A new pandemic origin report is stirring controversy. Here are key takeaways

Last week, journalists rushed to report on previously undisclosed genetic evidence that mammals sold at the Huanan Seafood Wholesale Market in Wuhan, China—possibly raccoon dogs—might have sparked the COVID-19 pandemic. But to the chagrin of the researchers who conveyed their findings confidentially to a World Health Organization (WHO) advisory group on 14 March, the news broke before they had finished analyzing the data, which consist of RNA and DNA sequences collected at the market in early 2020. Yesterday, however, they posted their complete 22-page report on Zenodo, an open repository of scientific research.

To the report’s authors, 19 evolutionary biologists from six countries, the data support the theory that SARS-CoV-2-susceptible mammals were in the right place at the right time to have passed the virus to humans, triggering the pandemic. And they and others, including WHO’s director-general, have blasted China for not sharing the Wuhan market data sooner. 

But critics, many of whom suspect SARS-CoV-2 may have escaped from the Wuhan Institute of Virology, say the new sequences offer no great insight beyond the fact that the seafood market also sold mammals. It is “just preposterous” to suggest this is evidence that animals were actually infected with SARS-CoV-2 and transmitted it to humans, computational biologist Erik van Nimwegen says. In a 2021 letter in Science, he and 17 other scientists—including two who issued the new report—called for a “balanced consideration” of the lab-leak hypothesis.

Several of the new report’s co-authors published two papers in Science in 2022 that pinned the pandemic’s origin on mammals sold at the Wuhan market, stressing that it is one of just four places in the city that sold wildlife susceptible to SARS-CoV-2. Those conclusions are bolstered by the new report, its authors say. “These arguments stand in stark contrast to the absence of evidence for any other SARS-CoV-2 emergence route,” their report concludes.

Regardless of how readers weigh the import of the new data, the Zenodo report clarifies details in some of the original media accounts and offers several fresh insights into the latest COVID-19 origin uproar. Below, Science examines some of the key issues.

How exactly were the data from 2020 found?

Chinese researchers uploaded the sequencing data from their market samples to GISAID, a virology database, in June 2022, in support of a preprint they had posted a few months earlier. The data were originally hidden from other GISAID users but became accessible in January 2023. Florence Débarre, an evolutionary biologist at CNRS, the French national research agency, who has become prominent on social media for sparring with lab-leak proponents, says she stumbled onto the data and shared them with colleagues. They analyzed the sequences and found the evidence for coronavirus-susceptible mammals at the market.

So why aren’t those genetic sequences public now?

A day after Débarre and colleagues told a member of the Chinese team what they had found, GISAID made the data invisible, apparently at the submitter’s request. In the Zenodo report, the researchers state their analysis is “not intended for publication in a journal” or meant to scoop the Chinese team’s paper, which is under review by the Nature family of journals. As the report explains, they have downloaded the data but are not making them public yet in hopes the Chinese researchers will soon do so. Still, the report states the group went public with its analysis because the scientists feel an “unreasonable” amount of time has passed without the sequences going public. “Because the data have been removed from GISAID, we cannot share them. But I wish that other scientists could explore these data, which are very rich,” Débarre says. “The more people work on these data, the more we can make them speak.”

What’s GISAID’s role in this?

The repository has become a key source for SARS-CoV-2 data, helping scientists analyze the evolution of variants and other aspects of the pandemic. But Débarre and colleagues take it to task in their report, accusing it of having “deviated from its stated mission” of speeding the sharing of virological data. For its part, GISAID claimed in a statement today that the researchers violated its access agreements and it has now “temporarily suspended” their access to the database. The disagreement appears to come down to GISAID’s assertion that the researchers did not follow its access agreement and “make best efforts to collaborate” with the Chinese team. The researchers insist they reached out to their Chinese colleagues in emails and chat requests, as well as during a meeting in which several of Débarre’s co-authors and the Chinese team were supposed to share data with WHO’s Scientific Advisory Group for the Origins of Novel Pathogens.

What does the genetic evidence in the report say?

Chinese researchers, as well as the Chinese government, have waffled about whether mammals were for sale at the market. The new data arguably provide the strongest evidence yet that key SARS-CoV-2-susceptible species were there when COVID-19 emerged. The 2020 Chinese team that visited the market collected 923 “environmental samples” from the market stalls’ containers, surfaces, and drains. In their report, Débarre and colleagues say 49 of those samples infected with SARS-CoV-2 RNA also contained mitochondrial DNA (mtDNA) that clearly identified five mammals: the common raccoon dog, Malayan porcupine, Amur hedgehog, masked palm civet, and hoary bamboo rat. They also found other DNA, as well as RNA from the mammals. “The co-occurrence of SARS-CoV-2 virus and susceptible animal RNA/DNA in the same samples, from a specific section of the Huanan market, and often at greater abundance than human genetic material, identifies these species, particularly the common raccoon dog, as the most likely conduits for the emergence of SARS-CoV-2 in late 2019,” the authors wrote. The group produced a “heat map” that shows the density of SARS-CoV-2 was “hottest” in market areas near stalls that sold the mammals.  

 

Reprinted map of Wuhan seafood market from Zenodo
This map from the COVID-19 origin report posted in Zenodo on 20 March shows the western area of the seafood market, which sold the mammals as indicated, had the highest density of samples that contained SARS-CoV-2. The mammals were identified by their mitochondrial DNA (mtDNA) in the samples. Researchers led by China’s Xiao Xiao reported in 2021 that they had observed these mammals at the market in the 2 years that preceded the pandemic, as they documented in 2021 in Scientific Reports. Reprinted from A. Crits-Christoph, et al., Zenodo, DOI:10.5281/zenodo.7754299, (2023)/CC BY 4.0

Why are raccoon dogs receiving so much attention?

Experiments have shown SARS-CoV-2 easily infects raccoon dogs—commonly raised for fur in China, but also sold for meat in “wet” markets like the one in Wuhan—and that they shed high levels of the virus. The report describes finding raccoon dog mtDNA in six samples from two different stalls in the Wuhan market. A sample from a cart that tested positive for SARS-CoV-2 also had “abundant” raccoon dog genetic material. Far less human genetic material was found in the same sample. The researchers say this suggests—but doesn’t prove—the raccoon dog or dogs on the cart were more likely to have spread the virus than humans working the stall or shopping near it. When they compared the mtDNA in the market samples with ones previously reported by other scientists, the closest match came from a wild raccoon dog, which is distinct from the subspecies raised for fur. This suggests that if raccoon dogs introduced the virus to the market, researchers investigating COVID-19’s origins should look to China’s wildlife trade, not the fur farms.

Do the market locations of the genetic sequences mean anything?

The mtDNA of the SARS-CoV-2 susceptible mammals was found in the southwest corner of the market that also had the “highest density” of SARS-CoV-2 positive samples. “We can now show that plausible animal hosts of SARS-CoV-2 were indeed right where we thought they were, in the small quadrant with the highest concentration of surfaces found to be positive for the virus and a hot spot for live mammal sales,” says report co-author Michael Worobey, an evolutionary biologist the University of Arizona. Human mtDNA was most abundant in other parts of the market. This raises the possibility that the animals transmitted the virus to the humans in the southwest corner of the market several weeks before the samples were taken, and those people had since recovered from their infections. The other infected people at the market, in this scenario, likely were infected by human-to-human transmission.

Will more unexplored sequencing data from the market emerge?

Worobey and his colleagues also found samples that do not have the “raw sequencing files” available. GISAID said in its statement they had downloaded “an incomplete portion of these data,” and indicated that a more “complete and updated data set will be made available as soon as possible to all GISAID users.” It did not say when these data might become public.  “All of these missing data could provide valuable information on the timeline of events at the Huanan market and the provenance of the virus,” Débarre and colleagues write.

source: sciencemag.org