Safety standards for the environmental release of genetically engineered organisms

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Consi&erufions (1986) Organization for Economic Development and Cooperation, Paris 4 Biotechnology Risk Assessment (1987) Available from CEFIC. 250 Avenue

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engineered Organisms into the Environment: Key Issues (1987) Council

Louise, Bte 71, B-1050, Brussels, Belgium 5 Heusler, K. (1986) Proceedings ofthe British Crop Protection Conference (Vol. 21, pp. 677-682, BCPC Publications 6 Introduction

of the National Academy of Sciences, National Academy Press, Washington 1 Yoxon, E. (1987) Trends Biotechnol. 5, 160-163

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SAFETY STANDARDS FOR THE ENVIRONMENTAL RELEASE OF GENETICALLY ENGINEERED ORGANISMS SIMON A. LEVIN The considerable debate that has been associated with proposals to introduce genetically engineered organisms into the environment obscures the fact that among most scientists there is strong basis for consensus concerning risks. Where disagreements exist, they are concerned less with what the historical record says than with which part of it is most relevant to introductions of organisms developed with the new genetic techniques (Ref. 1, and see Regal, this issue). It is generally acknowledged that the overwhelming majority of introductions is likely to be benign, but that some will be problematic; nonetheless, the question can still be posed as to whether extrapolations should be based upon the average case, which will be low in risk, or upon the extreme high risk cases, which will be low in probability. Fortunately, such a simplistic question need not be answered, since it presupposes an artificial dichotomy. Most informed discussion recognizes that biotechnology holds tremendous potential for improving the human condition, including environmental applications that offer significant opportunities to reduce the pollutant load associated with the use of chemicals. There is general agreement that most introductions will pose minimal environmental risk, and that thus there is no basis for generic arguments against the introduction of genetically modified organisms. On the other hand, there is no question that certain types of possible introductions pose a non-negligible degree of risk: thus, generic safety arguments must equally be rejected (see Simonsen and Levin, this issue). Certainly, new genetic technologies will allow the creation of genotypes that never before have appeared, and the introduction of genotypes into environments that are new for them. Thus. each Simon A. Levin IS at the Sewon of Ecology and Systematics and the Center for Environmental Research, 347 Corson Hall, Cornell University, Ithaca, NY 14853. USA.

The use of genetically engineered organisms holds considerable promise for environmental management and other purposes,provided wopriate safety standards are established and observed. The problem with much of the debate concerning deliberate releases has been the difficulty in getting down to specifics.Examples can be advanced that give causefor concern,or that demonstrate that introductions can be carried out safely; but none of these has the generality to apply to alf cases,Generic arguments for and againstthe safety of introductions must be rejected, and replaced by consideratjon of the properties of individual introductions. It is the properties of the introduced organism in relation to the environment that must renot the ceive attention, method by which the genetic modification was achieved. One must go beyond discussions that lump all possibleapplications together, and develop criteria that associateindividual cases with the risk categoriesmost appropriate to them. potential introduction must be evaluated on its own merits. The inescapable conclusion is that some consideration is needed of the risks associated with the deliberate introduction of organisms, and furthermore that evaluation of risks must be specific to the particular application. This conclusion is universal in applicability. It is independent of whether or not one feels that existing legislation and procedures are adequate - an issue that requires different considerations for different nations. Why is there debate?

Given

such

strong

elements

of

agreement regarding the basic issues, why has consensus been so long in developing? One reason, already suggested above, has been the inclination on all sides to generalize from special cases, and the fact that the special cases of choice are not the same for Some refer to the long everyone. history of safe introductions associated with breeding in agriculture; others point to the problems that have been associated with the deliberate and accidental introductions of exotics. The relevance of these particular referents will be discussed below; but the differences of opinion and perspective point again to the necessity to get down to the specifics of individual cases and classes of and to avoid broad introductions, generalizations. A second and related reason for the debate reflects a difference in points of view. Some argue that the risks associated with the products of biotechnology are no different in kind from those associated with conventional procedures, and that therefore no special attention is merited. Many who argue to the contrary accept the basic premise that there are no qualitative differences in risk, but emphasize the fact that there are risks in any introduction. They argue either for stricter controls on all introductions, or that lax procedures regarding other types of introductions do not justify extending this laxity to an even broader class of introductionsz. A third reason that consensus has not been immediate is a specious philosophical dichotomy concerning who bears the burden of proof. Environmentalists point to the problems that often attend new technologies, and argue that when new technologies are proposed, the burden of proof regarding safety should rest upon the proposer’s”. On the other hand, proponents of biotechnology argue that the discussion of problems is introductions with deliberate hypothetical, dealing with the possible rather than the probable. They argue

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that there have been no examples of environmental problems associated with any introductions of recombinant DNA organisms; indeed, only a handful of introductions have been carried out. Therefore. they conclude, the democratic process requires an assumption of innocence rather than &wilt, and the burden of proof should rest upon those who construct unlikely scenarios for disaster. Both of these lines of argument mislead. The fact is that we are not dealing with a new technolo&T when we are dealing with the introduction of modified organisms into the environment. Humans have modified organisms genetically for centuries by a variety of techniques. and the repertoire of available tools has evolved and grown continually. Recombinant DNA methods are the latest in the continuum of techniques, but do not represent anything inherently different from other advances that have occurred, except an ever-increased ability to carry out modifications efficiently and precisely. To the extent that increased efficiency leads ultimately to a change in the scale or frequency of introductions. that is worth consideration in terms of cumulative risks: indeed, it is the possible quantum increase in patterns of use that has been the major COIItern of many who have advocated caution. However, for any individual introduction, the characteristics of the engineered organism and its recipient environment, not the method by which the organism was moditied, should be the basis for risk assessment”. Thus, the appropriate line of argument, and one that leads much more rapidly to consensus. is as follows. We have sufficient understanding of the roles of genetics and environment in controlling the expressed phenotypic properties of an organism to allow us to state that it is not the method of modification that matters; what is relevant is the product, and how it will be used. Therrfore, as the recent US National Academy of Sciences” report con eludes: ‘The risks associated with the introduction of R-DNA-engineered organisms are the same in kind as those associated with the introduction into the environment of unmodified organisms and organisms modified bl other genetic techniques’. This is not to argue that those risks should be ignored, but simplv that the considerations are no different in kind than those that apply for other kinds ot introductions. Thus, we are not operating in an information vacuum; we have a large body of experience on which to draw for assessing risks.

Although there is a growing recognition that it is more appropriate to focus on the product and patterns of use rather than on the method of production (see Yang, this issue), and that this should be the most important principle underlying regulatory procedures, current practice in the United States and other countries has not completely adjusted. Recently, for example, the National Institutes of Heaith concluded that a researcher at Montana State University, Gary Strobe], had not violated their guidelines when he introduced a genetically modified bacterium into the environment as part of an effort to combat Dutch elm disease. The explanation was that the introduced organism, a non-pathogenic Pseudomonas syringae, was the product of mating a second organism, which was recombinant DNA-modified, with a Pseudomonas bacterium that was not. Technically, the end product, it was adjudged, was not recombinant. This legal legerdemain is the inescapable consequence of having decisions made by a committee, the Recombinant Advisory Committee (RAC), whose very title is based on method rather than product. The irony of the whole situation is that Strobel’s introduction of a known pathogen, the Dutch elm fungus, as part of the experiment, attracted virtually no attention because the fungus was not genetically engineered. Although Strobe1 took precautions to prevent the spread of the fungus, its introduction undoubtedly posed a greater hazard than did the introduction of the bacterium that was designed to control it, and a rational regulatory system should recognize that. What are the concerns, and their relevance to risk assessment? introduced

alien species

One of the most compelling concerns for ecologists has emerged from their awareness of the problems that sometimes have attended the deliberate or accidental introduction of species taken from other environments. Charles Elton, in his classic text on biological invasions”, was the first to bring focus to this problem. Increasingly, in a growing number of environments, invasions are being recognized as serious threats to the preservation of what we choose (by our choice of time scale) to regard as native fauna and flora (Ref. 7, and see Williamson, this issue). Although the great majority of accidental introductions undoubtedly fail to become established (the exact statistics are impossible to determine, since we generally do not know about failed

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introductions), a substantial number do become established, and some of these become serious pests. Examples are legion, yet the relevance of these examples to most cases of introduction of genetically modified organisms has been severely challenged, because the transfer of a species from one environment to another, lacking its coevolved biotic controls, involves fundamentally different considerations than does the reintroduction of a slightly modified species into the environment from which it was taken. Most introductions currently under consideration fall into the category of reintroductions; but certainly there will be introductions proposed that involve alien species, or that involve engineering to expand the range of some desirable species, such as popular sport fish. To address this, Levin and Harwell:’ introduced four categories of introductions, and argued that separate considerations must apply to each. Some, and probably most, introductions will be reintroductions of native species: for such introductions, the alien species model is not a very good one, and conventional experience in agriculture provides a much more appropriate basis for extrapolation. The other two major categories involve non-native species that are not found in the target environment because either (1) they cannot survive there without continual supplement, or (2) they can survive there, but never before have been introduced. It is the latter category that encompasses the destructive exam ples mentioned earlier, and presents the greatest cause for concern. The final category mentioned by Levin and Harwell is a catchall for the remaining cases, namely those that would be sufficiently novel to have no &se analogues in any environment. For these cases, no good basis for extrapolation exists. Pathogenic

microorganisms

It is well-recognized that small genetic changes in pathogenic species can convert non-virulent types into virulent ones, or can permit expansions of host range. Such small genetic changes underlie the outbreaks of new strains of human disease such as influenza, or of fungal pathogens such as the black stem rust of wheat. engineering of pathogenic Thus, organisms must be carried out with the utmost precaution, and with proper attention to safety. Similarly, if one non-pathogenic were engineering organisms with the intention of altering properties related to pathogenicity , similar care would be mandatory.

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However, if non-pathogenic organisms are being altered with respect to properties unrelated to pathogenicity or invasibility, the likelihood of accidentally producing a pathogenic organism is negligible; pathogenicity involves not one, but a complicated suite of characters5. Much of the confusion on this point centers around the definition of pathogen. To a pathologist, a non-virulent strain of a pathogen is still a pathogen, and should be handled with appropriate care. However, a single bacterial species, such as E. coli or Pseudomonas syringae, may contain both pathogenic and non-pathogenic strains that, despite their common taxonomic identification, are genetically very different , and not interconvertible. The complexities of this issue and the subtleties and inadequacies of bacterial systematics have made it dficult to clarify the regulatory issues, and current practice is not yet totally satisfactory. Weediness

Introduced weedy plants, such as Melaleuca or Hydrilla in the United States, are a familiar problem. However, weediness is highly unlikely to arise by accident when plants are being engineered for unrelated characteristics. A more substantial concern involves the possible exchange of genetic material between the domesticated targets of genetic engineering and their wild and weedy relatives. To evaluate this risk, one requires a detailed understanding of the ecological relationships in the particular environment. In the United States, for example, the potential for such exchange would be negligible for most row crops, although sorghum provides a striking counter-example. However, for forage grasses in the United States, the potential for introgression between wild and domesticated species varies widely8. In South America the situation would be far more problematic for row crops: there is considerable exchange and introgression between domesticated crop species and wild and weedy relatives . Properties such as herbicide resistance, if introduced into crop species (see Gaertner and Kim, this issue), could well find their way into weedy populations if they impart a fitness advantage to the bearer. Such transfer could exacerbate chemical pollution problems if it led to the need to apply new herbicides to the weedy populations. It should be said that this is not a problem that has anything to do with the method of genetic engineering per se; once again, it is the

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and in assuring that appropriate safeguards are in place. The possibilities are enormous for partnerships among genetic engineers, ecologists, microbiologists and agricultural scientists, not only in risk assessment, but also in the use of genetic engineering as a tool for ecological and evolutionary research, and in environmental management. Such cooperation is long overdue, and can assure both that Horizontal transfer Sexual exchange of material be- innovations are not prevented by tween domesticated plants and weedy over-regulation, and that legitimate relatives is but one of a variety of concerns are not submerged by overmechanisms of exchange known to enthusiasm. occur among species. Bacterial populations, which usually do not exchange chromosomal DNAg, can exchange mobile genetic elements Acknowledgments freely among species, and this has This publication is ERC- I59 of the Ecosystems been important in the evolution of Research Center, and was supported in part by pathogenic trait@. The most familiar the US Environmental Protection Agency, example of such exchange involves Cooperative Agreement CR8 I2685 with Corthe wide proliferation of antibiotic re- nell University. Additional support was provided by National Science Foundation grant DMSsistance among distinct bacterial 8406472 to the author. The work and concluspecieslo. Such transfer and spread is sions published herein represent the views of facilitated when there is selective the author and do not necessarily represent the pressure favoring it (see Miller, this opinions, policies, or recommendations of the issue), for example when the traits funding agencies. Thanks are extended to Clifford Gabriel for valuable comments on an earlier borne on plasmids impart a selective version of this paper, and Arthur Kelman for advantage in polluted environments; always illuminating discussions and for calling my thus the possibility for such spread attention to the Thompson paper. must be given serious consideration when the environmental conditions are likely to favor the spread of the References engineered trait. Although the fre- I Colwell,R.K. in Risk Analysis Approachesfor quency of horizontal exchange in na- Environmental Releases of Genetically ture is not established, such exchange Engineered Organisms (NATOAdvanced is unlikely to be an important consid- Science Institute Series, Vol. 1) (Fiskel, J. and eration in the absence of selective Covelo, V.T., eds.), Springer-Verlag(ii press) 2 Thompson, P.B. (1987)NationalCenter for advantage favoring spread.

properties of the introduced organism that are important, not how those properties were achieved. For any introduction of plants, whether of genetically modified or other organisms, what is needed is better information on the potential for exchange with wild and weedy relatives (see Ellstrand, this issue).

Conclusion

Ecological communities are dynamic assemblages, neither closed to invasion nor robust in the face of all perturbations. The relevant concerns of ecologists regarding the introduction of genetically engineered organisms into ecological communities are the same as would apply to organisms modified by any technique, or to unmodified organisms. Increasing our ability to anticipate which introductions will be successful, and which will lead to undesirable secondary effects, is needed both for risk assessment and for developing better products. The recent report by the US National Academy of Sciences5 recognized explicitly ‘that the establishment of many species . . . is unpredictable, and depends on the confluence of such factors as favorable weather, favorable sites, and suitable vectors or other means of transport’. The expertise of ecologists and agricultural scientists will be fundamental in reducing the unpredictability associated with introductions,

Food and AgriculturalPolicy DiscussionPaper No. FAP87-01 3 Levin, S.A. and Harwell, M.A. (1986)in Biotechnoloa: Implicationsfor Public Policy (Panem, S., ed.), pp. 56-72, Brookings Institution 4 Levin, S.A. (1986)in Proceedings of 1986 Washington International Conference on Bioiechnology (Russell, M.J., ed.), pp. 231-

244, Center for Energy and Environmental Management 5 Introduction of Recombinant DNAEngineered Organisms into the Environment: Key Isues, (1987) NationalAcademyof

Sciences Elton, C.S. (1958)The Ecology oflnvasions byAnimals and Plunts, Methuen 7 Mooney, H.A. and Drake, J.A., eds (1986)

b

Ecology of Biological Invasions of North America and Hawaii, Springer-Verlag 8 Mack, R.N. in Biological Invasions: A Global Perspective (Drake, J., di Castri, F., Groves, R., Kruger, F., Mooney, H. et al. eds),

J. Wiley (in press) 9 Selander, R.K., Caugant, D.A. and Whittam, T.S. (1987)in Escherichiacoliand Salmonella typhimurium: Cellular and Molecular Biology (Neidhardt, F.C., Ingraham,J.L., Low, K.B., Magasanik,B. . Schaechter, M. and Umbarger, H.E., eds), pp. 1625-1648, AmericanSociety for Microbiology IOLevy, S.B. (1982)Lanceti, 83-88