[ikt]

> The reason people think it was man-made have to do with strangely well-adapted protein sequences found on the virus with no known natural ancestors.

I was under the impression it was a natural sequence, I read about it way back in the beginning:

https://www.labmate-online.com/news/laboratory-products/3/br...

They found that the spike protein, a receptor-binding domain (RBD) that hooks onto host cells, had evolved to target ACE2, an enzyme founded on the outer surface of human cells that helps to regulate blood pressure. The team say the COVID-19 spike protein is so efficient at binding to human cells that it could only be a result of natural selection, not artificial engineering. Another tell-tale sign of natural origins is the molecular structure of COVID-19, which is substantially different from other known viruses. Rather than mimicking other viruses known to cause severe illness in humans, COVID-19 more closely resembles strains of coronavirus found in bats and pangolins.

"These two features of the virus, the mutations in the RBD portion of the spike protein and its distinct backbone, rules out laboratory manipulation as a potential origin for SARS-CoV-2" says Andersen.

[T-A]

The fact that the virus emerged already well adapted to human cells is a primary reason to suspect something's off. How could it be so well adapted right after making the jump to humans? And why have no closely related precursors been found in the wild?

A hypothesis which addresses both questions is that the virus evolved in humanized mice. That would also explain why it doesn't look genetically engineered; it wasn't, the mice were.

[sudosysgen]

Because it wasn't. It evolved to become this way. But on the path to this evolution it was not anything of note and no one would notice it.

[T-A]

Nobody noticed the precursors to SARS and MERS either, until those emerged in humans. But once they did, the precursors were quickly found in civets and camels, respectively.

A reminder: https://www.technologyreview.com/2021/03/26/1021263/bat-covi...

[sudosysgen]

It took half a decade for SARS. It wasn't immediate by any stretch of the imagination.

[T-A]

> It took half a decade for SARS. It wasn't immediate by any stretch of the imagination.

It took less than a year from outbreak to publication:

https://science.sciencemag.org/content/302/5643/276

[ctrlp]

Fauci emails reveal that Kristian Anderson originally raised concerns that it was a lab leak based on analysis of the virus before he was brought to heel by Peter Daszak. His later water-carrying for his GoF comrades was, I hope, the low point of his career.

[sterlind]

I don't understand that argument. Wouldn't serial passage through human lung cells produce efficient bindings? Is that sort of artificial selection not what they meant by "laboratory manipulation?" If they mean it's not the product of genetic engineering then sure, but leaving out the possibility of serial passage is misleading at best.

[sgt101]

The rapid evolution (gain) between the wild virus and Alpha and then Delta and now Delta+ indicates to me that if there was a gain of function experiment in the evolution of this virus then it was stopped far too early!

Also it seems tuned to infect Mustelidae - like the Mink in Belgium and Holland, and Ferret Badgers. The thing about that is that why would that be if you were passaging it through mice? Mustelidae are going to be a pretty difficult lab target in comparison to mice (they bite, they're big, they take a season to mature). The fact that Ferret Badgers were sold for meat in the Wuhan market is pretty interesting in this context (although none of the animals tested had Cov19).

[Amezarak]

Ferrets are commonly used in serial passaging and gain of function research.

https://nymag.com/intelligencer/article/coronavirus-lab-esca...

> In 2011, a tall, confident Dutch scientist, Ron Fouchier, using grant money from Fauci’s group at NIH, created a mutant form of highly pathogenic avian influenza, H5N1, and passaged it ten times through ferrets in order to prove that he could “force” (his word) this potentially fatal disease to infect mammals, including humans, “via aerosols or respiratory droplets.”

https://www.salon.com/2020/11/29/covid-19-mutations-spread-m...

> Because ferrets are the animals most like humans in terms of how their immune systems respond to influenza, scientists have experimented with them to make existing viruses more deadly, a biowarfare concept known as "gain of function" research.

[taneq]

I don’t know if it counts as “rapid” given the infected population and time scale involved. Getting from the original COVID-19 to Delta+ in a lab would take a long time compared to in the millions of infected humans ‘in the wild’.

[sudosysgen]

It's a single nucleotide mutation. I don't see how the dozens of nucleotides from before would have been easy but the last nucleotide would be impossible.

[loceng]

COVID-19 could be the base discovered that they saw in lab experiments gaining function, evolving rapidly, and so an ideal candidate as the base starting point - where now there's the four variants - and who knows how many more variants may escape with the mRNA vaccine most effective only for the original strain and arguably exponentially less effective against the evolving variants.

[wk_end]

That article is reporting on the letter by Andersen et al [1] that Nicolas Wade addresses in his article in the Bulletin of the Atomic Scientists [2] that was published a few weeks back, right around the time the lab hypothesis started gaining steam; it's still probably the strongest case that's been made for it. I think it dispatches the Andersen letter quite handily, but YMMV:

> A second statement that had enormous influence in shaping public attitudes was a letter (in other words an opinion piece, not a scientific article) published on 17 March 2020 in the journal Nature Medicine. Its authors were a group of virologists led by Kristian G. Andersen of the Scripps Research Institute. “Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus,” the five virologists declared in the second paragraph of their letter.

> [...] True, some older methods of cutting and pasting viral genomes retain tell-tale signs of manipulation. But newer methods, called “no-see-um” or “seamless” approaches, leave no defining marks. Nor do other methods for manipulating viruses such as serial passage, the repeated transfer of viruses from one culture of cells to another. If a virus has been manipulated, whether with a seamless method or by serial passage, there is no way of knowing that this is the case. Andersen and his colleagues were assuring their readers of something they could not know.

> [...] The two reasons the authors give for supposing manipulation to be improbable are decidedly inconclusive.

> First, they say that the spike protein of SARS2 binds very well to its target, the human ACE2 receptor, but does so in a different way from that which physical calculations suggest would be the best fit. Therefore the virus must have arisen by natural selection, not manipulation.

> If this argument seems hard to grasp, it’s because it’s so strained. The authors’ basic assumption, not spelt out, is that anyone trying to make a bat virus bind to human cells could do so in only one way. First they would calculate the strongest possible fit between the human ACE2 receptor and the spike protein with which the virus latches onto it. They would then design the spike protein accordingly (by selecting the right string of amino acid units that compose it). Since the SARS2 spike protein is not of this calculated best design, the Andersen paper says, therefore it can’t have been manipulated.

> But this ignores the way that virologists do in fact get spike proteins to bind to chosen targets, which is not by calculation but by splicing in spike protein genes from other viruses or by serial passage. With serial passage, each time the virus’s progeny are transferred to new cell cultures or animals, the more successful are selected until one emerges that makes a really tight bind to human cells. Natural selection has done all the heavy lifting. The Andersen paper’s speculation about designing a viral spike protein through calculation has no bearing on whether or not the virus was manipulated by one of the other two methods.

> The authors’ second argument against manipulation is even more contrived. Although most living things use DNA as their hereditary material, a number of viruses use RNA, DNA’s close chemical cousin. But RNA is difficult to manipulate, so researchers working on coronaviruses, which are RNA-based, will first convert the RNA genome to DNA. They manipulate the DNA version, whether by adding or altering genes, and then arrange for the manipulated DNA genome to be converted back into infectious RNA.

> Only a certain number of these DNA backbones have been described in the scientific literature. Anyone manipulating the SARS2 virus “would probably” have used one of these known backbones, the Andersen group writes, and since SARS2 is not derived from any of them, therefore it was not manipulated. But the argument is conspicuously inconclusive. DNA backbones are quite easy to make, so it’s obviously possible that SARS2 was manipulated using an unpublished DNA backbone.

> And that’s it. These are the two arguments made by the Andersen group in support of their declaration that the SARS2 virus was clearly not manipulated. And this conclusion, grounded in nothing but two inconclusive speculations, convinced the world’s press that SARS2 could not have escaped from a lab.

[1] https://www.nature.com/articles/s41591-020-0820-9

[2] https://thebulletin.org/2021/05/the-origin-of-covid-did-peop...

[sgt101]

1) A letter in Nature is not an opinion piece - it's a peer reviewed short article.

"Letter

A Letter reports an important novel research result, but is less substantial than an Article. Letters typically occupy four printed journal pages. This format begins with an introductory paragraph (not abstract) of 150 words maximum, summarizing the background, rationale, main results and implications. This paragraph should be referenced, as in Nature style, and should be considered part of the main text, so that any subsequent introductory material avoids too much repetition of the introductory paragraph. The text is limited to 2000 words, excluding the introductory paragraph, Methods, references and figure legends. As a guideline, Letters allow up to 30 references. Letters should have no more than 3–5 display items (figures and/or tables). A Methods section is published online-only, immediately following the main text and figures. It should be written in such detail that experiments can be reproduced by others.

Letters include received/accepted dates and may be accompanied by supplementary information. Letters are peer reviewed."

https://www.nature.com/nmat/about/content

It doesn't take long to discover the above - so why did Wade fail to do the work to check what it was he was attacking?

2) "Since the SARS2 spike protein is not of this calculated best design, the Andersen paper says, therefore it can’t have been manipulated." What I read was that the SARS2 protein doesn't work in theory, because the theory is wrong (a bad approximation that is subject to intensive research world wide - protein dynamics are a big step beyond the art of protein structure prediction as I understand it.) It would be irrational for a team to attempt to build a SARS2 binding protein - essentially they would be shooting into the dark. The space of random search for this kind of structure isn't just huge - it's incomprehensible, consequently the chance of coming upon the SARS2 protein by chance is vanishingly small. If Chinese scientists did have the capability to do dynamic bindings calculations that would have found the SARS2 spike I would think that they would be employing them for a number of decisive military innovations - as well as staggering commercial gain. We know that the Russians capabilities to do hypersonic flow calculations because we see this in their torpedoes and ICBM's.... we would see similar evidence in China for this. We don't.

3) "With serial passage, each time the virus’s progeny are transferred to new cell cultures or animals" but this is addressed Anderson et-al; in an entire section of their article : "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 vivo17. 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 system18."

Now - I count three arguments in that section of the article alone. Two of them are flatly ignored by Wade. It's almost as if he hasn't actually read Andersen's work.

[wk_end]

Look at the Andersen letter on Nature - it’s technically classified as “correspondence”, not a “letter”. So the relevant quote from your source is:

> The Correspondence section provides a forum for comment on issues relevant to the journal’s community. This format may not be used for presentation of research data or analysis. A Correspondence should not exceed more than two printed pages and can range from 300-800 words; it is limited to one display item and up to 10 references. Article titles are omitted from the reference list. Correspondence may be peer-reviewed at the editors’ discretion.

Given that, I don’t think Wade’s characterization is dishonest.

It’s funny that you’re accusing Wade of not reading Andersen et al’s work, because it reads like you didn’t read his work - or even the excerpt that I posted!

For instance, take this notion that SARS-CoV-2’s spike protein doesn’t “make sense” or that “the theory is wrong” and can’t explain it. First of all, that’s not what Andersen et al actually says at any point. It really does just say:

> [while] 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. 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

That is to say, accusing Wade of not reading the work he’s criticizing because he doesn’t address an argument made elsewhere (where?) is unfair at best.

That said, even if Andersen et al were saying what you’re saying they did, Wade clearly accounts for this in the very excerpt I posted: he claims that GoF researchers simply don’t design proteins like this. Serial passage as a mechanism in particular doesn’t seem to require some fantasy of Chinese scientists expertly constructing some bizarro inexplicably dangerous spike protein by hand.

I can’t defend Wade’s failure to connect these dots himself, but all of the other claims in the letter are similarly addressed explicitly or implicitly. Humanized mice, discussed in the article, have immune systems; if serial passage were conducted in them it wouldn’t be surprising if it looks like an immune system were indeed involved. And on the flip side, the polybasic furin cleavage site, which Andersen et al claim as evidence that the virus must be natural is actually one of the most damning pieces of evidence for manual manipulation: it’s well understood that this could make a virus more easily infect humans, that scientists know how to artificially add them, and its particular construction in SARS-CoV-2 (as discussed by Wade in great detail) looks very artificial.

Putting that together: WIV scientists deliberately adding the furin cleavage site to some bat coronavirus, possibly (though not necessarily!) RaTG13, to help it jump species and then conducting serial passage in humanized mice is a straightforward and plausible origin story for SARS-CoV-2, in line with the sort of work we know WIV was doing, that accounts for Andersen et al’s concerns completely.