JCI’s Conversations with Giants in Medicine: Peter Agre

Hello and thank you for tuning in to the next of the JCI series, Conversations with Giants in Medicine. I'm Ushma Neill. Peter Agrae, Director of the Johns Hopkins Malaria Research Institute, joins me today to talk about his extraordinary life in science. His humble roots starting as a Norwegian from Minnesota who happened to have gotten a D in chemistry, rising to later share the 2003 Nobel Prize in Chemistry. He once thought about running for U.S. Senate and here's to hoping that maybe he will take one of those roles in the future. I hope that we can hear a little bit about his travels throughout the world and his extraordinary life in science. Thank you so much for joining me today. You're welcome, Ushma. Thank you for your interest. Of course. So your Nobel autobiography, you start by calling yourself just a Norwegian from Minnesota. So do you think you can start at the beginning and tell me a little bit about what you were like as a kid and how you grew up? Well, I wasn't the only Norwegian in Minnesota actually. A quarter of the state is Norwegian and almost that much is Swedish and then the other people. So I was the oldest son of six children, named after my grandfather. So there was a little pressure growing up. Mother's a farm girl, never went to college. Dad was a college professor. So there was a little interesting discrepancy and emphasis at home. Dad was all science math and we'd go to his laboratory and learn how pH controls change of indicator dyes. You can do magical things. We'd understand it because it's scientific. And mother was much more into the humanities, reading the Bible and the classics. So I guess we grew up with both influences. Mother's very religious and was very concerned that we would use our talents for the well-being of others less fortunate. So it was a fun background. We lived in Northfield, Minnesota, just down the hill from St. Olaf College. There is a St. Olaf, it's a college, a very high quality school. And so my friends and I were like, remember the Spanky and Alfalfa movies? Well, we were like little Norwegian Spanky and Alfalfas swarming the college, climbing trees, going down the hills in our toboggans. It was a wonderful childhood. Now, did your father's role as a chemistry professor influence you at all to think that you had an early interest in science or where did that come from? Well, he definitely was a strong influence and I always felt totally intimidated by dad and his ability to do logarithms in his head. He was very gifted in some ways, but he was also very obstinate. You might have heard the term stubborn Norwegian, often wrong but never in doubt. Dad was like that. But there were some fascinating experiences we had. So we did, when I was nine years old, dad did a sabbatical at UC Berkeley. So we moved the whole family from Northfield to Berkeley. It was like Norwegian Beverly Hillbillies leaving Lake Wobegon for Sodom and Gomorrah. And we got to know these very well-known chemists that were on the West Coast, including dad's friend Linus Pauling. So that was an unforgettable experience to have Linus Pauling stay at our house. So I was just a kid. We knew he was in the news. This is when he was leading the protests against the hydrogen bomb testing. And so it was a pretty colorful experience. Now, I bet most might not know that you actually finished high school in night school while you were also studying Russian during the day, but driving the trucks for the evening shift for a company that was making dummy landmines and military equipment. Thank you for reminding me of all these scars in my background. All of that actually was true. I would write this off as youthful rebellion, questioning authority. When I was 17, I spent a summer traveling through Russia. And when I returned, it was with my high school German teacher and some of his university friends. And they were, of course, all of 24 or 25 years old. And so it was an extremely enlightening experience. And I stopped listening to some of the directions at home with the thought that there are bigger things there. But working in a factory, making more materials and going to night school was not a lot of fun. And in the end, I faced the reality that this is not going to lead to some glorious Raskolnikov revolutionary experience. And I enrolled in Augsburg College where Dad taught, which is a very good school. It's a working-class school. Most students have part-time jobs. Most are first-generation students and got a good background in science with the idea of going to medical school. And that seemed like a good dream. Dad had many students who went into the sciences, became industrial or university PhD scientists. And many others went into medicine. The Mayo Clinic had plenty of their doctors that came from Dad's classes at St. Olaf. And I remember distinctly applying for medical school, kind of being out of my league because, sorry. Augsburg was a small school with not a large number of pre-med students, but they all got into med school at the University of Minnesota. And so I applied, which is a very fine school. I did summer research there. But the interview stage was a lot less pleasant than this interview. The dean for admissions was a very nice man, but he had some very specific questions. And I felt in the interview that I answered all of his questions because I really did want to be a medical doctor. And then he said, do you have any questions for me? And I didn't come prepared with some questions. But I thought for a moment and I recalled that one of the requirements, and I think it may still be a requirement to attend the University of Minnesota, is to take the Minnesota Multiphasic Personality Inventory, which is the gold standard of psychological profiles. Three hours of questions, hundreds of questions, very personal questions, and restated differently later on. So I thought for a moment, I thought, gee, Dr. Sullivan, what did you learn about me from the MMPI? He looked into my file. He glared at me and said, these results indicate that you lie more than average. He looked down with a little smile. He says, but you lie less than the average medical student. So I don't know what that means. Maybe there's a representation issue there. Everything I'm telling you is the truth. Trust me. All right. Well, I'll take that under advisement. Now, you mentioned your trip with your high school German teacher, but you also finished Augsburg College a little bit early after you knew that you were going to have a spot at Hopkins Medical School and took another rather transformative trip around the world. Can you tell me a little bit about that? Well, it was kind of a lark, but not totally light-hearted. Staying at home, having part-time jobs in college, I could save a little cash, and I was accepted after the fall term for medical school. I'd really been interested in Southeast Asia, East Asia, South Asia, the Middle East, so I bought a one-way air ticket from Los Angeles to Madras, India. Actually, I got a standby to Honolulu, a one-way ticket, which costs like $450. At that time, you could get unlimited stops if you didn't exceed a certain number of miles. So I went to Japan, hitchhiked all around Japan for a month and a half, and Taiwan, and Hong Kong, and then traveled around Southeast Asia, rented a motorcycle up in the hills in Thailand, explored Cambodia, and made an unexpected bivouac to Vietnam with the Parrots Peak Invasion in May of 1970. Anyway, I made my way to India. I spent most of my time in India just sleeping on the train station platforms, and there were a lot of hippies back then. I guess I was a Norwegian equivalent. Eventually crossed Afghanistan, Iran, Turkey, Europe, and got back in time to start medical school. Wow. But I think I learned a lot in that trip, and my pre-med focus was sort of dead. It seemed like gutting it out for the next exam was no longer the highest priority. There's so many interesting things to do. So that reinforced my interest in third-world diseases and caused me to work in the laboratory. Now, I joined this wonderful laboratory, which is very exciting. We were able to make progress on this. But I have to say, if you work on diarrheal diseases, don't expect it to enhance your social life. I remember going to a mixer at Goucher College, which now is COED, but back then it was all women, a very good school, meeting an attractive young lady who seemed interested in me. We were talking, and she finally asked me that question, what kind of medical specialty are you interested in? I should have said neurosurgery or radiology, but I'm from Minnesota. I told her the truth. I said I'm interested in diarrheal disease, and that was the end of that relationship. Not really a keeper then? Well, I subsequently met my future wife, who grew up on a farm and worked in a laboratory at Johns Hopkins, who was not squeamish. Oh, she set some limits. If you're going to work on diarrheal diseases, don't bring your work home at night. Ah, that's a witty retort. Excellent. So you mentioned getting your first taste of research with Pedro Quattro Casas, but then you did move on to finish your full clinical training and in terms of an internship and then a clinical fellowship in hematology oncology. So did you ever consider running your life as an MD, a pure MD, just doing clinical work? I always had some trepidation that did I have the intellectual capacity and the drive, the organizational skills, to survive as a basic scientist. I was interested in clinical medicine. I didn't do this just for security sake, but the residency I did at Case Western Reserve where Charles Carpenter, a very revered Johns Hopkins professor, part of the cholera team had gone to become chairman of medicine. And so I got the clinical training with the idea that I would have probably more opportunities as a faculty member in a clinical department, since there were more faculty in those departments. And I really deeply cared for the patients. I used to stop and see patients on my way home from the hospital on my bicycle in Cleveland. It was not insincere, but I always felt that the diseases and the problems the patients had were pretty serious and there were probably better doctors than Peter Augry. So I kept that alive with the idea I would do mostly basic science and support myself with grants. And so when I joined the faculty at Johns Hopkins, it was a 75% research, 25% clinical. When the children were born, we made a family decision. Mary would stay home with the kids because the research was all consuming. And so we were living on my salary, which was a pretty modest salary, I can tell you. Dr. McKusick, the chairman of medicine, was astonished how low my salary was and gave me a raise. But to supplement this, in fact, I would work as a ringside physician at the professional boxing matches. And this was not Atlantic City or Las Vegas. These are the smokers. If you've ever seen the Rocky movies, the beginning, that was sort of like the Steelworkers Hall. And I was very interested in athletics, cross-country ski racing, bicycle racing, soccer. I'd never witnessed boxing. I had no idea how powerful these young fighters were. And they're from the inner city. Those who are not tall can't play basketball. Those that are not really big can't play football. But they could box. So these fights were pretty interesting. I got to know the fighters. The first time I went to one, there was a very impressive young light heavyweight named Reggie Gross. And he was a prospect. And he brought in a really promising young light heavyweight from Richmond named Bluford Spence. And these guys were boxing, hitting each other unbelievably hard. And I was supposed to provide medical care. And in a flash, so fast I didn't see it, Spence gets knocked through the ropes. He's on his back, fixed gaze, straight up. He's not breathing. So I hustle over there. I think, oh my god, he's dead. I didn't know what to do. And this was before cell phones were prevalent. This was maybe 1990. And I called the officials to get an ambulance. And at that point, Spence blinked, took a breath, and realized he was unconscious, but with his eyes open, would probably be able to recover. And after a few minutes, he sat up. And we walked him back to the locker room. And the fans were screaming, doc, are you going to let him continue? He said, no, this fight is over. So let's talk a little bit more about your lab and establishing it and its focus. So you did your training in hematology oncology. But around this time, and given the impact of some of your good medical school friends and who you worked with, Van Bennett, you started focusing in a little bit more on hematology-based problems. Well, Van, who's my closest friend, was my roommate in medical school. In part, we both had great interest in the physical life. And we used to go on bicycle rides in the countryside and have all these adventures. And he's a JCI editor, amazingly capable, insightful, creative scientist. But inside, that person is a raving maniac. Van and I used to do these really crazy things. We used to bike through the ghetto at night and on our way back home and all. Anyway, Van is also fearless as a scientist. He would ask the hardest questions. He would purify proteins which had never before been isolated. He would make specific physical chemical binding kinetics. So when you have a friend like that and you work at his lab, I work as his postdoc, actually, even though we were contemporaries. I did the clinical training and then joined him as a postdoc. He encouraged to be very basic in your work, but think of clinical issues, because Van is an MD-PhD. And he was working on red cells as a source of the protein ankerin, which is a major breakthrough. How does the cell skeleton bind to the cell membrane through ankerin? This is an amazingly important discovery. And so I as a hematologist thought, well, why don't we look, and Van suggested this, why don't we look at some of the inherited defects of cell shape, like spherocytosis and elliptocytosis. So that's how the research started. And I was a hematologist at UNC Chapel Hill and Van was at the Welcome Labs. And our pediatric hematology clinic had a wealth of patients from the countryside. A wonderful physician, he's now passed on, Campbell McMillan, bringing these families from little villages like Bug Hill, North Carolina. As one of the older residents told me, it's a swamp, more bugs than hill. Because of consanguinity, there was enough inter-family marriage that recessive diseases appeared. So we discovered that the molecular basis of spherocytosis, a structural protein named spectrin, was deficient. So that's what got me into that. It was actually Wendell Ross at Duke, a friend and chair of hematology, suggested we turn our attention to the rhesus blood group antigen, well-known clinically but never defined biochemically. So just one thing led to another. And through your studies of trying to figure out the molecular identity of the Rh factor, you stumbled onto this second protein, this 28 kilodalton protein, that would change the course of your career. Well, you know, it's interesting. I think oftentimes when I would give lectures, there seemed to be a lot of skepticism on the faces of the senior faculty. And I always wondered if they're trying to decide whether I was some idiot savant or just a garden variety idiot. Because everybody knew Rh was impossible. But we isolated a protein, 30 kilodaltons, by brute biochemical force. Liters of blood cells and huge columns. It was denatured and we got it, but it had a slight shadow that preceded it, which we assumed to be a breakdown product of 28 kilodaltons. And we raised antibodies, and the antibodies only reacted with the breakdown product. So it was like curses. We have an antibody to a protein which turns out to have an internal sequence unrelated to the Rh sequence that we established. It was a contaminant. So a wiser scientist, a more focused scientist, a better behaved scientist would have dropped it. But coming from where we came, that's the curiosity that drives science. And so I often am asked by journalists, do you identify with Albert Einstein? And I say, no, I guess I identify more with Huckleberry Finn. What's around the next bend is more curious. And by sheer luck, in conversations with really wonderful scientists like John Parker at UNC, we put it together. The 28K is the water channel. So that's the first, it's the archetypal water channel. These things are expressed in all life forms. Now, this protein was known as CHIP-28 until you came to the ASCI meeting where together we're speaking, you know, here in 2014. Is it true that it was at lunch before your student Greg Preston was about to give a plenary lecture talking about it, that the name aquaporin was born? Lucia, all that's exactly right. We should have conversations more often. You remind me of my life. It was exactly that way. Now, we first identified this protein of 28 kilograms, which we creatively named 28K. And then we realized it was tetrameric membrane spanning, possibly a channel. And there was a sequence homology with a protein known as major intrinsic protein, MIP. So we thought ours could be channel-like integral for CHIP, sort of a Beatrix Potter in flopsy mopsy. So we call it CHIP-28, which is sort of a description channel-like protein of 28 kilograms. But the name of a functional relevance is oftentimes very helpful. Spectrin, for example, the protein in red cells, when you lysed cells, wash away the hemoglobin, they have a ghost-like appearance of specter, spectrin. The anchoring protein, anchorin. So from the Greek or the Latin, these names oftentimes are useful. And we didn't have a very good name, CHIP-28. And it was at a lunch before Greg gave the first public disclosure at the ASCI in Baltimore in April 1992 that we're talking about this. And there were a number of people at the table. Mark Zeidel from Harvard was there, Mark Knepper from the NIH, a number of our lab team, and thinking maybe hydro or aqua or foreign, or someone thought maybe aquaforin. Someone said aquaporin, and everybody goes, that's it. Has it been frustrating at all that there haven't been any therapeutic uses for the aquaporin so far? Well, I wouldn't use the term frustrating. It is a disappointment. It's not that people aren't trying, but these things are sometimes very difficult. 1949, the year I was born, the first molecular disease was identified with the discovery of sickle hemoglobin by Harvey Itano and Linus Pauling. And they really nailed it. Heterozygotes of normal hemoglobin A and hemoglobin S. And they made a number of bold predictions. Well, anyway, so 65 years later, what good therapies has this led to? There are therapies, but they're probably not what we're really proud of, not things that really are transformational for the patients. I think there are things that we understand now. Landon King, in his work in our Presumably, this is one of the maturing features when corticosteroids are used to treat incipient labor of premature infants. So they use the steroids, but now we understand better why they work. But it has not led to marvelous new drugs. There's potential. Brain edema, maybe glaucoma. The work of Vonda Lennon, really important work. An Australian lady working at the Mayo Clinic led to the discovery of antibodies, circulating antibodies, having epitopin aquaporin 4 in patients with neuromyelitis optica, an optic tract spinal cord form of MS. We can now diagnose it with great precision. Before, it was very uncertain. So there's progress being made. And maybe there'll be some drugs. But, you know, when you graduate from college, oftentimes you pack up and you go on to new things. And science is always about the new adventure. In 2003, you were happily recognized by sharing the Nobel Prize in chemistry for your work on aquaporins. Your father had always talked about winning a Nobel Prize was like the holy grail. Was that what it was like for you? Well, I guess I became aware of the Nobel early on as a child because dad did mention this. And he invited Ernest Pauling to stay with us. And we followed it every year. He died in 95. So he was no longer alive. And I think some of my mother's skepticism about don't let it go to your head was because it would drive dad crazy. And he'd drive everybody else crazy. And let's keep it in perspective. But it was a really pleasant event. And there were quite a few clues that this might be happening, but no perfectly reliable predictors. And frankly, there's so much good science out there that the runners-up sometimes in subsequent years will get prizes and sometimes they don't. And so I try not to take it that seriously. Well, I did see a talk you gave once where you were talking about some of the hoopla that surrounded winning the prize. And you showed a slide that was the marquee of a liquor store that said, congrats, Dr. Agrae. And you stopped and took a picture of it. So surely there was a lot of hoopla, but you faced it with some humor. I saw that. Somebody else took a picture. It was Dr. William Zinkham from Johns Hopkins who took that and sent it to me. I didn't show it today because I was trying to be a little more serious in my talk. Obviously, I failed because people were laughing. But yeah, the implication that I'm Wells liquor store, a discount liquor store, the implication that I'm their best customer is a blatant exaggeration. All right. Well, we might have to disagree about that based on what I've heard. But listen, you mentioned Linus Pauling. Now he won a second Nobel prize for his work in talking about the nuclear arms race. What are you going to do or what are you aiming to do? What have you done now that you have this platform? Well, I'd always been interested in the public side of science, human rights, and global health, my initial objective. And the problem with being interested in human rights and public issues and sciences, who's going to pay the rent? And so there was an opportunity. I took one term as vice chancellor at Duke where I had a free reign in terms of activities. I was there to bolster the Duke scientific presence. I got to be good friends with Bob Lefkowitz. It was a wonderful experience. But I ran for the presidency of the American Association for the Advancement of Science, and I was elected. I had a term as president. And so it's probably in part because of the credibility you get with a Nobel. The interest was there before, but there's no plan to be Linus Pauling Jr. No one could do that. He was an amazing individual. When you took the malaria post at Hopkins, you were at a bit of a crossroads and you thought quite seriously about running for the U.S. Senate seat in Minnesota that subsequently was occupied by Al Franken. Yeah, it is occupied and he didn't run for reelection. My motivation was not a need for public adoration or attention. I grew up in Minnesota. Four generations of my family have lived in Minnesota. They're my ancestors from 1860 forward. They're all buried in Minnesota. So I feel strongly attached to Minnesota in 2008. The presidential election coincided with the Senate B seat in Minnesota. Paul Wellstone had been the senator for two terms. He was killed in a plane crash in 2002. He was much adored. He was quite a liberal figure. And his death in a plane crash led to the election of Norman Coleman, a democratic progressive mayor of St. Paul who had a complete change of character, became a right wing. The only candidate that stepped forward was Al Franken, who was actually a New Yorker. I've met Al Franken. He's a charming individual. He did as a child live in for some years. His father had a business there. The polls indicated that Franken could not win. In fact, the polls indicated neither of the candidates could win. They both maxed out at about 40 percent approval. And so it was the fear that Coleman would be reelected that caused me to step forward. And I talked to the DFL and they were interested, but they wanted a lot of promises. Running for public office is very difficult and it's to be encouraged, but I don't think starting at the Senate is very practical. In the end, I got a lot of good people to offer help, suggestions, but you're on your own. And we ran a political poll. Actually, it's very interesting. Paul Maslin, an associate who was Bill Richardson's pollster, Walter Mondale had used them. They ran some polls in Minnesota. What it showed is that Peter Augre could beat Norman Coleman in a one-to-one election. Probably any credible Democrat could win that election, except Al Franken. But Franken is a hard worker. He raised a lot of money and it was a very ugly campaign. And in the end, the third party candidate carried 18 percent of the vote. It was a retired bus driver named Dean Barkley. And Franken and Coleman tied. And after six months of court, Franken was announced the winner. And that was a very important court case, decided by 300 votes in the end, because Al Franken was the 60th vote for the Affordable Health Care Act. If it had gone out the other way, there'd be no Affordable Health Care Act. Now, I think the Affordable Health Care Act is a step in the right direction. Others may disagree. So what are your thoughts on current treatments for malaria? And what are you looking to accomplish at the Hopkins Malaria Research Institute? Well, the second question first, the Hopkins Malaria Institute has a broad approach. We're not just drug development or vaccine development or epidemiology. We have people doing multiple activities. And this is made possible by a fantastic, wonderful gift from the mayor of New York. Initially, it was made anonymously, but we were given permission to reveal the source. And at the School of Public Health, there were only two scientists studying malaria. Now, there are 20 with cell biological approaches, structural biology approaches, vaccine development, drug development, and very interesting mosquito research, looking for ways to disarm the Anopheles. Anopheles mosquitoes are the most dangerous animals in the world. So all this was made possible because of the gift. And of course, it allowed us to leverage a larger amount of money from the NIH and other foundations. So you mentioned that you spend about a third of the year in Zim and Zam, right? Zim and Zam, Zimbabwe and Zambia. And we're looking to extend the focus. I returned from Democratic Republic of Congo about three weeks ago, where there's an enormous malaria burden. And of course, an unstable political situation. But there in the Congo are good people working hard on malaria. But many of the villages, 90% of the children are infected. 85 million people with that burden of disease. There's no way that even if we had 10 times the resources in Zambia, we could keep it from coming back. So I find it emotionally and intellectually really engaging. And so I guess if I'm focused on anything, it's not the aquaporins, it's defeating malaria. Do you think we'll see that happen in our lifetimes? You're young, maybe. Maybe you'll see it. I don't expect to. But that's okay. This has always been the issue of what comes later in science. And sometimes it's years later. I think right now, with the public's sympathy and the interest of the philanthropists, and of course, Mr. Bloomberg has been enormously helpful to us, the Bill and Melinda Gates Foundation, the Ellison Foundation, there are others that want to play a role. I think we can tighten the thumbscrews, so to speak, on the epidemic. But it has to be achieved everywhere. And working in Cuba, for example, they were able to eliminate malaria by traditional public health measures there. It's an island. Sub-Saharan Africa is enormous. The approaches are not likely to be successful in my lifetime, but we've got to do it. Now you've mentioned Congo, Zim, and Zam, and Cuba. You must have quite the passport. Well, actually, someone at the Smithsonian apparently stole my passport. The last one, it was one of these thick ones with all kinds of visas. So I have a new one that's filling up fast. What is one of your favorite adventures? North Korea? Cuba? Well, they're interesting places to go. I think going to North Korea is often a little grim. It's cold. They don't heat the buildings. It's interesting, of course. Cuba, that's fascinating. You've met Fidel Castro. Not only that, I've danced to the Buena Vista Social Club. It's interesting. I guess there are multiple places that I enjoy. I like the places I visit, Lebanon, Tunisia. Congo was fascinating. So there's no one place I would prefer over all the others. I like going back to Norway, where our family is from. The people I've met have been really, really, very interesting. Castro may be the most interesting. If you had to do it all over again, and you couldn't be a medical doctor or a scientist, what other profession do you think might have intrigued you? I think if I'd been born in another family, I would have been attracted to international journalism because of the fascination with other countries and travel. I'm not sure I would have been successful because I don't know if I'm aggressive in the effective way, but that was interesting. Of course, you ask people what do they read for fun. It often tells you a lot about them. I read history, biographies. I read science, but more history and biographies. Well, listen, it has been an absolute pleasure hearing a little bit more about your life and your views and things. So thank you so much for taking this time to chat with me. Thank you so much for your interest. My cheeks hurt from laughing. That's fantastic. Yeah, you know, it's funny. Who are your role models? I told somebody once I'd like to be remembered as the Victor Borge of science.