If SARS-CoV-2 evolved on a farm, then shouldn't it be particularly easy to find an intermediate host? No need for wilderness expeditions, just go to the barn and start swabbing. But more than a year later, we're still waiting.
And how does that explain its affinity for human ACE2? At least initially (right after it makes the zoonotic jump), the virus would probably show highest affinity for its animal host, and lower affinity for human ACE2. But SARS-CoV-2 shows highest affinity for human ACE2, and only primates with ACE2 very similar to humans show comparable affinity:
> The very high classification had at least 23/25 ACE2 residues identical to human ACE2 and other constraints at SARS-CoV-2 S-binding hot spots (Materials and Methods). The 18 species predicted as very high were all Old-World primates and great apes with ACE2 proteins identical to human ACE2 across all 25 binding residues.
Yes, the thing I'm most pissed off at China about are the destruction of samples and the lack of investigation towards finding intermediate animals.
And we know that we didn't detect the virus early, it didn't originate in the wet market event. That market event was just big enough right in the middle of Wuhan so it made it unmistakable.
The only way you get that high of an affinity is through serial passage through actual humans, not through the lab.
And this should not be that surprising since we know that it takes several months for the virus to spread before it starts to cause massive numbers of deaths, the IFR is actually low compared to SARS-1 and MERS, and it tends to spread asymptomatically and undetected.
We know pretty much for certain now that it was spreading cyrptically in the area around Wuhan in Nov, and I would bet that the zoonotic jump was Oct or earlier.
And that is also why I suspect an intermediate animal with a more similar ACE2 to humans like minks being involved. So serial passage through one of those animals to get it close, followed by serial passage through humans to refine it.
Surely passage in human cell culture or in mice genetically engineered to express human ACE2 would also create that selection pressure in the lab? If SARS-CoV-2 was manipulated in the lab, that's the usual explanation I've seen given for that affinity.
Mink seem very unlikely to me, since I've seen papers reporting evidence of host adaptation on mink farms:
So if the virus first evolved in mink, it would have to have evolved enough in humans not just to favor human ACE2 but also to lose its affinity for mink (to the point it has to regain it later), all during that couple months of cryptic spread.
And do you really think China is doing a bad job looking for the intermediate host? I don't think that's impossible--for example, the true origin could be some agricultural practice so horrible that they consider the present uncertainty better than disclosing that. Lab origin has become strongly associated with anti-China political sentiment, though. (That seems stupid to me, considering that the USA was funding the WIV; but here we are.) So I'd be surprised that the CCP would pass up a chance to disprove that.
And how does that explain its affinity for human ACE2? At least initially (right after it makes the zoonotic jump), the virus would probably show highest affinity for its animal host, and lower affinity for human ACE2. But SARS-CoV-2 shows highest affinity for human ACE2, and only primates with ACE2 very similar to humans show comparable affinity:
> The very high classification had at least 23/25 ACE2 residues identical to human ACE2 and other constraints at SARS-CoV-2 S-binding hot spots (Materials and Methods). The 18 species predicted as very high were all Old-World primates and great apes with ACE2 proteins identical to human ACE2 across all 25 binding residues.
https://www.pnas.org/content/117/36/22311