Scientists Observe Flaws In System To Protect Labs Against Biohazards

They acknowledge a laxness in following and monitoring research safety guidelines, which could pose a serious risk to some investigators Last spring, when eight students at the University of Pennsylvania's veterinary school went to the school's rural New Bolton Center to castrate some lambs, they considered it to be business as usual. Likewise for the parents and teachers of a nearby preschool class that visited and petted the sheep. What neither group knew was that just a month before, Jorge F. Ferrer, a professor of microbiology at the vet school, had inoculated 14 of the newborn lambs with live HTLV-1 virus, the microbe that causes adult T-cell leukemia in humans. According to the research project's approved protocol, Ferrer was to keep these animals segregated from the rest of the flock, away from exposure to the public and certainly identifiable to any individuals operating on the animals. But the lambs had been returned to the flock, where more than 120 people may have been unknowingly exposed to the deadly virus. Scientists at Penn and across the country insist that the breakdown of this protocol resulted in little if any risk to those who came in contact with the animals. Indeed, colleagues say it is because sheep do not contract HTLV-1 that Ferrer was performing this experiment; he was hoping to identify and isolate the immunological compound that protects the sheep from the virus. And neither the vet students nor any of the others who have subsequently been tested are infected with HTLV-1. Any scientist fed up with the current regulatory system governing work with biohazards may want to take a page from plant pathologist Gary Strobel's book and disregard the system altogether. Though he broke the law and endangered all federally funded work at Montana State University, all Strobel has to show for it today are the souvenirs of a hero: increased recognition throughout the scientific community, some 200 letters of support from the public, and, most rewarding, the knowledge that his strategy worked. Back in 1987, in what has become a widely publicized experiment, Strobel released into the wild a genetically altered strain of the bacterium Pseudomonas syringae to test its ability to protect elm trees from the devastating effects of Dutch elm disease. Though Strobel was told that the Environmental Protection Agency required a 90-day review before sanctioning any field experiment, he says that he knew the experiment was a safe one and that, given the growth cycle season, waiting for approval would have lost him an entire year--a delay he wasn't willing to accept. Strobel readily admits he knew that in releasing the organism, he was violating the EPA regulation. "I guess for the first time in my life I felt I had to take a stand," he recalls. His protest was against a system in which the regulations governing experiments with biohazards were what he calls a morass of overlapping jurisdictions, incomprehensible written guidelines, and irrationally strict parameters. "My rationale was we had made--and released--this bug seven years before they were even thinking about regulation," Strobel says. "How could they presently restrict me from something that had already been released, that was innocuous, and that we could find biotypes similar to already in the environment? I had even eaten the organism, so I knew it was safe." As a result of what Strobel terms his "own little Boston tea party," several punitive measures were threatened. The EPA threatened to put him in jail, fine him, and revoke all federal funds from Montana State; the State Department, the National Institutes of Health, and the National Science Foundation all considered revoking his research grants; NIH, NSF, and Los Alamos National Laboratory notified him that he might be removed from national peer-review committees; the university could have revoked his endowed chair or even fired him. But none of these things happened. Strobel says that in the past three years it hasn't been any more difficult to obtain funding for his work, and his average of nine to 12 published articles per year has not fallen off. He retains his positions on a review committee at Los Alamos and a biotech committee at NSF, and the NSF Experimental Program to Stimulate Competitive Research, which Strobel has chaired for years, remains one of the most successful in the country. The donor of Strobel's endowed chair remains his ardent supporter. And while he admits that some of his peers "wanted his hide"--especially when all federal funding was jeopardized--Strobel says that little resentment remains among his colleagues. His act of rebellion even won him a hearing on Capitol Hill, where Strobel says he got a very warm reception from senators sympathetic to his frustration with bureaucracy. More important, there is evidence today that Strobel's strategy of blatant disregard for the law worked. This past year a number of federal agencies finally agreed on a set of definitions to be used in regulating biotechnology, and the Federal Register issued a cross-agency agreement on what biohazards will be regulated. Val Giddings, a senior geneticist at the United States Department of Agriculture who works on biotechnology regulation, says that these changes might not have come about so soon were it not for Strobel's well-publicized experiment. "Gary's field test increased the profile of a number of issues," says Giddings, adding that the EPA, which he partly blames for the confusion surrounding the Strobel incident, now handles issues more efficiently. "We've made enormous progress in revising the basis for biotech guidelines, and are in a much better position than I would have expected three years ago." But what about the public trust, that all-important pact a scientist takes into his hands when he works with potentially dangerous organisms? Strobel feels that his actions were justified even in this light. "I don't think it was irresponsible, and evidently the public doesn't, either," he says. "I have received 200 letters from people around the world, 99 percent of which are favorable. "It's nice to be regulated, but, more important, to be regulated in a fair, just, understandable, equitable, and rational manner." --S.L-J D. But the violation of this protocol, designed to control an experiment with a human pathogen, reveals some disturbing facts about the scientific community's regulation of work with biohazards and its attitude toward transgressions. Because there is little systematic procedure for monitoring such experiments, no one actually knows how frequently transgressions occur. Moreover, there is evidence to suggest that when violations do happen, as long as the risk of danger is not realized, they go unpunished. And, finally, an attitude widely held in the scientific community is that if any corrective measures are called for, they should be implemented against the laws, not the scientists who take them into their own hands. "I live in dread of something like [the Ferrer incident] happening," says Jerry Freed, chairman of the biosafety committee at Fox Chase Cancer Center in Philadelphia. "The whole question of keeping track of all that goes on in an institution like this is a very difficult one. We don't audit or inspect or in any consistent way police what is going on." Nelson Wivel, director of the Office of Recombinant DNA Activities at the National Institutes of Health, agrees that it is "almost impossible to know" whether scientists are following guidelines. But he and colleagues throughout the biosafety community insist that the dangers to the scientific enterprise of overregulation far outweigh the risk--both in terms of health and damage to public trust--from an occasional rogue scientist. "You just don't find a lot of underground, dirty science," asserts Gerard Spahn, director of occupational health and safety at the Salk Institute in La Jolla, Calif. Penn's confidentiality policy prohibits Ferrer or other vet school officials from discussing the incident until the school's investigation is completed, but Matt Finucane, director of the Office of Environmental Health and Safety at Penn, says, "Dr. Ferrer received a copy of our letter setting the work at level 2 [an NIH designation that, among other things, requires the sheep to be segregated]. But he told us that, based on his previous experience with bovine leukemia virus, he did not believe that there was any risk. He also did not notify the university lab animal resource committee that he had begun the research, so they couldn't follow up with their requirement that the animals be kept segregated as well." Responding to Finucane's comments, Ferrer contends that the approved protocol did not require him to notify the committee of the precise date that he initiated the experiment. Moreover, he says, a representative of the committee was aware that he had purchased the lambs and that the protocol stated that the animals had to be inoculated shortly after birth for the experiment to work. "There was nothing hidden or deceptive," Ferrer says. "I was just following the protocol as approved by the university." Biosafety officers around the country insist that such incidents almost never occur, and that they are justified in relying on the honor of scientists to ensure compliance with official guidelines. To be sure, the incentives to do so are many and various, and money is undoubtedly the most compelling. "There are so many people doing good science out there, if you're not, you'll lose your funding very quickly," says Spahn. And NIH has the authority to revoke all institute funds from an institution found to be in violation of its biosafety guidelines, which adds peer pressure and preservation of professional reputation to the arguments for conformity. Above all, officials insist that it is in no one's interest--least of all the principal investigator, whose livelihood depends on public funding and public trust--to flaunt the rules. But history suggests that such punitive threats may be hollow. Gary Strobel, a plant pathologist at Montana State University in Bozeman who became a national figure in 1987 when he illegally released an organism without Environmental Protection Agency sanction, reports three years after the fact that, professionally, he has paid little price for his actions (see accompanying story). Still, officials hesitate to institute a more stringent system for monitoring what happens in the lab. "We have to take a look at what the results are," says Barry Cooperman, vice provost for research at Penn. "If people are getting sick and dying, that is one thing. But if that's not happening, then the cure can be worse than the disease." Currently, monitoring at institutions around the country depends on infrequent lab visits and, more important, coworkers in the lab. Robert McKinney, director of the Office of Safety at NIH, says that his people investigate about six alleged violations per month--and most of these originate with a call from someone within the lab. The Penn infraction came to light in a different fashion: Another investigator was planning to use the flock in an experiment, and wanted to check the history of the animals before using them. Closer Supervision Though Penn officials insist that this episode was an "absolute anomaly," as a result of the incident researchers working with biohazards at Penn will be subject to closer supervision than they have been in the past. "Our inspections will be more comprehensive and more frequent," says Finucane, who is hiring an additional staff member to help him monitor the approximately 100 experiments that come under the auspices of the biosafety committee at Penn. The laboratory visits, which have always been announced to ensure that the principal investigator would be available, will now be conducted on a surprise basis, and a formal written report will be produced from each. But Penn appears to be one of the few institutions in the process of shoring up its supervisory system. And even Cooperman remains concerned with the issues presented by increased monitoring. The first of these is cost-effectiveness. Penn has expanded its safety office from one person to 16 over the past nine years--and most of these resources are committed to educating the scientists. This is appropriate, Finucane contends, in a system in which the vast majority of transgressions are minor ones, made out of ignorance or laziness. "People might not be sorting the autoclaved trash exactly according to the letter of the law, or pasteur pipettes could be thrown out with the normal trash instead of with the other sharps [sharp laboratory implements]," he says. Freed paints a similar scenario: "If somebody here is sent half a dozen transgenic mice in order to accomplish some collaborative experiment, it is entirely possible that I wouldn't be notified. People just don't realize that this animal, which had recombinant DNA inserted into it five generations previously, is still subject to control." Safety officers around the country echo Finucane's argument that it is education, not monitoring, that has improved safety records over the past decades, and that it is also the way to prevent these types of problems in the future. Cooperman recalls that when he was a graduate student, it was routine to put organic solvents down the sink. "Now," he says, "people don't work outside the hood with them." And at Salk, Spahn says that today spot inspections reveal just a few violations a year; as recently as three years ago he saw many more. He credits education with these statistics, and with what he calls a growing "camaraderie of safety" within the lab. "When throwing something away," he says, "there is no longer the perception that one's responsibility is done." Unmanageable Logistics In addition to the issue of cost-effectiveness, scientists argue that the logistics of increased monitoring would be unmanageable. "You have thousands of people every day doing an experiment," says Cooperman. "There is no way to have somebody monitoring that." Freed concurs: "We don't have anyone standing at the door saying, `What have you got in the box, doctor?' And I am not about to start a midnight hunt for transgenic mice." Finally, and of greatest concern, is the threat increased supervision would present to what Cooperman calls the "psychological environment of the institution." "It is inappropriate for a few major abuses to result in a system in which no one could get anything done," concurs Emmett Barkley, director of laboratory safety for the Howard Hughes Medical Institute in Bethesda, Md. To impose a system in which one could insure that violations never occur, he says, "would be so constraining on those who are acting responsibly that you are likely to have created an environment where there are more people who are likely to violate the specific rules." The biosafety officers are also concerned that the tension that already exists between their offices and some of the labs not be exacerbated. Some of this tension is unavoidable in any bureaucratic process, they say. Freed, whose responsibility it is to issue periodic memos reminding the principal investigators of the types of experiments that require registration with his office, is aware of this. "I have a feeling that people throw them in the trash, because they somehow just don't want to be bothered," he says. This tension is fed by the fact that experiments with biohazards are most often at the cutting edge of science. "Generally, these people are working with organisms for which they may be the most knowledgeable in the world," says Finucane. John Keene of Biohaztec Associates Inc., a biosafety consulting firm for industry in Midlothian, Va., says one needs to look at the situation from the perspective of the investigator. "The university scientist has facts at hand based on good science," he says. "He knows the risks and takes proper precautions. How do you walk in there and tell him that the rules have been changed by someone who has never set foot in a lab?" Indeed, in some cases it is the regulations themselves that undermine the credibility of the biosafety officers and promotes an attitude of disregard for regulations, these officials say. "In Pennsylvania," Cooperman notes, "a glass pipette is defined as an infectious agent even if it just had saline in it. That's the law, and we obey the law. But the people in the biochemistry lab think it's kind of dumb." Both Keene and Val Giddings, a senior geneticist working on biotech regulations at the United States Department of Agriculture, say that the regulatory situation is improving. Federal agencies are working together to delineate jurisdictions and reach a common set of definitions regarding work with biohazards. Regulations are being rewritten to reflect a more realistic assessment of risk. The NIH manual--Biosafety in Microbiological and Biomedical Laboratories--that delineates bio-safety levels will be revised in the near future, and new Occupational Safety and Health Administration regulations for blood-borne pathogens and other infectious agents are due out in May. Keene says that throughout these new guidelines he sees a welcome trend away from prescribed precautions toward establishment of a performance standard for safety. Increasingly, the methods of ensuring that standard will be left up to individual institutions and principal investigators. But questions about monitoring and enforcement remain, as well as concerns about the problem of renegade scientists and the danger they present to the scientific community and its somewhat shaky covenant with the public trust. "The system is based on mutual trust between the institution and the investigator," acknowledges Finucane. "It's based on the [presumption that] the PI [principal investigator] is a non-rogue, someone who works within the broad parameters the university sets. Essentially, it gets down to the fact that any human activity is only as good as the person who is performing it, and whether he complies with the regulations."

Scientists Observe Flaws In System To Protect Labs Against Biohazards

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