Molecular Medicine

Down the rabbit hole: what medicine will be like in the future.

The primitive nature of current medicine is usually hidden behind white lab coats and alien machinery. But typically, the knowledge of what is wrong with you is sorely lacking. Cancer treatment consists of shots in the dark, killing all growing cells with horrible poisons that in most cases still do not resolve metastisis and only add a few months of sickened life. More broadly, all sorts of syndromes from diabetes to cronic fatigue, depression, and autoimmune processes, to name a few, have very murky causes and again only trial and error treatments that palliate more than cure. The dizzying round-about of nutrition and diet advice is a symptom of this pervasive ignorance.

One might see the progression as going from big to small: from the wilds of intuition, with its often cosmic / astrological concepts, to scientific anatomy, to the advent of microbiology and cellular biology. The next step is molecular, where the real foundations of biology lie. Whether we have truly mastered the microbiological level is open to question, of course, with the recent measles and ebola outbreaks, the continued scandal of hospital-acquired infections, and our thoughtless use of antibiotics in animals.

What would a better world look like? First, we would know what we are seeing and doing, not just sort of, in a we-gave-it-a-name kind of way, but in a mechanistic, engineering sense. Second, we would have technology to truly address the many defects that can arise out of our systems, at those causal points, rather than farther down the line. Wouldn't it be better to re-instruct cancer cells to become normal again, rather than killing them and all their more or less distant relations? The second goal is far more difficult than the first, but depends entirely on the first being fulfilled.

Molecular medicine (some call it "precision medicine") will be the way to address these issues, and has four elements. First, everyone's genome will be sequenced as a matter of course and be a core part of the personal medical record. Then, wayward growths, infections, fluids, and other samples will be not just subject to the ever more advanced lab tests for metabolic and histologic evaluation, (second element), but will also be sequenced and compared with that genome reference sequence (third element) to nail down molecular alterations that lie at the root of many diseases.

But what would these sequences tell us? However advanced and cheap the sequencing technology, it does no good without knowledge behind it- the biological models of which gene does what, what pathway causes which disease, which mutation causes what effect. That is the fourth and most important element. The war on cancer was only a down-payment on this knowledge, funding the profusion of molecular biology scholarship and technique that has blossomed since the discovery of the structure of DNA in 1953. Unlike the two sequencing elements, which have discernable end-points in terms of creating complete, inexpensive sequences from our DNA samples, this third is essentially open-ended and ever-developing. It may take another hundred years to work out in a full engineering sense this (alien) technology that is human biology.

All this came to mind when reading a recent paper on the properties of one human mutation. A gene called HOXB13 is about 4,000 nucleotides long and encodes a protein that is 277 amino acids long. If you knock out its function completely, the organism is dead ... the protein is essential for early development. (Mice were used to find this out, thankfully.) But less severe defects, like, say, the mutation of deoxycytidine (C) 407 to deoxyguanosine (G), which causes the encoded protein to change at position 84 from glycine (G) to glutamate (E), have far more subtle effects, which require population studies, statistics, and much else to figure out.

Such studies say that the mutation raises the holder's chances of developing cancer, about five-fold in the case of prostate cancer. The authors give a chart of some of the other cancers that have been studied:

Effect of the position 84 mutation of HOXB13 on various cancers. The frequency in column 4, which is the rate of finding this mutation in those who have cancer, can be compared to a general population frequency of this mutation of about 0.45% The higher frequencies generate Odds ratios > 1 which denote a positive association between the mutation and the cancer, and the p-value estimates from the sample sizes how significant this odds ratio, or correlation, is (lower is better). For prostate cancer, not listed, the odds ration is about 4.5, with very well-attested significance.

The odds ratio is perhaps the most easily interpretable statistic, being the odds of some effect, given the hypothesized cause. It is a simple ratio of the rate of the effect in the "with" population over the "without" population. A value of 1 means that there is no connection, and higher values mean that there is a positive correlation. Here, the odds ratio of 3.3 for kidney cancer claims that having the mutation raises the odds of this cancer. For prostate cancer, the odds ratio is 4.51. The P-value is a helpful associated statistic, which tells you how much confidence to place in the odds ratio, since a small population in the study, for instance, may create a very skewed odds ratio, with little significance. The lower the P-value, the greater the significance. So when we get down to oral cancer and leukemia, the association with this mutation is negligable in all respects.

The mutation is very rare, occurring about 0.3% in European populations, and most prevalent in Northwestern European / Russian populations. The rarity is doubtless because of its bad effects, killing its bearers at significantly higher rates than the norm. But it may have other, conceivably beneficial effects- so much is not known. This gene is part of the extremely interesting HOX group that are transcription activators that help the body interpret where its parts are, and activate organ growth during development. This one is strongly turned on in the embryonic tail and urogenital system, including the prostate.

Expression locations of HOXB13 in the embryonic mouse.  UGS = urogenital system. HG =  hindgut.

So, why isn't there a definitive effect? Why are only risks increased, and all these statistics deployed? What could we do to gain a more accurate prognosis? It is likely that if the other three billion nucleotides in our genomes are put through a similar analysis, covering each of their four possible alleles(!), we could gain much better predictive value for each person's genome as a whole. The present statistics were gathered over a population that is essentially random with respect to every position other than this single one, and it may well be that this cancer-promoting effect arises from the interaction between several more or less rare mutations, or at least from biological settings that are more specific than just a random sample, either in genetic terms or other environmental respects. Drug development and treatment is heading in this direction, focusing on specific genotypes that have the most to gain from a particular drug, even if in a totally random population with the disease at issue, that drug may have little discernible positive effect.

But additionally, knowledge doesn't obviate stochasticity / randomness, which is unavoidable in biology as it is in any other complex process. Cancers arise from environmental insults, chemical accidents, and behaviors as much as from innate genetics. In future medicine, the presence and effects of our living conditions would be visible by way of thorough biological testing, taking the typical blood or urine test to a new level of insight to assess what the immune system has seen, for instance, whether nascent cancers have released a few cells, or what subtle imbalances the metabolic system is dealing with; even what you had to eat for lunch.

Once, say, a cancer is detected, (in a very early stage, given a far more sensitive fluid and tissue testing system), the knowledge that a patient has mutations like the one above would inform treatment, which could be assembled from a shelf full of gene-specific medicines that shut off or turn on each encoded protein respectively, as the data indicate, or even create novel activities. We may someday even be able to re-program the DNA of our cells, directly correcting this and the dozens of other mutations that will have conspired to form that particular cancer.

• What would you pay for a drug that actually cures?
• Our brains are not our own.
• Seminar on how the brain flushes & refreshes during sleep.
• Federal debt is OK, and austerity is madness. Greek austerity is even worse.
• The state of SDI and disability.
• On the obsolescence of top-down capitalism.
• The conscience of a conservative.
• The unholy mess in Argentina.
• "From 1960 to 1991, violent crime rose by 400 percent ..."
• Terror is not entirely a foreign concept, especially to conservatives.
• Are we seeing euthanasia of the rentier, at least on interest rates, if not on capital income?
• On the role of history in economics.
• "... those who have actually investigated the issue demonstrate that it is overwhelmingly the lenders and their agents who put the lies in “liar’s” loans."
• Containment of Russia, version 4.9.2.0
• Fossil fuels- is it love, or is it just high-maintenance?
• Graph of the week: unemployment trends in selected countries.

Men, Booze, and Cigarettes: The Autobiography of Lauren Bacall

One of the great memoirs, about the loves and wisdom of a dramatic life.

You wouldn't expect an outstanding memoir from a Hollywood starlet who took the nation by storm (giving it "the look"), snatched Humphrey Bogart from his third wife, and went on to an outstanding, if patchy, career in film and theater. But there it is. Bacall (originally Betty Bacal) was raised in very modest circumstances, in a solid New York (Bronx) Jewish familiy, but with the significant void of a father who left (was thrown out, really) very early in her life, between five and eight years old. Just old enough to remember him, but not old enough to understand why. She spent much of her life looking for father figures, with mixed success.

Bacall writes with incredible immediacy. Her heart is right there on the page, as she is smitten with movie stars in her childhood, has a gushing personal encounter with the surprisingly kind Betty White, and pursues acting relentlessly in her teens. But money is very tight, and she has to do modelling on the side. The big break comes with a cover in Harper's Bazaar, under the genius Diana Vreeland.

This cover led to several offers from far-off Hollywood, and just like that, Bacall was on the train and in the expert hands of Howard Hawkes. He was understandably pleased with what he saw, and cast Bacall in her first film, To Have and Have Not. Not only did Bacall turn out to have the looks, she also had the voice, the humor, and the acting skill to rise to the occasion (singing would always be a problem, though). While Bacall was in quite a different place when she wrote all this in the mid-seventies, she is obviously reliving this special time with acute memory and a unique dramatic sense, as she was smitten by co-star Humphrey Bogart who was, yes, old enough to be her father.

It turns out to be one of the love affairs of the century. Bogart was not just a character, but truly had character. They treated each other with great respect, and she describes a largely idylic life. He was a bit of a drinker when they met, having been beaten down by several bad marriages, especially his third, but drinks less as time goes on, now having children and his all-important sailboat to live for. Bacall's highest praise, in retrospect after future failures in love, was that she was married to a mature man. Unlike all the others.

But like all biography, the story of Humphrey Bogart ends tragically in his mid-fifties, from cancer clearly brought on by drinking and smoking. Within a year he wastes away to practically nothing, and Bacall writes so movingly of his illness and death that it is heartbreaking to read. All else, certainly her career, took a back seat to her personal life, and her Hollywood career never fully recovered. She was anxious to get back to work after Bogie's death, but the industry, the town, seemed uninterested, perhaps pigeonholing her as the wife, rather than the actor she was also. While it was frustrating for her to be out of work for long stretches, (eventually she made a new life on Broadway), it is a great loss to the rest of us to not see more of her on film.

Bacall did a good deal of falling apart and rebounding after Bogie died. She ran around with Frank Sinatra for a while, until he pathetically backed out of a marriage proposal- truly one of the "rat pack". Then, esconced on Broadway, Bacall met and fell in love with Jason Robards. This time, she succeeded in dragging him to the altar, but lived to regret it as his drinking kept right on going. She remarks that the only thing she could count on was that he would be at the theater he was appearing at a half hour before show time. Bacall, who prided herself on her motivation, character, and life sense, found herself treated shabbily, utterly unmoored, with up to six children to take care of at times.

It took six years, but she finally threw him out and embraced a single life, with occasional film roles, but mostly working on Broadway. Katherine Hepburn was a great friend, and indeed a mentor in how to live singly, and how to brush off the constant stream of negativity from critics, missed roles, the press. Bacall worked extremely hard on Broadway, even in musicals, and won a Tony eventually. But the time lost to bad men, and the adoption of a single life, clearly caused rankling regret, after her idyl with the king, which is to say her time of having it all- a great marriage, children, stardom, and a great social life, with Humphrey Bogart.

The theme of father figures is one of the more interesting in this story. Bacall denies seeing any physical (vocal, name ... ) resemblance between Bogart and Robards(!) At least Robards was her age. Anyway, she pays explicit homage at one point to the most influential & positive male figures in her life- her uncle Charlie Weinstein, Bogart, and Adelai Stevenson, whom she campaigned for, flirted with, and who all but offered himself as a partner after Bogie's death. She clearly valued, even hungered for, this influence, which puts her in contrast to the current trend of gender neutrality and anti-patriarchial agitation.

But the father figure is among the deepest archetypes, one we have worshipped forever, name: "God". I think it is fair to say that we all seek father figures through life- as mentors, leaders, power-brokers and status confer-ers, stabilizers. While the patriarchial complex has amplified this archetype out of all proportion, it is biologically programmed and not to be denied. But who can possibly fulfill the role? Very few. And the first ingredient is ... training with another father figure. So the cultural round keeps going, generally in very flawed and even destructive and tragic ways, but so very valuable when it does go right. Many of the ancient epics and fairy tales put a strong black / white frame around this- the good king, ruling a happy land, contrasted with the bad king, beset with bad luck, misery, defeat. Not only the lives of great women, but of whole cultures, hang on the quality of this training, acting, and being.

• To Have and Have Not: We can offer a job guarantee, and much more.
• Two Guys from Milwaukee: Rosy report about the job market, but are employers paying more?
• The Big Sleep: Right to die is gaining ground.
• Dark Passage: Why is the new TTP trade deal being kept so secret?
• Key Largo: Tax holiday for corporations practicing extortion?
• How to Marry a Millionaire: Conservatives and social mobility: peddling an illusion.
• Woman's World: Health insurance helps women particularly.
• The Cobweb: Net neutrality is on the way.
• Written on the Wind: The future is solar (+wind).
• North West Frontier: Why is the Taliban so resilient?
• Shock Treatment: Germany tells Greece to get lost. Exit is really the only solution.
• The Shootist, Appointment with Death: Is manhood about killing?
• Misery: The Fed has been wrong continuously, and could be poised for more policy errors.
• Prêt-à-Porter: The psychology of being middle class.

The Housing Gouging Distortion

We've got a problem in the US with housing. Overpricing, homelessness, financialization, inequality, all are affected by the shortage of real estate.

We don't usually take kindly to price gouging, defined as prices raised far beyond the cost of provision to what the market will bear, typically due to unusual circumstances like famine, natural disaster, etc. Taking undue advantage of the misfortune of others is unethical, as is forcing others into destitution by virtue of their basic necessities. Charging far more than the cost of providing a service or product is one of the primary justifications of markets and capitalist competition, and its failure raises serious questions.

However such gouging, in essence, looms large in the housing market. Land is inherently limited, and its shortage creates prices far above the cost of provision, which is, frankly, zero. Whoever has title gains value that they have no role at all in creating, that value being the network effect of everyone else wanting to live wherever there are other people, services, amenities, schools, etc. It is a classic case of incumbants reaping rewards they have little individual right to, keeping equally deserving outsiders at bay.

Inflated housing prices force everyone into an arms race of spending every available penny on real estate, housing being a necessity, after all. Those who lose out become homeless- an appalling sign of societal failure. The various incentives offered by the Federal government, such as the mortgage interest deduction, do little more than put more resources into this arms race, bidding up prices and leaving homeowners with no more money to spare than they would have had otherwise.

And the ever more dizzying high-wire financial engineering required to take on the debt involved plays right into the hands of one of our most destructive industries- the financial industry, a haven of small text, opacity, slight of hand, and offers that are way, way too good to be true. The recent financial crisis illustrates the point. Not only is typical housing debt too high, but gyrations in the housing market built on scarcity, and the mountain of credit that serves it, yield periodic crises that shake the whole economy.

The general economy is severely hobbled by this vortex of excess money going to the literal rentiers of society, and our cultural and civic institutions are particularly harmed by the lack of extra resources in the pockets of ordinary people. High housing costs are an engine of inequality and of societal decay.

What to do? It seems clear that were housing to be kept to what it actually costs to build, rather than the inflated cost of scarce land and restricted zoning, the average family would be much better off, and more housing could be built for the poor and homeless. Yet there is no way to get around the limitation of land, really, and the tendency of desirable locations to create bidding wars and price increases. Living in a very high-priced real estate market, I can appreciate that the despite all the harms, there is a natural evolution that gets us there, swathed in very politically correct talk of "preserving open space", "preserving communities", and limits of infrastructure, not to mention the interest of every single incumbant property owner in seeing the value of their land go up.

A classic proposal is a land tax that taxes away the "rent" or scarcity aspect of property values, leaving only the value of the built infrastructure to be captured by owners. It sounds very elegant, but I do not know enough about its feasibility to comment, really.

My proposal would be to force every county in the US to provision & zone sufficient land such that in those areas at least, developers can build and sell for the cost of construction, more or less. Counties would also be on the hook for infrastructure planning, making sure that the overall road and other systems are built that can support the requisite growth. In this way they can avoid rezoning and disturbing existing desirable areas. But there would be a mechanism to allow housing growth and keep a lid on area-wide real estate inflation.

In truly dense areas, such as Manhattan or San Francisco, this mandate could be fulfilled by building up instead of out, and in extremis, condeming older areas for redevelopment. But there is no reason not to have at-cost housing available all over the country, in ways that are reasonably local to every community, which would address workforce housing needs, homelessness (to some degree), and the overall rise in real estate prices.

This plan is reminiscent of the housing "project" boom in the 60's and 70's. But one difference is that it is all oriented to market-rate housing, not explicitly to free or subsidized housing, which has such problems with uncaring owners and tenants (not to mention architects). The idea is just to make sure that the market keeps up with population needs at all times, so it doesn't run away in a price spiral.

The current housing non-policy seems to function as a fundamental barrier to growth. Governments are not willing to build infrastructure, and tolerate traffic gridlock. Citizens in turn regard any mention of housing growth in this kind of restricted environment as crazy. Governments in turn get higher property tax revenues from real estate inflation rather than development growth, and so it goes in a spiral of stasis, and ultimately, sclerosis. It would take far-sighted leadership and some top-down policy to reverse the problem.

This is not to say that population, migration, and other forms of growth are automatically a good thing. Far from. But artificial housing price inflation is not a rational way to restrict what should better be restricted by other means, such as immigration control and educational development.

• Housing gyrations whipsaw the rest of the economy.
• Reich on FIRE.
• As long as there’s fear, we aren’t ready for atheism: "I think the main passion of the conservative mind is fear and there’s no greater fear than that the universe is without meaning."
• Stiglitz on the idiocy of austerity.
• The Republican version of "middle class economics": "Gov. Nikki Haley of South Carolina proposed a gas-tax hike on Jan. 21 to offset reducing the top state income-tax rate to 5% from 7%."

Epiphany Without a Cause: a Theory of Religion

Similarities between the near-death-experience, enlightenment, "spirituality", motivation, and the common core of religion.

I recently commented on near death experiences (NDEs), which have some very interesting characteristics. They are incredibly compelling, prompting both life changes in the person experiencing them, and gushing descriptions like "realer than real". They are highly emotional, typically positive, but sometimes negative. The subject feels love pervading the universe, and that this is knowlege which is not only true, but needs to be spread around to other people. But the experience is also vague, with a feeling of tremendous knowledge being gained, but an actuality of platitude after platitude, set in very stock archetypal images- angels, bright lights, butterflies, voices of god, telepathy, clouds.

Does this all sound familiar? It does to me. While one might take it, on the one hand, as evidence that religions are true in what they communicate, at least in some broad sense of a deep / alternate reality and motivation that unites them all, one might take it more skeptically as being a key to what makes humans so susceptible to religion and forms its internal wellspring, without being what it purports on its face.

But what is the point of such a mechanism, if we assume it is natural and biological, rather than a transmission from the beyond? The NDE may be the extreme form, by way of brain disconnection between areas that normally keep each other in check, of our normal positive motivational gestalt. As one is walking along, one occasionally reads into the landscape pleasant sensations- trees growing and birds singing, and more rarely, internal realizations and epiphanies of various kinds. We only know about some nice impression or great idea by way of an emotional reaction that wells up telling us that beauty or truth are at hand- that some nagging question has been solved, or some new perspective gained.

We must have a positive emotional system that is not simply the well-known, purely emotional reward system of drug addiction, but one that is more cognitively engaged, which labels our ideas and impressions with emotional valence and meaning. One might call it a key part of our imaginations. Untethered from inputs and more importantly, from its customary repression by normal cortical controls that harness it to only real, (or realistic) ideas, it might both gain intensity, and resort to dredging up archetypal dream-imagery for attachment.

Some partial form of this process might be at work in great art, and among the mystics of religion. Buddhists devote their lives to forms of meditation that fundamentally seek, I would suggest, to gain this NDE-like state of pure positivity and sense of vast knowledge and emotion, termed Nirvanna. Obviously, it is both extremely hard to attain, and all-to-fleeting when it happens. And it is not really knowledge of any this-world kind at all, merely the sense of knowledge.

This leads to a unifying theory of religion, where the NDE is merely the most intense form of a feeling that happens to everyone at various levels. Typically we seek to intensify this feeling through what are biologically and evolutionarily valid means- the true epiphany regarding a personal task which is indeed useful and oriented to the real world, and which gains us a precious practical advantage. But the lure of this feeling is strong. We can also seek it through what I would call false epiphanies, such as intense meditation, or the typical institutional religious apparatus of scripture, sermon, homilies, hymns, incense, etc. all purporting to vastly more meaning than they actually contain. Latter-day seekers even engage in postmodern philosophy!

This is reminiscent of Stephen Pinker's theory of music as being a kind of cheesecake for the mind. The evolutionary rationale of our capacity to make and appreciate music is not at all clear, but in any case, complex instruments like pianos that demand exquisite talent and dedication, and our unimaginable cultural wealth of composed and performed music, extend far beyond any evolutionary rationale. We are tickling pleasure centers whose original purpose was far more modest- perhaps the identification of a bird, or the seduction of a mate.

In similar fashion, religions seem to tickle a kind of meaning and positivity center in the brain, with more or less empty mantras and practices which yet carry intense meaningfulness. If they can inspire good morality, humility, and pleasant personal and communal feelings, that is wonderful. But religion can also form the nucleus of wider psychological complexes, attracting far darker tendencies like tribalism, magical thinking, superstition, intolerance, fanaticism, and patriarchial oppression, to generate thought and behavior systems that not only far outstrip their warrant, but go beyond all decency.

• A little pushback from the new atheists.
• Religion, violence, and psychological & moral primitivism.
• Religion, power, and Nietzsche.
• Religious morality is the least objective of all.
• Faith is a bad thing, generally.
• C. S. Lewis, revelation, heaven, etc.- uncritically reviewed.
• Greece has not been well-served by austerity. It can not "sink".
• Indoctrination, propaganda, and water-carrying for the 1% ... the war for home schooling.
• Terrorist or hero? You make the call.
• On the perpetuation of social class in the US.
• "Washington [state] now makes low-income families pay seven times the effective tax rate that the rich pay."
• Where does the Fed's free money go, and where should it go?
• Bill Mitchell on neo-feudalism and the degradation of our concept of citizenship.
• Gary Kasparov on the global culture clash, and why modern values are better than the other ones:

"It is less the famous clash of civilizations than an attempt by these 'time travelers' to hold on to their waning authority by stopping the advance of the ideas essential to an open society."

Nihilism, Elitism, and Moralism in Nietzsche

Review of "Living with Nietzsche", taking a positive view of Nietzsche.

Nietzsche gets rapped as a Wagnerian proto-Nazi and nihilist, not only declaring god to be dead, but engaging in a revaluation of all morals from which he appeared to arrive at an elitist, devil-take-the-hindmost stance with the Übermensch. But according to Robert Solomon, this view tends to mistake the bluster for the substance.

First, take nihilism. Solomon provides an extended exposition about how that term is routinely applied to any morality one disagrees with.

"It often functions as a kind of accusation, a bit of abuse. Some traditional but much in-the-news Christians use the term as a more of less crude synonym for 'secular humanism,' on the false assumption that a person without God must be a person without Christian values as well. ... But note that I say 'Christian' values, for the accuser might well allow, indeed insist, tha the nihilist does have values, subjective, self-serving,and securely narrow-minded though they be. ... Similarly, an orthodox Jewish friend of mine calls 'nihilists' any people without a self-conscious sense of tradition, assuming that others must lack in their experience what he finds so essential in his own. Marxists use the term (sometimes but not always along with 'bourgeois individualism') to indict those who do not share their class-conscious values. Aesthetes use it to knock the philistines, and my academic colleagues use it to chastise anyone with 'looser' grading standards and higher grading averages than themselves." 

"In the pseudo-book of Nietzsche's collected notes, 'The Will to Power', there are many indications about the scope and nature of the nihilism he describes. But perhaps the most important point is this one: for the most part, Nietzsche describes nihilism as a concrete cultural phenomenon rather than *endorsing it as a philosophy. So I want to bracket the above uses of nihilism ('push what is falling', and the urge to promote 'a complete nihilims') as more Nietzschean hyperbole, for as his texts make perfectly clear, Nietzsche's aim is to overcome nihilism, not promote it."

Obviously, Nietzsche was for something, filling his books with declarations and "shoulds" and "musts" of various sorts, the more florid the better. But what was this morality that he was striving for? Firstly, it was not based on tradition or on an objective source. It was fundamentally subjective. He had only bad things to say about Christianity, for example, though Solomon notes an implicit dedication to rather bourgeios values in terms of truth, duty, and artistic value. He thought Kant and most other philosophers fundamentally mistaken in their attempts to make up absolute moral rules, based on some rational treatment of the human condition. What could be more contradictory?

He was also far more congenial to Aristotle than is generally realized, being a thorough classicist, even if of a more Dionysian than Apollonian stripe. Aristotle was a product of his time, and promoted a typical virtue ethics, focusing on good character that achieves the mean between excesses that can turn any virtue into a vice. Be neither too brave (reckless) nor cowardly, neither too abstemious nor too hedonistic, and so on through all possible virtues. These did not have to be (and were not) based on any objective condition of the cosmos, on deities, etc., but rather simply upon the wisdom of what promotes happiness personally and generally. This justification is ultimately utilitarian, (and subjective), taking happiness in the broadest (terrestrial) sense as the condition that needs to be satisfied, even optimized.

One wrinkle in the classic system, however, is that it isn't the happiness of everyone that matters, but the happiness of the system as a whole, and especially of those who are its leading lights- who both raise the cultural level, and run the society, including writing its philosophy. Slaves certainly were of little account, and Aristotle and his class hardly thought much more about women or other lesser classes. They vied to tell the rulers what to do, Aristotle personally tutoring Alexander the Great, for example, in a tradition that reaches down to Machiavelli.

Nietzsche, despite his choleric and bombastic nature, was fundamentally pushing the same elitist program, seeking to free people from the resentful, leveling, "slave" ethos of Christianity. Nietzsche urged his Übermensch to excellence and competition, even war, though never crass bigotry or bad taste. It is a fundamental and interesting question in moral philosophy- even if you grant a utilitarian / subjective justification to the whole edifice, and even if you make its justification empathetically broad-based in the modern sense, what is the better system- ethical democracy, or ethical elitism?

On the one hand, recognizing the fundamental value and talents of each person seems like an all-around good thing, a bedrock of modern moral and political theory. It is the right thing to do. On the other hand, we have to recognize that people are not created equal, and that society gains far more from the cultivation of some than of others. Moreover, we retain in many spheres a relentlessly, even mortally, competitive system that gives hardly a glance to egalitarianism- the corporation, sports, economics, the marriage market. We are very confused in this respect, with our natures and institutions tugging in all directions.

Looking at our politics in particular, the conflict reaches absurdly affecting dimensions, with highly egoistic and talented individuals yearning for vast power power while vowing fealty to the basest prejudices, vanity, and superior judgement of the mass of voters, while at the same time promising unwavering attention to the upper crust- the moneyed class which funds their campaigns. One might call it checks and balances, but it is also a little schizoid.

Democracy is supposed to combine the benefits of both ethical systems, harnessing the cultural elite to do the bidding of the society at large. But it can also combine the worst of both ethical systems, weakening the power of (if it does not sicken and turn away entirely) the most talented leaders and institutions, while also exposing the state to mob rule when emotions run high.

Nietzsche took a rather one-sided approach, at least rhetorically, favoring the elitist, competitive side of the equation. This was in line with the tenor of his time, saturated with German romanticism, sentimentalism and nationalism, and was the kind of thing that did indeed lead straight into world war 1 and all its ensuing miseries. This ethic even rubbed off oddly onto the socialist strain of German romanticism, leading to the even more shocking horrors of communism- an ethical fox in sheep's clothing if ever there was one. While his affections may have been with Greece, his ethical model seems quite a bit more like Rome, which ran for so long on blood and conquest. So, while Nietzsche may be more subtle than his worst bluster makes him appear, and diagnosed significant ills of the philosophy and atmosphere of his time, his degree of overall wisdom remains highly questionable.

Aristotle is a much surer guide, (if transposed into a modern ethical setting), counseling moderation and balance. In the present time, the elite have once again gained the upper hand, and are threatening our political, cultural, and economic fabric with a neo-feudalism that coursens and degrades so much that we have achieved through communal action. A competitive landscape that benefits society can only happen when everyone has a fair start in life, with fair rules as it goes on, and where the many other features of our society that require common action and investment are respected, well-managed and not hobbled by the self-serving ideology of what passes as our current elite.

• Which side is more virtuous in politics? Which side is committed to narrative?
• Pity the religions, victimized by their believers!
• But does religion has just a little to do with our craziness?
• What keeps left economics outside of public policy? MMT is taking Washington by storm.
• How about a federal inflation constraint for budgeting, in place of a revenue constraint?
• We need thorough and long-ranging claw-back policies against officers of corporations.
• Krugman on weaponized, carbonized, and anything but humanized ... Keynesianism.
• Credit is part of the peonage, low-wage system.
• Water pollution, thanks to the "Halliburton loophole".
• New science-y word: "defaunation".
• The social cost of carbon is $220 per ton.
• The cloistered life is not for everyone... nuns gone bad.
• Map of the week: Who has what in Syria, from the wall street Journal.

Do Fruit Flies Dream of Piña Coladas?

The olfactory learning circuitry of the fly brain.

Our brains didn't come from nowhere, but rather out of hundreds of millions of years of evolutionary work that developed mechanisms for dealing rapidly and intelligently with the environment. Primitive organisms are fascinating to study as waystations along that long road, and their simplicity can clarify what in humans may still be beyond our intellectual or technical reach to study.

Fruit flies have only ~ 1-200,000 cells in their brains, compared with the maybe 100 billion in humans. Moreover, most of these neurons are laid down in totally genetically determined fashion, easing study, but also reducing the ability to learn. But one area of the fly brain appears to break that mold- the mushroom body, which is intermediate in the path from olfactory reception to behavior. It is sort of the fly's glimmer of higher intelligence. Indeed, flies can be trained in the traditional Pavlovian manner to associate otherwise meaningless or pleasant odors with torture like electric shocks, and thus avoid them. Researchers have spent decades teaching them other tricks like avoiding certain odors, heading towards sounds, lights, manipulating social status and fighting behavior, etc. Along the way they have given some of their mutants names like dunce and rutabaga.

Location of the mushroom body in the fly head/brain. Signals arrive through the antennal lobes, from the various hairs and other nerves on the mouth and antenna.

Fluorescence image of two labels, one on an annal lobe (AL) neuron (red), and another on a mushroom body (MB) neuron (green, left side), which labels more cells of the same type on the right side. The lateral horn (LH) is one destination for signals as they start going out again to muscles and behavior downstream.

A recent paper conducted a tour de force of anatomy, tracing every single neuron going to and from the mushroom body. The technique they used to do this is interesting in itself, called an "enhancer trap". Fly researchers have been generating a vast number of "lines", or inbred fly mutants, by inserting a two bits of DNA from yeast cells. The first is the gene encoding a transcription activator, GAL4. This is induced to jump randomly in the fly genome, hoping that lands downstream of the regulatory region of an endogenous gene, i.e. its enhancer or promoter. The second bit is a binding site for this GAL4 protein, linked to a gene that expresses some useful marker, typically a fluorescent protein like GFP. Since the yeast GAL4 protein works just fine to activate RNA transcription and gene expression in flies, the end result is that GFP gets expressed in reponse to a single enhancer somewhere else in the genome. Indeed researchers try to "saturate the genome", generating a huge number of lines with such mutations, hoping for mutants at every single enhancer in the fly genome, and even enslave their undergraduate students to that end.

Enhancer trap schematic. An introduced regulatory gene, GAL4 is hopped within the fly genome to random locations, some of which are downstream of enhancers (E1). The signal is received by another introduced gene, which expresses a marker (green fluorescent protein X in this case) in response to the production of GAL4. UAS = upstream activating sequence.

Screening with a fluorescence microscope, one will see the cells where GFP is expressed, and thus where the particular enhancer of that line is active. This might be anywhere and any time, in the egg or in the adult, in the brain or in the leg, or everywhere and all the time, or nowhere. This stage of the process tends to be very tedious, as is all the fly breeding leading up to it. The current researchers used 7000 such lines that had been built previously to screen for those showing GFP expression in neurons in or connected to the mushroom body.

Anatomical details of neurons leading through, and from the mushroom body, drawn from studies of many flies with many individually labelled neurons. Video here. Note the wide distribution of MBON (mushroom body output) neuron connections, and also the density of DANs, (dopaminergic neurons), which feedback to the MBONs from sensations elsewhere in the body.

The mushroom body is made up of ~ 2,000 of what are called Kenyon cells. Inputs come from the antennal lobe, where olfactory receptors from the fly's "nose" and face link to ~200 projecting neurons (diagrammed below). The Kenyon cells synapse to what are called the mushroom body output neurons (MBONs), and these same output axons get inputs both from other MBONs (making some recurrent loops) and from other neurons called DANs, which seem to be crucial for the feedback that leads to learning.

Wiring diagram of the olfactory learning system. Projection neurons (left) come from the nose and face, to the Kenyon cells of the mushroom body (KC). Then MBONs of various types (using different neurotransmitters in their synapses) come out (gray lines) to innervate the lateral horn and other downstream neurons. DAN neurons from other sensations are labelled for their valence. The colored boxes correspond to various anatomical bodies or sub-areas.

The key part of the organization is that while the layout and connections of the olfactory neurons and projection neurons are genetically determined, those of the Kenyon cells are not. They are a generic type of cell whose sporadic connections on both ends are made on the fly (sorry!) during development, and are not the same from one fly to the next, as are all the other cells. These connections are also plastic during adulthood, and the volume of the mushroom body on a gross level expands in response to usage in honey bees. The mushroom body is not essential to actions of the fly, really- the built-in programs for sensations and stereotypical behaviors lie elsewhere. The mushroom body system only biases those behaviors based on learned feedback, which arrives via the DAN neurons from positive and negative shocks / experiences.

This arrangement is pretty much what has long been called a "neural network", which is a computer science tool developed over several decades by analogy to how people thought neural systems work. They offer the unique capacity to learn from sample data, and to solve problems that are not well-specified or are complex. These feature a hidden array (or black box) of many "neurons", connecting inputs with outputs. The box is trained (iteratively) by providing it with (known) sample input and output data. Feedback of error values from the output vs input comparison is sent back through the network and adjusts the weights of those connections which then evolve through time, in their connections and connection strength, leading the network to arrive (slowly) at an approximation of the behavior desired, emitting the correct output for given inputs.

For instance, an image shape recognition program might be made as a neural network, with many examples fed in, and the outputs judged and signals sent back into the network to either reinforce connections that improve the match over previous trials, or weaken connections that reduce it. If a sufficiently broad range of input images are used, then the network stands a good chance of identifying those same shapes in images it has never "seen" before in training.

"... MBs are a paradigmatic case of reused neural networks in action."

"This model was built in a connectionist manner, obeying, although in a scaled version, the neurobiological topology. The model was initially built for showing basic learning and conditioning capabilities; subsequently it was found able to show other interesting behaviors, like attention, expectation, sequence learning, consolidation during sleep and delayed-matching-to sample tasks."

Likewise, in the mushroom body system, the DANs provide the essential feedback in real-life situations as the fly buzzes and walks about, smelling the wonderful world. If they can dampen neural connections among the Kenyon cells and their downstream targets that lead to painful results, and juice up those that lead to pleasure, we have a smarter, and more successful fly.

"The identification of the full complement of 21 MBON types highlights the extensive convergence of 2000 KCs onto just 34 MBONs, a number even smaller than the number of glomeruli in the AL. Thus, the high-dimensional KC representation of odor identity is transformed into a low-dimensional MB output. This suggests that the MBONs do not represent odor identity but instead provide a representation that may bias behavioral responses."

So, what is it like to be a fly? Are flies conscious? They are clearly responsive to their environment, and have what we would call "experiences", such as hunger, searches for food, mating, etc., and one would assume these experiences can be very intense. So I think it would be hard to count them entirely out of the consciousness department. But it would have to be an extremely small consciousness, with little association to past, let alone to future events, metaphorical, or conceptual abstractions. But feeling- that is likely to be there in some form.

• One problem with the rich ... they are well-hidden, even when they exercise their "free" speech.
• Martin Wolf on the injustice of housing shortages and zoning control by incumbents. It is the price of overpopulation, really.
• Everyone's a critic!
• Atheism- a little more dangerous than you might think.
• The economics of knowledge & organization.
• Exploitation and income.
• Want to know about a government boondoggle?
• California raises the bar on environmental responsibility.
• On the tension between science and humanity in economics.
• The sanctimonious disaster that is Jeffrey Sachs.
• On the power of satire & truth: "... the Chinese government decided to ban puns."
• In France, there is a culture war. It was not about "freedom", but about cultural dominance.
• Dirty jobs- better than clean jobs?

Realer Than Real

A second post on the topic of near death experiences, reviewing "Proof of Heaven" by Eben Alexander.

Santa Claus climbed down my chimney with a copy of "Proof of Heaven", another in a long line of books about the intense spiritual experiences that people have in many situations, but most frequently when close to death. The case is especially extraordinary in that the author is a practicing and scholarly neurosurgeon, and also in that his experience (NDE for short) was remarkably intense, lengthy, well-recalled, and unimpeded by inputs from the surroundings. There were no episodes of hearing what was actually going on in his room, rather just pure experiences of high and low spiritual engagement, interacting with god, angels, swamps, dark regions, etc.

There is no question that Alexander experienced all this, as he has recorded. The problem is with interpretation. His interpretation is absolute- that he was in contact with another reality, which he frequently describes as "realer than real", and "ultra-real", and that this reality was divine, culminating in god, and that he has an important message to bring back that we are loved, and that every one is important. This reality was outside his brain, and his good news is in part that "we are more than our physical body".

"Each and every one of us is deeply known and cared for by a Creator who cherishes us beyond any ability we have to comprehend. That knowledge must no longer remain a secret."

Alexander had long been an Episcopalian, and evidently an irregular church-goer while at the same time a somewhat religiously skeptical scientist. He is a bit unclear about his allegiences, really, but seems to have been a believer at some level (principally for family purposes, but not for scientific ones), and has spent his life in a church culture as well as in a scientific culture. The NDE dramatically confirmed him in his faith, but one has also to ask whether that long life of faith contributed to the content of, and especially to his interpretation of, the experience.

A good deal of interpretation turns on what various areas of the brain are responsible for, and when they were "off" or "on" during his (outer) coma and (inner) NDE. Alexander was in a coma for a week, and portrays his travels in NDE-land as taking place throughout this time, when his brain (the cortex, as measured by EEG and external responsiveness) was largely not active, by conventional metrics. Yet it is possible that it actually took place in a small portion of this time, say the last half hour before he woke up consciously. I certainly have had the experience of an intense, extensive dream taking place in a very brief time, clock-wise. Similarly, having one's life flash before ones eyes, as the expression has it, typically happens in a very brief clock time, but in a much longer subjective time. In short, our sense of time is another construction of the mind, and thus can not be taken at face value under these conditions.

He had a severe case of bacterial meningitis, from which he concludes that it was almost a perfect trauma for an NDE, debilitating the surface all over his brain, i.e. the cortex or higher functions, and possibly only in a layer-specific way. From this he concludes that none of his NDE experiences are possible by typically understood means, since all consciousness requires cortical functions, for instance for sensations of flying and seeing, hearing, etc. Even imagined and hallucinated experiences require their respective areas of the brain, as far as we know.

"The more I learned of my condition, and the more I sought, using the current scientific literature, to explain what had happened, the more I came up spectacularly short. Everything- the uncanny clarity of my vision, the clearness of my thoughts as pure conceptual flow- suggested higher, not lower, brain functioning. But my higher brain had not been around to do that work. 

The more I read of the 'scientific' explanations of what NDEs are, themore I was shocked by their flimsiness. And yet I also knew with chagrin that they were exactly the ones that the old 'me' would have pointed to vaguely if someone had asked me to 'expalin' what an NDE is. 

But people who weren't doctors couldn't be expected to know this.
...
Many others have seen that astonishing clarity of mind that often comes to demented elderly people just before they pass on, just as John had seen in his father (A phenomenon known as 'terminal lucidity'). There was no neuroscientific explanation for that."

That is all understandable, but I don't think we can be quite as categorical as he is. For the main issue is that we do not know quite how conciousness, let alone this kind of realer-than-real, trippy consciousness, works, even when clearly due to more mundane causes like LSD. It might well be an interplay between higher and lower brain functions, and it might additionally be that in consciousness, as in so many other aspects of cognitive science, cortical functions generally modulate and especially inhibit more central and primitive areas of the brain. The amygdala is a classic case, where its learning of fearful stimuli is permanent and gives rise to involuntary reactions, yet these can be damped by cognitive learning in higher levels of the brain, thereby keeping the subject on an even keel.

Similarly, one might imagine that some core of conscious awareness happens in the thalamic and lower regions of the brain, and that when the cortical brakes are off, that person might experience something precisely along the lines of the NDE- realer than real, incredibly moving, and patterned by very deep emotional archetypes and images, such as the flying through the air with angelic beings that Alexander experienced, among much else. It might be so moving that the person feels compelled to change his life or write books about it, and speaks of it as a scientific voyage, with great understanding and knowledge gained. But this knowledge boils down to very little in the end: that we are all loved by something. And that love seems, to put it mildly, inert, since people are still living and dying every day in misery, on our surface world. The only love in evidence out here is that which we give to each other.

Alexander is keen to recapture some of this experience, and does so in two ways. First is through greater church attendance. He movingly writes about realizing belatedly that he had not really appreciated the whole church experience, but that he now understands it as trying, in our mundane world, to recapture a glimmer of this spiritual experience, (whatever its interpretation), which some are fortunate enough to have intensely, but that all of us have some degree of appreciation for, accounting for the general celebrity of spiritual adepts, prophets, saints, etc. Second is an adventure into meditation, especially methods that claim to provide much faster achievement of out-of-body experiences than normal techniques provide. One has to ask, however, why repeating the experience is important if the knowledge he had gained was so certain, scientific, explicit, and useful. We don't repeat our greatest experiments in the lab just for the fun of it, typically.

Don't get me wrong, I would love to have eternal life and the ability to think outside the brain. Being eternally loved by some tremendous "Om" sounds a little less attractive, but OK. Alexander is understandably convinced by his overwhelming experience and his theological interpretation, but putting tradition & training aside, there is no theoretical reason from biology, computation, or physics, to take all this seriously as evidence of heaven or souls, etc. These are huge hypotheses (given the scientific corpus as it stands) that require different forms of evidence to address, particularly something less obviously subjective and archetypally templated. The weight of tradition may have arisen from a countless number of such mental / spiritual experiences, and if they are misinterpreted as I think they are, the tradition is not pointing us in the right direction, at least in scientific terms. That said, any encouragement we can have to not fear death is a good thing, since this is an important source of our worst characteristics- lack of courage, sentimentality about every reverse and misfortune, etc.

The heaven hypothesis, far from being proven, remains much more a matter of inner, archetypal reality than of any outer "real" reality, even on its own evidence. While it is true that much about the mind remains unexplained by science in its current state, that doesn't demand that vast hypotheses about alternate realities, and the invocation of quantum mechanics in consciousness (yes, Alexander even dabbles in this area) are reasonable, let alone proven. But it is such deep matter, and our consciousness remains such a mystery, both technically and theoretically, that it is understandable that those who go through the gauntlet of this ultimate, compellingly subjective experience would declare it not only real, but realer than real.

• Capitalism is not the only way.
• Stiglitz on credit, rent, and wealth. "It’s also true that people who make the most productive contributions, the ones who make lasers or transistors, or the inventor of the computer, DNA researchers — none of these are the top wealthiest people in the country. So if you look at the people who contributed the most, and the people who are there at the top, they’re not the same."
• Taxes have no effect on work effort.
• Demand-deficient recessions & stagnation are a scandal.
• Is god a proper name, or a form of capitalized cultural oppression?
• Good teachers are critically important.
• Millions of prime age workers are still on the sidelines.
• "We have managed to throw away between 5%-10% of the potential wealth of the North Atlantic, and we appear to have thrown it away permanently."
• "And that is tragic because if Alvin Hansen is right, and I think he is, the gap between these two lines represents an annual loss of output of approximately one trillion dollars."

A Spear-chucking Bacterium

Vibrio Cholerae impales its victims with a metal-tipped, poisoned, rifled, spear.

Life is tough all over, but particularly bad for microbes. Without a glimmer of consciousness, and with hardly any tools at hand, (or hands), they still struggle, suffer, and die in astronomical numbers. One of the more fascinating and classic areas of discovery in the field is the beauty and complexity of the T4 phage, which is a virus that infects bacteria like E. coli. It has a lunar-lander like structure that docks to its victim and injects the DNA (from a highly pressurized head chamber) which then kills it while producing hundreds of new viruses.

But it is only in recent years that a connection has been drawn between this phage injection mechanism and what bacteria do to each other. What has been sedately called the type VI bacterial secretion system, used by Vibrio cholerae and Pseudomonas aeruginosa, among many other species of bacteria, turns out to actually be a violent spearing mechanism they use to kill competing bacteria and also mammalian host cells during an infection.

Model of the spearing system, on right, compared with the T4 viral system on left. The spear is in purple, while the contractile sheath is in green, and the base is yellow. In later experiments (in movie, etc.) the sheath is tagged with a fluorescent protein (GFP), allowing it to be easily visualized in the light microscope.

This was recently described in an NIH talk by John Mekalanos, and also in various publications from his group. One representative film clip is linked below.

Still from movie of the Vibrio spear in action, link here.

One of the more remarkable aspects of this mechanism is its scale. Sausage-shaped bacteria typically are closest to each other at the side, so the apparatus begins assembling at the side of the Vibrio cell. This injector assembles clear across the interior of the cell, forming a thin thread almost 500nm long which has, in addition to the base plate that nucleates the process, an inside spear and an outside sheath.

Electron micrograph of a poised spear assembly in a Vibrio cell. Note the extraordinary length, of about 500 nm. The scale bar is 100nm. T6SS is type six secretion system, IM is inner membrane, and OM is outer membrane. Note the detail of the basal body at the top spanning both membranes.

The outside sheath is spring-loaded, and when triggered (how that happens is unknown) winds down in a matter of milliseconds to half its original length, thrusting out the spear, while also turning it like a drill. In his talk, Mekalanos showed that the spear is tipped by a pointed protein his lab had recently discovered, that contains a zinc-coordinated domain that gives it particular stability. Behind the tip, the spear also is festooned with a variety of toxins, because simply spearing a nearby cell is not enough to kill it. Vibrio injects both eukaryotic-directed toxins such as one that cross-links actin and thus paralyzes the cell and another that modifies the cAMP signalling system causing massive ion and water efflux, as well as several bacterial-directed toxins to clean out the competition, such as inhibitors of cell wall (peptidoglycan) synthesis.

Sample killing, where Vibrio (red) were mixed with Pseudomomas (green) cells. The spearing system sheath is labeled in red and green respectively. In each horizontal set of time lapse images, a spear from a Pseudomonas cell (green) impales a neighboring Vibrio cell and either causes it to swell locally or to lyse entirely, losing its optical contrast (arrows).

An interesting wrinkle in the story is that each bacterium that has this kind of system also has a complement of immunity proteins that neutralize the various toxins that it creates. The bacteria are not terribly bright, and live in close proximity, so they frequently spear each other. One wouldn't want that kind of thing to be fatal. But Vibrio doesn't need immunity from the eukaryotic-specific toxins, which do not affect bacteria, including itself.

Once the spear is thrown, another protein comes along to quickly disassemble the spent apparatus, and another one re-assembles from a new base plate somewhere else inside the bacterium. Quite a bit more is waiting to be learned here, like the triggering mechanisms, and the details of assembly, but not only is this knowledge helpful in addressing a significant pathogen, (though one we hope to not meet in the developed world), but it is an example of the breathtaking complexity, and even beauty, in biology, even in the midst of the most desperate dramas.


Papers:

• Description of the system.
• General review of the system.
• Immunity and warfare issues.
• Investigation of the system in a plant pathogen.

Notes in passing:

• NBA may exit feudal world, go socialist.
• Bird speech and human speech.. not so different, perhaps.
• Am I giving philosophy a bad rap, for being a home for insurgent theists?
• Free market short-term-ism and self-immolation, cont.
• $721 million in mid-term political funding came from fossil fuels. Thanks!
• Not just an increase in the minimum wage, but in overtime coverage as well.
• Religion as psychotherapy, cont. Some people need answers really, really badly.
• Bill Mitchell on Japan: "Let it be noted that the Japanese government 10-year bond yield hit 0.33 per cent overnight. That tells you that all the scaremongering that has been going on over the last twenty years about hyperinflation, the Japanese government running out of money, the bond markets dumping the yen, and the rest of it were self-serving lies designed to advance a particular ideological position at the expense of the broader social well-being."

Governance in Venice

Good governance gave Venice a thousand years of prosperity and renown.

The idea that the US is the oldest democracy in the world is far from the truth. Even if you qualify it as  "existing" or "continuously existing", the Swiss have one far older, (making allowances for a brief Napoleonic regime), as do the Icelanders. But more important is that forms of government are very plastic. What we call a democracy in the US is a far cry from actual self-rule, given the vastly greater influence of the moneyed classes and the advertising arts over who gets elected, than anyone in the demos. Oligarchy would be more like it. Republic it may be, but democracy it is not.

But oligarchies aren't all bad. Just think of the Catholic church, which has functioned continuously (give or take a few anti-popes) for about a thousand years, and with less historical certainty for another thousand back to the time of the first bishops of Rome. Its organizational stability has been impressive, even as it has gone through vast changes in theology, morals, and power.

Venice in its heyday was a somewhat similar republic / oligarchy, and an extremely well-ruled one. A wonderful history of Venice tells a story that I had never learned in school, of the long and proud reign of Venice over a commercial empire that grew across the Eastern Mediterranean and beyond. From its extremely humble origins in the 568 in a malarial lagoon, Venice developed a communal government as well as an adavanced (and state-run) ship manufacturing system which, combined with skillful seamanship, diplomacy, a dedication to business, and occasional military prowess, earned her a durable mercantile empire. This was centered on the India trade, which ran through several routes, such as the silk road, the Byzantine ports, and the Arab caravans. Venice was the home of the Polo family, which famously followed these routes to the ends of the earth.

Symbol of Venice, the winged lion of St. Mark.

In 1204, its power was such that, as a particularly horrific and misguided part of the fourth Crusade, Venice led her allies to attack and sack Constantinople, a theretofore unimaginable feat, given the reputation of its walls and military. This was, for the Eastern Empire, a disaster it never recovered from, after which it limped along till its final defeat under the scimitars of the Turks in 1453. Venice, too, was eventually boxed in by the Ottomans, who in their own prime ran a highly capable fleet and threatened Venice in the Adriatic and even its own lagoon, while relieving it of its Greek and other far-flung possessions.

What finally sent Venice into decline (well before being crushed by Napoleon and then assimilated into the modern state of Italy) was the Northern European revolution in navigation and trade, as the Portugese and then Dutch overtook the India trade directly by way of the horn of Africa. Thereafter, Venice became poorer, and more embroiled on its landward side with the complexities of Italian feudal feuds, including with various Popes.

Through it all, Venice had a remarkable system of government. "Byzantine" doesn't do it justice, as there were ten layers of elections to go through among various bodies before the supreme leader, the Doge (a variant of "Duke"), was elected. Each Doge was constitutionally restricted in his scope of independent action, and also given a specific document of restrictions, usually the fruit of past excesses or corruptions that the community had learned from. The civil service was very efficient, and many times over her history, when Venice found herself in a tight spot, she put out the call for various special taxes, donations, and forced loans, which were typically met with great generosity. Each Doge set an example by distributing vast amounts of his own wealth when elected, and many followed that up with other gifts to the city during their rule and in their bequests. The degree of civic committment at all levels is striking, especially in this day when some parties cry about the most infinitesimal increment of taxation.

At the base of the state was the Grand Council, whose membership of about 1500 was originally elected among the population at large, but by 1296 became hereditary to the Venetian nobility, i.e. the rich. Thereafter, new families were allowed in very sporadically, when the state was under stress, and for large payments, but generally, membership was tightly closed and formed the core of the oligarchy, and the voting base insofar as it was a republic. Various more select bodies such as the ministers to the Doge, the Senate, (sixty members), Zonta (sixty more members), and Venice's own Inquisition / Star chamber / NSC- the Council of Ten- were chosen from this Great Council.

One might note that the early Roman republican system was hardly less complex, and also led to hundreds of years of good, if, again relatively oligarchical, government. Universal sufferage was extremely uncommon in large bodies before modern times, partly for technical and ideological reasons, but also because universal education was equally uncommon. But given an oligarchy, the complexity of these great examples such as Venice seem to reflect relatively little cost, and provide an extensive filter of checks and balances that so frequently succeeded in putting the best people in charge.

The effect of this good governance was to provide durable prosperity and promote human values, even in the midst of terrible times, such as several severe bouts of the plague. Its commitment to great art and architecture was legendary. And while Venice was not an intellectual leader in the Renaissance, its enthusiastic and free printing establishments were the largest in Italy and played a central role in transmitting knowledge from the Byzantine archives to the scholars of Europe. In time of our own when political ideologues dream of drowing their own governments in bathtubs, and refuse to govern countries they themselves have conquered, it is important to remember what a blessing (and a lesson) good government is.

"The more one studies the domestic history of Venice, the more inescapable does the conclusion become: by whatever political standards she is judged, she compares favorably with any nation in Christendom- except, arguably, in the days of her final dotage. Nowhere did men live more happily, nowhere did they enjoy more freedom from fear. The Venetians were fortunate indeed. Disenfranchised they might be; they were never downtrodden. Although, being human, they might occasionally complain of their government, not once in all their history did they ever rise up against it; such few attempts as there were at rebellion were inspired by discontented nobles, never by the populace." 

"Alone of all the states of Catholic Europe, it had never burnt a heretic."

• We need a war on cars.
• "Christians more supportive of torture than non-religious Americans."
• Still some problems in the intersection of race and genetics.
• Investing vs disinvesting, in our environment, in ourselves.
• Just how hosed is the middle class in the US? Part 1.
• Does Obama gain anything by caving to cave dwellers?
• Bill Black #2: Appeals court says insider trading is OK.
• Sony lets the terrorists win.
• Death and youth.

The American dream comes true.