The Revenge of History

China's cyclical history and the practice of meta-politics.

I have been studying the basics of Chinese history, getting my dynasties straight. And one observation made by everyone is the cyclicity of this history- the way it swings between unity and division, rise and collapse. One might say, however, that the real through-line is that of strong-man rule. Whether during warring states or in a unified empire, there has never been democracy in China. The states may be small or large, but they are always run by the same principle- authoritarianism. Thus the political evolution of China has been more concerned with how to ameliorate authoritarianism, with Confucianism the major (and Taoism and Buddhism the minor) modes of an (aspirational) ethic of rule that is more humane than the legalist school of pure power.

For example, one can ask the question: Why in such an ancient culture with such a lengthy political tradition, could Mao and the communist party turn it all upside down in the 20th century? Clearly it was not quite the revolution that it seemed, bringing not another system, but another emperor to the throne, one of astonishing cruelty, who killed off roughly 1/20 to 1/10 of the population over his career.

China's history is certainly a retort to the "End of History" school of thought, which had hoped to find in Western-style democracy the final refuge of humanity. One that all people and nations would recognize and join after the collapse of the Soviet Union. Hopes were nurtured that Russia might find its way to democracy, as they were towards China as well, after we did so much to encourage its capitalist development. Neither were requited, and now we ourselves are slipping into the quicksand of authoritarianism. What is going on?

One can view the American founding as a sort of meta-politics, where the best and the brightest got together, not to wage a war for supremacy, but to conceive a system that would allow continuous political development without bloodshed. Make up a few rules, set a few precedents, and we were launched on a political voyage that only descended into civil war once, and otherwise has maintained a responsive and distributed system of political control. Such meta-politics attempts to evade "real" history, which is made up of naked contests for power. One can say that it "gamified" politics by taking it off the plane of warfare, and onto a more benign plane of electoral and civic argument. It has been a shining example of human efforts to rise above our base nature.

But there is a problem, which is that it is still a contest for power, and the more serious the participants, the more tempted they are to change the rules of the game, back to the naked forms of yore. It is only the revulsion of the public against defectors that can confine power to those willing to play by the game's rules. And that revulsion has steadily eroded over the recent decades. I would place the start of this process at Newt Gingrich, who first whipped his caucus into shape with a discipline that eliminated individual conscience, and who sharpened propaganda and flamethrowing into political art. The FOX-based media ecosystem has eviscerated truth and principle as political concepts, not to mention empathy, and now celebrates political criminality as a matter of course. We are at war.

Again, China has never known democracy, so its political culture vacillates merely between more or less benign autocracies. From the astonishingly brutal rule of the Qin, to the cosmopolitan states of the Tang and Song. The "mandate of heaven", which is to say, popular opinion, is important, but is usually expressed through the ability of a revolutionary strong man to gather support. Muslim political culture is similar, having few suggestions about how a ruler should be chosen, but assuming always that there will be a ruler. The overall theme is that, especially by the "realist" school of foreign policy, history and the normal course of events are composed of naked contests for power, won by the most ruthless, shameless, and cruel. The ideas of the enlightenment offered an end to this state of affairs, by making politics about what they should be about- the opinions of the governed- systematically and peacefully. But to do that, the opinions of the governed also need to be enlightened, capable of sanctioning a politician for breaching the rules of the game, even if that politician is on their side. And that is what is so clearly missing today, as we gradually slip back into history.

• A letter from China.
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• Russia's attitude towards peace.

Why Would a Bacterium Commit Suicide?

Our innate immune system, including suicide of infected cells, has antecedents in bacteria.

We have a wide variety of defense from pathogens, from our skin and its coating of RNase and antimicrobial peptides, to the infinite combinatorial firepower of the adaptive immune system, which is primed by vaccines. In between is something called the innate immune system, which is built-in and static rather than adaptive, but is very powerful nonetheless. It is largely built around particular proteins that recognize common themes in pathogens, like the free RNA and DNA of viral genomes, or lipopolysaccharide that coats most bacteria. There are also internal damage signals, such as cellular proteins that have leaked out and are visible to wandering immune cells, that raise similar alarms. The alarms lead to inflammation, the gathering of immune cells, and hopefully to resolution of the problem. 

One powerful defensive strategy our cells have is apoptosis, or cellular suicide. If the signals from an incoming infection are too intense, a cell, in addition to activating its specific antiviral defenses, goes a few steps further and generates a massive inflammasome that rounds up and turns on a battery of proteases that chew up the cell, destroying it from inside. The pieces are then strewn around to be picked up by the macrophages and other cleanup crews, which hopefully can learn something from the debris about the invading pathogen. One particular target of these proteases are gasdermins, which are activated via this proteolysis and then assemble into huge pores that plant themselves into the plasma membrane and mitochondrial membranes, rapidly killing the cell by collapsing all the ion gradients across these membranes. 

A human cell committing apoptosis, and falling apart.

A recent paper showed that key parts of this apparatus is present in bacteria as well. It was both technically interesting, since they relied on a lot of AI tools to discern the rather distant relations between pathogen (that is to say, phages- the viruses of bacteria) receptors from bacteria, and generally intriguing, because suicide is generally something thought to be a civilized behavior of cells in multicellular organisms, protecting the rest of the body from spread of the pathogen. Bacteria, despite living in mucky biofilms and other kinds of colonies, are generally thought to be loners, only out for their own reproduction. Why would they kill themselves? Well, anytime they are in a community, that community is almost certainly composed of relatives, probably identical clones of a single founding cell. So it would be a highly related community indeed, and well worth protecting in this way. 

A bacterial gasdermin outruns phages infecting the cell. Two kinds of cells are mixed together here, ones without a gasdermin (green) and ones with (black). All are infected at zero time, and a vital dye is added (pink) that only gets into cells through large pores, like the gasdermin pore. At 45 minutes and after, the green (control) cells are dying and getting blown apart by escaping phages. On the other hand, the gasdermin+ cells develop pores and get stained pink, showing that they are dead too. But they don't blow up, indicating that they have shut down phage propagation.

The researchers heard that some bacteria have gasdermins, so they wondered whether they have the other parts of the system- the proteases and the sensor proteins. And indeed, they do. While traditional sequence similarity analysis didn't say so, structural comparison courtesy of the AlphaFold program showed that a protease in the same operon as gasdermin had CARD domains. These domains are signatures of caspases and of caspase interacting proteins, like the sensor proteins in the human innate immune system. They bind other CARD domains, thus mediating assembly of the large complexes that lead to inflammation and apoptosis.

Structure of the bacterial CARD domain, courtesy of AlphaFold, showing some similarity with a human CARD domain, which was not very apparent on the sequence level.

The operon of this bacterium, which encodes the whole system- gasdermin, protease (two of them), and sensor.

The researchers then raised their AI game by using another flavor of AlphaFold to predict interactions that the bacterial CARD/protease protein might have. This showed an interaction with another protein in the same operon, with similarity to NLR sensor proteins in humans, which they later confirmed happened in vitro as well. This suggests that this bacterium, and many bacteria, have the full circuit of sensor for incoming phage, activatable caspase-like protease, and then cleavable gasdermin as the effector of cell suicide.

A comparison of related operons from several other bacteria.

Looking at other bacteria, they found that many have similar systems. Some link to other effectors, rather than a pore-forming gasdermin. But most share a similar sensor-to-protease circuit that is the core of this defense system. Lastly, they also asked what triggers this whole system from the incoming phage. The answer, in this case, is a phage protein called rIIB. Unfortunately, it is not clear either what rIIB does for the phage or whether it triggers the CARD/gasdermin system by activating the bacterial NLR sensor protein, as would be assumed. What is known, however, is that rIIB has a function in defending phage against another bacterial defense system called RexAB. This it looks as though this particular arms race has ramified into a complicated back and forth as bacteria try as best they can to insure themselves against mass infection.

• The move to quash mRNA vaccines is reprehensible. A black day.
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• Swampy Don.
• Not a quid pro quo, at all.
• Climate (and coal) graphs of the week, electricity sources of US vs China. Everyone has a very long way to go, especially China:

My Religion is Star Trek

Denial of death and the origin of evil- Ernest Becker on religion.

I have always wondered about the purpose of clothes. Nudists obviously do as well. Sometimes you need to keep warm. But most of the time, clothes are a cultural convention full of signifiers of taste, status ... and something else. That something else is the illusion that we are not animals. Positively, absolutely, something wholly different and on another plane of existence. Not animals. 

Even a century and a half after Darwin explained that we are animals, there are plenty of people who cling to various stories of denial. But these stories have purposes that go well beyond this ontological illusion. Because not only are we animals, but we are animals without meaning. Animals that will die. That is, no meaning is given objectively. So just as we clothe our bodies with fabric, we clothe our spirits with illusions of meaning, for otherwise we could not live. 

I have been following a provocative podcast series, which spent a couple of episodes on Ernest Becker, a mid-20th century philosopher in the US. He posited that we all follow a religion, in the anthropological sense that we live in cultural structures that give us meaning. Structures that are fundamentally illusory, because there is no there there. Meaning has always been generated by us, for us, subjectively by our psychological proclivities for social connection and drama. We are psychologically adapted to make and seek meaning, though in the final analysis, however powerful they feel, these are all conjured, not given. Take Disney as an example. Many people get highly involved with, and take solace from, the narratives Disney puts out, in its parks, cruise ships, movies, merchandise, and other channels. Relentless provision of mechanically assembled archetypes and other psychological triggers that activate / soothe, inspire, and motivate apparently has a substantial market. 

While atheists take no end of potshots at the absurdities and hypocrisies of formal religions, they also live (and must live) in some sort of illusion themselves. The idea that learning and science makes for a more "objective" value system and life of meaning may be less absurd, but is no more objective. These values come with a rationale and a story, one of service to ultimately human ends of knowledge and betterment. But that doesn't make them true- just another set of values that must be gauged subjectively. And when measured by the ironic criterion of Darwinian success in promoting reproduction, they often turn out to be lacking. At the most basic level, getting through the day requires some kind of motivation, and that motivation, when it goes beyond the most animal requirements, requires meaning, which requires us to have some story that narrates a purpose to a life whose end is otherwise irredeemably meaningless. 

There is a problem, however, to Becker. The more enveloping and functional the narrative of meaning, the more any competing narrative becomes alien and threatening. Indeed, threatening narratives become evil. Thus Judaism became the nemesis of Christianity, and Catholicism that of Protestantism. If the meaning of our lives, in a spiritual and eternal sense, is devalued by another story that has competing status, there is no limit to our horror at its doctrines or our dehumanization of its adherents. Thence to crusades, religious wars, pogroms, and the delicately named "communal violence". The management of narratives of meaning thus is perhaps the most critical aspect of human affairs, as all religious leaders have known forever.

One can see the US civil war through this lens. The people of the South, wedded to slavery, justified it through their theology and culture. They were mortally offended by the busybodies of the North who dared cast aspersions on their moral narratives and justifications, not to mention their economic basis. Where "Uncle Tom's Cabin" may have broken through the indifference of Northern culture, it was met with outrage in the South- a stout defense of their powerful cultural and religious narratives. The conflict was spiritual and existential.

Becker did not have terribly novel solutions to the problems of meaning and counter-meaning. Just the meta prescription that arose in the enlightenment, secularism and in all the branches of modern psychology. Which is that understanding this dynamic and taking one's stories less seriously is the path to social peace. It may not be the path to optimal personal meaning, however. How do you compare the smorgasbord of Disney, mainline religion, Western Buddhism, science, and a thousand other sects and value systems to a traditional society with one church, one story, and one universe? The power of social and spiritual unity must have been tremendously validating and comfortable. So there has been a big tradeoff to get to our current state of social and spiritual innovation, plurality, and anomie. It is evident that our political moment is one of deep spiritual revanchism- of revulsion (by the more traditional-minded) against all this plurality, back towards a more benighted unity.

• Only Catholics go to heaven.
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• Homelessness as a problem of affluence, gentrification, and too-good policing.
• But crime in DC? We know where that is.
• Cutting off our health to spite our libtards.
• The state of cars.

A Wonderland of RNA

A snoRNA mates with the 7SL RNA and mRNA to promote protein secretion.

As molecular biologists wander through the wilderness of the cell, they keep stumbling across RNAs. From early on, the ribosomal RNA (rRNA) and amino acid transfer RNA (tRNA) were obviously incredibly abundant, in their somewhat inefficient job of carrying on translation. Messenger RNAs (mRNA) were less abundant, but recognized from the start for their key role relaying information from the genome. But over the decades, more and more types of RNA kept popping up. Here is one tabulation of genes by type in humans:

• 22,700 protein-coding (along with 19,000 derelict "pseudogenes")
• 820         rRNA
• 659         tRNA
• 1,960 miRNA
• 2,100 snRNA
• 1,390 snoRNA
• 51,000 ncRNA
• 65         scaRNA, scRNA, piRNA

One big step in the realization of the prevalence of RNA was the ENCODE project, done as part of the human genome project. They found that most of the genome is transcribed to RNA, one way or another. Not all those products are important, or abundant, but just the fact that all this RNA is floating around was startling. This does not mean that there isn't junk DNA, (or junk RNA), but it does mean that a lot of potential function lurks waiting to be found. And the last couple of decades have seen many such finds. 

From the list above, microRNAs are small fragments that bind to matching mRNAs and repress their translation to protein. They have wide-ranging networks of regulation, mostly of a fine-tuning nature, but sometimes quite decisive and relevant to human biology and pathology. snRNAs are small nuclear DNAs, some of which function in RNA splicing. snoRNAs are small nucleolar RNAs, some of which mate with various sections of the ribosomal RNA as it is being assembled in the nucleolus, and guide chemical modifications made by enzymes, such as attachment of methyl and uridine groups. The non-coding (nc) RNAs are typically products of protein coding genes that, due to splicing or altered start sites, happen to not code for anything, and occasionally have significant regulatory roles. 

In general, RNAs may have a few different mechanisms of action: guide characteristics, where they mate with their antisense sequence in a target RNA and direct some other process like sequestration, cleavage, or chemical modification. Or they may bind to specific proteins, such as the RNAs that bind to chromatin and regulate X-linked dosage compensation. Or they have structural, even catalytic roles, like the ribosomal and spliceosomal RNAs. 

What should be clear that there are many more genes are recognizable by sequence than we understand. Only a couple hundred snoRNA genes are understood by their targets and activity. But there are well over a thousand in the genome. What do the rest do? A recent paper took on this quest, devising a novel way to isolate these snoRNAs and their partners from the welter of other material. They did this by crosslinking everything, ligating the RNAs locally to each other (which linked the snoRNAs to their targets) and then reverse-transcribing the RNAs before trying to capture them individually by custom anti-sense DNA probes, one per gene. It was a complicated procedure, but far more productive than trying to capture them directly as RNA with antisense RNA probes, since these snoRNAs are intensely structured (lots of hairpins and other duplexes) and expected to be tightly bound to other things.

Taking the most abundant snoRNAs, these researchers then looked for novel partners and functions. After seeing that they recovered plenty of the known interactions, the most interesting novel interaction they came up with was of a gene called SNORA73. This was found linked to two other RNAs, 7SL RNA and various mRNAs. 

Just another holdover from the RNA world. The SRP particle (in red) is built around the 7SL snRNA (helix). This particle detects the signal peptide (green) of the nascent protein emerging from the ribosome (beige, blue), and clamps on (right) to arrest translation. Translation is later resumed after the whole complex has successfully docked with the membrane receptor, allowing the SRP to be released, and the peptide to be threaded through the membrane. 

Funny story ... 7SL RNA is yet another snRNA that has a key role in translation. It is the core of the signal recognition particle (SRP), which binds to "signal" sequences in proteins as they come off the ribosome. These are a special code segement at the start that says "I want to be secreted across (or into) a membrane, not just located in the cytoplasm". The SRP captures this signal segment, and then sticks its head into the ribosome, stalling its translation. Then the whole mess goes off to the membrane (endoplasmic reticulum in eukaryotes, or plasma membrane in bacteria) where it docks with the SRP receptor complex. This is the signal for translation to restart, the SRP to come off, and the nascent protein to thread its way through the membrane to the other side. 

Incidentally, it is notable also that SRP is scaffolded by a large RNA, with a few proteins stuck on for decoration / specificity. This makes sense as an echo of early evolution, where not only did RNAs likely arise before proteins ever existed, but those RNAs had gotten quite large while the earliest proteins were still relatively small. The genetic code appears to have started as a two letter code, before the third letter was munged onto the end, vastly expanding the chemical repertoire of proteins and making them premier catalysts. 

A few results, indicating that knockdown of SNORA73 (with the anti-RNAs LNA-1 and LNA-2) dramatically decreases secretion of the proteins CLU and LGAL3BP. On left  are signals from proteins isolated from inside and outside the cells, as indicated. On right is a graph of the same data. The mRNA levels are not changed nor the protein levels. Only the level of secretion is altered.

So the implication of all this was that SNORA73 affects protein translation/secretion. This is indeed the case, when these authors assayed the secretion of one of the SNORA73-bound mRNA-encoded proteins in the presence of an inhibitor of SNORA73 (above). The mechanism is that SNORA73 serves as a special glue between the 7SL snRNA and the translating mRNA, with parts of its RNA sequence complementary to both a segment of the 7SL snRNA, and also to a small 10 base-long segment of the mRNA. The mRNA segment is hanging off the ribosome while the beginning of the message is being translated. The whole setup helps the SRP find these mRNAs efficiently and hold on to them effectively, increasing not their translation rate, but their secretion rate.

Models of the structures of SNORA73 (which is made by a pair of similar genes, A and B), as they bind to the 7SL snRNA, and the target mRNAs. These binding areas are far apart, to allow the mRNA tail (that is not yet in the ribosome) to reach the MBM binding site. The psi pocket is of uncertain function, but in other snoRNAs directs the uridine addition to target rRNA.

The mRNAs that have this 10 base (MBM) signal that binds to SNORA73 are a subset of those that express secreted proteins, though it is not really clear from this work what kind of a subset this is. Perhaps this mechanism makes up for weak signal sequences, or some other defect in the protein's access to the secretion machinery. Whatever that logic, we have here a conjunction of four RNAs, (7 SL snRNA, the SNORA73 snoRNA, the mRNA target, and the ribosomal RNA structure) all collaborating to promote the secretion of a target protein. This is just one of thousands of uncharacterized and conserved RNAs visible in our genome. It is startling to think what else might be going on.

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The Origin of Life

What do we know about how it all began? Will we ever know for sure?

Of all the great mysteries of science, the origin of life is maybe the one least likely to ever be solved. It is a singular event that happened four billion years ago in a world vastly different from ours. Scientists have developed a lot of ideas about it and increased knowledge of this original environment, but in the end, despite intense interest, the best we will be able to do is informed speculation. Which is, sure, better than uninformed speculation, (aka theology), but still unsatisfying. 

A recent paper about sugars and early metabolism (and a more fully argued precursor) piqued my interest in this area. It claimed that there are non-enzymatic ways to generate most or all of the core carbohydrates of glycolysis and CO2 fixation around pentose sugars, which are at the core of metabolism and the supply of sugars like ribose that form RNA, ATP, and other key compounds. The general idea is that at the very beginning of life, there were no enzymes and proteins, so our metabolism is patterned on reactions that originally happened naturally, with some kind of kick from environmental energy sources and mineral catalysts, like iron, which was very abundant. 

That is wonderful, but first, we had better define what we mean by life, and figure out what the logical steps are to cross this momentous threshold. Life is any chemical process that can accomplish Darwinian evolution. That is, it replicates in some fashion, and it has to encode those replicated descendants in some way that is subject to mutation and selection. With those two ingredients, we are off to the races. Without them, we are merely complex minerals. Crystals replicate, sometimes quite quickly, but they do not encode descendent crystals in a way that is complex at all- you either get the parent crystal, or you get a mess. This general theory is why the RNA world hypothesis was, and remains, so powerful. 

The RNA world hypothesis is that RNA is likely the first genetic material, before DNA (which is about 200 times more stable) was devised. RNA also has catalytic capabilities, so it could encode in its own structure some of the key mechanisms of life, therefore embodying both of the critical characteristics of life specified above. The fact that some key processes remain catalyzed by RNA today, such as ribosomal synthesis of proteins, spliceosomal re-arrangement of RNAs, and cutting of RNAs by RNAse P, suggest that proteins (as well as DNA) were the Johnny-come-latelies of the chemistry of life, after RNA had, in its lumbering, inefficient way, blazed the trail. 

In this image of the ribosome, RNA is gray, proteins are yellow. The active site is marked with a bright light. Which came first here-
protein or RNA?

But what kind of setting would have been needed for RNA to appear? Was metabolism needed? Does genetics come first, or does metabolism come first? If one means a cyclic system of organic transformations encoded by protein or RNA enzymes, then obviously genetics had to come first. But if one means a mess of organic chemicals that allowed some RNA to be made and provide modest direction to its own chemical fate, and to a few other reactions, then yes, those chemicals had to come first. A great deal of work has been done speculating what kind of peculiar early earth conditions might have been conducive to such chemistries. Hydrothermal vents, with their constant input of energy, and rich environment of metallic catalysts? Clay particles, with their helpful surfaces that can faux-crystalize formation of RNAs? Warm ponds, hot ponds, UV light.... the suggestions are legion. The main thing to realize is that early earth was surely highly diverse, had a lot of energy, and had lots of carbon, with a CO2-rich atmosphere. UV would have created a fair amount of carbon monoxide, which is the feedstock of the Fischer-Tropsch reactions that create complex organic compounds, including lipids, which are critical for formation of cells. Early earth very likely had pockets that could produce abundant complex organic molecules.

Thus early life was surely heterotrophic, taking in organic chemicals that were given by the ambient conditions for free. And before life really got going, there was no competition- there was nothing else to break those chemicals down, so in a sort of chemical pre-Darwinian setting, life could progress very slowly (though RNA has some instability in water, so there are limits). Later, when some of the scarcer chemicals were eaten up by other already-replicating life forms, then the race was on to develop those enzymes, of what we now recognize as metabolism, which could furnish those chemicals out of more common ingredients. Onwards the process then went, hammering out ever more extensive metabolic sequences to take in what was common and make what was precious- those ribose sugars, or nucleoside rings that originally had arrived for free. The first enzymes would have been made of RNA, or metals, or whatever was at hand. It was only much later that proteins, first short, then longer, came on the scene as superior catalysts, extensively assisted by metals, RNAs, vitamins, and other cofactors.

Where did the energy for all this come from? To cross the first threshold, only chemicals (which embodied outside energy cycles) were needed, not energy. Energy requirements accompanied the development of metabolism, as the complex chemicals become scarcer and they needed to be made internally. Only when the problem of making complex organic chemicals from simpler ones presented itself did it also become important to find some separate energy source to do that organic chemistry. Of course, the first complex chemicals absolutely needed were copies of the original RNA molecules. How that process was promoted, through some kind of activated intermediates, remains particularly unclear.

All this happened long before the last universal common ancestor, termed "LUCA", which was already an advanced cell just prior to the split into the archaeal and bacterial lineages, (much later to rejoin to create the most amazing form of life- eukaryotes). There has been quite a bit of analysis of LUCA to attempt to figure out the basic requirements of life, and what happened at the origin. But this ("top-down") approach is not useful. The original form of life was vastly more primitive, and was wholly re-written in countless ways before it became the true bacterial cell, and later still, LUCA. Only the faintest traces remain in our RNA-rich biochemistry. Just think about the complexity of the ribosome as an RNA catalyst, and one can appreciate the ragged nature of the RNA world, which was probably full of similar lumbering catalysts for other processes, each inefficient and absurdly wasteful of resources. But it could reproduce in Darwinian fashion, and thus it could improve. 

Today we find on earth a diversity of environments, from the bizarre mineral-driven hydrothermal vents under the ocean to the hot springs of Yellowstone. The geology of earth is wondrously varied, making it quite possible to credit one or more of the many theories of how complex organic molecules may have become a "soup" somewhere on the early Earth. When that soup produces ribose sugars and the other rudiments of RNA, we have the makings of life. The many other things that have come to characterize it, such as lipid membranes and metabolism of compounds are fundamentally secondary, though critically important for progress beyond that so-pregnant moment. 

• Notes on US history.
• The fascist playbook.
• Chemosynthetic life is doing very well.
• Decimation leads to decline.
• FYI, a discussion of phosphate.
• FYI, a discussion of hypothetical steps toward RNA self-replication.