Rod MacKinnon is a professor of molecular neurobiology and biophysics at the Rockefeller University in New York City and an investigator at the Howard Hughes Medical Institute. His big idea was to use X-ray crystallography to uncover the elusive structure of ion channels 鈥� proteins that perforate our nerve cell membranes and pump ions across the membrane, allowing electrical impulses to travel along the nerve. The potential impact of his work is enormous: if all goes well, expect a new generation of treatments for cardiac problems, nerve damage, epilepsy, and hormone secretion disorders.
So there you were in a lab at Rockefeller, out on your own with no one believing in your work. Didn鈥檛 you have a sinking feeling in your guts?
That鈥檚 it: Oh my God, what have I done? Because when I got here there was this beautiful lab and only me and one postdoc. Then my wife, who鈥檚 a chemist, saw my desperation and decided to work with me too. I was embarrassed. I just thought, 鈥淥h dear, what do I do?鈥� It became a joke. 鈥淭his is New York,鈥� my wife used to say. 鈥淭here are a lot of actors who are unemployed, maybe you could hire them to wear a lab coat and hold a pipette.鈥� The lab is 4000 square feet and there were three of us in it. I was truly embarrassed. I thought they were going to take it away.
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How did you cope with others having so little faith in what you were trying to do?
I think the way I was trained helped. Since I went to medical school and didn鈥檛 really have a formal science training, the only way I could learn was to teach myself. I would work hard on experiments during the day and I would spend hours studying at a very basic level, reading physics books and mathematics books. So I kind of got in the habit of teaching myself, and I still do that today. It makes a huge difference. I think I look at problems somewhat differently from the way other people do, and I think that鈥檚 because I鈥檓 always reading peripheral stuff that I feel is related to the subject.
Were you buoyed up by coming from a scientific family?
My father did a variety of jobs. He was a postal worker and didn鈥檛 go to college, but he became a self-taught computer programmer when I was young. My mother taught English in school part-time because she had a big family to raise. I鈥檓 the only scientist out of seven children. We all do very different things, ranging from art to teaching English, to business. I do have a brother who is an anaesthesiologist. My parents didn鈥檛 have the opportunity to get an advanced education, so they wanted to make sure that their kids had those opportunities, but they never put us under any pressure.
Just how non-standard has your career been? What was the trail that led you to that lonely lab in New York?
I never thought much about what I was going to do until I went to college. When I went to Brandeis University my eyes were opened to the idea of really using your mind to solve problems. And it鈥檚 then that I discovered that I really love science, because I鈥檓 good at it. The courses I took made me happier because they were smaller and their problems were better. I decided I wanted to become a biochemistry major, and as part of that I had the option of doing an honours thesis. I decided I wanted to do that and I met this young assistant professor who had just set up a lab. It was only Chris Miller, now professor of chemistry at Brandeis, and his dog in the lab at the time, and I joined as his undergraduate student. It was a wonderful time.
How influential has he been in the choices you鈥檝e made?
Very. It wasn鈥檛 as if he sat me down and said, you should do this or that, but there was a certain kind of environment there. I saw this guy who was just going into the lab and doing experiments and really having fun every day. There seemed to be no pressure. You do things that are fun and you get paid for it, and I thought, 鈥淭his is wonderful.鈥�
So what took you on to medicine?
I thought, quite naively, that medicine was like science. I thought it must be fun to be a physician, but I really didn鈥檛 know what that was like. Although I carried on through the training and I enjoyed it for what it offered, I kept looking back at my time in Chris鈥檚 lab and remembering the joyous feeling of what it was like to be doing experiments, and that drew me back. Also it was a slow realisation that practising medicine is a different kind of problem solving to the analytical kind you do in basic science.
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Well, I like the idea that you have a limited set of variables and that you can solve the problem. When you do that kind of problem solving you feel as though you are using a different part of the brain, and it鈥檚 a part of the brain that it really thrills me to use.
How difficult was it admitting you鈥檇 made a false step and then getting back into research?
Once you鈥檝e dedicated a number of years to something, it鈥檚 not easy to say, 鈥淭his is not what I want to do.鈥� It鈥檚 hard to bring yourself to do that. At that stage I was almost 30. Which is old to be starting science, because I had no formal training beyond my undergraduate training at Brandeis. Chris had told me when I was an undergrad that I was making a mistake going off and doing medicine. So when I came back eight years later I had to admit that he was right. I thought I鈥檇 have to get a PhD, but he pointed out that I was a doctor already so I didn鈥檛 need to.
You got your own lab in just three years. That鈥檚 pretty fast for someone with very little grounding in research science鈥�
Chris was a great mentor. But I came in with a sense that I had a lot of catching up to do, so I worked furiously and did a lot of experiments during the day and studying at night.
You鈥檇 built yourself a reputation because of your work on mutagenesis to produce variations of channels so you could work out the underlying structure. But then you dramatically changed direction again 鈥�
Yes, that mutagenesis technique worked beautifully for a few years and we learned a lot. But then we realised we were coming to the limit of what we could learn, and it was clear that we needed to know the chemistry. And to understand the chemistry of channels, we had to know the structure of these proteins. That was a big leap because there was a feeling that it was virtually impossible to work out the structures of membrane proteins. I started reading about different methods of working out structures and it became clear to me that X-ray crystallography was the technique. So I started studying it on my own. I took a graduate course at Harvard 鈥� a professor sitting in the back of the room and taking it very seriously. I decided that to learn crystallography for ion channels I should first crystallise a protein on my own and solve its structure.
But others didn鈥檛 share your view?
At first I worked alone on the structure of the soluble protein and then was joined by the one postdoc who was willing to move with me to Rockefeller. I literally had stacks of crystal trays in my office and borrowed an X-ray machine to study them. Also, I started thinking about moving from Harvard as a way of changing my whole environment, as a way to start anew, working on the problem of the structure of ion channels. Moving can make a big difference because you鈥檙e always tempted to stay with the thing that works. If you change everything, suddenly you really have no choice. I knew that I would focus completely on the problem. The other reason I moved is that realistically I needed to fund the work somehow.
Wasn鈥檛 Harvard interested?
Harvard is a great place, but nobody was about to give me the money to do this work. If I had written a grant proposal at the time, it wouldn鈥檛 have been funded and it shouldn鈥檛 have been funded, because I had no track record in X-ray crystallography. On top of that, I was proposing to work on something that people in general thought was impossible.
Did anyone think you were losing your mind?
There is no question: people in my lab didn鈥檛 want to go. When I came here to Rockefeller only one postdoc came with me, and he had just joined the lab so he didn鈥檛 have much choice. I never said to people, 鈥淵ou really should come,鈥� because inside I thought, 鈥淲ell, if they want to learn X-ray crystallography they should learn from somebody who is already good at it.鈥�
Weren鈥檛 you disappointed?
A couple of people initially said it sounded exciting. So I thought when I got here I would have a little group and we could all go at this together. When they dropped out one at a time, I guess, maybe that was the first reality strike.
So what made Rockefeller take a chance?
It was the foresight of Torsten Wiesel, who was then president of Rockefeller. In a casual conversation, I mentioned my plans to undertake ion channel structure. He responded by recruiting me.
Sceptics said that if the ion channel problem was solvable at all, it would take at least 10 years, but you鈥檝e done it in considerably less. How?
That time frame was just a guess 鈥� and it was my guess too, actually. I never had that doubt. I knew that it was some way doable. There was a lot of luck involved and we worked very hard. I just figured that somehow, some way, if you want strongly enough to get something done, you鈥檒l figure out how to do it.
So after all that effort, why is it important to know the structure of these proteins?
At an intellectual level we get to see a beautiful mechanism of nature solved. Ions don鈥檛 want to come out of the water and cross the cell membrane. It鈥檚 a very fundamental problem if you think about it, because in order to get the chemistry of life, you have to enclose the chemistry inside some sort of coat 鈥� a cell membrane 鈥� to hold everything in place. But as soon as you make such a coat, you have to have a specific mechanism to allow things like ions to cross.
What will your discovery do for people?
I want to emphasise that I view my work as foundation-level work, and it is several steps away from application. But I think that it is ultimately going to have important applications, because by having solved channel structures, people can identify compounds that affect channel function. People wonder if we could treat certain diseases or conditions, and there鈥檚 no question that we could, because ion channels underlie electrical activity in the nervous system and the heart, and in blood vessels. So by targeting channels there is the potential to help epileptics, people with hypertension, arrhythmia and problems with hormone secretion. There are many possibilities. But I want to say that I鈥檓 doing this because I feel, like most scientists, that it鈥檚 an exploration into nature.
You鈥檝e been tipped as a possible winner for a Nobel prize. How does that make you feel?
I don鈥檛 know, because I never won one before. It would be wonderful, but the joy of seeing these channels and understanding them can鈥檛 be topped by anything.
Your wife still works in your lab? How does that working relationship work out? Is it boss and employee?
It works very well. A lot of people say to me: 鈥淥h God, I could never work with my spouse,鈥� but it鈥檚 very good to be working with somebody who cares very much about what you do. Alice doesn鈥檛 have a PhD, she has an undergraduate degree in chemistry. We met in Brandeis as undergrads and she鈥檚 an organic synthetic chemist, but has become a very good protein chemist and so she works in the lab with me and with a postdoc on this, but she also manages my lab.
She seems to have been very supportive, but what did she say when you decided to jack in your medical career?
We had conversations about it that went: 鈥淲ait, you鈥檝e been studying medicine for seven years now, all your friends are getting jobs and you鈥檙e telling me you鈥檙e going to do a postdoc? How much are you going to earn? Even less than you鈥檝e been earning as a resident?鈥� Conversations like that. She had already worked to put me through medical school. I felt guilty about that. But then again, she didn鈥檛 complain, she just rolled her eyes and said OK.
That was very understanding!
She is very understanding, but I wasn鈥檛 irresponsible about it. I think she could see that I was truly passionate about it. It wasn鈥檛 just saying, 鈥淕ee, I don鈥檛 like this.鈥� I realised I loved science and it鈥檚 what I should be doing. I was almost 30 but I knew when I look back when I鈥檓 70, 30 will seem awfully young. So there is no reason not to do it. We actually went away on vacation together and talked about it, and she finally said: 鈥淵ou have to do this. What are you worried about? You have to do it.鈥� So she really is the most amazingly supportive person.