Dec 7, 2022·edited Dec 7, 2022Liked by Brian Mowrey

Coronaviruses tend not to score aberrantly high for mutation rate in the overall roster of sequenced RNA viruses, but I understood that was because they have a fairly effective copy-correction mechanism. The 4 common human coronaviruses - as I was told - have a fairly unique protein that modulates this protection. This in essence causes significant more 'bad' (infertile/broken) copies, but allows also for faster mutation. (COVID-19 does not have this protein BTW.) Hence, why the 4 common coronaviruses could reinfect humans over and over again.

At least that was the theory as I was told.

But if not true, then how can we get reinfected? Current doctrine suggests that immunity in the humoral parts of our body is for life. For flu we know it is, so I'm skeptical our memory CD4+ and CD8+ T cells for common corona are not effective for decades too.

Then if not mutations, then either cellular immunity in the throat/mucous has weaker memory that doesn't last as long as humoral immunity, or it has perhaps a too slow response there. After all somehow we get sick again.

I also do know that a Canadian study that followed some people for 20 years showed that pretty much everybody gets reinfected again with these common cousins of COVID-19. The frequencies ranged from 3 times in these 20 years to yearly and likely depend very much on your age and lifestyle. But still some of them had a yearly re-infection. So it seems that either the mutation rate must be fast enough to throw us off, or mucous immunity is indeed very weak.

That is important, as it is a predictor for COVID-19. Its spike doesn't seem to mutate very fast and even the help it got with Omicron's release did not materially change its antibody resistance. So, as it has no animal reservoir, it will become extinct if it has to rely on that.

But if it can rely on our throat/mucous cellular immunity memory being weak enough, it can become the 5th common corona yearly sneeze.

In that sense it is surprising, so little research has been done on throat/mucous cellular immunity vs humoral immunity.

(For flu BTW I was told its mutation freedom is the result of it not targeting a large protein and hence not having a receptor binding protein but targeting an amino-acid. And hence, our antibodies must target the nucleus giving flu more freedom to make its skateboard moves. Until as you pointed out in pt 1 it runs out and runs into the wall anyway.)

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SARS-CoV-2 still has the proofreading protein - exoribonuclease / nsp13 https://zhanggroup.org/COVID-19/index.html#table1 But it's very difficult to ascertain the relationship between replication fidelity and mutation rate, because the latter is still going to be driven by stabilizing selection - extinction of mutants that score low at THPS.

So the virus only needs replication fidelity because without it, it would be in fatal mutagenesis territory. With it, it still exists as this kind of endless loop animation of a tree growing from a seed while sliding down a slope into oblivion only to deposit a seed further up on the slope where it started again, X infinity. Without RNA fidelity the sliding down the slope would be too fast and the tree wouldn't be there any more, that's all.

So it's difficult to really "measure" mutation rate in any meaningful sense. It will certainly reflect diversifying selection (as in, natural selection how normally meant, including for immune evasion) as well as permissiveness of environment (removal of innate immunity, as in cell culture) and so you can tentatively infer a few things but tentative is all it is. But what you can't say is, coronavirus ranks as high-mutate-y in the RNA viruses that we've looked at.

I think our immune systems intentionally periodically leave an "open door" for previously encountered viruses. The mechanics of this - reduced IgA secretion vs. generic reduced innate immune anti-viral response - aren't super important, but there's certainly more evidence for the latter (since it rises after viral infections, it must have been lower than max before the infection). Why? It encourages more temperate immune-disabling traits in viruses, so they aren't so murderous on our old and young. It also makes "updating" immune recognition of viruses less extreme, though more frequent. This is discussed in my big Immune Equilibrium post but I don't find all the ideas in the post as exciting right now as I did when I wrote it https://unglossed.substack.com/p/burned-all-my-notebooks

Flu spike proteins / HA's are 100% constrained in the residues that directly bind with sialic acid. But as these aren't contiguous with each other, it can still evade RBD antibodies by changing the adjacent residues, and so that is what it does. Nucleocapsid antibodies are not likely "sterilizing" given that the 1958 and 1968 reassortments brought in "new" (re-introduced) HA's and NA's, but not NP's, and were basically 100% immune evasive for everyone born after ~1900. And so in the Webster, et al. table that is shown in full in Pt. 1 the NP scores low for coding changes; it's pretty conserved.

I will edit this comment if I can remember which of my links is a good citation for the part about the RBD.

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Dec 3, 2022·edited Dec 3, 2022Liked by Brian Mowrey

I don't know much about biology. Especially molecular biology. I've studied theories of evolution in kind of an outsiderish amateur way, and I know some things about dynamical systems and computer security in a more "serious" way. Squinting down through the fog from great heights of abstraction, a few rambling observations:

A virus is dependent on its host to reproduce. To even a greater extent than other (always ecologically situated) organisms, it has to co-evolve. With such a small genome, it can't hoard up a big bag of tricks allowing it to jump around on the fitness landscape, the way bacteria are known to do. Maybe a little bag of tricks. This landscape is determined by the hosts, and big lumbering multicellular guys like us change pretty slowly. On the other hand, our complex proteomes offer a vast "attack surface".

Viruses are definitely "swarms" in that they reproduce rapidly, in great numbers. Swarming doesn't, by itself, get you out of local fitness optima. You have to still do well enough in the sub-optimal valleys to survive to climb the next hill. A delicate little hopeful-mutant virus might not survive the immune onslaught.

Cultural factors (vitamin deficiencies, therapeutic fads, agricultural practices or other contacts with potential peer hosts) influence the overall landscape for human viruses. There are opportunities for "punctuated equilibria" to arise, at the decade-to-century scale. More so during periods of rapid change in material culture.

Some of this is just recapitulating your previous article. Did I get the gist? I'm enjoying these! Keep doubting the great doubts.

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Dec 8, 2022Liked by Brian Mowrey

I don't want to disagree just to disagree, but when I look at the genome of covid it looks really complicated to me and as if it could change in a lot of ways; it seems like it has a big genome. And although we may not change much very quickly, our gut bacteria could, and it seems that that could have the same effect as our changing.

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Influenza (in birds) and polio viruses should also theoretically be sensitive to microbiomes - in the case of the latter, the virus uses bacteria to help it get inside cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222156/ - And so while it is true that bacteria are part of the "host" that the virus co-evolves with, this doesn't seem to drive much variability in the viruses. Or it could be that the three strains of polio virus were already the reflection of the different fitness landscapes that result from changes in gut bacteria, so the virus is forced to be a specialist rather than being a "modular" tool that can adapt to change. But it's still a good point; and the Omicrons especially probably changed interaction with microbiome chemical milueau in ways we will never understand but that might contribute to increasing who was susceptible to it, vs Wuhan.

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Dec 8, 2022Liked by Brian Mowrey

"Big" and "little" are of course relative terms. The "genome" of any virus ("exosome"?) is teeny-tiny compared to even bacteria. Brian's done a pretty reasonable job of showing why most changes in the viral DNA would cause it to not replicate, or do so less efficiently. That's what keeps it as it is.

Your other point, about the gut bacterial ecosystem, is quite good, and I think adds to what I was saying about changes in human culture and behavior changing the "terrain" so to speak.

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I see, and raise your rambling observations.

What is interesting about highly successful bacteria is that their "bag of tricks" are genes that have to insinuate into the genome. So there must be some dynamic in asexual populations that prunes against these success-granting, niche-broadening genes. Something kind of like a genetic guild system where the mediocre crowd out the excellent. So it was in the self-interest of excellent genes to develop or co-opt horizontal gene transfer skills. And a lot of the richness of life might have been impossible without this.

I do think the Omicrons were in a swarm condition when released. As my origins "fictional model" puts it (https://unglossed.substack.com/p/omicron-origins-part-2) there was something about the genome of whichever Omi "they" meant to drop that essentially made it unfit for scale production, so the only way to get enough virus was to accidentally amplify these co-infecting genomes. Just a placeholder for whatever really happened.

There is not much to add to your comments on swarms, but in the origins post I also discuss how "valley mutants," even if they can't replicate, can act as a distinct genome with a self-interest in mutating out of the valley. This is more descriptive than it is significant for the likelihood of valley mutants making it to their potential new optimum.

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Dec 4, 2022Liked by Brian Mowrey

I agree that your article https://unglossed.substack.com/p/omicron-origins-part-2 is very interesting. I remember reading it and it did add a new candidate hypothesis in the world of possibilities as it was unfolding.

I am now still flirting with the idea of Couey about the impossibility of building a 'Contagion/12 Monkeys' killer-tiger out of coronavirus clones. That article of yours is parsimonious with the scenario of someone trying to start from a 100% clone 'mix' trying to build an Armageddon only to stumble on the harsh reality that there is no way to serial passage a swarm into ... a tiger.

Hence the Omicron kitten :)

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Where I am leaning is that the virus does tend to degenerate as suboptimal mutations will still crowd out the "pure"/optimal genome in the short term, even if the optimal is the only one that persists long term. So when you have a wave, that will usually be short-term suboptimal mutants. I'm reluctant to say that this dynamic guarantees milder infection (so that prevalence of severe infections = artificial purity) or that the virus should totally die out, though I think it's possible either or both could be true.

So my model will allow that Couey's might be correct (severe infections should be rare) but also select the VOCs as the key evidence for multiple releases.

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I wonder what you think of the wave that is now passing through the Palo Alto (and Gilroy, and Sunnyvale, and San Jose) regions of CA. Here is the county website with the chart (you have to click the arrow t get to Palo Alto): https://covid19.sccgov.org/dashboard-wastewater.

The spike is astounding. It was like a rocket shot, and it ended up higher (!) than the summer Omicron surge. And now it is dropping as fast.

So, it could be a new variant, that many people had little immunity to. According to the state of CA we are now shifting from BA.5 to BQ.1 and BQ1.1: https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/COVID-19/COVID-Variants.aspx.

Or it could be the something else that people have caught (maybe an earlier covid infection) has made an old variant more catchable.

I do wonder if the sewage data still tracks case numbers. Since they aren't counting cases anymore, how can they know? Maybe there are three people in Palo Alto who are producing a huge amount of virus bits in their sewage and it isn't otherwise widespread. I do know plenty of sick people; they are mostly exhausted and nauseated; nothing respiratory. Some are covid positive (per RAT tests), but most aren't.

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