Saturday, May 29, 2010

Note to fish: We can't see you!

The sea of slaugher keeps getting worse.

The current oil spill in the gulf of Mexico has been a tragedy of errors, none of which are more appalling than the out-of-sight, out-of-mind attitude taken towards sea life. News reports uniformly fear damage that might happen if the oil hits the shoreline, and breathe a sigh of relief if the mess appears to wash out into the Atlantic.

Adding insult to injury is the use of delicately named "dispersants" in the hundreds of thousands of gallons, in order to reduce the unsightliness of oil on the ocean's surface. Apart from the incenstuousness of BP insisting on using chemicals that it has a financial interest in, the whole idea is fundamentally troubling. ToxicA + ToxicB = ?less toxic situation?

Corexit (what a great name- as though this material was going to make a problem go away) is a mix of soaps and solvents, themselves toxic to all forms of life, doubtless more so the more one relies on water to live. It contains:

- 2-butoxyethanol, used as solvent in paints, inks, and cleaning products like Simple Green.

- Sulfonic acid, a kind of soap, which, well, let wikipedia tell the story:
"Sulfonic acids are typically much stronger acids than their carboxylic equivalents, and have the unique tendency to bind to proteins and carbohydrates tightly; most "washable" dyes are sulfonic acids (or have the functional sulfonyl group in them) for this reason."
- Propylene glycol, which is relatively non-toxic, being used in drugs and animal feed.

- And other proprietary ingredients, probably of a detergent-like nature.

It is hard to imagine that fish would like this material. But who cares about fish? For many kinds of wildlife, (birds, mammals, some fish), it is good to get oil off the surface where they spend a great deal of time, and where we like to go bird-watching. But adding further toxic, and ironically petroleum-derived chemicals to the disaster mix presents increased problems for everyone else in the ocean.
  • Some links on the oil-dispersant mess.
  • The beauty of Jellies and other denizens of the deep.
  • Palau asks to have its ocean back.
  • Bill Mitchell quote of the week:
"Unemployment is about a lack of jobs. If the private sector will not create enough jobs then there is only one sector left in town that can. Hellooooo! Its called the government sector.
They can do it directly (that is, hire the workers themselves and put them to work advancing public purpose – rebuilding community and environmental infrastructure; providing personal care services; etc). There is never a shortage of work – just a shortage of funding to pay the wages.
They can also do it indirectly by stimulating the private sector via tax cuts or targeted spending. Both approaches have advantages and disadvantages but the net effects are always overwhelmingly positive."
(Noting as usual that a fiat currency-issuing government can provide funding without limit when inflation is low.)

Saturday, May 22, 2010

Bullying Iran

Perhaps the US should take a breather from its vilification campaign against Iran.

US foreign policy can get curiously ossified at times. Our stance toward Cuba is an example, which after the trauma of the Bay of Pigs and Kennedy's assassination, seems to have drifted into auto-pilot, not thinking too hard of what would be best for our interests, let alone what would be best for Cuba and the region.

Likewise, we seem to be carrying on a long-term grudge against Iran, dating from their Khomeini-ite revolution. It is frankly embarrassing to see the US try to bully Iran, to little avail, on its uranium processing and nuclear weapons policy.

Barack Obama took a promising tack when he first come into office. His reduction of pressure resulted in a deep destabilization of the Iranian government during its fraught elections. The equation is clear- the more pressure we apply, the more recalcitrant the Iranian government is, and the more support it gets at home, squeezing just a little more mileage from those tired old great Satan slogans. Bullying by the biggest country on the block never looks very good.

But now, the Obama administration has tacked back to a campaign of vilification, with embarrassing speeches by Hillary Clinton at the UN about how terrible Iran is, and how the nuclear non-proliferation agreement is not a residuum of neo-colonialism, but the self-evident and permanent apotheosis of universally accepted international relations.

Unfortunately, it is all too transparent where this change in policy comes from- it comes from our symbiotic relationship with Israel, which is running scared over a nuclear threat from nearby governments that hate it. It is also a neocon hangover from the Bush years and before. It also comes from our own difficulties with Iran's role in Iraq and Afghanistan, on the borders of both of which it sits, and with Islamism in general.

What are the risks? First is the risk of Iran actually carrying out its threats of wiping out Israel with a nuclear bomb. I think it should be clear that the chances of this, even when Iran does aquire a bomb, are minuscule. The history of nationalistic and diplomatic bombast is a long and painful one, but rarely reflected in action. Iran, even while indulging in clownish rhetoric, has shown a pattern of measured power projection, including provocations on its borders and through its Shiite friends in Lebanon and Palestine. Its relationship with Syria was mostly strategic, when it was mortally threatened by their mutual neighbor, Iraq. The unanticipated benefit of gaining Arab street cred by irritating Israel via its Hezbolla clients was purely gravy.

Not to mention that Israel has plenty of deterrent capability in the form of nuclear bombs of its own, hopefully well-protected from attack, and quite a bit more to the point, from its own rather numerous religious crazies. So I'd assign this prospect to pure fantasy. As far as terrorist appropriation of such a weapon goes, we are into this scenario pretty deeply already with Pakistan, with no accidents to date. I'd rate Iran better run, with better technical and cultural coherence than Pakistan, and thus estimate that Iran could control its bombs at least as well.

Second is the risk of Iran rising to become a true regional hegemon, supplanting US influence to some extent. This is a more serious threat, and certainly has Saudi Arabia quaking in its boots, as well as Israel. The ironic aspect of this is that the more we bully Iran, the more credibility it gains, both at home and in the Arab world. On the other hand, the more doctrinaire its policies- the more theocratric and economically closed it is- the less likely it will gain and consolidate this kind of influence. The more open it is and accepting of modernizing influences, the more successful it will be economically and culturally in what is, after all, a rather diverse Arab world and one that is majority Sunni.

So I would see this threat as self-limiting, which to say that insofar as Iran is dangerous, it will not be attractive to others in the region, whatever its purely military power. Israel serves as an example, having all the military power one could hope for, yet hardly being a hub of local cultural or political influence, for obvious reasons. The only influence it does have is not due to its military power at all, but due to its democratic system which serves at least in form as a counter-example to all others in the region.

Additionally, the real problem with Iran's nuclear ambitions is local- with its volatile neighbors. It isn't the US that needs to worry about Iran's bomb. We have plenty of distance and bombs of our own. If we had our diplomatic wits about us, we would let the local powers (i.e. Saudi Arabia, Egypt, perhaps Iraq) take the lead, and have them ask the UN for relevant sanctions, etc. One could even imagine a common front between those countries and Israel, if Israel hadn't completely alienated everyone in the region. The nascent denuclearization movement in the Middle East is such a local initiative, and the US should support it rather than torpedoing it at the behest of Israel.

Compared to the risks, what are the opportunities? The grand prize is obviously flipping the Iranian state from its Khomeini-ist system to something more democratic and less militant. Any other opportunities pale in significance, such as prying Iran away from Russian influence, or cutting Iran's oil revenue by restricting trade and establishing green energy, etc. Such an enormous change came very close to happening in the last election cycle. The population seems deeply interested in such a resolution, though it is hard to tell what the true proportions of sentiment are. All of our policy should be aimed at promoting this process. As noted above, our bullying has the opposite effect, consolidating the current state, and accentuating its interest in getting exactly the weapon at issue. Unless we have a big stick to wield, (and we don't), we'd be better off speaking softly.

Our policy should be to speak the truth and engage where we can. We should not recognize the current state as legitimate, since it is not (ditto for Afghanistan, unfortunately). We should also not sign off on nuclear treaty compliance that doesn't exist. But our target should be the vast population that yearns for modernity and for a voice in the context of a fully autonomous and democratic Iran. We needn't encourage Iran to build a bomb, but should at least recognize their desire for such a deterrent, beset as they are with US forces on both sides, and having faught a catastrophic war just 25 years ago. Israel, for its part, would be better off mending its own wretched relationships with the Palestinians and the rest of the Arab world rather than egging us on to foolhardy diplomatic/military adventures.

Iran is a historically rich, sophisticated country with plenty of its own problems, like rebellious minorities, a corrupt and ideologically rotten elite, and energy needs that may outstrip its pace of energy development. The Khomeini-ist state is an unfortunate problem, for its subjects as much as for us. But it has shown a good deal of practicality over the years, and ultimately can't win against its own people, as they are increasingly aware of conditions and trends outside their country, and of their own power. It seems a good deal more fragile than, for example, the Chinese government, due to its internal complexity and an ideology that has diverged substantially from that of the public at large.

The risks are small, and the opportunities are large. My prescription would be to pursue quiet containment against the government of Iran while accentuating democratic, open principles at every turn in public, as we should universally in our foreign policy. We should promote travel between our countries, as well as non-sensitive trade and other exchanges. The enormous Iranian expatriate community in the US would probably welcome such an approach and be an important medium of improved relations as well as cultural change.

  • Who cheerleads for more bullying? What a feud. After the kindness of Cyrus, you would think they would be a little more grateful.
  • Afghanistan- still coming unraveled.
  • ...or perhaps not so much. Shalizi on Afghanistan- wealth of links, etc., including a detailed political network analysis.
  • Evolution- still a dirty word.
  • The Euro is on its death-bed. Dissolution, or pan-European government and fiscal policy- that is the stark choice.
  • More on the Euro.. mentioning its trend toward pre-Keynesianism. Why aren't we doing more post-Keynesianism here in the US?
  • A Keynesian prescription for Britain.
  • More on criminal, er, financial, racketeering.
  • Big government fights back against free information.
  • God is here .. at minute 26.
  • Bill Mitchell quote of the week, speaking of Europe particularly:
"So a classic mainstream argument that unemployment is caused by excessive real wages and government regulations. If you took time and analysed the shift to profit share over the period he analyses, you will realise that productivity was running ahead of real wages. So where was the real wage overhang?"

Saturday, May 15, 2010

Protein theology

I critique a scholarly article from the "intelligent design" camp.

One of the wonders at the heart of modern biology is our knowledge of protein function and structure. The fact that the linear genetic code produces protein molecules that spontaneously fold into complicated shapes, wander off to various corners of the cell, and then spontaneously do their complicated functions like metabolic reactions, holding things together, filtering ions, or replicating DNA. etc.- it is mind-boggling, and a little magical.

But it all had to come from somewhere, and I ran across a recent paper that takes up the issue. This is from a creationism house journal, BIO-Complexity, put out by the Discovery Institute. They have their own peers, thus this is darn well a peer-reviewed journal! Accompanying it is an honest-to-goodness experimental article, where the experimenters strive to not observe a phenomenon that they theorize doesn't happen .. and succeed!

Alright, sarcasm aside, the article, "The case against a Darwinian origin of protein folds", by Douglas Axe, is well-written and mildly interesting, though I take a highly critical attitude. It is a review- no new theories are proposed, let alone tested. He lays out (using the royal "we" throughout) the difficulty of protein domains arising from nothing, and claims to make a strong case that this was impossible within the Darwinian paradigm (presumably including early chemical evolution in the broader Darwinian theory).

Domains are the structural units of proteins- the smallest portions that fold by themselves and sometimes function by themselves in doing whatever, like catalyzing a reaction. Typically, proteins are composed of several domains, whose connection is critical in, for example, activating the catalytic activity of one domain in response to binding a regulatory chemical by another. The definition can be vague, since very small proteins (called peptides) may have important functions (like hormones) despite being unable to maintain a coherent fold/shape on their own. One might say they are protean! And there are large proteins that amount to very large domains, not easily broken down conceptually into independent folding / functioning sub-domains.

Axe spends quite a bit of time using average protein size statistics to marvel at the improbability of any protein-sized, or even domain-sized unit of protein sequence arising de novo. If we have 20 amino acids, and the average protein is 300 amino acids long, that amounts to 1E390 possible combinations. Finding the one of these that is a modern protein is like, well, it is simply impossible, there being only 1E150 particles in the entire universe, 4E20 microseconds since the big bang, etc. He likens it to finding a gemstone in a Sahara desert to the Nth power, and other elaborate comparisons.

Even if one cuts the search space down to the size of a domain, (average modern size ~ 100 amino acids), these numbers are astronomical, though Axe does not go into this correction in detail. But obviously, the origin of proteins at the dawn of life has never been hypothesized to involve the sudden appearance of 300 or even 100 amino acid-long enzymes for oxidative phosphorylation. This is a straw man from top to bottom.

Why is he and his community fixated on it? It seems to follow a model of a deity trying desperately to design our proteins from above, stabbing away over billions of years and uncounted quadrillions of organisms before getting it just right in the case of homo sapiens. If one lays out the premises explicitly, they dissolve before one's eyes. But with the ID community, all this is implicit as a religio-political "wedge" project, not a serious intellectual endeavor.

Over in the actual scientific community, the origin of protein coding capacity is commonly assumed to have extremely modest beginnings, as an extension of the RNA world, when RNA had the primary replicative and catalytic ability. This modest catalytic ability might then have been abetted by tiny peptides, painfully assembled by a set of primitive RNA enzymes, and then extended to slightly longer protein chains, which eventually and competitively, through their vastly superior chemical abilities, relegated RNA to what is now its mostly informational role. Indeed, the protein-translating ribosome remains a thoroughly RNA machine, using strings of mRNA as the template code, tRNA- mounted amino acids as the building blocks, and a catalytic core of rRNA for polymerization. This sort of gives the game away right there, if one cares to look.

The original genetic code is also likely to have had fewer than the 20 amino acids that are universal today. The messiness of this genetic code, with some amino acids encoded by only one of the 64 codons, and others encoded by six, indicates some late additions and jerry-rigging to the system. And since the code's establishment, more amino acids have come into use through chemical modifications, either before the amino acid is incorporated (selenocysteine), or afterwards (hypusine).

Axe never recognizes such realistic accounts of the primitive origin of proteins, however. He also assumes that successful proteins have to approach modern levels of efficiency, making any path from one folded form to another folded form (there are an estimated ~2000 classified folds) impossible, none in between being likely to have a well-honed function. Here again he fails to recognize the wider spectrum of hypotheses available. Many proteins have unstructured regions- floppy areas that may adopt structure only when binding some other partner, or adopt alternate structures under different conditions. Such alternate folding lies at the heart of Alzheimer's disease and prion diseases.

While one optimized folding structure is unlikely to turn into something completely different and coherent through direct evolutionary selection, there are many other resources for the emergence of novel domains, such as these floppy sections of working proteins, or random DNA segments that do not, for the moment, code for genes, or various fusions of working proteins (a fertile source of cancer), or duplicated coding genes with no selective constraints at the moment. Many accidents have happened to genomes over time.

Axe cites experiments showing that proteins can switch readily between quasi-stable folds, an important precursor to these innovations. But he dismisses such cases as not competitive in the modern Darwinian landscape. When a novel function is at issue, however, how primitive is too primitive? Some function is doubtless better than none, and that is how new functions (and structures) gain a toehold in the Darwinian paradigm. The starting point for any evolutionary optimization path is not an already-optimized functional protein, but one with any function at all, however glimmeringly small, compared to the lack of that function in competing organisms. This will often be an off-beat mutation of an existing protein conferring a novel, if weak, activity.

The idea that one sequence out of all 1E390 sequences is the one that evolution must find, and in a hurry, is fallacious in another way as well. All of phylogenetic analysis is based on the wide variation of sequences, to the point that functionally and structurally similar proteins may have no detectable similarity in their linear sequences. We have essentially no idea how big a swath of sequence space any function might require, even when it is optimized. Evolution certainly never samples all of it- that we can agree on.

But does it have to? No, it obviously does not. One of the wonders of molecular biology is that, as sequences were accumulated in databases, many of them turned out to be related to each other, elegantly recapitulating the phylogenetic tree that Charles Darwin had first sketched out so tentatively to extraordinary depth and detail. In addition to clearly tracking the divergence of species by the divergence of their homologous genes, this method also found countless deeper relationships- families of proteins that had diverged at ancient times from single ancestors through duplication, first sharing functions, but often diverging in function as well. Unfortunately, as indicated above, relationships between linear sequences go back only so far before becoming unrecognizable, despite being truly ancestral, so the full story of ancient protein domain diversification can not be revealed in this way.

Axe notes that every organism harbors, in addition to critical genes that are highly conserved, a population of others with no detectable relationships. A bold hypothesis from his perspective would be that it is these proteins that are the most important, showing that god remains at work, creating new protein structures for critical cellular functions, as has been his habit through the ages.

Unfortunately, another hypothesis is quite a bit more likely. These proteins are, in point of fact, the least important ones of the organism, prone to rapid mutation and divergence to the point of unrecognizability. These, in turn, might be exactly the kinds of proteins that generate new structures, folds, and functions, if they can outrun complete inactivation through mutation, yielding up the novel folds that the author seems so perplexed by.

Indeed, I'd suggest that the known collection of protein folds is reasonably definitive and represents the limited number of ways that small domains can fold coherently. The vast remaining unexplored sequence space is unlikely to add much, just as it is unlikely to add new secondary structures to the venerable alpha helix and beta sheet, due to basic physico-chemical constraints.

If Axe and his peers are interested in doing a real service, they would help save the huge fund of bio-diversity (including protein diversity) we are squandering by the day, rather than pursuing faux-science whose philosophical destination would indicate that god might be happy to reverse our degradation of the natural world with a wave of his magic wand. So, no worries!

Saturday, May 8, 2010

Religion: not so bad after all!

A paper discusses the correlations between large societies, market behavior, and world religions.

Humans have a difficult relationship with truth. We love it, we seek it, we respect it. We habitually claim to have it long before we really do. And in our heart of hearts, we also fear it. One fearsome truth is death. Another is the meaninglessness of existence. It is the highest irony that to escape such truths, humans have created countless other fibs, fantasies, and scams. Oh, what a web we weave!

The premier purveyor of these self-deceptions has been shamanism/religion, which may provide hope for transcendent justice, visions of a god-filled world of mythical drama, life after death, complex justifications for social power relations, social cohesion, and generous amounts of meaning. Can we live without it? That is the question of this secular time, when our self-consciousness has been raised to excruciating heights via evolutionary biology, existentialism, psychoanalysis, and other myth-shattering ideas.

Historically and pre-historically, we have not lived without it. Every society has harbored some kind of religious system, though some contemporary societies appear to have, perhaps for the first time ever, lost its services. From the simple beginnings of superstition and animism to the ever-more fantastic products of theology, we have experienced a crescendo of communal imagined meaning, charming to look back on as myth and fable, and still a matter of vibrant belief in some quarters.

Where do we go now? Will knowledge and self-knowledge keep undermining mythical sources of meaning and ultimately banish religion (the secularization hypothesis), or will religion (or some other ideology) tease (or force) the genie of consciousness back in to the bottle of blissful communal ideology? The answer lies not in any analytical framework, but in human nature- whether we continue to cultivate knowledge and value truth over comfort, and whether functional communal meaning can be devised in the absence of myth and surrender to the many shamans of our time- herbal healers, theologians, nationalist revolutionaries, Islamists, etc.

That digression was by way of introduction to a paper in a recent issue of Science, which offers a rationale for the tremendous parallel growth of "world" religions and world population. "Participation in a world religion is associated with fairness, although not across all measures. These results suggest that modern prosociality is not solely the product of innate psychology, but also reflects norms and institutions that have emerged over the course of human history."

As is usual in so-called social science, most of what they have to say is far from novel. I mean, how much of human culture is "innate psychology" in any case? It is essentially impossible to disentangle culture from innate psychology, other than wild-child cases, which indicate that we are cultured virtually to the core.

Anyhow, the authors make the case that the modern cosmopolitan culture depends on dramatically different norms than the typical hunter-gatherer band of prehistory, which we see modeled in some respects in surviving human indigenous cultures, and perhaps in some small way in the small-band stucture of chimpanzee society. The new norms of mass society are characterized by an ability to trust complete strangers and treat them fairly- to buy/sell food from them, to join them in political action, to join companies with them, to "Friend" them- to do all the things that make our large societies run smoothly (until fraudulent actors take advantage of everyone's accentuate-the-positive trust and take the economy to the cleaners!).

Paired with that trust is a new norm of punishment- punishing violators of the first norm even though the individual punisher may not directly benefit- combined the practice of broadcasting the (bad) reputations of violators. One critique I would have is that it is hard to imagine that these tendencies are specific to large societies. Small societies have extremely strong reputational mechanisms, (gossip), and while typically distrustful of outsiders, have carried on trade with immesely distant partners as far back as archeologists have been able to trace.

Small societies are typically very fair among themselves- positively socialistic on an extended family model. So the question may be much more the sense of membership that people have in increasingly large and abstract communities (e.g. nationalism) than any changes to the psychology of group behavior.

At the heart of paper are a set of experiments, done with the hapless members of widely varying societies all over the world, from hunter-gatherer (Hadza) to blue-collar (Missouri). The first core experiment is to give one person some money, and ask him or her to share it with a second person. Both are apparently brought face-to-face, though the article is unclear on this point. The amount shared is up to the first person exclusively (this is called the dictator game). The authors take higher sharing to imply higher "fairness", and sharing ranges from half (rare) to none (also rare).

But it would seem to me that this has little to do with fairness, and perhaps more with how prosperous and generous people feel- how generous they can be with the amounts of money at play in the experiment, and how connected the feel with their partners. The amount was set at one day's local wage, which seems like a well-controlled level. But one day's wage may represent quite different values to people with either no reserves, living hand-to-mouth, or with substantial financial reserves, access to credit, and other cultural supports (social security, etc.) that allow higher generosity. The values involved may also be different if money represents the common currency of all facets of life, as it does for us, or if it represents inessential luxury values for getting occasional tools and decorations. In different societies, money, even if numerically similar in value, may be quite differently valued. It is very hard to understand why the experimenters imagined their games where truly comparable across cultures.

The following graph shows how well the US stacks up in what I would term generosity in the dicator game, and how this value correlates with what the authors term market integration- the percentage of calories in the diet that are bought rather than self-gathered or grown.

This graphed relation is detectable- market integration correlates with generosity (though the spread is obviously very broad indeed, with the unintegrated Au of New Guinea approximating maximal levels). Generosity was less strongly correlated with membership in world religions, though here the statistics were extremely poor. Virtually all the subjects were members of world religions (the only group with less than 50% membership was the Hadza [0%], while the Au had 100% membership).

Further experimental setups explored punishment tendencies, and I won't get into them here, though the interesting conclusion from the authors is that "... we find that world religion is associated with significantly (P<0.05) more punishment, though market integration reveals no such relationship". Well, surprise, surprise! As one can tell just glancing at the religious landscape, though religious hierarchies may be loath to punish their own members, they are hotbeds of outwardly-directed punishment in defense of their moral "standards", and in support of (indeed expression of) their own cultural power.

One has to note as an aside that these anthropologists utterly ignore the validity of any religious doctrine they are dealing in. Moonies, Islam, Mormonism- it is all the same to them, as though they were looking at ants obeying a pheromone-laden queen. They are far above this fray, with the implication typical in academic circles that the validity of such doctrines is not worth considering.

So, if one takes this work seriously, the conclusions are that some mix of using money-based markets (i.e. buying food), and being nominally part of a world religion each account in some part for increased individual buy-in to the norms of large societies. As unifying ideologies, religions offer just such social norms, bringing disparate people into deeply meaningful community membership which carries with it the punishment of black sheep as well as love and devotion of loyal members. The world religions, by definition and by a sort of natural selection, have specialized in servicing large populations by way of organizational hierarchies, viral spreading memes, and strategic good-cop/bad-cop deployment of both violence and love.

On the other hand, it might simply be the actual act of trading and carrying on the day-to-day activities of larger societies that clues everyone in to the benefits of a new paradigm of higher trust and punishment (i.e. duties of citizenship, like jury duty, respect for legitimate authority, etc.). This realization is then cultivated formally and informally as it is in our schools and preschools, with the result that religion, while helpful in some areas of poor schooling/cultivation (such as striving Pentecostals in Latin America), is less helpful in the setting of a deeply educated and cosmopolitan modern secular culture, indeed impeding greater trust development by its parochial divisiveness, not to say occasional literal terrorism.

  • Fascinating segment on North Korea as an effective cultural belief system.
  • POTD takes on the British election.
  • Morality- present from the start.
  • Shutting off the thinking process.
  • The Bushies made an oopsie.
  • The deep tension between borders policy and social policy.
  • Interesting take on what the Fed has been up to.
  • Do we need some kind of wildlife reservation for ex-financiers?
  • This modern world, in financial engineering.

Saturday, May 1, 2010

A nervous switch

The structural basis of nerve conduction: voltage gated ion channels.

One of the grails at the junction of neurobiology and structural biology has been the physical basis of gating in voltage-gated ion channels. A recent paper seems to have cracked the problem for one of them, the potassium (K+) channel.

Nerves conduct impulses quite differently than do electrical wires. There are places where nerves are heavily wrapped with insulation (myelin) and electric pulses race along almost like they do through a wire, but those segments are very short, and the pulse still consists of a small voltage difference across the membrane, between inside the cell and outside, not a difference in voltage between one end of the wire and the other end, as in copper wires.

All the action is at the membrane, and it is driven by an interesting cast of ions and ion channels. Some channels pump ions against their natural gradients (using ATP) to maintain the resting state of the nerve cell. This state is high K+ inside and high sodium (Na+) outside (see animation here). Other channels then use this primed rest condition to propagate the transient nerve impulse, also called the action potential or spike. This begins with a rapid opening of Na+ channels to create a reversal in voltage, then closing of those channels, followed by rapid opening of K+ channels to bring the voltage back to the original state, then a brief refractory period, and then back to rest, ready to fire again.

The voltage reversal, or "spike" of an action potential induces nearby Na+ and K+ channels to do the same thing, unless they have just fired, in which case they are in their refractory period. It is the properties of these channels that gives the nerve impulse its form and forward direction. The nearby Na+ and then K+ channels fire because they are "voltage-gated", meaning that they are turned on by a small change of membrane voltage (another crude animation). In this respect, they are similar to transistors, which use a small voltage to regulate a larger current running through the main conduit.

Biologically, this is a very special type of ion channel control, different from other means of controlling channels, such as binding specific chemicals, temperature, light, or touching structures on other cells. Once open, the channel is passive, letting Na+ or K+ through as fast as it can, but also selective, having just the internal shape and electrical fields to allow that one ion through and no others.

When the membrane potential changes again, due the channel's own effects (high voltage flips another voltage gate to inactivate the Na+ channel while flipping the K+ channel on; then the low voltage re-established by the K+ channel closes it as well). All of which brings the local voltage back down a little below its resting state, with the Na+ and K+ channels closed again.

The current paper describes the physical mechanism of voltage gating of the K+ channel. Naively, one would think that a little charged lid might cover it at one end, but that isn't the case. What happens is that a long protein helix sitting next to the channel slides up through the membrane, levering an attached helix against the bottom of the channel, allowing it to open. The positive charge of this helix gives it its sensitivity. The authors begin by solving an X-ray crystal structure of the K+ channel with its voltage sensor in place, in the open position.

Let's start with images of the channel core in its open and closed positions. Imagine the membrane going horizontally through the picture, with the channel peeking out at top (outside of the cell) and bottom (inside).

The open form (O) is the structure they solved for this K+ channel protein from rat. The closed form (C) is a structure they model based on structures from similar channels (but solved without the voltage gating mechanism) in their closed forms. The potassium ions (tiny green dots) are in the center channel arriving from the outside, whether the bottom end is open or closed. It is only the bottom of the channel that changes shape substantially when closed- tightening into a sort of pucker. This structure can be seen in three dimensions at the protein databank (use the Jmol view tool, which gives full 3-D control and other animation/drawing options [closed form]).

The red helix at the bottom is a key piece of the voltage sensor, but not the whole thing. The sensor occurs in four copies around the channel, which is why there are four helices. Four proteins make up this structure, each contributing one-fourth of the core channel structure, but each contributing one voltage sensor on the periphery. The next structure shows the whole thing they solved- voltage sensors (two shown in red and gray) plus the open channel (blue).

You can see that the voltage sensor (S4) links to the channel bottom through the small helix S4-S5. Leverage up or down in the red sensor communicates to the channel through this linkage. The helices S3b and S4 are the most active parts of the sensor, which the authors deduce must descend dramatically through the membrane to physically push the S4-S5 helix to the other orientation and close the channel.

Then next image is the voltage sensor up close, showing the details of how these helixes fit together. Note that these structures are shows as "ribbon diagrams", only schematically showing the path of the protein backbone. There are many other ways of visualizing atomic structures, based on what one is interested in seeing.

Here they use the amino acid codes R for arginine, K for lysine (sorry about the confusion, chemists!), F for phenylalanine (green), E for glutamic acid and D for aspartic acid. The charges are critically important- lysine and arginine are both positively charged (blue- R and K), while the acids are negatively charged (red- E and D). In this open channel conformation, lysine 5 (K5) is parked comfortably opposite the negatively charged E and D and tucked under the green phenylalanine (F). Since this structure is otherwise enclosed by the oily membrane (gray bars on the sides), any charge on the protein likes to stick to an opposite charge if it can, and this F-pocket is particularly influential in allowing the positive charges R1 through K5 to ratchet down through the membrane, positive step by positive step.

The model that the authors present is that in response to membrane voltage changing, the string of positively charged amino acids from K5 to R1 descend, twist, and bind sequentially in the E+D+F pocket. This naturally wrenches the S4-S5 helix around and forces the channel closed.

The crux of the work is that the authors look at the structural model (along with decades of prior work in the field), and infer the dynamic action as outlined above. To provide some further evidence, they make a series of mutations of the R1 and K5 amino acids as well as the F position, and measure their electrical effects- what voltage it takes to open the channel, to close the channel, and even voltage associated with movement of the gating charges themselves (the "gating current"). Moving the series of positively charged R and K residues across the membrane reveals itself to extremely sensitive methods while the channel pore itself is chemically blocked.

They find that lysine (K) binds better to the E+D+F pocket than does R, so putting R at position 5 makes the channel easier to close (to move out of the open position), while putting K at position 1 makes the channel easier to keep closed. When both positions are K, the channel is harder both to open and to close, as shown by about 40 ms extra time for each process in the K1K5 mutant (D, below), compared to the R1R5 mutant (A).

Gating currents are measured for selected mutants in the 1 and 5 sites, showing that K on either end makes either opening (first half of trace) or closing (second half of trace) slower, presumably due to enhanced stability of binding in the F-pocket and reluctance to be dislodged.

It is beautiful work, and I can only touch on the surface here. The authors integrate structural and functional evidence in classic fashion, supporting the presented theory of how the voltage gate works in the K+ channel. Since this gating is one of the many pieces of machinery that lie at the heart of nerve function, of brain function, and thus of the mind, it is a worthy quest that has taken decades, journeying from awe and mystery to understanding.

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