Clay Armstrong

When Clay Armstrong was in medical school at Washington University in the late ’50s, he quickly grew bored. He failed to see “nice reasoning chains, that one thing was connected to the other.” His search for elegant scientific models eventually led him to research in electrophysiology and an intense interest in the work of 1963 Nobelists A.L. Hodgkin and A.F. Huxley.

Hodgkin and Huxley did groundbreaking work on squid to analyze the passage of electrical nerve impulses through cell membranes. Armstrong, a professor of physiology at the School of Medicine since 1975, built on the work of his forerunners to study ion channels, pores on the surface of cells that can either admit or block electrically charged particles. Ion channels play a basic role in muscle contraction, cardiac rhythm, hormone secretion, and many other vital bodily functions.

The Penn physiologist’s work shows what happens when you know how to channel your energy.

Photo by Candace diCarlo

It is now believed that all cells have ion channels to send signals, but at the time of Armstrong’s initial research, even the existence of these channels was a matter of some controversy. Armstrong’s theories, however, have recently been borne out by recent discoveries in molecular biology and X-ray crystallography by a colleague, Rockefeller University’s Roderick MacKinnon, M.D.

For his research, Armstrong, 65, along with the University of Washington’s Bertil Hille, Ph.D., and MacKinnon, received this month the Albert Lasker Award for Basic Medical Research, often thought to be a “Nobel predictor” (since 1962, more than half of those who won the Lasker Award went on to win the Nobel Prize). Though over the years his interest in many things has dimmed, Armstrong said, “Research is the one thing that has tested me.”

Q. Did you always know you would go into research?
A. After about the first year in medical school, I kind of lost interest in medical school. I got interested in electrophysiology. At that time I started by recording a particular type of brain wave, and I found that quite fascinating. Medicine, on the other hand, at that time particularly, was fragmented and empirical.

Q. How did you come upon the work of Hodgkin and Huxley?
A. I was fortunate in that a physiology course that I took was with a person who knew this work very well. He presented it to us and got mercilessly heckled by other members of the department from the back row while he was presenting it.

Q. Because the theory was controversial?
A. Well, it was very complicated. Hodgkin and Huxley’s work was very difficult to understand, so there was a lot of resistance to it. People who had established themselves in very important careers suddenly found that the thing that everybody was talking about they couldn’t understand. [laughs] So there are two ways: You can go and study it or get resentful and most people just got resentful.

Q. But it fascinated you?
A. Yes. And I couldn’t understand it either. But I was just starting [my career], so I had a lot of opportunity to work on it.

Q. Would you explain your work on ion channels?
A. For example, how does a potassium channel tell the difference between a sodium ion and potassium? That was one of the questions. There are two different types of salts, and the ability of the membrane to distinguish between them is essential to life. And it is the basis for all electrical signaling, which makes us what we are. Every sensation that you have, whether it be touch, vision, hearing, olfaction, taste, that involves some molecule that acts on a cell so that it changes the voltage of that cell.
   That’s the common currency for getting signals started in the nervous system. So every perception involves changes of voltage, which then reverberate around the nervous system.

Q. So your work helps us understand how the ion channels work?
A. It was not clear at the time that Bert Hille, a [Lasker Award] cowinner, and I were beginning our careers how ions penetrated a cell’s membrane. If the ions came in kind of a ferry boat -- rode it to the other side of the membrane and then let go -- that is one of the conceivable mechanisms. That’s called a carrier mechanism. Or whether the ions simply go through a hole. And the disadvantage of the hole idea is that it was hard to figure out how the hole was selective. Whereas the conductor for the ferryboat could look at the ion’s ticket and say, No, sorry. So that was controversial.
   So we provided evidence that there were many things you could explain if the mechanism were by means of a pore through the membrane.

Q. What medical uses does your research have?
A. Blocking ion channels is the mechanism by which, for example, local-anesthetic molecules and some of the cardioactive drugs work. It’s a big pharmaceutical pursuit to find specific blockers for ion channels. Potassium channels of many types are found in every cell in the body, so, for example, the potassium channels are very intimately involved in the process of controlling the secretion of insulin. In attempts to control diabetes the common drugs that are used -- not insulin itself -- but the ones that treat the milder forms of diabetes act on potassium channels and thereby control the secretion of insulin.

Q. So ion channels affect basically everything in your body?
A. Oh, you just can’t imagine. You can’t think, you can’t talk, you can’t have a heartbeat. There aren’t medical applications devised yet for many of these things, but we are what we are because of ion channels and electrical communication between cells. So my work has been in an early stage of this, just barely opening the door but helping to provide the understanding of how the signals are generated. But the medical uses will be just legion. There is a standard compendium, the “Merck Index,” which carries all of the drugs which are used commonly. I’ll bet you that a third of the drugs in that book, whose actions are not yet fully understood, act on membranes and ion channels: Valium, tranquilizers, antidepressants, many substances.

Q.And what is the nature of your current research?
A.I continue to work on ion channels. The field has been very heavily influenced by the genetic revolution, the possibility of cloning. So we’re pursuing experiments of that type. And mainly at Woods Hole, Mass., Marine Biological Laboratory, where I work on squid, I’m pursuing experiments of the retrogressive, older type, where there are still lessons.

Q. What does the Lasker Award mean to you?
A. [laughs] Well, it’s extremely nice to have the sense that this work which often seemed obscure even to me seems to have been of some use to the community. It’s a great feeling. It’s what I have certainly enjoyed doing and worked very hard at doing for a long period of time. Often research is a lonely business. You’re out there, working away, wondering if it will ever come to anything and many times it doesn’t. So to, more at less at the end of the road, to have it recognized as useful is terrific.

Q. What about the idea that the Lasker is a Nobel predictor? How does that make you feel?
A. Apprehensive. [laughs] I don’t know. I haven’t thought about that. I’m perfectly happy.

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Originally published on October 14, 1999