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James A. Shannon and the beginnings of the Laboratory of Kidney and Electrolyte Metabolism of the National Institutes of Health

1999; Elsevier BV; Volume: 55; Issue: 1 Linguagem: Inglês

10.1046/j.1523-1755.1999.00254.x

1523-1755

Thomas J. Kennedy,

Health and Medical Research Impacts

James A. Shannon and the beginning of the Laboratory of Kidney and Electrolyte Metabolism of the National Institutes of Health. This is a historical review of the beginnings of the intramural research program of the National Heart Institute (NHI), now the National Heart, Lung and Blood Institute (NHLBI), with particular emphasis on the organization's Laboratory of Kidney and Electrolyte Metabolism and the persona of the program's founder, Dr. James A. Shannon. The narrative is anecdotal, intended to evoke the atmosphere that prevailed as an old-line public health agency transformed itself into the modern National Institutes of Health. The article is based entirely on the personal recollections of the author, an early recruit. It details the period from 1949 to 1953, and more sketchily the subsequent seven years. Additionally, it provides the author's perceptions of the style, modus operandi, and personality of Dr. Shannon in the years before he assumed the directorship of the NIH in 1955. James A. Shannon and the beginning of the Laboratory of Kidney and Electrolyte Metabolism of the National Institutes of Health. This is a historical review of the beginnings of the intramural research program of the National Heart Institute (NHI), now the National Heart, Lung and Blood Institute (NHLBI), with particular emphasis on the organization's Laboratory of Kidney and Electrolyte Metabolism and the persona of the program's founder, Dr. James A. Shannon. The narrative is anecdotal, intended to evoke the atmosphere that prevailed as an old-line public health agency transformed itself into the modern National Institutes of Health. The article is based entirely on the personal recollections of the author, an early recruit. It details the period from 1949 to 1953, and more sketchily the subsequent seven years. Additionally, it provides the author's perceptions of the style, modus operandi, and personality of Dr. Shannon in the years before he assumed the directorship of the NIH in 1955. Since, unfortunately, confirmatory documents and records are sparse and spotty about the founding of the National Institute of Health (NIH) Laboratory of Kidney and Electrolyte Metabolism (LKEM), I have amassed a series of personal recollections calculated to evoke the atmospherics surrounding the Kidney and Electrolyte Laboratory's (K and E Lab’s) perinatal period and illuminate the persona of James A. Shannon, its founder. The fortuitous aspect of this state of affairs is that it gives me a lot of poetic license, with no one in a position to challenge me, except Bob Berliner, and he's too much of a gentleman to do it in public—I hope. The National Heart Institute first crossed my horizon on June 16, 1948, when an editorial appeared in The New York TimesFigure 1 announcing: Both houses of Congress have passed a bill which would establish a National Heart Institute to combat diseases of the heart and circulatory system through research, the training of physicians and other means. Even if the President signs a measure which harmonizes with his views on social security, we have no more than a declaration of good intentions in the absence of a specific appropriation. Fifteen million dollars is needed at once to do for heart disease what is now being done for infantile paralysis and cancer. If Congress provides the money before it adjourns, 9,000,000 who know that they have heart “trouble” will soon receive better medical care and the lives of 600,000 graver cases will be extended. Skipping some purple prose in which the national assault on heart disease was scathingly contrasted to the U.S. Department of Agriculture's annual expenditures of nearly $30,000,000 on animal and plant diseases, and noting that 10 times more was being spent on foot-and-mouth disease in cattle, black spot in chickens, and even thrips on gladioli than on diseases of the human heart, the editorial continued, somewhat redundantly as you can see, to embellish its opening paragraph. To be candid, at the time this item didn’t hold my attention for very long, but rereading the editorial at the remove of half a century is fascinating. The significance of its remarkably strident advocacy tone, even before legislation passed by the Congress had reached President Truman's desk, was entirely lost upon me at the time. In retrospect, however, one doesn’t need the acumen of a special prosecutor to suspect the presence of the fine Italian hand of Mrs. Lasker, effectively influencing the views of the editors of The Times. The imperious insistence on an immediate appropriation of a huge sum by the standards of those days, as well as the patent effort to influence the President's decision by asserting publicly and forcefully that The Times and the nation expected him to sign it, resonate with and prefigure the strategies subsequently adopted by the voluntary health agencies to increase public funding for biomedical research Figure 2 . In any case, President Truman did, in fact, sign the bill on the following day. The National Heart Institute next riveted my attention in an item that appeared in The Times on April 7, 1949 Figure 3 . The decision of Dr. James A. Shannon to become the director of intramural research at the new National Heart Institute came as a total surprise to his former students at the Goldwater Memorial Hospital, where Bob Berliner and I were then working under the aegis of Columbia University, and Steve Brodie and Julie Axelrod under NYU auspices. Dr. Shannon had shifted his departmental affiliation from physiology to medicine in 1940 and had assumed responsibility for the 100-bed Research Service of the (Third) New York University (NYU) Medical Division at Goldwater, a new 1,600-bed institution for patients with chronic diseases. He brought along a biochemical pharmacologist, Steve Brodie, and recruited a deputy, Bud Earle, from Dave Segal's Columbia Research Service, and two residents, John V. Taggart, from the University of Chicago, and Robert W. Berliner, from Columbia University. Studies on the pathophysiology of the kidney, including its functional organization in patients with chronic glomerulonephritis, were promptly initiated and at least one major paper published. However, this line of investigation had to be shelved when Pearl Harbor intervened. Shannon, after extended discussions with one of his heroes, E.K. Marshall, decided to participate in a large collaborative study on the chemotherapy of human malaria, a disease that threatened to severely compromise the combat effectiveness of U.S. troops in the South Pacific. NYU's Goldwater unit focused on the clinical pharmacology of agents emerging from animal screening of (mostly) newly synthesized compounds, and on clinical trials of the most promising of these in induced malaria. The staff grew substantially and included many medical officers assigned to the project by the U.S. Army for the clinical care of the experimental subjects, namely, volunteers from conscientious objector and prisoner populations and patients referred for the treatment of neurosyphilis. When World War II ended, Shannon left Goldwater to assume the chair of pharmacology at NYU, promptly resigned in a contretemps over resources, and less than a month later accepted the directorship of the Squibb Institute for Medical Research, a component of the pharmaceutical company, E.R. Squibb & Sons. The puzzlement of those of us still working on Welfare Island about what Shannon had in mind for the new venue didn’t last long. One morning in the early summer of 1949, while Bob, Jim Hilton, and I were running an experiment in dogs, Bob got a call from Bob Loeb, the Chair of Medicine at Columbia, telling him that Shannon was in Loeb's office at P and S and wished—if Berliner was willing—to discuss employment opportunities in the intramural research program at the National Heart Institute. As Berliner went out the door, I recall telling him that, whatever his inclinations, I wanted Shannon made aware that I might be interested in such a possibility. When, a month or so later, Shannon invited me to Bethesda, I hopped the first available train. For me, it was a memorable day spent together in his office on the second floor of Building 3. Early on, he recounted the reasons for his move to Bethesda. Shannon had gone to New Orleans in early December 1948 to attend, as a member, an off-site meeting of the NIH's Malaria Study Section that was being held in conjunction with the annual meeting of the American Society for Tropical Medicine. While there, he was taken to dinner by two old friends, Gene Dyer and Norm Topping, then the Director and the Associate Director for Intramural Research, respectively, of the NIH. They outlined the provisions of the recently enacted Heart Institute legislation and invited him to develop and operate its intramural research program. My impression, from this and several later conversations about this job offer is that Shannon immediately perceived a tremendous opportunity to build, de novo, a very large scientific research enterprise with excellent prospects for stable and growing long-term funding, and he grabbed it. Moreover, at the time, he was uncomfortable in his current job, feeling increasingly involved in corporate affairs, spending more and more time in Sqibb's Fifth Avenue headquarters, and having less proximity to and time for science. Dyer and Topping happily approached him with their proposition at precisely the crucial moment. Shannon did most of the talking that day, outlining his plans for the program, including its organizational structure, the three or four people he was trying to recruit to head each of the major units, and how he was going about the process of identifying talent in the fields he wanted to include in the enterprise. He also showed me the largest hole in the ground I’d ever seen—the beginnings of the Clinical Center, scheduled to open four years thence. Intramural Heart had been tentatively assigned about 15% of the beds and laboratory space in the structure. Shannon suggested that I give the K and E Lab a shot, and I accepted. Berliner and Brodie, who had also been invited to join Intramural Heart, continued to agonize over whether or not to take the plunge. Clearly, their careers were at a far more critical point than mine, and they faced much more weighty decisions. The prevailing climate then was not as it would become. Intramural NIH did not enjoy much of a reputation in the biomedical research community, even though isolated islands of excellence could be identified, particularly in microbiology, infectious disease, and synthetic organic chemistry. Shannon was fond of telling of the horror and dismay with which his friends in academe reacted when he took a position in industry in 1946, a reaction that paled to insignificance in comparison to the uproar following the announcement that he had accepted a government appointment. In the fall of 1949, Brodie accepted Shannon's offer. Julie Axelrod agreed to move down to open up his Bethesda labs, and I received orders to report in late December. At that time, the entire Intramural Heart program was contained within the second floor of Building 3, where space had been assigned to the Laboratories of Chemical Pharmacology, Cellular Biology, Technological Development, and K and E, with additional labs under renovation in the basement and third floor. When I arrived, the few of us on board were rattling around among the mostly vacant labs. Jim Davis, who had started his public health service career in Nathan Shock's Gerontology program and had later carved out a small research niche in Luther Terry's Medical Service at the Baltimore Marine Hospital, had first met Shannon during the course of a visit by the latter to the Marine Hospital. Davis expressed interest in coming to Bethesda to do research on heart failure, was soon recruited in the fall of 1949 as the first member of the K and E Laboratory. By the spring of 1950 occupancy rose abruptly, as the glittering array of talent Shannon had recruited began to settle into Building 3. Ernie Cotlove took over one of the slots in the lab and hired Nordica Green. Bob Berliner, who had finally succumbed to Shannon's blandishments, and Jack Orloff, originally recruited by Bob to work with him at Goldwater, moved midsummer into the renovated space on the third floor. Alma Bartol, Agnes Preston, and Harriet Coburn filled out the staff. After these many decades, it is difficult to recall precisely who joined the intramural research program when. As noted earlier, verification of memory from historical documents, dated photographs, etc., is not easy. However, perusal of my personal records has turned up one item that provides an indelible date when most of the charter professional members of the K and E Lab were aboard. Figure 4 shows Leah and Bob Berliner, Elaine and Ernie Cotlove, and Jack Orloff—Martha was still in Philadelphia—toasting my bride at our wedding reception on September 30, 1950. Also present are Alice and Jim Shannon as well as Alice and Bob Bowman. Ann and Jim Hilton and Doris and Saul Farber were erstwhile colleagues from Goldwater. Farber and Bowman had worked with Shannon in the department of physiology at NYU, when medical students and Saul had spent a couple of summers with him at the Marine Biological Laboratory on Mt. Desert Island. Adrian Hogben, whose training with Hans Ussing in Copenhagen prepared him to introduce a line of inquiry into the research programs of the K and E Lab, joined the group at about this time. Jim Davis recruited Dave Howell, while Robbie Jo Shires and Jack Kleh joined Henry Dickerson and me in my lab. Dan Tosteson first appeared on the scene at around this period, as did Hans Keitel. Space limitations precluded further expansion until the facilities in the Clinical Center opened in July of 1953. Just prior to that date, the first cohort of the clinical and research associates selected by Shannon arrived, and two of these, Ed Leonard and Bob Hyatt, associated themselves with K and E. During the years in Building 3, Bob, Jack, and I pursued our interests in potassium excretion, acidification, urinary CO2 tension, and related matters; Jim Davis embarked on a series of studies on the roles of the kidney, the adrenals, and hypophysis in the regulation of blood pressure. Ernie busied himself with studies on electrolyte transport into and out of muscle, and Adrian's lab worked on ion fluxes across skin and the gastric and intestinal mucosae. Gradually, the ancillary trappings of a research enterprise took shape. The first journal club, established in late 1950, proved to be too heterogeneous in membership to survive and, since the K and E group had not yet attained a critical mass, we participated for awhile in a journal club with colleagues from local medical schools and hospitals who shared kindred interests. We were also active in the periodic meetings of the local chapter of the Society for Experimental Biology, as were Frank Epstein, Holly Smith, and others stationed at the Walter Reed Army Medical Research Institute, and Mac Walser and Paul Doolan from the National Naval Medical Research Institute across the street. On the basis of Dr. Shannon's advice to keep our clinical skills honed, most of the physicians in our group, with his help, secured academic appointments and took on teaching responsibilities at local medical schools. During those early years, Dr. Shannon's presence was continuously and conspicuously palpable. He cruised the territory regularly, dropped into labs (ours and others) to find out what was going on and offer suggestions where he had them, or just to pick up company for lunch in the Building 1 cafeteria. He was very conscientious about keeping everyone abreast of the progress of his efforts to staff up the various labs and clinics. He took great pride in his recruits and always tried to escort each new staff member to a Shannon-arranged meeting with the NIH director, Gene Dyer. He could also be arbitrary. Exemplarily, one afternoon as I sat with him, Shannon personally designed a small set of highly stylized prototypic laboratories in detail that became the fixed menu from which Heart Institute investigators would be required to make selections in planning their assigned shell space in the Clinical Center. In a single afternoon, he defined the contours of intramural Heart's space configuration in Building 10 in a form in which it remained, with few changes, for the next several decades. He was also a marvelous facilitator of the research efforts of the staff. One afternoon, he dropped into the lab to tell us that he had just received a call from Frank Winton, the then Chair of Physiology at University College in London, with whom he had worked briefly in 1938 or 1939 and who was scheduled to visit Kingston, Jamaica, shortly on unrelated business. Shannon reminded us that Winton and he had tried, not very successfully, to find optimal conditions for using pump-lung-kidney preparations. Shannon wondered whether we’d be interested in having Winton stop over and work with us on re-examining the utility of the technique. This sounded like a good idea, especially with Bob Bowman right across the hall and keen to give it a shot, and so arrangements were quickly consummated. In due course Winton arrived, a cherubic dynamo who had forgotten infinitely more physiology, especially technique, than any of us had ever known. To make a long story short, we didn’t make much scientific progress but had a wonderful couple of weeks. Winton turned the lab upside down and had us and Bowman's crew in a continuous tizzy. And after work every evening, Winton was ready to play. When he didn’t have a dinner invitation, he headed toward the pop music scene in Georgetown, dragging along anyone who was free. The major onus of providing camaraderie fell most heavily on Jack, since he was the only bachelor, while the rest of us had either new brides or very young children at home. Jack would stagger in next morning, looking ghastly, with tales of having had to extricate Winton in the wee hours from the seat he had expropriated behind the drums on the bandstand of one of the Blues Alley nightclubs, and of pouring him onto the entrance to the Capitol Hilton. Half an hour later, Winton would appear, fresh as the proverbial daisy, ready to go and looking at us somewhat reproachfully for not having the experiment scheduled for the day already underway. Another sentinel event of this period began when a phone call from representative John Fogarty, a member and soon to be Chair of the House Appropriations Subcommittee having jurisdiction over the NIH, was transferred to Shannon from the office of C.J. Van Slyke, the Director of the National Heart Institute (NHI). Fogarty had been gazing out over the NIH campus from the tower of the National Naval Medical Center, where he was recovering from a myocardial infarction, and had started to wonder whether the new NIH entity, the NHI, for whose operations he had recently appropriated funds in Congress, might be able to do anything to improve his health. Shannon responded with a full court press. Fogarty was immediately invited over, an extensive work-up was prescribed, and every member of the staff with anything to contribute was enlisted in the task. Fogarty probably was the first patient ever to get a two meter chest film in Building 10. Construction being still in progress, the floor of the x-ray room was bare concrete and deep in dust. Ed Boyle, an American Heart Association Fellow in Anfinsen's Lab who had been christened “the Liberace of the Ultracentrifuge” by Orloff, earned back the cost of his Spinco a million times over on that day. A close and enduring personal friendship between Fogarty and Shannon was forged in the course of this encounter that lasted until Fogarty collapsed and died on the House floor in January of 1967, during the opening of the 1st session of the 90th Congress. It is likely that Shannon was the most influential person to introduce the concept into the NIH that physicians with several years of residency training under their belts be recruited for the around-the-clock care of patients hospitalized in the Clinical Center. This had been the practice on his service at Goldwater. His enthusiasm for the clinical and research associate programs as devices for developing physician/scientists and clinical investigators was boundless. He relied heavily on his friends in academe to give him access to their residents, and frequently recounted how helpful Walter Bauer, Bob Loeb, Walter Palmer, George Thorn and others had been. By all accounts, he was also very persuasive in selling residents on his program. Included in the first cohort to be signed up were Don Frederickson, Bob Hyatt, Bob Gordon, Ed Leonard, Elliott Middleton, and Jim Wyngaarden. Intramural Heart was a happy ship both during and after working hours. A Friday night poker club, involving people from all of the labs, took root in those days and continued for many years. The Shannons frequently had staff to dinner at their modest home on Sleaford Drive. Alice was a marvelous hostess and Jim's long reach facilitated the big martini pitcher getting to the rims of empty glasses. Conversation was always spirited, but perhaps never more so than on the occasion when Shannon was regaling his guests about his interview that day with a candidate to head the department of social service in the Clinical Center. “Can you imagine,” he said. “He wanted 5000 square feet of space for research. Social Service research.” “And why not,” challenged that veteran of the New York City social service scene (the Foster Home Bureau, inter alia). Mrs. B. Shannon's response of, “Oh, Leah, for heaven's sake, social service workers are grocery clerks” kept the dialogue lively for the rest of the evening. Bridge nights at the Berliners usually wound up at midnight with Mrs. B's apple pie and coffee (no decaffinated coffee and plenty of insomnia). Parties in Top Cottage in those days were frequent. Shannon usually showed up and stayed late. Television sets were luxuries that most of us had postponed buying, so at least half of the K and E staff repaired to the Berliner's house to watch Adlai Stephenson accept the presidential nomination in the summer of 1952. When the Officer's Mess at the National Naval Medical Center extended privileges to NIH staff, its Dining Room became a favorite luncheon spot. The food was good, the price right, and the obligato of clanging slot machines in the background was tolerable. I remember driving over one noontime while sandwiched in the front seat between those intrepid birders, Berliner and Orloff, when suddenly, in the middle of Rockville Pike, Berliner, who was driving, screamed “Magpie!” He abandoned the car in the middle of traffic, and dashed back toward Cedar Lane with Jack in hot pursuit, presumably to get a closer look at the bird. I turned the car around and picked them up at the “Victory Gardens” between the old Building T6 and Cedar Lane. Later, over lunch, they chortled in anticipation of breaking the news of their extraordinary sighting to Lawrence Kilham, a virologist at the National Microbiology Institute, and also, by avocation, a naturalist of considerable distinction who gave at least a score of species free run of his home, and shared his table and even his plate with some of them. During their tenure in Bethesda, Kilham had repeatedly trumped their aces in species spotting, and now they saw a chance to even the score. As soon as we got back to the lab, Jack put in a call to Kilham and announced that Kilham wouldn’t believe what he and Bob had just spotted. Kilham's reply: “You guys must have seen one of that pair of Western Magpies I released over the weekend!” Alas, the bargain lunches at the Navy were too good to be true. One noontime, we walked in to discover that prices had risen by a factor of five and that an eerie silence had descended on the dining room. Senator Estes Kefauver, later to become Adlai Stevenson's running mate in the 1956 presidential election, had been conducting a spectacular series of televised hearings on mob control of gambling, including slots and featuring colorful mobsters such as Greasy Thumb Guzack from Chicago. The commanding officer of the Medical Center—or perhaps a higher up official—apparently got nervous and ordered the slots loaded onto a naval vessel and deep-sixed outside continental limits. After the move of most of the K and E Lab to the Clinical Center, sorties to the Officers Club became just too inconvenient. Then, with no warning, in the autumn of 1952 Shannon was gone. The director of the NIH, Gene Dyer, had reached statutory retirement age. The heir apparent, Norm Topping (who later distinguished himself at the Universities of Pennsylvania and Southern California) was by-passed in favor of the nutritionist, Henry Sebrell, and decided to retire. Sebrell selected Shannon to succeed Topping as associate director for Intramural Research, and when Sebrell himself retired in 1955, Shannon became director of the NIH, a position he occupied for the next spectacularly productive 13 years. Despite the shock of Shannon's departure, life went on. Bob took over Intramural Heart while continuing to direct K and E. We moved to our new digs in Building 10. Patients were admitted to the 6 West Nursing Unit, and successive cohorts of clinical and research associates came through. New blood was infused—Steve Hajdu, Doug Davidson, Moe Berg, Norman Levinsky, Floyd Rector, Irv Cooperstein, Ned Dunham, Mac Walser, Bill Mohler, Bob Akers, John Janicke, Joe Hoffman, Dave Chalfin, Henry Wagner, Larry Earley, and others. The corridors sprouted chicken feathers and were populated by the ghosts of red cells. Collaborators—including John Stevenson, Murray Eden, Harold Morowitz—joined the luncheon seminars. Early visitors from abroad included Hans Ussing and E.J. Conway, and a long litany of major scientific contributions began. I have no doubt that historians will remember James A. Shannon as I remember him, as one of the truly heroic figures of 20th century medicine Table 1 . Nothing I could say could add to or detract from the luster attendant to his extraordinary accomplishments as a scientist, a mentor of budding young scientists, a leader of large-scale scientific projects and programs, the visionary architect of our nation's biomedical science policy, and the skillful manager of its execution. There can be no dispute that he was among, arguably primus inter pares, the small and talented group of physiologists—Homer Smith, A.N. Richards, E.K. Marshall, and Robert F. Pitts—who laid the foundations for modern renal physiology in the late 1920s and 1930s. The heritage of at least the renal physiologists who have been a part of the K and E Lab can unquestionably be traced to the work of Shannon and his students. But, let me try to articulate some unease about the pedigree implied in the title of “Shannon's Legacy” that has increasingly troubled me as I ruminated about the lab's history.Table 1Career highlights: James A. Shannon, M.D., Ph.D. I knew Shannon for almost 50 years, including his last 15 or so, during which we met frequently to, inter alia, tape–record his recollections of his career. Throughout this entire span, I had one and only one substantive discussion with him on the subject of the kidney physiology, when, in 1947, Bob and I went down to the Squibb Institute in New Brunswick to get his reaction to what we thought to be very exciting observations we had made on potassium excretion. What I had expected to be a stimulating and incisive critique turned out to be a perfunctory exchange with someone who appeared to be almost totally disengaged. At the end of the Second World War, Shannon knew as much about the treatment of malaria than anyone anywhere. Yet in subsequent years, I never heard him engage in any substantive discussion of malaria. After 1960, when in one or another capacity I worked in close proximity to him, I found in him the same consuming and creative intensity for the role he was currently playing that I was told had characterized his career as a renal physiologist, that I had personally observed when he was a malariologist and the research director for Intramural Heart, and that, as anybody around in those days could see, he devoted to directing intramural research across the whole NIH campus. However, Shannon rarely looked back on or spoke about his earlier careers. My perception is that once he moved on, his new job became his exclusive preoccupation. It was as though he had had no prior life, as though he had erased from memory everything not required for his new undertaking. In 1949, all he needed to remember about renal physiology was that it deserved conspicuous representation in any research program that purported to be a comprehensive approach to the problems of cardiovascular disease, and that top-notch leadership had to be identified to design the program details, to recruit the staff and to direct the effort. Whatever one may think of this modus operandi, Shannon's impact on every field in which he became engaged was large and enduring, but my perceptions about his behavior patterns convince me that the Laboratory of Kidney and Electrolyte Metabolism is Shannon's legacy only in the narrow technical sense of being one component of the organization he put together for Intramural Heart. To my way of thinking, the lab's rich history of important contributions to biomedical science more accurately and properly reflects the legacy of Robert W. Berliner, Shannon's most talented student, who he selected as K and E's first lab chief and who served with great distinction in that role for the first 12 years of the lab's existence. And I have no doubt that Jim Shannon would agree. Portions of this article were presented at the “Shannon Legacy: Renal Research at NHLBI” symposium, held at the National Institutes of Health on May 4–5, 1998.