Saturday, July 15, 2017

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.

Saturday, July 8, 2017

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.

Saturday, July 1, 2017

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.

Saturday, June 24, 2017

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?

Saturday, June 17, 2017


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?

Sunday, June 11, 2017

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.

Saturday, June 3, 2017

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.

Saturday, May 27, 2017

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.

Sunday, May 21, 2017

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.

Saturday, May 13, 2017

Hanging On For Dear Life

DNA synthesis on both the leading and lagging strands is done by an integrated, quasi-stable complex.

At the very heart of our hereditary and developmental lives is DNA synthesis- replication that copies one duplex into two. But each beautiful, classic DNA duplex has two strands, each of which needs to be copied. Not only that, but those two strands go in opposite directions. The one is the complement, or anti-sense, of the other one, and in chemical terms heads the other way. This creates a significant problem, since the overall direction of replication can only go one way- the direction of the fork where the parental duplex splits into two.

Complementarity of DNA. When one strand is synthesized in one direction, the other strand has to be synthesized in the opposite direction.

Replication of one of the resulting strands is easy- the "leading strand" is synthesized continuously from 5' starting phosphate onwards as the replication fork progresses. But the other strand, likewise synthesizing from 5' to 3', must head in the opposite direction, away from the replication fork. It is thus called the "lagging strand". Not only must it go in the wrong direction, but it has to work in pieces, synthesizing a short piece away from the replication fork, and then start over again once more single stranded template has been uncovered as the replication fork progresses. These units of newly synthesized DNA on the lagging strand, which are short and separated before they are later repaired and ligated together, are called Okazaki fragments, for the first person to observe and understand them, Reiji Okazaki.

Lagging strand being made in fragments. A helicase unwinding the fork is shown in gold, and the polymerases are show as beige doughnuts. The lagging strand polymerase has to go backwards, away from the direction of fork progression.

Naturally, DNA synthesis happens best when done on a smooth continuous basis, with as few interruptions and errors as possible. So the complexes assembled at the replication fork are quite stable, and held on by special protein clamps which surround the DNA like little doughnuts. An interesting finding was that in addition to the leading strand DNA polymerase, the replication complex also contains the polymerase used for lagging strand DNA synthesis, even while they are heading in opposite directions! This obviously helps keep the whole process orderly, but is a little hard to envision, since in DNA terms, the two polymerases can be hundreds of base pairs apart as they chug along their separate tracks.

More detail on the replication complex. The two polymerases (yellow) doing leading and lagging strand synthesis are actually tethered into one master complex (green), and the lagging strand polymerase, once done with one Okazaki fragment, is yanked back to start the next from near the replication fork. The clamps (red) are loaded by the green central complex in advance of each lagging strand re-initiation.

A recent paper investigated the notorious stability of these complexes. If you dilute an operating replication complex to homeopathic concentrations, the proteins will still stay on track, and continue synthesizing DNA. That indicates that the proteins do not spontaneously fall off by diffusion during their work, or even during the intricate switch between initiation points that is required in lagging strand synthesis. On the other hand, if you add inactive enzyme to ongoing replication complexes, they will grind to a halt, indicating that some kind of polymerase enzyme exchange is going on. What gives?

These authors used a microscopic method and fluorescently labeled polymerases to look at this question in detail. They were able to use a flow cell to stage replication as a visual process, watching a single molecule of DNA extend over time downstream as it was synthesized. With fluorescent polymerase, the progression is even clearer, and a hangup was observed at the first and second Okazaki fragment boundaries (C, the middle lines), since they had not added the ligases that could resolve those boundaries and free up the polymerase to return to the replication fork for another round.

A single DNA molecule being replicated, over time, to longer lengths from a tethered end. When the polymerase is fluorescently labeled, (bottom, purple), it shows the edge of the fork (top) and also the Okazaki fragment boundaries (lower lines).

When a mixture of two different fluorescent polymerases is used, (green and purple), they seem to exchange on the replicating complex, as it goes forth.

But when they used a mixture of two polymerases with different fluorescent colors, the interesting thing was that the colors changed while underway. A fork that started with purple polymerase changed suddenly to green, and then later back to purple. This is very odd for a stable complex. And if they fired a laser at the complex, bleaching its fluorophore permanently, the fluorescence eventually returned, indicating that a new polymerase molecule had hopped on and replaced the original one.

Lastly, if the progressing polymerase is zapped with permanently bleaching light, other fluorescent molecules take its place relatively quickly as the replication proceeds. Bottom is just a graph of the fluorescence intensity from the upper single molecule image.

The replication fork is thus a little like a basketball team. Substitutions can be made while the action is going on, but there can never be less than a full complement of players on the floor. The complexes are stable, but only if there is no other polymerase around. If there are, a new polymerase can jump into the existing fork / complex. It is a clever design that allows resolution of stalled complexes and defunct enzymes, while insuring that the process of replication goes forth as relentlessly and stably as possible.

  • GOP vs not just medicaid, and exchanges, but medicare too.
  • And then, naturally, lies about it.
  • Please stand up for net neutrality.
  • Facts, Schmacts.
  • Puerto Rico in the hands of a very few.
  • Timeline of the fraudulent firing.
  • Our president: "James Comey better hope that there are no "tapes" of our conversations before he starts leaking to the press!"
  • Krugman on our new, great, GOP.
  • Inequality diminishes our society.

Saturday, May 6, 2017

Thinking in Symbols, Speaking in Tongues

Theology, schmeology. Jimmy Swaggart's musical, tribal, shamanistic approach to religion.

What is church without music? Probably not much fun. Even Islam has smuggled in a musical tradition in the form of the call to prayer, which is often a virtuoso vocal performance. The important role music has in most religions is a sign that their gatherings are social bonding events, not scientific conferences. One of the clearest instances is the televangelism of Jimmy Swaggart, still going strong after 45 years. At its core are his amazing piano and vocal abilities, combined with a very tight band and other featured singers. A cousin of Jerry Lee Lewis, his talent was recognized early on, but instead of joining the recording industry, he built his own evangelical empire, whose broadcasts are heavy on the music, and light on the theology. The music is an extremely comforting, a sort of bluesy, (this is from Louisiana, after all), cross between Lawrence Welk and African American Church gospel. The focus is on praise and succor from god ("Take my hand, precious lord", "Jesus, use me", "I'll never be lonely again", "Sheltered in the arms of God", "What a friend we have in Jesus").

It is a little reminiscent of the gatherings of DeadHeads, finding a comforting sacrament of friendship and love in an endless bluesy/country jam, heavy on the sentiment. Yes, the Pentecostal / Swaggart version is a lot more conservative, and its love doesn't come from a puff of smoke, but the equally vaporous triumvarate of holy spirit, Jesus, and god. What theology there is is virtually stripped of any sense, however, consisting of archetypal references to give the whole jam more emotional power. It is, essentially, the power of shamanism.

For example, the creed of the ministry is:
“Dear Lord Jesus, I now realize that I am a sinner. I accept the fact that You died for me on the rugged Cross of Calvary. I now open my heart’s door and receive You as Saviour and Lord of my life. Please take full control of me and help me to be the kind of Christian You want me to be. Amen.”

Why "rugged"? How can Jesus take control when he no longer exists, and we do not know where he is or what he wants? OK, call me skeptical! Anyhow, the answer is always prayer, and the Swaggarts claim "Without a daily communication with our heavenly Father, we will only go so far in this Christian life, which won’t be very far, spiritually speaking." Prayer is the cell phone call to god, keeping Him up to date with what we want, and telling us what He wants. What does this really mean? It means one's conscience is going to do the talking, (at best), and its quality is going to be the tenor of our supposed talk with god. This might expain the problems that Swaggart himself has had in the sin department. It also means that anyone who can infiltrate our conscience and purport to tell us what god wants may end up with a great deal of control over our actions. For example, the ministry offers a wide range of "The truth about..." videos, telling the flock why Mormons, Catholics, Muslims, even Seventh-Day Adventists, are wrong and bad. The "full control of me" formulation could be taken as a little sinister, not just to keep the tribal boundaries clear, but to milk the flock for money, and drive a highly conservative political message that is in many respects rather uncharitable.

And control is surely what is going on here. The bonding is very strong and social, starting with the music and the TV shows, but extending to more intense "Camp Meetings" and other events around the country. Advertisements for youth events gush about how attendees feel the presence of the lord during the event. Theoretically, god is supposed to be everywhere, not anywhwere in particular, so these charismatic settings and climaxes are a clear sign of shamanism, not of any coherent theology, let alone philosophy.

The magazine, aside from advertisements for a rich assortment of ministry products, is full of word-salad theology, with submission urged to the will of Christ, or other spirits, so that the "Blood of the Lamb" can wash over the sinners in the pews, cleansing them of their sins. Sermons and blessings are "anointed", messages are "Spirit-baptized", and the "Powers of Darkness" are fought. This church is the "Bride of Christ", and good believers have "eyes of the spirit" to see "the things that lurk in darkness". The whole thing is a work of art, really- a poetry of metaphor which is highly meaningful without actually meaning anything concrete or real in this world. But when it comes to the prices, things are naturally far more explicit "Your price just $10 each".

Televangelism remains a remarkable phenomenon, drawing on the implicit cultural assumptions in favor of Christianity, on blues and gospel music, and on the power of personal magnetism and group bonding to comfort the lonely and lost. If the message were stripped down to the hymns alone, it would be a positive social force.
"If God Is Dead Who's This Living In My Soul?"

  • Our government, regular people not invited.
  • Even the National Review wonders about inequality. And then concludes that it should be made worse.
  • GOP busy making things worse.. Things which clearly could be better.
  • Making Afghanistan great again.

Saturday, April 29, 2017

The Rich Get Richer

Inequality is immoral and unjust: Review of "The Anatomy of Inequality: Its Social and Economic Origins- and Solutions", by Per Molander

Second only to global warming and our vast debt to the future of the biosphere, inequality is the most pressing issue of the day. The two issues incidentally interact, since the slide towards inequality has correlated with a glaring lack of care and empathy by the upper classes, not only towards their fellow citizens and humans, but towards all other life on the planet.

This book is the third of a powerful triumvarate of recent analyses of economic inequality, and of them perhaps the most profound. Its point is very simple- that inequality is absolutely intrinsic to our socio-economic relations, and proceeds naturally to extreme levels unless stopped by special political or social interventions. Inequality is not fair, it is not reasonable, just, or virtuous, but rather is a mechanistic and inexorable consequence of game theory, by which, as the title and the saying have it, the rich get richer.

Life is full of negotiations- with family members, with sellers of products, with employers. Not all negotiations are obvious, but when we are faced with a difficult choice, there is probably some kind of negotiation at the heart of it, influenced by other people. A paradigmatic negotiation is for a job. A seeker has labor to offer, and an employer has money to offer in return. What is the employer's need for labor vs the seeker's need for money? Already one can see a deep asymmetry at work. Add selective secrecy that hides the pay of other employees, an entire department of people devoted to getting the best deal for the company, and a social hierarchy based on seniority, and the result is clear- a lot of underpaid employees.

In negotiations, the more powerful / richer party is substantially advantaged. The employer may not only have the advantages above, but also have political influence to engineer other non-market advantages, from H1B visas to union-busting legislation and regulation (or non-regulation). This process was far more stark historically, obviously, as kings and other nobles gave themselves ownership of all the land, and made peasants into serfs. The advantages of a strong pre-existing negotiating position are so persistant that, in the natural state of affairs, inequality inexorably goes towards infinity, with the only limit being the dominant party's interest in keeping the whole iniquitous system going. As Molander puts it:
"There is no reason to believe that people in hunter-gatherer cultures have a different constitution or capacity to exert moral pressure that would curb the power of a ruling class. These societies are egalitarian quite simply because there is very little room for inequality when a society is close to the subsitance level. In societies with a larger suplus of goods, what restricts the power imbalance between the affluent and the impoverished is the former's interest in keeping the latter alive and reasonably fit for work."

Herein lies the two-income trap, the stagnation of wages over the last few decades, and the increasing share of wealth and income going to capital in the US. It is a mechanism analogous to natural selection, both of which amplify the smallest differences (or vagaries of fate and luck) into existential propositions. In any negotiation about economic issues, the person with a bigger cushion of money is better off, even when all other aspects are identical. Who needs the money more and will give in first? Clearly the person with less of it. Who is better able to take investment risks, and get higher long-term returns, even at the expense of volatility? Again, the one with more money. Having money, whatever its source, is like having the wind at your back, giving rise in turn to more money, higher status, more opportunities, and better bargaining positions vs others, and thus widening inequality.

While we in this new gilded age are nowhere near medieval serfdom, we hardly exist in a fair system, either. Take the example of Bill Gates. Smarter and more productive than your average person? Yes. But 80 billion times more? Probably not. His (borrowed) operating system was, even at the time, hardly the best available. But he parlayed a lucky industry paradigm and a strong but bumbling partner- IBM- into the world's biggest fortune.

Now, for all the money he is giving away, he can't help but make billions more each year from investments. Can you or I stand back and have billions come in the door? Probably not. Such passive income, derived not from investment risk (given the wealth backing him up, there is zero risk to practically any financial action) or from accumen (which can be purchased), is almost purely parasitic on the labors of everyone else in society. Add in the ability to bequeath this horde to his children, (think Paris Hilton, and the Republican obsession to eliminate estate taxes entirely), or to use it to derange our political and social system (think Kochs, or Mercers) and the corrosive nature of this concentrated and unearned wealth is obvious.

Historically, there have been several solutions to this ratchet of inquality. Catastrophes, such as plagues and wars, have been great levelers. Our own Depression, World War, and Cold War era was when many large fortunes dissolved and the stage set for several decades of low inequality and general prosperity. But in normal times, the ratchet of wealth accumulation runs inexorably and unfairly. Molander mentions the Jewish tradition of a debt Jubilee, which reset land ownership and debt bondage in Israel every 50 years. Outright revolution is another method, such as experienced in France and Russia, or the various democratic / demagogic episodes in Greek history. Or on a more modest scale, land reform, which shares out what was previously held by large landowners.

Molander notes that constitutions and social constracts are of limited help against this natural process of differentiation, which in his engineering terms is a positive feedback. We need more dynamic, negative feedback social mechanisms to resolve this fundamental economic and social injustice. The end of his book is taken up with peans to the social democracy of his native Scandinavia. But one problem is that social cohesiveness is both a product of, and a precondition for, substantial economic equality. We can not wait around for the number of social democrats in our national instutions to exceed one. As previously discussed, we in the US used to have, around our founding, the conditions of rough equality, which led in large part to the enlightened consitution and unwritten institutions we cherish and have benifitted by so much.

But now we don't, and our conditions, barring some unwelcome catastrophe, are trending strongly in the wrong direction. We need a new institutional structure that fights systematically against the natural ratchet of unequality. This would be something like the Federal Reserve, which has numerical targets that it is structured to hit in its management of the macroeconomy. For the Fed, this is the interest rate, of 2%, plus other goals of financial stability and (a very distant third) high employment. The Department of Economic Justice would target a basket of goals, including the Gini index (about 0.3), and employment (an unemplyment rate of nor more than 4%, or 10% in broad measures), and wealth distribution (no quintile owning more than the twice the next-lower quintile).

There are many tools that can be used to hit these targets. But it is significant at the outset that explicit, ambitious, and sustaintable targets be set. Some inequality is a good thing, fostering human development, work, and innovation. But too much degrades economic prosperity, and far more importantly, our social and political environment. The Department of Economic Justice may not have direct powers, perhaps only to report on conditions and propose legislation and regulation. Or it may have regulatory powers, such as for antitrust and fee or tax-based regulation of the financial industry. There are many available tools, from the obvious like taxing high incomes and taxing wealth directly, to financial transaction taxes, raising minimum wages, dramatically increasing public goods and infrastructure, and providing a job guarantee, which help raise the floor of economic conditions.

Molander provides a crucial service in reframing the inequality phenomenon as one that is natural and inexorable, but also mindless and unjust. The Galts of the world have very rarely invented the steel on which their fortunes rest, let alone the fortunes which their fortunes in turn make on a passive basis. We do not have to collectively put up with it.

  • Object lesson in the brutality of power inequality, in even small amounts.
  • Workers are underpaid.. what else is news?
  • Some great signs.
  • Honestly, are we capable of self-government?
  • News from Afghanistan, cont.: corruption rampant.
  • Reflections on truth.
  • Stiglitz on a modern welfare (or, perhaps, fair) state.
  • The last mask is off. The tax give-aways go to the rich and to Trump, not to his voters. But maybe they don't care.
  • Which makes Trump "perfect".

Saturday, April 22, 2017

How Speech Gets Computed, Maybe

Speech is just sounds, so why does it not sound like noise?

Even wonder how we learn a language? How we make the transition from hearing how a totally foreign language sounds- like gibberish- to fluent understanding of the ideas flowing in, without even noticing their sound characteristics, or at best, appreciating them as poetry or song- a curious mixture of meaning and sound-play? Something happens in our brains, but what? A recent paper discusses the computational activities that are going on under the hood.

Speech arrives as a continuous stream of various sounds, which we can split up into discrete units (phonemes), which we then have to reconstruct as meaning-units, and detect their long-range interactions with other units such as the word, sentence, and paragraph. That is, their grammar and higher-level meanings. Obviously, in light of the difficulty of getting machines to do this well, it is a challenging task. And while we have lots of neurons to throw at the problem, each one is very slow- a mere 20 milliseconds at best, compared to about well under a nanosecond for current computers, about 100 million times faster. It is not a very promising situation.

An elementary neural network, used by the authors. Higher levels operate more slowly, capturing broader meanings.

The authors focus on how pieces of the problem are separated, recombined, and solved, in the context of a stream of stimulus facing a neural network like the brain. They realize that analogical thinking, where we routinely schematize concepts and remember them in relational ways that link between sub-concepts, super-concepts, similar concepts, coordinated experiences, etc. may form a deep precursor from non-language thought that enabled the rapid evolution of language decoding and perception.

One aspect of their solution is that the information of the incoming stream is used, but not rapidly discarded as one would in some computational approaches. Recognizing a phrase within the stream of speech is a big accomplishment, but the next word may alter its interpretation fundamentally, and require access to its component parts for that reinterpretation. So bits of the meaning hierarchy (words, phrases) are identified as they come in, but must also be kept, piece-wise, in memory for further Bayesian consideration and reconstruction. This is easy enough to say, but how would it be implemented?

From the paper, it is hard to tell, actually. The details are hidden in the program they use and in prior work. They use a neural network of several layers, originally devised to detect relational logic from unstructured inputs. The idea was to use rapid classifications and hierarchies from incoming data (specific propositional statements or facts) to set up analogies, which enable drawing very general relations among concepts/ideas. They argue that this is a good model for how our brains work. The kicker is that the same network is quite effective in understanding speech, relating (binding) nearby (in time) meaning units together even while it also holds them distinct and generates higher-level logic from them. It even shows oscillations that match quite closely those seen in the active auditory cortex, which is known to entrain its oscillations to speech patterns. High activity at the 2 and 4 Hz bands seem to relate to the pace of speech.

"The basic idea is to encode the elements that are bound in lower layers of a hierarchy directly from the sequential input and then use slower dynamics to accumulate evidence for relations at higher levels of the hierarchy. This necessarily entails a memory of the ordinal relationships that, computationally, requires higher-level representations to integrate or bind lower-level representations over time—with more protracted activity. This temporal binding mandates an asynchrony of representation between hierarchical levels of representation in order to maintain distinct, separable representations despite binding."

This result and the surrounding work, cloudy though they are, also forms an evolutionary argument, that speech recognition, being computationally very similar to other forms of analogical / relational / hierarchical thinking, may have arisen rather easily from pre-existing capabilities. Neural networks are all the rage now, with Google among others drawing on them for phenomenal advances in speech and image recognition. So there seems to be a convergence from the technology and research sides to say that this principle of computation, so different from the silicon-based sequential and procedural processing paradigm, holds tremendous promise for understanding our brains as well as exceeding them.