Stanford M.D. Spring 1973 Vol. 12, No. 2 STANFORD MEDICAL ALUMNI ASSOCIATION I- .,"_ j -, .~--- ----II. ., .~ ."-~-".-, _ The Perfection of Man Social and ethical factors will be increasingly important in determining the application of new genetic advances. by JOSHUALEDERBERG, Ph.D. T HIS ESSAY is intended to be a glimpse of the future as a way of celebrating the history of an exciting era in biological science. The hazards of prophecy (not least to the prophets) are well known. Still, it would be a relatively simple task to post lookouts at the frontiers OF contemporary insight and knowledge in fields like genetics and molecular biology. If, mercifully, our range is confined to the next 2.5 years, shrewd observers may miss no more than half of the significant ques- tions that will unpredictably emerge and may score even better in outlining the solutions to some of the major problems that are clearly recognized-like the structure and development of the nervous system, im- munity, or neoplasia. We should, however, be uneasy (or delighted, according to one's temperament) about the prevalent mood that tells that most of the really exciting fundamental questions have been answered- for history teaches that this often foretells a new scien- tific revolution that could shake our beliefs to their very roots. This purview is based on an autonomous model of science that has uncertain durability. Perceived igno- rance (or error) is postulated to be the main orienting influence in scientific activity. Paradoxically, the more we know, the better we perceive what we do not; hence, the process is inherently autocatalytic. We should, then, be able to judge the main directions of scientific de- velopment as the exploration of the Known ~lnknoztin. The main uncertainty is the liability of all autocatalytic processes to burgeon unexpectedly in scale, or in clirec- tion, in response to imperceptible fluctuations. A glance at the national research budget over the last five years is enough to deflate the political plausibility of this model. The overall growth of science is clearly not autocatalytic, and, increasingly, other issues of po- litical and social choice override the opportunity pre- sented by perceived ignorance as determinants of in- vestment and support. On the one hand, the central flow and apportionment of research funds is increasingly tied to specific techno- logical missions, like cleaning up the environment or From Challenging Biological Problems, Directions Toward Their Solution. Edited by John A. Behnke. Oxford Univer- sity Press, New York, 197% @ American Institute of Bio- logical Sciences. Reprinted with permission. 12 curing cancer. On the other, the a~~tono~iiy of the re- search laboratory is increasingly caught up in irresist- ible pressures at the periphery for social goals that are orthogonal to scientific knowletlge: equal opportunity in ctlucation and employment for minority groups and women, amenities for the local community, and the ideals of participatory democracy. (The laboratory, of course, did ser1.c other masters in the past-vi[., the ego-aggrantlirement of the chief Forschcr, or the central motifs of the industrial-capitalist culture.) Specific re- search projects are also under increasingly severe scru- tiny by polarized cults of critics on issues like the ex- ploitation of human subjects, relevance (intended by the investigator or not) to the military capability of the country, or potential abuse in conflicts over welfare assistance and population policy. These pressures are bound to impinge on the conduct of science through their influence on institutional sup- port but, of equal importance, on the recruitment of students and perhaps, above all, on the morale of the investigators themselves. It follows, then, that the future course of biological research will be influenced only in limited measure by its technical opportunities, even as far as they can be observed from the existing frontier. The prophet must a so 1 foresee the outcome of complexly interwoven trentls in the ethics, politics, economics, and social struc- ture of the entire culture in which science is embedded. No contingency more dreadful than large-scale nuclear warfare can be imagined. If even this can hardly be dismissed with the confidence of a logically-rigorous demonstration, how much more precarious are our pre- dictions that bypass many other tempests. I am scarcely qualified to enlarge the reader's pre- visions of the larger scene. TVhat is manifest is that scientists will be less and less indulgetl as innocents, that they will be increasingly bewildered if they do not at- tend to the social forces that rive our milieu. Indeed, we may have to take a more positive role in leading the culture through the religious crisis that scientific skep- ticism has done much to edify. To understand how "society" will deal with science tlemantls a deeper un- derstantling of how science is perceived by the public, and how scientific progress influences the welfare of everyman. The noisiest grievances about science (or technology) have to do with weaponry and with en- vironmcntal ravagemcnt. An even more tlurable com- plaint may be the Ludtlitcs'-that new machines tlc- prive men of a sense of worth in their work by unregu- lated technical progress that ou~paccs human atlaptabil- ity. Scientists shoultl also seek a deeper understanding of their own profession-what inspiration ant1 discovery really consist ol' ant1 the forces that mold lhc choice of researchworthy problems. They may then be more likely to face up to the rationalization of their work (even in ways that may load to their own technological tlisplacemcnl); for example, through more efficient dis- semination of research literature or through the rlevcl- opment of romputers to undertake lower level "ccre- bral" functions (Feigenbaum et al., 1971). Can we believe that we have an ideal understanding of the innate talents and learned skills required for most effect% performance in different fields or that the dis- ciplines themselves are most effectively and adaptively organized? This preamble may be summari7etl with a presump- tuous assertion that limits to the development of sci- entific knowledge of life are no longer technical ones. The elucidation of the "secret" of heredity, the replica- tion of DNA, leaves no doubt that the basic principles of many other mysteries of biology are also tractable by similar- methods. We have no need to invoke an tln?z vi&d, other than sheer complexity of organization, to account for the special attributes of life. (That com- plexity remains, however, an effective and formidable guardian of the freedom of the individual will in any practical test.) It follows that further advances in biol- ogy will be dictated by the problems that biologists choose to attack; this, in turn, will be enforced by social policy to a far greater degree than in the past. An in- evitable corollary is exposure to the crossfires of polit- ical conflict over the definition of the social good. There are many signs to justify Aron's (1968) prediction that the fundamental conflict may be between relative- egalitarian versus absolute-efficient conceptions of ethi- cal utilities. (Which is preferable: to live in a levelled society free of disparity or a stratified one, whose pyra- mid may rise from a higher base?) Biologists, as imputed experts on the diversity of organisms, will face many dilemmas over this social conflict of equality and efficiency (Letlcrberg, 1972). The long-run possibilities of biological technology are unbounded-even mortality may become a matter of definition of the rate of change of memory and per- sonality (converging, then, with the consoling reassur- ances of the great religions), as we contemplate the gradual but increasingly foreplanned replacement of outworn molecules. But, in the short run, everyone still dies, and too many die prematurely according to any ethical standard. Futuristic pretensions about ge- netic engineering are a mockery to ;I mother who has delivered a trisomic child. And we arc still unable to tell the offspring of a Huntington's choreic whether he will transmit the disease to his children or, indeed, whether he will in some few years succumb himself. This disparity between present-day reality and eventual potentiality may arouse deep-seated resentments against that rosier future and even against contemporary scien- tists who are not quite able to bring it off-in time. Perhaps this is an argument against advertising the future, but too much indispensable planning hangs on clarifying the picture the best we can. The remainder of this essay will, however, focus on the challenges and horizons of the near future. According to popular legend, "anything possible will be done" if the technologists get their hands on it. Any- one who is trying to do anything substantial knows that the opposite is usually true. Absent the incentives of military applications, the more sophisticated the science the greater is the distance between its conceptual oppor- tunities and reduction to practice. One of the most egregious gaps between scientific potential and human needs is in agriculture. Formidable technical compe- tence and human importance attach to the new intro- ductions of dwarf wheat ant1 rice which have promoted the green revolution. Nevertheless, the scientific foun- dations of these breeding ventures go little beyond the rediscovery of Mendelism in 1900. Shrewd agronomic insight, and meticulous attention to detail in the selec- tion of parent stocks ant1 intermediate hybrid lines, rather than innovational genetic theory, were the roots of these successes. It is likely that many more oppor- tunities await- the intelligent application of the most straightforward techniques of plant breeding. They will, in fact, be indispensable, merely to retain our present position in the face of the evolution of parasites adapted to new and homogeneous genotypes. In principle, the cell- and molecular-genetics devel- oped in the last 25 years could make even more incisive contributions, but it has yet to make any significant impact. Some of the fault must be laid at the door of the agricultural research establishment. But the United States Department of Agriculture must, in turn, be responsive to a community that now puts increased crop efficiency very low on its list of priorities, since bumper crops prove to be economic disasters. We are, then, relatively backward in fundamental biochemical and genetic investigations of the development of seed proteins compared to their importance in human nu- trition. Until recently, the National Institutes of Health have been hard put to justify research grants on the amino acid sequence of zeins in different varieties of corn. But if we hat1 information of this kind, to the depth of, say, our knowledge of human hemoglobins, we should be much further along in designing more efficacious sources of plant protein. 13 This remark does too little credit to the empirical development (International Atomic Energy Agency Panel, 1969) of hi-lysine corn. The nutritional advan- tage of these mutants, which have visibly altered seeds, evidently depends on the diminution of Lein content and substitution by other proteins. However, the de- velopmental mechanisms involved are still poorly un- derstood, and we are still very far from a rational tlesign of a sect1 protein optimiLet1 for liiirr~an nutrition. With ii more detailed analysis of gene-controlled protein sequences, we would have ;I firm basis for the stepwisc accumulation of point mutations or recombinnnts towartl that optimum. The substitution of threonine for scrinc, or of lysine for arginine, in ;I seed Ijrotein would be expected to have little impact on its function for the plant compared to its utility for man. Plant breeding is, of course, burdened with logistic problems of assessing intact seedlings as the units of genie ex- pression and with the traditional problems of diploitl inheritance (need for back-crosses and multiple progeny tests). These might be averted by more attention to artificial haploids and to the manipulation of plant cells in culture, including cell fusion. Similar tech- niques have greatly advanced our knowledge of the genetics of a species, man, which few would have ex- pected to outstrip maize two decades ago. Viruses (as an exemplification of plasmagenes) may also play a role. (Indeed, they already do; for example, in the control of male fertility for the production of hybrid corn.) An example of genetic engineering of a virus that may eventually be important for improving the quality of plant protein is suggested by the claim of Rogers and Pfuderer (1968) of the engineering of ;I tobacco mosaic virus variant to which poly-A was ap- pended, with the concomitant production of excess polylysine. Well-defined clones of such variant viruses have not, however, been reported. A control long-run objective for molecular agrobiol- ogy is the maximization of protein yield at the expense of polysaccharides. The plant will have to be engi- neered into a kind of lactating organ in which just enough structural cellulose is invested to sustain the primary utility of protein synthesis. The dwarf va- rieties, indeed, exhibit this very principle. Human consumption of photosynthetic product amounts to about 300 M (3 x IOR) tons of fixed carbon per year. This is only about 5 percent of the total crop yield, most of this being waste tillage. Crops, in turn, make up only 10 percent of land-cover photosynthesis; it will be at least as difficult to expand this ratio as to improve the efficiency of already cultivated lands. A ris- ing population will have few alternatives more palat- able than the use of chemically recycled cellulose or fossil carbon for human, as well as industrial, fuel. The salvage of the world food resources is by all odds a mixed blessing, according to well-known Malthusian reasoning. It is difficult to see how striving countries will be induced to limit their population growth so long as the weight of numbc~-s is a l)olitical, and even :I military, weapon in interstate competition. The tech- nical IIIC;II~Y of contraception are improvable, but scarcely lacking now. I\`c have little basis for optimism except the hope that world ortlcr ;rntl economic niotl- erni/ation may atlvanc-e in spite of the population drag, and that these factors will e~icour;i~ge a demographic reversal. The natural xntl ~n;~n-~n;~tle disasters that hnvc afflictetl Beng;il al-e visions of the alternate paths. Another crushing affliction of most of the \vorltl is infeslation with animal par;isitcc, especially malaria, blood flukes, ant1 worms. Environmental sanitation, directed at vector control, has been the most effective public health measure th mitigate these tlcbilitations, but tropical countries are likely to remaitt burdened with them for ~nany years nevertheless. The well-tlc- fined life cycle of these par;lsites should make them biologically fascinating, as well as humanely rewarding, targets for more profound study with modern methods. The attenuated Iilutant already plays ;I central role in prophylaxis against virus infection by vaccination with- out the benefit of deep insight into the mechanism by which the parasitism is frustrated. I\`ith the flukes and worms, well-defined niorphogenetic stages are involved in the progress of a11 infestation, ;intl with the malaria plasmotlia, it should be even easier to superimpose bio- chemical analyses of the critically alteretl stages of at- tenuated mutants which could confer analogous bene- fits in the form of virus vaccines for the control of cor- responding diseases. The genetic engineering of Plas- medium falciparum vies with that of OryLa sativa as a further target of molecular genetics. From the standpoint of scientific nntl technical nc- cessibility and of clarity of ethical consequence, para- sites and domesticated animals and plants are clearly the most attractive targets for genetic design. However, utopian aspirations for the "biological improvement" of man were appended to the development of genetics even before its emergence as a rigorous experimental discipline. The eugenic aspiration, oE course, conflicted head 011 with theological doctrines of the origin of man in original sin and alternative recipes for salvation. It is refueled today by doctrines of the inevitability of evil in human nature that are fallacious deductions from ethological research. The most telling argutnent for eugenics is the fear that the existing human species is doomed to self-de- struction. But a culture that cannot evolve the political machinery to contain its weapons will hardly improve its competence for survival by adding biological engi- neering to its repertoire. Like many other messianic visions, eugenics is faulted by a confusion between the needs of an abstract WUI~- kind and those 0E individual men and women. In many 14 arenas, utopian aims for the ordering of human affairs might be ;rchicvetl at the sacrifice of intlivitlual liberties. In the economic sphere, "from each according to his abilities" is a plausible humanit;n%ln itleal, but it can be enforced only with the apparatus of a police state ant1 a11 arbitrary determination of what each has to contribute. Apart from the alrcatly fatal obstacles of political implementation, genetic planning fares frus- trations analogous lo the failures of ld;~nnetl economies, both with respect to technique ant1 to the validation of consensual purposes. In the real world, social movc- ments will continue to have much more incisive effects on the human gene pool than any conceivable technical atlvanccs that could bc labellctl as "tampering with the genes." Geneticists, in the main, have been so critical of largc- scale eugenics that they may forget that the allegation ol seeking to bred Supermen will be renewed in every popular discussion. Some of my own efforts to outline the difficulties ant1 paradoxes of genetic design have, for example, been misquoted (Ramsey, 1970) as advo- cacy. I will plead guilty to withholding categorical anathema on issues that are amenable CO deeper cx- ploration, both technically and morally. Social atti- tudes on questions like contraception ant1 abortion have changed too dramatically in one or two genera- tions to reinforce the posture of scmpiternity of our ethical pronouncements, above all in human biology. This is no assurance of ever-increasing permissiveness- the history of the tides of moral fervor shows more dis- placement than dissipation, and they may return once again to now-abandoned shores. Let it be clearly posited, nevertheless, that the re- making of man is an illusionary goal for the application of genetics in a liberal society. The principal task of genetics is scientific untler- standing; the principal target for its applications to man is the alleviation of individual distress-which the Idlysician cannot repudiate no matter what the gen- eral-state of the world. In pursuing his goals, it should go without saying that the geneticist is bound by the same set of ethical restraints that apply to other inno- vative branches of medicine. The surgeon does not use his scalpel by whim, and even in the chase after poten- tial knowledge, he is, above all, accountable by law and ethical tradition to the needs 01 his patient. Table 1 catalogs a number oE potential techniques that may relate to the prevention or therapy of genetic disease or which may influence genetic constitution. This is not a well-bounded arena, for all of medicine -indeed, all of culture-is potentially euphenic and eugenic. That is, they may (1) ameliorate the actual development and expression of genetic predisposition, and (2) thereby, indirectly influence the relative fre- quency of different genes in the population. The boundaries of what shouId be called "genetic" tlisezse ;irc also uncertain, for every pathology must have both ;I genetic and an cnvironmcnt;tl component. Many common diseases, as well as over;ill longevity, h~vc ;I significant heritability.. r\bout 5 percent of ol'er- all morbidity can be related to specific genetic defects with ;I relatively simple b:lsil;: if ICC also take accoutlt of the heritable component of pre\.alent diseases, like schizophrenia, diabetes, c-artlio~ascular tliscase, ant1 so on, at lea5t ;I fourth of total morbidit) (in mctlically atl- vanted comrnunitics) must be attributed to genetic inl- perfections. Genetic Load, Mutagenesis, and Environmental Hygiene The genetic load is, therefore, a forniitl;rblc p;irt of the problems that must be facctl by mct1ic;lI practition- ers ant1 tllcir patients. Plainly, preventive measures should have ;I high priorit),, if we could, thcrcby, pre- vent the intrusion of genetic defects in the first instance. This may not nl~v;rys be possible-an unknown part of the genetic load is "segreg;~tion;rl"; it derives fro111 hetcrosis; i.e., an advantage of the hclcro~ygote over either homo~ygote. Natut-al sclec tion, then, tends to keep both of the alternative alleles in the population, notwithstanding the inevitable quota of impaired homozygotes that must recur at cl'ery generation. Heterosis is important to framing reasonable cxpectn- tions for genetic improvement since 110 freely breeding population can then be composed exclusively of the healthiest (heterozygous) 1dienot)pes. The production of high-yielding corn is based on the careful nurturing of a number of rather weak, highly inbred strains as parent stocks which arc then crossed to 1"educe Yigor- ous hybrids. The farmer who tries to use the$e, in turn, as scctl coral courts tlisaster--n fact hardly in keeping with racist mythology or with the naiver forms ol eugen- icism. Furthermore, the heritability of different diseases gives no assurance that ;I single optimum genotype can exist. Susceptibility to cancer JJKIY rdlect a low excitn- bility of the immune mechanism; allerg). the converse. Total freedom, both from cancer ant1 allergy, may be physiologically unattainable. U'e have only provoca- tive data about mutual exclusions in predisposition to tliscasc, but WC can still be fairly sure that we have more choice about how, rather than whether, to die. These aspects of disease genetics are relatively inde- pendent of the mutation rate, responding mainly to natural selection. They offer some room for genetic in- sight, short of total amelioration, since the existing gene pool has evolved in 3 historical context of medical ant1 olher cultural determinants that ha~c changed far more rapidly than gene frequencies cati have respond- ed. Furthermore, Darwinian fitness, or reproductivity, is becoming less and less congruent with the stnntlartls of somatic quality by which we judge ourselves and our peers. 15 A. B. Table I !iclectivc 777nliP7g: 1) By phcnotypc of parents (assisted by biochemical and cytological assay) a) negative - distracting, discouraging, or steriliring tl1c "unfit" b) positivc- i) encouraging select pairs ii) with artificial insemination, donor ("rational germinal choice") iii) with oral or ovarian transplant iv) both ii and iii, or fertilimtion in ijill-0, followed by implantation x) extracorporeal gestation (test tube baby)--sPc nlso euphenics (i-v arc not very dilferent in tfieir ge77rtic consc- quences) 2) By genotype of parents-as above, with deeper analy- sis of parental constitution. Except for specific abcrra- tions, very little can be said at present about genetics of desimble traits. 3) By relationship of parents a) inbreeding-The main impact is to expose reces- sive, usually deleterious, genes: increase phenotypic variability of F1; decrease the gcnotypic variability of later generations. b) outbreeding-antithesis of (a). hlost cultures strong- ly encourage outbreeding. 4) By age of parents-to forfend accumulation of dcle- terious mutations and chromosome anomalies which increase with parental age 5) By phenotype or genotype of the zygote or of the fetus (antenatal diagnosis and voluntary abortion)-Earlier selections would a\:oid the trauma of aflorting an cs- tablishcd fetus. 6) By genotype of the gametes: e.g., separation of X from Y or normal from defect-bearing sperm 7) With sperm of other species (compare [l] [b] [iv])- Nothing is known of the consequences among primate species (possibly in vitro). All contemporary races of man appear to be freely infertile. Cross-pollination is, of course, a crucial technique in plant breeding. Innovutiof7s in Zygote Biology -Vegetative (asexual) f>ropagation. Cloning. (Almost unit ersal among plant W.) 1) Parthenogenesis-development of an unfertilised egg. (This might be genetically identical to the mother, or might be a product of meiosis, whicfl would be an in- tense form of inbreeding.) 2) Regeneration-development of a whole indivitfual from somatic tissues (as in some plants and lower ani- mals like eartflworms) 3) Differentiation of gametes from somatic tissues pre- viously subject to extensive genetic manipulation ,I) 5) 6) 7) Somatic reduction in gamctc-forming cells in culture (somatic inl,reeding)-should allow predictable out- come of further matings front :I gi\,cn parent ruhith is not now assured. Nuclear tr;insl'l;lnt;ltioll-rcliucle;ltion of a fertilized cnucleatetl egg. Genetically equiwleut to clauing Cram the s0urc.e of the nu( leus. Eull,r);o-splittiaF; to produce tlvins or multiplets. Not to be confused with multiple owlation (occasionally induced by fertility-promoting drugs). About one-third of sf)ontancous twins arc monozygotic, i.c., arise from the splitting of one cmlqo. Note also the of~f~osite p11en0men011. f~mbryo fusion (tliimcrism) -so tllat one indi~idu:~l comprises t\vo or more genotypes. `l-his grades into tissue tranapl;int;ition at later stages. It slloultl allow diffcrcnt genotypes a new latitude for mutual comple- mcntntion, e.g., n1cns s0?2(2 in co~~~~orc snflo. Somelvflnt less than l/ 1000 lir-e births arc spontaneous cflimcrns, but some of thcsc arise by other mechanisms. C. Adj77nct.s f)-on7 sonrrrfif roll bioloF)`-For eugenic applic;i- tions, these would I)c co~~pletl u'ltfl f~rocedures like B(5). For cuphenic effects, alter4 cells can be grafted back to a host or sonic manipulations done directly on his tissues. 2) 3) 4) .Ugeny-directed alterations of genes a) contro\.ersial claims of efferts of 1)X.-\ uptake in mammalian cells following a long tradition of ,ge- netic lvork lvith KIN.1 in bnctcria I,) incorporation of liruscs i) experimental tumor viruses ii) use of specially modified 1 irusrs 1) xiccination to induce immunity to viruses 2) \ irogcnic tflcrapy to replace missing genes 3) virogenic enhancement for superior pcr- formnncc-if we but knew the biochemistry thereof c) incorporation of chromosome fragments transmit- ted by cell fusion d) specifically induced mutations - No plausible ap- proaches arc now apparent. Random mutation and specific selection of cells with altered properties-fias full precedent in strain selcc- tion in microbes. Many uncertainties relating to pos- sible cancer potential of such implants. Cell fusion to form somatic hybrids-Tflcse cells may then lost various chromosomes to gi1.c many new forms. Extends scope of (2). Can be readily applied to fuse cells from "distant" species, c.g., fisfi and human. Development of symbiotic strains of lower species, with habitats that grade from the external world (e.g., crops) to internal to intracellular-Parasitic worms in man have evolved in this direction with tflc help of acfapta- tions to thwart immunological rejection. In principle, they might be domesticated. So also migfxt algae be trained to an intracellular habitat in man where they might photosynthesize essential nutrients, if not bulk calories, as they already do in primitive animals. * From Lederberg, 197lb; see also Davis, 19TO. 16 However, the "mutational" part of the genetic load must be considerable, and this is related to the rate of mutation (informational deterioration) in the genetic material. A certain level of mutation is an inevitable byproduct of molecular accidents in cell metabolism. However, if we argue from the relative incidence of en- vironmental, compared with intrinsic, carcinogenesis, which may be parallel phenomena, we may judge that four-fifths of our ambient mutation rate is of environ- mental origin and could be eliminatctl by environ- mental hygiene (relating to drugs, food additives, and possibly some natural foods, water, and air pollutants, certain virus infections). About 10 percent of that quota can be attributed to the natural radiation background, which is essentially not avoidable, and an equal propor- tion to artificial radiation. At one point, nuclear power development appeared to be the main source of in- creasing environmental radiation, but the newly adopt- ed standards of the AEC promise to keep this to a negli- gible proportion of the background. The major source of artificial radiation today, by far, is diagnostic X-rays which approximate half or more of the natural back- ground. Our increasing sensitivity to genetic hygiene will raise agonizing issues of the costs and benefits of c medical X-rays. These can hardly be answered by point- ing to the overall benefit which is irrefutable. They do demand an examination of the dispensable margin, be this 10 or 80 percent of the total level of manrads now dispensed. Many physicians believe that "defensive medicine," that is, the anticipation of lawsuits for mal- practice, is responsible for a needless volume of caution- ary X-rays. The present legal framework compensates the single patient who might have been benefited by a routine X-ray that was negligently withheld. It does nothing for the 10,000 others or their progeny who must eventually pay some price for having been X-rayed with unimportant results. Our skills at matching these costs and benefits can only be sharpened if we are first etlu- catetl to asking such questions in economic, rather than diabolic, terms. The same issues confront us in the formulation of policy about chemical additives to the environment- solvents, drugs, food additives, and so forth. It is not very useful to assert that a compound is mutagenic with- out proceeding to it more quantitative evaluation of its impact, and our data on human response to chemicals is even more fragmentary than to radiation. Before joining the bandwagon against synthetics, the geneticist must caution that natural foods need a similar exami- nation. The first authentic publication about chemical mutagenesis (Auerbach ant1 Robson, 1944) concerned allyl-isothiocyanate, a constituent of horseradish and mustard. (This compound has, moreover, been found to induce skin tumors after local application in mice.) Mustard has not, however, been subjected to the rigors of evaluation according to the Delaney Amendment, perhaps for fear that this woulcl overturn our simplistic approaches to a problem that is as complex biologically as it is vulnerable to the bias of vested interests. En- vironmental hygiene may be the most fruitful area of application of more sophisticated molecular genetic analysis. Options for Genetic Therapy Among these options, a few stand out for offering the most realistic opportunities for health benefits. They include: Antcnatal Diagnosis An increasing number of diseases will be reliably diagnosed by cytological and biochemical studies on cell cultures derived by amniocentesis (Dorfman, 1972). TYe already have exciting advances in the understanding of several neurochemical disorders which rely upon the identification of specific enzyme defects. The tech- niques of cell-fusion and of chromosome identification with fluorescent stains will strengthen our ability to trace mutant genes, and similar methods will also help identify high-risk parents. M'e can visualize more direct assays for specific information content of DNA with techniques for the isolation oC specific messenger RNA and, then, the homologous genes. The DNA segments can then, in principle, bc tcstctl in cell-free systems for protein synthesis or, perhaps, even subjected to direct analysis of their nucleotitlc sequences. This level of sophistication in the analysis of gene effects should, in many cases, lead to deeper under- standing of the disease and may provoke explicit thera- pies. Meanwhile, our main recourse is voluntary abor- tion of the impaired fetuses to allow a mother the best chance available to her of delivering ;I child free of malignant defect. Our experience with the antenatal diagnosis of sex should help correct overanxious predictions about the anticipated misuse of "genetic engineering." This has allowed a reliable method of voluntary control of the sex of offspring for some years. Whether the sex of the fetus has ever been a controlling factor in a decision about abortion, without more persuasive indications, simply has not surfaced as a significant social problem to warrant any special regulatory controls. The com- mon sense and patient-oriented values of the medical profession remain the most effective bulwark against nonsensical distortions of its tools. Actually, voluntary control of the SC): of offspring might encourage a limitation of family size (e.g., one boy, one girl) consistent with the social interest in over- all moderation of population growth. Then, a balanced sex ratio could be maintained even under voluntary choice. Transplantntim Many genetic defects involve cell populations as metabolic units that could be supplanted or restored 17 ( I , ; t / ; 1 \ by transplantation. For example, complete transfusion plays an important part in the therapy of Rh-hemolytic anemia (but is associated with a danger of graft- vs host- immune disease when applied to the fetus). The scope of tissue transplantation should not be judged by its present limited application which is constrained by the hazard of graft-rejection. Specific ways of mitigating rejection are bound to appear as a fruit of immunobio- logical and immunogenetic research. We will then have a simple, practical way, for example, to deal with sickle- hemoglobin disease - namely, by transplantation of normal erythropoietic marrow to the newborn or, per- haps, the fetus. We will also surely find that many other diseases, genetic or not, are amenable to relief by tissue and organ transplants-e.g., hepatocytes for PKU and for galactosemia, or insulin-secreting cells for diabetes. The last example illustrates the opportunities for therapy even where the transplanted organ may not be the primary seat of action of a defect. The growing popularity of transplantation of hair (auto- today; homo- tomorrow; hetero- yesterday [the obsolete fur coat]) attests to the same principle. Transplanted immunocytes are also likely to play a key role in the treatment of auto-immune disease (per- haps, after systemic elimination of offending cells) and in the prevention and treatment of neoplasms. In cell biology research, we have just begun to move into the arena of systematic work on the genetics of somatic cells. The discovery by Henry Harris (1970) of Oxford of powerful methods to induce the fusion of cells has attracted enormous interest in the conse- quences of mixing chromosomes of different genotypes and species and in their reassortment in various combi- nations. The way is, then, open to genetic analysis (and genetic engineering) of mammalian and human cells in a way that would have been technically and ethically impossible otherwise. We can also expect that domesti- cated lines of somatic cells will be important inputs to therapeutic applications of transplants. Vaccination and Virogenic Therapy Since 1798, vaccination has constituted an important medical application of the genetic modification of so- matic cells by viruses, though its practitioners to this day are often oblivious to its mechanism. Jenner found that inoculation with infectious lymph caused a mild disease, cowpox, immunity to which also protected against the dangerous smallpox. Many aspects of vaccination are still scientifically obscure, but we can now describe the process in terms of molecular genetics. The DNA of the cowpox virus is purposely introduced into certain cells which adopt the genetic information contained therein. These cells thereupon produce new gene products, encoded by the viral DNA, which stimulate other body cells to produce antibodies against them. The cross-immunity is then a byproduct of the virogenic alteration of some cells of the host. Live viruses are now widely used for vaccination against many other diseases, including polio, measles, and-in special cases or in the near future-rubella, mumps, rabies, and so on. Vaccination can be regarded as if it were a therapy to replace the functions of hypothetical genes not nor- mally present in the human organism, those that would endogenously stimulate the formation of antibodies. This idea can be extended, in principle, to other gene products, for example, enzymes that may be missing in certain gene-defect diseases like phenylketonuria and perhaps diabetes. Laboratory models for this kind of virogenic therapy are being perfected and rational trials for human disease can be anticipated shortly (Rogers, 1970). Although basic genetic principles underlie this technique and the genetic apparatus of somatic cells is altered, it is classified as euphenic because the germ cells are left unchanged, and there should be no effects in future generations. This is a matter of empirical ob- servation rather than necessary principle in biology, and it is quite conceivable that some inoculated viro- genes might also be inherited, as has already been pos- tulated for certain tumor viruses in rodents. This res- ervation applies with equal force to vaccination against infectious diseases about which we have little informa- tion in proportion to the enormous numbers of chil- dren involved. The recent discovery of "reverse transcriptases," which copy RNA information back to DNA, promises to simplify some of the technical problems of develop- ing virogenic agents. Differentiated cells should, under certain conditions, produce multiple copies of active messenger RNA molecules, and it will be easier to purify and test these than to attempt to dig out a single DNA gene from the complete chromosome set. (In clue course, however, this should also be facilitated by know- ing the chemical signals that distinguish the active from the inactive genes in a given cell.) Reverse transcrip- tion would then allow the recoding of the RNA message into DNA which would then be spliced to a virus for facilitated re-integration into chromosomes. Virogeny will be in competition with cell transplants for the replacement therapy for genetic defects, but each may have special advantages in particular cases. For example, the transplantation of neurones is not likely to be very helpful except at the earlier stages of development. Proposals for virogenic therapy reawaken many other questions about the use of live virus vaccines for mass prophylaxis - a public health measure that involves most of the world's population in contrast to the few subjects of experimental approaches to gene therapy. Inevitably, live viruses will carry a residual hazard of atypical reactions, and of passenger contaminants, al- 18 though these could be mitigated by more attentive re- search. On the other hand, the assumption that public smallpox vaccination can be safely abandoned is based on experience with the management of breakthroughs under almost optimum conditions. The notion that smallpox will be finally eradicated within the decade is hindered by serious geopolitical obstacles, ant1 we do not know what would happen if the virus should be reintroduced (1) in unusually virulent form; (2) into populations who are immunologically relatively naive with respect to other infections as well as smallpox; and (3) under contingencies of breakdown of public health services. The 1972 epidemic may bc a fortunate tocsin. Viruses used for prophylaxis in man have been de- veloped and monitored with scarcely more sophistica- tion than that available to Jenncr. The molecular bi- ologist should insist that the highest standards of chem- ical and biological purity and characterization avail- able in the research laboratory be applied to these agents. This will not be possible without a recognition that cheap vaccines will be worth what WC pay. The drug companies cannot be faulted if higher standards are not imposed uniformly on their competitors. Renucleation (Cloning) From the work of Briggs and King (1952) and of Gurdon (1968), we know that an activated egg may be renucleated with a nucleus taken from a somatic cell of an existing frog. From a genetic standpoint, the new embryo is like a cutting, or clone, of a rose plant. The question of renucleation of human eggs was first introduced (Lederberg, 1966) to make a rhetorical point. Many speculations hat1 been put forward about the possibilities of "genetic surgery"-of a kind that would require fantastic innovations in our knowledge of molecular genetics. Renucleation in frogs had, how- ever, been demonstrated long before, and it was also very plain that it would be available in man as a neces- sary prerequisite to more incisive techniques of genetic manipulation. It follows that, if one wishes to agonize about the likelier directions of futuristic change, he should attend to renucleation rather than genetic sur- F-Y. My erstwhile remarks that mice and men should not differ from frogs in amenability to renucleation may have been naive. Chromosome-inactivation, exempli- fied by the inactivation of one X in normal female cells, may play an even more important role in tissue dif- ferentiation in mammals compared to amphibia (Di Berardino and Hoffner, 1970). In that event, renuclea- tion may not bc technically possible until long after the achievement of other aspects of ontogenetic control which, in turn, may make renucleation relatively less useful for any practical problem. We may still discuss "cloning" if only as a speculative exercise. If it could be done today, it is hard to see where renucleation would have very important applica- tions, but this is precisely the kind of anticipatory study that needs to be done. On the positive side, it may give some otherwise sterile mates the opportunity of par- enthood. An anovulatory woman might borrow an otherwise wasted egg cell, renucleate it with one of her own, or her husband's somatic cells, and have it re- implanted into her own uterus. Or a fertile wife might offer an intact egg for microsurgical fertilization with ;I haploid spermatocyte nucleus from her azoospermic husband. We can properly understand the moral objections and justifications of such procedures only if we explore the whole continuum of technical interventions in hu- man reproduction. Ever since primitive man tliscoveretl the connection between sexual intercourse and concep- tion, human reproduction has entailed deliberate cxer- cise of purpose and intelligence, an unavoidable power and responsibility for the next generation. The guard- ing of such responsibilities against external intrusions is the essence of personal freedom. It goes without say- ing that we would abhor stateenforced reproduction of any kind. Conversely, to what extent sho~lltl individual patients be deprived of the possibility oE using techni- cal devices they, ant1 their professional counselors, be- lieve to be in their own and their offspring's interest? Many unanswered questions remain on the ethical or technical merits of renucleation. Popular discussion of cloning has probably overemphasized the significance of a common genotype: Monozygotic twins are not copies of an identical personality, especially if they have been reared separ:~tely. They do resemble one another more closely than other relatives, to be sure, ant1 re- nucleation could be a means of avoiding certain ge- netic defects that arise from segregation. If, for other valid reasons, renucleation is ever practiced, we can clear up many uncertainties about the interplay of heredity and environment: ant1 students of humAn na- ture will not want to waste SLICK opportunities. So man)- clevelopmental ha7artls may bc associated with renuclea- tion that very extensive animal studies ~voultl be the minimum prerequisite to ethically justifiable trials in man, and the interval gives us ample time to ponder the values in balance. Our consensual standards of an ethical mctlicd ex- periment require that it serve a reasonable humani- tarian purpose ant1 that it have the informetl consent of the individuals concerned. The problem of renuclea- tion sets into relief the general problem of pal-enthood. Who else can speak for the welfare of the individual not yet in being? Shoultl parents bc held in contempt if they procreate despite the knowledge that they arc risking a significant deformity in their offspring? Should they be encouraged to undertake :lrtificial mea- sures that will give their young an easier start? -Ant1 where is the boundary line between the responsibility 19 ." ---- "-_-- . . . I "". "._ ^" __- " __. DK.JOSIWA LEDERBERC,~ native of Montclair, ,Vew Jersey, anal a product oj lyezu York City publicschools, Columbia University, and Yale, won a 1958Nobel Prize "for stztdies on organization of the genetic material in bacteria." Dr. Lederberg is Joseph D. Grant pi-ojessor of genefics and biology and chairman of the Department of Gencfics of the Stanford University School of nledicine. He is also director of the Lt. Joseph P. Kennedy, Jr. Laboratories for Molecular Nedicine, dedicated to basic research in genetics, devclopmcntal biology, and neurobiology for a broad attack on the problem of mental retardation. He has related wsponsibilifies for research programs in instrumentation, computers for laboratory use and in the study of mechanized intelligence,and the defection of planetary life. Both he and Dr. Elliott Levinthal, director of the Instrumentation Reseawh Laboratory in thegenetics department, are parficipating in the design of science packages to carq out exploration of Mars on lriking'75 Project missions planned by the ,Vaiional Aeronauticsflnd Space Administration. of the parent and of the community for manipulating dictions about the long-range future of the species a child's development-the socialization or education might be substantiated as a side effect of medical care that predestines him to function as a particular kind of and other welfare measures that avert the pain of human being? natural selection. However, the pace of discovery in These questions are properly applied to the destinies genetics is so rapid, compared to that of biological evo- of particular individuals born day by clay. Gloomy pre- lution, that we-can afford to wait another 50 or 100 20 years before we tackle the species problem. We will then have sharper tools and, at least, as much wisdom about how to use them. Meanwhile, we have enough to do in trying to minimize the enormous burden of personal distress and anxiety that attends our genetic load as it is manifest birth by birth, death by death. Indeed, it is hard to see how we can make better sub- stantial progress toward an ideal of human improve- ment than by freeing individual families of the anxiety and the burden of known defects. The general ques- tions of human improvement (Lederberg, 197 1 a) apply with equal force to policies of education and even to the standards of health and nutrition promulgated by pediatricians. Summary Advances in molecular biology promise to enlarge our technical capacity to intervene in genetic problems. Social and ethical factors are, therefore, likely to play an increasingly important role in determining the ap- plication of new scientific advances in man. This is no cause for great alarm, for the same principle already applies to the use of surgery and of other medical inter- ventions that could, in theory, also be applied for ex- traordinary "renovations" of human nature. The evolution of wise policies for the use of genetic advances, and the surveillance of existing practices for compliance with consensual ethical standards, and for the anticipation of social injury, of course, require a widely disseminated understanding of the probable po- tentialities of various types of genetic intervention. The most important influences on the genetic com- position of the human species are likely to remain side effects of other global policies: the movement of popu- lations, transportation technology, the effects of war and of discrepancies in economic development and attention to preventive genetic hygiene, especially through the identification and elimination of principal environmental sources of gene mutation. Specific options for genetic therapy include the rapidly developing field of antenatal diagnosis (coupled with elective abortion of threatened fetuses); cell and organ transplantation; and virogenic ther-spy. The last would entail the introduction of desired DNA segments into domesticated strains of viruses; these would then serve for the vaccination of patients lacking a critical metabolic function which would then be restored un- der the influence of the added DNA. The renucleation of eggs (cloning) is also a theoreti- cal possibility, likely to be of more metaphorical than pragmatic interest. The discussion of cloning may help to illuminate the ethical problem of parenthood, gen- erally: What is the responsibility of each generation for the biological and educational predetermination of its successors? In any event, the central responsibility of the ge- neticist, qzrn physician, is to the welfare of his individ- ual patients. REFERENCFS I coultl not pretend to lrnve mastered all of the works that would have to be cited in a comprelrcnsive bibliography of tlrc subjects of this paPer. Indeed, tlie central issues might be obscured more than clarified by too detailed an claborn- tion. A comprehensive bibliography on bioetlzics is maintained by tire Kennedy Center for Bioethics, Georgetown University, W'aslrington, D.C. Further references may be found in tire bibliographies of the papers cited here and by using these, in turn, as keys for a citation-index search of current literature. This list of references has been limited to secondary sources and to a few titles essential for the clarity of the text. Tire most secure prediction that can be made about the near future is the early obsolescence of this bibliograpl~y. ARON, R. 1968. Progress nntl Disillusion-the Dinlcctics of Modern Society. Signet (N.A.L.), New York. AUERBACH, C. and J. M. ROBSON. 1944. Production of muta- tions by ally1 isothiocyanate. Nntzc7-e, 154: 81-82. BRIGGS, R. and T. J. KING. 1952. Transplantation of living nuclei from blastula cells into enucleatecl frogs eggs. Pro- cecding5 of the A'ntional Acndenzy of Sciences, lVnshi77g- ton, 38: 455-63. DAVIS, B. D. 1970. Prospects for genetic intervention in man. Science, 170: 1279-83. Dr BERARDINO, hI. A. and N. HOFF~EK. 1970. Origin of chro- mosomal abnormalities in nuclear transplants-a re-evalu- ation of nuclear differentiation and nuclear equivalence in amphibians. Deuelopnentnl Z?iology, 23: 185-209. DORFMAN, A. (ed.). 1972. Antenntnl Dingnosis. Uni\.ersity of Chicago Press, Chicago. FEICENBAUM, E. A., B. G. BUCHANAN, and J. LEDERBFRG. 1971. On generality and problem solving: A case study using the DENDRAL program. Machine Intelligence, G: 165-90. GURDO~, J. B. 1968. Transplanted nuclei and cell clifferen- tiation. Science, 219: 24-36. HARRIS, H. 1970. Cell Fusion. Harvard University Press, Cam- bridge, Mass. IAEA Panel. 1969. New approaches to breeding for improved plant protein. International Atomic Energy Xgency, Vi- enna. LEDERBERG, J. 1966. Experimental genetics and human el-o- lution. American h'ature, 100: 519-31. -. 1971a. Orthobiosis: the perfection of man. In: A. TISELIUS and S. NILSSON (eds.). The Plnce of Vnlue in n World of Facts. Nobel Symposium XIV. Wiley Intersci- ence, New York, pp. 29-58. . 1971b. Biomedical frontiers: genetics. In: The Chal- lenge of Life. Roche Jubilee Symposium, Basel, Switzer- land. 1972. The freedoms and the control of science: notes from the ivory tower. Southern Califow7in Lnru Rezlieru, 45: 569-614. RAMSEY, P. 1970. Fahicated Alan-the Ethics of Genetic Control. Yale University Press, h'ew Hayen, Corm. ROGERS, S. 1970. Skills for genetic engineers. xezti Scientist, 45: 194-96. and P. PFUDERER. 1968. Use of viruses as carriers of added genetic information. Notwe, 219: 749. 21