The Impossibility of Morality

We have dark sides and do bad things. How come we all think we are good people?

Part of our political, and temperamental, divide revolves around how seriously to take morality. How idealistic to be about goodness, how hard to try, or whether to be more realistic to be about our dark side. For all the platitudes and commandments, the sad fact is that morality is impossible, so the question is perhaps more how intensively we blind ourselves to darkness rather than how dark we will actually be.

Weird, right? But the closer you look, the more impossible it is to follow any system of morality. There are Jains who will not hurt a fly, let alone eat meat. But plants have feelings too. And our guts contain astronomical numbers of organisms in a roiling dance of macabre death. What about them? Existence as a human is unavoidably destructive. Simpler moral systems preach kindness to others. But again, existence requires feeding one's own fire, and that must come at cost to something, or someone. Every trade is unequal, even if voluntary. Employees are notoriously exploited to give more than their fair share. The Earth is relentlessly exploited. There is no end to our appetites, as long as we are alive.

Psychologically, we build up defenses to say that we are no worse than others, that we are good people. Even if we are bad people, we say that we have been driven to crime, and it is no worse than the rich people who thoughtlessly abuse others. Or if we are a presidential candidate, we say that we are saving the world, and making America great, and the subject of cruel witchhunts. Self-defense is one more essential part of living, even if it comes at the expense of seeing the world clearly. Unflattering visions of our way of life are rejected and repressed, the more so if they come as criticism from others.

Defensive blindness is integral to "modern" life. The agriculture and food processing industry keeps the slaughterhouses hidden, the feedlots and inhumane poultry coops under wraps. The less we know, the better we feel. Money is the ultimate screen against the squeems and qualms of existence, shielding us from the rapacious mining that our electronics drive in tropical forests, the slave labor that makes our clothes, and countless other immoral and destructive processes we are ultimately responsible for. Clear consciousness of all this would make the whole system collapse.

Protesters carrying the pine tree flag of Christian nationalism. While doing good things for the country.

Religions offer their own forms of defense. Confession in the Catholic church is a classic way to touch the darkness, but then to be absolved and feel good again. Exorcisms are offered as well. Protestant approaches tend to focus more on works, like community service, or in fringier precincts, on sermons of self-glorification. Everyone who is reborn in Christ is part of the club, and though a sinner, is also good, glorious, and heaven-bound. Possibly, even, in the Mormon system, himself a god. How they engage with moral darkness varies tremendously by religion, but the common need is to control it, in ourselves and others, sufficiently that our self-image of goodness and light can be preserved.

The extensive repression of moral darkness leads to the countervailing temptation to take another peek at it, under controlled conditions. It is the inspiration for much art- the detective thiller, the horror movie, the general apparatus of drama. Without darkness, there is no interest or light. And people differ markedly in their approach to such material. The more liberal and optimistic tend to focus on the light side, not the dark side, and do so politically as well. They have more moral idealism and hope, which means they have more repression of darker tendencies. Kumbaya is sung. Conversely, the more "realistic", conservative attitude scoffs at the do-gooder idealism of the left, and sees darkness around every corner- in foreigners, in sexual transgression and expression, in fluid social systems, in change itself. They recognize that moral aspiration is futile- such as the woke trend of recent times .. the bending over backwards to every minority group, micro-aggression, every insect and animal, and the climate.. is putting up an impossible and futile bar. That sticking to basics and tradition is going to get us further than such refusal to recognize the dark reality of human existence. 

These valences are apparent in the Palestinian dilemma. As the Palestinians were expelled from Israel during its establishment, the Jews proclaimed a right for Jews all over the world to come to Israel. Meanwhile, the UN created a right of return for Palestinians, to the very same land that formed Israel. It was the ultimate expression of bleeding heart unrealism, and has led (in part) to the existentially stuck misery of Palestinians for all these decades, as the UN took it upon itself to nurture an absurd dream of return and set up a now-permanent refugee apparatus of feeding, schools, and health care, all of which fuels the seething anger and terrorist dreams of ever-growing generations of Palestinians.

Another example is the US war in Vietnam- a curious and tragic mix of blindness, idealism, and realism. We wanted to help the (South) Vietnamese defend themselves from communism. In light of what happened in North Korea in the ensuing decades, this was not a bad goal. North Korea is moral darkness incarnate- a cruel and criminal dictatorship. But once the enormity of the task became clear, the moral realists took charge, with the aim of bombing Vietnam and its neighboring countries into submission. But even such extreme measures failed, leaving us with the ashes of horrible means used in the service of a futile goal. The US media was increasingly unwilling to hide the horrors, bringing into American consciousness all this darkness, which turned out to be unbearable.

So, is it better to blind ourselves to the darkness, and risk destruction and error, or better to be realistic, explore it, even celebrate it, as the Homeric epics do, and gird ourselves to deal with it, and deal it out to others? As in most things, societies are probably best off with a mix of perspectives. This mix is perennially expressed in our political spectrum, though of late the right seems to have gotten caught up in a peculiar reaction against the pieties of the left. As the left has gained the cultural and governmental high ground, as shown by the triumph of gay rights, ever-increasing concern for racial minorities, and a rising tide of official movement on environmental concerns, the right has turned apoplectic. They seem to be saying ... "We love our trucks, we won the continent fair and square, and we won the racial contest as well.."- leave us to our spoils, and don't be so concerned about "fairness" .. life isn't fair or moral, but goes to the darkest, baddest winner. (One can hear echos of the Confederate South in all this clearly enough.) Those on the left who are besotted with woke-ness and fairness will be singing a different tune when they are not at the top of the heap anymore, in their well-gentrified, rich and safe neighborhoods.

Perhaps this portrayal is extreme, but extreme concern for the moral fairness within a society can blind us to other issues, such as the competitive underpinnings of life, both within and verus other societies, and the ultimate impossibility of being totally fair, or moral, as historical actors. A balance of moral idealism and realism about unavoidable dark aspects is needed, but not in a conflict that tears the society apart. That depends on communication between the two sides, and less totalizing certainty from each side's respective mechanisms that repress doubt and screen (or valorize, in extreme cases) various different aspects of darker morality. Religion is notorious for reshaping its adherent's realities and protecting them psychologically from their own evil actions. But left wing certainty functions similarly, with its echo chambers and pieties. So, as usual, deeper insight is needed, mostly of our own blind spots and what they are hiding, but also of how such mechanisms work across the spectrum.

• Eating animals and loving them.
• Ready to be gouged more efficiently?
• Is your car really worth it?
• Corals are dying.

The Shadow War

We are in a new world-wide cold war. And ironically, the many new technologies from the West have given autocratic states extraordinary new powers. 

Paul Theroux had a remarkable passage in one of his travel books, as he was passing through Myanmar, a military dictatorship then and now, that illuminated attitudes towards China and from China. 

"I heard lots of praise for the United States in distancing itself from the regime, and lots of blame for China and Russia and Singapore in supporting it- China especially. But China's prosperity, its need for oil and wood and food, had created a new dynamic. China had no interest in any country's developing democratic institutions; on the contrary, it was a natural ally of repressive regimes. When the World Bank withheld funds from an African country because it was corrupt and tyrranous, demanding that it hold an election before it could qualify for aid, China would appear with money- 'rogue aid,' with no strings attached, and got the teak, the food, and the drugs." - Ghost Train to the Eastern Star, 2008

The world seems headed into another cold war, definitely rhyming with the last cold war. It is highly unfortunate, and testament to some defects in US management of the post-cold war era, to the surprising durability, even attractiveness, of authoritarian systems, and to the many weaknesses of democratic systems. This new cold war, which I will call the shadow war, features Russia and China as the main poles of opposition to democratic and developed countries, mostly in the West, but including many others. This time around, China is the stronger power by far, and both Russia and especially China are quite advanced in their development, so that the West no longer has a monopoly in any particular technology or kind of organization. China has adopted all the magic of capitalist market mechanisms to grow its wealth, and stolen (or forced the transfer of) huge amounts technology and knowledge to make itself a leader in all sorts of industries.

The West has lately begun to wake up to the problem. Our hope that capitalism was somehow related to, or a leading wedge for, democracy has been dashed several times over. Instead of China turning into Hong Kong, it is Hong Kong that is turning into China. Not only is capitalism, as has been tirelessly pointed out from the left, amoral and indifferent to human rights, (as we already knew from slavery in the US), but democracy is also far more fragile than we had hoped, requiring a wide range of civic understandings, media practices, and forms of education that are far from universal, or natural. We had, in the windup to the cold war, seen many countries make slow and fraught transitions to democracy (Philippines, Taiwan, South Korea, and Eastern Europe), but have more recently seen countries backtrack into autocracy (Russia, Hungary).

Naturally, the war in Ukraine has put the most urgent point on this conflict, where Russia, which is to say its autocratic leader, felt that the existence of an independent and democratic Ukraine next door was too much to bear. Now, China also tells us that it loves its brothers in Taiwan so much that re-unification will come, no matter what the Taiwanese themselves might want. Love certainly takes some strange forms!

But it is a much broader issue, spanning the globe, and the depths of human psychology. On one list of countries ranked by democratic governance, the median country is Armenia, with a "hybrid regime" and scores of roughly five out of ten. This is not a great situation, where half the world, in rough terms, lives in various states of miserable, oppressive government. And as the quote above suggests, the authoritarians have in some ways the stronger hand. What happened?

We in the West had thought that democracy was the natural harbor of all peoples- the end of history, indeed. But in the first place, people power is a very limited power, if whoever has power is authoritarian enough to use tanks against it. And in the second place, democracy is not natural in many cultures. The Muslim culture, for instance, for all its virtues, has a fundamentally patriarchal and tribal governance model, with little room for democracy, though there are, traditionally, various forms of freedom, for men at least. So however attractive democracy is in theoretical terms, and as a model in the West that people from authoritarian countries like to vacation to... as a cultural pattern, it is not universal. And authoritarian patterns are hardly foreign to the West either. The Catholic church is an example of the preserved archetypes of patriarchy and authoritarian strong-man rule.

The Chinese dream is highly militaristic, and rather threatening.

But more deeply, the archetypes we have of leadership and politics are authoritarian.. the king, the hero. Jungian psychology, aside from its focus on archetypes, deals in the shadow, which is our real needs and instincts, insofar as they run counter to our surface goodness and conscious ego construction. A person like Donald Trump exemplifies all these trends. Why on earth are we still saddled with this sociopath after a decade of drama-queenity? He clearly touches a lot of people's archetypal conceptions of strength and heroism. His powers of psychological projection, reflectively rejecting his own shadow, are immense. He is rubber, others are glue. And his fundamental bond with the followers, by licensing their shadow sides of hate and violence, makes his every pronouncement right no matter what. We in the US are facing a cataclysmic political season, trying to repress the shadow of humanity, which is so amply expressed around the world in political / power systems that follow the logic of strength, ending up in states of terror.

Modern technology hasn't helped, either. After a brief flush of excitement about the ability of social media to amplify people power, especially across the Muslim world, it all went to pot as the shallow-ness and disorganization of such movements became apparent. The powers of databases, personal identification, surveillance, and media manipulation have been much more useful to authoritarian governments than to their antagonists, making state terror more effective than ever. Authoritarian countries now control their internet and media environments with great precision, increasingly project their twisted narratives abroad, and even hunt down dissidents outside their borders using the new information tools. So while information may want to be free, it doesn't really have a say in the matter- those with power do.

What to do about it? We in the West have lost control of our media environments. While we are waking up to some extent the the malevalent media from abroad, domestic media is controlled by money, which in the current environment of yawning wealth inequality, political fissiparation, and clickbait "business models" is just as crazy and corrupt. So there should be two approaches to this. One is to strengthen quality media, like PBS and its cohorts, with more offerings and deeper reporting. The other is to restrict how corporations can control media. The right to individual free speech can be preserved while making corporations more sensitive to social goods. The Dominion case against FOX was a small example of the powers available. Liability for lying should be a broader effort in the law, specifically against corporations, which are creatures of the state, not natural persons. We need to recognize the deep psychological powers we are up against in preserving enlightened, respectful civil government and discourse.

Obviously getting our own house in order, against the atavistic forces of political authoritarianism, is the first order of business. Abroad, paradoxically, we need to project strength as a democratic and developed community, holding the line in Ukraine and Taiwan, and against all sorts of authoritarian encroachments, until temperatures are lowered, and the current nationalist fevers abate. For what China has right now is an imperialist fever. It has been weak for so long and surrounded by so many unfriendly countries, that one can understand that it sees its recent economic prosperity as a special opportunity to recover a leading position in its neighborhood, militarily and politically as well as economically. That would be fine if it were not also trying to subvert free political systems and prop up tyrannical ones. There are good reasons why its neighbors are fearful of China.

Like in the last cold war, I think time plays a key role. We have to believe that democracies, for all their weaknesses, are better, and are seen as better, by people around the world. While today's authoritarian powers may have greater durability than those of the communist era due to their embrace of, rather than flouting of, market principles and modern technologies, they are ultimately fragile and subject to the opinions of their own people. Putin will not last forever. Xi will not last for ever. (The Kim regime of North Korea may, however, last forever!) Change is the achilles heal of authoritarian conservatism. So we are in for a very long haul, to keep spreading people power and peace internationally.

• Trade theft and IP warfare.
• Myanmar is a typical case of China's influence and values.
• Religion and war.
• Food oligopoly.
• Ghost roads and the end of nature.
• What, exactly, is the problem?

Mopping up Around the Cell

What happens when proteins can't find their partners?

Cells have a lot of garbage disposal issues. There are lysosomes to digest large things like viruses, proteasomes to dispose of individual proteins, and lots of surveillance mechanisms to check that things are going as they should- that proteins coming off the ribosome are complete, that mRNAs are being spliced, that mitochondria are charged up as they should be, that the endoplasmic reticulum is making, folding, and secreting proteins as it should be, among many others. One basic problem that arises when cells have a lot of proteins that assemble and cooperate in the form of complexes, is that some of those subunits may be present in excess, or not join their intended complexes for other reasons such as misfolding. This can have very bad effects. Most protein binding makes use of hydrophobic surfaces, and having these floating around freely can lead to indiscriminate binding / agglomeration, like amyloid plaque formation, and cell death.

Bacteria have one partial solution, which is to encode proteins that are destined to the same complex from the same mRNA, made from what is called an "operon" of genes, like a train with successive gene-carriages. Each multi-protein-encoding message from such an operon is thus necessarily equally abundant, and, assuming simiar ribosomal rates of protein synthesis, the proteins should also be produced in equal quantities, providing at least one method to balance their abundance in the cell. But there are many other issues- proteins may have different life-spans, or different ribosomal production rates, or assembly into the complex may be slow and difficult, so bacteria still are not out of the woods. Eukaryotes do not use operons anyhow, so our more-finely regulated gene control mechanisms are called on to properly equalize (or adjust for) the ultimate subunit concentrations. 

But when all this fails, and there is more of some complex subunit than needed, what happens then? When experimenters over-produce some complex component in cells, it is typically short-lived. And if they impair its production, the rest of the complex tends to be short-lived. This implies mechanisms in the cell to dispose of incomplete complexes and their components. It turns out that there are some specific chaperone proteins that detect such orphan subunits, and tag them to be destroyed. Several prominent complexes, such as ribosomes and proteasomes, even have specifically dedicated mop-up chaperones. A recent paper described a chaperone protein dedicated to mopping up the excess or misfolded subunits of another large and abundant complex - the chaperonin complex. That makes this protein, ZNRD2, a sort of metachaperone.

Some structural (though not dynamic) views of the CCT complex. A shows top and side views, respectively. C shows a layout of how the equator of the complex looks, as coded by each of the subunits. At the ring-ring interfaces are the ATP binding sites (d). And lastly (e) a cut-away view of the inside show where substrate proteins are enclosed and encouraged to fold correctly.

The chaperonin complex, (also called CCT), is a large, hollow sphere that actively helps other proteins to fold correctly. The structural proteins actin and tubulin are the most prominent targets that need this help. When first synthesized, they are bound by adapters that ferry them to the chaperonin complex, which lifts its lid to allow the protein in. Then, ATP is used to induce dramatic cycling of the chaperonin structure, shifting from an internal hydrophobic structure to a more hydrophilic one. This allows the unfolded protein to alternately splay open over the hydrophobic surface, and then fold in piece-wise fashion, for as long as it takes till the barrel detects that it is fully folded and no longer sticking to the hydrophobic internal surfaces.

In the current work, the researchers drove the expression of several individual CCT subunits in cell lysates. Then they sent the products into a mass spectrometer to find out what was sticking to these "orphan" proteins. They found two major associated proteins, HERC2, and ZNRD2. HERC2 is known as a ubiquitin ligase, which is one of a large family of enzymes that tag proteins with ubiquitin, targeting them for disposal. But ZNRD2 was totally uncharacterized, known only as an auto-antigen reacted to by some people with Sjogren's syndrome or scleroderma. The question then was .. does HERC2 directly sense the presence of free-floating CCT subunits, or does it need a helper to do so, such as perhaps ZNRD2?

"... a sizable population of multiple CCT subunits are orphaned even under normal conditions, and the degradation of a subset of these can be stimulated by HERC2."

The researchers showed that deleting HERC2 strongly impaired the cleanup of most orphan CCT subunits. It is evident, however, that there are other chaperones not covered in this work that help clean up some of the other CCT subunits. Then they found that HERC2 interaction with the CCT proteins was dependent on ZNRD2, but that the reverse was not the case- ZNRD2 binds CCT subunits in any case. This, and other experiments, including mapping the location within the HERC2 protein that binds ZNRD2, showed that ZNRD2 is the adapter that does the detailed detection of orphaned CCT subunits. At only 199 amino acids, there is not much to it, and searches for domain signatures do not yield much. Its name reflects a structure that uses zinc ions for stabilization, but much of the protein is also disordered. It is notable for a high proportion of hydrophobic amino acids (alanine, leucine) and lots of prolines (15), which would contribute to a disordered structure. 

Thankfully, with the advent of AI and alpha-fold, these researchers could also investigate and model how ZNRD2 interacts with both the HERC2 ubiquitin ligase and with one of the CCT subunits, CCT4- all without doing any laborious structure determinations.

AI-calculated structures of the complex of the ubiquitin ligase HERC2 with the adaptor ZNRD2 and the target subunit CCT4. At right, the hydrophobic residues of CCT4 are colored yellow, showing that the ZNRD2 orphan subunit detector and adaptor binds to a hydrophobic pocket which would otherwise be completely buried with the full CCT structure. The interacting domain of HERC4 in green is termed a 7-bladed beta propeller.

"In the fully assembled CCT double ring, all potential ZNRD2 interaction sites are completely buried because they form the interface between the two individual rings."

 

They found that ZNRD2 binds to a hydrophobic pocket of CCT4, a pocket that is otherwise buried in the fully assembled CCT. This patch would also be exposed on partially assembled CCT complexes, indicating that this interaction is not only relevant for mopping up the individual subunit, but for several kinds of incomplete assembly of the entire complex, perhaps explaining why other subunits are also mopped up by this system. 

This kind of work is a good example of normal science. A gene about which nothing was previously known (ZNDR2) is now given a function in the cell, and a process circumstantially known to exist is fleshed out with actors and structures that explain it. Of the ~20,000 human protein-coding genes, roughly ten percent still have no annotation, and many more have only tenuous annotation, perhaps only drawn from structural analogy, not direct study. So there is a great deal more work needed to evaluate our parts list, even on the most basic level, even before getting into the complexities of how these proteins act and interact in tissues and pathways. 

• What are the hippos thinking?
• Vodka is apparently a thing.
• Just how low is this grift going?
• Who gets to reproduce, and who gets killed? Population control at the heart of the Jewish state.
• Genetics and parenting.
• No, absolutely not.. this can not be true.

Nominee for Most Amazing Protein: RAD51

On the repair and resurrection of DNA, which gets a lot of help from a family of proteins including RAD51, DMC1, and RecA.

Proteins do all sorts of amazing things, from composing pores that can select a single kind of ion- even just a proton- to allow across a membrane, to massive polymerizing enzymes that synthesize other proteins, DNA, and RNA. There is really no end to it. But one of the most amazing, even incredible, things that happens in a cell is the hunt for DNA homology. Even over a genome of billions of base pairs, it is possible for one DNA segment to find the single other DNA segment that matches it. This hunt is executed for several reasons. One is to line up the homologous chromosomes at meiosis, and carry out the genetic cross-overs between them (when they are lined up precisely) that help scramble our genetic lineages for optimal mix-and-matching during reproduction. Another is for DNA repair, which is best done with a good copy for reference, especially when a full double-strand break has happened. Just this week, a fascinating article showed that memories in our brains depend in some weird way on DNA breaks occurring in neurons, some of which then use the homologous repair process, including homology search, to patch things up.

The protein that facilitates this DNA homology search is deeply conserved in evolution. It is called RecA in bacteria, radA and radB in archaea, and the RAD51 family in eukaryotes. Naturally, the eukaryotic family is most closely related to the archaeal versions (RAD51 and DMC1 evolving from radA, and a series of other, and poorly understood family members, from radB). In this post, I will mostly just call them all RAD51, unless I am referring to DMC1 specifically. The name comes from genetic screens for radiation-sensitive mutants in human and other eukaryotes, since RAD51 plays a crucial role in DNA repair, as noted above. RAD51 is not a huge protein, but it is an ATPase. It binds to itself, forming linear filaments with ATP at the junction points between units. It binds to a single strand of DNA, which is going to be what does the hunting. And it binds, in a complicated way, to another double-stranded DNA, which it helps to open briefly to allow its quality as a target to be evaluated. 

This diagram describes the repair of double strand breaks (DSB) in DNA. First the ends are covered with a bunch of proteins that signal far and wide that something terrible has happened- the cell cycle has to stop.. fire engines need to be called. One of these proteins is RPA, which simply binds all over single-stranded DNA and protects it. Then the RAD51 protein comes in, displaces RPA, and begins the homology search process. The second DNA shown, in dark black, doesn't just happen, but is hunted for high and low throughout the nucleus to find the exact homolog of the broken end. When that exact match is found, the repair process can proceed, with continued DNA synthesis through the lesion, and resolution of the newly repaired double strands, either to copy up the homolog version, or exchange versions (GC, for gene conversion). 

This diagram shows how the notorious (when mutated) oncogene BRCA2 (in green) works. It binds RAD51 (in blue) and brings it, chain-gang style, to the breakpoints of DNA damage to speed up and specify repair.

There have been several structural studies by this point that clarify how RAD51 does its thing. ATP is simply required to form filaments on single-stranded DNA. When a match has been found and RAD51 is no longer needed, ATP is cleaved, and RAD51 falls off, back to reserve status. The magic starts with how RAD51 binds the single stranded DNA. One RAD51 binds for every ~3 bases in the DNA, and the it binds the phosphate backbone, so that the bases are nicely exposed in front, and all stretched out, ready to hunt for matching DNA.

A series of RAD51 molecules (in this case, RecA from bacteria) bound sequentially to single-stranded DNA (red). Note the ATP homolog chemicals in yellow, positioned between each protein unit. One can see that the DNA is stretched out a bit and the bases point outwards.

A closeup view of one of the RAD51 units from above, showing how the bases of the DNA (yellow) are splayed out into the medium, ready to find their partners. They are arranged in orientations similar to how they sit in normal (B-form) DNA, further enhancing their ability to find partners.

The second, and more mysterious part of the operation is how RAD51 scans double-stranded DNA throughout the genome. It has binding sites for double-stranded DNA, away from the single-stranded DNA, and then it also has a little finger that splits open the double-stranded DNA, encouraging separation and allowing one strand to face up to the single stranded DNA that is held firmly by the RAD51 polymer. The transient search happens in eight-base increments, with tighter capture of the double-strand DNA happening when nine bases are matched, and committment to recombination or repair happening when a match of fifteen bases is found.  

These structures show an intermediate where a double-stranded DNA (ends in teal and lavender, and separated DNA segments in green and red) has been captured, making a twelve base match with the stable single-stranded DNA (brown). Note how the double-stranded DNA ends are held by outside portions of the RAD51 protein. Closeup on the right shows the dangling, non-paired DNA strand in red, and the newly matched duplex DNA with green-brown colored base interactions.

These structures can only give a hint of what is going on, since the whole process relies so clearly on the brownian motion that allows super-rapid diffusion of the stablized single-strand DNA+RAD51 over the genome, which it scans efficiently in one-dimensional fashion, despite all the chromatin and other proteins parked all over the place. And while the structures provide insight into how the process happens, it remains incredible that this search can happen, on what is clearly a quite reliable basis, day and day out, as our genomes get hit by whatever the environment throws at us.

"Unfortunately, most RAD51 and RAD51 paralog point mutations that have been clinically identified are classified as variants of unknown significance (VUSs). Future studies to reclassify these RAD51 gene family VUSs as pathogenic or benign are desperately needed, as many of these genes are now included on hereditary breast and ovarian cancer screening panels. Reclassification of HR-deficient VUSs would enable these patients to benefit from therapies that specifically target HR deficiency, as do poly(ADP)-ribose polymerase (PARP) inhibitors in BRCA1/2-deficient cells."

Lastly, one paper made the point that clinicians need better understanding of the various mutations that can affect RAD51 itself. Genetic testing now is able to find all of our mutations, but we don't always know what each mutation is capable of doing. Thus deeper studies of RAD51 will have beneficial effects on clinical diagnosis, when particular mutations can be assigned as disease-causing, thus justifying specific therapies that would otherwise not be attempted.

• Let's make taxes public.
• A plea for less sugar.

Renewable Power in Africa

Prospects for growth in electricity access and in clean energy.

Africa is an enormous continent, notoriously larger than China, the US, and Europe combined. Its population is also large- as large as that of India, at about 1.4 billion people. This population is growing rapidly, while its social and economic systems are developing more slowly. But as we know, the main ingredient of an advanced economy is power, which as traditionally been drawn from fossil fuels. Advanced economies are in the painful and reluctant process of transitioning away from fossil fuels. We can do a lot to help Africa to leapfrog this history by front-loading renewable energy.

There was a recent paper about the hydropower prospects in Africa. It notes that there are many projects on the drawing board, with many undammed rivers on the continent. But as we have learned in the US, the implications of river damming are quite destructive and wide-spread. For example fish ladders simply do not work- not at the scale needed to keep fish populations (and fisheries) healthy. Then there are problems of siltation, water temperature, erratic flows, and population displacement. There is a movement in the US to remove dams wherever possible, to free ecosystems back to a functional state. 

"More than 300 hydropower plants, corresponding to an additional 100-GW power capacity, are under consideration across the continent."

The article made the basic point that, given the state of other renewable power sources, and the prospect of lower water levels and droughts due to climate change, that roughly half of the planned hydropower projects they know of are economically inviable, even putting aside environmental considerations. 

This leads to the question of what to do instead? Maybe the answer is microgrids. In the developed world, it is increasingly common for people to take control of their own electricity production through the use of solar power. But at a single house level, power inputs and consumption are both erratic and require a lot of storage capacity to furnish a reliable system. The typical system is highly reliant on the larger grid to manage this intermittency. Microgrids occupy a middle range between grid-scale power, which is subject to problems of centralized political and social development, and the individual house, where the expense of managing fully independent electrical supply is highest.

The current grid in Africa, colored for >66 kV (dark blue) and the rest light blue. Note the patchy regional distribution, with lots of underserved areas. The US has a much denser grid. 

A map that suggests likely locations for smaller microgrids in Africa.

These maps note that there are many underserved areas in Africa- some concentrated urban areas, and a great spread of rural areas. Electrification is well-advanced in South Africa and the heart of West Africa. But there are many rural areas that would be better served by microgrids of various scales. Microgrids can be altered over time and integrated into larger systems. Their production and storage capacities are both beneficial for larger grid stability and scalability. Africa is, naturally, positioned ideally for solar power, and the Sahara is a natural location for massive power installations, to serve both Europe, the Middle East, and Africa.

A proposal to run a super-grid around much of Africa, to harness supplies from the Sahara, among other sources.

One of the main characteristics of renewable power is that it has high up-front costs. The fuel is free, and clean. But the mechanisms to capture and store it are expensive. Thus if we want to encourage a more rapid transition to sustainable power systems in Africa, we would help pay for the up front costs, sharing capital investment in the interests of everyone, both here and there. Africa is currently a big exporter of oil and gas. As other regions transition away from those fuels, it is imperative that this production not be redirected and propped up by further Western investment, but rather replaced with better energy sources.

• Advanced nuclear power is not going to cut it.
• The heat pump song.
• Treason, again.
• On silence and isolation.
• Housing prices should not always go up.
• Medicare disadvantage.

Ideologies of Work

Review of Elizabeth Anderson: "Hijacked: How neoliberalism turned the work ethic against workers, and how workers can take it back."

We live by the sweat of our brow, though work. At least that has been the story after we were thrown out of the garden of Eden, where we had previously foraged without effort. By the time of Puritans, work had been re-valued as being next to godliness, in what became known as the Puritan work ethic. Elizabeth Anderson takes this as her point of departure in a fascinating historical study of the winding (and mostly descending) road that attitudes toward work took down the centuries, in the perennial battle between workers and parasites who have found ways to avoid sweating, yet eat just the same ... or better.

Anderson trots through all the classical economists and philosophers, down to John Stuart Mill and Marx, showing two main threads of thought. First is the progressive thread, in which the Puritans can (curiously) be classed, as can Adam Smith. They value work as both a cultural and meaningful activity, not just a means of sustenance. They think everyone should work, and criticize anyone, high or low, who shirks this responsibility. Genteel landowners who spend their time hunting rather than improving their estates are just as culpable as drunkards and other able-bodied peasants who fail to do their share. Learning and innovation are highly valued, as not just ameliorating the lot of those making improvements, but at the same time raising the wealth of, and standard of living for, all.

In contrast is the conservative thread. Anderson herself describes it trenchantly:

"From the conservative perspective, however, poverty reflected an individual's failure to filfill the demands of the work ethic. Society is at fault solely in establishing institutions that violate natural law in promoting vice through provisions such as the Poor Law. Conservatives agreed that the Poor Law must therefore be abolished or radically reformed. If poverty is caused by the vice of the poor, the remedy for poverty must be to force the poor to practice virtue, to live up to the demands of the work ethic. Conservatives differed somewhat on which virtue was most necessary for the poor to practice. Priestly focused on frugality, Bentham on industry, Malthus on chastity, Paley on contentment (understood as the opposite of covetous envy of the rich). Thus, Priestly hoped to convert poor workers into virtuous bourgeios citizens through a legally mandated individual savings plan. Bentham favored a workfare system that turned the working poor into imprisoned debt peons of capitalist entrepreneurs. Malthus advocated leaving the poor to starvation, disease and destitution, but offered them the hope that they could rescue themselves by postponing marriage and children. Burke and Wately agreed with Malthus, but attempted to put a liberal-tory paternalist veneer on their view. ...

"The moral accounting that assigns responsibilities to individuals without regard- and even in inverse proportion- to the means they have to fulfill them remains a touchstone of conservative thought to the present day. ...

"The ideology of the conservative work ethic is distinguished by a harsh orientation toward ordinary workers and the poor, and an indulgent one toward the 'industrious' rich- those who occupy themselves with making money, either through work or investment of their assets, regardless of whether their activities actually contribute to social welfare. in practice, this orientation tends to slide into indulgence toward the rich, whether or not they are industrious even in this morally attenuated sense. ...

"Here lies a central contradiction of the conservative work ethic. All the conservatives claimed that the key to overcoming poverty was to make the poor bourgeois in attitude. All they needed to do was adopt the work ethic, or be forced to adopt it, along with the spirit of competitive emulation, the desire to better others in the race for riches and ensure that one's children not fall beneath the standard of living in which they were raised. Poverty was proof that they hadn't adopted bourgeois virtues and aspirations. This presupposed that the poor suffered from no deficit in opportunities. The path to prosperity was open; the poor were simply failing to take it. Yet we have seen that, Priestly partially excepted, conservative policies knowingly reduced the opportunities of the poor to acquire or retain property, work for themselves, or escape precarity."

My major critique of Anderson's analysis is that putting all this conflict and history into the frame of the work ethic is inappropriate and gives the work ethic far more weight than it merits. Firstly, everyone thinks of themselves as working. The most sedentary rentier doubtless thinks of his or her choosing among investments as of critical importance to the health and future of the nation. Even his or her shopping choices express taste and support a "better" sort of business, in that way performing work towards a better community. The English royals probably see themselves as doing essential cultural work, in their choice of hats and their preservation of cherished traditions. Parenting, community associations, and political agitation can all, to an expansive mind, be construed as "work". And indeed some of our greater artistic and other accomplisments come from the labors of wealthy people who were entirely self-directed rather than grubbily employed. All this implies that a work ethic can be accommodated in all sorts of ways if markets are not going to be the standard, as they hardly can be in any philosophical or moral system of a work ethic. This makes work ethics rather subjective and flexible, as Anderson implicitly demonstrates through the centuries.

However a more serious problem with Anderson's analysis is that it leaves out the ethic of power. Her presentation laments the sad misuse that the work ethic has been subjected to over the years, (by conservatives), without focusing on the reason why, which is that a whole other ethic was at work, in opposition to the work ethic. And that is the power ethic, which values domination of others and abhors work as commonly understood. Or, at best, it construes the organization of society for the benefit of a leisured upper crust as work of momentous, even civilizational, significance. Nietzsche had a field day calling us to recognize and embrace the power ethic, and not hide it under sweeter-smelling mores like the Christian or work ethics.

Anderson does helpfully discuss in passing the feudal background to the Puritan work ethic, where the Norman grandees and their progeny parcelled out the land among themselves, spent their time warring against each other (in England or in France), and lived high off the labors of their serfs/peasants. No thought was given to improvement, efficiency, or better ways to organize the system. Conservatism meant that nothing (god-willing) would change, ever. Even so, the work of politics, of war, and of religious ideology was never done, and the wealthy could easily see themselves as crucial to the maintenance of a finely-balanced cultural and economic system.

Anderson also notes that the original rationale of the gentry, if one must put it in an economic frame, was that they were responsible for military support of the king and country, and thus needed to have large estates with enough surplus in people, livestock, horses, and food to field small armies. When this rationale disappeared with the ascendence of parliament and general (at least internal) peace, they became pure rentiers, and uncomfortably subject to the critique of the Puritan work ethic, which they naturally countered with one of their own devising. And that was essentially a restatement of the power ethic, that the rich can do as they please and the poor should be driven as sheep to work for the rich. And particularly that wealth is a signifier of virtue, implying application of the work ethic, (maybe among one's forebears, and perhaps more by plunder than sweat, but ... ), or transcending it via some other virtues of nobility or class. 

But in Locke and Adam Smith's day, as today, the sharpest and most vexing point of the work ethic is not the role of the rich, but that of the poor. By this time, enclosure of lands was erasing the original version of the job guarantee- that is, access to common lands- and driving peasants to work for wages, either for landowners or industrialists. How to solve extreme poverty, which was an ever more severe corollary of capitalism and inequality? Is it acceptable to have homeless people sleeping on the streets? Should they be given work? money? social services? education? Do the poor need to be driven to work by desperation and starvation? Or is the lash of work not needed at all, and lack of wealth the only problem? Malthus was doggedly pessimistic, positing that population growth will always eat up any gains in efficiency or innovation. Thus it requires the predatory power of the gentry to enable society to accumulate anything in the way of capital or cultural goods, by squelching the poor in sufficient misery that they will not over-reproduce.

The progressive view of work and the poor took a much more sanguine view. And here one can note that much of this discussion revolves around "natural" laws. Is the population law of Malthus true? Or is the natural communitarian tendency of humans also a natural law, leading to mutual help, spontaneous community formation, and self-regulation? Are some people "naturally" superior to others? Is a hierarchical and domineering social system "natural" and necessary? Adam Smith, in Anderson's reading, took a consistently pro-worker attitude, inveighing against oppressive practices of employers, collusion of capital, and cruel goverment policies. Smith had faith that, given a fair deal and decent education, all workers would strive to the best of their abilities to better their own condition, work diligently, and thereby benefit the community as well as themselves.

For the story of Eden is fundamentally wrong. Humans have always worked, and indeed valued work. Looking outside the window at a squirrel trying to get into the bird feeder ... is to see someone working with enthusiasm and diligence. That is our natural state. The only problem was that, as human civilization progressed, power relations, and then even more- industrialization- generated work that was not only cruel and oppressive, but meaningless. The worker, forced to work for others instead of him- or herself, and routinized into a factory cog, became fully alienated from it. How to get workers to do it, nevertheless? Obviously, having a work ethic is not a full solution, unless it is of a particularly astringent and dogmatic (or tyrannical) sort. Thus the dilemma of capitalist economies. For all their trumpeting of the "natural laws" of competition and "freedom" for employers to exploit and workers to be fired, capitalism violates our true natures in fundamental ways.

So the question should be, as Anderson eventually alludes to, do we have a life ethic that includes work, rather than just a work ethic? She states plainly that the most important product of the whole economic system is ... people. Their reproduction, raising, education, and flourishing. It is not consumption products that should be the measure of economic policy, but human happiness. And a major form of human happiness is doing meaningful work, including the domestic work of the family. The world of Star Trek is even alluded to in Anderson's last chapter- one where no one works for subsistance, but rather, people work for fulfillment. And they do so with zeal.

Anderson sees great potential in the more progressive forms of the work ethic, and in the social democratic political systems that implemented them after World War 2. She argues that this is the true legacy of Marxism (and of Thomas Paine, interestingly enough) and expresses the most durable compromise between market and capital-driven corporate structures and a restored work ethic. Some amount of worker participation in corporate governance, for instance, is a fundamental reform that would, in the US, make corporations more responsive to their cultural stakeholders, and work more meaningful to workers. Tighter regulation is needed throughout the private economy to make work more humane for the very low-paid, giving workers better pay and more autonomy- real freedom. More public goods, such as free education to university levels, and better provision for the poor, especially in the form of a job guarantee, would make life bearable for many more people. For my part, inheritance seems a key area where the ethics of the dignified work and equal opportunity run up against completely unjust and artificial barriers. In America, no one should be born rich, and everyone should grow and express themselves by finding a place in the world of work.

• Annals of capitalist control.
• Corporations and the royal we.
• More equal societies are better societies.
• The Stepford wife.
• The Supreme Court is dangerously wrong.

Getting Cancer Cells to Shoot Themselves

New chemicals that make novel linkages among cellular components can be powerful drugs.

One theme that has become common in molecular biology over the years is the prevalence of proteins whose only job is to bring other proteins together. Many proteins lack any of the usual jazzy functions, like catalytic enzyme, or ion channel, or signaling kinase, but just serve as "conveners", bringing other proteins together. Typically they are regulated in some way, by phosphorylation, expression, or localization, and some of these proteins serve as key "scaffolds" for the activation of some process, like G-protein activation, or cell cycle control, or cell growth. 

Well, the drug industry has caught on, and is starting to think about chemicals that can do similar things, resulting in occasionally powerful results. Conventional drug design has aimed to bind to whatever protein is responsible for some ill, and inhibit it. Such as an oncogene, or an over-active component of the immune system. This has led to many great drugs, but has significant limitations. The chemical has to bind not just anywhere on the target, but at the particular spot (the active site) that is its business end, where its action happens. And it has to bind really well, since binding and inhibiting only half the target proteins in a cell (or the body) will typically only have a modest effect. These requirements are quite stringent and result in many protein targets being deemed difficult to drug, or "undruggable".

A paradigm for a new kind of chemical drug, which links two functions, is the PROTAC class, which combines binding with a target on one end, with another end that binds to the cell's protein destruction machinery, thereby not just inhibiting the target, but destroying it. A new paper describes an even more nuclear option along this line of drug development, linking an oncogene with a second part that activates the cellular suicide machinery. One can imagine that this approach can have far more dramatic effects.

These researchers synthesize and demonstrate a chemical that binds on one end the oncogene BCL6, mutations of which can cause B cell lymphoma. This gene is a transcription repressor, and orchestrates the development of particular immunologic T cells called T follicular helper cells. One of its roles is to prevent the suicide of these cells when an antigen is present, which is when the cells are most needed. If over-expressed in cancer, these cells think they really need to protect the body and proliferate wildly.

The other end of this chemical, called TCIP1, binds to BRD4, which is another transcription regulator, but this one activates the cell suicide genes, instead of turning them off. Both ends of this molecule were based on previously known structures. The innovation was solely in linking them together. I should say parenthetically that BRD4 is itself recognized as an oncogene, as it can promote cell growth and prevent cell suicide in many settings. So it has ambivalent roles, (inviting a lot of vague writing), and it is somewhat curious that these researchers focused on BRD4 as an apoptosis driver.

"TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50 of 1–10 nM in 72 h" 

Here EC50 means the effective concentration where the effect is 50% of maximal. This value of 1.3 nano molar is a very low concentration for a drug, meaning it is highly effective. TP53 is another cancer-driving mutation, common in treatment-resistant cancers. The drug has a characteristic and curious dosage behavior, as its effect decreases at higher concentrations. This is because each individual end of the molecule starts to bind and saturate targets independently, reducing the rate of linkage between the two target proteins, and thus the intended effect.

Chemical structure of TCIP1. The left side binds to BRD4, a regulator of cell suicide, while the right side binds to BCL6, an oncogene.

The authors did numerous controls with related chemicals, and tracked genes that were targeted by the novel chemical, all to show that the dramatic effects they were seeing were specifically caused by the linkage of the two chemical functions. Indeed, BCL6 represses its own transcription in the natural course of affairs, and the new drug reverses this behavior as well, inducing more of its own synthesis, which now potentiates the drug's lethal effect. While the authors did not show effectiveness in animals, they did show that TCIP1 is not toxic in mice. Neither did they show that TCIP1 is orally available, but administered it by injection. But even by this mode, it would, if effective, be a very exciting therapy. Not surprisingly, the authors report a long series of biotech industry ties (rooted at Stanford) and indicate that this technology is under license for drug development.

This approach is highly promising, and a significant advance in the field. It should allow increased flexibility in targeting all kinds of proteins that may or not cause disease, but are specific to or over-expressed in disease states, in order to address those diseases. It will allow increased flexibility in targeting apoptosis (cell suicide) pathways through numerous entry points, to have the same ultimate (and highly effective) therapeutic endpoint. It allows drugs to work at low concentrations, not needing to fully occupy or inhibit their targets. Many possible areas of therapy can be envisioned, but one is aging. By targeting and killing senescent cells, which are notorious for promoting aging, significant increases in lifespan and health are conceivable. 

• Biden is doing an excellent job.
• Annals of mental decline.
• Maybe it is an anti-addiction drug.
• One gene that really did the trick.
• A winning issue.
• It is hard to say yet whether nuclear power is a climate solution, or an expensive distraction.

Ions: A Family Saga

The human genome encodes hundreds of proteins that ferry ions across membranes. How did they get here? How do they work?

As macroscopic beings, we generally think we are composed of tissues like bones, skin, hair, organs. But this modest apparent complexity sits atop a much greater and deeper molecular diversity- of molecules encoded from our genes, and of the chemistry of life. Management of cellular biochemistry requires strict and dynamic control of all its constituents- the many ions and myriad organic molecules that we rely on for energy, defense, and growth. One avenue is careful control across the cellular membrane, setting up persistent differences between inside and outside that define the living cell- one may say life itself. Typical cells have higher levels of potassium inside, and higher levels of sodium and chloride outside, for example. Calcium, for another example, is used commonly for signaling, and is kept at low concentrations in the cytoplasm, while being concentrated in some organelles (such as the sarcoplasmic reticulum in muscle cells) and outside. 

All this is done by a fleet of ion channels, pumps, and other solute carriers, encoded in the genome. We have genes for about 1,555 molecule transporters. Out of a genome of about 20,000 genes, this represents a huge concentration(!) of resources. One family alone, the solute carrier (SLC) family, has 440 members. Many of these are passive channels, which just let their selected cargo through. But many are also co-transporters, which harness the transport of one ion with that of another which may have an actively pumped gradient across the membrane and thus provide an indirect energy source for transfer of the first ion. The SLC family includes channels for glucose, amino acids, neurotransmitters, chloride, cotransport (or anti-transport) of sodium with glucose, calcium, neurotransmitters, hydrogen, and phosphate. Also, metals like zinc, iron, copper, magnesium, molybdate, nucleotides, steroids, drugs/toxins, cholesterol, bile, folate, fatty acids, peptides, sulfate, carbonate, and many others. 

It is clear that these proteins did not just appear out of nowhere. The "intelligent" design people recognize that much, that complex structures, which these are, must have some antecedent process of origination- some explanation, in short. Biologists call the SLC proteins a family because they share clear sequence similarity, which derives, by evolutionary theory, and by the observed diversification of genes and the organisms encoding them over time, from duplication and diversification. This, sadly, is where the "intelligent" design proponents part ways in logic, maintaining perhaps the most pathetic (and pedantic) bit of hooey ever devised by the dogmatic believer: "specified information", which apparently forbids the replication of information.

However, information replicates all the time, thanks to copious inputs of energy from the sun, and the advent of life, which can transform energy into profusions of reproduced/replicated organisms, including replication of all their constituent parts. For our purposes, one side effect of all this replication is error, which can cause unintended replication/duplication of individual genes, which can then diverge in function to provide the species with new vistas of, in this case, ionic regulation. In yeast cells, there are maybe a hundred SLC genes, and fewer in bacteria. So it is apparent that the road to where we are has been a very long one, taking billions of years. Gene duplication is a rare event, and each new birth a painful, experimental project. But a family with so many members shows the fecundity of life, and the critical (that is, naturally selected) importance of these transporters in their diverse roles throughout the body.

A few of the relatives in the SLC26A family, given in one-letter protein sequence from small sections of the much larger protein, around the core ion binding site. You can see that they are, in this alignment, very similar, clearly being in the same family. You can also see that SLC26A9 has "V" in a position in alpha helix 10, which in all other members is a quite basic amino acid like lysine ("K") or arginine ("R"). The authors argue that this difference is one key to the functional differences between it and SLC26A6.

A recent paper showed structures for two SLC family members, which each transport chloride ion, but differ in that one exchanges chloride for bicarbonate, while the other allows chloride through without a matched exchange (though see here). SLC26A9 is expressed in the gut and lung, and apparently helps manage fluid levels by allowing chloride permeability. It is of interest to those with cystic fibrosis, because the gene responsible for that disorder, CFTR, is another transporter, (of the ABC family), and plays a major role doing a similar thing in the same places- exchanging chloride and bicarbonate, which helps manage the pH and fluidity of our mucus in the lung and other organs. SLC26A9, having a related role and location, might be able to fill some of the gap if drugs could be found to increase its expression or activity.

SLC26A6 is expressed in the kidney, pancreas, and gut, and in addition to exchanging bicarbonate for chloride, can also exchange oxalate, which prevents kidney stones. Very little, really, is known about how all these ion transporters are expressed and regulated, what differentiates them, how they relate to each other, and what prompted their divergence through evolution. We are really just in the identification and gross characterization stage. The new paper focuses on the structural mechanisms that differentiate these two particular SLC family members.

Structure of two SLC transporters, each dimeric, and superimposed. The upper parts are set in the membrane, with the lower parts in the cytoplasm. The upper parts combine two domains for each monomer, the "core" and "gate" domains. The channel for the anion threads within the center of each upper part, between these two domains. Note how structurally similar the two family members are, one in green+gray, the other in red+blue.

Schemes of how SLC26A6 works. The gate domain (purple) is stable, while the core domain (green) rocks to provide access from the ion binding site to either outside or inside the cell.

Like any proper ion channel, SLC26A6 sits in the membrane and provides a place for its ion to transiently bind (for careful selection of the right kind of ion) and then to go through. There is a central binding site that is lined specially with a few semi-positively charged amino acids like asparagine (N), glutamine (Q) and arginine (R), which provide an attactive electronic environment for anions like Cl-. The authors describe a probable mechanism of action, (above), whereby the core domain rocks up and down to allow the ion to pass through, after being very sensitively bound and verified. This rocking is not driven by ATP or other outside power, but just by brownian motion, as gated by the ion binding and unbinding steps.

Drilling a little closer into the target ion binding site of SLC26A6. On right is shown Cl- in green, center, with a few of the amino acids that coordinate its specific, but transient, binding in the core domain pocket. 

They draw contrasts between these very closely related channels, in that the binding pocket is deeper and narrower in SLC26A9, allowing the smaller Cl- to bind while not allowing HCO3- to bind as well. There are also numerous differences in the structure of the core protein around the channel that they argue allow coupling of HCO3- transport (to Cl- transport in the other direction) in SLC26A6, while SLC26A9 is uncoupled. One presumes that the form of the ion site can be subtly altered at each end of the rocking motion, so that the preferred ion is bound at each end of the cycle.

While all this work is splitting fine hairs, these are hairs presented to us by evolution. It is evolution that duplicated the precursors to these genes, then retained them while each, over time, developed its fine-tuned differences, including different activities and distinct tissue expression. Indeed, the fully competent, bicarbonate exchanging, SLC26A6 is far more widely expressed, suggesting that SLC26A9 has a more specialized role in the body. To reiterate a point made many times before- having the whole human genome sequenced, or even having atomic structures of all of its encoded proteins, is merely the beginning to understanding what these molecular machines do, and how our bodies really work.

• A cult.
• The deep roots of fascism in the American Right.
• We are at a horrifying inflection point in foreign policy.
• Instead of subsidizing oil and gas, the industry should be charged for damages.
• Are we ready for first contact?

MRGA

Make Russia Great Again: Conservative, white, Christian, low levels of immigration, despotic ... what's not to love about Russia?

It would be unbelievable if it weren't true. The Republican party, which conducted the Red Scare of the 50's, and stood up for democracy, political conservatism, apple pie, patriotism, and militarism around the world, now stands for something quite different. A combination of hatreds- for Democrats, for immigrants, and, seemingly, for personal freedom- seems to have sent the Trumpy ecosystem into a very weird place, where Russia is good, autocracy is strength, and American democracy is weakness. What are real patriots to do?

Republicans in congress sure look like they are selling out Ukraine. After linking aid to southern border fixes, they realized that the fixes were going to be politically beneficial to Democrats, as would the Ukraine aid, so both were scuttled. The newest proposal appears to cut Ukraine aid, and not accept the Senate bill, but that is also stalled. We are, at best, in for a long negotiation, all furthering the interests of making Russia great again. And Trump himself was not shy about putting it all in words, declaring Putin's invasion of Ukraine "smart", and inviting invasion of more NATO countries.

This policy is, in essence, throwing away the whole post-war order and rationale for American power, stretching across our innumerable alliances from Europe to Japan. It is unimaginable to any serious student of American power and the last hundred years. But here we are, serving the interests of our enemies in the most blatant ways. Russia, needless to say, is not our friend. Could have been our friend, in the post-Cold War period, but Russia ended up under the thumb of Putin, whose hatred of the West appears foundational to his political success, and even more, to his KGB heart. 

What is the deeper thread behind this craziness? I think it goes back to the culture war. Republicans have decisively lost the overall culture war in America. Gay marriage is here to stay, diversity is mainstream, and even abortion is, after the overturning of Roe, a huge loser for Republicans. They are souring on America in a fundamental way, and looking elsewhere for inspiration. Like Nazi Germany, Hungary, and Russia. At least that is the way it looks and the way they, and especially Trump, talk. And with enough money and propaganda behind them, Republicans can to some extent buck the math and the good will of contemporary American democracy. The question is- how far? The last presidential election was razor-thin, but still, not a great indication that this strategy is going to be broadly popular, and recent elections have shown even worse results. 

In addition to straining to help Russia, this movement is doing anything but making America great again. Our friendships around the world are in tatters, with everyone nervously eyeing the next election. Republicans stand firmly behind making a sociopathic dolt president, for a second time. And their Supreme Court is authoring a new epoch of medieval jurisprudence. This is how empires crumble, when powerful factions decide that their hold on power is more important than the law, more important than petty democracy, more important than peace and stability, more important than truth, and that a little insurrection or civil war might not be such a bad way to force their views down everyone else's throats. When backed by oodles of money, shamelessness, and a relentless propaganda bullhorn, it is, needless to say, highly combustible.

• When people feel powerless.
• Oh, those innocent days.
• Platitude.
• Want to die in the arms of a corporation?
• Hunter Biden Hunter Biden Hunter Biden.
• Plastic is trash.
• Economic effects of the war in Russia.