Monday, April 15, 2024

Lab leak theory, once ‘political dynamite,’ gains credibility with recent publication

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The rejections kept coming. The coronavirus was a topic of intense scientific fascination, yet the four Australian researchers challenging conventional wisdom about how the pandemic originated couldn’t find a publisher for their study.

“We were quite stunned,” recalls one of that study’s authors, Dr. Nikolai Petrovsky, an endocrinologist at Flinders University in Australia who is also developing a coronavirus vaccine. The work he and his group had done only received what he called “blanket rejections.”

That finally changed late last month, when Nature Scientific Reports published their paper, “In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin.” The journal is part of the prestigious Nature family of publications. Acceptance there has given greater credibility to a theory that until recently was taboo: that the coronavirus could have emerged from a laboratory.

Some wonder why the study’s publication took so long. “It’s definitely concerning that the paper took over one year to be accepted for publication,” says Pat Fidopiastis, a microbiologist at California Polytechnic State University. “It’s important to continue asking questions and demand honest answers.”

The Australians’ findings were scientific but had major political ramifications. Using computer models, Petrovsky and his co-authors set out to learn which animal the virus may have originated from before infecting humans. Proponents of the zoonotic spillover hypothesis believed that the pathogen known as SARS-CoV-2 originated in bats and then made the leap to humans, possibly through an unknown intermediate species.

A bat

Scientists say that bats are a suspected source of viruses, including COVID-19, that have leapt the species barriers to humans. (Sia Kambou/AFP via Getty Images)

Throughout much of 2020, that was how most scientists assumed the pandemic began. A wet market in the Chinese city of Wuhan came to be seen as the likely site of the spillover that began the pandemic.

The Australians modeled how the distinctive spike protein that protrudes from the surface of the coronavirus binds to a receptor called ACE2, found on the membranes of human and animal cells. Essentially, the researchers’ computer model tried to calculate how tightly the key that was the SARS-CoV-2 spike protein would fit into the ACE2 keyhole of different species: monkeys, snakes, mice, bats and, of course, humans, along with many others. If the spike protein had trouble binding to the ACE2 receptors in a species, that species wasn’t likely to be the source of the coronavirus.

Petrovsky and his co-authors all but ruled out the notion of a direct zoonotic spillover from bats to humans, without an intermediate species involved, because the virus that was believed to have begun circulating in China in late 2019 had low binding affinity to the bat ACE2 receptor.

There was still the possibility that the virus had jumped from bats to another species before infecting humans, but none of the candidates the Australians tried seemed an especially good fit for that role.

“If the animal that bridges between bat and man cannot be found, the zoonotic explanation looks much less likely,” says David Winkler, a molecular biologist at the La Trobe Institute for Molecular Science and a co-author of the study with Petrovsky. That alone isn’t evidence of human intervention, Winkler says, but it does raise the question: If the virus didn’t come from nature, where did it come from?

One popular suspect had been the pangolin, a scaly relative of the anteater that is both eaten in China and used in traditional Chinese medicine. It performed well in the Australians’ computer models, with the coronavirus predicted to have the second-highest binding affinity for pangolin ACE2, after that of humans.

A pangolin

The pangolin, a scaly-skinned mammal once thought to have been the intermediate carrier of the coronavirus. (Themba Hadebe/AP)

Only this was a false lead in the search for the intermediate species, because the pangolin coronavirus does not resemble SARS-CoV-2. Crucially, it lacks a key genetic signature of SARS-CoV-2 called a furin cleavage site.

Also, pangolins are rare and, contrary to reports from early 2020, are not traded in the wildlife markets of Wuhan. Last month, a joint research team from Chinese and Western institutions published a survey of 47,381 different individual animals, from 38 species, sold at Wuhan markets between May 2017 and November 2019. During that time, not a single pangolin or bat was sold in the entire city.

“Pangolins were not likely the spillover host,” concluded the authors, two of whom are affiliated with an animal research laboratory at China West Normal University in Nanchong.

Tarik Jašarević, a spokesperson for the World Health Organization, told Yahoo News that the survey about which animals were sold in Wuhan markets “makes the hypothesis of a spillover through an intermediary host more likely” by demonstrating just how many different species of animal, including exotic ones, were on sale.

“The article confirms that many susceptible animal species were sold live in markets in Wuhan. Including badgers, weasels, mink, etc.,” Jašarević wrote in an email. “Many of them could have been playing the role of an intermediary species.”

The Australians, however, in addition to ruling out a number of species as potential intermediaries, found that the coronavirus hadn’t seemed to need an intermediate species in order to proliferate through the human population. Studying genomic data of human virus isolates from the very earliest stages of the pandemic in China, they saw that the coronavirus was already well adapted to infect humans, even at a stage where it is not thought to have infected more than a few hundred people in Hubei province. Such quick and efficient adaptation to humans meant the virus may “have arisen from a recombination event that occurred in a laboratory handling coronaviruses,” wrote the Australian group, which along with Petrovsky and Winkler included Sakshi Piplani and Puneet Kumar Singh.

Security personnel

The Wuhan Institute of Virology, where a WHO team investigated the origins of the coronavirus. (Thomas Peter/Reuters)

“Basically, you would expect a naturally derived virus to be less well suited to attaching to the human ACE2 receptor than the SARS-CoV-2 virus is,” says Dr. Jayanta Bhattacharya, a professor of medicine at Stanford who has routinely bucked popular opinion in the course of the pandemic. “Or if it is naturally derived, we should be able to find an intermediate virus that infects pangolins or bats about as well as humans.”

The Australian scientists did less to endorse the lab escape scenario than to discount the zoonotic one through a process of elimination. “We thought it was a pretty neutral, really fascinating paper,” Petrovsky told Yahoo News. “We thought this should be, you know, just grabbed by one of the top journals.”

Instead, it would be more than a year of rejections, frustrations, revisions and delays before the paper was finally published last month in a major scientific journal. Four of the top science journals in the world turned it down, even as their pages brimmed with other coronavirus-related studies. The authors believe that had nothing to do with the merits of their scholarship but rather with a long-standing resistance to the possibility that the coronavirus pathogen originated at the Wuhan Institute of Virology in Wuhan, China, or another biomedical institution in that city.

One of the other laboratories, the Wuhan branch of the Chinese Center for Disease Prevention and Control, is about a 20-minute walk from the Huanan Seafood Wholesale Market, where initial investigations focused. That may mean nothing in the end, but pointing out shortcomings in the zoonotic hypothesis is no longer “political dynamite,” as Petrovsky puts it.

The Wuhan Huanan Wholesale Seafood Market

The Wuhan Huanan Seafood Wholesale Market, where a number of people fell ill with a virus. (Dake Kang/AP)

Some fear that legitimating the lab leak hypothesis could exacerbate anti-Asian xenophobia that has been gaining force in recent months. Petrovsky flatly rejects the notion that the virus was engineered by Chinese scientists, a theory some House Republicans have forwarded without evidence. “That would be like saying that Chernobyl was deliberately exploded by the Russians,” he says, referring to the infamous 1986 partial nuclear meltdown that contributed to the collapse of the Soviet Union. “No one — no one — would deliberately do such things.”

But he also wants to remove insinuations of conspiracy and racism from the lab leak hypothesis. “This is not an unusual event, unfortunately. Lab leaks happen,” Petrovsky notes. That includes several in the United States. In 2014, eight mice infected with SARS or flu viruses escaped a laboratory at the University of North Carolina at Chapel Hill; that same year, monkeys at the Tulane National Primate Research Center near New Orleans were sickened with a dangerous bacterium that is thought to have clung to a worker’s clothes.

Opposition to the possibility of a lab leak has fallen away dramatically in the last several months in mainstream news publications.

“The COVID lab-leak theory goes mainstream,” went an Axios headline from May that captured the shifting mood.

Rhesus macaque monkeys

Rhesus macaque monkeys at the Tulane National Primate Research Center in Covington, La., where the focus of study has shifted to the COVID-19 pandemic. (Kathleen Flynn/Reuters)

Last year, Vanity Fair was one of many publications to flay conservatives for pushing the lab leak hypothesis; in June, the very same magazine published an 11,000-word report by investigative reporter Katherine Eban suggesting that China’s allies in the medical establishment and skittish U.S. government officials sought to avoid questions about how the pandemic began.

President Biden has said China must do more to solve that mystery. He has given the U.S. intelligence community 90 days to conduct an investigation of its own. An earlier investigation by intelligence analysts found that a lab escape was not outside the realm of possibility.

None of that means the lab escape accident is true. That hypothesis has plenty of gaps, and plenty of detractors. “The absence of an identified intermediate species is not a strong argument against the natural-spillover hypothesis,” says Dr. Richard Ebright, a chemist at Rutgers University who has sought a more complete investigation into the pandemic’s origins. He says the Australian group’s results are “consistent with both natural spillover and lab spillover hypotheses for the origin of SARS-CoV-2,” meaning that they are, in effect, inconclusive on that key question.

One way to quell speculation about how the pandemic originated would be to find the elusive intermediate species.

“It could be we will never know,” Petrovsky says. He points out that it took years for the Soviet Union to admit to an anthrax accident at a laboratory that killed dozens in the city of Yekaterinburg.

“With time, terrible mistakes are admitted,” he says.

China, for its part, has steadfastly denied responsibility for the pandemic, going as far as to suggest that if the virus did escape, it was from the bioweapons laboratory at Fort Detrick, Md., an assertion that lacks any evidence or credibility.

In the meantime, skepticism about the virus’s natural origins appears to be growing among Americans. A recent Yahoo News/YouGov poll found that 46 percent of Americans now believe that the virus escaped from a Chinese laboratory. Only 18 percent trust the zoonotic hypothesis. The rest are unsure.

Researchers like Petrovsky know full well that they are extremely unlikely to gain on-the-ground access to China. Several months ago, journalists for Western media outlets tried to enter an abandoned mine in Yunnan province that some believe housed bats carrying what we would come to know as the coronavirus. The journalists were trailed and turned away.

A mine shaft in China's Yunnan province

A mine shaft in China’s Yunnan province once harbored bats infected with the closest known relative of the COVID-19 virus. (Ng Han Guan/AP)

What virologists do have is genetic code. On June 6, physicist Richard Muller and physician Steven Quay published an article in the Wall Street Journal pointing out that the coronavirus contained a genetic sequence called double CGG that is a hallmark of laboratory experiments with viruses. That same sequence is rarely found in nature.

The double CGG sequence is found at the critical furin cleavage site — the very same feature that the Australians had found lacking in pangolin coronaviruses.

Fidopiastis, the CalPoly microbiologist, found the presence of that sequence curious as well. The coronavirus “doesn’t appear to have been circulating long enough prior to being noticed to have evolved a receptor so well optimized for human cells,” he told Yahoo News. “Thus, the lab manipulation scenario is far more likely than this happening by chance.”

Two weeks after publication of the hotly debated Wall Street Journal article, the American scientist Dr. Jesse Bloom of the Fred Hutchinson Cancer Center in Seattle announced he had discovered 13 genetic sequences from the early stages of the pandemic that had mysteriously disappeared from a National Institutes of Health database. Bloom concluded that “the Huanan Seafood Market sequences that are the focus of the joint WHO-China report are not fully representative of the viruses in Wuhan early in the epidemic.”

The report Bloom mentioned had been published by the WHO in late March. Investigators from the agency were allowed to visit the Wuhan Institute of Virology, but access to researchers and their records was highly limited. The only American on that team was Peter Daszak, chief executive of the EcoHealth Alliance, a New York-based organization that studies emerging diseases.

Peter Daszak and Thea Fischer

Peter Daszak and Thea Fischer, members of the World Health Organization team tasked with investigating the origins of the coronavirus, arriving at Wuhan Institute of Virology, Feb. 3, 2021. (Thomas Peter/Reuters)

Daszak’s role in discrediting the notion of a lab escape in the eyes of scientists, journalists and members of the public remains one of the more curious aspects of the pandemic. The WHO report published in March seemed to broadly reflect his views, calling a lab leak “extremely unlikely.”

EcoHealth’s work often involves collaborating with foreign entities. In the years before the pandemic began, EcoHealth had sent $700,000 in grants from the National Institutes of Health to the Wuhan Institute of Virology. NIH head Francis Collins recently testified that those funds could not be used for gain-of-function research — which involves changing a virus in some way to test it — but he seemed to concede that it was impossible to know exactly what was happening at the Chinese laboratory.

An NIH spokesperson told Yahoo News there was nothing improper about the grant to EcoHealth Alliance that was used to fund work at the Wuhan Institute of Virology. “NIH supports this type of research in other countries to learn more about viruses lurking in bats and other mammals that have the potential to spill over to humans and cause widespread disease,” the spokesperson said. “The viruses created did not gain any new attributes compared to the original virus.”

Daszak was also the organizing force behind a statement in the Lancet, perhaps the world’s preeminent scientific journal, published in February 2020, when relatively little was known about the coronavirus. The statement declared “solidarity with all scientists and health professionals in China,” where the virus had originated sometime in late 2019.

“We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin,” the Lancet statement said, in a clear rebuke of then-President Donald Trump.

Donald Trump

Trump at a coronavirus task force briefing at the White House, March 20, 2020. (Evan Vucci/AP)

Eban’s article in Vanity Fair described how Daszak “organized the influential Lancet statement, with the intention of concealing his role and creating the impression of scientific unanimity.” Just days after her investigation was published, the Lancet included an amended disclosure from Daszak.

Daszak did not respond to requests for comment from Yahoo News.

The Lancet was one of the journals that rejected the Australian paper on ACE2 receptors last year, several months after Daszak’s letter was published. In a statement to Yahoo News, a Lancet representative told Yahoo News that its “journals set extremely high standards and papers are selected for publication based on the strength of the science and the credibility of the scientific argument.” The representative would not say why, specifically, the Australian paper was rejected. “The Lancet group does not comment on papers it has not published,” the statement said.

“It is very important to talk about the scientific journals — I think they are partially responsible for the cover-up,” the French biologist Virginie Courtier-Orgogozo told the British journalist Ian Birrell last month. China has lavished millions on scientific journals in the West, Birrell wrote, while also providing those journals access to its own scientific institutions.

Nature Scientific Reports had first shown interest in the Australians’ paper last year but rejected the submission after one of the reviewers charged with assessing it made critical comments. The researchers appealed the rejection, and following a lengthy revision process, the paper was published in June.

A press representative from Nature forwarded a statement from Scientific Reports editor in chief Richard White to Yahoo News that read: “As with all our journals, Scientific Reports does not reject papers for political reasons. We cannot comment on the editorial history of any paper as we treat that information as confidential.”

Winkler readily admits that the computer models of binding affinities are “clearly not sufficient” to determine just how the coronavirus became so acutely adaptable to humans. Without a more complete investigation, that determination may never be made.


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