[Why many scientists say it’s unlikely that SARS-CoV-2
originated from a “lab leak”] [[link removed]]

CALL OF THE WILD   [[link removed]]

 

Jon Cohen With reporting by Kai Kupferschmidt.
September 2, 2021
Science Magazine
[[link removed]]


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_ Why many scientists say it’s unlikely that SARS-CoV-2 originated
from a “lab leak” _

Scientists have found a distant relative of SARS-CoV-2 in a horseshoe
bat they sampled in the countryside in Thailand., Adam Dean/Panos
Pictures

 

During the first year of the COVID-19 pandemic, the “lab leak”
theory gained little traction. Sure, U.S. President Donald Trump
suggested SARS-CoV-2 originated in a laboratory
[[link removed]] in
Wuhan, China—and called it “the China virus
[[link removed]]”—but
he never presented evidence, and few in the scientific community took
him seriously. In fact, early in the pandemic, a group of prominent
researchers dismissed lab-origin notions as “conspiracy theories”
in a letter in _The Lancet_
[[link removed](20)30418-9/fulltext].
A report from a World Health Organization (WHO) “joint mission,”
which sent a scientific team to China in January to explore possible
origins with Chinese colleagues, described a lab accident
as “extremely unlikely.”
[[link removed]]

But this spring, views began to shift. Suddenly it seemed that the
lab-leak hypothesis had been too blithely dismissed. In a widely read
piece, fueled by a “smoking gun” quote from a Nobel laureate, a
veteran science journalist accused scientists and the mainstream media
of ignoring “substantial evidence” for the scenario. The head of
WHO
[[link removed]] openly
pushed back against the joint mission’s conclusion, and U.S.
President Joe Biden
[[link removed]] ordered
the intelligence community to reassess the lab-leak possibility.
Eighteen scientists, including leaders in virology and evolutionary
biology, signed a letter published in _Science_
[[link removed]]_ _in May
that called for a more balanced appraisal of the “laboratory
incident” hypothesis.

Yet behind the clamor, little had changed. No breakthrough studies
have been published. The highly anticipated U.S. intelligence review
[[link removed]],
delivered to Biden on 24 August, reached no firm conclusions, but
leaned toward the theory that the virus has a natural origin.

Fresh evidence that would resolve the question may not emerge anytime
soon. China remains the best place to hunt for clues, but its relative
openness to collaboration during the joint mission seems to have
evaporated. Chinese officials have scoffed at calls from Biden and WHO
Director-General Tedros Adhanom Ghebreyesus for an independent audit
of key Wuhan labs, which some say should include an investigation of
notebooks, computers, and freezers. Chinese vice health minister Zeng
Yixin
[[link removed]] said
such demands show “disrespect toward common sense and arrogance
toward science.” In response to the increasing pressure, China has
also blocked the “phase 2” studies outlined in the joint
mission’s March report, which could reveal a natural jump between
species.

Despite the impasse, many scientists say the existing
evidence—including early epidemiological patterns, SARS-CoV-2’s
genomic makeup, and a recent paper about animal markets in
Wuhan—makes it far more probable that the virus, like many emerging
pathogens, made a natural “zoonotic” jump from animals to humans.

Some of those clues have led Michael Worobey, an evolutionary
biologist at the University of Arizona who has done groundbreaking
work on the origins of HIV and the 1918 flu, further away from the
lab-origin theory. Although he always viewed it as less likely, he
co-signed the _Science _letter calling for a more thorough
investigation of the lab-leak hypothesis. But like at least one other
signatory, he now has second thoughts about that plea, in part because
it heightened political tensions. “I think it probably did more harm
than good in terms of actually having relevant information flow out of
China,” he says.

Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer
Research Center who spearheaded the _Science _letter, says the
lab-origin theory will continue to thrive until the Chinese government
becomes more cooperative. “I don’t think Chinese scientists are
less trustworthy,” says Bloom, who has sharply criticized China for
attempting to “obscure” data
[[link removed]] about
early COVID-19 cases. “But it’s clear that, at least in relation
to this topic, they are operating under strong constraints imposed by
the government.”

AT ITS CORE, the lab-origin hypothesis rests on proximity. A novel
coronavirus, genetically linked to bats, surfaced in a city that’s
home to the Wuhan Institute of Virology (WIV), which has long
specialized in studying bat coronaviruses, and two smaller labs that
also handle those viruses. One or more lab workers could have become
infected by accident, then passed the virus to others. Lab accidents
are not unheard of, after all: SARS-CoV, the coronavirus that causes
severe acute respiratory syndrome (SARS), has infected researchers as
many as six times
[[link removed]] after
the global outbreak of that disease ended in July 2003.

A researcher’s infection with SARS-CoV-2 needn’t have happened in
Wuhan itself. Alina Chan, a gene therapy researcher at the Broad
Institute who also co-signed the _Science _letter, cites a study by
WIV researchers, published in 2018
[[link removed]],
that sampled blood from 218 people who lived 1000 kilometers from the
city near caves that were home to coronavirus-infected bats. Six of
these people had antibodies that suggested prior infections by
SARS-related bat coronaviruses, a branch of the family tree that
includes SARS-CoV, SARS-CoV-2, and close cousins. Wuhan researchers
have visited that area repeatedly and “easily could have picked up
something from a human who already carried a human-adapted form of a
SARS-related virus,” Chan says.

Shi Zhengli, the lead bat coronavirus scientist at WIV, denies that
anyone at the lab fell ill around the time SARS-CoV-2 emerged. In an
email interview with _Science _in July 2020
[[link removed]],
she wrote that “all staff and students in the lab” were tested for
SARS-CoV-2 and related coronaviruses and were negative.

Speculation about a lab leak has focused on the Wuhan Institute of
Virology, which has studied bat coronaviruses for years. Ng Han
Guan/AP Images

Still, in January, days before Trump left office, the U.S. Department
of State
[[link removed]] said
the “government has reason to believe that several researchers
inside the WIV became sick in autumn 2019.” And on 23 May, _The
Wall Street Journal_
[[link removed]]_ _reported
the existence of an “undisclosed U.S. Intelligence report” that
said three WIV researchers “sought hospital care” in November
2019. The story had no details about their illnesses, and some have
noted that Chinese hospitals provide care for all ailments, including
minor ones.

Virologist Robert Garry of Tulane University finds it improbable that
a Wuhan lab worker picked up SARS-CoV-2 from a bat and then brought it
back to the city, sparking the pandemic. As the WIV study of people
living near bat caves shows, transmission of related bat coronaviruses
occurs routinely. “Why would the virus first have infected a few
dozen lab researchers?” he asks. The virus may also have moved from
bats into other species before jumping to humans, as happened with
SARS. But again, why would it have infected a lab worker first?
“There are hundreds of millions of people who come in contact with
wildlife.”

Another data point argues against infected researchers playing a role,
Garry says. As the WHO joint mission report spells out, clusters of
early COVID-19 cases had links to multiple Wuhan markets
[[link removed]] around
the same time, which Garry says supports the idea of infected animals
or animal traders bringing the virus to the city. A lab worker with
COVID-19 would have had to make “a beeline not just to one market,
but to several different markets,” he says. “You can’t rule it
out, but then why the markets? Why not a soccer game or a concert or
100 other different scenarios?”

But David Relman, a Stanford University microbiome researcher who also
co-signed the _Science _letter, questions the “hopelessly
impoverished” data on the earliest COVID-19 cases. “I just don’t
think we have enough right now to say anything with great
confidence,” Relman says.

Linfa Wang, a molecular virologist at the Programme in Emerging
Infectious Diseases at Duke-NUS Medical School in Singapore who has
collaborated extensively with WIV on bat coronavirus studies, has a
simpler reason for dismissing the lab-leak hypothesis. “Accidents
can only happen when you already have a live virus in culture
that _can _leak,” Wang says. Bat coronaviruses are notoriously
hard to grow. Shi told _Science _last year that her lab had more
than 2000 bat fecal samples and anal and oral swabs that tested
positive for coronaviruses. But the lab had only isolated and grown
three viruses over 15 years, Shi said, and none closely resembled
SARS-CoV-2. Some have questioned Shi’s veracity—she may well be
under pressure from the Chinese government—and
noted inconsistencies in her statements
[[link removed]],
but several scientific collaborators outside China have high regard
for her integrity.

Wang also discounts reports that WIV has live bats. “Many years
back” the lab conducted immune studies on live bats, Wang says, but
these were not of the genus _Rhinolophus_—the only one found to
harbor SARS-related coronaviruses—which no lab has ever been able to
keep alive in captivity.

Accidents can only happen when you already have a live virus in
culture that _can_ leak. 

LINFA WANG DUKE -- NUS MEDICAL SCHOOL

A great deal of speculation
[[link removed]] about
the pandemic’s origin has centered on six men who developed severe
respiratory illnesses in 2012 after clearing bat feces from a copper
mine in Mojiang,
[[link removed]] in
China’s Yunnan province. Three of them died. Lab-origin proponents
have suggested the men were infected with a coronavirus, a belief fed
by a 2013 master’s thesis
[[link removed]] that
provided no direct evidence. That bat virus, they argue, either was
SARS-CoV-2 or was turned into it through genetic engineering.

When the miners fell ill, Shi and co-workers were asked to sample bats
at the mine, which they did on several occasions. They discovered nine
new SARS-related viruses (see sidebar
[[link removed]],
below). One of these, dubbed RaTG13, is 96.2% genetically identical to
SARS-CoV-2, the closest overall similarity yet found. A loose-knit
group whose members call themselves DRASTIC
[[link removed]]—for the Decentralized Radical
Autonomous Search Team Investigating COVID-19—has driven a heated
discussion about possible links between RaTG13 and SARS-CoV-2.

Shi has reported that her lab tested blood from the miners and did
not find evidence
[[link removed]] of coronaviruses
or antibodies to them. Wang, who helped with these analyses, finds the
assertion that the team suppressed evidence
[[link removed]] of
SARS-CoV-2’s link to the Mojiang mine preposterous. “We wanted to
prove that a coronavirus caused the deaths,” says Wang, who grew up
in Shanghai but is now an Australian citizen. “If we proved that
another SARS-like virus was in humans in China that would have been
scientifically brilliant,” he says. “It’s
a _Science _or _Nature _paper. No scientist is going to wait for
this to leak.”

Even Bloom agrees with that logic. “That’s one of the strongest
arguments you can make against a lab accident,” he says. “On the
other hand, I feel like a lot of these questions could be resolved
pretty easily by enhanced transparency.”

IN THE MOST ELABORATE lab-leak scenarios, SARS-CoV-2 is not a
naturally occurring virus, but was created at WIV. That would bring
worldwide condemnation on China, but it would also devastate the field
of virology. There has been an intense debate over the past decade
about the scientific value of “gain-of-function” (GOF) studies,
which deliberately create pathogens that are more virulent or more
transmissible to humans—or both—than their natural cousins. Some
say GOF studies can help identify and thwart future threats, but
critics argue the potential benefits don’t outweigh the risk of
creating and unleashing pandemic pathogens.

Shi has created chimeric viruses in the past to get around the
difficulty of growing coronaviruses isolated from bats. In work with
Peter Daszak of the EcoHealth Alliance and Wang, described in a 2017
paper in _PLOS Pathogens_
[[link removed]],
WIV made chimeras using the genetic “backbone” of one of the bat
coronaviruses her lab could culture and genes that coded for the
surface protein, called spike, from newly found coronaviruses.

Scientists disagree about whether this was GOF research. Shi says it
was not, because the hybrid viruses her group created were not
expected to be more dangerous than the original strains. Anthony
Fauci, head of the U.S. National Institute of Allergy and Infectious
Diseases, which helped fund the study, told Congress
[[link removed]] it
does not qualify as GOF research under NIAID’s guidelines. Relman
finds the GOF label “vague and confusing” and instead describes
this as “unnecessarily risky research.”

Definitions aside, if Shi was creating chimeric viruses, SARS-CoV-2
may have been one of them, lab-leak proponents say. They also note
biosecurity measures at the lab were relaxed. In her
2020 _Science _interview, Shi denied conducting chimeric virus
experiments beyond those reported in the 2017 paper, but she
acknowledged doing some coronavirus studies in biosafety level 2
facilities. That’s one level lower than even Ralph Baric
[[link removed]],
a coronavirus researcher at the University of North Carolina, Chapel
Hill, who has collaborated with Shi, thinks is appropriate. Shi
stressed that the work complied with all Chinese regulations.

Still, many scientists contend that SARS-CoV-2 can’t be a lab
concoction because no known virus is close enough to have served as
its starting material. Some have countered that RaTG13, the virus
found in the Mojiang mine, could have been that backbone. That makes
no sense, asserts a “critical review” by Garry, Worobey, and 19
other scientists that _Cell_
[[link removed](21)00991-0.pdf]_ _published
online on 19 August. More than 1100 nucleotides, the building blocks
of RNA, separate the genomes of the two viruses, and the differences
are scattered in a way that doesn’t suggest deliberate engineering.

“Nobody has the sort of insight into viral pathogenesis to design
something as really devious as SARS-CoV-2,” Garry says. Three other
bat viruses more similar to SARS-CoV-2 than RaTG13 in some key genomic
regions are also unlikely to have been used as a template for the
pandemic virus, according to the paper.

The “smoking gun” evidence that SARS-CoV-2 was engineered, in the
words of virologist and Nobel laureate David Baltimore, has not held
up either. Spike has a cleavage site, a spot where a human enzyme
named furin cuts the protein, which helps SARS-CoV-2 infect cells.
Since early in the pandemic, lab-origin proponents have claimed that
no SARS-related bat coronaviruses have this feature, leading to
speculation that a lab added the site to a virus so it could infect
humans. When retired _New York Times _writer Nicholas Wade
[[link removed]] made
the case for a lab leak this spring, the furin cleavage site,
buttressed by Baltimore’s provocative words, was an essential part
of the argument.

But it’s dead wrong, say many coronavirus specialists and
evolutionary biologists. The SARS-related coronaviruses are in the
beta genus, one of four in the Coronaviridae family. Several members
of that genus feature furin cleavage sites
[[link removed]],
which appear to have evolved repeatedly. And one SARS-CoV-2–related
virus, described in a _Current Biology_
[[link removed]]_ _paper
last year by a team led by Shi Weifeng of Shandong First Medical
University, has three of the four amino acids that constitute the
furin cleavage site, which is “strongly suggestive of a natural
zoonotic origin” for SARS-CoV-2, the authors concluded.

Baltimore has backpedaled
[[link removed]] the
statement. He did not know several bat beta coronaviruses have the
furin cleavage site, he acknowledged in an email to _Science_.
“[T]here is more to this story than I am aware of,” he wrote.
“The furin cleavage is the most ridiculous stuff,” Wang says.

Instead of genetically manipulating a virus, a lab could also have
created SARS-CoV-2 by passaging, a technique in which researchers grow
a virus in a lab dish or an animal, harvest it, and repeat the process
again and again, allowing mutations to accrue. But again, they would
have needed to start with a close relative of SARS-CoV-2. There’s no
evidence that this precursor existed in any lab. And passaging in cell
cultures often deletes the furin cleavage site or makes viruses
weaker.

Even the U.S. intelligence community during the Trump administration
discounted the suggestion that SARS-CoV-2 was “manmade.”
[[link removed]] The
report requested by Biden, which sought input from several groups in
the intelligence community, similarly concludes that the virus “was
probably not genetically engineered.” (It also said there was
“broad agreement” that it “was not developed as a biological
weapon.”)

THE JOINT MISSION REPORT from WHO, which runs more than 300 pages and
delves into everything from the viral sequences of the earliest cases
to pharmacy sales, has several little-noticed findings that make a
natural origin appear more likely than a lab leak, says Kristian
Andersen, an evolutionary biologist at Scripps Research who
co-authored the recent _Cell _paper with Garry and Worobey. “It
wasn’t the perfect report,” he says, but it was “a great start
to a collaborative study on understanding the origin of SARS-CoV-2.”

The earliest official announcement about the pandemic came on 31
December 2019, when Wuhan’s Municipal Health Commission
[[link removed]] reported
a cluster of unexplained pneumonia cases linked to the city’s Huanan
seafood market. The WHO report devotes much attention to details about
Huanan and other Wuhan markets, but also cautions that their role
remains “unclear” because several early cases had no link to any
market. But after reading the report, Andersen became more convinced
that the Huanan market played a critical role.

One specific finding bolsters that case, Wang says. The report
describes how scientists took many samples from floors, walls, and
other surfaces at Wuhan markets and were able to culture two viruses
isolated from Huanan. That shows the market was bursting with virus,
Wang says: “In my career, I have never been able to isolate a
coronavirus from an environmental sample.”

The report also contained a major error: It claimed there were “no
verified reports of live mammals being sold around 2019” at Huanan
and other markets linked to early cases. A surprising study published
in June [[link removed]] by
Zhou Zhao-Min of China West Normal University and colleagues
challenged that view. It found nearly 50,000 animals from 38 species,
most alive, for sale at 17 shops at Huanan and three other Wuhan
markets between May 2017 and November 2019. (The researchers had
surveyed the markets as part of a study of a tick-borne disease
afflicting animals.)

Live animals can more easily transmit a respiratory virus than meat
from a butchered one, and the animals included masked palm civets, the
main species that transmitted SARS-CoV to humans, and raccoon dogs,
which also naturally harbored that virus and have been infected with
SARS-CoV-2 in lab experiments
[[link removed]]. Minks—a
species farmed for fur that has acquired SARS-CoV-2 infections from
humans in many countries— were also abundant. “None of the 17
shops posted an origin certificate or quarantine certificate, so all
wildlife trade was fundamentally illegal,” Zhou and his colleagues
wrote in their paper. (Zhou did not respond to emails
from _Science_.)

It’s unclear why the international members of the WHO joint mission
were not told about the live market mammals by their Chinese
counterparts. “I’m really disappointed that came out after [the
report],” says WHO’s Maria Van Kerkhove, who acknowledges
contributing to the oversight herself because she mistakenly ignored a
draft of the paper that the authors sent her when they first submitted
it in October 2020.

Worobey says the paper played a key role in tilting his thinking away
from the lab-origin hypothesis. “The fact that early [COVID-19]
cases were linked to the market, and that the market was selling what
were very likely intermediate hosts?” he says. “All of that is
probably trying to tell us something.”

Worobey suspects that after a SARS-CoV-2 progenitor jumped from
animals to humans, it pingponged back and forth, steadily adapting to
its new host. This could have happened at the market and gone
unnoticed for weeks, as the outbreak only surfaced when several people
became severely ill, a relatively rare outcome of a SARS-CoV-2
infection. Or the virus could have first infected animal farmers in
remote villages. “If this happened in a small town, it’s quite
probable it would never have taken off,” says William Hanage, an
evolutionary biologist at Harvard University. Then animal traders
might have brought the virus to markets in Wuhan, a city of 11
million.

Linda Saif, a veterinarian at Ohio State University, Wooster, says
China’s enormous fur industry is at the top of her list of places to
hunt for SARS-CoV-2’s precursors. Saif cites a report
[[link removed]] showing
the vast majority of the world’s pelts from raccoon dogs and
foxes—both canids, a family readily infected with SARS-CoV-2—are
from animals farmed or trapped in China (see graphic
[[link removed]],
above). The country produces half of the world’s mink pelts, too.

SO WHERE TO NOW? Bloom would like more details about the earliest
human cases of COVID-19 and says WIV should share bat coronavirus
sequences in a database it removed
[[link removed]] from
the internet in September 2019, claiming the site had been hacked.
“That could put a lot of this to rest,” he says. Sales data from
Wuhan markets could help, too. If researchers could trace who farmed
or trapped the live animals sold there and who delivered them to the
markets, those people could be interviewed and perhaps sampled for
evidence of past infections.

In a comment published by _Nature_
[[link removed]]_ _on
25 August, the international members of the joint mission warned
it’s time to get on with “phase 2” because the window for some
studies is closing. But WHO is reconfiguring the team
[[link removed]].
It recently announced a new International Scientific Advisory Group
for Origins of Novel Pathogens (SAGO) that will provide “rapid
advice” to launch the follow-up studies described in the mission
report, but also study the origins of future outbreaks. The Chinese
government has shown no signs it will welcome SAGO members, but Wang
is hopeful it will have a change of heart: “In an ideal world, we
need a Chinese collaboration.”

Chinese scientists are conducting their own studies into potential
natural origins, but few outside the country know details.
“Unfortunately, finding out what is being done is getting harder by
the day because the lab-leak stuff has turned COVID origins into a
major political weapon,” says one Western researcher who asked not
to be identified. “My colleagues in China are nervous and feeling
great pressure.”

China has been pushing the theory that the virus came from another
country—maybe brought in on frozen food
[[link removed]], or, according
to baseless propaganda, concocted at a U.S. military lab. “It’s
comical,” Worobey says. “The big picture here is China is doing
everything it can to push the narrative that this pandemic started
outside of China.” He suspects that while rejecting the lab-leak
theory, the Chinese government is also unenthusiastic about pursuing a
natural origin, fearing that proof would expose China to further blame
for a pandemic even if the discovery exonerated Chinese scientists.
“I think at some point they thought, here’s the strategy: We try
to muddy the waters,” he says.

But even without China’s cooperation, there are ways to move ahead.
Some studies elsewhere have already yielded intriguing leads.
Researchers have found coronaviruses in bats in neighboring countries
that suggest evolutionary pathways from an ancestor of SARS-CoV-2 to
the pandemic virus. More clues may come from studies in Southeast Asia
of wild pangolins—the only other species to date found to harbor a
close SARS-CoV-2 relative.

Researchers can also hunt for cases outside of China that predate the
December 2019 outbreak. One possibility, Wang says, is to check the
blood of Wuhan visitors or residents who were in the city in the
months before, including the 9000 athletes from more than 100
countries who attended the Military World Games there in October 2019.
(A new antibody assay
[[link removed]] from
his lab, he says, can distinguish between SARS-CoV-2 and related
viruses that may have preceded it.)

The search will never lead us to patient zero, the first person to be
infected by SARS-CoV-2, Hanage says. “Humans are looking for a
story,” he says. “They want Columbo to come in and just somehow
get somebody to confess or show what actually happened.” Instead,
there are “possible stories” about SARS-CoV-2’s origin—some
more probable than others—and stories that can be excluded, Hanage
says. “And the space of possible stories in which there was a
natural origin in or around the markets is much larger than the space
of possible origins in which the Wuhan Institute of Virology is
involved.”

_JON COHEN is a staff writer for SCIENCE. _

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