The Intercept | 10 Sep 2021
by Sharon Lerner, Mara Hvistendahl, Maia Hibbett
DOCUMENTS OBTAINED BY The Intercept contain new evidence that the Wuhan Institute of Virology and the nearby Wuhan University Center for Animal Experiment, along with their collaborator, the U.S.-based nonprofit EcoHealth Alliance, have engaged in what the U.S. government defines as “gain-of-function research of concern,” intentionally making viruses more pathogenic or transmissible in order to study them, despite stipulations from a U.S. funding agency that the money not be used for that purpose.
Grant money for the controversial experiment came from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases, which is headed by Anthony Fauci. The award to EcoHealth Alliance, a research organization which studies the spread of viruses from animals to humans, included subawards to Wuhan Institute of Virology and East China Normal University. The principal investigator on the grant is EcoHealth Alliance President Peter Daszak, who has been a key voice in the search for Covid-19’s origins.
Scientists unanimously told The Intercept that the experiment, which involved infecting genetically engineered mice with “chimeric” hybrid viruses, could not have directly sparked the pandemic. None of the viruses listed in the write-ups of the experiment are related to the virus that causes Covid-19, SARS-CoV-2, closely enough to have evolved into it. Still, several scientists said the new information, which the NIH released after it was sued by The Intercept, points to biosafety concerns, highlighting a general lack of oversight for research on pathogens and raising questions about what other information has not been publicly disclosed.
“As a virologist, I personally think creating chimeras of SARS-related bat coronaviruses that are thought to pose high risk to humans entails unacceptable risks,” said Jesse Bloom, who studies the evolution of viruses at the Fred Hutchinson Cancer Research Center. Severe acute respiratory syndrome, or SARS, is a disease caused, like Covid-19, by an airborne coronavirus.
The experiment also raises questions about assertions from Fauci and NIH Director Francis Collins that NIH-funded projects at the Wuhan Institute of Virology did not involve gain-of-function research. In May, Fauci testified before Congress: “The NIH has not ever and does not now fund gain-of-function research in the Wuhan Institute of Virology.” The documents do not establish whether Fauci was directly aware of the work.
Scientists working under a 2014 NIH grant to the EcoHealth Alliance to study bat coronaviruses combined the genetic material from a “parent” coronavirus known as WIV1 with other viruses. They twice submitted summaries of their work that showed that, when in the lungs of genetically engineered mice, three altered bat coronaviruses at times reproduced far more quickly than the original virus on which they were based. The altered viruses were also somewhat more pathogenic, with one causing the mice to lose significant weight. The researchers reported, “These results demonstrate varying pathogenicity of SARSr-CoVs with different spike proteins in humanized mice.”
But the terms of the grant clearly stipulated that the funding could not be used for gain-of-function experiments. The grant conditions also required the researchers to immediately report potentially dangerous results and stop their experiments pending further NIH review. According to both the EcoHealth Alliance and NIH, the results were reported to the agency, but NIH determined that rules designed to restrict gain-of-function research did not apply.
The Intercept consulted 11 scientists who are virologists or work in adjacent fields and hold a range of views on both the ethics of gain-of-function research and the Covid-19 origins search. Seven said that the work appears to meet NIH’s criteria for gain-of-function research.
One said that the experiment “absolutely does not meet the bar” for gain-of-function research. “You can’t predict that these viruses would be more pathogenic, or even pathogenic at all in people,” said Angela Rasmussen, a virologist with the Vaccine and Infectious Disease Organization at the University of Saskatchewan. “They also did not study transmissibility at all in these experiments,” meaning that the scientists did not look at whether the viruses could spread across a population.
Three experts said that, while they did not have enough knowledge of U.S. policies to comment on whether the research met NIH criteria, the experiment involving humanized mice was unnecessarily risky.
One virologist, Vincent Racaniello, a professor of microbiology and immunology at Columbia University, said while he considered the mouse experiment described in the document to clearly fall into the gain-of-function category, he didn’t see it as problematic. “You can do some kinds of gain-of-function research that then has unforeseen consequences and may be a problem, but that’s not the case here,” said Racaniello.
Robert Kessler, communications manager for EcoHealth Alliance, denied that the work on the humanized mice met the definition of gain-of-function research. Kessler insisted that bat viruses are not potential pandemic pathogens because, he said, “a bat virus is not known to be able to infect humans.” The proposal justified the work on WIV1 by explaining that it is “not a select agent” — referring to a list of closely monitored toxins and biological agents that have the potential to pose a severe threat to public health — and “has not been shown to cause human infections, and has not been shown to be transmissible between humans.”
But the group’s bat coronavirus research was focused on the very threat that bat viruses pose to people. Kessler did acknowledge that, while the original bat coronavirus in the experiment did not spread among humans, the research was designed to gauge how bat coronaviruses could evolve to infect humans.
All but two of the scientists consulted agreed that, whatever title it is given, the newly public experiment raised serious concerns about the safety and oversight of federally funded research. “In my point of view, the debate about the definition of ‘gain-of-function’ has been too much focused on technical aspects,” said Jacques van Helden, a professor of bioinformatics at Aix-Marseille Université. “The real question is whether or not research has the potential to create or facilitate the selection of viruses that might infect humans.” The experiments described in the proposal clearly do have that potential, he said.
NIH spokesperson Elizabeth Deatrick said that the agency had considered the research — and decided not to restrict it under its own rules. “In 2016, NIAID determined that the work was not subject to the Gain-of-Function (GoF) research funding pause and the subsequent HHS P3CO Framework,” Deatrick wrote, referring to criteria put in place in 2017 to guide the agency’s funding decisions about research that involves, or is reasonably anticipated to involve, potential pandemic pathogens.
Republican members of Congress have alleged, without sufficient evidence, that gain-of-function research in Wuhan sparked the coronavirus pandemic. As part of an inquiry into the origins of the pandemic, they have twice grilled Fauci in Congress on his role as NIAID director.
In a heated exchange in July, Republican Sen. Rand Paul accused Fauci of lying when he claimed that NIH did not fund gain-of-function research at the Wuhan Institute of Virology.
Experts now say that the documents support the contention that NIH funded gain-of-function work, though not in the specific instance where Paul alleged it. “There’s no question,” said Racaniello, of Columbia University, who pointed to the decreased weight of the mice infected with the chimeric viruses that was described in the research summaries sent to NIH. “From the weight loss, it’s gain of function. Tony Fauci is wrong saying it’s not.”
But the documents do not prove Paul’s claim that Fauci was lying, as they do not make clear whether Fauci read them. Nor do they in any way support Paul’s allegation that Fauci was “responsible for 4 million people around the world dying of a pandemic” — or that anyone intentionally caused Covid-19. What is clear is that program officers at NIAID, the agency that Fauci oversees, did know about the research.
A paragraph describing the research, as well as two figures illustrating its results, were included in both a 2018 progress report on the bat coronavirus grant and an application for its 2019 renewal. And NIH confirmed that it reviewed them.
“NIH has never approved any research that would make a coronavirus more dangerous to humans,” the agency said in a statement, echoing remarks by Collins, the NIH director, posted to its website in May. “The research we supported in China, where coronaviruses are prevalent, sought to understand the behavior of coronaviruses circulating in bats that have the potential to cause widespread disease.” Similar research funded by NIH had aided in the development of vaccines against the coronavirus, the statement continued.
The White House did not respond to questions about the research.
Shifting Definitions, Growing Viral Load
The humanized mouse experiment fits with the overall goal of the $3.1 million grant, which was titled “Understanding the Risk of Bat Coronavirus Emergence” and aimed at preventing a pandemic by predicting the circumstances under which a bat coronavirus could evolve to infect humans. The researchers took an ambitious three-pronged approach: screening people with high exposure to wildlife, mathematical modeling, and lab experiments on viruses. Peter Daszak, the EcoHealth Alliance president, has worked closely with scientists in China for years, and roughly $750,000 of the grant was allocated for the Wuhan Institute of Virology. An additional nearly $300,000 went to East China Normal University, where researchers did field sampling.
In a 2005 paper, Daszak’s team showed that the first SARS virus originated in bats. Middle East respiratory syndrome, or MERS, is caused by a coronavirus that emerged in 2012 and also believed to come from bats, which are now a prime target for virologists trying to understand and combat emerging diseases. Daszak has long maintained that his research is critical to preventing outbreaks.
But the research on the bat viruses in Wuhan showed that infecting live animals with altered viruses can have unpredictable consequences. A report to NIH on the project’s progress in the year ending in May 2018 described scientists creating new coronaviruses by changing parts of WIV1 and exposing genetically engineered mice to the new chimeric viruses. Research published in 2017 in the journal PLOS Pathogen showed that, in cells in a laboratory, similar chimeric viruses reproduced less effectively than the original. NIH cited that research as one of the reasons the moratorium on gain-of-function research of concern didn’t apply to this experiment. “It was a loss of function, not a gain of function,” the email from NIH explained. (NIH also pointed out that the changes to the chimeric viruses “would not be anticipated to increase virulence or transmissibility in humans.”)
Inside the lungs of the humanized mice, however, the novel viruses appear to have reproduced far more quickly than the original virus that was used to create them, according to a bar graph shown in the documents. The viral load in the lung tissue of the mice was, at certain points, up to 10,000 times higher in the mice infected with the altered viruses than in those infected with WIV1. According to Deatrick, the NIH spokesperson, the difference in the rates of viral reproduction — which were particularly pronounced two and four days after the mice were infected with the virus — didn’t amount to gain of function because, by the end of the experiment, the amount of virus produced by the parent and chimeric strains evened out. “Viral titers were equivalent by the end of the experimental time-course,” Deatrick wrote. The email also said, “NIH supports this type of research to better understand the characteristics of animal viruses that have the potential to spill over to humans and cause widespread disease.”
Scientists The Intercept consulted expressed differing views on whether the increase in viral load could be translated to an increase in transmissibility, which relies on the virus’s ability to replicate. To some, the jump in viral load indicated that the modified RNA virus could replicate far more rapidly than the original in the lungs of the mice, likely leading to increased pathogenicity and spread. Rasmussen, of the Vaccine and Infectious Disease Organization, pointed out that viral load is not identical to reproduction rate, noting: “This shows the chimeric viruses replicated a little faster, but that tells us exactly nothing about transmissibility. Furthermore, WIV1 caught up by the end of the experiment. We see differences in the rate of viral replication all the time, but it is often not directly correlated with pathogenicity.”
Another figure in the documents suggests that at least one of the altered viruses not only enhanced viral reproduction, but also caused the humanized mice to lose more weight than those exposed to the original virus — a measure of the severity of illness.
NIH requires the increase in viral reproduction to be immediately reported, according to a note in the Notice of Award the agency issued in July 2016. “No funds are provided and no funds can be used to support gain-of-function research covered under the October 17, 2014 White House Announcement,” the note said. If any new MERS-like or SARS-like chimeras show “enhanced virus growth greater than 1 log over the parental backbone strain,” the note continued, the researchers were instructed to stop all experiments with the viruses and send the data to NIAID grant specialists, as well as to the Wuhan Institute of Virology biosafety committee. The enhanced growth of the chimeric coronaviruses in the humanized mice was, at one point, up to 4 log greater — or 10,000 times — the rate of the original virus. But there are no indications the research was stopped.
In fact, the bat coronavirus grant was renewed for a five-year period in 2019, although the Trump administration suspended funding in April 2020 amid the Covid-19 pandemic and spiraling concerns about its origins. (Funding was later reinstated but under strict conditions that Daszak said were impossible for his group to meet.)
Kessler, EcoHealth Alliance’s communications manager, also pointed to the fact that the grant was renewed in 2019 — after EcoHealth Alliance had twice submitted documents detailing the experiment — as evidence that the organization did nothing wrong. “If there had been any violations, they would not have done so,” he said.
Long History of Controversy
The practice of making chimeric viruses in order to study how they might become more contagious was under scrutiny long before the pandemic. Proponents of such gain-of-function research argued that it can help virologists better understand and defend against natural outbreaks. But critics said that they were unreasonably dangerous.
In October 2014, the federal government put a moratorium on funding gain-of-function research on potential pandemic pathogens that could be “reasonably anticipated” to lead to spread in humans, as outlined in a 2017 guidance from the Department of Health and Human Services. In December 2017, the moratorium was lifted and replaced with new guidelines for oversight of research using potential pandemic pathogens. The grantees reported that the humanized mouse experiment was done between June 2017 and May 2018. Gain-of-function research was thrust into the spotlight again in 2020, amid speculation that the Wuhan Institute of Virology had conducted such research and that it was somehow linked to the pandemic.
While the new information about the research on humanized mice does not provide the “smoking gun” for proponents of what has become known as the “lab leak theory,” it lends the hypothesis credence, according to Stuart Newman, a professor of cell biology who directs the developmental biology laboratory at New York Medical College. “Making chimeric coronaviruses, mixing and matching RBDs [a part of the virus that allows it to attach to receptors] and spike proteins is exactly the scenario imagined by many lab-leak scenario proponents,” said Newman. “The fact that this was an established research paradigm in the Wuhan lab … definitely makes the laboratory origin more plausible.”
The documents about the research were released by NIH after The Intercept submitted a Freedom of Information Act request in September 2020, later suing to have it fulfilled. The request sought copies of these and other grant proposals that Daszak submitted to the agency, as well as the agency’s communications about the proposals. NIH originally denied The Intercept’s request on the grounds that releasing Daszak’s proposals would undermine an ongoing investigation. Counsel for the agency later admitted that NIH had not reviewed many of the records before making that assertion.
“The contents of the grants raise serious questions about the review processes and oversight relating to risky pathogen research,” said Alina Chan, a Boston-based scientist and co-author of the upcoming book “Viral: The Search for the Origin of Covid-19.” The new information in the documents warrants further inquiry into whether researchers may have omitted information about other concerning experiments, she said. “The question is: What else did they do in more recent years that we’re not aware of?”
Documents referenced in this article:
Understanding the Risk of Bat Coronavirus EmergenceThe Intercept v. National Institutes of Health
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The Intercept | 10 Sep 2021
by Sharon Lerner, Mara Hvistendahl, Maia Hibbett
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