Peter Agre - Winner of the Nobel Prize in Chemistry 2003 and »just another person.«

Foto: Lizette Kabré

Interview Peter Agre, 21. september 2004.
Professor Agre visited
The Danish Biological Society and University of Copenhagen, Denmark and kindly gave this interview in the lobby of Hotel Admiral. Peter Agre is professor at Johns Hopkins University School of Medicine, Baltimore, USA.

- I prepared some questions that I think are of rather general interest.

Anything you like is fine

- Ok, so I will begin by asking you how was it to win the Nobel-prize and what happened how did you find out?

Well, it was sort of a surprise. I mean there have been a number of invitations to give lectures in Sweden over the last several years. In fact nine times I was invited. So in fact I had a secret hope that the nobel committee was interested but there was never any guarantee.
The biggest surprise was not when the medical committee did not call because they picked outstanding scientists who developed the MRI, I figured I am kind of young and these things take a lot of time and its only been 10 years so. Two days later the chemistry committee called me, and I am not a chemist. My father is chemist but he is deceased so I was wondering if maybe they called the wrong guy, they should have consulted a VG-board and asked him. ha-ha.
So it was delightful and a lot of recognition and excitement, and a lot of celebration in Stockholm which was magnificent.

- but do you remember where you were when you got the call?

Oh, the time of the announcement of course. They always call in the morning Stockholm time before they have their press conference its five thirty in the morning. I was asleep in bed.
And when the phone rings early in the morning in the nobel week every scientist wakes up and answers.
And the voice is at the other end. A somewhat serious voice, a ladies voice, 'This is a telephone call from Stockholm for professor Peter Agre, are you professor Agre.'
And I said 'Yes'.
She said 'Just a moment please, and then the nobel committee came on to congratulate me that I would be receiving the 2003 chemistry prize and I thanked them and asked if I would be sharing this with someone or who I would be sharing it with I assumed I would be sharing it. And they said Dr. Roderick MacKinnon at Rockefeller University, who is a terrific scientist. To share the prize with Rod was a huge honor in itself.
So it was early in the morning, so my wife and I hugged each other and cheered and woke up our daughter who was sleeping and wondered what all the noise was about.
And at the end of the telephone call that in 15 minutes they would have a press conference in Stockholm and that I should get ready for my day because it would become very busy soon.
So I sprinted to my shower and was almost dry putting on my clothes and the phone was ringing and a few minutes later reporters were knocking on the door and life as a private citizen was over.

- I think I will ask you a little later how it has changed your life, but maybe you could tell me about the discovery you made, how did you make it?

So the prize was awarded for the discovery of the water channels, these are proteins in the membranes of cells that allow water to enter or leave the cell. This is important in explaining a lot of fundamental biological event such as secretion of spinal fluid in our brains, tears by our eyes, sweat, to concentrate urine, and in other species the ability of roots of plants to take water from the ground. This was a long standing problem of physiology which no one had the answer, it was thought by some that channel proteins might exist, but it was mostly met with skepticism.
We discovered these proteins by sheer accident.
I am a blood specialist, a hematologist, and our laboratory was studying the Rh blood group antigens, this is the antigens that are very important in maternal fetal blood incompatibility Rh. And we developed a biochemical method for purifying the Rh and a second protein contaminated our preparations. The second protein had some curious properties that we kind of gradually explored.
So the first discovery of this new protein was in 1985, but it was not a high priority, it turned out to be a contaminant. Over the next couple of years we did some experiments and we discovered it was extremely abundant in red blood cells but also present in kidney cells. And we were just intrigued for no other reason than scientist are curious.

- but you still looked at it as a contaminant?

It was a sideshow, not our main event. But we found it to be abundant in kidneys and decided we would clone the DNA, the gene that encoded it. We wanted its primary sequence to know what this really was, because nothing like this had been reported.
Then we discovered that there were some similar proteins that had been reported, but no one knew the functions. These were in diverse species, so they are like cousins of our protein - from the eyes of beef cattle, another from the brains of insects, a protein that allowed bacteria to use glycerol as a carbon source and some fragments of genes from plants, but no one knew what they did.
But this idea - the roots of plants, kidneys, red cells - these are tissues that are water-permeable, so the idea that this might be fundamental water transport molecule was suggested to me really by a dear colleague - a friend - who had more expertise in physiology - so we tested this hypothesis by expressing the protein in Xenopus oocytes - these are the eggs of frogs. And the eggs of frogs are normally impermeable to water - they can be laid in fresh ponds and nothing happens. We inject the RNA for the protein gets made, now the frog egg is water-permeable. So if you take from a saline buffer into fresh water it has an osmotic shock.
This process we all learned about in middle school - osmosis - you have a biological membrane separating to chambers. Osmosis goes very fast when these water channels are present so when these oocytes expressed the water channel protein they would swell and explode, fast, very violent.
So our first experiment.

- so was that human DNA?

Yes human DNA injected, well it was actually not DNA but RNA. But that caused them to make this protein and swell and explode.
So what this proteins function is I like to refer to as the molecular equivalent of a water plumbing system - simple. The details are complicated but the function is simple. It is an elegant simple method for water to move into and out of cells.

- Was this experiment with the xenopus eggs the defining moment?

That was the defining moment, that was october 8th 1991. We knew we had it, but we didn't know how important it was. That unfolded over the following months and the next few years.
MANY groups got interested in it once we discovered it. Our work in the past had been kind of a quiet back-street in science with a small number of groups working, suddenly a lot of physiologists all wanted to work with it.

- so there was a huge competition?

Yes. The good is it was exciting it was an important discovery the is the competition were so strong and we were a small group. We felt we would be ignored or our contribution would be overlooked, but worked really hard and by collaborating with a number of outstanding scientist, including scientist here in Denmark. Particularly Søren Nielsen and his group in Århus our earliest collaborators we were able to define exactly where the protein was in the body, which gives us greater insight to what it does.
We also then identified many related human genes. There are 12 that have been worked out and had good ideas of what physiological processes that these were involved in. In collaborating with scientists from Switzerland and subsequently from Japan we were able to determine the atomic structure of it. We were able to find human mutations in these proteins and define what it was they were missing what problems they were suffering from.

- is there an example you can give me?

Well, so there are 12 human genes encoding members of this family. The one we studied, aquaporin 1, which is present in a number of tissues, functions in kidneys to allow the kidney to maximally concentrate urine.
So if we go to the bar and drink 2 liters of beer, we release large volumes of dilute urine. We clear the water. And if go out and exercise in hot weather we concentrate our urine so we have very highly concentrated urine with a small volume, so the kidney can regulate this and aquaporin 1 is involved in the regulation of that.
Then another member of this family, aquaporin2 is involved in an important fine tuning of this, so in each of those settings the patient suffers from mild or severe forms of kidney failure - they cant concentrate the urine.
Another member of the family, aquaporin 4, is present in the brain where it appears to be essential for the appearance and then the disappearance of brain edema, brain swelling if you fall and have a head injury.
There is an aquaporin thats present in sweat-glands, targeted disruption of this gene leads to mice that cant sweat. If they are thermally stressed it is problem. A lot of these things the individual can survive, but he is not quite as good as before. So these are not genes that are usually life or death. But the genes when they are expressed do what we need to exercise maximally, concentrate urine maximally, to keep the surfaces of our eyes and mouths clean from bacteria so they are important to life that way but they are not life or death.
Plants can take up water in their roots if the root aquaporins are diminished they send out many more roots to compensate.

- Alright so its not absolutely necessary?

No. But the problem with kidney concentration is a long standing issue in physiology and it was never clear how it is we can release large volumes of dilute urine or concentrate the urine. And these proteins are the major events involved in that process.

- Do you have an explanation why it took so many years to discover these proteins?

Thats an excellent question. In retrospect the most fundamental questions should be solved first. The problem with the logical solution of this is that water is ubiquitous. So to label water chemically is not possible. Using inhibitors of water channels they are not specific. And the measurement of water transport is actually technically difficult. So there were group that were trying to identify the molecular water channels but they all failed. So it is somewhat ironic that by sheer luck, by sheer blind luck an inexperienced investigator could solve the problem.
But thats the beauty of science - its sort of like the alternate player who makes the team because of an illness and comes in the world cup final and scores the goal.

- ha-ha

You know it happens. Its something like that. Its not like a long long heritage of this is the guy who is going to solve it. It was a big surprise.

- Is that how you like to describe yourself as a scientist?

Yeah. I see myself as an average scientist. But I have extraordinary good colleagues and the wisdom of the colleagues make us much better scientists. And secondarily I think I am extraordinarily lucky, but part of is being at the right place at the right time with your eyes open. And I guess I always felt I am good at having my eyes open.
I know that when I am at social occasions there are things that I observe that other people don't observe, thats just how I am. Of there are some things that I don't observe - where did I park the car? ha-ha Is this the day we pay our taxes? I cant remember you know.

- right these insignificant things. Maybe a long that line I would like to hear what led you into science in the first place?

Yes. So I really came to science because I wanted to be a medical doctor, my father was a chemistry professor at a small college and he encouraged my brothers and me to become medical doctors and we did. But I didn't have such strong education you know being a journalist or being a lawyer or other career options looked attractive. In the environment I grew up in out in Minnesota medicine was what gave you probably the best chance of having a great life and doing useful things in terms of taking care of sick people or doing research particularly related particularly to problems of the third world drew me into medicine. And while I was doing research actually on the problem with cholera I really discovered a love for science and I had a talent I didn't expect.
And it is very difficult, I find, to kind of evaluate my own talents and abilities because I still see myself as sort of a not such a great character not such great insight, but I am friendly and I get along with others well and together we bring about things that none of us might individually have done.
Thats how I sort of see myself.

- Is there a sort of a defining moment, you mentioned the problems of the third world?

Thats what got me interested in medicine. These problems that wipe out people in Africa and Asia, so I think there is a humanitarian need. And I still have this. Right now we are working on the aquaporins in malaria. The public may think that we just want a comfortable and a mercedes benz and I think in many cases there is an interest in doing something for the less fortunate to alleviate suffering that motivates many of us.
Often times I think that we can that better not by taken care of one patient at a time, although thats very admirable and some people are great at that, but if we can think of doing development of new therapies that might help thousands of people thats also another way of contributing.
So it was really my interest in medicine that took me to science, I never was a strong student in chemistry - I am sure you can trick me if you ask me some chemistry question.

- Oh no.

H2O I know what that is. You Julia who is here with me, we were high-school student together and she was the A student top student in chemistry I was sort of bad. She use to joke about that.

- and you end up getting the nobel prize in chemistry. ha-ha

Well you know surprise. I didn't feel I should argue about this when they called me. 'Hey wait a minute the chemistry prize no way, forget it' ha ha
You don't have a chance to choose, they choose.

- so about the nobel prize could you tell me a little bit about that. How was the event itself?

The event itself in Stockholm was glorious. My children were there with me, my brothers my sister, my mother my wife, we were all there together and it was very beautifully organized it is sort of the main event in Sweden every winter. And it was exhausting, they had conference, meetings, formal dinners, one after another for a week, and afterwards I was invited to the Scandinavian Universities to lecture including Copenhagen and I visited Uppsala, Oslo and Göteborg but I didn't have enough energy to also come to Copenhagen and Lund. It was too much, I was gone two weeks, so I promised Dan [Klærke] I would come back, initially thinking the spring but then we put it off for to the fall.
Its been glorious to be here, and this is one of the fun parts - visiting universities, but I never expected there to be so many. I have been invited to over 100 places and I cant do that so basically I go to the ones I feel the greatest empathy for - the scandinavian universities and then others as well - South America I am going back to South America in a few weeks and I been to Japan already a few times since the nobel.

- What is about the scandinavian universities?

My family is scandinavian so since I was a small child I have viewed myself as a new world norwegian.

- alright a viking?

Yeah, my father his ancestors were all norwegian and my mother was mixed from Skåne outside of Lund where we are going this afternoon and also she had some norwegian ancestors. So it is sort of my ancestral homeland and I refer to myself jokingly as a new world norwegian. Since I lived in a norwegian town in Minnesota my swedish roots have sort of been neglected.

- I am sure they will welcome you.

They are wonderful. I think this is a fundamental thing though. Many of my jewish colleagues in the United States have a tremendous empathy for Israel. Their ancestral homeland. It is a fundamental thing. Something we can all relate to if we been separated for some time.

- but you don't think of moving here are you?

If Bush is reelected I don't know what I will do. ha-ha-ha.
If he is reelected I will not be happy. I am speaking out very much against some of his hopelessly reckless policies. It is no longer funny.

- but I am afraid our government supports him as well.

You have some problems to take care of here in Denmark as well, because this guy deserves no support. He is playing russian roulette with the world. It is clear it is dangerous.

- How do you think the nobel prize has influenced your life, has it changed it completely or?

Well, the dog doesn't love me any more than before. My children I think for the first time in their life realize that I am not such a failure as they always thought. Hahaha.
It is easy to take yourself too seriously though. I dont want to do that. There are things, an interview like this, the interest by the public of who I am and what I am thinking is something new. I try to be responsible, because I am just another person. I am very lucky in many ways, but there are things that I feel very very passionate about and I think the opportunity to convey these and if people take it more seriously because of the nobel then thats fine.
I have very strong views on the importance on taking care of the environment - taking care of ground water, I mean we live in a biosphere which is primarily water and having the nobel seems to have given me sort of a pole where I can convey some of these things. A lot of my colleagues also share these views but they are not taken seriously, so it has given me a voice for things that I believed in for a long time. Thats the good thing.
It hasn't helped my scientific career at all,

- it hasn't?

I've been away from my lab and the young people in the lab are actually suffering because I am not helping them so much and getting grants is not easier

- its not???

Well I don't have the time to sit down and think about the science

- and the grants dont just come falling into your lab?

No definitely not and they shouldn't, there should be no entitlement. Science is competitive like athletics is competitive if you can perform then you get the chance if you cant perform then it is too late.
There is some loss of personal privacy which is at times difficult. Not this is fine.
But the point is I cannot do things in Baltimore without people noticing and we all want to have an anonymity go to the movies with our family just to be treated like a normal person. Not have people enquiring 'are you moving to another job?' - well maybe but its my business not their business.

- downside of being a celebrity I guess?

Yes this is kind of special small celebrity. Not like Britney Spears it is university kind of celebrity. But it is a special recognition, there are very small numbers as it turns, its not a surprise but it is a surprise, and mostly these go to older people. I was 54 when I got this, I felt middle age, but by nobel standard most of the winners are 65 or older. One was 87.

- Yes we had our own Jens Christian Skou.

Excellent choice, but the work was important in 1960, it took them awhile to figure out how it fit in, but it is no less important than it was.

- yours was actually pretty quick?

Yes, and Rod MacKinnon even faster I think 5 years prior he did the work. But he had won many awards, I had won a few but he'd won many other awards.
I think he was viewed as a likely nobel, myself included. I thought Rod would get the prize.

- Why do you think the two were given together?

Well, thats a good question. I think the committee saw this as a symmetry, because of the problem of biological fluids crossing - tears, urine, the sap of plants - these are 99 pct water but they have special salts and sugars. So Rod solved the structure of the Potassium channels and these were very interesting and important biological molecules. So thats how the salt crosses membranes, but he didn't discover these proteins he discovered their structure.
Biological fluids are mostly water so this together it were channels important for the transport of salt and water. I think those were the words actually of the committee. So biological fluids aren't just salt and aren't just water but together this explains complex physiological processes. So I was very honored to be sharing this with Rod but in fact I can see the symmetry.

- So how do you see your role and life in science today? Are you still a hematologist?

Well we have time in our lab, I dont see patients anymore, I stopped seeing patients 10 years ago. I have a lab with wonderful young people but I think we are going to pick a few problem to concentrate on. Problems that have more human relevance. The malaria problem, osteoporosis and I suspect that over the next few years I will be going more in leadership roles in terms of organization for the university.
The value of having a voice for science, to command some respect in Washington and to share the scientific viewpoint with the public is something I can do better not as a scientist in a lab, because there you are so busy with many details but in a more senior position where I can help steer the whole scientific ship. But I think this is natural for a scientist as he gets older, but they dont get a lot of opportunities I am getting a lot of opportunities now.
And I ready for that - a new adventure.

- How do you see science and society?

Well Actually I think the members of society are very interested in science but they are afraid they cant understand it. Most people feel it is too complicated I could never understand it. And I think as a laureate you could explain things and say this is the important. The details are not so important but the principles are often simple and elegant. And in that way as a spokesman for science I can bring that out to the average person. The average person who studied at high-school or university really can understand a lot of things how toxic elements in the environment disease states they dont have to rely on our government ministers to tell them this is safe or this is not safe.
And I think we as scientist are overdue at sharing our information with the public and I think by and large we have not been very good at it.

- where is the blame for that?

I think we as scientists are part to blame because we make it so complicated, you know we have to tell all the details about our work.
Well sometimes you dont need all the details, I dont know how the telephone works but I know the importance of it I know which buttons to push.
And I think the public would like to know more. In the United States I think we have the problem that the public is very lazy compared to scandinavian friends. What's the last thing you see when you get on an airliner in scandinavia? A stack of newspapers. Take a news paper.
This doesn't occur in the United States and the reason is people dont read news paper there. If they did they would be shocked and alarmed at what's going on. They are lazy. George Bush tells us the war in Iraq is progressing nicely and we are making big progress in the television. But the fact is if you read the in depth analysis this where journalist, your colleagues and yourself have a huge role in setting the record straight.
When I was a little child there was an era in the United States called the McCarthy era where government people and senator McCarthy in particular had this huge anti communist scare and many people were sent to prison and careers were ruined. And it was the journalists that finally called them on this. Edward R Murrow our famous news journalist who exposed this on television and said this is not substantiated and the people said you're right youre right. And it ended the career of McCarthy and it ended the era of McCarthy, but it was the journalists who brought the news to the public, so I think in terms of science the journalist have a big role to play.

I recently read that 80 pct of americans think cavemen and dinosaurs lived at the same time, because they saw it on the Flintstones. Its ridiculous. We are getting our scientific information from the Flintstones. I think if you asked George Bush the same question he would probably say yeah, they lived together. I am sure he doesn't read news papers, he says he doesn't, but I am sure he has seen the Flintstones.

- well Donald Duck used to be a pretty good source of information

Well there was some movie they made of Donald Duck and mathematics it was pretty interesting.

- do think scientist are interested and have time to convey what they think is really important?

I dont think they have had the time, because it is so difficult to get the grants and do the teaching. Hey Dan do you add the number of hours a week that is left after you do all these duties. And you have a family and 1,5 year old child. There is a life of science. But I am in a situation my children are grown and if I take a leadership position part of the negotiation is that I will have time and use it wisely not irresponsible.
I have no interest in stocks in companies that are gonna benefit from the environment, just as human as a citizen I am interested.
I think we should make time.
That is one the good things about the laureate if it can be used responsibly, because that hasn't always been the case, there have been laureates who have said crazy things. 'Denmark will win the world cup, I guaranty it.'

- So in future the environment, and third world problems like malaria is going to play a big role in your life?

Yes, the third world includes the inner cities in the United States. We have a huge population that live in poverty, not just financial poverty but also cultural poverty.
Five pct of young african american boys will be murdered, shot, before the age of 40. We have in our city of Baltimore 50.000 IV drug-abusers out of a city of 600.000. It is almost 20 pct of the men are using heroin. This is a huge problem. It is not third world but in a sense it is the third world because they are excluded from participation in our lives.
Maybe if I can bring some attention to this, it at least gets observed to some degree. Whether the politicians gets involved remains to be seen. So far I've made a big case for scientific colleague now in prison. It has not helped him so far as far as I can see He is in for two years and the government wants to make it 10 years.
He did nothing wrong, he studied the plague bacillus, Thomas Butler. This is the response to the bio-terror. Someone must be punished. It is unbelievable.

- he was just unlucky?

He was just unlucky.

- If you should give an advice to a young scientist?

I think science is not for everybody, but if you like adventure - seeing something no one else has seen and you have the concentrative ability to sort out things, what's important and what is not important and if you are interested in doing something beneficial to mankind this has to be one of the most appealing areas.
So young people that have those talents have the intellectual capacity and the feelings of altruism science is fantastic and they should go for it and never give up.
I would like to encourage people to seek out science.
In the United States we have less and less who are interested. It is a hard career its difficult, the pay is not so high, but it is still a great life you can travel the world meet with colleagues its a great life for the right person so I would like to encourage the young scientist: do not give up. To really give it everything they have.

- and fx somebody choosing a Ph.D., what should they focus on?

I think broad teaching is important. They have expertise in chemistry and biology and some mathematics is important. But to never become complacent about information to always be curious about gaining information and that means in the laboratory and the reading and in life.
Just because someone says it is this way it doesn't mean it have to be this way. Ten years ago if you opened any text book it would say well water diffuses through membranes sort of nonspecifically and now we know cells have this molecular plumbing system. No one had seen it before so it was great fun and I think it will be of benefit to mankind. So I'd like to encourage young people to consider science and think I also would like to have the public know that the money they put in their taxes to support science can be very useful to mankind.
Its not a waste. Its not some arrogant scientist doing trivial things. It really will benefit but we dont know if it will in 1 year or in 25 years.
Scientific information can be very good.

- Where do you see, and I think this will be my last question, where do you your own science or your own field go?

So I think the aquaporins are going to be part of this whole process by which fluids cross membranes. They are knew, no one knew they existed or not, but in fact they are not more important than any of the other transport proteins. So I think in fact their involvement in different clinical states and hope we will be able to develop inhibitors and prevent some of the consequences of brain swelling after injury, some of the causes of blindness like glycoma, problems with secretion of tears and sweat.

- and malaria?

All microorganisms have aquaporins these are potential new drug-targets, we dont know for sure if they will be feasible or not but they should be looked at. The aquaporins are new but they are just part of biology, so we have a new career pathway for molecules. And it will be important - it wont be the answer for what causes cancer, it wont be the answer for heart disease but it may provide information that may be useful along other parts of biology. They are exciting this last year because of the nobel, but in fact they will be another book on the shelf in library, but they are there forever now.
Scientists 200 years from now will be able to use this information in ways I probably cant even imagine so I think we have done something for the first time and left a permanent legacy and I am really pleased to have done that.

- Well thank you very much for your time

I am flattered by your interest Rasmus. ha-ha.

- It was very interesting.

This has been a wonderful stay, I love Copenhagen and our friend Søren came from Århus.

- did you have time to see anything?

Well this morning we had some time off so Dan suggested we went up to the Karen Blixen House.
It was wonderful I have always wanted to visit that and it was very interesting. I come back next year and I want to go back to Roskilde to the viking ship museum. I have been there before.
I want to sign up for the new boat that they are rowing to Ireland next year. I am staying fit, if you want to have a nobel laureate on board give me a tip.

Copyright © Rasmus Kragh Jakobsen