SA: Do you know of any pharmaceutical companies already trying to devise drugs that act on ion channels?

RM: There are many, actually. Many have contacted me for advice, for example. I usually only stay here in my lab and just concentrate on my own work, but that's my way. But yes, I do know that many are working on ion channels, in particular potassium channels as targets.

My understanding is that it will eventually work this way: You screen for molecules that will bind to a particular ion channel that you know is important to control some physiological process that goes abnormally--for example, a potassium channel in the nervous system that might affect the electrical activity of certain neurons. If you find a small molecule that can bind to that, through some screening assays and not direct use of the structure, you can then ask, "Does that molecule affect an abnormal condition?" to help it. Once you know that, the molecule might have the desired effect, but it might not be good for treating somebody because of undesired effects or maybe because the drug can't be swallowed, so you would like to come up with a version that people could take as pills.

What you might want to do is ask, "How is that drug working?" and ultimately, then, you could solve a crystal structure with the drug bound to it. And then you can understand which part of the molecule is important for binding and having this effect on the channel, and which part is not. And then chemists can look at this and decide, "OK, well, this part is important for binding, so we need to preserve that, but this part is not. So if we want to change the properties of the molecule, so maybe someday a pill could be made out of this, this is the part we can work on, and this is the part we cannot." So that's the way this structural information I think will end up feeding in.

Part III

SA: You were awarded the Lasker Award in 1999, just one year after you had solved the structure of the channel. Your colleague here at Rockefeller, G¿nther Blobel, received the Lasker Award in 1993, for work he did much earlier, in the '70s and '80s. Why do you think the jury members saw the significance of your work so easily? Why was it so obvious?

RM: I don't know [laughs], but I am very pleased that they did, to be perfectly honest. I feel very lucky that they did, and I can't really say why they did. I do know that in looking at the potassium channel structure, we could tell by some of the features that I've talked about (and, in fact, some that I haven't talked about) an enormous amount about the potassium channel.

One of the reasons the structure was so immediately interpretable was because ever since Hodgkin and Huxley published their work in 1952 on the theory of the nerve impulse, people have worked on ion channels and potassium channels, and they figured out a lot about the function of it. So there was a lot of imagination and a lot of nice thinking about what they ought to look like and how they might work. And then to finally see it was extremely satisfying. In some aspects, it was satisfying because many things were predicted, and in other ways it was satisfying because some things that were not predicted were almost more beautiful than anybody would have predicted. For example, the cavity and these helices were just a marvelous arrangement that Mother Nature used to solve this problem, you know, as if a very brilliant engineer did it all. I think that was very satisfying to see. Certainly it was to me, and I am happy that it seems other people appreciated it, but that's as much as I can say.

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