Now let’s take a step back. AIDS, fatal and terrifying and politically charged, brought on a new era in government-guided vaccine research, under the guidance of Anthony Fauci. A virologist at Rockefeller University, Stephen S. Morse, began giving talks on “emerging viruses” — other plagues that might be in the process of coming out of nature’s woodwork. In 1992, Richard Preston wrote a horrific account of one emergent virus, Ebola, in The New Yorker, which became a best-selling book in 1994; Laurie Garrett’s The Coming Plague: Newly Emerging Diseases in a World Out of Balance appeared that same year and was also a best seller. The idea seemed to be everywhere: We were on the verge of a wave of zoonotic, emergent plagues.
This new, useful term, emerging, began to glow in the research papers of some coronavirologists, who were out of the spotlight, working on common colds and livestock diseases. The term was useful because it was fluid. An emerging disease could be real and terrifying, as AIDS was — something that had just arrived on the medical scene and was confounding our efforts to combat it — or it could be a disease that hadn’t arrived, and might never arrive, but could be shown in a laboratory to be waiting in the wings, just a few mutations away from a human epidemic. It was real and unreal at the same time — a quality that was helpful when applying for research grants.
Take, for instance, this paper from 1995: “High Recombination and Mutation Rates in Mouse Hepatitis Viruses Suggest That Coronaviruses May Be Potentially Important Emerging Viruses.” It was written by Dr. Ralph Baric and his bench scientist, Boyd Yount, at the University of North Carolina. Baric, a gravelly voiced former swim champion, described in this early paper how his lab was able to train a coronavirus, MHV, which causes hepatitis in mice, to jump species, so that it could reliably infect BHK (baby-hamster kidney) cell cultures. They did it using serial passaging: repeatedly dosing a mixed solution of mouse cells and hamster cells with mouse-hepatitis virus, while each time decreasing the number of mouse cells and upping the concentration of hamster cells. At first, predictably, the mouse-hepatitis virus couldn’t do much with the hamster cells, which were left almost free of infection, floating in their world of fetal-calf serum. But by the end of the experiment, after dozens of passages through cell cultures, the virus had mutated: It had mastered the trick of parasitizing an unfamiliar rodent. A scourge of mice was transformed into a scourge of hamsters. And there was more: “It is clear that MHV can rapidly alter its species specificity and infect rats and primates,” Baric said. “The resulting virus variants are associated with demyelinating diseases in these alternative species.” (A demyelinating disease is a disease that damages nerve sheaths.) With steady prodding from laboratory science, along with some rhetorical exaggeration, a lowly mouse ailment was morphed into an emergent threat that might potentially cause nerve damage in primates. That is, nerve damage in us.
A few years later, in a further round of “interspecies transfer” experimentation, Baric’s scientists introduced their mouse coronavirus into flasks that held a suspension of African-green-monkey cells, human cells, and pig-testicle cells. Then, in 2002, they announced something even more impressive: They’d found a way to create a full-length infectious clone of the entire mouse-hepatitis genome. Their “infectious construct” replicated itself just like the real thing, they wrote.
Not only that, but they’d figured out how to perform their assembly seamlessly, without any signs of human handiwork. Nobody would know if the virus had been fabricated in a laboratory or grown in nature. Baric called this the “no-see’m method,” and he asserted that it had “broad and largely unappreciated molecular biology applications.” The method was named, he wrote, after a “very small biting insect that is occasionally found on North Carolina beaches.”
In 2006, Baric, Yount, and two other scientists were granted a patent for their invisible method of fabricating a full-length infectious clone using the seamless, no-see’m method. But this time, it wasn’t a clone of the mouse-hepatitis virus — it was a clone of the entire deadly human SARS virus, the one that had emerged from Chinese bats, via civets, in 2002. The Baric Lab came to be known by some scientists as “the Wild Wild West.” In 2007, Baric said that we had entered “the golden age of coronavirus genetics.”
“I would be afraid to look in their freezers,” one virologist told me.
Baric and Shi Zhengli of the Wuhan Institute of Virology, the two top experts on the genetic interplay between bat and human coronaviruses, began collaborating in 2015...
Baric’s safety record is good — although there was a minor mouse-bite incident in 2016, uncovered by ProPublica — and his motives are beyond reproach: “Safe, universal, vaccine platforms are needed that can be tailored to new pathogens as they emerge, quickly tested for safety, and then strategically used to control new disease outbreaks in human populations,” he wrote in a paper on public health. But the pioneering work he did over the past 15 years — generating tiny eager single-stranded flask monsters and pitting them against human cells, or bat cells, or gene-spliced somewhat-human cells, or monkey cells, or humanized mice — was not without risk, and it may have led others astray.
In 2006, for instance, Baric and his colleagues, hoping to come up with a “vaccine strategy” for SARS, produced noninfectious virus replicon particles (or VRPs) using the Venezuelan-equine-encephalitis virus (another American germ-warfare agent), which they fitted with various SARS spike proteins. Then, wearing Tyvek suits and two pairs of gloves each, and working in a biological safety cabinet in a BSL-3-certified laboratory, they cloned and grew recombinant versions of the original SARS virus in an incubator in a medium that held African-green-monkey cells. When they had grown enough virus, the scientists swapped out one kind of spike protein for a carefully chosen mutant, and they challenged their prototype vaccine with it in mice.
The scientists also tried their infectious SARS clones in something called an air-liquid interface, using a relatively new type of cell culture developed by Raymond Pickles of the University of North Carolina’s Cystic Fibrosis Center. Pickles had perfected a method of emulating the traits of human airway tissue by cultivating cells taken from lung-disease patients — nurturing the culture over four to six weeks in such a way that the cells differentiated and developed a crop of tiny moving hairs, or cilia, on top and goblet cells within that produced real human mucus. In fact, before infecting these HAE (human airway epithelial) cells with a virus, the lab worker must sometimes rinse off some of the accumulated mucus, as if helping the lab-grown tissue to clear its throat. So Baric was exposing and adapting his engineered viruses to an extraordinarily true-to-life environment — the juicy, sticky, hairy inner surface of our breathing apparatus.
SARS-2 seems almost perfectly calibrated to grab and ransack our breathing cells and choke the life out of them. “By the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission,” Alina Chan and her co-authors have written, whereas SARS, when it first appeared in 2003, underwent “numerous adaptive mutations” before settling down. Perhaps viral nature hit a bull’s-eye of airborne infectivity, with almost no mutational drift, no period of accommodation and adjustment, or perhaps some lab worker somewhere, inspired by Baric’s work with human airway tissue, took a spike protein that was specially groomed to colonize and thrive deep in the ciliated, mucosal tunnels of our inner core and cloned it onto some existing viral bat backbone...
Baric, Jonna Mazet, and Peter Daszak of EcoHealth worked together for years — and Daszak also routed Predict money to Shi Zhengli’s bat-surveillance team in Wuhan through his nonprofit, mingling it with NIH money and money from the U.S. Defense Threat Reduction Agency. In 2013, Mazet announced that Shi Zhengli’s virus hunters, with Predict’s support, had, for the first time, isolated and cultured a live SARS-like virus from bats and demonstrated that this virus could bind to the human ACE2, or “angiotensin-converting enzyme 2,” receptor, which Baric’s laboratory had determined to be the sine qua non of human infectivity. “This work shows that these viruses can directly infect humans and validates our assumption that we should be searching for viruses of pandemic potential before they spill over to people,” Mazet said.
In November 2015, Baric and colleagues published a collaboration paper with Shi Zhengli titled “A SARS-like Cluster of Circulating Bat Coronaviruses Shows Potential for Human Emergence.” Into a human SARS virus that they had adapted so that it would work in mice, Baric and Shi et al. inserted the spike protein of a bat virus, SHC014, discovered by Shi in southern China. They dabbed the mice nasally with virus and waited, looking for signs of sickness: “hunching, ruffled fur.” They also infected human airway cells with the mouse-adapted bat-spike-in-a-human-virus backbone. In both mice and human airway cells, the chimeric virus caused a “robust infection.”
This proved, Baric and Shi believed, that you did not need civets or other intermediate hosts in order for bats to cause an epidemic in humans and that therefore all the SARS-like viruses circulating in bat populations “may pose a future threat.” Peter Daszak, who had used Predict funds to pay Shi for her work on the paper, was impressed by this conclusion; the findings, he said, “move this virus from a candidate emerging pathogen to a clear and present danger.”
Richard Ebright was trenchantly unenthusiastic. “The only impact of this work,” he said, “is the creation, in a lab, of a new, non-natural risk.”
Early in 2016, Baric and Shi again collaborated. Shi sent Baric a fresh bat virus spike protein, and Baric inserted it into the backbone of a human SARS virus and then used that infectious clone to attack human airway cells. “The virus readily and efficiently replicated in cultured human airway tissues, suggesting an ability to potentially jump directly to humans,” reported the UNC’s website. This time, they also used the bat-human hybrid virus to infect transgenic humanized mice that grew human ACE2 protein. The mice, young and old, lost weight and died, proving, again, that this particular bat virus was potentially “poised to emerge in human populations.” It was “an ongoing threat,” Baric wrote. But was it? Civets and camels that are exposed to a lot of bat-guano dust may be an ongoing threat and a manageable one. But the bats themselves just want to hang in their caves and not be bothered by frowning sightseers in spacesuits who want to poke Q-tips in their bottoms...
Just before this issue of New York went to press, I reached Ralph Baric by phone and asked him where he now believed SARS-2 came from. (Anthony Fauci, Shi Zhengli, and Peter Daszak didn’t respond to emails, and Kristian Andersen said he was busy with other things.) Baric said he still thought the virus came from bats in southern China, perhaps directly, or possibly via an intermediate host, although the smuggled pangolins, in his view, were a red herring. The disease evolved in humans over time without being noticed, he suspected, becoming gradually more infectious, and eventually a person carried it to Wuhan “and the pandemic took off.” Then he said, “Can you rule out a laboratory escape? The answer in this case is probably not.”
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Originally Posted by Exarch
