What's the evidence against SARS-CoV-2 being engineered by humans?

Question

A couple of colleagues suggested in a discussion that the virus that causes COVID-19 appears to be made by humans, since nature could not have produced such an efficient virus — that spreads so fast and whose patients are contagious quite some time before showing signs of infection.

Since my knowledge of biology is very limited, my only counterargument for such a conspiracy theory was along the following lines:

• there is a consensus that the most probable source of the first infection was in an animal market in China.

• since that animal market was actually composed of a plethora of animals belonging to various species (mixed with humans), a virus had a bigger chance of evolving a mutation that might infect an individual from another species (a thing that is way less unlikely in the wild since many of those animals do not sit close to each others or next to humans).

Clearly, I have made a little story that might be quite far away from how SARS-CoV-2 infected humans, so I am interested in a scientific arguments to support my cause.

Question: What are the main scientific arguments that can be used to debunk COVID-19 being engineered by humans?

Answers that also include explanations more accessible to laymen are greatly welcomed.

Answer 1

At the moment, there is very little scientific literature about this, but I found two papers that address the problem and are fairly easy to understand. You can find them in the references. Reference 1 is probably the most interesting and is the basis for this answer. Edit: It is also interesting to read reference 2 on the origin of SARS-CoV-2; the article also addresses some of the conspiracy theories.

As far as I can see, there are a few major points taken up by conspiracy theories.

1. SARS-CoV-2 leaked from a lab in which research on the Bat CoV (RaTG13) was done:

Unlikely, since the viruses share only around 96% sequence homology, which translates into more than 1100 sites where the sequence of SARS-CoV-2 viruses is different from RaTG13. The mutations are distributed throughout the viral genome in a natural evolutionary pattern, making it highly unlikely that SARS-CoV-2 is a direct descendant from RaTG13. For comparison, the original SARS-CoV and the intermediate host palm civet SARS-like CoV from which it originated shared 99.8% sequence homology, showing a much closer relation.

2. The S (spike) protein from bat SARS-CoV cannot be used to enter human cells via the human ACE2 receptor and therefore has been adapted in the lab:

This is untrue, since a 2013 study of a novel bat coronavirus was published showing the ability of the virus to enter cells via the ACE2 receptor. See reference 3 for details.

3. The spike protein of SARS-CoV contains a unique inserted sequence (1378 bp) located in the middle of its spike glycoprotein gene that had no match in other coronaviruses:

As shown in reference 4, the sequence comparison of the SARS-CoV-2 with closely related other coronaviruses shows that this sequence is not unique to the new virus but is already present in older strains. It shows some difference due to inserted mutations.

4. The claim that SARS-CoV-2 contains four insertions from HIV-1:

The paper claiming this has now been retracted due to severe criticism, and additionally a renowned HIV expert published an analysis (reference 5) demonstrating that the HIV-1 claimed insertions are random rather than targeted.

5. The claim that the SARS-CoV-2 virus is completely man-made:

To design such a "weapon grade" virus in the lab, the design would usually start from a known virus backbone and then introduce logical changes (for example, complete genes from other viruses). This cannot be seen in the genome of the virus; rather, you see randomly distributed changes throughout the genome coming from virus evolution and not directed cloning. It is more likely that this virus originates from the recombination of a bat CoV (to which it is closely, but not directly related) and another, not yet known CoV in an intermediate host, like the palm civet for the 2003 CoV.

References:

1. No credible evidence supporting claims of the laboratory engineering of SARS-CoV-2
2. The proximal origin of SARS-CoV-2
3. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor
4. Is SARS-CoV-2 originated from laboratory? A rebuttal to the claim of formation via laboratory recombination
5. HIV-1 did not contribute to the 2019-nCoV genome

Answer 2

If you need more [counter]evidence, there's a newer paper "The proximal origin of SARS-CoV-2" by Andersen et al. (March, 17) that touches on the same topic. The paper brings up two reasons why SARS-CoV-2 is not "made in a lab". The first is the (relative) [in]efficiency of its spike protein; the second is somewhat more complex to explain and is related to cleavage site in said protein that is usually an indicator of rapid (but natural) evolution; this cleavage site is actually not found in the most related relatives of SARS-CoV-2 (the B-lineage of the betacoronaviruses), but only in the more distant A-lineage. Features related to this cleavage site also suggest that it was probably shaped by an immune system, something unlikely to happen in mere cell cultures.

Our comparison of alpha- and betacoronaviruses identifies two notable genomic features of SARS-CoV-2: (i) on the basis of structural studies and biochemical experiments, SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2; and (ii) the spike protein of SARS-CoV-2 has a functional polybasic (furin) cleavage site at the S1–S2 boundary through the insertion of 12 nucleotides, which additionally led to the predicted acquisition of three O-linked glycans around the site.

The receptor-binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome. Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and for determining the host range of SARS-CoV-like viruses. [...] Five of these six residues differ between SARS-CoV-2 and SARS-CoV. On the basis of structural studies and biochemical experiments, SARS-CoV-2 seems to have an RBD that binds with high affinity to ACE2 from humans, ferrets, cats and other species with high receptor homology. [cites 6 references in support]

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 [citing: Wan et al.] and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding. Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation.

Wan et al. indeed mention that

several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission.

Basically what Andersen et al. say is that if someone made SARS-CoV-2 in the lab, they could have made it better in terms of human transmission by using what we knew from previously studied SARS-like viruses, instead of coming up with a completely new and somewhat inefficient solution.

Another argument of Andersen et al. (somewhat similar to Chris' #4), which they only mention briefly is that

if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used. However, the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone.

As I mentioned in my first paragraph, Andersen also discuss that SARS-CoV-2 "borrows" a fairly distant feature, namely a polybasic cleavage site, which is only found in more remote "cousins" of the A-lineage of betacoronavirues:

The second notable feature of SARS-CoV-2 is a polybasic cleavage site (RRAR) at the junction of S1 and S2, the two subunits of the spike [...]. This allows effective cleavage by furin and other proteases and has a role in determining viral infectivity and host range. [...] Polybasic cleavage sites have not been observed in related ‘lineage B’ betacoronaviruses, although other human betacoronaviruses, including HKU1 (lineage A), have those sites.

And if you think this was an international manipulation, the trouble is that we still have no precise idea what that cleavage site does in SARS-CoV-2, although cleavage sites observed in other coronaviruses are thought responsible for cross-species infectivity and also are thought to be related to rapid evolution in highly dense populations.

Neither the bat betacoronaviruses nor the pangolin betacoronaviruses sampled thus far have polybasic cleavage sites. Although no animal coronavirus has been identified that is sufficiently similar to have served as the direct progenitor of SARS-CoV-2, the diversity of coronaviruses in bats and other species is massively undersampled. Mutations, insertions and deletions can occur near the S1–S2 junction of coronaviruses, which shows that the polybasic cleavage site can arise by a natural evolutionary process. For a precursor virus to acquire both the polybasic cleavage site and mutations in the spike protein suitable for binding to human ACE2, an animal host would probably have to have a high population density (to allow natural selection to proceed efficiently) and an ACE2-encoding gene that is similar to the human ortholog.

[...]

The acquisition of both the polybasic cleavage site and predicted O-linked glycans also argues against culture-based scenarios. New polybasic cleavage sites have been observed only after prolonged passage of low-pathogenicity avian influenza virus in vitro or in vivo. Furthermore, a hypothetical generation of SARS-CoV-2 by cell culture or animal passage would have required prior isolation of a progenitor virus with very high genetic similarity, which has not been described. Subsequent generation of a polybasic cleavage site would have then required repeated passage in cell culture or animals with ACE2 receptors similar to those of humans, but such work has also not previously been described. Finally, the generation of the predicted O-linked glycans is also unlikely to have occurred due to cell-culture passage, as such features suggest the involvement of an immune system.

Answer 3

A conclusive proof of CoV2's artificial origin would be finding lab records or samples dated before the epidemic, or finding an obvious unique marker sequence in the cDNA. To date there is no such conclusive proof.

All other "proofs" I have seen are just hypotheses, and they all can be explained by natural processes too. In fact, if your opponents refuses to consider natural causes, such hypotheses become infalsifiable, like the Russel's teapot: any naturally occurring coronavirus can also be recreated in the lab. Here's an article from 2003 in which researchers describe how they have recreated SARS-CoV using a panel of cDNA fragments, which produced a virus identical to the natural strain (except for marker mutations).

For instance, here's a closer look on the infamous "unique sequence in S protein" (called Receptor Binding Domain) of CoV2, compared to RaTG13 (bat coronavirus) and MP789 (pangolin coronavirus):

source

As you can see, the "uniqueness" of this sequence is questionable if we consider that RaTG13 could have combined with a part of MP789 (in the red frame) and accumulated some additional mutations to produce CoV2. The conclusion that such recombination happened artificially can only be drawn if you see no possibility those two viruses could have met in the wild.

There's also a philosophical side to what should be considered "artificial". Two viruses recombining in the wild is natural. How about two viruses recombining in a market? What about a lab cage or waste?