Reach Out and Touch Some Gene

How activation of RNA transcription works.

One of the great themes of molecular biology that was established quite early was the notion of flexible regulation over gene expression. Only eight years after the discovery of the structure of DNA, and contemporaneous with the discovery of the genetic code that it harbors, Jacob and Monod proposed the operon hypothesis, whereby proteins responsive to outside conditions or other important circumstances (in their case, a protein that bound the nutrient lactose) control the mechanism of transcription of the RNA message from the DNA genome. Jacob and Monod dealt with a repressor, (called lac), which sits on a gene that encodes various lactose import and metabolic proteins. When lactose binds, this protein detaches from the DNA and releases transcriptional repression, allowing the regular apparatus to bind and start mRNA production.

This focus on repressors misled the field for a little while, since it turns out that there are activators as well, in bacteria as well as very abundantly in eukaryotes. New mechanisms of transcriptional repression and activation keep being found, but the main themes have become reasonably settled. Humans encode an estimated 1500 proteins that bind DNA at specific sites and regulate transcription. Add to that all the other apparatus of generic transcription, chromatin management, and indirect regulators, and easily an eighth of our genome functions in transcriptional regulation, which is the dominant mode (though far from the only one) of distinguishing cell types, tissues, and developmental states from each other, responding to stresses and hormones, and generally managing the dynamic internal diversity that comes with being a multicellular organism.

Historically, similar realizations were being made on the genetic side, for instance when Edward Lewis studied a large developmental locus of Drosophila which he called the ultrabithorax complex. Rearrangements and mutations in this region caused numerous transformations of body parts, with such fine gradations, complex patterns, and wide-ranging effects that he concluded that these loci encode regulators of other genes, and that the locus itself was revealing further complexities of the regulation of these regulators. This work began to be published in the fifites, and onwards through the seventies.

One particular focus of studies of transcription over the last few decades has been how activation works. The 1970s saw a dawning realization that many regulators, especially in eukaryotes, activate transcription rather than repressing it, and do so in a synergistic way from modular cassettes of DNA binding sites (called enhancers) that could be tens of thousands of basepairs from the gene being regulated. This led to a looping model, where enhancers bind a mix of proteins that may be specific to some developmental event or stage, and which may comprise both activators and repressors. This DNA-bound complex of proteins then loop around the intervening DNA to help assemble the generic transcription machinery at the start site of the gene. If the activators outweigh the repressors, (in a fashion that is not at all systematic or rule-based, but is graded in its activity, and still not fully understood), then that machinery fires off, polymerizing its way down the gene, extruding the mRNA message as it goes.

But what is the nature of this touching interaction? Many "activation domains" have been isolated, and there hasn't been a very informative theme to emerge from these studies, at least no universal protein sequence pattern. Indeed such domains tend to be unstructured and poorly conserved, with hints of negative charge and hydrophobic character- not much to go on. On the receiving side, among a plethora of studies of the core transcriptional apparatus, a dedicated complex called "mediator" was found to be a central receiver of activating interactions. Since it has over two dozen components, it explains to some degree the lack of uniformity among the activating protein domains reaching from enhancers. 

A recent paper wraps up some of this story by characterizing activating domains in rather thorough fashion. Most interactions in the cell, such as those between DNA-binding proteins and their sites on DNA, are very specific and detailed lock-and-key interactions that make use of steric and electrostatic complementarity. But the activation domain interaction is more of a velcro-like affair, where a broad surface of hydrophobic amino acid side chains, supplemented by a fringe of basic amino acids, binds activation domains that are, as mentioned above, characterized as largely hydrophobic, unstructured, and peppered with acidic residues. The principal target (75% of the time) of all these activation domains is one protein, mediator MED15 (also called GAL11), which has four receiving domains, though other targets exist. This all means that activation can add up synergistically- the more activators are available, the more can bind, and the more strongly bound the whole complex is. It is the perfect system to accomplish graded, sensitive adjustments of activation from modular sets of activators that vary over developmental as well as evolutionary time.

Simple model of the looping interaction from upstream locations (can be tens or even hundreds of thousands of base pairs away) to mediator proteins that interact with "activation domains", here "TAD" on DNA binding proteins. One example of an activating domain is shown, (B), which adopts a helical conformation to expose the hydrophobic residues on one face, (yellow), fringed by acidic (blue, E, but also basic Q residues). The next steps then clear nucleosomes and assemble the polymerase complex at the transcription start.

These researchers used yeast cells to comprehensively find all available activation domains from all plausible DNA-binding proteins (164 in this smaller genome). They tested a tedious series of 53 amino acid-long pieces from these proteins to find specifically active protein segments, and then put them through empirical tests and computer comparisons, ultimately developing a neural network model of what makes a successful activation domain. While they did not find anything unprecedented, they characterized what they found with much greater thoroughness, and then docked it in structural terms with the other half of the interaction, the protein mediator 15

This shows two of the four domains on GAL11 which recieves the binding of activator domains. The colored dots indicate where specific amino acids of transcriptional activator domains dock, computationally. Blue is the charged aspartic acid, docking with positively charged target sites, while yellow and red are the hydrophobic phenylalanine and leucine, respectively. The point is that the locations form a diverse cloud, not fitting specifically into any particular matching structures, and also that the interface is relatively flat, ready to accommodate a similarly flat and variable- possibly even unstructured- activating domain.

This shows two of the four domains on GAL11 which recieves the binding of activator domains. The colored dots indicate where specific amino acids of transcriptional activator domains dock, computationally. Blue is the charged aspartic acid, docking with positively charged target sites, while yellow and red are the hydrophobic phenylalanine and leucine, respectively. The point is that the locations form a diverse cloud, not fitting specifically into any particular matching structures, and also that the interface is relatively flat, ready to accommodate a similarly flat and variable- possibly even unstructured- activating domain.

What was particularly powerful was this group's computer algorithm that was able to find other activation domains, thoughout the human genome, with an accuracy of >80%. This is valuable both as a way to better characterize our genomes and biology, and also to demonstrate a more thorough understanding of how these domains work. Once the GAL11 protein is anchored to an enhancer or set of enhancers via the activating interactions, it (as part of a very large complex of its own- over 20 proteins) loops over to the transcription start site, where it cooperates with other proteins that are able to open up the local nucleosomes and other debris, and attract or activate an RNA polymerase, including extensive phosphorylation of the polymerase's tail. This prompts release of the initiating polymerase from the start site and disassembly of the initiating mediator+other proteins complex, to go off and activate some other gene elsewhere.

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Where Does Surplus Value / Profit Come From in Capitalism?

Marxists say it is stolen from the worker. Capitalists say it comes from risk-taking and managerial work. Who is really doing the work?

One of the pillars of Marxism is that capitalists steal labor from workers. All profits come from excess labor done by workers by the sweat of their brow, which capitalists, through various nafarious means, appropriate for themselves. The workday, for instance, is an artificial construct. What if all the necessary work could be done in three hours? Well, the labor agreement means that the employer has the right to eight. Therefore, employers extract as much value as possible from that time regardless was really needed to fulfill the actual job- value that ends up as profit in the pockets of owners, who do no work at all.

On the opposite side, Chicago school economists hold to a theory of marginal value, where every factor in production is fairly paid for its individual contribution, through the magic of the various markets- commodity, labor, financial, etc.- that they come from. Each of these markets is assumed to be efficient, thus rendering each input to production fairly bid for its contribution, and leading also to a dynamic re-ordering of production systems when conditions change, such as when some inputs become scarce (and their price goes up), or new technologies expand the availability of other inputs, like, say, computation power.

It should be obvious that each of these theories is a fairy tale, (a panglossian one in the neoclassical case), heavily motivated by ideology, while carrying grains of truth. Labor markets are not efficient at all, and businesses work night and day to keep them that way. At the same time, businesses capture profits from countless other streams than the exploited labor of their workers. And in fact, the whole purpose of business is to exploit mis-priced market opportunities- otherwise profit could not exist.

A recent pair of posts on Bill Mitchell's blog delved into the Cambridge controversy- an economist's spat of the early 1960's which was formative in left-wing economics. Many tangential issues came up, such as whether economic growth is more demand-limited or supply limited. But it also dealt with issues of the value of capital, the source of profits, and the accuracy of marginal value theory. To summarize rather brutally, left-wing economists from Cambridge, England argued that business profits were not market-based, but based on social and power relations, cultural tradition, and many other factors besides the markets. Economists from Cambridge, Massachusetts (MIT) argued a classical theory that profits were based in marginal theory on all the market ingredients, and particularly could be approximated by the current interest rate, representing the default alternative to business investment- that is, the marginal value of capital.

The result of the controversy was that the British school successfully pointed out some flaws in the American analysis, which the Americans admitted, to the effect that the general profit rate does not always follow capital intensity, and nor does the individual firm's investment schedule necessarily follow the logic of interest rate-driven margins either. From this molehill, the left made a triumphant mountain, while the mainstream regarded it as a minor hiccup from their ever-more baroque modeling of perfect markets and ideal economies.

Joan Robinson, principal proponent of the Cambridge England end of the Cambridge controversies.

All that said, it is worth being more specific about where profit comes from, and here I confess to going off the reservation of economic convention. While stealing extra labor is surely one of the time-honored methods of making a profit, it is far from the only way. Indeed, businesses can be seen as miners, always on the hunt for those special gems in the environment that cost less than they should, or can be sold for more than they cost. And the opportunities of this sort are endless in variety and scale. 

• difference between supply and demand
• difference between efficient producers and inefficient
• difference between using family members and paying workers from the labor market
• difference between dumping toxic waste and disposing it properly
• difference between hiring an amoral accountant and a lawful one
• difference between buying lower grade inputs for manufacturing
• difference between lying to customers, or not
• difference between running marketing campaigns, or not
• difference between paying taxes, or not paying taxes
• difference between suing competitors successfully, or not
• difference between buying competitors or competing with them
• difference between doing research to find new technologies, or not spending that money, or stealing that technology
• difference between lobbying the government successfully to make protective laws, or not

The scope for finding  money and making profit goes far, far beyond the conventional notion of arbitrage between capital goods and interest rates. Labor is also only part of the picture. Being a typically large part of most company's costs, its treatment and mistreatment is, however, an endlessly fruitful area for losses and gains, not to mention wider social tension. Money and profit can be found under any number of rocks, which is where the mantra of a "business model" comes from. Everyone and every business has some angle by which they make a living.

Are these gems of profit fairly priced in their factor markets? Don't be ridiculous. A coal company only makes money because coal is free. The earth makes no contracts, and nor does the air for the pollution sent up by the power plant that burns the coal. Turning free things, like enslaved or cowed labor, or personal data, or natural resources, or computer power, or shady accounting, or corrupt laws, into money, is the essence of "business models". Finding a way around markets, by collusion, by substitution, by doing without, by corruption, even by clever new technologies, are a business person's top priorities. So not only are markets, when they are used, hardly "fair" in any financial or social sense, but they do not begin to address all the sources of business profit or return to capital.

We can grant that most of this work of finding profitable gems is done by the capitalist or her managerial minions, thus should be accounted to the returns of capital, not to wages stolen from workers. Only in the classical mass industrial enterprise where the raw material costs are negligible and labor is the overwhelming factor would these converge into the same thing as envisioned by Marx. (Though the modern fast food industry, and gig "economy" come to mind as well.) Some of these gems can be valued financially, and can be regarded as capital, obtained via savings and investment and even competitively priced in a marginal accounting. But many cost nothing, and characterize the pursuit of business as more than a dry exercise in accountancy or economics, but rather as a cultural mode, descended from a long tradition of opportunistic ownership / exploitation / employment of others, of technological innovation, trade, and plunder.

Not to put a fine point on it, business is about greed, and in its natural state reverts to rapine and pillage. The Vikings were consummate businessmen, converting earnings into capital- long-boats and other weapons-, which were the backbone of their centuries of pillage all over coastal Northern Europe. Today, we can see a similar process in Afghanistan. The Taliban leverages ruthless terror into power., plundering as it goes along. They can then tell everyone how to live, collect the taxes, and run their many businesses, corrupt or not. 

Whether their state is "business-friendly", their example points to the intertwined nature of state systems and business systems of exploitation. States set the rules, in the ideal case driving business from brutal mafia and gang activities, which are generally socially destructive, if not entirely zero-sum, towards level and transparent playing fields that are at least somewhat constructive, pulling their profits from the mute vaults of nature and its resources instead of from social oppression. But all this depends on the wisdom and foresight of the state. Many "business model" gems mentioned above involve skirting the law, or engaging in activities the law has not even (or yet) contemplated, to make a buck. There is a constant arms race going on, between the "innovation" of private greed, and the capacity of the state to conceptualize, measure, and legislate against new areas of long-term harm. When the business class and Republicans bleat about taxes and "freedom", they (and their pet economists) are explicitly taking one side of this conflict, the side of irresponsible regression to unregulated, irresponsible, and destructive styles of "business". 

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They Thought They Were James Bond

Review of Legacy of Ashes, a history of the CIA.

Why do we still have the CIA? Its track record is atrocious on both operational and moral grounds, and much of its role has been assumed by the NSA and by military intelligence. It is fundamentally contrary in principle to everything the US stands for, making its reputation, such as it is, damaging abroad, and making recruitment at home excruciatingly difficult. It is a testament, in the end, to bureaucratic inertia and its own skills in backroom politics and public relations that it survives at all.

Headquarters of a bloated bureaucracy

Tim Weiner tells a totally biased history of the CIA, proving a truism of intelligence that everything bad ends up on the front page and everything good remains under wraps. This book covers every disastrous escapade from the exploding cigars sent to Fidel Castro to the torture of prisoners in a farflung network of black prisons and those of our "allies" during the "war on terror". What is even worse, however, is how its sterling successes, like its fomented coup against Iranian prime minister Mohammad Mosaddegh, or the arming of Pakistani proxies in the Soviet-Afghan war, turned out, in the end, even more disastrous than its front-page disasters. The Bay of Pigs made the US a laughing stock. But the melt-down of Iranian democracy haunts us and the rest of the Middle East, even the world, to this day.

The CIA has routinely lied to congress and to the president. It has, at other times, lied to the entire nation and world on behalf of the president, such as during the runup to the Iraq war. Its daily brief is notoriously bereft of deep analysis, and its ranks notoriously short of foreign language and cultural skills. 

Towards the end of the book, even while recounting a rising tide of mediocrity and error, Weiner oddly throws in repeated denunciations, evidently drawn from his stable of CIA veteran interviewees, of the underfunding and underappreciation of the CIA over recent decades. All in all, it is a difficult book (and situation) to make sense of. Yet it is clear that the CIA is a disaster zone, and we need to think carefully about how America's intelligence community should operate on a restructured basis.

One thing to note is that the US is simply not adapted, culturally, to run a great intelligence apparatus, as, say, Russia is with its KGB/FSB/SVR/GU. We are an open society with a well-founded dislike of deceit, and are not skilled at it. We also are a lawful society, unwilling to instill the kind of fear / terror that it takes to staff and run such shady operations. Aldrich Ames, for example, is enjoying a pleasant retirement at a medium-security prison in Terre Haute. Jonathan Pollard is now living a heroic retirement in Israel.

So, maybe we need some of the functions of the current CIA. But they should be made as compact as possible, not subsumed in the current bureaucratic dinosaur. The main function it does not need is the gathering of mundane foreign news via newspapers, low-level contacts, and fake visa officers, to create master "intelligence estimates". All that can and should be done by the State Department. Indeed, such functions should be increased with the addition of open person-on-the street contacts all over the world. We are frequently blind-sided by developments that intelligence agencies fail to see based on their derring-do, tradecraft, and focus in the highest echelons, and which normal people in that other society can easily see coming. These functions may even be replicated into red-team/blue-team competitions, with retrospective evaluations carried out to grow successful teams. The understanding of foreign cultures is a difficult task, and putting it into the hands of a white-bread secretive bureaucracy has not been fruitful. 

What would then happen to all the under-cover intelligence that we gather, mostly via the NSA and the satellite services of the NRO? These have been independent of the CIA for a long time. The CIA has not been "central" for decades. So we should dispense with the charade of special knowledge and integrated deep analysis, leaving that to the State department and perhaps the Director of National Intelligence. The CIA should be confined to espionage and covert operation in a focused way on current and future crises. It should not be meddling in Central American countries, running its own private foreign policy. It should not be trying to span the world with agents all over the place. It should not be trying to carve out bureaucratic slices from the NSA and other agencies with better track records.

Whether the CIA can even be successful in such a truncated remit is highly questionable, given its history. But at least it can then be judged more accurately, without all the distractions of routine newspaper reading, world-wide reporting, etc. It should stand or fall in whether it can supply high-level intelligence from our major adversaries- China, Russia, Saudi Arabia, Israel, Iran, and North Korea, in any way beyond our technical resources. And naturally, it goes without saying that its covert operations need to be kept on a tighter leash, run not only by the president, but put on specific timelines of reporting to the NSC (cleared in advance) and select congressional oversight bodies (reported within thirty days). Malfeasance, either in reporting or in execution, would result in consequences such that the CIA fires poorly performing personnel, and keeps only a select and small cadre, perhaps in competing teams.

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Way Too Much Dopamine

Schizophrenia and associated delusions/hallucinations as a Bayesian logic defect of putting priors over observations, partly due to excess dopamine or sensitivity to dopamine.

It goes without saying that our brains are highly tuned systems, both through evolution and through development. They are constantly active, with dynamic coalitions of oscillatory synchrony and active anatomical connection that appear to create our mental phenomena, conscious and unconscious. Neurotransmitters have long been talismanic keys to this kingdom, there being relatively few of them, with somewhat distinct functions. GABA, dopamine, serotonin, glutamate, acetylcholine are perhaps the best known, but there are dozens of others. Each transmitter tends to have a theme associated with it, like GABA being characteristic of inhibitory neurons, and glutamate the most common excitatory neurotransmitter. Each tends to have drugs associated with it as well, often from natural sources. Psilocybin stimulates serotonin receptors, for instance. Dopamine is central to reward pathways, making us feel good. Cocaine raises dopamine levels, making us feel great without having done anything particularly noteworthy.

As is typical, scientists thought they had found the secret to the brain when they found neurotransmitters and the variety of drugs that affect them. New classes of drugs like serotonin uptake inhibitors (imipramine, prozac) and dopamine receptor antagonists (haloperidol) took the world by storm. But they didn't turn out to have the surgical effects that were touted. Neurotransmitters function all over the brain, and while some have major themes in one area or another, they might be doing very different things elsewhere, and not overlap very productively with a particular syndrome such as depression or schizophrenia. Which is to say that such major syndromes are not simply tuning problems of one neurotransmitter or other. Messing with transmitters turned out to be a rather blunt medical instrument, if a helpful one.

All this comes to mind with a recent report of the connection between dopamine and hallucinations. As noted above, dopamine antagonists are widely used as antipsychotics (following the dopamine hypothesis of schizophrenia), but the premier hallucinogens are serotonin activators, such as Psilocybin and LSD, though their mode of action remains not fully worked out. (Indeed, ketamine, another hallucinogen, inhibits glutamine receptors.) There is nothing neat here, except that nature, and the occasional chemical accident, have uncovered amazing ways to affect our minds. Insofar as schizophrenia is characterized by over-active dopamine activity in some areas, (though with a curious lack of joy, so the reward circuitry seems to have been left out), and involves hallucinations which are reduced by dopamine antagonists, a connection between dopamine and hallucinations makes sense. 

"... there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical." - Wiki

So what do they propose? These researchers came up with a complex system to fool mice into pressing a lever based on uncertain (auditory) stimuli. If the mouse really thought the sound had happened, it would wait around longer for the reward, giving researchers a measure of its internal confidence in a signal which may have never been actually presented. The researchers thus presented a joint image and sound, but sometimes left out the sound, causing what they claim to be an hallucinated perception of the sound. Thus the mice, amid all this confusion, generated some hallucinations in the form of positive thinking that something good was coming their way. Ketamine increased this presumed hallucination rate, suggestively. The experiment was then to squirt some extra dopamine into their brains (via new-fangled optogenetic methods, which can be highly controllable in time and space) at a key area known to be involved in schizophrenia, the striatum, which is a key interface between the cortex and lower/inner areas of the brain involved in motion, emotion, reward, and cognition.

Normal perception is composed of a balance of bottom up observation and top-down organization. Too much of either one is problematic, sometimes hallucinatory.

This exercise did indeed mimick the action of a general dose of ketamine, increasing false assumptions, aka hallucinations, and confirming that dopamine is involved there. The work relates to a very abstract body of work on Bayesian logic in cognition, recognizing that perception rests on modeling. We need to have some model of the world before we can fit new observations into it, and we continually update this model by "noticing" salient "news" which differs from our current model. In the parlance, we use observation to update our priors to more accurate posterior probability distributions. The idea is that, in the case of hallucination, the top-down model is out-weighing (or making up for a lack of) bottom-up observation, running amok, and thus exposing errors in this otherwise carefully tuned Bayesian system. One aspect of the logic is that some evaluation needs to be made of the salience of a new bit of news. How much does it differ from what is current in the model? How reliable is the observation? How reliable is the model? The systems gone awry in schizophrenia appear to mess with all these key functions, awarding salience to unimportant things and great reliability to shaky models of reality. 

Putting neurotransmitters together with much finer anatomical specification is surely a positive step towards figuring out what is going on, even if this mouse model of hallucination is rather sketchy. So this new work constitutes a tiny step in the direction of boring, anatomically and chemically, into one tiny aspect of this vast syndrome, and into the interesting area of mental construction of perceptions.

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Various policy scenarios of decarbonization in China, put into a common cost framework of carbon pricing (y-axis). Some policies are a lot more efficient than others. 

Zooming In On The Genome

Better sequencing methods bring the human genome to higher resolution and accuracy.

Most of the progress in DNA sequencing over the last two decades has come in what is known as "short read" sequencing. The dominant company, Illumina, produces massive machines that crank out huge amounts of data, but in the form of tiny individual reads, only about 90 bases long. That means that there is a lot of work on the back end for data analysis to piece everything together. And given the frequent occurence in our genomes of repeats and repetitive sequences in many forms and sizes, these reads are simply too short to fully make sense of it. No amount of assembly magic can make up for a lack of long-range information.

So there has been a second movement of "next generation" sequencing methods, pursuing long reads, of tens of thousands of bases. Several methods exist, but the leader is Pacific Biosciences, (PacBio), whose method tacks down a single polymerase into a special optical well and then uses fluorescence to detect each individual nucleobase incorporation as the polymerase chugs away at the given template. This is not a fool-proof process, being at the single molecule level. While the Illumina system greatly amplifies the DNA and thus raises the signal (which is also ultimately fluorescence-based) to a high and reliable level, these long-read methods tend to have lower reliability. A recent paper described a way around this, featuring a long read system which was used to analyze 34 human genomes to collect new information about large scale structure and variation.

The "weird trick" that PacBio uses is to circularize templates of about 15,000 bases, and then drive the polymerase reaction described above around those circles upwards of fifty times. This allows multiple passes around the same DNA to make up (in volume/repetition) for the inherent error rate of each individual pass. Reads of this size are big enough to surround most forms of repetition and low complexity in our genomes, or at least cover enough landmarks/variants that one repeat can be distinguished from others. Indeed, these researchers could even figure out, based on allelic variants peppered through the genome, which parent each sequence came from, assembling each of the subject's two copies of each chromosome separately. All this makes it possible to assemble whole genomes with unprecedented accuracy, (~1 error in a half-million bases), especially in terms of long-range features and variations.

And that has been a growing area of interest in human genetics- variations in structure that lead to extra copies of genes, insertions, deletions, and altered regulatory contexts.  It is a frontier that has had to wait for these new techniques, while millions of single nucleotide variants have been piling up. Cancers are notorious, for instance, for being caused by accidental fusions of two distant genes whereby some developmental or cell cycle gene function is put under novel and (usually) high activation by some other gene regulatory region. Down Syndrome is caused by a whole-chromosome duplication to trisomy. Smaller deletions and duplications have significant effects as well, naturally.

The new paper digs up twice as many structural variants as previous analyses (and does so from only 37 human genomes, compared to the >2000 genomes used by other analyses) - 107,590 insertion/ deletions over 50 bp in size; 316 inversions, 2.3 million insertions/deletions under 50 bp in size; and 15.8 million single nucleotide variants. Many of these count as normal alleles, of long-standing in the human genome, just difficult to piece together previously. In non-gene regions, these variants may have little effect. Per individual, and in comparison to the current reference human genome, they claim to see 24,653 large structural variants, 794,406 small insertions/deletions under 50 bases, and 3,895,274 single nucleotide variants. This is quite a lot in a genome of 3 billion bases, amounting to about 0.1% of all individual positions that are varying in the population, and almost a million other re-arrangements, deletions, etc.

An example of one transposon (top) that the current paper discovered has jumped several times in succession, from chromosome 3 to chromosome 1, then from that landing spot to two other locations on chromosome 1 and one spot on chromosome 17. Each jump brought along a bit of extra DNA from the originating locus.

The vast majority of these mutations arose from repair events, where the DNA broke and was then fixed either by repair using the other homolog sequence for reference (~65% of cases), or simple blunt end rejoining, with a few percent coming from errors that happen during replication, particularly of repetitive sequences. Another source of mutation is the movement of mobile genetic elements, which encode their own apparatus of transposition to new locations. These researchers found ~ 10,000 that were not present or not identified in the human reference genome (because this is what is generally called "junk"). Their detailed data, in comparison to outside references like the chimpanzee genome, allowed them to assess the ages and relationships of these mobile elements. Most are old fossils and no longer active due to mutation. But others have clear and recent lineages, and are still giving rise to mutations, even causing cancers. One can imagine that genome editing could eventually turn these off permanently, reducing one source of cancer and birth defect risk.

Close-up view of one part of chromosome 3, cytological band q29. Even in this small population sample (individual haplotypes listed down the left side, bottom), there is a flurry of structural variations, including inversions and duplications. (CNP = copy number polymorphism.) At top left is a map of genes located here in the reference sequence (hg38). The light arrow shows the direction of transcription, and the heavy vertical lines are the exons. For example. TNK2 is a protein kinase that relays signals inside cells, is active during brain development, and can be an oncogene when activated or overexpressed, as well as having a role in cell entry by some viruses.

An additional analysis was for trait loci associated with the newly found structural variants. As can be surmised from the sample genomic location diagrammed above, this kind of jumbling of the genome is likely to have functional consequences, either by breaking genes apart, joining them to foreign regulatory regions, or by duplicating or deleting them, in part or whole. The researchers found that roughly half of structural variants that map to known trait loci (called quantitative trait loci, or QTLs), were newly found in this study. So while the accuracy increase may not seem like a lot, it can have profound consequences.

The count of structural variants that differ by population. Superpopulation (region) count in light color, and population-specific in dark color.

Lastly, this new fund of variation data allows another look at human ancestry. As we know, the bulk of human variation remains in Africa, and that is reflected in structural variation as well as other forms of variation. Populations elsewhere are far less diverse, due to the small groups that founded those populations from the mother-continent, and perhaps also through the new selective pressures that swept those populations, either positively or negatively. Twenty years after the original human genome was published, it continues to be a clinical and research goldmine, but also requires ongoing work to bring to complete accuracy- something this work gets us much closer to.

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• Yes, collusion.

We Are Still Poisoning the World

Anthropogenic environmental poisonings, intentional or not.

We have an EPA and long-standing bureaucracies of environmental review, so our environment should be clean, right? Well, rivers may not be burning anymore, but that doesn't mean things are as tidy as they may look. Humanity has proven capable of inventing and selling innumerable chemicals, creating a situation that is far more complex than any kind of precautionary testing or policy making can address. Shocking issues have arisen in recent years that remind us that there is a great deal more to do if we are serious about caring for the biosphere.

6PPD is engineered to react with ozone to become 6PPD-quinone. That protects tire rubber, but kills salmon.

A recent paper showed that the decline of salmon all over the Western US is attributable to a completely unanticipated source. An obscure chemical from automobile and truck tires, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), reacts with ozone to form an incredibly toxic compound, which is killing salmon exposed to roadway runoff. This chemical makes up about 1% of tire formulas, and is meant to react with ozone to protect the rest of the rubber in the tire from degradation. The yearly rate of tire rubber degradation and emission is about a pound per person, leaving a great deal of this poison in the environment. So ... does anyone care? A web search for 6PPD yields very little news, despite this being a clear environmental crisis.

Putting the tire problem in perspective. LC50 is the lethal concentration where half of organisms die.

An even more complicated story came up recently from the southeast of the US, where eagles are dying from a mysterious neurological syndrome. It turns out that an invasive water weed, hydrilla, responds vigorously to agricultural nutrient runoff pollution, and accumulates bromine, of all things. This in turn leads to a bloom of an algal parasite, Aetokthanos hydrillicola which grows on the hydrilla, and produces, as cyanobacteria are wont to do, various toxins, in this case a highly brominated amino acid derivative which causes the eagles' lethal neurological disease.

AETX, a heavily bromimated derivative of the amino acid tryptophan. This is a toxin, causing myelinopathy in eagles after it bio-accumulates in the food chain from ducks and other aquatic browsers that eat the cyanobacterial-infested hydrilla. 

But this is just the tip of the iceberg, based on incredibly painstaking work by chemists newly armed with today's analytical chemistry tools to look at particularly dramatic cases of dead wildlife. What about the lead in firearm ammunition, which litters the countryside and shatters into poisonous shrapnel in its targets? What of the intentional poisonings by farmers and ranchers, that are killing condors in the Andes? What of the landfills and coal ash heaps, and whatever leaches out of them? And what of the mountains of plastic that are increasingly filling the planet's waterways and oceans? They are not just physical nuisances but leach out an uncountable array of obscure chemicals. 

These are slow-motion Chernobyls, which need to be taken seriously and mitigated by a more precautionary approach to new products, a life-cycle approach to collecting and reprocessing existing products, and more investment in cleaning and protecting the environment.

• Not quite alive, not quite dead ... what happens after you get that RNA vaccine injection. 
• Bach, slow and easy.
• Notes on antitrust.
• Are we heading towards a "managed" democracy?
• Carbon tax, now! Or maybe carbon neutral products at slightly higher prices?

Gears Within Gears Within Gears

What the Antikythera mechanism says about the technology and culture of Western antiquity.

A recent paper has laid out a complete reconstruction of the Antikythera mechanism, which was an astronomical computer made around 50 to 200 BCE. It is a machine of breathtaking scope and ambition, far beyond what the ancient world was thought capable of- a detailed model of the motions of all the planets of the day, sun, moon (with phases), plus on the back, detailed predictions of solar eclipses and, in true sports page fashion, schedules for the most popular panhellenic games. All this was available decades in advance, though a true modeling computer that the user could wind through at will, forward or back. As a bonus, an instruction manual was inscribed on the back.

An artist's rendition of the current researcher's proposals about the front face of the Antikythera computer. The moon (black and white) revolves around the earth at center, with phases reflected in its rotation. Outer rings and pointers successively portray the Sun, Mercury, Venus, Earth date, Mars, Jupiter, and Saturn. A knob at the side would have allowed the user to run it.

To understand the detailed mechanisms and proposals of this research group, watch their video. No one would have known about this technology had not some sponge divers found a ~75 BCE wreck off the coast of Antikythera in 1900. One of the many artifacts was a lump of bronze, with a clearly mechanism-like structure but heavily corroded. Indeed only a third of the original was ever found, and it has taken all this time, including recent intensive X-ray examinations of its inner workings and inscriptions, to figure out its full splendor.

A partial rendition of the computer's inner workings, with gears noted with their numbers of gear teeth. Eccentric motions were provided by bars connected to gear-mounted pins off-set from the gear's pivot center.

One of the more puzzling aspects of this device, on a purely technological level, is how the precise machining was done, all in bronze. The front face displays at least nine separately moving dials or pointers, each driven by one of a set of nested tubes making up the central shaft of the computer. Could the Hellenistic Greeks cast bronze to this kind of uniformity and thinness? Or did they have lathes with such precision? What can be assumed is that this mechanism is not alone, and must have been the product of an ongoing tradition of precision device manufacture- a long technological evolution that accumulated the numerous ingenious solutions and remarkable miniaturization evident in this device. How could such a tradition have otherwise so thoroughly evaded historians and archeologists? And what became of this tradition into Roman times?

The astronomy that this device is based on has its roots with the Babylonians, who were avid readers of the skys and its many cycles. The gears within accord with various grand cycles with which key events, like the position of the moon or planets, recur with regularity. For example, the Saros cycle is when the Earth, Moon, and Sun line up for an eclipse, and recurs every 18 years, 11 1/3 days. The gearing in the Antikythera mechanism goes through five different pairings to come up with the 940/4237 ratio that approximates the 18 year cycle every four turns of the crank. The Greeks naturally contributed their own astronomical theories, such as a conviction in the regularity / sphericity of the planetary orbits, despite their wayward motion.

All this tells us strongly that these ancient people were every bit as inventive and thoughtful as we are. But they had very different cultural conceptions and resources to work with. The most frustrating aspect to this amazing story is why this inventiveness did not lead to a more general technological revolution, instead sputtering out with the fall of Rome and the fallow Dark Ages, before technological development resumed at a high level during the later Middle Ages.

I think the answer needs to be put down to the class relations and nature of work in the ancient world. Capitalism certainly was not lacking. Antiquity was just as capitalistic as modern times, with an extremely free business sector able to finance wide-ranging trade and manufacturing operations, and merchants occupying the pride of place in Greek and Roman fora- the malls of their time. The story of Crassus extorting Romans of their burning properties in return for fighting the fire tells you all you need to know about the nature of capitalism in these times. It was red in tooth and claw. But that was not enough to foster technological development on a broad basis.

Rather, slavery and vast inequality made work a degraded, mean affair, beneath the dignity of aristocrats. Their minds were on government, law, military conquest, art, and philosophy. Anything but practical affairs of efficiency, improved production, and technological advancement. Work was secondary to power relations- the essence of a slave society. We have seen this in the Southern culture of the US under slavery. It was obsessed with pursuit of "refinements" and honor. Even though labor was expensive in the form of slaves, and its management a social imperative of the highest order, the idea of supplementing it or replacing it via technology does not seem to have been a high priority. The cotton gin was invented, not by a Southerner, but by Eli Whitney of Massachusetts.

It is a general problem of highly unequal societies, that the maintenance (and defense) of inequality takes on a large part of the mental space of the society, (particularly its educated elite), overtaking the motivations that in a more egalitarian society- where all participate in work and all are eager to adopt improved methods in the work they all share in- that promote the development and propagation of technological advancements. (Think of the revolutions in mechanized agriculture in midwestern America in the late 1800's.) In scholarship as well, the segregation of abstract philosophy and other written forms / stores of knowledge into ivory towers, as was common in Hellenistic culture, reflected the same cultural stratification and lack of concern with the day-to-day drudgery that formed the rather static basis of economic existence.

• Heat pumps.
• Anonymous member of Biden administration speaks out.
• Forests are falling.
• Marine ecosystems, dying.

Size and Consciousness

Are flies conscious? Are neurons conscious? How many neurons make up a thought?

Are animals conscious? Descartes thought not, consigning them to mere mechanism. But obviously, he was wrong, as the evidence of feeling and consciousness is all around, in the animals we can see frantically trying to get into our bird feeders, chasing each other around for play and sex, and raising their young with exquisite care. If they are mere mechanism, then so are we. Now, we consign only plants and invisible microbes to the zone of no-consciousness, though we could be mistaken there as well. Consciousness seems to be defined by some mental and emotional engagement with the world that is responsive, built around modeling of how things are and are wished to be, networked in a way that puts the emotions and the models in close relation with each other. Bacteria have desires too, but they do not have the apparatus of feeling about them and planning around them that would suggest that they are conscious.

Flies, however, are a different story. They hunt for food, victims, mates, avoid pain and escape danger, and in most cases have visual, tactile, and olfactory worlds of substantial complexity. Flies have become leading model systems for neurobiology, even up to studies of consciousness. A recent paper asked whether one of the leading theories of consciousness, integrated information theory, could be applied to flies. This theory posits that consciousness is not a single thing or location of mental processing, but the network flexibly binding together many mental modes such as feelings, sensations, memory, planning, and analysis to form that shifting, yet durable, sense of a self at the center of our being. Specifically, it posits that reductions of consciousness, such as induced by anaethesia or sleep, can be analytically, even quantitatively, characterized by reductions of network size that should be commensurate with the reduction of subjective consciousness. This idea has started to inform the quite practical problem of evaluating levels of anaesthesia in humans, as well as rare neurological conditions such as "locked-in" states, using scanning technologies and network analyses of remaining brain function.

The default hypothesis, of low complexity and no consciousness for a fly brain, would postulate a fully one-directional processing system, going from visual inputs to action outputs, with little networking or complexity in between. The rapid, and often stereotypical, reflexes of flies might support this kind of view. But we now know, after decades of trying to make video cameras smarter, that that is no way to build a visual system, let alone a generally intelligent brain. These researchers obviously find something quite different- complex feedback and integrated information systems, detectable with their electrodes which are mercilessly plugged into their subject's tiny brains.

"In stark contrast to a view which assumes feedforward architecture for insect brains, especially fly visual systems, we found rich information structures, which cannot arise from purely feedforward systems, occurred across the fly brain. Further, these information structures collapsed uniformly across the brain during anesthesia. Our results speak to the potential utility of the novel concept of an “informational structure” as a measure for level of consciousness."

Collapse of larger information structures on anaesthesia, in flies.

Flies have about 100,000 neurons, a far cry from the ~100 billion neurons we have. But as recent work has claimed, it only takes about 14 neurons to constitute a distinct thought or response, so flies have plenty of brains for thought, and quite possibly consciousness. The current workers do not, in the end, pronouce on the capability of flies to have consciousness, or have it in a way that resembles ours. But in addition to finding clear markers of integrated information networks that decline on anaesthesia, they cite past literature that shows that flies share molecular, cellular, and structural themes with mammalian brains, and show attention, memory, feature integration, and long term planning. So I think it is fair to assume that they are a good model for some modest level of consciousness, and perhaps we should regard them as more than nuisances.

• We all need to get on board, on climate change, and other biosphere issues.
• The evangelical toxic stew, etc.
• Liberals hate god.
• Thoughts on the Wuhan lab.
• Fossil companies will stop at nothing. Or do anything.
• Some Texas payback.

Worker Exploitation at the Krusty Krab

What does SpongeBob have to tell us about capitalism?

Capitalism is a total cultural system, not just an economic mode or principle. It encompasses class relations, media and consumer culture, and views on the importance of most aspects of life. That includes movies made for children, who are taught how to take their places, and stay in them, in this reigning system.  While SpongeBob SquarePants may have started out as a marine organism, he was animated into a loving friend and happy worker, getting into various scrapes and adventures with his octopus, starfish, and squirrel friends. Positivity is the main theme, since SpongeBob bounces back from every reverse and challenge with renewed enthusiasm, everything works out, and all adventures end happily.

The boss is Mr. Krabs. SpongeBob is the short-order cook, creating the Krabby Patties that draw the entire population of Bikini Bottom to their restaurant, the Krusty Krab. Especially, the patrons are drawn away from the other establishment, Sheldon Plankton's Chum Bucket. We may note at the outset that only one regular character in the series is accorded an honorary title- Mr. Krabs. Like Mr. Potter and other bosses of film lore, the boss position is not just an economic function, but a social pedestal. SpongeBob is the epitome of an exploited worker, happily filling orders, then scrubbing the whole kitchen down at the end of the day, while oblivious to his true value to the establishment. Is he paid fairly? Of course not. He is barely paid at all, and children are taught the lesson of complete abandonment of any hint of whining, disgruntlement, or entitlement to fair treatment in this workplace.

Archetypal capitalist, Mr. Krabs.

This pattern is, incidentally, painfully evident this weekend, as the NCAA tournament exhibits a billion dollar entertainment and gambling enterprise built on the unpaid labor of enthusiastic young athletes trapped in an exploitative system. Only when they join unions in the pro leagues will a few of them be paid fairly. Exploiting youth is still remarkably common, from the fast food industry to the research establishment.

In the current movie, SpongeBob does take some time off, for the important matter of tracking down his pet snail. The Krusty Krab promptly goes down the drain, and Mr. Krabs even goes so far as to join the crew in tracking down SpongeBob and friends to haul them back to Bikini Bottom. He even evinces some feelings. But any recognition of the business value, and monetary value of SpongeBob, in any way that leads to better pay, conditions, or partnership? Not on your life. Not in this ecosystem.

• Review of bad boss behavior.
• US policy in Afghanistan peddles fantasies.
• Happy Easter! 
• And more guns!
• Religion was the basic problem, not sex or race.

Transmission of SARS-CoV2

Reflections on viral spread.

This is a brief update based on studies of SARS-CoV2 transmission over the course of the pandemic. They mostly nail down features that we already know, and offer a comparison with influenza, which has interesting differences in its transmission. One observation is that influenza has been eradicated to an astonishing degree by our efforts to prevent SARS-CoV2 transmission, a testament not only to the lower transmissibility of influenza, but also to the regular round of death and illness that we have been putting up with for millennia without much complaint.

After all the hand-wringing about hand-washing, we gradually learned that this new virus is almost exclusively passed by aerosols through the air, with limited range in space and time. Also that, despite the infinitesimal size of the virus, that face masks of many kinds are effective in knocking down both emission and reception of viral innocula by several-fold. This is doubtless because both the viruses with their lipid coats, and the moist aerosols they reside in, are quite sticky, prone to capture by even rough cloth filters with channels many times the size of a viral particle. The notorious superspreader events are characterized by 

• indoors, close physical proximity to others
• limited air circulation
• an infected person, typically asymptomatic, engaging in
• vocal activity, like singing or loud talking
• with no mask

Scale drawing of surgical mask fibers, against viral and aerosol particle sizes.

Meditation is not conducive to transmission, nor do most infected people transmit their infection. Superspreaders seem to have a very high viral load in key areas of their vocal or respiratory tracts that leads to abundant aerosol emissions with high viral counts. For recipients, it takes numerous viruses to establish an infection- something like 300 for influenza, and something similar for SARS-CoV2. This is a live virus count, not counting inactive viruses, which are always part of the produced and transmitted population of particles. The reason is probably due to our various innate clearance mechanisms, both physical and molecular, meaning that only one virus may get through to successfully infect someone, out of a population of thousands that that person breathed in. 

SARS-CoV2 transmission vs influenza. SARS-CoV2 seems to survive longer in air, leading to more infections in enclosed spaces. Being outdoors subjects the aerosols to getting blown away, and to purifying UV light. This graph does not show it, but SARS-CoV2 also differs in having high viral loads prior to symptom onset, or sometimes without any symptoms, making isolation and contact tracing very difficult.

Additionally, infection by one or few viruses may present a speed problem, where they can not grow an infection fast enough relative to the ability of the immune system to respond and put out small fires. Only if the inoculum immediately generates a large conflagration (think Molotov cocktail) is the fire department overwhelmed, at least for a few days. This leads in turn to the fascinating prospect of mass inoculation with small doses of the virus. Understandably, this is not a popular idea, with its similarity to playing roulette. It resembles the old-fashioned method of small pox inoculation, which used to be done with small doses of actual small pox, not cow pox as was later introduced by Jenner. 

But it may be a significant explanation behind the enormous conundrum of the low impact of Covid-19 on tropical and low-income countries. These countries (India, Central America, Nigeria) show quite high seropositive rates, indicating wide-spread infection. But their death rates and hospitalization rates are very low, and they have escaped this pandemic with relative ease. While reporting issues and pre-existing immune exposure are possible explanations, so is a possible warmer outdoor culture with lower innocula and lower-severity infections. An interesting aspect of inoculum size is that it can have far-reaching consequences, with lower-level infections leading to smaller viral counts in the aerosols emitted, thereby causing smaller, less-severe infections in the next recipients.

The study of viral transmission and infectivity could have profound effects on how we deal with this and similar diseases, and one has to say that it has been frustrating that our knowledge of it remains haphazard, and has been so slow in coming, with such mediocre experiments, false starts and poor messaging.

• Restaurants? Don't do it.
• Reclining on an airplane? Don't bet on it.
• Future nuclear power.