human germ line therapy - the case for its development and use - burke zimmerman

8/4/2019 Human Germ Line Therapy - The Case for Its Development and Use - Burke Zimmerman

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BURKE K. ZIMME RM AN

HUMAN GERM-LINE THERAPY:THE CASE FOR ITS DEVELO PMENT A N D USE

ABSTRACT. The rationale for pursuing the development and use of germ-lineselection and modification techniques is examined in this essay. The argum ent isput forth that it is the moral obligation of the medical profession to makeavailable to the public any technology that can cure or preven t patho logy leadin gto death and disability, in both the present and future generations. Societyshould pursue the development of strategies for preventing or correcting, at thegerm-line level, genetic features that will lead to, or enhance, pathologicalconditions. Because prenatal screening and even early embryo screening andselection can prevent only a subset of known genetic disorders, direct geneticintervention is the only way in which certain couples can exercise their rights toreproductive health. Finally, the arguments most often raised against the pursuitof and use of me thods for germ-line intervention shall be discussed.Key Words: germ-line therapy, pre-implantation embryo screening gametemodification, risk and uncertainty

INTRODUCTION: WHY IS GERM-LINE INTERV ENTION NEEDED?So-called genetic diseases afflict approximately two percent of alllive birth s. Some of these are so severe th at th e victim faces on ly afew short years of painful existence. Oth ers, such as cystic fibrosisor sickle-cell disease, can be managed, with treatment which oftenbecomes more heroic with increasing age. Althoug h at presen t theafflicted face almost certain premature death, the outlook thatsuch treatments may soon include somatic-cell gene therapy isquite promising (Anderson, 1984). The first human experimentsinvolving the implantation of a genetic marker in tumor-infiltrat-ing lymphocytes have been carried out at the U.S. NationalInstitutes of Health (Rosenberg et ah, 1990) and clinical trials totreat patients with severely debilitating afflictions, such as ADAdeficiency, 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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594 Burke K. Zimmermanapproved in the United States by the Subcommittee on HumanGene Therapy of NIH 's Recombinant DN A Ad visory Comm ittee.While these trials represent milestone achievements in thedevelopment of molecular genetics as an important tool in humanmedicine, somatic-cell gene therapy is a treatment of existingpathology. But somatic-cell gene therapy cannot prevent geneticdisease. In fact, should it become widely successful, it will in-crease the number of homozygous desease gene carriers, who willface the certainty of passing problem genes to their children.Moreover, somatic cell therapy is a strategy that is only ap-propriate for the treatment of a subset of the wide scope of clinicaldisorders that have a clearly established genetic component.Disorders involving developmental abnormalities may not beadequately reversible, even if diagnosed during early pregnancy.Those problems involving organ or tissue structure and functionmay not be correctable at all, if intervention is not made early indevelopment. The bone marrow stem cells are easily accessibleand may be replaced by new populations, making them idealtargets for somatic cell therapy. But disorders involving solidtissues or a function intimately dependent on structure (e.g., thebrain) m ay be forever inaccessible to somatic cell therapy.

Clearly, if technically feasible, a strategy that can correct geneticanomalies before or during conception, or at the zygote stage, isone tha t wo uld achieve true preven tion. Even if such a strategy iscomplex and costly initially, the suffering and the costs in treating(even by somatic cell therapy) and caring for a severely hand-icapped individual is many times greater.STRATEGIES FOR H UM AN GERM-LINE INTERVENTION

There are thre e strategies tha t, in princip le, could attain the goal ofthe preven tion of genetic disorders:A. The screening and selection of early stage embryos, to ensure thatpregnancies begin with genetically healthy embryos. It is a matter ofdefinition whether or not embryo screening and selection shouldbe considered as 'germ-line therapy'. Nevertheless, such anapproach, which has already been used for sex determination(Handyside et ah, 1989; Ha nd ysid e et ah, 1990) and to avert preg-nancies involving several different genetic disorders (Coutelle etal, 1989; Monk et ah, 1989; Monk et ah, 1990), would be the

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The Case for Development 595simplest, safest, and most reliable means to prevent a largefraction of genetic disorders, particularly those involving simplemendelian genetics of homozygous recessive or autosomaldom inant genes (e.g., cystic fibrosis, H un ting ton 's disease, Lesch-Nyhan syndrome, Tay-Sachs disease, adenosine deaminasedeficiency, sickle-cell disease, and many more). It would be themethod of choice when a significant fraction of genetically normalembryos can be obtained following IVF (e.g., 25%).B. The direct modification of the DNA of early stage embryos, coupledwith IVF. In cases where the prospective parents are carriers ofgenetically more complex genetic disorders, perhaps involvingmore than one gene, or when both are homozygous for a par-ticular recessive trait (as will become more likely as somatic-cellgene therapy comes into general use), then the selection procedureund er 'A ' above will not be useful. In such cases, the mo st promis-ing alternative is direct genetic modification. In this discussion, itis assumed that (a) there are no intrinsic technical barriers todeveloping a reliable method for targeted gene replacement and(b) that any procedure include a n internal check to make sure thatthe desired correction is achieved before a pregn ancy is allowed tocontinue. Technical considerations, risk, and uncertainty of suchprocedu res are discussed below.C. The genetic modification of gametes in prospective (carrier) parents. Ithas been suggested that perhaps the way to avoid direct interven-tion in the process of reproduction itself, as in 'A' and 'B' above,would be to apply the techniques of somatic cell therapy nowunder development to the correction or replacement of faultygenetic messages in the germ cells themselves prior to conception(Lavitrano et ah, 1989). The number of technical obstacles toachieving a population of gametes that is 100% transformed andfree of unpredictable iatrogenic effects resulting from the presenceof vector DNA and genetic reassortment during meiosis, and theprobable limitation of the use of such methods to males, wouldseem to be too num erou s for the feasibility of the dev elopm ent ofsuch a method in the forseeable future. Space does not permit adetailed technical critique of this strategy in this essay. Instead,the focus of the ensuing discussion will be the development of acase for the development and use of techniques based on directgenetic modification of pre-implantation embryos ('B' above).

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596 Burke K. ZimmermanTHE CASE FOR THE DEVELOPMENT A ND USE OF METHODS

FOR DIRECT GENETIC MODIFICATION O FPRE-IMPLANTATION EMBRYOSThe case for the development and eventual use of germ-line genethera py (GLGT) rests on the following arguments.

A. It is the moral obligation of the medical profession to use the bestavailable methods and technology to prevent genetic pathology. It haslong been the acknowledged responsibility of the medicalprofession and public health practitioners in Western society totreat and, if possible, prevent infectious diseases and non-infec-tious diseases (such as cancer and atherosclerosis), using tech-niques proven to be efficacious and safe. Conversely, it is con-sidered to be unethical to withhold medical intervention that iskn ow n to be effective in the treatm ent or preven tion of pathology.Should not a similar responsibility apply to genetic disease? Infact, the borderline between the major non-infectious diseases andthe overtly genetic disorders is not a clearly defined one. Weknow, for example, that severe hyperlipidemia, leading to heartattacks at an early age, is in large part due to genetic factors(Angier, 1990). Recently, genetic defects leading to a high in-cidence of breast and other specific types of cancer have beenreported (Marx, 1990; Malkin et al, 1990; Hall et ah, 1990).Moreover, susceptibility to many infectious diseases, and theseverity of possible sequelae such as the auto-im mune destructionof vital tissue, hav e a v ery strong genetic bias.

The application of the principle that the medical professionm ust act prim arily in the interests of the patient clearly extends tothe welfare of prospective parents carrying a genetic disabilitywho seek restoration of reproductive health. A direct corollary ofthis responsibility is a broadening of the definition of 'patient7 toinclude the genetic health of their baby, and the ensuing futuregenerations. The criterion that must govern any strategies to beused is that the procedure must promise to help the patient morethan it m ay harm him . In this case, that criterion m ust a pply to theentire genetic legacy that may result from intervention in thegerm-line, which imposes rather stringent requirements on thedegree of unc ertainty acceptable in any such proc edu re.

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The Case for Development 597B. Direct intervention in the germ-line is medically necessary to preventcertain classes of disorders or in situations where screening and selectionprocedures will not work. While the most often discussed targets ofgenetic counseling and somatic cell therapy are the severehomozygous recessive disorders, the number of medical problemsthat are known to be genetically determined or predisposedcontinue to increase. Those involving complex genetics, cases w ithmore than one genetic locus, will not be readily amenable toscreening and selection. Parents, who may have been treated bysomatic cell therapy and are homozygous for the trait in question,can, at best, have a child who will at least carry the trait. GLGTwill allow genetically norm al children to result in all such cases.C. The principle of parental autonomy should permit parents to choose touse GLGT to ensure a normal child. At least in Western societies,parents are generally considered to have the right to have theirown child, and to choose to use whatever means, consistent withestablished norms of medical ethics, that will ensure a normalpregnancy and a healthy baby. While the concept of state pater-nalism has in some instances prevailed over maternal autonomywith respect to the right to terminate a pregnancy, or in prevent-ing a parental choice to withhold necessary m edical care, the rightof parental autonomy to nurture a pregnancy has been upheldoverwhelmingly; any public policies that would deny parentalautonomy in such cases would be grossly inconsistent withprevailing practices (Cook-Deegan, 1990). Just as parents withreproductive disabilities are free to choose in vitro fertilizationprocedu res, they shou ld also be accorded the right to subject theirviable embryos to screening and selection, or to direct geneticintervention, in order to guarantee the genetic health of theirchildren.D. Germ-line therapy is more efficient than the repeated use of somaticcell therapy in successive generations. Although many geneticdisorders are not amenable to treatment through somatic celltherapy, an increasing number are, enabling the afflicted to reachreproductive age themselves. By comparison, the somatic celltreatments now contemplated are heroic in dimension and accom-panied by sub stantial risk. Why subject each generation to hav ingto undergo major, invasive intervention, when elimination of the

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598 Burke K. Zimmermanculprit genes from the germ-line is possible? It is far moreefficient, in terms of suffering and discomfort, risk, and cost, andtechnically, to correct such disorders at the beginning of life(W alters, 1986).E. The prevailing ethic of science and medicine is that knowledge hasintrinsic value, and that its pursuit should not be impeded except underextraordinary circumstances. Knowledge, the result of basic researchinto the nature of things, is the foundation upon which anytechnology must be built. The process from principle to practice,however, first requires an intermediate stage, in which newtechniques and methods are developed. Moreover, since theresults of basic research are often unforeseen, the opportunities forapplication w ill expan d in unp redictable directions, as long as theenterprise of research rema ins healthy. But the developm ent of theneeded methodology and, hence, the useful applications, willgenerally not come about before the underlying phenomena areunderstood. Thus, major programs to direct research towardspecific goals before the basic knowledge was in place havegenerally not succeeded (e.g., the 'War on Cancer'), just so at-tempts to suppress the freedom of inquiry have failed. Yet thequestion of whether or not the concept of "forbidden knowledge"should be considered with respect to human germ-line therapyhas received recent discussion (Murray, 1983).

RISK AND UNCERTAINTYGerm-line gene therapy has generally been excluded from seriousdiscussions of strategies for ensuring genetic health, simplybecause there has been no reliable method that satisfies the criteriaof certainty and predictability required to justify even a singlehuman experiment. The techniques contemplated for somatic-celltherap y, or those used to make transgenic animals, wo uld be quiteunacceptable for germ-line applications. In terms of the NIH"Points to Consider", developed by the Recombinant AdvisoryCommittee (RAC) as a basis for evaluating proposals involvinggene therapy, no method has yet been demonstrated that wouldsatisfy the concerns of points one (expected benefit), four (safety),or six (long-term implications), but all of these concerns aretechnical in nature and will no doubt eventually yield to furtherresearch and development. The RAC identified no additional

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The Case for Development 599grounds that would preclude the acceptability of germ-linetherapy (Juengst, 1990).A judgment of whether a given procedure will be in the bestinterests of the patient depends on being able to predict theoutcome of a procedure with reasonable accuracy. New proce-dures can rarely be more than educated guesses, and even in so-called 'routine' procedures - e.g., general anaesthesia - there isalways an element of uncertainty. Thus it is expected that all newprocedures will undergo extensive testing in animal models, inorder to reduce the uncertainty of predicting the outcome inhumans, before the first human trial. Intervention in thereproductive process, so that the predicted genetic makeup of theoffspring will be altered, is no exception.In the case of contemplated germ-line therapy, there is anadditional dimension that must also be included in the risk-benefit calculation: Any genetic perturbation in the treated in-dividual (probably at the pre-implantation embryo stage) will betransmitted to the subsequent generations, with possible unpre-dictable effects that may differ from the desired expression of thecorrected gene. Thus in order for a procedure to be acceptable forhuman use, the risk to subsequent generations should be nogreater than that to a norm al (genetically healthy) ind ividu al. Thatis, the responsibility of the practitioner to treat and preventdisease in the prospectively afflicted patient - the child to beconceived - extends as well to all subsequent generations of thepatient. Hence, strategies that m ay be a pp rop riate for som atic celltherapy would very likely not be appropriate for germ-linetreatments. For example, strategies using retrovirus-derivedvectors, inserts at rand om sites, multiple copies of ad de d gene s, orprocedures that leave the defective genes in the patient, couldresult in undesirable genetic rearrangements with unpredictableconsequences. The object of germ-line therapy should, therefore,be to restore an 'original' healthy genetic topology to the treatedindividual, such that future procreation would proceed as if one'sprogenitors had never carried a genetic lesion.It is clear that the state of the art at present would not justifyany direct human germ-line genetic manipulation. This is, ofcourse, sufficient reason why such techniques should not beapplied to humans today. But how quickly can we expect mattersto change? W hen and on w hat criteria w ill we be able to considerdirected germ-line modification a feasible technique? Although

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600 Burke K. Zimmermanthe advance of knowledge is inevitable, the question faced bythose w ho formulate the science policies of national governments,is whether or not germ-line genetic manipulation techniquesshould be singled out for applied research, with the object ofreducing the technical uncertainties to the point where directgenetic intervention is comparable in predictability to the screen-ing and selection of pre-implantation emb ryos.

TECHNICAL CONSIDERATIONS FOR THE GENETIC MODIFICATIONOF HUM AN ZYGOTES

The most powerful strategy for the directed intervention into thegenetic makeup of human beings would entail the direct replace-m ent of the defective D NA segments in a fertilized hum an egg, orin all of the blastomeres that constitute an early-stage embryo,with the correct or missing segments. The specific genetic lesionspresent in each early-stage embryo can be determined using geneamplification methods and DNA probe techniques on a singleblastomere. DNA fragments can now be synthesized in thelaboratory to consist of any desired nucleotide sequence.For direct genetic modification, to be ethically permissable, itm ust satisfy the following requirem ents:(1) The inserted intact gene must be known to function nor-mally in its new environment, with the expression of the genebeing regulated in the same ways as a normal gene - that is, itm ust be exp ressed in the right tissues at the right time, and not ininappropriate tissues. This implies either that the insertion wouldbe at the site of the normal gene (or a correct genetic fragmentwould actually direct the repair of the defective region of astructural o r control gene), or the gene would be inserted togetherwith all necessary ds-acting prom oters an d reg ulatory sites so thatit can function normally, even if on another chromosome, or in adifferent site on the correct chromosome.(2) If not at th^ 'normal' site, the inserted gene must not itselfcause so-called 'insertional m utagenesis', that is, it must not split anormally functional gene so as to render its function inoperative.It should also be kept in mind that if functional genes are in-tegrated at sites other than at the locus of the genetic lesion,recombination and reassortment of genetic elements could occurduring meiosis such that the generation procreated by the subjectof germ-line therapy might be susceptible to the original genetic

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The Case for Development 601defect, or bear multiple copies of the functional gene at differentloci, the consequences of wh ich m ay not alway s be pred ictable.(3) There must be no lingering negative effects from the pre-existing genetic defect, such as the synthesis of a competitive butnon-functional enzyme.(4) The procedure of genetic insertion, including any vectorsused, must not induce any perturbations in normal geneticfunction. That is, if the possible genetic side-effects of a particularvector or insertional method are not known, or are expected to besignificant, this would argue against the use of the methods, evenin a hum an experiment. The use of modified viral vectors, such asthose 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 thevector in all human cells is absolutely benign and will not affectthe normal functioning of the genome in any way. Moreover,there must be no possibility of reassembling at some future timethe infectious properties of the viral vector (Temin, 1990). Suchvectors are potentially capable of being used to transfer DNA todividing zygote cells after the zona pellucida disappears, or incultured embryonic stem (ES) cells, but the effect of such extraDNA must be tested throughout the entire life of test animals toassess the importance of its presence in all cells and tissues at allstages of differentiation and function.The optimal strategy would be to develop a method of inser-tional recombinational repair of the defective gene. An insert thatcan recognize and recombine with DNA only if a specific se-quence is present is within the realm of possibility, and has beendemonstrated in animals (Mansour, 1988). The ultimate goal ofgerm-line modification would be the restoration of 'normal 7genetic structure, rather than the addition of extra functionalgenes.The following hypothetical strategy outlines a method thatsatisfies the above requirements, provided that certain technicalproblems can be overcome. Especially important to this methodare (1) precise site-specific genetic correction and (2) checks toconfirm that the desired result was ob tained p rior to im plantation .

(1) One cell would be removed from each of a number of earlystage pre-implantation embryos obtained by IVF.(2) While the remainder of each embryo would be retained forpossible future use, the cells taken would be used to culture a

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602 Burke K. Zimmermanlarge population of embryonic stem (ES) cells.

(3) The genetic status of each pop ulation w ou ld be determine d.(4) Each suitable population would be treated by a procedurewhereby specific DNA is taken up by the cells under conditionswhere site-specific recombination is favored.(5) Treated ES cells are screened and selected for those contain-ing the 'repaired' sequences and no other genetic alterations.Clones of the selected cells are g row n.(6) A population of cloned cells is aggregated into an 'artificialem bryo', which is then implanted into the m other's uterus.Building on rapid progress in methods for gene targeting(Thomas and Capecchi, 1987), steps 1-5 have been demonstratedin animals (Mansour, 1988). ES cells, following site directedgenetic modification, screening, selection and subcloning, havebeen successfully combined with untreated blastomeres to form achimeric embryo, which has then been successfully implanted infemale mice, giving rise to genetic mosaic animals. Differenttechniques for cellular aggregation have been tried, but none todate has successfully constructed a viable 'artificial' embryo

entirely from ES cells, even th ou gh the cells them selves seem to betotipotent. Moreover, the removal of the zona pellucida from anearly stage embryo greatly reduces the efficiency of implantation,per hap s as much as 90% (Gordon, 1990).One possible app roach wo uld be to render the untreated cells ofan early stage embryo incapable of further proliferation, perhapsby irradiation . Such treatme nt, how ever, still perm its the injectionof a large population of ES cells into the early embryo, with allmembranes intact, such that the right conditions are met, both forsuccessful implantation, and for proper differentiation to takeplace, but with all of the viable embryonic cells derived from thegenetically modified ES cells. This is an approach that could, ofcourse, be perfected in animals before extending it to humans.Moreover, through chorionic villi biopsy and/or amniocentesis, itcould also be determined with a reasonable degree of assurance,tha t the fetal cells all were d erived from the modified ES cells.In any case, these obstacles are technical, not conceptual. Untilthey are successfully overcome, the above strategy should not beattempted in hum ans . Howev er, in that the limitations are techni-cal, it is likely that all of the elements of the above approach, orsome variation on them , will be perfected in time. If and w hen theabove m etho ds are perfected, the tools are far more pow erful than

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The Case for Development 603simple selection and screening, enabling the treatment of morecomplex and subtle genetic problems. The procedure of modifica-tion and selection of ES cells could, in principle, be repeatedsequentially any number of times in order to modify DNAsequences in a nu m ber of different sites.What this means for any couple is that the procedure of IVF, EScell culture, modification and selection, and reimplantation mayonly have to be undertaken one time. That is, many geneticallyintact artificial embryos could be created at one time, with only afew implanted each time a pregn ancy is desired .

On the basis of current knowledge, the hypothetical proceduredescribed above would seem to be the most likely to be the firstdeveloped for use. It should not be assumed, however, that theoptimal techniques for GLGT will necessarily be done in thismanner. Given the pace of advancement in the methods of cellbiology and targeted DNA modification, a simpler, more direct,and highly reliable procedure may well be developed. What onecan say, however, is that it is unlikely that it will be necessary touse a procedure more complex than that described; furtherresearch and development will take us in the direction of greatersimplicity, higher reliability, lower risks , and lower costs.

WILL AN ACCEPTABLE ME THO D FOR HU M AN GERM-LINE THERAPYEVER BE PERFECT ED?

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, ifthere are any guidelines that allow us to guess accurately whattechnology 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 lastfifty years, or even in the last five. How many commonplacemethods today were not even imagined by the most visionary ofhalf a century ago. The discovery of DNA, and the elucidation ofits gross chemistry dates to 1942 - almost half a century ago. Itsidentification as the carrier of genetic information followed a fewyears later, and 39 years ago, the fundamental structure of DNAwas finally elucidated (Watson and Crick, 1953). The triplet codewas confirmed - marginally - by 1961 (Nirenberg and Matthei,1961) and the first attem pts a t gene splicing, following the elucida -tion of the mechanism of action of restriction enzymes (also not

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604 Burke K. Zimmermanimagined only a short time before) took place in the early 1970s atJohns Hopkins University (Smith et al, 1970; Kh oury et al, 1974)and at Stanford University (Cohen et al, 1973). Rap id sequencingmethods for DNA came a few years later (Maxam and Gilbert,1977). Now we can locate and characterize any desired segment ofDNA from any source, in as little as a few days but never morethan a few weeks, depending on the amount of helpful informa-tion available. PCR gene amplification techniques have essentiallyreduced the amount of DNA needed for a definitive assay to asingle mo lecule (Bradbury et al., 1990). The time it takes for any ofthese assays is continually shrinking as automated instrumentsimprove.I willingly accept the position that no direct human germ-lineintervention (GLGT) be attempted unless and until the stringentrequirements for precision and reliability that I have set forth inthe preceeding p ages can be met. To argue o therwise wou ld be aviolation of an ethical commitment to improve the genetic healthof future generations. How ever, the bu rden is on those who arguethat our technology will never be good enough to satisfy suchcriteria to point out just where the fundamental limitations maylie. In my view, we would indeed be falling into history's trap tosuggest th at these will neve r be achieved.

ARGUMENTS AGAINST GERM-LINE INTERVENTIONIn the present day, the subject of human germ-line interventioncan rarely be discussed against a neutral background. It hasalready be com e, in all respects, a 'loa de d' issue, in which the m ostinnocent statements can carry an enormous burden of invisiblebaggage when read and interpreted by the listener/reader. Theepitome of the fears engendered by the era of genetic manipula-tion are those regarding ANY human applications, regardless ofhow well intended such use may be. Thus the commentaries ongene therapy over the past decade include many summarydismissals of human germ-line applications of gene technology(Weatherall, 1988; Editorial in Nature, 1988; Therre, 1989), and afew that wonder why the concept is so offensive (Editorial inLancet, 1989).The fears, to the extent they have been articulated, are basedeither on risks resulting from the precipitous use of techniqueswith an uncertain outcome, or on the possibility of misuse, which

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The Case for Development 605different people define in a number of different ways, rangingfrom attempts to prevent relatively minor sub-clinical pathologyto a major redesign of the human species. Other arguments havealso been brought to bear against the development and use ofgerm-line gene therapy, based on considerations of the real needfor such methods, as well as with regard to the allocation oflimited medical resources. The major arguments are summarizedbelow.A. Human germ-line gene therapy is not needed. With the ongoingperfection and use of the screening and selection of pre-implantation emb ryos for the preve ntion of several serious geneticdisorders, the argument has been put forth that the availability ofsuch methods makes the use of direct germ-line interventionunnecessary. This argument is, however, centered very much inthe present, and does not anticipate the changing nature ofmedical practice. In the first half of this cen tury, th e major focus ofpreventive medicine was infectious disease, and especially thoseinvolved in major epidemics. While AIDS has not allowed us toforget the importance of microbial infections, the principal focusof western medicine during the past few decades has been themajor non-infectious diseases - cancer, and those related toatherosclerosis. With regard to genetic diseases, the majordebilitating diseases - cystic fibrosis, sickle-cell disease, Lesch-Nyhan disease, Huntington's disease, Tay-Sachs syndrome,muscular dystrophy, etc. - most are governed by simple single-gene genetics. There is no question that screening and selectionoffers a relatively simple and low-risk means to control thesediseases within families. In the future, however, when the in-cidence of these disorders has been greatly reduced or virtuallyeliminated, the emphasis will necessarily shift to the subtler andgenetically more complex disorders, for which screening andselection will be of little use. GLGT, on the other hand, offers thepossibility of greatly lowering the risk of heart attacks, manyforms of cancer, behavioral disorders, and auto-immune diseases.Any condition where a genetic relationship to cause or suscep-tibility exists wo uld be an ap propriate cand idate for GLGT. Theseclasses of disorders will constitute the frontier of medicinefollowing major reductions in infectious, non-infectious, andgenetic diseases amenable to prevention by sim pler strategies.

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606 Burke K. ZimmermanB. The uncertainty of outcome, and, therefore, the risk of GLGT willremain too great to permit its use on humans. There is general agree-ment that human germ-line intervention for any purpose shouldalways be governed by stringent criteria for safety and predic-tability of the proc edu re u sed, an d include a verification step. Theimportance of this has been discussed at length above. Certainly,even a few years ago, when transgenic animals were being madeby adding genes randomly into fertilized eggs, the extension ofsuch techniques to humans could not be seriously considered. Therate of advancement of all relevant sciences, however, now givesus a great deal of confidence that techniques can be perfectedw here th e outcom e can be predicted rathe r precisely, and verifiedbefore any pregnancy wa s begun.C. Once perfected, the techniques of germ-line modification will be usedfor purposes other than the prevention of pathology* Concerns havebeen raised that once the methods are available for directedhuman genetic germ-line modification and the knowledge ofhuman genome becomes more and more extensive, that peoplewill not stop at the prevention of pathology. The state ofknowledge concerning the relationship between the structure ofgenes and biological function continues to increase. Thisrelationship includes not only the physical function of the humanorganism, but the structure and physiology of the brain and,hence, cognative functions, m em ory, coordination, m usical ability,personality, and other behavioral traits, including, for example,aggression and com passion (Bouchard, 1991; Ho lden, 1991). Itshould be kept in mind that while the more common geneticpathologies may be governed by a single gene that obeys simplem endelian genetics, the genetic basis for cognative and behavioralcharacteristics is likely to be far more complex, involving tens orhundreds of different genes, and therefore increasing the com-plexity of intervention accordingly. Nevertheless, it is feared that'enhancement' modification may be ordered by parents, exercis-ing their right of parental autonomy, who wish to guarantee thattheir children will be significantly above average.Why does the notion that medical technology might give somechildren an advantage elicit such a strong negative reaction?Perhaps it is because the notion of fairness is well embedded inWestern 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 Case for Development 607the genetic cards held by the parents. But all parents are not thesame, and children do tend to reflect the traits of their parents.Some will always turn out to be gifted in one way or anotherwithout intervention. It would seem, therefore, that the use ofGLGT for such enhancement is viewed much in the same way ascheating at cards, or on one's income tax. But is there reallyanything wrong with it? What about the positive side, of increas-ing the number of talented people. Wouldn't society be better offin the long run?W hile the commitment to ensure political and social equa lity forall people cannot and should not depend on, or imply, biologicalequality, there is concern that if genetic enhancement procedureswere not equally available to all, the distribution of desirablebiological traits among different socioeconomic and ethic groupswould become badly skewed, resulting de facto in exacerbatedsocial and economic inequality. However, practically no societyhas succeeded in equalizing the differences in access of oppor-tunity to other factors affecting socioeconomic status (e.g., educa-tion, health services).D. Distributive justice. Let us leave the imponderable question of'enhancement' through germ-Une intervention and return to themuch more immediate problem of the responsibility of society toprovide services for the prevention of genetic disability to thoseparents at risk, and the matter of the availability of technology.The questipn of whether or not medical care is a right or aprivilege is viewed differently in different regions of the world . Insome countries, and under some medical insurance plans in theUnited States, IVF services are covered, at least up to a certain costlimit. In general, the poor or lower income families in the Westernworld utilize IVF far less often than the middle and uppereconomic classes. While genetic counseling is generally availableunder national health or health insurance p lans, w ith the option ofan assay of fetal tissue and abortion, its use is somewhat depen-den t on economic class.The strategies outlined above all involve at a minimum all ofthe components of IVF and implantation as now practiced. Theadded costs of screening and selection will make even thisstraightforward form of germ-line intervention quite expensive(ca. $ 10,000 per procedure or more). The ES-cell culture andgenetic modification strategy would be much costlier still. Even

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608 Burke K. Zimmermanthough we may expect a reduction in costs as techniques becomeperfected and auto mated, it is still an expensive proposition.To be weighed against these initial costs, however, should bethe costs of caring for and treating a genetically disabled person.The lifetime costs of treatment for one person afflicted with cysticfibrosis or sickle-cell disease are many times higher than the costsof any prospec tive strategy for preve ntion. If the case can be m adeto the politicians w ho set policy and app rove of budg ets that evenrelatively heroic means of prevention will be far less costly tosociety than an y form of long-term care, then enlightened nationalhealth policies should take such technology into account.E. Arguments based on religious dogma or 'absolute' morality: Hum angerm-line modification is intrinsically immoral. Most ethical decisionsmade by physicians in the practice of medicine are based on theassessments of the benefit of a procedure to the patient in relationto the risks of both the disease and the procedure itself. Such anapproach, applied in the discussion of gene therapy as well, isstrictly utilitarian. Other arguments, especially those presentedhere, have their roots in assumptions about the rights and respon-sibilities of individuals as they surface in theories of democracy,access to health care, and distributive justice generally. But heretoo, the arguments tend to be relative and are tempered bynumerous other considerations.One cannot, however, argue with a conclusion based on adominant, overarching premise that must be accepted as an act offaith. Thus, if an individual opposes the development and use ofmethods for germ-line intervention because it would require thedestruction of living pre-embryos (discarded because they containdefective genetic messages), wh ich in tu rn w ou ld be a violation of'thou shalt not kill', it must be accepted as a belief that is notsusceptible to change by any persuasive argument that does notalso accept the initial premise. Similarly, if someone believes thatit is a violation of some sacrosanct religious principle to interferein the natural reproductive process in any way, including themodification of the genetic messages of a prospective child, thenno utilitarian argu m ents or those based on the theory of rights willbe acknowledged as relevant to the discussion. Therefore, itw ou ld be quite futile to attemp t to construct argum ents in favor ofgerm-line intervention that try to accommodate the fundamentalpremises held by those who oppose such procedures on the basis

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The Case for Development 609of any religious or absolute moral premises. Such individuals,who have already been outspoken with respect to the abortionand in vitro fertilization issues, will no doubt continue to exercisetheir democratic rights in the opposition of germ-line therapy, a ndparticipate in the due processes of public decision making as theymay be defined in their countries of residence.

CONCLUSIONSArgum ents are presented for the developm ent an d e ventual use ofthe direct genetic modification of the human germ-line for thepurpose of the prevention of pathology based on aberrant genesor genetic configurations. It is acknowledged that the screeningand selection of pre-implantation embryos (which is now cominginto use) can prevent a great deal of the genetically-based pathol-ogy which n ow confronts society. Ho we ver, as the genetic basis ofa wide scope of human disorders becomes further elucidated,most of wh ich will not be amenable to screening a nd selection, theneed for a more direct means of correcting the germ-line willbecome increasingly important. This need reflects medicine'sresponsibility to use whatever resources are available to benefit itspatients which, in this instance, include n ot only th e responsibilityto provide parents with reproductive health care, but also tomaximize the health of their children and the subsequent genera-tions to which their children will ultimately donate geneticmaterial.Direct genetic manipulation of the pre-embryo should becarried out only if the methods used ensure with a very highprobability that (a) a specific correction of a defective gen e will bemade; (b) the procedure will not introduce any genetic errors ornew genetic material that could have unpredictable effects insubsequent generations; and (c) that such procedures include acheck to ensure that the procedure has been carried out as in-tended , before allowing a pregnan cy to proceed.One may conclude that, at this time, provided the technicalreliability of the procedures can be assured as stated above, thereis no compelling reason not to proceed with the development anduse of such methods, beginning with applications to preventsevere genetic pathology. As the methods become perfected, andthe knowledge of the relationship between genetic structure andbiological function increases, such methods can then be extended

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610 Burke K. Zimmermanto more complex and more subtle genetically-related disorders.

The use of germ-line techniques for purposes other than theprevention of overt pathology is considered, with the ac-knowledgement that to attempt to modify complex behavioral orcognative characteristics in a predictable manner will requiresubstantially more knowledge than we possess at present, andcould involve many genes. While there are no obvious inherentobjections to carrying out genetic 'enhancement' in individualcases, the social implications of any widespread use of suchmethods are profound. Therefore, policies that may governapplications of germ-line methods that go beyond the preventionof pathology require a thorough evaluation by society of criteriathat transcend the traditional considerations of principles ofindividual autonomy, the rights and responsibilities of indivi-duals, and distributive justice.

EPILOGUEPerhaps someday, a century from now perhaps, the ease ofdirected genetic determination will have advanced far from thescenarios presented in this discussion, so that it would be withinthe reach of all. But this will be another kind of society. We cannotpredict what human society will be like in a hundred years, anybetter than our great grandfathers could foresee life in 1991.Clearly, decisions on the availability of medical or reproduc-tive/genetic services will have to match the prevailing cultural,social and economic values of the times. It would be arrogantindeed to think that we could now set any policy that wouldremain valid into the distant future.

ACKNOWLEDGEMENTSSupport for the research project which stimulated this paper wasprovided by a grant from the Ethics and Values Studies Programof the National Science Foundation (RII-8511073), with cofundingfrom the National Institutes of Health. The views exp ressed in thisarticle do not necessarily reflect the views of NSF or NIH.

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human germ line therapy - the case for its development and use - burke zimmerman

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