Are Archaea Archaic?

It remains controversial whether the archaeal domain of life is 1 or 4.5 billion years old. That is a big difference!

Back in the 1970's, the nascent technologies of molecular analysis and DNA sequencing produced a big surprise- that hidden in the bogs and hot springs of the world are micro-organisms so extremely different from known bacteria and protists that they were given their own domain on the tree of life. These are now called the archaea, and in addition to being deeply different from bacteria, they were eventually found to be the progenitors of eukaryotic cell- the third (and greatest!) domain of life that arose later in the history of the biosphere. The archaeal cell contributed most of the nuclear, informational, membrane management, and cytoskeletal functions, while one or more assimilated bacteria (most prominently the future mitochondrion and chloroplast) contributed most of the metabolic functions, as well as membrane lipid synthesis and peroxisomal functions.

Carl Woese, who discovered and named archaea, put his thumb heavily on the scale with that name, (originally archaebacteria), suggesting that these new cells were not just an independent domain of life, totally distinct from bacteria, but were perhaps the original cell- that is, the LUCA, or last universal common ancestor. All this was based on the sequences of rRNA genes, which form the structural and catalytic core of the ribosome, and are conserved in all known life. But it has since become apparent that sequences of this kind, which were originally touted as "molecular clocks", or even "chronometers" are nothing of the kind. They bear the traces of mutations that happen along the way, and, being highly important and conserved, do not track the raw mutation rate, (which itself is not so uniform either), but rather the rate at which change is tolerated by natural selection. And this rate can be wildly different at different times, as lineages go through crises, bottlenecks, adaptive radiations, and whatever else happened in the far, far distant past.

Carl Woese, looking over filmed spots of 32P labeled ribosomal RNA from different species, after size separation by electrophoresis. This is how RNAs were analyzed, back in 1976, and such rough analysis already suggested that archaea were something very different from bacteria.

There since has been a tremendous amount of speculation, re-analysis, gathering of more data, and vitriol in the overall debate about the deep divergences in evolution, such as where eukaryotes come from, and where the archaea fit into the overall scheme. Compared with the rest of molecular biology, where experiments routinely address questions productively and efficiently due to a rich tool chest and immediate access to the subject at hand, deep phylogeny is far more speculative and prone to subjective interpretation, sketchy data, personal hobbyhorses, and abusive writing. A recent symposium in honor of one of its more argumentative practitioners made that clear, as his ideas were being discarded virtually at the graveside.

Over the last decade, estimates of the branching date of archaea from the rest of the tree of life have varied from 0.8 to 4.5 Gya (billion years ago). That is a tremendous range, and is a sign of the difficulty of this field. The frustrations of doing molecular phylogeny are legion, just as the temptations are alluring. Firstly, there are very few landmarks in the fossil record to pin all this down. There are stromatolites from roughly 3.5 Gya, which pin down the first documented life of any kind. Second are eukaryotic fossils, which start, at the earliest, about 1.5 Gya. Other microbial fossils pin down occasional sub-groups of bacteria, but archaea are not represented in the fossil record at all, being hardly distinguishable from bacteria in their remains. Then we get the Cambrian explosion of multicellular life, roughly 0.5 Gya. That is pretty much it for the fossil record, aside from the age of the moon, which is about 4.5 Gya and gives us the baseline of when the earth became geologically capable of supporting life of any kind.

The molecules of living organisms, however, form a digital record of history. Following evolutionary theory, each organism descends from others, and carries, in mutated and altered form, traces of that history. We have parts of our genomes that vary with each generation, (useful for forensics and personal identification), we have other parts that show how we changed and evolved from other apes, and we have yet other areas that vary hardly at all- that carry recognizable sequences shared with all other forms of life, and presumably with LUCA. This is a real treasure trove, if only we can make sense of it.

But therein lies the rub. As mentioned above, these deeply conserved sequences are hardly chronometers. So for all the data collection and computer wizardry, the data itself tells a mangled story. Rapid evolution in one lineage can make it look much older than it really is, confounding the whole tree. Over the years, practitioners have learned to be as judicious as possible in selecting target sequences, while getting as many as possible into the mix. For example, adding up the sequences of 50-odd ribosomal proteins can give more and better data than assembling the 2 long-ish ribosomal RNAs. They provide more and more diverse data. But they have their problems as well, since some are much less conserved than others, and some were lost or gained along the way. 

A partisan of the later birth of archaea provides a phylogenetic tree with countless microbial species, and one bold claim: "inflated" distances to the archaeal and eukaryotic stems. This is given as the reason that archaea (lower part of the diagram, including eukaryotes, termed "archaebacteria"), looks very ancient, but really just sped away from its originating bacterial parent, (the red bacteria), estimated at about 1 Gya. This tree is based on an aligned concatentation of 26 universally conserved ribosomal protein sequences, (51 from eukaryotes), with custom adjustments.

So there has been a camp that claims that the huge apparent / molecular distance between the archaea and other cells is just such a chimera of fast evolution. Just as the revolution that led to the eukaryotic cell involved alot of molecular change including the co-habitation of countless proteins that had never seen each other before, duplications / specializations, and many novel inventions, whatever process led to the archaeal cell (from a pre-existing bacterial cell) might also have caused the key molecules we use to look into this deep time to mutate much more rapidly than is true elsewhere in the vast tree of life. What are the reasons? There is the general disbelief / unwillingness to accept someone else's work, and evidence like possible horizontal transfers of genes from chloroplasts to basal archaea, some large sequence deletion features that can be tracked through these lineages and interpreted to support late origination, some papering over of substantial differences in membrane and metabolic systems, and there are plausible (via some tortured logic) candidates for an originating, and late-evolving, bacterial parent. 

This thread of argument puts the origin of eukaryotes roughly at 0.8 Gya, which is, frankly, uncomfortably close to the origination of multicellular life, and gives precious little time for the bulk of eukaryotic diversity to develop, which exists largely, as shown above, at the microbial level. (Note that "Animalia" in the tree above is a tiny red blip among the eukaryotes.) All this is quite implausible, even to a casual reader, and makes this project hard to take seriously, despite its insistent and voluminous documentation.

Parenthetically, there was a fascinating paper that used the evolution of the genetic code itself to make a related point, though without absolute time attributions. The code bears hallmarks of some amino acids being added relatively late (tryptophan, histidine), while others were foundational from the start (glycine, alanine), when it may have consisted of two RNA bases (or even one) rather than three. All of this took place long before LUCA, naturally. This broad analysis of genetic code usage argued that bacteria tend to use a more ancient subset of the code, which may reflect their significantly more ancient position on the tree of life. While the full code was certainly in place by the time of LUCA, there may still at this time have been, in the inherited genome / pool of proteins, a bias against the relatively novel amino acids. This finding implies that the time of archaeal origination was later than the origination of bacteria, by some unspecified but significant amount.

So, attractive as it would be to demote the archaea from their perch as super-ancient organisms, given their small sizes, small genomes, specialization in extreme environments, and peripheral ecological position relative to bacteria, that turns out to be difficult to do. I will turn, then, to a very recent paper that gives what I think is much more reasoned and plausible picture of the deeper levels of the tree of life, and the best general picture to date. This paper is based on the protein sequences of the rotary ATPases that are universal, and were present in LUCA, despite their significant complexity. Indeed, the more we learn about LUCA, the more complete and complex this ancestor turns out to be. Our mitochondrion uses a (bacterial) F-type ATPase to synthesize ATP from the food-derived proton gradient. Our lysosomes use a (archaeal) V-type ATPase to drive protons into / acidify the lysosome in exchange for ATP. These are related, derived from one distant ancestor, and apparently each was likely to have been present in LUCA. Additionally, each ATPase is composed of two types of subunits, one catalytic, and one non-catalytic, which originated from an ancient protein duplication, also prior to LUCA. The availability of these molecular cousins / duplications provides helpful points of comparison throughout, particularly for locating the root of the evolutionary tree.

Phylogenetic trees based on ATP synthase enzymes that are present in all forms of life. On left is shown the general tree, with branch points of key events / lineages. On right are shown sub-trees for the major types of the ATP synthase, whether catalytic subunit (c), non-catalytic (n), F-type, common in bacteria, or V type, common in archaea. Note how congruent these trees are. At bottom right in the tiny print is a guide to absolute time, and the various last common ancestors.

This paper also works quite hard to pin the molecular data to the fossil and absolute time record, which is not always provided The bottom line is that archaea by this tree arise quite early, (see above), co-incident with or within about 0.5 Gy of LUCA, which was bacterial, at roughly 4.4 Gya. The bacterial and archaeal last common ancestors are dated to 4.3 and 3.7 Gya, respectively. The (fused) eukaryotic last common ancestor dates to about 1.9 Gya, with the proto-mitochondrion's individual last common ancestor among the bacteria some time before that, at roughly 2.4 Gya. 

This time line makes sense on many fronts. First, it provides a realistic time frame for the formation and diversification of eukaryotes. It puts their origin right around the great oxidation event, which is when oxygen became dominant in earth's atmosphere, (about 2 to 2.4 Gya), which was a precondition for the usefulness of mitochondria to what are otherwise anaerobic archaeal cells. It places the origin of archaea (LACA) a substantial stretch after the origin of bacteria, which agrees with the critic's points above that bacteria are the truly basal lineage of all life, and archaea, while highly different and pretty archaic, also share a lot of characteristics with bacteria, and perhaps more so with certain early lineages than with others that came later. The distinction between LUCA and the last common bacterial ancestor (LBCA) is a technical one given the trees they were working from, and are not, given the ranges of age presented, (see figure above), significantly different.

I believe this field is settling down, and though this paper, working from only a subset of the most ancient sequences plus fossil set-points, is hardly the last word, it appears to represent a consensus view and is the best picture to date of the deepest and most significant waypoints in the deep history of life. This is what comes from looking through microscopes, and finding entire invisible worlds that we had no idea existed. Genetic sequencing is another level over that of microscopy, looking right at life's code, and at its history, if darkly. What we see in the macroscopic world around us is only the latest act in a drama of tremendous scale and antiquity.

• Platitude.
• There are a lot of single-celled eukaryotes.
• Hitting bottom.

Truth and the Silo

Living in a silo, and wondering what is outside.

The first season of Apple's Silo series was beautifully produced and thought-provoking. Working from a book series of the same name which I have not read, it is set in a devastated world where about 10,000 people live in a huge underground silo. As the show progresses, it is clear that the society got a little totalitarian along the way. We are introduced to a "pact", which is the rules set up ~150 years ago, when a revolution of some undescribed sort happened. Now there is a "judicial" department that sends out goons to keep everyone in line, and there are the rules of the pact, which seem to outlaw fun and inquiry into anything from the past or the outside. It also outlaws elevators.

On the other hand, the population has a window to the outside, which shows an extremely drab world. A hellscape, really. But due to the murky nature of political power and information control within the silo, it is hard to know how real that view is. I won't give away any spoilers because I am interested in exploring the metaphors and themes the show brings up. For we are all working in, living in, and raised in, silos of some sort. Every family is a world more or less closed, with its own mood and rules, generally (hopefully) unwritten. The Silo portrays this involution in an incredibly vivid way.

(Third) Sheriff Nichols meets with the (second) mayor in a lovingly retro-decorated set.

It is fundamentally a drama about truth. One could say that most drama is about seeking truths, whether in a literal form like detective and legal dramas, or in more personal forms like romance, coming of age, and quest-for-power dramas. The point is to find out something, like how attractive the characters are, who will betray whom, who has lined up the better alliances, what a person's character is really like. Why read a story unless you learn something new? Here, the truths being sought are in bold face and out front. What is outside? Who really runs this place? What built this place? Why are we here? Why is everyone wearing hand-knit woolens? And the lead character, Juliet Nichols, is the inveterate truth-seeker. A mechanic by inclination and training, she really, really, wants to know how things work, is proud of mastering some of that knowledge, and is dedicated to dealing with reality and making it work. This quest leads her into rebellion against a system that is typical for our time ... at least in China, North Korea, and Russia. A surveillance and control state that watches everyone, pumps out propaganda, outlaws contrary thought, symbols, and objects, imprisons those who disagree, and ultimately sends inveterate truth seekers outside ... to die.

The nature of truth is of course a deep philosophical question. A major problem is that we can never get there. But even worse, we don't necessarily want to get there either. We automatically form a narrative world around ourselves that generally suffices for day-to-day use. This world is borne largely of habit, authority, instinct, and archetypes. All sorts of sources other than a systematic search for truth. For example, the easiest truth in the world is that we and our group are good, and the other group is bad. This is totally instinctive, and quite obvious to everyone. Religions are full of such truths, narratives, and feelings, developed in the least rigorous way imaginable, ending up with systems fired in the crucible of personal intution, and the imperatives of group dynamics and power. But truth? 

Lighting tends to be a little dark in the Silo, as are the politics.

The Orwellian society is curious, in a way. How can people's natural thirst for truth be so dangerous, so anti-social, and so brutally suppressed? Due to the processes mentioned above, each person's truth is somewhat distinct and personal, each person's quest goes in a different direction. But a society needs some coherence in its narrative, and some people (say, our immediate former president) have an intense yearning for power and need to dominate others, thus to bend them to their own version of truth. Reality distortion fields do not occur only in the tech industry, but are intrinsic to social interaction. The Silo, with its literally closed society, is a natural hothouse for a social fight for dominance and control of reality. Oh, and it has a eugenic program going on as well, though that is not a big focus in the first season.

One can almost sympathise with the fascists of the world, who see truth as functional, not philosophical. Whatever glorifies the state and its leader, whatever keeps the society unchanging and sheltered from uncomfortable truths and surprises. Who needs those pesky and divergent people, who just want to make trouble? And the more baroque and unhinged the official narrative has become, the more dangerous and easy the work of the social sabateur becomes. If the emperor has no clothes, it only takes a child to ask one question. In the Silo, there are various underground actors and uneasy officials who are losing faith in the official line, but where can they go? Is their doubt and desire for the facts more important than the continuation of this very tenuous and smothered society? Could a free-er society work? But why risk it?

In our contemporary world, the right wing is busy making up a parallel universe of obvious and button-pushing untruths. The left, on the other hand, is pursuing a rather righteous investigation into all the mainstream truths we grew up with, and finding them lies. Is the US founded on genocide, slavery, and imperialism? Or on democracy and opportunity? Is capitalism salveagable in light of its dreadful record of environmental, animal, and human abuses? It is not a comfortable time, as the truths of our society are shifting underfoot. But is the left unearthing the true truth, or just making up a new and self-serving narrative that will in time be succeeded by others with other emphasis and other interests? 

History is a funny kind of discipline, which can not simply find something true and enshrine it forever, like the laws of gravity. There is some of that in its facts, but history needs to be continually re-written, since it is more about us than about them- more about how our society thinks about itself and what stories it selects from the past, than it is about "what happened". There are an infinite number of things that happened, as well as opinions about them. What makes it into books and documentaries is a matter of selection, and it is always the present that selects. It is a massive front in the formation / evolution of culture- i.e. the culture war. Are we a culture that allows free inquiry and diverse viewpoints on our history, and welcomes observations that undercut comfortable narratives? Or are we a more Orwellian culture that enforces one narrative and erases whatever of its history conflicts with it?

The top level dining room has a viewport to the outside.

The Silo is definitely a culture of the latter type, and its history is brutally truncated. Yet interestingly, character after character nurtures some object that violates the pact, representing a bond with the forbidden, hazy past - the forebears and former world that must necessarily have existed, even as nothing is officially known about them. The urge to know more, especially about our origins, is deeply human, as is the urge to keep one's society on an even keel with a unified and self-satisfied narrative. This tension is built up unceasingly in the Silo, which is as far as we know a unique and precious remnant of humanity. It asks the question whether its stability is worth so much oppression and ignorance.

Parenthetically, one might ask how all this connects to the dystopia outside. The Silo is only painting in extreme colors trends that are happening right now in our world. As the climate gets weirder, we spend more time inside, increasingly isolated from others, entertaining ourselves with streaming offerings like the Silo. Its apocalypse appears more nuclear than climatological, but for us, right now, a dystopia is unfolding. After decades of denial and greed, the truth of climate heating is no longer at issue. So what if the truth is known- has gotten out of the bag- but no one wants to act on it? Another form of courage is needed, not any more to uncover the truth, but to meet that truth with action- action that may require significant sacrifice and a fundamental re-design of our Silo-like system of capitalism.

• Leave your silo, please.
• How many lies can one person believe?
• How one Confederate resolved to move on in Reconstruction.
• Want to turn off your brain for a little while? How about some stutter house?

Missing Links in Eukaryotic Evolution

The things you find in Slovenian mud! Like an archaeal cell that is the closest thing to the eukaryotic root organism.

Creationists and "intelligent" design advocates tirelessly point to the fossil record. Not how orderly it is and revealing of the astonishingly sequenced, slow, and relentless elaboration of life. No, they decry its gaps- places where fossils do not account for major evolutionary (er, designed) transitions to more modern forms. It is a sad kind of argument, lacking in imagination and dishonest in its unfairness and hypocrisy. Does the life of Jesus have gaps in the historical record? Sure enough! And are those historical records anywhere near as concrete and informative as fossils? No way. What we have as a record of Christianity's history is riven with fantasy, forgery, and uncertainty.

But enough trash talk. One thing that science has going for it is a relentlessly accumulating process by which new fossils appear, and new data from other sources, like newly found organisms and newly sequenced genomes, arise to clarify what were only imaginative (if reasonable) hypotheses previously. Darwin's theory of evolution, convincing and elegantly argued as it was originally, has gained such evidence without fail over the subsequent century and a half, from discoveries of the age of the earth (and thus the solar system) to the mechanics of genetic inheritance.

A recent paper describes the occurence of cytoskeletal proteins and structures in an organism that is neither a bacterium nor a eukaryote, but appears to be within the family of Archaea that is the closest thing we have to the eukaryotic progenitor. These are the Asgard Archaea, a family that was discovered only in the last decade, as massive environmental sequencing projects have sampled the vast genetic diversity hidden in the muds, sediments, soils, rocks, and waters of the world. 

Sampling stray DNA is one thing, but studying these organisms in depth requires growing them in the lab. After trolling through the same muds in Slovenia where promising DNA sequences were fond, this group fished out, and then carefully cultured, a novel archaeal cell. But growing these cells is notoriously difficult. They are anaerobic, never having made the transition to the oxygenated atmosphere of the later earth. They have finicky nutritional requirements. They grow very slowly. And they generally have to live with other organisms (bacteria) with which they have reciprocal metabolic relationships. In the ur-eukaryote, this was a relationship with the proto-mitochondrion, which was later internalized. For the species cultured by this research group, it is a pair of other free-living bacteria. One is related to sulfur-reducing Desulfovibrio, and the other one is related to a simpler archaeal Methanogenium that uses hydrogen and CO2 or related simple carbon compounds to make methane. Anaerobic Asgard archaea generally have relatively simple metabolisms and make hydrogen from small organic compounds, through a kind of fermentation.

A phylogenetic tree showing relations between the newly found organisms (bottom) and eukaryotes (orange), other archaea, and the entirely separate domain of bacteria (red). This is based on a set of sequences of universally used / conserved ribosomal proteins. While the eukaryotes have strayed far from the root, that root is extremely close to some archaeal groups.

Micrographs of cultured lokiarchaeal cells, with a scale bar of 500 nanometers. These are rather amoeboid cells with extensive cytoskeletal and membrane regulation.

Another micrograph of part of a lokiarchaeal cell, showing not just its whacky shape, but a good bit of internal structure as well. The main scale bar is 100 nanometers. There are internal actin filaments (yellow arrowheads), lined up ribosomes (gray arrowhead) and cell surface proteins of some kind (blue arrowheads).

What they found after all this was pretty astonishing. They found cells that are quite unlike typical bacterial or even archaeal cells, which are compact round or rod shapes. These (termed lokiarchaeal) cells have luxurious processes extending all over the place, and a profusion of internal structural elements reminiscent of eukaryotic cells, though without membrane-bound internal organelles. But they have membrane-bound protrusions and what look like vesicles budding off. At only six million base pairs (compared to our three billion) and under five thousand genes, these cells have a small and streamlined genome. Yet there are a large number (i.e. 258) of eukaryotic-related (signature) proteins (outlined below), particularly concerning cytoskeletal and membrane trafficking. The researchers delved into the subcellular structures, labeling actin and obtaining structural data for both actin and ribosomes, confirming their archaeal affinity with added features. 

A schematic of eukaryotic-like proteins in the newly cultured lokiarchaeal Asgard genome. Comparison (blue) is to a closely related organism isolated recently in Japan.

This work is the first time that the cytoskeleton of Asgard cells has been visualized, along with its role in their amoeboid capabilities. What is it used for? That remains unknown. The lush protrusions may collaborate with this organism's metabolic partners, or be used for sensing and locomoting to find new food within its sediment habitat, or for interacting with fellow lokiarchaeal cells, as shown above. Or all of these roles. Evolutionarily, this organism, while modern, appears to be a descendent of the closest thing we have to the missing link at the origin of eukaryotes, (that is, the archaeal dominant partner of the founding symbiosis), and in that sense seems both ancient in its characteristics, and possibly little changed from that time. Who would have expected such a thing? Well, molecular biologists and evolutionary biologists have been expecting it for a long time.

• Fossil fuel consumption is still going up, not down.

Credit where Faith is Due

The enormous, and sometimes underrated, value of faith and credit in the US financial instruments and institutions.

To hear the chaos caucus in congress put it, the country can go to hell, because their pet peeves- abortion, culture war, gay rights, gun rights ... have already gone to hell, so how much worse can it really get? Well, it could get a lot worse. We are a rich country for many reasons, but an important one is good management at the federal level of our financial and monetary affairs. It is this stability that undergirds not only the currency, but also economic expectations of the future, as expressed in inflation, and markets such as the commodities, bond, and stock markets, not to mention political stability, such as it is.

Every dollar is a credit instrument, staked on the faith and credit of the United States. Without that faith, it is worthless. Even with that faith, it is a debt of the government, counted under the vast rubric of "the federal debt". The more money we have (or that is out in the wild somewhere), the more that debt is. And that money has proliferated remarkably. Quite a few small countries have formally dollarized their economies, such as Ecuador, Zimbabwe, Palau, and Panama. Many more countries use dollars as a defacto currency or black market currency, including much of the criminal world. Most countries hold large reserves of dollars to anchor their international trade and financial stability. So we should not be surprised that our federal debt is very large. Does anyone (maybe our children!?) have to "pay it back"? Not really, since all those dollars can keep floating around forever. That is, until some other country's currency becomes the reserve currency of the world, and those dollars become either worth less, or we buy them back with that new currency. Forestalling that day should be one of our major foreign policy and economic goals.

Another dimension of the credit of the US is the formal debt, in bonds that the Treasury department issues to account for spending that was not matched by incoming taxes. The Federal Reserve accumulates Treasury bonds as it issues new dollars, but these bonds come with the obligation to keep paying interest. While this makes it convenient and profitable for other countries and rich people to hold bonds instead of dollar bills, (and earns the Fed itself plenty of notional money), it puts us on the hook for endless payments (of newly minted dollars) to support those interest payments. This is a rather dangerous situation, since the level of interest is not always under tight control. Depending on your view of financial affairs, the interest rate is dictated by the market, or by the Fed, or by the general level of inflation, which in turn influences the actions of both the market and the Fed. In any case, the interest on thirty trillion dollars is a heck of a lot more at higher rates than at low ones. This strongly motivates the Fed to use all its tools to curtail inflation and keep long term interest rates under control.

A graph of the price/earnings ratio of the SP500 collection of stocks, over the long term. This ratio indicates the length of time holders of stock are willing to wait for their returns to come in, in years. Notice how in the last few decades, the P/E ratio has persisted at significantly higher-than-historical levels, indicating, despite ups and downs, increased faith in the long-term stability of the economic and financial system. There may be other reasons- better regulation, technological innovation, 401K rules, lowered taxes, etc. But financial markets like the stock market are sensitive indicators of the credit given to our institutions.

All this comes back to the sound management of our financial affairs. We have a lot of room to maneuver due to economic expansion, both at home and abroad, which makes ongoing federal debts a built-in necessity. But we do not have endless room, and taxation plays an important role in making up the difference between money we can freely spend/issue to satisfy growth without inflation, and the rest of the money needed for government operations. What that gap is, is difficult to say, in the same way that the causes and time course of inflation are hard to pin down, but there is a gap, which taxes cover. Incidentally, in the MMT view of things, taxes reduce the level of private spending and consumption to make room for government spending, vs actually "funding" the government, which issues the money in the first place. But either way, taxes are an essential part of the financial cycle, and haphazardly forgiving tax obligations (or hobbling enforcement) is just as bad management as profligate spending or lax control of interest rates and inflation.

All these factors are part of the credit of the United States, and have been under fire from the right wing for several decades. When they are not cutting taxes of the rich or spending mindlessly on the military, they are shutting the government down or muttering about the deep state, the evils of the civil service, and how we should get back on the gold standard. Meanwhile the whole stability of our position as a rich economy and leader among nations hangs in the balance when thoughtless policy and extreme politics encroach from the fringes. Can the US run things better? Absolutely. Are there tradeoffs between humane and cultural virtues and financial / economic success? Absolutely. But from our founding era, when the Treasury Department under Alexander Hamilton established the US debt as a powerful instrument of union and stability, the credit of the US has been an underappreciated pillar of our position both domestically and internationally. Toying with it, via artificial crises and bad policy, is correspondingly an under-appreciated danger to our way of life.

• Business needs more regulation.
• Misogyny has a new hero.
• Hospitals are becoming scarcer and poorer. In part due to medicare "advantage".
• My congressperson is on the job.
• The state of solar.

Melting Proteins Through a Wall

Peroxisomes use a trendy way to import their proteins.

As has been discussed many times in this space, membranes are formidable barriers ... at the molecular level. Having a plasma membrane, and organelles enclosed within membranes, means needing to get all sorts of things across them, from the tiniest proton to truly enormous mega-complexes like ribosomes. Almost eight percent of the proteins encoded by the human genome are transporters, that concern themselves with getting molecules from one place to another, typically across membranes. A critical type of molecule to get into organelles is the proteins that belong there, to do their day-in, day-out jobs. 

But proteins are large molecules. There are two ways to go about transporting them across membranes. One is to thread them across linearly, unfolding them in process, and letting them refold once they are across. This is how proteins get into the endoplasmic reticulum, where the long road to secretion generally starts. Ribosomes dock right up to the endoplasmic reticulum membrane and pump their nascent proteins across as they are being synthesized. Easy peasy.

However other organelles don't get this direct (i.e. cotranslational) method of protein import. They have to get already-made full-length proteins lugged across their membranes somehow. Mitochondria, for instance, are replete with hard-working proteins, virtually all of which are encoded in the nucleus and have to be brought in whole, usually through two separate membranes to get into the mitochondrial matrix. There are dedicated transporters, nicknamed the TOM/TIM complexes, that thread incoming proteins (which are detected by short "signal" sequences these proteins carry) through each membrane in turn, and sometimes use additional helpers to get the proteins plugged into the matrix membrane or other final destination. Still, this remains a protein threading process, (of the first transport type), and due to its need to unfold and the later refold every incoming protein, it involves chaperones which specialize in helping those proteins fold correctly afterwards.

Schematic of the nuclear pore. The wavy bits are protein tails that are F-G rich (phenylalanine-glycine) that are unstructured and form a gel throughout the pore, allowing like-minded F-G proteins through, which are the nuclear transport receptors. These receptors carry various cargo proteins in an out of the nucleus, without having to unfold them. "Nup" is short for nuclear pore protein; GLFG is short for glycine, leucine (another hydrophobic amino acid), phenylalanine, glycine.

But there is another way to do it, which was discovered much more recently and is used principally by the nucleus. The nuclear pore had fascinated biologists for decades, but it was only in the early 2000's that this mechanism was revealed. And a recent paper found that peroxisomes also use this second method, which side-steps the need to thread incoming proteins through a pore, and risk all the problems of refolding. This method is to use a curiously constructed gel phase of (protein) matter that shares some properties with membranes, but has the additional property that specifically compatible proteins can melt right through it. 

The secret lies in repetitive regions of protein sequence that carry, in the case of the nuclear pore, lots of F-G sequences. That is, phenylalanine-glycine repeated regions of proteins that form these transit gel structures, or pores. The phenylalanine is hydrophobic, the glycine is flexible, and the protein backbone is polar, though not charged. This adds up to a region that is a totally disordered mess and forms a gel that can keep out most larger molecules, like a membrane. But if encountered by another F-G-rich protein, this gel lets it right through, like a pat of butter through oil. It also tends to let small molecules through quite easily. The nuclear pore is quite permeable to the many chemicals needed for DNA replication, RNA production, etc.

Summary from current paper, making the case that peroxisomes use PEX13 to make something similiar to the nuclear pore, where targeted proteins can traverse easily piggybacked on carrier proteins, in this case PEX5. The yellow spaghetti is the F-G or Y-G protein tails that congregate in the pore to make up a novel (gel) phase of matter. This gel is uniquely permeable to proteins carrying the same F-G or Y-G on their outsides, as does PEX5. "NTR" is short for nuclear targeting receptor, to which nuclear-bound cargoes bind.

Peroxisomes are sites for specialty chemistry, handling some relatively dangerous oxidation reactions including production of some lipids. They combines this with protective enzymes like catalase that quickly degrade the resulting reactive oxidative products. This suggests that the peroxisomal membrane would need to be pretty tight, but the authors state that the gel-style mechanism used here allows anything under 2,000 Daltons through, which certainly includes most chemicals. Probably the solution is that enough protective enzymes, at a high local concentration, are present that the leakage rate of bad chemicals is relatively low. 

Experimenters purify large amounts of the Y-G protein segments from PEX13 and form macroscopic gels out of them. In the center is a control, where the Y residues have been mutated to serine (S). N+YG refers to the N-terminus of the PES13 protein plus the Y-G portion of the proteins, while Y-G alone has only the Y-G segment of the PEX13 protein.

For its gel-containing pore, the peroxisome uses (on a protein called PEX13) tyrosine (Y) in place of phenylalanine, resulting in a disordered gel of Y-G repeats for its structure. Tyrosine is aromatic, (thus hydrophobic) like phenylalanine and tryptophan, and apparently provides enough distinctiveness that nucleus-bound proteins are not mistaken in their destination. The authors state that it provides a slightly denser packing, and by its composition should help prevent nuclear carriers from binding effectively. But it isn't just the Y-G composition that directs proteins, but a suite of other proteins around the peroxisomal and nuclear pores that, I would speculate, help attract their respective carrier proteins (called PEX5 in the case of peroxisomes) so that they know where to go. 

Evolutionary conservation of the Y-G regions of PEX13, over a wide range of species. The semi-regular periodicity of the Y placements suggests that this protein forms alpha helixes with the Y chains exposed on one side, more or less, despite general lack of structure. 

The authors show some very nice experiments, such as making visible gels from purified / large amounts of these proteins, and then showing that these gels indeed block generic proteins, and allow the same protein if fused to PEX5 to come right through. The result shown below is strikingly absolute- without its peroxisome-specific helper, the protein GFP makes no headway into this gel material at all. But with that helper, it can diffuse 100 microns in half an hour. It is like making jello that you can magically pass your hand through, without breaking it up ... but only if you are wearing the magic glove.

Experimental demonstration of transport. Using macroscopic gel plugs like those shown above, the diffusion of green fluorescent protein (GFP) was assayed from a liquid (buffer) into the gel. By itself (center, bottom), GFP makes no headway at all. But when fused to the PEX5 protein, either in part or in whole, it diffuses quite rapidly into the Y-G gel.

• Some history on immigration, leading to our curious current positions.
• What is China's GDP, anyhow?
• Whence the Francophone world?
• Humanism.
• Humanism.
• Wind energy faces some headwinds.

One Pump to Rule ... a Tiny Vesicle

Synaptic vesicles are powered by a single pump that has two speeds- on and off.

While some neural circuits are connected by direct electrical contact, via membrane pores, most use a synapse, where the electrical signal stops, gets turned into secretion of a neurotransmitter molecule, which crosses to the next cell, where receptors pick it up and boot up a new electrical signal. A slow and primitive system, doubtless thanks to some locked-in features of our evolutionary history. But it works, thanks to a lot of improvements and optimization over the eons.

The neurotransmitters, of which there are many types, sit ready and waiting at the nerve terminals in synaptic vesicles, which are tiny membrane bags that are specialized to hold high concentrations of their designated transmitter, and to fuse rapidly with the (pre-) synaptic membrane of their nerve terminal, to release their contents when needed, into the synaptic cleft between the two neurons. While the vesicle surfaces are mostly composed of membranes, it is the suite of proteins on their surfaces that provide all the key functions, such as transport of neurotransmitters, sensing of the activating nerve impulse (voltage), fusing with the plasma membrane, and later retrieval of the fused membrane patches/proteins and recycling into new synaptic vesicles.

Experimental scheme- synaptic vesicles are loaded with a pH-sensitive fluorescent dye that tells how the V-ATPase (pink) is doing pumping protons in, powered by ATP from the cytoplasm. The proton gradient is then used by the other transporters in the synaptic vesicle (brown) to load it with its neurotransmitter.

The neurotransmitters of whatever type are loaded into synaptic vesicles by proton antiporter pumps. That is, one or two protons are pumped out in exchange for a molecule of the transmitter being pumped in. They are all proton-powered. And there is one source of that power, an ATP-using proton pump called a V-type ATPase. These ATPases are deeply related to the F-type ATP synthase that does the opposite job, in mitochondria, making ATP from the proton gradient that mitochondria set up from our oxygen-dependent respiration / burning of food. Both are rotors, which spin around as they carefully let protons go by, while a separate domain of the protein- attached via stator and rotor segments- makes or breaks down ATP, depending on the direction of rotation. Both enzymes can go in either direction, as needed, to pump protons either in or out, and traverse the reaction ADP <=> ATP. It is just an evolutionary matter of duplication and specialization that the V-type and F-type enzymes have taken separate paths and turn up where they do.

Intriguingly, synaptic vesicles are each served by one V-type ATPase. One is enough. That means that one molecule has to flexibly respond to variety of loads, from the initial transmitter loading, to occasional replenishment and lots of sitting around. A recent paper discussed the detailed function of the V-type ATPase, especially how it handles partial loads and resting states. For the vesicles spend most of their time full, waiting for the next nerve impulse to come along. The authors find that this ATPase has three states it switches between- pumping, resting, and leaking. 

Averaging over many molecules/vesicles, the V-type ATPase pump operates as expected. Add ATP, and it acidifies its vesicle. The Y-axis is the fluorescent signal of proton accumulation in the vesicle. Then when a poison of the ATPase is added (bafilomycin), the gradient dissipates in a few minutes.

They isolate synaptic vesicles directly from rat brains and then fuse them with smaller experimental vesicles that contain a fluorescent tracer that is sensitive to pH- just the perfect way to monitor what is going on in each vesicle, given a powerful enough microscope. The main surprise was the stochastic nature of the performance of single pumps. Comparing the average of hundreds of vesicles (above) with a trace from a single vesicle (below) shows a huge difference. The single vesicle comes up to full acidity, but then falls back for long stretches of time. These vesicles are properly loaded and maintained on average, but individually, they are a mess, falling back to pH / chemical baseline with alarming frequency.

On the other hand, at the single molecule level, the pump is startlingly stochastic. Over several hours, it pumps its vesicle full of protons, then quits, then restarts several times.

The authors checked that the protons had no other way out that would look like this stochastic unloading event, and concluded that the loss of protons was monotonic, thus due to general leakage, not some other channel that occasionally opens to let out a flood of protons. But then they added an inhibitor that blocks the V-ATPase, which showed that particularly (and peculiarly) rapid events of proton leakage come from the V-ATPase, not general membrane leakage. They have a hard time explaining this, discounting various theories such that it represents ATP synthesis (a backwards reaction, in the face of overwhelming ratios of ATP/ADP in their experiment), or that the inactive mode of the pump can switch to a leakage mode, or that the pump naturally leaks a bit while it operates in the forward direction. It appears that only while the pump is on and churning through ATP, it can occasionally fail catastrophically and leak out a flood of protons. But then it can go on as if nothing had happened and either keep pumping or take a rest break.

Regulation by ATP is relatively minor, with a flood of ATP helping keep the pump more active longer. But physiological concentrations tend to be stable, so not very influential for pumping rates. These are two separate individual pumps/vesicles shown, top and bottom. It is good to see the control- the first segment of time when no ATP was present and the pump could not run at all. But then look at the bottom middle trace- plenty of ATP, but nothing going on- very odd. Lastly, the sudden unloading seen in some of these traces (bottom right) is attributed to an extremely odd leakage state of the same V-ATPase pump. Not something you want to see, generally.

The main finding is that this pump has quite long dwell times (3 minutes or so) under optimal conditions, and switches with this time period between active pumping and an inactive resting state. And that the pumping dwell time is mostly regulated, not by the ambient ATP concentration, but by the proton gradient, which is expressed by some combination of the charge differential across the vesicle membrane and the relative proton concentration gradient (the chemical gradient). It is a bit like a furnace, which has only two speeds- on or off, though in this case the thermostat is pretty rough. They note that other researchers have noted that synaptic vesicles seem to have quite variable amounts of transmitter, which must derive from the variability of this pump seen here. But averaged over the many vesicles fused during each neuronal firing, this probably isn't a big deal.

The behavior of this pump is a bit weird, however, since most machines that we are familiar with show more gradual breakdowns under stress, straining and slowing down. But here, the pump just decides to shut down for long periods of time, generally when the vesicle is fully charged up, but sometimes when it is not. It is a reflection that we are near the quantum level here, dealing with molecules that are very large in some molecular sense, but still operating at the atomic scale, particularly at the key choke points of this kind of protein that surely involve subtle shifts of just a few atoms that impart this regulatory shift, from active to inactive. What is worse, the pump sometimes freaks out completely and, while in its on state, switches to a leaking state that lets out protons ten times faster than the passive leakage through the rest of the vesicle membrane. The authors naturally urge deeper structural studies of what might be going on!

• Our soylent future.
• India and the new world order.
• A war within.
• Greenland's ice is at risk.

America as Hegemon

The imperial track record is not good, but the hegemonic track record isn't all that bad.

I was recently visiting the USS Hornet, a WW2-era aircraft carrier now turned into a museum on San Francisco bay. Soon after, it was Fleet Week, when the US navy pays a visit to the Bay Area in force, capped by a Blue Angels air show. An appalling display of naked militarism, granted. But also an occasion to reflect on our world-wide empire, the nature of American power, the competence of our military, and the state of things internationally.

It was a little weird, seeing decades-old technology swooping up and down the bay, which has been, beneath this benevolent protection, so restlessly advancing the technological frontier in totally different directions- computers, phones, applications, streaming, social media. Which trends are more important for America's place in the world? Which technologies rule? What are we doing with all this military hardware? I tend to have pretty conservative views on all this, that the US is right to stick with the post-WW2 consensus that our military should be as strong as possible, and partner with like-minded countries around the world to advance the vision of that era, of human rights and democracy for all. 

When we have tried to do this task directly, in Vietnam, Iraq, and Afghanistan, however, it has generally turned out very badly. The Iraq war was misconceived from the start, and went downhill from there. Despite the laudible aim of sparing the Iraqi people from the continued depredations of Saddam Hussein, the lying and the incompetence at all levels made the cure far worse than the disease, with anarchy and hundreds of thousands dead. But let's write that one off as a George Bush-as-decider blunder.

The Afghanistan debacle is more painful to contemplate, in some ways, in what it says about our fundamental incompetence as an imperial power. Its rationale was straightforward, international support wide-spread, and our power there absolute in the opening acts of the takeover. Yet with all those advantages, we ended up, twenty years later, turning tail and watching our hand-built Afghan military melt away even before we left the country. The Russians had, frankly, a better record in their Imperial Afghan turn. 

It is an appalling track record, really. We evidently and thankfully do not have the advantage of ruthlessness that ancient Rome enjoyed, or modern day spoilers like Russia and Iran. But nor, apparently, do we have the advantage of friendly relations, favorable hearts & minds, and good intelligence. We were constantly led astray by "friends" with all kinds of personal vendettas and agendas. We pride ourselves in our independence from the rest of the world, and thus know little about it, which means that we go into these settings woefully unprepared, besotted by whatever ideological issue du jure is fashionable in the US. Our priorities in Afghanistan seemed to be to hold elections and educate women. But were those the right aims? And even if so, were they carried out with any kind of wisdom and sense of priorities and proper preparation?

Most concretely, our military relationship was a disaster. The US military tried to make the new Afghan military into its own image and graft onto it its own systems and capablities, creating a dependence that caused immediate failure when Afghans caught wind that we were really, actually, going to leave. This was an incredible result, especially after the US military had been responsible for "training" countless militaries all over the world for decades. 

What on earth were we doing? Similarly to the intelligence failures, the military failures came from some fundamental inability to understand the problem at hand, and work with the society as it existed. Instead of creating a sustainable, right-sized, and politically viable force, we just assumed we were the good guys and anything we did was good. There was an intrinsic tension between leaving the society as it was, thereby just funding a reboot of a Taliban-like (or northern alliance-like) force to keep the country pacified, and forcing some change, on social, political, economic, and technological levels, by changing the form of government and associated institutions. The US clearly did not invade Afghanistan to keep everything the same. But by overreaching, we essentially achieved nothing, allowing precisely the group we dethroned to come back into power, and casting the country back into its pre-invasion economic and social abyss. At least, thanks to other technological bequests of the US and the West, the Afghans now have cell phones.

So our military and other institutions do not come off well in any of their recent engagements. It is a case of losing every battle, while winning the war. For we still enjoy a hegemonic position, not thanks to our incompetent and technology-bedazzled military, but thanks to our friends, with whom we still lead the world. The core groups of the anglophone countries, NATO, and the East Asian alliances with Japan, South Korea, and Taiwan remain the core of the developed world, enjoying peaceful relations, democracy, and prosperous economies. China is advancing mightily to displace that grouping, but can not do so alone, and has little hope of doing so with streadfast friends like Russia and North Korea by its side.

Tiers of development. Blue is the developed world, yellow the middle-tier (developing), and red, the lower tiers of development (desperately developing, one might say).

The advantages of joining this developed core are so evident, that one wonders why it is under threat, both from the spoiler countries like Russia, and from endogenous authoritarians in the US, Poland, Hungary, India, and elsewhere. Two decades ago, we were looking at the end of history, when a futuristic society of peace and contentment would inherit the post-cold war earth, Russia would join NATO, and we would live happily ever after. But democracy is a cultural pattern that not everyone can easily understand, especially people who run (or want to run) undemocratic countries. As our framers understood so well, sovereign power is dangerous, and needs to be diluted among publicly competing branches, candidates, officers, and voters for it to be durably controlled, a bit like an atomic chain reaction. It takes wisdom and humility to figure that out and abide by such fundamental (constitutional) rules. 

It is tempting to take that power directly in hand, to satisfy a burning desire to "do something". In the US, a Republican minority has progressively lost its commitment to popular rule and the viability of contemporary governmental institutions. This is, incidentally, only possible because of their special relationship with sources of money and of media influence, without which they would have little popular purchase. In China, the communist party figured that, despite its own history of ravaging its country, it had developed a stable enough system of governance, and had obtained implicit popular support ... reflecting either brainwashing or acquiescence ... that it did not need actual elections or Western-style divided government. And in Russia, the bitterness of its descent into kleptocracy, under the poisoned banner of "capitalism", combined with various snubs from the West and general historical and cultural distance, rendered the idea of becoming a Western country too much to bear.

Each authoritarian system has, like an unhappy family, its own reasons, while the happy families of the West seem to, think along similar lines almost involuntarily, at least until some authoritarian mountebank comes along to solve all our problems by doing away with our safeguards. We are in a grand race to find out which systems are more stable. Those that rely on one person, such as the aging Vladimir Putin, for their decisions, or those that rely on popular will and a controlling set of institutions. The lessons of history could not be more stark, telling us that the former is the bigger crapshoot. Sometimes it turns out well, but more often not. That is why liberalism and deliberative democracy developed in the first place.

There remains a great deal of middle ground around the world. The muslim countries, for example, form a middle tier of populous and developing countries comprising, between Pakistan, Egypt, Indonesia, Bangladesh, Turkey, Iran, the Gulf states and others, well over a billion people. Our wars in Iraq and Afghanistan didn't help our relations there, but on the other hand, China is hardly making itself loved either, with its extermination campaign in Xinjiang. The cultural patterns of the Islamic world make it a particularly hard sell for Western democracy vs authoritariansim. Thus the brief Arab Spring came to a painful and inglorious end, mostly in whimpers, sometimes in horror. The liberatlization process took a long time in the West as well, measured perhaps from the French revolution, through the revolutions of 1848, culminating the aftermath of World War 2, with developmental delays in the Eastern European deep freeze. Ideas and new social patterns take a long time to take root, even when the templates (Switzerland, the US, ancient Greece) are at hand.

The American hegemony is little more than an agreement among like-minded and friendly nations to maintain their democratic systems, their prosperous (if environmentally rapacious and unsustainable) economies, and to largely offload their military responsibilities on the US. Whether those responsibilities have been well-stewarded is certainly doubtful. But up to this point, the agreement has been highly successful, mostly because the US has been a willing, stable, and vigorous anchor. Can the EU take our place? It is conceivable, but the EU is structurally less decisive. Bodies like the UN or the G20 are even less capable, in any executive sense. So, until we come up with something better, with a hot war against Russia and a cold one developing against China, and while other cultures are slowly chewing over their various problems with authoritarianism, it is critical that the US remain that anchor for the democratic developed world.

• What are the rules, anyhow?
• Bad intelligence.
• History is important to authoritarians, at least.
• Argentina is in the throes of inflation.
• The totalitarian speakership is bad for democracy, as well as being unworkable with thin majorities.

Empty Skepticism at the Discovery Institute

What makes a hypothesis scientific, vs a just-so story, or a religious fixation?

"Intelligent" design has fallen on hard times, after a series of court cases determined that it was, after all, a religious idea and could not be foisted on unsuspecting schoolchildren, at least in state schools and under state curricula. But the very fact of religious motivation leads to its persistence in the face of derision, evidence, and apathy. The Discovery Institute, (which, paranthetically, does not make any discoveries), remains the vanguard of intelligent design, promoting "skepticism", god, alternative evolutionary theories, and, due to the paucity of ways to attack evolution, tangential right-wingery such as anti-vaccine agitation. By far their most interesting author is Günter Bechly, who delves into the paleontological record to heap scorn on other paleontologists and thereby make room for the unmentioned alternative hypothesis ... which is god.

A recent post discussed the twists and turns of ichthyosaur evolution. Or should we say biological change through time, with unknown causes? Ichthyosaurs flourished from about 250 million years ago (mya) to 100 mya, with the last representatives dated to 90 mya. They were the reptile analogs of whales and dophins, functioning as apex predators in the ocean. They were done in by various climate crises well-prior to the cometary impact that ended the Cretaceous and the reign of dinosaurs in general.

Bechly raises two significant points. First is the uncertain origins of Ichthyosaurs. As is typical with dramatic evolutionary transitions like that from land to water in whales, the time line is compressed, since there are a lot of adaptations that are desirable for the new environment that might have been partially pre-figured, but get fleshed out extensively with the new ecological role and lifestyle. Selection is presumably intense and transitional fossils are hard to find. This was true for whales, though beautiful transitional fossils have been found more recently. And apparently this is true for the Ichthyosaurs as well, where none have been found, yet. There is added drama stemming from the time of origin, which is right after the Permian exinction, perhaps the greatest known extinction event in the history of the biosphere. Radiations after significant extinction events tend to be rapid, with few transitional fossils, for the same reason of new niches opening and selection operating rapidly.

Ichthyosaur

Bechly and colleagues frequently make hay out of gaps in the fossil record, arguing that something (we decline to be more specific!) else needs to be invoked to explain such lack of evidence. It is a classic god of the gaps argument. But since the fossils are never out of sequence, and we are always looking at millions of years of time going by with even the slimmest layers of rock, this is hardly a compelling argument. One thing that we learned from Darwin's finches, and the whole argument around punctuated equilibrium, is that evolution is typically slow because selection is typically not directional but conservative. But when selection is directional, evolution by natural selection can be startlingly fast. This is an argument made very explicitly by Darwin through his lengthy discussions of domestic species, whose changes are, in geological terms, instant. 

But Bechly makes an additional interesting argument- that a specific hypothesis made about ichthyosaurs is a just-so story, a sort of hypothesis that evolutionary biologists are very prone to make. Quite a few fossils have been found of ichthyosaurs giving birth, and many of them find that the baby comes out not only live (not as an egg, as is usual with reptiles), but tail-first. Thus some scientists have made the argument that each are adaptations to aquatic birth, allowing the baby to be fully borne before starting to breathe. Yet Bechly cites a more recent scientific review of the fossil record that observes that tail-first birth is far from universal, and does not follow any particular phylogenetic pattern, suggesting that it is far from necessary for aquatic birth, and thus is unlikely to be, to any significant extent, an adaptation. 

Ha! Just another story of scientists making up fairy tales and passing them off as "science" and "evolutionary hypotheses", right?  

"Evolutionary biology again and again proves to be an enterprise in imaginative story-telling rather than hard science. But when intelligent design theorists question the Darwinist paradigm based on empirical data and a rational inference to the best explanation, they are accused of being science deniers. Which science?" ... "And we will not let Darwinists get away with a dishonest appeal to the progress of science when they simply rewrite their stories every time conflicting evidence can no longer be denied."

Well, that certainly is a damning indictment. Trial and sentencing to follow! But let's think a little more about what makes an explanation and a hypothesis, on the scientific, that is to say, empirical, level. Hypotheses are always speculative. That is the whole point. They try to connect observations with some rational or empirically supported underlying mechanism / process to account for (that is, explain) what is observed. Thus the idea that aquatic birth presents a problem for mammals who have to breathe represents a reasonable subject for an hypothesis. Whether headfirst or tailfirst, the baby needs to get to the surface post haste, as soon as its breathing reflex kicks in. While the direction of birth doesn't seem to the uninitiated (and now, apparently to experts with further data at hand) to make much difference, thinking it does is a reasonable hypothesis, based on obvious geometric arguments and biological assumptions, that it is possible that the breathing reflex is tied to emergence of the head during birth, in which case coming out tailfirst might delay slightly the time it takes between needing to breathe and being able to breathe. 

This argument combines a lot of known factors- the geometry of birth, the necessity of breathing, the phenomenon of the breathing reflex initiating in all mammals very soon after birth, by mechanisms that doubtless are not entirely known, but at the same time clearly the subject of evolutionary tuning. And also the paleontological record. Good or bad, the hypothesis is based on empirical data. What characterizes science is that it follows a disciplined road from one empirically supported milestone to the next, using hypotheses about underlying mechanisms, whether visible or not, which abide by all the known/empirical mechanisms. Magic is only allowed if you know what is going on behind the curtain. Unknown mechanisms can be invoked, but then immediately become subjects of further investigation, not of protective adulation and blind worship.

In contrast, the intelligent design hypothesis, implicit here but clear enough, is singularly lacking in any data at all. It is not founded on anything other than the sentiment that what has clearly happened over the long course of the fossil record operates by unknown mechanisms, by god operating pervasively to carry out the entire program of biological evolution, not by natural selection (a visible and documented natural process) but by something else, which its proponents have never been able to demonstrate in the least degree, on short time scales or long. Faith does not, on its own, warrant novel empirical mechanisms, and nor does skeptical disbelief warrant them. Nor does one poor, but properly founded, hypothesis that is later superceded by more careful analysis of the data impugn the process of science generally or the style of evolutionary thinking specifically.

Imagine, for example, if our justice system operated at this intellectual level. When investigating crimes, police could say that, if the causes were not immediately obvious, an unnamed intelligent designer was responsible, and leave it there. No cold cases, no presumption of usual natural causality, no dogged pursuit of "the truth" by telegenic detectives. Faith alone would furnish the knowledge that the author of all has (inscrutibly) rendered "his" judgement. It would surely be a convenient out for an over-burdened and under-educated police force!

Evolution by natural selection requires a huge amount of extrapolation from what we know about short time scales and existing biology to the billions of years of life that preceeded us. On the other hand, intelligent design requires extrapolation from nothing at all- from the incredibly persistent belief in god, religion, and the rest of the theological ball of wax not one element of which has ever been pinned down to an empirical fact. Believers take the opposite view solely because religious propaganda has ceaselessly drilled the idea that god is real and "omnipotent" and all-good, and whatever else wonderful, as a matter of faith. With this kind of training, then yes, "intelligent" design makes all kinds of sense. Otherwise not. Charles Darwin's original hypothesis was so brilliant because it drew on known facts and mechanisms to account (with suitable imagination and extrapolation) for the heretofore mysterious history of biology, with its painfully slow yet inexorable evolution from one species to another, one epoch to another. Denying that one has that imagination is a statement about one's intelligence, no matter how it was designed.

• Only god can give us virulent viruses.
• The priest who knew it so well, long ago.
• A wonderful Native American Film- Dance me outside.
• With a wonderful soundtrack, including NDN Kars.
• We need to come clean on Taiwan.
• Appeasers, cranks, and fascist wannabes.
• Vaccines for poor people are not profitable.
• California is dumbing down math, and that will not help any demographic.