TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION, VOL. 125, 2014
GORDON WILSON LECTURE OPENING DOORS WORLDWIDE THROUGH MEDICAL SCIENCE PERSONAL REFLECTIONS PETER AGRE, MD BALTIMORE, MD
BACKGROUND The membership of the American Clinical and Climatological Association includes the leaders of American academic medical centers. Most have strong research programs that include international collaborations and multinational personnel. Indeed the medical sciences may be one of the most international of all human endeavors. But are the international efforts simply opportunistic, or is there potential for bringing nations closer? The year 2003 was difficult for the United States as viewed from abroad. A poll released by the Los Angeles– based Zogby firm confirmed this. When citizens of five Islamic nations were questioned about their general impressions of the United States, the great majority responded negatively with only 4% to 20% registering approval. Surprisingly, when the same individuals were questioned about US science and technology, up to 90% responded favorably. It is my firm belief that our international science contacts provide a unique opportunity to bring even adversarial nations together. MINNESOTA ORIGINS (1) My childhood experiences made me aware that the world is much larger than my home state of Minnesota. My father, Courtland Agre, was Chairman of Chemistry at St. Olaf College and Augsburg College, Correspondence and reprint requests: Peter Agre, MD, Dept of Molecular Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Room E5143, Baltimore, MD 21205; E-mail: [email protected]. Potential Conflicts of Interest: Funding for the laboratory studies was from multiple grants from the National Heart, Lung, and Blood Institute of the NIH. The International Center of Excellence for Malaria Research (ICEMR) in Southern Africa is supported from the National Institute of Allergy and Infectious Diseases of the NIH. Special funding for laboratory and field malaria work is provided by the Michael Bloomberg Family Foundation. Funding for the science diplomacy trips was provided by the Richard Lounsbery Foundation.
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and through him, my sibs and I came to meet prominent scientists from around the world. One unforgettable guest at our home was Linus Pauling, a unique 20th century scientist who achieved international recognition as a physical and biological chemist (1954 Nobel Prize in Chemistry) and as a peace activist for his role in the worldwide ban of nuclear testing in the atmosphere (1963 Nobel Peace Prize). Medical missionaries from our Norwegian Lutheran community were also an inspiration. These physicians, nurses, and surgeons worked for decades in the developing world where they founded hospitals and clinics that were often the only source of medical care for some of the poorest persons on earth. Among these medical missionaries were family members, friends, and even prominent Minnesotans. Our governor’s sister worked as a nurse for decades in rural Cameroon. Our Congressman was a physician who provided medical care in rural prerevolutionary China. RESEARCH AND CLINICAL TRAINING Seeking a career in international health, I applied to medical school at Johns Hopkins, an institution well established as the leader in tropical infectious diseases and health problems of the developing world. Investigators at the Johns Hopkins School of Medicine and School of Public Health were pursuing several fascinating research programs. Cholera is a horrible diarrheal disease that in the 1970s was sweeping through Asia where it killed tens of thousands of infants and small children. I came to greatly admire William B. Greenough and the other Johns Hopkins cholera researchers for their heroic work in rural Bangladesh where the oral rehydration therapy they pioneered was saving countless lives. The toxin released by Vibrio cholera had been isolated, but the cause of traveler’s diarrhea caused by some strains of E. coli remained unknown. I was very fortunate as a student to work in the lab of R. Bradley Sack where clinical isolates were cultured and crude toxigenic extracts were prepared and studied in vivo by injection into isolated loops of small intestine in rabbits. The ambitious goal of isolating and purifying the toxin molecule was undertaken in the lab of Pedro Cuatrecasas, a refugee from the Dictatorship of Francisco Franco in Spain. Pedro was already widely known for being the first to use affinity chromatography in biological research and had attracted a colorful group of young scientists from around the world — a Polish snake collector, a Parisian psychiatrist, a big wave surfer from Hawaii, a Rhodes Scholar from Winnipeg, an Indian chemist
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from Switzerland, a Spanish anarchist, and a suavely handsome Italian film actor/downhill ski racing champion who solved the most important biological problem any Italian male could fathom: the molecular basis of femininity by isolation of the estrogen receptor using affinity chromatography. Also joining the lab was a Palestinian from Lebanon who hated Israelis and the son of an orthodox rabbi from Brooklyn, NY, with pro-Zionist sympathies. I found it fascinating that by working together these two became the best of friends, having amended their world political views because of the humanity they experienced. With the strong support of Vann Bennett, my exceedingly talented medical school roommate, the isolation of the E. coli toxin was achieved with ganglioside-affinity columns. This led me to develop a potential diagnostic technique that I had hoped to test in rural Bangladesh. I remained an extra year at Hopkins as a postdoctoral fellow but was unable to perfect the assay in time for fieldwork. At that time I also fell in love with Mary Macgill, a biologist working in the Hopkins neurovirology lab. We were married in spring 1975 and soon thereafter packed up for 3 years of medical residency. Charles C.J. Carpenter Jr. had accepted the Chairmanship of Medicine at Case Western Reserve University Hospital in Cleveland, where he transformed the program into a leading infectious disease center. His expectation of impeccable clinical care with strong research focus gave me confidence to aim high professionally. A renowned cholera researcher and natural-born leader, Carpenter was a towering figure whom we referred to as “the tall man” (Figure 1). It was obvious to me that training in Carpenter’s department would allow me to transition back to the clinic in preparation for a career in international health. The opportunity of spending 1 year in clinical hematology and oncology at the University of North Carolina at Chapel Hill allowed me 2 subsequent years of research with Pedro and Vann who had moved to the Wellcome Laboratories in Research Triangle Park. Working with human red blood cells, Vann had purified and characterized ankyrin, the protein that binds the membrane skeleton to the anion transporter imbedded in the lipid bilayer. This breakthrough explained the important linkage between the protein scaffold and the surface of cells. JOHNS HOPKINS FACULTY Vann returned to Johns Hopkins in 1980, and I rejoined his research team the following year after receiving an early career K Award from the NIH. Mary and I scraped together our meager financial resources, and with our two little daughters, we relocated to Baltimore where we
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FIG. 1. Charles C.J. Carpenter Jr. (front center) and the 1975 class of medical house officers at Case Western Reserve University Hospitals of Cleveland. Photographed behind Carpenter’s right shoulder, I was standing on the second step.
have resided ever since. Together with Vann I began a series of studies of hemolytic disorders of red cell shape such as spherocytosis. This brought a faculty position in the Hematology Division, led by Jerry Spivak, in the Johns Hopkins Department of Medicine, chaired by Victor McKusick. Using human red cells, we purified and characterized the 32-kDa membrane protein that comprised the molecular Rhesus blood group antigen, a project suggested to me by Wendell Rosse, Director of Hematology at Duke. Our next objective was to analyze red blood cells in malaria, but those studies were postponed because of the serendipitous discovery of the first aquaporin water channel. AQUAPORIN WATER CHANNELS It was at first a disappointment that the 28-kDa membrane protein that copurified with Rh was a contaminant totally unrelated to Rh. The novel 28-kDa protein was abundant in red cell membranes and renal proximal tubules. When the cDNA was cloned, a homology with genetically related membrane proteins from diverse life forms became apparent. The thoughtful suggestion of John Parker at UNC Chapel Hill caused us to investigate a potential role in membrane water transport — a process that had perplexed physiologists and biophysicists for more than a century. This casual conversation led to the discovery of the aquaporin water channels and eventually a Nobel Prize.
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AQP1 Postdoctoral fellow Gregory Preston working with our Hopkins colleague William Guggino confirmed the hypothesis by expressing the protein in frog oocytes. After transferring the oocytes to distilled water, they measured the increased osmotic water permeability by video microscopy, a dramatic event that resembled the popping of popcorn. Subsequent biophysical demonstration of osmotic water permeability of purified AQP1 reconstituted into proteoliposomes was achieved in collaboration with my assistant Barb Smith, Suresh Ambudkar, an Indian national at Hopkins, and Mark Zeidel at Harvard. Our early studies in the autumn of 1991 catalyzed intense scientific interest and led us to collaborate with an international cast of scientists. The atomic structure of AQP1 was solved by membrane electron microscopy with our colleagues Andreas Engel and his student Tomas Walz at the Biozentrum at the University of Basel, Switzerland, in collaboration with Yoshinori Fujiyoshi at Kyoto University in Japan. These studies defined the unique aqueous pathway, termed “the hourglass.” Additional studies led by American scientists originally from Indonesia, United Kingdom, Germany, and Iran who elucidated the structures by X-ray crystallography and defined the water transport function through molecular dynamics simulations of AQP1 and multiple other aquaporin homologs. Studies that pinpointed the sites of AQP1 expression in renal proximal tubules and descending thin limb of the loop of Henle were achieved in collaboration with Søren Nielsen and his team at University of Aarhus in Denmark and Mark Knepper at NIH with anti-AQP1 by light microscopy and immunogold electron microscopy. Expression of AQP1 was subsequently shown in choroid plexus in the brain, non-pigmented epithelium in the eye, and the hepatobiliary epithelium. A conversation with Colvin Redman, a Dominican scientist working at the New York Blood Center, led to collaboration with David Anstee at the International Blood Group Referencing Laboratory in Bristol, United Kingdom. Humans lacking Colton blood group antigens were discovered to have knock-out mutations in the gene encoding AQP1. Landon King at Hopkins determined the clinical phenotype of AQP1-null humans when he defined constitutive defects in renal concentration and defects in water permeation of pulmonary capillary vasculature. Aquaporin water channels have been now identified in all life forms — vertebrates, invertebrates, plants, microorganisms, and even Archaea. These aquaporins are now being investigated by numerous laboratories worldwide. The human repertoire includes 13 homologs permeated by
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water (aquaporins) or permeated by water and glycerol (aquaglyceroporins). Each features the efforts of international scientists. AQP0 Work by a Chilean scientist working at UCLA established that the lens fiber cells are tightly linked by major intrinsic protein (MIP) now known as AQP0. Mutations in the gene were found by our colleague Shomi Bhatacharya, a Bengali working in London, to result in congenital cataracts in small children. AQP2 The cDNA encoding AQP2 was first cloned by workers in Tokyo. Expressed in renal collecting duct principal cells, AQP2 is regulated by vasopressin resulting exocytosis to the apical membrane. Humans with mutations were shown to suffer severe nephogenic diabetes insipidus by investigators in Nijmegen, the Netherlands. Workers in multiple labs have identified AQP2 overexpression in most forms of fluid retention and AQP2 underexpression in most forms of polyuria, including bedwetting by small children. AQP4 The cDNA encoding AQP4 was cloned by Jin Sup Jung, a Fogarty scholar from Korea working in our laboratory, and by workers at UCSF. The AQP4 protein was localized in brain to the perivascular astroglial endfeet by our colleagues Ole Petter Ottersen and Mahmoud Amiry-Moghaddam, an Iranian, at University of Oslo. Workers in Norway, Denmark, Italy, and the United States showed that defects in AQP4 expression confer resistance to injury-induced brain edema. Vanda Lennon, an Australian working at Mayo, discovered that circulating autoantibodies to AQP4 are implicated in neuromyelitis optica, an important disorder with episodic blindness and paralysis. AQP5 Surabhi Raina, a postdoctoral fellow in our lab from India, isolated the AQP5 cDNA from salivary glands. She also found the protein in apical membranes of lacrimal glands, sweat glands, and mucosal glands in lung. Lene Nejsum from Denmark showed that AQP5-null mice have reduced sweat release after stimulation. Our colleagues
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Kazuo Tsubota in Tokyo and Chris Delporte in Brussels identified mistaken AQP5 trafficking in biopsy specimens of lacrimal glands and salivary glands from some patients with Sjogren’s syndrome. This is not a universal finding because investigators in Bergen, Norway, found that other patients had normal AQP5 distribution but had reduced AQP1 in the surrounding myoepithelial cells. AQP6 Masato Yasui, a postdoctoral fellow from Tokyo, discovered a new aquaporin from alpha-intercalated cells of the renal collecting duct. Unlike other aquaporins, AQP6 exhibits anion permeation when stimulated by low pH. A role in renal excretion of acid is anticipated; however, a disease phenotype has not yet been identified. AQUAGLYCEROPORINS AQP3 Permeated by water plus glycerol, aquaglyceroporin AQP3 was localized to the basal level of skin by Johan Ågren, a sabbatical worker in our lab from Uppsala, Sweden. The beauty industry now markets skin care products alleged to maintain dermal hydration in sun exposed skin. AQP3 is also present in human red cells, but Yangjian Liu, a Chinese student in our lab, discovered that it was replaced by AQP9 in mouse red cells. AQP7 AND AQP9 The aquaglyceroporin AQP7 was identified in adipose cells by workers in Osaka. AQP9 was identified in liver by a Swiss investigator working in Boston. Together they provide for glycerol release from fat during fasting and glycerol uptake by liver for reconversion into glucose. Jen Carbrey from our team working in collaboration with Barry Rosen discovered that aquaglyceroporins were permeated by arsenite, and AQP9-null mice suffered premature death due to inability to excrete arsenic in feces. PLANTS AND MICRO-ORGANISMS The presence of aquaporins in plant rootlets, intracellular tonoplasts, and leaflets have been investigated by scientists from Belgium, France, and Germany. Novel pH-regulated gating has been proposed by scientists in Sweden. Yeast homologs have been identified in our lab by Jen Carbrey and Melanie Bonhiver, a postdoctoral fellow from
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Bordeaux, France, and Stefan Hohmann working in Gothenburg, Sweden. Bacterial aquaporin AqpZ was discovered in our lab by Giuseppe Calamita from Bari, Italy. AqpM from Archaea was discovered in our lab by David Kozono. MALARIA Our former postdoctoral fellow Eric Beitz, now in Kiel, Germany, identified PfAQP from Plasmodium falciparum. The protein is required for full virulence of malaria. Dominique Promeneur, a FrenchCaribbean member of our lab, showed that PfAQP is needed for synthesis of glycerolipids by parasites during the erythroid stages of malaria. Connie Liu, a Chinese member of our lab, identified multiple aquaporins in the malaria mosquito, Anopheles gambiae. Mosquito aquaporins are required for survival during acclimation to higher temperatures and reduced humidity. Use of this information for the control of malaria is being sought because approximately one half million small children will die from malaria each year in Sub-Saharan Africa. Most of these youngsters are from subsistence farm families struggling to support themselves in remote rural settings. This work has caused me to refocus my career entirely on the malaria problem, and my current position is Director of the Johns Hopkins Malaria Research Institute at the Bloomberg School of Public Health. One of the largest joys of this position is the time I spend in Africa each year where our major efforts are in Zambia and Zimbabwe. As Program Director for the International Center of Excellence for Malaria Research in Southern Africa, I participate in efforts at our research station at Macha, a backcountry village in southern Zambia. The Macha Research Trust is run by Philip Thuma, a Johns Hopkins– trained pediatrician who grew up in Zambia. Due to Phil’s major research and treatment efforts, the prevalence of childhood malaria in the region has declined by 97% over the past decade. Nevertheless, huge challenges remain. Zimbabwe had previously enjoyed successful malaria control; however, during the recent economic collapse and political instability, malaria has become resurgent in eastern Zimbabwe along the border with Mozambique. In northern Zambia along the border with the Democratic Republic of Congo (former Zaire), malaria remains highly endemic despite concerted efforts to bring it under control. Clearly our work as researchers is far from complete, and I expect to spend much of my remaining career working on malaria in Africa.
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AAAS PRESIDENCY From 2009 –2011, I served as President and Chair of the Advisory Board for the American Association for the Advancement of Science. This was the only elected office I ever formally sought, and the experience was gratifying. Of all the activities at AAAS, participation in the Center for Science Diplomacy stands out. Directed by Vaughan Turekian, an environmental scientist, with Special Advisor Norman Neureiter, former Science Advisor to the US Secretary of State, an impressive series of visits were made to nations with stated anti-US postures. Although sometimes debriefed by US government officials, we represented the AAAS as private citizens with no US government agenda. This formula proved productive, and we have visited several countries including Syria, Tunisia, Burma, and Iran. But visits to two other nations revealed very large potential for science to open doors to countries that had long been off limits to US citizens. CUBA Since the Cuban Revolution in 1959, US government policy has prevented our citizens from visiting and spending money in Cuba. Propped up by the Soviet Union, the Castro regime consistently sought the world stage to harangue against the US government and its policies. The collapse of the Soviet Union reduced the Cuban economy to a mere vestige. While aid in the form of discounted oil has been provided by Venezuela, that funding stream may soon end. But fierce determination and authoritarian control have kept the Castro regime in power despite imprisonment of dissenters and major human rights violations. Although apparent thaws in the relationship were anticipated during the Carter and Clinton administrations, pressure from the influential Cuban expatriate community threaten the outcome of US presidential elections due to the pivotal role played by voters in south Florida. The Obama administration cannot reverse the US policy without Senate approval; however, interpretations of the restrictions were liberalized allowing for limited scholarly and cultural visits to Cuba. With US Treasury Department licenses and invitations from the Cuban Academy of Sciences, a series of visits were made to Havana, the first in November 2009. During the four trips in which I participated, we visited the Cuban National Biotechnology Institute, the Carlos Finlay Vaccine Institute, the headquarters of the Cuban Academy of Sciences, and teaching hospitals. I was even honored to serve as Honorary President of Biotechnology Havana 2012. At all of these occasions, I was struck by the sincerity of the Cuban scientists. Despite
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major constraints on equipment and reagent procurement, they remained enthusiastic about science and optimistic that the political obstacles to interactions with their US counterparts will soon end. During these trips I became acquainted with Fidel Castro DiazBalart. Known as “Fidelito,” he is a Cuban physicist and the oldest son of former revolutionary leader and prime minister, El Comandante Fidel Castro Ruz. Fidelito invited me to lecture to the chemistry students at University of Havana, where I received an enthusiastic response, and afterwards approximately 100 students stormed the lecture podium to be photographed with me. Many of them pleaded for an opportunity to come to the United States for advanced scientific training, for while they receive excellent lectures in Cuba, the lab training is limited do to the lack of sufficient modern facilities. What followed was a fascinating event that Fidelito had arranged — an evening with his father, stepmother, and brother Antonio. Along with Alan Robock, an environmental scientist from Rutgers, I spent 3.5 hours listening to El Comandante Fidel Castro reflect at length on numerous topics, including the Bay of Pigs invasion, the Cuban missile crisis, his opinions of US presidents, great books, and even science. Although he seemed very curious about the work that led to my Nobel Prize, I cannot describe it as a conversation, since El Comandante did 99% of the talking, and to be certain, my job was to listen. But when asked if I had any questions, I inquired about the importance of health care to the revolution. El Comandante Fidel Castro explained that he was the illegitimate son of a wealthy Spanish born landowner and the maid, a peasant girl from the countryside. As a child who was raised both in the villa and in the village, Castro was aware of the huge discrepancies in prerevolutionary Cuba. At that time, no one could see a physician without paying in cash, and very few physicians practiced outside of Havana or the other principal cities. Castro insisted that one major reason for the revolution was to provide universal health care in Cuba and to provide Cuban physicians for other poor countries. In addition, he emphasized their focus on disease prevention through public health initiatives and vaccine development. Based on WHO statistics, Cuba has achieved average life expectancies equivalent to the United States. All Cuban babies are born in hospitals, and 100% vaccination compliance is achieved. So, although it is easy to criticize the Cuban government for known abuses, it is clear that in the area of health care they have a unique story. At the end of the evening Castro, an aged revolutionary, and I, an aging scientist, smiled and shook hands having discussed our common interest in global health.
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Overall, it should be made clear that despite the bad feelings between the Cuban government and the US government, the citizens of Cuba and the United States do not feel this way. The festering resentment of the Cuban expatriates from South Florida is directed to the Castro regime which has survived for 55 years. But Fidel at age 88 and Raoul at age 83 are not likely to survive much longer. Numerous people in Cuba spoke glowingly of the United States because a large fraction of them have relatives here. The students I met at the University of Havana bubbled with excitement for the possibilities of science, and none had anything political to say. With major changes soon to occur, it is my hope that firm relations between Cuban and US scientists will bring us closer together. Although I have no insight whatsoever into the significance (if any), my photograph is now permanently displayed on the mural above the bar at Hotel Nacional de Cuba in Havana. DEMOCRATIC PEOPLES REPUBLIC OF KOREA The DPRK (North Korea) is often described as the “Hermit Kingdom” because it exists in nearly total isolation. Despite disappointment over previous years, the inclusion of a Nobel laureate catalyzed invitations from the DPRK State Academy of Sciences (SAOS) for a series of scientific visits to Pyongyang. These were organized by the AAAS in collaboration with CRDF (US Civilian Research and Development Foundation). The trips provided an extremely rare view into life in the last surviving Stalinist state. DPRK only survives because of help from the Peoples Republic of China. Although it is commonly assumed in the United States that DPRK and China are closely aligned allies, this is not likely. Visas for entry into DPRK are only available at their Embassy in Beijing where flights to DPRK are possible. An advance meeting was arranged with the Chinese Foreign Ministry. This provided a cordial discussion where the Chinese view of DPRK was revealed. Indeed, the Chief of Mission freely acknowledged that China considers DPRK unreliable and even potentially dangerous. He implored us to pursue scientific diplomacy with DPRK and admitted that nothing else had worked. Their major interest in supporting DPRK was to prevent self-destruction of the regime, thereby bringing the Republic of Korea and the US military to the Yalu River border with China. Our first visit occurred early in December 2009, and it was very cold. Arriving in Pyongyang on Air Koryo in a vintage Soviet jetliner, we were greeted by dozens of security personnel wearing black fur earflap hats and long black wool military overcoats. Most of the luggage was
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freight, but we eventually received our bags; we were required to leave cell phones and laptops at Immigration. We were then met at the airport by our host, Ryun Gi Hong, a cheerful man who was Director of the International Section of SAOS (Figure 2). As the sun went down, the lack of streetlights made for a very dark trip into Pyongyang. Despite the darkness, ranks of soldiers were present along the roadside. With a standing army of 1.1 million soldiers and 8.1 million reserves, we were to see many platoons marching along the roadside, even stopping together to face away from the roadways as they urinated in unison. The twin 44-story towers of the Koryo Hotel where we stayed were nearly empty. Mr. Hong and four other DPRK personnel also stayed in the hotel and accompanied us the entire week. Although none of the
FIG. 2. With Ryun Gi Hong, Director of the International Section of the State Academy of Sciences of the Democratic Peoples Republic of Korea in Pyongyang, 2009.
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SAOS personnel were identified as intelligence agents, our American team of six were each assigned nonadjacent rooms and on alternate floors. Other than the hotel lobby, none of the buildings seemed to be heated, so I wore my long underwear under my suit each day and under my pajamas at night. Visiting Pyongyang was like visiting the Twilight Zone — the streets were nearly empty and it looked real but seemed artificial. At 5 AM, heroic vocal music was emitted from the central train station, imploring DPRK citizens to work hard for their country. We were strictly forbidden to go anywhere outside our hotel without an escort. Even a special ride on the beautiful Pyongyang metro was surprising. Running 100 meters underground to protect the line from a direct nuclear strike, the other passengers all looked away to avoid eye contact. But upon seeing us, a little boy holding his mother’s hand and pointed his finger at us like a pistol and made gunshot noises — obviously acting out what he had been conditioned to do. But over our week together I felt a bond of friendship form with Mr. Hong. When our requests were made, we were granted permission to visit several SAOS laboratories, the state universities, and the major teaching hospital. The scientific facilities seemed modest, but the scientists themselves seemed delighted to meet us. Nearly all, including the university presidents, confided that they had never previously met Americans. Whereas the DPRK scientists appeared shy during introductions, it became clear that we shared the same goal — to make the world a better place for our children and grandchildren. Pyongyang University of Science and Technology (PUST) is the only private university in DPRK and all instruction is in English. Founded by a Korean born American businessman, Kim Chin Kyung, his generous gift was intended to facilitate reunification of North and South Korea. The highly selected all male student body at PUST marched to class in military formation while singing patriotic songs. The instructors are volunteers, mostly American Evangelical Christians. When I first lectured, I began with a joke, but no one laughed. When I explained that I had just told a joke and it was funny, they all broke into laughter. Apparently DPRK students are not allowed to laugh without permission. On our way to one of our scientific visits south of Pyongyang, I asked our host Mr. Hong about the magnificent formal arch over the highway. He informed me that is known as “reunification gate” and lies on the road to Seoul, just 100 miles away. Mr. Hong was well travelled, but when I asked him if he had ever been to Seoul, he paused, and with sadness in his voice he stated, “No, Peter. That is not possible. So near but still so far.”
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The final morning of our first visit, Mr. Hong and I sat together and chatted at breakfast. He informed me that his 6-year old grandson lived with him. He explained that the little boy became alarmed when he was informed that his grandfather would spend a week in a hotel with Americans and said, “Grandfather, bring the rifle.” Having an unopened carton of granola bars, I gave them to Mr. Hong for the child and thought nothing more of the conversation. One and a half years later, I met again with Mr. Hong and members of the SAOS. We were granted permission by the US Department of State to meet with them at the Carter Center in Atlanta. Seated across from each other at a long table, Mr. Hong began the session reciting a stern rebuke that his government was not impressed with our visit to DPRK because no resources had become available for the proposed collaborations. Sensing a rehearsed protest, I sought to lighten the atmosphere. So my first response was “Mr. Hong, how is your grandson?” This provoked a slight smile, and he answered “Why, he is just fine.” This caused me to follow with, “Did he ask you to bring the rifle?” Now laughing, Mr. Hong replied, “No, he asked me to bring back some candy.” So maybe this is what science diplomacy is all about — two scientists who are also grandfathers come to be friends, and with any luck they may open doors between estranged nations. IN CLOSING Looking back on 40 years in academic medicine, it is clear to me that our discoveries and scholarly activities were important. But perhaps even more important are the people we met along the way. Many of these individuals are from counties around the world and became wonderful lifelong friends. Each of us here today has such a story, and I truly believe that these friends provide an important opportunity we should always keep in mind. Thank you for the privilege of presenting the 2013 Gordon Wilson Lecture. REFERENCES 1. Agre P. Autobiography and Nobel Lecture – Aquaporin Water Channels. In: Le Prix Nobel – The Nobel Prizes 2003, pp 168 –207. Stockholm, Sweden, Almqvist and Wiksell International, 2004, http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2003/ agre-bio.html, http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2003/agrelecture.pdf.
GORDON WILSON LECTURE OPENING DOORS WORLDWIDE THROUGH MEDICAL SCIENCE PERSONAL REFLECTIONS PETER AGRE, MD BALTIMORE, MD
BACKGROUND The membership of the American Clinical and Climatological Association includes the leaders of American academic medical centers. Most have strong research programs that include international collaborations and multinational personnel. Indeed the medical sciences may be one of the most international of all human endeavors. But are the international efforts simply opportunistic, or is there potential for bringing nations closer? The year 2003 was difficult for the United States as viewed from abroad. A poll released by the Los Angeles– based Zogby firm confirmed this. When citizens of five Islamic nations were questioned about their general impressions of the United States, the great majority responded negatively with only 4% to 20% registering approval. Surprisingly, when the same individuals were questioned about US science and technology, up to 90% responded favorably. It is my firm belief that our international science contacts provide a unique opportunity to bring even adversarial nations together. MINNESOTA ORIGINS (1) My childhood experiences made me aware that the world is much larger than my home state of Minnesota. My father, Courtland Agre, was Chairman of Chemistry at St. Olaf College and Augsburg College, Correspondence and reprint requests: Peter Agre, MD, Dept of Molecular Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Room E5143, Baltimore, MD 21205; E-mail: [email protected]. Potential Conflicts of Interest: Funding for the laboratory studies was from multiple grants from the National Heart, Lung, and Blood Institute of the NIH. The International Center of Excellence for Malaria Research (ICEMR) in Southern Africa is supported from the National Institute of Allergy and Infectious Diseases of the NIH. Special funding for laboratory and field malaria work is provided by the Michael Bloomberg Family Foundation. Funding for the science diplomacy trips was provided by the Richard Lounsbery Foundation.
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and through him, my sibs and I came to meet prominent scientists from around the world. One unforgettable guest at our home was Linus Pauling, a unique 20th century scientist who achieved international recognition as a physical and biological chemist (1954 Nobel Prize in Chemistry) and as a peace activist for his role in the worldwide ban of nuclear testing in the atmosphere (1963 Nobel Peace Prize). Medical missionaries from our Norwegian Lutheran community were also an inspiration. These physicians, nurses, and surgeons worked for decades in the developing world where they founded hospitals and clinics that were often the only source of medical care for some of the poorest persons on earth. Among these medical missionaries were family members, friends, and even prominent Minnesotans. Our governor’s sister worked as a nurse for decades in rural Cameroon. Our Congressman was a physician who provided medical care in rural prerevolutionary China. RESEARCH AND CLINICAL TRAINING Seeking a career in international health, I applied to medical school at Johns Hopkins, an institution well established as the leader in tropical infectious diseases and health problems of the developing world. Investigators at the Johns Hopkins School of Medicine and School of Public Health were pursuing several fascinating research programs. Cholera is a horrible diarrheal disease that in the 1970s was sweeping through Asia where it killed tens of thousands of infants and small children. I came to greatly admire William B. Greenough and the other Johns Hopkins cholera researchers for their heroic work in rural Bangladesh where the oral rehydration therapy they pioneered was saving countless lives. The toxin released by Vibrio cholera had been isolated, but the cause of traveler’s diarrhea caused by some strains of E. coli remained unknown. I was very fortunate as a student to work in the lab of R. Bradley Sack where clinical isolates were cultured and crude toxigenic extracts were prepared and studied in vivo by injection into isolated loops of small intestine in rabbits. The ambitious goal of isolating and purifying the toxin molecule was undertaken in the lab of Pedro Cuatrecasas, a refugee from the Dictatorship of Francisco Franco in Spain. Pedro was already widely known for being the first to use affinity chromatography in biological research and had attracted a colorful group of young scientists from around the world — a Polish snake collector, a Parisian psychiatrist, a big wave surfer from Hawaii, a Rhodes Scholar from Winnipeg, an Indian chemist
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from Switzerland, a Spanish anarchist, and a suavely handsome Italian film actor/downhill ski racing champion who solved the most important biological problem any Italian male could fathom: the molecular basis of femininity by isolation of the estrogen receptor using affinity chromatography. Also joining the lab was a Palestinian from Lebanon who hated Israelis and the son of an orthodox rabbi from Brooklyn, NY, with pro-Zionist sympathies. I found it fascinating that by working together these two became the best of friends, having amended their world political views because of the humanity they experienced. With the strong support of Vann Bennett, my exceedingly talented medical school roommate, the isolation of the E. coli toxin was achieved with ganglioside-affinity columns. This led me to develop a potential diagnostic technique that I had hoped to test in rural Bangladesh. I remained an extra year at Hopkins as a postdoctoral fellow but was unable to perfect the assay in time for fieldwork. At that time I also fell in love with Mary Macgill, a biologist working in the Hopkins neurovirology lab. We were married in spring 1975 and soon thereafter packed up for 3 years of medical residency. Charles C.J. Carpenter Jr. had accepted the Chairmanship of Medicine at Case Western Reserve University Hospital in Cleveland, where he transformed the program into a leading infectious disease center. His expectation of impeccable clinical care with strong research focus gave me confidence to aim high professionally. A renowned cholera researcher and natural-born leader, Carpenter was a towering figure whom we referred to as “the tall man” (Figure 1). It was obvious to me that training in Carpenter’s department would allow me to transition back to the clinic in preparation for a career in international health. The opportunity of spending 1 year in clinical hematology and oncology at the University of North Carolina at Chapel Hill allowed me 2 subsequent years of research with Pedro and Vann who had moved to the Wellcome Laboratories in Research Triangle Park. Working with human red blood cells, Vann had purified and characterized ankyrin, the protein that binds the membrane skeleton to the anion transporter imbedded in the lipid bilayer. This breakthrough explained the important linkage between the protein scaffold and the surface of cells. JOHNS HOPKINS FACULTY Vann returned to Johns Hopkins in 1980, and I rejoined his research team the following year after receiving an early career K Award from the NIH. Mary and I scraped together our meager financial resources, and with our two little daughters, we relocated to Baltimore where we
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FIG. 1. Charles C.J. Carpenter Jr. (front center) and the 1975 class of medical house officers at Case Western Reserve University Hospitals of Cleveland. Photographed behind Carpenter’s right shoulder, I was standing on the second step.
have resided ever since. Together with Vann I began a series of studies of hemolytic disorders of red cell shape such as spherocytosis. This brought a faculty position in the Hematology Division, led by Jerry Spivak, in the Johns Hopkins Department of Medicine, chaired by Victor McKusick. Using human red cells, we purified and characterized the 32-kDa membrane protein that comprised the molecular Rhesus blood group antigen, a project suggested to me by Wendell Rosse, Director of Hematology at Duke. Our next objective was to analyze red blood cells in malaria, but those studies were postponed because of the serendipitous discovery of the first aquaporin water channel. AQUAPORIN WATER CHANNELS It was at first a disappointment that the 28-kDa membrane protein that copurified with Rh was a contaminant totally unrelated to Rh. The novel 28-kDa protein was abundant in red cell membranes and renal proximal tubules. When the cDNA was cloned, a homology with genetically related membrane proteins from diverse life forms became apparent. The thoughtful suggestion of John Parker at UNC Chapel Hill caused us to investigate a potential role in membrane water transport — a process that had perplexed physiologists and biophysicists for more than a century. This casual conversation led to the discovery of the aquaporin water channels and eventually a Nobel Prize.
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AQP1 Postdoctoral fellow Gregory Preston working with our Hopkins colleague William Guggino confirmed the hypothesis by expressing the protein in frog oocytes. After transferring the oocytes to distilled water, they measured the increased osmotic water permeability by video microscopy, a dramatic event that resembled the popping of popcorn. Subsequent biophysical demonstration of osmotic water permeability of purified AQP1 reconstituted into proteoliposomes was achieved in collaboration with my assistant Barb Smith, Suresh Ambudkar, an Indian national at Hopkins, and Mark Zeidel at Harvard. Our early studies in the autumn of 1991 catalyzed intense scientific interest and led us to collaborate with an international cast of scientists. The atomic structure of AQP1 was solved by membrane electron microscopy with our colleagues Andreas Engel and his student Tomas Walz at the Biozentrum at the University of Basel, Switzerland, in collaboration with Yoshinori Fujiyoshi at Kyoto University in Japan. These studies defined the unique aqueous pathway, termed “the hourglass.” Additional studies led by American scientists originally from Indonesia, United Kingdom, Germany, and Iran who elucidated the structures by X-ray crystallography and defined the water transport function through molecular dynamics simulations of AQP1 and multiple other aquaporin homologs. Studies that pinpointed the sites of AQP1 expression in renal proximal tubules and descending thin limb of the loop of Henle were achieved in collaboration with Søren Nielsen and his team at University of Aarhus in Denmark and Mark Knepper at NIH with anti-AQP1 by light microscopy and immunogold electron microscopy. Expression of AQP1 was subsequently shown in choroid plexus in the brain, non-pigmented epithelium in the eye, and the hepatobiliary epithelium. A conversation with Colvin Redman, a Dominican scientist working at the New York Blood Center, led to collaboration with David Anstee at the International Blood Group Referencing Laboratory in Bristol, United Kingdom. Humans lacking Colton blood group antigens were discovered to have knock-out mutations in the gene encoding AQP1. Landon King at Hopkins determined the clinical phenotype of AQP1-null humans when he defined constitutive defects in renal concentration and defects in water permeation of pulmonary capillary vasculature. Aquaporin water channels have been now identified in all life forms — vertebrates, invertebrates, plants, microorganisms, and even Archaea. These aquaporins are now being investigated by numerous laboratories worldwide. The human repertoire includes 13 homologs permeated by
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water (aquaporins) or permeated by water and glycerol (aquaglyceroporins). Each features the efforts of international scientists. AQP0 Work by a Chilean scientist working at UCLA established that the lens fiber cells are tightly linked by major intrinsic protein (MIP) now known as AQP0. Mutations in the gene were found by our colleague Shomi Bhatacharya, a Bengali working in London, to result in congenital cataracts in small children. AQP2 The cDNA encoding AQP2 was first cloned by workers in Tokyo. Expressed in renal collecting duct principal cells, AQP2 is regulated by vasopressin resulting exocytosis to the apical membrane. Humans with mutations were shown to suffer severe nephogenic diabetes insipidus by investigators in Nijmegen, the Netherlands. Workers in multiple labs have identified AQP2 overexpression in most forms of fluid retention and AQP2 underexpression in most forms of polyuria, including bedwetting by small children. AQP4 The cDNA encoding AQP4 was cloned by Jin Sup Jung, a Fogarty scholar from Korea working in our laboratory, and by workers at UCSF. The AQP4 protein was localized in brain to the perivascular astroglial endfeet by our colleagues Ole Petter Ottersen and Mahmoud Amiry-Moghaddam, an Iranian, at University of Oslo. Workers in Norway, Denmark, Italy, and the United States showed that defects in AQP4 expression confer resistance to injury-induced brain edema. Vanda Lennon, an Australian working at Mayo, discovered that circulating autoantibodies to AQP4 are implicated in neuromyelitis optica, an important disorder with episodic blindness and paralysis. AQP5 Surabhi Raina, a postdoctoral fellow in our lab from India, isolated the AQP5 cDNA from salivary glands. She also found the protein in apical membranes of lacrimal glands, sweat glands, and mucosal glands in lung. Lene Nejsum from Denmark showed that AQP5-null mice have reduced sweat release after stimulation. Our colleagues
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Kazuo Tsubota in Tokyo and Chris Delporte in Brussels identified mistaken AQP5 trafficking in biopsy specimens of lacrimal glands and salivary glands from some patients with Sjogren’s syndrome. This is not a universal finding because investigators in Bergen, Norway, found that other patients had normal AQP5 distribution but had reduced AQP1 in the surrounding myoepithelial cells. AQP6 Masato Yasui, a postdoctoral fellow from Tokyo, discovered a new aquaporin from alpha-intercalated cells of the renal collecting duct. Unlike other aquaporins, AQP6 exhibits anion permeation when stimulated by low pH. A role in renal excretion of acid is anticipated; however, a disease phenotype has not yet been identified. AQUAGLYCEROPORINS AQP3 Permeated by water plus glycerol, aquaglyceroporin AQP3 was localized to the basal level of skin by Johan Ågren, a sabbatical worker in our lab from Uppsala, Sweden. The beauty industry now markets skin care products alleged to maintain dermal hydration in sun exposed skin. AQP3 is also present in human red cells, but Yangjian Liu, a Chinese student in our lab, discovered that it was replaced by AQP9 in mouse red cells. AQP7 AND AQP9 The aquaglyceroporin AQP7 was identified in adipose cells by workers in Osaka. AQP9 was identified in liver by a Swiss investigator working in Boston. Together they provide for glycerol release from fat during fasting and glycerol uptake by liver for reconversion into glucose. Jen Carbrey from our team working in collaboration with Barry Rosen discovered that aquaglyceroporins were permeated by arsenite, and AQP9-null mice suffered premature death due to inability to excrete arsenic in feces. PLANTS AND MICRO-ORGANISMS The presence of aquaporins in plant rootlets, intracellular tonoplasts, and leaflets have been investigated by scientists from Belgium, France, and Germany. Novel pH-regulated gating has been proposed by scientists in Sweden. Yeast homologs have been identified in our lab by Jen Carbrey and Melanie Bonhiver, a postdoctoral fellow from
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Bordeaux, France, and Stefan Hohmann working in Gothenburg, Sweden. Bacterial aquaporin AqpZ was discovered in our lab by Giuseppe Calamita from Bari, Italy. AqpM from Archaea was discovered in our lab by David Kozono. MALARIA Our former postdoctoral fellow Eric Beitz, now in Kiel, Germany, identified PfAQP from Plasmodium falciparum. The protein is required for full virulence of malaria. Dominique Promeneur, a FrenchCaribbean member of our lab, showed that PfAQP is needed for synthesis of glycerolipids by parasites during the erythroid stages of malaria. Connie Liu, a Chinese member of our lab, identified multiple aquaporins in the malaria mosquito, Anopheles gambiae. Mosquito aquaporins are required for survival during acclimation to higher temperatures and reduced humidity. Use of this information for the control of malaria is being sought because approximately one half million small children will die from malaria each year in Sub-Saharan Africa. Most of these youngsters are from subsistence farm families struggling to support themselves in remote rural settings. This work has caused me to refocus my career entirely on the malaria problem, and my current position is Director of the Johns Hopkins Malaria Research Institute at the Bloomberg School of Public Health. One of the largest joys of this position is the time I spend in Africa each year where our major efforts are in Zambia and Zimbabwe. As Program Director for the International Center of Excellence for Malaria Research in Southern Africa, I participate in efforts at our research station at Macha, a backcountry village in southern Zambia. The Macha Research Trust is run by Philip Thuma, a Johns Hopkins– trained pediatrician who grew up in Zambia. Due to Phil’s major research and treatment efforts, the prevalence of childhood malaria in the region has declined by 97% over the past decade. Nevertheless, huge challenges remain. Zimbabwe had previously enjoyed successful malaria control; however, during the recent economic collapse and political instability, malaria has become resurgent in eastern Zimbabwe along the border with Mozambique. In northern Zambia along the border with the Democratic Republic of Congo (former Zaire), malaria remains highly endemic despite concerted efforts to bring it under control. Clearly our work as researchers is far from complete, and I expect to spend much of my remaining career working on malaria in Africa.
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AAAS PRESIDENCY From 2009 –2011, I served as President and Chair of the Advisory Board for the American Association for the Advancement of Science. This was the only elected office I ever formally sought, and the experience was gratifying. Of all the activities at AAAS, participation in the Center for Science Diplomacy stands out. Directed by Vaughan Turekian, an environmental scientist, with Special Advisor Norman Neureiter, former Science Advisor to the US Secretary of State, an impressive series of visits were made to nations with stated anti-US postures. Although sometimes debriefed by US government officials, we represented the AAAS as private citizens with no US government agenda. This formula proved productive, and we have visited several countries including Syria, Tunisia, Burma, and Iran. But visits to two other nations revealed very large potential for science to open doors to countries that had long been off limits to US citizens. CUBA Since the Cuban Revolution in 1959, US government policy has prevented our citizens from visiting and spending money in Cuba. Propped up by the Soviet Union, the Castro regime consistently sought the world stage to harangue against the US government and its policies. The collapse of the Soviet Union reduced the Cuban economy to a mere vestige. While aid in the form of discounted oil has been provided by Venezuela, that funding stream may soon end. But fierce determination and authoritarian control have kept the Castro regime in power despite imprisonment of dissenters and major human rights violations. Although apparent thaws in the relationship were anticipated during the Carter and Clinton administrations, pressure from the influential Cuban expatriate community threaten the outcome of US presidential elections due to the pivotal role played by voters in south Florida. The Obama administration cannot reverse the US policy without Senate approval; however, interpretations of the restrictions were liberalized allowing for limited scholarly and cultural visits to Cuba. With US Treasury Department licenses and invitations from the Cuban Academy of Sciences, a series of visits were made to Havana, the first in November 2009. During the four trips in which I participated, we visited the Cuban National Biotechnology Institute, the Carlos Finlay Vaccine Institute, the headquarters of the Cuban Academy of Sciences, and teaching hospitals. I was even honored to serve as Honorary President of Biotechnology Havana 2012. At all of these occasions, I was struck by the sincerity of the Cuban scientists. Despite
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major constraints on equipment and reagent procurement, they remained enthusiastic about science and optimistic that the political obstacles to interactions with their US counterparts will soon end. During these trips I became acquainted with Fidel Castro DiazBalart. Known as “Fidelito,” he is a Cuban physicist and the oldest son of former revolutionary leader and prime minister, El Comandante Fidel Castro Ruz. Fidelito invited me to lecture to the chemistry students at University of Havana, where I received an enthusiastic response, and afterwards approximately 100 students stormed the lecture podium to be photographed with me. Many of them pleaded for an opportunity to come to the United States for advanced scientific training, for while they receive excellent lectures in Cuba, the lab training is limited do to the lack of sufficient modern facilities. What followed was a fascinating event that Fidelito had arranged — an evening with his father, stepmother, and brother Antonio. Along with Alan Robock, an environmental scientist from Rutgers, I spent 3.5 hours listening to El Comandante Fidel Castro reflect at length on numerous topics, including the Bay of Pigs invasion, the Cuban missile crisis, his opinions of US presidents, great books, and even science. Although he seemed very curious about the work that led to my Nobel Prize, I cannot describe it as a conversation, since El Comandante did 99% of the talking, and to be certain, my job was to listen. But when asked if I had any questions, I inquired about the importance of health care to the revolution. El Comandante Fidel Castro explained that he was the illegitimate son of a wealthy Spanish born landowner and the maid, a peasant girl from the countryside. As a child who was raised both in the villa and in the village, Castro was aware of the huge discrepancies in prerevolutionary Cuba. At that time, no one could see a physician without paying in cash, and very few physicians practiced outside of Havana or the other principal cities. Castro insisted that one major reason for the revolution was to provide universal health care in Cuba and to provide Cuban physicians for other poor countries. In addition, he emphasized their focus on disease prevention through public health initiatives and vaccine development. Based on WHO statistics, Cuba has achieved average life expectancies equivalent to the United States. All Cuban babies are born in hospitals, and 100% vaccination compliance is achieved. So, although it is easy to criticize the Cuban government for known abuses, it is clear that in the area of health care they have a unique story. At the end of the evening Castro, an aged revolutionary, and I, an aging scientist, smiled and shook hands having discussed our common interest in global health.
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Overall, it should be made clear that despite the bad feelings between the Cuban government and the US government, the citizens of Cuba and the United States do not feel this way. The festering resentment of the Cuban expatriates from South Florida is directed to the Castro regime which has survived for 55 years. But Fidel at age 88 and Raoul at age 83 are not likely to survive much longer. Numerous people in Cuba spoke glowingly of the United States because a large fraction of them have relatives here. The students I met at the University of Havana bubbled with excitement for the possibilities of science, and none had anything political to say. With major changes soon to occur, it is my hope that firm relations between Cuban and US scientists will bring us closer together. Although I have no insight whatsoever into the significance (if any), my photograph is now permanently displayed on the mural above the bar at Hotel Nacional de Cuba in Havana. DEMOCRATIC PEOPLES REPUBLIC OF KOREA The DPRK (North Korea) is often described as the “Hermit Kingdom” because it exists in nearly total isolation. Despite disappointment over previous years, the inclusion of a Nobel laureate catalyzed invitations from the DPRK State Academy of Sciences (SAOS) for a series of scientific visits to Pyongyang. These were organized by the AAAS in collaboration with CRDF (US Civilian Research and Development Foundation). The trips provided an extremely rare view into life in the last surviving Stalinist state. DPRK only survives because of help from the Peoples Republic of China. Although it is commonly assumed in the United States that DPRK and China are closely aligned allies, this is not likely. Visas for entry into DPRK are only available at their Embassy in Beijing where flights to DPRK are possible. An advance meeting was arranged with the Chinese Foreign Ministry. This provided a cordial discussion where the Chinese view of DPRK was revealed. Indeed, the Chief of Mission freely acknowledged that China considers DPRK unreliable and even potentially dangerous. He implored us to pursue scientific diplomacy with DPRK and admitted that nothing else had worked. Their major interest in supporting DPRK was to prevent self-destruction of the regime, thereby bringing the Republic of Korea and the US military to the Yalu River border with China. Our first visit occurred early in December 2009, and it was very cold. Arriving in Pyongyang on Air Koryo in a vintage Soviet jetliner, we were greeted by dozens of security personnel wearing black fur earflap hats and long black wool military overcoats. Most of the luggage was
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freight, but we eventually received our bags; we were required to leave cell phones and laptops at Immigration. We were then met at the airport by our host, Ryun Gi Hong, a cheerful man who was Director of the International Section of SAOS (Figure 2). As the sun went down, the lack of streetlights made for a very dark trip into Pyongyang. Despite the darkness, ranks of soldiers were present along the roadside. With a standing army of 1.1 million soldiers and 8.1 million reserves, we were to see many platoons marching along the roadside, even stopping together to face away from the roadways as they urinated in unison. The twin 44-story towers of the Koryo Hotel where we stayed were nearly empty. Mr. Hong and four other DPRK personnel also stayed in the hotel and accompanied us the entire week. Although none of the
FIG. 2. With Ryun Gi Hong, Director of the International Section of the State Academy of Sciences of the Democratic Peoples Republic of Korea in Pyongyang, 2009.
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SAOS personnel were identified as intelligence agents, our American team of six were each assigned nonadjacent rooms and on alternate floors. Other than the hotel lobby, none of the buildings seemed to be heated, so I wore my long underwear under my suit each day and under my pajamas at night. Visiting Pyongyang was like visiting the Twilight Zone — the streets were nearly empty and it looked real but seemed artificial. At 5 AM, heroic vocal music was emitted from the central train station, imploring DPRK citizens to work hard for their country. We were strictly forbidden to go anywhere outside our hotel without an escort. Even a special ride on the beautiful Pyongyang metro was surprising. Running 100 meters underground to protect the line from a direct nuclear strike, the other passengers all looked away to avoid eye contact. But upon seeing us, a little boy holding his mother’s hand and pointed his finger at us like a pistol and made gunshot noises — obviously acting out what he had been conditioned to do. But over our week together I felt a bond of friendship form with Mr. Hong. When our requests were made, we were granted permission to visit several SAOS laboratories, the state universities, and the major teaching hospital. The scientific facilities seemed modest, but the scientists themselves seemed delighted to meet us. Nearly all, including the university presidents, confided that they had never previously met Americans. Whereas the DPRK scientists appeared shy during introductions, it became clear that we shared the same goal — to make the world a better place for our children and grandchildren. Pyongyang University of Science and Technology (PUST) is the only private university in DPRK and all instruction is in English. Founded by a Korean born American businessman, Kim Chin Kyung, his generous gift was intended to facilitate reunification of North and South Korea. The highly selected all male student body at PUST marched to class in military formation while singing patriotic songs. The instructors are volunteers, mostly American Evangelical Christians. When I first lectured, I began with a joke, but no one laughed. When I explained that I had just told a joke and it was funny, they all broke into laughter. Apparently DPRK students are not allowed to laugh without permission. On our way to one of our scientific visits south of Pyongyang, I asked our host Mr. Hong about the magnificent formal arch over the highway. He informed me that is known as “reunification gate” and lies on the road to Seoul, just 100 miles away. Mr. Hong was well travelled, but when I asked him if he had ever been to Seoul, he paused, and with sadness in his voice he stated, “No, Peter. That is not possible. So near but still so far.”
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The final morning of our first visit, Mr. Hong and I sat together and chatted at breakfast. He informed me that his 6-year old grandson lived with him. He explained that the little boy became alarmed when he was informed that his grandfather would spend a week in a hotel with Americans and said, “Grandfather, bring the rifle.” Having an unopened carton of granola bars, I gave them to Mr. Hong for the child and thought nothing more of the conversation. One and a half years later, I met again with Mr. Hong and members of the SAOS. We were granted permission by the US Department of State to meet with them at the Carter Center in Atlanta. Seated across from each other at a long table, Mr. Hong began the session reciting a stern rebuke that his government was not impressed with our visit to DPRK because no resources had become available for the proposed collaborations. Sensing a rehearsed protest, I sought to lighten the atmosphere. So my first response was “Mr. Hong, how is your grandson?” This provoked a slight smile, and he answered “Why, he is just fine.” This caused me to follow with, “Did he ask you to bring the rifle?” Now laughing, Mr. Hong replied, “No, he asked me to bring back some candy.” So maybe this is what science diplomacy is all about — two scientists who are also grandfathers come to be friends, and with any luck they may open doors between estranged nations. IN CLOSING Looking back on 40 years in academic medicine, it is clear to me that our discoveries and scholarly activities were important. But perhaps even more important are the people we met along the way. Many of these individuals are from counties around the world and became wonderful lifelong friends. Each of us here today has such a story, and I truly believe that these friends provide an important opportunity we should always keep in mind. Thank you for the privilege of presenting the 2013 Gordon Wilson Lecture. REFERENCES 1. Agre P. Autobiography and Nobel Lecture – Aquaporin Water Channels. In: Le Prix Nobel – The Nobel Prizes 2003, pp 168 –207. Stockholm, Sweden, Almqvist and Wiksell International, 2004, http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2003/ agre-bio.html, http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2003/agrelecture.pdf.
