Massachusetts, vote NO on Question 1

Ballot Question 1: A YES vote would reduce the state personal income tax rate to 2.65% for the tax year beginning on January 1, 2009, and would eliminate the tax for all tax years beginning on or after January 1, 2010.

I know, I know. I hate paying income tax, too. I dislike government waste, too. It would be nice to have a little extra money in my pocket. It would be nice to see the state get leaner. In a world full of magical money fairies that preserved essential state programs in the absence of revenue, the Question 1 proposal might be a good idea. But there are no magical money fairies, and the only rational vote in response to question 1 is No.

I freely admit that I don't dislike taxes as much as the next guy might. The State provides me services that protect my meager wealth and support my standard of living. Accordingly, I favor the support of those services through fair taxation and fiscal responsibility. However, virtually every state in the nation, in addition to programs that support the public good, also funds programs that do little more than support public servants. Massachusetts, like any other state, is beset by waste, corruption, and appalling incompetence. Perhaps if we put the state on a starvation diet by squeezing off one of its chief revenue sources, it would force the government to trim unnecessary programs and waste.

Perhaps.

But you, and I, and anyone who has ever encountered government in any of its forms, know that's not going to happen. Oh, there may be some trimming here, some squeezing there, but the deep cut, the major restructuring, is not going to happen. What's going to happen instead is a restructuring of the tax system. Money that used to flow into state and community coffers from the income tax system will now be obtained via increased sales and property taxes.

"Higher sales taxes don't matter," you say, "I'll just drive up to New Hampshire to shop." And maybe you will, but that's not an option for everyone. Those who do their shopping in-state will end up paying more for less. Retailers will either have to cut prices to compensate, or just accept reduced sales. More people go out of state to shop, and those who stay will have reduced purchasing power.

"Property taxes don't matter," you say, "I rent, anyway." But somebody owns the property you lease, and when their taxes go up, so will your monthly rent. The heightened cost of ownership will drive some people to sell their property, increasing demand in the rental market and driving up prices that way. And even if your landlord doesn't hike your rate, the squeeze means something, be it maintenance, landscaping, or snow removal, will have to go. Moreover, the higher property taxes will be passed along to Massachusetts businesses that own or rent their stores. Higher prices or staffing cuts will follow.

The government of Massachusetts could and perhaps should be smaller. The tax burden of state citizens should perhaps also be lower. Getting there by eliminating the income tax, however, is akin to trying to lose weight by cutting off your legs. Precipitous, intemperate action of this kind will only raise the cost of living in Massachusetts, while adversely affecting the economy and standard of life. No matter how much you hate taxes, the only responsible vote on Question 1 is "No".

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Silent Hill's twists unravel

A writer takes a significant risk when he adds a plot twist to a story. In the best-case scenario, the secret that changes everything gives the audience a feeling of revelation. Everything clicks into place and suddenly makes sense. Laying the groundwork for that feeling is a tricky business, though. It's very easy to sell the setup too hard, making what's coming too obvious. In this case the twist merely bores the audience, which is not the worst thing that can happen. If the writer works too hard in the other direction, and does not give enough basis for the change-up, the audience may reject the surprise, in which case you lose them entirely. Beyond these considerations, the big reveal has to be timed well, so that it builds rather than deflates the emotions of the audience. Silent Hill: Homecoming has two twists that don't work out as well as they could. Their failures owe much to the nature of the medium itself, so it's interesting (to me at least) to examine them.

If you think I'm going to go through this without spoiling the surprise, then you'd best prepare yourself for a shocking twist.

The first surprise that Homecoming springs on the player is the fact that its protagonist, Alex Shepherd, is not a special forces soldier. He is in fact an escapee from a mental hospital, wearing his father's old dog tags. This revelation is primarily used to set up the later, more significant twist, so it doesn't end up clarifying much about the game's situation. Unfortunately, what it reveals does not mesh well with the player's experience.

In contrast to previous entries in the series, Homecoming features a dynamic combo system. This arguably improves the combat experience, and certainly accelerates it. Alex and his monstrous opponents move quickly, strike quickly, and dodge quickly. Also, firearms now come with a targeting reticule, and precision shots are key to dispatching certain enemies. All of this makes a great deal of sense and feels very natural if Alex really is a special forces soldier, much less so if he is some schlub who sneaked out of the mental ward. The player's entire experience of Alex strengthens the impression that he is a well-trained soldier, versed in the use of multiple weapons. It simply doesn't make any sense, in terms of this interaction, for Alex to be something else. In short, the game does too good a job of convincing us that Alex is who he believes himself to be. If the player had been burdened with the cumbersome combat of earlier Silent Hill games, by contrast, he probably would have already started to doubt that Alex was a highly trained veteran. In this sense, the move to the new combat system, despite the improvement to the gameplay, was probably a mistake.

Of course, the entire plot of the game could just be one of Alex's delusions. The fact that all the clocks in his hometown are stopped at 2:06, connecting with the suggestion that he was in room 206 at the hospital, would seem to support this idea. Yet this idea doesn't seem to lead us anywhere further. For one thing, Alex continues to fight like a super-soldier even after he learns that he isn't one. For another, the monsters inhabiting Alex's hometown don't really seem to reflect any psychology. Silent Hill 2 featured a man roaming through a town populated by the demons of his own mind, but the secondary characters of the game helped provide a map to his psyche. Here we have nothing to go on. Do the ferals represent the family dog? Did someone's smoking habit produce the Smog? The Nurses might symbolize Alex's unpleasant time in the hospital, and the Schisms might be saying something about Alex's conflicted feelings towards his parents. Overall, however, the monsters just feel like monsters, thrown into a game because they look frightening. If they attacked differently (if the Lurkers tried to pull him under water) or were differently armed (why not give the nurses drills or icepicks?) the lines might have been more clearly drawn. Unfortunately, while the monster designs are reasonably scary they seem to have little to do with Alex's soul.

The news that Alex isn't a soldier ends up being just too hard to swallow. The mechanics of the game do too much to convince the player that Alex really is a trained killer, and the presentation doesn't really sell the player on the idea that the whole game is in Alex's head. The devil of it all is that it's such an unnecessary choice. Would it have cost the story so much for Alex to have really been a soldier? It's a needless twist, poorly supported. The most interesting lesson here is that the gameplay is a core reason why the twist doesn't work well. The player's experience simply can't be ignored when you're trying to set up a surprise like this.

Homecoming's second, more shocking revelation is that Alex's brother Josh, whom he has been pursuing and trying to save throughout the game, died some time back in an accident for which Alex was responsible. His bad psychological reaction to this event was why Alex ended up in the mental hospital to begin with. The game's writers did a good job setting this up: when you learn this it causes many of the game's events to click into place, just as you would want. For the Silent Hill fan, however, this revelation is surprising only for the sheer audacity of the choice to recapitulate the central twist of an earlier game. Problems in the cutscene itself, and poor design choices around it, also conspire against the central twist.

The cinematic in which we learn what happened to poor Joshua simply didn't work for me. One key issue was that the Alex Shepherd of this scene didn't seem to exist anywhere else in the game. In the game itself, Alex comes across as very serious and adult, which admittedly could be the product of maturity. However, in other flashbacks Alex also seems to be mature and caring. These perceptions simply don't fit with the childish speech and behavior Alex displays in the flashback to Josh's death. The Alex we see on the boat in the cutscene acts and speaks like a 10-year-old; although physically recognizable, he is psychologically unrelated either to the Alex we see in the game or the Alex we see in other glimpses of the past. The flashbacks and found materials should have been put to use to get us acclimated to this character.

The scene also lacks a certain internal logic. Why has Alex rowed them onto the lake? Even a few fishing rods in the boat would have made this into a non-issue, but instead this question is allowed to hang over the whole scene. It becomes even more difficult to swallow if you've explored the town hall. Reading material found there suggests that Alex himself might have very good reasons to be afraid of the water. In an almost painful error, the writers have Josh actually ask Alex the question, forcing the player to confront the scene's logical failing.

Inconsistencies in character and plot make the revelatory cutscene needlessly difficult to swallow. Realizing the angle that the writers decided to take makes the surprise seem obvious and disappointing — this series already had a main character who killed a loved one and forgot that he'd done so. Although various scenes in the game and the found materials do an excellent job of supporting this development, the big reveal itself nonetheless manages to find the worst of both worlds by being at once too obvious and too absurd.

The reveal has a timing issue as well. Alex spends the whole game trying to save his younger brother. When the big twist gets revealed, that quest gets deflated. Josh is dead; nothing Alex can do will save him. Immediately after this revelation, we have the big, final boss fight. The thing is, the twist completely deflates this battle. Knowing that the main character's principal motivation has evaporated, it's difficult to see why he would struggle to survive at all. Why should I force him to fight, when victory would still mean failure?

So I didn't. I let Alex die, and turned off the XBox.

I eventually came back and tried out the various endings, of course, but I never felt right fighting Amnion. Alex's singular determination to save Josh had caused his psychotic break and propelled him through legions of hellish demons. With that determination gone, I was left searching for a reason for him to continue, and it just wasn't there. I don't contend that this is the only proper reaction or interpretation, but it is a valid one. In a movie or a book, continuing through the battle with Amnion isn't a problem, but in a game the player's emotional reaction to the flashback really ought to be considered, especially in a game where the player is making choices about Alex's emotional reaction to his journey home. If the developers were absolutely committed to the idea of putting this cutscene where it was, they should have offered the player the option to accept death from Amnion. Several of the game's existing endings could conceivably follow from such an outcome. Moreover, an ending wherein Alex trades his own life for Josh's using the powers of the town could have been profoundly affecting.

Alternately, the big reveal could be moved to after the fight with Amnion. If Amnion were to swallow Joshua in front of the player, an act that would have symbolic meaning, it would provide a strong motivation to win the final battle. Seeing Josh tumble, drowned, from Amnion's body would be a sensible stimulus for Alex's final flashback. Better yet, it would shift the disorienting emotional shock to a moment when the player can actually try to process it, rather than just diving straight into apocalyptic combat.

The decision to hit the player with the revelatory flashback just before the final battle feels at odds with the requirement that the player win that battle. Giving the player the option to progress by losing (it is survival horror after all), or shifting the flashback to the end of that fight would help sustain the emotional momentum of the story. For a game, that momentum is critical because the player is the agent who continues the story. You have to keep him on board.

For all the criticism I've leveled here, I didn't think Silent Hill: Homecoming has a bad story, or even particularly bad twists. As an effort to integrate the occult drama of Silent Hill 3 with the psychological horror of Silent Hill 2, it largely succeeds. The problem is that the play and structure of the game don't agree very well with the two main twists. They might work perfectly fine in print, or even on film, but these change-ups just don't play well. As a result, Homecoming feels like less than it could have been.

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Making a molecular switch

The practical aim of the investigation of allostery is the manipulation of this property as a means to aid human health and industry. We already have in hand the sequences of numerous enzymes that carry out unique and useful chemical reactions, and recent advances suggest that we will in the near future be able to design man-made enzymes that efficiently carry out completely novel reactions. Making the fullest use of these abilities demands that we be able to regulate the enzymatic activity of interest. Fortunately, just as nature possesses a rich array of enzymatic activities, it also holds a number of binding proteins, so we don't have to start from scratch. The trick is that there must be some way to communicate the binding event from one domain into the active site of the other domain. In last week's edition of Science researchers from the University of Pennsylvania and the University of Texas Southwestern Medical Center claim to have achieved just that.

The core idea of their approach is disarmingly simple. Identify a protein that has a long-range conformational response to a binding event, and locate the distal region on its surface where this response gets read out. Then, on an enzyme of interest, find a region of the surface that has an energetic connection to the active site. Join the proteins at these surfaces and voila! Now you have a regulatory switch for your enzyme!

The reality, of course, is likely to be trickier. In order for efficient communication between sites to occur via these pathways, the structural dynamics of allostery at the points of attachment must be compatible. For nearly all proteins, the precise nature of the conformational reactions that drive communication are essentially unknown. Thermodynamic mutant cycle analysis cannot provide detailed mechanistic information, and structural dynamics experiments from NMR and other techniques can provide only general information about what occurs on these pathways. Only molecular dynamics simulations are likely to give us the information we need to tune the allosteric control precisely. Absent that, all you can do is just stick things together and hope for the best, which is essentially what Lee et al. did.

Of course, they didn't go in totally blind. Lee et al. used the statistical coupling analysis (SCA) technique pioneered by Dr. Ranganathan to identify distal surface sites linked to the light sensitivity of a PAS domain and the enzymatic activity of a bacterial dihydrofolate reductase (DHFR). I've mentioned this technique before in connection with Ranganathan's research on the PDZ domain. The SCA results indicated that a surface loop of DHFR was energetically linked to its active site. The analysis also indicated that a region encompassing the N- and C- termini of the LOV2 PAS domain was likely to be a readout for its detection of light. These results accorded with existing knowledge about these proteins. The result with the PAS domain was particularly convenient. Because the N- and C- termini are adjacent, it meant that the PAS domain could simply be inserted at a loop site. Also conveniently, the surface identified for DHFR was a loop.

Thus, Lee et al. inserted the PAS domain at two sites in DHFR. One was the loop identified by SCA, and the other was a control site equally distant from the active site but not predicted to be linked. Figure 3 of the paper shows the key result: insertion of the PAS domain at the SCA-identified site (A site), but not the control location (B site), resulted in a modest light-dependence of the hydride transfer rate for DHFR. All of the A site chimeras had substantially reduced DHFR activity, similar to the effect of a G121V mutation. Interestingly, shifting the insertion site by even a single residue completely abolished the light-dependence of the activity.

Granted, the light dependence is less than twofold at room temperature; this approach did not generate a genuine light-dependent on/off switch for DHFR. However, for the reasons I mentioned before, a perfect switch is hardly something that could have been expected. What this experiment does do is prove that this approach is workable. Conceivably, with further tuning the hybrid PAS-DHFR can be made to carry out its catalytic function exclusively in the presence (or absence) of light. Since PAS domains bind a wide array of ligands, the approach can probably be adapted for various chemical triggers.

On a more fundamental level, the authors claim that this result supports the view that specific surface locations in many domains may be evolutionarily-conserved loci for allosteric control. This does not mean that every PAS domain (or PDZ domain, or DHFR) actually possess allosteric properties, but it does imply that all of them have the potential to exert or receive allosteric influences. If this is true, then it may be possible to adapt a wide array of binding modules as allosteric regulators for natural and designed enzymes. As our understanding of intradomain signaling improves, our ability to make use of these approaches will only increase.

J. Lee, M. Natarajan, V. C. Nashine, M. Socolich, T. Vo, W. P. Russ, S. J. Benkovic, R. Ranganathan (2008). Surface Sites for Engineering Allosteric Control in Proteins Science, 322 (5900), 438-442 DOI: 10.1126/science.1159052

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The masonry of moments

Tim is on a journey to find the Princess. You have heard this story before, in games other than Braid. She was kidnapped, you see, or perhaps she left. Tim can't really remember; the past gets so blurry when it may be the future. If you're confused, that's only natural. Jonathan Blow's Braid is a metaphorical puzzle, full of worlds that contain platforming puzzles that you solve to get puzzle pieces that you assemble to reveal more of the game's core riddle. It is not layered so much as coiled, like a diamondback with a taste for its own rattle. Its dense, ambiguous narrative provides rich ground for interpretations to grow. Is it about a breakup? The atom bomb? A stalker? Or is it about something more fundamental?

Braid is Tim's quest for the Princess, a journey that in which he must surmount obstacles by manipulating time. Each "world" of the game makes use of a different time alteration. In all of them Tim can rewind time to undo most of his mistakes, but some worlds introduce objects that are immune to this trick. In one world, the direction of time depends on the physical direction Tim is walking; in another, a shadowy doppelganger repeats Tim's actions when he rewinds. There is little reward for merely crossing a world; in order to reach the Princess, Tim must gather and assemble its puzzle pieces.

But who, or what, is the Princess? She appears in the game's final level, when we learn that she was fleeing Tim, and that the identity of monsters depends on time's arrow. The character of the Princess seems to change in each piece of text. Here, she is a lover, there, a mother, elsewhere, nature itself. Tim loves only her. Tim loves someone else, but seeks the Princess anyway. Finding the Princess in the text is almost a greater challenge than finding her in the field of play. Perhaps she isn't a literal woman at all, but rather enlightenment, an understanding of the universe and of other people. I say this because, more than a quest for a person or a place, Braid is a journey of learning.


We learn by reading. We learn by observing. We learn by trying. Braid demands that the player do all these things. The world occasionally provides hints, but only the most trivial mechanics and controls are ever explained directly. Getting a puzzle piece rarely requires any particular platforming skill; rather, each requires that the player carefully look at how the world reacts to what he does, and develop a plan. The text that prefaces each world provides a metaphorical hint of the experiences to come, and the object of each world is the assembly of an image that represents that world's ideas. In one, a young man makes a mistake, in another a boy sits sullenly in an airport while his doppelganger chatters happily with strangers. The music contributes perspective as well. In one world we are presented layouts reminiscent of early platformers, layered in with Braid's native time mechanics. Lullabies play in the background: we are looking in on an artform's infancy. The player's progress and success in each levels depends on a scientific attitude towards the world; the player's understanding of what this means depends on an artistic view.

Art and science. Tim seems to understand one, but not the other. He can dissect the angles and the lighting, but the emotion of film passes by him. When the Princess lies within his reach, longing for his grasp, he cannot see her; half of the universe lies beyond his ken. He is busy putting tungsten posts into the brains of monkeys and splitting the atom. Yet each step forward takes him further away from her. The puzzles of Braid's worlds escalate in complexity, and solving them requires ever greater acuity. However, the Princess can only be found at the beginning of World 1, a world without any puzzles at all, which presents the game's purest platforming sequence. Tim is closest to the Princess when the player operates off reflex and instinct. Once he begins manipulating time, Tim can only get further away from her. The paradox is that each step away, by revealing more of the narrative and art, nonetheless brings Tim closer to the Princess. Braid is his purgatory, in which the skills of the scientist must be made to unlock the reflections that allow him to approach the Princess again, for the first time.


Braid ends with Tim's decision to build a castle from his experiences, an edifice of ideas. He has already encountered many such palaces in his travels, each inhabited by a metaphorical dinosaur from the old school of thought it embodies. Should we wonder how Tim's castle will look? Or have we already seen the interior, gazed at the key moments that form its structural walls? You know what they say about a man's home...

Is Braid too difficult, too inaccessible? Possibly so — understanding the game means the player must think deeply in divergent modes. Success requires that the physical world of Braid be taken literally, but its art and literature must be interpreted symbolically. The platforming and puzzles are physically and mentally demanding, and ultimately some players will not be able to make their way through.

But what Braid asks of us is difficult. The gap between the artistic and scientific views of the world seems so wide that many would say they have nothing (or little) to offer one another. Braid argues that either approach is insufficient, that if we look at things only one way, we cannot see the Princess. Without a piercing examination we cannot understand the physical reality. Unless we understand the physical reality we cannot make the art. Without the art we cannot find enlightenment. No one strand of reality is enough alone; they must be woven together, into a braid.

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Guanidinium alters the water landscape

Protein stability studies that rely on the use of cosolutes to effect chemical denaturation typically use either urea or the guanidinium ion (Gdm⁺). Both of these chemicals unfold proteins through a process involving multiple, low-affinity binding events, but guanidinium has the larger effect. While this could be attributed simply to the strength of the interactions, it could also be a result of other chemical properties. In an upcoming paper in the Journal of Physical Chemistry, a team of researchers from the University of Pennsylvania suggest that a reorganization of hydrogen bonds in water may be partially responsible for its greater denaturing power.

The reason water is a liquid rather than a gas is the existence of significant networks of transient hydrogen bonds between water molecules. Typically, water forms these bonds proficiently at a wide range of angles, which means an energetic benefit without a high entropic cost. The range of bond angles in use can be tested by assessing their vibrational frequency using infrared (IR) spectroscopy. The core of this paper comes from an experiment Scott et al. perform in which they measure the dependence of these vibrational frequencies on the concentration of Gdm⁺ and the temperature of the solution.

They find that the presence of Gdm⁺ significantly alters the IR spectrum of water at high temperatures, shifting the overall peak to a lower wavenumber and causing the appearance of a shoulder around 3300 cm^-1, near the main peak of the ice spectrum (Figure 2). The effect of the Gdm⁺ ion appears to be less at lower temperatures; as a result the appearance of the water spectra changes less at high Gdm⁺ concentrations than in the absence of the solute. These spectral characteristics are not observed when another positive ion (potassium) is used instead of Gdm⁺.

The authors interpret these changes in the IR spectrum as an increase in the number of short, linear hydrogen bonds, and back this up with quantum chemical simulations. If this is correct, then it implies that Gdm⁺ rearranges the hydrogen bonding network of water, changing the structure to emphasize strong hydrogen bonds of a particular geometry. Moreover, this change in structure appears to be relatively resistant to changes in temperature. This is significant because the creation of protein tertiary structure is thought to be a mechanism by which systems avoid forming highly-structured networks of water hydrogen bonds. If Gdm⁺ induces significant water structuring, might that entropically favor the unfolding of proteins?

Because urea does not appear to induce this kind of change in water structure, it should be possible to test this experimentally. The effect of Gdm⁺ is clearly most pronounced at higher temperatures. So one could perform a comparison of the temperature dependence of Gdm⁺ and urea denaturation of a protein. Proteins tend to be more stable at lower temperatures, as a result we would expect the denaturant concentration at which half of the protein population is unfolded (D_1/2) to increase as the temperature decreases. If the structuring of water is significant, then the change in D_1/2 should be larger for Gdm⁺ than for urea, because Gdm⁺ is decreasing in effectiveness as the temperature goes down. The direct interaction may also be temperature-dependent, but it may be possible to control for this by measuring the energy released when guanidine interacts with an intrinsically unfolded protein.

Unfolding experiments typically are not interpreted in a way that that depends on the precise mechanism by which Gdm⁺ breaks down protein structure. Nonetheless, the specifics of this process are important if we want to use chemically denatured states as models of in vivo unfolded states. As we gain a better understanding of in vivo water structure, the characteristics of denaturant solvation may be an important consideration in experimental design.

J. Nathan Scott, Nathaniel V. Nucci, Jane M. Vanderkooi (2008). Changes in Water Structure Induced by the Guanidinium Cation and Implications for Protein Denaturation Journal of Physical Chemistry A DOI: 10.1021/jp8058239

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The Attention-Deficit RPG

Last weekend I finished Namco-Bandai's Tales of Vesperia for the XBox 360, a game which delivers the "Tales of" series' characteristic action-chaos combat, lovely anime-flavored visuals, and little else. That's not how things begin: Vesperia presents a deeply unjust world and a genuine moral conflict about how to change it. The game's meandering, inattentive writing, however, leaves this initial promise unfulfilled. As a consequence the story is endlessly boring and deeply disappointing.

Spoilers follow, but trust me, there's not that much to spoil.

The world of Vesperia, Terca Lumireis, is politically dominated by an Empire that maintains its power through a monopoly on the distribution and sale of magical devices called blastia. Because Terca Lumireis is inhabited by numerous and exceedingly vicious monsters, blastia are believed to be absolutely necessary to survival: nearly all humans live in towns protected by "barriers" (there's no indication of how agriculture functions in these conditions). The Empire is very stratified, with a caste of nobles having crushing dominance over the commoners. As a result, many people choose to give up their citizenship and live in cities run by the Guilds. In tribute to MMO convention, each Guild is a group of adventurers with similar interests, not an organization dedicated to monopolistic domination of crafts and the exploitation of child labor. Blastia are exclusively artifacts that must be excavated, but all the world's archaeologists belong to a Guild, making the origin of the Empire's monopoly on the devices a curious and unexplored mystery.

The main protagonist of the game, Yuri Lowell, is a citizen of the Empire who once joined its corps of knights to try and redress the grievances of the common citizen, but left because he could not embrace their rigid adherence to protocol. By contrast, his childhood friend Flynn Scifo stuck with it and is now a celebrated member of the knights. Yuri has not managed to change the lot of the common man since leaving the knights, but Flynn hasn't had any success either. Like many RPG heroes, Yuri isn't able to simply stand aside when he sees injustice. Fortunately, he doesn't possess the excessive enthusiasm or angst typical of the genre. Rather, he comes across as a grounded individual, talented with a sword, who is profoundly dissatisfied with the state of the world and unsure how to change it.

In the course of the game, Yuri comes to a kind of answer, in that he murders two of the Empire's less redeemable officials, demonstrating his teleological approach to ethics. Flynn, pinch-hitting for deontology, acknowledges that the victims are criminals who escaped justice with the help of a corrupt system, but points out that if the system isn't transformed then it will just produce more untouchable criminals. Yuri can't kill them all. The story doesn't pick sides between the two men. Flynn achieves some good despite his inability to fully correct the system. Yuri, by contrast, is depicted as being cruel (especially in killing Cumore), and his approach is taken to its logical conclusion by the principle villains Alexei, who decides to get rid of the Empire by killing everyone in it, and Duke, who decides to correct a man-made environmental disaster by killing everyone everywhere.

The Guilds seem to be the natural alternative to the Empire, but as the history of the young character Karol illustrates, they don't have a system to support people who haven't found themselves. In the Empire such a person can at least scrape by; Karol simply gets abandoned. Moreover, the Empire manages to lurch forward even without an Emperor, while the Guilds descend into chaos after the death of the strongman who held them together.

You could do things with this, especially in light of the fact that the character Estelle is one of the candidates for the imperial throne (the worst-hidden twist of the game), but the social justice angle fades in the late game without really getting resolved. Instead, the endgame focuses on the side-effects of the blastia technology. There is an explanation for this, involving enough magibabble to make a Star Trek writer blush, but the primary upshot is that if the blastia continue to be used the world will be destroyed by a gigantic monster. There seems to be an pass made at a metaphor for anthropogenic global warming here, but it never connects because all the major problem-solving takes place off-screen, and nobody really seems to resist the destruction of their entire way of life... not even the ones who must literally die in order for the plan to work. Moreover, the connection between the social injustice of the Empire and the environmental destruction caused by the goods that give it power is never seriously explored.

If the larger dynamics get short shrift, then you would think that the characters would get a fuller development. Unfortunately, most relationships between characters are only lightly drawn, with the exception of that between Yuri and Flynn. Although he doesn't ooze angst, Yuri is a very calm, restrained character in most scenes. The breakdown of this control does a good job showing the connection between the two of them. Unfortunately, the writers frequently use Flynn as a tool to move the story along or magically solve problems, meaning that he must be an NPC. As a result, we are treated to only brief encounters.

The characters in the party clearly develop a sort of squabbling family relationship, with Yuri as the ersatz father, but none of the individual connections come close to that between Yuri and Flynn. Rita and Estelle clearly develop some kind of connection, but the strongest demonstrations in that relationship tend to get obscured by the plot. Yuri and Repede have a bond, but there's just no getting around the fact that Repede is a dog. Yuri and Karol begin to connect, but this sort of peters out after Zopheir Drifts. In every case, the development of these relationships is significantly hindered by the meandering of the narrative and the flatness of the character arcs.

In an RPG of Vesperia's construction, the purpose of the story is to keep the action moving between dungeons, to motivate the player to finish each dungeon, and to imbue important battles with emotional impact. This narrative has trouble with all three. One major problem is that each time a town is entered, the story stops dead as the player must wander around trying to find and talk to each member of the party. These conversations rarely move the story forward and often repeat themselves (more on this in a moment). Momentum is also drained by the fact that the narrative meanders significantly. There are times when you firmly know where to go next and why you are going there, but there are also too many times when it's not clear where to go or why you would bother going there.

The absence of a strong direction for the general plot also sinks down into the individual character stories, which I hesitate to call "arcs" because that would imply a trajectory that is nowhere to be found. Rather, the characters remain in stasis until a critical event, and then adopt a new stasis afterwards. The effect of this is to repeatedly begin the character's development. Estelle is indecisive and impulsive; Yuri and Judith challenge her to make a firm decision. This is fine the first time, but after this has been repeated for the fifth time it wears very thin. Then, after a particular event, this characteristic simply isn't mentioned again. It almost seems like the writers forgot that they'd already shown us a scene in which Yuri demands that Estelle decide whether or not to continue her journey, so they just keep treating us to nearly identical dialogue in town after town after town ad nauseam. Similarly, the fact that Karol is a coward gets repeatedly repeated until you'd rather stab yourself in the eye than suffer through hearing it discussed again. Then a particular boss battle occurs and suddenly he's not a coward anymore.

The repetition involved here would get to be dull and annoying even if there was any doubt about how Karol and Estelle would eventually turn out; in the absence of that doubt it is almost unbearably boring. Moreover, this kind of behavior flattens character development. There's no building of tension here, no character arc at all: the characters just stay the same until they abruptly fall off a cliff into a new state and are different. On the other hand, most of the characters never find that cliff at all. Yuri, Judith, Raven, and Rita all seem to make it through the story without experiencing any significant growth beyond the occasional clichéd revelation.

The inattentiveness of the writing really shows through in the vast collection of loose ends the story picks up from very early on. The motivation for Estelle to leave Zaphias with Yuri is that she has some warning she absolutely must convey to Flynn; once she leaves the city this is never mentioned again, not even when our heroes do at last catch up to him. The Knights become very well aware of Yuri's murder habit, but after a number of speeches about how he will have to face the consequences of his actions, from Flynn himself no less, no action is ever taken. Several of the characters form their own guild, but despite how important they make this obligation seem, nobody mentions it as they discuss their plans to go their own ways after the final confrontations. Then we have the essential abandonment of the social justice theme that dominated the early action, the biggest loose end of all. It's easy to overlook this if you're not paying attention to the story, but if the story only works when the player pays no attention to it, why have one in the first place?

The other main failing of the narrative in Tales of Vesperia is that it never manages to truly embody the actual antagonist. It is not Alexei who must be opposed, nor Duke, nor even the Adephagos per se. The system is the enemy, the entire way the denizens of Terca Lumireis have been living. An abstraction like that can't be engaged in combat, but one could assemble a cast of villains who represent the evils of that system, or who stand in the way of correcting it. The desperate chaos of the combat system would mesh well with such cathartic battles. Instead, Vesperia regularly forces you to defeat your allies in battle—the few systemic representatives it presents mostly die by Yuri's hand in cutscenes. Knowing this, you often feel like you shouldn't complete the current dungeon. Moreover, the largest boss battles seem meaningless, because you never confront the real enemy. The story makes these fights seem like empty exercises rather than important confrontations.

The consistent thread in all of this is a lack of care and attention. The constant repetition of character moments makes it seem like the writers forgot what they'd already done. The loose ends make it feel like they couldn't remember what they promised. The fact that the major themes never really get tied together, although it could easily be done, makes it seem like they just couldn't be bothered to put in the effort. So why should you?

Despite it's lame, scatterbrained story, Tales of Vesperia isn't a terrible game. The high-action, Smash Bros.-style combat works as well as ever, although the frequency of enemies in dungeons and the unusual difficulty of avoiding them turned the game into a bit of a slog at some points. The anime-inspired visuals are solid, the voice actors do an excellent job, and the score is lovely (if badly handled on occasion). Those aspects seem wasted, however. There's no reason to have an art department create an overworld, towns, and NPCs, no point to hiring quality voice talent, no reason to make anything other than battle music, if this lame tale is all you're going to use them for. You'd do just as well to excise those things completely, package up the battles and character progression into a rail-movement dungeon crawl and sell the whole thing as a combat minigame collection.

The greatest disappointment is that things didn't have to turn out this way. Tales of Vesperia has atypical heroes, some strong relationships, a genuine sense of moral conflict, and a setting that links aggressive social and economic injustice to environmental abuse. You could take those elements and create a deep, compelling story, if you paid attention to what you were doing.

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Hit the road, Jack

Schadenfreude and gloating pervaded the online gaming world last week when the news broke that prominent anti-gaming crusader Jack Thompson would be permanently disbarred on or before October 25. While Thompson has challenged this decision in Federal court (accusing the justices of the Florida Supreme Court of persecuting him), it seems unlikely that he can do anything to save his right to practice law in Florida. Some optimists in the larger gaming community seem to feel that Thompson will be gone for good after this, but grandstanders of his ilk rarely depart so easily. Legally, Thompson is still entitled to file lawsuits like anyone else, and because he has become so notorious it is doubtful that he will be pushed out of the public square. This is much to the detriment of the debate on video game violence, because he did, and does, far more to harm the cause of those concerned about graphic violence than he ever did to help.

Of course, the critics of video game violence are legion, but few, if any, of them could rival Thompson for sheer volume or nastiness. Like many such critics he had a tendency to play fast and loose with the facts, famously asserting that the Virginia Tech massacre had been inspired by first-person shooter games and holding to this view in the face of definitive evidence to the contrary. His partaking in the brain-dead excesses of conservative punditry was not nearly as troublesome as Thompson's deep, almost disturbing lack of professionalism, good taste, and basic decency. His demand that Janet Reno tell him whether or not she was a lesbian is a well-known matter of public record. Less famous, but just as unsettling, was his conduct towards judges and fellow lawyers, carefully described in his bar trial (of which you can read selected transcripts at Gamepolitics). It is clear from the record that no boundary of decency or good behavior deterred Thompson from the pursuit of litigation based on the idea that video game violence caused real life violence.

That isn't a completely absurd contention like creationism. The psychological effects of violent media (including video games) constitute a serious area of scientific study. While reasonable people can disagree on the quality of particular experiments and the proper interpretation of their results, there is no serious scientific disagreement that violent media produce at least short-term changes in feelings of aggression and attitudes towards violence. The long-term effects of violent video games on normal people are still disputed, and there are a number of moral, economic, and artistic considerations that have an important bearing on the subject. Nonetheless, it should be possible to have a rational, constructive dialogue about whether and how much violence in games ought to be acceptable to the audience, the creators, and yes, even the government.

But constructive dialogue is precisely the sort of thing people like Jack Thompson prevent. The bullying attack mentality at the core of his behavior turns the issue into an emotional one, making every side too angry to engage in a calm, rational assessment of evidence. Because of this, Jack Thompson got in the way of addressing the violence issue every time he showed his face. Admittedly, if the court has a remedy for your harm these tactics can pay off in some instances. However, suppressing video game violence through legal means has not been, and will never be, a viable strategy in America. Thompson's attitude poisoned any chance that he could personally effect a change in the quantity of violence in video games. Even if he had been effective in recovering money from video game developers, the end result would have been an interminable process of swatting flies; attempting to punish the games industry for violence every time an exemplar showed its head. Profitable for a professional litigator, perhaps, but not a way to effectively change the industry's attitude towards the portrayal of violence.

Thompson also poisoned the larger debate by being a kook and a villain. He made himself easy to hate, a figurehead for gamers to revile, and also did his best to demonize both gamers and his personal critics. In this way he brought a needlessly adversarial relationship to the various sides of the issue. Because his attacks were accompanied by distasteful personal behavior and a fundamental unwillingness to deal in fact, Thompson also made himself a ready caricature. He enabled gamers and game developers to regard everyone who held his position as being just as out of touch, hateful, and ridiculous as he was. Hatred and ridicule both have the effect of dehumanizing the other side, and ending any serious effort at consideration or collaboration.

So I'm glad that Thompson has been disbarred. I'm not glad because it hurts Thompson, and it doesn't matter to me that the dignity of the Florida Bar has been upheld. I'm happy about this result because it discredits Mr. Thompson and is the first step towards removing him from the debate entirely. That's the best possible outcome for gamers, game developers, and organizations that are genuinely interested in decreasing the violent content of games and keeping violent games out of the hands of children. Jack Thompson did nothing but harm to those efforts; it is to be hoped that in his absence a friendlier environment, in which the participants in the discussion seek common ground rather than mutual destruction, will develop.

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Bailing into the lifeboat

A few weeks back, when I posted about the necessity of raising taxes and cutting spending in order to reign in the national debt, I did not anticipate that the market would force us to take such an enormous step towards insolvency. The bailout proposed by the Bush administration would cost us $700 billion, but many predict that its actual cost, after Congress adds its own trimmings and attempts to include some relief for homeowners in danger of default, will reach $1 trillion or more of money that we don't have. The irony of paying for bad debt with more debt might inspire a grim sort of humor if we weren't in such a big hole already. The plan as initially proposed is completely outrageous, but I have little doubt that Congress will find some way to make it worse.

The fundamental problem is that a mortgage-backed security is not a mortgage. The holder of a mortgage has the right to foreclose on the property (thus recovering real assets) if the loan is not repaid, but the holder of a MBS does not appear to necessarily have this right. The security spreads the risk from a pool of mortgages among a pool of investors; as such, no single investor can be said to "own" a particular mortgage (except in the case that he owns all the securities from a given pool). It's not clear whether the owners of MBS own anything other than debt; it is possible that they do not own the underlying loans. And these are the simplest vehicles assembled from residential mortgages... the real value of more exotic derivatives may be impossible to assess. This has serious implications for the proposed bailout, because there is a very real chance that we taxpayers will end up paying billions of dollars for smoke and mirrors. Before we release one penny from the Treasury for this rescue effort we must ensure that what we purchase with our money will give us a right to the underlying property, as well as the authority to modify the mortgages so as to diminish the default rate. We must not be left holding a bag of air.

The uncertain relationship between the securities and the actual mortgages underscores the unseemly nature of the whole affair. People who did not have the wherewithal to own homes got mortages from unscrupulous lenders who should never have given them out. These mortgages were packaged into vehicles that were treated like gold by credit raters, and then purchased by investors who probably should have known better. Only a fool could have imagined that the housing boom would continue indefinitely. The push by credit providers to make bankruptcy declarations more difficult for individuals had the unexpected side effect of increasing defaults. Holding negative equity on their homes in a plunging market, homeowners simply turned off the lights and walked out. The invisible hand failed to reign in the cascade of short-sightedness, stupidity, and outright malfeasance, and the credit market landed on its head with an audible crunch.

This would be bad enough on its own, but it set off a chain reaction leading to ever more violent flailing on the part of the Treasury department and the market players themselves. Because the securities had been insured, AIG took a hit and needed billions of dollars of government money just to die quietly. The failure of Lehman Brothers left money market funds holding worthless paper; the Reserve Primary Fund broke the buck and skittish investors started to flee. With all business in danger of grinding to a halt because of the shortage, the Treasury insured these investments with the Exchange Stabilization Fund. Because this insurance is not capped, small banks are now worried that panicked customers may move all assets in excess of $100,000 into the money market, leaving them short on cash.

Keating Five member John McCain, long a friend to unscrupulous financiers and enemy to the kinds of regulatory oversight that might have prevented this crisis, has been difficult to pin down on this issue, in large part because his position changes every time the sun comes up. His initial position, that we should stop bailing out financial giants, is understandable and at least has the virtue of being consistent with his free-market philosophy. His later attitude, an acceptance of the reality that these companies must be bailed out in order to protect the investors who acted in good faith, was more realistic. Exposure to the toxic mortgage-based securities put the other assets of these companies at risk, and it would be unconscionable to destroy the investments of good actors as punishment for the deeds of bad actors who had already escaped on golden parachutes.

(In McCain's defense, at least he said something, even if it was insane, and Joe Biden's response tracked a similar trajectory. As for the other presidential candidate, Barack Obama couldn't manage anything better than "I'll get back to you on that." Who will you choose in November: the madman or the slacker?)

Bailing out rich people stinks, but it stinks more when we don't really have any money to do it with. Section 10 of the proposed legislation increases our national debt limit for the fiscal year to $11,315,000,000,000. Given the authority to hit that ceiling, I have no doubt that the Treasury department will do so, meaning that our interest outlay in the next budget will be even higher than previously anticipated. Every new program you've heard politicians mention during this election cycle has just evaporated. The cost of a bailout is a credit crunch on the government, at the worst possible time. I've already proposed the solution to the problem: we must increase income and cut outlays. Otherwise, we're just bailing water from the yacht into the lifeboat. Specifically, the wealthiest Americans must be willing to pay higher taxes, because it is they that benefit most from the financial institutions the rest of us will be breaking the bank to rescue, and it was their exploitation of those markets that got us into this mess.

Of course, I haven't yet gotten to the most malodorous part of the whole proposal. It's bad that we don't know whether what we're buying will be worth anything, and it's worse that we'll significantly increase the national debt to do so. But the really despicable part of the legislation is this:

Sec. 8. Review.

Decisions by the Secretary pursuant to the authority of this Act are non-reviewable and committed to agency discretion, and may not be reviewed by any court of law or any administrative agency.

You know, at least with the absurdly-named Patriot Act these Republican pricks had some kind of flimsy excuse for their totalitarian actions. This is sticking a thumb in the eye of Democracy just to show you can. It was a lack of transparency and honesty that got us into this whole mess; we cannot get out of it by spending $700,000,000,000 at the sole discretion of faceless bureaucrats from an abominably opaque and secretive administration. The estimated cost of the Iraq War to date is around $582 billion, a massive number but still less than the amount proposed in this legislation. It defies reason and sense to insulate the choices made with this massive amount of money from oversight and accountability. The very request for opacity suggests that the whole operation is being undertaken in bad faith.

Bernanke and Paulson continue to insist that Congress must act immediately. Nothing in their past behavior, however, suggests that they possess the competence to make this analysis, or the honesty to accurately convey their analysis to the media or to the legislature. Clearly, something must be done, but handing out $700 billion to the same nitwits that got us into this mess, without anything even resembling appropriate oversight, is more likely to bring economic disaster than salvation.

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Where do new enzymes come from?

Biochemists often rave about the great wonders of enzymes, lavishing praise on the prodigious rate enhancements they produce, and their exquisite positioning of functional groups. One can quite reasonably ask how such magnificently useful proteins came into being. One accurate answer, of course, is that after a couple hundred million years evolution can get almost anything right. Another answer is that most enzymes come from other proteins, via a process called gene duplication. The genetic changes that follow one of these duplications turn two copies of one protein into two completely different proteins with diverse activities.

Gene duplication events are infrequent errors of DNA replication or repair. Diploid eukaryotes such as ourselves carry two copies (or near-copies) of most genes as a matter of course, but gene duplications produce extra copies beyond that. In theory, the presence of these extra copies of a gene means that one of them can mutate freely, without the pressure of carrying out its normal job. When it drifts into a useful function, selective pressure is again applied, causing a refinement of the active site to maximize the efficiency of the new activity. The overall scheme looks something like this:

Duplication → Divergence → Refinement

It may seem incredible that a vast diversity of protein structures and activities can arise simply by making copies, even imperfect copies. However, certain quirks of the translation machinery mean that small changes in DNA can amount to enormous changes in a protein's topology. For instance, an insertion or deletion of a single base can cause a frameshift mutation, producing a protein that bears no resemblance to its progenitor despite having only 1 different base pair. Many DNA triplets that normally encode amino acids are only a single base-pair mutation away from becoming a stop codon, truncating a protein and likely changing its structure significantly. Similarly, stop codons can be easily eliminated, producing much larger proteins. In eukaryotes, point mutations near the borders between introns and exons can cause new regions of DNA to be translated into protein. Of course, drastic changes like these mostly just produce useless junk, but occasionally a novel fold or function arises.

More conservative alterations of a gene sequence can still produce significant changes. As I've mentioned before on this blog, some members of the Cro family of proteins have very high sequence identity and yet possess different structures. I also have not yet tired of reminding you that the chemokine lymphotactin has two different structures with a single sequence, either of which can be stabilized into an exclusive fold by a point mutation.

Additionally, research from the lab of John Orban shows that a mere 7 mutations are required to convert the engineered protein GA88 (PDB) into a completely different structure, GB88 (PDB) (1). These proteins were previously shown to have different folds and functions, but the contrast between the high resolution structures (shamelessly stolen figure on the right) is striking. Moreover, the Orban lab has refined this system so that the structural conversion can be effected with only three mutations, rather than seven. What all this research indicates is that the transitions that convert a sequence from one fold into another may be sharper than previously realized; even a relatively small number of fairly conservative mutations may be able to completely transform a protein's structure.

For all that, most new enzymes arising via gene duplication resemble their ancestors in identifiable ways. Often the two proteins perform the same chemical steps, and the novel function amounts to a different substrate specificity. This suggests the possibility of an alternate mechanism of gene duplication, in that a protein could evolve a novel specificity while retaining its original function. Diversifying its activities in this way would probably limit an enzyme's catalytic effect in both reactions, but a subsequent gene duplication event would allow each copy to refine its particular reaction. The scheme would look like this:

Diversification → Duplication → Refinement

The advantage of this model, from an adaptationist's perspective, is that it brings selective pressure to bear at every step. Once a new function has evolved in response to environmental conditions, duplicating the gene may provide an organism a concrete advantage. After duplication, the advantage of separately refining the two activities is obvious.

The two models are not as different as they might seem at first glance, because nearly every enzyme catalyzes two reactions anyway, that is, the forward and reverse reactions of an equilibrium. A "new" activity for a given enzyme can therefore result from something as simple as being targeted to a different cellular compartment or a change in specificity that involves an oppositely-oriented equilibrium.

The most obvious objection to the latter model is that during the period of gene sharing prior to duplication, neither protein function will be very efficient. As a matter of fact, the appearance of a new activity does not always impair an enzyme's ability to do its original job (and indeed can even enhance that activity). Still, because of the exquisite tuning of enzyme active sites we can expect that many modifications to this region will reduce catalytic power. That being the case, how might an organism survive or thrive during the gene-sharing period? The answer, which always seems obvious in retrospect, is to make more of the less efficient enzyme, as was demonstrated in a recent paper by Sean Yu McLoughlin and Shelley Copley (2).

McLoughlin and Copley took a strain of E. coli that lacked an enzyme, ArgC, that is critical for glucose metabolism. They treated these bacteria with a strong mutagen and then picked a colony that grew well on uncomplemented glucose. After showing that these bacteria had developed a novel activity equivalent to ArgC, they isolated the "new" enzyme and found that it was actually an existing enzyme, ProA, which performs similar chemistry. This enzyme had gained the ability to take over the tasks of the missing ArgC, enhancing the rate of that reaction 12-fold. The actual chemistry of these reactions was quite similar, but in gaining the ability to operate on ArgC's substrate, the activity of ProA towards its own substrate was reduced 2800-fold. The bacteria compensated for this by upregulating the production of the enzyme. A second mutation in the promoter region of the gene was helpful, but not necessary, in this respect.

Because enzymes are catalysts, a small increase in protein concentration can result in a significant increase in the availability of the reaction products. Biochemists often say, seeing a 3000-fold reduction in activity, that an enzyme is dead. The reality is that it's just slower, and a living thing can compensate for that in ways not available to an isolated reaction in a test tube. Organisms have shown that they have ways to survive what an enzymologist might see as fatal.

Of course, modern bacteria benefit from a number of well-tuned regulatory and feedback mechanisms that allow them to sense when particular metabolites are running low and to increase the production of proteins that can replenish them. Earlier, more primitive organisms might not have had these expedients available. Could they have survived gene sharing?

Too little is known about early life forms to answer such a question definitively. However, it is interesting to note that one method of making more protein is to make more of the gene. That is, the concentration of a deficient enzyme can be increased via gene duplication. By a fortuitous coincidence, a single mechanism could both enable an organism to tolerate reduced enzymatic efficiency and allow the evolutionary process to independently refine its activities.

It is also worth bearing in mind that just as ancient organisms did not necessarily resemble modern ones, ancient proteins might not have resembled the modern item. The exquisite positioning of functional groups that characterizes modern enzymes requires a rigid fold and contributes significantly to the rate accelerations they produce. However, substantial rate enhancements can still be achieved in the absence of a stiff native state.

One occasional result of mutations is the formation of a molten globule, a protein that lacks a stable fold but still exists in a collapsed state with something resembling a hydrophobic core. Although that doesn't sound particularly useful, many molten globules have enzymatic or other functional activities. Recent computational studies on a molten-globule mutant of Methanococcus jannaschii chorismate mutase suggest that realistically low energy barriers can be achieved by a broader array of structural states in these proteins (3).

Researchers from the lab of Arieh Warshel used a simplified model to sample the conformational space available to the molten globule enzyme (mMjCM) and a stably folded form of the enzyme (EcCM). As you might expect, the lowest-energy conformations are much more diverse for mMjCM than for EcCM. Roca et al. then computed the energy barrier for catalysis for conformations that closely resembled the ideal structure (region I), conformations which had most of the groups in the right general position but were significantly removed from the ideal (region II), and conformations that did not resemble the ideal at all (region III). For EcCM, only structures in region I had energy barriers low enough to plausibly allow catalysis. The molten globule, however, had energy barriers that would allow catalysis in region I and region II. You can see this in the figure below, which I shamelessly stole from their paper: the dotted orange line corresponds to a 16 kcal/mol energy barrier, what they felt to be the largest barrier reasonable for a catalyst. The results for mMjCM are on the left, EcCM on the right.



The upshot of this is that molten globules may be able to maintain catalytic power in the face of structural diversity that causes folded proteins to fail. While the stable fold produces greater rate enhancements (note that EcCM has lower energy barriers), the molten globule tolerates a wider array of structural conditions. Consequently, proteins of this kind may be much more amenable to the addition of new functions. So long as an appropriate orientation of functional groups is reasonably likely, a protein without a rigid conformation can still achieve impressive rate enhancements.

Conceivably, an early molten globule enzyme could have the ability to catalyze several different reactions, switching between the required conformations as needed, without a significant loss of catalytic power to any of them. Duplication of a multi-functional molten globule like this would allow each chemical function to be refined independently, with additional duplications and refinements giving rise to substrate specificity.

The different models of gene duplication each have their own explanatory advantages, and the available evidence suggests that new proteins and enzymatic activities have evolved (even within the last century) using both routes. As this is one of nature's favored methods of generating novel activities, so it is becoming ours. The artificial enzymes recently produced by David Baker's lab were designed onto an existing protein scaffold in what could be taken as a computational mimicry of the gene duplication process.

1. Y. He, Y. Chen, P. Alexander, P. N. Bryan, J. Orban (2008). NMR structures of two designed proteins with high sequence identity but different fold and function Proceedings of the National Academy of Sciences, 105 (38), 14412-14417 DOI: 10.1073/pnas.0805857105

2. S. Y. McLoughlin, S. D. Copley (2008). A compromise required by gene sharing enables survival: Implications for evolution of new enzyme activities Proceedings of the National Academy of Sciences, 105 (36), 13497-13502 DOI: 10.1073/pnas.0804804105

3. M. Roca, B. Messer, D. Hilvert, A. Warshel (2008). On the relationship between folding and chemical landscapes in enzyme catalysis Proceedings of the National Academy of Sciences, 105 (37), 13877-13882 DOI: 10.1073/pnas.0803405105

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Upside down

As a very important source of strength and security, cherish public credit. One method of preserving it is, to use it as sparingly as possible; avoiding occasions of expense by cultivating peace, but remembering also that timely disbursements to prepare for danger frequently prevent much greater disbursements to repel it; avoiding likewise the accumulation of debt, not only by shunning occasions of expense, but by vigorous exertions in time of peace to discharge the debts, which unavoidable wars may have occasioned, not ungenerously throwing upon posterity the burthen, which we ourselves ought to bear. The execution of these maxims belongs to your representatives, but it is necessary that public opinion should cooperate. To facilitate to them the performance of their duty, it is essential that you should practically bear in mind, that towards the payment of debts there must be Revenue; that to have Revenue there must be taxes; that no taxes can be devised, which are not more or less inconvenient and unpleasant; that the intrinsic embarrassment, inseparable from the selection of the proper objects (which is always a choice of difficulties), ought to be a decisive motive for a candid construction of the conduct of the government in making it, and for a spirit of acquiescence in the measures for obtaining revenue, which the public exigencies may at any time dictate.

—George Washington, Farewell Address

The next President and Congress of the United States must raise taxes and cut spending.

The last time I checked, the national debt was about $9.6 trillion, but it's probably higher now. The interest on this debt presently amounts to nearly 10% of the federal budget, which admittedly is less than half of we spend on defense, but still easily exceeds $200,000,000,000. According to the Congressional Budget Office, the interest outlay in 2007 could have covered the entire federal expenditure on supplemental security income, child tax credits, unemployment, food stamps, family support, child nutrition, and foster care, with almost enough left over to pay for veteran's benefits. Of course, the magnitude of the debt (and the associated interest payments) will only increase when Medicare and Social Security payments start to exceed revenues. The federal government has run a deficit every year since 2001, and none of the people running for office now have done enough to stop it. Nor do they propose to do enough to stop it.

Instead, our candidates propose hosts of new projects, proposing no financing beyond the sunshine and rainbows that adorn their professionally-coiffed speeches. They shoo away the petty earmarks while the great consumers — Medicare, Social Security, Defense — gnaw the budget to the bone, unmolested in their gluttony. Most candidates who are willing to tax are unwilling to stop spending; most candidates who are willing to cut expenditures also want to lower taxes. Either way is insane, but many candidates want the whole pie: more spending, less taxes, damn the torpedoes, full speed ahead!

It has become almost obligatory, especially among those seeking office for the first time, to blame the present excesses on fat cats in the capital, but simply pointing the finger at Washington doesn't cut it. Irresponsible big spenders do not reach office by magic; they get there because we elect them. This is not a problem of other people in other districts who have bad judgment and choose lousy representatives. This is your problem in your district, and it is a problem because we have failed to do as George Washington asked. A man who tells you that our budget problems can be solved without any pain is either a fool, or a liar who thinks that you are a fool. But when a candidate gets up and acknowledges that taxes must be raised, that favored spending must be restrained, he is hated by an electorate that ought to applaud him for his honesty.

So the politicians lie. They cut taxes and spend more. They raise taxes and outspend that. And all along we grumble and complain about "Washington insiders" and "Beltway bandits". Well, throw the bums out! That's in your power, isn't it? If you're reading this post you have access to the internet. Find out how your congressman voted during his term. Read the text of the bills he voted on. Find out what questions he asked in committee and what speeches he made on the floor. Dig up the things that interest you, no matter how obscure. The behavior of state legislators and other officials is often more difficult to track, but these records exist. You as a voter have a duty to find and evaluate them, because terribly few politicians are honest about their record or intentions. Even if they are inclined to tell the truth, they dare not speak it because we voters are all too happy to punish harsh truths and reward pleasant lies.

Paying down the national debt is a personal obligation. We owe it to our children and grandchildren, our nieces and nephews, not to leave them a country upside down on its loans. More than that, however, it is a patriotic obligation. We owe it to our parents and grandparents, our soldiers and our founders, not to let the country they worked so diligently to build and preserve crumble due to debt and dissipation.

The next President and Congress of the United States must raise taxes and cut spending. Any candidate for any national office who refuses to acknowledge this truth does not deserve your vote.

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Love your Playstation with Odin Sphere

The big news this week belongs to the XBox 360, of course. As the internets knew, like, three weeks ago, all XBox models have a price drop coming on Friday, with the Arcade hardware (note: do not buy the Arcade hardware) dropping to $199, less than the Wii. The standard hardware will come in at $299, a price that is sure to help with sales for the upcoming holiday season. But, maybe you don't have $300 for a next-gen console, or even $60 for a next-gen game. Maybe all you've got is $20 burning a hole in your pocket and a PS2 that needs a good workout. If so, then you just might get your money's worth from this week's "Greatest Hits" re-release of Odin Sphere, a hybrid side-scrolling brawler/RPG from Atlus. That's an excellent deal on one of the most beautiful and interesting games of the last hardware generation.

I've written about Odin Sphere on this page before, discussing both its effective use of the cycle motif (spoilers in that post) and its rather less effective coding. I rarely make a case for a sale on this blog, as I prefer to simply discuss what I feel is going on in terms of story and imagery, but I make an exception in this case because Odin Sphere is, well, exceptional. The quality of the visual presentation cannot be overstated — this is one of those cases in which the game in motion looks better than the screenshots. The soundtrack by Basiscape is just fantastic. This presentation frames a deep and moving story that harkens back to Norse mythology and Wagnerian epics without quoting them so directly that it seems simply recycled.

That said, Odin Sphere is also deeply flawed, beset with terrible framerate reduction in some boss fights and long loading times. The apparent absence of cancels from the combat system exacerbates the frustration arising from the framerate problem. The inventory should have been larger; the recipe systems for food and alchemy should have been better refined. Some of these errors amount to mere niggling annoyances, but others can be quite exasperating. I can see why someone might be dubious about investing $40 or more into a game that puts those kinds of obstacles in the way of its glorious art. And, of course, the dreaded JRPG label probably scared away a few folks too.

A flawed diamond, however, is still a diamond. Odin Sphere's problems mean it will never sit atop the list of best games of all time. It is, however, a compelling story presented with largely enjoyable gameplay and stunning visuals and music. Even if you don't usually like RPGs, that's a combination that's worth 20 bucks.

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An enzyme with a monkey's tail

It is rare, but not unheard of, for a human baby to be born with a tail. Atavism of this kind is generally understood to be the result of mutations in regulatory genes that cause an ancestral pattern of development to re-emerge. A physiological step backwards through the path of descent is often easy to recognize, because many of the evolutionary relationships are known. It should also be possible to identify atavistic events in particular molecules. For instance, one can imagine that a mutation to CLC-0 might result in a reversion to the ancestral transporter function. In a recent article in PLoS Biology, researchers from Florida State University and Brandeis University identify just such a relationship in the bi-functional enzyme inosine monophosphate dehydrogenase (IMPDH). PLoS Biology is an open-access journal, so open it up and follow along.

IMPDH plays a critical role in the synthesis of guanine nucleotides, an essential component of DNA. Two reactions take place in the active site — first, the inosine ring is oxidized to xanthosine, forming a covalent linkage with the enzyme, and then this bond is broken by a hydrolysis. The enzyme active site changes shape to carry out the reaction, bringing a catalytic arginine (R418) into position to activate the water for nucleophilic attack. Any time you see a complicated mechanism like this, it's natural to wonder how such a system could have evolved. Min et al. performed simulations and experiments to find out.

Using a crystal structure of IMPDH as a starting point, Min et al. performed hybrid QM/MM simulations in which the atoms taking direct part in the reaction were treated with quantum mechanics, and the rest of the protein was simulated using molecular mechanics. As one would expect given the enormous reduction in catalytic rate that occurs when R418 is mutated, the reaction proceeded through the arginine when the simulation had a neutral R418 side chain. The water is stabilized by two additional side chains from T321 and Y419, and reacts almost instantaneously, without the formation of a stable hydroxide intermediate. Although this is unusual, this prediction of the simulation is consistent with isotope effect experiments.

When the arginine was replaced by a glutamine in the simulation, the mechanism changed, naturally. Under these conditions, it was Y419 that activated the water for the hydrolysis, although the energy barrier was much higher (leading to a slower reaction). Again, the characteristics of the reaction indicated by the simulation line up pretty well with the results of biochemical experiments. Of course, Y419 enters the active site the same way R418 does, so the question of how the hydrolase activity could have evolved remains open.

Something very interesting, however, happens when the simulation is performed with R418 in a charged state. A fully protonated arginine will have a very hard time activating water for a nucleophilic attack. The simulation indicated that under these conditions, T321 performed this role, after being activated by a nearby glutamate (E431). T321 is adjacent to cysteine 319, which is essential for the oxidation reaction, and is not located on the mobile flap. If T321 really can catalyze hydrolysis, this would mean that it is possible that IMPDH possessed an (inefficient) hydrolysis activity before it evolved the mobile flap.

Because T321 only plays a signficant role in catalysis when R418 is protonated, blocking this pathway should result in decreased IMPDH activity at low pH. This is precisely what Min et al. observe in enzymatic assays (Figure 5) on a mutant in which E431 is mutated to glutamine. There is other experimental support as well: IMPDH enzymes that have been mutated at R418 usually have large isotope effects, which makes sense in light of the fact that the alternative T321 pathway involves the simultaneous transfer of two protons (rather than just one).

Things get even more interesting when IMPDH is compared to one of its cousins, GMP reductase. Although GMPR catalyzes a very different reaction, the C319/T321/E431 triad is also present there. This, along with other data from sequence alignment, suggests that these three residues were also present in a similar configuration in the ancestor of these modern proteins. Over time, progressive optimization of the two proteins resulted in the T321 pathway being supplanted by the more effective R418 in IMPDH, while remaining essential in GMPR.

If T321 really is a remnant of an earlier water-activating pathway, why is it conserved now that IMPDH has a much more efficient catalytic residue available? T321 is probably preserved because it stabilizes the water while it is being activated by R418. However, the other essential residue of that activating pathway (E431) is usually an inactive glutamine in eukaryotic forms of IMPDH (and some prokaryotes, as well). In these species the T321 activation pathway has been completely supplanted by the arginine pathway. Yet in the other forms of IMPDH this alternative mechanism still lingers, perhaps because of the additional activity it affords at low pH, or because it confers resistance to a particular inhibitor of the enzyme. In that sense, IMPDH's "tail" might provide an adaptive advantage quite different from that which gave rise to hydrolytic activity in the first place.

Donghong Min, Helen R. Josephine, Hongzhi Li, Clemens Lakner, Iain S. MacPherson, Gavin J. P. Naylor, David Swofford, Lizbeth Hedstrom, Wei Yang, Daniel Herschlag (2008). An Enzymatic Atavist Revealed in Dual Pathways for Water Activation PLoS Biology, 6 (8) DOI: 10.1371/journal.pbio.0060206 OPEN ACCESS
Disclaimer: Although I have little contact with Dr. Hedstrom's group, I am also working at Brandeis.

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