Prestin: Purveyor of Pianissimo

How hearing happens in the inner ear.

Why are mammals so soft and unprotected, ourselves most of all, being naked? One answer, evolutionarily, is that we are high instrumented, with exquisite senses of vision, touch, smell, position, and hearing, which project our defenses outward, from a hard exoskeleton to an over-the-horizon system, to put it in modern military parlance. Mammals have, for example, far better hearing than reptiles or other preceeding animals, both in frequency range and sensitivity. What is a lawnmower to us would be softly audible to a lizard, while what is pianissimo to us would not be audible at all. This was one of the super-powers that kept small insectivorous mammals going through the age of dinosaurs, both on the hunt and on defense against the velociraptors. High frequency hearing has been taken to particular extremes by cetaceans and bats.

A recent paper described the atomic structure of prestin, the key protein of the power-amplifier of mammalian hearing. But to understand its role, one needs some appreciation of the ornate engineering of our hearing apparatus, particularly the cochlea. The cochlea is the small snail-shaped organ that sits inside the hardest bone of our bodies. It is tonotopic, meaning that sound pitch is interpreted in order along its coiled length, as though it were an inverse piano keyboard. The highest frequency sounds are picked up at the beginning, near the oval window where the stapes connects with the cochlea, while lower-pitch sounds are detected at the tiny apex. 

Schematic of the outer, middle, and inner ear. Note the direction of sound flow, first through the scala vestibuli of the cochlea, then around the apex, back through through the scala tympani, and to the pressure reliever of the round window. The basilar membrane sits in the middle, allowing excitation of itself when the frequency of the sound matches its intrinsic stiffness, which varies continuously along its length.

Sound comes in via the eardrum and the small bones of the middle ear. Waves then propagate from the oval window through the fluid passages of the cochlea, (scala vestibuli), around the apex, and back out through the scala tympani to the round window, which is the final pressure reliever. Sound receptors are arranged along the central organ of Corti, (green), where the various frequencies are separately mapped and detected by the inner hair cells.

A Nobel prize was awarded in 1961 for the first viable explanation of how the cochlea works. At the core of the organ of Corti is the basilar membrane, whose width and stiffness varies continuously as its ribbon furls through the cochlea.

"When flattened and straightened, the basilar membrane appears wedge shaped, with its width gradually increasing from the cochlea’s “input” end (its base) toward the far end (its apex). The change in width results in a 1e4-to 1e5-fold reduction in the membrane’s stiffness from base to apex. This stiffness is conferred by the membrane’s dense strands of collagen fibers running perpendicular to the long dimension and making the membrane highly anisotropic"

An exaggerated standing wave excites its frequency-dependent point along the basilar membrane of the cochlea, here notionally stretched out for illustration. Lower frequencies are detected farther from the base.

It is this stiffness that acts as a frequency selector, with each frequency exciting a standing wave at its own characteristic point along this basilar membrane, and thus along the length of the cochlea. The standing wave is detected by inner hair cells, which convert motion to electrical signals that go to the brain for processing and perception.

Cross-section of the basilar membrane, scala media, and associated cells, including especially the inner hair cells (IHC) which perceive sound and conduct resulting electrical signals to the brain, and the outer hair cells (O), which perceive sounds and set up a sympathetic positive feedback vibration, amplifying soft sounds thousands-fold, to assist the function of the inner hair cells.

So far so good. But the cochlea also harbors outer hair cells, which are specific to mammals, and amplify our hearing by roughly 50 decibels. Yet these hair cells have far fewer nerve connections to the brain, and those connections do not map to the same auditory decoding areas as those from the inner hair cells. What gives? Well, it took till the 1970s to realize that the cochlea is not a passive organ, it is an active organ, one interesting sign of which are cochlear emissions. These are sounds coming out of the cochlea as a sort of amplified echo based on incoming lower amplitude sounds. It turns out that outer hair cells (which outnumber the inner hair cells on the basilar membrane) are not sensing nerve cells in the usual sense. Rather, they sense incoming sound and rapidly compress / decompress themselves, thus amplifying the signal vibration for the benefit of the inner hair cells, which then can relay a signal at far higher sensitivity than they could unassisted. This behavior is called electromotility.

Scanning electron micrograph (left) of outer hair cells with their cili at the top.  DC are helper cells. At right is a dissected outer hair cells, with the stereocilia at top, cuticular plate, and nucleus at bottom.

And how to outer hair cells perform this feat? Aside from a complex set of cilia at their tops, connecting to each other and to the tectorial membrane, plus alot of other intricate ionic physiology, they are covered (75% of their membranes along one side) with the protein prestin, which functions as a piezioelectric transducer. This protein is evolutionarily derived from a large family of anion transporters, so has 14 helical transmembrane protein segments that anchor it in the membrane, and has a sort-of-pore, which binds to anions like sulfate, chloride, and an inhibitor, salicylate. But this pore does not conduct any ions through the membrane. Instead, the change of local membrane voltage, which is induced by the firing of ion channels in the tips of the cilia, causes only a shape change, calculated via this new structure, of ~740 square angstroms reduction when electrically excited, which is about 10% of its total area. This is why the outer hair cell can contract extremely rapidly in reponse to the incoming frequency-discriminated sound signal. The energy for all this does not come (immediately) from ATP, as would be typical (but far to slow). No, it comes from an ionic environment that is specially tuned within the organ of Corti vs the neighboring fluid-fillled sound conduction channels (the scala vestibuli and the scala tympani directly underneath the basilar membrane), which create a potassium and charge gradient that allow the outer hair cells to fire without draining their own energy reserves.

Structures of prestin in activated (left) and relaxed (right) conformations. The overall area change of the protein induced by membrane charge changes leads to the contraction of the entire outer hair cell, in synchrony with the sound being perceived.

Our hearing system is magnificent. One would tempted to call it a miracle of senstivity and discrimination, except that its long and painful evolution is clear, and its current incarnation remains subject to various deficiencies, like the various maladies of loss of hearing in old age, or the gain of tinnitus.

"The efficiency of conversion from mechanical force to electrical charge is estimated to be ~20 fC nN−1, four orders of magnitude greater than the efficiency of the best man-made piezoelectric material"

"The action of prestin is also orders of magnitude faster than that of any other cellular motor proteins."

• We need both.. both individual climate action and collective climate action.
• Climate change leads to murder.
• The pandemic is still going.
• Who and what Trump is.
• New look, old corruption.
• How about calling their bluff?

We Can be Heroes, Just for One Day

Activating the archetypes through fantasy and magic, in science fiction.

Why is science fiction so full of magic? The Force, warp drive, transporters, replicators, spider-spinning webs, other Marvel super-powers ... a genre that supposes itself to be science-based is anything but. Sure, we may hope for some of these technologies. The tablet computer was prefigured on Star Trek. But most of this magic violates basic physics- it is never going to be realized. I am running through some of the Star Wars ouvre, and it has been striking to watch this fantastical conjunction of the hero tale with magic and archetypal elements and characters. Why?

The hero tale forms a classic template, not just dramatically, but psychologically. It conveys a series of (usually male-centric) value judgements on what and who is important, and more significantly conveys hope to the unformed youngster that she or he too can unearth such powers within, can find such friends and helpers, and can do such important tasks. Heroes enact a drama to which we relate empathically, and thus adopt as a possibility for ourselves. Thus the need for a rousing climax where good triumphs over evil, just deserts are meted out, and all the other apparatus of the genre. The cultural significance and importance of such dramas is hard to overstate. And likewise, the impact of our more jaded and cynical media landscape of today is significant and bodes ill for our dreams of the future.

People need templates on how to live, what to strive for, what is important, what unimportant. Without inspiring stories, we are left with a diminished existence. The archetypal stories need to be told for their archetypal images to activate our  archetypal instincts in sympathy, to encourage and raise our vision of what is possible and socially significant. While fragments of these images may arise in dreams, they do not generally cohere and encourage in a dream setting as they do in a purposefully composed heroic story. Our dreams, frankly, beat us down more often than they raise us up. Good story tellers mediate in this space between the inchoate internal world that is neither consistently positive nor very socially conscious, and conscious reality, which is where the great deeds need to be done.

But how about all the magic? One can take that is simply hopeful, positive thinking, totally in line with the rest of the hero fantasy. Humans have wanted to fly forever, and our dreams are full of it. Yet never in a million years has that fantasy involved baggage checks, shoe removal, and flimsy tray tables. The real dreamers take to hang gliding. Would I like to use a transporter? Absolutely! Science or not, the fantasy / hero tale can make it so. Magical elements express in particularly clear fashion the positive-thinking aspect of the fantasy genre, which is meant, as above, to be encouraging to we ... who are otherwise generally stuck and oppressed in our battle with day to day existence, including whatever frustrations the ambient technology presents.

Children generally lack confidence, being on the losing end of power struggles with others most of the time. Encouraging tales, templates, and examples are essential to unlock coherent and socially positive dreams about the future. Whether as cowboys and Indians, or as rebels with the Force of love and good intentions, or as crime fighters, healers, wizards, etc., the roles that we present to children through the media are immensely influential for our future cultural health. 

The hero tale has a special place for friends and helpers as well, who may arise in unlikely guises. The encouragement to seek help and be alert to help and sympathy from unlikely sources is another great strength of this genre. Like the hopefulness of magic, which may be an unanticipated power from within or without, the appearance of tricksters, helpers, and friends is an encouraging aspect that prepares the young viewer to integrate that heroic dream into a constructive social setting, encouraging maturity as well as heroism.

One more angle of fantasy magic is the spiritual or religious aspect- dramatic powers that reach beyond the human, whether from gods, or in other cultural settings, super-advanced beings, usual forces, etc. The hero may possess some magical powers and have magical friends, but there clearly are limits. One task is to find out what they are- to explore this odd world the hero finds her or himself in, a task which mirrors that of growing up and coming to terms with the complexity of adulthood. The greater powers may be mysterious and perhaps need to be respected, since the wellsprings of reality are beyond the hero's comprehension, as they are beyond ours. But where we generally take them for granted and ignore them, the hero drama can personify them and make us think about their strangeness and wonder.

So, nothing science about it, just the oldest trick in the book in making up a great story that is full of hopeful elements at all levels, personally, physically, socially, and morally.

• Have we lied so brazenly throughout the Afghan war?
• Young people can tell.. things are getting worse.
• Critique of the Afghan exfiltration.
• Carbon capture is expensive- far more than preventing emissions. Which might be a good benchmark for carbon taxation.
• Cars can be banished.
• Death panels, at last.

The Hunt for Enemy RNA

How our cells tell foreign RNA from friendly RNA, in a truly baroque process.

RNA is hot these days. It is the active ingredient of the leading and innovative coronavirus vaccines, it appears to be the primordial molecule at the origin of life, and it keeps cropping up in new permutations in molecular biology, with every year bringing new acronyms for novel roles it plays in our cells. Half of viruses use RNA for their genomes, making it an important target of the immune system as well. We have several mechanisms that sense viral RNAs, and likewise several mechanisms to differentiate self-RNA from foreign RNA. It is evident that an arms race of military intelligence has been taking place over the evolutionary eons. 

Among the common ways we have to tell friendly RNA from foe are special "caps" chemically attached to the front end of message RNAs, further methylation modifications of the front end of RNAs, and the existence of double-stranded RNA, which is generally rare in our cells. Most RNA viruses have single-standed genomes, but they usually have a double-stranded RNA intermediate in their replication process. Eukaryotic cells focus intently on recognizing that double-stranded RNA, doing so with proteins named RIG1 and MDA5. RIG1 is an RNA helicase that binds and recognizes double-stranded RNA, and then triggers the production of interferons, the primary signaling molecules telling cells that there is a viral infection, and which induce production of a wide range of other antiviral proteins.

But with our own RNA all over the place, it naturally happens that some double-stranded RNA forms accidentally, from our own sequences. What to do about that? One mechanism is RNA editing, where selected "A" residues are chemically switched to "I" or inosine, which base pairs differently from A, and destabilizes double-stranded RNA. This editing is performed by an enzyme called ADAR1. For coding mRNAs, these edits can alter their meaning, so it is also called RNA recoding, and  routinely affects the sequences of several important proteins. 

ADAR gene products and isoforms (left) all perform RNA editing of A (adenine) to I (inosine) in double-standed RNA regions of self-RNAs, (right), to prevent them from causing false alarms of our internal antiviral surveillance systems.

Another mechanism to protect friendly RNA is the attachment of methyl groups to A residues, (m6A), which also shields them directly from RIG1 surveillance. The m6A modifications are applied by enzymes METTL3 and METTL14, and are detected by YTHDF1, which binds them and can increase their expression by speeding up translation, or destabilize them, or have other effects on their expression. The logic of the various proteins that recognize m6A modifications is diverse and remains rather unclear, actually, though the general trend is one of increasing expression of recognized messages. 

One has to suppose that these editing and modification systems are relatively slow, so that incoming viral RNAs can be recognized before they themselves are modified and turned into invisible infiltrators. So there must be some very careful tuning involved, and great incentives for viruses to encode such modification systems for themselves. For example, coronaviruses encode in their tiny genomes several proteins that put "friendly" chemical caps on the front ends of their own RNAs.

Getting back to the editing and m6A systems, genetic mutations generating defective ADAR1 cause severe auto-immune disorders, where the anti-viral interferon system is over-activated. What recent researchers found curious, however, was that defects in YTHDF1 cause similar effects, over-activating antiviral immune systems, even though YTHDF1 is not inherently part of the core systems of protecting self-RNA from recognition by all these antiviral detectors. It turns out that YTHDF1's effect is mediated by just one of its gene targets- ADAR1. Translation of the ADAR1 mRNA is enhanced by YTHDF1 after it binds to m6A modifications on that mRNA. This in turn promotes the ADAR1- catalyzed edits of other cellular RNAs, especially double-stranded ones, preventing them from getting caught up in the RIG1-activated red alert system of interferons and viral response.

In this way, one system of self-identification and protection is tied into another system, for reasons that are truly hard to fathom, and are only a tiny part of a far more elaborate system. I think it is an example of evolution run amok, developing one bureaucracy on top of other ones, on top of yet other ones, in a gerry-rigged system that has had billions of years to accumulate. Yes, it is all very finely tuned, thanks to the necessities of natural selection and the struggle against predation by invaders. But it is the farthest thing from being designed.

• Is liberalism over?
• How to be married.
• The fight for the Mormon soul.
• Congress runs a computer competition for high school students.
• Don't worry- China will only use AI for good things!
• Bernie's economist, Stephanie Kelton, on MMT.
• Oh, sorry- I thought American business was built on lying.

Being American

With apologies to those outside the US, throughout the Americas, naturally.

The meaning of being an American is obviously a bit fraught right now. The US had a heyday in the post-WW2 era, when we ruled the world and enjoyed breakneck technological and economic growth. Many seem to think that the conditions of that era are some kind of birth-right, that a lifestyle of mainline Christianity, hamburgers, and trucks is a cultural patrimony worth fighting for, against the existential changes wraught by demography, immigration, climate change, and education. We have come a quite a way from the days of the Civil War, when a similar fight revolved around the right to keep Black people in bondage, but the current historical predicament does rhyme, as they say.

The US is still an incredibly rich country, and a technological leader in countless fields. But at the same time, other countries with lower military budgets and fewer world policing duties show us up in better living conditions, and more progressive political systems. But that is obviously not what grates on the right wing base- that other countries may be more liberal, prosperous, and happy. (Though in fairness, such competing countries are typically also less diverse, and thus have higher social solidarity, from a tribal / ethnic perspective, which does seem to be striking a chord with the right wing). No, what grates is that their god-given right to the American way is dissolving, for all kinds of reasons, but none that completely irresponsible policy, cynical politics, and general greed and obtuseness can't make go away, at least for a little while.

During the Civil War, Lincoln through his Gettysburg address and other writings tried to forge a new vision of what America was about, one with world-wide significance that left behind the stasis and meanness of slavery for the promise of equal opportunity and human development in an abundant and growing land. It was that vision that propelled the US through the next century, through railroads, flight, military might, the oil age, and to our current age of computer and biomedical technological frontiers.

It is clear that we again need a new vision, now that our peak of relative military and economic power is waning. There is no going back. Climate change is making sure of that, even if the Chinese don't follow it up with other unpleasant facts on the ground. The US of old is irrevocably gone, and pining for it isn't going to bring it back, especially if destroying our democracy is the method chosen to get there. What is worse, our moral authority is even more imperiled than those harder forms of power and influence.

Atlanta Olympics opening ceremonies, featuring lots of Stetson hats and pickup trucks.

Remember the 1996 Atlanta Olympics? Dreadful generally, but what sticks in my mind is the fleet of pickup trucks that were featured in the opening ceremony. How incredibly tone-deaf, and what an homage to greed and planetary destruction. But now, a quarter century on, we are still fighting that same fight, between those looking to the past, and those looking to the future. The past was one of abundance, thanks to the bountiful nature that the US was endowed with (or stole brutally from its occupants). The future looks a bit less abundant, because of the damage we ourselves have wrought on the way to all these technological wonders. Also because our population is itself unsustainable, and needs to be smaller, even after we adhere to more sustainable lifestyles and technologies. The future is going to be difficult, no question, and it will require us to think harder, and feel more keenly about others and the environment around us. Merely raping the environment will no longer do (just as chaining and whipping other humans no longer did a century and a half ago). We will have to work with it and in many cases, make sacrifices to heal it. Even pay reparations.

Land-grant colleges endowed throughout the US, courtesy of far-thinking Republicans of the Civil War era.

That is pretty clearly where the new vision of America should be going. To a prosperous future that is sustainable at the same time that it is abundant and equitable. This is a hard task, politically as well as technically, far more difficult than the great things we have accomplished in the past, like the Manhattan project or the Apollo program. And one can sense that the younger generations are ready for this task- they just need a little encouragement and vision to get us there.

• The Taliban is better at politics than the US, or its Afghan allies, were. Politics, Islamic-style.
• On the importance of spirit and core values.
• Realignments in Asia.
• What do you do if your party is a minority?
• Natural selection at work.
• "Valuing your bodily integrity"- idiots with degrees.
• Trash-talking Larry Summers.

Where did all the Diversity go?

The Lewontin Paradox says that, by the neutral theory of evolution, large populations should show large molecular diversity... but they don't. Where does it go?

One of the pillars of modern evolutionary theory is the theory of neutral evolution, which is a complement to that of natural selection. It posits that most mutations have no significant effect, so most evolution on a molecular scale is a random walk of mutations appearing, disappearing, or rising in frequency in the population. Occasionally they may take over the whole population, which is called "fixing" their frequency at 100%. This in turn has given rise to the concept of the molecular clock. If the neutral evolution process is truly random and constant through time, then it can be used to date phylogenetic events, by assuming that the divergence between species in their neutral molecular sequences rises monotonically through time and reflects the time since their divergence as species, not different selective trajectories.

Molecular clocks have various problems, like mutation rates that can be variable between species, but on the whole, they have worked very well and have generated numerous successful predictions of phylogenetic branching patterns and dates of key events. But there is another corollary of neutral evolution theory that is less supported. That is its prediction of overall molecular diversity in contemporary populations. Since mutations arise constantly, the molecular diversity of a population should be roughly proportional to the population size, given as N. But that is not what is seen, at all. Natural populations actually have a small range of variation, of a couple orders of magnitude, while their actual sizes can obviously range over many, many orders of magnitude, from small populations of charismatic species like polar bears to astronomical populations of mice, ants, and protozoa.

This is called Lewontin's paradox, after a biologist who pointed it out most succinctly. And this "missing diversity" has been a topic of discussion for the five ensuing decades. Several papers over the last decade tackled it again, and are reviewed here. One would think with the flood of molecular data that this kind of molecular conundrum could be easily solved. Sequence enough members of a large population, and see what happened, or happens, over time. But the issue is not the fact of the missing diversity, but rather the mechanisms explaining why it occurs. 

A graphic statement of the paradox. The expected degree of diversity is marked in the gray band, whereas the observed diversity is marked by the colored dots.

One side of the debate is the selectionist camp. They argue that selection is the missing ingredient. Selection not only drives down the diversity of selected alleles, whether they are deleterious or beneficial, but it also has a "hitchhiker" effect where nearby molecular variation that is not itself selected is carried along during selection events and thinned out just as the selected alleles are. Hitchhiking is limited by recombination, which is the process by which parts of our chromosomes are broken apart during meiosis and stitched together with those from the other parent. Over (long periods of) time, recombination allows alleles to separate from nearby baggage so that they can be selected on their own merits. But since recombination happens on average only a few times per chromosome per meiosis, this rate of isolation by recombination is quite slow. Typically, humans inherit alleles in large batches within "haplotypes" of nearby genes and their alleles, which is one reason why some traits tend to occur together.

The authors offer their quantitative model of how much decreased molecular diversity positive selection and linkage to neighboring loci could supply, in the blue band. While this model approximates actual values for very large populations, it does not for mid-size populations, so is still insufficient as a general explanation.

While there is a lot to be said for selectionist arguments, a couple of authors have pointed out that, in quantitative terms, selectionists have not yet resolved the problem fully. There are many possible explanations, however, each contributing to the ultimate solution. The model of full population diversity is based on a variety of idealized assumptions- a fully mixed, randomly mating population, with no selection, and constant population size through time. None of these assumptions are realistic, and it falls to population geneticists to figure out how real populations relate to this ideal. They have come up with a concept called the "effective population size" to adjust for various non-idealities. For example, the effective population size of humanity is about 10,000 individuals. This is radically smaller than the actual human population, largely due the recency of our population growth. Humans went through a bottleneck of very few individuals during the glacial minimums of the last few million years, and the recent expansion in population has not substantially added to that diversity, at least yet. Numbers do not equal diversity.

Could this be a more general property? Do all populations go through enough seasonal or millennial variation in numbers that their true effective population sizes are much smaller than their current numbers lead us to believe? Could this be true for ants, and termites, and protozoa? That is unlikely, really. The paradox is universal, not only applying to big species, but to all species. One might also note that the level of the grey band in the graphs above, at large population sizes, is inherently unrealistic, positing that essentially every position in the genome varies within large populations- those with more individuals than nucleotides in their genome. Were this the case, it would be hard to define a species at all. So the very coherence of the species concept is at stake here, in finding mechanisms that keep species from exploring the entire space of molecular possibilities.

This is where the paradox rests right now, amidst some controversy in the field. But in principle, the sitution is not so unclear. The neutral theory is certainly correct in terms of the numbers of mutations arising in any population- that they are proportional to the population size, and should keep accumulating over time, up to a clearance rate by neutral (i.e. random) drift. And it is equally clear that there are no magical processes that eliminate that variation- rather, that some combination of non-ideal population dynamics and selection account for the loss, though the accounting has not reached mathematical completeness yet. I would favor putting more weight on selection, while others invoke more population dynamics such as assortive mating, seasonal bottlenecks, or winner-take-all mating systems. The most recent author states:

"Given that I find that models of linked selection are incapable of explaining the observed relationship between 𝑁𝑐 and 𝜋, this supports the hypothesis the diversity across species are shaped primarily by past demographic fluctuations."

And a prior author writes, in a similar vein: 

"... Instead, predicted diversities fall mostly along the x = y line — the result that we would expect if linked selection had only a limited impact on levels of diversity in large populations and diversity levels scaled with effective population sizes estimated in the absence of linked selection. This finding is consistent with the idea that demographic fluctuations are the principal determinant of levels of diversity among species. Interestingly, selfing species seem to show the best evidence of large reductions in diversity due to linked selection, perhaps due to their much reduced effective rate of recombination"

These authors generally grant a one or two magnitude effect to selection, which is only a partial solution. Unfortunately, leaving the remainder of the problem to population fluctuations is somewhat hand-waving. In fact, the demographic diversity of the many species affected, and the high uniformity of the loss of diversity, suggest that something more systematic is going on. 

One of the more recent analyses proposed an interesting idea along selectionist lines. This article reviewed work on fruit flies, which have vast population sizes and show the paradox most acutely. Thanks to artificial selection, fruit flies have come up with insecticide resistence traits in a matter of decades, when faced with the armamentarium of commercial fruit growers. And they have done so many times independently, generating the same mutations, a combination of which is needed for optimal resistance. This in a 140 million base pair genome that is expected to mutate at a little less than one mutation per fly per generation. What this author pointed out was that purifying selection against negative traits is fundmentally asymmetric vs positive selection for positive traits. Positive selection carries along its local hitchhiking variants to a much higher proportion of the population- i.e. to 100 %. Negative selection, which generally pares bad alleles down from already very rare frequencies, has a much lower hitchhiking effect. More importantly, positive selection ignores the "effective" population size, and can gain beneficial alleles as they arise from the entire existing population, leading to sweeps of positive selection that become more frequent the bigger the population is. Thus it may be that the rate of positive selection is higher than the modelers above have given it credit for.

• Why is biological diversity so much higher in warm latitudes? It isn't faster evolution. Perhaps slower extinction and fewer bottlenecks? This may be an argument for population fluctuations over selection as forces curtailing species diversity, if not molecular diversity.
• Evolution.
• On economic fetishes.
• What we have done to Haiti.
• Did you know that leaded fossil fuel is still being used?
• The full Covid death toll.
• Evacuation flights from California will be starting Sept 15.
• Quote from Keynes in 1933:

"If I had the power to-day, I should most deliberately set out to endow our capital cities with all the appurtenances of art and civilization on the highest standards of which the citizens of each were individually capable, convinced that what I could create, I could afford–and believing that money thus spent not only would be better than any dole but would make unnecessary any dole. For with what we have spent on the dole in England since the war we could have made our cities the greatest works of man in the world."

The Last Mammoth

Well, perhaps not the last last, but a fascinating study of one mammoth in the twilight of the species.

We are so far away from having another ice age at this point, that we can only look back at the last one with wonder. And one of its major wonders was that there were mammoths. One of many megafauna species, mammoths reigned through millions of years, weathering a dynamic climate of ice ages and integlacial periods with ease. Yet the arrival of humans spelled their doom. A recent paper in Science discussed the fate of one mammoth, based on atomic /isotopic analysis of its tusks and teeth, telling us where it was born, roamed, and died. 

Ice ages come and go, but something unusual caused the extinction of innumerable megafauna after the last one.

The remains of this mammoth were found north of the Brooks Range in Alaska. Tusks are teeth that grow continuously through life, so the length of a tusk represents a chronological sequence of deposition, which these researchers analyzed for strontium, oxygen, and other isotope ratios, which reflect the animal's diet and thus its location, since these ratios differ across the landscape. In this case, they were able to guess that this mammoth was born well south of the Brooks Range, around the middle Yukon river. It then spent its youth roaming the area, out to what is now the pacific coast, and eventually inland as well to what is now Fairbanks. At some point it ranged north as well, above the Brooks Range. Finally, in what the researchers surmise was a late spring in its ~28th year, this mammoth succumbed to old age just north of the Brooks range and gave us its almost complete remains.  

Figure describing the haunts of one late Pleistocene mammoth, from strontium isotopes in its tusks. The black lines are "best walks" between the various isotope identified site, and somewhat fanciful idea of how this mammoth may have ranged through its life.

It is fascinating to have such an intimate look into the life history of such a distant and mysterious creature, which clearly ranged freely and widely. But it was not really the last mammoth, living 17,000 years ago when populations were robust and humans had only begun to encroach on its realm. No, the last mammoth remains are thought to be those of St. Paul island in the middle of the Bering sea (far lower left white dot in the accompanying map), dating to about 5,600 years ago. Why an island? Well, that is clearly because they had been hunted down everwhere else, leaving only isolated populations stranded after the sea level rise ending the last ice age flooded the rest of the Bering land mass.

Humans have been causing ecological catastrophe for a very long time. But with climate change, we are operating on an entirely new scale of lethality to the biosphere. It may have begun with charismatic megafauna, but whole ecosytems are now in the crosshairs.

• Lesson from Afghanistan.. more guns? Or perhaps that is just how our domestic Taliban views things.
• Three cheers for the Taliban- from Pakistan, of course.
• It is like saying Gerald Ford lost Vietnam.
• Next up, protecting our precious bodily fluids.
• Fighting the good fight.
• Evolution? Yes.

All Facts are Theories, But Not All Theories are Facts

Are theories and facts different in kind, or are they related and transform into each other?

During the interminable debates about "Intelligent Design" and evolution, there was much hand-wringing about fact vs theory. Evolution was, to some, "just" a theory, to others a well-attested theory, and to others, a fact, whether in the observation of life's change through time (vs the straight creationists), or in the causal mechanism of natural selection (vs the so-called intelligent design proponents). Are theories just speculations, or are they, once accepted by their relevant community, the rock-like edifice of science? And are facts even plain as such, or are they infected by theory? Our late descent into unhinged right-wingery poses related, though far more complex, questions about the nature of facts and who or what can warrant them. But here, I will stick to the classic question as posed in philosophy and science- what is the distinction and or relation between facts and theories? This follows, but disagrees with, a recent discussion in Free Inquiry.

The official scientific organs (NCSE) have generally taken the position that theories are different from facts, making a pedagogically bright line distinction where things like tectonic plate theory and evolution are theories, while rock compositions and biochemistry are facts. In this way, science is made up, at a high level, of theories, which constantly evolve and broaden in their scope, while the facts they are built on arrive on a conveyor belt of normal scientific progress, via lab experiments, field work, etc. Facts help to support or refute theories, which are such abstract, dynamic, and wide-ranging bags of concepts that they can not rightly be regarded as facts.

All very pat, but what are facts? It turns out that nothing we observe and call a fact escapes some amount of interpretation, or the need to be based on theories of how the world works. We grow up with certain axiomatic and built-in conditions, like gravity, vision, and physical cause and effect. Thus we think that anything we "observe" directly is a fact. But all such observations are built on a history of learning about how things work, which is in essence starting with a bunch of theories, some instinctively inborn, which are gradually satisfied by evidence as we grow up ... to the extent that we take many things for granted as fact, like being able to count on gravity as we are walking, that the sun comes up every day, etc. Facts are not automatic or self-attested, but rather are themselves essentially theories, however simple, that have been put to the test and found reliable.

And therein lies a clue to how we, and especially scientists, evaluate information and use the categories of fact and theory in a practical and dynamic way. Lawyers often talk of coming up with a theory of the case, which is to say, a story that is going to convince a jury, which has the job of finding the facts of the case. When the jury finds the theory convincing, and vote for the lawyer's side, the facts are found insofar and the law is concerned. Their determination may come far short of philosophic rigor, but the movement is typical- the movement from theory to fact. 

On the other hand, what is a theory? I think it can be described as a proposed fact. No one would propose a theory if they didn't think it was true and explanatory of reality. Whether broad or narrow, it is a set of interpretations that seek to make sense of the world in a way that we limited humans can categorize, into our store of knowledge. For instance, Freudian theories of repression, Oedipal complexes, castration fears, etc. would have been, if borne out, facts about our mental lives. Being rather vague, they may have needed a great deal of refinement before getting there, but all the same, they were proposed facts regarding what we feel and do, and the psychic mechanisms that lead to those feelings. 

In science, it is the experiment and its communication that is the key event in the alchemy of transforming theories into facts. Science is unusual in its explicit and purposeful interaction with theories that are unproven. Tectonic theory was once a mere theory, and a crackpot one at that. But as observations came in, which were proposed on the basis of that theory, or retroactively appreciated as support for it, such as the lengthy hunt for mid-ocean ridges where tectonic plates separate, and other faults where they converge, that theory gained "fact-ness". Now it is simply a fact, and the science of geology has gone other to other frontiers of theory, working to transform them into fact, or back off and try some others.

The mid-Atlantic ridge, straining to be understood by observers equipped with the theory of plate tectonics. Also, a video of the longer term.

Another example is the humble molecular biology experiment, such as cloning a gene responsible for some disease. The theory can be so simple as to be hardly enunciated- that disease X is in part genetic, and the responsible mutation must occur in some gene, and thus if we find it, we can establish a new fact about that disease as well as about that gene. Then the hunt goes on, the family lineages are traced, the genetic mapping happens, and the sequencing is done, and the gene is found. What was once a theory, if an unsurprising one, has now been transformed into a fact, one perhaps with practical, medical applications.

But the magic of experiments is usually only discernable to the few people who are sufficiently knowledgeable or interested to appreciate the transformation that just happened. The boundary between theory and fact depends on the expertise of the witnesses, and can be sociologically hazy. Does homeopathy cure disease? Well, hemeopathic practitioners regard that as fact, and have gone on to an elaborate practice and pharmacopeia of dilute solutions to effect various cures. Others disagree and regard the whole thing as not only a theory, but a stunningly wrong-headed one at that- as far as can be imagined from having gained fact-hood. Real science revolves around experiments done to what is essentially a standard of philosophical proof. Techniques are reported and consistently applied, controls are done to isolate variables of interest, materials are described and made publicly available, and the logic of the demonstration is clarified so that readers knowledgble in the arts of the field can be confident that the conclusions follow from the premises. And the practitioners themselves are culturally vetted through lengthy apprenticeships of training and critique. 

The practice of peer review is a natural part of this series of events, putting the experiment through a critique by the (hopefully) most knowledgeable practitioners in the field, who can stand in for the intended audience for whom the experiment is supposed to perform this alchemical transformation of theory. The scientific literature is full of the most varied and imaginative efforts to "factify" hypotheses, hunches, and theories. Very few of these will ever be appreciated by the lay public, but they lay the ever-advancing frontier of facts from which new hypotheses are made, new theories tested, and occasionally, some of their resulting facts are discovered to be useful, such as the advent of gene therapy via the Crisper/Cas9 gene editing system, liposomes, and associated technologies. 

Another aspect of the public nature of science and peer critique is that if a knowledgeable observer disagrees with the theory-fact transition purported by some experiment, they are duty-bound and encouraged to replicate those experiments themselves, or do other experiments to demonstrate their counter-vailing ideas. On a cheaper level, they are welcome and encouraged to ask uncomfortable questions during seminars and write tart letters to the editors of journals, since pointing out the errors of others is one of the most enjoyable activities humans pursue, and doubles as a core of the integrity that characterizes the culture of science. In this way, facts sometimes reverse course and travel back into the realm of theory, to sweat it out in the hands of some disgruntled grad student and her overbearing supervisor, destined to never again see the light of day.

Experiments crystallize most clearly the transition from theory to fact. They create, though careful construction, a situation that banishes incidental distractions, focuses attention on a particular phenomenon, and establishes a logic of causation that forms (hopefully) convincing evidence for a theory, transforming it into fact, for knowledgeable observers. They create controlled and monitored conditions where knowlegeable people can "see" the truth of a theory being put to a decisive test. Just as we can now see the truth of the heliocentric theory directly with the use of spaceships sent out across the solar system, the observation of a fact is a matter of the prepared mind meeting with a set of observations, either tailored specifically in the form of an experiment to test a theory, or else taken freely from nature to illuminate a theory's interpretation of reality. Nothing is intrisically obvious, but needs an educated observer to discern truth. Nothing is completely theory-free. Nevertheless, facts can be established.

• Lies are power.
• On social contagion.
• Code red.
• The electricity interconnect of the Eastern US slowly grapples with reality.
• How many has Covid killed?
• In Afghanistan, the US has spent decades building a political and military paper tiger.

Covid Will Never End

But it will be a very small problem, once everyone is vaccinated.

It should be obvious by now that Covid-19 is endemic and will be with us forever. At a fatality rate of roughly 2% for the unvaccinated, it is better than the bubonic plague (50%) and smallpox (30%), but far worse than influenza (0.1%), not to mention colds and other minor respiratory infections. With vaccination, the fatality rate is reduced to, in very rough terms, 0.05%. Thus, with vaccination, Covid-19 is a much less significant public health problem, superceded by influenza, whose vaccine is much less effective.

(This calculation, of the death rate, in vaccinated people, is rather fraught, because the infection rate is hard to gauge. But assuming that over the four months when roughly one third to one half the population has become vaccinated, and exposure rates of this population similar to that of the unvaccinated and productively infected population, the overall death toll was roughly 50,000 people, of which 1,263 were vaccinated, for a ratio of 40:1)

While breakthrough infections and consequences like hospitalization and death (and possibly long covid, though that is unclear) are not impossible for vaccinated people, they are rare enough that we can resume normal activities. Current policies to limit the spread of the virus, even by vaccinated people who can carry and transmit it via light infections, is mostly aimed at the remaining unvaccinated population, who will be ending up in the hospital at much higher rates, and creating the public health burden. So no wonder patience is wearing thin with the unvaccinated, who will eventually just be cut loose to take their chances while the rest of society moves on in a new world where covid is as or even more manageable than influenza.

Why is Covid less severe in children? ACE2, the key receptor for the virus seems to have lower expression naturally, and is driven even lower by incidental conditions like asthma and allergies. Other cold viruses, to which children are widely exposed, may have "pre-vaccinated" them to the new coronavirus. And children seem to produce fewer inflammatory cytokines, producing a less exaggerated immune response, which is the main factor in later Covid pathology.

Why all the breakthrough infections? One issue is that vaccination primes the immune system, which does not prevent infection, actually. What it does is to shorten the time that the body needs to fight an infection that has already occurred, by pre-educating the immune system about the target it is facing. So vaccinated people are going to be infected at normal rates, but they just won't show symptoms nearly as frequently. And second, as widely discussed, the vaccines have great, but not perfect effectiveness. It stands to reason, as has been widely reported, that more vaccines are better than fewer, and as the virus mutates to meet our weapons of social distancing and vaccination, new editions of covid vaccines will be needed. There can never be enough education of our immune systems against these evolving threats. With the advent of successful mRNA vaccines that can be rapidly programmed with new immunogens, we have the opportunity to increase our protection against both new threats, in form of yearly (or more) covid boosters, and against old threats, like influenza, whose vaccines are stuck in a time warp of antiquated technology and poor effectiveness.

This all implies that we (the vaccinated population) will be spreading around covid on an ongoing basis. It will be endemic, and our protection will be by vaccination rather than isolation. The virus has little interest in killing us, so it will likely evolve to be more benign, as our countless cold viruses have done, thereby spreading more effectively in a well-mixed population.

The extremely urgent need for universal vaccination raises the question of why the FDA has not been faster in its authorizations. All children should have already been cleared for vaccination, and full authorization should already have been granted for adults. The safety and efficacy data is present in overwhelming amounts, and if not, (in the case of children), the studies should have been started much sooner, and run on compressed schedules. One gets the impression that this is a bureaucracy that is overly wedded to process, rather than data- particularly the critical interpretation of data that comes from actual use in the field, rather from corporate reports. And this slowness has implications for future vaccines, such as ones against influenza, as well. We deserve better from our public institutions.

• R0, vaccination rates, etc.
• Can vaccinated people get long covid? Maybe.
• What are those breakthrough cases like?
• Two is better than one.
• Variants and vaccines.
• Ever wonder why religious people are gullible?
• Crypto is not a currency, it is a gamble and tax dodge.
• Gene editing is now a thing.

RAD51 and the DNA Hokey-Pokey

DNA repair and recombination rely on homology search between separate DNA molecules, one of which is double-stranded. How is that done?

BRCA2 is one of the more significant cancer-causing genes, when mutated. It is a huge protein of 3,418 amino acids, with lots of interactions, and functions that are not, even at this late date, very well understood. Like many eukaryotic proteins, it does alot of facilitation and organization of other proteins, roles which have clearly snowballed over evolutionary time. But its core function seems to be to bind right at the site of DNA breaks, and load the recombination protein RAD51 onto the ragged single stranded end. RAD51 then coats the remaining single stranded DNA and does the important work of helping it to find matching DNA elsewhere in the nucleus, which can then be copied to properly repair the break.

It is clear that DNA repair is a critical and highly regulated process, thus the continuing elaboration of proteins like BRCA2 which have mangerial roles. But RAD51 has the more fascinating structural role to play. How does it enable a job that seems impossible- to search efficiently through a whole genome of 3 billion basepairs, crammed in a crowded and jostling nucleus, and wound into double-stranded form on nucleosomes and other chromosomal proteins, to find the exact partner with which to pair and perform the dance of filling in the missing bit of DNA?

RAD51 is, unlike BRCA2, highly conserved, from bacteria to humans. Due to the different genetic methods used to find it, it is named RecA in bacteria, (for a specifically recombination-oriented screen), but is called RAD51 in eukaryotes, following a screen done in yeast cells for all sorts of mutants sensitive to high-energy radiation. Work over the last couple of decades has clarified the structure of RecA/RAD51 and thus how it functions.

Schematic of a DNA break, after processing, searching and finding a homolog to complete the repair. Not mentioned in this post, but the two ends need to be held in a coordinated way to facilitate repair across the break, even while the single stranded ends engage in a nucleus-wide homology search.

RAD51/RecA coating DNA, in scanning electron microscopy. Note how linear and stiff it is. Comparison is with similar DNA coated with another protein, single-strand binding protein, which imposes much less structure.

As mentioned above, RAD51 coats the single stranded end left after a DNA break has been detected and processed / cleaned up by the initial enzymes, and after BRCA2 binds to the recessed junction where the single strand starts. RAD51 forms a stiff and bulky filament, holding the DNA in a stretched conformation that is a thousand times stiffer than single stranded DNA, and 20 times stiffer than double stranded DNA. Interestingly, the single stranded DNA is held deep within the RAD51 filament, quite hard to see from the outside. Only the bases peep out, in triplet sets, amongst the protein structure that holds it so tightly. RAD51 is an ATP-ase, using the energy of ATP to polymerize and construct the filament, and also to de-construct it, but not for the searching operations.

Structure of a RAD51/RecA filament- macro above, and micro below. The single stranded DNA whose homolog is being sought is in orange, tucked deep within the protein filament. In closeup, a slight opening of the incoming double stranded DNA (blue) allows its bases to sample a little bit of the target. The pinkish blobs are positively charged lysines / argenines, ready to mate with the negatively charged incoming DNA backbone. Video here.

So much for the single strand doing the homology search. What about the double stranded DNA being searched against? The RAD51 filament makes provision for that as well, binding it lightly (in the proper directional orientation) and additionally having local splaying interactions that encourage its strands to separate slightly, binding the non-searching single strand, and allowing the searching strand to pair with the triplets peeking out from the core RAD51 filament. At this atomic scale, there is a lot of brownian motion / jostling- the DNA does breathe a bit naturally- so this is not very hard to do in a rapid way. But RAD51 obviously facilitates this in an optimized way.

Another structural view of the core sampling interaction, emphasizing the DNA strands. In brown is the target single strand DNA. In green is the slightly opened strand from the incoming double stranded DNA doing the sampling of one target triplet (with its single strand complement in red held off a little to the side). Note how the target DNA is held in very stretched form, with triplets of bases separated by slight gaps, which are RAD51 protein residues.

The binding of the invading double strand DNA is then very heavily dependent on how well it pairs with the single strand triplets. Pairing with three exposed bases is not a big deal. But pairing with eight consecutive bases stabilizes the match, and pairing with 26 or more seals the deal to be a long-lived match, which can induce de-polymerization of RAD51 and the arrival of repair polymerases. It is clear that RAD51 coordinates a complex dance of on-off sampling of nearby double stranded DNAs, including non-specific capture of local DNA, detailed samping by encouraging strand opening, as well as linear back and forth shifting, allowing some linear scanning as well. These diffusion mechanisms somehow add up to a thorough search of the nucleus for the right partner.

In bacteria, with genomes of a few million base pairs, sequences of 15 nucleotides are usually unique. In a genome of three billion bases, longer sequences are needed to be sure of true homology, nuclear volume is much larger, and there is more complex chromatin to deal with. Yet, the homology search time is not much less- about an hour. Why this is is not yet really clear. In eukaryotes, homologous chromosomes may typically reside close to each other in a semi-stable nuclear architecture. Or other aspects of the chromatin milieu may facilitate the search, paradoxically. And how damaging is an incorrect match? If a closely related sequence is chosen, (sequences which in eukaryotes are common due to replication errors, recombination errors, gene amplification and duplication, and repetitive sequences of many other kinds), it may not matter at all, depending on the size of repair span being copied from the intact homolog. Tract lengths repaired by copying from the other homolog are typically between 50 to 800 nucleotides long.

An even more focused view of the evolving match between a RAD-51 bound single strand (red) and an incoming DNA from a double-stranded sequence match (blue).

• Work from home? It varies.
• Yes, vaccines should be required.
• Signs of social isolation.
• Signs of idiocy.

American Occupations and Preoccupations

Douglass North on the role of institutions in our society, part 2. "Understanding the process of economic change". Also, "Violence and Social Orders". American occupations of Germany, Japan, and Afghanistan and Iraq are case studies of institutions at work. 

In part 1, I discussed the role of ideology and thought patterns in the context of institutional economics, which is the topic of North's book. This post will look at the implications for developmental economics. In this modern age, especially with the internet, information has never been more free. All countries have access to advanced technological information as well as the vast corpus of economics literature on how to harness it for economic development and the good of their societies. Yet everywhere we look, developing economies are in chains. What is the problem? Another way to put it that we have always had competition among relatively free and intelligent people, but have not always had civilization, and have had the modern civilization we know today, characterized by democracy and relatively free economic diversity, for only a couple of centuries, in a minority of countries. This is not the normal state of affairs, despite being a very good state of affairs.

The problem is clearly not that of knowledge, per se, but of its diffusion (human capital), and far more critically, the social institutions that put it to work. The social sciences, including economics, are evidently still in their infancy when it comes to understanding the deep structure of societies and how to make them work better. North poses the basic problem of the transition between primitive ("natural") economies, which are personal and small-scale, to advanced economies that grew first in the West after the Renaissance, and are characterized by impersonal, rule-based exchange, with a flourishing of independent organizations. Humans naturally operate on the first level, and it requires the production of a "new man" to suit him and her to the impersonal system of modern political economies. 

This model of human takes refuge in the state as the guarantor of property, contracts, money, security, law, political fairness, and many other institutions foundational to the security and prosperity of life as we know it. This model of human is comfortable interacting with complete strangers for all sorts of transactions from mundane products using the price system to complex and personal products like loans and health care using other institutions, all regulated by norms of behavior as well as by the state, where needed. This model of human develops intense specialization after a long education in very narrow productive skills, in order to live in a society of astonishing diversity of work. There is an organized and rule-based competition to develop such skills to the most detailed and extensive manner. This model of human relies on other social institutions such as the legal system, consumer review services, and standards of practice in each field to ensure that the vast asymmetry of information between the specialized sellers of other goods and services that she needs is not used against her, in fraud and other breaches of implicit faith. 

All this is rather unlike the original model, who took refuge in his or her clan, relying on the social and physical power of that group to access economic power. That is, one has to know someone to use land or get a job, to deal with other groups, to make successful trades, and for basic security. North characterizes this society as "limited access", since it is run by and for coalitions of the powerful, like the lords and nobility of medieval Europe or the warlords of Afghanistan today. For such non-modern states, the overwhelming problem is not that of economic efficiency, but of avoiding disintegration and civil war. They are made up of elite coalitions that limit violence by allocating economic rewards according to political / military power. If done accurately on that basis, each lord gets a stable share, and has little incentive to start a civil war, since his (or her) power is already reflected in his or her economic share, and a war would necessarily reduce the whole economic pie, and additionally risks reducing the lord to nothing at all. This is a highly personalized, and dynamic system, where the central state's job is mostly to make sure that each of the coalition members is getting their proper share, with changes reflecting power shifts through time.

Norman castles locations in Britain. The powers distributed through the country were a coalition that required constant maintenance and care from the center to keep privileges and benefits balanced and shared out according to the power of each local lord.

For example, the Norman invasion of Britain installed a new set of landlords, who cared nothing for the English peasants, but carried on an elite society full of jealousies and warfare amongst themselves to grab more of the wealth of the country. Most of the time, however, there was a stable balance of power, thus of land allotments, and thus of economic shares, making for a reasonably peaceful realm. All power flowed through the state, (the land allotments were all ultimately granted by the king, and in the early days were routinely taken away again if the king was displeased by the lord's loyalty or status), which is to say through this coalition of the nobles, and they had little thought for economic efficiency, innovation, legal niceties, or perpetual non-political institutions to support trade, scholarship, and innovation. (With the exception of the church, which was an intimate partner of the state.)

Notice that in the US and other modern political systems, the political system is almost slavishly devoted to "the economy", whereas in non-modern societies, the economy is a slave to the political system, which cavalierly assigns shares to the powerful and nothing to anyone else, infeudating them to the lords of the coalition. The economy is assumed to be static in its productivity and role, thus a sheer source of plunder and social power, rather than a subject of nurture and growth. And the state is composed of the elite whose political power translates immediately into shares of a static economic pie. No notion of democracy here!

This all comes to mind when considering the rather disparate fates of US military occupations that have occurred over the last century, where we have come directly up against societies that we briefly controlled and tried to steer in economically as well as socially positive directions. The occupations of Germany, Japan, Afghanistan, and Iraq came to dramatically different ends, principally due to the differing levels of ingrained beliefs and institutional development of each culture (one could add a quasi-occupation of Vietnam here as well). While Germany and Japan were each devastated by World War 2, and took decades to recover, their people had long been educated into an advanced instutional framework of economic and civic activity. Some of the devastation was indeed political and social, since the Nazis (as well as the imperial Japanese system) had set up an almost medieval (i.e. fascist) system of economic control, putting the state in charge of directing production in a cabal with leading industrialists. Yet despite all that, the elements were still in place for both nations to put their economies back together and in short order rejoin the fully developed world, in political and economic terms. How much of that was due to the individual human capital of each nation, (i.e. education in both technical and civic aspects), and how much was due to the residual organizational and institutional structures, such as impersonal legal and trade expectations, and how much due to the instructive activities of the occupying administration?

One would have to conclude that very little was due to the latter, for try as we might in Iraq and Afghanistan, their culture was not ready for full-blown modernity (elections, democracy, capitalism, rule of law, etc.) in the political-economic sense. Many of their people were ready, and the models abroad were and remain ready for application. Vast amounts of information and good will is at their disposal to build a modern state. But, alas, their real power structures were not receptive. Indeed, in Afghanistan, each warlord continued to maintain his own army, and civil war was a constant danger, until today, when a civil war is in full swing, conducted by the Taliban against a withering central state. The Taliban has historically been the only group with the wide-spread cultural support (at least in rural areas), and the ruthlessness to bring order to (most of) Afghanistan. Its coalition with the other elites is based partly on doctrinaire Islam (which all parties across the spectrum pay lip service to) and brutal / effective authoritarianism. When the US invaded, we took advantage of the few portions outside the existing power coalition, (in the north), arming them to defeat the Taliban. That was an instance of working with the existing power structures.

But replacing or reforming them was an entirely different project. The fact is that the development of modern economies took Western countries centuries, and takes even the most avid students (Taiwan, South Korea, China to a partial degree) several decades of work to retrace. North emphasizes that development from primitive to modern political-economic systems is not a given, and progress is as likely to go backward as forward, depending at each moment on the incentives of those in power. To progress, they need to see more benefit in stability and durable institutions, as opposed to their own freedom of action to threaten the other members of the coalition, keep armies, extort economic rents, etc. Only as chaos recedes, stability starts being taken for granted, and the cost of keeping armies exceeds their utility, does the calculus gradually shift. That process is fundamentally psychological- it reflects the observations and beliefs of the actors, and takes a long time, especially in a country such as Afghanistan with such a durable tradition of militarized independence and plunder.

So what should we have done, instead of dreaming that we could build, out of the existing culture and distribution of power, a women-friendly capitalist modern democracy in Afghanistan? First, we should have seen clearly at the outset that we had only two choices. First was to take over the culture root and branch, with a million soldiers. The other was to work within the culture on a practical program of reform, whose goal would have been to take them a few steps down the road from a "fragile" limited access state- where civil war is a constant threat- to a "basic" limited access state, where the elites are starting to accept some rules, and the state is stable, but still exists mostly to share out the economic pie to current power holders. Indeed the "basic" state is the only substantial social organization- all other organizations have to be created by it or affiliated with it, because any privilege worth having is jealously guarded by the state, in very personal terms.

Incidentally, the next step in North's taxonomy of states would be the mature limited access order, where laws begin to be made in a non-personal way, non-state organizations are allowed to exist more broadly, like commercial guilds, but the concepts of complete equality before the law and free access to standardized organization types has not yet been achieved. That latter would be an "open access order", which modern states occupy. There, the military is entirely under the democratic and lawful control of a central state, and the power centers that are left in the society have become more diffuse, and all willing to compete within an open, egalitarian legal framework in economic as well as political matters. It was this overall bargain that was being tested with the last administration's flirtation with an armed coup at the Capital earlier this year.

In the case of Afghanistan, there is a wild card in the form of the Taliban, which is not really a localized warlord kind of power, which can be fairly dealt out a share of the local and national economic pie. They are an amalgam of local powers from many parts of the country, plus an ideological movement, plus a pawn of Pakistan, the Gulf states, and the many other funders of fundamentalist Islam. Whatever they are, they are a power the central government has to reckon with, both via recognition and acceptance, as well as competition and strategies to blunt their power.

Above all, peace and security has always been the main goal. It is peace that moderates the need for every warlord to maintain his own army, and which nudges all the actors toward a more rule-based, regular way to harvest economic rents from the rest of the economy, and helps that economy grow. The lack of security is also the biggest calling card for the Taliban, as an organization that terrorizes the countryside and foments insecurity as its principal policy (an odd theology, one might think!). How did we do on that front? Well, not very well at all. The presence of the US and allies was in the first place an irritant. Second, our profusion of policies of reform, from poppy eradication, to women's education, to showpiece elections, to relentless, and often aimless, bombing, took our eyes off the ball, and generated ill will virtually across the spectrum. One gets the sense that Hamid Karzai was trying very hard to keep it all together in the classic pattern of a fragile state, by dealing out favors to each of the big powers across the country in a reasonably effective way, and calling out the US occasionally for its excesses. But from a modern perspective, that all looks like hopeless corruption, and we installed the next government under Ashraf Ghani which tried to step up modernist reforms without the necessary conditions of even having progressed from a fragile to a basic state, let alone to a mature state or any hint of the "doorstep conditions" of modernity that North emphasizes. This is not even to mention that we seem to have set up the central state military on an unsustainable basis, dependent on modern (foreign) hardware, expertise, and funding that were always destined to dry up eventually.

So, nation-building? Yes, absolutely. But smarter nation-building that doesn't ask too much of the society being put through the wringer. Nation-building happens in gradual steps, not all at once, not by fiat, and certainly not by imposition by outsiders (Unless we have a couple of centuries to spare, as the Normans did). Our experience with the post-world war 2 reconstructions was deeply misleading if we came away with the idea that those countries did nothing but learn at the American's knee and copy the American template, and were not themselves abundantly prepared for institutional and economic reconstruction.

• Tax evasion: our solemn duty and right.
• Defending our precious bodily fluids.
• Signs of isolation and loneliness.