Another Eukaryotic Gene Regulator Turns up in Archaea

Leucine zipper proteins as gene regulators in Archaea, regulated by nutrient-binding PAS domains.

In this day of AI, it is a pleasure to read an elegantly constructed and written paper that breaks new ground in biology. A group in Berkeley has discovered that a common gene regulatory family in eukaryotes, the leucine zipper proteins, have clear antecedents that were impossible to detect with pure sequence comparisons, but which turned up during their work on the nutritional regulation in archaeal methanogens. They note that archaea are now well-known to be the progenitors of the nucleus and nuclear functions of eukaryotes, (as well as translation, the cytoskeleton and much else), but that there has been a shortage of known regulators to account for the complex lifestyles of archaeal cells, particularly these methanogens.

Methanogens, as one might guess, give off methane, creating small amounts of the natural gas we take to be a mineral resource. For them, methane is an electron dump, (instead of oxygen, as it is for us), from food sources such as methanol, methylamine, and many other methylated compounds, which are slightly digested to form CO2 and methane. Methanogens are anaerobic, meaning they are poisoned by oxygen and originated from the early epochs of earth history before there was much free oxygen. It is naturally critically important for these organisms to know what kind of food is out there, since digestion of methylamine calls for different enzymes than the digestion of methanol. The authors thus had the hypothesis that there should be some regulatory apparatus for sensing methylamine (in this case) and activating the right genes to digest it. 

These authors performed a laborious laboratory evolution experiment, looking for mutant bacteria which were able to switch between food sources faster than the wild type Methanosarcina acetivorans, which take about four days to switch from methanol to trimethylamine. There were replicate populations, repeated passages of these slow-growing bacteria to new cultures with different food sources, (all under anaerobic conditions), and sequencing of the resulting strains. And then CRISPER-based specific mutagenesis to confirm the mutations that caused the phenotype of more rapid food switching. In the end, they obtained strains that took only 17 hours to switch food sources- much faster than the wild-type. The most common gene that was mutated was MA2561, which is a repressor of a methyltransferase specific to trimethylamine. These mutations disable the repressor and allow this gene to be expressed all the time, which would be expensive for the archaea in the wild, but in the lab, dramatically shortens the time needed to acclimate to the new food source. They renamed this gene amzR, for amazing regulator!, er, actually ... "archaeal metabolite-sensing zipper-like regulator".

The interesting thing is that this regulator and its family had not been recognized in archaea or in this species previously, even with all the computational power available to find homologs of any kind of protein. But once it was found by this functional screen, and the authors paid some attention to it, and put it through the alpha-fold program, then everything became clear. It is structurally similar to a large family of eukaryotic DNA-binding gene regulators called leucine zipper or b-zip proteins. This is because they contain a dimer of stiff alpha helices that wind around each other (using hydrophobic leucines at key contact positions) and make a scissor-like fork whose (basic) end binds to DNA. 

Comparison of leucine zipper structures. The authors provide an overview of structures. A is a garden-variety eukarotic b-zip protein, (GCN4), a regulator of amino acid biosynthetic genes. B is a more complex basic semi-zipper protein that combines DNA binding with PAS domains that are, in this case, sensors for oxygen levels, with significant psychiatric implications. C shows the newly found amzR repressor, in full dimeric mode with its PAS and GAF domains, which appear to sense trimethylamine. Lastly, D shows a helix-turn-helix DNA regulator that is characteristic of bacteria, though common in archaea and eukaryotes as well.

In addition, amzR has a couple of other domains- a PAS domain and a GAF domain, which are similar to each other, and are common motifs that bind small molecules, in this case likely the trimethylamine that causes the whole chain of events. The authors show that amzR binds DNA, that it represses the MT1 gene that allows growth in trimethylamine, and that it binds to trimethylamine itself, which impairs DNA-binding, presumably through structural shifts in dimerization or the orientation of the dimer. Thus, it is what is quite common in archaea and bacteria- the one-component-regulator which both senses and effectuates some kind of control in response to environmental conditions. 

A somewhat indirect, but effective, demonstration of ligand binding. The amzR protein melts at high temperature, here tracked by its fluorescence. The melting temperature shifts significantly upward if a (presumably stabilizing) ligand is offered to bind. NS = no substrate; MMA = monomethylamine; DMA = dimethylamine; TMA = trimethylamine.

They also find, using the new sequence, that direct homologs of amzR are common among methanogen archaea, and speculate that more distant relatives may account for some fair portion of the missing regulatory capacity that was remarked upon above. Unfortunately, given the inability of sequence comparisons alone to find these homologs, given the deep divergence in time among all these organisms, it remains difficult to speculate just how widespread this regulatory motif is in methanogens, or in archaea generally. But this work gives some hope that other whole families of regulators remain to be found, filling out what is obviously a complex regulatory apparatus in these organisms. Alpha-fold and other AI tools will likely be helpful in that quest.

The authors offer a basic model of control, where amzR (aka MA2561) binds to and represses the multi-gene operons controlling trimethylamine digesting methyltransferases among others. The inducing chemical, TMA, binds to and inactivates this repressor, turning on the operons.

• Thoughts on retirement savings. But honestly, we could blame the trillionaires and billionaires as well.

Towards bourgeois liberalization

China 3: Xi Zhongxun and the transformation of communism.

To add to my China theme, another outstanding biography that came out recently was Joseph Torigian's "The Party's Interests Come First", about Xi Zhongxun (pronounced She jong-shuhn). This book is, in style, quite a bit drier than the memoir by Chang Kuo-t'ao, but drama still seeps out. Of course, Xi Zhongxun is the father of Xi Jinping. But he had a tumultuous political career himself, purged twice, rehabilitated once, and working at the highest levels of the Communist state structure. He was another cadre with unshakable dedication to the revolution, almost Job-like in his faith and tribulations. The book has a chapter or two about Jinping, but mostly, it stays focused on the father.

Xi was a politician through and through. A personable and loquacious glad hander, he made friends easily. In the grand scheme of PRC politics, he tended to be on the "right" side, meaning the less doctrinaire, less controlling side of things, compared the hard-line "leftist" communists who pushed for collectivization, assimilation of ethnic groups, strict economic control, and, ultimately, cultural revolution. He attained political office very early, and tended to be the youngest of his leadership groups, up until his first purge, around 1963. 

As head of the Northwest bureau in the nascent PRC, Xi was a driving force behind the cultivation / co-optation of the Panchen Lama as a counterweight to the Dalai Lama, who so perfidiously fled the Communist embrace of Tibet. But by 1952, Xi was called to the central government, to help Mao play various political games in balancing other leaders like Deng Xiaoping. It was a difficult life, divining where the political wind was blowing, which is to say, always knowing Mao's shifting mood. China under the PRC has had, despite the formal succession of party leaders, essentially three emperors or paramount leaders: Mao, then Deng, and now Xi Jinping. Xi Zhongxun spent a good deal of his time refining (or setting up from scratch) the state's legal structures, to smooth governance despite the lack of clear legal / constitutional structure at the top. Unfortunately, due to a mishap of miscommunication, Xi approved publication of what amounted to a dissident novel, (Liu Zhidan)- which is to say, one that revealed various unpleasant truths about early communist history- by a real firecracker of an author. It was a decision that really hit the fan, and Xi was purged, as one of the opening moves of the Cultural Revolution, spending over a decade in exile, sometimes imprisoned in solitary confinement, sometimes sent to factory work in the hinterlands. His family was also punished, with Xi Jinping denied countless opportunities and abused by his friends and teachers. 

Xi Zhongxun in 1967, being humiliated as part of the cultural revolution, for being a rightist.

When he returned to the good graces of the Party, that is, of Deng Xiaoping, in 1978, he was assigned as governor of Guandong province, in the South. It is hard to over-emphasize the momentous effects and after-effects of the cultural revolution. True, the Chinese communists didn't murder their colleagues in Stalin's cold-blooded and wanton fashion. But just as the Kruschev era was a post-traumatic reckoning, so were the decades after Mao's death, when the first and foremost goal of the Party and its members was to never repeat the awful destruction, cruelty and chaos of the cultural revolution. One might say that the old cadres mellowed with age, going from the rabid enthusiasm of youth (egged on by Mao) to a more benevolent model of emperorship. The reaction accelerated economic opening, and one of the leading areas was Guangdong, which contains the vast Pearl river bay, host to Hong Kong on one side, Macau on the other, and Guangzhou at its head. 

A growing problem in the 70's, as Xi took over, was the flight of workers in Guangdong to Hong Kong. The book paints the fascinating contrast with East Germany, whose solution to fleeing workers was to build a wall and man it with dogs and machine guns. East Germany had put out an appeal to China, back during the famines associated with the Great Leap forward, for butter, so that its people would be less antsy. That did not fall on sympathetic ears. Nor did Xi follow East Germany's playbook in this instance. His solution, backed by the central government, was to foster economic growth, using special economic zones to pioneer the general economic opening of China, into what one might call its novel form of Leninist capitalism. These policies (with due respect to the Western economic models and technologies they are based on) were stunningly successful. A little freedom can do wonders!

But then came even more opening. Gorbachev was letting things go in the Soviet Union and the Eastern Bloc, and the flowers of dissent were blooming in China as well. Xi was in the central government by this time (the 80's), part of the sub-echelon that was not the CCP central committee, but among its immediate sub-organizations, including the parliament, which implemented the central committee's policies. 1989 brought the acceleration of these opening trends, culminating in the events of Tienanmen Square. Xi Zhongxun was very much on the rightist side here, urging dialog and adjustment to form a more open China. But while debates were raging among the leadership about what to do about the unruly students, (with the label "bourgeois liberalization" being applied to those favoring more Western-style mechanisms of government), Deng Xioping was moving as head of the military to quash the protests and save the system. He could see that this opening was going in an existential direction, and would spell the death of the one-party state, as it did in the Soviet Union two years later. 

Xi was not sent down to factory work, imprisonment, or public humiliation and "struggle sessions", but he was exiled again from Beijing, confined to Guandong for almost a decade before being allowed near the capitol. Deng himself had to unfreeze the Party a bit by making his "Southern Tour" in 1992 to re-assert the intention to open economically, while still repressing politically.

What really struck me about this whole story was the persistence of politics and its polarization in different systems. Just as we have our right and left poles, So has China had a range different views over its peculiar right-left spectrum, which reflects natural variation in people's temperaments, but also the natural process of politics by which we negotiate a middle ground given the ancient cultural patterns, and the overlaid political institutions and transient personalities. The big difference is the nature of control and rejuvenation of the PRC political system. Where we in the US have regular elections and turnover of political personnel, Communist China has never developed a formal and regular mechanism to transfer power. Nor is its power accountable to the people, again in any formal, regular way.

There are 100 million members of the party, not to mention rigorous surveillance of the internet and all other modes of communication, so it certainly has its ear to the ground. But it also plies its population with relentless propaganda and curated news, and prohibits free speech in the political arena. Its governance amounts to a series of grand bargains- economic prosperity and relative freedom for political control; a single party state in exchange for relative long-term stability and rule by well-vetted, competent officials. While Western democracies are always on the political low boil, China's political system seems more pressurized. Modern technologies may allow such a pressure cooker to deliver good results, but if it blows, it is prone to dramatic results. The lack of a succession mechanism is particularly problematic, injecting uncertainty into everything, as exemplified by China's extremely high savings rates. Xi Jinping has blown through the weak succession mechanisms that had been in place, and what succeeds him is a great unknown- whether a lesser technocrat, or a great whirlwind. Xi Jinping thought, his intellectual legacy, (or, "Xi Jinping Thought on Socialism with Chinese Characteristics for a New Era"), boils down to two propositions: The communist party shall be in charge of China, and second, Xi Jinping shall be in charge of the Chinese Communist Party. The legacy of Xi Zhongxun, however, points to some hope that at the crucial juncture, some might favor a more open and legalistic path.

• A rare mutation, and lethal anesthesia.

At the Birth of Chinese Communism

China 2: Review of the autobiography of Chang Kuo-t'ao

Before the Chinese Communism was overtaken by Mao, and then the cult of Mao, it was an idealistic glimmer, and stepchild to the world-wide revolution fostered by Soviet Russia. It was founded by students disgusted with the weakness of Qing China and inspired, as were so many others, by the supposedly progressive, modernizing, and anti-imperialistic movement communism was taken to be at this time. Chang Kuo-t'ao (now translated as Zhang Guotao) was generally second-in-command of the Chinese Communist party from its founding through the first united front with the Kuomintang, until differences with Mao forced him out. Ultimately he settled in Canada, and wrote what I have to say is a scintillating memoir of those early days, rich in detail and well-written. He even translated it into English largely himself. He was clearly a formidable intellect, having risen to prominence originally as one of the main student leaders of the May 4th movement. It is astonishing, really, that this significant book is out of print.

He takes it as given that the progressive causes we all hold dear- labor rights, national sovereignty for countries such as China (against colonial powers and interlopers like Japan and Britain), economic fairness, and democracy (in a manner of speaking) would be served by communism. He strives through these pages to take leadership of labor unions and labor associations, and thereby build the political capital that will lead to the worker revolution. To bind together all the oppressed workers of China- the railway workers, factory workers, the foundry workers, into the Marx-prescribed conscious worker class that takes over the state and bring the next dispensation.

But early on, he travels to Russia right after its civil war, to attend a "Toilers of the East" conference of the Comintern, (surely an inspiration for Newspeak), and it is a decidedly jarring experience. The conditions are unbelievably primitive, the people are suffering, and the hand of the state is not so benevolent. Later, during the days of the NEP, conditions improve, and Chang can look on Russia with a bit more admiration. But here, now, it is a mess. He also meets Lenin during this trip, remarking immediately on his intelligence and approachability, in contrast to most of the others he is seeing. Unfortunately, the Comintern officials sent by Russia to baby-sit the Chinese Communist Party (CCP) are a series of abrasive or scheming characters, often out more for the interests of Russia than those of China or even the CCP. But since the Comintern was providing much of their funding, it got to have a lot of say as well. 

Mao Zedong also attended the inaugural conference of the CCP, but Chang characterizes him as a country bumpkin, and this first volume of his memoir hardly mentions Mao further at all. That comes in volume 2, which this review does not cover. The major issues of the time were- how to grow the organization in the teeth of almost universal opposition by the conservative and economic elites, leading frequently to police attacks and imprisonment? This warlord epoch had a silver lining, however in its diversity- the rulers in Beijing tended to be more conservative, but those in Shanghai and Guandong were more sympathetic and lenient. The second issue was whether and how to align with the Kuomintang- the main nationalist party under Sun Yat Sen, who had been staging revolts against the Qing for decades, and was the first president (however briefly) of the Republic of China.

Chang does not say a great deal about the growth issue, except to say that he led the party's efforts to organize worker's unions and bind them into larger national associations. This led to exponential growth over the middle 1920's, where each successive year's conference would have ten-fold more participants. He has a great deal more to say about relations with the Kuomintang- the so-called united front. From Sun Yat Sen's perspective, the more the merrier. The communists were, while he was alive, a minor, activist, and intellectual element in his coalition. Critically, it was also a politically visionary and progressive element. While the Kuomintang had largely lost its political reason for existence with the fall of the Qing, and was becoming a party of everyone against Japan, the communists had a much more activist and forward-thinking political program. A program that was specifically strong enough to enforce dominance over their military efforts. No communist general ever became a rogue warlord.

On the other hand, for the communists, alliance with the Kuomintang was existential. The Russian advisors constantly urged them to formally become Kuomintang members. To mix in, and eventually become so strong as to take over the whole organization. But Chang was always opposed and reluctant. Serving two masters was no way to keep the purity of the communist faith. And one could easily foresee that the stronger the communists became, the more friction would enter into the relationship, and the more resistance would come from conservative elements of the Kuomintang, of which there were many. That is certainly how it turned out. The communists were purged twice over- once in the 1927, and again after the two parties allied during World War 2 to drive out the Japanese.

What struck me most about this whole story was the importance of a strong political program. The warlord periods and actors in Chinese history are characterized by elite competition in the baldest terms. Warlord A is based in one region and has a local base of the armies and elites of his region. warlord B has the same elsewhere. Whoever is the cannier general, or more scheming maneuverer among various corruptible officials and generals, wins the prize and claims the mandate of heaven. But suppose that one of these generals has a truly popular political program of systematically freeing the peasants of their age-old chains. That would be an entirely different proposition, and brings a whole new level of political power to bear, both internally and externally.

Comparison with the Americal Revolution is instructive. The Americans had a relatively coherent political program- freedom from the English yoke, and a dedication to doing self-goverment even better than the English, with enlightened institutions and enunciated, limited, powers. The political dominance over their military instruments was absolute. George Washington spent the whole war complaining and wheedling the Continental Congress for more of everything, but he never entertained the thought of taking over the revolution, like a prefigured Napoleon or Chiang Kai-shek. 

Conversely, the example of "our side" in Vietnam. The Southern government offered a political program of corruption, landlord-ism, anti-Buddhism, and alliance with the imperialist foreigners. That was not a winning formula!

So far, so good. But what was the nature of the communist political program? This was in the end, another imperialist import from the West, a particularly poisoned chalice. Chang writes frequently of organizing and taking control of other organizations such as unions and union federations, as though it was the most natural thing in the world. Democracy is confined, at best, to the communist central committee, which votes on various important topics. But cultivation of true democracy, mild governance, and respect for the base of their party? There isn't much of that at all. Far more attention is devoted to the propaganda department, as the modern way to generate political support. The "dictatorship of the proletariat" is never defined, never expanded into model of governance, but left as a slogan, to be wielded by the most ruthless among the communist leadership to mean alot of dictatorship and not much proletariat. 

Chang describes his own regrets as follows:

"And I, so enthusiastic then about the Communist ideal and one of the founders of the movement, who for eighteen years was to labor as a coolie in its service under terrible difficulties, could never have believed that I would have no choice but to leave this CCP after it had been poisoned by Stalin and Mao Tse-tung. 

How could there have been such fantastic developments? Readers will find the answer in the narrative that follows. Generally speaking, when a small number of people launch an armed insurrection, a revolution of force that leads to the establishment of this or that brand of revolutionary state power and practices dictatorial rule, they must eventually abandon their idealistic principles and righteous beliefs of their early period and replace them with concepts of power, treachery and plotting, terror and cruelty, etc. The Communist movement is inseparably linked with the proletarian dictatorship; and so the Communist system of dictatorship must produce such despots as Stalin and Mao Tse-tung. Saying that they poisoned the CCP is tantamount to saying that the ugly realities of dictatorship have buried the beautiful future perspective of communism. The major inherent lesson is that the CCP has suffered from the incurable disease of dictatorship."

Both the Soviet Union and China, as communist dictatorships, also ended up wielding an imperialist sword over their near-abroad, imposing immense suffering on subject peoples and ethnic groups. A deep irony for movements that were fundamentally anti-imperialist in their origins and rhetoric. Chang was clearly caught up in the intellectual currents and enthusiasms of his day, which to us seem almost inexplicable, and do not compare well with better eras of the enlightenment.

An Alternative Vision of China, Past and Future

An appreciation of Chen Jiongming.

China has had a tumultuous and sad history over the last couple of centuries. There was humiliation at the hands of colonial powers, then partial occupation by Japan, followed by Communist revolution, civil war, famine, cultural revolution, and finally its re-adoption of capitalism and rise to immense commercial power, under an autocratic political system. One ray of hope was the first republic, founded in 1912 as the Qing dynasty was overthrown. This was inspired by and initially run by Sun Yat Sen, though he soon bowed out in favor of the warlord Yuan Shikai. Sadly, this republic was just a brief phase in a larger warlord period where competing armies all over China tried to out-maneuver the others. Ultimately, Sun Yat Sen's "nationalist" movement came back to power after his death in 1926 under the leadership of Chiang Kai-shek, who turned out to be little more than another warlord after jettisoning the major principle of democracy from the "Nationalist" platform. 

Well, one leader during this time who paid a bit more attention to the political foundations of China's future was Chen Jiongming. He was part of the great student movement of progressive ideas in the early 1900's, exemplified by the May Fourth movement, the massive student-led revulsion at the sell-outs of China's interests by the Versailles treaty ending World War 1. He was elected to the Guangdong provincial assembly in 1909, and after one abortive attempt at revolution in service to the coming republic, was elected commander of and army based in Hong Kong and aimed to taking over Guangdong province. This he finally did successfully in late 1911. He eventually became the local governor, where he led a brilliant administration devoted to restoring the peace, building the economy, and putting progressive ideals into practice, such as women's political rights. 

After several reverses, particularly after Yuan Shikai clarified his intention to become emperor, Chen was put at the head of another army, which gained control over southern Fujian, next door to Guangdong, in 1918. The next four years would see him take over Guangdong again, and again put in place an efficient and progressive administration. Chen's main principle during this time was federalism, the idea that it would be best to nurture democracy and modernization in single provinces or small areas like Guangdong, rather than devoting all efforts, (as Sun Yat Sen was doing), to take over all of China. The warlord competition was one that seemed to corrupt its participants. When winning is the only goal, other principles get sacrificed, if there were any there to begin with. Few of the warlords had strong political ideals or any kind of progressive basis at all, other than winning. Already Yuan Shikai had shown himself to be afflicted by that virus, and Chiang Kai-shek would take the Nationalists more or less down the same road, after they had indeed conquered all of China and then faced the Japanese and Communists in succession.

Chen Jiongming

Chen was clearly going in a different direction, hoping that successful government and modernization in one area could lead more peacefully and gradually to the similar liberation of other areas. Rather than sacrificing all for power, he wanted to put good government first and stay on the military defensive while tending to an area that is perhaps the premier commercial area of China, which would later lead the way to the PRC's curious blend of capitalism and communism, and whose delta hosts Hong Kong, Macau, and Guangzhou (aka Canton). 

The problem in China, in this and other epochs, is that there are few natural barriers that, in the parlance of biology, foster speciation in geographic isolation. It is too easy to invade other areas, and very difficult to differentiate, grow, and succeed before one's riches are plundered by someone else. The zero-sum logic of warlordism is rampant, and all the people can do is to wait for one of them to win, and hope the winner can be turned to more or less benevolent directions. Chiang Kai-shek and the Nationalists were far from benevolent or competent when their turn came, and their system collapsed in the face of a true peasant revolution (finally, an understandable and broadly appealing political basis, however fleeting) led by Mao Zedong. But that regime turned out to be far, far from benevolent in its turn, and only much later turned its attention to making life better for the Chinese, who are now trapped in an economically growing autocracy, whose leaders are petrified that the people will someday turn on them and recover their natural rights.

It is interesting to note that the Tiananmen square incident happened just as Taiwan was, after a long authoritarian phase of its own, establishing truly functional democratic institutions. Deng Xiaoping, however, crushed the protesters and nascent liberalization in the PRC. Two paths were diverging. Each avoided chaos, but which was the better one?

Perhaps Sun Yat Sen was right to dismiss federalism as a pipe dream in China, given the long history and the political situation at the time. Perhaps it was either eat or be eaten, on this vast and bloody stage. But it is fascinating to consider that an alternate road was in the offing- one that promised far less bloodshed, far less suffering, and a far more civilized outcome.

• Whence Taiwan?
• Can we sue the oil industry into oblivion?
• Or not.. 
• Art with power.

Towards a More Perfect Genome

The human reference genome is still evolving and improving. 

The original human genome, when issued to great fanfare in 2000, was an incomplete draft, covering only 92% of the sequence. It caught the most important parts, surely- most of the protein-coding genes- but sequencing technology was not up to the task of doing a complete job. To understand why, imagine the genome as a jigsaw puzzle. The number of pieces corresponds to the sequencing technology- the number of consecutive nucleotides (nt) that can read from the genome at one go. The dominant technology then (and still now) is short read sequencing, which reads about 200 nt at a time, from a randomly sheared up pile of DNA from the genome. Perhaps 300 or 400 if lucky. This means that the 3 billion nucleotide genome is chunked into ~15 million pieces, and that our one-foot jigsaw puzzle has 4,000 pieces per side, each one about 0.08 mm on a side. That is very small. Imagine trying to put together a puzzle like that! Computers are helpful, but they can only do so much.

And like a really hard jigsaw puzzle, our genome has large areas of uniform color- those sky-blue regions and large clouds. Those are the repetitive sequences, which, all together, make up about half of the genome. These are mostly defunct transposons, but also pure repetitive DNA that makes up structural features like centromeres and telomeres. For instance, the sequence GAATGn (where "n" stands for any nucleotide), goes on repetitively for 28 million nucleotides on chromosome 9. That is not an easy puzzle to solve, using tiny sequence reads, no matter how much computer power you have.

A map of some of the repetitive areas of the genome, focusing on centromeres. Panel A gives a color code for different kinds of repetitive sequence. Panel C gives compositions of the centromere of each chromosome, which are highly variable and different in length as well. Centromeres are underlain by piles of genomic junk, really, with a few key functional sequences.

So the original project did what it could and released the draft, which was both a huge accomplishment and a large boon to biology ever since. This draft has been patched up several times with improvements. In 2022, finally, a complete genome emerged, which advertised itself as end-to-end, or "T2T", for telomere to telomere. This genome still has a gap on the Y chromosome, which is a degenerate mess. But otherwise, it fills in all gaps, brings in a hundred more protein-coding genes, two thousand other genes, and fixes innumerable other sequencing errors. What got us to this point?

The new technology was long-read sequencing, which is an amazing advance based on threading a single DNA molecule through a tiny pore (a nanopore, which is actually a bacterial protein). You can read the electrical resistance as each base passes through. Each base is ever-so-slightly different electrically, making it possible to figure out the sequence, step-by-step. These methods have been refined to the point that they can read 100,000 nucleotides routinely, and even attain four million nucleotides at a single go. That is revolutionary for closing difficult, repetitive genome gaps.

Reading sequence, sequentially, as it passes through a tiny pore.

This long-read nanopore sequencing also benefits from using relatively unprocessed, native molecules (not extensively amplified/copied) helps to reduce errors, though this method has its own error problems, mostly due to the fact that taking electrical readings off the pore is extremely sensitive and tricky. It is also hard to scale up, mostly due to the slow process of threading DNA through those pores, so long-read sequencing has not challenged the huge bulk sequencers for lowest-cost or greatest scale. But when you have to finish a sequence, one that is problematic, with low complexity, long-read sequencing is perfect. 

Lastly, what is all that junk DNA doing in our genomes? Mostly, it is honest-to-goodness junk, just carried along out of inertia and lack of selective attention (though there is the story of piRNAs). Transposons can occasionally re-activate and create new mutations, but there are way too many of them to get rid of. They also can gain significant functions, giving rise to new, functional genes and regulatory controls over other genes. So they are a sort of a junk heap / pick-n-pull that can be very useful from time to time. The satellite sequences in the image above are concentrated in structural areas like the centromere, where they do not have classical "gene" type functions, but facilitate equally important processes like genome division and distribution to new cells. 

Unfortunately, as we learned from the draft genome, it is not a holy grail full of secrets that will, of themselves, solve our medical mysteries and confer immortality. Its use is as an armature on which we can hang the accumulating knowledge of biology. Each nucleotide in the genome has its own story, of how it got there, what processes it plays in, and how it can affect our health and happiness. The system built upon the sequence is far more involved and interesting than just the sequence.

• More on taxes and inequality.
• Who is Mr. Kremlev?

Origins of The Trumpocene: Something in the Air?

I have a theory about our predicament.

How did we get here? With a madman as president, a cabinet of incompetants and sycophants, a supine legislature barely able to keep the lights on, and a dominant block of voters that see nothing wrong with it? This president has, for no discernable reason, decided to wage a trade war against basically the entire world, with special emphasis on our closest friend, Canada. This president launched an idiotic war against Iran that has destroyed our military and diplomatic status, and isn't doing much for our economy either. This president has launched vendettas against anyone with brains, such as colleges, medical researchers, military, diplomatic and intelligence professionals. And this president has made past corruption scandals look like penny ante with shameless shakedowns, pump-and-dumps, and quid-pro-quos reaching into the billions.

It's not good, and stands at the end of a political tradition with far higher accomplishments. We used to expect complete sentences, coherent thoughts, and reasoned policies. All that is now out the window. The civil war era and the revolutionary era were both characterized by excellent, sometimes great writing, lengthy and reasoned debates, and careful argument. Just think of the Federalist papers, the Lincoln-Douglas debates, and other works of Abraham Lincoln. Even into the end of the 20th century, we accomplished great things, and had elevated goals, such as fostering a world-leading research enterprise, and addressing poverty. 

Today, politics revolves around zingers and memes, and we can hardly hold things together while our madman in chief burns down one institution after another. But therein lies a clue- what is in the air? What is making us crazy? As we pass the September 11 anniversary, we recall, inter alia, the devastating effects of pollution around ground zero. Among its many health effects are cognitive impairment and dementia. There is a large literature on the cognitive impairments caused by particulate pollution, particularly in the young. That is a clue.

Long ago, someone had the bright idea to add lead to gasoline. Lead was already known as a neurological poison, but cars were king, and already exquisitely dangerous, so it hardly seemed significant to add an entirely different kind of risk to the fuel mix. Lead was never added to diesel fuel, as diesel is supposed to auto-combust from engine compression. But gasoline is supposed to, instead, be ignited by the spark plug, not compression. An "octane" rating was even devised to make higher-lead gasoline more attractive at the pump. 

Leaded gasoline proceeded to pollute our landscapes, increasingly as car use rose during the 20th century. Urban areas were particularly hard-hit, though agricultural areas can also be highly polluted. There is a well-supported theory connecting this pollution with rises in crime in the US, and later declines as lead was removed from gasoline and gradually the environment. The phaseout of lead was gradual, so if we take its peak in the mid-70's to 80's, then the generation exposed to the most lead in childhood would have been at prime criminal age in the mid-90's. That is one reason why crime has been dropping since that time. But prime criminal age is only one stage of life. Our political system is run by older adults, and the prime voting age is more like fifties and sixties. Thus a peak of criminality in the mid 90's due to the cognitive ravages of lead would correspond to a peak of political influence right about now. 

This is not to say that our president is suffering from lead poisoning. He has other, and far more serious issues with psychopathy and Hitler/Putin worship. (Though he is remarkably touchy about not being very bright.) But the political generation that elected him and forms his base- our political generation- may well be afflicted, explaining to some degree why our political environment is so degraded right now. We are not entirely up to scratch. 

But it isn't just about lead. Particulate pollution is pervasive, from all sorts of fossil fuel burning. We used to think nothing of cooking with natural gas, but it is a major source of indoor pollution. Coal burning spewed vast amounts of mercury, another neurotoxin, among many other pollutants. The bottom line is that the clean energy transition can not come soon enough, if not for our planet, then for our political sanity. 

• Alternative ruminations on origins.
• To Russia, with love.
• Truly bottom of the barrel.
• The Supreme Court may be afflicted as well.
• Our real strength.

Institutions of Truth

Society is built up around institutions, which come in several varieties.

We gather together to do more than we can possibly so alone, into families, tribes, and nations. As human capabilities increased through time, and our populations increased, ever-more diverse and specialized groups assembled to deal with the incredibly complex opportunities at the technological and social frontier. Putting astronauts on the moon required a vast organization with all sorts of skills, but especially technical skills. Such an institution runs on truth. Managers need to get truthful statements from the financial bean counters, the astronauts need to have confidence in the testing and engineering operations, the engineers need to count on the vendors and technicians for quality products and work. 

As a scientist, I often think of my own community as the epitome of truth-seeking and moral righteousness. But all human communities are truthful in their own way, though rarely so explicitly and doggedly. The legal system, for example, is predicated on a search for truth. Granted, it uses an adversarial system that relies on each side bending the truth to its interests, which is an ethic and practice that can easily get out of hand. Even politics is a sort of truth-finding system, not in its speechifying and rhetoric, but in gauging the feelings of an electorate- how it views its problems and who it thinks might solve them, assuming that voting is truly secret and civically engaged. It has been fascinating to see the lies of our current president, so meaningful to his base, functioning as permission to be their worst selves- racist, greedy, incontinent, misogynist, hateful, ignorant.

The news media is an explicitly truth-seeking and publishing enterprise, but can be compromised, both by its market incentives and by political pressures and interests. Markets and business are likewise truth-seeking, not in that they always tell the truth, but that they are predicated on finding a ground truth of what makes money- what is the most efficient and useful thing to be done at this moment. And connected with this is advertising, apparently one of the best ways to make money, and the financial foundation of the news media. Advertising is a curious phenomenon. Its practitioners are paid to tell lies, but only little lies, that skirt the boundaries of fraud. Their art is more typically to insinuate their lies rather than state them outright. That pretty women will flock to the owner of this watch or that car, or that betting at this casino will make you both handsome and rich. 

The arts dispense with explicit truths entirely, and tell human truths though imagined stories. The mark of great art is that it cuts to the heart of the human condition using all its artifice and archetypes. The Matrix is a great example of a wildly creative and frankly insane story that poses the central moral dilemma- can we take the truth, and can we- do we even want to- overcome pleasant illusions to get there?

At the bottom of it all is religion, which offers spiritual purpose and community, founded on pure fantasy. It used to be, in pagan times, that religions were not taken so literally and seriously. Each cult coexisted with the others, and none claimed to be more than an art of the archetypes whereby people could get in touch with a sense of binding social and philosophical purpose. A civic pleasure and ceremonial. But then came Christianity, child of the collision between Judaism and Egyptian and Greek philosophies. Christianity claimed a true historical story, even though it was fabricated more or less out of whole cloth. It claimed absolute truth, certain life after death, and salvation for something... apparently, the human condition was not good enough and had to be redeemed, by blood and death. It certainly was dramatic, but truth? Only on some campy (and masochistic) emotional level.

This institution has had incredibly pervasive effects on our view of truth, and it has taken hundreds of years to extricate ourselves from its presumptions and bizarre claims. Even now there is a rump movement of biblical literalists who are wreaking evil on our politics and society. All in the name of a hot mess of fabrications and primitive morals. We need to take a closer look at the role that truth plays in our day-to-day lives and society, in our moral lives and imaginations. 

• Progress on post-viral syndromes.

Every Cell Has Its Antenna

Some cilia are for motion, others are for sensing.

The classic image of eukaryotic cilia is of a paramecium covered in its motile fur. These are cilia, and they are composed of an elegant bundle of microtubules, with cross-bridging and dynein / kinesin motors. In our bodies, we have motile cilia in only a few places, like the airway epithelium, the ventricles of the brain, the female reproductive tract, the flagellum of sperm cells, and the ear, both in the middle ear epithelium and the stereocilia of the cochlea. Each of these have very specific roles, generally to move fluids around the cell, or the cell through fluids. 

Classic differential interference contrast image of a paramecium.

Cross sectional structures of a motile cilum (left) and primary, non-motile cilium (right). This 9+0 arrangement further degrades and reduces as one travels outwards to the distal end of primary cilia.

But there is another kind of cilium, called the primary cilium, (or sensory cilium), because virtually all cells have one and only one of them. These are less elegant, and generally immobile. They seem to be a relic of our free-living cellular past, but are hardly without function. There is a class of obscure diseases called ciliopathies that trace their origin to defects in primary cilia and have related and overlapping characteristics. For example, they often feature the mirror reversal of internal organs, which originates from (a lack of) directional fluid flow caused by these cilia (in their only known motile role) in very early embryogenesis. Another common feature is obesity, thought to be due to lack of critical sensing of satiety by the hypothalamus through the primary cilia of its neurons. 

All cilia contain microtubules, and also contain traveling globs called IFT, or intra-flagellar transport complexes. These move up and down the cilium, hitched to motor proteins, carrying the various proteins that make up the cilium, after they were synthesized in the endoplasmic reticulum and sent through the golgi sorting system, into vesicles addressed to the base of the cilium. So, the cilium has its own long-standing growth and internal transport system. 

Cargoes to maintain the cilium are ferried up and down the cilium in rafts.

Some of the specialized proteins of primary cilia are sensory, such as PC1, or polycystin 1, which is a sensor of fluid flow and generates critical signals, such as to mTOR, which is a global regulator of cell energy management and proliferation. The lack of signaling when there are ciliary defects causes over-stimulation of mTOR, which leads to over-proliferation in certain places, such as the kidney, causing polycystic kidney disease, another aspect of many ciliopathies.

Immunofluorescence image of the length-influencing kinase CDKL5 (bottom) and merged with another protein that is known to mark cilia (top). Note how there is only one primary cilium on this mouse fibroblast cell.

The primary cilium is so tiny and sparse that it has been difficult to study physically, despite its functional importance. It is shorter, thinner, and much less organized than motile cilia. But recent papers have shown it in both electron microscopy and fluorescence microscopy.

Electron micrographs of one primary cilium. Note how the well-organized structure at the base (left) gets thinner towards the distal end. The middle panel tracks which microtubules from the base peter out along the cilium length. Below, note the thick raft-like structures of the intraflagellar transport system.

These images show that the microtubule structure is pretty solid at the base, but then progressively degrades along the ciliary length. So, the structure is not much to write home about. It is the cilium's role as a signaling hub, probably of very ancient origin, which is its main importance in most cells. For example, a recent paper delves into CDKL5 deficiency disorder, or CDD. As the authors state, "... patients with CDD variably present with cranial facial and hand anomalies, have significant gastrointestinal dysfunction and sleep disorders along with recurrent pneumonia and respiratory disease. The affected gene is X-linked, and most patients are females. CDKL5 is a protein kinase that is conserved across ciliated organisms including the green alga Chlamydomonas reinhardtii, where CDKL5 localizes to flagella and its loss causes the flagella to be abnormally long." These genetics suggest that males with only one copy of the affected gene are dead, (one X), while females are heterozygous, and still have one good copy. 

The CDKL5 protein is located in both motile and primary cilia, and appears to restrict their length/growth, as its most obvious phenotype. It is concentrated at the base, and may restrict the activities of the intraflagellar transport system, while being transported by it as well. It is a protein kinase that likely regulates some aspect of the IFT by phosphorylating one or more IFT proteins. The authors find that CDKL5 is inhibited by another protein kinase, CDK20, which is tied to the cell cycle and cell proliferation. CDK20 is an oncogene upregulated in many cancers, thus making one more connection between cilia and the wider mechanisms of cellular growth control.

So, a tiny organelle common to all our cells is a bit like the radio antenna on our cars.. a bit antiquated and curious to look at, but still critical for some functions. It is hard to believe that its functions could not be re-engineered to happen on the plasma membrane, which has, if needed, other localization mechanisms like lipid rafts and caveolae, but design is not part of the equation here, rather, making do with and elaborating on whatever has worked in the past is always the way forward.

• Whence the debt?
• The organization of visual processing and abstraction may be vectorial, but not be sequential.
• Some problems with beef.
• What is happening to our institutions of truth?
• Bill Mitchell on why bond sales by our government are unnecessary.

Curious Computation

A biologist and former employee of IBM visits the Computer History Museum, in Mountain View, California.

Walking into the Computer History Museum, it seems unassuming enough- a slightly clean aesthetic, some open space, an early Waymo. But it is one of the most intense religious shrines I have been to. If Silicon Valley is a religion, one of industry, hope, and salvation, this is its interpretive and devotional reliquary. It honors the efforts of countless acolytes who have put their hearts into the technical organization of knowledge, from punch cards to SQL to data centers. And it honors its prophets, above all Thomas Watson and Steve Jobs. While the Silicon Valley religion has fallen on tumultuous times now that its powers have grown so intrusive, even reviled, and fallen into decidedly lesser hands, its eschatology has never been closer, as its greatest monastic centers are working towards "general" artificial intelligence, humanoid robots, and (ironically) the end of work. 

In the last century, IBM (with Thomas Watson as its benevolent dictator) was the leader of creating and handling mechanized information. Punch cards were a wonder of their day, allowing for efficient storage and flexible tabulation of huge amounts of data. Businesses quickly became dependent on them for modeling (and forecasting) their inventories, employees, payrolls, and financial streams. There was a tinge of omniscience and prophecy in the powers these machines could bring. But IBM was slow to get into electronics, slow to get into relational databases, and slow to get into small/personal computers. Particularly heartbreaking to me was the exhibit on SQL. Researchers at IBM invented the relational database and its SQL language. But IBM didn't see its advantage over its existing, less flexible data search/organization methods, and let Larry Ellison steal the idea and set up Oracle corporation, now as large as IBM itself.

The IBM system 360 was a revolution in style as well as computation.

The museum has a special room devoted to Apple and Steve Jobs, the quintessential prophet of Silicon Valley and its positive message of hope through technology. He has died and gone to heaven, but who has not stared into his handiwork? Who can say that he is not living still among us? Seeing the small beginnings and flickering flame of Apple's early challenges, before it became what one may now say is the official religion of technologically advanced society, well ... it was stirring, to say the least. 

Is that a halo?

The collection of the museum is very rich, dealing as it does with the relatively recent past (other than the abacus collection!). Indeed, I have a minor version of it in my basement. It is remarkable how diverse the flow of ideas was in the early computer age, with computers made in Japan, Germany, along analog as well as digital lines, by countless designs. There was a ferment that is characteristic of nascent technological fields (and, not incidentally, of biological radiations and innovations) where new possibilities are interpreted in various ways, and different prophets try out contrasting visions of the future, some regimented (like IBM), some more free flowing (like the home-brew computer club).

But the scope of the museum is also a bit confining, focused as it is on the human-built apparatuses of data processing. Information and computation is a larger subject, and as a biologist, I have to say that the finest computers at the Computer History Museum were walking around, not in the display cases. We are computers, and darn good ones. The fact that AI companies with their Sauronic datacenters can not accomplish what one person can with one brain, powered by little more than a burrito, means that some fundamental aspect of intelligence is missing in what is so blithely called AI. Computers have far surpassed what humans can do in data storage, and in mathematical computation. But in other areas our intelligence remains untouched. Technology will undoubtedly get there, but I don't think it will get there in the current dispensation, just by "scaling". 

So, for the moment, biology still wins. Indeed, information is so fundamental that biology has from the start created information systems. The simplest bacterium senses its environment and can tell whether there is food, or danger. The Cambrian explosion featured eyes- one of the most powerful weapons in the battle of life. Humans are naked in part because of our advanced sensing and cognitive abilities. We don't need shells, scales, or even fur. We can see far away, into the future, and around corners. We can organize flexibly to defeat any opponent on the planet, to the point that we now pine for those monsters we have lost, and are still losing. Information is power.

Not only that, but biology is doubly about information, since life has not only persistently created computational machinery, it is a computational machine, with that four-bit code at its heart. While software developers have a cycle of [ write - test - fix ], biology uses reproduction to get around the fixing part. Good programs are replicated/manifested, bad ones die. The cycle is [ reproduce - test ]. That is it, with ineluctable variation thrown into the "reproduce" part of the process. Simplicity itself, but profoundly transformative to the Earth, not to mention creating the greatest computers currently in existence. Of course, some physicists will say the universe is a big computer as well. It is computers all the way down!

The Silicon Valley religion is, as all religions are, about ourselves, really, and the image of ourselves that we see and strive for. That is why the quest for artificial intelligence is so haunting. Originally, that vision was progressive- one that achieves the deep yearning of the defeat of all enemies, of poverty, of conflict, of limitation and bounded-ness. That achieves freedom. Does Amazon help us achieve freedom? Does Netflix? Yes, a little, and so the works and wonders keep coming, even though they may come out of decidedly unfree channels. And some of the leaders have, sadly, gone in a different direction, preaching freedom as libertarianism, coarseness, even racism.

So there is a dark side to this religion, as the powers of all this technology conjure up greed and conflict, surveillance and control. IBM's biggest customer was the government, after all, and it happily sold to Nazi Germany. Religions, especially ones that promise power, can turn bad, and they have to consitute an ongoing conversation that comes back to people, not technology, to determine what the future should look like. The Computer History Museum houses an immensely positive story, about people who helped us overcome age-old limitations and achieve incredible dreams. But look in the mirror- we are the real subjects and agents of this story.

• Corruption, lies, impunity.
• The Manchurian director of national intelligence.

Sensing Unfolded Proteins

Do cells take joy in tidying? Absolutely! But how can they tell where the messes are?

Any household knows that without cleaning and disposal, nothing else is possible. Things pile up, messes accumulate, everything comes to a standstill. Cells are the same, needing a constant flow of new materials in, trash out, recycling, and cleanups. One of the major kinds of mess in cells is unfolded proteins, which when they accumulate can cause aggregations and diseases like Huntington's, other dementias, atherosclerosis, and inflammation generally. While there are a lot of mechanisms (chaperones, chaperonin cage complexes, proteasomes) dedicated to proper folding, sometimes they are not enough, and excess junk in the form of unfolded proteins builds up. One major response this is the unfolded protein response, or UPR, which is centered at the endoplasmic reticulum (ER).

Why the ER? This is where countless ribosomes dock to feed in nascent proteins destined for secretion, the plasma membrane, and many locations inside the cell other than the cytoplasm. So it is a key organelle for protein synthesis and distribution, and thus for sensing how cellular proteins are doing. This sensing, the UPR, starts with a sensor protein, called IRE1 (also called ERN1), which sits on the inside face of the endoplasmic membrane. IRE1 binds to unfolded proteins inside the ER, and when the concentration rises high enough, it gathers into condensates of its own that trigger a variety of responses that include, in the extreme, cell death. Yes, lack of timely tidying can have serious consequences!

IRE1 is multifunctional, containing a kinase that activates AMPK and JNK, proteins which influence metabolism and inflammation. It also contains an RNAse enzymatic activity, which activates a whole other program by altering the mRNA of XBP1, which then becomes active and produces a transcription regulator that starts building more ER, more chaperones, and more protein folding capacity generally. The RNAse also digests other mRNAs indiscriminately, lightening the load of translation and thus incoming nascent proteins. So IRE1 is a key homeostatic regulator that adjusts the size of the ER to cellular needs, and informs the rest of the cell how things are going in the ER. 

One structure of IRE1, luminal domain only. This is a dimer, with halves shown symmetrically across the middle. How does this bind unfolded proteins?

But how does IRE1 sense unfolded proteins? A recent paper went through a modeling study to show how IRE1 operates. Sitting in the ER membrane, the enzymatic, signaling parts of the protein are outside, while the sensor is inside, called the core luminal domain (cLD). The authors demonstrate that this domain binds unfolded proteins directly, using them as bridging elements to bring multiple IRE1 proteins together and form the glob that nudges aside the inhibitory protein BiP and promotes the phosphorylation activity and thus activation, of IRE1. BiP also binds to unfolded proteins itself, so forms another sensor that indirectly activates IRE1 under stress conditions. 

Firstly, IRE1 is a dimer, and the luminal domain is where it dimerizes. The structure (just of the luminal domain, above) shows a beta ribbon core and peripheral unstructured areas and alpha helices. After running the crystal structure (shown) though very brief molecular dynamics simulations, the unstructured areas flop around dramatically, while the core and dimeric structure remain stable. Intriguingly, the beta stranded center of the dimer resembles (between the blue helices, above) the peptide binding cleft of MHC molecules- those that present random antigens to T-cell receptors of the immune system. Yet the authors show that unfolded proteins bind differently to IRE1. They flop across the whole central region, attracted by negative charge as well as the open hydrophobic surface. The next image shows molecular dynamics before/after shots of various unfolded peptides known to bind IRE1 in vitro, showing how after starting straight across the central region, they each find different comfort zones, mostly over this central region, but some off to a side. 

Collection of IRE1 structures (gray) with unstructured peptides of various kinds bound to the luminal face. t=0 is the starting point for the molecular dynamics simulation, which went for one microsecond. End points are below. In each case, the unfolded peptide stayed bound, and settled into some comfortable position, based on the hydrophobic and negatively charged landscape of the IRE1 face. 

The intriguing thing about this binding is that the structure of IRE1 itself is unaffected. The dimer interface remains stable and open, leading to the hypothesis that these peptides form bridges by becoming the meat of a two-dimer IRE1 sandwich. And it is this that then displaces the inhibitory protein BiP and leads to condensation and activation, by bringing together multiple IRE1 kinase domains (on the outside of the ER), and activating their kinase/signaling functions, turning on the various downstream pathways.

A helpful model from another lab, describing how, once the unfolded proteins are bound inside the ER (by mechanisms unknown at the time), the outside domains would gather, trans-phosphorylate, and activate downstream pathways. 

• Those flock cameras.
• As if charging for previews of presidential posts wasn't corrupt enough.

Our Loopy Way of Learning

Different ways of learning go through different parts of the brain.

Humans are champion learners. Other animals are smart, but we are smarter, spending more time in childhood soaking up the mysteries of the world around us, and storing them in a larger and better brain. Learning is our calling card, allowing us to adapt to any environment and defeat any foe. Indeed, we have overwhelmed the earth's biosphere, and need to exercise some deeper and longer vision by pulling back from our successes in mastering every possible resource.

But how the brain does all this is something we have yet to fully learn about. Our sense organs bring in tons of information, but as we have learned in computer science and AI, it takes a lot more to create usable information than just amassing data. How do the various parts of our brains work together to create actionable models of the world out of that data? An innovative theory was elaborated a quarter century ago by Kenji Doya, who has apparently gone on to a research sideline on soccer(!)

The problem began with, in part- what does the cerebellum do? From lesion data, it has long been clear that this small part of our brain has a big role in motor accuracy and coordination. But cerebellar neurons project all over the brain, not just to motor areas, and it gradually became clear that the cerebellum affects those other areas as well, helping us learn and manage many cognitive tasks. But structurally, the cerebellum is a peculiar organ, highly repetitive, with relatively linear and parallel processing, a bit like a GPU. It is clearly specialized for something- some kind of fine tuning, but what?

Doya's theory about the distinct learning styles contributed by different parts of the brain.

Doya proposed a general theory about learning in the brain, which splits learning up into three types. One type is supervised learning, which is what the cerebellum facilitates. We grab something, we recognize an error in eye-hand coordination, and we learn to grasp better. There is a loop involved, both physically and logically, by which some task is evaluated, and error signal sent back to the source, and a small adjustment is made for the next iteration. Humans have great hand coordination, partly thanks to our advanced cerebellar-cortical connections. 

The second form of learning is reward-based learning. This prototypically features dopamine, and is centered in the basal ganglia, where emotions are processed, but which is also a major switchboard for connections upwards to the cortex and downwards to the brainstem, and is also critical for motion control. Parkinson's and Huntington's diseases both affect this region. Doya proposed in broad terms that this area doesn't do the kind of error correction that the cerebellum does, but rather learns by reward- whether the action's goal was reached. If the goal was reached, a spurt of dopamine is issued, which reinforces whatever connections helped that action happen.

Interestingly, there is a progressive temporal aspect to this learning. As an action is learned, the reward happens sooner, given the predictive capability of our learning / cognitive systems. The whole point, after all, is to figure out as early as possible what will be happening in the future. If a bell is associated with food, at first the food prompts the reward. But as learning happens, and the bell is reliably associated with the later food, and the bell starts to set off the reward all by itself. Gradually, the sight of the person getting about to ring the bell, or the expected time of day, sets off the reward... it is cast progressively back to whatever the perceived cause is, going back in the learned causal chain. Eventually, as everything becomes rote and the novelty wears off, reward lessens, and learning is complete. Mealtime is here, as it is every day... boring.

Lastly, the third type of learning is unsupervised learning. This is the job of the cortex, and is the most interesting and subtle form of learning. The world has patterns, and the cortex's job is to figure out what those patterns are. No one outside tells it what is right or wrong, what is or is not real. It has to figure all this out from the stream of input, including its own blundering actions and experiments. Unsupervised learning is thought to be well suited to the basic mechanism of the brain, its Hebbian circuitry where activity reinforces any active connection. There are a lot of mathematical methods that have been devised to approximate such processes, like principal component analysis. Data can be binned / categorized in various ways to simplify and organize reality, and eventually we have ... language and concepts, labels and abstract understanding. This categorization of the world is immensely powerful, if always inaccurate and approximate. 

Doya's model of the cerebellum. Purkinje cells at the center are also conceptually at the center, as the only cells that are plastic in this scheme, able to change their connection weights due to input from the other layers, which in turn get input from other brain areas including the cortex and thalamus. This has been likened to a perceptron in computer science terms.

Doya thus created an influential heuristic that divided up learning styles / mechanisms by anatomy in the brain. Obviously, all these mechanisms work closely with each other. The cerebellum doesn't know anything without conceptual categorizations coming from the cortex, which provide the foundation of error signals. Similarly, whether goals have or haven't been reached has to be informed by conceptual data from the cortex (or food signals, or other sensations from elsewhere in the body). Learning is a whole-brain activity, and while it is prodigious and effortless early in life, it continues to be essential throughout, lest we be overwhelmed by the fresh challenges the world keeps presenting to us.

• Recent work fleshing out this theory.
• Thought crime.
• Empathy as crime.
• .. or as being Democratic.
• Scrap all fossil cars now.
• China is going after their rich.