What Does it Mean to be Supernatural?

What was once a reasonable hypothesis has become an epistemological trash heap. And, if something "points beyond itself" does anyone know where it is pointing?

After having exhausted the possibilities of "discernment" as a theological buzzword, philosophical believers have moved on to a new expression, that anything real "points beyond itself" to whatever they think animates the world's workings beneath the surface. Which is to say, god. It is an empty expression, reflecting an indoctrinated mindset more than an analysis of anything outside the theological system.

This is not to say that there are not hidden realities that we have inferred with some, even great, warrant. We have a universe flooded with neutrinos which we can only barely detect. There is dark enery and dark matter that eludes any detection at all, but still is inferred to be there. And the origin of the universe itself is far from being explained.

Back in the day, before humanity discovered evolution, electricity, atoms, uniform force fields, and all the other apparatus by which so much of reality is now reasonably and mechanically explained, the sheer number of wonders in the world that required explanation was truly prodigious. Invoking magic, in the form of heroic or father-beings, was reasonable enough, though already faintly ridiculous. Some ancient philosophers may have dabbled in atomic theory and evolution-like ideas, but even they had hardly more going for their theories, in actual content, observation, and detail, than the mythicists did.

A trinity, with cherubim. A theory of reality, or something else entirely?

Now things are quite different, and it is significant to note that in the intervening time, none of the newly found mechanisms of reality have had anything to do with gods or other supernatural mechanisms. Plenty of odd things have been found, but none with any theological character. So the batting average of what was, a priori, an attractive hypothesis, is now zero, with a lot of scientific "discernment" under our belts. Yet theological theorists and believers press on with their trinities, spirits, and gods, invoking supernatural realms of which our puny science knows nothing.

A more modern trinity, participating in another archetypal savior story.

But what does it mean to be supernatural? Nothing positive, that's for sure. It is void of knowledge filled with whatever is unknown or imagined, yet for which reasonable, testable models of reality have no place. A place for the archetypal father-gods, the prayers that don't work, the grace and hope that saves one person in an airplane crash while killing all the others, the creator who nudges evolution to make one being in god's image- us. How obvious. Yet human psychology is so reliable and flawed, and the slick supernatural dreams of theology so well-honed over the millennia, that people skilled in the arts of pursuasion and confidence gain converts still at this very late date.

• De-institutionalizing security on an internet of value, and also, meanwhile, killing the banks.
• On the other hand, if we leave it to Amazon, music will die.
• Trump- hero or antihero?
• Health care still costs too much.
• Due to lack of competition, and lack of a public option.
• Class, capitalism, and pay-for-performance, cont.
• Fighting dirty, in energy.
• Accountability or secrecy? Secret settlements are wrong.
• Good news from the Philippines.
• Lack of competition makes productivity look worse.

Donuts and Zippers for DNA Repair

How the protein RAD52 conducts homologous search and rescue of damaged DNA. And what we can do with that knowledge.

Our bodies are full of wonders. Despite being about fifty years into the age of molecular biology, we are still only scratching the surface of the complexity that lies within. Remember that when you hear that someone has found a gene "for" a disease. That gene and the protein it encodes have a lengthy and intricate story to tell about what it does in the normal organism, how it got to that point in evolution, and maybe a multitude of ways in which mutations might drive it off track. Linking it to one disease is only a small part of a much larger tale.

BRCA2 is an example of this: a pre-eminent gene "for" breast cancer. But what does it do? The point of its existence is hardly to make us miserable. No, it participates in DNA repair, and thus some mutations in its sequence, or full deletions, can leave cells open to a cascade of further mutations, which can lead to cancer.

Recent work has shown that BRCA2 is synthetically lethal with a better understood protein called RAD52. Being synthetically lethal (in mice in this case, where genetics can be done) means that a mutation or deletion of either one of the genes is not lethal by itself, but the combination of both *is lethal. Such an observation implies that the two proteins participate in the same process, at least partially. One can "cover" for defects in the other one, in a pinch. But take away both, and the organism can not survive.

So BRCA2 and RAD52 do similar things, which is helpful to know, since RAD52 is actually better understood. Yeast cells, which are even easier to study than mice, have RAD52 but no BRCA2, which seems to have arisen more recently in evolution. We'll get back to BRCA2 briefly below, but I will focus on RAD52- a protein that conducts that amazing process that is homology-driven DNA repair.

Homologous DNA repair happens when a mutation is detected, such as a double-strand break, a missing nucleotide (and consequent single strand break), or even just where a mis-matching nucleotide was inserted by the DNA polymerase by mistake. Perhaps the sequence goes CAGCT on one strand, and GGTTG on the other, antiparallel strand. There is a G:T pair in here that is an error- not part of the official Watson-Crick regime!

A mismatch happens (orange).

What was the right sequence? The sequence of this duplex does not tell you, unfortunately, anymore. In some cases, there are chemical marks like methylation that can be used to tell the difference between the newly synthesized strand and the other one that has been around the block, and this is used in some forms of post-replication repair. But if the mutation slipped through that process, or happened at a different time, again we would not know where to turn for the right way to correct such an error.

But there is one place to turn ... another copy of that DNA, if the organism has one. Diploid organisms always have another copy of every gene lying around, and other organisms, even bacteria, do as well, if they have already replicated their DNA but not divided the cell, quite yet. This is called homologous DNA repair, because the other copy is called a homolog of the first. Organisms have developed ornate methods of homology detection, strand invasion, copying, and repair to use the information from a good version to repair a defective one. And one of the key actors is RAD52, or its colleague, BRCA2.

Structure of RAD52. The ring is composed of multiple subunits of the same protein, each colored differently here. DNA, in single stranded form, can wind around the outside.

RAD52 looks like a big donut. Well, in relation to DNA, at least. The DNA doesn't thread though the middle, as it does in some other important machinery, but rather winds around the outside, in single-stranded form. That way, RAD52 can expose the single stranded DNA to other donuts with their respective single stranded DNA, and figure out which ones match. It is evident that the energetics of DNA-DNA binding and DNA-RAD52 binding are engineered to be very similar, so that DNA engaged in mismatches does not get tangled up in unproductive knots, but prefers to wrap around these massive protein donuts. But then on the other hand, when a true DNA-DNA duplex match is found, it smoothly zippers up, out of the Rad52-wrapped state.

Model of the energetics of SS DNA binding to RAD52, with subtle transitions from SS and protein-bound, to double-stranded if a proper match is found (pink).

This is the mechanistic secret of homology search between DNA stands, at least in principle. How this happens at the scale of full super-coiled duplex genomes, in the crowded milieu of the cell, with the DNA studded with countless other proteins and complexes, plus a few chemical alterations, remains a bit hard to understand, however. And the rest of the repair story, of directing a large invasion of homologous DNA into the defective duplex, editing out the defective strand, re-duplicating the donor DNA, flushing the ends, and all the other odds and ends, are of course another story entirely.

In the current paper, the researchers looked for inhibitors of RAD52, intended for breast cancer treatment. On of the traditional treatments is to break the patient's DNA with toxic chemicals, because the cancer cells typically are missing the function of some DNA repair proteins like BRCA2, or BRCA1 which acts in the same pathway. Missing this repair function has generated the cancer in the first place by creating new mutations, but there can be too much of a good thing. That is, an excess of DNA damage causes cells- even cancer cells- to kill themselves or to die outright. So it would be helpful in this mode of therapy to be able to turn off what turns out to be, for humans, a backup DNA repair pathway- RAD52.

"RAD52 forms an oligomeric ring, where the primary ssDNA binding site is located in the narrow groove spanning the ring circumference. We designated this ssDNA-binding groove as the feature to be targeted by small molecule inhibitors. While disrupting the protein-ssDNA interaction with small molecules presents a formidable challenge that has only been overcome in a handful of cases, the ssDNA binding groove of RAD52 is a promising target and is distinct from the ssDNA binding sites of other ssDNA binding proteins."

The technique to screen for RAD52 inhibitors used fluorescence energy transfer. Donor and acceptor fluorophores were put on opposite ends of 30-nucleotide DNA strands. This happens to be exactly the length that fits around one RAD52 donut, so when the DNA binds to RAD52, the ends meet and the acceptor efficiently absorbs fluorescent photons from the donor, and re-emits at its own characteristic wavelength. Wow!

Compound found by screening for impaired fluorescence energy transfer between ends of DNA wrapped around RAD52 protein complexes.

Example of screening data, showing that binding of double-stranded DNA (gray) is unaffected by the compound "1", while the binding of single-stranded DNA is strongly impaired, at very low concentrations. The assay (Y axis) is fluorescence by the red fluorophore, which is excited by the green fluorophore only when the green fluorophore is nearby and also excited by the researchers shining appropriate (green) wavelength light onto the experiment.

After screening a bunch of chemicals, they came up with one that really works well, at low concentration. It clearly inhibits single strand DNA winding around RAD52. It also, in other work, interacts directly with RAD52, indicating that, as it looks quite a bit like a couple of DNA bases, it probably just binds better than DNA itself. By computational modelling they find that this compound binds into the single-stand DNA binding groove of RAD52, very snugly positioned in a way that is tightly bound and will keep anything else at bay.

 Model, using the known structure of both RAD52 and compound "1", of how they fit together. The chemical fits tightly in a groove that would otherwise bind single stranded DNA.

Finally, they ask whether this candidate drug works in cells. In tissue culture cells, the very low concentration of 500nM makes the cells behave as though they had no RAD52 at all, which is very promising indeed. Indeed, it kills cells lacking BRCA2, if treated with a chemotherapy regime, validating the idea of the work. How all this will work in whole animals and in humans is, of course another story entirely, in a long road to drug development. But this is an example of beautiful work with its origins in studies in model organisms (yeast) and structures in basic molecular biology.

"We also show that [compound] ‘1’ selectively kills cells depleted of BRCA2, further supporting the importance of the RAD52-ssDNA interaction in BRCA deficient cells and the potential therapeutic value of RAD52 inhibition."

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• Religion as fully imaginary... and for some, that is OK. "Secret knowledge that everyone else was too blind to see" "God is the ultimate transitional object".
• The decades of lies and meanness that led to this.
• Who are you gonna believe?
• Of ~400 districts in Afghanistan, the Taliban controls 40 and is actively fighting to control 44 more.
• Costa Rica- a beautiful, just, peaceful, and low-carbon country... "Traffic is offensive."
• Is there a problem with the sources of Islam, and our understanding of its history?
• Our friends the Saudis, cont... balkanizing the Balkans.
• Krugman detects evil and greed on the GOP side.
• In return, one of the steps of grief ... denial and lashing out.
• Is America breaking bad?
• Obama leaves a great deal undone.

I Like Looking at Westerns, Not Being In One

Where are the gun nuts taking us?

I admit it.. I love Westerns. The classics channels have my number. When you carry the law on your hip, drama is liable to break out at any moment. For a family show, Bonanza sure stacked 'em up. For dramatic purposes and moral edification, the Western is one of the finest genres, right up there with medieval-ish science fiction-ish power-drama. If our love of drama (like our experience of dreams, in part) is about social play and modelling, focused on training to face tough choices that come up rarely in real life, but have extraordinary consequences when they do, the payoff from Westerns is obvious.

But watching is one thing. Being in the middle of it is something else. The point of our communal "real" life, politics, law, etc., as opposed to our dramatic alter-lives, is to make horrible choices, compelling a they are dramatically, as rare as possible, not more common. I get it that you as a gun-toting open-carry-ist are the last hero standing between my precious bodily fluids and that cold-blooded robber. Or worse yet, a Hillar-ized jack-booted federal agent. But the reality is quite different.

The reality is that guns make us less safe, not more. The police are going into conniptions about facing an ever increasing tide of guns. They don't want the "help" from all those open-carry-ists. The Republican convention is a no-gun zone. Why? Not because crime won't happen. It is because guns are dangerous to everyone around them, even to the very well-trained. Western towns set up gun controls as soon as they could- as soon as the law became stronger than the outlaws. Why? Because guns are unsafe, and if everyone has one, someone with less training and dedication to the constitution than the dedicated, well-trained, and articulate gun nut is going to come stumbling out of a saloon and shoot up the town for whatever purpose, or none. Look at Afghanistan, a country awash with guns, and a sort of contemporary wild west. Is that a safer place to live? A better place to live?

Unfortunately, addressing the fantasy life of gun nuts is easier said than done. Apparently statistics and reason doesn't make you stop wanting to buy, clean, stroke, and carry your gun around. And this fantasy extends to insurrection and terrorism. A blog I follow regularly issues threats, both veiled and explicit, against the "gun-grabbers". Unique among grievances in our country, the gun nuts think the very power they are guarding so zealously is the means of its and their defense, leading naturally to revolutionary rhetoric- the kind of thing that would be unconscionable in any other community or venue:

"Yea, Hopkins just went from being a stooge to being an enemy.  Understand, Hopkins, that universal background checks will bring out the guns, and not in a good way, if you know what I mean.  That is a line that cannot be crossed by anyone.  It won’t happen, and your willing adultery with the Bloomberg position is most disappointing."

"Finally, it gives me amusement and pleasure to point out the obvious.  You can never effect this outcome because we have the guns.  Understand?  You can’t take them from us because you eschew them and we don’t.  What?  You didn’t really think we’d give them up, did you?  And you didn’t really think those cops would want to be gunned down as they try to confiscate weapons, did you?"

"God grants me the right (and even duty) to go armed and conduct myself in a manner consistent with self defense.  Not you, and not the constitution, and not black robed tyrants.  That means that whatever the outcome of this “day in court” to which you refer, the right to self defense is still present because God said so."

"But it’s not over with.  Know who your local police are.  Make sure to let them know in no uncertain terms, without them knowing who you are, that it is all just beginning.  Make your points in the shadows, not in the light of day.  Make it clear to them that you will not tolerate infringements on your God-given rights. ... Make your points until the police no longer want to wage war on otherwise peaceable citizens.  Make your points in the shadows. That’s how this should go down.  Do you understand?"

And this is not to mention Donald Trump's recent casual incitement of the assassination of his opponent.

So we are faced with a heady macho-psycho-Freudian-theological brew of perceived potency, with strong ties to American history and heritage, but also to much more deeply seated emotional issues.  Other countries have been able to lower the temperature around guns. Why not us?

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• On the triumph of Bayes, of induction and of guessing generally.
• IBM fail.
• Leotard watch.
• Essential curriculum: empathy.
• The Afghan hinterlands count too.
• Yet another market failure.
• Is Italy next-it?
• Human memory is very bad.

No, I do Not Really Feel Your Pain

Where is pain in the brain, and is empathic pain in the same domain?

Our culture has gone through some interesting evolutions in the experience of pain. From antiquity through medieval times, inflicting pain was entertainment and justice, in forms such as gladiatorial fighting, bull-fighting, burning at the stake, trial by torture, and plain old torture. In modern times we seem to have softened to the point of respecting human rights, one of which is to not inflict gratuitous pain, even on deserving criminals. Perhaps this is due to the subjugation of pain in medical and dental settings, which has raised our expectations for an untroubled existence. Or perhaps it is due to dominance of secularism which continues to guide moral innovation and refuses to countenance twisted theistic rationalizations for our painful existence, let alone explicit theological torture. With the current election, we seem to be taking a step backward in the excruciating-ness department, but still one may hope for the best!

Despite such variation in cultural tolerance of pain, (especially that of others), our intrinsic capacities are naturally long-standing and common to most animals. In particular, pain is perhaps the most immediate and insistant instance of consciousness, and thus a particularly interesting case for investigating the nature of consciousness and its presumptive basis in the brain. One thing we have learned is that pain comes in many forms, from vague itches to excruciating burns. And in addition, we experience various abstract pains, such as bereavement, the sudden horror of devastating news, and the empathy we feel for the pain of others- at least some people, in some cutural settings(!)

So it is not a simple field. A recent paper made some new observations about empathic pain. Prior work has shown substantial overlap of self-pain and empathic pain as represented in the brain, leading to theories that it is involuntary and almost as vivid as one's own. But we know that that is not quite true- that spectators at the colosseum could, though social training and construction, view the torture and dismemberment of unfortunate gladiators with enthusiastic bloodlust rather than squeamish sympathy.

So where is it, and how do we feel pain of both types? These authors discuss various defects with the current model, particularly that brain locations that have been noted as activated during both own-pain and empathic pain are not really pain centers per se, but are activated by many non-pain events, to the point of being some of the most frequently activated areas in the brain across all fMRI studies.

"Only a small minority of dACC neurons are pain-related, and the dACC encodes emotional events, including rejection and general negative emotion, in a way that is distinct from how it encodes pain."

Indeed, the best anatomical correlate of pain perception in the brain is not found at a single anatomical location, but in a network (the Neurologic Pain Signature or NPS) that is something of an abstract, deduced entity, built up out of statistical measures of where the hurt shows up, specifically and reliably, in fMRI. The authors try to refine these anatomical claims with their own fMRI studies.

"The NPS has over 90% sensitivity and specificity in predicting somatic pain relative to several other salient states, including non-painful warmth, anticipated pain, pain recall, social rejection, and general negative emotion."

Active sites from actual, somatic heat-induced pain on the subject's arms or legs.

Their hapless subjects where seared on their forearms or feet with about 10 seconds of high temperature (46, 47, pr 48˚C, which is 115, 117, 118˚F). This doesn't sound too bad, really, perhaps just noticeable. The vicarious / empathic pain was more interesting: being shown pictures of a person putting a shovel through their foot, or cutting a finger with a knife, and asked to imagine this happenening to themselves. Trained actors were used, I assume. What they showed certainly causes a chill to go down your spine, but it does not share specific aspects with the experienced pain. The vicarious pain was not heat- better to show someone taking a blowtorch to their extremeties. Interestingly, however, the researchers claim to be able to differentiate between pain vicariously induced at the arm vs the leg. Even by this very indirect means, there are site/anatomy-specific signatures evident in the brain signals.

For exprienced pain, they validated the NPS network, seeing it reliably show up in their scans. But the vicarious / empathic pain was a different story. In fact, they found that the NPS areas were negatively correlated with empathic pain, and devised a newly calculated network to describe what was activated, which they call the vicarious pain signature, or VPS. Helpfully, however, they compared their VPS pattern with those prompted by negative affect pictures, and by romantic/social rejection and found no correlation. So evidently, fMRI is getting good enough to distinguish between several negative emotions.

Active sites from vicarious pain, i.e. from pictures of other people doing painful things to themselves. Note the quite different patterns of activation vs above.

Global correlations between experimental fMRI patterns and the modeled networks of the NPS or VPS. Note the complete lack of correlation of the somatic pain with the VPS, and conversely the vicarious pain with the NPS.

One question is how high-level the NPS network is. Does it represent the actual physical pain but not the consciousness of it, or does it represent both? In prior work, the same lab showed that they also saw complete distinction between NPS and efforts the subject might make to cognitively control that pain, seen as dampening from the frontal cortex. Insofar as the subjects of these studies could manage their pain, it did not affect the NPS intensity at all, but worked at another, higher level. So no, while the NPS correlates with some aspects of pain and its cognition, it does not seem to encompass the highest level processes of conscious pain management, and perhaps even perception.

But back to the main study. The authors observed the NPS quite consistently, and saw its intensity increasing with increasing amounts of applied pain. And as noted, the VPS was quite different. But it did overlap in very few areas- the anterior insula (aINS) and the dorsal anterior cingulate cortex (dACC). These have been previously cited as the points of overlap, thus as sites showing that we feel the pain of others. The aINS is a profound part of our brain, functioning in awareness, consciousness, sense of self, and sociality and other emotions, like the sense of importance of things- meaning. Thus it is natural that it might be activated in both these experimental regimes, without "meaning" quite the same thing.

Likewise, the dACC also functions in emotion and consciousness, as well as reward evaluation, internal conflict, and impulse control. Again, functions that might come up in both experimental scenarios without meaning quite the same thing. Whether a pain is on your own body or elsewhere, at some very high level it is just another input to evaluate for what we are going to decide to do next. In any case, the researchers give additional evidence from lack of correlation on the finest voxel-level scales within both regions to suggest that what is going on in these locations is quite different in the two pain scenarios.

So, despite our mirror neurons and the best intentions, pain is not readily shared, and counts quite a bit less when it happens in others rather than in ourselves. Which is good, since being incapacitated by someone else's pain would probably help neither person. It also points to the importance and privacy of personal consciousness. While we keep coming up with technologies to share / immerse our mental selves in other worlds (telling stories, books, movies, VR), we do so because our capacity to do so unaided is quite limited. We are naturally wired first and foremost to feel ourselves.

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Animals Don't Care about Global Warming

It is entirely a human problem.

Global warming is the biggest problem of our time and the next one too. The icons of this problem may be the stranded polar bears, the ravaged coral reefs, the species ranges moving steadily northwards. But what do the animals think about this? Not much, really. Only we have the conscious scope and appreciation of future and past to recognize what is happening. Only we can stand back in awe and horror at what we ourselves are doing, and deem it bad.

Stranded polar bear.

So while the problem of global warming affects the biosphere, killing off species and decimating ecosystems, it is only we who can care about it. Whether our care focuses on the harm that this heating is doing to us directly, via hotter living conditions, drought, impaired agriculture, disease, war, etc., or whether our care focuses on other aspects of the biosphere that we appreciate from a more aesthetic and nature-loving perspective, it is all on us.

Back when we were killing off the North American megafauna, humans themselves probably had almost as little consciousness of what they were doing as the animals they were killing. Except, perhaps, for a twinge about hunting out one area and having to move on to the next, a process that may have encouraged the remarkably rapid settlement of the Americas clear down to Monte Verde.
https://en.wikipedia.org/wiki/Monte_Verde

But now things are different, and the cultural, political, and economic divide comes down between those who do not want to look and those who do, and who see devastating loss. The temptation of keeping our consciousness under wraps, and of denying our hard-won conception of the vast reality around us so that we can consume endlessly and reproduce geometrically, is hard to fight, when all the other side has to offer is an aesthetic, pro-nature and pro-posterity viewpoint.

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• And who needs monetary policy anyhow?
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• But is it treason?
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• Tobin tax, Si!
• Our egghead in chief.

Another Go-Around With Free Will

Is free will a problem, for whom, and what does it take to solve it?

As previously noted, the problem of free will isn't much of a problem, but theists continue to be perplexed by it and horrified by the naturalist answer that there really isn't any free will. Their perplexity often results in torrents of poor philosophy and moralistic tendentiousness. This perplexed perspective is well-explained and exemplified by a recent blogger.

Towards the end of the essay, he gets to the crux, which is not whether free will exists or can be called an illusion, but how to reconcile the third person perspective (no free will) with the first person perspective (subjective free will).

"We are left with a huge problem that no philosopher has ever solved, namely, the integration of the first-person and third-person points of view. How do they cohere? No philosopher has ever explained this satisfactorily.  What can be seen with clarity, however, is that subjectivity is irreducible and ineliminable and that no solution can be had by denying that we are irreducibly conscious and irreducibly free. One cannot integrate the points of view by denying the first of them."

Philosophers may have no idea about this, but scientists do: demote the subjective perspective as the superior one that is irreducible and uneliminable. Our subjective states are notoriously variable, drug- alterable, and quite eliminable. Every sleep wake cycle is a big exercise in eliminability. They are also clearly a reducible state of their substrate- the matter of our minds and brains. Different people have subjective consciousness to different extents, varied by stroke, senility, and other physical impairments in ways that clearly show their reducibility, to the point of eliminability. So while their nature is of great interest, on personal and other levels, they are no philosophical bedrock. Quite the opposite. I think, therefore I am fortunate enough to have my wits about me still, but will not have them forever, or even through the night.

This is not to say that free will and subjectivity are "illusions". That is the wrong word, as this writer argues well (though in fairness, optical illusions are often so persistent that they also can not be shed, only understood despite their persistence). They are perspectives from inside a system. A special and unique position, but not philosophically superior to other perspectives that may have a firmer grasp of the larger context of what is going on, especially what is giving rise to precisely that subjective perspective in the first place- the physical brain. We can not shed the subjective perspective, as we might an optical illusion. But that doesn't make it a philosophically unanalyzable vantage point.

"...  All indications are that the problem of free will is simply insoluble, a genuine aporia,  and that we ought to be intellectually honest enough to face the fact.  It is no solution at all, and indeed a shabby evasion, to write off the first-person point of view as illusory."

If we take it as given that we have a perspectival problem here, such that the view from inside is different from that from outside, it seems incorrect, indeed cowardly, not to say narcissistic, to hide behind the sovereignty of the subjective perspective to say that it is irreducible and unanalyzable. When it is so clearly a product of the machinery of the brain. It is reminiscent of Ayn Rand so charmingly saying that "I will not die, the world will end". This is, sadly, another instance of theism leading people astray, as this is a theist writer, and free will is basically a theist problem- to think that there is a real "I", hidden behind and separate from the mechanism that is the neurobiology of the brain. It is the attachment to souls, to supernatural magic, and to unexamined beliefs and poor standards of evidence that get us into this particular mess, and into so many messes in philosophy and elsewhere.

It isn't just theism, though, but intutition, which is the fount of theism in the first place. It all hangs together as a perspective- I experience the world subjectively, and I feel via my intuitive consciousness to be a free, floating point- a soul, unattached to the material miasma of nature. And the only logical (and psychologically intuitive) sponsor of this kind of magic is a deity, likewise free and unattached, which has implanted this bit of divine essence into me. It hangs together with a denigration of nature as lesser and dirty compared to the Apollonian and the logos. It hangs together with all sorts of social-intuitive traditions like patriarchy, monarchy, and priestly hierarachy.

But is it true? And even if we regard these intuitions and their derived theologies as false once we wrench ourselves away from the subjective, narcissistic, intuitive perspective, might they nevertheless promote human dignity more than a naturalistic view? That remains an open question, with plenty of historical examples on both sides of the ledger. Yet the bedrock of philosophy, among many other pursuits, is that the search for and attainment of truth is not only a virtue in its own right and a part of our fundamental human purpose, but also operationally good and conducive to better individual and communal life.

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Animals Use Their Genes Differently

Distal/distant enhancers really only took off in the animal lineage of eukaryotes.

Only 21,000 genes? What a paltry inheritance we have as humans. That is only twice the number of the honeybee, and three times that of yeast cells. How can a complicated, high-maintenance animal like us get by with so little genetic material? Much of the answer lies in how we use our genes, not in how many we have. There has been an explosion of regulatory complexity, even as there has been such a modest rise in the number of genes, from more humble species.

Evolutionary tree over eukaryotes, showing animals at the bottom, and Filozoa, which contain Capsaspora, nearby.

A recent paper discussed the genetic contents of a eukaryote called Capsaspora, which is thought to be sort of the last stop among the protists before we get to the multicellularity of animals. Not much is known about the filastereans, of which this species is a member, other than that in molecular terms, they are among the very closest eukaryotes to metazoans, while still being single-celled. But they are branching out, so to speak, with their filamentous processes and amoeboid form. They are parasites, (or symbionts), a bit like malaria, infecting the blood of a certain freshwater snail.

Its genome is only 28 megabases, compared to 3 gigabases for humans, so much more compact. And its count of genes is about 8,700, on par with yeast cells. The prior paper on its genome also points to a gradual increase through these lineages of new protein domains that become prominent in animals, like G-protein signalling components, cell-cell adhesion, meiosis, and developmental transcription factors. It has recently been reported to have a limited multicellular aggregation stage, when grown under agitating conditions, accounting for some of these evolutionary developments.

Capsaspora, in all its glory.

Nevertheless, these are not animals, and the authors asked what the genomic differences are that seem most relevant to the distinction. Given the large disparity of genome size, and relatively small difference in gene numbers, it seemed reasonable to look at the intergenic regions, where animals have a great deal of regulatory apparatus, not to mention junk DNA. This is where animals have enhancer cassettes that bind various transcription regulators, all of which loop around to cooperate with regulators bound at the promoter, the region directly around the transcription start site. Enhancer cassettes can come at many distances from their target gene, up to megabases away, and in many iterations, used alternately or combinatorially to drive gene expression in various developmental or inducible settings.

The authors, after having sequenced the genome of this organism previously, mapped regulatory regions all over using state-of-the-art techniques. And the upshot, as diagramed below, is that the upstream regions are indeed quite different in these organisms. Capsaspora has very little distal/distant intergenic regulatory matter (the green slice of the pie), while humans have vast amounts. Ditto for regulatory sites downstream (3' UTR) and in internal introns (intron, non-1st). Naturally, given the small genome size, coding sequences (tan or orange) take up one-third of the Capsaspora genome, but only a tiny 1% of the human genome. And the regulatory sites that Capsaspora does have are smaller, covering only 74 bases on average per gene, compared with 60 bases in humans.

Main findings, showing the dearth of distant enhancers (B; green) and the small size of regulatory elements (A) in Capsaspora, compared to its bigger relatives.

This is the evolutionary story in a nutshell. Growing new tissues and complex modes of cell-cell cooperation (and even brains!) doesn't take a lot of new material. Rather, it all uses cells- gussied up in many instances, but still basically eukaryotic cells- whose genes are put under tremendously more complex regulatory regimes so that these cells can be and do novel things in the thousands of new environments that multicellular organisms create internally.

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Religion as Science Fiction

What if theology is regarded as SciFi?

How seriously do you take science fiction? Obviously, being called "fiction", it is neither science nor any other kind of truth. Yet it is full of "truthiness"- plausible-ish technologies, settings related to our own, typically in the future, and human dramas more or less rich. It also often offers sweeping, even eschatological-scale, plots. But how can science fiction deal in human meaning if it does not deal in theology, given that the religiously inclined naturally think that meaning is given to us, not by our own ideas or efforts, but by a theos?

Obviously, one can turn that around and claim that theologies are themselves made up, and, far from scientifically observing a meaning given from on high, are exercises in making meaning, all the more effective for denying their underlying fictionality. In any case, I think science fiction is clearly the closest genre to religion, and caters to readers/viewers who have basically religious needs and temperaments.

From Jesus and Mo.

It is the science fiction fans who expect philosophical ruminations on what it means to be human, tales of a far future when humanity will have escaped the bonds of earth, often magical events and capabilities, and unimaginably powerful alien beings. Subspace, mind-melds, apocalyptic wars ... it is just a another word for supernatural.

Likewise, our ancestors clearly had the same idea(s). How better to illustrate their dreams, both bad and good, but with inflated archetypal beings and conflicts? The Ramayana reads like a Hollywood SciFi blockbuster. Why are there two versions of the Garden of Eden? It isn't because each is scientifically accurate. It is a clear statement that both are science fictions- tales of an idyll, and of an archetype.

Rama, flying in his vimana.

Why our cultures should have harbored such humorless, spiritually dead people as to take these tales seriously is beyond me. It is probably a testament to the bureaucratic mindset- the organization-alized person who clutches at tradition and order, (and certainty/explanation), over imagination and play. And over time, the original imaginative, introspective impulse is so crusted over that even the most sensitive and insightful people have no choice but to take the truth-dogma seriously as an external or historical reality, and proceed to make nonsense of what began as a wonderful work of art.

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SPOC vs MEN: Mechanics of Cell Division

Some of the self-regulating mechanisms underlying the cell division process, including the spindle position checkpoint.

Cell division looks elegantly choreographed, and indeed, "alive". Yet we know in principle that it is also a mechanical contrivance, composed entirely of chemical reactions that through their slowly evolved complexity have achieved a highly reliable, self-checking mechanism of DNA and cytoplasmic segregation. Figuring out just what that mechanism is continues to fascinate many researchers.

Yeast cell spindle, combined fluorescence and DIC image. Microtubules (alpha tubulin) are green, pushing the respective DNA/nuclei to opposite ends of the incipient mother (large) and daughter (small) cells. Gamma tubulin, which is a special component of the core of the spindle pole body, is red, and the DNA is blue.

A couple of recent papers studied one of these homeostatic mechanisms- also called checkpoints- by which each side of the mitotic spindle knows that it has gotten to the right place in the cell, and can initiate disassembly. The spindle is the complex of microtubules in all eukaryotic cells that is nucleated from the centrioles/basal bodies/astral center/MTOC/spindle pole body and extends to the individual chromosomes, holding them in an organized array (the metaphase plate) before pulling each divided half apart into the two nascent cells, at which point it disassembles again, allowing nuclei to re-form around the DNA of each new cell. (Though unlike in other eukaryotes, yeast nuclei never break down, but are divided and dragged to their destination intact.) Several points of this process have checkpoints to prevent further steps from taking place before the current one is complete. No mitosis can be going on, and the cell must have reached some new threshold of size, before a new round of DNA synthesis can be kicked off for a new cell division. All the DNA has to be replicated before microtubules can engage at the centromeres. All the chromosomes have to be captured before separation between the homologs can be initiated. And so forth.

The particular checkpoint dealt with here is called the SPOC, or spindle position checkpoint. Each side of the spindle, centered at its respective spindle pole body, needs to know somehow that it is at a site within the new cell, rather than just floating around in the old cell. In yeast, where this work was done, the new cell starts off as a little bud that fills with cytoplasm for a while before the DNA replication and segregation process happens. So there is a pre-prepared site for the new cell spindle pole body to go, and that site is marked by a special molecule, called Lte1.

How one end of the spindle knows to get into the bud, and the other end to remain in the mother, is a different story we won't get into here. At any rate, as long as neither end has made it into the daughter bud, a complex of molecules enforce the SPOC. How this works is that protein kinase Kin4 is also asymmetric, located in the mother cell, and inhibits a key function at the centriole. The protein Spc72 is a dock for the core tubulin (gamma) at the centriole, which in turn attracts the major alpha tubulin. Spc72 also is the docking point for Kin4, allowing it to encourage (by preventing their inactivation by CDC5, one of the classic cell division cycle kinases) the activity of Bfa1/Bub2, two proteins that in combination are key inhibitors of Tem1, a GTPase that begins the molecular cascade of the mitotic escape network, or MEN.

Model of SPOC to MEN transition, where the spindle pole (gold) that gets into the daughter bud (green) triggers / undergoes the molecular steps that license entry into anaphase, or exit from mitosis. 

But as soon as one of the spindle ends has made it into the daugher bud, it escapes the influence of Kin4, and enters the zone of Lte1 activity. Lte1 inhibits the kinase activity of Kin4 directly, and also apparently activates Tem1 since it has the exact opposite activity (guanine exchange factor, or GEF) from the Bfa1/Bub2 pair, which constitute a GTPase-activating complex (GAP). Tem1 then activates the escape from mitosis, (MEN), which includes disassembly of the spindle, decondensation of the DNA,  as well as the closing and abscission of the bud neck. Thus yeast cells have taken advantage of their unusual shape characteristics to create a clean, if in our terms still complicated, system to enforce the correct placement of the daughter's genetic material.

While one of the recent papers was a better analysis of the system, doing some very intricate ablation of select microtubules in tiny dividing yeast cells to conclude that the SPOC is not so much a measure of spindle mis-alignment as it is a brake while both spindle ends are still in the mother, the other paper looked at the molecular structure at the centriole with a particularly interesting method.

It is difficult to get structural details about systems like this, unless one is willing to do a great deal of protein crystalization. But a few workarounds have been developed, one of which is fluorescence energy transfer, or FRET. If you engineer a pair of molecular sites, such as two proteins, with emitting and absorbing fluorophores, such that the one is close to the other, (in the 10 to 100 ångstrom range), and such that the one emits at wavelengths that the other absorbs, then you can roughly measure the distance between them at angstrom scales simply by exciting the emitter, and measuring the degree of local quenching by the absorber. And this can be done in live cells and in real time.

Model derived from FRET and other data, suggesting that Bfa1 under SPOC conditions is prevented from interacting with Spc72 by a Kin4 phosphorylation that allows interaction with Bmh1 and allows continued inhibitory activity of Bfa1/Bub2 over Tem1 and the MEN.

Using the fluorophores positioned on Bfa1 and either Spc72, Cnm67 or Nud1 (all stably associated centrosomal proteins), these authors find that Bfa1 is clearly closest to the Spc72 protein, and also near the Nud1 protein, and not detectably close to the Cnm67, which serves here as a control. In addition, they found that while the association of Bfa1 with Nud1 is more or less stable through the SPOC and MEN process, its proximity to Spc72, which as noted above is the docking site for the SPOC-activating Kin4, is reduced when in the active presence of Kin4, presumably due to the arrival of yet another protein, Bmh1, which can bind to Bfa1 once Bfa1 has been phosphorylated by Kin4.

In addition, they deploy yet another fluorescence technique, photo-bleaching, to show that in the absence of Kin4, the Bfa1 association with the whole centrosome, including Spc72 and Nud1, is loosened substantially. They bleached the region close to one spindle pole, and waited for natural exchange and diffusion to restore fluorescence and especially FRET from the spindle pole site. In settings where Kin4 is not active, they see six times the speed of exchange, indicating that phosphorylation of Bfa1 by Cdc5, even though it correlates with closer proximity to Spc72, also correlates with an overall loosening of Bfa1 attachment, which makes sense given that its presence is key to promoting SPOC and inhibiting MEN via its inhibition of Tem1.

The molecular system of the cell cycle was first worked out in the yeast model system, and it is gratifying to see continued, if slow, progress in this system on a variety of fronts to work out its details.

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Extremism is no Accident

Gun owners and Muslims have something in common.

One of the watershed events leading up to the American Civil War was the caning of Senator Charles Sumner by Senator Preston Brooks of South Carolina, in 1856. Sumner was an outright abolitionist from Massachusetts, and had just given a landmark speech on the fate of Kansas, upon which the future direction of the nation hinged. Sumner let it all hang out, portraying Kansas as a virgin raped by the slave powers which were working to corrupt its institutions and force it to come into the union as a slave state. Hours long and shooting insults in all directions, it was quite extreme for its time. Two days later Brooks attacked Sumner in the Senate chamber with a metal-topped cane and beat Sumner, who was trapped at his desk, about the head to within an inch of his life. Brooks was assisted by a colleague, congressman Henry Edmundson from Virginia, who held off Sumner's supporters with a pistol.

No event illustrated quite so markedly the depths to which the sectional divide had sunk, or the clash of cultures between the industrializing, striving North, and the feudal South. The action was extremist, but clearly arose from the respective tribal affiliations and ideologies at work. Southerners apparently welcomed it as honor vindicated, while to the North, it exemplified the barbarity inherent in the slave system, not only embodied in the abject subjugation of slaves, but in the moral coursening of their masters.

Turning to today's ideological battles and extremist events, the rote responses by the various communities implicated in the Orlando shootings bring up the issue of collective responsibility. Does being Muslim implicate you and your beliefs in such an event? Does being a member of the NRA with its opposition to controlling military-grade weapons? If a group's ideology is exemplified by such an event, what is the degree of individual responsibility and culpability?

One can turn to the German question as another, closer, historical example. Germans today still bear a stigma and responsibility deriving from the disastrous world wars of the last century. That is as it should be. Germany and Germans are not pacifist, but they have taken on an extra measure of responsibility for restitution viz-a-vis Jews and Israel, and for peace in Europe. Their economic policies may be tending in the opposite direction, but on the whole, they have meant well over the post-war decades, forging a close relationship with France and various structures of European cooperation.

People are part of groups for a reason, and bear both the costs and benefits of their groups. Homosexuals may be so stigmatized by their membership (which is, unlike some other groups under discussion, not a voluntary membership) that they deny that membership and stay in the closet. Southerners dedicated to the perpetuation of slavery were rarely extremist, but derived benefits from extremist acts. The brutality at the margins, vs escaped slaves, exhibitions of black pride, and unsympathetic whites, kept the system intact, for the benefit all those who didn't want to get their hands dirty.

Membership in Islam is less directly culpable, given the large size of the group compared to the proportionately small numbers of extremists. For example, polls that show that a majority of Muslims do not support ISIS, yet the remainder amounts to “roughly 50 million people [who] express sympathy”. Which is quite a large pool of people to draw on, and more importantly a significant problem for the community of Islam as a whole, not to mention the rest of us. The scriptures of Islam are a well from which countless fundamentalists have learned to hate, and to see violence as both beneficial and sacred. While some forms of Islam, notably Sufi-ism, have renounced these aspects of their tradition in wholesale fashion, the dominant forms of Islam today have not. The strain coming from Saudi Arabia is particularly filled with negativity- towards women, towards apostates, towards Shia, towards infidels.

Extremists are not opposed to their group. As a rule, they believe that most members are insufficiently dedicated to the group’s overall goals and ideology. Fundamentalism, be it gun nuttery or Islamism, is usually couched in original scriptures, and a dismissal of the wishy-washy-ness of the mass of members who value civility and moderation over principle. The ideology of the group leads directly to the occurrence of extremists, if only in a minority of cases. It is the ideology that is at fault if, taken seriously, it leads what the rest of us characterize as extremism. And historically, extremism in Islam has been highly successful, providing the military motivation and success that makes so many people Muslim today. Moderates benefit from extremism.

In ideological terms, ideologies such as religions tout themselves as truth in both moral and scientific senses. The latter is naturally absurd, while the former is just as wrong, since morality is never a closed book. However, given the truths that the Koran provides, it is only natural to hate infidels, apostates, and love God, his messenger, and the jihad that will convert the world. Only an attitude of skepticism about these truths would prompt someone to take a more moderate stance, such as accepting the legitimacy of non-Muslim narratives and approaches to life. Why would a community want to foster such skepticism? That would be counter-productive. Thus extremists are countenanced as their over-enthusiastic brethren, as maybe a political problem with regard to the outside world, but far from an ideological or theoretical problem. This makes communities unable to successfully reprove their extremists, be they anti-abortion zealots, islamic terrorists, or gun-rightists.

This is why we need to pay attention to the tenor of the entire community from which extremists spring. It is not Islamophobia to see a fundamental ideological problem within Islam which fosters bigotry, regressive institutions, and violence so pervasively in the Middle East. Turning back to our Civil War, the extremist violence that occurred in the Senate in 1856 was not an isolated incident, but part of a pattern of discontent and insurrection that had been building in the South, especially South Carolina, for decades. Slavery was at the core of a culture that had diverged to a startling degree from that in the North, and elsewhere in the Western world- a relic of feudalism or worse. Its desperation to persist in a fundamentally immoral institution, and spread it to other sections of the frontier, was inimical to modernity and to decency. The ideologies of the North and the South were incompatible, and the sparks of extremist acts such as the caning of Sumner, and the raid on Harper’s Ferry, were harbingers of the cataclysm to come, as well as cultural and ideological divides we still struggle with today.

Postscript: As for gun ideology, it is not as directly militant as fundamentalist Islam. In fact, it entertains a sort of apple pie fantasy, where all gun owners are rock-ribbed patriots standing with their exquisite training and dedication to the CONSTITUTION athwart the forces of chaos and tyranny. The problem here is not (mostly) what the ideology includes, but what it leaves out- which is reality.  Every empirical study shows that the more guns there are, the more deaths, for a variety of causes like suicide, domestic violence, and accidents, not to mention mass murders, where in every recent case the guns were recently purchased for the purpose. Guns are extremely dangerous, and not everyone who has them makes a fetish of personal firearms training and lock-down security.  Clutching their pearls when some extremist uses a legally purchased semi-automatic to mow down innocent people is a clearly insufficient response to the problem by the gun community. A fantasy of responsibility can not hide a reality of frequent irresponsibility and utterly unnecessary danger.

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