Saturday, August 30, 2014

Life's Deepest Divergence

Why do the membrane chemistries of Archea and Bacteria differ so much?

Hypotheses for the origin of life increasingly tend away from quiet ponds & soups and towards the more dramatic undersea vents with their billowing pumes of geochemicals. Life needs energy, and these have energy in abundance, in the form of chemicals rather than light, which took much longer to harness. Perhaps the leading current hypothesis speculates that a constant stream of highly reduced and alkaline brew of sulfides and carbon compounds allowed nascent chemical complexity to build up in this roiling, rocky boundary zone.

That may form the basis of another post. But one aspect of this theory is that membranes were relatively late to the party. Semi-isolated nodules / holes could occur in the rocky matrix that allowed just the right amount of flow of small metabolic chemicals while anchoring the larger organic, (pre-biotic) macromolecules. Only the transition to living free in the ancient seas necessitated increasingly tight membranes, cell walls, etc.

A recent paper uses this theory as the springboard for a theory for the divergence which is the deepest among currently living organisms- that between Archaea and Bacteria. Eukaryotes were an immensely complicated fusion of Archaeal and Bacterial cells which happened much later on, and is another story altogether. Archaea and Bacteria share a vast majority of core systems such as DNA-based genetics, RNA-based transcription and translation, ribosomes, circular DNA, lack of internal organelles, and most of the basic, carbon-based metabolism, with phosphate energy carriers on ATP and its relatives. They differ in their use of RNA polymerases (Archaea have three, as do Eukaryotes), in their transcription factors and histones (Archaea have histones, and more complex transcription factor system, simlar to that of Eukaryotes), and in details of DNA replication. Their cell walls have different chemistries, and most oddly, their membranes have quite different chemistries. It is noteworthy that Archaea tend to inhabit the most extreme environments of temperature, salinity, acidity, etc., suggesting that they may reflect their ancient heritage in ecological terms more so than do Bacteria.

The chemistries of membrane lipids are strikingly different between Archaea and Bacteria. The lipid, head group, and linkages on either end of the glycerol core are each distinct.

Membranes have magical properties. In modern organisms, they keep all large molecules, and many small ones, out of the cell using only the thinnest layer of two molecules- the bilayer. This bilayer molecule has a charged or polar headgroup (the P and glycerol / 3-C backbone above) which keeps water happy on one side. And it has fatty tails, which is to say long (CH2)n chains, which make water very unhappy, and form the stable center of the bilayer sandwich, which repells all sorts of charged ions as well as water.

Since such a membrane seals out ions, which are the life-blood of metabolism and of life in general, such a membrane presupposes a large cast of (protein) ion channels which allow selected ions in/out, or in advanced cases, pump them actively. Thus the well-sealed membrane can not have been a terribly early event in the story of life. The current authors propose that early membranes were quite different, and quite leaky, establishing the sort of partial, controlled traffic that the earliest cells needed to replicate or supplement their early rocky homes. Thus the transition to tightly sealed membranes occurred later on, after life had gotten quite far along, and after the Archaeal / Bacterial split.

What are these reactions that could happen in a leaky cell, at a sea-floor vocanic plume? To introduce this requires take a brief detour into the chemiosmotic theory- one of the most elegant and significant theories in biology, after those of evolution and DNA structure. ATP had long been known to be the basic energy currency of biological organisms, being converted to ADP and AMP in a constant cycle of re-use. But in 1961 Peter Mitchell proposed another biological energy currency- electricity in the form of ionic differences around membranes. The issue was where the cell's ATP charging capacity comes from. It seemed localized to mitochondria in Eukaryotes, but the mechanism was unknown.

An ATPase in the mitochondrial membrane diligently manufactures ATP from the chemical burning of food that happens in the mitochondrial matrix, but how the energy from the one process fuels the other was quite mysterious. And when this ATPase was studied more closely, the mysteries only piled up. It is an ion transporter, of H+, of all things, and is present in all cells, indeed conserved from the original ancestor of all life. It can break up ATP (giving it the "-ase" name) in the lab, when spinning freely with no H+ gradient, but in real life it is tightly stuck and oriented in the (inner) mitochondrial membrane, using the significant H+ gradient across the membrane as its fuel to run in the opposite direction, synthesizing ATP. And that is the heart of the story. The mitochondrion acts like a battery, in that its ATP production driven by H+ pumping is indirectly coupled the H+ production that is a product of glycolysis and the Krebs cycle elsewhere. In this way, the Krebs cycle can do its thing, at its own rate, and build up the fuel of high H+ outside without having to be physically linked to the ATP-producing enzyme complex. This concept also applies to chloroplasts and to all non-Eukaryotic cells. As weird as it seemed for cells to be spending their hard-earned fuels just pumping protons willy-nilly into the outside (i.e. into the ocean for single-celled organisms), the energetics work out. The cell (or mitochondrion for Eukaryotes) is a tiny battery.

That is the closely coupled system with an internal H+ generation system and a tightly sealed membrane. But suppose we are at an earlier stage, when energy didn't come from a well-worked out internal food-burning Krebs cycle, but from a kind of arbitrage on outside chemical gradients? Then having a sealed membrane would be counter-productive. The scenario the authors envision is where a proto-cell is lodged in the rocky vent matrix, with geochemical fluids passing on one side, at, say pH 10, and sea water on the other side at, say, pH 7. A three pH unit difference is very large; enough free energy to do a great deal of work, if harnessed to an ATPase that runs off the H+ gradient.

Author's model for their simulations, where the lower flow is the alkaline geochemical vent product, and the upper half is sea water, more or less. The wide H+ gradient between them provides energy to the green ATPase that produces ATP from ADP.

In this scenario, the membrane needs to be semi-permeable to allow all the ions to pass. Its only real role is to tether the ATPase, which the authors assume still conducts H+ orders of magnitude more readily (while generating ATP) than the semipermeable membrane does. The authors run numerous simulations of permeabilities, pH gradients, ATPase concentration, and of ancillary ion transporters. For example, as proton permeability declines, the usable gradient declines to zero, since even as the ATPase uses the protons coming in, they have no where to go back out of the cell, nor can OH- ions come in to neutralize them. (Run your own simulations using their software!)

"However, 1%–5% [surface area of the membrane covered by] ATPase in a leaky membrane (10−3 cm/s) retains a −ΔG of close to 20 kJ/mol. With 3–4 protons translocated per ATP synthesized, this gives a −ΔG for ATP hydrolysis of 60 to 80 kJ/mol, similar to modern cells and sufficient to drive intermediary biochemistry, including aminoacyl adenylation in protein synthesis."

As membrane permeability declines (colored cases), the energy available via the simple H+ gradient (Y-axis) drops to zero with time through the simulation (X-axis).

The next innovation is to introduce a Na+ / H+ antiporter, which is a protein in the membrane that exchanges sodium for protons 1:1. This is electronically and typically energetically neutral, but has dramatic effects on the ability of this protocell to manage its permeability and use the H+ gradient. Sodium has much greater difficulty getting across even a leaky membrane than the smaller H+. I should note that the authors assume that the ATPase can use Na+ as well as H+, which has some plausibility given the primitiveness of the system. They also assume that all their protein transactions only happen on the acid (sea water) side of the cell, which is much less plausible. Given the high H+ gradient from the acid side of the cell, it drags Na+ out, creating a supplementary gradient of high Na+ outside to inside, which the ATPase can use, in addition, to the protons, to generate ATP.

The net effect of all this is three-fold. It immediately raises the available energy of the H+ gradient by about 50%. It also sends the cell on a selective trajectory towards sealing its membrane, since the ion flows can now be managed entirely through the proteins in the membrane, and the H+ gradient yields more energy the more H+ are funneled through the ATPase. Lastly, it favors the generation of active H+ and Na+ pumps that expel these ions under some conditions, such as metabolic energy from light or from eating other life forms. Naturally this sets the stage for freeing the nascent cells from the vent ecosystem, if they can find another source for H+ gradients, i.e. food.  It also incidentally explains the universal property of our cells having very low Na+ concentrations, though our ionic levels otherwise approximate those of sea water.

When a Na+ / H+ antiporter (SPAP) is present, the energetics of the H+ gradient improve markedly in the author's simulation. But the effect is available only at highly alkaline conditions (graphs B and C).
"Crucially, SPAP [sodium / proton anti-porter] is also a necessary preadaptation for the active pumping of protons, and for decreasing membrane permeability towards modern values. Whereas pumping H+ in the absence of SPAP gives no sustained benefit in terms of −ΔG, the presence of SPAP in a leaky membrane allows pumping of H+ to pay dividends. −ΔG now markedly increases with decreasing permeability, for the first time giving a sustained selective advantage to higher levels of pumping and tighter membranes."
With the Na+ / H+ anti porter present, and with an additional pump (powered by some kind of novel metabolism) that exports H+ or Na+, dropping the permeability of the membrane (X-axis) pays consistent dividends (blue).

Needless to say, if tightening the permeability of the cell membrane was a later development after so many other critical mechanisms (genetic coding, enzyme production, leaky membrane maintenance, crude energy metabolism) had developed, then it stands to reason that the principal chemical components of the modern biological membrane might differ between forms of life that had already diverged into what became the two earliest domains of life.

The paper is a bit unclear, though reading the methods helps tremendously, supplying needed detail and organization. The overall scenario for the origin of life in these very dynamic and energy-rich settings is reasonably persuasive, and it is good to see people taking the next step to figure out how nascent cells might have gotten over some of the notable humps of the process.

"Our findings allow us to propose a new and tightly constrained bioenergetic route map leading from a leaky LUCA [last universal common ancestor] dependent on natural proton gradients, to the first archaea and bacteria with highly distinct ion-tight phospholipid membranes. These bioenergetic considerations give striking insights into the nature of LUCA, and the deep divergence between archaea and bacteria."

Saturday, August 23, 2014

Das Krazy Kapital

Reflections on Marx's economic text, Das Kapital.

Well, his heart was in the right place. After the French revolution and its complex aftermath had gone grievously astray from its égalité promises, Marx decided that the immense wealth generated in the epoch of industrialization was going to finally be sufficient to bring the utopia to pass. If only it were rationally organized! I am working from a classic heavily abridged edition put out by the Modern Library and edited by Max Eastman at perhaps the height of Communist respectibility in the English speaking world, 1932.

It is very hard to believe that this book launched a thousand demonstrations, millions of AK47's, dozens of dictatorships, and a century of misery for millions of people. It shows the incredible power of confident obfuscation and false hope. Yes, religions have known this forever, but still, having it framed in this pseudoscience-y way really hurts. It reads like a crank manifesto, with occasional gems of lucidity set within a vast heap of intellectual-sounding blather. Quite a bit of time is spent creating cracked accounts of national income, profit and loss, the circulation of capital, etc. The bottom line is that Marx was in no way an economist, but a polemicist and propagandist of great political rather than economic acuity. His work on the 18th Brumaire, not to mention the Communist Manifesto itself, far transcends his economic work, even if Das Capital contains a few seeds of economic insight.

His touchstone is the conviction that all surplus value comes from labor. Nothing else "makes" money. Not the free resources lying on the ground, not the inventiveness of the entrepreneur, not the far-sightedness of the capitalist, not the marketing & trading accumen of the merchant. Every dollar that the capitalist makes is on the back of some laborer who is made to work partly for his own bread, and during the balance of his employment time, for the capitalist. It is one of those great monomaniacal theories of everything that the monomanic batters like a ram through every wall of reason's ramparts.

The surprising thing is that he does provide a rather sensible (if exceedingly brief) presentation of one aspect of the opposing view at the time:

"The French economist Condillac wrote in 1776, in an essay on commerce and government: 'It is false taht, in the exchange of commoditiies, equal value is given and obtained. The contrary is true. Each of the two contracting parties, invariably gives a smaller value for a greater one ... Why? The value of things resides solely in their relation to our wants
Exchange value appears primarily as the quantitative relation in which values in use of one kind are exchanged against values in use of another kind. A definite quantity of one commodity is regularly exchanged for a specific quantity of another: that constitutes its exchange value- a relation which changes constantly according to time and locality. Thus does exchange value seem to be something accidental and purely relative, i.e. (as Condillac expressed it) it seems 'to consist solely in the relation of the commodities to our wants.' A value in exchange inherent in commodities appears thus an impossibility. Let us consider the question more closely. 
[... there follows a couple of turgid pages of implausible sylogisms ...] 
Thus it is only the quantity of labor or of working time socially necessary for its production which determines the exchange value of a commodity."

So Marx starts in reality, and ends up in his own private world of economics, which, being volume 1, chapter 1, forms the premise of everything that follows, more or less. While all this is flattering to the worker, and conducive to a labor-centric and mechanistic view of economics, it is nevertheless so far from reality that one wonders how anyone could possibly read onwards. But there are certainly flashes of interest, such as damning quotes from earlier writers:

"As early as 1696 John Bellers says: 'For if one had a hundred thousand acres of land and as many pounds in money, and as many cattle, without a laborer, what would the rich man be, but a laborer? And as the labourers make men rich, so the more labourers, there will be the more rich men ... the labour of the poor being the mines of the rich.'  So also Bertrand de Mandeville at the beginning of the eighteenth century (1728): 'It would be easier, where property is well secure, to live without money than without the poor; for who would do the work? ... As they ought to be kept from starving, so they should receive nothing worth saving. ... it is in the interest of all rich nations, that the greatest part of the poor should almost never be idle, and yet continually spend what they get ... for as too little will, according as his temper is, either dispirit or make him desperate, so too much will make him insolent and lazy. ... it is requisite that great numbers of them should be ignorant as well as poor; knowledge both enlarges and multiplies our desires, and the fewer things a man wishes for, the more easily his necessities may be supplied."

Well, this certainly lays it all out, eh? Labor is certainly a necessary ingredient to all economic activity and wealth. But its value is devilishly hard to measure, indeed impossible most of the time, and all sorts of other activities in the economic (and governmental) system both create and destroy value. But Marx presses on...

"There is not a single atom of its [capital] value that does not owe its existence to unpaid labor. ... When viewed as a transaction between the capitalist class and the working class, it makes no difference that additional labourers are employed by means of the unpaid labour of the previously employed laborers []. The capitalist may even convert the additional capital into a machine which throws the workmen who made it out of work, and which replaces them by a few children. In every case the working class creates by the surplus labor of one year the capital destined to employ additional labor in the following year. 
The accumulation of the first additional capital of $10,000 presupposes a value of $50,000 belonging to the capitalist by virtue of his 'primitive labor', and advanced by him. The second additional capital of $2,000 [all this assumes an annual return/profit of 20%] assumes, on the contrary, only the previous accumulation of the $10,000 of which the $2,000 is the surplus value capitalized. The ownership of past unpaid labour is henceforth the sole condition for the appropriation of living unpaid labor on a constantly increasing scale. The more the capitalist has accumulated, the more is he able to accumulate."

Well, well- shades of Thomas Piketty. Of course, the self-perpetuating nature of wealth and privilege was hardly news in his day any more than in ours. Marx gives it a faux-quantitative gloss by way of a wealth of assumptions, but loses in the process virtually everything of interest about the capitalistic system.

Marx did see other self-feeding aspects of the process, such as the way fewer workers end up doing more work:

"The production of a relative surplus population, or the setting free of labourers, goes on therefore yet more rapidly than the technical revolution of the process of production that is accelerated by the advance of accumulation; and more rapidly than the corresponding diminution of the variable part of capital as compared with the constant.[]  In proportion as the productiveness of labor increases, capital increases its supply of labor more quickly than its demand for laborers. The over-work of the employed part of the working class swells the ranks of the reserve, whilst conversely the greater pressure that the latter by its competition exerts on the formaer, forces these to submit ti over-work and to subjugation under the dictates of capital."

He spends some insightful pages on the transition from feudalism, where the lower classes had some right to sustenance and to land, at the cost of freedom and low status, to the modern system of private property, where the former feudal owners may have cleared the estates of farmers in favor of sheep, and in any case took ownership in the radical modern notion untethered by any social obligation. The poor were then turned into "independent contractors", i.e. sharecroppers, or out entirely to form the proletarian army of the industrial age.

"The laborer could only dispose of his own person after he had ceased to be attached to the soil and ceased to be the slave, serf, or bondman of another. To become a free seller of labour power, who carries his commodity wherever he finds a market, he must further have escaped from the regime of the guilds, their rules for apprentices and journeymen, and the impediments of their labor regulations. Hence, the historical movement which changes the producers inot wage-workers, appears, on the one hand, as their emancipation from serfdom and from the fetters of the guilds, and this side alone exists for our bourgeios historians. But, on the other hand, these new freemen became sellers of themselves only after they had been robbed of all their own means of production, and of all the guarantees of existence afforded by the old feudal arrangements. And the history of this, their expropriation, is written in the annals of mankind in letters of blood and fire."

Again, Marx's strength is not in accountancy and technical economics. It is in broad social critique with historical awareness and incendiary sarcasm. To finish up, I'll add a quote on national debt, showing a bit of Marx's woozy analysis while he has his finger on something truly important. Something Alexander Hamilton, for example, understood far better.

"The system of public credit, i.e. of national debts, whose origin we discover in Genoa and Venice as early as the middle ages, took possession of Europe generally during the manufacturing period. The colonial system with its maritime trade and commercial wars served as a forcing-house for it. Thus it first took root in Holland. National debts, i.e. the alienation of the State- whether despotic, constitutional, or republican- marked with its stamp the capitalistic era. The only part of the so-called national wealth that actually enters into the collective possessions of modern peoples is thier national debt. 
The public debt becomes one of the powerful levers of primitive accumulation. As with the stroke of an enchanter's wand it endows barren money with the power of breeding and thus turns it into capital, without the necessity of its exposing itself to the troubles and risks inseparable from its employment in industry or even in usury. The State-creditors actually give nothing away, for the sum lent is transformed into public bonds, easily negotiable, which go on functioning in their hands just as so much hard cash would. But further, apare from the class of lazy annitants thus created, and from the improvised wealth of the financiers, middlemen between the government and the nation- as also apart from the tax-farmers, merchants, private manufacturers, to whom a good part of every State loan renders the service of a capital fallen from heaven- the national debt has goven rise to joint-stock companies, to dealing in negotiable effects of all kinds, and to agiotage [speculation and stock manipulation], in a word to stock-exchange gambling and the modern bankocracy."

Marx goes on for a couple of pages of meandering outrage, but fails to clearly analyze the nature of this particular beast. Which basically goes for the rest of this work as well.

I guess the real issue is that money and its concentrated form, capital, has a somewhat mesmerizing physicality which misleads us into thinking that it constitutes something intrinsically valuable and real. But it is a notional / legal accounting for labor and other goods owed- a matter of credit to its very core. If the future workers on whom this claim is made fail to see the claim as legitimate, due to any number of causes- the corrupt way it was concentrated, the age-old privilege and unjust social rules that give it to the idle and worthless- then they may revolt against this entire system of accumulated credit and decide to work for themselves instead.

Unfortunately, the extreme complexity and lack of resilience of the existing economic system makes blowing it up virtually unthinkable. We are all enmeshed in it, and can not imagine reconstituting even its most essential operations with any speed from new principles and with new actors. Thus the choice of revolution is the direst and most destructive extremity. Our real choice is typically between sclerotic decline at the hands of incumbent receivers of rent, (and social and political power), or continuous reform driven by those who have power and both understand the system thoroughly and are disinterested enough to wish for its general and durable prosperity. Which is not an easy combination to attain, now or ever. Communism's most enduring, positive legacy was to serve as the spectre that prodded reform in the liberal West, towards the modern regulatory, social welfare, middle class state. But no sooner did that spectre vanish at the end of the cold war than the old forces of rapacious capital retook the fields of ideology and power.

"More than 90% of the young black men killed by gunfire today are not killed by police but by other black men."

Saturday, August 16, 2014

Soup to Silk- How do Spiders do it?

The molecular magic of spider silk production.

One might think that spiders would be an important tool in agricultural pest control. But that doesn't seem to be the case. Like cats, they can't be herded around, and probably are not so interested in the usual aphids, borers, hoppers, and other banes of typical crops. And they get killed off by pesticides even more than the target insects ... the usual horrorshow.

But they are amazing creatures, with stunning design sense, incredible patience and persistence, acrobatic eight-leg coordination, parental instincts, and WWE-worthy mating rituals. Their silk is as strong as high-grade steel, but one-sixth the weight, and comes in numerous varieties, from soft egg protecting, to sticky prey capture, to strong dragline support. Each type comes out of a separate gland and spinneret from a protein brew that is clearly quite special.

Anatomy and specialization of spider silk glands.

There is no spinning involved ... silks are secreted in a high-tech/nanotech process that magically transforms a gooey protein solution into finished silk, ready for the spider to dangle from in mid-air. A recent paper extended a good bit of prior work that shows that a key transformation of the extrusion process is performed by pH- the gradual acidification of the protein solution as it is drawn down the quite lengthy gland, causing crucial changes in the protein components.

Dissected spider silk gland, with secretion and storage gland in yellow and the duct to the outside spinneret in tan. Measured pH values are noted, though measuring in such tiny spaces is difficult and impossible in thinnest parts. So pH values are very approximate, and thought to be a bit lower farther down the duct. Bar is 1 mm. This is the major ampul late gland from Nephila clavipes.

Those proteins are called spidroins, and they are all similar, with variations due to evolutionary divergence. The front and back ends (N- and C-termini of the proteins, respectively) are complex conserved protein domains, while the middle is a highly repetitive alternation of alanine-rich and glycine/proline-rich segments. The alanine-rich segments fold into very strong, almost crystalline, structures called beta-sheets (yellow, below), while the glycine/proline segments form a jumble of turns and tight 3/10 helices. The detailed structure of spider silk is thus a sort of spaghetti interspersed with bundles of uncooked ramen- however, ramen that is intensely crosslinked within its block.

Calculated structure of silk protein after production, with beta sheet structures in yellow.

Calculated structure of silk protein after production, and after stretching just short of breaking.

When pulled, the tangles smoothly stretch to maybe twice their resting length, and ultimately all the beta sheet segments align with the direction of pulling. The key to all this is the hydrogen bond, which is only a tenth to a twentieth as strong as covalent chemical bonds, but when added up over a clever structure full of them, in hierarchical fashion, you get very high strength. In constrast, high-strength fibers like Kevlar or cellulose are fully covalent molecular strings. It is a bit like velcro, where if you have a big enough structure made out of it, it can hold a great deal of weight, even though its individual bonds are weak.

Cartoon of spidroin proteins during extrusion. The dimerized C-terminal domains are in red, while the blue N-terminal domains dimerize only while the proteins are underway through the "spinning" duct, principally under the influence of acidic pH. In this paper, the authors propose that the C-terminal domains do not remain dimerized, but change structure as well, binding to the bulk of the protein's beta sheets while underway through the duct.

"Along the length of the duct, Na+ drops from 3.1 mg g−1 dry weight in the ampulle (where the spidroins are stored) to 0.3 mg g−1 in the fiber, and K+ increases from 0.75 to 2.9 mg g−1 (6). Phosphate concentration also increases at least 5-fold, whereas flow velocity and shear force increase (especially near the end) because of the tapered geometry of the duct (5, 7). Importantly, pH drops from 7.2 in the storage region to 6.3 in the first 0.5 mm of the duct and reaches an unknown value by the end of the ~20-mm duct (8). Collectively, these chemical and physical forces induce the spidroin molecules to align with the direction of flow, form β-sheets, and partition out of the aqueous phase to form a solid fiber"

The spidroins have to join together in a controlled & rapid way, so they don't solidify before coming out of the spinerett. The C-terminal ends of the protein join together into dimers immediately after being synthesized. This paper provides evidence that the C-terminal domain switches dramatically from its alpha-helical dimeric structure in the gland, to something more amyloid-like with beta sheet structures that interweave with and help organize the bulk of the internal repeats as the solution passes down the acidifying duct.

The C-terminal domain re-organized dramatically when pH is lowered. The Y- axis here is the fluorescence of a chemical that binds to beta sheets specifically, indicating that this protein segment, which is originally largely alpha-helical, switches to a beta-sheet conformation, more rapidly as the pH is lowered.

The N-terminal ends undergo a constrasting transformation. They do not dimerize in the storage gland, ensuring that the solution, though highly concentrated, does not turn solid. However as the solution gets pulled down the duct, it gets progressively acidified, which causes the N-termini to dimerize. The solution also gets exposed to a few other ionic changes and squeezing/pulling force that cause the nano-elements to line up and helps them bind to each other. The new paper focuses on this acidification process, finding that the enzyme carbonic anhydrase, which generates carbonic acid from water and CO2, is concentrated all along the duct. With the duct's length and narrowness, it appears that the pH of the nascent fiber plunges down from about 7-8 in the gland to some unknown value far below 5.5 by the time it comes out, sterilizing the silk as well as fashioning it structurally into a fiber.

Cross-sections of some sample silk ducts, stained for cells (blue) and for the acidifying enzyme carbonic anhydrase (black dots).

One might ask, if purely ionic and pH effects generate silk from soluble proteins, why doesn't the silk melt again in the morning dew or any time pH rises again? One answer is that external pH of dew and open air is slightly acidic, due to the ambient CO2, so conditions are typically favorable. But mostly, it is a matter of hysteresis / tangling, where a process that easily goes in one direction has great difficulty going in reverse. Silks need to be boiled in alkaline solution to melt, and even then they are a rather tangled mess, difficult to use for other purposes.

"In summary, the spidroin N- and C-terminal domains show synchronous and opposite structural changes in response to the physiological conditions of the spinning duct. CT unfolds into β-sheet nuclei that can trigger rapid polymerization of the spidroins, whereas gradually locked NT dimers alleviate the need for rapid diffusion, firmly interconnect the spidroins, and allow for propagation of pulling forces along the peptide chains. These events are driven by CO2 and proton gradients that ensure temporal and spatial confinement of the divergent structural changes of CT and NT. This novel lock and trigger mechanism elegantly explains how silk formation can occur at a very high speed, more than 1 m/s, and at the same time be confined to the very distal part of the spinning duct."

A good deal remains mysterious, but it is fascinating to learn bit by bit how amazing things such as silk production happen. What seems like magic turns out, as usual, to have very material, explicable, and interesting tricks behind it.

"Mr. Ryan's plan is a better solution and a win for both sides of the aisle. Democrats can point to a progressive tax policy that provides substantial gains for low-income workers, and Republicans can boast of raising wages without burdening employers."

Saturday, August 9, 2014

Where is the Social Value in Economics?

What do we lose when money is the only thing that talks?

Reading the Arthurian tales of Sir Mallory, one is struck by the essential political nature of economics, at least its economics. Those who are in, get money and lands. Those who are out, have them stripped. It really puts the political into political economics. The Norman conquest of England was a decidedly non-romantic example of this, with all the plum estates going to the French invaders. Today, economics has been on a centuries-long quest to remove politics from economics, making of our society a mechanism of pure market and money relations. While that process has many advantages, it is very destructive to social structures that were so rich in times when economics was a by-product of the main priority, which was political and social standing.

We get the benefit of money talking ... that anyone can go to a restaurant or hotel and be served, no matter what their social standing. We get reductions in corruption, and increases in economic efficiency, as business decisions can be made without reference to politics or other considerations. We get the freedom of creating businesses to address the most varied and obscure needs, and of being customers on the receiving end. On the other hand, social standing has become itself a creature of money, rather than of other virtues. Our politics have become a chase for money, rather than the reverse. There are advantages on both sides, but the new system only works if money really rewards activities that are socially virtuous. And that is highly questionable.

These days, money derived from crime, from financial fraud, from legal tax evasion and corporate cronyism and abuse of customers and employees, from environmental pillaging ... all smells as sweet as money from government service, nursing care, or technological innovation. Economic distinctions are no longer made on the basis of virtue, and indeed the most nurturing professions are typically paid the worst while the most pathological are paid best. Perhaps that is because normal people are unwilling to undertake, or unskilled in, the darker arts of making money the modern way, such as evading the law in every possible way, destroying every unwritten bond of civility and trust among companies, customers, and employees, and lying about it as a matter of course through public relations.

Surely it is difficult work. Does that mean it should also be well-paid work?

While economic efficency by way of ruthless capitalistic competition is a good thing in many ways, our society could use extra mechanisms to reward socially beneficial work, (and discourage harmful pursuits), beyond the current motivators of self-satisfaction, the occasional medal, and a smattering of non-profits and government functions dedicated to non-market goods. The applicable negative motivators are typically regulation and legal prosecution, which are surely good but woefully insufficient.

The classic and brutal way to align social and economic objectives is to nationalize everything, and have the state direct all work with its social goals first in mind. China exemplified this method until giving in and going with the capitalist system in the 1980's. It is just not a practical method of organizing a large economic system, or even a small one, really, with its lack of proper information leading to poor and arbitrary decisions, even if well-intentioned. It is conceivable that an eventual computerized economy might correct this defect and allow planning at the requisite scale and detail. But since the core issues and drivers are human desires, frequently of the most inchoate nature, this is still unlikely.

Another method one might consider is to pay everyone the same. Competition could take place on many other levels, such as power, pleasantness of work, spiritual reward, etc. But the take-home pay of everyone employed in the economy would be the same, and if work does not generate enough money to pay that wage, that work would, and probably should, remain undone. I think that there are a lot of good points to such a system. It diverts competition to far more interesting and rewarding aspects of life and work than money at the same time that it provides dramatic fairness across the economy. The current pay structure is far more socially constructed than the ideology would have it, and far less tethered to anything like "worth" or "performance". Would the flow of talented people going to Wall Street to waste their lives be as torrential if the pay were not an issue? But it is also impractical since, as we see in the political system, pay can be rendered in many forms, under the table, etc. And what to do about investment income, entrepreneurs, self-employed novelists, and all the other forms of making a living? It would become a serious mess, though perhaps not so much more of a mess than our current tax and income system.

Something more modest might be a more active taxation scheme that relieves those in beneficial professions from taxation while raising taxes on those in socially damaging professions. The government would develop a massive schedule of lines of work, and each line would be assigned some appropriate tax rate. But how? It might be conceivable to do this in a democratic fashion by adding an extra poll to the census that asks people's opinions of various lines of work. Such a popular opinion of everything from lawyers (perhaps by sub-type) to fast food workers to defense contractors could be used to put a number on that profession's overall social benefit index, used to figure its tax rate. Unfortunately, there are an infinite number of types of work, and different conditions within each, making such blanket judgements highly suspect, even if a popular poll were not involved.

So we are left with nibbling around the edges of the great capitalist monster, with Pigovian interventions such as a hefty Tobin tax on all financial market transactions, which would dampen the bonfires of Wall Street. And taxes on carbon, cigarettes, strong regulations against financial fraud, etc. And of course strong Keynesian and supplementary policies that insure employment for everyone at a decent living, whether private or public. But more should be done, and squaring that circle is a great continuing project in political economics.

The bourgeoisie, wherever it has got the upper hand, has put an end to all feudal, patriarchal, idyllic relations. It has pitilessly torn asunder the motley feudal ties that bound man to his “natural superiors”, and has left remaining no other nexus between man and man than naked self-interest, than callous “cash payment”. It has drowned the most heavenly ecstasies of religious fervour, of chivalrous enthusiasm, of philistine sentimentalism, in the icy water of egotistical calculation. It has resolved personal worth into exchange value, and in place of the numberless indefeasible chartered freedoms, has set up that single, unconscionable freedom — Free Trade. In one word, for exploitation, veiled by religious and political illusions, it has substituted naked, shameless, direct, brutal exploitation.

Saturday, August 2, 2014

91.8% of the Human Genome is Junk

In other words, 8.2% is selectively constrained. What is in there?

Even after we know all the letters, the human genome remains a very mysterious place, encoding in runic digital form unimaginably complex developmental processes and subtle behavioral traits, on top of the bread & butter cells, organs, metabolism, etc. Much has been learned, but much remains unknown. One perennial question about the genome is ... how much of it has any function at all? We know there is a great deal of free-riding junk: old transposons, repetitive recombination errors, dead genes, and other unidentifiable regions.

We also know there are only about 22,333 protein-encoding genes, which to experts seems an unimaginably small numer. I mean, yeast cells have 6,275 genes, and do we seem a mere 3.5 times as complicated? This coding portion takes up about 1.5% of the genome. We have another maybe 2,000 non-protein-coding genes like RNA regulators, which come in numerous types. Then there is a lot of other material, like regulatory regions that control whether nearby genes get turned on, functional parts of introns, centromere and telomere structures, etc. There are also a few mysterious ultra-conserved elements with no known function. One might imagine that "function" is a graded concept, with some vague regulatory tweeks having little function, in constrast to ribosomal components that have immutable must-have function. So any number we put on this is going to be fuzzy.

Perhaps the best way to define what is functional and what isn't is to go back to Darwin ... whatever is conserved in evolution is important, and whatever changes rapidly is not (with the exception of the occasional positively selected mutations, but these are, in the bulk of the DNA, extremely rare). A recent paper has pursued this analysis over many mammalian lineages to come up with the estimate of functional human DNA in the title above. Their technical approach is to compare the occurrence of alterations in sequence, especially insertions / deletions (indel), in actual genomes versus a calculated control genome with no conserved elements.

Over time, in a pair of imaginary (control) genomes with no important elements at all, mutations accumulate all over, and the average distance between zones of similarity declines to progressively smaller values. Actual genomes have far more regions of DNA where such indels are not allowed, a sign of purifying selection that eliminates mutation and preserves statistically unusual information. This leads to their statistic of constraint, meaning the portion of the actual genomes constrained from random change by purifying selection which removes organisms with mutations in those important nucleotides.

Portion of the human genome under various constraints. The X axis refers to divergence of sequences in the authors' neutral model, where 1.0 would be total divergence. The axis can be thought of as time going backwards to the right, though the relationship might not be linear. The Y axis is their measure of selective constraint which is the fraction of nucleotide sites (here displayed as the actual megabases of the 3.23 gigabase human genome) that are under purifying selection. Coding regions are blue and hardly vary with time or with the divergence of less constrained areas, while in red are shown non-coding regions that have some constraint. As divergence goes on, less of the latter are detectable.

Further breakdown of constrained regions by type. The Y-axis here is in terms of turnover during evolution, which is another measure of constraint. Protein coding regions turn over the least, then sites that are DNase sensitive (promoters, protein binding sites on DNA, etc.), then the average genome, then Promoters overall, then UnTranslated Regions, which are transcribed near genes on both sides, then Transcription Factor Binding Sites, then regulatory enhancers, which can be much farther away from genes than promoters, and lastly long noncoding RNA species, which have modest function at best. "TE" refers to transposable elements, which have no constraint to lose or turn over.

As shown above, different types of known genetic elements obviously have different levels of conservation, and in the second diagram, probability of loss over time, from conserved status to unconserved. Indeed the authors make the interesting point that of all this more-or-less conserved material, we only share a minority of it, about 23%, with mice. There is no surprise that coding regions are far more constrained than others. What is interesting is that these authors were willing and able to put a number on the global level of constraint, saying that, while the 91.8% of the genome with little evolutionary constraint may not be entirely without function, it can fairly be called "junk".

"If we make the assumption that the exponential decay model of functional sequence applies outside of the range of divergences we examined, then by extrapolating back to zero divergence we can estimate the total proportion of human genomes that is under present-day purifying selection with respect to indels. ... We therefore estimate that 8.2% of the human genome (253 Mb; 95% CI 7.1%–9.2%, 220–286 Mb) is presently under purifying selection with respect to indels."

This conclusion is controversial, because many labs have done functional analyses of what is actually transcribed from the genome, and find that practically all of it gets transcribed at some level. So most of the genome is "active" in some sense. The problem is that just because a stretch of DNA is transcribed to RNA doesn't make it a gene, or particularly important. The RNA may not get translated or have any further effect. All processes in the cell are messy, and it is quite likely that transcription is the same way, creating lots of noise and waste that signifies relatively little. That little may have activities to some modest degree that escapes strong selective constraint and bears investigation, but on the whole, I agree with these authors that evolutionary conservation is the best measure we have of importance vs junk.

  • GOP knows power, even if it know-nothings all else.
  • Pakistan fires artillery into Afghanistan ... sounds a little like the Russia-Ukraine situation.
  • Federal reserve president (Texas) keeps being wrong about inflation. This is simple class warfare.
  • "This report provides little evidence of any pick-up in wage growth. ... While a tightening labor market should eventually allow workers to see some gains in real wages, the economy does not appear to be at this point yet."
  • Towards a maximum wage.
  • Skills shortage? No way, Jose. It looks more like a slave shortage.
  • Microsoft apparently not so desperate for skilled workers as its H1B propaganda would have you believe; fires 18,000.
  • Autopsy of NAFTA ... not so great for either side, but not so bad either.
  • And generally, globalization vs democracy.
  • The fables of Reagan, and his children.
  • In Ukraine, the Russian operatives had a hard time gaining local support: "The people who supported this were marginal people, communists, lumpen, some of the Orthodox priests."
  • This week in the WSJ.. GOP candidate for California governor wonders where the jobs are.
"I walked for hours and hours in search of a job, giving me a lot of time to think. Five days into my search, hungry, tired and hot, I asked myself: What would solve my problems? Food stamps? Welfare? An increased minimum wage? 
No. I needed a job. Period. Like others, I have often said the best social program in the world is a good job. Even though my homeless trek was only for a week, with a defined endpoint, that statement became much more real for me. A job was the one thing that could have solved my food, housing and transportation problems."
[He might ask his GOP brethren in Washington, who slept at the fiscal wheel during the recession and do everything in their power to make America worse off, especially the worst off. And he might also ask why having a job leaves many workers still on food stamps and other public assistance.]