Saturday, December 30, 2017

A Crime Against Humanity

Climate protection is the moral issue of our time.

One Christmas book that came my way was "Facing Climate Change", by Jeffrey Kiehl. It is a Jung-meets-the-climate-problem book. Evidently we should all hug a tree and get in touch with our Selves. It is, in short, preaching to the choir, and that in the gentlest possible way.

While the problem is principally psychological, the climate problem will take more aggressive thought and action to solve. At the same time, it is soluble. A recent New Yorker article focused on negative carbon- ways to remove CO2 from the atmosphere, which is what we need to have any hope of keeping biospheric catastrophe at bay. It will take country-sized infrastructures and improved technologies to solve, but is solvable. Given the collective will to solve it, there are plenty of policy and technical tools at our disposal.

The main problem is neither technical nor depth-psychological. It is moral, and reminds me of slavery in the US, and the resulting Civil War. Both sides knew it was wrong, and both sides benefitted from it economically. One side had the moral fiber to stand up and say that slavery was wrong, so wrong that it needed to, at least, be confined to the South, and ideally, abolished as an institution. The abolitionists were viewed as extremists and whackos at the time, unrealistic, weak, and sentimental. The other side prevaricated, rationalized, and ultimately fought tooth and nail to keep that system of incredible rapacity, greed, and injustice intact.

We are all implicated in climate change. We all know it is real, even if CO2 is invisible and its consequences relatively nebuous and distant. Denial, among the denialists, is but a stage of grief, for the greedy and wasteful freedoms we all grew up with and would like so much to maintain. The current Trumpian moment is one last hiatus from reason and responsibility, the dead end of an old and immoral regime. The US limped on for decades through the slavery crisis, reaching compromise after compromise, in hopes of saving a divided nation from the bloodbath that came. We have so far limped through two and a half decades, more or less, from the time when global warming was widely recognized, with analogous, if less heated, controversies, denial, and compromises.

Temperatures, decade by decade, and getting hotter.

Thankfully, addressing climate change will not require a war. Those poor nations most affected by it are far more likely to yearn to join the polluters than they are to start a war agaist them. In the US of the eighteenth century, the slaves likewise did not revolt in any successful way- the issue was not pressed by its victims, but by morally engaged onlookers- the abolitionists. Those economic interests most entwined with fossil fuels, at least in the US, are not politically independent, and while their corrupt influence is enormous, they are not unreachable by democratic governance.

What we need is a clear moral statement about the matter, in the vein of Uncle Tom's Cabin. That novel cast a new, brutal light slavery as it had never been lit before- as morally depraved and unsupportable by any civilized person. Climate change is a crime against the biosphere and against future generations of humanity, of vast proportions. We are slowly destroying whole ecosystems and ways of life, and robbing our children, en masse and comprehensively, of a healthy biosphere.

Al Gore started the process with his "Inconvenient Truth". It established the problem as undeniable, and moved many people with its moral urgency. But evidently we need more- a more compelling statement of the impossibility of being a moral person while denying climate heating or leaving it to someone else to solve. Most Americans agree, generally, but not with the urgency that leads to voting or action, and those who are most powerful seem to be most irresponsible on this front. Thus we are very close to a tipping point, and defining the issue with greater moral clarity could push us towards action.

Polar bears can help, but images and anecdotes are not enough.. there has to be a stronger comprehensive narrative around the issue.

With slavery, the logical end point was clear, even though it was also highly unpopular- the full enfranchisement and integration of African Americans into American society. With climate change, arbitrary lines have been drawn, but need to be periodically re-drawn as we spew our way through CO2 concentration limits and temperature thresholds. Two degrees? Or two and a half? This is one more way that this problem is devilishly easy to ignore and evade. The accords that have been reached so far, in Kyoto and Paris, have fallen far short of what is needed, and the only way to change that is through moral suasion- making it morally impossible to do otherwise than what is responsible to our future selves and progeny.

Saturday, December 23, 2017


Yes, they really did fly- the amazing world of pterosaurs.

National Geographic recently had a beautiful spread on pterosaurs- those ungainly creatures that nobody thought could fly, until, apparently, we realized they really did fly. Indeed, they ruled the skies for over 160 million years- far longer than birds have. They operated a good deal like bats, with wings of membrane spread between modified fingers, which also stretched back to their legs. But a crucial difference is that, unlike bats, pterosaurs used only a modified fifth finger to carry the outside of the wing. The other fingers made up a strong hand about mid-wing that could be used for walking and lifting off. Thus pterosaurs were much better walkers than bats, and could also lift off from a standstill more effectively.
Reconstruction of the largest known pterosaur, Quetzalcoatlus, as tall as a giraffe, from the late Cretaceous.

What remains astonishing is how much apparent weight these animals carried, especially in front. The largest known pterosaur, Quetzalcoatlus, weighed about 440 pounds and had an enormous head. The head may have been quite thin, but, with neck, takes up roughly half its length. All pterosaurs tended to have large heads, and frequently added remarkable crests or horns, as if snubbing their beaks at aerodynamics. But looks are deceiving, since, like the toucan's bill, pterosaur crests and bones are hollow, very thin (1 mm), and thus were very light. The classic Pteranodon, with a crest almost as long as its enormous bill, is estimated to have weighed only 25 pounds, easily carried by a wingspan of 25 feet. Whether they could have carried off the hapless Zara Young is another matter.

Beautiful specimen of Rhamphorhynchus, from the Jurassic, with impressions of wing and tail membranes.

What is almost as compelling as the fossils of pterosaur bones are fossilized trackways, which show them in action. Over thirty walking tracks have been found, and one paper even describes what the authors interpret as a landing track. Typical pterosaur walking tracks show the heavier hind feet on the inside, and the wing/hands much more lightly on the outside. At each stride, the rear feet pull up roughly parallel to where the wing/hands have just left (b, in the figure). In these novel tracks, which begin abruptly, there are only hind feet for two strides, before the wing/hands appear. Secondly, the first hind feet tracks have elongated claw marks. Thirdly, the first two or three hind foot track sets are parallel and show a very short stride, different from typical walking gaits, of which the rest of this track is an example. These characteristics all lead to the idea that this pterosaur was landing, and hopped a couple of times with both feet before transitioning to a walking gait.

150 million year-old tracks from France. Top is an interpretation of the middle tracks, as evidence of landing. Below is a typical walking sequence and interpretation from the same location / source. The scale bar at bottom is 10 cm, so this pterosaur was relatively small.

This is not new work, dating from 2009, but the message is still a little hard to wrap one's head around- that tens of millions of years went by with these incredible creatures carrying on the battle for survival, with great success, and high style as well.

Nyctosaurus gracilis, reconstructed, from the late Cretaceous.

  • A dumber nation- Thanks, Scott Pruitt!
  • Xmas notes on another flying life form.

Saturday, December 16, 2017

Structure of the Polytene Chromosome

Fly researchers have had a special microscope on their genetic subject for a century. Now we know why.

The DNA of our cells is enormous, and at the same time it is microscopic. Our 3 billion basepair genome is six feet long. Yet each of our cells contains a copy that is exquisitely wrapped up and so difficult to observe that it took X-ray crystallography and decades of experiment and inference to divine its true nature. Fruit fly researchers had a significant head start, however, with their recognition that a few fly cells make a form of their genome that can be observed with relative ease.

A "squash" of Drosophila polytene chromosomes. The upper left inset shows condensed normal mitotic chromosomes for comparison- they are very small. What do the bands signify?

Polytene chromosomes are made by larval insects in their salivary glands, apparently for the purpose of amplification of gene expression. Rather than develop ways to super-express the salivary protein products they need so much of from the usual single DNA copy, these cells re-duplicate their DNA many times, (about 1000-fold), while keeping it joined in a sort of synaptic alignment, which would normally only be apparent during cell division. They can then express selected genes to high levels with less regulatory effort. These "on" genes are apparent as puffs in the chromosomes when they are prepared with special stains and visualized under a regular microscope.

A "puff" of opened and expressing DNA is visible at upper left. The three panels are 1: staining with a general fluorescent DNA dye (green) along with a specific red dye targeted to a gene of interest (red; see arrows- this was a DNA-primer-based detection, so quite direct). 2- the customary orcein / Giemsa stain for visible light microscopy. 3- a light filter specific for the fluorescent red dye in the first panel bring out its locations.

The great Red Book of Drosophila genetics offers a comprehensive mapping of genes with respect to the "cytology" of these polytene chromosomes. The figure above was prepared by modern molecular biology reagents, which makes locating a gene of interest easy. But before all that, genetic mapping was done by tracking visual changes in the polytene chromosomes and mutations that befell gross genetic loci and had phenotypic consequences, such as re-arrangements of DNA that cut a gene in half. Decades of such work, correlated with more standard genetic mapping by recombination, resulted in a dense roadmap of genetic markers distributed along the characteristic banded pattern of the Drosophila polytene chromosomes.

But why were the polytene chromosomes banded in the first place? What were these landmarks that everyone relied upon? A recent paper re-opens this issue and links the interband zones (the lighter areas in both the green-stained and the orcein-stained preparations above) to the specific molecule function of transcriptional insulation. "Bands" are richer in DNA, while the interbands have less DNA. What do they have instead? Evidently proteins, of a particular sort.

Genes are packed pretty tightly in the DNA of our genomes, and are regulated by sites in the DNA that are typically nearby and upstream with respect to the direction of transcription. But "nearby" could mean tens of thousands of basepairs away. Thus it has been found that a great deal of looping goes on to bring such distant regulatory sites close to the gene start site where they have their effect. This naturally raises the question of why such regulatory sites don't just loop over to some other gene distant on the chromosome, or even on a different chromosome. In the tight confines of the nucleus, such things are doubtless quite possible.

Enter the "insulator". These appear to be special proteins that bind DNA situated between gene regions, keeping the regulatory apparati of each functionally distinct. The authors of this work reviewed the field and then carried out new crosslinking experiments that track genome-wide which DNA segments are close to others, or to specific proteins. That means that they essentially "froze" the 3-D structure of the DNA relationships with a chemical that promiscuously crosslinks any DNA or proteins close to each other. They then cut and joined those proximate DNA segments to each other with ligase, and sequenced the junctions at large scale to determine all the junction points.

The fact is that polytene chromosomes are sort of blown-up representations of normal DNA in the nucleus, which is normally not just randomly jumbled about, but is arranged in loci and loops organized around gene regions. That means that this kind of experiment, which was conducted on early Drosophila embryo cells, and not on the salivary cells that generate polytene chromosomes, is looking at the native looping and regional structure in normal cells, at least at that particular developmental stage, which will have its unique pattern of genes turned on and off.

They found it was easy to discern topological structure in these nuclei, just as others have before. Specific regions of DNA are in close contact, while others are not. It is not a random jumble. More importantly, there are a set of about 5,000 zones that had high local interaction, but less interaction with others- they termed these topologically associated domains (TADs). The boundaries between these correlate with other work finding high accessibility to DNase, and finding proteins bound that are called insulators. Yet other work on the polytene chromosomes found that they exhibit about 5000-6000 visible bands, the borders of which are again highly accessible to DNase, and the sites of insulator protein binding.

The hallmark of insulator proteins is that when DNA sites for their binding are engineered between enhancers and the gene they typically regulate, they tend to cut that communication. The mechanism behind this is not clear yet. It could be because looping is a progressive process, starting locally and scanning out to the nearest gene, in a kind of sewing machine model.

In any case, the authors draw on all this work to put the pieces together, and claim that polytene banding, as detected by DNA and other stains, show this structure at the visible level, with topological gene units housed in the dark bands, and the light units housing intergeneic segments, with insulators in between. Since Drosophila has almost 16,000 genes, this indicates that many of these topological units house multiple genes, an example of which is the homeobox complex, where complex and coordinated regulation extends over several nearby genes.

Correlation between polytene banding and cross-link contacts, in one segment of the genome. Banding is on top, and cross-link contacts are show in color. The crosses form out of topological localities with high internal contact rates, and lower external contact. At bottom is shown a gene track of the region from Flybase. Blue vertical bits are exons.

Correlation between polytene banding and cross-link contacts, in one segment of the genome. Banding is on top, and cross-link contacts are show in color. The crosses form out of topological localities with high internal contact rates, and lower external contact. At bottom is shown a gene track of the region from Flybase. Blue vertical bits are exons.

This is problably not news to the field, which is why this paper was buried in an obscure journal, but it is nice to see new methods make sense of quite old historical problems, and to recognize that we were looking at significant and functional genomic features all the time, from the first staining of these giant chromosomes in 1881.

Saturday, December 9, 2017

Native American Cleansing, Army-Style

Review of Keith Murray's "The Modocs and Their War".

It was a brief national sensation during the Grant administration, but now a forgotten episode in the ethnic cleansing of the West. A tiny band of obscure Native Americans in Northern California resisted the US army for a year, engaging over ten times their own numbers, turning whole army units into demoralized fleeing cowards. A splinter group of the Modocs, numbering about 65 fighting men, were induced to go to a reservation in Oregon around 1865, but naturally found the experience unappealing, and decided to return to their native lands. With the US distracted by the Civil War and its aftermath, they were left alone for several years, while the settlers that were encroaching on their lands threw up increasingly bitter complaints.

Lava beds at Tule lake

One feature of these native lands, around Tule lake on the border with Oregon, are lava beds with very rugged topography. While barren, these also make excellent natural fortifications. The Modoc band, with their leader Captain Jack, made thorough use of them to hold off a determined Army attack on January 16 and 17, 1873, inflicting about 50 casualties while suffering none of their own. In fact, the Modocs throughout this episode ran circles around their enemies in tactics, logistics, scouting, and intelligence. In contrast, the Army of the West was a notorious home to cast-offs and hirelings, with little motivation and very great expense. There was an actual F-Troop involved, bringing quite appropriately to mind the old TV show about Western Army incompetence and corruption.

Eventually, the Army brought in hundreds of soldiers, plus units of friendly Native Americans, and hunted the Modocs down after they had thoroughly exhausted their supplies, not to mention their shaman's spiritual powers. Four of the leaders were hanged, and the rest shipped off by train to a reservation in Oklahoma, where the Modoc nation survives, barely.

I highly recommend this book, which dates from 1959. It is painstakingly researched, clearly told, and well-, sometimes sardonically, written. Murray reflects on the failings of the US Army, when faced with highly motivated and guerrilla resistance. He reflects:
"When the student of the Indian troubles turns from men or events to generalizations, he is struck with the obvious fact that the most serious aspect of the Modoc War was that the government had clearly learned nothing from its experience. Even while Captain Jack was awaiting execution at Fort Klamath, the civil government of Oregon expressed concern over the actions of certain Nez Percés of Joseph's band living in the Wallowa Valley of northeastern Oregon" .. which then led to similar mistreatment, broken promises, incompetence, and a long and tragic war of resistance.

The portents for Vietnam are alarming here, not to mention the displacement and mistreatment of the Palestinians. But to stick to domestic affairs, the overall dynamic was one of moral turpitude and greed on a national level, which the Army was put in a hopeless position to manage and mitigate. While the (Northern) US is justly proud of its moral position in the Civil War, its position towards Native Americans was one of ethnic cleansing, not to say extermination. The press of manifest destiny and the homesteading / settler movement encroached relentlessly on Native American lands. Treaty after treaty was signed, then ignored or reneged, boxing Native Americans into smaller and smaller reservations. We may call them concentration camps. They are on the worst possible land, in the most remote corners of the nation.
Territories of the Nez Percé. Green shows original treaty lands,  while the inner orange shows what they are left with today.

The irony is that only a few decades after the last of the Indian wars, the country woke up, in some very small degree, to its destruction and rapine of its natural inheritance and started establishing national parks to preserve a few of the most beautiful areas. If the Native Americans had been treated with decency and fairness, with large national lands that were protected from the depredations of settlers, we would today have a much more significant system of wild areas, in addition to preserving many more Native Americans and their diverse cultures. We can only be thankful that the freed slaves were not likewise driven onto barren reservations in the West, over trails of tears.

  • The lies are the message, and the power.
  • The tax bill is an impeachable offense.
  • Fraud is now OK.
  • Medicare is next.
  • Is collusion with Israel worse than with Russia?
  • Cable, unbound.

Saturday, December 2, 2017

Truth and Enlightenment

What the Enlightenment and Modernity have wrought, and who has problems with it.

As our values of truth and honesty are slipping, it seems worthwhile to review how we got here. People generally have a tenuous relation to reality. What we see through our eyes is only its surface. We can see plants all our lives and yet have no understanding of how they work and how they came to be. Such knowledge has to come through painstaking inference into a mental model, based on clues, experiments, mutations, exceptions, and the like. Humans are champions of inference, as attested by conspiracy theories and religion- ways that our need to for theories of reality outstrips our actual knowledge, sometimes flagrantly.

Historically, there have been occasional periods when intellectuals had the prosperous and calm conditions to make progress on this front, out of the mire of preconceptions, superstitions, and traditions, and into a more measured and rational view of reality. Not that there is ever a perfectly rational view, but there are clearly more and less rational views possible. The ancient Greeks experienced one such period, founding schools of philosophy that lasted hundreds of years, and fostering the greatest scientist, teacher, and thinker of the ancient world, Aristotle. But the greatest such period was the Renaissance and subsequent Enlightenment of Western Europe, when the learning of the ancient world combined with mounting prosperity and technological development to dispell the fog of Christian theology, and made of scholarship an independent, rigorous, and institutional pursuit that continues today.

Painting is an example of this movement. The Renaissance painters learned perspective, and reveled in new powers of realistic portrayal. Realistic painting may now be old-hat, even déclassé, but after the rude iconography of the Middle Ages, it was revolutionary, reminiscent of the incredibly naturalistic statuary of Greece and Rome at their heights. Similar movements in all areas of intellectual life, including science, philology, history, politics, and social thought generally, and philosophy, brought us to modernity, where our relationship to nature is fundamentally transformed, from that of a mystified and dependent spectator, to that of a deeply understanding (if not always respectful) steward. While morals and ethics are not themselves a matter of truth and natural observation, (though they have a lot to do with integrity and honesty), the same truth-finding ethic trained on social institutions brought down, step by step, the superstitious hold of the religio-monarchical system, to the constitutional / social contract systems of today.

Francesco di Giorgio, ~1490, an idealized architectural view.

But some are not happy with this change in perspective. There were obviously losers in this process of cultural and intellectual maturation. Principally religion, which tried mightily to understand the nature of reality, while mediating our relation to it, but couldn't help putting the cart of dogma and power ahead of the horse of intellectual integrity. For honesty and truth begin in the method of getting there. True humility, not the false and preening humility of putting one's god before all other gods and considerations, is the first step to being able to even see the subtle stirrings of nature, and then to follow them out. Charles Darwin was orginally intended for the parsonage, but as he unfurled the relentless mechanism of biology, and experienced its stabs in his own life, he ended up an evident atheist, woken up to a more sober, mature, and we might say enlightened, view of our nature and situation.

Reality isn't always pretty. Facing it takes fortitude and work. Thus the astonishingly durable, if slipping, hold of religion into this, the twenty-first century. Thus also the attraction of fake news and con artists, not to mention religion. Far easier to have comfort and hope in false and familiar beliefs than to accept uncertainty and ignorance, and do the work required to resolve them, even partially. Who would have thought that, at the so-called end of history, when the US won the cold war, and spread its blend of capitalism, relative freedom, and intellectual ambition across the world, that such moral rot would set in here at home, with our plutocrats, (with the connivance of Russia, of all things!), standing at the head of an army of resentful religious traditionalists, straining every nerve to spread distrust, small-mindedness, and lies over the land?

  • Intellectuals- the first targets of authoritarians and fascists.
  • And State is the department of intellectuals, at least till now.
  • Which country takes the cake for lying?
  • But our Republicans are in contention as well.
  • What's the matter with Kansas.. will soon be the matter with the rest of us.
  • ... Until the revolution.

Saturday, November 25, 2017

The Purpose-Driven Pastor

Robert Price answers Rick Warren, in The Reason-Driven Life.

We are all seekers for purpose and meaning. But what happens if someone has the answer? We react, naturally, with a good bit of suspicion and skepticism. For we know instinctively that this search is not only difficult and unlikely to yield definitive answers, but also highly personal. Those peddling pat answers and coookie-cutter solutions may have confidence, but rarely have true answers.

So it is with Rich Warren and his book The Purpose-Driven Life. This has been a fundamentalist staple now for one and a half decades, with sales to rival the Bible itself. "You Were Planned for God's Pleasure." Wow! But what pleasures God? Well, now that we are done with sacrificing chickens and committing genocide, it seems that God is most pleasured by people joining fundamentalist churches like Rick Warren's, imagining they are abasing themselves before God, while lording it over all the sorry sinners who haven't gotten the message. Then they are sent out to spread the word and get more people to join up. Warren's ultimate message is to be a drone for the church: "You Were Made for a Mission". As Robert Price quotes:
'World-class Christians are the only fully alive people on the planet.' The outrageous arrogance of this insane boast never seems to dawn on him. Eric Hoffer has Warren pegged: 'The impression somehow prevails that the true believer, particularly the religious individual, is a humble person. The truth is that the surrendering and humbling of the self breed pride and arrogance. The true believer is apt to see himslef as one of the chosen, the salt of the earth, the light of the world, a prince disguised in meekness, who is destined to inherit the earth and the kingdom of heaven too. He who is not of his faith is evil; he who will not listen shall perish.'

But Robert Price isn't just taking pot-shots. He is a post-fundamentalist, biblical scholar, and church-goer, as well as an atheist. He has great respect and love for the Bible, enabling a critique that makes Warren's literalism and pretensions to a biblical foundation ludicrous. Time and again, citations that seem so pat are exposed as far more complex, even contradictory, both among themselves, and to the points Warren is making. Warren quotes: "He is a God who is passionate about his relationship with you" Exodus 34:14. But his source is a custom version of the Bible for Warren's fundamentalists. The real translation is " The LORD, whose name is Jealous, is a jealous God", which lies among a discussion of how the Israelites should storm and desecrate the shrines of other religions.
Image result for yahweh

Likewise, Warren cites "What pleases the LORD more: burnt offerings and sacrifices, or obedience to his voice? It is better to obey than to sacrifice." 1 Samuel 15:22. The language here is accurate, but this is no invitation to tea and scones, or to a Saddleback encounter group. The obedience demanded in this passage is genocide against the Amalek. One wonders whether this is a god that Warren's parishoners have any knowledge of or desire to get to know. The fact is that the Bible is a cobbled-together melange of historical and poetic texts, riven with inconsistencies, cross-purposes, and moral evil. To believe that one can take it literally, as Warren does, (most hilariously with the Noah story), is intellectually dishonest and incoherent.

And that is the fundamental lesson, in this age of fake news. The internet was hardly the first method of purveying falsehoods. Historians such as Homer and Herodotus never let truth get in the way of a good story, and standards were no higher among the many ancient story tellers and scribes who contributed to the Bible. They all had agendas, as does Rick Warren. Their narratives often begin in fact, and then veer into myth and fantasy, as most evident in the book of Revelations. The whole Jesus story is so full of archtypes and "purpose-driven" fables that it is impossible at this point to separate anything out that might have had to do with an actual person.

No, the Bible is an amazing cultural document, from our brutish and benighted, yet hopeful, forebears. It documents substantial moral and intellectual progress on its pages, in its transition towards a more or less pacifist dispensation (though whether that was by choice, or by Roman force is another matter). We have continued that progress in the modern age by, ironically, leaving its fervid fantasies behind and basing our intellectual life on the firmer foundations of empiricism and humanistic empathy. Fundmentalists work double-time to "prove" that their literal views of God and the Bible are true, but they are doomed to failure. That general intellectual failure is seen both in their amazingly corrupt bargain with Donald Trump and the revanchist Republicans, and in the declining numbers of parishoners in the pews. The decline of religion has been far slower than many had imagined, given that its intellectual foundations have been defunct for centuries, but is ever so slowly coming to pass, however purposeful its pastors.

Saturday, November 18, 2017

Economics is All About Redistribution

And new economies need new methods of redistribution.

"Redistributionist" is a dirty word for the right, like gun-grabber, bleeding heart, tree hugger, and statist. Yet we are currently treated to the spectacle of a Republican congress redistributing income, foregone taxes, and wealth to the tune of trillions, upwards towards the wealthy and well-connected. What does repealing the estate tax have to do with putting manufacturing workers back to work, or solving the opioid crisis? Nothing, naturally.

In a state of nature, everyone has a job, which is to wrest bare sustenance from a rich, but complex and mystifying world. No one is "employed", since everyone is self-employed. And if you or the small family you rely on fail in that task, the end comes relentlessly. This represents the primitive "job guarantee". Everyone has a job, and failure to do that job is penalized harshly.

A developed economy has a different relation to work. Most people still live by their labor and wits, but there is so much wealth and technological prowess that most people's work is completely dispensible. Whether we have lawyers, rock bands, and toothpaste is a matter of significant, but not existential, importance. Even the food production system is so broadly based that no single person's work is existentially important to anyone, even themselves, given a modest safety net. And this system can support large numbers of people with no jobs at all, with ease. Yet income remains tied to work, despite the fact that we are moving to a future where the ratio of work needed to labor available is plunging, taking the labor market and incomes with it.

Who runs this system? Whom does it serve?

The trajectory of all this is quite clear. Those with wealth receive the benefits of industrial productivity, which is increasingly capital-based rather than labor-based. Those with only labor to offer, even of a specialized and educated nature, get increasingly locked out of the income / redistribution system. Whether this will lead to a Keynesian crisis of lack of overall income and spending is not clear. The rich spend much less than their income, as witnessed in the recent revelations of overseas tax shelters holding trillions. But so far, the Fed and other institutions (here federal deficits play a critical role) are working mightily to keep the system churning, despite the extensive replacement of good jobs with bad jobs, and consequent declining worker pay (relative to productivity). The system is no longer working- labor is no longer an effective way to keep everyone employed and paid in a manner that befits an advanced society as productive as ours.

This is what the current class war is all about. Republicans are shamelessly doubling down against the very voters who thought they were supporting a better deal on jobs and a restoration of the middle class. Rather, this administration is pulling every available lever to entrench the rich/capital and pull the rug out from under workers, leaving them even more powerless and destitute than before. Who would have thought?

What should we be doing instead? Some propose a basic income, whereby every citizen gets a small income, merely for existing. This neatly cuts the connection between labor and income, but has many problems. First, it is not a decent income, but extremely minimal. So it ends up being miserable welfare, at best, for the poor, and an unnecessary gift to the rich. Second, it does not provide the reciprocal benefits to society, or the individual, that work does. To let so much personal energy go to waste, paying people to do nothing, presents both a moral hazard an an enormous social loss. We can do much better.

Social Security could be cited as an example of a very successful basic income, given to all. But it is explicitly tied to previous work, and serves a specific social function of supporting those who can not work any more. Public services like roads, public buildings, scientific research, and the like are also good examples of implicit income given to all, and surely health care should come under the same universal service category. But income for working-age people represents something quite different- it is the source of their freedom, and represents their service to the larger society. We need to find a way to preserve and enhance those relations while gradually disentangling it from the semi-feudal work-as-labor model in capitalism.

Basically, people should be paid for a wider range of activities. For example, voting could be paid. Serving on juries could be paid, far better than currently. Sending children to school could be paid. Positive social activities should be paid for, not just classed as volunteer activities or duties. Perhaps the biggest opportunity is in the non-profit sector. If the government funded non-profits on a broad basis, while enforcing governance, management, and mission rules, we could end up with endless opportunities for public service and fairly paid work.

Where would the money for all this come from? The main actor in the economic system is, to be frank, the government, not the private sector. The government prints the money, runs the central bank, and has first rights to production such as defense spending, police functions, and other necessities (which becomes particularly clear in war-time). The fact that capitalist enterprise and competition has been a beneficial and innovative way to organize the private economy to provide the bulk of most people's needs does not mean this will always be the case or needs to be the sole form of work and income. As mentioned above, capital is concentrating and the need for labor is gradually uncoupling from the need to produce goods. But it shouldn't be uncoupled from doing social good. Indeed, the capitalist system has led to enormous social harm, and seems to have led to an appalling revolution in values, putting the greediest and most predatory people in the most successful positions.

Thanks to mind-boggling political and intellectual corruption by which they have gained power through a supposedly populist political movement, these arch-capitalists are right now trying to entrench their feudal powers over workers by relieving themselves of taxes, by empowering corporations to rule more of our lives, enhancing the legal immunities of corporations and relieving them of any public purpose (especially in the case of media companies), by weakening our democracy and the state, and by keeping the labor market weak and workers dependent on the private sector for income. It is the last gasp of a system that will either turn towards an even uglier feudalism, or be turned back and regulated into a progressively smaller share of our economic, social, and political lives.

  • Paradise papers and the so-called rule of law.
  • But why shelter your riches from taxes when you've got a congressman in your pocket?
  • And for that matter, why not appoint a tax evasion expert to head the IRS?
  • "The United States, he noted, currently has one of the highest levels of inequality in the history of the world."
  • Which Republicans want to make hereditary.

Saturday, November 11, 2017

How Did I Get Here? (From the Primordial Soup)

Review of recent speculations about the origins of protein translation.

DNA may be the biological master code, but proteins are the soul of the machine- the shakers and makers that do everything, or almost everything, around a cell. Given how different these chemicals are in their roles and nature, how did they arise in evolution, and come to the indirect but essential relationship they have today? That is the story of translation and the origin of life. One of the exceptions to the current ubiquity of proteins in active roles is the ribosome- seat of protein synthesis- whose catalytic core is RNA throughout. Indeed the only molecule that can do it all- code for information, survive for reasonable lengths of time, (at least under acidic conditions), and do catalytic reactions, is RNA. This has led to a rough consensus that the very beginnings of chemical reproduction and life-ish chemistry began with an "RNA world". This does not exclude other chemicals, like amino acids and membrane-like lipids participating, but they would not be active in the central reproductive and coding operations that characterize life.

Envisioning the addition of DNA is easy. DNA is similar enough to RNA that there are only a couple of alterations needed to make this far more durable form. Copying is also similar enough to whatever mechanism RNA had to copy itself that the transition between the two is relatively straightforward to envision. And of course, RNA remains the universal carrier of transitory codes- between the durable DNA store and the translation system.
The modern flow of biological information: DNA->RNA->protein.

But getting from the RNA world to the protein world of today remains very hard to envision. There has been quite a bit of recent speculation on the matter, presenting several divergent stories for how this key transition came about. It is an interesting time to take a look at the field, even though it is possible that we may never have a definitive, or even consensus, answer.

The first interesting point to make is that copying RNA is intrinsically a perilous and questionable practice. We naturally think of nucleic acid copying with the model of DNA in mind: making the reverse complement by zipper-like Watson-Crick base pairing. This is the strongest form of nucleic acid interaction, and it takes helicases or other energy typically to pry the resulting duplex nucleic acid pair apart. The product of this reaction is also only a reverse complement, not a precise copy of the original. To copy a functional ribozyme, a second reverse complement would be needed to come up with a true copy of the original. This leads several authors to speculate about "direct" RNA copying systems, where the reverse complement is avoided, thereby sparing the system from these two perils, the first of which is actually the more serious. Reverse complementary sequences form a black hole of stable pairing, from which their originators would have a very difficult time extricating themselves under pre-biotic conditions.

One author (Taylor) proposes an obscure set of base pairing bonds, less strong than the Watson-Crick base pairs, that might form a basis for direct instead of reverse copying. This is highly speculative, and such effective pairing is not shown explicitly in the model, or elsewhere to my knowledge. Thankfully, this property plays no role in his model, which goes on to draw on tRNAs as models for an RNA-based adapter that might have originally brought their nucleotide ends to a ribozyme to carry out this parallel replication into direct RNA copies. This naturally leads to an evolution into carrying amino acids, and the replicative ribozyme transforms into a ribosome.
Proposal from Noller for a double-bridging system for RNA replication that uses a minimal system of adapter RNAs, which are then pre-adapted for later use in ribosomal protein synthesis. 

Another author (Noller) later proposed a similar RNA replication mechanism that produces direct copies at the cost of a similarly non-direct mechanism. In this theory, two identical tRNA-like structures serve as the intermediate bridge between the template and product RNAs in an early RNA replicase, cleverly using short (and normal Watson-Crick) base-pairing interactions to build the copied product RNA, triplet by triplet. Again, the proposal of an indirect (not zippering basepair-mediated) mechanism solves the problems of making reverse complement copies and two-stage copying, at the cost of substantial complexity. But it also obviously lays the foundation of the future ribosome, which uses a similarly indirect (tRNA) means to bring amino acids together bit by bit as directed by a coding RNA template.

Not so fast, claims another group (Harish and Caetano-Anolles). They do an exhaustive analysis of the phylogenetic history of all the RNA and protein components of the ribosome, and come to the somewhat startling conclusion that proteins were there from the very start, co-evolving with the ribosomal core and playing roles in the origin of translation. They allude to non-ribosomal peptide synthesis as a possible source for the early portions of this partnership, which seems under-developed. Phylogenetic analysis is notoriously murky at these early times, especially using RNA sequences, and can be confused with conserved functionality. Perhaps most pursuasive, however, is their specific set of findings that various protein and RNA portions of the ribosome each have, as one would expect, a variety of different ages, and that the oldest protein portion is in contact with the oldest RNA portion, at the mRNA decoding and ratcheting region. This implies not only that proteins were very early partners in whatever this ribozyme was at the time, but also that the peptidyl transfer center, previously thought to be the most ancient heart of the ribosome, only came later. They suggest that this complex was at the time an RNA replicase, but avoid saying much about it.

This raises more insistent questions about how useful, large, and ultimately conserved proteins could be devised at a time before the ribosome arrived, and also, if proteins were present, why weren't their superior catalytic capabilities used to engineer the (later-arriving) peptidyl transferase site, instead of the RNA-based mechanism that still exists?

Lastly, a fourth proposal (Ma) takes another approach to the bridging RNA system, proposing that small RNAs were capable of binding amino acids from very early times, and could have been used for a primitive form of templated protein synthesis. Indeed, they may have started out as RNA-bound co-factors for special ribozyme reactions, rather than as units for peptide synthesis at all. But the amino acid carriers then became standardized, and once they exposed an anticodon, could be harnessed into templated protein synthesis, given some energy, perhaps from the "charged" state by which their amino acids were attached. This theory is a tRNA-first class of theory, and leaves a great deal unsaid and unaccounted for, yet has the virtue of simplicity, plus the recognition that amino acids were common in the prebiotic soup, and likely played some kind of important role from early times.

As one can tell, this field is in ferment, with very interesting ideas deployed to explain a momentous transition of which we can see (and feel and experience) the consequences, but have only the most speculative view of its ingredients, key problems, and context. Origin of life research is a little like string theory in that respect, with little hope of experimental validation, premised on a faith that drawing out the consequences of what is known about the world must, (with a little guessing about what is not known), clarify a world that is at its heart remorselessly logical.

  • Corrupt cronyism, against CNN.
  • Elite blind spots- the Wykehamist fallacy.
  • Charity is not going to rebuild the Caribbean.
  • Conservative media- think of them as the brownshirts.
  • Economic graph of the week. Labor force composition by age- the kids are not alright.

Saturday, November 4, 2017

Travels up the Cilium, and Back Down Again

Cilia are far more than wavy arms.  They are key sensory organs for most cells and have complex internal dynamics.

Cilia are the fuzz of Paramecia, and the sweepers of our respiratory system. They can be flagella, but are structurally unrelated to bacterial flagella. They are yet another eukaryotic innovation, bound by a membrane and composed of a microtubule bundle with complex boundary and transport mechanisms to construct themselves and provide unique functions. While some cells have lots of cilia, virtually all eukaryotic cells have at least one, and that one is called the primary cilium. It arises from the microtubule organizing center left over after cell division, which then migrates to the cell surface (via a vesicle intermediate) and grows a new bundle of microtubules pointed outside to create a key sensory organ. Indeed, primary cilia are the eyes, ears and noses of many eukaryotic cells.

Comb jellies move using cilia.

The cilium membrane is kept distinct from the bulk membrane of the cell via a collar or "necklace" of proteins around the base, implying special transport mechanisms for membrane components as well as for the many internal components needed to build and maintain cilia. This allows various signaling molecules to specialize to the cilium, forming a concentrated and specialized sensory platform.

For example, the photoreceptors in our retinas sit inside modified primary cilia, elaborated and evolved from the more primitive sensory system common to all eukaryotic cells. Fat cells have a primary cilium that displays G-protein coupled signal receptors that receive status updates from the body, and are defective in at least one genetic syndrome of obesity. Other genetic syndromes of ciliary function result in developmental defects, kidney disease, diabetes, and cancer.
The primary cilium is a product of the centriole or MTOC previously used in cell division.

A recent paper (review) investigated the intgernal dynamics that makes all this possible, a train system of cargo carriers that travel up and down the microtubule bundles of cilia. The microtubules are oriented in a single direction, minus at the base to plus at the tip. Two classes of motor proteins go in opposite directions, kinesins going up towards the plus end, or anterograde, and dyneins going in opposite fashion, towards the base, or retrograde. How cargoes attach themselves to these motors, and how their transport is regulated, makes up a very interesting field of study.

This paper observed the transit time of transport carrier complexes (IFT) at the tip, before heading back down to the cilium base.

These researchers used a fluorescent technique to look at individual cargoes as they were making this trip. If cargoes are made fluorescent, and then most of them are bleached out by overexposure, then a few remaining ones can be tracked. Their questions were mainly about how long these materials spent at the tip, and how the decision was made to reverse course. The operative acronym here is IFT, for intra-flagellar transport. Multiple cargoes seem to gang up into literal trains, which seems to depend a special coupling mechanism. For example, the authors labeled one of these dedicated transport proteins, called intraflagellar transport 27, or IFT27. They found that it takes about three seconds for this protein to hold up at the tip before being re-organized into a retrograde train. One of the cargoes being carried up the cilium is dynein, the motor required for all the return trips.

Experimental image set, showing time slices (going down). The fluorescent train comes up the cilium (towards the right) a first, then waits around for a couple of seconds at the tip, before dissociated fluorescent components start their return trips (on two different train sets, here) going back towards the left.

On the other hand, kinesin, which powers the trip up the cilium, does not get actively carried back down, but diffuses back, which is ten times slower. The authors suggest that this may be the rate limiting step restricting cilium length, since as the cilium grows, more of the kinesin is clogging its length, and less is available at the base to serve new anterograde trains. but since kinesin is expressed cytoplasm-wide, this is not an entirely compelling speculation.
In contrast to the train protein tracked above, fluorescently labeled kinesin powers its way up the cilium, but then dilly-dallies about, diffusing slowly back down without joining any powered trains.

What regulates all this? The motors and train proteins are nucleotide binders of various sorts, powered by ATP or GTP, so there is ample precedent for fine regulation using such systems. Perhaps just coming to the (+) end of a microtubule fiber sets switches in the kinesin and train proteins, priming them for the return conformation. What turns the dyneins on at the right time, and what regulates cargo attachment/detachment is still a mystery, however. As for cargo proteins like signaling receptors, some are known to have special targeting sequences which let them bind to the vicinity of the ciliary base, where they are transferred to the IFT train system. Others are sent to the primary cilium via the golgi protein sorting and vesicle generation system. If the targeting is high enough in affinity, such receptors can be essentially vacuumed from the rest of the cell and localized entirely to the cilium, thereby explaining the extreme localization/specialization of some signaling pathways and receptors to the primary cilium.

Saturday, October 28, 2017

The Sierra Club as a Religious Organization

Yes, and a good one, too.

The divides in the US have many dimensions, but a significant one is religious. Conservatives crow about their traditional religion- Christianity- and then, bizarrely, vote for Trump. What they really seem to be for is patriarchy and its traditional society-wide hierarchy (based on male-ness, but also on its accessory patriarchal religion and on race). Their model in the South shows that a bare-majority or even minority race can maintain power for decades in an ostensibly democratic society if enough levers of social, political, overt, violent, as well as covert power are used consistently. The movement against Confederate monuments is a watershed in consciousness of the thoroughgoing way the social gestalt of the South has been shaped by its treasonous and revanchist elite.

As far as rural and Southern America are concerned, the bicoastal elite live in another country entirely. In that country, we tend to think we have no narrative, no gestalt at all, but purely a functional this-is-the-way-it-is approach to reality and truth. A committment to reason, science, innovation, good public policy, social justice, etc. But of course, that can not be true. We have a narrative as well, and nothing illustrates it better than the Sierra Club.

This is the home of the shamans of environmentalism- the tree-huggers, whale watchers, and activists, inhabiting a completely different narrative from that of traditional Christianity and patriarchial conservatism. Its roots go deep into paganism and the natural reverence humans have for nature. It is a nature religion, but not animistic. There are no anthropomorphic deities or weird powers. We are the gods, but are fallen, now that we have inherited this awe-ful responsibility of taking care of a world that we have so hopelessly befouled. There is no bearded or other male figure behind the curtain. The Sierra Club conducts pilgrimiges, has its saints, sacred places and its version of the end-times, preaches to its believers, and expounds at every opportunity an ideology of love of and care for nature. It has its fetishes for untrammeled, unspoiled locations, its secret misanthropy, its revelations of human insignificance. And even jihad, if you count GreenPeace in the same sect.

A recent article by Gary Kamiya in the Sierra Club organ makes its religious nature particularly clear:
... Which takes us back to the wilderness within. No matter how refined we may think ourselves, at some level we are all still wild creatures, made up of the same materials as the mountains, the deserts, the oceans, the distant stars. "Wilderness" carries a connotation of chaos and anarchy, but that's misleading. Our inner wilderness is no more disorderly than the world itself is. A wild mind is a balanced mind. The wild world may be deeper and more heterogeneous than the city world, but the difference is only a matter of degree. The sense of wilderness is our birthright, and we can experience it anywhere. "The wilderness as a temple is only a beginning," Snyder writes. "One should not dwell in the specialness of the extraordinary experience . . . to enter a perpetual state of heightened insight." The real goal, he says, is to see all the land around us, whether in the country or in the city, as "part of the same territory—never totally ruined, never completely unnatural." 
Of course there is still absolutely nothing like a face-to-face encounter with deep wilderness. Once at Buck Lake, I was awakened by the screaming call of a pack of coyotes racing unseen through the 3 A.M. darkness, the shrill sound moving fast along the mighty granite ridge across from my campsite, then fading into the distance. That sound still rings in my memory, a quicksilver affirmation of the strangeness and holiness of the world.

The language and sentiments are clearly religious. But there is no theology, no theos at all. It suits the "spiritual-but-not-religious" mindset, whose sprituality is affective and natural, not burdened by over-thought (yet underbaked) theology and relic supernaturalism. Science isn't a problem here, but another way to appreciate the glory of what we love on so many levels- our world and biosphere.

Is all this good? People are naturally religious, creating and needing frames of meaning beyond mere subsistence and reproduction. The Republican Party and current administration shows what can happen when such a frame becomes completely moribund, paying lip service to Catholic and generally Christian dogmas while throwing any semblence of actual moral principle to the wind and practicing shameless greed. It is a revolting spectacle on every level. True religion fosters empathy and puts us in touch with our core values and commonality, not just among males, or with fellow countrymen, or even with humans, but with all beings.

  • Silent holocaust.
  • More lies.
  • Are human desires endless, and therefore work endless? Only if money is distributed equitably.
  • Does all our productivity get channelled to the top, or to those doing the work?
  • How to design drugs with knowledge and computers.

Saturday, October 21, 2017

Not the Last Dark Age- the One Before That

Review of 1177 B.C., by Eric Cline, about the decline and fall of the Bronze age around the Eastern Mediterranean

In this time of cultural and political decline, it is useful to contemplate previous cultural cataclysms. While "the Dark Ages" typically denotes the roughly five hundred year hiatus between the fall of Rome and the resurgence of wider cultural ties and development in Western Europe, that was hardly the only extended collapse of high level civilization. A previous Dark Age had followed the collapse of the Bronze Age circa 1200 BCE, leading to the several historically empty centuries before we hear about the classical Greek civilization rising from the ashes in the 700s BCE.

The Greeks cherished their dramatic sagas dating from that prior, heroic epoch, much as the English later looked backwards romantically via the Arthurian saga, going do far as to send Arthur to defeat the Romans in battle. But the battle of Troy was no fantasy- it really happened. The only question is whether it was part of the destruction of the Bronze age, or part of its normal, competitive, affairs.

In fact, it is astonishing what we do know about this age, given its distance from us and the ensuing civilizations. Eric Cline has assembled an excellent guide to this period, the late Bronze age, dredging up a great deal of scholarship old and new on the many civilizations clustered around the Eastern Mediterranean from Italy to Egypt. We owe particular debts to the writing developed earlier in this age, both the hieroglyphic style in Egypt, and the cuneiform style from Babylon, which was adopted by the Hittites and others. The clay tablets so amenable to preservation (especially after fires) have been a gold mine of knowledge about the affairs and attitudes of the time.

Hittite writing from about 3300 years ago, using cuneiform script.

We have correspondence between kings as well as more mundane accounts. We have in some cases both sides of a diplomatic exchange, even a momentous peace treaty between Egypt and the Hittite empire. It is quite amazing. These unearthed records paint a picture of extensive contacts and trade between the states of Cyprus (Minoans), the Mycenaeans of mainland Greece, the Hittites of Anatolia, the Assyrians, the Ugaritic state in what is now the northern Syrian coast, the Canaanites, and Egypt. It is easy to get carried away with globalization analogies and complexity theory. But unfortunately, we have very little to go on when it comes to what ended this period. The Egyptians record enormous battles with "the Sea Peoples", which seems to have been a coalition of several enemies. But they also say they won this war, and the pharoah, Ramses III, was laid to rest in high style, though murdered in an internecine plot. Cline goes through a large amount of archealogical evidence, which shows earthquakes, drought and climate change, internal revolt as well as external invasions during these times. It is, in sum, hard to finger any single cause for the eventual decline of all these cultures into several hundred years of relative silence and decreptitude, (not to mention tomb-robbing), though there may have been a combination.

It was once fashionable to cite the Sea People as the instigators, in an orgy of rapine and destruction, as is related in the Iliad, and the Egyptian annals. It is not clear who the Sea Peoples were, however. They may have been Myceneans, but evidently encompassed other groups as well, maybe even free-booting pirates. And the various destroyed cities of this age were not all invaded, let alone by these groups. The Hittites were sacked by other enemies.

Ramses III mortuary relief showing prisoners from battles with the "Sea Peoples". Note the diverse head-dresses.

Cline resorts to the decline of trade, and complexity theory in his speculations. But a problem is that, despite the excitement of finding trade relations between these states, and royal correspondence, it is highly unlikely that a state like Egypt was substantially dependent on outside trade or other assistance. Such relations were icing on the cake, but hardly fundamental to its perpetuation. The cause has to be found elsewhere, either in general theories of cultural sclerosis and decline, or perhaps in disease or technological innovation. Also, if invasions or revolts were at issue, why did some other state not take advantage of them? The preceding centuries had seen a constant tug-of war between Egypt and the Hittites for control up the Levant, indicating that, were one weakened, others would rush to take up the slack. Yet both went into decline, and the Hittites vanished completely. It may indeed just be a coincidence that many cultures had reached a high level simultaneously, and then at similar times were overcome by ruder powers less inclined to leave historical traces.

The stage of the Bronze age was originally set by the migration of Indoeuropean peoples into the Middle East, founding the Mycenean and Hittite cultures, among others. Their earlier spread was enabled by a suite of decisive technological innovations like horse riding, wheeled carts and chariots, mobile warfare, and herding, which enabled mobility and military success. By the late Bronze age, these were no longer novel and had diffused all over the region. But perhaps some other innovation, like improved and larger ships or nascent iron working, may have tipped a critical balance. Secondly, herding and livestock domestication generated a variety of new diseases, which eventually played such a large role in the destruction of the native peoples of the New World. Perhaps one of these diseases had yet to burn its way through the late Bronze age Mediterranean. It must be said, however, that such an event would probably show up in the Egyptian annals, and also that other cultures managed to recover within a generation or two from devastating plagues, such as the black plague.

Lastly, cultural decline might be inevitable after a long period of stability. Stability breeds complacency and a cultural dynamic where the powerful stay powerful, with ever less merit and justification as time goes on. Their corruption, combined with the resentment of the powerless, can lead morons into power, a bad sign in any age and a sure path to decline, for all their protestations of greatness.

Sunday, October 15, 2017

What Adulthood Looks Like in the Brain

A gene expression turning point in the mid-20's correlates with onset of schizophrenia, among other things.

Are brains magic? No. They may be magic-al in how they bring us the world in living color, but it is mechanism all the way down, as can be seen from the countless ailments that attack the brain and its functions, such as the dramatic degradation that happens in boxers and football players who have been through excessive trauma. All that amazing function relies on highly complex mechanisms, but we are only beginning to understand them.

One way to look at the brain is through its components, the proteins expressed from our genomes. Those proteins run everything, from the structural building program to the brain's metabolism and exquisitely tuned ion balances. Current technology in molecular biology allows researchers to tabulate the expression of all genes in any tissue, such as the brain or parts thereof. This is sort of like getting a quantitative parts list for all the vehicles active in one city at a particular time. It might tell you a little about the balance between mass transit and personal cars, and perhaps about brand preferences and wealth in the city, but it would be hard to conclude much about detailed activity patterns or traffic issues, much less the trajectories or motivations of the individual cars- why they are going where they are going.

So, while very high-tech and big-data, this kind of view is still crude. A recent paper deployed these methods to look at gene expression in the brain over time, in humans and mice, to find global patterns of change with age, and attempt to correlate them with diseases that are known to have striking age-related characteristics, like schizophrenia.

They duly found changes of gene expression over time, and tried to concentrate on genes that exhibit dramatic changes, reversing course over time, or plateauing at times that they call turning points. Below are a few genes that show a dramatic decline in mice, from youth to adolescence.

Expression of selected proteins in frontal cortex of mice, with age, showing turning points in early adulthood, which is about five months here in mice. These genes each have variants or other known associations with schizophrenia.

Perhaps the most interesting result was that, if they tabulate all the cases of turning points, most seem to occur at early adulthood. The graphs below show rates of genes with turning points at various age points. One can see that by about age 30 and certainly 40, (about age 7 months in mice), the brain is set in stone, gene-wise. There is little further change in gene expression.

Number of genes by age when their expression shifts direction, either up, down, or plateauing.

In contrast, age 15 to 30 is a very active time, with the most genes changing direction, and the largest changes of expression peaking about age 28. Given the many genes and complex patterns available, the authors reasoned that they could do some reverse engineering, predicting a sample's age from its expression pattern. And using only 100 genes, they show that they can reliably estimate the age of the source, within about 5 years. Secondly, they broke the gene sets down by the cell type where they are expressed, and found distinct patterns, like genes typical of endothelial cells attaining peaks of expression very early, before 10 years of age, as physical growth of the brain is maximal, while genes typical of pyramidal neurons, one of the most important and complex types of neurons, reach their inflection points much later, in the mid-twenties.

Types of genes and their rough times of expression shift, by age. Most key neuronal genes seem to settle into unchanging patterns in early adulthood. PSD is post-synaptic density, typical of synapses where learning takes place.

Particularly interesting to the authors are genes associated with post-synaptic density, part of the learning and plasticity system where connections between neurons are managed. These genes were especially enriched with turning points in early adulthood, and also feature a disproportionate number of genes implicated in schizophrenia, whose onset occurs around this time. The genes tended to be turned down at this time, in neurons. While these observations correlate with the age-specific nature of schizophrenia, they do not go much farther, unless it could be shown that the genetic variants that confer susceptibility are perhaps mal-regulated and more active than they are supposed to be, or some other mechanism that makes the connection between the defect (all of which so far which have very weak effects), and the outcome. For example, one such variation was found to increase expression of its gene, which is present and functional in the post-synaptic densities.

It is interesting to see the developmental program of our brains portrayed in this new way, but it is only a glimpse into issues that require far more detailed investigation.