Table of contents

COVID-19 lab leak theory

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The Wuhan Institute of Virology

The COVID-19 lab leak theory proposes that SARS-CoV-2 (the virus that causes COVID-19) escaped from a laboratory in Wuhan, China, resulting in the COVID-19 pandemic.[1][2] The idea developed from the circumstantial evidence that the Wuhan Institute of Virology (WIV) is close in proximity to the pandemic's early outbreak[3] and from suspicions about the secretiveness of the Chinese government's response to the pandemic.[4] Scientists from the WIV were known to have collected SARS-related coronaviruses; the allegation that the institute performed undisclosed risky work on such viruses is central to some versions of the idea.[5][6] Some versions (particularly those alleging human intervention in the SARS-CoV-2 genome) are based on speculation, misinformation, or misrepresentations of scientific evidence.[7][8][9][10]

The idea that the virus was released from a laboratory, either accidentally or deliberately, appeared early in the pandemic. It gained popularity through its promotion by political figures such as US president Donald Trump and other members of the Republican Party, as well as its dissemination in American conservative media, fomenting tensions between the United States and China. It was subsequently widely dismissed as a conspiracy theory.[2][11]

The idea of an accidental lab leak regained scientific and media attention in 2021.[1] In March, the World Health Organization (WHO) published a report into the origins of the virus which found the possibility to be "extremely unlikely", although Tedros Adhanom, Director-General of the WHO, said that its conclusions were not definitive and data had been withheld from investigators.[12] In June 2021, the WHO announced plans for a second phase of investigation that would include audits of laboratories and research institutions, which China rejected.[4][13]

In August 2021, the results of an intelligence community probe into the origins ordered by US president Joe Biden were declassified. The probe assessed that the Chinese government did not have foreknowledge of the outbreak.[14] Overall, the probe assessed both "natural exposure to an infected animal" and "laboratory-associated incident" as plausible, but did not render conclusive results on the origins. Of eight assembled teams, one leaned towards a lab leak explanation (with moderate confidence), four others (and the National Intelligence Council) leaned towards zoonotic origins (with low confidence), and three were unable to reach a conclusion.[15][16][17][18]

Most scientists have remained skeptical of the idea, describing it as a remote possibility; citing a lack of supporting evidence and believing that a natural origin is far more likely.[19] Some scientists, despite being concerned about the risks of politicization,[20][21] agree that the possibility of a lab leak should be examined as part of the ongoing investigations into the origin of COVID-19.[22][23]

Contents

- 1Background

- 2Versions

- 2.1Accidental release of a natural virus

- 2.2Release of a genetically modified virus

- 2.2.1Accidental release

- 2.2.2As a bio-weapon

- 3Timeline

- 3.1First appearance

- 3.2Renewed media attention

- 4Claims and rebuttals

- 4.1Pre-adaptation to humans

- 4.2Inadequate safety procedures

- 4.3Gene database going offline

- 4.4Missing intermediate host

- 5See also

- 6External links

- 7References

Background

Main article: Severe acute respiratory syndrome coronavirus 2 § Reservoir and origin

Most new infectious diseases begin with a spillover event from animals,[20] and COVID-19 is considered by scientists to be "of probable animal origin".[24] COVID-19 has been classified as a zoonotic disease (naturally transmissible from animals to humans), but, because the natural reservoir of SARS‑CoV‑2 has not yet been found,[25] some scientists have argued the classification is premature.[24] The first known human infections from SARS‑CoV‑2 were discovered in Wuhan, China.[26] The original source of viral transmission to humans remains unclear, as does whether the virus became pathogenic (capable of causing disease) before or after a spillover event.[27][28][29] Because many of the early infectees were workers at the Huanan Seafood Market,[30][31] it was originally suggested that the virus might have originated from bats or pangolins sold at the market.[29][32] It was later determined that no bats or pangolins were sold at the market.[33] Bats are not commonly eaten in Central China.[34]

Bats, a large reservoir of betacoronaviruses, are considered the most likely natural reservoir of SARS‑CoV‑2.[35][36] Differences between bat coronaviruses and SARS‑CoV‑2 suggest that humans may have been infected via an intermediate host.[32] Research into the natural reservoir of the virus that caused the 2002–2004 SARS outbreak has resulted in the discovery of many SARS-like coronaviruses circulating in bats, most found in horseshoe bats. Analysis of related viruses indicates that samples taken from Rhinolophus sinicus show a resemblance of 80% to SARS‑CoV‑2.[37][38][39] Analysis also indicates that a virus collected from Rhinolophus affinis in a cave in Yunnan province, designated RaTG13, has a 96% resemblance to SARS‑CoV‑2.[26][40][41] The RaTG13 virus genome is the closest known sequence to SARS-CoV-2,[35][42] but it is not its direct ancestor.[7] Other closely-related sequences were also identified in samples from local bat populations in Yunnan province.[43] One such virus, RpYN06, shares 97% identity with SARS-CoV-2 in one large part of its genome, but 94% identity overall. Such "chunks" of very highly identical nucleic acids are often implicated as evidence of a common ancestor.[44][45]

The Wuhan Institute of Virology (WIV) had been conducting research on SARS-like bat coronaviruses since 2005,[46] and was involved in 2015 experiments that some experts (such as Richard Ebright) have characterized as gain-of-function.[6][47] Others (including Ralph Baric) have disputed the characterization, pointing out that the experiments in question (involving chimeric viruses) were not conducted at the WIV, but at UNC Chapel Hill, whose institutional biosafety committee assessed the experiments as not "gain-of-function".[48] Baric did acknowledge the risks involved in such studies, writing, "Scientific review panels may deem similar studies building chimeric viruses based on circulating strains too risky to pursue ... The potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens."[6][49]

As early as 2017, some scientists expressed concerns about the risk of pathogens escaping from the WIV.[50] This, along with other circumstantial evidence such as the proximity of the lab to the pandemic's early outbreak in Wuhan,[51] and the fact that the research at WIV was being conducted under the less stringent biosafety levels (BSL) 2 and 3,[6][52] has led to speculation that SARS-CoV-2 could have escaped from the Wuhan lab.[5]

Previous novel disease outbreaks, such as AIDS, H1N1, SARS, and the Ebola virus have also been the subject of conspiracy theories and allegations that the causative agent was created or escaped from a laboratory.[53] On several known occasions, such as the 2007 foot-and-mouth outbreak in the UK, laboratory leak incidents have occurred.[54] However, no epidemic has been caused by the leak of a novel virus; the only possible incident of research activity causing an epidemic was the 1977 Russian flu.[3] Molecular biologist Richard Ebright notes that the SARS virus has escaped from high-level biocontainment laboratories in China multiple times.[50]

Versions

Accidental release of a natural virus

This theory suggests the virus arose in humans from an accidental infection of laboratory workers by contact with a sample extracted from a wild animal or by direct contact with a captive animal or its respiratory droplets or feces.[11]

Other research indicates that the market may have only served as a jumping off point for a virus that was already circulating in Wuhan, facilitating rapid expansion of the outbreak.[27][55] A WHO-convened report, written by a joint team of Chinese and international scientists and published in March 2021,[22] stated that human spillover via an intermediate animal host was the most likely explanation, with direct spillover from bats next most likely. Introduction through the food supply chain and the Huanan Seafood Market was considered another possible explanation, though considerably less likely, and introduction through a laboratory incident was assessed to be "extremely unlikely".[35]

In March 2021, the WHO-convened report described this scenario as "extremely unlikely" and not supported by any available evidence.[35][56] The report also stated that the possibility could not be wholly ruled out without further evidence.[11] Nature News described the 300-page report as the result of a "major investigation", stemming from the work of 34 international scientists, SARS-CoV-2 genome tests in early patients, analyses of nearly 1,000 samples from the Huanan Market and from hundreds of market animals, analyses of death certificates, and interviews with researchers at the WIV.[57] A small number of researchers said that they would not trust the report's conclusions because it was overseen by the Chinese government, and some observers felt the WHO's statement was premature.[4] Other scientists found the report convincing, and said there was no evidence of a laboratory origin for the virus.[57] WHO Director-General Tedros Adhanom stated that the team had experienced difficulty accessing raw data on early COVID-19 cases and that the least likely hypothesis, a lab leak, required additional investigation because "further data and studies will be needed to reach more robust conclusions".[12][22][58]

The leader of the WHO investigatory team, Peter Ben Embarek, stated that although the team had been under political pressure from both inside and outside China, he had not felt pressed to remove anything from the final report. Ben Embarek later said that he supported further investigation into the lab leak idea because of the way the Chinese government had "tried to suppress all research in this area".[59] Dominic Dwyer, another scientist from the WHO team, said there was "no obvious evidence" the virus had started at the Wuhan Institute of Virology.[12]

The United States, European Union, and 13 other countries criticized the WHO-convened study, calling for transparency from China and access to the raw data and original samples.[60] Chinese officials described these criticisms as "an attempt to politicise the study".[61] Scientists involved in the WHO report, including Liang Wannian, John Watson, and Peter Daszak, objected to the criticism, and said that the report was an example of the collaboration and dialogue required to successfully continue investigations into the matter.[61]

Release of a genetically modified virus

Accidental release

See also: COVID-19 misinformation § Gain-of-function research, and Gain-of-function research § COVID-19 pandemic

One idea used to support a laboratory origin invokes previous gain-of-function research on coronaviruses. The idea of an experiment conducted in 2015 on SARS-like coronaviruses being the source of the pandemic was reported in British tabloids early in the pandemic.[62] Virologist Angela Rasmussen writes that this is unlikely, due to the intense scrutiny and government oversight gain-of-function research is subject to, and that it is improbable that research on hard-to-obtain coronaviruses could occur under the radar.[51] The exact meaning of "gain of function" is disputed among experts.[48][63][64]

In May 2020, Fox News host Tucker Carlson accused Anthony Fauci of having "funded the creation of COVID" through gain-of-function research at the Wuhan Institute of Virology (WIV).[63] Citing an essay by science writer Nicholas Wade, Carlson alleged that Fauci had directed research to make bat viruses more infectious to humans.[65] In a hearing the next day, Kentucky Senator Rand Paul alleged that the US National Institutes of Health (NIH) had been funding gain-of-function research in Wuhan, accusing researchers including epidemiologist Ralph Baric of creating "super-viruses".[63][48] Both Fauci and NIH Director Francis Collins denied that the US government supported such research.[63][64][65] Baric likewise rejected Paul's allegations, saying his lab's research into cross-species transmission of bat coronaviruses did not qualify as gain-of-function.[48] While a 2017 study of chimeric bat coronaviruses at the WIV listed NIH as a sponsor, NIH funding was only related to sample collection.[48] A Washington Post fact-checker commented that "EcoHealth funding was not related to the experiments, but the collection of samples", and that "statements about Baric's research appear overblown".[48]

An August 2021 report made by the minority staff of the US House Foreign Affairs Committee working for its Republican Party members alleged that SARS-CoV-2 emerged as a result of gain-of-function research made on the RaTG13 virus, collected in a cave in Yunnan province in 2012, which was afterwards accidentally released some time before 12 September 2019, when the database of the Wuhan Institute of Virology went offline.[66][67] The report also estimated that SARS-CoV-2 was circulating in Wuhan as early as late August 2019.[66] That same month, an intelligence probe on the origins of COVID-19 requested by President Biden assessed that the Chinese government did not have foreknowledge of the outbreak.[14] Overall, the probe did not render conclusive results on the origins. Of eight assembled teams, one leaned towards a lab leak theory, four others (and the National Intelligence Council) were inclined to uphold a zoonotic origin, and three were unable to reach a conclusion.[15][16][17][68]

As a bio-weapon

See also: COVID-19 misinformation § Bio-weapon

Claims of deliberate engineering of the virus were spread as early as February 2020, and gained the support of various anti-vaccine activists. Li-Meng Yan was an early proponent of deliberate genetic engineering, releasing widely criticised[69][70] preprint papers in favor of this. Judy Mikovits and James Lyons-Weiler, two prominent figures of the movement, both claimed that SARS-CoV-2 was created in a laboratory, with Mikovits going further and stating, in Plandemic, a 2020 conspiracy theory film, that the virus was both deliberately engineered and deliberately released.[53] Weiler's analysis, where he argued that a long sequence in the middle of the spike protein of the virus was not found in other coronaviruses and was evidence for laboratory recombination, was dismissed by scientists, who found that the sequence in question was also found in many other coronaviruses, suggesting that it was "widely spread" in nature.[71]

Additional claims made to support such an hypothesis include the alleged presence of HIV sequences in the genetic material of the virus. This claim was notably promoted by Luc Montagnier, a controversial French virologist and Nobel laureate, who contended that SARS-CoV-2 might have been created during research on a HIV/AIDS vaccine.[72][73] Bioinformatics analyses show that the common sequences are short, that their similarity is insufficient to support the hypothesis of common origin, and that the identified sequences were independent insertions which occurred at varied points during the evolution of coronaviruses.[11][74][75]

Some allegations of deliberate engineering rest on the presence of a cytosine-guanine-guanine (CGG) codon doublet (which translates into two arginine amino acids) in the virus' RNA, more precisely in the crucial furin cleavage site. Proponents of this idea, including journalist Nicholas Wade, claim such a codon is evidence for a laboratory experiment, because of the documented lower presence of cytosine-guanine sequences in human pathogens.[7][53] This has been disputed by scientists, who note that the CGG codon is also present (and even more frequent) in other coronaviruses, including MERS-CoV,[76] and that a codon being rare does not mean it cannot be present. Furthermore, the large advantage in transmissibility gained by the presence of the furin cleavage site largely outweighs concerns that such sequences trigger disadvantageous immune responses from B-cells.[77][11]

Timeline

First appearance

See also: Investigations into the origin of COVID-19

The idea of a laboratory origin for SARS-CoV-2 was one of the earliest to emerge about the pandemic: the earliest known tweet to suggest the idea was published on 5 January 2020.[78]

The first media reports suggesting a SARS-CoV-2 lab leak appeared in the Daily Mail and The Washington Times in late January 2020.[78] In a 31 January 2020 interview with Science Magazine, Professor Richard Ebright said there was a possibility that SARS-CoV-2 entered humans through a laboratory accident in Wuhan, and that all data on the genome sequence and properties of the virus were "consistent with entry into the human population as either a natural accident or a laboratory accident".[79] A 5 February report from Caixin described these rumors as originating from two sources: a preprint paper by an Indian scholar posted to bioRxiv that was later withdrawn, and a BBC China report. The BBC China report stated that on 14 February, Chinese president Xi Jinping proposed for biosafety to be incorporated into law; the following day, new measures were introduced to "strengthen the management of laboratories", especially those working with viruses.[80][81]

According to scientists and reporters contacted by The British Medical Journal, "objective consideration of COVID-19's origins went awry early in the pandemic, as researchers who were funded to study viruses with pandemic potential launched a campaign labelling the lab leak hypothesis as a "conspiracy theory".[1] In February 2020, a letter was published in The Lancet by 27 co-authors that labelled alternate origin theories as conspiracy theories. Filippa Lentzos said some scientists "closed ranks" as a result, fearing for their careers and grants.[1] The letter was criticized by Jamie Metzl for "scientific propaganda and thuggery",[82] and by Katherine Eban as having had a "chilling effect" on scientific research and the scientific community by implying that scientists who "bring up the lab-leak theory ... are doing the work of conspiracy theorists".[83][84]

The lab leak theory was disseminated in early 2020 by United States politicians and media, particularly US president Donald Trump, other prominent Republicans, and conservative media (such as Fox News pundit Tucker Carlson, and former Breitbart News publisher and White House chief strategist Steve Bannon). All these groups had a reputation for using conspiracy rhetoric to blame other countries for American problems.[2][84] Trump had also referred to the virus as "kung flu",[85] and the administration also expressed the intention to sanction China.[86] In April 2020, Trump claimed to have evidence for the theory, but refused to produce it when requested.[84][87] At that time, the media did not distinguish between the accidental lab leak of a natural virus and bio-weapon origin conspiracy theories. In online discussions, various theories – including the lab leak theory – were combined to form larger, baseless conspiracy plots.[2] Facebook enacted a policy to remove discussion of the lab leak theory as misinformation; it lifted the ban a year later, in May 2021.[1][88][89] A collection of internet activists supporting the lab leak idea, named DRASTIC, also contributed to its promotion, particularly via Twitter.[90]

The origin of COVID-19 became a source of friction in China–United States relations. In April 2020, The Guardian reported that China had taken steps to tightly regulate domestic research into the source of the outbreak in an attempt to control the narrative surrounding its origins and encourage speculation that the virus started outside the country.[91] In May 2020, Chinese state media carried statements by scientists countering claims that the seafood market and Institute of Virology were possible origin sites, including comments by George Gao, director of the Chinese Center for Disease Control and Prevention.[92] The Chinese government had reacted slowly to the initial outbreak, downplaying the risk of human transmission and censoring criticism of its response.[93][94]

Renewed media attention

In early 2021, the hypothesis returned to popular debate due to renewed media discussion and circumstantial evidence.[2] Specifically, the resurgence was prompted by two events. Firstly, an article published in May by The Wall Street Journal claimed that several lab workers at the Wuhan Institute of Virology had fallen ill in November 2019 with COVID-19-like symptoms. The report was based on off-the-record briefings with intelligence officials.[2][84][95] The cases would have preceded official reports from the Chinese government stating the first known cases were in December 2019, although unpublished government data suggested the earliest cases were detected in mid-November.[96] The Guardian stated that the WSJ article did little to confirm, in terms of good, quality evidence, the possibility of a lab leak.[97] Secondly, it was shown that Peter Daszak, the key organiser of the February 2020 statement in The Lancet, had not disclosed connections to the Wuhan Institute of Virology.[1][2][84][98] An addendum was later published by The Lancet, in which Daszak listed his previous cooperation with Chinese researchers.[99]

After the publication of the WHO-convened report, politicians, talk show hosts, journalists, and some scientists advanced unsupported claims that SARS-CoV-2 may have come from the WIV.[20] In the United States, anti-China misinformation spread on social media, including baseless bio-weapon claims, fueled aggressive rhetoric towards people of Asian ancestry,[100] and the bullying of scientists.[20] Some scientists were worried their words would be misconstrued and used to support racist rhetoric.[85] In a letter published in Science, a number of scientists, including Ralph S. Baric, argued that the accidental laboratory leak hypothesis had not been sufficiently investigated and remained possible, calling for greater clarity and additional data.[101] Their letter was criticized by some virologists and public health experts, who said that a "hostile" and "divisive" focus on the WIV was unsupported by evidence, was impeding inquiries into legitimate concerns about China's pandemic response and transparency by combining them with speculative and meritless argument,[7] and would cause Chinese scientists and authorities to share less rather than more data.[20]

Since May 2021, some media organizations softened previous language that described the laboratory leak theory as "debunked" or a "conspiracy theory".[102] However, the prevailing scientific view is that while an accidental leak is possible, it is extremely unlikely.[19][20] Some journalists and scientists have said that they dismissed or avoided discussing the lab leak theory during the first year of the pandemic as a result of perceived polarization resulting from Donald Trump's embrace of the theory.[85][102][103][104] The Chair of the Board of Governors of the American Academy of Microbiology, Arturo Casadevall, has said that, he (like many others) had previously underestimated the lab leak hypothesis "mainly because the emphasis then [early in the pandemic] was on the idea of a deliberately engineered virus". However, by May 2021 it had been a "long-simmering concern" in scientific circles, and that he perceived "greater openness" to it.[105]

On 27 May 2021, US President Joe Biden ordered the US intelligence community to investigate the origins of COVID-19, including this hypothesis, and provide a report within 90 days.[106] Halfway into the investigation, an anonymous source told CNN that several Biden administration officials considered the lab leak theory as credible as the natural origins theory, but that hasty conclusions should be avoided.[107]

In July 2021, a Harvard–Politico survey indicated that 52 percent of Americans believed that COVID-19 originated from a lab leak, while 28 percent believed that COVID-19 originated from an infected animal in nature.[108]

On 15 July 2021, WHO Director-General Tedros Adhanom Ghebreyesus said that the COVID-19 lab leak theory had been prematurely discarded by the WHO, following his earlier statements that a potential leak requires "further investigation, potentially with additional missions involving specialist experts".[109] He proposed a second phase of WHO investigation, which he said should take a closer look at the lab leak idea, and asked China to be "transparent" and release relevant data.[110] Later on 17 July, Tedros called for "audits of relevant laboratories and research institutions" in the area of the initial COVID-19 cases.[111] China refused saying it showed "disrespect" and "arrogance towards science".[112] On 22 July 2021, Zeng Yixin of China's National Health Commission (NHC) replied stating China would not cooperate with the second phase, denouncing it as "shocking" and "arrogant".[110][113] The United States criticised China's position on the follow-up origin probe as "irresponsible" and "dangerous".[114]

On 12 August 2021, the leader of the WHO investigatory team, Peter Ben Embarek, told Danish television channel TV 2 that "An employee of the lab gets infected while working in a bat cave collecting samples. Such a scenario, while being a lab leak, would also fit our first hypothesis of direct transmission of the virus from bat to human."[115]

Claims and rebuttals

Pre-adaptation to humans

In a 26 March 2021 interview with Sanjay Gupta on CNN, former CDC director Robert R. Redfield said that in his opinion the most likely cause of the virus was a laboratory escape, which "doesn't imply any intentionality", and that as a virologist, he did not believe it made "biological sense" for the virus to be so "efficient in human to human transmission" from the early outbreak. CNN aired a response from Anthony Fauci saying that the virus could have adapted itself for "efficient spread" among humans in two ways, either "in the lab", or via the more likely possibility of "below the radar" community spread going unnoticed for several weeks or months before it was first recognized clinically.[116]

University of Utah virologist Stephen Goldstein has criticized the scientific basis of Redfield's comments, saying that SARS-CoV-2's spike protein is very effective at jumping between hosts, so this ability to transmit efficiently among humans is not particularly unusual. Goldstein noted "If a human virus can transmit among mink, there's no basis to assume a bat virus can't transmit among humans. Us humans may think we're very special – but to a virus we are just another mammalian host."[117]

Published research suggests an ancestor of SARS-CoV-2 likely acquired "generalist" binding to several different species through adaptive evolution in bats and an intermediate host species.[118][119][120]

Estimates based on genomic sequences and contact tracing have placed the origin point of SARS-CoV-2 in humans as between mid-October and mid-November 2019.[121][122] Some scientists (such as Fauci above and CIRAD's Roger Frutos) have suggested slow, undetected circulation in a smaller number of humans before a threshold event (such as replication in a larger number of hosts in a larger city like Wuhan) could explain this lack of an apparent adaptation period.[11]

Inadequate safety procedures

According to a number of scientists, including Ian Lipkin, the Wuhan Institute of Virology performed work on bats and bat SARS-like coronaviruses using inadequate safety procedures, including experiments on chimeric bat coronaviruses that were performed under suboptimal laboratory safety conditions.[6] One reason, according to Richard Ebright, that lower-containment BSL-2 laboratories are sometimes used is cost and inconvenience of high-containment facilities.[6][123] Australian virologist Danielle Anderson, who was the last foreign scientist to visit the WIV before the pandemic, said the lab "worked in the same way as any other high-containment lab". She also said it had "strict safety protocols".[124]

Gene database going offline

According to Reuters, the Wuhan Institute of Virology's (WIV) decision to take offline its gene sequence and sample databases in 2019 is an important part of the lab leak theory.[125]

Missing intermediate host

The fact that scientists have not been successful in finding an intermediate host that picked up the virus from bats and passed it to humans is seen as evidence that support a lab leak, according to The Guardian.[126]

See also

- China COVID-19 cover-up – for perceived efforts of the Government of China and the Chinese Communist Party (CCP) to hide information about the outbreak of the COVID-19 pandemic and the origins of SARS-CoV-2.

External links

- Executive summary of the US intelligence community report on COVID-19 origins

- The Origins of COVID-19: an investigation of the Wuhan Institute of Virology - report by US House Foreign Affairs Committee Minority Staff

- World Health Organisation report on the origins of COVID-19

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CALL OF THE WILD

Why many scientists say it’s unlikely that SARS-CoV-2 originated from a “lab leak”

- 2 SEP 2021

- BYJON COHEN

Scientists have found a distant relative of SARS-CoV-2 in a horseshoe bat they sampled in the countryside in Thailand.ADAM DEAN/PANOS PICTURES

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A version of this story appeared in Science, Vol 373, Issue 6559.

During the first year of the COVID-19 pandemic, the “lab leak” theory gained little traction. Sure, U.S. President Donald Trump suggested SARS-CoV-2 originated in a laboratory in Wuhan, China—and called it “the China virus”—but he never presented evidence, and few in the scientific community took him seriously. In fact, early in the pandemic, a group of prominent researchers dismissed lab-origin notions as “conspiracy theories” in a letter in The Lancet. A report from a World Health Organization (WHO) “joint mission,” which sent a scientific team to China in January to explore possible origins with Chinese colleagues, described a lab accident as “extremely unlikely.”

But this spring, views began to shift. Suddenly it seemed that the lab-leak hypothesis had been too blithely dismissed. In a widely read piece, fueled by a “smoking gun” quote from a Nobel laureate, a veteran science journalist accused scientists and the mainstream media of ignoring “substantial evidence” for the scenario. The head of WHO openly pushed back against the joint mission’s conclusion, and U.S. President Joe Biden ordered the intelligence community to reassess the lab-leak possibility. Eighteen scientists, including leaders in virology and evolutionary biology, signed a letter published in Science in May that called for a more balanced appraisal of the “laboratory incident” hypothesis.

Yet behind the clamor, little had changed. No breakthrough studies have been published. The highly anticipated U.S. intelligence review, delivered to Biden on 24 August, reached no firm conclusions, but leaned toward the theory that the virus has a natural origin.

Fresh evidence that would resolve the question may not emerge anytime soon. China remains the best place to hunt for clues, but its relative openness to collaboration during the joint mission seems to have evaporated. Chinese officials have scoffed at calls from Biden and WHO Director-General Tedros Adhanom Ghebreyesus for an independent audit of key Wuhan labs, which some say should include an investigation of notebooks, computers, and freezers. Chinese vice health minister Zeng Yixin said such demands show “disrespect toward common sense and arrogance toward science.” In response to the increasing pressure, China has also blocked the “phase 2” studies outlined in the joint mission’s March report, which could reveal a natural jump between species.

Despite the impasse, many scientists say the existing evidence—including early epidemiological patterns, SARS-CoV-2’s genomic makeup, and a recent paper about animal markets in Wuhan—makes it far more probable that the virus, like many emerging pathogens, made a natural “zoonotic” jump from animals to humans.

Some of those clues have led Michael Worobey, an evolutionary biologist at the University of Arizona who has done groundbreaking work on the origins of HIV and the 1918 flu, further away from the lab-origin theory. Although he always viewed it as less likely, he co-signed the Science letter calling for a more thorough investigation of the lab-leak hypothesis. But like at least one other signatory, he now has second thoughts about that plea, in part because it heightened political tensions. “I think it probably did more harm than good in terms of actually having relevant information flow out of China,” he says.

Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Research Center who spearheaded the Science letter, says the lab-origin theory will continue to thrive until the Chinese government becomes more cooperative. “I don’t think Chinese scientists are less trustworthy,” says Bloom, who has sharply criticized China for attempting to “obscure” data about early COVID-19 cases. “But it’s clear that, at least in relation to this topic, they are operating under strong constraints imposed by the government.”

AT ITS CORE, the lab-origin hypothesis rests on proximity. A novel coronavirus, genetically linked to bats, surfaced in a city that’s home to the Wuhan Institute of Virology (WIV), which has long specialized in studying bat coronaviruses, and two smaller labs that also handle those viruses. One or more lab workers could have become infected by accident, then passed the virus to others. Lab accidents are not unheard of, after all: SARS-CoV, the coronavirus that causes severe acute respiratory syndrome (SARS), has infected researchers as many as six times after the global outbreak of that disease ended in July 2003.

A researcher’s infection with SARS-CoV-2 needn’t have happened in Wuhan itself. Alina Chan, a gene therapy researcher at the Broad Institute who also co-signed the Science letter, cites a study by WIV researchers, published in 2018, that sampled blood from 218 people who lived 1000 kilometers from the city near caves that were home to coronavirus-infected bats. Six of these people had antibodies that suggested prior infections by SARS-related bat coronaviruses, a branch of the family tree that includes SARS-CoV, SARS-CoV-2, and close cousins. Wuhan researchers have visited that area repeatedly and “easily could have picked up something from a human who already carried a human-adapted form of a SARS-related virus,” Chan says.

Shi Zhengli, the lead bat coronavirus scientist at WIV, denies that anyone at the lab fell ill around the time SARS-CoV-2 emerged. In an email interview with Science in July 2020, she wrote that “all staff and students in the lab” were tested for SARS-CoV-2 and related coronaviruses and were negative.

A security guard outside WIV holds up a hand to block the camera.

Speculation about a lab leak has focused on the Wuhan Institute of Virology, which has studied bat coronaviruses for years.NG HAN GUAN/AP IMAGES

Still, in January, days before Trump left office, the U.S. Department of State said the “government has reason to believe that several researchers inside the WIV became sick in autumn 2019.” And on 23 May, The Wall Street Journal reported the existence of an “undisclosed U.S. Intelligence report” that said three WIV researchers “sought hospital care” in November 2019. The story had no details about their illnesses, and some have noted that Chinese hospitals provide care for all ailments, including minor ones.

Virologist Robert Garry of Tulane University finds it improbable that a Wuhan lab worker picked up SARS-CoV-2 from a bat and then brought it back to the city, sparking the pandemic. As the WIV study of people living near bat caves shows, transmission of related bat coronaviruses occurs routinely. “Why would the virus first have infected a few dozen lab researchers?” he asks. The virus may also have moved from bats into other species before jumping to humans, as happened with SARS. But again, why would it have infected a lab worker first? “There are hundreds of millions of people who come in contact with wildlife.”

Another data point argues against infected researchers playing a role, Garry says. As the WHO joint mission report spells out, clusters of early COVID-19 cases had links to multiple Wuhan markets around the same time, which Garry says supports the idea of infected animals or animal traders bringing the virus to the city. A lab worker with COVID-19 would have had to make “a beeline not just to one market, but to several different markets,” he says. “You can’t rule it out, but then why the markets? Why not a soccer game or a concert or 100 other different scenarios?”

But David Relman, a Stanford University microbiome researcher who also co-signed the Science letter, questions the “hopelessly impoverished” data on the earliest COVID-19 cases. “I just don’t think we have enough right now to say anything with great confidence,” Relman says.

Linfa Wang, a molecular virologist at the Programme in Emerging Infectious Diseases at Duke-NUS Medical School in Singapore who has collaborated extensively with WIV on bat coronavirus studies, has a simpler reason for dismissing the lab-leak hypothesis. “Accidents can only happen when you already have a live virus in culture that can leak,” Wang says. Bat coronaviruses are notoriously hard to grow. Shi told Science last year that her lab had more than 2000 bat fecal samples and anal and oral swabs that tested positive for coronaviruses. But the lab had only isolated and grown three viruses over 15 years, Shi said, and none closely resembled SARS-CoV-2. Some have questioned Shi’s veracity—she may well be under pressure from the Chinese government—and noted inconsistencies in her statements, but several scientific collaborators outside China have high regard for her integrity.

Wang also discounts reports that WIV has live bats. “Many years back” the lab conducted immune studies on live bats, Wang says, but these were not of the genus Rhinolophus—the only one found to harbor SARS-related coronaviruses—which no lab has ever been able to keep alive in captivity.

quotation mark

Accidents can only happen when you already have a live virus in culture that can leak.

- LINFA WANG

- DUKE-NUS MEDICAL SCHOOL

A great deal of speculation about the pandemic’s origin has centered on six men who developed severe respiratory illnesses in 2012 after clearing bat feces from a copper mine in Mojiang, in China’s Yunnan province. Three of them died. Lab-origin proponents have suggested the men were infected with a coronavirus, a belief fed by a 2013 master’s thesis that provided no direct evidence. That bat virus, they argue, either was SARS-CoV-2 or was turned into it through genetic engineering.

When the miners fell ill, Shi and co-workers were asked to sample bats at the mine, which they did on several occasions. They discovered nine new SARS-related viruses (see sidebar, below). One of these, dubbed RaTG13, is 96.2% genetically identical to SARS-CoV-2, the closest overall similarity yet found. A loose-knit group whose members call themselves DRASTIC—for the Decentralized Radical Autonomous Search Team Investigating COVID-19—has driven a heated discussion about possible links between RaTG13 and SARS-CoV-2.

Shi has reported that her lab tested blood from the miners and did not find evidence of coronaviruses or antibodies to them. Wang, who helped with these analyses, finds the assertion that the team suppressed evidence of SARS-CoV-2’s link to the Mojiang mine preposterous. “We wanted to prove that a coronavirus caused the deaths,” says Wang, who grew up in Shanghai but is now an Australian citizen. “If we proved that another SARS-like virus was in humans in China that would have been scientifically brilliant,” he says. “It’s a Science or Nature paper. No scientist is going to wait for this to leak.”

Even Bloom agrees with that logic. “That’s one of the strongest arguments you can make against a lab accident,” he says. “On the other hand, I feel like a lot of these questions could be resolved pretty easily by enhanced transparency.”

IN THE MOST ELABORATE lab-leak scenarios, SARS-CoV-2 is not a naturally occurring virus, but was created at WIV. That would bring worldwide condemnation on China, but it would also devastate the field of virology. There has been an intense debate over the past decade about the scientific value of “gain-of-function” (GOF) studies, which deliberately create pathogens that are more virulent or more transmissible to humans—or both—than their natural cousins. Some say GOF studies can help identify and thwart future threats, but critics argue the potential benefits don’t outweigh the risk of creating and unleashing pandemic pathogens.

Shi has created chimeric viruses in the past to get around the difficulty of growing coronaviruses isolated from bats. In work with Peter Daszak of the EcoHealth Alliance and Wang, described in a 2017 paper in PLOS Pathogens, WIV made chimeras using the genetic “backbone” of one of the bat coronaviruses her lab could culture and genes that coded for the surface protein, called spike, from newly found coronaviruses.

Scientists disagree about whether this was GOF research. Shi says it was not, because the hybrid viruses her group created were not expected to be more dangerous than the original strains. Anthony Fauci, head of the U.S. National Institute of Allergy and Infectious Diseases, which helped fund the study, told Congress it does not qualify as GOF research under NIAID’s guidelines. Relman finds the GOF label “vague and confusing” and instead describes this as “unnecessarily risky research.”

Definitions aside, if Shi was creating chimeric viruses, SARS-CoV-2 may have been one of them, lab-leak proponents say. They also note biosecurity measures at the lab were relaxed. In her 2020 Science interview, Shi denied conducting chimeric virus experiments beyond those reported in the 2017 paper, but she acknowledged doing some coronavirus studies in biosafety level 2 facilities. That’s one level lower than even Ralph Baric, a coronavirus researcher at the University of North Carolina, Chapel Hill, who has collaborated with Shi, thinks is appropriate. Shi stressed that the work complied with all Chinese regulations.

Still, many scientists contend that SARS-CoV-2 can’t be a lab concoction because no known virus is close enough to have served as its starting material. Some have countered that RaTG13, the virus found in the Mojiang mine, could have been that backbone. That makes no sense, asserts a “critical review” by Garry, Worobey, and 19 other scientists that Cell published online on 19 August. More than 1100 nucleotides, the building blocks of RNA, separate the genomes of the two viruses, and the differences are scattered in a way that doesn’t suggest deliberate engineering.

“Nobody has the sort of insight into viral pathogenesis to design something as really devious as SARS-CoV-2,” Garry says. Three other bat viruses more similar to SARS-CoV-2 than RaTG13 in some key genomic regions are also unlikely to have been used as a template for the pandemic virus, according to the paper.

An outdoor market with animal furs.

A worker processes skins at a fur market in Tongxiang, China. Three species commonly farmed for fur—foxes, raccoon dogs, and minks—can be infected with SARS-CoV-2.FEATURE CHINA/BARCROFT MEDIA/GETTY IMAGES

The “smoking gun” evidence that SARS-CoV-2 was engineered, in the words of virologist and Nobel laureate David Baltimore, has not held up either. Spike has a cleavage site, a spot where a human enzyme named furin cuts the protein, which helps SARS-CoV-2 infect cells. Since early in the pandemic, lab-origin proponents have claimed that no SARS-related bat coronaviruses have this feature, leading to speculation that a lab added the site to a virus so it could infect humans. When retired New York Times writer Nicholas Wade made the case for a lab leak this spring, the furin cleavage site, buttressed by Baltimore’s provocative words, was an essential part of the argument.

But it’s dead wrong, say many coronavirus specialists and evolutionary biologists. The SARS-related coronaviruses are in the beta genus, one of four in the Coronaviridae family. Several members of that genus feature furin cleavage sites, which appear to have evolved repeatedly. And one SARS-CoV-2–related virus, described in a Current Biology paper last year by a team led by Shi Weifeng of Shandong First Medical University, has three of the four amino acids that constitute the furin cleavage site, which is “strongly suggestive of a natural zoonotic origin” for SARS-CoV-2, the authors concluded.

Baltimore has backpedaled the statement. He did not know several bat beta coronaviruses have the furin cleavage site, he acknowledged in an email to Science. “[T]here is more to this story than I am aware of,” he wrote. “The furin cleavage is the most ridiculous stuff,” Wang says.

Instead of genetically manipulating a virus, a lab could also have created SARS-CoV-2 by passaging, a technique in which researchers grow a virus in a lab dish or an animal, harvest it, and repeat the process again and again, allowing mutations to accrue. But again, they would have needed to start with a close relative of SARS-CoV-2. There’s no evidence that this precursor existed in any lab. And passaging in cell cultures often deletes the furin cleavage site or makes viruses weaker.

Even the U.S. intelligence community during the Trump administration discounted the suggestion that SARS-CoV-2 was “manmade.” The report requested by Biden, which sought input from several groups in the intelligence community, similarly concludes that the virus “was probably not genetically engineered.” (It also said there was “broad agreement” that it “was not developed as a biological weapon.”)

THE JOINT MISSION REPORT from WHO, which runs more than 300 pages and delves into everything from the viral sequences of the earliest cases to pharmacy sales, has several little-noticed findings that make a natural origin appear more likely than a lab leak, says Kristian Andersen, an evolutionary biologist at Scripps Research who co-authored the recent Cell paper with Garry and Worobey. “It wasn’t the perfect report,” he says, but it was “a great start to a collaborative study on understanding the origin of SARS-CoV-2.”

The earliest official announcement about the pandemic came on 31 December 2019, when Wuhan’s Municipal Health Commission reported a cluster of unexplained pneumonia cases linked to the city’s Huanan seafood market. The WHO report devotes much attention to details about Huanan and other Wuhan markets, but also cautions that their role remains “unclear” because several early cases had no link to any market. But after reading the report, Andersen became more convinced that the Huanan market played a critical role.

One specific finding bolsters that case, Wang says. The report describes how scientists took many samples from floors, walls, and other surfaces at Wuhan markets and were able to culture two viruses isolated from Huanan. That shows the market was bursting with virus, Wang says: “In my career, I have never been able to isolate a coronavirus from an environmental sample.”

Could fur farms be part of the origin story?

China’s fur industry, the biggest in the world, processes animals that are potential hosts for SARS-CoV-2.

(GRAPHIC) K. FRANKLIN/SCIENCE; (DATA) YUAN-CHIH LUNG & SOPHIE LIN/ACT ASIA, CHINA’S FUR TRADE AND ITS POSITION IN THE GLOBAL FUR INDUSTRY, JULY 2019

The report also contained a major error: It claimed there were “no verified reports of live mammals being sold around 2019” at Huanan and other markets linked to early cases. A surprising study published in June by Zhou Zhao-Min of China West Normal University and colleagues challenged that view. It found nearly 50,000 animals from 38 species, most alive, for sale at 17 shops at Huanan and three other Wuhan markets between May 2017 and November 2019. (The researchers had surveyed the markets as part of a study of a tick-borne disease afflicting animals.)

Live animals can more easily transmit a respiratory virus than meat from a butchered one, and the animals included masked palm civets, the main species that transmitted SARS-CoV to humans, and raccoon dogs, which also naturally harbored that virus and have been infected with SARS-CoV-2 in lab experiments. Minks—a species farmed for fur that has acquired SARS-CoV-2 infections from humans in many countries— were also abundant. “None of the 17 shops posted an origin certificate or quarantine certificate, so all wildlife trade was fundamentally illegal,” Zhou and his colleagues wrote in their paper. (Zhou did not respond to emails from Science.)

It’s unclear why the international members of the WHO joint mission were not told about the live market mammals by their Chinese counterparts. “I’m really disappointed that came out after [the report],” says WHO’s Maria Van Kerkhove, who acknowledges contributing to the oversight herself because she mistakenly ignored a draft of the paper that the authors sent her when they first submitted it in October 2020.

Worobey says the paper played a key role in tilting his thinking away from the lab-origin hypothesis. “The fact that early [COVID-19] cases were linked to the market, and that the market was selling what were very likely intermediate hosts?” he says. “All of that is probably trying to tell us something.”

Worobey suspects that after a SARS-CoV-2 progenitor jumped from animals to humans, it pingponged back and forth, steadily adapting to its new host. This could have happened at the market and gone unnoticed for weeks, as the outbreak only surfaced when several people became severely ill, a relatively rare outcome of a SARS-CoV-2 infection. Or the virus could have first infected animal farmers in remote villages. “If this happened in a small town, it’s quite probable it would never have taken off,” says William Hanage, an evolutionary biologist at Harvard University. Then animal traders might have brought the virus to markets in Wuhan, a city of 11 million.

Linda Saif, a veterinarian at Ohio State University, Wooster, says China’s enormous fur industry is at the top of her list of places to hunt for SARS-CoV-2’s precursors. Saif cites a report showing the vast majority of the world’s pelts from raccoon dogs and foxes—both canids, a family readily infected with SARS-CoV-2—are from animals farmed or trapped in China (see graphic, above). The country produces half of the world’s mink pelts, too.

An epidemic of African swine fever virus in pigs might also, indirectly, have helped spark the pandemic, a perspective in the 27 August issue of Science suggests. China’s mass culling of pigs because of that virus led to record high pork prices in November 2019. Food consumers and producers may have resorted to alternative types of meat, leading to "increased wildlife-human contacts."

SO WHERE TO NOW? Bloom would like more details about the earliest human cases of COVID-19 and says WIV should share bat coronavirus sequences in a database it removed from the internet in September 2019, claiming the site had been hacked. “That could put a lot of this to rest,” he says. Sales data from Wuhan markets could help, too. If researchers could trace who farmed or trapped the live animals sold there and who delivered them to the markets, those people could be interviewed and perhaps sampled for evidence of past infections.

In a comment published by Nature on 25 August, the international members of the joint mission warned it’s time to get on with “phase 2” because the window for some studies is closing. But WHO is reconfiguring the team. It recently announced a new International Scientific Advisory Group for Origins of Novel Pathogens (SAGO) that will provide “rapid advice” to launch the follow-up studies described in the mission report, but also study the origins of future outbreaks. The Chinese government has shown no signs it will welcome SAGO members, but Wang is hopeful it will have a change of heart: “In an ideal world, we need a Chinese collaboration.”

Chinese scientists are conducting their own studies into potential natural origins, but few outside the country know details. “Unfortunately, finding out what is being done is getting harder by the day because the lab-leak stuff has turned COVID origins into a major political weapon,” says one Western researcher who asked not to be identified. “My colleagues in China are nervous and feeling great pressure.”

China has been pushing the theory that the virus came from another country—maybe brought in on frozen food, or, according to baseless propaganda, concocted at a U.S. military lab. “It’s comical,” Worobey says. “The big picture here is China is doing everything it can to push the narrative that this pandemic started outside of China.” He suspects that while rejecting the lab-leak theory, the Chinese government is also unenthusiastic about pursuing a natural origin, fearing that proof would expose China to further blame for a pandemic even if the discovery exonerated Chinese scientists. “I think at some point they thought, here’s the strategy: We try to muddy the waters,” he says.

But even without China’s cooperation, there are ways to move ahead. Some studies elsewhere have already yielded intriguing leads. Researchers have found coronaviruses in bats in neighboring countries that suggest evolutionary pathways from an ancestor of SARS-CoV-2 to the pandemic virus. More clues may come from studies in Southeast Asia of wild pangolins—the only other species to date found to harbor a close SARS-CoV-2 relative.

Researchers can also hunt for cases outside of China that predate the December 2019 outbreak. One possibility, Wang says, is to check the blood of Wuhan visitors or residents who were in the city in the months before, including the 9000 athletes from more than 100 countries who attended the Military World Games there in October 2019. (A new antibody assay from his lab, he says, can distinguish between SARS-CoV-2 and related viruses that may have preceded it.)

The search will never lead us to patient zero, the first person to be infected by SARS-CoV-2, Hanage says. “Humans are looking for a story,” he says. “They want Columbo to come in and just somehow get somebody to confess or show what actually happened.” Instead, there are “possible stories” about SARS-CoV-2’s origin—some more probable than others—and stories that can be excluded, Hanage says. “And the space of possible stories in which there was a natural origin in or around the markets is much larger than the space of possible origins in which the Wuhan Institute of Virology is involved.”

*Update, 7 September, 2:15 p.m.: The story has been updated to mention the possible role of a 2019 pork shortage in increasing wildlife trade in China.

*Correction, 3 September, 5 p.m.: An earlier version of this article misstated Raph Baric's affiliation. It also originally reported that Michael Worobey was “neutral” about the different hypotheses, the wording about his position has been clarified.

With reporting by Kai Kupferschmidt.

RELATED STORY

The hunt for SARS-CoV-2’s ancestors heats up

BY JON COHEN

Whether SARS-CoV-2 jumped into humans by way of a lab accident or a natural infection from animals, something close to the virus likely still circulates in an unidentified host. Bats harbor its closest known relatives, but those viruses differ so much from SARS-CoV-2 that many researchers suspect an additional species, or maybe several, served as way stations en route to a human-adapted virus. Scientists are now hunting for these links in the viral chain.

The chain likely begins with Rhinolophus, or horseshoe bats, which are infected with a plethora of coronaviruses and are widespread in Asia. “We have an equal chance to find the progenitor virus inside southern China or outside in Southeast Asia, because the bats are similar in the region,” says Linfa Wang, an emerging disease specialist at the Duke-NUS Medical School in Singapore.

One widely discussed virus is RaTG13, found in 2013 in an R. affinis bat in a Yunnan province mine by Shi Zhengli and colleagues at the Wuhan Institute of Virology (see main story, above). RaTG13 is closer to SARS-CoV-2 than any virus found to date, but differences in their genetic sequences suggest they’re separated by decades of viral evolution.

In the same mine, Shi’s group in 2015 discovered eight close cousins of RaTG13—one in R. affinis and seven in R. stheno—described in a May preprint. In a paper published in Cell on 19 August, evolutionary biologist Edward Holmes from the University of Sydney and Shi Weifeng of Shandong First Medical University described two viruses that are closer to SARS-CoV-2 in several genes, but not overall. They were found in bat species elsewhere in Yunnan named R. malayanus and R. pusillus.

Researchers keep returning to Yunnan for a reason. A 2019 review published by Shi Zhengli’s team noted that bat coronaviruses had been found in more than a dozen Chinese provinces, but only the ones from Yunnan could attach to the angiotensin-converting enzyme 2 (ACE2) receptor on human cells, which both SARS-CoV-2 and SARS-CoV—the virus that caused the 2003 outbreak of severe acute respiratory syndrome—depend on to establish infections. “Certain areas in Yunnan province are hot spots for spillover,” the authors warned.

Other teams are hunting for origin clues outside China. In Cambodia, investigators found two SARS-CoV-2–related sequences in R. shameli bats sampled in 2010. Veasna Duong of the Pasteur Institute of Cambodia has blood, tissue swabs, and fecal samples from other wild mammals in protected areas and the rangers who work there, as well as from people who collect bat guano, which is sold as fertilizer. He’s awaiting official permission to study them. Other groups have found SARS-CoV-2–like bat viruses in Thailand and even Japan.

Meet the relatives

Researchers have found a host of coronaviruses similar to SARS-CoV-2 in bats and pangolins in China and neighboring countries. The closest relative, RaTG13, was found in a bat living in a cave in Yunnan province.

Virus: RshSTT182, RshSTT200

R. shameli

Virus: Pangolin-CoV-GD

M. javanica

*

Virus: ZXC21, ZC45

R. pusillus

Virus: Rc-0319

R. cornutus

Virus: RacCS203

R. acuminatus

Virus: RpYN06

R. pusillus

Virus: RmYN02

R. malayanus

Virus: RaTG13, RaTG15

R. affinis

Virus: Pangolin-CoV-GX

M. javanica

*

Wuhan

Yunnan

CHINA

MONGOLIA

RUSSIA

KAZAKHSTAN

CAMBODIA

THAILAND

JAPAN

Horseshoe bat (Rhinolophus)

Pangolin (Manis)

*Pangolins were confiscated by customs officers in China but were captured elsewhere.

(GRAPHIC) K. FRANKLIN/SCIENCE

Scientists remain fascinated by the role of pangolins. Studies have found intriguing relatives of SARS-CoV-2 in these ant-eating mammals, which are prized in traditional Chinese medicine for their leathery scales and, as a result, trafficked and endangered. Pangolins confiscated by Chinese customs had viruses that showed up to 92.4% similarity to SARS-CoV-2, and one peculiarity jumped out: Their viral surface proteins have a section, the receptor-binding domain, that strongly attaches to human ACE2 receptors and more closely matches the same area in SARS-CoV-2 than in related bat viruses.

It’s unclear whether the pangolins became infected in the wild or by other animals trafficked with them, says molecular virologist Tommy Lam of the University of Hong Kong, who helped identify some of these viruses. Lam suggests a bat coronavirus could have spread to pangolins, acquired mutations that made it a better fit for human ACE2, moved to other species, and then mutated into the precursor of the pandemic virus. A wide range of species, from raccoon dogs and minks to pigs, cows, and cats, can be infected with SARS-CoV-2 and could have been the host that infected humans.

Infectious disease epidemiologist Gregory Gray of Duke University has long-standing collaborations in China, Malaysia, and Vietnam that he hopes will start SARS-CoV-2 origin studies once the pandemic abates—and political sensitivities subside. He is most keen to find out whether people who have “intense exposure” to domestic or wild animals, including animal market workers, have telltale antibodies to novel coronaviruses. “Those are rare studies and they’re hard to do,” Gray says, because people are “afraid that we might find something that would harm their businesses.”

None of these studies may uncover the origin of SARS-CoV-2 anytime soon, Lam says. But, he adds, “Those who are not patient are not really interested in the truth.”