The Mysterious Case of the COVID-19 Lab-Leak Theory – The New Yorker

There are twelve hundred different mutations between the genomes of RaTG13 and SARS-CoV-2—scattered variations that demonstrate the messiness of evolution. The number and distribution of these mutations are too large for RaTG13 to be the direct progenitor of SARS-CoV-2; they split from a common ancestor at least twenty years ago. But its genetic proximity means “we should look for the ancestors of SARS-CoV-2 in locations where relatives like RaTG13 are found,” Jesse Bloom, an evolutionary biologist at Fred Hutchinson Cancer Research Center, told me in September. “At this point, the closest relatives of SARS-CoV-2 are known to have existed in two locations: bat caves in Yunnan, and at the Wuhan Institute of Virology.”

Geography aside, the nature of the experiments undertaken by the W.I.V. and its partners has raised concerns. In 2015, Shi was a co-author on a groundbreaking study, in Nature, with Ralph Baric, a coronavirus expert at the University of North Carolina. Through the use of pioneering genetic technology, Baric examined which viral structures could give a coronavirus the ability to infect humans. The work involved synthesizing what is known as a chimeric virus, named for the mythical beast with its parts taken from various animals; in this case, a modified clone of SARS was combined with a spike protein taken from one of the bat coronaviruses that Shi had discovered in Yunnan.

Their research took place during a fraught time for virologists. Four years earlier, a Dutch scientist named Ron Fouchier decided to see if he could make the lethal avian influenza virus, H5N1, more transmissible. After failing to genetically reëngineer the virus, Fouchier turned to a classic method: he passaged the virus through live ferrets repeatedly, forcing the virus to evolve in its new host. After ten rounds, the virus was airborne. He had created a pandemic-ready pathogen in his lab.

The experiment, which constituted a type of research known as “gain-of-function,” provoked alarm. There were high-level meetings, op-eds, and reports decrying such work as far riskier than it was valuable. In 2014, President Barack Obama mandated a pause on gain-of-function studies involving influenza, SARS, and MERS, until a new regulatory process could be created. Baric, however, was in the middle of his chimeric-virus experiment. He petitioned the N.I.H. biosecurity board, which granted him, and other researchers, an exemption from the pause.

When Baric tested the chimeric virus in a culture of human airway cells, its spike protein proved able to bind to the cell receptor ACE2, suggesting that the virus was now poised to jump species. In live mice, it caused disease. Given this unexpected outcome, Baric concluded, “scientific review panels may deem similar studies building chimeric viruses based on circulating strains too risky to pursue.”

That didn’t happen. Baric’s experiments, which the N.I.H. had determined were not gain-of-function, continued at the University of North Carolina. Shi’s lab developed its own platform for creating chimeric viruses. She crossed another bat coronavirus from Yunnan—named WIV1—with clones of different novel spike proteins, and tested the creation in humanized mice. The viruses quickly replicated. One made the mice emaciated, a sign of severe pathogenesis. What made this work especially risky was that WIV1 was already known to be potentially dangerous to humans. Baric himself had made this clear in a 2016 study titled “SARS-Like WIV1-CoV Poised for Human Emergence.”

Some of these experiments at the W.I.V. were funded by the U.S. government, according to Shi’s published papers, as well as N.I.H.-funded grant applications and progress reports obtained by the Intercept. In 2014, N.I.H. had awarded a New-York-based nonprofit called the EcoHealth Alliance a five-year, $3.7-million grant, a portion of which—roughly six hundred thousand dollars—went to the W.I.V. Fauci and the N.I.H. have maintained that the W.I.V.’s work, like Baric’s, did not qualify as gain-of-function research, and so did not violate the Obama-era pause. (The Trump Administration lifted the pause in 2017, after three years of workshops and deliberations across multiple agencies resulted in a new regulatory process.) “Don’t mislead people by saying we haven’t taken this seriously for years,” Fauci told me, his voice rising. “According to our definition, it was not gain-of-function, period. If you don’t like the definition, let’s change the definition.”

In recent months, skeptics of natural origins have pointed to the fact that Shi was running her chimeric-virus experiments in a Biosafety Level 2 lab, which, compared to Biosafety Level 3, doesn’t require the same precautions, such as full P.P.E., medical surveillance for researchers, mandatory biosafety cabinets, controlled airflow, and two sets of self-closing, locking doors. (Shi did conduct live-animal experiments in a BSL-3 lab at a separate facility.) Because they were working with novel bat viruses rather than viruses known to infect humans directly, the low biosecurity setting was in accordance with Chinese laws. But Susan Weiss, a coronavirus expert at the University of Pennsylvania’s medical school, who co-authored a recent paper with Andersen and others that outlines the evidence for a natural origin, was surprised when I told her that they had been working in BSL-2. “That’s not a good idea,” she said.

Still, none of Shi’s documented work on chimeric viruses resulted in the creation of SARS-CoV-2. (“If you’re trying to say that that particular experiment could have led to SARS-CoV-2, that’s completely impossible,” Fauci said.) The chimeric viruses that the W.I.V. engineered are far from SARS-CoV-2 on the coronavirus family tree. According to Shi, the W.I.V. has only isolated and grown in culture three novel coronaviruses out of their nineteen thousand samples. What this chapter of her work demonstrates, however, is a high tolerance for risk. “They were essentially playing Russian roulette with the virus that the world’s expert had labelled poised for human emergence,” David Relman, a microbiologist at Stanford, said. “It’s the willingness to manipulate them without due concern.”

In January, the World Health Organization sent a team of international scientists to Wuhan to conduct the first phase of a search for SARS-CoV-2’s origins. The group’s report, published in March, ranked a zoonotic spillover—from a bat, through an intermediate animal, to a human—as the most likely origin pathway. They ruled a lab incident as “extremely unlikely,” dedicating just three of more than a hundred pages in the primary report to the theory. As Andersen frequently says when surveying the evidence, “Anything is possible, but I’m interested in what’s plausible.”

First, a natural origin has historic precedence. SARS spilled over from bats to civets at an urban market in November, 2002. MERS, which emerged in Saudi Arabia, in 2012, went from bats to camels to people. The civet was identified as the most probable source of SARS within four months of the outbreak; camels were identified within nine months of MERS. And yet, SARS-CoV-2’s intermediate animal—among the only things, at this point, that could definitively prove that it did not originate in the Wuhan labs—has not been found. Such a discovery is becoming less likely, too. As members of the W.H.O. mission wrote in an August letter to Nature, “The window is rapidly closing on the biological feasibility of conducting the critical trace-back of people and animals inside and outside China.”

One member of the W.H.O. team was Peter Daszak, the president of the EcoHealth Alliance, which is dedicated to mitigating the emergence of infectious diseases. Since the first SARS outbreak, he has been one of the W.I.V.’s closest partners, facilitating the N.I.H. subcontracts and working extensively with Shi and her team in the field. He has unwaveringly vouched for Shi, and led the charge to call any suggestion of a lab accident a conspiracy theory. “The problem with this lab-release hypothesis,” he told me, “is that it depends on a critical thing: that the virus was in the lab before it got out. But I know that that virus was not in the lab.”

Daszak, a widely published disease ecologist, also knows that the diversity of viruses in nature is nearly limitless. Most recently, he and other EcoHealth scientists built a model analyzing how frequently coronaviruses might spill over from bats to people across southern China and southeast Asia. They overlaid the habitats of all twenty-three bat species known to harbor SARS-related coronaviruses with maps of human populations. Based on bat-human contact and antibody data, they estimated that roughly four hundred thousand people could be infected with SARS-related coronaviruses annually. “People are getting exposed to them every year,” Daszak told me. “They may not know it. They may even get sick and die.”

In other words, spillovers happen far more often than anyone realizes. People are exposed to bats when they shelter in caves, harvest bat guano—the world’s best fertilizer—and hunt, butcher, and eat bats, which is a well-documented practice in various pockets across the region. “These small villages are at the edge of disappearing forests,” Kendra Phelps, a bat biologist with the EcoHealth Alliance and a co-author on the recent study, told me. “Inside that forest is densely packed wildlife, which is super stressed by things like encroaching palm oil and rice monocultures.” Stressed animals (just like us) are more likely to get sick and shed virus.