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.

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.

• Our institutions are shabby enough already.
• Republicans without a clue.
• Haidt on group affiliation and the greatest generation.
• One of whom was Jimmy Carter.
• A sad day.
• De-industrialization has been devastating.
• If heartland voters thought Trump will serve their interests, they have another think coming. And if they thought Hillary was corrupt ...
• Some problems with Democrats.

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.

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.

Obama's Greatest Error

Syria can be laid at his doorstep.

I have generally given Barack Obama very good marks. He has been a steady hand in the middle of political crazy the defies historical comparison. A compassionate and intelligent leader at home and abroad, while faced with endless vitriol whose source lies uncomfortably deep in the body politic, somewhere. His method has been the classic boxer's rope-a-dope, feinting when the Republicans punch, letting them hang themselves with fatuous House bills and hateful rhetoric from organs like FOX news and the editorial page of the Wall Street Journal.

The idea is that the more the Republicans show their true colors, the more the real players in the game, the observant American people, will wake up and recognize who is serving their true interests. But it hasn't worked out that way, really. The right wing-o-sphere has been so hermetic, so well-funded and so well-gerrymandered that it has not had to face the music of its own madness. Not until now. The advent of Donald Trump has brought the full mariachi out of the basement and into plain view, and it hasn't been pretty, on either the policy or the personal levels. Yet Trump will still carry some states, which, after all we have seen and heard, is unfathomable and disgusting.

But Obama's policy is tinged with weakness. He is playing a long game, dependent on his own imperviousness to scandal and superior sanity. He is not attacking his opponents directly. This is laudible and perhaps effective in domestic policy, but has its limits in international policy. Waiting for international opinion to catch up with bad actors like ISIS or Russia is waiting for Godot, especially when that opinion often sways to strength rather than to goodness.

This has all come to a head in the case of Syria. While Obama has been pursuing low-level campaigns on many military fronts, against Al Qaeda, the Taliban, ISIS, Libya, Pakistan, Iran, etc., he is unwilling to go to greater lengths where it seems most pressing: Syria.

Syria has been a multi-dimensional cataclysm, brought on by a collision between hope and entrenched, ruthless power, sectarianism, millenarian Islam, and other currents. Obama originally spoke eloquently about freedom for the next generation in the Islamic world, about the horror of the Syrian reaction, and his wish for the reign of Assad to end. But what of it? He has had plenty of reasons to not get involved. The example of Iraq, for one. The example of Libya, for another. Our interventions seem to always go wrong, especially in the Islamic world where our intellectual understanding and moral capital is so low. Iraq has been especially disastrous, going from abhorrent stability to US-sponsored anarchy, and now to Shia-led sectarianism, incompetence and corruption. What's a decent and powerful country to do?

The lesson is, as usual, that every case is different, and while being cognizant of our weaknesses and of the bitter lessons of history, we should also not lose hope of influencing world events for the better. In Syria, there was, and remains, a compelling case for a no-fly zone to prevent the bad actors who have air power- Assad and Russia- from maintaining their bombing campaigns on civilians and rebels. Doing so now would be extremely difficult, with Russia already in the air. But doing so at the start, when Assad was alone and dumping chemical weapons of various sorts on rebel areas, would have been far more possible, in practical and political respects.

We could have directly forestalled tens of thousands of casualties, swung the balance of the war significantly, and most importantly, kept Russia out of it, all while maintaining our campaign against ISIS to whatever extent we wished. I think there was at the time a clear humanitarian as well as strategic rationale that should have swayed Obama to take such action. The drawback, as we saw in Libya, is that even if successful against Assad and/or ISIS, we had little or no influence over the ultimate outcome, which could just as well have empowered some other ISIS variant or Iranian client as well as whatever democratic opposition might exist. That would have been an opportunity to shape events politically, making the case internationally for some reasonable coalition of Syrian parties. But we haven't wanted to do that work either.

The Arab spring was a gift. Like the Ukrainian, Russian, and most other color revolutions, it ended in tears mostly due to overwhelming cultural inertia and the entrenched power, both military and cultural, of the traditional autocrats. But we didn't help much either, with our mixed signals and dithering. The tragedy of Bengazi was not that we lost an ambassador and other personnel in horrific circumstances, but that we had so few resources there in the first place for the nation-building effort. For that is what Libya so clearly needed. Such things as a model for governance, disarmament of the various militias, basic bureaucracy, technology and utility management, etc. There is a long list where we and the Europeans could have been far more involved and helpful in the transition from anarchy to organization. granted, our credentials based on our occupation of Iraq were not sterling. But have we learned absolutely nothing, either?

The Egyptian case is likewise very painful, and shows Obama in a particularly poor light. Here, as later with Assad, he pronounced Mubarak to be illigitimate, but unlike the case of Assad, someone believed him, and the Egyptians took it as a green light to remove Mubarak from power. So far so good. But did we follow up to help broker relations between the military, which has long been far too strong in Egyptian society, and the new Muslim Brotherhood government? Did we help guide the new Morsi government in its constitutional predicaments? No. Cultural inertia, particularly of the military and bureaucracy, was the main problem here, as well as a total political disconnect between Morsi and the rest of the country. The US kept its hands off, listened to the nay-sayers from the Israeli right, and the result was that Egypt under its new military regime is in even worse shape than it was under Mubarak- more repressive and in greater economic distress ... even if it is now more pro-Israel than ever.

These cases are hard to second-guess, because our influence was truly small, partly due to our principled stand of non-interference, and partly due to our political capital in the Muslim world being so low. The Obama administration's continued, if grudging, support for Israel and its military occupation of Palestine is perhaps the leading reason for this, and another failure to lead the world to a better future. We should be cutting aid, not increasing it. And this lack of leadership had a direct connection to our bad relations Egypt in general and Egypt in the period of the revolution in particular.

So there is a pattern of doing just enough to keep the status quo going, attempting modest positive change, and not entangling ourselves in new quagmires. Which has its good points, certainly. But look at Russia. Russia is not in a quagmire in Syria. Quite the opposite. They are in it to win, and have brought the Assad regime back from the dead with a relentless and ruthless military compaign. Russia is gaining international power by applying its power strategically, supporting its friends in an effective fashion. And now the Phillippines wants to be their friend too. Power gains more power, if it is intelligently used, while leading from behind eventually turns into not leading at all.

• Left, against a no-fly zone.
• Britain can do infrastructure... why can't we?
• Stiglitz on Trump- the economic pain is real, even if the candidate isn't.
• Some notes on Bernie.
• Some notes on Republicans.
• Hillary is doing OK.
• Despite the relentless right-ward frame of the last debate.
• Where are our forests going?
• Economics vs morality.
• Economic comparisons of well-being.
• Skills? The real skill is having luck.
• Hope for the world, on piano.
• A woman in science.
• Reflections on Afghanistan. A land called hope, but a neighbor called Pakistan.

The Odd Stripes

In the early fly embryo, a gene called odd-paired (opa), is essential for the transition from 7 to 14 segments.

Scientific data is sometimes boring, but other times quite aesthetic, even stunning. Astronomy can be a matter of graphs and spectra, but it can also be revelatory images from distant galaxies, or from weirdly amazing planets and moons in our own solar system. Fly embryology and genetics is one of the more conceptually, technically, and also aesthetically advanced areas of biology, leading the way in the understanding as well as visualization of early animal development.

Segmentation is a body plan principle shared by all chordates, most insects, and some worms. It provides a convenient blend of modularity that allows for repetition of a basic plan to organize cells into an extended, worm-like body, while also allowing variation and specialization in each segment, to the point that organisms like us end up not seeming segmented at all as adults. It may have evolved independently in those three lineages, though also shares some strategies and molecular details, so the full evolutionary story is not quite settled.

General plan and progression of fly embryogenesis, from rough location determination to finer and more precise specification. During this time what starts as a large mass of egg cytoplasm turns into a synctium of positioned, divided nuclei, which then lead to cell formation around the inner surface, and the beginning of tissue formation.

In each phylum, there is a progressive front-to-back and gross-to-fine scale process that is a little like an image coming into focus. A cascade of transcriptional regulation and related molecular events first decide which end of the fertilized egg is front. Then, as cell proliferation proceeds, this cascade subdivides the embryo into about seven zones, (in the fruit fly), and lastly divides those zones into fourteen parasegments, which eventually lead to formation of the ultimate physical segments, with their particular cells and organs, whether common or specialized.

A recent paper focused on one gene that participates in this process: the odd-paired gene of fruit flies. When this gene is missing, embryos don't form the 14 parasegments, but only the seven larger bands. Development is arrested, fatally. Yet odd-paired is expressed all over the body. It does not have the kind of localized segmental or parasegmenal expression that was expected, and is found for the other "pair-rule" genes, at least until quite a bit later on. How does that work?

Incidentally, the odd-paired gene is the homolog (or rough equivalent by sequence, and presumably, function) of a significant gene of humans, GLI1, which is found mutated in cancers, especially glioblastoma. It is typical for master regulators of early development, when cell proliferation is very high and differentiation is low, to be involved in cancer if they are activated through some kind of error at a later time, helping to re-create that embryonic condition in an uncontrolled form.

"Through gene regulation, the GLI1 family of proteins regulates a number of important cellular processes, such as, neural development, cell proliferation, oncogenesis, survival, epithelial-mesenchymal transition (EMT), migration, invasion and metastasis."

Detection of gene expression (mRNA) of selected pair rule genes in early embryos. Red is the odd-skipped gene, green is even-skipped, purple is runt, and turquoise is the paired gene. The time period in this panel (t4) is a slightly earlier stage of development vs the panel below (t6). The patten of seven stripes for each gene, offset slightly to its particular sub-location in the nascent double-segment, is very clear.

Under the influence of odd-paired, (wild-type case), the stripes from above have doubled after about 1.3 hours vs the panel above. 

The cascade of segmentation refinement is mostly a matter of gene expression. Transcription regulators are expressed in various places along the body axis, and their combination, overlapping in some places, absent in others, dictates (through their binding to enhancers at DNA of target genes, thus activating them) a refined pattern for the next step, which consists mostly of another set of transcription regulators. The "gap" genes each regulate portions of the ~seven broad bands of expression, and their combinations activate the next set of "pair-rule" genes that are typically expressed in the same seven bands, which over time (involving mutual back and forth regulation) resolve to and help form fourteen parasegments, each of which comprise the front half of one future physical segment, and the back half of another. Lastly, a set of "segment-polarity" genes are activated in one-cell wide stripes to specify one or the other side of each of these fourteen parasegments, preparatory to the more complex work of specifying the details of cell types, and tissues that are to reside there.

Expression of odd-paired (green) is all over the trunk, while another gene, odd-skipped, is nicely restricted to nascent double-segment zones. The phases refer to time points of embryogenesis, indicating that odd-paired comes on rather suddenly during this process.

The locations of gene expression can be visualized by constucting DNA molecules complementary to the expected mRNA from the respective pair rule or other genes. That DNA is labelled with a tag that can later be reacted to produce the intense fluorescent signals seen in the figures. This DNA (probe) is physically diffused into the chemically stabilized/fixed embryos under warm conditions so that it selectively hybridizes to the target mRNA, thus showing where it is located.

It is the endogenous refining transition of the "pair-rule" genes from seven to fourteen zones of expression that interested these researchers. They reason that perhaps the appearance of the odd-paired mutant, which misses features of each odd-numbered segment, indicating that it participates in specifying the parasegments, arises not from its own location of expression, but from its critically timed regulation of the other pair rule genes. It is known to come on right when this focusing event takes place, and binds to and regulates several of the pair-rule genes, as well as cooperates with them in their mutual regulation.

Embryos mutant for odd-paired (opa) compared to the normal wild-type (wt) case. Opa5 is a partial mutant, opa8 is more severe. The neat stripes in the wild-type are progressively deranged, and lack doubling during this later embryonic phase, gastrulation.

Unfortunately, the data of this paper consists entirely of anatomical expression patterns, rather than the enhancer structure and activation data they would need to support the final model, which was essentially replicated by another lab around the same time (and amplifies existing work). The model is that odd-paired cooperates selectively, and in a strictly timed fashion with the other pair-rule genes to regulate pair-rule as well as genes in the next level down, the segment polarity genes, to accomplish the positional refinement and particularly the band doubling that is absent when odd-paired is absent. The phenomenology, as seen in the expression visualizations, is very striking, and reflects circuitry at the level of gene regulation that, while painstaking to analyze, would give definitive answers about exactly what each of the actors in this process does.

"In the even parasegment, our data support a combinatorial model wherein Ftz [fushi terazu] activates en [engrailed] expression and odd [odd-skipped] restricts this activation to the anterior-most Ftz-expressing cells. An essential facet of this model is that Opa [odd-paired] must repress odd transcription in a specific cell, the anterior-most Ftz-expressing cell, to allow induction of en by Ftz. The Run [runt] pair-rule protein is a candidate for a cofactor with which Opa may cooperate to specifically repress odd." (from Benedyk, et al.)

While the data relies on molecular biology for the visualization and modeling, it carries on a grand tradition of anatomy and genetics as well, in its beautiful micrographs and focus on the physical structure of the later organism, which at the points pictured here is quite invisible, only incipient in the molecular patterning that is going on incognito, as it were.

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