Money For Nothing: Two Views of Crypto

Is crypto more like gold or a simple scam?

I have to confess some perplexity over crypto. Billed as currencies, they are not currencies. Billed as securities, they are not securities, either. They excite a weird kind of enthusiasm in libertarian circles, in dreams of asocial (if not anti-social) finance. From a matter of fringe speculation, they are migrating into the culture at large, influencing our politics, and becoming significant economic actors, with a combined market cap now over three trillion dollars. For me, there are two basic frames for thinking about crypto. One is that they are like gold, an intrinsically worthless, but attractive object of fascination, wealth storage, and speculation. The other is that they are straight Ponzi schemes, rising by a greater-fool process that will end in tears.

Currencies are forms of money with particular characteristics. They are widely used among a region or population, stable in value, and easy to store and exchange. They are typically sponsored by a government to ensure that stability and acceptance. This is done in part by specifying that currency for incoming taxes and outgoing vendor and salary payments. They are also, in modern systems, managed elastically, (and intelligently!), with ongoing currency creation to match economic growth and keep the nominal value stable over time. Crypto entities would like to be currencies. However, they have far from stable value, are not easy to work with, and are not widely used. Securities, on the other hand, have a basis in some kind of collateral (i.e. the "security" part) like business ownership, a contract of bond interest payments, etc. Crypto does not have this either. Crypto has only its own scarcity to offer, a bit like cowrie shells, or gold. Crypto entities are not investments in productive activity. Indeed, they foster the opposite, as their only solid use case has been, at least to date, facilitating crime, as demonstrated by the ransomware industry, which asks to be paid in Bitcoin.

So how about gold? Keynes railed against gold as the most useless, barbaric form of wealth, inducing people to dig holes in the earth and cause environmental degradation. And for what? A shiny substance that looks good, and is useful in a few industrial applications, but mostly was, at the time, held by governments in huge vaults, notionally underpinning their currency values. Thankfully we are past that, but gold still holds fascination, and persists as a store of value. Gold can be held in electronic forms, making it just as easy to hold and transfer as crypto entities, if one is so-inclined. Critically, however, gold is also physical, and humanity's fascination with it is innate and enduring. Thus, after the apocalypse, when the electricity is off and the computers are not connected anymore, gold will still be there, ready to serve as money when crypto has evaporated away. 

Bitcoin barely recovered from an early crisis. 

How durable is the fascination with crypto, as a store of wealth, or for any other purpose, under modern, non-apocalyptic conditions? Bitcoin is the grand-daddy of the field, and seems to have achieved dominance, certainly the field of criminal money laundering and transfer, as well as libertarian speculation. It appears to have a special mystique, whether from the blockchain, its "mining" system, or its mysterious pseudonymous founder. The other forms of crypto range from respectible to passing memes. There is a fascinating competition in the attention space that constitutes the crypto markets. Since they do not have intrinsic value, nor governmental buy-in, they float entirely on buyer sentiment, in a greater-fool cycle of rises and falls. Crashes in the stock market are halted by fundamental value of the underlying asset. As the speculative fervor wanes, vultures step in to, at worst, liquidate the assets. But for crypto, there are no assets. No fundamental value. So crashes can and do go to zero.

There are also external factors, like the fact that many crypto entities have been outright scams, or the environmental costs of Bitcoin, or their facilitation of criminality, which may eventually draw popular and regulatory scrutiny. Boosters have been trying to get the Federal Reserve and other validating entities to buy into the crypto craze, and political contributions from newly crypto-riche holders and exchanges have transformed the landscape to one that seems increasingly sympathetic, especially on the Republican side. Thankfully, the smaller memecoins have market caps in the low millions, so do not present a threat as yet to the financial system, in the almost certain event of their evaporation once each meme passes. This blasé acceptance of "securities" that are pure schemes of speculation is a sad commentary on our current age. The sophisticated investor of today would not study corporate efficiency, market prospects, or finances. He or she would be conversant in current memes on social media, ready to jump on the newest one, and sensitive to the withering of older memes, in an endless conveyor belt of booms and busts. 

It is weird how people fail to learn the lessons of the past, from the tulip craze and other speculative booms. Where there is no value, there is likely to be a very deep crash. The libertarians among us, who may have been gold bugs in the past and now have flocked to the new world of crypto, may represent a psychological type that is ineradicable, so motivated to ditch the humdrum official currency for anything that offers a whiff of notional independence, (though being tethered to the new crypto infrastructure of exchanges and wallets is not for the faint of heart or independent-minded), that they can float these crypto entities indefinitely. But in the absence of deeper value, might their psychologies change to those of hawkers who get in at the ground floor and make out, while the schlubs who buy at the top are left holding the bag? It comes down to human psychology in the end- what is personally and socially valuable, who you think your counterparts are on the other ends of all these trades, and who (and what sort of motivation) is making up the institutions and communities of crypto.

• Star Trek was fighting the cold war.

Inside the Process of Speciation

Adaptive radiations are messy, so no wonder we have a hard time reconstructing them.

Darwin drew a legendary diagram in his great book, of lineage trees tracing speciation from ancestors to descendants. It was just a sketch, and naturally had clear fork points where one species turns into two. But in real life, speciation is messier, with range overlaps, inter-breeding, and difficulties telling species apart. Ornithologists are still lumping and splitting species to this day, as more data come in about ranges, genetics, sub-populations, breeding behavior, etc. And if defining existing species is difficult, defining exactly where they split in the distant past is even harder.

Darwin's notebook sketch of speciation, from ancestors ... to descendants.

The advent of molecular data from genomes gave a tremendous boost to the amount of information on which to base phylogenetic inferences. It gave us a whole new domain of life, for one thing. And it has helped sharpen countless phylogenies that not been fully specified by fossil and morphological data. But still, difficulties remain. The deepest and most momentous divergences, like the origin of life itself, and the origin of eukaryotes, remain shrouded in hazy and inconclusive trees, as do many other lineages, such as the origin of birds. It seems to be a rule that when a group of organisms undergoes rapid evolution / speciation, the tree they are on (as reconstructed by us from contemporary data) becomes correspondingly unclear and unresolved, difficult to trace through that tumultuous time. In part this is simply a matter of timing. If dramatic events happened within a few million years a billion years ago, our ability to resolve the sequence of those events is going to be weak in any case, compared to the same events spread out over a hundred million years.

A recent paper documented some of this about phylogeny in general, by correlating times of morphological change with times of phylogenetic haziness, which they term "gene-tree conflict". That is to say, if one samples genes across genomes to draw phylogenetic trees, different genes will give different trees. And this phenomenon increases right when there are other signs of rapid evolutionary change, i.e. changing morphology.

"One insight gleaned from phylogenomics is that gene-tree conflict, frequently caused by population-level processes, is often rampant during the origin of major lineages."

They identify three mechanisms behind this observation: incomplete lineage sorting (ILS), hybridization, and rapid evolution. Obviously, these need to be unpacked a bit. ILS is a natural consequence of the fact that species arise not from single organisms, but from populations. Gene mutations that differentiate the originating and future species happen all over the respective genomes, and enter the future lineage at different times. Some may happen well after the putative speciation event, and become fixed (that is, prevalent) later in that species. Others may have happened well before the speciation event, and die off in most of the descending lineages. The fact is that not every gene is going to march in lock step with the speciation event, in terms of its variants. So phylogenetic inference is best done using lots of genes plus statistical methods to arrive at the most likely explanation of the diverse individual gene trees.

Graphs drawn from different sources relating gene conflicts in lineage estimation, (top), versus rate of morphological change from the fossil record, (bottom), in birds, and over time on the X axis. There are dramatic upticks in all metrics going back towards the end-Cretaceous extinction event.

Similarly, hybridization means that proto-species are still occasionally interbreeding with their ancestors or other relatives, (think of Neanderthals), thereby mixing up the gene trees relative to the overall speciation tree. This can even happen by gene transfer mediated by viruses. "Rapid evolution" is not defined by these authors, and comes dangerously close to using the conclusion (of high morphological change during periods of "gene-tree conflict") to describe their premise. But generally, this would mean that some genes are evolving rapidly, due to novel selective pressures, thus deviating from the general march of neutral evolution that affects most loci more evenly. This rate change can mess up phylogenetic inferences, lengthening some (gene) tree branches versus others, and making a unitary tree (that is, for the species or lineage as a whole) hard to draw.

But these are all rather abstract ideas. How does this process look on the ground? A wonderful paper on the tomato gives us some insight. This group traced the evolutionary history of a genus of tomato (Solanum sect. Lycopersicon) in the South American Andes (plus Galapagos islands just off-shore, interestingly enough). These form a tight group of about thirteen species that evolved from a single ancestor over the last two million years, before jumping onto our lunch plates via intensive breeding by native South Americans. This has been a rapid process of evolution, and phylogenies have been difficult to draw, for all the reasons given above. The tomatoes are mostly reproductively isolated, but not fully, and have various specializations for their microhabitats. So are they real species? And how can they evolve and specialize if they do not fully isolate from each other?

Gene-based phylogenetic tree of Andean tomato species. The consensus tree is in black at the right, while alternate trees (cloud) are drawn from 2,745 windows of 100 kb across the tomato genomes, clearly giving diverse views of the lineage tree. Lycopersicon are the species under study, while Lycopericoides is an "outgroup" genus used as a control / comparison. 

In the graph above, there is, as they say, rampant discord among genomic segments, versus the overall consensus tree that they arrived at:

"However, these summary support measures conceal rampant phylogenetic complexity that is evident when examining the evolutionary history of more defined genomic partitions."

For one thing, much of the sequence diversity in the ancestor survives in the descendent lineages. The founders were not single plants, by any means. Second, there has been a lot of "introgression", which is to say, breeding / hybridization between lineages after their putative separation. 

Lastly, they find a high rate of novel mutations, often subject to clear positive selection. Ten enyzmes in the carotenoid biosynthesis pathway, which affects fruit color in a group that has evolved red fruits, carry novel mutations. A UV light damage repair gene shows strong signs of positive selection, in high-altitude species. Others show novel mutations in a temperature stress response gene, and selection on genes defending plants against heavy metals in the soil. 

Their conclusion (as that of the previous paper) is that adaptive radiations are characterized by several components that scramble normal phylogenetic analysis, including variably preserved diversity from the originating species, post-divergence gene flow (i.e. mating), and rapid adaptation to new conditions along with strong environmental selection over the pre-existing diversity. All of these mechanisms are happening at the same time, and each position in the genome is being affected at the same time, so this is a massively parallel process that, while slow in human time, can be very rapid in geologic time. They note how tomato speciation compares with some other well-known cases:

"Nonetheless, based on our crude estimates within each analysis, we infer that relatively small yet substantial fractions of the euchromatic genome are implicated in each source of genetic variation. We find little evidence that one of these processes predominates in its contribution, although our estimates suggest that de novo mutation might be relatively more influential and cross-species introgression relatively less so. This latter observation is in interesting contrast with several recent studies of animal adaptive radiations, including in Darwin’s Finches [18], Equids [14], and fish [13], where evidence suggests that hybridization and introgression might be much more pervasive and influential than previously suspected, and more abundant than we detect in Solanum."

Naturally, neither of these studies go back in time to nail down exactly what happened during these evolutionary radiations, nor what caused them. They only give hints about causation. Why the stasis of some species, and the rapid niche-finding and filling by others? Was the motive force natural selection, or god? The latter paper gives some clear hints about possible selective pressures and rationales that were at work in the Andes and Galapagos on the genus of Solanum. But it is always frustratingly a matter of abstract reasoning, in the manner of Darwin, that paints the forces at work, however detailed the genetic and biogeographic analyses and however convincing the analogous laboratory experiments on model, usually microbial, organisms. We have to think carefully, and within the discipline of known forces and mechanisms, to arrive at intellectually honest answers to these questions, insofar as they can be answered at all.

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• Do wingnuts love the lockdown of educational institutions in Hungary because of the increased quality of research?

Capitalism on the Spectrum

Prospects for the new administration.

Political economics can be seen as a spectrum from anarchic gangsterism (Haiti) to total top down control such as in communism (Cuba, North Korea). Neither works well. Each end of this spectrum ends up in a state of terror, because each is unworkable on its own terms. Capitalism, in its modern form, is a compromise between these extremes, where free initiative, competition, and hierarchical relations (such within corporations) are allowed, while regulation (via the state and unions) makes humane what would otherwise a cutthroat system of gangsterism and corruption. The organization and stability allowed by state-sponsored legal systems raises system productivity far above that of the primeval free-for-all, while the regulatory rules also make it bearable to its participants- principally the workers. The magic comes from a dynamic balance between competition and guardrails to keep that competition focused on productive ends (that is, economic/business competition), rather than unproductive ones (war, assassination, corruption, capture of the state, etc.)

The new Trump administration promises to tear up this compromise, slash regulations, and cut government. That means that the workers that voted for this administration, and who are the primary beneficiaries of the regulatory state, will be hurt in countless ways. The grifting nature of so many in this incoming administration is a blazing alarm to anyone who pays attention. Whether it is stiffing workers, bloviating on FOX, hawking gold sneakers, making a buck off of anti-vax gullibility, defrauding the government of taxes, promoting crypto, or frankly asking for money in return for political favors like petroleum deregulation, the stench of corruption and bad faith is overwhelming. Many of them, starting from the top, see capitalism as a string of scams and frauds, not exactly Milton Friedman's vision of capitalism. An administration of grifty billionaires is unlikely to rebuild US manufacturing, help workers afford housing, or fulfill any of the other dreams of their voters. Indeed, a massive economic collapse, on the heels of bad policy such as crypto deregulation, or a world-spanning trade war, is more likely, and degraded conditions for workers all but certain.

Freedom for capitalists means permission for companies to abuse workers, customers, the environment, the law, and whatever else stands in the way of profit. We have been through this many times, especially in the gilded age. It can spiral into anarchy and violence when business owners are sufficiently "free" from the fetters of norms and laws. When the most powerful entities in the economy have only one purpose- to make money- all other values are trampled. That is, unless a stronger entity makes some rules. That entity can only be the government. It has been the role of governments from time immemorial to look to the long term interests of the collective, and organize the inherent competition within society into benign and productive pursuits.

OK, more than a little ironic, but you get the idea.

On the other hand, there is a problem even at the golden mean of governmental rule-making over the capitalistic free-for-all, which is that the quality of the rule makers and their rules, their attention to real conditions, and their prompt decision making, all can decline into bureaucratic inertia. While this may not be a Stalinist system of top-down planning and terror, it still can sap the productive energies of the system. And that is what we have been facing over the last few decades. For instance, there is the housing crisis, where home construction has not kept up with demand, mostly due to zoning stasis in most desirable places in the US, in addition to lagging construction after the 2008 financial and real estate crisis. Another example is public infrastructure, which has become increasingly difficult to build due to ever-mounting bureaucratic complexity and numbers of stakeholders. The California high speed rail system faces mountainous costs and a bogged-down legal environment, and is on the edge of complete inviability.

Putting rich, corrupt, and occasionally criminal capitalists at the head of this system is not, one must say, the most obvious way to fix it. Ideally, the Democrats would have put forward more innovative candidates in better touch with the problems voters were evidently concerned with. Then we could have forged ahead with policies oriented to the public good, (such as planetary sustainability and worker rights), as has been the practice through the Biden administration. But the election came up with a different solution, one that we will be paying for for decades. And possibly far worse, since there are worse fates than being at a well-meaning, if sclerotic, golden mean of governmental regulation over a largely free capitalist system. Hungary and Russia show the way to "managed democracy" and eventual autocracy. Our own history, and that of Dickensian Britain, show the way of uncontrolled capitalism, which took decades of progressivism, and a great depression, to finally tame. It would be nice to not have to repeat that history.

• Daniel P. Moynihan was for the job guarantee.
• Housing in New Zealand.
• Nature's key scientists of 2024.
• A grumpy Krugman signs off.
• Notes on crypto and its grifting community.
• Who is for workers?
• MAGA to kill off the greatest public health advance, ever.

Cranking Up DNA, One Gyration at a Time

The mechanism of DNA gyrase, which supercoils bacterial DNA.

Imagine that you have a garden hose that is thirty miles long. How would you keep it from getting tangled? That is unlikely to be easy. Now add randomly placed heavy machinery that actively twists that hose as it travels / pulls along, causing it to wind up ahead, and unwind behind. And that machinery can be placed in either direction, often getting into head-on conflicts, not to mention going at quite different speeds. That is the problem our cells have, managing their DNA. 

They use a set of topoisomerases to manage the topology of DNA- that is, its twist-i-ness. One easy method is to nick the DNA on one of its two strands, allowing it to relax by spinning around the remaining phosphate bond, before resealing it back to a double strand and sending it on its way. But what if you encounter coils or knots that can't be resolved that way? The next level is to cut one entire DNA molecule, not just one side/strand of it, and pass the conflicting one though it. All organisms contain topoisomerases of both kinds, and they are essential.

How DNA gets twisted. While most topoisomerases relax DNA (top) to resolve the many twisty problems posed by transcription and replication, gyrase increases twist by grabbing and holding a quasi-positive twist, then cutting and resolving it, as shown at bottom.

Bacteria have an additional enzyme that we do not have, called gyrase, to crank up the supercoiling of their DNA, to make it easier to open for transcription. Gyrase works just like a type II topoisomerase that cuts a double-stranded DNA and lets another DNA through, but it does so in a special way that puts a twist on the DNA first, so instead of relaxing the DNA, it increases the stress. How exactly that works has been a bit mysterious, though gyrases and the general principles they operate under have been clear for decades. Gyrase uses ATP, and grabs onto two parts of a DNA molecule, one of which is pre-twisted into coil, after which one is cut and the other passed through to create a change (-2) in the twisting number of that DNA.

A general model of gyrase action. The G segment of DNA is firmly held by the gyrase dimer in the center.  The same DNA is forcibly twisted about, around the pinwheel structures, and bent back around to enter through the N-gate (as the T segment). Then, the N gate closes, paving the way for the G-segment to be cut and separated (step 3). ATP is the energy source behind all this structural drama. The T-segment then passes through the cut, enters the C-gate, and the cycle is complete.

A recent paper determined the structure of active gyrase complexes, and was able to trace the pre-twisted conformation. This, combined with a lot of past work on the ATPase and cleavage functions of gyrase, allows a reasonably full picture of how this enzyme works. It is a symetric dimer of a two-subunit protein, so there are four protein chains in all. There are three major regions of the full structure. The N-gate at top where one segment (the T-segment) of DNA binds, then the central DNA gate, where the other (G-segment) DNA binds and is later cut to let the T-segment through, and the C-gate, where the T segment ends up and is released at the end of the cycle. 

Focus on the pinwheel structure that dramatically pre-twists the DNA around between the G and T segments, pre-positioning the complex for strand passage and increased supercoiling.

The magic is that the T-segment and the G-segment of DNA are parts of the same DNA molecule, by being wrapped around the ears of the protein, which are also called pinwheels. That is what the newest structure solves in greatest detail. These pinwheels essentially allow the enzyme to yank an otherwise normal DNA strand into a pre-knotted (positive supercoil) form that, when cut and resolved as shown, results in a negative increment of supercoiling or twist. If they mutated the pinwheels away, the enzyme could still hold, cut, and relax DNA, but it could not increase its supercoiling. It is the ability of the pinwheel structures to set up a pre-twisted structure onto the DNA that makes this enzyme a machine to increase negative supercoiling, and thus ease other DNA transactions. 

Topoisomerase enzymes through evolution, from gyrase (left) to human topoII on the right. Note how the details of the protein structure are virtually unrecognizable, while the overall shape and DNA-binding stays the same.

Bacteria also have more normal type II topoisomerases that cut DNA merely to relax it, so one might wonder how these two enzymes get along. Well, gyrase is responsible for the overall negative supercoiling of the bacterial genome, while the other topoisomerases have more localized roles to relieve transient knots and over-twisting. Indeed, if you negatively twist DNA enough, you can separate its strands entirely, which is not usually desirable. Further research shows that too much of either topoisomerase is lethal, and that they are kept in balance by transcriptional controls over the amount of each topoisomerase. This suggests a futile cycle of DNA winding and unwinding, as the optimal condition in bacterial cells when both are present in just the right amounts. 

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• De-growth will require a radical change in the governance of capitalism.
• Business as usual.

To the Stars!

Reviews of "Making it So", by Patrick Stewart, and "The Silent Star" from DEFA films.

When I think about religion, I usually think about how wrong it all is. But at the same time, it has provided a narrative structure for much of humanity and much of human history, for better or worse. It could be regarded as the original science fiction, with its miracles, and reports of supernatural beings and powers. Both testaments of the Bible read like wonder tales of strange happenings and hopeful portents. While theology might take the heavenly beings and weird powers seriously, it is obvious these were mere philosophical gropings after the true gears of the world, while the core of the stories are the human narratives of conflict, adversity, and morality.

In our epoch features a welter of storytelling, typically more commercially desperate than culturally binding. But one story has risen above the rest- the world of Star Trek. From its cold war beginnings, it has blossomed into a rich world of morality tales combined with hopeful adventure and mild drama. The delightful recent autobiography by Patrick Stewart brought this all back in a new way. Looking at the franchise from the inside out, from the perspective of a professional actor who was certainly dedicated to his craft, but hardly a fan of the franchise- someone for whom this was just another role, if one that made him an international, nay galactic, star- was deeply interesting. Even engaging(!)

As a Shakespearean actor, Stewart was used to dealing with beloved, culturally pivotal stories. And this one has become a touchstone in Western culture, supplying some of the models and glue that have gone missing with the increasing irrelevance of religion. It is fascinating how heavily people depend on stories for a sense of what it should, can, and does mean to be human, for models of leadership and community. Star Trek, at least for a certain segment of the population, has provided a hopeful, interesting vision of the future, with well-reasoned moral dramas and judgments. Stewart embodied the kind of leadership style that was influential far beyond the confines of Starfleet. And his deeply engaged acting helped carry the show, as that of Leonard Nimoy had taken the original series beyond its action/adventure roots.

Where the narrative of Christianity is obscurantist, blusteringly uncertain how seriously to take its own story, and focused on the occasional miracles of long-ago, Star Trek values the future, problem solving and science, while it makes little pretense of realism. On the other hand, it is fundamentally a workplace drama, eliding many important facets of humanity, like family and scarcity. Though in the Star Trek world money is worthless and abundance is the rule, posts on starships remain in short supply. There always will be shortages of something, given human greed and narcissism, so there is always going to be something subject to competition, economics, possibly warfare. Christianity hinges on preaching and conversion, based on rather mysterious, if supposedly self-serving, personal convictions. Its vision of the future is, frankly, quite frightening. Star Trek, on the other hand, shows openness to other cultures, diplomacy, and sharing in its eschatological version of the American empire, the Federation. (Even if they get into an inordinate number of fights with un-enlightened cultures.)

The Star Trek story is so strong that it keeps motivating people to make spaceships. Just look at Elon Musk, who, despite the glaringly defective logic of sending humans to Mars, persists in that dream, as does NASA itself. It is a classic case of archetypal yearnings overwhelming common sense, not to mention clear science. But that is a small price to pay for the many other benefits of the Star Trek-style world view- one where different cultures and races get along, where solving problems and seeking knowledge are the highest pursuits, where leadership is judicious and respectful, and humans know what they stand for.

In a similar vein, the Soviets, who led humanity into space, had their own fixations and narratives of space and the future. I recently watched the fascinating movie from the East German DEFA studios, The Silent Star, (1960), which portrays a voyage to Venus. It strikingly prefigures the entire Star Trek oeuvre. There are the scientists on board, the handsome captain, the black communications officer, the international crew from all corners of the earth, the shuttle craft, the talking computer, the communications that keep breaking up, and the space ship that rattles through asteroid fields, jostling the crew. While there are several pointed comments on the American bombing of Hiroshima to set the geopolitical contrast, there is, overall, the absolute optimism that all problems can be solved, and that adventuring to seek the truth is unquestionably the most exciting way to live. One gets the distinct sense that Star Trek was not so original after all.

It was time when technology had pried open the heavens for direct investigation, and what humanity found there was stunningly unlike what had been foretold in the scriptures. It was a vast and empty wasteland, dotted with dead planets and lacking any hint of deities. We had to create an alternative narrative, with warp drive and M-class planets, where humans could recover a sense of agency and engagement with a future that remains tantalizing, even if sober heads know it is as wishful as it is fictional. It is the story, however, that is significant, in its power to give us the fortitude to go forth, not out among the stars, but into a better, more decent community here on earth.

• The long Soviet fixation on Venus.
• The Star Trek that could have been.
• Some atheist cinema is, however, not so great.
• Biden's economic policies have been very good.
• Wrong. Vaccines did the work.
• We could have really stood with Ukraine.

Things Shouldn't be This Difficult in Retirement

Social Security is engineered to cheat a lot of people. Why?

Social Security was one of the great and enduring accomplishments of the New Deal. It followed European models of progressive policy, insuring old age income for what was at the time a very low cost- a 2% tax on wages. It is fundamentally a semi-progressive program, with payouts indexed to what you earned (and paid in as taxes) while working, but using a formula of sharply diminishing returns at higher income levels. As we live longer and have fewer children, the finances of Social Security have had to be shored up a few times, with higher taxes, longer waits till retirement, and other revisions. One of the most devious of these has been the offer to get early benefits for a lower payout.

Basic Social Security rules: The monthly benefit payment is constructed out of a set of tiered rates, by income level, to define the "primary insurance amount", or PIA. The income level is based on the highest ten years of earnings. The lowest level of income (here up to $774 monthly) is paid back at 90%, for example.

A recent opinion column (with followup) noted that while 90% of people would be better off waiting to take their benefits, only 10% do, missing out on a large amount of lifetime income. The deal is that full retirement age is (now) pegged at 67 years of age. If you take benefits at the earliest time, age 62, you will get 70% of the full payout, forever. On the other hand, if you wait till age 70, you will get 124% of the full payout, (plus some extra based on inflation and other factors), which works out to almost double the lowest payout, each month. The life-time payout is of course highly dependent on when one dies, and the break-even point ends up at about age 77, after which everyone would do better waiting than taking the early payout. For example, if you make it to age 85, you would be 30% ahead in lifetime benefits having waited to take payments till age 70.

This is, as the columnist notes, a fraught policy. Psychologically, it resembles some of the most classic marshmallow experiments, testing self control in children. Just as most children don't have the self-control to wait for the two marshmallows, most retirees apparently do not have the foresight to maximize their ultimate income. And this is quite understandable. Principally, the future holds a great deal of uncertainty. Who knows (or wants to know) when one will die? Even if the average life expectancy, upon reaching age 62 is ~83, well past the breakpoint noted above, it is easy to rationalize taking the money while one can. Poorer people tend to have worse jobs, that they really want or need to retire from as soon as possible. The poorer one is, the less savings one is likely to have to tide one through from 62 to 70. And the poorer one is, the poorer health one is likely to be in, with a shorter prospect of collection. All in all, it can be an attractive, even compelling, deal.

But statistically, this ends up being a regressive policy, cancelling much of the otherwise progressively engineered system. Poorer retirees are in this way snookered out of possible income, on top of getting lower payouts to begin with (due to their lower incomes and contributions), and typically having shorter lives. It seems akin to the ever-loosening restrictions on gambling, sports betting, sub-prime lending, and the like, one more way to separate the poor from their money, via financial chicanery, aka engineering. It was a policy gradually developed over several Social Security reforms, from 1961 onward, and may have seemed a fair way to offer the option of earlier benefits to workers, to meet what can be rather urgent needs. But the psychology of it is very problematic and has produced what is described above- bad decisions by most people.

Some alternative models, accentuating their progressivity. Current Social Security is shown in red. A simple pay-in/payout plan is show in dashed lines, with no progressive aspect at all. And the solid line shows a flat payout scheme, where everyone is paid the same benefit. This was done by the Social Security administration in 2009, and notes that "... the program's progressivity has declined in recent decades."

How could all this be improved? There are innumerable ways to cut this cake, but the one I see as most promising is to go back to basics. Make the retirement age 65, and make the payout the same for everyone, across the board, at whatever level retains system viability. Then perhaps a special request board could be set up to offer earlier retirement, in cases of hardship or disability, related to the SSDI system already in place. This would be a way to reduce the complexity of the existing system, reduce the bad incentives, and make it more progressive at the same time. It would also strongly increase the incentive, at the lower end of the income distribution, to attain the needed work credits to participate in the system, which amounts to ten years of work that pays Social Security taxes. Death makes us all equal in the end anyhow, so a retirement system that brings that fundamental equality forward by a few years seems not just reasonable, but even a little poetic.

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• Jesus is Black.

Hubris, Terror, and Disaster in Afghanistan

Review of "The American War in Afghanistan", by Carter Malkasian.

This book is a nightmare to read. It records one bad decision after the next, through two decades of a slow-moving debacle. Should we have invaded at all? Should we have set up a puppet government? Should we have let the mission expand to incredible society-changing scope? Should we have built a sustainable Afghan military? Could any government have stood up to the Taliban? A million questions and pointed fingers follow such a comprehensive loss. Each of the four Presidents who presided over the war made grievous errors, and tried to muddle through the resulting quagmire, until Biden finally threw in the towel.

In the end, even Mullah Omar reportedly considered whether it had been wise to refuse the US demand to turn over or turn against Bin Laden and Al Qaeda. It is a poignant coda to a national tragedy. But what could we have done differently? I will divide this question into several areas, including mission creep, Islam and the Taliban, the Afghan army, and the Afghan government. At the very outset there was a sad narcissistic paradox, in the "war on terror". War is terrorism, pure and simple. The idea that others are terrorists, and that we are not when we drop bombs on them, is a curious, but typical bit of American exceptionalism. Our whole adventure in Afghanistan was colored by the vast gulf in how we saw ourselves (righteous, moral, good), and how Afghans saw us (depraved infidels who violated every norm of civilized behavior).

Mission Creep

It is startling to look back at the progression of our goals in Afghanistan. First, we asked them to give up Al Qaeda. Then we overthrew the Taliban government and installed a new one. Then we sought to establish a democracy. Then we sought to hunt down not just Al Qaeda, but also the Taliban- the former government and a significant cultural and Islamic movement. Then we sought to advance women's rights, fight corruption, and set up a competent government and army. All these things were desirable, but replicated what we could not accomplish in either Vietnam or in Iraq, working with similarly bad partners. Contrast this with our occupations of Germany and Japan, where we put a few of the former leaders on trial, policed with a pretty light touch, kept political development local at first, and concentrated on economic reconstruction. While the cultural alignments were obviously much closer, that should have moderated our ambitions in Afghanistan, not, as it happened, stimulated them progressively to "civilize" the Afghans. This is especially true when the national will and funding to deal with Afghanistan was so impaired by the Bush administration's adventure in Iraq, and later by the tortured path of Afghanistan itself. It is somewhat reminiscent of the defeat the Democrats experienced in the recent elections- a party that got a little overextended in its missions to affirm every virtue, identity and interest group, far beyond the core issues.

Islam

That Afghanistan is an Islamic country is and was no mystery, but that did not seem to get through to those setting up our progressively more invasive policies, or the new government. Poll after poll found that the Taliban had continuing support, and if not support, at least respect, because they were seen as truly Islamic, while the government we installed was not. Malkasian points out that as religious scholars, the Taliban tended to not be infected by the fissiparous tribal conflicts of Afghanistan, which Hamid Karzai, in contrast, tended to encourage. This also led the Taliban to nurture a very strong hierarchical structure, (patterned on madrassa practices), also unusual elsewhere in Afghan society. These three properties gave them incredible morale and sway with the population, even as they were terrorizing them with night letters, assassinations, suicide bombings, and other mayhem. As long as the government represented the infidel, and however well-intentioned that infidel was, the population, including the police and army, would be reluctant supporters.

The only way around all this would have been to allow one of the Northern Alliance leaders to take control of the country after they helped defeat the Taliban, and then get the hell out. But this would have invited another civil war, continuing the awful civil war Afghanistan suffered through before the Taliban rose to power. The deep conflict between the Pashtuns and the northern Tajiks, Uzbeks and other groups would never have allowed a stable government to be established under these fluid conditions, not under the Tajiks. So we came up with the magic solution, to appoint a Pashtun as president, over a nominally democratic system, but with US support that, instead of tapering off over time, rose and rose, until we got to the surge, a decade into our occupation, with over a 100,000 US soldiers.

That was never going to win any popularity contests, even if it did put the Taliban on the back foot militarily. Why was the government never seen as truly Islamic? Malkasian does not explain this in detail, but in Afghan eyes, more tuned to the US as foreign infidels than to the formal conditions of Islamic jurisprudence, the question answers itself. Democracy is not inherently un-Islamic. Consultative bodies that advise the leadership are explicitly provided. Whether they promote women's rights, or accept foreign soldiers, night raids, and legal immunity of foreigners is quite a different matter, however. Whatever the form of the government, its obvious dependence on the US, as painfully illustrated by Karzai's incessant and futile complaints about US military transgressions, was the only evidence needed that the Afghan government was, in popular terms, un-Islamic. It was the same conundrum we experienced in Vietnam- how to be a dominant military partner to a government that had at best a tenuous hold on the affections of the populace, which were in turn poisoned by that very dependence? It is an impossible dilemma, unless the occupying power is ruthless enough to terrorize everyone into submission- not our style, at least not after our dalliance in the Philippines.

The Armed Forces

Because the government never managed to get true popular support, its armed forces were hobbled by low morale and corruption. Armies and police forces are only expressions of the political landscape. Afghans are, as the Taliban shows, perfectly capable of fighting, of organizing themselves, and of knowing which way the wind blows. The army dissolved when faced with its true test. The most powerful solution would clearly have been to have a more effective and popular government that either included or sidelined the Taliban. But could there have technical solutions as well?

The air force was emblematic. The US experience in Afghanistan from start to finish showed the immense power of air attacks, when combined with ground forces. So we planned for an Afghan air force. But we seem to have planned for a force that could not maintain its own equipment, relying in perpetuity on Western contractors. Nor was the selection of assets well-organized. The Afghans mostly needed close air support craft, like attack helicopters and A10 gunships. They should have focused on a very few models that they could fully sustain, with financial and parts support from the US. But that assumes that the US, and the Afghan government, had more thoughtful long-range planning than actually existed.

Always a difficult relationship

The Government

Apart from being seen as a puppet and un-Islamic, the government was riven with tribal and regional conflicts. Karzai spent most of his time managing and trying to win tribal contests. Malkasian repeatedly shows how major decisions and mental energy went into these issues, to the exclusion of attention to the armed forces, or the resurgent Taliban, or resolving corruption, among much else. 

Overall, however, the main issue was that the US installed a top-down quasi-democracy without giving the people true power. Unlike the local political reconstruction in the post-WW2 occupations, let alone our own system, the new Afghan government was explicitly centralized, with provincial and district heads appointed by Karzai. Karzai was really the new king of Afghanistan, more or less foisted on the country, though he had a significant amount of national credibility. There was a great deal of effort to sell this to the people as democracy, and foster "communication" and collaboration, and buy-in, but the people were never allowed into a true federal system with full electoral control of their local districts. Perhaps this was done for good reason, both from the monarchical Afghan tradition, and in light of the strong tribal tensions frequently at work. But it sapped the mutual support / accountability between the people and their government.

Karzai himself broached the idea of bringing Taliban into the system early on, but was rebuffed by the US. We went on to lump the Taliban in with the other "terrorists", and they, like Ho Chi Minh, used their natural legitimacy (with enormous helpings of terror, suicide bombings, and other guerilla tactics .. yes, terrorism again!) to eventually get the upper hand. How much better it would have been to have drawn a relatively generous line against allowing the former Taliban top echelon into official capacities, suppress militias and all forms of political violence, and let the rest re-integrate and participate in a truly ground-up federal system? It was those excluded from the system who holed up in Pakistan, seethed with resentment, and organized the return to power that started in earnest in 2005/2006. The Taliban may have been a bad government and in bed with Al Qaeda and the rest of it. They were not particularly popular with people in many areas of the country. But they were also very nationalistic, highly Islamic, and made up a fair slice of Afghanistan's educated demographic. 

A common theme through all these issues is American hubris, and lack of listening / empathy / respect for / understanding of local conditions. We insisted on making the Taliban the enemy, then insisted on rooting them out through night raids, Guantanamo imprisonment, exile to Pakistan, and other degradations. And were frequently getting fraudulent intelligence to base it all on. We thought that more military power, and more money, would get what we wanted. But what we wanted was Afghans to want to work on behalf of their own country in a free, stable, and prosperous system. How could that system be built on our money and blood? It couldn't. I had to be built by the Afghans, in their own way.

• Global leadership is in play.
• Private jets are abominable. Gas taxes, anyone?
• The planet simply can not take it.
• Meritocracy... good or bad? I would offer that is a lot better than the alternative. But can it be improved?
• Drilling for the climate: geothermal power is coming along, at large scale.

Rings of Death

We make pore-forming proteins that poke holes in cells and kill them. Why?

Gasdermin proteins are parts of the immune system, and exist in bacteria as well. It was only in 2016 that their mechanism of action was discovered, as forming unusual pores. The function of these pores was originally assumed to be offensive, killing enemy cells. But it quickly became apparent that they more often kill the cells that make them, as the culmination of a process called pyroptosis, a form of (inflammatory) cell suicide. Further work has only deepened the complexity of this system, showing that gasdermin pores are more dynamic and tunable in their action than originally suspected.

The structure is quite striking. The protein starts as an auto-inhibited storage form, sitting around in the cell. When the cell comes under attack, a cascade of detection and signaling occurs that winds up expressing a family of proteases called caspases. Some of these caspases can cut the gasdermin proteins, removing their inhibitory domain and freeing them to assemble into multimers. About 26 to 32 of these activated proteins can form a ring on top of a membrane (let's say the plasma membrane), which then cooperatively jut down their tails into the membrane and make a massive hole in it.

Overall structure of assembled gasdermin protein pores.

Simulations of pore assembly, showing how the trapped membrane lipids would pop out of the center, once pore assembly is complete.

These holes, or pores, are big enough to allow small proteins through, and certainly all sorts of chemicals. So one can understand that researchers thought that these were lethal events. And gasdermins are known to directly attack bacterial cells, being responsible in part for defense against Shigella bacteria, among others. But then it was found that gasdermins are the main way that important cytokines like the highly pro-inflammatory IL-1β get out of the cell. This was certainly an unusual mode of secretion, and the gasdermin D pore seems specifically tailored, in terms of shape and charge, to conduct the mature form of IL-1β out of the cell. 

It also turned out that gasdermins don't always kill their host cells. Indeed, they are far more widely used for temporary secretion purposes than for cell killing. And this secretion can apparently be regulated, though the details of that remain unclear. In structural terms, gasdermins can apparently form partial and mini-pores that are far less lethal to their hosts, allowing, by way of their own expression levels, a sensitive titration of the level of response to whatever danger the cell is facing.

Schematic of how lower concentrations of gasdermin D (lower path, blue) allow smaller pores to form with less lethality.

Equally interesting, the bacterial forms of gasdermin have just begun to be studied. While they may have other functions, they certainly can kill their host cell in a suicide event, and researchers have shown that they can shut down phage infection of a colony or lawn of bacterial cells. That is, if a phage-infected cell can signal and activate its gasdermin proteins fast enough, it can commit suicide before the phage has time to fully replicate, beating the phage at its own race of infection and propagation. 

Bacteria committing suicide for the good of the colony or larger group? That introduces the theme of group selection, since committing suicide certainly doesn't do the individual bacterium any good. It is only in a family group, clonal colony, or similar community that suicide for the sake of the (genetically related) group makes sense. We, as multicellular organisms, are way past that point. Our cells are fully devoted to the good of the organism, not themselves. But to see this kind of heroism among bacteria is, frankly, remarkable.

Bacteria have even turned around to attack the attacker. The Shigella bacteria mentioned above, which are directly killed by gasdermins, have evolved an enzymatic activity that tags gasdermin with ubiquitin, sending it to the cellular garbage disposal and saving themselves from destruction. It is an interesting validation of the importance of gasdermins and the arms race that is afoot, within our bodies.

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• Bill Mitchell on our Depression job guarantee: "So for every $1 outlaid the total societal benefits were around $6 over the lifetime of the participant."
• US sanctions are scrambling our alliances and the financial system.
• Solar works for everyone.

Jews Demand Signs and Greeks Look for Wisdom, but We Preach Christ Crucified

Review of God of the Mind, by Rob Haskell

This blog had its start in a religious discussion, pitting a Christian perspective against an atheist one. That discussion never ended because these viewpoints inevitably talk past each other, based as they are on fundamentally different epistemologies and axioms. Is truth facts, or is it a person? Does it have a capital "T", or a little "t"? Does reality come first, or does faith? With this election, this conflict, usually politely ignorable at the cultural sidelines, has come front and center, as half the country has transferred a Christian style of reasoning to politics, with catastrophic consequences.

I very much wish I had had this book by Rob Haskell back in the day. It lays out in a concise and thorough way all (well, let's say many of) the philosophical and psychological deficiencies of god-belief. It is hands-down the best discussion I have ever read on the subject- well-written, with humor and incisive insight. For example, he provides the bible quote that I have used to title this post, in a discussion of Christianity's approach to reason and intellect. While reams of theology support Christianity with reasons, at the end of the day, any honest theologian and Christian thinker will say that reason doesn't get you there. Faith needs to come first. Only then does all else follow. And this "all" is laced with superstition, suspension of normal rules of evidence, submission to authority, and a need to convert the whole world to the same system of belief. It is, implicitly, a preference for unity and power over truth. No wonder they were marks for the charismatic authority of Donald Trump.

One of the most disturbing aspects of the whole debate is the moralism that creeps into what is ostensibly a reasoned discussion of viewpoints and philosophy. If one does not accept god, Christians have been taught to believe that there is a reason. Not a logical reason, but a moral reason. Depravity is a word that comes up. Lack of belief betrays a moral failure, because god is the foundation of all moral law (those twelve commandments!). Those outside the fold merely want their false freedom to enjoy debauchery and crime, without the nagging conscience, which is apparently implanted not by god at birth, (let alone by evolution, or by moral reasoning), but by regular sermons, loudly professed faith, and bible reading. A bible, we might note, that is full of militarism, sexual abuse, deceit, and political authoritarianism. The whole proposition is absurd, from the ground up, unless, of course, you are of the religious tribe, in which case it has an irresistible logic and allure.

No wonder Christians feel good, right, and justified. And feel a birthright to rule over all, to claim that the US is (or should be) a Christian nation. One where resistance to its moral imperatives would, at last, be futile.

But here we are, getting off track! Rob Haskell is a former protestant missionary and minister, graduate of Regent College, and came to his new positions through deep personal engagement and turmoil. He knows intimately of which he speaks. An interesting aspect of his book is that he is almost more focused on psychology than on philosophy. For it is psychology that drives religious conversion, drives people to prostrate themselves before the void, and drives a faith that calls itself truth. Without the indoctrination by families, for example, no religion would amount to much- certainly not Christianity. And indoctrination of the young is obviously a highly irrational process, combining the most powerful psychological forces known- peer pressure, parental pressure, authority, tradition, community, repetition, fancy costumes. Who could resist? And yet Christians have no problem claiming that the result of all this is belief in truth, with a capital T. 

Haskell recounts an educational experience he had inviting Mormon missionaries to an extended discussion of why he should take up Mormonism. They tout the book of Mormon, which Haskell knows very well is a absurd fabric of early nineteenth century prejudices and speculations. They tout the archeological work a few believers have undertaken to prove their scripture, which is highly dubious, to say the least. But at last, when reason fails and argument slackens, Haskell is urged to pray. Pray hard enough, and the light is sure to shine. And for Mormons, brought up with all the pressures and templates ready-made for their belief, such prayer is very likely to work, activating the archetypes and feelings conducive to agreement with their culture. Will the story or the prayer work for others? Rarely, but occasionally it does strike a nerve, especially in the psychologically vulnerable. Haskell recognizes, uncomfortably, that while the stories are different, the psychological methods used by the Mormons and by him as a missionary are eerily similar.

"This points back to what I've already described, namely that in evangelical thinking, and possibly in all religious thinking, the acceptance of certain crucial and non-negotiable ideas comes first. Then, after that acceptance comes the search for evidence that supports it. But that evidence always gets the short end of the stick. Evidence is great when it affirms the things that are accepted by faith. But here isn't a lot of interest in evangelical circles in evidence itself, or in thinking clearly about evidence. And when the evidence falls short, the believer goes back to where it all started: not evidence but faith. So, it's really a matter of wanting to have your cake and eat it too. There's a built-in permission to be sloppy. 'We like evidence!' says the evangelical, 'so long as it proves our point. but when the evidence brings up difficult questions, we reserve the right to toss it out and appeal to faith.' ... How can you have a serious conversation with someone who thinks like this? It's like talking with your teenager."

Rationalization and confirmation bias are fundamental aspects of human psychology. Science has developed an organized and reasonably effective way to address it, but other institutions have not, notably the echo chambers of current news and social media. We do it all the time, (I am certainly doing it here), and it is no wonder that Christians do it too. The problem is the lack of humility, where Christians revel in their fantastical story, impugn anyone so dense (if not evil) as to not get it, and twist the very vocabulary of epistemology in order to declare that "Truth" comes, not out of reality, but precisely out of unreality- a faith that is required to believe in things unseen and tales thrice-told.

• And he writes a blog, too.
• Example of typical religious condescension, by J D Vance's mentor, James Orr.
• The Discovery Institute will try anything...
• Then there is the no true Scotsman defense.
• The Supreme Court lowers itself still further.
• What makes a human brain?
• We continue speeding ever faster to disaster.
• Poisonous propaganda + AI = our future.

A Hunt for Causes of Atherosclerosis

Using the most advanced tools of molecular biology to sift through the sands of the genome for a little gold.

Blood vessels have a hard life. Every time you put on shoes, the vessels in your feet get smashed and smooshed, for hours on end. And do they complain? Generally, not much. They bounce back and make do with the room you give them. All through the body, vessels are subject to the pumping of the heart, and variations in blood volume brought on by our salt balance. They have to move when we do, and deal with it whenever we sit or lie on them. Curiously, it is the veins in our legs and calves, that are least likely to be crushed in daily life, that accumulate valve problems and go varicose. Atherosclerosis is another, much more serious problem in larger vessels, also brought on by age and injury, where injury and inflammation of the lining endothelial cells can lead to thickening, lipid/cholesterol accumulation, necrosis, calcification, and then flow restriction and fragmentation risk. 

Cross-section of a sclerotic blood vessel. LP stands for lipid pool, while the box shows necrotic and calcified bits of tissue.

The best-known risk factors for atherosclerosis are lipid-related, such as lack of liver re-capture of blood lipids, or lack of uptake around the body, keeping cholesterol and other lipid levels high in the blood. But genetic studies have found hundreds of areas of the genome with risk-conferring (or risk-reducing) variants, most of which are not related to lipid management. These genome-wide association studies (or GWAS) look for correlations between genetic markers and disease in large populations. So they pick up a lot of low-impact genetic variations that are difficult to study, due to their large number and low impact, which can often imply peripheral / indirect function. High-impact variations (mutations) tend to not survive in the population very long, but when found tend to be far more directly involved and informative.

A recent paper harnessed a variety of modern tools and methods to extract more from the poor information provided by GWAS. They come up with a fascinating tradeoff / link between atherosclerosis and cerebral cavernous malformation (CCM), which is distinct blood vessel syndrome that can also lead to rupture and death. The authors set up a program of analysis that was prodigious, and only possible with the latest tools. 

The first step was to select a cell line that could model the endothelial cells at issue. Then they loaded these cells with custom expression-reducing RNA regulators against each one of the ~1600 genes found in the neighborhood of the mutations uncovered by the GWAS analyses above, plus 600 control genes. Then they sequenced all the RNA messages from these single cells, each of which had received one of these "knock-down" RNA regulators. This involved a couple hundred thousand cells and billions of sequencing reads- no simple task! The point was to gather comprehensive data on what other genes were being affected by the genetic lesion found in the GWAS population, and then to (algorithmically) assemble them into coherent functional groups and pathways which could both identify which genes were actually being affected by the original mutations, and also connect them to the problems resulting in atherosclerosis.

Not to be outdone, they went on to harness the AlphaFold program to hunt for interactions among the proteins participating in some of the pathways they resolved through this vast pipeline, to confirm that the connections they found make sense.

They came up with about fifty different regulated molecular programs (or pathways), of which thirteen were endothelial cell specific. Things like angiogenesis, wound healing, flow response, cell migration, and osmoregulation came up, and are naturally of great relevance. Five of these latter programs were particularly strongly connected to coronary artery disease risk, and mostly concerned endothelial-specific programs of cell adhesion. Which makes sense, as the lack of strong adhesion contributes to injury and invasion by macrophages and other detritus from the blood, and adhesion among the endothelial cells plays a central role in their ability / desire to recover from injury, adjust to outside circumstances, reshape the vessel they are in, etc.

Genes near GWAS variations and found as regulators of other endothelial-related genes are mapped into a known pathway (a) of molecular signaling. The color code of changed expression refers to the effect that the marked gene had on other genes within the five most heavily disease-linked programs/pathways. The numbers refer to those programs, (8=angiogenesis and osmoregulation, 48=cell adhesion, 35=focal adhesion, related to cell adhesion, 39=basement membrane, related to cell polarity and adhesion, 47=angiogenesis, or growth of blood vessels). At bottom (c) is a layout of 41 regulated genes within the five disease-related programs, and how they are regulated by knockdown of the indicated genes on the X axis. Lastly, in d, some of these target genes have known effects on atherosclerosis or vascular barrier syndromes when mutated. And this appears to generally correlate with the regulatory effects of the highlighted pathway genes.

"Two regulators of this (CCM) pathway, CCM2 and TLNRD1, are each linked to a CAD (coronary artery disease) risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. ... Specifically, we show that knockdown of TLNRD1 or CCM2 mimics the effects of atheroprotective laminar blood flow, and that the poorly characterized gene TLNRD1 is a newly identified regulator in the CCM pathway."

On the other hand, excessive adhesiveness and angiogenesis can be a problem as well, as revealed by the reverse correlation they found with CCM syndrome. The interesting thing was that the gene CCM2 came up as one of strongest regulators of the five core programs associated with atherosclerosis risk mutations. As can be guessed from its name, it can harbor mutations that lead to CCM. CCM is a relatively rare syndrome (at least compared with coronary artery disease) of localized patches of malformed vessels in the brain, which are prone to rupture, which can be lethal. CCM2 is part of a protein complex, with KRIT1 and PDCD10, and part of a known pathway from fluid flow sensing receptors to transcription regulators (TFs) that turn on genes relevant to the endothelial cells. As shown in the diagram above, this pathway is full of genes that came up in this pathway analysis, from the atherosclerosis GWAS mutations. Note that there is a repression effect in the diagram above (a) between the CCM complex and the MAP kinase cascade that sends signals downstream, accounting for the color reversal at this stage of the diagram.

Not only did they find that this known set of three CCM gene are implicated in the atherosclerosis mutation results, but one of the genes they dug up through their pipeline, TLNRD1, turned out to be a fourth, hitherto unknown, member of the CCM complex, shown via the AlphaFold program to dock very neatly with the others. It is loss of function mutations of genes encoding this complex, which inhibits the expression of endothelial cell pro-cell adhesion and pro-angiogenesis sets of genes, that cause CCM, unleashing these angiogenesis genes to do too much. 

The logic of this pathway overall is that proper fluid flow at the cell surface, as expected in well-formed blood vessels, activates the pathway to the CCM complex, which then represses programs of new or corrective angiogenesis and cell adhesion- the tissue is OK as it is. Conversely, when turbulent flow is sensed, the CCM complex is turned down, and its target genes are turned up, activating repair, revision, and angiogenesis pathways that can presumably adjust the vessel shape to reduce turbulence, or simply strengthen it.

Under this model, malformations may occur during brain development when/where turbulent flow occurs, reducing CCM activation, which is abetted by mutations that help the CCM complex to fall apart, resulting (rarely) in run-away angiogenesis. The common variants dealt with in this paper, that decrease risk of cardiovascular disease / atherosclerosis, appear to have similar, but much weaker effects, promoting angiogenesis, including recovery from injury and adhesion between endothelial cells. In this way, they keep the endothelium tighter and more resistant to injury, invasion by macrophages, and all the downstream sequelae that result in atherosclerosis. Thus strong reduction of CCM gene function is dangerous in CCM syndrome, but more modest reductions are protective in atherosclerosis, setting up a sensitive evolutionary tradeoff that we are clearly still on the knife's edge of. I won't get into the nature of the causal mutations themselves, but they are likely to be diffuse and regulatory in the latter case.

Image of the CCM complex, which regulates response to blood flow, and whose mutations are relevant both to CCM and to atherosclerosis. The structures of TLNRD1 and the docking complex are provided by AlphaFold. 

This method is particularly powerful by being unbiased in its downstream gene and pattern finding, because it samples every expressed gene in the cell and automatically creates related pathways from this expression data, given the perturbations (knockdown of expression) of single target genes. It does not depend on using existing curated pathways and literature that would make it difficult to find new components of pathways. (Though in this case the "programs" it found align pretty closely with known pathways.) On the other hand, while these authors claim that this method is widely applicable, it is extremely arduous and costly, as evidenced by the contribution of 27 authors at top-flight institutions, an unusually large number in this field. So, for diseases and GWAS data sets that are highly significant, with plenty of funding, this may be a viable method of deeper analysis. Otherwise, it is beyond the means of a regular lab.

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• And why it matters.
• Jan 6 was an attempted putsch.
• Trumpies for Putin.
• Solar is a no-brainer.
• NDAs are blatantly illegal and immoral. One would think we would value truth over lies.