Image: Scanning electron microscope image showing SARS-CoV-2 (round gold objects) emerging from the surface of cells cultured in the lab. Credit NIAID-RML
INSIGHT
Introduction
One of the questions currently being debated about the origin of COVID-19 is whether the U.S. National Institutes of Health (NIH) funded research on bat coronaviruses that could cause a virus to become more infectious or more dangerous to humans. This is separate from the question of whether SARS-CoV-2 is a naturally occurring bat coronavirus that jumped to humans or whether the virus was accidentally released from a lab.
One example of claims dealing with this question came from Fox News talk show host Tucker Carlson. On 10 May 2021, Carlson claimed that gain-of-function research funded by the NIH had been carried out at the Wuhan Institute of Virology. Carlson’s basis for this claim was an opinion piece by Nicholas Wade, formerly a staff science journalist at the New York Times, even though Wade himself pointed out in his opinion piece that there is no direct evidence for this hypothesis.
Another instance occurred on 11 May 2021, when Anthony Fauci, the director of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), testified before the U.S. Senate concerning the U.S. COVID-19 response. During his testimony, Senator Rand Paul questioned Fauci over claims about a link between the Wuhan Institute of Virology and the NIH.
Paul specifically claimed that “For years, Dr. Ralph Baric, a virologist in the U.S., has been collaborating with Dr. Shi Zhengli of the Wuhan Virology Institute, sharing his discoveries about how to create super-viruses. This gain-of-function research has been funded by the NIH.”
Fauci denied this. “Senator Paul, with all due respect, you are entirely and completely incorrect,” he replied, “the NIH has not ever and does not now fund gain-of-function research in the Wuhan Institute of Virology.”
Following this exchange, this claim that the Wuhan Institute of Virology received money from the NIH was again shared on Instagram, Twitter and Facebook (for example here by Paul himself and here).
A third recent example of this claim was made by Liz Wheeler, in her video podcast “The Liz Wheeler Show” on 26 May 2021, claimed that the NIH funded research to “weaponize” bat coronaviruses to attack humans. She claimed that gain-of-function experiments were carried out at the Wuhan Institute of Virology, including manipulating the genome of viruses that naturally infect animals to allow them to infect humans. Wheeler claimed that this work would make the manipulated coronaviruses more dangerous for humans.
In this article, we discuss what is known and what is debated about the research at the Wuhan Institute of Virology and whether parts of it are considered gain-of-function research.
The Wuhan Institute of Virology was a sub-contractor of an NIH grant
We know that the Wuhan Institute of Virology received funding from the NIH, albeit indirectly. Between 2015 and 2019, the Wuhan Institute of Virology received $814,608 as a sub-awardee from grants awarded by the NIH. Records of this are displayed under Sub-Awards on the website USAspending, which is maintained by the U.S. government, shows. For one grant, the prime recipient was the University of California, Irvine. For five other grants, the prime recipient was EcoHealth Alliance Inc.
The NIH awarded a $3.4 million grant to the non-profit organization EcoHealth Alliance Inc. over six years, funding research to study the risk of bat coronavirus emergence. This sum of money was administered by the National Institute of Allergy and Infectious Diseases (NIAID), the institute of the NIH directed by Fauci. EcoHealth Alliance then awarded part of the money to the Wuhan Institute of Virology ($598,500 over five years).
As Robert Kessler, a spokesman for EcoHealth Alliance, explained to the Washington Post, the organization “was funded by the NIH to conduct study [sic] of coronavirus diversity in China. From that award, we subcontracted work with the Wuhan Institute of Virology to help with sampling and lab capacity.” In April 2020, the grant to EcoHealth Alliance was terminated by the Trump administration. The grant was later reinstated, but funds can only be used if conditions set by the NIH are met.
Summing up, the Wuhan Institute of Virology received funding from the NIH, via a grant awarded to EcoHealth Alliance.
Gain-of-function research alters traits to better understand pathogens; the definition of gain-of-function research depends on who you ask
In her video, Wheeler claimed that the NIH funded research intended to “weaponize” bat coronaviruses and make them more dangerous for humans. Wheeler added that this work is referred to as gain-of-function research.
However, there is controversy among scientists over whether the NIH-funded work carried out at the Wuhan Institute of Virology is considered gain-of-function research.
The term gain-of-function research reflects the goal of such research. Specifically, it involves manipulating a virus in a way that it improves the virus’ ability to do something, for example increase its transmissibility. Such experiments allow scientists to better predict emerging infectious diseases, plan how to combat a virus, and develop potential vaccines or therapeutics.
One example of gain-of-function research that has been done is in flu vaccine development. For example, when researchers grow the human influenza virus, isolated from a nasal or throat swab, in a fertilized chicken egg, they can select for a virus clone that has accumulated mutations which enable the virus to “gain the function” of growing in a chicken egg. This long-standing approach is used for producing the influenza vaccine[1].
Gain-of-function research came under scrutiny in 2012 when two teams of scientists made a version of the H5N1 avian flu strain that could spread between ferrets while trying to understand how the virus may be transmitted between humans[2,3].
In 2014, NIH funding for new gain-of-function virology studies that alter a pathogen to make it more transmissible or deadly was paused for three years. During this pause, gain-of-function research was defined thus in this statement by the White House: “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.”
The pause was intended to provide time to address the risks and benefits of this kind of research, to develop a policy for weighing risks, and to improve biosafety and biosecurity protocols for funded projects.
“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 clarified in its announcement.
What kind of research is risky and where the line is drawn for “reasonably anticipating” that a change enhances pathogenicity or transmissibility was subject to debate. In a Nature news article from October 2014, Arturo Casadevall, then a microbiologist at the Albert Einstein College of Medicine and now at Johns Hopkins, said 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.”
The U.S. government’s funding pause was lifted on 19 December 2017. The U.S. Department of Health and Human Services announced a framework for funding research on so-called enhanced potential pandemic pathogens (PPP).
This framework defined PPP as a pathogen that is “likely highly transmissible” and “likely highly virulent and likely to cause significant morbidity and/or mortality in humans”. An enhanced PPP is one that results “from the enhancement of the transmissibility and/or virulence of a pathogen”. Under this framework, enhanced PPPs do not include pathogens that are naturally circulating and have been recovered from nature.
As described above, gain-of-function research is hard to define. For all intents and purposes, work that increased transmissibility or enhanced pathogenicity fell under the NIH’s definition of gain-of-function research, based on the definition given during its funding pause.
Grant for research at the Wuhan Institute of Virology didn’t fall under the NIH’s definition of gain-of-function research
While funding for gain-of-function research was paused, the EcoHealth Alliance project that was carried out with the Wuhan Institute of Virology was reviewed by the NIH, according to a statement by the NIH to the Washington Post from 19 May 2021. It was determined that this work did not involve gain-of-function research. In this statement, the NIH also said that:
“NIH has never approved any grant to support ‘gain-of-function’ research on coronaviruses that would have increased their transmissibility or lethality for humans.”
The NIH told the Wall Street Journal what work the specific studies carried out by EcoHealth Alliance and the Wuhan Institute of Virology involved.
“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.”
As Alina Chan, a molecular biologist at the Broad Institute of MIT and Harvard, explained, the EcoHealth Alliance/Wuhan Institute of Virology research did not fall under the moratorium because it was using natural viruses and it could be reasonably argued that these were not likely to be highly transmissible and highly virulent in humans.
Stanley Perlman, a microbiologist at the University of Iowa, told FactCheck.org that EcoHealth’s research was about “trying to see if these viruses can infect human cells and what about the spike protein on the virus determines that.” According to FactCheck.org, Perlman did not think there was anything in the EcoHealth grant description that would be gain-of-function research.
As shown above, the definition of gain-of-function research is difficult to pin down. But in relation to the NIH’s definition of gain-of-function research, the research described in EcoHealth’s grant application didn’t fall under the NIH’s definition from 2014.
No evidence that coronaviruses were engineered to be more dangerous for humans
A 2017 study published by researchers at the Wuhan Institute of Virology, listing the NIH as a funding body, appears related to this grant[4]. The researchers wanted to test whether the spike protein of new wild coronaviruses, which they isolated in bats, would allow the coronaviruses to enter human cells.
The problem with studying coronaviruses is that they are hard to culture in the lab[5]. To carry out their study, the researchers used the genetic sequence of a coronavirus (WIV1) that does replicate in vitro (in the lab) and inserted the spike proteins of the newly isolated viruses. In this way, they could test whether the newly isolated viruses could replicate in human cells in a lab dish.
Data included in the publication[4] showed that these experiments did not enhance the viruses’ infectivity. The experiments therefore did not make viruses more dangerous to humans or more transmissible.
All parties involved in the NIH grant to EcoHealth Alliance and the Wuhan Institute of Virology stated that this work did not involve gain-of-function research, according to a fact check by PolitiFact. The NIH told PolitiFact that:
“The research supported under the grant to EcoHealth Alliance Inc. characterized the function of newly discovered bat spike proteins and naturally occurring pathogens and did not involve the enhancement of the pathogenicity or transmissibility of the viruses studied.”
However, Richard Ebright, professor of chemistry and chemical biology at Rutgers University and a critic of gain-of-function research, told the Washington Post that “the research was—unequivocally—gain-of-function research. The research met the definition for gain-of-function research of concern under the 2014 Pause.”
And Kevin Esvelt, a biologist at the MIT Media Lab, stated in a fact-check by PolitiFact that “certain techniques that the researchers used seemed to meet the definition of gain-of-function research”.
On the other hand, Joel Wertheim, an evolutionary biologist at the University of California San Diego, told PolitiFact that the experiments carried out in the 2017 study, despite using recombinant RNA technology, don’t meet the criteria for gain-of-function research in virology.
This is because the researchers didn’t allow the created viruses to keep on replicating in human cells, which would enable them to adapt and enhance the viruses’ transmissibility or pathogenicity. According to Wertheimer, similar approaches as employed in the 2017 study – inserting virus surface proteins into the backbone of other viruses – are also used in other instances, such as making vaccines, which do not qualify as gain-of-function research.
“The work ultimately was not aimed at creating viruses that were more infectious. It was taking parts of natural viruses and studying them in well-characterized virus genome backbones,” Chan wrote about the EcoHealth/Wuhan Institute of Virology research.
Esvelt also emphasized that the research involved in this 2017 study couldn’t have led to the emergence of SARS-CoV-2. According to Esvelt’s statement to PolitiFact, the work reported in the Wuhan Institute of Virology’s 2017 study[4] didn’t lead to the creation of SARS-CoV-2, because the genetic sequences of the virus studied in the paper and SARS-CoV-2 differ too much.
The closest known relative to SARS-CoV-2 is yet another bat coronavirus, called RaTG13, which was discovered after miners in the Yunnan Province of China developed pneumonia[6]. The group of researchers at the Wuhan Institute of Virology collected and sequenced RaTG13. The genetic sequence of SARS-CoV-2 is 96% similar to that of RaTG13[6]. As a Health Feedback review from March 2021 pointed out, this genetic gap between RaTG13 and SARS-CoV-2 is too wide to be bridged by engineering.
In the same review, Robert Garry, a professor of microbiology at the University of Tulane, concurred: “While 96% sounds close, in evolutionary terms, it is quite distant, and it would take decades of evolution for the genome of RaTG13 to resemble that of SARS-CoV-2. The difference is about 1,200 bases or 400 amino acids. Gain-of-function research cannot close that gap.” He added, “This would require a virus much closer than RaTG13, at least 99% similar or more likely 99.9% similar.”
Conclusion
The NIH indirectly funded research at the Wuhan Institute of Virology, a sub-contractor to a grant awarded to EcoHealth Alliance. This grant was reviewed during the NIH’s funding pause on gain-of-function research, and was determined to not fall under the definition of gain-of-function research used by the NIH for the funding pause.
There is controversy among scientists whether a study from the Wuhan Institute of Virology, carried out with NIH funding, used gain-of-function techniques. However, this study did not work on making the virus more infectious for humans. The research involved in this study couldn’t have led to the emergence of SARS-CoV-2, as the two viruses are too different.
REFERENCES
- 1 – Breithaupt et al. (2014) Flu season. EMBO Reports.
- 2 – Herfst et al. (2012) Airborne transmission of influenza A/H5N1 virus between ferrets. Science.
- 3 – Russell et al. (2012) The potential for respiratory droplet-transmissible A/H5N1 influenza virus to evolve in a mammalian host. Science.
- 4 – Hu et al. (2017) Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLoS Pathogens.
- 5 – Zeng et al. (2016) Bat severe acute respiratory syndrome-like coronavirus WIV1 encodes an extra accessory protein, ORFX, involved in modulation of the host immune response. Journal of Virology.
- 6 – Zhou et al. (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature.