To Sleep- Perchance to Inactivate OX2R

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

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

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

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

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

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

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

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

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

 

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

Many Ways There are to Read a Genome

New methods to unravel the code of transcriptional regulators.

When we deciphered the human genome, we came up with three billion letters of its linear code- nice and tidy. But that is not how it is read inside our cells. Sure, it is replicated linearly, but the DNA polymerases don't care about the sequence- they are not "reading" the book, they are merely copying machines trying to get it to the next generation with as few errors as possible. The book is read in an entirely different way, by a herd of proteins that recognize specific sequences of the DNA- the transcription regulators (also commonly called transcription factors [TF], in the classic scientific sense of some "factor" that one is looking for). These regulators- and there are, by one recent estimate, 1,639 of them encoded in the human genome- constitute an enormously complex network of proteins and RNAs that regulate each other, and regulate "downstream" genes that encode everything else in the cell. They are made in various proportions to specify each cell type, to conduct every step in development, and to respond to every eventuality that evolution has met and mastered over the eons.

Loops occur in the DNA between site of regulator binding, in order to turn genes on (enhancer, E, and transcription regulator/factor, TF).

Once sufficient transcription regulators bind to a given gene, it assembles a transcription complex at its start site, including the RNA polymerase that then generates an RNA copy that can float off to be made into a protein, (such as a transcription regulator), or perhaps function in its RNA form as part of zoo of rRNA, tRNA, miRNA, piRNA, and many more that also help run the cell. Some regulators can repress transcription, and many cooperate with each other. There are also diverse regions of control for any given target gene in its nearby non-coding DNA- cassettes (called enhancers) that can be bound by different regulators and thus activated at different stages for different reasons. 

These binding sites in the DNA that transcription regulators bind to are typically quite small. A classic regulator SP1 (itself 785 amino acids long and bearing three consecutive DNA binding motifs coordinated by a zinc ions) binds to a sequence resembling (G/T)GGGCGG(G/A)(G/A)(C/T). So only ten bases are specified at all, and four of those positions are degenerate. By chance, a genome of three billion bases will have such a sequence about 45,769 times. So this kind of binding is not very strictly specified, and such sites tend to appear and disappear frequently in evolution. That is one of the big secrets of evolution- while some changes are hard, others are easy, and it there is constant variation and selection going on in the regulatory regions of genes, refining and defining where / when they are expressed.

Anyhow, researchers naturally have the question- what is the regulatory landscape of a given gene under some conditions of interest, or of an entire genome? What regulators bind, and which ones are most important? Can we understand, given our technical means, what is going on in a cell from our knowledge of transcription regulators? Can we read the genome like the cell itself does? Well the answer to that is, obviously no and not yet. But there are some remarkable technical capabilities. For example, for any given regulator, scientists can determine where it binds all over the genome in any given cell, by chemical crosslinking methods. The prediction of binding sites for all known regulators has been a long-standing hobby as well, though given the sparseness of this code and the lability of the proteins/sites, one that gives only statistical, which is to say approximate, results. Also, scientists can determine across whole genomes where genes are "open" and active, vs where they are closed. Chromatin (DNA bound with histones in the nucleus) tends to be closed up on repressed and inactive genes, while transcription regulators start their work by opening chromatin to make it accessible to other regulators, on active genes.

This last method offers the prospect of truly global analysis, and was the focus of a recent paper. The idea was to merge a detailed library predicted binding sites for all known regulators all over the genome, with experimental mapping of open chromatin regions in a particular cell or tissue of interest. And then combine all that with existing knowledge about what each of the target genes near the predicted binding sites do. The researchers clustered the putative regulators binding across all open regions by this functional gene annotation to come up with statistically over-represented transcription regulators and functions. This is part of a movement across bioinformatics to fold in more sources of data to improve predictions when individual methods each produce sketchy, unsatisfying results.

In this case, mapping open chromatin by itself is not very helpful, but becomes much more helpful when combined with assessments of which genes these open regions are close to, and what those genes do. This kind of analysis can quickly determine whether you are looking at an immune cell or a neuron, as the open chromatin is a snapshot of all the active genes at a particular moment. In this recent work, the analysis was extended to say that if some regulators are consistently bound near genes participating in some key cellular function, then we can surmise that that regulator may be causal for that cell type, or at least part of the program specific to that cell. The point for these researchers is that this multi-source analysis performs better in finding cell-type specific, and function-specific, regulators than is the more common approach of just adding up the prevalence of regulators occupying open chromatin all over a given genome, regardless of the local gene functions. That kind of approach tends to yield common regulators, rather than cell-type specific ones. 

To validate, they do rather half-hearted comparisons with other pre-existing techniques, without blinding, and with validation of only their own results. So it is hardly a fair comparison. They look at the condition systemic lupus (SLE), and find different predictions coming from their current technique (called WhichTF) vs one prior method (MEME-ChIP).  MEME-ChIP just finds predicted regulator binding sites for genomic regions (i.e. open chromatin regions) given by the experimenter, and will do a statistical analysis for prevalence, regardless of the functions of either the regulator or the genes it binds to. So you get absolute prevalence of each regulator in open (active) regions vs the genome as a whole. 

Different regulators are identified from the same data by different statistical methods. But both sets are relevant.

What to make of these results? The MEME-ChIP method finds regulators like SP1, SP2, SP4, and ZFX/Y. SP1 et al. are very common regulators, but that doesn't mean they are unimportant, or not involved in disease processes. SP1 has been observed as likely to be involved in autoimmune encephalitis in mice, a model of multiple sclerosis, and naturally not so far from lupus in pathology. ZFX is also a prominent regulator in the progenitor cells of the immune system. So while these authors think little of the competing methods, those methods seem to do a very good job of identifying significant regulators, as do their own methods. 

There is another problem with the author's WhatTF method, which is that gene annotation is in its infancy. Users are unlikely to find new functions using existing annotations. Many genes have no known function yet, and new functions are being found all the time for those already assigned functions. So if one's goal is classification of a cell or of transcription regulators according to existing schemes, this method is fine. But if one has a research goal to find new cell types, or new processes, this method will channel you into existing ones instead.

This kind of statistical refinement is unlikely to give us what we seek in any case- a strong predictive model of how the human genome is read and activatated by the herd of gene regulators. For that, we will need new methods for specific interaction detection, with a better appreciation for complexes between different regulators, (which will be afforded by the new AI-driven structural techniques), and more appreciation for the many other operators on chromatin, like the various histone modifying enzymes that generate another whole code of locks and keys that do the detailed regulation of chromatin accessibility. Reading the genome is likely to be a somewhat stochastic process, but we have not yet arrived at the right level of detail, or the right statistics, to do it justice.

• Unconscious messaging and control. How the dark side operates.
• Solzhenitsyn on evil.
• Come watch a little Russian TV.
• "Ruthless beekeeping practices"
• The medical literature is a disaster.

Profiles in Pusillanimity

China, its communist party, and our free speech. Review of America 2nd, by Isaac Stone Fish.

Why are there always spoilers on the international scene? Some country is always unhappy with the way things are, and does its best to shake up the system. That shaking can be as detrimental to itself as to any other nation, but greed and ambition are always with us. After the Cold War, Russia descended into criminal chaos, with little real help from the West, and, once it had finally pulled itself together, turned around with veangence on its mind to refashion its imperial / security sphere. Russia could have been a nice country, tied into the European cultural and defense system. But no, the nostalgia for satellites and empire were just too strong. Putin spent a decade and more pulling Ukraine into the Russian orbit, only to be finally rebuffed in a people-powered revolution. Now he is trying to do it the hard way, and will take and keep whatever he can grab, little though that may be.

All that is peanuts compared with the game brewing between us and China. While Russia is playing for its neighborhood, the stakes in this next game are the whole world. That is, who runs the "international system", such as it is, and who plays the dominant role over the next century. The US has spent the last couple of decades trying to pull China into the existing trade and security system, in hopes that it would change into a "nice" country, aligning with the US, Europe and our developed allies all over the world in a quest for peace and lawful security. That has not happened. Even less so than with Russia, which at least has a long strand of pro-European sentiment, China learned its lessons from the Russian debacle, and its own Tienanmen square brush with democracy, and resolutely stayed in the Leninist camp- of absolute and unapologetic party power. It was hardly even tempted by European values.

In his book "America 2nd", Isaac Fish is eloquent about how deep China's resentments vs the West go. China suffered a century or more of humiliating vassalage over the 19th century, mired in poverty, opium, and weakness vs colonial powers. Then it suffered again at the hands of imperial Japan, and then several decades on its own account under Mao enduring the Western ideology of Marxism-Leninism. Maybe the last part is projected on the West as well, I am not sure. But China has plenty of ground to make up, and the last few decades of managed capitalism have been, as all can see, completely transformative.

China has already attained number one status in pollution, in population, (though later overtaken by India), and will soon attain that status in GDP. China is busy projecting its power and values via foreign aid, "Wolf Warrior" diplomacy, their takeover of the South China sea, propaganda, intelligence, and hard-ball economic warfare. The question Fish asks is- why are we supporting this policy and the propaganda of the Chinese Communist Party (CCP)?

Recall the quaint old days of "linkage", when the US considered using some points of leverage with Russia to influence Soviet policies we didn't like? China has no such qualms. Everything is linked, and particularly, China's great economic engine is linked with CCP propaganda. US companies that say anything the CCP does not like lose business and IP. The NBA went through a humiliating episode when Darryl Morey of the Houston Rockets criticized CCP repression in Hong Kong. The CCP promptly cancelled NBA air time and business in China, until the NBA comprehensively groveled back into its good graces, and has ever since kept its mouth shut. Black lives may matter, but Tibetan lives, Uyghur lives, Hong Kong lives... not so much, when a totalitarian power waves its big stick.

China can make its own jingoistic media as well. This is Wolf Warrior 2, whose tag line runs: "Anyone who offends China, no matter how remote, must be exterminated."

Far more damaging is the capitulation of Hollywood. After dabbling with tailoring films for the Chinese market, it turned out that it was easier, and not at all influenced by CCP pressure to project a positive world wide image, for Hollywood studios to get fully on board with CCP censorship for all releases, not portraying China or Chinese in a negative way. So, after a brief and now thoroughly repressed few years of agitation on behalf of Tibet a couple of decades ago, the film industry, one of the premiere arms of American soft power, has been turned and cowed, into a lapdog of the CCP. Not a peep about Tibet any more, indeed DreamWorks brought out a thoroughly whitewashed Tibet-adjacent feature in 2019 that suggests everything there is perfectly fine, thanks to Han characters who protect the region.

Capitulation has been the rule across the business world, as each business faces the brutal choice of playing with the CCP, or being barred from Chinese markets, and even hobbled in other ways as China gains power abroad. But this has not been enough. China has been busily corrupting the US government itself, masterfully using former officials to press its case for Western acquiescence. Henry Kissinger is the pioneer in this effort, but former presidents and many other officials have spared no effort in setting up post-career "consultancies" that assiduously advise any and all comers that resistance is futile- China will rule the world and we must accommodate ourselves to that fact. 

"There are plenty of antagonists in this story, some Chinese, some not. For those upset with Beijing's influence in America, understand this: by helping normalize corruption among our former diplomats and warping American perception of China over the last four decades, Henry Kissinger has done more harm to American interests than every ethnically Chinese businessman, hacker, spy, whether they hold American or Chinese citizenship."

It is ironic, with all the current complaints about cancel culture, free speech for fascists, woke restrictions, etc. that we are actually being policed in our speech by our geopolitical opponent, China, and do not seem to think anything amiss about that.

The ancient Art of War recommends winning by shaping the battlefield and the minds of the opponents- whereby not a shot needs to be fired. Fish emphasises the United Front operations of the CCP and its propaganda arms, which seek influence in many ways, not just media. The seduction of foreign officials and fixers comes under this area of government work, for instance, as does the pressuring of speech and behavior by foreign corporations. Everything is linked, as is proper under a totalitarian system, and every oar pulls in the same direction of keeping the CCP in power and gaining influence across the world.

The CCP has a great deal to answer for, both historically, and in its brutal approach to its current rule, even given its huge successes in economic growth and allowing the modernization of China. A democratic and free China would look very different, and could flourish just as well. We should not be taken in by the propaganda of identity between the CCP and China, or the permanence of CCP rule. We need to be able to think and speak freely, and facilitate the freedom of others. And this should start with Taiwan, whose freedom is in the crosshairs of the CCP. We should not acquiesce to the narrative that Taiwan must/will be assimilated into China, or that it is not, in fact, an independent nation with every right to self-determination. The CCP's track record of cultural genocide in Tibet, actual concentration camps and genocide in Xinjiang, and the decapitation of Hong Kong shows clearly enough what would be in store for Taiwan, and for the rest of us, were China to gain even more leverage.

• More of the same, and Maurice Greenberg is always at hand to support China.
• India is only marginally better.
• Should we end the drug war?
• Maybe we should just leave nature alone.
• Fascism is coming.
• But Scientology is ... aready here.

Hair! An Evolutionary Story

What happened in genomes of mammals who lost their hair?

Hair is characteristic of mammals, and forms part of our advanced sensor suite that so effectively replaces the need for armor, shells, and the like. We can have very soft skin, and use hair for warmth, protection, sensing, display, nesting, and other things. But for some mammals like whales and dolphins, hair became a nuisance and has almost wholly been shed. Why it happened is pretty clear, both functionally and by the theory of natural selection. But figuring out how it happened requires delving into the respective genomes of these animals, including us- who, while hardly hairless, have much less than the common mammal. And the genomes tell an interesting story about how evolution works.

The premise of a recent study that tackled this issue (review) is that convergent evolution, that is the development of the same trait in distinct lineages, usually happens in similar ways, mutating the same genes that are key ingredients or regulators for that trait. So, given the many genomes that have now been sequenced across all the mammals, they asked whether a bunch of hairless mammals share some genetic mechanisms behind hairlessness. While there are several sudden appearances of hairlessness in dog breeds and mice, traceable to specific mutations/genes, the authors were not really interested in the genetics of hair itself, but how during actual evolution, hairlessness came about. 

An example of a large-scale map of syntenic regions that match between human and mouse genomes, by chromosome. Recombination and shuffling between regions and chromosomes happens frequently over long periods of time, in addition to smaller-scale mutations, making it challenging to do this mapping, which is a first step to analyses like those discussed here.

They are looking for signs such as significantly decreased or increased evolutionary rates in particular regions of a genome, which might mean either that that region has escaped selection, perhaps because the need for hair has disappeared, so selection is now indifferent to the maintenance of its genetic ingredients, or because the region is under positive selection, perhaps because the need for hairlessness is urgent, not just a matter of indifference. This method also assumes that corresponding regions of different mammalian genomes (called syntenic regions) can be identified, despite a great deal of rearrangement that will have happened over these long spans of time. 

A rough rundown of the anatomical location of expression of genes which had significant evolutionary speedups in hairless species. The Y axis is a measure of enrichment of that location of expression vs a null hypothesis of expression everywhere, for the set of 27 accelerated genes. Skin and hair expression are clearly favored by genes found in this analysis.

It is the convergence aspect, comparing several different lineages that evolved to similar states, that is hoped to weed out the hair-specific changes from all the other riffraff that happens over the ages. (While they also tried to cancel out the marine-heavy and large size-weighting of their selected species.) Each species has many other challenges, after all, and specific trajectories for each of its genes, and most mutations are meaningless. Selective comparison should help focus on the regions that really matter. The authors found 27 genes with accelerated changes, none of which had signs of positive selection. Half of these genes became defunct- they turned into pseudogenes, which is definitive evidence for relaxation of evolutionary selective constraints, rather than positive selection for new constraints. 

In the following, I give their ranked top genes for evolutionary rate acceleration, divided by those changing in their coding regions, and those changing most in nearby non-coding regions.

== Coding sequence acceleration ==

• FGF11   - fibroblast growth factor, with no previously known role, but is here the top statistical match. FGF5, FGF7, FGF18, and FGF22 are known to participate in hair growth in mice, so this is likely another regulator of hair growth.
• GLRA4 - is one of the pseudo genes, in humans is a glycine receptor and a pseudogene
• KRT2      - keratin
• KRT35    - keratin
• PKP1       - plakophilin, known to be important for skin formation, causes skin fragility when absent- related to intermediate filament system.
• PTPRM - protein tyrosine phosphatase, transmembrane receptor, cell adhesion and related signaling, in hair cells.
• ANXA11  - cell growth / survival regulatory protein causal for ALS disease and epithelial sarcoidosis.
• MYH4      - myosin heavy chain motor protein, known to be involved in hair growth. "... out of 69 KRTs and KRTAPs for which noncoding enrichment could be calculated, 66 showed accelerated evolution in both protein-coding sequence and noncoding regions"

== Noncoding sequence acceleration ==

• ELF3 - transcription regulator, known to be involved in hair development
• FOXC1 - transcription regulator, known to be involved in hair development
• CCDC162-SOHLH2 - readthrough into a transcription regulator
• FAM178B - unknown
• UVSSA - transcription regulator
• OLFM4 - extracellular matrix, promoting cell adhesion
• ADRA1D - hormone receptor and regulator of cell proliferation
• mir205 - translation regulator, known to be involved in hair development 
• .. and numerous other microRNAs

So a theme is emerging here, which is that some of the central players in hair development and hair structure received extra mutations in their coding sequences. Keratins, which make up hair, are an obvious case. The other altered genes have more obscure connections, but it is evident that FGF11 plays some important role in hair development, analogous to its relatives that are all local signaling molecules that instruct cell type and proliferation.

Genes found in this study, spread over a non-coding acceleration vs coding region acceleration in their mutation (evolution) rate. In orange are all the keratin genes, some of which have high rates in their coding sequences, but pretty much all of which have high rates in nearby non-coding DNA. In blue and red are other genes with nearby non-coding rate acceleration, with ones known to participate in hair functions marked in red.

On the other hand, regulators of other genes involved in hair development- a series of transcription regulators and micro-RNAs- were altered in their own regulation, which happens in non-coding areas of genes, but not in their coding sequences. This is because these regulators have many other roles, which would be disrupted by changing their coding sequences. Their special sauce lies in where and when they are expressed, which then leads to the complex combinatorial interactions they have with batteries of other regulators converging at their target genes. A great deal of evolution consists of twiddling with dials, rather than hammering on the machinery, or yanking it out.

So, over the tens of millions of years that mammals have been around, the loss of hair appears to come down to tweeks over many different genes, some of which are thrown out entirely (becoming pseudogenes), others of which are disabled in different ways in their protein sequences (keratins, FGF11), and others that are merely relocated in their expression, so that while most of their roles are untouched, their role in hair development is toned down or eliminated. The genome is an orchestra with a lot of players, whose contributions to the whole is sometimes loud and clear (keratin), but more often indirect and obscure, rewarding deeper forms of music appreciation.

• China is making high level pro-China propaganda.
• But we are as well.
• Conventional economics: wrong!
• Joe Biden, TCB. Or G2G?

Portents of Overpopulation

The many ways we can tell humans have overrun the planet.

I was reading a slight book on the history of my county, built around photos from our local historical society. What struck me was how bucolic it used to be, more agrarian and slow paced, yet at the same time socially vibrant. A scarcity of people makes everyone more positive about meeting and being with other people. Now the region is much more built-up, with more amenities, but less open space and seemingly less social mixing. All this got me thinking about the social indices of overpopulation.

There are many ways to evaluate human overpopulation. Famine and starvation is perhaps the simplest, a specter that was thought to be imminent in the 1970's, with "The Population Bomb". Lately we have become aware of more subtle problems that the planet has due to our numbers, like pervasive plastic pollution, deranged nitrogen and other chemical cycles, and climate heating. There has been a constant descent down ladders of resource quality, from the mastodons that were hunted out thousands of years ago, then fisheries destroyed, then ranges overgrazed, to the point that we are making hamburgers out of peas and soy beans now. Minerals follow the same course, as we go farther afield to exploit poorer ores of the critical elements like copper, aluminum, rare earth elements, helium, etc. 

Sustainability is not just a word or a woke mantra. It is a specter that hangs over our future. Will humans be able to exist at our current technological level in a few hundred years? A thousand? Ten thousand? There is no way that will be possible with our current practices. So those practices unquestionably have to change. 

But apart from the resource constraints that overpopulation presents, I have been struck by the sociological factors that point in the same direction, and are spontaneous responses to what is evident in the environment. In my community and the state of California, there is a vocal debate about housing. Localities have settled into a comfortable stasis, where no new housing is zoned for, existing housing values go up, and existing residents are happy. But the population of the state continues to go up, housing becomes increasingly unaffordable, and the homeless lie all over the streets and parks. There seems to be a psychological state where most current residents see the current situation as sufficiently dense- they are not interested in more growth, (We don't want to become LA!). They instinctively sense that we have collectively reached some kind of limit, given our technological setting and psychology.

Declining birth rates across the developed world point in the same direction. Perhaps the expense of raising a child into the current lifestyle is too high, but there may be something more basic going on. Likewise the broad acceptance of gay / LGBTQ lives, where previously the emphasis was on "natural" and fertile growth of the human population, without any consciousness of limits. People seem less social, less likely to go out from their cocoons and streaming pods. Political divisiveness may also be traceable to this sociological turning point, since if growth is off the table, the pie is static, and political and economic competition is increasingly zero-sum instead of collective and growth-oriented. Public works fall into this trap as well, with public agencies increasingly sclerotic, unable to plow through conflicting entrenched interests, and unable to grow, or even maintain, our infrastructure. One could invoke a general anti-immigrant sentiment as another sign, although anti-immigrant campaigns have featured periodically throughout US history, usually mixed, as now, with racial selectivity and animus.

Imaginatively, dystopias seem to rule over the science fiction universe, as Hollywood seems to take for granted a grim future of some kind, whether inflicted by aliens or AI, or by ourselves. Heroes may fight against it, but we do not seem to get many happy endings. The future just looks too bleak, if one is looking far enough ahead. It is hard to generate the optimism we once had, given the failure of the technological deliverances of the twentieth century (fossil fuels, nuclear power, fusion power) to provide a truly sustainable future. Everyone can sense, at an intuitive level, that we are stuck, and may not get a technological fix to get us out of this jam. Solar power is great, but it is not yet clear that the triumvirate of wind, solar, and batteries are truly enough to feed our need for power, let alone the growing appetites of the not-yet-fully developed world. And if it is? Human populations will doubtless grow to the point that those technologies become untenable in turn, with a hat-tip to Thomas Malthus. 

We should be proud of the many great things that this period of prosperity has allowed us to accomplish. But we should grieve, as well, for the costs incurred- the vast environmental degradation which at the current pace is accelerating and compounding through many forms. Humans are not going to go extinct from these self-induced crises, but we will have to face up to the absolute necessity of sustainability over the long term, or else "the environment" will do so for us, by reducing our populations to more sustainable levels.

• Similarly in China...
• A turning point in Chinese attitudes.
• The Gym Industrial Complex.