Did Covid-19 Emerge from the Wuhan Institute of Virology?

I’m going to address this topic with a minimum of drama. Go away if you’re a conspiracy buff. Stick around if you’re interested in a frank, somewhat introspective take on this question from a dude (albeit a low-impact dude) who has actually tinkered with viruses. For "safety", I'll spell out my #1 point right here: scientists have knee-jerk responses too. For even more safety, let me also spell out the following at the start: I still find it unlikely that the virus emerged from the Wuhan Institute of Virology.

There are two widely disseminated documents from credentialed authors providing arguments against and for the notion that Covid-19 was lab-generated. On the “against” side, we have a Nature article from March of 2020. On the “for” side, we have Nicholas Wade’s take.

I recall reading the Nature article last year, shaking my head at some of the refutations within, and then moving on to other topics. Wade’s article reminded me of my early skepticism. I’ll affirm two of Wade’s points:

1) The Nature article argues that the absence of a “previously used virus backbone”* within Covid-19 provides evidence that there was no lab-manipulation. Let me say: this is malarkey and, at best, an embarrassment for Nature. I’ve generated “backbone” free viruses myself (on dengue, to be specific). You insert the viral sequence into a plasmid, perform in vitro transcription, and infect cells with the resulting RNA. If you designed the plasmid correctly, there should be no evidence of “backbone.” Even if you erred, the virus may quickly shirk garbagy, non-optimal sequences upon multiple passaging (it can be frustrating to insert “loss of function” mutations into a virus, as the virus might dispense with them surprisingly quickly, if they don’t kill the virus from the very beginning).

In case anyone wishes to nitpick: yes, the 30kb length of coronaviruses makes ordinary plasmid insertion tricky, if not impossible. But there are plenty of methods to generate these long viruses without evidence of a backbone.

It’s hard to believe that the esteemed authors of the Nature article weren’t aware of these viral basics. Why did they choose to offer this lame argument?

2) The argument is made that the spike protein’s interaction with the ACE2 receptor is not optimal; therefore, Covid-19 could not be the product of manipulation.

Again, this is absurd. You have to assume that any and all lab experiments involving Covid-19 would involve insertion of the theoretically optimal (for ACE2 binding) spike protein sequence. Here’s an example of an experiment that I would consider interesting: perform some sort of guided evolution to generate a myriad of spike protein sequences, and test them ALL for both ACE2 affinity and infectivity**. Take the “winners” of this process, insert them into the virus, and write a paper. That’s just one of a near infinite number of experiments you could perform.

Let’s imagine that Dr. Evil is indeed behind the Covid-19 pandemic. He, like any competent virologist, would not automatically assume that the virus that best binds ACE2 has the highest potential to wipe out the human race. It wouldn’t surprise me at all to find that such a virus would be severely handicapped, refusing to let go of ACE2 at any step, and unable to perform its various pleiotropic functions.

Again, it’s odd that virologists would even attempt to pass this argument off in a Nature article.

There’s further lameness in the Nature article. For example: some of the mutations in Covid-19 haven’t been mentioned in the literature as yet. The idea, I guess, is that any lab-generated mutations would already have been described. I won’t even bother refuting that.

I have to question at least one of Wade’s other arguments, however. This regards the appearance of a furin cleavage site within the virus. This is supposed to be some sort of smoking gun for lab experimentation. The site is only 4 amino acids long. It’s not easy to estimate the probability that nature would come up with this mutation. Bear in mind that coronaviruses are the absolute champions of a process called “RNA recombination.” Without going into detail, the furin site doesn’t have to emerge via a step-wise series of mutations…it could enter in one fell swoop. Again, if there’s any “garbage” RNA left over from recombination, it could be eliminated quickly via evolution, including further recombination. If a paper attempts to address the furin cleavage site appearance from a probabilistic perspective, be skeptical about the underlying assumptions about what viruses do and don’t do.

On the other hand, everybody in the virology world inserts furin cleavage sites in their viruses and “replicons.” It’s something we do.

So, where do I stand? The most dramatic thing I can say without feeling guilty is this: we’re far from eliminating the possibility of a lab-generated Covid-19. Nothing I’ve seen convinces me that the virus couldn’t have emerged from the lab in Wuhan. Certainly not the Nature commentary.

I’ll take Wade at his word when he says that the Wuhan lab is China’s #1 coronavirus research facility. Rather odd, no? The counter-argument, I guess, might be that Wuhan is an optimal location to study coronaviruses, because that region of China is coronavirus heaven. I don't know.

To be clear, there’s a huge difference between a lab accident and intentional release. I don’t see any reason to assume the latter. How has China emerged from this mess? With an economy that’s not any stronger than anyone else’s, and the clunkiest vaccines on the market. Infections have been minimized in China, but the emergence of variants threatens that. India surprised everyone with a minimum of infections and deaths…last year.

Returning to the question of why Nature published its lame refutation, let me offer a bit of introspection. I don’t want a lab accident to be the cause of Covid-19 and I feel compelled to argue against the possibility. Just as a big-time developer tires of apparently nit-picky regulations covering endangered insect species, virologists don’t want further restrictions on their activities. We feel like we know what we’re doing. I suspect that the authors of the Nature article feel the same.

Finally, if you point a gun at my head and inquire as to the most probable source of Covid-19, I'd have to lean strongly on the side of natural origin. If you've read the above and have concluded I'd think otherwise, sorry to disappoint. There are plenty of arguments to support the natural origin of Covid-19; most of them, unfortunately, are not very accessible to layfolk. Here's the one that I find most difficult to refute: the 97% similarity between Covid-19 and its closest relative, RatG13, means that Covid-19 diverged from RatG13 no later than the early 1980's, and probably earlier. Thus, Dr. Evil (or Dr. Carelessness) would need to introduce about 1,000 mutations into RatG13 over the years. Whether by site-directed mutagenesis, lab passaging, or directed evolution, that's a figure that nearly unimaginable to virologists. Note also that these sequence differences are spread all over the viral genome; there's no sign that, for example, the spike protein was singled out for special treatment.

Given the above, if you're dead-set on blaming the Wuhan Institute, the only remotely possible scenario that I see would be the following: WIV scientists gathered the Covid-19 virus, or something very closely related, and brought it into the lab, whereupon it escaped with few or no mutations. Given that folks have not identified any virus with higher Covid-19 similarity than RatG13, one might surmise that such a virus may have been collected outside of China. There are indeed studies wherein WIV scientists gathered viruses outside of China (e.g. Africa). Now, if Covid-19 has a natural origin in China, what's more likely: it spread in the chaotic environment of a wet-market, or it spread in the controlled environment of a virology institute? In the case of import from outside of China, one could accuse the WIV of carelessly handling a virus to which the local population may have little immunity. All very speculative, with no evidence at all at this point.

*I note that some metavirology folks use the term "backbone" to refer to the conserved portions of a viral sequence. However, that's not the case in the Nature paper, which points to a paper on Coronavirus construction methods, not broad sequence comparisons, following the term "backbone".

**In fact, a bit of Googling shows that the folks at Wuhan are familiar with Selex, a method that lets evolution, as opposed to "rational design", determine an experimental outcome. Check out, for example, A SELEX-Screened Aptamer of Human Hepatitis B Virus RNA Encapsidation Signal Suppresses Viral Replication. To be clear, this particular paper optimizes RNA, not a protein.

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