Let’s look at the evidence.

Was the emergence of the novel coronavirus SARS-CoV-2 a natural event, a spillover from the bats that naturally host close relatives of the virus? Or did a virology lab in Wuhan accidentally release the virus in the course of studying it?

In the U.S., those questions are being raised in an atmosphere of increasing suspicion of China, coupled with a slow and flawed pandemic response at home. But what’s the evidence?

Bats or Virology Lab Accident?

The argument for the first scenario — spillover from bats — is two-fold. First, it has happened at least twice before, with SARS and MERS. Second, the genetics of SARS-CoV-2 suggest that the best explanation of the current structure of the virus is some sort of transfer from animals, before or after natural selection that gave rise to some distinctive and possibly clinically relevant features.

The argument for the second — a lab accident — is more indirect. First, the Wuhan Institute of Virology — in the city where SARS-CoV-2 was first detected — has a biosafety level 4 (BSL-4) lab that has been studying bat coronaviruses. Second, U.S. experts had flagged some safety concerns about the lab after a visit two years before SARS-CoV-2 appeared.

The lab argument is less plausible, according to Amesh Adalja, MD, of the Johns Hopkins University Center for Health Security, although it can’t be ruled out entirely.

“The more likely possibility is that this is something that is following a SARS-like pattern,” Adalja told BreakingMED, although it’s impossible to quantify that possibility with the evidence at hand.

“The fact that this lab happens to be in Wuhan is confounding the issue,” he said, noting that safety concerns — and sometimes outright breaches of biosafety — are common with all labs dealing with what he called “high-consequence pathogens,” including many in the U.S.

Indeed, a litany of errors was reported in recent years, including CDC labs where workers were exposed to anthrax in one instance and to Ebola in another. Not reported, in general, are outcomes of inspections aimed at finding flaws before an error, but Adalja said it’s common for inspectors to raise concerns.

“Raising questions about biosafety is important,” he said, but “I don’t think there’s enough evidence to justify” leaping to the conclusion that the Wuhan lab played a role in the current outbreak.

Bioweapons Experiment?

The darker theory, proposed in some unofficial circles, is that SARS-CoV-2 was part of a bioweapons experiment. But that, on the basis of genetic evidence, is highly unlikely, according to Kristian Andersen, PhD, of the Scripps Research Institute, La Jolla, California, and colleagues.

In the first major analysis of the genetics of SARS-CoV-2, Andersen and colleagues debunked the bioweapon idea, concluding “the evidence shows that SARS-CoV-2 is not a purposefully manipulated virus.”

Had it been, they argued in Nature Medicine, it would have been based on known reverse-genetics systems for betacoronaviruses, but the genetics of SARS-CoV-2 show it is “not derived from any previously used virus backbone.”

In particular, a highly variable element of coronaviruses is the receptor binding-domain (RBD); the original SARS had an efficient way to bind to its receptor, the human molecule ACE2, and SARS-CoV-2 is “optimized” for binding to the same molecule — but in a different manner.

That suggests it arose through natural selection, either in humans or some intermediate animal host, rather than through lab manipulation, Andersen and colleagues concluded. That doesn’t rule out an escape, however; it just means that if there was an escape, the virus that got out was not yet SARS-CoV-2 and still had some evolutionary distance to go.

SARS-CoV-2 is about 96% similar to a bat coronavirus dubbed RaTG13, whose RBD is different enough to suggest it might not bind efficiently to human ACE2. On the other hand, some viruses isolated from pangolins — small, scaly, and endangered mammals — share very similar RBDs with SARS-CoV-2, although they are otherwise dissimilar.

Those findings suggest that some elements needed for SARS-CoV-2 are part of the natural order of things and only needed combining. What’s missing, Andersen and colleagues noted, is evidence of what’s called a “functional polybasic (furin) cleavage site” on the spike protein of SARS-CoV-2.

The spike protein is what the virus uses to enter its target cells; it includes the binding proteins and a fusion unit. The polybasic cleavage site has been proposed as part of the mechanism by which the virus avoids the immune system; it’s absent in the original SARS.

Importantly, it also hasn’t been seen in wild coronaviruses, Andersen and colleagues said, although the “diversity of coronaviruses in bats and other species is massively undersampled” — absence of evidence might not be evidence of absence.

A Tale of Two Possible Pathways

The presence of the site in SARS-CoV-2 suggests it arose via one of two pathways, they argued:

  • An intermediate animal host that developed the site through natural selection on a bat coronavirus and then passed on the resulting pathogen to humans as an essentially complete form of SARS-CoV-2.
  • A progenitor virus that made the leap to humans first and then developed the cleavage site that turned it into SARS-CoV-2.

The two possibilities have different ramifications, they noted. In the first case, a virus very like SARS-CoV-2 still lurks in an unidentified host and could restart outbreaks at any time.

The second case is more reassuring — if it took a series of mutations in humans for the cleavage site to arise, the exact process is unlikely to repeat itself in the event the progenitor virus is passed to us again.

Importantly, Andersen and colleagues argued, the cleavage site probably did not arise through passage through cultures in a lab; the pressure of an immune system is essential for the selection process.

The politics of the issue aside, however, it’s probably not important right now how it originated, according to Adalja. “The response would be the same for either possibility, because we now have a community-spreading respiratory virus that has led to a pandemic,” he said.

Michael Smith, Contributing Writer, BreakingMED™

Cat ID: 125

Topic ID: 79,125,730,933,125,190,520,926,192,927,151,928