Iran: Pawn in the Great Game

Review of Iran: A Modern History, by Abbas Amanat. Part 1- the great game and a history of victimization.

The lure of victimization narratives is a little hard to pin down, though it is universal. No matter how much power Republicans acrue, they always seem to feel victimized by the still-ascendent liberal culture, by rational or compassionate argument, and indeed by anyone who disagrees with them. Victimization is an assertion of moral righteousness, sometimes proven more pure and righteous in its defeat by forces of darkness than by its triumph. Christianity is a victimization narrative par excellence- of a savior tragically unrecognized in his own day, callously sold out and executed by the ruling powers, but ultimately, though the intercession of miracles, energetic preaching, and what have you, ready to save you if only you too believe this story. Victimization can be as callous and unthinking an ideological postition as its opposite- domination- excusing any extremity and moral lapse in the service of the restoration of what was lost or been suppressed. Indeed, victimization narratives exist in a complex dance with domineering ideologies, and are frequently used by them, as suggested above. The Nazis, after all, were victimized by the Jews.

But how much more intoxicating is all this if you really are a victim? Iran, in its long history, has played many roles. But over the last few centuries, that of victim has been predominant. Its early cultures, before and after the Indo-European invasions of the second millenium BC, usually played second fiddle to the Sumerian, Assyrian, and Babylonian cultures to the west. Then came the high point of the Persian Achaemenid Empire in the mid-first millenium BC, which spread over the entire Middle East, from Afghanistan to Egypt and Greece, and was memorialized extensively in both Greek and Jewish literature. Cruelly truncated by the invasion of Alexander the Great, Persia then went through extended domination by the Greeks in the Seleucid Empire, followed by somewhat cosmopolitan domination by the Parthians, a Scythian tribe from the East, before regaining most of its former extent under the Sassanian Empire, which was truly Persian in origin and culture again. Only to be brutally crushed by the Arab invasion. Gradually, Persian culture re-asserted itself, forming the backbone of the Islamic Golden Age, which whithered amid the Mongol invasions and a reversion to doctrinaire Islam. One hardly knows which oppression to bemoan first.

The Azadi tower. Take that, Brandenburg gate! This is perhaps the most durable and iconic bequest of the second Shah's rule, adopted by all sides in Iran, whether protesting for or against the powers that be.

The coronavirus lockdown has brought me one consolation, which is this lengthy tome on Iranian history, borrowed just before the boom came down, and which the library shows no sign of wanting back. Amanat takes up the story at 1500 CE with the rise of a militant Shiite ruler, Ismail I, who set the tone for Iranian culture up to today: a full-on victimization passion play, with oppressors ranging from Abu Bakr and Yazid I to the United States, heart-rending mourning, and self-flagellation. The story of Iran is one of a small country with big ambitions, which it occasionally fulfills. Why didn't Persia remain a large empire and culture, like Rome did, even after its formal fall? On the one hand, there were too many other competing cultures about. The Persians could not quite put together a world-leading coalition. The Achaemenids, under Cyrus the great, came closest, setting a cosmopolitan standard that was widely attractive and powerful. At least the Jews gave it good press. But it fell apart amid civil war and the usual bane of early empires- dysfunctional or non-existent methods of transferring power. The Safavid dynasty, begun in 1501, set Shi'ism as the national religion of Iran. This had the twin effects of being highly motivational to the "base", while being rather isolating vs the wider world, including the Sunni majority across Islam. The course was thus set for Iran to be a small-to-mid-sized power, a box they are still trying to break out of today, to little effect.

Over the last few centuries, Iran's major antagonists have been the much greater empires of Russia, Great Britain, and the US. While there have been occasional raids from, and forays to, the East, towards Afghanistan and India, generally relations in that direction have been calm, and Persian culture has had significant influence in Afghanistan and Mughal India. On the other hand, expansionism and colonialism from the West and North have been devastating. Iran was barely able to hang on to its territorial and cultural integrity at the worst of times. Russia dealt Iran a comprehensive military defeat in 1826, took parts of the North, and threatened the rest of the country. Through the nineteenth century, Iran tried its best to play the big powers off against each other, playing its part in the great game. But just as often, the British and Russians would make their own agreements to carve up the local countries into spheres of influence, if not zones of occupation. They also engaged in destructive loans, saddling Iran with unpayable debts and increasing foreign ownership of its infrastructure, customs, and other means of paying them back. Russia sponsored a pro-shah coup in 1908. Britain especially forced Iran into a series of bad trade deals, privileged treatment, and forced imports, killing off the Iranian silk industry, among much other economic and cultural damage. And once Britain smelled oil, and switched its navy from coal to oil, (during world war 1), its regard for the integrity and interests of Iran fell even further. Russia and Britain each occupied large parts of the country during both world wars, without so much as a by-your-leave.

What saved Iran was an unexpected favor from Russia. The communist revolution led to an immediate evacuation of Russia's occupation of Northern Iran and cancellation of its debts, and, at least for a brief period, much friendlier relations. But it also led to simmering communist political and guerrilla insurgencies for the next century. Iran kept being knocked about between the great powers, with the US taking an increasing role during and after world war 2. The US had previously been one of the friendlier countries to Iran, providing critical financial advice and political support during its constitutional phase, during the Shuster appointment as treasurer, back in 1911. And the US was naturally thought to be supportive of constitutionalism, rule of law and democracy. But world war 2 changed all that, making the US more or less the inheritor of the British empire. When the first Reza Shah government finally collapsed and a nascent constitutional system arose, one of its first and most popular pieces of business, under Mohammed Mosaddegh, was nationalization of the oil industry. Britain, which ran the Iranian oil fields outright, sharing a paltry 16% with Iran, was outraged. The US, caught in the middle, was unfortunately more sympathetic to Britain than Iran. The US offered a 50% deal, in line with others in the region. This would have been a good compromise, but Mosaddegh had painted himself into a corner. And made many enemies across the political spectrum, not being, at base, a particularly good politician. His ouster, amid a coup staged explicitly by the Iranian military, but with support from the British and Americans, was not a big surprise at the time. Only in retrospect, after the subsequent regime of the second Shah dragged on, decade after decade, with unstinting US support, no matter the excesses of the secret services or oppression of the people, and with the backdrop of the US's brutal wars in Vietnam and Cambodia, did the narrative of the great Satan take shape. It was an understandable, yet also facile, and ultimately misguided response to yet another episode in Iran's long and often tragic history of international relations.

We won't get into the next parts of the story in this post, but reflect that size matters in international relations. The Shah stuck with the US through thick and thin, creating a rare stable environment for Iran internationally. No one questioned Iran's sovereignty, or its position in the cold war. None of its neighbors attacked. But when that sponsorship fell apart amid the Islamic revolution, and Iran started pissing off each of its neighbors near and far, things did not go so well, and remain perilous today. On the other hand, the US played a large part in the Shah's failure to manage internal affairs, losing sight of our principles (as we also did in Vietnam, then again in Iraq) and blindly funding a despot. Our best cases from this period were the various countries (South Korea, Indonesia, Philippines, Taiwan) that got away belatedly, through popular protests, out of US-sponsored dictatorships and towards democracy. Is that the best we could have done?

• Some notes on Iran's process of conversion to Islam.
• Studies in Shiite propaganda.
• Another dysfunctional country failing to deal effectively with the virus.
• And now, for a bit of science.

Origin of Life- RNA Only, or Proteins Too?

Proteins as Participants in the Origin of Life

After going through some momentous epochs in the history of life in the last two weeks (the origin of eukaryotes, and the nature of the original metabolism), we are only part of the way to the origin of life itself. The last common ancestor of all life, (LUCA), rooted at the divergence between bacteria and archaea, was a fully fledged cell, with many genes, a replication system and translation system, membranes, and a robust metabolism based on a putative locale at hydrothermal vents. This is a stage long after the origination of life, about which our concepts remain far hazier, at the chemical interface of early Earth.

A recent paper (and prior) takes a few more speculative shots at this question, (invoking what it calls the initial Darwinian ancestor, or IDA), making the observation that proteins are probably as fundamental as RNA to this origination event. One popular model has been the "RNA world", based on the discovery that RNA has some catalytic capability, making it in principle capable of being the Ur-genetic code as well as the Ur-enzyme that replicated that same code into active, catalytic molecules, i.e., itself. But not only has such a polymathic molecule been impossible to construct in the lab, the theory is also problematic.

Firstly, RNA has some catalytic ability, but not nearly as much as it needs to make a running start at evolution. Second, there is a great symmetry in the mechanisms of life- proteins make RNA and other nucleic acids, as polymerases, while RNA makes proteins, via the great machine of the ribosome. This seems like a deep truth and reflection of our origins. It is probable that proteins would, in theory, be quite capable of forming the ribosomal core machinery- and much more efficiently- with the exception of the tRNA codon interpretation system that interacts closely with the mRNA template. But they haven't and don't. We have ended up with a byzantine and inefficient ribosome, which centers on an RNA-based catalytic mechanism and soaks up a huge proportion of cellular resources, due to what looks like a historical event of great significance. In a similar vein, the authors also find it hard to understand how, if RNA had managed to replicate itself in a fully RNA-based world, how it managed to hand off those functions to proteins later on, when the translation function never was. (It is worth noting that the spliceosome is another RNA-based machine that is large and inefficient.)

The basic pathways of information in biology. We are currently under siege by an organism that uses an RNA-dependent RNA polymerase to make, not nonsense RNA, but copies of itself and other messages by which it blows apart our lung cells. Reverse transcriptases, copying RNA into DNA, characterize retro-viruses like HIV, which burrow into our genomes.

This thinking leads to a modified version of the RNA world concept, suggesting that RNA is not sufficient by itself, though it was clearly central. It also leads to questions about nascent systems for making proteins. The ribosome has an active site that lines up three tRNAs in a production line over the mRNA template, so that the amino acids attached on their other ends can be lined up likewise and progressively linked into a protein chain. One can imagine this process originating in much simpler RNA-amino acid complexes that were lined up haphazardly on short RNA templates to make tiny proteins, given conducive chemical conditions. (Though conditions may not have been very conducive.) Even a slight bias in the coding for these peptides would have led to a selective cycle that increased fidelity, assuming that the products provided some function, however marginal. This is far from making a polymerase for RNA, however, so the origin and propagation mechanisms for the RNA remain open.

"The second important demonstration will be that a short peptide is able to act as an RNA-dependent RNA polymerase."
- The authors, making in passing what is a rather demanding statement.

The point is that at the inception of life, to have any hope of achieving the overall cycle of selection going between an information store and some function which it embodies or encodes, proteins, however short, need to participate as functional components, and products of encoding, founding a cycle that remains at the heart of life today. The fact that RNA has any catalytic ability at all is a testament to the general promiscuity of chemistry- that tinkering tends to be rewarded. Proteins, even in exceedingly short forms, provide a far greater, and code-able, chemical functionality that is not available from either RNA (poor chemical functionality) or ambient minerals (which have important, but also limited, chemical functionality, and are difficult to envision as useful in polymeric, coded form). Very little of the relevant early chemistries needed to be coded originally, however. The early setting of life seems to have been rich with chemical energy and diverse minerals and carbon compounds, so the trick was to unite a simplest possible code with simple coded functions. Unfortunately, despite decades of work and thought, the nature of this system, or even a firm idea of what would be minimally required, remains a work in progress.

• Thus, god did it.
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• Choir practices are a spreading setting.

Turning Biochemistry on its Head in Search of the Origin of Life

Early earth was anoxic. That means that metabolic reactions ran backwards, compared to what we regard as normal.

Following up on last week's post on the origins of eukaryotes, I ran across a brilliant body of work by William Martin and colleagues, which explores both that and the related topic of the origin of life, all of which took place on an early earth very different from our own. Perhaps the most fundamental theme in any biochemistry course, especially when it comes to metabolism, is controlled oxidation. We in our bodies recapitulate the action of fire, by transforming (reduced) hydrogen-rich carbon compounds (carbo-hydrates, fats, etc.) to the most oxidized form of carbon, CO2, which we regard as a waste product and make- from our food, and now by proxy out of our ramified economic metabolism- in prodigious amounts. Our rich metabolic inheritance essentially slows down and harnesses this energy-liberating process that, uncontrolled, runs wild.

But early earth was anoxic. There was no free oxygen, and this metabolism simply could not exist. The great oxygenation event of roughly 2 to 3 billion years ago came about due to evolution of photosynthesis, which regards CO2 as its input, and O2 as its waste product. Yet plants metabolize the other way around as well, (often at night), respiring the reduced carbon that they painstakingly accumulate from CO2 fixation back to CO2 for their growth and maintenance. Plants are firmly part of this oxidized world, even as they, in net terms, fix carbon from CO2 and release oxygen.

An energy rich, but reducing, environment, full of sulfides and other hydrogen-rich compounds.

In a truly anoxic world, the natural biochemical destination is reduced compounds, not oxidized ones. The deep-ocean hydrothermal vent has been taken as a paradigmatic setting, at least as common on the very early earth as today. Here, reduction is the order of the day, with electrons rampant, and serpentinzation a driving mineral process, which liberates reducing power, and generates methane and hydrogen sulfide. This is one home of anaerobic life- an under-appreciated demimond of micro-organisms that today still permeate deep sediments, rocks, hydrothermal vents, and other geologic settings we regard as "inhospitable". An example is the methanogens- archaea that fix CO2 using the local reducing power of hydrogen, and emit methane. Methane! A compound we in our oxygen atmosphere regard as energy-rich and burn in vast amounts, these archaea regard as a waste product. The reason is that they live where reduction, not oxidation, is the order of the day, and they slow down and harness that ambient (chemical gradient) power just as we do in reverse. This division of aerobic vs anaerobic, which implies metabolisms that run in opposite directions, is fundamental, accounting for the hidden nature of these communities, and why oxygen is so toxic to their members.

By now it is quite well known that not only was the early earth, and thus early life, anoxic; but the broadest phylogenies of life that look for our most distant ancestors using molecular sequences also place anaerobes like methanogenic archaea and acetogenic bacteria at the earliest points. Whether archaea or bacteria came first is not clear- they branch very deeply, and perhaps earlier than any phylogenetic method using the molecular clues can ever tell. Thus the archaeal progenitor of the eukaryotic host appears to have been anaerobic, and may have entered into a dependence with a hydrogen-generating, methane-using bacterium which had already evolved an extensive metabolism compatible with oxygen, but not yet dependent on it. It was only later that the oxygen-using capacity of this partner come to such prominence, after oxygen came to dominate the biosphere so completely, and after the partner had replaced most of the host's metabolism with its own enzymes for heterotrophic use (i.e. fermentation) of complex carbon compounds.

This overturns the image that was originally fostered by Darwin, in a rare lapse of prophetic skill, who imagined life originating in a quiet sunlit pool, the primordial soup that has been sought like a holy grail. The Miller-Urey experiments were premised on having complex compounds available in such a broth, so that heterotrophic nascent cells just had to reach out an choose what they wanted. But these ideas above end up proposing that life did not begin in a soup, rather, it began in a chemical vortex, possibly a very hot one, where nascent cells built an autotrophic metabolism based on reducing/fixing carbon from CO2, (the dominant form of carbon on early earth), using the abundant ambient reducing power, and local minerals as catalysts. Thus the energetics and metabolism were established first, on a highly sustainable basis, after which complexities like cell formation, the transition from mineral to hybrid mineral/organic catalysts, and the elaboration of RNA for catalysis and replication, could happen.

Much of this remains speculative, but one tell-tale is the minerals that underpin much of metabolism. Iron-sulfur complexes still lie at the heart of many electron transfer catalysts, as do several other key metals. RNA is also prone to oxidation, so would have been more robust in an anoxic world. More generally, this theory may widen our opinions about life on other planets. Oxygen may be a sign of some forms of life, and essential for us, but is hardly necessary for the presence of life at all. Exotic places with complex chemistries, such as the gas giant planets, may have fostered life in forms we are unfamiliar with.

• Maybe, there are too many of us.
• Order vs justice.
• American institutions, dying of bureaucratic sclerosis, politics, and corruption.
• What serious contact tracing would look like.

Mother of us All- the Eukaryotic Ancestor

A new archaeon looks very much like an early transitional form between archaea and eukaryotes.

Even more than the invention of photosynthesis or the transition to multicellularity, the transition from bacteria to eukaryotes was perhaps the most dramatic and momentous evolutionary event after the origination of life. Bacteria are everywhere, and still dominate the biosphere in many respects with an unparalleled range of biochemistries. But they have severely limited prospects, being so streamlined in their genetic and sexual practices that they seem unable to escape their single-celled, remorselessly competitive fate.

Eukaryotes are known to have originated in the fusion of at least two different bacteria-like microorganisms, one perhaps an amoeba-like hunter, the other the bacterium that became our mitochondrion. Plus another that in plants became the chloroplast. There are several theories about the details, of which several propose metabolic symbiosis- that the original exchange between the mitochondrial progenitor and its host was actually not amoeboid engulfment, but quite gradual and voluntary, uniting a methanogenic partner that used small organic compounds and hydrogen as its inputs- making methane- with a methanotrophic host that produced various organic compounds from methane plus CO2 without complaint.

But once joined, eukaryotes did so much more, generating countless innovations in cell organization, sex, genetic control, organelle subspecialization, membrane management, cytoskeletal structure, among others, that it is hard to believe this event ever happened, and difficult to reconstruct its steps. In this regard, it is similar to the origination of life, where several obstacles (enclosure of a cell with selective transport, replicative mechanism, and metabolic power, perhaps among others as yet unappreciated) all had to be surmounted in some fashion before something that we would call life existed- a process that remains a topic of wide-ranging speculation.

But the starting point for eukaryotes seems to have been an archaeon- a member of the third major kingdom of life discovered only in the 1970's, which are unicellular like bacteria, but have many distinct molecular and genetic mechanisms that are more closely related to eukaryotes than to bacteria. These seem to be our nuclear ancestors, with a lot of bacterial genetic material added later on, either from the early mitochondrial symbiont, or from other transfers, which enriched their biochemical range. The big questions are- what caused the unification of these two life forms, and why did it result in such an extensive profusion of other innovative traits? A recent paper (review) is devoted to the first question to some degree, discovering a new archaeal species that is the closest yet to such a transitional form.

"We confirmed the presence of 80 eukaryotic signature proteins, which are also observed in related Asgard archaea."

To do this, they cultivated deep marine sediments from around Japan in an oxygen-free bioreactor, feeding methane (plus a bunch of antibiotics, to kill off any bacteria) in order to cultivate organisms that are notoriously hard to cultivate. They were looking for anaerobic archaea that die in oxygen, and live off of methane, which they get typically from partner bacteria. The hydrogen that the former (methanotrophs) produce from methane is toxic in large amounts, so having a partner to use it and give methane in return is a partnership made in heaven. Those partners (at first, methanogens) eat hydrogen and CO2, or other small organic molecules and produce methane. The new methanotroph is not just picky about conditions it will grow in, but extremely slow-growing, doubling in the best of conditions in about 20 days. These are not E. coli! Indeed, the whole project took a decade.

The idea to culture such obscure and obdurate organisms comes from two sources. First were existing hypotheses about how eukaryotes got started, in the form of metabolic collaborations described above, between disparate micro-organisms, centering on the use and exchange of methane and hydrogen, in addition to electrons and other compounds. Second were surveys of marine sediments and many other habitats for raw DNA, which has been sequenced in vast amounts. Such DNA is obviously a messy mixture, but given enough patience and computer power, one can re-assemble many interesting distinct genomes out of it, and some transition-like genomes have been glimpsed in this way. But what could be the corresponding organism? That was the question.

The author's phylogenetic tree across all kingdoms, using ribosomal proteins, highlighting the new organism's (red) position as sister group between archaea and eukaryotes. Note how relatively deep the divergence (X-axis) is between bacteria at the bottoms, and all other life forms.

One key analysis was to put this new organism into a phylogenetic tree, using the incredibly well-conserved sequences of the ribosomal proteins. The diagram above shows that the new organism, dubbed MK-D1, sits right at the threshold of the eukaryotic group, just as one would expect for an ancestor. It constitutes, to date and in molecular terms, the closest organism to eukaryotes that is not one itself. The diagram also shows, yet again, the vast molecular gulf between bacteria (at the very bottom) and archaea, which occupy most of the middle. While eukaryotes (top) are clearly a sister group of archaea, it is the divide between archaea and bacteria that is the most profound within the whole biosphere.

These new organisms are unexpectedly small- tiny, indeed. They are not the huge phagocytic amoeba that have often been imagined engulfing hapless bacterial partners about to be taken hostage. No, the methanogenic partners that are co-cultured by these researchers are far larger, by roughly ten-fold. But the new methanotroph has some interesting behaviors, such as putting out extensive cell projections and curious vesicles. It also has, as expected, a variety of genes that characterize eukaryotes, such as actin, profilin, Ras, G-beta like protein, TPR motifs, Zinc finger and HTH proteins, core transcription proteins like TFIIB, SMC, Ankyrin motifs, histones, SNARE-like proteins, signal recognition factor.

Micrographs of the new organism, MK-D1. Left is a high-magnification electron micrograph showing membrane vesicles budding off the main cell. Scale, 200 nm. Right is a scanning electron micrograph of two or three cells with dramatic projections emerging, plus some previously budded vesicles lying about. Scale, 1 micron.

Of course, this organism exists now, a couple billion years after its imagined ancestor occured in a lineage that we speculate was related to one that led to eukaryotes. So it is a stretch to make this diagnosis of a transitional form. Except that relict forms seem to litter the biosphere, such as the stromatolites that still crop up in Australia, and the vast hordes of bacteria and archaea that remain the metabolic engines of the biosphere, in perpetual competition, yet also largely frozen in their lifestyles and roles.

When free oxygen was introduced into the biosphere by nascent photosynthesis, starting roughly two and a half billion years ago, the putative methane-exchanging organisms all needed extra partners to detoxify it, for instance bacteria which oxidize (using O2) organic compounds to CO2. This, finally, was the motivating force for the partnership with the true mitochondrion, which performs the same service today, providing enormous amounts of energy along the way. The transition from the loose partnership cultured by the current researchers to the one that truly gave rise to eukaryotes is a bit murky under their class of hypotheses, but there are other hypotheses that make a more direct job of it.

• Get out of those cars.
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• New ideas in coronavirus pathogenesis and treatment.
• Why do we have a constitution and a judicial branch, anyhow?
• Remember the Russian-backed coup in Iran? And then the then the one after that?
• Remembering early work on oncogenes.
• What is a troll?

SARS E!

How does this virus assemble and get out of the cell? The key proteins are named S, M, N, and E.

True to their tiny size, viruses typically have short genomes and short names for their genes, which are relatively few. Coronaviruses generally have two halves to their genomes- a big polyprotein that gets translated right away from the genome RNA, and encodes key proteins, some of which interfere with host functions, and others of which include its own replicase, and proteases that cleave itself into those pieces. The other half of the genome is expressed later, into the proteins that make up the baby virions- the envelope and nucleocapsid, along with a slew of smaller proteins that have other, and sometimes still unknown, functions.

Once all this has gotten going, the virions have to assemble and escape from the cell- a complicated and interesting process, not completely understood, though blowing up the cell through inflammation, apoptosis, and general tissue destruction certainly helps. Genomic viral RNAs, as they are made in the cell cytoplasm by the viral replicase, get bound by the N protein, which is the viral protein that binds and packages the genome, and also has binding sites for the M protein, which organizes the outside envelope. N has other roles in controlling host processes, but this is its major function. These N+genome RNA complexes (which are regarded as the nucleocapsid) find their M partners sticking out of the endoplasmic reticulum (ER, or actually a post-ER compartment called ERGIC) that is the major site in cells of protein synthesis of membrane proteins and secreted proteins. Binding promotes budding of the genome complex into the ER, forming a nascent virion, now inside the ERGIC.

Final portion of the SARS life cycle. Virion proteins are made by ribosomes (green) from gene-sized portions of the viral genome, at lower left. The nucleocapsid protein (yellow) gathers up the replicated RNA genomes into packages, and then docks onto the membranes of the ERGIC, or endoplasmic reticulum-golgi intermediate membrane compartment, specifically on the M proteins (red) exposed there, that have been translated into the endoplasmic reticulum and formed homogenous rafts. Then all that is left is to follow the endocytic pathway out of the cell, or wait for the cell to blow up by other means. In actual virions, there are many more M proteins than S proteins, and extremely few E proteins.

The M protein has in the mean-time been synthesized in vast amounts and has several important properties, being the main protein that constitutes and drives formation of the viral envelope. It is an integral membrane protein, and associates with itself, in a particular array that prefigures the complete virion and excludes non-viral membrane proteins. M protein also, in these rafts of itself, makes space for the S protein- the surface spike which gives the virus its name (corona) and which binds to the next target cell- in someone else's lung tissue. And it binds to the N protein, so that the virus envelope engulfs the packaged genome as it docks from the cytoplasm.

E protein from original SARS. That is it! Red denotes hydrophobic amino acids, blue hydrophilic, and stars the charged amino acids.

That leaves the E protein.. what is it doing? It is a tiny (76 amino acid) membrane protein, important, though not essential, for viable viruses. Indeed it is so important that viruses with this gene experimentally removed, while able to limp along at low levels, quickly evolve a new one from scratch. But it is present in virions only in very small amounts. Its structure indicates one transmembrane domain, but predictions have been ambiguous- some methods predict two, some only one. This may suggest that this protein truly has somewhat ambiguous membrane localization, which might suggest a key function in the budding process, encouraging the last, critical transition from membrane invagination to true, fully enclosed virion.

You might not need many E proteins to do this, just a small ring around the final lip of the M-protein led vesicle. E binds to M protein, and the two of them alone are sufficient to make virion-like particles in experimental cells. N protein is not needed at all, nor a genome! Yet E is thought to also be able to bind to S, helping anchor it in the viral envelope. E can also bind to itself in complexes form membrane pores, one of whose effects is to promote inflammation and apoptosis, i.e. cell death. As if that weren't enough, E protein also contains a regulatory domain (PBM) that can bind hundreds of cellular proteins to regulate cell function, particularly dysregulating cell-cell junctions to form multi-cellular synctia that allow viral spread to neighboring cells, while impeding immune responses. A lot to do for such a small protein!

Virions lacking E, made with only M, are abnormally shaped, and ones made with mutant E proteins have novel, still abnormal, shapes. This leads to the idea that M forms flat sheets, and E helps the viral envelope curve, as it must to form the spherical virion. As mentioned above, it is also quite possible that E helps with the ultimate encirclement of the virion, the final membrane-fusing stage of budding that is actually rather tricky to accomplish and requires specialized machinery in the cell and in most membrane-envelope viruses. So there remains quite a bit to learn about the machinery of this virus, for all we know so far. And we are naturally even more curious about more practical matters, like whether all this can help create a vaccine, how exactly it spreads, whether it provides immunity after infection and for how long, and how much each of our protective measures, like masks, gloves, washing, disinfecting, etc., really help.

• Social networks, evolution, the friendship paradox, and epidemic modeling.
• Coronaviruses remain viable for over an hour in aerosol, and for many hours on hard surfaces. So they spread everywhere, mask or no mask.

Birth of a Gene

Where do genes come from? Well, lots of them rise right out of the muck- the junk of the genome, according to one paper.

Can genes arise out of nothing? The intellegent design folks spent a lot of sweat and pseudo-math showing that that was absolutely impossible. But here we are anyhow. They got their physics and math wrong. New genes arise all the time, mostly from pre-existing genes, by duplication events which are rampant, given the capacity of biological systems to replicate their constituent molecules. The human genome carries vast fleets of genes whose origin is duplication over evolutionary time - hundreds of zinc finger transcription factors, hundreds of odorant receptors, not to mention tens of thousands of duplicated transposons and viral remnants. And yet, can genes arise from nothing at all?

A recent paper says that yes, many functional genes have come from completely non-functional DNA, rather than pre-existing genes. While not the same as assembling a gene from the primordial soup, an event that remains difficult to reconstruct while singular in its global impact, this claim does suggest that the long-term plasticity of our genomes and of biological functions is even higher than many biologists appreciate. These researchers use synteny as their touchstone- the tendency of genes to stay in the same place on chromosomes through time, to conclude that most genes that lack homologs in other species did not arise by duplication, but by the conversion of some junk DNA to a functional state.

Syntenic relations of some of the human chromosomes, with those of chimpanzee. Lines indicate concordant / homologous positions. Note several massive inversions, and a few smaller segments that have jumped from one location to another. But on the whole, our genomes are highly similar in gross structure.

Humans and chimpanzees have strongly syntenic chromosomes, since we are so closely related. Most chromosomes line up precisely, with a few dramatic inversions (places where a portion of a chromosome in one lineage flipped orientation by recombination), and a few gaps and migrations of segments to new locations. This means that it is easy to trace which gene is ancestrally related to which gene in the other species. But not just genes, all nearby portions of the DNA are similarly lineally related, even if they are not well-conserved, as the cores of genes typically are. The researchers used human, fly, and yeast lineage tracing, benefiting from the large numbers of genomes that have now been sequenced from closely related species. This allowed them to determine the origin of novel genes lacking homologs among other species, but situated between normal, and normally homologous, genes. Either that novel gene arose in place, from the materials available, or else it came from elsewhere as a duplication or gene conversion event, with recognizable antecedents.

At a gene with no recognizable homolog (green), synteny helps to tell us that its origin was from a pre-existing gene, not from junk DNA.

Given all that information, one can then ask- did this gene decay from some known gene that is homologous to others among many species, and if so, how long did that decay take? At this point we need to define gene similarity. Typically software programs can give quantitative answers to how similar two protein sequences are, or two nucleotide sequences. But there is a twilight zone where similarity is so low that it can not be computationally recognized- like a game of telephone after too many transfers. But that does not mean that the two sequences are not lineally related, or even that they don't have the same function. There are many examples of protein pairs with no discernable sequence similarity, but very similar structures and functions. So evolution can go places our computers can not quite follow, though that may change once we solve the protein folding problem.

The authors portray the estimated time to gene degradation for orphan genes they studied, based on their presumed ancestors identified by synteny analysis. A very long time, in any case, but even longer for humans. my = millions of years. and the Y axis is proportion of the genome, going up to 10%.

The researchers show that this time to gene decay is much faster in flies and yeast than it is in humans. What takes 200 million years in yeast or 400 million years in flies (10% of lineage-ancestral, syntenic genes decayed to unrecognizeable similarity) takes an extrapolated 2 billion years in human genes. This may be due to the vastly different generation times of these species, considering that meiosis may be the most likely time for genome rearrangements.

An example (MNE1) of a large protein coding gene (in single letter code) that has essentially no recognizable sequence similarity, but still has synteny and functional homology with its relative (here, from S. ceverisiae to K. Lactis, both yeasts).

The next question was- how many of the novel genes across the genome came from that decay process of pre-existing genes, and which did not, rather (by default) coming from de novo origination out of the local DNA segment? It is a complicated question, a function of how one calculates similarity, and models synteny across related species. Do lineages where the matching syntenic DNA disappeared rather than decayed count towards the de novo origin hypothesis, or do they count as similar DNA that supports the decayed gene hypothesis? Since one partner in the homology pair is absent, the analysis depends on having enough other lineages fully sequenced to figure out what happened in detail. The authors' conclusion is that, on the whole, only one-third of novel genes arose from decay processes, and the rest arose de novo. That is a stunning conclusion, and sort of buried in the paper, which focuses on the decay processes that are easier to analyze, and comprise all the figures.

Unfortuntely, their logic breaks down when it comes to this conclusion. Yes, genes degrade to various degrees over time when they fail to see strong selection for function. That is given. But their key assumption is that their derived rate of gene decay at syntenic positions (let us say X) can be extrapolated over the entire genome. They thus claim that since, from separate analysis, Y is the number of genes in the entire genome that are novel (or orphan, lacking recognizable relatives), that Y - X is then the proportion that did not degrade from pre-existing genes, but rather arose denovo from other non-gene genetic elements. From this, they offer an estimate of roughly Y = 3*X, leaving 2/3 of Y coming from somewhere else, presumably de novo formation. The problem is that degradation of a gene at a syntenic position is a special case, compared to the also quite frequent duplication of genes and other sequences to distant locations which is another source of pseudogenes and ultimately of gene degradation and novel or orphan sequences. The mutation rates that apply to these cases are likely to be different, because the syntenic case never involves gene duplication, at least not in the recent past, by definition. Duplication is far more likely to lead to an immediate loss of function and selection than is degradation in a syntenic location.

So I do not think we can conclude what this paper (and an accompanying review) claim. They have not demonstrated at all the de novo origin of novel genes, but only suggested such origins from highly questionable negative evidence. Nevertheless, the topic is an interesting one, and someone is likely to study it with more care than was done here. Many tiny open reading frames and other stray genetic proto-elements litter our genomes, and other studies have shown that practically all of them are expressed at some level, at least as RNA, if not as proteins. So the question remains- whether and at what rate any of them gain an actual selected function, rising to the level of a gene of significance to the organism.

• I wonder what a psychopathic clown melt-down looks like.
• Never waste a chance to be utterly corrupt.
• Making America number 1 ... in disorganized health care and coronavirus deaths.
• Government operates mostly in an economy of blame, not of wealth or effectiveness.

We Live in Each Other's Heads

Family, faith, abuse, and gaslighting- review of "Educated", by Tara Westover.

Memoir can be a powerful form, combining truth with the most personal urgency. Westover's coming of age saga tells of a prepper childhood spent far away from any school or doctor, in an isolated Mormon family in Idaho- a patriarchy of one. It was also idylic, with a mountain to themselves, horses, seven children, and the freedom roam and explore. The children, though not taught formally, were also free to roam intellectually, if they could do so on their own. The trajectory of Tara's childhood appears distinctly downhill, however, as she matures from carefree child to a girl who needs to be squeezed into the appointed role of a Mormon woman, wife, mother. The story revolves most strongly around the social pressures that she gradually comes to realize are choking her- love that curdles into control, so that time-honored roles are fulfilled, and life can go on as always.

The family eventually splits into two halves- three children who escape into the larger world, get educations, live independently, and are forced, because the family can love only those who are obedient, to break ties. And the four children who not just stay behind, but work for the family business. Tara has the most spectacular escape, getting a PhD in history at Cambridge, and using her scholarly skills to write this book which lays so much bare. She also learns a lot of philosophy ... and is no longer a Mormon.

Oh, how things have changed- the Oprah interview.

But it took a lot of agony, and some therapy, to get there. The core of the book is really about physical and mental battles with the male patriarchs- the father, Gene, and the brother, Shawn. The father is one of those cranky autodidacts who figure everything out for themselves, and then insist they are right (even writing blogs about it!) and speaking on God's behalf. He runs a junk yard, salvaging copper, iron, and other materials from junked cars in the most unsafe ways, getting various family members injured in the process. Finally, he manages to get himself half-incinerated by taking a blowtorch to unemptied gasoline tank, and, while surviving by the grace of his wife's diligent care, is hobbled for life. More striking, however is his prediction that the Y2K crisis will bring on the Days of Abomination. He is convinced that the end-times are near, society will break down, and they, on their mountain will happily be both safe and vindicated. Lectures on these themes go on endlessly. But as he and Tara watch TV that millennium night, nothing happens, and she sees him visibly diminish, brought down by a cruel reality.

The father provides the baseline fundamentalism and ultimate leadership in the family dynamic. But Shawn brings the muscle. His relationship with Tara has mostly been very close and positive. But it is also clear that he is a psychopath, and Tara's maturation brings out a dark, controlling and vindictive side. He makes a practice of calling her a whore for any transgression of the patriarchal code, then nigger if she has gotten dirty in the junk yard, then abusing her in cruel and physical ways. Afterwards, he says it was all in good fun, and she can just tell him to stop any time, right? We now call this gaslighting, though no one had a name for it back then. For a teen age girl, it was shameful, degrading, and confusing. And it is fully backed up by the family, since the father doesn't see anything wrong with a bit of horseplay and role enforcement, and the mother- well, the mother can not cross the father.

Years on, after some degree of consciousness raising, Tara has the temerity to call Shawn on his behavior. The father goes on an extensive campaign to close the family ranks, and finally comes to Tara to give he the climactic choice of the book- accept his priestly blessing, which is to say accede to the patriarchal hierarchy and squelch her own memories and growing self, or else be ostracized. Westover has told this story in excruciating detail in order to make sense of this moment, to show how powerful social control can be, capable of turning people against themselves and against their very knowledge of reality.

Why? The evolutionary argument is reasonably clear- people, living in social systems, need to have some shared understandings of each other and reality. These understandings are tied up with power and who gets to run these systems- whose interests are served. And it is historically clear that those who are disagreeable enough to buck the established narrative very often end up dead- burned at the stake, forced to drink the hemlock, run out of town, ostracized. The line between justice in some necessary civic sense, and totalitarian measures against deviance, impiety, and disobedience is not a clear one. It is a modern innovation to separate the state from religious conceptions of the social order, now leaving each religious community to police its own congregants with other tools. But over the long arc of human history and pre-history, these were closely intertwined, indeed indivisible. Being trapped in one's family and tribe meant getting along with its reality, whatever that might be.

Tara is almost crushed by the choice, and the dissonance of being loved by people who increasingly seem both untethered from reality, and intensely controlling of their communal version of it. She goes through years of depression and doubt, torn to the core between loyalty to family, and loyalty to what she is shaping as her new self, fostered on intellectual adventures that go unimaginably beyond what her former (and alternate) self could have achieved. Is it worth it? That is the frequent problem of waking up from a religion (or a family) - that one has to lose its comforts and support in order to understand it more fully and overcome its glaring limitations.

• You don't have to be smart to run a cult.
• Thanks, Tea Party.
• Stupidity is generally not the answer.
• How many times does this president need to be impeached?
• Bill Mitchell on the job guarantee, and on bandwagons.
• How's your sky?
• Some more nice piano.

How do we Get Out of Here?

It is hard to tell just yet how the coronavirus lockdown will end. Some scenarios.

With the US having frittered away its early opportunity to contain incoming travel and the spread of SARS-CoV-2, we lost containment and now have an endemic pandemic. Nor are our health authorities pursuing definitive contact tracing and quarantine of all cases/contacts- some regions of the country are even well beyond this possibility. Time lines for the lockdown are being progressively extended, without a clear end-game in sight. Where will it end?

The China Solution
China has done draconian quarantines and close tracking, contact tracing, and isolation. And they have stamped out the epidemic, other than a tickle of cases, supposedly mostly coming from abroad. How ironic, but also impressive. They have used institutions and norms of close social control, sometimes rather blunt and indiscriminate, to get the upper hand over this contagion. The prospects for us doing the same are dim. Neither our public officials nor population have the stomach for it. Thus this is not a realistic scenario as an endgame for the US pandemic.

Slow burn
No, we take a more relaxed approach, hoping that the pandemic will magically recede. But that is unlikely to happen, given the vast reservoir of uninfected people, and the virus's high infectivity. So far, the US has ~300,000 cases, and ~8,000 deaths. Assuming that the reported case rate is one-tenth of actual cases, there might be three million people who have been exposed and recovered, out of a population of over 300 million. Exposing everyone would thus result in roughly a million deaths. This will happen no matter how good our social isolation is, or how long it lasts, because the minute anyone pokes their head out, they will be exposed. Without comprehensive tracking and isolation of cases/contacts, our laissez-faire approach leads to a slow burn (also termed flattening the curve) where our hospitals might be able to keep up with the extended crisis, but we still take an enormous hit in illness and death.

Exposure testing
One supplement to the slow burn scenario is the addition of exposure testing, for antigens to SARS-CoV-2. If these tests were broadly offered, like at grocery stores and by home delivery, we could at least recognize a large population that is immune and thus can move freely, (perhaps wearing a scarlet letter!), helping to re-establish economic and other essential activities. This is like having some amount of herd immunity, without waiting for the entire population to have been exposed. But it would not significantly curtail the slow burn, since we are still unwilling to keep everyone else out of circulation in a comprehensive fashion.

County quarantine
Some areas of the country are doing much better than others, and could set up local clean zones and boundaries. Once cases were reduced to a small trickle, the health departments could do what they failed to do at the outset, which is to block and test at all borders, and comprehensively trace contacts and enforce isolation internally. Given the large and necessary traffic of deliveries of goods, especially food, this is quite unlikely to happen, and would represent a sort of breakdown of our political society. But the behavior of the Federal administration, giving a "you're on your own" message to states and localities, does make this scenario more likely. It also ends up being a sort of slow burn, since any locality can not forever keep up such isolation. It would have to continue until the advent of a final solution- a vaccine or treatment.

Vaccine or treatment
This is the magic solution everyone is waiting for. The antivax movement isn't looking so good at this moment,when everyone's attention is focused on virology, epidemiology, and public health. Candidate vaccines are easy to dream up- any protein from the virus could be expressed in some heterologous system (like in E. coli cells or yeast cells) in massive amounts, and injected into people to generate immune responses. But effective vaccines are another story. Coronaviruses and other respiratory viruses tend not to generate strong and durable immune responses. That means that their ingredients just are not that immunogenic- they have devious ways to hide from immune surveillance, for one thing. Indeed, we still do not have good vaccines (or treatments) against the common cold. So a good vaccine will need to use all the tricks of the trade, such as multiple protein pieces, both invariant and variable, and immune-stimulating adjuvants/additives, to make an effective vaccine. It may take a year, but it may also take several years.

It looks like we will be in this lockdown for a very long time, with reduced economic and social activity. And the more effective our social distancing, the longer we will have to stay isolated, as the flatter curve extends out in time. If we go down the China route with more draconian methods to stamp it out before it burns through the whole population, we will be in a very precarious situation until a treatment emerges, given the wide-spread, now endemic, presence of this virus world-wide if not in continuing hot spots in the US.

• For those locked in ..
• How China is controlling spread while getting back to work.

Atheism, or Archetype?

Religion is built on a series of inborn archetypes and intuitions. Does that mean it is inevitable?

Religion is natural, but is it right? Increasing numbers of people in the US are giving up the practice and belief, if polls are to be believed. Hellfire and damnation is sure to follow, according to those left in the pews, at least those of the farthest evangelical congregations. As a student of Carl Jung, I appreciate the psychology of religion, seeing its processes as deeply reflective of our individual and communal psychologies, as well as the consequence of a complex evolutionary process whose aim has been as much social solidarity and reproduction as much, or more than, philosophical truth. At base, we are not rational beings, and follow a variety of themes and images, termed archetypes in the Jungian system, which persistently guide our dreams,  motivations, and cultures. We are not just economic units driven by profit and loss, but have richer dramatic lives and needs.

Father

What could be more obvious? We grow up in households with father figures who are unimaginably powerful. Food just appears, housing, furniture, love, care, and power and discipline. It is no wonder that, once we grow up, there is a father-shaped hole in our view of the world. In the usual patriarchial culture, the father stands alone, at the top, as both creator and moral disciplinarian, in an archetype that is expressed over and over again in cultures throughout the world, from Zeus to Allah, as it is in our political systems naturally as well. But the mother archetype is also in play, especially in Catholic and Hindu cultures, in the Marys and various powerful devas. Is it possible to see the world without using these instinctive lenses? That is what the scientific revolution and enlightenment attempted, in a cognitive revolution that remains, evidently, incomplete. Take prayer. In the form of requesting something from the father in the sky, it is pathetically immature and retrograde, however understandable in primitive conditions of complete existential mystery. On the other hand, some meditation, joy, and gratitude for the wonders of existence are surely healthy and consistent with mature knowledge of where we stand in the universe. Involvement with this archetype reflects quite directly how far one has gotten along the developmental road from childhood to maturity.

Heaven

The afterlife used to be a rather drab, depressing affair, in the classical Greek and Jewish systems. Then it was progressively gussied up into a lottery jackpot, in the Islamic and Christian systems. Buddhists and Hindus also find life after death, in the form of reincarnation, to be absolutely central to their philosophies. The magic of consciousness is incredibly hard to give up, and hard to get rational perspective on. It takes stringent dedication to naturalism and the evident facts of the world to accept, deep down, that death is really going to be the end- of everything. One need only think about animals- they are obviously conscious, and there are levels of consciousness all the way down the scale of evolution, to infinitesimal, then finally to nothing at all. How does that work, other than in direct proportion to their physical, brain-based endowments? What could be more clear, and in stark contravention of our intuitive and (weirdly) hopeful dream of life after death?

Tribe

We are not just endowed with intellect, but with a social nature, which focuses our striving and loyalty on the tribe. Our tribe is right and good, theirs is bad and wrong. Tribalism founds and plagues every new religious sect or philosophical school, which strains to show how it is right and its predecessors wrong. Jung vs Freud, Analytical vs Continental, Shiite vs Sunni, in endless profusion. Religions lack even the veneer of factual basis which characterize other divides like political polarizations or academic disputes. Doctrine, orthodoxy, and heresy are freely defined by whoever has social power. If one's village is Evangelical, woe to Catholics. If one's family is Seventh-Day Adventist, mere contact with outsiders is forbidden. Tribes have totemic symbols and artistic traditions as part of their identification / bonding apparatus, tokens of the archetypal processes at work.

Magical or zodiacal symbols in an Islamic Book of Wonders, circa 1400. 

Magic

Living in an enchanted word is natural, and wonderful. We all start there in childhood and treasure the dramatic, humanistic power of seeing the world through archetypal lenses- in animals with special totemic powers, crystals that heal, trees that listen. This is truly where traffic with archetypes is most fluid and explicit- bringing dreams to narrative life. Religious superstition raises this drama to existential levels, putting the magic on a celestial level of god(s), all-powerful father figures, and alternatives of eternal hell-fire or bliss. The chances of all this actually describing any kind of reality is nil- we are talking total fantasy. But its evident grip on billions of people shows just how powerful magical thinking is and how far we are from being rational.

Truth

All claim truth, but few prove it. Religions are notorious for splitting into sects, each possessing the final truth, the real story. Interestingly, atheists do not splinter in this way. There is plenty of bickering, about what humanism entails or is, how liberal humanists should be, etc., but there are no Seventh-Day atheists, or Twelver atheists, or other miscelleneous schools. Communism was atheistic, but was in truth a quasi-religious, authoritarian cult all its own. Once one has discarded attachment to these archetypes and the theologies they underpin, and to the need for truth as a matter of self-identification, why then it is easier to agree on what is actually true, as well as on the many areas where we just don't know, without the need to make up stories. This need, a dire need, for answers, especially to "big" questions, is a tipoff that we are dealing with archetypal energies, not with a rational level of thought.

One could compare atheism to the concept of nirvana in Buddhism and Hinduism- the release from the cycle of rebirth, from attachment to the archetypes, and escape to a level of intellectual / emotional freedom. Escape from rebirth is implicit, since the atheist doesn't believe in rebirth, heaven or afterlife at all. It focuses attention on this life, this moment, and compassion here rather than later. But to escape the causes of suffering, (especially the infliction of suffering upon others!), by regarding the archetypes intellectually and skeptically, and by distancing one's self from them, is far more important. To leave behind the seductive entanglements of archetypal belief and the often-abusive social relations they entail is personally momentous, and a healing balm for a planet full to the brim with faithful dogmatists.

• One moving, harrowing, story of escape.
• Viral data dump from a skeptic.
• Administration cut funding for surveillance before outbreak.
• Graph for New York.
• Unemployment-ocolypse.

The Extermination of Tibet

China is culturally cleansing Tibet. "Seven Years in Tibet", by Heinrich Harrer, and "My Land and My People", by the Dalai Lama.

It may be falling off the world's radar screen, but Tibet remains a tragically oppressed land, well worth our remembrance and sympathy. Two books, "Seven Years in Tibet", and "My Land and My People" describe the heartbreaking slide from a happy, innocent, and isolated region to the Orwellian horrors that succeeded and continue today. One of the first significant acts of the new communist government of China, fresh from its civil war against the government that actually faught the Japanese, was to fulfill not any orthodox communist aims or development for its people, but the most rapacious and ancient ambition of Chinese governments, to subjugate its neighbor to the West, Tibet. Amid a blizzard of lies, China invaded the virtually defenseless state, oppressing Tibetans from the start in an ever-escalating war of cultural extermination. After almost ten years of trying to get along with the overlords and calm the waters, amid general rioting, the Dalai Lama fled in a dramatic escape from occupation, to welcome refuge in India, where he and the Tibetan exile community remain today.

Tibet was, frankly, a medieval culture, with economic relations ranging from nomadic to feudal. But medieval in the best sense, of a people thoroughly engaged in a set of archetypes that yielded a richly nourishing, dramatic life experience as well as a durable social structure. Tibetan Buddhism is very demanding, taking a fair fraction of men and resources into monasteries where they live off the rest of population and devote themselves to philo/theological hairsplitting. But they also devote themselves to various traditional arts, and most of all to the cultivation of peace and compassion- the touchstones of Buddha's solution to the suffering of this world. After a long and martial history, Tibet eventually put itself under the control of its most respected leaders, the Lamas, creating a system that was peaceful and benevolent, if also hidebound and conservative.

Take the story of how the current Dalai Lama was found and put in power. It is a veritable fairy tale of portents, dreams, signs and wonders. It has a sort of Wizard of Oz quality, which obviously resonanates, not only with us as a romantic tale, but with Tibetans as a great origin myth. And one can make a case on a practical level that choosing a humble and obviously bright peasant child to rule one's land may be a superior method to one which relies on the most ambitious people to sell themselves in some way to various institutions of power, and to the populace every four years. How often do we fantasize that any halfway intelligent person could do as good a job as the current office holder? Especially if that person were from early on steadfastly dedicated to the cultivation of peace and compassion in him or herself and others?

Likewise, the Dalai Lama's secret and arduous escape from Tibet was again the stuff of legend, binding him to his own people, and endearing him to people around the world. The Tibetan system values spiritual attainment, expressed in the extremely pacifist ideology of Buddhism, combined with a great deal of pre-buddhist folk religion and symbology. The culture was thus temperate and peaceful, perhaps too peaceful for its own good, but surely a model to emulate in our spiritually unbalanced times. The Chinese, in contrast, brought rapacious domination, racism, and cruelty. They were and remain atheist. But it seems that their compassionless spiritual vacuity (which is quite a different thing) was more important, leading them (especially through the cultural revolution) to despoil the cultural treasures, institutions, and people of Tibet.

We may wonder whether China is more culpable in all this than the US was in its virtual extermination of Native Americans and their many cultures. The answer is clearly yes. The gulf between the American cultures was far wider, and the state of historical consciousness lower. Native Americans had no continent-wide governments of centuries standing, no meticulously recorded written histories and philosophical traditions, and little basis for common ground or negotiation with the colonists and their successors. We have belatedly granted Native Americans limited sovereignity in their institutions and barren territories, while China keeps pouring more Han Chinese into Tibet and keeps 100% social control. The world had just fought a war to end all wars, and to liberate peoples from totalitarian military oppression, including those of South Korea. But Tibet was a bridge too far- we could not lift a finger in China's back yard, and now hardly say a peep.

• Some numbers.
• Expert talk.
• This, as most other times, would be a good time for a job guarantee.
• Who is in charge here?
• How dare she?
• Poor people deserve less.
• Buddhist action thriller of the week- Milarepa.

Coronavirus Testing Update

A review of how testing is done, and where we are at.

We in the US are flying blind through the current epidemic, with cases popping up all over, testing done on very few people, and the rest ranging between nervousness and panic. What is the death rate? We still do not know. Did China contain its outbreak by draconian measures, or by wide-spread infection and natural burnout? How about South Korea, or Taiwan? Everyone claims the former, but it far from certain what actually happened. We need more testing, and particularly scientifically sampled population testing, and post-infection exposure testing. The basics of epidemiology, in other words.

SARS-CoV-2 is the virus, and COVID-19 is the disease. Most people do not seem to have mortality risk from infection, other than the elderly and infirm. In these respects, and in its great infectiousness, this disease resembles influenza. Testing from patient samples is done by RT-PCR, which stands for reverse-transcription polymerase chain reaction. The reverse transcription part employs specialized enzymes to copy the viral genomes, which are RNA, from the patient sample, into DNA, the more stable molecule that can be used in PCR. And PCR is the revolutionary method that won a Nobel prize in 1993, which uses a DNA polymerizing enzyme, and short segments of DNA (primers), to repetitively (and exponentially) replicate a chosen stretch of DNA. In this way, a minuscule amount of a pathogen can be processed to an easily detectable amount of DNA. The FDA mandates using three target regions of the new Coronavirus N protein encoding gene for its tests, but will accept one target, if the test is otherwise properly validated. They point test makers to the NAID resource that provides positive control material- RNA genomes from SARS-CoV-2.

 Just the primers, Ma'am. These tubes contained dried DNA- the short primers with specific sequences needed to amplify specific portions of the SARS-CoV-2 viral genome. Using these requires quite of bit of other laboratory equipment and expertise.

Schematic of PCR, the exponential amplification of small amounts of DNA to huge amounts. Primers are in green, nucleotides are light blue, and the target template is dark blue.

So far, so good. But there are a range of test technologies and ways to do this testing, from the bare-bones set of primers, to a roboticized, fully automated system, each appropriate to different institutions and settings. To use the basic primer set, the lab would have to have RNA extraction kits or methods to purify the viral genomes from patient samples, then a reverse transcription kit or method, then a PCR machine and the other materials (nucleotides, high-temperature DNA polymerase, purified water and other proper solution ingredients). The PCR machine is basically a heater that cycles rapidly between the low temperature required for polymerizing and primer annealing, and the higher temperature required to melt all the DNA strands apart so that another round of primer annealing can take place. And all this needs to happen in very clean conditions, since PCR is exceedingly sensitive (of course) to small amounts of contamination. Lastly, the DNA product is typically detected by trace fluorescent markers that light up only double-stranded DNA, and can generally be detected right in the tube, with an advanced PCR machine.

Automated sample handling machines are used in clinical labs.

Virtually all of this can be mustered by any competent molecular biology lab. Results would take a few days, due to the work involved in all the setup steps. The PCR itself and analysis of its results would take a few hours. But such labs do not operate at the requisite scale, or for this purpose. That is the province of clinical testing labs, which come in various sizes, from a small hospital in-house operation to a multinational behemoth. The latter run these tests on a vast, mechanized scale. They might manufacture the DNA primers themselves, or buy them in bulk, and have the proper logistical structures to do these tests from scratch in a reproducible way, to a high standard. Providers at these scales need different kinds of materials for their testing. A small provider may need a turn-key solution that comes with pre-packaged cassettes that just need the sample added before plugging into the machine, while a larger provider would save costs by using bulk reagents and massively robotized sample handling and PCR machines.

A one-hour test in a turn-key package. But at relatively high cost.

So who are the players and what is the status? The CDC did not, for some reason, use the WHO test, or tests already developed in China, whose capacity for such manufacturing and testing is prodigious. The CDC at first didn't allow anyone else to run the tests, and when they did, they did not work correctly. It has been a bad scene and much valuable time has been lost- time that resulted in the US losing any chance of containment. Now, the FDA is authorizing others to run these tests, with detailed instructions about sampling, extraction, and machinery to be used, and is slowly granting authorization to selected manufacturers and kit makers for more kinds of tests.

Large suppliers like Roche and ThermoFisher have just been approved to supply clinical labs with testing systems. Most significant is Roche, whose tests are pre-positioned and ready to go already at clinical labs around the country. The biggest clinical lab, ominously named LabCorp, offers a home-made test, but only "several thousand tests per day", which is not yet the capacity needed. So capacity for testing will rise very rapidly, and soon enable the diagnostic and surveillance testing that is so important, and has been missing to date.

• Notes on previous pandemics.

Post script:

An aspect I forgot to include is how to select the portions of the viral genome sequence to include in testing kits. Different institutions have clearly come up with primers to different genes, few as they are, and regions within those genes. For example, "The primers currently target the N1, N2, and RP genes of the virus, but these are subject to change."; "In particular, the test detects the presence of SARS-CoV-2’s E gene, which codes for the envelope that surrounds the viral shell, and the gene for the enzyme RNA-dependent RNA polymerase." There is a balance between finding regions and primer sites that are unique to the particular virus you are interested in, so cross-reaction to other viruses is 100% eliminated, and the problem of viral drift and mutation. Some regions of viral genomes mutate much more rapidly than others, but these viruses tend to mutate at pretty high rates overall, so keeping a test current from one year to the next can be challenging. That is also what our immune systems have to deal with, as cold and flu viruses change continually to evade our defenses. So the specific DNA primer targets of a test need to be relatively highly conserved, but not too highly conserved, to put it in evolutionary terms, and the regulating agencies have to keep a close eye on this issue as they approve various test versions, to find a proper balance of high specificity and long-term usability.

Post-Post script:
Yet more significant testing solutions have emerged by late March, including a rapid (~10 minute) system from Abbot, and rapid antigen testing kits that also render results in the ~10 minute range. This speed is enormously helpful, obviously, from the patient, provider, and health system perspectives. The Abbot system is based on something called isothermal PCR, which gets rid of the temperature cycling described above. It is run at an intermediate temperature (~60 degrees C) where the DNA is somewhat loose, and primers can invade duplex strands, and also used a DNA polymerase that can displace duplex DNA as it plows ahead. This plus some other clever tricks allows the DNA amplification process to happen continuously in the reaction tube, going to completion in the rapid time quoted for these tests. These tests also tend to be tough- relatively robust to junk in the samples, and variations in temperature and other conditions.

The antigen tests that are coming on line are particularly significant, since they can be used for wide-spread population surveillance, to figure out what proportion of the population has been exposed, even if no active infection is present. Due to what seems like a complete or virtually complete lack of contact tracing + quarantine, the current pandemic will only stop once most of the population has been exposed, providing herd immunity. Before that point, anytime we give up self-isolation, it will start over again, due to the relatively high rate of low- or asymptomatic cases, and their lengthy course. Health care workers that have been exposed and recovered will have a special role before then by being able to freely staff hospitals that otherwise may be in dire straights.