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

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.



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BIOMEDICAL POLITICS 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 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.

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS 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.

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BIOMEDICAL POLITICS 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 Fran çois 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

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS 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

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BIOMEDICAL POLITICS Commentary Dorothy Nelkin The Asilomar conference of February 1975 was a pivotal event in the controversy over the potential hazards of recombinant DNA research. In a commendable and responsible act, several scientists had called attention to possible risks. The subsequent conference at Asilomar was organized to develop a scientific consensus on interim guidelines to assure standards of safety. Scientists were stunned and dismayed at the public response and the widespread indications of mistrust. What then was the social meaning of Asilomar? Was the conference and the subsequent struggle over the safety of this research an isolated “threat” to the relationship between biomedical science and society? Or did these events simply express existing tensions between science and society? Have biomedical science and society restored “their mutually beneficial entente,” as Fredrickson says? Or was the incident the beginning of an even more strained relationship? Asilomar was about the autonomy of science. Stanley Cohen expressed the intent of the scientists who organized the conference: “If the collective wisdom of this group doesn't result in recommendations, the recommendations may come from other groups less well qualified. ” It was, in many ways, a symbolic event. It symbolized the sense of social responsibility among scientists concerned about the potential hazards of their research. It demon- Dorothy Nelkin is a University Professor at New York University, affiliated with the department of sociology and the School of Law.

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BIOMEDICAL POLITICS strated that scientists were able to mobilize an enormous international effort to shape research decisions—or, as Fredrickson puts it, to “march in ranks” in the face of external threats to their autonomy. But above all, Asilomar, and the highly publicized events in its wake, crystallized growing public concerns about the wisdom of allowing scientists to regulate themselves. Scientific autonomy was the issue at stake. The Asilomar conference was neither the beginning nor the end of public efforts to constrain the autonomy of science. During the 1970s biomedical scientists conducting experiments on the effect of antibiotics on the human fetus were indicted for “grave-robbing.” Public pressure forced the termination of a Harvard Medical School project to test the association between certain chromosomal abnormalities and predisposition to antisocial behavior, and protest groups obstructed research on the effect of psychotropic drugs on behavioral disorders. Even the teaching of evolution in public schools came under persistent attack. In the 1980s, public pressure persisted—recall the public hearings that challenged science-based programs such as genetic screening of workers in chemical plants, and the critical questions, aired in the media, about the appropriate methods of research to detect carcinogens in food additives. In recent years, the remarkable growth of the animal rights movement and its significant influence on research practices hardly suggest a “mutually beneficial entente.” Indeed, many issues, long perceived as internal to science—methods of research, control of fraud, sharing of research data—are now aired in the public arena. For better or worse, the public is entering decisions about the practices as well as priorities of science. These public pressures on science reflect several types of concerns. The Asilomar decisions dealt rather narrowly with one issue, the containment of potentially pathogenic organisms. Such fears about risks to human health remain at the center of many disputes. But public concerns about science also extend well beyond the fear of risk. Some disputes reflect a growing uneasiness about the social implications of scientific knowledge—the fear that research findings may be put to harmful use. Other disputes occur when people consider scientific research to be morally dubious—a threat to traditional values or religious beliefs. Still others crop up when science appears to infringe on the rights of individuals, threatening, for example, the right to privacy. Whatever the concern, disputes over research decisions are challenging the autonomy of scientists, as activists call for greater regulation and public involvement in decisions concerning research priorities and practices. The relationship between science and society has been one in which the public provided research support but made limited demands for accountability and control. This relationship rested on a set of assumptions about science as a source of objective, disinterested knowledge. Science has been considered an agent of the general public, removed from political biases and economic

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BIOMEDICAL POLITICS interests. Whether myth or reality, this was the image that sustained the acceptance of scientific autonomy. But recent changes in the way the public perceives science have increasingly involved scientists in economic and political liaisons with special interest groups. As these liaisons develop, issues of patenting and property, of ownership and control, are inevitable. In this changing context, scientists will find it more and more difficult to project the image of objectivity and neutrality that in the past has served them so well. Current controversies reveal a growing cynicism about science as critics talk of the “commodification” and the “inhumanity” of science, its “corporate culture,” and the erosion of its moral authority. The economic and policy implications of scientific research, the dominance of costly projects in the research infrastructure, and the increased involvement of commercial interests evident in industry-university relationships and the involvement of scientists in biotechnology firms will exacerbate changes in the autonomy of science. Ironically, the more directly science is called upon to contribute to specific economic and policy goals, the less it can effectively retain its image of moral authority as a source of disinterested, unbiased information. The more science is valued as a political and economic resource, the less scientists can expect to avoid increasing public control. In this context, the Asilomar conference and the events it subsequently provoked were more a beginning than an end. For they were events that called very wide attention to the public character of science, its potential implications, and the need to set priorities that reflect the public will.

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BIOMEDICAL POLITICS Commentary Paul Slovic Donald Fredrickson's chronicle of the Asilomar conference brings us to the end of the beginning of the debate about the acceptability of risks from recombinant DNA technology. As the conference faded into history and safety guidelines for research were being prepared, a new and even more turbulent era began. News of the scientists' concerns about the possibility of serious, unpredictable consequences of crossing natural genetic barriers triggered strong opposition to DNA research in many communities and led legislators to begin drafting strict regulation to control the specter of risk raised at Asilomar. Despite an exemplary record of safety, public perceptions of risk have had a continuing impact on recombinant DNA research and development. Early battles in what have been labeled the “gene-splicing wars” (Zilinskas and Zimmerman, 1986) focused on containment of genetically altered organisms in the laboratory. Subsequent confrontations have focused on the perceived risks from deliberate release of such organisms into the environment. For example, a field test of frost-retarding bacteria was declared safe by an NIH expert committee in 1983 but was prevented from taking place until 1987 by lawsuits and public hearings. This delay prompted one observer to comment: “Perhaps the most ironic aspect of this long-running controversy is that the Paul Slovic is president of Decision Research in Eugene, Oregon and professor of psychology at the University of Oregon.

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BIOMEDICAL POLITICS brilliant minds that figured out this world-transforming technology in the first place have yet to figure out a way to ease public fears about it” (Hall, 1987). Recombinant DNA technology is not unique in its problems with perceived risks. After smooth sailing in its first two decades of development, nuclear power became embroiled in risk-based opposition, triggered by its association with weapons of destruction and by scientists ' worst-case accident scenarios. The opposition was subsequently maintained by the cumulative impacts of numerous small and few and not so small accidents. Alvin Weinberg (1976) has observed: “As I compare the issues we perceived during the infancy of nuclear energy with those that have emerged during its maturity, public perception and acceptance appears to be the question that we missed rather badly. This issue has emerged as the most critical question concerning the future of nuclear energy.” During the past decade, public concern and dissatisfaction have also become increasingly associated with the production, use, transport, and disposal of many types of chemicals. At present, nuclear power and chemical technologies are under siege in the United States and many other countries, whereas biotechnology, despite past controversies, is flourishing. What accounts for the differences in public perception and acceptance of these technologies? What does the future hold for biotechnology? I do not pretend to have complete answers to these questions, but I shall speculate about them from the perspective of research on risk perception. THE NATURE OF PERCEPTION Serious studies of risk perception began in the mid-1970s, about the same time as the Asilomar conference. These studies have sought to determine why the public is anxious about some technologies (e.g., nuclear power) but not others (e.g., dams, motor vehicles) and why people's concerns are often unrelated to what experts believe they should worry about. Early research demonstrated that people's judgments of probability and risk are strongly determined by the ease with which adverse consequences can be imagined (Tversky and Kahneman, 1973; Lichentenstein et al., 1978). Both nuclear power and biotechnology prove vulnerable in this regard because of associations with improbable but highly imaginable scenarios such as nuclear explosions and viral epidemics. Other studies have found that the public has a different, and in some sense richer, conception of risk than do the experts (Slovic, 1987). Public perceptions and acceptance of risk are intimately connected to the qualities or nature of the hazard—that is, whether exposure is voluntary, whether the risks are familiar, controllable, catastrophic, dread, known to science and to those exposed, fair (in the sense of risks being borne equitably by those who bene-

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BIOMEDICAL POLITICS fit from the hazardous activity), and so on. Experts' assessments of risk, in contrast, are driven by probability and magnitude of adverse consequences and tend not to be related to the qualities of risk that concern the public. Although one can draw many parallels between nuclear power and recombinant DNA technologies (both transform matter in powerful ways that can be used for good or evil), nuclear power is perceived somewhat more negatively on the qualities that most strongly determine perceptions of risk. Nuclear power's risks are judged to be less controllable, more dread, more catastrophic, and less equitably distributed among those who benefit from the technology. However, biotechnology risks are judged less well known and less understood. Close examination of specific hazards within a particular domain such as radiation or chemicals shows that perceptions of risk are not homogeneous. Within the domain of radiation hazards, nuclear power and nuclear waste are perceived much more negatively than medical x-rays and radon gas. Similarly, industrial and agricultural uses of chemicals are perceived far more negatively than prescription drugs and vaccines. The favorable view of x-rays and medical uses of chemicals indicates that acceptance of risks is conditioned by familiarity, by perceptions of direct benefits, and by trust in the managers of the technology—in this case the medical and pharmaceutical professions. Those in charge of managing nuclear power and nonmedical chemical technologies are clearly less trusted. In addition, the benefits of these technologies are not highly appreciated; hence, their risks are less acceptable. The public's apathetic response to the risk from radon appears to result from the fact that it is of natural origin, occurring in a comfortable, familiar setting with no one to blame. Biotechnology, of course, encompasses an enormous range of activities ranging from familiar fermentation technologies to deliberate release of genetically altered microorganisms into the environment. Based on the above findings, one would expect that perceptions of risk and benefit would vary considerably across these various activities, with application in medicine being perceived most favorably. One would also expect that the benefits of many nonmedical applications would not be apparent to the public, no matter how obvious they appear to scientists and industrialists. When benefits are not perceived as significant, the public is intolerant of any risk, even a small one. THE EFFECTS OF PERCEPTIONS Whether or not one agrees with public risk perceptions, they form a reality that cannot be ignored. During the past decade, research has shown that individual risk perceptions and cognitions, interacting with social and institutional forces, can trigger massive social, political, and economic impacts. Risk analyses typically assess the impacts or seriousness of an

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BIOMEDICAL POLITICS unfortunate risk event (e.g., an accident, a discovery of pollution, an adverse drug reaction) in terms of direct harm to victims or property. Yet the adverse impacts of a risk event sometimes extend far beyond these direct harmful effects and may include indirect costs to the responsible government agency or private company that far exceed direct costs. In some cases, all companies in an industry are affected, regardless of which company was responsible for the mishap. In extreme cases, the indirect costs of a mishap may even affect companies, industries, and agencies whose business is minimally related to the initial event. Thus, an unfortunate event can be thought of as a stone dropped in a pond. The ripples spread outward, encompassing first the directly affected victims, then the responsible company or agency, and, in the extreme, extending beyond industry boundaries. Some events make only small ripples; others make big ones. The challenge is to discover characteristics associated with an event and the way it is managed that can predict the breadth and seriousness of these effects. Early theories equated the magnitude of impact to the number of people killed or injured, or to the amount of property damaged. The accident at the Three Mile Island (TMI) nuclear reactor in 1979, however, provided a dramatic demonstration that factors besides injury, death, and property damage impose serious costs. Despite the fact that not a single person died at TMI, and few if any latent cancer fatalities are expected, no other accident in our history has produced such costly societal impacts. The accident at TMI devastated the utility that owned and operated the plant. It also imposed enormous costs on the nuclear industry and on society through stricter regulation, reduced operation of reactors worldwide, greater opposition to nuclear power, and increased costs of subsequent reactor construction and operation. The proliferation and spread of ripple effects is a phenomenon that has been termed “the social amplification of risk” (Kasperson et al., 1988). It appears that multiple mechanisms contribute to social amplification, causing even “small ” events to have significant effects on industries and society. One such mechanism is the finding that the perceived seriousness of an accident or other unfortunate event, the media coverage it gets, and the long-range costs and other high-order impacts on the responsible company, industry, or agency appear to be determined, in part, by what the event signals or portends. Signal value reflects the perception that the event provides new information about the likelihood of similar or more destructive future mishaps. The informativeness or signal value of an event, and thus its potential social impact, appears to be systematically related to the characteristics of the hazard. An accident that takes many lives may produce relatively little social disturbance (beyond that caused to the victims, families and friends) if it occurs as part of a familiar, well-understood system (e.g., a train wreck). However, a small accident in an unfamiliar system (or one perceived as poorly understood), such as a nuclear reactor or a recombinant DNA laboratory,

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BIOMEDICAL POLITICS may have immense social consequences if it is perceived as a harbinger of further and possibly catastrophic mishaps. In a recent survey of college students, “DNA research” was rated highest among 97 activities with respect to “risks unknown to science.” It was also highest in terms of a direct judgment of signal value (the degree to which an accident would increase one's perception of the likelihood of similar or more destructive future mishaps). This survey implies that the first evidence that recombinant DNA activities pose real physical risks is likely to result in strong, restrictive sociopolitical responses. Francis Black's position (i.e., his willingness to risk losing five or ten lives in recombinant DNA research as a small price for the number of lives that might eventually be saved) was thus unwise (see Fredrickson, footnote 25). “Small” fatal accidents in the early stages of this activity could have stymied its development for many years. In this light, the cautious approaches recommended at Asilomar and thereafter were indeed justified. A second important mechanism of social amplification is the action of special interest groups, which bring risk issues to public attention and then try to keep them there. Fredrickson notes the involvement of one such group, Science for the People, which urged the Asilomar contingent to allow the public to participate in the regulation of biological research. Many activists and groups subsequently played a role in the “recombinant-DNA wars” of 1976-1978 (Zinder, 1986). Now there are many more such groups, and they are increasingly well funded and more sophisticated in getting their message across to the public, legislators, and regulators. Many believe that the gene-splicing wars are over. I disagree. For better or for worse, our society manages risk through public controversy and adversarial confrontation (recall the “chilling landscape of legal liability” described by the lawyers at Asilomar). Members of the public, acting individually or through powerful special interest groups, increasingly demand control over the risks to which they may be exposed. Technical assessments of risk carry little weight, unless those who construct them and those who present them are deemed trustworthy. In fact, trust is in short supply, hard won (by actions such as those of Asilomar), and quickly lost in the adversarial arena. Technologies that alter genetic material will be watched carefully for ominous signs of imperfection and danger and will be treated roughly when such signs appear. On the positive side, people will tolerate what they perceive to be significant risks if the benefits appear to be commensurate—and biotechnology certainly promises great benefits in medicine and other domains. Although many have labeled public perceptions of risk uninformed or irrational, research on this topic paints a different picture. Whereas experts define risk in a narrow, quantitative way, the public has a broader view, incorporating legitimate value-laden considerations such as uncertainty,

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BIOMEDICAL POLITICS controllability, catastrophic potential, and equity into the risk-benefit equation. The impacts of public perceptions of risk cannot be lessened without drastic, politically unacceptable changes in the structure of our society. Thus, we must learn to treat perceptions as legitimate. We must attempt to understand them and to incorporate public concerns and wisdom into decision making, along with the wisdom gleaned from scientific assessments of risk. REFERENCES Hall, S. 1987. One potato patch that is making genetic history. Smithsonian 18(5):125-136. Kasperson, R. E., O. Renn, P. Slovic, H. S. Brown, J. Emel, R. Goble, J. X. Kasperson, and S. Ratick. 1988. The social amplification of risk: A conceptual framework. Risk Analysis 8:177-187. Lichentenstein, S., P. Slovic, B. Fischoff, M. Layman, and B. Combs. 1978. Judged frequency of lethal events. Journal of Experimental Psychology: Human Learning and Memory 4:551-578. Slovic, P. 1987. Perception of risk. Science 236:280-285. Tversky, A., and D. Kahneman. 1973. Availability: A heuristic for judging frequency and probability. Cognitive Psychology 5:207-232. Weinberg, A. M. 1976. The maturity and future of nuclear energy. American Scientist 64:16-21. Zilinskas, R. A., and B. K. Zimmerman, eds. 1986. The Gene-Splicing Wars: Reflections on the Recombinant DNA Controversy New York: MacMillan. Zinder, N. D. 1986. A personal view of the media's role in the recombinant DNA war. In The Gene-Splicing Wars: Reflections on the Recombinant DNA Controversy R. A. Zilinskas and B. K. Zimmerman, eds. New York: MacMillan.