Saturday, July 30, 2016

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.

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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  • Past annals of climate change.
  • Who's carrying those pitchforks?
  • Gun nuttery reductio ad absurdum.
  • Could central banks take over all basic banking?
  • And who needs monetary policy anyhow?
  • In-depth on Turkey and the Gülenists.
  • But is it treason?
  • Which side is Hillary on? At least she's not on Putin's side.
  • Can we keep going down the capitalist road? The problem isn't capitalism per se, but the capture of the media, culture, and politics by its winners- the 1%, which leads to an unwillingness to regulate it properly.
  • Tobin tax, Si!
  • Our egghead in chief.

Saturday, July 23, 2016

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.

Saturday, July 16, 2016

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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  • Big data and health insurance, etc.
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  • On the line from the French revolution through Hegel to Marx, and on to the new terror.
  • The wages of austerity.
  • Are conventions just big sleezefests?

Saturday, July 9, 2016

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.

  • Religion and big data.
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  • More thoughts on Brexit.
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  • Our friends the Saudis.
  • Another theologian employed at a public university- heaven knows why.
  • Fox and Friends. Or frenemies.

Sunday, July 3, 2016

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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  • Economic graph of the week. Income trends for various percentiles of the global population, over the last 20 years.