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The Paul Berg Papers

Recombinant DNA Technologies and Researchers' Responsibilities, 1973-1980

[Paul Berg and Maxine Singer at NIH Director's Advisory Committee meeting on Recombinant DNA]. [9-10 February 1976].
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By the late 1960s, biochemists and molecular biologists had made astonishing advances in their understanding of DNA, RNA, and the vast selection of enzymes that enabled their replication and carrying of genetic codes. Viable virus DNA and RNA had been synthesized in vitro by Arthur Kornberg and Sol Spiegelman, respectively. These exciting advances also raised many concerns for the public and the scientific community about the possible hazards of such work; if viruses could be created in a test tube, what would happen if the synthetic creations turned out to be pathogenic for humans or animals? In the 1970s, recombinant DNA (rDNA), which included genes from several different species, seemed to carry even more potential for unanticipated trouble; could this new technology change normally innocuous microbes into human pathogens, by introducing genes that rendered them resistant to antibiotics, or enabled them to make dangerous toxins, or transformed them into cancer-causing agents? Public fears were fed by science fiction scenarios such as Michael Crichton's The Andromeda Strain.

Even before his 1972 paper on recombinant technique was published, Berg's work in progress provoked a strong response from a colleague at Cold Spring Harbor, Robert Pollack. Pollack worried that lab workers might be at risk if recombinants containing tumor genes (from the SV40) found their way into cultures of E. coli, the bacterial species most widely used in laboratory research--and also commonly found in human digestive tracts. Though he had not planned to deliberately place his recombinants into bacteria, Berg was persuaded to hold off on further research with them because he could not say with certainty that he and his research staff were not at risk. He was also aware that researchers working with viruses and recombinants were, increasingly, biochemists who regarded the organisms more as chemical reagents and thus were not accustomed to employing the standard safety measures of microbiologists. To begin evaluating the possible risks, Berg organized a conference to discuss biohazards in biological research, held in January of 1973, at the Asilomar Conference Center in Pacific Grove, California. The conference focused on laboratory design and safety measures to protect lab workers dealing with the new engineered life forms. Two years later Berg would organize a better-known conference at Asilomar to discuss rDNA specifically.

Meanwhile, Cohen, Boyer, and others moved quickly along with recombinant work; by the summer of 1973 they had engineered a plasmid carrying genes for tetracycline resistance and inserted it into E. coli, where it retained its ability to replicate and to express the resistance genes. The first cloning experiment, it led several participants in the Gordon Conference on Nucleic Acids that year to call on the National Academy of Sciences president Philip Handler to address the situation. Handler, in turn called on Berg to advise him. In April 1974, Berg convened at MIT seven scientists from the first Asilomar conference, including James Watson and David Baltimore, to discuss Handler's request. The MIT group produced an open letter to the scientific community (subsequently known as "the Berg letter") requesting a moratorium on rDNA research until the hazards of such research could be assessed by an international conference of scientists, and procedures developed for containment of possible hazards. The letter appeared in Science on July 26, 1974, and provoked a wide range of commentary, as well as protests from many scientists; nevertheless, the voluntary moratorium--the first in the history of science--was universally observed.

The Asilomar Conference on Recombinant DNA Molecules, organized by Berg, Maxine Singer, and Richard Roblin, met in February 1975. In addition to an international group of 150 scientists, the participants included lawyers (including Daniel Singer, Maxine Singer's husband) to help consider legal and ethical issues, and 16 journalists to cover the four-day event. A primary aim of the group was to consider whether to lift the voluntary moratorium and if so, under what conditions research could proceed safely. The participants concluded (though not unanimously) that rDNA research should proceed but under strict guidelines. Their recommendations went to a National Institutes of Health committee chaired by NIH director Donald Fredrickson and charged with formulating those guidelines, which were issued in July 1976.

For each type of experiment within three general classes ("shotgun" experiments with E. coli, use of recombinants to insert genes from viruses, plasmids, and organelles into E. coli, and use of animal virus vectors), the guidelines assigned both a physical level of containment, designated P1 to P4, and a biological level designated EK1 to EK3 (after the E. coli K-12 strain commonly used in labs). Physical containment P1 consisted of standard microbiological practice, P2 required a few extra precautions, such as not creating aerosols, and P3 called for putting the entire lab under negative air pressure. The highest category, P4, involved techniques such as airlocks, protective clothing, and showering on exit, which are used in handling the most dangerous known pathogens. The lowest level of biological containment, EK1, required use of the standard K-12 strain of E. coli, which is unlikely to colonize the human bowel; EK2 stipulated the use of K-12 strains genetically altered so that on average only one bacterium in 100 million would be expected to survive in the environment outside the lab. At the EK3 level, the safety of the EK2 organisms used had to be verified by test feeding them to animals.

Although federal, state, and local legislators proposed a variety of different legal controls to contain the possible threats of rDNA research during the 1970s, none became law. Instead, the scientific community regulated itself, under the guidance of the NIH Recombinant DNA Advisory Committee. This self-regulation depended on scientists' sense of professional obligation, and on the fact that they were already accustomed to guidance from various NIH committees. Besides this, the NIH, which funded the vast majority of rDNA projects, could also exert control by withholding support. The guidelines proved to be an effective mechanism for avoiding potential problems while still allowing researchers a maximum amount of freedom in their investigations.

The guidelines also included a provision for amending them as researchers gained experience with engineered genes. Within a few years their experience showed that the dangers were minimal, as many scientists expected. As Berg later noted, the ultimate success of rDNA technologies may owe much to the early efforts of scientists to err on the side of caution. The voluntary moratorium on research slowed progress briefly, but having a standard set of rules helped things move safely forward afterward, and the efforts of the scientific community to deal responsibly with the potential dangers of their research did much to assuage public concerns about rDNA. Berg has remained deeply committed to the cause of scientific responsibility as genetic engineering and related technologies have evolved.


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