Evolution Sweeps Away Diversity

Natural selection carries off a large portion of neutral genetic diversity in large populations.

One would expect that large populations accumulate much more genetic diversity than small ones, over time. But if you watch those nature shows about herds of wildebeest roving over the Serengeti, it is very hard to see that variation. They behave as one, and look highly similar. Indeed, contrary to naive theory, larger populations tend not to have proportionately more genetic diversity than small ones. Why? The classical equilibrium law of population genetics assumes that larger populations naturally would have more variation, proportional to the number of members and the lengths of their various separate lineages. To balance this out, it also takes longer for any single new mutation to spread through such a population, so the ultimate rate of fixation of new mutations is no faster in large populations that it is in small ones.

"Under the assumptions of the neutral model of molecular evolution, the amount of variation present in a population should be directly proportional to the size of the population. However, this prediction does not tally with real-life observations: levels of genetic diversity are found to be substantially more uniform, even among species with widely differing population sizes, than expected."

But empirically, this expected high level of variation has not been true, even for neutral (unselected) alleles. This difference between theory and reality has been termed a paradox, and a recent paper (review) recounts the arguments above, showing that it is natural selection which constantly clears off accumulated variation, including completely neutral alleles that have no selective effect at all. This paper is not the first to address this whole paradox theoretically, but is the first to give an definitive quantitative solution.

"We show that genomic signature of natural selection is pervasive across most species, and that the amount of linked neutral variation removed by selection correlates with proxies for population size. We propose that pervasive natural selection constrains neutral diversity and provides an explanation for why neutral diversity does not scale as expected with population size."

Comparison of two species, one with large population size (fruit fly, A) and one with very small population size (Przwalski's horse, B). The gray dots are estimates drawn from 500k basepair windows across each genome of the local recombination rate (X axis), which can vary a great deal along chromosomes, and the local level of mutation and variation (Y axis). In a completely neutral theory, these measures should not correlate with each other (red line). The model developed in the paper is shown in the blue lines, where in a large population with lots of selection going on, regions with relatively low recombination show dramatically less variation, consistent with the rare selected mutation in those areas (whether positively or negatively selected) carrying a large number of neutral alleles with them, either to fixation (positive selection) or to their demise.

The issue is one of linkage. Imagine a long chromosome, with lots of genes and mutations. If one of those mutations is bad, then all the other mutations near it will be carried along with the bad one into oblivion, even if they did no harm themselves. The degree of linkage is a matter of the local recombination rate. Some areas of our genome recombine much faster than other areas, and thus allow more fine (selective) separation between nearby mutations, as they end up in different gametes and individuals due to the recombination that happens during meiosis.

So these researchers took a census of multiple genomes from many different species, (63 billion sequencing reads in all), measuring local recombination rates and mutation rates. They found that the bigger the species' population, the more clearly the prediction of correlation between the two measures came out in the data. Thus fruit flies, with a vast natural population, have roughly two-thirds the genetic diversity one would naively expect. The rest seems to have ended up shot down, innocent victims standing a little too close to more deleterious mutations.

In smaller populations, selection is just as fierce, but the level of neutral genetic diversity isn't expected to be as large in the first place, so loss by random drift plays a stronger role than loss as a byproduct of selection.

Humans are an good example. Now we are a huge population, but in genetic terms, we are practically clones compared to most other species. This is mostly because we were a very small population not long ago, and have only reached seven billion in an evolutionary eyeblink. So we have the genetics of a small population. But even in small populations, selection will have this diversity reducing effect, at a lower level. The intense selective evolution we went through over the millions of years prior not only kept populations small, but spread attractive and advantageous features through the population, at the expense of some of the other variation that was lying about.

In a way, this is an explanation for why species remain coherent entities through time. Their genetic diversity doesn't just grow endlessly into genetic chaos, but stays centered, in some abstract sense. Recombination and mating keep the genetic elements of the population continually mixing in a cloud of closely related forms, but it is selection that trims the outliers, both neutral and deleterious, keeping the cloud coherent, even as it also moves the entire cloud in new directions over the evolutionary landscape.

• The progress of inequality. (with graphs). Did supply-side mean 1%-side?
• Some sharp words for those new atheists.
• But people will believe anything. In for a penny, in for a pound with Scientology.
• A hopeful sign towards a more equitable world.
• Theology remains utterly absurd.
• Keynes on inequality, interest, the lower bound, and demand.
• Pay what you wish: the IRS is now toothless.
• "Redistribution", or justice?

RNA, RNA Everywhere

The enhancers that drive transcription are themselves transcribed, in a regulatory process.

The last decade or two have not only brought a genomic revolution in molecular biology, but also remarkable discoveries in RNA, finding micro RNAs, conserved long non-coding RNAs, piRNAs, siRNAs, snoRNAs, and now eRNAs, for enhancer RNA. Even though most of the genome is junk and remains junk, 80% of it is transcribed, so the cell turns out to be a flurry of all sorts of incredibly diverse RNAs beyond the classic molecular biology trinity, which is: mRNA to carry the gene sequence from the DNA, tRNAs that serve as the plug-in adapters between triplets on those mRNA messages and the amino acids they will become in the protein, and the rRNA that forms the body and catalytic core of the ribosome, operating the converyor belt that brings together the first two RNAs to synthesize proteins.

In retrospect, we perhaps should not have been so surprised, since RNA has been there from the most ancient period of life, and the messiness of biology tends to elaborate complexity, using any wrinkle or handle as a regulatory process. But for a couple of decades we were blinded by the preponderant relative mass (and, to be fair, importance) of the RNA trinity in the cell, and only recently have we had the technical means to find the great diversity lurking beneath.

A recent review catalogues the findings and hypotheses about the newest member of this tribe, eRNA, in detail. In eukaryotes, especially as they become more complicated, genes are driven by quite elaborate collections of "enhancers", which are DNA segments typically far upstream, by thousands to hundreds of thousands of base pairs, that bear a cluster of DNA binding sites where regulatory proteins bind, which either turn that gene off or on. One gene may have many separate enhancers, each typically devoted to one phase of development and/or one location in the body where it drives the activity of its target gene.

Schematic of gene control, showing an enhancer (LCR) that has several colored regulatory proteins bound to it. At the same time that it loops through space to contact its target (ßmaj gene), it is also transcribed to short RNAs (red) by RNA polymerase (P). The small discs all over the place are histones (H), which are modified with various colored methyl and acetyl groups in another regulatory process.

Enhancers can do this because they form loops from their distant sites, to contact the start point of their target gene, at what is called the promoter (pictured above as a bold elbow+arrow, when active). This arrangement means that it hardly makes much difference how far away the enhancer is- the proteins it binds can ignore the many kilobases, sometimes hundreds of kilobases, of linear distance in the DNA between themselves and the target gene's start site. But it also means that there needs to be some way to "insulate" one gene and its gaggle of far-off enhancers from those of other genes, which one wouldn't want crossing over into each other's territory and turning each other on. That is a story for another time.

The new and quite paradoxical finding is that enhancers are themselves transcribed, and that these resulting eRNAs are not just accidental junk, but play a significant role in the operation of the enhancer and the regulation of its target gene. As pictured above, (in red), eRNAs come streaming off the enhancer long before the target gene gets turned on. And if those eRNAs are degraded by an experimenter's intervention, typically (and ironically) by programming siRNAs against them, then the target gene turns on much less than otherwise. So it is not just the act of enhancer transcription that is important, though that is thought to have some regulatory effects as well, but the products themselves, at least in some cases.

eRNAs are thought to interact with another level of regulation, which operates through the histones which typically package all eukaryotic DNA. Any protein that binds to a specific site needs to get through this packaging, which can happen in some cases by detecting the DNA on the outside of the histone, or by waiting for a stochastic loosening of the histone from the DNA. But after the pioneer proteins find their sites, they can attract other regulators that specifically modify lysines (K) on the histone with methyl and ethyl groups, neutralizing their charge and lowering their binding affinity to the negatively charged DNA. This process "opens" up the chromatin for other regulatory proteins to bind. The specific lysines that are modified on histones constitute a complex code that marks areas in chromatin for various stages of transcriptional and other activity. The eRNAs have yielded mixed behavior in this pathway, sometimes being required for histone modification at target genes, though not typically at the enhancer region.

Much is still unknown about these eRNAs- how general their occurrence is, how they work, what these little RNAs are doing in the enhancer-promoter complex, and what drives their own transcription. It is like wheels turning within wheels, within wheels- where does the gene activation process ultimately begin?

• Bonus reference on eRNA.
• The NCAA competition is wonderful, but its organization and inequality are not. This should be nationalized.
• Like lots of other things.
• Bibi has a screw loose.
• Yes, religion doesn't make any (rational) sense. And, yes, theological institutions are a farce, educationally.
• In case you were clueless about the NBC saga.
• Pilots are another abused class of worker. No wonder one gets depressed.
• Austerity correlates with recovery ... negatively.
• Open carry? Not at the NRA convention.
• People are instinctively socialist, and fair. Image from the talk, on inquality:

Our Drug War: Ignoring Social Poverty and Exporting Paranoia

How our horrible drug war became everyone's nightmare: Johann Hari on Point of Inquiry.

Unusually, this is a podcast review, rather than a book review. But you never know where something interesting is going to come from. Johann Hari has written a book about the war on drugs- its origins and rationale, and was interviewed on the atheist podcast, Point of Inquiry. The story is remarkable and shocking.

Way back, when the Victorians such as Arthur Conan Doyle were doing cocaine and opium, no one thought to criminalize such drugs. If you wanted to kill yourself, go ahead. But temperance (vs alcohol) set the stage for the criminalization concept, (and its utter failure), in an extreme case of historical irony. As Hari portrays it, the end of prohibition led its leaders and bureaucratic apparatus to look for other ways to retain power and stay occupied. Presto.. the heightened criminalization of heroin and marijuana, which had begun in with the Harrison Narcotics act in 1914. Note that the most addictive drugs of all were left untouched and continue to kill millions of people yearly ... nicotine and alcohol.

There is no question that this is a class-based construction, and Hari cites intense racism as a motivating factor, as the "hard" drugs such as opium, heroin, and marijuana were thought to be favored by the lower classes. Billy Holiday is a big focus of story.

But the irony is that these addictions are not as deterministic as we have been led to believe. Rats as the model organism are brought in to show that while in the original experiments, they certainly preferred drug-laced water to plain water, these were run in bare cages where the rats were bored out of their minds, anxious, unhappy. If the same experiment is run in more normal conditions, in a physically and socially enriched environment, rats do not become addicted. They prefer a real, normal existence to one that is zonked out.

Hari also cites the experience of Switzerland, which has maintained a medical model of drug treatment (which we used to have, before it was taken over by the mania of the drug war). Addicts get their drugs prescribed, take them daily, and go about their lives. They also tend to quit on their own eventually, again preferring reality to a drugged life. It is a very low-stress solution to the problems of addiction. Much lower stress than the warfare that the US has used its leading post-war position to export around the world, severely damaging countries such as Colombia and Mexico in an effort to criminalize and stamp out what clearly can not be stamped out.

But the main issue is one of class and social support. When large swathes of the population are alienated, degraded, discarded, and dehumanized, drug addiction can naturally become a large-scale, scary problem. We would be tempted to treat it with zero tolerance, with mass incarceration, and a world-wide attempt to interdict the offending substances. Yet the problem lies not in the drugs, but in ourselves.

• Organized crime, or organized religion?
• Europe's little ice age may not have happened. But current warming is happening.
• Not every employee at Citi was/is a criminal.
• If corporations are people, they aren't very good people.
• Market failure or government failure? The ideology of monetarism.
• One reason why education will never solve inequality: " the continuing tragedy of adjunctification".
• A glimmer of hope against the neonicotinoids.
• Why does anyone take Putin's nuclear blackmail seriously?

Thomas Piketty: We Are Heading Into a World Where We Do Not Want to Be, Pt 2

I review Piketty's Capital in the 21st Century, second and concluding part.

Thomas Piketty's "Capital in the Twenty-First Century" is the landmark economics book of our time, not because it is especially advanced in an academic sense, but because it situates basic questions of wealth and its distribution within a very long historical perspective, raising questions about where we want to be and go as a society. The profession of economics rose to prominence in the twentieth century, when high growth was the norm and when very significant disruptions happened which had reduced the role of inherited, accumulated capital. This turns out not to be a regime that could go on forever, but rather a very unusual condition that has blinded the profession to other forms of capitalism. Through the longer history, low growth and a very heavy weight of inherited capital, combined with its strongly unequal distribution, was the norm, creating feudal or feudal-like conditions. With the Occupy movement, this realization of where we are headed hit the wider culture, but Piketty provides the data, the in-depth research, the historical perspective, and the prescription for what to do about it.

While one cause of all this inequality was, traditionally, straightforward war and seizure (think of the Norman invasion of Britain), the other reason, and why such inequality becomes so entrenched, is (apart from political and social factors) that capital always commands a price, roughly 5% (typically as land rent, in the old days). So if an economy grows at only 1% or less, which is traditional, and capital returns 5%, then capital will grow continuously, relative to the rest of the economy, in perpetuity. And indeed, the more capital one starts with, the more efficiently it can be managed and the higher return it yields.

It is a bit like a casino where the house always earns 5%. Now imagine that the doors are shut and no one can leave. All the chips eventually find their way to the house, and economic activity winds down to nothing (or solely what the house spends for its own consumption, which may be minimal) due to the immiseration of the gambling masses. If the house makes loans to its customers, this only delays the inevitable, since they those customers will never have the means to repay. In the very old days when kings ruled the land, their generosity was critical for economic functioning. If they spent all their time hording their treasure instead of distributing it, everyone else lived in abject poverty.

The only countervailing factors are disruptions like war and revolution, unusual growth either demographic or technological, or, at the terminus after very high accumulation, a slackening of the return on capital, if there is truly too much of it relative to a slackening economic activity. Marx, incidentally, realized this, and assumed that wealth increases forever, and thus requires a revolution for corrective redistribution. Hopefully we can do better. The irony is that the French revolution, by Piketty's data, did very little to redistribute wealth, even as it did so much to redistribute heads. And the Soviet revolutions revealed the significant importance that private capital does have, even if it tends to become maldistributed over time.

All this was touched on in part 1. Now that capital has recovered in the rich countries since the disruptions of the twentieth century to a roughly normal level of five to eight times annual national income, the process of its concentration is proceeding to create a rentier society where a large aristocracy of wealth controls the economic system. In addition, it bids to control the political system as well, and will inevitably reshape the social system to reflect its dominance. Piketty also points out that such inequality saps the ability of a middle class to exist, exacerbates financial instability, and reduces overall prosperity due to a lack of income among the majority of the population. One only has to compare our current time, or the Belle Epoch of France, (for example as portrayed in the novels of Marcell Proust, whose narrator is endlessly besotted with social climbing up the aristocratic ladder of his day), to the very middle class post-war era in the US to understand this remarkable contrast.

"The history of the progressive tax over the course of the twentieth century suggests that the risk of a drift toward oligarchy is real and gives little reason for optimism about where the United States is headed. Is was war that gave rise to progressive taxation, not the natural consequences of universal sufferage. The experience of France in the Belle Époque proves, if proof were needed, that no hypocrisy is too great when economic and financial elites are obliged to defend their interests- and that includes economists, who currently occupu an enviable place in the US income hierarchy. Some economists have an unfortunate tendency to defend their own private interests while implausibly claiming to champion the general interest. Although data on this are sparse, it also seems that US politicians of both parties are much wealthier than their European counterparts and in a totally different category from the average American, which might explain why they tend to confuse their own private interest with the general interest. Without a radical shock, it seems fairly likely that the current equilibrium will persist for some time. The egalitarian pioneer ideal has faded into oblivion, and the New World may be on the verse of becoming the Old Europe of the twenty-first century's globalized economy."

So, here we are, and it isn't pretty. What does Piketty propose to do about it? He has several axes to grind, actually. But above all he points out the absurdity of living in an epoch of supposedly democratic capitalism, and not knowing who owns what ... not knowing where the money is. We have an income tax that reveals in quite thorough fashion (to the government, at least) what each person's income is. But wealth? That is a completely different story. Piketty has had to piece together his academic wealth data from all sorts of odds and ends, mostly unsatisfactory. He even descends to using the Forbes list of billionaires, hardly a rigorous trove of data. So goal one is basic transparency, so that we, as citizens, can see what is going on.

Second, and drawing his most vituperative comments, are the existence of tax havens like the tiny countries of Europe, Luxembourg, Switzerland, Cyprus, etc., which parasitise on their larger neighbors by relieving them of the taxes of their richest citizens. For us in the US, the Cayman Islands come to mind, home to much of Mitt Romney's wealth. This race to the bottom of financial governance is appalling, and has no place in a just and well-run world.

Third comes the actual aim of mitigating large fortunes so that they do not grow without end to create a parasitic class of rentiers. These aims come together in his proposal of a global annual wealth tax of, say, 1%. It would require reporting and thus transparency. Indeed it would involve reporting directly from the accounts held, much as income is currently reported directly and automatically by the W2 form in the US. It would be global and thus eliminate the possibility of escape, subterfuge, and regulatory competition. And it would be substantial, stemming the natural process of feudalization that is the path we are on, not just in the US, but world-wide.

Over a generation, this tax would be roughly equivalent to a 30% estate tax, which in my view is, frankly, not enough. Piketty does recommend that this tax be progressive, rising to as high as 5% on very large fortunes. But if their return is in the 5-10% range, then their growth will only be slowed, not stemmed. The very idea that priviliged children get not only their genes from their parents, and a lifetime of educational and social advantages, but also enormous piles of money, is abhorrent as well as wasteful. If they are so talented by way of their natural advantages, why should they, of all people, not benefit society by working? As a society, our interest is in harnessing the talents of everyone to the fullest extent. Allowing substantial wealth inheritance flies completely against this principle, and isn't very healthy for the recipients of such largesse, either. As a "rights" issue, the rights of the parent to bequeth as he or she sees fit should not extend to the right of children to come into enormous estates just because they happen to be born to Thistlewaite and Ambrosia Moneybags. Society at large needs to come in between to restore some semblence of justice here. It is the epitome of what used to be called "unearned income".

"In other words, Liliane Bettencourt, who never worked a day in her life, saw her fortune grow exactly as fast as that of Bill Gates, the high-tech pioneer, whose wealth has incidentally continued to grow just a rapidly since he stopped working. Once a fortune is established, the capital grows according to a dynamic of its own, and it can continue to grow at a rapid pace for decades simply because of its size. ... Money tends to reproduce itself."

Along the way, Piketty devotes a brief chapter to the public debt crisis. As an MMT acolyte, I am not sure why he regards it as a crisis, (apart from Europe, where the confused system of not-really-sovereign debt truly is in crisis), or why paying it off is seen as good, or what point there is in calculating the net wealth position of the public sector. (Which is zero:  public assets are typically balanced by public debt). Since it prints the currency and manages the entire monetary as well as military and taxation system, the wealth of a truly sovereign state is effectively (potentially) infinite, depending only on our collective desires and productivity. Piketty's biggest beef is that the public is obliged to pay its public bondholders interest in perpetuity- money that could be better spent elsewhere, like on education- and that the rich should be paying this money in taxes rather than lending in return for continual income. Which is a fair point. He offers that a one-time wealth tax of roughly 15% would suffice to eliminate public debt entirely. Not a bad thing, I am sure, but hardly the most important policy need, other than in Europe. I guess the basic issue is whether the interest paid on public bonds is onerous or not. It has been an extra burden during the time when inflation was winding down from the high of the seventies, involving a bonus payment for inflation risk, and monetary lag. But now, with rates roughly at zero, and probably destined to remain at the inflation level for a long time to come, the net burden for truly sovereign debt seems to be relatively low.

Piketty secondly promotes the idea of higher taxes on income at the highest brackets, going back to roughly 80%. He spends quite a bit of space demonstrating that the wealth divergence in the US owes more, as yet, to the amazing income of high-level executives than to the build-up of "old money". Old money will surely come as a maturing vintage, as it has in France. These super-high incomes are not due to the super-talented artists, athletes, and inventors. No, it is (95%) the suited class of high-level corporate managers, by far: people Piketty terms "super-managers". Not because they manage particularly well- the data shows conclusively that that is not the case. But "super" from how much corporate wages and profits they have been able to capture, out from under the noses of workers on one side, and shareholders on the other. And one proven way to discourage such greed - perhaps better called embezzlement - is to place confiscatory tax rates on excessively high incomes.

It goes without saying, of course, that unearned income such as dividends, interest, and capital gains, should be taxed at least as high, if not higher, than labor income. How we all got bamboozzled by the Reagan era's pro-capital ideology (double-taxation! entrepreneurialism!) is frankly hard to understand. (Piketty engages in a subtle discussion of the point of corporate income taxation while dividends and capital gains are simultaneously taxed.) When all is said and done, the Piketty program would thoroughly undo the "Reagan Revolution" of greed, which led as surely as night follows day to the inequality, the high indebtedness, the corporate short-term-ism, the lower-class misery, the public poverty, and the financial instability we see today. The question is whether our politics have already been so captured by the 1% that Piketty's program is as impossible as the entire commentariat seems to think. Stranger things have happened, in the US, not so long ago.

• Piketty on student debt. Another mechanism of class war.
• Piketty on Piketty.
• There's nothing quite like the death tax.
• Krugman on recent GOP budgets, involving trillion dollar asterisks: "Think about what these budgets would do if you ignore the mysterious trillions in unspecified spending cuts and revenue enhancements. What you’re left with is huge transfers of income from the poor and the working class, who would see severe benefit cuts, to the rich, who would see big tax cuts. And the simplest way to understand these budgets is surely to suppose that they are intended to do what they would, in fact, actually do: make the rich richer and ordinary families poorer."
• GOP, right on cue ... let's eliminate capital gains taxes!
• The media landscape of modern authoritarianism.
• We evidently have too much oil for our own good, let alone coal.
• Burned on both ends.. the real cost of coal.
• Defects in market capitalism, continued ... hospitals.
• We know it's fake, but do theology anyhow.
• Maybe the norms in housing and mortgage lending got out of hand.
• Let your people go!

Thomas Piketty: We Are Heading Into a World Where We Do Not Want to Be

I review Piketty's Capital in the 21st Century. Part 1

The tome of the (new) century turned out to be a surprisingly easy read. Perhaps Piketty pulls his punches, and dumbed the subject down a bit. He certainly has tried hard to make his arguments accessible, never tiring of citing Balzac and Jane Austin. His book is pleasantly clear and rewarding to attentive reading.

The Wall Street Journal sneers at the "redistributionists" among us, who are ready to steal the hard-earned wealth of the gifted and talented, pissing it to the wind of the poor who will always be with us. But that obviously assumes a few things about both the rich and the poor. Piketty's project is to map the evolution of wealth (and, to a lesser extent, income) over the last few centuries and across as much of the world as provides decipherable data. He makes many points, but perhaps the most significant is that over the vast majority of time, (which includes the past and future), wealth tends to be extremely unequally held, and is gained through inheritance and passive investment, not through boot-strap pulling, stick-to-it-tiveness, disruptive innovation, or other bromides of the comfortable set.

No, feudalism is the norm, and if we don't want a feudal society, (means of production being, in good Marxian terms, the template of social relations), we will have to do something positive about it. The mid-twentieth century was, in Piketty's analysis, an extremely rare time- something we look back on as a golden age that escaped this default feudalism, for several reasons. First was war and pillage, which obviously destroyed much of the wealth that had been built up over the guilded age, Belle Époch, and prior generations. Second was rapid population growth, which naturally increased the economic pie and diluted fortunes. Third is economic growth via technological advancement, which was truly astonishing through this time, and had the same effect of diluting old money with new. And last was war and rapine again, by way of the communal spirit it instilled, which inspired and justified remarkably progressive rates of taxation.

Piketty shows that during this unusual period, work was strongly rewarded, since even at the highest levels of wealth, (1%, 0.1%), it was labor income that was the principal source of income, rather than capital income. It takes generations for levels of wealth to rise from such a catastrophe back to the amount (of about eight times annual national income) that characterizes most societies, and is starting to characterize ours once again. Now, in these leading demographics of the 1% and above, which used to be termed the aristocracy, inheritance is becoming once again a more important source of income than labor. Incidentally, one might note the perspective this casts on the minority and especially black experience in America, which is one of perpetual oppression, especially economic, also generations in the making, which will take generations to remedy.

The structural reasons that Piketty supplies are relentless. Since capital tends to earn very regular returns, of about 5%, and still does, even with the vast amounts of capital floating around, thanks to the great elasticity of capital / labor subsitution in our age; and since economic and demographic growth are returning to more normal levels of about 1-2%, capital will always grow during normal periods.

There has always been some perplexity about what to do about this structural dominance of capital. Indeed, this book gave me a clearer understanding of the ancient antipathy towards usury:

Rent is not an imperfection in the  market: it is rather the consequence of a "pure and perfect" market for capital, as economists understand it: a capital market in which each owner of capital, including the least capable of heirs, can obtain the highest possible yield on the more diversified portfolio that can be assembled in the national or global economy. To be sure, there is something astonishing about the notion that capital fields rent, or income that the owner of capital obtains without working. there is something in this notion that is an affront to common sense and that had in fact perturbed many number of civilizations, which have responded in various ways, not always benign, ranging from the prohibition of usury to Soviet-style communism.

He also notes that in Victorian times, the rich at least didn't hide behind the fig leaf of meritocracy as they do now in a blame-the-victim ideology (job creators!, Steve Jobs!). No, they scrambled for good marriages and rich inheritances with hardly a look back at the immiserated masses or any "duty" to economic or social utility. But I would counter that the ideology of nobility and blood was even more pernicious than that of capitalist meritocracy.

Secondly, there are strong economies of scale to capital which Piketty illustrates using American university endowments. The biggest endowments like Harvard use professional managers and complex strategies for hedging, diversification, and finding unusually lucrative investments. And they make roughly double the return (~10%) as the smallest endowments, which afford virtually no money for management and make do with typical mutual fund returns of 5-6%. Thus inequality grows over time, as the bigger fortunes lose significantly less both to investment mediocrity as well as to consumption.

In addition to the purely structural reasons why, barring catastrophe or specific policy, capital tends to grow and inequality tends to grow along with it, the social pattern follows the pattern of production (or non-production in this case) to also favor capital. The Reagan revolution dramatically lowered rates of taxation, which are now, over most of the country in comprehensive terms, not progressive at all. Estate taxes have been lowered, and managers and financiers been unleashed to prey on working people who thought, for instance, that they were actually buying houses.

But what is the problem with all this anyhow? If some people save while others spend their way to the poor house, shouldn't each get her just reward? One problem is that these rewards take many generations to fully accrue, and it is simply impossible to justify the wealth of those who had no role in building it, even granting for the sake of argument that it was accrued in some virtuous fashion originally. A second problem is about the value of work in the society. If we have a class of essentially parasites who live off of capital, who are in addition the leading demographic of the whole society, that leads to the devaluation of labor and effort. It is not just that the talents of these people (whatever those might be) are lost to the common weal, but that their pinacle position, infects the society generally with an ethic of class over utility.

Returning to the mid-twentieth century, growth rates were extremely high, the social ethos was egalitarian and public-spirited, an historically unique middle class took hold, and the top tax bracket in the US was near 90%. Were companies managed better then, or now? I think they were managed better then, with a more balanced sense of stakeholders, and less intense focus on the short-term stock price. Certainly, US companies did very well in those days, without paying their managers obscenely. And this was a conscious social policy borne of the Depression, war, and slightly left-tinged social consciousness of the day- that extremely high pay to managers was obscene and economically counter-productive, thus should be strongly discouraged by way of confiscatory taxes. High tax rates also applied to estates, with no obvious detriment to our way of life. Equality turns out to be good economic as well as social policy.

But the causes, other than progressivism, were highly unusual conditions, (Depression, war), not ones that we want to see again. And sure enough, we are headed into what Piketty shows are historically normal conditions, where the top 10% own 70% of all wealth, the top 1% own 35 to 50%, and the bottom 50% own nothing. Someone like Bill Gates can't possibly spend his fortune, and seems to be unable to give it away fast enough. It just grows and grows, gobbling up more shares of global income and wealth. Were he interested in politics, we would have a very serious problem on our hands.

Next week, we will continue, considering Piketty's recommendations of what to do about it.

• More ways to blame the victim, and avoid the real work of redistribution.
• Most (good) governments do more redistribution than we do.
• Rent and position in the corporation.
• Inequality is corrosive, even morally obnoxious.
• Monetary ideology and class war, continued. Continued...
• ... Mixed with southern revanchism, continued.
• Active government is the key to development.
• But should regulators be for sale?
• Not only is governance a significant void (or free-for-all) in Islam, so is any definitive interpretation of Sharia more generally, for fear of supplanting Muhammed.
• Economic image of the week: The art formerly called currency in Zimbabwe.

Power, Glory, and Terror

Why all the terror, and why is religion involved?

What drives the Jihadists? It is a little hard to imagine, viewed from the comfortable vantage of the West, where the most salient issues tend to be the next iPhone or Playstation model rather than the pursuit of totalitarian power, let alone a stringent image of the deity. (Which is to say, taking for granted the overwhelming power of the West in virtually all aspects of modernity.) The package of power and religion is a heady one, however, and picking it apart from such a vast cultural distance is both difficult and essential, since we are mired in the fight.

The ideal Muslim society is a blend of piety and power, with Muslims in charge, but not through what we in the modern West would recognize as organized or legitimate means. Meetings of elders might result in the election of a leader, but just as valid is the taking of power by force. It is hard to remember, but in the West as well, holy warfare was common, and torture, in trials by fire, boiling, etc., justified by the theology of favor. The king has God's favor as long as he is popular and powerful, for instance. Enormous effort was devoted to methods of augury, but results would always speak loudest. It is a peculiar conflation of Darwinian fitness and theism. But the element of spiritual force (or communal psychology) is not to be denied. Those with deep commitment, even unshakable faith in their cause and in their talents, are vastly more powerful than those with mere technology.

One source of spiritual force might be culturally accepted forms of divination, augury and the like, providing some tentative positive thoughts. But another source is straight out bigotry by way of belief that one's scriptures are perfect, one's race pure, one's religion true, and one's enemies evil. Tribalism is not exclusively the province of religion, but religion tends to be the most powerful binder of groups, at least on par with nation states and soccer teams. All else pales before the transcendent purposes of the universe.

But why all the terror? That is what is most striking about today's jihadists, their method of projecting power through unspeakable cruelty, not to mention lovingly tended web sites and advanced video techniques. In the West, we have just gone through an extensive mea culpa / handwringing about torturing a few of those who have terrorized us (or, by our incompetence, who are innocent). We think it is bad, but clearly others have fewer qualms, notwithstanding their own propaganda using our practices of torture to paint us as unspeakable villains. They know it is bad, but that doesn't stop them from beheading and raping and pillaging. What exactly is going on?

It looks very much like our qualms are being turned against us. We have nuclear bombs after all, and could dispose of the problem very easily, were our morals sufficiently lax. If one is insulated against what might be called weakness, i.e. moral qualms that rise as one's level of civilization, empathy, and responsibility rise  ... by way of, say an ideology that tells one with absolute certainty that one is good even while one is doing evil acts... why then one can win the race to the moral bottom, and bend innocents to one's will, gathering power of the basest kind.

Power, in the form of coercing others to do what you tell them, on pain of death or harm, is the most execrable level of social relations, which grade upward through respectful competition, tolerance, self-interested cooperation, communal cooperation, and love. Why anyone would consider mixing a putatively great religion with such evil moral practices (outside of self-defense) is a significant question. One answer is that the scripture and early history of Islam in particular is no stranger to violence and terrorism. Unbelievers are terrorized on every page with visions of hell, discrimination, and ultimately, direct violence from believers.

Does this mitigate the attraction of the doctrine? Evidently not. That is what is so curious. Power is itself attractive. We record the history of the powerful, and forget all others. It hardly matters how cruel and blood-soaked the reign, the top cultural rungs are occupied by those who succeeded most thoroughly in terrorizing their friends and enemies- Genghis Khan, Alexander the Great, Napoleon, etc. and so forth. If Hitler had won, doubtless the same would have happened. His terror was evidently not thorough enough. The Darwinian logic of all this is depressingly clear- that power is its own reward and rationale.. nothing succeeds like success. Other societies like Rome and the Jim Crow South used terror as a regular feature of power within the social order. One might say this of most societies, really. Terror goes hand in hand with the enforcement of social order- even among us with our amazing rate of brutal incarceration, and our large and desperate homeless population.

Another answer is that practically any situation can be constructed as self-defense. We have to bomb people in far-away lands because of their destabilizing influence on the general world order, which we as the dominant power are committed to uphold. That is a bit of a weak rationale, but at least somewhat more reasoned than that of "homeland protection", which is entirely beside the point in our current engagements. For Muslims, their abject loss of cultural dominance vs the West is in itself an affront that constitutes victimization and justifies violent defensive measures. The influences of the West are infiltrating everywhere, in communications, in depraved art, in philosophical skepticism, and most horrifyingly, in women's rights. Where will it ever end?

Terror is then a natural method of force projection, multiplying influence when "normal" means of mass killing are not available, and "normal" status quo-supporting ideological constructs are not desirable or sufficient. Its rationalization by way of total-izing ideologies or self-defense is all too easy. But in a revolutionary context like the current Jihadist campaign, it also has very limited scope. Shock (and its attendant demoralization) only lasts so long, and soon this demonstration of ruthless dedication (and localized power) calls forth revulsion and regular military power from among its opponents, both inside and outside the Muslim world, if they have courage and their own ideological resources.

• Saudis spawned the purer forms ... ISIS.
• Al Qaeda negotiated regularly with Pakistan: "God is with us".
• God sure is a great therapist. But "is" it?
• GOP clown posse and the Ayatollahs... brothers from another mother?
• Re-segregation is in full swing in the schools. Private schools need to be abolished.
• This week in the WSJ, "There’s no need for the FCC to override the free-market agreements that make the Internet work so well."
• Genetics of savings propensity.
• Piketty on the Euro: "It can't work."
• On the institutional politics of capital, feudalism, slavery, etc. And the case for taxation.
• Wingnuts vs Obamacare: be careful what you wish for.
• The unique logic of Keystone: Give us that pipeline or we start blowing up cities.
• Dividend tax cut causes zero increase in investment.
• Homelessness.
• "... prison is a penalty that cannot be reimbursed by the corporate employer."
• Alice Rivlin on fighting the last (monetary) war.
• Economics graph of the week, on Federal social spending:

Brain Waves and Thought: Correlation or Causation?

A few studies start to use interventions to figure out what that symphony in the head is doing.

Electrical brain oscillations (waves) have been observed for over a hundred years, but it has been hard to pin down what they do. It has been extremely attractive to hypothesize that they knit together various areas of the brain in cognitive coalitions. The brain hosts a great deal of resting activity, and by this kind of theory, it is typically disorganized. The long-range rhythmic harmonization of various areas could form integrated cognition out of all this noise, both conducting information and linking it together, thus solving the binding problem in an elegant way that accords with the speed and spontenaity thought.

"Recently, it has become evident that these brain rhythms are not just a generic sign of the brain-at-work, but actually reflect a highly flexible mechanism for information encoding and transfer. In particular, it has been suggested that oscillatory synchronization between different areas of the cortex underlies the establishment of task-relevant networks."

But how can we tell whether all this is actually going on? Brain scanning can say what is active and when, to a rough degree, so we can trace a long train of activities that follow, say, the presentation of a face to someone's vision. But we can not see what is contained in those oscillations- the code remains rather secret. There are also many different oscillations, doing quite different things. Sleep involves some very heavy-duty slow waves, muscle coordination seems to involve medium frequency waves, as does restful but inattentive wakefulness, while the cognition-related hypotheses above generally invoke the higher frequency gamma waves.

Experimenters have started doing intervention studies that try to get beyond the correlation conundrum by actively manipulating electrical activity in the brain. Obviously, this is quite difficult to do. In rare instances, people are getting electrodes implanted in their brains for other reasons like treatment for epilepsy or Parkinson's, and allow limited research as a side project. The other option is to use transcranial magnetic fields or electrical stimulation, (shades of Frankenstein!), which are obviously rather gross interventions with little ability to focus effects to defined volumes inside the brain. Thankfully, however, some of the interesting activity of the brain happens close to the surface / skull.

The current researchers (review) use "transcranial alternating current stimulation", or tACS, which is pretty much putting current directly through the head with electrodes, presumably at low levels. They ask whether such stimulation, with its alternating current timed either in synchrony with the endogenous gamma rhythm (40 Hz), or against it, can alter a subject's perception according to the theory that brain oscillations constitute the cognitive binding of disparate brain regions.

Schematic of experiments. The visual area is in the rear of the brain.  Subjects were shown ambiguous dot designs that are interpreted as horizontal motion half the time. Then they were given direct electrical stimulation with electrodes at the back of the head, either in phase or out of phase with the endogenous gamma rhythm.

The perception they decide to use is visual motion, which has been correlated with gamma oscillation coherence between the right and left visual areas of the brain. An ambiguous motion on a screen can be interpreted as either vertical or horizontal motion, roughly half the time each. The subject is asked which one it is, and this reflects more about the state of their brain than it does about the visual stimulus. Some increased amount of coherence of gamma oscillations is known to correlate especially with (subjective) horizontal motion, intriguingly enough, and the researchers track that through their own subjects.

Then they apply the jumper cables. "A sinusoidally alternating current of 1,000 µA (peak-to-peak) was applied at 40 Hz continuously for 20 minutes during each session." What they found was that the perceived motion could be slightly, but significantly, shifted in the expected direction if brain oscillations are causally important to cognition. When applied in phase with the subject's endogenous cross-brain rhythm, subjective horizontal motion increased, while when it was applied out of phase, thus decreasing the cross-brain coherence, subjective horizontal motion decreased.

The result, that perception of motion is affected by the phase of the applied current.

Incidentally, the applied current causes slight but measurable change to the gamma coherence between the rear visual areas.

A couple of other papers use open-brain studies to reach the same conclusion, for other aspects of cognition:

"We found increases in high gamma (HG) power (70–250 Hz) time-locked to trial onset that remained elevated throughout the attentional allocation period over frontal, parietal, and visual areas. These HG power increases were modulated by the phase of the ongoing delta/theta (2–5 Hz) oscillation during attentional allocation. Critically, we found that the strength of this delta/theta phase-HG amplitude coupling predicted reaction times to detected targets on a trial-by-trial basis. These results highlight the role of delta/theta phase-HG amplitude coupling as a mechanism for sub-second facilitation and coordination within human fronto-parietal cortex that is guided by momentary attentional demands."

"Neocortical-ATN theta oscillatory phase synchrony of local field potentials and neocortical-theta-to-ATN-gamma cross-frequency coupling during presentation of complex photographic scenes predicted later memory for the scenes, demonstrating a key role for the ATN in human memory encoding."

So the role of high-frequency brain oscillations looks increasingly secure as a mode of information transfer, binding and management within the brain. Whether this phenomenon also constitutes conscious perception, forming the thoughts whose contents and sources are so disparate and wide-spread through the brain and body will be the next enormous question to tackle.

• What's up with the enlightenment, and the party of postmodernism and the ID?
• Too much of a good thing: people.
• What's so bad about inequality?
• Wingnut: Yes, I am a terrorist. And yup, I still want my guns. By the way, Christianity is true, Islam is a fairy tale.
• Rules, bureaucracy, freedom.
• "Several [studies] find that liberals score higher than conservatives on the need for cognition, which captures the individual’s chronic tendency to enjoy effortful forms of thinking."
• Judges caught taking millions to send children to private jails. Banks happy to do the money laundering.
• Lying ... pays extremely well.
• Worker's comp- another victim of class warfare.
• Grumpy bashes the US internet industry.
• Can one person drain a swamp of corruption?
• Can one person drain the world of hokum, lies, and magical thinking?

Epic Genetics

Lineage, nobility, destiny in the Shahnameh

Traditionally, people have had great respect for genetics. Traits run in families, and every culture has had its class system of assortive mating that segregated the nobility from the other classes down the line to peasants. The modern world is unusual in its insistence on equality and democracy, which arose when the old nobility system had so absurdly overreached its original justification (if indeed there was any) and put such mediocre people at the head of affairs that the whole thing naturally collapsed. Now we value diversity and, to put it in genetic terms, hybrid vigor over pure blood lines. Echos still resound at the Westminster Kennel club, but for humans, purity seems out.

As recently as in the novels of Marcel Proust, the importance of lineage is paramount, as endless pages go by of the narrator besotting himself over the faded charms of count this, baron that, or princesse whatever. The class system has had a long, lingering death in Europe. Here in the US, we are re-inventing class relations on a business model, which is a thinly veiled feudalism with lords of the manor in suits, whose most successful exemplars shine forth in all their condescension in the foundational funding announcements on NPR, not to mention running the political system by buying all that "free" speech.

But at least they don't (to my knowledge) have harems of women to flood the next generation with. Bill Gates has not (yet) devised a way to clone himself into shrink-wrapped copies with which to win the genetic race for the future.

But the rulers of old certainly did. I have been reading the Shahnameh, which is the lengthy epic of Persia, recounting the reigns of its Kings from the mythical to the Muslim conquest. The themes of linage are a constant refrain, telling how handsome, strong, wise, and just each prince and king in turn is. How beautiful and modest the women in his harem. One infant is even sent down the Tigris in a box and raised by humble peasants, only, Harry Potter-like, to instinctively take up fighting, horse riding, and other knightly pursuits in defiance of his guardian and in clear sign of his royal lineage.

It really is one of our oldest and most perennial themes- the Cindarella or foundling-prince in the rough, not only recognized eventually by merit, but documented to have royal blood all along. But obviously, the actual differences are typically vanishingly small, when education and culture are accounted for. But we focus and thrive on minor differences, defining (and "othering") tribal groups in arbitrary ways, and judging each other with the greatest subtlety in the race for status and mates. The fiercest battles are typically of brother against brother; French and German, Russian and Ukrainian, Jewish and Arab, and so on.

What did all this harem-keeping and status seeking accomplish, anyhow? Well, beauty was one object, duly attained, I think. Each nationality has its distinctive look of nobility, from Japan to England. But in terms of temperament, I think much less was accomplished, indeed negative results were attained. The most successful leaders were typically mad with ambition, so we have ended up with a lot of Shakesperean plots and palace intrigue at the head of affairs. No wonder the good king was such a rare and precious find! Power may corrupt, but assortive mating can corrupt as well, when the standards for selection are so contrary to what societies most need. And when taken to extremes of inbreeding, as in Egypt and Europe, the results have been disastrous on any level one cares to consider.

Thus the madness for lineage accomplished far more in terms of public relations than it ever did in genetics. The PR value of the Shahnameh was inestimable, training generations of Iranians in the celebrity culture of their day and thus stabilizing the feudal hierarchy / patriarchy. While the overall competition for status and success has probably been an engine for beneficial genetic selection, its manifestation at the very top of the hierarchy is another story entirely.

• On Ashkenazi genetics.
• Those damn Anglo-Saxons.
• ... became the arch capitalists of modernity.
• What you inherit is luck anyhow.
• Religion- an ongoing problem. Just because something gives you meaning doesn't mean that it is right.
• A lot of uncomfortable dancing around texts of terror, and not facing up to them at all.
• Integrated fiscal / monetary policy just makes sense.
• What does education do to you?
• No austerity over there ... China to be the new world hub.
• Then I dreamed about god.
• Only in banking ... bonus handed out for criminal activity, prompts use of "transparent" tax havens.
• Inequality due to cronyism and rent collection, not from education, productivity, or justice. " ... all the big gains are going to a tiny group of individuals holding strategic positions in corporate suites or astride the crossroads of finance."
• Bob Cringely on the jobs shortage and the STEM non-shortage. But he doesn't wade into macroeconomics. "Same for the banking and mortgage crisis of 2008 where the bankers took more and more until the host they were sucking dry — the American homeowner — could no longer both pay and survive. Tony Soprano was smarter than the bankers."
• Things just keep getting worse for active stock pickers and personal wealth parasites.
• Staying at optimal growth and prosperity is hard.

Where Does it Hurt?

The mystifying cognitive biology of pain.

Pain is perhaps the bedrock of consciousness. If we want to know we are awake, we pinch ourselves. And torture is the use of inflicted, involuntary consciousness of pain against the person's higher faculties, interests, and desires. Before there was cogito ergo sum, there was morsus ergo sum. But that hasn't made pain any easier to locate and analyze as an activity of the brain and greater nervous system. There is no "pain center" in the brain, for instance.

But the brain is central to pain. Sure, we have local reflexes that respond involuntarily and unconsciously. But if pain is consciously experienced, it comes through the brain, no matter how far away in the toes it might be mapped. It is remarkable, indeed, that our brain can tell us to feel something in our toes based on signals that the toe sends from several feet away. For all our complex knowledge of the pain receptors and their circuitry on the way to the brain, the conscious experience remains mysterious.

The best approximation to date is something called a "neurologic pain signature" (NPS), which comes from neuro-imaging and consists of a variety of locations in the brain that associate specifically with the most immediate experience of pain. It is not a point, but a large network of activities and locations, all of which are often involved in other things as well. Just like consciousness in general, there is no little incubus in there, but a specific pattern of activity, that must be the experience of pain.

A recent paper and review about our ability to manipulate our pain experience through distraction, placebo effects, and other high-level cognitive mechanisms outlined these issues. The paper basically divides the pain system into two parts- a basic reception part that gets signals from the body, (and corresponds to the NPS mentioned above), and a cognitive part that happens when those signals hit yet other parts of the brain, especially in the frontal system. This latter part, which can be engaged successfully to dampen a subject's pain experience, upon appropriate instruction, had big effects on the subjective experience of pain, but no effect on the activity of the NPS, as observed in brain scans.

"This means that whatever information is used in the NPS decoding, it doesn't simply represent the subjective experience of pain. Instead, the authors found that the influence of modulation is reflected in different brain regions—notably the nucleus accumbens and ventromedial prefrontal cortex (in brief, greater activity reflects less pain)."

"Thus, our NAc-vmPFC [frontal area] pathway findings may reflect evaluative processes that play an important role in the construction of pain experience and in shaping long-term motivated behaviors and outcomes."

Diagram from the paper, showing the subjective pain ratings (left, bottom) compared to the neurologic pain signature by brain scanning (right, bottom). Subjective ratings were modestly affected by conscious training. Part A shows the overall schematic, that the NPS, a brain core network, doesn't budge when one tries to consciously either dampen to increase the pain, while certain locations in the frontal areas (blue) are more active when trying to dampen the subjective pain experience.

So subjective pain is something else again, not really the NPS alone, though clearly derived from it somehow. Are these small frontal areas that light up caused by the effort involved in modulating the pain, or are they more directly associated with the subjective pain itself? Likely the former. The brain is full of mechanisms to shut out distracting stimuli, since only a small portion of all the sensory modes and data coming in ever make it to consciousness. The frontal areas are frequently a big part of this filtering and habituating process. Thus the NPS may still constitute pain consciousness, whose access or presentation is regulated, much as vision or hearing is regulated, by other parts of the brain in a (slightly) top-down way.

• Mortgage fraud and Gresham's dynamics, cont. (Notes on Gresham's law.)
• Star trek, welfare, motivation, and work.
• Ideology precedes scientology, so to speak.
• The state of bank reserves.
• Conditions in Afghanistan remain violent.
• Meanwhile we have our own terrorists and insurrectionists.
• One micro-RNA wins the battle against cancer.
• A seminar on the formidable and diverse genetics of autism.

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.