For Baric, that research started in the late 1990s. Coronaviruses were then considered low risk, but Baric’s studies on the genetics that allowed viruses to enter human cells convinced him that some might be just a few mutations away from jumping the species barrier.
That hunch was confirmed in 2002–’03, when SARS broke out in southern China, infecting 8,000 people. As bad as that was, Baric says, we dodged a bullet with SARS. The disease didn’t spread from one person to another until about a day after severe symptoms began to appear, making it easier to corral through quarantines and contact tracing. Only 774 people died in that outbreak, but if it had been transmitted as easily as SARS-CoV-2, “we would have had a pandemic with a 10% mortality rate,” Baric says. “That’s how close humanity came.”
As tempting as it was to write off SARS as a one-time event, in 2012 MERS emerged and began infecting people in the Middle East. “For me personally, that was a wake-up call that the animal reservoirs must have many, many more strains that are poised for cross-species movement,” says Baric.
By then, examples of such dangers were already being discovered by Shi’s team, which had spent years sampling bats in southern China to locate the origin of SARS. The project was part of a global viral surveillance effort spearheaded by the US nonprofit EcoHealth Alliance. The nonprofit—which has an annual income of over $16 million, more than 90% from government grants—has its office in New York but partners with local research groups in other countries to do field and lab work. The WIV was its crown jewel, and Peter Daszak, president of EcoHealth Alliance, has been a coauthor with Shi on most of her key papers.
By taking thousands of samples from guano, fecal swabs, and bat tissue, and searching those samples for genetic sequences similar to SARS, Shi’s team began to discover many closely related viruses. In a cave in Yunnan Province in 2011 or 2012, they discovered the two closest, which they named WIV1 and SHC014.
Shi managed to culture WIV1 in her lab from a fecal sample and show that it could directly infect human cells, proving that SARS-like viruses ready to leap straight from bats to humans already lurked in the natural world. This showed, Daszak and Shi argued, that bat coronaviruses were a “substantial global threat.” Scientists, they said, needed to find them, and study them, before they found us.
Many of the other viruses couldn’t be grown, but Baric’s system provided a way to rapidly test their spikes by engineering them into similar viruses. When the chimera he made using SHC014 proved able to infect human cells in a dish, Daszak told the press that these revelations should “move this virus from a candidate emerging pathogen to a clear and present danger.”
To others, it was the perfect example of the unnecessary dangers of gain-of-function science. “The only impact of this work is the creation, in a lab, of a new, non-natural risk,” the Rutgers microbiologist Richard Ebright, a longtime critic of such research, told Nature.
To Baric, the situation was more nuanced. Although his creation might be more dangerous than the original mouse-adapted virus he’d used as a backbone, it was still wimpy compared with SARS—certainly not the supervirus Senator Paul would later suggest.
In the end, the NIH clampdown never had teeth. It included a clause granting exceptions “if head of funding agency determines research is urgently necessary to protect public health or national security.” Not only were Baric’s studies allowed to move forward, but so were all studies that applied for exemptions. The funding restrictions were lifted in 2017 and replaced with a more lenient system.
Tyvek suits and respirators
If the NIH was looking for a scientist to make regulators comfortable with gain-of-function research, Baric was the obvious choice. For years he’d insisted on extra safety steps, and he took pains to point these out in his 2015 paper, as if modeling the way forward.
The CDC recognizes four levels of biosafety and recommends which pathogens should be studied at which level. Biosafety level 1 is for nonhazardous organisms and requires virtually no precautions: wear a lab coat and gloves as needed. BSL-2 is for moderately hazardous pathogens that are already endemic in the area, and relatively mild interventions are indicated: close the door, wear eye protection, dispose of waste materials in an autoclave. BSL-3 is where things get serious. It’s for pathogens that can cause serious disease through respiratory transmission, such as influenza and SARS, and the associated protocols include multiple barriers to escape. Labs are walled off by two sets of self-closing, locking doors; air is filtered; personnel use full PPE and N95 masks and are under medical surveillance. BSL-4 is for the baddest of the baddies, such as Ebola and Marburg: full moon suits and dedicated air systems are added to the arsenal.
“There are no enforceable standards of what you should and shouldn’t do. It’s up to the individual countries, institutions, and scientists.”
Filippa Lentzos, King’s College London
In Baric’s lab, the chimeras were studied at BSL-3, enhanced with additional steps like Tyvek suits, double gloves, and powered-air respirators for all workers. Local first-responder teams participated in regular drills to increase their familiarity with the lab. All workers were monitored for infections, and local hospitals had procedures in place to handle incoming scientists. It was probably one of the safest BSL-3 facilities in the world. That still wasn’t enough to prevent a handful of errors over the years: some scientists were even bitten by virus-carrying mice. But no infections resulted.
In 2014, the NIH awarded a five-year, $3.75 million grant to EcoHealth Alliance to study the risk that more bat-borne coronaviruses would emerge in China, using the same kind of techniques Baric had pioneered. Some of that work was to be subcontracted to the Wuhan Institute of Virology.