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Peter Agre:From aquaporins to advocacy

As Peter Agre might ask, have you ever considered how your life is sustained every moment by the distribution of water within your own body: in the secretion of cerebrospinal fluid, in the filling of ocular space with aqueous humor, in forming urine, in salivating, in humidifying the airways, in crying and sweating? And, if you are a biologist, Agre might ask still more specifically what thought you have given to something called aquaporins.

It was for his discovery of aquaporins, the molecular channels that regulate water transport across cell membranes, that Agre shared the Nobel Prize in Chemistry in 2003. Last year he visited the GlaxoSmithKline R&D centre in Research Triangle Park, North Carolina, to discuss his work.

He was helping to inaugurate the day-long, twice-yearly “SciNovations” symposia at GSK, where keynote addresses like his are given at a GSK R&D site and Webcast to GSK scientists at sites in other countries. These events also feature presentations and poster displays by GSK scientists across their many disciplines. Vying to be part of the day, the scientists submit abstracts of their research, as they would before any scientific congress, for review by an internal panel of peers.

Agre is Director of the Johns Hopkins Malaria Research Institute at the Johns Hopkins Bloomberg School of Public Health. He talked with Marathons about the research path that led to aquaporins, the medical relevance of that work, the mutual interests of academia and industry, and the uses of a Nobel Prize.

Marathons: How did you get interested in science?

Agre: I had the good fortune of being born into a family where science was considered important. Both my parents were the offspring of Norwegian farming families, and they grew up surrounded by the science of plants and animals in a farming context.
 
Dad became an industrial chemist and eventually became a Professor of Chemistry at Augsburg College. He always raved that (Linus) Pauling's accomplishments were the greatest, and he instilled in us his view that the Nobel Prize is the closest thing to the Holy Grail.  As a youngster my brothers and I were fortunate. We would go up to his lab after school and do little experiments such as dropping acid into a solution which would turn magically pink.  These phenomenal things just caught my interest, and despite my rocky adolescence, I managed to get back into science. It must have been in my blood -- I remember at the age of about eight a school teacher asked us to draw a picture of what we would do when we grew up and became adults.  Since my Dad was my hero, I drew a picture of a chemist with test tubes.  My good friend, Jay Petersen, whose father was a professor of biology, was sitting next to me, and I saw him drawing a picture of a burglar!

But you actually went on to study medicine initially?

I decided to become a medical doctor, in part, because I did not think that I had what it took to become a successful scientist.  But ultimately my interest in medicine drew me to laboratories to work on science, and after college, I proceeded along that pathway, first with Wellcome Laboratories as a Haematology Oncology Fellow at UNC (University of North Carolina), Chapel Hill, then as a Wellcome employee. For a short spell I had the privilege of working in the medical division, led by Trudy Elion.

When did the science begin to get interesting?

I was assigned to the tumour necrosis factor (TNF) project with a young Wellcome scientist named Fred Kull.  As a sideline, I worked with Vann Bennett, who was doing some pioneering work on red cell membrane structural proteins.  This part time project with Vann connected in that as a haematology trainee at Chapel Hill, I had met and taken care of patients with a variety of defects in red cell membranes.  We didn’t know what the defect was.  One of the families had a very severe form of hereditary spherocytosis, described as haemolytic anaemia, where the cells are misshapen and very fragile.  Working with Vann, we identified the molecular defect responsible.

And that discovery prompted a move to Johns Hopkins?

Yes, I followed Vann, who had gone to the Cell Biology Department at Johns Hopkins, to continue working on spherocytosis. As part of our research, we did the first biochemical purification of the Rh blood group antigen. As a sideline to that project, a contaminating protein fell into our laps.  That protein is now known as aquaporin-1, the first water channel protein discovered by sheer serendipity by someone who was not really expecting to make such a discovery. 

Why do you say that?

Just an observation about how science works. You come to the laboratory every day, and sometimes being lucky, you find things you didn’t expect. I am not saying that science is a random walk through life – you need some process – but you can’t predict it.  Certainly in my early days at Wellcome, the tumour necrosis factor project was stuck, but that gave me the freedom to work on red cell membranes.  That freedom allowed us to get going in an area that has proven to be more exciting for me than the TNF project because TNF was solved by others.

Is that the difference between industry and academia, freedom?

Industry has an obligation to find something that will be profitable in the market place; otherwise it can’t survive. Companies are experts at turning ideas into marketable products.  Universities can pursue creative projects, but they still need to lead to something important, and plenty of discoveries made at universities would stop right there if industry were not there to take them forward. Take the discovery of insulin by a laboratory at the University of Toronto. If it weren’t for a pharmacologist from Indianapolis named Eli Lilly, they would have got nowhere.  Lilly had the capacity to process the pancreas from slaughterhouse specimens and to isolate insulin. Either side by itself would have failed, but together they had something that was remarkable.           

There is a great deal of discussion now, and some folks would vilify industry as being impure and capitalist.  On the other hand, universities also are trying to achieve prosperity through grant support, philanthropy, and partnerships which sometimes obscures the reality that we are in it together. For that matter, universities are the breeding ground for the young scientists.  I suspect the great majority of scientists that work here at GSK are university graduates.

Even in academia you have the responsibility to do something worthwhile with your freedom. The reward for doing so is called ‘tenure’.  In the end the responsibility to achieve is there, and there is no perfect safety net.  People have to perform. Yet the challenge is to make the demands reasonable so that people are stimulated and motivated and not scared to death.

How has partnership helped you?

When we discovered aquaporin-1, we had clear ideas for our next steps that were very ambitious, and by collaborating with other groups we achieved almost all of our aims.  We were not able as a small group to do all the things we initially planned, so we teamed up with leading laboratories in Scandinavia, Switzerland and Japan and were able to do a host of studies that we could never have done ourselves.. I came to realise that the creative process requires careful thought and discussions with other scientists, and it became a whirlwind tour which has never really ended.  I was in Puerto Rico yesterday, I go to Prague on Thursday and then to Germany, Pakistan and Sri Lanka. 

I guess lots of people want to work with a Nobel Prize winner?

Since the announcement, life has certainly been interesting, there is no denying it.. But to keep my feet on the ground, I like to say that our dog doesn’t love me any more than before!

Getting a Nobel Prize did change things, though.  It has certainly helped my work in human rights, which I was already involved with before my work on aquaporins. I work with a group that intercedes on behalf of scientists, engineers and healthcare professionals around the world who are persecuted, imprisoned, and even murdered with no charges brought forth.  In fact, I was working on the defence of a former colleague who was being investigated on bioterrorism charges when the announcement came for the prize. The case had been getting relatively little attention, then suddenly the press was in my living room asking what I was going to do with the money. In Europe and South America, that was the headline, not the aquaporin discovery - ‘Nobel prize winner supports persecuted scientist’.

Another responsibility I have been given is to increase access to science for taxpayers and stockholders. It is not like money comes from nowhere to do the work, so I make a point to educate audiences on investments in science that have had benefits for society. You don’t have to look far to see what science has achieved. Often people are caught up in their lives, athletics on television, paying taxes. They forget that just 200 years ago, not so many generations ago, life was much shorter and far more miserable. The advances came from science, not the church or the state. I read this wonderful book by Michael Bliss about the discovery of insulin. The discovery team treated children who were on their death beds. All the children responded, and one of these youngsters lived another 59 years! Of course, there are many places in the world where life is still fairly short and often miserable, and so there is much work still to do.

The downside of the prize is the over-hype and the weight of expectation. The Nobel is like winning the lottery to be truthful. You were there, you were in the right place at the right time, you had your eyes wide open, but it is not like luck didn’t have a lot to do with it. My background is not in any way exceptional.  It worked out for me because we are fortunate and others helped. I hope that young scientists relate to me and can imagine themselves accomplishing great things.

Is all of this taking you away from science?

I go wilderness canoeing in the Arctic and cross-country ski-ing, I have administrative responsibilities, and I’m engaged politically, so I do get a little over-extended with both scientific and societal interests.  But I am still actively working on new scientific discoveries. My team has just found a potential new pathway for the treatment of malaria, targeting the glycerol-transporting version of aquaporin. All life forms have aquaporin family members, and some have the versions that transport water, some have the glycerol-transporting members, and some have both. It turns out that each species of the malaria organism has its own particular glycerol transporter, which is not absolutely essential for the organism to grow and divide, but when it is knocked down the organism is at a great disadvantage. Maybe this will be a new therapeutic pathway. I would feel rewarded if we could make even a small advance in this disease.  I do feel our work has had a lot of visibility, credit, and recognition, and that has been wonderful, but I don’t think we have yet done anything practical to help a single soul.  If we could do that, it would be really gratifying.

We are also hoping that the basic information on aquaporins could be useful to industry in development of agents to prevent or ameliorate brain oedema, the swelling that occurs after a stroke or head injury. Problems such as dry eye are also uncomfortable, and individuals that have an inability to release saliva, which is very common after radiotherapy for cancer, often die of aspiration pneumonia because they cannot chew and digest their food.  The clinical potential is there, but now comes the hard part. This is where organisations like GSK with a large team and investment could make a difference. 

What other plans do you have?

Who knows what will turn up? Doing science for its own sake is joyful -- it’s fun making a discovery, no matter how trivial it may seem at the time, something no-one has seen before. Hey, that’s how it works, and you never know. So I’ll stay in science because it is motivating, although I fear that for me to do science I need a protected environment.  I am probably one of these people that as a youngster would now be diagnosed as ‘attention deficit’!  It is clear I have too many interests.

I am also focused on trying to bring science to others, particularly non-scientists.  I go to a fair bit of effort to bring it to the public, or at least to be in the public eye in a positive way, and to legislators who are often not scientists and often poorly informed.

Apart from that I have a strong interest in how the fortunes of mankind are faring.  That sounds very grandiose. But here we are: We have deterioration of a lot of institutions like our schools, the environment is now clearly being damaged, and these are things we could take care of. The book ‘Bowling Alone’ by Robert Putnam chronicles the loss of community. Everybody is working incredibly hard and our level of prosperity is high.  People have two large cars, vacations to the Bahamas, but no money in the bank - maybe we could slow down a little and enjoy things more. I can point the finger at my own kin when I say that. My Dad was at the other extreme - exceedingly frugal.  It would have been nice if he had taken my mother out to dinner more than once in 40 years!

I don’t know if Nobel prize winners are particularly well-suited to getting involved in public life, but I feel that we could be doing a lot better!

Aquaporins

Aquaporins are a large family of proteins that form the channels through which water molecules cross the cell membranes of plants, animals, bacteria, and yeast. The selectivity of these channels for water is determined by channel architecture and electric charge. One example of the importance of water channels in human physiology is found in the kidneys, where about 150 to 200 liters of water need to be resorbed every day.

The discovery of aquaporins opened up new avenues of biochemical, physiological and genetic research in bacteria, plants and mammals at the molecular level. Since a 1992 paper in Science by Agre and Johns Hopkins physiologist Bill Guggino, which documented the discovery of the first water channel protein, 10 more have been found in mammals and more than 150 have been sequenced. In Agre's lab alone, aquaporins have been discovered to be part of the blood-brain barrier and also associated with critical water transport in skeletal muscle, lung and kidney. Researchers around the world have linked aberrant water transport to a multitude of human diseases and conditions such as nephrogenic diabetes insipidus, salivary gland dysfunction (Sjogren's syndrome), cataracts, and altered water transport in the brain and the lungs.

Peter Agre has remarked that his discovery of aquaporins was “sheer blind luck.” Patrick Vallance, who heads Drug Discovery at GlaxoSmithKline, doubtless gets nearer the truth when he ascribes the discovery to “a sharp mind and a clear eye.” In the mid-1980s, Agre and his colleagues were trying to isolate Rh blood group antigens when they happened across an abundant and slightly smaller protein. The researchers isolated the protein from red blood cells and renal tubules. Proof that the protein was a component of cellular water channels then came in an experiment with frogs' eggs bathed in a water solution. Eggs expressing an aquaporin, following injection of aquaporin RNA, absorbed water, swelled, and burst, but eggs without the aquaporin did not swell.

Passage of water molecules through the aquaporin AQP1. The relatively large
size of other molecules or their positive electrical charge prevent them from passing through the tight, positively charged channel.
(Courtesy Nobelprize.org)

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