A Deep Dive Into DNA Binding

How do transcription regulators bind DNA, and how does this binding in the test tube compare with binding in cells?

There has been a lot of speculation about special conditions inside cells that affect searching and binding by DNA-binding regulators. The fundamental sequence-specific affinity of a protein can be recapitulated in a test tube, (that is to say, "in vitro", even though test tubes are all plastic these days, not vitreous), but the cytoplasm / nucleoplasm is a different environment. The highly crowded nature of the environment is one issue. Another are specific factors like nucleosomes, chromatin structure, and the many other proteins that might compete with the binding protein on the DNA or alter the DNA shape, such as with twisting, bending, or chemical modifications. There are a lot of possible variables, and it has also been difficult to even assess quantitatively how well binding in the test tube compares with binding in cells.

A recent paper tries to delve into these issues in great detail, with rather confounding, if interesting results. I should say right off that this is a poorly written paper, with the kind of florid over-indulgence of figures that reminds me of my first poster. Anyhow, there were a few interesting points.

The regulator (or "transcription factor" as is historical / customary in the field) that they choose for this work is KLF1. This is a hugely influential regulator that orchestrates the maturation of erythrocytes from their progenitor cells, among other tasks. Knockouts of this gene leave mouse embryos dead at around 14 days, with profound lack of hemoglobin. Red blood cells undergo amazing development, ramping up hemoglobin production while they cut production of everything else, and finally eject their nuclei to become the streamlined and shapely pucks of oxygen-carrying goodness we are familiar with. KLF1 is part of a large family of proteins (that is to say, proteins that originated by accidental duplication from one long-ago parent through the history of life) that bind to DNA via three zinc fingers, shown as the gray bars in the diagram below. Zinc fingers are compact structures that bind to about three bases of DNA each, and, as the name suggests, contain a zinc ion that organize their structure. The human genome encodes over 8,000 zinc fingers. For a 3D look at a representative zinc finger structure in detail, go to the protein data bank.

Diagram of the protein domains found in SP/KLF family members, in humans. While these regulators all share a highly similar DNA-binding core of three zinc fingers, (gray bars at right), they are otherwise a riot of ancillary protein domains, which are generally involved in contacting other proteins of the transcription apparatus, forming cooperative complexes to either activate or repress transcription.

So KLF1 binds to a site of about nine informative bases, though these authors go on to show that a couple of extra bases on the sides are also significant to binding affinity. They do a thorough in vitro scan of all the sequence variations of KLF1's target sequence, coming up with a quantitative presentation of its "consensus", or ideal binding sequence, shown below. This sequence is rich in C's, and poor in T and G. 

KLF1 binds to this "consensus" sequence, via its three zinc fingers, as noted at the top. Each position of the binding sequence has its preferred and non-preferred bases, as indicated by the colored letters and their heights. 

They find that KLF1 has a pretty short residence time on its site, of about 2 minutes, thus is easily competed off by other DNA or other KLF1 proteins. Additionally, they look over the flanking DNA and find that not only do the two bases on each side of the consensus DNA sequence carry a lot of weight (presumably by directly binding KLF1 at its edges), but more distant flanking DNA has influential effects as well. These effects have a strong 10.5 base periodicity, indicating that they occur on one side of the DNA- the same side as the target binding site. But the preferred sequences at these distant positions are the opposite of the binding consensus, tending toward A and T. After considering a few hypotheses, the authors settle on a model where KLF1 searches for its binding site by hopping around on and near the DNA. The more semi-similar sites there are nearby, the more time this search takes, so it is better to bias the nearest locations against the consensus sequence.

But the main question they are asking is.. do all these in vitro parameters reflect also what is going on in vivo- in relevant erythroid human cells? For this, they use artificial DNA constructs with multiple KLF1 binding sites, and a methylation-protection technique where the bound protein physically "protects" its DNA site from methylation by an introduced enzyme (not to be confused with traditional DNA footprinting). These methylation sites are then read out by a complicated sequencing method, and displayed horizontally as shown below. Since the residence time of KLF1 is so short, the experiment was run as quickly as possible, with two minutes the minimum time point. Each of the KLF1 consensus sites (teal blocks, at top) were clearly protected from the methylase, while portions/lanes in between (15 bases long) were not, showing that these sites appear to have been specifically bound by KLF1 or one of its very close family members. This effect wore off quickly as KLF1 dropped off the DNA, (likely due to death of the cells/system they were working with, due to the methylation technique), and was hard to discern at fifteen minutes. So they conclude that the residence time of KLF1 is very similar between laboratory and in-cell settings. Incidentally, they show also that the consensus, flanking and distant flanking effects are also operative in cells, and thus the raw sequence-specificity of KLF1 binding to DNA is similar overall. 

"Footprinting" of KLF1 sites in cells. The DNA region is spread horizontally in these depictions, on the X axis, and white marks note methylation events, or non-protection from the methylase. The 15 bp borders between the KLF1 consensus DNA binding sites are white, while the sites themselves are dark or protected. In F, the control with mutated consensus KLF1 sites, there is protection all over the DNA, which the researchers interpret as a stable nucleosome plopped on this site instead of the specifically bound KLF1.

But suppose fewer KLF1 sites are used, instead of seven sites? What then? In vitro, binding of KLF1 is strictly linear with motif number (below). In vivo, on the other hand, binding is very poor to one or two sites, and only rises once three or more are available. The authors interpret this as showing competition against other binding proteins, principally nucleosomes (as above, right). And they also argue that this is not due to direct binding by the multiple KLF1 proteins vs the nucleosome, but is mediated by some other proteins (aka factors, in green, below), that bind to KLF1 and help to budge off local nucleosomes. KLF1 is a so-called "pioneer" factor which has this power, doubtless due not to its own structure alone, but due to the goons it calls in to help, such as nucleosome-displacing SWI/SNF or CHD1 complexes. 

In the test tube, affinity of KLF1 to its site is linear with the number of sites.

On the other hand, in cells, KLF1 has little occupancy until there are three or more sites available to bind (B, C). In D is shown the author's explanation, which suggests that large nucleosomes typically block the site and can only be evicted if several KLF1 binding sites and proteins cooperate to bring in some extra machinery (green).

Lastly, does all this work allow these researchers to predict where KLF1 binds within cells naturally? Not at all. They publish a fascinating analysis of the correlation between observed locations of KLF1 binding at its normal sites in normal cells (via the ChIP method) versus predicted sites in the genome from their in vitro analysis. And the correlation is pretty much zero (below). So KLF1 is only one actor, if an important one, in a flurry of activity going on in the nucleus, many aspects of which can supervene over its raw DNA binding preferences. Trying to predict all this, with an AI or other model, remains, as yet, quite out of reach.

Correlation between actual binding locations of KLF1 in normal cells (Y axis) vs predicted binding sites (X axis). Note the lack of correlation.

• Maybe things aren't so bad.

Document Number 9 and the China Dream

China 4: Kevin Rudd on "Xi Jinping Thought on Socialism with Chinese Characteristics for a New Era".

If the subhead to this post reads a little Orwellian, it should. It is the formal title of Xi Jinping's magnum opus- his leadership philosophy all about gaslighting the Chinese people and the world that ... capitalism is socialism, dictatorship is democracy, and brother Xi should lead China forever. Kevin Rudd has very impressively followed his prime ministership of Australia with graduate career studying China and Xi Jinping. This book is evidently part of his thesis work. So it is not really a popular book, but rather a more turgid close reading of all the "banner terms" of modern Chinese communism- the slogans that seem to drive Chinese politics. These slogans are deeply meaningful, but not easily parsed. It takes some expertise to know what is going on, as would be true in the US for a slogan like "Make America Great Again".

Let us dig into Xi's slogan a little. "Xi Jinping Thought" is unusual, in that only three modern leaders have had their names tied to a banner term. There have been "Theory of Three Represents", the "Great Leap Forward", even the "Two Whatevers", and many others, but only "Mao Zedong Thought" and "Deng Xioping Theory" were named for the individual leaders. And clearly, Xi has outdone them all in the length of his banner phrase! "Socialism with Chinese Characteristics" harkens back to Mao's split from the Soviets, when Chinese communism was proclaimed to be something a bit different, more peasant-based, and one might say a little emperor-based as well. This through-line in PRC political philosophy was naturally strengthened when the Soviet Union imploded, and the PRC forged its own path, discarding Marxism in favor of capitalism, which is essentially what socialism with Chinese characteristics now amounts to, economically speaking. Politically however, Leninism reigns supreme.

Lastly, "a New Era" is a highly significant statement by Xi about the phases of socialism. Deng Xiaoping posited that China would have to go through a long phase of a "Primary phase of socialism", by which he meant capitalism, which would make China rich. Once China was rich, the party could think about how to divide the pie. But it was clear that socialism, as practiced either in China or in Russia, was never going to get them to a sufficiently prosperous state to gain any of the blessings of modernity, (or to a state of power vs its international adversaries), upon which Marx had after all based his ideal state. Deng noted that this primary phase might take generations- even hundreds of years. The idea was usefully vague. But Xi has cut the time line rather drastically, stating that China has already entered a new era (phase), that his plan is for China to be a moderately prosperous country by 2035, and a country by 2050 that is "a great modern socialist country that is prosperous, strong, democratic, culturally advanced, harmonious, and beautiful". This all means that "Opening and Reform" which had led to the pell-mell (and increasingly technocratic) capitalism of the Deng and post-Deng period can be dialed back, and that the preferences of the state / party (aka Xi Jinping), including some action against inequality, can be put on the agenda again. 

So, just because it sounds Orwellian doesn't mean that there is nothing behind it. As for its content, Xi Jinping thought is a wide-ranging stew of platitudes, sharp policy reversals, and everything in between. But the central theme is putting the party (CCP) back in charge of everything again. Xi has instituted an unprecedented rolling, perpetual purge of the party from top to bottom to enforce discipline, prosecute corruption, and empower his allies. Xi recognizes that everything flows from ideology. If the ideology has become rotten, as it did in the Soviet Union, and has threatened to do in China during the wild-west capitalism of the last few decades, then faith declines, discipline declines, and the system becomes vulnerable to collapse. Thus Xi has focused on issuing a confident and sweeping ideology of how things should be run, with himself in charge of the party, the party in control of the state and country. This ideology incidentally does a great deal to rehabilitate Mao, mention Marx as often as humanly possible, and claim that it is socialism that the CCP is building in China. 

You may have noticed that the word "democracy" entered into the statement above of the "Chinese dream". While the dream is mainly about power- personally, domestically, and internationally- it is also about quality of life. (Indeed, Xi goes so far as to accuse the West of "spiritual impoverishment".) Just as the word "Republic" figures into the name of the PRC, the word democracy figures (sparingly) into this national ideology. But it is not any kind of democracy we would recognize. It is the spirit of the people as expressed in the party- a "whole-process people's democracy". In fact, Xi has quashed all nascent practices of voting and internal democracy which had been sprouting within the party over the last few decades, to go with his bulldozing of collegial decision making at the top and term limits. (However, there is a significant history of protests in modern Chinese history, up to the current time, that can happen when the political strain is sufficiently great.)

All this became especially explicit in Document number 9. Kevin Rudd draws on many writings and speeches by Xi, but this document is particularly telling, as it was leaked from an internal set of deliberations early in Xi's reign (2012). It describes the ideology not so much in the glowing terms given publicly, but in far more existential terms as critical to prevent the rot and eventual fall of the party. Discipline over everything, as well as a fighting spirit to take the battle to the enemy, which is ... Western values. Out of this arose the "Wolf Warrior" phase of Chinese diplomacy, which was a sort of Trumpy, and rather counterproductive, reset of everything the Chinese diplomatic corps had known for decades, under Deng's "Hide and Bide" policy. They would turn the tables, by the usual magic of authoritarian projection, and claim themselves as the victim of bullying by the West, for their reasonable, scientific, and ancient cultural values.

As an aside, Deng's policy made, and still makes, eminent sense. Why? Because the US had shaped an extremely benevolent environment in Asia since World War 2. Shipping routes were free and open, trade was free and open. Japan was pacified. Asian tigers one by one took advantage of this environment to climb to prosperity. The US tried, in its ham-fisted way, to fight the bullies, whether they descended from North Korea, or from North Vietnam (governments that remain extraordinarily durable and repressive). The US was happy to educate millions of Chinese students and send them back with all the modern skills they could use to build China, capitalist or otherwise. The US was less happy, but still willing, to de-industrialize if that meant getting goods from China that were cheap. The only request in return was that China abide with the peaceful regime, particularly regarding Taiwan. And there was the natural hope that Western values would indeed spread and infiltrate into modern China along with capitalism, to bring China into the Asian system of alliances and friendly trade relationships.

Obviously, that did not happen. Xi Jinping is now furiously back-peddling on the whole deal, preaching "struggle" against Western values and a China Dream that has China not only solve its internal problems, but solve those of the next international order, by quashing human rights, elections, inefficiency, privacy, and all other encumbrances on the Chinese way of governance (helpfully summarized as the Seven Don't Mentions). Most ironically, China has twisted its own resurgence under capitalism as a peculiar justification of Marxism, Leninism, and Chinese culture. Kevin Rudd paints a stark picture of the sweeping nature and evolution of Xi Jinping Thought. Under the Orwellian rubric of "win-win" diplomatic relations and a "Community of Common Destiny", China is bullying its neighbors around the South China sea, bullying the UN, and other countries around the world such as in Africa. One senses a new mission, even an exceptionalism reminiscent of American exceptionalism, but quite a bit darker. As Kevin Rudd puts it: "... now the party's wider definition and vision of social justice was available to the world at large, delivered though the alternative international system that China was now building. For Xi, this will be China's 'city on a hill'".

One needn't deny the great accomplishments of China, in adopting capitalism to pull itself out of poverty, in establishing a technocracy that can build a remarkable high speed rail system and run it on time. And in keeping its government stable and attentive to its people's needs amidst great change internally and abroad. But the idea that Chinese governance by the CCP is a model for the future of the entire world does give one pause. Its foreign policy has not made it many friends. Its only true partners on the world stage are Russia and North Korea. For all its rhetorical dedication to non-interference in the internal affairs of other countries, and to their territorial integrity, it has allied itself not with Ukraine, which is being invaded, but with Russia, which is invading. (Of course, the fact that Donald Trump, contrary to the wishes of the US population and its Congress, has allied himself with Russia as well- and has not been impeached over it- doesn't speak very highly of our own values at the moment.) China's model is not attractive to people across the world, though it is very attractive to authoritarians of all stripes, who wish to rule their people without their consent and in perpetuity. China's trade practices are also costing it influence, as it progresses up the value chain and floods the world with products that other countries want to retain viable industries in, such as auto production.

There is a long history of influence-shaping in CCP practice, some of which is straight propaganda, but part of which goes by "United Front Work", going back to the very founding of the party. It involves infiltrating other organizations and gaining power in them, co-opting friendly segments of enemy organizations and countries, such as in Taiwan, and generally presenting as anodyne a face as possible in order to gain acquiescence before revealing one's true intentions. Previously, the scope was narrow, targeting groups such as the Kuomintang, the leaders of Tibet and Xinjiang. But now, the targets are the UN, other international organizations, countries of the global South, and a blizzard of "friendly" initiatives, including Belt and Road, and the Global Security,  Global Development, and Global Civilization (!) initiatives. It is nothing if not audacious. But as noted above, the effort is not gaining much purchase, since it is fundamentally unattractive, at least on a popular level. And Xi Jinping's wolf warrior approach hasn't helped either. Internally, Xi's Leninist retrenchment is degrading China's economic prospects and trading cultural vibrance for rigid discipline and adherence to "the mass line". Abroad, the dividends of Xi's rule have clearly been conflict rather than harmony, and propaganda only goes so far in a world that still (as yet) values truth, empathy, and harmony. 

I will close with a summary by Kevin Rudd: "By contrast, Xi Jinping saw this potential political future for China and did not like what he saw. He understood what his predecessors were seeking to do by leaving the democratic door open for the next generation and decided instead to slam it tightly shut. Xi, as an intelligent man, also understood the costs of doing so. But he saw these social economic, and international reputational costs as well worth paying to preserve the power of the CCP for the long term. ... For him, the cost-benefit analysis of preserving China's Marxist-Leninist nationalist model was self-evident." "In Xi's belief system, the absolute power of a Leninist party remains axiomatic to the survival, strength, and success of both the party and the nation."

• AI is fundamentally illegal.
• Whence math?
• Whence money?

Binding Memories and Decision Context in the Temporal Lobe

Invasive detection of single human neurons allows analysis of their role in decision making.

Is AI as good as human brains? No and no- AI is not as energy efficient by a long shot, not as flexible, and particularly not equipped with sufficient world models (aka general common sense and context) to be dependable in decision making outside its narrow areas of expertise, such as coding and hacking through computer security barriers. But both are black boxes to some degree, with the brain being particularly hard to study, even for adepts.

A recent paper provided an example of advanced research in human brains. Sadly, it relies on people with epilepsy, whose cases are so severe that they are getting brain surgery to remove the epilepsy-activating locus. As they are already being given a highly invasive treatment, with electrodes probing likely areas of their opened brains in order to find the smallest possible excision site, there is a long history of researchers asking for access to these patients for unrelated studies in general neurobiology. This paper uses 16 such patients to read electrodes inserted into their medial temporal lobes, including the entorhinal cortex and hippocampus, areas well known to function in memory and its integration into navigation and other kinds of decisions. Fortunately or unfortunately, the entorhinal cortex is the most common activating nucleus location for temporal lobe epilepsy, the most common kind of focal epilepsy.

The testing procedure was relatively bare-bones. The subjects were first shown a large number of images to find responsive cells from among their implanted electrodes. Then the experimenters set up a task system. They would ask a question first, and the subject would have to remember that question as two pictures were then presented successively. These questions required some kind of comparison, such as "Which person shown is older", or "Which item is more expensive?". The idea was to track how the picture-responding cells (and other cells) activated while the items were being presented and the decisions were being made. But the researchers were particularly interested in other cells- those that responded to the question being asked, or perhaps responded to some combination of the question plus the image. In finding such cells, they could investigate how memory and subject binding between context and object is handled in the brain. 

The figure above shows the firing of individual cells. On the left is a cell that responds only to the image of a cookie. Other pictures (below) do not activate it, and nor do any of the context-leading questions, to any special degree. On the right is a cell that is quite special- it responds to a combination of one image (the train) and one question, but not any of the other questions, and not any of the other pictures. 

The figure above shows another kind of neuron firing- one that responds only to one question/context: is the person in picture one older than the one in picture one? But it does not respond to any picture in particular way, nor to the other questions. The dotty portions of the figure show the detailed firing of these cells, which is counted/binned/summarized in the graphs at the bottom.

This Venn diagram shows the counts of neurons with particular characteristics, from among the total of 3,109 neurons that were probed in these 16 patients. Due to the pre-experiment screening procedure, cells that respond to images (the "stimulus") were predominant. But cells that respond to the questions asked (the "contextual stimulus") also came up surprisingly frequently. In green are cells that respond to one or more questions only. Cells that responded to some combination of both picture and question are represented by the smallest circle, giving various possible computations of the decision being asked for. 

These graphs show a summary of the experiment through time, from where the question was asked, to the presentation of each picture, and to the decision being made about four seconds down the line. In the bottom, picture-specific neurons fire separately as they are stimulated by each picture in succession. What is interesting is the top graph, showing activation of context-stimulated neurons, not just as the question is being asked, but then re-activated as the subjects need to recall the question in the context of each picture. The control graph (red) is where the experimenters shuffled the data (pictures and questions) randomly, getting a net null level of activity. Note that there is a delay of about 40 milliseconds between the picture-driven activity peak and the question/context activity peak, indicating some time span for evaluation that is taking place, all followed by about a second until (on average) the decision finally arrives from the subject (at the end of the graph). In addition, note how the context neuron firing becomes (on average) even more intense as the trial progresses, from its original activation as the question is asked, through the presentation of each picture. This suggests that these neurons are not so much for storage of memories as for their activation and use in decision-making.

The main finding is that neurons corresponding to what is needed for a decision in this instance are clearly available if one looks carefully in the brain. There are neurons that "see" the picture, regardless of other distractions, neurons that "understand" the question, regardless of other pictures or questions (and remember that question later on), and there are neurons that get the binding of both conditions, between the picture and the question. Additionally, the researchers find that the stimulus neurons were primarily located in the entorhinal cortex, while the context neurons arose mostly in the hippocampus. This tracks with the memory functions (heavily concentrated in the hippocampus) helping to keep the question in mind as the trial went forth. On the whole, we are seeing "binding"- that mythical beast in the philosophy of consciousness, and of mental processes more generally.

• Universities should have nothing to do with business schools.
• What is our political system about, after all?
• Report number 9.
• Triple win from the Norwegian wealth tax.

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.