Shi, nicknamed the ‘Bat Woman’ is said to have sequenced the genes of the new coronavirus in three days after the epidemic emerged in China, but was then gagged by her boss.

The warning was part of a research paper submitted by Shi, the deputy director at the institute, and three co-authors in January, 2019.

It was published in March by MDPI who print peer-reviewed, open access journals.

In the article, the team emphasised the likelihood of another coronavirus epidemic in China by analysing three large-scale outbreaks caused by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Swine Acute Diarrhea Syndrome (SADS) respectively.

It said that all three pathogens were coronaviruses and could be traced back to bats, and two of them had originated in China.

The researchers said: “Thus, it is highly likely that future SARS- or MERS-like coronavirus outbreaks will originate from bats, and there is an increased probability that this will occur in China.

“Therefore, the investigation of bat coronaviruses becomes an urgent issue for the detection of early warning signs, which in turn minimises the impact of such future outbreaks in China.”

The  scientists also indicated that China's size, population and biodiversity could propel the spread of the potential bug.

It also underlined the Chinese tradition of favouring fresh meat.

“Chinese food culture maintains that live slaughtered animals are more nutritious, and this belief may enhance viral transmission,” the paper read.

Covid-19, the disease caused by the new coronavirus, has infected more than two million people worldwide and killed over 145,000 since the pandemic began in Wuhan in December last year.

The £34million Wuhan Institute of Virology, which is affiliated to the Chinese Academy of Sciences, has become the centre of the controversy as the pandemic rages on around the world.

Theories are currently circulating that claim the virus came from the institute, which has the highest biosafety level of P4.

US President Donald Trump said on Wednesday that Washington was trying to determine if the coronavirus first crossed to humans accidentally during experiments involving bats at the Wuhan centre.

However, China has stated that the World Health Organization (WHO) had found no evidence the novel coronavirus was man-made.

A team led by Shi already discovered in 2018 that humans might be able to catch the coronavirus directly from bats after conducting studies, according to Beijing News.

While scientists believe that the virus jumped to humans from wild animals sold as food in a market about 10 miles from the lab, this hasn’t stopped some wild conspiracy theories circulating.

Some people claim that the virus, formally known as SARS-CoV-2, could be a biological warfare weapon engineered there. Others suspect that it escaped from the lab.

Shi told the press in February that she “guaranteed with her own life” that the outbreak was not related to the lab.

China also refuted reports which named Huang Yanling, a researcher at the Institute of Virology, as 'patient zero' – the first person to be infected.

Many international experts have dismissed claims that SARS-CoV-2 originated in a lab.

“Bat coronaviruses resembling SARS and the new SARS-CoV-2 have been isolated by many groups of legitimate scientists, including the Wuhan lab and plenty of US investigators.

"This is a far cry from making and releasing the new virus," Dr Gerald Keusch, a Boston-based professor previously told MailOnline.

A researcher works in a lab of Wuhan Institute of VirologyCredit: EPA

Why Would the US Have Funded the Controversial Wuhan Lab?

Reports about the connection between the U.S. National Institutes of Health and the Wuhan Institute of Virology risk feeding conspiracy theories about the origins of COVID-19.

Newsweek recently put out some surprising reports that the U.S. National Institutes of Health (NIH) had funded the controversial Wuhan Institute of Virology (WIV). The WIV is the level four research facility suspected by some of being a possible source for the coronavirus that causes COVID-19. U.S. Secretary of State Mike Pompeo has already been on record confirming and defending this funding, saying it was “to protect American people from labs that aren’t up to standard.”

According to Newsweek, funding for the WIV occurred in two phases. The first took place from 2014 to 2019, through a $3.7 million project for collecting and studying bat coronaviruses. This work was largely led by Dr. Zhengli Shi, known to many as “bat woman” for her years investigating caves in search of new bat viruses. The second phase began shortly after, with another $3.7 million. Unlike the first, this project appears to have included work on “gain-of-function”: research that investigates how a virus can gain the ability to infect a new type of animal.

Anyone with a vague sense of current events would, understandably, be concerned that COVID-19 might have been produced through this research. The connections to the NIH would also be unsettling, offering the possibility that the U.S. government may be complicit, having unnecessarily “outsourced” dangerous research. Although strong denials by both Chinese and American officials and several pieces of scientific research have concluded COVID-19 is not man-made, the connection between the NIH and WIV still behooves critical examination. Why would the NIH want to fund the WIV to begin with?

The first, and perhaps most important reason, may be just as Pompeo said: to help bring Chinese labs up to higher safety standards. As a professor of cell biology at Dongseo University in South Korea and an ex-director of the Tan School of Genetics at Fudan University in China, I have had the opportunity to visit many science facilities across Asia. I can say with some authority that safety standards can, in many cases, fall short of what you would expect in the United States. Whether these shortcomings would necessarily apply to highly sensitive environments like the WIV I cannot say, as my experiences are limited to academic contexts. Nevertheless, I must concede it is possible, especially in 2014, when the NIH funding began, that the WIV may have needed some help in establishing better safety protocols.

The need for outside help is by no means abnormal, as many countries in the process of establishing new science programs often need to invite outside experts to help build them. The department I am associated with at Dongseo University, for example, drew heavily on the expertise of German professors from the Technische Universität Berlin for building both curricula and research projects. No doubt the WIV would have needed similar assistance, especially early on in its development. A common method is to invite one’s old mentors and colleagues to help advise and monitor progress. With most Chinese scientists, including Dr. Shi, having received their degrees abroad, such invitations would, most likely, have focused on foreign experts, perhaps providing links to people associated with the NIH.

Another reason the NIH may have decided to provide funding is to help foster international cooperation and better communication. In modern times, science funding is not merely a means for buying equipment and hiring workers; it is also a tool for diplomacy. Providing funding often obligates the recipient lab to disclose its findings and allow visits and inspections. In many respects, this access and increased transparency is much preferred to having a lab operate in secret, especially when the subject is potentially dangerous. Scientists working at WIV would, no doubt, also have preferred having experienced foreigners coming in periodically to evaluate the facility, confirming its safety.

A third reason could be the fact that the United States has long held a fierce debate about the ethics and risks of gain-of-function (GOF) research. Critics, such as Harvard epidemiologist Marc Lipsitch, have argued that such work “entails a unique risk that a laboratory accident could spark a pandemic, killing millions.” These objections motivated the Obama administration to halt all domestic GOF research in 2011, a restriction that was later lifted in 2017, following the implementation of new safety protocols. Although we do not know exactly what went into the decision to fund the WIV during this moratorium, it is likely that domestic restrictions may have played a role, forcing the proponents of such work to seek opportunities abroad. These proponents are of the opinion that GOF research is worth the risk, being the best way to understand, prevent, and treat pandemics, an argument that is not without merit.

Unfortunately, from the public’s perspective, reports about the connection between the NIH and WIV are at risk of feeding conspiracy theory fires. With some Chinese officials already blaming the United States for the pandemic and the Trump administration appearing intent on blaming China in return without divulging any decisive evidence, it is quite difficult, even for experts, to develop a fully-informed opinion about what exactly happened. And therein lies a dangerous problem: unanswered questions can only deepen peoples’ suspicions about science.

In the United States, for example, there have already been widespread reports of citizens across the country rejecting or doubting the legitimacy of the pandemic. Some have labelled COVID-19 a liberal media hoax, while others have taken the extraordinary measure of lining up in front of hospitals to accost medical staff and accuse them of being “actors.” Although these opinions seem to be restricted to a small minority, it is difficult to imagine how such opinions can be held without some level of suspicion or doubt about science. Both I and others have reported about the important relationship between scientific literacy and belief in the pandemic, with a decrease in the former likely fueling a decrease in the latter, sometimes adversely affecting compliance with virus containment efforts.

Put simply, the circumstantial evidence surrounding the WIV and its connections to the NIH are a bad look for science. Even if the virus didn’t come from the facility, as Dr. Shi claimed in interviews with Scientific American, I think there is a burden of proof that must be undertaken to convince the public. If there is absolute certainty, please show us the evidence. It is our duty as scientists to be transparent. No doubt there will be some who will never be convinced, but there is also likely a sizable audience that would be receptive to new information, making the effort worthwhile.

As the pandemic rages on, the worst possible thing is for the rumor mill to latch onto uncertainties and convince more people that the voice of science is not to be trusted. COVID-19 may have begun in a lab, or not. Either way, the only thing that remains certain is that science will be the brightest light guiding us out of the pandemic. Since there will be plenty of time to divvy blame later, I implore that we stay focused on the monumental task at hand without getting bogged down in the politicization of science.

Justin Fendos is a professor at Dongseo University in South Korea.

Wuhan lab’s ‘Bat Lady’ denies US intel on collaboration with Chinese military

The top Chinese scientist at the Wuhan Institute of Virology denied that her lab has been conducting classified research with the Chinese military, contradicting claims from the U.S. intelligence community that the Wuhan lab carried out secret projects with the People’s Liberation Army for years.

Fauci's emails don't prove a Wuhan conspiracy, but raise further questions

Why were U.S. scientists so quick to dismiss the possibility of bioengineering as the potential origin of the Covid-19 virus?

Dr. Anthony Fauci, on Capitol Hill on May 26.  Sarah Silbiger / Pool via AP

June 4, 2021, 2:47 PM EDTBy Ken Dilanian, Amy Perrette and Denise Chow

It was Jan. 31, 2020, and a leading infectious disease expert, Kristian Andersen, had been examining the genetic characteristics of the newly emerging SARS-CoV virus.

“Some of the features (potentially) look engineered,” Andersen wrote in an email to Dr. Anthony Fauci, noting that he and other scientists “all find the genome inconsistent with expectations from evolutionary theory.”

But, he added, “we have to look at this much more closely and there are still further analyses to be done, so those opinions could still change.”

Change they did. Just four days later, Andersen gave feedback in advance of a National Academies of Sciences, Engineering, and Medicine letter that was referenced in the prestigious Lancet medical journal to argue against the idea that the virus had been engineered and brand it a conspiracy theory.

In his email, Andersen called the ideas that the virus was engineered “crackpot theories,” writing, “engineering can mean many things and could be done for basic research or nefarious reasons, but the data conclusively show that neither was done.”

That initial email, which was released to The Washington Post and BuzzFeed this week under the Freedom of Information Act, has been seized on by conservative news organizations as a smoking gun, proving that top officials and scientists covered up the origins of the Covid-19 virus.

On its own, the email doesn’t prove that or any other conclusions. it does raise questions about why Andersen and other scientists came down so firmly in defense of the natural origins hypothesis.

The U.S. government has since accused China of withholding significant information that has prevented a thorough investigation into how the virus emerged. And U.S. intelligence officials — while seeing no evidence the virus was genetically modified — say the possibility that the virus leaked from a lab in Wuhan is one they have not ruled out, and continue to investigate.

After the emails were made public, Andersen, a professor at the Scripps Research Institute, tweeted this week that "we seriously considered a lab leak a possibility," but reconsidered upon further review of the evidence.

“Significant new data, extensive analyses, and many discussions led to the conclusions in our paper,” he said. “What the email shows, is a clear example of the scientific process.”

Andersen’s use of the term “lab leak” could be confusing, however, because he was talking in the emails about the question of whether the virus had been modified or engineered. Another theory, experts say, is that scientists at the Wuhan Institute of Virology were studying samples of the virus taken from bats, and a mishap allowed it to escape without it ever having been modified. That could mean it arose in nature, but leaked from the lab.

Most scientists who have examined the virus don’t see any evidence that it was genetically modified. Scientists who argue against the lab leak theory have often conflated the two distinct scenarios. In fact, no examination of the virus’s genetic footprint can reveal whether the virus, taken from its natural state, was being studied in a lab. Nor can the virus’s genetic makeup speak to whether it spread to humans in Wuhan as a result of a lab accident.

Jamie Metzl, a former Clinton administration official who has long called for a full investigation into the origins of Covid-19, says the emails do not reflect well on Andersen. Metzl questions how much new data could have arisen in the four days between the email and Andersen's feedback for the National Academies of Sciences, Engineering, and Medicine letter.

In an interview with NBC News, Metzl said he believes that Andersen and other scientists, perhaps reacting to inflammatory rhetoric by then-President Donald Trump, were too quick to dismiss reasonable questions about whether the virus could have escaped from a lab in Wuhan, and even whether it could have been modified in that lab.

Andersen did not respond to a request for comment.

A fact sheet put out by the State Department at the end of the Trump administration in January — which was vetted by intelligence agencies and has not been disavowed by the Biden administration — says there is circumstantial evidence for a lab leak.

It has since emerged that the U.S. identified three employees of the Wuhan Institute of Virology who sought treatment at a hospital for symptoms consistent with Covid-19, contradicting the head of that lab, who said none of her workers got sick.

The State Department also said the lab was doing secret experiments on behalf of the Chinese military and was working on "gain of function" research that could make viruses more contagious in humans. WIV-head Shi Zhengli, who has been dubbed the “bat lady” in some circles because she studied viruses in bats, has denied working with the military.

Many scientists continue to argue that Covid-19 most likely arose in nature.

“There’s no new evidence that would really support a lab leak hypothesis,” said Robert Garry, a virus expert at Tulane University. “It’s more conjecture, suspicion and accusations.”

“Clearly there are parts of the natural origin theory that are missing,” Garry added. “We’re missing the intermediate species, if it does exist. We’re missing the bat progenitor, which almost surely does exist. But the question of finding that is going to take years, or decades, even …

"There certainly needs to be a whole lot more done, and it needs to be an international effort like no other to keep us from having another outbreak and pandemic like this one. With the lab leak, I think we do need to investigate that, too.”

President Joe Biden has asked intelligence agencies to redouble their efforts to get to the bottom of Covid-19's origins and report back to him in 90 days.

The recently released emails don’t shed much light on what Fauci was saying privately about the lab leak theory, in part because many of his emails are redacted.

Publicly, Fauci, director of the National Institute of Allergy and Infectious Diseases, leaned into the idea that the virus jumped from animals to humans in nature. More recently, he has acknowledged that the evidence is inconclusive and called for more investigation.

One email that has drawn attention went to Fauci on April 18, 2020, from the head of a research group which partners with the Wuhan Institute of Virology.

Peter Daszak, a zoologist and president of the EcoHealth Alliance, who has been among the most vocal critics of the idea of a lab leak, wrote, “I just wanted to say a personal thank you on behalf of our staff and collaborators, for publicly standing up and stating that the scientific evidence supports a natural origin for COVID-19 from a bat-to-human spillover, not a lab release from the Wuhan Institute of Virology.”

Daszak, who has collaborated with Shi Zhengli and the WIV, was also part of the World Health Organization delegation that spent time in China this year to investigate the origins of pandemic. After the WHO team initially ruled out a lab leak, only to be overruled by the agency chief, critics accused Daszak of having a disqualifying conflict of interest, something he disputes.

“From my perspective, your comments are brave, and coming from your trusted voice, will help dispel the myths being spun around the virus’s origins," Daszak wrote to Fauci.

The next day, Fauci wrote back: “Many thanks for your kind note.”

CORRECTION (June 5, 2021, 9:45 a.m. ET): A previous version of this article misstated who Kristian Andersen was providing feedback to in an email on Feb 4, 2020. He was providing feedback for a National Academies of Sciences Engineering and Medicine letter, which was then referred to in the Lancet article. He was not providing feedback to an article in the Lancet.

Ken Dilanian

PUBLIC HEALTH

How China’s ‘Bat Woman’ Hunted Down Viruses from SARS to the New Coronavirus

Wuhan-based virologist Shi Zhengli has identified dozens of deadly SARS-like viruses in bat caves, and she warns there are more out there

• By Jane Qiu on June 1, 2020

Credit: Richard Borge

The mysterious patient samples arrived at the Wuhan Institute of Virology at 7 P.M. on December 30, 2019. Moments later Shi Zhengli’s cell phone rang. It was her boss, the institute’s director. The Wuhan Center for Disease Control and Prevention had detected a novel coronavirus in two hospital patients with atypical pneumonia, and it wanted Shi’s renowned laboratory to investigate. If the finding was confirmed, the new pathogen could pose a serious public health threat—because it belonged to the same family of viruses as the one that caused severe acute respiratory syndrome (SARS), a disease that plagued 8,100 people and killed nearly 800 of them between 2002 and 2003. “Drop whatever you are doing and deal with it now,” she recalls the director saying.

Shi, a virologist who is often called China’s “bat woman” by her colleagues because of her virus-hunting expeditions in bat caves over the past 16 years, walked out of the conference she was attending in Shanghai and hopped on the next train back to Wuhan. “I wondered if [the municipal health authority] got it wrong,” she says. “I had never expected this kind of thing to happen in Wuhan, in central China.” Her studies had shown that the southern, subtropical provinces of Guangdong, Guangxi and Yunnan have the greatest risk of coronaviruses jumping to humans from animals—particularly bats, a known reservoir. If coronaviruses were the culprit, she remembers thinking, “Could they have come from our lab?”

While Shi’s team at the Wuhan institute, an affiliate of the Chinese Academy of Sciences, raced to uncover the identity of the contagion—over the following week they connected the illness to the novel coronavirus that become known as SARS-CoV-2—the disease spread like wildfire. By April 20 more than 84,000 people in China had been infected. About 80 percent of them lived in the province of Hubei, of which Wuhan is the capital, and more than 4,600 had died. Outside of China, about 2.4 million people across 210 or so countries and territories  had caught the virus, and more than 169,000 had perished from the disease it caused, COVID-19.

Scientists have long warned that the rate of emergence of new infectious diseases is accelerating—especially in developing countries where high densities of people and animals increasingly mingle and move about. “It’s incredibly important to pinpoint the source of infection and the chain of cross-species transmission,” says disease ecologist Peter Daszak, president of EcoHealth Alliance, a New York City–based nonprofit research organization that collaborates with researchers, such as Shi, in 30 countries in Asia, Africa and the Middle East to discover new viruses in wildlife. An equally important task, he adds, is to hunt down other pathogens to “prevent similar incidents from happening again.”

OUTSIDE A BAT CAVE in China's Guangxi province in 2004, Shi Zhengli releases a fruit bat after taking a blood sample. Credit: Shuyi Zhang

THE CAVES

To Shi, her first virus-discovery expedition felt like a vacation. On a breezy, sunny spring day in 2004, she joined an international team of researchers to collect samples from bat colonies in caves near Nanning, the capital of Guangxi. Her inaugural cave was typical of the region: large, rich in limestone columns and—as a popular tourist destination—easily accessible. “It was spellbinding,” Shi recalls. Milky-white stalactites hung from the ceiling like icicles, glistening with moisture.

But the holidaylike atmosphere soon dissipated. Many bats—including several insect-eating species of horseshoe bats that are abundant in southern Asia—roost in deep, narrow caves on steep terrain. Often guided by tips from local villagers, Shi and her colleagues had to hike for hours to potential sites and inch through tight rock crevasses on their stomachs. And the flying mammals can be elusive. In one frustrating week, the team explored more than 30 caves and saw only a dozen bats.

These expeditions were part of the effort to catch the culprit in the SARS outbreak, the first major epidemic of the 21st century. A Hong Kong team had reported that wildlife traders in Guangdong first caught the SARS coronavirus from civets, mongooselike mammals that are native to tropical and subtropical Asia and Africa.

Before SARS, the world had only an inkling of coronaviruses—so named because their spiky surface resembles a crown when seen under a microscope, says Linfa Wang, who directs the emerging infectious diseases program at Singapore’s Duke-NUS Medical School. Coronaviruses were mostly known for causing common colds. “The SARS outbreak was a game changer,” Wang says. It was the first emergence of a deadly coronavirus with pandemic potential. The incident helped to jump-start a global search for animal viruses that could find their way into humans. Shi was an early recruit of that effort, and both Daszak and Wang have been her long-term collaborators.

With the SARS virus, just how the civets got it remained a mystery. Two previous incidents were telling: Australia’s 1994 Hendra virus infections, in which the contagion jumped from horses to humans, and Malaysia’s 1998 Nipah virus outbreak, in which it moved from pigs to people. Wang found that both diseases were caused by pathogens that originated in fruit-eating bats. Horses and pigs were merely the intermediate hosts. Bats in the Guangdong market also contained traces of the SARS virus, but many scientists dismissed this as contamination. Wang, however, thought bats might be the source.

In those first virus-hunting months in 2004, whenever Shi’s team located a bat cave, it would put a net at the opening before dusk and then wait for the nocturnal creatures to venture out to feed for the night. Once the bats were trapped, the researchers took blood and saliva samples, as well as fecal swabs, often working into the small hours. After catching up on some sleep, they would return to the cave in the morning to collect urine and fecal pellets.

Credit: Richard Borge

ON THE SAME 2004 trip, a group of researchers prepare bat blood samples that they will screen for viruses and other pathogens. Credit: Shuyi Zhang

A DANGEROUS MIX

In many bat dwellings Shi has sampled, including Shitou Cave, “constant mixing of different viruses creates a great opportunity for dangerous new pathogens to emerge,” says Ralph Baric, a virologist at the University of North Carolina at Chapel Hill. In the vicinity of such viral melting pots, Shi says, “you don’t need to be a wildlife trader to be infected.”

Near Shitou Cave, for example, many villages sprawl among the lush hillsides in a region known for its roses, oranges, walnuts and hawthorn berries. In October 2015 Shi’s team collected blood samples from more than 200 residents in four of those villages. It found that six people, or nearly 3 percent, carried antibodies against SARS-like coronaviruses from bats—even though none of them had handled wildlife or reported SARS-like or other pneumonialike symptoms. Only one had traveled outside of Yunnan prior to the sampling, and all said they had seen bats flying in their village.

Three years earlier Shi’s team had been called in to investigate the virus profile of a mine shaft in Yunnan’s mountainous Mojiang County—famous for its fermented Pu’er tea—where six miners suffered from pneumonialike diseases and two died. After sampling the cave for a year, the researchers discovered a diverse group of coronaviruses in six bat species. In many cases, multiple viral strains had infected a single animal, turning it into a flying factory for new viruses.

“The mine shaft stunk like hell,” says Shi, who, like her colleagues, went in wearing a protective mask and clothing. “Bat guano, covered in fungus, littered the cave.” Although the fungus turned out to be the pathogen that had sickened the miners, she says it would have been only a matter of time before they caught the coronaviruses if the mine had not been promptly shut.

With growing human populations increasingly encroaching on wildlife habitats, with unprecedented changes in land use, with wildlife and livestock transported across countries and their products around the world, and with sharp increases in both domestic and international travel, pandemics of new diseases are a mathematical near certainty. This had been keeping Shi and many other researchers awake at night long before the mysterious samples landed at the Wuhan Institute of Virology on that ominous evening last December.

More than a year ago Shi’s team published two comprehensive reviews about coronaviruses in Viruses and Nature Reviews Microbiology. Drawing evidence from her own studies—many of which were published in top academic journals—and from others, Shi and her co-authors warned of the risk of future outbreaks of bat-borne coronaviruses.

NIGHTMARE SCENARIO

On the train back to Wuhan on December 30 last year, Shi and her colleagues discussed ways to immediately start testing the patients’ samples. In the following weeks—the most intense and the most stressful time of her life—China’s bat woman felt she was fighting a battle in her worst nightmare, even though it was one she had been preparing for over the past 16 years. Using a technique called polymerase chain reaction, which can detect a virus by amplifying its genetic material, the team found that samples from five of seven patients had genetic sequences present in all coronaviruses.

Shi instructed her group to repeat the tests and, at the same time, sent the samples to another facility to sequence the full viral genomes. Meanwhile she frantically went through her own lab’s records from the past few years to check for any mishandling of experimental materials, especially during disposal. Shi breathed a sigh of relief when the results came back: none of the sequences matched those of the viruses her team had sampled from bat caves. “That really took a load off my mind,” she says. “I had not slept a wink for days.”

By January 7 the Wuhan team had determined that the new virus had indeed caused the disease those patients suffered—a conclusion based on results from analyses using polymerase chain reaction, full genome sequencing, antibody tests of blood samples and the virus’s ability to infect human lung cells in a petri dish. The genomic sequence of the virus, eventually named SARS-CoV-2, was 96 percent identical to that of a coronavirus the researchers had identified in horseshoe bats in Yunnan. Their results appeared in a paper published online on February 3 in Nature. “It’s crystal clear that bats, once again, are the natural reservoir,” says Daszak, who was not involved in the study.

Since then, researchers have published more than 4,500 genomic sequences of the virus, showing that samples around the world appear to “share a common ancestor,” Baric says. The data also point to a single introduction into humans followed by sustained human-to-human transmission, researchers say.

Given that the virus seems fairly stable initially and that many infected individuals appear to have mild symptoms, scientists suspect that the pathogen might have been around for weeks or even months before severe cases raised the alarm. “There might have been mini outbreaks, but the viruses either burned out or maintained low-level transmission before causing havoc,” Baric says. Most animal-borne viruses reemerge periodically, he adds, so “the Wuhan outbreak is by no means incidental.”

IN YUNNAN PROVINCE, CHINA, scientists from EcoHealth Alliance, an international group that searches for diseases that can jump from animals to people, hunt for pathogens in a bat cave. Credit: EcoHealth Alliance

This article was originally published with the title "Chasing Plagues" in Scientific American 322, 6, 24-32 (June 2020)

doi:10.1038/scientificamerican0620-24

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ABOUT THE AUTHOR(S)

Jane Qiu is an award-winning science writer based in Beijing.

Coronavirus: Meet the legend, the Chinese 'Bat Woman'

Prof Shi Zhengli, who spent years studying bats, is now at the centre of COVID-19 storm

ADMIRED, MALIGNED: Prof. Shi Zhengli gained the epithet as Chinese "Bat Woman" (inset, a horseshoe bat). She's been credited for her pioneering work in the discovery of SARS (in 2005).Image Credit: Gulf News/Nature/Public Domain

DUBAI: It’s been a frustrating time for China’s "Bat Woman", Shi Zhengli. For the past five months, she has been caught in the global COVID-19 storm.

Prof. Zhengli certainly has a fascinating persona; she earned her moniker years ago, when she discovered the link between SARS-COV and bats.

Being one of the world's foremost bat virus experts, she is recognised for her contribution to bat virology. Her credentials, scientific endeavors are beyond reproach.

Now, Prof. Zhengli is celebrated and hated, in equal measure, in her home country.

She was on a team of scientists that collected and compared strands of coronavirus. These specimens were kept in a lab, the Wuhan Institute of Virology (WIV), in Wuhan China, "ground zero" of the first infections of the novel coronavirus in late 2019.

Zhengli, along with other clinical researchers, suggested the antiviral remdesivir and anti-malaria drug chloroquine effectively inhibit the recently-emerged novel coronavirus in vitro.

Q: Who is Shi Zhengli?

Prof. Shi Zhengli, 55 (born May 26, 1964) is a Chinese virologist.

Q: How did the novel coronavirus contagion begin?

When the viral outbreak first occurred in Wuhan, central China, in late 2019, samples were collected and sent to the WIV. The contagion was causing atypical pneumonia. Prof Zhengli was quoted by The Scientific American as recalling the director of WIV called her and said, “Drop whatever you are doing and deal with it now.”

Prof. Shi Zhingli, 55, is a legend, discoverer of the SARS virus and China’s top guru on coronaviruses (Photo Credit: Wuhan Institute of Virology)Image Credit: Wuhan Institute of Virology

The professor hopped on a train from Shanghai, where she was attending a conference at the time, to Wuhan. She was baffled too, she told the publication.

Her studies had shown that the subtropical areas of Guangdong, Guangxi and Yunnan — not Wuhan — posed the greatest risk of a transmission of a coronavirus from an animal to a human.

Back in her Wuhan lab, the whole thing had seemed an unlikely event. She, too, wondered if it came from her lab.

Q: What did Prof Zhengli say that she did upon returning to her lab?

She insisted that she then put her lab to work. Her main objective: sequence the genomes of SARS-CoV-2 from infected patients. Next, compare these with records of the experiments they had conducted on site.

Scientific American quoted the virologist as saying she didn't find a 100% DNA match between the viruses her team was working on and the new infection from patients.

"That really took a load off my mind," she told the magazine. "I had not slept a wink for days."

Q: So what’s the storm all about? 

The Wuhan lab worked with a close relative of SARS-CoV-2 — a bat coronavirus called RaTG13.

During the current (2019–20) coronavirus pandemic, Zhengli Shi and other WIV scientists formed an expert group on the research of SARS-CoV 2 (SARS-CoV-2). In February 2020, researchers led by Zhengli published an article in Nature titled "A pneumonia outbreak associated with a new coronavirus of probable bat origin". (Zhengli led a team of 29 researchers at the WIV (3 February 2020).Image Credit: Image: Public domain

That's according to evolutionary virologist Edward Holmes, of the Charles Perkins Center and the Marie Bashir Institute for Infectious Diseases and Biosecurity at the University of Sydney (as quoted by the Australian Media Center).

But Holmes said of the novel coronavirus: "The level of genome sequence divergence between SARS-CoV-2 and RaTG13 is equivalent to an average of 50 years (and at least 20 years) of evolutionary change." (That means that in the wild, it would take about 50 years for these viruses to evolve to be as different as they are.)

Back in 2015, an experiment involving Prof. Zhengli, who worked with a number of collaborators in the US (i.e. University of North Carolina at Chapel Hill, North Carolina, USA, in a study led by Dr. Ralph S Baric and designed/analysed by Dr Vineet D. Menachery), showed the ability of a bat coronavirus surviving and evolving to thrive in a human cell.

Prof. Baric, who works in UNC's Department of Microbiology and Immunology, is known to have also worked in "rewired TRN SARS-CoV mutants" with proceedings published in 2018.

The 2015 paper (accessed 1.89 million times as of April 20, 2020) published in the journal Nature Medicine, the researchers, described it as a "hybrid virus".

Dr Vineet D. Menachery, now works as Assistant Professor at the Department of Microbiology & Immunology of the University of Texas Medical Branch.

In the virology community, their project is known as "chimeric coronavirus", eerily similar to COVID-19. This chimera is created in a petridish, reportedly with the "surface spike protein (S protein) of a coronavirus found in horseshoe bats, called SHC014, and the backbone of a SARS virus that could be grown in mice".

Dr Vineet D. Menachery (left), Assistant Professor at the Department of Microbiology & Immunology of the University of Texas Medical Branch. Dr. Ralph S Baric, who works for the University of North Carolina's Department of Microbiology and Immunology, is known to have also worked in "rewired TRN SARS-CoV mutants" with proceedings published in 2018.

The team refered to the chimeric CoV (coronavirus) as "SHC014-MA15". The study lists the following as authors: Vineet D Menachery, Boyd L Yount Jr, Kari Debbink, Sudhakar Agnihothram, Lisa E Gralinski, Jessica A Plante, Rachel L Graham, Trevor Scobey, Xing-Yi Ge, Eric F Donaldson, Scott H Randell, Antonio Lanzavecchia, Wayne A Marasco, Zhengli-Li Shi & Ralph S Baric.

Menachery designed, coordinated and performed experiments, completed analysis and wrote the manuscript, according to Nature Medicine.

Here's the scary bit about the chimeric CoV: In the lab (not clear which one), researchers said, this new coronavirus was found so potent it could infect and replicate in human airway cells "naturally". It also infected mice lung cells. It's one of the experiments which prompted Prof Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris, to warn that such research is "misleading" and "irrational", stating thus: “The consequence of any accident would be anywhere from a handful of infections to a catastrophic pandemic.”

Q: When did Prof Zhengli say she completed sequencing the DNA of the novel coronavirus?

It was on January 7, 2020, Prof. Zhengli told Scientific American.

During the current (2019–20) coronavirus pandemic, Prof. Zhengli and other WIV scientists formed an expert group on the research of SARS-CoV 2 (SARS-CoV-2).

[Note: In February 2020, her team published an article in Nature titled "A pneumonia outbreak associated with a new coronavirus of probable bat origin" (29 researchers at the WIV were listed as authors of this study, 3 February 2020].

CAPTION AS WRITTEN IN NATURE: (a) Metagenomics analysis of next-generation sequencing of BALF from patient ICU06. (b) Genomic organization of 2019-nCoV WIV04. M, membrane. (c) Similarity plot based on the full-length genome sequence of 2019-nCoV WIV04. Full-length genome sequences of SARS-CoV BJ01, bat SARSr-CoV WIV1, bat coronavirus RaTG13 and ZC45 were used as reference sequences. (d) Phylogenetic tree based on nucleotide sequences of complete genomes of coronaviruses. MHV, murine hepatitis virus; PEDV, porcine epidemic diarrhea virus; TGEV, porcine transmissible gastroenteritis virus. The scale bars represent 0.1 substitutions per nucleotide position. Descriptions of the settings and software that was used are included in the Methods Image Credit: Nature

Soon, the report claimed, an email went out from Yanyi Wang, Director of the Wuhan Institute of Virology, to staff members. The email had a stern message: all the recipients were under strict orders not to disclose information on the disease.

Wang's email reportedly came with words of caution, i.e.  that "inappropriate and inaccurate information was causing general panic". "The National Health Commission 'unequivocally requires that any tests, clinical data, test results, conclusions related to the epidemic shall not be posted on social media platforms, nor shall [it] be disclosed to any media outlets including government official media, nor shall [it] be disclosed to partner institutions'," Wang reportedly added.

Zhengli has been vilified by many mainland citizens on social media, blamed for her role in supposedly "releasing" the virus later called SARS-CoV-2. On February 2, as rumors began to circle of an escaped contagion, Zhengli posted on her WeChat account: “I swear with my life (the virus) has nothing to do with the lab.”

Just as the chatter was dying down, however, a notice from the Chinese Ministry of Science and Technology came on February 15, 2020, calling on all labs to enhance its management of viruses, reported Quartz, sparking more suspicion.

Q: What does the journal Nature Medicine  say about Prof. Shi Zhengli-Li credentials?

She is a virology scholar, listed as representing the “Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.”

She came to international prominence as "bat woman" afer Zhengli and her colleague, Cui Jie, found the SARS virus originated in bats.

Zhengli is a member of the Virology Committee of the Chinese Society for Microbiology. She is also sits in the editorial board of Virologica Sinica, the Chinese Journal of Virology, and the Journal of Fishery Sciences of China.

Chinese scientists found all the genetic building blocks of SARS in a single population of horseshoe bats.Researchers analysed strains of SARS virus circulating in horseshoe bats, such as this one (Rhinolophus sinicus), in a cave in Yunnan province, China.Image Credit: Via Nature / Libiao Zhang/Guangdong Institute of Applied Biological Resource

Q: What's the significance of her study on SARS-Cov?

From 2002, Dr. Zhengli and her team of researchers chased the origin of the deadly SARS virus in a remote cave in Yunnan province. In 2005, after years of hunt across China, they finally found their "smoking gun".

The virologists have identified a single population of horseshoe bats that harbours virus strains with all the genetic building blocks of the one that jumped to humans in 2002, killing almost 800 people around the world.

Their results were published in Science in 2005, and the Journal of General Virology in 2006.

Interestingly, in February 2020, her team also published a paper in Cell Research showing that remdesivir, an experimental drug owned by Gilead Sciences, had a "positive effect" in inhibiting the novel coronavirus in vitro, and applied for a patent for the drug in China on behalf of the WIV.

Q: What happened to her "gain-of-function" research on SARS and coronavirus?

Zhengli was involved in an investigation of bat coronaviruses, specifically "gain of function" (GOF) experiments involving both the SARS and bat coronaviruses, a joint research of University of North Carolina and Wuhan Institute of Virology.

In 2014, funding for the project in the US had been paused due to the moratorium on risky virology studies with influenza, MERS & SARS viruses, announced by the US government that year.

Q: What did the results of the 2015 study she conducted with US counterparts say?

In the 2015 study, the abstract states: “The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV.”

“Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein.”

“On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.”

Q: What did the researchers say about the rapid spread of highly pathogenic viruses and the threat they pose to human populations?

“The emergence of SARS-CoV heralded a new era in the cross-species transmission of severe respiratory illness with globalization leading to rapid spread around the world and massive economic impact," they wrote in the introduction.

“Since then, several strains—including influenza A strains H5N1, H1N1 and H7N9 and MERS-CoV — have emerged from animal populations, causing considerable disease, mortality and economic hardship for the afflicted regions5. Although public health measures were able to stop the SARS-CoV outbreak4, recent metagenomics studies have identified sequences of closely related SARS-like viruses circulating in Chinese bat populations that may pose a future threat".

CAPTION FROM AN ILLUSTRATION IN THE 2015 NATURE STUDY: (a) The full-length genome sequences of representative CoVs were aligned and phylogenetically mapped as described in the Online Methods. The scale bar represents nucleotide substitutions, with only bootstrap support above 70% being labeled. The tree shows CoVs divided into three distinct phylogenetic groups, defined as α-CoVs, β-CoVs and γ-CoVs. Classical subgroup clusters are marked as 2a, 2b, 2c and 2d for the β-CoVs and as 1a and 1b for the α-CoVs. (b) Amino acid sequences of the S1 domains of the spikes of representative β-CoVs of the 2b group, including SARS-CoV, were aligned and phylogenetically mapped. The scale bar represents amino acid substitutions. (c,d) Viral replication of SARS-CoV Urbani (black) and SHC014-MA15 (green) after infection of Calu-3 2B4 cells (c) or well-differentiated, primary air-liquid interface HAE cell cultures (d) at a multiplicity of infection (MOI) of 0.01 for both cell types. Samples were collected at individual time points with biological replicates (n = 3) for both Calu-3 and HAE experiments. (e,f) Weight loss (n = 9 for SARS-CoV MA15; n = 16 for SHC014-MA15) (e) and viral replication in the lungs (n = 3 for SARS-CoV MA15; n = 4 for SHC014-MA15) (f) of 10-week-old BALB/c mice infected with 1 × 104 p.f.u. of mouse-adapted SARS-CoV MA15 (black) or SHC014-MA15 (green) via the intranasal (i.n.) route. (g,h) Representative images of lung sections stained for SARS-CoV N antigen from mice infected with SARS-CoV MA15 (n = 3 mice) (g) or SHC014-MA15 (n = 4 mice) (h) are shown. For each graph, the center value represents the group mean, and the error bars define the s.e.m. Scale bars, 1 mm.Image Credit: https://www.nature.com/articles/nm.3985/figures/1

Q: What did they say about building a 'chimeric virus' encoding a new zoonotic CoV spike protein? 

“However, sequence data alone provides minimal insights to identify and prepare for future prepandemic viruses. Therefore, to examine the emergence potential (that is, the potential to infect humans) of circulating bat CoVs, we built a chimeric virus encoding a novel, zoonotic CoV spike protein — from the RsSHC014-CoV sequence that was isolated from Chinese horseshoe bats — in the context of the SARS-CoV mouse-adapted backbone."

"The hybrid virus allowed us to evaluate the ability of the novel spike protein to cause disease independently of other necessary adaptive mutations in its natural backbone."

"Using this approach, we characterized CoV infection mediated by the SHC014 spike protein in primary human airway cells and in vivo, and tested the efficacy of available immune therapeutics against SHC014-CoV. Together, the strategy translates metagenomics data to help predict and prepare for future emergent viruses.”

"ZOONOTIC"

From "zoonosis": A disease that can be transmitted from animals to people or, more specifically, a disease that normally exists in animals but that can infect humans. Some examples include: anthrax, ascariasis, brucellosis, coronaviruses (SARS-CoV/MERS-CoV/SARS-CoV-2), plague, echinococcosis, Lassa fever, listeriosis, Lyme disease, monkeypox, psittacosis. rabies, salmonellosis, trichinosis. toxoplasmosis, typhus and West Nile fever.

Q: What did the researchers say about viral replication in human lungs (of the “chimeric virus” that they developed)?

[We’re just copying in toto, the main discussion in the story published in Nature “A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence”, https://www.nature.com/articles/nm.3985. Published November 2015. A Corrigendum to this article was published on 06 April 2016).

“The sequences of SHC014 and the related RsWIV1-CoV show that these CoVs are the closest relatives to the epidemic SARS-CoV strains; however, there are important differences in the 14 residues that bind human ACE2, the receptor for SARS-CoV, including the five that are critical for host range: Y442, L472, N479, T487 and Y491.”

“In WIV1, three of these residues vary from the epidemic SARS-CoV Urbani strain, but they were not expected to alter binding to ACE2. This fact is confirmed by both pseudotyping experiments that measured the ability of lentiviruses encoding WIV1 spike proteins to enter cells expressing human ACE2 and by in vitro replication assays of WIV1-CoV."

“In contrast, 7 of 14 ACE2-interaction residues in SHC014 are different from those in SARS-CoV, including all five residues critical for host range."

“These changes, coupled with the failure of pseudotyped lentiviruses expressing the SHC014 spike to enter cells, suggested that the SHC014 spike is unable to bind human ACE2."

“However, similar changes in related SARS-CoV strains had been reported to allow ACE2 binding suggesting that additional functional testing was required for verification.”

Therefore, we synthesized the SHC014 spike in the context of the replication-competent, mouse-adapted SARS-CoV backbone (we hereafter refer to the chimeric CoV as SHC014-MA15) to maximize the opportunity for pathogenesis and vaccine studies in mice.

- https://www.nature.com/articles/nm.3985#change-history

“Therefore, we synthesized the SHC014 spike in the context of the replication-competent, mouse-adapted SARS-CoV backbone (we hereafter refer to the chimeric CoV as SHC014-MA15) to maximize the opportunity for pathogenesis and vaccine studies in mice.”

“Despite predictions from both structure-based modeling and pseudotyping experiments, SHC014-MA15 was viable and replicated to high titers in Vero cells.”

“Similarly, to SARS, SHC014-MA15 also required a functional ACE2 molecule for entry and could use human, civet and bat ACE2 orthologs."

“To test the ability of the SHC014 spike to mediate infection of the human airway, we examined the sensitivity of the human epithelial airway cell line Calu-3 2B4 to infection and found robust SHC014-MA15 replication, comparable to that of SARS-CoV Urbani.

“To extend these findings, primary human airway epithelial (HAE) cultures were infected and showed robust replication of both viruses. Together, the data confirm the ability of viruses with the SHC014 spike to infect human airway cells and underscore the potential threat of cross-species transmission of SHC014-CoV.” [https://www.nature.com/articles/nm.3985]Q: 

HUMAN AIRWAY EPITHELIUM

HUMAN AIRWAY CELLS: Oxygenated air enters through the mouth or nose and passes into the trachea. The trachea branches into two bronchi, which lead to each lung. The bronchi divide into progressively smaller branches, called bronchioles. At the end of bronchioles are alveoli, sacs that mediate the exchange of oxygen and carbon dioxide. A layer of epithelial cells lines the respiratory tract. This epithelium provides a barrier against the external environment and protects against infection from airborne pathogens. Defective barrier function or viral infection can lead to respiratory tract disease. Image Credit: Lifeline Cell Technology / https://www.lifelinecelltech.com/the-respiratory-system-and-the-latest-human-airway-cells-research/

Q: What honours did she receive?

Shi Zhengli is a multi-awarded scientist. Among her distinctions are:

• 2016 Chevalier of the Ordre des Palmes académiques
• 2018 State Natural Science Award (Second Class)
• February 2019 Fellow of the American Academy of Microbiology (AAM)[28]

Image Credit: https://bit.ly/2VoXgQJ

Q: Did US officials warn about the Wuhan Institute of Virology?

Yes.

In 2018, according to a Washington Post report, US officials sent to the WIV had dispatched two diplomatic cables back to Washington which “warned about the safety and management weaknesses at the WIV lab”.

The cable noted that the US officials met with Prof. Zhengli. The cables also stated: “The researchers also showed that various SARS-like coronaviruses can interact with ACE2, the human receptor identified for SARS-coronavirus. This finding strongly suggests that SARS-like coronaviruses from bats can be transmitted to humans to cause SARS-like diseases.”

Q: What's the takeaway from Prof Shi Zhengli, the Chinese 'Bat Woman'?

It's easy to point fingers at her, though the story about her endorsement of remdesivir to treat COVID-19 (caused by SARS-CoV-2), and WIV's patent application for the antiviral drug, are interesting.

In some of her closely scrutinized projects, she clearly did not work alone.

Numerous scholars within China, and from around the world, had collaborated with her. The gain-of-function studies she conducted with US scientists enjoyed funding from American taxpayers.

The controversial 2015 experiments on SARS-like "chimeric coronaviruses" by a team including Zhengli, were designed, coordinated and performed by Dr. Vineet D Menachery, an Indian-American scientist who now teaches at University of Texas.

What's clear is that particular study targeted the primary human airway epithelial (HAE) cultures as a route for infection — with results confirming the ability of "viruses with the SHC014 spike to infect human airway cells and underscore the potential threat of cross-species transmission of SHC014-CoV.”

Virology and genetic engineering are highly specialized fields. It's no secret that big powers and big pharma desire to master and use these to their hegemonic or commercial advantage.

POSTSCRIPT

Research on organisms/viruses with pandemic potential is the exclusive domain of the scientific fraternity. There's little known by the public — who are at the receiving end of any major outbreak — about how viral samples are stored, amplified, used and secured.

Given the nature of transcontinental travel (until COVID-19 killed it), GOF studies on viruses certainly need greater oversight, if only to to guard against unintended, horrifying releases.

No, such specialized knowledge is not up to the experts alone to do with as they wish, or handle with blithe disregard for untold risks.

Scientific knowledge should be kept open. It's part of the common good. This highly pathogenic coronavirus that keeps us confined for weeks now just underscores the need for the world to come together. It highlights the need for a continued global surveillance of zoonotic viruses, including "chimeric", lab-made ones.

It calls for the world's scientific resources to be marshalled for the good of all. That, however, exists in an ideal world.

Now, it's up to the gene sequencing experts to show and re-confirm to the global community the direct link — or lack of it — between the GOF research, or anything like it, and the current SARS-CoV-2 pandemic.

And we can only hope that this orgy of death and the ravaging of economies and jobs across the world end sooner, rather than later.

NHUNG LE 

 by: Jane Qiuarchive page 

February 9, 2022

On a foggy morning in early February last year, dozens of journalists from around the world gathered outside the Wuhan Institute of Virology. Some walked around to find the best camera position; others climbed a ladder to peer into the fenced-off compound, its tall red-brick buildings hidden behind a thick mist. Security guards in blue uniforms lined the winding driveway leading to the entrance. 

The crowd was gathered because a team of international disease detectives selected by the World Health Organization (WHO) to hunt for the origins of covid-19 was on its way to visit. 

“They will be here in a minute,” a journalist working for Japan’s Tokyo Broadcasting System Television said after checking her phone. Her voice was brisk and slightly shaken; her eyes sparkled with nervous excitement. “My colleagues just told me. They’re chasing the WHO cars.” 

Soon enough, the motorcade burst through the fog. As it approached the institute’s main gate, a journalist in a blue down jacket and white face mask sprinted alongside as if he were running for his life, pointing a video camera toward the cars, his rucksack bouncing up and down on his back. A dozen photographers flocked to the lead car, pushing against one another and forcing the convoy to a stop. The guards tried herding them away to get the cars moving again. “Comments, please!” several journalists shouted. 

Inside the car, Peter Daszak—a disease ecologist and president of the EcoHealth Alliance, a New York-based nonprofit that works with scientists around the world to study viruses in wildlife—was filming the scene on his cell phone. 

He was a member of the WHO team, and when we’d spoken the week before, he'd cautioned that the Wuhan trip was just a first step in trying to figure out where covid-19 came from. “It can take years or even decades to find the cause of a new infectious disease,” said Daszak, who has collaborated with the Wuhan Institute of Virology for more than 15 years and is now himself caught up in the debate over the disease’s origins. “Sometimes we just never know.” 

But the world wanted quick answers.

The institute holds a critical place in the story of the covid-19 pandemic. A leading center for coronavirus research, it was the first facility to isolate the new virus, and the first to sequence its genome. One of its labs, led by virologist Shi Zhengli, focuses on coronaviruses that live in bats, and has spent years sequencing viral genomes, isolating live viruses, and—through genetic mixing and matching—trying to understand how they may evolve to gain the ability to infect humans. Over the past 18 years, her team has collected more than 20,000 samples from bat colonies across China.

Shi’s work, which has earned her the nickname China’s bat woman, has been at the center of controversy. Some have suggested that her bat samples could be the source of the covid-19 virus, which scientists call SARS-CoV-2. They have claimed that the virus could have hitched a ride to Wuhan by infecting one of her team members in their fieldwork collecting samples from bats. Or, some speculate, the live viruses her team cultured in the lab, including—more worryingly—the ones they created by genetic tinkering, could be the source of the pandemic.

All eyes were on the WHO, the leading international public health agency, to probe covid-19’s origins. The team’s mission was to examine when and where the outbreak had started and how the new virus crossed over to humans. The report, which was released last March, concluded it was “extremely unlikely” that covid-19 could have been caused by a lab accident. The situation the team ranked most likely was that it had jumped from bats to humans via some intermediary animal. Their results, supported by research published in peer-reviewed journals and by ongoing studies, suggest that the pandemic probably started at the Huanan Seafood Wholesale Market in central Wuhan, where live mammals were sold and where most of the early covid-19 cases emerged.

Not everybody agrees, but the majority of virologists and infectious-disease experts, especially those working directly on the origins question, lean toward that theory, barring the emergence of new evidence that persuades them otherwise.

Spillover from animals to humans “was how almost every major epidemic got started in the past decades,” says Shi’s longtime collaborator Linfa Wang, an expert on emerging infectious diseases at the Duke–National University of Singapore Medical School and a member of the WHO team that in 2003 investigated the origins of SARS, a deadly infectious disease caused by a coronavirus now known as SARS-CoV-1. That illness sickened 8,000 people worldwide and killed nearly 800 between 2002 and 2004. “It’s a common and well-documented pathway,” he says.

But one year after the WHO’s visit to Wuhan, the disease detectives have yet to find the guilty animal or other indisputable evidence of natural origins. Critics also question the conclusion of the agency’s mission team partly because one of its members, Daszak, who is a prominent advocate of the natural origins theory, has potential conflicts of interest. Speculation over the possibility of a lab accident has surged. Inflaming the suspicions are concerns over biosafety procedures at the Wuhan lab, political tensions between China and the US, and a general sense that the Chinese government is not to be trusted. 

By trying to understand the process and context of Shi’s work—and to find out who she was—I wanted to learn what role, if any, China’s bat woman had in the origins of covid-19.

Scientists like David Relman, an expert on microbiology and biosecurity at Stanford University, are dismayed at the way the lab leak theory has been dismissed. He helped organize a group of 18 scientists to sign a letter published in Science last May calling for further investigation of a possible accident. (At least two of those involved later sought to distance themselves from the letter after seeing how it had been used to promote the lab leak theory.) Soon afterwards, President Joe Biden directed the US intelligence community to intensify its probe into the pandemic’s origins. The declassified report released in October shows that it reached no firm conclusion.

In December 2020, a month before the WHO visit, I too embarked on a search for answers. I talked to dozens of top scientists and biosafety experts worldwide. I spent six weeks in Wuhan, where I interviewed Shi and her team for a total of more than 40 hours. I had a private meeting with three members of the WHO mission. I visited the Wuhan Institute of Virology half a dozen times, often on the spur of the moment, and went with the scientists on a virus-sampling trip to a bat cave. By trying to understand the process and context of Shi’s work—and to find out who she was—I wanted to learn what role, if any, China’s bat woman had in the origins of covid-19.

Probing covid-19’s origins will not only help us understand how coronaviruses work but shine a bright light on the human behaviors—including the types of scientific research—that risk causing a pandemic in the future.

Like the WHO team, I have not gone through Shi’s freezers or lab books, and therefore I cannot prove or disprove whether activities associated with her research caused the pandemic. It’s more about providing additional perspectives—having Shi and her team tell their side of the story on the record, and in the most detail to date, so that the world can better understand how this deeply entrenched controversy has come about and how we can move forward.

Meeting China’s bat woman

I met Shi Zhengli in person for the first time on a cold afternoon in December 2020. We had spoken earlier that year for an article published in Scientific American. The level of access she has given me is unparalleled. She rarely speaks with the press, and her interaction with journalists writing for the Western media has been largely confined to emails and texts. She told me she spoke to me because my strong science background allows me to grasp the nuances and complexity of her work, because I understand China, and because we can communicate in Chinese, our native tongue, in which I conducted the interviews.

We met for lunch and then went for a walk in a nearby park. A few days later, I visited the institute’s city campus in central Wuhan—approximately 12 miles from the suburban site that the WHO team later toured. Her lab was on the second floor of a solemn-looking cream-colored building. The main room had rows of benches with weighing machines, polystyrene ice boxes, and desktop centrifuges. Bottles of chemicals and solutions were tightly packed on the shelves. One student was typing away on a computer, while another was pipetting a tiny amount of colorless liquid from one test tube to another. The scene gave me a sense of déjà vu—I’d spent a decade working as a molecular biologist, including six years as a postdoc. It reminded me of my days in the lab. 

“It’s probably not that different from where you worked,” said Shi, as if she could read my mind.

Shi is petite, with short wavy hair that is neatly combed. Her voice is high and light, with the sparkle of a soprano (she is an amateur folksinger). That day she wore a beige sweater and blue jeans. As we went on to other parts of her lab—the deep freezers that held bat samples, and the rooms for culturing cells in petri dishes—she explained that her team had about three dozen researchers. That’s a lot for a Chinese lab, but it’s not the gigantic operation that many outsiders imagine. “I do not have an army of researchers and unlimited resources,” she said. Until the pandemic hit, coronavirus research was not a trendy subject and could not easily attract funding. 

Shi is one of the rare breed of virologists who are just as comfortable in the field as in the lab. She grew up in a small village in central China’s Henan province and spent most of her childhood roaming the hills. She doesn’t regard herself as ambitious. When she graduated from the prestigious Wuhan University in late 1987, she told me, “I thought I had achieved my career goal and the next stage was to get married and have kids.” The main reason she went on to study at the Wuhan Institute of Virology was to stay in the same city as her then boyfriend. But as China invested in sending promising young scientists abroad to pursue doctoral degrees, Shi grabbed the opportunity.

In 2000, she got her PhD at Université Montpellier 2 in France. Studying there was an unusual decision since she didn’t speak French, and a difficult one because it meant leaving her young son behind in China; the stipend was not enough to support a young family. But the experience left a positive imprint; she particularly appreciated the Western culture that prized “critical thinking, independent-mindedness, and not following the crowd,” she told me. “You can’t do great science without any of these. This is what China really needs to get better at.”

Afterwards, she returned to the Wuhan institute, where she focused mainly on aquaculture pests until 2004. At that time, the world was still reeling from SARS, and Wang, the Duke-NUS infectious-disease specialist, was working in Australia and looking for a virologist in China to help hunt for the origins of the new disease. Shi jumped at the opportunity, joining an international team to collect blood, urine, saliva, and feces from bat colonies in mountainous areas across China. They found SARS-like coronaviruses in bats within a year, but it took nearly a decade to prove that bats were the source of the contagion. Through their collaboration, Shi and Wang became friends; colleagues knew them for their karaoke duets, and they earned the nicknames “bat woman” and “bat man,” respectively. 

As Shi showed me around her lab, she pointed to the deep freezers where the team kept tens of thousands of bat samples in chemical soups. She told me how virus-containing samples are kept frozen in the field, either on dry ice or in liquid nitrogen, before being transferred to dedicated, double-locked deep freezers in the Wuhan lab. Only designated personnel can access those samples; they need approval from two senior staff members, each of whom is in charge of a separate key to the two locks. All access to the samples is logged.

The core of her research over the past 18 years, she explained, has been to look for bat viruses that are closely related to SARS-CoV-1, and to understand how they could evolve new features that allow them to infect humans. She talked me through that process, which begins with testing each bat sample to see if it contains a coronavirus—using the same PCR-based technique as many covid-19 tests. All coronaviruses contain a gene that encodes an enzyme called RNA-dependent RNA polymerase, or RdRp, which helps viruses replicate by making more copies of their genomes. If the characteristic RdRp shows up in a bat sample, it’s a telltale sign that a coronavirus is present. 

At first glance I was concerned by the sheer size of Shi’s collection of more than 20,000 bat samples. But she explained that on average only 10% contain coronaviruses, and only 10% of those are closely related to SARS-CoV-1: in all its years, the team has identified approximately 220 such viruses. The findings, say virologists such as Edward Holmes of the University of Sydney, have provided valuable insight into the evolutionary history of coronaviruses and the way they generate genetic variants.

Whenever the team found a bat relative of SARS-CoV-1, Shi says, she asked the same questions: How threatening is it to other animal species, including humans? What would it take for the virus to become one that, like SARS-CoV-1, can cause major epidemics?

The real thing

An important way to test if a coronavirus can evolve into something more threatening is to see whether its spike proteins—the weapons of invasion that give the virus a crown-like appearance—can latch onto a molecule called angiotensin-converting enzyme 2, or ACE2, which is present on the surface of cells in most vertebrates. To find out about a virus’s potential to infect people, Shi’s team would sequence its spike gene, compare it with that of SARS-CoV-1, and study on a computer its structure and ability to bind to ACE2. 

The researchers also used pseudoviruses—viruses whose ability to copy their genomes is disabled—to test whether the spikes could help them enter cells from various animals. Scientists all over the world use this approach to study new pathogens without resorting to live viruses. It can be conducted with relatively inexpensive biocontainment precautions at what’s known as biosafety level 2, or BSL-2: researchers wear gloves and lab coats, and they work in cabinets that have air filtration and are under negative pressure to keep pathogens inside.

The first step for this type of work is to extract genetic material for genomic sequencing, which would inactivate all the microbes in the sample. This and subsequent cell-entry studies using pseudoviruses are well-established, safe methods.

But while pseudoviruses are a great tool, spikes—it’s become increasingly clear—are not the only factor that determines a virus’s ability to infect cells. The approach also can’t show, for instance, how exactly a virus makes cells sick, how it spreads from one cell to another, or how a pathogen might evade the body’s immune response. Those questions, which are critical for the development of drugs and vaccines, can be addressed only by using the real thing—a fully functional virus. And it’s this more dangerous work that has become the center of the controversy around Shi.

Isolating live coronaviruses from bat samples is notoriously tricky—mostly because only a small fraction of samples contain even a whiff of the viruses (whereas specimens from people with SARS or covid-19 are often teeming with coronaviruses). The process of culturing viruses involves providing them with cells they can infect. Several labs around the world have tried to get live bat coronaviruses and failed. Until January 2021, the Wuhan lab was the only one that had managed the feat, according to Stephen Goldstein, a coronavirus expert at the University of Utah in Salt Lake City. And the person with the green thumb was Yang Xinglou, a senior research scientist on Shi’s team.

I met Yang at the institute’s maximum-biocontainment campus on the outskirts of Wuhan on a muggy afternoon last May. He came to pick me up at the main gate wearing a turquoise-colored T-shirt and jeans. In his mid-30s, Yang was slim and of medium height. His hair was neatly trimmed, but in a sudden breeze, his bangs danced over a forehead dominated by thick brows. I filled out a registration form and showed the security guards my national identity card, and we walked to his office across the neatly manicured campus. 

Instead of walking along the winding, camera-lined driveway meant for cars, we stepped onto a narrow path that ran by a small lake. On the far side I could see an austere-looking square building, about four floors high, sturdy, with silver siding and few windows. Inside it was China’s flagship BSL-4 lab—the crown jewel of the country’s microbiology work.

I did not go inside the BSL-4 facility: there are strict protocols that make it difficult for any visitors to get in, let alone the press. I did, however, visit the nearby BSL-3 lab, which handles less deadly pathogens. After undergoing further security checks, we entered its control room, where large screens revealed what was inside: a preparatory room, three rooms for culturing cells, a room for working with small animals such as mice and rats, a dedicated space for disinfection, and the entrances to both the lab and the control room itself. While I watched, one researcher put materials into a decontamination chamber, and two scientists in white full-body protective suits sat in front of a biosafety cabinet, working with rows of small vials behind a glass screen. A black tube on the back of their suits delivered filtered air to their face masks. 

It was here, on January 5, 2020, that Yang first successfully isolated SARS-CoV-2 from a patient sample—the first isolate of the new coronavirus. “Which room did you use?” I asked. “Cell culture room 3,” he told me, pointing at one of the screens. “It was in that cabinet.” 

It was just an ordinary cabinet in an ordinary room, with two bottles of disinfectant and two biohazard garbage bins behind the glass screen—but it’s now a landmark in the battle against the biggest pandemic in a century.

It was here, on January 5, 2020, that Yang first successfully isolated SARS-CoV-2 from a patient sample—the first isolate of the new coronavirus.

Yang has worked at the institute with pathogens in bats and rodents since 2008, developing and refining virus-catching techniques. There were lots of failures along the way, but in 2012, he hit the jackpot: a sample his team retrieved from a bat cave near Kunming successfully infected a type of monkey kidney cells called Vero E6, which has high levels of ACE2 on its surface. Once a live virus was at their disposal, the scientists could test directly whether it posed a potential threat.

It was a major breakthrough: for the first time researchers were able to demonstrate that bat coronaviruses in a petri dish could also infect cells from other species, including pigs and humans, by binding to their ACE2 receptors. The virus was 95% identical to SARS-CoV-1. The team named it WIV1 to indicate that it was isolated at the Wuhan Institute of Virology. Their study, published in Nature in 2013, provided strong evidence that SARS-CoV-1 originated in bats. 

In all his years of work, Yang has managed to isolate only three bat coronaviruses—all of them close relatives of SARS-CoV-1. More recently, the team managed to synthesize three bat coronaviruses from their genomic sequences. All six are close relatives of SARS-CoV-1. None of them, said virologists MIT Technology Review spoke to, could have been the source of SARS-CoV-2: they’re just too different. 

There was, however, one other virus in a bat sample that is a lot closer to SARS-CoV-2—96% identical. It has its own curious origin story, and in some parts of the scientific community and beyond, it’s become a prime suspect in the hunt for the pandemic’s origins. It’s called RaTG13.

Mine mystery

In late April 2012, a strange disease emerged from an abandoned copper mine near the town of Tongguan in Mojiang county, a region in China’s southwestern province of Yunnan. Six workers who had been cleaning up bat guano in the mine fell ill with pneumonia-like symptoms—coughs, headaches, fevers, and aching limbs—and were admitted to a hospital in Kunming, the provincial capital. One died in 12 days, and two recovered in a month, followed by another death on June 12. 

A week later, the country’s leading respiratory clinician, Zhong Nanshan, joined a clinical consultation remotely with colleagues at the Kunming hospital to determine how to treat the remaining two Mojiang patients. Zhong, the former director of the Guangzhou Institute of Respiratory Diseases, had played an instrumental role in the fight against SARS. He noted that the miners’ lab tests and CT scans were uncannily similar to those of patients with SARS, which hadn’t been seen since 2004. The clinicians in Kunming, he told me, suspected that a fungus had caused their illness—because cave-associated fungal infections happen in Yunnan every now and then—but Zhong thought a virus might be involved. He asked Shi’s team to test the patient samples for viral infections, but they couldn’t find any evidence of infection by coronaviruses or other known viruses. 

In 2020, with the pandemic raging, some scientists—including Stanford’s Relman—wondered if Shi had been wrong. Perhaps, they say, a SARS-like coronavirus was to blame. Perhaps there was even a link between the disease that affected the Mojiang miners and covid-19. 

That suspicion was bolstered in May 2020, when the anonymous owner of the Twitter handle @TheSeeker268—who claimed to me in Twitter texts that he is a 30-year-old man trained in architecture and filmmaking and lives in the Indian city of Bhubaneswar—dug up a 2016 PhD thesis by Huang Canping from the Chinese internet. Huang was a student of George Gao, director-general of the Chinese Center for Disease Control and Prevention in Beijing, and his thesis cited the Wuhan Institute of Virology as claiming that four of the Mojiang miners had antibodies against SARS-CoV-1. Scientists like Monali Rahalkar, a microbial ecologist at the MACS Agharkar Research Institute in Pune, India, and a strong proponent of the lab leak theory, said that this suggests the miners were infected by a SARS-like coronavirus. Social media and the press teemed with suspicion that Shi tried to hide the fact.

A model of the spike protein of the bat coronavirus RaTG13

SCIENCE PHOTO LIBRARY

The scientists directly involved in the work deny that speculation. Shi said her team did not find such antibodies, although she said some early tests did produce false positives that were corrected when the assays were fully validated. MIT Technology Review has been unable to locate Huang, but Gao said his lab never analyzed the miners’ antibody status, and that Huang’s statement—possibly based on the false-positive results, which Shi discussed at an internal meeting in 2012—was erroneous. After covid-19 struck, Shi’s team went back to the Mojiang samples to look for traces of SARS-CoV-2 proteins and found none. 

“Many pathogens can cause pneumonia-like symptoms similar to SARS and covid-19," Zhong told me. Some local clinicians, he adds, still suspect it was a fungus that had sickened the miners. “It remains a mystery to this day.”

It’s not unusual for respiratory illnesses to have an unknown cause, but even though Shi couldn’t figure out what had sickened the Mojiang miners, her instinct told her that something interesting might be going on. “What viruses were lurking in the cave?” she remembers wondering. Between 2012 and 2015, her team undertook more than half a dozen trips to the mine shaft, about 1,100 miles from Wuhan, and collected 1,322 bat samples.

They looked for the coronavirus-specific RdRp gene, and when they found it, they investigated further. In the end, the bat samples turned out to contain nearly 300 coronaviruses. Nine belonged to the same group of viruses as SARS-CoV-1—known as beta-coronaviruses—even though their RdRp genes were quite different: they were “distant cousins,” Shi told me.

“Why are you so different?” Shi wondered, but eventually she put the sample back in the freezer.

Eight of the nine were closely related to each other, but one—from a single fecal sample labeled “4991”—had a very distinct genomic signature. “Why are you so different?” Shi wondered, but eventually she put the sample back in the freezer. Her work was to look for bat viruses that could potentially cause SARS-like epidemics, and none of the Mojiang sequences appeared to be “directly relevant to our inquiry,” she told me. “So they were not the focus of our research.”  

In 2018, though, 4991 was brought back out again. The Wuhan Institute of Virology had bought a new desktop sequencing machine, which made it much faster and cheaper to get a complete view of a virus’s genomic secrets, and 4991 was among the first batch of samples to be sequenced with the new device. The analysis confirmed that the virus residing in the sample was very different from SARS-CoV-1; they are 80% identical to each other across the genome. (The genomes of the other eight Mojiang viruses, which were sequenced after the pandemic, show they are only about three quarters identical to both SARS and covid-19 viruses across the genome.) It was always interesting to find new viruses, but there didn’t seem to be anything special for the researchers to write up, Shi said: “It didn’t seem to be a remarkable virus.” 

It was so unremarkable, in fact, that it was expendable: In their attempts to piece together its genomic makeup, the scientists used up all the sample. By 2018 the virus existed only as a sequence in the Wuhan institute’s database. 

In most cases, that would be the end of the story: the obscure, irrelevant virus would fade into oblivion. Except that it didn’t.

“I didn’t want to screw up”

At 5:30 in the morning on January 2, 2020, Si Haorui, a student on Shi’s team, headed toward the institute to start his day’s work. It was cold, and the white cloud of his breath danced around as he walked on the dark, empty street. 

Si is not a morning person. He rarely emerges before 10:30. But on that frigid January morning, he had a battle to fight. Two and half days earlier, clinicians at Wuhan Jinyintan Hospital, the city’s infectious-disease center, had sent samples to the virology institute for urgent analysis.

They were from seven patients in serious condition who had been recently hospitalized for a mysterious pneumonia.

The following day, December 31, the Wuhan Municipal Health Commission issued its first public statement about the outbreak, saying it was probing the cause of 27 pneumonia cases. Shi’s lab was among the first to officially investigate the illness, and Si was part of the team racing to pinpoint the cause. Working around the clock, team members had found coronavirus RdRp genes in five out of the seven patients’ samples; their next step was to sequence the viral genome. “That’s my specialty,” said Si, a slim man in his mid-20s whose eyes curve into two arcs when he smiles, the day we met at the institute’s sequencing facility. “I knew the stakes were high. I didn’t want to screw up.” 

(Shi’s lab was one of the four teams designated by China’s National Health Commission to work in parallel to pin down the cause of the new disease. This was a high-profile assignment, and only the commission had the authority to declare outbreaks of an emerging infectious disease and to release the relevant information.)

Stepping into the sequencing room felt like being a soldier stepping onto the battlefield, Si recalled. He had laid out his weapons the night before—the software he had tweaked for piecing together the genomic sequence of unknown pathogens. The machine was still running, busy reading short fragments of the genetic material from the bugs in those patients’ samples. The low humming sound of the machine filled the room. Si’s eyes were fixated on the sequencer. It reached the final stage of sequencing. It began processing the files. It took forever. Time seemed to stand still. Eventually it was done, and with a slightly shaky hand, he inserted a flash disk and copied the files over. He bolted upstairs to his office, where he could link to the institute’s supercomputer for the analysis. 

By 8:30 a.m., the genomic makeup had emerged. One sequence, now known as WIV04, was almost complete and of high quality: it was a coronavirus. 

Shi entered the sequence into the institutional and international databases to see if it was new. The closest match was the sequence from sample 4991, which the team had taken from Mojiang in 2013. The virus, no longer obscure or irrelevant, now deserved an official name. The team called it RaTG13—Ra for the bat species it was found in, Rhinolophus affinis; TG for Tongguan, the town where it was found; and 13 for the year of its discovery. It was, as they reported in Nature a month later, 96% identical to the coronavirus found in the new patients.

The fact that RaTG13 is so similar to SARS-CoV-2 has aroused suspicion. Critics like Alina Chan—a molecular biologist specializing in gene therapy at the Broad Institute of MIT and Harvard University in Cambridge, Massachusetts—wonder why Shi’s Nature paper published in February 2020 didn’t mention that RaTG13 came from the Mojiang mine where people had come down with the mysterious pneumonia. Chan, who leans strongly towards the lab leak theory, has helped it spread far and wide, and signed the Science letter calling for further investigation of the possibility. She said in Viral, a book she co-authored with the British science writer Matt Ridley, that the Wuhan institute had been “economical with the truth” about this. 

Shi attempted to head off this kind of suspicion by publishing an addendum detailing her Mojiang studies in Nature in November 2020 to show that the team had not detected any sign of coronavirus infection in the miners’ samples. But that didn’t help squelch the speculation.

The overall similarity between the two viruses, however, is not evidence that RaTG13 is the source of covid-19, according to an article published in Cell last September, authored by two dozen or so leading virologists and infectious-disease experts. The two viruses may be related, but they sit on different evolutionary branches that diverged half a century ago, says David Robertson, a virologist at the University of Glasgow in the UK. “RaTG13 couldn’t have naturally morphed into SARS-CoV-2,” he says. Neither could anybody have used RaTG13 as the backbone to engineer SARS-CoV-2, as some proponents of the lab leak theory have argued: the two viruses are different in 1,100 or so nucleotides spread across their whole genomes—a gap too large for any realistic effort. Making SARS-CoV-2 from RaTG13, says virologist Angela Rasmussen of the University of Saskatchewan in Canada, “would have required a feat of unprecedented genetic engineering.”

Meanwhile, evidence for the natural origins theory continues to mount. In the past year, several teams independent of the Wuhan institute have uncovered more than a dozen close relatives of SARS-CoV-2 in China, Japan, Laos, Thailand, and Cambodia. In a preprint paper posted in September 2021, a team of Laotian and French scientists reported the discovery of viruses in Laos that, according to Robertson, shared a common ancestor with SARS-CoV-2 as recently as a decade ago. These new discoveries are evidence that SARS-CoV-2 most likely evolved in the wild, says Robertson, who was not involved in the study. “We are closing in on the SARS-CoV-2 progenitor,” he says. 

But even if none of the bat coronavirus samples from Shi’s team are to blame for the pandemic, they aren’t the only viruses the scientists work with. Part of their research involves studying how the machinery of viruses works; and that has involved genetic mixing and matching of different pathogens to probe the function of viral genes. Could one of those chimeric viruses have been the source of the pandemic? To find out, I needed to talk to Shi.

Genetic tinkering

Bat woman takes her nickname seriously. A bat key ring lay on the desk in her office when I visited. A picture of her releasing a bat during a virus-hunting expedition hung near the window. Above the door was a green and yellow ceramic plate depicting a flying bat, which Shi bought on a field trip in Sichuan province. 

“Bats are a symbol of blessing in traditional Chinese culture,” she told me. They are called bian fu, meaning “flat” and “blessing,” respectively. “We often see bat motifs in jewelry, ceramics, and buildings in remote villages,” she said.

As the researchers’ collection of bat coronavirus sequences grew—especially after 2012, when they first managed to culture live viruses—they wanted to pinpoint the genetic ingredients that allow those viruses to infect humans, so scientists could develop drugs and vaccines to counter them. 

Shi was particularly interested in whether the spike protein was the sole factor that affected a coronavirus’s ability to infect cells, or whether other parts of the pathogen’s genome also had a role. One of her bat coronavirus sequences, SHC014, seemed ideal for such an inquiry. It was 95% identical to SARS-CoV-1 across the genome, but its spike was very different, and pseudovirus studies showed it was unable to facilitate entry into cells from several species, including humans. Did this mean that it was unable to infect humans? 

Scientists could not test this question directly because they hadn’t managed to isolate a live virus from the bat sample. But two genetic approaches could help shed light. One was to synthesize the virus from its genomic sequence; the other was to see whether SARS-CoV-1 could still cause disease if its spike was replaced with that of SHC014.

Shi didn’t have the necessary tools to do this type of genetic work, so in July 2013 she emailed Ralph Baric—a towering figure in viral genetics at the University of North Carolina at Chapel Hill—about joining forces along those lines of inquiry. 

The collaboration with Baric was not a close one, Shi told me: there was no exchange of laboratory staff, and Shi’s main contribution was to provide SHC014’s genomic sequence, which was yet to be published at the time. The findings, published in Nature Medicine in 2015, were surprising. It turned out that both the synthesized SHC014 and the SARS-CoV-1-SHC014 chimera were able to infect human cells and make mice sick. Both were less lethal than SARS-CoV-1, but—worryingly—existing drugs and vaccines that worked against SARS were unable to counter their effects. 

Meanwhile, Shi’s team was attempting similar tinkering in her own lab in a project funded by the US National Institutes of Health, which aimed to probe the genetic ingredients that could allow bat viruses to cause SARS-like diseases in humans. But while Baric focused on the human pathogen SARS-CoV-1 in the Nature Medicine paper, Shi used only its bat relatives—mostly WIV1, the first bat coronavirus the team had isolated. Their real-world risk to humans was unknown. By the time the pandemic broke out, her team had created a total of a dozen or so chimeric viruses by swapping WIV1’s spike with its counterpart from newly identified sequences of bat coronaviruses, only a handful of which could infect human cells in a petri dish. 

There were more surprises in store. In an unpublished experiment, released by the NIH in response to a Freedom of Information Act lawsuit brought by The Intercept, the researchers tested the ability of three such chimeras to infect mice expressing human ACE2. Compared with their parental strain, WIV1, the three chimeric viruses grew a lot more quickly in the mouse lungs in the early stage of the infection, but WIV1 caught up by the end of the experiment. 

The differences surprised Shi, but what puzzled her the most was that the chimera causing the most weight loss in infected mice—an indicator of its pathogenicity—was WIV1-SHC014, whose spike was most dissimilar to that of SARS-CoV-1. The one whose spike was most similar had no effect on the animals’ weight.

The results from genetic studies in both Baric’s and Shi’s labs—both collaborating with the New York–based EcoHealth Alliance—have provided compelling evidence that the spike protein is not the only factor in whether a virus can make an animal sick, researchers say. “We can’t assess the emergence potential of viruses using only pseudovirus assays or predictions based on genomic sequences and molecular modeling,” Shi told me. 

None of the chimeras created in Shi’s labs was closely related to SARS-CoV-2, and therefore, none could have been the cause of the pandemic. But it does seem that the team created at least one chimeric virus, WIV1-SHC014, with a functional gain—that is, increased pathogenicity—relative to the parental strain, WIV. Critics like Richard Ebright, a molecular biologist at Rutgers University, regard this as the type of gain-of-function research that ought to be subject to strict regulatory oversight. But Shi says that in none of those studies—including her collaborations with Baric and with EcoHealth—did the teams intend to create more dangerous viruses. None of the chimeras had been reasonably anticipated at the time of proposal to have increased transmissibility or pathogenicity in mammals. 

According to an NIH spokesperson, the grant Shi jointly applied for with the EcoHealth Alliance—the only one with a sub-award to the Wuhan institute—“was reviewed and determined by experts to fall outside the scope” of its regulatory framework for gain-of-function research.

Virologists such as the University of Utah’s Goldstein argue that such genetic studies could help protect us from future pandemics. In the past year, research teams including Baric’s have demonstrated the possibility of developing so-called pan-coronavirus vaccines that could simultaneously block a group of coronaviruses—including SARS-CoV-1, SARS-CoV-2, their bat relatives that Shi has discovered, and potentially other relatives that are yet to be identified. Last September, NIH announced an award of $36.3 million to further such work. Discovering novel viruses in the wild and using genetic techniques to probe their function in the lab, researchers say, could point toward ways of mitigating and treating future disease outbreaks similar to SARS and covid-19. 

Biosafety challenges

Even though none of those chimeric viruses was the source of covid-19, there are still concerns that the biosafety standards in the Wuhan lab might not have been rigorous enough to prevent research activities from causing the pandemic.

Studies involving live viruses and genetic tinkering are inherently risky. Accidents can happen even with the most stringent biosafety precautions in place. Scientists might get inadvertently infected in the lab; genetic mixing and matching might unexpectedly create a superbug whose ability to escape overmatches the biosafety designation of its parental strains.

I asked Shi how China regulates coronavirus research to minimize the risks. 

“China doesn’t have a blanket biosafety regulation on all coronavirus research,” she said. “Everything is assessed on a case-by-case basis.” Studies of SARS-CoV-1 and SARS-CoV-2, for instance, have to be done in BSL-3 labs, whereas the human coronaviruses that cause the common cold are handled under BSL-2 conditions. What about bat viruses? 

The Wuhan institute’s biosafety committees ruled a decade ago that while work with animals must be carried out in BSL-3, molecular and cell-culture work involving bat coronaviruses can be done in BSL-2, albeit in biosafety cabinets with air filtration and under negative pressure to keep viruses inside.

Some scientists, like Ebright, regard this as unsafe. Bat coronaviruses are, as he puts it, “uncharacterized agents” with unknown virulence and transmissibility. “The only acceptable approach is to start with a high biosafety-level assignment … and to lower the biosafety-level assignment only if and when it is determined it is prudent to do so,” he told me in an email. 

Others, however, don’t think Shi’s work indicates lax biosafety standards in China. The dominant view among scientists worldwide was—and to some extent still is—that bat coronaviruses would most likely have to evolve in an intermediate animal first before they could infect humans. “Every institute’s biosafety committee has to balance the real risks with the potential risks,” says the University of Saskatchewan’s Rasmussen, adding that the Wuhan institute’s biosafety designation was reasonable at the time. 

And it’s not uncommon for labs around the world to culture uncharacterized animal viruses in BSL-2 facilities. Ebright told me in an email that current US guidelines place only three coronaviruses—SARS-CoV-1, SARS-CoV-2, and MERS-CoV—under BSL-3 rules. Some contagious animal coronaviruses that can infect human cells in a petri dish, including deadly pig viruses that originated in bats, are—like Shi’s viruses—designated BSL-2 agents. (In the US, culturing rabies virus, another deadly pathogen that often lives in bats, is also designated as a BSL-2 task even though the virus has a fatality rate of nearly 100% in humans.)

Rasmussen told me that the emergence of covid-19 means we should reevaluate those biosafety standards for viruses with unknown risks. “I think the pandemic has changed that risk-benefit equation,” she said. 

China’s high-level laboratories face other challenges besides the difficulty of making biosafety judgment calls. Money is one major issue. While there’s often ample funding to purchase cutting-edge equipment and build state-of-the-art laboratories such as the Wuhan institute’s BSL-4 facility, scientists often struggle for funding to train workers or to cover the cost of running those labs. 

Such obstacles are hardly a secret. When the US embassy in Beijing sent a delegation to visit the Wuhan Institute of Virology in early 2018, managers of the institute lamented about them to embassy staff. And Yuan Zhiming, director of the BSL-4 facility, detailed the challenges of high-level biosafety laboratories in China in a paper in September 2019.

Some have painted such challenges as a clear sign of lax standards. In an article published in April 2020, Washington Post columnist Josh Rogin wrote that after the US officials’ visit of the Wuhan institute in 2018 they “sent two official warnings back to Washington about inadequate safety at the lab.” According to Rogin, unnamed sources familiar with the unclassified cables “said that they were meant to sound an alarm about the grave safety concerns,” and one anonymous Trump administration official told him the cables “provide one more piece of evidence to support the possibility that the pandemic is the result of a lab accident in Wuhan.” 

The newspaper column marked a turning point in the debate over covid-19’s origins, catapulting the lab leak theory into the mainstream. Several mainstream media outlets have used its assertions as evidence that the Wuhan institute has a record of “spotty” or “shoddy” biosafety practice.

The cables themselves, which were publicly released several months later (with some parts redacted), cautioned about inadequate staffing but didn’t identify any specific dangerous biosafety practices. One cable, sent on January 19, 2018, mentioned the shortage of trained staff “needed to safely operate this high-containment laboratory” in a section that discussed how a lack of trained workers could “impede research.” According to the second cable sent three months later, this “opens up even more opportunities for expert exchange.” The January cable also noted the Wuhan institute’s ability “to undertake productive research despite limitations” and said that the work “makes the continued surveillance of SARS-like coronaviruses in bats and study of the animal-human interface critical to future emerging coronavirus outbreak prediction and prevention.”

Some scientists are appalled by what they perceive as misrepresentation of the embassy cables. “The concerns raised in the cable did not appear to focus on any specific safety concerns or egregious activities within the laboratory by current staff,” Jason Kindrachuk, an infectious-disease expert at the University of Manitoba in Winnipeg, Canada, told me in an email. It highlighted, he adds, how “these current limitations may be remedied through” additional help from the international community, including the US. In any case, Bill Hanage, an infectious-disease expert at Harvard, told me in an email that he doesn’t think the existence of the cables shed any light on the covid-19 origins debate. 

Rogin told MIT Technology Review in an email that he stands by his reporting in his 2020 article.

Shi says that the lack of trained staff means that China cannot make the most out of the facility, but it doesn’t mean that it was using untrained personnel to work in BSL-3 or BSL-4 labs. The Wuhan institute, she adds, abides by the international norms of biosafety governance and that her research before the pandemic was geared toward bat viruses closely related to the original SARS virus. “RaTG13 was the closest SARS-CoV-2 relative we had ever had,” she said. “We could not have leaked what we did not have.”

Shi also denied suggestions that the first human infection could have involved someone from her team—who caught the virus either in the lab or in the field. Between the beginning of the outbreak in Wuhan and the first vaccine shots, she told me, every member of her team was tested multiple times for viral nucleic acids to detect ongoing infections and for antibodies that would indicate past exposure. “Nobody was tested positive,” she said. “None of us has been infected by coronaviruses under any circumstances, including while sampling bats in the field.”

Politics of mistrust

Many scientists are dismayed by the way Shi and the Wuhan Institute of Virology are often portrayed in Western media. Even those with no connection to Shi or the Wuhan institute—such as the University of Glasgow’s Robertson and the University of Saskatchewan’s Rasmussen—call it shockingly biased and say it is driven partly by geopolitical motives and deep-rooted prejudice.

To China experts like Joy Zhang, a sociologist at the University of Kent in Canterbury, UK, who specializes in science governance in China, it’s hard to separate the specific allegations against Shi from the general suspicions of China. “Shi is a victim of the Western mistrust of China and Chinese science,” she says. 

Such mistrust of Chinese scientific practices is obvious among some. Filippa Lentzos, a biosecurity expert at King’s College London, told me in February last year that “it’s simply too late” to find out what happened because “everything, for instance, in the Wuhan Institute of Virology freezers would have been cleared out. The data records would have been scrubbed or cleaned up.” She says it’s still her view now.

Shi finds Lentzos’s allegations that her lab would destroy critical records “baseless and appalling.” 

“If that’s what they think, then there is nothing we can do to convince them otherwise,” she told me. “Even if we gave them all the records, they would still say we have hidden something or we have destroyed the evidence.”

Some in the West agree. “I’m quite distressed by people throwing this kind of extremely serious allegation around,” Nancy Connell, a microbiologist and member of NIH’s National Science Advisory Board for Biosecurity, told me in February last year, when she was with the Johns Hopkins Center for Health Security. “It’s highly irresponsible.” 

But even if the lab leak theory is partly fueled by a deeply rooted mistrust of China, the country’s questionable credibility record and a sequence of curious missteps have not helped. 

During the SARS outbreak in 2002-’03, Chinese officials downplayed its extent for months until a prominent military surgeon blew the whistle. At the onset of covid-19, China also obscured information about the early cases and clamped down on domestic debate. This was exacerbated when, in March 2020, a number of Chinese ministries ruled that scientists had to seek approval to publish any work related to covid-19 research. 

Meanwhile, several Chinese institutions, including the Wuhan Institute of Virology, instructed their scientists—with rare exceptions—not to speak to the press. For some, this was something of a relief. Conducting interviews on politically sensitive subjects in English is prohibitively daunting to many Chinese speakers, as any language errors, especially regarding tenses and auxiliary verbs, can easily be misconstrued—with grave consequences. At the same time, many Chinese scientists had become reluctant to talk to Western journalists for more straightforward reasons: the majority of reporters who had contacted them, they said, didn’t seem to understand the intricacies of the science and showed strong preconceived ideas. 

“I just wanted to put my head down and concentrate on my work,” Shi told me. “I thought the storm would just blow over after some time.” 

Some of the Wuhan institute’s behavior has certainly raised red flags. In February 2020, for example, it took its virus databases offline, and they remain unavailable to outsiders—prompting some to suggest that they might contain information critical to covid-19’s origins. Shi told me that the part of the databases that had been publicly available before the pandemic contained only published information; the Wuhan institute, like research organizations in other parts of the world, had unpublished data that could be shared upon request via portals for academic collaborations. The institute, she says, took the databases offline because of security concerns; there had been thousands of hacking attempts since the beginning of the pandemic. “The IT managers were really worried somebody might sabotage the databases or, worse, implant virus sequences for malicious intent,” she said.

Instead of tackling the publicity crisis directly, China has exacerbated mistrust by running obfuscation and disinformation campaigns of its own.

Still, the University of Kent’s Zhang says, China’s behavior has to be understood in the country’s larger political, media, and cultural context. China, with its totally different media tradition, “has neither the vocabulary nor the grammar of the Western press to deal with a publicity crisis,” she told me. “The first instinct of Chinese officials is always to shut down communication channels.” To them, she said, this often seems safer than dealing with the situation proactively. Several top Chinese scientists, who asked not to be named for fear of political repercussions, told me that this also reflects a lack of confidence among China’s top leaders. “While eager to assert itself as a global power, China is still terribly insecure,” one of them said.

Instead of tackling the publicity crisis directly, China has exacerbated mistrust by running obfuscation and disinformation campaigns of its own. Its foreign ministry, for instance, has insinuated that biomedical labs at a military base in Maryland may have created SARS-CoV-2 and leaked it to the public. Then there are the apparent falsehoods. The Chinese members of the WHO mission insisted in their report that “no verified reports of live mammals being sold [at the Huanan market] around 2019 were found.” In June, however, a paper published in Scientific Reports showed that many vendors sold live mammals illegally at several markets in Wuhan, including the Huanan market, just before the pandemic. 

Many scientists in the West are dismayed by such obfuscation. Even those who consider the lab leak theory highly unlikely are adamant that this behavior is unacceptable. “If China is lying about this, what else is it lying about?” says one virologist who strongly supports the natural origins theory. 

Wu Zhiqiang—a virologist with the Beijing-based Institute of Pathogen Biology at the Chinese Academy of Medical Sciences and a member of the WHO mission—denies that his team lied. He told me that tracking down illegal wildlife trade was beyond the scope of the scientific mission. “We had to work with the information provided by the various ministries and were unable to verify the sale of live mammals at the Huanan market,” he says. Studies of disease origins, he adds, are always based on incomplete data, but Chinese scientists are following up clues to probe the market link: “It takes time and patience to learn the scientific truth.”

Adding fuel to the mistrust, though, is the role of the EcoHealth Alliance’s Daszak. His close ties with Shi’s lab and his role as a member of the WHO mission’s international team are potentially in conflict. Critics say he can also be less than forthcoming. In February, for instance, he told several media outlets that he was impressed with China’s openness—at a time when the team was under tremendous pressure to conform to the Chinese narrative. While giving the impression that he knows very well what’s going on at the Wuhan institute, Daszak and his organization have also provided incorrect statements about its research activities.

Such incidents, critics say, have raised questions about whether Daszak had a disproportionate—or even misleading—role in the WHO mission. But scientists like the University of Utah’s Goldstein, who do not collaborate with Daszak, told me that there is no evidence that Daszak “wielded disproportionate influence” in the 11-member team.

Daszak told me in an email that his potential conflicts of interest had been declared to the WHO before he joined the mission team. He says that there is lots of misreporting about him and his work in the media and that he is often not given the chance to respond to accusations. EcoHealth Alliance, he adds, has acted “with scientific integrity and honesty.” 

“It’s now over two years since the first efforts to willfully politicize the pandemic origins, and to undermine science and the work that scientists do in often difficult circumstances,” says Daszak. “All of us have lost due to this politicization. When you mix politics with science, you get politics.”

“Clear and immediate threat”

On a hot July afternoon last year, I joined Shi and her team on a virus-hunting trip to a bat cave in Hubei province. (The team does not want the exact location of the cave disclosed, to avoid unwelcome media attention.) Dusk was falling fast, and the air smelled acrid and musty. Thousands of horseshoe bats clung to the cave ceiling—quiet, motionless, and evenly spaced out, like fighter jets on an airfield waiting for orders to take off. 

To capture bats, researchers used a gigantic net made of fine nylon mesh suspended between two poles. Shi and Yang pushed the poles against the entrance of the cave, adjusting their position to cover the gaps between the net and the rocks. We switched off our headlamps and waited in the dark. Moments later, a fluttering sound ricocheted above us. A shadow swirled around and shot into the net, like insects flying into a spider web. The bat immediately got tangled. “Here we go,” shouted Shi. “Our first catch!” 

The cave, at the bottom of a lush hill in a small village, is Shi’s home base. She uses it for sampling viruses, training students, and developing technologies that trace the movements of bats and the pathogens they carry. So far, it has yielded only distant relatives of known coronaviruses; their significance is unclear. (Bats in another cave in Hubei, however, have yielded SARS-like viruses.) “We are just collecting pieces of the jigsaw puzzle,” Shi told me. “We never know what will cause the next pandemic.” 

And the team keeps doing that work. The pandemic has lent extra urgency to one aspect of its research: determining the exposure risks that rural people face. In previous studies, Shi and her colleagues found that up to 4% of people living close to bats and working closely with wildlife in southern China were infected with dangerous animal-borne viruses, including coronaviruses; the infection rate was 9% among butchers. The Laotian and French team that discovered close relatives of SARS-CoV-2 found that one in five people who’d had direct contact with bats and other wildlife had coronavirus antibodies.