The Recombinant DNA Controversy: T"\1/Enty Years Later

Paul Berg Maxine Singer

ebruary of this year was the 20th anniversary of parable bodies in other countries.4 the Asilomar Conference that considered the The primary motivation for the prompt actions taken Fpublic health implications of what was then a by scientists and governments in the period 1973-76 new genetic technology-recombinant DNA was to protect laboratory personnel, the general public, Paul Berg is the Looking back now, this unique conference marked the and the environment from any hazards that might be Cahill Professor in beginning of an exceptional era for science and for the directly generated by the expe1iments. In particular, Cancer Research public discussion of science policy--one that contin• there were speculations that normally innocuous mi• and Biochemistry ues unabated to this day. This year alone saw a scientist crobes could be changed into human pathogens by at Stanford tum back $614,000 in research grants as a measure of introducing genes that rendered them resistant to then• University Medical what he perceives as the possible misdirections of available antibiotics, or enabled them to produce dan• Center, Stanford, current molecular genetics, and a call, by religious gerous toxins, or transformed them into cancer causing California 94305, leaders representing 80 different faiths and denomina• agents. The uncertainties stimulated a sometimes turbu• and Maxine Singer tions, opposing "the patenting of genetically engi• lent debate. Public fear was fanned by the popularity of is president of the neered animals and human genes, cells, and organs." The Andromeda Strain, and the myriad "what ifs" Carnegie Institu• This 20th anniversary is then an important opportunity to floated by both serious and demagogic commentators. tion of Washing- reflect on the history ofthat occasion and its ramifications. Also plaguing the debate over the necessity for, or ton, 1530 P Street, What events led to the conference? Eight months adequacy of, the measures proposed to minimize imag• N. W., Washington, earlier, in July 1974, a call for a voluntary moratorium ined risks was the ignorance even in the scientific D.C. 20005. on certain scientific experiments using the emerging community about the properties of cells and viruses This article is recombinant DNA technology startled the worldwide containing foreign genes, including whether such cells reprinted with scientific community .1 This unprecedented action by a and viruses posed any risk at all. permission from group of American scientists echoed reservations ex• Some scientists, and public officials as well, were the Proceedings of pressed at a Gordon Conference on nucleic acids the certain that recombinant DNA research was flirting the National summer before.2 Both groups acknowledged that the with disaster and that lifting the moratorium was a Academy of new technology created extraordinary novel avenues blunder. Others, reflecting their intuition and expertise, Sciences U.S.A. for genetics and could ultimately provide exceptional argued that such cells, viruses, and recombinant DNAs 92: 1149-51. opportunities for medicine, agriculture, and industry. posed no risk at all. The ove1whelming assessment Nevertheless, the scientists were concerned that unfet• today is that the latter view was correct. Literally tered pursuit of this research might engender unfore• millions of experiments, many even inconceivable in seen and damaging consequences for human health 1975, have been carried out in the last twenty years and the Earth's ecosystems. In spite of widespread without incident. No documented hazard to public consternation among many scientists about the pro• health has been attributable to the applications of re• scriptions, the validity of the concerns, and the manner combinant DNA technology. Moreover, the concern of in which they were announced, the moratorium was some that moving DNA among species would breach universally observed. One goal of the moratorium was customary breeding baniers and have profound effects to provide time for a conference that would evaluate on natural evolutionary processes has substantially dis• the state of the new technology and the risks, if any, appeared as the science revealed that such exchanges associated with it. occur in nature. That conference, held at the Asilomar Conference The use of recombinant DNA technology now domi• Center on California's Monterey peninsula, included nates research in biology. It has altered both the way scientists from throughout the world, lawyers, mem• questions are formulated and the way solutions are bers of the press, and government officials. One aim of sought. The isolation ofgene s from any organism on our the meeting was to consider whether to lift the volun• planet, alive or dead, is now routine. Furthermore, the tary moratorium and, if so, under what conditions the construction of new variants of genes, chromosomes, research could proceed safely. Although there were and viruses is standard practice in research laboratories, few data on which to base a scientifically defensible as is the introduction of genes into microbes, plants, and judgment, the conference concluded, not without out• experimental animals. Equally profound is the influ• spoken opposition from some of its more notable ence it has had in many related fi elds. Even a brief look participants, that recombinant DNA research should at journals in such di verse fields as chemistry, evolu• proceed but under strict guidelines.3 Such guide• tionary biology, paleontology, anthropology, linguis• lines were subsequently promulgated by the Na• tics, psychology, medicine, plant science, and, surprisingly tional Institutes of Health (Bethesda, MD) and com- enough, forensics, information theory, and computer sci-

ence shows the pervasive influence of this new paradigm. were not as simple as was thought, and learning how to But the most profound consequence• of the recombi• manipulate genes for useful purposes presented unex• The primary nant DNA technology has been our increased knowl• pected difficulties. Since the mid-1980s, however, the edge of fundamental life processes. No longer is the number of products has increased continually. Hor• motivation for gene an abstract notion, nor is it as enigmatic as mones, vaccines, therapeutic agents, and diagnostic interstellar dark matter or black holes. Genes, and tools are enhancing medical practice. The production the prompt chromosomes of which they are a part, are describable and consumption of genetically engineered food plants in precise chemical terms. Even more significantly, are realities. A thriving biotechnology industry has genes can be synthesized in test tubes, manipulated, created products, interestingjobs, and wealth for scien• actions taken by and reintroduced into the cells of living organisms, tists and others. This intensive commercial activity and enabling us to link genes with specific physiological its intimate relation to science and research ha5 also scientists and functions. An even abbreviated enumeration of the modified the relations between universities and indus• extraordinary advances stemming from the recombi• try. Some see the changes as beneficial while others governments in nant and associated technologies is beyond the scope of worry about an undesirable blurring of the traditionally this commentary but a few brief examples can provide different roles of universities and for-profit corpora• the period 1973- a sense of the breadth of the research's implications. tions. There are reasons to think that these complex new (I) The ability to isolate genes readily and to deter• arrangements challenge our ability to maintain the mine their chemical structure unexpectedly revealed openness and trust that are an essential assumption of 7 6was to protect that genetic messages-the genes---of vertebrates, in• fundamental research. cluding humans, are filled with interruptions, a feature Frequently heard in the l 970s were criticisms of laboratory that is largely missing from genes of "simpler" organ• scientists for assuming leadership in formulating poli• isms. These interruptions must be edited out before the cies that were matters of public concern. This led some personnel, the genetic messages make sense, and because the editing scientists to believe that the public debate itself was a process can occur in a variety of ways, many genes great threat and that the fallout of claim and counter• encode multiple functions. Consequently, the amount claim would bring debilitating restrictions, or even general public, of genetic information contained in mammalian genomes prohibitions on molecular biological research. In truth, is considerably greater than previously thought. many scientists grew impatient with the time-consum• and the (2) Complex multicellular organisms develop from ing, contentious debates. Yet the effort to inform the seemingly simple beginnings, a single fertilized egg, public also encouraged responsible public discussion, environment by an orderly, genetically preordained process. The which succeeded in developing a consensus for the recombinant DNA and associated technologies allow measured approach that many scientists supported. from any hazards the identification of genes controlling the establish• Restrictive national legislation was avoided, and in the ment of the embryo's body plan and the subsequent long run, scientists benefited from their forthrightness elaboration of fully functional newborns. Furthermore, and prudent actions in the face of uncertainty. that might be whether recovered from worms, flies, mice, or hu• One of these benefits was the willingness of govern• mans, genes governing the formation of the skeleton, ment officials to adopt guidelines that were initially directly generated the brain, and central nervous system are closely re• strict-they included proscriptions of certain Jines of lated in structure and function. Remarkably, even research and required rigorous physical and biological by the genes in yeast cells and mammals are similar and can containment, but allowed for timely relaxation as knowl• replace one another functionally-although the last edge about the modified organisms accumulated. Con• common ancestor of these organisms was likely to sequently, after twenty years of research and risk experiments. have existed two billion years ago or more. a<;sessment, most recombinant DNA experiments are, (3) For a long time, the events controlling the cell today, unregulated. Such experiments are now even cycle, the transitions through which every cell passes part of the curriculum in good high schools. Members when it divides into two, were mysterious. Today, the of Congress, a former Secretary of State, and the cell cycle is understood as a progression of molecular President of the United States have all experienced the transformations, each rigorously controlled by genes excitement of recombinant DNA experiments. The and nutritional cues. Some signals drive the cells to fear of "Andromeda strains" has disappeared. multiply, while others act as brakes to proliferation. Just as the recombinant DNA techniques marked a Disturbances in this delicate balance lead either to cell paradigmatic shift in science, so could the approach to death or uncontrolled cellular multiplication. Remark• their regulation be more broadly adopted. For example, ably, progress in understanding the mechanisms regu• the regulation of environmental hazards is sometimes lating cell division has been synergistic with major imposed only after materials are identified as danger• advances in cancer research. Indeed, cancer is best ous through dramatic undesirable consequences. In understood as a genetic disease arising from inherited other instances, strict regulations are left in place even or acquired mutations in normal genes-mutations after a risk is known to be minimal. It would be more that impair the machinery controlling cell prolifera• effective, especially in the face of uncertainty, to pro• tion. Some 100 such "cancer genes" (oncogenes and vide guidelines that will undergo timely changes in tumor suppressor genes) have been identified, and the response to new scientific knowledge. characterization of these, as well as of others that are One felicitous outcome of the public debates on likely to be discovered, offers the best hope for ulti• recombinant DNA is the increased public interest in mately controlling cancer. biomedical research and molecular genetics. Genetics At the time of Asilomar, scientists optimistically and its vocabulary is evident in the daily press and predicted that the recombinant DNA methods would television news and a good deal of the reporting is of soon yield important products. In fact, such develop• high quality. On the positive side, widespread reporting ments took longer than anticipated. The experiments stimulates knowledgeable public discussion ofsome of

the social, political, and environmental issues that are, about molecules and biological organisms as well as Today, however, •and will be, emerging from genetic medicine and the the conflict between religious precepts and the moral use of genetically modified plants in ag1iculture. On the imperative to do all we can to improve mankind's lot concern 1s downside is the tendency of repo11ers, sometimes with and relieve human suffering. the aid of scientists, to overstate the findings or the Another widely expressed concern stems from the focused on the immediacy of applications to human problems. This growing ability to associate particular mutations or inclination is exacerbated hy the very competitive characteristic features in genes with disease manifesta• situation with respect to grants, and hy interests in tions or predispositions and the societal stresses, medi• ethical, legal, and commercialization. cal challenges, and personal anxieties expected to The public discussion of the implications of genetic accompany their disclosure. Protection of individuals environmental manipulations initiated by scientists twenty years ago against new fo1ms of discrimination (e.g., in employ• focused mainly on the novelty of the techniques them• ment opportunities and availability of adequate health issues raised by selves. Consequently, government agencies respon• and life insurance) will be needed to mitigate against sible for assuring the safety of foods, drugs, chemicals, these possibilities. In time, new therapies, now woe• and agricultural plants evaluated the products of re• fully lacking, will make the possihilities for early the rapid pace of combinant DNA methods with special c1iteria. While detection more attractive and desirable. some of these approaches have been changed, others But perhaps the most deeply felt concern is that genetic advances have not. For example, there are less stringent require• genetic research in general and the institution of broad ments for the use of plants that have been modified by based genetic testing will spur a malevolent renewal of and the increasing traditional breeding programs and thus likely to contain interest in eugenics. This view stems from the pre• unknown genetic changes than for those containing sumption that current attempts to perform gene therapy use of genetically precise, known genetic alterations introduced by re• by modifying the genetic constitution of somatic cells• combinant DNA methods. Widespread scientific illit• i .e., the nonreproductive cells of the body, a goal that eracy has perpetuated this scientifically indefensible most people find acceptable-will ultimately lead to modified animals legacy. Thus, while distinguished American chefs out• attempts to make alterations in human germ line genes• spokenly oppose genetically engineered foods, they i.e., those passed on to future generations via sperm and and plants. readily accept similar new products derived by less eggs. There are technical reasons for believing that the predictable but classical breeding methods. value of such modifications for humans is questionable An often-voiced criticism of the early recombinant and therefore unnecessary. lndeed, many scientists DNA discussions was the fai lure to consider the ethical agree that in the absence of any evidence of indisput• and legal implications of genetic engineering of planl~, able therapeutic utility and without absolute a~surance animals, and humans. This choice of agenda was due of complete safety, attempts at human germ line modi• neither to oversight nor unawareness, it was deliberate: fication should not even be considered. pai1ly because of lack of time at Asilomar and partly lnferring evil intent and calling for bans on genetic because it was premature to consider applications that research denies the value of such research in fulfilling were so speculative and certainly not imminent. In human dreams for improved health and the sustenance 1975, the principal and more urgent concern for those of a growing human population. Vigorous, informed gathered at Asilomar was the possible effects of recom• public debate on all these issues should be fostered, as binant DNA on public health and safety. it is by the ELSI (ethical, legal, and social implications) Today, however, concern is focused on the ethical, program of the Human Genome Project. The need for legal, and environmental issues raised by the rapid pace this debate is one reason to encourage widespread of genetic advances and the increasing use of geneti• improvement in science education in American cally modified animals and plants.5·6 Discussion of schools. these issues is confounded by the clash of some reli• In retrospect, very few of those attending the gious and philosophical beliefs with scientific goals Asilomar Conference foresaw the pervasive, com• and practical opportunities. For example, some geneti• plex, robust, and rich ramifications of recombinant cally engineered animals are essential research tools for DNA technology. Nor could most have predicted the the investigation of human disease while others pro• pace at which fundamental understanding of biology duce valuable therapeutic agents; similarly, some ge• has deepened. As with all changes in human thought netically modified plants are vital for research and and technological developments, we are left with others promise environmentally sound and economi• new and unanticipated issues. And, as so often in the cally attractive production of important materials. Yet past, science, which itself is a uniquely human en• a coalition of religious leaders now seeks to impede deavor, is challenging traditional ideas and values. these developments by proposing a ban on patenting of References human genes, cells, organs, and genetically modified I. Berg, P .• D. Baltimore, H.W. BoyerS.N. Cohen, R.W. Davis, D.S. organisms; their argument is that these are creations of Hogncss, D. Nathans, R. Roblin. J.D. Watson. S. Weissman. and God and not inventions of humans. But scientists who N.D. Z inder. 1974. PolentiaJ biohazards of recombinant DNA molecules. Science 185:303. synthesize genes by chemical techniques in their laho• 2. Singer, M. and D. Soll. Letter from the members of the Gordon ratories and recognize the near identity of genes be• Conference to the presidents of the National Academy of Sciences tween humans and other mammals, do not think of and the Institute of Medicine. 197:l. Science 181:1 114. 3. Berg, P., D. Baltimore, S. Brenner. R.O. Rohlin. and M.F. Singer. human DNA molecules as holy. Moreover, reaping the Asilomar conference on recombinant DNA molecules. 1975. Sci• benefits of the new technologies requires commercial ence 188:991-994. 4. NIH Guide lines for Research Involving Recombinant DNA Mol• sector participation and that commitment may not ecules. June 1976. Federal Register41:2791 I. occur without the protection of financial investments 5. Mathews, J. Ready for the genome. Washinfi(on Post, Nov. 6. J 994, that patents provide. We shall, therefore, have to re• p. C -7. 6. Kolata, G. Ethicists wary over new gene technique'sc(mscquences. solve the conflict between religious and scientific views The New York Times, Nov. 22, 1994, p. C- 10.

"1"134 B10/fECHNOLOGY VOL. 13 OCTOBER 1995