Behind the science and origin of Covid

Alina Chan isn’t saying the coronavirus definitely leaked from a lab in China. What she is saying is something that more scientists have grown comfortable discussing publicly: There’s no clear evidence either way.

« I know a lot of people want to have a smoking gun, » said Chan, a postdoctoral associate at the Broad Institute of MIT and Harvard who specializes in genetic engineering and has been vocal about the need to investigate the possibility of a lab leak. « It’s more like breadcrumbs everywhere, and they’re not always leading in one direction. It’s like the whole floor is covered in breadcrumbs. »

She was one of 18 scientists who published a letter in the journal Science in May calling for a more in-depth investigation into the virus’s origin that takes into account theories about both natural occurrence and laboratory spillovers. That letter helped kick-start a fresh round of calls to investigate the « lab leak hypothesis, » including demands from President Joe Biden and several leading scientists.

And while public discussion of a potential lab leak has shifted significantly in recent months, as more people pay attention to a theory that was originally promulgated by former President Donald Trump and his followers, the scientific evidence has remained unchanged, according to interviews with five virologists who have experience in microbiology, infectious disease ecology and viral evolution.

The researchers offered near-uniform summations that few conclusions can be drawn based on the available scientific evidence, but noted that the context and circumstances  of the origin debate have changed, particularly as critics point out that China has not been fully transparent about the earliest days of the pandemic.

The shift reflects how some scientists who previously avoided the topic, or were quick to dismiss it, are grappling with enduring uncertainties about the virus’s origin, free from the politicization that clouded such discussions under the Trump administration.

Chan said there had been trepidation among some scientists about publicly discussing the lab leak hypothesis for fear that their words could be misconstrued or used to bolster racist rhetoric about how the coronavirus emerged. Trump fueled accusations that the Wuhan Institute of Virology, a research lab in the same city where the first Covid-19 cases were reported, was connected to the outbreak, and on numerous occasions called the pathogen the « Wuhan virus » or « kung flu. »

 « At the time, it was scarier to be associated with Trump and to become a tool for racists, so people didn’t want to publicly call for an investigation into lab origins, » she said.

Now, more scientists are comfortable confronting the gamut of plausible theories — particularly given China’s opacity on the topic — though many still caution that entertaining the idea of a lab leak requires clear scientific proof, which has not yet materialized.

« There has been no new evidence over the past 16 months that the virus had a lab origin, » said Maciej Boni, an associate professor of biology at Penn State University, who specializes in tropical disease epidemiology and viral evolution.

The hypotheses in play

A number of theories about how the virus may have emerged have been thrown out, but most that remain fall under three possible scenarios:

The virus evolved naturally before spilling over into humans from an infected animal.

The virus evolved naturally but an employee at the lab became infected from a sample and accidentally « leaked » it into the community.

Scientists at the lab were manipulating virus samples and accidentally or intentionally released the pathogen.

What makes the virus’s origin a complicated matter is that the various threads can be difficult to reconcile. While most of the virologists who spoke to NBC News said the coronavirus probably evolved in nature, they agreed that it’s reasonable to probe the possibility that the pathogen came from a lab. 

At the heart of those suspicions is the Wuhan Institute of Virology, a research facility founded in the 1950s that was the first in China to receive the highest level of biosafety clearance. The institute’s lab has a biosafety level of 4 (known as BSL-4, the highest possible level), meaning that it is equipped to study the world’s highest-risk infectious agents and toxins, ones that require the strictest biocontainment measures. It’s that very designation, and the lab’s location in the city where the outbreak was first reported, that made the institute an early suspect.

« If we had a pandemic that was sourced near to a BSL-4 lab in the U.S., the first thing you would be asking is if they were working with that pathogen in that lab, » said Andrew Read, a professor of biology at Penn State and an expert on evolutionary genetics of infectious diseases. 

Still, he cautioned that while a lab leak is plausible, that does not necessarily mean it’s the most probable explanation.

Boni said it’s still more likely that the virus passed from an animal, such as a bat, into humans. He added that his experiences conducting field epidemiology work on avian influenza in Vietnam from 2008 to 2016 showed how close contact with wildlife, such as in « wet markets » around the world where outdoor stalls sell meat, seafood and live animals for consumption, can create easy opportunities for pathogens to spill into human populations.

« Going back over the past 25 years of emerging viruses that have crossed species boundaries from animals to humans, the most common route is something like a wet market or farm, or some other form of human and animal contact, » he said. « These are far more common than lab accidents. »

Animal origins

The first cluster of Covid-19 infections was traced to the Huanan Seafood Market in Wuhan, leading to early speculation that this may have been where the virus jumped from animals into humans. But Chinese researchers have since found that several of the earliest known cases of Covid-19 in the city were unrelated to the seafood market, meaning the virus may have been already spreading in the community.

Earlier this year, a joint investigation by the World Health Organization and China focused on the possibility of a zoonotic, or animal, origin. The team’s report, released in March, found that the virus probably emerged in bats and jumped to an intermediary animal before it spread to humans.

The team also downplayed the theory that the virus leaked from the Wuhan institute, describing that scenario as « extremely unlikely. » But the WHO-led investigation was heavily criticized for not doing enough to probe all plausible hypotheses. And the validity of the findings was questioned because the investigation hinged on China’s cooperation, and the Chinese government did not give researchers access to full records and raw data.

The letter in Science signed by Chan and 17 other scientists, including Ralph Baric, a virologist at the University of North Carolina, Chapel Hill, David Relman, a microbiologist at Stanford University, and Akiko Iwasaki, an immunologist at Yale University, was a response to the shortcomings of the WHO report.

Within the scientific community, the letter was seen as something of a turning point, lending credibility to the hypothesis that the virus may have escaped from the lab.

« I think it had a big effect, » Chan said. « I think It literally helped all the people who wanted to investigate this by saying: This is not bogus. Top scientists think this is plausible. »

IIlnesses spark suspicion

Calls for a more in-depth investigation into both the natural origin theory and the lab leak hypothesis have been fueled, at least, in part by a growing collection of circumstantial evidence uncovered over the last year by a band of anonymous internet sleuths. 

Last year, a member of this amateur investigative team, which calls itself DRASTIC (short for Decentralized Radical Autonomous Search Team Investigating Covid-19), combed through online records and found a 2013 thesis by a postgraduate student at Kunming Medical University in China that described six workers at a mine in Yunnan province who fell ill with severe pneumonia caused by a « SARS-like » coronavirus.

Three of the mine workers eventually died, but not much else is known about the situation. In research published in November 2020 by scientists at the Wuhan institute, serum samples from four of the mine workers were tested and showed no trace of SARS-CoV-2, the virus that causes Covid-19.

Separately, a U.S. intelligence report disclosed that three researchers at the Wuhan institute sought treatment at a hospital after falling ill in November 2019, as was first reported by The Wall Street Journal in May.

During the WHO-led probe earlier this year, officials at the Wuhan institute said all staff members at the lab tested negative for Covid-19 antibodies. Its leaders have been adamant that the virus did not escape from their facility, but the Chinese government’s reticence to share records and test results have cast suspicion over what the lab’s scientists knew — and when.

Though far from conclusive, both the intelligence report and the mine workers’ mysterious illnesses have been presented as circumstantial evidence that scientists at the Wuhan institute were studying risky coronaviruses similar to SARS-CoV-2, and that the virus may have escaped from the lab, perhaps after an employee became infected.

Genetic manipulation?

The mine incident also drew attention to a separate SARS-like virus that was collected by Chinese researchers in 2013 from a bat in Yunnan province. Shi Zhengli, a prominent bat researcher who directs the Center for Emerging Infectious Diseases at the Wuhan Institute of Virology, co-wrote a paper published in February 2020 detailing the virus, known as RaTG13.

The genomes of RaTG13 and SARS-CoV-2 were found to be 96.2 percent alike, prompting some to wonder if the pandemic had been caused by lab experiments on RaTG13 that had gone awry. The similarities between the two viruses also raised questions about the possibility that Chinese researchers were conducting « gain of function » experiments, which involve manipulating viruses in a lab to make them more dangerous or more transmissible in order to understand the inner workings of these pathogens.

Gain of function research is not altogether uncommon in virology, but such experiments are controversial because of the associated risks. A scientist could, for example, unwittingly or by design create a pathogen that is better adapted to invade human cells or cause more severe infections. But there are real benefits to gain of function research, said Robert Garry, a virologist at Tulane University in New Orleans. For one, understanding the characteristics of a virus and its transmissibility are critical to developing vaccines and lifesaving drugs, he said.

He added that most virologists take the responsibility of such experiments seriously. 

« It’s not the Wild West, » he said. « It’s very highly regulated. »

In 2014, the U.S. National Institutes of Health imposed a moratorium on gain of function research after two separate lab accidents involving anthrax and a strain of H5N1 bird flu occurred at the Centers for Disease Control and Prevention. Funding for gain of function experiments was paused for three years while the government conducted safety assessments. The ban was reversed in January 2017, under the Trump administration, after an independent science advisory panel found that the overall risk to public safety was low.

While it’s possible that scientists at the Wuhan institute were making genetic tweaks to samples, a coronavirus like RaTG13 that is 96.2 percent similar still can’t easily be altered to create SARS-CoV-2, according to Garry.

« Taking a virus that is 96 percent similar and sequencing and converting it to SARS-CoV-2 is impossible, » he said. « That kind of evolution takes maybe three to five decades in nature. You just can’t force that in a lab. »

Dr. Charles Chiu, a virologist at the University of California, San Francisco, added that the differences between RaTG13 and SARS-CoV-2 exceed the current capabilities of genetic engineering.

« The differences are scattered throughout the genome, » he said. « There’s a big difference between 96 percent similar and 100 percent identical. We just don’t have the ability to make those kinds of changes. »

In other words, the experts say, it’s unlikely that scientists could snip and splice bits of a virus or tweak a pathogen’s genome in such a way that would create SARS-CoV-2, even if researchers were using closely related coronaviruses.

« We’re very good at imitating nature — we have, for instance, been able to synthesize polio virus — but our ability to manipulate or change the sequence of viruses is still limited, » Chiu said.

The investigation continues

Chan, of the Broad Institute, wasn’t ready to rule out the possibility of genetic engineering, saying that if minor tweaks were being made to virus samples, it could be difficult to detect the fingerprints of such work.

« You can do recombination without leaving a trace, » she said. « Basically it’s like you can 3D-print clothing with no seams, so it’s difficult to tell if anything has been manipulated or stitched together in a lab. »

She acknowledged that it’s « definitely possible » that the virus evolved in nature, but added that all options should be kept on the table because neither the natural origins theory nor the lab leak hypothesis can be ruled out.

« All the evidence right now is circumstantial and it’s consistent with both lab and natural origins, » Chan said. « There’s precedents for lab leaks, the genetic data could swing either way, and the epidemiological data, which is how it unfolded in Wuhan, can also swing either way. None of this is pointing in any one direction. »

And it may be years, or even decades, before scientists have any clarity on the topic. The Ebola virus, which was discovered in 1976, is thought to have spread to humans from bats or nonhuman primates, but scientists still have not identified the origin from a specific animal host. 

« The key issue here is that we simply don’t have the information to make really firm conclusions, » Chiu, of the University of California, San Francisco, said referring to Covid-19. « Unless we know exactly what happened, we’re simply making guesses. »