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Presentation of the Julius M. Friedenwald Medal to Ralph A. Giannella, MD

2005; Elsevier BV; Volume: 128; Issue: 7 Linguagem: Inglês

10.1053/j.gastro.2005.04.036

1528-0012

Mitchell B. Cohen,

Medical History and Research

The Julius M. Friedenwald Medal, named for the distinguished Baltimore gastroenterologist who served as the eighth president of the American Gastroenterological Association (AGA), is the highest honor bestowed by our society. It is a lifetime achievement award given to a member for his or her enduring contributions to the field. The AGA has awarded the 2005 Friedenwald Medal to Ralph A. Giannella, MD, for his distinguished career as a researcher, educator, and clinician and for his leadership, in many capacities, of the AGA. In addition to recognizing his leadership skills, those who know Ralph speak of his warmth and ability to engage people, his depth of knowledge, and his integrity and kindness. Most impressive is his ability to listen to different points of view, organize his thoughts, and articulate them in a concise, eloquent, and clarifying manner. Ralph spent his early years in Paterson, NJ, where his parents, Mario and Josephine Giannella, had emigrated from Italy. Ralph’s father, who died in 1980, was a baker and developed a flourishing baking and Italian delicatessen business. His mother, who still lives in New Jersey, was a seamstress and homemaker. They both valued the importance of a formal education and taught him that if one works hard, one will achieve. Ralph attended high school in inner-city Paterson and chose to go to Cornell University, in part because it was not in the inner city. There he majored in zoology but especially enjoyed courses in music appreciation and history of architecture. He has remained a person who excels in multiple fields, both arts and sciences; ie, he is a Renaissance man. Ralph always knew he wanted to be a physician. Therefore, after graduation from Cornell, he attended Albany Medical College of Union University, in Albany, New York. Ralph found intellectual challenges and problem solving the most attractive side of medicine. He attributes his initial interest in academic medicine to favorable early influences from Ken Olsen, John Balint, and Richard Beebe. Each played a critical role in the early 1960s. Olsen was a stimulating summer research mentor, and, as is often true with successful mentorship programs for young trainees, the return on his investment was long-lived. Balint, who had become Chief of Gastroenterology at Albany Medical College, had enthusiasm and passion and was a powerful teacher. He was especially motivating to a nascent gastroenterologist. Beebe, a hematologist and the Chair of Medicine, was a consummate diagnostician and had an encyclopedic fund of knowledge. It was this fundamental process of probing, listening, and focusing that leads to discovery that so excited Ralph—an excitement that he has clearly embraced and taught to his students. After graduation with honors and second in his class at Albany Medical College, Ralph went to Boston, where there were a number of dominant figures in gastroenterology. He did a medical internship and residency at the Boston City Hospital in 1965–1967. There was a strong intermingling of and access to the combined teaching faculty, including such luminaries as Franz Inglefinger, Maxwell Finland, and William Castle. The experience at Boston City Hospital was a critical formative influence. Ralph was one of a number of future leaders in gastroenterology training at that time; contemporary house officers included Bob Glickman, Sidney Cohen (2002 Friedenwald Medal recipient), Ralph Bernstein, and Montgomery Bissell. It was traditional to spend a third year at a different institution, so Ralph took his senior residency at the Boston Veterans Affairs (VA) Medical Center at Jamaica Plain. During this year, he was further influenced by the teaching of Eli Schimmel and the monthly gastrointestinal (GI) conferences given by Franz Inglefinger and Bob Donaldson (1969 and 1987 Friedenwald Medal recipients, respectively). He entered gastroenterology training with a fellowship in the combined Mallory Gastroenterology Laboratory and the Thorndike Memorial Laboratory at Boston City Hospital. Norman Zamcheck was the fellowship director, and Selwyn Broitman was Ralph’s research mentor. He was attracted to these individuals because of their strong personalities and their love of clinical medicine and research. Zamcheck was a nonconformist and a skeptic; he urged his fellows to think for themselves. Broitman was an expert in host-pathogen interactions and experiment design. Ralph’s first article, coauthored with Zamcheck and Broitman, described vitamin B12 uptake by intestinal bacteria. These observations suggested that a variety of enteric organisms, not requiring exogenous B12, played a role in the pathogenesis of vitamin B12 malabsorption seen in small bowel bacterial overgrowth. This frequently cited work appeared in the Journal of Clinical Investigation, but not until Zamcheck had edited 13 drafts. The environment during his fellowship at Boston City Hospital was exhilarating. There was an opportunity to interact with faculty, including Irving Rosenberg, Richard Admirand, Bob Donaldson, Jerry Trier (1999 Friedenwald Medal winner), Roger Lester, Don Small, Lauren Harris, and Phil Kramer. Contemporary trainees who have also gone on to distinguished careers in gastroenterology included Don Castell, Sidney Cohen, Dave van Thiel, Martin Kagnoff, and Martin Carey. Those in training were exhorted to pursue excellence, work hard, and achieve, achieve, achieve. Ralph had already learned this creed from his parents, so it resonated. Ralph was shortly to become one of the young leaders in the field of diarrheal diseases. During his fellowship, he consulted on a patient with salmonellosis and profuse watery (cholera-like) diarrhea. Further study of this patient identified the presence of hypochlorhydria and vitamin B12 malabsorption. This led to several articles that identified a role for reduced gastric secretion in the pathogenesis of Salmonella infection. The particular Salmonella strain isolated from the Boston City Hospital patient, labeled Salmonella typhimurium TML, has been distributed to investigators all over the world and is now a standard investigative strain. It is in use in our laboratory today. With the encouragement of William Castle, Chief of Medicine at the Thorndike and Hematologist-in-Chief, Ralph subsequently went on to study patients with pernicious anemia and to describe the importance of the gastric acid barrier in other enteric infections. Ralph further directed his attention to the pathogenesis of Salmonella diarrhea, and he made a career-defining decision to pursue these studies at the Walter Reed Army Institute of Research (WRAIR) in Washington, DC, where he encountered a series of important new influences. There he worked with Sam Formal, the Director of the Department of Bacterial Diseases and the father of the study of enteric infections in the United States. It was at WRAIR that Ralph truly blossomed as an investigator and launched his subsequent career as a distinguished scientist and an international authority on intestinal infections, food-borne illness, and diarrheal disease. His research contributions at WRAIR include elucidating the mechanisms by which Salmonella and Shigella species alter the gut and cause diarrhea. He was the first to propose the hypothesis that bacteria that invade the intestine cause diarrhea by virtue of the inflammatory process they induce. These studies at WRAIR included important initial descriptions of this intestinal inflammatory response, including the effects on the adenylate cyclase-mediated and prostaglandin-mediated secretory pathways. This work has led to a major area of research involving the study of components of the inflammatory reaction and the inflammatory cells of the lamina propria and their modulating effects on the transport functions of the epithelium. His talents were soon recognized, and he was appointed Chief of the Department of Gastroenterology. The group in gastroenterology was guided and supported by Sam Formal, who recalls that Ralph was one of the most organized, talented, and enjoyable individuals at WRAIR. Formal shared with me a number of years ago that “Ralph had the capacity to work on 20 problems at the same time, and he could organize a group to get things done without everyone fighting.” Clearly, his leadership skills—which would subsequently benefit other academic institutions, the AGA, and our specialty—were already evident. The GI group at WRAIR included Alan Charney, Ronald Gots, W. Robert Rout, and M. Dean Kinsey. WRAIR housed an ensemble of talented physiologists and clinical investigators, and this synergy was fueled by the can-do attitude and lack of budgetary restraints at the time. It was an outstandingly interactive and productive community. A fortuitous interaction occurred when Ralph sought out Phil Toskes, also at WRAIR, in the Department of Hematology. Ralph identified their common interest after reading an article published by Toskes in 1971 in the New England Journal of Medicine on vitamin B12 malabsorption in chronic pancreatic insufficiency. They became lifelong friends and began a collaboration that resulted in a series of articles defining the pathophysiology of small-bowel bacterial overgrowth. These studies provided what are now textbook descriptions of the microscopic and histochemical abnormalities in bacterial overgrowth and the mechanisms for protein, carbohydrate, and B12 malabsorption in this disorder. Their seminal findings identified that the consequences of small-bowel bacterial overgrowth included both luminal and mucosal abnormalities. While in Washington, DC, Ralph also met Bill Dobbins, Chief of GI at George Washington University. With an academic appointment in his division, Ralph participated in a weekly citywide evening GI conference. He and Toskes combined an evening out and attendance at this lecture series held at the George Washington University Hospital. It is this collegiality combined with the pursuit of knowledge that has been central to Ralph’s career as an academic gastroenterologist. Other memorable contemporary participants and friends included Alan Ginsberg, Stuart Danovitch, and Jim Finklestein. After 3 years and 19 manuscripts, Ralph completed his service and training at WRAIR. Before leaving in 1974 to take a position at the University of Kentucky, Ralph recruited Mark Donowitz and Rick MacDermott to be his successors at WRAIR and to continue the strong academic tradition. Donowitz, who has worked with Ralph in a number of subsequent capacities, is eager to praise Ralph not only for his tireless leadership of the AGA, but also for his contributions to the field. He notes, “Ralph is at the essence a fair-minded person. He is a round-table leader; everyone at the table has equal access. He listens to all and endeavors to see what is important for all of gastroenterology and all its participants.” John Banwell was the thoughtful and affable Chief of Gastroenterology at the University of Kentucky and shared with Ralph an interest in the pathogenesis of bacterial diarrhea. Ralph was recruited to be Chief of Gastroenterology at a new VA hospital and was enthusiastic about the opportunity to establish his own laboratory. Within a year of arriving, Ralph was promoted to associate professor and rose to full professor after only 5 years at the University of Kentucky. John Hutton, who recognized his talent and was later to become his dean at the University of Cincinnati, was Chief of Medicine at the VA hospital in Lexington at the time. With Banwell, Ralph began a series of epidemiological and bacteriologic studies on the etiology of Escherichia coli diarrhea in the United States. It was during these studies of diarrheagenic E coli that Ralph began to focus on the pathophysiology of E coli heat-stable enterotoxin (ST). This toxin, elaborated by enterotoxigenic E coli, is a major worldwide cause of infant and traveler’s diarrhea. These studies also provided another important reference strain, E coli strain 18D, isolated from a patient with human disease. Ralph’s subsequent work on ST has stood the test of time and grown in importance. His laboratory accomplishments included purification and sequencing of ST, characterization of the suckling mouse bioassay, and development of a radioimmunoassay and enzyme-linked immunosorbent assay for ST. His continued work defined the process by which ST induced secretion and demonstrated that receptors for ST exist on the surface of intestinal enterocytes. Ralph was trained as a physiologist but appreciated the rapid pace of scientific advancement and welcomed molecular biology as an important tool to advance the field. He later (1989–1990) took a sabbatical in the Center of Excellence in Molecular Biology (National Heart, Lung and Blood Institute), Department of Molecular Genetics, Biochemistry, and Microbiology, at the University of Cincinnati with Jerry Lingrel. Subsequently Ralph’s laboratory characterized and cloned the intestinal ST receptor and developed a mouse with a targeted deletion of this receptor. His more recent studies have also helped to lay the groundwork for our understanding of the role of ST in bicarbonate secretion and intestinal cancer. He has spent the last quarter century advancing our knowledge of E coli diarrhea and the interactions of ST in the intestine. Because of these and his prior studies, Ralph has been invited to give more than 100 lectures and seminars at many conferences and symposia around the world; his research and teaching skills have also resulted in more than 60 visiting professorships. In recognition of these contributions, he has been elected to membership in the American Society for Clinical Investigation, the Association of American Professors, and the American Clinical and Climatological Association. In 1980, Ralph accepted the offer by Marty Goldberg, Chief of Medicine, to be the third director of the Digestive Diseases Division at the University of Cincinnati as the Mark Brown Professor of Medicine. Leon Schiff, who founded the division, had won the Friedenwald Medal 7 years earlier, and Gene Jacobson, a 1998 Friedenwald Medal winner, was the associate dean. Ralph continued to lead the division for 23 years. Immediately before Ralph’s arrival in Cincinnati, Bill Balistreri had been recruited back and named the Director of Gastroenterology and Nutrition at the Cincinnati Children’s Hospital Medical Center across the street. Ralph began the first of several mentoring experiences with pediatric gastroenterology fellows. He and Bob Rothbaum described the intestinal epithelial structural changes in infants with enteropathogenic E coli infection. This classic description of the attaching and effacing lesion was subsequently extended with the collaboration of Harley Moon and others to address the pathogenesis of E coli diarrhea in animals, a disease of tremendous veterinary importance. When I arrived in Cincinnati in 1983 as a pediatric GI fellow, I asked Bill Balistreri to help me select a research mentor, and he fortunately both introduced me to Ralph and supported my research fellowship in Ralph’s laboratory. My good fortune resulted in a series of studies with Ralph relating to the mechanisms of ST-mediated secretion and the reasons why the response to ST is more severe in the immature intestine. Thanks to Ralph’s strong early influence and his sustained mentorship, I have continued to investigate the role of ST and the related mammalian peptides guanylin and uroguanylin in human health and disease. Our collaborative relationship and strong friendship continues today, and he remains my teacher. During my training in Ralph’s laboratory, I shared a bench with the remarkable pediatric gastroenterologist Alfredo Guarino, who is now in charge of the Operating Unit for Children with Infectious Diseases and AIDS at the Department of Pediatrics of the University Federico II of Naples, and he is Eastern Hemisphere Editor-in-Chief of the Journal of Pediatric Gastroenterology and Nutrition. In addition to his other outstanding work relating to human immunodeficiency virus infection and short-gut syndrome, Guarino has also continued to focus on the mechanism of ST action in the intestine stemming from his experience in Ralph’s laboratory. Ralph was every bit the mentor to us as his giants had been to him. Guarino recalls that Ralph taught us to be both curious and strict and to appreciate the need for straightforward answers. He was nurturing of beginning investigators, yet appropriately critical if the science or direction merited criticism. Similarly, he taught us to be respectful of senior investigators but to maintain the healthy skepticism he had learned from Zamcheck. In Cincinnati, Ralph initially recruited Bennett Blitzer from Yale to run the Liver Study Unit; the Hepatology and Liver Transplant Medicine Unit was formed as an outgrowth of this and was eventually led by another recruit, Ken Sherman, who under Ralph’s tutelage has more recently become the fourth director of the division. Other notable members of the division have included Fred Weber, who originally worked with Ralph in Lexington, Steve Zucker, Charlie Mendenhall, Bob Weesner, Rifat Pamukcu, Chuck Ulrich, Norman Gilinsky, David Wolf, John Long, Jaime Aranda-Michel, Charles Schron, Lehel Somogyi, Brian Bleau, Steve Martin, and Elizabeth Mann. During this tenure, Ralph trained more than 65 fellows in gastroenterology from the United States and around the world, a number of whom are leaders in gastroenterology today. Many of these former trainees have recently honored Ralph by donating to the AGA Research Scholar Award Endowment in his honor. Many of his brightest fellows chose careers in clinical practice and have contributed to the field of gastroenterology in clinical care. His humility, diagnostic acumen, grasp of the larger picture, and genuine concern for patients were evident to all in training and are another critical part of his legacy. The Friedenwald Medal is the premier award from the AGA because it honors those who have contributed most to the profession as well as to the organization. Ralph’s leadership contributions to the AGA have been extraordinary, and his participation spans 35 years. Ralph presented his first abstract at the AGA in 1970, has been a member since 1971, and published his first article in Gastroenterology in 1972. He has served extensively, enthusiastically, and with distinction in many capacities. Highlights of this service include Chairman of the Research Committee (1986–1988), 2 tours on the Governing Board (1988–1991 and 1997–2004), 2 tours on the Nominating Committee (1984 and 1991), Chairman of the AGA/Gastroenterology Research Group Joint Committee on DDW Structure (1984–1985), which envisioned the current structure of DDW, associate editor of Gastroenterology (1991–1996), and chairman of the Organizing Committee AGA Consensus Conference on “E. coli O157:H7 infections: An Emerging National Health Crisis?” (1994). He has also frequently lectured at AGA postgraduate courses at Digestive Disease Week (DDW), as state-of-the-art lecturer, and in symposia and clinical forums. Also, in 1994, Ralph led the AGA in the development of a program in food-borne illness that ultimately, with the hard work of other individuals, led to a major financial contribution from the National Beef Board. This contribution was then used to leverage the National Institutes of Health to establish an Request for Applications (RFA) for food-borne illnesses ($2.4 million total). The capstone of his service to the AGA was as president in 1999–2000. During his tenure, a number of important and long-lasting decisions were made, and programs were set up that are ongoing today. Some of these include the establishment of major initiatives in nutrition and obesity and gastrointestinal oncology and the purchase of an AGA headquarters building. He established and chaired 2 task forces (the Task Force on Research and the International Task Force) that established priorities for the future of the AGA in these areas. Also during his tenure, the AGA established the lay magazine Digestive Health & Nutrition, now under the aegis of the Foundation for Digestive Health and Nutrition, successfully negotiated with the DDW Council the arrangement for the AGA to manage DDW, and acquired major funding from TAP for the GI Burden of Disease Study, which has proven to be important in developing funding and a research agenda for gastroenterology. Ralph has been tapped for leadership roles in a number of other capacities as well. He has served on the editorial boards of the journals Gastroenterology, the American Journal of Physiology, Digestive Diseases & Sciences, Revista Espanola Enfermadades Digestivas (Spain), Gastroenterologia Integrada (Spain), GastroHep.com (United Kingdom), and Edizione Minerva Medica (Italy). He has also served on the Steering Committee of the Gastroenterology Research Group and as its president from 1995 to 1997, was a member of the National Institutes of Health General Medicine A2 study section, and was a member of the VA Merit Review Board in Gastroenterology. His service to the University of Cincinnati College of Medicine, the Cincinnati VA Hospital, and a number of other organizations has been similarly extensive. Ralph has truly accomplished a great deal for Cincinnati, for the AGA, and for gastroenterology. Throughout his career, the advice, support, probing, and counsel of his wife have clearly facilitated Ralph’s accomplishments. Ralph has always appreciated critical thinkers, which is certainly one of the many reasons he married Patricia (Pat) Ann Barker in 1969, during the middle of his productive fellowship. They had met earlier while Ralph was an intern at Boston City Hospital and Pat was a nurse. Pat is a marvelous woman with a sense of care and concern that is awesome. She is disarming, loyal, analytical, extremely clever, and a free spirit. When someone is hurt, physically or emotionally, she is there to mend the body and the soul. She is selfless and one of those truly righteous people. Ralph can be a man of few words—in fact, one of Ralph’s many quotable aphorisms is that “No one ever complained that a lecture ended early.” In contrast, Pat would prefer to go the distance and is never at a loss for conversation; it is hard to leave a room when Pat is there. I recall one AGA when Pat was not able to accompany Ralph. Dozens upon dozens of times, Ralph was approached by friends and colleagues, greeted, and then asked about Pat. Their disappointment was evident when he replied that Pat had not come that year. Pat can light up a room with her effervescence. Although there are aspects of their personalities that are balanced and complementary, they both equally share a tremendous love and pride for their 2 sons and their families. Andy is an attorney who lives with his wife, Sally, a public relations and marketing professional, in Cincinnati. Chris is a computer scientist at the University of Maryland, who lives with his wife, Erin, a folklorist, and the Giannellas’ first grandchild, Tillman, in Baltimore. In summary, one can list Ralph’s considerable scholarly accomplishments, invited teaching opportunities, and leadership positions in numerous organizations, but that only partially describes his gifts. Ralph is a healer who strives to understand the physiology of health and disease while remaining keenly aware of the human needs of his patient. He understands the need for a strategic plan to combat illness, and he has the right measure of knowledge and intuition to help devise and initiate an appropriate action plan. He approaches other opportunities in life with the same special qualities. These skills, combined with his integrity, deft wit, thoughtfulness, and dedication to excellence, are among the leadership qualities that have helped guide our field and the AGA to higher ground.