Wherever Did the Pandemic Go?

Covid has attenuated. But is that from its own evolution, or from our immune reactions to it?

Looking at recent gatherings such as the political conventions and the Olympics, it is evident that the pandemic is over. A graph from the CDC says that mortality from Covid-19 is now similar to influenza- not great, but not catastrophic either, running at roughly a thousand deaths a week, and this with negligible public precautions.

Overall mortality of Covid-19 in the US.

A fundamental scientific and policy question about this is why: did the virus evolve to a less virulent state, or have we evolved (or engineered) enough immunity to fend off the worst? Even after the intense focus on this virus and all the research that has been done, this is a difficult question to answer. There has been a parade of variants, one supposedly more virulent and dangerous than the last, except that we are less affected and increasingly able to ignore them. The scientific community is evidently divided on this causal question, with no good ways to test these basic hypotheses.

I am personally very much in the viral evolution camp, believing that this virus has on its own evolved to be less virulent, even as it gained in transmissibility and ability to evade our immune systems. Surveillance of the virus shows quite high levels this summer, even while its effects are minor, overall. The logic is that this kind of virus does not gain from people shutting themselves up at home and being miserable, let alone dying. Much better for us to be surreptitiously infected and infectious, and able to go about our business, at work and play. We recall that Covid was markedly more lethal at the very outset of the pandemic, before the first set of variants developed. Other cold-type viruses seem to have followed a similar path, and the many zoonotic infections we have picked up (including this one) come from other organisms which carry these pathogens without much difficulty, doubtless after a long evolutionary standoff.

But the graph above makes a different argument, since the vaccines came online around the spring of 2021, reached about fifty percent of the population in late 2021, which is followed by the dramatic drop in covid mortality in spring of 2022. Some researchers point to the lack of attenuation of other pathogens, like HIV, tuberculosis, and smallpox, to say that the evolutionary argument does not hold water. After a pathogen has replicated and spread, (in the case of Covid, in the first week of infection, roughly), it doesn't care what happens to the host- literally whether it lives or dies. They would say that it was the immunization campaign that saved us, and continued infection leading to herd immunity that has created a population increasingly resistant to Covid mortality.

Testing these hypotheses would require Covid-naive populations, which would be ideally split into two study sets, one with vaccination followed by infection, and the other infected directly. This kind of thing may happen as a natural experiment somewhere, and perhaps the closest we can come is the release of Covid restrictions in China. In late 2022/early 2023, China switched abruptly from a zero-tolerance policy of social contact and infection, to a zero-tolerance policy towards bad publicity and accurate mortality reporting, while relaxing anti-Covid restrictions. The result was a surge in death rates, to levels estimated to be higher than those elsewhere, including in the US. This argues that during the restrictive period, the virus had not significantly attenuated via its natural evolution, though then the subsequent mass infection and inoculation did eventually lead in China, as it has elsewhere, to the lower mortality rates seen around the world. 

So, despite the rapidity of viral evolution, one has to conclude that over the short term, the immune hypothesis appears superior to the viral evolution hypothesis, as an explanation of general attenuation of Covid mortality. (Robert Kennedy may disagree, of course!) The evolution of virulence is closely related to the whole lifecycle of a pathogen, especially the way it spreads, making comparisons with other pathogens hazardous. Respiratory pathogens have the opportunity to spread without damaging the host too much, and that seems, in principle, like an advantageous evolutionary path. So I would still hypothesize that over the long term, Covid will settle into a less virulent form that triggers less immune activation (the most lethal aspect of Covid infection), in favor of high transmission and co-existence with our immune systems. Other viruses seem to have followed a similar path. How it interacts with further naive populations would be dispositive, though there may not be any left at this point.

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Aging and Death

Our fate was sealed a very long time ago.

Why do we die? It seems like a cruel and wasteful way to run a biosphere, not to mention a human life. After we have accumulated a lifetime of experience and knowledge, we age, decline, and sign off, whether to go to our just reward, or into oblivion. What is the biological rationale and defense for all this, which the biblical writers assigned to the fairy tale of the snake and the apple?

A recent paper ("A unified framework for evolutionary genetic and physiological theories of aging") discusses evolutionary theories of aging, but in typical French fashion, is both turgid and uninteresting. Aging is widely recognized as the consequence of natural selection, or more precisely, the lack thereof after organisms have finished reproducing. Thus we are at our prime in early adulthood, when we seek mates and raise young. Evolutionarily, it is all downhill from there. In professional sports, athletes are generally over the hill at 30, retiring around 35. Natural selection is increasingly irrelevant after we have done the essential tasks of life- surviving to mate and reproduce. We may participate in our communities, and do useful things, but from an evolutionary perspective, genetic problems at this phase of life have much less impact on reproductive success than those that hit earlier. 

All this is embodied in the "disposable soma" theory of aging, which is that our germ cells are the protected jewels of reproduction, while the rest of our bodies are, well, disposable, and thus experience all the indignities of age once their job of passing on the germ cells is done. The current authors try to push another "developmental" theory of aging, which posits that the tradeoffs between youth and age are not so much the resources or selective constraints focused on germ cell propagation vs the soma, but that developmental pathways are, by selection, optimized for the reproductive phase of life, and thus may be out of tune for later phases. Some pathways are over-functional, some under-functional for the aged body, and that imbalance is sadly uncorrected by evolution. Maybe I am not doing justice to these ideas, which maybe feed into therapeutic options against aging, but I find this distinction uncompelling, and won't discuss it further.

A series of unimpressive distinctions in the academic field studying aging from an evolutionary perspective.

Where did the soma arise? Single cell organisms are naturally unitary- the same cell that survives also mates and is the germ cell for the next generation. There are signs of aging in single cell organisms as well, however. In yeast, "mother" cells have a limited lifespan and ability to put out daughter buds. Even bacteria have "new" and "old" poles, the latter of which accumulate inclusion bodies of proteinaceous junk, which apparently doom the older cell to senescence and death. So all cells are faced with processes that fail over time, and the only sure bet is to start as a "fresh" cell, in some sense. Plants have taken a distinct path from animals, by having bodies and death, yes, but being able to generate germ cells from mature tissues instead of segregating them very early in development into stable and distinct gonads.

Multicellularity began innocently enough. Take slime molds, for example. They live as independent amoebae most of the time, but come together to put out spores, when they have used up the local food. They form a small slug-like body, which then grows a spore-bearing head. Some cells form the spores and get to reproduce, but most don't, being part of the body. The same thing happens with mushrooms, which leave a decaying mushroom body behind after releasing their spores. 

We don't shed alot of tears for the mushrooms of the world, which represent the death-throes of their once-youthful mycelia. But that was the pattern set at the beginning- that bodies are cells differentiated from the germ cells, that provide some useful, competitive function, at the cost of being terminal, and not reproducing. Bodies are forms of both lost energy and material, and lost reproductive potential from all those extra cells. Who could have imagined that they would become so ornate as to totally overwhelm, in mass and complexity, the germ cells that are the point of the whole exercise? Who could have imagined that they would gain feelings, purposes, and memories, and rage against the fate that evolution had in store for them?

On a more mechanistic level, aging appears to arise from many defects. One is the accumulation of mutations, which in soma cells lead to defective proteins being made and defective regulation of cell processes. An extreme form is cancer, as is progeria. Bad proteins and other junk like odd chemicals and chemically modified cell components can accumulate, which is another cause of aging. Cataracts are one example, where the proteins in our lenses wear out from UV exposure. We have quite intricate trash disposal processes, but they can't keep with everything, as we have learned from the advent of modern chemistry and its many toxins. Another cause is more programmatic: senescent cells, which are aged-out and have the virtue that they are blocked from dividing, but have the defect that they put out harmful signals to the immune system that promote inflammation, another general cause of aging.

Aging research has not found a single magic bullet, which makes sense from the evolutionary theory behind it. A few things may be fixable, but mostly the breakdowns were never meant to be remedied or fixed, nor can they be. In fact, our germ cells are not completely immune from aging either, as we learn from older fathers whose children have higher rates of autism. We as somatic bodies are as disposable as any form of packaging, getting those germ cells through a complicated, competitive world, and on to their destination.

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Oh, to Be Normal

It is a greater accomplishment than commonly appreciated.

The popular media make a fetish of condemning normality. Chase your dream, dare to be different, don't settle for average. Well, that is laudable, and appropriate for the occasional genius, but militates against much larger forces toward uniformity. Just look at styles in clothing, cars, architecture. "Keeping up" with fashions and the times is a marker of, not just normality, but of being alive and part of the larger social community. Achieving normal means not being fossilized in wig and breeches, or bell bottoms. The period of middle school and high school is when these pressures are most acute, as children find places in the wider society, staking their claim with clothing and all the other markers of being "normal". Especially against parents, who have by this time fallen a little back in their ability or desire to keep up with current standards.

But the point I am more interested in is genetic. In genetic terms, normal is typically stated as "wild-type", which is the opposite of mutant. Any particular gene or trait can be construed as normal or defective, with the possibility of being improved in some way over the "wild-type" being exceptionally rare. But summed over an entire genome, one can appreciate that not every gene can be normal. We all have mutations, and thus deviate from normal. In this sense, normality is an impossible, unattainable standard, and as anyone can observe, we all labor under some kind of deficiency. The only question is how severe those deficiencies are, relative to others, and relative to the minimum level of competence we need to survive.

That is where these two threads come together. Young people are continually competing and testing each other for fitness, gauging each other's ability to keep up with the high standard that constitutes "normal" for a culture. It is the beauty queens, and the popular kids, who find themselves at the top of the heap, shining standards of normality in a sea of mediocrity and deficiency. At least until they find out that they might have other, less visible weaknesses, like, perhaps, alcoholism. 

So, not to be all conformist about it, but for all the praise showered on diversity and innovation, there is a lot to be said for standards of normality, which are rather higher than they seem. They actually set significant challenges for everyone to aspire to. They represent, for example, a wide gamut of competencies that undergird society- the ability of people to get along in professional and intimate settings, and the basic knowledge and judgement needed for a democratic political system. Making up for one's deficiencies turns out to be a life-long quest, just as significant as making use of extraordinary gifts or pursuing competitive excellence in some chosen field.

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Modeling Cell Division

Is molecular biology ready to use modeling to inform experimental work?

The cell cycle is a holy grail of biology. The first mutants that dissected some of its regulatory apparatus, the CDC mutants of Saccharomyces cerevisiae (yeast), electrified the field and led to a Nobel prize. These were temperature sensitive mutants, making only small changes to the protein sequence that rendered that protein inactive at high temperature (thus inducing a cell cycle arrest phenotype), while allowing wild-type growth at normal temperatures. In the fifty years since, a great deal of the circuitry has been worked out, with the result that it is now possible, as a recent paper describes, to make a detailed mathematical model of the process that claims to be useful in the sense of explaining existing findings in a unified model and making predictions of places to look for additional actors.

At the center of this regulatory scheme are transcription activators, SBF/MBF, that are partly controlled by, and in turn control the synthesis of, a series of cyclins. Cyclins are proteins that were observed (another Nobel prize) to have striking variations in abundance during the cell cycle. There are characteristic cyclins for each phase of the cell cycle, which goes from G1, a resting phase, to S, which is DNA replication, to G2, a second resting phase, and then M, which is mitosis, which brings us back to G1. Cyclins work by binding to a central protein kinase, Cdc28, which, as regulated by each distinct cyclin, phosphorylates and thus regulates distinct sets of target proteins. The key decision a cell has to make is whether to commit to DNA replication, i.e. S phase. No cell wants to run out of energy during this process, so its size and metabolic state needs to be carefully monitored. That is done by Cyclin 3 (Cln3), Whi5, and Bck2, which each influence whether the SBF/MBF regulators are active. 

Some highly simplified elements of the yeast cell cycle. Cyclins (Cln and Clb) are regulators of a central protein kinase, Cdc28, that direct it to regulate appropriate targets at each stage of the cell cycle. Cyclins themselves are regulated by transcriptional control (here, the activators SBF and MBF), and then destroyed at appropriate times by proteolysis, rendering them abundant only at specific times during the cell cycle. Focusing on the "START" process that starts the process from rest (G1 phase) to new bud formation and DNA replication (S phase), Cln3 and Bck2 respond to upstream nutritional and size cues, and each activate the SBF/MBF transcription activator.

As outlined in the figure above, Cyclin 3 is the G1 cyclin, which, in complex with Cdc28 phosphorylates Whi5, turning it off. Whi5 is an inhibitor that binds to SBF/MBF, so the Cyclin 3 activation turns these regulators on, and thus starts off the cell cycle under the proper conditions. Incidentally, the mammalian version of Whi5, Rb (for retinoblastoma), is a notorious oncogene, that, when mutated, releases cells from regulatory control over cell division. SBF and MBF bind to genes for the next series of cyclins, Cln1, Cln2, Clb5, Clb6. The first two are further G1 cyclins that orchestrate the end of G1. They induce phosphorylation and inactivation of Sic1 and Cdc6, which are inhibitors of Clb5 and Clb6. These latter two are then the initiators of S phase and DNA replication. Meanwhile, Cln3 stays around till M phase, but is then degraded in definitive fashion by the proteases that end M phase. Starvation conditions lead to rapid degradation of Cln3 at all times, and thus to no chance of starting a new cell cycle.

Charts of the abundance of some cyclins through the cell cycle. Each one has its time to shine, after which it is ubiquitinated and sent off to the recycling center / proteasome.

Bck2 is another activator of SBF/MBF that is unrelated to the Cln3/Whi5 system, but also integrates cell size and metabolic status information. Null mutants of Cln3 (or Bck2) are viable, if altered in cell cycle, while double null mutants of Cln3 and Bck2 are dead, indicating that these regulators are each important, in a complementary way, in cell cycle control. Given that little is known about Bck2, the modelers in this paper assume various properties and hope for the best down the line, predicting that cell size (at the key transition to S phase) is more affected in the Cln3 null mutant than in the Bck2 null mutant, since in the former, excess active Whi5 soaks up most of the available SBF/MBF, and requiring extra-high and active levels of Bck2 to overcome this barrier and activate the G1 cyclins and other genes.

The modelers are working from the accumulated, mostly genetic data, and in turn validate their models against the same genetic data, plus a few extra mutants they or others have made. The models are mathematical representations of how each node (i.e protein, or gene) in the system responds to the others, but since there are a multitude of unknowns, (such as what really regulates Bck2 from upstream, to cite just one example), the system is not really able to make predictions, but rather fine-tunes/reconciles what knowledge there is, and, at best, points to gaps in knowledge. It is a bit like AI, which magically recombines and regurgitates material from a vast corpus based on piece-wise cues, but is not going to find new data, other than through its notorious hallucinations.

For example, a new paper came out after this modeling, which finds that Cln3 affects Cln2 abundance by mechanisms quite apart from its SBF/MBF transcriptional control, and that it regulates cell size in large part at M phase, not through its G1/S gating. All this comes from new experimental work, unanticipated by the modeling. So, in the end, experimental work always trumps modeling, which is a bit different than how things are in, say, physics, where sometimes the modeling can be so strong that it predicts new particles, forces, and other phenomena, to be validated later experimentally. Biology may have its master predictive model in the theory of evolution, but genetics and molecular biology remain much more of an empirical slog through the resulting glorious mess.

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Welcome to Lubyanka!

Another case of penal systems illuminating their culture.

Most of Aleksandr Solzhenitsyn's In the First Circle is a desultory slog, at least if you have already read the Gulag Archipelago. But there are a few glorious set-pieces. One is the mock trial of Prince Igor of Kiev that the prisoners stage in their free time, a bitter satire of the Soviet judicial system. The second is a meticulous description of how prisoners are brought into and introduced to the Lubyanka prison- the central prison of the KGB/FSB/Cheka/GPU/OGPU/NKVD/NKGB, etc.. the frequently renamed, but never-changing organ of the Russian government.

The character is Innokenty Volodin, a Soviet diplomat who has recently had second thoughts about the rightness of the Soviet system, and has placed a call (around which the book's plot, such as it is, mostly revolves) to the Americans to prevent Russia from obtaining certain critical atomic secrets. Solzhenitsyn carefully prepares the way by portraying Volodin's rarified position and luxurious life. As was customary, Volodin is lured into his arrest under false pretenses, and finds himself driven to the prison almost before he knows what has happened. Then, with almost loving detail, Solzhenitsyn describes the not just systematic, but virtuosic process of degradation, step by step, shred by shred, of Volodin's humanity, as he is inducted into Lubyanka.

One cardinal rule is that prisoners must have no contact with other prisoners. Even to see others is forbidden. As they are conducted from one cell to the next, they are shoved into mini phone-booth cells if another prisoner is being conducted in the opposite direction. Their possessions are gradually taken away, down to buttons, belts, and steel shoe shanks. They are shorn. They are sleep deprived. They are relentlessly illuminated by glaring bulbs. They are spied on constantly. They are moved relentlessly from place to place and disoriented. In the middle of the night, the building is abuzz with activity, as though this were the very nerve center of the Soviet empire. 

While the rest of Russian society is mired, or cowed, in mediocrity, this is a shining point of competence. The purest expression of its obsessive leader, and the product of decades of careful study and accumulated wisdom. It is also a deeper expression of the nature of Russian society- its reflexive despotism and its strange infatuation with suffering. The closest thing we have is mafia culture, with its honor codes, brutality, and constant battle for dominance. Chess, the emblematic game of Russia, expresses this view of life as a pitiless contest to crush one's opponent. There may be a lot of historical reasons for this nature, such as the long centuries of Mongol rule, the many invasions, both ancient and modern, and the perceived success of leaders such as Ivan the Terrible and Stalin, but it is a deep and disturbing aspect of the Russian psyche. 

Should we have expected anything else, in the long road of declining relations after the cold war? Should the Russian people give thanks to the ruthlessness of their national leadership and psyche for the current position of relative power they wield in the world, far out of proportion to their population or economic strength? Other countries with larger populations peacefully mind their own business, avoid outside entanglements, and eschew invading their neighbors. It is the bullies, the intransigent, and the cruel, who appear to account for most of the drama in the world. Should we understand them, or fight against them?

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