Are the conclusions in "The proximal origin of SARS-CoV-2" legit?

In summary, the authors are saying the complete opposite of "human intervention".

While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding.

The interaction with ACE2 is taking place on the Spike protein (S) in both COVID-19 and SARS-Cov. The S protein is very different between COVID-19 and SARS both in terms of sequence and COVID-19 includes an additional furin cleavage site, meaning structurally it is quite distinct. The "computational analysis predicts" is difficult because there is no crystal structure for COVID-19 S protein therefore modelling ligand binding is essentially guess work, particularly as it comprises an additional (furin) cleaved domain. What the authors appear to conclude is that they cannot map ACE2-Spike binding of COVID-19 using an established SARS S protein structure. I assume they are homology modelling SARS-CoV onto COVID-19 S protein sequence data. In my personal opinion there is no way to homology model an additional furin protease cleavage site (furin is a host protease) so it would be difficult for "good fit" to occur, but it is just my opinion and the authors may have established methods to overcome this notable limitation, e.g. similar phenomena occur in influenza.

Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection..

Their conclusion of "natural selection" is not strictly accurate and should be "Darwinian positive selection", but its a small issue. What they are saying is Darwinian adaptation has occurred as opposed to "purifying selection, i.e. conservation. Thus they are definitely excluding human intervention because that is not "natural selection"

Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used

They appear to be saying that if a synthetic virus was constructed it would be created using an established reverse genetics system, and all those produced to date look nothing like COVID-19.

The phylogenetics argument is always a stronger argument than either of the above (although my opinion isn't entirely objective). Phylogeneticists have had a long history in opposing conspiracy theories, e.g. polio vaccination, HIV and the list goes on, so it is much more natural territory. An example of such an argument is here which @terdon helpfully pointed out.

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To address the questions of @Hans

Question 1

• Purifying selection = any evolutionary change is deleterious, so the virus is less able to transmit between humans. The vast majority of mutations are deleterious in classical Darwinian thinking*
• Adaptation = the amino acid change occurs to ensure the virus is better able to transmit between humans. In phylogenetics this is called 'positive selection' which is detected at a nucleotide level, this is however a very stringest test.

*, There is something called nearly neutral theory, but thats just complicated

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Question 2

What we are talking about is a virus infectious clone system. For a 30kb virus this would not be trival at all, but I agree for 10kb viruses it much easier. However, the phylogenetics are opposed to this, because SARS-CoV-2 is 5% divergent from a virus (RaTG13) isolated a long time before the current epidemic. You can't just engineer a virus that is 5% divergent from a bat virus across the entire genome and never been seen before. It would be a work of genius the likes we have never seen using bioinformatics as yet unheard of, because what would happen is you would encounter endless deleterious mutations. Even if you got over all those, how do you know what fitness traits you are aiming for?

Serial passage This level of change is doable by serial passage of the virus, but this leads to attenuation of virus (less dangerous) not increased fitness. The yellow fever virus vaccine was created in this way. Even if a virus had been serially passaged we could tell, because we know the mutational patterns of other serially passaged viruses.