Reconsidering Asilomar

Paul Berg Regulating biotechnological discoveries hasn't gotten any easier since scientists and policymakers faced their first major challenge 25 years ago. In 1973, recombinant DNA technology burst onto the scene.1 The response was remarkably swift. A group of scientists led by Paul Berg, now director of the Beckman Center for Molecular and Genetic Research at the Stanford University School of Medicine, called for an international moratorium on recombinant DNA research, fearing that the technology could be dangerous if handled improperly.2 In February 1975, an elite group of scientists, policymakers, and journalists assembled for the now-famous Asilomar meeting in Pacific Grove, Calif., to discuss what they knew and didn't know about the technology and to draw up guidelines that they hoped would let the science proceed without undue risk. Although contentious and grueling, the meeting and its resulting guidelines were generally regarded as a success, though recombinant DNA technology turned out to be much more harmless than many had suspected. Nevertheless, Asilomar remains an important scientific landmark, a rare if not unique instance of scientists independently questioning and successfully regulating their own cutting-edge work. In February of this year, bioethicists, scientists, lawyers, and journalists came together to mark the 25th anniversary of the original Asilomar at the original site; they assessed the meeting's significance and asked how the generally successful "Asilomar model" might apply to current pressing biotechnology issues such as gene therapy and genetically modified organisms. Alexander Capron What worked in 1975 that's not working today? Might a glimpse into a past success provide answers for concerns with today's biotechnology, which the discovery of recombinant DNA and Asilomar both helped to promote? The general consensus: not likely. Alexander Capron, the conference organizer and an attendee at the original conference, cites two major reasons: a more informed public that demands to be involved, and the increasing encroachment of entrepreneurial and corporate sponsorship into the scientific enterprise. Scientists' widespread allegiances to biotechnology companies creates ample conflict of interest, and convening a completely unbiased group of scientists to objectively assess a technology would be nearly impossible today. Capron offers one scenario: A scientist with commercial ties calls for a moratorium on a particular type of research; observers respond critically, suspecting that he did so to let his own company "catch up" with its competitors. "The whole subject of conflict of interest is one that's worth reviewing and coming to terms with," admits Michael Werner of the bioethics council of the Biotechnology Industry Organization (BIO), an attendee of the recent Asilomar meeting. "It's something that our industry is going to be looking at and trying to develop some thoughts on over the next several weeks or months." RAC Regulation Commercial interests have, indeed, tainted the activities of Asilomar's closest descendant, the Recombinant DNA Advisory Committee (RAC), which continues to have problems overseeing increasingly controversial gene therapy experiments. At the recent Asilomar conference, California Institute of Technology president David Baltimore declared that the field of gene therapy has moved too quickly; Salk Institute gene therapy researcher Inder Verma agreed. Some even suggested that part of the reason companies have clung to ineffective gene therapy vectors has to do with the considerable amount of money invested. At the RAC's most recent meeting--held on March 8, 9, and 10--topics of discussion included the safety and toxicity of adenoviral vectors, a review of new safety protocols, and the review of a proposal for a temporary moratorium on some gene therapy protocols involving viral vectors--an indirect response to the recent highly publicized gene therapy death at the University of Pennsylvania.3 RAC members chose not to endorse the proposed moratorium. "History is filled with examples of scientific and medical discoveries that took years, if not decades, to perfect," said Werner in his testimony to the commission. But RAC has no real power to enforce regulations, causing some to question its usefulness. The National Institutes of Health formed the committee to enforce the recombinant DNA guidelines that grew out of Asilomar. As scientists found that the technology was relatively harmless, the commission lost importance. To make better use of RAC, the NIH put gene therapy experiments under the commission's purview--gene therapy researchers were, after all, using recombinant DNA technology, only in people. Former NIH director Harold Varmus soon realized, however, that RAC had no teeth and was therefore of little influence. He considered eliminating the body, but many wanted it to remain in place to monitor gene therapy. RAC's remaining intact has both complicated and clarified the issues. Because it's a public body, all information released to RAC is in the public domain. Investigators doing clinical trials may actually consider an adverse reaction during a clinical trial to be proprietary information and may therefore choose to not inform RAC to prevent competitors from acquiring it. Only the Food and Drug Administration, whose holdings are confidential, must have all trial information. The incident has helped encourage a revamping of an often cumbersome RAC-FDA interplay. At the March RAC meeting, Werner proposed a new BIO- sponsored system for reporting adverse events to the FDA and the NIH; RAC would remain an advisory and educational body. Attempts at improving gene therapy oversight do, however, continue: On March 7, the NIH and FDA announced two new safeguards for gene therapy trial participants: a clinical trial monitoring plan that requires sponsors of gene therapy trials to submit their monitoring plans to the FDA, and a series of gene transfer safety symposia intended to enhance patient safety by providing an additional forum for sharing data from gene transfer research. Maxine Singer Rushing to Market Commercial interests may have likewise had an adverse effect on the regulation and acceptance of genetically modified (GM) foods, a topic discussed at the recent Asilomar meeting. By cutting corners to get their products to market as quickly as possible, companies may have set themselves up for the recent backlash. "They weren't thoughtful," comments Maxine Singer, an organizer of the original conference, referring to GM food companies. "And they didn't pay attention up front to the kinds of concerns people might have." Singer, current president of the Carnegie Institution of Washington, D.C., suggests that companies' poor decision making has set back GM foods, which she believes to be harmless, at least a decade. "Scientists are not very experienced or adept at dealing with some of these issues," says Singer, referring to the impact of commercial interests on science decisions. "They tend not to do some of the self-examination they should be doing with respect to their interests and their biases." Companies certainly haven't been the only bodies accused of poor regulation. Institutional review boards (IRBs), crucial regulating bodies used in both academia and industry, have been called too lax and undiscriminating. A 1998 report from Health and Human Services deputy inspector general for evaluation and inspections George Grob called for widespread IRB reform. It said that the panels, which are both independent and in companies, universities, and hospitals all over the country, don't follow up on research that's been approved, review too quickly and with little expertise, have a tough time handling an increased workload, and spend little time on self-evaluation.4 One big reason for all of these flaws, according to the report: In the last 20 years, rising costs at academic health centers and hospitals have made corporate sponsorship much more attractive. "IRBs feel pressure to accommodate these sponsors who are looking for quick turnaround of their research and for whom time is money," Grob stated. The report called for better federal oversight of IRBs, better protections for research subjects, and better training for research investigators and IRB members. According to Grob, though there has been something of a crackdown on lackluster IRB efforts in the two years since the report, much remains to be done. Public Demands Commercial interests and regulatory failings aside, Asilomar, according to Singer, arose at a unique time and out of a unique set of circumstances. Today, issues such as gene therapy and GM foods are firmly anchored in the public consciousness. People in the 21st century, suggests Singer, are much more skeptical about scientific developments. While there are plenty of meetings and workshops on biotechnology, it's unlikely that such nonlawmaking bodies could ever come up with research guidelines that the entire scientific community would respect, as was the case with Asilomar. "Today, you have these hardened, entrenched views," remarks Berg, referring to the array of political forces and lobbying groups. Few people, he says, knew anything about recombinant DNA when the technology was first developed; there weren't vastly differing opinions. However, elements of the "Asilomar model" may yet be revived. David Magnus, an attendee of the recent Asilomar meeting and director of graduate studies at Penn's Center for Bioethics, and his colleagues are trying to spearhead an effort to bring together scientists from industry and academia to regularly discuss selected controversial topics, draw up guidelines, and possibly even offer some do's and don'ts. They might, for example, identify allergens that should be excluded from processed food. He cites as a possible model a recent bioethicist-scientist collaboration on research from The Institute for Genomic Research (TIGR) in Rockville, Md. TIGR scientists published a paper in Science on preliminary findings related to creating the minimal genome required for life; a panel of bioethicists from Penn and Stanford University accompanied the paper with their own paper on potential bioethical problems with "creating life."5 But it remains to be seen whether any independent group of experts could convince today's scientists to listen and comply. For better or worse, the idealism of Asilomar is likely a thing of the past. Eugene Russo can be contacted at erusso@the-scientist.com. References 1. S.N. Cohen et al., "Construction of biologically functional bacterial plasmids in-vitro," Proceedings of the National Academy of Sciences, 70:3240-4, 1973. 2. P. Berg et al., "Potential biohazards of recombinant DNA molecules," Science, 185:303, 1974. 3. Nadia S. Halim, "Gene therapy institute faces uphill battle," The Scientist 14[3]:1, Feb. 7, 2000. 4. hhs.gov/progorg/oig/testimony/irb/irbtest.pdf 5. E. Russo, "Minimalizing the genome," The Scientist, 14[1]:12, Jan. 10, 2000.

Reconsidering Asilomar

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