonomy from the motivation of the public health community (i.e., distinguish reproductive choices from the public health concern to decrease the incidence of the disease or the gene in the population), and led to discrimination by employers, including the military, as well as the loss of insurance. The development of the screening program for gene for Tay–Sachs disease in the Jewish community benefited from the sickle cell experience and has resulted in successful population-based screening with high community acceptance and minimal adverse effects (23).

Before population-based screening for genetic conditions occurs, programs should consider five points (41). First, screening programs should clearly state their purpose and goal. Second, peer-reviewed pilot studies are necessary to demonstrate that the stated goals of the program can be achieved at a reasonable cost and with few adverse effects. This proposed safeguard may come under pressure, because the potential of screening for literally hundreds of genetic traits or susceptibilities creates pressure to begin screening prior to either adequate review of pilot studies or public debate. Third, the target population must be educated about the disease or condition in question and receive counseling about the risks and benefits of screening. Fourth, the traditional standards of informed consent must be observed. Screening should remain voluntary. Individuals must be able to exercise their "right not to know." Fifth, confidentiality of the individual must be maintained. In addition, although Fost does not specifically address this concern, universal access to testing must be ensured by public health agencies if genetic technologies are not to exacerbate existing social inequalities.

A national policy for genetic screening should have procedural mechanisms in place at both the state and federal levels to prevent harm to the individual being screened (42). Discrimination as a consequence of genetic testing has been documented (6). The health and life insurance industries use genetic test results to deny coverage, and the presence of preexisting condition clauses in many policies have led to "job lock" for families or the loss of coverage for either the individual with a genetic disease or the carrier of a gene for a disease. Stigmatization in the form of loss of services or entitlement has also been reported.

The use of fetal tissue transplants for Parkinson's disease has prompted considerable debate by the public and within scientific communities. In 1987 the NIH submitted a request to the Assistant Secretary of Health seeking approval for fetal tissue transplantation. In May 1988, however, a moratorium on federal funding was declared on fetal tissue transplant research. Although at least one center voluntarily discontinued its research in response to the moratorium, two centers, at Yale and at the University of Colorado, elected to use private funds to continue research efforts with fetal tissue transplants (1). The central objection to the use of fetal tissue is political rather than scientific. Because the tissue is obtained from aborted fetuses, it is the source of the tissue rather than its use that creates conflict.

Political responses and both public and scientific debate about fetal tissue transplants for Parkinson's disease patients clearly illustrates the shift from the physician and patient-based bioethic to one influenced by social and political interests. Indeed, the 1993 lifting of the ban on fetal tissue research by the Clinton administration both was responsive to public debate and guarantees that the debate will continue, while permitting research protocols to be judged on scientific merit rather than political precepts.

The genes responsible for schizophrenia, bipolar disorders, and Alzheimer's disease have yet to be clearly elucidated, though familial predispositions have been identified. The etiology of schizophrenia and affective disorders is unknown. These conditions are probably heterogeneous, resulting from both biologic and environmental components. The cause of Alzheimer's disease is also unknown but may have several genetic etiologies.

Family studies involving the affective disorders have confirmed clear genetic factors, including: increased risks for early-onset probands versus late-onset probands; an increased risk for unipolar depression in women and a slightly increased risk for bipolar depression in women; an increased risk for women who have first-degree relatives with a bipolar disorder for developing bipolar disease while no such association has been noted for unipolar conditions; relatives of bipolar probands have a higher risk of affective disorders (primarily unipolar) than do relatives of unipolar probands; affected relatives of unipolar probands usually have unipolar depression; and an increased risk (50–75%) is present when both parents have bipolar disorders (32).

Hereditary risks are also present in schizophrenia. Empiric risks are dependent upon the relationship to the affected individual. Second-degree relatives have the lowest risk (about 2–3%), whereas an individual with an affected identical twin has a 40–60% chance of developing the condition. The individual with one affected parent has about a 10–15% risk for schizophrenia.

In the late 1980s, the genetic material responsible for schizophrenia was mapped to chromosome 5 and bipolar disorders were mapped to chromosome 11. This work could not be replicated, and the initial findings were discovered to have been reversed in the original samples. The data further polarized the debate of the role of genetics in psychiatric conditions. The arguments of nurture versus nature resurfaced in the mental health community.

Alzheimer's disease fared better with pathophysiological characterization of b-amyloid-containing plaques and eventual mutation identification of early-onset Alzheimer's disease on chromosome 21 and another early-onset gene on chromosome 14. A late-onset gene has been mapped to chromosome 19.

Alzheimer's disease demonstrates that genetic studies can be applied to psychiatric conditions despite the confounding factors of genetic heterogeneity, ascertainment of late-onset conditions, and variable ages of onset.

Psychiatric disorders are complex and will probably result in the identification of complicated rather than straightforward modes of inheritance and uncertainty in defining inherited psychiatric conditions (38).

The preventive ethics model is again well-suited to these complex conditions. Psychiatric genetic research poses two specific issues that other genetic conditions do not—namely, the subject's competence to participate in research and determining the legal and ethical acceptability of substituted judgment for subjects not competent to consent (34).

Legal requirements of competence must be met; and if a research participant is not competent to consent, provisions could be obtained from a legally authorized representative approved by the local internal review board (IRB) in accordance with prevailing state regulations. Harper's guidelines previously reviewed do not address the competency issue. Psychiatric conditions also may involve the circumstance where clinical information is communicated to a third party for the subject's safety. Consent documents might include a section allowing the subject to designate a physician or allowing another individual to receive such information.

The protection of the rights of the individual are not unique to psychiatric disorders or genetic conditions but pose significant issues in the context of genetic research and discovery of the genes responsible for psychiatric disorders.

The preventive ethics paradigm provides a model for considering clinical and scientific conduct which accommodates more than the factors immediately apparent in a particular circumstance. By anticipating ethical concerns, seeking comment from the relevant parties, and examining background social factors and institutional structures, preventive ethics anticipates the effects of policies and practices on people of different social, economic, and educational backgrounds. By adopting an anticipatory (rather than a reactive) stance, the preventive ethics model encourages the development of policies governing genetic research and the provision of genetic services which build upon the experience of health-care providers and researchers in nongenetic contexts. Finally, in seeking to anticipate and minimize ethical conflict and to explore possible ethical solutions to problems before actual conflicts develop, preventive ethics seeks to provide individuals with the opportunity to make use of genetic and other medical technologies in the pursuit of their life plans in accordance with their sets of values.

published 2000