Saturday, December 31, 2016

Make America Decline Again

Where is Trump going, and where are our institutions going?

My recent reading of Medieval history was particularly interesting in its analysis of the growth of institutions in Western / Northern Europe. It was a very slow, painful process, as the vacuum of Rome was replaced first by German kings with very primitive notions of the state and society, co-existing, with monks in their cloisters. Then came nascent states that used more bureaucratic structure (increasingly integrated with services from the church) to provide state services to larger territories and more people. Charlemagne built a great state, but it did not yet have the institutional staying power to last much beyond his sons. But over time, bigger and more effectively run states (Norman England, Capetian France) won the struggle for power in Europe, and generated not only bigger armies and bloodier wars, but also more peaceful and prosperous conditions at home.

Many of these institutions by which we live in peace with each other are written down, in constitutions and laws. But many are not. For example, the fact that a majority of votes in the Senate or House passes a bill is understood and obvious, but not actually written down in the constitution. It appears only by default when a 2/3 majority is required for such things as a passing a constitutional amendment or overriding a veto, and would be implicit in the ability of each chamber to make its own rules for administration. More topically, nothing prevents a president from having all sorts of business interests and foreign entaglements that might corrupt his or her administration. It is merely up to the voters to decide, and later the Congress to take up the matter if they have a mind to impeach.

Institutions live not only in our officials and constitutions, but in everyone's implicit expectations of how their society should run. The town meeting is a hallowed institution, by those who take part in it, as the only reasonable way to run a small political entity. They would not dream to call in a dictator from the outside, as was common practice in Medieval Italy.

Corruption is what happens when unwritten as well as written institutions weaken and go by the wayside, allowing the immediate motivations of greed and ego to replace the carefully honed traditions- if those traditions be worthy- and even common decency. An example is gerrymandering. It is obvious that the original intent, and the intent of any fair-minded person, would be that legislative districts should be evenly and regularly allocated to group together people who live close together. But well-gerrymandered state can scientifically allocate voters such that the party responsible gains far more seats that they deserve, which are then impregnable till the next census and the next exercise in drawing districts.

North Carolina's 12th district.

Corruption is not only an offense against fair play and moral decency, but typically against truth as well. No one is proud of being corrupt and abusing written and unwritten institutions. The trick is to claim one's fidelity while subverting in reality. And the cost of our large political system is that people are so out of touch with each other that they can no longer judge closely, or care to judge, or may not be educationally equipped to judge, the candidates for office, who each make the same claims to fidelity, truth and good character.

Which all makes our recent election so difficult to digest. The Democrats surely had their issues with fidelity to public institutions, with Hillary Clinton eagerly feeding at the golden trough of Goldman Sachs, and her husband raking in (charitably, of course) millions from foreign and other politically interested donors, a haul that one assumes is likely to dry up quite dramatically in the coming year.

However, all this pales in comparison to the orchestrated war on our basic institutions and our very understanding of truth that the Republicans have led for decades. Donald Trump campaigned openly on a platform of lies and execrable character. His business history is one of repeated bankruptcy, betrayal, cheating, and bullying. His knowledge of our institutions, and indeed of reality itself, is marginal. His abilty to articulate rational public policy was and remains nil, suited only to emotional outbursts via the 140-character medium of twitter. His emotional makeup was clearly unstable, and evidently psychopathic. And people voted for him.

Why? The battlefield had been softened up by decades of smear operations mounted by the Republican party through FOX news and other organs of the right. It turns out that hate sells, and thus leads to a sustainable business model of purveying emotionally tinged lies, leading to mis-directed hate, leading to more listener engagement, and more advertising dollars. It is reminiscent of the interwar period in Germany, when scapegoats were sought for: who lost World War I. They came up with the Jews, and a general lack of teutonic authoritanianism, in a self-feeding cycle of hate which polarized society to great, deadly extremes.

For decades, the Republicans have been seeking scapegoats for: who lost the culture war? Why are Americans becoming increasingly compassionate towards blacks, towards gays, towards atheists? What is going on, and could the clock be turned back- to make America great again? The backbone of this movement was naturally the right-wing religious believers, who, being temperamentally authoritarian, and having already swallowed one pack of lies, had little problem with a few more, like the whole wishlist from the business community, that wealthy people are the job creators, that government regulation is the main thing standing between rural people and good jobs, and that unions are evil. And that Donald Trump means anything he says or has an ounce of morals. And that the Clintons are unspeakably vile- far more so than those fine business organizations who sold so many fraudulent loans and other toxic waste that we are barely coming out of the recession they caused. And that global warming is a hoax, and that Bengazi was Hillary's fault, and ... well, the appalling list goes on, ad infinitum. They have a great deal of airtime to fill, after all.

The Republican war on our institutions has had a self-reinforcing quality. Given that they want to debilitate governmental institutions, whenever they get their hands on one, like the House of Representatives or the Senate, they make it non-functional, and in a self-fulfiling prophecy, the government indeed doesn't work, and the base can be riled up all over again to attack their chosen targets of hate. The base doesn't seem to make the connection between cause and effect, except when that connection is glaring, such as the government shutdowns that ultimately damaged Newt Gingrich- perhaps the earliest and most vociferous destroyer of American instutions in our generation.

The vacancy on the Supreme court stands as the absolute lowest point of Republican subversion. A shameless plot against norms and practices in place since the founding, in a doomed quest to reverse the course of social development. For however conservative and extreme the court gets, America at large is never going back to the image that conservatives have of it. Similarly, Donald Trump is busily appointing to each department a head who seeks to debilitate it and subvert its purposes and norms, so that corruption by the business elite can flourish. Education will see corporations in charge of charter schools, the EPA, corporations in charge of climate change policy, and the Labor department will see union busters in charge. The tax system as a whole will doubtless see giveaways to corporations and the wealthy that will make the Reagan administration look like a Trotskyite regime.

Is this what his voters wanted? I would hope and assume not. But they knew they were electing a con man, right? How could a ruthless billionaire with no previously recorded ounce of compassion for anyone outside his family do other than he has, hiring those he likes and trusts to run our country, which already is one of the most unequal in the developed world?

While all of politics is a matter of lies and half-truths; banal rhetoric with maximal tone and minimal content, the degree to which Trump could play this game with complete shamelessness and emptiness is not a matter of his talent alone, but of the decades-long evisceration of our public discourse and institutions, and particularly the Ministry-of-Truth programming that his base has been fed so effectively from the right-wing media. They do it not only in the service of their conservative ideals, but also for their true power base- the wealthy and corporations, who could never carry an election with their own votes, but if they destroy enough of our democratic and cultural institutions, and brain cells, can win anyhow, free and fair.

  • Is compassion dead?
  • Yes.
  • Honestly, do we really need a middle class?
  • How about some happy thoughts?
  • "Liberalizing policies are justified in theory only by the assumption that political decisions will redistribute some of the gains from winners to losers in socially acceptable ways. But what happens if politicians do the opposite in practice?"
  • Christmas is pagan.

Saturday, December 24, 2016

Repression Makes Us What We Are

Notes on polycomb and histone interaction in developmental gene control.

While we have shockingly few genes in the genomes which engender our complexity, most of them are also turned off most of the time. It is repression, just as much as activation, that generates the patterns of gene expression that allow developmental ramification and specialization. This repression comes in several forms, from individual gene switches to the sequestering of whole chromosomes, such as in female X-inactivation. The stronger forms of repression can be what is called "epigenetic", which simply means they can last a long time, such as through several cell division cycles, or even across a generation. That means that they begin to mimick true genetic effects. However unlike true mutations, they can be programmatically reversed at some future time- otherwise they would not have any function. Thus "epigenetic" features are part of an organism's phenotype, not its genotype.

One general mechanism of long-term and long-range (that is, may extend over many neighboring genes, and large chromosomal regions) gene repression is the polycomb system, named after phenotypes conferred by some of its mutations in fruit flies, whose males have sex combs. This is a system that may descend on a chromosomal region if it is never needed again in the development of an organism, and keeps those genes off, locked up tight. This effect is also called "gene silencing", for obvious reasons.

There are several proteins that make up polycomb complexes, each with its own super-powers. Most of these powers revolve around working with histones- the small proteins that are the smallest packaging units of DNA in eukaryotic cells. Histones are not passive spools around which DNA wraps, however, but through a vast number of possible chemical modifications (methylation, acetylation, ubiquitination, at numerous different positions) are pivotal levers of control over on the availability of DNA to all the other denizens of the nucleus.

One typical core complex of histones, acting as a spool for our DNA. The DNA is actually much larger, covering most of the histone surface. Yet the histone tails stick out, ready to be modified and recognized by various other regulatory proteins.

One of the special characteristics of polycomb action is that it can spread along the DNA from a initiating site to nearby locations, in a progressive fashion. This is unlike a normal gene repressor, which just acts locally within a mixture of activators and repressors for one enhancer site upstream of one gene. How does polycomb do this, and how does it know where to stop?

There are two parts to the system, polycomb complex 1 and complex 2 (PRC1, PRC2). PRC2 acts first, binding to other proteins at particular DNA sites called polycomb response elements, and methylates the local histones H3 on lysines (K) 9 and 27, which are on the tails sticking away from the DNA and thus accessible. How does this get turned on? The targetting proteins are the ones that are themselves regulated to initiate the whole repression process. A second activating change is methylation of the local DNA, at CG dinucleotides, which tends to concentrate at silenced genomic locations, and helps initiate that silencing.

Methylation has a specific charge effect, eliminating the positive charge on the affected lysines, (or negative charge at the CpG DNA sites), thus helping the histones repel each other less, and pack together. But the marking of histones by various methyl, acetyl, and other groups on their tails has more subtle effects, since each modification is specifically recognized by other proteins, creating a complex code that regulates gene activity at very fine scales.

The second step, carried out by PRC1, which finds and binds to histone H3 methylated on lysine 27, is ubiquitination of histone H2A on lysine 119. As ubiquitin is a small protein, its attachement is a much more dramatic change than modifications like methylation or ethylation. And though ubiquitin is generally associated with marking proteins for destruction, here is doesn't have that effect, but rather has a regulatory role in stablizing and compacting chromatin structure. However, as a large complex with several activities, PRC1 may do other things to promote repression which are not yet known.

A recent paper delved into this a bit to ask how PRC1 is composed, and what activates it. It is not a stable or uniform complex, but a consortium of several proteins that converge when needed and whose components come in several flavors. It is apparent that repression even in this general polycomb class comes in different forms. Representative components are:

  • RING1 or RING1B- this is the ligase that enzymatically attaches ubiquitin to Histone H2A
  • PCGF1- This is a helper for the RING ubiquitin ligase activity.
  • CBX2 or RYBP- a protein that binds to the H3 methylation site, and binds other proteins, especially PCGF1, and YY1. YY1 is one of the targeting transcription factors that can bind the polycomb response elements and help initiate repression.
  • KDM2B- an enzyme that can de-methylate histone lysines, and binds to the CpG dinucleotides that, in part, target polycomb repression. It also has a protein domain with a role in targeting ubiquitination of other proteins (the F-box).
  • BCOR- This protein interacts with other histone de-acetylases.

The point of this particular paper was to demonstrate the composition of one particular version of the PRC1 complex, and to show that the core subunits of RING1B and PCGF1 are sufficient for histone ubuquitination, but that they are stimulated by the addition of the subunit RYBP. The other subunits don't help ubiquitination in vitro, but have other roles (whether known or unknown) in regulating and directing the complex's activity in cells.

One example of a PRC1 complex, which ubiquitinates H2A histones. B shows an electrophoretic gel that separates the proteins by size. kD is kilo-Daltons. C shows a mass-spectrographic study of cross-linked complexes showing which parts of which components interact directly with which other ones.

Another finding is that the PRC2 complex recognizes not only the initiating factors at the polycomb response elements, but also the ubiquitinated histones left by PRC1. This is likely to be part of the positive feedback "spreading" mechanism by which polycomb extends its area of repression from those initiating sites on the DNA / chromatin. Unfortunately, the details of initiation, the exact mechanism of spreading, the implications of ubiquitination, and the reasons for limits on the dimensions of polycomb-repressed regions are still largely unknown, or only hinted at, so far.

That gives you a taste of the state of the field, from this recent paper. The polycomb system has been known for a long time, having been established genetically in fruit flies over 70 years ago, with the discovery of the original polycomb mutation. It is unfortunate that this field is not farther along, in the understanding of the individual components, and how this form of repression is initiated and limited.

  • Yes, he has his own brown shirts.
  • Meet your new friends.
  • Cultures of stupidity.
  • To hell with the whole thing...
  • We can make all the jobs we want.
  • Apparently, a feminized culture is a bad thing.
  • Scientific epistemology, the value of negative results, and the canonization of facts.
  • Institutional development in China, vs freedom.
  • Can we call it treason, already?
  • Religion is part of the reason for our new love of Putin.
  • Mergers are good for someone, but not you.
"By utilizing new techniques to isolate the effects of mergers, they find no evidence that mergers increase efficiency, but do find evidence that they increase market power, meaning they allow companies to generate higher profits by raising prices."

Saturday, December 17, 2016

Encounter With Aristotle

Leading Western cultures encountered Aristotle at critical times. What was the result?

This is a continuation of last week's appreciation of Norman Cantor's "The Civilization of the Middle Ages", which devotes a great deal of space to the renaissance of the twelfth century. This was when most of the extant writings of Aristotle- an enormous corpus- reached Europe, from various sources, including translations from Arabic and then later, translations from the original Greek, which had remained on file in Christian Byzantium.

I can not claim any expertise on Aristotle whatsoever; it is a mountain I have yet to climb. But his central position in both ancient and later philosophy is clear. This episode of recovery and rediscovery by Western Europeans after their long intellectual darkness is particularly interesting and momentous in many ways, not just to philosophy.


Aristotle was the proto-scientist, to Plato's idealist. Christian thought had developed as a fusion of Judaism and Platonism. Ideals such as god, categories, spheres, were to Plato not only real, but the only real things at all, with particular, empirical manifestations being of far less interest, merely the deficient instantiations of ideals and inferences which an intensely abstract intellectual would find the only compelling things. Imagine that you had just discovered gravity. The examples of it in everyday life are interesting, but the universal idea of it is vastly more powerful and conceptually deep.

On the other hand, Aristotle, while not dismissing Platonic idealism, matched it with a regard for empirical complexity and existence. His biology is a good example, where actual observations and even dissection support a classification scheme without a lot of idealistic baggage. Aristotle believed in god, but in a sort of deistic version- the prime mover. Nor did he think we have immortal souls, but that all life forms have souls in various gradations that are just our vital motive forces, and which, at best, reunite with a universal soul at death, but in most instances die with the body. One can portray Aristotle as a stage in humanity's maturation, from childish magical thinking, where all concepts have to revolve around the self, to an ability to deal with reality forthrightly, with fewer mythical crutches, and more humility.

His huge and advanced corpus was clearly far beyond what the local philosophers and scientists of the Muslim, Jewish, or Western European worlds had achieved. Naturally, it challenged them in fundamantal ways. The greatest intellects of each tradition grappled with Aristotle and wrote commentaries: Averroes, Maimonides, and Thomas Aquinas. Cantor writes:
"In both Moslem and Jewish thought, the attempts of great thinkers to deal with the relationship of revelation and the new Aristotelian science thus ended in defeat and disaster at the beginning of the thirteenth century. Islam turned away from science because it was considered heretical by religious leaders who were able to obtain the assistance of fanatical princes to destroy rational speculation. The general decline of vigor in Islamic civilization undoubtedly also played a part in the termination of the great scientific and philosophical movement in the Arabic world. Judaism at the same time turned its back on science and secular thought, partly again because of the hostility of orthodox leaders and partly because of the ghettoization of European Jewry which began in the twelfth century."

The result here was that, for all the heroic efforts of Averroes and Maimonides (and their followers and colleagues) to blaze a compatibalist path that shoehorned the two systems together, the larger community was not having it. Any shoehorning of elements of the faith, especially of the Koran, was unacceptable. One can surmise that the social functions of the respective faiths were recognized as such, and as more important than free searches for truth that were clearly sowing the seeds of heresy if not total obliteration of the faith.

Saint Thomas Aquinas.

On the other hand, the European scholastics such as Aquinas, in their innocence, had such faith in the truth of their faith that they did not even consider that another truth, whatever its source, could threaten it. Heresy was untrue, but true things necessarily had to be consistent with the Gospel and church. So Aquinas adopted Artitotelianism in large part, and insisted on compatibalist solutions- on the soul, on natural morality, on sensory empiricism. This took quite a bit of interpretive effort, but was rewarded by everlasting fame and sainthood- quite a different result than in the other religious traditions. Aquinas is still a bedrock of Catholic theology.
"It was his Aristotelian epistemology that allowed Aquinas to work his way to his conclusion. His whole system rests on the principle that knowledge comes not from the illuminating participation of the mind in pure and divine ideas, as was held by Augustinian Platonism, but that it is primarily built up out of sensory experience. As an Aristotelian he could not accept that Platonic theory of forms; to him it was not scientific, and any Christian philosophy that was based on a false epistemology would fail, as the twelfth-century realists had failed, in the face of nominalist attack. ... He admitted that  there are certain ultimate areas of the Christian faith to which reason cannot penetrate: it is impossible to prove the miracle of the Incarnation or the Trinity. But it is possible to prove rationally the existence and many of the attributes of God. Aquinas presented five proofs for the existence of God, all of which were based on the Aristotelian argument for the existence of a first cause. ... He proceeded to argue, with a validity that was doubted by many, that from this premise could be derived the Christian attributes of God as perfect, omniscient, omnipotent, and free.... Similarly, he proceeded from Aristotelian causality by way of logical argument to prove creation ex nihilo, and similarly from Aristotelian psychology to the human soul, and from Aristotelian ethics to Christian virtue."

Yet acceptance of the innovations of Aristotle, of natural theology and rational ethics, etc., obviously also sowed the seeds of theological destruction, since if god is read in his or her works- the book of nature- the more carefully you read, the less you may find, if that god does not actually exist there, and faith was the key ingredient all along. First the Protestants insisted in reading the books of nature and scripture for themselves, and then scientists discarded scripture entirely. Now here we are in the post-Newtonian and post-Darwinian epoch, shorn of any (natural) rationale for god other than Aristotle's wan prime mover, though even that remains only as an unknown possibility rather than a necessity.

Lastly, what of the status of Aristotle in the culture where his writings were originally preserved- Eastern Rome, or Byzantium? Obviously, despite their wealth and institutional stability, they had no more of a scientific or philosophical revolution in the first millenium than the Western Europeans had. They were just as, and perhaps more, besotted with Christian theology, in characteristically "byzantine" disputes over iconography in particular, such that free thought seems to have been in very short supply. There was evidently just enough attention paid to the classics to keep them in print, but little more.

The endless and exceedingly complex ruminations about the nature of the soul through all this time were especially remarkable and saddening in their vacuity. They expressed little more than a profound ignorance of biology, which is understandable, as we still are some ways from understanding how it all works. The vegetable, animal, and rational souls of the Aristotelian system were reasonable stabs at classifying the levels of consciousness / biological being. Nor did they, in Aristotle's hands, appear to be immortal, with all due respect to Aquinas's efforts, but at best universal as "forms" by way of Plato's idealism / realism about such things, not individually. Death, is, after all, such an obvious and final fact of life. The centrality of the afterlife- the promises on which the whole Christian corpus and attraction is based- led to the very unfortunate dominance of intuition and magical thinking over simple reasoning, which haunts us to this day.

  • Champion of workers, or of extremely rich CEOs?
  • After Pizzagate, one gun is not enough.
  • Yes, the media are easily led.
  • Could Trump be the messiah, after all those Christians voted for him?
  • Thoughts about integration.
  • Prospective cabinet has a "total net worth that exceeds the combined wealth of more than one-third of all Americans."
  • The costs of a good foreign policy.

Saturday, December 10, 2016

Why Were the Dark Ages so Dark?

Review of "The Civilization of the Middle Ages", by Norman Cantor.

Everyone thinks they are living in the modern age, at the cusp of technological and social development. At least till they get older, and realize that everything is, instead, going to pot. While we are always at the edge of time, we also live within the institutions and ideas of the past. That became painfully apparent with the recent election, when the electoral college went one way, and the popular vote went dramatically the other way, by a 2% margin.

Our culture and its institutions have been under development for thousands of years, and while the events of much of that time were not very well documented, that doesn't mean they weren't important. Norman Cantor's not terribly scholarly, but highly opinionated and readable overview of the Middle Ages (~500 to 1500) is one of the best sources I have read to understand this period. He takes an analytical view of why institutions developed the way they did, and offers frank views on what was helpful and what was not, in the cause of overall Western progress. No wonder this book is still in print, after over two decades.

His major theme seems to be the establishment of large, competent states as the endpoint of successful social progress. Each epoch is judged by the coherence of its political institutions, from the height of Rome, to the depths of post-German invasion Europe. Cantor is dismissive of the Germanic institutions of government, which were little more than tribal councils and endless warfare. Thus the tension between the new invaders and the inheritance they were so close to, from Rome proper, and from the rump Eastern Roman empire, aka Byzantium.

The invaders (apparently pushed by other invaders to their rear, like the Huns) didn't mean to destroy Rome, really- they just wanted to share in the bounty as well as in its institutions. But Rome didn't have a very welcoming immigration policy, and ended up fighting itself into oblivion. There are many interesting elements to the subsequent story, but I will focus on just a couple- the role of the church, and nature of law.

Once we get into the 500's and beyond, as Rome let go of England and other territories, and was sacked separately by the Visigoths, Vandals, and Ostrogoths, and then was reconquered for good measure by the Byzantines, things had really fallen apart. Various Germanic tribes were in charge of most parts of what was previously the Western Roman Empire, with little institutional memory descended from the Roman epoch. What was the one functional institution? The church. But it was a very long time before the church realized that it had a role to play in the general organization of society.

10th century depiction of St. Gregory, d. 604 at work in his scriptorium, with the help of the dove of the holy spirit.

The Benedictine order is by far the oldest form of Western monasticism, originating around 530 with the innovative communal organization, as opposed to the lonely ascetic hermit mode of the East. It was the Rule which organized each house, and gave it a strong, independent, and self-sufficient government. This was in marked contrast to the ambient governments outside its walls, which rose and fell with each dynastic squabble, and whose legal and bureaucratic concepts were virtually non-existent. Only after three hundred more years did the Franks under Charlemagne briefly raise the level of governance, with a Europe-wide kingdom that began a significant alliance with the papacy and developed rudimentary bureaucratic forms to keep the ship running in the personal absence of the king.

While that empire promptly fizzled within a generation or two, the seeds for greater alliance between the educated class (i.e. monks from the Benedictine houses) and the various Germanic rulers had been sown, and as we get into the later 900's and 1000's, monks are the standard administrators for governments across Germany and France. This enabled the Pope to gain power over the kings, whose ministerial staffs were at least partly loyal to the Pope. But the general effect was to raise the level of bureaucracy over the most basic to non-existent level it was at before, and give each state some institutional memory as well as a pan-European perspective (the language was Latin, after all).

By the time of the Cluniacs, (~1100) monks were really riding high on the hog, living well, in great demand, and running affairs all over Europe. In parallel, Cantor emphasizes the enormous innovations conducted by William the Bastard, conqueror of Britain in 1066. He set up a government of unprecedented thoroughness and durability that offered order at the cost of relentless taxation, not to mention the reduction of the previous Anglo-Saxon nobility to serfdom. This renovation of Germanic institutions of law and government was to serve as the springboard for English power for centuries to come.

Cantor also mentions the discovery of the Code of Justinian as an epochal event in Europe, around this same period. This finding did not have much influence in England, but elsewhere on the continent, it quickly provided a whole new view of law and the legal profession. For a newly urbanizing culture, it provided a newly relevant and exceedingly detailed template of jurisprudence from the urban cultures of Rome and Byzantium. And for kings, it provided a ruler-centric vision of law, as the extension of the will of the emperor. Thus the distinction that still exists between English law, with its juries of commoners, and continental law, where judges run the whole show. For the urban elite, it provided a new profession- that of lawyer, which together with the university system, slowly propagated bureaucratic, legal, and scholarly skills beyond the abbey.

What is important in all of this is that our institutions are precious achievements. Government may be the casual target of unending grumbling, abuse and criticism. But virtually any government is better than none at all. Freedom is not the absence of government, but quite the opposite, given that we are each other's primary predators and irritators. The union of justice with power has been the principal achievement of great civilizations, and is what has allowed all the other benefits, advancements, technologies, arts, and sciences to grow like a garden of flowers from a secure and prosperous populace.

  • Jobs and work are a fundamental good.
  • Against anti-knowledge in economics.
  • "The bottom half of the income distribution in the United States has been completely shut off from economic growth since the 1970s"
  • "For babies born in 1980 — today’s 36-year-olds — the index of the American dream has fallen to 50 percent: Only half of them make as much money as their parents did."
  • Trauma and stuttering.
  • Post-truth ... say it ain't so!

Saturday, December 3, 2016

The Poisoned Pen

Jefferson and the Republicans had their own (early) version of FOX news.

I am reading the McCullough biography of John Adams, which is a real hagiography. But it is also well-written, packed with information and insightful in many respects. His portrait of Thomas Jefferson is particularly harsh, as would be natural because he and Adams became bitter antagonists. Jefferson's main tool in their fights was the press. Specifically, secret relationships with the National Gazette, and its successor, the Aurora General Advertiser.

The polical parties of that time broke down along centralizing, pro-government (Federalist) and pro-agrarian, decentralizing, and Southern (Republican / Democratic). The latter were also, at least in the person of Jefferson, much more enamored of the French Revolution. Adams immediately saw the mob nature of that revolution, so different from that of the Americans, and forsaw chaos as well as its eventual descent into dictatorship. But there were many other sources of conflict such as the basic party splits over Southern vs Northern interests and ideologies, personal enmities, and personal ambitions.

The vitriol that came pouring out, once the founding era was swept away and the two-party system was established, is truly disturbing to behold. Secretary of State Jefferson employed Phillip Freneau in the State Department as a translator, but with little work. Freneau spent his main energies as publisher of the National Gazette smearing Jefferson's (and James Madison's) enemies within the administration, including Alexander Hamilton, John Adams, and George Washington. (On the other side, Hamilton gave his favored printer, John Fenno of the Gazette of the United States, a large government printing contract.)

They made a great deal of hay out of a long debate fostered by John Adams as vice president on the proper forms of address towards the president. Adams favored something a little more grand like his highness, or something of the kind. For this he was painted as being a monarchist and wanting to subvert the independence that had so recently been achieved. Also that his lengthy stay in Europe as ambassador to France, the Netherlands, and Britain may have turned his head.

The language of these attacks was often hyperbolic and scurrilous. A birthday party for Washington was described as "a forerunner of other monarchical vices." Adams was described as being among the men who proposed "the principles of monarchy and aristocracy, in opposition to the republican principles of the Union and the republican spirit of the people." There was a reference to the "corrupt sqadron of the Treasury," and to Hamilton as "a vile sycophant". The Federalists proposed laws that are "injurious to liberty and enslaving to the happiness of the people." And Republicans concluded that "our Constitution was galloping fast into Monarchy."

It was a combination of party rivalry and tribalism, along with honest fears that the fragile experiment of American self-government could, if entrusted to the wrong hands, or blown off course by a crisis, end in tears. Today, we have a more settled system, indeed well-neigh an imperial system with its own problems of vast size, corruption, and unmanageability. And, thanks to the poisoned press of our own age, a president-elect far from the founder's ideals.

A lot has been made of how the elite media was out of touch from the angry Trump voters. But Trump was covered incessantly during the campaign, with the helpless passivity of a star-struck media long-used to a commercial role and to reality-TV imperatives. Just as in the founder's day, there were political operatives pulling the strings behind the faux-news curtain, such as Roger Ailes and Steve Bannon- operatives whose regard for the system and nation as a whole took a distant back seat to their vitroloic personal and tribal campaigns.

For all the complaints about political correctness, which seems to be the animating animus of the alt-right troll brigade, political correctness was a stranger to this campaign, and we are now the worse for it. Civility and decorum are not just fusty relics of a puritanical age, but basic ingredients, even institutions, of an operating political system. Strength and manliness are not indicated by grossness of expression, nor are honesty and truthfulness. There was no better con man than the insurgent candidate, Trump, whose obvious contradictions, lies, and mean-ness seem to have been swallowed with equal relish by media and supporters alike with the complimentary condiment of "controversial".

When the going got really rough, during the Quasi-War with France in the late 1790's, Adams and the Federalist party passed the Alien and Sedition acts, which allowed the administration to jail and fine anyone, especially those in the media, who insulted the President or otherwise made what were deemed false statements critical of the government. And Adams has rightly been pilloried then and since for not vetoing this obviously unconstitutional legislation, hardly a decade after passage of the first amendment.

So the internet is not a new thing, in its capacity to foster rumors, spread lies and invective, and keep its readers in thrall to a mean-spirited and partisan echo chamber. We have survived such media from the start. But that doesn't mean it isn't a problem. The US was blessed with a special period of media civility in the mid-twentieth century, due to the cultural bonds of the world wars and depression, and also to the uniquely restrictive technical landscape of radio and TV, which only allowed a few channels and thus special federal rules for equal time and public interest in media behavior. That was a time when corporatism in the media industry largely served the stability of political system.

Now is different, and we need to think hard about ways to preserve some sanity in a media landscape so incredibly diverse and free, yet at the same time so starved of resources that in-depth reporting, balanced perspectives, and public interest investigations are disturbingly scarce. Where corporatism has turned the media into a thoughtless race for clicks, if not the plaything of retrograde billionaires, and where trolls use twitter to win political office. We need to fight against this creeping post-truth condition, which was a continues to be exemplified by the information practices of the Soviet, and now Russian, state.

While the first amendment prohibits government from meddling with the freedom of other's speech, it does not prohibit it from sponsoring public interest media. We need a segment of distinterested media that is not driven by an ulterior agenda such as greed, partisanship, or more obscure ideology. Non-profits would be ideal purveyors of this, but they do not on their own have the resources to address this quite large need. The public providers PBS and NPR stand as great accomplishments of the last fifty years. This is where we can build a better media landscape, perhaps expanding them into print and enhanced, deeper reporting. The BBC is a model of such expansion, to evolve towards broader news organizations.

The danger, of course, is that the wrong hands at the top could break down the barriers of independence at these institutions, and turn them into especially powerful cudgels of partisan warfare- new Ministries of Truth. On the other hand, even if not explicitly directed by the government, their government funding might make them reluctant to look too deeply into offical corruption and instritutional breakdowns. One can already see this in the tendency of PBS and NPR news to avoid breaking dramatic stories about government problems. Yet who broke the Flint water crisis story? It was the ACLU, reported by NPR affiliate Michigan Radio.

The landscape we face now desperately needs better media. Abigail Adams wrote a remarkable passage to Thomas Jefferson late in his presidency, after a newspaper writer whom he had previously supported and colluded with to smear John Adams turned against him, extorted him and exposed Jefferson's correspondence as well as his relationship with Sally Hemmings:
"The serpent you cherished and warmed, bit the hand that nourished him, and gave you sufficient specimens of his talents, his gratitude, his justice, and his truth. When such vipers are let loose upon society, all distinction between virtue and vice are leveled, all respect for character lost."

Saturday, November 26, 2016

Sleep Brain Waves Are Not Only Slow, But Circular

Memories are delicate physical structures in the brain, and get cleaned up / thrown out / enhanced during sleep- but how?

The mysteries of sleep are slowly becoming unraveled, and not a minute too soon, since we are both depriving ourselves of sleep as never before, and using such deprivation as an instrument of torture. Sleep seems essential for refreshing the brain in multiple ways- tidying in both physical and logical respects. A "glymphatic" system that operates at night, when the cellular volume of the brain shrinks slightly, to physically drive cleaning fluid through the brain to clear out garbage, has been one remarkable finding. Sleep is also when memory "consolidation" happens, which means reinforcing the more important ones, re-distributing or copying them from the hippocampus to the cortex, and deleting less important ones. Then there is dreaming, that link to the deep unconscious which sleep facilitates, with perhaps higher psychological functions.

A well-known feature of sleep is its brain waves, which are especially strong and slow. They appear to function as part of the memory consolidation system, but really, we know very little about them. There are two types of significant sleep waves- the sleep spindles that happen in stage 2 sleep, and the very slow delta waves that happen in the deepest level, stage 3.

A recent paper looked at the geometric pattern of the spindle waves, using epileptic patients who have had their skulls opened extensively for investigation, and allowed the researchers to apply a large field of electrodes to one hemisphere for this tangential study. It finds that instead of the whole brain pulsating with simultaneous spikes and troughs, there is a moving, circular pattern of activation, progressing from the lower temporal cortex, to the parietal cortex, on to the frontal cortex, and back to the start. This makes sense causally, in that there are always conduction delays from one place to another, so it is difficult to imagine one pacemaker (in this case the thalamus) running simultaneous electrical oscillations all over the brain.

Example of sleep spindle propagation. A shows one spindle sequence and the electrode locations, B shows the time course, and D shows averaged vector directions of propagation over all subject and readings, notably in a temporal -> parietal -> frontal direction.

The interesting thing is that this paper argues that this pattern also makes sense functionally, in that it helps consolidate connections between distant points much better than simultaneous activation would. I find their case hard to understand as well as doubtful, but it revolves around the timing issues of long-term potentiation (LTP) and depression (LTD) among neurons.

Spike timing-dependent plasticity is the name for a broad theory of how neuronal connections are managed. If two neurons are connected to each other in the usual fashion, with dendrites from A exciting the axonal network of B, the relative timing of firing of A and B has great influence on whether their connection (synapse) is strengthened for future events, or weakened. If A fires ~10 ms (milliseconds) before B, then the synapse is strengthened. This makes obvious functional sense, implying that A *caused or helped cause B to fire, a successful event that would presumably be good to enshrine in a more permanent connection. Conversely, if A fires anywhere from 10 to 50 ms after B fires, then the logic is reversed, and the physical effect is also reversed: the synaptic connection is made weaker.

Proposed theory, whereby synchronized spindles (top) would result in troughs falling on the evoked action potentials of the original targets (EPSP), causing depression / weakening of all connections. But in B, which resembles the actual state of affairs, successive spindles, when hitting the target neurons, would be at peak value, (assuming that targets of the original neurons and the spindle wave are traveling in the same direction), and thus foster strengthening of all connections.

Given that the sleep spindle waves happen at ~11-15 Hz, or about 80 ms intervals, the authors argue that if they just propagated point to point from the thalamic pacemaker out to points in the cortex, they would arrive at various times, but their effect on secondary targets- the targets of the immediately driven cells, whose firing is delayed by, say, 20 ms- would be to cause chronic long-term depression of those target connections, since the next spindle peak falls roughly into the zone of LTD.

On the other hand, if the spindle waves propagate in a wave-front fashion through the cortex, then (B in figure) the target cells would be hit more or less simultaneously by the evoked firing from the A cells excited by the spindle wave, and then the spindle wave itself as it progressed to hit them as it moved through the cortex.

The researchers go on to find, beyond from the rotational progress of the sleep spindles, that these 11-15 Hz waves entrain gamma waves as well, and they imply that over 2.5 hours of sleep which they observed in one subject, these gamma waves strengthened in a way that supports their hypothesis that the sleep spindles are progressively reinforcing neural connections, including memories.

I find this work very hard to take seriously, though it comes from a very serious lab. If the neural network is 3-dimensional and extensive across the cortex, there is no way to predict the transmission time (estimated above at 20 ms) from one neuron to the next. Nor does the orientation of each particular sub-network necessarily have anything to do with the circular rotation scheme seen in the electrical recordings. That geometric data is much more easily explained as a mechanistic consequence, even side-effect, of not being able to activate all areas of the brain at the same time. Lastly, the idea that sleep spindles, or any process, indiscriminately strengthen all neural connections seems unhelpful, since the point of the "consolidation" process is both to discard old and minor memories / connections as well as to enhance more significant ones.

Graphs of spindle wave phase, taken 5.6 minutes apart in one subject. This suggests to the authors that coherence is progressively enhanced through the stage 2 sleep process, presumable due to positive neural connections being strengthened. Related videos and data are at the publication site.

At the same time, I do not have a counter-theory about how these waves accomplish their function, which certainly is connected with memory management. (Please comment if you have greater insight into these processes or this paper!) So we have a great deal to learn. It is a fascinating area of research, trying to build a unified theory of how the anatomical connections in the brain, and the electrical functions including oscillations of various periods, function to make our minds function, and refresh.

Saturday, November 19, 2016

Fighting the Civil War, Over And Over Again

Reflections on the election.

There- we have had our election, and the rednecks (and orange haired) won. Why the bitterness? Why the perpetual lack of understanding of what the other side values and thinks? Why the deep differences of values in the first place? Coalitions may have always been fluid in the US, but the divides between North and South, and between rural and urban, have been relatively durable. There are differences of interest, of upbringing, of tone, and education reflected in this geographic segregation. It is a typical path for any promising young person to leave the country, go to college, and make a new life in the urban, elite centers, forsaking and perhaps even repudiating the culture she or he sprang from.

On top of that rural/urban, or heartland/bicoastal split is the North-South split, which is more cultural in origin: the culture of slavery, to be specific. The many poisons of slavery- its devaluing of humans and casual terrorism, its terror of disruption of a hierarchical social order, its lazy economics of privilege and stasis, its pathetic, patriarchal, and false romances of militarism, chivalry, and the lost cause, seeped so deeply that we continue to fight the Civil War, over and over and over again.

Many cultures have drawn durable victimization narratives from traumatic loss, such as the Muslim Shia's defeat in the battle of Karbala in 680, or the Serb defeat in the battle of Kosovo in 1389, or the Jewish episodes of slavery in Egypt, exile in Babylonia, and final loss of Jerusalem. Such narratives tend to be pathetic, racist, romantic, unrealistic, and for all those reasons, highly effective.

It is evident that politics is conducted in narratives, not policy. Hillary may have had her 23 point plans, and they surely would have served Trump's voters better than Trump's own policies, which as far as we can tell, consist of giving lots of money to rich people like himself, (no wonder he isn't taking the salary!). But the media decided that the email controversy was a better hook with which to explore her personal narratives of secretiveness and control. How they squared this with a bemused attitude towards Donald Trump, who was actually in court for fraud, among a countless other number of obvious scandals, is hard to understand. The media clearly did not understand the nature of Trump's methods or message. This, after two decades of FOX news.

In the absence of narratives on the scale of world wars, which did so much to unify the country in the 20th century, the US political system is structured in a particularly bad way for a politics of emotional narratives. Our two-party, winner-take all system amplifies very small differences into momentous swings in power, focuses campaigns on only a few swing states and small populations, and sets the two parties as a duopoly that excludes new ideas / narratives and rheifies a binary tribal split in the electorate.

So, the perpetually disgruntled South makes a reliable partner in the modern Republican party for the CEO and financial class, united only in their fear of progress- social or regulatory, respectively- towards a modern state that would foster a fairer, more equitable nation by ameliorating the ravages and inequities of the free market, and the inherited social and economic disabilities that keep the class and racial structure so entrenched.

Barack Obama almost sank his first presidential campaign when he was recorded as saying that the rural folks cling to their guns and religion. It was a classic gaffe- as impolitic as it was true. The divide is real. Is the distain deserved? As a liberal atheist in favor of gun control, my natural inclination is yes, it is deserved. This election proves it yet again, that a tasteless, racist, and shallow blowhard could propose a set of policies almost totally at odds with the interests of his voters, not to mention the country and the world, yet win on narratives of hate and revanchism.

Is the distain from the other side deserved- that the US has become a feckless, feminized country of politically correct pansies? Are the elites incompetent? Yes, that has its truth as well. Just looking at the state of public management, where public employees get over-generous pay and pensions, as though the last forty years had never happened, yet accomplish so little, which is apparent as sclerotic breakdowns of public institutions and infrastructure, and the impossibility (or astronomical expense) of building anything new. It is an easy, perhaps lazy critique, but our infrastructure is symptomatic of a nation whose public policy is not keeping up with public needs, or an optimistic, future- and growth-oriented outlook.

All of which does not justify this step into a political abyss, however. Does progress in reason-, law- and process-based public policy necessarily end up in gridlock, as an excess of process and attention to every possible stakeholder, including corrupt interests and non-human species, extends decision times to infinity? No, it is the political gridlock that is far more damaging, since where there is a coherent will, there is a way. With the (white) South firmly in its pocket due to a hermetic social and media atmosphere, and supporting regressive policies in general, the Republican party has now spent decades as the party of shameless, regressive, and especially, destructive politics. It is an inheritance from Newt Gingrich, and from Roger Ailes at FOX. The refusal to consider Obama's last Supreme Court nominee was the epitome of partisan depravity. The Bengazi investigations were a witch hunt in the purest sense, and have now at long last paid their final dividend.

It is worth noting that during and after the Civil War, the Republican party (what a different party, then!) led a surge of progressive public policy, from land grant colleges and banking to railroads. The nation was suddenly unshackled from the political weight of the South, and though the necessities of war had their dramatic effects, the philosophy of the Republican (prior Whig) party were also an important ingredient. One wonders what might have happened had the South succeeded in its secession. We might have become a spectrum of Americas from the progressive and industrial Canada and Union nations to the more feudalistic Confederacy and Mexican nations.

  • We are now a banana republic.
  • Krugman, horrified.
  • A little history.
  • Globalization needs a rethink.
  • It has been harder to find a job and switch jobs, as companies have more power in the labor market.
  • Even Japanese workers have little bargaining power, despite a tight labor market.
  • Who needs banks? The next economic institution of security: blockchain.

Saturday, November 12, 2016

The Lineage History of India

India is a complex mixture of humanity, but genetics can tease out the main themes.

Humans have been migrating all over the place for thousands of years, yet there are still distinct geographic differences in human phenotypes, and now visible with molecular technology, genotypes. This allows us to look back in time to infer large migrations that happened long before the historical periods, like late and post-Roman times where many migrations in and around Europe are documented, if scantily.

Out of Africa. A process that started about 70,000 years ago.

India is a particularly interesting subject for this kind of analysis, because it has been a crossroads for tens of thousands of years, first for the migration out of Africa that led to the peopling of Australia, and then other influxes from all directions, most recently from the north, with the Indo-Europeans and then the Arab invasion. Secondly, India has also had an unusual degree of stasis since these migrations, embodied in its caste system, which may have frozen some of these genetic signals in static communities.

A recent paper continues a body of work that looks at these issues, and concludes that there are four different population signatures detectable in the mainland Indian population, and that the caste system has been in genetic terms a relatively recent development- in the last thousand years or so.

They sample hundreds of thousands of variable genetic markers (snps) from 367 people of 18 recognized ethnic groups of India. This data is put through a traditional statistical analysis of related-ness to come up with 69 sub-populations, and four principal components: those differences in the data that most efficiently explain the most differentiation into the least number of large groups. The main graph is below:

The green elipse identifies Indo-European populations, such as Brahmins from Gujarat and West Bengal, Khatri, and Maratha. The red elipse identifies Dravidian-speaking tribal populations. The turquise elipse identifies South-East Asian-influenced populations, such as Korwa, Birhor and Gond which are a Dravidian mixture. Lastly, the blue elipse identifies Tibeto-Burman originating populations such as Jamatia, Tripuri, and Manipuri, living in the northeast.

None of this is very surprising, given the clear ethnic diversity and the local neighborhood of India. More interesting are their reflections of the stability of these groups. There is very low mixture, though the sampling was modest, with an average of 20 people per ethnic group and 5 per inferred sub-population. The hypothesis, drawn from literary and historical sources, is that there was originally substantial mixing between the North and South Indian populations, but that this ceased with the gradual establishment of the caste system. The researchers use haplotypes to track how much mixture there has been, and how long it has been going on, or been in abeyance. (Though there are other views.)
"We estimated that all upper-caste populations, except MPB from Northeast India, started to practice endogamy about 70 generations ago. The length distributions of the AAA blocks and the ASI blocks within any one of these populations (GBR, WBR, IYR) were very similar. The most parsimonious explanation of this is that the practice of gene flow between ancestries in India came to an abrupt end about 1,575 y ago (assuming 22.5 y to a generation). This time estimate belongs to the latter half of the period when the Gupta emperors ruled large tracts of India (Gupta Empire, 319–550 CE)."

Thus the golden age of India, which happened during this time, seems to correspond with a hardening of the social order. What effect the latter had on the former, or the decline of the former, is perhaps food for thought.

Saturday, November 5, 2016

Time is a Great Mystery, But the Self is an Even Greater One

What is time? And can a physics professor harness it for spiritual speculation? A review of Richard Muller's book about the nature of time, entitled "Now".

We are all critics and all cranks. Some just get a wider audience. Richard Muller, distinguished professor of physics at Berkeley, recounts a good deal of his pathbreaking research in his latest book, as well as roles in founding and inspiring the work of others, some of which / whom went on to win Nobel prizes. Along the way, he provides a high level and very pleasant introduction to the highlights of twentieth century physics. But he can't seem to resist going down some very personal tangents as well, like free will, Richard Dawkins, and a profession of faith.

His views on time are obviously the theme of the book, and the tease as well. He keeps the meat of the matter till the last few pages. To put it most simply, he dismisses the common idea that the progression of time in the universe is connected to the increase of entropy that is expressed in the second law of thermodynamics. Instead, he proposes that time, having been created with the advent of the big bang, as was space itself, represents the continual expansion of that four-dimensional construct that is our universe. Thus we all exist in a "now" that is the bleeding edge of cosmic 4-D expansion, just as space itself is continually expanding. Looking outward at anything, however close or far, is always looking back in time into areas of the universe that have already happened. And just as there is no center or edge to the expansion of space, there is also no edge to the progression of time- all points in space progress through "now", leaving aside the relativistic oddities of some "nows" getting slowed down by relative spatial or gravitational acceleration.

I find this idea very attractive. It is far more sensible than the entropy idea, and probably the best thing going, until we gain a deeper understanding of the mysteries of cosmic origins, the structure of space, and of quantum physics in particular. The latter still resists both unification with other aspects of physics and, frankly, common sense. Yet this edge-of-the-big-bang is far from a theory- it is just a hunch, with minimal predictions, the main one of which is that time might be accelerating along with the accelerating expansion of the universe, if space and time happen to be linked in that way.

However, when it comes to amateur philosophy, the book makes a good deal less sense. Muller spends an effective few chapters on the limits of science and philosophical physicalism- the great deal that we don't know, and perhaps can't know. The nature of the origin of the big bang, given that it originated both the time and space that we are familiar with, is surely one. The various mysteries of quantum physics are others. But some of his other suggested limits edge into very questionable territory.

Combined with other known limits, like the indeterminacy of quantum mechanics, and Gödel's theorems of incompleteness, we end up with large areas of reality that are essentially unknowable, at least in a scientific sense. One of these is the future. Because of quantum indeterminacy, as well as chaos theory, physics turns out to not be deterministic as the classical physicists had believed since the time of Newton. This provides, in Muller's eyes, openings for things like qualia, free will and souls.

There is a long discussion of the "what it is like to see red" question, featuring Mary, who is raised in a grey world but knows didactically everything there is to know about color vision. When she first sees color as a mature adult, does she learn anything new? Muller's answer is yes, and he takes that as an intrinsic limit on human knowledge.

The whole qualia question, which is what the "seeing red" exercise is about, seems to me to say much less than Muller and others think. He believes that it points to something beyond our physical constitution that characterizes us- a soul. For the same reason, he claims that he would not want to be transported à la Star Trek, for even if his physical body were reconstituted down to the smallest detail, he might not end up being "himself". Again, a non-material soul lies at the bottom of this, which he explicitly claims, even though he is doubtful whether it survives death:
"When I see blue, do you see blue? That is not a scientific question. Does that make it invalid? This issue is related to the difference between the brain and the mind. Is there something beyond the brain, something behind the circuitry, something more than the physical, mechanical set of atoms, something that can not only see, but knows what a color looks like? I can't prove to you that such knowledge exists. I can only attempt to pursuade you."

To me, there seems to be no reason whatsoever to propose anything beyond the physical mechanism to account for all this. We can grant that subjective experience is utterly different from didactic knowledge. That is intrinsic to beings with consciousness and experiences, and is covered by a difference of perspective. I, looking into your brain, will never have the experiences that you are having subjectively via that brain. It is like expecting someone reading the computer code behind World of Warcraft to experience gaining powers and making alliances. That supposition is a simple, but profound, category error.

Should we care about so much (subjective) knowledge and experience going up in smoke every second and every lifetime? Surely it is a tragedy, which we try to remedy by sharing subjectivity via conversation, writing, the arts, and other ways. But the fact that, being perspectivally enclosed, it is beyond science (certainly with current technologies) means neither that it is an illusion, nor that its reality is somehow "beyond the physical". Its complete dependence on the physical is clear from the biology of stroke, dementia, development, mental time delays, and innumerable other phenomena.

The wonderfulness of its construction, and its tendency to lull us into flights of subjective omnipotence or is no excuse for not taking the biology seriously. This is true even if one appreciates that physics (let alone biology) can not explain, or even represent, everything. There are many things that they can still properly explain, and many things that they put very tight boundaries on even if complete explanations are not yet available.

But there is more...
"There is a spiritual world separate from the real world.  Wave functions from the two worlds are entangled, but since the spiritual world is not amenable to physical measurement, the entanglement can't be detected. Spirit can affect physical behavior- I can choose to build or smash a teacup; I can choose to make war or seek peace- through what I call free will." 
"It is remarkable how often you run into the phrase "Science says..." to support an idea that actually has no foundation in science. It is often physicalism in disguise "Science says we have no free will." Nonsense. That statemen is inspired by physics, but it has no justification in physics. We can't predict when an atom will disintegrate, and the laws of physics, as they currently exist, say that this failure is fundamental. If we can't predict such a simple physical phenomenon, then how can we imagine that someday we will be able to show that human behavior is completely deterministic?"

The weakest aspect of the book is its numerous discussions of free will. Muller seems to have  a particularly unexamined notion of it. He cites quantum indeterminacy as providing an opening for free will, since it means that the universe is not determined. But how does randomness and indeterminate-ness help the cause? How does our ability to make choices and affect the flow of events relate to reality's constitutive randomness? An inability to predict or compute the future does not imply that our physical mechanism can not and does not make choices, including meaningful ones. For example, computers make choices all the time, and increasingly sophisticated, random-event influenced, and, to us, unintelligible ones.

If everything were determined, that would not even affect our sensation of free will. That is the Greek tragedy, where key events are pre-ordained, but still the actors feel themselves to be acting meaningfully, until the end when the hand of fate is revealed to all. Even such slim (and fictional) concessions to fate are out of the question when the future is truly unknown due to all the physical principles Muller cites.

But determined or not, it is not clear what this free will really is. In the worst-case scenario, everything is determined, and we can also predict the future- a future that we can do nothing to change, because everything up to that point as been determined as well. But how would that really feel? I think it would still feel as though we had free will, since we would have reasons for doing what we are going to do, which feel compelling, leading to exactly the actions that we are taking, predicted or not.

I think the secret is that free will is, particularly here in Muller's book, but also more generally, a code word for "soul". It is another, and even more vague, way to make claims for a non-physical entity that lies behind our most important actions and deepest feelings. The intuition is that mere mechanism can not conjure the sovereignity of choice, and is somehow separate from the all-important "I", whose immateriality and freedom are so intutively self-evident.
"Am I simply a wood chip caught in a complicated machine, bouncing around as the gears turn, confusing my rapid action with my importance?"

Why an eminent physicist feels the need to posit special, extra-scientific hypotheses around the issue of consciousness is truly unfortunate. His inability to explain the big bang does not prompt similar flights of intuition unbound, yet his lack of knowledge about biology and inability to bridge the far more modest conceptual gap between subjective consciousness and what we know scientifically (exemplified by the qualia/Mary exercise) does. It is ironic that intuition is so particularly susceptible to error and inflation when trying to analyze itself.

  • If Europe can't adjust relative currency values, how is it going to fix large trade imbalances?
  • Hotline to Russia, from Trump Tower.
  • More people are getting MMT.
  • Unemployment isn't what it used to be.
  • A coup from the top- Erdogan shows his true colors.
  • Egypt is in crisis. Sisi, who claimed "Only I can fix it"... doesn't have a clue.

Saturday, October 29, 2016

Better Than Nanites: Custom T-cells

Rather startling developments in the use of our internal maintenance cells to target cancer or other problems.

I am a watching a very nice science fiction series, about a motley crew in space who try to be kick-ass and all, but deep down are just ... very nice people. Because they are Canadian, of course! Every show seems to steal another plot from past classics, like the Bourne Identity, Star Trek Deep Space 9, and even one featuring Zombies.

One crew member is an android, (named "Android"), but is touched with a bit of schizophrenia, a la Commander Data or Seven-of-Nine or Spock, about the virtues of humanity and being humanely idiosyncratic. She also features nanites- apparently tiny machines in her high-tech body that run around and repair things when she takes a hit for the ship.

Android to android: another android, shooting the ship's Android. Repair will now commence.

Such nanites are quite a stretch, current technology having nothing remotely similar, and Android's body being rather inhospitable to anything running around among all the wires, metal, electricity, and whatnot. Such nanites would have to have some kind of master plan for guidance, which would be pretty difficult to fit into a nano package.

Yet our own bodies do have nanites, called the cells of the immune system. This system as a whole is an organ that has no fixed location or shape, but travels around the body in the blood stream, lymph and elsewhere between cells- anywhere where damage occurs. These cells have a highly complex communication system that finds damage, detects what type, cleans out the damage, attracts other helper cells as needed, reads the local developmental and tissue patterns to help local cells do the fix correctly, and gradually turns itself off when finished.

One of the central actors of this system are helper T-cells, which intermediate between the damage signals, which come from normal tissue as well as specialized cells that roam around looking for damage, and the inflammatory and damage repair system, such as cells that create antibodies (B-cells), or that phagocytose and kill infected or damaged cells directly (CTL cells, macrophages). Some T-cells activate immune system actions, and other T-cells dampen them, and they do this over the whole time course of the damage reaction. HIV is an infection mostly of T-cells, killing them and leading to the collapse of the whole immune system.

One of the magic properties of T-cells is specificity. Like the antibody system of B-cells, T-cells use genetic/genomic trickery to generate a galaxy of specific receptors, called, as a family, the T-cell receptor, which can recognize specific molecules, such as proteins from viruses and bacteria. Each T-cell generates and shows one such variant on its surface, and thus the right individual T-cell has to go to the right place to initiate its response, part of which is rapid growth and replication into an army of T-cell clones (do that, nanite!). There is also a process, carried out mostly in the thymus, which deletes all the newly-born T-cells whose specificity is against proteins from its own body rather than against foreign entities.

Given all this, it has been interesting to learn that the immune system often acts against cancers as well. While composed of the body's own DNA and cells, cancers can express various altered proteins due to their mutations and deranged regulation, and also may express stress molecules that tip off parts of the immune system that those cells should be killed. On the other hand, cancers can also, though natural selection, cleverly express other signal molecules that turn the immune system off, thus shielding themselves from destruction. That is a serious problem, obviously.

So many researchers have been casting about for ways to get the immune system to overcome such barriers and attack cancers in a more robust way, especially in resistant cases. And after a lot of false starts, these approaches are starting to bear remarkable fruit. Some are drug-based approaches, but more direct are methods that re-engineer those cells to do what we want.

Since they are travelling cells, T-cells can be taken out of the patient. This allows new genes to be introduced, mutations made, etc., especially using the new CRISPER technologies. One approach is to add a receptor specific to the patient's cancer, such that the refreshed T-cells target it directly, and get activated by the tumor environment, and start to resolve the tumor. This approach has been quite successful, to the point that some patients undergo tumor lysis syndrome- a somewhat dangerous consequence of the tumor getting destroyed too quickly for the body to handle the resulting trash.

A recent paper elaborated this re-engineering approach to make it far more broad. Researchers introduce not only a new receptor to direct the T-cells to particular targets, but a multi-gene system to perform any additional function desired in response to targeting, such as pumping out a toxin, or a regulator / activator of nearby cells. This promises to supercharge the T-cell therapy approach, beyond the native scope of action of normal T-cells, however well-targeted.

For example, in a demonstration experiment, mice were given tumors on two sides of their bodies, one of which contained an additional genetic marker- the fluorescent protein GFP expressed on its surface. This is not a mammalian protein at all, but from an obscure bacterium, and would have no effect, if the experimenters had not also engineered a batch of that mouse's T-cells to express a combination of new genes.

One was a version of the common protein receptor Notch, which had its cell-external receptor portion replaced by a receptor for GFP, and its cell-interior portion replaced with the transcription factor Gal4. When the exterior portion of Notch proteins are activated, the internal portion gets cleaved off and typically travels to the nucleus to do its thing- activate a set of responsive genes. The other engineered gene was a Gal4-responsive gene expressing a cancer-fighting drug called Blinatumomab. This is an antibody specific to a B-cell antigen, which is appropriate since the introduced tumor is B-cell derived.

Demonstration of tumor targeting with engineered T-cells; description in the text.

The synthetic receptor is shown in green (synNotch), exposing a GFP receptor on the outside and a cleavable transcription regulator on the inside. Upon encountering the GFP-expressing tumor (green), it activates transcription of an antitumor drug (custom antibody) abbreviated BiTE, which attacks cells expressing the cell surface receptor CD19, which these tumors do. The green tumor regresses within two weeks, while the control tumor does not.

The demonstration shows that this engineered treatment can address practically any target that can be specifically distinguished from normal cells (indeed, one can imagine multiple engineered receptors being used in combination), and generate any gene product to treat it.

It also shows the increasingly expensive direction of medical care. Not only is the expressed gene product one of those recently-developed, highly expensive cancer drugs, but the T-cell extraction, reprogramming, and re-introduction has to be done on a custom basis for each patient, which is likely to be even more expensive.

  • The NRA has a screw loose ... arm in arm with Wayne LaPierre!
  • Guess which constitutional amendment is the most important?
  • Smoking still at fault for 30% of cancer deaths ... after all this time.
  • We are in deep CO2.
  • Financial regulation works.
  • The disorder has a name.
  • And a bitter end is in sight.