Genetics Society of America August 31, 1967 Friends, colleagues, and disparate genotypes. Marshall Nirenberg did me the favor of providing the very best possible introduction to the remarks I would like to make tonight in the form of an editorial that appears over his signature in the 11 August issue of Science, and I would like to ask you to hear me first read that editorial, It's entitled "Will Society Be Prepared?" All of the foregoing is a quotation from Marshall W. Nirenberg. I have quoted Dr. Nirenberg's remarks because they make a good stalking horse for some criticisms which I would like to offer, and not in the spirit of any kind of personal criticism of Dr. Nirenberg himself. I must say that in self -.-__ defense, because his own accomplishments in this particular field are so vast and so well known that I would hardly dare to stand up against him in his absence without some sort of reminder that I may be exaggerating the import of his remarks, . p and that further elaboration on his part might given a different interpretation than for the sake of discusiion I choose to put upon them at the present time. Never- his theless, I think %-he language V will evoke a familiar chord +th- -* I think there is a reaction of fright about man's control of his own destiny, in particular about the use of genetic as compared to other forms of biological intervention, and I think it is important that we succeeti in achieving a realistic point of view about what we can do, what we should do, what is likely to come about, the kinds of information that we need to find for ourselves to lead indeed to the wisest possible application of these new kinds ma of discovery. I will take a few of texts from these remarks, and comment on them. 2. The most awesome phrase, and I have heard it at least twice tonight, and hear it every day, and I use it myself on frequent occasions, is the reference to*man:s power to shape his own biological desting This is an awesome statement, kfh . . and it is probably true, s I'm not sure what it means. . central question about man's biological destiny is whethisr we will have a posterity able and willing to commend us for our foresight, intel- ligence and good wh&.l. Molecular genetics undoubtedly plays a role in the ultimate answer to this question. Even more do politics, military technology, and what we human might call the religious aspects of mmx culture generally. The way what we deal with Indian famine and with Chinese nuclear power may be even more relevant to whether there is a biological destiny of man on earth. We also know that that destiny is finite in any absolute sense of the term, either with respect to catastrophic accidents of our own making, or with respect to the long term future of the solar system, and unless we, for example, and propagandize the universe, we do have a finite, ultimate destiny. I say these remarks in hopes of achieving a certain re-focus about the nature of the problems that we should be concerned about;if we look too far in the future we may overlook the Tbeam in our own eye. The phrase "the betterment of mankind" also offers many difficulties of reference in any circumstances, and particuhrly when we're talking in evolutionary terms, which is the framework in which I choose to interpret Dr. Nirenberg's remarks. I could ask whether it was for the betterment of apekind when pre= hominids left the trees and moved on the ground, and had arms available for the acquisition and inspection of objects. Will any intelligent species stop evolution; in the conservative attitude that change is likely to destrw the existing framework of the species? Will it insist on having a completely rational view of the events that concern the existence of future generations many years, centuries, millenia hence, &gain the frameworklzhich we must judge any issues 3. that concern the evolution of our own kind. But if we do insist on that rational possibly outlook, how can we/anticipate the mown social and technological milieu of 4 existence of such future generations? The one principle that we can probably . . find common ground on for all of us is to avoid rash irrevoc&LlQ& of the de- cisions that we make. Unless the very exiaence of scientific thinking is 2 with included in th irrevocable w we might wish to/hold in order to avoid change, no isolated experiments can be regarded as globally irrevocable steps. In fact, they are indispensable for the wisdom needed to judge which institutions I' should be set up. When Nirenberg rticerrrcr recommends that when man becomes capable of instructing his own cells he must refrain from doing sd: I believe we should trcanslate that into "We should be very cautious" about instituting of social and political frameworks/change which constitute irrevocable steps for the entire species". 41s" But these remarks could very easily be interpreted, and point of view some of us might be misled into adopting a flraalafl that suggests that we not undertake any isolated experiments whatsoever in an area so full of 7 'stique. the genetic programming of human cells, unt&B we can under- stand all of the implications. How will we ever learn what these implications + might be if we never do any such experiments? We must distinguish the rash from irrevocability of isolated events in other spheres &m those which would apply to experimentation with single organisms of our own species. History tells us that a nation infected with nuclear power has no choice but to use and develop it in the existing context of world affairs. A single nuclear detonation was an irrevocable event for the politics of our time. It is doubtful, but not certain, that any nation would make quite such a threatening use of genetic weapons, and they are likely to be less immediately impactful, and to have much longer time scales than the physical ones, which will permit some possibility of . . intervention in theAsocial misapplication v . . e%ahea of single standard of biological control. 4. With respect to future developments, Dr. Nirenberg makes some remarks that I must characterize as imprecise. He refers to thel'synthesis of'messagei, and their possible use in programming * cells. Whether the messages are synthetic or natural, so long as they are calculatedly used, would been to me to make very little difference. I think when we talk about programming cells, and talk about messages, we should inquire for some greater precision into just what kinds of messages we are talking about, and what impact they will have on respective organisms. And the harm is that language of this kind read by laymen, read by political leaders, read by religous leaders, may be misunderstood, that very important distinctions may be blurred, and that we may end up with significant restrictions on our sense of freedom of action and experimentation, which in turn, as I have already remarked, is what we must have if we are ever to achieve the kind of wisdom that has been alluded to. Some of these distinctions are with respect to somatic,vs. germinal effects of hhese messages. Are we talking about the now conventional messages of the messenger R&(the its nits/information to the protein synthetic machinery) or means by which DNA trans- - are we talking about the a message which is implicit in the Da structure of the cell? And are we talking a about somatic effeete or germinal effects? In general somatic effects are highly pe_rsonU, An RNA me&age that I may use for the repair of many of my own genetic defects is something that may help me live, but will surely die with me, and it is very difficult for me to distinguish the social relevance of the use of an FUTA message for the remedy of such a defect in my own person from that of any other aspects of medbcine, eAn fact, many therapeutic agents are already involved in this kind of meddling with my somatic genetic programming. If, for example, according to most contemporary theories, I were to partake of the use of a hormone, its purpose is to elicit the calculated production of specific messages in certain of my cells in order to make protein synthesis occur in cells in which it otherwise would not. If I were a diabetic and could anti- 5. cipate the possibility of taking a single shot of the appropriate messenger RNA to reprogram the synthebis of insulin in some of my liver cells after my pancreas gave out, I think I might resent any blockage to my taking advantqge of this on the vague grounds that this is in some general way a genetic message that we should refrain from using until we may know for sure whether it will ultimately be for the benefit of mankind. If we are to use that criterion, we should use the criterion with respect to every medical intervention for individual + human betterment. In fact, I think it must be stressed that the point of view which is implied in the presentaUon of this editorial runs counter to the funda- . . mental responsibilities of medicine: Tc & the care of the individual patient. It is certainly the concern of the rest of the social milieu thatthhe sum of ikx care of individual patients works to the benefit of the entire community, but a literal following out of the pre- scription that Dr. Nirenberg has presented would be the total stoppage of medical 41 practice. Now when we come to germinal effects, of course we must have some much clearer idea of what we're doing than might be the case with the personal intervention of somatic repair. If ause of a medicament B has an implica- tion not only on-q health and my survival and my longevity, and mu ability to perform, but also that of my progeny, then of course we would insist, e that we have a clearer idea of what we're up to. Here we are already guilty of some sins, I think most geneticists would deplore the sometimes careress use of anti-can&r agents, for example, that are known to cause chromosome breakage, and are known to cause mutations, sometimes possibly in patients who may still have progeny, and of course we have had a very necessary and very important furor about the indiscriminate use of radiation. If the reports about the breakage of chromosomes by LSD are correct, there might indeed be a very strong rationale for social control of the use of this agent, or for the compulsory 6. sterilization of individuals who insist on receiving LSD, because they may then a be laying a basis for/very severe penalty that society as a whole must adopt with respect to the increased incidence of congenital malformation.in the next generation. Here again, I don't think this is what Nirenberg was driving at; if he was concerned primarily about genetic messages with germinal effect, I don't believe that either he or I would be that greatly exerciselabout the pos- an sibility of some transgression in xas~ experimental context. The occurrence of an occasional individual whose genotype is other than it might have been h as at a result of the use of genetic message of calculated composition &II some point It is in its formation just does not have that kind of social impact. Something m m to be cautious about, but it is a caution already within the framework of CR medicine as it is now practiced. A more precise statement of what I trust are his concerns would be a caution against the imposed s 1 control of those techniques, those apparent benefits, those advances that molecular biology may help to bring about. And in this we have a certain analogy with rational germinal choice, as has been advocated by by Huxley and Muller, for example, CllrL q Muller was constantly being misquoted with respect m to his advocacy of the use of the technique of artifical insemination of chosen donors. He had in mind individual choice of specific genotypes & as sources of sperm for the production of what he hoped might occasionally be superior kinds of individuals and he was constantly misinterpreted as advocating social imposition of such germinal choice on families that would have preferred to make their own mistakes rather than . . adopt those of the community in which they lived. Neu+b ay v , G rthat distinctinn isn't as easy as it = might appear. The mere introductton of an attractive technique, of a technique which seems to confer a dertain degree of social benefits, and which has unkmorm social hazards, may lead to its social adoption, XIf this is the problem, this is what ought to be stated, and this is what we should attack. I think, though, 7. that most of us would agree that while isolated modificattons of existing genotypes in either a random way, or in a calculated way,can increase the range of variability and sometimes bias the range of candidates for natural selection to operate, B the overwhelming source of man's biological destiny in the sense of the over- of whelming basis of the changes in gene frequencies SXE the changes of the genotype of the human species come from our physical and cultural environment operating by natural selection; that differential reproduction is overwhelmingly a more important source of the definition of the next generation than any isolated changes in availability of individual genotypes. Now Nirenberg says it has T- not A een possible to program mammalian cells. That remark,strictly within the context of his statement,is correct. He was talking about the use of isolated DNA operating to replace mutant genes by other mutant genes or by normal alleles, by ana&agy with the well known pneumococcus transformation experimenta Y( that possibility has been known for twenty-nine years, It did not require the development of synthetic maMhalian cells, in the sense of introducing genetic information of known import, calculated to produce an explicit purpose related to the genetic . machinery?. dp we- , already practice biological = engineering on a very large scale, and we are doing a rather sloppy job of it, and since this particular element of applied biology may indeed be a prototype for the way in which we may end up broadcasting favorable genes in other ways in the future, I would like to spend a little more time on it. I am talking about viruses used for Mnunization. Polio virus particles, measles virus particles, any of a number of other agents have been developed in forms whihh have been attenuated in order to reduce their acute pathogenicity, -1 2 5 8 so as to make convenient the job of immunizing children so that they will not come down with frank disease. W,: don't want to rock the boat on this ques- tion; I still think Immunization is a good thing &W&Q, and I don't deplore its c- s development or its application at the present time. But I think I must speak out for a much more intense study than now exists of the human impact of these practices. It is very sloppy, it is unconscionably sloppy, considering the scope with which this form of biological engineering ;is carried out at the present time. The use of live virus is 8, sloppy first of all because mf the techniques of production, monitoring, specification, characterization of live . . viral agents belongs to the dark ages, &+' +hsL proximately a+h&&-~ half Qe a billion doees of a SV-40 virus were included in the polio virus immunization of the last decade. / This was a passenger virus, originally, in fact constantly present in the monkey kidney cells that we used for growing both the SW&n and the Salk vaccines. It proved to be more resistant to formaldehyde than polio virus, and therefore was partricularly prevalent in Salk vaccine preparations since these were used at a higher dose in terms of to&al virus particles. It was also present in the Sabin preparations. It may have been a subject of greater concern in the SAlk virus because this is administered parenterally,and the SV-40 would not have to face the barrier of penetrating the intestinal mucosa before it entered into the % general circulation. SU-40 is a tirus which seems to be a harmless passenger the 11 in the rhesus monkeys used as I smunees of tissue cultures for growing the polio xmmminm UiIWS - in fact, it is very difficult to demonstrate the virus in that species and very difficult to demonstrate it using human material, and one needs the green monkey to obtain good plamques with enough cytolytic action -- to demonstrate it. It's a notorious virus because it will induce cancer when injected into newborn hamsters, but after the hs&er is a few days old, it has no known important effect on these organisms. 9. It is a little late in the day to raise any alarums about this particular subject. Nothing very catastrophic actually seems to have happened, in spite of the fact that many millions of children and adults have received rather large doses of this virus in past history. The Public Health Service thinks badly enough of the procedure that it now prohibits the presence of SV-40 virus in current batches of vaccine, so with one hand we have expert assurance that it can do no harm, but on the other,*well,we'd better not have any more of it:' I deplore the fact that we have no way of knowing whether either e&the SV-40 virus - ae sv-w - or even the attenuated polio virus - have caused more subtle deleterious effects on mankind. We may never know whether the use of these vaccines was for the betterment of mankind, because we don't collect the kind of data that could enable us to reach this conclusion. It seems rather likely, judging from ohher characteristics of the present generation, that these viruses may have caused a reduction in IQ of the contemporary generation. Mh&km~~ If that were a matter of 20 points on the IK usual scales, we miglst have discovered it. If it were a matter of 2 points, we couldn't possibly have discovered it. And yet an average reduction of 2 points of IQ, ,,L-r---,,*na m =tRtpmpnt, would surely be regarded as something most deleterious to mankind. Well, it could have happened. It could also have happened that the IQ's imr went up by4$%!0, and our current generation may be too smart to want to bother with taking such '9 tests very aggressively! One of the principle indictments that I would make in our contemporary exercises in genetic engineering is that we don't realize that we're doing it, add we're not following what's happening. One of the reasons for this is that at we are looking too far in the future instead of/yesterday and today for the kind of wise outlook on'what is happenaing right now in the species in the use of contemporary applied 3k# biology so that we can ask the right questions on I a large enough population base that perhaps we could tell that what's going on 10. is for better or for worse. Now, it's not implausible that polio virus might get into some of the neurones of a developing child and beve some specific morphogenetic effects,-- In fact, it's even possible that the neurone count of children who have received these viruses is larger than that of other individuals in the . population, by 10 or 15X, and we would have no way of knowing it from our existing data. I can't stress this point too strongly, that we do not watch our populations closely enough to see exmn major movements taking place within them. My second criticism has .to do with the way that these agents are prepared, v ,,C wW:e are not taking advantage of the kind of techniques that Nirenberg and Kornberg and I and others like to use daily in our own laboratories in a more rarified research context. There is no excuse for virus preparation being as contaminated as POliO ViNS WSS, from the difficulties of detection, the only way it could possibly happen is that we are content to use biological reagents of enormous potency without taking any real care to see that they are pure, homogeneous and ghat they are intended to be 4 physical chemical -- criteria. It was enough that the polio virus preparations produced the right kind of plaques on a selective group of tissue culture media for them to be authenticated as being pure polio virus. es. .-.z wee virus agents used for this kind of genetic engineering applied on a large scale to our population are crude culture filtrates. They are subjected to no biological or chemical purification whatsoever before they are packaged in sugar cubes and passed out to the kids in school. And I don't see anY excuse for it except the fact there is a that virus 11. imauniza$ion programs are mass medicine, tN'&, 1 -- Y E i: -* and of course they're not at all to be labelled E3 as biological engineering having anything whatsoever to do with the new 58 w molecular biology. However, before we become to exercised about biological 34 $34 engineering and its hazards and a lack of decision in our understanding of $5 the mechanisms that we're using on such a large scale, I think we ought fi also to remember that we practice psychological engineering also on a very, 32: 34 very large scale. -f 3: 35s m It's compulsory. It's mostly pretty-well prograaaaed from reasonably 3ii central authorities. z: It's equally unscientific,and we call it education. c tti Q1: I think we should consider very literally that education shapes the child, tz shapes the character of the next generation in just as explicit a sense as any tz $3 of the biological innovations that we have in mind and possibly if you believe H some theories of the nature of learning, even from a morphological point of 24 view, that is if you believe learning has something to do with the morpho- 8 $8 genesis of the central nervous system as many people do. pl If we try to look beyond the specifications of what Dr. Nirenberg has laid out so con- veniently for me to use as a point of exposure, might ask what else would I quarrel with him about. I've already quarrelled with him on the time scale. He says something twenty-five years in the future and I've tried to point out that we're talking about events that were well launched dive years ago or ten years ago. The future events that he's talking about happened yeaterday. in.- , permit me,,to indulge in some of my own lib- hypotheses of sources of evolutionary innovation. Let me begin with the -u most explicitly germinal& changes, 12. Here I would like to go back to viruses. Sore of you may have been pustled exactly why I called the virus Citation an exaxple of gexetic engineering. Uell, let 1~ illustrate what I reant by a hypothetical proposal that was put 5 forward moat explicitly recently by -8 He found that in tissue culture the uirue will, c 9 as all viruses do, Induce the formation of certain special extyxes, mauy of which have a perceptible relationship to specific virus grovth in the cells in qlae8tion. Ifauy viruses for example induce a uxique 4+&&Aktnw Most of the bacteri$hagee induce unique DNA polwrases that have properties 8omwhat different from the typical DNA pol+msrase of the bacteria that they previously infect, aud so on. So, in fact, it 18 no?regarded as comouplace to think that one of the crpecial functions of the information ix a virus particle is to impose a few special enzymes that are related to the uuique replicabllity of the viral nucleic acid as compared to that of the how. I4 Ix addition, the virus generates a capauprotain to protect itself outaida of the infected cell, axd that's what viruses are all about. Induced euxyms ayxthesis by viruses in a rather nou-huuu coutext are very familiar now. Dr. godgers at Oak Ridge noted, aud I believe others have as wall, that the Sh "p" virus iu tissue culture would alao in induce another amym, o rgltwae, which haa no obvious adaptive & k f% virus, but we take it for granted that * s due to our ouu myppla that we areunable to aaa why It's there. That vu a stepping-atone to auother fixding of his, nmly, this vaa reported iu lature last December, that a cousiderable numbsr of people who have used the ShopC virus in the laboratory had very low serum %f i&l* WY la-1 Q- pretty convincing '+a e that they are statistically different from the < ,c~ I+.+b c i4 d-7 ti /LcAL+? , Lo> LL+& 13. rest of us, and-ghough I do not believe he has definately demonstrated that 14 this is the same phenomenon as has been demonstrated tissue culture, it's indeed very plausible that virus workers in the laboratory have acquired infections with the Shake virus which is known to have no effect in & CA Cl -; Man, but that they have indeed been wfi infected gat some of W been to c . tiddue cells have/induced/m form a particularly active argenase- . 8 This has had no perceptual effect on the performance of these individuals unless their pre- occupation with the Shoke visus is somehow *-heir low serum zrgenase) al&hounh VP don't sf '.- m---u. But you could not have told them apart by looking at them or by watching the "I you had to measure their serum arg$?to know that they'd had CFF any previous experience of this kind. W, this may have been the first understood example in Man of the iw appearance of a virus-induced enzyme as an augmentation of the genotype of these IndividuUs, at least with respect to the s&aatic behavior, these individuals are rrp+ stigmatized by the fact that they have some additional genetic information than what they were born with, the information coded by the Shop virus for the pro- % duction of this specific protein. And&U+ a- -we don't know * of any use for argenase in Man, L&R'* hali8vm +w imy,so we can't cure any known metabolic defect,Tf we could just x find one it might make a very nice case for using Sh'#e viruses in a constructive sense. mL-1: J wbether or 14. P Rodgers proposed tJa&s look for viruses that make more useful enzymes, for example, rer that mxkm will induce the formation of phenylalanine hydroxglas+dyou all know that we could then cure x PKU at a fundamental level, s might even want to get into the fetus and not wait for the birth of the recessive homozygote who might be impaired in his nrental development because of his accumulation of phenylalanine on an ordinary diet. And if we can't find such viruses we really are just in the brink of being able to make them, that is a possibility of splicing a messenger RNA that codes for ordinary human phenylalanine hydroxalase to the viral KN4,of one or another infectious virus seems like a very plausible ,,j CL .." <*;. * < . c pus&b%, botbin the point of view of the chemical steps needed to fabricate such hybrids and from the point of view of the likely persistance of such xixmmm viruses themselves in much the same fashion as the original passenger viruses would have done. So this would have see&to me the nearest thing on the horizon by way of the calculated ya's6-t q -rLLL~ c- of viruses for genetic engineering+ anAs exactly what we are already doing for immunization purposes. The only difference is that the induced enzyme which Rodgers is calling forq is, in fact, an induced antigenic protein ,-be >> encoded by the viral nucleic acid-&m we would like to see px&al prodaced in the human being who receives this information ,Ion a life- long basisc so we don't have to reimmunize +t& Ge purpose of introducing I that protein is to evoke an antibody that responds against it so that you will have immunity covering against infection by other virus pxm particles. But 15. it< fundamental biological operation is exactly the same as that of the late addition of the gene to the organism so the calculated production of the specific protein encoded by that genetic information. This has colpe to the top of my list aszcandidate phenomenon for human intervention because it's already here. It's hard to think of explicit ways in which e germinal changes,C might be brought about under calculated control. One wonders exactly how we are going to introduce nucl&* changes into germ cells so that they get into the zygote, m- xwithout doing something else first, namely enabling the vegatitive propagation of an existing organism. My argument is that we will somehow, if we are ever to get to the stage of the kind of genetic surgery that I think was in the back of Dr. (\lirenberg's mind, have to be able to manipulate nuclei of specified origin to do s-thing to themBand then put them into an egg so that they +bL==-._,, can operate in the normal development ai-4 e if we can do that, even if we don't alter the genetic composition of that nucle@b, we have already accomplished a major deviation in the reproductive habits of our species from an evolutionary standpoint,because ( 'I, we will have introduced vegetative copying of existing genotypes,amd+bat W As a matter of fact- already been done long since, L..e \ but so far only in amphibia. I'm talking about Briggs and )< ,'lrCt 5 experiment on nuclei/L, transplantation.ue * * 16. tissues, put them into eggs and get normal development. t found very considerable restrictions on develop t they always do report a few cases of seemingly normal de*pment from such transplanta- tions, and rent species has had considerabl ,and what's outstanding about Gurden's my mind, is the frequency with which be obtained from the nuclear transplan- sometimes even adult origin into enucleated -------- __,^"_.--. I,.._ _ .-.-. " .,, ,. _ _ ._ So that vegetatively reproduced frogs are almost a commonplace, but how long will it be before they are commonplace in may who can tell,# &t I don't think any of you can give me any fundamental biological reason why man should differ from amphibia in this particular respects kil y nuclPs/L- transplantation should work any differently in man than it does in an$ihibia. eis would be a prototype of the base-line experiment that would have to have been realized in order to exercise genetic surgery by any route I'm able to think of at the present time, and I think it'll be there first. Hopefully with connected/m this is a p+irqx topic that has fascinated a few people in every biological generation. I'm reminded that- Holdan$referred to it and Mrs. Holdan if- , Helen Spurway, actually attempted a demographic survey to look for the possiblity of parthenogenesis in man. She found that there was a certain confusion about what _ ' * T,' 1 L b1c-k actually ,,"' ,'. -meet. You may recall she advertised lb+&&/ r examples of this over the BBC about 12 or 13 or so years ago. She did4so not because &4b'~+~eibU&+- earthenogenesis was a new idea, but +trrr because a diagnosis of it) became possible by the development of our udderstanding of the genetic transp1antation.r ab& LO m to- purant; one +esphmm -=f!w-P-L1 &M% Her idea was that if any example of pgported parthenogenesis 17. passed the otper B then she ought to try reciprocal skin transplan- tations, and if they worked in one direction at 1east)which is the expecta- tion for parthenogenetic -&dk$ost any mechanism e,than corroborative it uould be pretty good lrkrittfrt evidence that it actually happened. Her failure to find an un equivocal example, "a)`3 nothing about the future, either on a rmndom or a contrived basis. And I was really quite excited to A see an article in last months hcenetics by Olson &.A44 v, on parthenogenesis in turkeys,where he remarks that the Ugkxfxm highest frequencyof parthenogenesis in these birds is a fundtion of the simultaneous presence of an appropriate genotype and of the fi~'-~~$virus infecting these ' birda. &te substantiel yields of e turkey eggs parthenogenetically produced, are capable in quite a few cases ;- _ ,' of developdmg into normal male adults, 1 1-e Well, again, if it can happen in turkeys, it's gping QT to happen in man,I'm quite sure. -any evolutionist looking at what has happened particularly at plant species is likely to remark that experiments in vegetative propogation are likely to have a much more prolound evolutionary impact on the further developnaent of the species than is the occurrenceof any other sort of variability of genotypes present at any given time. These of course can work together, but the point about 'eoduction of course ?%%?$$ers. It the way is that it is such a a-+:dbLf answer to the ug of expanding an indiately adaptive genotype to the circumstances th& existing, which is of course what the&genesis %' '--kl .,. __ _..,._-. s- re crying for, and well, you worry later about what happens when the emmironment changes or gour ideals change. S a very reasonable predicate for future development . m besides the viruses that we may introduce for 0 somatii& we\ c we may have to generalize our concept of the virus in a couple of directions ) is that it takes very little 18. to turn * a virus into a plaf3 It's only necesrary that the virus be very adherent to the embryo on its way through or be passed through the ail% or be actually present within the cell of the egg as well es other cells of the body. There are any number of viruses which &facto are inherited as if they were D &mmogens even though I believe in mana la there is no mA61i'C' , example of actual i+-w5-- oval~-+~rant3miseion of a virus particle. I may be wrong about that and I'm not sure that pragmatically it * matters very much from the point of view of the potential human impact. If it is in fact trued that mothers who are infected with a virus ~~f~~~~~~~~'*$. introduced are going to pass that infection onto their offspring, it's hair- &A splitting to pethe question whether that was done through some external odium enviro-t or internallr/~e~&~~~>. Well we may find it desirable to incorporate trruaizing viruees in this way, xxx& but as a matter of fact the odds are &hat we would prefer to avoid it. The reason we will want to ,)avoid it xxx is that by all odds we want to keep the next generation of -c infants from being builtin polio virus e&gin, which they are likely to be if that antigen is present w *6-& .\ut that ~ also suggests the kinds of antigeythat we-k indeed want to be sure s pretty regularly transmitted, ti< imagine, for example, wanting to produce viruses that have a --I, capability of coding the more cotton hietocompatibity antigens m, % s to give these kids fresh kidneys when they are adults and their old kidneys have been worn out. But w- this kind of engineering does represent a very plausible way of getting around em of the other engineering problem of building genetic information into existing m chromommee. %n other way to do &hat lo to avoid uaing/zsting,cbromos-4 and put in another one. And what I envisage &e 1y113/ the next step along this line.18 building sm very small chromosomes with just a few genes on them and transmitting these f=m cell to cell, for example by fusion which is already a very well 19. authenticated technique, and is able to produce /j w somatic cell hybrids between forms ai distantly related as fish and man in tissue culture. These hybrid A ?A k-types do undergo very striking hangeqf once they are produced they eventually shake down to a at the number of SWU&C o&line~f& we're just/very beginning of understanding how to control this and what it takes to produce a balanced type that is able to be well adapted to the circumstances of tissue culture 1iEe of any one kind. I think you can see what can lie behind that,by way of very detailed nanipulations not of the molecular biological level, but at the level of chromoeord introduction for producing new genotypes. Combine that again tu~?%.t.cI~ with m transplantation and we really do have --?L":" ',' L& .i genetic engineering on a very large scale. . r Up to a few years ago I think gametic selection would have b n /+ / near the top of the list of anyone who wanted to look past the usu&~ opera- tion of contrived sourtic selection that is the of somatic phenotypes. This is, in fact, t le88t promising of all. It does look as if th are expeesseing ' a very erall pmeportion of all of their genes being in such a way that moment at least, you've for 8ny other purpose, we reach too rapidly at that would have been p tion in man we could g and using sacsort of oomatic selection on This aoundrr so weak these days by comparison with the other 20. @ And I'm sure that any of you to this kind of joint psych&elic exercise would be able to add some of your own experience# many other ways in which ue could contrive to do a conuiderable amount of genetic engineering in man if we jrut remember that man is an organism and not very different from your in own typical subject of experimental investigation, except tidt/hie reelstance to being experiiented with. d@ Cell and tissue culture -that resistance work seem8 to dieeapear and you can do a lot of your antie&btpr&ithout running iocial interdiction, pr\ * 47 EWWUR I so far stress what I called eugenic effect8 A+ I-=-- germinal modifications and I wonder about th8 long-term relexnnae of that distinction. Mow it's a little hard for geaeticbt to pl8y it downt our image, our unique dietinction~ from all the reet of the biologists is our ability to foist that m distinction on all the re8tof pu. What ia genetic and germinal is something w-, very different frem what io somatic developmental. There is 8aathing permanent WA& about the *w upecte of an organism. But I'm not sure whether this sot will/beceme ebaolete in the framework of -+h=p-N-- the reuoning I would put forward is along the same linesthat you would now \ S regard certain genetic differences as already eubetantially irrelevant in man* I hope, for example, that the amount of hair on my he&l, which I do believe 18 under 8Qlt genetic control, really is not very important because I can -r*ey eculture replace6 biological en&ument in the wnduct of our own afaire. The more we learn about developwat the M deeper that's going to be. The medical example,of this -W@ bre well known and are sometimes U dp4bu4. It's also lees m I now if I'm a diabetic because we know about &asulin and better ensuline have cm along, other kinds of drugs have corn along, we sort of on the edge of thinking about using cell transplants to take the place of a failed l-u and so on. Andwhilethiewill entail a certain amount of extra cost it's jur;t part of the cost of keeping civilization going that a& webeoome dependentouitin so many ways. U&&&&leie W the lowest level of -notypic irrelevance, the technicological substitution of other kdsda of artificee to the things we us&ally depend on. It isn't terribly iqortant that we have great strength anymore, we have machines to take g-d their plaoe. We have o utmbilee to take the place of/legs, and so on snd so forth. (There are eo&&cte to good legs:) wv &o ??????? ???? > ? *? $mued&!t this kindof developrental interventionend -how firmly opposed it is to eugenics,1 try to coin a sufficiently opposite nams, so c I thought'enpheniu, but enphenics is really the sue thing as medicine. @ lkphenics is beginning to acquire the hind of resources that nke it relevant to the most fundamsntal aspects of hurrr persaxality. N'N' here, or all things I've talked about so far, &if@ into ineignificance by cemparison with the one thing that distinguishes msn frem the other species1 andtbat is his brain. We are just beginning to get the faintest gluclv of what it is that controls the developrant of the brain. And the things we do as soon as we do understand that control, as soon as we know which horaaeszlved inprogrdgthe developmentofthebrain, what relevance will bhere be to the existing assortment of genes that control the count of nenrons that we might have or the other much more coqlicated ways to determine what our performance on an IQ test is going to be. We so far just do mot intervene at all, we don't even provide ressonable support for the most important of our developrental processes. Mostly because we don't 22. anderetand it at ill. Ue are just beginning to inwmtigate it, we have such f-in86 a6 one nerve growth factor finally being gotten out in rea6On&$y pure form, some understanding of it6 nature a6 a protein home. Ue are obliged to believe that a sfmllar tiad of prograaing is going to apply to the central nerveus ayatem geaerally. l&at only will existing genotype6 for the develop- ment of intelligence Cc irrelevent, it's to be expected that there will be (&-w&&&d P=='I effects. Ue+u U our eatim6te of genotyplc performance in term6 U-what happen6 in the relatively uucontrolled situation of a normal ge6tatlon with no external hormone coutrol of braln developrent,& & fact, until reuouably recently it was rather importart that the child not be born with too large a braln, because if he did he'd run into ObStetric6ldfficUltieS.' Well these are all points that we of course ca6 get arouud to in considerable extent by medical and surgical intervention and there will be no relationship (0 between the response of the end@nouB development of the organism, which i6 what I6 now aaaured,and what will happen when we are putting in an d explicit progr-. We can u6e variation6 of genotype a6 a controlflbraln development to learn a great deal ab,out the developm6nt of the brain, I- \ CGe ttwt /(rfWW/rg henylalanine b ts mental development is one of the kind of r+. things we can't afford to ignore. But I can see very little place for , velopwnt;;of 6n what will happ -I . ..__.- --- - , treasuring too mu& the existing getiotypes for I-(th' 8 intellectual performance in terms of their probable relevance to the contra 4 wortd of ? * 23. brain development. Now there are going to be some paradoxes and dilemaaas in this field a6 there are anywhere else. There's a price to be paid for almost any kind of advance and here we're talking about soxething that sort of happened yesterday also. There are soue fascinating reports from Dr. Money's labora- tory, John Hopkins, about the iupact of houmonal virilization on intellectuaA1 developuent. Though his data really are not very good, I'll pretend that they aret they are just hints; you really can't rely on them as being affirmative truths.lor intellectual.developuent the situtation is must too coupllcated for that to happen easily. But these are pointed at series of cases for which there has been either a natural accident, for example the idiopathic virilization syndrome in which girls with an excessive output of or, where in fact there has been a contrived euphenic intervention where little girls were exposed to ew6 while in utero in order to have them be born at all. This is thexpnx N indicated as a ueaaa of sustaining a pregnancy in the face of a threatened abortion on the part of the gother. It has been known for soue tiue that the administration of this hormone could lead to anatomical or development of excessively large e LLmh.3 surgically which could be a-~diminished m ilnportant evidence that this resulted in any deleterious Money has changes in later developuent. Well, iuqxk6x6 found two things about some of these girld as they grew up to be young wouen. First of all, by the kinds of tests that as a psychologist he uas able to aduinister, they were touboys. They had adopted a uasculine point-of-view about the world and if this arexplicit influence of a hormone and the parts of the brain that are concerned with gender identification, it will of course be of extra- ordinary interest in that light alone. Now, life is too complicated to draw such a simple conclusion. Of course the parents of these girld knew souething about their history, and they've learned souething about it theu- selves, and we don't know to what extent the social uilieu was the vehicle 24. psychological s immuni&3~ Together with that I think none of you might be # too Surprised to find that they also had an exaltation of their IQ's. The reason one shouldn't be surprised is thatwith the biological endowment of a complete set of X chromosomes and with some of the pagnacity of the male, how I CR can you beat that kind of female. Well, there's already enough of a hint that this work6 that I if there are any pregnant women here tonight,- -tht some of t T/YOU qy4.J contemplate trying to masculinize your feGes at the present time, particularly if you knew that they were girls! w 9 we have a culture that recognizes male values very much more than it does e our female, and most of/eugenic efforts are dedicated to producing super man and the hell with the women. (Are you going to go alon with that or not?) 3 q Until we can res&lve that very simple issue of human values as to whether we have a bisexual society or a unisexual society in fact, I think we have to be very restrained about the other interventions that we want to mmke in human performance. And I should perhaps also remind you that everyding by which we now calibrate human genotypes is in the framework of our existing culture, our existing educational system, and all of the rest of it, & one of these days we are going to find out something about education, and = I wonder then if any of the ground rules of that calibration are going to be relevant at all,along the same lines of argument that I had with respect to euphenics. I would like to revert to the main thrust of Dr. Nirenberg's concerns, and that is, should we wait to use genetic messages for the programming of human cells until we can understand all of the condequences and be able to make a final judgement about human betterment? I would reiterate my concern about rash irrevocability of any of the steps we take, and I would like to ask for the most sympathetic consideration and for the most savage 25. intellectural criticism of individual experiments that go to the roots of human nature. Unless, in fact, we do use genetic messages in an intelligent way to do these kinds of experiments, you will never learn anything about the man himself and we will have no future other than/endowment that we received at the time that intelligence first appeared in the species. I do not think we want to characterize ourselves as mop, the uniquely conservative animal. Thank you.