Debating the origins of the COVID-19 virus: What we know, what we don’t know

Confronting Dr. Anthony Fauci at a Senate committee hearing on the COVID-19 pandemic, Sen. Rand Paul argued that the United States collaborated with the Wuhan Institute of Virology in China to make a more deadly coronavirus.

The Kentucky Republican made the explosive allegation the day after Fox News talk show host Tucker Carlson made another far-reaching accusation, stating that a recent article "makes it clear that, more than any other single living American, Tony Fauci is responsible for the COVID-19 pandemic."

"Dr. Fauci, we don't know whether the pandemic started in a lab in Wuhan or evolved naturally, but we should want to know," Paul said in a Senate hearing. "To arrive at the truth, the U.S. government should admit that the Wuhan Virology Institute was experimenting to enhance the coronavirus' ability to infect humans.

"Juicing up super-viruses is not new," Paul continued. "Scientists in the U.S. have long known how to mutate animal viruses to infect humans. 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, director of the NIH’s National Institute of Allergy and Infectious Diseases and the federal government’s leading voice on COVID-19, rebutted Paul by saying: "The NIH and NIAID categorically have not funded gain-of-function research to be conducted in the Wuhan Institute of Virology."

In an interview with PolitiFact at United Facts of America: A Festival of Fact-Checking shortly after the hearing, Fauci called Paul’s accusation "preposterous." 

"He was saying we funded a kind of research in China that could lead to dangerous research; that’s not the case. So, what he was saying was just absolutely not true," Fauci said. 

Fauci added: "So, in a very minor collaboration, as part of a subcontract of a grant, we had a collaboration with some Chinese scientists. And what he conflated is that therefore we were involved in creating the virus, which is the most ridiculous, majestic leap I’ve ever heard of."

Asked if he was confident the virus developed naturally, Fauci said, "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. ... I’m perfectly in favor of any investigation that looks into the origin of the virus."

While there is no hard evidence that the COVID-19 virus was developed in a lab, the Wuhan lab did use reverse genetics on bat coronaviruses, which some scientists believe fits the definition of gain-of-function research. 

Proponents of this form of study, which involves forcing the evolution of a pathogen, sometimes to boost its infectivity and lethality, say it helps researchers spot potential threats to human health and allows them to figure out ways to tackle a new virus. Critics claim that the practice constitutes a massive biosafety risk. 

The conversation around gain-of-function gathered new momentum from an 11,000-word article, posted on Medium on May 2, by Nicholas Wade, a former science writer and editor for the New York Times. It argues that evidence is stronger that the virus leaked from a lab than that it occurred naturally. 

Officials and researchers are also paying more attention to the possibility that the virus somehow leaked from the lab. But there’s still nothing conclusive.

"Ultimately, without any proper and thorough investigation having been conducted, the origins of COVID-19 remain a completely open question," said Nikolai Petrovsky, director of endocrinology at Flinders Medical Centre and professor of medicine at Flinders University in Australia. 

Here’s a look at what we know and don’t know about the origin of the virus that produced COVID-19.

RELATED: Can scientific uncertainties about COVID-19 be fact-checked?

The basis for Paul’s attack is federal funding for a 2014 project at the lab in Wuhan, the city where the coronavirus outbreak was first documented. PolitiFact has previously looked into unproven claims about U.S. research funding and the lab. 

In 2014, the National Institute of Allergy and Infectious Diseases, the NIH arm that Fauci heads, awarded a $3.4 million grant to the New York-based EcoHealth Alliance, which aims to protect people from viruses that jump from species to species. The alliance has projects across 30 countries, including Thailand, Vietnam and China. 

The group hired the virology lab in Wuhan to conduct genetic analyses of bat coronaviruses collected in Yunnan province, about 800 miles southwest of Wuhan. The research was considered crucial in part because coronaviruses had previously emerged in China and begun to spread among humans. EcoHealth Alliance paid the lab $598,500 over five years. The lab had secured approval from both the U.S. State Department and the NIH. 

Fauci has advocated for gain-of-function research in the past. In a 2011 article he co-wrote for the Washington Post, he promoted it as a means to study influenza viruses. 

All parties involved in the grant to the Wuhan Institute of Virology have denied that it involved gain-of-function research. The grant was approved in May 2014. Five months later, the Obama administration announced it would not fund new projects that involved gain-of-function research, citing safety and security risks, though there’s an exception in the moratorium that allows it for research "urgently necessary to protect public health or national security."

Early in the pandemic, the consensus among public health experts was that the COVID-19 coronavirus evolved naturally in a bat and jumped to humans through an intermediary species. But since then, amid calls by Fauci and others for deeper investigation of what happened in China, scientists have publicly raised questions about whether a virus was collected at the Wuhan lab and then escaped. Those questions remain unanswered.

More attention is being paid to two key questions about the origin of this coronavirus: 

• Could the virus have leaked from a lab?

• Did gain-of-function research create SARS-CoV-2, the virus that causes COVID-19?

So far, there is no hard proof to support either the theory that the virus had natural origins or the theory that it leaked from a lab, said Richard Ebright, a professor of chemistry and chemical biology at Rutgers University, who has frequently been cited by proponents of the lab-leak hypothesis, including Paul. 

"At this point in time, all scientific data related to the genome sequence of SARS-CoV-2 and the epidemiology of COVID-19 are equally consistent with a natural-accident origin or a laboratory-accident origin," he told PolitiFact.

Scientists open to the lab-leak theory have cited three pieces of circumstantial evidence in support of the hypothesis: 

The first is simply the site of the outbreak. The city of Wuhan is, according to Ebright, "tens of kilometers from, and outside the flight range of, the nearest known horseshoe bat colonies." Furthermore, the first cases of the coronavirus occurred in September when cold temperatures drive horseshoe bats into hibernation. 

Second, the first outbreak occurred close to the Wuhan Institute of Virology, where researchers studied bat coronaviruses, including the world’s closest relative to SARS-CoV-2. The laboratory searched for horseshoe bat colonies in caves in Yunnan province, and then brought those viruses back to Wuhan, where they were mass-produced, genetically manipulated and studied. 

Third, Ebright says, some of the bat-SARS-related coronavirus projects at the Wuhan Institute were conducted at biosafety standards that would pose a potentially high risk of infection if laboratory staff were to come in contact with the virus.

Skeptics of the lab-leak theory, however, have argued that an alternate explanation is better founded in evidence. In their view, it’s more likely that the coronavirus evolved naturally in bats and then jumped to humans either directly or by way of an intermediary species such as pangolins or raccoon dogs. Past diseases, including SARS, a similar coronavirus, have infected humans through intermediaries.

An intermediary species could have been brought to Wuhan and infected a human at a wildlife market. The first cases of SARS-CoV-2 "were connected to not one but several markets where (people) sold wildlife or wildlife products," said Robert Garry, a virologist at Tulane Medical School. In fact, two different genetic lineages of SARS-CoV-2 were circulating early — both linked to wildlife markets, he said. 

It seems unlikely, Garry said, that two distinct strains of a new virus leaked from the Wuhan lab and made their way to two different places that sold animals susceptible to SARS-CoV-2. 

However, it’s still not obvious that the pandemic began in a wildlife market. An early and massive outbreak of the coronavirus did occur at Huanan Seafood Market in Wuhan, which was previously speculated to be the origin site of the pandemic. But a team of investigators from the World Health Organization sent to dig into the pandemic’s origins did not find any animals infected with the coronavirus at a market, and neither have Chinese researchers who have tested tens of thousands of specimens. This means that there’s no proof of animal-to-human transmission at Huanan or at other markets.

"To my knowledge, no one has reported finding the virus in a live animal (or a frozen body part of an animal) in even one market, whether in Wuhan, elsewhere in Hubei province, or south in Kunming city, or elsewhere in Yunnan province or anywhere else in China or outside China," said Daniel Lucey, an infectious-disease specialist at Georgetown University. 

Joel Wertheim, an evolutionary biologist at the University of California San Diego and proponent of the naturally-occurring theory, acknowledged that this theory leaves unanswered questions about the virus’ origins, such as the missing intermediary species and the route the virus took to Wuhan.

"But not having answers to difficult scientific questions shouldn’t force us to default to conspiracy theories," he said. "It took scientists decades of research to find the chimpanzee host populations for the HIV/AIDS pandemic."

The lab leak theory is distinct from the hypothesis that gain-of-function research created the new coronavirus, said Alina Chan, a molecular biologist at the Broad Institute of Harvard University and the Massachusetts Institute of Technology.

The lab leak theory "can be as simple as a researcher being infected by an animal or even another infected person in remote areas, and then bringing it into one of the most densely populated cities on Earth." The gain-of-function hypothesis supposes both that a virus leaked from the Wuhan Institute and that scientists there tampered with it in ways that could have made it more infective or deadly. 

This isn’t to say that scientists believe that the new coronavirus is a bioweapon designed to wreak havoc on human society. But some have entertained the possibility that a virus, modified through well-intentioned but risky experiments, escaped its enclosure and had the same effect. 

The closest known relative to SARS-CoV-2 is a bat coronavirus called RaTG13, which was discovered after miners cleaning bat guano in Yunnan Province developed pneumonia. RaTG13 was collected and sequenced by researchers at the Wuhan Institute of Virology. The genetic makeup of RaTG13 is 96% similar to that of the new coronavirus. 

"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," Garry told Health Feedback in March 2021. "The difference is about 1,200 bases or 400 amino acids. Gain-of-function research cannot close that gap. This would require a virus much closer than RaTG13, at least 99% similar or more likely 99.9% similar."

Lab-leak-theory proponents have alleged that gain-of-function research was conducted on RaTG13 or one of eight SARS-like coronaviruses collected in Yunnan to create the new coronavirus at the Wuhan lab. 

There’s no hard evidence that research of this kind created the novel coronavirus. Even scientists relatively open to the theory have been restrained in their speculation and have pushed back on those who have claimed that some "smoking gun" proves that the virus was manipulated. 

However, some scientists told PolitiFact that the Wuhan lab did conduct gain-of-function research on bat viruses, some of which was funded by the Ecohealth Alliance grant.

MIT biologist Kevin Esvelt reviewed a paper that was published with financial assistance from the grant for PolitiFact in February. According to Esvelt, certain techniques that the researchers used seemed to meet the definition of gain-of-function research, but their work was not related to the virus that causes COVID-19. Esvelt told PolitiFact that "the work reported in this specific paper definitely did NOT lead to the creation of SARS-CoV-2," because the genetic sequences of the virus studied in the paper differ from that of the new coronavirus. 

Ebright, the Rutgers biologist, also said that the work described in the paper met several definitions of gain-of-function research. "The work is far outside the bounds of normal biomedical research," he added. 

On the other hand, Wertheim and Garry said they didn’t believe the paper referenced gain-of-function experiments. "Although this study uses recombinant RNA technology, I would not consider it a gain-of-function study," said Wertheim. The researchers "did not continue to let these viruses propagate in cell lines to adapt and enhance their pathogenicity or transmissibility." 

It might seem strange that scientists could disagree over a question as seemingly clear-cut as whether or not a specific experiment involved gain-of-function research. However, the term "gain-of-function" refers to a wide variety of interventions, and the definition has shifted over time, making it easy for scientists to talk past one another. 

The original definition of gain-of-function included "any selection process involving an alteration of genotypes and their resulting phenotypes," which, according to Alina Chan, "covers a ton of research that doesn't even come close to risky pathogen research." Subsequent definitions have narrowly targeted obviously dangerous experiments that would enhance the transmissibility and deadliness of "potential pandemic pathogens." 

What the paper shows is that the researchers at the Wuhan Institute used reverse genetics to create coronaviruses that do not exist in nature and then tested whether they could replicate in human cells. However, Wertheim said, "similar recombinant RNA approaches — inserting virus surface proteins into the backbone of other viruses" are used in other scientific methods, such as generating vaccines. "I wouldn’t qualify these … as gain-of-function, either," he said.  

David Relman, a microbiologist at Stanford University, said that the investigators in the paper did not appear to be motivated by the deliberate goal of making a more deadly virus; however, he still viewed the research as "highly risky." 

According to Relman, "the general technique is frequently used and not necessarily problematic. But this particular application of it is problematic," because of the distinct possibility that the researchers could have made a virus more dangerous for humans. 

Another point of debate among scientists is whether unusual aspects of the virus leave open the possibility that the virus was artificially manipulated. Scientists have generally agreed that the virus doesn’t show clear signs of tampering. However, some argue that extremely competent forms of gain-of-function research wouldn’t necessarily leave telltale signs of manipulation, making it hard to rule out the claim that the virus was somehow engineered. 

One strange feature of the virus — called the furin cleavage site — has been the focus of lab-leak proponents, including Wade. Gain-of-function researchers have added furin cleavage sites to viruses in the past, and the coronavirus’s site is unusual. But Kristian G. Andersen, a microbiologist at the Scripps Research Institute, has pointed out that furin cleavage sites are also found in distantly related coronaviruses.

Petrovsky, the Australian expert, believes that SARS-CoV-2 was unusual among pandemic viruses in that it was "already very well adapted to human infection and human transmission ... This raised questions of whether this could have happened by rare chance, in an unrecognised host species or whether this adaptation might have occurred due to natural selection or genetic engineering in a laboratory environment."

Wertheim, on the other hand, told us that the virus’s genome doesn’t bear any marks of human intervention, genetic manipulation or laboratory passage. "SARS-CoV-2 was not supremely adapted to humans, (or) guaranteed to cause a pandemic, when it first showed up in Wuhan. In fact, we’ve seen this virus adapt to infecting and transmission among humans again and again throughout this pandemic."

Relman offered perhaps the most definitive answer to the question of whether gain-of-function had been performed on the virus:

"I have no idea. Nor does anyone else. We don’t have the needed data to be able to say."

We asked Baric, a professor in epidemiology, microbiology and immunology at the University of North Carolina at Chapel Hill and a top authority on coronaviruses, about  Paul’s characterization of his work during the Senate hearing. Baric’s response said that his work involved a very different strain of coronavirus than the one that causes COVID-19, and that the study followed all safety protocols and was considered low risk. 

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 and not China."

Baric told PolitiFact in a statement that he believed that "SARS-CoV-2 is a zoonotic virus that passed from bats to humans based on the primary sequence of the virus, its phylogeny and relationship to other bat strains, historic precedent and it’s incredibly complex disease mechanisms. Consequently, I do not believe it was generated from gain of function research, while also noting that many independent research groups have demonstrated that SARS-CoV-2 is distinct from any of the recombinant coronaviruses being studied prior to 2020."

Baric has said he thought the virus came from bats in southern China, perhaps directly or possibly via an intermediate host, and that he suspected the disease evolved in humans over time without being noticed. Eventually a person carried it to Wuhan "and the pandemic took off," Baric told New York magazine in January. "Can you rule out a laboratory escape? The answer in this case is probably not."

Baric, Chan and Relman are among 18 prominent biologists who signed a letter published May 14 in the journal Science stating that "greater clarity about the origins of this pandemic is necessary and feasible to achieve," and that an investigation that considers "both natural and laboratory spillovers" should be done.

Much uncertainty remains about the origins of COVID-19. For those who encounter conspiracy theories about the disease, it’s best to keep the following (fairly nuanced) points in mind:  

• SARS-CoV-2 was first noticed in Wuhan, close to a lab where bat coronaviruses were being studied and far from the location where naturally occurring relatives of the virus were found. However, there are other plausible explanations of how the virus could have made its way to Wuhan besides a lab leak.

• Researchers at the Wuhan lab used reverse genetics on bat coronaviruses to create viruses not found in nature. Some of this research was funded by a grant provided by the National Institutes of Health. However, there’s no evidence that this research led to the creation of SARS-CoV-2. 

• Scientists who have studied the coronavirus have generally concluded that it resembles naturally occurring viruses. However, we can’t completely rule out that the virus was somehow manipulated. Some extremely competent forms of gain-of-function research don’t leave signatures or telltale signs of manipulation. 

• The early outbreak of the coronavirus was linked to various wildlife markets, which lends support to the claim that the virus jumped from animals to humans. However, scientists haven’t yet identified an intermediate host animal that could have incubated the virus before it jumped to humans. 

In any event, none of this amounts to hard proof of either theory. Some scientists have argued that the lab-leak hypothesis deserves to be taken much more seriously than it was earlier in the pandemic, and that dismissals of it as conspiracy theory were premature. Claims of complete certainty on either side remain unfounded.

UPDATE: This report was updated soon after initial publication to include comments from Dr. Ralph Baric.