Mutations That Make Us Human

The ongoing quest to make biologic sense of genomic regions that differentiate us from other apes.

Some people are still, at this late date, taken aback by the fact that we are animals, biologically hardly more than cousins to fellow apes like the chimpanzee, and descendants through billions of years of other life forms far more humble. It has taken a lot of suffering and drama to get to where we are today. But what are those specific genetic endowments that make us different from the other apes? That, like much of genetics and genetic variation, is a tough question to answer.

At the DNA level, we are roughly one percent different from chimpanzees. A recent sequencing of great apes provided a gross overview of these differences. There are inversions, and larger changes in junk DNA that can look like bigger differences, but these have little biological importance, and are not counted in the sequence difference. A difference of one percent is really quite large. For a three gigabyte genome, that works out to 30 million differences. That is plenty of room for big things to happen.

Gross alignment of one chromosome between the great apes. [HSA- human, PTR- chimpanzee, PPA- bonobo, GGO- gorilla, PPY- orangutan (Borneo), PAB- orangutan (Sumatra)]. Fully aligned regions (not showing smaller single nucleotide differences) are shown in blue. Large inversions of DNA order are shown in yellow. Other junk DNA gains and losses are shown in red, pink, purple. One large-scale jump of a DNA segment is show in green. One can see that there has been significant rearrangement of genomes along the way, even as most of this chromosome (and others as well) are easly alignable and traceable through the evolutionary tree.

But most of those differences are totally unimportant. Mutations happen all the time, and most have no effect, since most positions (particularly the most variable ones) in our DNA are junk, like transposons, heterochromatin, telomeres, centromeres, introns, intergenic space, etc. Even in protein-coding genes, a third of the positions are "synonymous", with no effect on the coded amino acid, and even when an amino acid is changed, that protein's function is frequently unaffected. The next biggest group of mutations have bad effects, and are selected against. These make up the tragic pool of genetic syndromes and diseases, from mild to severe. Only a tiny proportion of mutations will have been beneficial at any point in this story. But those mutations have tremendous power. They can drag along their local DNA regions as they are positively selected, and gain "fixation" in the genome, which is to say, they are sufficiently beneficial to their hosts that they outcompete all others, with the ultimate result that mutation becomes universal in the population- the new standard. This process happens in parallel, across all positions of the genome, all at the same time. So a process that seems painfully slow can actually add up to quite a bit of change over evolutionary time, as we see.

So the hunt was on to find "human accelerated regions" (HAR), which are parts of our genome that were conserved in other apes, but suddenly changed on the way to humans. There roughly three thousand such regions, but figuring out what they might be doing is quite difficult, and there is a long tail from strong to weak effects. There are two general rationales for their occurrence. First, selection was lost over a genomic region, if that function became unimportant. That would allow faster mutation and divergence from the progenitors. Or second, some novel beneficial mutation happened there, bringing it under positive selection and to fixation. Some recent work found, interestingly, that clusters of mutations in HAR segments often have countervailing effects, with one major mutation causing one change, and a few other mutations (vs the ancestral sequence) causing opposite changes, in a process hypothesized to amount to evolutionary fine tuning. 

A second property of HARs is that they are overwhelmingly not in coding regions of the genome, but in regulatory areas. They constitute fine tuning adjustments of timing and amount of gene regulation, not so much changes in the proteins produced. That is, our evolution was more about subtle changes in management of processes than of the processes themselves. A recent paper delved in detail into HAR5, one of the strongest such regions, (that is, strongest prior conservation, compared with changes in human sequence), which lies in the regulatory regions upstream of Frizzled8 (FZD8). FZD8 is a cell surface receptor, which receives signals from a class of signaling molecules called WNT (wingless and int). These molecules were originally discovered in flies, where they signal body development programs, allowing cells to know where they are and when they are in the developmental program, in relation to cells next door, and then to grow or migrate as needed. They have central roles in embryonic development, in organ development, and also in cancer, where their function is misused.

For our story, the WNT/FZD8 circuit is important in fetal brain development. Our brains undergo massive cell division and migration during fetal development, and clearly this is one of the most momentous and interesting differences between ourselves and all other animals. The current authors made mutations in mice that reproduce some of the HAR5 sequences, and investigated their effects. 

Two mouse brains at three months of age, one with the human version of the HAR5 region. Hard to see here, but the latter brain is ~7% bigger.

The authors claim that these brains, one with native mouse sequence, and the other with the human sequences from HAR5, have about a seven percent difference in mass. Thus the HAR5 region, all by itself, explains about one fourteenth of the gross difference in brain size between us and chimpanzees. 

HAR5 is a 619 base-pair region with only four sequence differences between ourselves and chimpanzees. It lies 300,000 bases upstream of FZD8, in a vast region of over a million base pairs with no genes. While this region contains many regulatory elements, (generally called enhancers or enhancer modules, only some of which are mapped), it is at the same time an example of junk DNA, where most of the individual positions in this vast sea of DNA are likely of little significance. The multifarious regulation by all these modules is of course important because this receptor participates in so many different developmental programs, and has doubtless been fine-tuned over the millennia not just for brain development, but for every location and time point where it is needed.

Location of the FZD8 gene, in the standard view of the genome at NIH. I have added an arrow that points to the tiny (in relative terms) FZD8 coding region (green), and a star at the location of HAR5, far upstream among a multitude of enhancer sequences. One can see that this upstream region is a vast area (of roughly 1.5 million bases) with no other genes in sight, providing space for extremely complicated and detailed regulation, little of which is as yet characterized.

Diving into the HAR5 functions in more detail, the authors show that it directly increases FZD8 gene expression, (about 2 fold, in very rough terms), while deleting the region from mice strongly decreases expression in mice. Of the four individual base changes in the HAR5 region, two have strong (additive) effects increasing FZD8 expression, while the other two have weaker, but still activating, effects. Thus, no compensatory regulation here.. it is full speed ahead at HAR5 for bigger brain size. Additionally, a variant in human populations that is responsible for autism spectrum disorders also resides in this region, and the authors show that this change decreases FZD8 expression about 20%. Small numbers, sure, but for a process that directs cell division over many cycles in early brain development, this kind of difference can have profound effects.

The HAR5 region causes increased transcription of FZD8, in mice, compared to the native version and a deletion.

The HAR5 region causes increased cell proliferation in embryonic day 14.5 brain areas, stained for neural markers.

"This reveals Hs-HARE5 modifies radial glial progenitor behavior, with increased self-renewal at early developmental stages followed by expanded neurogenic potential. ... Using these orthogonal strategies we show four human-specific variants in HARE5 drive increased enhancer activity which promotes progenitor proliferation. These findings illustrate how small changes in regulatory DNA can directly impact critical signaling pathways and brain development."

So there you have it. The nuts and bolts of evolution, from the molecular to the cellular, the organ, and then the organismal, levels. Humans do not just have bigger brains, but better brains, and countless other subtle differences all over the body. Each of these is directed by genetic differences, as the combined inheritance of the last six million years since our divergence versus chimpanzees. Only with the modern molecular tools can we see Darwin's vision come into concrete focus, as particular, even quantum, changes in the code, and thus biology, of humanity. There is a great deal left to decipher, but the answers are all in there, waiting.

• Who's the poodle?
• We are going totally tin-pot.

Fifty Trillion Dollars Are Missing!

Bernie Sanders says that the last fifty years have seen a massive wealth transfer... to the rich.

Bernie Sanders has a new hook for his discussion of inequality. The Rand (AKA Bland) corporation has a study out that shows that the share of income going to workers over the last fifty years has declined to the point that, cumulatively, fifty to eighty trillion dollars have gone missing. Well, they have not gone to workers, but rather to non-workers: capitalists, shareholders, parasites; generally the 1%. 

The basic mechanism here is that capitalism is built on top of a labor market, where workers are paid only what the competition among them renders suitable to sort them into needed jobs. It is not built to fairly share the gains from their work or anyone else's work. In fact, it is built to skim off all the gains / profits and send them to shareholders, owners, managers ... anyone who has power in the capitalist system, which the workers surely do not. Workers get other rewards, but a share of the profits is not one of them. They are regarded as a necessary expense, like feedstocks and machinery, and their cost is to be minimized assiduously, now with robots and AI where possible. I learned this in dramatic fashion when a company I worked for, where the CEO chummily addressed us a team members and collaborators in the grand adventure of bioinformatics, sold the company and took all the winnings for himself.

With that in mind, it becomes obvious where the 50 trillion has gone to. It has been shared out among those who have real power in the capitalist system. First comes management. Managers hold the keys to the finances and the profits. They tell the board what is going on. They have been theoretically upgraded over the last seventy years from employees to entrepreneurs, and have taken shockingly increased amounts from the till during that time. Second come the shareholders, who have been theoretically upgraded from stakeholders in the corporate enterprise to the sine qua non of the corporation- its very soul and purpose, not as a "company" of people, or or a part of a wider culture, or a service rendering organization, but as a money gathering entity. Money that is raked up from whatever the "business model" might be into the pockets of shareholders, with the management as a necessary, if unfortunate, intermediary, and employees as an afterthought.

Ownership is the medium of power in capitalism. The shareholders are part-owners, and their interests are built into the stock market system, which is a perpetual readout of the value of each share. Analysts are constantly sifting through the value of each enterprise in terms of current assets and future potential. Corporations buy each other based on these valuations, and bankruptcy awaits those who lose control of their business model and fail to send money back to the shareholders. What the company produces, or its quality of work life, are completely irrelevant to its value. Whatever money is made over costs is shipped out to shareholders, in the form of dividends, share buybacks, or re-investment towards future growth and greater value. Managers have some power in this system, and have been able to capture quite a bit of the winnings, but workers have essentially none.

Labor markets tend to settle on what employees need to get by, rather than on the worth of what they produce. No compensation review or salary offer makes any reference to productivity or worth of the product. They are always keyed to what the market will bear.. the job market, that is. And job applicants are always in a weak position, since unemployment is such a catastrophic prospect. The choice at most interviews, especially the crucial first one out of school, is some pay or no pay. Employers work very hard to avoid competing for labor, with all kinds of illicit agreements among each other, and a carefully cleansed information landscape where workers don't know what others are being paid. Especially at the low end, this leads to workers competing for crappy jobs that pay little, because the there is always someone who is unemployed who, in light of their dire plight, can make do with even less. 

So, as the US economy has grown, growing things, making things, and gaining productivity year over year, little of that has trickled down to workers. Look at people's lives on the lower end of the economic ladder, and conditions have not visible improved. Indeed, homelessness and hunger are increasingly, instead of decreasingly, common. The middle classes have some increment of technology, like computers, smart phones, and streaming, but the living standard otherwise has not advanced noticeably, even while population pressures increase and the natural world has degraded. This arises simply from the structure of capitalism, when it is taken seriously and grows into the kind of untouchable gestalt it has become over the recent decades. 

And it is obvious that this is bad. Bernie Sanders is completely correct to point out that Americans across the spectrum could be much better off if the 1% got less of the income and wealth, and the rest of the citizenry got more. Inequality is obviously corrosive socially and politically, quite aside from the misery it causes at the lower end of the economic ladder. The capitalist system as we practice it is a relic of feudalism, when capital was scarce, sword and blood trumped merit, and serfs knew their place.

There are many ways to approach this problem, which is incredibly systemic and entrenched. Obviously we need to start with a bit of a cultural reboot that reconceives corporations as cultural entities with important roles and stakeholders that go beyond just making a dollar. We need a minimum wage that pays not just subsistance, but a normal, civilized living. Unions are another, if quite fraught, way for workers to retake power in the capitalist ecosystem. We need a tax system that values labor income over passive, unproductive income, and which taxes accumulated wealth as well. Employees should have a seat at the table in all companies- the corporate board table. We need serious regulation and enforcement that levels the playing field for companies that play by the rules, and sets rules that not only sustain, but build, society and the environment over the long haul.

Another idea that is quietly gaining revolutionary steam is employee ownership. There is an excellent book that discusses this, as it is currently practiced by hundreds of companies in the US. One example is the Publix supermarket chain, which has been wholly employee owned through five decades of growth, and is by far the largest such company. While the ESOP (employee stock ownership plan) model may start with a company stock buying plan, the serious work comes with majority ownership by employees. There are about 14 million employees in the US with some kind of company stock ownership plan, and 650,000 who majority-own their companies. This is usually arranged by a loan-financed buyout from a founder or other owners. Then the proceeds of the business pay off the loan as the employees accumulate distributed stock. This mode of buyout is an excellent way to transition from the early entrepreneurial phase of a company to a mature business, as it keeps the company culture intact and avoids the many problems of private equity, which may debt-strip a target company and leave it in bankruptcy, or of public stock ownership, which leads to disinterested owners that demand short-term financial performance over long-term health. 

This book is a bit thin on how such companies are managed and how the stock allocations and valuations are made. The stock is partially restricted against outside sale, (though some ESOP companies are publicly traded in part), so companies typically engage experts to value themselves each year. Employees gain stock with time, so it becomes a seniority system, a bit like waiting for a pension or union seniority. That is again not entirely fair to employees who may contribute more despite being young. At any rate, these companies still have professional management, but since it is all employees on the board, and with open financials, there is a track record of fewer layoffs, better morale, more cooperation, and ultimately, better financial performance. And critically, profits are not dispersed to faceless and uninterested "investors", but to the employees.

Imagine if every mature company was not buffeted by stock market analysts and fads, not bled dry by stock buy-backs to fund rich investors, nor haunted by the specter of a private equity strip-and-dump, but was owned wholly by its own employees, who reaped the profits of their collective work and controlled its conditions as well. As increasing numbers of companies become employee-owned, one can imagine a phase transition (analogous to the universality of certain benefits like health insurance) where people just would not want to work anymore for other kinds of companies. Small and startup companies would have to share equity, (as they used to do in Silicon Valley), and would naturally progress as they grew to broad ownership by every employee. That would be amazing! 

• Predation, chaos, and crime are the policy.
• Unitary, schmoonitary.
• Half an hour on how terrible medicare advantage is.
• A new way to heat, together.

Students Deserve Mentors

The best form of education is personal mentoring. More of our educational and work system should get back to that model.

We learned some important things from the Covid pandemic. One is that fiscal stimulus really works. Another is that mRNA vaccines are highly effective, and their rapid and flexible development cycle makes them a superior platform for future vaccines. And another is that social interaction is deeply important, especially for young people. We all got used to Zoom, but for school children, that was a poor substitute, when it was even possible. Children were left significantly behind both academically and socially.

A recent segment on the PBS NewsHour touched on this in a discussion of adolescent development. Its message was that learning requires challenging opportunities and human relationships. Adolescents are going on a heroic quest to become adults. They thrive on active engagement with the world and need models of successful adulthood to learn from. How to provide these key functions in an optimal way? We know how to do this- by apprenticeship and mentorship. This model has been understood forever, from the schools of Athens to the medieval trade guilds to the graduate schools of contemporary academia. My grandfather was a baker in Germany, and in his turn trained many apprentices and journeymen to be bakers. I went to graduate school, which turned out to be a glorified apprenticeship under a renowned researcher, then went on to a journeyman position (aka post-doc) with another mentor. This model is an education in many dimensions- the technical ingredients of a craft, the management practices that make a successful organization, how to participate in a larger community that pursues socially important goals, and the discipline and moral integrity it takes to be a competent adult, capable of leadership.

Example of a certificate of attainment of mastery, 1927, for a bricklayer, attested by his mentors and examiners.

However, as a society, we are reluctant to make these kinds of investments in children and adolescents. Efficiency demands that class sizes be large, colleges impersonal, and money squeezed out of the system. Companies clamor for fully trained job candidates, expecting students to go into debt in trade schools before being hired into a paying job. Few young people get the kind of lengthy, personal training that they would most benefit from. Mentorship becomes a hazard of chance, if a boss in an early job takes an interest, or a teacher decides to make extra time.

Principally, I fault the corporate system, which has sloughed off its civic responsibilities to train people and propagate cultural knowledge. The economy is full of interesting and important jobs representing exquisite technical knowledge and other expertise. As a culture and economy, we are not going to maintain a high standard if we keep losing these skills and knowledge with every generation. Just look what has happened to the industries we have ceded to China. Innovation hubs like Silicon Valley are successful in part because training becomes a shared enterprise. New companies benefit from a large pool of experienced workers, who can switch between organizations with ease. No individual company carries the whole burden of training, but as companies become larger and more specialized, they have to take on the costs of training a larger proportion of their incoming employees. Yet they still benefit from the cross-fertilization of being in a highly skilled employment ecosystem.

To better serve young people, we need to make integration into corporate skills training more accessible and normal. The idea that students should be battling for unpaid internships is absurd and insulting- all internships should be paid, and they should be longer as well. The German trades system is an example, where companies and government cooperate in providing training to young people. The companies get a much better familiarity with future hires, who are also better trained. Many trades/sectors have a communal "training tax", which all companies pay, and which funds salaries to trainees and other training costs. This is one accomplishment of the union system in Germany, which is much stronger and better integrated into their industries than that in the US.

This model could be made more general in the US as a federal program, crossing all organizations in the public and private sector, funding internships and training for more students than is now done, setting up a more lengthy and regular apprenticeship system. The training/salary costs would grade over the first few years of employment from tax-supported to company-supported. Lowering the burden of a young first hire, both in financial terms and terms of knowing the candidates better, should encourage more hiring and more training by employers. 

Companies are often citadels of hermetic wisdom, when they are not going off the rails as predatory enterprises. Integrating more young people and an additional purpose of training into US corporate culture would counteract both of these problems, while helping the youth and preserving / propagating cultural knowledge more effectively.

• Mentoring, Shanghai style.
• Surrender Dorothy!
• Mini-me and the future of Ukraine.
• Free buses work.
• Crypto, on the other hand, remains a criminal enterprise.
• Biology is not so easy. Really.

Ground Truth for Genetic Mutations

Saturation mutagenasis shows that our estimates of the functional effect of uncharacterized mutations are not so great.

Human genomes can now be sequenced for less than $1,000. This technological revolution has enabled a large expansion of genetic testing, used for cancer tissue diagnosis and tracking, and for genetic syndrome analysis both of embryos before birth and affected people after birth. But just because a base among the 3 billion of the genome is different from the "reference" genome, that does not mean it is bad. Judging whether a variant (the modern, more neutral term for mutation) is bad takes a lot of educated guesswork.

A recent paper described a deep dive into one gene, where the authors created and characterized the functional consequence of every possible coding variant. Then they evaluated how well our current rules of thumb and prediction programs for variant analysis compare with what they found. It was a mediocre performance. The gene is CDKN2A, one of our more curious oddities. This is an important tumor suppressor gene that inhibits cell cycle progression and promotes DNA repair- it is often mutated in cancers. But it encodes not one, but two entirely different proteins, by virtue of a complex mRNA splicing pattern that uses distinct exons in some coding portions, and parts of one sequence in two different frames, to encode these two proteins, called p16 and p14. 

One gene, two proteins. CDKN2A has a splicing pattern (mRNA exons shown as boxes at top, with pink segments leading to the p14 product, and the blue segments leading the p16 product) that generates two entirely different proteins from one gene. Each product has tumor suppressing effects, though via distinct mechanisms.

Regardless of the complex splicing and protein coding characteristics, the authors generated all possible variants in every possible coded amino acid (156 amino acids in all, as both produced proteins are relatively short). Since the primary roles of these proteins are in cell cycle and proliferation control, it was possible to assay function by their effect when expressed in cultured pancreatic cells. A deleterious effect on the protein was revealed as, paradoxically, increased growth of these cells. They found that about 600 of the 3,000 different variants in their catalog had such an effect, or 20%.

This is an expected rate of effect, on the whole. Most positions in proteins are not that important, and can be substituted by several similar amino acids. For a typical enzyme, for instance, the active site may be made up of a few amino acids in a particular orientation, and the rest of the protein is there to fold into the required shape to form that active site. Similar folding can be facilitated by numerous amino acids at most positions, as has been richly documented in evolutionary studies of closely-related proteins. These p16 and p14 proteins interact with a few partners, so they need to maintain those key interfacial surfaces to be fully functional. Additionally, the assay these researchers ran, of a few generations of growth, is far less sensitive than a long-term true evolutionary setting, which can sift out very small effects on a protein, so they were setting a relatively high bar for seeing a deleterious effect. They did a selective replication of their own study, and found a reproducibility rate of about 80%, which is not great, frankly.

"Of variants identified in patients with cancer and previously reported to be functionally deleterious in published literature and/or reported in ClinVar as pathogenic or likely pathogenic (benchmark pathogenic variants), 27 of 32 (84.4%) were functionally deleterious in our assay"

"Of 156 synonymous variants and six missense variants previously reported to be functionally neutral in published literature and/or reported in ClinVar as benign or likely benign (benchmark benign variants), all were characterized as functionally neutral in our assay "

"Of 31 VUSs previously reported to be functionally deleterious, 28 (90.3%) were functionally deleterious and 3 (9.7%) were of indeterminate function in our assay."

"Similarly, of 18 VUSs previously reported to be functionally neutral, 16 (88.9%) were functionally neutral and 2 (11.1%) were of indeterminate function in our assay"

Here we get to the key issues. Variants are generally classified as benign, pathogenic/deleterious, or "variant of unknown/uncertain significance". The latter are particularly vexing to clinical geneticists. The whole point of sequencing a patient's tumor or genomic DNA is to find causal variants that can illuminate their condition, and possibly direct treatment. Seeing lots of "VUS" in the report leaves everyone in the dark. The authors pulled in all the common prediction programs that are officially sanctioned by the ACMG- Americal College of Medical Genetics, which is the foremost guide to clinical genetics, including the functional prediction of otherwise uncharacterized sequence variants. There are seven such programs, including one driven by AI, AlphaMissense that is related to the Nobel prize-winning AlphaFold. 

These programs strain to classify uncharacterized mutations as "likely pathogenic", "likely benign", or, if unable to make a conclusion, VUS/indeterminate. They rely on many kinds of data, like amino acid similarity, protein structure, evolutionary conservation, and known effects in proteins of related structure. They can be extensively validated against known mutations, and against new experimental work as it comes out, so we have a pretty good idea of how they perform. Thus they are trusted to some extent to provide clinical judgements, in the absence of better data. 

Each of seven programs (on bottom) gives estimations of variant effect over the same pool of mutations generated in this paper. This was a weird way to present simple data, but each bar contains the functional results the authors developed in their own data (numbers at the bottom, in parentheses, vertical). The bars were then colored with the rate of deleterious (black) vs benign (white) prediction from the program. The ideal case would be total black for the first bar in each set of three (deleterious) and total white in the third bar in each set (benign). The overall lineup/accuracy of all program predictions vs the author data was then overlaid by a red bar (right axis). The PrimateAI program was specially derived from comparison of homologous genes from primates only, yielding a high-quality dataset about the importance of each coded amino acid. However, it only gave estimates for 906 out of the whole set of 2964 variants. On the other hand, cruder programs like PolyPhen-2 gave less than 40% accuracy, which is quite disappointing for clinical use.

As shown above, the algorithms gave highly variable results, from under 40% accurate to over 80%. It is pretty clear that some of the lesser programs should be phased out. Of programs that fielded all the variants, the best were AlphaMissense and VEST, which each achieved about 70% accuracy. This is still not great. The issue is that, if a whole genome sequence is run for a patient with an obscure disease or syndrome, and variants vs the reference sequence are seen in several hundred genes, then a gene like CDKN2A could easily be pulled into the list of pathogenic (and possibly causal) variants, or be left out, on very shaky evidence. That is why even small increments in accuracy are critically important in this field. Genetic testing is a classic needle-in-a-haystack problem- a quest to find the one mutation (out of millions) that is driving a patient's cancer, or a child's inherited syndrome.

Still outstanding is the issue of non-coding variants. Genes are not just affected by mutations in their protein coding regions (indeed many important genes do not code for proteins at all), but by regulatory regions nearby and far. This is a huge area of mutation effects that are not really algorithmically accessible yet. As a prediction problem, it is far more difficult than predicting effects on a coded protein. It will requiring modeling of the entire gene expression apparatus, much of which remains shrouded in mystery.

• Oh, no! Not the shopping cart!
• Jevons and Malthus will have their say, if we do not get our act together.
• It is time to scrap GDP, and the mania for growth.
• Blaming the victim.
• Everything crypto will be just perfect.
• Can I play piano with my mind?
• We are killers.

The Submission Drive

Humans have a drive for social and intellectual submission, which is extremely dangerous.

There was a time when psychological "drives" were all the rage. The idea that humans have instincts much as other animals do was just entering the scientific consciousness, so finding and classifying them was an important task- the great work of figuring out the human unconscious, or subconscious. Drives for food, security, sex, dominance, and much else were found. Freud even elaborated a "death drive". But our current political epoch suggests another one- a submission drive.

To an independent minded scholar and skeptic, the behavior on the Republican side of the political spectrum is revolting. Falling all over themselves to fawn over a narcissistic megalomaniac? Check. Thinking nothing of flagrant corruption that makes Warren Harding look like a choir boy? Check. Explaining away gross incompetence and pointless cruelty across the entire policy space from economics to foreign policy? Check. What causes people to join and defend what amount to cults? For that matter, what causes people to join religions?

At one level, submission is eminently rational. Groups are always more powerful than individuals. The American archetype of the loner, the Clint Eastwood or John Wayne character riding alone to mete out justice and bucking the system- that is a fantasy. It is powerful precisely because it is so romantic and unrealistic. It is compensatory psychic food for the hemmed-in and submissive. In reality, the system always wins. Militaries win when they can gather up a bigger army than the other guys. Corporations win when they have bought all their competition and become the biggest on the block. Our social instincts lead us to join groups to gain power. 

But the submission drive seems to go way beyond this, allowing us to swallow alternate realities and even seek domination by others. An interesting form is when whole cultures convert their religion. Many times, such as during the colonial era, during the Christian conquests of Northern Europe, and during the Muslim conquests, the winning power foists its religion on another culture, a culture that grows quite rapidly to accept and adopt it as its own. Was one religion true-er or better than the other? Not at all. The new one is often significantly worse in many dimensions than the old. This is purely a power transaction where those who had submitted themselves to one archetype and narrative of cultural and supernatural power find themselves convinced that social and military coercion is a pretty important form of power too, perhaps signifying a new narrative that they should submit to. But once converted, the same psychic events happen. Leaders are idolized, scriptures are memorized, vestments are accessorized. In return, those who submit seek safety and guidance, buying into a (new) father figure archetype.

Joining a group inserts you into a hierarchy of domination. There are rewards for working your way up the ranks, being able to get others to serve you, having more influence and status. This most obvious in the military, with its obsession with colorful gradations, decorations, and uniforms. But it is true everywhere- in corporations, politics, organized crime, families. Submission is the price of entry, and it seems that to properly submit, one has to take on the a great deal more than just a signed contract. Members of organizations are constantly being tested for their loyalty, their buy-in to the ethics and goals of the organization, and its wider world-view. At IBM, they used to sing the company song. Modern corporate life is a complex compromise where some of the submittee's personal life is allowed to be separated from corporate control, and many boundaries are set by legal regime to prevent the organization from turning into a criminal entity and bar total domination of its employees, customers, business partners. 

However, other organizations are not so limited. Religion and politics are a bit less hemmed-in, and demand sometimes extraordinary kinds of fealty for the rewards on offer. In their variety of styles and cultures, they attract different temperaments of devotee. Overall, one has to say that people more prone to submission and participation in hierarchies tend to go to right-wing political, military, and religious organizations. Contrary to the cultivated image of hard-headedness and independence, conservatives turn out to submit more readily to domination by others. It is notorious that organizing Democrats is like herding cats. Likewise, university faculty tend towards independence and disorganization. Liberal churches are notoriously light on discipline and free with their theology. 

Conversely, Republican and conservative organizations spring up like weeds and have, aside from gobs of funding, remarkable discipline. The MAGA swoon for the current president is just one example of the lengths to which thought patterns can be bent in favor of the dominant leader of the moment. The corollary of greater mental submission by the followers is greater rewards and wider scope of action for the leaders. Making it to the top of such disciplined heap seems to turn psychology on its head, from submission to domination. Napoleon is a case study, working his way up the ranks, literally, to a position of ultimate power. Which promptly went to his head, causing him to veer in a conservative direction, and to wreck half of Europe. Cult leaders have time and again shown how poorly adapted we are to this much-sought after, but rarely successful, psychological transition.

The fascist/authoritarian moment that is glowering around the world has reactivated these extreme domination/submission dynamics, such as between Russia and Ukraine, and within so many far-right movements and the poitical systems they target. Fortunately, there are just fundamental temperamental barriers to the attractiveness of such movements, forcing them to take extra-legal measures if they are truly dedicated to overcome the resistence of the less submissive members of their societies.

• Much of this is drawn from a classic book, "Instincts of the Herd in Peace and War".
• Report card on the courts.
• Waymo is hitting the highway.
• Plastic.

Links Only

Due to the press of other activities, only links this week.

• Wingnut medicine.
• Video of a fault slipping during an earthquake... look in the background.
• The original unitary executive.
• How about some free mid-day electricity?
• More Supreme injustice.
• Jay Bhattacharya is a stooge.

Modeling Human Attention

How attention works in the brain is becoming clearer through empirical and computer modeling work.

The current World Series is a tour de force of mental concentration and attention. Batters intently watch a pitch, and have milliseconds to decide that it isn't any good. Pitchers study the opposing batters for any signs of gullibility. Managers face excruciating decisions on when to pull a pitcher in danger. Spectators decide whether to get drawn into the pitcher's duel, or chat with their neighbors. Advertisers measure attention in dollars and cents.

The economics of attention may have reached a fever pitch, but the physiology of attention is only slowly being revealed. Attention is obviously closely aligned with consciousness, so progress on one implies progress on the other as well. The current paper is a computer modeling project, trying to simulate the core connections and behavior between the thalamus and cortex that are involved in sensory perception. For instance, mice are given a slight push on a whisker. If they respond to that, it shows they perceived it. At a very light threshold level, the chances of perception can tuned to 50%, and perceptual events can have more to do with the mental status of the mouse and the history of whisker stimulation than it does with the (consistent) strength of the stimulus. A similar threshold phenomenon holds in other forms of sensing and perception, such as binocular rivalry. Indeed, in binocular rivalry of vision, there is a slow switching back and forth between each image, based on neural accommodation after a few seconds attending to one of the images. Such threshold levels of perception are the bread and butter of research on attention.

"Given the ubiquity of the thalamocortical circuit architecture across sensory modalities, we, along with others, have proposed that reverberant bursting activity in L5PT [thick-tufted layer 5 pyramidal-tract neurons]– matrix thalamus loops may be a necessary component part in a domain general mechanism of perceptual awareness."

"Optogenetic excitation of the apical dendrites reduced the animal’s threshold for awareness, increasing both hits and false-alarms. In turn, pharmocological inhibition of the apical dendrites and POm [posteromedial thalamic nucleus] (a matrix-rich higher-order thalamic nucleus with closed loop connections to barrel cortex) increased the animal's perceptual threshold."

The model was based on the physiology of thalamo-cortical loops, which are very common in sensory, motor, and other circuits. Attention is not something that "happens" in one place, but rather appears to be a state of the network, after negotiation between upper and lower levels. Strong stimuli, such as the roar of the crowd after a home run, push their way to the top of the attention chain. Conversely, a quest for a hot dog can lead to highly focused top-down attention on planning and making a trip to the concession stand, while ignoring everything else going on in the game.

A bit of physiology, showing how mouse neurons connect between cortical and thalamus levels, and how they look at various levels within the cortical sheet. 

These researchers found that by making a faithful model of the neurons and connections found by physiology, they could then functionally model quite faithfully the actions of this loop, including its perceptual thresholds, stochastic activation, and tendency to accommodate (dampen) repeated stimuli. A key aspect of the physiology is the layering of the cortex. Evolution has left clear marks in brain areas of various vintages, in the form of layer organization. The most primitive areas like the brain stem and cerebellum have no layering at all, but rather have anatomical structures, bulbs, and sub-nuclei. Less primitive subcortical (limbic) areas have roughly three layers of cells, whereas the neocortex has a structure that is a uniform sheet, modularized not so much into structural bulbs, knobs, etc, but in a more regularized arrangement of six distinct layers, with columns of activity for parcellation of function. This regular arrangement is replicated all over the cortex and (re-)used for innumerable functions, from sensation and motor control to decision making and emotional control. In general, the middle layer (4) contains the most cell bodies, (called the granular layer), and connects extensively to the other layers. The upper layers (numbered 1,2,3, and closest to the outside of the brain) receive inputs from the thalamus and other areas, while the lower layers (5 and 6 ) send outputs to lower areas of the brain, for motor control, attention control, etc.

The authors simulate cells and connections from the known physiology. Cortical levels shown on left, and an example of one set of connected, active, firing cells on right.

The thalamocortical loop, therefore, as illustrated by the authors, is a cycle of connections from the thalamus into cortical layer 1, which connects to cells stationed in layer 5, which then send axons out back to the thalamus. The thalamus is a large structure nested within/under the hippocampus, basal ganglia, and corpus collosum, that mediates cortical signals to and from the rest of the nervous system, including senses. The authors basically find that they can reproduce the signature bursting behavior of this circuit that others have argued is a sign of attention. That is, the brief set of six pulses between 0.1 and 0.2 seconds above, which is quickly shut down by continuing activity from the inhibitory basket cells (orange, BC). I can't speak to the details either of the modeling or the physiology it is based on, but the authors try their best to hew to realistic cells and physiological circuits, making the case that the neural behavior they get out is a realistic simulation, which can then be used for other perturbations and studies of this system. 

A question that arises is the relationship of consciousness with attention. Are the neural patterns characteristic of attention all that is required to also be conscious? A review of the field says no, they are different, or at least that consciousness is a broader concept that contains attention, but also can contain bare awareness without specific focus. I am not so sure, since attention can presumably be directed inside to our own thoughts and memories, that constitutes the floating kind of awareness of bare consciousness. Without attention to anything, we lack conscious content, and thus, perhaps consciousness itself. The idea that we can meditate our way to a content-less consciousness is time and again disproven by the practice of meditation. It finds that a focus is essential, not to empty the mind of all contents, which I believe is impossible, but to control those mental contents and attain a controlled level of lucid dreaming or mantra-driven reduced consciousness that seems to be the goal of meditation.

The authors of this paper mention that their view of attention is very compatible with each of several reigning theories of consciousness, inchoate as those are, so we do seem to be heading, ever so slowly, towards a solution of this long-standing problem.

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The First Invasion by the US

History pre-peated itself in our 1775 invasion of Canada.

Rick Atkinson's enormous history of the American Revolutionary war is stuffed with fascinating detail. Some may not be entirely documentary in origin, but his color and flair are undeniable. Having but begun this long read, I was struck by an early episode, the invasion of Canada. The colonies had not quite yet declared independence, nor had they resolved the seige of British-occupied Boston. They were undersupplied, short of manpower, and still on shaky ground politically with a large loyalist population. Yet, they got it into their heads to storm Montreal and then Quebec in the middle of winter, 1775 to 1776, expecting to be greeted by adoring natives as liberators. The fact that our 47th president has once again threatened to invade Canada can be taken as evidence that the expedition did not go as expected.

Within the thirteen colonies, the revolution began in a promising landscape. British governors were hated up and down the Atlantic seaboard, many reduced to bobbing offshore on Navy vessels while they begged for reinforcements that might, in their imaginations, turn the population back in their favor. Rebel congresses were formed, including the Continental Congress, which from Lexongton and Concord onwards realized that it was more than a political body- it was also a military body, responsible for fending off British attempts to cow the colonists with superior naval might, well-trained troops, ability to raise mercenaries all over Europe, and reserves of good will with loyalists and Native Americans. 

But the US is nothing if not a land-greedy society, and the Continental Congress cast its eyes northward, imagining that the recently (fifteen years before) captured colony of New France might want to cast its lot with the American rebels rather than its British overlords. However the way they went about this project spoke volumes. Instead of sending diplomats, rabble-rousers, or writers, they sent an army. In all, about three thousand men tramped north to subjugate the province of Quebec. 

Map of the campaign.

A virtually undefended Montreal was successfully besieged, and surrendered in November, 1775. Quebec, to the north, was another matter, however. It was far more stoutly defended, well supplied, and had competent walls and entrenchments. Conversely, the Americans were farther from their bases, camped in miserable conditions in the middle of winter, beset by disease, and could not make headway against even modest resistance. When the first British relief ship sailed into the harbor after breakup on the St Lawrence, the jig was up, and the Americans fled in disarray.

Transport was awful, with a lot of portaging between rivers.

Meanwhile, the American rule over Montreal hardly won the US any friends either. The governor treated the inhabitants like enemies, even closing Catholic churches. Benjamin Franklin was sent North to awe the natives and save the situation in April 1776, but the time for diplomacy was long past. 

Does all this sound familiar? What starts with high hopes and condescension, looking to win hearts and minds with guns, ends up winning nothing at all. The Philippines, Vietnam, Iraq, Afghanistan.. one wonders whether the invasion of Quebec was ever taught to US military students, or remembered by its politicians.

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When the Battery Goes Dead

How do mitochondria know when to die?

Mitochondria are the energy centers within our cells, but they are so much more. They are primordial bacteria that joined with archaea to collaborate in the creation of eukaryotes. They still have their own genomes, RNA transcription and protein translation. They play central roles in the life and death of cells, they divide and coalesce, they motor around the cell as needed, kiss other organelles to share membranes, and they can get old and die. When mitochondria die, they are sent to the great garbage disposal in the sky, the autophagosome, which is a vesicle that is constructed as needed, and joins with a lysosome to digest large bits of the cell, or of food particles from the outside.

The mitochondrion spends its life (only a few months) doing a lot of dangerous reactions and keeping an electric charge elevated over its inner membrane. It is this charge, built up from metabolic breakdown of sugars and other molecules, that powers the ATP-producing rotary enzyme. And the decline of this charge is a sign that the mitochondrion is getting old and tired. A recent paper described how one key sensor protein, PINK1, detects this condition and sets off the disposal process. It turns out that the membrane charge does not only power ATP synthesis, but it powers protein import to the mitochondrion as well. Over the eons, most of the mitochondrion's genes have been taken over by the nucleus, so all but a few of the mitochondrion's proteins arrive via import- about 1500 different proteins in all. And this is a complicated process, since mitochondria have inner and outer membranes, (just as many bacteria do), and proteins can be destined to any of these four compartments- in either membrane, in the inside (matrix), or in the inter-membrane space. 

Textbook representation of mitochondrial protein import, with a signal sequence (red) at the front (N-terminus) of the incoming protein (green), helping it bind successively to the TOM and TIM translocators. 

The outer membrane carries a protein import complex called TOM, while the inner membrane carries an import complex called TIM. These can dock to each other, easing the whole transport process. The PINK1 protein is a somewhat weird product of evolution, spending its life being synthesized, transported across both mitochondrial membranes, and then partially chopped up in the mitochondrial matrix before its remains are exported again and fully degraded. That is when everything is working correctly! When the mitochondrial charge declines, PINK1 gets stuck, threaded through TOM, but unable to transit the TIM complex. PINK1 is a kinase, which phosphorylates itself as well as ubiquitin, so when it is stuck, two PINK1 kinases meet on the outside of the outer membrane, activate each other, and ultimately activate another protein, PARKIN, whose name derives from its importance in parkinson's disease, which can be caused by an excess of defective mitochondria in sensitive tissues, specifically certain regions and neurons of the brain. PARKIN is a ubiquitin ligase, which attaches the degradation signal ubiquitin to many proteins on the surface of the aged mitochondrion, thus signaling the whole mess to be gobbled up by an autophagosome.

A data-rich figure 1 from the paper shows purification of the tagged complex (top), and then the EM structure at bottom. While the purification (B, C) show the presence of TIM subunits, they did not show up in the EM structures, perhaps becuase they were not stable enough or frequent enough in proportion to the TOM subunits. But the PINK1+TOM_VDAC2 structures are stunning, helping explain how PINK1 dimerized so easily when it translocation is blocked.

The current authors found that PINK1 had convenient cysteine residues that allowed it to be experimentally crosslinked in the paired state, and thus freeze the PARKIN-activating conformation. They isolated large amounts of such arrested complexes from human cells, and used electon microscopy to determine the structure. They were amazed to see, not just PINK1 and the associated TOM complex, but also VDAC2, which is the major transporter that lets smaller molecules easily cross the outer membrane. The TOM complexes were beautifully laid out, showing the front end (N-terminus) of PINK1 threaded through each TOM complex, specifically the TOM40 ring structure.

What was missing, unfortunately, was any of the TIM complex, though some TIM subunits did co-purify with the whole complex. Nor was PARKIN or ubiquitin present, leaving out a good bit of the story. So what is VDAC2 doing there? The authors really don't know, though they note that reactive oxygen byproducts of mitochondrial metabolism would build up during loss of charge, acting as a second signal of mitochondrial age. These byproducts are known to encourage dimerization of VDAC channels, which naturally leads by the complex seen here to dimerization and activation of the PINK1 protein. Additionally, VDACs are very prevalent in the outer membrane and prominent ubiquitination targets for autophagy signaling.

To actually activate PARKIN ubiquitination, PINK1 needs to dissociate again, a process that the authors speculate may be driven by binding of ubiquitin by PINK1, which might be bulky enough to drive the VDACs apart. This part was quite speculative, and the authors promise further structural studies to figure out this process in more detail. In any case, what is known is quite significant- that the VDACs template the joining of two PINK1 kinases in mid-translocation, which, when the inner membrane charge dies away, prompts the stranded PINK1 kinases to activate and start the whole disposal cascade. 

Summary figure from the authors, indicating some speculative steps, such as where the reactive oxygen species excreted by VDAC2 sensitise PINK1, perhaps by dimerizing the VDAC channel itself. And where ubiquitin binding by PINK1 and/or VDAC prompts dissociation, allowing PARKIN to come in and get activated by PINK1 and spread the death signal around the surface of the mitochondrion.

It is worth returning briefly to the PINK1 life cycle. This is a protein whose whole purpose, as far as we know, is to signal that mitochondria are old and need to be given last rites. But it has a curiously inefficient way of doing that, being synthesized, transported, and degraded continuously in a futile and wasteful cycle. Evolution could hardly have come up with a more cumbersome, convoluted way to sense the vitality of mitochondria. Yet there we are, doubtless trapped by some early decision which was surely convenient at the time, but results today in a constant waste of energy, only made possible by the otherwise amazingly efficient and finely tuned metabolic operations of PINK1's target, the mitochondrion.

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The Role of Empathy in Science

Jane Goodall's career was not just a watershed in ethology and primate psychology, but in the way science is done.

I vividly remember reading Jane Goodall's descriptions of the chimpanzees in her Gombe project. Here we had been looking for intelligent alien life with SETI, and wondering about life on Mars. But she revealed that intelligent, curious personalities exist right here, on Earth, in the African forest. Alien, but not so alien. Indeed, they loved their families, suffered heartbreaking losses, and fought vicious battles. They had cultures, and tools, deviousness and generosity. 

What was striking was not just the implications of all this for us as humans and as conservationists, but also what it overturned about scientific attitudes. Science had traditionally had a buttoned-up attitude- "hard science", as it were. This reached a crescendo with behaviorism, where nothing was imputed to the psychology of others, whether animals or children, other than machine-like input/output reflexes. Machines were the reigning model, as though we had learned nothing since Descartes. 

Ask a simple question, get a simple answer.

This was appalling enough on its own terms, but it really impoverished scientific progress as well. Goodall helped break open this box by showing in a particularly dramatic way the payoff possible from having deep empathy with one's scientific object. Scientists have always engaged with their questions out of interest and imagination. It is a process of feeling one's way through essentially a fantasy world, until one proves that the rules you have divined actually are provable via some concrete demonstration- doing an experiment, or observing the evidence of tool use by chimpanzees. It is intrinsically an empathetic process, even if the object of that empathy is a geological formation, or a sub-atomic particle. 

But discipline is needed too. Mathematics reigns supreme in physics, because, luckily, physics follows extremely regular rules. That is what is so irritating and uncomfortable about quantum mechanics. That is a field where empathy sort of fails- notoriously, no one really "understands" quantum mechanics, even though the math certainly works out. But in most fields, it is understanding we are after, led by empathy and followed by systematization of the rules at work, if any. This use of empathy has methodological implications. We become attached to the objects of our work, and to our ideas about them. So discipline involves doing things like double-blind trials to insulate a truth-finding process from bias. And transparency with open publication followed by open critique.

In the 20th century, science was being overwhelmed by the discipline and the adulation of physics, and losing the spark of inspiration. Jane Goodall helped to right that ship, reminding us that scientific methods and attitudes need to match the objects we are working with. Sure, math might be the right approach to electrons. But our fellow animals are an entirely different kettle of fish. For example, all animals follow their desires. The complexities of mating among animals means that they are all driven just as we are- by emotions, by desire, by pain, by love. The complexity may differ, but the intensity of these emotions can not possibly be anything but universal.

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Cycles of Attention

 A little more research about how attention affects visual computation.

Brain waves are of enormous interest, and their significance has gradually resolved over recent decades. They appear to represent synchronous firing of relatively large populations of neurons, and thus the transfer of information from place to place in the brain. They also induce other neurons to entrain with them. The brain is an unstable apparatus, never entraining fully with any one particular signal (that way lies epilepsy). Rather, the default mode of the brain is humming along with a variety of transient signals and thus brain waves as our thoughts, both conscious and unconscious, wander over space and time.

A recent paper developed this growing insight a bit further, by analyzing forward and backward brainwave relations in visual perception. Perception takes place in a progressive way at the back of the brain in the visual cortex, which develops the raw elements of a visual scene (already extensively pre-processed by the retina) into more abstract, useful representations, until we ... see a car, or recognize a face. At the same time, we perceive very selectively, only attending to very small parts of the visual scene, always on the go to other parts and things of interest. There is a feedback process, once things in a scene are recognized, to either attend to them more, or go on to other things. The "spotlight of attention" can direct visual processing, not just by filtering what comes out of the sausage grinder, but actually reaching into the visual cortex to direct processing to specific things. And this goes for all aspects of our cognition, which are likewise a cycle of search, perceive, evaluate, and search some more.

Visual processing generates gamma waves of information in an EEG, directed to, among other areas, the frontal cortex that does more general evaluation of visual information. Gamma waves are the highest frequency brain oscillations, (about 50-100 Hz), and thus are the most information rich, per unit time. This paper also confirmed that top-down oscillations, in contrast, are in the alpha / beta frequencies, (about 5-20 Hz). What they attempted was to link these to show that the top-down beta oscillations entrain and control the bottom-up gamma oscillations. The idea was to literally close the loop on attentional control over visual processing. This was all done in humans, using EEG to measure oscillations all over the brain, and TMS (transcranial magnetic stimulation) to experimentally induce top-down currents from the frontal cortex as their subjects looked at visual fields.

Correlation of frontal beta frequencies onto gamma frequencies from the visual cortex, while visual stimulus and TMS stimulation are both present. At top left is the overall data, showing how gamma cycles from the hind brain fall into various portions of a single beta wave, (bottom), after TMS induction on the forebrain. There is strong entrainment, a bit like AM radio amplitude modulation, where the higher frequency signal (one example top right) sits within the lower-frequency beta signal (bottom right). 

I can not really speak to the technical details and quality of this data, but it is clear that the field is settling into this model of what brain waves are and how they reflect what is going on under the hood. Since we are doing all sorts of thinking all the time, it takes a great deal of sifting and analysis to come up with the kind of data shown here, out of raw EEG from electrodes merely placed all over the surface of the skull. But it also makes a great deal of sense, first that the far richer information of visual bottom-up data comes in higher frequencies, while the controlling information takes lower frequencies. And second, that brain waves are not just a passive reflection of passing reflections, but are used actively in the brain to entrain some thoughts, accentuating them and bringing them to attention, while de-emphasizing others, shunting them to unconsciousness, or to oblivion.

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