The COVID Lab Leak Hypothesis

Humans abhore uncertaintly like nature abhores a vaccum. The exact origin of the SARS-CoV-2 virus that is responsible for the COVID pandemic is still a bit of a mystery, which leaves the issue open for lots of storytelling. And what makes for a better story: that the virus arose naturally, or that it was released from (and maybe engineered by) a Chinese lab? If I were making a movie, I know which plot I would use. However, my position is like that of a lot of scientists: that a lab leak is possible, but that a natural origin is more likely. It is nevertheless amusing how adamant some people are that the virus could not have just come from nature. The issue is a complicated one, but I think this article from FactCheck.org is a nice summary: The Facts – and Gaps – on the Origin of the Coronavirus

I just want to make a few additional comments. Some have asserted that the furin cleavage site in the Spike protein is evidence that the virus was engineered. More specifically, they point out that two arginine amino acids in a row are coded by the DNA sequence CGG. The FactCheck article addresses the CGG part (and if you want to dig in further, check out this archived Twitter thread), but I want to make something more explicit.

If you look at the figure of the furin cleavage site, you will see the DNA sequence of this region along with the amino acid translation. The insertion into the SARS-CoV-2 sequence is in red and underlined. Notice that the novel sequence appears to split apart the original serine codon, moving the A (green and italicized) to the end [1]. There doesn't seem to be any logical reason for this from a genetic engineering point of view. If you wanted to insert a DNA sequence to create those PRRA amino acids, you would most likely do it in a way that didn't disturb the surrounding codons, such as what I've shown on the bottom [2]. I'm not saying that this PROVES anything one way or another. I'm simply saying that this is a weird way to genetically engineer a furin site into the protein, and in my mind it cuts against the idea.

One further point not addressed in the article is the argument that the CGG-CGG sequence results in a restriction enzyme site (FauI) that could be useful in laboratory genetic manipulations. Since each arginine could be coded by any of 6 DNA codons, that means that there are 36 possible DNA sequences to code for RR. Isn't it suspicous that this one codes for the FauI site?

I took a look at all 36 possible combinations. To begin with, there are 2/36 ways to get a FauI site. So now we're down to 1/18 vs 1/36. But more importantly, I found that an additional 15 possible codon combinations resulted in the presence of a restriction enzyme site that was as good (or better) as FauI for the presumed laboratory manipulations [3]. In other words, that FauI site isn't so special after all because if all codon combinations were equally likely, it is roughly a flip of a coin as to whether a potentially useful restriction site would be created in the RR of the furin cleavage site. And that's not taking into account additional possibilites that could be created by different codons for the flanking P and A amino acids.

So for now I end where I started. I think it is most likely that SARS-CoV-2 was transmitted to humans in a natural chain of events, but a lab leak is theoretically possible and difficult to disprove. We may never know with absolute certainty.

Notes:
1. I say 'appears' because it might not be that straightforward. The A at the end of the new sequence isn't necessarily from the original serine.
2. To be clear, I'm not saying that you would expect that exact DNA or amino acid sequence if the furin site was a product of human engineering. I'm saying that it would be spliced in differently.
3. Since FauI is a 5-cutter (i.e. recognizes a sequence of 5 nucleotides), I only considered enzymes with a recognition site of at least 5 nucleotides.