SCIENCE
Environmental, Policy Issues Still Plague Biotechnology Research AAAS symposium aired views of ecologists to government officials, but no genetic engineers participated, and little agreement was reached Rudy M. Baum, C&EN San Francisco
Biotechnology continues to spark spirited discussions about its potential risks, its proper application, and how it should be regulated. Many of the current environmental and public policy issues surrounding biotechnology were examined at a symposium at the recent American Association for the Advancement of Science annual meeting in Los Angeles. A number of points of view were aired at the symposium. Speakers included several ecologists, two government officials, the president of a biotechnology firm, and the director of a public interest group. Curiously, however, no one actually involved in genetic engineering research participated. The lack of such participation left something of a gap, particularly during the sessions focusing on concerns of ecologists about the environmental effects of organisms containing recombinant DNA. The consensus from those sessions was that scientists involved in the genetic manipulation of crop plants and microorganisms for use outside the laboratory are not generally well versed in ecological principles and are not adequately considering the potential environmental risks of releasing their creations. Another consensus, however, was that, despite significant improvements in the methodology of ecology over the past decade, the science
Risch: arguments inconsistent is not yet able to offer specific predictions about the environmental fate of a given organism. Frances E. Sharpies, an ecologist at Oak Ridge National Laboratory, Oak Ridge, Tenn., compared the environmental fate of introduced species and genetically engineered organisms. Although much information exists on the introduction of exotic species into new environments, Sharpies says, it still is not possible to predict the ultimate outcome of a specific release. Nevertheless, Sharpies maintains that ecological models based on exotic species are valid for assessing the risks of releasing genetically engineered organisms. Sharpies addressed a number of objections that have been raised against the validity of such models. For instance, one argument is that an organism containing one or two new genes is not the ecological equivalent of an organism such as an exotic that is completely new to an environment. "The presump-
tion," Sharpies says, "is that one or two genes are not that important." That presumption simply isn't true, she maintains, because it is not the number of genes but their function that is important. A single gene for antibiotic resistance can have a significant effect on the environmental fate of an organism. Another such argument is that no natural controls exist for exotic species. By contrast, this argument goes, a species chosen for genetic engineering will be returned to its natural environment with new traits and will be subject to natural controls. However, Sharpies points out, many of the traits of interest to biotechnology, such as salt or frost tolerance or resistance to pesticides in plants, are not minor from an ecological point of view. Manipulating them, in fact, is an effort to circumvent natural controls. Additionally, she says, many recombinant organisms will be used in highly disturbed environments, which is where natural controls are least likely to be intact. Stephen J. Risch addressed a number of the same points. Risch, an assistant professor in the division of biological control at the University of California, Berkeley, says that some of the most often cited arguments for the safety of release of genetically modified organisms are highly inconsistent. For instance, he says, one argument is that the genetic modifications are so minor that the organisms will be harmless. On the other hand, the view is that modified organisms will be so abnormal as to be unable to survive under most conditions. Or, to take another example, one view holds that nature is so well balanced that genetically modified species will be eliminated. And yet another argument is that nature is June 17, 1985 C&EN
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Science so unbalanced that any damage caused by genetically engineered organisms will be insignifcant. Risch pointed out that genetically engineered crop plants are often cited as examples of modified organisms with almost no potential for environmental damage. However, the difference between a weed species and a crop species often is not biologically significant, Risch says. Many weeds are closely related to crops, and in many cases, what is a weed in one place is a crop in another. Therefore, the potential for exchange of genetic material between crops and weeds exists. For example, an introduced trait such as herbicide resistance could wind up being transferred from a crop to a weed making the weed that much more difficult to control. Such factors should be taken into consideration when assessing the risk of putting an altered crop into the environment, Risch says, and often they are not. Sharpies and Risch believe that ecologists should be involved from the inception of genetic engineering projects, not brought in at the end to attempt to assess risk. "Ecologists should be recognized as an integral part of the developmental process with knowledge that goes beyond simple risk assessment," Sharpies says. Such knowledge can be applied to the design of organisms that do what they are sup-
Robbins: new regulations needed were dedicated largely to mechanisms to regulate biotechnology while still promoting its growth and maintaining the lead that U.S. biotechnology firms have over foreign competitors. After a review of the types of risk posed by different aspects of genetic engineering, Bernadine Healy, deputy director of the Office of Science & Technology Policy, concluded that appropriate regulation must be decided on a caseby-case basis. That conclusion p r e t t y m u c h dovetails with the conclusions of the ecologists. Where Healy and the
Ecologists should be recognized as an integral part of the developmental process with knowledge that goes beyond simple risk assessment posed to do under real-world conditions, the two researchers maintain. In truth, it seems the ecologists are feeling a bit left out of the new biology. They believe that they have important contributions to make, but that their discipline is losing out in the scramble for research funds to the more glamorous biological disciplines encompassed by biotechnology. Other sessions of the symposium 34
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ecologists seem to part company, however, is in her contention that assessing the risks associated with genetically e n g i n e e r e d microorganisms and plants is relatively straightforward. The major concern expressed by Healy is maintenance of the U.S. competitive advantage in biotechnology. That leadership could be harmed by overregulation, she says. In sharp contrast to Healy's sanguine view, Anthony Robbins, a
staff member of the House Committee on Energy & Commerce, delivered a stinging attack on the biotechnology industry. The lure of profits can distort safety considerations, Robbins says, and although industry maintains that government should regulate biotechnology on the basis of regulations drafted before development of the science, that just is not realistic. New regulations are needed, Robbins says, and he calls on environmental activists to press Congress for those regulations. Robbins also argues that a technology developed largely with public funds has been turned over to an industry that will not now develop useful products if the perception is that the profit associated with a given product is low. Robbins cited vaccines as examples of such products that are not being developed. Another example, he says, is products that mainly benefit countries "without the hard currency to pay for them." "Congress needs a constituency to speak for the people-oriented goals of biotechnology," Robbins told the symposium. George B. Rathmann, president of Amgen, a biotechnology firm in Thousand Oaks, Calif., took issue with Robbins' suspicion of "those with a profit motive in mind." Biotechnology, Rathmann says, holds the promise to solve many of the world's problems in health care, agriculture, and energy. Unnecessary regulatory barriers to addressing those problems should be removed, he says. "It is the belief of virtually every scientist and businessman associated with this field and many of the government's scientists and policy makers that policies should address successful applications of biotechnology rather than focus exclusively on assessing low-probability risks," Rathmann says. Domestic policies should address how the U.S. can maintain its leadership position in the field. In other words, men and women of good will still disagree on appropriate policies toward biotechnology. Throughout the symposium, one wondered: Where are the scientists responsible for this brouhaha? D
Researchers custom-design proteins Researchers using a variety of tech niques to tinker with protein struc ture are beginning to make prog ress toward designing proteins with specific new properties, according to speakers at the AAAS annual meeting. Although the researchers caution that they are still a long way from their ultimate goal of de signing proteins with, for instance, a given catalytic activity, their ef forts suggest that that goal is attain able. Many such researchers work at the level of the gene encoding a natural protein. Using recombinant DNA techniques, they change the nucleotide sequence of the gene and hence the amino acid sequence of the protein it encodes. Another ap proach, says Bruce W. Erickson, is "to apply organic chemistry to mak ing new proteins from scratch." Erickson, a biochemistry profes sor at Rockefeller University, New York City, says there are two ad vantages to the organic chemistry approach: It is not limited to natu ral amino acids, and it allows syn thesis of protein structures that do not occur naturally. Erickson and coworkers at Rocke feller University and at Duke Uni versity, Durham, N.C., have de signed a new family of small pro teins they call betabellins, a name derived from beta-barrel bell-shaped
Erickson: organic chemistry route
proteins. The proteins consist of two identical /3-pleated sheets that are linked together at one end. The two sheets form a barrel that is closed at one end by the linking amino acid, hence the bell shape. The researchers use a continuousflow synthesis apparatus to construct two identical amino acid chains si multaneously. The antiparallel type /3-sheets are achieved by alternat ing hydrophobic and hydrophilic amino acids. Each sheet consists of 31 amino acids arranged in four strands with tight turns between each strand. Because the betabellins are syn thesized from scratch, the research ers can introduce amino acids at will to alter the structure of the proteins and facilitate their charac terization. For instance, the most successful betabellin to date, Erick son says, contains a cysteine resi due in each sheet; a disulfide bridge forms spontaneously between the two sheets and stabilizes the bar rel shape. In future molecules, the research ers plan to alter the hydrophobicity of the inner sheet faces and replace the L-proline and L-asparagine resi dues that form the turns between each strand with their D-isomers. Erickson points out that such a re placement would be impossible using genetic engineering tech niques. The open end of the barrel in the betabellins is the target for intro duction of selective binding affini ty or catalytic activity. Instead of attempting to synthesize a single protein with the desired activity, the researchers plan to use what Erickson calls parallel combinatory synthesis of a mixture of betabel lins. The strategy then will be to isolate the betabellin that exhibits activity. John H. Richards, chemistry pro fessor at California Institute of Tech nology, pursues protein engineer ing using recombinant DNA tech niques. Richards points out that one can follow two approaches. One ap proach is to change a gene to create a specific change in the protein of interest. Alternatively, one can cre ate a large number of mutants of a
Richards: recombinant techniques given gene and search the resulting mutant proteins for altered func tion. This latter approach is particu larly useful, Richards explains, "be cause we do not know enough to predict accurately what function will follow from a given structural change." Richards and his coworkers have pursued both routes in their studies of β-lactamase, the protein respon sible for bacterial resistance to pen icillin and cyclosporin. They have focused on the residues that flank the catalytic serine at position 70 in jS-lactamase. Richards points out that most tech niques of random mutagenesis cause base changes such that the original amino acid in a protein will be replaced by one of four to seven new amino acids. To explore the effect of all 20 amino acids at a given site in a protein, the researchers use syn thetic oligonucleotides containing the appropriate combination of bas es to encode the desired amino acid change or changes. The synthetic DNA is inserted between two re striction sites in the gene. In their work with /^-lactamase, the researchers have found that a large number of mutant proteins possess some catalytic activity. Of particular interest is a protein con taining two amino acid changes that, compared to the wild type, appears to confer increased resistance to the antibiotic cephalothin. π June 17, 1985 C&EN
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