H U M A N G E N E T H E R A P Y 1:163-170 (1990) Mary Ann Liebert, Inc., Publishers
H u m a n
G e n e Therapy and Congress
ROBERT M U L L A N COOK-DEEGAN
ABSTRACT
Congress was the scene of conspicuous debate about human gene therapy during the 19 Congressional interest was sparked primarily by concerns about germ-line gene therapy expressed by clerics and public interest groups. The initial debate was provoked by Martin Cline's misadventures in 1980 and rekindled in 1983 by congressional resolution against germ-line intervention sponsored by Senator M a r k Hatfield. T h efirsthearing on gene therapy was held upon the release ofthe President's Commission report Splicing Life, in November, 1982, before a House subcommittee chaired by Congressman Albert Gore, Jr. Representative Gore later requested a report on gene therapy, which was released by the Office of Technology Assessment in December, 1984. H e also sponsored the legislation that established the Biomedical Ethics Board and Biomedical Ethics Advisory Committee, Congress's abortive attempt to reestablish a federal bioethics commission. Implications of advances in h u m a n genetics, including gene therapy, were to be a m o n g the first topics addressed. Congress passed no substantive legislation affecting gene therapy research or clinical trials, but served principally as a national theater for debate. If and when germ-line gene therapy is contemplated, Congress will be faced with difficult choices, but will likely take no action to block trials that appear safe and are intended to produce clinical benefit for particular individuals.
OVERVIEW S U M M A R Y Because ofthe public's concern about h u m a n genetic engineering, Congress has taken an active role in evaluating the public policy issues surrounding h u m a n gene therapy. Cook-Deegan, particularly during his tenure at the O T A , has himself been a key figure in this evaluation. In this article Cook-Deegan examines the role Congress has played in the past and is likely to play in the future with regard to h u m a n gene therapy.
INTRODUCTION The 1980s began with bright hopes that it would be the decade of gene therapy. As the decade ended, however, there had been but one pair of premature and illegal trials of gene therapy to mark its beginning, and a single approved protocol for gene transfer near its end. The first trial of gene therapy was postponed into the 1990s because of unforeseen technical obstacles.
Senior Research Fellow, Kennedy Institute of Ethics, Georgetown University, and Expert, National Center for Human Genome Research, National Institutes of Health, Bethesda, M D 20892. 163
COOK-DEEGAN Human gene therapy and gene transfer are interesting case examples of anticipatory action by the federal government. Those concerned about the rapid proliferation of technology often point to the fact that developments frequently outstrip policy change. Policy change is usually reactive, developed only after the technology is widespread. Gene therapy is a counterexample—a technology for which the regulatory apparatus has long been in place and has waited for the technology to catch up. Public policy has developed because the technology was anticipated and broadly discussed long before it was actually in place. Part of that discussion directly involved Congress, whose power to set federal rules, to fund science agencies, and to direct regulatory agencies gave it broad influence over policy regarding gene therapy.
T H E PRESIDENT'S COMMISSION REPORT Congress first became involved in gene therapy in the wake of Dr. Martin Cline's 1980 attempts to do gene therapy in two patients with thalassemia, one in Italy and the other in Israel. Dr. Cline proceeded in these experiments while supported, at least in part, by grants from the National Institutes of Health. His experiments with human subjects were thus subject to federal regulations (Code of Federal Regulations). H e was obliged to secure approval from the Institutional Review Board at his h o m e institution, the University of California, Los Angeles. H e proceeded without this approval, however, in a clear violation that stirred a national controversy (Wade, 1980, 1981a,b; Talbot, 1982; Fletcher, 1983). A s a result, two federal grants were terminated and Dr. Cline resigned as chief of the hematology division. The religious leaders of three large denominations—the U.S. Catholic Conference, the Synagogue Council of America, and the National Council of Churches—wrote to President Carter in 1980 expressing concern about rapid advances in genetics and the absence of a federal oversight mechanism. The letter was referred to the newly formed President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (President's Commission) (President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1982). The President's Commission released a report on human gene therapy, Splicing Life, at a congressional hearing in November, 1982, before House subcommittee chairman Albert Gore, Jr. (U.S. House of Representatives, 1982). That landmark report articulated the principal public policy positions that stand to this day. The President's Commission highlighted the distinction between somatic and germ-line gene therapy, asserting that somatic cell gene therapy was morally equivalent to other forms of therapy. Germ-line therapy might never be technically feasible, and should be subject to broad public debate before being adopted. The President's Commission also noted the need for a review mechanism of experiments and also recommended a permanent federal bioethics commission. The President's Commission ceased to operate in March, 1983, after issuing a summary volume and 10 reports on a wide variety of issues in biomedical ethics. In June, 1983, 56 clerics and 8 scientists signed a resolution and sent it to Congress, urging that "efforts to engineer specific genetic traits into the germ line ofthe human species should not be attempted" (Foundation on Economic Trends, 1984). The resolution was introduced by Senator M a r k 0 . Hatfield on June 10 (Hatfield, 1983). The resolution was sent to Congress with a discussion paper written by Jeremy Rifkin, largely based on his recently released book Algeny (Rifkin, 1983). The book, the resolution, and the controversy generated when several signatories ofthe resolution disavowed some ofthe ideas contained in the discussion guide (which most had not seen and did not k n o w was to accompany the resolution) combined to focus attention on gene therapy once again (Richard A. McCormick, personal communication, Kennedy Institute of Ethics, Georgetown University, September 1984; Nelson, 1984). In light of the renewed confusion, Representative Gore requested that the congressional Office of Technology Assessment ( O T A ) undertake a study of h u m a n gene therapy in March, 1984.
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H U M A N GENE THERAPY A N D CONGRESS THE OTA REPORT OTA responded to Mr. Gore's request by scheduling a workshop of outside experts. A panel of 17 scientists, clinicians, genetic counselors, family members, ethicists, lawyers, historians, theologians, and public policy experts met on September 25, 1984, to discuss the issues related to gene therapy. Discussion centered on several papers prepared for the meeting. Nanette Newell of O T A had prepared a review of relevant animal experiments. Lawrence Wissow, a physician from Johns Hopkins, identified what diseases might be targets for gene therapy and outlined the clinical criteria for beginning clinical trials. I had prepared some summary materials as study director. The panel agreed that a n e w document was needed to synthesize the contents ofthe papers and to incorporate n e w information. I had principal responsibility for the rewrite, with substantial help from Nanette Newell and several other O T A staff. Teresa Schwab wrote several technical notes and drew several diagrams. Eleanor Pitts, w h o had recently left the Washington Post and soon left for medical school at Dartmouth, wrote an appendix on diagnostic technologies and a technical note. L. Val Giddings wrote a short note on the biological meaning of species barriers, and Steven Eckman, a s u m m e r fellow from the Wharton School, wrote a long appendix on the confidentiality of genetic information. T h e draft was reviewed by 70 outside experts including the original workshop panel (Office of Technology Assessment, 1984). The report was released on December 10, 1984, as one of the last acts as a m e m b e r of the House of Representatives performed by M r . Gore, w h o had been elected to the U.S. Senate the previous month. T h e O T A report largely restated the moral positions of the President's Commission, augmented by several publications written in the meantime (many in response to the President's Commission report). It noted the shift in focus from disorders of hemoglobin to the genetic forms of immunodeficiency caused by adenosine deaminase and purine nucleoside phosphorylase deficiency, and to Lesch-Nyhan disease. The report listed several scientific, clinical, and public policy criteria to be met by gene therapy protocols. Several religious, medical, and other groups had agreed that somatic cell gene therapy for the treatment of fatal or seriously disabling conditions was acceptable in principle, following the trail blazed by the President's Commission. These statements and technical developments were noted in a large bibliography. The main thrust ofthe report was that somatic cell gene therapy does not raise issues distinct from other treatments, but it might enable treatment of previously untreatable conditions. The O T A report sidestepped the issue of germ-line gene therapy. This was, in part, a political decision. Review of the theological concerns about gene therapy leading to the President's Commission and O T A reports m a d e it clear that the pressing issue was not ethical acceptability of gene therapy, but rather concerns about its impact on future generations. The tack taken by both the President's Commission and O T A was to present concrete reasons to consider gene therapy at all, and to prevent the foreclosure of options if gene therapy research were not pursued. It was relatively easy to show the potential importance of somatic cell therapy, and the bright-line distinction (somatic versus germ-line intervention) was useful to show there was at least one case on which everyone could agree—treatment of a fatal genetic disease in a w a y that did not cause inherited change. It was also important to show that there was an open and public process for reviewing the safety, efficacy, and ethical implications ofthe first trials: the multitiered N I H , F D A , and local review mechanisms. Discussion of germ-line therapy was ducked to focus on a more immediate prospect. The moral basis for separating germ-line and somatic treatment was not clear, but moral consensus vanished in the face of germ-line interventions. In O T A ' s subsequent survey of public opinion, the acceptance of gene therapy did not change significantly if the changes were inherited or not (indeed, approval increased slightly for inherited changes) (Office of Technology Assessment, 1987). In contrast, approval was quite sensitive to the severity of disability treated. This suggested that concern was more about whether the technology would be used increasingly for cosmetic purposes rather than fear of an impact on the "human germ plasm."
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COOK-DEEGAN For purposes of public policy, however, a protracted discussion of germ-line gene therapy was highly speculative and fraught with uncertainties, both technical and moral. The technical barriers to applying germ-line gene therapy were formidable, requiring an improvement of several orders of magnitude in efficiency of inserting a desired gene into a given embryo or egg cell. A n y germ-line interventions would, in all likelihood, require research on human embryos, raising a spate of policy complications. Federal funding for such research was then, as it is now, subject to a federal funding moratorium. Further, research on any embryo obtained following in vitro fertilization was precluded without approval from an Ethics Advisory Board, and no such board had existed since early 1980 (nor will one exist in the foreseeable future, according to James Mason, Assistant Secretary for Health). It was also unlikely that there would be any clinical reason to attempt germ-line therapy until it was highly reliable and there was no option of selecting normal embryos following a genetic test to screen out those affected with a genetic disease. For all of these reasons, the discussion on germ-line gene therapy was brief in the O T A report, concluding that substantial technical improvements would be needed before germ-line gene therapy forced a policy choice.
NIH A N D FDA REVIEW OF PROTOCOLS The Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health (NIH) formed a working group to study and respond to the President's Commission report. It began late in 1983, and worked concurrently with the O T A staff. The chairman ofthe R A C working group, LeRoy Walters, also chaired the O T A workshop. O T A staff attended all R A C working group meetings, and members of the R A C working group reviewed the O T A draft. The two groups were grappling with the same issues simultaneously, but with different ends. The O T A report was a policy statement to Congress, while the working group, later reconstituted as a subcommittee of R A C , had the task of writing guidelines for review of protocols that might be submitted to N I H . The R A C working group produced a document for prospective investigators entitled "Points to Consider in the Submission of Protocols for Somatic Cell Gene Therapy" in 1985, and revised the document in 1989 in light of experience following approval ofthe first gene transfer protocol (Subcommittee on H u m a n Gene Therapy, 1989). The Food and Drug Administration ( F D A ) is responsible for ensuring the safety and efficacy of foods and drugs involved in interstate commerce in the United States. In practice, this authority is broadly intepreted, giving the F D A purview over gene therapy. After some discussion in the period 1984-1985 about parallel review by N I H (through R A C ) and F D A , F D A clearly signaled its intention to review gene therapy protocols. The F D A process extends beyond that subject to mandatory N I H review. Research facilities that receive federal funds for recombinant D N A research must get prior approval for gene transfer protocols from N I H . F D A covers not only these but also any private firms engaged in interstate commerce or using reagents so obtained, in effect covering most conceivable applications. The N I H and F D A reviews both center on safety and efficacy, but the processes are somewhat different. The N I H review is open and highly public; each meeting has been attended by at least a few journalists (and several meetings have been widely covered). The F D A review process is modeled on that used for new drugs and biologies. F D A review is confidential. T h e parallel authority of F D A and N I H has become clearer, and the logistics of the multiple reviews began to be worked out as the first protocol for gene transfer transited by system in 1988 and 1989.
T H E BIOMEDICAL ETHICS ADVISORY C O M M I T T E E A N D BIOMEDICAL ETHICS B O A R D In Splicing Life, the President's Commission recommended that Congress establish a standing body to study the public policy implications of developments in reproductive medicine, genetics, and other areas. 166
H U M A N GENE THERAPY A N D CONGRESS Congress deliberated through 1983 and into 1984, failing to reach consensus on a proper mechanism. Representative Gore, in the wake of his 1982 hearing, introduced a bill to create a n e w President's Commission for this purpose. In the Senate, there was some difficulty reaching an agreement. Senate conservatives were displeased with some of the reports from the President's Commission, particularly positions taken on termination of treatment and access to health care. A search for alternatives was launched, and letters were sent to O T A and to the Institute of Medicine ( I O M ) asking if those institutions were capable of performing the task. I O M and O T A both replied that they could do the job, but the responses were lukewarm because of fear that these institutions would be dragged into the m u c k of abortion politics. Senator Kennedy included a provision adding bioethics to its O T A ' s mandate in the Senate version ofthe 1983 N I H authorization bill, and Gore's proposal for a President's Commission was folded into the House version. T h e bills were passed and went to a House-Senate conference committee for resolution of differences. A compromise emerged from the conference committee—a n e w Biomedical Ethics Board (BEB), comprised of 12 M e m b e r s of Congress (3 Democrats and Republicans from each house), and a Biomedical Ethics Advisory Committee ( B E A C ) , comprised of 14 outside experts. This was generally modeled on O T A , which is also a part ofthe Congress, has a congressional board, and has an outside advisory committee. The conference bill was accepted by both houses, and vetoed in November 1984. A n almost exact replica was reintroduced, passed, vetoed again, and passed over President Reagan's second veto to become law in M a y 1985 (Public L a w 99-158). (The vetoes were not due to the bioethics components, but rather to resistance to creating a n e w arthritis institute at NIH.) Another change was added in conference. B E B and B E A C were given the task of making recommendations on fetal research, specifically on the language about the standard forriskacceptable in research involving fetuses. It took roughly a year to appoint the Members of Congress to B E B , and another 18 months for B E B to appoint the first 12 members of B E A C . The final two appointments, to fill two slots for lay representatives on B E A C , consumed most of another year. B E A C met for the first time on 26 and 27 September 1988, 4 days before its authorization lapsed. B E B and B E A C were reauthorized in the final minutes ofthe 100th Congress, and given access to funds appropriated in previous years but never used. Another addition to the mandate was included in that act—a study on termination of food and fluids administered to dying patients. This brought to three the number of reports mandated by statute in the 2-year authorized existence of B E A C and B E B : a report on implications of h u m a n genetic engineering, on federal guidelines for fetal research, and on nutrition and hydration of dying patients. B E A C met one more time, on February 17 and 18, 1989. Discussion on February 17 was largely devoted to implications of h u m a n genetics. LeRoy Walters described the process for reviewing gene therapy protocols, including the then-recent approval of a 10-patient protocol for insertion of a marker gene to study the treatment of metastatic malignant melanoma. Walters went on to discuss gene therapy. H e noted the unanimous acceptance of somatic cell gene therapy in official statements by governments and religious bodies from around the world. H e explained w h y germ line therapy was not imminent, and recommended that B E A C focus its attention on the more pressing issues related to genetic testing, genetic screening, and provision of genetic services. B E A C accepted these recommendations, and was preparing to deal with gene therapy by recapitulating previous reports, updating the technical discussion by review of the scientific literature, and beginning to analyze the specific clinical situations, if any, in which germ-line gene therapy might be contemplated (Biomedical Ethics Advisory Committee, 1989). Following a congenial and productive meeting in February, B E A C prepared to focus most of its effort on issues related to genetic testing and screening, and to consider the implications of mapping and sequencing the h u m a n genome. B E A C started the process to gather data about confidentiality of genetic information, including h o w genetic tests might be used in health insurance, life insurance, and other insurance contexts, and also in making employment decisions. The cooperative ambience ofthe B E A C was in stark contrast to the 167
COOK-DEEGAN divisive politics and insurmountable distrust that had built up in the governing congressional board. The committee was on the verge of commissioning several papers on roughly a dozen topics when political paralysis ofthe congressional board, B E B , became evident on March 8, 1989. The Senate members of B E B met to elect a chairman, but the discussion devolved to unproductive acrimony and the members found themselves deadlocked. B E B never met again, and B E A C was asked to bide its time until B E B became functional. It never did, and funding for B E A C in 1990 was contingent on several actions by B E B , namely election of a B E B chairman and vice-chairman and appointment of a member of B E A C to fill a vacancy. None of these actions is likely ever to be achieved. B E A C quietly closed its office in the Hart Senate Office Building on September 29, 1989, given loss of spending authority beginning October 1. Barring some unforeseen breakthrough, B E B and B E A C will never function again.
PROSPECTS FOR G E R M LINE G E N E THERAPY: TECHNICAL OBSTACLES A N D A CLINICAL SCENARIO The demise of a federal bioethics commission should have little impact on the immediate prospects for gene therapy. There remains a strong consensus in favor of somatic cell gene therapy for seriously disabling disorders. There is a regulatory process for reviewing clinical protocols. More to the point, B E A C as the federal body charged with reviewing the ethical implications of gene therapy had agreed in principle that somatic cell therapy did not raise new issues and could be handled by summarizing existing statements. Germ-line gene therapy would have been analyzed, but not given great emphasis because of its technical remoteness in comparison to more pressing issues raised by genetic testing and genetic screening. Congress had thus accepted the notion of somatic cell gene therapy. Senator Gore noted this in B E A C hearings before the House Appropriations Committee in January 1989 (Gore, 1989). Congress will become interested in germ-line therapy if its application seems imminent. It is worth considering h o w it might react. The issue will likely surface in the context of a specific clinical context. Germ-line therapy will almost certainly presuppose a means of testing for the presence of a genetic defect. Either a normal embryo will be selected, obviating a need for gene therapy, or the embryo will be tested after treatment to ensure effective treatment. It is difficult to imagine such an experiment being done blindly. There are at least two situations in which the ability to test for and select normal embryos will not resolve the problem of germ-line therapy: (i) The parents are opposed to discarding an affected embryo, on moral or other grounds, or (ii) both parents are homozygous, or for some other reason all progeny would be affected (so selection of an embryo without the genetic defect is not possible). Consider the options facing Congress. In the first case, it is difficult to imagine a direct congressional action to trump the moral judgments of parents w h o are opposed to abortion. It should not do so. The second case is more complex. Suppose, for example, that two young people meet in a genetics support group and fall in love. One m a y have sickle cell disease and the other hemoglobin C disease, or some other combination of hemoglobin disorders that n o w have life expectancies well into the years of reproductive activity. Alternatively, both parents might have phenylketonuria—the essential feature is that both parents are homozygotes for disease-related alleles. What are the public policy options? Congress, or more likely State legislatures, could proscribe marriages of those with genetic diseases. Or the law might proscribe marriage between those heterozygous for specified conditions. Either option would involve specifying a particular group of disorders—ignoring the clinical variability and subject nature of assessing a disorder's impact—and would also put the state in the business of having to mandate premarital genetic testing. These are draconian options fraught with potential for creating a stigma for those identified and subject to cultural bias masquerading as medical judgment. The list of conditions would have to be short to avoid including a
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H U M A N GENE THERAPY A N D CONGRESS significant fraction ofthe population (thus hampering overall reproductive fitness). But even if the technical issues could be resolved, these options are ethically repulsive. O n e of the lessons from the era of eugenics and racial hygiene is that intermarriage laws are morally unacceptable. There is broad consensus that preventing classes of people from marriage on grounds of genetic impact is no business for the law. A legislature could attempt to pass a law to prevent such couples from mating, following the Nazi example, but this is even more intrusive, moving public policy from the social institution of marriage to the extremely private act of intercourse. M a n y religious traditions would m a k e such interference within marriage not only suspect but in fact utterly backward. Public policies could be devised to deny treatment to a homozygous couple's children once born, on the grounds that the parents have knowingly caused children with genetic diseases to be born. Such denial of reimbursement would be highly inconsistent with m a n y other choices w e allow parents and prospective parents to m a k e , which choices are covered through public subsidy and private insurance. W e do not and should not stop treatment of a child with a neural tube defect or hydronephrosis against the wishes of the parents just because the defect was detected prenatally. T o be fair and consistent, there cannot be a public policy to prevent birth of a child with a genetic disease, and costs of care after birth should be covered to the same extent as for other children. A n y other position would be highly problematic. If measures were taken to prevent birth or conception of children born to homozygous parents, it would be an odd message indeed to the parents, both of w h o m would be not only carry, but have the very defect whose presence is used as justification to prevent birth. This strongly resembles the "life not worth living" arguments ofthe racial hygiene period. M a n y parents would not desire treatment, but at least a few probably would. That parents would wish to treat their child so as to prevent a disability they themselves possess does not imply that society should be able to constrain their freedom to choose to have that same child. If there were reliable germ-line therapy, would Congress wish to preclude such therapy because it alters the germ line? It seems unlikely. The state interest in treating the disease of an actual person or person-to-be clearly overrides the possible impact on future generations of that person's family. This is particularly the case w h e n the intervention would likely have either benefit (a functional gene) or no impact at all in subsequent progeny, rather than harms. The benefits 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. If presented with such a clinical scenario, Congress might well refrain from taking action. The argument would likely be that parents should decide what is best for their children. After all, the parents would suffer from the disease in question, and thus be in a position directly to judge the desirability of treatment. T h e impact on future generations would be an expected but not directly intended consequence of treatment. T h e immediate purpose of treatment would be to relieve the suffering of a specific individual, not to alter the gene pool. Congress could, in good conscience, invoke the doctrine of double effect, and protect the reproductive autonomy of two homozygous parents. A n y action to prevent germ-line therapy in this scenarioriskssystematic discrimination against those with genetic disabilities. This is the discredited core ideal of racial hygiene. It seems unjust to hold those with genetic disabilities hostage to speculative dangers if this clinical scenario ever becomes technically feasible. Such a clinical situation m a y never arise, because it presupposes immense technical advances in the ability to insert D N A into embryos or gametes. Such insertion would have to occur in a very high proportion of treated cells, and there would have to be substantial evidence that the procedure had no untoward side effects. Both these constraints put the prospects m a n y years in the future. Thus, Congress will likely not face a debate about germ-line gene therapy in the foreseeable future, and so it m a y not have to revisit the somatic-germ-line distinction. The future debate in Congress as at N I H , F D A ,
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and elsewhere, will properly center on when gene therapy is being used to treat a disease versus enhan desirable human trait, rather than whether it affects the germ line or not.
REFERENCES BIOMEDICAL ETHICS ADVISORY COMMITTEE, US CONGRESS. (1989). Transcript of a meeting, February 17 and 18, 1989. (Washington, DC) February 17 and 18, 1989. C O D E O F FEDERAL REGULATIONS, Title 45, Part 46. FLETCHER, J.C. (1983). Moral problems and ethical issues in prospective human gene therapy. Virginia Law Rev. 69, 515-546. F O U N D A T I O N O N E C O N O M I C TRENDS. (1984). "The Theological Letter Concerning the Moral Arguments Against Genetic Engineering of the Human Germ-Line Cells," reprinted in Taking Sides: Clashing Views on Controversial Bio-Ethical Issues. (Dushkin, Giulford, CT) pp. 276-280. GORE, S E N A T O R A L B E R T (1989). Testimony before the Subcommittee on Legislative Branch, Committee on Appropriations, US House of Representatives (Committee Report, House Report No. 101-179) U S Congress. HATFIELD, S E N A T O R M A R K O. (1983). Congr. Rec, 97th Congress (June 10, 1983), S 8202-S 8205. NELSON, J.R. (1984). The Human Problem ofHuman Genetic Engineering. (Boston, M A ) . Address to Genetics and the Law, III, April 2-4, 1984. OFFICE O F T E C H N O L O G Y ASSESSMENT, U S CONGRESS. (1984). "Human Gene Therapy." OTA-BP-BA-32. (Government Printing Office, Washington, DC). OFFICE O F T E C H N O L O G Y ASSESSMENT, US CONGRESS. (1987). "Public Perceptions of Biotechnology." (Government Printing Office, Washington, DC). PRESIDENT'S COMMISSION 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 BIOMEDICAL A N D B E H A V I O R A L RESEARCH. (1982). Splicing Life: The Social and Ethical Issues of Genetic Engineering with Human Beings. (Government Printing Office, Washington, DC). RIFKIN, J. (1983). Algeny. (Viking, New York). S U B C O M M I T T E E O N H U M A N G E N E THERAPY, R E C O M B I N A N T D N A ADVISORY C O M M I T T E E , NATIONAL INSTITUTES O F HEALTH. (1989). Points to Consider in the Submission of Protocols for Somatic Cell Gene Therapy. Office for Recombinant D N A Activities, US National Institutes of Health. TALBOT, B. (1982). Testimony at a hearing before the Subcommittee on Investigations and Oversight ofthe Committee on Science and Technology, US House of Representatives November 16-18, 1982 (97th Congress, Committee report No. 170). U.S. H O U S E O F REPRESENTATIVES, U.S. CONGRESS. (1982). Human Genetic Engineering. (Government Printing Office, Washington, DC) Committee Report No. 170, 97th Congress. W A D E , N. (1980). U C L A gene therapy racked by friendly fire. Science 210, 509-511. W A D E , N. (1981a). Gene therapy caught in more entanglements. Science 212, 24-25. W A D E , N. (1981b). Gene therapy pioneer draws mikadoesque rap. Science 212, 1253. Address reprint requests to: Dr. Robert Mullan Cook-Deegan 7717 Goodfellow W a y Derwood, M D 20855 Received for publication January 23, 1990; accepted February 23, 1990.
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H u m a n
G e n e Therapy and Congress
ROBERT M U L L A N COOK-DEEGAN
ABSTRACT
Congress was the scene of conspicuous debate about human gene therapy during the 19 Congressional interest was sparked primarily by concerns about germ-line gene therapy expressed by clerics and public interest groups. The initial debate was provoked by Martin Cline's misadventures in 1980 and rekindled in 1983 by congressional resolution against germ-line intervention sponsored by Senator M a r k Hatfield. T h efirsthearing on gene therapy was held upon the release ofthe President's Commission report Splicing Life, in November, 1982, before a House subcommittee chaired by Congressman Albert Gore, Jr. Representative Gore later requested a report on gene therapy, which was released by the Office of Technology Assessment in December, 1984. H e also sponsored the legislation that established the Biomedical Ethics Board and Biomedical Ethics Advisory Committee, Congress's abortive attempt to reestablish a federal bioethics commission. Implications of advances in h u m a n genetics, including gene therapy, were to be a m o n g the first topics addressed. Congress passed no substantive legislation affecting gene therapy research or clinical trials, but served principally as a national theater for debate. If and when germ-line gene therapy is contemplated, Congress will be faced with difficult choices, but will likely take no action to block trials that appear safe and are intended to produce clinical benefit for particular individuals.
OVERVIEW S U M M A R Y Because ofthe public's concern about h u m a n genetic engineering, Congress has taken an active role in evaluating the public policy issues surrounding h u m a n gene therapy. Cook-Deegan, particularly during his tenure at the O T A , has himself been a key figure in this evaluation. In this article Cook-Deegan examines the role Congress has played in the past and is likely to play in the future with regard to h u m a n gene therapy.
INTRODUCTION The 1980s began with bright hopes that it would be the decade of gene therapy. As the decade ended, however, there had been but one pair of premature and illegal trials of gene therapy to mark its beginning, and a single approved protocol for gene transfer near its end. The first trial of gene therapy was postponed into the 1990s because of unforeseen technical obstacles.
Senior Research Fellow, Kennedy Institute of Ethics, Georgetown University, and Expert, National Center for Human Genome Research, National Institutes of Health, Bethesda, M D 20892. 163
COOK-DEEGAN Human gene therapy and gene transfer are interesting case examples of anticipatory action by the federal government. Those concerned about the rapid proliferation of technology often point to the fact that developments frequently outstrip policy change. Policy change is usually reactive, developed only after the technology is widespread. Gene therapy is a counterexample—a technology for which the regulatory apparatus has long been in place and has waited for the technology to catch up. Public policy has developed because the technology was anticipated and broadly discussed long before it was actually in place. Part of that discussion directly involved Congress, whose power to set federal rules, to fund science agencies, and to direct regulatory agencies gave it broad influence over policy regarding gene therapy.
T H E PRESIDENT'S COMMISSION REPORT Congress first became involved in gene therapy in the wake of Dr. Martin Cline's 1980 attempts to do gene therapy in two patients with thalassemia, one in Italy and the other in Israel. Dr. Cline proceeded in these experiments while supported, at least in part, by grants from the National Institutes of Health. His experiments with human subjects were thus subject to federal regulations (Code of Federal Regulations). H e was obliged to secure approval from the Institutional Review Board at his h o m e institution, the University of California, Los Angeles. H e proceeded without this approval, however, in a clear violation that stirred a national controversy (Wade, 1980, 1981a,b; Talbot, 1982; Fletcher, 1983). A s a result, two federal grants were terminated and Dr. Cline resigned as chief of the hematology division. The religious leaders of three large denominations—the U.S. Catholic Conference, the Synagogue Council of America, and the National Council of Churches—wrote to President Carter in 1980 expressing concern about rapid advances in genetics and the absence of a federal oversight mechanism. The letter was referred to the newly formed President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (President's Commission) (President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1982). The President's Commission released a report on human gene therapy, Splicing Life, at a congressional hearing in November, 1982, before House subcommittee chairman Albert Gore, Jr. (U.S. House of Representatives, 1982). That landmark report articulated the principal public policy positions that stand to this day. The President's Commission highlighted the distinction between somatic and germ-line gene therapy, asserting that somatic cell gene therapy was morally equivalent to other forms of therapy. Germ-line therapy might never be technically feasible, and should be subject to broad public debate before being adopted. The President's Commission also noted the need for a review mechanism of experiments and also recommended a permanent federal bioethics commission. The President's Commission ceased to operate in March, 1983, after issuing a summary volume and 10 reports on a wide variety of issues in biomedical ethics. In June, 1983, 56 clerics and 8 scientists signed a resolution and sent it to Congress, urging that "efforts to engineer specific genetic traits into the germ line ofthe human species should not be attempted" (Foundation on Economic Trends, 1984). The resolution was introduced by Senator M a r k 0 . Hatfield on June 10 (Hatfield, 1983). The resolution was sent to Congress with a discussion paper written by Jeremy Rifkin, largely based on his recently released book Algeny (Rifkin, 1983). The book, the resolution, and the controversy generated when several signatories ofthe resolution disavowed some ofthe ideas contained in the discussion guide (which most had not seen and did not k n o w was to accompany the resolution) combined to focus attention on gene therapy once again (Richard A. McCormick, personal communication, Kennedy Institute of Ethics, Georgetown University, September 1984; Nelson, 1984). In light of the renewed confusion, Representative Gore requested that the congressional Office of Technology Assessment ( O T A ) undertake a study of h u m a n gene therapy in March, 1984.
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H U M A N GENE THERAPY A N D CONGRESS THE OTA REPORT OTA responded to Mr. Gore's request by scheduling a workshop of outside experts. A panel of 17 scientists, clinicians, genetic counselors, family members, ethicists, lawyers, historians, theologians, and public policy experts met on September 25, 1984, to discuss the issues related to gene therapy. Discussion centered on several papers prepared for the meeting. Nanette Newell of O T A had prepared a review of relevant animal experiments. Lawrence Wissow, a physician from Johns Hopkins, identified what diseases might be targets for gene therapy and outlined the clinical criteria for beginning clinical trials. I had prepared some summary materials as study director. The panel agreed that a n e w document was needed to synthesize the contents ofthe papers and to incorporate n e w information. I had principal responsibility for the rewrite, with substantial help from Nanette Newell and several other O T A staff. Teresa Schwab wrote several technical notes and drew several diagrams. Eleanor Pitts, w h o had recently left the Washington Post and soon left for medical school at Dartmouth, wrote an appendix on diagnostic technologies and a technical note. L. Val Giddings wrote a short note on the biological meaning of species barriers, and Steven Eckman, a s u m m e r fellow from the Wharton School, wrote a long appendix on the confidentiality of genetic information. T h e draft was reviewed by 70 outside experts including the original workshop panel (Office of Technology Assessment, 1984). The report was released on December 10, 1984, as one of the last acts as a m e m b e r of the House of Representatives performed by M r . Gore, w h o had been elected to the U.S. Senate the previous month. T h e O T A report largely restated the moral positions of the President's Commission, augmented by several publications written in the meantime (many in response to the President's Commission report). It noted the shift in focus from disorders of hemoglobin to the genetic forms of immunodeficiency caused by adenosine deaminase and purine nucleoside phosphorylase deficiency, and to Lesch-Nyhan disease. The report listed several scientific, clinical, and public policy criteria to be met by gene therapy protocols. Several religious, medical, and other groups had agreed that somatic cell gene therapy for the treatment of fatal or seriously disabling conditions was acceptable in principle, following the trail blazed by the President's Commission. These statements and technical developments were noted in a large bibliography. The main thrust ofthe report was that somatic cell gene therapy does not raise issues distinct from other treatments, but it might enable treatment of previously untreatable conditions. The O T A report sidestepped the issue of germ-line gene therapy. This was, in part, a political decision. Review of the theological concerns about gene therapy leading to the President's Commission and O T A reports m a d e it clear that the pressing issue was not ethical acceptability of gene therapy, but rather concerns about its impact on future generations. The tack taken by both the President's Commission and O T A was to present concrete reasons to consider gene therapy at all, and to prevent the foreclosure of options if gene therapy research were not pursued. It was relatively easy to show the potential importance of somatic cell therapy, and the bright-line distinction (somatic versus germ-line intervention) was useful to show there was at least one case on which everyone could agree—treatment of a fatal genetic disease in a w a y that did not cause inherited change. It was also important to show that there was an open and public process for reviewing the safety, efficacy, and ethical implications ofthe first trials: the multitiered N I H , F D A , and local review mechanisms. Discussion of germ-line therapy was ducked to focus on a more immediate prospect. The moral basis for separating germ-line and somatic treatment was not clear, but moral consensus vanished in the face of germ-line interventions. In O T A ' s subsequent survey of public opinion, the acceptance of gene therapy did not change significantly if the changes were inherited or not (indeed, approval increased slightly for inherited changes) (Office of Technology Assessment, 1987). In contrast, approval was quite sensitive to the severity of disability treated. This suggested that concern was more about whether the technology would be used increasingly for cosmetic purposes rather than fear of an impact on the "human germ plasm."
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COOK-DEEGAN For purposes of public policy, however, a protracted discussion of germ-line gene therapy was highly speculative and fraught with uncertainties, both technical and moral. The technical barriers to applying germ-line gene therapy were formidable, requiring an improvement of several orders of magnitude in efficiency of inserting a desired gene into a given embryo or egg cell. A n y germ-line interventions would, in all likelihood, require research on human embryos, raising a spate of policy complications. Federal funding for such research was then, as it is now, subject to a federal funding moratorium. Further, research on any embryo obtained following in vitro fertilization was precluded without approval from an Ethics Advisory Board, and no such board had existed since early 1980 (nor will one exist in the foreseeable future, according to James Mason, Assistant Secretary for Health). It was also unlikely that there would be any clinical reason to attempt germ-line therapy until it was highly reliable and there was no option of selecting normal embryos following a genetic test to screen out those affected with a genetic disease. For all of these reasons, the discussion on germ-line gene therapy was brief in the O T A report, concluding that substantial technical improvements would be needed before germ-line gene therapy forced a policy choice.
NIH A N D FDA REVIEW OF PROTOCOLS The Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health (NIH) formed a working group to study and respond to the President's Commission report. It began late in 1983, and worked concurrently with the O T A staff. The chairman ofthe R A C working group, LeRoy Walters, also chaired the O T A workshop. O T A staff attended all R A C working group meetings, and members of the R A C working group reviewed the O T A draft. The two groups were grappling with the same issues simultaneously, but with different ends. The O T A report was a policy statement to Congress, while the working group, later reconstituted as a subcommittee of R A C , had the task of writing guidelines for review of protocols that might be submitted to N I H . The R A C working group produced a document for prospective investigators entitled "Points to Consider in the Submission of Protocols for Somatic Cell Gene Therapy" in 1985, and revised the document in 1989 in light of experience following approval ofthe first gene transfer protocol (Subcommittee on H u m a n Gene Therapy, 1989). The Food and Drug Administration ( F D A ) is responsible for ensuring the safety and efficacy of foods and drugs involved in interstate commerce in the United States. In practice, this authority is broadly intepreted, giving the F D A purview over gene therapy. After some discussion in the period 1984-1985 about parallel review by N I H (through R A C ) and F D A , F D A clearly signaled its intention to review gene therapy protocols. The F D A process extends beyond that subject to mandatory N I H review. Research facilities that receive federal funds for recombinant D N A research must get prior approval for gene transfer protocols from N I H . F D A covers not only these but also any private firms engaged in interstate commerce or using reagents so obtained, in effect covering most conceivable applications. The N I H and F D A reviews both center on safety and efficacy, but the processes are somewhat different. The N I H review is open and highly public; each meeting has been attended by at least a few journalists (and several meetings have been widely covered). The F D A review process is modeled on that used for new drugs and biologies. F D A review is confidential. T h e parallel authority of F D A and N I H has become clearer, and the logistics of the multiple reviews began to be worked out as the first protocol for gene transfer transited by system in 1988 and 1989.
T H E BIOMEDICAL ETHICS ADVISORY C O M M I T T E E A N D BIOMEDICAL ETHICS B O A R D In Splicing Life, the President's Commission recommended that Congress establish a standing body to study the public policy implications of developments in reproductive medicine, genetics, and other areas. 166
H U M A N GENE THERAPY A N D CONGRESS Congress deliberated through 1983 and into 1984, failing to reach consensus on a proper mechanism. Representative Gore, in the wake of his 1982 hearing, introduced a bill to create a n e w President's Commission for this purpose. In the Senate, there was some difficulty reaching an agreement. Senate conservatives were displeased with some of the reports from the President's Commission, particularly positions taken on termination of treatment and access to health care. A search for alternatives was launched, and letters were sent to O T A and to the Institute of Medicine ( I O M ) asking if those institutions were capable of performing the task. I O M and O T A both replied that they could do the job, but the responses were lukewarm because of fear that these institutions would be dragged into the m u c k of abortion politics. Senator Kennedy included a provision adding bioethics to its O T A ' s mandate in the Senate version ofthe 1983 N I H authorization bill, and Gore's proposal for a President's Commission was folded into the House version. T h e bills were passed and went to a House-Senate conference committee for resolution of differences. A compromise emerged from the conference committee—a n e w Biomedical Ethics Board (BEB), comprised of 12 M e m b e r s of Congress (3 Democrats and Republicans from each house), and a Biomedical Ethics Advisory Committee ( B E A C ) , comprised of 14 outside experts. This was generally modeled on O T A , which is also a part ofthe Congress, has a congressional board, and has an outside advisory committee. The conference bill was accepted by both houses, and vetoed in November 1984. A n almost exact replica was reintroduced, passed, vetoed again, and passed over President Reagan's second veto to become law in M a y 1985 (Public L a w 99-158). (The vetoes were not due to the bioethics components, but rather to resistance to creating a n e w arthritis institute at NIH.) Another change was added in conference. B E B and B E A C were given the task of making recommendations on fetal research, specifically on the language about the standard forriskacceptable in research involving fetuses. It took roughly a year to appoint the Members of Congress to B E B , and another 18 months for B E B to appoint the first 12 members of B E A C . The final two appointments, to fill two slots for lay representatives on B E A C , consumed most of another year. B E A C met for the first time on 26 and 27 September 1988, 4 days before its authorization lapsed. B E B and B E A C were reauthorized in the final minutes ofthe 100th Congress, and given access to funds appropriated in previous years but never used. Another addition to the mandate was included in that act—a study on termination of food and fluids administered to dying patients. This brought to three the number of reports mandated by statute in the 2-year authorized existence of B E A C and B E B : a report on implications of h u m a n genetic engineering, on federal guidelines for fetal research, and on nutrition and hydration of dying patients. B E A C met one more time, on February 17 and 18, 1989. Discussion on February 17 was largely devoted to implications of h u m a n genetics. LeRoy Walters described the process for reviewing gene therapy protocols, including the then-recent approval of a 10-patient protocol for insertion of a marker gene to study the treatment of metastatic malignant melanoma. Walters went on to discuss gene therapy. H e noted the unanimous acceptance of somatic cell gene therapy in official statements by governments and religious bodies from around the world. H e explained w h y germ line therapy was not imminent, and recommended that B E A C focus its attention on the more pressing issues related to genetic testing, genetic screening, and provision of genetic services. B E A C accepted these recommendations, and was preparing to deal with gene therapy by recapitulating previous reports, updating the technical discussion by review of the scientific literature, and beginning to analyze the specific clinical situations, if any, in which germ-line gene therapy might be contemplated (Biomedical Ethics Advisory Committee, 1989). Following a congenial and productive meeting in February, B E A C prepared to focus most of its effort on issues related to genetic testing and screening, and to consider the implications of mapping and sequencing the h u m a n genome. B E A C started the process to gather data about confidentiality of genetic information, including h o w genetic tests might be used in health insurance, life insurance, and other insurance contexts, and also in making employment decisions. The cooperative ambience ofthe B E A C was in stark contrast to the 167
COOK-DEEGAN divisive politics and insurmountable distrust that had built up in the governing congressional board. The committee was on the verge of commissioning several papers on roughly a dozen topics when political paralysis ofthe congressional board, B E B , became evident on March 8, 1989. The Senate members of B E B met to elect a chairman, but the discussion devolved to unproductive acrimony and the members found themselves deadlocked. B E B never met again, and B E A C was asked to bide its time until B E B became functional. It never did, and funding for B E A C in 1990 was contingent on several actions by B E B , namely election of a B E B chairman and vice-chairman and appointment of a member of B E A C to fill a vacancy. None of these actions is likely ever to be achieved. B E A C quietly closed its office in the Hart Senate Office Building on September 29, 1989, given loss of spending authority beginning October 1. Barring some unforeseen breakthrough, B E B and B E A C will never function again.
PROSPECTS FOR G E R M LINE G E N E THERAPY: TECHNICAL OBSTACLES A N D A CLINICAL SCENARIO The demise of a federal bioethics commission should have little impact on the immediate prospects for gene therapy. There remains a strong consensus in favor of somatic cell gene therapy for seriously disabling disorders. There is a regulatory process for reviewing clinical protocols. More to the point, B E A C as the federal body charged with reviewing the ethical implications of gene therapy had agreed in principle that somatic cell therapy did not raise new issues and could be handled by summarizing existing statements. Germ-line gene therapy would have been analyzed, but not given great emphasis because of its technical remoteness in comparison to more pressing issues raised by genetic testing and genetic screening. Congress had thus accepted the notion of somatic cell gene therapy. Senator Gore noted this in B E A C hearings before the House Appropriations Committee in January 1989 (Gore, 1989). Congress will become interested in germ-line therapy if its application seems imminent. It is worth considering h o w it might react. The issue will likely surface in the context of a specific clinical context. Germ-line therapy will almost certainly presuppose a means of testing for the presence of a genetic defect. Either a normal embryo will be selected, obviating a need for gene therapy, or the embryo will be tested after treatment to ensure effective treatment. It is difficult to imagine such an experiment being done blindly. There are at least two situations in which the ability to test for and select normal embryos will not resolve the problem of germ-line therapy: (i) The parents are opposed to discarding an affected embryo, on moral or other grounds, or (ii) both parents are homozygous, or for some other reason all progeny would be affected (so selection of an embryo without the genetic defect is not possible). Consider the options facing Congress. In the first case, it is difficult to imagine a direct congressional action to trump the moral judgments of parents w h o are opposed to abortion. It should not do so. The second case is more complex. Suppose, for example, that two young people meet in a genetics support group and fall in love. One m a y have sickle cell disease and the other hemoglobin C disease, or some other combination of hemoglobin disorders that n o w have life expectancies well into the years of reproductive activity. Alternatively, both parents might have phenylketonuria—the essential feature is that both parents are homozygotes for disease-related alleles. What are the public policy options? Congress, or more likely State legislatures, could proscribe marriages of those with genetic diseases. Or the law might proscribe marriage between those heterozygous for specified conditions. Either option would involve specifying a particular group of disorders—ignoring the clinical variability and subject nature of assessing a disorder's impact—and would also put the state in the business of having to mandate premarital genetic testing. These are draconian options fraught with potential for creating a stigma for those identified and subject to cultural bias masquerading as medical judgment. The list of conditions would have to be short to avoid including a
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H U M A N GENE THERAPY A N D CONGRESS significant fraction ofthe population (thus hampering overall reproductive fitness). But even if the technical issues could be resolved, these options are ethically repulsive. O n e of the lessons from the era of eugenics and racial hygiene is that intermarriage laws are morally unacceptable. There is broad consensus that preventing classes of people from marriage on grounds of genetic impact is no business for the law. A legislature could attempt to pass a law to prevent such couples from mating, following the Nazi example, but this is even more intrusive, moving public policy from the social institution of marriage to the extremely private act of intercourse. M a n y religious traditions would m a k e such interference within marriage not only suspect but in fact utterly backward. Public policies could be devised to deny treatment to a homozygous couple's children once born, on the grounds that the parents have knowingly caused children with genetic diseases to be born. Such denial of reimbursement would be highly inconsistent with m a n y other choices w e allow parents and prospective parents to m a k e , which choices are covered through public subsidy and private insurance. W e do not and should not stop treatment of a child with a neural tube defect or hydronephrosis against the wishes of the parents just because the defect was detected prenatally. T o be fair and consistent, there cannot be a public policy to prevent birth of a child with a genetic disease, and costs of care after birth should be covered to the same extent as for other children. A n y other position would be highly problematic. If measures were taken to prevent birth or conception of children born to homozygous parents, it would be an odd message indeed to the parents, both of w h o m would be not only carry, but have the very defect whose presence is used as justification to prevent birth. This strongly resembles the "life not worth living" arguments ofthe racial hygiene period. M a n y parents would not desire treatment, but at least a few probably would. That parents would wish to treat their child so as to prevent a disability they themselves possess does not imply that society should be able to constrain their freedom to choose to have that same child. If there were reliable germ-line therapy, would Congress wish to preclude such therapy because it alters the germ line? It seems unlikely. The state interest in treating the disease of an actual person or person-to-be clearly overrides the possible impact on future generations of that person's family. This is particularly the case w h e n the intervention would likely have either benefit (a functional gene) or no impact at all in subsequent progeny, rather than harms. The benefits 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. If presented with such a clinical scenario, Congress might well refrain from taking action. The argument would likely be that parents should decide what is best for their children. After all, the parents would suffer from the disease in question, and thus be in a position directly to judge the desirability of treatment. T h e impact on future generations would be an expected but not directly intended consequence of treatment. T h e immediate purpose of treatment would be to relieve the suffering of a specific individual, not to alter the gene pool. Congress could, in good conscience, invoke the doctrine of double effect, and protect the reproductive autonomy of two homozygous parents. A n y action to prevent germ-line therapy in this scenarioriskssystematic discrimination against those with genetic disabilities. This is the discredited core ideal of racial hygiene. It seems unjust to hold those with genetic disabilities hostage to speculative dangers if this clinical scenario ever becomes technically feasible. Such a clinical situation m a y never arise, because it presupposes immense technical advances in the ability to insert D N A into embryos or gametes. Such insertion would have to occur in a very high proportion of treated cells, and there would have to be substantial evidence that the procedure had no untoward side effects. Both these constraints put the prospects m a n y years in the future. Thus, Congress will likely not face a debate about germ-line gene therapy in the foreseeable future, and so it m a y not have to revisit the somatic-germ-line distinction. The future debate in Congress as at N I H , F D A ,
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and elsewhere, will properly center on when gene therapy is being used to treat a disease versus enhan desirable human trait, rather than whether it affects the germ line or not.
REFERENCES BIOMEDICAL ETHICS ADVISORY COMMITTEE, US CONGRESS. (1989). Transcript of a meeting, February 17 and 18, 1989. (Washington, DC) February 17 and 18, 1989. C O D E O F FEDERAL REGULATIONS, Title 45, Part 46. FLETCHER, J.C. (1983). Moral problems and ethical issues in prospective human gene therapy. Virginia Law Rev. 69, 515-546. F O U N D A T I O N O N E C O N O M I C TRENDS. (1984). "The Theological Letter Concerning the Moral Arguments Against Genetic Engineering of the Human Germ-Line Cells," reprinted in Taking Sides: Clashing Views on Controversial Bio-Ethical Issues. (Dushkin, Giulford, CT) pp. 276-280. GORE, S E N A T O R A L B E R T (1989). Testimony before the Subcommittee on Legislative Branch, Committee on Appropriations, US House of Representatives (Committee Report, House Report No. 101-179) U S Congress. HATFIELD, S E N A T O R M A R K O. (1983). Congr. Rec, 97th Congress (June 10, 1983), S 8202-S 8205. NELSON, J.R. (1984). The Human Problem ofHuman Genetic Engineering. (Boston, M A ) . Address to Genetics and the Law, III, April 2-4, 1984. OFFICE O F T E C H N O L O G Y ASSESSMENT, U S CONGRESS. (1984). "Human Gene Therapy." OTA-BP-BA-32. (Government Printing Office, Washington, DC). OFFICE O F T E C H N O L O G Y ASSESSMENT, US CONGRESS. (1987). "Public Perceptions of Biotechnology." (Government Printing Office, Washington, DC). PRESIDENT'S COMMISSION 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 BIOMEDICAL A N D B E H A V I O R A L RESEARCH. (1982). Splicing Life: The Social and Ethical Issues of Genetic Engineering with Human Beings. (Government Printing Office, Washington, DC). RIFKIN, J. (1983). Algeny. (Viking, New York). S U B C O M M I T T E E O N H U M A N G E N E THERAPY, R E C O M B I N A N T D N A ADVISORY C O M M I T T E E , NATIONAL INSTITUTES O F HEALTH. (1989). Points to Consider in the Submission of Protocols for Somatic Cell Gene Therapy. Office for Recombinant D N A Activities, US National Institutes of Health. TALBOT, B. (1982). Testimony at a hearing before the Subcommittee on Investigations and Oversight ofthe Committee on Science and Technology, US House of Representatives November 16-18, 1982 (97th Congress, Committee report No. 170). U.S. H O U S E O F REPRESENTATIVES, U.S. CONGRESS. (1982). Human Genetic Engineering. (Government Printing Office, Washington, DC) Committee Report No. 170, 97th Congress. W A D E , N. (1980). U C L A gene therapy racked by friendly fire. Science 210, 509-511. W A D E , N. (1981a). Gene therapy caught in more entanglements. Science 212, 24-25. W A D E , N. (1981b). Gene therapy pioneer draws mikadoesque rap. Science 212, 1253. Address reprint requests to: Dr. Robert Mullan Cook-Deegan 7717 Goodfellow W a y Derwood, M D 20855 Received for publication January 23, 1990; accepted February 23, 1990.
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