Iran and Saudi Arabia

Modern propaganda and ancient hate.

Frontline has an excellent three-hour series on the conflict between Iran and Saudi-Arabia. They come off like minuature versions of the US and the Soviet Union- superpowers of the Muslim world enmeshed in an ideological and tribal battle that is fought through proxy forces throughout the Middle East, making a hash of smaller countries and making strange bedfellows with the likes of Israel.

The Shia-Sunni split was always an undercurrent in the Islamic world, but was sharpened by the advent of modern fundamentalism. While the Saudis have always been fundamentalist in theory and corrupt in fact, Iran plunged into total fundamentalism with the revolution of 1979. The documentary discusses how sharply this changed the dynamics in the Muslim world, with Iran suddenly vaulted into the vanguard of the fundamentalist movement. This perennial "back-to-basics" feature of religion became a deeply ideological and psychological response to the muddled end of colonialism and the general failure of modernity in the Muslim world. We hear mostly of its Sunni / Salafist incarnation, as ISIS, Al Qaeda, the Muslim Brotherhood, etc. But for the Shia, it had an extra edge of tribal revolt against Sunni oppression.

Shia make up roughly 1/3 of Muslims in the Middle East, with populations in each country. They are a majority in Bahrain, though they have no role in the government. That was the situation in Iraq as well until recently. Iran's fundmentalism is sectarian, not pan-Muslim. Thus, despite ethnic divisions, it has been an instrument to unite Shia populations across the region, such as the Hezbolla party in Lebanon and the now-ruling parties in Iraq. Iran's reach is obviously limited by this sectarian character, but they have been willing to arm their friends to the hilt and send their minions into battle for the most dubious causes, especially the Assad government in Syria, which is composed of another Shia sect.

Saudi Arabia is petrified by all this, partly because they have their own Shia population, but more because their own power projection has been so bungled in comparison. They have assiduously funded fundamentalist madrassas and terrorists, and what do they have to show for it? Hatred from the West, yes, but also quite a lot of hatred from their own spawn, such as Osama Bin Laden, whose disgust with the top-heavy, spoiled, corrupt Saudi institutions was emblematic. Their best friend, the US, conquered Iraq and not only botched the whole project disastrously, but left the country in Shia hands. And in Pakistan, one of their most successful test beds of miseducation, does all the fundamentalism add up to a strong state or a good friend? No, it has led to chaos, double-dealing, and misery.

One of the themes going through this story is propaganda. No one in Iran gets Lebanese Hezbolla fighters to die in Syria for Assad without a very heavy dose of propaganda. A bunch of Saudis do not fly into the World Trade Center without lengthy indoctrination. Fundamentalism in general is the triumph of poorly thought-through ideals and archetypal images over reason and basic decency. The Palestinian cause, now in its twilight, was one long piece of performance art- of grievance and rage as policy and, occasionally, power. And the long Saudi / Wahhabi campaign of Jesuit-style fundamentalist eduction has only furthered the weakness and backwardness of the Muslim world in general, not to mention its violence, particularly against women. The record is appalling, but the mechanism teaches universal lessons- that people can be led in disastrous directions by well-crafted propaganda, based on supposedly profound fantasies.

It is something we are learning in the US as well, to our peril. Does free speech mean that private broadcast networks can spew the most pleasing, and scurrilous, falsehoods? Just how much bilge can the internet contain, and not blow up? Conflicts like the one above, between Iran and Saudi Arabia, are made possible by propaganda, which moves people to extraordinary emotion and effort. World War 2 remains a textbook example, with Germany and Italy transformed by deeply emotional, false, and effective, propaganda. We are in the US at a tipping point, with half the population feeling themselves part of the Republican team, whose life support comes from propaganda that seems, at least to this biassed observer, unworthy of any political discourse or intellectual respect, headed by a President who lies so casually and habitually that we now take it as absolutely normal. How can reason and empathy penetrate this jungle of mean self-righteousness?

Returning to the topic, the current administration's support for Saudi Arabia and hatred for Iran is not easy to understand, on the face of it. Saudi Arabia is at least as destabilizing a force in the world and in the Middle East. Both are explicitly fundamentalist, and both seek to export their ideologies abroad. Both are sources of oil, though the Saudis have far more and play the lead role in world oil prices. We do not care that much on our own behalf anymore, but have strong interests in keeping the oil infrastructure (political, military, and physical) of the Middle East intact on behalf of the developed world, for much of which (Europe, Japan) we have explicit defense responsibilities. So sure, we want to be friendly with Saudi Arabia and continue to have military bases in the area. But we have interest in friendship with Iran as well, which has far greater human and intellectual potential. Both countries have a fraught relationship with Israel, though Saudi Arabia has of late been much more accommodating, in its cynical and conservative/authoritarian way. But Iran's problems with Israel seem similarly superficial, just a way to gain credibility with the Palestinians and other disaffected Muslims. And our own difficult history with Iran, and their vitriolic propagada against us, is hardly reason to fall in line with Saudi Arabia's sectarian program. It would be better to turn the other cheek, as the Obama administration started to do.

If the struggle for supremacy in the Middle East were prompting a flowering of cultural, scholarly, and scientific advances, that would be one thing. But the reality is far more tawdry, where the Saudis just buy more arms from the US to dump on Yemen, and Iran coopts and arms Shia communities in the neighborhood, destroying Lebanon in the process, and bidding to do the same in Iraq, Syria, and Yemen. The collision of irrational ideologies, served by up-to-the-minute propaganda methods, run by governing structures ranging from dysfunctional to medieval, is a toxic brew not likely to enhance the culture or living conditions of those in the region any time soon.

• The next level for propaganda.
• What happens when police don't care.

Science is not the Answer

Bryan Appleyard has some complaints about the new priesthood and its corrosive effects on the old verities, in "Understanding the Present: Science and the soul of modern man".

This is a genuinely exciting book (dating from 1993) about modernity- our age where science in all its facets has not only transformed practical existence, but also our spiritual lives, de-mystifying nature and tossing religions, one after the next, onto the scrap heap. Appleyard is not happy about it, however- far from. He is tortured by it, and while he can not stomach going back to religious orthodoxy, whether of fundamentalist or mildly liberal varieties, nor can he accept the new regime, which he views, somewhat mistakenly, as scientism. That is the belief, fostered (in Appleyard's view) by the gushing popularizers like Carl Sagan, Jacob Bronowski, and Richard Dawkins, that science can not only solve all our questions of knowledge, but forms a new technocratic morality of reasonable-ness and tolerance which, if properly worshipped, could resolve our social, political, and spiritual problems as well.

The first half of the book is far better than the second. Setting up the problems of modern spirituality is far easier than solving them. In broad strokes, humanity used to be at home in heavily archetypal religious realities. While actual reality did intrude from time to time, the fables of Christianity, to take the main example in the West, were (and for some, still are) magical tales which gave us hope of a benevolent meta-reality and a pleasant afterlife. But intellectuals kept trying to make sense of them, until they "sensed" them completely out of existence. Appleyard cites Thomas Aquinas as perhaps the finest of these intellectuals in the theological tradition. His main work was to reconcile Aristotle, the pre-eminent scientist of antiquity, with Christian orthodoxy. This was taken as the height of theology, not to mention truth in general. But it planted the seed of modernization and logic- if something is logically or empirically true, it must necessarily be consonant with the Catholic religion, which is by definition true. Thence downwards through the enlightenment, Newton, the  industrial revolution, existentialism, liberal theology, to the plague of atheists we see today. The Catholic church tried to draw the line with Galileo and the heliocentric model, but that did not go well, and a few hundred years down the road, they gave up and said they were sorry.

"Science was the lethally dispassionate search for truth in the world whatever its meaning might be; religion was the passionate search for meaning whatever the truth might be."

All religious pretensions to scientific truth have been exploded, and the only choices left, as Appleyard sees it, are regression into fundamentalism, continuation to the endpoint of modernist anomie where humans are morally worthless or even negative destroyers of pristine nature, an acceptance of science itself as humanity's triumphalist project, which through its powers and gifts can give us all meaning, ... or something else. Appleyard spends much of the second half of the book on the fourth option, discussing quantum weirdness, chaos theory, computational incompleteness theories, and related fields which put the lie to the determinist dreams of nineteenth century science. Science does not know everything, and can not know everything, thus there is some gap for us as humans to be free of its insidious, deadening influence- a humanist space.

There are many things wrong with Appleyard's take on all this, some of which are contained in his own arguments and writing. Science has long held to the fact/value distinction, as he discusses at length. Even such a solidly scientistic enterprise as Star Trek recognizes regularly that Spock can neither supply all our values, nor even on his own terms operates without idiosyncratic values and meaning. The world of Star Trek is morally progressive and rational, but its motivations and meaning come from our human impulses, not from an algorithm. Exploration, skimpy uniforms, and great fight scenes are who we are.

"The key to the struggle, it cannot be said too often, is the way in which science forces us to separate out values from our knowledge of the world. Thanks to Newton we can not discover goodness in the mechanics of the heavens, thanks to Darwin we cannot find it in the phenomenon of life and thanks to Freud we cannot find it in ourselves. The struggle is to find a new basis for goodness, purpose, and meaning."

But then Appleyard frequently decries the new scientistic regime as having destroyed morals in general.

"... all moral issues in a liberal society are intrinsically unresolvable and all such issues will progressively  tend to be decided on the basis of a scientific version of the world and of values. In other words they will cease to be moral issues, they will become problems to be solved. The very idea of morality will be marginalized and, finally, destroyed."

This makes no sense, as he himself concludes by the end of the book. It seems to be a matter of looking for morals and meaning in all the wrong places. After a long excursion through the death of scientific determinism, he consoles us that science doesn't, and can't know everything. Thus we can go about our lives with our own values, desires, and dreams without paying much mind to any moral teachings from the scientific priesthood, which didn't exist anyhow. Whew! Determinism is a complete red herring here. Science studies all of reality, whether complicated or simple. If broad swathes can be subsumed into the master equation of gravity, that is wonderful- empowering on practical and psychological levels. But sometimes the result of all this study is a large database of genes and their properties, whose complicated interactions preclude easy prediction or codification (harkening back to the cataloguing of Aristotle and Linnaeus). Or sometimes it is a prediction system for weather which, despite our best efforts, can only see a limited distance into the future, due to inherent limitations to any model of a chaotic reality. That is OK too. Such pursuits are not "not science", and nor does such ignorance furnish us with free will- that comes from adaptability. The results of our studies of reality do not imply much about our meaning and values in any case, even as they defang the oddly materialistic superstitions and totems of yore. Our powers of understanding may be amazing, and fetishized by the educational system and science popularizers, but are not the foundation of our moral humanity.

Scientific studies of ourselves have, however, been enlightening, uncovering the unconscious, Darwinian designs, ancient urges, and a great diversity of ways of being. They have also clarified the damage we are doing to our environment via the wonders of modern life. This has informed our self-image and hopefully our values, but hardly determined them. Humility is the overall lesson, as it has been from all the better religious traditions. Appleyard decries relativism, the liberal tendency towards excessive humility- suspicion of one's own culture, and excessive regard for those of others. But isn't that merely a slight overshoot / correction from the madness of colonialism, slavery, genocide, rampant technology, greed, and war that has been the Western history over the last couple of centuries? Isn't it a spiritually healthy step back? In any case, it is an example of human values at work, perhaps more influenced by our prosperous condition than by any dictates from science.

Appleyard's fundamental complaint is against the new priesthood that has taken over management of the wonders of creation, but has at the same time failed to address our human needs for solace and meaning. Indeed, some of its high theologians delight in telling us that the universe, and ourselves, are utterly meaningless. Appleyard constantly weaves god into the discussion, while taking no exlicit pro-god position. He can not bring himself to bite that bullet, but rather is content to complain about being thrown out of Eden for the sin of too much knowledge. Well, it was always a cheap trick to read our fate in the stars or in goat entrails, and to read our meaning in ancient wonder-tales. These methods were merely externalizing values that came from within. The patriarchial systems of theology express most clearly the interests and desires of the men who run them. So we are, in the modern dispensation, merely reduced to a state of honesty about stating what we want, without the false veils of magic, authority, and supposed moral objectivity. And that change seems, at least to me, beneficial for our moral situation, overall.

• Can morality be reasonable? Which animals are worth helping?
• Typical enviro screed about saving space for nature...
• Forest loss continues apace.
• Roubini forcasts disaster, as usual. With details.
• We saved the wrong people in the last financial crisis.
• Financial sleaze.
• Who cares about truth anymore?
• Our common economic statistics are not cutting it.
• Japan is doing very well, thank you.

On Vacation

Just a few links for this week:

• Let's protect marine life.
• Notes on experts.
• Altruism, for me!
• Making China great again.
• Religion as a disease.
• What on earth has happened to freedom of speech?

Arthur Kornberg

Notes on a great biochemist.

One thing that has made America great is our biomedical research establishment. Over the second half of the 20th century, the US created a uniquely effective set of funding institutions, and grew a large cadre of scientists who have led the world in the adventure of figuring out what makes us tick. Biology, at the molecular level, is an alien technology, based on chemistry, yes, but otherwise utterly unlike to any technology we have developed or been previously familiar with. It has taken decades to get to our current incomplete level of knowledge, and it will take decades more to unravel such complex processes as the detailed genetics of early development, or of schizophrenia, or the nature of consciousness.

Yes, it has led to biotechnology and growing prospects for improved medicine. But the historical significance of this epoch lies in the knowledge gained, of finding and exploring a vast and ancient new world. One of the leading scientists of the early days of enzymology and molecular biology was Arthur Kornberg, whom I learned from through his textbook on DNA replication. It was a model of clarity and focus, filled with apt illustrations. It was the rare textbook that didn't try to cover everything, and thus could treat its proper subject with loving care and detail.

The cover depicts a micrograph of replicating viral DNA, the new duplex forming in a loop in the middle, and much of the DNA covered with proteins that help the process along.

Kornberg was the subject of both an autobiography and a biography / hagiography. The latter was written by a fellow scientist, but steers only gingerly into the science, sticking mostly to the story of Kornberg's life, times, and relationships. And what science there is is rather biased. For example, several years after the Watson-Crick model of DNA came out, Kornberg's lab developed a compositional assay for their short snippets of replicated DNA made in the test tube, and deduced that replication was anti-parallel. That is, one DNA strand of the duplex runs in one direction, chemically speaking, while the other strand runs in the opposite direction. This is portrayed as a discovery, for which Crick was very grateful in correspondence. But the Watson-Crick model had already posited the anti-parallel nature of DNA as an intrinsic property, and the model had been richly supported by that point, so Kornberg's work was at best confirmatory. Crick was just being polite.

An interesting side-light is that this epoch in biochemistry and molecular biology was substantially enabled by the scientific and technological breakthroughs of the Manhattan project and nuclear physics. It was isotopes like phosphorous-32 and sulphur-35 that allowed far more sensitive assays for nucleic acids than ever before, allowing tiny amounts of enzyme to be tracked down. DNA sequencing began with ladders of size-selected nucleic acids digested chemically from longer molecules and visualized by X-ray film thanks to radioactive P-32 enzymatically attached to the ends.

Early days, Arthur (right) and his wife Sylvie, who played a central, though unheralded, role in his laboratory and work.

One irony of the story is that Kornberg was so stuck in his system that he was resistant to the new fields it gave birth to, i.e. molecular biology. In his prime, he ran a factory of a lab, indeed a whole department, (first at Washington University, St Louis, then at Stanford), devoted to finding and characterizing the enzymes of nucleic acid synthesis and particularly DNA replication. These groups purified enzymes on a massive scale from E. coli cells, which were broken open, filtered, and then passed over various charge-selective and size-selective media, in extensive multi-step protocols to come out at the end with more or less pure single proteins or complexes of proteins. Some of these enzymes turned out to be extremely useful in biotechnology, for the cutting, copying, ligating, repairing of DNA, etc. As time went on, scientists realized that enzymology, while an important part of understanding how things work in cells, is usefully supplemented by the many methods of genetics and cell biology, which resulted in a hybrid field called molecular biology.

For example, Kornberg's Nobel prize was won, and name was made, on DNA polymerase I from E. coli. This enzyme replicates DNA, but not very well. It tends to fall off a lot. Some years later, another lab created a mutant E. coli strain that lacked the gene encoding this enzyme. And lo and behold, the cells were fine. They reproduced and replicated their DNA. It turned out that E. coli encodes five DNA polymerases, of which DNA polymerase I is among the least important- a repair enzyme that finishes gaps and other problems in the duplex, leaving the bulk of replication to other, far more ornate enzyme complexes. It was genetics that provided the critical clues in this story, showing how an integrated and diverse approach to research questions provides more productive answers.

Master of his realm, in later years, with fruit-themed computer.

Kornberg ran a family-style system in his departments. He had drawn most of its members (at Stanford) from among his own post-docs and students. It had communistic, but also authoritarian, elements. Space was shared, reagents were shared, even funding was shared- something unheard of today. At the same time, Kornberg had the last word on everything and was a ferocious micromanager. Researchers who wanted to make a name for themselves and build their own empires had to leave. But Kornberg picked well, and many of his colleagues had very influential careers, especially Paul Berg, a pioneer of recombinant DNA methods. Kornberg's strong dedication to his field and his system- his sense of meaning and purpose- was a precondition of success, communicating itself to all around him and fostering an unquestioned work ethic and community ethic. The Stanford department was legendary in its day, and inspired many other researchers to become enzymologists and use the laborious methods of protein purification to get their hands on the very gears and cogs of life.

• Steve McCarroll on contemporary biochemistry.
• Reformation and enlightenment as coincidences.
• Failure to deal with white collar crime may have led to a white collar criminal in the White House.
• Racism, yes.
• Who could have expected any better?
• The Chicago school, now for banking regulation?
• How much of military spending is waste, even on its own terms?
• Secular stagnation? Hogwash. Response, Wiki page. Response.
• MeToo and Kavanaugh. And perjury.

Striptease by HIV

How the virus disrobes is an important part of its life cycle, secrets of which are still being uncovered.

For such a tiny entity, HIV-1 has a very complicated life. Its study has generated numerous drugs that interfere with key life events, and have brought it under control in most developed areas of the world. But there is a lot left to learn. While its fusion with target cell membranes and eventual replication have received the most study, less is known about what happens in between.

The layers of HIV. Outside is a membrane, which features proteins like gp120 that binds to T-cell receptors.

The virus has several layers. On the outside is a membrane coat, designed to protect the virus in moist environments, but more imporantly to expose surface proteins that seek out T-cells specifically, and then to fuse with their membranes, thus entering them. Inside the lipid membrane and its supporting proteins is the capsid, a protein coat that protects the HIV genome from attack by internal T-cell defenses like RNases, helicases, RNA sensing proteins, interferons, and their various downstream effects. This capsid finally lets go if its cargo at the nucleus, where the viral genome, now transformed into double stranded DNA, integrates itself into the cell's genome.

Electron micrograph of HIV particles. The capsid sits inside the membrane coat, all of which is about 120 nm in diameter.

Innermost is the genome, composed of RNA, not DNA. Packaged alongside it are key enzymes integrase, RNase H, and reverse transcriptase. Once HIV enters the cell, and meets the rich mother-lode of ATP and other nucleotides, including deoxy-ribonucleotides that are the building blocks of DNA, the reverse transcriptase can begin its work. It copies the  genome in a complex sequence of starts within the linear RNA, hops to the other end of the RNA, continuation, and finally termination. All the while, the RNase digests the original RNA genome, in a remarkable process of self-transmutation. It is thought that synthesis of the complementary DNA strand only begins after the virus rides the cell's light rail system (microtubules) to the nucleus, where it leaves its capsid behind.

Some recent papers shed a bit of light on the nature of the HIV capsid, which is more interesting than previously understood. It was not previously clear whether the capsid uncoats at the membrane during original entry, or only at the nucleus, or even inside the nucleus. But one paper shows quite definitively that the capsid remains intact through the first strand of DNA synthesis, thus through most or all of the virus's trip from the outside membrane the nucleus. This work required rather difficult assays for capsid integrity, judged by the inclusion of fluorescent protein GFP into the viral genome. Most of this protein escaped during viral fusion with the membrane, since most of the free volume of the virus is outside the capsid. But a small portion remained visible as long as the capsid remained intact.

One hexamer of the capsid protein CA. At the center is pore, accommodating a very small molecule of ATP, in yellow/orange. The surrounding blue parts of the protein are positively charged, ideally suited to attract nucleotides and the IP6 stabilizing molecule.

Another paper took a closer look at the stability and composition of the capsid. It is known to be composed of roughly 1500 copies of the viral CA protein, in multimeric (hexameric and pentameric) rosettes. The structure above shows that at the center of these rosettes is a small pore, big enough to let in ATP- suggesting clearly that the deoxynucleotides needed for reverse transcription can enter even while the capsid is intact, providing the virus with the best of both worlds- protection from the cell's various specific antiviral defenses, but also food for its replication. In the lab, these capsids have been remarkably unstable, however, leading some to believe that the virus uncoats soon after it enters the cell. But these authors find that a chemical that is obscure, but common in cells, IP6, is shaped just right, and negatively charged just right, to sit in these rosette pores and stabilize the whole structure, extending the lifespan of capsids in the test tube to hours instead of minutes.

Two mysteries remain- first is how deoxyribonucleotides get in if IP6 is blocking the pores and stabilizing the structure. The likely answer is simply that these small molecules are not plugs. They have more stochastic behavior, jumping on and off frequently enough to allow other small molecules occasional access. The second question is what finally causes the capsid to unravel at the nucleus and release its now-DNA genome to join that of the cell. It is thought that these capsids are too large to go through the nuclear pore, so they may dock in some fashion and only transmit their contents, probably using special signals that mimick one of the many other proteins and molecules that are regularly imported into the nucleus. That process is currently unknown, and may be another avenue of viral inhibition and drug development.

• We are all replicants.
• Carbon emissions not only keep going up, but up at an ever-increasing rate.
• Textbook regulatory capture. And in record time!
• Remember Bernie Madoff?
• China may be starting to wean off of coal .. or not.

Alexander Wilson, Ornithologist

Curiosity drove Wilson to study, describe, and paint birds- founding scientific ornithology in America.

What makes birds so compelling? Birding can be a matter of fanticism, with competitive list making, and expensive and arduous travels. They are both beautiful and talented, endowed with the magic of flight, which humans have only learned laboriously over the last century. They are cheerful and communicative, singing and chattering in notes we can relate to, if not understand. And they are extremely diverse, and turn out to be the successors of some of the charismatic animals of all time- the dinosaurs.

But in colonial times, birds were more appreciated for food than for watching. Countless wild birds ended up sold at market, one fate that sealed the doom of the passenger pigeon. Alexander Wilson (1766-1813) was no slouch in the hunting department, as a crack marksman who shot countless specimens, and dined on many of them. But for his time, he was also a pioneer in sensitivity towards birds, perhaps not surprising as ornothology was his second career choice, after poetry. A recent biography, though rather disorganized, is an excellent introduction to his work and times.

Wilson was a weaver and poet in Ireland, and then a schoolmaster in America, but finally found his calling when he came in contact with William Bartram, the leading naturalist of the newly minted US. Bartram was just the gentle, dedicated, and respected lover of nature that Wilson needed as a mentor. His gardens were extensive and his travels through much of the Southern countryside a model for Wilson's future years of tramping through all areas east of the Mississippi in search of birds ... and also customers.

One plate from Wilson's work. Note the phenomenal detail and realistic poses.

For publishing in Wilson's time was on the kickstarter model. The 9-volume American Ornithology was accepted by the publisher only on condition of Wilson collecting sufficient subscriptions to fund its production, which was lavish. Each volume had about nine plates, engraved and over-painted with color, in addition to Wilson's text describing the features and habits of the  pictured birds. Wilson therefore went on long trips to drum up interest and subscriptions, focusing on the wealthy elite of each region, who would be most likely to have the means to buy his expensive production. The subscribers would then receive copies of Wilson's columes as they came off the press in subsequent years.

Notably, Wilson had very little luck with the tight-fisted New Englanders. But he had much better luck at the President's House, paying a visit to Thomas Jefferson. Jefferson had himself published a guide to the birds of Virginia, and was keenly interested in Wilson's work and book. Indeed, he made his cabinet officers take out subscriptions as well! It was in a related vein that Jefferson later ordered the Lewis and Clark expedition to study the geography and biology of the vast Louisiana Purchase territory and points west to the Pacific. Imagine such intellectual depth and engagement in our current age!

Wilson's portrayal the the Pileated, Red-headed, and Ivory-billed woodpeckers.

Wilson studied as many of his specimens in their natural habitat as he could, and took many captive for further study. His detailed descriptions and paintings were, at their best, far more realistic and accurate than anything that had come before. He asked penetrating questions and resolved mysteries with detailed investigation, creating new species or uniting badly named and split species as needed. In his intense curiosity and willingness to pursue evidence and experiments he is reminiscent of that great naturalist to come, Charles Darwin. In one episode, Wilson wounded and captured an ivory-billed woodpecker, the largest woodpecker of all and a species now sadly extinct.

"Not far from Wilmington [North Carolina], he shot and killed two Ivory-billed woodpeckers and slightly wounded a third. With the two specimens in his pack, he wrapped the injured bird in his coat, placed it in front of him on the saddle where he could keep hold of it, and rode into Wilmington where he planned to spend the night. As he rode through the streets and up to the hotel, the piteous cries of the woodpecker attracted a worried crowd. They joined the landlord in a relieved laugh when Wilson dismounted and unfolded his coat, revealing the furious woodpecker. 

After he registered, Wilson took his pack and his woodpecker to his room, then left to tend his horse. Upon his return, ho could hear chopping sounds as he ascended the stairs to his room. He opened the door and the woodpecker cried out, possibly in frustration at being discovered in its effort to escape. It had climbed the window frame and cleared a fifteen inch square section of plaster that now lay in chunks on the bed. It had also cut a hole larger than a man's fist through the lathing and begun chiseling on the back side of the exterior weatherboards. In less than an hour it would have escaped."

Some birds are not the cheerful songsters around the yard, but ferocious and spirited. But whatever their temperament, between habitat destruction, rampant pesticide use and other pollution, light pollution, the introduction of invasive species, and now global warming, we have fewer species and individuals now than Wilson experienced, in a steady rain of ecological destruction.

• A culture of complete white collar impunity.
• Whatever happened to freedom of religion?
• Optimists are at fault!
• Why the east side is the bad side.
• Treason? Yes, it is obvious.
• Vietnam all over again.. a delusional military.
• Taxes affect income. They do not affect propensity to work.
• Do sleazy people make better capitalists and capitalism? No.

Blood Tests For Cancer

"Liquid biopsies" for cancer are coming to the clinic.

Cancer remains the winner in the war on cancer. New molecularly-driven precision treatments have improved outcomes for a few types of cancer, and the reduction in smoking has provided substantial improvements in death rates, but the overall statistics remain grim, most treatments are dreadful, and early detection is more a mirage than reality. One promising, though still experimental, area of progress is in detecting cancers using blood samples.

Cancer trends in the US, overall.

Early detection has been a holy grail, with enormous resources devoted to mammography and PSA tests, among much else, which have turned out to be of marginal utility, or far less than touted. I do not believe there is currently any cancer for which a reliable medical test of any kind provides detection before symptoms or manual / visible detection is possible. After the various reliable and unreliable methods of detection, assessment of cancers involves biopsy, which is far more invasive and disruptive than it sounds, piercing the putative site / organ with a large sampling needle which can cause permanent damage. Biopsy should be regarded as a full surgical procedure in its own right.

Both of these problems could be alleviated with effective blood tests for cancer presence, type, and progression. A significant development in the research field over the last decade or two has been the realization that cancers shed material constantly. Cells are sloughed off in live and dead form, and DNA from tumors is generally in circulation. One corollary is that metastasis is more a matter of these cells finding a congenial home than of their dispersal from their primary source. A second is that blood tests can detect these DNAs and cells on a routine basis.

The root method for doing so is PCR- that revolutionary method in molecular biology that harnesses DNA replication to amplify nucleic acids exponentially, allowing detection of infinitesimal amounts. One of the papers under review in this post claims that a single molecule of cancer cell DNA can be detected in 5 ml of blood. This is astonishing, but also puts bounds on the ultimate utility of this method, since they also say that less than half of grade 1 cancers provide even such a tiny signal. It turns out that, as one might expect, earlier and smaller cancers shed less material than later ones do.

Early stage cancers are hard to detect, but not impossible. The lowest Y-axis levels correspond to one molecule in the sample.

This landmark paper tests patients with many different types of cancer to evaluate the possibility of a relatively blood test for certain known cancer mutations. They find that brain cancers are particularly poorly represented- their shed materials are likely to be confined due to the blood-brain barrier system, plus the glymphatic system. But other cancers are quite amenable to blood testing, at least when in an advanced state. This would at least be a boon to recurrence tracking, and treatment monitoring, for which (repeated) biopsy is either impractical or impossible.

Which cancers give usable blood-born DNA samples?

"... 47% of patients with stage I cancers of any type had detectable ctDNA, whereas the fraction of patients with detectable ctDNA was 55, 69, and 82% for patients with stage II, III, and IV cancers, respectively."

For early screening, blood testing is not, as of this paper in 2014, truly reliable. On the other hand, it finds half of stage 1 cancers, which otherwise might not be found at all, raising the question of how such a cancer should diagnosed and found if a blood test finds, for example, that a common mutation (for example, in the gene TP53) is found to be afoot in a patient. Such mutations, which drive many different cancers, could come from virtually any organ. Some more sleuthing would be in order.

One such approach came up recently, in studies of regulatory markings on DNA, which some call "epigentic" marks. C nucleosides in DNA can be methylated and then derivitized from there to 5-hydroxymethyl 5-formyl, 5-carboxyl, and finally identified by the DNA repair pathway and excised / replaced. Typically, methylation is a repressive signal, part of the cellular machinery that turns off gene expression. In contrast, 5-hydroxymethy modified C residues seems to be associated with higher gene expression. At any rate, both modifications are dramatically reduced in cancer cells, and their patterns can be informative about the cancer's tissue of origin and prognosis/stage. There is even the possibility that the relative positions of 5-methyl-C and 5-hydroxymethyl-C in very small segments of DNA (detected by FRET, no less) could be informative on these issues, though that is more esoteric.

So far, these methods are plumbing the blood samples for specific DNA mutations in specific genes known to drive cancer, and thus have high specificity, but limited utility as general screening tools for patients who have not yet been diagnosed and could have any (or several) of thousands of different mutations. To do that, a far larger panel of genes needs to be assayed, possibly even whole genome sequencing, with an unbiased analysis of their mutations. But that begs the question of how to separate the cancer-derived DNA from all the other junk floating around in a blood sample. Methylation marks may be biased in cancer-derived DNA in useful ways, but they do not have categorically different characteristics usable for separating the wheat from the chaff. This is the big problem right now in cancer blood testing. On a practical level, it will start being used for already-diagnosed patients, to track their treatment and relapse. The cancer selection problem will likely be solved in a brute-force way by sequencing everything in the blood sample and sifting through that data using a growing catalog of cancer-causing mutations. But if some mark or characteristic can be found that is specific to cancer DNA, then general and convenient cancer screening via blood tests will come much sooner.

• Rules are for little people.
• Such as immigrants. Who are Christians, right?
• Does Amazon need to be split up?
• Go ahead and stretch ... every day.
• Skateboard therapy.
• More bullying and sleaze.
• Studies in groveling and sycophancy. What causes this temperament?
• Remember Martha Mitchell?
• The Taliban is winning.
• Meanwhile, Japan has a problem of not asking questions.
• Capitalism is so not working.
• Aretha on piano.
• In California, old-money landlords make out like bandits.

Was Jung an Atheist?

Short answer: yes. Understanding religion, and believing in it, are two different things.

Jung was highly sympathetic to religion- Christianity in particular- seeking to explain its psychology and origins, and even to replicate it. There is an old joke among Jungians. A child asks her Analyst parent.. are we Christians? And the parent answers: "heavens no, we are Jungians!" While Freud was a rather vociferous atheist, Jung took a much more ambiguous, understanding approach to religion. Rather than a pack of lies, it was a truth, just not about the cosmos. What makes Jungians distinct is their respect for the power and psychology of religion, which they are generally obsessed with, and devoted to understanding. They are more anthropologists of religion than disparagers.

It is common for god and religion in general to embody the psyche of its practitioners. Even atheists take god's name in vain, to express strong emotions. Intellectuals customarily make of god whatever most interests them. Einstein and Spinoza took god to be the universe. Jung took it to be the self. While religion touches on many archetypes and psychic complexes, the nexus around which it all revolves is the self. Am I saved? Will I live ever after? Am I good? Is anyone? What is the meaning of my life? Jung took these questions to be significant and deep, not just the superficial reflections of repressed sexuality. Indeed, his view of the unconscious was much more positive than Freud's, seeing it as a fount of deep insight and healing, whose therapeutic power is not just the exposure and extinguishing of childhood traumas and instinctive conflicts. The unconscious has its own perceptual apparatus and methods of communcation (symbols, images) which can be seen as an autonomous entity within ourselves. I.e. god.

This is why symbology and ritual are so much more important in religion than is theology. All the Western attempts to rationalize the concept of god are so much wasted effort, not only because they are intellectually bankrupt due to the non-existence of the cosmic god they posit. They operate on a typically intellectual level that is totally inappropriate to the subject at hand.

An image painted by Jung, from his Red Book. The unconscious holds dark shadows as well as  compassion.

God is indeed real and an autonomous thing, at the same time it is a psychological construct, arising from our own selves and depths. The psychological concepts that Jung fostered, about an immense and fertile unconscious, which partakes not only of individual concerns, but of communal and cosmic ones, represents a significant and irreversible step in our understanding of religion and its panoply of symbols, motivations, gods, and other artistic paraphernalia.

Late in his career, Jung offered an interpretation of the evolution of Christianity, in "Answer to Job". God, as the manifestation of Israel's unconscious longings and strivings, is in the Pentateuch a thin-skinned, and fickle tyrant. He is immature, and when Job calls him to moral account for the Trumpian way he has toyed with his devoted subject, all god can do is blow up in an insulting twitter-esque rage. This exchange raises to consciousness the primitive nature of the god-concept in this culture, and rankles for several hundred years, at which point the solution becomes to make a better man of god by making him (notionally) into a real man. So, Pinocchio-like, he comes to Earth as Jesus, does good deeds, expresses some compassion, (though unimaginable ego seeps through in the commands for followership and claims of overlordship), and then ritually offers his self-sacrifice to assure us that he has really changed his ways and is now meek as a lamb.

Another self-explanatory image from the Red Book.

Obviously, this made a pretty modest impression on Jews at the time and since. But the combination of monotheism and a quasi-charitable, egalitarian form of god, leavened by Greek gnosticism and other intellectual additions, spread like wildfire through a West enervated by the relentless brutality of Roman civilization, and its fractured spiritual resources.

Many gods have come and gone, as cultures evolve and elaborate new images of themselves and their ideals. While Jung dabbled in some mysticism along the way, and was frustratingly ambiguous and unscientific in his writings on the subject, he laid what we can take as a very trenchant foundation for understanding religion as a psychological phenomenon. In this he followed the lead of William James, who recognized that it is a special area, so heavily subjective that philosophy has little hold. Like other freelance religious practitioners, Jungian analysts today split their time between writing books of uplift and psychological insight, and listening to clients bring up their difficulties, whether shallow or deep. They provide spiritual solace to the lost, while trying to heal the larger culture by bringing to consciousness the powers, compassion, and insight that lie within.

• The planet is burning.
• Workers, citizens, unite!
• An emotion in every chord.
• How China beat the recession- classic Keynes.
• What makes unemployed farmers so much better than other unemployed people?
• And why is the Labor party giving up on labor?
• Resignation- an excellent precedent!
• A difference between just desserts and business models.

Where RNA Goes to Die

The exosome, which exorcises aged, defective, and short-lived RNAs, and also plays a part in maturation of ribosomal RNAs.

Much of the excitement in biology focuses on biosynthesis- the duplication of DNA, the growth of cells and organisms. But intrinsic to a dynamic, complex system like our cells are mechanisms to get rid of trash, which we produce in abundance. Trashy chemicals (like drugs and other complex toxins) are broken down by special enzymes in the liver. Old and broken-down proteins are sent to a cellular structure called the proteosome. And RNA also has a life cycle, which ends up at a small structure called the exosome.

RNA is intrinsically an unstable molecule, less chemically stable than DNA, which as archeologists, even paleotologists, have been finding, can survive for millions of years. But on a cellular time span, the spontaneous decay of RNA is hardly fast enough to provide critical regulation over key messages, which may need to be turned down in a matter of minutes. On the other hand, sometimes RNAs start out badly, with errors that jam up the translational machinery- there are several mechanisms in cells to figure out which RNAs should have short half-lives, are damaged, and are causing havoc, which generally send them to the exosome for degradation.

Human cells are full of RNA, much of it junk. By far the vast majority of RNA in a cell (90%) is ribosomal RNA and tRNA- the structural and functional cores of protein translation. Since translation is a rather slow and inefficient process, (as inherited from some extremely early ancestor), cells need tons of ribosomes, which typically make up a fair fraction of the dry mass of cells- up to 30% in bacteria. Exosomes are key processing centers that trim the ribsomal RNA and degrade excess bits. But other classes of cellular RNA are more diverse and interesting. Indeed, the encode project and similar projects have found that most of our genomes are transcribed to RNA. Some of these newly found RNAs are functional, but most is junk- junk RNA transcribed by a smart, but rather promiscuous transcription process, into junk RNA. Which does little harm if it gets sent right into the trash can.

A recent paper extended a lengthy trail of work into the structure of the exosome, reconstituting the full complexes from human and from yeast, and obtaining a new structure from the human form. Reconstitution means that the complex was not purified from cells or tissues as a whole, but that the individual proteins composing it were purified, here from bacterial cells or human cells carrying the encoding genes, and then later mixed to produce the full complex of about nine proteins.

Straight from the bench. Proteins are stained/displayed in blue, sorted by their molecular size by being electrophoresed (driven by an electric voltage) through a gel, from top to bottom. Smaller proteins (markers on left, marked in kilo Daltons) head toward the bottom. The middle lane is the yeast reconstituted exosome, the right lane is the human complex. The ten proteins of each complex are marked on the far right.

The complexes were then put into an electron microscope to get detailed pictures, which through the magic of superposition, averaging, and atomic modeling, can infer atomic-scale structures. The also created inactive mutatants of key proteins in the complexes, and then could add RNA to them to visualize where the RNA lies in the complex.

They found, as you can see, that the human and yeast complexes are very similar. The paths that the RNA takes within them is similar, but a bit longer in the human form, due to some accessory proteins like hMMP6, which protects a bit more of the RNA threaded through the middle from outside access. The active ribonucleases in all this are hRRP6, positioned towards the top right of the shown complexes, in red, and hDIS3, at the bottom in pink. hDIS3 is a processive RNAse, working from the 3' end to the 5' end and is also an endonuclease, meaning that it can cut in the middle of an RNA if necessary, while hRRP6 is less processive, and can nibble when needed. Also in the complex is a helicase (hMTR4) that can unwind double-standed RNAs, which is a frequent natural condition. One can see that these activities make up a directional machine, with RNAs getting fed into the top and consumed at the bottom (and side, if there is a second strand). The helicase opens the possibility of extracting jammed RNAs from polymerases and ribosomes, as though they were office printers. Enhancer RNAs, a recently-recognized class of junky RNA made at gene regulatory elements accumulates in hybrids to the enhancer DNA if not rapidly pulled off and degraded by exosomes.

Exosome structures from yeast (right) and human (left and middle). RNA is in black on right, and in schematic turquoise on left. The main digesting nuclease is at bottom in pink, while the unwinding helicase is in blue at top.

As mentioned above, chopping up RNA is not very chemically difficult. The hard part is controlling this process to separate the sheep from the goats. There is lots of good, even essential, RNA that needs to be kept around in the cell for as long as possible. All that ribosomal and rRNA is expensive to produce and should not be recycled until absolutely necessary. What regulates access to the exosome?

• Normal RNA processing prevents degradation. For example, as protein-coding mRNAs are made, they are spliced (introns removed) and polyadenylated and 5' O-methyl capped. The latter two processes protect them from degradation. Indeed, the length of the poly-A tail is in rough terms a timer for the livespan of that RNA, with longer tails on longer-lived mRNAs. Any problem in transcription and subsequent processing delays the addition of these markers and opens that RNA to attack by proteins that find uncapped and under-adenlyated RNAs and ferry them to exosomes.
• Exosomes are part of normal RNA processing in some cases. Ribosomal RNAs are trimmed by exosome versions, up to a point, where they are released and then modified and further processed into the pre-ribosomal structures, all in the nucleosome. The same goes for other small stable RNAs. Their mature structures are evidently stable enough to prevent excessive degradation. Special protein factors may facilitate this regulation as well, preventing, instead of encouraging, exosome activity beyond a certain point.
• Other special features of RNAs may be recognized by helper proteins that bring such RNAs to the exosome for degradation. For example, a complex called "PPC" recognizes short poly-A sequences, as would be common for timed-out normal mRNAs and many other RNA polymerase II transcripts that are not fully processed or stabilized by other means. It plays a big role in degrading lots of the junky RNA made from miscelleneous regions of the genome.

The cell is a sustainable chemical system, and part of that means having ways to dispose of trash. The exosome is the primary RNA disposal unit in eukaryotic cells, and has enabled the rather promiscuous transcription that has misled some people to think that we have far more genes or functional genetic elements than are actually there.

• Stories about abortion.
• What's it like to be a liberal Catholic?
• Our treatment of migrants is unlawful and cruel.
• Let's exempt Russia from sanctions.
• Denuclearize? Whoever said denuclearize?
• It's starting to feel like Georgian England around here.
• Should we have bailed out Lehman? No.
• Hey, who cares about the minus sign when you're talking about trillions of dollars?

The Quiet People

People who can focus, who invent and run today's technological world, who seek deeper insights and meanings, and who are introverted. Bad or good?

America is notoriously extroverted. A country of movers and shakers, networkers and gladhanders. We have a duty to be cheerful, competitive, and team-players. Everyone must sell, and the brand is one's self. Those who are quiet, introspective are not fit for this race, maybe damaged or not properly raised, losers. Middle and high school are generally where these tropes are pursued with greatest fervor, setting life-long patterns. Schools are "owned" by the popular students jocks, etc., who fulfill the partying and playing mantras of mindless youth. Later, workplaces are run likewise by extroverts, who come from sales and promote networking, "brainstorming" and open offices.

Who gets left out? Who cares? A landmark book on all this by Susan Cain, Quiet, came to the defense of introverts. Introverts are not antisocial. Quite the opposite- they are highly empathetic and value quality over quantity. They may not be the life of the party, but they are frequently the life-line of their best friend. They may not think on their feet so well, but think more deeply, if they are not constantly bothered. "Flow" is their métier. Introverts are not "wrong" or bad. Every species has them in large proportion- evolution has consistently tuned populations to benefit from the diversity of the adventurous and the careful, the brash and the thoughtful, each of whom contribute to survival and success, especially in our species.

Recent presidents offer instructive examples. Barack Obama is, by and large, an introvert. As president, he valued his quiet home life, studied briefing materials and pending issues carefully and deeply, and took time coming to decisions. He was notoriously uninterested in backslapping and entertaining with congressional delegations. He was cool, and a bit formal. Trump, on the other hand, has the attention span of a gnat, gets his briefing materials from FOX talk shows, and exhibits unparalleled aesthetic and intellectual shallowness. Which is the better presidential temperament?

Geeks have of late gained some recognition and cultural respect, through the computer industry, gaming, hacking, and the like. Even Big Bang Theory. But have schools become less frenetic and extrovert-oriented? Have workplaces dropped the open offices and the lets-have-a-meeting default setting for any problem? Do they pay introverts what they are worth? We have a very long way to go. The internet has had interesting and mixed effects. It has enabled telecommuting, a huge advance for those able to take advantage. It has also enabled thoughtful, self-paced learning and connection to others, not to mention anonymity for the shy. But the facebooks and twitters have turned these tools to a much darker place, with spewing ads, social competition for likes, and click-driven flaming, trolling, and bullying. It has been an object lesson in the limits of an extroverted philosophy of boundless connection.

This is a case where we can really all get along, given a little understanding, however. Yes, introverts need to work a bit on connecting with others, depending on their needs and capacities. But they also deserve a world that does not devalue them with unthinking prejudice and structures of social torture.

• Competition isn't everything.
• Malthus and the decline of empires.
• Apartheid as a solution for democracy.
• What is wrong with us? Revenge against meritocracy and decency.
• Wage growth is rather uneven.
• The state of antitrust.
• Full employment is a worthy, critical goal. UBI may keep people off the streets, but jobs give them (and us) dignity.
• Is there no decency left in this Republican party?
• Trump and Russia go way back.

The Water is Wide

Proper molecular dynamics simulations require lots of water.

What is hydrophobicity? We know it as the separation of oil and water. But what underpins the phenomenon is not any problem of oil, but peculiarities of water, which is a polar solvent. The hydrogen and oxygen comprising water have very different electronegativities, which produce a highly polar compound with partial charge separation across the H-O bond. The electrostatic attraction between these tiny charges leads water to have a networked structure with lots of attractive forces between molecules. This keeps water in a liquid state at far higher temperatures than other liquids of similar molecular mass (think of liquid nitrogen). This hydrogen bonding network also makes of water a sort of clique that expels those uncool molecules that can't hook up in the same way and participate in the bonded network. That is why oil ends up the odd droplet out, forced to stand aside while all the water molecules madly pair up and network, handing out their business cards.

Polar water forms a network that repels non-polar molecules.

These forces are crucial to protein structure and function as well. Typically, proteins that swim in the water-based cytoplasm fold with a zone of hydrophobicity on the inside, and a shell of electrically polar groups that can interact with water on the outside. One of the best known proteins is hemoglobin, which not only follows this rule, but also has an intricate mechanism of cooperativity that depends on hydrophobic interactions.

Proteins generally organize themselves with hydrophobic cores and hydrophilic exteriors.

Hemoglobin doesn't just float about by itself, but forms a tetrameric complex that cooperates in binding oxygen. When one oxygen binds to one of the four units, the other units gain affinity and bind oxygen much faster. Conversely, when carbon dioxide builds up and drives peripheral pH down, (more acidic), it drives the structure to lose affinity for oxygen, and the rest of the oxygens leave faster as well. This helps our blood efficiently unload O2 in the tissues while taking it up in the lungs. The differences between these structures (with high or low affinity for oxygen) are well known, but their detailed transitions (called allosteric, being structural changes induced by outside compounds) are not quite understood, as the structural techniques for which hemoglobin and its relatives have been pioneer molecules (principally X-ray crystallography) yield only static pictures.

Full tetramer of hemoglobin shifts between oxygen-bound and not-bound states. This structural shift has functional consequences for cooperative binding, increasing oxygen affinity once one O2 binds.

This where molecular dynamics come in. This is an entirely computational method that uses first principles of statistical mechanics and chemistry to model how a structure (known from other methods) changes with time, as it is buffeted by ambient motions of temprature, i.e. Brownian (or Einsteinian) motion. A recent paper resolved a decades-long difficulty in this field by finding that the allosteric transitions of hemoglobin are deeply intwined with hydrophobic / electronic aspects of its environment which can not be properly modeled by the standard few waters sprinkled around the structure, but need a much wider swath of solvent to become apparent. The precise issue is the spontaneous transition between these structures (the base state being called "T0" and the oxygen-accommodating state being called "R0") in the absence of oxygen. The T0 state is known to be more stable and the R0 -> T0 transition happens in 20 microseconds. But in simulations done to date, the R0 state is more stable, and the transition never happened. What was wrong?

Box sizes from cited article, showing how many or few waters are involved.

Why is the standard practice to use so few waters? They move a lot, and there are a lot of them, making it very computationally draining to add to a molecular dynamics simulation. For instance, the authors cite that their small 75 Å box contains 39,439 atoms in all, while their largest 150 Å box contains 318,911 atoms, an almost order of magnitude increase. The small box, which contains the full hemoglobin tetramer plus 10,763 water molecules is unable to simulate the conformational shift that is so well known to happen, while the larger ones are. The message from the paper is that if the waters surrounding the hemoglobin protein are not occupied by their wider network of hydrogen bonding interactions extending out into the bulk medium, then (in the simulations with small boxes) those waters tend to attack critical structural elements of the protein, at its ionic and polar self-interactions, creating a mistaken impression of instability for the T0 conformation, and generally of hemoglobin's structural dynamics. Obviously this has general implications for the molecular simulation method, which presumably can be fixed by the addition of more computers.

Idle waters do the devil's work! Right box is without hemoglobin, while the left box is with. The curves represent numbers of hydrogen bonds by waters, (X-axis), which are sharply reduced in small box sizes. Those waters then go on to pester the protein and destabilize it.

• Who is emitting carbon?
• Go, Pussy Riot.
• Political money goes darker.
• A Russian intelligence asset is president- what is Congress doing?
• Islam is still rather hate-filled.

Gone watching...

Apologies.. the press of world cup watching has put this week's post on hold; links only.

Cristiano Ronaldo boots the perfect free kick.

 

• Krugman on the job guarantee.
• Jobs? We are muddling along.
• And now, toady on the court.
• Endless hypocrisy and meanness and corruption.
• When will this person be impeached?
• Stress test failure is no problem!
• Dogs, copper, and genetics.
• Organic chemistry.. not so difficult!
• Posh people and the poor.