EXPERT Q&A: The origins of SARS-CoV-2

Q: What evidence do we have about the origins of COVID-19? 

"There are a number of lines of evidence that are swaying most virologists towards an animal origin of SARS-CoV-2. This is what we know so far:

• Most viruses that have emerged in the last 50 years or so have an animal origin, including viruses in Australia. This includes many bat viruses.
• Coronaviruses that infected humans pre-COVID-19 have likely animal origins eg the ‘common cold’ CoVs, SARS and MERS. Coronaviruses of varying degrees of genetic relatedness can be readily detected in a wide range of land, air (and water) animals, and can jump species.
• Many animals support the growth of various human coronaviruses, including SARS-CoV-2, and animal-human-animal cross-over has been described.
• SARS-CoV-2 can infect many animal species, including some of the animal species in the Wuhan wet market, or trapped at border stations. Live wild animals known to be capable of harboring coronaviruses have been identified for sale in the Wuhan wet market prior to the outbreak.
• Genetic material from a range of wild farmed animals and SARS-CoV-2 were detected in environmental sampling in the Wuhan market (this says both were contemporaneously present, but doesn’t confirm the virus was in the animals). 
• Bats support many many coronaviruses (including what are called SARS-related CoVs or SARSr-CoVs, as well as coronaviruses known to infect humans). Bats are numerous, live in large groups and have an immune system that seems to prevent them from illness from coronaviruses.
• Some bat coronaviruses from a number of different countries (mostly SE Asia, China)  are close relatives to SARS-CoV-2 (either for the whole virus, or in specific genetic regions) although so far still distant enough to not be the direct ancestor of SARS-CoV-2.
• It is reasonably easy to obtain full or partial genetic sequences from bats, but they can be hard to isolate in the lab (lab accidents tend to occur when viruses are being isolated in tissue cultures). The bat RATG13 genetic sequence, one of the closest relatives to SARS-CoV-2, has not been isolated in tissue culture.
• Virological sampling of animals in general is much less complete than from humans, so there is plenty more out there. Bats in particular are under-sampled in many countries, including Australia.
• The early human cases were geographically linked to the market, even though not all of the early cases gave a history of direct market exposure
• Evidence is emerging that people who come into significant contact with animal coronaviruses have immune responses to these viruses, suggesting past infection. It is likely that spill-over of coronaviruses (and indeed other animal pathogens) into humans is more frequent than we think, but spill-over in itself doesn’t mean that significant ongoing transmission to other humans has occurred or needs to occur
• Two ‘lineages’ of SARS-CoV-2 were identified in the environmental sampling of the market, and in the early human cases, suggesting more than one cross-over event. This is more likely to happen in the crowded market environment than with a lab accident with a single virus in tissue culture.

Many unknowns remain. In particular, if SARS-CoV-2 comes from bats did it enter humans via intermediate animals (eg those sold in markets) or was it direct bat to human? In my opinion, the latter is less likely as human-bat direct contact is not that common. The virus from bats could have been circulating in intermediate animals for a while (accumulating mutations that make it more likely to spread in humans) before jumping across into humans."

Q: What is the Furin cleavage site and what does it tell us about the origins of the virus? 

"Furin is a type of enzyme that can cut other proteins at specific sites. Many viruses have sites that this enzyme can cut, known as full or partial furin cleavage sites, including various animal coronaviruses. SARS-CoV-2 has a furin cleavage site on the spike protein. Cutting (or cleaving) this furin cleavage site is an important step in the SARS-CoV-2 virus entering human cells, and is part of what makes it so infectious. The cleaving exposes a site on the spike protein that helps the virus to interact with a receptor on the surface of our cells called ACE2.  Because furin cleave sites have not yet been found in SARS-CoV-2-related coronaviruses in bats, scientists are interested in how this site developed in SARS-CoV-2. But we also know that furin cleavage sites are present in many other human and animal coronaviruses and in some influenza viruses.
 
Many animal coronaviruses can also use the human ACE2 receptor on cells even without a furin cleavage site."

Q: Is it still possible that the virus could have originated in a lab?

"It could be possible, which is why it remains ‘on the table’. Nothing yet has emerged to prove a lab leak (or that gain-of-function work to create furin cleavage sites has been performed) as being more likely than an animal origin (eg. bat to intermediate animal to humans). 
 
It is appropriate to keep all hypotheses as to origins on the table, but the weighting towards an hypothesis has to be evidence-driven to drive further work. Such evidence can take a long while to accumulate."

Q: Is there a scientific consensus on the origins of the SARS-CoV-2 virus? 

"I'm not sure anyone has measured this consensus, but scientists, in general, have backed away from aspects of the lab leak theory, especially those conspiratorial in nature. I estimate that the majority of scientists with virology expertise support the animal origin, but appreciate that there is yet no ‘smoking gun’ to definitively answer the questions. The work needs to continue, collaboratively and openly, but the ability to do this is challenged by often aggressive commentary. Most pathogens that have emerged in the last 50 or so years are of animal origin. This includes a number of coronaviruses."

Q: How do scientists come to conclusions like this and is it normal for them to change their minds over time? 

"It’s about assessment of the data as it comes in, being prepared to shift ideas based on data (rather than supposition), and understanding that these studies take time. Whether people change their minds or not can be a complex issue, but sensible people balance the evidence. There’s nothing wrong with scientists having opinions about virus origins, but you have to have the science behind the opinions and understand how science works. It is normal for scientists to change their opinions on an issue over time as evidence (or lack of) emerges. Changing opinions does not indicate a cover-up or conspiracy and making such claims sets a bad precedent for planning for the next pandemic