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Institute of Medicine (US) Committee to Study Decision Making; Hanna KE, editor. Biomedical Politics. Washington (DC): National Academies Press (US); 1991.

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Biomedical Politics.

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Asilomar and Recombinant DNA: The End of the Beginning

Donald S. Fredrickson

I remember the Asilomar Conference as an event both exciting and confusing. Exciting because of the scale of the scientific adventure, the great expanses which had opened to research, and because no one could be indifferent to the debate over the powers and responsibilities of scientists. Confusing because some of the basic questions could only be dealt with in great disorder, or not confronted at all. On the frontiers of the unknown the analysis of benefits and hazards were locked up in concentric circles of ignorance . . . how could one determine the reality . . . without experimenting . . . without taking a minimum of risk? 1

Philippe Kourilsky

At noon on February 27, 1975, the curtain descended on the first act of what is likely to go down in the history of science as the recombinant DNA controversy. The setting was the chapel of a conference center in the peaceful California coastal town of Pacific Grove. The cast included about 150 molecular biologists from some of the world's premier laboratories, and the final scene showed an agreement being struck among these scientists regarding the resumption of genetic experimentation, which they had voluntarily stopped six months before. Yet despite this difficult and commendable achievement, the succeeding episodes of this real-life drama rather suddenly took a turn for the worse. Laypersons, scientists, and legislators, on one side or the other, engaged in an angry struggle over the resumption of research. Numerous hearings, forums, and town meetings were held. In townships, states, and Congress, bills governing laboratory research were drafted and debated at length, and injunctions to forbid all such experimentation were sought in the courts. Half a decade of recriminations and anxiety passed before society and biomedical science patched up the largest rents in their mutually beneficial entente. Why did this happen? Could it have been avoided? Can we be sure that such a threat to such a sensitive relationship will not happen again?

The objective of this essay is to reconstruct, from an abundant record, 2 the story of the climactic event of the first act, the Asilomar conference of 1975. The subject should be viewed in the broadest context; therefore, we must zoom in on it from the past, using a wide-angle lens.

THE COMING OF AGE OF MOLECULAR BIOLOGY

In 1944, two noteworthy but unrelated events occurred that precipitated important changes in biomedical research. One was a scientific achievement, the other a political decision. The scientific achievement was the discovery of the chemistry of genes. When the first cautious report was absorbed and accepted, it snapped into focus genetics research of the past 80 years (if one counted the careful notes the monk Gregor Mendel put aside in 1865). Following a much earlier trail of research, especially a clue that different strains of pneumococcus were able to exchange certain characteristics like coat appearance and virulence, Oswald Avery, Colin MacLeod, and Maclyn McCarty at the Rockefeller Institute established that the exchanger was a sticky macromolecule or polymer made up of sugar, bases, and phosphoric acid, known as deoxyribonucleic acid, or DNA. The necessary confirmation that their “transforming principle” was, indeed, the stuff of the gene came eight years later with observations that when viruses (bacteriophages) infected bacteria only, the viral DNA entered the host and there led to expression of the complete virus. 3

The symbolic political event in 1944 was a directive from President Franklin Delano Roosevelt to his chief of wartime research, Vannevar Bush, to find a way to continue federal financing of medical and other scientific research, which proved so successful after the nation's laboratories had been mobilized for war in what historian Hunter Dupree calls the Great Instauration of 1940. 4 Many members of Congress and the heads of at least one government agency, the Public Health Service, were poised to take full advantage of a positive decision to continue this unprecedented effort. The constitutional silence on a federal mandate to support science for its own sake was forgotten. Academic leaders and scientists were ready to overcome a long-held suspicion that taking government money was bound to mean the sale of academic freedom. The details of how this new policy began with the National Institutes of Health (NIH) in 1945 and how this agency became a magician's wand whose touch gave biomedical research an exponential rate of growth for more than 10 years thereafter are major stories in themselves. The overall result was florid expansion of the capacity of America's academic institutions to carry out research and to train young researchers. The greatest growth occurred in basic research, a high-risk activity dependent on public funds.

This burgeoning scientific community quickly discovered that prewar fears of government interference with scientific freedoms were groundless. From the first, the new resources were primarily distributed to individual scientists on the basis of judgments on their proposals by scientific peers, managed on a national basis. The briskly expanding network of basic scientists, widely scattered in universities or nonprofit laboratories, was largely self-regulating and united in a worldwide profession with the same objectives and intrinsic ethic. Indeed, this shared belief in the autonomy and right of internal regulation of scientific investigation became the central dramatic theme of the recombinant DNA controversy. By restricting themselves voluntarily the scientists jeopardized the freedom that was absolutely necessary for the vitality and success of their enterprise.

Structure of DNA

In the midst of what became the scientific boom years of the 1950s, another epochal scientific event occurred in England. With dazzling deduction and splendid showmanship, the helical form and base-pairing structure of DNA were unveiled by James Watson and Francis Crick in Cambridge in 1953. 5 The carefully offhand postscript in their report of discovery, noting how this structure might explain the replication of the gene, stimulated resurgence of the crusade to bring back the answers to fundamental questions of living matter and the evolution of the species.

Such a dramatic expansion of the scientific horizon was perfectly timed to the swelling of the ranks of biomedical researchers. A large fraction of the best and the brightest of the decade's graduate students had begun to move into this pool. Being highly competitive, they shared with budding investment bankers and other entrepreneurs the knack for perceiving where the harvest would someday be most bountiful. As a career, experimental research involves a long apprenticeship to acquire specialized techniques that are applicable to one particular subdiscipline. Thus, the young scientist must select his or her special area of interest with care, so that when embarked on a lifetime adventure in independent research, his or her chosen field will be ripe in opportunities for discovery.

By the early 1950s an increasing number of aspirants chose to move to the frontier where the outer edges of genetics, biochemistry, and microbiology were merging, alongside a flood of new technologies such as electron microscopy, crystallography, cell culture, and virology, and in parallel with increased capabilities for information storage and analysis. By mid-century, the center of this fluid, expanding field became known as molecular biology, a term arguably attributed to the English x-ray crystallographer W. T. Astbury, who used it in 1950 to describe studies of “the forms of biological molecules and their ascent to higher and higher levels of organization.” 6 Already the most interesting molecular forms were the genes, around which a limitless series of questions were framed. What was the full nature of genes? How were they organized in the chromosomes? Were they conserved in evolution? Were they interchangeable among species? What were the mysterious codes they carried? How were they translated? How was expression regulated with such exquisite timing to produce differentiation throughout the growth and decline of such a complex machine as man? What were the nature and origin of abnormal genes that failed in their assignments or caused disease?

The birth and early growth of the discipline now centering on genetics were hastened and greatly enlivened by the participation of scientists, many of them British or European, who were attracted to biology from such disciplines as mathematics, physics, and chemistry. Their presence among the leaders on the new frontier helped lend élan and eminence to the cadre of young scientists calling themselves molecular biologists. 7

Fruit Flies, Corn, and Molds

The techniques available to get at the gene, however, were crude and cumbersome, and it took some time for the field to mature. In early studies of gene recombination—which is an important process for reproduction—pioneers like Thomas Hunt Morgan had profitably used the fruit fly (drosophila), creatures that are still invaluable for this purpose today. Others, like Barbara McClintock, turned to corn or other plants to learn about the organization of genes in the chromosomes and their mobility or susceptibility to rearrangement. In their classical work in the 1930s and 1940s, George W. Beadle and Edward L. Tatum used bread molds (neurospora), which are easy to culture and reproduce rapidly by genetic crosses. Simple as they were, the molds taught these pioneer geneticists the fundamental tenet of the central dogma: one gene controls the structure of one protein. 8

The Need for Germs

Those researchers who were primarily interested in studying growth, differentiation, and genetics in mammalian tissues, including humans, now turned by necessity to the microbiological world for answers. The inhabitants of this ancient kingdom of living things had been the most instructive tutors of biologists since the promulgation of the germ theory of disease by Pasteur and Koch in the nineteenth century. Bacteria were readily available, had short generation times, and were cheap and simple to culture as well as generally predictable and reliable in behavior. Until 1950 a large share of the growth in understanding of biochemistry and nutrition and the great maturation of enzymology was attributable to studies of bacteria.

For genetic studies there are fundamental differences between the bacteria and viruses and most other living things. The former are termed prokaryotes because they have no cellular nucleus and the chromosomes are free in the cell juice, or cytoplasm. In bacteria some of these genes are in circular DNA molecules, or plasmids, which are often exceptionally mobile and can transfer genes to other bacteria. All the other cellular forms are called eukaryotes, and their cell nuclei hold all but a few of their genes arranged in a certain number of pairs of chromosomes. All the genes of either a prokaryote or a eukaryote are known collectively as the genome. In 1950 the major processes of exchange of genetic characters between organisms, so-called transductions or transformations, could only be observed in a few strains of microorganisms, one of which was the intestinal bacterium Escherichia coli, a laboratory partner in many invaluable studies. Of particular importance was, and still is, a stable strain of E. coli known as K-12, which was cultured from a patient at Stanford Hospital in the 1920s and eventually used in laboratories around the world. It was in this strain that a precocious Joshua Lederberg, while studying with Tatum at Yale, observed a third method of the transfer of genetic characters, called conjugation. In this process—the first intimation of sexuality in bacteria—a “male” and “female” E. coli bacteria join together side-by-side, and an end of the male chromosome enters the female. The entering DNA recombines with the host genome, and, after replication and cell division, the new recombinant cell has genetic features of the two parental DNAs. 9

Viruses also began to make invaluable contributions to molecular biology after techniques for cultivating cells in culture were devised in the 1940s. Viruses are invisible packets of genes and proteins so small they can pass through filters that capture bacteria. In the simplest sense, the virus is a “transportable genome,” stealing entry into the host cell where the viral genes replicate and sometimes combine with the host genome but invariably direct the cell machinery to synthesize their products, called virions, which in turn enable the viral genes to be transferred to other cells. Certain viruses are the only organisms in the biosphere that utilize a genome that contains not DNA but RNA (ribonucleic acid). RNA molecules are complementary to DNA in structure and have essential functions in the translation of the DNA code to proteins. The RNA viral genome of one class of RNA viruses, the retroviruses, contains the code for the enzyme reverse transcriptase, which transcribes RNA to DNA. 10 The DNA from such retroviruses may also recombine with DNA in the host genome. By such “natural” recombinations, retroviruses and mammalian cells may exchange and activate cellular genes called oncogenes (the expression of which may underlie cancerous transformation in the host). 11

Viruses have long been known to cause tumors in animals—indeed, as long ago as 1906, when Peyton Rous found a retrovirus that causes sarcoma in chickens. Since then many other RNA and DNA viruses that are tumorigenic in animals, particularly rodents, have been identified. The Epstein-Barr virus, a DNA virus isolable from a rare tumor called Burkitt's lymphoma, is one of the few viruses suspected of being tumorigenic in man.

The potential hazards of infections from bacteria and viruses did not retard early work in molecular biology. By the second decade after the transforming principle had been enunciated, the laboratories of virologists and microbiologists had been thoroughly infiltrated by biochemists, geneticists, and cell and molecular biologists. The whir of the Sharples centrifuge, surrounded by its misty aerosol of Escherichiae in harvest, was commonplace in the most advanced laboratories and a sign that higher science was in progress. Viruses were handled on open laboratory tables, and—there being as yet no better methods—cultures were transferred by mouths separated from the contents of the pipette by a cotton plug. The microbiologists had learned, in their apprenticeships, respectful behavior toward organisms known to cause disease (pathogens) and compulsively washed down the lab tops and their hands if a drop of viral culture was spilled. Outside of the effects of the later extensive use of antibiotics, however, a general belief prevailed that man and microbes had reached a state of equilibrium that was not likely to be easily upset by human manipulation.

The interests of most of the molecular biologists did not lie in classical bacteriology, and many had received only rudimentary instruction in handling pathogens or in the ecology of microorganisms. Any anxieties they harbored were directed more toward maintaining a competitive edge in the hunt for new paradigms, and their laboratory technique with respect to germs often reflected this priority.

The possibility of using the insights and methods of molecular biology to better the lot of mankind was already being discussed by the mid-1960s. 12 It would only be a little longer before the discovery of restriction enzymes, tools capable of cutting DNA selectively and with precision at points along the chain. 13 And just a few years later, a particularly useful enzyme of this type would be the precipitating cause of the recombinant DNA controversy.

An International Frontier

The ever-expanding territory of molecular biology spread across two continents and occupied floors in the top universities and research centers of a number of countries. A half-dozen British laboratories, including ones at Cambridge, London, and Edinburgh, largely supported by the Medical Research Council, were highly productive. Europe was developing a European Molecular Biology Laboratory (EMBO), with a major communal laboratory in Heidelberg. In the 1950s and 1960s France also had its centers, particularly in Paris, at both the university and the Pasteur Institute. At the latter there were many workers, such as Andrè Lwoff and François Gros, whose speciality was bacteriophages, viruses that can live parasitically with bacteria, sometimes fatally turning upon their host. At the Pasteur Institute, the laboratories of François Jacob and Jacques Monod were a particularly popular center of intellectual ferment that attracted many Americans for training and later collaborative work. Here an elegant conception of how the expression of (bacterial) genes is regulated was being shaped. First, bacteria, prominently including E. coli, were exposed to mutagens, including ultraviolet light; then their capacity to adapt to stringent change in growth media was tested. From these experiments gradually emerged the concept of the operon, a cluster of genes controlled by a single promoter. This idea led to an understanding of repression and induction of gene expression. 14

By far the largest number of molecular biologists were working in the United States in laboratories extending from Boston and Cold Spring Harbor in New York to southern California. NIH was a major source of support, and NIH grants also went to European laboratories, including those of Jacob and Monod. In addition, the NIH intramural laboratories committed substantial resources to molecular biology in the 1960s, with the heaviest concentration being in virology. The National Cancer Institute (NCI) would soon erect one of the very few maximum security laboratories in the world to search for the elusive viruses some thought were at the root of human cancers.

The National Science Foundation (NSF) at this time was also providing important financial support to nonmedical scientists. During the 1960s Herman Lewis, the head of its Section on Cellular Biology, organized an informal Human Cell Biology Steering Committee (HCBSC). Its stated purpose was to offer advice on establishing large-scale cell cultures at different sites to foster a scale-up of studies in molecular biology, but it was also a clearinghouse for ideas of some of the leaders in the field. The HCBSC met fairly regularly, usually in Washington, D.C., and its membership included several faculty members from Stanford University. 15 It was at Stanford in the early 1970s that experimentation in molecular biology would first lead to serious controversy.

SETTING THE STAGE: THE EXPERIMENT AND ITS EFFECTS

In the late 1960s, Paul Berg, professor of biochemistry at Stanford, took sabbatical leave to work in the laboratory of virologist Renato Dulbecco at the Salk Institute. Berg had worked on molecular aspects of protein synthesis and was no stranger to the use of E. coli mutants. Like many others, he had become interested in the molecular genetics of viruses. His curiosity about whether a virus might be used to transfer a foreign gene into eukaryotic cell cultures led him to become familiar with simian virus 40 (SV40). Berg considered the relationship between phage and bacteria to be closely analogous to that between SV40 and eukaryotic cells, and he wondered if the virus might work more efficiently as a vector for a bacterial gene. The chosen gene already existed in highly enriched form in the bacterial plasmid. Berg enlisted two co-workers to determine if they could insert a bacterial galactose operon gene held by a modified lambda phage into the SV40 genome. Janet Mertz, a graduate student newly arrived from the Massachusetts Institute of Technology (MIT), was intrigued by the possibility that SV40 chromosomes would be reproduced in bacteria. Krimsky describes the Stanford laboratory activity at that time, including Mertz's growing ambivalence about such an experiment. 16

SV40 was first isolated from monkeys in 1960 and was carried in cultured monkey kidney cells. Within a short time researchers discovered that the virus-infected cells caused tumors in hamsters. 17 This finding was of exceptional interest to the makers of poliomyelitis vaccine because monkey kidney cells had been indispensable for cultivating the poliovirus for the first vaccine. When investigators began to look for the virus, they soon found that the level of contamination of rhesus monkey kidney cells with SV40 was, indeed, high. It was by then no surprise, yet still a most unpleasant revelation, that some lots of the vaccine also contained the simian virus. A survey in 1961-1962 revealed that many of the recipients of the vaccine had antibodies to both the poliomyelitis and SV40 viruses.

Using the fairly cumbersome techniques then available, Berg and his co-workers were able to delete portions of the circular, helical coils of the SV40 genome in mapping studies. In spring 1971 they began to make preparations to couple SV40 genes to bacterial galactose genes for insertion into eukaryotic cell cultures.

Critique

In June, Mertz attended a workshop at Cold Spring Harbor and while there discussed the proposed experiments at Stanford with other students and her instructor. John Lear opens his book with a full-stop rendition of the outcome of her revelation: “On the afternoon of Monday, June 28, 1971, Robert Pollack, a 31-year-old microbiologist on the research staff of the Cold Spring Harbor Laboratory, Long Island, made a telephone call that would fundamentally change the relationship of American science to the society that sheltered it.” 18 Pollack's call was to Paul Berg and it did not catch Berg completely by surprise, for Mertz had already relayed to him some of her instructor's criticisms. Pollack told Berg in effect that he should “put genes into a phage that doesn't grow in a bug that grows in your gut,” and reminded him that SV40 is a small-animal tumor virus that transforms human cells in culture and makes them look like tumor cells. Pollack later described the idea as a “pre-Hiroshima condition—it would be a real disaster if one of the agents now being handled in research should in fact be a real human cancer agent.” 19 At the end of the course, Pollack is said to have complained in his final lecture that “[n]o one should be permitted to do the first, most messy experiments in secret and present us all with a reprehensible and/or dangerous fair accompli at a press conference.” 20

After Pollack's call Berg undertook further opinion sampling of other peers about the proposed experiment and renewed discussions he had had much earlier about the general nature of such research. In 1970 Berg dined at the home of Maxine Singer, a molecular biologist at NIH, and her husband, a lawyer and trustee of the Hastings Institute. 21 Another guest was Leon Kass, who in 1971 was to publish a widely read article on the social consequences of the new biology. 22 Kass and Berg later exchanged correspondence over the subject of their dinner conversation. On a later trip to Washington in 1971, Berg paid a visit to scientists in the so-called Memorial Laboratories of Building 7 on NIH's Bethesda, Maryland, campus, which was dedicated to several scientists who had contracted fatal diseases during laboratory or field studies. There he talked to virologists working on SV40, one of whom was Andrew Lewis. Lewis still remembers Berg's admission that some of the scientists he had talked to felt that there was some line in the process of manipulating the genome that should not be crossed until more was known. 23

The Encounter

Shortly before Berg's visit Lewis had been reminded of the rising tensions in the competitive field of molecular biology. In August 1971 he had gone to Cold Spring Harbor to make a presentation of his work on hybrids of adeno-SV40 viruses. (Adenoviruses are large viruses that cause respiratory infections.) Experiments in which these viruses had been grown in monkey kidney cells for purposes of preparing vaccines had led to the discovery of hybrid viruses, in which the genomes of adenoviruses also were contaminated with the genes of SV40. Most of these hybrids were defective, that is, unable to reproduce, and for a decade they had attracted little attention. Lewis's hybrids, however, were nondefective, and therefore capable of independent growth. Because these hybrids were much more likely to lead to information about the tumorigenic property of the virus, interest in them was steadily rising at laboratories like Cold Spring Harbor. Berg's proposed experiment was now well known at this institution and Dan Nathans, who was at the same meeting, described headway in dissecting the circular SV40 genome with one of the first restriction enzymes.

After his presentation Lewis had an unexpected encounter—extraordinary for a young and unknown scientist—with one of the Wunderkinder of molecular biology. Lewis had never met and did not recognize Watson, who had recently become director of Cold Spring Harbor Laboratory. Without introduction, Watson expressed his displeasure that Lewis had failed to share samples of the viruses with Cold Spring Harbor and proceeded to enumerate ways by which he could force Lewis to provide them. Lewis responded by relating his concerns about the possible hazards of the recombinant DNA in these nondefective hybrids and his reluctance to share samples without agreement by the recipients to acknowledge the possible hazards and follow certain precautions. The next month he supplied samples of the hybrids to the Cold Spring Harbor labs, and stepped up efforts to convince his NIH superiors that they should endorse a policy requiring a memorandum of understanding to accompany the sharing of nondefective hybrids and other potentially hazardous viruses. Lewis's friends and co-workers at NIH did not all share his serious concerns about the hazards of his experimental material, but NIH eventually undertook such precautions. 24

When Berg returned to his laboratory in fall 1971 he informed his co-workers that he had concluded that they should postpone the part of their proposed experiment that would transfect the SV40-lambda hybrid into E. coli. He called Pollack and told him, and asked him to help organize a conference on the hazards of tumor viruses the next year. The departure of Berg's co-worker David Jackson to start a new laboratory at Ann Arbor, Michigan, in spring 1972 made the postponement of the original experiment indefinite.

The “First” Asilomar Conference

In 1972 the controversy over recombinant DNA was still well contained within the community of molecular biologists, and there had been no organized attempt to deal with the major single source of anxiety—the DNA of cancer viruses. Paul Berg, however, refused to let the matter drop. In August 1972 the HCBSC informed its members that a meeting on containment would be held in Asilomar on January 22-24, 1973. As Herman Lewis remembers it, the idea for the conference had come from Berg. NSF was willing to pay for the conference, but Alfred Hellman of NCI wanted his agency to participate, and NCI therefore shared the costs. Pollack, Hellman, and Michael Oxman of the Children's Medical Center in Boston proposed names of participants to Berg, who selected the final list and handled most or all of the preliminaries. It is certain that he picked the location, for the conference center at Pacific Grove had long been a favorite of campus scientists at Stanford.

Sometimes dubbed Asilomar I, the January 1973 meeting involved about 100 biomedical scientists, all but one or two of whom were Americans. There was no effort to invite the press, but the proceedings were edited by Pollack, Oxman, and Hellman and later published. Up-to-date information on many viruses was summarized by the experts, and there was thorough vetting of the evidence (or lack of it) that the known viruses, either pathogens or those studied in the laboratory, caused human cancer. In the end there was no evidence to support a single case. In the case of the polio vaccine that had been contaminated with SV40 in the late 1950s, the available information about the several million recipients of the vaccine did not suggest any alteration in cancer rate or type. It was obvious, however, that a fuller epidemiological search would someday be required to raise the level of certainty. Finally, safety precautions, especially for those engaged in the search for any virus causing human cancer, were outlined. In closing, Berg stated that “prudence demands caution and some serious efforts to define the limits of whatever potential hazards exist.” Recombinant DNA experiments were not mentioned in the proceedings. Asked for his impression of the effect of the exercise, Andy Lewis answered, “After the conference we felt less concerned about the hazards of [laboratory] viruses causing cancer.” Some of the recorded comments or exchanges from the conference floor, however, indicated that other anxieties were causing tempers to fray, and there was concern that fear was being spread unnecessarily. It was also evident that many scientists were becoming alarmed that research money would not be adequate to cover potentially escalating costs of new containment facilities, epidemiological studies, or other safety requirements. 25

EcoRI

In spring 1972, R. N. Yoshimori, working on his doctoral thesis in the University of California, San Francisco, laboratory of Herbert Boyer, isolated from E. coli a new restriction enzyme that he designated EcoRI. The enzyme was quickly shared with other laboratories, and at Paul Berg's suggestion, John Morrow examined its action on the SV40 genome. He found that the SV40 DNA was cleaved at a unique site, and this finding provided a reference site for mapping the SV40 genome. To her great excitement, Mertz discovered that when EcoRI cleaved the circular DNA, it produced a linear segment with “sticky” ends that adhered to other ends that had been similarly cleaved. Electron microscopist Ronald Davis quickly confirmed her impression, and Boyer immediately came to see. Within a short time his associate, Howard Goodman, showed how EcoRI cuts left complementarity of the bases in DNA, which allows perfect splicing with other DNA that has been similarly cut. 26

Scientific Exchange and Scrutiny

At the end of September 1972, about 50 molecular biologists from 12 countries, including nearly a score from the United States, attended an EMBO workshop in Basel on DNA restriction and modification. One evening of the workshop was devoted to “an open discussion of the use of restriction endonuclease to construct genetic hybrids between DNA molecules . . . [and] the implications this may have as a useful tool in genetic engineering and the potential biohazards.” A few weeks later Honolulu was the site of a three-day U.S.-Japanese conference devoted to all aspects of plasmids, including recombination and genome transformation. 27 This latter meeting also gave Boyer and Stanford's Stanley Cohen the opportunity to discuss collaboration in experiments to probe EcoRI's utility in plasmid manipulation. Within a few months the partnership established that the enzyme uniquely cleaved a local plasmid (named pSC101—for Stanley Cohen) and combined two antibiotic-resistant plasmids, inserting the hybrid genes into E. coli. 28

These international scientific meetings in the autumn of 1972 were but two examples of the constant worldwide information exchange among scientists, interactions that sometimes foster long-range collaborations but that are also vital to maintain parity among scattered workers in fast-moving fields of research. Experimental science is an open process that has an existential quality that is the antithesis of secrecy. A scientist who has made a discovery can usually be counted on to make it known. Proof to support a claim, a full report of the evidence, and its submission to confirmation and validation by others are required to ensure the precious priority of discovery that is still the paramount personal reward of scientific research. The worldwide scientific community, including the corps of peer-reviewed publications that serve the different fields, judges and protects these priorities as international properties.

Key judgments about the worth and priority of a scientist's work as criteria for support are largely national decisions, however. Judgments of the ethics or morality of individual scientists or their experiments likewise remain within national boundaries. The major reason for this insularity is the national or regional character of public support for scientific research. Cultural expectations are a major force in the maintenance of fiscal support of science. The continuing public approval of generous appropriations through agencies like NIH is based on expectations of improved public health and the conquest of particular diseases. Basic research, which laypersons cannot always identify as keyed to their aspirations, is nevertheless tolerated and tacitly understood to be necessary to maintain the tide on which practical benefits eventually arrive. The currency of these transactions is the continued credibility of scientists and the ultimate satisfaction of the consumer public, including the public's pride of sponsorship of a worthwhile, popular enterprise. In the early 1970s, the biomedical community began to experience concern about increasing tension in the vital public-science connection. 29

THE 1973 GORDON CONFERENCE ON NUCLEIC ACIDS

The most effective, continuous self-monitoring of the scientific tribes derives from regular gatherings of its warriors and elders to examine in depth recent performance and progress. One of the favorites among such meetings is the Gordon research conferences, which have played a formative role in the careers of nearly all biomedical researchers. For a week in the summer, members of a subdiscipline take over a number of New England schools and engage in highly informal, intensive review of their particular field. On June 13, 1973, the Gordon Conference on Nucleic Acids began in New Hampton, New Hampshire. The first three days were dedicated to synthesis of DNA, the structure of RNA, and the interaction of proteins and DNA, themselves topics in which movement was rapid and fascinating. The fourth day was given over to bacterial restriction enzymes in the analysis of DNA. In a session chaired by Daniel Nathans, Herbert Boyer was scheduled to speak. According to John Lear, Stanley Cohen had obtained Boyer's promise to say nothing at the Gordon conference about the current work of their partnership. Krimsky, however, cites chairperson Maxine Singer, who recalled how Boyer had shared with the conferees information about the capabilities of the restriction enzyme EcoRI to splice DNAs of different origin and how two plasmids bearing genes specifying resistance to two different antibiotics had been joined. 30 It was after Boyer's comments that someone loudly sounded the excited comment, “Now we can combine any DNA.”

Other reactions to this hint that biology was approaching something akin to the nuclear physicists' chilling arrival at “critical mass” were delayed until late afternoon, when two researchers at the Cambridge Molecular Biology Laboratory, Ed Ziff and Paul Sedat, sought out the two conference chairpersons, Maxine Singer of NIH and Dieter Söll of Yale. Ziff and Sedat urged the chairs to schedule a discussion of the potential hazards in the experiments disclosed in the afternoon's session. With only a half day to go in the conference, Singer and Söll nevertheless agreed to take up the matter at the beginning of the Friday morning session. Within about a half hour, the conference participants who were still on hand voted to ask the National Academy of Sciences (NAS) and the Institute of Medicine 31 to establish a committee to consider the problem of recombinant DNA research and recommend specific actions or guidelines. 32 The participants also agreed to publish the letter of request.

As later drafted by Singer and Söll and approved by the conferees, this letter began as follows:

We are writing to you, on behalf of a number of scientists, to communicate a matter of deep concern. Several of the scientific reports at this year's Gordon Research Conference on Nucleic Acids . . . indicated that we presently have the technical ability to join together, covalently, DNA molecules from diverse sources. . . . This technique could be used, for example, to combine DNA from animal viruses with bacterial DNA, or DNAs of different viral origin might be so joined. In this way new kinds of hybrid plasmids or viruses, with biological activity of unpredictable nature, may eventually be created. . . .

The letter further noted that the experiments might advance fundamental knowledge and alleviate human health problems but that some hybrid DNA molecules might prove hazardous to laboratory workers and the public.

The die was cast. The Gordon conference reaction was unprecedented, and its expression of deep concern could not go unheeded. The train of events thus was set in motion that brings us to the principal subject of this narrative. 33

THE ACADEMY'S TURN

Receipt of the Singer-Söll letter, dated July 17, 1973, was acknowledged by NAS president Philip Handler a few days later. 34 The conference letter appeared in the September 13 issue of Science. (Quite coincidentally, an editorial in the same issue by Amitai Etzioni dealt with a recent poll of public attitudes toward institutions and concluded that friends of science had no grounds for “hysterical alarm.”)

Having consulted with the NAS council in late August, Handler informed the executive committee of the new Assembly of Life Sciences (ALS) that he was referring the Singer-Söll letter to it. Paul Marks, chairman of ALS's Division of Medical Sciences, replied that he agreed that ALS should establish a study committee and indicated that he was “as concerned with the potential hazards of certain of the hybrid molecules being studied as I am with the potential of unreasonably gloomy predictions [of] these hazards.” 35 The ALS executive committee heard directly from Maxine Singer in September and, when asked for a suggestion as to who might head the study committee, she suggested Paul Berg. Handler requested the latter to take charge, and early in January Berg informed the ALS that he had decided to bring together a small group (fewer than 10 individuals) for a one-day planning meeting to consider mechanisms for reviewing potential dangers (as well as benefits) stemming from the ability to generate hybrid DNA molecules. 36

Berg convened the meeting he had in mind at MIT on April 17, 1974. The six other participants selected by Berg independently were David Baltimore, James Watson, Dan Nathans, Sherman Weissman, Norton Zinder, and Richard Roblin. Herman Lewis of NSF was also there as an observer; Maxine Singer was unable to attend. Much has been written about this historic one-day meeting—for example, that James Watson had wanted an international meeting, that Berg recalled Norton Zinder saying, “If we had any guts at all, we'd tell people not to do these experiments,” and how Roblin came to participate. 37 The details of this historic event were overshadowed, however, by its conclusions, which were contained in the report released three months later in a press conference at NAS on July 18, 1974. 38

The report began with a summation of recombinant achievements since the July Gordon conference: the creation of new bacterial plasmids carrying antibiotic resistance markers; the insertion of toad ribosomal DNA into E. coli, where it synthesized RNA that was complementary to the inserted DNA; and unpublished experiments involving incorporation of drosophila DNA into DNA from plasmids and phage ready to be inserted into E. coli. 39 The summation was followed by the planning committee's conclusion that this type of unrestricted activity could create artificial recombinant DNA molecules that might prove biologically hazardous. As an example, the report cited the possibility that E. coli might exchange new DNA elements with other intestinal organisms with unpredictable effects.

The committee made four recommendations, which are summarized below:

1.

Establish a moratorium on certain experiments. The committee commented that such a moratorium was “most important, that until the potential hazards of such recombinant DNA molecules have been better evaluated or until adequate methods are developed for preventing their spread, scientists throughout the world [should] join with the members of this committee in voluntarily deferring” these experiments. Two types of experiments were to be deferred: (1) those involving the creation of new, autonomously replicating plasmids that could carry antibiotic resistance to strains not now having such genes or that could enable toxin formation in now innocent strains (type I) and (2) experiments linking DNA from oncogenic or other animal viruses to plasmid or other viral DNAs (type II).

2.

“Carefully weigh” experiments to link animal DNA to plasmid or phage DNA.

3.

Request the director of NIH to establish an advisory committee to evaluate hazards of recombinant DNA, develop procedures to minimize those risks, and devise guidelines for work with recombinant DNA.

4.

Hold an international meeting of all involved scientists early in the coming year (1975) to discuss appropriate ways to deal with the potential hazards of recombinant DNA molecules.

The relationship of Berg's committee to the Academy and the endorsement of its recommendations by the ALS-NRC, as well as the stress on the international nature of the proposed conference, were important touches added at the final stages of report preparation and review. 40 They were a credit both to the NAS and to the committee and helped to materially buffer possible inferences that a gang of seven (or perhaps, in the end, eleven) American scientists had impulsively doused the boiler of what arguably would become the most powerful scientific engine of the century.

THE ASILOMAR CONFERENCE

On September 10, 1974, the committee appointed to organize the February 1975 Asilomar meeting gathered in room E17 of the MIT Center for Cancer Research. The committee, which consisted of chairman Paul Berg, David Baltimore, Richard Roblin, Maxine Singer, Sherman Weissman, and Norton Zinder, was joined by several other scientists. Donald Brown, Richard Novick, and Aaron Shatkin had been summoned because they were to play key roles as chairmen of three working groups (on plasmid-cell DNA recombinants, plasmid-phages, and animal viruses, respectively) that would issue formal reports. Herman Lewis attended in his familiar role as patron and rapporteur for the HCBSC (many of whose members were directly involved in the conference). William Gartland was present as an observer for NIH, the conference's principal underwriter.

The first order of business was a discussion of foreign participation, ending with two additions to the organizing committee: Sydney Brenner of the Molecular Biology Laboratory at Cambridge and Nils Jerne, chairman of the EMBO council. (Jerne, however, was unable to participate in the committee or the conference.) Brenner, a highly articulate and gifted molecular biologist, was also a member of the Ashby Working Party in Britain, which had been set up by the Medical Research Council to determine how British science should react to the Berg committee report. 41

A nearly complete format for the three-and-a-half-day conference was produced by the time the meeting ended. 42 Berg solicited suggestions for possible participants, but the final invitation list was his (see the appendix). The slate was in keeping with the intent expressly stated in the July 1974 report: an international meeting of involved scientists. About 90 of the invitees were American; another 60 came from 12 different countries. All were among molecular biology's elite. No organizations were represented per se. Sixteen members of the press were invited, all accepting the condition that no copy would be filed until the conference ended. 43

The three discussion panels were asked to present completed draft reports at the conference and thus met in November to begin work. Novick's plasmid panel began an extensive analysis that finally would cover most of the potential areas of hazard. Shatkin's animal virus panel, however, apparently misunderstood the work schedule: when they arrived in Asilomar on the Sunday night preceding the conference, they were unaware that their draft report was to have been completed. Organizing quickly, they gathered after dinner to draw one up.

Monday, February 24—Opening Day

The conference's organizing committee had decided at their September meeting that there would be no publication of the conference (because of the manpower and time required), although audiotape recordings of the sessions would be maintained as an archive. Any conferee could ask that recording be suspended during his or her discourse, but none so requested. When the participants then noticed the small forest of microphones set up by members of the press, the discussion ended by permitting the press to use their recorders for preparation of their stories. Allowing any part of the tapes to be broadcast, however, was declared to be against the rules.

David Baltimore opened the conference on Monday morning. He gave a short history of how the meeting had come about and described its auspices and organizers. He noted that conference participants had been invited to the meeting on the basis of their expertise or involvement in the science. He then explained that the meeting had been convened to lay out the existing technology and what had been done to answer the question of what (experiments) should or should not be done, and to determine what should be done before an experiment is undertaken. Baltimore emphasized that the balance of risks and benefits would be considered but that discussion of the hazards was more important than either the benefits or molecular biology per se. His summary of the program ended with the observation that, on the last morning, the organizing committee expected to present a summary statement, including general guidelines for discussion and consensus. Baltimore reminded the audience that if it could not reach consensus, there was no one else to whom it could turn. Paul Berg next stepped to the podium to review the basics of recombinant DNA technology. This discussion set the tone of much of the first three days of the meeting, the format and content tending toward the highly technical, with presentations in the traditional style of experts talking to experts. It reflected scientists doing what they do best—talking about their own work. There was another requirement to be satisfied by such intercourse, however, and that was the need of the participants to be exposed to the different techniques, personalities, and scientific jargon peculiar to each of the three or four major subcultures assembled: the virologists, the “plasmid engineers,” the specialists in phage (“lambda people”), and the eukaryotic cell biologists. The insularity of these narrow subspecialities predictably bred suspicions that one's own area of research could emerge from such a meeting unfavorably restricted by strangers.

The expertise on hand at Asilomar was impressive (see the appendix). Speaking after Berg was Stanley Falkow, who combined a medical background with an encyclopedic knowledge of bacteria. After him came Ephraim Anderson from the Public Health Laboratory Service in Britain, who also had medical training and had dealt with epidemics of intestinal infections before concentrating on plasmids. Anderson had taken umbrage at the type I recommendations in the Berg committee report, partly because, in the version printed in Nature, a dropped word led to the interpretation that his long-time research had been banned. As soon as he read it, Anderson shot off a note to the journal, which appeared in the next edition, expressing the wish that the “NAS statement had been presented less pompously.” At Asilomar, Anderson and a British colleague, William Smith, were asked to present their experimental evidence that E. coli K-12 had a low risk for transferring plasmids to other enteric bacteria. After it was all over, however, Anderson's criticism of the conference remained unmitigated. 44

Another speaker on the first day, Roy Curtiss from the University of Alabama, had displayed a very different reaction to the Berg report. A month after it appeared he had sent a 16-page memorandum to the signatories and distributed hundreds of copies to the world community of molecular biologists, in which he stated, “I heartily endorse the aims, but not necessarily the scope of your recommendations. . . . I personally pledge to cease Type I experiments (to construct bacterial plasmids that are not now known to exist) that I was currently engaged in . . . and not to initiate Type II experiments. . . . ” 45 Curtiss moreover argued for specific heightening of the restrictions and spelled out conditions under which he believed E. coli might be hazardous. Berg and many others responded to the Curtiss letter, and the reiteration of prior arguments now enriched the debate. The last speaker in the postdinner session that first evening—after presentations by Boyer and Cohen—was Ken Murray of the team of molecular biologists in Edinburgh, who described phages as cloning vehicles. Murray had published a companion (but more conciliatory) note to accompany Anderson's in the July issue of Nature, which he closed with a line from the Manchester Guardian's earlier comment on the Berg report: “While welcoming the NAS initiative . . . if we follow the moderate tone set by the NAS we shall be careful not to oversell the social benefits devolving from the recent experiments.” 46

When Berg began his session on the morning of the first day, he mused aloud that the writers of the original letter had not anticipated how it would affect the scientific community and that the organizing group was not prepared or experienced in how to arrive at a decision. He said therefore that a panel of lawyers arranged by Dan Singer would present views on law and public policy issues on the third day. Harold Green, another Washington lawyer and a trustee of the Hastings Institute, spoke after lunch on the first day, however, and told the scientists that the conference and its unique moratorium on research—for which he gave them high praise—would serve as a moral precedent and a model of how science should deal with such issues. He was asked several questions about how the responsibilities for risk, or the framework for proceeding with experimentation, should be determined, and he offered his opinion that the government ultimately would determine the public policy. To end his presentation, Green held out astringent balm to any injured by this forecast by noting that “all institutions in society are imperfect and of these the government is the most imperfect.” 47

Tuesday, February 25—Getting Down to Guidelines

The second day began with Richard Novick's presentation of the report of his working group “Potential Biohazards Associated with Experimentation Involving Genetically Altered Microorganisms, with Special Reference to Bacterial Plasmids and Phages.” 48

The conclusions of this first of the working group reports were most conservative. The document contained extensive recommendations for classifying, monitoring, and designing many classes of experiments, and it would later serve as a template for the future recommendations of the NIH Recombinant DNA Advisory Committee. The mass of information it contained, however, seemed to overwhelm the absorption capacity of the participants. A day later, the organizing committee found it necessary to amend its construction in order to propose a framework for consensus. Long after Asilomar, the comment would continue to be made that the conference had failed to consider the unlikelihood that E. coli K-12 could be converted to a dangerous enteric pathogen or engage in harmful genetic transmission to other organisms under normal circumstances in vivo. The working group report did not neglect such calculations, but the pace of the Asilomar debate outstripped the time for adequate reflection on them. It would not be until 1977 (the Falmouth conference) that similar deductions led to the dismissal of this conversion as a serious hazard.

The mesh of protection proposed by the plasmid-phage panel grated on some of the listeners. Michael Rogers, the correspondent from Rolling Stone, later reported some sample reactions. Josh Lederberg rose to express grave concern about the danger of the panel's recommendations “crystallizing into legislation”; Ephraim Anderson then demanded that the panel indicate, by a show of hands, which of its members “had experience with the handling and disposal of pathogenetic organisms capable of causing epidemic disease.” When the panel members rather sheepishly admitted that they had all probably had too little, their tormentor added insult to injury by nipping away at the grammar and syntax of the report. Suddenly James Watson uttered a call for an end to the moratorium—moreover, “without the kind of categorical restrictions called for in the plasmid report.” Rogers recalled that Maxine Singer was on her feet immediately to ask what had changed in the last six months to cause Watson to abandon the movement he had helped to launch. 49

In line with the assessment of a number of subsequent commentators, Rogers admired Sydney Brenner (“the single most forceful presence at Asilomar”) and described him as rising shortly thereafter to ask waverers in the crowd, “Does anyone in the audience believe that this work—prokaryotes at least—can be done with absolutely no hazard?” After a dramatic pause, Brenner continued, “This is not a conference to decide what's to be done in America next week; if anyone thinks so, this conference has not served its purpose.” During the afternoon, Brenner led a session on the desirability of “biological containment,” the designing of plasmids, phages, or other vectors that could not survive in a new ecological niche and thereby do mischief if they escaped the “physical containment” that had been thus far discussed. It was not a completely new idea, but Brenner's enthusiasm stimulated much discussion and encouraged thinking about other ways to open up the blocked channels of research. That night a group of “lambda people,” concerned that the plasmid group had overly emphasized crippled plasmids in their proposals for biological containment, worked late and by morning had a design on paper for a potentially safer phage vector. 50

A heavy barrage of virology was laid down in the late afternoon and evening session of the second day. Undoubtedly, in the minds of some scientists—especially those to whom viruses were unfamiliar territory—any anxieties over E. coli-triggered epidemics paled in comparison with concerns about human cancer being caused by some devilish recombination of DNA from tumorigenic viruses. Among the presentations was that of Andrew Lewis, who described his work on the adeno-SV40 hybrids, accompanied by the precautions he considered desirable for the use and sharing of the nondefective forms of these organisms. But after Aaron Shatkin came forward with the recommendations of the virus working group, the panel appeared to disappoint some who considered viruses to be the greater menace. The report consisted of two pages, the first signed by all but one member of the panel, and began with a reaffirmation of the potential benefits of such research, a theme the organizers at Asilomar had requested be muted. The preamble to the report read as follows:

The construction and study of hybrid DNA molecules offer many potential scientific and social benefits. Because the possible biohazards associated with the work are difficult to assess and may be real, it is essential that investigations be re-initiated only under conditions designed to reduce the possible risks. Although the need for the development of new and safer vectors is clear, we believe that the study of these recombinant DNAs can proceed with the application of existing National Cancer Institute guidelines for work involving oncogenic viruses . . . with the exceptions noted below [highly pathogenic viruses] we recommend that self-replicating recombinant DNA molecules be handled according to guidelines for moderate risk oncogenic viruses . . . the vast majority of experiments will fall into the moderate risk category.

The second page of the report was Andrew Lewis's minority report of one, which called for experiments on recombination of DNA from animal viruses to take place in moderate-risk facilities as defined by NCI, and only when theoretically safe vectors had been developed. A day later, an amended report was issued by the viral group that endorsed the desirability of both physical and biological containment for experiments inserting viral or eukaryotic cell DNA into prokaryotic hosts. The number of signatories of this unanimous statement had increased to eight. 51

Time would prove whether Andrew Lewis was right or wrong. It should be noted, however, that although there were other participants at Asilomar who expressed conservative views (e.g., Curtiss, Falkow, and Robert Sinsheimer), Andrew Lewis was the one “dove” who most clearly and steadfastly maintained his convictions against a popular tide.

Wednesday, February 26—Dissonance and Lessons in the Law

On the morning of the third day copies of several communications were passed out, one of which was an open letter to the conference from Science for the People, a grass-roots science watchdog organization. Its principal message was that “decisions at this crossroad of biological research must not be made without public participation” and that the signers did “not believe that the molecular biology community . . . is capable of wisely regulating this development alone.” It called for a continuation of the moratorium until several proposals for widening public input were put into effect. The authors were bacterial geneticists and molecular biologists, among whom was Jonathan Beckwith. (In 1969 a Beckwith team had became the first to isolate a gene, the lac operon.) There was no formal discussion of the letter at the conference, however, and scientific presentations filled the morning. 52

After lunch Donald Brown presented the report of the Working Group on Eukaryotic Recombinant DNA. This group believed recombinant eukaryotic DNA could be hazardous in three ways:

1) a gene could function in the bacteria in which it is cloned and produce a toxic product; 2) a DNA component could in some way enhance the virulence or change the ecological range of the bacterium in which it is cloned; or 3) a DNA component could infect some plant or animal, integrate into its genome, or replicate, or by its expression could produce a modification of the cells of the organism. 53

As they were painfully aware, however, the scientists here were grappling with questions for which existing knowledge was woefully inadequate, and the very experiments proscribed as potentially hazardous were the ones from which the answers ultimately would have to come. Already there was skepticism that E. coli might simply replicate animal genes and never translate them into proteins, but the fundamental difference between translation of DNA by prokaryotes and eukaryotes had yet to be discovered. The frustration engendered by the tireless invention of scenarios invited baroque and temporary constructions. The recommendations of the working group included a classification of three major levels of hazard, with additional subclasses, to which a complicated hierarchy of containment conditions was arbitrarily applied. “Shotgun” experiments, in which a vector might be exposed to pieces of the total genome of a eukaryotic cell, were all consigned to the highest hazard class, with mammalian DNA being particularly suspect because it “more likely contained pathogens for humans.” Such rulings caused dismay among researchers who would now be forced to carry out their experiments inside scarce high containment facilities. Disagreements over classification of hazards quickly cropped up and continued until the final hour of the conference.

After dinner, at the evening session, the chair introduced Daniel Singer, who presided over a small panel of lawyers he had selected in hopes of strengthening the framework for the final discussion the following morning. Singer began by complimenting the scientists on the exercise of public responsibility he perceived in their undertaking. He reminded them that the benefits and risks of their research were not only scientific but social issues, and the public, which was paying for the research, would have to have its say. Alexander Capron, professor of law at the University of Pennsylvania, began with his impressions of the conference, likening it to typical scientific meetings (highly technical in content—”like Cold Spring Harbor”). “In other words,” Capron snapped, “counter-phobic behavior.” He too believed that the public would have to become involved, and “the public” meant government and the law. Capron then coursed across the terrain of regulation, rule making, and legislation, concluding that he hoped he had led the scientists to accept three things: some regulation is necessary, it may lead to restrictions, and public and governmental bodies would insist on having a say.

The third speaker, Roger Dworkin, professor of law at Indiana University, led the scientists into the chilling landscape of legal liability. He described dangerous crevasses with names like proximate cause, negligence, and strict liability, and created courtroom litigation scenes. Dworkin hit a particularly sensitive nerve when he discussed worker's compensation and regulatory agency involvement, including the roles of the Occupational Safety and Health Administration. Here he off-handedly suggested that even the secretary of labor might have final authority over the rules for recombinant DNA research. Like Banquo's ghost, this specter reappeared several times before the discussion ended late that evening. Listening to the lawyers predict what might happen to the decisions to be made on the morrow, the scientists stiffened their resolve to close ranks so that the world would see that the scientific community was able to finish what it had begun. And more than the others, the members of the organizing committee now realized that the product of their long, last-evening's work had to be definitive.

Thursday, February 27—The Final Hours

The final session opened at 8:30 a.m. Keenly conscious that his deadline was noon, Paul Berg began by recapitulating the three responsibilities the organizing committee had accepted: (1) to organize the conference to bring experts together for a discussion of the risks of recombinant DNA research; (2) to determine what consensus existed and to embody this in a statement; and (3) to prepare a statement to the NAS concerning the outcome of these deliberations. Each participant had received a copy of the provisional statement that the organizing committee had spent the night preparing. There were six sections in the statement, and Berg opened discussions on the first. It was a statement of scientific accomplishments and an intimation that the situation was somewhat clearer than it had been the previous July. Several participants, however, immediately raised procedural questions about how to handle inputs to the wording. Others inquired if all chance for modification ended with the close of the session. A member of the organizing committee reminded the conferees that the committee's report was not “written in a vacuum, but reflected the Committee's views of what seemed to have been agreed upon thus far.” “Will we get to vote on each paragraph?” someone asked, and the chairman replied that he would prefer a more informal means to arrive at consensus.

Notwithstanding his reluctance to begin a series of time-consuming ballots, Berg quickly found that a vote was being forced by Brenner's suggestion that reaction to the following statement be tested: “Work should proceed, but with appropriate safeguards; the pause is over.” Hands went up, and the chairman said he would record an overwhelming consensus on this statement. There was also a palpable sense of relief at this forward movement, and discussion turned to the second point. It too was greeted by suggestions for improvement of grammar and form. After the participants, however, had been encouraged to concentrate on substance, they allowed the chair to decree general agreement with the statement, “with reservations, some form of experiments should proceed; some, however, should not.” The discussion began to deteriorate, it moved to issues of actual levels of containment for experiments, but the chair gamely kept order. He patiently listened to great differences of opinion on details and permitted polls whenever it appeared they might be useful. Feelings ran high. There were numerous attempts, for example, to amend some definitions of hazard from the floor. A voice cried out to protest that the carefully prepared statement of his working group had “been prostituted.”

As the first lunch bell sounded, the moment for the final question could no longer be delayed. Berg, making himself heard over the commotion that had begun, said, “All those in favor of this as a provisional statement, please raise your hands.” Stanley Cohen protested loudly that he could not support something without seeing the wording of it. “All those opposed to the statement,” Berg now demanded. Roberts counted “somewhere about four hands.” Two of these belonged to Lederberg and Watson. A third was Cohen's. Waclaw Szybalski recalls, “I was strongly opposed, vocally objected, and raised my hand when negatives were requested.” Philippe Kourilsky, agreeing with the count of “four or five,” says his was also a negative vote. Thus, the statement with which they had begun the morning—although frayed and variously patched along the way—had made it through, still holding to the framework fashioned by the organizing committee in their last night's vigil. 54

Someone had asked the Russian delegates to remain to the end. A spokesman for the group rose and, in a brief statement, said that a world partitioned politically could nevertheless hold an undivided scientific community. 55

By 12:15 p.m. on February 27, 1975, Asilomar II had ended.

A press conference was held the following day. The members of the press who had attended throughout (earning honorary degrees in molecular biology) were now freed from their imposed silence and released generally laudatory, respectful commentary. The same day, the new NIH Recombinant DNA Advisory Committee met for the first time and adopted the provisional statement of the conference as interim rules for federally supported laboratories in the United States.

CONCLUSION

The conference organizing committee—Berg, Baltimore, Brenner, Roblin, and Singer—submitted the final report of the Asilomar Conference on Recombinant DNA Molecules to the NAS Assembly of Life Sciences under a cover letter from Berg, dated April 29, 1975. In keeping with Academy policy, the report was reviewed on this occasion by members of the ALS executive committee, who also received some comments from Academy president Handler. It was approved on May 20 and appeared in the June 6, 1975, edition of Science and the Academy Proceedings as a “Summary Statement.” 56

Read today, this statement still stands as a lucid, fair description of the conference consensus. It does not seek to go beyond the facts as they were considered by the participants, neither in predicting benefits nor in dismissing any of the biohazards considered possible at the time. As Handler commented in passing the report to the ALS, it was written “only to the cognoscenti in the field” and was not concerned with ensuring that other audiences understood the conclusions. 57

Fifteen years have now passed since the participants in the Asilomar conference went home to explain to anxious co-workers and laboratory staff what the new restrictions meant. Many also went to university leaders and institute administrators to argue for the new security facilities now required for their work. A few soon found themselves “on the barricades” in their own communities like Ann Arbor, Cambridge, and the Pasteur Institute, where tensions were rising. As fears diffused among the general population, not only laypersons but dissident scientists as well turned militant, and—as the lawyers had predicted—representatives of government in the United States and several other countries rose to play their different roles.

The Asilomar agreements were not substantively relaxed until the end of 1978. Indeed, elements of the original final consensus remain in the NIH guidelines that still govern the public and private use of recombinant DNA technology in the United States. In February 1990, the NIH Recombinant DNA Advisory Committee held its forty-second meeting, the first in this sixteenth year of its existence. The principal items on the agenda were possible revision of the definition of recombinant DNA molecules (unchanged since 1976) and the consideration of extension of an experiment to insert a recombinant gene into patients as a marker for new therapeutic approaches to cancer. One member (the Environmental Protection Agency) of the quintet of federal agencies forming the Biotechnology Science Coordinating Committee, which was established in 1986 to coordinate the regulation of recombinant DNA biotechnology in the United States, has declared it will no longer attend meetings until the committee is reformed. In England, the Advisory Committee on Genetic Modification advises the Health and Safety Executive and Ministry of Environment, the statutory authority for regulation of use of recombinant DNA technology in Her Majesty's government. In Brussels, proposed council directives dealing with “contained use of genetically modified organisms” and “deliberate release to the environment of genetically modified organisms” have been sent to a commission. On the basis of these directives, as amended, all member states are expected to enact statutes that provide for harmonization of the rules for recombinant DNA technology throughout the European Economic Community.

Long before the outcomes of the Asilomar conference could be properly assessed, lists of its putative deficiencies or limitations as a policymaking model for the recombinant DNA debate were being compiled. 58 Yet hindsight, though a powerful weapon, can easily be warped by time. Judgments of the Asilomar conference must be conducted using tight rules of what is admissible as evidence. Certainly, there should be no mention of the lack of appearance over the 15 or so years since the conference was held of any of the hypothetical hazards that were so earnestly debated there. Likewise, evidence of the bottomless cornucopia of invaluable new knowledge that these same techniques have already provided and will continue to supply to humankind must also be scrupulously barred. The scales that weigh Asilomar have to be calibrated using the context of all that contributed at that time to give the event its significance as the climactic end of the beginning of recombinant DNA research.

APPENDIX

Participants in the International Conference on Recombinant DNA Molecules Asilomar Conference Center, February 24–27, 1975

Organizing Committee

Paul Berg (Chair), Professor, Department of Biochemistry, Stanford University Medical Center

David Baltimore, American Cancer Society Professor of Microbiology, Center for Cancer Research, Massachusetts Institute of Technology

Sydney Brenner, Scientific Staff of the Medical Research Council, United Kingdom, Cambridge, England

Richard O. Roblin III, Professor of Microbiology and Molecular Genetics, Harvard Medical School, and Assistant Bacteriologist, Infectious Disease Unit, Massachusetts General Hospital

Maxine F. Singer, Biochemist, National Institutes of Health

Domestic Participants

Edward A. Adelberg, Department of Microbiology, Yale University

W. Emmett Barkeley, Head, Environmental Control Section, National Cancer Institute

Louis S. Baron, Chief, Department of Bacterial Immunology, Walter Reed Army Institute of Research

Michael Beer, Department of Biophysics, The Johns Hopkins University

Jerome Birnbaum, Basic Microbiology, Merck Institute

J. Michael Bishop, Professor of Microbiology, University of California Medical Center, San Francisco

David Botstein, Cold Spring Harbor Laboratory

Herbert Boyer, Department of Microbiology, University of California Medical Center, San Francisco

Donald D. Brown, Staff Member, Department of Embryology, Carnegie Institution of Washington

Robert H. Burris, Professor of Biochemistry, University of Wisconsin, Madison

Allan M. Campbell, Department of Biology, Stanford University

Alexander Capron, University of Pennsylvania School of Law

John A. Carbon, Professor of Biochemistry, Department of Biological Science, University of California, Santa Barbara

Dana Carroll, Department of Embryology, Carnegie Institution of Washington

A. M. Chakrabarty, Physical Chemistry Laboratory, General Electric Company

Ernest Chu, Department of Human Genetics, University of Michigan Medical School

Alfred J. Clark, Department of Molecular Biology, University of California, Berkeley

Eloise E. Clark, Division Director, Division of Biological and Medical Sciences, National Science Foundation

Royston C. Clowes, Professor of Biology, Institute for Molecular Biology, The University of Texas at Dallas

Stanley Cohen, Associate Professor, Department of Medicine, Stanford University Medical School

Roy Curtiss III, Department of Microbiology, University of Alabama Medical Center

Eric H. Davidson, Department of Developmental Biology, California Institute of Technology

Ronald W. Davis, Assistant Professor, Department of Biochemistry, Stanford University Medical Center

Peter Day, Connecticut Agricultural Experiment Station, New Haven

Vittorio Defendi, Chairman, Department of Pathology, New York University Medical Center

Roger Dworkin, Department of Biomedical History, University of Washington Medical School

Marshall Edgell, Department of Bacteriology, University of North Carolina, Chapel Hill

Stanley Falkow, Department of Microbiology, University of Washington School of Medicine, Seattle

W. Edmund Farrar, Jr., Department of Medicine, South Carolina Medical University

Maurice S. Fox, Department of Biology, Massachusetts Institute of Technology

Theodore Friedman, Department of Medicine, University of California, San Diego

William Gartland, National Institute of General Medical Sciences

Harold Green, Fried, Frank, Harris, Schriver, and Kampelman, Washington, D.C.

Irwin C. Gunsalus, Professor of Biochemistry, University of Illinois, Urbana

Donald R. Helinski, Professor, Department of Biology, University of California, San Diego

Robert B. Helling, Department of Botany, University of Michigan

Alfred Hellman, Head, Biohazards and Environmental Control, National Cancer Institute

David S. Hogness, Professor, Department of Biochemistry, Stanford University Medical Center

David A. Jackson, Department of Microbiology, University of Michigan Medical School

Leon Jacobs, Associate Director for Collaborative Research, National Institutes of Health

Henry Kaplan, Department of Radiology, Stanford University Medical Center

Joshua Lederberg, Professor, Department of Genetics, Stanford University Medical Center

Arthur S. Levine, Head, Section on Infectious Diseases, National Cancer Institute

Andrew M. Lewis, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases

Herman Lewis, Head, Cellular Biology Section, Division of Biological and Medical Sciences, National Science Foundation

Paul Lovett, Department of Biological Sciences, University of Maryland, Baltimore

Morton Mandel, Department of Biochemistry and Biophysics, University of Hawaii School of Medicine

Paul Marks, Vice President, Medical Affairs, College of Physicians and Surgeons, Columbia University

Malcolm A. Martin, Head, Physical Biochemistry Section, National Institute of Allergy and Infectious Diseases

Robert G. Martin, Biochemist, National Institute of Arthritis, Metabolism, and Digestive Diseases

Carl R. Merril, Laboratory of General and Comparative Biochemistry, National Institute of Mental Health

John Morrow, Department of Embryology, Carnegie Institution of Washington

Daniel Nathans, Boury Professor and Director, Department of Microbiology, Johns Hopkins University School of Medicine

Elena O. Nightingale, National Academy of Sciences Resident Fellow, Division of Medical Sciences

Richard P. Novick, Department of Microbiology, Public Health Research Institute, New York

Ronald Olsen, Department of Microbiology, University of Michigan

Richard J. Roberts, Cold Spring Harbor Laboratory

William Robinson, Department of Infectious Diseases, Stanford University Medical Center

Stanfield Rogers, Department of Biochemistry, University of Tennessee Medical Units

Bernard Roizman, Professor of Microbiology and Biophysics, University of Chicago

Joe Sambrook, Cold Spring Harbor Laboratory

Jane Setlow, Brookhaven National Laboratory

Philip Sharp, Center for Cancer Research, Massachusetts Institute of Technology

Aaron J. Shatkin, Roche Institute of Molecular Biology

George R. Shepherd, Los Alamos Scientific Laboratory

Artemis P. Simopoulous, Staff Officer, Division of Medical Sciences, National Research Council

Daniel Singer, Vice President, Hastings Institute of Society, Ethics, and Life Sciences

Robert L. Sinsheimer, Chairman, Division of Biology, California Institute of Technology

Anna Marie Skalka, Associate Member, Department of Cell Biology, Roche Institute of Molecular Biology

Mortimer P. Starr, Department of Bacteriology, University of California, Davis

Dewitt Stetten, Jr., Deputy Director for Sciences, National Institutes of Health

Waclaw Szybalski, McArdle Laboratory, University of Wisconsin, Madison

Charles A. Thomas, Jr., Department of Biological Chemistry, Harvard Medical School

Gordon M. Tompkins, Professor of Biochemistry, Department of Biochemistry and Biophysics, University of California, San Francisco

Jonathan W. Uhr, Professor and Chairman, Department of Microbiology, University of Texas Southwestern Medical School

Raymond C. Valentine, Assistant Professor in Residence, Department of Chemistry, University of California, San Diego

Jerome Vinograd, Professor of Chemistry and Biology, California Institute of Technology

Duard Walker, Department of Medical Microbiology, University of Wisconsin, Madison

Rudolf G. Wanner, Associate Director for Environmental Health and Safety, Division of Research Services, National Institutes of Health

James Watson, Professor, Department of Biology, Harvard University

Peter Weglinski, Department of Biology, Massachusetts Institute of Technology

Bernard Weisblum, Professor, Department of Pharmacology, University of Wisconsin Medical School, Madison

Sherman Weissman, Professor, Department of Medicine, Biology, and Molecular Biophysics, Yale University

Pieter Wensink, Brandeis University

Frank Young, Department of Microbiology, University of Rochester

Norton D. Zinder, Professor, The Rockefeller University

Foreign Participants

Ephraim S. Anderson, Director, Enteric Reference Laboratory, Public Health Laboratory Service, London, England

Toshihiko Arai, Department of Microbiology, Keio University, Shinjuku, Tokyo, Japan

Werner Arber, Department of Microbiology, University of Basel

A. A. Bayev, Academician, Institute of Molecular Biology, Moscow, U.S.S.R.

Douglas Berg, Département de la Biologie Moléculaire, Université de Genève, Geneva, Switzerland

Yuriy A. Berlin, Professor, M. M. Shemyakin Institute of Bioorganic Chemistry, Academy of Sciences of the U.S.S.R., Moscow, U.S.S.R.

G. Bernardi, Institut de la Biologie Moléculaire, Faculté des Sciences, Paris, France

Max Birnstiel, Institute of Molecular Biology II, University of Zurich, Switzerland

Walter F. Bodmer, Genetics Laboratory, Department of Biochemistry, Oxford, England

N. H. Carey, G.D. Searle and Company, Ltd., Research Division, England

Y. A. Chabbert, Professor, Bacteriology Department, Institut Pasteur de Paris, France

François Cuzin, Institut Pasteur de Paris, France

Julian E. Davies, Professor, Département de la Biologie Moléculaire, Université de Genève, Switzerland

Ray Dixon, ARC Unit of Nitrogen Fixation, University of Sussex, Brighton, England

W. A. Englehardt, Professor, Institute of Molecular Biology, Academy of Sciences of the U.S.S.R., Moscow, U.S.S.R.

Walter Fiers, Laboratorium voor Moleculaire Biologie, Ghent, Belgium

Murray J. Fraser, Professor, Department of Biochemistry, McGill University, Montreal, Quebec, Canada

W. Gayewski, Professor, Department of Genetics, Warsaw University, Ujazdowskie, Poland

Stuart W. Glover, Department of Psychology, University of Newcastle-upon-Tyne, England

Walter Goebel, Professor Gesellschaft für Molekularbiologische Forschung, Braunschweig, West Germany

Carleton Gyles, Department of Veterinary Microbiology and Immunology, The Ontario Veterinary College, University of Guelph, Ontario, Canada

Gerd Hobom, Institut für Biologie II der Universität Freiburg, West Germany

Peter H. Hofschneider, Professor, Max-Planck-Institut für Biochemie, München, West Germany

Bruce W. Holloway, Department of Genetics, Monash University, Victoria, Australia

H. S. Jansz, Professor, Nederlandse Dereniging voor Biochemie, Amsterdam, The Netherlands

Mikhail N. Kolosov, Academician, M. M. Shemyakin Institute of Bioorganic Chemistry, Academy of Sciences of the U.S.S.R., Moscow, U.S.S.R.

Philippe Kourilsky, Institut Pasteur de Paris, France

Ole Maaloe, Professor, Department of Microbiology, University of Copenhagen, Denmark

Alastair T. Matheson, Senior Research Officer, Division of Biological Sciences, National Research Council, Ottawa, Ontario, Canada

Kenichi Matsubara, Department of Biochemistry, Kyushu University, Fukuoka, Japan

Andrey D. Mirzabekov, Professor, Institute of Molecular Biology, Academy of Sciences of the U.S.S.R., Moscow, U.S.S.R.

Kenneth Murray, Senior Lecturer, Department of Molecular Biology, University of Edinburgh, Scotland

Haruo Ozeki, Department of Biophysics, Faculty of Sciences, University of Kyoto, Japan

James Peacock, Division of Plant Industries, CSIRO, Canberra City, Australia

Lennart Philipson, Department of Microbiology, The Wallenberg Laboratory, Uppsala University, Sweden

James Pitard, Department of Microbiology, University of Melbourne, Parkville, Victoria, Australia

Mark H. Richmond, Head, Department of Bacteriology, University of Bristol, England

A. Rorsch, Department of Biochemistry, Leiden State University, The Netherlands

Vittorio Sgaramella, Instituto di Genetica, Pavia, Italy

Luigi G. Silvestri, Gruppo Lepetit, Milan, Italy

Lou Siminovitch, Department of Medical Genetics, University of Toronto, Toronto, Ontario, Canada

H. Williams Smith, Houghton Poultry Research Station, Huntingdon, England

Peter Starlinger, Institut für Genetik der Universität Köln, Germany

Pierre Tiollais, Institut Pasteur de Paris, France

Alfred Tissières, Professor, Département de la Biologie Moléculaire, Geneva, Switzerland

John Tooze, EMBO, Heidelberg, West Germany

Alex J. van der Eb, Laboratory of Physiological Chemistry, Leiden, The Netherlands

Robin Weiss, Imperial Cancer Research Fund Laboratories, London, England

Charles Weissmann, Professor, Institut für Molekularbiologie, Universität Zurich, Switzerland

Robert Williamson, Beatson Hospital, Glasgow, Scotland

Ernest Winocour, Professor, Department of Genetics, Weizmann Institute of Science, Rehovot, Israel

E. L. Wollman, Institut Pasteur de Paris, France

Hans G. Zachau, Professor, Institut für Physiologische Chemie und Physikalische Biochemie, Universität München, West Germany

Press Participants

George Alexander, Los Angeles Times

Stuart Auerbach, Washington Post

Jerry Bishop, Wall Street Journal

Graham Chedd, New Scientist and Nova

Robert Cooke, Boston Globe

Rainer Flohl, Frankfurter Allgemeine

Angela Fritz, Canadian Broadcasting Corporation

Gail McBride, Journal of the American Medical Association

Victor McElheny, New York Times

Colin Norman, Nature

Dave Perlman, San Francisco Chronicle

Judy Randal, Washington Star-News

Michael Rogers, Rolling Stone

Cristine Russell, Bioscience

Nicholas Wade, Science

Janet Weinberg, Science News

Footnotes

1. Philippe Kourilsky, Les Artisans de L'Hérédité (Paris: Editions Odile Jacob, 1987), pp. 143-144. One of six French participants at Asilomar, Kourilsky provides a foreign scientist's view of this American conference, including his concern that missing among the participants were “ecologists with a global point of view.” See also Philippe Kourilsky, “Manipulations génétiques in vitro: compterendu de la conference de Pacific Grove,” Biochimie 57, No. 2 (1975): vii; and the transcript of an interview with Philippe Kourilsky, March 20, 1976, contained in the Massachusetts Institute of Technology (MIT) Archives, MIT Recombinant Historical Collection, Box 9, Folder 113.

2. At least four books on the early history of the recombinant DNA controversy contain detailed descriptions of the 1975 Asilomar conference: Michael Rogers, Biohazard (New York: Knopf, 1977); John Lear, Recombinant DNA: The Untold Story (New York: Crown, 1978); Nicholas Wade, The Ultimate Experiment: Man-made Evolution (New York: Walker, 1979); and Sheldon Krimsky, Genetic Alchemy (Cambridge, Mass.: MIT Press, 1982). In the preparation of this essay the author also made extensive use of other sources: the MIT Recombinant DNA Historical Collection at the MIT Archives; the Archives of the National Academy of Sciences, including the original tape recordings of the conference; the National Institutes of Health (NIH) Central Files; and the collections of the National Library of Medicine. Between November 1989 and June 1990, the following conference participants were interviewed in person or by telephone: William Gartland, Leon Jacobs, Philippe Kourilsky, Arthur Levine, Andrew Lewis, Herman Lewis, Malcolm Martin, Robert Martin, Anna Marie Skalka, Waclaw Szybalski, and Pierre Toillais.

3. The clue came from F. Griffith, “The significance of pneumococcal types,” J. Hygiene 27 (1928):113-159. The key discovery is described in Oswald Avery, C. M. MacLeod, and M. McCarty, “Studies on the chemical nature of the substance inducing transformation of pneumococcal types,” J. Exp. Med. 79 (1944):137-158. The confirmation appears in A. D. Hershey and M. Chase, “Independent functions of viral protein and nucleic acid in growth of bacteriophage,” J. Gen. Physiol. 36 (1952):39-56.

4. A. Hunter Dupree, “The great instauration of 1940: the organization of scientific research for war,” in The Twentieth Century Sciences, Gerald Holten, editor (New York: Norton, 1970).

5. J. D. Watson and F. H. C. Crick, “A structure for deoxyribonucleic acid,” Nature 171 (1953):737-738.

6. W. T. Astbury, “Molecular biology or ultrastructural biology?” Nature 190 (June 17, 1961):1124-1125.

7. Horace Freeland Judson has composed an unparalleled romance on early molecular biology (The Eighth Day of Creation [New York: Simon and Schuster, 1979]) in which he introduces us to a galaxy of performers, including, among many others, John Kendrew and Max Perutz, crystallographers who worked out the structures of myoglobin and hemoglobin; Erwin Schrödinger, the mathematician considering the adaptation of quantum mechanics to living organisms (What Is Life? The Physical Aspect of the Living Cell [Cambridge: University Press, 1944]); Max Delbrück, the phage expert whose early training was with the atomic physicist Niels Bohr; Leo Szilard, who was with Fermi at the Manhattan Project before he took up the study of phage and became an ardent pilgrim among the biologists; and Francis Crick, who first read physics but fortunately turned to the study of living things and was the perfect complement to James D. Watson, a very young biologist who came to Cambridge after obtaining his doctorate under Salvatore Luria at Indiana University. Among many others who coursed in and out of room 103 in the Austin Wing of the Cavendish Laboratory—where the helical model of Crick and Watson was rising—were Linus Pauling, the Nobel Prize-winning chemist, who was in hot pursuit of the crucial structure of DNA, and Sydney Brenner, the South African scientist destined to play a catalytic role at Asilomar.

8. These three classical geneticists eventually would receive Nobel prizes in physiology or medicine: Morgan in 1933, McClintock 50 years later in 1983, and Beadle and Tatum (with Lederberg) in 1958. The increasingly rapid succession of Nobel honors thereafter show the surging importance of molecular genetics up to the time of the Asilomar conference: Arthur Kornberg in 1959; Crick, Watson, and Wilkins in 1962; Jacob, Lwoof, and Monod in 1965; Holley, Khirana, and Nirenberg in 1968; and Delbrück, Hershey, and Luria in 1969. Four of the molecular biologists who participated in the Asilomar meeting subsequently received Nobel awards: Baltimore, 1975; Nathans, 1978; Berg, 1980; and Bishop, 1989.

9. Joshua Lederberg, “Gene recombination and linked segregations in Escherichia coli,” Genetics 32 (September 1947):505.

10. David Baltimore, “The strategy of RNA viruses,” Harvey Lect. Series 70 (1974-1975):57-74; Howard Temin, “On the origin of the genes for neoplasia: the G. H. A. Clowes Memorial Lecture,” Cancer Res. 34 (November, 1974):5842-5846.

11. R. C. Parker, H. E. Varmus, and J. M. Bishop, “Cellular homologue (c-src) of the transforming gene of Rous sarcoma virus: isolation, mapping, and transcriptional analysis of c-src and flanking viruses,” Proc. Natl. Acad. Sci. USA 78 (September, 1981):5842-5846.

12. See the description of a meeting at Rockefeller University, October 2, 1966, reported in the MIT Archives, MIT Recombinant DNA History Collection, Box 16, Folder 204.

13. M. Meselson and R. Yuan, “DNA restriction enzyme from E. coli,” Nature 217 (March 23, 1968):1110-1114.

14. The international traffic to and from the Pasteur Institute and the charisma of the late Jacques Monod is poignantly revived in the recollections of his colleagues edited by André Lwoff and Agnès Ullmann, Un Hommage à Jacques Monod: Les Origines de la Biologie Moléculaire (Paris-Montreal: Etudes Vivantes, 1980).

15. Among the members of the HCBSC were Paul Berg, James Darnell, Gerald Edelman, Phillip Robbins, Harry Eagle, William Sly, Matthew Scharf, James Watson, Herbert Weissbach, Charles Yanofsky, and Norton Zinder.

16. Krimsky, Genetic Alchemy, pp. 26-29.

17. B. H. Sweet and M. R. Hilleman, “The vacuolating virus SV40,” Proc. Soc. Exper. Biol. Med. 105 (1960):420; R. J. Huebner, R. M. Chanock, B. A. Rubin, and M. J. Casey, “Induction by adenovirus type 7 of tumors in hamsters having the antigenic characteristics of SV40 viruses,” Proc. Natl. Acad. Sci. USA 52 (1964):1333-1340.

18. Lear, Recombinant DNA—The Untold Story, p. 1.

19. Wade, The Ultimate Experiment: Man-made Evolution, p. 33; Nicholas Wade, “Microbiology: hazardous profession faces new uncertainties,” Science 182 (November 9, 1973):566.

20. Lear, Recombinant DNA: The Untold Story, p. 28.

21. Krimsky, Genetic Alchemy, p. 33.

22. Leon R. Kass, “The new biology: what price relieving man's estate?” Science 174 (November 19, 1971):779-788.

23. Interview with Andrew M. Lewis, NIH, Bethesda, Maryland, November 17, 1989.

24. The NIH Biohazards Committee was established in 1972, with Robert Martin as the first chairman. The committee's jurisdiction was restricted to intramural operations. It approved Andrew Lewis's concept that viral cultures should be shared with those outside investigators who signed and returned a memorandum of understanding, but a number of the researchers failed to live up to the agreement.

25. These tensions are evident in the published record of the meeting, edited by A. Hellman, M. N. Oxman, and R. Pollack, Biohazards in Biological Research: Proceedings of a Conference at Asilomar, January 22-24, 1973 (New York: Cold Spring Harbor Laboratory, 1973). Several excerpts appear below:

M. N. Oxman: “Almost any form of biological research involves some potential biohazards. [This has] only recently become of concern to many people outside of those few laboratories that are directly involved with agents of known pathogenicity for man and other animals. This sudden expansion of concern in the absence of adequate information has resulted in a good deal of fear and confusion. . . .”

Francis Black (Yale): “We have come to realize that the cost will inevitably reduce the number of grants available and increase the time available to reach our ultimate goal. If we do believe in our mission of trying to control cancer, it behooves us to accept some risks . . . if five or ten people were to lose their lives, this might be a small price for the number of lives that might be saved.”

James Watson (Cold Spring Harbor): “I'm afraid I can't accept the five to ten deaths as easily as my colleague across the aisle. They could easily involve people in no sense connected with the experimental work and most certainly not with the recognition and fame (for discovery of) the cause of human cancer . . . NCI has to face up to paying for the costs of safety or declaring all the viruses we work with as not dangerous. . . .”

26. Janet E. Mertz and Ronald W. Davis, “Cleavage of DNA by RI restriction endonuclease generates cohesive ends,” Proc. Natl. Acad. Sci. USA 69 (November 1972):3370-3374; A. Dugaiczyk, H. W. Boyer, and H. M. Goodman, “Ligation of EcoRI endonuclease-generated DNA fragments into linear and circular structures,” J. Mol. Biol. 96 (July 25, 1975):171-184.

The volume of recombinant DNA research at Stanford at that time is indicated by the fact that, as the paper by Mertz and Evans was sent to the Proceedings of the National Academy of Sciences by sponsor Paul Berg, a report of similar findings from another department was on its way to the same journal (Vittorio Sgaramella, “Enzymatic oligomerization of bacteriophage p22 DNA and of linear simian virus 40 DNA,” Proc. Natl. Acad. Sci. USA 69 [November 1972]:3389-3393).

27. EMBO workshop on DNA restriction and modification, Basel, Switzerland, September 26-30, 1972, reported in the MIT Archives, MIT Recombinant DNA History Collection, Box 16, Folder 205. U.S.-Japan conference on bacterial plasmids, Honolulu, 1972, reported in the MIT Archives, MIT Recombinant DNA History Collection, Box 16, Folder 206.

28. Lear, Recombinant DNA: The Untold Story, pp. 64-65. See also Stanley N. Cohen, Annie C. Y. Chang, Herbert W. Boyer, and Robert B. Helling, “Construction of biologically functional bacterial plasmids in vitro,” Proc. Natl. Acad. Sci. USA 70 (November 1973):3241-3244.

29. From the onset of its extramural grants program, NIH protected to the utmost the autonomy and freedom of basic researchers. The clinical investigators—who many molecular biologists considered a foreign culture—were meanwhile feeling governmental restraints. Beginning in 1966, all institutions receiving NIH, and later any federal, support had to have a local institutional review board (IRB) approve their clinical experiments. Soon at least one member of the IRB had to come from outside the institution. (After Asilomar, a similar requirement would be imposed on recombinant DNA experimentation.) Potentially far more serious was the appearance in the early 1970s of the first proscriptions of federally funded research. First, studies of abortifacients were forbidden; then in 1974 all fetal research was proscribed. These prohibitions remain in force today.

30. Lear, Recombinant DNA: The Untold Story, p. 69; Krimsky, Genetic Alchemy, pp. 72-73, citing the transcript of an interview with Maxine Singer, July 31, 1975, contained in the MIT Archives, MIT Recombinant DNA Historical Collection, Box 13, Folder 151.

31. The Institute of Medicine (IOM) was in the third year of its existence as a new partner of NAS and the National Academy of Engineering. The president of IOM responded to the letter of Singer and Söll with the suggestion that their request should be handled by the National Research Council (NRC). (See the letter from John Hogness to Maxine Singer and Dieter Söll, August 1973, contained in the NAS Archives, Folder ALS [Assembly of Life Sciences], Committee on Synthetic Nucleic Acids: Ad Hoc, Proposed, 1973.) Rather than IOM, a new organization within the academies had that year been created to oversee NRC activities in biology and health. This Assembly of Life Sciences had yet to have its first meeting when the communications from the Gordon conference arrived.

32. Maxine Singer and Dieter Söll, “Guidelines for hybrid DNA molecules,” Science 181 (September 21, 1973):1114.

33. Both Lear (Recombinant DNA: The Untold Story, pp. 69-74), and Krimsky (Genetic Alchemy, pp. 73-80) describe the origins and depth of concern for the ethics of science held by the Gordon conference chairperson, Maxine Singer. (For his sources, Krimsky makes particular use of a transcript of an interview with Maxine Singer on July 31, 1975 [MIT Archives, MIT Recombinant DNA Historical Collection, Box 13, Folder 151] and a transcript of an interview with Daniel Singer, July 28, 1975 [MIT Archives, MIT Recombinant DNA History Collection, Box 13, Folder 150].) Singer recollected that when she and Söll had been confronted by the two scientists, she had no doubt that the conference should seriously consider the concerns they had raised.

34. Letter from Philip Handler to Maxine Singer and Dieter Söll, July 20, 1973, contained in the NAS Archives, Folder ALS, Committee on Synthetic Nucleic Acids: Ad Hoc, Proposed, 1973.

35. Letter from Paul Marks to Philip Handler, August 30, 1973, contained in the NAS Archives, Folder ALS, Committee on Synthetic Nucleic Acids: Ad Hoc, Proposed, 1973.

36. Letter from Paul Berg to Leonard Laster, January 2, 1974, contained in the NAS Archives, Folder ALS, Committee on Recombinant DNA Molecules: Ad Hoc, 1974.

37. See Wade, The Ultimate Experiment: Man-made Evolution, and Rogers, Biohazard, p. 44. Richard Roblin had met Berg at Dulbecco's laboratory in the 1960s. In the course of preparing a lecture on bioethics, he remembered the letter from the Gordon conference and wrote to the Academy inquiring what had happened to the issue (letter from Richard Roblin to Leonard Laster, March 20, 1974, contained in the NAS Archives, Folder ALS, Committee on Recombinant DNA Molecules, Ad Hoc, 1974). Roblin was referred to Berg, who suggested that he attend the planning committee meeting. Thereafter Roblin served as scribe, one of his tasks being the reworking of the several drafts of the committee's report before it was released by the Academy.

38. P. Berg, D. Baltimore, H. W. Boyer, S. N. Cohen, R. W. Davis, D. S. Hogness, D. Nathans, R. Roblin, J. D. Watson, S. Weissman, and N. D. Zinder, “Potential biohazards of recombinant DNA molecules,” Science 185 (July 26, 1974):3034. See also Proc. Natl. Acad. Sci. USA 71 (July 1974):2593-2594. The “Berg letter,” as it is often called, was signed by more scientists than the seven who met at MIT as the planning committee. Lear says that when Stanley Cohen learned Berg had been invited by the Academy to form a committee, he asked to be a member. Reportedly, Berg declined his offer, saying that the committee would consist of cancer workers. Cohen appeared at MIT one day after the planning committee meeting and learned from David Baltimore that no plasmid experts had been in attendance. Concerned that the committee's actions might selectively harm research in his area of interest, Cohen threatened to write his own letter and asked Boyer to join him. Berg then called Cohen and asked him to join in endorsing the report of his committee. A number of other scientists at Stanford thereafter asked to be included, and Berg eventually invited Hogness, Davis, and Boyer to sign the report as well (Lear, Recombinant DNA: The Untold Story, pp. 83-84).

39. Annie C. Y. Chang and Stanley N. Cohen, “Genome construction between bacterial species in vitro: Replication and expression of staphylococcus plasmid genes in Escherichia coli,” Proc. Natl. Acad. Sci. USA 71 (April 1974):1030-1034; John F. Morrow, Stanley N. Cohen, Annie C. Y. Chang, Herbert W. Boyer, and Howard Helling, “Replication and transcription of eukaryotic DNA in Escherichia coli,” Proc. Natl. Acad. Sci. USA 71 (1974):1743-1747; and unpublished data of David R. Hogness, Ronald W. Davis, and Herbert W. Boyer cited in Berg et al., “Potential biohazards of recombinant DNA molecules.”

40. Documents in the NAS archives (especially Folder ALS, Committee on Recombinant DNA Molecules, Ad Hoc, 1974) record interesting efforts in late May 1974 to adjust to concerns on the part of NAS president Philip Handler, who was determined that the report of the planning committee not appear to be a private letter from the scientists to their colleagues. As one part of such efforts, the committee agreed to be constituted immediately as an ad hoc committee of the ALS. In addition, a comparison of Richard Roblin's drafts of the report suggests that the ALS reviewers helped stress the international importance of follow-up to the document and improved the stance of the report, replacing an impression of self-sacrifice on the part of the signers with a call to all scientists to join in the moratorium.

41. The French government also reacted quickly to the publication of the Berg letter. The Délégation Générale de Recherche Scientifique et Technique (DGRST) set up an organization for some form of control over “research which nobody denies can be dangerous.” Two committees were formed. One was to consider ethical problems arising from the research; it was chaired by Jean Bernard and included Monod, Jacob, Gros, Monier, Ebel, Chabbert, and Slonimsky. The second committee of 15 experts, researchers, physicians, and biologists later defined the safety limits of recombinant research using the Asilomar guidelines. DGRST reviews of research grants in the summer of 1974 imposed a moratorium along the lines proposed by the Americans (“Asilomar and the Pasteur Institute [from La Recherche],” Nature 256 [July 3, 1975]:5; P. Kourilsky, personal communication).

42. See R. Roblin's notes on the planning meeting for the Asilomar conference, and Herman Lewis's notes on the biohazard conference organizing committee meeting, MIT, September 10, 1974, contained in the MIT Archives, MIT Recombinant DNA History Collection, Box 16, Folder 207.

43. Lear, Recombinant DNA: The Untold Story, pp. 115-118, describes how the press coverage was arranged.

44. “NAS ban on plasmid engineering,” Nature 250 (July 19, 1974):175; Ephraim S. Anderson, “Indiscriminate use of antibiotics has exerted more pressure on the bacterial population than could be wielded by all research workers in the world put together,” Nature 250 (July 26, 1974):279-280, and “Viability of, and transfer of a plasmid from, E. coli K12 in the human intestine,” Nature 255 (June 5, 1975):502-506; William H. Smith, “Survival of orally administered E. coli K12 in alimentary tract of man,” Nature 255 (June 5, 1975):500-502. A few months after the Asilomar conference Anderson presented his impression of the proceedings in an interview with Charles Weiner. (The transcript of the interview on May 31, 1975, is contained in the MIT Archives, MIT Recombinant DNA History Collection, Box 1, Folder 2.) Anderson notes:

In some ways, the Asilomar meeting reminds me of Bernard Shaw's definition of the English gentleman hunting the fox: the unspeakable in pursuit of the uneatable. When I say that, I'm not actually decrying the people who were considering the problem. But here was a bunch of people, with no experience in the handling of pathogens, virtually, with the sole exception of a mere handful, considering hazards that were not even known to exist. There's a certain comic atmosphere about it. It's true that this is the first occasion on which such hazards have been considered possible. But, in fact they were a bunch of innocents abroad.

When interviewed by telephone at his home in London on February 6, 1990, Anderson emphasized that he did not intend his remarks to be unkind but that he still felt strongly that the conference was seriously hampered by an insufficient number of participants with experience in handling pathogens and infectious disease. Asked how he had voted on the final show of hands on the provisional statement, Anderson answered, “Aye, because I hadn't had time to consider all the issues, and therefore couldn't be completely negative. One had to leave the matter open at that moment.”

45. Roy Curtiss III memorandum to Paul Berg et seq., August 6, 1974, “On potential biohazards of recombinant DNA molecules,” contained in the NIH Central Files, Box Comm-4-4-7-1A.

46. K. Murray, “Alternative experiments?” Nature 250 (July 26, 1974):279.

47. H. Green, transcribed from the tape recording of the Asilomar conference, February 1975, NAS Archives.

48. The members of the Plasmid-Phage Working Group were R. C. Clowes, S. N. Cohen, R. Curtiss III, S. Falkow, and R. Novick (chairman). I am indebted to Andrew Lewis for copies of the original reports of the working groups.

49. Rogers, Biohazard, pp. 62-65.

50. Among the “lambda people” at Asilomar were D. Botstein, A. Campbell, P. Kourilsky, A. Skalka, and W. Szybalski.

51. The members of the Animal Virus Working Group were M. Bishop, D. Jackson, A. Lewis, D. Nathans, B. Roizman, J. Sambrook, and A. Shatkin (chairman).

52. Open letter to the Asilomar conference on hazards of recombinant DNA from Science for the People, contained in the MIT Archives, MIT Recombinant DNA History Collection, Box 17, Folder 219. The signers of this letter from the Genetic Engineering Group of Science for the People were Fred Ausubel, Jon Beckwith, and Luigi Gorini (Harvard); Kostia Bergmann, Kaaren Janssen, Jonathan King, Ethan Signer, and Annamaria Torriani (MIT); and Paulo Strigini (Boston University). Although there are differences in their reports, Krimsky (Genetic Alchemy, pp. 110-111) and Lear (Recombinant DNA: The Untold Story, p. 124) agree that Berg extended an invitation to Jonathan Beckwith to attend the conference, although the latter did not attend. The record is not clear whether Jonathan King was invited. He was not present.

53. The members of the Plasmid-Cell DNA Recombinant Working Group were S. Brenner, D. D. Brown (chairman), R. H. Burris, D. Carroll, R. W. Davis, D. Hogness, K. Murray, and R. C. Valentine.

54. Sources of the voting tallies are Lear, Recombinant DNA: The Untold Story, p. 145; Rogers, Biohazard, p. 100; P. Kourilsky, personal communication; W. Szybalski, personal communication.

55. Five Soviet scientists attended the Asilomar conference (see the appendix). A. A. Bayev, a well-known nucleic acid chemist, spoke for the delegation. He and his colleagues were in accord with the consensus, he said. His remarks also gave the wistful impression, however, that molecular biology was lagging in the Soviet Union. As all the participants knew, research in genetics had been gravely damaged during the Stalin era, a stark reminder of the vulnerability of science in a totalitarian milieu. In 1978, I visited Bayev at the U.S.S.R. Academy of Sciences' Institute of Molecular Biology in Moscow and delivered a copy of proposed revisions of the NIH recombinant DNA guidelines.

56. Paul Berg, David Baltimore, Sydney Brenner, Richard O. Roblin III, and Maxine F. Singer, “Summary statement of the Asilomar conference on recombinant DNA molecules,” Science 188 (June 6, 1975):991; also Proc. Natl. Acad. Sci. USA 72 (June 1975):1981-1984.

57. Letter from Philip Handler to James Ebert, May 20, 1975, contained in the NAS Archives, Folder ADM, International Relations, International Conferences, Recombinant DNA Molecules, Organizing Committee, Report.

58. A summary of Krimsky's list of the severe limitations of Asilomar as a policymaking model for the recombinant DNA debate covers the selection of participants, clarity of the decision-making process, boundaries of discourse, public participation, and control of dissent. He suggests some alternatives that could have been employed: nominations from health organizations in the relevant areas (infectious diseases, immunology, and medical microbiology); open requests for papers; contacting environmental organizations for expertise; and soliciting participation from organizations concerned about occupational health. He admits, however, that opening up the process in this way posed the risk of losing control of the issues (Genetic Alchemy, p. 151).

Donald S. Fredrickson was the director of the National Institutes of Health from 1975 to 1981, where he was responsible for the establishment of the NIH Guidelines for Recombinant DNA Research. Presently, he divides his time between consulting and scholarship, including research and writing as a Scholar of the National Library of Medicine.

Copyright © 1991 by the National Academy of Sciences.
Bookshelf ID: NBK234217

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