Addiction, Exorcism, and the American Dream

Review of Beautiful Boy.

Why is drug addiction such a widespread and dangerous scourge? A lot has been made of the despair of the working class especially in declining rural areas- a crisis of meaning and survival at the short end of the capitalist system. But there is higher anxiety everywhere in our unequal, precarious, and atomized system. Even in wealthy Marin, where the story of this movie originates, parents are in what seems like fight to the death to get their offspring into colleges to fulfil an overwhelming set of competitive expectations. No wonder young adults, even when well-to-do, already feel themselves in a rat race which it would be pleasant to check out of, momentarily. Then add in the viciousness of modern drugs like crystal meth and fentanyl, and you have a lethal witches' brew.

Still from the movie. Timothee Chalamet playing Nic Sheff, and Steve Carrel playing David Sheff.

We used to regard Russia as a demographic basket case, with declining population riven with alcoholism in the wake of the Soviet collapse. Now we are facing a similar downward dynamic- a social rot punctuated by self-destruction through drugs and suicide. The ultimate source seems to be broad insecurity, which was precisely the point of the economic and cultural reforms of the recent Republican epoch, starting with Ronald Reagan. The benefits of competition and division were trumpeted, and the rich were feted as job creators and entrepreneurs, and given absurd benefits like a tax rate on investment profits half as high as the rate on labor income. Companies developed an ideology of serving profits to the exclusion of all other goals, which meant the destruction of stable life schedules, stable jobs, and stable communities. The Reagan era gave rise to wide-spread homelessness, the ultimate warning to labor to keep its head down. And a broad reduction of safety nets of all sorts, from corporate pensions to onerous rules for welfare, which was divided into a puzzle of ungenerous programs.

How ironic, then, that Donald Trump offered to fix all this for workers, restoring the greatness and jobs of America. Who suspected that he came from a Republican tradition whose first order of business, when given power, has been to hand money to the rich? Who suspected that his policy ideas came more from the tabloid headlines of the 80's and 90's (not to say his fascist forebears in the 30's) than from the issues the working class face today? Who suspected that the greatest epoch in American history, after World War 2, was actually our period of highest taxation, culminating in, not coincidentally, the Apollo space program, which was hardly a capitalist venture?

Reagan, George W. Bush, and Trump each cloaked themselves as shamans for an anxious society, ready to exorcise the demons of economic malaise and insecurity, as well as those of Vietnam. While Democrats offered laundry lists of melioration, Republicans could do no such thing, their object being to strengthen hierarchy and help the better-off. They have instead lighted on a more tribally / religiously tinged approach, offering a broad ideology of conservatism (however radical the implementation, and departure from the existing system) and order, which would by some mystery of compassionate conservatism redound to the benefit of all after generous payouts to the few.

On the military front, they authored a series of military misadventures that climaxed with the criminal debacle in Iraq. On the economic front, they pushed hard-line capitalism as the cure-all to bring economic growth, starving the state with deregulation, outsourcing, and bitter budget / deficit battles as a purgatorial nostrum that would rejuvenate an ailing system. Curiously, however, the treatment never worked for the middle class and poor, keeping them economically static and ever more insecure, while the rich and super-rich pocketed all the proceeds.

Economic vitality needs some dynamism and destruction. But people and communities need stability and a basic level of egalitarianism to feel human and have basic freedoms. The founders foresaw that rising wealth and inequality might make of America the same class-ridden culture they had fled in Europe. Their hopes were tied not just to the new republican structure they were building, but also, in economic terms, to the frontier- the jobs-for-all program of its day- which would continue to offer all Americans (and immigrants from all over the world) the option of a decent and hard-working living, preventing excessive inequality.

Now the frontier is gone, the population continues to rise, and the only solution from the "conservative" right is to squeeze the middle class and poor relentlessly in a spiral of anxiety that drives everyone to work and live under ever less humane conditions. We need a better balance that builds more unifying social structures and public goods, reels back the excesses of extreme capitalism, and gives people breathing space and freedom to dream of being more than cogs in a machine.

RB: Short Name For a Complicated Protein

A key cancer protein operates in a huge network of regulatory protein interactions.

RB stands for retinoblastoma, one of the first diseases tied to a causal oncogene, now also called RB. For lack of time, this will be a very short post about a very lengthy story- how complicated one protein can be. The RB protein doesn't really do much on its own. It isn't an enzyme, or bind DNA, or do other dramatic things. But it binds to a lot of other proteins- 322 have been documented to date. And one protein that it binds to and represses, the transcription factor (family) E2F, is a key activator of cell division, promoting transcription of many other genes including cyclins and cyclin-dependent kinases that run the cell cycle. So RB is typically a key actor that keeps cells quiescent in G1 phase, the normal non-dividing state most of our cells are in. And this is how mutations in RB promote cancer, by removing this brake.

A recent paper expanded this story by investigating some of the regulation of the RB protein, which has at least 15 sites where it gets a phosphate group added (phosphorylated) by regulatory proteins called kinases. The most prominent regulatory kinases are the cell cycle dependent kinases, or CDK. Naturally when a cell does really want to divide, these function to turn RB off, via certain of these phosphorylations. The authors erased each of these phosphorylation sites, and then restored one at a time, asking what binds to them and their effect is. The upshot is that each site turned out to show a distinct pattern of downstream effects, indicating that different proteins bind more or less well to each phosphorylated form. These proteins include transcriptional regulators of a wide variety of kinds, and affect differentially the expression of key genes like BRCA1, 2, and MSH2, and processes ranging from DNA repair to oxidative phosphorylation to protein secretion.

Diagram of the sites of phosphorylation of RB by other proteins. The amino acid sequence goes from left to right, and functional regions of RB that bind to other proteins are colored.

"Collectively, this mass spectrometric analysis identified 438 proteins with a statistically significant enrichment in complexes with at least one of the 16 forms of RB examined. The 22 proteins significantly enriched with all forms of RB included multiple E2F and DP [E2F partner] proteins."

Evolution has had several billion years to tinker with these systems. So while the solution sometimes has been elegance incarnate, (like the DNA molecule), other times it is a messy network of sprawling and mystifying scope. It is one reason why biologists will remain tied to their benches for decades to come.

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Patterns of American Extremism

John Calhoun and the coming of the Civil War. Review of "Heirs of the Founders", by H. W. Brands.

Our politics are straining under back-breaking burdens. We are still saddled with several undemocratic compromises of the founders, are corrupted by money and corporate interests, and profess a democracy which in even its best incarnations is, historically, a brief reprieve betwixt tyrannies and oligarchies of various forms, inevitably brought down by the greed, fears, and passions of its subjects. We are experiencing division to a degree not seen since the civil war, and corruption, even treason at the highest levels of government. Where is all this going?

A recent multi-biography focused on the leading politicians of the early to mid-1800's: Daniel Webster, from Massachusetts, Henry Clay, from Kentucky, and John Calhoun, from South Carolina. Yoking them together this way is common in the teaching of this era, but it does something of a disservice to their strikingly divergent contexts and paths. Webster was a natural supporter of Northern interests, including Union, tariffs, but not abolition. He eventually agreed with the compromise of 1850 that enforced the fugative slave policy of the South, since that policy was written explicitly into the constitution. Clay was the most ambitious of the set, leading the Senate through decades of policy and legislative compromise. His lodestar was also Union, made increasingly difficult by the relative economic decline of the South, the entrenchment of slavery, and the fatal compromises that had already been made in the original constitution.

Mysterious, Romanesque bust of John Calhoun, senator and vice president from South Carolina.

John Calhoun was different altogether. While the others tacked repeatedly to maintain the Union and its institutions, Calhoun lit out towards a bitter and uncompromising pro-Southern, pro-slavery position. He was the one who repeatedly threatened secession before the Congress. He was the one who turned intellectual and moral summersaults to defend slavery as consonant with the constitution, the founders, and human decency and progress. This was a time, of course, when Native Americans did not even get this level of discussion- they were packed off to Oklahoma with hardly a bleeding heart on their side. Racism was endemic, and the point of America was not harmony, but the manifest destiny of the Europeans who were remaking the continent. Still, the blatant FOX-news quality of Calhoun's arguments is unmistakable. Here he compares the state of African Americans in Massachusetts to those in the South:

"By the very latest authentic accounts, there was one our of every twenty-one of the black population in jails of houses of correction, and one out of every thirteen was either deaf and dumb, blind, idiot, insane, or in prison. ... The condition of the African race throughout all the states where the ancient relation between the two races has been retained enjoys a degree of health and comfort which may well compare with that of the laboring population of any coiuntry in Christendome; and it may be added that in no other condition or in any other age or country, has the negro race ever attained so high an elevation in morals, intelligence, or civilization."

All this led to a clear break:

"I have, Senators, believed from the first that the agitation of the subject of slavery would, if not prevented by some timely and effective measure, end in disunion. Entertaining this opinion, I have, on all proper occasions, endeavored to call the attention of each of the two great parties which divide the country to adopt some measure to prevent so great a disaster, but without success. The agitation has been permitted to proceed, with almost no attempt to resist it, until it has reached a period where it can no longer be denied or disguised that the Union is in danger. You have thus forced upon you the greatest and the gravest question that can ever come under your consideration: How can the Union be preserved?"

Calhoun brooked no embarrassment or qualm about slavery. As an institution, it was good, not bad; growing, not dying. While Clay and the founders generally hoped that it would wither away, though economic evolution and plain moral decency, Calhoun stood for its unrepentant expansion. The constitution was also behind him. The constitution gave Southern states the representation of 3/5 of its slaves, but none of their voting. The constitution said nothing about any powers the Union might have to restrict slavery in new states. The constution explicitly forbade the harboring of runaway slaves. The country had lost sight of its duties to the South, and were the abolitionists not muzzled from speaking their inconvenient moral truths, the South would have no more of it.

It is a story of a whole section of America gone off its moral rocker, in service of plain greed and conservatism. A religion has also evolved in the South that seems to blend the authoritarianism and social conservatism of Catholicism with independent elite governance and a scrim of protestant theology. When the South did secede, the Union government let loose a torrent of progressive legislation. One senses strongly that we could and would do the same today but for the anchor of a Southern political culture still petrified by true equality, dedicated to feudal economic relations, and to defend itself, still spouting the mantra of state's rights. The map of Red states tells the story.

Political divisions over the last sixty years, by presidential election.

But it is the media and media leaders that serve to normalize immoral positions. Climate change is only an example, but perhaps the clearest and most dire of our time. Failure to act is simply criminal- an act of sabatoge against the future of every citizen and the entire biosphere. A fair portion of our culture, driven by right wing media and its nexus of money and fear, drives an utterly immoral political culture of denial, mean-ness, and blind conservatism. Trump has nowhere near the intellect or facility of John Calhoun, but the brazen support of palpably destructive policies, the headlong divisiveness, the antipodean moral compass have a certain resemblance.

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Deranged Transcription

.. in autism, schizophrenia, and bipolar syndromes.

It is clear that human evolution over the last few millenia has been particularly rapid for mental/cognitive traits. This seems to have created the hazard of unintended consequences in the form of mental illness, when this high-strung and finely tuned system goes haywire. There has been a steady stream of genome variants discovered to be associated with prominent mental illnesses like schizophrenia, autism, and bipolar disorder. These variants are inherited (not sporadic, like the mutations responsible for most cancers) and tend to be either rare or have very slight effects, for obvious reasons.

"The majority of disease-associated genetic variation lies in noncoding regions enriched for noncoding RNAs (ncRNAs) and cis-regulatory elements that regulate gene expression and splicing of their cognate coding gene targets."

One feature that stands out among the genetic variants that have been found to date are that they are rarely in coding regions, thus do not affect the sequence of the protein encoded by the affected gene. Instead, they affect regulation- the delicate mechanisms by which genes are turned on and off in particular places and times. It is now common knowledge that humans have hardly more genes than fish or potatoes. It is gene regulation that makes us what we are, and recent decades have revealed whole new mechanisms and participants in this regulation, such as long non-coding RNAs.

A recent paper conducted a fishing expedition to find how gene regulation varies among people with mental illness, in a quest to find causal changes and molecular patterns characteristic of these syndromes. They had access to thousands of brain samples, and put them through a modern analysis of transcripts, including from 16,541 protein-coding genes and 9,233 genes expressing short or long regulatory RNAs. One theme that came up is that they found many differences among gene splice forms. Most eukaryotic genes are spliced after they are transcribed, being composed on the genome of a series of separate coding exons. This splicing (removing the intervening intronic RNA and joining the coding exons) is highly regulated and for many genes, fundamentally influential on what protein they ultimately produce. Some genes have dozens of different splice forms, many with significantly different roles. For example, a key functional domain like an inhibitor or a DNA-binding region may be left out of one form, converting its encoded protein into one that performs functions precisely opposite to those of the full-length form.

Screen shot from the NIH gene resource, showing the human gene titin, which encodes the largest known protein, which structurally spans the muscle sarcomere. Each green segment is an exon, totalling 363. Each horizontal line is a distinct splice form, varying in which exons are included. Skeletal and cardiac muscle express different splice forms of this protein, and sequence variations in this gene are responsible for some syndromes such as dilated cardiomyopathy.

After putting their brain tissue samples through purification and sequencing of all the RNAs, and alignment with known sequences, the authors came up with a set of differences of gene expression between affected and control subjects. They claim that a quarter of all the genes they looked at were noticeably affected by one of the three disorders they looked at- autism, schizophrenia, and bipolar disorder. Naturally, this finding may be a consequence of wide-spread structural and functional changes in affected brains that may be well downstream from any causative factor. There was relatively little overlap between the three. Schizophrenia showed the most differentially expressed genes/splice forms by far (several-fold more than the others), and shared about half of those seen differentially expressed in bipolar disorder, and one-fifth of those in autism. One might speculate that on the whole, schizophrenia is a more severe disorder which would lead to more dramatic differences in gene expression in an absolute sense.

"Notably, 48 DS [differentially spliced] genes (10%; FDR = 8.8 × 10−4) encode RNA binding proteins or splicing factors, with at least six splicing factors also showing DTE [differential overall transcript expression] in ASD [autism spectrum disorders] (MATR3), SCZ [schizophrenia] (QKI, RBM3, SRRM2, U2AF1), or both (SRSF11)."

Interestingly, the authors also tested (in animals) whether drugs used to treat these major disorders could generate the differences seen above. The answer was no- differential expression was somewhat affected by lithium, but not significantly by the others tested. Secondly, the authors wheeled in a separate method, sifting through genomic variations to find other genes with variations known to be causally associated with these diseases, and guess whether these variations (aka mutations) might affect transcriptional expression. The results did not overlap very well. For bipolar disorder, none of the 17 genes identified by this latter method overlapped with the differentially expressed genes identified by the first method.

Part of the general scheme of the experiment, and schematic results. Isoforms of some genes show differences in disease vs control tissues, and patterns from many such genes and differences can be assembled to diagnose particular cells or processes that are being notably affected. But note in the middle panel that the quantitative difference in the alternative splicing pattern between disease and control for this particular example is minuscule- in the 1 to 4% range. It may be statistically significant, but could be minor in effect. The last panel illustrates fold-change ranges for non-coding long RNAs among the different syndromes and known patterns of cell-type expression, in a schematic sense. Genes known to be expressed in microglia showed particularly significant changes.

So what did they get? Mainly a lot of little fish, and quite a few that had already been suggested to be important for brain function by other methods. One prominent theme was the involvement of immune-related genes. Genes characteristic of astrocyte and microglia cell expression, and of interferon responses, among other signatures, were significantly up-regulated. This agrees with other work indicating that inflammatory mechanisms are used to prune synapses and cells generally in the brain, and this process is over-active in schizophrenia. An example gene is complement C4A, which encodes part of a key immune system that identifies and clears foreign material with the help of phagocytes. It used to be thought that the central nervous system was immune-privileged, i.e. not surveiled by it or affected by it. But that turns out to be very far from the truth, and this gene's overexpression is genetically identified as a causal factor for schizophrenia.

Another big fish they caught was a gene called RBFOX1. Certain spliced forms were significantly less abundant in the affected tissues, supporting a long line of work identifying variations in this gene as candidate causal factors for autism, and its function as an RNA binding protein that regulates the alternative splicing of other genes as well as their later transcript stability and lifetime. Reduced function of this protein is known to increase neuronal excitability and increase seizures. It seems thus to be a key node in neuronal development and functional regulation, through its control of the expression of other genes.

Did these authors find anything new? That is naturally hard to say at this point, since such conclusions would require quite a bit of followup work to analyze the function of novel genes that were found. The expedition showed that it was technically capable of hauling in not only a lot of fish, but many known already to be significant in these syndromes, either causally or as markers and downstream effects. Choosing which to track down to their actual biology is a difficult question- one that must come next. It is a catch that may provide sustenance for many students and post-docs to come.

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Music Notation Needs a Redo

Music notation can be better.

Music notation is one of those conventions that solidified long before it was critically analyzed, and well before the advent of even remotely modern usage. The fact that sharps and flats involve special symbols, either in the key signature or as "accidentals", is a sure sign of a hack that has ossified into a standard- one that is painful to learn and use. But the most painful aspect of modern music notation is that the same note appears in contrasting places in different octaves- on different staffs, and in different locations on a single staff. For example, for normal piano music, where both treble and bass staffs are provided, and the note "C" sometimes hits a line, but elsewhere sits between lines. The position alternates going up the staves because the (C) major scale on which the notation is based has an odd number of notes- seven per octave.

Early music notation, dating from roughly 1000 CE. We don't need no sharps or flats!

These characteristics make note reading, not to mention sight reading, very difficult to learn, a big turnoff to the young students who may otherwise be quite enthusiastic about making music. Ranging from the central hand position is made substantially more difficult by the precisely opposite locations that the farther-ranging notes have in this notation system. All this becomes second nature eventually for advanced and professional musicians, but it is clearly a long and arduous process, needlessly difficult. Indeed, many famous musicians never learned to read music, maybe in part because of its notational difficulty.

One solution is to make smaller staffs, only one per octave, with a one-tone gap between each. This would make each octave look identical, and successive octaves could be stacked as needed. Modern printing could surely make such a system as compact as the current 5-line staff, which carries two octaves, if one counts one supplementary line below and two above.

A chromatic notation with each of the twelve tones on its own level, and an even number of notes occupying a full staff, ready to repeat in a regular way to other octaves.

Another solution is to lay out the whole chromatic scale, which has a separate position for each note in the customary Western 12-tone scales including sharps and flats, as separate notes. The number of notes per octave becomes even (twelve), providing consistency in note position. And the need for sharp and flat notation is reduced if not obviated. A downside is that the representation of chords would change dramatically, relative to the typical triads or sevenths that look so regular on a conventional staff.

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