A new paper in Nature Medicine has some incredibly important insights on the origins of SARS-CoV-2 (Covid19). I suggest a read, no matter how adverse you are to STEM topics. The paper is short, concise and compelling. It is easily digestible by the lay person. The authors’ hypothesis — Covid19 has been circulating in human populations before 2019. The central thesis is that the molecular evolution of a polybasic cleavage site (Critical for the viruses increased infectivity of human cells) is inconsistent with a short circulation time in humans. They also conclude, importantly, that this polybasic cleavage site was almost certainly not created in a lab by humans. (Whew!)
These cleavage sites are common in many human viruses like flu, RSV etc. and they work like a molecular machine. When un-cleaved the viral spikes are in a high energy state and upon engagement with a cell they’re quickly cleaved and release like a spring to harpoon their receptor (ACE2 in humans). The transition state is very rapid and this also makes generating protective antibodies more difficult.
The tone of the paper is measured and balanced. There are many more experiments that are needed to confirm a recent zoonotic transmission versus one longer ago. However, their molecular evolutionary analysis strongly support a much earlier transmission (years), followed by circulation in human populations. This longer time frame gave the virus a time to optimize cleavage sequence of the spike protein by standard evolutionary biology processes (Mutation — Selection — Mutation — Selection repeat).
Again, lots more work to do to prove anything one way or the other (Except the Bioweapon theory, thank goodness), but this is a hypothesis I’ve had since this all started.
Here are some conclusions from the authors:
Recent Zoonotic Transmission
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 coronaviruses22, 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.
Longer Circulation in Humans
It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the genomic features described above through adaptation during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off and produce a sufficiently large cluster of cases to trigger the surveillance system that detected it1,2.
All SARS-CoV-2 genomes sequenced so far have the genomic features described above and are thus derived from a common ancestor that had them too. The presence in pangolins of an RBD very similar to that of SARS-CoV-2 means that we can infer this was also probably in the virus that jumped to humans. This leaves the insertion of polybasic cleavage site to occur during human-to-human transmission.
Why is this important? Well, if SARS-CoV-2 has been circulating for much longer (a couple of years… more?) than our epidemiological models are out of whack at least at understanding the origins of the pandemic. It also has major implications on immunity for individuals and populations of indivduals. Also from the authors:
In the midst of the global COVID-19 public-health emergency, it is reasonable to wonder why the origins of the pandemic matter. Detailed understanding of how an animal virus jumped species boundaries to infect humans so productively will help in the prevention of future zoonotic events.
You should read the paper whether or not you have any background in science at all.