Jonathan Singer and the Cranky Book

An eminent scientist at the end of his career writes out his thoughts and preoccupations.

Jonathan Singer was a famous scientist at my graduate school. I did not interact with him, but he played a role in attracting me to the program, as I was interested in biological membranes at the time. Singer himself studied with Linus Pauling, and they were the first to identify a human mutation in a specific gene as a cause for a specific disease- sickle cell disease. After further notable work in electron microscopy, he reached a career triumph by developing, in 1972, the fluid mosaic model of biological membranes. This revolutionized and clarified the field, showing that cells are bounded by something incredibly simple- a bilayer of phospholipids that naturally order themselves into a remarkably stable sheet, (a bubble, one might say), all organized by their charged headgroups and hydrophobic fatty tails. This model also showed that proteins would be swimming around freely in this membrane, and could be integrated in various ways, ether lightly attached on one side, or spanning it completely, thereby enabling complex channel and transporter functions. The model implied the typical length of a protein alpha helix that, by virtue of its hydrophobic side chains, would naturally be able to do this spanning function- a prediction that was spot-on. He could have easily won a Nobel for this work.

I was intrigued when I learned recently that Singer had written a book near the end of his career. It is just the kind of thing that a retired professor loves to do in the sunset of his career, sharing the wisdom and staving off the darkness by taking a stab at the book biz. And Singer's is a classic of the form- highly personal, a bit stilted, and ultimately meandering. I will review some of its high points, and then take a stab of my own at knitting together some of the interesting themes he grapples with.

For at base, Singer turns out to be a spiritual compadre of this blog. He claims to be a rationalist, in a world where, as he has it, no more than 9% of people are rational. Definition? It is the poll question of whether one believes that god created man, rather than the other way around. Singer recognizes that the world around him is crazy, and that the communities he has been a part of have been precious oases amid the general indifference and grasping of the world. But changing it? He is rather fatalistic about that, recognizing that reason is up against overwhelming forces.

His specific themes cover a great deal of biology, and then some more mystical reflections on balance and diversity in biology, and later, in capitalism and politics. He points out that the nature/nurture debate has been settled by twin studies. Nature, which is to say, genetics, is the dominant influence on human characteristics, including a wide variety of psychological traits, including intelligence. Environment and nurture is critical for reaching one's highest potential, and for using it in socially constructive ways, but the limits of that potential are largely set by one's genes. Singer does not, however, draw the inevitable conclusion from these observations, which is that some kind of long-term eugenic approach would be beneficial to our collective future, assuming machines do not replace us forthwith. Biologists know that very small selective coefficients can have very big effects, so nothing drastic is needed. But what criteria to use- that is the sticky part. Just as success in the capitalist system hardly signals high moral or personal qualities, nor does incarceration by the justice system always show low ones. It is virtually an insoluble problem, so we muddle along, destined probably for continued cycles of Spenglerian civilizational collapse.

Turning to social affairs, Singer settles on "structural chaos" as his description of how the scientific enterprise works, and how capitalism at large works. With a great deal of waste, and misdirected effort, it nevertheless ends up providing good results- better than those that top-down direction can provide. He seems a sigh a little that "scientific" methods of social organization, such as those in Soviet Russia, were so ineffective, and that the best we can do is to muddle along with the spontaneous entrepreneurship and occasional flashes of innovation that push the process along. Not to mention the "monstrous vulgarity" of advertising, etc. Likewise, democracy is a mess, with most people totally incapable of making the reasoned decisions needed to maintain it. Again, the chaos of democracy is sadly the best we can do, and the duty of rational people, in Singer's view, is to keep alive the flame of intellectual freedom while outside pressures constantly threaten.

Art, and science.

What can we do with this? I think that the unifying thread that Singer was grasping for was competition. One can frame competition as a universal principle that shapes the physical, biological, and social worlds. Put two children on a teeter-totter, and you can see how physical forces (e.g. gravitation) compete all the time, subtly producing equilibria that characterize the universe. Chemical equilibria are likewise a product of constant competition, even including the perpetual jostling of phospholipids to find their lowest energy configuration amidst the biological membrane bilayer, which has the side-effect of creating such a stable, yet highly flexible, structure. With Darwin, competition reaches its apotheosis- the endless proliferation, diversification, and selection of organisms. Singer marvels at the fragility of individual life, at the same time that life writ large is so incredibly durable and prolific. Well, the mechanism behind that is competition. And naturally, economics of any free kind, including capitalism and grant-making in science, are based on competition as well- the natural principle that selects which products are useful, which employees are productive, and which technologies are helpful. Waste is part of the process, as diversity amidst excess production is the essential ingredient for subsequent selection. 

And yet.. something is missing. The earth's biosphere would still be a mere bacterial soup if competition were the only principle at work. Bacteria (and their viruses) are the most streamlined competition machines- battlebots of the living world. It took cooperation between a bacterial cell and an archaeal cell to make a revolutionary new entity- the eukaryotic cell. It then took some more cooperation for eukaryotic cells to band together into bodies, making plants and animals. And among animals, cooperation in modest amounts provides for reproduction, family structure, flock structures, and even complex insect societies. It is with humans that cooperation and competition reach their most complex heights, for we are able to regulate ourselves, rationally. We make rules. 

Without rules, human society is anarchic mayhem- a trumpian, dystopian and corrupt nightmare. With them, it (ideally) balances competition with cooperation to harness the benefits of each. Our devotion to sports can be seen as a form of rule worship, and explicit management of the competitive landscape. Can there be too many rules? Absolutely, there are dangers on both sides. Take China as an example. In the last half-century, it revamped its system of rules to lower the instability of political competition, harness the power of economic competition, and completely transformed its society. 

The most characteristic and powerful human institution may be the legislature, which is our ongoing effort to make rational rules regulating how the incredibly powerful motive force of competition shapes our lives. Our rules, in the US, were authored, at the outset, by the founders, who were- drumroll please- rationalists. To read the Federalist Papers is to see exquisite reasoning drawing on wide historical precedent, and particularly on the inspirations of the rationalist enlightenment, to formulate a new set of rules mediating between cooperation and competition. Not only were they more fair than the old rules, but they were designed for perpetual improvement and adjustment. The founding was, at base, a rationlist moment, when characters like Franklin, Hamilton, Madison, and Jefferson- deists at best and rationalists through and through, led the new country into a hopeful, constitutional future. At the current moment, two hundred and fifty years on, as our institutions are being wantonly destroyed and anything resembling reason, civility, and truth is under particularly vengeful attack, we should appreciate and own that heritage, which informs a true patriotism against the forces of darkness.

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The Fire Inside: Eukaryotic Locomotion

The GTP-based Rho/Rac system of actin regulation runs in unseen waves of activation.

One of the amazing capabilities of eukaryotic cells, inherited in part from their archaeal parents, is free movement and phagocytosis. These cells have an internal cytoskeleton, plus methods to anchor to a substrate, (via focal adhesions), which allows them to manipulate their membrane, their shape, and their locomotion. The cytoskeleton is composed of two main types of fibers, actin and microtubules. Microtubules are much larger than actin and organize major trackways of organelle movement around the cell (including the movement of chromosomes in mitosis), and also form the core of cilia and flagella. But it is actin that does most of the work of moving cells around, with dynamic networks that generate the forces behind spiky to ruffly protrusions, that power things like the adventuresome pathfinding of neurons as they extend their axons into distant locations.

Schematic of the actin cytoskeleton of a typical eukaryotic cell.

Actin is an ATPase all by itself. ATP promotes its stability, and also its polymerization into filaments. So, cell edges can grow just by adding actin to filament ends. Actin cross-linking proteins also exist, that create the meshwork that supports extended filopodia. But obviously, actin all by itself is not a regulated solution to cell movement. There is an ornately complex system of control, not nearly understood, that revolves around GTPase and binding proteins. These proteins (mainly RhoA, Rac1, and Cdc42, though there are twenty related family members in humans) have knife-edge regulation, being on when binding GTP, and off after they cleave off the phosphate and are left binding GDP (the typical, default, state). Yet other proteins regulate these regulators- GTPase exchange factors (GEFs) encourage release of GDP and binding of GTP, while GTPase activating proteins (GAPs) encourage the cleavage of GTP to GDP. The GTP binding proteins interact (depending on their GTP status) with a variety of effector proteins. One example is a family of formins, which chaperone the polymerization of actin. At the head of the pathway, signals coming from external or internal conditions regulate the GTPases, creating (in extremely simplified terms) a pathway that gets the cell to respond by moving toward things it wants, and away from things it does not want. 

This is a very brief post, just touching on one experiment done on this system. Exploring its full complexity is way beyond my current expertise, though we may return to aspects of this fascinating biological pathway periodically in the future. An important paper in the field hooked up fluorescent dyes to one of the effector protein domains that binds only GTP/active RhoA. They tethered this to the (inside) membrane of their cultured cells, and took movies of what the cell looked like, using a microscopy method that looks at very thin sections- only the membrane, essentially not the rest of the cell. RhoA, though graced with a small lipid tail, is typically cytoplasmic when inactive, and travels to the membrane when activated. They were shocked to find that in resting cells, without much locomotion going on, there were recurring waves of activation of RhoA that swept hither and yon across the cell membranes. 

Four examples of RhoA getting bound in its active state in a wave-like way, over 7 1/2 minutes in a resting cell. GEF-H1 is ARHGEF2, one of the regulators that can turn RhoA on. The first three panels have ARHGEF2 versions that are operational, but the fourth (bottom right) is of a cell with an anti-RNA to ARHGEF2, turning its expression level down. In this cell, the waves of RhoA activation and recruitment to the membrane are substantially dampened.

These pulses were made even more intense if the cells were treated with nocodazole, which disrupts microtubules, destabilizes the cytoskeleton, and makes the actin regulatory / structure system work harder. They found that myosin (the motor protein that moves cargoes over actin filaments) was also rapidly relocalized, mirroring some of what happened with RhoA. They also found that ARHGEF2 contained two RhoA binding domains, (one binding active RhoA, one binding inactive RhoA), enabling it to feedback-amplify the positive activation of RhoA, thereby explaining some of the extremely dynamic activity seen here. 

And they also found that the arrival of negative regulators such as ARHGAP35 was delayed by a couple of seconds vs the activation of RhoA, providing the time window needed to see wave formation out of a mechanism of positive feedback followed by squelching by a negative regulator. Lastly, they found that these dynamics were significantly different if the cells were grown on stiffer vs softer substrates. Stiffer substrates allowed the formation of stronger surface attachments, concentrating RhoA and myosin at these adhesion locations. 

These researchers are clearly only scratching the surface of this system, as there are endless complexities left to investigate. The upshot of this one set of observations is that neurons are not the only excitable cells. With a bit of molecular / experimental magic, heretofore unseen intracellular dynamics can be visualized to show that eukaryotic cells have an exquisitely regulated internal excitation system that is part of what drives their shape-shifting capabilities, including processes like phagocytosis and neuronal growth / path-finding. 

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3:10 to Yuma

The classic Western, and our moral moment. Spoiler alert!

Americans of my vintage were raised on Westerns. Looking at the Wiki page on TV westerns, it is astounding how many there were, and that isn't even counting their science fiction progeny. I recently watched a classic- 3:10 to Yuma, which is unbearably tense, beautifully shot and acted, and just a crystaline example of the form. It reminded me of the morality that lies at the heart of the American experience. 

Glen Ford (as Ben Wade) heads a gang of outlaws who rob a stagecoach and kill its drivers. Local farmer Dan Evans (played by Van Hefflin) witnesses this with his two sons, and stands clear. Later, the marshal and the owner of the stagecoach line (Mr. Butterfield) capture Wade, who has boldly wandered into town, and get up a posse, which includes farmer Dan Evans, to bundle him off to justice in Yuma. Only, the rest of the gang is still out there, and is ready to shoot whoever stands in the way of getting their leader back. Various plot twists later, Ben is being guarded by Dan in a hotel room close to the Yuma train stop, waiting for the train to come through. 

Glen Ford plays Wade as Satan incarnate- a smooth talking, woman seducing, suave and heartless killer. He keeps up a patter of warnings and blandishments to Dan, telling him that the rest of the posse will desert him (they do) and that Butterfield will also desert him (he does), as Wade's gang closes in around town. 

It is a morality play of power in its most corrupt form, vs civilization and decency. Evans has built a homestead and a family, with salt-of-the-earth wife Alice. Filmed in starkly beautiful black and white, the morality is likewise stark. Yet out here, in the real world, we suddenly are faced with a government that proudly wears the black hats, killing the innocent (and lying about it) and reveling in extortion across the domestic and foreign landscapes. A government that makes a principle of bad policy, selling out our future for donations from the oil industry, and straining every nerve enrich the rich, particularly cronies, and impoverish and denigrate the poor.

It is noteworthy that religion has no role in 3:10 to Yuma. The morality, good and bad, needs no reference to the supposed foundations of morality, sources in higher powers, or advice from clergy. No, morality is, in truth, a secular process, needing only eyes to see and a heart to feel. What is more, our current political depravity has been largely brought about by religious communities, out of their false sense of desperation and victimization. They have hitched their wagon out of grievance over losing the culture wars- to women who can not understand why they should be second class citizens, to minorities, who can not understand why they should be forever trodden upon, to scientists, who won the Dover decision that said that facts, not theology under any guise or subterfuge, should be taught in schools, and to Hollywood, which leads all too often with empathy and inclusion.

For the secret ingredient in all this is truth. 3:10 to Yuma shows how morality is about truth- who has power and how it is used, who is willing to look it in the eye and stand up to it. The first step of predators like our current administration is to gaslight the population, making white black and black, white. The president's every utterance is an exercise in projection, blaming others for his own defects, especially moral ones, to excuse his own depravity. Resistance means sticking to the truth. While predators are only possible in a society that is generally truthful and moral, (since a society of predators would have no one to rob or anything to take), they can only exist if that society is blinded to their true nature, or cowed by their power.

The president may have learned his methods of lying in real estate, but his base learned it in religion. When faith and authority are the standard, truth takes a back seat. Victimization narratives run rampant, when religions are merely up against people who have a higher standard of truth than they do. That includes empathy, which is a form of truth- that of recognizing the true existence of others and extending to them the decency / respect of allowing them their own perspectives and feelings. The evangelical base is so aggrieved by the decline of religion and its (rightful) dismissal by liberal, thinking people, that it is clearly willing to throw all other principles to the wind. They have made a corrupt bargain for power, with a man who hasn't a particle of moral, let alone religious, feeling, and whose greed degrades everything he touches. One would have thought that the base had learned a lesson from their support of George W. Bush, who made tax cuts for the rich and foreign debacles in Iraq and Afghanistan his contribution to American history. No, the evangelical base, triggered by the reign of Barack Obama, doubled down, and is fully on the side of the devil now.

3:10 to Yuma does not deserve its happy ending. But the movie is not about the reality of gunmen and shooting angles. It is about character, and the limit reached by good people when faced with evil people. The settlers of the West were hardly unblemished, trampling as they did in the wake of exterminated and displaced Indians. But in the national mythos that I grew up with, they were the quiet and courageous builders who brought law to wild regions and grappled with the many dimensions of building a new society. They overcame corrupt ranchers, shady miners, gunslingers and gangsters to make the placid Midwest and western farming regions we know today. To think that their descendents would so forsake these principles on the altar of tin-pot fascism is truly hard to fathom.

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Tiny Tunings in a Buzz of Neural Activity

Lots of what neurons do adds up to zero: how the cerebellum controls muscle movement.

Our brains are always active. Meditating, relaxing, sleeping ... whatever we are up to, the brain doesn't take a holiday, except in the deepest levels of sleep, when slow waves help the brain to reset and heal itself. Otherwise, it is always going, with only slight variations based on computational needs and transient coalitions, which are extremely difficult to pick out of the background (fMRI signals are typically under 3% of the noise). That leads to the general principle that action in a productive sense is merely a tuned overlay on top of a baseline of constant activity, through most of the brain.

A recent paper discussed how this property manifests in the cerebellum, the "little" brain attached to our big brain, which is a fine-tuning engine especially for motion control, but also many other functions. The cerebellum has relatively simple and massively parallelized circuitry, a bit like a GPU to the neocortex's CPU. It gets inputs from the places like the the spinal cord and sensory areas of the brain, and relays a tuned signal out to, in the case of motor control, the premotor cortex. The current authors focused on the control of eye movement ("saccades") which is a well characterized system and experimentally tractable, in marmoset monkeys. 

After poking a massive array of electrodes into their poor monkey's brains, they recorded from hundreds of cells, including all the relevant neuron types (of which there are only about six). They found that inside the cerebellum, and inside the region they already knew is devoted to eye movement, neurons form small-world groups that interact closely with each other, revealing a new level of organization for this organ.

More significantly, they were able to figure out the central tendency or vector for Purkinje (P) cells they ran across. These are the core cells of the cerebellar circuit, so their firing should correlate in principle with the eye movements that they were simultaneously tracking in these monkeys. So one cell might be an upward directing cell, while another one might be leftward, and so forth. They also found that P cells come in two types- those (bursters) that fire positively around the preferred direction, and others (pausers) that fire all the other times, but fire less when eyes are heading in the "preferred" direction. These properties are already telling us that the neural system does not much care to save energy. Firing most of the time, but then pausing when some preferred direction is hit is perfectly OK. 

Two representative cells are recorded, around the cardinal/radial directions. The first of each pair is recorded from 90 degrees vs its preferred direction, and adding up the two perpendicular vectors (bottom) gives zero net activity. The second of each pair is recorded from the preferred direction (or potent axis), vs 180 degrees away, and when these are subtracted, a net signal is visible (difference). Theta is the direction the eyes are heading.

Their main finding, though, was that there is a lot of vector arithmetic going on, in which cells fire all over their preferred fields, and only when you carefully net their activity over the radial directions can you discern a preferred direction. The figure above shows a couple of cells, firing away no matter which direction the eyes are going. But if you subtract the forward direction from the backward direction, a small net signal is left over, which these authors claim is the real signal from the cerebellum, which signals a change in direction. When this behavior is summed across a large population, (below), the bursters and pausers cancel out, as do the signals going in stray directions. All you are left with is a relatively clean signal centered on the direction being instructed to the eye muscles. Wasteful? Yes. Effective? Apparently. 

The same analysis as above, but on a population basis. Now, in net terms, after all the canceled activity is eliminated, and adding up the pauser and burster activity, strong signals arise from the cerebellum as a whole, in this anatomical region, directing eye saccades

Why does the system work this way? One idea is that, like for the rest of the brain, default activity is the norm, and learning is, perforce, a matter of tuning ongoing activity, not of turning on cells that are otherwise off. The learning (or error) signal is part of the standard cerebellum circuitry- a signal so strong that it temporarily shuts off the normal chatter of the P cell output and retunes it slightly, rendering the subsequent changes seen in the net vector calculation.

A second issue raised by these authors is the nature of inputs to these calculations. In order to know whether and how to change the direction of eye movement, these cells must be getting information about the visual scene and also about the current state of the eyes and direction of movement. 

"The burst-pause pattern in the P cells implied a computation associated with predicting when to stop the saccade. For this to be possible, this region of the cerebellum should receive two kinds of information—a copy of the motor commands in muscle coordinates and a copy of the goal location in visual coordinates."

These inputs come from two types of mossy fiber neurons, which are the single inputs to the typical cerebellar circuit. One "state" type encodes the state of the motor system and current position of the eye. The other "goal" type encodes, only in case of a reward, where the eye "wants" to move, based on other cortical computations, such as the attention system. The two inputs go through separate individual cerebellar circuits, and then get added up on a population basis. When movement is unmotivated, the goal inputs are silent, and resulting cerebellar-directed saccades are more sporadic, scanning the scene haphazardly.

The end result is that we are delving ever more deeply into the details of mental computation. This paper trumpets itself as having revealed "vector calculus" in the cerebellum. However, to me it looks much more like arithmetic than calculus, and nor is the overall finding of small signals among a welter of noise and default activity novel either. All the same, more detail, and deeper technical means, and greater understanding of exactly how all these billions of dumb cells somehow add up to smart activity continues to be a great, and fascinating, quest.

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