The Curious Wavefunction

Constancy of the discodermolide hairpin motif

noreply@blogger.com (Wavefunction) — Wed, 11 Nov 2009 23:12:00 +0000

Our paper on the conformational analysis of discodermolide is now up on the ACS website. The following is a brief description of the work.

Discodermolide (DDM) is a well-known highly flexible polyketide that is the most potent microtubule polymerization agent known. In this capacity it functions very similar to taxol and the epothilones. However the binding mode of DDM will intimately depend on its conformations in solution.

To this end we have performed multiple force field conformational searches on DDM and the first surprising thing we noticed was that all four force fields located the same global minimum for the molecule in terms of geometry. This is surprising because, given the dissimilar parameterization criteria used in different force fields, minima obtained for flexible organic molecules are usually different for different force fields. Not only that, but all the minima closely superimposed on the x-ray structure of DDM which we call the "hairpin" motif. This is also surprising since the solid state structure of such a highly flexible molecule should not generally bear resemblance to a theoretically calculated global minimum.

Next, we used our NAMFIS methodology that combines parameters from conformational searches to coupling constants and interproton distances obtained from NMR data to determine DDM conformations in two solvents, water and DMSO. We were again surprised to see the x-ray/force field global minimum structure existing as a major component of the complex solution conformational ensemble. In many earlier studies, the x-ray structure has been located as a minor component so this too was unexpected.

However, this same structure has also been remarkably implicated as the bioactive conformation bound to tubulin by a series of elegant NMR experiments. To our knowledge, this is the first tubulin binder which has a single dominant preferred conformation in the solid-state, as a theoretical global minimum in multiple force field conformational searches, in solution as well as in the binding pocket of tubulin. In fact I personally don't know of any other molecule of this flexibility which exists as one dominant conformation in such extremely diverse environments; if this happened to every or even most molecules, drug discovery would suddenly become easier by an order of magnitude since all we would have to do to predict the binding mode of a drug would be to crystallize it or to look at its theoretical energy minima. To rationalize this very pronounced conformational preference of DDM, we analyze the energetics of three distributed synthons (methyl-hydroxy-methyl triads) in the molecule using molecular mechanics and quantum chemical methods; it seems that these three synthons modulate the conformational preferences of the molecule and essentially override other interactions with solvent, adjacent crystal entities, and amino acid elements in the protein.

Finally, we supplement this conformational analysis with a set of docking experiments which lead to a binding mode that is different from the earlier one postulated by NMR (as of now there is no x-ray structure of DDM bound to tubulin). We rationalize this binding mode in the light of SAR data for the molecule and describe why we prefer it to the previous one.

In summary then, DDM emerges as a unique molecule which seems to exist in one dominant conformation in highly dissimilar environments. The study also indicates the use of reinforcing synthons as modular elements to control conformation.

Jogalekar, A., Kriel, F., Shi, Q., Cornett, B., Cicero, D., & Snyder, J. (2009). The Discodermolide Hairpin Structure Flows from Conformationally Stable Modular Motifs Journal of Medicinal Chemistry DOI: 10.1021/jm9015284

Warren DeLano

noreply@blogger.com (Wavefunction) — Fri, 06 Nov 2009 14:41:00 +0000

This is quite shocking. I just heard him speak at the eChemInfo conference two weeks back and talked to him briefly. His visualization software Pymol was *the* standard for producing and manipulating beautiful molecular images, and almost all images in all my papers until now were created using Pymol.

This is shocking and saddening. He could not have been more than in his late 30s. I have heard him give talks a couple of times and talked to him at another conference; he was naturally pleased to see Pymol used all over my poster. I think everyone can vouch that he was a cool and fun person. I really wonder what's going to happen to Pymol without him.

Here is a brief note posted by Dr. Axel Brunger in whose lab he greatly helped contribute to the programs X-PLOR and CNS for crystallography and modeling.

Dear CCP4 Community:

I write today with very sad news about Dr. Warren Lyford DeLano.

I was informed by his family today that Warren suddenly passed away at home on Tuesday morning, November 3rd.

While at Yale, Warren made countless contributions to the computational tools and methods developed in my laboratory (the X-PLOR and CNS programs),
including the direct rotation function, the first prediction of helical coiled coil structures, the scripting and parsing tools that made CNS a universal computational crystallography program.

He then joined Dr. Jim Wells laboratory at USCF and Genentech where he pursued a Ph.D. in biophysics, discovering some of the principles that govern
protein-protein interactions.

Warren then made a fundamental contribution to biological sciences by creating the Open Source molecular graphics program PyMOL that is widely used throughout the world. Nearly all publications that display macromolecular structures use PyMOL.

Warren was a strong advocate of freely available software and the Open Source movement.

Warren's family is planning to announce a memorial service, but arrangements have not yet been made. I will send more information as I receive it.

Please join me in extending our condolences to Warren's family.

Sincerely yours,
Axel Brunger

Axel T. Brunger
Investigator, Howard Hughes Medical Institute
Professor of Molecular and Cellular Physiology
Stanford University

A wrong kind of religion; Freeman Dyson, Superfreakonomics, and global warming

noreply@blogger.com (Wavefunction) — Wed, 04 Nov 2009 13:29:00 +0000

The greatest strength of science is that it tries to avoid dogma. Theories, explanations, hypotheses, everything is tentative, true only as long as the next piece of data does not invalidate it. This is how science progresses, by constantly checking and cross checking its own assumptions. The heart of this engine of scientific progress is constant skepticism and questioning. This skepticism and questioning can often be exasperating. You can enthusiastically propound your latest brainwave only to be met with hard-nosed opposition, deflating your long harbored fervor for your pet idea. Sometimes scientists can be vicious in seminars, questioning and cross questioning you as if you were a defendant in a court.

But you learn to live with this frustration. That's because in science, skepticism always means erring on the safer side. As long as skepticism does not descend into outright irrational cynicism, it is far better to be skeptical than to buy into a new idea. This is science's own way to ensure immunity to crackpot notions that can lead it astray. One of the important lessons you learn in graduate school is to make peace with your skeptics, to take them seriously, to be respectful to them in debate. This attitude keeps the flow of ideas open, giving everyone a chance to voice their opinion.

Yet the mainstay of science is also a readiness to test audacious new concepts. Sadly, whenever a paradigm of science reaches something like universal consensus, the opposite can happen. New ideas and criticism are met with so much skepticism that it borders on hostility. Bold conjectures are shot down mercilessly sometimes even without considering their possible merits. The universal consensus separates scientists into a majority who provide a vocal and even threatening wall of obduracy against new ideas. From what I have seen in recent times, this unfortunately seems to have happened to the science of global warming.

First, a disclaimer. I have always been firmly in the "Aye" camp when it comes to global warming. There is no doubt that the climate is warming due to greenhouse gases, especially CO2, and that human activities are most probably responsible for the majority of that warming. There is also very little doubt that this rate of warming has been unprecedented into the distant past. It is also true that if kept unchecked, these developments will cause dangerous and unpredictable changes in the composition of our planet and its biosphere. Yet it does not stop there. Understanding and accepting the details about climate change is one thing, proposing practical solutions for mitigating it is a whole different ball game. This ball game involves more economics than science, since any such measures will have to be adopted on a very large scale that would significantly affect the livelihood of hundreds of millions. We need vigorous discussion on solutions to climate change from all quarters, and the question is far from settled.

But even from a scientific perspective, there are a lot of details about climate change that can still be open to healthy debate. Thus, one would think that any skepticism about certain details of climate change would be met with the same kind of lively, animated argument that is the mainstay of science. Sadly, that does not seem to be happening. Probably the most recent prominent example of this occurred when the New York Times magazine ran a profile of the distinguished physicist Freeman Dyson. Dyson is a personal scientific hero of mine and I have read all of his books (except his recent very technical book on quantum mechanics). Climate change is not one of Dyson's main interests and has occupied very little of his writings, although more so recently. To me Dyson appears as a mildly interested climate change buff who has some opinions on some aspects of the science. He is by no means an expert on the subject, and he never claims to be one. However he has certain ideas, ideas which may be wrong, but which he thinks make sense (in his own words, "It is better to be wrong than to be vague"). For instance he is quite skeptical about computer models of climate change, a skepticism which I share based on my own experience with the uncertainty modeling even "simple" chemical systems. Dyson who is also well known as a "futurist" has proposed a very interesting possible solution to climate change; the breeding of special genetically engineered plants and trees with an increased capacity for capturing carbon. I think there is no reason why this possibility could not be looked into.

Now if this were the entire story, all one would expect at most would be experts in climate change respectfully debating and refuting Dyson's ideas strictly on a factual basis. But surprisingly, that's not what you got after the Times profile. There were ad hominem attacks calling him a "crackpot", "global warming denier", "pompous twit" and "faker". Now anyone who knows the first thing about Dyson would know that the man does not have a political agenda and he has always been, if anything, utterly honest about his views. Yet his opponents spared no pains in painting him with a broad denialist brush and even discrediting his other admirable work in physics to debunk his climate change views. What disturbed me immensely was not that they were attacking his facts- that is after all how science works and is perfectly reasonable- but they were attacking his character, his sanity and his general credibility. The respected climate blogger Joe Romm rained down on Dyson like a ton of bricks, and his criticism of Dyson was full of condescension and efforts to discredit Dyson's other achievements. My problem was not with Romm's expertise or his debunking of facts, but with his tone; note for instance how Romm calls Dyson a crackpot right in the title. One got the feeling that Romm wanted to portray Dyson as a senile old man who was off his rocker. Other bloggers too seized upon Romm-style condescension and dismissed Dyson as a crank. Since then Dyson has expressed regret over the way his views on global warming were overemphasized by the journalist who wrote the piece. But the fact is that it was this piece which made Freeman Dyson notorious as some great global warming contrarian, when the truth was much simpler. In a Charlie Rose interview, Dyson talked about how global warming occupies very little of his time, and his writings clearly demonstrate this. Yet his views on the topic were blown out of proportion. Sadly, such vociferous, almost violent reactions to even reasonable critics of climate change seems to be becoming commonplace. If this is how the science of global warming is looking like, then it's not a very favourable outlook for the future .

If Dyson has been Exhibit A in the list of examples of zealous reactions to unbiased critics of climate change, then the recent book "Superfreakonomics" by economists Steven Levitt and Stephen Dubner (authors of the popular "Freakonomics") would surely be Exhibit B. There is one chapter among six in their book about global warming. And yet almost every negative review on Amazon focuses on this chapter. The authors are bombarded with accusations of misrepresentation, political agendas and outright lies. Joe Romm again penned a rather propagandish and sensationalist sounding critique of the authors' arguments. Others duly followed. In response the authors wrote a couple of posts on their New York Times blog to answer these critics. One of the posts was written by Nathan Myhrvold, previously Chief Technology officer of Microsoft and now the head of a Seattle-based think tank called Intellectual Ventures. Myhrvold is one of the prominent players in the book. Just note the calm, rational, response that he pens and compare it to one of Joe Romm's posts filled with condescending personal epithets. If this is really a scientific debate, then Myhrvold surely seems to be behaving like the objective scientist in this case.

So are the statements made by Levitt and Dubner as explosive as Romm and others would make us believe? I promptly bought the book and read it, and read the chapter on climate change twice to make sure. The picture that emerged in front of me was quite different from the one that I had been exposed to until then. Firstly, the authors' style is quite matter of fact and not sensationalist or contrarian sounding at all. Secondly, they never deny climate change anywhere. Thirdly, they make the very important general point that complex problems like climate change are not beyond easy, cheap solutions and that people sometimes don't readily think of these; they cite hand washing to drastically reduce infections and seat belts to reduce fatal car crashes as two simple and cheap innovations that saved countless lives. But on to Chapter 5 on warming.

Now let me say upfront that at least some of Levitt and Dubner's research is sloppy. They unnecessarily focus on the so-called "global cooling" events of the 70s, events that by no means refute global warming. They also seem to cherry pick the words of Ken Caldeira, a leading expert on climate change. But most of their chapter is devoted to possible cheap, easy solutions to climate change. To tell this story, they focus on Nathan Myhrvold and his team at Intellectual Ventures who have come up with two extremely innovative and interesting solutions to tackle the problem. The innovations are based on the injection of sulfate aerosols in the upper atmosphere. This rationale is based on a singular event, the eruption of Mount Pinatubo in the Phillipines in 1990 which sent millions of tons of sulfates and sulfur dioxide into the atmosphere and circulated them around the planet. Sulfate aerosols serve to reflect sunlight and tend to cause cooling. Remarkably, global temperatures fell by a slight amount for a few years after that. The phenomenon was carefully and exhaustively documented. It was a key contributor to the development of ideas which fall under the rubric of "geoengineering". These ideas involve artificially modulating the atmosphere to offset the warming effects of CO2. Geoengineering is controversial and hotly debated, but it is supported by several very well known scientists, and nobody has come up with a good reason why it would not work. In the light of the seriousness of global warming, it deserves to be investigated. With this in mind, Myhrvold and his team came up with a rather crazy sounding idea; to send up a large hose connected to motors and helium balloons which would pump sulfates and sulfur dioxide into the stratosphere. Coupled with this they came up with an even crazier sounding idea; to thwart hurricanes by erecting large, balloon like structures on coastlines which would essentially suck the hot air out of the hurricanes. With their power source gone, the hurricanes would possibly quieten down.

Are these ideas audacious? Yes. Would they work? Maybe, and maybe not. Are they testable? Absolutely, at least on a prototypical, experimental basis. Throughout the history of science, science has never been fundamentally hostile to crazy ideas if they could be tested. Most importantly, the authors propose these ideas because the analysis indicates them to be much cheaper than long-term measures designed to reduce carbon emissions. Solutions to climate change need to be as cheap as they need to be scientifically viable.

So let's get this straight; the authors are not denying global warming and in fact in their own words, they are proposing a possible solution that could be cheap and relatively simple. And they are proposing this solution only to temporarily act as a gag on global warming, so that long-term measures could then be researched at relative leisure. In fact they are not even claiming that such a scheme would work, only that it deserves research attention. Exactly what part of this argument screams "global warming denial"? One would imagine that opponents of these ideas would pen objective, rational objections based on hard data and facts. And yet almost none of the vociferous critics of Levitt and Dubner seem to have engaged in such an exercise (except a few). Most exercises seem to be of the "Oh my God! Levitt and Dubner are global warming deniers!!" kind. Science simply does not progress in this manner. All we need to do here is to debate the merit of a particular set of ideas. Sure, they could turn out to be bad ideas, but we will never know until we test them. The late Nobel laureate Linus Pauling said it best; "If you want to have a good idea, first have lots of ideas, then throw the bad ones away". Especially a problem as big as climate change needs ideas flying in from all quarters, some conservative, some radical. And as the authors indicate, cheap and simple ideas ought to be especially welcome. Yet the reception to Superfreakonomics to me looked like the authors were being castigated and resented for having ideas. The last thing scientific progress needs is a vocal majority that thwarts ideas from others and encourages them to shut up.

Freeman Dyson once said that global warming sometimes looks like a province of "the secular religion of environmentalism" and sadly there seems to be some truth to this statement. It is definitely the wrong kind of religion. As I mentioned before, almost any paradigm that reaches almost universal consensus runs the risk of getting forged into a religion. At such a point it is even more important to respect critics and give them a voice. Otherwise, going by the almost violent reaction against both Dyson and the authors of Superfreakonomics, I fear that global warming science will descend to the status of biological studies of race. Any research that has to do with race is so politically sensitive and fraught with liabilities and racist overtones that even reasonable scientists who feel that there is actually something beneficial to be gained from the study of race (and there certainly is; nobody would deny that certain diseases are more common to certain ethnic minorities) feel extremely afraid to speak up, let alone apply for funding.

We cannot let such a thing happen with the extremely important issue of climate change. Scientific progress itself would be in a very sad state if critics of climate change with no axe to grind are so vilified and resented that they feel inclined to shut up. Such a situation would trample the very core principles of science underfoot.

That is verboten

noreply@blogger.com (Wavefunction) — Tue, 03 Nov 2009 15:10:00 +0000

I have been poring over some manuscripts recently and realized that there are some words which are best avoided in any scientific paper. Hopefully I would not use them myself and I would find myself grimacing if someone else used them.

Probably the most verboten word is "prove". There is no proof in science, only in mathematics. Especially in science where almost everything we do consists in building a model; whether it is a protein-ligand interaction model, stereoselective organic reaction model, or transition state model. A model can never be "proven" to be "true". It can only be shown to correlate to experimental results. Thus anyone who says that such and such a piece of data "proves" his model should get the referees' noose right away.

So what would be a better word? "Validate"? Even that sounds too strong a word to me. So does "justify". How about "support"? Perhaps. I think about the best thing that all of us can say is that our model is consistent with the experimental data. This statement makes it clear that we aren't even proposing it as the sole model, only as a model that agrees with the data.

Even here the comparison is tricky since all pieces of data are not created equal. For instance one might have a model of a drug bound to a protein that's consistent with a lot of SAR data but somehow does not seem to agree with one key data point. The question to ask here is what the degree of disagreement is and what the quality of that data point is. If the disagreement is strong, this should be made clear in the presentation of the model. Often it is messy to tally the validity of a model with a plethora of diverse data points of differing quality. But quality of data and underreporting of errors in it is something we will leave for some other time.

For now we can try to keep the proofs out of the manuscripts.

Tautomers need some love

noreply@blogger.com (Wavefunction) — Wed, 28 Oct 2009 00:30:00 +0000

Now here's a paper about something that every college student knows about and which is yet not considered by people who do drug design as often as it should- tautomers. Yvonne Martin (previously at Abbott) has a nice article about why tautomers are important in drug design and what are the continuing challenges in predicting and understanding them. This should be a good reminder for both experimentalists and theoreticians to consider tautomerism in their projects.

So why are tautomers important? For one thing, a particular tautomer of a drug molecule might be the one that binds to its protein target. More importantly, this tautomer might be the minor tautomer in solution, so knowing the major tautomer in solution may not always help determine the form bound to a protein. This bears analogy with conformational equilibria in which the conformer binding to a protein more often than not is a minor conformer. Martin illustrates some remarkable cases in which both tautomers of a particular kinase inhibitor were observed in the same crystal structure. In many cases, quantum chemical calculations indicate a considerable energy different between the minor protein-bound tautomer and its major counterpart. A further fundamental complication arises from the fact that solvent changes hugely impact tautomer equilibria, and not enough data is always available on tautomers in aqueous solution because of problems like solubility.

Thus, predicting tautomers is crucial if you want to deal with ligands bound to proteins. It is also important for predicting parameters like logP and blood brain barrier penetration which in turn depend on accurate estimations of hydrophobicity. Different tautomers have different hydrophobicities, and Martin indicates that different methods and programs can sometimes calculate different values of hydrophobicity for a given tautomer, which will directly impact important calculations of logP and blood-brain penetration. It will also affect computational calculations like docking and QSAR where tautomer state will be crucial.

Sadly, there is not enough experimental data on tautomer equilibria. Such data is also admittedly hard to obtain; the net pKa of a compound is a result of all tautomers contributing to its equilibrium, and the number of tautomers can sometimes be tremendous; for instance 8-oxoguanine which is a well known DNA lesion caused by radiation can exist in 100 or so ionic and neutral tautomers. Now let's say you want to dock this compound to a protein to predict a ligand orientation. Which tautomer on earth do you possibly choose?

Clearly calculating tautomers can be very important for drug design. As Martin mentions, more experimental as well cas theoretical data on tautomers is necessary; however such research, similar to solvation measurements discussed in a past post, usually falls under the title of "too basic" and therefore may not be funded by the NIH. But whether funded or not, successful ligand design cannot prevail without consideration of tautomers. What was that thing about basic research yielding its worth many times over in applications?

Martin, Y. (2009). Let’s not forget tautomers Journal of Computer-Aided Molecular Design DOI: 10.1007/s10822-009-9303-2

The model zoo

noreply@blogger.com (Wavefunction) — Tue, 20 Oct 2009 01:08:00 +0000

So I am back from the eCheminfo meeting at Bryn Mawr College. For those having the inclination (both computational chemists and experimentalists), I would strongly recommend the meeting for the small group and consequent close interaction. The campus with its neo-gothic architecture and verdant lawns provides a charming environment.

Whenever I go to most of these meetings I am usually left with a slightly unsatisfied feeling at the end of many talks. Most computational models to describe proteins and protein-ligand interactions are patchwork models based on several approximations. Often one finds several quite different methods (force fields, QSAR, quantum mechanics, docking, similarity based searching) giving similar answers to a given problem. The choice of method is usually made on the basis of availability and computational power and past successes, rather than some sound judgement allowing one to choose that particular method over all others. And as usual it depends on what question you are trying to ask.

But in such cases, I am always left with two questions; firstly, if several methods give similar answers (and sometimes if no method gives the right answer), then which is the "correct" method? And secondly, because there is no one method that gives the right answer, one cannot escape the feeling at the end of a presentation that the results that were obtained could have been obtained by chance. Sadly, it is not even always possible to actually calculate the probability that a result was obtained by chance. An example is our own work on the design of a kinase inhibitor which was recently published; docking was remarkably successful in this endeavor, and yet it's hard to pinpoint why it worked. In addition a professor might use some complex model combining neural networks and machine learning and may get results agreeing with experiment, and yet by that time the model may have become so abstract and complex that one would have trouble understanding any of its connections to reality (that is partly what happened to financial derivatives models when their creators themselves stopped understanding why they are really working, but I am digressing...)

However, I remind myself in the end about something that is always easy to forget; models are emphatically not supposed to be "correct" from the point of view of modeling "reality", no matter what kind of fond hopes their creators may have. The only way in which it is possible to gauge the "correctness" of a model is by comparing it to experiment. If several models agree with experiment, then it may be meaningless to really argue about which one is the right one. There are metrics suggested by people to discriminate between such similar models, for instance employing that time-honored principle of Occam's Razor where a model with fewer parameters might be better. Yet in practice such philosophical distinctions are hard to apply and the details can be tricky.

Ultimately, while models can work well on certain systems, I can never escape the nagging feeling that we are somehow "missing reality". Divorcing models from reality, irrespective of whether they are supposed to represent reality or not, can have ugly consequences, and I think all these models are in danger of falling into a hole on specific problems; adding too many parameters to comply with experimental data can easily lead to overfitting for instance. But to be honest, at this point what we are trying to model is so complex (the forces dictating protein folding or protein-ligand interactions only get more and more convoluted like Alice's rabbit hole) that this is probably the best we can do. Even ab initio quantum mechanics involves acute parameter fitting and approximations in modeling the real behavior of biochemical systems. The romantic platonists like me will probably have to wait, perhaps forever.

New Book

noreply@blogger.com (Wavefunction) — Mon, 19 Oct 2009 21:46:00 +0000

Dennis Gray's "Wetware: A Computer in every Living Cell" discusses the forces of physics, chemistry and self-assembly that turns a cell into a computer like concatenation of protein networks that communicate, evolve and perform complex functions. The origin of life is essentially a chemistry problem and it centers on self-assembly.

At the Bryn Mawr eCheminfo Conference

noreply@blogger.com (Wavefunction) — Sat, 10 Oct 2009 18:12:00 +0000

From Monday through Wednesday I will be at the eCheminfo "Applications of Cheminformatics & Chemical Modelling to Drug Discovery" meeting at Bryn Mawr College, PA. The speakers and topics as seen in the schedule are interesting and varied. As usual, if anyone wants to crib about the finger food I will be around. I have heard the campus is quite scenic.

Coyne vs Dawkins

noreply@blogger.com (Wavefunction) — Sat, 10 Oct 2009 03:50:00 +0000

This year being Darwin's 200th birth anniversary, we have seen a flurry of books on evolution. Out of these two stand out for the authority of their writers and the core focus on the actual evidence for evolution that they provide; Jerry Coyne's "Why Evolution is True" and Richard Dawkins's "The Greatest Show on Earth". I have read Coyne's book and it's definitely an excellent introduction to evolution. Yet I am about 300 pages into Dawkins and one cannot help but be sucked again into his trademark clarity and explanatory elegance. I will have detailed reviews of the two books later but for now here are the main differences I can think of:

1. Dawkins talks about more evidence than simply that from biology. He also has evidence from history, geology and astronomy.

2. Dawkins's clarity of exposition is of course highly commendable. You would not necessarily find the literary sophistication of the late Stephen Jay Gould here but for straight and simple clarity this is marvelous.

3. A minor but noteworthy difference is the inclusion of dozens of absorbing color plates in the Dawkins book which are missing in Coyne's.

4. Most importantly, Dawkins's examples for evolution on the whole are definitely more fascinating and diverse than Coyne's, although Coyne's are pretty good too. For instance Coyne dwells more on the remarkable evolution of the whale from land-dwelling animals (with the hippo being a close ancestral cousin). Also, Coyne's chapter on sexual selection and speciation are among the best such discussions I have come across.

Dawkins on the other hand has a fascinating account of Michigan State University bacteriologist Richard Lenski's amazing experiments with E. coli that have been running for over twenty years. They have provided a remarkable window into evolution in real time like nothing else. Also marvelously engaging are his descriptions of the immensely interesting history of the domestication of the dog. Probably the most striking example of evolution in real time from his book is his clear account of University of Exter biologist John Endler's fabulous experiments with guppies in which the fish evolved drastically before our very eyes in relatively few generations because of carefully regulated and modified selection pressure.

Overall then, Coyne's book does a great job of describing evolution but Dawkins does an even better job of explaining it. As usual Dawkins is also uniquely lyrical and poetic in parts with his sparkling command of the English language.

Thus I would think that Dawkins and Coyne (along with probably Carl Zimmer's "The Tangled Bank" due to be published on October 15) would provide the most comprehensive introduction to evolution you can get.

As Darwin said, "There is grandeur in this view of life". Both Coyne and Dawkins serve as ideal messengers to convey this grandeur to us and to illustrate the stunning diversity of life around us. Both are eminently readable.

The 2009 Nobel Prize in Chemistry: Ramakrishnan, Steitz and Yonath

noreply@blogger.com (Wavefunction) — Wed, 07 Oct 2009 11:50:00 +0000

Source: Nobelprize.org

Venki Ramakrishnan, Ada Yonath and Tom Steitz have won the Nobel Prize for chemistry for 2009 for their pioneering studies on the structure of the ribosome. The prize was predicted by many for many years and I myself have listed these names in my lists for a couple of years now; in fact I remember talking with a friend about Yonath and Ramakrishnan getting it as early as 2002. Yonath becomes the first Israeli woman to win a science Nobel Prize and Ramakrishnan becomes the first Indian-born scientist to win a chemistry prize.

The importance of the work has been obvious for many years since the ribosome is one of the most central components of the machinery of life in all organisms. Every school student is taught about its function in acting as the giant player that holds the multicomponent assembly of translation- the process in which the code of letters in RNA is read to produce proteins- together. The ribosome comes as close to being an assembly line for manufacturing proteins as something possibly can. It is also an important target for antibiotics like tetracycline. It's undoubtedly a highly well-deserved accolade. The prize comes close on the heels of the 2006 prize awarded to Roger Kornberg for his studies of transcription, the process preceding translation in which DNA is copied into RNA.

The solution of the ribosome structure by x-ray crystallography is a classic example of work that has a very high chance of getting a prize because of its fundamental importance. X-ray crystallography is a field which has been honored many times and as people have mentioned before, if there's any field where you stand a good chance of winning a Nobel Prize, it's x-ray crystallography on some important protein or biomolecule. In the past x-ray crystallography on hemoglobin, potassium ion channels, photosynthetic proteins, the "motor" that generates ATP and most recently, the machinery of genetic transcription, have all been honored by the Nobel Prize. It's also the classic example of a field where the risks are as high as the rewards, since you may easily spend two decades or more working on a structure and in the end fail to solve it or worse, be scooped.

However, when this meticulous effort pays off the fruits are sweet indeed. In this case the three researchers have been working on the project for years and their knowledge has built up not overnight but incrementally through a series of meticulous and exhaustive experiments reported in top journals like Nature and Science. It's an achievement that reflects as much stamina and the ability to overcome frustration as it does intelligence.

It's a prize that is deserved in every way.

Update: As usual the chemistry blog world seems to be be divided over the prize with many despondently wishing that a more "pure" chemistry prize should have been awarded. However this prize is undoubtedly being awarded primarily for chemistry.

Firstly, as some commentators have pointed out, crystallography was only the most important aspect of the ribosome work. There were a lot of important chemical manipulations that had to be carried out in order to shed light on its structure and function.

Secondly, as Roger Kornberg pointed out in his interview (when similar concerns were voiced), the prize is being awarded for the determination of an essentially chemical structure, in principle no different from the myriad structures of natural and unnatural compounds that have been the domain of classical organic chemistry for decades.

Thirdly, the ribosome can be thought of as an enzyme that forms peptide bonds. To this end the structure resolution engaged knowing the precise locations of catalytic groups that are responsible for the all-important peptide bond formation reaction. Finding out the locations of these groups is no different from determining the catalytic parts of a more conventional enzyme like chymotrypsin or ornithine decarboxylase.

Thus, the prize quite squarely falls in the domain of chemistry. It's naturally chemistry as applied to a key biological problem, but I don't doubt that the years ahead will see prizes given to chemistry as applied to the construction of organic molecules (palladium catalysis) or chemistry as applied to the synthesis of energy efficient materials (perhaps solar cells).

I understand that having a chemistry prize awarded in one's own area of research is especially thrilling, but as a modified JFK quote would say, first and foremost "Wir sind Chemiker". We are all chemists, irrespective of our sub-disciplines, and we should be all pleased that an application of our science has been awarded, an application that only underscores the vast and remarkably diverse purview of our discipline.

Update: Kao, Boyle and Smith

noreply@blogger.com (Wavefunction) — Tue, 06 Oct 2009 12:05:00 +0000

Seems nobody saw this coming but the importance of optical fibers and CCDs is obvious.

It's no small irony that the CCD research was done in 1969 at Bell Labs. With this Bell Labs may well be the most productive basic industrial research organization in history, and yet today it is less than a mere shadow of itself. The CCD research was done 40 years back and the time in which it was done seems disconnected from the present not just temporally, but more fundamentally. The research lab that once housed six Nobel Prize winners on its staff can now count a total of four scientists in its basic physics division.

The 80s and indeed most of the postwar decades before then seem to be part of a different universe now. The Great American Industrial Research Laboratory seems like a relic of the past. Merck, IBM, Bell Labs...what on earth happened to all that research productivity? Are we entering a period of permanent decline?

The 2009 Nobel Prize in Physiology or Medicine

noreply@blogger.com (Wavefunction) — Tue, 06 Oct 2009 02:12:00 +0000

Source: Nobelprize.org

The 2009 Nobel Prize in Physiology or Medicine has been awarded to Elizabeth Blackburn (UCSF), Carol Greider (Johns Hopkins) and Jack Szostak (Harvard) for their discovery of the enzyme telomerase and its role in human health and disease.

This prize was highly predictable because the trio's discovery is of obvious and fundamental importance to an understanding of living systems. DNA replication is a very high fidelity event where new nucleotides are added to the new DNA helix being synthesized with an error rate of only 1 in 10*9. Highly efficient repair enzymes act on damaged or wrongly structured DNA strands and repair them with impressive accuracy. And yet the process has some intrinsic problems. One of the most important problems concerns the shortening of one of the two newly synthesized strands of the double helix during every successive duplication. This is an inherent result of the manner in which the two strands are synthesized.

This shortening leads to shortened ends of chromosomes, termed telomeres. As our cells divide in every generation, there is progressive shortening of the chromosomal ends. Ultimately the chromosomal ends become too short for the chromosomes to remain functional and the cell puts into the motion the machinery of apoptosis or cell death which eliminates cells with these chromosomes. The three recipients of this year's prize discovered an enzyme called telomerase that actually prevents the shortening of chromosomes by adding new nucleotides to the ends. Greider was actually Blackburn's PhD. student at Berkeley when they did the pioneering work (not every PhD. student can claim that his or her PhD. thesis was recognized by a Nobel Prize). The group not only discovered the enzyme but actually demonstrated through a series of comprehensive experiments that mutant cells and mice lacking the enzymes had shortened life spans and other fatal defects, indicating the key role of the enzyme in preventing cell death. At the same time, they and other scientists also crucially discovered that certain kinds of cancers, brain tumors for instance, had high levels of telomerase. This high level meant that cancer cells repaired their chromosomes more efficiently than normal cells, thus accounting for their increased activities and life spans and their ability to outcompete normal cells for survival (As usual, what's beneficial for normal cells unfortunately turns out to be even more beneficial for cancer cells; this need to address similar processes in both cells is part of what makes cancer such a hard disease to treat)

The work thus is a fine example of both pure and applied research. Most of the work's implications lie in an increased understanding of the fundamental biochemical machinery governing living cells. However, with the observation that cancer cells express higher levels of telomerase the work also opens up possible chemotherapy that could target increased levels of telomerase in such cells using drugs. Conversely, boosting the level of the enzyme in normal cells could possibly contribute toward slowing down aging.

The prize has been awarded for work that was done about twenty years ago. This is quite typical of the Nobel Prize. Since then Jack Szostak has turned his focus on to other exciting and unrelated research involving the origins of life. In this field too he has done pioneering work involving for instance, the synthesis of membranes that could mimic the proto-cells formed on the early earth. Blackburn also became famous in 2004 for a different reason; she was bumped off President Bush's bioethics council for her opposition to a ban on stem cell research. Given the Bush administration's consistent manipulation and suppression of cogent scientific data, Blackburn actually wore her rejection as a proud label. Catherine Brady has recently written a fine biography of Blackburn.

Update: Blackburn, Greider, Szostak

noreply@blogger.com (Wavefunction) — Mon, 05 Oct 2009 12:17:00 +0000

A well-deserved and well-predicted prize for telomerase
Again, I point to Blackburn's readable biography

The evils of our time

noreply@blogger.com (Wavefunction) — Fri, 02 Oct 2009 23:46:00 +0000

So yesterday over lunch me and some colleagues got into a discussion about why scientific productivity in the pharmaceutical industry has been perilously declining over the last two decades. What happened to the golden 80s when not just the "Merck University" but other companies produced academic-style high quality research and published regularly in the top journals? We hit on some of the usual factors. Maybe readers can think of more.

1. Attack of the MBAs: Sure, we can all benefit from MBAs but in the 80s places like Merck used to be led by people with excellent scientific backgrounds, sometimes exceptional ones. Many were hand-picked from top academic institutions. These days we see mostly lawyers and pure MBAs occupying the top management slots. Not having a scientific background definitely causes them to empathize less with the long hairs.

2. Technology for its own sake: In the 90s many potentially important technologies like HTS and combi chem were introduced. However people have a tendency to worship technology for its own sake and many have fallen in love with these innovations to the extent that they want to use them everywhere and think of them as cures for most important problems. Every technology works best when it occupies its own place in the hierarchy of methodologies and approaches, and where a good understanding of its limitations wisely prevents its over-application. This does not seem to have really happened with things like HTS or combi chem.

3. The passion of the structuralists: At the other end of the science-averse managers are the chemical purists who are so bent on "rules" for generating leadlike and druglike molecules that they have forgotten the original purpose of a drug. The Lipinskians apply Lipinski's rules (which were meant to be guidelines anyway) to the extent that they trump everything else. Lipinski himself never meant these rules to be absolute constraints.

What is remarkable is that we already knew that about 50% of drugs are derived from natural products which are about as un-Lipinskian as you can imagine. In fact many drugs are so un-Lipinskian as to defy imagination. I remember the first time I saw the structure of Metformin, essentially methyl guanidine, and almost fell off my chair. I couldn't have imagined in my wildest dreams that this molecule could be "druglike", let alone of the biggest selling drugs in the world. I will always remember Metformin as the granddaddy of rejoinders to all these rules.

The zealous application of rules means that we forget the only two essential features of any good drug; efficacy and safety, essentially pharmacology. If a drug displays good pharmacology, its structure could resemble a piece of coal for all I know. In the end the pharmacology and toxicity are all that really matter.

4. It's the science stupid: In the 80s there were four Nobel Prize winners on the technical staff of Bell Labs. Now the entire physics division of the iconic research outfit boasts a dozen or so scientists in all. What happened to Bell Labs has happened to most pharmaceutical companies. The high respect that basic science once enjoyed has now been accorded to other things like quarterly profits, CEO careers and the pleasure of stock holders. What is even more lamentable is the apparent mentality that doing good science and making profits are somehow independent of each other; the great pharmaceutical companies in the 80s like Merck clearly proved otherwise.

Part of the drive toward only short term profits and the resulting obsession with mergers and acquisitions has clearly arose from the so-called blockbuster model. If a candidate is not foreseen to be making a billion dollars or more, dump it overboard. Gone are the days when a molecule was pursued as an interesting therapy that would validate some interesting science or biochemical process, irrespective of its projected market value. Again, companies in the past have proved that you can pursue therapeutic molecules for their own sake and still reap healthy profits. Profits seem to be like that electron in the famous double slit experiment; if you don't worry about them, they will come to you. But start obsessing about them too much and you will watch them gradually fade away like that mystical interference pattern.

We ended our discussion wondering what it's going to take in the end for big pharma to start truly investing in academic style basic science? The next public outcry that emerges from drug-resistant strains of TB killing millions because the drugs which could have fought them were never discovered in the current business model? It could be too late then.

That time of the year

noreply@blogger.com (Wavefunction) — Wed, 30 Sep 2009 04:15:00 +0000

So it seems the Nobel speculations have started again. I have been doing them for some years now and this year at a meeting in Lindau in Germany I saw 23 Nobel Prize winners in chemistry up close, none of whom I predicted would win the prize (except the discoverers of GFP, but that was a softball prediction).

As I mentioned in one of my posts from Lindau, predicting the prize for chemistry has always been tricky because the discipline spans the breadth of the spectrum of science, from physics to biology. The chemistry prize always leaves a select group of people upset; the materials scientists will crib about biochemists getting it, the biochemists will crib about chemical physicists getting it. However, as I mentioned in the Lindau post about Roger Kornberg, to me this selective frustration indicates the remarkable purview of chemistry. With this in mind, here goes another short round of wild speculation. It would of course again be most interesting if someone who was not on anybody's list gets the prize; there is no better indication of the diversity of chemistry than a failure to predict the winner.

1. Structural biology: Not many seem to have mentioned this. Ada Yonath (Weizmann Institute) and Venki Ramakrishnan (MRC) should definitely get it for their resolution of the structure of the ribosome. Cracking an important biological structure has always been the single best bet for winning the Nobel (the tradeoff being that you can spend your life doing it and not succeed, or worse, get scooped), and Yonath and Ramakrishnan would deserve it as much as say Roderick McKinnon (potassium channel) or Hartmut Michel (light harvesting center)

2. Single-molecule spectroscopy: The technique has now come of age and fascinating studies of biomolecules have been done with it. W. E. Moerner and Richard Zare (Stanford) seem to be in line for it.

3. Palladium: This is a perpetual favorite of organic chemists. Every week I get emails announcing the latest literature selections for that week's organic journal club in our department. One or two of the papers without exception feature some palladium catalyzed reaction. Palladium is to organic chemists what gold was to the Incas. Heck, Suzuki and perhaps Buchwald should get it.

4. Computational modeling of biomolecules; Very few computational chemists get Nobel Prizes, but if anyone should get it it's Martin Karplus (Harvard). More than anyone else he pioneered the use of theoretical and computational techniques for studying biomolecules. I would also think of Norman Allinger (UGA) who pioneered force fields and molecular mechanics. But I don't think the Nobel committee considers that work fundamental enough, although it is now a cornerstone of computational modeling. Another candidate is Ken Houk (UCLA) who more than anyone else pioneered the application of computational techniques to the study of organic reactions. As my past advisor who once introduced him in a seminar quipped, "If there's a bond that is broken in organic chemistry, Ken has broken it on his computers".

Among other speculations include work on electron transfer in DNA especially pioneered by Jacqueline Barton (Caltech). However I remember more than one respectable scientist saying that this work is controversial. On a related topic though, there is one field which has not been honored:

5. Bioinorganic chemistry: The names of Stephen Lippard (MIT) and Harry Gray (Caltech) come to mind. Lippard has cracked many important problems in metalloenzyme chemistry, Gray has done some well-established and highly significant work on electron transfer in proteins.

So those are the names. Some people are mentioning Michael Grätzel for his work on solar cells, although I personally don't think the time is ripe for recognizing solar energy. Hopefully the time will come soon. It also seems that Stuart Schreiber is no longer on many of the lists. I think he still deserves a prize for really being the pioneer in investigating the interaction of small organic and large biological molecules.

As for the Medicine Nobel, from a drug discovery point of view I really think that Akiro Endo of Japan who discovered statins should get it. Although the important commercial statins were discovered by major pharmaceutical companies, Endo not only painstakingly isolated and tested the first statin but also was among the first to propound the importance of inhibiting HMG-CoA reductase as the key enzyme in cholesterol metabolism. He seems to deserve a prize just like Alexander Fleming did, and just like penicillin, statins have literally saved millions of lives.

Another popular candidate for the medicine Nobel is Robert Langer of MIT, whose drug delivery methods have been very important in the widespread application of the controlled delivery of drugs. A third good bet for the medicine prize is Elizabeth Blackburn who did very important work in the discovery of telomeres and telomerases. Blackburn is also a warm and highly ethical woman who was bumped off Bush's bioethics committee for her opposition to the ban on stem cell research. Blackburn proudly wears this label, and you can read this and other interesting aspects of her life in her biography.

And finally of course, as for the physics prize, give it to Stephen Hawking. Just give it to him. And perhaps to Roger Penrose. Just do it!!

Update: Ernest McCullough and James Till also seem to be strong candidates for the Medicine prize for their discovery of stem cells. They also won the Lasker Award in 2005, which has often been a stepping stone on the path to the Nobel. McCullough seems to be 83, so now might be a good time to award him the prize.

For chemistry, Benjamin List also seems to be on many lists for his work in organocatalysis, but I personally think the field may be too young go be recognized.

Another interesting category in the physics prize seems to be quantum entanglement. Alain Aspect who performed the crucial experimental validations of Bell's Theorem definitely comes to mind. Bell himself almost certainly would have received the prize had he not died very untimely of a stroke.

Previous predictions: 2008, 2007, 2006

Other blogs: The Chem Blog, In The Pipeline

First potential HIV vaccine

noreply@blogger.com (Wavefunction) — Thu, 24 Sep 2009 11:58:00 +0000

This just came off the press:

A new AIDS vaccine tested on more than 16,000 volunteers in Thailand has protected a significant minority against infection, the first time any vaccine against the disease has even partly succeeded in a clinical trial...Col. Jerome H. Kim, a physician who is manager of the army’s H.I.V. vaccine program, said half the 16,402 volunteers were given six doses of two vaccines in 2006 and half were given placebos. They then got regular tests for the AIDS virus for three years. Of those who got placebos, 74 became infected, while only 51 of those who got the vaccines did. Results of the trial of the vaccine, known as RV 144, were released at 2 a.m. Eastern time Thursday in Thailand by the partners that ran the trial, by far the largest of an AIDS vaccine: the United States Army, the Thai Ministry of Public Health, Dr. Fauci’s institute, and the patent-holders in the two parts of the vaccine, Sanofi-Pasteur and Global Solutions for Infectious Diseases.

However this also came off the same press:

Scientists said they were delighted but puzzled by the result. The vaccine — a combination of two genetically engineered vaccines, neither of which had worked before in humans — protected too few people to be declared an unqualified success. And the researchers do not know why it worked...The most confusing aspect of the trial, Dr. Kim said, was that everyone who did become infected developed roughly the same amount of virus in their blood whether they got the vaccine or a placebo. Normally, any vaccine that gives only partial protection — a mismatched flu shot, for example — at least lowers the viral load.

Nevertheless, after a decade of failures, at least it's a definite starting point scientifically.

The emerging field of network biology

noreply@blogger.com (Wavefunction) — Sun, 20 Sep 2009 14:49:00 +0000

One of the things I have become interested in recently is the use of graph theory in drug discovery. I had taken a class in graph theory during my sophomore year and while I have forgotten some of the important things from that class, I am revising that information again from the excellent textbook that was then recommended- Alan Tucker's "Applied Combinatorics" which covers both graph theory and combinatorics.

The reason why graph theory has become exciting in drug discovery in recent times is because of the rise of the paradigm of 'systems biology'. Now when they hear this term many purists usually cringe at what they see as simply a fancy name given to an extension of well-known concepts. However, labeling a framework does not reduce its utility. The approach should be better named 'network biology' in this context. The reason why graph theory is becoming tantalizingly interesting is because of the large networks of interactions between proteins, genes, and drugs and their targets that have been unearthed in the last few years. These networks could be viewed as abstract graph theoretical networks possibly utilizing the concepts of graph theory and predictions based on the properties of these graphs could possibly help us to understand and predict. This kind of 'meta' thinking which previously was not much possible because of the lack of data can unearth interesting insights that may be missed by looking at molecular interactions alone.

The great power and beauty of mathematics has always been to employ a few simple principles and equations that can explain many diverse general phenomenon. Thus, a graph is any collection of vertices or nodes (which can represent molecules, proteins, actors, internet web pages, bacteria, social agents etc.) connected by edges (which represent interactions between the vertices). In the field of network analysis this has been manifested in a singularly interesting observation; the observation that many diverse networks, from protein-protein networks to the internet to academic citation networks, are scale-free. Scale free networks demonstrate a topology which as the name indicates is independent of the scale. From a mathematical standpoint the defining quality of scale free networks is that they follow a power law. That is, the probability of any node having k connections goes as k to some power -γ, where γ is usually a number between 2 and 3.

Thus, P(k) ~ k^-γ

The scale-free property has been observed for a remarkable number of networks, from the internet to protein-protein interactions. This property is counterintuitive since one would expect the number of connections to follow a normal or Poisson like distribution, with P(k) depending more or less exponentially on k, and nodes having a large number of connections being disproportionately small in number. The scale-free property however leads to a valuable insight; that there are a surprisingly large number of nodes or 'hubs' which are quite densely connected. This property can have huge implications. For instance it could allow us to predict the exact hubs in an internet network which could be most vulnerable to attack. In the study of protein-protein interactions, it could tantalizingly allow us to predict which protein or set of proteins to hit in order to disrupt the maximum number of interactions. A recent study on the network of FDA approved drugs and their targets suggests that this network is scale-free; this could mean that there is a privileged set of targets which are heavily connected to most drugs. Such a study could indicate both targets which could be more safely hit as well as new targets (sparsely connected nodes) which could be productively investigated. Any such speculation can of course only be guided by data, but it may be much more difficult to engage in it without looking at the big picture afforded by graphs and networks.

However the scale-free property has to be very cautiously inferred. Many networks which seem scale-free are subnetworks whose parent network may not be scale-free. Conversely a parent network that is scale-free may contain a subnetwork that is not scale-free. The usual problem with such studies is the lack of data. For instance we have still plumbed only a fraction of the total number of protein-protein interactions that may exist. We don't know if this vast ultimate network is scale-free or not. And of course, the data underlying such interactions comes from relatively indirect methods like yeast two-hybrid or reporter gene assays and its accuracy must be judiciously established.

But notwithstanding these limitations, concepts from network analysis and graph theory are having an emerging impact in drug discovery and biology. They allow us to consider a big picture view of the vast network of protein-protein, gene-gene, and drug-protein and drug-gene interactions. There are several more concepts which I am trying to understand currently. This is very much a field that is still developing, and we hope that insight from it will serve to augment the process of drug discovery in a substantial way.

Some further reading:
1. A great primer on the basics of graph theory and its applications in biology. A lot of the references at the end are readable
2. Applied Combinatorics by Alan Tucker
3. Some class notes and presentations on graph theory and its application in chemistry and biology
4. A pioneering 1999 Science paper that promoted interest in scale-free networks. The authors demonstrated that several diverse networks may be scale-free.

One day left before the singularity

noreply@blogger.com (Wavefunction) — Sun, 20 Sep 2009 14:04:00 +0000

From a January 2009 post on another blog which I forgot to cross-post here:
As I have discussed with friends often, the reason why we start liking certain sitcoms so much is not just because they remain intrinsically funny, but because we gradually start to become friends with the characters and anticipate their actions and words. That certainly happened with Seinfeld. With me that also happened with F.R.I.E.N.D.S., at least till the sixth season. But for this to be so, the lines have to be genuinely creative and witty and most importantly, actors have to inhabit the characters almost perfectly, which seldom happens.

Now it seems to be happening again. The Big Bang Theory has enormously entertained me since it kicked off last year. While it may seem that it would appeal only to science-type nerds, it has potential to get a much more general audience hooked. The premise is not entirely novel but is beautifully packaged. Two brilliant physicists at Caltech, Sheldon Cooper and Leonard Hofstadter, are living a life of total nerdiness; speaking in nerd-speak all the time, analyzing every statement literally, playing Halo every Thursday, collecting tons of actions figures, and attending role-playing medieval games. Needlessly to say, their social ineptness figures in the nth power of ten. Leonard (an experimentalist) is a little more normal, while Sheldon (a theoretician) who is the most brilliant of them all is infinitely annoying and exasperating, being unable to understand simple linguistic devices like sarcasm and metaphor in spite of (or because of) his incandescent brilliance.

Their total lack of social tact and immersion in science is only helped by their two best friends also from Caltech, Howard Wolowitz, an obsessive womanizer and total loser who in spite of his repeated failures will never stop trying to get every attractive woman in bed with him, and an Indian named Raj Koothrapalli who is so scared of attractive women that he can't talk in front of them...unless he is drunk. Between Howard trying to fend off his mother with whom he lives and Raj trying to fend off his parents who are hell-bent on getting him into an arranged marriage, the four friends usually hang out at Sheldon and Howard's apartment, stay away from most human beings, have lunch everyday at the university cafeteria and in general exemplify the epitome of nerdiness.

But things change dramatically when an attractive, not-so-bright (but often having more common sense than the geniuses) blonde named Penny moves in next door to Sheldon and Leonard. How their state of equilibrium is suddenly disturbed by this violent perturbation and how the event has several manifestations of various kinds is the general subject of the episodes. Throw in ample science-speak, the typical lives of awkward geniuses, fun at physics quizzes and desperate dates gone embarrassingly bad, and you have one entertaining sitcom.

It's been a while since I was this entertained. As I noted before, the series works because of clever lines and the actors' ability to almost perfectly inhabit their characters, so that they gradually form a distinct identity in your mind that allows you to start appreciating and anticipating their tics and lines. Hopefully the series will find a large enough fan following to continue playing for a long time.

The Big Bang Theory plays at 9:30 p.m. on Mondays on CBS.

Missile shield to be scrapped

noreply@blogger.com (Wavefunction) — Thu, 17 Sep 2009 12:30:00 +0000

It's a great day. This piece of news makes me feel extremely gratified as I am sure it does many others. Missile defense against ICBMs has been an eternal bug that has bitten almost every President since 1960. The Bush administration had aggressively pushed plans to implement a missile shield in Poland and the Czech Republic. There has always been evidence that the efficacy of such a shield will ultimately be severely limited by the basic laws of physics, and that the adversary can essentially and cheaply overwhelm the defense with decoys and countermeasures.

I have written about these limitations and studies about them several times before (see below). The best article arguing against the European missile shield is a May 2008 article by Theodore Postol and George Lewis in the Bulletin of the Atomic Scientists (free PDF here).

And as arms expert Pavel Podvig succinctly wrote in the Bulletin of the Atomic Scientists only three days back, it's not just about the technology, but it's about a fundamentally flawed concept:

"The fundamental problem with the argument is that missile defense will never live up to its expectations. Let me say that again: Missile defense will never make a shred of difference when it comes to its primary mission--protecting a country from the threat of a nuclear missile attack. That isn't to say that advanced sensors and interceptors someday won't be able to deal with sophisticated missiles and decoys. They probably will. But again, this won't overcome the fundamental challenge of keeping a nation safe against a nuclear threat, because it would take only a small probability of success to make such a threat credible while missile defense would need to offer absolute certainty of protection to truly be effective...It's understandable that people often talk about European missile defense as one of the ways in which to deal with the missile threat posed by Iran. Or that someday missile defense could provide insurance for nuclear disarmament--this is the vision that Ronald Reagan had. When framed in this way, missile defense seems like a promising way out of difficult situations. But this promise is false. If a real confrontation ever comes about (and let's hope it never happens), we quickly would find out that missile defense offers no meaningful protection whatsoever".

Now the Obama administration has decided to scrap the unworkable shield and has decided to replace it with a much more realistic defense against short-range missiles. I cannot imagine how gratified this must make the scores of scientists, engineers and policy officials who have long argued against the feasibility of the shield. It also signals a huge shift in Bush-era foreign policy. Notice how the administration has diplomatically and shrewdly avoided mentioning the basic failures of the earlier system.

Unfortunately, the sordid history of missile defense and the inherent satisfaction that seems to stem by arguing in favor of a "shield" to protect the population makes me skeptical in believing that the concept is dead forever. But for now, there is peace in our time and this is a significant breakthrough.

Past posts on missile defense:
Made For Each Other
Missile Defense: The Eternal Bug
Holes in the Whole Enterprise
Czechs halt missile shield progress

First pentacene, now this

noreply@blogger.com (Wavefunction) — Wed, 16 Sep 2009 01:45:00 +0000

It just seems to get better. Last week a stellar AFM picture of pentacene showing the molecules with unprecedented resolution made the news. This week the picture seems to get even deeper

The pictures, soon to be published in the journal Physical Review B, show the detailed images of a single carbon atom's electron cloud, taken by Ukrainian researchers at the Kharkov Institute for Physics and Technology in Kharkov, Ukraine.

This is the first time scientists have been able to see an atom's internal structure directly. Since the early 1980s, researchers have been able to map out a material's atomic structure in a mathematical sense, using imaging techniques.

Quantum mechanics states that an electron doesn't exist as a single point, but spreads around the nucleus in a cloud known as an orbital. The soft blue spheres and split clouds seen in the images show two arrangements of the electrons in their orbitals in a carbon atom. The structures verify illustrations seen in thousands of chemistry books because they match established quantum mechanical predictions.

David Goldhaber-Gordon, a physics professor at Stanford University in California, called the research remarkable.

"One of the advantages [of this technique] is that it's visceral," he said. "As humans we're used to looking at images in real space, like photographs, and we can internalize things in real space more easily and quickly, especially people who are less deep in the physics."

To create these images, the researchers used a field-emission electron microscope, or FEEM. They placed a rigid chain of carbon atoms, just tens of atoms long, in a vacuum chamber and streamed 425 volts through the sample. The atom at the tip of the chain emitted electrons onto a surrounding phosphor screen, rendering an image of the electron cloud around the nucleus.

Whenever I see something like this I always wonder how utterly exhilarated and astonished Dalton, Boltzmann, Maxwell, Heisenberg, Bohr, Einstein and others would have been if they had seen all this. I remember that Stuart Schreiber's life trajectory was set when he saw orbitals first presented as gorgeous lobes in class. The Schreibers of the twenty-first century could have much more to be excited about. Man's dominion over the understanding and manipulation of matter sometimes seems almost mythical.

Update: After thinking about this a little more and looking at the comment in the comment section my exhilartion has been tempered by skepticism (for a good scientist it should ideally be the other way around...I am still learning). The orbitals look perfect, and I would be interested in knowing what kind of actual techniques they use to process the initial raw data into this finished image. Plus, what about sp3 hybridization?

Norman Borlaug (1914-2009)

noreply@blogger.com (Wavefunction) — Mon, 14 Sep 2009 12:59:00 +0000

A scientist whose name has been heard by few and yet one who gave more people life than almost any other scientist in the twentieth century
NYT obituary

Can natural sciences be taught without recourse to evolution?

noreply@blogger.com (Wavefunction) — Sat, 12 Sep 2009 16:53:00 +0000

That's the question for a discussion over the American Philosophical Society museum website. I think the answer to the question would have to be no. Now of course that does not mean it's technically impossibly; after all before Darwin natural sciences were taught without recourse to evolution. But evolution ties together all the threads like nothing else, and to teach the natural sciences without it would be to present disparate facts without really connecting them together. It would be like presenting someone with a map of a city without a single road in it.

In fact natural sciences were largely taught to us without recourse to evolution during our high school and college days. Remember those reams of facts about the anatomy of obscure animals that we had to memorize. If it wasn't the hydra it was the mouse. If not the mouse then the paramecium. I can never resent my biology teachers enough for not connecting all these animals and their features through the lens of evolution. What a world of difference it would have made if the beauty of the unity of life would have been made evident by citing the evolutionary relationships between all these exotic creatures.

In fact "Evolution" was nothing more than a set of two clumsy textbook chapters that got many of the details wrong and left countless other facts wanting. Granted, some of the teachers at least had good intentions, but they just didn't get it. Teaching biology without constantly referring to evolution is like asking someone to learn about a world without using language. Would you teach physics without recourse to mathematics? Then you should not teach biology without recourse to evolution, at least not in the twenty first century.

Olivia Judson on "Creation"

noreply@blogger.com (Wavefunction) — Thu, 10 Sep 2009 20:00:00 +0000

Olivia Judson is a science writer and research associate at Imperial College London who has written excellent articles on biology and evolution for the NYT as well as the entertaining and informative book "Dr. Tatiana's Sex Advice to all Creation". She seems to like the new movie on Charles Darwin, "Creation", in which the real life couple of Jennifer Connelly and Paul Bettany star as Darwin's wife Emma and Charles. Interestingly Bettany did a fine job playing a Darwin-like naturalist and doctor in the film "Master and Commander".

Darwin's relationship with his wife was admirable and interesting because although she was always devoutly religious and he increasingly was not, their marriage was largely warm and affectionate throughout their lives. In typical scientific fashion, he had drawn up a list of pros and cons before marrying her and decided the pros outweighed the cons. Emma who had taken piano lessons from Chopin provided marital stability while Charles labored over The Origin.

In the movie, I think Connelly is too attractive to play Emma but that's a relatively minor point. My greater concern was with the scientific accuracy in the movie and whether it might turn out to be overwrought and unduly dramatised. However Judson largely mitigates my fears.

Unlike most biographies of Darwin, its central event is not the publication of the “Origin,” but the death of Darwin’s adored eldest daughter, Annie, at the age of 10. She died in 1851 after nine months of a mysterious illness; at the time of her death, she was not at home, but in the English spa town of Malvern, where she had been sent for treatment.

Annie’s death is also the central event of this beautifully shot film. For “Creation” is not a didactic film: its main aim is not the public understanding of Darwin’s ideas, but a portrait of a bereaved man and his family. The man just happens to be one of the most important thinkers in human history.

Which isn’t to say that Darwin’s ideas don’t feature. We see him dissecting barnacles, preparing pigeon skeletons, meeting pigeon breeders and talking to scientific colleagues. He visits the London zoo, where he plays a mouth organ to Jenny, an orangutan; at home, he takes notes on Annie as a baby (Does she laugh? Does she recognize herself in the mirror?). He teaches his children about geology and beetles, makes them laugh with tales of his adventures in South America, and shows them how to walk silently in a forest so as to sneak up on wild animals.

At the same time, we see his view of nature — a wasteful, cruel, violent place, where wasps lay their eggs in the living flesh of caterpillars, chicks fall from the nest and die of starvation, and the fox kills and eats the rabbit.

But all this is merely the backdrop to the story of a man convulsed by grief.

Thus the movie really seems to focus on Darwin's relationship with his family and especially with his beloved and favorite daughter who unfortunately died an untimely death as a child. According to most accounts, this was a focal point in Darwin's conversion to being a non-believer and the movie seems to dwell on the pain and conflict that Darwin experienced during this event.

It's probably easy to forget that along with being one of the greatest minds in history, Darwin was also an unsually kind, modest and gentle soul and a devoted family man. Seems like this movie will do a good job of underscoring this fact as well as entertaining audiences with some of Darwin's scientific explorations.

Impressionist thoughts on Rosetta

noreply@blogger.com (Wavefunction) — Tue, 08 Sep 2009 23:27:00 +0000

Here is Bosco Ho, a postdoc at UCSF comparing Rosetta to the Impressionists, my favorite cabal of artists. Along the way praise and disappointment are also exuded toward GROMOS, an earlier protein modeling program

THE GUTS OF ROSETTA

In the last two CASP meets, David Baker from the University of Washington, using his program Rosetta has come first by a hefty margin in the New Fold category. The success of Rosetta has electrified the protein-folding community.

Yet, there are theorists out there who feel slightly queasy when poking through the innards of Rosetta. Theorists such as Wilfred van Gunsteren, write programs such as GROMOS, which have the richness of 17th century Dutch paintings. Just as Vermeer was fetishistically obsessed with painting every detail of the Dutch bourgeoisie, right down to the hem-line of the chamber-maid's dress, GROMOS is obsessed with modeling every detail of 21st century atomic physics, right down to the quadruple expansion of the electron shells of polarizable atoms. The problem with programs like GROMOS is that they are lumbering giants, bloated programs that devour all the computing that you could ever offer, and still beg for more. Although GROMOS is used for many things, attempts to fold a protein have lurched to a stuttering halt, even after agos of computing time.

Programs like Rosetta, on the other hand, are more like Impressionists paintings, virtuoso dabs of paint that trick the eye into seeing a protein fold in no time at all. For instance, whereas GROMOS fastidiously models all 6 atoms in carbon rings attached to the protein and each atom in the ring is allowed to wobble, Rosetta models the carbon ring as one fat unmovable atom. Water molecules surrounding the protein? No problem, says Rosetta, we'll just ignore them. Rosetta also uses a clever trick by folding similar proteins from different species of animals, and then averaging all the structures to obtain a consensus structure. In reality, when proteins like hemoglobin fold inside your body, they don't get to watch how hemoglobin folds in rats or flies in order to come to a consensus.

Now don't get me wrong; impressionism is my favorite art style, but somehow I am always going to be a little uncomfortable about a program that relies more on statistics than physics to simulate protein folding. I already have this hang up about models in general which I have articulated before. Although modeling reality is what models are supposed to do, ultimately you can still be in for a nasty surprise if you are not paying too much attention to the actual physics and chemistry behind the molecular interactions.

As an aside, I have used Rosetta a little and it can be hideously user-unfriendly. Why the authors never sought to collaborate with a software company who would design a nice GUI for it is something I have never understood. Now in spite of the above rants let me not be misleading here; I think Rosetta is a fantastic program that has achieved some spectacular results reported in places like Nature and Science; perhaps its most stunning achievement was designing an enzyme from scratch that would catalyze a Kemp elimination reaction, a reaction that no other enzyme in nature is known to catalyze. It's just that I think that using it, at least for people who are not members of David Baker's group, might be like flying a highly sophisticated spaceship whose workings are somewhat mysterious. It could be a problem when those ill-understood cumulonimbus (or Romulans) start looming on the horizon.

Can you at least get the solvation energy right?

noreply@blogger.com (Wavefunction) — Wed, 02 Sep 2009 20:55:00 +0000

Basic physical property measurement and prediction is not supported at the granting level and is considered too far from the issues directly affecting drug development to have been pursued by industry. This has left a critical gap in the basic scientific method that drives theoretical methods forward, that is, the observation, hypothesis, and testing methodology that Bacon, al-Haytham, and others championed and that Galileo applied to great effect in the formulative years of modern science...if basic physical science is supported in this area there is great potential for improvement and eventual achievement of long-desired goals of molecular modeling in the pharmaceutical industry- Prescient Soothsayers of Solvation

Sometimes it's a wonder computational predictions of protein and ligand activity work at all. Consider the number of factors we still don't have a good handle on; among other things, calculating protein conformational entropy is virtually beyond reach, calculation of hydrogen bond strengths that depend intimately on the surrounding environment is still quite tricky and calculation of favourable hydrophobic entropy gain because of expulsion of water molecules from the the active site is still a murky area.

But there are things even simpler than these which we have not learnt to calculate well. Foremost among these is a crucial factor influencing every instance of protein ligand binding, the interaction of both assemblies with bulk water. If we can't even get the aqueous solvation energy right, can we make a statement about progress in modeling protein-ligand interactions at all? Water has been probably the most studied solvent for decades and dozens of water models have sprung up, none of which is significantly superior in calculating the properties of this stunningly deceptively simple liquid.

The two foremost implicit methods (as opposed to explicit solvent methods like MD) currently used for calculating solvation energy are the Born solvation method and ones based on the Poisson-Boltzmann equation. Calculating solvation energy ultimately will involve getting the basic science right. With this view in mind, a group from OpenEye and Astra Zeneca narrate their successes and failures in a blind test for calculating solvation energies of 56 druglike organic molecules called SAMPL1. They do a fine job in investigating individual cases and talking about the effect of two crucial variables on the solvation energies; atomic radii (which inversely relate to the solvation) and even more importantly, charges. The group essentially fiddle around with these two variables, modifying the charges and the atomic radii until they get the solvation energy about right. It's a classic case of both the virtues and pitfalls of parametrization and indicates that real parameterization should not involve blindly adding terms to get experimental agreement but instead focus on the two or three scientifically most interesting and important variables.

Believe it or not, but there are a dozen different methods for calculating atomic charges in computational chemistry. Fixed charge models don't capture a very important phenomenon- polarization- that can profoundly affect bond strengths and especially hydrogen bond strengths. In real life charges on atoms don't stay constant in a changing environment. At the same time there is no one "correct" charge model, and as in the case of models in general, what matters ultimately is a model that works. In an earlier blind test, the group had used a particular quantum chemical method called AM1-BCC to calculate charges, and this gave them a mean error of about 2 kcal/mol in the solvation energy. The AM1-BCC method is a well-established semiempirical method that actually calculates slightly overpolarized charges, thus fortuitously and conveniently mimicking the change in charge distribution for a molecule as it transfers from the gas to the aqueous medium. In this paper the group calculate charges at the DFT level and find that this makes a significant difference for a large subset of the previous molecules.

Another interesting phenomenon investigated in the study is the effect of conformations on the calculation of solvation energy. The first axiomatic truth to realize is that molecules exist as several different conformations in both gas and aqueous phases. But low energy conformations for a typical organic molecule in the gas phase will be very different from aqueous conformations. Conformations calculated in the gas phase are typically 'collapsed' and have oppositely charged polar groups too close for comfort because of the lack of intervening solvent that would usually break them up. If you want to use only one conformation for a solvation energy calclation, you would use a collapsed gas phase conformation and a relatively extended aqueous phase conformation. Ideally though you should be more realistic and should use multiple conformations. In the study, the effect of multiple conformations for calculating the vacuum and aqueous phase partition functions and solvation free energy was studied. Interestingly the results obtained with multiple conformations are generally worse than the results obtained with single conformations! There must probably be some added noise that is introduced from unrealistic calculated conformations. The authors also find out, not surprisingly, that using different charges for different conformations of the same molecule can make a difference, although not much. At the same time charges for certain atoms don't change much if the atoms are buried; a failure to realize this leads to two screaming outliers, which however only provides a good opportunity to learn what's wrong.

There are several interesting paragraphs on how the authors played with the atomic radii and the charges and how they explained and were puzzled by outliers. In the end, a particular combination of DFT charges along with a particular combination of radii (termed ZAP10 radii) provided the smallest error in calculation of solvation energies. Interestingly some radii had to be maintained at their default Bondi radii values (which are derived from crystal data) in order to work well.

What I like about this study is that it is told from the real-time viewpoint and illustrates the calculation as it actually evolved. The pitfalls and the possibilities are cogently explored. Certain functional groups and atom types seem to perform better than others. It is clear that much care is devoted to understanding the basic science.

The basic science is also going to involve the accurate experimental determination of solvation energies. Such measurements are typically considered too mundane and basic to be funded. And yet, as the authors make clear in the paragraph quoted at the beginning, it's only such measurements that are going to aid the calculation of aqueous solvation energies. And these calculations are going to be ultimately key to calculating drug-protein interactions. After all, if you cannot even get the solvation energy right...

Nicholls, A., Wlodek, S., & Grant, J. (2009). The SAMP1 Solvation Challenge: Further Lessons Regarding the Pitfalls of Parametrization The Journal of Physical Chemistry B, 113 (14), 4521-4532 DOI: 10.1021/jp806855q