Living on the Edge of Chaos

 Consciousness as a physical process, driven by thalamic-cortical communication.

Who is conscious? This is not only a medical and practical question, but a deep philosophical and scientific question. Over the last decades and century, we have become increasingly comfortable assigning consciousness to other animals, in ever-wider circles of understanding and empathy. The complex lives of chimpanzees, as brought into our consciousness by Jane Goodall, are one example. Birds are increasingly appreciated for their intelligence and strategic maneuvering. Insects are another frontier, as we appreciate the complex communication and navigation strategies honeybees, for one example, employ. Where does it end? Are bacteria conscious?

I would define consciousness as responsiveness crosschecked with a rapidly accessible model of the world. Responsiveness alone, such in a thermostat, is not consciousness. But a nest thermostat that checks the weather, knows its occupant's habits and schedules, and prices for gas and electricity ... that might be a little conscious(!) But back to the chain of being- are jellyfish conscious? They are quite responsive, and have a few thousand networked neurons that might well be computing the expected conditions outside, so I would count them as borderline conscious. That is generally where I would put the dividing line, with plants, bacteria, and sponges as not conscious, and organisms with brains, even quite decentralized ones like octopi and snails, as conscious, with jellyfish as slightly conscious. Consciousness is an infinitely graded condition, which in us reaches great heights of richness, but presumably starts at a very simple level.

These classifications imply that consciousness is a property of very primitive brains, and thus in our brains, is likely to be driven by very primitive levels of its anatomy. And that brings us to the two articles for this week, about current theories and work centered on the thalamus as a driver of human consciousness. One paper relates some detailed experimental and modeled tests of information transfer that characterizes a causal back-and-forth between the thalamus and the cortex, in which there is a frequency division between thalamic 10 - 20 Hz oscillations, whose information is then re-encoded and reflected in cortical oscillations of much higher frequency, at about 50 - 150 Hz. It also continues a long-running theme in the field, characterizing the edge-of chaos nature of electrical activity in these thalamus-cortex communications, as being just the kind of signaling suited to consciousness, and tracks the variation of chaoticity during anesthesia, waking, psychedelic drug usage, and seizure. A background paper provides a general review of this field, showing that the thalamus seems to be a central orchestrator of both the activation and maintenance of consciousness, as well as its contents and form.

The thalamus is at the very center of the brain, and, as is typical for primitive parts of the brain, it packs a lot of molecular diversity, cell types, and anatomy in a very small region. More recently evolved areas of the brain tend to be more anatomically and molecularly uniform, while supporting more complexity at the computational level. The thalamus has about thirty "nuclei", or anatomical areas that have distinct patterns of connections and cell types. It is known to relay sensory signals to the cortex, to be central to sleep control and alertness. It sits right over the brain stem, and has radiating connections out to, and back from, the cerebral cortex, suggestive of a hub-like role. 

The thalamus is networked with recurrent connections all over the cortex.

The first paper claims firstly that electrical oscillations in the thalamus and the cortex are interestingly related. Mouse, rats, and humans were all used as subjects and gave consistent results over the testing, supporting the idea that, at very least, we think alike, even if what we think about may differ. What is encoded in the awake brain at 1-13 Hz in the thalamus appears in correlated form (that is, in a transformed way) as 50-100+ Hz in the cortex. They study the statistics of recordings from both areas to claim that there is directional information flow, not just marked by the anatomical connections, but by active, harmonic entrainment and recoding. But this relationship fails to occur in unconscious states, even though the thalamus is at this time (in sleep, or anesthesia) helping to drive slow wave sleep patterns directly in the cortex. This supports the idea that there is a summary function going on, where richer information processed in the cortex is reduced in dimension into the vaguer hunches and impressions that make up our conscious experience. Even when our feelings and impressions are very vivid, they probably do not do justice to the vast processing power operating in the cortex, which is mostly unconscious.

Administering psychedelic drugs to their experimental animals caused greater information transfer backwards from the cortex to the thalamus, suggesting that the animal's conscious experience was being flooded. They also observe that these loops from the thalamus to cortex and back have an edge-of-chaos form. They are complex, ever-shifting, and information-rich. Chaos is an interesting concept in information science, quite distinct from noise. Chaos is deterministic, in that the same starting conditions should always produce the same results. But chaos is non-linear, where small changes to initial conditions can generate large swings in the output. Limited chaos is characteristic of living systems, which have feedback controls to limit the range of activity, but also have high sensitivity to small inputs, new information, etc., and thus are highly responsive. Noise is random changes to a signal that may not be reproducible, and are not part of a control mechanism.

Unfortunately, I don't think the figures from this paper support their claims very well, or at least not clearly, so I won't show them. It is exploratory work, on the whole. At any rate, they are working from, and contributing to, a by now quite well-supported paradigm that puts the thalamus at the center of conscious experience. For example, direct electrical stimulation of the center of the thalamus can bring animals immediately up from unconsciousness induced by anesthesia. Conversely, stimulation at the same place, with a different electrical frequency, (10 Hz, rather than 50 Hz), causes immediate freezing and vacancy of expression of the animal, suggesting interference with consciousness. Secondly, the thalamus is known to be the place which gates what sensory data enters consciousness, based on a long history of attention, ocular rivalry, and blind-sight experiments.

A schematic of how stimulation of the thalamus (in middle) interacts with the overlying cortex. CL stands for the ventral lateral nucleus of thalamus, where these stimulation experiments were targeted. The greek letters alpha and gamma stand for different frequency bands of the neural oscillation.

So, from both anatomical perspectives and functional ones, the thalamus appears at the center of conscious experience. This is a field that is not going to be revolutionized by a lightning insight or a new equation. It is looking very much like a matter of normal science slowly accumulating ever-more refined observations, simulations, better technologies, and theories that gain, piece by piece, on this most curious of mysteries.

• Narrowing down the neurons that do word recognition in the brain.
• The consequences of zoning restrictions are homeless people and functionally gated communities.
• They aren't even trying any more.
• The court's immunity is total immunity.

Links Only

 Due to the press of other business, only links this week:

• We are heading into a bipolar world.
• The scammy (and Trumpy) side of tech.
• What happens when employers run job training programs.
• It is an emergency.
• Hypocrisy piled onto hypocrisy.
• Chinatown.

Incidentally, decades of work in hundreds of labs has resulted in an integrated view of how RNA transcription from DNA begins.

Where Did Flowers Come From?

Are angiosperms 135 million years old, or 275 million years old?

We live among a hodgepodge of plants from different evolutionary epochs, with flowering plants being the most recent, (including the even more recently evolved grasses), alongside the more ancient conifers, cycads, ferns, mosses, and lichens. All have a place in diverse ecosystems, but what is their true history? This has been difficult to establish in more than broad outlines, due, as usual, to the patchy nature of the fossil record, and the difficulties of aligning it with what we now have as the molecular record. Angiosperms have been a particular sore spot, ever since Darwin, who recognized that the sudden appearance and radiation of flowering plants, roughly 130 million years ago, was a problem for evolutionary theory.

A paper from a few years back offered a carefully aligned molecular and fossil analysis of angiosperms, coming to the conclusion that they actually originated ~275 million years ago (MYA), and must have persisted in some cryptic fashion through the ensuing 150 MY before making a splash in the fossil record. How is this kind of analysis done? First, the best early fossils are tabulated, with secure dating and clear characteristics that include them among angiosperms. The most ancient example is a sample of pollen, from roughly 125 million years, which looks strongly like it came from angiosperms. These fossils are also assigned to plant lineages, so that their appearance can inform the branching points of the phylogenetic diagram, whether that diagram is based purely on these fossils and their morphology, or based on molecular data.

Then a set of gene sequences is collected, which are conserved between all the surveyed species, and aligned so that their changes can be fed into a program that counts all the differences. It was clear through this work that some lineages changed faster than other ones (the faster ones are marked with blue flares towards the right. Since the sampled species are all ones that exist now (time 0), being able to provide DNA, and since the branch points are in any case shared between the lineages that descend from them(at their origination points), faster change / evolution in one lineage vs another will be readily apparent, and the researchers just have to make up some rules to judge where to come down in time assignments when faced with such discrepancies. The more serious problem is that such different speeds can totally derange this kind of analysis, making a faster-changing lineage seem much older than it is. So pinpointing the branch points between lineages is extremely important to pin down such hard-to gauge branch lengths. 

Biologically, it is now well known that lineages vary substantially (up to ten fold, less so in longer lineages and time spans) in their speed of molecular change.. molecular evolution is not a clock. Faster change tends to happen when populations are small, and when big evolutionary transitions have happened. For example, plants, and specifically angiosperms, have gone through whole-genome duplications that represent major evolutionary watersheds. These duplications supplied raw material for countless diversifications and specializations of genes, with especially rapid change in molecular sequences either released from previous selective constraints, or subject to new ones via new roles.

Integrated phylogenetic diagram of the evolution of angiosperms, marking key fossils that inform branch point timing (lettered blue circles), and ranges of possible branch points derived from the molecular alignments (red circles). At bottom is time, in millions of years before present.

What can explain the big gap in estimated angiosperm origins? There are three basic hypotheses. First is that the molecular data is correct, which implies that there is an extremely long (150 million years) history of cryptic angiosperms that have not (yet) been detected in the fossil record. There are smatterings of findings in the literature that suggest that such fossils may be (or may have been) found, but I don't think these have been widely accepted yet (especially when they come from highly questionable sources).

The second hypothesis is that something about the very early evolution of angiosperms (like the very early evolution of eukaryotes, and the very early diversification of macroscopic animals) was accelerated in molecular terms, (as discussed above in terms of differing rates between lineages), rendering the apparent molecular phylogeny much longer than the real one. That includes the prodigious radiation of the many lineages in the diagram above, all before the first fossil is found.

The third hypothesis, much beloved of creationists, is that god did it. A mystery like this is ripe for invoking the solution to all mysteries, which is it does not need to be explained in the normal mechanistic terms of the natural world, but rather can be chalked up to the author of all things, god. While this hypothesis, at least for believers, solves this one nagging mystery, it brings on a few others. Why does the rest of biology through this vast lineage still follow the plodding path of gradual (if uneven) development? Why jump in to create this mystery when so many other lineages in the fossil record do not present similar mysteries? Why did god insist upon, (presumably for the ultimate appearance of us as humans), the whole four billion year process of life's plodding development, when the whole thing could have been authored at once and at the start? What amazing societies we could have developed with a four billion year head start!

It is clear, therefore, that some hypotheses create more problems than they solve. Inviting scientists to consider and comment on harebrained hypotheses is not going to end well. The solution to this problem is going to be some combination of the first two hypotheses, of rapid molecular evolution at the start of a major radiation, and some as-yet missing material in the fossil record. Innovative organisms are very likely to be rare, though whole cryptic lineages surviving for many tens of millions of years is hard to posit without more evidence. Yet it is also a given that fossils will necessarily appear after the actual events of lineage branching, thus will always post-date the calculated molecular branching point.

• World albatross day.
• As if FOX wasn't bad enough.
• Ignorance (and cruelty) is MAGA.
• My vote is going to count.

The Quest for the Perfect Message, in E. coli

Translation efficiency has some weird rules, and a tortured history.

One would think we know everything there is to know about the workhorse of bacterial molecular biology, Escherichia coli. And that would be especially true for its technological applications, like the expression of engineered genes, which is at the very heart of molecular biology and much of biotechnology. Getting genes you put into E. coli expressed at high levels is critical for making drugs, and for making enough for structural and biochemical studies. For decades, the wisdom of the field was to design introduced genes using the codon adaptation index (CAI). This is a measurement of the three-letter codes (codons of the genetic code) that are used in highly expressed genes. They tend to correspond to tRNAs that are more abundant in the cell. So, for example, the amino acid leucine is encoded by six different codons, any of which can be chosen at intended leucine positions in the intended protein. In E. coli, CTG is over ten times more frequently used than CTA, however. Thus, even though they code for the same amino acid, one is more common, perhaps because its cognate tRNA is more common and more easily used during translation. This is basically a diffusion-based argument, that translation will be easier if the tRNA that carries the next amino acid is easier to find.

A recent paper provides a remarkable review of this field. For one thing, it turns out that use of the CAI has virtually no effect on translation efficiency. Whether using rare or common codons, translation is equally efficient for introduced genes. Needless to say, this is quite surprising. It seems as though the role of common vs uncommon tRNAs/codons is more to manage the health of the cell by relieving bottlenecks to translation in a global sense and managing the free pool of ribosomes, rather than regulating the efficiency of translation of any particular mRNA message. tRNAs are highly abundant generally, so there are significant savings possible by managing their levels judiciously, and reducing investment in some versus others.

So what does affect the efficiency of translation? Some messages are better translated than others, after all. The authors point to a completely different mechanism, which is the melting stability of the first ten codons of the mRNA message. RNA can form hairpin and other secondary structures / shapes, and this can apparently strongly affect the ability of ribosomes to find initiation sites. While eukaryotic ribosomes scan in from the 5 prime cap of the mRNA, bacterial ribosomes bind directly to a sequence slightly upstream of the initiating AUG codon. And this can be inhibited by mRNAs that are not neatly ironed out, but knotted up in hairpins and loops. 

Ratio of occurrence of nucleosides in the third codon position of the first ten codons of high versus low expressing genes in E. coli. This was not run on native E. coli genes, but on a large panel of transgenes engineered from outside. The strong bias towards A at this position in high expressing genes shows a preference for initiating sequences to have weak secondary structure, allowing better ribosome access.

Use of A-rich sequences around the ribosomal initiation sites and the first ten codons, then, dramatically increases the translation efficiency, (via the initiation efficiency) of introduced genes, and provide a much more robust method to control their expression. But then the authors make another observation, which is that the bacteria themselves do not seem to use this mechanism for their own genes. In a massive analysis of data from other labs, (below), there is actually a negative correlation between the quality of the initiation region (X- axis) and the abundance of the respective protein (Y- axis). Again, quite a surprising result, which the authors can only speculate about. 

There is negative correlation between the initiation codon quality (X- axis), as shown above, and the native E. coli gene expression level (Y- axis). So these cells are not optimizing their translation at all in accordance with the findings above.

The picture that they paint is that highly expressed genes in E. coli benefit from consistent, smooth translation. This depends less on maximal initiation speed than on the holistic picture of translation. The CAI optimal codons (called translationally optimal in this paper, or TO) tend to be poor at initiation, but have good codon-anticodon pairing and thus low A content. So there are conflicting pressures at work, in basic chemical terms, where different codons are intrinsically good for initiation, and complementary ones for elongation. The obvious solution is to use the initiation-optimal codons for the first ten codons, and translationally optimal codons the rest of the way. But that is not what is found either. The authors claim that, for native proteins, lower levels of initiation are actually beneficial for smoother protein production with less noise from time to time and cell to cell. 

Additionally, lower initiation rates preserve free ribosome levels globally, another important goal for the cell, via evolutionary selection. The authors find, for instance, a correlation between low variability of initiation (low noise) and low initiation rate. This is a bit mystifying, since ribosomes should always be present in excess, and it is not immediately apparent why holdups to translation initiation would lend themselves to more even initiation. Perhaps the search process by which ribosomes find free mRNAs is inefficient, so that those with slower initiation sequences have a constant backlog of incoming, bound and poised ribosomes, while after they get past the initiation region, those ribosomes progress rapidly and rejoin the free pool. That would be one way of setting up a smooth production process, suitable for essential protein products, that is relatively insensitive to the free ribosome concentration and other variations in the cell.

Technologists trying to express some drug-associated protein in bacteria don't care about smoothness and noise, but just want to maximize production while not killing the cell (or before killing the cell). So all these subtle considerations that go into the evolution of the native gene complement of E. coli and its high or low expression levels don't apply. But for researchers trying to predict the expression level of a given natural gene, it is maddening, since it seems currently impossible to predict the expression level (via translation) of a gene from its sequence. It is one more case where modeling of what is going on inside cells is surprisingly difficult, even for a system we had thought we understood, in one of the simplest and most well-studied bacteria. As researchers never tire of saying ... more research is needed.

• War suits Russia very well.
• The same old Microsoft.

A Membrane Transistor

Voltage sensitive domains can make switches out of ion channels, antiporters, and other enzymes.

The heart of modern electronics is the transistor. It is a valve or switch, using a small electrical signal to control the flow of other electrical signals. We have learned that the simple logic this mechanism enables can be elaborated into hugely complex, even putatively intelligent, computers, databases, applications, and other paraphernalia of modernity. The same mechanism has a very long history in biology, quite apart from its use in neurons and brains, since membranes are typically charged, well-poised to be sensitive to changes in charge for all sorts of signaling.

The voltage sensitive domain (VSD) in proteins is an ancient (going back to archaea) bundle of four alpha helices that were first found attached to voltage-sensitive ion channels, including sodium, potassium, and calcium channels. But later it became fascinatingly apparent that it can control other protein activities as well. A recent paper discussed the mechanism and structure of a sodium/hydrogen antiporter with a role in sperm navigation, which uses a VSD to control its signaling. But there are also voltage-sensitive phosphatases, and other kinds of effectors hooked up to VSD domains. 

Schematic of a basic VSD, with helix 4 in pink, moving against the other three helices colored teal. Imagine a membrane going horizontally over these embedded proteins. When voltage across the local membrane changes, (hyperpolarized or de-polarized), helix 4 can plunge by one helical repeat unit in either direction, up or down.

One of the helixes (#4) in the VSD bundle has positive charges, while the others have specifically positioned negative charges. This creates a structure where changes in the ambient voltage across the membrane it sits in can cause helix #4 to plunge down by one or two steps (that is, turns of the alpha helix) versus its partners. This movement can then be propagated out along extensions of helix #4 to other domains of the protein in order to switch on or off their activities.

The helices of numerous proteins that have a VSD domain (in red) are drawn out, showing the diversity of how this domain is used.

While the studied protein, SLC9C1, is essential in mammalian sperm for motility, the paper studied its workings in sea urchin sperm, a common model system. The logic (as illustrated below) is that (female) chemoattractants bind to receptors on the sperm surface. These receptors generate cyclic GMP, which turns on potassium channels that increase the voltage across the membrane. This broadcasts the signal locally, and is received by the SLC9C1 transporter, which does two things. It activates a linked soluble adenylate cyclase enzyme, making the further signaling molecule cAMP. And it also activates the transporter itself, pumping protons out (in return 1:1 for sodium ions in) and causing cytoplasmic alkalinization. The cAMP activates sodium ion channels to cancel the high membrane voltage (a fast process), and the alkalinization activates calcium channels that direct the sperm directional swimming responses- the ultimate response. The latter is relatively slow, so the whole cascade has timing characteristics that allow the signal to be dampened, but the response to persist a bit longer as the sperm moves through a variable and stochastic gradient.

A schematic of the logic of this pathway, and of the SLC9C1 anti-porter. At top, the transport mechanism is crudely illustrated as a rocking motion that ensures that only one H+ is exchanged for one Na+ for each cycle of transport. The transport is driven thermodynamically by the higher concentration of Na+ outside.

But these researchers weren't interested in what the sperm were thinking, but rather how this widely used protein domain became hitched to this unusual protein and how it works there, turning on a sodium/hydrogen antiporter rather than the usual ion channel. They estimate that the #4 helix of the VSD moves by 10 angstroms, or 1 nm, upon voltage activation, which is a substantial movement, roughly equivalent to the width of these helices. In their final model, this movement significantly reshapes the intracellular domain of the transporter, which in turn releases its hold on the transporter's throat, allowing it to move cyclically as it needs to exchange hydrogen ions for sodium ions. This protein is known to bind and activate an adenylyl cyclase, which produces cAMP, which is one key next actor in the signaling cascade. This activation may be physically direct, or it may be through the local change in pH- that part is as yet unknown. cAMP also, incidentally, binds to and turns up the activity of this transporter, providing a bit of positive feedback.

Model of the SLC9C1 protein, with the VSD in teal and a predicted activation mechanism illustrated (only the third panel is activated/open). Upon voltage activation, the very long helix 4 dips down and changes orientation, dramatically opening the intracellular portion of the transporter (purple and orange portion). This in turn lets go of the bottom of the actual transporter portion of the protein (gray), allowing alkalinization of the cytoplasm to go forth. At the bottom sides, in brown, is the cAMP binding domain, which lowers the voltage threshold for activation.

There are a variety of interesting lessons from this work. One is that useful protein domains like VSD are often duplicated and propagated to unexpected places to regulate new processes. Another is that the new cryo-electron microscopy methods have made structural biology like this far easier and more common than it used to be, especially for membrane proteins, which are exceedingly difficult to crystalize. A third is that signaling systems in biology are shockingly complex. One would think that getting sperm cells to where they are going would take a bare minimum of complexity, yet we are studying a five or more part cascade involving two cyclic nucleotides, four ions, intricate proteins to manage them all, and who knows what else into the mix. It is difficult to account for all this, other than to say that when you have a few billion years to tinker with things, and have eons of desperate races to the egg for selective pressure, they tend to get more ornate. And a fourth is that it is regulatory switches all the way down.

• A tale of two empires.
• Epicureanism
• UCP1 and the evolution of warm-bloodedness.
• Can your amoeba do this?
• Bonkers discussion of consciousness and panpsychism.

Imperialism for Thee, but Not for Me

Realism, idealism, and false realism in the Ukraine war.

The Ukraine war has been a disaster. That much is certain. But who caused it, and could it have been averted with better policy from us? And what would the costs of such a policy have been? There is a large school of foreign policy "realists" (exemplified by John Mearsheimer) who think that Russia was driven to this war by the inexorable encroachment of NATO towards the Russian borders. Thus we are at fault, just as much as Russia, which is actually dropping bombs on Ukraine and cutting a blood-soaked swath through its eastern and southern regions. The imperialism of Russia over its neighbors is perfectly understandable, realistic, and OK. By this argument, Russia has been crystal clear that offering Ukraine the distant prospect of NATO membership, as we did in 2008, was a declaration of war (by us!). Russia has tried to negotiate in good faith all through this time, and kept working for peace, even as it could see its interests eroded, and the necessity of war increasing. Till at last, it was forced by our policy to take over Crimea, and ultimately, in the face of increasing infiltration by Western interests in Ukraine, launch the full scale war we see today.

While this is one perspective on the level of grand strategy and traditional balance of power views, it leaves out one of the actors in the drama, and is a curious way to apportion blame for manifest evil. The actor it leaves out is Ukraine, which might want to have some say in its own destiny. And the evil is the way in which this realist school casually consigns countries to "spheres of influence", fated to be sat upon by their neighboring bullies. Perhaps world history is one long story of bullies fighting it out over riches and territory. But does it have to be? It does not, and therein lies the difference between war and peace, blame and praise.

Realists point to America's own empire, perhaps most explicitly outlined in the Monroe Doctrine. This statement by John Quincy Adams claimed the entire Western Hemisphere to be a special zone where European meddling was unwelcome, and defended by the nascent power of the United States. This was largely aspirational at the time, and European imperialist powers continued meddling in the hemisphere nevertheless, even invading the US itself in the war of 1812. And of course, the Monroe doctrine was not intended to set up a US empire at all, but was rather an anti-imperialist document, promoting the self-determination of the countries of South and Central America. We have since certainly done our share of meddling, taking several large portions of Mexico for our own territory, corrupting various Central American countries in commercial and anti-communist quasi-empires. But on the other hand, for the most part we have had friendly and peaceful relations, even (the shambolic Bay of Pigs invasion aside) keeping our hands off of Soviet-allied Cuba.

Evolution of the Russian empire, over the centuries. Whether the areas under Russian occupation ever wanted to be there, or now wish to stay there, remains a live question.

It is clear that our view of empire is not, currently, a traditional one. We have lots of friends, lots of allies, and lots of power, of soft and hard kinds. But we have not set up a barrier of involuntary client states against regional threats. NATO is emblematic as a voluntary alliance. It was and remains a collective (if US-dominated) alliance of countries trying to deter a third world war. Such a war was first contemplated to arise from the European antagonists who had just fought the two preceding wars - Germany, France, and the UK. But as they rebuilt their societies on both an economic and moral basis, it quickly became clear that the real threat was going to come from the new Soviet Empire, which had quickly swallowed up all of Eastern Europe. 

Each of these Eastern European countries had their dreams of freedom crushed in the wake of Germany's defeat, and each was correspondingly eager to leave the Soviet Empire when the cold war, at long last, came to an end. Vladimir Putin blames Mikhail Gorbachev for loosening the reins and thoughtlessly letting the empire crumble. The current Russian state celebrates its greatest holidays around the high water mark of another leader, more the Putin's taste- Joseph Stalin, when Russian power was at its (relative) peak. Putin's idea of power is expressed in his relation with Belarus- a thoroughly cowed and pliant frontier, from which Russian conveniently launched a large portion of its invasion of Ukraine. It is typical of this curdled and "realist" perspective that the wishes of the people involved count for nothing. Their aspirations and well-being are irrelevant, the imperial state and its power are what matter. 

As an aside, Michael Kimmage has recently written a book-length analysis of Ukraine. It is a quite balanced history of the whole run-up to the war, laying out the moves, thoughtless or not, taken by both sides. Here, one gets a sense that Putin was sensing weakness in the West, in the wake of our Iraqi and Afghan debacles. But where this book really shines is in its epilogue, which is a pean to the power of history itself.

"Countries invariably conceive their foreign policies in reaction to earlier conflicts. They are led by their sense of who was wrong and who was right, of what the core problem was and what the solution to that problem was, fighting the last war until it is no longer the last war. The preoccupation with the past can be the path to wisdom, of learning from history, or it can leave countries trapped in their interpretations of the past. To investigate the origins of an ongoing war, then, is not just to chart the present moment. It is to peer, however uncertainly, into the future."

Kimmage recounts how Germany turned historical analysis on its head after World War 1 to claim that others had started it, and others were responsible for Germany's defeat, thus setting the table for a second round. Similarly, it is Putin's potted analysis of the cold war and its appalling aftermath for Russia that forms the motivation for his current war. Just like realism, this theory of the power of historical narrative serves to explain motivations and actions, and by understanding absolve the actors, to some degree, of culpabilty, making the current conflict seem inevitable. In this case, the West was doltishly uninformed and sleepwalked into an unnecessary war. 

But history is not a given. It is, in places like Russia, a product of the propaganda organs, not the science organs. It is narrated with a grievence and a point in mind, and can be, in the right hands, tailored to lead to practically anything the leader wishes to happen. The idea that we should be beholden to the historical analysis of another country or its leader, and thus be on the hook for appeasing their "legitimate" demands, feelings, etc. is absurd. However much such understanding helps us analyze what other actors have in mind, it should not bind our analysis of the same history, or of the broader functioning of the international system.

Returning to the realist perspective, it recognizes the lowest common denominator in an anarchic environment- raw power. It is the mafia approach to foreign relations. Well, we have an answer to that, which is a modern perspective, modeled in a modern state that has and uses overwhelming policing power against aggressors. It is enlightenment values that have suffused Europe, providing the peace seen on the continent among the members of NATO and the EU. We have gotten so used to living amidst civilized values that a Russian invasion of Ukraine seemed unthinkable, despite a long train of preliminary invasions, explicit policy statements from Russia, and propaganda preparation. Europe should have used its power to immediately push Russia back out of Ukraine. That would have been the ideal scenario to safeguard the values that Ukraine was aspiring to, and that the West embodies.

So, what about nuclear weapons and World War 3? Russia has been rattling its nuclear saber, resorting to any threat it can to keep Ukraine weak and friendless. Needless to say, it would not be wise of Russia to use nuclear bombs in Ukraine. Whatever grievances / justification Russia has for its invasion, even internally, would collapse immediately. I think everyone recognizes that nuclear weapons exist for mutual and existential deterrence, notionally protecting Russia (in this case) from invasion by other countries. Fine. Helping Ukraine rid itself of a cruel bully, restoring its independent and original borders, is, conversely, fully justified and is the kind of aim that lends itself to a limited war. At very least at this point, we should provide Ukraine with the wherewithal for air superiority over its own territory.

Russia exemplifies old thinking from the anarchic world order. It (and China as well) want to drag the world back into that world, recreating the glory days of Stalin's empire. Or even Catherine the Great's. It is in the power of the West, as a growing collective of democratic and prosperous countries, to deny these aims, rather than appeasing them. And the expeditious and effective use of police power in Ukraine would yield dividends into the future, strengthening the collective power of the West to foster the freedom and self-determination of other nations. Could this protective concept allow movement the other way? Sure- Hungary, for instance, might want to join the Russian orbit and leave the EU. And good riddence! They would be welcome to do so. These alignments should not be determined by war, (nor, hopefully propaganda and corruption), but by national sentiment and interest.

The primitive mafia mindset is also one that afflicts certain precincts of US politics, notably the Republican presidential candidate, who can't see beyond "strength" and machismo, and seems more likely to support Putin than NATO or Ukraine. It is another case of cavalier disregard not only of decades of collective work by the West to sustain a civilized international order, but of elementary concepts of justice and self-determination. Maintaining a just peace takes steadfastness, work and sacrifice. If we do nothing, then sure, the bullies will win and the world will go right back to one where bullies have only other bullies to be afraid of. If last week's Memorial day means anything, however, it is that collective sacrifice over the long arc of US history has always served, at least in principle, more freedom and less tyranny- for others, not just ourselves.

• Incredibly, Voyager 1 is back on track and transmitting. From 162 astronomical units (0.94 light day) from earth.
• The reason why our country is in this perilous position is ... lying liars.
• The state of corruption today.
• Alito throws wife under the bus.

Nascent Neurons in Early Animals

Some of the most primitive animals have no nerves or neurons... how do they know what is going on?

We often think of our brains as computers, but while human-made computers are (so far) strictly electrical, our brains have a significantly different basis. The electrical component is comparatively slow, and confined to conduction along the membranes of single cells. Each of these neurons communicate with others using chemicals, mostly at specialized synapses, but also via other small compounds, neuropeptides, and hormones. That is why drugs have so many interesting effects, from anesthesia to anti-depression and hallucination. These properties suggest that the brain and its neurons began, evolutionarily speaking, as chemically excitable cells, before they became somewhat reluctant electrical conductors.

Thankfully, a few examples of early stages of animal evolution still exist. The main branches of the early divergence of animals are sponges (porifera), jellies and corals (ctenophora, cnidiaria), bilaterians (us), and an extremely small family of placozoa. Neural-type functions appear to have evolved independently in each of these lineages, from origins that are clearest in what appears to be the most primitive of them, the placozoa. These are pancake-like organisms of three cell layers, hardly more complex than a single-celled paramecium. They have about six cell types in all, and glide around using cilia, engulfing edible detritus. They have no neurons, let alone synaptic connections between them, yet they have excitable cells that secrete what we would call neuropeptides, that tell nearby cells what to do. Substrances like enkephalins, vasopressin, neurotensin, and the famous glucagon-like peptide are part of the managerie of neuropeptides at work in our own brains and bodies.

A placozoan, about a millimeter wide. They are sort of a super-amoeba, attaching to and gliding over surfaces underwater and eating detritus. They are heavily ciliated, with only a few cell types divided in top, middle, and bottom cell layers. The proto-neural peptidergic cells make up ~13% of cells in this body.

The fact is that excitable cells long predate neurons. Even bacteria can sense things from outside, orient, and respond to them. As eukaryotes, placozoans inherited a complex repertoire of sense and response systems, such as G-protein coupled receptors (GPCRs) that link sensation of external chemicals with cascades of internal signaling. GPCRs are the dominant signaling platforms, along with activatable ion channels, in our nervous systems. So a natural hypothesis for the origin of nervous systems is that they began with chemical sensing and inter-cell chemical signaling systems that later gained electrical characteristics to speed things up, especially as more cells were added, body size increased, and local signaling could not keep up. Jellies, for instance, have neural nets that are quite unlike, and evolutionarily distinct from, the centralized systems of animals, yet use a similar molecular palette of signaling molecules, receptors, and excitation pathways. 

Placozoans, which date to maybe 800 million years ago, don't even have neurons, let alone neural nets or nervous systems. A recent paper labored to catalog what they do have, however, finding a number of pre-neural characteristics. For example, the peptidergic cell type, which secretes peptides that signal to neighboring cells, expresses 25 or more GPCRs, receptors for those same peptides and other environmental chemicals. They state that these GPCRs are not detectably related to those of animals, so placozoans underwent their own radiation, evolving/diversifying a primordial receptor into hundreds that exist in its genome today. The researchers even go so far as to employ the AI program Alpha Fold to model which GPCRs bind to which endogenously produced peptides, in an attempt to figure out the circuitry that these organisms employ.

This peptidergic cell type also expresses other neuron-like proteins, like neuropeptide processing enzymes, transcription regulators Sox, Pax, Jun, and Fos, a neural-specific RNA polyadenylation enzyme, a suite of calcium sensitive channels and signaling components, and many components of the presynaptic scaffold, which organizes the secretion of neuropeptides and other transmitters in neurons, and in placozoa presumably organizes its secretion of its quasi-neuropeptides. So of the six cell types, the peptidergic cell appears to be specialized for signaling, is present in low abundance, and expresses a bunch of proteins that in other lineages became far more elaborated into the neural system. Peptidergic cells do not make synapses or extended cell processes, for example. What they do is to offer this millimeter-sized organism a primitive signaling and response capacity that, in response to environmental cues, prompts it to alter its shape and movement by distributing neuropeptides to nearby effector cells that do the gliding and eating that the peptidergic cells can't do.

A schematic of neural-like proteins expressed in placozoa, characteristic of more advanced presynaptic secretory neural systems. These involve both secretion of neuropeptides (bottom left and middle), the expression of key ion channels used for cell activation (Ca++ channels), and the expression of cell-cell adhesion and signaling molecules (top right).

Why peptides? The workhorse of our brain synapses are simpler chemicals like serotonin, glutamate, and norepinephrine. Yet the chemical palette of such simple compounds is limited, and each one requires its own enzymatic machinery for synthesis. Neuropeptides, in contrast, are typically generated by cleavage of larger proteins encoded from the genome. Thus the same mechanism (translation and cleavage) can generate a virtually infinite variety of short and medium sized peptide sequences, each of which can have its own meaning, and have a GPCR or other receptor tailored to detecting it. The scope of experimentation is much greater, given normal mutation and duplication events through evolutionary time, and the synthetic pipeline much easier to manage. Our nervous systems use a wide variety of neuropeptides, as noted above, and our immune system uses an even larger palette of cytokines and chemokines, upwards of a hundred, each of which have particular regulatory meanings.

An evolutionary scheme describing the neural and proto-neural systems observed among primitive animals.

The placozoan relic lineages show that nervous systems arose in gradual fashion from already-complex systems of cell-cell signaling that focused on chemical rather than electrical signaling. But very quickly, with the advent of only slighly larger and more complex body plans, like those of hydra or jellies, the need for speed forced an additional mode of signaling- the propagation of electrical activity within cells, (the proto-neurons), and their physical extension to capitalize on that new mode of rapid conduction. But never did nervous systems leave behind their chemical roots, as the neurons in our brains still laboriously conduct signals from one neuron to the next via the chemical synapse, secreting a packet of chemicals from one side, and receiving that signal across the gap on the other side.

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Emergency- Call UCP!

Uncoupling proteins in mitochondria provide a paradoxical safety valve.

One of the great insights of biochemistry in the last century was the chemiosmotic theory, which finally described the nature of power flows in the mitochondrion. Everyone knew that energetic electrons were spun off the metabolism (burning) of food via the electron transport chain, ending up re-united with oxygen (creating the CO2 we breathe out). But how was that power transmitted to ATP? The key turned out to be a battery-like state across the mitochondrial membrane, where protons are pumped out by the electron transport chain, and then come back in while turning the motor of the ATP synthase to phosphorylate ADP into ATP. It is the (proton) concentration and charge difference (that is, the chemiosmotic gradient) across the inner mitochondrial membrane that stores and transmits this power- a clever and flexible system for energizing the mitochondrion and, indirectly, the rest of the cell.

Schematic view of the electron transport chain proteins, as well as the consumer of its energy, the ATP synthase. The inside of the mitochondrial matrix is at top, where core metabolism takes place to generate electrons, resulting in protons pumped out towards the bottom. Protons return through the ATP synthase (right) to power the phosphorylation (so-called oxidative phosphorylation) of ADP to ATP.

Chemiosmotic theory taught us that mitochondria are always charged up, keeping a balance of metabolism and ATP production going, all dependent on the tightness of the inner mitochondrial membrane, which was the "plate" that keeps the protons and other ions sealed apart. But over the years, leaks kept cropping up. In the human genome, there are at least six uncoupling proteins, or UCPs, which let protons through this membrane, on purpose. What is the deal with that?

One use of these proteins is easy enough to understand- the generation of heat in brown fat. Brown fat is brown because it has a lot of mitochondria, which are brown because of the many metal- and iron-hosting enzymes that operate at the core of metabolism. UCP1 is present in brown fat to generate heat by letting the engine run free, as it were. It is as simple as that. But most of the time, inefficiency is not really the point. The other UCP proteins have very different roles. On the whole, however, it is estimated that proton leaks from all sources eat up about a fourth of our metabolic energy, and thus evidently play a role in making us warm blooded, even apart from specialized brown fat.

A more general schematic that adds UCP proteins to the view above. Leaks also happen through other channels, such as the membrane itself, and also the ANT protein, at low and non-regulated rates..

One big problem of mitochondria is that they are doing some quite dangerous chemistry. The electrons liberated from metabolism of food have a lot of energy, and the electron transport chain is really more like a high voltage power station. The proteins in this chain are all structured to squeeze all the power they can out of the electrons and into the proton gradient. But that runs the risk of squeezing too hard. If there is a holdup anywhere, things can back up and electrons leak out. If that happens, they are likely to combine with oxygen in an uncontrolled way that generates compounds like peroxide, superoxide, and hydroxy radicals. These are highly reactive (customarily termed ROS, for reactive oxygen species) and can do a great deal of damage in the cell. ROS is used in some signaling systems, such as the pathway by which glucose stimulates insulin secretion in the pancreas, but generally, ROS is very bad for the cell and rises exponentially with the severity of blockages in the electron transport chain. Many theories relating to aging and how to address it revolve around the ongoing damage from ROS.

Thus the more important role for the other UCP proteins is to function as a safety valve for overall power flow through mitochondrial metabolism- a metaphorical steam valve. UCP proteins are known to be inducible by ROS, and when activated, allow protons to run back into the matrix, which relieves the pressure upstream on all the electron transport chain proteins, which are furiously pumping out protons in response to the overall metabolic rate of fat/sugar usage. While metabolism is regulated at innumerable points, it is evident that, on a moment-to-moment basis, an extra level of regulation, i.e. relief, is needed at this UCP level to keep the system humming with minimal chemical damage to the rest of the cell.

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The Lucky Country

The story of California, the story of the US, and optimism about free frontiers.

I am reading "California, the great exception". This classic from 1949 by Cary McWilliams is stoutly jingoistic and pro-California. But it also provides a deeper analysis of the many things that made California such an optimistic and happy place. Mainly, it boils down to free land and rapid settlement by ambitious working people. The Native Californians were so weak, and so ruthlessly extirpated, that they did not present the irritating conflict that happened elsewhere in the US. California's gold was so widely and thinly distributed (as placer in streams) that mining was a matter of small partnerships, not huge businesses, as it became elsewhere in the West, in the deep hard rock silver and later copper mines of Nevada (Carson city and the Comstock lode) and Montana (Butte). The immigrants were of working age and enthusiastic to work, dismissing slavery and corporatism in favor of a rapacious entrepreneurialism. 

California never had a paternal territorial government, but transitioned directly from self-rule to statehood, its riches speaking volumes to the national government in Washington. And the national government was anxious lest secessionist sentiment spread to the still far-distant west, so it funded the building of a transcontinental railway, during the civil war when money must have been extremely tight. That feared secession was not to join the South, but rather to found a new and prosperous nation on the West Coast. San Francisco went on to serve as the financial capital of the West, particularly of western mining, creating almost overnight a collusus to rival the centers of the East. In due time, gushers of oil also appeared on the California landscape. It is no wonder that Californians became fundamentally optimistic, ready to take on huge challenges such as water management, building a great education system, and the entertainment of the world.

California was also blessed by weak neighbors on all sides. There were no foreign policy predicaments or military threats. It could nurse its riches in peace. It was, in concentrated form, the story of America- of a new continent limited more by its ability to attract and grow its population than by its land and the riches that land held. An isolated continent that wrote its society almost on a blank slate- a new government and a melting pot of people from many places. 

Bound for California, around 1850.

How stark is the contrast to a country like Ukraine, neighbor of imperialist Russia and before that host to the Scythians, Goths, and Huns. A flat land exposed on all sides, that has been overrun countless times. A fertile land, but always contested. The idea that history would stop, that Ukraine could join the West, and enjoy its riches in peace and security- that turns out to have been a dream that bullies in the neighborhood have a different view on. Better to beat up on the little "brother" than to build up both nations and economies through beneficial exchange and prosperity. Better for both to go down in flames than that the little "brother" escapes the bully's clutches into a more humane world.

But the happy place of the US and Calfornia has hit some rough patches too. It turns out that our resource riches are not endless after all. The foundation of material wealth- the agricultural land, the mines, the lumber- underwrote social and technological innovation. No wonder the US was first in flight, and led the way in electricity, automobiles, the internet, the cell phone. Now we have an innovation economy, and get much of our materials and lower-grade goods from far-off places. The people we have attracted and continue to attract are the new wealth, but therein lies a conflict. Places like California have huge homeless populations because we have ceased to grow, ceased to embody the hope and optimism of our lucky past. Conflict has raised its head. There is no more free land, or gold in the streams. Now, with the land all parcelled up and the forests mowed down, everyone wants to hold on to what they have, and damn those who come after. Prop 13 was the perfect expression of this sour and conservative mood- let the newcomers pay for public services, not us.

California is transitioning from a visionary frontier into a cramped, normal, and not especially lucky place. The fabulous climate is suffering under fire and drought. The population is growing significantly older, while next generation is educated less well then their parents. The app innovation economy has fostered a nightmare of surveillance and social dysfunction. The pull of a new frontier is so strong, however, that some of our richest people now imagine it on other planets. The irony of sending rockets, fueled by vast amounts of fossil carbon and compressed oxygen, to other worlds where there isn't even air to breathe, let alone plants to cut down, begs belief. It is the final gasp of a dream that somewhere, out there, is another lucky country.

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Neutrophils Ask: How Did I Get Here?

With apologies to the Talking Heads... how the amoeboid cells of our immune system travel around in response to outside cues like cytokines.

Amoeboid cells seem so alive and even conscious. They seek out prey, engulf, and kill it. How is that done, and what are they thinking? Molecular biologists naturally come at this from a molecular perspective, asking what the signals are, how are they received, what pathways relay them to the cytoskeleton, and so forth. No soul is assumed, and none has been found, despite the great complexity of these cells and their activities.

The story starts with receptors at the surface, which can sense many of the cytokines of the immune system, of which there are roughly a hundred. These have many roles, including pro-inflammatory and anti-inflammatory effects. Neutrophils, which are the subject of today's paper, also have receptors that directly sense pathogens, like bacterial cell coats, viral double stranded RNA, and also broken cells, like DNA out in the environment where it shouldn't be. One question is how these cells sense shallow gradients- they can orient properly with as little as two percent difference in concentration between back and front. This is thought to involve pretty strong feedback systems that accentuate the stronger signal and then keep strengthening it in concert with the cytoskeleton that the receptors ultimately organize and orient. But that then leads to the next question of what turns this feedback process off, preventing locking on one target, so that neutrophils can turn on a dime and pursue a new target, if needed?

The molecular basics of cell orientation in eukaryotes have taken a long time to establish. The cell surface receptors typically activate G proteins, specifically the beta/gamma subunit, which can activate an enzyme called PI3 kinase (PI3K). This enzyme puts a phosphate group on the membrane lipid inositol, generating inositol triphosphate, or IP3. This lipid is a sort of beacon, which attracts a variety of other proteins to come to the membrane, among which is DOCK2, and other members of its family of guanine exchange proteins, which in turn activate RAC, by encouraging it to release GDP and bind GTP. RAC is a key node here that is active with GTP. RAC then activates other proteins like WAVE and PAK1, which go on to activate ARP2 and its family members, which are, finally, the proteins which nucleate extension and branching of actin in filaments, which provide the actual power behind cell protrusions and movement.

A sketch of the signaling cascade from outside the cell to cytoskeletal re-orientation. R stands for receptor. One form of feedback is shown, which is positive reinforcement from locally active Rac and actin, back to PI3K. This helps the local front stay coherent in pursuit of prey or gradients of signals.

It has also been found that both RAC and actin have some kind of local positive feedback effect on neutrophils, allowing migrating cells to establish stable fronts that respond to gradients of stimulating molecules. At the same time, there is a global negative regulation system, mostly due to the tension from actin and on the cell membrane, which encourages retraction of cellular fronts that are not experiencing stimulating signals. All this obviously contributes to the ability of cells to go one way, and have their back ends follow. 

The current paper asked in a little more fine grained detail how the front mechanism works- how does it avoid locking up from positive feedback, and how does it allow other areas of the cell to take over if they see stimulation on their sides? They set up a remarkable system of light-activated PI3 kinase, where they could shine blue light on one side of the engineered cells and see them move in that direction, from the excess PI3K activity. This system derives from an obscure bacterial protein that rearranges a flavin cofactor under blue light, in a way that can allow binding surfaces to be hidden or revealed. 

In the key experiement, they shined light on one side of their cells, then turned it off for a bit, and the shined light on the entire cell. This tests whether there is a residual effect from the prior stimulation. Would the cells be entrained to keep going where they were going before? Or would they not care, or would they try something new? The answer clearly (and reproducibly) was that they struck off in a new direction. This shows that there is a habituation or inhibition mechanism at work, over some slow time period, which acts in activated regions. 

 The source for this video is the main paper behind this post. The dashed circle indicates where the researchers shined their blue light which induces local PI3K activity. Note how at first, they are leading the cell by just the front. When this cell gets to the midline, they switch to illuminating the whole cell, to ask whether there is residual activation or inhibition from the earlier illumination. The observation that the cell then veers off opposite to the original stimulation indicates that inhibition is the residual effect from the former activation.

 

Such habituation is a critical piece of behavior that follows gradients. It gets used to what it just saw, and if the next unit is the same intensity, it doesn't care that much (though probably will keep going). If the next unit of stimulation is increased, then it will keep going. But if it is decreased, then the inhibition kicks in and the front slows down, allowing other areas of the cell to expand if they are seeing increased gradients. Thus temporal and spatial gradients can both be negotiated, using a finely tuned mix of positive and negative feedbacks.

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