Nicholas Wade is an author and former science writer for The New York Times.
The SARS-CoV-2 virus has disrupted people’s lives around the world for more than a year. But there’s no clear answer on one of the most important things about it: where it came from.
In fact, if you brush away all the politics about the issue — Donald Trump said it came from a lab, therefore it can’t have — and look just at the scientific facts, a reasonably likely answer is buried there. I’ll try to explain what it is and sort out some of the consequences.
There are two theories about the origin of SARS2, as the virus can be called for short. One is that it jumped naturally from bats to people, as the SARS1 epidemic did in 2002. The other is that it escaped from an experiment in the Wuhan Institute of Virology, China’s leading center of research on bat-type viruses.
The natural-emergence theory has long held the upper hand, in part because of strong statements made by virology experts from early on.
“We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin,” a group of virologists and others wrote in The Lancet on Feb. 19, 2020, when it was really far too soon for anyone to be sure what had happened.
Scientists “overwhelmingly conclude that this coronavirus originated in wildlife,” they said, calling for readers to stand with Chinese colleagues on the front line of fighting the disease.
It later turned out that the Lancet letter had been organized and drafted by Peter Daszak, president of the New York City-based EcoHealth Alliance. Daszak’s organization funded coronavirus research at the Wuhan Institute of Virology. If the SARS2 virus had indeed escaped from research he funded, Daszak would be potentially culpable. This acute conflict of interest was not declared to The Lancet’s readers. To the contrary, the letter concluded, “We declare no competing interests.”
Virologists have a significant stake in the origin issue because they have for years enhanced the danger of natural viruses in their laboratories.
Their rationale is that they could get ahead of nature by discovering the few tweaks that will let an animal virus infect humans. This knowledge, they argued, would help predict and prevent pandemics.
So if in fact one of these souped-up viruses is the cause of the COVID-19 pandemic, virologists everywhere, not just in China, will have a lot of explaining to do. “It would shatter the scientific edifice top to bottom,” MIT Technology Review editor Antonio Regalado said in March 2020.
Bat Lady and the Wuhan Institute of Virology
As it happens, virologists at the Wuhan Institute of Virology in China were doing exactly these kinds of experiments. The program was headed by Dr. Zheng-li Shi, known as Bat Lady in China because of her intense interest in bat viruses. Dr. Shi had gathered many coronaviruses, the type to which SARS2 belongs, from caves in Yunnan in southern China. Her research focused on the spike proteins which stud the surface of the virus and latch on to its target cells.
The exact nature of the spike proteins determines which kind of animal species the virus can infect. Shi was taking spike protein genes from different viruses, inserting them into a series of virus backbones, and trying to find the combination that would best attack humans.
She tested her viruses out not on real people but on cultures of human cells and on humanized mice — mice that have been genetically engineered to carry in the cells of their airways the human protein that’s the target of SARS-type viruses.
Unfortunately, Shi was on track to create viruses far more infectious than she realized, very possibly including SARS2.
“It is clear that the Wuhan Institute of Virology was systematically constructing novel chimeric coronaviruses and was assessing their ability to infect human cells and human-ACE2-expressing mice,” says Richard H. Ebright, a molecular biologist at Rutgers University and leading expert on biosafety.
“It is also clear,” Dr. Ebright said, “that, depending on the constant genomic contexts chosen for analysis, this work could have produced SARS-CoV-2 or a proximal progenitor of SARS-CoV-2.”
“Genomic context” refers to the viral backbone being used.
How do we know for sure that this is what Shi was doing? Because, by a strange twist in the story, she was funded by grants from the National Institutes of Health — channeled through Daszak. And these grant proposals, a matter of public record, spell out exactly what experiments she planned to do.
Not only was she generating dangerous viruses, she was doing so in arguably unsafe conditions. There are many Internet photos of Shi working in a bubble suit in the highest-level safety lab, known as a BSL4. But these labs are a pain to work in, and all her coronavirus work, she has said, was done at lower safety levels, including one known as BSL2.
But despite the fancy acronym, BSL2 doesn’t require very much. You have to wear a lab coat and gloves, put up a biohazard warning, and that’s about it.
“It is clear that some or all of this work was being performed using a biosafety standard — biosafety level 2, the biosafety level of a standard US dentist’s office — that would pose an unacceptably high risk of infection of laboratory staff upon contact with a virus having the transmission properties of SARS-CoV-2,” says Ebright.
So the lab-escape scenario is not the conjecture of some conspiracy theorists. It’s not based on someone pointing to the Wuhan Institute of Virology and saying, “Yeah, I think the virus could have come from there.” It rests on the specific program of research that Shi was known to be pursuing, and on the fact that she was working in minimal, probably inadequate, safety conditions.
Meanwhile, the rival scenario, that of natural emergence, has been looking less likely by the month. Viruses that jump from an animal host to humans usually leave a trail of signatures in the natural environment. When SARS1 jumped from bats to civets to people in 2002, researchers could track in fine detail how the virus improved its infectivity for human cells by gaining one helpful mutation after another. In the case of SARS2, no one has yet found any trace of its existence in the natural environment.
Chinese authorities had every incentive to present any such evidence to the World Health Organization when it visited Beijing in February of this year. But despite a presumably intensive search, they had nothing to offer. They had discovered no bat colony infected by the source virus, no intermediate host animal, and no human population exposed to the virus as it gathered strength.
Testing the Two Scenarios
So matters stand at an impasse. There is no direct evidence for either the natural-emergence or lab-escape scenario. And until Chinese authorities unlock the records of the Wuhan Institute of Virology, there is no proof that the virus escaped from Dr. Shi’s lab, however plausible that might seem.
In the absence of direct evidence, the best approach is to take various important facts about the pandemic and ask which of the two scenario provides the better explanation. Here are three tests of the two scenarios:
The bats that harbor the closest known relatives of SARS2 live in caves in Yunnan in southern China. If the pandemic had started by infecting people living around the caves, that would strongly favor natural emergence. But the pandemic broke out nearly 1,000 miles away in Wuhan, at a time of year when bats go into hibernation. Under the natural-emergence scenario, it’s hard to see how the virus broke out naturally somewhere outside Wuhan, and then popped up in the city without leaving any trace of its origin elsewhere. With lab escape, it’s a no-brainer: Researchers at the Wuhan Institute of Virology were cooking up hyper-dangerous viruses in inadequate safety conditions, and one escaped.
2. Natural history
For viruses jumping to new hosts, it usually takes a lot of time and many mutations to perfect their adjustment to the new target species. This process has been mapped in detail for the SARS1 virus. But researchers looking for the same adaptation in SARS2 made a strange discovery. From the moment it first appeared, the SARS2 virus was almost perfectly adapted to human cells and has changed hardly at all since.
This is hard to explain under the natural-emergence scenario. But from the lab-escape scenario it’s pretty obvious: The virus was being grown in humanized mice so of course was well adapted to people from the start.
3. The furin cleavage site
Without getting too deeply into the details of the SARS2 virus’ anatomy, there is a small region of its spike protein called the furin cleavage site, just 12 units of its 30,000-unit genome.
A virus usually acquires inserts like this by accidentally exchanging genomic units with another virus when both invade the same cell. But no other known virus in SARS2’s group has this 12-unit insert.
Proponents of natural emergence argue that the virus could have acquired the insert from human cells after it had jumped to people. Maybe, but no one has yet found the human population in which the virus might have evolved this way. The insert also contains entities known as arginine codons, which are common in humans but not in coronaviruses like SARS2.
Under the lab-escape scenario, the insert is easy to explain. “Since 1992 the virology community has known that the one sure way to make a virus deadlier is to give it a furin cleavage site,” writes Dr. Steven Quay, a biotech entrepreneur interested in the origins of SARS2. At least 11 such experiments have been published, including one by Dr. Shi.
“When I first saw the furin cleavage site in the viral sequence, with its arginine codons, I said to my wife it was the smoking gun for the origin of the virus,” said David Baltimore, an eminent virologist and former president of the California Institute of Technology.
“These features make a powerful challenge to the idea of a natural origin for SARS2,” he said.
Who was at fault?
The lab-escape scenario explains the facts above far more easily than does natural emergence. So let’s ask who is to blame, provisionally, if the virus did indeed escape from a lab.
The first in line are Dr. Shi and her colleagues. They were generating dangerous viruses in unsafe conditions. True, they were following the same international rules as are used by virologists everywhere. But they should have made their own assessments of the risks they were running.
Second in line for rebuke are the Chinese authorities, who have done their utmost to conceal the nature of the tragedy and their responsibility for it.
Third are virologists around the world who knew better than anyone the dangers of enhancing natural viruses but couldn’t resist the temptation. Their assurance that the benefits were real and the risks containable were not correct. The benefits have been zero and the risk, it would seem, catastrophic.
Fourth may be the US National Institutes of Health, which funded Shi’s research via Daszak, despite a moratorium from 2014 to 2017. The reporting system that replaced the moratorium required funding agencies to mention hazardous research but the NIH did not do so. If the SARS2 virus did indeed escape from Shi’s lab, the NIH will be in the unenviable position of having funded research that has killed 3 million people worldwide, including 500,000 US citizens.
What should happen now? Perhaps Western governments should tell China they will now assume the virus originated from the Wuhan lab, absent evidence to the contrary, and ask China to open up all its records or forever forfeit the West’s trust.
China has an interesting fall-back position: OK, we let the virus escape, but you funded this dangerous research on our territory. Might this be the face-saving formula under which both sides could then focus on ensuring no such pandemic is ever unleashed again?