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The laboratory leak speculation defined

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

It's one of the pandemic's most persistent secrets. The debate about this among academics, policy makers, journalists, amateur internet detectives and the general public has reignited with new revelations and new voices in the mix.

Most recently, emails from the Washington Post and BuzzFeed showed that the director of the National Institute of Allergy and Infectious Diseases, Anthony Fauci, corresponded back in January 2020 with a scientist investigating the possibility that SARS-CoV-2, the virus causing Covid-19 may have been developed in a laboratory. An article in Vanity Fair highlighted how efforts to investigate a laboratory leak have been suppressed in parts of the US government as some officials feared a laboratory in Wuhan, China that received US funding could have been the source.

Scientists argued last year that the most plausible explanation is the "natural origin" of the SARS-CoV-2 virus: it jumped from bats or some intermediate species to humans sometime in 2019. Many still hold this view. and some have become even more confident along the way.

Multiple media outlets, including Vox, also downplayed the possibility the virus was caused by human error in 2020 after many scientists with relevant experience described the idea as extremely unlikely. In February 2020, 27 scientists signed a letter in The Lancet reaffirming their belief in a natural origin for the virus and rejecting efforts to put the blame for the outbreak on Chinese scientists.

A note in the appendix to an article on bat coronavirus in the journal Nature Medicine confirms the hypothesis of the natural origin of SARS-CoV-2.

Natural medicine

Over the past few weeks, however, more scientists – including some who had previously not weighed each other – have come out on the possibility that the virus may have escaped a laboratory in China, arguing that this scenario has not been adequately studied.

The Covid-19 pandemic has shown that science is essential to managing the disease, but also that experts can make mistakes. For example, the World Health Organization said in January 2020 that there was "no clear evidence" of the transmission of SARS-CoV-2 between people. The U.S. surgeon general told Americans in February 2020 that face masks won't slow the spread of the disease. It could therefore be that the rejection of laboratory origin for the virus among some experts was premature, given the rapid pace of developments in the early stages of a global outbreak.

"We need to take hypotheses about natural and laboratory spillovers seriously until we have enough data," said a letter published in Science magazine in May 2021, co-authored by 18 researchers.

Some scientists had hesitated to publicly address the "laboratory leak" hypothesis, in part because the Trump administration, without clear evidence, reaffirmed its confidence in the theory when it tried to hold China responsible for the pandemic and take control of it Pandemic distracting The White House's improper handling of the crisis. The idea also broke down into conspiracy theories, such as the notion that the virus was deliberately released as a bioweapon.

The laboratory leak hypothesis "is really not a marginal theory," Marc Lipsitch, epidemiology professor at Harvard School of Public Health and co-signer of the letter, told CNN. "It was considered fringe theory because it was advocated by some people with fringe political agendas."

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

Hector Retamal / AFP via Getty Images

Lipsitch and other researchers urging further investigation say the Chinese government has not shared critical details about its coronavirus research; It also ordered the destruction of some early laboratory samples of the virus and censorship of coverage of the outbreak. Scientists' demands for greater transparency led the Biden administration to order US intelligence agencies to investigate the possibility of an accidental laboratory leak. The answer to the question of how the virus originated has just as much political as scientific significance.

At the most basic level, the reasoning for the virus's natural origin rests on incomplete evidence, while the laboratory leak hypothesis rests on the gaps in that very evidence.

A natural route of exposure for SARS-CoV-2 still seems much more likely to many scientists, but a satisfactory answer one way or another may never converge as the first infections go down in history and China continues to withhold data and records from those early days . Scientists still haven't determined which animal the virus jumped onto humans, but they haven't found any trace of SARS-CoV-2 before it appeared in a laboratory either. The strained US-China relationship emerges during the investigation and threatens to slow down the search for answers.

Many prominent voices from academia, politics, and national security are now heavily invested in enforcing this investigation. Here's how some of the researchers currently involved in the conversation are analyzing the evidence, what they see as some of the most important lines of inquiry into the future, and what they think we will never learn.

Why some scientists say a laboratory origin deserves a closer look

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

The possibility of a lab leak occurred to Shi Zhengli, a renowned virologist in the Wuhan lab. She told Scientific American last year that she remembered being informed of a mysterious pneumonia caused by a coronavirus that was spreading in Wuhan city in December 2019, and wondering if the pathogen was spreading came from her laboratory.

There have been reports that researchers at the institute conducted gain-of-function experiments in which a natural virus was modified to become more virulent or to better infect humans. This research seeks to identify possible ways a virus could mutate and lead to an outbreak, allowing scientists to get a head start on fighting a potentially dangerous pathogen. But such research is dangerous and controversial. The National Institutes of Health declared a moratorium on funding for gain-of-function research in 2014 and lifted it in 2017 for experiments that are reviewed by a panel of experts.

US officials insisted that US funding did not support functional gains research at the Wuhan Institute or anywhere in the world. NIH director Francis Collins said in a May statement that US health research agencies would never have approved "a grant that would support 'gain-in-function' research on coronaviruses that would have increased their transmissibility or human lethality."

Scientists from the Wuhan Laboratory were known to be working with an international team to develop chimeric versions of various coronaviruses to investigate the potential for a human outbreak, although they say that these chimeric viruses did not increase their pathogenicity and therefore do not represent a gain in functionality . The chimeras in the experiment were also created in the US, not China. Researchers at the Wuhan Institute also published a paper in 2017 reporting 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. This study was funded by the US National Institutes of Health.

If you look at these studies, there are scientists who say such experiments fit the definition. "The research was – clearly – gain-of-function research," Richard Ebright, a microbiology researcher at Rutgers University, told the Washington Post.

There is also the possibility that other, more direct, gain-of-function experiments were conducted with other funding sources, but there is no evidence to support this.

The laboratory leak hypothesis "was viewed as marginal theory because it was advocated in a marginal way by some people with political intentions" (Marc Lipsitch, epidemiologist)

However, the laboratory leak hypothesis does not depend on risky gain-of-function research being carried out in the laboratory, explained Alina Chan, a researcher at the Broad Institute and co-signer of the Science Brief.

"Perhaps a few people think there might have been some gain-of-function research, but I would say that many scientists who ask for an investigation say that this was a laboratory accident that was largely natural or entirely." Of course , Virus, ”said Chan.

You 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 first that a researcher from the Wuhan Institute of Virology was exposed to bat coronavirus while collecting samples in the field and accidentally brought the infection back to Wuhan. The field, in this case, is the home of bats in the southeastern provinces of China, more than 1,000 miles from Wuhan. Second, scientists in the laboratory may have been exposed to a sample of SARS-CoV-2 that was examined and then transmitted the virus to others.

In fact, dangerous pathogens have leaked out of laboratories several times, and human error is a constant risk in any research facility. “The only labs that don't have accidents are labs that aren't working,” Chan said.

She pointed out that there has been a previous occurrence in China of someone unknowingly contracting a virus that is being examined in a laboratory. In 2004, a researcher contracted SARS after working at the Chinese National Institute of Virology in Beijing. The researcher infected her mother and a nurse in the hospital who then infected others, resulting in 1,000 being quarantined or under medical supervision.

Another concern was that the Wuhan Institute of Virology handled coronavirus samples with biosafety level 2 precautions, while most other labs recommend a biosecurity level of 3 or higher. At Biosafety Level 2, access to the laboratory is restricted, researchers are required to wear personal protective equipment such as gloves, lab coats and eye protection, and much of the experimental work is carried out in biological safety cabinets that filter air rather than on open laboratory benches.

Biosecurity level 3 includes all the precautions of the lower levels and adds medical supervision for laboratory workers, the use of respirators, and access to the laboratory with two sets of self-closing and locking doors. Level 3 biosecurity measures are aimed at controlling potentially fatal airway pathogens that spread through the air, while Level 2 biosecurity is aimed at "medium risk" pathogens.

Seeing that the Wuhan lab was handling viruses that can travel through the air at a level of safety that was not designed to alarm some observers. "When scientists hear about this, they really get freaked out," said Chan.

W. Ian Lipkin, a virologist at Columbia University, was the co-author of a Nature Medicine paper in March 2020 that reported that the most likely origin of the virus in humans is a natural excess of animals. But he told journalist Donald McNeil in May 2021 that he was alarmed to learn that the Wuhan Institute of Virology was researching similar viruses with a lower level of protection.

"People shouldn't 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 pointed out that the Huanan Seafood Wholesale Market in Wuhan was originally suspected to be the location where animal-to-human SARS-CoV-2 spillover took place, but to date no infected animal has been identified and Chinese researchers have this as the origin of the virus. The initial outbreak could have occurred because so many people were in the busy market in close proximity, but the virus may have made the leap to people elsewhere.

There are also allegations that the Chinese government was not open in the early days of the pandemic and withheld critical information from investigators, making it difficult to rule out a laboratory leak as a possibility. "I can be convinced of a natural origin, too, if it is properly investigated," Chan said in an email. "The problem is that the most definitive evidence is in China, where we currently don't have access."

A World Health Organization team that visited China in January and February of this year reported that it was struggling to get all of the information it wanted about the origins of SARS-CoV-2.

"In my conversations with the team, they have expressed the difficulties they have encountered in accessing raw data," said WHO Director General Tedros Adhanom Ghebreyesus during a briefing in March. "I expect future collaborative studies to include a more timely and comprehensive exchange of data."

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

Why the laboratory leak theory is getting so much attention now

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

Earlier this year, New York Magazine (owned by Vox Media) published a long article by writer Nicholson Baker that the virus may have leaked from a laboratory in China. Journalist Nicholas Wade made a similar case in an article published on Medium in May. The letter published by Science in May calling for a more thorough study of the hypothesis was another driver of the conversation. A few days after the letter, an article resurfaced in the Wall Street Journal US intelligence reports on three researchers from the Wuhan Institute of Virology seeking medical help for flu-like symptoms in November 2019. That's earlier than the first confirmed case of Covid-19, which happened on December 8, 2019, according to Chinese officials. (However, there is no evidence that the researchers had Covid-19.)

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 den of bat guano. The Wuhan Institute of Virology was commissioned to conduct the investigation. Laboratory researchers tested bats from the mine for coronavirus and found an unidentified strain similar to SARS; several bats were infected with more than one virus. This created opportunities for recombination, in which viruses undergo rapid, large-scale mutations that create new pathogens.

"The problem is that the most definitive evidence is in China, where we currently have no access" – Alina Chan, molecular biologist

One of the unidentified viruses called RaTG13 was later found to have a genetic overlap of 96.2 percent with SARS-CoV-2, suggesting that it may have been a predecessor. A WHO team reported that the laboratory was unable to cultivate the virus and only had its genetic sequence. If you believe these reports, it means that the institute did not have an infectious ancestor of SARS-CoV-2 in its care.

In the wake of these media reports and rising public interest, President Biden last month directed U.S. intelligence agencies to step up their efforts to investigate the potential for a laboratory origin of SARS-CoV-2 and to report in 90 days.

For some scientists, the resurgent interest in a laboratory leak has been frustrating rather than enlightening. "In all fairness, in the last few days we've seen more and more media discourse with terribly little breaking news, evidence, or new material," said Michael Ryan, World Health Organization Program Executive Director, Health Emergencies, during a May 28 press conference.

But for others it has been confirmed. Former director of the U.S. Centers for Disease Control and Prevention Robert Redfield told Vanity Fair that he received death threats last year after publicly stating that he believed the virus came from a laboratory.

And for other researchers, the subject remains too debatable to discuss publicly. A scientist contacted for this article declined to comment on the data set for fear of harassment. Still, it seems unlikely that this new attention will go away anytime soon.

Why other scientists are skeptical of the laboratory leak hypothesis

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

Some scientists in the US explored this possibility as early as the early days of the pandemic. Kristian Andersen, a professor at the Scripps Research Institute, exchanged emails with Fauci in January 2020 about his suspicion that the SARS-CoV-2 virus was constructed because, according to documents received, its genetics did not match what it found in nature suspected by BuzzFeed and the Washington Post. "I should mention that Eddie, Bob, Mike, and I all find, after our discussions today, that the genome is inconsistent with evolutionary expectations," Andersen wrote to Fauci.

Andersen then investigated the possibility and co-authored the March 2020 Nature Medicine paper on the origins of SARS-CoV-2 virus with Lipkin, which reported that the most likely origin of the virus was spillover from an animal. In contrast to Lipkin, Andersen is only more convinced that the virus entered humans through a natural route of exposure.

"We cannot categorically say that SARS-CoV-2 has a natural origin, but based on the available scientific data, the most likely scenario by far is that SARS-CoV-2 originates from nature," said Andersen in an E- Mail to Vox. "No credible evidence has been presented to support the hypothesis that the virus was manufactured in a laboratory or leaked from a laboratory – such statements are based on mere speculation."

Then what would it take to prove that the virus escaped a laboratory?

"Proof that (the Wuhan Institute of Virology) or another Wuhan virology lab had SARS-CoV-2 or something like that would be the smoking weapon," Robert Garry, a virologist at Tulane University and another co-author of Nature Medicine paper said in an email. "There is no evidence that SARS-CoV-2 or any immediate precursor virus existed in any laboratory prior to the pandemic."

He, too, has become more convinced that the virus has spread to humans somewhere outside the laboratory. "The only change since we wrote our manuscript on the proximal origins of SARS-CoV-2 is that I now consider any of the laboratory leak hypotheses extremely unlikely," he said.

Shi Zhengli of the Wuhan Institute of Virology told Scientific American that she had instructed her team to sequence the genomes of all viruses they examined in her laboratory and compare them to sequences from Covid-19 patients. None of them fit. “That really blew me away,” she says. (Shi didn't respond to a Vox request for comment.)

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

Johannes Eisele / AFP via Getty Images

Several other factors indicate a natural origin for SARS-CoV-2, according to Vincent Racaniello, a virologist at Columbia University. This includes the fact that the SARS virus outbreak in 2003 set a precedent for a coronavirus that spreads from bats to humans via an intermediate species. In this case, the intermediary – civets – was identified; Scientists have warned for years that a similar scenario could easily recur.

Further animal experiments showed that there are a number of viruses such as SARS-CoV-2 in bats not only 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 are constantly mutating, and the more spread they are, the more changes can occur. Seeing a related virus over such a large area shows that it had ample opportunity to spread and mutate in nature before making the final leap into humans.

The WHO also noted that in the earliest days of the pandemic, during the outbreak in Wuhan, China, in 2019, there were two different lineages of the virus with different patterns of transmission in the region. "That tells us that either there were two sources of wildlife or that the virus passed from one animal to another early on," Racaniello said. “It's very difficult to understand with a laboratory background. In my opinion this is really strong evidence that this came from nature because it's a simpler scenario. "

He also pointed out that although pathogens had leaked out of laboratories in the past, they were known diseases at the time: "A new virus has never come out of a laboratory."

As for the circumstances indicating a laboratory leak, some scientists still find it unconvincing. For example, while the Wuhan Institute of Virology handled coronaviruses at biosecurity level 2, none of the viruses the lab is known to have examined have leaked, nor is there any evidence that the lab has had any contact with SARS-CoV-2.

“It's not really new that the Wuhan Institute has treated these viruses in BSL-2. It's in the methods of their papers that go back years, ”said Stephen Goldstein, a virologist at the University of Utah. "I don't see how people can hold that up as specific evidence for a particular scenario."

Similarly, investigators say they have known for months about reports that scientists from the Wuhan Institute of Virology were seeking treatment for an unknown disease. Virologist Marion Koopmans, a member of the WHO investigation team who visited China earlier this year, told NBC News that they had investigated these infections and ruled these infections out as early cases of Covid-19. "There have been illnesses occasionally because that's normal," she said. "There was nothing conspicuous."

China's reluctance to work and share information with outside investigators could be a sign that a lab leak is being covered up. But it could also come for reasons unrelated to the virus, perhaps a consequence of wider international tensions.

And although the WHO's initial investigation was not comprehensive, researchers are planning another trip to China to examine the origins of the virus. This time the team wants to examine blood samples from two years and examine them for antibodies against SARS-CoV-2. This would allow scientists to map previously unknown transmission chains of the virus and narrow down the scope of possible origins.

We can take steps to stop a future pandemic without knowing where it is coming from

If SARS-CoV-2 escaped in a laboratory accident, it is urgently necessary to find out the exact course and take precautions, especially since there are other laboratories around the world researching dangerous pathogens. "If the laboratory leak hypothesis is put aside because it is too controversial, laboratory safety and particularly risky research will continue to be ignored," wrote David Relman, an infectious disease researcher at Stanford University and co-signer of the Science Letter Wednesday in the Washington Post. "We cannot afford to stick our heads in the sand about a possible cause for the development of Covid-19 just because it is politically sensitive."

On the other hand, there is no reason why laboratories should wait for the results of such an investigation to take action to prevent future accidents. You could conduct safety audits and ensure that experiments are conducted under the correct biosafety levels. In the long term, virus research facilities such as the one in Wuhan could even be relocated from metropolitan areas.

Security guards 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

Policymakers could also take steps to prevent natural spillover effects. As humans continue to venture into wilderness areas to cultivate land and resources, the likelihood of a previously unknown virus spreading from animals to humans increases. The wildlife trade and venues like Wet Markets certainly don't help. In a way, even a “natural origin” of SARS-CoV-2 can be traced back to human causes. "All of these spillovers, wherever they are, are due to human activity interfering with animal activities," Racaniello said.

While exploring all possible origins of a deadly global disease would be ideal, it may not be practical. Given that one route has evidence and another does not, some scientists say it is better to focus on the more likely routes.

"It is a mistake to weight these possibilities equally, and there is a risk that the studies on animal sources of this virus, which we really need to understand the pathways and cut them off, provide insufficient resources," said Goldstein.

Tracking the animal origins of SARS-CoV-2 is already a monumental and arduous task for scientists. It requires immense resources and cooperation with the authorities in China, which can be compromised if a laboratory leak investigation is not carried out with the utmost care.

“Of course, the laboratory 'examines' it. But waving your arm over an oft-mentioned "forensic" investigation (whatever that means) doesn't help, "Garry said in an email.

More answers on the roots of the pandemic could emerge in the coming months, but it is likely that further inquiries will not be enough to keep everyone happy. Even after the pandemic has subsided, the virus that caused it can be long frustrating and confusing.

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