Many Ways There are to Read a Genome

New methods to unravel the code of transcriptional regulators.

When we deciphered the human genome, we came up with three billion letters of its linear code- nice and tidy. But that is not how it is read inside our cells. Sure, it is replicated linearly, but the DNA polymerases don't care about the sequence- they are not "reading" the book, they are merely copying machines trying to get it to the next generation with as few errors as possible. The book is read in an entirely different way, by a herd of proteins that recognize specific sequences of the DNA- the transcription regulators (also commonly called transcription factors [TF], in the classic scientific sense of some "factor" that one is looking for). These regulators- and there are, by one recent estimate, 1,639 of them encoded in the human genome- constitute an enormously complex network of proteins and RNAs that regulate each other, and regulate "downstream" genes that encode everything else in the cell. They are made in various proportions to specify each cell type, to conduct every step in development, and to respond to every eventuality that evolution has met and mastered over the eons.

Loops occur in the DNA between site of regulator binding, in order to turn genes on (enhancer, E, and transcription regulator/factor, TF).

Once sufficient transcription regulators bind to a given gene, it assembles a transcription complex at its start site, including the RNA polymerase that then generates an RNA copy that can float off to be made into a protein, (such as a transcription regulator), or perhaps function in its RNA form as part of zoo of rRNA, tRNA, miRNA, piRNA, and many more that also help run the cell. Some regulators can repress transcription, and many cooperate with each other. There are also diverse regions of control for any given target gene in its nearby non-coding DNA- cassettes (called enhancers) that can be bound by different regulators and thus activated at different stages for different reasons. 

These binding sites in the DNA that transcription regulators bind to are typically quite small. A classic regulator SP1 (itself 785 amino acids long and bearing three consecutive DNA binding motifs coordinated by a zinc ions) binds to a sequence resembling (G/T)GGGCGG(G/A)(G/A)(C/T). So only ten bases are specified at all, and four of those positions are degenerate. By chance, a genome of three billion bases will have such a sequence about 45,769 times. So this kind of binding is not very strictly specified, and such sites tend to appear and disappear frequently in evolution. That is one of the big secrets of evolution- while some changes are hard, others are easy, and it there is constant variation and selection going on in the regulatory regions of genes, refining and defining where / when they are expressed.

Anyhow, researchers naturally have the question- what is the regulatory landscape of a given gene under some conditions of interest, or of an entire genome? What regulators bind, and which ones are most important? Can we understand, given our technical means, what is going on in a cell from our knowledge of transcription regulators? Can we read the genome like the cell itself does? Well the answer to that is, obviously no and not yet. But there are some remarkable technical capabilities. For example, for any given regulator, scientists can determine where it binds all over the genome in any given cell, by chemical crosslinking methods. The prediction of binding sites for all known regulators has been a long-standing hobby as well, though given the sparseness of this code and the lability of the proteins/sites, one that gives only statistical, which is to say approximate, results. Also, scientists can determine across whole genomes where genes are "open" and active, vs where they are closed. Chromatin (DNA bound with histones in the nucleus) tends to be closed up on repressed and inactive genes, while transcription regulators start their work by opening chromatin to make it accessible to other regulators, on active genes.

This last method offers the prospect of truly global analysis, and was the focus of a recent paper. The idea was to merge a detailed library predicted binding sites for all known regulators all over the genome, with experimental mapping of open chromatin regions in a particular cell or tissue of interest. And then combine all that with existing knowledge about what each of the target genes near the predicted binding sites do. The researchers clustered the putative regulators binding across all open regions by this functional gene annotation to come up with statistically over-represented transcription regulators and functions. This is part of a movement across bioinformatics to fold in more sources of data to improve predictions when individual methods each produce sketchy, unsatisfying results.

In this case, mapping open chromatin by itself is not very helpful, but becomes much more helpful when combined with assessments of which genes these open regions are close to, and what those genes do. This kind of analysis can quickly determine whether you are looking at an immune cell or a neuron, as the open chromatin is a snapshot of all the active genes at a particular moment. In this recent work, the analysis was extended to say that if some regulators are consistently bound near genes participating in some key cellular function, then we can surmise that that regulator may be causal for that cell type, or at least part of the program specific to that cell. The point for these researchers is that this multi-source analysis performs better in finding cell-type specific, and function-specific, regulators than is the more common approach of just adding up the prevalence of regulators occupying open chromatin all over a given genome, regardless of the local gene functions. That kind of approach tends to yield common regulators, rather than cell-type specific ones. 

To validate, they do rather half-hearted comparisons with other pre-existing techniques, without blinding, and with validation of only their own results. So it is hardly a fair comparison. They look at the condition systemic lupus (SLE), and find different predictions coming from their current technique (called WhichTF) vs one prior method (MEME-ChIP).  MEME-ChIP just finds predicted regulator binding sites for genomic regions (i.e. open chromatin regions) given by the experimenter, and will do a statistical analysis for prevalence, regardless of the functions of either the regulator or the genes it binds to. So you get absolute prevalence of each regulator in open (active) regions vs the genome as a whole. 

Different regulators are identified from the same data by different statistical methods. But both sets are relevant.

What to make of these results? The MEME-ChIP method finds regulators like SP1, SP2, SP4, and ZFX/Y. SP1 et al. are very common regulators, but that doesn't mean they are unimportant, or not involved in disease processes. SP1 has been observed as likely to be involved in autoimmune encephalitis in mice, a model of multiple sclerosis, and naturally not so far from lupus in pathology. ZFX is also a prominent regulator in the progenitor cells of the immune system. So while these authors think little of the competing methods, those methods seem to do a very good job of identifying significant regulators, as do their own methods. 

There is another problem with the author's WhatTF method, which is that gene annotation is in its infancy. Users are unlikely to find new functions using existing annotations. Many genes have no known function yet, and new functions are being found all the time for those already assigned functions. So if one's goal is classification of a cell or of transcription regulators according to existing schemes, this method is fine. But if one has a research goal to find new cell types, or new processes, this method will channel you into existing ones instead.

This kind of statistical refinement is unlikely to give us what we seek in any case- a strong predictive model of how the human genome is read and activatated by the herd of gene regulators. For that, we will need new methods for specific interaction detection, with a better appreciation for complexes between different regulators, (which will be afforded by the new AI-driven structural techniques), and more appreciation for the many other operators on chromatin, like the various histone modifying enzymes that generate another whole code of locks and keys that do the detailed regulation of chromatin accessibility. Reading the genome is likely to be a somewhat stochastic process, but we have not yet arrived at the right level of detail, or the right statistics, to do it justice.

• Unconscious messaging and control. How the dark side operates.
• Solzhenitsyn on evil.
• Come watch a little Russian TV.
• "Ruthless beekeeping practices"
• The medical literature is a disaster.

Profiles in Pusillanimity

China, its communist party, and our free speech. Review of America 2nd, by Isaac Stone Fish.

Why are there always spoilers on the international scene? Some country is always unhappy with the way things are, and does its best to shake up the system. That shaking can be as detrimental to itself as to any other nation, but greed and ambition are always with us. After the Cold War, Russia descended into criminal chaos, with little real help from the West, and, once it had finally pulled itself together, turned around with veangence on its mind to refashion its imperial / security sphere. Russia could have been a nice country, tied into the European cultural and defense system. But no, the nostalgia for satellites and empire were just too strong. Putin spent a decade and more pulling Ukraine into the Russian orbit, only to be finally rebuffed in a people-powered revolution. Now he is trying to do it the hard way, and will take and keep whatever he can grab, little though that may be.

All that is peanuts compared with the game brewing between us and China. While Russia is playing for its neighborhood, the stakes in this next game are the whole world. That is, who runs the "international system", such as it is, and who plays the dominant role over the next century. The US has spent the last couple of decades trying to pull China into the existing trade and security system, in hopes that it would change into a "nice" country, aligning with the US, Europe and our developed allies all over the world in a quest for peace and lawful security. That has not happened. Even less so than with Russia, which at least has a long strand of pro-European sentiment, China learned its lessons from the Russian debacle, and its own Tienanmen square brush with democracy, and resolutely stayed in the Leninist camp- of absolute and unapologetic party power. It was hardly even tempted by European values.

In his book "America 2nd", Isaac Fish is eloquent about how deep China's resentments vs the West go. China suffered a century or more of humiliating vassalage over the 19th century, mired in poverty, opium, and weakness vs colonial powers. Then it suffered again at the hands of imperial Japan, and then several decades on its own account under Mao enduring the Western ideology of Marxism-Leninism. Maybe the last part is projected on the West as well, I am not sure. But China has plenty of ground to make up, and the last few decades of managed capitalism have been, as all can see, completely transformative.

China has already attained number one status in pollution, in population, (though later overtaken by India), and will soon attain that status in GDP. China is busy projecting its power and values via foreign aid, "Wolf Warrior" diplomacy, their takeover of the South China sea, propaganda, intelligence, and hard-ball economic warfare. The question Fish asks is- why are we supporting this policy and the propaganda of the Chinese Communist Party (CCP)?

Recall the quaint old days of "linkage", when the US considered using some points of leverage with Russia to influence Soviet policies we didn't like? China has no such qualms. Everything is linked, and particularly, China's great economic engine is linked with CCP propaganda. US companies that say anything the CCP does not like lose business and IP. The NBA went through a humiliating episode when Darryl Morey of the Houston Rockets criticized CCP repression in Hong Kong. The CCP promptly cancelled NBA air time and business in China, until the NBA comprehensively groveled back into its good graces, and has ever since kept its mouth shut. Black lives may matter, but Tibetan lives, Uyghur lives, Hong Kong lives... not so much, when a totalitarian power waves its big stick.

China can make its own jingoistic media as well. This is Wolf Warrior 2, whose tag line runs: "Anyone who offends China, no matter how remote, must be exterminated."

Far more damaging is the capitulation of Hollywood. After dabbling with tailoring films for the Chinese market, it turned out that it was easier, and not at all influenced by CCP pressure to project a positive world wide image, for Hollywood studios to get fully on board with CCP censorship for all releases, not portraying China or Chinese in a negative way. So, after a brief and now thoroughly repressed few years of agitation on behalf of Tibet a couple of decades ago, the film industry, one of the premiere arms of American soft power, has been turned and cowed, into a lapdog of the CCP. Not a peep about Tibet any more, indeed DreamWorks brought out a thoroughly whitewashed Tibet-adjacent feature in 2019 that suggests everything there is perfectly fine, thanks to Han characters who protect the region.

Capitulation has been the rule across the business world, as each business faces the brutal choice of playing with the CCP, or being barred from Chinese markets, and even hobbled in other ways as China gains power abroad. But this has not been enough. China has been busily corrupting the US government itself, masterfully using former officials to press its case for Western acquiescence. Henry Kissinger is the pioneer in this effort, but former presidents and many other officials have spared no effort in setting up post-career "consultancies" that assiduously advise any and all comers that resistance is futile- China will rule the world and we must accommodate ourselves to that fact. 

"There are plenty of antagonists in this story, some Chinese, some not. For those upset with Beijing's influence in America, understand this: by helping normalize corruption among our former diplomats and warping American perception of China over the last four decades, Henry Kissinger has done more harm to American interests than every ethnically Chinese businessman, hacker, spy, whether they hold American or Chinese citizenship."

It is ironic, with all the current complaints about cancel culture, free speech for fascists, woke restrictions, etc. that we are actually being policed in our speech by our geopolitical opponent, China, and do not seem to think anything amiss about that.

The ancient Art of War recommends winning by shaping the battlefield and the minds of the opponents- whereby not a shot needs to be fired. Fish emphasises the United Front operations of the CCP and its propaganda arms, which seek influence in many ways, not just media. The seduction of foreign officials and fixers comes under this area of government work, for instance, as does the pressuring of speech and behavior by foreign corporations. Everything is linked, as is proper under a totalitarian system, and every oar pulls in the same direction of keeping the CCP in power and gaining influence across the world.

The CCP has a great deal to answer for, both historically, and in its brutal approach to its current rule, even given its huge successes in economic growth and allowing the modernization of China. A democratic and free China would look very different, and could flourish just as well. We should not be taken in by the propaganda of identity between the CCP and China, or the permanence of CCP rule. We need to be able to think and speak freely, and facilitate the freedom of others. And this should start with Taiwan, whose freedom is in the crosshairs of the CCP. We should not acquiesce to the narrative that Taiwan must/will be assimilated into China, or that it is not, in fact, an independent nation with every right to self-determination. The CCP's track record of cultural genocide in Tibet, actual concentration camps and genocide in Xinjiang, and the decapitation of Hong Kong shows clearly enough what would be in store for Taiwan, and for the rest of us, were China to gain even more leverage.

• More of the same, and Maurice Greenberg is always at hand to support China.
• India is only marginally better.
• Should we end the drug war?
• Maybe we should just leave nature alone.
• Fascism is coming.
• But Scientology is ... aready here.

Hair! An Evolutionary Story

What happened in genomes of mammals who lost their hair?

Hair is characteristic of mammals, and forms part of our advanced sensor suite that so effectively replaces the need for armor, shells, and the like. We can have very soft skin, and use hair for warmth, protection, sensing, display, nesting, and other things. But for some mammals like whales and dolphins, hair became a nuisance and has almost wholly been shed. Why it happened is pretty clear, both functionally and by the theory of natural selection. But figuring out how it happened requires delving into the respective genomes of these animals, including us- who, while hardly hairless, have much less than the common mammal. And the genomes tell an interesting story about how evolution works.

The premise of a recent study that tackled this issue (review) is that convergent evolution, that is the development of the same trait in distinct lineages, usually happens in similar ways, mutating the same genes that are key ingredients or regulators for that trait. So, given the many genomes that have now been sequenced across all the mammals, they asked whether a bunch of hairless mammals share some genetic mechanisms behind hairlessness. While there are several sudden appearances of hairlessness in dog breeds and mice, traceable to specific mutations/genes, the authors were not really interested in the genetics of hair itself, but how during actual evolution, hairlessness came about. 

An example of a large-scale map of syntenic regions that match between human and mouse genomes, by chromosome. Recombination and shuffling between regions and chromosomes happens frequently over long periods of time, in addition to smaller-scale mutations, making it challenging to do this mapping, which is a first step to analyses like those discussed here.

They are looking for signs such as significantly decreased or increased evolutionary rates in particular regions of a genome, which might mean either that that region has escaped selection, perhaps because the need for hair has disappeared, so selection is now indifferent to the maintenance of its genetic ingredients, or because the region is under positive selection, perhaps because the need for hairlessness is urgent, not just a matter of indifference. This method also assumes that corresponding regions of different mammalian genomes (called syntenic regions) can be identified, despite a great deal of rearrangement that will have happened over these long spans of time. 

A rough rundown of the anatomical location of expression of genes which had significant evolutionary speedups in hairless species. The Y axis is a measure of enrichment of that location of expression vs a null hypothesis of expression everywhere, for the set of 27 accelerated genes. Skin and hair expression are clearly favored by genes found in this analysis.

It is the convergence aspect, comparing several different lineages that evolved to similar states, that is hoped to weed out the hair-specific changes from all the other riffraff that happens over the ages. (While they also tried to cancel out the marine-heavy and large size-weighting of their selected species.) Each species has many other challenges, after all, and specific trajectories for each of its genes, and most mutations are meaningless. Selective comparison should help focus on the regions that really matter. The authors found 27 genes with accelerated changes, none of which had signs of positive selection. Half of these genes became defunct- they turned into pseudogenes, which is definitive evidence for relaxation of evolutionary selective constraints, rather than positive selection for new constraints. 

In the following, I give their ranked top genes for evolutionary rate acceleration, divided by those changing in their coding regions, and those changing most in nearby non-coding regions.

== Coding sequence acceleration ==

• FGF11   - fibroblast growth factor, with no previously known role, but is here the top statistical match. FGF5, FGF7, FGF18, and FGF22 are known to participate in hair growth in mice, so this is likely another regulator of hair growth.
• GLRA4 - is one of the pseudo genes, in humans is a glycine receptor and a pseudogene
• KRT2      - keratin
• KRT35    - keratin
• PKP1       - plakophilin, known to be important for skin formation, causes skin fragility when absent- related to intermediate filament system.
• PTPRM - protein tyrosine phosphatase, transmembrane receptor, cell adhesion and related signaling, in hair cells.
• ANXA11  - cell growth / survival regulatory protein causal for ALS disease and epithelial sarcoidosis.
• MYH4      - myosin heavy chain motor protein, known to be involved in hair growth. "... out of 69 KRTs and KRTAPs for which noncoding enrichment could be calculated, 66 showed accelerated evolution in both protein-coding sequence and noncoding regions"

== Noncoding sequence acceleration ==

• ELF3 - transcription regulator, known to be involved in hair development
• FOXC1 - transcription regulator, known to be involved in hair development
• CCDC162-SOHLH2 - readthrough into a transcription regulator
• FAM178B - unknown
• UVSSA - transcription regulator
• OLFM4 - extracellular matrix, promoting cell adhesion
• ADRA1D - hormone receptor and regulator of cell proliferation
• mir205 - translation regulator, known to be involved in hair development 
• .. and numerous other microRNAs

So a theme is emerging here, which is that some of the central players in hair development and hair structure received extra mutations in their coding sequences. Keratins, which make up hair, are an obvious case. The other altered genes have more obscure connections, but it is evident that FGF11 plays some important role in hair development, analogous to its relatives that are all local signaling molecules that instruct cell type and proliferation.

Genes found in this study, spread over a non-coding acceleration vs coding region acceleration in their mutation (evolution) rate. In orange are all the keratin genes, some of which have high rates in their coding sequences, but pretty much all of which have high rates in nearby non-coding DNA. In blue and red are other genes with nearby non-coding rate acceleration, with ones known to participate in hair functions marked in red.

On the other hand, regulators of other genes involved in hair development- a series of transcription regulators and micro-RNAs- were altered in their own regulation, which happens in non-coding areas of genes, but not in their coding sequences. This is because these regulators have many other roles, which would be disrupted by changing their coding sequences. Their special sauce lies in where and when they are expressed, which then leads to the complex combinatorial interactions they have with batteries of other regulators converging at their target genes. A great deal of evolution consists of twiddling with dials, rather than hammering on the machinery, or yanking it out.

So, over the tens of millions of years that mammals have been around, the loss of hair appears to come down to tweeks over many different genes, some of which are thrown out entirely (becoming pseudogenes), others of which are disabled in different ways in their protein sequences (keratins, FGF11), and others that are merely relocated in their expression, so that while most of their roles are untouched, their role in hair development is toned down or eliminated. The genome is an orchestra with a lot of players, whose contributions to the whole is sometimes loud and clear (keratin), but more often indirect and obscure, rewarding deeper forms of music appreciation.

• China is making high level pro-China propaganda.
• But we are as well.
• Conventional economics: wrong!
• Joe Biden, TCB. Or G2G?

Portents of Overpopulation

The many ways we can tell humans have overrun the planet.

I was reading a slight book on the history of my county, built around photos from our local historical society. What struck me was how bucolic it used to be, more agrarian and slow paced, yet at the same time socially vibrant. A scarcity of people makes everyone more positive about meeting and being with other people. Now the region is much more built-up, with more amenities, but less open space and seemingly less social mixing. All this got me thinking about the social indices of overpopulation.

There are many ways to evaluate human overpopulation. Famine and starvation is perhaps the simplest, a specter that was thought to be imminent in the 1970's, with "The Population Bomb". Lately we have become aware of more subtle problems that the planet has due to our numbers, like pervasive plastic pollution, deranged nitrogen and other chemical cycles, and climate heating. There has been a constant descent down ladders of resource quality, from the mastodons that were hunted out thousands of years ago, then fisheries destroyed, then ranges overgrazed, to the point that we are making hamburgers out of peas and soy beans now. Minerals follow the same course, as we go farther afield to exploit poorer ores of the critical elements like copper, aluminum, rare earth elements, helium, etc. 

Sustainability is not just a word or a woke mantra. It is a specter that hangs over our future. Will humans be able to exist at our current technological level in a few hundred years? A thousand? Ten thousand? There is no way that will be possible with our current practices. So those practices unquestionably have to change. 

But apart from the resource constraints that overpopulation presents, I have been struck by the sociological factors that point in the same direction, and are spontaneous responses to what is evident in the environment. In my community and the state of California, there is a vocal debate about housing. Localities have settled into a comfortable stasis, where no new housing is zoned for, existing housing values go up, and existing residents are happy. But the population of the state continues to go up, housing becomes increasingly unaffordable, and the homeless lie all over the streets and parks. There seems to be a psychological state where most current residents see the current situation as sufficiently dense- they are not interested in more growth, (We don't want to become LA!). They instinctively sense that we have collectively reached some kind of limit, given our technological setting and psychology.

Declining birth rates across the developed world point in the same direction. Perhaps the expense of raising a child into the current lifestyle is too high, but there may be something more basic going on. Likewise the broad acceptance of gay / LGBTQ lives, where previously the emphasis was on "natural" and fertile growth of the human population, without any consciousness of limits. People seem less social, less likely to go out from their cocoons and streaming pods. Political divisiveness may also be traceable to this sociological turning point, since if growth is off the table, the pie is static, and political and economic competition is increasingly zero-sum instead of collective and growth-oriented. Public works fall into this trap as well, with public agencies increasingly sclerotic, unable to plow through conflicting entrenched interests, and unable to grow, or even maintain, our infrastructure. One could invoke a general anti-immigrant sentiment as another sign, although anti-immigrant campaigns have featured periodically throughout US history, usually mixed, as now, with racial selectivity and animus.

Imaginatively, dystopias seem to rule over the science fiction universe, as Hollywood seems to take for granted a grim future of some kind, whether inflicted by aliens or AI, or by ourselves. Heroes may fight against it, but we do not seem to get many happy endings. The future just looks too bleak, if one is looking far enough ahead. It is hard to generate the optimism we once had, given the failure of the technological deliverances of the twentieth century (fossil fuels, nuclear power, fusion power) to provide a truly sustainable future. Everyone can sense, at an intuitive level, that we are stuck, and may not get a technological fix to get us out of this jam. Solar power is great, but it is not yet clear that the triumvirate of wind, solar, and batteries are truly enough to feed our need for power, let alone the growing appetites of the not-yet-fully developed world. And if it is? Human populations will doubtless grow to the point that those technologies become untenable in turn, with a hat-tip to Thomas Malthus. 

We should be proud of the many great things that this period of prosperity has allowed us to accomplish. But we should grieve, as well, for the costs incurred- the vast environmental degradation which at the current pace is accelerating and compounding through many forms. Humans are not going to go extinct from these self-induced crises, but we will have to face up to the absolute necessity of sustainability over the long term, or else "the environment" will do so for us, by reducing our populations to more sustainable levels.

• Similarly in China...
• A turning point in Chinese attitudes.
• The Gym Industrial Complex.

What's Inflation For?

Why do we have, and want, inflation?

I recently watched some of a documentary- "The Monopoly of Violence"- an attack on the state from a libertarian perspective. It is the kind of thing Elon Musk and fellow Ayn Randians love to go on about- how jackbooted and totalitarian the evil state is, over the little people and wonderful entrepreneurs of our sadly oppressed Western countries. How compulsory taxation, schooling, and legal responsibility is an affront to the natural rights of man. Maybe it is better somewhere else less governed, like maybe Haiti, or Mars! The absurdity of it is grating, as they rant from comfortable chairs, protected by the innumerable services of the state.

One such service is management of the monetary system. Back in the wonderful days of unregulated money, anyone could found a bank, and any bank could issue money. Sounds nuts, right? Well it was nuts, and led to numerous booms and busts in the 1800's, and countless smaller bank failures, lost fortunes, swindles, etc. Early Mormon history gives us just one small example, where Joseph Smith set up the Kirtland Bank on a fraudulent basis, issued an ocean of notes, and collapsed less than a year after founding. As the old saying has it, man is wolf to man. And anarchy, while sometimes conducive to self-organization and initiative, is more often the province of con men, swindlers, gangs- criminals of all kinds.

The recent inflation scare brought the topic of inflation front and center in the news again, after a couple of decades in remission. The Fed has a target of two percent, which seems arbitrary. Why not something else? Why not zero? If you read lots of history or Victorian novels, it becomes apparent that this idea of having, even wanting, ongoing inflation, is a modern idea. Economies used to run on a gold standard, on the pound sterling, or the Roman denarius, which were stable in value (barring debasements in the coinage) for centuries. What happened?

Modern economics happened, along with heightened trust in government institutions such as the Federal Reserve. Where we once relied on the perceived and relatively constant value of rare minerals like gold and silver for money, we have spent the last century getting off that standard and graduating to a standard simply of trust in collective insitutions to issue, manage, and account for .. notional (fiat) money such as the dollar. With that transition, we now have far more flexible ways to manage the value of this money, both preventing large swings during crises, (such as crises of balance of payment, or lack of gold mines, or episodic depressions in the business cycle), and seeking that inflation rate mentioned at the top.

John Maynard Keynes played a large role in this change, explaining why the gold standard was a barbaric relic, and that the central banks failed to mentally leave the gold standard world behind in their mismanagement of the Great Depression. He helped design the post-war Bretton Woods arrangement of exchange rates, which gradually helped wean the world off the gold standard fully, to where we are today, with fully floating exchange rates and fully fiat government issued currencies, unbacked by crystals, metals, coconuts, or anything else. 

Lots of inflation is, naturally, bad.

But why do these issuers seek inflation? Under mismanagement, inflation can easily run rampant, as the government creates money for itself to spend, beyond the economy's capacity to absorb, and beyond what its taxation policies bring back in. It is exceedingly tempting, but in the US, the citizenry and media are quite negatively inclined towards inflation, limiting our government's profligacy in that direction. But low inflation, that is a different story entirely. The Fed's two percent target is founded on several beneficial consequences:

• Low and consistent inflation encourages investment, as opposed to hoarding cash. If cash loses value continually, then savers need to find places to put their money where it can grow and that means investing in hopefully productive pursuits like stocks, bonds, businesses, real estate, etc... things that make our economy go around.
• Low and consistent inflation takes money from workers, silently. It is a subtle way to sink the general wage scale, lowering pay for non-innovative sectors and increasing (relative) productivity, as more dynamic sectors engage in more active wage negotiations and give higher pay. This effect is mitigated by union negotiations that seek to make up for inflation losses, and sometimes exceed them, thus accelerating inflation.
• Low and consistent inflation guards against deflation, giving the central bank more scope to lower interest rates in a crisis. At two percent inflation, interest rates may be at four percent, so setting rates at zero in a crisis would have a stimulatory effect, which would not be possible if inflation were already at zero. Granted, the Fed and the Federal government has plenty of other tools to prevent deflation, but deflation is also far more dangerous than inflation, thus a preference for low inflation as a consistent policy target.
• Low and consisten inflation creates a psychological impression of growth, as the monetary value of things goes inexorably up. Real estate is most obvious, but everything is worth "more" over time, and, like the wage theft argument, people think generally in nominal (monetary) values, giving a subjective impression of gains in wealth. Values like this can be baked into the language, in terms like "millionaire".

So, while it is weird to live in a world where the value of money goes continually down and the monetary value of things continually goes up, there are positive aspects to it. At two percent, values double every 35 years and go up ten-fold every 115 years. So someday, the dollar will either become a notional, almost valueless currency, or we will want to rebase it by a couple of orders of magnitude. At any rate, monetary consistency is the gift that the state brings us, deploying its many powers to keep the monetary system stable, and thus a critical support for a flourishing society where people do not have to think too much about fluctuations in the value of their money.

• Was it monopoly power and greedflation?
• No getting away from our masters and servants.
• Is nuclear the only answer?
• Breaking news... homelessness tied to high housing costs.

Haiti is Desperate

Let's help Haiti, and try to do nation building right this time.

We have a desperate situation on our doorstep, in Haiti. Governance has broken down, and anarchy is rampant, with the usual sad story of gangs, kidnapping, killing, looting, and mayhem. While the US has no formal obligation to help, and we have a long history of trying to help (as well as harm) Haiti, it is hard to stand idly by. The US has a frought history with "nation-building". We started in the nation-destroying business, laying waste to one Native American nation after another. Then we had a turn at destroying our own nation in the Civil War. After that came the quasi-imperial ambitions in the Philippines, the United Fruit Empire of Central America, including Panama and the Canal. The high point was our reconstruction of both German and Japanese societies after the second world war, though these societies were definitely not reduced to anarchy, only to temporary leaderless-ness and penury after the defeats of their somewhat abberrant fascist governments. Our more recent attempts to run countries like Vietnam, Iraq, and Afghanistan have been thoroughgoing disasters, ending in various degrees of embarrassment. Why ask for more?

Notable US activities in Haiti:

• Sided with Whites in Haiti's war for independence (i.e. the slave revolt) ~ 1800
• Waited ~60 years to recognize the resulting Haitian government.
• Occupied Haiti 1915-34.
• Colonial-style trade with France and the US continued to immiserate Haiti, ongoing.
• Occupied Haiti 1994-97 to prop up elected president Jean-Bertrand Aristide. 
• Aristide was later ousted in a coup by the Haitian military, which had been extensively supported by the US.

One reason for all this failure is that our nation-building work has never been very conscious. We were faced with weak allies or vanquished enemies, and wanted little more than to have military access for our jihad du jur, and to get out as soon as possible. The social and the long-term was, perhaps with the exception of the post-WW2 reconstructions, always secondary to military objectives. But as we learn, the military is always ultimately political and social as well. As a super-power, we have a naturally narcissistic mind-set, caring little about the dynamics of other countries and having little patience with their deep histories and un-American ways. This has been particularly evident in our building of other nation's militaries, those in Vietnam and Afghanistan being made in our image and promptly failing in our absence.

But another thing that has been evident through all these adventures is that nation-building is very, very important. Our own revolutionary experiment fed us a civic myth of tremendous power and durability. Our many failures, bottoming out with Donald Rumsfeld's scorn of nation-building in Iraq as it melted down in flaming anarchy, should have taught us by now that attending to nation-building is a top priority in any military relationship, and in most international relationships generally. There is no military effectiveness without a national moral and civic ethos behind it. 

That leads to the question of whether any nation can "nation-build" for others. Like teenage development, nations develop typically in opposition to others, via revolutions, wars, conquest. "Help" is rarely relevant, and mostly harmful. But hope springs eternal, and sometimes desperate situations call out for a special effort.

What is the situation in Haiti? I am far from an expert, but it is mostly one of collapse of institutions (never competent to start with), amid repeated natural disasters, (indeed, eco-cide on a large scale), huge inequality and corruption, extreme poverty- even starvation, and a custom of right-wing military coups and meddling. We can not expect democracy to be the immediate solution, given the depth and long history of the dysfunction. Some kind of stabilization and gradual re-introduction of governance and civic society needs to be envisioned.

Gang-based governance is not working well in Haiti.

So, contrary to our last few nation-building projects, the one in Haiti needs to be a partnership between a minimal military or police presence and extensive social, civic, economic, and especially governmental / political support. The current administration has announced a very low-key plan of aid and consultation, but no prospect of fixing the underlying dysfunctions. Indeed, food aid and similar kinds of aid are notorious for degrading indigenous agriculture and other non-dependent economic activities. Current development aid is necessarily channeled through the existing structures of the target society, and this tends to increase the divisions and inequality of those societies, introduce corruption, and foist foreign ideas that are sometimes quite harmful. The US project in Afghanistan was certainly well-meaning in its focus on the rights and position of women in the society. But harping on this theme was immensely destructive with respect to any influence we were seeking in conservative areas. In the end, cosmopolitan Kabul collapsed pathetically in the face of traditional values. Engaging Haitians and people with knowledge of Haiti, and willingness to keep an open mind and an ear to the ground, would be essential as we navigate this process. 

I would envision a high level commission, of mixed composisiton, with people like Barack Obama, leading Haitians from various sectors, and knowledgeable Biden administration officials, dedicated to going to Haiti and spending a half year or year doing a bottom to top assessment of needs and prospects for reform, principally in government and the economy. It might be a bit reminiscent of the peace process in Northern Ireland that we participated in. The group would issue a recommendation / plan, covering constitutional changes, civic development, security, educational development, and economic development. They also might recommend some sort of conservatorship over higher levels of the government, run through the UN, or the US itself, including peace-keepers, hopefully not carrying cholera, or other temporary security help. At this point, some pressure might have to be brought to bear to force some of the changes and personnel into implementation. 

Democracy can't be the first order of business, as conditions and civic culture are so dire. So perhaps a program of progressive democratic development, from local institutions at the start, to progressively higher level elections and political development, could be envisioned, as security and civic conditions improve. A "foster" system might be a bit like the Chinese communist system, where democracy is not front and center(!), but competence is, and the higher levels spend a lot of time figuring out who is effective at lower levels of governance, including aspects such as managerial competence, lack of corruption, people skills, ability to work in an established legal system, economic vision, among much else. 

In Haiti, economic reconstruction would not be based on huge influxes of outside aid, but a be concerted effort, as part of the more general governance project, to determine and build the infrastructure for a sustainable indiginous economic basis, perhaps in light industry and agriculture- something like the relationship the US has with Mexico, minus the drugs and immigration. Subsistence agriculture is very popular in Haiti, and presents a fundamental choice for the nation. While the independence and simplicity it represents are understandably attractive, (indeed, consonant with a lot of red state rhetoric from the US), subsistence agriculture can not support an advanced economy. It can not support imports that are obviously desired, and may not even support Haiti's current population with the best security and governance. But whatever the economic choices Haiti makes, better governance would improve its people's conditions and happiness.

One long-term focus would be education. Education in Haiti is run almost entirely on a private basis, at best, via international NGOs. That would not change very soon, but clearly universal, compulsory, and free education is important for improving Haiti's future. General literacy is hardly above 50%. Education stands at the root of Haiti's problems- its lack of economic development as much as its tragic governance. There are many other issues, such as the proliferation of NGOs with private agendas and lack of cooperation with the government, and the way food aid from the US has destroyed native agriculture. Governance is not the only issue, in this extremely poor, ill-educated, and traumatized country, but it is a function that must be fixed if any other aspect of the society is to progress.

Lastly, there is the perennial problem of whom to trust. Foreigners coming into a country, however good-willed, do more harm than good if they do not have good information. Our occupation of Afghanistan was notorious for repeatedly killing the wrong people, because we got information from those who had private grudges or competing interests. Without adopting a state of surveillance and/or terror, how are we to sift wheat from chaff? This is where expertise comes into play, and why sending the military in to run things tends to go haywire, with illusions of power. So we need people who know the language, and something about Haiti. There are a lot of emigre Haitians in the US who could be helpful in that regard.

If we took such a project seriously as a long-term and cooperative venture, we could do a great deal of good in Haiti, which would be positive not only for Haiti, but for the US and our wider interests. Our relations throughout the hemisphere have been strained for decades, ridden with excessive militarism, condescention, colonialism, and the US-sponsored spread of drugs, gangs, and guns. We have a lot to answer for, and should make a greater effort to bring positive change to our friends in this hemisphere.

• Jamaica is another country with slow development.
• In the coming cold war, we need all the friends and skills we can get.
• Fake science is coming for the children.
• Santa does get some people worked up.
• Is big tech going to do us all in?

A Hard Road to a Cancer Drug

The long and winding story of the oncogene KRAS and its new drug, sotorasib.

After half a century of the "War on Cancer", new treatments are finally straggling into the clinic. It has been an extremely hard and frustrating road to study cancer, let alone treat it. We have learned amazing things, but mostly we have learned how convoluted a few billion years of evolution can make things. The regulatory landscape within our cells is undoubtedly the equal of any recalcitrant bureaucracy, full of redundant offices, multiple veto points, and stakeholders with obscure agendas. I recently watched a seminar in the field, which discussed one of the major genes mutated in cancer and what it has taken to develop a treatment against it. 

Cancer is caused by DNA mutations, and several different types need to occur in succession. There are driver mutations, which are the first step in the loss of normal cellular control. But additional mutations have to happen for such cells to progress through regulatory blocks, like escape from local environmental controls on cell type and cell division, past surveillance by the immune system, and past the reluctance of differentiated cells to migrate away from their resident organ. By the end, cancer cells typically have huge numbers of mutations, having incurred mutations in their DNA repair machinery in an adaptive effort to evade all these different controls.

While this means that many different targets exist that can treat some cancers, it also means that any single cancer requires a precisely tailored treatment, specific to its mutated genes. And that resistance is virtually inevitable given the highly mutable nature of these cells. 

One of the most common genes to be mutated to drive cancer (in roughly 20% of all cases) is KRAS, part of the RAS family of NRAS, KRAS, and HRAS. These were originally discovered through viruses that cause cancer in rats. These viruses (such as Kirsten rat sarcoma virus) had a copy of a rat gene in it, which it overpoduces and uses to overcome normal proliferation controls during infection. The viral gene was called an oncogene, and the original rat (or human) version was called a proto-oncogene, named KRAS. The RAS proteins occupy a central part of the signaling path that external events and stresses turn on to activate cell growth and proliferation, called the MAP kinase cascade. For instance, epidermal growth factor comes along in the blood, binds to a receptor on the outside of a cell, and turns on RAS, then MEK, MAPK, and finally transcription regulators that turn on genes in the nucleus, resulting in new proteins being expressed. "Turning on" means different things at each step in this cascade. The transcription regulators typically get phosphorylated by their upstream kinases like MAPK, which tag them for physical transport into the nucleus, where they can then activate genes. MAPK is turned on by being itself phosphorylated by MEK, and MEK is phosphorylated by RAF. RAF is turned on by binding to RAS, whose binding activity in turn is regulated by the state of a nucleotide (GTP) bound by RAS. When binding GTP, RAS is on, but if binding GDP, it is off.

A schematic of the RAS pathway, whereby extracellular growth signals are interpreted and amplified inside our cells, resulting in new gene expression as well as other more immediate effects. The cell surface receptor, activated by its ligand, activates associated SOS which activates RAS to the active (GTP) state. This leads to a kinase cascade through RAF, MEK, and MAPK and finally to gene regulators like MYC.

This whole system seems rather ornate, but it accomplishes one important thing, which is amplification. One turned-on RAF molecule or MEK molecule can turn on / phosphorylate many targets, so this cascade, though it appears linear in a diagram, is acutally a chain reaction of sorts, amplifying as it goes along. And what governs the state of RAS and its bound GTP? The state of the EGFR receptor, of course. When KRAS is activated, the resident GDP leaves, and GTP comes to take its place. RAS is a weak GTPase enzyme itself, slowly converting itself from the active back to the inactive state with GDP. 

Given all this, one would think that RAS, and KRAS in particular, might be "druggable", by sticking some well-designed molecule into the GTP/GDP binding pocket and freezing it in an inactive state. But the sad fact of the matter is that the affinity KRAS has to GTP is incredibly high- so high it is hard to measure, with a binding constant of about 20 pM. That is, half the KRAS-bound GTP comes off when the ambient concentration of GTP is infinitesimal, 0.02 nano molar. This means that nothing else is likely to be designed that can displace GTP or GDP from the KRAS protein, which means that in traditional terms, it is "undruggable". What is the biological logic of this? Well, it turns out that the RAS enzymes are managed by yet other proteins, which have the specific roles of prying GDP off (GTP exchange factor, or GEF) and of activating the GTP-ase activity of RAS to convert GTP to GDP (GTPase activating protein, or GAP). It is the GEF protein that is stimulated by the receptors like EGFR that induce RAS activity. 

So we have to be cleverer in finding ways to attack this protein. Incidentally, most of the oncogenic mutations of KRAS are at the twelfth residue, glycine, which occupies a key part of the GAP binding site. As glycine is the smallest amino acid, any other amino acid here is bulkier, and blocks GAP binding, which means that KRAS with any of these mutations can not be turned off. It just keeps on signaling and signaling, driving the cell to think it needs to grow all the time. This property of gain of function and the ability of any mutation to fit the bill is why this particular defect in KRAS is such a common cancer-driving mutation. It accounts for ~90% of pancreatic cancers, for instance. 

The seminar went on a long tangent, which occupied the field (of those looking for ways to inhibit KRAS with drugs) for roughly a decade. RAS proteins are not intrinsically membrane proteins, but they are covalently modified with a farnesyl fatty tail, which keeps them stuck in the cell's plasma membrane. Indeed, if this modification is prevented, RAS proteins don't work. So great- how to prevent that? Several groups developed inhibitors of the farnesyl transferase enzyme that carries out this modification. The inhibitors worked great, since the farnesyl transferase has a nice big pocket for its large substrate to bind, and doesn't bind it too tightly. But they didn't inhibit the RAS proteins, because there was a backup system- geranygeranyl transferase that steps into the breach as a backup, which can attach an even bigger fatty tail to RAS proteins. Arghhh!

While some are working on inhibiting both enzymes, the presenter, Kevan Shokat of UCSF, went in another direction. As a chemist, he figured that for the fraction of the KRAS mutants at position 12 that transform from glycine to cysteine, some very specific chemistry (that is, easy methods of cross-linking), can be brought to bear. Given the nature of the genetic code, the fraction of mutations that go from glycine to cysteine are small, there being eight amino acids that are within a one-base change of glycine, coded by GGT. So at best, this approach is going to have a modest impact. Nevertheless, there was little choice, so they forged ahead with a complicated chemical scheme to make a small molecule that could chemically crosslink to that cysteine, with selectivity determined by a modest shape fit to the surface of the KRAS protein near this GEF binding site. 

A structural model of KRAS, with its extremely tightly-bound substrate GDP in orange. The drug sotorasib is below in teal, bound in another pocket, with a tail extending upwards to the (mutant) cysteine 12, which is not differentiated by color, but sits over a magnesium ion (green) being coordinated by GDP. The main job of sotorasib is to interfere with the binding of the guanine exchange factor (GEF) which happens on the surface to its left, and would reset KRAS to an active state.

This approach worked surprisingly well, as the KRAS protein obligingly offfered a cryptic nook that the chemists took advantage of to make this hybrid compound, now called the drug sotorasib. This is an FDA-approved treatment for cancers which are specifically driven by this particular KRAS mutation of position 12 from glycine to cysteine. That research group is currently trying to extend their method to other mutant forms, with modest success. 

So let's take a step back. This new treatment requires, obviously, the patient's tumor to be sequenced to figure out its molecular nature. That is pretty standard these days. And then, only a small fraction of patients will get the good news that this drug may help them. Lung cancers are the principal candidates currently, (of which about 15% have this mutation), while only about 1-2% of other cancers have this mutation. This drug has some toxicity- while it is a magic bullet, its magic is far from perfect, (which is odd given the exquisite selectivity it has for the mutated form of KRAS, which should only exist in cancer tissues). And lastly, it gives, on average, under six months of reprieve from cancer progression, compared to four and a half months with a more generic drug. As mentioned above, tumors at this stage are riven with other mutations and evolve resistence to this treatment with appalling relentlessness.

While it is great to have developed a new class of drugs like this one against a very recalcitrant target, and done so on a highly rational basis driven by our growing molecular knowlege of cancer biology, this result seems like a bit of a let-down. And note also that this achievement required decades of publicly funded research, and doubtless a billion dollars or more of corporate investment to get to this point. Costs are about twenty five thousand dollars per patient, and overall sales are maybe two hundred million dollars per year, expected to increase steadily.

Does this all make sense? I am not sure, but perhaps the important part is that things can not get worse. The patent on this drug will eventually expire and its costs will come down. And the research community will keep looking for other, better ways to attack hard targets like KRAS, and will someday succeed.

• PR, AI, hype, and the end of the world.
• Whether masks are effective at all against respiratory infection remains contentious and uncertain.
• Can America be militarily and politically successful at the same time?
• The lonely solar house.

Eco-Economics

Adrienne Buller on greenwashing, high finance, and the failures of capitalism viz the environment, in "The Value of a Whale".

This is a very earnest book by what seems to be an environmental activist about the mistaken notion that capitalism gives a fig about climate change. Buller goes through the painstaking economic rationales by which economists attempt to value or really, discount the value of, future generations. And how poorly carbon taxes have performed. And how feckless corporations are about their climate pledges, carbon offsets, and general greenwashing. And how unlikely it is that "socially conscious" investing will change anything. It is a frustrated, head-banging exercise in deflating illusions of economic theory and corporate responsibility. Skimming through it is perhaps the best approach. Here is a sample quote from Buller's conclusion:

Given this entrenched perspective, it is unsurprising that resistance to the kinds of bold change we need to secure a habitable planetary future for all and a safe present for many tend to focus on what we stand to lose. Undeniably, available evidence suggests that 'addressing environmental breakdown may require direct downscaling of economic production and consumption in wealthier countries'. This is an uncomfortable idea to grapple with, but as philosopher Kate Soper writes: 'If we have cosmopolitan care for the well-being of the poor of the world, and a concern about the quality of life for future generations, then we have to campaign for a change of attitudes to work, consumption, pleasure, and self-realization in affluent communities.' There is a sense that this future is necessarily austerian, anti-progress, and defined by lack. Indeed, the same media study cited above found discussion of economies defined by the absence of growth to focus on bleakness and stagnation. Comparatively little attention is directed at what we stand to gain - but there is much to be gained. Understanding what requires us to ask what the existing system currently fails to provide, from universal access to health case and education, to basic material security, to free time. It certainly does not offer a secure planetary future, let alone one in which all life can thrive. And it does not offer genuine democracy, justice or freedom for most. Absent these, what purpose is 'the economy' meant to serve?

Unfortunately, the book is not very economically literate either, making its illusions something of a village of straw men. Who ever thought that Royal Dutch Shell was going to solve climate change? Who ever thought that a $5 dollar per ton tax on CO2 emissions was going to accomplish anything? And who ever thought that the only reason to address climate heating was to save ourselves a dollar in 2098? All these premises and ideas are absurd, hardly the stuff of serious economic or social analysis. 

But then, nothing about our approach to climate heating is serious. It is a psychodrama of capitalism in denial, composed of cossetted capitalist people in the five stages of grief over our glorious carbon-hogging culture. Trucks, guns, and drive-through hamburgers, please! Outright denial is only slowly ebbing away, as we sidle into the anger phase. The conservative Right, which mixes an apocalyptically destructive anti-conservative environmental attitude with a futile cultural conservatism, is angry now about everything. The idea that the environment itself is changing, and requires fundamental cultural and economic change, is an affront. The eco-conscious left is happy to peddle nostrums that nothing really has to change, if we just put up enough solar panels and fund enough green jobs. 

Objectively, given the heating we are already experiencing and the much worse heating that lies ahead, we are not facing up to this challenge. It is understandable to not want to face change, especially limits to our wealth, freedoms, and profligacy. But we shouldn't blame corporations for it. The capitalist system exists to reflect our desires and fulfill them. If we want to binge-watch horror TV, it gives us that. If we want to gamble in Las Vegas, it gives us that. If we want to drive all around the country, it makes that possible. Capitalism transmutes whatever resources are lying around (immigrant labor, publically funded research, buried minerals and carbon, etc.) to furnish things we want. We can't blame that system for fouling up the environment when we knew exactly what was going on and wanted those things it gave us, every step of the way.

No, there is another mechanism to address big problems like climate heating, and that is government. That is where we can express far-sighted desires. Not the desire for faster internet or more entertaining TV, but deep and far-reaching desires for a livable future world, filled with at least some of the animals that we grew up with, and maybe not filled with plastic. It is through our enlightened government that we make the rules that run the capitalist system. Which system is totally dependent on, and subservient to, our collective wisdom as expressed through government. 

So the problem is not that capitalism is maliciously ruining our climate, but that our government, representative as it is of our desires, has not fully faced up to the climate issue either. Because we, as a culture, are, despite the blaring warnings coming from the weather, and from scientists, don't want to hear it. There is also the problem that we have allowed the capitalists of our culture far too much say in the media and in government- a nexus that is fundamentally corrupt and distorts the proper hierarchy of powers we deserve as citizens.

The US games out in 2012 how various carbon taxes will affect emissions, given by electricity production. These are modest levels of taxation, and have modest effects. To actually address the climate crisis, a whole other magnitude of taxation and other tools need to be brought to bear. The actual trajectory came out to more renewables, no growth for nuclear power, and we are still burning coal.

Let me touch on just one topic from the book- carbon taxes. This is classic case of squeemish policy-making. While it is not always obvious that carbon pricing would be a more fair or effective approach than direct regulation of the most offensive industries and practices, it is obvious that putting a price on carbon emissions can be an effective policy tool for reducing overall emissions. The question is- how high should that price be to have the effect we want? Well, due to the universal economic consensus that carbon pricing would be a good thing, many jurisdictions have set up such pricing or capping schemes. But very few are effective, because, lo and behold, they did not want to actually have a strong effect. That is, they did not want to disrupt the current way of doing things, but only make themselves (and ourselves) feel good, with a slight inducement to moderate future change. Thus they typically exempt the most polluting industries outright, and set the caps high and the prices low, so as not to upset anyone. And then Adrienne Buller wonders why these schemes are so universally ineffective.

Carbon prices in California are currently around $30 per ton CO2, and this has, according to those studying the system, motivated one third of the state's overall carbon reductions over the current decade. That is not terrible, but clearly insufficient, even for a forward-thinking state, since we need to wring carbon out of our systems at a faster pace. Raising that price would be the most direct way for us as a society to do that. But do we want to? At that point, we need to look in the mirror and ask whether the point of our policies should be addressing climate heating in the most effective way possible, or to avoid pain and change to our current systems. Right now, we are on a sort of optimal trajectory to avoid most of the economic and social pain of truly addressing climate change, (by using gradualist and incremental policies), but at the cost of not getting there soon enough and thus incurring increasing levels of pain from climate heating itself- now, and in a future that is measured, not in years, but in centuries. 

The second big point to make about this book and similar discussions is that it largely frames the problem as an economic one for humanity. How much cost do we bear in 2100 and 2200, compared with the cost we are willing to pay today? Well, that really ignores a great deal, for there are other species on the planet than ourselves. And there are other values we have as humans, than economic ones. This means that any cost accounting that gets translated into a carbon price needs to be amplified several fold to truly address the vast array of harms we are foisting on the biosphere. Coral reefs are breaking down, tropical forests are losing their regenerative capability, and the arctic is rapidly turning temperate. These are huge changes and harms, which no accounting from an economic perspective "internalizes". 

So, we need to psychologically progress, skipping a few steps to the facing-it part of the process, which then will naturally lead us towards truly effective solutions to get to carbon neutrality rapidly. Will it cost a lot? Absolutely. Will we suffer imbalances and loss of comforts? Absolutely. But once America faces up to a problem, we tend to do a good job accepting those tradeoffs and figuring out how to get the results we want. 

• An earth systems perspective.
• I hope you are appreciating this free-range, hand-made, artisanal prose.
• Loneliness.
• Plastic is a thing too.
• Natural gas and the future of Europe.
• Maybe having cars parked everywhere isn't the best idea.
• Thoughts on the drug war.

Where Does Oxygen Come From?

Boring into the photosynthetic reaction center of plants, where O2 is synthesized.

Oxygen might be important to us, but it is really just a waste product. Photosynthetic bacteria found that the crucial organic molecules of life that they were making out of CO2 and storing in the form of reduced compounds (like fats and sugars) had to get those reducing units (i.e. electrons) from somewhere. And water stepped up as a likely candidate, with its abudance and simplicity. After you take four electrons away from two water molecules, you are left with four protons and one molecular oxygen molecule, i.e. O2. The protons are useful to fuel the proton-motive force system across the photosynthetic membrane, making ATP. But what to do with the oxygen? It just bubbles away, but can also be used later in metabolism to burn up those high-energy molecules again, if you have evolved aerobic metabolism.

On the early earth, reductants like reduced forms of iron and sulfur were pretty common, so they were the original sources of electrons for all metabolism. Indeed, most theories of the origin of life place it in dynamic rocky redox environments like hydrothermal vents that had such conducive chemistry. But these compounds are not quite common enough for universal photosynthesis. For example, a photosynthetic bacterium floating at the top of the ocean would like to continue basking in the sun and metabolizing, even if the water around it is relatively clear of reduced iron, perhaps because of competition from its colleagues. What to do? The cyanobacteria came up with an amazing solution- split water!

A general overview of plant and cyanobacterial photosystems, comprising the first (PSII), where the first light quantum hits and oxygen is split, an intervening electron transport chain where energy is harvested, and the second (PS1), where a second light quantum hits, more energy is harvested, and the electron ends up added to NADP. From the original water molecules, protons are used to power the membrane proton-motive force and ATP synthesis, while the electrons are used to reduce CO2 and create organic chemicals.

A schematic of the P680 center of photosystem II. Green chlorophylls are at the center, with magnesium atoms (yellow). Light induces electron movement as denoted by the red arrows, out of the chlorophyll center and onwards to other cytochrome molecules. Note that the electrons originate at the bottom out of the oxygen evolving complex, or OEC, (purple), and are transferred via an aromatic tyrosine (TyrZ) side chain, coordinating with a nearby histidine (H189) protein side chain.

This is not very easy, however, since oxygen is highly, even notoriously "electronegative". That is, it likes and keeps its electrons. It takes a super-oxidant to strip those electrons off. Cyanobacteria came up with what is now called photosystem II (that is, it was discovered after photosystem I), which collects light through a large quantum antenna of chlorophyll molecules, ending up at a special pairing of chlorophyll molecules called P680. These collect the photon, and in response bump an electron up in energy and out to an electron chain that courses through the rest of the photosynthetic system, including photosystem I. At this point, P680 is hungry for an electron, indeed has the extreme oxidation potential needed to take electrons from oxygen. And one is conducted in from the oxygen evolving center (OEC), sitting nearby.

A schematic illustrating both the evolutionary convergence that put both photosystems (types I and II) into one organism (cyanobacteria, which later become plant chloroplasts), and the energy levels acquired by the main actors in the photosynthetic process, quoted in electron volts. At the very bottom (center) is a brief downward slide as oxygen is split by the pulling force of the super-oxidation state of light-activated P680. After the electrons are light-excited, they drop down in orderly fashion through a series of electron chain transits to various cytochromes, quinones, ferredoxins, and other carriers that generate either protons or chemical reducing power as they go along. Note how the depth of the oxygen-splitting oxidation state is unique among photosynthetic systems.

A recent paper resolves the long-standing problem of how exactly oxygen is oxidized by cyanobacteria and plants at the OEC, at the very last step before oxygen release. This center is a very strained cubic metal complex of one calcium and four manganese atoms, coordinated by oxygen atoms. The overall process is that two water molecules come in, four protons and four electrons are stripped off, and the remaining oxygens combine to form O2. This is, again, part of the grand process of metabolism, whose point is to add those electrons and protons to CO2, making the organic molecules of life, generally characterized as (-CH2-), such as fats, sugars, etc. Which can be burned later back into CO2. Metals are common throughout organic chemistry as catalysts, because they have a wonderful property of de-localizing electrons and allowing multiple oxidation states, (number of extra or missing electrons), unlike the more sparse and tightly-held states of the smaller elements. So they are used in many redox cofactors and enzymes to facilitate electron movement, such as in chlorophyll itself.

The authors provide a schematic of the manganese-calcium OEC reaction center. The transferring tyrosine is at top, calcium is in fuschia/violet, the manganese atoms are in purple, and the oxygens are in red. Arrows point to the oxygens destined to bond to each other and "evolve" away as O2. Note how one of these (O6) is only singly-coordinated and is sort of awkwardly wedged into the cube. Note also how the bond lengths to calcium are all longer than those to manganese, further straining the cube. These strains help to encourage activation and expulsion of the target oxygens.

Here, in the oxygen evolving center, the manganese atoms are coordinated all around with oxygens, which presents the question- which ones are the ones? Which are destined to become O2, and how does the process happen? These researchers didn't use complicated femtosecond X-ray systems or cyclotrons, (though they draw on the structural work of those who did), but room-temperature FTIR, which is infrared spectroscopy highly sensitive to organic chemical dynamics. Spinach leaf chloroplasts were put through an hour of dark adaptation, (which sets the OEC cycle to state S1), then hit with flashes of laser light to advance the position of the oxygen evolving cycle, since each flash (5 nanoseconds) induces one electron ejection by P680, and one electron transfer out of the OEC. Thus the experimenters could control the progression of the whole cycle, one step at a time, and then take extremely close FTIR measurements of the complexes as they do their thing in response to each single electron ejection. Some of the processes they observed were very fast (20 nanoseconds), but others were pretty slow, up to 1.5 milliseconds for the S4 state to eject the final O2 and reset to the S0 state with new water molecules. They then supplement their spectroscopy with the structural work from others and with computer dynamics simulations of the core process to come up with a full mechanism.

A schematic of the steps of oxygen evolution out of the manganese core complex, from states S0 to S4. Note the highly diverse times that elapse at the various steps, noted in nano, micro, or milli seconds. This is discussed further in the text.

Other workers have provided structural perspectives on this question, showing that the cubic metal structure is bit more weird than expected. An extra oxygen (numbered as #6) wedges its way in the cube, making the already strained structure (which accommodates a calcium and a dangling extra manganese atom) highly stressed. This is a complicated story, so several figures are provided here to give various perspectives. The sequence of events is that first, (S0), two waters enter the reaction center after the prior O2 molecule has left. Water has a mix of acid (H+) and base (OH-) ionic forms, so it is easy to bring in the hydroxyl form instead of complete water, with matching protons quickly entering the proton pool for ATP production. Then another proton quickly leaves as well, so the waters have now become two oxygens, one hydrogen, and four electrons (S0). Two of the coordinated manganese atoms go from their prior +4, +4 oxidation state to +3 and +2, acting as electron buffers. 

The first two electrons are pulled out rapidly, via the nearby tyrosine ring, and off to the P680 center (ending at S2, with Mn 3+ and Mn 4+). But the next steps are much slower, extricating the last two electrons from the oxygens and inducing them to bond each other. With state S3 and one more electron removed, both manganese atoms are back to the 4+ state. In the last step, one last proton leaves and one last electron is extracted over to the tyrosine oxygen, and the oxygen 6 is so bereft as to be in a radical state, which allows it to bow over to oxygen 5 and bond with it, making O2. The metal complex has nicely buffered the oxidation states to allow these extractions to go much more easily and in a more coordinated fashion than can happen in free solution.

The authors provide a set of snapshots of their infrared spectroscopy-supported simulations (done with chemical and quantum fidelity) of the final steps, where oxygens, in the bottom panel, bond together at center. Note how the atomic positions and hydrogen attachments also change subtly as the sequence progresses. Here the manganese atoms are salmon, oxygen red, calcium yellow, hydrogen white, and a chlorine molecule is green.

This closely optimized and efficient reaction system is not just a wonder of biology and of earth history, but an object lesson in chemical technology, since photolysis of water is a very relevant dream for a sustainable energy future- to efficiently provide hydrogen as a fuel. Currently, using solar power to run water electrolyzers is not very efficient (20% for solar, and 70% for electrolysis = 14%). Work is ongoing to design direct light-to-hydrogen hydrolysis, but so far uses high heat and noxious chemicals. Life has all this worked out at the nano scale already, however, so there must be hope for better methods.

• The US carried off an amazing economic success during the pandemic, keeping everything afloat as 22 million jobs were lost. This was well worth a bit of inflation on the back end.
• Death
• Have we at long last hit peak gasoline?
• The housing crisis and local control.
• The South has always been the problem.
• The next real estate meltdown.