A Spear-chucking Bacterium

Vibrio Cholerae impales its victims with a metal-tipped, poisoned, rifled, spear.

Life is tough all over, but particularly bad for microbes. Without a glimmer of consciousness, and with hardly any tools at hand, (or hands), they still struggle, suffer, and die in astronomical numbers. One of the more fascinating and classic areas of discovery in the field is the beauty and complexity of the T4 phage, which is a virus that infects bacteria like E. coli. It has a lunar-lander like structure that docks to its victim and injects the DNA (from a highly pressurized head chamber) which then kills it while producing hundreds of new viruses.

But it is only in recent years that a connection has been drawn between this phage injection mechanism and what bacteria do to each other. What has been sedately called the type VI bacterial secretion system, used by Vibrio cholerae and Pseudomonas aeruginosa, among many other species of bacteria, turns out to actually be a violent spearing mechanism they use to kill competing bacteria and also mammalian host cells during an infection.

Model of the spearing system, on right, compared with the T4 viral system on left. The spear is in purple, while the contractile sheath is in green, and the base is yellow. In later experiments (in movie, etc.) the sheath is tagged with a fluorescent protein (GFP), allowing it to be easily visualized in the light microscope.

This was recently described in an NIH talk by John Mekalanos, and also in various publications from his group. One representative film clip is linked below.

Still from movie of the Vibrio spear in action, link here.

One of the more remarkable aspects of this mechanism is its scale. Sausage-shaped bacteria typically are closest to each other at the side, so the apparatus begins assembling at the side of the Vibrio cell. This injector assembles clear across the interior of the cell, forming a thin thread almost 500nm long which has, in addition to the base plate that nucleates the process, an inside spear and an outside sheath.

Electron micrograph of a poised spear assembly in a Vibrio cell. Note the extraordinary length, of about 500 nm. The scale bar is 100nm. T6SS is type six secretion system, IM is inner membrane, and OM is outer membrane. Note the detail of the basal body at the top spanning both membranes.

The outside sheath is spring-loaded, and when triggered (how that happens is unknown) winds down in a matter of milliseconds to half its original length, thrusting out the spear, while also turning it like a drill. In his talk, Mekalanos showed that the spear is tipped by a pointed protein his lab had recently discovered, that contains a zinc-coordinated domain that gives it particular stability. Behind the tip, the spear also is festooned with a variety of toxins, because simply spearing a nearby cell is not enough to kill it. Vibrio injects both eukaryotic-directed toxins such as one that cross-links actin and thus paralyzes the cell and another that modifies the cAMP signalling system causing massive ion and water efflux, as well as several bacterial-directed toxins to clean out the competition, such as inhibitors of cell wall (peptidoglycan) synthesis.

Sample killing, where Vibrio (red) were mixed with Pseudomomas (green) cells. The spearing system sheath is labeled in red and green respectively. In each horizontal set of time lapse images, a spear from a Pseudomonas cell (green) impales a neighboring Vibrio cell and either causes it to swell locally or to lyse entirely, losing its optical contrast (arrows).

An interesting wrinkle in the story is that each bacterium that has this kind of system also has a complement of immunity proteins that neutralize the various toxins that it creates. The bacteria are not terribly bright, and live in close proximity, so they frequently spear each other. One wouldn't want that kind of thing to be fatal. But Vibrio doesn't need immunity from the eukaryotic-specific toxins, which do not affect bacteria, including itself.

Once the spear is thrown, another protein comes along to quickly disassemble the spent apparatus, and another one re-assembles from a new base plate somewhere else inside the bacterium. Quite a bit more is waiting to be learned here, like the triggering mechanisms, and the details of assembly, but not only is this knowledge helpful in addressing a significant pathogen, (though one we hope to not meet in the developed world), but it is an example of the breathtaking complexity, and even beauty, in biology, even in the midst of the most desperate dramas.


Papers:

• Description of the system.
• General review of the system.
• Immunity and warfare issues.
• Investigation of the system in a plant pathogen.

Notes in passing:

• NBA may exit feudal world, go socialist.
• Bird speech and human speech.. not so different, perhaps.
• Am I giving philosophy a bad rap, for being a home for insurgent theists?
• Free market short-term-ism and self-immolation, cont.
• $721 million in mid-term political funding came from fossil fuels. Thanks!
• Not just an increase in the minimum wage, but in overtime coverage as well.
• Religion as psychotherapy, cont. Some people need answers really, really badly.
• Bill Mitchell on Japan: "Let it be noted that the Japanese government 10-year bond yield hit 0.33 per cent overnight. That tells you that all the scaremongering that has been going on over the last twenty years about hyperinflation, the Japanese government running out of money, the bond markets dumping the yen, and the rest of it were self-serving lies designed to advance a particular ideological position at the expense of the broader social well-being."

Environmentalism is anti-American

Book Review of the biography of Rachel Carson, "On a farther shore".

Are we part of nature, or above it? Did god give it to us for our domination, or did we wriggle from its bosom to the condition of (bare) consciousness and power that threatens to undo the patient work of millions of years of evolution? Thousands of years ago, we had already killed off all our immediate ancestors in the hominid line and countless other species of megafauna. Now we have taken over most of the arable land of earth, comandeered much of the fresh water, polluted the rest of it, as well as the oceans, killed off many more species, doubled the concentration of CO2 in the atmosphere and the fixed nitrogen in the biosphere, and are facing ocean acidification and dramatic climate heating as an irreversible future fate.

But two generations ago humanity (and that would be the US) created the most immediately alarming and noxious dangers of all- nuclear weapons with their attendent radioactivity, and a fusilade of biocides and other poisons emerging from the postwar chemical industry- pesticides, herbicides, plastics, drugs, "food" additives, cleaners, etc. After a cavalier start to the era, when Las Vegas visitors turned out with their sunglasses to watch nuclear tests, the far-reaching dangers came increasingly to public consciousness, resulting in the above-ground nuclear test ban treaty of 1963, and the establishment of the EPA in 1970 and banning of DDT in 1972.

The reduction of nuclear radiation has been enormously successful, with negligible impact from current uses. The Chernobyl and Fukushima nuclear disasters have been the sole, and very large, blots on a very good record of radiation control (negligible amounts were released in the Three Mile Island disaster). Whether we want to use more nuclear power or not for the sake of climate change is a reasonable question.

Our record on control of biocides and other environmentally harmful chemicals, on the other hand, is far less impressive. Their use is less individually dramatic than that of nuclear technology, but their scale is mind-boggling. Every home and garden center hosts a biocide department that reeks to high heaven. DDT may have been banned, but an endless supply of other biocides have been concocted that are applied over the best land to kill all insects on it. The holocaust is ongoing.

"In 2006 and 2007, the world used approximately 5.2 billion pounds of pesticides"

Rachel Carson played a large role in our budding environmental awareness, both in her early work in books like "The Sea Around Us" that celebrated the beauty and interest of the natural environment, and in her last prophetic work on the dangers of the new pesticides, "Silent Spring". This biography is a worthy testament to her drive and talent which formed out of very unlikely materials (being a self-made professional woman in the 1950's) an earth-shaking message.

Indeed she could even be regarded as a significant religious leader, inspiring love for the world, and issuing prophetic warnings about its mistreatment at the hands of humanity, due in part to a lack of spiritual awareness, or misdirection. Humans have an innate religious sensibility about nature, and all the old religions treat it with reverence. The Celts had their sacred groves, worship of trees, and custom of bringing holly and mistletoe to their dwellings at the winter solstice. Unfortunately, the monotheisms, with their worship of a blown-up self-image, put nature into the shade as something to be dominated, something lost anyhow (Eden), even dirty and unclean. The unholy mix with post-war technologies allowed the dream to become a reality ... to "purify" the world of insects, vermin, disease, and all kinds of uncleanliness.

Obviously there is a great deal of good in cleanliness. But we learn that even our own health benefits from some amount of infection and dirt, lest our immune system idly turn its attention on our own tissues by mistake. Which is not to mention the wider ecological benefits of moderation and species diversity, and particularly in less wanton destruction of insects and other unheralded organisms that may not be the "stars" of our nature shows.

While we have banned the most noxious chemicals, (thalidomide, DDT, aldrin, lead arsinate, etc.), our systems and policies are simply not up to the task of protecting ourselves or the environment in a more comprehensive way. They are not precautionary, but rather wait for some dramatic harm to come to light before starting studies and investigations that take forever. The neonicotinoid insecticides are still being applied by the ton, despite their clear harm to bees (not to mention to all other insects).

Why? Principally, it is the agricultural and chemical interests, and their conservative allies, that fight chemical control policies every step of the way. There was once a time, when the EPA was founded, when conservatives were true to their name and cared about conservation, not only of their power, but of the environment as well. Those times are long gone, as the interests of the 1% diverge increasingly from those of the rest of society, indeed of humanity in general. Their loud patriotism tells us that government is bad, taxes always too high, scientists are all lying, and corporations always tell the truth. The worship of self has turned from a projected image of god to the even worse god of Mammon.

"It had only taken a few short centuries to move from a time when we gazed out at the ocean and wondered what was over the horizon. Now, she said, "our whole earth has become only another shore from which we look out across the dark ocean of space, uncertain what we shall find when we sail out among the stars." Based on the experience of her own generation- which had brought the world to such a dangerous crossroads- Carson said it was now time for the inheritors of earth and it many difficulties to finally prove human mastery not of nature, but of itself. "Your generation," she said, "must come to terms with the environment."

• Wildlife is in dramatic decline.
• Bees are in especially dramatic decline ... collapse.
• Fly less to fight climate change.
• On the psychology of evil, corruption, ideology, contradiction, hypocrisy, and other forms of humanity.
• In the new economy, nice guys finish last.
• Cute kids ... these days.
• The recent US military campaign has little immediate effect. ISIS keeps gaining ground, and "One estimate puts the number of overall desertions for the Iraqi Army at over 90,000."
• How and why the Fed shores up the global dollar system.
• But banks run the Fed, so of course ... the Fed serves Goldman.
• Goldman, Lehman, Enron.
• AIG as a money-laundering bailout. "Alternatively, maybe Mr. Geithner simply felt that Goldman and the like had a more legitimate claim to billions of dollars in funds than the taxpayers who were footing the bill."
• Bonanza gets one in against the bankers (Episode 284, The Trackers)
• Pray our way, or the highway.
• To screw workers, employers talk out of both sides of their mouths.
• This week in the WSJ, annals of irony: "But does anybody in the government feel it is necessary to be truthful about anything anymore?"   
• Economic graph of the week.. just how dramatically our economy has changed over the last 60 years. We've already had a class war, and we lost.

The Origin of Life

Some papers on the earliest steps from geology to biology.

One of the great questions, second only to the origin of the universe (multiverse) and perhaps the nature of thought in the brain, is how life got started on Earth. (Leaving aside, of course, the even more daunting question of peace in the Middle East.) Of the three, the mind is well on its way to definitive solution, and the origin of the universe is rather unlikely to ever be solved, or at least there is no prospect that I can see, despite enormous advances in cosmology. The origin of life occupies a middle ground, so far off in time that certainty may be impossible, but bounded enough by our knowledge of the ambient conditions and their rich aftermath that detailed and plausible theories can be, and have been, advanced.

The papers reviewed here are not new, (dating from from 1997 and 2003), but provide background for my post two weeks ago about the divergence of Archaea and Bacteria, and constitute what I think remains the leading hypothesis for the origin of life (elaborated in more recent papers 1, 2, 3). (Other recent origin of life refs 1, 2, 3, 4, 5.) This hypothesis situates the scene of action at thermal vents at the ocean floor, where highly reduced and alkaline geological fluids percolate up into an ocean that was, at that time, far less oxidizing than today, but still, due to the prevalence of CO2, several logs more oxidizing and acidic than the geochemical fluid.

As still seen today, this fluid deposits rich chimneys of iron sulfide wherever it emerges, in a porous matrix that could host untold chemical complexity. And there are / were a full spectrum of more moderate vents, with lower temperatures and less harsh chemistries. These locations attract theorists of the origin of life because they provide a great deal of potential energy, in a form that life still uses: the electro-chemical gradient in the form of acid / base (protons) and oxidation / reduction (electrons).

They also provide the key elements (sulfur, iron, nickel, tungsten) that are needed, and the kinds of enclosed, yet semipermeable, spaces that would be needed to accumulate the compounds needed as proto-cells. So the 1997 paper by Russell and Hall delves into the kind of proto-metabolism that the energy gradients and structures at these locations might have provided. The Earth was saturated with CO2 at the time, as free oxygen had not yet been photosynthesized into existence.

But let's take a step back and ask what is needed for life. The basics are a membrane or some other compartment to keep inside and outside apart, an energy source, a metabolic system to harness that energy to create the molecules on the inside, like complex carbon molecules of our form of life, and a genetic replication system that controls the metabolism and other characters, so that they can be selected via Darwinian evolution.

Not all of these things have to happen at the same time, and the goal for figuring out how geology generates life is to locate conditions where as many of the earliest requirements are present for free in the geological environment, and deduce what had to happen at which stage thereafter. A great deal has been made of the RNA world (references 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) as a near-certainty in the progression from proto-life to the last common ancestor of all life. Our ribosome, for one thing, carries its clear signature. But this is a very late stage in the origin of life. The RNA world presupposes metabolism, a cell structure, and a replication system, even while it gives rise to a translation system that sets forth on the protein- and DNA-centric course we are on today.

So, energy is a must. Nothing can happen without it, but it can take many forms, from lighting discharges to sunlight, to chemical gradients from stable geological sources. As discussed in the previous post, chemical gradients remain the bread and butter of cellular energy, and are the most likely original form, leading to the hypothesis that undersea hydrothermal vents are an excellent candidate setting for consistent gradients of pH and redox, among other chemicals, approximating our current chemiosmotic metabolism.

Overview of Russell & Martin theory, with CO2 reduction occurring in mineral "bubbles" at the hydrothermal / oceanic interface.

Prior to biological, lipid-based membranes, such vents also supply porous rocks and somewhat sealed bubbles of rock that could serve as chambers or "cells" for pre-biotic chemistry. And lastly, they provide the actual enzymatic chemicals that remain at the core of our coupled redox metabolism- condensed iron and sulfur complexes that conduct electrons between proteins and across membranes while pumping protons in the opposite direction or reducing carbon compounds.

Example of a contemporary iron-sulfur  (Plus nickel) cluster that forms the heart of many enzymes that reduce (or oxidize) carbon compounds, in this case carbon dioxide to carbon monoxide, given water and a proton acceptor such as ferredoxin, another iron-sulfur protein.

What was the most elementary metabolism? Somehow, carbon compounds must have been reduced from the high level of CO2 and CO on early Earth to the sugars and polymers that form the basis of life, such as ATP, NAD, ribose, and the various metabolic intermediates of the Krebs cycle (which we use to break down food to CO2). The authors present a reverse Krebs cycle as the founding metabolism, where carbon compounds are built up (i.e. reduced) using electrons as well as catalytic surfaces furnished by Fe-S minerals mediating between external acid to internal alkaline conditions.

Basic energy scheme where a chemical gradient is used by iron-sulfur compounds to do enzymatic work, such as hydrogenating (reducing) CO2.

"It is the interfacing of the alkaline hot springs with the acid ocean that brings about the precipitation of an iron monosulphide (mackinawite) membrane. Electrons could have been transferred across such a membrane. Also the hydrogenating potential of the mackinawite could have been enhanced by the presence of nickel (Kouvo et al. 1963; Vaughan 1969; Morse & Arakaki 1993)." 

"Iron monosulphides such as mackinawite can contain up to 20% nickel (or cobalt and copper), probably tetrahedrally bonded between the sulphur-sulphur layers (Vaughan 1970). The FeS membrane considered here may have only adsorbed a few per cent of nickel, enough to force the cleavage of the hydrothermal hydrogen at the nickel site with the production of a transient hydride. The left-over proton would be neutralized with hydroxide in the protocytoplasm. The electrons could be transported through the membrane along the iron layer situated along (001), conducting
toward the final electron acceptor such as Fe(III) on the outside of the membrane. The atomic hydrogen could then hydrogenate the CO2 molecules bound on adjacent iron sites."

"In particular, Shock (1992, 1996) has carefully calculated the metastabilities of carboxylates, ketones and alcohols as inorganic carbonate in seawater mixes with hydrothermal solutions, with their fugacities buffered by both quartz–magnetite–fayalite (QFM) and the more oxidized pyrite–pyrrhotite–magnetite (PPM) mineral suites. The fugacity of carbon dioxide is taken as 10 bars, the presumed atmospheric pressure in the Hadean (Walker 1985; Kasting et al. 1993). ... Shock (1996) demonstrated that the possible synthesis of organic molecules between 50 and 250degC is sensitive to the fugacity of the hydrothermal solution, which must be buffered by QFM for all inorganic carbon to be converted to organic molecules. This is still a conservative choice, since 4.2 billion years ago the redox state of the mantle was probably two or three log fO2 units below that of the quartz–fayalite–magnetite buffer (Arculus & Delano 1980). Remarkably, Shock (1996) demonstrated that at temperatures below about 150degC, the longer chained polymers (dodecanoate is the longest chain considered so far) will theoretically be most represented of all the organic molecules, and that they could be generated at no energy cost."

An imagined reverse TCA or Krebs cycle, where carbon compounds are grown from humble beginnings using the free energy of the redox and pH gradients at the vent structures. What would guide the soup in any direction or to any particular compounds (including chirality) is not clear.

Given the right conditions, things might have proceeded quite rapidly ... millions of years would not be needed.

"The far-from-equilibrium conditions in which these geo- chemical processes and mechanisms operated would have been widespread for a limited period of Earth history, and would have provided ample opportunity for such a unique sequence of events leading to the minimal cell, the common ancestor of all life on this planet. Although coupled to a long-lived hydrothermal system, the actual gestation period for organic synthesis and the self-assembly of organic protocells capable of fledging and replication from within the iron monosulphide hatcheries would have to have been rapid, and may have taken weeks or months, rather than the millions of years normally assumed for the emergence of life."

The second paper takes the story onward through subsequent steps of probiotic evolution, where the metabolism becomes more ramified with phosphate (on ATP) as another energy currency, and  nascent protein and RNA enzymes develop out of the organic soup. And finally the mineral membranes are supplemented and replaced by organic ones, given some ion channels and membrane-bound enzymes to carry out metabolism. This sets the stage for escape as free-living organisms.

Cartoon of the general model of Russell and Martin, with organic pro to-metabolism generating carbon compounds which then undergo chemical evolution towards the RNA world, and eventually to organic membranes and cell walls that allow complete escape from the mineral womb at the hydrothermal vent setting.

I can hardly convey the entire theory, and at an outline level it seems reasonable. But what was the force or principle that made the carbon compounds become more complex and self-organize into an RNA world with enzymes and coding / reproduction schemes? That remains a major question (but see the collection of RNA world references cited above). Energy alone, even when channeled in some approximation of the later major microbial metabolism to a profusion of organic molecules, does not, on the face of it, direct complexity or productive competition between mineral bubbles. (The authors have a later paper that claims that conditions "forced" life to emerge, but its details are not available, and the argument seems geochemical, not biological, so it does not seem to address the competitive issue.) We can refer to the anthropic principle to say that whatever led to us must have survived somehow, but that is a far weaker theory than one that drives events based on the chemistry of the time. So I think these concepts are a strong start to a theory of the origin of life, but as yet far from the whole thing.

• Above the law- why pardoning Nixon set a bad precedent.
• Realism and Ukraine.
• "There was so much more reason for the U.S. to respond to 9/11 by invading Pakistan than there was Afghanistan."
• Who should pay for Detroit?
• "For middle-class Americans trying to save for retirement in a 401(k), bank fees take about $2 of every $5 over a lifetime of investing."
• Japan continues its curious ways of monetary sovereignty.
• The Chicago school thinks deflation is not so bad.
• MSM getting a little lefty!
• Our divided country- is speech speech, or is money speech?
• Did Apple solve payment security via biometrics?
• Quiverfull education.. a bit oxymoronic.
• Watch out: Deepak is really pissed, and has a nonphysicalist ontology on his side.
• Enron echoes "In short, Congress has consistently eroded the disincentives designed to keep corporate managers from lying to their shareholders and creditors"
• This week in the WSJ: Even someone at the Hoover institution recognizes the lack of prosecution, and the utter corruption of the financial system. "We also point out that when the Fed finally acted, it not only rescued the banks, it also bailed out their shareholders as well as the executives who had helped steer the banks and country into the crisis. In contrast, when the government rescued General Motors, it forced shareholders and bondholders to take huge financial losses and executives to be fired."

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."

• Our own form of renewable energy is going mainstream.
• PSA on sugar.
• The ladder of shameless media lies, from facebook to fox.
• Greece, New York descends into appalling entanglement with religion.
• Couple of columns on replacing welfare/EITC with universal basic income.
• Unemployment statistics ain't what they used to be.
• Unemployment maps of Europe ... a disaster.
• Even in the best of times and places, sclerosis reigns. California is ridden with public unions, systemic corruption, and weak public management.
• Defrauding the government, Microsoft version.
• Krugman: "It’s not just facts that have a liberal bias; so does careful, open-minded analysis."
• The tide turns against shareholder value maximization.
• WSJ- fraud of "only" $9 billion should not be prosecuted.

West Antarctic Ice Sheet: Who Cares?

So the oceans rise by nine feet ... we all will be long dead.

One hears occasionally about the West Antarctic ice sheet "collapse". That seems pretty far off and over-wrought. How can ice sheets collapse? That doesn't make much sense. If an ice sheet is already over the ocean, then its melting wouldn't affect the water level anyhow. So what is the deal?

In this case, the sheet is a large land-based glacier (not an ice shelf, like the Ross ice shelf) whose bottom lies far below sea level by nearly 4,000 feet, though its top rises up over sea level by another mile. This glacier holds about a half million cubic miles of water. Its collapse is going to take maybe 400 years: fast if you are a geologist, but pretty slow for most other people, so it is a bit of a misnomer. Perhaps megamelt might be a better term.

Thwaites glacier forms most of the West Antarctic ice sheet that is shrinking and being undermined.

The problem is that most of the glacier is over land that is far below sea level. Over the last (cold) millennia, it has pushed all the sea water out and stabilized as an enormous glacier. But with climate heating, sea water has begun infiltrating under the glacier, and, with its salt, is going to undermine the whole glacier, melting it far more rapidly than the rest of Antarctica is going to melt in response to rising air temperatures. That is what the observers are talking about.

Cross section view showing how much of the glacier is under sea level and prone to  "collapse".

The researchers in a recent paper describing this situation do two things. They state that based on its recent flow and water loss, that this glacier has already begun collapsing / being undermined by sea water. Secondly, they put together some modelling of the melting process and estimate that even without more global warming, this glacier will unload all its water within 200 to 900 years, contributing on its own about 9 feet to higher global sea levels. Naturally, the rest of the glaciers in the world aren't sitting on their hands either, so it is just one more nail in the coffin of our lovely biosphere as it has been for the last few thousand years since the last ice age. And over the last

It is a classic slow-motion, far away, hidden-under-a-pile-of-ice process, particularly ill-suited to our communal forms of decision-making, i.e. politics. While in terms of geology and evolutionary biology, the melting is going at lighting speed, it is glacial in terms of our day-to-day public policy concerns and decision making. So Barack Obama's heroic regulations of vehicle emissions and power plant emissions are pushing against a vast conspiracy of apathy, inertia, greed, and myopia. They are far too little, far too late, though better than nothing. If CO2 were purple, we would naturally be much, much farther along by now.

Earth's CO2 history, inferred from various fossil and geologic data and models. Present time is on the far left. I have added a teal line at about 500 ppm CO2, which is where we will be in 2050, and which exceeds what Earth has seen for the last ~20 million years (the period marked "N" for Neogene).

And the response really has to be at the level of public policy, nationally and globally. Without a carbon tax or regulated cap, and without natural shortages of fossil fuels (which seem to be in much larger supply than the atmosphere can take), any CO2 that one virtuous tree-hugger spares the atmosphere simply reduces the price of fuels, helping some one else to use more. If renewable energy sources reach economic parity with essentially free fossil fuels, this situation may change. But for now, fossil fuels always win on pure, amoral, economics. Any effective solution has to be common across all users, to address this mounting tragedy of the commons.

And what does morality have to do with it? Why are tree-huggers regarded as virtuous? It is not out of sheer asceticism. It is pertinent to note that the most significant metric & consequence of global heating isn't geology, or climatology, or economics ... it is biology. The problem is not that rocks are getting warmer, or that ocean water is getting acidic. And the problem is not, (mostly), that humans will have to move a few miles inland or start growing crops in Siberia. All that can be accommodated, or has no moral consequence. The real problem is that climate heating is destroying our biosphere with increasing thoroughness, leaving only weeds and jellyfish behind.

We have already done a bang-up job of biological destruction, starting with the megafaunal extinctions of the Pleistocene (courtesy of human hunters). The last couple of centuries have seen a new mass extinction event gathering steam, as humans have commandeered the entire arable biosphere as well as rangelands, ocean productivity, and forests. Then we poisoned everything with DDT, radioactivity, and currently the neonicotinoid insecticides. Now we are placing the final nails, driving up temperatures beyond where they have been in millions of years, and shredding whole ecosystems by acidifying the ocean. It is going to be a doozy of an extinction event, up there with the greatest of all time. What seems to us slow motion is just an instant in the tapestry of life's history on earth- an incredibly destructive one.

When you see iconic species trotted out as examples of saving rare species, like pandas, condors, and tigers, you can be pretty sure that they are the walking dead. Their populations are so small and habitats so vestigal that they have lost genetic & ecological viability. Unless enormous amounts of healthy habitat are set aside, (and air conditioned!), they will go fully extinct sooner or later. One of the basic values of humanity has always been an appreciation for the beauty of nature and a recognition of the bonds we share, from its incredibly varied resources to its spiritual sustanance. We are animals, and we are dust, after all. Another basic value has been to provide for our children and the ensuing generations, which constitutes one the basic drives of life. But if we eat & heat their environment now, what will they have left? Even if we manage to keep our world on an even keel in social terms and refrain from incinerating ourselves in a nuclear war, we will, at the current pace, leave them a pale shadow of the nature that we inherited, and that is a deep and depressing shame.

• Global warming ... is politically global.
• National Review: To hell with planet Earth.
• The arctic? It's melting, too.
• Yes, the stupid party, and proud of it.
• Truth dawns in Saudi Arabia.
• Tyson and scientism.. we don't discover meaning, we construct it.
• Our electricity system needs a regulatory overhaul.
• As wealth concentrates upward, debt concentrates downward. The poorer you are, the more you need it, the worse the terms, and the more predatory the sharks.
• Anatomy of the financial crisis, in official narratives.
• The story behind the (lack of) cramdown, in 2008.
• Marx was sort of right.. capitalism could use another big war right about now. Or at least intelligent economic policy.
• About all those new jobs... they aren't very good.
• This week in the WSJ, Warmists = Hitler.

The Naked One: Jainism

The sramana movements of ancient India- Buddhism, Yoga, and Jainism.

What is the best religion? One's own, doubtless. But supposing that you had to choose a different one or had none to start with, which ones do the best job of promoting human flourishing and peace, in some general and long-term sense? Most of the prime candidates (i.e. the least blood-soaked, the most philosophical) come from the East. Which is sort of a bitter pill for a Westerner to swallow. But perhaps our tendency to crazy religion bred its opposite as well- the desire to throw its chains off entirely. Be that as it may, it seems fairly obvious that peacefulness and calm are particular specialties of Eastern practices like Taoism, Confucianism, and Buddhism. And the philosophical cores of some of these are even non-theistic, which is remarkable in a culturally durable religion, considering the popularity of gods in all times. Indeed, theistic elements have crept back into most of these religions, sometimes floridly so, as has polytheism in the West.

The Axial age was a time of great religious innovation, when history starts in earnest across multiple cultures, and religious thought and doubt is first extensively recorded. Greece transitioned from Homer to Pericles, Persia adopted Zoroastrianism, China brought forth Confucious and Lao Tzu, and Buddhism was born in India, along with the Upanishads. It was perhaps humanity's first brush with broad cosmopolitanism, which brought new questions and perspectives. A new focus on the individual and the pursuit of spirituality for its own sake rather than as a quid-pro-quo for some harsh and demanding god made room for true philosophy and philosophically driven life styles. Perhaps the most peaceful of all these movements were the Jains of India, also first recorded during this time.

Jainism, Buddhism, Yoga, as well as the Ajivika and atheistic Carvaka movements, were part of a broad reaction to Brahmanic Hinduism, called the Sramana movements (from sram, or making effort, such as the various austerities that typify its practices, maybe at an asram). Its wellsprings may go back to before the Aryan invasion that generated the Brahmanic / Vedic system, but at any rate, it constituted a sort of dramatic reformation / alternative to the dominant system. It renounced caste entirely, refused to recognize the higher status of the Brahmins or their sacrificial rituals, and set up what one might term a merit-based system of spiritual attainment, typically characterized by austerities like celibacy, begging for sustenance, minimal clothing, lack of possessions ... the opportunities are endless. It also generated the idea of life as a problematic cycle of suffering, karma and rebirth, with the goal of release from rebirth.

Jina, 11th century, unspecified, Gujarat.

The origins of Jainism are rather obscure, but the story is that there were twenty-four Jinas, who are the Jains of highest merit, having achieved liberation (from rebirth, from ignorance, etc.) through their meditative and mortifying efforts. They are typically portrayed in utterly peaceful sitting or standing meditation, clothed or naked according either of two Jain branches (Svetambara and Digambara, respectively). The last Jina, Mahavira (540-468 BCE), is most historically attested, and was a contemporary of Siddhartha Gautama. He was not the Jain founder, however, so the religion had a long and hazy history prior, of which he was a reformer and proselytizer. Indeed, Siddhartha Gautama seems to have a student of the Jains in his formative period, prior to breaking with all the strenuous penance and founding his own philosophical school / religion. Which may indeed just have been a variant of Jainism at the time. Yoga is similarly an ascetic strain of non-Brahmanic practices, even more inwardly focussed than Jainism.

The first of the twenty four Jinas, Rishaba, is of particular iconographic interest, as he is the only one with long flowing hair, which Jain monks pluck out when joining, and keep short generally. But Rishaba tends to get the aboriginal / Rastafari treatment, which to me is a striking tie to the deep history of humanity.

Jina Rishaba in standing meditation, ~3rd century, Bihar.

The philosophical focus of Jains is on a sober life and strict morality towards all living beings. The jewels are non-harming, asceticism, and non-absolutism. They theorize that bad actions (even inadvertant ones) harm the person in a physical way, accumulating karma-icules which are tiny bits of physical matter that stick to one's soul, bind one to the cycle of rebirth, and induce spiritual blindness. Their aversion to harming all life forms extends to complete vegetarianism for all practitioners, lay and monk, and even an avoidance of root crops whose harvesting (at least traditionally) involved more disruption of the ground & animals than other crops. One couldn't imagine a stronger repudiation of the classic Vedic rituals of animal sacrifice.

One wonders what Jains make of modern microbiology, not to mention their entrapment in a modern world where any participation in normal life implicates one in vast slaughter and mass extinction. They rate self-starvation to death a highly meritorious act, which goes somewhat against the human flourishing part of my criteria above, even while general abstemiousness and consciousness of ecological harm is in the long run a very positive ethic. One can tell that these philosophies had a revolutionary effects on Indian history & philosophy, for example on Mahatma Gandhi.

Jains originated in the Kshatriya caste, of warriors and administrators, one step below the Brahmins. Being a warrior is obviously not consistent with their philosophy, and Jains have gravitated toward commerce, where they have been very successful. Through history, they also have benefitted from strong alliances with some rulers, who often had political and cultural conflicts with the Brahmanic system. They have built extensive temple complexes at sites reputed to be where various Jinas attained enlightenment, and which serve as pilgrimage sites for all Jains.

Example of a pilgrimage site painting, which is displayed once a year for lay Jains who may not have a chance to go on an actual pilgrimage, and can attain some merit by viewing this portrayal of the site, full of pilgrims. No date or origin given. The location is Shatrunjaya, in Gujarat.

Their doctrine of non-absolutism deserves special comment, as it is a very mature philosophical approach completely unlike the bombastic Ja-way-or-the-highway approach one finds in typical, and especially Western, religions. It proclaims un-certainty. That any truth is provisional and different from different perspectives. Some truths may be partial rather than universal. For example, the Buddhist proposition that change-is-the-only-eternal, and the contrasting permanence of the Brahman in Hinduism each have some merits, depending on what one is talking about, from the Indian / Jain perspective. And that is surely an appropriate way to deal constructively with complex ideas with a great deal of imaginative content. It also leads to a distinct lack of a missionary impulse, one reason why Jainism remains small in number (maybe ~5 million adherents).

Over time, as is natural, Jains have made up stories about their Jina's pre-existing divinity and virgin births from which they arrived to the acclamation of various Hindu gods, etc. and so forth. It is par for the course, and has led to some remarkable art. But the basic philosophy is far less complicated, and well-versed practitioners do not expect anyone to listen to their devotions and prayers- they are understood to be meditational acts of self-improvement, not transactions with beings occupying the void. The Jinas have disappeared completely.

Many religions, indeed all social systems, harness guilt to promote good behavior, conformity, and a stable hierarchy. Jainism does take this aspect to extremes, though in light of our current planetary woes, it does so in a relatively constructive way, in a program of reducing its adherent's footprint of social violence and ecological harm. It easily ranks as the outstanding religion, if one must have one, for the present and future.

Jina, ~900, unspecified, from Karnataka or Tamilnadu.

• Same as it ever was... Chesterton was "disappointed" with the atheists of his day! "They are doubtful in their very doubts. Their criticism has taken on a curious tone; as of a random and illiterate heckling. ... Their suggestions are more vapid and vacant than the most insipid curate in a three-act farce... Their whole atmosphere is the atmosphere of a reaction: sulks, perversity, petty criticism. They still live in the shadow of the faith and have lost the light of the faith."
• Honor among traders- why some cultures don't get capitalism.
• Keynes was right about the 1980's, but who was paying attention?
• " ... people who lost their jobs in 2009, when unemployment peaked at 10 percent, had a 30 percent chance of ending up long-term unemployed."
• Sometimes, government does things better.
• Guess who worships the almighty dollar ... yes, the jihaddis.
• Peak fish: global fisheries peaked back in 1988.
• News flash: pesticides kill insects.
• Corporate felony means no one goes to jail, or even loses a job, or any pay.
• A little background on the Kochs. And present-day practice.
• The minimum wage is a human rights issue.
• Even France works harder than the US, thanks to better policy.
• DeLong on Piketty and the PikettyWorld.
• This week in the WSJ: 

"A March Gallup poll finding that most Americans worry about climate change "a little" or "not at all" is consistent with other surveys showing that the issue is not even close to being a top priority for U.S. voters." ... But when 67% want wealth in the US more equally distributed, then the majority is perhaps not always right after all.

What is the oldest cell?

Some comparisons of the most ancient lineages of life- Archaea, Bacteria, and Eukaryotes.

Take your mind back.. way back.. four billion years back. Now fast-forward over chemical evolution, or whatever happened to cause the origin of life, a few hundred million years, on to the first cellular life. Now stop- what was that? A recent paper argues from a novel analysis of protein domain lineages that, of the major domains of life, the Archaea (also called archaebacteria) are in some respects closest to that original form, and that the other domains- Bacteria (also called eubacteria) and Eukaryotes- are more distant. (Apologies that biologists use the term "domain" in these two very different senses.) This is an interesting hypothesis, since up till now, it has been indeterminate which of the two bacterial lineages came first, or at least, most resembles the ur-life form, also called the progenote.

Tree of life, deep edition. Note that while eukaryotes arose from Archaea, (with plenty of later additions from Bacteria by engulfment / symbiosis, but that is another story), the root between Archaea and Bacteria as shown here is indeterminate. Which was really first, or is that even a reasonable question to ask? The current paper also disputes that Eukaryotes derived from Archaea as diagrammed, and puts Archaea at the root of the tree.

Non-biologists may not get excited about the distinction between Archaea and Bacteria, but molecular biologists regard it as the most fundamental division of life, far more consequential than vertebrates / invertebrates, plants / animals, etc. All of the latter you can see in the little brown stubs far to the right of the diagram above. In molecular and deep phylogenetic terms, they don't contribute much to the diversity of life.

The Archaea / Bacteria division was only recognized relatively recently, however, since the nature of Archaea was not appreciated until the 1970's when ribosomal RNA began to be sequenced. It provided the first primitive molecular sequence that was common to every single form of life and thus provided a metric of diversity and geneology. The great American microbiologist Carl Woese labored to gather these sequences from obscure organisms and bacteria of all sorts. He made the shocking discovery that there were "bacteria" out there that were very, very different from the usual run of laboratory bacteria- the E. coli and various other disease-causing and easily-cultured bacteria that were the staff of biology since Pasteur. When he plotted out the sequences, these "bacteria" had ribosomal RNA that was a little more like animal sequences than bacterial, but not terribly similar to either. They weren't from another planet, but they were different enough that he took the very bold step of claiming an entirely new domain of life, co-equal with the heretofore only domains of life, Bacteria and Eukaryotes.

He named them Archaebacteria, on a hunch that they had something important to say about the origin of life. This name has subsequently been shorted to Archaea, so that the traditional bacteria can just be called Bacteria. These Archaea look like Bacteria, however- they are the same tiny cells whose wonders are not apparent from their looks. They are super-diverse, living in all sorts of environments from the coldest to the hottest known. They have phenomenal metabolic diversity, creating the methane in our guts and living off rocks, sulfur, and other obscure chemicals. Some have a primitive form of photosynthesis. They are typically sensitive to oxygen, a sign of their preference for a world predating the oxygenation of the atmosphere about 2 billion years ago (and making them very difficult to culture).

They also share most of their informational machinery (transcription, translation) with Eukaryotes, indicating strongly that Eukaryotes derived from Archaea that later engulfed bacteria (which eventually turned into mitochondria and chloroplasts) that provided some of the remarkable resources, both genetic and metabolic, for the eukaryotic triumph over the macroscopic world.

But ribosomal RNA, as convenient and informative as it is, has some problems. It is only a single, if large, molecule, among the thousands of other genes an organism has, and its sequence is somewhat inaccurate as a "clock" for molecular evolution. Few other sequences, such as those encoding proteins, are as completely universal among all life forms, however. The authors of a recent paper take a broader approach to the question of sharpening the universal geneology (or, tree of life) by treating whole complements of proteins and their domain, or "fold" sub-sections as geneological markers, testing which protein domains arose when, and which were lost in various lineages.

This gets around the issue of aligning individual sequences, to some extent, taking a wider lens view of the evolutionary process. A view that is well-suited to this question of the ultimate priority of the most ancient life forms. Protein domains / folds have been generated and lost quite frequently on this time scale, though there are core domains that are universal over all life forms. Eukaryotes are particularly prolific in generating new protein domains. About 3% of protein domains are unique to primates, for instance, though this may have as much to do with sampling & investigation bias as with reality.

"In fact, recruitment of ancient domains to perform new functions is a recurrent phenomenon in metabolism."

A protein with two domains. This one binds to DNA. The domains fold independently, have structure that is distinct from other domains, and can be easily linked, making them easy to re-shuffle in evolution, hooking functions together, leggo-like.

The authors assembled a compendium of about 2400 protein domain, or fold "families" from 420 sequenced organisms of all kinds, and used well-known methods to arrange them into trees based on their occurrence in the individual organisms (though sometimes a fold might be missed even if present, if its sequence diverged from its family consensus pattern too far). The gain and loss of such folds is a particularly powerful method of lineage analysis, giving more information than the comparison of sequences can, if those sequences are distant, with all the problems of alignment, assumed modes of mutational change, etc. Thirteen of their folds were present in every single organism, and 62 more were recognizably present in 95% or more.

A Venn diagram showing the distribution of fold families among the three domains of life, whether shared or not. Note than a large core is shared by all life forms, while Eukaryotes take the prize for the development of new protein domains, despite originating after the divergence of Bacteria and Archaea.

"To determine the relative age of FF [fold family] domains in our dataset, we reconstructed trees of domains (ToDs) from the abundance and occurrence matrices used in the reconstruction of ToLs [trees of life]. The matrices were transposed, treating FFs as taxa and proteomes as characters. The reconstructed ToDs described the evolution of domains grouped into FFs and identified the most ancient and derived FFs. ... Specifically, it considers that abundance and diversity of individual FFs increases progressively in nature by gene duplication (and associated processes of subfunctionalization and neofunctionalization) and de novo gene creation, even in the presence of loss, lateral transfer or evolutionary constraints in individual lineages. Consequently, ancient domains have more time to accumulate and increase their abundance in proteomes. In comparison, domains originating recently are less popular and are specific to fewer lineages."

The next diagram shows the phylogenetic tree they deduce from all this data, with time along the horizontal axis, and species ordered up the side. The two trees were created from the same data by slightly different methods. Note how in both of these trees, the Eukaryotes (green) split from the Bacteria (blue) only a short time after the Bacteria split from the Archaea (red). The lavender arrows are mine. Both trees also show (the numbers, which are percentage of time their simulations came out the same way) that this split is relatively less clearly supported than some of the other major divergences.

Author's phylogenetic trees.

Returning to the Venn diagram, the Archaea-only group of folds is tiny, and does not seem particularly ancient, even though their trees put Archaea first. The hypothesis is that the other groups (The BE and AB (or AE) groups) generated far more protein diversity later on, whereas the Archaea did not, indeed losing quite a bit of the original complement of protein domains. In this way, Archaea end up resembling the progenote somewhat more than the Bacteria that diverged from the progenote simultaneously, but were more active in later evolution, in molecular terms.

Both the Bacteria and Archaea took the streamlining route in evolution, casting off quite a bit of machinery, focusing on small-ness of size and specialization of metabolism. The Eukaryotes, in contrast, branched off from the Archaea after the Bacteria did, and retained a good deal of the transcriptional, replicational, and translational machinery that the bacteria particularly lost or reduced (at least, by the conventional theory). And Eukaryotes in general took the opposite route with respect to streamlining, retaining molecular diversity & sloppiness, metabolic generalization, great physical size, gaining sex as a means to more effective evolution, and gaining the final upper hand with the endosymbiosis of two different Bacteria- the proto-mitochondrion, and the proto-chloroplast. These properties led eventually to multicellularity and the invasion of land. It was (depending on what one values!) a triumph of complexity and cooperation over brutal, cost-cutting competition.

The authors plot their organisms in an "economic" space. This is based on two scores- the number of protein folds occurring that are unique (economy), and the redundancy of protein folds occurring in each organism (flexibility), with the ratio between them serving as the last measure (robustness), which is, frankly, sort of an amplification of the flexibility score. Obviously, Eukaryotes will do very well in these measures.

Since in the author's scheme the AE goup of domains appeared very late, and the BE group was the first to branch off from the universal ancestors, they hypothesize that Eukaryotes branched off from Bacteria, and their informational-class resemblance to Archaea is due either to later lateral transfer, or to comprehensive loss in many Bacterial lineages (though the latter is very unlikely). To me this seems hard to swallow, as this class of functions is particularly unlikely to be transferred wholesale between organisms.

"Informational FFs were significantly over-represented in the AE taxonomic group and appeared during the late evolutionary epoch. This suggested that both Archaea and Eukarya work with a very similar apparatus for decoding their genetic information, which is different from Bacteria. However, as we explained above, all these innovations occurred in the late epoch (nd>0.55), highlighting ongoing secondary adaptations in the superkingdoms. In comparison, the BE taxonomic group was enriched in metabolic FFs (Figure 2A). This toolkit was probably acquired via HGT [horizontal gene transfer] during endosymbiosis of primordial microbes rich in diverse metabolic functions."

This idea would significantly alter / extend the well-known endosymbiotic hypothesis, in that the Eukaryotic precursor would presumably have to acquire not only the proto-mitochondrial cell, but also the proto-nuclear cell that provided these informational functions, from Archaea. It is hard to know what would characterize this original precursor at all ... why not just take the crucial Archaeal additions as the benchmark of the whole lineage? Wouldn't the large protein repertoire commonality between Bacteria and Eukaryotes be better accounted by the known endosymbiosis than by this proposed lineage derivation? The authors have very little to say about what this early Eukaryotic stem organism might be, other than that it was quite advanced and had escaped the brutal streamlining that characterizes both the Archaeal and Bacterial lineages. Thus it, whatever it was, might represent the closest thing to the progenote, in some respects, before the vast elaborations that have been added in that line since, and the massive losses that took place in the other two domains.

"Thus, the primordial stem line, which was already structurally and functionally quite complex, generated organismal biodiversity first by streamlining the structural make up in Archaea (at nd = 0.15), then by generating novelty in Bacteria (nd = 0.26), and finally by generating novelty and co-opting bacterial lineages as organelles in Eukarya (nd less than 0.55)". [nd is their measure of time, from beginning (0) to now (1).]

In the end, the progenote is heavily veiled from our view. The common repertoire of sequences common to all cells is small, (484 fold families in this analysis), and not enough to model what it may have been like, other than to say it had a membrane, functioning metabolism, and informational / genetic system likely similar to what archaebacteria have today. It may have been a good deal more complex, depending on how one interprets the intervening events- as ones primarily of loss, or ones of gain.

• From Russia, with love.
• What happens when you tune your own brain.
• Secularism invades the last preserve of religious freedom, with moral injunctions. Sorry about that!
• Annals of imaginary religious victimhood.
• Legal representation for the non-rich leads to prejudicial witch hunt.
• Computer language that knows a lot. Though less than advertised.
• Martin Wolf: Democracy is for grownups.
• What are the prospects in Afghanistan?
• The 1% can't understand why their rule is not uncontested. Noblesse oblige, right?
• Krugman: Feudal drudgery does not equal "opportunity".
• Does the casino of Wall Street help or hinder economic growth?
• Economic quote of the week: "More unequal societies have slower and more fragile economic growth."
• Economic graph of the week. Demand components in the US: