The Controversy over the Regulation of Recombinant DNA Research, 1975-1981

During his tenure as director of NIH, Donald Fredrickson found himself at the center of a controversy over the most far-reaching advance in molecular biology up to that time: the development of recombinant DNA technology. By the early 1970s, scientists had learned to use restriction enzymes to cut viral and bacterial DNA molecules at specific sites to produce linear segments of DNA with "sticky" ends. The ends could be spliced together to form strings of hybrid viral and bacterial DNA not found in nature. Hybrid strings, called recombinant DNA (rDNA), could then be reinserted into viruses or bacteria, thereby changing their characteristics and action. The new technique of recombining DNA, one of the most powerful in the history of biology, held great promise for the study of the genetics of microorganisms, for genetic engineering, and for genetic therapy.

At the same time, researchers involved in rDNA experiments feared that they might produce unpredictable occupational and environmental hazards, for example, by increasing the virulence of viruses or the resistance of bacteria to treatment with antibiotics. The fear that gene splicing could produce epidemic pathogens was heightened by the fact that biologists were using microorganisms in their recombinant DNA research that have human hosts, most notably the bacterium E. coli.

Recognizing this risk, several molecular biologists assembled at the Gordon Conference on Nucleic Acids in New Hampshire in the summer of 1973 called on their fellow scientists to voluntarily suspend recombinant experiments with E. coli and certain other organisms. This self-imposed moratorium was endorsed in February of 1975 by over 140 prominent molecular biologists and geneticists from the United States and twelve other countries who had assembled at Pacific Grove, California, for the Asilomar conference on the dangers of genetically reengineered microorganisms, organized by future Nobel laureate Paul Berg. It was the first time that scientists in any discipline had voluntarily adopted a moratorium on experiments in a new field of research.

The task of developing the principles formulated at Asilomar into detailed technical guidelines on containment facilities and safety procedures in rDNA research fell to the new NIH director, Donald Fredrickson. As the main funding agency for rDNA research, and the leading biomedical research facility in the country, NIH had both the institutional resources and the scientific authority to set laboratory standards in the United States. Fredrickson, who at first knew little about rDNA, faced his greatest challenge in trying to regulate the new technology of gene splicing. In his own estimate, mediating the rDNA controversy consumed a third to a half of his working hours between 1976 and 1978.

Some scientists, including the prominent biochemist Erwin Chargaff, warned against regulation by NIH. In his eyes, it was an irreconcilable conflict of interest and an encroachment on the freedom of scientific inquiry for the agency that funded most rDNA research to also be the agency that regulated such research. Other scientists, including Nobel laureates James D. Watson, David Baltimore, and Stanley N. Cohen, called upon NIH in the pages of Science to devise guidelines for the containment of rDNA molecules so that researchers around the country could adhere to a common, predictable standard in conducting their experiments.

The controversy soon spread beyond the walls of the laboratory, involving local citizens, public organizations, and politicians. In the summer of 1977, the city council of Cambridge, Massachusetts, held contentious hearings on rDNA research conducted at the city's universities. It created the Cambridge Biohazards Committee to conduct site visits and review containment measures for all proposed experiments, in the name of protecting residents from potential health risks. Similar measures were urged by Science for the People, an organization of community health activists in Ann Arbor, Michigan, home of the University of Michigan. The environmental organization Friends of the Earth brought suit demanding that rDNA research proceed only after NIH issued a comprehensive Environmental Impact Statement, a time-consuming and complex task. Other critics opposed rDNA research on ethical grounds, arguing that it amounted to an attempt to upset the order of nature by manipulating DNA, the code of life.

Like these local governments, federal lawmakers were troubled about the possible dangers of rDNA technology. Between 1976 and 1979, no fewer than twelve bills were introduced in the U.S. Congress providing for statutory regulation of rDNA research, only the first and most modest of which was drafted by Fredrickson's staff. That bill's main intent was to preempt local regulations of genetic research with federal provisions, and to make these provisions temporary. It was quickly superseded by more ambitious proposals. Congress was as divided over the issue of regulating rDNA research as American society at large, with some members favoring strong legislation and penalties, while others trusted scientists to regulate their own work, or deferred to local jurisdiction. As a result of these divisions, no law was enacted.

In the eyes of the NIH director, such actions by local governments and Congress threatened to stifle rDNA research under a maze of conflicting local restrictions or under inflexible national laws prompted by a mixture of fear and ethical concerns, rather than by scientific evidence. As the first chairman of the NIH's newly-formed Recombinant DNA Advisory Committee, or RAC, Fredrickson became the key negotiator among these competing interests. With the help of a close circle of NIH advisers, the so-called "kitchen RAC", Fredrickson sought to forge compromise and public consensus in five ways. First, and most important, he insisted that rDNA research be controlled through guidelines--prescriptions for proper laboratory set-up and procedures to which scientists adhere as a matter of professional obligation as well as for fear of losing NIH funding--rather than through laws and regulations, which are legally binding and carry formal penalties. Not only were guidelines more acceptable to scientists accustomed to freedom of research, but guidelines could be more easily revised than regulations, an important consideration in a rapidly evolving area of science like rDNA research.

Secondly, Fredrickson was convinced that no new regulatory machinery, other than RAC, was needed to supervise rDNA research. Scientists, he was convinced, were familiar with and supportive of centralized decision-making by panels of NIH experts. Third, he concluded that in order to gain public support for genetic research and avoid charges of secrecy, RAC deliberations were to be open to the public and their transcripts to be published in Recombinant DNA Research, a multi-volume compilation of correspondence, legislative bills, drafts, and media accounts of the rDNA controversy. Fourth, Fredrickson prevailed upon President Gerald Ford to establish a Federal Interagency Committee on Recombinant DNA Research, with the goal of replacing the uncoordinated approaches of various departments that sponsored rDNA research with a single set of guidelines. Fifth, judging that it was most urgent to allow rDNA research to proceed, Fredrickson decided to issue the guidelines before completion of an Environmental Impact Statement.

The NIH Guidelines on recombinant DNA were released by Fredrickson on June 23, 1976, an event that made for front-page news. A draft Environmental Impact Statement was submitted in September 1976, a final statement in October 1977. Canada and several western European nations agreed to adhere to the guidelines as well. Using their regulatory powers, the Food and Drug Administration and other federal agencies compelled the small number of private laboratories then using rDNA technology to abide by the NIH guidelines. The guidelines contained detailed technical instructions for building containment laboratories, ranging from level-one laboratories suitable for DNA experiments with organisms considered harmless, to level-four laboratories requiring elaborate ventilation systems, airlocks, and protective clothing for experiments with infectious pathogens.

A revised set of guidelines took effect on January 1979, in particular easing containment requirements for rDNA experiments with E. coli after no such experiments had produced harmful side-effects. The revised guidelines also laid out procedures for ongoing revision, and shifted responsibility for interpretation and enforcement to researchers' home institutions.

In 1978, Secretary of Health, Education, and Welfare Joseph A. Califano, Jr., requested that RAC be expanded to include lay members, among them the chairman. Fredrickson accepted this expansion with reservations, fearing that laymen would be unable to fully assess the complexities of rDNA technology. He later came to support the change when he realized that the inclusion of laymen under the able leadership of the new chairman, former Congressman Ray Thornton, helped to diffuse the political tensions surrounding genetic experimentation.

The NIH guidelines remain in force today, and continue to be overseen by RAC. No new epidemic pathogen has been inadvertently produced in the course of three decades of rDNA research. The struggle of Donald Fredrickson and the other participants in the rDNA controversy to find a compromise that would at once preserve scientific freedom, the public's health, and ethical values is a case study in the ways in which a democratic society manages risks and ethical conflicts raised by advances in science. It is a problem of abiding concern that is at the center of today's debate over stem cell research, genetic cloning, and genetically modified foods.