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 A BRIEF HISTORY OF BIOTECHNOLOGY RISK DEBATES AND POLICIES IN THE UNITED STATES

http://cbs.umn.edu/~pregal/GEhistory.htm

Philip J. Regal (c) 1998
Biological Sciences
University of Minnesota
St. Paul, Minnesota 55108

Scope of this Historical Synopsis

 The Earliest Voiced Concerns. Analyses by scholars and scientists of the future impacts of genetic engineering* divided early into the following range of concerns:

 Additional Concerns as the Nature of the Biotech Community Changed. Changes in the biotech community in the late 1970s and 1980s began to raise a host of additional questions about the ability of molecular biology to police itself given the growth of conflicts of interest, political influence, competitive pressures, the need for continual large direct and indirect subsidies, and the need to maintain a positive public image to maintain subsidies, investments, and political power (Krimsky 1991, 1996, Regal 1987, 1996).
     By the 1980s, factions that advocated aggressive competition, so-called 'free-markets,' and deregulation had become quite powerful in parts of Europe and the the United States. The pressure was strong to 'privatize' the public investment in the development of biotechnology as much as possible. Molecular biologists had become entrepreneurs and not merely consultants to industry. Many had bet their personal finances as well as their careers on the financical success of biotech. The line between university reseach, government research, and industry was becoming more thin.

 The Limited Scope of the Following Historical Analysis. All these concerns for the future are still very much alive. But the present report will focus on the history of the second of the above five areas that have seriously concerned scholars and scientists -- the biohazard and biosafety concerns. Little will be said here about the issue of food safety because this is an issue that was little appreciated and discussed among independent university scientists or publically until the late 1990s. I  deal with the complex scientific and historical issues in a separate essay. 

The Engineering Ideal in Biology
     The ideal of reducing life completely to human control was promoted most vigorously and thoroughly by Jacques Loeb in the 1920s after he had moved from the University of Chicago to the Rockefeller Institute, during an era when it seemed that technology could and would domesticate the planet.
     Then in the 1930s the Rockefeller foundation under physicists Max Mason and Warren Weaver began to recruit chemists and physicists to create the new science of what would be called molecular biology. The expansive Rockefeller program began with the highly idealistic assumption that nearly all human problems could all be solved by genetic and chemical manipulations. (Abir-Am 1987, Kay 1993, Pauly 1987, Regal 1987, 1996)
     The agenda for molecular biology and the engineering of life thus was infused with complete optimism from the start, and there was only a positive view of the promise of the new science and of the bio-technologies that it was supposed to produce eventually. Risks and other negative developments were not considered or planned for.
     Mason and Weaver had left research in physics in disgust with quantum mechanics and turned to administration. Weaver wrote that they had kept their faith that nature would be found to be simple and sought to infuse this faith into a new Molecular Biology. The faith that they sought to preserve had been motivating physical scientists since at least the 17th century, but it had been seriously shaken philosophers of science by the earliest 20th century (see discussions and references in Regal 1989, 1990b,1996).
     Physicists and chemists had long shared a very old and seductive ‘reductionist' and ‘determinist' dream that had extended even to biology. It had been promoted by philosopher/scientists such as Rene Descartes, who argued in his 1637 Discourse on Methods, for example,

     But the history of physics and chemistry in fact came to prove that nature is more frustratingly subtle than the dreams of simplicity. As Sir Arthur Eddington quipped in the 1930s, "We used to think that if we knew one, we knew two, because one and one are two. We are finding that we must learn a great deal more about ‘and.'"
     This is to say that it had been turning out that simple facts did not necessarily combine in ways that a simple logic would predict. Descartes, for example, predicted that there could not be space empty of matter, because "A vacuum is repugnant to reason." Yet physicists eventually had to face the fact that space is not filled with ether, as they had long reasoned (quotes from Mackay 1977).
     In the case of DNA, this molecule is stable in a test tube. But it is not stable in populations of reproducing organisms. One cannot reduce the behavior of DNA in living organisms to its chemical properties in a test tube! In living systems, DNA is modified, or ‘destabilized' if one prefers, at a minimum by mutation, gene flow, recombination, and natural selection. This would make it extremely difficult or even impossible to have a true genetic engineering, in the sense of which it had been spoken. Many molecular biologists certainly ‘knew' facts about mutation and natural selection as abstract facts, but they were not a working part of their professional consciousness.

Phase I: Early Safety Concerns -- The Germ Warfare, Biohazard Connection
     Much of this section has been well-covered in Wright's 1994 history, and Grobstein 1979, 1986.

 1960s: Concerns about Germ Warfare. American scientists first began to question in the 1960s whether recombinant DNA technology would always be used safely. At this time the military in the United States began to show an interest in using recombinant techniques to make 'designer weapons' that would transcend the limits of the old biological weapons (E.g. Wright 1994, p.118).
    [ Designer weapons designated, for example, diseases that would resist antibiotics, selectively kill one race, etc. To illustrate: the Associated Press reported scientific testimony before the Reconciliation Commission that the white government of South Africa had research programs in place to engineer diseases that would only kill blacks. Just before the presidential election, the United States and Britain tried to convince the government to destroy their stockpiles, but the program was not terminated until Mandela became president (Associated Press 1998). Some scientists estimate that the early use of biological weapons is likely to be against crops and livestock, and that the potential to damage and disrupt is on the scale of nuclear war. Iraq's efforts to develop biological weapons prior to the Gulf War included anticrop weaponry. The U.S. has programs to develop pathogens that it is hoped will specifically kill crops that produce drugs such as cocaine, marijuana, and heroine. "The greatest concern, however, is that the developmnet of a capability to destroy drug crops with plant pathogens will inevitably provide a wealth of knowledge and practical experience that could readily be applied in much more aggressive offensive biological warfare targeting food crops." (Rogers et al. 1999).]
    [Ken Alibek was the Deputy Chief of Biopreparat in the Soviet Union from 1988 to 1992, before he moved to the United States to work in biodefense. According to him, the USSR biological warfare program was stimulated in 1972/1973 when the possibilities of recombinant DNA for designer weapons were independently realized by Soviet scientists. Military sponsorship in turn gave Soviet molecular biologists support to join at least in some way in the genetic engineering research that was creating so much excitement in the West. The budget for biological weapons research soon quadrupled and included dozens of installations around the USSR, staffed by tens of thousands. Alibek has written that he came to feel that American intelligence agencies did not know about the Soviet programs until 1991, and that the American counterpart programs were insignificant at the time. If this is correct, then the American military interest in biological weapons from the 1960s to the 1990s did not translate into large programs under direct military control as some suspected it would. But military interest in the USSR and China, at the least, did generate rDNA-based biological warfare programs there. (Alibek 1999)]
    [Alibek also wrote that, I have encountered an alarming level of ignorance about biological weapons. Some of the best scientists I've met in the West say it isn't possible to alter viruses genetically to make reliable weapons, or to store enough of a given pathogen for strategic purposes, or to deliver it in a way that assures maximum killing power. My knowledge and experience tell me that they are wrong. I have written this book to explain why. (Alibek 1999, p. xi) I had long heard the same naive opinions from leading American biotech advocates when I asked them how they justified to themselves promoting the dramatic proliferation of this technology with its distrubing potential to cause a biological weapons arms race and ultimately perhaps uncountable deaths. My sense is that many of them had talked themselves into sincerely believing that rDNA had no weapons potential, because they felt constantly on the defense and felt a need to protect the image of biotechnology and to protect their own faith in it the benign nature of their community. Their arguments spreat and soon became a misleading  'common wisdom' among American biotechnologists. Thus, it is possible that the differences in self-interest between Soviet and American scientists led to very different consequences in terms of  arms development in the two counties.]

 Fear of the Public. The American scientists discussed concerns in small meetings that were not attended by the press. The discussions led to broader questions in the late 1960s about the potential misuse of the new technology.
     The reactions of those who were to become the leaders of molecular biology set the tone for the future. They argued that risks should not be discussed in public or the public might end the freedoms of the research scientists and cut funding for recombinant DNA research. They argued that so much good would come from the research that it was worth great risks.

 1972: Nervous Laboratory Workers. The first genes were spliced in 1971 and recombinant techniques were soon widely used. Many laboratory workers began to wonder if what they were doing was safe. When they would gather at meetings and discuss specific projects, serious questions were raised that could not be answered.
     It should be kept in mind, again, that molecular biology grew out of physics and chemistry. These physical scientists who were starting to rearrange the molecules of heredity knew little about living organisms, and some of them were starting to become concerned about the limitations of their discipline. Some of their concerns may have been over-reactions, while others were entirely appropriate.
     There were only private meetings about safety in the early 1970s.

 1973: Biohazard Controversies Get out of Hand. Discussions at a June 1973 Gordon Conference led the organizers to call for moratorium on some recombinant research and for the U.S. National Academy of Sciences to set up a committee to study questions about the safety of certain laboratory projects.
     Concerns over the safety of some genetic engineering projects began to be discussed in publications for the general scientific community.
     Wright's research found that leaders of the scientific community then began to express concerns that a 'panic response' would develop.
     Leaders of the scientific community, such as the president of the National Academy of Sciences, became troubled over the uncontrolled debate and sought ways to keep the control of molecular biology and its controversies within the scientific community. The result, however, was that, "decisions on whether to slow research were being made by the very people on whom pressures to pursue genetic engineering were the strongest" (Wright 1994, p.137).
     Scientists began to talk in 1974 about containment of experiments and about using 'disarmed' laboratory host organisms in order to be doubly safe.
 Those in favor of taking the risks began to argue that while the risks could not be exactly predicted,

 1975: Asliomar -- The Public Sees Part of the Debates.
 It was clear by 1974 that the diverse controversies would grow and could not be contained by the scientific leadership. So a conference that would be attended by the press was scheduled at Asilomar, California for February 1975. The conference was a success for the leadership.  The negative consequence of the Asilomar conference was that a number of serious issues were neglected and passed on for the future to discover again. As Clifford Grobstein put it,     Concerns over the possible social, economic, and other problems from genetic engineering were reduced to the simple technical matter of containment and to the improbable concern that a biohazard scenario would emerge. Grobstein warned that the result of this 'success' was to fence the issue within the turf of a special interest group within the scientific community and to prevent further effective deliberation by other scientists and the educated public of the complicated and serious social issues that lay ahead. (Regal 1996)

Phase II: 1984 -- The New Deliberate Release Problem
     The issue of 'deliberate release' or 'deliberate introduction' was among those issues that faded from view as a result of the Asilomar and RAC focus on contained laboratory experiments and disarmed laboratory organisms.
     Thus it came as a surprise to many biologists in 1983-1984 that the technology had advanced greatly and that the genetic engineers were contemplating the 'release' or 'introduction' of ecologically competent genetically engineered organisms (GEOs) into the environment, where it was planned that they would thrive.
     It was disturbing that essentially the same types of arguments were being used to argue that ecologically competent GEOs would cause no problems, as had previously been used to argue that ecologically incapacitated laboratory GEOs would not cause problems.
 These facts were collectively surprising for several reasons.
 

 1984: 'Deliberate Release' -- Ecological Discussions. The first meeting between leading university ecologists and molecular biologists, genetic engineers in industry, and representatives from government agencies took place at the Cold Spring Harbor Banbury Center in August 1984 and was organized by Philip Regal and John Fowle III.
     The participants at the Banbury Conference quickly confirmed that the arguments that had been used to estimate that ecologically specialized laboratory GEOs were unlikely to cause ecological problems could not be used to estimate that releases of ecologically competent GEOs would be safe. There would be dangers and the consequences could in some cases be substantial (Brown et al. 1984).
     The United States Government was at the brink of deregulation, but this and subsequent conferences, such as one in Philadelphia in June of 1985, confirmed that the potential for dangers was a serious matter scientifically (Halvorson et al. 1985).
     Unknown to many scientists outside of Washington, D.C. there had earlier been Congressional hearings on the risks of introducing GEOs into the environment and a Congressional Report concluded that the probability of risks was low, but that the consequences could be extremely great (House of Representatives 1984). This conclusion was in agreement with an earlier internal Environmental Protection Agency document by Frances Sharples, eventually published in the Recombinant DNA Technical Bulletin (Sharples 1983).
     The participants at the Banbury Conference concluded that the intellectual issues were more challenging than many would at first suppose and that it would be a major task to educate the scientific community to deal with the future.

 The Demise of Generic Safety Arguments. A variety of theoretical arguments were being used from about 1974-1986 to insist that all releases of GEOs would be safe.
 These generic safetly arguments were criticized systematically at a series of scientific symposia, workshops, and in professional publications by Professors Philip Regal of the University of Minnesota, Robert Colwell, then at the University of California, Berkeley, and Richard Lenski, then at the University of California, Irvine (Colwell 1989: Lenski 1993; Regal 1985, 1986, 1988, 1993, 1994; Colwell 1989).
     As a result, these generic safety arguments are seldom used anymore in discussions among experts.
     However, they are still in circulation among scientists who have not studied the technical issues, and they are still used by biotech public relations persons, and so they should be briefly listed. Criticisms are referenced and summarized (in bold italics) following each model.
 

           These theoretical arguments have been in error because for the most part they have been based on:      The Ecological Society of America conducted a review and issued a report in 1989 (Tiedje 1989) that outlined in detail the implications of progress in ecological concepts for the GEO risk issue. The preface to the publication explains that the manuscript was widely circulated among and and approved by ESA members.

Phase III: The Continuing Quandary over Regulations
     (The following leans heavily on my experiences and my close involvement advising on the scientific aspects of ecological risk assessment throughout the formative period of the 1980s.)

 Deregulation Categories? The immediate reaction of many in the biotech industry to the demise of generic safety arguments was to want to get on with their work. 'Just tell us what we can and can not do. Give us two lists -- a yes list and a no list.' The regulators were under pressure to devise categories for introduced GEOs that would not need regulation. But in each attempt the criteria for classification proved to be too simple.
     The following are examples of the categories for deregulation that were discussed in the mid-1980s; and some problems with them are listed briefly below each proposal in brackets. Ironically, many are proposed-based categories (in the sense that they do not ask what are the actual biological properties of the GEO product itself, but 'how was it made?' --'from what?') first proposed by those who were also arguing that there was no need to regulate on the basis of process. Some problems with each category are briefly discussed and appear in bold italics following each proposal.
 

             Thus, after many years of deliberation it has not been possible to make a simple list of GEOs that it can be predicted would be categorically safe.

 'Case-by-case' Reviews Necessary. It seemed impossible to make comprehensive lists of all possible safe and unsafe GEOs, including lists based strictly on how, from what, the GEO was made. Thus the frustrating conclusion was that GEOs would have to be evaluated on a case-by-case basis. Case-by-case does not necessarily mean that every strain of GEO must be studied extensively, but it does mean that every 'type' of project should be evaluated in terms of its own particularities by experts with a broad understanding of organismal biology and ecology.
     Obviously there are no universal rules about how to make case-by-case evaluations for all the possible types of GEOs that might be constructed. And there is no universal definition for what a 'type of project' or 'situation' is or when 'enough' information has been provided.
     The devil is in the details. Case-by-case means that the scientific community will have to be assured that each 'situation' has been reviewed by an appropriate mix of qualified experts that has articulated its collective decision with scientifically acceptable reasoning and is prepared to be accountable for its decision.
     There has been considerable complaint that the regulatory agencies have not been using scientifically comprehensible criteria in making risk assessments to date (Doyle et al. 1995, GAO 1988, Rissler and Mellon 1993, 1996, PEER 1995, Regal 1994, Wrubel et al. 1992).
     This lapse stems in part from the fact that the agencies have been under enormous political pressure to expedite the progress of genetic engineering. As a result they have not adequately staffed themselves with experts from the proper ecological and other scientific disciplines and built the infrastructure to deal with the difficult scientific challenges ahead, let alone with the volume of paperwork expected.

The Familiarity Pitfall
     It is commonly agreed that 'familiarity' with the parent organism of the GEO or the GEO itself should be a key consideration in risk assessment.
     The pitfall is that 'familiarity' means different things to different people. One can be familiar with an organism in terms of its taxonomy, molecular structure, agronomic features, marketing characteristics, and so on. None of these forms of familiarity are will be key to making sound biosafety evaluations. That is, there are many forms of scientific expertise that may be quite inappropriate for making sound safety evaluations.  An ecologically oriented plant systematists may have a familiarity with the parent of a GEO that is valuable in one case, and a traditional economic botanist in another case. And in some cases the familiarity of agronomists or geneticists with the parent plant may be of only tertiary value.
     Moreover, names do not necessarily mean what they might seem. For example, many scientists call themselves microbial ecologists because they study interactions of two or more species, as in fermentation processes. But they may not be familiar with modern concepts of the dynamics of natural communities. A tradional economic botanist should know a great deal about the systematics, biogeography, and ecology of crop plants and their relatives. But other economic botanists will not be familar with this sort of information and they will be much too specialized to be valuable resources for risk evaluations.
     It is often said naively that a GEO will be safe if the parent is familiar, and or that various previous engineerings of the parent 'did not cause problems.' Yet it is not enough to have grown a GEO or its parent under simple conditions, even for years, to be able to predict how it may interact in nature.
     The type of familiarity that would be a valid aspect of risk assessment would be familiarity with those particular characteristics of the parent and the GEO that could influence its ecological future and its effects on health, as suggested in Table 1.
     Often, "The Principle of Familiarity" is used to suggest that since something is known about the unmodified, parent, organism or about closely related organisms, the GEO will behave in the same manner. The Principle of Familiarity comes from the chemical industry, where, if the structure and activity of a chemical is known, then closely related chemicals, with nearly the same chemical structures, will likely behave the same way. This often, but not always, works for chemicals. But it rarely works for organisms.
     Simple inorganic chemical reactions always occur in the same manner in a constant environment. But organisms adapt and change with amazing regularity. Mutation, recombination, genetic drift, and natural selection are always at work in reproducing populations. Add to this the fact that genetic engineering has an implicit uncertainty regarding where transgenes insert, how many transgenes will insert, how much mutation they will cause, how errors produced by the transgenes will be corrected or buffered by the host, and it is highly doubtful when this Principle of Familiarity could ever be applied to GEOs.
     Further, if engineered organisms are different enough from all other organisms to be patentable, then it follows logically that parent and GEO are not similar enough to use the Principle of Familiarity. The Precautionary Principle may make more sense: 'First do no harm," or 'If you don't know how something works, don't use it.'
     The criterion of 'familiarity' may sound superficially reasonable, but it must be defined and the definition must be spelled out or it can only mislead.

The False Sense of Security Trap
 Scientists began to express concerns over the the future of genetic engineering some 30 ago, even before the most simple gene splicing had become possible. There has been a common progression among persons who begin to study genetic engineering safety issues, and this progression can result in a false sense of security.
 

     Individuals have often gone through this progression over the last 30 or so years. But whole groups have also gone through a similar progression.
     Great concerns about various dangers from genetic engineering were expressed by molecular biologists in the days before Asilomar. There was no careful analysis of future risks at the time and so the concerns that were orgininally often well focused were easily oversimplified by a leadership preoccupied with calming the community. The concerns were easy to dismiss in their oversimplified form. They were:      Once it could be said that thousands of GEOs had been made in the laboratory without any accidents, many scientists and journalists whose concerns had been vague began to feel by the 1980s that they had foolishly overreacted. They became reluctant to become identified with the 'kooks' who their leadership held up as examples of those who had concerns about safety.
     They became reluctant to inform themselves about the new biosafety concerns over deliberate releases that began to emerge in 1984.
    When one combines this widespread lack of understanding among the scientists with an aggressive public relations campaign to present a highly positive image of genetic engineering, to trivialize risk concerns, and to create the impression that there was an adequate government regulatory structure in place the result could only be tragic for society. In some sense the biotech community painted itself into a corner where it is today stuck without a clear vision of the future with regard to dealing with risks, public concerns, and deep divisions in the scientific community, and without the spirit or expertise for working out a satisfactory agenda for future regulatory needs and research programs to narrow the margins of scientific uncertainty.
     Sociologist I. Rabino surveyed 430 recombinant DNA scientists and reported in 1991 that 61% felt that however inconvenient, the general controversies over safety had made the genetic engineering community become more responsible. Only 24% felt that the controversies had been over-all harmful to genetic engineering. 72% felt that the advice of ecologists should be sought on safety issues, and many of these felt that this was important to do even if it meant that the United States would lose its competitive edge because of the controversies over recombinant DNA. It was only a small minority did not want research/industry to seek ecological advice (Rabino 1991).
     Rabino's findings are consistent with the experiences of my colleages and myself  in working closely with the genetic engineering community for over a decade. But we would add that the small minority that is opposed to ecological input have tended to be much more vocal and more active in government politics and with the investment community -- to be 'better connected' and more influential -- than the majority of research scientists.
     The fact that so many recombinant scientists answered in the Rabino poll that they were willing to risk having the United States lose its competitive edge may not mean as much as it superficially seems. 'America's competitive edge' is a slogan, and many workers feel that it does not have precise meaning outside of the context of getting local and federal support for biotech. Biotech may well be destined to become dominated by multinational companies. American genetic engineers are intimately aware that their colleagues may well be speaking loudly in patriotic terms one day, and actively selling their ideas or small companies to Japanese- or European-based corporations the next.
     Yet the overall outcome of the progression from strong concerns to the fear of overreacting has been to promote a false sense of security, a tendency to avoid serious study of the issues, and to impede and divert potential progress toward the development of a scientifically sound biosafety infrastructure.
 

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* The terms GEO and transgenic used here closely follow traditional definitions such as those endorsed by the American Chemical Society and other scientific organizations. For example:

 Genetic engineering: (... "The formation of new combinations of heritable material by the isolation of nucleic acid molecules, produced by whatever means outside the cell, into any virus, bacterial bacterial plasmid or other vector system so as to allow their incorporation into a host organism in which they do not naturally occur, but in which they are capable of continued propagation." (P. 110. Quoting the 1978 Genetic Manipulation Regulations.)

 Transgenic animal: "An animal whose genetic composition has been altered to include selected genes from other animals or species by methods other than those used in traditional animal breeding." (p.238) [The use of ‘transgenic' to include hosts altered with artificial genes, or organelles, for example, is looser than this definition, but is unmistakably in the same spirit.]