Grodin MA, Laurie GT. Susceptibility Genes and Neurological DisordersLearning the Right Lessons From the Human Genome Project. Arch Neurol. 2000;57(11):1569-1574. doi:10.1001/archneur.57.11.1569
Copyright 2000 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2000
Current estimates suggest that the Human Genome Project (HGP) will be completed in 2003, by which time a comprehensive physical map of the 80,000 to 100,000 genes that constitute the entire human genome will be actualized. Few deny that this knowledge holds great promise. This advance will undoubtedly represent the beginning of a better understanding of the genetic basis for human disease processes and perhaps one day will lead to better therapies and effective cures for conditions influenced by genetic factors. Unfortunately, however, the promise of the HGP is frequently portrayed as though it will reveal the essence of humanity and unlock the secrets of our destiny and who we are as human beings. This will not happen. Such a reductionist view places too much store in the influence of genetics in determining the human condition. It is fortunate, therefore, that the law has generally resisted such an approach.
Arguments about genetic determinism in the commission of crimes have received short shrift in US criminal courts, where the attempt to reduce an accused individual to nothing more than the sum total of his or her genes has been largely rejected.1 For example, in the celebrated case of Mobley v State, 2 the Supreme Court of Georgia rejected a plea by the accused to offer evidence based on "very recently" published articles and scientific studies that suggested a possible genetic basis for violent and impulsive behavior in certain individuals. The court upheld the finding that the theory behind the request would not reach a scientific stage of verifiable certainty in the near future and that the accused could not show that such a stage would ever be reached. Yet even within the scientific community itself there has been a tendency toward reductionist accounts of genetic knowledge. Researchers and clinicians often speak of the search for "the specific gene that causes" a particular condition. In fact, it has become apparent as more work has been done on the HGP that while many human diseases have a genetic component, this operates in tandem with other factors, such as environment, to bring about disease. Moreover, most "genetic" diseases do not fall into the straightforward categories of dominant or recessive disorders, but rather are part of the burgeoning category of multifactorial diseases, for which the causes are numerous and complex. Thus, the simple nature vs nurture dichotomy, appealing though it might be, is an increasingly outmoded and inaccurate model with which to make sense of the knowledge gleaned from the HGP. Nowhere is this more true than in the context of neurological disorders.
Conditions such as Huntington disease and phenylketonuria have been offered as paradigmatic examples of genetic neurological disorders, and the experiences of dealing with this kind of genetic knowledge (dominant and recessive disorders, respectively) and the families affected by these diseases have served as models for dealing with many other conditions in which genetics is an operative factor. However, more recent work on Alzheimer disease and Parkinson disease has shown that straightforward indices of risk—such as a 50% risk of an individual with Huntington disease having affected progeny, or a 25% risk that a couple who are carriers for phenylketonuria will have an affected child— have little application to these conditions.3 Although the etiology of these diseases might involve a genetic component, genes are neither necessary nor sufficient to cause disease by themselves. Moreover, while so-called susceptibility genes might play a role in the onset of diseases such as these, they are not necessarily any more significant or determinative in the causal mechanism than the role of other factors, such as the environment or the interaction of a number of genes. For example, the discovery that the ApoEϵ4 allele can be operative in certain cases of late-onset Alzheimer disease (50% of affected people) reveals nothing more than the fact that the variant in such cases is only responsible for approximately 15% of susceptibility to the disease.4 Moreover, it is estimated that few, if any, of the other susceptibility genes that are likely to be discovered will make more of a contribution to disease onset than the ApoEϵ4 allele.5
This knowledge has a direct bearing on the nature, scope, and limits of the ethical and legal responses we should have to such discoveries. Primarily, it leads us to reflect on how such knowledge should be used, for it has a direct impact on the ethical appropriateness of applying current models of genetic information to all of the knowledge generated by the HGP. One thing is clear: no single model will be appropriate for all possible types and uses of genetic information. Certain common features are, nonetheless, discernible. For example, the potential impact of using genetic information on families as well as on individuals is a factor unique to this area of inquiry; this is true irrespective of the kind of genetic knowledge involved. The traditional focus of both ethics and law in the United States as a paradigm example of a society nurtured in the western liberal tradition—has been on the rights of the individual to determine for himself or herself the course of his or her life, with minimal interference by others and provided that no significant harm to others is incurred. This notion is challenged by increased availability of genetic information. Since genetic information relates not only to the person from whom it is derived but also to the blood relatives of that person, multiple interests may be at stake, and this means not only a greater likelihood of conflict, but also the prospect of "group" (family) claims to access and control of familial information, possibly at the expense of individual interests. Any disclosure or use of genetic information has the potential to have an impact on the rights and interests of a proband as well as his or her family, and accordingly, all parties have a claim to limit or control such disclosures or uses. The role of the law, informed by ethics, is to guide a course between such potentially competing interests. This is by no means an easy task, and it is complicated all the more when societal interests are considered, such as those surrounding the integrity of a community's gene pool. For example, the traditional stalwart of bioethics — the principle of respect for persons and their autonomy — may be of limited value in this context because it pits the choice of party A against the choice of party B, when neither necessarily carries sufficient weight to trump the other. An appeal to autonomy alone is, therefore, unlikely to prove useful. Other values, such as privacy, while helpful, can also serve different sets of interests. Individual privacy might be compromised by a family claim to knowing genetic information, while family privacy interests might be compromised if an individual reveals what is essentially familial information to third parties when this might have adverse consequences for family members (eg, revelations to employers and insurers). To date, the law has done little to effectively address these matters at the federal level. Most legislative initiatives in the United States have focused on concerns about genetic privacy and discrimination arising from misuse of genetic information in the employment and insurance contexts. By January 1999, 44 states had introduced laws concerning genetic privacy or discrimination.6 And while 110 bills seeking to protect genetic privacy were introduced in the 105th session of Congress,7 none was debated beyond the subcommittee stage.8 Currently, the Department of Health and Human Services is considering a proposed rule for standards for privacy of individually identifiable health information. These regulations are designed to strike a balance between effective protection of personal privacy on one hand and adequate access to valuable data for the health industry and researchers on the other. They would also represent the first federal initiative in this area. The consultation period for these provisions ended in February 2000, at which time the schedule for implementation of the provisions remained undecided. In the absence of effective law, therefore, we must fall back on ethics as our guide.9
Advances in genetic knowledge also pose a threat to the pre-existing, and essentially individualistic, ethical paradigms that have traditionally served for resolving medical and moral dilemmas. There will be no easy answers. But in the search for those answers, there is much need for public discourse about the problems we face. This assumes, of course, that these problems can be adequately identified, which is a crucial first step. Thereafter, such discourse should involve a proper examination of the nature and content of the full range of interests that are in jeopardy, and it should be undertaken within a framework of mutually agreed values arrived at by all concerned parties. We all have a role to play in this process, for the matters under scrutiny and their solutions are neither essentially, nor even primarily, scientific or legal lines of inquiry. The ethical values that underpin optimal solutions are matters about which each of us has an opinion. Therefore, it is of paramount importance that public discussion be encouraged to facilitate this process. Of central concern is the perennial conundrum that challenges almost every area of scientific endeavor: should we do things simply because we can? While many objections have been raised about certain genetic advances, for example, in the fields of cloning,10 or about research into the genetic influences on intelligence11 and sexuality,12 the clarion call that such research should be outlawed completely is a knee-jerk reaction that is short on foresight and unlikely to prove effective. Like most measures to outlaw undesirable practices, such uses of the law serve only to drive the practices underground, and thereby beyond any further reach of the law or of regulation. A more judicious use of the law is to seek to regulate undesirable practices and build a framework of control within which science and the knowledge that it generates can be monitored and more easily diverted from unacceptable ends. Traditionally, however, the United States has preferred a hands-off approach to regulation of the health sciences. Consider the lack of regulation of the provision of reproductive services.13 Many lessons can, and should, be learned from such a noninterventionist approach, and we should seriously question its application to the field of genetics.
The multiplicity of interests at stake also requires that we consider with additional vigor the utility of new genetic information. In the context of neurological disorders, when the knowledge we gain raises more questions than it answers, we must differentiate between 2 possible uses: those that further research of diseases, and those that purport to offer a benefit in a clinical setting.
The detection of susceptibility genes for neurological disorders permits researchers to focus on the causal elements of the genome whose dysfunction results in disease. Indeed, in all cases, determining how genetic elements affect the organism as a whole permits scientists to begin to understand how any given disease process works, and therefore how it can be prevented. For example, the discovery that the most common form of cystic fibrosis is caused by a mutation in the transmembrane conductance regulator (CFTR) protein in the CF gene (which reduces the efficacy with which chloride levels are controlled by the cell) has led to a concentration of research on the biochemical pathway responsible for this chloride channel. In other words, the focus on causality for research purposes represents a valid endeavor toward further knowledge that, hopefully, will ultimately be of use in the clinical setting in the form of therapies or cures.
Does the raw knowledge from the HGP concerning a possible genetic causal factor in neurological disorders represent any direct clinical benefit? Should this knowledge enter the clinical setting at all? The most immediate benefit that is perceived to result from new genetic knowledge is the availability of testing to determine the relative risk for individuals or their families of developing a genetic disease or passing one on to their progeny. Counseling before and after testing ensures that the choice to test is fully informed, and that the prospective proband is psychologically prepared for the test results and the consequences of receiving such knowledge. It is the perceived value of predicting future ill health that is the perceived benefit in such cases. Frequently, it is argued that even in the absence of a therapy or cure, relative risk data can allow individuals to prepare emotionally and otherwise for the onset of disease. Moreover, reproductive decisions can be affected by such knowledge. However, while this might be true in the context of dominant and recessive disorders, whose index of risk is high and easily determinable, the same is not true for susceptibility genes, which are more indicative of neurological disorders. This gives rise to several fundamentally important questions: What precisely does susceptibility information reveal? What is the disease in asymptomatic genetic testing? How much, and how, should people be told, or should they be told anything at all?
Individualized risk assessment is not possible for neurological disorders. At best, estimates of risk can only reflect results gleaned from family studies, which are currently inconclusive. Thus, while 1 in 100 persons in the general population will develop schizophrenia, we know that there is a 10-fold higher risk if a first-degree relative is also affected. Within a particular family, however, this reveals nothing of further significance to members of that family, nor will the detection of a susceptibility gene necessarily furnish individuals with more detail about their own particular risk of becoming ill. In the abstract, therefore, one can only meaningfully talk about risk within the population as a whole, while on the individual level it is unclear what benefit information of this kind affords. Currently, little is done in the way of genetic counseling for neurological disorders; this is primarily because clinicians know that little can be realistically said to offer benefit. This calls into question any initiative to institute a screening program for susceptibility to neurological disorders; the cost-effectiveness alone would be hard to justify. At present, the impracticability of providing sufficient counselors for a range of screening programs stands as a de facto barrier to the implementation of such programs. But a more principled objection nonetheless needs to be raised, for cost containment is not an immutable or insurmountable hurdle over time. As a starting point, the current cautious approach of clinicians is to be welcomed. Indeed, the key role of medical practitioners in informing ethical debate cannot be underestimated. Good ethics begin with good facts, and the function of law in regulating uses and abuses of genetic information can only be properly achieved with guidance from ethics informed by those facts. The limits of genetic knowledge should therefore dictate the limits of law, and those who best understand that knowledge should occupy a position of responsibility to ensure that limits are explicated and understood by law and policy makers.
If testing is to be carried out for genes that are causal in neurological disorders, a number of points should be considered regarding the persons who are to be tested. First, if these persons already suffer from a neurological disorder, problems in obtaining informed consent might arise. The touching of a patient is only permissible, both ethically and legally and absent a proxy, once the patient has given his or her voluntary informed consent to that touching, and this requires that the patient be informed of the risks, possible benefits, and alternatives involved. It is also the obligation of the person obtaining consent to ensure that the prospective proband understands what she or he is being told and is capable of giving the necessary consent. If the person's capacity to do so is undermined by a neurological disorder, and these criteria cannot be met, then testing should not proceed. Testing in the absence of consent and in the face of incapacity can then only be obtained if necessary, or with the consent of a proxy exercising substituted judgment, or if it is deemed to be in the best interests of the patient. Yet these constructs are unlikely to prove helpful in the present context. For example, in the absence of an effective therapeutic intervention or some other tangible benefit, it is difficult to imagine any situation involving an imperative to carry out a genetic test. Moreover, in light of the questionable benefits of testing for susceptibility genes, it is far from clear that testing would necessarily be in the person's best interests, and a proxy might similarly find it hard to exercise substituted judgment in all good conscience within such a system of disputed value.
Similarly, young children who are incapable of giving informed consent to medical procedures are incapacitated in the eyes of the law and so, as above, can only be treated if it is necessary to do so or if it is in their own best interests (proxy consent is inappropriate here, there being no judgment to substitute). However, to test a child for a condition that does not manifest itself until adulthood and for which there is no effective intervention during childhood is generally thought to be unethical.14 This deprives the child of his or her right to choose for himself or herself what to know, and can lead to adverse consequences if parents treat the child as if she or he were already ill even when the child remains asymptomatic.15 The imperative to protect the child's privacy is all the stronger when testing would reveal nothing more than marginal increases in knowledge about risk. Of course, matters are very different if testing can lead to beneficial treatment. However, a presumption of nontesting and nondisclosure is ethically indicated in these circumstances, requiring those who would test to discharge a burden of proof by offering evidence that it would be more beneficial than not for testing to occur. The Genetic Privacy Act, which was drafted by members of the Department of Health Law at Boston University as a federal initiative in 1995, included measures that embodied protection of minors in this regard.16 However, no legislation along these lines has been implemented to date.
The consequential effects of offering new knowledge to individuals should never be underestimated, even when testing is carried out consensually. Studies show, for example, that adverse psychological sequelae can follow disclosure of test results even when these reveal that a person is not carrying a disease gene, and when the tests in question involve a high degree of accuracy and certainty (such as the test for Huntington disease).17"Survivor guilt" can be a real possibility for nonaffected family members.18 Other forms of psychological harm can result from the uncertain nature of genetic test results, and this is likely to be especially true for persons who are told that they are at increased risk of neurological disorders, however slight. They may suffer trauma and may develop a fatalistic view of their own health status. While genetic disease might remain a slight possibility, a person might nevertheless experience illness as a result of being exposed to genetic information. The interest people might have in not knowing information about themselves should be properly understood and respected.19
Of course, it might be argued that the primary role of the health care professional is to present as accurately as possible the current benefits and limits of technology and testing, and to allow an individual to make up his or her own mind about whether she or he would wish to be tested or to know the results of testing. To do otherwise and decide on the patient's behalf might be seen as paternalistic. However, the principle of respect for autonomy requires only that we respect choices once they are made. It does not require that we facilitate choices. Yet to offer a battery of tests, especially when there is little one can do about adverse test results, is to facilitate choices in individuals. And this, just as much as a decision not to offer those tests, is also a paternalistic gesture. We must be clear about this. Furthermore, to offer testing in many cases can thwart the interest individuals might have in not knowing information about themselves. As Wertz and Fletcher20 have said:
. . . [t]here is no way . . . to exercise the choice of not knowing, because in the very process of asking, "Do you want to know whether you are at risk . . . ?," the geneticist has already made the essence of the information known.
. . . [t]here is no way . . . to exercise the choice of not knowing, because in the very process of asking, "Do you want to know whether you are at risk . . . ?," the geneticist has already made the essence of the information known.
Finally, such an offer might amount to a form of coercion, in that testing is offered with the intention or aim that a particular choice be made. This is in no way a means of respecting individuals.
The attractiveness of genetic testing as a means of facilitating choice is seen most clearly in the context of prenatal testing. Reproductive freedom is often hailed as the value that underpins the claims of prospective parents to have access to a battery of tests to assure themselves of their baby's health. The social implications of allowing unfettered access to testing cannot, however, be ignored: In the absence of an effective therapeutic intervention, a positive test result for a genetic condition or an indication of increased susceptibility to disease facilitates only the choice to continue or to terminate the pregnancy. And though we need not go as far as to restrict a woman's right to choose to continue or terminate her pregnancy, nor should we remain blind to the possibility of coercive uses of genetic testing. While it is likely that large-scale eugenic practices are have been consigned to the annals of history, less obvious but no less invidious policies designed to eliminate the unhealthy or "undesirable" from society may emerge in a piecemeal fashion under the guise of choice and reproductive freedom. Facilitating reproductive decision making by offering choice when the only choice available is between a fetus that has been labeled less than normal and the termination of the pregnancy is for many a choice that cannot be exercised free of undue influence. Indeed, the prospect of large-scale introduction of state or federal screening programs for incurable or immutable conditions betrays an attempt to bring societal influence to bear on a woman's right to choose. The availability of prenatal susceptibility testing would equally send a message that abortion is acceptable even when the risk of disease is minimal, and it ignores other causal factors that often have more to do with disease than genetics. Such testing practices arguably give an illusion of enlightened control, when in fact the only control, at present, is the termination of pregnancy. Furthermore, in circumstances in which such control is not exercised, there is a real risk that women will be stigmatized for their "irresponsible" decisions to carry a "defective" child to term. To label as "bad" those who already suffer from neurological disorders—people already seen by many as "mad" — compounds the cultural phenomenon by which the language we use predisposes us to certain value judgments of persons and their actions. Stigmatization of people with neurological disorders is a significant social problem requiring urgent action. It does not require further fueling of prejudices and misguided applications of genetic knowledge.
This is not to say that valuable work involving these kinds of conditions is not done using genetic knowledge, nor indeed that such research should be halted because of fears about particular uses for which the knowledge might be applied. But an important distinction should always be borne in mind between research applications of genetic knowledge — which will hopefully one day produce treatments — and short-sighted "clinical" uses of genetic knowledge that represent little in the way of actual benefit to patients. While every effort should be made to facilitate research that develops cures and therapies for genetic diseases, we should be wary of encouraging uses of genetic knowledge at an earlier stage in this process, when the direct clinical benefit to those tested is negligible or even nil and the net effect betrays a value-laden judgment of the lives of those who live with genetic disease.
The generation of new genetic information has led to a preoccupation with cause and control. We imagine that because we can discover the cause for a disease, we can ultimately exercise control over it, and when we cannot exercise control, we imagine that we can nevertheless eliminate in other ways the harms that diseases can do, such as by facilitating preparedness. In the clinical setting this is not necessarily an undesirable goal. Outside that setting, however, where one individual's disease can have an impact on the interests of third parties, and when genetic knowledge is seen as a means to minimize or eliminate such harm, then there is much potential for abuse. For example, the perceived predictive value of genetic information has led employers and insurers to seek access to genetic test results and to request testing in circumstances in which the onset of genetic disease is thought to represent a threat to their (financial) interests. Such a view is predicated, however, on a belief that genetic knowledge offers degrees of insight, certainty, and predictability not available from other sources. As we have pointed out, however, the work of the HGP reveals that this is not necessarily true. It is particularly not true of neurological disorders. Cause is always a matter of degree, and a failure to appreciate this can lead to stigmatization and discrimination against those who receive genetic information about themselves. Even if we leave aside the question of the legitimacy of claims by employers and insurers to have access to personal genetic data that may have an impact on their interests (and this is far from assured given the considerable counterimpact that such access can have on individual interests), we should not ignore the legitimization that testing can bring to pre-existing prejudices and beliefs. The confirmation by genetic testing that a person has, or is likely to have, a neurological disorder may be all that is required to give rise to discriminatory practices or stigmatizing behavior among those best placed to significantly injure the interests of individuals who have undergone testing. Accuracy of information has never been a prerequisite for discrimination or stigmatization. Nonaccess to and adequate security of information are therefore the best safeguards against evils such as these. However, as with most problems in the field of genetics, the current law is almost entirely deficient and much remains to be done.
In the search for appropriate responses to advances in human genetics, it is imperative that the disciplines of medicine, science, ethics, and law work together to finding solutions. Most importantly, the professionals of each of these disciplines have obligations to society at large to ensure that their knowledge, experience, and skills are brought to bear on the entire enterprise with as much utility as possible. The Decade of the Brain has generated considerable amounts of new knowledge about the biology and genetics of neurological and psychiatric diseases. Those lessons must not go unheard within the wider professional and lay communities, where the starting point of good ethical and legal responses to genetics is found in well-informed debate about the kind of society we want for ourselves and for those who will inherit it from us.
Accepted for publication April 4, 2000.
Corresponding author: Graeme T. Laurie, PhD, Visiting Scholar, Department of Health Law, School of Public Health, Boston University and Lecturer in Law, University of Edinburgh, Edinburgh Law School, Faculty of Law, University of Edinburgh, Old College, South Bridge, Edinburgh EH8 9YL, Scotland (e-mail: Graeme.Laurie@ed.ac.uk).