H U M A N G E N E T H E R A P Y 1:425-433 (1990) Mary Ann Liebert, Inc., Publishers
The N I H
" P o i n t s to C o n s i d e r " a n d t h e L i m i t s
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of H u m a n
Gene
Therapy
ERIC T. JUENGST
ABSTRACT In this essay, I examine the sources and reach of the N I H "Points to Consider." These guidelines are based on normative considerations inherited from two sets of science policy deliberations that took place in the United States during the 1970s: the discussion of research with h u m a n subjects and the recombinant D N A debate. T h e combined lessons of those deliberations provide six criteria by which to evaluate h u m a n gene therapy proposals. While these criteria could be used to reject proposals to attempt germ-line gene therapy or enhancement engineering today, they provide no principled basis for publicly proscribing the development of these forms of genetic intervention. Instead, they will ultimately lead us to approach the moral limits of gene therapy as a professional policy question about the goals of medicine, rather than as a social policy question about the public good.
OVERVIEW S U M M A R Y The Points to Consider document (see Hum. Gene Ther. 1, 93-102,185-189) was written in the mid 1980s to provide guidance in the review of h u m a n gene therapy clinical protocols. It has stood the test of time well. Juengst examines this document, and analyzes the historical roots that influenced its creation and content and the framework it provides in reviewing gene therapy protocols. H e then reflects on the directions that policy/ethical discussions are likely to go.
INTRODUCTION The ethics of "human genetic engineering" has been a standard topic in bioethics for the last 20 years. Its discussion, however, has followed an unusual course. It has resembled neither the steady movement of deliberations over the limits of life-sustaining treatment, nor the persistent occlusiveness of the abortion debate. Instead, bioethical deliberations about gene therapy have cycled through two very different active phases, separated by almost a decade of relative silence. Several observers have already begun to sketch this natural history from different perspectives (cfi, Areen, 1985-1986; Fletcher, 1990; Murray, 1990). In this essay I use it to illuminate the ethical context ofthe discussion's most recent critical node: the development of the NIH's "Points to Consider" (Subcommittee on H u m a n Gene Therapy, 1990). I argue that, when faced with the next phase of the gene therapy discussion—bioethical deliberations over germ-line interventions and
The National Center for Human Genome Research, Human Genome Program, Ethics Office, National Institutes of Health, Bethesda, M D 20892. 425
JUENGST enhancement engineering—the ethical framework informing that document will lead us to interpret the moral limits of gene therapy as functions of the goals of medicine, rather than as matters of public science policy.
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T H E E M E R G E N C E OF A N ETHICAL F R A M E W O R K FOR H U M A N G E N E THERAPY One ofthe most striking features ofthe bioethical literature on human gene therapy is the metamorphosis it underwent between the early 1970s and the 1980s. The first wave of writing, at the "threshold" of the discussion in the yearsflanking1970 (Fletcher, 1990), was characterized both by awe in the face ofthe knew biology,' and by a sense of being ethically disoriented by its prospects. For example, Paul Ramsey sums up the topic during this period by saying "Before us, then, opens up the dizzy, abysmal prospect that m e n can be present where the foundations of the world were laid" (Ramsey, 1972). This literature's response to these challenges was a sweeping reach of reflection that quickly took authors to questions of theology, philosophical anthropology and social philosophy in search of moral bearings (cfi, Ramsey, 1970; Fried, 1973; Gustafson, 1973). M u c h of this early work is still fresh and valuable at those deeper levels, but it was difficult to translate into practical policies for scientific research. Instead, the prominence of human gene therapy in the bioethics literature faded dramatically during the 1970s, in favor of more tractable questions of clinical medical ethics and health policy. B y the end of the decade, observers even began asking about the future of genetic engineering's career as a bioethical topic (Callahan, 1979). In fact, however, the discussion of human gene therapy rebounded quickly in the early 1980s. It was driven by the news of Martin Cline's experiment (Kolata and W a d e , 1980) and lured by the prospect of coming clinical trials for somatic cell gene therapy at N I H (Anderson and Fletcher, 1980). This second generation of literature is captured best by the reports on the topic by the President's Commission (1983) and the Office of Technology Assessment (1984), and culminates in the NIH's "Points to Consider." In this literature, the community no longer seems ethically disoriented by the issues it faces. Instead, authors are actively about the business of specifying the criteria and questions to use in evaluating proposals to conduct gene therapy experiments. In fact, as Alex Capron points out, the literature could suddenly provide a "framework for action" robust enough to reassure m a n y of those still harboring the kinds of concerns that Ramsey expressed (Capron, 1990). The literature seemed to have gained a moral compass that could allow its authors to get their bearings in the n e w biology without having to triangulate against deep questions of individual belief. A s a result, Capron writes: "From the present vantage point, it m a y be hard to remember that in 1980, when the Commission began its work, critics (including respected religious groups) argued that "fundamental dangers" were posed by any alteration of human genes" (Capron, 1990). The sudden development of this "framework for action" with respect to human gene therapy is interesting, because it does not seem to have its origins within the older literature on "human genetic engineering." Instead, it is the hybrid product of two (largely successful and strikingly parallel) sets of national bioethical deliberations that occurred during the 1970s: the discussion of biomedical research with h u m a n subjects and the debate over the uses of recombinant D N A technology (cfi Areen, 1985-1986). Neither of these discussions were conducted with human gene therapy in mind, but together they provided the authors of the 1980s with a repetoire of widely recognized and well-grounded relevant moral considerations that was simply unavailable to the authors ofthe first phase. The separate stories of those two policy-making episodes have been told in detail elsewhere (cfi Krimsky, 1982; Levine, 1986). Both episodes were inaugurated in 1972, by the public revelation of the infamous Tuskeegee Syphilis Study on the one hand, and the announcement, on the other, of the invention of the recombinant D N A technique by Stanley Cohen and Paul Berg. The Tuskeegee revelation lead to Congressional concern about the conduct of research with human subjects which resulted, in 1974, in the 426
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T H E N I H POINTS T O C O N S I D E R establishiment of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. The Cohen and Berg announcement stimulated a prospective assessment oftherisksof recombinant D N A research by the scientific community that resulted, also in 1974, with the establishment of the Recombinant D N A Advisory Committee ( R A C ) at the N I H to develop guidelines for this work. Beginning in 1976, both entities began to publish guidelines and reports that would come to be the primary sources of regulation for these forms of research. With the formation of the RAC's Working Group on H u m a n Gene Therapy, these two histories came together, bringing with them the moral considerations that had become central to their separate developments. Collectively, these considerations n o w form the ethical framework against which protocols for somatic cell gene therapy are n o w being evaluated. They will also form an important context for the next phase of deliberations: what to do about germ line and enhancement applications of gene therapy techniques. T o that extent, they also suggest the direction that deliberations about the limits of h u m a n gene therapy should move.
T H E ETHICAL F R A M E W O R K OF THE "POINTS T O CONSIDER" Because of its stark form as a set of review questions, the NIH "Points to Consider" display the ethical framework that gene therapy inherited from the 1970s particularly clearly. This framework can be distilled into six sets of moral considerations. From the discussion of research with human subjects came concerns about clinical benefits, informed consent, and fair subject selection, while from the recombinant D N A debate came considerations of biosafety, public oversight, and long-rangerisks.These considerations seem to work together well in the assessment of somatic cell gene therapy protocols. But, as w e shall see, they also carry some internal tensions that will become exacerbated as they are brought to bear on the limits of gene therapy. The moral considerations stemming from the development of human subjects research regulations are easiest to articulate, since that national project ended with an explicit enunciation of its guiding principles in a form that has become canonical for discussions of human subjects research ethics (National Commission, 1978). Considerations reflecting each of those principles are explicitly evident in the "Points to Consider" document: 1. Concern for clinical benefit to the subject. This consideration reflects a committment to the regulatory principle that "risks to the subjects [must be] reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that m a y be reasonably be expected to result." (45 C F R , Section 46.11 la). Thus, the R A C says in the introduction to its "Points to Consider": In their evaluation of proposals involving the transfer of recombinant D N A into human subjects, the R A C and its subcommittee will consider whether the design of such experiments offers adequate assurance that their consequences will not go beyond their purpose, which is the same as the traditional purpose of all clinical investigations, namely to protect the health and well-being of individual subjects being treated while at the same time gathering generalizable knowledge (Subcommittee, 1990, p. 96). This element of the framework received the most attention in the Points to Consider document, and has dominated the discussions of gene therapy that have been conducted under it. In practice, it means that prospective gene therapists must have enough prior knowledge to believe that the probable benefits to the patient/subject outweigh both the possiblerisksof the experiment and the known benefits of the alternative treatments available. Thus, it lies behind the document's questions about, and the community's discussion of, the safety and efficacy of somatic cell gene therapy techniques (cfi Anderson and Fletcher, 1980; Temin, 1990), the adequacy of preliminary animal studies (Anderson et aL, 1986; Cornetta et al., 1990; Osborne etaL, 1990) and the relative value ofthe emerging therapeutic alternatives (Blaese etal., 1990). 427
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JUENGST 2. Concerns about the free and informed participation of subjects. Since Nuremburg, the biomedical research community has accepted an increasingly strong obligation to insure that the participation of patients in research protocols is voluntary and informed (Faden and Beauchamp, 1986). In its deliberations, the National Commission underscored the need for special protections w h e n research subjects are enlisted on the strength of "proxy consent" by others. The Commission's distinction between parental "permission" and the "assent" of minor research subjects, and its insistence on both, are explicitly reiterated in the section of the "Points to Consider" that asks researchers to "indicate h o w patients will be informed about the proposed study and h o w their consent will be solicited.77 (Subcommittee, 1990, p. 100). 3. Concerns about fair subject selection. The development of national policies for research with h u m a n subjects during the 1970s was motivated in part by a concern that the burdens of participating in nontherapeutic biomedical research were distributed unfairly a m o n g particularly vulnerable populations within society—concerns that do not arise in the therapeutic context of the "Points to Consider," where the study population will be defined by the target disease. However, the scarcity of any developing gene therapy techniques poses distributive questions of its own: questions about fair access to the potential benefits of research participation. A s L e R o y Walters notes: With rare genetic diseases, although the potential patient pool will be small, choices will need to be m a d e from a m o n g multiple candidates. Thus, fairness in the selection of subjects m a y be an important issue even in the earliest trials of h u m a n gene therapy (Walters, 1986). Thus, the "Points to Consider" includes instructions to investigators to "describe recruitment procedures and patient eligibility requirements, paying particular attention to whether these procedures and requirements are fair and equitable" (Subcommittee, 1990, p. 100). A s prominent as the three sets of h u m a n subjects research considerations are a m o n g the R A C ' s "Points to Consider," the considerations that reflect its o w n institutional history as a product of the recombinant D N A debate are no less evident. The guiding considerations of that debate have never been as clearly codified as the h u m a n subjects research concerns. But the three reflected in the R A C ' s deliberations all flow from the two themes that informed it: a recognition ofthe special nature of research with recombinant D N A molecules and an effort to evaluate genetic research within its wider social and environmental context. 4. The needfor special "biosafety" precautions in face of genetic uncertainty. O n e of the striking legacies of the recombinant D N A debate is the acceptance of the need to prepare for unforeseen as well as predictable risks in designing molecular genetic research (cfi Cohen, 1979). Thus, for example, scientific authors still write that: There are often unexpected effects of n e w technologies. . . The use of retrovirus vectors for somatic therapy of h u m a n genetic diseases can be looked upon as either a novel improvement on present means of drug delivery or as the introduction of potentially dangerous technology. Although scientists and physicians m a y believe thefirstcharacterization is correct, I a m convinced that w e must act as if the second characterization is correct. W e must design vector systems and protocols so that even quite unrealistic fears about safety are allayed (Temin, 1990). A s this quotation suggests, in the discussion of gene therapy this concern has focused on anticipating possible risks involved in the delivery and integration of exogenous D N A into the subject's cells, and on designing viral vector systems that will avoid theserisks(Anderson, 1984). In the "Points to Consider," the bulk of the risk assessment questions posed to investigators are designed to address just these concerns (Subcommittee, 1990, pp. 97-99). 5. The need for public participation in genetic research policy. It was in the context of the recombinant D N A debate that m a n y of the early, inchoate concerns about the implications of genetic research began to be laid to rest (cfi Stich, 1979). B y the time the President's Commission's Splicing Life report criticized worries about "playing God," "violating evolutionary wisdom," and "stealing forbidden knowledge," both the 428
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T H E NIH POINTS T O CONSIDER analytic arguments and the practical experience it used had been worked out in the course of discussing, developing, and implementing the R A C and the N I H Guidelines for r D N A research. Nevertheless, a recurrent theme from both those arguments and that experience was the importance of public participation in science policy decisions of this sort (Schmeck, 1986). A s one commentator put it: "The principle of democratic oversight is basic to our society, and its application is essential for producing popular information and popular decisions. The social consequences ofthe recombinant D N A technology are too enormous and important to be left to specialists alone" (Nader, 1986, p. 159). The establishment ofthe R A C itself and the review process which the "Points to Consider" guide are both basic manifestations of this continuing committment to public oversight in this area. The "Points" continue the tradition in several ways: by requiring the publication of protocols for public comment prior to N I H review; by conducting proposal review publicly; and by instructing investigators to address two "special issues" "beyond the normal purview of local IRBs," concerning their plans to "ensure that accurate and appropriate information is m a d e available to the public with respect to such public concerns as m a y arise from the proposed study" (Subcommittee, 1990, p. 101). 6. The need to consider broad and long range research consequences. Finally, a third legacy of the r D N A controversy is the imperative to consider the possible impact of any gene therapy research on other people beside the research subject. Here, the public health, environmental, and evolutionary concerns debated during the discussion of gene transfer experiments with E. coli are echoed as concerns about the nosocomial dangers, social costs, and dysgenic effects of gene therapy. Thus, the literature argues that: The n e w therapy should not result in harm to the general population. W e need to consider the possibility for formation of a novel and infectious virus during somatic cell gene therapy of h u m a n disease with retrovirus vectors, the costs of such therapy, the possible evolutionary effects of such therapy (by means such as inadvertent infection ofthe patient's germ-line), and unforeseen complications (Temin, 1990). "Accordingly," the Points to Consider conclude on this score, "this document requests information that will enable the R A C and its Subcommittee to assess the possibility that the proposed experiments will inadvertantly affect reproductive cells or lead to infection of other people" (Subcommittee, 1990, p. 96). In some respects, the Points' two complements of ethical considerations fold together nicely: Biosafety considerations are just specifications of general concerns for clinical benefit, informed public oversight is a logical extension of informed participation by subjects, and one way to frame concerns about extended risks is as a problem of distributing research burdens and benefits fairly across populations. Nevertheless, they do differ importantly in orientation: The ethic of human subjects research is committed to protecting the interests ofthe individual patient/subject, while the r D N A offers considerations on behalf of the greater public health. A s w e shall see, that difference leaves the "Points to Consider" ill-equipped to establish the commonly accepted moral limits of gene therapy as public policy. Instead, I argue, the R A C will ultimately have to cede the definition and defense of those limits to the medicine, as a function of that profession's o w n goals.
GERM-LINE GENE THERAPY, ENHANCEMENT ENGINEERING, A N D T H E POINTS T O CONSIDER Most ofthe practical work ofthe second phase of bioethical deliberations over human gene therapy has been devoted to the discussion and evaluation of somatic cell gene therapies. A s a result, the other logically possible forms of h u m a n genetic engineering—germ-line gene therapies and enhancement engineering (of either somatic or germ-line cells)—have been left comparatively underdiscussed. The "Points to Consider," like other recent statements (Danielson, 1988) simply assert that "the R A C and its Subcommittee will not at present entertain proposals for germ line alterations" (1990, p. 95). They are completely silent on enhancement engineering (though their first version did ask investigators to assess the likelihood that somatic 429
JUENGST
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cell therapy would lead to "the enhancement of human capabilities through genetic means" (DHHS, 1985). As new work on both these fronts suggest, however, it will be these topics, and the limits to gene therapy they are taken to mark, which will preoccupy the third, emerging generation of bioethical deliberations over this technology (cfi Anderson, 1989; Fowler etal., 1989). The "Points'" current ban on germ-line gene therapy proposals probably rests on a combination of concerns about clinicalrisksand biohazards, research involving preembryonic subjects of uncertain moral status, and long-rangeriskto future generations. The arguments against attempting germ-line gene therapy in the face of our current low levels of relevant moral insight, scientific knowledge, and technical expertise are persuasive (Fowler etal., 1989). However, if the case against germ-line intervention is exhausted by therisksof clinical and genetic accidents and the morally uncertain status of preembryos, then it is not a line that can be drawn in principle and forever. Clinical and geneticrisks,even multigenerational ones, are problems that can succumb to new knowledge. The development of tissue-targeted vector systems might eventually make the germ-line (i.e., reproductive) cells of adults accessible, avoiding the need to manipulate preembryos (Lavitrano et aL, 1989). In this far future, the only complaint the RAC's descendents might bring against a germ-line gene therapy proposal is that it does indeed "attempt to introduce genetic changes into the germ (reproductive) cells of an individual, with the aim of changing the set of genes passed on to the individual's offspring" (Subcommittee, 1990). That is, it would run afoul of the "Points'" sixth concern not to endanger the (yet unknown) genetic interests of future populations by knowingly modifying their genetic resources. But under these conditions, the patient-centered ethic of clinical research and the public health ethic begin to disassociate themselves within the framework ofthe Points. In this scenario, the germ-line therapy would be an attempt to help an individual—the adult subject of the therapy—overcome a reproductive health problem: theriskhe or she faces of conceiving children with a genetic disease. That is, the subject would be in the same position as a patient requesting the aid of genetic counseling or prenatal diagnosis to address the same reproductive problem. In those situations, the interests ofthe gene pool are given lower priority than the considered value judgements of the presenting patient, for a number of good professional, ethical, and epistemic reasons (Juengst, 1989). To do otherwise, i.e., to protect the interests ofthe future by prohibiting potentially dysgenic actions by the patient, is to subscribe to a coercive form of eugenics. This is equally true whether the prohibited parental choice involves perpetuating, through child-bearing, a potentially deleterious gene or deleting, through gene therapy, a potentially adaptive one. As some observers now acknowledge, The benefits [of germline gene therapy] to the treated individual could be dramatic and immediate, while the possible harms are indirect, quantitatively insignificant, and could be avoided by future reproductive choices. It makes little sense to foreclose a therapeutic option to preserve the "human germ plasm" or to prevent some other vaguely unsettling but unspecified consequence (Cook-Deegan, 1990, p. 169).
Although the line against enhancement engineering can be more firmly drawn by the moral resources ofthe "Points," the arguments they provide still face a similar problem. The primary danger of enhancement engineering, once it is safe and effective, is also itsrisksto other people beyond the subject. However, the mainrisksof enhancement engineering are not so much its possible dysgenic effects on future generations as its immediate effects on the social health of the subject's contemporaries. Enhancement engineering, by associating desirable physical traits with socioeconomic access to this form of health care, would exacerbate for others the very problems of social inequality it would be intended to address in the subject. As Areen and King point out, "If enhancement engineering ever does move from the realm of science fiction into science fact, extremely serious issues of access to and fair distribution of such possibilities will arise" (Areen and King, 1990). In the face of its mandate to consider these issues of fairness, the R A C might justifiably disapprove proposals for enhancement engineering, on the grounds that its benefits could not be distributed fairly across variously vulnerable populations, and would only serve to magnify current social inequalities. 430
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T H E NIH POINTS T O C O N S I D E R On the other hand, the social risks of enhancement engineering, like its clinical risks, still only provide contingent barriers to the technique. In a society structured to allow the realization of our moral commitment to social equality in the face of biological diversity—that is, for a society in which there was both open access to this technology and no particular social advantage to its use—these problems would show themselves to be the side issues they really are. In such a society (perhaps even further from our o w n than the one in which germ-line gene therapy becomes feasible) where the question before the R A C is the bare question of whether it is ever appropriate to use medical technology to enhance an individual's traits, the "Points" would provide no guidance. Like the question of whether the 'reproductive health problems' that genetic counselor's address are proper problems for medicine, the problem of enhancement engineering falls through the ethical framework of that public policy document, into the hands of the practioners themselves.
T H E LIMITS O F G E N E THERAPY A N D T H E GOALS OF MEDICINE The day when public concerns regarding the limits of human gene therapy are moot is clearly a long way off. However, in principle at least, the definition of those limits should be as m u c h a challenge for medicine as society, because the questions it poses are ultimately questions about the profession's goals: W h a t sort of 'reproductive health problems' fall within the province of medicine? For example, does medicine's commitment to 'help people have healthy babies' depend on any professional particular understanding of "health"? Where do 'medical indications' for treatment stop and 'patients' preferences' begin in the context of reproductive health care? For example, would ever be appropriate, in the absence of any social advantage, to increase the height of a short normal patient? These are questions on which society can have tremendous influence, because they partly turn on the social role that health professionals are asked to play. But they are ultimately questions for professional conscience and vision, not public policy. Fortunately, they are also questions that, unlike the techniques themselves, are already available for analysis in multiple, less exotic variants (cfi. Kass, 1981; Underwood and Sherman, 1986; Juengst, 1988; Asch, 1989). T o prepare for the discussion of the limits of h u m a n gene therapy that one would eventually like to have, it is in the direction of these professional reflections about the meaning of health care that the gene therapy literature should n o w move.
ACKNOWLEDGMENTS Ancestral versions of this paper have been delivered at Stanford University, the University of San Francisco, and Kutztown University. Support for the research project which stimulated it was provided by a grant from the Ethics and Values Studies Program ofthe National Science Foundation (RII-8511073), with cofunding from the National Institute of Child Health and Development. The views expressed here do not necessarily express the views of N S F or N I H .
REFERENCES ANDERSON, W.F. (1984). Prospects for human gene therapy. Science 226,401-409. A N D E R S O N , W.F., and F L E T C H E R , J.C. (1980). Gene therapy in human beings: When is it ethical to begin? N. Engl. J. Med. 303, 1293-1297. A N D E R S O N , W.F., (1989). Human gene therapy: W h y draw a line? J. Med. Philos. 14,681-695. A N D E R S O N , W.F., K A N T O F F , P., EGLITIS, M., etal. (1986). Gene transfer and expression in nonhuman primates using retroviral vectors. Cold Spring Harbor Symp. Quant. Biol. 51,1065-1073. A R E E N , J. (1985-1986). Regulating human gene therapy. W . Virginia Law Rev. 88, 153. 431
Human Gene Therapy 1990.1:425-433. Downloaded from online.liebertpub.com by Childrens Hospital on 12/09/14. For personal use only.
JUENGST AREEN, J., and KING, P. (1990). Legal regulation of human gene therapy. Hum. Gene Ther. 1, 151-161. ASCH, A. (1989). Reproductive technology and disability. In Reproductive Laws for the 1990s. S. Cohen and N. Taub, eds. (Humana Press, Clifton, NJ), pp. 69-124. BLAESE, R.M., C U L V E R , K., and A N D E R S O N , W.F. (March 29, 1990) Submission of Responses to Subcommittee Review (unpublished memorandum to Nelson Wivel, NIH Office of Recombinant D N A Activities). C A L L A H A N , D. (1979). The moral career of genetic engineering. Hastings Center Rep. 9, 21. C A P R O N , A.M. (1990). The impact ofthe report, Splicing Life. Human Gene Ther. 1, 69-73. C O H E N ,C.(1979)Onthe dangers of inquiry and the burden of proof. In The Recombinant D N A Debate D. Jackson and S. Stich, eds. (Prentice-Hall, Englewood Cliffs, NJ) pp. 303-337. C O O K - D E E G A N , R.M. (1990). Human gene therapy and Congress. Human Gene Ther. 1, 163-170. C O R N E T T A , K., M O E N , R.C., C U L V E R , K., et al. (1990). Amphotropic murine leukemia retrovirus is not an acute pathogen for primates. Human Gene Ther. 1, 15-31. DANIELSON, H. (1988). Gene therapy in man: Recommendations ofthe European medical research councils. Lancet i, 1271-1272. D H H S . (Jan. 22, 1985). Recombinant D N A Research; Request for Public Comment on "Points to Consider in the Design and Submission of Human Somatic Cell Gene Therapy Protocols." Fed. Reg. 50, 2940-2945. F A D E N , R., and B E A U C H A M P , T. (1986). A History and Theory of Informed Consent. (Oxford University Press, New York). FLETCHER, J.C. (1990). Evolution of ethical debate about human gene therapy. Human Gene Ther. 1, 55-69. F O W L E R , G., JUENGST, E., and Z I M M E R M A N , B. (1989). Germ-line gene therapy and the clinical ethos of medical genetics. Theoret. Med. 10, 151-165. FRIED, C. (1973). The need for a philosophical anthropology. In Ethical Issues in Human Genetics. B. Hilton et al., eds. (Plenum Press, New York) pp. 261-267. G U S T A F S O N , J.M. (1973). Genetic engineering and the normative view ofthe human. In Ethical Issues in Biology and Medicine P. Williams, ed. (Schenkman Pub. Co., Cambridge, M A ) pp. 46-59. JUENGST, E. (1988). Prenatal diagnosis and the ethics of uncertainty. In Medical Ethics: A Guide for Health Professionals. J Monagle and D. Thomasma, eds. (Aspen Pub., Rockville, M D ) pp. 12-25. JUENGST, E. (1989). Patterns of reasoning in medical genetics. Theoret. Med. 10, 101-107. KASS, L. (1981). The pursuit of health and the end of medicine. In Concepts of Health and Disease: Interdisciplinary Perspectives A. Caplan, H.T. Engelhardt, and J. McCartney, eds. (Addison-Wesley, New York) pp. 3-31. K O L A T A , G., and W A D E , N. (1980). Human gene treatment stirs new debate. Science 210,407. K R I M S K Y , S. (1982). Genetic Alchemy: The Social History of the Recombinant D N A Controversy (MIT Press, Cambridge, M A ) . L A V I T R A N O , M., C A M A I A N O , A., FAZIO, V., et al. (1989). Sperm cells as vectors for introducing foreign D N A into eggs: Genetic transformation of mice. Cell 57, 717-723. LEVINE, R.J. (1986). Ethics and Regulation of Clinical Research (2nd Edition). (Urban & Schwarzenberg, Baltimore). M U R R A Y , T.H. (1990). Human gene therapy, the public and public policy. Human Gene Ther. 1, 49-55. N A D E R , C. (1986). Technology and democratic control: The case of recombinant D N A . In R. Zilinskas and B. Zimmerman, eds. The Gene Splicing Wars: Reflections on the Recombinant D N A Controversy (Macmillan Pub. Co., New York) pp. 139-167. N A T I O N A L C O M M I S S I O N F O R T H E PROTECTION O F H U M A N SUBJECTS O F B I O M E D I C A L A N D B E H A V IORAL RESEARCH. (1978). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. D H E W Publication No (OS) 78-0013. (US Government Printing Office, Washington, DC). OFFICE O F T E C H N O L O G Y ASSESSMENT. (1984). Human Gene Therapy: A Background Paper. (US Government Printing Office, Washington DC). OTA-BP-BA-32. O S B O R N E , W.R.A., H O C K , R.A., K A L E K O , M., etal. (1990). Long-term expression of human adenosine deaminase in mice after transplantation of bone marrow infected with amphotropic retroviral vectors. Human Gene Ther. 1, 31-43. PRESIDENT'S C O M M I S S I O N FOR T H E S T U D Y O F ETHICAL P R O B L E M S IN MEDICINE A N D B I O M E D I C A L A N D B E H A V I O R A L RESEARCH. (1983). Splicing Life. (US Government Printing Office, Washington, DC). R A M S E Y , P. (1970). Fabricated Man: The Ethics of Genetic Control (Yale University Press, New Haven, CT). R A M S E Y , P. (1972). Genetic therapy: A theologian's response. In: The New Genetics and the Future of Man. M . Hamilton ed. (Wb Eerdmans, Grand Rapids, MI) pp. 157-179. S C H M E C K , H. (1986). Recombinant D N A controversy: The right to know—and to worry. In The Gene-Splicing Wars: Reflections ofthe Recombinant D N A Controversy. R. Zilinskas and B. Zimmerman, eds. (MacMillan Publishing Co New York) pp. 93-109. STICH, S. (1979). The recombinant D N A debate: some philosophical considerations. In: The Recombinant D N A Debate. D. Jackson and S. Stich, eds. (Prentice Hall, Inc., Englewood Cliffs,) 183-203. 432
T H E NIH POINTS T O CONSIDER SUBCOMMITTEE ON HUMAN GENE THERAPY, RECOMBINANT DNA ADVISORY COMMITTEE, NATIONAL INSTITUTES OF HEALTH (1990). Points to consider in the design and submission of protocols for the transfer of recombinant D N A into the genome of human subjects. Human Gene Ther. 1, 93-103. TEMIN, H.T. (1990). Safety considerations in somatic gene therapy of human disease with retrovirus vectors, Human Gene Ther. 1,111-123. U N D E R W O O D , L., and S H E R M A N , B. (1986). Controversies in the treatment of short stature. In Human Growth Hormone: Progress and Challenges. L. Underwood, ed. (Marcel Dekker, Inc., N e w York) pp. 145-178. W A L T E R S , L. (1986). The ethics of human gene therapy. Nature 320, 225-227.
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Address reprint requests to: Eric T. Juengst, Ph.D. 9510 Ewing Drive Bethesda, M D 20817 Received for publication September 28, 1990; accepted after revision October 11, 1990.
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The N I H
" P o i n t s to C o n s i d e r " a n d t h e L i m i t s
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of H u m a n
Gene
Therapy
ERIC T. JUENGST
ABSTRACT In this essay, I examine the sources and reach of the N I H "Points to Consider." These guidelines are based on normative considerations inherited from two sets of science policy deliberations that took place in the United States during the 1970s: the discussion of research with h u m a n subjects and the recombinant D N A debate. T h e combined lessons of those deliberations provide six criteria by which to evaluate h u m a n gene therapy proposals. While these criteria could be used to reject proposals to attempt germ-line gene therapy or enhancement engineering today, they provide no principled basis for publicly proscribing the development of these forms of genetic intervention. Instead, they will ultimately lead us to approach the moral limits of gene therapy as a professional policy question about the goals of medicine, rather than as a social policy question about the public good.
OVERVIEW S U M M A R Y The Points to Consider document (see Hum. Gene Ther. 1, 93-102,185-189) was written in the mid 1980s to provide guidance in the review of h u m a n gene therapy clinical protocols. It has stood the test of time well. Juengst examines this document, and analyzes the historical roots that influenced its creation and content and the framework it provides in reviewing gene therapy protocols. H e then reflects on the directions that policy/ethical discussions are likely to go.
INTRODUCTION The ethics of "human genetic engineering" has been a standard topic in bioethics for the last 20 years. Its discussion, however, has followed an unusual course. It has resembled neither the steady movement of deliberations over the limits of life-sustaining treatment, nor the persistent occlusiveness of the abortion debate. Instead, bioethical deliberations about gene therapy have cycled through two very different active phases, separated by almost a decade of relative silence. Several observers have already begun to sketch this natural history from different perspectives (cfi, Areen, 1985-1986; Fletcher, 1990; Murray, 1990). In this essay I use it to illuminate the ethical context ofthe discussion's most recent critical node: the development of the NIH's "Points to Consider" (Subcommittee on H u m a n Gene Therapy, 1990). I argue that, when faced with the next phase of the gene therapy discussion—bioethical deliberations over germ-line interventions and
The National Center for Human Genome Research, Human Genome Program, Ethics Office, National Institutes of Health, Bethesda, M D 20892. 425
JUENGST enhancement engineering—the ethical framework informing that document will lead us to interpret the moral limits of gene therapy as functions of the goals of medicine, rather than as matters of public science policy.
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T H E E M E R G E N C E OF A N ETHICAL F R A M E W O R K FOR H U M A N G E N E THERAPY One ofthe most striking features ofthe bioethical literature on human gene therapy is the metamorphosis it underwent between the early 1970s and the 1980s. The first wave of writing, at the "threshold" of the discussion in the yearsflanking1970 (Fletcher, 1990), was characterized both by awe in the face ofthe knew biology,' and by a sense of being ethically disoriented by its prospects. For example, Paul Ramsey sums up the topic during this period by saying "Before us, then, opens up the dizzy, abysmal prospect that m e n can be present where the foundations of the world were laid" (Ramsey, 1972). This literature's response to these challenges was a sweeping reach of reflection that quickly took authors to questions of theology, philosophical anthropology and social philosophy in search of moral bearings (cfi, Ramsey, 1970; Fried, 1973; Gustafson, 1973). M u c h of this early work is still fresh and valuable at those deeper levels, but it was difficult to translate into practical policies for scientific research. Instead, the prominence of human gene therapy in the bioethics literature faded dramatically during the 1970s, in favor of more tractable questions of clinical medical ethics and health policy. B y the end of the decade, observers even began asking about the future of genetic engineering's career as a bioethical topic (Callahan, 1979). In fact, however, the discussion of human gene therapy rebounded quickly in the early 1980s. It was driven by the news of Martin Cline's experiment (Kolata and W a d e , 1980) and lured by the prospect of coming clinical trials for somatic cell gene therapy at N I H (Anderson and Fletcher, 1980). This second generation of literature is captured best by the reports on the topic by the President's Commission (1983) and the Office of Technology Assessment (1984), and culminates in the NIH's "Points to Consider." In this literature, the community no longer seems ethically disoriented by the issues it faces. Instead, authors are actively about the business of specifying the criteria and questions to use in evaluating proposals to conduct gene therapy experiments. In fact, as Alex Capron points out, the literature could suddenly provide a "framework for action" robust enough to reassure m a n y of those still harboring the kinds of concerns that Ramsey expressed (Capron, 1990). The literature seemed to have gained a moral compass that could allow its authors to get their bearings in the n e w biology without having to triangulate against deep questions of individual belief. A s a result, Capron writes: "From the present vantage point, it m a y be hard to remember that in 1980, when the Commission began its work, critics (including respected religious groups) argued that "fundamental dangers" were posed by any alteration of human genes" (Capron, 1990). The sudden development of this "framework for action" with respect to human gene therapy is interesting, because it does not seem to have its origins within the older literature on "human genetic engineering." Instead, it is the hybrid product of two (largely successful and strikingly parallel) sets of national bioethical deliberations that occurred during the 1970s: the discussion of biomedical research with h u m a n subjects and the debate over the uses of recombinant D N A technology (cfi Areen, 1985-1986). Neither of these discussions were conducted with human gene therapy in mind, but together they provided the authors of the 1980s with a repetoire of widely recognized and well-grounded relevant moral considerations that was simply unavailable to the authors ofthe first phase. The separate stories of those two policy-making episodes have been told in detail elsewhere (cfi Krimsky, 1982; Levine, 1986). Both episodes were inaugurated in 1972, by the public revelation of the infamous Tuskeegee Syphilis Study on the one hand, and the announcement, on the other, of the invention of the recombinant D N A technique by Stanley Cohen and Paul Berg. The Tuskeegee revelation lead to Congressional concern about the conduct of research with human subjects which resulted, in 1974, in the 426
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T H E N I H POINTS T O C O N S I D E R establishiment of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. The Cohen and Berg announcement stimulated a prospective assessment oftherisksof recombinant D N A research by the scientific community that resulted, also in 1974, with the establishment of the Recombinant D N A Advisory Committee ( R A C ) at the N I H to develop guidelines for this work. Beginning in 1976, both entities began to publish guidelines and reports that would come to be the primary sources of regulation for these forms of research. With the formation of the RAC's Working Group on H u m a n Gene Therapy, these two histories came together, bringing with them the moral considerations that had become central to their separate developments. Collectively, these considerations n o w form the ethical framework against which protocols for somatic cell gene therapy are n o w being evaluated. They will also form an important context for the next phase of deliberations: what to do about germ line and enhancement applications of gene therapy techniques. T o that extent, they also suggest the direction that deliberations about the limits of h u m a n gene therapy should move.
T H E ETHICAL F R A M E W O R K OF THE "POINTS T O CONSIDER" Because of its stark form as a set of review questions, the NIH "Points to Consider" display the ethical framework that gene therapy inherited from the 1970s particularly clearly. This framework can be distilled into six sets of moral considerations. From the discussion of research with human subjects came concerns about clinical benefits, informed consent, and fair subject selection, while from the recombinant D N A debate came considerations of biosafety, public oversight, and long-rangerisks.These considerations seem to work together well in the assessment of somatic cell gene therapy protocols. But, as w e shall see, they also carry some internal tensions that will become exacerbated as they are brought to bear on the limits of gene therapy. The moral considerations stemming from the development of human subjects research regulations are easiest to articulate, since that national project ended with an explicit enunciation of its guiding principles in a form that has become canonical for discussions of human subjects research ethics (National Commission, 1978). Considerations reflecting each of those principles are explicitly evident in the "Points to Consider" document: 1. Concern for clinical benefit to the subject. This consideration reflects a committment to the regulatory principle that "risks to the subjects [must be] reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that m a y be reasonably be expected to result." (45 C F R , Section 46.11 la). Thus, the R A C says in the introduction to its "Points to Consider": In their evaluation of proposals involving the transfer of recombinant D N A into human subjects, the R A C and its subcommittee will consider whether the design of such experiments offers adequate assurance that their consequences will not go beyond their purpose, which is the same as the traditional purpose of all clinical investigations, namely to protect the health and well-being of individual subjects being treated while at the same time gathering generalizable knowledge (Subcommittee, 1990, p. 96). This element of the framework received the most attention in the Points to Consider document, and has dominated the discussions of gene therapy that have been conducted under it. In practice, it means that prospective gene therapists must have enough prior knowledge to believe that the probable benefits to the patient/subject outweigh both the possiblerisksof the experiment and the known benefits of the alternative treatments available. Thus, it lies behind the document's questions about, and the community's discussion of, the safety and efficacy of somatic cell gene therapy techniques (cfi Anderson and Fletcher, 1980; Temin, 1990), the adequacy of preliminary animal studies (Anderson et aL, 1986; Cornetta et al., 1990; Osborne etaL, 1990) and the relative value ofthe emerging therapeutic alternatives (Blaese etal., 1990). 427
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JUENGST 2. Concerns about the free and informed participation of subjects. Since Nuremburg, the biomedical research community has accepted an increasingly strong obligation to insure that the participation of patients in research protocols is voluntary and informed (Faden and Beauchamp, 1986). In its deliberations, the National Commission underscored the need for special protections w h e n research subjects are enlisted on the strength of "proxy consent" by others. The Commission's distinction between parental "permission" and the "assent" of minor research subjects, and its insistence on both, are explicitly reiterated in the section of the "Points to Consider" that asks researchers to "indicate h o w patients will be informed about the proposed study and h o w their consent will be solicited.77 (Subcommittee, 1990, p. 100). 3. Concerns about fair subject selection. The development of national policies for research with h u m a n subjects during the 1970s was motivated in part by a concern that the burdens of participating in nontherapeutic biomedical research were distributed unfairly a m o n g particularly vulnerable populations within society—concerns that do not arise in the therapeutic context of the "Points to Consider," where the study population will be defined by the target disease. However, the scarcity of any developing gene therapy techniques poses distributive questions of its own: questions about fair access to the potential benefits of research participation. A s L e R o y Walters notes: With rare genetic diseases, although the potential patient pool will be small, choices will need to be m a d e from a m o n g multiple candidates. Thus, fairness in the selection of subjects m a y be an important issue even in the earliest trials of h u m a n gene therapy (Walters, 1986). Thus, the "Points to Consider" includes instructions to investigators to "describe recruitment procedures and patient eligibility requirements, paying particular attention to whether these procedures and requirements are fair and equitable" (Subcommittee, 1990, p. 100). A s prominent as the three sets of h u m a n subjects research considerations are a m o n g the R A C ' s "Points to Consider," the considerations that reflect its o w n institutional history as a product of the recombinant D N A debate are no less evident. The guiding considerations of that debate have never been as clearly codified as the h u m a n subjects research concerns. But the three reflected in the R A C ' s deliberations all flow from the two themes that informed it: a recognition ofthe special nature of research with recombinant D N A molecules and an effort to evaluate genetic research within its wider social and environmental context. 4. The needfor special "biosafety" precautions in face of genetic uncertainty. O n e of the striking legacies of the recombinant D N A debate is the acceptance of the need to prepare for unforeseen as well as predictable risks in designing molecular genetic research (cfi Cohen, 1979). Thus, for example, scientific authors still write that: There are often unexpected effects of n e w technologies. . . The use of retrovirus vectors for somatic therapy of h u m a n genetic diseases can be looked upon as either a novel improvement on present means of drug delivery or as the introduction of potentially dangerous technology. Although scientists and physicians m a y believe thefirstcharacterization is correct, I a m convinced that w e must act as if the second characterization is correct. W e must design vector systems and protocols so that even quite unrealistic fears about safety are allayed (Temin, 1990). A s this quotation suggests, in the discussion of gene therapy this concern has focused on anticipating possible risks involved in the delivery and integration of exogenous D N A into the subject's cells, and on designing viral vector systems that will avoid theserisks(Anderson, 1984). In the "Points to Consider," the bulk of the risk assessment questions posed to investigators are designed to address just these concerns (Subcommittee, 1990, pp. 97-99). 5. The need for public participation in genetic research policy. It was in the context of the recombinant D N A debate that m a n y of the early, inchoate concerns about the implications of genetic research began to be laid to rest (cfi Stich, 1979). B y the time the President's Commission's Splicing Life report criticized worries about "playing God," "violating evolutionary wisdom," and "stealing forbidden knowledge," both the 428
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T H E NIH POINTS T O CONSIDER analytic arguments and the practical experience it used had been worked out in the course of discussing, developing, and implementing the R A C and the N I H Guidelines for r D N A research. Nevertheless, a recurrent theme from both those arguments and that experience was the importance of public participation in science policy decisions of this sort (Schmeck, 1986). A s one commentator put it: "The principle of democratic oversight is basic to our society, and its application is essential for producing popular information and popular decisions. The social consequences ofthe recombinant D N A technology are too enormous and important to be left to specialists alone" (Nader, 1986, p. 159). The establishment ofthe R A C itself and the review process which the "Points to Consider" guide are both basic manifestations of this continuing committment to public oversight in this area. The "Points" continue the tradition in several ways: by requiring the publication of protocols for public comment prior to N I H review; by conducting proposal review publicly; and by instructing investigators to address two "special issues" "beyond the normal purview of local IRBs," concerning their plans to "ensure that accurate and appropriate information is m a d e available to the public with respect to such public concerns as m a y arise from the proposed study" (Subcommittee, 1990, p. 101). 6. The need to consider broad and long range research consequences. Finally, a third legacy of the r D N A controversy is the imperative to consider the possible impact of any gene therapy research on other people beside the research subject. Here, the public health, environmental, and evolutionary concerns debated during the discussion of gene transfer experiments with E. coli are echoed as concerns about the nosocomial dangers, social costs, and dysgenic effects of gene therapy. Thus, the literature argues that: The n e w therapy should not result in harm to the general population. W e need to consider the possibility for formation of a novel and infectious virus during somatic cell gene therapy of h u m a n disease with retrovirus vectors, the costs of such therapy, the possible evolutionary effects of such therapy (by means such as inadvertent infection ofthe patient's germ-line), and unforeseen complications (Temin, 1990). "Accordingly," the Points to Consider conclude on this score, "this document requests information that will enable the R A C and its Subcommittee to assess the possibility that the proposed experiments will inadvertantly affect reproductive cells or lead to infection of other people" (Subcommittee, 1990, p. 96). In some respects, the Points' two complements of ethical considerations fold together nicely: Biosafety considerations are just specifications of general concerns for clinical benefit, informed public oversight is a logical extension of informed participation by subjects, and one way to frame concerns about extended risks is as a problem of distributing research burdens and benefits fairly across populations. Nevertheless, they do differ importantly in orientation: The ethic of human subjects research is committed to protecting the interests ofthe individual patient/subject, while the r D N A offers considerations on behalf of the greater public health. A s w e shall see, that difference leaves the "Points to Consider" ill-equipped to establish the commonly accepted moral limits of gene therapy as public policy. Instead, I argue, the R A C will ultimately have to cede the definition and defense of those limits to the medicine, as a function of that profession's o w n goals.
GERM-LINE GENE THERAPY, ENHANCEMENT ENGINEERING, A N D T H E POINTS T O CONSIDER Most ofthe practical work ofthe second phase of bioethical deliberations over human gene therapy has been devoted to the discussion and evaluation of somatic cell gene therapies. A s a result, the other logically possible forms of h u m a n genetic engineering—germ-line gene therapies and enhancement engineering (of either somatic or germ-line cells)—have been left comparatively underdiscussed. The "Points to Consider," like other recent statements (Danielson, 1988) simply assert that "the R A C and its Subcommittee will not at present entertain proposals for germ line alterations" (1990, p. 95). They are completely silent on enhancement engineering (though their first version did ask investigators to assess the likelihood that somatic 429
JUENGST
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cell therapy would lead to "the enhancement of human capabilities through genetic means" (DHHS, 1985). As new work on both these fronts suggest, however, it will be these topics, and the limits to gene therapy they are taken to mark, which will preoccupy the third, emerging generation of bioethical deliberations over this technology (cfi Anderson, 1989; Fowler etal., 1989). The "Points'" current ban on germ-line gene therapy proposals probably rests on a combination of concerns about clinicalrisksand biohazards, research involving preembryonic subjects of uncertain moral status, and long-rangeriskto future generations. The arguments against attempting germ-line gene therapy in the face of our current low levels of relevant moral insight, scientific knowledge, and technical expertise are persuasive (Fowler etal., 1989). However, if the case against germ-line intervention is exhausted by therisksof clinical and genetic accidents and the morally uncertain status of preembryos, then it is not a line that can be drawn in principle and forever. Clinical and geneticrisks,even multigenerational ones, are problems that can succumb to new knowledge. The development of tissue-targeted vector systems might eventually make the germ-line (i.e., reproductive) cells of adults accessible, avoiding the need to manipulate preembryos (Lavitrano et aL, 1989). In this far future, the only complaint the RAC's descendents might bring against a germ-line gene therapy proposal is that it does indeed "attempt to introduce genetic changes into the germ (reproductive) cells of an individual, with the aim of changing the set of genes passed on to the individual's offspring" (Subcommittee, 1990). That is, it would run afoul of the "Points'" sixth concern not to endanger the (yet unknown) genetic interests of future populations by knowingly modifying their genetic resources. But under these conditions, the patient-centered ethic of clinical research and the public health ethic begin to disassociate themselves within the framework ofthe Points. In this scenario, the germ-line therapy would be an attempt to help an individual—the adult subject of the therapy—overcome a reproductive health problem: theriskhe or she faces of conceiving children with a genetic disease. That is, the subject would be in the same position as a patient requesting the aid of genetic counseling or prenatal diagnosis to address the same reproductive problem. In those situations, the interests ofthe gene pool are given lower priority than the considered value judgements of the presenting patient, for a number of good professional, ethical, and epistemic reasons (Juengst, 1989). To do otherwise, i.e., to protect the interests ofthe future by prohibiting potentially dysgenic actions by the patient, is to subscribe to a coercive form of eugenics. This is equally true whether the prohibited parental choice involves perpetuating, through child-bearing, a potentially deleterious gene or deleting, through gene therapy, a potentially adaptive one. As some observers now acknowledge, The benefits [of germline gene therapy] to the treated individual could be dramatic and immediate, while the possible harms are indirect, quantitatively insignificant, and could be avoided by future reproductive choices. It makes little sense to foreclose a therapeutic option to preserve the "human germ plasm" or to prevent some other vaguely unsettling but unspecified consequence (Cook-Deegan, 1990, p. 169).
Although the line against enhancement engineering can be more firmly drawn by the moral resources ofthe "Points," the arguments they provide still face a similar problem. The primary danger of enhancement engineering, once it is safe and effective, is also itsrisksto other people beyond the subject. However, the mainrisksof enhancement engineering are not so much its possible dysgenic effects on future generations as its immediate effects on the social health of the subject's contemporaries. Enhancement engineering, by associating desirable physical traits with socioeconomic access to this form of health care, would exacerbate for others the very problems of social inequality it would be intended to address in the subject. As Areen and King point out, "If enhancement engineering ever does move from the realm of science fiction into science fact, extremely serious issues of access to and fair distribution of such possibilities will arise" (Areen and King, 1990). In the face of its mandate to consider these issues of fairness, the R A C might justifiably disapprove proposals for enhancement engineering, on the grounds that its benefits could not be distributed fairly across variously vulnerable populations, and would only serve to magnify current social inequalities. 430
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T H E NIH POINTS T O C O N S I D E R On the other hand, the social risks of enhancement engineering, like its clinical risks, still only provide contingent barriers to the technique. In a society structured to allow the realization of our moral commitment to social equality in the face of biological diversity—that is, for a society in which there was both open access to this technology and no particular social advantage to its use—these problems would show themselves to be the side issues they really are. In such a society (perhaps even further from our o w n than the one in which germ-line gene therapy becomes feasible) where the question before the R A C is the bare question of whether it is ever appropriate to use medical technology to enhance an individual's traits, the "Points" would provide no guidance. Like the question of whether the 'reproductive health problems' that genetic counselor's address are proper problems for medicine, the problem of enhancement engineering falls through the ethical framework of that public policy document, into the hands of the practioners themselves.
T H E LIMITS O F G E N E THERAPY A N D T H E GOALS OF MEDICINE The day when public concerns regarding the limits of human gene therapy are moot is clearly a long way off. However, in principle at least, the definition of those limits should be as m u c h a challenge for medicine as society, because the questions it poses are ultimately questions about the profession's goals: W h a t sort of 'reproductive health problems' fall within the province of medicine? For example, does medicine's commitment to 'help people have healthy babies' depend on any professional particular understanding of "health"? Where do 'medical indications' for treatment stop and 'patients' preferences' begin in the context of reproductive health care? For example, would ever be appropriate, in the absence of any social advantage, to increase the height of a short normal patient? These are questions on which society can have tremendous influence, because they partly turn on the social role that health professionals are asked to play. But they are ultimately questions for professional conscience and vision, not public policy. Fortunately, they are also questions that, unlike the techniques themselves, are already available for analysis in multiple, less exotic variants (cfi. Kass, 1981; Underwood and Sherman, 1986; Juengst, 1988; Asch, 1989). T o prepare for the discussion of the limits of h u m a n gene therapy that one would eventually like to have, it is in the direction of these professional reflections about the meaning of health care that the gene therapy literature should n o w move.
ACKNOWLEDGMENTS Ancestral versions of this paper have been delivered at Stanford University, the University of San Francisco, and Kutztown University. Support for the research project which stimulated it was provided by a grant from the Ethics and Values Studies Program ofthe National Science Foundation (RII-8511073), with cofunding from the National Institute of Child Health and Development. The views expressed here do not necessarily express the views of N S F or N I H .
REFERENCES ANDERSON, W.F. (1984). Prospects for human gene therapy. Science 226,401-409. A N D E R S O N , W.F., and F L E T C H E R , J.C. (1980). Gene therapy in human beings: When is it ethical to begin? N. Engl. J. Med. 303, 1293-1297. A N D E R S O N , W.F., (1989). Human gene therapy: W h y draw a line? J. Med. Philos. 14,681-695. A N D E R S O N , W.F., K A N T O F F , P., EGLITIS, M., etal. (1986). Gene transfer and expression in nonhuman primates using retroviral vectors. Cold Spring Harbor Symp. Quant. Biol. 51,1065-1073. A R E E N , J. (1985-1986). Regulating human gene therapy. W . Virginia Law Rev. 88, 153. 431
Human Gene Therapy 1990.1:425-433. Downloaded from online.liebertpub.com by Childrens Hospital on 12/09/14. For personal use only.
JUENGST AREEN, J., and KING, P. (1990). Legal regulation of human gene therapy. Hum. Gene Ther. 1, 151-161. ASCH, A. (1989). Reproductive technology and disability. In Reproductive Laws for the 1990s. S. Cohen and N. Taub, eds. (Humana Press, Clifton, NJ), pp. 69-124. BLAESE, R.M., C U L V E R , K., and A N D E R S O N , W.F. (March 29, 1990) Submission of Responses to Subcommittee Review (unpublished memorandum to Nelson Wivel, NIH Office of Recombinant D N A Activities). C A L L A H A N , D. (1979). The moral career of genetic engineering. Hastings Center Rep. 9, 21. C A P R O N , A.M. (1990). The impact ofthe report, Splicing Life. Human Gene Ther. 1, 69-73. C O H E N ,C.(1979)Onthe dangers of inquiry and the burden of proof. In The Recombinant D N A Debate D. Jackson and S. Stich, eds. (Prentice-Hall, Englewood Cliffs, NJ) pp. 303-337. C O O K - D E E G A N , R.M. (1990). Human gene therapy and Congress. Human Gene Ther. 1, 163-170. C O R N E T T A , K., M O E N , R.C., C U L V E R , K., et al. (1990). Amphotropic murine leukemia retrovirus is not an acute pathogen for primates. Human Gene Ther. 1, 15-31. DANIELSON, H. (1988). Gene therapy in man: Recommendations ofthe European medical research councils. Lancet i, 1271-1272. D H H S . (Jan. 22, 1985). Recombinant D N A Research; Request for Public Comment on "Points to Consider in the Design and Submission of Human Somatic Cell Gene Therapy Protocols." Fed. Reg. 50, 2940-2945. F A D E N , R., and B E A U C H A M P , T. (1986). A History and Theory of Informed Consent. (Oxford University Press, New York). FLETCHER, J.C. (1990). Evolution of ethical debate about human gene therapy. Human Gene Ther. 1, 55-69. F O W L E R , G., JUENGST, E., and Z I M M E R M A N , B. (1989). Germ-line gene therapy and the clinical ethos of medical genetics. Theoret. Med. 10, 151-165. FRIED, C. (1973). The need for a philosophical anthropology. In Ethical Issues in Human Genetics. B. Hilton et al., eds. (Plenum Press, New York) pp. 261-267. G U S T A F S O N , J.M. (1973). Genetic engineering and the normative view ofthe human. In Ethical Issues in Biology and Medicine P. Williams, ed. (Schenkman Pub. Co., Cambridge, M A ) pp. 46-59. JUENGST, E. (1988). Prenatal diagnosis and the ethics of uncertainty. In Medical Ethics: A Guide for Health Professionals. J Monagle and D. Thomasma, eds. (Aspen Pub., Rockville, M D ) pp. 12-25. JUENGST, E. (1989). Patterns of reasoning in medical genetics. Theoret. Med. 10, 101-107. KASS, L. (1981). The pursuit of health and the end of medicine. In Concepts of Health and Disease: Interdisciplinary Perspectives A. Caplan, H.T. Engelhardt, and J. McCartney, eds. (Addison-Wesley, New York) pp. 3-31. K O L A T A , G., and W A D E , N. (1980). Human gene treatment stirs new debate. Science 210,407. K R I M S K Y , S. (1982). Genetic Alchemy: The Social History of the Recombinant D N A Controversy (MIT Press, Cambridge, M A ) . L A V I T R A N O , M., C A M A I A N O , A., FAZIO, V., et al. (1989). Sperm cells as vectors for introducing foreign D N A into eggs: Genetic transformation of mice. Cell 57, 717-723. LEVINE, R.J. (1986). Ethics and Regulation of Clinical Research (2nd Edition). (Urban & Schwarzenberg, Baltimore). M U R R A Y , T.H. (1990). Human gene therapy, the public and public policy. Human Gene Ther. 1, 49-55. N A D E R , C. (1986). Technology and democratic control: The case of recombinant D N A . In R. Zilinskas and B. Zimmerman, eds. The Gene Splicing Wars: Reflections on the Recombinant D N A Controversy (Macmillan Pub. Co., New York) pp. 139-167. N A T I O N A L C O M M I S S I O N F O R T H E PROTECTION O F H U M A N SUBJECTS O F B I O M E D I C A L A N D B E H A V IORAL RESEARCH. (1978). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. D H E W Publication No (OS) 78-0013. (US Government Printing Office, Washington, DC). OFFICE O F T E C H N O L O G Y ASSESSMENT. (1984). Human Gene Therapy: A Background Paper. (US Government Printing Office, Washington DC). OTA-BP-BA-32. O S B O R N E , W.R.A., H O C K , R.A., K A L E K O , M., etal. (1990). Long-term expression of human adenosine deaminase in mice after transplantation of bone marrow infected with amphotropic retroviral vectors. Human Gene Ther. 1, 31-43. PRESIDENT'S C O M M I S S I O N FOR T H E S T U D Y O F ETHICAL P R O B L E M S IN MEDICINE A N D B I O M E D I C A L A N D B E H A V I O R A L RESEARCH. (1983). Splicing Life. (US Government Printing Office, Washington, DC). R A M S E Y , P. (1970). Fabricated Man: The Ethics of Genetic Control (Yale University Press, New Haven, CT). R A M S E Y , P. (1972). Genetic therapy: A theologian's response. In: The New Genetics and the Future of Man. M . Hamilton ed. (Wb Eerdmans, Grand Rapids, MI) pp. 157-179. S C H M E C K , H. (1986). Recombinant D N A controversy: The right to know—and to worry. In The Gene-Splicing Wars: Reflections ofthe Recombinant D N A Controversy. R. Zilinskas and B. Zimmerman, eds. (MacMillan Publishing Co New York) pp. 93-109. STICH, S. (1979). The recombinant D N A debate: some philosophical considerations. In: The Recombinant D N A Debate. D. Jackson and S. Stich, eds. (Prentice Hall, Inc., Englewood Cliffs,) 183-203. 432
T H E NIH POINTS T O CONSIDER SUBCOMMITTEE ON HUMAN GENE THERAPY, RECOMBINANT DNA ADVISORY COMMITTEE, NATIONAL INSTITUTES OF HEALTH (1990). Points to consider in the design and submission of protocols for the transfer of recombinant D N A into the genome of human subjects. Human Gene Ther. 1, 93-103. TEMIN, H.T. (1990). Safety considerations in somatic gene therapy of human disease with retrovirus vectors, Human Gene Ther. 1,111-123. U N D E R W O O D , L., and S H E R M A N , B. (1986). Controversies in the treatment of short stature. In Human Growth Hormone: Progress and Challenges. L. Underwood, ed. (Marcel Dekker, Inc., N e w York) pp. 145-178. W A L T E R S , L. (1986). The ethics of human gene therapy. Nature 320, 225-227.
Human Gene Therapy 1990.1:425-433. Downloaded from online.liebertpub.com by Childrens Hospital on 12/09/14. For personal use only.
Address reprint requests to: Eric T. Juengst, Ph.D. 9510 Ewing Drive Bethesda, M D 20817 Received for publication September 28, 1990; accepted after revision October 11, 1990.
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