For elucidating the functional and structural architecture of ion channel proteins, which govern the electrical potential of membranes throughout nature, thereby generating nerve impulses, and controlling muscle contraction, cardiac rhythm, and hormone secretion.
Biologically speaking, human beings are frequently described in a number of ways. We are flesh and bone. We are comprised of essential life-giving organs neatly arranged beneath a sheath of skin—itself an organ of astounding complexity. We are made up of cells, genes, DNA.
It is less common to think of humans as electrical beings, but the description is equally apt. Like any good machine, humans are controlled by electricity—bodies made up of a vast network of interactive electrical components that surely surpass in intricacy those of any supercomputer.
This year’s winners of the Albert Lasker Award in Basic Medical Research bring to their work a unique appreciation of biology and a keen understanding of electricity.
Clay Armstrong is honored for his work in “cell membrane excitability” and the elucidation of “ion channel gating kinetics.” Armstrong himself puts it more simply: “My research involves electricity. Electrical signals are used throughout the nervous system and activate muscle cells. Essentially, we studied the electrical system that underlies all thinking and movement.”
As a medical student at Washington University in the late 1950s, Armstrong was captivated by lectures on the physiology of nerve impulses and by the work of A.L. Hodgkin and A.F. Huxley, who did pioneering studies of the squid, an elegant model for analysis of the passage of nerve impulses through cell membranes. Hodgkin and Huxley showed that the action of nerve cells is dependent on electrical conductance changes in the cell membrane. But the physical structures underlying these changes remained mysterious.
That is where Armstrong took the field to its next level, extending the Hodgkin-Huxley hypothesis as he himself adopted the squid as his experimental model for biophysical studies of the electrical system. Throughout, he always kept in mind the potential application to medicine of lessons learned from squid. “If all nervous system cells operate electrically, then determining the electrical mechanism has to be important,” he thought. Ion channels were the first step.
In order to understand the significance of the work of Armstrong and his co-winners, Hille and MacKinnon, it is important to understand ion channels as the basic component of the body’s electrical system. It is a concept that many people find difficult to grasp. Again, Armstrong makes it simple. “Ion channels are little holes in the membrane of all cells. The channels open and close to either permit or block certain ions from crossing the membrane. Sodium, potassium, calcium, and chloride channels are among the most important molecules in the electrical signaling system.”
Joseph Goldstein, Clay Armstrong, Roderick MacKinnon, Bertil Hille
Award presentation by Denis Baylor
It’s a pleasure to introduce the winners of this year’s Albert Lasker Basic Medical Research Award: Clay Armstrong, Bertil Hille, and Roderick MacKinnon. Clay, Bertil and Rod have made outstanding discoveries about some of the most important molecules in living cells: ion channels. Ion channels are specialized protein molecules in cell membranes. They generate electrical signals in nerve cells and muscle fibers, produce the cardiac rhythm, and instruct glands to secrete. An individual channel molecule is an on/off switch that controls the flow of ions across the membrane. When switched on, it allows a specific type of ion—Na, K, or Cl—to cross the membrane. These ion movements produce small electrical currents that change the membrane voltage and transmit information from one place to another.
An ion channel is a remarkable molecular machine. Typically it sorts ions one at a time, yet allows the preferred species to pass through at a rate of a million per second, far higher than the speed at which the best enzymes can process their substrates. One of several types of signal can activate channels. Some switched on by the membrane voltage itself have a voltage sensitivity tenfold higher than that of the logic gates in a spanking new computer. Wonderful as they are, channels do not always work properly, and malfunctions produce an expanding list of diseases that includes epilepsy, cardiac arrythmias, and cystic fibrosis.
Before Clay, Bertil and Rod’s work, physiologists knew that ion channels are important, but what channels actually are and how they work were only understood at the level of the formalisms that Hodgkin and Huxley had enunciated two decades earlier. Hodgkin and Huxley’s work, which earned the Nobel Prize in 1963, had revealed that separate pathways allow ions of different types to cross the membrane, and that, for certain neuronal channels, the voltage across the membrane determines whether ions are allowed to pass or not. It was not clear how ions pass through channels, how channels achieve their remarkable selectivity for ions, nor how the voltage across the membrane instructs the channel to allow ion flow or to block it. The complete molecular structure of a channel? Forget it! This of course was before our awardees came on the scene.
Interview with Clay Armstrong and Denis Baylor
Denis Baylor, Professor, Department of Neurobiology, Stanford University, interviews Clay Armstrong, who shares the 1999 Albert Lasker Basic Medical Research Award with Bertil Hille and Roderick MacKinnon, November 1999. Dr. Armstrong is a professor of physiology at the University of Pennsylvania in Philadelphia.
Part 1: Ion Channels in Medicine and Biology
“I think that ion channels are the most important single class of proteins that exist in the human body or any body for that matter,” Dr. Armstrong tells a hypothetical skeptic from medical school.
Baylor: So, Clay, it’s really good to talk to you today.
Armstrong: Well, thank you, Denis, it’s mutual.
Baylor: Well, I have a tentative plan for this interview, so I’ll tell you in an outline what the tentative plan is. We can follow it more or less closely, depending on how it evolves. I wanted to ask you a little bit about how you see the place of ion channels in biology and medicine and then ask you a little bit about your family background and your family today. Then talk a little bit about your education and training in science—mainly the places and the people. And then really get into the meat of the science after that and talk about how you came to your wonderful insights into channel structure and function. And then talk a bit about what you’re up to currently. And then the future. And then what you see the future of ion channel work being and what advice you might have for young people that are considering a career in science. Would that be reasonable?
Armstrong: Okay. Yes. That sounds fine.
Baylor: That’s some outline of what we might do.
Baylor: So, about the place of ion channels in biology and medicine. Suppose that a skeptical medical student came up to you and said, “Okay Dr. Armstrong I have too much to do. Why should I care about ion channels?” What would you say? (Laughter.)
Armstrong: Well, I’m confronted with that situation quite frequently. I’ll be aggressive about it—I think that ion channels are the most important single class of proteins that exist in the human body or any body for that matter. And of course, the question is something like saying, “Which is the most important part of a car, the tires or the carburator?” You can’t do without either. But all of the higher functions, all of the communication between the parts of the body, depend very crucially on the function of ion channels, and every perception, for example, is encoded in electrical form through the function of ion channels. Of course in your wonderful work on the retina and on the visual receptors, that’s certainly the case that the ion channels are involved in the initial transduction of light into electrical impulses, which are then dealt with by the brain. The heartbeat is another example. It is an electrical timing system dependent on ion channels that produces a heartbeat. All of our thoughts, all of our motions involve the action of millions of ion channels—billions. Endocrine secretion. All of these are, of course, are in addition to the more basic functions of ion channels, which are involved in the very life of the cell—of every cell. No cell could exist without ion channels. So I regard it as extremely important and also medically important.
Baylor: Definitely. And it seems that these ion channels now have an increasing significance in medicine, because a lot of neurological diseases turn out to involve mutations in ion channels, don’t they?
Armstrong: Yes, yes indeed. Well, epilepsy, for example, is one clear case. Myasthenia gravis is another. Various of the paralyses and myotonias. And that’s leaving out, of course, the big one—which is not neurologically related—but the function of the heart, which is certainly one of the most important medical problems to be encountered.
Baylor: Definitely. And so the channels also, I guess, are going to be very important, increasingly important drug targets for medical therapies of one kind and another.
Armstrong: Yes, well that certainly seems clear, Tranquilizers, of course, are one of the more (important categories)—I think no one really knows. With some of the tranquilizers it’s clear what the function is, but looking through the Merck index there are, oh, thousands of compounds that have been discovered empirically that do not have clear functions. And I would suppose that very large numbers of those must modify the action of ion channels in one way or another. Potassium channels are becoming clear targets of therapeutic intervention in, for example, diabetes and also in problems of arrhythmias of the heart. And again, going through the list of things that we don’t understand. Thought, for example. Well, nobody knows in any precise detail how thought occurs, but that thought involves the use of ion channels seems very clear since all communication between cells and all communication within cells depends on ion channels. Well, it’s just beginning. The only reason that the medical student could possibly think that it is not important is that we don’t know enough yet.
Armstrong: And also I think that it is not a very popular subject. So generations of preceding medical students have told the hypothetical students that I’ve just encountered (in your question) that you don’t really need to know that because it—in a sense it’s perfectly reasonable—there’s not enough that you can do about it at present. But that’s definitely not the case in the heart or in the case of diabetes.
Baylor: And it really seems a certainty that down the road these ion channels will be essential—that medical students must know them cold in order to be good physicians.
Armstrong: Well yes, and to be medical scientists. The medical schools are supposed to be training medical scientists who will take things forward. So (for) all of those students who are hoping to shape the future of medicine, I think this is definitely a place where one should look. The problem generally speaking is that medical students, I think, have very good minds. They have retentive minds, but they tend to be somewhat less analytical than the students who go into physics and other pursuits like that. So they are not at present well trained in some of the things that one needs to know in order to get over the hurdle of understanding ion channels.
Baylor: I agree. Well, I think that’s a pretty convincing answer. If the student doesn’t believe you now, then maybe he shouldn’t be in medical school.
Armstrong: Well, I would get read off of the faculty here if I said that too loudly, but I think one has to convince (not coerce).
Bertil Hille interviewed by Eric Kandel
Eric Kandel, Senior Investigator, Howard Hughes Medical Institute, and Professor, Center for Neurobiology and Behavior, Columbia University, interviews Bertil Hille, who shares the 1999 Albert Lasker Basic Medical Research Award with Clay Armstrong and Roderick MacKinnon. Dr. Hille is a professor of physiology and biophysics at the University of Washington in Seattle.
Part 1: Growing Up At Yale
Dr. Hille recounts this early years at Yale as the son of faculty member in the mathematics department. At 16, a colleague of his father’s puts him to work in a science lab.
Kandel: I’ve outlined nine topics, and maybe I would just go through them with you and you can add and subtract, and then we can get into the actual discussion of these points. So I thought it would be good if you were to begin with a discussion of your life before the Rockefeller—a little bit about your upbringing, your family life, etc. Your father and mother, and your father’s influence on you; your undergraduate experience; and then of course Rockefeller, which was so important.
And that would lead into your first research project on excitable membranes, the sodium and potassium conductance pathway separation and would allow you to bring in the scene that you suggested we talk about, and that is online computing and development of your own instrumentation, which I gather you began at Rockefeller. And then on to the size and shape of the pore, that is, the different size organic and inorganic ion experiments. Then the selectivity filter, multi-ion occupancy, the modulated receptor hypothesis. Then maybe we would stop and speak a little bit about the interactions with Clay and Rod and then more recent work. And then perhaps end up with your thoughts about the influence on you and on the field of your earlier reviews and of the book. Does that sound reasonable?
Hille: Sounds terrific.
Kandel: Why don’t we begin.
Hille: I’m going to run out of voice before I get through all that.
Kandel: I doubt that. So tell me all about your youth.
Hille: My father was a mathematician at Yale and my mother, I would say, was an intellectual who was the wife of a faculty member. And in our household we always had scientists and mathematicians from Yale. Always people at the highest level. There were people like Lars Onsager, who invented irreversible thermodynamics. The Onsager family, his father and mother, were friends of my mother’s father and mother, and so that goes back generations. My father was a reader of his thesis. So there are many people who came through the house and were excellent scientists; the idea of science was just a given. My mother was also, although she wasn’t a scientist by training, she was also excellent in knowing causality and thinking about the laws of physics and making things follow from each other and being interested in all kinds of science.
Kandel: Are you an only child?
Hille: No, I have an older brother, who is now a linguist. He is a translator or terminology specialist at the UN. And he got his languages because my father was Swedish and my mother was Norwegian. They were both brought up in their home countries, and the first languages that we both heard were Norwegian and Swedish at home in the United States. Then we traveled to Europe many times, and we both went to school in France and in Germany and in Sweden, and in each case, we got another language and another culture. And that was a very European style of upbringing in a way. Instead of the other half of the world, it was just something we had lived in and knew how they thought in a way.
One of the new faculty members who came at the very same moment that my mother came, marrying my father, was Ed Boell who was a zoologist and embryologist at Yale. And he was a very good friend… they were very good friends of my family. And he said when Bertil gets to be 16, he can come into my laboratory. So when I was a kid at 16 in high school, I began something which maybe went on for six years, which was to work in Ed Boell’s laboratory at Yale. And that went on until I graduated with a bachelor’s degree in ’62. And so I sort of skipped adolescence and just went right to being a scientist in a laboratory, which for me was wonderful.
Kandel: So what sort of problems were you working on with Ed Boell?
Hille: He was interested in sort of development physiology. And so he wanted to see whether gills were important for the development of salamanders, whether they needed them. Whether they could survive at low oxygen tensions without gills. So I got these embryos and took off their enveloping membranes and put them in what is called a Warburg apparatus, which was a real ancient thing—a beautiful machine that measured how much oxygen they consumed. I also studied ion fluxes, which began me on the kinds of problems that I am still working on today. We had radioactive tracers and soaked the embryos, with and without gills and various things, in these different tracer ions. And I measured uptake and effluxes and then decided to make mathematical models describing saturation processes and all kinds of things, which I guess never came to anything, but it was good for a kid to learn how to do all that. It was very exciting and very formative for me.
Kandel: And how did you think of going to Rockefeller as a graduate? Excuse me one second before we get on that. So you presumably got your degree in biology at Yale?
Hille: Yes, so let’s go over Yale a little bit. At Yale, I took zoology as my bachelor’s degree. But I decided that I would do all the courses that were necessary for a degree called biophysics. And in the biophysics line their emphasis was things like thermodynamics, information theory, quantum mechanics, modern physics, relativity, those things. So I actually took rather nice courses in all of those subjects, which most zoologists wouldn’t do.
Roderick MacKinnon interviewed by Dr. Miller
Part 1: Early Education and Medical School
Dr. MacKinnon describes his upbringing in suburban Boston, his early interest in science and his earliest years in Dr. Miller’s lab at Brandeis. He also discusses his decision to go to medical school and its impact.
Miller: So why don’t you just tell a little bit about your personal background and sort of the trajectory by which you arrived at the place you are at now.
MacKinnon: An unlikely trajectory. I was born in Burlington, Massachusetts. I’m a Massachusetts boy. The middle of a family of seven children and grew up in Burlington, Massachusetts. Went to the public school there, and my parents moved to Cohasset when I was in high school, in ninth grade, (they) moved to the South Shore of Boston. So I’m a Boston suburbanite, all my life. And related to science, you know my parents are not scientists, and I, in fact, didn’t know any scientists when I was young, but I always loved science. They were my favorite courses in school. And I guess you could say that it became clear that something wasn’t quite right when in junior high I wanted to go to summer school because it was a science enrichment course, and I got to have a microscope there, and I could take the microscope home for the summer. I used to like to go around and look at pond water and blades of grass, and I was thoroughly amused by these things.
I think I was a very typical average little kid in most respects. But when I really did get turned on to science is when I went to college, to Brandeis University. And there I went from public schools in suburban Boston to Brandeis University, and that was a real eye opening experience for me. There were a lot of my peers there, my classmates, who were from different backgrounds and I just… It was a real good time. It was from 1974 to 1978. Brandeis was a wonderful place to be then. I had a lot of fun, and it was a real intellectual experience, and my exposure to classroom science was very good there. But in particular, Chris, as you well know, I came to your lab and worked on calcium pumping in the sarcoplasmic reticulum. I was the third member of your lab, you being the first, Gribet your dog the second, and I was the next. When you had just set it up. And it was a special time. I have a lot of emotions attached to that, actually, in the little lab.
Miller: We both do.
MacKinnon: It was a very bright lab, big windows. The sun would pour in, and it was just a happy place to be. It was a wonderful time. I ended up going to medical school.
Miller: Against my strong advice, if you remember.
MacKinnon: I remember very well. In fact, I think the real reason I went to medical school was not because I was ever pushed to do that, but I was naive enough to think that the practice of medicine was close to the carrying out of scientific experiments, and I learned that it’s quite different. You use a different part of your brain in solving problems in medicine than in solving problems in a more analytical kind of way. Here’s the puzzle, can you solve it? That’s what I loved about science and do love about science. But I think I went to medical school because that’s what everybody seemed to be doing, and I did think it was a lot like laboratory science. It took me a long time to figure out that it’s very different. It’s very special in its own way. I don’t have any regrets, but I know that when I came back to you eight years later and said, “You know I’ve been thinking about what you said, and that is that I should get a PhD” You know it’s a funny story, and it’s absolutely true. I came back eight years later and said, “You know, you were right.” And, fortunately, because then I could get a postdoc.
Miller: Yeah, you didn’t realize that. You thought you had to go back to graduate school. And I said, “You dummy, you don’t have to get a doctorate, you already have a doctorate.”
MacKinnon: I had completed medical school in four years and three years of residency with the plans to practice medicine. And although I felt like I was getting old at the time, close to 30 years old, I just thought about, “Gee, when I’m much older than this, I’ll look back and say, gee, that was actually young. So just go for it.” So I thought I should go to graduate school and get a PhD, and you advised me that I wouldn’t need to do that. So that’s when I came to do the postdoc at Brandeis with you, in the same lab, and started working on potassium channels.
Miller: I think your medical education actually gave you a tremendous kind of insight that allowed you to do some of this work in a way that was very different than if you had gone through the sort of way that I had suggested.
MacKinnon: Well, I think it did in the following way: One of the things that I did in medical school… Well what it did, it taught me to teach myself very well. A little background to that is that while I was going through medical training, I felt I had a need to exercise my mind in a certain way, and I applied mathematics. It became a hobby of mine, and I kept studying those things, and that was good for me. And then when I came to your lab, I had a real sense that I was way behind. And so I read and read and studied and, you know, I’m very diligent about these things. I have stacks of notebooks where I derived things, and I just wanted to make sure I understood things completely. In a way, what that did for me is it taught me to be very independent by just going to learn something. And I think if maybe had I gone to get a PhD, I would have… I don’t know what would have happened, but this way I certainly know I learned to fearlessly pick up books, go get books and learn a subject, and that certainly came in handy as time went on. That sort of approach.