Prophetic Diagnosis

Using MRI to detect brain damage that leads to temporal lobe epilepsy.

Magnetic resonance imaging has been an amazing and flexible technology. It has been tailored to varying chemical targets and environments, so that both chemical and anatomical details can be visualized. A recent paper (review) deployed tractology, which uses MRI to trace water diffusion in lengthy neurons and related cells, to vizualize detailed brain organization.

They were looking for traces of damage or change that could predict or correlate with epilepsy. Their model was mice, whom they injected with kainate in their hippocampi. Kainate over-excites and rapidly kills neurons, and this particular injection is known to induce temporal lobe epilepsy, a syndrome that can be brought on by genetics or trauma in humans, and is known to cause not only seizures, but also other problems such as memory loss, depression, personality changes, and hyper-religiosity. Whether the mice start propounding new religions is naturally unknown.

Time course after injecting damaging chemicals into the hippocampus of mice, and then tracing the growth of new glia oriented cross-wise (green, in box) versus the native neural tracts.

What they did find is that they can track damage in the mice quite easily, and this brain damage takes the form, in part, of new tracts of (glial) cells that grow cross-wise versus the native neural pathways. This helps to rationalize what may be causing the epilepsy, and was supported by finding similarly deranged tracts of glia in the brains of humans suffering from temporal lobe epilepsy and hippocampal sclerosis, which is the main physiological finding associated with such epilepsy, especially forms that can not be treated by drugs. And the severity of the lesion, which in the mouse system is traceable from very early times, prior to the onset of epilepsy, correlates in both systems with the severity of the eventual epilepsy.

Our study demonstrates for the first time that the extent of epileptogenesis-associated tissue alterations in the hippocampus directly mirrors the ensuing severity of intractable mTLE [mesial temporal lobe epilepsy].

This may provide and early way to check out brain damage that may lead to this syndrome, though what to do about it is a separate question, typically answered in these cases by surgically removing the mis-grown scar tissue that was studied here.

• Lies and more lies.
• Maybe cynical corruption (and mean-ness and greed) is all the "there" there is.
• War criminals? What war criminals?
• In praise of solitude.
• Wages are not a free or rational market.
• Except when they are.
• Productivity may not measure particularly interesting things.

What if Coal Were All We Had?

What if there was no renewable energy, or sustainable options to keep advanced civilization afloat?

I was reading an article about coal country, and the tradeoffs, dreams and delusions surrounding it, when it struck me what a different position we would be in if coal was all we had. Our civilization floats on a miasma of oil, gas, and coal, with some nuclear and hydropower thrown in. Wind and solar are growing, but fossil fuels make up 80% of energy resources, and will for years to come, especially as India and China continue to commit to more coal-based power. For all the oil we guzzle in transportation, heating, chemicals, and other uses, we use more than twice as much coal, to the tune of roughly ten billion tons per year.

But what if we lived in an alternate world where we did not have fracked natural gas, or renewables, or even oil? What if coal were all we had? Our industrial development would be a different place, clearly. Though World War 2 demonstrated that one can make practically anything from coal that can be made from oil, the processes are quite a bit more difficult. We would have more trains and streetcars, and fewer automobiles. More importantly, though, we would be facing much different choices in global warming, and pollution generally.

We would be in a world more like Victorian England, and contemporary China, where coal pollution is choking. The irony is that installing scrubbers to take out the most noxious pollutants, not to mention sequestering the CO2, is very expensive, not only in financial terms, but in energy terms, wasting even more of the fuel that in this world would be so precious. Coal would still be a limited resource, with a time horizon of maybe 200 to 300 years in all. Foresightful planning would regard this as an extremely precious resource, if not substitute were available, ever.

So from both the foresight and the pollution standpoints, we would be forced to conserve energy- that would be the solution to such a noxious resource. We would be much farther along in taxing carbon/coal to reduce usage to amounts consistent with local human health and future global health, even if strip-mining it were cheap and its many local costs acceptable. Hopefully, natural beauty would not be a distant memory in such a world, if we made these decisions in time- a time much earlier than we have the luxury of doing today. Would the human population be as high as currently? Given that the poorest areas of the world typically have the highest population and population density, that is quite likely. We would just all be poorer, crimped by a resource base that would be dirtier and scarcer than the one we have today.

Thankfully, we have a much brighter future in reality. In the developed world, pollution is not an in-your-face threat to human existence, but rather an invisible, subtle menace that needs to be met with responsibility and foresight if we wish to preserve much of the natural world that we evolved in, and have known in our own lifetimes, intact.

• Notes on the moral conservative perspective.
• For-profit health insurance destroyed everything.
• And then corrupted everyone.
• Mainstreaming alt facts and alt media.
• I am inherently patriotic.
• And Russia is my best friend.
• Oh, no! A pot shortage!
• Wages are not a normal economic concept.
• A beautiful take on Harry Potter, from Japan.

Who Are the Real Wealth Creators?

Technologists, of course.

Of the various indignities of the campaign last year, the economic ignorance displayed and accepted was particularly galling. The Trump voters of the hinterlands, supposedly angry about their compromised economic position, elected a party and person whose avowed goal is to take more money from our public institutions, the poor, and the middle class, and give it to the rich. This after a near-decade of total intransigence by the same party against restarting an economy that was floored in the banking meltdown and has been limping since. It has taken a decade to get back to more or less normal conditions- time lost to economic growth in general and to countless individual traumas.

Who and what creates economic growth? Is it the "job creators"? Is it Goldman Sachs? Is it the 1%? That is a big question facing the nation, both politically and in straight economic policy. The new administration says yes, yes, yes, arguing that giving the rich hefty tax breaks, not to mention reducing regulations of all sorts in financial and environmental sectors, will help economic growth. Will it? Obviously we have been through all this before, under G. W. Bush and Reagan as well. And the answer is no, it does not increase economic growth. Money going to the rich is money that is, largely, invested in low-risk assets like bonds and real estate.

More generally, does the managerial class create wealth by their organizational prowess? Is Amazon better than Staples, which is better than Pat's Stationery store down the street? Organizational differences make only minor advances in overall wealth, and seem mostly to facilitate the redistribution of labor earnings to ever fewer and richer capitalists. As previously discussed, the power of capital is that it always wins, through good times and bad, in every negotiation, since versus labor, it is always taking less risk.

What Amazon has that Pat's establishment does not is, mostly, new technology. The internet came along and showed that everyone could be connected, instantly. How about using that connection to sell things on a nationwide scale, especially things that are easy to ship? Sears would have been the natural founder of this franchise, based in their nationwide catalog roots, but they had become too invested in their stores to pay attention. Capitalists only deploy the technology that exists. They do very little to generate new technology- that is left to academics and the government. It is technology that keeps revolutionizing our lives and raising our standards of living- our collective wealth. And when it comes to distributing new technology, sometimes the market does a worse job than the government, such as with roads. We could have much better internet infrastructure if it were managed in the public interest as a utility.

Where would the "job creators" be without their cell phones? Where would they be without databases and spreadsheets? Where would they be without electricity? They would doubtless be riding herd over an estate of serfs. They would be just as wealth-creating in relative terms, but all in a much poorer society. The dark ages were dark not because entrepreneurs had lost their will to manage others, but because technological, scholarly, and governing instututional development ground to a halt with the dissipation of the Western Roman Empire. It took centuries of slow, accreting technological progress to make cities as large as they were in Roman times, and make societies as wealthy. By that point, the process took on a life of its own in the West as an ideology of Enlightenment and material and moral progress took hold, maintaining support for learning and innovation which reached unimaginable heights in the twentieth century.

Looking back, we can rue that the fuel of all this transformative progress and wealth creation has been buried reduced carbon, which as our waste product, CO2, is now befouling the biosphere. Our collective wealth has also begotten a vast and completely unsustainable increase in human population, whose many appetites are destroying much else of the biosphere. These are the problems of prosperity, and are, if we are morally responsible, now foremost in our public and private intentions and actions to transition to a sustainable as well as prosperous future.

• Who needs clean water?
• Who will sue on behalf of the public interest?
• Free? We are not free. We are under the feudal thumb of corporations. "Likewise, the origin and success of the factory lay not in technological superiority, but in the substitution of the capitalist’s for the worker’s control of the work process and the quantity of output, in the change in the workman’s choice from one of how much to work and produce, based on his relative preferences for leisure and goods, to one of whether or not to work at all, which of course is hardly much of a choice."
• Trump is the weakling.

A Cleanser For Tau Clumps

Alzheimer's disease is caused in part by protein clumps including amyloids and tau fibrils. We have an enzyme for that!

The iPhone appeared a decade ago, and gained ground so definitively because it provided a general platform (and large screen) for which others could develop rich applications. The ramifying copying, diversification, and specialization of those apps is reminiscent of evolution in general, and particularly of the "apps" present in every cell. Proteins are based on a generic/genetic platform of DNA coding and RNA translation, and self- assemble into countless shapes and sizes, complexes and pathways, to do all sorts of tasks to make life better for the organism. Where once there must have been very few or even none (in the RNA world), proteins have diversified over evolutionary time by endless rounds of copying, stealing, mutating, and specializing to constitute our current biospherical profusion.

Our bodies are filled with protein apps that generally keep their heads down and do their work without complaint. But a few can make trouble. Most notorious are the prions, which, as bizarrely misfolded versions of natural, functional proteins, can encourage other proteins to join them on the dark side, and even infect other organisms, causing unusual brain diseases and panics over epidemic transmission. Less notorious, but far more devastating, are various dementias such as Alzheimer's. These appear to be caused by the accumulation of junky proteins which clog cellular processes, and eventually kill brain cells, destroying the organ from within. The exact cause of this accumulation and how, or even whether, it kills cells are both still under study, but deposits of this junk (amyloid plaques and tau tangles/fibrils) are universally diagnostic of these dementias and prime candidates for research and treatment.

Proteins are constantly growing old and getting sent to the garbage, in all cells. The problem with the Alzheimer's-related proteins seems to be that they escape this disposal process, either because they accumulate too rapidly, or because they condense into crystalline entities that can no longer be pried apart by the various chaperones and other proteins that constitute our sanitary services. A recent paper discusses one human protein that seems able to clean up junk composed of the tau protein, even at its worst, and might be the kind of thing that could be injected or increased by genetic therapy to treat such syndromes.

Proline, the only amino acid that cyclizes back to the peptide chain, creating kinks in protein structures. The bond that Cyclophilins wrench back and forth is resonance-stabilized, making this trick a bit harder than it looks.

Cyclophilins are a class of protein chaperone (which are proteins that assist the folding of other proteins) that catalyze the switching of proline peptide bonds from cis to trans (see above). Proline is the stiffest amino acid, and plays a major role in generating kinks, turns, and other rigid aspects of protein structure. So cyclophilins help loosen up such structures and get proteins back on track if they have gone down a tangled path. That seems to be the case with tau, which is the crystallized conformation of fragments of a protein that in its normal state is a membrane protein thought to participate in synapse formation. Naturally, the accident of causing dementia in old age is, in evolutionary terms, a minor issue as it takes place well after reproduction has occurred, allowing such evident genetic defects to persist in our population.

The authors diagram how the tau protein (red and gray) might get its turns loosened up by CyP40, (black), allowing the tight beta-sheet structure to dissolve.

The authors run through a series of experiments to show that one cyclophilin, CyP40, is particularly effective in dissolving tau fibrils, one form of protein aggregation seen in Alzheimer's. It dissolves them in the test tube, it dissolves them when infected via a virus into the brains of mice, and it reduces neuron damage and cognitive decline that happens in these mice, which are engineered with extra human tau protein expression, and exhibit a rapid dementia-like progression.

When CyP40 is added (red), tau fibers can be dissolved in the test tube. FKB51 and -52 are other cycophilins that do not have this particular activity, serving as controls.

Engineered tau-expressing mice (red) can have their cognitive abilities improved after a virus carrying the CyP40 expressing gene was injected into their brains. The Y-axis is rate of errors in a water maze test, done at 3 months, which is relatively late in life for these mice.

It is an impressive and promising piece of work, to go from molecular structure to medically significant function, though it took 19 authors to get there. One notable aspect of this protein is that it does not require ATP- its mechanism is very efficient and the protein is relatively small- properties that are helpful when the targeted protein clump is outside of cells or in dying or dead cells. It is also part of family of 41 such proline isomerase enzymes in humans, so others may be found that operate on the other major culprit in Alzheimers, amyloid beta protein. On the other hand, we already encode and make Cy40 and it relatives. Why are they not being turned on and expressed in our brains where and when they are so desperately needed? The authors are silent on that score, and have taken out a patent for the therapeutic possibilities of the exogenously supplied version.

• Ignorance is strength.
• And isn't going to prevent some illogical hypocrisy.
• Or cruel policy. 
• Where is it all headed? To a new and permanent feudalism / authoritarianism.
• Much ignorance is due to corporate media, whose interests are not ... the public interest.
• Fake logic finds a home at the Supreme Court.
• What is to become of the next Afghanistan surge?
• The Russia story goes deeper.

Worried About Truth? Try Programming

Programming as a continual lesson in reality and humility.

The reality principle has been taking a beating recently, with an aged child in the White House throwing tantrums and drama in all directions. Truth itself is under direct assault, as lies big and small emerge shamelessly from the highest levels of our institutions and media. What to do? Reality is still out there, and will surely have its revenge, though that may well drop in another time and place, missing the perpetrators of these outrages while ensnaring the rest of us in its consequences.

For now, you may need a psychological and spiritual cleanse, and what better way than to redouble one's engagement with reality than to drop into a totally artificial world- that of programming? Well, many ways, surely. But nothing teaches discipline in service of the reality principle quite like dealing with a perfectly, relentlessly logical device. Truth is not an aspiration in this world, it is a bread and butter reality, established routinely in a few lines of code. In larger projects, it is a remorseless taskmaster, failing on any misplaced character or weakly developed logic. You get out precisely what you put in, whether that was well thought through or not.

No, it doesn't usually look like this.

One lesson is that every bug has a cause. I may not want to hear about it, but if I want that code to work, I don't have any choice but to address it. I may not be able to find the cause easily, but it is in there, somewhere. Even if the bug is due to some deeper bug, perhaps in the programming language itself or the operating system, and is hard to find and impossible to fix, it is in there, somewhere. Coding is in this way one of many paths to maturity- to dealing honestly with the world. While the profession may have an image of child-men uneasy with social reality, it has its own extreme discipline in the service of realities both formal, in the internal structures they are grappling with, and social, in the needs the code ultimately addresses, or fails to address.

Science is of course another way of dealing with reality in a rigorous way. But, compared to programming, it exists at a significantly larger remove from its subject. It can take years to do an experiment. There may be numerous conscious and unconscious ways to influence results. The superstructures of theory, training, and pre-supposition required to obtain even the smallest step into the unknown are enormous, and create great risks of chasing down fruitless, if fashionable, avenues, such as, say, string theory, or multiverses (not to mention ESP!). The conventional literatures, expecially in drug studies and social science, are notoriously full of false and misleading results. Nor is much of this as accessible to the layperson as programming is, which makes engagement with code an accessible as well as effective tonic to our current national vertigo.

• What happened in 2016? Mainly, lots of lying.
• Trump is hardly alone in not caring about the public good.
• What kind of a democracy is this?

Briefly....

Just a short post, on digestion.

There was a mildly interesting paper about food choice and nutritional sensing, using the worm C. elegans. The researchers describe how these worms avoid dead bacteria as food, but like live bacteria. One of the labile elements present in live bacteria but missing in the dead bacteria is the vitamin B2, aka riboflavin. It turns out that lack of B2 down-regulates (via the key metabolic regulator TORC1, in turn via decreased levels of ATP) some key proteases in the worm's gut, which naturally impairs their digestion and appetite. Unfortunately, the paper does not go on, as promised, to explain issues of food choice and nutrient seeking, which might be mediated by general lethargy, but may also be directed by more specific neural pathways connecting the gut with the brain- an area of significant interest these days.

• Sclerosis and corruption at UC.
• Should wars be long or short?
• Can residential architecture be interesting?
•  ...  a lobbyist for Tyson Foods was injured at the Republican baseball practice.
• A freight train seems to be headed for Trump, because the feudal Putin model doesn't work here (or at least, not yet).
• In civil rights, the Federal government has been captured by the South.
• And the EPA, by industry.
• The solution, as usual, is more guns.
• Emotion, behavior and intelligence as biological traits.
• Economic graph of the week: wage share and profit share, in Australia.

Wage share vs profit share, in Australia, very similar to other economies. What would it take to make developed economies great again?

Grumpy Catholic Loses Culture War

Grappling with "truth"- a review of Charles Chaput's "Stranger in a Strange Land". 

Charles Chaput is archbishop of Philadelphia, a Benedict appointee and thorough conservative. In this book he bemoans what has become of America and offers an extended homily of Catholic platitudes and scripture to gird his flock for their swim against the tide of cultural depravity. A theme he returns to repeatedly, if not obsessively, is court decision Obergefell, which made gay marriage constitutionally protected and is evidently the final straw in Chaput's recognition that the culture war is lost, and his people are now wanderers in a hostile wilderness. All this despite the outsized dominance of Catholics on the Supreme Court and other institutions of public life. Add a sprinkling of disparaging references to Barack Obama, Saul Alinsky, and the "state" in general, and his position on the political spectrum is clear.

As a study in the vicissitudes of social power, and the remarkable rhetoric of self-serving institutions and world views, it is an interesting book. One topic Chaput hammers on, ironically, is truth. We all know that truth has taken a beating over the last few years. Between the internet and its unusual avatar who is now our president, we have had a lesson in an unmoored and uncurated media landscape, where each person can hide from unpleasant views, and descend with ever more certainty into a comfortable world view. But it was ever thus, and the Church is surely one of the most amazing examples of relentless and effective propaganda for a truly bizarre version of reality.

"These problems are the outward signs of deeper issues that implicate us as citizens. The weakness of the individual citizen is only partly coerced by democracy's structure. It's also freely chosen, because we find it convenient. It allows us to assign blame to others and escape our own responsibility. It's easier to accept lies by invoking the misguided alibi of tolerance and mutual respect than live outside the cone of public approval. This is clear in every recent national debate ober abortion, marriage, family, sexuality, and rights in general. Many of us are happy to live with half-truths and ambiguity rather than risk being cut out of the herd. The culture of lies thrives on our own complicity, lack of courage, and self-deception."

Very true in principle, but what are these truths being alluded to? He tries to be as diplomatic as possible, but his truth is that gay marriage is completely immoral, and disastrous to society, as is abortion and contraception, that Christianity is true in every particular, and that the Church, as keeper of all these truths, should have far more power over its own adherents and, logically, over society in general, if it were, ideally, to adhere to "truth".

"There is no justice, no beauty, no goodness, without truth, because truth is the voice of God's authentic reality." 

"Simply put, once a higher purpose and standard of human behavior are lost, moral judgements are nothing by personal opinions. In a nation of sovereign individuals, nobody's opinion is inherently better than anyone else's. All moral disagreements become rationally irresolvable because no commonly held first principles exist."

How convenient it is for Chaput to think that his and his church's opinions are "truth"! What a simpler and better world that was when that was the common definition of truth! And what a remarkable ploy to insert God into every possible crevice of one's argument, making of reality and of our human and moral natures a superstitous ghost-ridden confusion.

The fact of the matter is that religions such as Catholicism have never proven their many propositions, either on a philosophical level or a social one. The Holy Spirit, the resurrection, and the second coming, which Chaput refers to with some anticipation, are all phantasms of once-fevered, and now institutionalized, imaginations. They are prime examples of "fake news" parading as "good news", not to mention "truth". And the societies which have most completely thrown off these fantasies, i.e. European nations such as France, and the Scandanavian countries, are also evidently the most rational and happest places to live.

Heaven, by Fra Angelico

But all the same, I sympathize with a great deal of what Chaput writes. American society has significant problems, one of which is the loss of social cohesion. Religions are, at core, ways for people to connect and found institutions based on humanistic and moral ideologies. We are communal beings, despite the relentless propaganda, particularly strong in the US, of individualism. We have not thought deeply enough about giving our society over to corporations as the primary unit of social organization. Corporations which have no moral scruples or humanistic ideology, and have flooded our communal media with lies, (which is to say, advertisements), and are rapidly taking over our government as well.

Must all social groups be founded on an ideology that is fundamentally untrue, a narrative that puts meaning into the otherwise empty vessel of "truth"? The answer to that is probably yes, but with the caveat that different narratives can have wildly different levels of untruth. The Western secular narrative of technological and moral progress, based on rights that we award to each other and a vision of human dignity and prosperity, is hardly "true" in an objective sense. Our technological development has plunged the Earth into an almost irremediable crisis of biosphere-wide destruction. And our moral development took some seriously wrong turns in the 20th century, which have taken a couple of generations to recitify. Only to run into critics like Chaput who take the view that, morally, things have been going downhill every since the so-called enlightenment!

That may simply be the self-serving view of an instution that has been battered by modern skepticism and individualism, but it can not be discounted as "false", either. For all the objective measures of violence going steadily down over the recent centuries, and health and well-being going steadily up, judgements on our moral condition are, intrinsically, subjective.

Other ideologies like communism were much farther afield from reality, putting the utopian cart before the horse of present-day charity and humanity. And religions, such as Catholicism, take the cake in their profusion of extra-terrestrial doctrines, saints, relics, rituals, transfigurations, trinities, and other claims they force their believers to swallow. The enlightnment has thankfully forced most of this material into safely supernatural precincts, where it does little harm to "God's authentic reality", such that Catholic scientists can, for instance, press on in good faith with their endeavors. As long as there are skeptics around to dampen outrageous claims, and an educational system that trains children with a modicum of rationality, (and scandals which religious institutions regularly self-inflict), the problems of religious ideologies going to social and philosophical extremes will be minimized, while the social good of religious bonding preserved.

But as Chaput notes and as many have observed, that religious bonding is in general decline. What are alternative forms of social capital, with which we can fight for our communal, human interests, against the amoral leviathan of the corporation? Chaput, as a hard-line conservative, is dismissive of the state filling this role, as its moral ideology is little more than a weathervane of public sentiment. Even the non-profit sector has been taken over by an army of rich people setting up their vanity foundations, with little coordination or rationale. Organizing grass-roots activities around various grievances is also not a promising or durable approach. Something like educational institutions as a life-long hub of relationships and activism might fit the bill, but I do not have a good answer yet to this deep and troubling issue.

• Another view of Chaput.
• Thank you, Pakistan!
• What happened to truth, and good faith?

Massage and the Future of Medicine

Trigger point therapy for muscles. Brief review of "The Frozen Shoulder Workbook", by Clair Davies.

For anyone with muscle issues, trigger point therapy can be a profound experience. This is the palpation, detection, and deep massage of any muscle that has "knots" in it, which are also called trigger points. Such knots can arise from overuse or trauma, and can last for years, impairing use of the muscle, and, in the case of the shoulder, causing a cascade of impairment that comes to be known as frozen shoulder syndrome. Clair Davies' book is a thorough guide through this thicket, and brings to light issues that mainstream medicine seems to be rather slow in picking up.

Indeed, one could imagine that every general physical appointment, which now focuses on a few metrics of internal medicine, such as blood pressure and blood chemistry, might start with lengthy session of skilled massage. This would bring therapeutic massage into the medical setting, where it belongs, relax the patient while attending to key muscle issues that have been building up over the preceeding year, and also provide an entry to many other medical issues the patient may be having, like skin lesions and internal pain.  Something a little shamanic, but also holistic and integrative, changing the medical encounter for the better.

• Army life.
• A very different relationship with Russia.
• Conventional finance wisdom is wrong.
• We have a public management crisis.
• We can do single payer in one state.
• We can do spectrum and cell phone costs better, too.
• Proud to be a Californian.

Cromwell, Superman

A brief review of Wolf Hall.

The press of business prevents a longer post, so just a few words on a novel I have been laboring over, Wolf Hall, by Hillary Mantel. First, the style- it is offensively eliptical and unclear, not indicating dialog or who is speaking or thinking. How it could have been the rage of the prize committees and reviewers a few years ago is simply beyond me. Edgy, yes. But respectful of the reader, no. Comparing it to another bit of current reading, Thomas Hardy's Far From the Maddening Crowd, couldn't make the contrast starker. Hardy treats his reader as well as his subjects with great respect. Humor, yes, and deep insight, but first of all clarity, and rich context and exposition. 

Ann Boleyn, secondary subject of Wolf Hall.

Mantel, in contrast, plays games with the reader, telling the story through a straw of cynical mannerism, hiding far more than she tells. Thomas Cromwell, the main character, is made out to be a 100% pargon of competence and compassion, and all other characters are given temperatures directly in proportion to how close they are to him. Those he hates are vile, those he likes are good and virtuous. Yet the story is not really told from his perspective, but from Mantel's snarky omnicient voice, making all this characterization absurd as well as historically unbelievable. I assume that the BBC production was able to, thankfully, jettison virtually all the novelistic apparatus and return to whatever of the history was presentable, using only the broadest outlines of Matel's selection of scenes and personalities.

• Which god do we worship, cont.?
• Healthcare is now up to the Senate.
• With Allah's grace and support ...
• Clarence Thomas does something decent, for once, because of identity.
• From the annals of the new feudalism.
• A president who should be in jail. But will his supporters wake up?
• The man who mainstreamed post-modernism.
• Freedom for me, but not for thee.

Sponges Are Animals Too

A brief look at some innovations at the bottom of the animal evolutionary tree.

Of the many great innovations in evolution, the development of multicellular animals ranks pretty high. It was based on the many innovations that had previously generated eukaryotes and their ramifications into protists and other complex single cells. It was a big step to realize (unconsciously!) that, however big and complex one could make a lone cell, (think of a paramecium), possibilities of greater scale and specialized organization were being left on the table. Sponges are the most primitive animal that currently exists. To us, sponges are small and simple. But to their protist brethren, they are giants- vacuum cleaners of the sea that suck up protists and other detritus like so many dust mites.

Sponges have several distinct cell types, like outer epidermal cells, pore cells, and interior collar cells that have the flagella that keep water moving through the pores. Sponges also contain wandering cells that secrete collagen in the intersitial areas- the same protein that keeps our bodies together as well. And they have primitive muscle cells / myocytes, which can cause contractions to close pores when needed, and also the larger openings of some species. These myocytes necessarily have some electrical communication, to coordinate their activities around the osculum. So, not exactly Brad Pitt, but they have quite a bit of anatomical complexity

A sponge.

Key innovations of this (relatively) massive and complex organism were not just the novel molecules, such as collagen, and skeletal "spicule" molecules, but the regulatory apparatus that generates different cell types and keeps them at their work, diligently pumping, or waving, or opening/closing, etc. A recent paper looked at this regulatory system and found that sponges already have most of the special mechanisms that other animals use to specify cell fates and body organization.

Those mechanisms revolve around gene control. In the human genome, about 1% of the DNA codes for proteins- the actual stuff of our bodies. Roughly about 7 to 10% of the genome functions in other ways, principally as regulatory regions, RNA-encoding genes, etc. The rest seems to be junk, more or less. The sponge that has been sequenced to date has a genome with roughly the same number of genes as ours (20,000), in 1/20 the genome size. So there is quite a bit less junk and complexity, but still a very large tool chest.

Particularly, it has plenty of regulatory control, and the researchers explore its use of one hallmark of metazoan gene control- histone modification. While the basic role of histones is very simple- to act like tiny wheels around which the DNA wraps, keeping it both secure and compact- its position also allows it to regulate the access to that DNA by other proteins, especially regulators of expression. Higher metazoans have a dizzyingly complex "histone code", composed of chemical modifications to the positively charged tails. These modifications include methylation, di- and tri-methylation, and acetylation, on lysines at positions 4, 5, 9, 14, 20, 27, 79, and 122 of one of three different histones. Each modification and position means something different, and combinations can mean other things again, all affecting the degree and type of gene activity.

A small part of the Amphimedon queenslandica genome, with DNA positions on the X-axis, and annotation tracks in separate rows. Description and codes below.

One example of their data is show above. They tested the locations of five different histone modifications, (H3K4me3 and similar rows), as well as the RNA polymerase (RNAPII) that is the ultimate target of all the regulation. Also laid along the small segment of the genome (X-axis) are rows (tracks) that describe the predicted locations of genes (bottom rows, purple) and the expression of each location of the genome into RNA (dark and light orange, next rows up). At the very top, under the genomic coordinates, are predictions about chromatin states, based on the histone modification analysis, using knowledge from other (higher) animals. The code for this analysis is shown below

Codes for the top annotation tracks above.

The color codes for inferred chromatin states. "Active TSS" means an active transcription start site, or gene being expressed. "Transcr. at gene 5' and 3'" indicates signatures for boundaries of transcription units, though this is clearly not very precise. "Genic activated enhancers" mark upstream regulatory elements that regulate a local transcription start site, sometimes from far away. "Weak enahancers" mark the same, but less active. The "Bivalent/poised" notations indicate non-active transcription units or enhancers, which may have RNA polymerase parked, but not active. Lastly, the gray annotations indicate states of chromative repression of gene activity which are very important, and regulated by histone modification, but not relevant in this genomic location at the (adult) stage sampled.

A few sponge genes with differential expression in larval vs adult stages. Expression in orange and blue,  and the histone marks (H3K4me3) in purple at top. Genes are in purple at the bottom, complete with their complex exon-intron structure.

Another example of their data shows the developmental difference in a small genomic region between larva and adult stages. The triple methylation of Histone H3 at lysine 4 (H3K4me3) turns out to be the most clearly informative chromatin marker, and comes up reliably at active gene start sites/promoters, where it plays a role in activating transcription.

All this goes to show that the tools and knowledge that have been accumulated over the last couple of decades for the study of model animals like mice, fruit flies, and humans, are also totally relevant for the study of sponges at the base of the animal tree. And in turn, that sponges already had and have complex molecular mechanisms that drive their developmental and morphological complexity, such as it is.

If this study revolved around the histone code alone, it would not have been very novel, since yeast cells share much of this apparatus, and are tenaciously unicellular. But the researchers also delve into several other properties that are more diagnostic of animals, such as the the locations of enhancer elements. This sponge genome can have enhancers over 10,000 basepairs away from the sites they regulate, which allows multiple enhancer cassettes can operate on the same gene to provide complex combinatorial and developmentally variable control. Additionally, the large set of gene regulatory proteins is more reminiscent of the set available in animals, many of which themselves have complex enhancer-influenced control.

The large number of introns (interruptions in the blue coding areas in the diagrams above) is another sign of animal-like organization, and in the sponge turn out to be where many of the enhancers live that regulate genes at a distance. Lastly, the researchers mention that about 60 pairs of sponge genes are similarly paired in other animal species, (i.e., they are micro-syntenic), indicating another level of unexpected conservation over about 700 million years. These are some of the ingredients that molecular biologists are learning are important to climb the organizational ladder to multicellularity.

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