Are we all the Same, or all Different?

Refining diversity.

There has been some confusion and convenient logic around diversity. Are we all the same? Conventional wisdom makes us legally the same, and the same in terms of rights, in an ever-expanding program of level playing fields- race, gender, gender preference, neurodiversity, etc. At the same time, conventional wisdom treasures diversity, inclusion, and difference. Educational conventional wisdom assumes all children are the same, and deserve the same investments and education, until some magic point when diversity flowers, and children pursue their individual dreams, applying to higher educational institutions, or not. But here again, selectiveness and merit are highly contested- should all ethnic groups be equally represented at universities, or are we diverse on that plane as well?

It is quite confusing, on the new political correctness program, to tell who is supposed to be the same and who different, and in what ways, and for what ends. Some acute social radar is called for to navigate this woke world and one can sympathize, though not too much, with those who are sick of it and want to go back to simpler times of shameless competition; black and white. 

The fundamental tension is that a society needs some degree of solidarity and cohesion to satisfy our social natures and to get anything complex done. At the same time, Darwinian and economic imperatives have us competing with each other at all levels- among nations, ethnicities, states, genders, families, work groups, individuals. We are wonderfully sensitive to infinitesimal differences, which form the soul of Darwinian selection. Woke efforts clearly try to separate differences that are essential and involuntary, (which should in principle be excluded from competition), from those that are not fixed, such as personal virtue and work ethic, thus forming the proper field of education and competition.

But that is awfully abstract. Reducing that vague principle to practice is highly fraught. Race, insofar as it can be defined at all, is clearly an essential trait. So race should not be a criterion for any competitive aspect of the society- job hunting, education, customer service. But what about "diversity" and what about affirmative action? Should the competition be weighted a little to make up for past wrongs? How about intelligence? Intelligence is heritable, but we can't call it essential, lest virtually every form of competition in our society be brought to a halt. Higher education and business, and the general business of life, is extremely competitive on the field of intelligence- who can con whom, who can come up with great ideas, write books, do the work, and manage others.

These impulses towards solidarity and competition define our fundamental political divides, with Republicans glorying in the unfairness of life, and the success of the rich. Democrats want everyone to get along, with care for unfortunate and oppressed. Our social schizophrenia over identity and empathy is expressed in the crazy politics of today. And Republicans reflect contemporary identity politics as well, just in their twisted, white-centric way. We are coming apart socially, and losing key cooperative capacity that puts our national project in jeopardy. We can grant that the narratives and archetypes that have glued the civic culture have been fantasies- that everyone is equal, or that the founding fathers were geniuses that selflessly wrought the perfect union. But at the same time, the new mantras of diversity have dangerous aspects as well.

Each side, in archetypal terms, is right and each is an essential element in making society work. Neither side's utopia is either practical or desirable. The Democratic dream is for everyone to get plenty of public services and equal treatment at every possible nexus of life, with morally-informed regulation of every social and economic harm, and unions helping to run every workplace. In the end, there would be little room for economic activity at all- for the competition that undergirds innovation and productivity, and we would find ourselves poverty-stricken, which was what led other socialist/communist states to drastic solutions that were not socially progressive at all.

On the other hand is a capitalist utopia where the winners take not just hundreds of billions of dollars, but everything else, such as the freedom of workers to organize or resist, and political power as well. The US would turn into a moneyed class system, just like the old "nobility" of Europe, with serfs. It is the Nietzschian, Randian ideal of total competition, enabling winners to oppress everyone else in perpetuity, and, into the bargain, write themselves into the history books as gods.

These are not (and were not, historically) appetizing prospects, and we need the tension of mature and civil political debate between them to find a middle ground that is both fertile and humane. Nature is, as in so many other things, an excellent guide. Cooperation is a big theme in evolution, from the assembly of the eukaryotic cell from prokaryotic precusors, to its wonderous elaboration into multicellular bodies and later into societies such as our own and those of the insects. Cooperation is the way to great accomplishments. Yet competition is the baseline that is equally essential. Diversity, yes, but it is competition and selection among that diversity and cooperative enterprise that turns the downward trajectory of entropy and decay (as dictated by physics and time) into flourishing progress.

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Cellular Package Logistics

Some new insights on how vesicle fusion occurs with target membranes.

Membranes were one of the founding inventions of life. Every cell has a membrane, and many viruses do as well. Whether they were present from the start, or were a later innovation when the nascent chemical reactions of life, begun in some rocky pore, freed themselves into the open ocean, the fatty bilayer membrane is now fundamental. And from a proper perspective, it is a formidable barrier. If you were a water molecule, a typical membrane would be a sixty-five foot wide mass of repellent goo.

A typical cellular membrane, with the fatty bilayer core and a few proteins and other molecules sprinkled about, all of which move freely in the plane of the membrane.

Eukaryotes, as usual, took this innovation to whole new level, developing a variety of internal membranes and organelles that were entirely unknown to their bacterial forebears. Foremost of which is the mitochondrion- the symbiotic bacterium that turned into a powerful organelle. But there are many others, like the endoplasmic reticulum, the nucleus, the lysosome, phagosome, and the golgi apparatus. There is constant traffic among these organelles, with small membrane vesicles being emitted, traveling around, and finding and then fusing with their target destination membranes. It is like a tiny FedEx system within each cell, complete with addresses, carriers, cargoes, and grateful recipients.

A cartoon about the some of the internal membranes of eukaryotic cells. Note all the traffic going about. The lysosome, for instance, receives incoming vesicles from the plasma membrane, as things to digest, and from the golgi apparatus, as packages of new enzymes to do its work- enzymes that only turn on in the acidic environment inside the lysosome. This traffic requires a great deal of vesicle formation, transportation and fusion with targets, whose molecular detail is being gradually revealed. The golgi apparatus is a central sorting and distribution center.

Vesicles can exist because they are generally not prone to fuse with each other. Each membrane has a electrical charge-rich exterior that keeps it happily hydrated and slightly stand-offish vs other membranes. So something extra is needed to provide the push to fuse with a target membrane. And this barrier also provides the possibility of regulation, getting the right vesicle to fuse with the right target. A recent paper discussed one small part of this quite complicated process- the structure of tethering proteins that bring cargo vesicles and target membranes together. The research group focused on vesicles destined for the lysosome. The lysosome is the target of two major types of vesicles. One type brings in the enzymes needed for the lysosome to digest food for the cell. The other type are endosomes coming from the plasma membrane, and other sources of cellular garbage, which go to the lysosome to be digested, much like food is digested in our stomachs.

A schematic of the SNARE proteins that operate at the core of membrane fusion. One (here, synaptobrevin) is attached to the cargo vesicle. Another (here, syntaxin) is attached to the target membrane. A third, SNAP-25, supplies two more alpha helices to the 4-helix structure that winds up and brings the two membranes ever closer. The extra protein (synaptotagmin) is a regulator, in this case at the neuronal synapse, which directs fusion to happen in response to electrical neural activation, thereby helping secrete a neurotransmitter and thus propagate the neural signal.

Vesicle fusion is, at core, conducted by proteins called SNARE proteins. One extends from the cargo vesicle, another extends from the target membrane, and a third joins in, complexed with the second. Their alpha helical structures strongly and progressively inter-twine together to drive the membranes together, forcing fusion. Energetic studies show that at least three of these complexes are needed to get two membranes fused. After the fusion event, the SNARE proteins are recovered by special chaperone proteins that expend ATP to unwind the SNARE helices and reset them for another round of action.

Part of the regulation of this process (of which a great deal remains unknown) is provided by "tethering" complexes- proteins that grab hold of membranes of the right sort, extend across the gap to the target membrane, and also bind the SNARE proteins to orchestrate the fusion process. This research group studied one such tethering complex called HOPS, from yeast cells, which is composed of six proteins, Vps11, 16, 18, 39, 41, fall named for vacuole protein sorting. In yeast cells, the lysosome is called the vacuole, and these were all picked up by genetic screens for defects in getting proteins to the vacuole. Thus HOPS is essential for the fusion process, even though it plays a helping, orchestrating role.

New structures of the HOPS complex, which helps direct cargo vesicles to lysosomes. It is composed of six Vps proteins, all similar, which reach in three directions- to each membrane, and to the SNARE proteins as well. A three-handed helper, as it were.

The researchers found that the HOPS complex is fundamentally a triangle. Two of the ends (green, above) extend to the membranes to be fused, while the third end (brown) engages the SNARE proteins and helps them do their thing when the right geometry has been attained. The shape almost tells the story of what is going on, with the SNARE proteins sitting right in the middle, at the presumptive cleft between the two membranes. The structure has an interesting profusion of beta-propeller structures on all its ends. These are bulky protein domains very commonly used for protein-protein interactions. The shared structures also show that these proteins are deeply related to each other, probably all evolved from a single ancestor. 

Model of HOPS function, as it joins the two membranes, and also orchestrates SNARE action.

The HOPS complex tethers to Ypt7 proteins on both membranes. But Ypt7 is itself highly regulated, and not always "on", i.e. receptive for docking. It is turned on by other proteins that specify that it is in the right place and near the right partner to activate. But that is another story, and one still developing.

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Why do we Put up with the Specter of Unemployment?

A post by Paul Krugman got me thinking... why do we allow unemployment at all?

Paul Krugman has been ruminating a lot about inflation- why it went up, and why it is back down. One insight is that, asssuming that interest rate increases are supposed to work by raising unemployment, they have not evidently accomplished anything, yet inflation is back down and has been at 2-3 % for the last year, on a month to month basis. Perhaps the rate increases operated through other channels, like dampening the real estate market or general confidence. Or perhaps the rate increases had as much inflationary as deflationary effect, which is to say none at all, and our current state is simply due to the working-out of all the supply chain disruptions, emergency federal spending, and opportunistic profit-making brought on by the pandemic. As was, incidentally, supposed by the MMT school from the start.

But why make workers the focus of inflation policy in the first place? And why use unemployment as the index of inflation-fighting effectiveness? Why have unemployment at all? Unemployment is a central and classic feature of capitalism, certainly not of our natural state. Chimpanzees never experience unemployment- there is always something to do. But when it comes to capitalism, once workers have bought into the labor-rental scheme, they are dependent on the specific employer for pay, and on the employer class as a whole for the existence of a labor market. While employers like nothing better than to "discipline" workers with the prospect of sleeping on the streets, we can do better.

The Phillips curve, of unemployment related to inflation (the non-accelerating inflation rate level of unemployment, or NAIRU). A somewhat mythical and protean concept that used to be taken as a "law" of economics, that low unemployment drives higher inflation, via hotter labor market and wage increases. Even the Fed doesn't take this seriously any more.

Capitalists manage to pay themselves pretty well, to the point that our whole economy and social life (and politics) has been deranged by whole new classes of super-rich and their lackeys. So an allergy to income is not generally the problem- merely parting with money to pay others fairly. It is clear from the recent minimum wage increases that paying the lower end more has very little inflationary effect- it is peanuts on top of peanuts. But is immensely meaningful for those on the receiving end.

Similarly, the provision of a job guarantee, (as previously posted), thereby eliminating involuntary unemployment, would help workers on the low end of the scale with much greater security. The government would be the employer of last resort, at a decent wage, offering a wide range of work, from street cleaning and park maintenance to non-profit collaborations and technical operations appropriate to whatever skills are on offer. Looking around the country, there is no end of work that needs doing. The Great Depression, which gave us so much innovative legislation, also gave us a model of public works and public jobs programs- something well worth learning from and using on a permanent basis.

Such a job guarantee would automatically provide a floor for the minimum wage, (and also a floor for work conditions, hours, and benefits), and replace most unemployment insurance and other benefit programs. If a person didn't want the jobs offered, they could take a lower basic welfare-type income. But the work would not be designed to either onerous or easy- the point is to get some useful work done for society, and take in the bottom level of the labor market as needed from fluctuations in the private market. It is an insurance system, just as we have for health, for property hazards, and, as embodied in the Federal Reserve, for the banks and US capitalism writ large. Such a guarantee of work is, I think, far superior to the current unemployment insurance system, which is grudgingly funded by employers, pays people to not work, which is morally perverse and heavily abused. Private employers would naturally be able to bid workers off the system with higher pay.

Such a system would have little effect on the Fed's interest rate policies, (assuming they are effective in the first place), since unemployment is really just an index of economic activity, not the point of interest rate increases. Economic slowing would be reflected in higher numbers of people thrown into the job guarantee, and presumably getting lower (but still decent) pay. (A pay scale that would, incidentally, be more anti-cyclical than current policies.) And would be reflected in a myriad of other slowdowns that would contribute, if needed, to inflation control. 

The irony is that welfare reform of the last few decades focused relentlessly on "work requirements", and of the decades prior to that on "job training". The latter was a boondoggle, and the former forced the poor into appalling, coercive, and low-paying jobs- the very bottom end of the capitalist system. Which was the design, no doubt. I can imagine that capitalists would yell "communism" about a program where governments give decent work with decent income and benefits to anyone willing to work. Well, if that is communism, we need more of it.

Unemployment is currently used as a potent weapon- both by capitalists, given its dire consequences, and paradoxically by unions as well, which walk off the job and strike as a way to pressure employers who may find it inconvenient to hire scabs in a short time. A job guarantee could transform such conflict by taking the most dire consequences off the table. Everyone could maintain their livelihoods, and negotiations could proceed with less drama and coercion. And that is what our society should be about, promoting freedom and civility by removing forms of unjust and pernicious coercion, whether political, criminal, military, or economic.

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Keeping Cellular Signals Straight

Cells often use the same signaling systems for different inputs and purposes. Scaffolds come to the rescue.

Eukaryotic cells are huge, at least compared with their progenitors, bacteria. Thanks to their mitochondria and other organizational apparatus, the typical eukaryotic cell has about 100,000 times the volume of a bacterium. These cells are virtual cities- partially organized by their membrane organelles, but there is a much more going on, with tremendous complexity to manage. One issue that was puzzling over the decades was how signals were kept straight. Eukaryotic cells use a variety of signaling systems, proto-typicaly starting with a receptor at the cell surface, linking to a kinase (or series of kinases) that then amplifies and broadcasts the signal inside the cell, ending up with the target phosphorylated proteins entering the nucleus and changing the transcription program of the cell. 

While our genome does have roughly 500 kinases, and one to two thousand receptors, a few of them (especially some kinases and their partners, which form "intracellular signaling systems") tend to crop up frequently in different systems and cell types, like the MAP kinase cascade, associated with growth and stress responses, and the AKT kinase, associated with nutrient sensing and growth responses. Not only do many different receptors turn these cellular signaling hubs on, but their effects can often be different as well, even from unrelated signals hitting the same cell.

If all these proteins were diffusable all over the cell, such specificity of signaling would be impossible. But it turns out that they are usually tethered in particular ways, by organizational helpers called scaffold proteins. These scaffolds may localize the signaling to some small volume within the larger cell, such as a membrane "raft" domain. They may also bind multiple actors of the same signaling cascade, bringing several proteins (kinases and targets) together to make signaling both efficient and (sterically) insulated from outside interference. And, in a recent paper, they can also tweak their binding targets allosterically to insulate them from outside interference.

What is allostery vs stery? If one protein (A) binds another (B) such that a phosphorylation or other site is physically hidden from other proteins, such as a kinase (C) that would activate it, that site is said to be sterically hidden- that is, by geometry alone. On the other hand, if that site remains free and accessible, but the binding of A re-arranges protein B such that it no longer binds C very well, blocking the kinase event despite the site of phosphorylation being available, then A has allosterically regulated B. It has altered the shape of B in some subtle way that alters its behavior. While steric effects are dominant and occur everywhere in protein interactions and regulation, allostery comes up pretty frequently as well, proteins being very flexible gymnasts. 

GSK3 is part of insulin signaling. It is turned off by phosphorylation, which affects a large number of downstream functions, such as turning on glycogen synthase.

The current case turns on the kinase GSK3, which, according to Wikipedia... "has been identified as a protein kinase for over 100 different proteins in a variety of different pathways. ... GSK-3 has been the subject of much research since it has been implicated in ... diseases, including type 2 diabetes, Alzheimer's disease, inflammation, cancer, addiction and bipolar disorder." GSK3 was named for its kinase activity targeting glycogen synthase, which inactivates the synthase, thus shutting down production of glycogen, which is a way to store sugar for later use. Connected with this homeostatic role, the hormone insulin turns GSK3 off by phosphorylation by a pathway downstream of the membrane-resident insulin receptor called the PI3 kinase / protein kinase B pathway. Insulin thus indirectly increases glycogen synthesis, mopping up excess blood sugar. The circuit reads: insulin --> kinases --| GSK3 --| glycogen synthase --> more glycogen.

GSK3 also functions in this totally different pathway, downstream of WNT and Frizzled. Here, GSK3 phosphorylates beta-catenin and turns it off, most of the time. WNT (like insulin) turns GSK3 off, which allows beta-catenin to accumulate and do its gene regulation in the nucleus. Cross-talk between these pathways would be very inopportune, and is prevented by the various functions of Axin, a scaffold protein. 

Another well-studied role of GSK3 is in a developmental signal, called WNT, which promotes developmental decisions of cells during embryogenisis, wound repair, and cancer, cell migration, proliferation, etc. GSK3 is central here for the phosphorylation of beta-catenin, which is a transcription regulator, among other things, and when active migrates to the nucleus to turn its target genes on. But when phosphorylated, beta-catenin is diverted to the proteosome and destroyed, instead. This is the usual state of affairs, with WNT inactive, GSK3 active, and beta-catenin getting constantly made and then immediately disposed of. This complex is called a "destruction" complex. But an incoming WNT signal, typically from neighboring cells carrying out some developmental program, alters the activity of a key scaffold in this pathway, Axin, which is destroyed and replaced by Dishevelled, which turns GSK3 off.

How is GSK3 kept on all the time for the developmental purposes of the WNT pathway, while allowing cells to still be responsive to insulin and other signals that also use GSK3 for their intracellular transmission? The current authors found that the Axin scaffold has a special property of allosterically preventing the phosphorylation of its bound GSK3 by other upstream signaling systems. They even re-engineered Axin to an extremely minimal 26 amino acid portion that binds GSK3, and this still performed the inhibition, showing that the binding doesn't sterically block phosphorylation by insulin signals, but blocks allosterically. 

That is great, but what about the downstream connections? Keeping GSK3 on is great, but doesn't that make a mess of the other pathways it participates in? This is where scaffolds have a second job, which is to bring upstream and downstream components together, to keep the whole signal flow isolated. Axin also binds beta-catenin, the GSK3 substrate in WNT signaling, keeping everything segregated and straight. 

Scaffold proteins may not "do" anything, as enzymes or signaling proteins in their own right, but they have critical functions as "conveners" of specific, channeled communication pathways, and allow the re-use of powerful signaling modules, over evolutionary time, in new circuits and functions, even in the same cells.

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The Curious Path of German Socialism

From Marx to Hitler to Honecker, and beyond.

As I was listening to a podcast about the Civil War, a character jumped out- August Willich. Willich was a Union general, both loved and respected, who had been born as a Prussian aristocrat and attended the Prussian military academy. But then he took a turn, along with many Germans of his generation, and fell in with the socialists and communists (including, later in England, Karl Marx), and the revolutionaries of 1848, going to far as to command a revolutionary corps with fellow-Prussian Friederich Engels at his side. This era was a confused mess of motivations, (maybe a bit like the 1960's), inspired by the nationalist and socialist/ liberal ideals of the French revolution, while fighting against the monarchies that the Napoleonic era had ultimately, by its defeat, propped up all over Germany. The simultaneous nationalistic revolution in Italy was a template, as was the prosperous development of democracy in the US. The philospher Georg Hegel had even chimed in, a few decades before, putting the progressive and liberal spirit of the French revolution into sufficiently turgid terms to inspire a generation of German philosophers and social reformers.

The revolutions of 1848 in Germany were crushed, but the reformers found other outlets. Willich fled through Switzerland to England, as had his fellow-Prussian, Karl Marx. This communist league was concerned with far more than nationalism, finding in the new capitalist system another, and perhaps even worse, feudalism spreading across the continent, crushing traditional cultures as it ground workers to dust. While one branch of this movement continued to plot and feud and agitate in Europe, (with Vladimir Lenin as its ultimate expression), others became social democrats and found ways to work within the gradually loosening political systems. Many German socialists (as did Willich) went to America, a fertile territory for self-government as well as the battle with capitalism. And they saw the fight for the Union as the same old pattern- of the joined forces of the planter aristocracy (plus a particularly soul-less form of capitalism) fighting liberal progress and social justice. Several prominent generals of the Civil war, and many whole regiments, were of German origin.

August Willich, during the Civil War.

In fact, there was a large influx of prominent and educated Germans to the US around this time, which led to to a heavy concentration of Germans in the Midwest, especially Wisconsin. Milwaukee became a stronghold of (democratic) socialism in the later 1800's and early 1900's. Like the democratic socialists of Germany, they introduced the old age pensions, health and unemployment insurance, public housing, and other public works that typify the reform era. It is something of a lost story, how these reforms that we take for granted today had significant origins in the migration of progressive-spirited Germans in the wake of the 1848 revolutions. For example, they propagated the Turnverein, sometimes now named Turner halls, which were early gyms and community centers.

Naturally, all this innovation came under a cloud when Germany turned into the enemy of the US and much of the rest of the world, not once, but twice, in the 20th century. I often marvel at the growing practice of pronouncing Hispanic names and words properly in the media these days. If such care were devoted to German names, the media would sound quite different! All that is to say that there is another inheritance to appreciate.

Ethnic composition of the US.

Back in Europe, socialists took various paths, as noted. The extreme and involuted form that became communism and bolshevism was successful only once- in Russia, to cataclysmic consequences. Elsewhere, democratic socialists were the dominant type, with a great deal of popular support. Bismark, no socialist himself, put forth the first national health insurance system, and old age and accident insurance, as ways to coopt the socialists in Germany at the time. The continuing superiority of labor laws and practices in Germany today, compared with the US, speaks to the strong historical influence of socialism. This influence also led to the curious choice by Hitler's party to call itself national socialism, though we would regard them today as quite on another end of the political spectrum. But socialism was held in high esteem and spoke strongly to the solidarity that Germany needed in the wake of economic and military disaster, so that it apparently could be twisted to fascist ends. They just discarded the politically liberal elements, and focused on the economically (and militarily) communal ones. One can conjecture that socialism generally hearkens back in somewhat atavistic fashion to the tribal and village societies/economies that, while doubtless harsh, were highly personal and arguably more humane than the pitiless and impersonal operations of modern capitalism.

The sad irony is that German-originated socialism, in the form of communism that had filtered through Russian theory and experience, came back in force over Eastern Germany after World War 2, back to its Prussian homeland, more or less. And boy, what a system it had turned into by that point. Its rhetoric of solidarity had turned into empty propaganda, its nationalist aspirations into a Russian prison, and its hope of freeing workers into a state of the most stringent surveillance and terror.

Socialism today remains variable and amorphous, depending on where and who you are. Its formal definition of public ownership of the means of production (as opposed to communism, where everything is owned communally and distributed centrally) seems nowhere in sight in the West. That part of the program seems a dead letter, and what is left, for the democratic socialists, is more in line with the Social Democratic reform movements in Germany and the US; progressive reform to sand some edges off the capitalist system. That program has been stunningly successful in making capitalism both reasonably humane and highly productive, but it took place, historically, under the impetus of great extremism at the fringes- the labor wars, the bombings, and most of all, the spectre of communism looming over the early 20th century. Can we find a reasonable and reasoned path to reform now, without the fires of a revolution glowing in the distance?

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