How risky is ‘gain of function’ research? Congress scrutinizes China.

As questions mount over whether the COVID-19 pandemic could have started with a Chinese lab leak, members of Congress are shining a bright spotlight on controversial virus research often referred to as “gain of function.” 

Lawmakers are increasingly concerned that researchers who experiment with viruses in an effort to understand them and avert future pandemics could end up making them more lethal or transmissible to humans – potentially causing the types of outbreaks they were seeking to prevent. Members of Congress have especially focused on whether U.S. taxpayers funded such research in China. 

At the center of the spotlight is Dr. Zhengli Shi at the Wuhan Institute of Virology, who collaborated on U.S.-funded grants that involved manipulating coronaviruses to understand their transmissibility to humans. She, her American colleagues, and National Institute of Health (NIH) officials have unequivocally rejected allegations that the work involved gain-of-function research or led to the outbreak of COVID-19, denouncing such claims as politicized misinformation.

Scientists don’t agree on how exactly to define gain-of-function research, but generally it involves enhancing a pathogen to make it more virulent or transmissible. Critics say the NIH is using a narrow interpretation of what counts as gain of function, and has not provided ample transparency into the grant review process for such research. 

Debate over gain-of-function experiments involving viruses that could cause a pandemic was once largely confined to scientific journals, workshops, and advisory boards. But now, amid heightened concerns about biosafety, lawmakers see a need for greater oversight. A key ethical question is whether the benefits outweigh the risks, and if so, how scientific institutions and governments should best regulate it.

The issue came to a head last month when Republican senators led by Rand Paul of Kentucky grilled Dr. Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases, in a congressional hearing about the Wuhan lab’s U.S.-funded activities. Sen. Roger Marshall of Kansas compared a U.S.-China exchange of such knowledge, which could potentially be used for bioweapons, to working with the Soviet Union on nuclear technology. Two weeks later, Democrats joined Republicans in passing an amendment proposed by Senator Paul permanently banning U.S. funding of gain-of-function research in China, after which the Senate chamber erupted in cheers.

While the House and president would need to approve the measure for it to become law, the support in the Senate indicates lawmakers’ level of concern about such research and desire to establish guardrails. On June 22, Rep. Brad Wenstrup, an Ohio Republican, introduced a similar bill to ban U.S. funding of gain-of-function research in nations considered U.S. adversaries.

But scientists say it’s important for their community to take the lead so that the science is not left to Congress.

“You can’t expect a legislative aide in the middle of the night to define the technical features of the kinds of risks we’re talking about here,” says David Relman, a professor of microbiology and immunology at Stanford University.

“I’m worried that if we scientists – together with the NIH – don’t get out ahead of this, we’re going to have this legislated for us,” he adds. “The bottom line for me is that we haven’t pursued this sufficiently. Now would be a pretty good time to do this.”

“One of the most dangerous viruses you can make”

In 2011, an NIH-funded researcher in the Netherlands set off alarm bells with a paper describing how he had made, in his words, “probably one of the most dangerous viruses you can make” by enhancing an avian flu virus in a way that made it more transmissible to mammals. Together with a similar NIH-funded study in Wisconsin, it triggered a debate about the risks of conducting such experiments and what could happen if that knowledge got into the wrong hands. 

The work was eventually published, but a leaked letter from a member of the advisory board that reviewed it raised concerns that the NIH was more focused on extracting itself from controversy than resolving the underlying issues, a criticism the NIH rejected.

Several years later, a series of safety lapses involving avian flu, smallpox, and anthrax sparked fresh debate. In July 2014, the Cambridge Working Group, headed by Harvard epidemiologist Marc Lipsitch, called for experiments involving potential pandemic pathogens to be curtailed pending an assessment of the risks. A group calling themselves Scientists for Science pushed back with a statement of their own, arguing that such research was essential to preventing and treating disease, and noting that significant resources had already been devoted to ensuring safety, including special lab facilities.

Some scientists see additional restrictions as more of a hindrance than a protection, hampering academic freedom and potentially blocking scientific discoveries they say could save lives. Also, absent an international framework involving certification and inspections, any domestic limits could create a competitive disadvantage for the U.S., both intellectually and commercially. 

“Whenever you talk about limiting scientific research or controlling scientific research, there are a lot of antibodies that come out,” says Andrew Weber, former assistant secretary of defense for nuclear, chemical, and biological threats under the Obama administration. 

But concerns were high enough that, several months later, the U.S. government put a moratorium on funding gain-of-function research involving influenza, MERS, and SARS, subject to a review period. 

The moratorium was lifted in 2017, and the Department of Health and Human Services (HHS) issued new guidelines for research involving “enhanced potential pandemic pathogens.” Under the guidelines, the funding agency is supposed to flag all grant proposals involving such research. Those flagged are then subject to an HHS-managed review process that must consider whether the project is ethically justifiable, whether there are any alternative methods that would be less risky but “equally efficacious,” and if not, whether the potential benefits outweigh the risks. 

While oversight proponents see HHS’s 2017 framework as a step of progress, concerns remain. 

Critics say funding agencies such as the NIH are essentially self-policing when deciding which proposals to flag for broader HHS review, and that the process is subjective and lacks transparency. Even some top experts don’t know the names and number of individuals on the HHS review committee, how they are appointed, or how they arrive at their decisions about whether proposed research could be “reasonably anticipated” to create, transfer, or enhance pathogens that could cause a pandemic. There is no independent biosafety authority outside the government departments overseeing the research, which increasingly include other departments besides HHS, as well as private-sector actors. 

“The fact that we have no independent body that can say, ‘NIH, CDC, USDA – hey, don’t do this,’ is a problem,” says Rocco Casagrande, managing director of Gryphon Scientific, which produced a 2015 report at the NIH’s request on the risks and benefits of gain-of-function research involving influenza, MERS, and SARS in U.S. labs. “There’s no one that is without conflict of interest that can stop risky experiments.”

The Wuhan Institute of Virology

Now, the debate over gain-of-function research and lab safety has gained new urgency over questions about the Wuhan Institute of Virology (WIV). 

Lawmakers and others are pressing for answers on the scope of WIV’s work with coronaviruses – particularly whether any of it could have enhanced their virulence or transmissibility, and if so, whether that work was funded by NIH. Growing circumstantial evidence, and particularly China’s unwillingness to release relevant information, has heightened suspicions that COVID-19 could have started with a leak from the Wuhan lab. So far, no evidence has emerged to definitively prove or disprove the lab leak hypothesis, but a wide array of scientists and government officials now say it warrants investigation. 

A Trump State Department fact sheet said the WIV had a track record of conducting gain-of-function research and not being transparent about its work with viruses most similar to SARS-CoV-2, which causes COVID-19. It added that the WIV “has engaged in classified research ... on behalf of the Chinese military since at least 2017.” The Biden administration has not walked back any of the fact sheet’s key assertions.

At the May 11 congressional hearing, Senator Paul questioned the wisdom of U.S. grant money funding collaboration with Chinese scientists on such research. 

“You’re fooling with Mother Nature here. You’re allowing superviruses to be created,” said Senator Paul at the congressional hearing.

Dr. Fauci repeatedly and emphatically denied the senator’s assertions. “With all due respect, you are entirely incorrect,” he said. “The NIH has not ever and does not now fund gain-of-function research in that [Wuhan] institute.” 

Members of Congress say he is parsing words. They have requested documents that could provide more insight into the kind of work WIV was doing, such as the original grant proposal, but so far the NIH has not released them. 

In a written statement to the Monitor, the NIH said that pre-funding review of grant proposals is not made public “to preserve confidentiality and to allow for candid critique and discussion.” 

“Viruses do not respect borders”

Critics such as Senator Paul have focused on Dr. Shi’s collaboration with two U.S. scientists: Ralph Baric of the University of North Carolina at Chapel Hill (UNC), one of the world’s leading researchers on bat coronaviruses, and Peter Daszak of EcoHealth Alliance in New York, a nonprofit that seeks to prevent pandemics through its research.

In a U.S.-funded study published in 2015, Dr. Baric, using virus sequences provided by Dr. Shi, created a hybrid version of a bat coronavirus that showed the potential to infect humans. The NIH had approved the study, but it raised eyebrows among some scientists. UNC’s School of Public Health said in emails to the Monitor that there was no gain of function and the hybrid virus was not sent to China.

Dr. Shi also collaborated with Dr. Daszak’s nonprofit on an NIH-funded study published in 2017 that created hybrids between a virus which had previously been deemed as having the potential to infect humans – and others with unknown properties.

“To me, if you’re already starting with something that is poised for human emergence, you don’t go messing around with it – even if the chances of creating something bad are 1 in 100,” says Stanford’s Dr. Relman. 

In written statements to the Monitor, EcoHealth Alliance and Dr. Baric defended their work as essential to preventing disease outbreaks and developing treatments and vaccines.  

“There are many strains of viruses (including SARS-like betacoronaviruses) that exist in nature, and if we are to develop a drug that is broadly effective against all or most of these strains, we must be able to test such a drug against various strains in the laboratory setting,” said Dr. Baric. He says that his team’s early work enabled the U.S. to quickly find the first successful treatment for COVID-19 and contributed to the U.S. development of a vaccine.

Even with high safety standards in place, lab leaks involving viruses have led to outbreaks. 

“In China, the last six known outbreaks of SARS-1 have been out of labs, including the last known outbreak, which was a pretty extensive outbreak that China initially wouldn’t disclose that it came out of lab,” said Scott Gottlieb, the former commissioner of the Food and Drug Administration, on CBS’s “Face the Nation.” He also noted that “mishaps” had occurred in U.S. labs.

From 2007-17, there were two dozen incidents and accidents at U.S. labs involving influenza, SARS, and MERS, according to documents obtained through the Freedom of Information Act by Lynn Klotz, a senior science fellow at the Center for Arms Control and Non-Proliferation, and shared with the Monitor. Ten of those occurred at UNC Chapel Hill, all involving SARS and featuring a range of scenarios, including infected mice briefly escaping from a cabinet or a researcher’s hand. 

In a statement to the Monitor, the School of Public Health said that the viruses were mouse-adapted strains that pose a lesser risk of infection to humans and that it notified the proper oversight agencies and took corrective action as needed.

“The University of North Carolina at Chapel Hill takes its responsibility as a leading global research institution seriously,” the statement said. “Carolina’s researchers are committed to safety and operate under stringent biosafety and biosecurity procedures and practices.”  

However imperfect the U.S. biosafety system may be, experts note, the fact that it requires such reporting and corrective actions sets it apart from China.

“That’s what we’re not seeing in China,” notes Gregory Koblentz, director of George Mason University’s Biodefense graduate program, who is working on developing an international architecture for biosafety standards, certification, and inspections. “And that legitimately feeds concerns about this type of research, because we don’t see the same kind of mechanisms for reporting and accountability in the Chinese biosafety system as we see in the U.S. and other countries.” 

Amid criticism that U.S. scientists shouldn’t be cooperating on such risky research with scientists working in China, EcoHealth Alliance stressed the need for a global approach to preventing future pandemics.

“To isolate ourselves from the rest of the world would be shortsighted,” it said in its statement to the Monitor. “Viruses do not respect borders – truly effective research to identify and characterize them necessarily involves international collaboration. This is exactly the work EcoHealth Alliance does.”

Dr. Fauci also defended U.S. funding of WIV’s work on bat coronaviruses in a group Zoom call with reporters organized by the Nieman Foundation at Harvard, and said it would have been an abdication of responsibility for health officials not to study the place and animals where SARS originated.

“You need to study bat-human interface in the setting where it occurs. That’s China. ... You don’t want to study bats in Fairfax, Virginia,” he said on the June 8 call, while reiterating that the research NIH funded in the Wuhan lab had “nothing to do” with the outbreak of COVID-19. 

“Having said that,” Dr. Fauci added, “we cannot account for everything that goes on in Chinese labs.”