Break

I am in Boston for a kinase inhibitors conference this week, so I may not be able to blog, except when I want to complain about some kinase inhibitor speaker. Enjoy the fall.

The Unbearable Heat Capacity of Being

There is a peculiar connection in my mind; that between thermodynamics and Beethoven's 5th symphony. I was in my final year of high school and it was a rainy and stormy night outside. I had to desperately study thermodynamics for my final exam. The only light that was on was from my table lamp. I was also listening to Beethoven's 5th symphony for the 2nd or 3rd time. Somehow within the mystical shadows and strange shapes manifested by the light, the strains of the strings and the equations of entropy formed a hybrid meld in my mind that has never dissociated. After that night, whenever I read thermodynamics, I don't always remember Beethoven's 5th. But whenever I listen to Beethoven's 5th, I am immediately transformed to that night, into the middle of a fluid energy landscape if you will.

Since then thermodynamics has been an enduring interest of mine. Another reason why it has been an interest of mine is because I don't understand it very well. In my opinion thermodynamics is one of those difficult subjects like quantum mechanics, where a great deal of effort has to be put into understanding abstract concepts and even then concepts remain elusive. Maybe it's a feature of all those sciences that are intimately bound with the fabric of matter and life. It is relatively easy to colloquially grasp entropy as an increase in disorder- we can grasp this point every time we put ice in our drink even as we struggle to understand thermodynamic principles- but much harder to get the physical meaning of the derivative of the pressure with respect to the entropy or some similar expression. Enter the Maxwell relations.

Over the years I have found myself coming back to thermodynamics and repeatedly trying to understand its fine points. I have a long way to go but I am confident I am going to continue my frequently ineffectual efforts. There are some classic books which I have encountered on the way that have served as guides, sometimes strict and sometimes gentle- Enrico Fermi's "Thermodynamics" is a jewel still in print, the thermodynamics treatment in Alberty and Silbey's physical chemistry book is quite nice and Ken Dill's Molecular Driving Forces has the best treatment of statistical thermodynamics applied to chemical and biological systems that I am aware of. There's also an old book on thermodynamics which is gold- Samuel Glasstone's "Thermodynamics for Chemists".

I cannot deny the value of thermodynamics and what it has taught me. Thermodynamics has been immensely useful in understanding computational chemistry, conformational changes in biomolecules and especially protein-ligand binding. All that really matters for protein ligand binding and the orchestration of the actions of numerous naturally occurring ligands and drugs is the free energy change ∆G. More than any other, there is one overriding goal today among the groups of people who are in the business of prediction- to predict binding affinity from first principles. Free us they say, free us from the constraints of predicting free energy.

There is an all-pervasive equation relating ∆G to the equilibrium constant of a reaction- ∆G=-RTlnK. This is perhaps the single most compelling equation in biology. Why? Because it tells you that life lives within a roughly 3 kcal/mol energy window. All the jiggling that transmits signals, folds proteins, docks molecules, makes neurons buzz, mainly happens within a 3 kcal/world. That does not of course mean that no process can have a ∆G of more than 3 kcal/mol, but it does mean that fragile life is pretty tightly constrained and can call the shots only within a limited thermodynamic domain. The reason is that a difference in ∆G of 3 kcal/mol means that the favourable product in any reaction exists to the extent of 99.96%. The exponential dependence of K on ∆G takes care of this. 3 kcal/mol is all a protein needs to toss at a ligand to decisively shift the equilibrium to the side of the bound ligand. It can of course toss more but 3 is enough. One of the reasons why prediction of binding affinity is still so difficult is because 'small' errors of 1 kcal/mol or so translate into huge differences in equilibria. Nature with its fondness for exponentials has doomed life- and chemists- to operate in a straitjacket.

But this same fondness has also made it possible to modulate different reactions and binding events in living systems with exquisite precision. The 3 kcal/mole value perfectly encapsulates the workings of such critical interactions as hydrogen bonds and Van der Waals forces. Expulsions of water, making and breaking of salt bridges, dispersion interactions, peptide hydrogen bond formation; everything can take place within 3 kcal/mol. At the same time the magic number of 3 also ensures that these interactions can be fleeting and rapidly annihilated and molecular partners can dissociate whenever necessary. What reins us in also frees us to explore an ever-widening energy landscape of weak interactions that strike the precise balance. By consigning our lives to whimsical energetic windows, we have finally liberated ourselves from the temptation of falling for monstrous blooming thermodynamic calamities that would have snuffed life out. We can be fortunate that we are not asymptotically free.

But ∆G is like statistics (or some would say like skirts); it hides much more than it reveals. Most techniques can give you ∆G but unraveling the details of a molecular process can immensely benefit from the knowledge of ∆H and ∆S, two crucial components that make up another of biology's key equations- ∆G=∆H-T∆S. Contrast ligand binding with ballroom dancing- what matters is not only how steadily you can hold on to your partner but also how flexible you concomitantly are. The correct combination of motion and attraction in this case can provide a cascade of favourable events. Ditto for ligand binding. Techniques like calorimetry can provide these valuable details. Theoretically, an infinite combination of ∆H and ∆S can add up to a ∆G value, which is all the more reason for finding out the exact composition that makes up a particular value. Two isoenergetic processes need not be either isoenthalpic or isoentropic. In a future post, I will mention a review that explores this aspect; suffice it for now to say that subtle differences in structure may give us the same ∆G but very different decomposition of ∆H and ∆S. Generally intermolecular forces contribute the most to ∆H while hydrophobic effects and the freeing up of water contribute dominantly to ∆S.

And so life lives and breathes, supported on two stilts. These two equations, one endowing biological reactions with the correct equilibria and the other modulating biological action by injecting the precise dosage of two key quantities are like the Magi. They bring us great gifts of understanding and insight. They ask only that we give them a patient ear.

Off the list

Nobody gets a prize for predicting the Chemistry Nobel this year; it was as much of a softball prediction as you can imagine. But at least there's one less person to gossip about now, and hopefully no acrimonious debates.

2008 Medicine Nobel: Montagnier finally wins

If you knew little about the Nobel prizes, you could be easily forgiven for assuming that somebody must have already won the Nobel for discovering the AIDS virus. Many people probably do assume this. It just seems hard that such an important discovery has not already been recognized by the prize.

And yet, those who know the history know about the acrimonious dispute between Frenchman Luc Montagnier and American Robert Gallo about priority. The two were involved in a protracted and cantankerous debate with both camps claiming that they were the ones who discovered HIV and demonstrated its action. When I read the history, to me it was always clear that it was Montagnier whose team not only undoubtedly first isolated the virus, but actually proved that HIV causes AIDS, an absolutely crucial step in establishing the identity of a causative agent and a diagnostic step for the disease. While Gallo also played an important role in the latter, the history also indicated to me that he had engaged in some pretty cunning and disingenuous political manipulation to claim priority for the discovery.

It didn't really seem that the prize would be awarded to both of them. It may well have not been awarded to any of them. The Nobel committee usually steers clear of controversial people and topics. But it seems to have realized that it can no longer neglect the truly important people behind such an obviously groundbreaking discovery. So Luc Montaginer, along with Francois-Barre Sinoussi have finally been awarded the 2008 Nobel Prize for Physiology and Medicine. Barre-Sinoussi first isolated HIV. The committee clearly is trying to avoid controversy by specifically saying that the prize is for discovering HIV. Even Gallo should not have a problem conceding that it was Montagnier and Barre-Sinoussi who first saw and isolated the virus.

The other half deservedly goes to Harald Zur Hausen, discoverer of the human papilloma virus which causes cervical cancer.

I would recommend reading Virus, Montagnier's story of his life and his work.

Emory in a little, Nemeroff in big, trouble

One of the perks of becoming an academic professor is the side income which you can generate by consulting for companies, especially pharmaceutical companies. While that is a healthy way of supplementing your income and in fact provides some incentive for people to go into academia, it would be imperative to disclose any conflict of interest you may have, and in fact most authors do so in journal articles for example. This would be absolutely key if you were using a company's products in your supposedly fair, unbiased and balanced academic research.

Apparently Charles Nemeroff, Chair of the Psychiatry Department at Emory University, does not think so. I was a little shocked at the news partly because these days I am reading the classic psychopharmacology textbook that he co-authored with Alan Schatzberg and finding it quite eye-opening. But nothing in the book opened my eyes wider than this piece of news from the NYT:

One of the nation’s most influential psychiatrists earned more than $2.8 million in consulting arrangements with drug makers from 2000 to 2007, failed to report at least $1.2 million of that income to his university and violated federal research rules, according to documents provided to Congressional investigators.

The psychiatrist, Dr. Charles B. Nemeroff of Emory University, is the most prominent figure to date in a series of disclosures that is shaking the world of academic medicine and seems likely to force broad changes in the relationships between doctors and drug makers.

In one telling example, Dr. Nemeroff signed a letter dated July 15, 2004, promising Emory administrators that he would earn less than $10,000 a year from GlaxoSmithKline to comply with federal rules. But on that day, he was at the Four Seasons Resort in Jackson Hole, Wyo., earning $3,000 of what would become $170,000 in income that year from that company — 17 times the figure he had agreed on.

And why was disclosing this windfall deathly important for Dr. Nemeroff? Well, because:

Dr. Nemeroff was the principal investigator for a five-year $3.9 million grant financed by the National Institute of Mental Health for which GlaxoSmithKline provided drugs.

So Nemeroff was on an NIH grant that involved using GSK drugs, and was getting paid princely sums by GSK at the same time. It's hard to have a better definition of conflict of interest. And even in an age when the sum of 700 billion$ is being bandied around rather casually, 2.8 million$ is still a lot of money.

It also does not seem to be the first time that he has blurred the line. In 2006 he seems to have stepped down from the editor's position of the journal Neuropsychopharmacology when he published an article using a device whose manufacturer was paying him. As detailed above, he also had had an incident with Emory in 2004 when he promised not to make too much money off his consulting. Dr. Nemeroff regularly gives talks in which he discusses the benefits of drugs like Paxil.

It's also interesting that some people suspect that Nemeroff may have had a hand in David Healy being denied his position at the University of Toronto. Healy has written a very interesting book called "Let them eat Prozac" which rather meticulously and candidly documents the alarming incidence of suicide attempts by patients on SSRIs. Apparently Healy faced a lot of hostility from the establishment and...surprise...from pharma when he tried to go public with these findings. It's all disturbing.

I really hope Emory takes some drastic action against what seems to be a repeated violation of some extremely important and time-honored guidelines of research. It's getting uncomfortable, and fingers are being pointed at the school for not noticing this and taking action earlier. The sooner the university acts, the better it can save face and avoid embarrassment.

But the gnawing questions remain. Since the line between a productive and honest and unholy academic-corporate nexus seems to be thin indeed, who regulates such collaborations and how can they do this? Sadly we know all too well who pays.

Other links: The Carlat Psychiatry Blog, University Diaries, Pharmalot

Fizz or Fizzle: The 2008 Nobels

It's that time of the year again. I have already made predictions in 2006 and 2007 and the last year hasn't exactly seen a windfall of novel discoveries that would suddenly add 10 new names to my list. So the lists largely hold. But what does happen in one year is that the Nobel Committee's moral baggage becomes indisputably heavier. When for example are they going to seek repentance for their misses by acknowledging:

Roger Tsien

Martin Karplus

The Palladium Gang (Heck, Sonogashira, Suzuki)

Stuart Schreiber

Ken Houk

As for Sir Fraser Stoddart, I personally think that he may get it in the future when a few more practical applications are found for his toys and methods (On the other hand I still claim credit for mentioning his name if he wins it)

Like last year, fields can also get rewarded through individuals; I personally would be buoyant if my favourite fields- computational chemistry, biochemistry and organic chemistry- win. I also think that Robert Langer can get it for medicine and single molecule spectroscopy may win for either physics or chemistry. Some x-ray structure of an important protein always stands a chance. The interesting thing about the Nobels is that they often reward things that are so important and widespread that we have all taken them for granted and therefore never think of them; no blogger thought of RNAi for example.

But whoever wins, every time the Nobel committee awards the prize, they inevitably commit a grave injustice since somebody deserving is left out. But then that's the nature of man-made accolades. Fortunately most scientists don't depend on such honors and instead are rewarded by nature's sure award; the kick that one gets from scientific discovery, as this guy can describe very well.



And so it goes.

Update: Here's a dark horse prediction for me- geochemistry or climate chemistry. As far as I know, the last climate chemistry prize was won a pretty long time ago for the discovery of the effects of CFCs on the ozone layer.

Links: Other and similar predictions- The Chem Blog and the Skeptical Chymist. The Coronenes have rightly rose above the committee and awarded their own prize. Now that's the kind of assertiveness that we need.