Whose fault is it, again?

Don't let your view of the Bush administration color your picture of reality

Usually I find myself vigorously nodding my head when I read most New York Times Op-Eds and columns. I share the Times's disdain for the Bush administration's policies and usually think they are right on spot when they criticize them. But in this particular case, I think they have let their rightly justified Bush-phobia lead to an unreasonable response.

The story is painful but straightforward. A woman was given the widely prescribed anti-nausea drug Phenergan by injection. When it did not work, the doctor opted for a riskier procedure during which his assistant accidentally punctured an artery in the woman's arm. Gangrene set in, and her entire right arm and hand tragically had to be amputated. Sneezing from a few allergies is hardly worth losing an arm.

The woman rightly sued the physician and his assistant and received a healthy out-of-court settlement. But then she also sued Wyeth, the drug's manufacturer. Why? For "failing to warn the clinicians to use the much safer “IV drip” technique, in which the drug is injected into a stream of liquid flowing from a hanging bag that already has been safely connected to a vein, making it highly unlikely that the drug will reach an artery". The trial court even awarded her a whopping 6.7 million dollars worth of damages. The NYT supports the court's decision and objects to Wyeth's displeasure:

Now Wyeth, supported by the Bush administration, has asked the Supreme Court to reverse the verdict on the grounds that Wyeth complied with federal regulatory requirements.

We do not buy Wyeth’s argument that it did everything it needed to, or could have done, to warn doctors about the dangers involved in the treatment Ms. Levine received. Wyeth did warn of some dangers of the drug treatment, in words approved by the F.D.A., but the state court was well within its rights to conclude that those warnings were insufficient.

So let me get this straight. Wyeth is being sued because the physician did not know what was the safest and best protocol to use and because his assistant botched up the operation?

In fact here's the shocker. Wyeth does have a strong warning against such an injection on its label.

"Under no circumstances should PHENERGAN Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene"

What more do you want the company to do? Emphasize "under no circumstances" three times? Were they also supposed to say, "Do not inject this drug directly into the heart"? I find this case outright bizarre.

Somehow the NYT also ties this event to the Bush administration's argument that companies should be protected from lawsuits if the FDA has completely approved their drug and the way it's prescribed. If anything, shouldn't the FDA be sued for not making sure that the company had all the warnings adequately written on the label here? I share the NYT's general contempt for industry-protecting Bush policies. But in this case the policy seems to make sense to me. If the FDA is supposed to be the "decider" when it comes to approving drugs, why should companies bear the brunt of failed drugs if the FDA has already approved them?

It is sad when general opinions that are justified lead to specific views that are not.

Selective vs Multitargeted Kinase Inhibitors: Still in the Stone Age

In the conference on kinase inhibitors I attended recently, there was a panel discussion on the second morning (why do these discussions have to start at 7:30 a.m.?) about the utility of selective vs multi- target directed inhibitors. The conventional wisdom has been that selective inhibitors- or any selective drugs for that matter- are best, since off-target effects can cause toxicity. The fight against cancer has largely been about finding selective and therefore safe drugs that hit targets only in cancer cells. It is a measure of how less we have accomplished in cancer therapy in spite of the countless amounts of dollars spent that we still are far from rationally designing reliable, selective and safe cancer drugs.

The discussion we had did not end in any consensus. While selective drugs may clearly be good in certain cases, there are cases in which drugs designed for selectivity ended up promoting their action by being non-selective and targeting multiple targets, but only in retrospect. Gleevec, the revolutionary drug for treating chronic myeloid leukemia, is a classic example. Initially supposed to be a "magic bullet" that targeted only a mutated kinase named Bcr-Abl in cancer cells, Gleevec later turned out to also potently target two other kinases, c-Kit and PDGFR. Interestingly these two targets are valuable targets in cancer therapy of two other cancers, renal cell carcinoma of the kidneys and glioblastoma of the brain.

In any case, the consensus was that we are still far away from designing drugs for a specifically chosen subset of targets. Something like staurosporine that hits almost every kinase out there is going to be undoubtedly gratuitously toxic. But inhibitors hitting a very specific subset of kinases could target a few crucial choke-points in disease pathways, thus serving as valuable drugs. But we are still far from rationally designing such inhibitors. Indeed, in the first place we don't even know what specific subset of kinases to hit for treating a particular disease. First comes target validation, then modulation. Most of the specific subset targeting kinase inhibitors seem to be discovered only in retrospect. In my own project where we are trying to target only one kinase selectively, we are now being skeptical about whether the beneficial effects we are observing are due to multi-target binding.

The other unrelated point we discussed was whether anybody knew kinase inhibitors which were near clinical trial phase completion for areas other than oncology. The silence around the table spoke for itself.

The bottom line is; as far as targeting specific subsets of kinases with inhibitors or even knowing which specific subset to target is concerned, we are still in the Stone Age of kinase drug discovery. The drugs which we have are largely still stone and tree branches. We have a long way to go before discovering tools and bronze.

In the next post, I will talk about a recent effort that overcame the rational multi-kinase inhibitor design for two very different kinases. It points the way forward.

History

Image: New York Times

Till I was about 13 or 14 years old, my readings of American history consisted only of offerings from the history of the United States during World War 2, an old and enduring historical interest of mine. It was when I picked up Harold Evans's The American Century, a superb and magisterial illustrated history of the country during the twentieth century, that I became painfully and woefully aware of the injustice that African-Americans faced in this country for two hundred years. I was horrified to read about Jim Crow, the dog squads and water hoses on the streets of Montgomery, Alabama, the lynchings in Mississippi. As a boy who was about the same age then, I was especially sickened and completely shaken by the relatively recent story of Emmet Till, a story that has been vividly seared into my mind ever since.

I could not believe that this was the country enshrined in the Declaration of Independence, the land which first and foremost looked at the integrity of one's character and his or her abilities and not where he or she came from. And yet I saw hope and fundamental human decency in Martin Luther King and the Civil Rights movement. But since then, I have often felt whether any event or moment in the United States could possibly mentally transport me to a pre-Harold Evans time when I had a singularly auspicious and pristine perception of this country. Such a moment would never come because one cannot erase the scars inflicted on this country's character for two hundred years. But I feel convinced that if there would be a moment closest to such a moment in my life, that moment would be yesterday night.

At midnight, I stood on the 15th floor of the Hyatt Regency Hotel and amid the car horns constantly blaring on the street downstairs, I strained my ears to catch every word that he spoke on the TV screen. The overriding feeling among everyone around me was one of peace and relief and tears even more than elation.

He looked tired, relieved and happy but not jubilant. He knows the difficult task that lies ahead and knows that celebration right now is premature. He knows that there's much to be done and that this is just the beginning. He knows that he may not be able to bring about a sea change in the way things have been done. But he knows that he will nudge the country in the right direction by valuing and fostering rationality and honest debate. He knows he will be upfront and forthright about what he thinks and he understands the value of the journey, even if the final destination may not be known. He understands the value of incremental progress.

And he knows that his extraordinary story culminating in yesterday's night healed at least some of the internal divisions among his own people and will go a long way in reviving his country's image in the world as the land of opportunity, diversity and respect.

He did it. Now we have to do it. Now we can get back to our lives.

Save Science on Tuesday

It was Richard Nixon who got rid of the Presidential Science Advisory Committee during his tenure, which has not been resurrected since. In the 80s, Ronald Reagan embraced the idealistic vision of Star Wars, a pipe dream that did not have a valid scientific basis. In the 90s, Congress got rid of the Office of Technology Assessment which is supposed to provide the country's political leaders with bipartisan scientific advice. Science on the whole in the last twenty five years has been on a downhill path as far as respect for it in political circles has been concerned.

Although George Bush's administration has been the single-largest malefactor of science and all it stands for and in general although Republicans have done more damage to science, all administrations since the 1970s have overall been lax and negligent in supporting science and its essential spirit. As I have written before, the issue goes far beyond the important one of providing funding for basic scientific research. It has to do with trusting unbiased advice that tries to give you a picture of the world as it is, and not how you would like to see it. It has to do with promoting and respecting open-mindedness and true bipartisan debate. Thus science has always stood opposite dogma, a fact that is usually hard to swallow for most politicians who would want to color the world with their own ideological brush. This is a wholly fatalistic attitude because a disrespect for science means an abandonment of informed decision making, eventually a sure path for a country's spiral into regress.

Barack Obama is not good for science because he is a liberal Democrat. He is good for science because he largely stands for all that science traditionally has; open minds, patient and careful thought, forthcomingness and respect in listening to dissenting opinions, a mistrust of blind reliance on authority and a willingness to listen to all sides of the debate before taking an informed decision. Obama also knows he is not perfect and embodies another key aspect of science; the ability to understand one's deficiencies and limitations and seek the best possible advice to overcome them. There is scarce doubt that he will bring knowledgeable science advisors into the White House and that he will take seriously the advice of people with whom he may not agree. At the same time he will weigh all the options and sides and try to take as unbiased a decision as he can. In an age of climate change, evolution, food crises, energy crises, drug resistance and nuclear terrorism, science is going to become an increasingly key and vocal part of the national debate and the future of this country. Obama understands this. Maybe that's why, a few days ago, 76 Nobel Prize winners represented by the great physicist Murray Gell-Mann wrote an open letter to the American people and endorsed Obama as most prudent for science in this country.



The American people need to reclaim their lost preeminence in science and technology and their respect for learning and rationality. They need to reaffirm their place in the world as the land where open minds meet unlimited resources and intellectual capital. The time has come when this land needs to save science from itself. With this in view, anyone who deeply cares about science, reason and objective thought should vote for Barack Obama on Tuesday.

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.