Wednesday, February 03, 2021

Molecular Demons and Gedankenexperiments

 What caffeine does to the brain. 

This question has popped up in short ‘vacant spaces’ (periods of quiet without other junk thoughts) the past few months with all these various virus variants (couldn’t resist the redundancy) popping up. This morning I saw this Twitter thread echoing the same questions. 

Then I had a Gedankenexperiment, a thought experiment. It appeared to me that if we can determine the molecular configuration of these virus variants, we should also be able to computationally predict those with high probability of becoming thermodynamically stable or increased fitness. This is used in predicting ligand docking (protein conformational fit with target protein, aka ‘ligand’) for drug development. 

We could then do automatic searches in newly submitted virus variant genome sequences for such candidates. Why else would one mutation and consequent conformation change in the spike protein be independently popping everywhere? Because it is a top thermodynamically fit conformation. And given the vast uncontrolled landscape in which the virus can ‘choose’ a random mutational configuration that increases transmission offers evidence that the virus is winning within a relatively short time. Especially when TWO adventitious mutations come together.  (See Twitter screenshots below)

It’s the Molecular Demons in information theory. 

Now back to mundane life.


Bats and viruses co-evolved!

Bats harbor many viruses and are a source of old and new emergent viral diseases in humans. Why? 

Two papers review the unique bat immunology summarize what we know thus far, as well as some as yet untested theories. In short, a bats' immune system is competent at confusing and tricking virus biology, and we don't quite fully understand all of it. 

Given their herculean immune system, viruses have to 'work hard' to fool and evade their immune system to actually cause disease, without, of course, killing them. (A virus that kills its host quickly is a dead end for a virus. It may be able to replicate a few times, but it can't transmit all those new virions to other hosts after it dies. So, dead end.)

One way for viruses to test the the bat immunity barriers is a random process of mutations and evolving behavior of the virus to successfully infect and replicate (fitness). I'll explain some of that in another post (information theory). One of those barriers is heat: viruses don't like heat. One immunity mechanism of mammals to fight virus infection is a fever. It may not kill all viruses, but it slows their biological trajectory to infect cells and replicate. Another component of that is it buys time for the rest of the immune system to respond and bring in the artilleries: antibodies, T-cells, etc. They attach to and disable or kill virus particles, and destroy already infected cells so that the little new virions inside the cells die, too. 

This was one of two approaches I used to rid very important plants (nuclear stock) of viruses before they went to certified nurseries for mass propagation and sale to industry growers and commercial nurseries (1980's-1990's). The approach was to expose a plant to high heat in a growth chamber, the hottest temperature it could stand, then take 1mm size pieces of the apical meristem (growing point) and grow them on tissue culture media containing an anti-viral, now known as Ribavirin. (Protocol developed by me and collaborator at university in CA.)

So now that I have established some credible evidence for the relationship of heat and viruses, albeit in plants, keep that in mind in this next part. 

Five scientists from US, UK and AUS methodically detailed over five pages a hypothesis of why bats and viruses co-evolved together(1). It actually makes sense, although not good for other mammals, especially humans. 

I recall from reading a review last year that viruses must be super-evolvers, aka go through many and numerous random mutations, in order to successfully infect and evade the bat immune system. By the time some of those viruses jump from bat to another animal, especially another mammal, they are super-duper viruses and often deadly to humans. 

Think about the first SARS-1 virus pandemic: a short-lived pandemic because it was less transmissible than the current SARS-2, but it was also more deadly. Short-lived because countries quickly contained and eliminated it. Also consider MERS, another bat coronavirus that emerged after SARS-1. Very deadly, and very poorly transmissible. It, too, was quickly controlled. That it was a deadly virus contributed to that. 

A decade later a new SARS-like virus emerges: it's highly transmissible, not as deadly, but it spreads like wildfire. It has, however, been able to also evade part of our immune system if the latter is in any way compromised, including obesity, diabetes, etc. Two other important factors helping it along is the relatively poor and/or belated human response in controlling spread, and its stealth: it can infect mammals, replicate and transmit to others while not inducing any or many symptoms. A caveat to the latter is we now know that some infected people of all ages may have had little to no symptoms but still developed some tissue damage (e.g. cardio myelitis, kidney, etc) that occurred slowly enough not to elicit recognizable symptoms. l can see this as a stealthy way to evade the bat immune system, too. 

Back to co-evolution of bats and viruses. This is a good summary from their abstract: 

 "We hypothesize that flight, a factor common to all bats but to no other mammals, provides an intensive selective force for coexistence with viral parasites through a daily cycle that elevates metabolism and body temperature analogous to the febrile response in other mammals. On an evolutionary scale, this host–virus interaction might have resulted in the large diversity of zoonotic viruses in bats, possibly through bat viruses adapting to be more tolerant of the fever response and less virulent to their natural hosts."

And, 

" We hypothesize that the increased metabolism and higher body temperatures of bats during flight might serve as an evolutionary adjuvant to their immune systems, providing a powerful selective force against virulence and promoting the diversity of viruses that infect bat populations. Perhaps counter-intuitively, this would enable bats to tolerate a greater diversity of viruses that have a high potential for virulence when transmitted to other mammals.

The hypothesis also might help explain why co-evolved bat viruses cause high pathogenicity when they spill over into other mammals because the bat-derived viruses might survive well under both febrile and cooler conditions."

Pretty respectable! Actually, it's brilliant. Don't blame the bats, or their viruses. It's just another biological ecosystem that we are not meant to get involved in. So leave the bats and their habitats alone. Many of those viruses become zoonotic because we tend to invade their habitats. 

Isn't science beautiful? 😁


1. Bat Flight and Zoonotic Viruses, O’Shea, et. al. Emerging Infectious Diseases, Vol. 20, No. 5, May 2014.

Further reading on bat immunology:

Novel Insights Into Immune Systems of Bats, A. Banerje, et. al. Frontiers in Immunology, Vol. 11, No. 26, January 24, 2020.

The bat-virus detente, R. Ehrenberg, Knowable Magazine, June 19, 2020.