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. Wyeth has decided to appeal the case in front of the Supreme Court. 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"? Did the court even read the label? 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.

CHARITY BEGINS IN THE UNIVERSITY

I mentioned in the last post how the transition time between academic science---->industrial technology needs to be accelerated, and it struck me that there were so many things in the conference which were being talked about by pharma scientists, which originally came from academia. Ketki has also mentioned the increasing collaboration between academia and industry, and I cannot help but think of technologies that people in pharma currently rave about, all of which were developed in academic laboratories.

Consider the recent use of NMR spectroscopy in studying the interaction of drugs with proteins, a development that has really taken place in the last five to ten years. NMR is essentially an academic field which has been around for almost fifty years now, originally developed by physicists who worked on radar and the bomb, and then bequeathed to chemists. It is the humdrum tool that every chemist uses to determine the structure of molecules, and in the last twenty years it was also expanded into a powerful tool for studying biomolecules. What if pharma had actually gone to the doorstep of the NMR pioneers twenty years back, and asked them to develop NMR especially as a tool for drug discovery? What if pharma had funded a few students to focus on such an endeavor, and promised general funding for the lab? What if Kurt Wuthrich had been offered such a prospect in the early 90s? I don't think he would have been too averse to the idea. There could then have been substantial funding to specially focus on the application of NMR to drug-protein binding, and who knows, maybe we could have had NMR as a practical tool for drug discovery ten years ago, if not as sophisticated as it is now.

Or think of the recent computational advances used to study protein-ligand interaction. One of the most important advances in this area has been the protocol called docking, in which one calculates the interactions that a potential drug has with a target in the body, and then thinks of ways to improve those interactions based on the structure of the drug bound to the protein. These programs are not perfect, but they are getting better every day, and now are at a stage where they are realistically useful for many problems. These docking protocols are based on force fields, which are programs that calculate the energies and structures of molecules. The paradigm in which force fields are developed, called molecular mechanics, was developed by Norman Allinger at UGA, and then improved by many other academic scientists. Only one very effective force field was developed by an industrial scientist named Thomas Halgren at Merck. During the 80s and 90s, force fields were regularly used to calculate the energies of simple organic molecules. One can argue that at that point they simply lacked the sophistication to tackle problems in drug discovery. But what if pharmaceutical companies had then channeled millions of dollars into these academic laboratories for specifically trying to focus on adapting these force fields for drug-like molecules and biomolecules? It is very likely that academic scientists would have been more than eager to make use of those funding opportunities and dedicate some of their time to exploring this particular aspect of force fields. The knowledge from this specific application could have been used in a mutually beneficial and cyclic manner to improve basic characteristics of the force fields. And perhaps we could have had good docking programs based on force fields in the late 90s. Pharma could also fund computer scientists in academia to develop parallel processing platforms specifically for these applications, as much of the progress in the last ten years has been possible because of exponential rise in software and hardware technology.

There are many other such technologies; fabrication, microfluidics, single molecule spectroscopy, which can potentially revolutionize drug discovery. All these technologies are being pursued in universities at a basic level. As far as I know, pharma is not providing significant funding to universities for specifically trying to adapt these technologies to their benefit. There are of course a few very distinguished academic scientists who are focused on shortening the science--->technology timeframe; George Whitesides at Harvard and Robert Langer at MIT immediately come to mind. But not everybody is a Whitesides or Langer, both of whom have massive funding from every imaginable source. There are lesser known scientists in lesser known universities who may also be doing research that could be revolutionary for pharma. Whitesides recently agreed to license his lab's technologies to the company Nano-Terra. Nano-Terra would get the marketing rights, and Harvard would get the royalties. There are certainly a few such examples. But I don't know of many where pharma is pouring money into academic laboratories to accelerate the transformation of science into enabling technology.

In retrospect, it's actually not surprising that future technologies are being developed in universities. In fact it was almost always the case. Even now-ubiquitous industrial research tools like x-ray crystallography, sequencing, and nuclear technology were originally products of academic research. Their great utility immediately catapulted these technologies into industrial environs. But we are in a new age now, with the ability to suddenly solve many complex problems being manifested through our efforts and intellect. More than at any other time, we need to shorten the transition time between science and technology. For doing this, industry needs to draw up a checklist of promising academic scientists and labs who are doing promising research, and try to strike deals with them to channel their research acumen into specifically tweaking their pet projects to deliver tangible and practical results. There would of course be new problems that we would need to solve. But such an approach in general would be immensely and mutually satisfying, with pharma possibly getting products on their tables in five instead of ten years, and academia getting funded for doing this. It would keep pharma, professors, and their students reasonably happy. The transition time may not always be speeded up immensely. But in drug discovery, even saving five years can mean potentially saving millions of lives. And that's always a good cause isn't it.

BOSTON AHOY. PHARMA AHOY.


(Above: The view across from the bridge at the World Trade Center and Below: The always scenic view across the Charles in front of MIT)

I am finally back from a trip that was both professionally and personally immensely satisfying, and if there's one place I was really sad to leave, it was this one. I can keep on talking about how great a place Boston is- the place where I stayed and the historic places cruise I took around the harbor were just fantastic- but my praise has also been somewhat tempered by two realisations. Firstly, the boss paid the tab which makes it a little easier to have a good time. Secondly, everybody says that it's only in these four months that Boston is the best place on earth. Anytime after that and the enjoyment quickly starts to dwindle because of the pretty nasty weather. So if I could get a part time dream job where I could work in Boston only for four months, that really would be it. Dream on.

One of the good things about this conference was that our patent on a new (potential) anti-cancer compound just got filed days before the conference. That made it possible for me to present the work. The work was well-received, although as is always the case, there's miles to go before we can possibly sleep.

The conference itself was great, and it was held in a scenic location- the World Trade Center by the side of the harbor (although almost everything in Boston seems to be harbor-side). It was the first time I got a preview of what it's like to work in industry. I was happy to see that a camarederie similar to that among academic scientists exists in the pharmaceutical industry too. However, I also got the feeling that that camaraderie is more guarded, and also a little more exclusive. I may possibly have been the only graduate student there among about a hundred participants. I was also surprised to see, perhaps not so surprisingly in retrospect, that folks in industry do almost exactly the same kind of work that we do, at least in the very initial stages of drug design. But where they really get a head start is in validating early models by having massive in-house facilities and personnel for things like pharmacokinetics (investigating the properties of the drug in the body) and x-ray crystallography (having a structure of the drug bound to the protein which it is supposed to inhibit). So they can decide relatively early on whether to pursue or drop a prospective candidate. We are now planning to put our own compounds in animals, and I would have given anything to have a crystal structure and pharmacokinetic data in the early stages when we had the lead. Pharma can do this, and they learn a lot from it.

The downside of working in pharma? You cannot talk! About 60% of the presentations in the conference did not have a single chemical structure in them. In most cases the only structure displayed was an already well-known one. It's really frustrating to be a chemist and not see what are the structural characteristics that are leading to all those tantalizing pieces of biological and clinical data. And it looks like it's only going to get more proprietary. That's the only thing that makes me a little wary of working in pharma, the fact that you often cannot talk to people outside even if you know that they could have the answers to your questions. Also, the fact is that many of the technologies that are now roaring in pharma have their origin in basic science developed in academic labs. I always keep on imagining how much the science--->technology transit time would have been reduced if there could have been collaboration between pharma and those academic labs in the initial stages. Of course there are IP issues, but one cannot help but think about this.

But all in all, a very fruitful experience. I look forward to attending more of this next year.