Shi Zhengli has spent years at the Wuhan Institute of Virology researching coronaviruses that live in bats. Her work has come under fire as the world tries to understand where covid-19 came from.
by Jane Qiu
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. Advertisement
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. Advertisement
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.Advertisement
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.
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