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H U M A N G E N E T H E R A P Y 1:55-68 (1990) Mary Ann Liebert, Inc., Publishers

E v o l u t i o n o f Ethical D e b a t e a b o u t Gene

H u m a n

Therapy

JOHN C. FLETCHER

ABSTRACT Ethical issues generally evolve through four stages: threshold, open conflict, extended debate, and adaptation. T h e history of the ethical debate on h u m a n gene therapy is examined. T h e threshold was the Nirenberg appeal in 1967. The open conflict centered around two early controversial cases: those of Rogers and Cline. The extended debate has lasted from 1980 to the present, but n o w adaptation, i.e., a public policy, for somatic cell gene therapy is emerging.

OVERVIEW S U M M A R Y The ethical debate on human gene therapy has a long history. Fletcher examines this history and explains h o w the various events that have occurred can be interpreted as fitting into specific evolutionary stages of the debate. Somatic cell gene therapy is reaching the final stage of its history as an ethical issue, while the discussion of germ-line gene therapy and enhancement genetic engineering is still in the early stages.

INTRODUCTION Four issues have been paramount in the ethical debate about human gene therapy: (i) the ethics of human experimentation as applied to somatic cell and germ-line gene therapy, (ii) whether there is an ethical obligation to future generations to prevent transmission of genetic diseases, (iii) whether reasonable moral lines can be drawn n o w and in the future between the use of genetic knowledge to treat or prevent genetic diseases and uses for "enhancement genetic engineering," and (iv) whether modern societies have the capacity to direct the uses of human genetic knowledge to ethically acceptable ends and still maintain scientific and academic freedom.

Departments of Internal Medicine and Religious Studies, University of Virginia, Charlottesville, V A 22908. Some of the material in this article has appeared in BioLaw, Ref. 1. 55

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FLETCHER Ethical issues have a history. Progress has been made in ethical considerations of somatic cell gene therapy, and it is likely that the history of debate about germ-line gene therapy will eventually follow a similar course. This article traces the evolution of ethical debate about h u m a n gene therapy from the emergence of gene therapy as an ethical issue to considerations of experiments to give recombinant D N A s to live-bom h u m a n subjects. M y views on the ethics of research involving h u m a n pre-embryos and the potential of germ-line alterations are fully expressed in another place/n Ethics and "genicity" "Ethics" is a complex term with several levels or dimensions. I distinguish between the terms "morality" and "ethics" in that the latter involves critical examination of moral conflicts, codes, and other patterns of received morality. "Ethics," write Beauchamp and Childress,(2) "is a generic term for several ways of examining the moral life." S o m e major sources of ethical thought are found in religious, philosophical, and socio-political traditions. Other sources include the individual and corporate reflections of scientists on ethics and protest movements against science that draw eclectically on various political and social traditions. Systems of ethical thought, despite their variability, have at least three clear levels: (i) foundational premises drawn from views ofthe world, h u m a n nature, and good and evil; (ii) sets of general normative ethical guidance, such as basic ethical principles or virtues, etc., that are related directly or indirectly to these foundations, and (iii) "applied ethics" or recommendations for practical approaches to actual moral problems in cultural life. The debate about gene therapy primarily involves applied ethics. The disputants' world views and general ethical positions, though extremely relevant to the issues, are not described. Ethical "issues" are subjects of socio-moral conflict and debate. Debate about h u m a n genetics is often marked with inflamed claims and rhetoric. The huge literature and public comment on h u m a n gene therapy, which has never yet been tried in a socially approved experiment, signals that emotions are at work as well as rational thought processes. The "emotional" is a fourth level for ethics. All ethical problems arise in part from and are accompanied by strong emotions. Issues in h u m a n genetics especially arouse strong emotions. Capron coined the term "genicity,,(3) to capture this reality in relation to h u m a n genetics. Debate about h u m a n genetics frequently evokes metaphors, symbols, or collective memories with starkly negative meanings, e.g., Frankenstein's monster, Nazi eugenic experiments, and nuclear destruction. "Genicity" can also evoke positive or redemptive symbols, such as "liberation" or "revolution," because of hope of deliverance from the great burdens of genetic disease. Stages in the history of ethical issues Ethical issues have histories. They evolve generally in four stages: threshold, open conflict, extended debate, and adaptation. At the threshold of an issue, conditions for moral conflict exist: i.e., clear dangers are present and differing convictions about moral obligations are only perceived. At this stage, leaders or prophetic individuals anticipate ethical problems that only later are more widely appreciated. In the conflict stage, significant or notorious cases m a y arise that epitomize what was predicted, differing moral convictions collide and lead to polarization about what practices should be followed. In the third stage, social and ethical debate spreads, usually in attempts to clarify moral 56

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EVOLUTION OF ETHICAL DEBATE lines. If emotions about the issue do not overwhelm debate, then ethical principles and practices are sought, tested, and readied to ground and back up the line-drawing. In the fourth stage, moral adaptation occurs and public policies are shaped that embody the moral priorities represented by the moral line. After this stage, all n e w cases that arise help test and clarify the moral lines that had been drawn, and lead on to n e w choices to strengthen or reshape the line. Ethical debate almost always involves "line-drawing" disputes, which occur most intensely in the earlier evolutionary stages of the dispute. Moral lines employ distinctions that separate permissible from impermissible actions. With a moral line one is able to show, in actual cases, choices that are morally objectionable or acceptable. In the h u m a n gene therapy debate, m a n y years passed before a moral line was well-defined between research relevant to treatment using somatic cell alterations and all other research alternatives involving germ-line cells, yet which did not morally condemn the possibility of altering germ-line cells to treat and prevent the transmission of genetic disorders. The two issues—somatic cell gene therapy and germ-line gene therapy—had to be distinguished and separated for purposes of debate and public policy considerations. However, in the early stages, somatic cell gene therapy and germ-line gene therapy frequently were merged.

THE E M E R G E N C E OF THE H U M A N GENE THERAPY DEBATE (1967-1980) Threshold of the debate In 1967, Marshall Nirenberg, a Nobelist w h o first described the "language" ofthe genetic code, was also the first to signal the promise and danger of this newly acquired understanding/^ My guess is that cells will be programmed with synthetic messages within 25 years. . . .The point that deserves special emphasis is that m a n m a y be able to program his o w n cells long before he will be able to assess adequately the long-term consequences of such alterations, long before he will be able to formulate goals, and long before he can resolve the ethical and moral problems which will be raised. W h e n m a n becomes capable of instructing his o w n cells, he must refrain from doing so until he has sufficient wisdom to use this knowledge for the benefit of mankind. . . .Decisions concerning the application of knowledge must ultimately be m a d e by society. Nirenberg's first appeal was for restraint, because he was referring to alterations in cells that were "inheritable," i.e., germ-line alterations. Second, he cautioned that any deliberate attempt to "program cells," i.e., aiming to correct the expression or the transmission of one or more harmful genes at the molecular level, presupposes knowledge or "wisdom" of h o w to use genetic alterations for beneficent purposes. Such a state of affairs presumes a moral line that differentiates between beneficial and harmful uses of genetic knowledge, a line that society itself ought to have a strong hand in shaping. Nirenberg's references to "society" in his appeal for restraint and wisdom were not empty rhetoricalflourishes.B y 1966, it was clear that leaders in the United States, including m a n y scientists as well, wanted more social control of activities at the moral line between research and 57

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FLETCHER treatment. Heretofore, scientists were entrusted with the moral authority to decide when research ought to begin. Clinical investigators m a d e virtually all decisions about what research was most beneficial and least harmful, which research subjects should be approached to participate, and even whether these subjects should be informed or not about studies done upon them. Not surprisingly, m a n y types of harm to research subjects resulted, which were documented in the early literature on h u m a n experimentation by prophetic figures like Beecher and Pappworth/5) Research ethics in the United States and other nations became an issue that itself developed through the four stages outlined above. After a period of open conflict and debate, leaders in science and Congress took steps in shaping public policy to assure more active protection of research subjects and investigators. Accordingly, public policy and Federal regulations eventually changed. The n e w policy was that before scientific review and funding decisions by the U S Public Health Service, research to involve h u m a n beings should receive a "prior group review" (to concentrate on ethical considerations) in an applicant's institution.(6) The group, later called an Institutional Review Board (IRB), was required to be both cross-disciplinary and reflect community values. At least one noninstitutional m e m b e r was required in a m i n i m u m of five members. A second level of national review, an Ethical Advisory Board ( E A B ) , was required by Federal regulations in 1975 to advise the Secretary of the Department of Health and H u m a n Services ( D H H S ) about ethical and other issues related to research in vulnerable populations.(7) The E A B was founded in recognition that local IRBs were not equipped to consider the long-range social, legal, and ethical implications of n e w research, such as that envisioned in h u m a n gene therapy. D u e to political controversy about abortion, fetal research, and embryo research, no E A B has existed since 1980. The significance of this loss and its relevance to the future of h u m a n gene therapy is discussed in another place/0 Since 1966, prior group review has evolved, with society's support and approval, to an ethically normative requirement for h u m a n experimentation. N o research involving h u m a n subjects, whether funded by public or private sources, is considered even minimally acceptable, from an ethical perspective, without prior group review. This rule is widely respected by refusal of journals to publish results from research that has not been properly reviewed. Also, review groups and their experience became building blocks in the creation of public wisdom about the ethics of research, including research in h u m a n gene therapy, along with a n e w literature on the subject. The evolution of the ethical requirement of prior group review and the ethical debate about h u m a n gene therapy are interwoven.

Conflict about early cases of attempted gene therapy T w o famous cases at the beginning and end of this period (1970 and 1980) were occasions for open conflict about the ethics of experimentation and h u m a n gene therapy. These cases are outlined below. In each, an American investigator, working abroad, attempted to treat genetic disorders. The first experiment used an indirect method, i.e., injection of a virus thought to stimulate genetic expression. The second was a true genetic experiment, i.e., aimed to transfer copies of r D N A s containing normal genes. The first case preceded required prior group review of research; the second was after the practice was well established. The Rogers' Case: In 1969, Terheggen, a German physician, described(8) two sisters (18 months and 5 years) suffering from hyperargininemia whose parents were related. T w o other 58

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EVOLUTION OF ETHICAL D E B A T E unaffected children had intermediate levels of arginine. The two affected sisters and a third affected girl b o m in 1971 were unsuccessfully treated with injections of Shope papilloma virus (SPV) between 1970 and 1973, with the assistance of an American scientist, Dr. Stanfield Rogers, w h o had earlier observed that researchers working with this vims have low blood arginine/9) Rogers described S P V as a "passenger" vims that does no harm to the cells it infects, although earlier experiments in rabbits given high doses of S P V caused cancer/10) N o other S P V experiment for hyperargininemia has been reported. In 1970, news reports appeared about Dr. Roger's case.(11) In 1971, Senator Walter Mondale introduced a bill for a "National Commission on Health, Science, and Society" to investigate and study the legal, social, and ethical implications of medical research, including the aims of geneticists. Mondale's testimony referred to the dangers of genetic manipulation/12) Also in 1971, Canon Michael Hamilton of the Washington Cathedral convened the first national conference, "The N e w Genetics and the Future of Man."(13) There the Rogers' case was sharply debated by W . French Anderson and Paul Ramsey. Anderson saw "little question about moral justification" given his appraisal of the harmless nature of S P V and the affliction of the German sisters, but he cautioned that "success here might encourage less justified attempts at premature gene therapy."(14) H e pointed to the "larger question .... What about other genes, other vimses? Where does one draw the line?" Anderson presumed that insertion in germ-line cells would be feasible. H e asked w h o is to decide what are good and bad uses. Anderson said that correcting a genetic defect is a good use, while inserting a gene for "blond hair" would be a bad use. A n d he described other "bad uses" as inserting genes for larger size, military purposes, or infecting enemy populations. H e noted that there m a y be an attempt to "improve intelligence" but made no moral judgment about this goal. Anderson favored an advisory commission on genetics rather than a regulatory body to "centralize control" in genetics. H e pointed to the lack of consensus about therapeutic abortion as a precedent for the inability of a small group to reach "wise and just" decisions about. . . "influencing the hereditary characteristics of ourselves and our future generations." H e endorsed Mondale's proposal as a public forum to establish goals and safeguards, along with a slow, deliberate public education process until science was ready for experiments in gene therapy. His final conference statement was reminiscent of Nirenberg's: This area holds such promise for alleviating human suffering, and yet is so basic to the needs and emotions of all men, that no individual or group of individuals should take it upon themselves to make the decisions. Only the conscience of an informed society as a whole should make these decisions/15) Ramsey, noting the cancer risks of SPV, nonetheless approved Rogers' attempt with the youngest child, based on a chance of benefit. H e criticized the attempt in the older child(16) in w h o m the disease had fully progressed as unjustified genetic experimentation using a retarded child. Ramsey opposed investigative research with children as a violation of the consent requirement/17) Predicting that scientists cannot resist the temptation of intervention in germ-line cells, he described the dangers in a cascade of metaphors: e.g., "untold human suffering, dehumanization, exploitation, radical alteration of the conditions of human existence, genetic SSTs and Lake Eries."(18) H e doubted that society, through an advisory commission, could contain the dangers caused by a "laissez-faire system of biomedical investigation." H e desired a moral line to prohibit any human experimentation with gametic cells, since "the unknown and 59

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FLETCHER unforeclosed risks to future generations may outweigh any benefit that might be secured to the individual patient." T o do any germ-line research, Ramsey added, " W e need to k n o w that there are norisks(italics added)." Clearly, on this premise, no research in germ-line gene therapy could ever occur. Ramsey's theology was the source of his ethical position on germ-line therapy. H e was willing to forsake knowledge of whether germ-line therapy is possible and risk depriving future individuals of health rather than, in his view,risklosing the faith that life is "created" and erosion (in his view) of the ethical imperative to save and care for genetically impaired people. Ramsey did raise an unexplored ethical question about the Rogers' case: i.e., the choice of subjects. With prior group review, both patient selection and reasonable scientific doubt about the S P V experiment, stated later by Friedman and Roblin,(19) would have been more thoroughly discussed. In m y view, Rogers did nothing unethical. H e acted openly, after peer discussion, aiming to given an unknown but minimally promising "innovative therapy" to suffering patients. At this time, no restrictions were placed on the activities of U S scientists abroad. H e acted within the ethical constraints of his era. Oversight of Recombinant D N A Research: After the Rogers' case, a revolution in recombinant D N A (rDNA) technology opened the way to research on delivery of gene therapy on the molecular level. Areen's law review article on human gene therapy describes these events and their sequalae,(20) i.e., a self-imposed moratorium in 1973-1974 and subsequent regulation of D N A research. The National Institutes of Health (NIH) took the regulatory initiative, despite its conflict of interest in being a main actor and founder in r D N A research. However, scientists trusted the N I H more than any other seat of regulation, and the Congress was then unwilling to challenge the NIH's self-interest. Shaped by a Recombinant D N A Advisory Committee ( R A C ) to the Director, N I H , guidelines were published in 1976,(21) and applied to Federally funded institutions conducting r D N A research, regardless of souce of funds for the research. The guidelines defined ascending levels of biohazard in r D N A research that required review by a new entity in the applicant's institution called an Institutional Biosafety Committee (IBC). Relevant to research in gene therapy, any r D N A experiment supported by N I H funds that also introduced r D N A molecules into human beings required approval by both local IBC and an IRB, before approval by the R A C itself. The N I H guidelines also applied to projects done abroad if they are supported by N I H funds. Dr. Cline's cases: In September, 1980, the N I H learned that, earlier that year, Dr. Martin Cline tried human gene therapy with r D N A molecules in bone marrow transplants on two patients with hereditary blood disorders in Israel and Italy/22) In M a y , 1979/23) Dr. Cline asked the IRB ofthe University of California at Los Angeles ( U C L A ) to review a project to treat patients with sickle cell disease and other inherited blood disorders with a triple-combination r D N A arrangement. While still under review, the protocol was then altered in September, 1979, by Cline to "delink" the plasmid vector to permit "naked" insertion of the globin and herpes vims thymidine kinase genes. This change appeared to remove the requirement for approval by the U C L A IBC, since the r D N A vector would be removed. However, the protocol remained on the agenda of the IBC, which was waiting for the IRB to approve before considering the protocol. The N I H refused to intervene to make a judgment, desiring that U C L A ' s IRB first consider the human experimentation aspects of the protocol. The N I H expected to have the final word on whether the Cline r D N A experiment would be done at all. At any rate, in the same request to alter the protocol, Cline acknowledged his responsibility to attain separate approvals by both the IRB and the IBC in his 60

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EVOLUTION O F ETHICAL D E B A T E own institution. UCLA's IRB disapproved the protocol in July, 1980, agreeing with outside consultants that more animal studies were needed. In March to July, 1980, Dr. Cline arranged to treat patients abroad. H e used the original three-combination r D N A approach. Italy had no review committees at that time. In Israel, a research ethics committee composed entirely of physicians received the request. Dr. Cline gave them the "delinked" version of the protocol altered for the U L C A IRB. Familiar with the N I H r D N A guidelines, Israeli authorities tried to verify that the experiment did not involve recombinant D N A molecules. A telex was sent from U C L A to Israel stating that Dr. Cline's protocol (the "delinked" version) did not involve such r D N A s . Dr. Cline then, in fact, injected the r D N A form of the genes into the patients. H e explained that he used the original protocol: . . because I believed that they (the recombinant genes) would increase the possibility of introducing beta-globin genes that would be functionally effective, and would impose no additionalriskto the patient, since it was known that pieces of D N A are efficiently linked in all combinations once they are taken into cells. I made this decision on medical grounds/24) Dr. Cline violated several ethical norms, beginning with evasion of prior group consideration and deception of Israeli and U C L A IRBs. A s noted above, IRB review has a premise that patients are better protected when clinical researchers are not sole arbiters of when clinical research ought to begin in human beings. Self-interest and zeal to treat can and does cloud research judgments. A strong moral consensus existed for this premise at the time/25) Dr. Cline also deceived the two research patients, in that the consent he obtaned did not accurately explain the full nature ofthe experiment, or that r D N A was to be given to human beings for the first time. Other criticisms and judgments about of Dr. Cline's cases are in the literature.(26,27) T o his credit, Dr. Cline regretted his actions, admitting that he used "poor judgment."(28) In a larger sense, Dr. Cline violated the ethos of restraint in human gene therapy begun with Nirenberg's appeal, protected by IRB review, and embodied in the N I H regulations. For this violation he was severely censured and punished. H e resigned his department chairmanship. N I H cancelled his current grants and for a period of years attached a report of its investigation to all of his applications for grant support. After the Cline experiment and at the recommendation of the President's Commission for the Study of Ethical Problems in Medicine,(29) the N I H added a Working Group on H u m a n Gene Therapy to provide national review of the first experimental human gene therapy protocols/30) The Working Group's (now called the H u m a n Gene Therapy Subcommittee) guidelines will be discussed in the final section.

EXTENDED DEBATE A B O U T H U M A N G E N E THERAPY (1980-1989) Since Cline's cases, no somatic cell gene therapy experiments have been done for scientific and ethical reasons. Basic scientific criteria in animal experiments have not been satisfied, which is required before tests in humans can ethically begin/31) Also, debate continued about society's capacity to control r D N A technology and the goals of genetic alterations in human cells. In the early 1980s, a "slippery slope" argument against gene therapy tended to influence clergy and other 61

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FLETCHER opinion leaders. According to this view, successful somatic cell gene therapy would inevitably lead to premature or even wholesale attempts at germ-line gene therapy with unknown and inheritable harms. There was broad-based concern, at least as signaled by religious leaders, about h u m a n gene therapy. For these reasons, a unique national oversight system arose for experimental human gene therapy to assess the scientific and ethical acceptability ofthe first somatic cell gene therapy experiments. Broad-based concerns merit national review In 1980, three leading religious leaders brought their concerns about r D N A technology and human gene therapy to the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Interrupting its planned agenda, the Commission responded to their appeal to consider the social, legal, and ethical implications of r D N A research and its application to h u m a n beings. The Commission's subsequent report, entitled Splicing Life,(29) strongly defended the continuation of r D N A research. The report answered an oft-heard charge that r D N A research was "playing G o d " by the strategy of distinguishing between acceptable and unacceptable consequences ofthe research. Somatic cell human gene therapy was among the most desirable consequences named by the Commission. The Commission recommended that no research be undertaken in human germ-line cells, but that it not be banned. It further recommended that N I H oversight of r D N A research and its h u m a n applications be broadened to include the consideration of ethical and social implications of h u m a n gene therapy. Following the Commission's report, a stronger ethical consensus in the United States arose to encourage experiments in somatic cell gene therapy. Evidence that biohazards in research with r D N A could be safely contained strengthened consensus. Most commentators saw somatic cell gene therapy in continuity with new departures in treatment like bone marrow or organ transplantation. Authorities in science, religion, and public policy agreed/32'33'26) Polarization: Efforts to ban germ-line experiments During this period, the social activist Jeremy Rifkin became the focus of opposition to r D N A research and to h u m a n gene therapy. T o some extent, he influenced public opinion, as measured by editorials that appeared at the time. H e aimed a consequentialist argument against all forms of human gene therapy, including somatic cell gene therapy. H e wrote: Once we decide to begin the process of human genetic engineering, there is really no logical place to stop. If diabetes, sickle cell anemia, and cancer are to be cured by altering the genetic makeup of an individual, w h y not proceed to other "disorders": myopia, color blindness, lefthandedness? Indeed, what is to preclude a society from deciding that a certain skin color is a disorder?(34) Rifkin saw "ethics" as totally determined by social forces, a by-product of a technological society. H e wrote: . . . ethics are designed to be compatible with the way people organize the world around them. Moral codes keep people's future behavior in line with the way society goes about organizing and assimilating its environment/35) 62

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E V O L U T I O N O F ETHICAL D E B A T E

Rifkin's remedy, similar to but more radical then Ramsey's, was not to permit gene therap even at the loss of treatment. H e described dangers of "degradation" by engineering people in the image of culturally desirable traits. H e asked, in a secular voice echoing Ramsey's theology, "Is guaranteeing our health worth trading away our humanity?"(36) A s chances for somatic cell gene therapy improved, Rifkin tempered his view of it as the cliff of a "slippery slope." B y this time (1983), religious leaders tended to support somatic cell gene therapy. H e needed clergy support for a proposed ban on germ-line genetic experiments. A sympathetic editorial in The N e w York Times proposed a public policy prohibiting "inheritable alterations to the h u m a n gene set."(37) Then, 75 prominent religious leaders signed a resolution, written by Rifkin, to the U S Senate asking for a ban on germ-line experiments/38) Capron published an appeal that Congress not ban any r D N A experiments/39) H e argued that the resolution w a s based on "false assumptions" and would involve the government directly in medical and reproductive decisions, a result that the sponsors ofthe resolution themselves would want to avoid. Capron sharply criticized a premise in the resolution that it would soon be technically possible to do genetic engineering on a mass scale. The mass-scale premise also was in a study document from a Panel on Bioethical Concerns of the National Council of Churches that remains unmatched for "genicity." For example: It is now possible to alter all life forms, intentionally, with a precision and speed never before k n o w n to humankind. It is also possible to alter life in such a way that it affects not only the present generation, but also the gene pool of all future generations as well. W o r d s that once were primarily the language of the church are n o w also the words ofthe current biological revolution. "Life, Death, Creation, N e w Life, N e w Day, N e w Earth" are n o w in the vocabularies of biological science, biotechnology, andbiobusiness/40) Fallacies in reasoning Arguments for a ban on germ-line genetic research are frequently marked by flaws in reasoning. These arguments stress: (i) that technology causes moral problems in h u m a n genetics, (ii) that attempts to engineer h u m a n reproduction by germ-line methods are inevitable, since clear moral lines cannot be drawn due to subjective aspects in defining disease and disability, and (iii) that social ethics is determined by the imperatives of technological societies. The latter idea is often expressed by the slogan, "If it can be done, it will be done." N o one of these claims is logical or supportable by evidence. D o e s Technology Cause Moral Problems? Moral conflicts do frequently arise about technology, but these concern the best w a y to apply technology and prevent abuses. Technology is an occasion for moral problems but not the cause. T o m a k e technology itself a moral problem is to displace the cause, i.e., to locate the problem in a thing or person, thus creating a scapegoat for fears b o m in genicity. Is Drawing Moral Lines in Gene Therapy Impossible? Is it impossible to draw clear lines between genetic disorders and conditions that are genetically determined to some degree but have little to do with disease? Anderson(41) writes that "enhancement genetic engineering" is also possible with somatic cell techniques. Lines will have to be drawn about the uses of somatic cell gene therapy. B y doing so, society will gain experience in line-drawing that will protect eventual germ-line gene therapy, if it is feasible, from abuse. 63

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FLETCHER In human gene therapy, the most cmcial moral distinction is between uses of genetic knowledge that m a y relieve patients' suffering, morbidity, and mortality, and those potential uses that would alter characteristics having little or nothing to do with disease. O n the permissible side of genetic experiments would be those disease candidates that dominate h u m a n lives, foreshorten them, and plague the sufferer with pain and disability. Wissow(42) assembled a spectmm of diseases for human gene therapy in terms of feasibility: 1. Protocols expected in the next several years: immunodeficiencies caused by adenosine deaminase or purine nucleoside phosphorylase that destroy the capacity of the child to fight infection, Lesch-Nyhan syndrome, urea cycle defects (citrullinemia and ornithine carbamoyl transferase [OCT]). 2. Might be attempted in foreseeable future: phenylketonuria, familial hypercholesterolemia, urea cycle defects other than citrullinemia or O C T , arginnemia, mucopolysaccharidoses and other defined metabolic defects, Gaucher disease, metachromatic leukodystrophy, Hunter syndrome, and branched-chain ketoaciduria. 3. Farther off because protein expression m a y require regulation: hemoglobinopathies (e.g., sickle cell disease, hemoglobin S C disease, alpha and beta thalassemia). 4. Farther off because gene product m a y be easily available for administration, thus diminishing the need for gene therapy: growth hormone deficiency; hemophilias. 5. Unlikely without n e w discoveries or requiring germ-line therapy: Tay-Sachs disease and other metabolic defects that primarily affect the brain, cystic fibrosis, type 1 A growth hormone deficiency; most dominant disorders (e.g., Huntington disease, Marfan syndrome, achondroplasia). 6. M a y not be applicable: chromosomal disorders: D o w n syndrome; environmental and mucigenic disorders, e.g., hypertension, diabetes. Contrast these disorders and their devastating consequences with conditions probed by Glover, an Oxford moral philosopher, as he explores genetically designed changes of characteristics associated with troubled human nature but not with diseases/43) Can lines be drawn? Thinking about the optimal "start of life" (germ-line genetic engineering), he argues for cautious willingness "to change what w e are like." H e is open-minded about some gene experiments to alter intellectual capacity or aggression. His values are personalistic, i.e., concerned with "self-development and self-expression; certain kinds of contact with other people; the development of consciousness." However, these conditions are not diseases and have no relation to disease states. T o commit social resources to alter such conditions would be prima facie unfair, would it not, as long as there are persons w h o undeservedly suffer from biologically inherited disorders, like those on the Wissow spectmm above? Could not a line be drawn in public policy to prevent "enhancement genetic engineering," based on a distinction rooted in morbidity, mortality, pain, and suffering? Anderson(41) gives three examples of enhancement engineering of somatic cells: (i) a genetically enhanced brain chemical to improve m e m o r y capacity, (ii) growth hormone genes for an adolescent whose parents are both 5 feet tall, and (iii) genetically enhanced resistance for workers continually exposed to an industrial toxin. H e argues that whether the scenario is individuals requesting such help for themselves or for their children (in germ-line therapy), three problems would be paramount: (i) medical hazards from inserting foreign genes into the genome 64

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EVOLUTION OF ETHICAL DEBATE of a person, (ii) moral hazards in deciding which person(s) should receive the therapy, and (iii) social hazards in terms of discrimination against persons identified at highest geneticriskand w h o were thus treated. For these reasons, he draws the line at enhancement genetic engineering. There will be difficult cases that lie in a morally gray area, such as in the use of gene therapy for h u m a n growth. But the overall task of drawing lines is clearly not impossible. Anderson goes further in a 1985 article about ethics and h u m a n gene therapy. H e is open to attempts at germ-line therapy and, in the same article, uses three criteria to define conditions that would be ethically necessary before germ-line experiments to treat and prevent real genetic disorders: First, there should be considerable previous experience with somatic cell gene therapy that clearly establishes the effectiveness and safety of treatment of somatic cells; second, there should be adequate animal studies that establish the reproducibility, reliability, and safety of germline therapy, using the same vectors and procedures that would be used in humans; and third, there should be public awareness and approval of the procedure/44) The same restraint can be expected in this line of research, indeed even greater than with somatic cell experiments. C a n Society Control Science? Can society guide the goals of human gene therapy? Is ethics determined by desires blindly driven by technological imperatives? Four counterexamples of ethically based restraint of science and technology are worth noting, especially since each is strongly supported by public opinion, regulations, or laws. First, m u c h could be learned about teratogenesis and other environmental harms from uninhibited research on fetuses destined for abortion. But prohibitions exist in the United States and m a n y nations against any high-risk or deliberately harmful experiment with a fetus to be aborted. Unlimited fetal research "can be done" in the context of abortion, but it is not done for ethical reasons. Second, although mandatory genetic screening could prevent m u c h disease, no society has required it/45) U S Federal law will not permit funding of genetic screening programs unless these are voluntary/46) Selection of research subjects is a third example. Prisoners, children, and the mentally retarded were once convenient subjects for highlyriskyresearch, but this situation has radically changed primarily for ethical reasons. Federal regulations strongly protect such vulnerable groups/47) The fourth example is restraint (except for one investigator) in premature attempts at somatic cell h u m a n gene therapy. This example extends to experiments to alter germ-line cells. This possibility could have been seized upon in the United Kingdom, where pre-embryo research is being done under the oversight of an "Interim Licensing Authority" as a substitute for a Statutory Authority as called for by the W a m o c k Report/48) However, the guidelines of the Interim Authority state explicitly that "modification of the genetic constitution of a pre-embryo" will not be approved.

PUBLIC POLICY ON HUMAN GENE THERAPY As discussed above, the President's Commission recommended that the NIH respond to public concern about h u m a n gene therapy with a public policy of second-level, national ethics review of 65

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FLETCHER the first gene therapy protocols. There being no EAB since 1980, the NIH RAC has added a H u m a n Gene Therapy Subcommittee, chaired by a bioethicist, Leroy Walters. A document published by the Subcommittee for those w h o would submit protocols for gene therapy, "Points to Consider,"(49) defined somatic cell therapy and germ-line alterations, drawing an important moral distinction between them, and adapting the distinction to public policy: A distinction should be drawn between making genetic changes in somatic cells and in germ-line cells. The purpose of somatic cell gene therapy is to treat an individual patient, e.g., by inserting a properly functioning gene into a patient's bone marrow cells in vitro and then reintroducing the cells into the patient's body. In germ-line alterations, a specific attempt is m a d e 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. The R A C and its working group will not at present entertain proposals for germ-line alterations but will consider for approval protocols involving somatic cell gene therapy. The text then cited the strong societal and religious support that exists for somatic cell gene therapy, its continuity with other modes of treatment, and its consistency with the traditional purpose of clinical research, i.e., to benefit the individual subject and gain knowledge. The two most harmful (unintended) consequences cited by the document were seen as: (i) changes in reproductive cells and (ii) exposure of others to viral infection due to the technique used to transfer the treatment genes to the patient. The Subcommittee's position on germ-line experiments is procedural rather than a judgment that they are intrinsically unethical. This view differs widely from that taken in drafts of proposed laws for the Parliamentary Assembly of the Council of Europe stating that each individual "has a right to a genetic inheritance that has not been artificially manipulated."(50) This view stems from a "natural law" argument applied to the h u m a n genome. O n e could argue for the utmost care and caution in ever experimenting with alterations in germ-line cells designed to be inheritable. But to argue that it should never be done at all is unreasonable at the least, examined from the standpoint ofthe well-being of future generations. O n e generation can learn if germ-line therapy is feasible. In their o w n time, other generations can deccide if an h o w to use this knowledge. The same restraint and societal oversight of h u m a n gene therapy must be followed in any case.

NOTES 1. Fletcher, J.C. Ethics and human gene therapy. Past, present, and future. BioLaw (in press). 2. Beauchamp, T.L., and Childress, J.F. (1989). Principles of Biomedical Ethics, 3rd ed. (New York: Oxford University Press, 1989) p. 9. 3. Capron, A.M. (1985). Unsplicing the Gordian knot. Legal and ethical issues in the new genetics. In: Genetics and the Law III, A. Milunsky, and G.J. Annas, eds. (New York: Plenum Press) p. 24. 4. Nirenberg, M . (1967). Will Society Be Prepared? Science 157, 633. 5. Beecher, H.K. (1968). Ethics and clinical research. N. Engl. J. Med. 278, 1354-1360; Pappworth, M.H. (1967). H u m a n Guinea Pigs. (London: Routledge and Kegan Paul). 6. Surgeon General, U S Public Health Service, Public Policy Order No. 129. (1966). Investigations Involving Human Subjects, Including Clinical Research. Requirements for Review to Insure the Rights and Welfare of Individuals, July 1. 66

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EVOLUTION OF ETHICAL DEBATE 7. 45 Code of Federal Regulations Part 46:204 Ethical Advisory Boards, revised as of March 8, 1983. 8. Terheggen, H.G., Lowenthal, A., Schwenk, A., etal., (1969). Argininaemia with arginase deficiency. Lancet ii, 748-749. 9. Rogers, S. (1970). Skills for genetic engineers. N e w Scientist 45 194;Rogers, S. (1976). Reflections on issues posed by recombinant D N A molecule technology II. Ann. N Y Acad. Sci. 265, 66-67. 10. Rous, P., and Beard, J.W. (1935). The Progress to carcinoma of virus-induced rabbit papillomas (Shope). J. Exp. Med. 62, 523-548. 11. Schmeck, H. (1970). Virus is injected into 2 children in effort to alter chemical traits. The N e w York Times, September 20, p. 28. 12. U S Congress, Committee on Government Operations. (1968). Hearings Before the Subcommittee on Government Research, SJ. Resolution 145 90th Congress, pp. 5, 8. 13. Hamilton, M . (1972). ed., The N e w Geneticsand the Future of Man. (Grand Rapids, MI: WilliamB. Eerdmans). 14. Anderson, W.F. (1972). Genetic therapy. In Hamilton, op. cit., pp. 118-119. 15. Anderson, op. cit. p. 121. 16. Ramsey, P. (1972). Genetic therapy. A theologian s response. In Hamilton, op. cit., p. 163. 17. Ramsey, P. (1970). The Patient as Person. (New Haven, CT: Yale University Press) pp. 11-19. 18. Ramsey, P. (1972). In Hamilton, op. cit., p. 166. 19. Friedman, T.A., and Roblin, R. (1972). Gene therapy for human genetic disease. Science 175, 949-953. 20. Areen, J. (1985-1986). Regulating human gene therapy. West Virginia Law Review 88, 153. 21. Milewski, E. (1984). The N I H Guidelines for Research Involving Recombinant D N A Molecules, available through the Office of D N A Activities, (Bethesda, Maryland: National Institute of Allergy and Infectious Diseases). 22. Kolata, G.B., and Wade, N. (1980). Human gene treatment stirs new debate. Science 210,407. 23. National Institutes of Health. (1981). Report of the N I H A d Hoc Committee on the U C L A Report Concerning Certain Research Activities of Dr. Martin J. Cline (memorandum), M a y 21. 24. NIH, Cline Report, op. cit., p. 8. 25. Tranoy, K.E. (1983). Is There a Universal Research Ethics? In Research Ethics K. Berg and K.E. Tranoy, eds. (New York: Alan R. Liss) pp. 3-12. 26. U S Congress, Office of Technology Assessment. (1984). H u m a n Gene Therapy. A Background Paper (Washington, D C : OTA-BP-BA-32, Superintendent of Documents, U S Government Printing Office) December, p. 46. 27. Williamson, B. (1982). Gene therapy. Nature 298,418. 28. NIH, Cline Report, p. 16. 29. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. (1983). Splicing Life (Washington, D C : U S Government Printing Office) pp. 60-89. 30. Office of Technology Assessment, H u m a n Gene Therapy, p. 80. 31. Anderson, W.F., and Fletcher, J.C. (1980). Gene therapy: W h e n is it ethical to begin? N. Engl. J. Med. 303, 1293-1297. 32. Friedman,T.A. (1983). Gene Therapy .Fact and Fiction (Cold Spring Harbor, N Y : Cold Spring Harbor Laboratory). 33. U.S. Congress. (1982). H u m a n Genetic Engineering, Hearings Before the Subcommittee on Investigations and Oversight of the Committee on Science and Technology. (Washington, D C : U S Government Printing Office) p. 301-346. 34. Rifkin, J. (1983). Algeny (New York: Viking) p. 232. 35. Rifkin, op. cit., p. 54. 36. Rifkin, op. cit., p. 233. 37. Editorial. (1982). Whether to make perfect human beings. The N e w York Times, July 22, p. A22; The rules for reshaping life, December 29, p. A17. 38. Norman, C (1983). Clergymen urge ban on altering germline cells. Science 220, 1360-1361. 39. Capron, A.M. (1983). Don't ban genetic engineering. Washington Post, June 26, p. A26.

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FLETCHER 40. Panel on Bioethical Concerns, National Council of the Churches of Christ/USA. (1984). Genetic Engineering. Social and Ethical Consequences (New York: Pilgrim Press) pp. 1-2. 41. Anderson, W.F. (1989). H u m a n gene therapy: W h y draw a line? J. Med. Philos. 14, 681-693. 42. Wissow, L., Examples of disease for which gene therapy might be considered, In Office of Technology Assessment, H u m a n Gene Therapy—A Background Paper, op. cit., p. 26. 43. Glover, J. (1984). What Sort of People Should There Be? (Penguin Books) pp. 185, 158, 133-134. 44. Anderson, W.F. (1985). Human gene therapy: Scientific and ethical considerations. J. Med. Philos. 10, 275-291. 45. Wertz, D . C , and Fletcher, J.C. (1989). An International Survey of Attitudes of Medical Geneticists Toward Mass Screening and Access to Results, Public Health Reports 104 (January-February), pp. 35-44. 46. National Genetic Diseases Act, Title IV, U.S. Public Law 94-278, April 22, 1978,90 Statutes, p. 407; Andrews, L.B. (1985). Sickle cell screening laws and regulations. In State Laws and Regulations Governing Newborn Screening (Chicago: American Bar Foundation) pp. 147-155. 47. 45 Code of Federal Regulations, Part 46. Subpart C, Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects; Subpart D, Additional Protections for Children Involved as Subjects in Research. Revised as of March 8, 1983. 48. Interim Licensing Authority. (1989). The Fourth Report for H u m a n In Vitro Fertilization and Embryology. (Eastbourne, East Sussex: Sumfield & Day, Ltd.) Available from V L A Secretariat, 20 Park Crescent, London, W I N 4AL. 49. National Institutes of Health. (1985). Points to consider in the design and submission of human somatic-cell gene therapy protocols. Fed Reg. 50, 33463-33467. 50. Parliamentary Assembly of the Council of Europe. (1989). Recommendation 934 (1982) O n Genetic Engineering; cf. Embryos And Fetuses: The European View, Institute of Medical Ethics Bulletin, No. 51, June, pp. 13-14. Address reprint requests to: Dr. John C. Fletcher B o x 348 Health Science Center University of Virginia Charlottesville, V A 22908 Received for publication October 12, 1989; accepted November 10, 1989.

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Evolution of ethical debate about human gene therapy.

Ethical issues generally evolve through four stages: threshold, open conflict, extended debate, and adaptation. The history of the ethical debate on h...
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