The Wuhan Lab and the Gain-of-Function Disagreement
By Lori Robertson
Posted on May 21, 2021
A disagreement between Republican Sen. Rand Paul and Dr. Anthony Fauci has put $600,000 of U.S. grant money to the Wuhan Institute of Virology back into the spotlight, while making “gain-of-function” research a household term — all amid calls for more investigation into the origins of SARS-CoV-2.
At issue is whether the National Institutes of Health funded research on bat coronaviruses that could have caused a pathogen to become more infectious to humans and, separately, if SARS-CoV-2 — the virus that causes the disease COVID-19 — transferred naturally from bats to humans, possibly through an intermediate host animal, or if a virus, a naturally occurring one or a lab-enhanced one, was accidentally released from the Wuhan lab.
There are a lot of unknowns, speculation and differences of opinion on these topics. But let’s start with what we do know: In 2014, the NIH awarded a grant to the U.S.-based EcoHealth Alliance to study the risk of the future emergence of coronaviruses from bats. In 2019, the project was renewed for another five years, but it was canceled in April 2020 — three months after the first case of the coronavirus was confirmed in the U.S.
EcoHealth ultimately received $3.7 million over six years from the NIH and distributed nearly $600,000 of that total to China’s Wuhan Institute of Virology, a collaborator on the project, pre-approved by NIH.
Wuhan, of course, is where the SARS-CoV-2 pandemic emerged in late 2019.
The Wuhan Institute of Virology has studied bat coronaviruses for years and their potential to ultimately infect humans, under the direction of scientist Shi Zhengli, as the Scientific American explained in a June 2020 story. Such zoonotic transfer — meaning transmission of a virus from an animal to a human — of coronaviruses occurred with the SARS and MERS coronaviruses, which led to global outbreaks in 2003 and 2012. Both viruses are thought to have started in bats, and then transferred into humans through intermediate animals — civets and racoon dogs, in the case of SARS, and camels in the case of MERS.
Experts have suspected the SARS-CoV-2 virus similarly originated in bats. Researchers in China — including at the Wuhan Institute of Virology — have said the virus shares 96% of its genome with a bat virus collected by researchers in 2013 in Yunnan Province, China. (While that’s quite similar, Dr. Stanley Perlman, a professor of microbiology and immunology at the University of Iowa who studies coronaviruses and a pediatric infectious disease physician, told us it would be “impossible” to take such a virus and make the kind of changes required to turn it into SARS-CoV-2 in a lab. One would need a virus that’s 99.9% similar, and “in theory it might work.”)
An article published in Nature Medicine in March 2020 said that the virus likely originated through “natural selection in an animal host before zoonotic transfer,” or “natural selection in humans following zoonotic transfer.” The researchers, who analyzed genomic data, said SARS-CoV-2 “is not a laboratory construct or a purposefully manipulated virus.” While they said an accidental laboratory release of the naturally occurring virus can’t be ruled out, they said they “do not believe that any type of laboratory-based scenario is plausible.”
In an April 2020 statement, University of Sydney professor Edward Holmes, who was involved in mapping the genome of SARS-CoV-2, responded to “unfounded speculation” that the bat virus with 96% similarity was the origin of SARS-CoV-2. He said: “In summary, the abundance, diversity and evolution of coronaviruses in wildlife strongly suggests that this virus is of natural origin. However, a greater sampling of animal species in nature, including bats from Hubei province, is needed to resolve the exact origins of SARS-CoV-2.”
The U.S. Intelligence Community said in an April 30, 2020, statement that it “concurs with the wide scientific consensus that the COVID-19 virus was not manmade or genetically modified,” and that it “will continue to rigorously examine emerging information and intelligence to determine whether the outbreak began through contact with infected animals or if it was the result of an accident at a laboratory in Wuhan.”
The zoonotic transfer theory hasn’t been proven; for example, no intermediate animal host, as was the case for SARS of MERS, has yet been identified. Lab-accident theories haven’t been proven either — whether a lab worker could have been infected by a naturally occurring virus and then transmitted it outside the lab, or, as Paul and others suggest, a lab-manipulated virus could be the origin.
But recently there has been renewed debate over the origin. On May 14 the journal Science published a letter from 18 scientists calling for “more investigation” to determine how the SARS-CoV-2 pandemic began. “Theories of accidental release from a lab and zoonotic spillover both remain viable,” they wrote. “Knowing how COVID-19 emerged is critical for informing global strategies to mitigate the risk of future outbreaks.”
Jesse Bloom, one of the organizers of that letter, who studies viral evolution at the Fred Hutchinson Cancer Research Center in Seattle, told us in an email: “We know that SARS-CoV-2 is similar to other coronaviruses that circulate in bats, so the deep origins of the virus are definitely from bat coronaviruses. As far as the immediate proximal origins, we simply don’t know the details.”
Bloom said zoonotic transfer either directly from a bat to a human or through an intermediate host animal is possible, as is a lab accident from research of similar viruses. “Because we don’t know the details for either of these scenarios, it’s not possible to say whether a hypothetical lab accident would have involved a virus exactly identical to that isolated in nature, or one that had been grown or somehow modestly manipulated in a lab. At this point, all of these are hypothetical scenarios, and while different scientists may have different guesses at how likely each scenario is, we need more information before anyone can be certain.”
The scientists are hardly alone in calling for more investigation.
As the letter noted, the U.S. government, along with 13 other countries, also had called for more inquiry into the origins in a March statement this year.
“It is critical for independent experts to have full access to all pertinent human, animal, and environmental data, research, and personnel involved in the early stages of the outbreak relevant to determining how this pandemic emerged,” the statement said. “With all data in hand, the international community may independently assess COVID-19 origins, learn valuable lessons from this pandemic, and prevent future devastating consequences from outbreaks of disease.”
The European Union made a similar statement. Both came in response to the release of a report by an international team convened by the World Health Organization. That report said a laboratory leak of a virus, involving “an accidental infection of staff,” was “an extremely unlikely pathway,” but the WHO director-general said that he didn’t believe the evaluation “was extensive enough.”
“Although the team has concluded that a laboratory leak is the least likely hypothesis, this requires further investigation, potentially with additional missions involving specialist experts, which I am ready to deploy,” WHO Director-General Tedros Adhanom Ghebreyesus said the day the report was publicly released on March 30. “Let me say clearly that as far as WHO is concerned all hypotheses remain on the table.”
In a May 11 Senate hearing, Paul raised the issue of the origins of SARS-CoV-2 and said some in the government weren’t interested in investigating the lab-leak theory. The Kentucky senator said that “government authorities, self-interested in continuing gain-of-function research say there’s nothing to see here.” He went on to assert a tie between U.S. researchers and the Wuhan Institute of Virology and accused them of “juicing up super-viruses,” asking Fauci, director of the National Institute of Allergy and Infectious Diseases, if he still supported “the NIH funding of the lab in Wuhan.”
Fauci responded that “the NIH has not ever and does not now fund gain-of-function research in the Wuhan Institute of Virology.”
In a subsequent interview on “Fox & Friends” on May 13, Paul said he didn’t know whether SARS-CoV-2 came from a lab. “Nobody knows,” he said. But he posited that if it did, Fauci, among others, “could be culpable for the entire pandemic,” adding, “I’m not saying that happened. I don’t know.”
Paul made the money-is-fungible argument, saying the NIH gave money to the lab, regardless of what that particular grant funded. But then asserted that NIH funding furthered risky gain-of-function research. The answer to the question of whether it did or didn’t depends on whom you ask and their definition of gain-of-function.
Hours after his May 11 exchange with Paul, Fauci said at a fact-checking conference hosted by PolitiFact.com that it would “almost be irresponsible” to not collaborate with Chinese scientists given that the 2003 SARS outbreak originated in China. “So we really had to learn a lot more about the viruses that were there, about whether or not people were getting infected with bad viruses.”
He called the EcoHealth collaboration “a very minor collaboration as part of a subcontract of a grant,” and said Paul conflated that with the claim that “therefore we were involved in creating the virus, which is the most ridiculous, majestic leap I’ve ever heard of.”
Fauci said he wasn’t convinced that the coronavirus developed naturally. “I think that we should continue to investigate what went on in China until we find out to the best of our ability exactly what happened.”
Fox News’ Tucker Carlson raised these issues on his show on May 11, saying: “The guy in charge of America’s response to COVID turns out to be the guy who funded the creation of COVID. We’re speaking of Tony Fauci and the gain-of-function experiments at the Wuhan laboratory that the U.S. government with his approval paid for.” There’s no evidence that the Wuhan laboratory, with or without funding from an NIH grant, created SARS-CoV-2.
The night before, Carlson referred to a May 2 article on Medium by former New York Times science writer Nicholas Wade. In that piece, Wade wrote about “two main theories” of SARS-Co-V-2’s origin: “One is that it jumped naturally from wildlife to people. The other is that the virus was under study in a lab, from which it escaped.” Wade asserted that the “clues point in a specific direction” — a lab-leak. But he said at the outset: “It’s important to note that so far there is no direct evidence for either theory. Each depends on a set of reasonable conjectures but so far lacks proof.”
Gain-of-function is a term that could describe any type of virology research that results in the gain of a certain function. But the type that’s controversial, including among scientists, is research that causes a pathogen to be more infectious, particularly to humans.
In 2014, the U.S. government put a pause on new funding of gain-of-function research, which it defined this way: “With an ultimate goal of better understanding disease pathways, gain-of-function studies aim to increase the ability of infectious agents to cause disease by enhancing its pathogenicity or by increasing its transmissibility.” A 2016 paper on the ethics of gain-of-function research said: “The ultimate objective of such research is to better inform public health and preparedness efforts and/or development of medical countermeasures.”
The pause — intended to provide time to address concerns about the risks and benefits of these studies — applied to certain research on influenza, MERS and SARS.
“Specifically, the funding pause will apply to gain-of-function research projects that may be reasonably anticipated to confer attributes to influenza, MERS, or SARS viruses such that the virus would have enhanced pathogenicity and/or transmissibility in mammals via the respiratory route,” the White House said in an Oct. 17, 2014, announcement.
As a Nature article at the time explained, there had been fierce debate among scientists on exactly what research should be deemed too risky. And some confusion on where the line would be drawn for this pause.
“Viruses are always mutating,” the article said, “and [Arturo] Casadevall [then a microbiologist at the Albert Einstein College of Medicine in New York City], says that it is difficult to determine how much mutation deliberately created by scientists might be ‘reasonably anticipated’ to make a virus more dangerous — the point at which the White House states research must stop.”
In July 2014, a group of scientists and experts called the Cambridge Working Group issued a statement calling for such a pause of “[e]xperiments involving the creation of potential pandemic pathogens … until there has been a quantitative, objective and credible assessment of the risks, potential benefits, and opportunities for risk mitigation, as well as comparison against safer experimental approaches.”
Well over 300 scientists have since signed on to the statement, which expressed concern about the risk of accidental infection in lab studies that created “highly transmissible, novel strains of dangerous viruses, especially but not limited to influenza.”
Paul cited the Cambridge Working Group in his May 11 and 13 remarks. But the group has not made “any statement … about work in Wuhan,” Marc Lipsitch, an epidemiologist at the Harvard T.H. Chan School of Public Health and one of the founder members of the group, said on Twitter.
Lipsitch further said that some members of the working group “may categorically oppose all GOF studies that enhance virulence, transmission, or immune escape. My personal view is that some such studies can be justified on risk-benefit grounds, while those on flu to date cannot.”
On Dec. 19, 2017, the U.S. government’s pause, or moratorium, was lifted. The Department of Health and Human Services announced a framework for evaluating whether funding should be granted for research involving “enhanced potential pandemic pathogens,” or PPPs. It said research on PPPs was “essential to protecting global health and security,” but the risks needed to be considered and mitigated.
The framework defined a “potential pandemic pathogen” as one that was both “likely highly transmissible and likely capable of wide and uncontrollable spread in human populations” and “likely highly virulent and likely to cause significant morbidity and/or mortality in humans.” And an enhanced PPP was a PPP “resulting from the enhancement of the transmissibility and/or virulence of a pathogen.”
The framework said enhanced PPPs don’t include “naturally occurring pathogens that are circulating in or have been recovered from nature.”
So, did the NIH’s grant to EcoHealth fund gain-of-function research at the Wuhan lab? There are differing opinions on that. As noted above, whether research is “likely” or “reasonably anticipated” to enhance transmissibility can be subjective.
EcoHealth and the NIH and NIAID say no. “EcoHealth Alliance has not nor does it plan to engage in gain-of-function research,” EcoHealth spokesman Robert Kessler told us in an email. Nor did the grant get an exception from the pause, as some have speculated, he said. “No dispensation was needed as no gain-of-function research was being conducted.”
The NIAID told the Wall Street Journal: “The research by EcoHealth Alliance, Inc. that NIH funded was for a project that aimed to characterize at the molecular level the function of newly discovered bat spike proteins and naturally occurring pathogens. Molecular characterization examines functions of an organism at the molecular level, in this case a virus and a spike protein, without affecting the environment or development or physiological state of the organism. At no time did NIAID fund gain-of-function research to be conducted at WIV.”
And in a May 19 statement, NIH Director Dr. Francis Collins said that “neither NIH nor NIAID have ever approved any grant that would have supported ‘gain-of-function’ research on coronaviruses that would have increased their transmissibility or lethality for humans.”
Richard Ebright, a professor of chemistry and chemical biology at Rutgers University and a critic of gain-of-function research, told the Washington Post that the EcoHealth/Wuhan lab research “was — unequivocally — gain-of-function research.” He said it “met the definition for gain-of-function research of concern under the 2014 Pause.” That definition, as we said, pertained to “projects that may be reasonably anticipated to confer attributes to influenza, MERS, or SARS viruses such that the virus would have enhanced pathogenicity and/or transmissibility in mammals via the respiratory route.”
Alina Chan, a molecular biologist and postdoctoral researcher at the Broad Institute of the Massachusetts Institute of Technology and Harvard, said in a lengthy Twitter thread that the Wuhan subgrant wouldn’t fall under the gain-of-function moratorium because the definition didn’t include testing on naturally occurring viruses “unless the tests are reasonably anticipated to increase transmissibility and/or pathogenicity.” She said the moratorium had “no teeth.” But the EcoHealth/Wuhan grant “was testing naturally occurring SARS viruses, without a reasonable expectation that the tests would increase transmissibility or pathogenicity. Therefore, it is reasonable that they would have been excluded from the moratorium.”
Chan, who has published research about the possibility of an accidental lab leak of the virus, also said: “But we need to separate this fight about whether a particular project is GOF vs whether it has risk of lab accident + causing an outbreak.”
The University of Iowa’s Perlman told us the EcoHealth research is trying to see if these viruses can infect human cells and what about the spike protein on the virus determines that. (The spike protein is what the coronavirus uses to enter cells.) The NIH, he said, wouldn’t give money to anybody to do gain-of-function research “per se … especially in China,” and he didn’t think there was anything in the EcoHealth grant description that would be gain of function. But he said there’s a lot of nuance to this discussion.
“This was not intentional gain of function,” Perlman said, adding that in this type of research “these viruses are almost always attenuated,” meaning weakened. The gain of function would be what comes out of the research “unintentionally,” but the initial goal of the project is what you would want to look at: can these viruses infect people, how likely would they be to mutate in order to do that, and “let’s get a catalog of these viruses out there.”
Perlman also said that making a virus that could infect human cells in a lab doesn’t mean the virus is more infectious for humans. Viruses adapt to the cell culture, he said, and may grow well in a cell culture but then, for instance, not actually infect mice very well.
Back in February, MIT biologist Kevin Esvelt told PolitiFact.com that a 2017 paper published with the help of the EcoHealth grant involved, as PolitiFact described it, “certain techniques that … seemed to meet the definition of gain-of-function research.” But Esvelt said “the work reported in this specific paper definitely did NOT lead to the creation of SARS-CoV-2,” because of differences between the virus studied and SARS-CoV-2.
In the May 11 hearing, Paul also pointed to the work of Ralph S. Baric, a professor of epidemiology and a microbiologist who studies coronaviruses at the University of North Carolina. Paul described Baric’s research as “gain of function” in collaboration with the Wuhan lab. A 2015 paper by Baric, Shi and others, published with NIH funding in the journal Nature Medicine, examined the potential of SARS-like bat coronaviruses to lead to human disease. Researchers created a “chimeric virus” with the spike protein of the bat coronavirus and a mouse-adapted SARS backbone and found viruses could replicate in human airway cells. The study said “the creation of chimeric viruses … was not expected to increase pathogenicity.”
Fauci told Paul at the hearing: “Dr. Baric does not do gain-of-function research, and if it is, it’s according to the guidelines and it is being conducted in North Carolina, not in China.”
In a statement to us, Baric said: “Our work was approved by the NIH, was peer reviewed, and P3CO reviewed,” meaning reviewed under the HHS 2017 framework. “We followed all safety protocols, and our work was considered low risk because of the strain of coronaviruses being studied. It is because of our early work that the United States was in a position to quickly find the first successful treatment for SARS-CoV-2 and an effective COVID-19 vaccine.”
Kelsey Cooper, Paul’s communications director, told us “there is ample evidence that the NIH and the NIAID, under his direction, funded gain of function research at the Wuhan Institute of Virology,” citing Ebright’s statements. “In light of those facts, the question Dr. Paul asked was whether the government has fully investigated the origin of the disease, which it clearly has not. This research and the lab should be thoroughly investigated and opened to public scrutiny.”
Perlman told us that he thought Fauci’s response in the May 11 exchange was correct — that no money was given for gain-of-function research. But, he added, there’s a scientific discussion to be had on the benefits and risks of research making recombinant viruses, which involves rearranging or combining genetic material. The politicization of the issue, Perlman said, “doesn’t do anybody good.”
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