December 4, 2021, 16:08

The lab leak hypothesis, explained

The lab leak hypothesis, explained

Where did the virus that causes Covid-19 come from?

It’s one of the most persistent mysteries of the pandemic. The debate about it among scientists, policymakers, journalists, amateur internet sleuths, and the general public has reignited with new revelations and new voices in the mix.

Most recently, emails obtained by the Washington Post and BuzzFeed showed that National Institute of Allergy and Infectious Diseases Director Anthony Fauci was corresponding with a scientist as early as January 2020 investigating the possibility that SARS-CoV-2, the virus that causes Covid-19, may have been engineered in a lab. An article in Vanity Fair highlighted how efforts to probe a lab leak were suppressed within parts of the US government as some officials worried that a lab in Wuhan, China, that received US funding may have been the source.

Scientists last year argued that the most plausible explanation is the “natural emergence” of the SARS-CoV-2 virus: It jumped from bats, or an intermediary species, to humans in a random event sometime in 2019. Many still hold this view, and some have become even more confident in this pathway.

Several media outlets, including Vox, also downplayed in 2020 the possibility that human error launched the virus, after many scientists with relevant experience described the idea as extremely unlikely. In February 2020, 27 scientists co-signed a letter in The Lancet affirming their belief in a natural origin of the virus and decrying efforts to pin the blame for the outbreak on Chinese scientists.

A note appended to an article about bat coronaviruses in the journal Nature Medicine affirms the natural origin hypothesis of SARS-CoV-2.

Nature Medicine

But in recent weeks, more scientists — including some who had not weighed in until now — have spoken up about the possibility that the virus may have escaped a laboratory in China, and argued that this scenario has not been adequately investigated.

The Covid-19 pandemic has illustrated that science is essential for grappling with the disease, but also that experts can get things wrong. For example, the World Health Organization in January 2020 said that there was “no clear evidence” of transmission of SARS-CoV-2 between people. The US surgeon general told Americans in February 2020 that face masks were not effective in slowing the spread of the disease. It could be possible, then, that the dismissal of a laboratory origin of the virus was premature among some experts amid the flurry of developments in the early stages of a global outbreak.

“We must take hypotheses about both natural and laboratory spillovers seriously until we have sufficient data,” reads a letter published in the journal Science in May 2021, co-authored by 18 researchers.

Some scientists had been reluctant to publicly broach the “lab leak” hypothesis in part because the Trump administration had asserted, without clear evidence, its confidence in the theory, as it tried to find ways to blame China for the pandemic and deflect scrutiny from the White House’s mishandling of the crisis. The idea also collapsed into conspiracy theories, like the notion that the virus was deliberately released as a bioweapon.

The lab leak hypothesis “really is not a fringe theory,” Marc Lipsitch, an epidemiology professor at the Harvard School of Public Health and a co-signer of the letter, told CNN. “It had been viewed as a fringe theory because it was espoused in fringe ways by some people with political agendas.”

Thea Fischer (left), Peter Daszak (right), and other members of the World Health Organization team arrive at the Wuhan Institute of Virology to investigate the origins of Covid-19 on February 3.

Hector Retamal/AFP via Getty Images

Lipsitch and other researchers pushing for further investigation say that the Chinese government hasn’t been forthcoming with critical details about its research on coronaviruses; it also ordered some early lab specimens of the virus to be destroyed and censored reporting around the outbreak. The calls for more transparency from scientists prompted the Biden administration to order US intelligence agencies to investigate the possibility of an accidental lab leak. The answer to the question of how the virus originated has as much political import as it does scientific.

At the most basic level, the case for the natural origins of the virus rests on incomplete evidence, while the lab leak hypothesis rests on the gaps in that very evidence.

A natural exposure route for SARS-CoV-2 still seems far more likely to many scientists, but a satisfying answer one way or another may never coalesce as the initial infections recede into history and China continues to withhold data and records from those early days. Scientists still haven’t determined from which animal the virus hopped into humans, but neither have they found any trace of SARS-CoV-2 in a laboratory prior to its emergence. All the while, the tense US-China relationship looms over the investigation, threatening to throttle the search for answers.

Many prominent voices in science, politics, and national security are now deeply invested in seeing this investigation through. Here’s how some of the researchers currently engaged in the conversation are parsing the evidence, what they see as some of the most important lines of inquiry going forward, and what they say we may never know.

Why some scientists say that a lab origin deserves a closer look

The term “lab leak” refers to the possibility that the SARS-CoV-2 virus or a close relative was at some point being studied at a laboratory in China prior to the Covid-19 pandemic and then later escaped. In particular, investigation proponents are interested in the Wuhan Institute of Virology near the original epicenter of the Covid-19 outbreak. After the 2003 SARS outbreak, the facility increased its focus on emerging diseases, including respiratory infections caused by coronaviruses.

The possibility of a lab leak crossed the mind of Shi Zhengli, a renowned virologist at the Wuhan lab. She told Scientific American last year that she recalled being told in December 2019 about a mysterious pneumonia caused by a coronavirus spreading in the city of Wuhan and wondering if the pathogen came from her lab.

There have been reports that researchers at the institute were performing gain-of-function experiments, where a natural virus is modified to become more virulent or to better infect humans. This research tries to map potential ways a virus could mutate and lead to an outbreak, allowing scientists to get a head start on countering a potentially dangerous pathogen. But such research is dangerous and controversial. The National Institutes of Health declared a moratorium on funding gain-of-function research in 2014, lifting it in 2017 for experiments that undergo review by an expert panel.

US officials have been adamant that US funding did not support any gain-of-function research at the Wuhan Institute, or anywhere in the world. NIH Director Francis Collins said in a May statement that US federal health research agencies have never “approved any grant that would have supported ‘gain-of-function’ research on coronaviruses that would have increased their transmissibility or lethality for humans.”

Scientists at the Wuhan lab were known to be working with an international team on creating chimeric versions of different coronaviruses to study the potential of a human outbreak, though they say that these chimeric viruses did not increase in pathogenicity and therefore do not constitute gain of function. The chimeras in the experiment were also created in the US, not China. Wuhan Institute researchers also published a paper in 2017 reporting on a bat coronavirus that could be transmitted directly to humans, with researchers creating chimeras of the wild virus to see if they could infect human cells. That study had funding from the US National Institutes of Health.

Looking at these studies, there are scientists who say such experiments meet the definition. “The research was — unequivocally — gain-of-function research,” Richard Ebright, a microbiology researcher at Rutgers University, told the Washington Post.

There is also a possibility that other, more direct gain-of-function experiments were conducted with other funding sources, but no evidence has emerged for this.

The lab leak hypothesis “had been viewed as a fringe theory because it was espoused in fringe ways by some people with political agendas” —Marc Lipsitch, epidemiologist

That said, the lab leak hypothesis doesn’t hinge on risky gain-of-function research being conducted at the lab, explained Alina Chan, a researcher at the Broad Institute and a co-signer of the Science letter.

“Maybe a few people think that there could’ve been some gain-of-function research, but I’d say that a lot of scientists who are asking for an investigation say that this was a lab accident of a mostly natural, or completely natural, virus,” Chan said.

She and other scientists want to investigate the possibility that SARS-CoV-2 or a very closely related virus escaped during normal laboratory operations. The two strongest possibilities, according to Chan, are, one, that a researcher at the Wuhan Institute of Virology was exposed to a bat coronavirus while collecting samples in the field and inadvertently brought the infection back to Wuhan. The field, in this case, is the native habitat of the bats in the southeastern provinces of China, more than 1,000 miles from Wuhan. And two, scientists at the lab could have been exposed to a sample of SARS-CoV-2 that was under study and then spread the virus to others.

Indeed, dangerous pathogens have leaked out of laboratories several times before, and human error is a constant risk in any research institution. “The only labs that don’t have accidents are labs that are not functional,” Chan said.

She pointed out that someone unwittingly falling sick with a virus under study in a lab has happened before in China. In 2004, a researcher contracted SARS after a stint working at the Chinese National Institute of Virology in Beijing. The researcher went on to infect her mother and a nurse at the hospital who went on to infect others, leading to 1,000 placed under quarantine or medical supervision.

Another concern was that the Wuhan Institute of Virology was handling coronavirus samples at biosafety level 2 precautions when most other labs recommend a biosafety level of 3 or higher. At biosafety level 2, lab access is restricted, researchers must wear personal protective equipment like gloves, lab coats, and eye protection, and much of the experimental work is conducted in biosafety cabinets that filter air rather than open lab benches.

Biosafety level 3 includes all the precautions of lower levels and adds medical surveillance for lab workers, the use of respirator masks, and lab access controlled with two sets of self-closing and locking doors. The biosafety level 3 measures are aimed at controlling potentially lethal respiratory pathogens that spread through the air, while biosafety level 2 is meant for pathogens that pose a “moderate hazard.”

So seeing that the Wuhan lab was handling viruses that can travel through the air at a safety level not designed for it alarmed some observers. “When scientists hear about this, they get really freaked out,” Chan said.

W. Ian Lipkin, a virologist at Columbia University, co-authored a Nature Medicine paper in March 2020 that reported the most likely origin of the virus in humans was a natural spillover from animals. But he told the journalist Donald McNeil in May 2021 that he was alarmed when he learned that the Wuhan Institute of Virology was conducting research on similar viruses at a lower level of protection.

“People should not be looking at bat viruses in BSL-2 labs,” Lipkin said. “My view has changed.”

An epidemiological laboratory in Wuhan, China, in 2017.

Johannes Eisele/AFP via Getty Images

Chan also noted that the Huanan Seafood Wholesale Market in Wuhan was initially suspected as the location where a SARS-CoV-2 spillover from animals to humans occurred, but to date, no infected animal has been identified and Chinese researchers have ruled it out as the origin of the virus. The initial outbreak could have occurred because so many people were in close proximity at the bustling market, but the virus may have made the leap to humans elsewhere.

There are also allegations that the Chinese government hasn’t been forthright about the early days of the pandemic and has withheld critical information from investigators, making it hard to eliminate a lab leak as a possibility. “I can also be convinced of a natural origin if that is properly investigated too,” Chan said in an email. “The problem is that the most definitive pieces of evidence would be inside of China where we currently have no access.”

A team from the World Health Organization that visited China in January and February of this year reported that they had difficulty getting all the information they wanted about the origins of SARS-CoV-2.

“In my discussions with the team, they expressed the difficulties they encountered in accessing raw data,” WHO Director-General Tedros Adhanom Ghebreyesus said during a briefing in March. “I expect future collaborative studies to include more timely and comprehensive data sharing.”

Properly investigating the possibility of a laboratory leak, if only to rule it out, would help answer critical scientific questions while also bolstering public confidence in the process, proponents argue. “We have to show that we have the will to investigate whenever something like this happens and that we have a system in place,” Chan said.

Why the lab leak theory is getting so much attention now

Questions about whether SARS-CoV-2 may have escaped from a lab have been simmering since the beginning of the pandemic, but several recent developments catapulted the debate back into the news, and even into Congress.

At the beginning of the year, New York Magazine (which is owned by Vox Media) published a long article by the novelist Nicholson Baker making the case that the virus may have leaked from a lab in China. Journalist Nicholas Wade made a similar case in an article published on Medium in May. The letter published by Science in May, which called for a more thorough investigation into the hypothesis, was another driver of the conversation. A few days after the letter, an article in the Wall Street Journal resurfaced US intelligence reports about three researchers at the Wuhan Institute of Virology who sought medical care for influenza-like symptoms in November 2019. That’s earlier than the first confirmed case of Covid-19, which occurred on December 8, 2019, according to Chinese officials. (There’s no evidence that the researchers had Covid-19, however.)

Shortly thereafter, the Wall Street Journal highlighted the case of six miners in China who fell ill in 2012 after being hired to clear a cave of bat guano. The Wuhan Institute of Virology was called in to investigate. Researchers from the lab tested bats from the mine for coronaviruses and found an unidentified strain resembling SARS; several bats were infected with more than one virus. That created opportunities for recombination, in which viruses undergo rapid, large-scale mutations that create new pathogens.

“The problem is that the most definitive pieces of evidence would be inside of China, where we currently have no access” —Alina Chan, molecular biologist

One of the unidentified viruses, called RaTG13, was later found to have 96.2 percent genetic overlap with SARS-CoV-2, hinting that it may have been a predecessor. A WHO team reported that the lab wasn’t able to culture the virus, and was only in possession of its genetic sequence. If these reports are to be believed, that means the institute didn’t have an infectious ancestor to SARS-CoV-2 in its custody.

In the wake of these media reports and rising public interest, President Biden ordered US intelligence agencies last month to increase their efforts in investigating the potential of a laboratory origin of SARS-CoV-2 and report back in 90 days.

For some scientists, the resurgent interest in a lab leak has been frustrating, rather than illuminating. “Quite frankly, over the last number of days, we’ve seen more and more and more discourse in the media with terribly little actual news, evidence, or new material,” said Michael Ryan, executive director of the World Health Organization’s health emergencies program, during a May 28 press conference.

But for others, it has been validating. Former US Centers for Disease Control and Prevention Director Robert Redfield told Vanity Fair that he received death threats last year after stating publicly that he thought the virus originated in a lab.

And for still other researchers, the issue remains too contentious to discuss publicly. One scientist contacted for this article declined to comment on the record in part out of fear of harassment. Nonetheless, this renewed attention seems unlikely to go away anytime soon.

Why other scientists remain skeptical of the lab leak hypothesis

Despite the concerns and unknowns around the activities at the Wuhan Institute of Virology, there is no evidence SARS-CoV-2 ever passed through the laboratory; rather, the circumstances only indicate that a lab leak was possible.

Some scientists in the US were already looking into this possibility in the early days of the pandemic. Kristian Andersen, a professor at the Scripps Research Institute, exchanged emails with Fauci in January 2020 about his suspicions that the SARS-CoV-2 virus was engineered because its genetics didn’t resemble what he thought would occur in nature, according to documents obtained by BuzzFeed and the Washington Post. “I should mention that after discussions earlier today, Eddie, Bob, Mike, and myself all find the genome inconsistent with expectations from evolutionary theory,” Andersen wrote to Fauci.

Andersen then investigated the possibility, and co-authored the March 2020 Nature Medicine paper on the origins of the SARS-CoV-2 virus with Lipkin that reported the most likely origin of the virus was a spillover from an animal. Unlike Lipkin, Andersen has only become more convinced the virus came into humans via a natural exposure route.

“We cannot categorically say that SARS-CoV-2 has a natural origin but, based on available scientific data, the most likely scenario by far is that SARS-CoV-2 came from nature,” Andersen told Vox in an email. “No credible evidence has been presented to support the hypothesis that the virus was engineered in, or leaked from, a lab — such statements are based on pure speculation.”

Then what would it take to demonstrate that the virus escaped a lab?

“Evidence that [the Wuhan Institute of Virology] or another Wuhan virology lab had SARS-CoV-2 or something 99% similar would be the smoking gun,” Robert Garry, a virologist at Tulane University and another co-author of the Nature Medicine paper, said in an email. “There is no evidence that SARS-CoV-2 or an immediate progenitor virus existed in any laboratory before the pandemic.”

He, too, has become more convinced that the virus jumped to humans somewhere outside the lab. “The only change since we wrote our manuscript on the Proximal Origins of SARS-CoV-2 is that I now consider any of the lab leak hypotheses to be extremely unlikely,” he said.

Shi Zhengli at the Wuhan Institute of Virology told Scientific American she instructed her team to sequence the genomes of all the viruses they were studying in their laboratory and compare them to sequences obtained from Covid-19 patients. None matched. “That really took a load off my mind,” she said. (Shi did not respond to a Vox request for comment.)

Chinese virologist Shi Zhengli seen inside the epidemiological laboratory in Wuhan in 2017.

Johannes Eisele/AFP via Getty Images

Several other factors point toward a natural origin of SARS-CoV-2, according to Vincent Racaniello, a virologist at Columbia University. Among them is that the 2003 SARS virus outbreak established a precedent for a coronavirus jumping from bats to an intermediary species to humans. In that case, the intermediary — civet cats — was identified; scientists have been warning for years that a similar scenario could easily occur again.

Further animal investigations showed that there are a number of viruses like SARS-CoV-2 in bats, not just in China but also in Thailand, Cambodia, and Japan. These viruses are not direct ancestors of SARS-CoV-2, but they are closely related. Viruses mutate all the time, and the more widespread they are, the more changes can occur. Seeing a related virus over such a wide area shows there was ample opportunity for it to spread and mutate in nature before it made the final jump into humans.

The WHO also found that in the earliest days of the pandemic, during the outbreak in Wuhan, China, in 2019, there were two distinct lineages of the virus with different transmission patterns through the region. “That tells us that there were either two wildlife sources or that, early on, the virus switched from one animal to another,” Racaniello said. “That’s very difficult to make sense of with a lab origin. In my opinion, that’s really strong evidence this came from nature, because it’s a simpler scenario.”

He also pointed out that while there have been leaks of pathogens from laboratories in the past, those were known diseases at the time: “There has never been a new virus to come out of a lab.”

As for the circumstances that hint at a lab leak, some scientists still don’t find them compelling. For instance, while the Wuhan Institute of Virology was handling coronaviruses at biosafety level 2, none of the viruses the lab was known to be studying have leaked, and, again, there is no evidence the lab had any contact with SARS-CoV-2.

“It’s not actually news that the Wuhan Institute was handling these viruses at BSL-2. It’s in the methods of their papers going back years,” said Stephen Goldstein, a virologist at the University of Utah. “I don’t see how people can hold that up as a specific piece of evidence for any given scenario.”

Similarly, investigators say they were aware for months of reports that scientists at the Wuhan Institute of Virology sought treatment for an unknown illness. Virologist Marion Koopmans, a member of the WHO investigation team that visited China earlier this year, told NBC News they investigated and had already ruled out those infections as early cases of Covid-19. “There were occasional illnesses because that’s normal,” she said. “There was nothing that stood out.”

China’s reluctance to cooperate with outside investigators and share information could be a sign of a cover-up of a lab leak. But it could also stem from reasons that have nothing to do with the virus, perhaps a consequence of broader international tensions.

And while the WHO’s initial investigation was not comprehensive, researchers are in the planning stages of another trip to China to study the origins of the virus. This time, the team wants to look at blood samples going back two years and screen them for antibodies to SARS-CoV-2. That could allow scientists to map previously unknown chains of transmission of the virus and narrow the scope of possible origins.

We can take steps to stop a future pandemic without knowing where this one came from

If SARS-CoV-2 did escape via a laboratory accident, it’s urgent to try to figure out exactly how it happened and to take precautions, especially given that there are other laboratories conducting research on dangerous pathogens around the world. “If the lab-leak hypothesis is put aside because it is too contentious, laboratory safety and especially risky research will continue to be ignored,” David Relman, an infectious disease researcher at Stanford University and a co-signer of the Science letter, wrote Wednesday in the Washington Post. “We cannot afford to bury our heads in the sand about one possible cause of the origins of Covid-19 simply because it is politically sensitive.”

On the other hand, there is no reason why laboratories would need to wait on the outcome of such an investigation to take steps to prevent future accidents. They could conduct safety audits and ensure experiments are conducted under the proper biosafety levels. Over the long term, facilities researching viruses like the one in Wuhan could even be relocated away from major population centers.

Security personnel stand at the entrance of the Wuhan Institute of Virology during a visit by members of the World Health Organization on February 3.

Ng Han Guan/AP

Similarly, policymakers could take steps to prevent natural spillovers. As humans venture further into wilderness areas to cultivate land and resources, the chances grow of a previously unknown virus crossing over from animals into people. The wildlife trade and venues like wet markets certainly aren’t helping. In a sense, even a “natural origin” of SARS-CoV-2 stems from human causes. “All these spillovers, wherever they are, it’s because human activity is encroaching upon animal activity,” Racaniello said.

While it would be ideal to investigate all possible origins of a deadly global disease, it may not be practical. Given that one pathway has evidence for it and another does not, some scientists say it’s better to focus on the likelier routes.

“It is a mistake to weight these possibilities equally, and it risks underresourcing the investigations into animal sources of this virus that we really need so we can understand the pathways of emergence and cut them off before this happens again,” Goldstein said.

Tracing the animal origins of SARS-CoV-2 is already poised to be a monumental and tedious task for scientists. It will require immense resources as well as cooperation with authorities in China, which may be jeopardized if an investigation into a lab leak isn’t handled with tact.

“Sure ‘investigate’ the lab. But, arm-waving about an often mentioned ‘forensic’ investigation (whatever that means) is not helpful,” Garry said in an email.

More answers about the roots of the pandemic may emerge in the coming months, but it’s likely that further inquiries won’t be enough to satisfy everyone. Even after the pandemic fades away, the virus that caused it may long frustrate and confound.

Sourse: vox.com

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