IN THE MOST ELABORATE lab-leak scenarios, SARS-CoV-2 is not a naturally occurring virus, but was created at WIV.
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.
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.
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.
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.
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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. Huanan market played a critical role.
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.”
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.)
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.
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."
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".
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