Evolution Under (Even in) Our Noses

The Covid pandemic is a classic and blazingly fast demonstration of evolution.

Evolution has been "controversial" in some precincts. While tradition told the fable of genesis, evolution told a very different story of slow yet endless change and adaptation- a mechanistic story of how humans ultimately arose. The stark contrast between these stories, touching both on the family tree we are heir to, and also on the overall point and motivation behind the process, caused a lot of cognitive dissonance, and is a template of how a fact can be drawn into the left/right, blue/red, traditional/progressive cultural vortex.

This all came to a head a couple of decades ago, when in the process of strategic retreat, anti-evolution forces latched onto some rather potent formulations, like "just a theory", and "intelligent design". These were given a lot of think tank support and right wing money, as ways to keep doubt alive in a field that scientifically had been settled and endlessly ramified for decades. To scientists, it was the height of absurdity, but necessitated wading into the cultural sphere in various ways that didn't always connect effectively with their intended audience. But eventually, the tide turned, courts recognized that religion was behind it all, and kept it out of schools. Evolution has more or less successfully receded from hot-button status.

One of the many rearguard arguments of anti-evolutionists was that sure, there is short-term evolution, like that of microbes or viruses, but that doesn't imply that larger organisms are they way they are due to evolution and selection. That would be simply beyond the bounds of plausibility, so we should search for explanations elsewhere. At this point they were a little gun-shy and didn't go so far in public as to say that elsewhere might be in book like the Bible. This line of argument was a little ironic, since Darwin himself hardly knew about microbes, let alone viruses, when he wrote his book. The evidence that he adduced (in some profusion) described the easily visible signs of geology, of animals and plants around the world, (including familar domestic animals), which all led to the subtle, yet vast, implications he drew about evolution by selection. 

So it has been notable that the vistas of biology that opened up since that time, in microbiology, paleontology, genetics, molecular biology, et al., have all been guided by these original insights and have in turn supported them without fail. No fossils are found out of order in the strata, no genes or organisms parachute in without antecedents, and no chicken happens without an egg. Evolution makes sense of all of biology, including our current pandemic.

But you wouldn't know it from the news coverage. New variants arise into the headlines, and we are told to "brace" for the next surge, or the next season. Well, what has happened is that the SARS-COV2 virus has adapted to us, as we have to it, and we are getting along pretty well at this point. Our adaptation to it began as a social (or antisocial!) response that was very effective in frustrating transmission. But of late, it has been more a matter of training our immune systems, which have an internal selective principle. Between rampant infections and the amazing vaccines, we have put up significant protective barriers to severe illness, though not, notably, to transmission.

But what about the virus? It has adapted in the most classic of ways, by experiencing a wide variety of mutations that address its own problems of survival. It is important to remember that this virus originated in some other species (like a bat) and was not very well adapted to humans. Bats apparently have countless viruses of this kind that don't do them much harm. Similarly, HIV originated in chimpanzee viruses that didn't do them much harm either. Viruses are not inherently interested in killing us. No, they survive and transmit best if they keep us walking around, happily breathing on other people, with maybe an occasional sneeze. The ultimate goal of every virus is to stay under the radar, not causing its host to either isolate or die. (I can note parenthetically that viruses that do not hew to this paradigm, like smallpox, are typically less able to mutate, thus less adaptable, or have some other rationale for transmission than upper respiratory spread.)

And that is clearly what has happened with SARS-COV2. Local case rates in my area are quite high, and wastewater surveilance indicates even higher prevalence. Isolation and mask mandates are history. Yet hospitalizations remain very low, with no one in the ICU right now. Something wonderful has happened. Part of it is our very high local vaccination rate, (96% of the population), but another part is that the virus has become less virulent as it has adapted to our physiology, immune systems, media environment and social practices, on its way to becoming endemic, and increasingly innocuous. All this in a couple of years of world-wide spread, after billions of infections and transmissions.

The succession (i.e. evolution) of variants detected in my county. 

The trend of local wastewater virus detection, which currently shows quite high levels, despite mild health outcomes.

So what has the virus been doing? While it has many genes and interactions with our physiology, the major focus has been on the spike protein, which is most prominent on the viral surface, is the first protein to dock to specific human proteins (the ACE2 cell surface receptor), and is the target of all the mRNA and other specific subunit vaccines. (As distinct from the killed virus vaccines that are made from whole viruses.) It is the target of 40% of the antibodies we naturally make against the whole virus, if we are infected. It is also, not surprisingly, the most heavily mutated portion of the virus, over the last couple of years of evolution. One paper counts 45 mutations in the spike protein that have risen to the level of "variants of concern" at WHO. 

"We found that most of the SARS-COV-2 genes are undergoing negative purifying selection, while the spike protein gene (S-gene) is undergoing rapid positive selection."

Structure of the spike protein, in its normal virus surface conformation, (B, C), and in its post-triggering extended conformation that reaches down into the target cell's membrane, and later pulls the two together. Top (in B, C) is where it binds to the ACE2 target on respiratory cells, and bottom is its anchor in the viral membrane coat (D shows it upside-down). At top (A) is the overall domain structure of the protein, in its linear form as synthesized, especially the RBD (receptor binding domain) and the two protease cleavage sites that prepare it for eventual triggering.

The spike protein is a machine, not just a blob. As shown in this video, it starts as a pyramidal blob flexibly tethered to the viral surface. Binding the ACE2 proteins in our respiratory tracts triggers a dramatic re-organization whereby this blob turns into a thin rope, which drops into the target cell. Meanwhile, the portion stuck to the virus unfolds as well and turns into threads that wind back around the newly formed rope, thereby pulling the virus and the target cell membrane together and ultimately fusing them. This is, mechanistically, how the virus gets inside our cells.

The triggering of the spike protein is a sensitive and adjustable process. In related viruses, the triggering is more difficult, and waits till the virus is engulfed in a vesicle that taken into the cell, and acidified in the normal process of lysosomal destruction / ingestion of outside materials. The acidification triggers these viral spike proteins to fire and release the virus into the cell. Triggering also requires cleavage of the spike protein with proteases that cut it at two locations. Other related viruses sometime wait for a target host protease to do the honors, but SARS-COV2 spike protein apparently is mostly cleaved during production by its originating host. This raises the stakes, since it can then more readily trigger, by accident, or once it finds proper ACE2 receptors on a target host. One theme of recent SARS-COV2 evolution is that triggering has become slightly easier, allowing the virus to infect higher up in the respiratory system. The original strains set up infections deep in the lung, but recent variants infect higher up, which lessens the systemic risks of infection to the host, promotes transmissibility, and speeds the infection and transmission process. 

The mutations G339D, N440K, L452R, S477N, T478K, and E484K in the spike region that binds to ACE2 (RBD, or receptor binding domain) promotes this interaction, raising transmissibility. (The nomenclature is that the number gives the position of the amino acid in the linear protein sequence, and the letters give the original version of the amino acid in one letter code (start) and in the mutated version (end)). Overall, mutations of the spike protein have increased the net charge on the spike protein significantly in the positive direction, which encourages binding to the negatively charged ACE2 protein. D614G is not in this region, but is nearby and seems to have similar effects, stabilizing the protein. The P681 mutation in one of the cleaved regions promotes proteolysis by the enzyme furin, thus making the virus more trigger-able. 

What are some other constraints on the spike protein? It needs to evade our vaccines and natural immunity, but has seemingly adapted to a here-and-gone infection style, though with periodic re-infection, like other colds. So any change is good for the purpose of camouflage, as long as its essential functions remain intact. The N-terminal, or front, domain of the spike protein, which is not involved directly in ACE2 binding, has experienced a series of mutations of this kind. An additional function it seems to have is to mimic a receptor for the cytokine interleukin 8, which attracts neutrophils and encourages activation of macrophages. Such mimicry may reduce this immune reaction, locally. 

In comparison to all these transmissibility-enhancing mutations, it is not clear yet where the mutations that decrease virulence are located. It is likely that they are more widely distributed, not in the gene encoding the spike protein. SARS-COV2 has a remarkable number of genes with various interactions with our immune systems, so the scope for tuning is prodigious. If all this can be accomplished in a couple of years, image what a million, or a billion, years can do for other organisms that, while they have slower reproduction cycles and more complicated networks of internal and external relations, still obey that great directive to adapt to their circumstances.

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What Binds to DNA?

Large scale studies of what binds to DNA over whole genomes.

Biology is full of codes. There is the genetic code, but there are many others. There are protein localization codes- short sequences on many proteins that tell them where they should transported to, such as to the mitochondrion, lysozome, the exterior, or the nucleus. There are kinase codes- the positions on many proteins where modification by phosphate changes their behavior. There is a histone code, which is the set of acetylations and methylations on histone tails which have wide-ranging influence on transcription of DNA to RNA. There is a sugar code- the many glycosyl modifications of proteins displayed externally on cells, which affect how they are seen and work in that space. Lastly, there is a code of short sites on DNA where specialized proteins bind, and by which transcription and other processes are regulated. Humans have roughly 1600 loci, out of their 20,000 genes, which appear to encode such proteins, and each binds somewhere and does something in our biology. 

The important cancer-suppressing gene p53 (green), binding to DNA (orange).  To the right is a closeup, showing a few of the detailed base contacts, with dashed black lines. Proteins that bind to DNA in sequence-specific ways feel their way around by making many such shape and charge-guided physical contacts.

The study of how and where these proteins bind has a long history, with many such proteins now exceedingly well characterized, to the atomic level. But at the genomic scale, it is still something of a crapshoot to guess where and whether some DNA site binds a regulatory protein. Such proteins have rather flexible requirements, which researchers express in "motifs". These motifs are short and typically variable, or "degenerate". That is, each position in such a motif can be one of the four bases, and frequently more than one base is allowed. In the motif shown below, for the protein ZBTB33, only one G is absolutely required. The other positions are variable to some degree. Outer areas of a binding site tend to be less selective, naturally, as they are less strongly bound by the protein. Some proteins can bind to two different motifs, and some can be accessorized by partners of various kinds to bind yet other sites. Evolution is the great tinker, and in this system, interactions are frequently kept rather loose and fluid, enabling precision where needed, (partly by complexing numerous regulatory factors & binding sites with each other in large casettes), but also flexibility and adaptability elsewhere.

A representation of what DNA sequences the zinc finger protein ZBTB33 binds to. Each position along the DNA site is shown as the collection of possible bases seen in functional sites, with each shown in proportion to its frequency of occurrence. The central G is the only absolutely required base, though several others are nearly invariant.

So the question of what binds where is not an easy one to answer, just going from the sequence of the genome. Naturally, this has been the subject of recent advances in large-scale biology, enabling researchers to, for instance, identify all the binding sites of a given protein across the genome (in a given cell type and culture condition). Or alternately to identify all the "accessible" sites across a genome (and also in a given cell type and culture condition), which would be locations where chromatin is "opened" up due to the binding of whatever regulatory proteins. This latter style of experiment naturally leads to the question- what is doing all that binding?

A recent paper comes from that field, deploying the latest machine learning and convoluted neural nets to find the answer, at least on a statistical basis. They combine a series of bulk open-chromatin experiments with a database of known transcription regulator motifs to match genomic sites with plausible proteins that bind there. In usual machine learning fashion, they reserve some of the training data for testing and validation, enabling the production of ROC statistics for accuracy and for comparison with other methods, of which there are many. But what they do not do is actually test the accuracy of their data in the lab, with actual cells and proteins. That would hard for a bioinformatics lab! So their talk of "accuracy" is rather untethered from reality, though fine enough for the journal they published in, which is Public Library of Science, Computational Biology. 

All that said, this is a code that is going to be very difficult to crack, since regulatory proteins are not just highly diverse and their sites degenerate, but they are themselves regulated in many ways, by phosphorylation, sumoylation, ubiquinylation, methylation, complexing with partners, the generation of variable isoforms through transcription, and cleavage, among others. The same protein that activates transcription here may repress it there. So the "motif" is a bit of a chimera, as is its effect on gene expression. The great tinkerer has gone so far down the rabbit hole that even "Deep Mind" is going to have a hard time following it down, without further empirical advances ... such as a massive upgrades in methods to identify specific protein binding sites across the genome.

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Tangling With the Network

Molecular biology needs better modeling.

Molecular biologists think in cartoons. It takes a great deal of work to establish the simplest points, like that two identifiable proteins interact with each other, or that one phosphorylates the other, which has some sort of activating effect. So biologists have been satsified to achieve such critical identifications, and move on to other parts of the network. With 20,000 genes in humans, expressed in hundreds of cell types, regulated states and disease settings, work at this level has plenty of scope to fill years of research.

But the last few decades have brought larger scale experimentation, such as chips that can determine the levels of all proteins or mRNAs in a tissue, or the sequences of all the mRNAs expressed in a cell. And more importantly, the recognition has grown that any scientific field that claims to understand its topic needs to be able to model it, in comprehensive detail. We are not at that point in molecular biology, at all. Our experiments, even those done at large scale and with the latest technology, are in essence qualitative, not quantitative. They are also crudely interventionistic, maybe knocking out a gene entirely to see what happens in response. For a system as densely networked as the eukaryotic cell, it will take a lot more to understand and model it.

One might imagine that this is a highly detailed model of cellular responses to outside stimuli. But it is not. Some of the connections are much less important than others. Some may take hours to have the indicated effect, while others happen within seconds or less. Some labels hide vast sub-systems with their own dynamics. Important items may still be missing, or assumed into the background. Some connections may be contingent on (or even reversed by) other conditions that are not shown. This kind of cartoon is merely a suggestive gloss and far from a usable computational (or true) model of how a biological regulatory system works.

The field of biological modeling has grown communities interested in detailed modeling of metabolic networks, up to whole cells. But these remain niche activities, mostly because of a lack of data. Experiments remain steadfastly qualitative, given the difficulty of performing them at all, and the vagaries of the subjects being interrogated. So we end up with cartoons, which lack not only quantitative detail on the relative levels of each molecule, but also critical dynamics of how each relationship develops in time, whether in a time scale of seconds or milliseconds, as might be possible for phosphorylation cascades (which enable our vision, for example), or a time scale of minutes, hours, or days- the scale of changes in gene expression and longer-term developmental changes in cell fate.

These time and abundance variables are naturally critical to developing dynamic and accurate models of cellular activities. But how to get them? One approach is to work with simple systems- perhaps a bacterial cell rather than a human cell, or a stripped down minimal bacterial cell rather than the E. coli standard, or a modular metabolic sub-network. Many groups have labored for years to nail down all the parameters of such systems, work which remains only partially successful at the organismal scale.

Another approach is to assume that co-expressed genes are yoked together in expression modules, or regulated by the same upstream circuitry. This is one of the earliest forms of analysis for large scale experiments, but it ignores all the complexity of the network being observed, indeed hardly counts as modeling at all. All the activated genes are lumped together into one side, and all the down-regulated genes on the other side, perhaps filtered by biggest effect. The resulting collections are clustered by some annotation of those gene's functions, thereby helping the user infer what general cell function was being regulated in her experiment / perturbation. This could be regarded perhaps as the first step on a long road from correlation analysis of gene activities to a true modeling analysis that operates with awareness of how individual genes and their products interact throughout a network.

Another approach is to resort to a lot of fudge factors, while attempting to make a detailed model of the cell /components. Assume a stable network, and fill in all the values that could get you there, given the initial cartoon version of molecule interactions. Simple models thus become heuristic tools to hunt for missing factors that affect the system, which are then progressively filled in, hopefully by doing new experiments. Such factors could be new components, or could be unsuspected dynamics or unknown parameters of those already known. This is, incidentally, of intense interest to drug makers, whose drugs are intended to tweek just the right part of the system in order to send it to a new state- say, from cancerous back to normal, well-behaved quiescence.

A recent paper offered a version of this approach, modular response analysis (MRA). The authors use perturbation data from other labs, such as the inhibition of 1000 different genes in separately assayed cells, combined with a tentative model of the components of the network, and then deploy mathematical techniques to infer / model the dynamics of how that cellular system works in the normal case. What is observed in either case- the perturbed version, or the wild-type version- is typically a system (cell) at steady state, especially if the perturbation is something like knocking out a gene or stably expressing an inhibitor of its mRNA message. Thus, figuring out the (hidden) dynamic in between- how one stable state gets to another one after a discrete change in one or more components- is the object of this quest. Molecular biologists and geneticists have been doing this kind of thing off-the-cuff forever (with mutations, for instance, or drugs). But now we have technologies (like siRNA silencing) to do this at large scale, altering many components at will and reading off the results.

This paper extends one of the relevant mathematical methods (modular response analysis, MRA) to this large scale, and finds that, with a bit of extra data and some simplifications, it is competitive with other methods (mutual information) in creating dynamic models of cellular activities, at the scale of a thousand components, which is apparently unprecedented. At the heart of MRA are, as its name implies, modules, which break down the problem into manageable portions and allow variable amounts of detail / resolution. For their interaction model, they use a database of protein interactions, which is a reasonably comprehensive, though simplistic, place to start.

What they find is that they can assemble an effective system that handles both real and simulated data, creating quantitative networks from their inputs of gene expression changes upon inhibition of large numbers of individual components, plus a basic database of protein relationships. And they can do so at reasonable scale, though that is dependent on the ability to modularize the interaction network, which is dangerous, as it may ignore important interactions. As a state of the art molecular biology inference system, it is hardly at the point of whole cell modeling, but is definitely a few steps ahead of the cartoons we typically work with.

The authors offer this as one result of their labors. Grey nodes are proteins, colored lines (edges) are activating or inhibiting interactions. Compared to the drawing above, it is decidedly more quantitative, with strengths of interactions shown. But timing remains a mystery, as do many other details, such as the mechanisms of the interactions

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A Road of Grass- Migrations Along the Asian Steppe

Genomics data confirms that the Avars were of East Asian origin before taking over the Carpathian basin.

Historians have gradually accorded increasing respect to the various Central Asian groups that swept in and terrorized Europe for a millenium, including in turn the Scythians, Huns, Avars, Mongols, and Turks. The Mongols particularly created a golden age of commerce across the Silk Road, which Marco Polo traveled to such great adventure. This history is both extremely dynamic, and poorly documented, as these nomadic cultures left little behind, especially writing. Their roots range from Iran and the Indo-Europeans to the Mongolian and Tungusic regions. A putative "Altaic" language group extends from Hungary all the way to Korea and Japan, though it is a disparate group arising more from interchange and borrowing than from a single origin- testament to the frequent traffic along the steppes.

To settled cultures, both in Europe and in China, these nomads were terrors, living on their horses, infinitely mobile, and possessing powerful weapons like their composite bows. The continual succession of these cultures (unlike, say, the long stability of ancient Egypt) also indicates that they fought constantly among themselves, in true Darwinian fashion. Success revolved around not only technical innovation and a martial culture, but also social abilities to forge groups large and cohesive enough to control vast regions, despite the tendency of warriors to fight ... with each other.

The Avars were one of this succession, historically known as invaders of the Carpathian Basin who set up a brief empire (~570 to 790 CE) after defeating Goths who had in turn succeded the Huns, who had replaced the Romans of Pannonia. At their height, the Avars ruled from Turkey to Austria, but were within two hundred years defeated by the Franks, who were soon followed by the Magyars, who finally stayed to found what is now Hungary. One can see that the Balkans, which lie in this region and towards the Adriatic, have had a tumultuous history. The Avars had reputedly come from the far East, after the nascent Turks defeated the Hunnic / Rouran center, of which the Avars were supposedly a successor, offshoot, or client group. Historians have been divided, though, since there is little evidence of far Eastern influences in the Carpathian archeology, and competing accounts put their origin more Westerly, around the Urals or Caspian basin. 

"The Rourans were defeated by the Turks, who had been their subjects, in 552–555. Their empire fell apart and, according to the contemporary Chinese sources, the core Rouran population was brutally massacred. Some of the Rourans fled to China and soon disappeared from sources. Another group of the Rourans is commonly thought to have migrated westwards and become the Avars of European history"

But a recent paper (largely authored by Hungarians) has settled the matter. They sequenced DNA from numerous burials dated through the Avar era, and compared them to a variety of samples from across the steppes. They find that indeed, the earliest and richest graves of the Avar era have almost exclusively far East Asian DNA markers, from what is now roughly Mongolia, while later remains show increasing admixture with the local Western Europeans. 

"All of the early-Avar-period individuals (DTI_early_elite), except for an infant and a burial with typical characteristics of the Transtisza group, form a tight cluster with a high level of ANA (ancient North East Asian) ancestry. They are located between present-day Mongolic- (e.g., Buryats and Khamnigans) and Tungusic/Nivkh-speaking populations (e.g., Negidals, Nanai, Ulchi, and Nivkhs) together with the only available ancient genome from the Rouran-period Mongolia."

"The remaining 9 late-Avar-period individuals show minor (<40%) to almost negligible (<5%) admixture with ANA-related sources, while the major ancestry component can be approximated by one of the preceding local groups for most of the individuals"

In discussions of these eras, hundreds of years can go by rather quickly. Still, the mobility and dynamism of these peoples is astonishing. Rome had already experienced the knock-on effects of tribes such as the Scythians driving other peoples westward before them. And the Indo-European invasions were something similar, farther back in the mists of time. Such migrations and conquests kept on happening, thanks to the love these people had for their horses, the endless flatness of the landscape, and the rich pickings available among settled cultures around their periphery.

The Steppe region marked in brown. Sites of burial remains that were sequenced are marked, extending clear across Asia, allowing the authors to classify particularly early and high-status burials in the Carpathian basin (left-most) as most related to a far eastern origin.

Today, Russia (whose lengthy period under Mongol rule strongly shaped its culture) has resumed the mortal competition for empire among the flatlands of Central Asia and Eastern Europe. While we can marvel at the relentless valor of Huns and Avars, seeing such ruthlessness up close in our own time isn't abstract history, it is thoroughly appalling.

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Join Ukraine

It is time to make Ukraine part of NATO and dispense with the charade of arms-length relations.

The war in Ukraine has been a pure crime from the start, founded on lies and imperialism of the most old-fashioned sort. The West has long shied from directly allying itself with Ukraine, because Ukraine is so physically and culturally close to Russia. So in deference to old ideas of neighborhoods, spheres of influence, and defensive buffers, and the like, we have respected that we might create a large mess by taking NATO so close up to Russia's borders and self-interest. 

Well, the mess has happened, and not by our doing. Ukraine has on its own progressively rejected the Russian sphere over the last decade, and for a variety of very good reasons taken steps to become an independent, functional Western-aligned democracy. (Unlike, say, Belarus.) Russia has in response taken the most brutal approach to bullying- killing and maiming what they can not take by corruption, threats, and diplomacy. Ukraine has fought back valiantly, but will be trapped in an endless frozen / slogging conflict unless it gets definitive help from the West.

There are two endgames in sight. One is that Russia keeps up its attack, in an effort to destroy or at least hobble Ukraine, physically and politically, perhaps even genocidally. Russia at this point has taken the worst the West has to offer, and the best defense the Ukrainians have to offer. It has been beaten off partially, but far from completely. From what we have seen, Putin can, and probably intends to, keep up the pressure on Ukraine indefinitely. Ukraine would become another Chechnia or Syria. This is not a good end-game, either for Ukraine or for the future of international relations among civilized countries- a wolf stealing back an empire, sheep by sheep.

Current state of the war in Ukraine.

Another endgame is that the US and allies intervene, make Ukraine peremptorily a member of NATO, join the fight, and definitively eject Russia from Ukrainian territory, including the Donbas and Crimea. Given what we have seen so far, this is for NATO a militarily achievable objective. These allies would naturally make it clear that attacking Russia proper is not our aim, though may be necessary if Russia attacks other NATO countries or persists in raining missiles / aircraft from across the border. 

The major question is how Russia might choose to escalate / retaliate. It has threatened nuclear war, in not so many words. I think such a course is highly unlikely, since Russia is trying to build a historical legacy here, not destroy one, or destroy itself. Deterence still holds, on both sides. Not to mention the fact that Western bombs are much more likely to be actually operational, given what we have seen of the Russian military. Additionally, adding Ukraine to the NATO umbrella with its various explicit guarantees will provide that much more deterrence against a nuclear attack on Ukraine, arguably forestalling such a worst-case outcome, even given the madness at hand.

Far more likely would be an assortment of alternative spoiler activities, like increased cybercrime and perhaps attacks in space on our satellites, maybe a few potshots into Europe, at the Baltics, etc. Projection to other areas of the world is highly unlikely, given that Russia would have its hands full on its neighboring front, and will lose a great deal of military capability over time. All these are acceptable costs, I think, for the durable lesson a repulse of wanton criminality would teach both Russia and China.

On the other hand, we should never demonize Russia per se or bar its future entry into Europe, given a change of government and heart. Their main problem is Putin and his imperial / delusional / autocratic system, not the people at large. Just as Ukraine (barely) beat off Putin-style corruption in their political system, Russia could as well, some day, and durable peace in Europe depends entirely on this happening as soon as possible. Which will in turn be brought closer, the sooner Russia is definitively evicted from Ukraine.

Remember the first Iraq war? Iraq had invaded Kuwait to take over its oil fields, and generally to express its contempt and superiority, including a historical claim that it was not, actually, a separate country. The US argued that this was in intolerable violation of sovereign borders and international norms. But the motivation was really just about the oil, not to preserve the democratic government of Kuwait, of which there was none. Nor was there a pre-existing alliance, but rather we conjured one on the spot out of convenience, cobbled together out of our various friends and petro-clients. The current case for alliance with and defense of Ukraine is far more compelling.

---

As this post was going to press, an opinion piece appeared by Jeffrey Sachs, promoting negotiation. He sees the same destructive stalemate developing as outlined above, (as do many others), and his solution is for the West to offer one thing- a guarantee to Russia that Ukraine will not join NATO. In return, Russia would vacate Ukraine to pre-war boundaries. Some may recall Sachs as a key advisor of the post-Soviet transition, and exponent of rapid transitions to capitalism, i.e. shock therapy. While the approach produced a transition, it is commonly looked at, retrospectively, as excessively shocking, and conducive to the uncontrolled and corrupt disposition of assets that led directly to the wild west of the post-Soviet transition, rise of the oligarchs, and the ensuing kleptocracies, the worst of which is Russia itself. So the track record is not great. In the current case, it is hard to make out an actual negotiating position from what Sachs proposes. Russia is in Ukraine, certainly by this point, for far more than a promise -cross our hearts- that Ukraine stays out of NATO. It is clear that Putin's aim is to quash Ukrainian democracy and freedom, so that Russia will not have a peskly neighbor better off and better governed than itself. It wants another Belarus, either by decapitation or by decimation.

My proposal above would form, on the other hand, an actual negotiating position vis-a-vis Russia. The West would offer two options. The first is that Russia vacate Ukraine to the 2021 lines and stay out, and that Ukraine remains independent and outside NATO, at least for the time being, but without future assurances. The other is that we immediately ally NATO with Ukraine, join in force with air and land power, and push Russia out of the Donbas and also out of Crimea, forceably and permanently. Again, we would make it clear that while attacks into Russia might be necessary to gain airspace control and repel artillary, etc., the ultimate lines would be set in advance, and not go into Russian proper, pre-2013. This would be a productive negotiating position, capable of inducing Putin to think carefully about his options. Losing Crimea would be the fulcrum, as well as the prospect of rapid integration of Ukraine into NATO as its front-line state.

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Love Beauty Truth

Book review of "Finding your Feet after Fundamentalism", By Darrell Lackey. With apologies to the other book.

An old friend has published a book. We had an epistolary relationship, fretting about creationism, intelligent design, and related topics back when those were livelier issues than today (and it directly inspired the birth of this blog). He was on his way out of Christian fundamentalism, and into something more liberal, even post-modern. His new book is a somewhat autobiographical account of the problems of fundamentalism, and of leaving fundamentalism as one's tradition. Naturally, evangelism dies hard, and takes this new form of broadcasting the good news of a more moderate and decent Christianity.

The book hits hardest on the issue of Donald Trump. No scandal has so thoroughly demonstrated the ultimate hypocrisy of fundamentalism than its allegiance to Trump. The transaction has given religious conservatives control of the Supreme Court, (though perhaps that owed more to Mitch McConnell), but in return, they showed their support for the most morally vile and incompetent person ever to hold the job. Lackey relates how he was fully in the FOX news orbit in the 90's, happily imbibing its bile. But then something snapped, and by the time of the Trump election, he had fully left fundamentalism and its communities behind. Living in California might have something to do with it, since liberalism, at least of a lip-service sort, is the dominant way of life here. Something that Republicans have learned the hard way. 

Yet the interesting part is how strenuously Lackey hews to Christianity, proclaiming that liberal versions are not gateway drugs to atheism. Quite the contrary- close attention to the actual New Testament provides ample justification for things like supporting marginalized communities, helping the poor, afflicting the rich, and viewing one's enemies as possibly reasonable human beings, if not friends in the making. He mentions how false it is for evangelicals to be so eager to spread the good word, but at the same time so deaf to the words of others that actual relationship is impossible- an evangelism of a closed-off community. 

For what are the fundamental values? Lackey cites love and beauty. Love is clear enough, (and damning enough regarding the FOX- driven culture of conservative Christianity), but the role of beauty needs a little more explaining. Religious thinkers have spared no effort in extolling the beauty of the world, but in the current world, serious artists are rarely Christian, let alone make Christian art. Why is that? Perhaps it is just intellectual fashion, but perhaps there is a deeper problem, that art, at least in our epoch, is adventurous and probing, seeking to interrogate narratives and power structures rather than celebrate them. Perhaps it is a problem of overpopulation, or of democracy, or of living in late imperial times, or of modernism. But whatever the framework, contemporary Christian communities have become the opposite of all this- anti-intellectual, tone-deaf, and art-hostile (not to mention power-mad). It must be exasperating to someone with even the least appreciation for finer things and for art that is "interesting".

Jean-Michel Basquiat- too messy for insensitive temperaments.

Beauty has deep Christian connotations. The world is god-made, good, and thus beautiful, as indeed we all feel it to be. But life is also messy, competitive, and dark. Death and suffering are part of it as well. If we refuse to own those aspects of the world, and of ourselves, we become blinded to the true nature of things, and expose ourselves to unintended and invisible expressions of the dark side, as we see in the deep hypocrisy on the subject of Trump, on sexual morals, and countless other areas within fundamentalism / evangelicalism. Lackey ticks off a lengthy list of subjects where conservative Christians have become blind to the obvious teachings of Jesus while fixated on relatively minor cultural flashpoints and red meat- symptoms of a general moral blindness borne of, arguably, flaccid aesthetic and intellectual habits.

So I would like to offer another value, which is truth. As a scientist, it is a natural place for me to start, but I think it is both illuminating of, and interrelated with, the other virtues above. What modern artists seek is to express truths about the human condition, not just ring out positive affirmations and hallelujas. Truths about suffering as well as truths about beauty. What scientists seek to do is to find how this world we find ourselves in works, from the cosmos down to the gluon. And they do so because they find it beautiful, and, like addicts, would like to unlock more of that beauty. Beauty inspires love, and love ... can only survive on truth, not lies. So I think these values live in a reinforcing cycle.

All that implies that there is another step to take for someone who has left fundamentalism. That is, to re-evaluate Christianity as a whole. While the achievement of decency (and better taste) by the renunciation of FOX and its religious satellite communities is an enormous step, indeed a momentous one for the preservation of our country's sanity, grappling seriously with the value of truth would suggest an extra leg to the trip. Not to put too fine a point on it, but Christianity as a whole is a questionable proposition, philosophically. As a narrative and moral system, it clearly has positive as well as negative potentials. But as a "truth"- with its miracles, resurrections, triune deity, and salvation at the end of the line, (whether for the elect, the saved, the good, or for all)- well, it is impossible to take seriously without heavy doses of tradition and indoctrination.

For his part, Lackey has headed in another direction, into the Eastern Orthodox church, finding a place that richly satisfies the fundamentalist urge to return to one of the most traditional and historically continuous churches in existence, and also one that does not tie itself into intellectual knots about literal truth, living biblically, and the like. Orthodoxy accepts mystery, and cherishes its ancient rites and structures as sufficient theology. It is not modernist, or goaded by the enlightenment to make a rational system of something that so obviously resists reason. 

For there is a fine line between lies, illusions, and truths. As anyone who is married will understand (or a citizen of a country, or part of a corporation, or part of any social structure), truth is not the only or necessarily best virtue. A bit of illusion and constructive understanding can make a world of difference. Narrative, ideology, framing, etc. are essential social glues, and even glues of internal psychology. So, given that illusions are integral, the work to identity them, bring them into consciousness, and make positive choices about them is what matters, especially when it comes to social leadership. Do we choose narratives that are reasonably honest, and look forward with hope and love, or ones that go down the easy road of demonization and projection? And what role should the most traditional narratives in existence- those of the ancient religions- have in guiding us?

• Beautiful? You be the judge.
• Kasparov on freedom and evil.
• Kids should be able to navigate neighborhoods.
• Lies and disinformation are a public health crisis.
• More variants are always coming along.
• We are not doing enough against climate heating.

Exploring the Engram

A little more on how memories are stored, with notes on homeostasis.

Neuroscience is in a golden age, where age-old problems are yielding to new technologies and accumulated insight. Where are memories stored? Well, in the brain- we have known that for a long time (but not forever!). Then came the beautiful discovery of neurons, as investigated and drawn by Ramon Cajal. More recently, there has been a realization that memories reside in "engrams", or patterns of neurons which can be created by coordinated firing, and later re-activated by firing some fraction of those engram neurons to trigger re-activation of the full memory. Does that mean they are stored in individual synapses, the connections between neurons? Not really- synapses apparently turn over quite frequently, so long-term memories need a more stable substrate, such as a set of neurons whose synaptic connections, while plastic and turned over periodically, are kept generally consistent- perhaps by periodic re-activation of the engram or other means.

A neuron, in the artistry of Ramon Cajal, complete with plenty of dendrites and spines (tiny nubs) which are where synapses have been constructed to talk to incoming signals. The main output (axon) is probably the slightly thicker process going upward.

A recent paper explored by simulation how such a system would work. The reigning paradigm is Hebbian, per Donald Hebb, where neurons that fire coordinately increase the strength of their connections, while others do not. This rule would create, out of a random matrix of neurons, engram-resembling assemblies of neurons that have stronger connections and get re-activated when the original stimulus comes along. But there is a problem, which is that activation under such a simple theory would be unbounded, creating run-away assemblies that fire constantly and gradually take over the whole brain. There has to be a homeostatic mechanism that balances out the firing characteristics so that the memory is "hidden", in the sense that it does not produce unusual activation characteristics unless specific activating inputs come along. 

That is what this paper explores, modeling a neuron/synapse system that is notionally auto-balancing, in that it reduces the connection of the engram neurons with outside neurons even while it increases their internal connectivity to represent the engram. The net effect is that spontaneous firing over the tissue (model) as a whole, from random inputs, is unchanged even though a memory trace is resident and can be called out any time with a specially coordinated set of inputs.

A modeled set of neurons, including an engram. At top is a representation of each neuron as a dot, activated as time goes by on the X axis. Looks a bit like old-fashioned TV snow, as do most brain signals. The black bars show the activation of a memory engram, where its set of neurons fire a bit more than average (green line) and get connected to each other slightly better. This is immediately followed by a compensating decrease of connectivity which kicks in to isolate the engram a bit from the surrounding network, thus rebalancing overall activity back the snow pattern. Panel C shows an overall decrease in synapses as the compensation mechanism is modeled, and Panel D shows connectivity, which is increased among the engram cells (green), and decreased slightly between the engram and other cells (gray), and unchanged on average overall (blue).

The researchers find this a pretty realistic portrayal and model of what might be going on IRL, as it were. The mechanism behind this, as stated at the top, is not just a single synapse, but a whole network of connectivity among some (small) set of neurons, as carried out by transcriptional programs, new protein synthesis and the development of new synapses here, fewer there, and so forth, among many connected neurons. It is maintained by repeated recall / re-activation, as happens during dreaming, and conversely can degrade and be forgotten in the absence of such reinforcement, as new engrams are over-written on the tissue. What is the size of such neuron engram sets, and how are neurons selected to participate? The Hebbian theory posits that the more strongly active neurons would be pulled into such a network, automatically, at the moment of memory creation. Given a rather even, snow-like pattern of default activity in neural tissue, such activation would naturally be distributed evenly as well, avoiding existing engrams (due to their reduced outside connectivity) unless some explicit similarity were present in the new pattern. The researchers' model had 10,000 neurons, of which a random 1,000 were used to activate memory ensembles (the model also had 2,500 inhibitory neurons interlaced, for homeostasis).

Lastly, there is the fascinating question of generalization. Memories are useful only if they are not too specific. If they are only recalled under the precise conditions of creation, there is hardly much point to keeping them. If they are triggered by every other, or loosely related, experience, however, you have PTSD, which is also not good. The system needs to possess a balance so that a memory can be recalled by a sufficiently similar experience or situation, such that it can usefully inform some choice that the organism is facing in a novel environment, or be recalled at a dinner party without too much re-enactment being required. This is another area of homeostasis, by which the brain keeps things humming by carefully balancing competing needs / processes. A bit of recent work found two genes which are expressed in different cells within memory engram collections, and which mark the apparently competing subsets as either prone to generalization (Fos) by getting exciting inputs, or prone to restriction/specialization (Npas4) by getting inhibitory inputs. Thus each engram is composed of competing components, all in the ultimate interest of balance so that we have useful access to important memories, forget unimportant ones, and are not overwhelmed with traumatic ones.

• Pay people to be deprogrammed?
• Trumpists very strong? More like wet noodles.
• Top Republicans, compared.
• We have not exactly defunded the police.
• More on covid infectiousness.
• More details on the job guarantee in MMT.
• Graph of the week... our emissions keep going up, not down.

E. O. Wilson, Atheist

Notes on the controversies of E. O. Wilson.

E. O. Wilson was one of our leading biologists and intellectuals, combining a scholarly career of love for the natural world (particularly ants) with a cultural voice of concern about what we as a species are doing to it. He was also a dedicated atheist, perched in his ivory tower at Harvard and tilting at various professional and cultural windmills. I feature below a long quote from one of his several magnum opuses, Sociobiology (1975). This was putatively a textbook by which he wanted to establish a new field within biology- the study of social structures and evolution. This was a time when molecular biology was ascendent, in his department and in biology broadly, and he wanted to push back and assert that truly important and relevant science was waiting to be done at higher levels of biology, indeed the highest level- that of whole societies. It is a vast tome, where he attempted to synthesize everything known in the field. But it met with significant resistance across the board, even though most of its propositions are now taken as a matter of course ... that our social instincts and structures are heavily biological, and have evolved just as our physical features have.

A Brief History of DNA Sequencing

Technical revolutions that got us to modern DNA sequencing.

DNA is an incredibly elegant molecule- that much was apparent as soon as its structure came out. It is structurally tough, and its principles of information storage and replication are easy to understand. It is one instance where evolution came with, not a messy hack, but brilliant simplicity, which remains universal over all the life that we know. While its modeled structure was immediately informative, it didn't help to figure out its most important property- its sequence. Methods to sequence DNA have gone through an interesting evolution of their own. First were rather brutal chemical methods which preferentially cut DNA at certain nucleotides. Combined with the hot new methods of labeling the DNA with radioactive P32, and of separating DNA fragments by size by electically pushing them (electrophoresing) through a jello-like gel, this could give a few base pairs of information.

A set of Maxam-Gilbert reactions, with the DNA labeled with 32P and exposed to X-ray film after being separated by size by electrophoresis through a gel. Smallest are on the bottom, biggest fragments on on the top. Each of the four reactions cleaves at certain bases, as noted at the top. The intepretation of the sequence is on the right. PvuII is a bacterial enzyme that cleaves DNA, and this (palindromic) sequence noted at the bottom is the site where it does so.

Next came the revolution led by Fred Sanger, who harnessed a natural enzyme that polymerizes DNA in order to sequence it. By providing it with a mixture of natural nucleotides and defective ones that terminate the extension process, he could easily develop far bigger assortments of DNAs of various lengths (that is, reads) as well as much higher accuracy of base calling. The chemistry of the Maxam-Gilbert chemical process was quite poor in base discrimination. This polymerase method also eventually used a different isotope to trace the synthesized DNAs, S35, which is less powerful than P32 and gave sharper signals on film, which was how the DNA fragments were visualized after laid out and ordered by size, by electrophoresis.

The Sanger sequencing method. Note the much longer read length, and cleaner reactions, with fully distinct base specificity. dITP was used in place of dGTP to help clarify G/C-rich regions of sequence, which are hard to read due to polymerase pausing and odd behavior in gel electrophoresis. 

There have been many technological improvements and other revolutions since then, though none have won Nobel prizes. One was the use of fluorescent terminating nucleotides in place of radioactive ones. In addition to improving safety in the lab, this obviated the need to generate four different reactions and run them in separate lanes on the electrophoretic gel. Now, everything could be mixed into one reaction, with four different terminating fluorescent nucleotides in different colors. Plus, the mix of synthesized DNA products could now be run through a short bit of gel held in a machine, and a light meter could see them come off the end, in marcing order, all in an automated process. This was a very significant advance in capacity, automatability, and cost savings.

Fluorescent terminating nucleotides facilitate combined reactions and automation.

After that came the silicon chip revolution- the marriage between Silicon Valley and Biotech. Someone discovered that silicon chips made a good substrate to attach DNA, making possible large-scale matrix experiments. For instance, DNA corresponding to each gene from an organism could be placed at individual positions across such a chip, and then experiments run to hybridize those to bulk mRNA expressed from some organ or cell type. The readout would then be fluorescent signals indicating the level of expression of each gene- a huge technical advance in the field. For sequencing, something similar was attempted, laying down all possible 8 or 9-mers across such a chip, hybridizing the sample, thereby trying to figure out all the component sequences of the sample. The sequences were so short, however, that this never worked well. Assembling a complete sequence from such short snippets is nearly impossible.

What worked better was a variation of this method, where the magic of DNA synthesis was once again harnessed, together with the matrix layout. Millions of positions on a chip or other substrate have short DNA primers attached. The target DNA of interest, such as someone's genome, is chopped up and attached to matching primers, then hybridized to this substrate. Now a few amplification steps are done to copy this DNA a bunch of times, all still attached in place to the substrate. Finally, complementary strands are all melted off and the single DNA strands are put through a laborious step-by-step chemical synthesis process, similar to how artifical DNA is made to order, across the whole apparatus, with chemicals successively washed through. No polymerase is used. Each step ends with a fluorescent signal that says what the base that just got added was at that position, and a giant camera or scanner reads the plate after each pass, adding +1 to the sequence of each position. The best chemical systems of this kind can go to 150 or even 300 rounds (i.e. base pairs), which, over millions of different DNA fragments from the same source, is enough to then later re-assemble most DNA sequences, using a lot of computer power. This is currently the leading method of bulk DNA sequencing.

A single DNA molecule being sequenced by detecting its progressive transit through a tiny (i.e. nano) pore, with corresponding electrical readout of which base is being wedged through.

Unfortunately, our DNA has lots of repetitive and junky areas which read sizes of even 300 bases can not do justice to. We have thousands of derelict transposons and retroviruses, for instance, presenting impossible conundrums to programs trying to assemble a complete genome, say, out of ~200 bp pieces. This limitation of mass-sequencing technologies has led to a niche market for long-read DNA sequencing methods, the most interesting of which is nanopore sequencing. It is almost incredible that this works, but it is capable of reading the sequence of a single molecule of single stranded DNA at a rate of 500 bases per second, for reads going to millions of bases. This is done by threading the single strand through a biological (or artifical) pore just big enough to accommodate it, situated in an artifical membrane. With an electrical field set across the membrane, there are subtle fluctuations detectable as each base slips through, which are different for each of the four bases. Such is the sensitivity of modern electronics that this can be picked up reliably enough to read the single thread of DNA going through the pore, making possible hand-held devices that can perform such sequencing at reasonable cost.

All this is predicated on DNA being an extremely tough molecule, able to carry our inheritance over the decades, withstand rough chemical handling, and get stuffed through narrow passages, while keeping its composure. We thought we were done when we sequenced the human genome, but the uses of DNA sequencing keep ramifying, from forensics to diagnostics of every tumor and tissue biopsy, to wastewater surveillance of the pandemic, and on to liquid biopsies that promise to read our health and our future from a drop of blood.

• Is originalism progressive?
• Crypto is insane- a climate disaster, ponzi-ridden, crime-facilitating, sanctions-busting.
• Who lies, and who believes them? It tends to be a consistent demographic.
• The insurrection is not over.
• "The Capitalist system was never designed to satisfy societal needs."
• How do you pronounce "mayonnaise"?
• Big box and big parking lot solar? Obviously a good thing.
• Jane Fonda is onboard.

(No) Sympathy for the Devil

Blaming ourselves for Russia's attack on Ukraine.

Here we are, in a time warp back almost a century. A European country has elected an authoritarian leader, on the support of a doddering president. That leader went on to resolve the economic and politicial crisis of the country, mostly by taking complete control himself and forming an increasingly repressive fascist state. Nationalist propaganda and lies were ceaselessly conveyed through the state media, paving the way for attacks on other countries, generally portrayed as critical to protect fellow countrymen being oppressed there. The aggression and the lying escalated until here we are, in a full scale international war, with distinct chances of becoming a world war. 

In the US, there are strange convergences of support for the Russian side of this conflict. Those on the fringe left can not tear themselves away from respect for the Russia that was the Soviet union and vanguard of world communism. Nor can they resist bashing the US. The far right is infatuated with the new Russia, with its super-Trump leadership, free-wheeling criminality, and clever propaganda, as many Americans were of Hitler back in the day. But a third stream comes from the foreign policy establishment- the realists, who think spheres of influence are the most normal, god-given organizing principles of international affairs. Thus China should be given its suzerainty over South East Asia, including Taiwan, and Russia over its near abroad, whatever the people actually living there may think. We are to blame for pushing NATO to Russia's borders, we are to blame for injuring Russia's sensitivities and pride, and we have caused their invasion of Ukraine, by luring Ukraine to the West with our sweet blandishments.

Well, each of those views is out of touch in its own way, but the last is especially curious. For what was the post-World War 2 order about, if not about civilized behavior among nations, letting each seek prosperity and freedom, in peace? The realist view would plunge us back into medieval power relations, or perhaps the three-sphere world of George Orwell's 1984. It consigns small countries to the depredations of bullies like Russia, who can not make friends in a civilized manner, but, in Ukraine, has strained every nerve to corrupt its political system, destroy its internet, and obliterate its sovereignty and economy.

It is obvious to all, including Russia, that NATO was and remains a defensive alliance, of countries intent above all else to rebuild after World War 2 without further aggressive encroachment by Russia. And once the Soviet Union fell apart, the Eastern Bloc countries fled as fast as they could to the West, not because they wanted to attack Russia in a new World War 3, but quite the opposite- they wanted to pursue the promise of freedom and prosperity in peace, without bullying from Russia. Russia's much vaunted "sensitivities" are nothing more than toxic, domineering nostalgia for their former oppressive empires, of both Czarist and Soviet times. As the largest country in the world, one would think they have enough room, but no, their sense of greatness, unmatched by commensurate cultural, economic, or moral accomplishment, demands bullying of its neighbors. More to the point, their current system of government- autocracy / fascism by ceaseless lying and propaganda, would be impaired by having their close neighbors have more open, civilized systems. 

All this has a religious aspect that is interesting to note as well. Ukraine recently extricated itself from domination by the Moscow orthodox church, becoming autocephalic, in the term of art. The process shows that even in this supposedly supernatural sphere of pure timeless principle, tribalism and politics are the order of the day. Not to mention propaganda, and fanciful philosophy and history. The narratives that Russia as spun about Ukraine and its invasion are particularly virulent, unhinged, and insulting, insuring that Ukraine would never, in any sane world, want to have anything to do with their neighbor. It is one more aspect of the Russian aggression that spares us from needing to sympathize overly with its "sensitivities".

So, what to do? It is not clear that Ukraine can withstand Russian attacks forever. They have stopped Russia in its tracks, thanks to a lot of Western assistance. They have millions of men under arms, compared to a much smaller invasion force. They have motivation and they have the land. But they need heavier weapons and they need to preserve their air power. With those two things, they could turn the tide and drive Russia out. Without them, they will probably only manage a stalemate. Western sanctions have imposed highly justifiable pain on Russia itself, but historically, such sanctions tend to have as much countervailing effect, consolidating pro-government attitudes, as the opposite. So barring a dramatic turn of events at the top of the Russian system, which is highly unpredictable and rather unlikely, we are facing a very drawn out and destructive war in Ukraine.

In a larger sense, we are facing something far more momentous- the rise and assertion of autocracy (not to say fascism 2.0) as a competing world order. Russia's pattern has been clear enough (and historically eerie)- escalate their aggression and ambition as far as they can get away with. And China is watching carefully. The ability of the West to punish Russia for its completely immoral and cruel attack on Ukraine, and deter future repetitions, will shape the next century. Russia has decisively broken the borders and tranquility of the post-World War 2 order, and that has caused many, especially in Europe, to wake up and realize that coasting along on US coat tails is not enough- they have to actively participate in sanctioning Russia, in resolving their dependence on Russian fossil fuels (as if that had not been patently obvious before), and strengthening the collective defence, as expressed in NATO. Western leaders should make it clear that Putin and his key lieutenants will never be allowed to personally enter the West without being shipped off the Hague for trial. And we should give Ukraine what it needs to defend itself.

Finally, what of our own culpability? Not so much in mistreating Russia, which we have done only to a slight degree, but in committing war crimes of our own, in attacks of our own, based on lies of our own, on innocent countries far distant. I am speaking of Iraq (which ranks first among several other cases). While our justification for that war was far better than Russia's in Ukraine, it was still poor, still caused hundreds of thousands of deaths, was grievously misconceived and mismanaged, and has left a political ruin, not to mention a geopolitical mess. This alone should make George W Bush rank among the worst of US presidents- significantly lower than Trump, who for all his destructiveness, did not destroy whole countries. We should be willing to put Bush and others who made those decisions to an historical and international account for their actions, in a spirit of historical rectitude.

• In praise of Washington's teaming minions.
• New thoughts on an old book.
• A song for Ukraine.

DNA Damage Domain Declines to Bind DNA

How one protein domain changed through time.

The BRCA1 and BRCA2 genes are notorious for harboring mutations that increase susceptibility to breast cancer (thus their name, breast cancer type 1 (or 2) susceptibility protein). They have therefore been intensively studied for what they do in the normal course of our cellular lives. Their common naming does not mean they are similar- their structures are completely different. They play related, but distinct, roles in DNA repair, which is naturally influential in our susceptibility to cancer caused by DNA mutations.

An article some time back delved into the history of one domain of the BRCA1 protein, tracing how its functions have changed significantly over evolutionary time. BRCA1 is a large gene encoding a large protein, (1863 amino acids long), composed of several domains. Proteins frequently possess several domains in order to integrate several functions in an orderly way, such as binding a few different partners that together form a complex and carry out some function. Modular protein domains facilitate evolution by being easily duplicated, transferred, and generally being able to be passed around, thanks to rearrangement mutations. BRCA1 has domains that bind to at least 11 other proteins,  most of which play some role in DNA damage responses. So it is a key protein, and damage to it has correspondingly bad effects. 

The domains of BRCA1. Each one has some role in the protein's function, which integrates responses to DNA damage. The BRCT domains are on the very end, right side. NLS is nuclear localization (import) sequence, and NES is the nuclear export signal. These would be typically regulated by other interacting proteins or phosphorylation, to control the access of BRCA1 to the nucleus.

The domain of interest here is the BRCT, or BRCA1 C-terminal domain. It is ~90 amino acids long and BRCA1 has two of them, side by side. Other work has shown that it binds to other proteins, but only after they have been modified by phosphate addition. The DNA damage sensor ATM is one such kinase that adds phosphates to BRCA1 targets such as Abraxis. Thus the BRCT domain plays the key role of bringing this DNA damage repair integrating protein to the right sites, where there is DNA damage to repair. 

Structure of the BRCT double domains in BRCA1 (E). The pocket that binds a phosphorylated serine residue on a partner protein such as abraxis is shown in teal, and in (C), close up. (B) shows a single BRCT domain.

This paper did a sensitive computer search for all possible versions of this domain in all available species and proteins, finding it in 23 human proteins, and in species all the way back to bacteria, so is quite ancient. And the phylogeny they reconstruct indicates that the original versions of these domains had a different function, which was to bind DNA directly, at sites of DNA damage! Such frayed ends also have phosphate groups, so it isn't a huge leap from one function to another. Additionally, other examples of BRCT domains have dispensed with phosphate-dependent binding altogether, but simply bind other proteins regardless. This transition may have happened after phosphorylation became the central way to alert the cell, and key proteins, to the existence of DNA damage, instead of dealing with it solely through enzymes that find & fix such damage directly. This transition allowed a much more robust response by cells, which now includes halting the cell division cycle and activating other stress responses to help the cell recover.

Some of the BRCT domains (along with many others) found in various species and their proteins.

The BRCT domain is mostly used among proteins involved in DNA repair, and even in humans some versions bind DNA directly (PARP1, RFC1). So through the long path of evolution, this single domain has stuck generally to its original role, while it also- along with the organisms and proteins it acts within- diversified and ramified in its functions. From an initial role in direct DNA damage and end recognition, it has become a card-carrying member of the bureaucracy of the cell, playing regulatory and organizing roles within numerous actors important to DNA handling and repair. It is a classic story of how eukaryotes used their surfeit of energy and material resources to develop whole orders of novel molecular, and concomitant outward, complexity.

• There are a lot of places we shouldn't get our energy from.
• But we are hopelessly dependent and immature.
• Partisan hack on the Supreme Court.
• What the Russians think of negotiation.
• Is it more than a job? Should it be?
• Ruminations on war.

Toxic Nostalgia

Making Russia great again.

What is it about the past? Even though we are condemned to live in the future, we can't stop fantasizing and fetishizing the past, and wanting to go back. On the gentle side, Proust wrote nothing but loving remembrances of his (sometimes mortifying) past, trying to evoke its moods, textures, smells, and feelings. But why does nostalgia so often curdle into bloodlust and terror? For that is where the Russian autocrat is going with his nostalgia for the Soviet era when Stalin ruled even more autocratically over a well-cowed populace extending from Hungary to the Pacific. Ah, those were the days!

It isn't just our current crisis- far from. The Trumpists want to make America great... again. The Muslim jihadists are bent on reproducing the pre-eminent dominance of Islam of 1300 years ago. The Serbs hearken back to their own grand empire of 700 years ago. Shia muslims fetishize their losses and in a theology of repair and redemption. Jews have both bemoaned their losses of their great kingdoms two millennia ago, and militantly sought their promised land back. And fundamentalists of all stripes yearn to get back to the basic tenets of their faith- the pure origins of incendiary belief and miracles.

It all seems a little over-determined, as though the operative emotion isn't nostalgia exactly, but powerlust, seizing on whatever materials come to hand to say that we as some tribe or culture are better and deserve better than we've got. While the future remains ever shrouded, the past is at least accessible, if also rather protean in the hands of dedicated propagandists. In Russia's case, not only did Stalin help start World War 2 by co-invading Poland, but the prior holocaust/famine in Ukraine, followed by the transplacement of millions of Russians into Ukraine.. well, that all makes this current bout of nostalgia far from sympathetic, however well-twisted it has been for internal consumption. Of course the propaganda and the emotion is mostly instrumental, in a desperate bid to fend off the appearance of happy, secure, and prosperous democracies on Russia's borders, which is the real danger at hand, to Putin and his system.

In remembrance of Russia's great patriotic war, which it helped start.

Yet, such nostalgia is strongly culturally binding, for better or worse. Rising states may have short histories and short memories, resented as the nouveau-rich on the world stage. They are not "as good" in some essential way as those whose greatness has passed into the realm of nostalgia. Worth is thus not in the doing but in some ineffible essentialist (read nationalist/tribal) way that is incredibly resistant to both reason and empathy. It is analogous to "nobility" in the class structure within most societies. In the US, we seem on the cusp (or past it) of our time atop the world stage. Do we then face hundreds of years of regret, comforting ourselves with tales of greatness and seething resentment?

With echos of a deeper past.

• Could the West have been smarter; more generous?
• Apparently, we are all going to die.
• Tires are bad.