In 2013, the American virologist Ralph Baric approached Zhengli Shi at a meeting. Baric was a top expert in coronaviruses, with hundreds of papers to his credit, and Shi, along with her team at the Wuhan Institute of Virology, had been discovering them by the fistful in bat caves. In one sample of bat guano, Shi had detected the genome of a new virus, called SHC014, that was one of the two closest relatives to the original SARS virus, but her team had not been able to culture it in the lab.

Baric had developed a way around that problem—a technique for “reverse genetics” in coronaviruses. Not only did it allow him to bring an actual virus to life from its genetic code, but he could mix and match parts of multiple viruses. He wanted to take the “spike” gene from SHC014 and move it into a genetic copy of the SARS virus he already had in his lab. The spike molecule is what lets a coronavirus open a cell and get inside it. The resulting chimera would demonstrate whether the spike of SHC014 would attach to human cells.

If it could, then it could help him with his long-term project of developing universal drugs and vaccines against the full spectrum of SARS-like viruses that he increasingly considered sources of potential pandemics. A SARS vaccine had been developed, but it wasn’t expected to be very effective against related coronaviruses, just as flu shots rarely work against new strains. To develop a universal vaccine that will elicit an antibody response against a gamut of SARS-like viruses, you need to show the immune system a cocktail of spikes. SHC014 could be one of them.

If you study a hundred different bat viruses, your luck may run out.

-Ralph Baric, University of North Carolina

Baric asked Shi if he could have the genetic data for SHC014. “She was gracious enough to send us those sequences almost immediately,” he says. His team introduced the virus modified with that code into mice equipped with the human receptor for such viruses and into a petri dish of human airway cells. Sure enough, the chimera exhibited “robust replication” in the human cells—evidence that nature was full of coronaviruses ready to leap directly to people.

While Baric’s study was in progress, the National Institutes of Health announced that it would temporarily halt funding for “gain of function” research—experiments that make already dangerous viruses more virulent or transmissible—on SARS, MERS (which is also caused by a coronavirus), and influenza until the safety of such research could be assessed. The announcement brought Baric’s work to a standstill.

Baric was a legend in the field, but no matter how many safety precautions are taken, there is always a chance that a never-before-seen virus can escape and trigger an outbreak. Baric felt that the extreme measures he took in the lab minimized the risk, and in fact made his work categorically different from the high-risk influenza work the NIH had been targeting. He also felt that his research was urgent: new cases of MERS, spread by camels, were even then popping up in the Middle East. Eventually the NIH agreed, waving him forward.

His 2015 paper, “A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence,” was a tour de force, utilizing bleeding-edge genetic technology to alert the civilized world to a looming danger on its periphery. It also revived concerns about gain-of-function experiments, which Baric had known it would. In the paper, he spelled out the extra precautions he’d taken and held up the research as a test case. “The potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens,” he wrote. “Scientific review panels may deem similar studies building chimeric viruses based on circulating strains too risky to pursue.”

The NIH decided the risk was worth it. In a potentially fateful decision, it funded work similar to Baric’s at the Wuhan Institute of Virology, which soon used its own reverse-genetics technology to make numerous coronavirus chimeras.

Unnoticed by most, however, was a key difference that significantly shifted the risk calculation. The Chinese work was carried out at biosafety level 2 (BSL-2), a much lower tier than Baric’s BSL-3+.

What caused the covid-19 pandemic remains uncertain, and Shi says her lab never encountered the SARS-CoV-2 virus before the Wuhan outbreak. But now that US officials have said the possibility of a lab accident needs to be investigated, the spotlight has fallen on American funding of the Wuhan lab’s less safe research. Todaya chorus of scientists, including Baric, are coming forward to say this was a misstep. Even if there is no link to covid-19, allowing work on potentially dangerous bat viruses at BSL-2 is “an actual scandal,” says Michael Lin, a bioengineer at Stanford University. 

The simmering concern that the US

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By: Rowan Jacobsen
Title: Inside the risky bat-virus engineering that links America to Wuhan
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Published Date: Tue, 29 Jun 2021 09:00:00 +0000