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Two complementary studies published in Science provide the latest evidence against the idea that COVID-19 leaked from a Chinese lab, and instead point to the Huanan market in Wuhan, China, as the early epicenter of the virus.

Researchers conducted spatial, environmental, and molecular analyses that led them to their conclusion, and the findings were the result of collaborative efforts from scientists across four continents, including insights from researchers within China.

During a media briefing with the researchers on Tuesday, Joel Wertheim, PhD, of University of California San Diego and an author on the study looking at the , said the researchers analyzed the genomic diversity of SARS-CoV-2 within and outside of China, starting with the earliest sampled genomes in December 2019 and extending through mid-February 2020.

In the beginning, there were just two genetic lineages -- A and B -- which only differed from each other by a couple of mutations, he said. Lineage A was more genetically similar to related bat coronaviruses, but lineage B appears to have started spreading earlier in humans, particularly at the Huanan market.

"Our analysis of the molecular clock ... shows that Lineage A could not have been the first and only introduction of SARS-CoV-2 into humans," Wertheim said.

To address the issue, Wertheim and his fellow researchers simulated SARS-CoV-2-like epidemics, and compared the genomes of simulated viruses to their real-world counterparts, he said. The simulations showed that there wasn't a way for lineage A to evolve into lineage B within humans or vice versa. Rather, they were "far more consistent with the distinct and separate introductions of lineage A and lineage B."

He then explained why it sounded as though he was saying a once-in-a-generation event could have happened twice in quick succession.

"Pandemics are indeed rare," Wertheim said. "But once all the conditions are in place, that is a zoonotic virus capable of both human infection and human transmission that is in close proximity to humans, the barriers to spillover have been lowered such that multiple introductions we believe should actually be expected."

Researchers estimate that there were likely eight, but possibly as many as two dozen, introductions of SARS-CoV-2 that preceded successful transmission chains.

"This study is not proof-positive of multiple zoonotic origins of SARS-CoV-2, [but] the multiple introduction scenario presents the most complete and comprehensive explanation for the origins of COVID-19," Wertheim said.

Findings from the studies were originally published as preprints in February, and by The New York Times.

Michael Worobey, PhD, of the University of Arizona and an author on the study, said during the Tuesday briefing that when the researchers looked at all the places the early cases could have lived within the greater Wuhan area, "it turned out ... there was this extraordinary pattern."

"The highest density of cases was both extremely near to and very centered on this market," Worobey said.

He said the research team also ran statistics, such as taking the population of the city and looking at where people of the same age who had COVID-19 in December 2019 lived and the densities of the different neighborhoods. When plotting 155 people over and over again in the city, it would be extremely unlikely to get such a cluster of cases on the Huanan market, said Worobey.

"Crucially, this applies both to all cases in December and also to cases that had no known link to the market," he explained. "Those cases ... were even actually more clustered to the market than cases who worked there. This is an indication that the virus starting spreading in people who worked at the market, but then started to spread into the local community."

Both lineage B and lineage A were closely linked to the market, he said.

"What we're looking at here is not unusual at all," said Kristian Andersen, PhD, of Scripps Research in San Diego.

In 2002 and 2003, SARS-CoV-1 spilled over into the human population, and was also associated with the wildlife trade, he said. The early stages of the pandemic look very similar to that. However, the difference is that SARS-CoV-2 is much more transmissible, resulting in ending up with a pandemic rather than the sporadic epidemics and outbreaks seen with SARS-CoV-1.

In the case of SARS-CoV-2, in addition to the very tight clustering outside the Huanan market, Andersen said that there were raccoon dogs and other animals susceptible to infection with SARS-CoV-2 being sold at the market before the pandemic began.

"Everything upstream of this, which animals, where did they come from, how is it all connected, is completely unknown at this stage," Andersen concluded. "It really is one of these examples where more collaboration, international collaboration and cooperation, which of course will include collaborations between U.S. scientists and Chinese scientists, is absolutely required in order to figure out the next steps so we can better understand and more fully understand the origins of this pandemic."

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