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.

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• 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.

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• Bad intelligence.
• History is important to authoritarians, at least.
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• 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.
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• 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.