Diamonds in the Junk: Medically Important Sites in Intergenic Regions

Finding human genomic variants that are relevant to disease, in regulatory regions.

The human genomes remains a complicated place, and to simplify its study, many researchers and medical screeners stay in the shallow end- the coding regions or "exome", which comprises what is transcribed from protein-coding genes. But there is much more in there, from the introns and other critical elements inside and near genes, to regulatory elements spread over millions of basepairs around their target genes, to junk DNA with no function known at all, yet.

A recent paper offered an improved analysis of these large intergenic regions, and claimed to find medically interesting mutations. The issue is that the vast regions surrounding genes are largely what could be called junk DNA, with occasional quite small and variable regulatory sites that are difficult to find. So mutations are frequent, yet most have no effect. Figuring out which might have medical significance is one of those finding-needles-in-haystacks problems. And doing it over a whole genome to an informative level is unprecedented.

Example of a mammalian genomic region (A) featuring 700,000 bases between neighboring genes. The genes are grey: Nom1, Lmbr1, Rnf32, Shh, Rbm33, Cnpy1, and En2. In color are various regulatory sites (enhancers), coded by their location and the region (B) where they activate gene expression of Shh in a mouse embryo. It is noteworthy that Shh is driven by enhancers lying throughout the intergenic region, and even within the Lmbr1 gene, 850 kbp away.

The researchers start with a few genomes from five people who have allowed their data- genomic and medical- to be used in the public domain. The other starting material is knowledge about 657 DNA-binding transcription regulator proteins, which is about half of all the regulators known in humans; especially what kind of DNA sequences they tend to bind to. Then they add in a phylogenetic conservation analysis of 33 other mammals, which allows them to find putative regulatory regions and sites in their human genomes.

The procedure is then to comb each genome, asking which probable sites in the vast non-coding areas differ from the average or reference human genome. And then of those, which sites are conserved with respect to chimpanzee and other species, indicating that the site is significant over evolutionary time, but was mutated in the person whose genome is being studied.

The innovative part of their analysis, aside from the scale being attempted in terms of numbers of sites, merging of evolutionary and regulatory binding pattern methods, and whole genome coverage, is in their statistical treatment. The object at this point was to describe the various mutated sites that were found in terms of possible medical or biological significance. This routinely depends on the annotation of the nearest gene, which would be the regulatory target and confer whatever ultimate function the site has. It has been customary to address only regulatory sites close to genes, since the demarcation from one gene's regulatory region to its neighbor's is not yet easily predictable from the gnome sequence alone.

Parenthetically, one can note that this demarcation is performed by "insulators". These nucleo-skeletal-tethered sites in the intergenic DNA are bound by specific proteins that form boundaries which keep nearby genes regulated independently. They are under study and will be the subject of a future post.

A second problem is that, if one does range widely over the intergenic spaces to look for relevant mutations and biologically significant sites, it can be statistically hazardous to equate the sum of annotations from huge regions (which tend to surround developmentally important genes, for instance) against the necessarily smaller sets that would come from regions where genes happen to be close together. A correction for the size of the sampled area is called for. These researchers have constructed tools that specifically correct for these and other issues, and sample up to two megabases of intergenic DNA. Their rule is that a gene's core region is 5,000 bases upstream and 1,000 bases downstream of the site where its transcription starts, and everything up to a megabase on either side, or to the core region of the next gene, is fair game for finding associated regulatory sites. This is a rather broad zone, but can only be improved once the insulator sites are better defined.

Since the three billion base human genome contains roughly 22,000 genes, there is an average of 136 kilobases per gene. So a two megabase bound per gene, while large and perhaps sometimes not capturing the largest possible extent of a heavily & diversely regulated gene, should easily capture most regulatory regions and cover most of the genome.

Cranking through the whole analysis, they come up with specifically enriched annotations tied to genes whose conserved regulatory regions have suffered detectable mutations, in each of the five people (acronymized as CoBELs). And the question is whether these annotations match the respective medical histories and problems. With only about 5,000 to 6,000 sites found for each person, these researchers are probably only scratching the surface of genomic variation, picking the very easiest fruit off this tree. It is thus is important that their data come up with significant matches, since if this data is not significant, more and deeper data is unlikely to be any better. And this is what they claim to do.

Outline of results from five individuals, correlating regulatory variants from this whole-genome analysis with their medical syndromes.

The total numbers of variant sites that were flagged by this analysis was:

• Stephen Quake: 6,321
• George Church: 5,291
• Misha Angrist: 5,775
• Rosalynn Gill: 5,861
• James Lupski: 6,447

Thus they come up with statements like:

"Prominent in Stephen Quake’s medical records is a family history of arrhythmogenic right ventricular dysplasia/cardiomyopathy, including a possible case of sudden cardiac death. Strikingly, when Quake’s set of CoBELs is analyzed using GREAT, the top phenotype enrichment (using default parameter settings, optimized for inference power in the original GREAT paper) is “abnormal cardiac output” (57 CoBELs, false discovery rate Q = 1.69 x 10−4). This enrichment is suggestive of susceptibility to heart diseases responsible for reduced cardiac output. Meaningful associations between CoBELs and personal medical records are in fact observed for all five genomes" 

"For example, 33 genes in the human genome are annotated for “abnormal cardiac output”. Their GREAT assigned regulatory domains cover 0.45% of the genome. Of the 6,321 Quake CoBELs, 28 (0.45%) are expected in the regulatory domains of these 33 genes by chance, but 57 CoBELs, over twice as many, are in fact observed." 

"The top enrichment for George Church, who suffers from narcolepsy, is “preganglionic parasympathetic nervous system development” (23 CoBELs, Q = 1.18 x 10−4). The autonomic nervous system is strongly suspected to be involved in narcolepsy. Misha Angrist, whose personal reporting indicates possible keratosis pilaris, a follicular condition manifested by the appearance of rough, slightly red, bumps on the skin, has “epithelial cell morphogenesis” as his top biological process enrichment (60 CoBELs, Q = 1.38 x 10−5)."

This analysis provides something that has been a dream up till now- a way to rigorously evaluate whole personal genomes, not just the coding areas, for medically relevant mutations. There is far more to do, since the 657 DNA binding regulators and their sites are far from the only action in town. There are more functions hidden in the intergenic DNA, like epigentic marks and non-gene transcription units. But this is a very promising start that can be scaled up and added to retail-scale analysis of anyone's fully sequenced genome, not only finding syndromes and weaknesses before they appear for individuals, but also helping the medical research enterprise find disease-causing mutations and pathways.

• Butterfly wings evolve by enhancer shuffling / variation.
• A remembrance of Scalia.
• We once took anti-black terrorism and nullification more seriously. A chilling account of the Klan.
• Trump and the white working class. Maybe the problem is bigger than Trump.
• Speaking of insularity, if orthodox economic models are wrong, why keep using them?
• Romers, Keynes, Freidman. And more on Keynes- imbeciles and delirium.
• Piketty on the Eurozone.. it is a mess.
• Example: Finland.
• Globalization, trade, and World War 1.
• This is why Bernie exists.
• The deeper psychology of Bernie.
• The Russian model for Syria: Chechnya.
• Clinton, State, and the IG.
• Carbon taxes work.

Philosophy on the Magic Mountain

Will humanists and theists be fighting forever?

Thomas Mann's Magic Mountain is a somewhat dreary, rigidly routine-ized, and heavily allegorical sanitarium in Davos, Switzerland. Its inmates while away their days waiting for (or not, as the case may be) clean bills of health from the ruler of this little state- the doctor, who performs occult operations to monitor their tuberculosis.

The hero of the book, Hans, comes to adopt the very static, passive, indeed patient, ethic of the place as a chosen way of life, drifting ever farther from normal conceptions of time, and from any regard for or social conenction with the "flatlands" below. The only fire in his story comes from a pair of philosophers who battle ceaselessly for Hans's mind (his soul is diverted by other temptations, such as a woman). Lodovico Settembrini is the die-hard humanist, atheist, and inheritor of the Italian enlightenment. Reason, and hatred of the old orders of aristocracy, church, and hierarchy are his watchwords. Later on in the book, his antagonist, Leo Naphta makes his appearance, a former Jesuit  and crypto-Marxist given to the most florid romanticism.

It is fair to say that Settembrini is given the best lines, and the most heroic action. Thomas Mann's sympathies are evident. But he portrays Naphta very thoughtfully, in perhaps the most interesting intellectual battle since the Brothers Karamazov.

"For even if the state's ungodliness were not branded on its brow, one need only note a simple historical fact- that its origins can be traced to the will of the people and not, as those of the Church, to divine decree- and thereby proves that the state is, if not exactly a manifestation of evil, then at least a manifestation of dire necessity and sinful shortcomings."

"The state, my dear sir-- "

"I know what you think of the nation-state. 'Above all else, love of the fatherland and a boundless hunger for glory.' That is Virgil. You amend him with a little liberal individualism, and call it democracy; but your fundamental relationship with the state remains completely untouched. you are apparently not disturbed that money is its soul. Or would you contest that? Antiquity was capitalist because it idolized the state. The Christian Middle Ages clearly saw that the secular state was inherently capitalist. 'Money will become our emperor'- that is a prophecy from the eleventh century. So you deny that it has literally come true, making life itself a veritable hell?"

...

"Can it be that your Manchester eyes have failed to notice the existence of a social theory that promises that victory of man over economics, a social theory whose principles and goals coincide exactly with those of the Christian City of God? The Church father called 'mine' and 'your' pernicious words, describe private property as usurpation and thievery. they repudiated private ownership, since, according to the divine law of nature, the earth is the common property of all mankind and therefore it fruits are likewise intended for the common use of all. They tought that only greed, itself a consequence of the Fall, defends the rights of property, since it also invented exclusive ownership. They were human enough, anticommercial enough, to call economic activity per se a danger to the salvation of the soul, that is, to humanity. They hated money and finance and called capitalist wealth fuel for the fires of hell. With all their hearts they despised the economic principle that declares price is the result of the workings of supply and demand, and they damned those who lived by the fluctuations oft he market as exploiters of their neighbors. Even more blasphemous in their eyes was another form of exploitation, that of time- the monstrosity of receiving a bonus, that is interest paid on money, from the simple passage of time and thereby perverting a universal divine institution, time itself, to one's own advantage and the detriment of others."

...

"Well, then- after having been buried for centuries, all these economic principles and standards have been resurrected in the modern movement of communism. The correspondence is perfect, down to the meaning of international labor's claim of dominion over international marketeering and speculation. In the modern confrontation with bourgeois-capitalist rot, the world's proletariat embodies the humanity and criteria of the City of God. ... Its work is terror, that the world may be saved and the ultimate goal of redemption be achieved: the children of God living in a world without classes or laws."

...

"'Form!', he said. And Naphta grandiloquently responded, 'Logos!'".

...

"In caustic words, Naphta forbade Herr Settembrini to call himself an 'individualist', because he denied the polarity of God and nature, and defined the question of humanity, the problem of man's interior conflict, as simply the conflict between the individual and the larger social units, and so was wedded to a bourgeois morality that was tied to life, understood life as an end to itself, saw its sole purpose in unheroic utility, and viewed all moral law as invested in the state; whereas he, Naphta- well aware that mankind's inner conflict was based instead on the contradiction between what the senses register and what transcends the senses- represented true, mystical individualism and was in actuality the genuine man of freedom and subjectivity."

...

"And at this Naphta begged them to forgive him for laughing out loud. The nihilism of the Church, had he said? The nihilism of the most realistic system for exercising authority in the history of the world? Could it be that Herr Settembrini had never been touched by that breath of human irony with which the Church continually made concessions to the world, to the flesh, cleverly acquiescing in order to disguise the ultimate consequences of the ascetic principle and letting the influence of the Spirit establish order by not opposing nature too sternly? And so he has never heard of the refined priestly concept of indulgence, under which even a sacrament was included- marriage, to be precise, which unlike the other sacraments was not a positive good, but a defense against sin, conferred solely to limit sensual desire and to instill moderation, so that the ascetic principle, the ideal of chastity, might be affirmed without defying the flesh with unpolitic severity?"

Etc... round and round they go, in a never-ending battle that remains just as active today between partisans of the transcendent Logos, and those of the embodied mind. Is a utilitarian, economically literate and politically moderate system sufficient for humanity, or is a romantic, mystical transcedence necessary? The truth of romantic & mystical propositions is quite beside the point. The Church was never a scientific institution. Religion cares about a truth behind the veneer of reality- however one calls it, it is a long-standing human fixation both to see ulterior conspiracies and realities behind all phenomena, and to demand the heightened drama and meaning from our lives and world that such fantastical realities generate.

It seems to be, in the end, a temperamental issue, between people with more imagination than sense, and others with more sense than imagination. Intuitions and artistic sensibilities point in one direction, and the facts of history and nature point in another. Whether we need both perspectives is a vexed question, but that we have them and may continue to have them perpetually is pretty clear.

The conflict between Settembrini and Naphtha is also, I think, infused with an allegorical relationship with World War 1 (spoiler alert!). Eventually, the combatants get so worked up that Naphta feels his honor impugned, and insists on a duel. Though Hans tries to mediate and diffuse tensions, seconds are chosen, arms are acquired, and the absurd ritual continues till the fateful morning comes. Settembrini has the first shot and fires into the air, declaring no intention to kill anyone. Naphta is so consumed by the conflict, his honor, and the romantic drama that he shoots himself in the head.

While one might view the rational side of the cataclysm in the system of alliances that were, not all the peaceful nations against the aggressor, as NATO is arranged now, but rather the Metternichian "balance" of the triple alliance vs the central powers, etc. But it was the romantic notions of a cleansing, dynamic, and manly militarism that were probably the more powerful motives toward that world war, and even more, the second.

***

Incidentally, Mann provides a Trumpian figure in this book as well, in the person of Pieter Peeperkorn. Given to great generosity and cryptic nonsensical utternances, Peeperkorn impresses everyone around him, especially Hans, who finds him charismatic and full of feeling, a welcome contrast to the ceaseless pedantry of Naphta and Settembrini. Indeed, Peeperkorn is irresistably magnetic, even if uncouth, incoherent, and generally oblivious, except when it comes to the deepest feelings, where he attacks mercilessly, or kindly, as his spirit moves.

• Thomas Paine on the fraudulence of all religions.
• DeLong on Piketty.
• Euthanasia of the rentier ... some numbers.
• House hunting while black...
• Bill Black on Wall Street's shocked disbelief that millennials are infatuated with Bernie. How could they be so blind?
• Let's pay a little attention to Rubio.
• Trump and the stupid party / religion.
• Lindsey Graham lets loose on the stupid party.
• FOX and its clown posse.
• Russia and the new cold war.
• Afghanistan, heading downhill.
• Is this who we are, lackeys of despots?

Mechanics of Influenza

The more we learn, the more amazing this tiny virus seems.

One of the few regular and severe diseases still prevalent in the developed world among people of all ages is influenza. It causes misery to millions and significant mortality, and can occasionally mutate to pandemic strains that kill millions; 2% of the human population in 1918. Nor is the current vaccination system very effective. We need something better.

What a simple organism it is, though! Only nine genes, in a genome of less than 15,000 bases, enveloped in a membrane coat carrying a couple of proteins on its surface. How does it cause all this misery? Well, each of its genes is intricately designed and multifunctional. The principal outer coat protein, for instance, called hemagglutinin or HA, is specially shaped to bind to the sialic acid on the surface of our respiratory mucosa cells. Then, when ingested into the endomsome/lysosome of the poor cell, it acrobatically flips its structure to thrust out a hydrophobic spear that punctures the lysozomal membrane. This same protein then refolds its shape once again to bring the viral membrane and the lysozome membrane into close enough contact that they fuse, releasing the viral contents into the cell. Not only that, but the HA protein plays a special role in mutating all the time in different viral strains so as to retain function on the exterior of the envelope, but evade the host immune system.

Sequence of refolding and membrane fusion events, by the surface HA protein. It takes only about three HA molecules to carry out membrane fusion between the surface of the virion and the endosomal membrane.

There are many other molecular functions encoded in this tiny parasite, such as a polymerase that both replicates itself and copies itself to message RNAs, an enzyme on the surface that allows the virus to eat through the mucus in our respiratory tract, structural proteins that assemble the new viral particles, an enzyme that steals the caps of cellular mRNAs and plants them on viral RNAs, and even a proton channel protein that allows the virus to equilibrate with the low pH of the endosome/lysozome and trigger disassembly of the virion, so that, given that the membrane fusion has taken place at the same time, its genome can get out to take over the cell.

Electron micrograph of two influenza particles inside an endosome, waiting for their chance to escape and take over the cell.

The inhibition of the host immune system deserves special mention, for its deviousness. The interferon response is one of the most powerful immune and especially antiviral responses, which influenza takes special care to counter-attack. This is a rapid and non-adaptive ("innate") part of the immune system, where once a virus is detected, a program of hundreds of genes is activated that renders a cell strongly primed to shut down viral replication and commit suicide. While the virus eventually succumbs to the much slower adaptive immune response, (B cells, antibodies, killer T cells, etc.), that only happens after it has already replicated and been sneezed back out to other targets. Evading the more prompt early immune response is absolutely essential, and is partly mediated by a viral protein called non-structural protein 1 (NS1). So-called because at the time it was discovered, researchers had no idea what it did.

Now, they know that it has at least four, and possibly more, functions.

1. It binds to a shuts down cellular TRIM25, a key part of the detection system that turns the interferon response on. 
2. It also binds to and shuts down cellular PKR, which is one of the prime components of the interferon response downstream, which shuts down most translation, including viral translation. PKR also promotes cell suicide and amplifies the interferon response through NFkB. 
3. Thirdly, NS1 binds and shuts down cellular CPSF4, which processes and tags cellular mRNAs for export from the nucleus. So while the interferon system is trying to shut down viral and cellular translation, the virus, through this single protein, is specifically shutting down cellular translation, and also shutting down the interferon response. 
4. Some researchers claim a fourth function is most important, which is the ability of NS1 to bind to double-stranded RNA, like the genome of the virus and its replication and transcription structures. This binding seems to hide the RNA from OAS, an interferon-induced protein that would otherwise bind the double-stranded RNA and initiate an RNAse L response to destroy it. 
5. Fifth, NS1 binds to and inhibits another cellular protein, PAF1, which is a regulator of transcription that has a central role in antiviral gene expression. 
6. Sixth, NS1 binds to and activates PI3K, a kinase that promotes cell survival, which is helpful in the face of attempts by the host cell to commit suicide. 
7. Seventh, a small portion of NS1 from some strains of influenza binds to PDZ domain-containing proteins DLG1 and LIN7C, thereby disrupting tight junctions between cells, and possibly helping the virus spread to other cells and tissues. 

It is simply astonishing that a small protein of 230 amino acids could do so much, and wreak such havoc.

Complete structure of NS1, colored by position in the protein, from the N terminal to the C terminal.

Portion of NS1 that binds to RNA, bound to RNA. The tiny stick molecules are  glycerol molecules from the crystallization mixture.

That is just a taste of the complexities that are known, and there is surely much else as yet unknown. But what to do about it? The current system of annual viral surveillance and specific vaccine production is routinely outsmarted by this tiny speck of a virus. We probably need a more serious program of vaccine research and testing from all parts of the virus, under the assumption that there may be epitopes not in the usually studied surface antigens that might be helpful in preventing infection, assuming that some cells manage to kill themselves and display the internal viral proteins to the adaptive immune system.

Likewise, study of all the virus products and screening of small molecule drugs against them in all their facets would be a significant research program directed to treat an infection once it has begun. This needs a broad approach that is possible with current technology, since it is hard to predict what all the functions of the virus are or which ones are most vulnerable in the body. The interfaces between the NS1 protein and its various targets are examples presenting many possible forms of therapy. Current drugs like Tamiflu are only modestly effective, if at all. This kind of commitment is something we should be doing much more actively as part of the NIH system. It would have higher and quicker payoffs than the war on cancer, while still at much lower cost.

• One reason that states have been going red.
• And going a little nuts.
• Scalia and the petulant right.
• Is willful stupidity part of the strategy? No, just a quest for bad government. Or no government.
• Next stop, civil war?
• Social Democracies do it better.
• War in Afghanistan ... between the Taliban and ISIS.
• On the duty to cheat on taxes.
• In appalling interview, the "reasonable" candidate Kasich vows to bring America together by supporting the Senate Supreme Court blockade.
• Bernie's economics are the real deal.
• Ideas matter.

Say's Law

The convolutions of economics, cranks, and class.

The class war has deep roots, and is fought on many fields, in many guises. One of the most interesting and influential is the field of economic theory, which as Paul Krugman persistently points out, has undergone startling episodes of battle, tide turning, and forgetting over the last century. One battle is over the meaning, interpretation, and validity of Say's law.

Enunciated by Jean Baptiste Say, who lived through the French revolution as an economist and businessman, and founded the first business school, the law states that production calls forth demand. If an excess of some good is produced, someone is sure to want it, at some price. More importantly, in general, if production in an economy increases, that production will be eagerly sold by its producers and bought by someone, even if the price might be less than expected. For instance, if a technological change makes it much cheaper to make computer memory, demand for that memory is sure to materialize, even as its cost and price go down. And if productivity decreases the prices of many goods, that allows consumers to buy more of other things, and have higher living standards. To some degree, this law makes assumptions about human psychology- that entrepreneurs meet a market, and that prices provide the flexible mechanism to bring supply and demand into agreement, pretty much at all times.

Unfortunately, Maynard Keynes claimed by the 1930's that Say's law was invalid. Then classical-minded economists tried to reclaim its validity by the 1950's and the debate has proceeded onwards, though mainstream economists give it little explicit credence these days. Its significance lies in the issue that if one grants that production can occasionally and on a wide scale be glutted, or demand be deficient in aggregate, that opens the door to solutions that come from elsewhere than the free, unfettered market- i.e the state as a manager of the macroeconomy. And this causes ideological heartburn to many on the right.

The Great Depression was an obvious case in point. Why did economic activity grind to a virtual standstill? The people still had the same needs they had before, and the skills, factories, and materials were the same as well. Yet a plague of unemployment and, frankly, deficient demand ripped through the economy causing misery for millions. Conventionally-minded economists, called "liquidationists" maintained that the financial fever would quickly work itself out if all businessmen cut their costs to meet the new (lower) demand, and if workers accepted the lower wages that they deserved given the reduced business conditions. A new equilibrium would be found at a new, if lower, level. Indeed, they argued that it was the perverse reluctance of workers to accept lower wages that led to the whole problem, preventing a new equilibrium from being achieved rapidly.

But we need to go back a step to the start of the process. How is it that business conditions could deteriorate so dramatically in the first place, if production always calls forth appropriate demand? Keynes didn't dispute that a supply-demand equilibrium, particularly of labor, would eventually be achieved, in the long run. But when? His quip was that in the long run, we are all dead. An event like the Depression, caused by a dramatic collapse of the financial system which drained wealth, consumption and investment, and thus effective demand out of a system whose actual, human demand was unchanged caused unprecedented misery, though milder depressions were common enough through economic history. This misery is prima facie evidence that Say's law is invalid in the short term in macroeconomic terms. Demand can be dramatically deficient, especially in modern economies with enormous financial superstructures whence investment and credit flow (or don't flow).

So why the continuing discussion? There are strong ideological forces at work. The Mises, Rand, Hayek, Austrian wing of the right, seeing themselves as the last pillars of human freedom, find it hard to accept that, into this breach of deficient demand should step the only actor with the wherewithal to do so: the state. Not only that, but the amelioration of the misery of the working class (though also the much more modest misery of the business class) by way of public works and other forms of macroeconomic management, (even including the printing of paper money in place of proper gold!), reduces the power of the employer class. Which is certainly relevant to the class war. This attitude is ironic, if one defines human freedom as the freedom of most humans, but that is how the class war works. It is the freedom of the upper, employer, feudal overlord class that concerns the Austrians and conservatives, not that of the workers who are dependent upon them. Under this system of thought, there can be no such thing as involuntary unemployment, there being always some work somewhere at some wage, for the worker willing to take it. If only workers were willing to be paid pittances, everyone could be happy!

Thus one gets quotes like: "The short answer is that there is still need and place to assert Say's Law whever anybody is foolish enough to deny it. It is itself, to repeat, essentially a negative than a positive proposition. It is essentially the rejection of a fallacy. It states that a general overproduction of all commodities is not possible. And that is all, basically, that it is intended to assert." - Henry Hazlitt, "The Failure of the 'New Economics'", 1959. Hazlitt's book is little more than a screed, but can still be found in my local library, proudly placed right next to Keynes' general theory, a sign of the seriousness with which it once was taken, and perhaps is, in some quarters.

Say's law was reflected more recently in the ideology of supply side economics, whose contention was that prosperity arises from unleashing job creators from taxes, regulation, unions, and other obstacles, so that production can increase and the benefits trickle down to everyone. Subsequent history has not been kind to this theory either, yet it remains the cornerstone of Republican platforms in this year's campaign, for obvious reasons of the class war.

Unfortunately, Keynes had an even deeper insight about Say's law, which was that even if the employers had their way, and reduced worker wages and positions as rapidly as they liked to bring their businesses back into equilibrium with demand, they would not, on a macroeconomic basis, be successful any more rapidly. As wages sank, so would demand, since over the whole economy, income equals demand minus savings. As income heads south in a massive depression, so would demand, in a downward spiral whose limit is reached when something changes in this dynamic- when money comes out of mattresses for consumption and capitalists eat into savings, setting a floor for demand, given the (reduced) stocks of money available.

How much more civilized if the demand can be made up before all the parties are reduced to extremis- if the state steps in with a tool kit that can include public works, tax cuts, reduced interest rates, and all the money required to make it happen, when the private financial system goes through one of its regular collapses. But that requires a state with great technical and moral resources. That was the work of the New Deal and the Greatest Generation, who not only won World War 2, but demonstrated in doing so that the state could dramatically re-establish demand through the economy and keep it going through efforts like building the interstate highway system and winning the Cold War.

One can argue whether the prosperity of that era was due to tremendous technological advances, the artifical demands generated by wars hot and cold, and / or the newly installed Keynesian macroeconomic management. But its wide demographic distribution was a matter of the power of workers, which was aided at the time by strong unionization and the Keynesian economic policy. These conditions required some decency on the part of the elite, to recognize their choice between reform and revolution.

The US has always been run by a rich elite, from the founding onwards. The question is whether these elites work for all, as Washington and FDR did, or for themselves, as the slaveholders did who wrote the evil lines into our constitution which took so much blood to expunge. The retreat and even forgetting of Keynes, under the assault from Milton Friedman, the Chicago school, and other ideologues of the right, which has resulted in the withering of the position of workers and the vast inequality seen today, results from a callous and short-sighted (not to mention corrupted) elite culture, mostly on the right, whose current candidates to a man (and woman) promote the interests of the rich in the most blatant ways, such as planning big federal deficits to give them money through the tax system.

So, we have to ask what is the point of freedom, and of the economic system. Governments are certainly capable of destroying freedom in a quest for economic and moral perfection (and power). At the same time an unfettered, unregulated capitalistic system destroys the freedom of its workers just as surely, ending up in feudalism. Predators are on every side. Say's law and the other ideological structures of classical and right-wing economics hide a presumption in favor of the capitalist, championing the freedom of the 1% while treating labor as a faceless, disposable commodity. We need a middle way, as exemplified by the mid-20th century compromise, and indeed the social democracies of Europe, where the democratic state acts as the balance-wheel to promote the freedom of all classes in rough proportion, as well as their prosperity.

• Continuing relevance and reaction to Keynes.
• The great depression before the Great Depression.
• The monetary straightjacket comes from abject and destructive fiscal failure.
• Message from the markets: We are looking at being Japan for the new decade or more, with little growth, especially in Europe. That is not good for any future-denominated investment. 
• Vulgar scientism, in economics.
• How to help Trump voters? Elect a Democrat.
• The Big Short, and what is legal.
• Low wages plus EITC plus food stamps ≠ American Dream.
• Koch enterprises.. the evil deepens.
• State of the UAW.
• State of the Russian economy.
• State of acid rain ... worse than it could have been.
• The Super Bowl halftime shows where America is going ... tie dye pinwheels and black power.
• Bill Mitchell on exchange rates and inflation.
• Quote of the week, on who is progressive.

"Twitter chatter aside, when it comes to judging who's more progressive than who, political scientists have an app for that—at least for those who've served in Congress, as Sanders and Clinton both have. It's the DW-Nominate first dimension, scaled from +1 to -1, which explains the lion's share of how members vote. For the two years when they served in the Senate together, Sanders had a score of -.717, making him far and away the most liberal member. Number two, Sheldon Whitehouse had a score of -.507, while number 15, Hillary Clinton had a score of -.403. The difference between Sanders' score and Clinton's was greater than the difference between Clinton and Evan Bayh, the second-most conservative member of the Democratic caucus at the time. So in short, the difference between them in terms of who is most progressive is both objective and huge."

• For instance, the Fed and Bernie Sanders.

Clean(er) Nuclear Power?

Thorium as a better nuclear power system.

The US has made progress reducing carbon emissions, mostly by substituting fracked gas for coal. This is not a long-term solution however, only cutting carbon emissions to half, instead of to zero. The climate needs more help faster, if the biosphere is to survive the anthropocene.

Renewable power sources have become economically viable, but not quite system-viable, since they are intermittent. Progress on grid-scale power storage has been very slow. The best power storage system remains gravitational water pumping/storage, which is available in relatively few places. In the absence of a good power storage and intermittancy management solutions, solar and wind energy simply can not be relied on for more than about 25% of grid energy. While most of the carbon emissions problem is one of public policy and communal action, this is an example of a remaining technical hurdle.

While I hope those issues are solved, the rest of the world, especially the developing world, keeps turning to coal, which is a planetary disaster. We need something better, in operational, economic, and planetary terms. One solution that has been floating around the margins has been nuclear power from thorium. We are familiar with nuclear power from enriched uranium- the pressurized water reactors that have been chugging away for decades both on the power grid and in aircraft carriers and submarines. (Related reactors) These reactors require quite a bit of uranium 235 (using the same systems as bomb-grade enrichment but to lower levels, and generate quite a bit of extremely long-lived waste, especially trans-uranic waste products like plutonium. Indeed, one of the reasons they were selected was that they generate plenty of bomb-making material.

On the other hand, there is another method of nuclear power generation, using thorium. Thorium is not fissile itself, and is four times as abundant as uranium, and doesn't need to be enriched. Indeed, there are virtually limitless supplies. Once placed in a running reactor and bombarded by neutrons, thorium breeds uranium 233 which is fissile, and generates power. The decay series of this isotope is far more favorable than uranium 235, in terms of making far fewer transuranic products, (fewer bombs), and allowing better recycling. Indeed, the ultimate amounts of long-term waste from a thorium reactor are about a thousandth of that from a U235 reactor. The reactor design is very hot, but unpressurized, and comes with safety features that significantly outstrip U235 reactors. (The gung-ho nerd-tube version.)

Since the main issues of conventional nuclear plants are safety and waste disposal, this is all very good news. How does it all work? A demonstration plant was built and run by the US in the 1960's, but was shut down because it did not provide a path to bomb making materials. This seems now a bit short-sighted, yet the basic principles were demonstrated. The main features are that the fissile fuel exists as a liquid rather than a solid, at rather high temperature (600˚C to 700˚C, which leads to higher electricity generation efficiency), and needs an extra circulating loop of another fluid to transfer heat to turbines. This second fluid has typically been lithium/fluoride/berylium mixture, (the same as the fuel, only without the thorium/uranium), of which berylium is particularly toxic. But apparently the berylium could be left out, so this might not be a necessary element of the design.

The fuel cycle is that unenriched thorium 232 is either included in the liquid fuel, or blanketed around the outside of the reactor. It captures neutrons which transmute it to protactinium 233, which decays in a matter of weeks to U233, whose half-life is 160,000 years. U233, the actual fissile fuel, is then burned to completion in the system, leading to various smaller waste products including noble gasses, cesium, strontium, and other elements whose longest half-lives are on the order of 30 years, (though quite toxic and hard to handle). Very little of the waste is up-converted to transuranic elements like plutonium and neptunium that are especially long-lived. Indeed so little is produced that such elements can be added right back to the fuel, along with recycled U233, to be destroyed by further fission. This assumes an on-site method of pyroprocessing or distillation that can separate the burnt waste from the fissile material to be recycled, to the tune of about 200 kg of fuel elements reprocessed per day. The overall cycle leads to far more efficient use of the fuel, however, hundreds-fold less waste, and particularly less long-lived waste relative to the conventional U235 reactor cycle.

A second significant problem is how to start these reactors, given the need to generate the U233. The Oak Ridge experimental reactor was seeded with U235, for instance. Starting up a fleet of such reactors from scratch would require quite a bit of our stockpiles of enriched uranium. And while melt-down is impossible, given the already melted state of the fuel and the ease of diluting it or spreading it to a non-critical state, it presents significant shielding and handling problems, like any nuclear reactor. Here is a point-by-point critique.

Time scales of the budgets of various elements in a thorium/U233 reactor. If initiated with transuranics like plutonium, (yellow), they would burn off to a low steady state by about 50 years. That level is a small fraction of the total fuel mass, and never needs to be disposed of as long as the reactor is running and its fuel is thoroughly reprocessed. Th=thorium, U=uranium, Pu=plutonium, Np=neptunium, Pa=protactinium, Cm=curium, Am=americium TMSR=thorium molten salt reactor.

The thorium reactor is extremely complex- there is no doubt about that. It is unlikely to be made into a plug-and-play system that could be transported to remote or undeveloped areas, or run with little expertise. It would take a decade or more of serious research to make practical utility scale designs and plants. Not only is there a great deal of high-temperature, high-radiation plumbing, but it needs onsite fuel reprocessing of materials that are extreme gamma emitters, and thus can not be handled directly, even with gloves. Additionally, parts of the reactor like key graphite neutron reflectors & heat exchangers would need to be replaced or refurbished every few years.

The current light water pressurized U235 reactor technology is also complex, and has proven itself to be highly problematic. It generates large amounts of unimaginably long-lived waste, demands large amounts of hard-to-enrich fuel, and has been demonstrated to be unsafe in the short and long terms, requiring heroic levels of engineering for utility use. This is what broke the back of current reactor technology around the world, making it economically inviable, despite the fact that a large fleet of plants are being run ever more efficiently (with due respect to the Fukushima and other disasters like Three Mile Island and the San Onofre plant in California.)

Compared with the tens of billions of dollars that have been spent on fusion power research, the thorium system is significantly more realistic, addressing the need for baseline power that is extremely pressing. Perhaps renewable power and power storage will be solved and take the place of fossil fuels. I certainly hope so- we need to get to zero carbon as soon as possible.

• Climate change is by far our most important problem.
• The Republican approach to solar power.
• Another cause of Flint- lax local news media.
• Financial reform... unfinished business remains.
• Shenanigans ... or fraud?
• Liar's loans are even coming back.
• The Sanders frame for political change.
• Sanders knows about MMT, which may be transformative.
• An excess of testosterone?
• Things really are better in social democracies.
• Economists in denial.
• Our friends in Afghanistan: "... officers and other members of the Afghan army are selling weapons and other materiel to the Taliban. U.S. military commanders and advisers say the practice is systematic and widespread."
• Government-enabled feudalism in IT.

Where do Morals Come From?

Objective, or subjective? And why are we having this argument?

What is good? What does it mean for something to be good? When you judge something to be good, do you look it up in a book? Many philosophers and especially theologians insist that what is good is not a personal judgement, or subjective, but is an objective state: a fact. Whether we properly recognize such facts is the main problem of humanity, thus they strain to train children in systems of "proper" objective morality.

It seems fair to say that most philosophers have promoted an objective view of morality, from Plato onwards. Religion has a great deal to do with this, as it posits an invisible world from which these objective facts flow, despite their unobservable and apparently non-objective nature. It also posits, in some versions, law-givers such as gods who are the identifiable source of objective good, whose commands we have but to follow to be and do good.

So a great deal of one's view of morality is going to depend on one's view of religion, and the plausibility of supernatural realms which somehow undergird reality and influence us, or at least the occasional prophet and teacher. One can also mention the social virtues of objective theories of morality, for if the ethical system is given and immutable, then the social system derived from it is likewise well-founded, and revolution becomes unthinkable.

On the other hand, the decline of religion and the rise of evolutionary theory to explain life and our own formation leads to drastically different theories of morality. It becomes a genetic/psychological mechanism for group sociality. And what we think of as its (our) flaws do not come from the interference of Satan, or insufficient attention to revealed scripture, but rather from a diversity of strategies that are cleanly and clearly modelled by game theory. Cheating may at first be rewarded, but then punished by policing, in order to attain a stable cooperating society with low, but inescapable, levels of defection and badness.

But even given an evolutionary theory, are morals subjective or objective? It is an interesting question. Optimal game theory strategies are not a matter of subjective choice- they just are, like mathematics (whether you regard mathematics as objective discovered systems or not). On the other hand, our personal judgements of value, while often agreeing with the findings of game theory, (hiring police, regulating vices, rewarding virtues), never originate there. They originate in our feelings about what is good, and what would be good for us in the future.

Prohibition is a classic example, when the US experimented with total abolition of alcohol. Alcohol was causing, and still causes, great harm, personally and societally. Yet it has positive moral and hedonistic functions as well, which turned out to be so strong that a vast criminal & popular underground developed to evade its prohibition. While unintended consequences destroyed Prohibition, the original policy (and moral stance) was born out of a great deal of pain, and the reasonable judgement that overall, we would be better off as a dry country. (Muslim countries are putatively dry today, for instance- for better or worse.) Would that the harms from global warming were as immediately apparent. The lesson is that morals are at base utilitarian, with respect to our perceived/estimated future happiness.

And game theory, while documenting strategies that evolution has time and again put into practice in our moral (or amoral) natures, does not say anything about what these strategies are actually aiming for. What is good to aim at comes, evolutionarily, from the axiomatic conditions & purposes of life: survival, flourishing, reproduction. That is why things that make us happy are so carefully engineered to also be good for us or for making more of us. The system has gone a little awry in our altered industrial & hypersocial environment, but the fact that there are 9 billion humans, swarming all over the earth, is testament to its success, at least in Darwinian terms, if not in moral terms. We are continually challenged to relearn and retrain ourselves, morally and otherwise, to accommodate this new world.

So does that mean that the evolutionary axioms are objectively good, and that our moral natures boil down to the "objective" goals of greed and power? Well, a funny thing happened along the way to biological complexity, which is that morality became intrinsically complicated, including quite a bit of cooperation, empathy, and other positive elements that allow societies to arise from individuals. Our moral natures are also implanted as intuitions and instincts, and whatever the underlying axioms might be, these natures function autonomously. That is our resource to judge and teach what is good, not a theoretical axiom of evolution, however explanatory that is in retrospect. Thus if we feel like adopting a foster child, in flagrant contravention of Darwinian selfishness, that is what we will do and judge good into the bargain.

This fundamental aspect of our moral instincts- the intuitive atoms of morality, as it were- means that whatever their origins, their expression is, to us, subjective. Moral judgement is not read from a book, or from the stars, but from our hearts. This applies to the objectivist argument as well. For when do people do (and think right) what others tell them, what game theory tells them, or what scripture tells them? Pretty much never. Divine command theory has never worked. While god may judge us in some morbid fantasy of the afterlife, we judge god the rest of the time, and the judgement has not always been positive (see the Book of Job). Scriptures, parents, and other cultural influences have their role, but it is to shape our instincts so that we become better judges, not to supplant them.

What remains is to explain why moral objectivity is so attractive and so common, including among philosophers. Firstly, it is simply operationally advantageous to decare that your judgements are not just an opinion, but objectively correct and factual. Talk about a successful power-play! States, upper classes, and religions have been playing this card from time immemorial, to great success. Nothing creates genocide quite as rapidly as a full-throated propaganda campaign about how execrable, subhuman, and depraved the target group is, given as fact. Or how divinely favored, deserving, and unquestionably righteous the perpetrating group is. The more objective the framing of each of these judgements is, the more powerful.

Secondly, like our cognitive illusion of a disembodied soul, we likewise have a moral illusion of being right for objective reasons. Our apparatus of feeling right about something, like a technical solution or math problem, extends to the rightness of moral judgements. Killing is simply wrong, right? Who could possibly doubt this? Yet what happens when killing becomes the highest calling and honor in a military situation? How objective was that after all? We then come up with caveats and legalistic rules / rationalizations that make great sense from an intuitive and utilitarian perspective. But we are simply exploring our feelings, not mapping an objective territory. Something that could be said about religion generally.

• Calculations of cooperation & morality.
• Democracy is fragile, is perishable, conflicts with capitalism, and needs help. Great talk by Yanis Varoufakis.
• How about making corporations pay taxes in the form of stock?
• Corporations as net savers ... a disaster for the future.
• Wall Street OK with Hillary, not so much with Bernie.
• The Taliban is still "negotiating".
• On idealism. FOX news hammered away at its ideals for years and decades, and it moved the needle on the whole political system. Sanders is FOX for the other side- agenda for the 99%.
• Screwing workers = "economic gains".
• Apotheosis of Republican "small government" in Flint ... if it was not already clear during Katrina.
• Zombie policy at the Fed.
• Tax cuts are Keynesian policy, done regressively and inefficiently.
• Fossil fuels were a unique economic multiplier of growth and living standards.
• Megafaunal overkill hypothesis gets more support.
• Bernie and (lack of) religion.
• This week in the WSJ: Peggy Noonan finally sort of gets Bernie. But can't bring herself to say the word... Occupy, which is when the 99% realized the game was rigged.

Where do Genes Come From?

How did DNA odds and ends become new genes in the human lineage?

Every new genome is like a jigsaw puzzle made from extremely modern, sometimes unrecognizable, art. Fitting the physical pieces together, out of millions of short DNA sequencing reads, is the relatively straightforward task and is done entirely by computers these days. Identifying genes encoded from that DNA, however, is a bit more difficult. This can be done partly by computers by looking for conserved sequences similar to genes or other genomic features known in other species. Yet there are always a bunch of left-over pieces- sequences, and possibly genes, that are novel in each species. A significant problem is finding such genes, which have no reliable structural signature, and may only become apparent with intensive functional studies based on what they do.

How do such genes arise from nothing, which is to say from the large amount of junk DNA lying about in the genome? Most genes arise by duplication and specialization, like the profusion of hundreds of olfactory receptor genes. But not all. A recent paper trolled through several mammalian genomes to look at the process of entirely new gene creation. The question is- how does random DNA get turned into a useful, transcribed, and translated gene?

The transcribed part is not so difficult, actually, since it has been found that most of the genome of any eukaryote is typically transcribed at a low rate. Not only genes, but all sorts of junk and useless DNA are transcribed into  messages that are quickly discarded. Apparently, the cost of low-level promiscuous RNA production is less that that of tightening down the controls to restrict transcription only to bona fide, gold-plated genes. And such noise may be an important evolutionary resource as well.

The authors gathered up lots of this transcribed RNA, sequenced it in bulk, and filtered for a minimum length (300 nt), from human, chimpanzee, and macaque, and mouse tissues. Running all this through a computer which condensed duplicate reads and compiled the distinct RNAs, they came up with about 100,000 candidate transcripts from about 35,000 candidate coding regions per species, substantially higher than the roughly 22,000 genes known to exist. They note that the noisy excess they find accounts for about 2% of transcriptional production, vs RNA production from known genes, so the extra transcription is low level, and pretty low cost. True gene regulation causes much higher rates of transcription, at least where and when expression is really needed.

The next step was to try to identify new, novel genes within this mess of noise. This involved discarding anything previously recognized as a gene, or related to genes in other species, by comparison to various sequence databases. This whittled the collection down to 634 in humans specifically, and 2,714 genes in humans, chimpanzees, or both (not shared with macaque or mouse). These are genes that seem to be regularly transcribed, at some length, but have not been previously recognized or annotated and are unique to their respective species. That is quite a lot, actually, for a few million years of evolution. What are they and where have they come from?

The researchers work quite hard to check whether these genes are expressed into proteins, and find evidence, for the human species, that only 21 seem to be translated. That does not mean that the others are not, but is a disappointing rate. They also find evidence for natural selection, in that the mutation rate these putative genes (though only the few that were validated above as being translated to protein) is lower than for junk DNA, indicating that it has adopted some kind of usefulness.

One theory for the origin of such novel genes is that they may come from existing gene regulatory regions that fire in both directions. Firing bidirectionally is quite common, but typically, only the downstream (sense) direction is conserved and useful, (i.e. the conserved gene), while the upstream sequences vary quickly through evolution and do not encode genes or anything else useful. In this study, they did not find any enrichment for close opposite-strand positioning of their de novo genes with existing genes, so concluded that conversion of such divergent transcripts to something useful was not a common mechanism of gene creation.

Occurrence of selected regulatory protein binding sites upstream of the putative genes. TSS denotes the transcription start site, and negative coordinates count the bases upstream on the X axis. Each regulator is noted at right, with a different color. While elevated, the frequencies hardly crack 1%, so again, this evidence suggests that only a small proportion of the collection of putative genes are actually regulated by these proteins.

What they did find was that certain DNA-binding protein regulator sites came up quite frequently upstream of the novel genes. These sites were for CREB, JUN, RFX, and M1/M2(TFIIB), rather common regulators. They also show that these sites are new just as the genes are, being typically absent from the same regions in the macaque genome, compared to the novel gene regions in chimpanzee and human. This leads to the theory that the random generation of such very short binding sites might have been the spark that originated these genes from unprepossessing DNA, after which they became more highly transcribed and attracted other regulator sites, some kind of function based on possible protein translation, and so forth into the Darwinian light.

Binding sites of the respective regulatory proteins, in logos format. This format indicates by the letter size how essential and selective a particular base is at that position of the protein binding site.

 
Unfortunately, none of their genes or proteins are more definitively assigned a function, and they dejectedly point out that the gene complements of organisms and lineages tend to be relatively stable, with lots of conserved genes, so that these novel (and putative) genes are rarely brought up to important/essential function, but rather keep being refreshed in a treadmill of molecular birth and death.

• Another paper on the translation of promiscuous transcripts.
• We need to fix the drug industry, with more public research, fewer patent protections, more negotiation.
• Theories of low growth.
• Median income in the US peaked back in 2000.
• Are we responsible for Egypt?
• Pakistan is a terrorist state.
• What good did Hillary do in foreign policy? "In the case of Clinton there hasn’t been a major foreign policy decision in the Middle East she pushed for that didn’t end up being a disaster both at home and the countries she advocated meddling in."
• Does realism mean that Hillary concedes all ideals in advance, or does idealism offer nothing but false hope because Republicans will never move? Which side is more astute?
• David Bowie has a bit of fun, miming other singers.
• Themes in evolution and economics.
• Annals of stuttering while black ...

Once Upon a Time, There Was (Not) a Ribosome ...

A new paper traces the history of the ribosome to its deepest origins.

The ribosome is one of the most precious relics we have. Not gilded or nicely framed, or even visible to the naked eye, but it shows, in its tiny structure, a past not a few hundred or thousand years ago as do our cultural relics, or many millions of years as do fossil skeletal relics, but a past over four billion years ago, around the very origin of life on Earth. While roughly three hundred quintillion quadrillion ribosomes exist in the biosphere, visualizing even one and understanding its workings has taken decades. 

Image of a complete ribosome structure. The large subunit RNA is in grey, the small subunit in turquise. Proteins stuck on the outside are purple and deep blue respectively, the 5S accessory RNA is towards the top in deep purple, and one tRNA is visible in the middle in orange. Note how exceedingly convoluted the RNA is.

Its convoluted RNA is both the contemporary site of protein synthesis in all cells, and a record of an extremely obscure past that preceeds many other key events in the history of cellular, or even pre-cellular, life, like the use of DNA for information storage, and the use of RNA as a temporary copy for that information. But how to read this record? That is a contentious question, which recent papers battle over. 

Frame from an animation that illustrates the structure and activity of the ribosome.

An animation from the ribosome wiki page illustrates its basic activities and structure. First, L-shaped tRNAs (dark blue, held by some helper enzymes in light blue) arrive at the cleft between the large subunit (green) and the small subunit (yellow), each bearing their single amino acid. Only the tRNA that matches the mRNA (black) codon held by the small ribosomal subunit gets to stay and lend its cargo to a growing protein chain, which emerges through a lengthy tunnel upwards and out the back of the large subunit. Eventually, since we are in this case making a secreted or membrane-bound protein, the emerging protein chain is captured by an adaptor which sends the whole ribosome over to the endoplasmic reticulum, (wavy black membrane molecules), where it docks to a channel that allows the new protein to be extruded right through the membrane as the rest of it is synthesized.

The main paper (by group A) provides a fascinating story of the origin of the ribosome, from the ground up, using a couple of structural rationales that allow them to deduce which portions of RNA structure come before or after others. The first rule is that existing RNA helices do not get disrupted by later additions. New additions tend to pop out orthogonally, as shown below, into new helices that are attached to the precursor, but don't disrupt its structure. Due to this phenomenon, the linear sequence of a ribosomal RNA is quite difficult to map onto to its three dimensional structure. Researchers tend to make startingly intricate diagrams to do so.

Growth of one small segment of ribosomal RNA, from bacteria (E. coli and P. furiosus) to eukaryotes (S. cerevisiae and H. sapiens). In blue is shown the bacterial core structure, to which in archaeal bacteria is added the green extension. Eukaryotes then added the orange and red extensions. Note how the extensions do not alter the preceding structures, but tack on either by lengthening existing helices or popping out orthogonally.

The second rule concerns interactions that later RNA segments can have with prior ones, the A-minor stabilization effect. While the RNA double helix is relatively stable, it can be further anchored by supportive hydrogen bonds from another base that swings into the minor groove from another helix. Examples are shown below:

One type of interaction where an adenosine from another helix (yellow) nestles close to a pre-existing duplex (blue), interacting with it by hydrogen bonds at several points and increasing the overall structural stability. This is one way to make something stable out of a lot of spaghetti-like RNA.

A more complex example of A-minor interactions that come from helix H-86 (yellow, green, brown) into the minor groove of helix H-75 (teal, grey). Note how some of the A bases (brown) are swung out of their own duplex to provide this interaction. Their partner bases have presumably found other interactions in the larger structure.

These rules make it conceivable to track one's way backward through the current enormous and complicated structure to its earlier precursors. The method can also be validated with a comparison between the eukaryotic and bacterial ribosomal RNAs, which clearly have an ancestral relationship that is reflected in just such structural expansions and new interactions, as shown above.

Another group (B) of researchers begs to differ, however, and published a disparaging paper about how these techniques are subjective and error-prone. This group appears to use more traditional phylogenetic methods, such as sequence comparisons, plus some kind of energy minimization, but claims that even using group A's stated methods, they would come to different conclusions. In particular, the crucial difference is whether the peptidyl transfer center (PTC), which is where protein synthesis from amino acids is actually carried out, was the first bit of the ribosome to exist (group A), or whether another part was primordial, a part that helps the ribosome rock between one tRNA and the next, an essential part of overall mechanism.

While I am no expert and have not delved into the details of each model, I would tentatively side with group A in this spat, and it is a very significant one. Their model of the ribsome beginning as a non-specific protein synthesizer makes sense in many ways. Their methods also make a more sense than sequence or structural stability methods used by group B that are fine for short-range phylogenetic work, but are notoriously off the mark when it comes to deep phylogenies, especially for RNA. group B also has tendecy to self-cite to a fault. On the other hand, whatever method one chooses, group B is right that it is quite a stretch, and perhaps ultimately subjective, how one gets to the very start of the process- the first few helices of RNA that began as the nucleus of the large ribosomal subunit. While an origin at the PTC is a very sensible proposal, even given the structural methods it is hardly incontestable.

Putting aside this conflict, the proposal from group A, which should be regarded as educated speculation, is an elegant model of ribosomal and translational origins. As shown above in the animation, the two ribosomal subunits work together but do very different things. The small subunit holds into the mRNA message, and thus the three-base codon end of each tRNA (technically, the anti-codon loop) which reads the message. The large subunit holds onto the other end of each tRNA, which is charged with an amino acid, catalyzes its polymerization into a growing protein chain, and conducts that chain out through a tunnel that keeps it from gumming up and folding prematurely. Each time translation completes, the two halves of the ribosome separate, indicating their functional and historical independence.

Thus the earliest stages of the proposed scheme have the large and small subunit evolving entirely independently. The primoridal large subunit's peptide transfer center is proposed to have been making uncoded, unspecific mini-proteins or peptides, possibly in a bid to create a cell surface, food storage, or some other function, even waste disposal. It goes without saying that all this assumes the existence of a pre-cellular RNA world, where RNAs have been functioning as enzymes and inheritance units, and perhaps other necessities, for some time. The proto-small subunit is in the simple business of binding to other RNAs, which is not an unlikely scenario.

The second step of the model is the key phase where the various partners come together. A nascent tRNA helix that had been carrying amino acids to the proto-large subunit for non-specific polymerization gains a helical extension that lets it mediate over to the proto-small subunit carrying short coding RNAs. Whether there were exchangeable, readable RNAs (what are now mRNAs) is doubtful at first, but just the ability to make a consistent protein product based on any code available, even the small subunit's own structural RNA, might have been an advantage. While this was happening, the exit tunnel from the peptide transfer center was also lengthening and tightening as the large subunit evolved, preventing fouling of the apparatus by newly made peptides.

Lastly, the small subunit adopted the switchable code mechanism, which made it a generic partner in the protein synthesis, presenting mRNA produced elsewhere. What the virtue of this might have been in an RNA world, without DNA, is a bit hard to understand, but assuming that such RNAs were specially marked, and not just anything floating around, this might have usefully expanded the protein repertoire. Then we are off in normal evoutionary directions, stabilizing the structure with added RNA and proteins, adding a multitude of factors that check-point the process with respect to starting and completing full protein chains, adding energy, allowing docking to membranes, increasing efficiency and fidelity, generating more mRNAs of ever greater complexity, installing DNA as the repository of mRNA codes, etc.

Interested readers are urged to read the original paper, which goes into much more detail about these steps and the various strucures involved. While speculative, this study opens very interesting vistas on the origin of life, on which the ribosome is such a valuable, if cryptic, window.

• We are killing the golden pollinators.
• High-end physics may have reached the end of the line.
• Virtual reality to the rescue.
• Corporations lie about climate change, and fund other liars.
• A tiny bit of thanks to anti-trust enforcement.
• Macro policy is empirically too tight.
• Yes, the Fed made a mistake. "Given that, the US Federal Reserve’s decision to tighten monetary policy looks like an important blunder."
• Stiglitz on the last year in global trade & policy.
• Republicans on poverty- absurdist postmodernism.
• Republicans blame others for their own terrible economic policy.
• How the class war gets waged and won, Martin Feldstein edition.
• A diagnosis of narcissism.
• Deconstructing Rubio.
• Kids for Trump, with Ameritude: warning, painful video.
• Krugman on inequality.
• A basic discussion of investment economics, savings, the zero bound, stagnation, and public spending.
• Indeed, the drop in oil investment is causing a macro slowdown, even though the savings in oil prices should be causing prosperity and growth. "U.S. capital investment—which never really recovered from the housing bust—has been hit particularly hard by cutbacks in oil-field capital expenditures. That took 44 basis points off real U.S. output in the first quarter of 2015, 88 basis points in the second, and 33 basis points in the third."
• And with oil prices cratered, there is no better or more important time for a carbon tax.
• Time to let go of the Saudis. But does that just open the door for others to make the Middle East even worse?