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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• Earth in the far future.
• Electric or not, cars are still bad.
• Our non-political and totally not corrupt supreme court.
• The nightmare of building in California.

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.

• Our lethal roads.
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• Can there be a science of consciousness? Is there one? Or will AI get there first?

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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• Some statistics.
• When insurrection becomes policy.
• Think of the children...

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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• We have a lot of work to do:

Better Red Than Dead

Some cyanobacteria strain for photosynthetic efficiency at the red end of the light spectrum.

The plant world is green around us- why green, and not some other color, like, say, black? That plants are green means that they are letting green light through (or out by reflection), giving up some energy. Chlorophyll absorbs both red light and blue light, but not green, though all are near the peak of solar output. Some accessory pigments within the light-gathering antenna complexes can extend the range of wavelenghts absorbed, but clearly a fair amount of green light gets through. A recent theory suggests that this use of two separated bands of light is an optimal solution to stabilize power output. At any rate, it is not just the green light- the extra energy of the blue light is also thrown away as heat- its excitation is allowed to decay to the red level of excitation, within the antenna complex of chlorophyll molecules, since the only excited state used in photosynthesis is that at ~690 nm. This forms a uniform common denominator for all incoming light energy that then induces charge separation at the oxygen reaction center, (stripping water of electrons and protons), and sends newly energized electrons out to quinone molecules and on into the biosynthetic apparatus.

The solar output, which plants have to work with.

Fine. But what if you live deeper in the water, or in the veins of a rock, or in a mossy, shady nook? What if all you have access to is deeper red light, like at 720 nm, with lower energy than the standard input? In that case, you might want to re-engineer your version of photosynthesis to get by with slightly lower-energy light, while getting the same end results of oxygen splitting and carbon fixation. A few cyanobacteria (the same bacterial lineage that pioneered chlorophyll and the standard photosynthesis we know so well) have done just that, and a recent paper discusses the tradeoffs involved, which are of two different types.

The chlorophylls with respective absorption spectra and partial structures. Redder light is toward the right. Chlorophyll a is one used most widely in plants and cyanobacteria. Chlorophyll b is also widely used in these organisms as an additional antenna pigment that extends the range of absorbed light. Chlorophylls d and f are red-shifted and used in specialized species discussed here. 

One of the species, Chroococcidiopsis thermalis, is able to switch states, from bright/white light absorbtion with normal array of pigments, to a second state where it expresses chlorophylls d and f, which absorb light at the lower energy 720 nm, in the far red. This "facultative" ability means that it can optimize the low-light state without much regard to efficiency or photo-damage protection, which it can address by switching back to the high energy wavelength pigment system. The other species is Acaryochloris marina, which has no bright light system, but only chlorophyll d. This bacterium lives inside the cells of bigger red algae, so has a relatively stable, if shaded, environment to deal with.

What these and prior researchers found was that the ultimate quantum energy used to split water to O2, and to send energized electrons off the photosystem I and carbon compound synthesis, is the same as in any other chlorophyll a-using system. The energetics of those parts of the system apparently can not be changed. The shortfall needs to be made up in the front end, where there is a sharp drop in energy from that absorbed- 1.82 electron volts (eV) from photons at 680 nm (but only 1.72 eV from far-red photons)- and that needed at the next points in the electron transport chains (about 1.0 eV). This difference plays a large role in directing those electrons to where the plant wants them to go- down the gradient to the oxygen-evolving center, and to the quinones that ferry energized electrons to other synthetic centers. While it seems like more waste, a smaller difference allows the energized electrons to go astray, forming chemical radicals and other products dangerous to the cell. 

Summary diagram, described in text. Energy levels are described for photon excitation of chlorophyll (Chl, left axis, and energy transitions through the reaction center (Phe- pheophytin), and quinones (Q) that conduct energized electrons out to the other photosynthetic center and biosynthesis. On top are shown the respective system types- normal chlorophyll a from white-light adapted C. thermalis, chlorophyll d in A. marina, and chlorophyll f in red-adapted C. thermalis. 

What these researchers summarize in the end is that both of the red light-using cyanobacteria squeeze this middle zone of the power gradient in different ways. There is an intermediate event in the trail from photon-induced electron excitation to the outgoing quinone (+ electron) and O2 that is the target of all the antenna chlorophylls- the photosynthetic reaction center. This typically has chlorophyll a (called P680) and pheophytin, a chlorophyll-like molecule. It is at this chlorophyll a molecule that the key step takes place- the excitation energy (an electron bumped to a higher energy level) conducted in from the antenna of ~30 other chlorophylls pops out its excited electron, which flits over to the pheophytin, then thence to the carrier quinone molecules and photosystem I. Simultaneously, an electron comes in to replace it from the oxygen-evolving center, which receives alternate units of photon energy, also from the chlorophyll/pheophytin reaction center. The figure above describes these steps in energetic terms, from the original excited state, to the pheophytin (Phe-, loss of 0.16 eV) to the exiting quinone state (Qa-, loss of 0.385 eV). In the organisms discussed here, chlorophyll d replaces a at this center, and since its structure is different and absorbance is different, its energized electron is about 0.1 eV less energetic. 

In A. marina, (center in the diagram above), the energy gap between the pheophytin and the quinone is squeezed, losing about 0.06 eV. This has the effect of losing some of the downward "slope" on the energy landscape that prevents side reactions. Since A. marina has no choice but to use this lower energy system, it needs all the efficiency it can get, in terms of the transfer from chlorophyll to pheopytin. But it then sacrifices some driving force from the next step to the quinone. This has the ultimate effect of raising damage levels and side reactions when faced with more intense light. However, given its typically stable and symbiotic life style, that is a reasonable tradeoff.

On the other hand, C. thermalis (right-most in the diagram above) uses its chlorophyll d/f system on an optional basis when the light is bad. So it can give up some efficiency (in driving pheophytin electron acceptance) for better damage control. It has dramatically squeezed the gap between chlorophyll and pheophytin, from 0.16 eV to 0.08 eV, while keeping the main pheophytin-to-quinone gap unchanged. This has the effect of keeping the pumping of electrons out to the quinones in good condition, with low side-effect damage, but restricts overall efficiency, slowing the rate of excitation transfer to pheophytin, which affects not only the quinone-mediated path of energy to photosystem I, but also the path to the oxygen evolving center. The authors mention that this cyanobacterium recovers some efficiency by making extra light-harvesting pigments that provide more inputs, under these low / far-red light conditions.

The methods used to study all this were mostly based on fluorescence, which emerges from the photosynthetic system when electrons fall back from their excited states. A variety of inhibitors have been developed to prevent electron transfer, such as to the quinones, which bottles up the system and causes increased fluorescence and thermoluminescence, whose wavelengths reveal the energy gaps causing them. Thus it is natural, though also impressive, that light provides such an incisive and precise tool to study this light-driven system. There has been much talk that these far red-adapted photosynthetic organisms validate the possibility of life around dim stars, including red dwarves. But obviously these particular systems developed evolutionarily out of the dominant chlorophyll a-based system, so wouldn't provide a direct path. There are other chlorophyll systems in bacteria, however, and systems that predate the use of oxygen as the electron source, so there are doubtless many ways to skin this cat.

• Maybe humiliating Russia would not be such a bad thing.
• Republicans might benefit from reading the Federalist Papers.
• Fanny Willis schools Meadows on the Hatch act.
• "The top 1% of households are responsible for more emissions (15-17%) than the lower earning half of American households put together (14% of national emissions)."

Gone Fishing

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

• The power of reading.
• It is amazing that there are any redwoods left.
• Props to Orwell.
• And the indictment.. spells it all out. A play in 161 acts.
• Corruption is just a matter of course in this family.
• Cartoon of the week:

Euthansia of the Rentier

It is bad enough when business models make people rich for destroying the planet. Do we have to enrich those who do nothing at all?

John Maynard Keynes had a famous quip in his central work, The General Theory.... which goes, slightly re-arranged:

"Interest today rewards no genuine sacrifice, any more than does the rent of land. The owner of capital can obtain interest because capital is scarce, just as the owner of land con obtain rent because land is scarce. But whilst there may be intrinsic reasons for the scarcity of land, there are not intrinsic reasons for the scarcity of capital. ... It would be possible for communal saving through the agency of the state to be maintained at a level which will allow the growth of capital up to the point where it ceases to be scarce. Now, while this state of affairs would be quite compatible with some measure of individualism, it would mean the euthanasia of the rentier, and consequently, the euthanasia of the cumulative oppressive power of the capitalist to exploit the scarcity value of capital."

Keynes assumed that this day would naturally come as capitalism developed and piled up endless riches in the form of money. But recently Thomas Piketty came along and stated that this day will never come, because for some curious/mysterious reason, returns on capital are persistently higher than they have a right to be, and higher than the economic growth rate. That means that the rich keep getting richer, on a magic escalator, forever, and the only way to change this, historically, has been the horsemen of the apocalypse- war, pestilence and famine. Economic depressions can be pretty effective as well. Sadly, we have rendered all these mechanisms less effective than they have been in the past, so need to come up with something else for this modern age.

It is quite clear that advanced economies have plenty of capital. Companies routinely give money back to shareholders or buy back stock, for lack of anything better to do with their mountains of money. Interest rates tend to be low. The Federal Reserve has campaigned mightily over the last three decades to raise interest rates, to what they deem "normal" rates, which are roughly 5%. The Fed is heavily influenced by the private banking industry, which benefits (perhaps) from higher rates, as do rentiers. Each time, however, some catastrophe has intervened and sent rates back to zero. Whether the latest push turns out be the charm is not clear, but Paul Krugman expects rates to eventually return to very low levels. Japan has had near-zero rates for a couple of decades, with little harm to its domestic economy. So it seems as though the natural interest rate in this era, among stable, peaceful economies, seems actually to be very low, approximately equal to the inflation rate, and thus approximately zero.

History of US interest rates and Japanese interest rates. We keep flirting with zero rates.

This abundance of capital has sent investors to the stock market as a better bet for growth. This has sent stock valuations higher, with price/earning ratios coasting at much higher than historical levels. There is a metric called the "Buffet index", which relates stock valuations to total GDP, and this is also unusually high, twice what it has been historically. Whether all this reflects overall wealth, or the greater profitability of current corporations (due to monopolies, lack of regulation, repeated stock buy-backs, shortchanging workers, etc.), or the push of too many investors into this market, it is a worrisome situation over the long term, as returns may fail to justify expectations.

At any rate, the question is.. how to address inequality and particularly the basically unjust income of rentiers, and bring Keynes' prophecy to fruition? The recent tax changes by the Democratic congress, to impose a cost on stock buy-backs, is a tiny step in the right direction. The the fact that federal taxes on income from work (except when that work is done for hedge funds!) is twice that on investment is a clear bias, inherited from the Reagan era, that needs to be eliminated. Outright wealth taxes are also needed, as are programs against off-shore wealth hiding and abuse of trusts. There is a very long list of ways to reduce the ratchet of wealth, and especially inherited wealth, that fundamentally corrodes the basic equality on which our social and political system is (or should be) based.

The modern monetary theory community has long advocated for another policy that would address this problem, which is to end the issue of federal government bonds. They see these bonds as a relic of past times when we were on the gold standard, and really had to borrow money from the public to make ends meet. With a fiat currency, closely managed by the Federal Reserve, the federal government has no need to borrow at all. It can and does print as much money as needed ("print" being a metaphor for creating mostly electronic forms of money). State and local governments, on the other hand, are financially constrained, and need to put out bonds if they want money for large projects, beyond what taxes bring in. In 2022, the federal government spent 476 billion dollars on interest payments on the debt, which may increase drastically if inflation rises on a durable basis. 

Who holds US federal bond debt?

Whom do these interest payments go to? Well, the Fed itself and the Social Security Administration hold huge amounts- no real loss there. Foreign countries hold huge amounts- China, for example, has a trillion dollar's worth; so does Japan. But then come banks, pension funds, and mutual funds- rich investors who like these low but extremely reliable returns. The mainstream argument for bond issuance, in the absence of a gold standard, is that bonds drain demand from an economy, preventing inflation that would result were the government to not "balance" its spending with borrowing that brings that money back into its coffers. What MMT proponents point out is that those who invest in government bonds are already rich and don't need the money they are parting with. Bonds are not displacing effective demand in the economy, just productive (or unproductive) investment. Secondly, federal bonds are a fully liquid market- the money is not actually tied up in a way that prevents it from turning into economic demand.

These are the classic rentiers, whom we are collectively paying roughly half a trillion dollars a year that could be much, much better spent on other things. The last time that the federal bond market came into doubt, as the Clinton administration, under pressure from the deficit scolds, went into surplus and started paying back the "debt", who raised a hue and cry? The banks, of course, who could not imagine a world without this manna falling from heaven. Well, the fact of the matter is that the foreign countries, and the banks, and all the other rentiers, could just as well hold the fundamental debt instrument of the US government- the dollar, instead of bonds. We don't have to pay all these entities a premium to take dollars off our hands, if that is what they want.

What keeps us from ending these bond payments? It isn't economics, it is purely legislative fiction, the same kind of fiction that makes congress go through the absurdities of raising the "debt" ceiling. The US federal debt is the obverse of economic growth, for which more currency needs to be issued. The Fed and treasury issue new dollars into the economy, channeled through federal spending, and a notional debt is created. The current law just means that one debt (dollar bills) must be traded for rentier-paying debts (bonds) ... because ... we used to do so. But it is no different than the debt implied by every dollar bill: that the government, and the economy in total, stand behind each dollar bill as a manifestation of faith and credit (and good federal management). The debt does not need to be "paid off", it will not drag down future generations, and most of all, it shouldn't be compounded with interest payments to the least deserving recipients imaginable.

• Maybe some de-oligarchization is in order.
• Loneliness is a political risk.
• A curious conference just happened.
• After holding out the hope of carbon capture for decades, it is now not "deployable".
• Perhaps maturity is better than growth.
• How do you think?
• They should come up with something better than they.

Bukharin's Lesson in Communism

A review of "The ABC of Communism", by Nikokai Bukharin and Evgenii Preobrazhensky, 1920.

Nikokai Bukharin was one of the 1917 revolutionaries that brought communism to Russia. He was in New York (as was Leon Trotsky) in February 1917, as the news of the budding revolution spread around the world, and joined that revolution in May. He and Trotsky were penning a socialist newspaper at the time, and were particular fans of the New York public library- a great example of a public-private partnership, (not to mention free speech), which houses countless products of private enterprise, in a public facility. Back in Russia, they helped establish the world's first socialist and communist state, destroying the nascent parliamentary system of Karensky, and then the arrayed forces of the old aristocracy in the Russian civil war. They did this by promising something even better than parliamentary democracy- a proletarian state that would forever place workers in power, and end the power of capital and the aristocracy. 

A convenient document of the thinking behind all this is the "The ABC of Communism", by Bukharin and Evgenii Preobrazhensky, put out in 1920 and republished long thereafter to provide a popular argument for communism and the soviet system. It encapsulates the economic and political theories that animated, at least at a conscious level, the new rulers. Bukharin was relatively young, regarded as a leading theoretician, and somewhat on the liberal side, not quite as ruthless as Stalin and Lenin. An autobiography and film about his wife tried to paint a positive image of him and of what things would have been like if Bukharin had managed to not get murdered by Stalin. So this work should present a relatively coherent and attractive case for communism.

Bukharin (center) in happier days, in Soviet leadership.

Well, I have to say that it is not very impressive as either economics or politics. While it provides insight into some capitalist dynamics, it fundamentally fails to understand the most basic drivers of economic systems, and obviously has not engaged with Adam Smith, who had written almost 150 years before. 

On the plus side, there is a lengthy treatment of the economies of scale, which rightly describes the advantages that large industrial enterprises have over smaller ones. The point of this, however, is mostly political, to show why anarchism, which was one of the many revolutionary threads still active at the time, made little sense. The Bolsheviks were besotted by industry and large-scale industrialization, which was at least one area where they put a lot of resources and accomplished a great deal, saving their skins in world war 2, later on.

"Consequently, THE LARGER THE UNDERTAKING, THE MORE PERFECT IS THE TECHNIQUE, THE MORE ECONOMICAL IS THE LABOUR, AND THE LOWER IS THE COST OF PRODUCTION."

Secondly, the author's treatment of cyclical crises in capitalism is not too far off the mark. They pin the problem on over-production, which then leads to workers getting laid off, loss of income and buying power, loss of credit, loss of ancillary business, and the downward spiral of depression. Whether lack of demand or over-supply, imbalances of this kind are indeed central to this kind of crisis. The author's solution? Better organization, in the form of state control over every aspect of the economy. They ceaselessly rail against the waste of capitalism- the competition with similar products, the disorganized manner of production by competing and cut-throat capitalists, the lack of overall harmonious coordination for the public good. But what of Adam Smith? It turns out that the chaos of capitalism has its beauties, and its efficiencies, squeezing every drop out of the environment, and out of workers, in its Darwinian competition.

Thirdly, they make a great deal out of the ambient excesses of capitalism, which were truly horrific, and were clear enough all over the world, leading to the communist's program of world-wide revolution by the working class. The monopolies, the strike-breaking, the child labor, the inhuman conditions, and the vast inequality- these were unquestionable evils, some of which remain endemic to capitalism, others of which have been ameliorated through reform in (relatively) democratic countries. As is typical, criticizing is easy, and there were, and remain, plenty of problems with capitalism and with democracy as well. The question is whether Bukharin plumbs the essential depths of economics sufficiently to come up with a better economic system, or of its associated politics to come up with a better form of the state.

And here the answer has to be, as history demonstrated, no. In their discussion of large scale enterprise, they go through a rather particular example to show the power of scale.

"How great is the advantage of this system was made manifest by some American researches instituted in the year 1898. Here are the results. The manufacture of 10 ploughs. By hand labour: 2 workers, performing 11 distinct operations, worked in all 1,180 hours, and received $54. By machine labour: 52 workers, performing 97 operations (the more numerous the workers, the more varied the operations), worked in all 37 hours and 28 minutes, and received $7.90. (We see that the time was enormously less and that the cost of labour was very much lower.) The manufacture of 100 sets of clock wheels. By hand labour: 14 workers, 453 operations, 341,866 hours, $80.82. By machine labour: 10 workers, 1,088 operations, 8343 hours, $1.80. The manufacture of 500 yards of cloth. Hand labour: 3 workers, 19 operations, 7,534 hours, $135.6. Machine labour: 252 workers, 43 operations, 84 hours, $6.81."

... "All these advantages attaching to large-scale enterprise explain why small scale production must invariably succumb in capitalist society. Large scale capital crushes the small producer, takes away his customers, and ruins him, so that he drops into the ranks of the proletariat or becomes a tramp. In many cases, of course, the small master continues to cling to life. He fights desperately, puts his own hand to the work, forces his workers and his family to labour with all their strength; but in the end he is compelled to give up his place to the great capitalist."

If we read this carefully, and do the math in the case of the ploughs:

$54 / 1180 hours = 4.58 cents per hour in wages

$5.40 per plough in cost

$7.90 / 37.5 hours = 21.1 cents per hour in wages

$0.79 per plough in cost

... we can see that not only is the plough almost ten-fold cheaper (some of which is presumably shared with the buyer in the market), but the workers were paid almost five-fold more per hour. How is this a bad reflection on capitalism? This is by way of telling why small scale production dies in a capitalist system ... it doesn't stand a chance. But the authors fail to mention that, in their own example, some of these gains are apparently shared with workers. So the gains in efficiency are shared quite widely- with customers, with workers, and also with the managers and capitalists, since this new form of work requires much greater contributions of management and capital equipment.

Bukharin and Preobrazhensky are "doctrinaire" communists, blind to a gem hidden in their own data that tells us how and why the capitalist system really works. Why did workers flock to the cities when there were agricultural jobs to be had? It was higher pay. Were the new capitalists holding workers as serfs against their will? Not at all. In the US likewise, whatever the horrors of capitalism, it did not hold a candle to the horrors of slavery.

More broadly, Bukharin and the communists generally had little appreciation for the difficulties and role of management. The surplus labor theory of Marxism leaves no room for management contributions of value to the final product- it is all excess labor stolen from the worker, to be restored in the idealized worker state/paradise. The capitalists are parasites:

"In communist society parasitism will likewise disappear. There will be no place for the parasites who do nothing and who live at others' cost."

Rentiers may be parasites, but managers are not. Theirs is the job to locate the resources, drum up the customers, to build the factories, to negotiate the wages, to run the work and fire the lazy. It is not an enviable or simple position to be in, rather is perhaps the most complex in the capitalist system, or any economic system. (And it is noteworthy that failures of management are endemic in government, of even the most enlightened kind, where crucial parts of this constricting set of incentives are often lacking.) It is the competitive forces pressuring on all sides- from customers, from workers, from government, from the financial markets, etc., that are integrated by the petty bourgeoisie / kulak class into a solvent enterprise, and are the soul of the capitalist system, for which they take a premium of profits off the top.

Bukharin and colleagues never pause to consider why capitalism is so dominant:

"Contemporary capitalism is world capitalism. All the countries are interconnected; they buy one from another. We cannot now find any country which is not under the heel of capitalism; we cannot find any country which produces for itself absolutely everything it needs."

Why is this? There was no shortage of experiments in the 1800's in socialistic styles of life, extending from the Shakers and the Owenites to the Tolstoyans. Few of them even survived very long, and none had a broader impact, let alone rising to the organic level of country-wide economic system. Religious monasteries are probably the only example of successful long-term socialistic organizations, though most are run on more or less totalitarian lines, with a whole separate set of emotional and personal committments. This starkly unsuccessful track record should have been a red flag- forgive the pun!- that while socialist utopianism is very popular, it is not practical.

This cavalier disregard of management and the elementary aspects of human economic demand (aka desire, aka greed) naturally came back to bite the communist Soviets, when, in the absence of a well-thought out way to run things in the wake of winning power on the back of their fantasy of a perfectly (and apparently easily, thanks to a mythical "statistical office") ordered and efficient economic system, they fell to the lowest device in the manager's toolbox- terror.

Bukharin on his way to execution, after having helped Stalin hound Trotsky to death.

Why the loose economics, fantastical pronouncements, and embarassing lack of realism? The reason becomes apparent as you read through "The ABC of Communism", which is that its main purpose is to inspire hate. It is a political tract that, as was current among communists then and since, seeks to frame an enemy, inspire hatred of that enemy, and support for the valiant vanguard that will vanquish that enemy. 

"What civil war can compare in its destructive effects with the brutal disorganization and devastation, with the loss of the accumulated wealth of mankind, that resulted from the imperialist war? MANIFESTLY IT IS ESSENTIAL THAT HUMANITY SHALL MAKE AN END OF CAPITALISM ONCE AND FOR ALL. WITH THIS GOAL IN VIEW, WE CAN ENDURE THE PERIOD OF CIVIL WARS, AND CAN PAVE THE WAY FOR COMMUNISM, WHICH WILL HEAL ALL OUR WOUNDS, AND WILL QUICKLY LEAD TO THE FULL DEVELOPMENT OF THE PRODUCTIVE FORCES OF HUMAN SOCIETY."

... "We are thus confronted by two alternatives, and two only. There must either be complete disintegration, hell broth, further brutalization and disorder, absolute chaos, or else communism."

Millions of people all over the world were thoughtless enough to accept this poisoned chalice, and went down the road of economic brutalization, famine, mass terror, and the gulag. Communism turned out to be a power play, not an economic Oz. It was a bright and shiny political lie. We are in the US becoming familiar with the power of such lies- their use of the basest and most powerful instincts- hate, and hope. Their ability to cut straight through any rational and empathetic analysis, and their ability to make seemingly reasonable people believe the flimsiest absurdities.

• China is looking at some serious problems.
• Utopias should be strictly for thinking, not doing.
• Wait, I can't live in an exclusive neighborhood?
• Is it OK for lawyers to engage in insurrection?

To Sleep- Perchance to Inactivate OX2R

The perils of developing sleeping, or anti-sleeping, drugs.

Sleep- the elixir of rest and repose. While we know of many good things that happen during sleep- the consolidation of memories, the cardiovascular rest, the hormonal and immune resetting, the slow waves and glymphatic cleansing of the brain- we don't know yet why it is absolutely essential, and lethal if repeatedly denied. Civilized life tends to damage our sleep habits, given artificial light and the endless distractions we have devised, leading to chronic sleeplessness and a spiral of narcotic drug consumption. Some conditions and mutations, like narcolepsy, have offered clues about how sleep is regulated, which has led to new treatments, though to be honest, good sleep hygiene is by far the best remedy.

Genetic narcolepsy was found to be due to mutations in the second receptor of the hormone orexin (OX2R), or also due to auto-immune conditions that kill off a specialized set of neurons in the hypothalamus- a basal part of the brain that sits just over the brain stem. This region normally has ~ 50,000 neurons that secrete orexin (which comes in two kinds as well, 1 and 2), and project to areas all over the brain, especially basal areas like the basal forebrain and amygdala, to regulate not just sleep but feeding, mood, reward, memory, and learning. Like any hormone receptor, the orexin receptors can be approached in two ways- by turning them on (agonist) or by turning them off (antagonist). Antagonist drugs were developed which turn off both orexin receptors, and thus promote sleep. The first was named suvorexant, using the "orex" and "ant" lexical elements to mark its functions, which is now standard for generic drug names. 

 This drug is moderately effective, and is a true sleep enhancer, promoting falling to sleep, restful sleep, and length of sleep, unlike some other sleep aids. Suvorexant antagonizes both receptors, but the researchers knew that only the deletion of OX2R, not OX1R, (in dogs, mice, and other animals), generates narcolepsy, so they developed a drug more specific to OX2R only. But the result was that it was less effective. It turned out that binding and turning off OX1R was helpful to sleep promotion, and there were no particularly bad side effects from binding both receptors, despite the wide ranging activities they appear to have. So while the trial of Merck's MK-1064 was successful, it was not better than their exising two-receptor drug, so its development was shelved. And we learned something intriguing about this system. While all animals have some kind of orexin, only mammals have the second orexin family member and receptor, suggesting that some interesting, but not complete, bifurcation happened in the functions of this system in evolution. 

What got me interested in this topic was a brief article from yet another drug company, Takeda, which was testing an agonist against the orexin receptors in an effort to treat narcolepsy. They created TAK-994, which binds to OX2R specifically, and showed a lot of promise in animal trials. It is a pill form, orally taken drug, in contrast to the existing treatment, danavorexton, which must be injected. In the human trial, it was remarkably effective, virtually eliminating cataleptic / narcoleptic episodes. But there was a problem- it caused enough liver toxicity that the trial was stopped and the drug shelved. Presumably, this company will try again, making variants of this compound that retain affinity and activity but not the toxicity. 

This brings up an underappreciated peril in drug design- where drugs end up. Drugs don't just go into our systems, hopefully slipping through the incredibly difficult gauntlet of our digestive system. But they all need to go somewhere after they have done their jobs, as well. Some drugs are hydrophilic enough, and generally inert enough, that they partition into the urine by dilution and don't have any further metabolic events. Most, however, are recognized by our internal detoxification systems as foreign, (that is, hydrophobic, but not recognizable as fats/lipids that are usual nutrients), and are derivatized by liver enzymes and sent out in the bile. 

Structure of TAK-994, which treats narcolepsy, but at the cost of liver dysfunction.

As you can see from the chemical structure above, TAK-994 is not a normal compound that might be encountered in the body, or as food. The amino sulfate is quite unusual, and the fluorines sprinkled about are totally unnatural. This would be a red flag substance, like the various PFAS materials we hear about in the news. The rings and fluorines create a relatively hydrophobic substance, which would need to be modified so that it can be routed out of the body. That is what a key enzyme of the liver, CYP3A4 does. It (and many family members that have arisen over evolutionary time) oxidizes all manner of foreign hydrophobic compounds, using a heme cofactor to handle the oxygen. It can add OH- groups (hydroxylation), break open double bonds (epoxidation), and break open phenol ring structures (aromatic oxidation). 

But then what? Evolution has met most of the toxic substances we meet with in nature with appropriate enzymes and routes out of the body. But these novel compounds we are making with modern chemistry are something else altogether. Some drugs are turned on by this process, waiting till they get to the liver to attain their active form. Others, apparently such as this one, are made into toxic compounds (as yet unknown) by this process, such that the liver is damaged. That is why animal studies and safety trials are so important. This drug binds to its target receptor, and does what it is supposed to do, but that isn't enough to be a good drug. 

 

• Crime in Connecticut.
• Some classic Bowie/Queen.