Instead of a single ominous variant lurking on the horizon, experts are nervously eyeing a swarm of viruses — and a new evolutionary phase in the pandemic.This time, it’s unlikely we will be barraged with a new collection of Greek alphabet variants. Instead, one or more of the multiple versions of the omicron variant that keep popping up could drive the next wave. They are different flavors of omicron, but eerily alike — adorned with a similar combination of mutations. Each new subvariant seems to outdo the last in its ability to dodge immune defenses.“It is this constant evolutionary arms race we’re having with this virus,” said Jonathan Abraham, an assistant professor of microbiology at Harvard Medical School.The pace of evolution is so fast that many scientists depend on Twitter to keep up. A month ago, scientists were worried about BA.2.75, a variant that took off in South Asia and spawned a cloud of other concerning sublineages. In the United States, BA.4.6 and BF.7 have been slowly picking up steam. A few weeks ago, BQ.1.1 started to steal the spotlight — and still looks like a contender to take over this fall in Europe and North America. A lineage called XBB looms on the sidelines, and threatens to scramble the forecast.To focus too much on any one possible variant is, many experts argue, missing the point. What matters is that all these new threats are accumulating mutations in similar spots in what’s called the receptor binding domain — a key spot in the spike protein where virus-blocking antibodies dock. If those antibodies can’t dock, they can’t block. Each new mutation gives the virus a leg up in avoiding this primary line of immune defense.
This is what was concerning as soon as COVID variants started popping up. This thing isn't over yet and it may never be.
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Evolution
For the science wonks, a bit about evolution and chemical space. The initial isolate of SARS-CoV-2 from Wuhan, China has a 29903 nucleotide, single stranded RNA genome. That is typical for a Coronavirus. That makes the COVID genome about average for viruses, some of which are smaller and some larger.
For each nucleotide in the 29903 locations, there are four possible nucleotides. If there is a mutation at one of those positions, that is evolution. Mutational evolution is blind and can kill the organism, have no effect or be helpful in some way. Selection for survival of non-lethal mutations in the next generations is not blind. Probably about 50% of mutations will kill the virus. That prevents that particular mutation from being passed to subsequent generations of viruses. Other mutations will have no effect on the virus due to degeneracy of the genetic code.
RNA viruses tend to have high mutation (evolution) rates, as this 2018 article, Why are RNA virus mutation rates so damn high?, discusses:
RNA viruses have high mutation rates—up to a million times higher than their hosts—and these high rates are correlated with enhanced virulence and evolvability, traits considered beneficial for viruses. However, their mutation rates are almost disastrously high, and a small increase in mutation rate can cause RNA viruses to go locally extinct. .... The fabled mutation rates of RNA viruses appear to be partially a consequence of selection on another trait, not because such a high mutation rate is optimal in and of itself.
Chemical space
Chemical space is a concept that refers to the space spanned by all possible molecules and chemical compounds adhering to a given set of construction principles and boundary conditions. Translated into English, it refers to all possible chemical structures that would fit within some defined space that a certain kind of molecule fits in. The thing to understand is that if one takes a fairly simple organic molecule such as a steroid and considers space for it and small to modest sized chemical variants (say up to ~500 Daltons[1]), the number of compounds that fit in that space are in the billions or trillions. One could loosely think of a chemical variant of a steroid as akin to a 'mutation' of the steroid.
The RNA genome of COVID is big compared to a steroid. The number of possible nucleotide mutations that COVID can contain in its chemical space is beyond gigantic, 4 to the 29903th power. Translated into English, that means 4 multiplied by 4 a total of 29903 times. That is the chemical space that the COVID genome has to play around and evolve in. 4 times 4 seven times is 16,384. Do that another 29,896 times and that's the space COVID has to evolve in. It's freaking HUGE.
In English, we are probably seeing just the very beginning of a period of rapid evolution of COVID in both humans and other animals it can infect. Translated into English, that means, get boosted every time a COVID booster vaccine contains RNA from the local or regional variant du jour that is infecting people and killing some of them and long hauling some others. Periodic new boosters are probably going to be coming out every ~5-10 months for a long time to come.
Darned evolution . . . . grumble, grumble . . . . . I've been vaccinated 5 times now against a grand total of three different COVIDS (the original strain and two omicron variants). That pipsqueakery is looking more and more like five shots is just the beginning. (cluck of grumpy disapproval)
Footnote:
1. Wikipedia says this about the size of chemical space for most pharmaceutical small molecule drugs:
A chemical space often referred to in cheminformatics is that of potential pharmacologically active molecules. Its size is estimated to be in the order of 1060 molecules. There are no rigorous methods for determining the precise size of this space. The assumptions [3] used for estimating the number of potential pharmacologically active molecules, however, use the Lipinski rules, in particular the molecular weight limit of 500. The estimate also restricts the chemical elements used to be Carbon, Hydrogen, Oxygen, Nitrogen and Sulfur. It further makes the assumption of a maximum of 30 atoms to stay below 500 Daltons, allows for branching and a maximum of 4 rings and arrives at an estimate of 1063.
Drug companies have made a heck of a lot more than 1,063 small molecule drug candidates. There have been well over 1063 variants of steroids, statins, antibiotics, lipids, vitamins, signal transmitters (melatonin, serotonin, etc.), etc. What has been made so far is a paltry ~49 million molecules as of July 2009. Some of those are drug candidates and some are for other purposes, e.g., food additives, plastics, catalysts, fuels, etc.
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