Do three new studies add up to proof of COVID-19’s origin in a Wuhan animal market? | Science

Three new studies offer one indisputable conclusion about the origin of SARS-CoV-2: Despite the passage of 2 years and the Chinese government’s lack of transparency, data that can shed light on the pandemic’s greatest mystery still exist. And although these new analyses don’t all reach the same conclusion for how COVID-19 was sparked, each undercuts the theory that the virus somehow escaped from the Wuhan Institute of Virology, long a focus of suspicions.

The studies examine different aspects of the viral spread at the Huanan Seafood Market in Wuhan, China, the city where the first cases were detected. Two international efforts build the case that SARS-CoV-2 jumped to people from infected animals—a zoonotic leap—at the market, likely twice, at the end of 2019. A third, largely Chinese effort details early signs of the coronavirus in environmental and animal samples from the market but suggests the virus was imported there, perhaps from outside the country—a conclusion the University of Arizona’s Michael Worobey, an evolutionary biologist who is a corresponding author of the two international studies, calls “a huge disconnect.”

The studies were posted as preprints and are not peer reviewed, but scientists, biosecurity experts, journalists, and others are already intensely examining their details. “I have been brought closer to the zoonosis side with these preprints,” says Flo Débarre, an evolutionary biologist at the French national research agency, CNRS, who has followed the origin debate closely and not thrown her lot with either the natural-origin or the lab-leak camp. Evolutionary biologist William Hanage of Harvard University agrees these studies “will be taken as a blow” to the lab-leak hypothesis. “They substantially move the needle on the origins in the direction of the market,” Hanage says.

Skeptics of the natural origin theory maintain the market cluster could merely be a superspreader event touched off when a person infected with a lab-escaped coronavirus visited it. But Worobey thinks further data could make that contention even less tenable. A more transparent analysis of the market’s genetic sampling data, in particular, might identify exactly which species of animals sold there carried the virus.

In one study, Worobey and colleagues describe two subtly different lineages of SARS-CoV-2 that were found in people at the Huanan Seafood Market in late 2019, which they take as a sign that the virus jumped twice from animals to humans there. Their other study offers a geospatial analysis of the earliest human cases that pinpoints the market as the “epicenter” of SARS-CoV-2’s emergence, showing both lineages infected people who had links to the market or lived near it. It also connects the specific stalls at the market where live animals were sold to environmental samples known to have tested positive for the virus. “Together, these analyses provide dispositive evidence for the emergence of SARS-CoV-2 via the live wildlife trade and identify the Huanan market as the unambiguous epicenter of the COVID-19 pandemic,” they conclude.

Worobey and colleagues had hoped to release their preprints in the next week but sped up their plans, choosing a preprint server that posts without any delays, when the Chinese study was posted on 25 February on the Research Square site. Led by George Gao of the Chinese Academy of Sciences and co-authored by 37 other scientists (one is from Canada), that research—which builds on data earlier leaked to the media but never officially published—offers the most detailed description yet of the environmental samples the Chinese Center for Disease Control and Prevention obtained at the Huanan Seafood Market between 1 January and 2 March 2020.

In the new preprint, Gao and colleagues analyzed 1380 samples from 188 animals in the market and the environment, including sewer wells, the ground, feather removing machines, and “containers.” They found SARS-CoV-2 in 73 samples. But because all were from the environment, not the animals themselves, they assert that humans introduced the virus to the market. The authors call the market an “amplifier,” not the source, of SARS-CoV-2. 

Hewing closely to government assertions on COVID-19’s origin, the preprint by Gao and colleagues notes studies that have reported evidence of SARS-CoV-2 in other countries before it surfaced in Wuhan, making no mention of critiques that attribute that evidence to contamination. It also floats a widely disputed theory that frozen food imported to China might have been the original source. (Authors of the paper, including Gao, did not respond to requests to discuss the work.)

The coronavirus lineage analysis from Worobey and colleagues refines an argument posited by virologist Robert Garry last year. In data on the early human cases, Garry had identified two different forms of SARS-CoV-2, differing by just two mutations, which he argued surfaced at different Wuhan markets in December 2019. The new work, which includes Garry as a co-author and cites evidence from the Gao study, reshapes that scenario significantly. It concludes that both lineages, dubbed A and B, originated at the Huanan Seafood Market and soon spread in nearby neighborhoods. B likely jumped from animals to humans in late November 2019, leading to the first detected case on 10 December, and lineage A a few weeks later, the group concludes. Either way, the team argues the almost simultaneous emergence of two lineages challenges the lab-origin thesis, as it would require two different viruses leaking at roughly the same time. (Gao and colleagues also found both SARS-CoV-2 lineages in their environmental samples.)

The second preprint from the international team builds on a June 2021 Chinese-led study that spent 2 years documenting a tick fever disease in mammals for sale at a specific stall in the market. The new study pinpoints for the first time where species susceptible to SARS-CoV-2—including raccoon dogs, hedgehogs, badgers, red foxes, and bamboo rats—were sold and maps those sites to the positive environmental samples, including in one “container” the authors believe was a cage. “To anyone who really grasps what is in all of those three papers, I think it’s very hard to dismiss that this is a very, very, very strong case that this pandemic started at that market,” Worobey says.

Others say they are not definitive. “They are interesting studies, but I don’t think they close the case on what happened with the origins of the virus,” says Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Research Center who has criticized colleagues for too blithely dismissing the lab-origin hypothesis. “I’m especially skeptical of the conclusion that there must have been two zoonotic jumps.”

He notes that in about 10% of human transmissions of SARS-CoV-2, the virus acquires two mutations, which means a second lineage could have emerged after the infection of the first human rather than two zoonotic jumps. Worobey, Garry, and colleagues did a computer simulation that challenges Bloom’s assertion. They modeled what would have happened if there was an introduction of a single lineage and compared that with the viruses sequenced from Wuhan cases through 23 January 2020. By matching the sequence data from the actual epidemic, they found there was only a 3.6% chance that a single lineage mutated into a second one.

The environmental samples from the Wuhan market that tested positive for SARS-CoV-2 might resolve the stalemate over the virus’ origin if they can reveal a specific animal source of the virus. “If you find a positive sample with, say, lots of raccoon dog DNA, you’ve got a hit,” on the likely source of SARS-CoV-2, says evolutionary biologist David Robertson of the University of Glasgow, who co-authored the epicenter paper.

But the preprint by Gao and colleagues only notes that those samples contain DNA from many animals without specifying which one—other than humans. “The authors have already done the analysis, they have just not put all the results needed to interpret them in their paper,” says evolutionary biologist Andrew Rambaut of the University of Edinburgh, a co-author of both studies. “This will undoubtedly be fixed if the paper gets through peer review.”

Still, Worobey and his co-authors concede, even that evidence might not be enough to end this polarizing debate. “With the way that people have been able to just push aside any and all evidence that points away from a lab leak, I do fear that even if there were evidence from one of these samples that was full of red fox DNA and SARS-CoV-2 that people might say, ‘We still think it actually came from the handler of that red fox,’” Worobey says.