Heredity (1981), 47 (2), 283-292

1981. The Genetical Society of Great Britain

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RECOMBINANT DNA AND GENETIC EXPERIMENTATION. (Proceedings of a Confer-ence at Wye, April 1979). Joan Morgan and W. H. Whelan (Eds.). Pergamon Press(For COGENE), 334 pp. Price £24.00.

(i) Introduction

This is not just another book-of-a-conference. For much of it is aboutpolitics rather than experimental science; but it is the politics of science,in the field made notorious for its political entanglements in the later1970's. It is worth considering by researchers in other fields as well, fornowadays one does not know where external entanglements of researchscience will occur next. That episode of attempted self-regulation of DNAresearch is just about over now. Although other problems may well arisein the future, the excitement that started with the "Berg letter" of 1974has subsided. It is a thus a part of history, but a history that is still veryrelevant to policies of the present and imminent future.

The present consensus of the leading American scientists is that thepublic warning of 1974 was a mistake. Their advice to scientists nowcontemplating such a move is "Don't". Their painful memories nowfunction as the most influential version of the history of the episode. Thusthe history of the past inevitably shapes the future; and the task of thehistorical researcher is no less demanding of skill and responsibility thanthat of the scientist. If by detached and skilful historical scholarship wecan discover which were the truly avoidable errors, and how much wasjust the inevitable cost of a learning experience, we might make all theparticipants somewhat less sad and yet be collectively more wise, in facingthe next event.

The book under review here is by no means an history of the affair;rather it is a recent and rich source of testimony about it. It is also adocumentary record of a political activity designed to conclude that phaseof DNA research; but that is only of incidental interest here. I shall takethe liberty of using the book mainly as a source for materials (since it islikely to be the most accessible such source). I shall briefly sketch thehistory of the DNA debate (partly in the light of this material), and thendraw some lessons from it.

My own qualifications for this task are relevant, since I am not aresearch scientist in this field. For some years I had been writing on thesocial and ethical problems of modern science; this led to a post at theCouncil for Science and Society (1973-76) and a report (1977) on "TheAcceptability of Risks" drafted by myself. Probably because of this exper-tise I was nominated to serve on GMAG, for 1977 and 1978. Fortunately,I was already engaged for a visiting post at the Institute for AdvancedStudy in early 1977, and so I could personally witness the dramatic eventsin America then. From the beginning it seemed highly unlikely to me thatthe recombinant material in research laboratories would present asignificant hazard (except perhaps to technical staff); my main interest has

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been in the adequacy of society's response to the variety of challengespresented by a nascent technology.

(ii) The early history

There must still be many scientists who cannot imagine how historycould be anything but just finding out how it all happened. A reading ofsome of the contributions here would be quite educational. James Watson(p. 187) is the most avowedly autobiographical. For him the whole affairof the "Berg letter" was simply a reflection of the anxiety of certaintumour-virus researchers, partly about conceivable hazards of the work,but equally about their liberal conscience and image. His recollection wasthat the whole thing was "done in a hurry" because of the ease of DNAexperimentation. Norton Zinder (p. 193) reserved his position on thedetails of the crucial meeting of April 1974, and also disagreed explicitlyon the involvement of infectious-diseases experts in the crucial early periodbefore the big Asilomar conference. He had spoken to many of them inthe course of his duties; and he found that they had no easy answers, forthe problem was so novel, but they did have real worries. (In the event,these were never incorporated systematically into the discussions ofhazards).

Charles Weiner, the historian at M.I.T., who is the master of thearchives, produced more correctives: distinguished scientists, includingsome who now view the whole exercise as a politically-motivated blunder,were willing to lend their names to public approval of the measures taken,even up to the first set of NIH Guidelines (p. 281).

Hence we may say that present memories of past events are influencedby the needs of the present as well as by the traces of the past. Even thesevarious accounts of the 197 3/4 period omit (except in one hint by Watson)a very pressing concern of that time: that "cowboys", irresponsible and/oruntrained researchers, would move into virological work, flouting theprocedures and precautions thc had become standard in that field. Theintensity of that problem as perceived then is conveyed in the account ofAsilomar by Michael Rogers in his piece "The Pandora's Box Congress"in Rolling Stone of 19 June 1975. Reminding his readers that: "If medicalscience has learned anything about viruses thus far, it is that they aretricky", he quotes Paul Berg at Asilomar: "Eight months ago the telephonecalls were coming into our laboratory daily: 'Send us pSC1O1 (a variety ofplasmid used for recombinant engineering).' 'What do you want to do?'we'd ask. And we'd get a description of some kind of horror experiment,and you'd ask the person whether in fact he'd thought about it and youfound that he really hadn't thought about it at all. And that's not to calldown criticism on anybody because two years earlier I had been in thesame position."

Few commentators remark on how the perceived hazards problemchanged in those crucial years 1974-75. It had started with a concern overthe unskilled handling of particular viruses; it then (in the "Berg letter")generalised to micro-organisms whose pathogenicity might be enhancedby recombinant techniques. By Asilomar, the problem was seen as a totalone of any and all potentially hazardous recombinants. The solution wasthen envisaged as a comprehensive system of techniques (physical barriers

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and enfeebled hosts) and procedures. It was this solution, enshrined withNIH Guidelines promulgated in 1976, that helped convince critics thatthere was a real hazard to be regulated, and also quickly convincedAmerican researchers that something had gone wrong. It is important toidentify the source of that error, so that the right lessons may be drawnfrom the experience.

(iii) Power-politics—A silomar and after

The shape of the American regulatory effort was determined by theconsensus at the conference at Asilomar in February, 1975. This is not sowell covered here, but one comment is illuminating. E. L. Woilman(p. 233) (of the Institut Pasteur) naively went to Asilomar expecting adiscussion of the possible hazards and misuses of a new technology. ButDavid Baltimore defined the problems in the narrowest terms of laboratoryhazards, and Woilman came away with embittered remarks on comparisonswith the state and prospects of atomic physics in 1938.

The degree of involvement of infectious-diseases experts at Asilomaris still a matter of controversy. E. H. Lennette (p. 261) here recalls thesurprise and even astonishment among the relevant professionals, at thesequence of actions in 1975. He believes that enough was known eventhen about infectivity for most of the scientists' concerns to have beenallayed, and the public's fears to have been avoided altogether. Appropri-ately for this position, he stresses skill and discipline, rather than formalguidelines, as the genuine means of containment of pathogens.

In wilful ignorance of such advice, the American DNA scientists pro-ceeded to the construction of a detailed taxonomy of experimental hazardsin an inevitably a priori fashion, hoping that the creation of "crippled"versions of the standard hosts would ease the rigours of their control.

This organism was eventually produced in the form of the famous E.coli X1776 of Roy Curtiss. But the "guidelines" for containment werethe source of endless wrangles, and of very serious embarrassment lateron. Also, they suffered from an astonishing blunder in their drafting, asStetten (p. 157) tells here: they included no machinery for their revision.So every change (always an easing) had to be accomplished by a specialprocedure, increasing the suspicion of those critics who were gainingstrength in 1976 and after. If there is to be any further autobiographicalconfession in this story, it could well be on the Guidelines Committee of1976, which produced its schemata in that splendid isolation from expertisewhich characterises the Americans' style throughout.

In America the political debate over the regulation of DNA researchin 1976 and 1977 was fierce in places, but brief. The victory of the scientistswas inevitable, given that they determined the terms of debate (hazards oflaboratory-created epidemic pathogens), and laid the burden of proof onthe critics. Opposition was mainly local, in particular University towns;and the broader issues were never heard except on rare occasions whenthey were forcibly injected. However, debate was somewhat more seriousthan an ordinary American political free-for-all. Many of the scientists hadstrong liberal commitments, and were personally wounded at accusationsof being self-serving or negligent of the public interest. Furthermore, thescientists had some justification in seeing a Creationist lurking behind every

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opponent who declaimed against their "Playing God". The debate thenbecame unusually bitter and polarized, leaving very few of the leadingAmerican scientists even now able to regain some detached perspectiveon the affair (as does Maxine Singer (p. 233) here).

(iv) Risk analysis, five years on

This volume gives a strong indication of how the leading scientistsconceive and evaluate their present task in regard to the possible hazards.It is simply, to dismantle the set of restrictions as quickly as possible; fortheir views on those hazards completely changed shortly after the NIHguidelines were drafted. This official version has enough jokes and heavyhints to convey an atmosphere; those who were present will recall expletivesthat have been deleted from this text, such as the chairperson of theRecombinants Advisory Committee saying "it will not be allowed to dieas a committee, until we have vomited enough". (I am indebted to thenotes of Dr E. Yoxen for this.)

The conference recorded a number of experiments whose conclusionwas that the insertion of possibly pathogenic materials into weakened orcrippled strains of E. coli does really reduce their virulence. It recordsothers that are quite breathtaking in their simplicity, indeed banality; thesewere reported in March 1979. We learn (p. 215) that in sewage, inmammalian intestines, and on laboratory bench-tops, the weakened orcrippled strains do very badly indeed. For this we had to wait five or sixyears? Had there but been such a programme in the early days, togetherwith a comparison of the hazards of laboratory and hospital environments(available from Dr Lennette all this time), then much labour of erectionand dismantling of guidelines, with its attendant personal and politicalcosts, could have been avoided. And the debate could have been on"genetic engineering" rather than hypothetical lab hazards.

At first this seems like a monumental blunder; in this the historianagrees with the participants, while locating the crucial event slightlydifferently. But even blunders have their causes, in acts committed andomitted; and the historian is obliged to look into them, using whateverevidence s/he can muster. Such evidence is to hand, in the attitudes andpractices of the leading scientists as they try to undo their early regrettedworks.

One sign is the treatment given to Dr Lennette. Even though his lecture(delivered for him) gave much support to the scientists' case by refutingalarmist claims made by Jonathan King, response was perfunctory, asidefrom Walter Bodmer's (p. 271) immediate criticism of the one sort ofhazard that Lennette still allowed. Another is the absence of any criticalpresence, except for some British members of GMAG who contributed tothe discussion. Yet again there was confusion of the position of the Press,with Roger Lewin (p. 273) telling a convincing story of an earlier exclusionchanged only in a last-minute flurry and muddle.

Most important of all, as a test of attitude, is the nearly total omissionof the special British contribution to the analysis of hazards. To be sure,Sir Gordon Wolstenholme was invited to give his very statesmanlike surveyof GMAG as an institution. But of GMAG's system for moving towards

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a scientifically based scheme of classification, not a word was offered exceptfor a mention provided by a GMAG member in discussion (p. 237).

Its absence cannot be simply blamed on a policy of exclusion by theorganisers. For Dr Sydney Brenner, who initially conceived the system,had been invited to participate. But, he has informed me, he declinedbecause he considered it pointless to present his ideas to a gathering wherethe British members were generally as hawkish as the leading Americans.No replacement for Dr Brenner was found by the organisers, and so wemust conclude that the GMAG system of hazards assessment was notconsidered an essential agendum for this conference on the hazardsproblem.

This is indeed rather strange. During 1978, one of the two standard-setting agencies in the field produced a system for a practical resolution ofthe hazards problem. Six months after its announcement, a conference onthat same problem is held in that same country. No special effort is madeto include it among the formal papers, and it is scarcely mentioned in thediscussion. Why?

Two possibilities can be considered. One is that the scheme is so badthat it is kinder to ignore it. Once its originator had declined the invitationto participate, his brain-child could be allowed to rest in obscurity. Butthe GMAG system was not merely Dr Brenner's fancy. It was studied andmodified by a strong subcommittee of GMAG, adopted and published bythe Group, and it now has the legal force of the Health and Safety Executivebehind it. If it is now not even worthy of serious consideration and criticism,then British scientists should be warned that they are being regulated bya radically incompetent agency.

Such a harsh judgment on GMAG and its efforts would be unfair andobviously inaccurate; we must therefore consider another explanation forthe silence over the GMAG system. Perhaps the system was simplyirrelevant to the goals of the conference. The question there was not somuch how best to regulate the hazards of the research, but how to accom-plish an operation there described as "re—entry"—returning to the "nor-mality" of totally unregulated research. A variant on the unfortunate NIHGuidelines could raise the question of whether an effective system, relaxingsafeguards as and when relevant scientific evidence appeared, was worthconsidering. This would have gone against the consensus that had ruledthe research community for some four years previously. As such, it wouldhave been a diversion and a nuisance.

Going further along the same line, we may speculate whether GMAGitself would be considered an irrelevant nuisance by the conferenceorganisers. Its constitution and style of operation entail a very real elementof sharing of power by research scientists with others including CivilServants and Trade Unionists. And, if there has been one consistent featureof the activities of the leading American researchers, it has been tokeep the hazards operation firmly under their own control. (The Britishresearchers, while naturally less strident in their pronouncements, here showthemselves committed to the same policies (p. xx).)

We may recall that those excluded from the organised hazards studieswere not merely the Public Health officials as Dr Lennette, who may wellhave been viewed as alien, affiliated to a totally foreign sector of science.Even distinguished academic bacteriologists, themselves keen public sup-

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porters of DNA research, could on occasion complain of being frozen out.Thus Bernard D. Davis of Harvard opened his lecture at the AcademyForum of 1977 with a remark on the exclusion of infectious-diseases expertsfrom Asilomar and the continued neglect of that field (Davis, 1977). Thesescientists could have prevented the mishaps of the early American Guide-lines exercise; but from first to last their contribution was not desired. Theclassic blunder of the Americans was not in "going public" in the warningsof 1974, as they now believe, but in "keeping private" in the hazardsoperation from then to now. But whether it was a blunder depends onyour point of view. It may have misdirected and crippled the movementfor societal control of a nascent technology; but it did keep outsiders out.(Those non-experts and "public-interest" members who came onto theRecombinant Advisory Committee in America did so after the basic issuehad been settled; and they have been unable to accomplish anything inthe regulation of large-scale genetic engineering.)

There is nothing new in this tactic; any vested interest, be it commercial,bureaucratic or professional, sees external controls as an infringement orthreat. It always finds it easy to convince itself that by the quality of itsskill, and the purity of its motives, it is uniquely competent to regulate itsown activity. What is new here is that a group of scientists may be behavingin that thoroughly traditional way, about an activity hitherto consideredoutside the realm of crass power-politics: the conduct of research. But theproblems of ethics of such research are new (though they have been withus a long time in the case of sentient experimental subjects), and so wemust expect novelty in the scientists' response.

From this perspective, the whole affair, from near the beginning to theend, becomes quite comprehensible. The groans of the scientists underthe harsh and arbitrary system of NIH Guidelines which they themselveshad so casually created, should not be seen as Popperian scientifichypotheses to be tested. Rather, they are claims for the autonomy of avested interest, analogous to the threats by Dickens' "Coketown" manufac-turer to "pitch his property into the Atlantic" should anyone interfere withhis liberty to chop up his workpeople. Ever since the practical consequencesof the well-intentioned Berg letter were realised, the motto has been "Keepaway". In its terms, all the blunders and anomalies, from then to now, arecoherently explained.

The DNA research scientists, even before the present phase of indus-trialisation of the work, were not isolated seekers after truth or glory. Eachwas a member of a complex, hierarchical social institution, with manyrelationships of prestige, authority, finance and power. To call in outsideexperts on the hazards of their research would involve the sharing of powerwith them: each scientist would have to accept someone else's opinion onthe proper running of his lab. The competitive and proud molecularbiologists were the least likely of all scientists to accept the inconveniences,possible delays, and surrender of prestige that would follow such a step.As they had previously mastered and exploited the techniques of so manyother fields, so now (in the mid-70's) they would manage the hazardsproblem. But the problem was not one of a developed science awaitingappropriation: hazards are a different thing altogether, a type case ofproblems that partly lie beyond laboratory science, where facts and policiesare inextricably entwined. Lack of awareness of the novelty of their task,

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combined with the human motives of self-protection, led to those blunderswhich we now see as critical.

(v) The lessons

One cannot help but sympathise with those scientists whose goodintentions led them into such a mess. But good intentions, acting in theabsence of awareness about self-interest, and in wilful ignorance of technicalinformation, can pave the way to far worse situations than this. In the ageof "big science" the successful scientist had to become something of anentrepreneur. Now s/he must become something of a politician as well:to the "art of the soluble" in knowledge, science must add the "art of theresolvable" in policy.

For policy, as much as fact, is a determinant of decisions on risks; andon this basic philosophical point there seems very little awareness amongthe DNA scientists even now. On the one hand there is a commonrecollection that attitudes to the hazards changed radically within a yearafter the framing of the NIH Guidelines, on the basis of an extremely smallset of experimental results. Yet there is still a consensus that the issue isin principle susceptible to decision on the basis of scientific fact. Amongmany, there is a conviction that the issue has been settled once and forall by the modest collection of results already achieved.

Although it is nearly ten years since Alvin Weinberg (1972) coined theterm "trans-science", the concept is still not widely appreciated. It refersto problems which are capable of a scientific statement, but are beyondtechnical feasibility for their solution. Hazards which are low-level or evenconjectural, yet on which there is justifiable concern, are the paradigmcase for "trans-science". Everything in the training of research scientistsinhibits an understanding of "trans-science", and this is reinforced by theirpractice as researchers. Hence when they are confronted by such a problem,their natural reaction is one of incomprehension. In all fairness, sincetrans-science involves such a very different set of attitudes and expectations,the delay in appreciation is only natural, however regrettable its short-termconsequences.

The DNA scientists suffer from yet another defect of awareness: thenature of the social activity of their research, present and forthcoming.One could go right through this volume and never know that industrialapplication of genetic-engineering techniques is proceeding very rapidly;and that the traditional demarcation between academic researchers andcommercial entrepreneurs is already very blurred in the case of many ofthe leading scientists. For the public, for each other, and perhaps even forthemselves, they project the image of slightly otherworldly researcherswhose well-intentioned attempts at self-regulation were thwarted by anexcitable public and a mischievous press. (Maxine Singer's piece is strongon this.) That may well have been a generally fair portrait in 1975; butin 1980, when biotechnology, including these techniques as part of itsarmoury, is expanding very rapidly with the active assistance of some ofthe leading scientists here, the tweedy image is becoming misleading.

Those of the DNA scientists who persist in defining the problem as oneof small laboratory hazards to be managed within the research family, whenthe scale of the activity and scope of the problems become technological,

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are in fact in the position of trying to reap the benefits of industry whileretaining the immunities of scholarship. This is recognisably close to theformula, power without responsibility. This is a very real hazard; andunfortunately the Wye conference proceedings show no sign of its beingrecognised.

REFERENCES

DAVIES, B. D. 1977. Epidemiological and evolutionary aspects of research on recombinantDNA. In NationalAcademy of Sciences, Research with Recombinant DNA, WashingtonD.C.

WEINBERG, A. 1972. Science and trans-science. Minerva, 10, (2).

JEROME R. RAVETZReader in the History & Philosophy of Science, The University, Leeds

THE PRINCIPLES OF HUMAN BIOCHEMICAL GENETICS. 3rd Edition. Harry Harris.Elsevier/North Holland Biomedical Press, 1980. Pp. 554. Price: Paperback £12.65;Hardback £31.05.

It is impossible to do full justice to a book of this kind in a short review.Here we have the fully revised third edition of a book which receivedexcellent reviews when it first appeared in 1970 and maintained its highreputation in a second edition in 1975. Considerable developments in thefield of human biochemical genetics have occurred during the past six yearsbut Professor Harry Harris has once again produced a masterly up-to-dateaccount of the principles of the subject.

The general arrangement of this edition follows that of its predecessorsbut a great wealth of new material and several new sections have beenwelded together by lucid prose and a good selection of new illustrations,to form a splendid volume which is only slightly larger, by about 80 pages,than previous editions. As in earlier volumes, Professor Harris is not afraidof going into a considerable amount of detail on the topics which he haschosen to describe in order to elicit the principles, but the clear and easystyle of the text and the liberal use of headings and subheadings withineach chapter prevent the reader getting lost and allow the book to be usedeasily as a source of reference.

The text has been thoroughly revised so that in quite familiar areas oneis frequently surprised, and pleased, to come across a fresh nugget ofinformation which provides a new look to an old problem. This new editionincludes useful updates on the two appendices, one of which outlines themain features of about 130 disorders due to specific enzyme deficienciesand the other which lists more than 70 human enzyme and other proteinpolymorphisms, complete with references. The new sections and mostextensive revisions are to be found in the chapters on the inborn errors ofmetabolism, with a treatise on the receptor defects found in hyper-cholesterolaemia, on the thalassaemias, and in the chapter on enzyme andprotein diversity in human populations which includes an account of theHLA system, polymorphisms detected in tissue proteins and in DNA andthe causes of allelic diversity. There is also an enlarged section on the