Saturday, September 28, 2013

Protein shimmy & shake

Hemoglobin is a complicated puzzle, not just a carrier of oxygen.

Hemoglobin- the stuff of love and horror, cupid's arrows and Dracula's lust.. what makes it tick? What even makes it red? It certainly isn't the protein. 16,000 daltons of clear protein carry a clear ~700 dalton heme group, whose iron, neatly caged in the middle, only absorbs green to blue light strongly when bound to oxygen. So a very small, if critically important, bit of the protein complex is responsible for all of its color. A bit like the heart being responsible for all of our love.

But the encasing protein does a lot more than just lug the heme ring and its iron around. It is responsible for a few special effects that make our breathing more efficient. These are called allosteric effects, for the way miscellaneous molecules can reshape or regulate a protein, especially its binding of other molecules. One is the Bohr effect, where CO2 (and acidity in general) regulates the oxygen affinity of hemoglobin. In the high CO2 / elevated acid environment of the peripheral tissues, oxygen affinity is reduced, while in the more neutral environment of the lungs, it is raised, appropriately enough.

Another is the cooperativity of the hemoglobin tetramer. Binding one oxygen increases the affinity of the other (and quite distant) three sites for oxygen, again helping speed the process of loading and unloading oxygen in the appropriate places. And a third is the Haldane effect, where, conversely to oxygen, the binding of CO2 is increased in the acidic environment of the periphery. CO2 doesn't bind to the central iron-heme site, but elsewhere on the protein molecule, facilitated by several acid-sensitive histidines.

Fourth is the action of carbon monoxide, which is not really allosteric, but simply competitive, binding 200 times better than oxygen to the central iron binding site, and thereby shutting it down completely, suffocating the victim. The encasing protein of course has other functions as well, and we see one in sickle cell anemia, where the normally cleanly separated tetramers that float around in the red blood cell at very high concentration (35 grams per 100g of packed red blood cells) start to gum up and aggregate due to a single point mutation, (when present in both genetic copies), leading to misshapen red blood cells, and all the other morbidities of this disease.

While most of this molecular intricacy is understood in rough terms, researchers are still nailing down details, and a recent paper used novel statistics and molecular modelling to tease out some more of them. Hemoglobin could be thought of having two stable shapes, called T (tense, with low oxygen affinity, high CO2 affinity), and R (relaxed, with high oxygen affinity, low CO2 affinity). The issue is that in the tetrameric hemoglobin complex of two alpha chains and two beta chains, binding one oxygen in the T state nudges not just its own unit of the tetramer, but all four, toward the R state.

Obviously this requires some complicated transmission mechanism, and that remains the subject of research, including this one. Here is a picture: 
Animation of a hemoglobin tetramer shape changes, focusing on one subunit (reddish) and especially its heme group as it binds O2 (teal).
The researchers tried to break down all the motions of the protein chains into two categories- those that change the relative positions of the four subunits, (quaternary), and those that only affect the internal shape of one subunit, (tertiary), without jutting out to affect the others. This was done with computer simulations based on the many known structures of this protein. Hemoglobin was naturally one of the first protein structures ever solved at the atomic level.

What they found was that they could statistically boil down each of these two classes of shape change into one main value (a principal component). Then the question was how these values and detailed motions relate to each other as the major transition goes along from state to the other. One aspect of the internal (tertiary) motions were clearly correlated to the inter-subunit repositioning, and so could be taken to be part of the allosteric mechanism by which one subunit communicates its binding of oxygen to the others. Much of this analysis is unfortunately cloaked on mathematical abstrusities, ensembles, hyperplanes, etc., so I can neither evaluate it nor fully present it.

They decide that they can differentiate between individual "pushing" and "pulling" contacts between subunits, which significantly channel the interaction. The whole story begins with the binding of oxygen, which pushes away protein arms that reach towards the central heme, and also induces that heme to bend from a bent, to a flat, planar shape:

Edge-on view of hemoglobin heme complex, bent without bound O2, and flat when O2 binds, along with a few other local rearrangements.

Table of dynamic contacts within and between hemoglobin subunits that stretch or switch as oxygen binds and the shape changes from R to T. The amino acids are referred to by single letter codes.

A pushing contact ...
 "A clear example for this is the interaction of lysine 82 of beta 1 and lysine 82 of beta 2 we observed: Close to the T-state both side chains are pointing into the solvent. While moving along cQ [the quaternary-only axis], the two chains approach each other and bring both positively charged side chains unfavourably close. The motion along cTew [the tertiary-only axis] relaxes this repulsive interaction by bending the N-terminal ends of the F helices (the helix notation goes back to Watson, Kendrew and Perutz [16]). Experimental studies introduced cross-links between the two lysines [17], [18]. The derived structure was described to be an intermediate between T- and R-state with characteristics of both states but no cooperativity."

 A pulling contact ...
 "These contacts only stay intact if the system moves along cQ [the quaternary-only axis] and cTew [the tertiary-only axis] together, but break if moving in one or the other direction independently. This is the expected behaviour for contacts which must remain intact for the allosteric mechanism to function. Exemplarily, this was observed for phenylalanine 117 of the alpha subunits and argenine 30 of the beta subunits. The hydrogen bond between the carboxylic oxygen of Phe and the side chain of Arg breaks while moving from the T-state towards the off-diagonal intermediate artificial states (see Figure 3), and forms again when approaching the R-state." 

 Which is to say that the contact stays intact during the actual transition, but was broken here in virtual model terms as the experimenters pursued one or the other of their axes (tertiary or quaternary) alone. It is a sign that this contact helps keep things together in a smooth and concerted fashion as the protein starts to change shape on one side.

A more dramatic type of contact is one that switches during the transition. In the alpha-beta interface, (shown below), contact between apartate 94 on the alpha subunit and tryptophan 37 on the beta subunit (in the T state) is broken and the tryptophan 37 switches to contact asparagine 102 on the beta subunit in the R state. These kinds of distinct shifts help stabilize each of the quasi-stable states, T and R, and the researchers identified four such "switching" contacts.

Cartoon of the subunit border area where tryptophan (W) 37 switches from asparagine (N) 102 to aspartate (D) 94 during the oxygen binding transition, among other changes.

It is remarkable that two atoms- O2- can switch the conformation of an enormous complex with an atomic weight of ~64,000. But it is all in a day's work for proteins, whose structures to start with are relatively floppy in the intense jostling of brownian motion. Putting those flops to work by evolving into structures with two stable states, tickle-able by joined-at-the-hip partners.. that is a bit more challenging, but obviously a life-saver given the absurdly inefficient breathing apparatus we are stuck with.

  • On the development of capitalism, its inequality, and its morality.
  • Misleading information is highly, highly effective.
  • "What was the response to your coming out as an atheist? An enormous number of Christians have threatened to do physical harm to me."
  • Xerces: Effects of neonicotinoid insecticides on agriculturally important beneficial insects.
  • High time to do low-carbon web design.
  • Music makes you better.
  • A program for restoration of accountability, civil liberties and privacy.
  • Rational expectations is pretty much the opposite of what the data shows. "To understand the past and avoid a recurrence of the devastating events we lived through so recently, we need to acknowledge that investors and financial markets do not behave the way rational asset price theory implies."
  • But the rich.. yes, they have rational expectations, of privilege.
  • Corporate profits at all-time high.
  • Non-regulation by the bank regulators. No wonder we are still on FIRE.
  • Outsourcing mortgage & foreclosure fraud- the nightmare continues.
  • Dumbest retirement policy in the world. And don't forget, Social security is going to screw post-'60 baby boomers as well. The new retirement age is 70.

Saturday, September 21, 2013

Horses running wild

Reaping the harvest of an unbalanced ecosystem.

A fascinating review in Science recently laid out the condition of the federal Wild Horses and Burros program. It isn't a pretty sight. The program is severely fenced in by its legal structure. Firstly, the number of wild horses must be kept down to about 30,000, over various Bureau of Land Management (BLM) lands centered around Nevada. This limits both competition with ranchers, and prevents disturbing scenes of mass starvation and overpopulation were the herd to expand to its ecological potential. Second, the excess horses can't be killed, but must be put up for adoption or put out to (non-wild) pasture on the BLM dime, in perpetuity.

Map of BLM lands with wild horses.

The BLM at this point is offering prospective owners $500 to adopt their mustangs, but still can't find nearly enough takers. The agency maintains a population of roughly 43,000 horses (males are castrated) in captivity, having removed a total of 200,000 horses from the wild over the last forty years. And it spends about $46 million on its captive horses, a number that is destined to go up, by the analysis of this article, due to increasing reproduction and capture rates from the wild herds.

This is all a little nuts. While it is admirable that US citizens, speaking through their representatives, dislike the prospect of killing horses that we capture from the wild for a wider ecological (and rancher) benefit, this squeamishness is very expensive, and hardly prevents much suffering, assuming that not all the captive pastures are run under ideal conditions, and that humane methods of killing (let's say euthanizing!) the horses exist.

Now the article authors and others (humane society, NRC) call for massive contraceptive intervention on the wild herd, shooting them up with a vaccine that can reduce reproduction when properly applied to domestic horses, though how it would actually be carried out from a distance (say, helicopters) is not at all clear. Again, another enormous commitment in perpetuity to manage a population that lacks the key element needed for natural balance: an appropriate predator.

Where is the wolf? Extirpated in Nevada. Where are the cougars? In the mountains, and not very interested in hunting horses. They are also managed closely and have their paws full dealing with an enormous population of deer. Where are the cheetas? Back in Africa.  Where are the bears? Mostly extirpated. So it is either us or disease & starvation that is going to limit the wild horse population.

It brings to mind the question of why horses died out in the Americas in the first place. We really have no good explation. After evolving here for tens of millions of years, the horse left for good around 12,000 years ago, along with the rest of the American megafauna. One gets the distinct impression that they were hunted to extinction by our less-squeamish ancestors, but it is rather hard to square such a theory with the horse's subsequent success across Asia.

We have no problem killing untold millions of other animals- cows, sheep, chickens- to eat and wear, and even manage to euthanize our pets. Why not horses? We seem under the spell of an archetype here- of the wild, born-to-be-free animal totem of a world that is long gone. I for one would be all for restoring a bit of that world in the form of predators to make up a more balanced ecosystem. We need more wolves. But if we don't want wolves on the prowl through the Western ranges, we need to step up and do the job ourselves, rather than telling a bureaucracy to do the impractical or impossible, to hide the problem in far-off corrals and pastures.

"So what happened on October 10 [2008]? The finance ministers and central bank governors of the Group of Seven leading high-income countries, meeting in Washington, declared that they would “take decisive action and use all available tools to support systemically important financial institutions and prevent their failure” (my emphasis). The core global financial system became the ward of the states. The idea that this was a private system was revealed to be an illusion. Taxpayers woke up to discover that bankers were exceptionally highly paid and out-of-control civil servants."
  • And, from Edward McClelland:
"Between 1970 and today, the share of the nation’s income that went to the middle class – households earning two-thirds to double the national median – fell from 62 percent to 45 percent."

Saturday, September 14, 2013

State and Firm: the transition from predation

As governments become more democratic and accountable, do workplaces?

The classic interpretation of the state is that of gradual transition (hopefully progress!) from the Hobbesian war of all against all, to organized banditry, to stationary banditry, to feudalism & aristocracy, and ultimately, by degrees, to increasing regard and accommodation to the populous subjects of the state, to the point where in a democracy, the ruled are, and control, the rulers for the broadest interest of all. A nice story, though the current rule by Wall Street looks like a step backwards in some respects. Corruption serves as another method of predation, more or less organized, available to individuals and state organizations at most levels of the progression.

The firm could be viewed similarly, coming from a Marxist perspective (thanks to Bill Mitchell for a couple of blogs on the topic). As feudalism wore down, its forms of control split between the public state and private capitalism. A transitional example of the latter was the plantation economy of the American South. Capitalists need to exploit labor, as the feudal lords exploited their serfs and other subjects. How is this done, other than through management? Management wears the two faces of, on the one hand, guiding and facilitating the work of the firm, putatively something salable on the open market, and thus of positive social value both to customers and to the workers who create it (assuming they are voluntarily employed). The other face is that of guardian of the interests of capital, extracting as much surplus value as possible from the workers, and paying as little as possible. Making use of the labor market, such as it is, and the political system, and any other tools, including in the not too distant past, physical violence, to keep labor powerless, subservient, and poor. Additionally, other resources than labor are  treated similarly. Public goods are expropriated or destroyed for private profit, patents poached, public officials corrupted, public institutions coopted, and media blanketed with disinformation, for any possible advantage.

My question is whether the predation of the firm has replicated the more or less progressive trajectory of the state, or whether progress in that relationship has stagnated over recent decades. For the state, the world has been swept by democracy. Even the Arab world has caught wind of this trend, though it is ending in tears in some precincts. Civil rights have expanded, to ethnic minority populations, to women, and to sexual and other minorities. Even with the sclerosis and backsliding we see in the US political system, with the top-heavy security state and war establishment, the people, in their media-addled state, are in control when they want to be.

To the original question, one would have to say, no. Death is no longer a routine part of predatory capitalism- workplaces have become safer for most workers. But the economic divide between workers and those they work for has grown enormously, which shows heightened predation over the last few decades. All labor productivity gains have gone to capital, and none to labor. Peonage has made a comeback in the form of predatory lending. This is hard to defend on any rational or moral basis, and one has to conclude that, through the many tools of politics, media, corporate governance, and ideology, capital has grown more predatory rather than less, contrary to the trend of lower predation by the public state.

Ironically, the ideologues of the capital have used the language of civil rights, equal play, and freedom from the evil public predatory state to defend the capacity of capital and employers to predate on workers. The entrepreneur is celebrated as the free spirit who brings immeasurable value to the masses, and whose freedom to organize must not be impinged. Yet the worker's freedom to organize and create a counter-capital power structure that, among other things, raises pay - that is a different story! Collusion in the boardroom, to pay each other in crony capitalist terms and evade accountability ... no problem there. But collusion among the cubicles is not to be tolerated. The irony continues as labor gets paid less, and can buy less, leading to a seizure of the macro-economic cycle that the entrepreneur was supposed to be leading by his miraculous "supply-side" efforts. Which only serves to unmask the whole exercise as one of simple greed by the top end of town.

Of course the Marxist question is whether this whole setup was fair in the first place. Does the mere possession of money entitle a person to the perpetual future flow of more money, via rents and profit streams? Is this truly consistent with human values and just deserts? Back when capital was scarce, this practice / ideology may have made more sense. But today, when capital is not at all scarce, (as shown by the level of interest rates), the economic and political machinations required to keep & even grow power in the hands of capital appear to be an unseemly anachronism, counter to the public interest.

But putting aside the deservedness of the capitalist and the managerial class, and assuming that private firms do work that serves the public interest, (or could be appropriately regulated to do so), perhaps a more fundamental question is on the labor side. How many workers need the specter of poverty, low-wage jobs, and social stigma to be lashed to work? Could our society function if everyone who works was paid decently by their employer, and not forced to collect extra money from the government to relieve their employer of the burden? Could our society function with public service jobs offered to everyone wanting to work at a decent floor wage, and with a lower maintenance payment to those unable to meet even a basic work standard? Could private employers function having to pay more for labor? Would having fewer fast food establishments and other services, and higher food prices be an acceptable price for having everyone live in dignity? Would the number forsaking the private workforce for public service jobs exceed the number that has been involuntarily thrown out of work by the business cycle? And if so, would that be a bad thing?

Most people want to work. They want to be useful and not on any dole. But the current system, controlled for the interests of capital, (and also by the blind vagaries of the free market, leading to highly damaging booms and busts), generates a large army of unemployed and underemployed. Which in turn leads to immediate waste and disgruntlement, and long-term generational dysfunction. We can build a better system, and with a modicum of management in the public interest, which our government has proven itself capable of in the past, we can create not only a far more compassionate country, but one with higher prosperity and economic well-being for the vast majority of citizens.

  • Rich people in a democracy.. the use of idiot populism.
  • Stiglitz chimes in- inequality is engineered, and poisonous.
  • Just who gets to collude / organize in the modern economy?
  • Poverty is still very high.
  • Brainwashing and Christianity. Sort of a system of terror. Especially in Texas.
  • Hell:  the psychology is way too strong to just do away with it.
  • Carbon and business as usual- not a happy future.
  • Let's get rid of coal.
  • Renewables are still approaching parity.
  • The Taliban is now using clear-and-hold.
  • Those selfless non-prosecutors, non-regulators at the SEC. And derelict reporters into the bargain. And why isn't the NSA snooping at the real evil-doers?
  • We still need that Tobin tax.
  • Subprime is right back in the saddle.
  • Chemical corruption in the US.
  • Economic quote of the week, from Paul Krugman
"So what can be done? For the moment, the kind of transformation that took place under the New Deal — a transformation that created a middle-class society, not just through government programs, but by greatly increasing workers’ bargaining power — seems politically out of reach. But that doesn’t mean we should give up on smaller steps, initiatives that do at least a bit to level the playing field..., for example,... universal prekindergarten education, paid for with a small tax surcharge on those with incomes over $500,000. ... For extreme inequality is still on the rise — and it’s poisoning our society."
  • Economic graph of the week, showing the trillions of output and income (roughly 5 to 10 trillion at current count) that have been stolen / lost due to the economic debacle caused by our leading financial institutions, including derelict regulatory officers and instutions. All to keep the casino going for the top end.

Saturday, September 7, 2013

Bach: a book

Review of Eric Siblin's "The Cello Suites"

This is a good book, a little over-written, and a little self-indulgent. Siblin presents parallel portraits of Johann Sebastian Bach, composer of his six famous cello suites, and Pablo Cassals, who resurrected them into the top-drawer recital pieces they remain today.

It is extremely interesting, and probably the material on Cassals was added to fill out the void that is our knowledge of Bach's personal life. But to me it seemed a strongly tragic story, with Bach unrecognized as a great composer in his lifetime, and his wife dying in paupery. How could this be? Now, Bach is all the rage, with full releases of his hundreds of cantatas, and thorough scholarship of his over one thousand-work catalog. But in his day, GF Handel couldn't be bothered to visit Bach even when passing through a town 25 kilometers away. And those famous suites where pretty much unknown for almost two hundred years after being written.

It makes you wonder whether disco is going to take the world by storm in some future epoch. Music goes in and out of fashion, and in Bach's time, his music was very much going out of fashion, which was travelling from sacred polyphony to popular opera and homophonic song (in the early 1700's). He was as fusty in his musical tastes as in his politics, religion, and dress. But the music, ah! Bach also didn't get around much. After visiting the Hamburg area in his youth, he spent his whole life in his homeland of Saxony. Having 20 children probably didn't leave much time for travel.

Speaking of which, the notorious genetics of the Bach family are a clear indication of eugenics (or at least assortative mating) at work. That musical talent is heritable seems as clear as the heritability of intelligence, height, and all sorts of other behavioral and physical traits. Whether we have the philosophical or moral foundation to even want to put such principles into practice is a separate question, but the potential is obvious enough.

Bach is, moreover, characteristic of great composers and great periods of composition in that he was paid more or less by the yard. Like the great broadway composers, (Richard Rodgers comes to mind), or the Motown era, it was simply expected, in the competitive system of the day, to crank out music continously, on demand. And the fascinating thing is that some composers rise remarkably to such conditions.

And, heartbreakingly enough, some unknown portion of Bach's work is lost. Siblin tells stories of Bach manuscripts found used for wrapping paper and for potting plants. His son C. P. E. Bach was the most filial and successful, but even his collection of his father's manuscripts was sold off under the auction hammer in 1788.

What makes music transcend its time? Innate quality is the first ingredient. But someone has to recognize it and perform it, which can demand going against fashion. The appreciation of other musicians finally turned the situation around for Bach's legacy. He was loved and appreciated by Beethoven and Mozart, but only really popularized by Felix Mendelssohn, who, in 1829, properly put on and publicized Bach's St. Matthew Passion.

Ever since, we have been treated to a flowing bach of music that seems as endless as it is astounding.

"So the ideological push to make capitalism appear to be fair led to the development of marginal productivity theory. Thus, the theory became that people are paid according to their contribution to production. That was then represented as a fair system and was used politically to negate the claims that workers were being exploited."