這是發表在The New Yorker 雜誌上的一篇文章。文章的題目是：《The Mysterious Case of the COVID-19 Lab-Leak Theory》 作者是Carolyn Kormann。這篇文章的中文譯文也在網上可以找到。
但是，這類文章不受待見，比較難找到。所以，我抄在了下面。
鏈接如下：https://www.newyorker.com/science/elements/the-mysterious-case-of-the-covid-19-lab-leak-theory?utm_source=NYR_REG_GATE&utm_brand=tny&utm_mailing=TNY_Daily_Control_101221&utm_campaign=aud-dev&utm_medium=email&utm_term=tny_daily_recirc&bxid=5f7bc988b5e371726e0744c0&cndid=62376034&hasha=197857684012727d6f14c11bd06e5573&hashb=a187ef94acfdaec7f72a1d2f81636839b7a41a88&hashc=7d07050e4f2fa78f65680918db86d94b5e20e84045a6be71e3b940e528d7cb25&esrc=bounceX&mbid=CRMNYR012019
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 with 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.
AdvertisementBefore the pandemic, President Xi Jinping promoted wildlife farms as a means of poverty alleviation, and the industry, which was largely unregulated, employed more than fourteen million people. “There’s this incredible network of people involved in farming and raising animals and trying out new ideas,” Daszak told me last year. “It’s entrepreneurial, it’s chaotic, it’s the sort of farms that are half falling apart, with mixed species in them.” The W.H.O. report stated that some wild-meat suppliers to Wuhan were located in south China, where horseshoe bats that host SARS-like coronaviruses primarily reside. Perhaps that is where the virus crossed from bats to animals, and those sickened animals were brought to Wuhan, where they were sold in Huanan and the city’s three other known live-animal markets. “The big missed opportunity, clearly,” Andersen said, “was testing potential reservoirs—intermediate hosts at these markets, not just at Huanan market but across Wuhan, as well as the farther-flung farms where these animals came from, which, to my knowledge, was officially not done.”
The Chinese government shuttered and sanitized the Huanan market on January 1, 2020, essentially destroying a crime scene. China’s officials told W.H.O. investigators that no live mammals were sold there—a position they still maintain. But a virologist at Hubei University of Traditional Chinese Medicine had been, he wrote, “serendipitously” conducting monthly surveys to identify the source of a severe tick-borne disease. In June, he published a study containing documentary evidence that, in the two years prior to the emergence of SARS-CoV-2, nearly fifty thousand live animals representing thirty-eight wild species—many of which are now known to be susceptible to SARS-CoV-2—were sold and butchered in Wuhan markets, including Huanan.
In February, 2020, China banned the trade and consumption of live wild animals. Tens of thousands of farms were shut down throughout the country. A farmer in Yunnan said that the government had bought and killed his mischief of bamboo rats. Chinese officials have not shared the extent to which they tested the farm animals and workers before the mass slaughter. This makes “any evidence of early coronavirus spillover increasingly difficult to find,” the W.H.O. mission noted in its report. Chinese officials told the W.H.O. that their scientists did test more than eighty thousand livestock, poultry, and wild-animal samples, across thirty-one provinces, collected both before and after the outbreak, but found no evidence of SARS-CoV-2.
The world’s most trafficked animal, the pangolin, was initially thought to be a likely contender in the intermediate-animal search, not because they were sold at Huanan market but because, in early 2020, tissue samples from a group of pangolins—confiscated from smugglers at China’s southern border—tested positive for a coronavirus. There are coronaviruses particular to all sorts of animals, but this one was weird. Part of its spike protein, the receptor binding domain, could bind more tightly to human ACE2 than SARS-CoV-2’s. Back in February, 2020, Andersen had been suspicious of SARS-CoV-2’s ACE2 binding strength. The pangolin-coronavirus discovery helped change his mind. If the pangolin had naturally evolved a coronavirus primed for binding to ACE2, then SARS-CoV-2 could have naturally evolved such a feature as well. (The rest of the pangolin coronavirus was too distinct from SARS-CoV-2 to be its source.)
Since then, close relatives of SARS-CoV-2 have been identified in China, Thailand, Cambodia, and Japan. But the most significant finding supporting a natural origin was announced in September. Scientists in Laos—just south of the border from Yunnan—found a horseshoe-bat coronavirus that is genetically closer to SARS-CoV-2 than the virus from the Tongguan mine. It might have split from a common ancestor with SARS-CoV-2 sometime in the last decade or so. Alarmingly, their spikes are identical and bind with equal efficiency to human ACE2 receptors. The discovery “completely blows away many of the main lab-leak arguments about Yunnan being special,” Andersen said. “These types of viruses are much more widespread than we initially realized.”
Bloom questioned the significance of the discoveries in Laos. “I don’t think it really, again, tells us exactly how these viruses got to Wuhan,” he said. But China’s wildlife trade could have been both an incubator and a transit system for a virus like SARS-CoV-2, which has proved not so necessarily adapted to humans but to mammals more generally. Coughing tigers tested positive for COVID-19 at the Bronx Zoo, then eight congested gorillas at the San Diego Zoo. White-tailed deer have SARS-CoV-2 antibodies. In the Netherlands, the virus devastated mink farms, infecting sixty-eight per cent of farm workers and hastening a permanent end to the country’s fur trade. China is the world’s largest fur producer. Could mink farms have been the problem? Raccoon dogs, another source of fur and exotic meat in China, are susceptible. “We’ve seen this virus jump into all kinds of animals with no adaptation, no evolution,” Andersen told me. “It’s a generalist. It had to be, otherwise it probably couldn’t cause a pandemic. It’s a unique beast.”
On September 21st, DRASTIC published a startling new revelation. In 2018, Daszak, at EcoHealth Alliance, in partnership with Shi, Baric, and Wang, had submitted a $14.2-million grant proposal to the U.S. Defense Advanced Research Projects Agency (DARPA). The proposal—which was obtained from an anonymous whistle-blower—detailed an ambitious plan to identify, model, and test the spillover risk of novel SARS-related bat coronaviruses, then develop vaccines for the horseshoe bats themselves, to preëmpt viruses from jumping into other animals or people. What stood out was their plan to insert “human-specific” furin cleavage sites into SARS-like bat coronaviruses. The furin cleavage site is the single most distinguishing feature of SARS-CoV-2. It’s “the magic sauce of this virus,” Michael Worobey, an evolutionary biologist at the University of Arizona, said recently. “Whether it’s natural or genetically modified, this is why this virus is circulating in humans.”
Before SARS-CoV-2 emerged, research suggested that a furin cleavage site broadens the range of host species that a virus can successfully infect, and increases its contagiousness (a hypothesis that the pandemic has confirmed). In order for a coronavirus to enter a cell, its spike must undergo a fragile metamorphosis, in which it is cut into two pieces. Only then can the virus fuse to the host cell’s membrane, and unload its genetic material, or RNA. A virus with a furin cleavage site can use a host’s furin—an enzyme that the human body readily produces—to quickly cut apart its spike. Worobey said that this “kind of puts the virus on a hair trigger so that once it binds to the cell, it can get in and be very effective.”
The DARPA proposal stated that scientists would introduce furin cleavage sites into lab-created versions of SARS-related coronaviruses, recovered from bats in Yunnan. They planned to fully sequence and generate clones of three to five novel bat viruses each year. Then they would test the altered viruses in human respiratory cells, and, potentially, in humanized mice. “This describes work that is, like, ‘Let’s go out and discover new viruses,’ ” Andersen said, “and do things like furin cleavage sites. So, yes, that’s why this is relevant to the wider conversation.”
SARS-CoV-2 is the only virus known to possess a furin cleavage site in its section of the coronavirus family tree. “We now know that there are full-length bat CoVs similar to SARS-CoV-2 that bind well to human ACE2,” Bloom said, referring to the Laos viruses, “but only lack the furin cleavage site.” The W.I.V. was collecting many viruses each year. What if researchers had found one even more similar to SARS-CoV-2, with the same binding affinity for human ACE2, then swapped a furin cleavage site into a clone of that virus in the lab? Such work could have led directly to the creation of SARS-CoV-2. “A novel furin cleavage site might have been the extra ingredient for a natural virus to spill over from animals to humans and cause a pandemic,” Alina Chan, a postdoc in molecular biology and gene therapy at the Broad Institute of M.I.T. and Harvard, tweeted recently. “It could also have been the extra ingredient for a lab virus to jump into a researcher and be carried out of the lab unnoticed.”
AdvertisementChan is the co-author of the forthcoming book “Viral: The Search for the Origin of COVID-19,” and has been, since the spring of 2020, one of the most tenacious researchers of a possible lab accident. “The question has to be asked,” she tweeted, “why people in the know didn’t think it was urgent & important, in Jan 2020, to let the world know there was research that could have plausibly led to the emergence of SARS2 in Wuhan.”
The proposal was rejected. A DARPA project manager explained that its “key strengths are the experienced team and the selected coronavirus hotspot caves that show high prevalence for novel bat coronaviruses.” But, they wrote, the team “does not mention or assess potential risks of Gain of Function (GoF) research.” That is, the group didn’t have a plan for the event that their experiments created a novel, pandemic-ready virus. Reviewers within DARPA “were really shocked” by the “irresponsible” nature of the proposal, and its lack of consideration for the risks that gain-of-function research would entail, an official, who was not authorized to speak to reporters, told me.
In the spring of 2020, when President Donald Trump started promoting the lab-leak theory, hijacking it from any reasonable discussion, someone told him that EcoHealth’s N.I.H. grant funded the W.I.V. The N.I.H. abruptly cancelled the grant. I spoke to Daszak at that time about the politicization of science and how the decision would affect his organization’s ability to function. He said that it halted collaboration with the W.I.V. on important work that was directly related to developing drugs for COVID-19, tracing the origin of the virus, and preventing the next pandemic. It also meant, he said, that EcoHealth scientists would no longer have access to the W.I.V.’s data. “It’s a very complex thing,” he said, describing EcoHealth’s work in China, “Chinese scientists will try and do my work, but it won’t be the same work, and it won’t be the work that we need to really understand the next one.”
Despite the fact that furin cleavage sites have been the subject of much debate for the past year and a half, Shi, Baric, and Wang never publicly mentioned that they had proposed these experiments. Daszak, despite being a member of the W.H.O. investigation, said nothing. (“All of that sort of furin-cleavage-site work was supposed to be done in North Carolina, not at the Wuhan Institute of Virology,” an EcoHealth spokesman said.) Andersen emphasized that there is no evidence to suggest that any of the work described in the proposal was actually done. But he added, “I was quite appalled, actually, to see it released now. I think the U.S.-based researchers that were on this particular grant have done a huge disservice by not releasing this information earlier.” (The EcoHealth spokesman told me that “the DARPA proposal was not funded” and that “the work described was not ever done.”)
Wang, at Duke-N.U.S. Medical School, was the first member of the DARPA proposal to publicly discuss it. He recently joined Bloom, Worobey, and Chan for a debate hosted by Science and live-streamed online. Both Bloom and Chan asked why the proposal’s existence was not shared earlier. Wang, who was born and raised in China, holds Australian citizenship, and now lives in Singapore, said that he didn’t know “the proper procedure of releasing the information” from a failed DARPA grant. When Jon Cohen, a writer for Science and the moderator of the debate, pressed him on transparency, Wang said the furin cleavage sites were not his part of the proposal. “From Day One, I said, to engineer a coronavirus in a lab, technically that is possible. But to engineer SARS-CoV-2 from existing knowledge? That’s not possible.”
It used to strike me as strange that, with current technology, virologists couldn’t look at the SARS-CoV-2 genome and determine whether it had been engineered. When I mentioned this to a French virologist who studies coronaviruses, he said, deadpan, “The secret is if you just look closely enough, you can see a tiny Wuhan Institute of Virology signature.” Proponents of a lab leak rest most of their arguments on the assumption that Chinese officials, the W.I.V., and Shi Zhengli are lying about the viruses they had, and the work they did, in a massive coverup. The natural-origin proponents assume that the W.I.V. has shared everything. “It’s not that the scientists would not have wanted to share,” Relman, who has refrained from taking a position on the question of SARS-CoV-2’s origin, said. “It’s that they wouldn’t have been allowed.”
The stakes are high on all sides. From one perspective, proving the virus has a natural origin is even worse for China. If wildlife farms were responsible for the pandemic, that would implicate the policies of President Xi Jinping. If there was a lab leak, just one, or a few, scientists are culpable of an accident. Either way, it is likely that the Chinese government prefers a storm of swirling theories, within which they can continue to push their own: that U.S. soldiers brought the virus to Wuhan in October, 2019, during the World Military Games, or that the American government manufactured the virus in Fort Detrick, Maryland. Or they can blame imported frozen food. The conspiracy theories branch out from there, in their own kind of evolutionary tree.
Without greater transparency from China, it will be difficult, if not impossible, to find the truth. Beijing “continues to hinder the global investigation, resist sharing information and blame other countries, including the United States,” the intelligence community states, in the declassified summary. “These actions reflect, in part, China’s government’s own uncertainty about where an investigation could lead as well as its frustration the international community is using the issue to exert political pressure.” President Biden, in a statement, said that the U.S. and its allies would continue to “press the P.R.C. to fully share information,” and to coöperate in the second phase of the W.H.O.’s investigation, both of which, so far, Beijing has refused to do.
For now, the battle between two theories rolls onward. As a friend said to me recently, “Why does it seem like we have to pick a side?” Both camps share a desire to understand the origins in order to prevent the emergence of the next pandemic. But, between them, there are some differences of emphasis.
The lab leakers tend to be more interested in biosecurity, transparency, and human hubris. They exhibit an admirable drive to follow the money, to upend centralized power, to overturn academic hierarchy, and to expose the injustices of oppressive governments. Some are China hawks. By and large, they have not done virus-hunting field or lab work.
On the natural-origin side, most people have done the kind of field and lab work that the W.I.V. pursued—and are regularly bowled over by nature’s endless diversity. They believe in scientific precedent, as opposed to uncertainties that have yet to be resolved. Many people in this camp have devoted their careers to conservation, biodiversity, and public health, and have been warning about a future pandemic for years. Spillovers most often happen because of land-use change, or human encroachment into previously wild places, which is happening on pretty much the entire planet, but particularly in areas that are developing rapidly, like south China and southeast Asia.
More than one virologist reminded me that nature is the best bioterrorist. It’s far more creative than humans are. With enough time, evolution is capable of anything we can imagine, and everything we can’t. “If you look at a platypus, you can very clearly realize that that’s not something somebody would have designed, right?” Andersen said. “Because it’s too absurd. It’s a bit of a disaster. But it works pretty well.” It occupies its own ecological niche. Some of the notable features of SARS-CoV-2, Andersen said, make it “the platypus of coronaviruses.”
Still, humans have changed the equation. Calling viruses zoonotic obscures the role we play in their evolution, whether in the wilderness, a wet market, or a lab. What is an ecological niche when humans have their hands in everything? Nature’s staggering diversity includes human nature. Somehow, SARS-CoV-2 found its ecological niche in us.
More on the CoronavirusCOVID is likely to become an endemic disease. How will our immune systems resist it?
The case for masking up again indoors in New York City.
Suddenly, (some) Republicans are all in on the vaccine.
The outlook for life in a half-vaccinated country.
A dreamy, disorienting reopening in New York.
What does the Delta variant mean for the economy?
Sign up for our daily newsletter to receive the best stories from The New Yorker.
Leave a Reply