Cryptochrome: Not Just for Circadian Rhythm Anymore?

The annual movements of birds are frequently cited as one of the great wonders of nature, and rightly so. This widespread behavior's initial evolution and subsequent refinement into the amazingly specific systems we observe in the modern world are testaments to the enormous power of natural selection to shape not only the physiological systems that enable long-range directional flight, but also the social mechanisms that specify destination and mode of travel. In general terms, we understand what biological components enable migratory behaviors, but the specifics of the system are not yet completely understood. We know that birds have a magnetic compass, and that their choice of direction is also light-dependent to some extent. Today in PLoS ONE, Miriam Liedvogel and colleagues attempt to eplain this linkage with biophysical experiments.

The target of their studies is cryptochrome, a eukaryotic protein related to the bacterial DNA repair protein photolyase. Cryptochrome is a blue-light photoreceptor, known to play a role in light-detection in plants, and important for circadian rhythm in mammals. Eukaryotic cryptochromes have a photolyase-like domain that contains a flavin chromophore, and a large, intrinsically unstructured C-terminal domain that is important for signaling. The lovely and talented Carrie Partch showed that photoreception in the photolyase homology region disrupts stable structure in the C-terminal domain of arabidopsis cryptochrome, and that this is important for signaling (shameless promotion). Liedvogel et al. show in their paper that the flavin nucleotide reacts to the incidence of blue light by forming pairs of radicals. This is important because the electronic behavior of these radicals can be affected by external static or oscillating magnetic fields. Moreover, cryptochromes may be active in the eye during magnetic orientation, as Mouritsen's lab showed previously.

Liedvogel et al. demonstrate the existence of radical pairs using a transient absorbance experiment following irradiation of a 20 µM cryptochrome solution with a blue laser. Their Figure 1 (to see it, follow the link above—PLoS is free) shows absorbance maxima characteristic of flavin radicals that persist for a few milliseconds following excitation. These peaks are not present in absorbance spectra averaged over a longer period of time (Figure 3). Liedvogel et al. propose that these radicals, though persisting for only a few milliseconds, nonetheless last long enough to plausibly interact with the earth's magnetic field.

So... problem solved? Not exactly—Liedvogel et al. do a pretty good job explaining the limitations of this research and the attendant models. Although this work opens up some intriguing possibilities it certainly leaves us with more questions than answers. Specifically, it would be nice to know whether this radical-pair formation actually causes some kind of signal; given the relatively short lifetime of these species this is not at all certain. Also it would be important to determine whether the presence of magnetic fields in any way modulates cryptochrome signaling. This is also a case where the nature of the experiment may be misleading us—a dilute solution excited by a laser may not really resemble a cellular milieu stimulated by ambient light. To be fair, this cuts both ways; cofactors present in the cell could inhibit or enhance radical formation.

In this regard, it will be important to perform in vivo experiments, at least at the level of cultured cells. Experiments of that nature are likely to be very difficult, however, given the highly specific context in which the signaling occurs. Given that the experiment entailed the creation of a cDNA library from bird retinal cells under the appropriate signaling conditions, a yeast two-hybrid screen under conditions of blue-light irradiation may be a possibility.

The subsequent challenge will be to test whether and how a magnetic field alters signaling. The problem there is one of controls—the earth's magnetic field is pretty difficult to escape. However, once signaling partners are isolated, one could set up experiments involving NMR spectrometers... not as direct devices for investigation, but rather as part of the experimental setup. The magnetic field inside (and thus, with an unshielded instrument, outside) an NMR spectrometer has a directionality, and not all of them are oriented the same way. Some point away from the core of the earth, others towards it. The magnetic field of a typical MRI machine is oriented parallel to the ground. In addition, the field of almost any superconducting magnet is vastly greater than that of the earth. Growth experiments performed in the leaking field outside of these spectrometers could be compared to experiments performed in the ambient magnetic field in order to gain insight into the effects of external polarization on cryptochrome signaling. Dilute-solution experiments performed within an NMR spectrometer may also be of value.

Liedvogel et al. argue that the cryptochrome would have to be tethered or immobilized in some way in order for its interactions with the magnetic field to encode information. This is certainly the simplest possibility, but may not go far enough. Simply tethering the molecule is unlikely to prevent isotropic or near-isotropic tumbling, especially considering the unstructured nature of the c-terminal domain that seems to govern signaling. However, tethering the protein at a single point might work if the actively signaling species is short-lived, experiences primarily local interactions, and is dispersed along a line or plane of tissue. In this case, the averaging due to tumbling might be countered by a gradient imposed by the arrangement. This is especially attractive because this form of activation appears to be low-yield: increased average activity of a tethered ensemble rather than a rare specific signal incidence might be the mechanism.

This is an interesting paper that amounts to a feasibility study. Liedvogel et al. demonstrate that blue-light stimulation can induce the formation of radical pairs, and it is known that the behavior of these species are affected by magnetic fields. This shows that it is possible for cryptochromes to play a direct role in migratory magnetic navigation. Additional evidence suggests that they play some role, but this may be coincidence; for instance, magnetic compass calibration may be a system controlled by the circadian rhythm function of cryptochromes. Actually proving the existence of a direct role for cryptochromes in orientation control will require substantially more work.

Liedvogel M, Maeda K, Henbest K, Schleicher E, Simon T, et al. (2007) Chemical Magnetoreception: Bird Cryptochrome 1a Is Excited by Blue Light and Forms Long-Lived Radical-Pairs. PLoS ONE 2(10): e1106. doi:10.1371/journal.pone.0001106

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The evolution of watches

PZ Myers is one the internet's most sarcastic and unapologetic atheists, and occasionally this leads him to say things I find extremely disagreeable. His lightning-rod status, however, means that he occasionally picks up some very interesting stuff from the interwebs. By this I do not mean his regular e-mails from the religious fringe, but instead the stuff he finds in support of evolution. As a case in point, this post where he gets an interesting video in which watches are evolved in silico from random parts. You should go check it out; it will take about 10 minutes for an entertaining explanation. Particularly note the way that the evolution plays out—relatively stable forms persist for huge numbers of generations and then rapidly change into completely different forms. Apply this knowledge the next time someone trots out the "no transitional fossils" argument.

Also, RIP Arthur Kornberg, Nobel Prize winner and great biochemist. Despite his gifts, his own research might be his secondary contribution, as his biological and scientific progeny may prove the greater. They already include another Nobelist. As scientists, we are always tempted to see our own work as being of paramount importance, but the training we give to our students and the spirit of enquiry we impart to our children are truly our greatest gift. Any scientist who neglects these aspects of his or her legacy is a failure, no matter how many splashy publications decorate his or her CV.

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An organizational problem

A clever little experiment appeared in this week's JACS preprints, from an Italian group at the University of Bologna. Their efforts concern fluorescent nanoparticles, specifically ones in which the fluorophores have been encapsulated in a silica substance. The advantage of this sort of construct is twofold: it concentrates a large number of fluorescent molecules in the same spot, and also it sequesters them from ions in the solution that might quench their fluorescence. The latter effect could be maximized if you synthesized a nanoparticle that had a fluorophore-doped center and a fluorophore-free shell. Rampazzo et al. have accomplished just this, and demonstrated that the system can be tuned to produce some interesting effects.

Using a pyrene derivative that was only weakly fluorescent in oxygenated water, Rampazzo et al. constructed a reaction to create a doped nanoparticle. In an initial case, they added the dye to about 0.1%, and then grew nanoparticles up to a size of about 90 nanometers. The dye was almost completely incorporated into the particles, and the quantum yield correspondingly increased in an almost linear fashion. Similarly, the results of light-scattering experiments indicated that the particles were growing with a rate equal to that of the increase in quantum yield. The interesting feature here is that although these rates are equal, the fluorescence plateaus significantly before the apparent particle radius reaches its maximum. This result indicates that the fluorescent dye is incorporated relatively early but that the particle continues to grow after this supply is exhausted, thus creating precisely the kind of shell we wanted (A, B, C below):


This success seems to be based entirely on a fortuitous choice of dye concentration. What if that concentration is changed? Rampazzo et al. changed the concentration by an order of magnitude and produced another interesting effect. It turns out that when there are a number of these dye molecules close to one another, they form excimers with an emission maximum at a wavelength of light ~100 nm longer than the monomer. When the dye constitutes 1% of the reaction mixture, there is an initial decrease in emission from the monomer that occurs with roughly the same rate as an increase in excimer emission and in particle radius. Later the monomer emissions recover, and all three processes plateau at approximately the same time. This suggests the formation of a heterogeneous particle as shown in D, E, F above.

This time the dye is not sequestered entirely from the solution, but local concentration at the core of the particle is so high that an unusual fluorescent property is observed. It's a conceptually simple little experiment, but it has an interesting result, and one that will have to be considered in future efforts to construct nanoparticles of this kind.

At the same time, if extreme local concentrations of some molecule have fortuitous or useful properties, this potential problem for nanoparticle construction might become an advantage. Consider if you have some molecule of interest that forms an excimer or exciplex with a known dye. Taking a sample containing traces of this molecule, one could use the encapsulation technique to construct a highly sensitive fluorescent detector.

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Playing it safe

Is it really such a big deal that Dumbledore was crushing on young Gellert back in the heady, free-loving days before the war? Does it really change anything about the books? Heck, does it even change anything about the fans' perceptions of the books? Rowling commented, "God, the fanfiction," but that just shows she's never heard of rule 34. The body of fanfiction based on the Potter novels is so vast as to be beyond the comprehension of any sane man, and at least a quarter of it is probably porn. Rowling, imaginative as she may be, could not possibly conceive of anything that fanfic writers have not already turned into treacly, overwrought prose riddled with misspellings, atrocious grammar, and cell-phone language.

I don't doubt that this will add more fuel to the fire of fundamentalists already out to burn the books for daring to mention witchcraft and to promote tolerance. And I have already been subjected to a diatribe accusing Rowling of using this to "drum up publicity" for the books, which is patently ridiculous. For one thing, Harry Potter has so thoroughly permeated popular culture that it is almost certainly impossible to publicize it further. For another, J.K. Rowling is already wealthier than the Queen of England. If your personal wealth overmasters that of a family that spent centuries sucking dry the marrow-bones of indigenous peoples then you hardly need the extra publicity a gay controversy will give you.

Even in the context of the books, this is a minor fact. It fills out the story of Dumbledore's fascination with Gellert, but this is hardly necessary as the books themselves give a strong account of his feelings. It casts an interesting light on his relationships with Snape and Harry, but it doesn't really make any more sense of them. While it might be interesting for the fans to know that Rowling thought of Dumbledore as gay, knowing this doesn't really add much to the depth of the story.

I've even seen some comments saying that it was brave of Rowling to admit that Dumbledore was gay. Well, it fits her books' themes of tolerance. But "brave"? For admitting that a secondary character was gay months after the final volume of her series wrung its billions from the best-seller list? Not a chance. "Brave" would apply if Harry had secretly crushed on Oliver Wood, gotten beaten up for glancing one too many times at the other blokes in the Quidditch showers, and shyly asked Ron to be his date at the Yule Ball. But Rowling never took such chances.

For all that can be praised about the Potter books, it's important to realize that Rowling always played them perfectly safe. The teenage romance was chaste and hardly emotional. The abuses Harry suffered in his adoptive home were never of a kind that truly threatened his well-being. Neither Harry nor any of his friends was ever truly tempted by evil. She rarely played with ambiguity — with very few exceptions, Harry's foes were completely unhinged monsters or obstinately ignorant to the point of irrationality (or, like Umbridge, both). Neither Harry nor the reader was ever remotely tempted to take their side. I'm not criticizing her for this — were I lucky enough to be in her position I might take the same approach. But let's not make the Potter novels into something they're not. And let's not give Rowling's pronouncements about them more than the momentary notice they're due.

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James Watson is a terrible old man

I won't give the disgusting old bastard the benefit of a link; even leading the modest readership of this blog to his vile comments is too much a service to them. You'll probably find them on your own before too long. I don't want to apply clearly fallacious reasoning to the man's own abominable beliefs, but please, when you read his dismissals of Rosalind Franklin as an autistic harpy, remember that the man is an ill-informed racist pig.

There are heroes in the world of structural biology, but Watson is no longer one of them, if ever he was. Crick at least had a chance to make his voice heard so that history will always know his side of the story. I pity poor Rosalind Franklin, who will probably be lost to the future because of Watson's endless denigration of her personality and work.

In other news, I seem to finally have made the fold feature work.

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The Game as Art — Silent Hill 2

James Sunderland arrives at the deserted town of Silent Hill. He has received a letter from his wife, Mary, though she has been dead for three years, stating that she will meet him there. As he searches for her, he finds others like himself—others who have been called to the town, even though there should not be, can not be, anything there for them. He is tempted by a woman named Maria who looks and sounds like his wife, but in personality is everything she is not. He is pursued by a monstrous, invincible symbol of sexual violence, which repeatedly kills and tortures the temptress. The companions he has found choose death over life, and he realizes the lie he has been living.

Spoilers below the fold.

Silent Hill 2 is a game for mature players, not because it is frightening or because it is violent. Rather, it is because the game deals with so many subjects that are only meant for the mature. Her dialogue and the visual themes surrounding her leave no doubt that Angela was sexually abused by her family. At one junction you find her in an underground room with walls that look like flesh and a row of running pistons around the top; the player must defend her from a strange creature that resembles two people sewn into a bedframe. This monster only recurs later on at a hotel that had romantic meaning for James and Mary. As I mentioned, Pyramid Head himself is an image of sexual violence, and his actions are also violent in a sexualized way. His weapons, a knife and a spear, are phallic, and a woman is his frequent victim.

James himself has been called to Silent Hill because he killed his terminally ill wife. This has unhinged him and he believes her to have died of her illness years before, shortly after they first visited Silent Hill (at that time it was a resort town). Many of the monsters James encounters are symbols of the hospitals where she stayed and the sexual frustration he felt during that time—"patients" trapped in straitjackets of their own flesh, over-sexualized hideous nurses, and bizarre mannequin-like creatures that have only a torso and four legs. Pyramid Head is derived from the historical executioners of a local prison.

The exact circumstances and reasons surrounding Mary's death depend to a certain extent on the player. However, the nature of this crime and the idea that Mary might forgive him for it are not something most children or teenagers are really ready for.

Would Silent Hill 2 be better off as a movie, or a miniseries? Perhaps so, though the first try at it failed miserably. The gameplay itself is competent but not fantastic, and though the fetch quests are designed so as to maximize the player's experience of the environment, most of the puzzles do not add to the atmosphere. The great artistic strength of Silent Hill 2, aside from the visuals, is the story, and this could perhaps be conveyed equally well by a movie. Indeed, the brevity of film would probably force the excision of Eddie Dombrowski, who does not significantly serve the story.

However, two things probably could not be done in a movie that are strengths of the game. The first is a construction of atmosphere. Silent Hill is very foggy, and quite full of monsters, who are preceded in their appearance by a buzzing of static from an apparently broken radio. The difficulty of seeing and the radio gimmick would probably just be annoying in a film, but in the game they inspire a fascinating paranoia and dread. Silent Hill 2 doesn't really rely on the visual flashes and cheap thrills that provoke a burst of fear, though there are a few such moments. Instead, the 'horror' of Silent Hill 2 is built up from a pervasive feeling of dread. You do not know what you will encounter next, but you know it will not be good, and yet the story provides an impulse to continue. There are some subtler tricks as well—James continues to carry Mary's letter, and the further into the game you are, the less of it there is, until it becomes only blank paper.

The other aspect of the game that could not be replicated in film is the collaborative aspect of its storytelling—the conclusion of the story depends on actions in the game. The most interesting part about this is the complexity of the calculus: unlike other games, there is no clear moment of choice that determines how the story ends. Instead, the game looks at how you have played. The story adjusts itself in response not to explicit decisions the player makes, but rather to what appears to interest the player in the context of the story. If you are intrigued by Maria, and keep protecting her and checking up on her, James leaves with her. If you are drawn by Angela's self-destructive nature, James himself commits suicide. If the player makes choices that re-emphasize both his love of Mary and the choice of life, James leaves town with the young girl Mary had planned to adopt.

In the end, despite its flaws, I believe Silent Hill 2 is a good work of art. The story that it tells is moving, and the visual symbolism used to convey the story is fascinating. The dialogue has very few awkward spots, and the voice actors all do a good job. The soundtrack is very high quality. But the thing that makes it art as a video game is its clever use of participation in two ways. Because the player must move his character through the fog and past the monsters, the work's ability to inspire dread increases. Because it is the player who decides how the story ends, the work is tuned for the greatest emotional impact. Carefully done, Silent Hill could be a good film, but without the participatory aspects it would not be as good a film as it is a game.

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Policy and the law of prudence

The one thing I find most infuriating in debates about anthropogenic warming is the inevitable point in the conversation when the denialist states that we shouldn't do anything because we aren't really sure that humans cause global warming. If you point out to him that the vast majority of scientists believe the evidence supports this conclusion, he will either point out that scientists 30 years ago were wrong about something relating to climate (the "global cooling" gambit), or that people have been wrong about things before ("everyone believed the earth was flat"). Both these points are irrelevant: forecasting technology has improved vastly, and it was not scientists who believed the earth was flat (most educated people knew it to be a sphere), but backwards hicks like himself. But there's a more important point to be made: when it comes to policy decisions, it doesn't matter whether we cause global warming or not.

In the first case, most of the things we need to do about climate change are just plain good ideas, whether the earth is warming or not. We need more efficient ways to grow and transport our food. We need to end our dependence on the finite resource of fossil fuels. We need to make our cities better filters of their own pollution. We need better water management. We need to end suburban sprawl. We need to control the global population of human beings. It doesn't matter whether our planet is warming, cooling, or staying the same: almost all mitigation policies make sense in any context. For policymakers to sit on their hands and ignore these steps is inexcusable, regardless of their belief in anthropogenic warming.

When it comes to emissions caps, however, the typical denialist will draw his line in the sand. Why ruin the economy if we aren't sure that warming is our fault? Leaving aside the fact that economic forecasts are at least as unreliable as climactic ones (and therefore just as bad a reason to make decisions), there is a very good reason to alter our policies to eliminate emissions of all kinds. This is the law of prudence: If you don't know how it works, don't mess with it, especially if you're stuck with it.

You don't try to jack around in the engine before you board your passenger flight to Miami. You don't screw with the wheels before you get into a roller coaster. Why not? Because you don't know how it works, and once you get on that thing you can't get off. The same principle applies here. We're stuck on this planet; we can't leave and start over. If we ruin it, we will all die. Thus, if you truly believe that our best scientists really don't know enough about this planet to say how its climate system works, then your only rational choice is to minimize our impact on that system.

Denialists love to argue that we're uncertain about climate change as if ignorance is a reason for inaction, but this does not follow. Inaction is a decision, and it is the wrong decision to make when faced with uncertainty. When ignorant of an essential system's mechanics, we do not want to damage it, and that means not screwing with it. The reduction of all forms of pollution (including carbon) as rapidly as possible is the best decision we can make if we're unsure of what's going on with our environment. If, as is the case, we suspect or believe that our actions are outright harmful, then elimination of emissions is the only reasonable option.

You'll hear the uncertainty argument again; in fact, you've probably already heard it once today if you've had a discussion about Gore's Nobel Prize or the environment generally. Uncertainty is always used as an justification for inaction, but it actually supports the opposite.

For Blog Action Day...

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The new Nobelity

I try not to pay too much attention to the Nobel Prizes, because the recipients are usually either boring, obvious choices or stupid ones. This time around, most fell into the former category. The choice of Capecchi, Evans, and Smithies for their development of the genomic knockout mouse was as unassailable as it was inevitable, and Fert and Grünberg's award for giant magnetoresistance shared both those properties. Gerhard Ertl's work, which probably sounds dull or obvious to the layman, is in fact of staggering significance, and his prize too was richly deserved, if not particularly exciting to read about. I can't recall ever having read anything by Doris Lessing, but this is true of most Nobel Literature Prize winners. I have always been confused by the idea of awarding a literary achievement prize to anyone who is still alive, anyway (more on that in another post, perhaps). Some have complained about her award, but the controversy on this prize is muted, especially compared to the storm that broke with today's announcement of the Nobel Peace Prize. No doubt you've heard that the prize was given to Al Gore, just days after a British judge debunked his film, which reflects poorly on our media. In fact, Gore was a co-recipient with the Intergovernmental Panel on Climate Change, and the judge, though he found that the film advocated a viewpoint and contained nine errors (most of them insignificant or understandable), did not dispute its central message. These facts are related, and understanding that relationship is, I think, essential.

The finding that An Inconvenient Truth advocates a viewpoint is unsurprising, because Al Gore is unapologetically an advocate for controlling anthropogenic warming. He is not a scientist, but a man who uses science (sometimes disputed science) to send a message. The Peace Prize has been awarded to advocates before, and justly so. Indeed, it would be completely unreasonable to award it to someone who was not some kind of advocate — gazing at your navel and saying "Apartheid is bad" does not qualify you for any kind of award, while getting thrown in prison for trying to end it arguably does.

On these grounds it would be inappropriate to give the Prize to the IPCC on its own. The IPCC is a scientific organization, and advocacy or even the appearance of advocacy would significantly undermine its mission. Gore and his allies make use of the IPCC's findings, and indeed without the weight of the IPCC consensus their fight against anthropogenic warming would go the same way as the awakening that followed the publication of Silent Spring. Gore is a strong, visible advocate, the sort of person or organization that deserves the prize, but though the IPCC did all the hard work, it is not an advocate, and would be practically invisible without the help of Gore and his friends. Without the scientists, the advocacy would be ignored, and without the advocates the scientists would be ignored. As such, if a Peace Prize is to be given for the fight against warming, both must be honored. That is what the committee did.

Was it justified to give a Peace Prize for this? At first blush, it might not seem that warming has all that much to do with peace. Of course this isn't particularly relevant — the Peace Prize has been awarded in the past for innovative banking approaches, service to the poor, and agricultural research. But if you want to be a stickler nonetheless, you should know that the effects of anthropogenic warming are likely to be a significant threat to security in this century, and perhaps the largest threat. If you think I'm not a credible witness on this point, perhaps you will listen to Gen. Gordon R. Sullivan, Adm. Frank Bowman, Lt. Gen. Lawrence P. Farrell Jr., V. Adm. Paul G. Gaffney II, Gen. Paul J. Kern, Adm. T. Joseph Lopez, Adm. Donald Pilling, Adm. Joseph W. Prueher, V. Adm. Richard H. Truly, Gen. Charles F. Wald, and Gen. Anthony C. Zinni. If you don't want to read their report detailing the security threat to the United States from warming, I'll give you the short version.

Climate change will cause agricultural disaster and population displacements in some of the most unstable places in this world. Rising sea levels will push millions of refugees out of Bangladesh. Changing rainfall/snowfall patterns will cause water shortages in Africa, Asia, and the Middle East, and these droughts will be accompanied by famine and disease. The cruel fact is that the countries hardest hit by global warming will probably be those least capable of mitigating its effects. The natural result of this tumult will be resource wars, including the possibility of wars involving nuclear powers such as India, Israel, Pakistan, Russia, and China. Famine, disease, and war will displace millions in these regions, leading to increased competition for resources in more habitable regions and an increasing strain of immigrants in nations where the effects of climate change have not been so dire.

In my own view, it is likely that societies facing this degree of resource scarcity will fracture along ethnic or tribal lines, leading to repeated incidents of genocide much like that we have seen in Darfur. Hopefully the situation will not advance to the point of nuclear war, but it is entirely possible that unhinged tribalists in unstable countries like Pakistan will decide that if they cannot have the resources, nobody can. Unchecked, global warming may well lead to war and an era of genocide unlike anything the world has yet known, including the unthinkable prospect of a second nuclear war. Only this time, the victim will be able to return fire in kind.

Was this the committee's justification? I couldn't tell you. It probably contributed, but it's equally fair to say that they were likely motivated by a political desire to tweak the Bush administration. It's fair to say that Bush deserved it, as his attitude towards the problem has been abominably stupid. More broadly, they may have meant the endorsement to help silence global warming deniers, though at this point the outright denial of warming is so far to the fringe that it will likely have no effect among stalwarts. At this point the essential debate concerns the policies that ought be adopted in light of the warming trend — in my view, the committee's action will add weight to the IPCC recommendations. The choice is still rightfully controversial, but it isn't outrageous or improper. They've made worse decisions.

The Gore-IPCC Peace Prize will be widely discussed for some time, and it is to be hoped that by awarding this prize the committee will encourage new efforts on greenhouse gas reduction and climate change mitigation. But the committee has tried to use the prize in such a way before, without success.

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The motes in their eyes

If you want proof that the workings of congress are almost totally inexplicable, you need look no further than the committee vote to declare the Armenian genocide a genocide. Now, in the most basic terms I have no objection to the idea of calling a spade a spade, even though the Turks clearly do. This probably has something to do with their nationalist laws forbidding insult to "Turkishness". At the same time, I wonder what business it is of our government to legislate the application of historical terms, even when the proper use is obvious. Moreover, the timing of this vote is fantastically ill-advised, given the tensions between Turkey and the Kurds, which may soon be coming to a head. Now is not the time to be alienating an ally who could easily make the situation in Iraq substantially worse.

But what gets me most is the planks in our own eye, the sins we rarely acknowledge. We tried to destroy a native people, too, and if we mean to criticize Turkey for "the elimination of the over 2,500-year presence of Armenians in their historic homeland", then we ought to discuss more openly and frequently what we inflicted on the Cherokee and other native people. But that resolution languished, never even escaping committee in the House, despite its mild language. And one of the men most responsible for those crimes? Well, he's on our twenty-dollar bill.

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Rationality

Also, if I may indulge in the fallacy of appeal to authority, this week's edition of Nature also contains a commentary and article reinforcing two points I just can't shut up about. The commentary points out the fallacy of producing ethanol from corn, still widely touted as a biofuel initiative by the slate of incompetents running for President. The second article, on the more rational initiatives involving jatropha, reinforces the need for agronomic research to underpin mitigation responses generally, and biofuel/biodiesel plans specifically. Politicians in all nations and from all parts of the political spectrum are jumping onto the biofuel bandwagon and proposing grandiose schemes that aren't supported by science or even a modicum of rational thought, and without regard for the potential consequences. Biofuels sound green, but the reality is that for the most part the plans of our presidential hopefuls amount to new clothes for old subsidies.

If you're trying to figure out which candidates are actually interested in and capable of fighting global warming, look for emissions caps (even cap-and-trade is something) and mandatory advances in fuel-efficiency. Those plugging biofuels or mandatory ethanol content are either morons or just looking for the farm vote; this is not yet a plausible means of fighting the greenhouse effect. Indeed, it is not clear how achieving significant ethanol content is even possible, in the short term, given the absence of production and distribution networks. I know a couple of candidates are spouting off about an "Apollo program" to fight climate change, and I agree that a strongly-funded (and well-managed) research initiative is a great idea. However, unless there are concrete policy suggestions to fill in the short term before the research program comes up with its magic answer, this "plan" generally just amounts to empty rhetoric by a politician who has no idea what to do.

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I haved a cake, but I eated it

A pair of articles in this week's Nature weaved an interesting picture of the evolution of language. Biologists will find the key discovery of both papers relatively unsurprising: the rate of a word's evolution is inversely related to the frequency of its use. This is precisely analogous to the interpretive principle of evolutionary studies, in that the best-preserved amino acid residues across time and speciation are assumed to be essential to a protein's function. It appears that a similar principle is at work in the evolution of language, the most used (essential) parts of a language also seem to be highly resistant to change.

The more general and esoteric paper is by Pagel, Atkinson, and Meade, studying the divergence of modern languages from the Indo-European root language. This is roughly equivalent to a study of divergent evolution or speciation. They used a Bayesian Markov Chain Monte Carlo algorithm (words that will likely strike fear into the hearts of all current Kern Lab members) to create a model of word evolution that closely matched observations. Between different Indo-European languages and within the languages of Spanish, English, Russian, and Greek they found that frequency of replacement of a given meaning/use was dominated by frequency, with a slight secondary effect from what part of speech it was. Conjunctions and prepositions seem to be most susceptible to change, with numbers least likely to evolve over time.

A more entertainingly-written study by Erez Lieberman et al. examines the regularization of verbs in English over time, from the Old English of Beowulf to the modern era. This is more like studying convergent evolution. Grabbing 177 irregular verbs from the old language, they related the percentage that had regularized to their frequency of use, and discovered that the probability of regularization scaled with the square root of the frequency of usage, as seen in their figure here. Again, frequency and evolution rate are inversely related.


What gives rise to this apparently universal effect? The authors of the studies suggest a few possibilities, the first being that familiarity brings stability. We're less likely to screw up words we use constantly, and probably prone to making up words to replace the ones we forget. Usage frequency will dictate how often a "new" word is needed, and whether the new word will be tolerated. A similar principle may also be at work in verb regularization. Remembering the irregular form of a verb requires a certain amount of effort for each verb, while a generalized rule requires only the effort to remember the single rule for all words. Unless a word is frequently encountered, the neural potential containing its irregular forms will not be reinforced, and the word will slide into regularity.

Moreover, because it is difficult to remember the proper irregular form, the (incorrect) regular form will be easily recognized (and therefore tolerated) in speech. So while my little title, composed of top-tier words, probably struck you as instantly wrong, it's likely you passed over the technically incorrect "weaved" of the first sentence (should have been "wove") without realizing it. In fact, regularized forms (such as "weaved") of many of the lower-frequency irregular verbs are already in wide use.

It will be interesting to see what effect the use of the internet has on this. The web is known for creating words with ease — "leet" and "pwned" are some common examples — and yet these words seem to mostly be transients, disappearing from usage almost as soon as they are adopted. And while the sheer volume of text and rapidity of typing on the internet would seem to serve the error-prone processes that produce new words, the easy availability of references and the ubiquity of pricks willing to point them out would seem to work against the evolution of new language. Now that we are past the alarmist stage where the internet is accused of destroying English, it will be interesting to see where it leads the evolution of the language.

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Ming Lei, artist of the molecular age

It's sometimes said that constructing the right figure for your paper is an art, and on occasion that statement really proves to be accurate. Thus it is that I present to you postdoctoral fellow Ming Lei's masterwork "Improperly Parameterized Adenylate Kinase Dynamics Overlay" - electrons on magnetic media, 2007.

For those who are interested, this was meant to be an overlay of many snapshots of Adk from a molecular dynamics simulation, on its way from an open state to a closed state. Doro wanted some motion blur on it, but before he got to that point Ming accidentally created this view, which I feel has its own artistic merits. Biophysics departments in need of a computational researcher, or art departments in search of a fresh voice, should be aware that Dr. Lei is a skilled visionary with several high-profile publications on the way, and would be a fabulous addition to any faculty.

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Resistance: Fall of Tamiflu

The past decade, and in particular the past five years, has seen a steadily increasing drumbeat of concern over the possibility of another influenza pandemic. Avian flu has been a topic of special concern, but the American health system's inability to deal effectively with even normal flu variants has led to significant efforts to upgrade capacity to manufacture the flu vaccine, as well as improve the supply and distribution of the neuraminidase inhibitor oseltamivir phosphate, better known as tamiflu. Because there are so few effective antiviral drugs, tamiflu is an essential line of defense in case vaccination fails. Unfortunately, it appears that the influenza virus can develop resistance to tamiflu treatment, which would be a serious blow to efforts to control the disease in an emergency. The wise course is to use tamiflu sparingly and at a high enough dosage that the infection does not have time to adapt. But will this be enough?

Tamiflu has the interesting property that the drug in the tablet is ineffective against the influenza virus. Tamiflu gains function inside the body due to chemical processing in the liver that reveals a reactive moiety. If you have an influenza infection, some proportion of the oseltamivir molecules will end up binding to neuraminidase, but the remainder will be excreted without further modification. This means that every time you are dosing a person with tamiflu you are also dosing the environment with it. That could be trouble, because some strains of influenza incubate in the wild, among ducks, for instance, who are likely to be swimming on the rivers or ponds where excreted tamiflu might be expected to end up. If these animals are constantly exposed to very low doses of tamiflu, it is quite conceivable that the viruses within them could evolve resistance to it without losing neuraminidase activity.

The question then becomes whether anything in the environment might degrade tamiflu before it reaches the ducks. We have one advantage in this regard: we generally treat our sewage before we let it go. In an experiment I do not envy one little bit, a Swedish team led by Jerker Fick tested actual sewage to see if oseltamivir carboxylate (the active form of the molecule) would break down in it (the article is open source on PLoS ONE). They took raw sewage, as well as samples of sewage at various stages of treatment, added oseltamivir, and incubated them with a similar temperature and duration to what they might experience in the treatment plant. The results were not encouraging: the amount of tamiflu they were able to recover from these samples was as much as or more than what they could recover from plain tap water incubated under the same conditions. Moreover, they found that the UV/visible light absorbance spectrum of tamiflu would not be conducive to photolysis in the environment. The conclusion from this is that we cannot expect any help from our water-treatment facilities in eliminating oseltamivir from water supplies that might eventually reach host organisms for influenza.

This puts us in a bit of a bind. It is impossible to use tamiflu without releasing it to the environment, even if it is used in accordance with rigorous guidelines designed to prevent resistance from arising in people. Yet, the more tamiflu that reaches the environment, the more likely it is that continued exposure among waterfowl will lead to the development of resistance. Although this is bad news for the future of tamiflu, it doesn't necessarily herald the inevitable onset of some kind of superflu. For one thing, some of the mutations that confer tamiflu resistance also diminish the ability of the influenza virus to infect hosts. Moreover, there's no guarantee that tamiflu in the environment will end up dosing avians — it might break down in their stomachs, even if it doesn't in the sewage plant.

Also, some mutations that confer this kind of resistance leave neuraminidase vulnerable to other inhibitors such as zanamivir (Relenza). Granted, Relenza does not appear to be as effective as Tamiflu, but the fact that resistance is not necessarily shared is an encouraging sign that it will be possible to continue developing improved inhibitors even if the worst happens.

However, the results of this paper and the fact that tamiflu-resistant strains can be transmitted to people who have never used tamiflu indicate that we should be making a greater effort to prepare ourselves for the appearance of resistance. Much has been made about efforts to stockpile tamiflu in case of a pandemic, and while there is nothing wrong with that idea per se, it is foolish to assume that tamiflu is some kind of panacea. If a pandemic does occur, with the attendant explosion of evolutionary possibilities for the influenza virus, the chances of a rapid development of resistance in humans may be quite high. At that point it will be too late to start developing alternatives. In the near term, we should do as has been suggested — use tamiflu sparingly and aggressively to minimize the chances of developing resistance in humans. But we should also provide incentives or a mandate to develop a back-up plan in case tamiflu fails.

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Allosteric inhibition in medicine

If you wanted to keep someone from driving off in their car, how would you do it? There are some obvious answers: you could put some kind of blockage in front of and behind it, or you could slash the tires, or you could damage the engine, or you could empty out the gas tank. All of these approaches directly interfere with the mechanisms that allow the car to move. Alternately, you could take a more indirect approach: you could break the doors so they don't open, or remove the steering wheel, or take out the brake and accelerator pedals, or remove the stickshift. None of these latter approaches make it impossible for the car to move — the engine and wheels still function — but by removing the means that allow human beings to control the car these approaches still manage to ensure that the vehicle cannot be driven.

The traditional approach in structure-based drug design is to attempt to block the active site of a protein or important interacting sites, analogous to the "direct" approaches I outlined above. By adding a lump of stuff that obstructs enzymatic activity, ion transport, or (more recently) binding interactions these drugs attempt to interfere directly with the biochemistry of the target protein. This approach has been pretty successful, and certainly no reasonable person would want to depart from it, but there are some weaknesses here. For one thing, many diseases don't originate from enzymes or ion channels, and developing drugs that obstruct binding interactions can be pretty tricky.

Imagine your disease arises in the following system. You have some kind of receptor (R in my little cartoon over to the side there) that can bind a ligand (L). Binding of L activates R in some way so that it can bind to a partner (P) and this causes some gene to be activated. This cartoon roughly represents the way in which hormone receptors (like for estrogen or testosterone) function. Now, suppose something has occurred to derange this system: perhaps too much of L is being made, or R and P have been aberrantly expressed in some tissue where the gene they activate is toxic or causes inappropriate cell proliferation.

If we come at this by the conventional approach of targeting the L-binding pocket, we have a problem, because any drug that has an affinity for R high enough to displace the natural ligand is likely to produce the same or similar conformational changes that cause P to bind. We could, of course, try to develop a drug that interferes with P's binding directly, but this approach has its own problems. For one thing, these binding surfaces are often quite large and highly structured, features that are often difficult to replicate with a small molecule. You can create a drug that inserts itself into the site somehow and gets in the way of P binding, but it's not always possible to design such an agent that specifically hits only your protein. A peptide mimic of R might work, but these are also difficult to deliver.

But there's another strategy that might work, too. Rather than try to block R from binding L or P directly, what if we could cause some other change in R that prevents P binding whether or not L is around? Just like removing the accelerator or stickshift from the car of my example, this doesn't directly block either function of the molecule. R can still bind L, and the binding surface P interacts with is still present. However, our drug (D) has caused a new change in R's conformation that prevents the binding of P. A simplified cartoon is at left.

This is precisely what seems to have happened in a study on the androgen receptor (AR) appearing the October 9 issue of PNAS and reported by Eva Estébanez-Perpiña and coworkers from UCSF and St. Jude's. Interestingly, this group of researchers was initially seeking to produce a direct inhibitor — in this case, a drug that would bind to the part of AR that interacts with its coregulators. This interaction is therapeutically interesting because aberrant AR activity plays a role in prostate cancer, among other things. Several promising compounds were found that produced substantial inhibition of AR activity at relatively low concentrations. The surprise was that only some of these preferred to bind the targeted site (AF-2). Instead, a number of them were found to locate preferentially to a previously unsuspected site at the top of the molecule, now called binding-function 3 (BF-3), which you can see in the figure I shamelessly stole on the right here.

The reason that this appears to work is that binding to BF-3 changes the structure of AF-2, via an allosteric interaction. Rather than directly getting in the way of the essential reaction, the drug acts at a distance to disrupt the binding surface. Although much still needs to be done to refine these lead compounds into usable drugs, this is a significant demonstration that such an approach has therapeutic potential. In this case, the discovery of allosteric inhibitors was made by accident, but as our understanding of protein structure and allostery improves, expect to see more efforts to approach drug design in this way.

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