Prospects for Hydrogen

What are the prospects for hydrogen as part of a sustainable, green economy?

Hydrogen is perennially spoken of as a fuel of the future- clean, renewable, light. It is particularly appealing in an environment (like that of California) where solar energy is having a huge impact on the grid and causing rising portions of solar production to be "curtailed". That is, turned off. But even in California, solar power has hardly scratched the surface. Only few roofs have solar and the potential for more power production is prodigious. Over time, as more renewable sources of energy come on line, the availability of excess power at peak times will rise dramatically, prompting a huge need for storage, or other ancillary uses for excess power. Many storage schemes exist or are under development, from traditional water pumping to batteries, flywheels, gravitational weights, etc. Hydrogen is one of them, spoken of as a versatile storage and fuel medium, which can be burned, or even more efficiently put through fuel cells, to return electrical power.

A typical day on California's electrical grid. The top teal line is total demand, and the purple zone is power not supplied by renewables like wind, hydropower, and solar. During the mid-day, most power now comes from solar, an amazing accomplishment. Roughly 2 GW are even turned off at the highest peak time, due to oversupply, either locally or regionally. How could that energy be put to use?

Unfortunately, as a fuel, hydrogen leaves much to be desired. We have flirted with hydrogen-powered cars over the last couple of decades, and they have been a disaster. Hydrogen is such an awkward fuel to store that battery-powered electric vehicles have completely taken over the green vehicle market, despite their slowness in refueling. The difficulties begin with hydrogen's ultra-low density. The Sun has the gravitational wherewithal to compress hydrogen to useful proportions, at the equivalent of 100,000 earth atmospheres and up. But we on Earth do not, and struggle with getting hydrogen in small enough packages to be useful for applications such as transport. The prospect of Hinden-cars is also unappealing. Lastly, hydrogen is corrosive, working its way into metals and weakening them. Transforming our natural gas system to use green hydrogen would require replacing it, essentially.

The awkwardness, yet usefulness, of (reduced) hydrogen as an energy currency in an oxygenated atmosphere is incidentally what led life during its early evolution to devise more compact storage forms, i.e. hydro-carbons like fats, starches and sugars. And these are what we dug up again from the earth to fuel our industrial, technological, and population revolutions.

But how useful is hydrogen for strictly in-place storage applications, like load balancing and temporary grid storage? Unfortunately, the news there is not good either. Physical storage remains an enormous problem, so unless you have a handy sealed underground cavern, storage at large scales is impractical. Second, the round-trip efficiency of making hydrogen from water by electrolysis and then getting electricity back by fuel cell (both rather expensive technologies) is roughly 35 to 40%. This compares unfavorably to the ~95% efficiency of electrical batteries like Li ion, and the 80% efficiency of pumped water/gravity systems. Hydrogen here is simply not a leading option.

Does that mean we are out of luck? Not quite. It turns out that there already is a hydrogen economy, as feedstock for key chemical processes, especially ammonia and fertilizer production, and fossil fuel cracking, among much else. Global demand is 80 million tons per year, which in electrical terms is 3-4 tera watt hours. That is a lot of energy, on the order of total demand on the US electric grid, and could easily keep excess power generator's hands full for the foreseeable future. Virtually all current hydrogen is made from natural gas or coal, so the green implications of reforming this sector are obvious. It already has storage and pipeline systems in place, though not necessarily at locations where green energy is available. So that seems to be the true future of hydrogen, not as a practical fuel for the economy in general, but as a central green commodity for a more sustainable chemical industry.

• Unions
• Afghanistan, inexorably going back to the Taliban.

The Autism of Politics

Our politics is an inarticulate communal search for expression of emotion.

I recently saw "A Brilliant Young Mind", a British take on growing up with autism. It is one of the most beautiful movies I have ever seen, exploring themes of family, loss, and love with wrenching sensitivity. The challenge of expressing, even feeling, one's own emotions is at the heart, naturally enough, for people on the spectrum. There is a fight by family members to crack that shell, to establish communication that expresses the love they know is there, and which will build warmth and confidence.

One theme is the power of speech- the bullying in school, the words of love from a parent. We may have recited the saying about sticks and stones, but it isn't true. Humans feel and use speech as touch, like Chimpanzees use grooming, to soothe each other. Music functions similarly, to touch others with shared emotions, strengthening essential bonds of trust and empathy. We also use speech also to attack each other, and climb the social hierarchy on the bodies of those cut down by words. 

Well, politics is a natural extension. We feel strongly that there should be someone in charge of each political unit- one person who embodies and expresses our feelings about the whole. It is not just a job, or an executive position, but a strongly archetypal role, which includes the work of binding us together through speech, or not, as our collective mood dictates. We have just been through an administration dedicated to the destructive power of speech, firing off tweets to cut down friends and enemies, formulating cryptic messages supporting inequality, tribalism, and racism. 

But political speech is hobbled by the vast population it addresses. The movie above spoke to me, perhaps because I felt familiar with many of its themes and dilemmas, or happened to appreciate its artistic approach. But it may not speak to you. Politics is about finding the largest possible audience, using the vaguest possible formulations to which listeners can impute their feelings about the body politic. It is thus necessarily painfully awkward, smothered in platitudes, and minimally communicative. In short, a little autistic. 

A still from the movie, with the main character and his mother in a typical pose.

So we as citizens are all in the position of wanting the collective to satisfy a some very deep needs for connection, security, and self-realization and expression. But we are reading a cryptic body politic and leadership for clues of true intention, hidden beneath what may be a voluble exterior of near-meaningless speech, and at the same time confounded by a lack of transparency and radical lack of personal access to those people who are the leaders. Conversely, those leaders are sequestered in their security and network bubbles, wanting (ideally) to understand and share the feelings of their constituents, but unable, simply by the scale of the enterprise, to do so. And anyhow, seeking the average feeling or attitude in a democracy ends inevitably in a muddled middle. Thus leaders are confined to rhetoric that in recent inaugurations, state of the union addresses, and so forth has been bland and weak, as uninspired as it is uninspiring. 

Our political / psychological needs seem to differ along temperamental / party lines, with Democrats forever searching for the healing leader who can reach out across the divide to bring a larger coalition together to accomplish empathetic ends, for the downtrodden, for the environment, and for the future. On the other hand, Republicans seem, since at least the time of Goldwater, to be unhopeful about change, and the future in general, indeed motivated by fear. Their quest is for a leader who will advocate for the hard truths of the inherent and useful infairnesses of life to restore the social hierarchical order, keep out aliens, and keep down the restive and poorly paid masses. The last administration was unusually forthright about the whole program, thus speaking into an intense rapport with its "base", while foresaking the traditional mincing "compassionate conservative" or "city on a hill" gestures that have in the past served to sugar-coat that message.

But speaking to the base turned out to be a disastrous political strategy, losing the House, Senate, and Presidency in turn. However powerful in expressing, even generating, rare emotional responses in that base, it failed to follow the most basic principle of political math. So we are back now to the anodyne stylings of a new Democratic administration, back to a normal relationship, which is to say not much of a relationship, between the leader and the led. Which is a great relief on the national level, even if it would be maddening and unsatisfying on any personal level.

• Are you on the spectrum?
• That music in our heads.
• The true nature of conservative jurisprudence.
• Myths, magic, and gods- right or wrong?
• Hamsterkauf?
• Bill Mitchell on inflation and other historical matters.
• Some delightful piano.

There Are no Natural Rights

Rights are always a political construct, which we devise and grant each other.

American politics is drenched with "rights". The Bill of Rights, natural rights, god-given rights, human rights. Both right and left use "rights" language to claim victimization and seek restitution. But the history goes back much farther, to the Magna Carta and beyond, into the heart of being a social species. Sociality means compromise, giving up some powers in return for other things, some of which are called rights. Good civilized behavior and diligent work entitles us to membership in the group, and benefits such as collective defense and shared resources. Since there can be long time lags between service and repayment, even extending over a lifetime or even multiple generations, a way is needed to keep track of such obligations. One way is to proclaim rights, such as a right to communal fields and pastures for members of the group, in perpetuity.

Thus rights are generally keenly felt as obligations and matters of long-standing, even eternal, usage. But all are social agreements, as our proclivity to murder and execute each other makes clear. If one does not even have an inalienable right to life, what are the others worth? They are neither natural nor god-given, but entirely human-given. They are rhetorical constructs meant to structure our communal relations, hopefully for good of all and the durable continuance of the system, but sometimes, not so much. Indeed, rights can be brutally oppressive, such as those of Brahmins in the Indian caste system, among many others.

Gun nuts frequently make a fetish of their rights- to guns, self defense, and in various convoluted ways to religious rights and duties. When rights have been written into the law, such as our constitution, that moves them into another rhetorical level- the legal system. But that just expresses and codifies agreements that exist elsewhere in the social system, and which the social system can, through its evolution, change. Gay rights have been an outstanding example, of the destruction of one rights system- that of normative sexuality and marriage rights- and the rise of a new set of rights oriented to personal freedom in the expression and practice of sexuality. Where in ancient times, fecundity was of paramount importance, that need has naturally fallen away as a societal imperative as our societies and planet creak under loads of overpopulation.

This mutability and social basis of rights leads to a lot of one-upmanship in rights discourse, like the attempts to found abortion rights in presumptively more universal or fundamental rights like privacy, autonomy, or women's rights, versus competing formulations of rights to fetal life with related arguments about the legal and life-like status of embryos and fetuses. All this speaks to the fact that rights are not discovered on tablets handed down by either god or Darwin, but are continually developed out of our feelings about our communities- what is fair based on what is required from each of us to live in them, and what they can reasonably demand and give in return.

• Let's hear it for the neurodivergent.
• Cattle are unsustainable.
• Good riddance.

Squeezing Those Electrons For All They've Got

How respiratory complex I harnesses electron transfer from NADH to quinone to power the mitochondrial battery.

Energy- we can't live without it, we can't make it ourselves, and we use all sorts of complex technologies to harvest and store it. Solar power is reaching a crisis as we realize that it isn't going to work without storage. Life faced similar crises billions of years ago, and came up with core solutions that we know now as the chemical transformations of photosynthesis and metabolism. Plants make storage compounds from sunlight, which we in turn eat for energy, transforming them into a series of currencies from short- to long-lived, such as NADH, protons, ATP, glucose, and finally, fat.

Within us, the mitochondrion is the engine, not making energy, but burning it from the food we eat. The core citric acid cycle disassembles the reduced carbon compounds that serve as our food and longer-term storage compounds into oxidized CO2 and energy carriers NADH, FADH. While used widely in the cell for specialized needs, these compounds are not our core energy stores, and are generally sent to the electron transport chain for transmutation into a proton gradient that serves as the battery of the mitochondrion, which is in turn used to synthesize our general energy currency, ATP. ATP is used all over the cell for general needs, including the synthesis of glucose, glycogen, and fat as needed for longer term storage.

The discovery of the proton battery was one of the signal achievements of 20th century biochemistry, explaining how mitochondria, and bacteria generally, (from which they evolved), handle the energy harvested via the electron transport chain from food oxidation in an organized and efficient way, without any direct coupling to the ATP synthesis machinery. The electron transport chain is a series of protein complexes embedded in the innermost mitochondrial membrane that receive high-energy electrons from NADH / FADH made in the matrix through the citric acid cycle and use them to pump protons outwards. Then the ATP synthetase enzyme, which is another highly specialized and interesting story, uses the energy of those protons, flowing back in through its rotary structure, to synthesize ATP. The proton gradient is short-lived, a bit like our lithium batteries, continually needing to be recharged- a key form of storage, but just one part of a larger energy transformation system.

A recent pair of papers from the same lab, capitalizing on the new technologies of atomic structure determination, describe in new detail the structure of respiratory complex I, which is a huge complex of 45 proteins that receives NADH, conducts its two electrons to ubiquinone, and uses that energy to pump out four protons from the mitochondrial matrix. Not all questions are answered in these papers, but it is a fascinating look into the maw of this engine. Ubiquinone (often abbreviated as Q) is then later taken up by another respiratory complex that squeezes out a few more protons, while transferring the electrons to cytochrome C, which goes to yet another respiratory complex that squeezes out a final few protons.  Like in our macroscopic world, a lot of complicated machinery is needed to keep a power system humming. 

The complex hinges literally on the Q binding site, which is at the elbow between the intracellular portion that binds NADH, and the series of proteins that all sit in the membrane. When Q binds, the bend is larger, (called the closed form), and when it leaves, the bend is smaller (called the open form). The electron path through the paddle is reasonably well understood, going through several iron-sulfur and flavin mononucleotide complexes that have special overlapping quantum tuning to allow extremely efficient electron transport. The key to the whole system is how the transfer of electrons from NADH through the paddle domain down to Q, which protonates it to QH2 and makes it leave to travel through the membrane to its other destinations, is coupled with a long-range physical and electrostatic shift through the rest of the complex to run the proton pump cycle. 

Structure of complex I, emphasizing the electron path in the paddle (upper right) and the many possible proton conduction paths in the membrane-resident part of the complex (bottom). The Q binding site is shown in brown at the elbow. Each protein subunit is named and given a distinct color. A conductive "wire" through the middle of the membrane components is isolated from the solvent, but connected to each membrane side with dynamically gated pathways. Whether these gates have more of a physical character or an electrostatic character, or both, remains uncertain.

The membrane domain, made up of several similar proteins all side-by-side, seems to have a sort of wire running through the middle, made up of charged amino acid side chains and water molecules, capable of conducting protons parallel to the membrane. It also has specific proton conduction paths within each subunit that provide the possible entry and exit paths for protons getting pumped from the interior outwards. The authors propose that there is a sort of hokey-pokey going on, where one bent form (the open form, with Q ejected) of the machine exposes the matrix-side proton channels, while the other bent form (closed form, with Q present) closes those channels and opens a corresponding set of four channels on the other side that let those same protons out to the cell. The internal wire, they propose, may possibly redistribute the protons to buffer the input channels. Or it might even allow all four to exit on the last, fourth pump complex. In any case, this in essence is the core of biological pump designs, opening channels in one direction to capture protons from one side, (by diffusion), and then executing a switch that closes those and opens ports to the other side, again using diffusion to let them go, but in a new direction. It is the physical cycle that translates energy into chemical directionality, aka pumping.

Proposed mechanism, with the insertion or ejection of Ubiquinone Q dictating the  proton channel accessibility along the membrane proton pump subunits of complex I. Protons enter from the mitochondrial matrix in the blue structures (closed), and exit via the other side in the green structures (open).

Closeup of one of the membrane proton pump segments, showing the dynamic formation of one proton conduction channel in the "open" state (left) vs the closed state (right, circled). The somewhat dramatic turning of the center protein helix carrying residues M64 and F68 opens the way

• Astronomical de-twinkling.
• New SARS-CoV-2 spike variant is twice as good at getting into human cells.
• What the future of Covid looks like: decreasingly lethal, and more cold-like.
• A political poem.
• Rough breakdown of residential CO2 emission sources.
• Table of the week.. Are we as free as China? Are we great yet? A comparison of the US and China in key Covid measures, taken Feb 9.

Rank	Country	Total Cases	New Cases	Total Deaths	New Deaths	Total Recovered	Active Cases	Serious, Critical	Tot Cases/1M	Deaths/1M
1	USA	27,798,163	+93,759	479,726	+3,219	17,631,858	9,686,579	21,446	83,682	1,444
83	China	89,720	+14	4,636	0	84,027	1,057	18	62	3

Competition

Balancing collaboration and competition for a healthy society.

The ongoing discussions about race and caste in America are plumbing the depths of who we want to be as a society, and of the human psychology of hierarchy and competition. As Darwin taught, competition is inherent to life. Winners don't just feel good, they live to fight another day and reproduce another generation. Competition is naturally at the core of human psychology and development as well. We only learn to know our selves against a backdrop of challenges overcome, and people to compare ourselves with. We celebrate the winners in art, music, politics, sports, business. Excellence only exists in comparison.

America was conceived from the first as a winners versus losers project. White Europeans, already sailing all parts of the known world in search of treasure and plunder in competition with each other and the other great Asian cultures, found a virgin land. At least virgin in that it hardly offered any competition, with peoples who were summarily exterminated or enslaved. That this domination was transferred to Africa as a convenient source of losers to be utterly dominated, and ultimately branded as an inferior caste in perpetuity, is at once spiritually shameful and also a natural consequence of the competive drive that inheres in all people.

Idealists then came up with a competing dream of socialism and communism, which was to be a sweeping antidote to all these racial, economic, and social injustices. But competition inexorably reared its ugly head, moving the field of play from its traditional moorings to the political and existential levels, even to the very nature of reality and truth, as seen in the Stalinist systems, and the numerous appalling dictatorial systems that copied it. There was no getting around the need to prove that some are more equal than others.

However we run our formal systems of government and economics, we live in countless competitive settings- socially, economically, sexually, in families and outside. No one loves unconditionally, or serves without reward. So the genius of civilization has been to tame and channel competitive structures and impulses to positive ends. Fairly rewarding work, or setting a standard of one sexual partner in marriage, are examples of rough attempts to forge stable, just, and positive social outcomes out of competitive instincts that if given freer license would destroy us. 

Slavery was a system that, while mostly stable and marginally productive, was also profoundly unjust. One tribe simply declared itself dominant, and used every insidious tool of indoctrination, oppression, and violence to maintain that position. Over time, the original source of the competitive superiority, (whether that was just or not), became irrelevant, and the disparity became as unearned by the oppressors as it was undeserved by the oppressed. It served in no way to expose the natural talents of either in a fair environment of self-expression and actualization through competitive effort. 

So over the history of our country, we have fitfully been waking up to this injustice and expression of erstwhile competitive success, and fighting over how to forge a new social contract. That is perhaps the main reason our political system is so bitterly divided right now. "Freedom" rings from the mouths of both sides. But for one it is typically the freedom to continue enforcing their inherited inequities and privileges. For the other, it is the quest to escape exactly those inequities, which have reified, (as they have similarly in India's caste system, over centuries), into a vast network of debilities, social dysfunctions, ingrained or instinctive attitudes, artistic modes and motifs, economic and geographic patterns.

The new social contract is obviously modeled on modern meritocracy, where all are educated as far as possible, all participate freely in the many markets that pervade our lives, from mating to consuming to job-finding and politics, and all benefit in proportion to their contributions as regulated by those markets. Historical inequities would have little influence in this world, while individual talent and character count for all. This assumes that such a meritocracy is a fair ideal, which many dispute, as the fate of the losers remains uncertain, and in our current version, unbelievably harsh.

But there is no ridding ourselves of competition, however blessed we are with countervailing instincts of empathy and cooperation. It is a rock of human nature, and of our personal development. The best we can do is to regulate it to be fair and moderate. That is, expressing the competitive success of the individual, not her forebears or tribe. And allowing enough benefits to winning to provide motivation towards excellence and success, without destroying the portion of society that necessarily will be losers in various markets. This is the perennial conflict (and competition) between right and left, Republican vs Democrat.

• What happens when the poor are concentrated on one place- East Lake Meadows.
• How long Taiwan?
• Fond memories of the Trumpers.
• What will become of our empire?
• Ten days of quarantine is plenty. Even eight would be OK.
• FOX- another reason to cut the cable cord.

On the Transition to Godhood

Kicking and screaming, humanity is being dragged into a god-like state.

We thought that harnessing electricity would make us gods. Or perhaps the steam engine, or the first rocket ship, or the atomic bomb. But each of those powerful technological leaps left us wanting- wanting more, and wanting to clean up the messes each one left behind. Next are biotechnology, gene editing, and robotics. What to do?

The fact is that we have powers that traditionally were only given to gods. Vast raw physical powers, the ability to fly, and the ability to communicate with anyone, anywhere, instantly, and to know practically anything at a touch. But the greatest of all is our power to derange the entire biosphere- destroying habitats, exterminating species, filling our geologic layer with plastic and radioactive debris, and changing the composition and physics of the atmosphere. 

We have not come to terms with all this power. Indeed half of our political system can't stand the thought of it, and lives in the fantasy that nothing has changed, humanity is not trashing its home, and we can live as profligately as we wish, if only we don't look out the window. Even more disturbingly, this demographic generally holds to a fantasy god- some bearded male archetype- who will either make magically sure that everything comes out OK, or alternately will bring on the end times in flames of wrath and salvation for the select, making any rational worry for the environment we actually live in absurd.

Judgement day is coming!

This, at a moment when we need to grow into our awesome responsibilities, is naturally disheartening. Growing up out of an infantile mind set, where our parents made everything OK, is hard. Adulthood takes courage. It takes strength to let go of fantasy comforts. But the powers of adulthood are truly god-like, especially in this age. We make and remake our environments, look deep into space, into the past and the future, know and learn prodigiously. We make new people. 

Is is clear, however, that we are not taking these powers seriously enough. Overpopulation is one example. We simply can not go on having all the children we want, taking no responsibility for the load they are putting and will put on our home, the biosphere. As nascent gods, we need to survey our domain holistically and responsibly, looking to its future. And right now, that future is rather bleak, beset by irresponsible actors resistant to their higher calling.

• What to do about all the lies?
• Another view of god.
• Don't drive everywhere.
• General breakdown.
• How did South Korea do so well? Rigorous contact tracing and quarantine enforcement.
• Greed in shorts.
• Direct air capture of CO2.

Tale of an Oncogene

Research on a key oncogene of melanoma, MITF, moves from seeing it as a rheostat to seeing it as a supercomputer.

The war on cancer was declared fifty years ago, yet effective therapies are only now trickling in. And very few of them can be characterized as cures. What has been going on, and why is the fight so slow? Here I discuss one example, of melanoma and one of its drivers and central players, the gene MITF.

Melanocytes are not really skin cells, but neural crest cells, i.e. originating in the the embryonic neural tube and giving rise to various peripheral neural structures in the spine, gut, and head. One sub-population migrates off into the epidermis to become melanocytes, which generate skin pigment in melanosome packets, which they distribute around to local keratinocytes. Evolutionarily, these cells are apparently afterthoughts, after originally having developed as part of photoreceptor systems. This history, of unusual evolution and extensive developmental migration and eventual invasion into foreign tissues, has obvious implications for their capacity to form cancers later in life, if mutations re-activate their youthful propensities.

 

Above is shown a sketch of some genes known to play roles in melanoma, and key pathways in which they act. In red are oncogenes known to suffer activating mutations that promote cancer progression. In grey are shown additional oncogenes, ones whose oncogenic mutations are simpler loss-of function, not gain of function, events. And green marks ancillary proteins in these pathways that have not (yet) been found as oncogenes of any sort. MITF is a transcription regulator that drives many genes needed for  melanocyte development and melanosome formation. It also influences cell cycle control and cytoskeletal and cell surface features relevant to migration and invasion of other tissues. This post is based mostly on reviews of the molecules active in melanoma, and the more focused story of MITF.

MITF binds to DNA near target genes, often in concert with other proteins, and activates transcription of the local gene (in most cases, though it represses some targets as well). The evidence linking MITF with melanoma and melanocytes is mostly genetic. It is an essential gene, so complete deletions are lethal. But a wide variety of "mi" mutations in mice and in humans lead to unusual phenotypes like white hair color, loss of hearing, large head formation, small blue eyes, osteopetrosis, and much else. Originally researchers thought there were several different genes involved, but they all resolved down to one complex locus, now called MITF, for mi transcription factor. Certain hereditary mutations also predispose to melanoma, as do some spontaneous mutations. That the dose of MITF also correlates with how active and aggressive a melanoma is also contributes to the recognition that MITF is central to the melanocyte fate and behavior, and also one of the most central players in the disease of melanoma.

The MITF gene spreads over 229,000 base pairs, though it codes for a protein of only 419 amino acids. The gene contains nine alternate transcription start sites, 18 exons (coding regions), and five alternate translation start sites, as sketched above. This structure allows dozens of different forms of the protein to be produced in different tissues and settings, via alternative splicing. The 1M form (above, bottom) is the main one made in melanocytes. Since the gene is essential, mutations that have the phenotypes mentioned above tend to be very small, affecting one amino acid or one splice site, or perhaps truncating translation near the end of the protein. Upstream of the MITF gene and in some of its introns, there are dozens of DNA sites that bind other regulators, which either activate or repress MITF transcription in response to developmental or environmental cues. For example, a LEF1/TCF site binds the protein LEF1, which receives signals from WNT1, which is a central developmental regulator, driving proliferation and differentiation of melanocytes from the stem neural crest cells.

That is just the beginning of MITF's complexity, however. The protein contains in its sequence codes for a wide array of modifications, by regulatory protein kinases (that attach phosphate groups), and other modifiers like SUMO-ylation and ubiquitination. Key cellular regulators like GSK3, AKT, RSK, ERK2, and TAK kinases each attach phosphates that affect MITF's activity. Additionally, MITF interacts with at least a dozen proteins, some of which also bind DNA and alter its target gene specificity, and others that cooperate to activate or repress transcription. One of the better-known signaling inputs is indirectly from the kinase BRAF1, which is a target of the first precision melanoma-fighting drugs. BRAF1 is mutated in half of melanoma cases, to a hyper-active form. It is a kinase responsive to growth factors, generally, and activates a core growth-inducing (MAP) kinase cascade (as shown above), among other pathways. BRAF1 has several effects on MITF by these pathways, but the dominant one seems to be its phosphorylation and activation of PAX3, which is a DNA-binding regulator that activates the MITF gene (and is, notably, absent from the summary figure above, showing how dynamic this field remains). Thus inhibition of BRAF1, which these precision drugs do, effectively reduces MITF expression, most of the time.

Then there are the gene targets of MITF, of which there are thousands, including dozens known to have significant developmental, cell cycle, pigment synthesis, cytoskeletal, and metabolic effects. All this is to say that this one gene participates in a bewilderingly complex network of activities only some of which are recognized to date, and none of which are understood at the kind of quantitative level that would allow for critical modeling and computation of the system. What has been found to date has led to a "switch", or rheostat hypothesis. One of the maddening aspects of melanoma is its resistance to therapy. This is thought in part to be due to this dynamic rheostat, which allows levels of MITF to vary widely and send individual cancer cells reversibly into several different states. At high levels of MITF, cancer cells are pigmented and proliferative (and sensitive to BRAF1 inhibition). But at medium levels of MITF, they revert more to their early migratory behavior, and become metastatic and invasive. So melanoma benefits from a diversity of cell types and states, dynamically switching between states that are both variable in their susceptibility to therapies like anti-BRAF1, and also maximally damaging in their proliferation and ranging activities (diagrammed below).

The theme that comes out of all this is enormous complexity, a complexity that only deepens the more one studies this field. It is a typical example in biology, however, and can be explained by the fact that we are a product of 4 billion years of evolution. The resulting design is far from intelligent- rather, it is a compendium of messy contraptions, historical compromises, and accreted mechanisms. We are very far from having the data to construct proper models that would critically analyze these systems and provide accurate predictions of their behavior. It is not really a computational issue, but a data issue, given the vast complexity we are faced with. Scientists in these fields are still thinking in cartoons, not in equations. 

But there are shortcuts of various kinds. One promising method is to analyze those patients who respond unusually well to one of the new precision treatments. They typically carry some hereditary alteration in some other pathway that in most people generates resistance or backup activity to the one that was drug-treated. If their genomes are fully sequenced and analyzed in depth, they can provide insight into what other pathway(s) may need to be targeted to achieve effective combination treatment. This is a lesson from the HIV and tuberculosis treatment experiences- that the redundancy and responsiveness of biological systems calls for multiple targets and multiple treatments to meet complex disease challenges.

• Bill Mitchell on the evasions of main stream economists.
• Senate budget committee chair: Bernie.
• Stuttering in high office.
• Amanda Gorman ... complete performance art.
• Cultists feeling lost.

Hunting for Lost Height

Progress in sequencing technologies and genetic analysis nails down the genetic sources of variability in the trait of human height.

PBS has an excellent program about eugenics- the push by some scientists and social reformers in the early 1900's to fix social problems by fixing problematic people. Both the science and the social ethics fell into disrepute, however, and were completely done in by the Nazi's version. While the stigma and ethical futility of eugenics remains, human genetics has advanced immeasurably, putting the science on much firmer footing. One example is a recent announcement that one research group has found all the sources of genetic variation that relate to human height.

Height is obviously genetic, and twin studies show that it is 80% heritable. There has been an interesting literature on the environmental effects on height, to the extent that whole populations of malnourished immigrants find that, after they move to the US, their children grow substantially taller. So genetic influences are only apparent (as indicated by the 80% figure) in the absence of over-riding environmental constraints. 

The first attempts to find the genetic loci associated with height took off after the human genome was sequenced, in the form of GWAS studies (genome-wide association study). It was easier in this era to probe short oligonucleotide sequences against the sampled genomic DNA, rather than sequence whole genomes of many people. So GWAS typically took a large sample of about 500,000 locations through human genomes that were variant, and used them to test which of those variants a set of human populations had. A massive correlation analysis was done versus the traits of those people, say their height, or weight or health, to see which markers (i.e. variants) correlated with the trait of interest. 

Such studies only found about 5% to 25% of the heritability of height, perplexing researchers. They were sampling the entire genome, if sparsely. The 500,000 markers corresponded to about one every 6,000 base pairs, so should be near enough to most genes, if they have significant effects on the trait of interest. And since most human genome regions are inherited as relatively large blocks, (haplotypes), due to our near-clonal genetic history, the idea was that sampling a sparse set of markers was sufficient to get at any significant effect from any gene. Later work could then focus in on particular regions to find the actual genes and variations that were responsible for the trait in question.

But there was a big problem, which was that the variants selected to go into the marker pool were from a very small population of a few hundred people. Recall that sequencing whole genomes was very expensive at this time, so researchers were trying to wring as much analysis out of as little data as possible. By 2018, GWAS type studies were still only finding genetic causes for about 25% of the variability of height, clearly short of what was known from simple genetic analysis of the trait. Not only that, but the number of genes implicated was rising into the thousands, each with infinitesimal effect. The first 40 genes found in these studies only accounted for about 5% of the variation in height. 

The large effect of rare alleles. MAF (minor allele frequency) in the human population, plotted against the trait variance it accounts for. The color code (LD, or linkage disequilibrium) indicates selection against the locus (if high) and other predicted characteristics of the variation, in the color scheme. It is very rare protein-altering variants (blue) that have the strongest individual effects.

The current work (review, review) takes a new approach, by virtue of new technologies. They sequence the full genomes of over 20,000 people, finding a plethora of rare alleles that had not been included in the original marker studies- alleles that have significant effects on height. They find variations that account for 79% of height heritability, which is to say, all of it. It turns out that the whole premise of the GWAS study, that common markers are sufficient to analyze diverse populations, is incorrect. The common markers are not as widely distributed, or as well-linked to rare variants, as was originally assumed. The new technologies allow vastly more depth of analysis (full genome sequencing) and broader sampling (20,000 vs a few hundred) to find rare and influential variants. We had previously learned that using common variants confines the GWAS analysis to uninteresting variants- those that are not being selected against. This may not be an enormous issue in height trait, (though these researchers find that many of their new, rare loci are being selected against), but it was a big issue in the analysis of disease-linked genetic loci, like for diabetes or alcoholism. While these traits may be common, the most influential genetic variants that cause them are not, for good reason.

One can imagine that over time, everyone will have their genome sequenced, and that this data will lead to a fuller, if not complete, understanding of trait genetics. But what are the genes responsible for the traits? All this is still an abstract mapping of locations of variability (what used to be called mutation) correlated with variations of a trait. This newest data identifies thousands of influential variants covering one third of the genome. This means that, like most interesting traits, the genetics of human height are dispersed- a genetic fog. All sorts of defects or changes can influence this trait to infinitesimal degrees, making it a fool's errand to look for a gene for height.

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• Stories, data, and emotion.
• God, guns, and lunacy ... a match made in heaven.

Viruses Have Always Been With Us

Some researchers argue that viruses form their own kingdom of life, and originated prior to the last common cellular ancestor.

Viruses are all about, even more of them than bacteria. The pandemic has focused our attention on one of them, but they are truly astronomical in diversity and numbers. Where did they come from? This has historically been thought a pointless question, since, even if one concedes that they are life forms of a sort, they mutate and evolve quite a bit faster than cells and organisms do, erasing most of their history. Additionally, they have been thought to exchange genes at a high rate with their hosts, also tending to erase whatever history they retain. But an article published back in 2015 fought back against all this pessimism, and made the case that virus histories can be reconstructed on a global scale and have some very interesting things to tell us.

Their first point is that gene exchange between viruses and hosts is less confusing than thought. Cells certainly have adopted viral genes at a high rate. Our own genomes are chock full of retroviral remnants, for instance. But functional genes are a different story. Relatively few seem to have gone either way (though see Koonin et al., arguing that many viral capsid and coat proteins were adopted from cellular genomes). The core viral replication proteins, such as the SARS-CoV2 RNA polymerase, for instance, is not related to cellular enzymes, and seems to be very ancient. The authors suggest that such key components originated even before the last common cellular ancestor- the point of divergence between archaea, bacteria, and eukaryotes.

To overcome the main technical hurdle of rapid evolution, the authors use protein fold analysis. Instead of studying DNA sequences, (which evolve quite rapidly), or protein sequences, (which evolve more slowly), this uses the shape of the protein, which tends to persist even after sequence similarity is completely lost. This is one way to get at very deep phylogenies, and they claim that it points to a substantial set of protein folds that are specific to viruses and wide-spread within viral families. They point out additionally that these proteins tend also to be confined to families of viruses, one more indication that virus evolution has not been promiscuous, but rather remarkably traceable through time. Viruses are classified into major families by their mode of replication. Thus RNA viruses and DNA viruses appear to have, for instance, distinct and ancient lineages.

One way to make sense of these observations and claims is that viruses were actually cells at very early times. It is common for parasites to progressively lose functions that are needed in the free-living state but become unnecessary when living off one's parents, er some other fully competent cell. The closer the symbiotic or parasitic association, the fewer functions the parasite needs. If the parasite is intracellular, then a huge amount of cellular overhead can be dispensed with. Mitochondria evolved this way, from free-living bacteria to organelles now with only about 33 genes. 

Viruses come in all sorts of sizes, from nearly cell size, encoding a thousand genes, down to specks of RNA only 250 nucleotides long. This diversity suggests the plausibility of their origination as cells, and subsequent down-scaling through a parasitic lifestyle.

But what were those cells, and whom did they parasitize? The distinct and peculiar gene complements and mechanisms of viruses, particularly the RNA viruses, suggests that they originated prior to the major split of existing cellular kingdoms. It stands to reason that cellular life has been saddled with parasites and viruses almost since the advent of cells, so some of these virus families may predate the advent of DNA, thus the prevalence of RNA viruses. The authors do an analysis of ages of the protein folds they find and their distribution, and suggest that those folds shared in all domains of life (viruses, archaea, bacteria, and eukaryotes) show that those from this set found in RNA viruses are significantly older than those found in DNA viruses. Such protein folds that are universal would be the most ancient, so finding differention among which viruses have them suggests that the major virus lineages come from different epochs of this most ancient era of cellular evolution. Interestingly, the pattern they do not find is one reflecting the cellular domains of life, which would be the case if viruses arise continuously or in relatively modern times from their cellular milieu.

Phylogenetic tree of protein folds from all domains of life, including viruses. Note the close clustering of RNA viruses near the root, and the early distribution of other viruses, compared to the later divergence of cellular domains. This kind of stretched phylogenetic tree is unfortunately symptomatic of an unsually high evolutionary rate, which is also a viral property. So it is not clear whether these authors have fully resolved this issue with their protein fold-based methods.

 

The upshot is that these authors promote the idea that viruses should constitute their own superkingdom of life, in parallel with the major cellular superkingdoms- archaea, bacteria, and eukaryotes. The rooting/ordering of the cellular tree remains quite controversial, but viruses are clearly something else again. They exchange a fair amount of genetic material with cells, but retain noticeable traces of early protein and RNA evolution. The idea that they arose from primitive or proto-cells also makes sense as a general proposition, for otherwise it is difficult to imagine their origin, such as from naked nucleic acids. This whole view remains quite controversial in the field, however, given the difficulties of the molecular analysis and the general prejudice against viruses as proper forms of life. But I think time will bear out this view and add a significant feature to early, as well as current, evolution.

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• Who writes better then Barack Obama? Michelle Obama.

The Parables of Octavia Butler

Review of Parable of the Sower, and Parable of the Talents, about earily familiar dystopias and the religions they call forth.

Octavia Butler is having a moment. The late science fiction author published the parable books in 1993 and 1998, not even knowing of the coming G. W. Bush administration, let alone that of Donald Trump. But her evangelical-supported right wing presidential candidate issues a call to "Make America great again". Her insight and prescience is head-spinning, in books that portray an America much farther gone into division, inequality, corporate power, and chaos (all owing to climate change(!)) than we in actual reality are- yet only by degrees. That is only the window dressing and frame, however. Her real subjects are religion and human purpose. I will try to not give away too much, since these make dramatic and interesting reading.

The books introduce heroine Lauren Olamina, who is totally together and possessed of a mission in life. She grows up in a neighborhood compound walled off from the chaos outside, but quite aware of the desperate conditions there. Her father is a pastor, and both she and her brother become, through the books, preachers as well. The brother in a conventional Christian mode, but Lauren founds a new religion, one maybe tailored for the generally skeptical science fiction audience. God is change. That is it. Lauren emphasizes empathy, usefulness, education, and the shaping of change, but there is no god as traditionally conceived. It is a sort of buddhistic philosophy and educational / communal program rather than a supernaturalist conjuring, and love (or fear), of imaginary beings.

One question is whether such a philosophy would actually gain adherents, form communities and function as a religion. I get the sense that Butler would have dearly loved for her ideas to gain a following, to actually ripen, as did those of fellow science fiction writer L. Ron Hubbard, into an actual religion (however horrible his escapade actually turned out to be!). But their difference is instructive. Hubbard's Dianetics/Scientology is a floridly imagined narrative of super-beings, secret spiritual powers, and crazy salvation. Absolute catnip to imaginative seekers wanting to feel special and purposeful. On the other hand, Olamina's system is quite arid, with most of the motive force supplied, as the book relates, by her own determination and charisma. Her philosophy is true, and therein lies a big, big problem. Truth does not supply purpose- we already knew that scientifically. Natural selection is all about change, and makes us want to live, flourish, and propagate. Change is everpresent, and while it might be healthy to embrace it and work with it, that is hardly an inspiring and purpose-filling prospect, psychologically. As the books relate in their narrative of Lauren's life, change is also often quite terrible, and to be feared.

But the more important question is what role people such as Lauren play, and why people like her followers exist. People need purpose. Life is intrisically purposeless, and while we have immediate needs and wants, our intelligence and high consciousness demands more- some reason for it all, some reason for existence, collectively and individually. An extra motive force beyond our basic needs. We naturally shape our lives into a narrative, and find it far easier and more compelling if that narrative is dramatic, with significance beyond just the humdrum day-to-day. But such narratives are not always easy to make or find. Classic epics typically revolve around war and heroic deeds, which continue to make up the grist of Hollywood blockbusters. Religion offers something different- a multi-level drama, wrapped up in collective archetypes and usually offering salvation in some form, frequently a hero, if not a militaristic one. Last week's post mentioned the life of Che Guevara, who found purpose in Marxism, and was so fully seized by it that he bent many others, possibly the whole nation of Cuba, to his will / ideology. Lauren Olamina is a similar, special person who has, through her own development and talents, discovered a strong purpose to her life and the world at large that she feels compelled to share, pulling others along on her visionary journey. Are such people "strong"? Are their followers "weak"? 

Human social life is very competitive, with the currency being ability to make others think what you want them to think, and do what you want them to do. Our ideology of freedom was built by a founding class of dominant, slave-holding rich white men who wanted only to come to a reasonable accommodation for political power within their class, not extend freedom to women, blacks, or the poor. This ideology was highly successful as a sort of civic religion, coming down to us in two traditions- the "winning" tradition of native American extermination, ruthless capitalism, and growing international empire- all set within a reasonably stable elitist political system. And the second "freedom" tradition, which gave us abolitionism, the civil rights movement, and the modern Democratic party, which takes Jefferson's ideals at their word, however little he actually meant them.

Religion is a particularly powerful engine of political and social ideology, making people go through ridiculous rituals and abasements to keep on the safe side of whatever the powerful tell them. So yes, domineering social personalities like Lauren and Che, (and Trump), are very powerful, deservedly treated as larger-than-life, charismatic figures. Their powers are archetypal and dangerous, so it falls to skeptics and free-thinkers to offer antidotes, if their charisma goes off the rails. Butler offers a hero who is relentlessly good and positive, as well as charismatic and strong, so the only competition comes from ignorance, conventional wisdom, and from the competing religious powers like traditional Christianity. But the power of artificial purposes, and of the charismatic figures who propound them, is almost uniformly corrupting, so Lauren's opposition is, in the end, far more realistic as a portrayal of what we are facing, now and in the future.

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• Obstruction of justice, in a continuing saga of impeachable offenses.