More on the origin of SARS-CoV-2:
http://www.mattridley.co.uk/blog/where-did-the-virus-come-from/
New research has deepened, rather than dispelled, the mystery surrounding the origin of the coronavirus responsible for Covid-19. Bats, wildlife markets, possibly pangolins and perhaps laboratories may all have played some role, but the simple story of an animal in a market infected by a bat that then infected several human beings no longer looks credible.
A study published in early May by scientists at the Broad Institute in Cambridge, Mass., and at the University of British Columbia has uncovered an unusual feature of the virus’s recent development: It has evolved too slowly. The genomes of viruses sampled from cases during the SARS epidemic of 2002-2003 showed rapid evolutionary change during the early months of the epidemic, as the virus adapted to its new host, followed by much slower change later. By contrast, samples taken from recent cases of the new coronavirus, SARS-CoV-2, have comparatively few genetic substitutions compared with an early case from December.
The authors, Shing Hei Zhan, Benjamin Deverman and Yujia Alina Chan, write: “We were surprised to find that SARS-CoV-2 exhibits low genetic diversity in contrast to SARS-CoV, which harbored considerable genetic diversity in its early-to-mid epidemic phase.” This implies, they argue, that “by the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV.”… That leaves little time for evolutionary adaptation, so the months during which the virus fine-tuned its ability to infect human beings were presumably before this and somewhere other than the market in Wuhan…
Nikolai Petrovksy and colleagues at Flinders University in Australia have found that SARS-CoV-2 has a higher affinity for human receptors than for any other animal species they tested, including pangolins and horseshoe bats. He suggests that this could have happened if the virus was being cultured in human cells, adding that “We can’t exclude the possibility that this came from a laboratory experiment.”
Petrovsky came to this conclusion based on theoretical calculations of binding energies between the SARS-CoV-2 receptor binding domain (RBD) and angiotensin converting enzyme (ACE2), the receptor the virus uses to enter host cells:
https://arxiv.org/pdf/2005.06199.pdf
However, he doesn’t cite a study of actual binding affinities determined experimentally that comes to a very different conclusion:
https://www.nature.com/articles/s41423-020-0400-4#Fig4
The authors, using a recombinant RBD protein from SARS-CoV-2, reported that affinity for bat ACE2 was comparable to that for human, and most strikingly, the affinity for bat ACE2 was higher than the affinity for SARS-CoV, the 2003 virus, for human ACE2. Also, another study of binding energies came to the conclusion that SARS-CoV-2 could bind with reasonable affinity to a wide variety of non-human ACE2 sources, though they didn’t actually incorporate these sources in their models. This latter study also noted that receptors other than ACE2 are likely to be important in the viral infection:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221370/
Finally, even Petrovsky’s data show that the binding energy for the bat virus is comparable to that of several other species which have been shown to be capable of infection by SARS-CoV-2, including cats, which exhibit high infectivity and the characteristic lung disease. So I don’t find his arguments that SARS-CoV-2 could not have originated in bats convincing.
I'll just add that this is the nub of the argument Baltimore and I had earlier. He believes that SARS-CoV-2, or a virus very similar, could not have directly infected humans from bats, based largely on the supposed inability of the RBD to bind to ACE2. I don't regard this question as settled.
But in any case, Petrovsky’s suggestion that the virus could have been designed in a lab by passing it through cell culture is pretty far out. The Nature Med paper that was discussed in this thread earlier, which concluded the virus could not have been intentionally designed, did consider the cell culture scenario as a possibility that could have led to a lab accident releasing the virus to the local population. However, they provided several reasons against it, including that it would be very unlikely to have resulted in the polybasic cleavage site that is a key to viral entry to cells. And to this can be added that if a researcher wanted to design a highly infectious virus, direct genetic engineering would seem to be the more certain way to go, and as the Nature Med paper discussed, the structure of SARS-CoV-3 doesn’t seem to be consistent with that.
So what did happen? At present, the evidence is pointing tentatively to a chain of person-to-person infections occurring somewhere outside a city before somebody brought the virus to Wuhan, where the market acted as an amplifier. The first case could have been a rural farmer or possibly a bat researcher collecting samples for virologists. Or it is possible that another animal was involved in some way, with the virus bouncing between a farmer and his animals, or a wildlife smuggler and his poor pangolins.
Let me provide some more details for this scenario. As noted by the Nature Med paper, the RBD for a pangolin virus is much more similar to that for SARS-CoV-2 than the RBD for bats. The problem is that the rest of the pangolin virus has less sequence similarity. This leads Petrovsky, and some other scientists, to doubt that pangolins were the intermediate host that directly infected humans. Another possibility is that SARS-CoV-2 could have resulted from recombination between the bat virus—which has a very high sequence homology with SARS-CoV-2 outside of RBD--and the pangolin virus. This is possible, but would be rare. An infected bat or pangolin would have to become infected by a second virus, and Petrovsky provides some reasons why he thinks this is unlikely. However, if it did occur, the recombined virus might have jumped to humans from either bats or pangolins. The polybasic cleavage site might have evolved either in one of these animals, or possibly, in humans.
The only way to settle this debate definitively will be to demonstrate the existence of SARS-CoV-2, or a virus far closer to it in sequence than anything else yet reported, in some animal species. There could be such a virus in a bat, or a pangolin, or possibly some other species, but it could be a long time, if ever, that it’s found.
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