Stricter US guidelines for ‘gain-of-function’ research are on the way — maybe
Some scientists would like more rigorous oversight of risky pathogen research conducted at high-level biosecurity facilities.Credit: Patrick Semansky/AP/Shutterstock
A long-awaited report on how US health officials should regulate research involving dangerous pathogens has been approved — sort of. A panel of experts at a 27 January virtual meeting of the US National Science Advisory Board for Biosecurity (NSABB) met with the expectation of voting on a set of recommendations developed over the past two years by a pair of working groups. So many concerns were lodged, however, that the meeting ended with an agreement to modify the report, but without a firm plan for how to do so.
Risky ‘gain-of-function’ studies need stricter guidance, say US researchers
Panel members — a mix of infectious-disease researchers, biosecurity experts and bioethicists — and other scientists expressed discomfort at the meeting with how the draft report’s vague language and recommendations for expanded oversight of such experiments could stifle crucial research, slowing scientists’ ability to respond to public-health emergencies. They also worried about issues such as how privately-funded risky research would be regulated, the role of research institutions in identifying potentially dangerous research, and whether institutions within and outside the United States would have sufficient funding to meet US biosafety standards.
Once the report is finalized, the NSABB will send it to the US Department of Health and Human Services (HHS) for consideration while HHS crafts new policy guidelines. The HHS is “going to have to provide the ‘how’ level of details”, said NSABB chair Gerry Parker. But when that will happen is unclear.
Given how the meeting ended, there could still be a long road ahead to even finalize the report, a frustration for attendees. “The momentum is such that nobody wants to have another meeting to discuss it, even though some serious suggestions and criticisms were raised,” says Gigi Kwik Gronvall, an immunologist at the Johns Hopkins Bloomberg School of Public Health in Washington DC who attended the meeting.
Year of contention
The NSABB report is the culmination of a process that began more than a decade ago amid an uproar over a pair of publications1,2 describing how researchers had engineered flu viruses to become more transmissible in order to understand how they might evolve in the wild. In response, the US National Institutes of Health (NIH) abruptly halted funding in 2014 for around two dozen projects involving so-called ‘gain-of-function’ research that could enhance a pathogen’s transmissibility or deadliness.
Which COVID studies pose a biohazard? Lack of clarity hampers research
The agency lifted the moratorium in December 2017, after the HHS proposed a new framework that extended review of research involving certain pathogens with the potential to start a pandemic. Since then, only three projects — all of which involved influenza virus research — have undergone the official review process put in place by the HHS.
That low number concerns Marc Lipsitch, an epidemiologist at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts. “The big loophole at this stage is that most things never get to the stage of being reviewed,” he says. He points to recent experiments at the NIH that attempted to evolve a monkeypox virus to see whether certain mutations could make it more lethal to mice, as well as a non-peer-reviewed study3 in which researchers inserted a gene from the Omicron variant of SARS-CoV-2 into an earlier strain of the virus to understand how Omicron causes disease. Neither underwent the HHS’s extended review process.
The COVID-19 pandemic has highlighted the difficulty of designing guidelines that protect against research that is unreasonably risky without hampering otherwise crucial studies with regulatory red tape. It has also put an intense spotlight on risky pathogen research, with concerns raised over safety and transparency of practices at laboratories in China that investigate bat coronaviruses.
“Before COVID, we were thinking of [pandemics as] something in the future that may happen,” says Arturo Casadevall, a microbiologist at Johns Hopkins University in Baltimore, Maryland. “The amount of damage to the world has been unbelievable.”
Myriad concerns
The new report’s recommendations include increased transparency in the review process, a role for research institutions in evaluating the risks and benefits of proposed experiments and improved regulation of NIH-funded research performed in other countries.
The report also suggests that HHS reevaluate its long-established list of 15 agents and toxins that could have ‘dual-use’ as biological weapons and therefore require special review before certain experiments can be performed. Instead, the report advises that the HHS evaluate all experiments that could be “reasonably anticipated” to make a pathogen more transmissible or dangerous.
The shifting sands of ‘gain-of-function’ research
Lipsitch says this vague wording is useful — after all, scientists don’t always initially know where their research is going to lead. “We’re talking about low-probability, but high-consequence, events,” he says. He remains concerned, though, that the wording could also allow high-risk research to proceed without extended review, depending on how the phrase is interpreted.
On the other hand, Gronvall worries that “reasonably anticipated” could be interpreted so broadly that it could delay a wide swathe of experiments, such as those involved in vaccine development during an outbreak, or even those used in synthetic biology to engineer bacteria so that they produce biomaterials. “Almost all things are dual-use,” she says. “By not doing this research, we’re not making ourselves safer.”
At the NSABB meeting, board member Mark Denison, an infectious-disease expert at Vanderbilt University Medical Center in Nashville, Tennessee, also mentioned the difficulty of determining what experiments could be risky. If identifying the function of a common protein might reveal that a mutation could make it more dangerous, for instance, would that identification constitute a risk? “We need a better definition of gain-of-function,” he said.
Visible hesitancy
Gronvall’s concerns echo those of a separate, 18 January report from the US Government Accountability Office (GAO), which recommended that HHS develop a clear, public standard for what “reasonably anticipated” means. The GAO called for more transparency around the HHS’s evaluation process, and said that the US Centers for Disease Control and Prevention should evaluate whether exemptions for public-health emergencies constitute a risk.
US government lifts ban on risky pathogen research
Gronvall and others also question the report’s recommendation that the HHS evaluate the safety of research involving pathogen surveillance and vaccine development, which are currently exempt from these regulations. “What got us out of the pandemic as quickly as it did was all the scientists who jumped in,” says Michael Imperiale, a microbiologist at the University of Michigan in Ann Arbor. “I don’t want to see any guidance ending up throwing sand in the gears of important experiments that need to be done because people don’t want to jump through hoops.”
At the meeting, after NIH acting policy chair Lyric Jorgenson said that rejecting the report would require a new gathering, the panel members — some with visible hesitancy — voted to approve the report with modifications. But when or how those modifications would be made, or which of the panel’s many concerns they would address, was not clear.
In the meantime, scientists working with pathogens worry that the intent of the research is being lost in the debate. “The thing you have to remember is that if I’m not running a safe lab, the people most at risk are me and the people in my lab,” Imperiale says.
Some scientists would like more rigorous oversight of risky pathogen research conducted at high-level biosecurity facilities.Credit: Patrick Semansky/AP/Shutterstock
A long-awaited report on how US health officials should regulate research involving dangerous pathogens has been approved — sort of. A panel of experts at a 27 January virtual meeting of the US National Science Advisory Board for Biosecurity (NSABB) met with the expectation of voting on a set of recommendations developed over the past two years by a pair of working groups. So many concerns were lodged, however, that the meeting ended with an agreement to modify the report, but without a firm plan for how to do so.
Risky ‘gain-of-function’ studies need stricter guidance, say US researchers
Panel members — a mix of infectious-disease researchers, biosecurity experts and bioethicists — and other scientists expressed discomfort at the meeting with how the draft report’s vague language and recommendations for expanded oversight of such experiments could stifle crucial research, slowing scientists’ ability to respond to public-health emergencies. They also worried about issues such as how privately-funded risky research would be regulated, the role of research institutions in identifying potentially dangerous research, and whether institutions within and outside the United States would have sufficient funding to meet US biosafety standards.
Once the report is finalized, the NSABB will send it to the US Department of Health and Human Services (HHS) for consideration while HHS crafts new policy guidelines. The HHS is “going to have to provide the ‘how’ level of details”, said NSABB chair Gerry Parker. But when that will happen is unclear.
Given how the meeting ended, there could still be a long road ahead to even finalize the report, a frustration for attendees. “The momentum is such that nobody wants to have another meeting to discuss it, even though some serious suggestions and criticisms were raised,” says Gigi Kwik Gronvall, an immunologist at the Johns Hopkins Bloomberg School of Public Health in Washington DC who attended the meeting.
Year of contention
The NSABB report is the culmination of a process that began more than a decade ago amid an uproar over a pair of publications1,2 describing how researchers had engineered flu viruses to become more transmissible in order to understand how they might evolve in the wild. In response, the US National Institutes of Health (NIH) abruptly halted funding in 2014 for around two dozen projects involving so-called ‘gain-of-function’ research that could enhance a pathogen’s transmissibility or deadliness.
Which COVID studies pose a biohazard? Lack of clarity hampers research
The agency lifted the moratorium in December 2017, after the HHS proposed a new framework that extended review of research involving certain pathogens with the potential to start a pandemic. Since then, only three projects — all of which involved influenza virus research — have undergone the official review process put in place by the HHS.
That low number concerns Marc Lipsitch, an epidemiologist at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts. “The big loophole at this stage is that most things never get to the stage of being reviewed,” he says. He points to recent experiments at the NIH that attempted to evolve a monkeypox virus to see whether certain mutations could make it more lethal to mice, as well as a non-peer-reviewed study3 in which researchers inserted a gene from the Omicron variant of SARS-CoV-2 into an earlier strain of the virus to understand how Omicron causes disease. Neither underwent the HHS’s extended review process.
The COVID-19 pandemic has highlighted the difficulty of designing guidelines that protect against research that is unreasonably risky without hampering otherwise crucial studies with regulatory red tape. It has also put an intense spotlight on risky pathogen research, with concerns raised over safety and transparency of practices at laboratories in China that investigate bat coronaviruses.
“Before COVID, we were thinking of [pandemics as] something in the future that may happen,” says Arturo Casadevall, a microbiologist at Johns Hopkins University in Baltimore, Maryland. “The amount of damage to the world has been unbelievable.”
Myriad concerns
The new report’s recommendations include increased transparency in the review process, a role for research institutions in evaluating the risks and benefits of proposed experiments and improved regulation of NIH-funded research performed in other countries.
The report also suggests that HHS reevaluate its long-established list of 15 agents and toxins that could have ‘dual-use’ as biological weapons and therefore require special review before certain experiments can be performed. Instead, the report advises that the HHS evaluate all experiments that could be “reasonably anticipated” to make a pathogen more transmissible or dangerous.
The shifting sands of ‘gain-of-function’ research
Lipsitch says this vague wording is useful — after all, scientists don’t always initially know where their research is going to lead. “We’re talking about low-probability, but high-consequence, events,” he says. He remains concerned, though, that the wording could also allow high-risk research to proceed without extended review, depending on how the phrase is interpreted.
On the other hand, Gronvall worries that “reasonably anticipated” could be interpreted so broadly that it could delay a wide swathe of experiments, such as those involved in vaccine development during an outbreak, or even those used in synthetic biology to engineer bacteria so that they produce biomaterials. “Almost all things are dual-use,” she says. “By not doing this research, we’re not making ourselves safer.”
At the NSABB meeting, board member Mark Denison, an infectious-disease expert at Vanderbilt University Medical Center in Nashville, Tennessee, also mentioned the difficulty of determining what experiments could be risky. If identifying the function of a common protein might reveal that a mutation could make it more dangerous, for instance, would that identification constitute a risk? “We need a better definition of gain-of-function,” he said.
Visible hesitancy
Gronvall’s concerns echo those of a separate, 18 January report from the US Government Accountability Office (GAO), which recommended that HHS develop a clear, public standard for what “reasonably anticipated” means. The GAO called for more transparency around the HHS’s evaluation process, and said that the US Centers for Disease Control and Prevention should evaluate whether exemptions for public-health emergencies constitute a risk.
US government lifts ban on risky pathogen research
Gronvall and others also question the report’s recommendation that the HHS evaluate the safety of research involving pathogen surveillance and vaccine development, which are currently exempt from these regulations. “What got us out of the pandemic as quickly as it did was all the scientists who jumped in,” says Michael Imperiale, a microbiologist at the University of Michigan in Ann Arbor. “I don’t want to see any guidance ending up throwing sand in the gears of important experiments that need to be done because people don’t want to jump through hoops.”
At the meeting, after NIH acting policy chair Lyric Jorgenson said that rejecting the report would require a new gathering, the panel members — some with visible hesitancy — voted to approve the report with modifications. But when or how those modifications would be made, or which of the panel’s many concerns they would address, was not clear.
In the meantime, scientists working with pathogens worry that the intent of the research is being lost in the debate. “The thing you have to remember is that if I’m not running a safe lab, the people most at risk are me and the people in my lab,” Imperiale says.
