A Conversation with Peter Agre, MD

Mukesh Jain, MD: Hello everyone. My name is Mukesh Jain. I'm the Chief Academic Officer at University Hospital. And it's really an honor and privilege for me to be here today speaking with Dr. Peter Agre, a brilliant scientist, Nobel Laureate, and science activist. Dr. Agre is an alumnus of University Hospitals, where he gained his internal medicine training. And I'm just delighted to have this conversation with him in advance of his visit in early November when he will be delivering the inaugural UH Distinguished Scientist Lecture. Welcome, Dr. Agre.

Peter Agre, MD: Thank you. It's a privilege to be engaged in conversation with you, Mukesh. It brings back memories of the fondest times in Cleveland.

Mukesh Jain, MD: Well, thank you, Peter, for joining us, and maybe I can start our conversation and you to share a little bit about you personally. You grew up, if I recall, in Minnesota. Can you tell us a little bit about your family and childhood?

Peter Agre, MD: Sure. I was born in Northfield, Minnesota, a small college town south of Minneapolis. My dad was the Chairman of chemistry at St. Olaf College. And we didn't know the people across town at Carleton College; they were considered sort of dangerous or wicked. It’s just a myth of our college rivalry. But it was an idyllic place to be young child, and having a father who was a chemistry professor provided some special opportunities. My brothers and I would oftentimes go up to his laboratory, and he would have little experiments rigged. Something funny, something interesting, something eye-catching. I distinctly recall him taking us to his laboratory, where he had a beaker of water, and he put a drop of a colorless solution. So it looks like he is dropping water into water, but the beaker suddenly turned brilliant pink. Then he took a drop of another solution and dropped it in, and the pink disappeared. It was incredible. Of course, this is an indicator dye, and that was protonated and deprotonated, so there's an explanation. So my view of magic as a childhood of science, chemistry, and I remember being so caught up with this idea that in second or third grade, we were asked to draw a picture of ourselves when we're grown up in our careers. And I carefully drew a picture of a chemist, test tube, the laboratory bench. That was because my father was my hero.

And I noticed sitting beside me was my great friend Jay Peterson, whose father was a professor of biology, and Jay was drawing a picture of a burglar. All of us wondered what came of Jay. It turns out he became a primate biologist at the zoo in Chicago. He didn't become a burglar, fortunately. And it was a fascinating time in history because in October of 1957 when I was in second grade was when Sputnik was launched. And there was a major shift in American priorities.

Suddenly, the US that viewed itself as culturally and scientifically in every way, superior to our adversaries, the Soviet Union, had been beaten us into space. And you think a second grader would not notice that. Well, I noticed it because my father decided then and there he was going to do a sabbatical to increase his scientific credibility. He trained at the University of Minnesota, and was an experimental scientist at DuPont station, back to Minnesota. And so he had been in contact with Linus Pauling at Cal Tech, and the original plan was he would join Pauling’s lab. But it turned out, Pauling was never in his lab in those years. He was traveling all around because he was advocating the termination of testing of nuclear weapons. So the Agre family packed up the old station wagon. I like to remember this is kind of a Norwegian version of The Beverly Hillbillies. We drove across the country and lived in Berkeley, California, for a year. The change from Northfield to Berkeley is about like leaving Lake Wobegon for Sodom and Gomorrah, is a completely different culture and vibrant. So, I was fortunate that way—early childhood emphasis on science.

And even as an adolescent, when I became a Boy Scout, my dad would help the troop by arranging to have the camp physicals. It was required by the Boy Scouts of America that the night before camp, a final, just quick check-up to make sure everybody's well. And they had to have a doctor do that. Which, for many working class troops, was not that easy. At that point, we lived in Minneapolis. Our troop was, it really was a working-class troop. And my dad, with all this audacity, had Charles Mayo (son of the founder) and a contemporary from the Mayo Clinic come up and examine the boys for Troop 185 to certify that they were ready for Boy Scout camp. So there was some familial encouragement.

Mukesh Jain, MD: That is so wonderful and it's so interesting that your father was your childhood hero turned you on to science and chemistry.

Peter Agre, MD: [laugh] There’s something called adolescence that changes all that, but we don’t need to go into the Wonder Years.

Mukesh Jain, MD: Clearly, it had an impact, but we'll get to that in a few minutes. When did you develop an interest in becoming a physician, and were there specific events or individuals that might have inspired that career path?

Peter Agre, MD: Well, dad was chairman of chemistry, but he had a large number of the pre-medical students at St. Olaf who were chemistry majors. This is really before the revolution in biology. So, biology was mostly zoology and classifications of descriptions, but not at a molecular level. So many of his best students went to graduate school or medical school. And so, getting to know these people was encouraging. They were family friends, so it was always an intriguing option. As I grew older, certainly by the time I was in high school, I recognized that being a medical doctor is a very special privilege. It's a great career with many different possible directions and universally acclaimed by the populace, very important in the lives of citizens. So it'd be kind of hard not to be interested in being a medical doctor. And I didn't have any exceptional talents, I was not a great athlete or renowned singer, and I was just another kid with an interest with some unusual connections to science but medicine, grabbed my fancy. So I think from about ninth grade on, that was my career goal. In particular, I think medical research.

Mukesh Jain, MD: Great, and those comments serve as a wonderful segue to my next question. So you at a relatively young age, as you described, developed an interest in medicine, and following your medical training at Hopkins, you completed your residency at UH. So tell us about the experience at Hopkins and then your experience at UH and what influenced your decisions to come here.

Peter Agre, MD: Sure. So, I think it was long winters in Minnesota, and I stayed at home for high school and for college. Then my dad had taken on a new challenge. He was the Chairman of chemistry at Augsburg College in Minneapolis, now it's called Augsburg University, but it is a small Lutheran college. The experiences of doctors in far-off exotic places was something I found really interesting. And in our community, there were a number of individuals who became medical missionaries, medical doctors and nurses who went off to places like Cameroon or northern India to work for decades.

Now I wasn't much of a churchgoer, but I thought the idea of world health or global health, it was at a point that no one was talking about it in the 1960s, but that seemed appealing. And when I graduated from college, I finished early, so I had the better part of a year of traveling in East Asia, Southeast Asia, South Asia. I got to see some of the catastrophic health problems that poor people in the world were dealing with firsthand. And as a medical student, I became interested in cholera. In 1970, the toxin released by vibrio cholera was isolated and purified by Richard Finkelstein at the University of Texas.

I worked in a research laboratory at Johns Hopkins with Brad Sack, who was involved in the Johns Hopkins cholera research station, that was in Calcutta, then moved to Dhaka, Bangladesh. And so, I, as a medical student, was working in Brad's lab, and we proposed that we try to purify the toxin that some strains of E.coli released. It was well known that the clinical element, which currently is described as travelers’ diarrhea, was like cholera, but somewhat less severe. But strains of E.coli had been implicated, but no one had been able to isolate the toxin.

My roommate in medical school, Vann Bennett, was doing a PhD and an MD. Hopkins at that time did not have an MD/PhD program, but there were a few individuals who did an MD and did a PhD as well. He was working in the laboratory of Pedro Cuatrecasas, a young Spanish-born investigator who was using affinity chromatography for the very first time in biological systems to separate molecules.

It was a really powerful experience. I ended up staying a year after medical school to work on the project. Hopkins and Case Western Reserve University Hospitals had made a strong connection because Charles Carpenter, who was very revered at Hopkins, he was the Chairman of medicine at the Baltimore City Hospital and accepted the professorship at Case. It was clear to me that this was the opportunity to have some research connections and work for someone that I greatly respected.

We moved to Cleveland and had a lovely apartment up Euclid Heights. I would just ride my bicycle down the hill to University Hospitals. It was a good match for me. I think it was a program with strong academic credentials but also very pleasant people to work with. It was a natural fit. And I think I had spent so much time working in the lab as the medical student. I tried to catch up in class, but it was clear that my interest in science was going to lead me to a different career from most of the residents.

Mukesh Jain, MD: Are there experience, mentors or colleagues who stand out to you from your time at University Hospitals?

Peter Agre, MD: Sure, first and foremost Chuck Carpenter, who we called the tall man. I like to show a slide of the internship class in terms of residents in 1976 or 1977. Chuck is in the front row standing, and I'm standing behind him, two steps higher, and we're the same height. I’m 5’9,” and he was 6’6”. And he was a wonderful role model and source of strength. He pushed the residents to take responsibility, and it was a very inspiring experience.

I also worked in the lab with Jim Carter. Jim had trained at Mass General and was interested in hepatocytes and liver biochemistry. I had arranged to do a tour with a new program that they had in global medicine. The plan was to continue the work on the E.coli toxin and set up a testing assay in Ethiopia. The Ethiopia opportunity was canceled due to the unrest and political instability. I ended up working at Jim's lab in Cleveland, and he was a very wonderful mentor.

Another internship and residency group, Michael Lederman, who is still on your faculty. He was a very inspiring colleague. He was my resident when I rotated through the VA hospital. I had the greatest respect and admiration for Mike, and I still do.

Mukesh Jain, MD: Well, I think the feeling is mutual, and I know Michael is very much looking forward to your visit. So it'll be great for the two of you to catch up.

Peter Agre, MD: Thank you.

Mukesh Jain, MD: So, you finish residency, and you completed hem/onc fellowship at UNC-Chapel Hill, and then returned to Hopkins in the lab of Vann Bennett in the department of cell biology. At this point, were you pretty set on a career as a physician-scientist, or were there other events that happened that convinced you that this was your calling?

Peter Agre, MD: In fact, it was a unique opportunity. So Vann was my roommate in medical school. We became best friends the first week of med school because we had so many shared interests. He was a superb chemistry student at Stanford and knew he wanted to make a career in biomedical research, but during the Vietnam era, if he had enrolled in graduate school, he would have been drafted. So his view of the MD part was basically to get background for his research interests.

Vann very much encouraged me when I joined the UNC hematology-oncology program to do my research at the Wellcome Laboratories. Burroughs Wellcome, at that time, was an independent pharmaceutical manufacturer, but they had a very interesting tradition. The stockholders of Burroughs Wellcome were the Wellcome Trust, so profits were deposited in the Wellcome Trust, and then they use this to fund research in the United Kingdom and the Commonwealth. So it was a drug company that had a conscience.

I joined the Wellcome labs, specifically, so I could work with Vann, who, following medical school, had done a one-year postdoctoral fellowship at Harvard University in the biology department with Daniel Branton, and was working on red cell membranes. And being a hematology fellow, I had access to patients, and of course, we all know that sickle cell anemia has to do with a hemoglobin problem, but there are other diseases of the red cells that resulted in misshapen cells, and the cause was not known. And working with Vann, we were able to identify major structural defects in red cells from patients with hereditary spherocytosis. Working with Vann as a post-doc was quite interesting because he is actually a contemporary. He was way ahead of all of us in terms of his background in science, and Vann decided to return to Hopkins to join the cell biology department because of a wonderful scientist, Tom Pollard who was coming down from Harvard to rebuild the anatomy and cell biology research enterprise, and it was an exciting time.

And so, it was clear from working with Vann that red cells was a major opportunity for research scientists because you could get pure membranes. And it's not a simple task to isolate membranes from most cells, but red cells you can isolate and wash away the hemoglobin and have a pure prep. Of course, the most serious disease of red cells is malaria. And so I was interested in malaria and began to work on malaria. But along the way we made some discoveries in the red cell that caused it to go in a new direction. That was the discovery of aquaporin, specifically aquaporin 1, and that came at a point in my career where I had to make some decisions.

I completed my residency and research fellowship that I had a faculty position at Johns Hopkins hematology with most of my time protected for research; of course, I had to fund that with grants to pay my salary. But those were different times; it was not as difficult as it is today.

The discovery of the aquaporin was an example of serendipity. And it was a chance for us to take a new direction that led to a lot of interest worldwide. And some prizes as well.

Mukesh Jain, MD: Can you share if there was a specific experiment that you could describe in simple terms for the rest of us that led you to realize that you must be onto something because people have been looking for the water channel for a long time.

Peter Agre, MD: Well, not a lot of people were looking for the water channel, but biophysicists and physiologists realized that membrane water permeability varied. In some cells, like the surface epithelium, there's limited water permeability. If we soak in a hot tub and we may get a little bit of fluid intake but very minor, but other cells, such as our red cells, have enormous water permeability. That's why they lyse so easily. Also, if you drop a red cell into a hypertonic buffer, it'll shrink. And it was actually on a family vacation where I had a conversation in Chapel Hill with John C. Parker, my former hematology mentor, who himself was a very gifted membrane physiologist studying calcium influxes in red cell membranes. I had taken the family to Disney World and camping in the Everglades, and on the long drive back, we stopped in Chapel Hill, and I had a conversation with John.

I described this new protein of 28 kilo Daltons mass abundant in red cells but didn’t stain with Coomasie. And it was also present in renal tubules, and we did a gene search, and there were fragments of DNA from diverse sources brains of insects, plants, and bacteria that were genetically similar. It was John Parker who put it all together and a conversation that I'll never forget. He had been the attending in the intensive care unit. I called ahead to arrange a meeting. He had been up all night, but we had this conversation. It was almost like a light bulb went off in his head. He said, “You know Peter, these tissues with this new protein are highly permeable to water. Have you considered this might be the long-sought water channel?” Not me; I never heard of water channel used to describe a unique entity. And so clearly, it was John's insight. And then he made some very nice suggestions. He had a colleague from the graduate program at Duke who was in the physiology department at Johns Hopkins, Bill Guggino. He strongly encouraged me to contact Bill and see if we can explore this new protein was a water channel. And Bill is my age, we were both young scientists at the time, this was 1991, so 30 years ago. And we set about expressing this new protein in Xenopus laevis Oocytes, frog eggs. Bill was quite an authority on the Xenopus laevis system since he was using it to study the cystic fibrosis transmembrane regulator, the important membrane transporter which is the cause of cystic fibrosis. We had an exceptionally enthusiastic postdoctoral fellow, Gregory Preston, a graduate of the University of Connecticut, who came to my lab as a post-doc. We put Greg on the water channel project, and he was masterful in terms of his ability to get experimental systems to work.

And the first test, six test Oocytes, six control Oocytes and it was obvious that the test Oocytes all exploded rapidly and were exposed to distilled water, whereas the control Oocytes were swelling very slowly. It was a dramatic moment. That's really changed things for our lab.

Mukesh Jain, MD: That's a fascinating story from your conversation with Dr. Parker to working with a colleague and leveraging studies in fundamental organisms to make a remarkable discovery.

Peter Agre, MD: Oh, Mukesh, it also is really clear that if we didn't have the intellectual support from John Parker, Bill Guggino, or Greg Preston, the post-doc, it would have failed.

Mukesh Jain, MD: Right.

Peter Agre, MD: Their insight, their generosity and enthusiasm made it happen.

Mukesh Jain, MD: Understood. Well, I guess this was in the late 80s early 90s. Fast forward a little more than a decade and lets talk about October 2003. And you received the call and tell us since so few people will ever get that call. Tell us what it's like to get that call at presumably five in the morning or so.

Peter Agre, MD: Well, I suspect I was not alone in having daydreams about pleasant calls from Stockholm. It never seemed realistic, so I never spent much time obsessing over the fact that prizes were sometimes awarded for discoveries that I could be involved in. But there were very positive responses when I would lecture about this new water channel protein, the aquaporin. And it was at Wright State University in Ohio, Peter K Lauf, Director of Physiology, invited me to give a seminar. And afterward, he came up to me and said, “You know this is really important. I think you're going to get a Nobel Prize.” I didn't really even think about it. And then it happened a few more times. So, it seemed like I had been in the right place at the right time with the mentors that I described and just that sheer luck that it all fit together.

But when the call came, it was not a total surprise because they're very careful. These Swedes don't gossip, they take in information, they maintain perfect confidentiality. But there was a conference organized by the chemistry committee, the Nobel chemistry committee of the Royal Society Sciences held outside of Stockholm in August of 2003. The presentations came from all the leading membrane transport laboratories. Roderick MacKinnon was one of the presenters. It seemed like there was a chance that somebody in the room was being scrutinized.

Then in the autumn, I got a call from an investigator from Sweden. I didn't know the name, I didn't recognize it, and I sent an email to a Swedish colleague said, do you know who Bengt Nordén is? He asked to visit our laboratory. I got a thoughtful reply, no, you probably don't know Bengt Nordén, he is a physical chemist, but you might be interested to know that he's the chair of the Nobel chemistry committee. What, he wants to visit me? And Bengt, in turn, shared a little information. It was part of a visit, his daughter was working in Los Angeles, and he wanted to stop by and visit a few laboratories. He actually had just come from New York; he met somebody, it was probably Rod MacKinnon. And then, after meeting with me, he wanted to meet with Andy Fire at the Carnegie Institution.

Of course, in retrospect, he was getting information. It was never made clear that you will get this prize, but there was enough clue that I could sort of feel that I had to be ready. Of course, you never tell the press that because it sounds very immodest, “Oh, I always knew that this would happen.” I don't think anybody can say that they always knew it would happen, surely not me.

Mukesh Jain, MD: How does winning the Nobel change your life?

Peter Agre, MD: Well, it has some positive features and some negative features. Certainly, the joy of celebrating science and being contact with hundreds of people from my past, even my grade school classmates. All is very wonderful, but there's also a loss of privacy that comes with intense media attention, the expectations that you're going to say something brilliant. At least I felt that I didn’t have any brilliant thoughts, and I was glad to share my opinions, but I didn't really feel totally prepared for the intensity of the interest. In part, Hopkins had gone through a long dry spell in terms of Nobels. In 1978, Daniel Nathans and Hamilton Smith shared the Nobel with a scientist from Switzerland for the discovery of the restriction enzymes. That was 25 years ago for a Nobel. So there's a lot of celebration at Hopkins, and it wasn't just in our department; it was throughout the medical school, security guards, and the hospital staff. It was something that was good for the community, and I liked that.

Mukesh Jain, MD: Yes, that is wonderful. What advice would you give young trainees who are embarking on their medical and research careers?

Peter Agre, MD: Yeah, I think it's important to identify a mentor that you can look up to in a genuine way; admire what they're doing, and also who is in the group. That would be helpful because you're going to spend more time talking to the lab members and the lab chief, but both are quite important.

I feel like I've had some outstanding mentors. I talked about John and Vann. I did a sabbatical to learn DNA Technology. I worked in the laboratory of Steve McKnight at the Carnegie Institution. He took me in for a year in his laboratory. We did a nice paper on the Leucine Zipper DNA binding motif, but it was really an opportunity to get the technology to do molecular biology in my own laboratory.

Mukesh Jain, MD: So, certainly winning the Nobel changes one's life as you indicated, and following that, you have moved your professional life in a number of directions. One is as a strong ambassador for science. And you've been involved in fostering international scientific collaborations sometimes in nations where the United States did not necessarily have a very favorable interaction. What inspired you to do this? Was there an event? Was it just personal motivation or an inspirational figure?

Peter Agre, MD: Well, I think, from the very beginning, it was clear that some scientists had credentials that the public looked up to. Linus Pauling was a classic example. If you ask a student today about Linus Pauling, he is remembered for his work on vitamin C, which is regarded as a mistake. But he was fearless in terms of traveling and sharing his views on science and, in particular, the dangers of nuclear weapons testing. I had no delusion that I would be Linus Pauling's counterpart in this extension of a fascination and travel.

When I was 17 years old, I was part of a group of university students that traveled to the Soviet Union and camped in campgrounds. It was organized by my high school German teacher, Horst Momber went on to become a high school principal in Seattle. I had the notion that faraway places are accessible and very interesting. So that was my mindset and also my dad, also, in his summers, he would sometimes teach in Indian universities, and so that also underscored the value of international travel.

When I was elected the president of the American Association for the Advancement of Science (AAAS), a new program and science diplomacy had just been started. My predecessor, David Baltimore led a group that visited Syria, and they met with everybody, the president of Syria, Bashar al-Assad, who is himself was an eye surgeon. As his successor, the group at AAAS, in collaboration with CRDF International, a nonprofit in Washington, we had worked together to get an invitation to visit North Korea. And so, I joined their efforts, and we went to North Korea, been back a couple of times since, and made scientific friendships with leading scientists in North Korea. Of course, it is impossible to contact them directly and discuss things, but sooner or later, North Korea will have a change in government, and knowing their leading scientists could be very helpful. So it was multiple interests.

Mukesh Jain, MD: Sure. So, I'm sort of wrapping up our conversation. I wanted to end with an interesting fact about you, which is not quite on par with winning the Nobel, but it's a big deal nonetheless. You were on The Colbert Report in 2006, and you spoke about the need for the public to appreciate the benefits of science. Do you think that perception has changed? And obviously, we've been through one of the most visible demonstrations of the impact of science with the pandemic. So, has that perception changed? Or should we, as a community, be doing more?

Peter Agre, MD: I think we should be doing more. So there was a workshop that you organized at the National Academy of Sciences two years ago, and at that event, this topic came up. I recall my main concern was that we really didn't have a champion for science. I mentioned that Tony Fauci was perhaps the most visible scientist. Well, of course, Tony Fauci has become a rock star for science. There was some political opposition, but by and large, he provided straight information to the American public, and the public needed the information and wanted the information. So I think, Tony Fauci deserves special recognition for guiding us through this horrible pandemic. But Tony is eighty years old, and he's still very youthful, but it's going to be time soon to have new representatives of science. I think the physician-scientists have a particularly important role because they have expertise in two areas. Of course, now we've faced a pandemic, the worst in a century, but there'll be more problems, infectious diseases, viruses. And I think the arguments about being ready for these, overwhelmingly, supportive of more science and involvement of scientists in the decision-making process. There's no guarantee. I see Senator Rand Paul, who himself is a medical doctor, a Duke University graduate, has his Twitter feed liked because of sharing misinformation. So one of our own in a high position is abusing this situation. I think the public would like to know. They need to hear from someone who's good at explaining it. I am not that person. I have developed Parkinson's disease, and it's not easy to speak clearly, but we have plenty of talent, and I think the public will be very grateful if younger physician-scientists followed the tradition of Tony Fauci and make themselves available to speak responsibly and clearly. And I'm optimistic that young scientists will emerge.

Mukesh Jain, MD: Well, you know, you're absolutely right. For the audience, the meeting that Peter is referencing occurred on February 20, 2020, just before, the pandemic really shut us down, but it was a very important meeting on physician-scientists. Dr. Agre, along with a number of leading authorities and leaders in science and medicine, had convened. So I appreciate the comment Peter and that we need that next generation of individuals like yourself or Tony, who are ambassadors for science, for medicine, but also public health policy which is so vitally important and needed and to be able to communicate, science and medicine clearly, and in a simple manner to the public. So vitally important because there's so much misinformation these days that we really need those ambassadors to be out there. So an important charge from you to the rest of us and the next generation of physician-scientists.

Peter Agre, MD: Oh, no pressure. We’re counting on you, Mukesh. I know you will deliver and you are already delivering.

Mukesh Jain, MD: All right. Peter, I think that wraps up our conversation. I just want to take a moment, at a personal level having gotten to just thank you. First for your time and your commitment to science, medicine and physician-scientists. Second, for your kindness, your modesty and your generosity as you described your science. It’s very refreshing, decidedly uncommon, and very inspiring. For that, I just wished to thank you, certainly for myself and for so many that think you the same way. So thank you for your time and all that you do.

Peter Agre, MD: I am grateful for the opportunity and very much looking forward to the visit.