BURKE K.

ZIMMERMAN

HUMAN GERM-LINE THERAPY: THE CASE FOR ITS DEVELOPMENT AND USE

ABSTRACT. The rationale for pursuing the development and use of germ-line selection and modification techniques is examined in this essay. The argument is put forth that it is the moral obligation of the medical profession to make available to the public any technology that can cure or prevent pathology leading to death and disability, in both the present and future generations. Society should pursue the development of strategies for preventing or correcting, at the germ-line level, genetic features that will lead to, or enhance, pathological conditions. Because prenatal screening and even early embryo screening and selection can prevent only a subset of known genetic disorders, direct genetic intervention is the only way in which certain couples can exercise their rights to reproductive health. Finally, the arguments most often raised against the pursuit of and use of methods for germ-line intervention shall be discussed. Key Words: germ-line therapy, pre-implantation embryo screening gamete modification, risk and uncertainty

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INTRODUCTION: WHY IS GERM-LINE INTERVENTION NEEDED?

So-called genetic diseases afflict approximately two percent of all live births. Some of these are so severe that the victim faces only a few short years of painful existence. Others, such as cystic fibrosis or sickle-cell disease, can be managed, with treatment which often becomes more heroic with increasing age. Although at present the afflicted face almost certain premature death, the outlook that such treatments may soon include somatic-cell gene therapy is quite promising (Anderson, 1984). The first human experiments involving the implantation of a genetic marker in tumor-infiltrating lymphocytes have been carried out at the U.S. National Institutes of Health (Rosenberg et ah, 1990) and clinical trials to treat patients with severely debilitating afflictions, such as ADA deficiency, have begun (Fox, 1990). Such trials have been

Burke K. Zimmerman, Ph.D., Spectrum International, P.O. Box 120, SF-02631 ESPOO, Finland. The Journal of Medicine and Philosophy 16:593-612,1991. 1991 Kluwer Academic Publishers. Printed in the Netherlands.

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approved in the United States by the Subcommittee on Human Gene Therapy of NIH's Recombinant DNA Advisory Committee. While these trials represent milestone achievements in the development of molecular genetics as an important tool in human medicine, somatic-cell gene therapy is a treatment of existing pathology. But somatic-cell gene therapy cannot prevent genetic disease. In fact, should it become widely successful, it will increase the number of homozygous desease gene carriers, who will face the certainty of passing problem genes to their children. Moreover, somatic cell therapy is a strategy that is only appropriate for the treatment of a subset of the wide scope of clinical disorders that have a clearly established genetic component. Disorders involving developmental abnormalities may not be adequately reversible, even if diagnosed during early pregnancy. Those problems involving organ or tissue structure and function may not be correctable at all, if intervention is not made early in development. The bone marrow stem cells are easily accessible and may be replaced by new populations, making them ideal targets for somatic cell therapy. But disorders involving solid tissues or a function intimately dependent on structure (e.g., the brain) may be forever inaccessible to somatic cell therapy. Clearly, if technically feasible, a strategy that can correct genetic anomalies before or during conception, or at the zygote stage, is one that would achieve true prevention. Even if such a strategy is complex and costly initially, the suffering and the costs in treating (even by somatic cell therapy) and caring for a severely handicapped individual is many times greater.
STRATEGIES FOR HUMAN GERM-LINE INTERVENTION

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There are three strategies that, in principle, could attain the goal of the prevention of genetic disorders:
A. The screening and selection of early stage embryos, to ensure that pregnancies begin with genetically healthy embryos. It is a matter of

definition whether or not embryo screening and selection should be considered as 'germ-line therapy'. Nevertheless, such an approach, which has already been used for sex determination (Handyside et ah, 1989; Handyside et ah, 1990) and to avert pregnancies involving several different genetic disorders (Coutelle et al, 1989; Monk et ah, 1989; Monk et ah, 1990), would be the

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simplest, safest, and most reliable means to prevent a large fraction of genetic disorders, particularly those involving simple mendelian genetics of homozygous recessive or autosomal dominant genes (e.g., cystic fibrosis, Huntington's disease, LeschNyhan syndrome, Tay-Sachs disease, adenosine deaminase deficiency, sickle-cell disease, and many more). It would be the method of choice when a significant fraction of genetically normal embryos can be obtained following IVF (e.g., 25%). B. The direct modification of the DNA of early stage embryos, coupled with IVF. In cases where the prospective parents are carriers of genetically more complex genetic disorders, perhaps involving more than one gene, or when both are homozygous for a particular recessive trait (as will become more likely as somatic-cell gene therapy comes into general use), then the selection procedure under 'A' above will not be useful. In such cases, the most promising alternative is direct genetic modification. In this discussion, it is assumed that (a) there are no intrinsic technical barriers to developing a reliable method for targeted gene replacement and (b) that any procedure include an internal check to make sure that the desired correction is achieved before a pregnancy is allowed to continue. Technical considerations, risk, and uncertainty of such procedures are discussed below. C. The genetic modification of gametes in prospective (carrier) parents. It has been suggested that perhaps the way to avoid direct intervention in the process of reproduction itself, as in 'A' and 'B' above, would be to apply the techniques of somatic cell therapy now under development to the correction or replacement of faulty genetic messages in the germ cells themselves prior to conception (Lavitrano et ah, 1989). The number of technical obstacles to achieving a population of gametes that is 100% transformed and free of unpredictable iatrogenic effects resulting from the presence of vector DNA and genetic reassortment during meiosis, and the probable limitation of the use of such methods to males, would seem to be too numerous for the feasibility of the development of such a method in the forseeable future. Space does not permit a detailed technical critique of this strategy in this essay. Instead, the focus of the ensuing discussion will be the development of a case for the development and use of techniques based on direct genetic modification of pre-implantation embryos ('B' above).

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THE CASE FOR THE DEVELOPMENT AND USE OF METHODS FOR DIRECT GENETIC MODIFICATION OF PRE-IMPLANTATION EMBRYOS

The case for the development and eventual use of germ-line gene therapy (GLGT) rests on the following arguments.
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A. It is the moral obligation of the medical profession to use the best available methods and technology to prevent genetic pathology. It has

long been the acknowledged responsibility of the medical profession and public health practitioners in Western society to treat and, if possible, prevent infectious diseases and non-infectious diseases (such as cancer and atherosclerosis), using techniques proven to be efficacious and safe. Conversely, it is considered to be unethical to withhold medical intervention that is known to be effective in the treatment or prevention of pathology. Should not a similar responsibility apply to genetic disease? In fact, the borderline between the major non-infectious diseases and the overtly genetic disorders is not a clearly defined one. We know, for example, that severe hyperlipidemia, leading to heart attacks at an early age, is in large part due to genetic factors (Angier, 1990). Recently, genetic defects leading to a high incidence of breast and other specific types of cancer have been reported (Marx, 1990; Malkin et al, 1990; Hall et ah, 1990). Moreover, susceptibility to many infectious diseases, and the severity of possible sequelae such as the auto-immune destruction of vital tissue, have a very strong genetic bias. The application of the principle that the medical profession must act primarily in the interests of the patient clearly extends to the welfare of prospective parents carrying a genetic disability who seek restoration of reproductive health. A direct corollary of this responsibility is a broadening of the definition of 'patient7 to include the genetic health of their baby, and the ensuing future generations. The criterion that must govern any strategies to be used is that the procedure must promise to help the patient more than it may harm him. In this case, that criterion must apply to the entire genetic legacy that may result from intervention in the germ-line, which imposes rather stringent requirements on the degree of uncertainty acceptable in any such procedure.

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B. Direct intervention in the germ-line is medically necessary to prevent certain classes of disorders or in situations where screening and selection

procedures will not work. While the most often discussed targets of genetic counseling and somatic cell therapy are the severe homozygous recessive disorders, the number of medical problems that are known to be genetically determined or predisposed continue to increase. Those involving complex genetics, cases with more than one genetic locus, will not be readily amenable to screening and selection. Parents, who may have been treated by somatic cell therapy and are homozygous for the trait in question, can, at best, have a child who will at least carry the trait. GLGT will allow genetically normal children to result in all such cases. C. The principle of parental autonomy should permit parents to choose to use GLGT to ensure a normal child. At least in Western societies, parents are generally considered to have the right to have their own child, and to choose to use whatever means, consistent with established norms of medical ethics, that will ensure a normal pregnancy and a healthy baby. While the concept of state paternalism has in some instances prevailed over maternal autonomy with respect to the right to terminate a pregnancy, or in preventing a parental choice to withhold necessary medical care, the right of parental autonomy to nurture a pregnancy has been upheld overwhelmingly; any public policies that would deny parental autonomy in such cases would be grossly inconsistent with prevailing practices (Cook-Deegan, 1990). Just as parents with reproductive disabilities are free to choose in vitro fertilization procedures, they should also be accorded the right to subject their viable embryos to screening and selection, or to direct genetic intervention, in order to guarantee the genetic health of their children. D. Germ-line therapy is more efficient than the repeated use of somatic cell therapy in successive generations. Although many genetic disorders are not amenable to treatment through somatic cell therapy, an increasing number are, enabling the afflicted to reach reproductive age themselves. By comparison, the somatic cell treatments now contemplated are heroic in dimension and accompanied by substantial risk. Why subject each generation to having to undergo major, invasive intervention, when elimination of the

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culprit genes from the germ-line is possible? It is far more efficient, in terms of suffering and discomfort, risk, and cost, and technically, to correct such disorders at the beginning of life (Walters, 1986).
E. The prevailing ethic of science and medicine is that knowledge has intrinsic value, and that its pursuit should not be impeded except under
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extraordinary circumstances. Knowledge, the result of basic research into the nature of things, is the foundation upon which any technology must be built. The process from principle to practice, however, first requires an intermediate stage, in which new techniques and methods are developed. Moreover, since the results of basic research are often unforeseen, the opportunities for application will expand in unpredictable directions, as long as the enterprise of research remains healthy. But the development of the needed methodology and, hence, the useful applications, will generally not come about before the underlying phenomena are understood. Thus, major programs to direct research toward specific goals before the basic knowledge was in place have generally not succeeded (e.g., the 'War on Cancer'), just so attempts to suppress the freedom of inquiry have failed. Yet the question of whether or not the concept of "forbidden knowledge" should be considered with respect to human germ-line therapy has received recent discussion (Murray, 1983).
RISK AND UNCERTAINTY

Germ-line gene therapy has generally been excluded from serious discussions of strategies for ensuring genetic health, simply because there has been no reliable method that satisfies the criteria of certainty and predictability required to justify even a single human experiment. The techniques contemplated for somatic-cell therapy, or those used to make transgenic animals, would be quite unacceptable for germ-line applications. In terms of the NIH "Points to Consider", developed by the Recombinant Advisory Committee (RAC) as a basis for evaluating proposals involving gene therapy, no method has yet been demonstrated that would satisfy the concerns of points one (expected benefit), four (safety), or six (long-term implications), but all of these concerns are technical in nature and will no doubt eventually yield to further research and development. The RAC identified no additional

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grounds that would preclude the acceptability of germ-line therapy (Juengst, 1990). A judgment of whether a given procedure will be in the best interests of the patient depends on being able to predict the outcome of a procedure with reasonable accuracy. New procedures can rarely be more than educated guesses, and even in socalled 'routine' procedures - e.g., general anaesthesia - there is always an element of uncertainty. Thus it is expected that all new procedures will undergo extensive testing in animal models, in order to reduce the uncertainty of predicting the outcome in humans, before the first human trial. Intervention in the reproductive process, so that the predicted genetic makeup of the offspring will be altered, is no exception. In the case of contemplated germ-line therapy, there is an additional dimension that must also be included in the riskbenefit calculation: Any genetic perturbation in the treated individual (probably at the pre-implantation embryo stage) will be transmitted to the subsequent generations, with possible unpredictable effects that may differ from the desired expression of the corrected gene. Thus in order for a procedure to be acceptable for human use, the risk to subsequent generations should be no greater than that to a normal (genetically healthy) individual. That is, the responsibility of the practitioner to treat and prevent disease in the prospectively afflicted patient - the child to be conceived - extends as well to all subsequent generations of the patient. Hence, strategies that may be appropriate for somatic cell therapy would very likely not be appropriate for germ-line treatments. For example, strategies using retrovirus-derived vectors, inserts at random sites, multiple copies of added genes, or procedures that leave the defective genes in the patient, could result in undesirable genetic rearrangements with unpredictable consequences. The object of germ-line therapy should, therefore, be to restore an 'original' healthy genetic topology to the treated individual, such that future procreation would proceed as if one's progenitors had never carried a genetic lesion. It is clear that the state of the art at present would not justify any direct human germ-line genetic manipulation. This is, of course, sufficient reason why such techniques should not be applied to humans today. But how quickly can we expect matters to change? When and on what criteria will we be able to consider directed germ-line modification a feasible technique? Although

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the advance of knowledge is inevitable, the question faced by those who formulate the science policies of national governments, is whether or not germ-line genetic manipulation techniques should be singled out for applied research, with the object of reducing the technical uncertainties to the point where direct genetic intervention is comparable in predictability to the screening and selection of pre-implantation embryos.
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TECHNICAL CONSIDERATIONS FOR THE GENETIC MODIFICATION OF HUMAN ZYGOTES

The most powerful strategy for the directed intervention into the genetic makeup of human beings would entail the direct replacement of the defective DNA segments in a fertilized human egg, or in all of the blastomeres that constitute an early-stage embryo, with the correct or missing segments. The specific genetic lesions present in each early-stage embryo can be determined using gene amplification methods and DNA probe techniques on a single blastomere. DNA fragments can now be synthesized in the laboratory to consist of any desired nucleotide sequence. For direct genetic modification, to be ethically permissable, it must satisfy the following requirements: (1) The inserted intact gene must be known to function normally in its new environment, with the expression of the gene being regulated in the same ways as a normal gene - that is, it must be expressed in the right tissues at the right time, and not in inappropriate tissues. This implies either that the insertion would be at the site of the normal gene (or a correct genetic fragment would actually direct the repair of the defective region of a structural or control gene), or the gene would be inserted together with all necessary ds-acting promoters and regulatory sites so that it can function normally, even if on another chromosome, or in a different site on the correct chromosome. (2) If not at th^ 'normal' site, the inserted gene must not itself cause so-called 'insertional mutagenesis', that is, it must not split a normally functional gene so as to render its function inoperative. It should also be kept in mind that if functional genes are integrated at sites other than at the locus of the genetic lesion, recombination and reassortment of genetic elements could occur during meiosis such that the generation procreated by the subject of germ-line therapy might be susceptible to the original genetic

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defect, or bear multiple copies of the functional gene at different loci, the consequences of which may not always be predictable. (3) There must be no lingering negative effects from the preexisting genetic defect, such as the synthesis of a competitive but non-functional enzyme. (4) The procedure of genetic insertion, including any vectors used, must not induce any perturbations in normal genetic function. That is, if the possible genetic side-effects of a particular vector or insertional method are not known, or are expected to be significant, this would argue against the use of the methods, even in a human experiment. The use of modified viral vectors, such as those now planned for use in somatic cell gene therapy (Anderson, 1986) may be entirely unsuitable for germ-line vectors, unless it can be shown unequivocally that the presence of the vector in all human cells is absolutely benign and will not affect the normal functioning of the genome in any way. Moreover, there must be no possibility of reassembling at some future time the infectious properties of the viral vector (Temin, 1990). Such vectors are potentially capable of being used to transfer DNA to dividing zygote cells after the zona pellucida disappears, or in cultured embryonic stem (ES) cells, but the effect of such extra DNA must be tested throughout the entire life of test animals to assess the importance of its presence in all cells and tissues at all stages of differentiation and function. The optimal strategy would be to develop a method of insertional recombinational repair of the defective gene. An insert that can recognize and recombine with DNA only if a specific sequence is present is within the realm of possibility, and has been demonstrated in animals (Mansour, 1988). The ultimate goal of germ-line modification would be the restoration of 'normal7 genetic structure, rather than the addition of extra functional genes. The following hypothetical strategy outlines a method that satisfies the above requirements, provided that certain technical problems can be overcome. Especially important to this method are (1) precise site-specific genetic correction and (2) checks to confirm that the desired result was obtained prior to implantation. (1) One cell would be removed from each of a number of early stage pre-implantation embryos obtained by IVF. (2) While the remainder of each embryo would be retained for possible future use, the cells taken would be used to culture a

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large population of embryonic stem (ES) cells. (3) The genetic status of each population would be determined. (4) Each suitable population would be treated by a procedure whereby specific DNA is taken up by the cells under conditions where site-specific recombination is favored. (5) Treated ES cells are screened and selected for those containing the 'repaired' sequences and no other genetic alterations. Clones of the selected cells are grown. (6) A population of cloned cells is aggregated into an 'artificial embryo', which is then implanted into the mother's uterus. Building on rapid progress in methods for gene targeting (Thomas and Capecchi, 1987), steps 1-5 have been demonstrated in animals (Mansour, 1988). ES cells, following site directed genetic modification, screening, selection and subcloning, have been successfully combined with untreated blastomeres to form a chimeric embryo, which has then been successfully implanted in female mice, giving rise to genetic mosaic animals. Different techniques for cellular aggregation have been tried, but none to date has successfully constructed a viable 'artificial' embryo entirely from ES cells, even though the cells themselves seem to be totipotent. Moreover, the removal of the zona pellucida from an early stage embryo greatly reduces the efficiency of implantation, perhaps as much as 90% (Gordon, 1990). One possible approach would be to render the untreated cells of an early stage embryo incapable of further proliferation, perhaps by irradiation. Such treatment, however, still permits the injection of a large population of ES cells into the early embryo, with all membranes intact, such that the right conditions are met, both for successful implantation, and for proper differentiation to take place, but with all of the viable embryonic cells derived from the genetically modified ES cells. This is an approach that could, of course, be perfected in animals before extending it to humans. Moreover, through chorionic villi biopsy and/or amniocentesis, it could also be determined with a reasonable degree of assurance, that the fetal cells all were derived from the modified ES cells. In any case, these obstacles are technical, not conceptual. Until they are successfully overcome, the above strategy should not be attempted in humans. However, in that the limitations are technical, it is likely that all of the elements of the above approach, or some variation on them, will be perfected in time. If and when the above methods are perfected, the tools are far more powerful than

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simple selection and screening, enabling the treatment of more complex and subtle genetic problems. The procedure of modification and selection of ES cells could, in principle, be repeated sequentially any number of times in order to modify DNA sequences in a number of different sites. What this means for any couple is that the procedure of IVF, ES cell culture, modification and selection, and reimplantation may only have to be undertaken one time. That is, many genetically intact artificial embryos could be created at one time, with only a few implanted each time a pregnancy is desired. On the basis of current knowledge, the hypothetical procedure described above would seem to be the most likely to be the first developed for use. It should not be assumed, however, that the optimal techniques for GLGT will necessarily be done in this manner. Given the pace of advancement in the methods of cell biology and targeted DNA modification, a simpler, more direct, and highly reliable procedure may well be developed. What one can say, however, is that it is unlikely that it will be necessary to use a procedure more complex than that described; further research and development will take us in the direction of greater simplicity, higher reliability, lower risks, and lower costs.
WILL AN ACCEPTABLE METHOD FOR HUMAN GERM-LINE THERAPY EVER BE PERFECTED?

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History is replete with corroboration of the notion that mankind, for all of its relatively recent excursions into the land of 'science' fiction, has always tended to underestimate the future. In fact, if there are any guidelines that allow us to guess accurately what technology will be able to do in ten, twenty, or fifty years hence, we have only to look back on the rate of achievement in the last fifty years, or even in the last five. How many commonplace methods today were not even imagined by the most visionary of half a century ago. The discovery of DNA, and the elucidation of its gross chemistry dates to 1942 - almost half a century ago. Its identification as the carrier of genetic information followed a few years later, and 39 years ago, the fundamental structure of DNA was finally elucidated (Watson and Crick, 1953). The triplet code was confirmed - marginally - by 1961 (Nirenberg and Matthei, 1961) and the first attempts at gene splicing, following the elucidation of the mechanism of action of restriction enzymes (also not

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imagined only a short time before) took place in the early 1970s at Johns Hopkins University (Smith et al, 1970; Khoury et al, 1974) and at Stanford University (Cohen et al, 1973). Rapid sequencing methods for DNA came a few years later (Maxam and Gilbert, 1977). Now we can locate and characterize any desired segment of DNA from any source, in as little as a few days but never more than a few weeks, depending on the amount of helpful information available. PCR gene amplification techniques have essentially reduced the amount of DNA needed for a definitive assay to a single molecule (Bradbury et al., 1990). The time it takes for any of these assays is continually shrinking as automated instruments improve. I willingly accept the position that no direct human germ-line intervention (GLGT) be attempted unless and until the stringent requirements for precision and reliability that I have set forth in the preceeding pages can be met. To argue otherwise would be a violation of an ethical commitment to improve the genetic health of future generations. However, the burden is on those who argue that our technology will never be good enough to satisfy such criteria to point out just where the fundamental limitations may lie. In my view, we would indeed be falling into history's trap to suggest that these will never be achieved.
ARGUMENTS AGAINST GERM-LINE INTERVENTION

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In the present day, the subject of human germ-line intervention can rarely be discussed against a neutral background. It has already become, in all respects, a 'loaded' issue, in which the most innocent statements can carry an enormous burden of invisible baggage when read and interpreted by the listener/reader. The epitome of the fears engendered by the era of genetic manipulation are those regarding ANY human applications, regardless of how well intended such use may be. Thus the commentaries on gene therapy over the past decade include many summary dismissals of human germ-line applications of gene technology (Weatherall, 1988; Editorial in Nature, 1988; Therre, 1989), and a few that wonder why the concept is so offensive (Editorial in
Lancet, 1989).

The fears, to the extent they have been articulated, are based either on risks resulting from the precipitous use of techniques with an uncertain outcome, or on the possibility of misuse, which

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different people define in a number of different ways, ranging from attempts to prevent relatively minor sub-clinical pathology to a major redesign of the human species. Other arguments have also been brought to bear against the development and use of germ-line gene therapy, based on considerations of the real need for such methods, as well as with regard to the allocation of limited medical resources. The major arguments are summarized below.
A. Human germ-line gene therapy is not needed. With the ongoing

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perfection and use of the screening and selection of preimplantation embryos for the prevention of several serious genetic disorders, the argument has been put forth that the availability of such methods makes the use of direct germ-line intervention unnecessary. This argument is, however, centered very much in the present, and does not anticipate the changing nature of medical practice. In the first half of this century, the major focus of preventive medicine was infectious disease, and especially those involved in major epidemics. While AIDS has not allowed us to forget the importance of microbial infections, the principal focus of western medicine during the past few decades has been the major non-infectious diseases - cancer, and those related to atherosclerosis. With regard to genetic diseases, the major debilitating diseases - cystic fibrosis, sickle-cell disease, LeschNyhan disease, Huntington's disease, Tay-Sachs syndrome, muscular dystrophy, etc. - most are governed by simple singlegene genetics. There is no question that screening and selection offers a relatively simple and low-risk means to control these diseases within families. In the future, however, when the incidence of these disorders has been greatly reduced or virtually eliminated, the emphasis will necessarily shift to the subtler and genetically more complex disorders, for which screening and selection will be of little use. GLGT, on the other hand, offers the possibility of greatly lowering the risk of heart attacks, many forms of cancer, behavioral disorders, and auto-immune diseases. Any condition where a genetic relationship to cause or susceptibility exists would be an appropriate candidate for GLGT. These classes of disorders will constitute the frontier of medicine following major reductions in infectious, non-infectious, and genetic diseases amenable to prevention by simpler strategies.

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B. The uncertainty of outcome, and, therefore, the risk of GLGT will remain too great to permit its use on humans. There is general agreement that human germ-line intervention for any purpose should always be governed by stringent criteria for safety and predictability of the procedure used, and include a verification step. The importance of this has been discussed at length above. Certainly, even a few years ago, when transgenic animals were being made by adding genes randomly into fertilized eggs, the extension of such techniques to humans could not be seriously considered. The rate of advancement of all relevant sciences, however, now gives us a great deal of confidence that techniques can be perfected where the outcome can be predicted rather precisely, and verified before any pregnancy was begun. C. Once perfected, the techniques of germ-line modification will be used for purposes other than the prevention of pathology* Concerns have been raised that once the methods are available for directed human genetic germ-line modification and the knowledge of human genome becomes more and more extensive, that people will not stop at the prevention of pathology. The state of knowledge concerning the relationship between the structure of genes and biological function continues to increase. This relationship includes not only the physical function of the human organism, but the structure and physiology of the brain and, hence, cognative functions, memory, coordination, musical ability, personality, and other behavioral traits, including, for example, aggression and compassion (Bouchard, 1991; Holden, 1991). It should be kept in mind that while the more common genetic pathologies may be governed by a single gene that obeys simple mendelian genetics, the genetic basis for cognative and behavioral characteristics is likely to be far more complex, involving tens or hundreds of different genes, and therefore increasing the complexity of intervention accordingly. Nevertheless, it is feared that 'enhancement' modification may be ordered by parents, exercising their right of parental autonomy, who wish to guarantee that their children will be significantly above average. Why does the notion that medical technology might give some children an advantage elicit such a strong negative reaction? Perhaps it is because the notion of fairness is well embedded in Western culture. We of course accept that people are different, reflecting the randomized deal of the genes and the matching of

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the genetic cards held by the parents. But all parents are not the same, and children do tend to reflect the traits of their parents. Some will always turn out to be gifted in one way or another without intervention. It would seem, therefore, that the use of GLGT for such enhancement is viewed much in the same way as cheating at cards, or on one's income tax. But is there really anything wrong with it? What about the positive side, of increasing the number of talented people. Wouldn't society be better off in the long run? While the commitment to ensure political and social equality for all people cannot and should not depend on, or imply, biological equality, there is concern that if genetic enhancement procedures were not equally available to all, the distribution of desirable biological traits among different socioeconomic and ethic groups would become badly skewed, resulting de facto in exacerbated social and economic inequality. However, practically no society has succeeded in equalizing the differences in access of opportunity to other factors affecting socioeconomic status (e.g., education, health services). D. Distributive justice. Let us leave the imponderable question of 'enhancement' through germ-Une intervention and return to the much more immediate problem of the responsibility of society to provide services for the prevention of genetic disability to those parents at risk, and the matter of the availability of technology. The questipn of whether or not medical care is a right or a privilege is viewed differently in different regions of the world. In some countries, and under some medical insurance plans in the United States, IVF services are covered, at least up to a certain cost limit. In general, the poor or lower income families in the Western world utilize IVF far less often than the middle and upper economic classes. While genetic counseling is generally available under national health or health insurance plans, with the option of an assay of fetal tissue and abortion, its use is somewhat dependent on economic class. The strategies outlined above all involve at a minimum all of the components of IVF and implantation as now practiced. The added costs of screening and selection will make even this straightforward form of germ-line intervention quite expensive (ca. $ 10,000 per procedure or more). The ES-cell culture and genetic modification strategy would be much costlier still. Even

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though we may expect a reduction in costs as techniques become perfected and automated, it is still an expensive proposition. To be weighed against these initial costs, however, should be the costs of caring for and treating a genetically disabled person. The lifetime costs of treatment for one person afflicted with cystic fibrosis or sickle-cell disease are many times higher than the costs of any prospective strategy for prevention. If the case can be made to the politicians who set policy and approve of budgets that even relatively heroic means of prevention will be far less costly to society than any form of long-term care, then enlightened national health policies should take such technology into account.
E. Arguments based on religious dogma or 'absolute' morality: Human germ-line modification is intrinsically immoral. Most ethical decisions

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made by physicians in the practice of medicine are based on the assessments of the benefit of a procedure to the patient in relation to the risks of both the disease and the procedure itself. Such an approach, applied in the discussion of gene therapy as well, is strictly utilitarian. Other arguments, especially those presented here, have their roots in assumptions about the rights and responsibilities of individuals as they surface in theories of democracy, access to health care, and distributive justice generally. But here too, the arguments tend to be relative and are tempered by numerous other considerations. One cannot, however, argue with a conclusion based on a dominant, overarching premise that must be accepted as an act of faith. Thus, if an individual opposes the development and use of methods for germ-line intervention because it would require the destruction of living pre-embryos (discarded because they contain defective genetic messages), which in turn would be a violation of 'thou shalt not kill', it must be accepted as a belief that is not susceptible to change by any persuasive argument that does not also accept the initial premise. Similarly, if someone believes that it is a violation of some sacrosanct religious principle to interfere in the natural reproductive process in any way, including the modification of the genetic messages of a prospective child, then no utilitarian arguments or those based on the theory of rights will be acknowledged as relevant to the discussion. Therefore, it would be quite futile to attempt to construct arguments in favor of germ-line intervention that try to accommodate the fundamental premises held by those who oppose such procedures on the basis

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of any religious or absolute moral premises. Such individuals, who have already been outspoken with respect to the abortion and in vitro fertilization issues, will no doubt continue to exercise their democratic rights in the opposition of germ-line therapy, and participate in the due processes of public decision making as they may be defined in their countries of residence.
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CONCLUSIONS

Arguments are presented for the development and eventual use of the direct genetic modification of the human germ-line for the purpose of the prevention of pathology based on aberrant genes or genetic configurations. It is acknowledged that the screening and selection of pre-implantation embryos (which is now coming into use) can prevent a great deal of the genetically-based pathology which now confronts society. However, as the genetic basis of a wide scope of human disorders becomes further elucidated, most of which will not be amenable to screening and selection, the need for a more direct means of correcting the germ-line will become increasingly important. This need reflects medicine's responsibility to use whatever resources are available to benefit its patients which, in this instance, include not only the responsibility to provide parents with reproductive health care, but also to maximize the health of their children and the subsequent generations to which their children will ultimately donate genetic material. Direct genetic manipulation of the pre-embryo should be carried out only if the methods used ensure with a very high probability that (a) a specific correction of a defective gene will be made; (b) the procedure will not introduce any genetic errors or new genetic material that could have unpredictable effects in subsequent generations; and (c) that such procedures include a check to ensure that the procedure has been carried out as intended, before allowing a pregnancy to proceed. One may conclude that, at this time, provided the technical reliability of the procedures can be assured as stated above, there is no compelling reason not to proceed with the development and use of such methods, beginning with applications to prevent severe genetic pathology. As the methods become perfected, and the knowledge of the relationship between genetic structure and biological function increases, such methods can then be extended

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to more complex and more subtle genetically-related disorders. The use of germ-line techniques for purposes other than the prevention of overt pathology is considered, with the acknowledgement that to attempt to modify complex behavioral or cognative characteristics in a predictable manner will require substantially more knowledge than we possess at present, and could involve many genes. While there are no obvious inherent objections to carrying out genetic 'enhancement' in individual cases, the social implications of any widespread use of such methods are profound. Therefore, policies that may govern applications of germ-line methods that go beyond the prevention of pathology require a thorough evaluation by society of criteria that transcend the traditional considerations of principles of individual autonomy, the rights and responsibilities of individuals, and distributive justice. EPILOGUE Perhaps someday, a century from now perhaps, the ease of directed genetic determination will have advanced far from the scenarios presented in this discussion, so that it would be within the reach of all. But this will be another kind of society. We cannot predict what human society will be like in a hundred years, any better than our great grandfathers could foresee life in 1991. Clearly, decisions on the availability of medical or reproductive/genetic services will have to match the prevailing cultural, social and economic values of the times. It would be arrogant indeed to think that we could now set any policy that would remain valid into the distant future.
ACKNOWLEDGEMENTS

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Support for the research project which stimulated this paper was provided by a grant from the Ethics and Values Studies Program of the National Science Foundation (RII-8511073), with cofunding from the National Institutes of Health. The views expressed in this article do not necessarily reflect the views of NSF or NIH.
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