Another need for nuclear energy

<a href=”http://www.nature.com/news/2007/071213/full/450926b.html”>This</a> is what happens when there is inertia towards construction of reactors for peaceful purposes:<blockquote>”Hospitals across North America have been forced to cancel tests for cancer and heart disease because the unexpected closure of a Canadian nuclear reactor has led to a sudden shortage of medical isotopes. The 50-year-old National Research Universal (NRU) reactor located in Chalk River, Ontario, was shut down on 18 November for scheduled maintenance and was due back online by mid-December. But Atomic Energy Canada, which owns and operates the facility, extended the outage to install safety-related equipment, including upgrades to the reactor cooling pumps. The reactor supplies about 60% of the molybdenum isotopes used in medical applications globally, including molybdenum-99, which decays into technetium-99m and is used in about 16 million nuclear medicine procedures annually in the United States…The shortage has reignited a discussion over securing the US supply of medical isotopes by building a reactor in the United States.”</blockquote> Again, there’s no sense if the debate about nuclear weapons and terrorist attacks is regularly conflated with peaceful and necessary uses of nuclear energy.

The last humane act?

I have always had mixed feelings about capital punishment. On one hand, I think it causes unnecessary suffering to a lot of people and reflects a kind of hubris in judging people on our part. On the other hand, I find it hard to argue the value it has for deterrence; one problem in assessing deterrence is that because it necessarily involves people who might have been deterred because of possible retribution, it’s always difficult to pinpoint how valuable it has been because we never get to know the wannabes who never were.

In any case, one thing which we all can agree upon is that whatever capital punishment is meted out, it needs to be humane. Electrocution, death squads, hanging, and gas chambers in my opinion always have been grotesque and cruel methods, a blot on our humaneness. I used to think that lethal injection is “better” than these methods, but somehow could not shun a dissenting thought about how humane it really is.

Now, a morbid sounding but important editorial from the freely available PLOS journal PLOS Medicine offers a critique of lethal injection that should be carefully pondered by policy makers and officials as well as by common citizens. It basically questions the use of the procedure and points out that especially the first step- considered to be the key step in making the procedure humane- may not be so foolproof and benign after all.

This first step is the induction of anesthesia by an injection of thiopental which is administered to the condemned man in order to supposedly ease the next two steps; an injection of pancuronium which paralyzes the muscles, including the respiratory ones, and then a final injection of potassium chloride that causes cardiac arrest. In the absence of anesthesia, the victim would feel an extreme asphyxiation and muscle spasms.

The PLOS editorial first points towards an article published in 2005 in the distinguished journal Lancet, whose conclusions if true are horrible and alarming to say the least. Let the abstract speak for itself:

“Anaesthesia during lethal injection is essential to minimise suffering and to maintain public acceptance of the practice. Lethal injection is usually done by sequential administration of thiopental, pancuronium, and potassium chloride. Protocol information from Texas and Virginia showed that executioners had no anaesthesia training, drugs were administered remotely with no monitoring for anaesthesia, data were not recorded and no peer-review was done. Toxicology reports from Arizona, Georgia, North Carolina, and South Carolina showed that post-mortem concentrations of thiopental in the blood were lower than that required for surgery in 43 of 49 executed inmates (88%); 21 (43%) inmates had concentrations consistent with awareness. Methods of lethal injection anaesthesia are flawed and some inmates might experience awareness and suffering during execution.”

What the journal is saying is clear; the procedure seems to be administered sloppily, with basically no concern for the dying man. The fact that the concentrations of thiopental in the blood were lower even than those in surgery patients sounds outrageous, because ideally, the thiopental administered to condemned men is supposed to be at a dosage much higher than that for surgery patients, to ensure the kind of anesthesia that would be considered deadly for surgery patients. But this study shows that it is even lower than in surgery patients, which seems to indicate negligence bordering on criminal behaviour.

What is even more frightening is the second article referenced in the editorial, published in the same issue. This more clearly indicates that the level of anesthesia would depend on how long the procedure took, and if the procedure took very long because of whatever reason, the anesthesia would not be enough and the victim could actually be aware. Even more significantly and morbidly, the main thrust of this article is that the three lethal compounds do not always act in a strict sequential manner. Thus, both potassium chloride and thiopental may not have done their job before pancuronium starts acting. The implication is horribly obvious; the victim undergoes death by chemical asphyxiation, being aware of it all the time. However, because he was under anesthesia, he would not even be able to indicate his suffering.
The fact is that very little research has been done in standardising the protocols of lethal injection, and more importantly, intensive research has not been thought to be necessary. All in all, it is a great travesty if true. The whole point of lethal injection was to make the procedure humane, and such kind of negligence of simple protocols might show that in fact it’s supposed to be the opposite.

However, in the end, the PLOS editorial makes a compelling point:

“As editors of a medical journal, we must ensure that research is ethical, and there is no ethical way to establish the humaneness of procedures for killing people who do not wish to die…”

That is, we have a kind of paradox here, namely that even in the absence of research, it would at the same time be considered unethical to conduct research and “standardize” the conditions for lethal injection by performing experiments, admittedly even on animals.

And this is the real heart of the matter which the PLOS editors are getting at, that no forcible killing can be humane. Admittedly, whether we believe in their stance on abolishing the death penalty or not, this is an extremely important matter, and it does not seem to be doing humanity’s moral record any good. Personally, even if it might sound macabre, I think that the only possible humane way to kill a human being may be to bring him within ten meters of an atomic explosion, with instant flash incineration. The ludicrousness of this thought itself indicates how thorny and immoral the shades of this issue are.

These studies highlight the inherently oxymoronic nature of the whole matter. Humane killing? Can any method of killing someone against his or her will be considered humane? Let’s face it, capital punishment can never be humane. Something to think about.

THE LAST HUMANE ACT? I have always had mixed feel…

THE LAST HUMANE ACT?

I have always had mixed feelings about capital punishment. On one hand, I think it causes unnecessary suffering to a lot of people and reflects a kind of hubris in judging people on our part. On the other hand, I find it hard to argue the value it has for deterrence; one problem in assessing deterrence is that because it necessarily involves people who might have been deterred because of possible retribution, it’s always difficult to pinpoint how valuable it has been because we never get to know the wannabes who never were.

In any case, one thing which we all can agree upon is that whatever capital punishment is meted out, it needs to be humane. Electrocution, death squads, hanging, and gas chambers in my opinion always have been grotesque and cruel methods, a blot on our humaneness. I used to think that lethal injection is “better” than these methods, but somehow could not shun a dissenting thought about how humane it really is.

Now, a morbid sounding but important editorial from the freely available PLOS (Public Library of Science) journal PLOS Medicine offers a critique of lethal injection that should be carefully pondered by policy makers and officials as well as by common citizens. It basically questions the use of the procedure and points out that especially the first step- considered to be the key step in making the procedure humane- may not be so foolproof and benign after all.

This first step is the induction of anesthesia by an injection of thiopental which is administered to the condemned man in order to supposedly ease the next two steps; an injection of pancuronium which paralyzes the muscles, including the respiratory ones, and then a final injection of potassium chloride that causes cardiac arrest. In the absence of anesthesia, the victim would feel an extreme asphyxiation and muscle spasms.

The PLOS editorial first points towards an article published in 2005 in the distinguished journal Lancet, whose conclusions if true are horrible and alarming to say the least. Let the abstract speak for itself:

“Anaesthesia during lethal injection is essential to minimise suffering and to maintain public acceptance of the practice. Lethal injection is usually done by sequential administration of thiopental, pancuronium, and potassium chloride. Protocol information from Texas and Virginia showed that executioners had no anaesthesia training, drugs were administered remotely with no monitoring for anaesthesia, data were not recorded and no peer-review was done. Toxicology reports from Arizona, Georgia, North Carolina, and South Carolina showed that post-mortem concentrations of thiopental in the blood were lower than that required for surgery in 43 of 49 executed inmates (88%); 21 (43%) inmates had concentrations consistent with awareness. Methods of lethal injection anaesthesia are flawed and some inmates might experience awareness and suffering during execution.”

What the journal is saying is clear; the procedure seems to be administered sloppily, with basically no concern for the dying man. The fact that the concentrations of thiopental in the blood were lower even than those in surgery patients sounds outrageous, because ideally, the thiopental administered to condemned men is supposed to be at a dosage much higher than that for surgery patients, to ensure the kind of anesthesia that would be considered deadly for surgery patients. But this study shows that it is even lower than in surgery patients, which seems to indicate negligence bordering on criminal behaviour.

What is even more frightening is the second article referenced in the editorial, published in the same issue. This more clearly indicates that the level of anesthesia would depend on how long the procedure took, and if the procedure took very long because of whatever reason, the anesthesia would not be enough and the victim could actually be aware. Even more significantly and morbidly, the main thrust of this article is that the three lethal compounds do not always act in a strict sequential manner. Thus, both potassium chloride and thiopental may not have done their job before pancuronium starts acting. The implication is horribly obvious; the victim undergoes death by chemical asphyxiation, being aware of it all the time. However, because he was under anesthesia, he would not even be able to indicate his suffering.
The fact is that very little research has been done in standardising the protocols of lethal injection, and more importantly, intensive research has not been thought to be necessary. All in all, it is a great travesty if true. The whole point of lethal injection was to make the procedure humane, and such kind of negligence of simple protocols might show that in fact it’s supposed to be the opposite.

However, in the end, the PLOS editorial makes a compelling point:

“As editors of a medical journal, we must ensure that research is ethical, and there is no ethical way to establish the humaneness of procedures for killing people who do not wish to die…”

That is, we have a kind of paradox here, namely that even in the absence of research, it would at the same time be considered unethical to conduct research and “standardize” the conditions for lethal injection by performing experiments, admittedly even on animals.

And this is the real heart of the matter which the PLOS editors are getting at, that no forcible killing can be humane. Admittedly, whether we believe in their stance on abolishing the death penalty or not, this is an extremely important matter, and it does not seem to be doing humanity’s moral record any good. Personally, even if it might sound macabre, I think that the only possible humane way to kill a human being may be to bring him within ten meters of an atomic explosion, with instant flash incineration. The ludicrousness of this thought itself indicates how thorny and immoral the shades of this issue are.

These studies highlight the inherently oxymoronic nature of the whole matter. Humane killing? Can any method of killing someone against his or her will be considered humane? Let’s face it, capital punishment can never be humane. Something to think about.

Can someone tell me how to get rid of this disgust…

Can someone tell me how to get rid of this disgusting damn popup that started showing up suddenly without any input on my part? My blog’s reputation is being catapulted from non-existent to bad!

Disgusting damn popups

Can someone tell me how to get rid of this disgusting damn popup that started showing up suddenly without any input on my part? My blog’s reputation is being catapulted from non-existent to bad!

How do you choose a good crystal structure for docking?

The first step in much of SBDD, including docking, is the selection of a good crystal structure if it exists. The crystal structure is used as the starting point for seeking new leads and optimizing them. Consider any docking method evaluation paper in J. Med. Chem. and one will come across a benchmarking set of protein structures that are used as starting models for testing the docking protocols.

Now crystal structures are frequently as close as you can get to “reality”, but even they are models and should be treated with some skepticism. But the more obvious question for such a study when multiple crystal structures of a protein are available is, which crystal structure among those should you use?

The short answer to this question is, choose one with good resolution (preferably 2.0 A or less), which does not have missing portions, and which is preferably also unencumbered by the presence of a whole lot of counterions, stabilizing molecules, and other ligands.

But is that really all? Maybe not. Recently, I was playing around with docking some molecules into kinase crystal structures. I was trying to see if docking scores can correlate with the selectivity for one related protein over the other. Usually they don’t, but I was going to look at similar proteins and similar structures, so I though it may be worth a shot. I was particularly looking at cyclin-dependent kinases (CDKs) which share a lot of homology especially in their ATP binding pocket. CDK2 is probably the most well-characterised CDK among the CDKs, and there are at least four to five different high-resolution CDK2 structures in the PDB. Also, I was more keen on using CDK2, because it was one of the proteins used for benchmarking the docking program.

So I decided upon two structures, both of high resolution. One had ATP docked into it, the other one had Staurosporine. I took an inhibitor which was known to be selective for another CDK over CDK2. First I docked it into that other CDK, and into the CDK2 structure that had ATP bound to it (without the ATP of course). I noted that the score for the other CDK was higher (which actually means more negative, since it is supposed to reflect the free energy of binding). That was consistent with the experimental data, which showed that the inhibitor was in fact more selective for the other kinase. But then, I docked it into the other CDK2 structure, and now the score was much better than for the other kinase. So the two docking runs gave two opposite results for the same protein. One predicted that the inhibitor would be less selective for CDK2, and the other one predicted that it would be more selective.

Now one of the things this says is that you cannot trust docking scores much. But this still was weird, because the question persists; which CDK2 structure should I use if I am going to do some SBDD and selectivity studies? I don’t know the answer to this question, but I took a look at the two structures to try to figure out. In the one with the ATP, the adenine region of ATP nicely made two hydrogen bonds with the hinge region of the kinase, and so did my inhibitor which was supposed to be an ATP mimic. In the other one however, the backbone carbonyl that was supposed to form the hydrogen bond to the inhibitor was rotated by almost 90 degrees upwards. It did not form a bond with stauroporine, and it did not have to, because staurosporine does not “look” like ATP. And needless to say, it could not hydrogen bond with my inhibitor too. That’s why the docking score was much worse.

What’s the solution for circumventing such a problem? One quick answer that comes to my mind is; if you are docking a ligand that is “similar” to ATP, use the protein structure that has ATP bound to it. However, “similarity” can be a tricky concept, and should be considered carefully. Also, it may be slightly easy for kinase inhibitors, because there are literally hundreds of very typical planar, heterocyclic amino-pyrimidine based kinase inhibitors that share some very obvious similarity to ATP (or not…)

But probably the best message to take home from this from a computational standpoint is that rigid protein docking not surprisingly can get you into some bad trouble. Not allowing the protein to move means that you are going to preconstrain the protein based on its preconstrained conformation in the crystal. To test this thought, I did an induced-fit docking run on both structures with the inhibitor. Gratifingly, both the runs converged on the same protein-ligand structure.

Choosing a PDB x-ray structure may not be as easy as we think, and may have to be done critically. And more importantly as usual, what we put in is what we get out. Rigid docking is ok if there’s only one crystal structure, and then only because there’s no other choice. But in other circumstances, always allow the protein to move. That’s closer to nature.

IT’S NOT ABOUT THE SCIENCE A pretty amazing debat…

IT’S NOT ABOUT THE SCIENCE

A pretty amazing debate has been going on in the webpages of Amazon.com. But first, a little about what it is about. The webpage is the one displaying Michael Behe’s “Darwin’s Black Box”, a book that has stirred up unnecessary muck, although not unpredictably. Behe is a biochemist with some credible credentials, but incredible assertions. He is the infamous guy who popularised the concept of “irreducible complexity” in the late 1990s. Behe’s contention simply put was (and is) that the biological world is so complex, that only a designer could have made it. That’s because if we considered any one of the tiny, fundamental units of life, such as an eye, it is quite clear that taking away any one of the myriad parts that comprise the eye would render it completely non-functional. Thus, it is inconceivable (to Behe) that the eye could have actually evolved gradually, and that all the parts should have been put together, already formed, by some intelligent designer. Enter ID, creationism in a dapper although embarrassingly ostentatious outfit.

There are holes as big as empty space in Behe’s whole framework. In one fell swoop, he pushes so many issues under the rug that the rug can no longer bear the presence of all of them, and splits wide open. Behe makes a general philosophical argument, gives it a fancy name, and simply proclaims that it is true by default, the classic demonstration of the “argument from ignorance”. He does not look at any contradictory evidence, and even when it is overwhleming, deems it insufficient without any justification. Most importantly, Behe offers not one iota of positive evidence for his own assertions, including the stupendous lack of explanation for the complexity of his intelligent designer who designed such a complex world. Science only partially progresses by elimination of alternatives. It needs solid positive proof to be useful and real. Also, a scientific theory does not collapse only because some detail in it is simply challenged. There are many details in evolution that are debated by scientists. But that does not mean that they don’t believe in evolution itself, because there’s monumental evidence from a stunning variety of scientific disciplines in support of the truth of evolution. In fact, it is staggering how many different questions in different fields seem to come under the purview of evolution as their answers are revealed everyday. In this context, I have to say that the efforts of Behe and his cronies to discredit evolution are an abomination upon science, and display at most a juvenile understanding of the scientific method.

But needless to say, Behe has been the poster boy for creationists in the last decade, who want to furtively bring creationism to the schools under the guise of scientific jargon. Behe deliberately has chosen the field of biochemistry for his crusade (and crusade is the right word, because his spiels are all based on faith), because he wants to enter creationism through the backdoors of hard science. Most of his creationist patrons probably don’t even understand what he says, but no doubt dance with glee when they hear him citing scholarly notions and hijacking them to support his purpose.

Behe was also an apologist for the creationists in the infamous Dover creationist trial of two years ago, where twelve parents of school children had brought a suit against the teaching of creationism in science class. Behe was a defendent for the creationists, and among others, Kenneth Miller the Brown University Professor was an expert witness for the plaintiffs. One of Behe’s arguments in Darwin’s Black Box is that the immune system is too complex to have evolved by natural selection, ergo, it must have been, by default, designed. During the Dover trial, Behe was shown more than fifty peer reviewed journal publications that dealt with the evolution of the immune system. Not only could he not refute them, but he confessed that he had not read any of them. In the end, the attorney for the plaintiffs as well as the judge roundly scolded Behe and his ilk, and cited their “breathtaking inanity” for simply touting that complex structures arose by the work of an intelligent designer, and for implying that there surely could not be any need to actually study where they came from. In an embarrassing moment for Behe, the plaintiffs’ attorney said that while serious scientists were engaged in studying the evolution of the immune system and finding new therapies for diseases, Behe and his sympathizers were not only misleading the public, but were doing absolutely nothing to advance the future of science and medicine. In fact, I feel more pity than anger for Behe, who is clearly an intelligent and educated person, and yet wants to waste his time advancing crackpot causes and not actually making a difference by doing scientific research.

The most vocal opponent of Behe has been Brown University professor Kenneth Miller, and I would strongly recommend his book “Finding Darwin’s God” for anyone who wants a good understanding of evolution (including a clear refutation of the belief that evolution is a product of chance), as well a very spirited and convincing reply to Behe’s assertions of irreducible complexity. The bacterial flagellum, probably the only example of a true motor in nature, is an astounding factoid of life’s complexity. Without doing any research, Behe had again simply proclaimed that it was irreducibly complex. However, Miller showed that there are several examples of other flagella in nature, which show some of the components of the bacterial flagellum and yet work, even if not as well; what is most bothersome that Behe has frequently either not just been aware of the literature, or more believably has shown deliberate ignorance of it. This principle extends to all those other systems which Behe claims are irreducibly complex. The bottom line is, yes, many complex structures in nature can be shown to be made up of independently functioning partial components, and we can follow an evolutionary history for the presence of all these components. For those which are not, there is no reason whatsoever to believe that they were designed by any Yahweh or Zeus.
The humble and yet stunning eye was always one of the favourite targets of creationists, and they used to cite Darwin’s own quip about his incredulity at the eye’s functioning:

“To suppose that the eye with all its inimitable contrivances for adjusting the focus to different distances, for admitting different amounts of light, and for the correction of spherical and chromatic aberration, could have been formed by natural selection, seems, I freely confess, absurd in the highest degree.”

They also conveniently ignore what he said next:

“Reason tells me, that if numerous gradations from a simple and imperfect eye to one complex and perfect can be shown to exist, each grade being useful to its possessor, as is certainly the case; if further, the eye ever varies and the variations be inherited, as is likewise certainly the case and if such variations should be useful to any animal under changing conditions of life, then the difficulty of believing that a perfect and complex eye could be formed by natural selection, though insuperable by our imagination, should not be considered as subversive of the theory.”

There it is; The Reluctant Mr. Darwin demolished irreducible complexity a hundred and fifty years ago.

So, if Darwin himself laid to rest all such troubling questions about irreducible complexity more than a century ago (it is truly remarkable to discover how prescient- and right- the man was), why is there a 85 comment debate on the Amazon.com webpage showcasing Behe’s book? The debate is in the comments section of a certain J.M. Ridlon, who seems to know evolution inside out. Incidentally, and again it should not be surprising, the book has received four stars and 575 reviews, which means that most of the reviews have been favourable. This can mean several things; firstly, that sensible people simply did not comment. But what I am more certain about is that most of the reviews were probably written by intelligent folks, probably and unnecessarily fence-sitters, who got impressed with Behe’s scientific exposition and felt convinced that at the least, there were serious flaws with evolution. It’s very sad if such a thing happened. To these of course we can gently say only one thing; read a good book. Start with Climbing Mount Improbable, that alone will suffice and help you understand evolution a little better.

On the other side of the debate is a cabal of dissenters who keep asking Ridlon to prove with complete certainty all the assertions that he makes. What surprises me is that even these dissenters seem to be intelligent and well-read, and yet they show a deliberately woeful ignorance of the scientific method. However, after trudging through the 83 comments and being highly impressed with Ridlon’s knowledge of evolution, it becomes clear; these dissenters don’t really want to prove evolution wrong and creationism right. In fact, the comments clearly show that they steer clear from trying to affirmatively expound upon creationism; not surprising since they don’t have a shred of evidence for the existence of an intelligent designer. All they do is take potshots,some quite learned sounding ones, at evolution. And then it becomes clear; they want to create “reasonable doubt” about evolution to then allow creationism to be also taught as an “alternative theory” in classes. As it is with many other creationists, they want educators to “teach the debate” where there is none, and they are mustering every effort they can to try to actually convert their arguments into a true debate. After every comment, J.M. Ridlon has given a detailed response, showing how their arguments are wrong.

But now, I have a suggestion for him; J. M. Ridlon, don’t bother. These folks are just out to make a political point, not a scientific one. This is not science, it is the manifestation of the dredges of human nature. So no matter how much you convince them about the known certainty of evolution, all they will do is ask, “But, are you one hundred percent certain?”. When you, as a good scientist will say that of course not, but that does not tarnish evolution, they will simply turn Bill O’Reillyesque and shout “That’s it! That means the whole theory is wrong. We are right, you are wrong!” Now, do we watch Bill O’Reilly except when we want some ‘white noise’ in the background to help us sometimes fall asleep? Then, J. D., I suggest that you do the same about this comment-fest. It’s not about science.

A DIFFERENT QUESTION Much is being written about …

A DIFFERENT QUESTION

Much is being written about the underrepresentation of women in the IITs, and Nanopolitan has done some quite gruelling analysis of the whole matter. However, the original question was related to judging the caliber of the JEE and whether it has any inherent bias against women. However, the lack of women in the IITs can at least in theory be explained by several factors not related to the JEE, and one of those factors certainly could be the “culture” in the IITs.

So the question is, is the culture in IIT such that it may be biased against women? While such a question is surely bound to raise some hackles, let me hasten and add that an affirmative answer to this question would not reflect negatively on any particular gender. The point is, there are many institutions and fields which have been male dominated, and while that says something critical about the institution, it does not necessarily say anything bad about the individuals comprising it.

Questions whose answers may involve any accusation of bias for or against a particular gender are always considered uncomfortable. But I ask this question only because I am familiar with another hotly-debated topic; the underrepresentation of women in science. When this topic is brought up, we are inevitably reminded of Lawrence Summers’s unfortunate comments that sparked a storm. But sometime back, I had written a post about a Nature article in which the author talked about the fierce “alpha male” culture that exists in science, that has made science traditionally a man’s game. There was no accusation in that article, and yet I agreed with its premises. Science has been a man’s game, there can be a lot of vituperative criticism and aggressiveness inherent in scientific competition and meetings. Essentially because of historical circumstances, women unfortunately have been dissuaded from a lot of scientific research.

Sometimes, observation trumps a lot of hypothesizing, and one thing I have to say is that for some reason, I have seldom seen even very intelligent girls trying to diligently get through the JEE. Exceptions abound of course, but within my acquaintances, I can think of very few girls who were first in their class (or in the city, state etc.), had the mettle to beat the male competition and get into the best engineering colleges in the country, but did not even appear for the JEE. So irrespective of the reasons, I think that there is something that keeps a lot of girls away from the JEE. One simple factor which comes to mind, and this is in fact true for boys too, is that parents sometimes balk at the thought of sending their son or daughter away to a far away place like Kanpur or Kharagpur. Another factor, and this is something a friend of mine told me, is that with predominantly boys appearing for the JEE, it is difficult for girls to form a study group.

Anyway, this is my take on it. But the men and women of the IITs can enlighten things more for me. I definitely think that traditionally, the IITs have always been perceived as a man’s game, quite apart from whether that perception makes sense or is true, and this in its various implications and manifestations has kept girls way from the IITs, and consequently from the JEE. Things may change in the future, and they emphatically should.

MISSILE DEFENSE: THE ETERNAL BUG Some bugs never …

MISSILE DEFENSE: THE ETERNAL BUG

Some bugs never seem to die, especially those of the Presidential type. The missile defence bug is surely one of these. It has bitten almost every President from JFK to GWB, sapped away billions of taxpayer dollars from the nation’s coffers, and regularly evaded the attempts of dozens of eminent experts to declare it futile and ominous.

It started in 1957, when Sputnik blazed across the sky. For the next thirty years or so, US Presidents projected a false ‘missile gap’ to the nation, and devoted manpower and an immense amount of money to building bigger and better missiles that could carry thermonuclear warheads across continents and initiate global nuclear conflict. This was inspite of the fact that the perceived missile gap was never a gap in the middle days of the Cold War. By banning the development of ballistic missiles as well as nuclear weapons, the United States could have retained a clear advantage over its opponents. But bugs as we know can be all-pervasive and recalcitrant. In the 60s, the Cold War reached new heights with the Cuban Missile Crisis, and the testing of many new missiles. Mercifully, nuclear tests in the atmosphere, underwater, and in space were banned in an important 1963 test ban.

The Chinese had been engaged in nuclear weapons research since the 1950s, and affairs had come to a head in 1950 during the Korean War. In 1964, China had detonated its first atomic bomb. After the Soviet Union, it was seen as the biggest threat to the US. Sometime in the 1960s, the bug caught the imagination of Washington, and plans were made to employ a huge anti-ballistic missile (ABM) system that could deflect a potential Chinese nuclear attack. The plans were first conducted in secret, and then, even before China really had the requisite technology to engage in such attacks, were heavily publicised by Defense Secretary Robert McNamara, thus giving the Chinese carte blanche to go ahead.

Missile defense can be a tricky concept. On the face of it, it seems to guarantee a nation’s safety from first nuclear strikes. But this sense of safety is misleading, for several reasons. First of all, technical ones; it was shown repeatedly, most strikingly in 1968 in a Scientific American article by the great physicist Hans Bethe and Richard Garwin, that almost any countermeasure that the US could take against such an attack could be defeated by ‘countercountermeasures’ by the enemy. This could include the use of any number of decoys, from aluminium foil to fake explosions and warheads, to mislead defensive missiles. On a very local scale, missile defense could be partially successful, but the authors showed that the marginal expense necessary for deflecting missile attacks was much more for the US than for the enemy. In other words, it was relatively easier for the enemy to thwart defensive missiles than for the US to thwart offensive ones.
The more important problem with missile defense is political. By employing such a defense, the US gives out a signal to other countries that since it is now securely defended, it may not have a problem launching a first nuclear strike itself. The result of such an impression is predictable; the enemy would put even more resources into developing more and better missiles and weapons to penetrate the system. If there is a good way to initiate another nuclear arms race, this way would be close to the top of the list. For example, in 1968, one could not have blamed the Chinese for accelerating their own missile development after hearing of US plans to develop such a defense system. In fact, it would have been a nice excuse for them.

In any case, the 1960s system fortunately did not work out, but not before millions of dollars were spent on it. A respite came in 1972, when Richard Nixon signed the Anti-Ballistic Missile Treaty, that limited the numbers of deployable ballistic missiles on both sides. But like other treaties, this treaty also contained a slippery slope, because it said nothing about developing more sophisticated missiles, simply about deploying them. Also, it did not say anything about the number of nuclear warheads that a single missile could carry. This loophole (probably intentionally left in) led to one of the most dangerous developments of the Cold War; Multiple Independently targeted Reentry Vehicles (MIRVs), in which a single missile such as the Minuteman could carry upto 10, independently targetable warheads. This probably was not much better than the situation before the treaty.

But the icing on the cake was laid by the charismatic Ronald Reagan, with his espousal of a really ridiculous, unfeasible, and prvocative system- the famous “Star Wars”, or Strategic Defense Initiative. Star Wars envisioned hundreds of missiles and weapons based in space. It got rescued from early demise by a new invention, the X-ray laser, which could shoot its gigawatt beam across miles of space and supposedly blow out missiles and thermonuclear warheads into oblivion.
However, after Reagan enthusiastically took up the gospel, it began to become apparent that the project had been oversold, and scientists who worked on it had been pressured into remaining silent about its limitations. While hawkish Edward Teller lobbied for it, the resourceful Hans Bethe and his colleagues again rose to the cause, and published another article in Scientific American on the same lines as before, arguing yet again that the enemy could always emply suitable decoys and defeat the system, and that it would lead again to an accelerated arms race.

Nuclear weapons have been brought in check somewhat by various treaties since then. But needless to say, George Bush has inherited the mantle from his esteemed Cold War predecessor and has gloriously validated it. In 2002, after honouring the anti-ballistic missile treaty for 30 years, the administration withdrew from it in an ominous development. Part of the reason was a short-lived but dangerous resurgence of “small” nuclear weapons R & D. These “low-yield” weapons called “bunker busters” were intended to bust underground enemy bunkers. However, it was convincingly argued that contrary to what their proponents would have everyone believe, they were no “safer” or “contained” than conventional nukes, and in some respects even less so.

The most important reason for withdrawing from the treaty obviously is the renewed interest in another missile defense system, “Son of Star Wars”, this time ostensibly against North Korea and Iran, and this time based in both Europe and the US.
Yet another article was published by Bethe’s collaborator Richard Garwin in Scientific American in 2004, arguing against the proposed system. Again, the most important objection is political. What kind of signal is the US giving to N. Korea and Iran? It’s clearly an invitation for these nations to become even more suspicious of the US, and get the perfect pretext for developing their own missiles.

Perhaps the US wants to adopt the Cold War strategy to try to economically bleed these nations out by making them spend huge sums on missiles, a justification that is often made in support of this endeavor. But this strategy is not only dubious but misguided. Firstly, there is no guarantee that another nation would not atack the US in any way until it faces economic collapse, so that the overall risk to the US increases. Secondly, even if it does not attack, it would develop any number of weapons and missile systems and possibly help them proliferate. This brings us to the third and most pertinent point. In this age of nuclear terrorism, it is highly unfeasible that Iran or N. Korea wil use nuclear warheads on missiles to attack the US if they really wanted to wage war against it. It would be suicide for them. Instead, as the late Carl Sagan, an outspoken opponent of missile defense used to point out, these states would smuggle in a low yield or dirty bomb through a suitcase or through diplomatic pouch. Graham Allison also affirms this in his highly readable Nuclear Terrorism. In fact, it is highly unlikely that these states would do something like this that would threaten to drop the curtain on their own existence. The real threat is from independent terrorist groups with no return labels and fear of retaliation. And it is almost impossible and ludicrous that they would use missiles to attack the US. However, nations like N. Korea and Iran would happily and anonymously provide the technology which they have developed to these terrorists.

In the latest developments, the US is pressurizing Vladimir Putin and other European leaders to employ missile defense in Europe. I commend Putin and these leaders for not giving in to this inane and misguided demand. One must not forget that it was the presence of Jupiter missiles in Turkey which threatened the Soviet Union in 1961, and became one of the causes of the missile crisis. By again employing missiles in Europe, the US is only going to make itself and the world a less safer place.

Times have changed, but the US still very much seems to be living in Cold War times. It still has about 10,000 warheads, many on hair-trigger 15 minute launch alerts. The threatening nature of this state of affairs has been certified by both conservatives and liberals. The strategies of missile defense that it’s trying to employ are Cold War era tactics. And they were unworkable and dangerous during the Cold War, and are dangerous right now. One would think that statesmen would have learnt from such a long experience of dealing with possible death and destruction. But, like bacteria, these bugs don’t die out. They can be resisted and rooted out though, but statesmen don’t have the intelligence and conviction to resist them, and would rather let the bugs turn them into zombies.

Schrodinger’s equation

A friend of mine just returned from a conference in New York organised by Schrodinger, and I have to say that Schrodinger really seems to be poised to be the one-stop shop for all things computational.

They already have some great programs in their Maestro suite, including Glide for docking, which you find folks in industry using more and more these days. In their next revisions, they are going to introduce a program named PrimeX for doing crystallography, which will perform analysis similar to CNS, which will be groovy if it brings such analysis to the desktop. They are also going to introduce electron-density fitting for loop refinement in proteins. Right now, loop refinement of, say a 10 residue loop takes forever. But with PrimeX and friends, one can have constraints effected by electron density to restrict conformational searching, thus greatly speeding up the process.

Other products include the very impressive new Glide XP docking protocol. I have been glued to their site ever since they published their admirable paper in 2006. I have already written about the capabilities of GlideXP. This is really the best of computational chemistry applied to docking, where you find chemists trying to include as many experimental parameters as they can in a program. Schrodinger is definitely one company whose chemists have a firm and steady hand on experimental variables.

A very important development is going to be the interfacing of William Jorgensen’s MCPRO, a program for doing free energy perturbation (FEP) calculations. FEP calculations are as close as you can come to accurately reproducing experimental binding free energies, one of the holy grails of computational methodology. While GlideXP astoundingly claims to also be able to do that, it would be super to have a GUI and easy operability for a good FEP program at your fingertips. Admittedly, FEP works only for ligand which differ little in their structure (eg. Me vs H). But that’s also the phenomenon which we understand the least, how “similar” ligands can have great differences in binding affinity, something which FEP should help us understand.

Other improvements will include better parameters in standard docking, and a new force field, OPLS 2008, which will be “better than MMFF”. Considering that the force behind this field is Tom Halgren, the same guy who meticulously crafted MMFF, I would be looking forward to it. There is also talk of a new MD program comparable to Gromacs, AMBER etc. which can do millisecond MD efficiently. That would probably complete the list of capabilities in one program that almost any computational chemist could want.

What I like best about Schrodinger is that it has people at its helm who are among the best that computational chemistry has to offer, most importantly Richard Friesner and Tom Halgren. Looking at their papers, it’s clear that like ideal computational chemists, they thoroughly understand experimental data, and clearly know what the limitations of their programs are.