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A worker in a biosafety level 3 lab.

A worker in a biosafety level 3 lab.

Maggie Bartlett/NHGRI

Biosecurity board grapples with how to rein in risky flu studies

BETHESDA, MARYLAND—Fuzzy definitions, deep disagreement about risks and benefits, and an unfortunate acronym: All bedeviled an expert panel as it met here last week to examine whether the United States should fund certain risky pathogen experiments. Researchers largely praised a massive, recently released risk assessment of so-called gain-of-function (GOF) research, and a draft plan for reviewing the riskiest studies. Many had concerns about the details, however, and the meeting provided little clarity on one key issue: if and when the U.S. government will decide whether to lift a now 15-month-old moratorium on a handful of U.S.-funded virology experiments.

To some, the deepest flaw in a draft proposal on GOF studies from a working group of the National Science Advisory Board for Biosecurity (NSABB) was its imprecise effort to define those studies that are so dangerous that they should not be allowed. Wording such as “potentially” risky and “a pathogen that is highly transmissible, significantly virulent, and likely to be resistant” to public health controls leaves too much to interpretation, many said. “The real question is: What are those studies?” said Stanford University in Palo Alto, California’s David Relman, a critic of GOF studies.

The NSABB meeting was the latest step in a debate that began in late 2011, when two labs revealed they had engineered the potent H5N1 avian influenza to spread more easily among mammals. The NSABB ultimately concluded that those GOF studies, aimed at helping experts prepare for possible pandemics, should be published, despite the risks if the engineered viruses escaped the lab. But concerns flared again in 2014 after several accidents at federal high containment labs. In October 2014, U.S. officials halted National Institutes of Health (NIH) funding for 18 GOF projects on influenza virus and the coronaviruses severe acute respiratory syndrome and Middle East respiratory syndrome, and launched a broad review of such studies.

draft report released last month by an NSABB working group finds that only a “small subset” of GOF studies pose serious risks, and that the United States has an effective framework for managing such work, but that tighter oversight may be needed.

At last week’s meeting, researchers generally praised a 1000-page risk-benefit analysis conducted by Gryphon Scientific, a contractor in Takoma Park, Maryland, as background for the NSABB report. It draws on a huge amount of data, from the likelihood of a punctured glove to historical reports of lab break-ins, to put numbers on the low odds of an accidental or deliberate lab release and resulting risks to the population. “I didn’t think it was doable, but Gryphon did a good job,” said virologist Ronald Fouchier of Erasmus University in Rotterdam, the Netherlands, who led one of the 2011 H5N1 studies and has a current NIH-funded project on hold. However, Fouchier felt the review overlooked enhancements in his biosafety level 3 lab, such as special cabinets, that make it as safe—if not safer—than BSL-4, the highest safety category for the most dangerous agents. Because the risks in his lab are “negligible,” the benefits easily outweigh them, Fouchier argued.

Yoshihiro Kawaoka of the University of Wisconsin, Madison, who also conducts H5N1 GOF research and conducted one of the controversial 2011 studies, made the case that new rules aren’t needed. As an example, he described the review that one of his proposed H5N1 grant proposals, which aimed to increase the virus’s transmissibility in ferrets, underwent after peer review. A panel of the Department of Health and Human Services (HHS), which included experts from eight agencies, decided that a subset of proposed experiments included in the proposal were too risky and should be removed. That process shows that the U.S. government “has an effective policy framework in place,” he says. (Critics complain that the HHS reviews are not public.)

Opponents of GOF studies, for their part, claimed that Gryphon overstated benefits from GOF influenza studies in part because the company mainly interviewed experts favoring this research. These critics called for more detailed data on how GOF findings have been used for flu vaccine development and surveillance. Relman and Harvard University epidemiologist Marc Lipsitch also argued that NSABB should drop one criterion for allowing a risky GOF study—whether the agent can be stopped with vaccines and antivirals—because developing countries likely won’t have access to such countermeasures.

One concern shared by all sides was that the Gryphon analysis compared potential pandemic risks with those from the 1918 influenza, which killed tens of millions of people. That is too high a bar—risks should probably be compared with a milder pandemic, such as the 2009 H1N1 influenza outbreak, many said. Participants also agreed that that the term the working group draft uses for the risky studies—GOF “of concern”—is problematic because of how one possible acronym, “GoFoc,” would be pronounced.

Above all, participants called for the NSABB working group to sharpen its definition of worrisome experiments. Philip Potter of St. Jude Research Children’s Research Hospital in Memphis, Tennessee, which had an influenza contract that was initially stopped by the October 2014 pause, eventually learned from NIH that all of it studies could continue. To avoid such confusion, NSABB’s report “has to be so clear that even a relative novice” can understand it, he said. Others added, however, that the document also must be flexible enough to allow for new pathogens.

The NSABB working group will now refine its report and submit it for review by the second of two National Academies of Sciences, Engineering, and Medicine meetings in March. NSABB expects to issue final recommendations by the end of May.

The U.S. government will then settle on a new policy for risky GOF studies—ideally “very fast,” says Carrie Wolinetz, NIH associate director for science policy. That policy will then be used to determine whether the paused GOF projects can resume. Fouchier, who noted at the meeting that European science agencies recently found no need for a European Union moratorium on GOF studies, told Science that he is willing to wait a few more months to resume his U.S.-funded studies. But after that, he may seek non-NIH funding. “If the U.S. government decides not to fund this work, it will simply go on elsewhere. Including for me,” he says.