Interview, December 2018

“Huckleberry Finn is my role model”

Peter Agre was awarded the chemistry prize for discovering aquaporins, channels that allow water to travel between our body’s cells. In this interview he speaks about how he became interested in science, and shares his influences and inspirations – both fictitious and real.

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Nobel Prize Talks: Peter Agre

Released 2014-02-27

The battle against malaria is a long and arduous one. Peter Agre, 2003 Nobel Laureate in Chemistry, is part of the worldwide community committed to that fight. Speaking from a research institute in Zambia, he expands on the challenging state of global health, the promising shift towards an increasing number of women engaging in scientific research, and why scientists need to get involved in politics.

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Transcript of the interview

Welcome to the Nobel E-Museum and also to this interview, Professor Peter Agre and Roderick MacKinnon. I would like to congratulate you to the Nobel Prize. It’s a prize of the scientific community to the most prominent scientists in the community, I would say. And I would like you to tell us: What is it like to be a scientist? Professor MacKinnon?

… being a scientist is like being an explorer …

Roderick MacKinnon: I always say to my students that being a scientist is like being an explorer and I really mean that, because in a sense I think in science we explore the world, the universe around us. Some people look at big things and other people look at very small things, but in a sense we’re all trying to understand the world around us. In a sense we’re looking in little corners and places that nobody has ever looked before. And that’s a lot of fun. We go to work and we have problems that we’re interested in.

And when I say we, from my kind of work, I run a laboratory and that means there are people who have come to the laboratory to work with me because they’re interested in the same problems. It’s like a family, if you will, interested in problems. And we get excited about things and we figure out how to do experiments to test them.

What would you say?

Peter Agre: I agree. I think being a scientist is having fun. And I think it’s like having adventures. I think … sometimes people ask me what is it like, is it like being Einstein or something? I think it’s a lot more like being Huckleberry Finn. Adventures. You don’t know what the answers are. But if it’s intriguing and it’s worthwhile and it’s fun, then we do it.

So how do proceed, how do you make a discovery actually?

Roderick MacKinnon: I think different discoveries happen in different ways. A lot of them happen because, you know, most of them … It’s a good question because a lot of times, at the end of something when we’ve finally shown something, like there is a beautiful structure here that does a certain thing and people look at it and say Oh that’s very beautiful. Have you thought of this, and it led to this … but often times actually what happens is you have this idea and you start to pursue it. It’s in an area. And then you think you know how something works, so you do tests. And actually you find out what you thought was wrong.

For most of the time.

Roderick MacKinnon: For a lot of the time but then you pay close attention to what your experiment told you and you think about it and you said well there’s a hint here that it’s this way. So you start to pursue that way and you find out that that’s right or partly right and partly wrong and you find out in the experiments where it’s wrong. And it goes on like this. Like a random walk. But hopefully an intelligent random walk. In other words – when you make a step, you evaluate it, and say is this right or is this wrong. By wrong I mean was what I was thinking wrong and then you make a decision to test it in another way.

So it’s kind of a journey, like an explorer would do. And you end up in this exploration. In a sense I always say Let your experiment speak to you. What I mean by that is I, actually we, or at least I’m not smart enough actually to guess how nature is working, but by looking and doing the right experiments and paying close attention to the subtleties of it you start to catch on. The experiments teach you and you find your way. And so then you end up finding your way to something very interesting. And then you write a paper about it. And it’s a discovery but the pathway was a very circuitous pathway of errors and corrections.

Would you describe yourself as Huckleberry Finn too?

Roderick MacKinnon: Somewhat. I mean I know exactly what Peter means by that, because you try things and they go awry and it’s an adventure in a sense. But I guess the analogy more seems to me I feel as I’m let off on a new continent and describing what I see. And by saying that I don’t mean to say it in any grandiose way. It’s more that I mean to say that if anybody is put in a totally new place with all kinds of new things to see, you make discoveries, actually. You can’t help it. You get excited about it.

What would you say about this styles of doing science?

… the discoveries sometimes discover us …

Peter Agre: Well there are different styles and there are different types of discoveries. There is an incremental advance in an area. It’s been said that hypothesis has driven research is greatly overrated. I think Al Gilman said that. But you have to have a hypothesis in order to go to work. We don’t just randomly do things. Rod said a random walk with a purpose. But that’s where science stops engineering, because the engineer has a goal. He has to build the bridge at this location. He’s not out there to look for landscaping or for archaeological sites. He has a goal. And that must be achieved. But in science we purposely pursue goals. We have meaningful objectives we want to achieve. But the discoveries sometimes discover us.

The unforeseen like Rod says talk to your experiments or let your experiments talk to you because you can force things out and that’s usually predictable science. But the big breaks in sciences have always been the unpredictable events. And Alexander Fleming had a Petri dish that was uncovered and a mould happened to land on it and killed the bacteria. That was an unpredicted event. That was a big discovery.

What about aquaporins, your discovery?

Peter Agre: In our case I consider the aquaporins was what I consider a real discovery because we were doing I thought very knowledgeable and a logical approach to studying the human RH blood group antigen and red cells. I’m a blood specialist in my earlier career. And we found something that didn’t fit and it turned out to be unrelated and had some curious properties. And we were given enough free time – the demands at being an administrator at that point in my career was smaller – and we let the experiments talk to us. It was extremely abundant red cells. No one had ever seen it before. Wasn’t supposed to be there. And I like to tell people it’s like driving in a remote area of Northern Sweden and you come across a city of 200 thousand people that’s not on the map. It gets your attention. And so this was the discovery. Then we figured it out. But it was not part of my life plan. It’s probably much better than it would have been if I had a life plan.

When you solved the ion channels you had an idea of what picture you were looking for.

Roderick MacKinnon: That’s right. It was somewhat different than Peter’s in that his was a discovery of something that there were hints of but no one knew was there. It was a complete discovery actually. And in my case it was known that there were these ion channels. Scientists who came before me, more than 50 years ago Hodgkin and Huxley and describe the theory of the action potential and in that theory they said the membrane of a cell has ion permeability changes. And then scientists followed them and asked what are those. Scientists like Clay Armstrong and Bertil Hille. And through very careful and elegant experiments said that this conductants have to be through pores. And there have to be channels in the membrane. So we knew they were there. And in fact molecular biologists starting discovering them. The genes for them. And electro physiologists continued to do very nice experiments to look at what they do in terms of function so in a sense I came into the field at this time.

But what was still a dream was what do these look like and what is the chemistry and how do they work? And that was at that time considered to be a very hard problem and how do you go about doing it? And I was studying the function of channels for many years, the electrical activity. And then my curiosity was so peaked and I knew that I wouldn’t understand for example how a potassium channel works unless I could see its atomic structure. And my feeling was OK, I have to learn and use the techniques to determine the structure even if I know it’s a very difficult thing to do. There were small discoveries along the way but it was more … knowing that it’s there already but asking what is it? What does nature have there? What does it look like really? Then in a sense discovery comes in once you see it and you say Ah ha now I see why the selectivity filter selects for the potassium ion. So there are discoveries built into that process. But it was a long term goal of wanting to see this little piece of nature.

And then the New Year’s Eve came with the actual discovery.

Roderick MacKinnon: That story of the New Year’s Eve isn’t that I alone first saw the potassium channel on New Year’s Eve. I always tell people, actually I was working with my post doctoral colleagues in the lab and we were working together. And that was slow in coming.  So over months, even after we had crystals, we finally started to determine what’s called the phases and could see the structure. See the basic skeleton, but what we didn’t see is where the ions are or if they were sitting in there. That’s what happened at the New Year’s Eve.

Can you tell us the story?

Roderick MacKinnon: Everybody likes that story because it makes me look like a nut.

Peter Agre: He is a nut.

Roderick MacKinnon: The longer version of the story is a group from my lab made a trip to the Synchrotron,  the Cornell High Energy Synchrotron source. It was João Morais Cabral … and Declan Doyle and myself and I think Jiayun Chen. We went up and we were planning to do a specific experiment that would allow us to see the ions. And actually they had terrible problems with the synchrotron. It’s a technical detail with the line where the flux was very low and we couldn’t do our experiment. They said they couldn’t fix it. We had to go home. And I said if you can put a new silicon crystal in and you can get any flux for us, call me back.

One o’clock in the morning we went to go to sleep and the phone rang …

We drove all the way back to New York City and just before unloading the car I said to Declan, one of the post docs, If I get a call in the night do you want to go? And he said absolutely. One o’clock in the morning we went to go to sleep and the phone rang. The operator at Chess said if you want you can have your last 24 hours. We have it going, it’s not optimal. Called Declan. Let’s go. Declan myself and actually my wife Alice went up because she knew we’d be tired after 24 hours of collection and she’d drive us back. We collected the data. She drove us back. It was New Year’s Eve or the day before New Year’s Eve. Declan was leaving the next morning for London. Alice had to go to Boston to be with her family. And I stayed in New York and started processing data, because I couldn’t sleep. This was late at night. It was the data we had just collected.

That event was a case of we had collected the data, and I was processing it, and very tired in the night, and it came to a point to where I get to first look at it and I wasn’t excited yet at all because I didn’t think the experiment would work. You know in principle it should work but in principle lots of things should work. You know, it would be too good to be true to work but it did. And when it did I could see the ions and this flat graph. It’s a very simple way of plotting it. And this is where I became so shaky and I had difficulty using the keyboard to convert the file format to look at it in another way. But in looking at it, it was very beautiful because I knew experiments from almost 50 years before by Hodgkin and Canes where they did very simple experiments on potassium in squid axons and they determined by simple measurement but thought hard about it and said whatever this mechanism is that allows potassium’s to cross the membrane it has to involve something like two to three ions in a queue. That was 50 years ago.

I was sitting there in the lab by myself at two o’clock in the morning looking at three ions in a queue. And you know I was running around in the lab with hysteria and joy, you know, having seen this. And as the story goes I went home and finally asleep. But the first thing I thought of when I woke up in the morning was that I had had a beautiful dream and that it wasn’t true. But when I saw my clothes on the floor I realised that that had to be true. I pulled the clothes on and went back to the lab. I was living two minutes from the lab at that time. And it was still on the computer screen. Of course a lot of work from several of us led up to that. It wasn’t as if all by myself I’d solved the potassium channel structure one night. It’s not that way. It was one of the steps that allowed me to have that ah-ha in the middle of the night, but it was a very beautiful moment.

That’s a joy that scientists and very few others will ever have in their lives …

Peter Agre: But you know I think you said it was a very difficult problem. I’d say this was a problem others considered impossible. And frankly, you had the courage to do what others should have been trying. It was so difficult that they didn’t do what you said in your lecture. They didn’t just give it a try. Better to fail having tried than not to do it at all. And you know you’ve shown in the discovery whether it’s something that people had predicted and had made some suggestions what it would look like, you saw it for the first time. Like you know these crazy movies, I don’t know if you like them, but Indiana Jones. He knows it’s out there somewhere. It’s not like he’s just wandering through the jungle. There is an objective. It’s extremely difficult to get there. Everyone else has given up but you got there. It was the middle of the night and that makes it particularly dramatic. But you probably had the most intense joy in your heart. You’ve seen something that people have looked for for decades. Generations. The first time. That’s a joy that scientists and very few others will ever have in their lives.

Roderick MacKinnon: That’s right. You hear a lot of scientists say the same thing. It doesn’t have to be a big thing because the thing about being a scientist is even the little things are big things to us. I mean there are things that we might explain to you that you’d say why is that important. And you could say well maybe it’s not so important but actually it’s important in a small way. And we’ve wanted to know this and to see it and to realise that you’re getting it. You’re getting a little logic of nature for the first time. It’s such an exciting feeling.

In the context of science that’s why people don’t maybe understand what is the big problem with this.

Roderick MacKinnon: Because it’s a regular life in a way.

Peter Agre: I think the problem is that the people are confused with the details of science and confused that that’s everything. They fail to recognise that the principles of science are elegant and simple. So Rod’s structures, in fact solving these are enormous calculations. Detailed work over months and months. And I think the non-scientist may say that sounds pretty dreadful. But in the end when you see the beautiful structure, I’m not in Rod’s exact field, but when he showed those yesterday in the lecture and the model tilted, and you could see the four ions there lined up, it’s gorgeous. It’s the best thing as a scientist to imagine. And I think young people when they would see something like this for the first time, something very beautiful, they would show that kind of joy. And the principle in retrospect that Rod has established is very simple and could be clearly understood by anybody interested in biology or chemistry. It’s the details that get in the way. And I think that’s where maybe as scientists we tend to talk in details and people go yohh.

In science you end up worrying about details but actually when you love something the details are details …

Roderick MacKinnon: And the details are important but actually, and this is a message I’d say to young people wondering whether they would like to be scientists, you know the details are very important. In science you end up worrying about details but actually when you love something the details are details. You work through them. They’re not what dominate your day to day life. You might spend your day to day life with these details. But it’s not as if as a scientist we are going to say how am I going to deal with this list of details today. It’s not like that. It’s more the thought that what you’re after. Then if you really want to do something you get there and you figure out the details. And in fact I think Peter and I are pretty good examples of probably when we were back in medical school we never would have imagined we’d be receiving a Nobel Prize in Chemistry, wouldn’t you say?

Peter Agre: I would say the chances are less than zero.

Roderick MacKinnon: But I know for me and I have a feeling for Peter it’s a matter of following your nose and following what you love. It wasn’t a matter of saying I like to pursue these certain details. It’s actually more of the fun of it that led us to what we do.

Would you agree with that?

Peter Agre: Yes. Yesterday at the press conference we were asked to talk about the greatest moment in science and I decided that what probably for me was the greatest moment is the point where I went from thinking I should be a scientist, and should know about all these facts, to be a medical doctor to thinking I really like this group. They’re doing exciting things and they’re making it possible for me to do things I could never have done. And having that realisation was terrific. It’s a complex thing. I think in part if people have the courage to follow their hearts they’re going in the right place. That will take you to where you want to be. Science is about as exciting as anything I can imagine.

What would you say about the relation between science and society?

Peter Agre: I think science owes a lot to society but society owes a lot to science. To be a scientist we’re doing research activities in laboratories that are very expensive. To have staff, time in the synchrotron, laboratory space in New York City you know we’re talking about enormous amounts of money but society chooses to do that. The poor countries in the world have no choice. They cannot pursue discovery level science in poor countries. And the people from those poor countries who are creative and inquisitive end up leaving and coming to place like Sweden, Western Europe, the United States. We happen to be lucky in that we were born in the US where all these things were made available by society. The taxpayers’ dollars. But in return we need to be thinking of things that are not only fun for us to do. That’s where Huckleberry Finn ends. Things that are actually good for people. You don’t always know immediately what will be good or how good it will be.

Two of my professors when I was a medical student, Dan Nathans at Hammersmith won the Nobel Prize 25 years ago this week for the discovery of the restriction enzymes. The enzymes that cut DNA which permitted this whole revolution in biology to occur. But when they first discovered it was a bacterial protein that cut up some viral DNA samples. It seemed very basic. They used it practically and in a limited manner. And they knew they would be important. But they weren’t running off saying this will lead to breakthroughs in cancer, and gene therapy which of course they have. So I think we need to provide things to society that are worth wile. But I don’t think we should worry minute by minute how will the structure of the potassium channel lead to an improved society or will the water channel proteins be immediately useful. There are many discoveries that are very important for which we still haven’t been able to use it too well. I think an example that I share with the medical students is the discovery of sickle cell haemoglobin by Linus Pauling in 1949. Fundamental advance. We could understand what causes this horrible disease but we still can’t treat it well.

Do you think that scientists should be kept responsible for the applications of their results? For example what kind of medicines.

We’ve discovered something that most people didn’t believe …

Peter Agre: Responsible in the sense that they have a mission that they need to convey. And I suspect one of the reasons that Rod and I are here in Stockholm this week is not to pat ourselves on the back for being good scientists and making important things but to share the love of science and to encourage young scientists. Frankly in terms of my work in the water channel proteins, the aquaporins, I think what we’ve done is the easy work. We’ve discovered something that most people didn’t believe. We know they’re important, but how can we use that? How can we apply that to improve the lives of people? To improve the agricultural output for countries where people are living in hunger. I can’t take full responsibility for that. I do take responsibility for sharing the level of this and exciting the young people and challenging them to step up. They’re the ones who are going to do the next level of research. They’re the future of science.

Roderick MacKinnon: I agree and I would say that scientists have to act responsibly in the way they do science. In other words not be doing experiments that are of immediate obvious danger to themselves or people around them. But at the same time I wouldn’t say that scientists before doing experiments should try to think ahead of all the possible applications to decide whether or not they should do that experiment. I think the reason for that is that none of us are smart enough to think that far ahead. We can all think of examples of things, discoveries that have been used for very good purposes and for very bad purposes. I think scientists shouldn’t be making this decision before they do experiments. We should be curious and trying to discover the world around us and responsible in the way that it would be very special if we can point some of our work in some way to application. Wouldn’t that be wonderful? After all it would be fantastic to be able to help people.

Peter Agre: I think often times others will see the usefulness of the discoveries we’ve made and designing inhibitors of ion channels. It’s probably not something that will come from your lab.

Roderick MacKinnon: Probably not.

Peter Agre: But they’re going to be following the information that you’ve discovered and the coordinates that you’ve established and in that way I guess we do contribute to the next step. We have to report accurately what’s there. I think at this point a lot of what we should be doing is exciting others that this is important.

Roderick MacKinnon: I couldn’t agree more.

If you could dream about the application of aquaporins for example, what would this be?

Peter Agre: There are a lot of things I would dream for. If I had to pick one I would hope that the aquaporins present in the malaria organisation would be useful drug targets because this is a horrible disease, malaria. Three million children die every year in Africa of malaria. And the current drugs are no longer so useful. Not that they’re expensive but the organism is becoming resistant. We need new ideas. That’s one thing that I could dream of I would dream for that.

Do you have any such dreams?

Roderick MacKinnon: Again it would be a case of others applying the work. That we reach a level where we can alter the function of channels and I’m sure structure should help in being able to modify compounds to do that in ways that will help conditions that afflict people.

I know that you’re engaged in social and political activities outside science. Can you tell us what you’re going to do with part of your Nobel Prize money?

Peter Agre: They asked me that the morning of the announcements and I have been involved in some human rights activities. This is not a major issue in terms that I’ve quit my day job, but I have been very concerned. There is a community in the National Academy of Sciences of Human Rights which I’ve participated in. Torsten Wiesel, originally here from Sweden is the Chair of that. In particular I have been very active in the case of Thomas C. Butler, an American scientist who’s facing life in prison from having lost some samples from his laboratory and consequences of that which I feel our government has unfairly presented and manipulated. Butler by the way has strong Swedish roots. His wife Elizabeth is a Stockholm university graduate. He himself was a sabbatical worker at Karolinska and I knew him as a student. He’s a very fine person. It’s impossible not to become active in that. We’re supporting his legal defence fund as much as we can and we hope others will as well.

Let’s hope for that. You point out that the pleasure and point of doing science is to do it together with other people. Tell us about your route.

… the first best part of being a scientist is you’re going to work in exploring and doing things that are just fun …

Roderick MacKinnon: People often ask what’s fun about being a scientists and I always say that the first best part of being a scientist is you’re going to work in exploring and doing things that are just fun. You love to do. And you’re finding out about nature. The second is that people come from all over the world because they have the same interest. From all over the world they come to work with you on the same thing and because they’re interested in it. And how many people can actually say that about their profession. My lab is completely international. And people have come from all over just because they’re so excited and it makes a great atmosphere. It’s energetic. It’s exciting. In the lab working people help each other and when people get tired and we all sense we need it we go out and have parties. My laboratory is really like my family.

What about your group?

Peter Agre: I’ve been fortunate to work with an outstanding group of scientists and this is one of the things that got me interested in science very early and that’s the passion of other scientists for their work. And the international aspects. When I was a medical student part of the reason I left medicine and went into science is because I worked with this wonderful group of other scientists who came from all over the world to work in the laboratory at Johns Hopkins. They included a conservative Jew from Brooklyn. A Palestinian refugee from a camp in Lebanon. A Spanish revolutionary. An Italian actor who wanted to solve the molecular basis of femininity. They’ve come to Stockholm and we’ve remained lifelong friends. I think seeing their passion is very important. And I think having teams of our own. We’re now senior scientists. We think of ourselves as always being young but we’re like captains of these wonderful teams of scientists who have great times together.

It sounds wonderful. How do you keep such a heterogenic group together?

Peter Agre: Well that’s the interesting thing it just happens. The best people you’re not trying to track them down and drag them to the labs, they actually want to come and work in the laboratories. They apply. They ask is it possible I can work in your laboratory. I can’t imagine more flattery than that.

Roderick MacKinnon: It’s true. I have somewhat of a system where when somebody applies if things look right and they seem enthusiastic in their application I then invite them to the lab for a day. I talk to them. Just talk about science. And then they give a little talk to the lab. Then they go around and talk to everybody in the lab who tells them all about their projects so they can learn about the lab and then we go out to dinner as a big group and we all have a big dinner at some restaurant in New York. Then they stay over. Then we say goodbye and they leave the next day. We get together and say what do you think?

A new family member?

Roderick MacKinnon: No, because that’s before the decision has been made. Part of it is the person excited about science, but also will they be a kind individual in the lab.

Science is very much a social endeavour …

Peter Agre: I think the latter part is incredibly important. And often not understood by non scientists. Will this be a part of our team, a part of our family, because we’re going to be together for years working hard but having fun as well. And if you get the wrong person in that’s too aggressive or very forceful it doesn’t work. Science is very much a social endeavour. I think the teams of scientists, no scientist does anything alone at this level, have to work together like a family.

Roderick MacKinnon: And it’s a very intense relationship. A good but intense because you’re all together working and thinking and you say but you’ve got to run your job better than that. We got to do this experiment. Why wasn’t that controlled there? To each other and me to them and them to me. It’s a very intense relationship like brothers and sisters actually.

What about the competition within this group?

Roderick MacKinnon: You have to make sure people are not working on the same thing. At least if things are related they know what their boundaries and what is theirs because people will do the best work if they feel they’re doing this as part of them. They want to make it beautiful. So you have to make that clear that people know what is coming from their mind and from their efforts.

Peter Agre: I think competition within the group is a big problem in some labs. Avoiding that is essential. I think when the young people enjoy each other they help each other a lot. Just like brothers and sisters will help each other. The parents are there. They set out the guidelines. But I learned a lot of things from my brother growing up but my father and my mother really weren’t concerned about. Couldn’t advise me. The teams are like that. If there is a sibling rivalry that can be disruptive. I don’t think you see that in the better labs.

Roderick MacKinnon: But if you keep objectives, even if they’re related, if you keep the main objectives separate in what people want to pursue. If two people come in and say they want to work on the exact same thing you say no. If somebody came to me and said I want to work on this but somebody is working on it I would say that’s a very good idea but you know somebody in my lab is working on that. And you can talk to them about it. And anybody who wouldn’t understand that you wouldn’t want to be working with anyway. And so what happens in terms of when somebody’s project really starts to work. It’s taking off. For example they finally get to diffract the crystals and getting a structure everyone else in the lab gets so excited. It revs them up. They’re excited for that person and they’re also more energised about their own project. It just happens.

Thank you very much for this interview.

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