There is a link between Oliver Wendell Holmes' poem “The One-Hoss Shay” (1) and every patient with diabetes who has ever received a kidney or pancreas transplant. Yet, most of the 4,128 diabetes patients in the U.S. who received renal transplants in 2011 (2) and the 1,051 diabetes patients who received a pancreas transplant in 2011 (3) do not know how Dr. Frederick C. Goetz (1922–2012) used this delightful poem as parallel to how the medical profession viewed patients with diabetes. Dr. Goetz, who always preferred to be addressed as “Fred” by any who knew him, played a seminal role in assuring that both renal and pancreas transplantation were available to suitable patients with diabetes. While today this is considered a standard of clinical care, Fred maintained his equanimity in the face of much skepticism and criticism—often from friends and colleagues. This profile outlines Fred’s role in the history of renal and pancreas transplantation, but also strives to capture some of the “essence” of Frederick C. Goetz—as a caregiver, physician, scientist, and teacher. This profile is written from the perspective of three physicians, each of whom first met Fred while they were medical students at the University of Minnesota and whose collective observations and collaboration with Fred spanned more than three decades of his academic career.
Fred was born and raised in Fond du Lac, WI. He graduated from Harvard College (1943) and Harvard Medical School (1946). He served in the U.S. Army as a physician in Korea where he met his future wife, Mary Rose Riordan. After a residency, chief residency, and fellowship (with Dr. George Thorn) at Massachusetts General Hospital, he joined the University of Minnesota as the Director of Diabetes Research. His career was focused on diabetes and its complications. His personal life was filled with interests outside of the academic community. Along with his training and skills as a physician-scientist, he was an accomplished pianist and often played for and with family and friends. He read widely. He was an avid sailor and kept his sailboat in Bayfield, WI, for annual sailing trips in the Apostle Islands. His appreciation of craftsmanship was evidenced by the fact the he lovingly took the time to care for his wooden sailboat each year. He was an active member of the Basilica of St. Mary in Minneapolis for 45 years. His regular comments about Mary Rose and his four children in conversations with colleagues were clear evidence of his love for family; throughout his career, Fred modeled a well-managed work–life balance.
Renal Transplantation in Diabetes Mellitus
Although renal transplantation was gaining acceptance for multiple types of renal failure in the mid-1960s, during that era patients with diabetes were excluded from consideration as potential recipients. The prevailing concept was that the complications of diabetes so ravaged the individual patient that providing transplant in the setting of diabetes not only put the transplanted organ at risk for recurrent nephropathy, but would also be the “waste of a good organ” (B.J.H., D.M.K., personal communication). Fred noted that patients were not like the Deacon’s one-hoss shay—in which every part collapsed at the same time as described at the end of this classic poem:
You see, of course, if you 're not a dunce,
How it went to pieces all at once,—
All at once, and nothing first,—
Just as bubbles do when they burst.
End of the wonderful one-hoss-shay.
Logic is logic. That's all I say. (1)
Fred was not bound by the prevailing “logic” that diabetes patients collapse “all at once” and thus he made the observation that patients with type 1 diabetes were not all like the Deacon’s shay. Although many patients had renal disease and profound metabolic defects that were often difficult to manage, some lacked evidence of other significant diabetes—presumably glycemia-related—complications. He shared his point of view with many and found a supporter in his surgical colleague, Dr. Richard Lillehei, an innovative and creative surgical leader. After lengthy discussions and planning, they undertook a study in which 10 patients would be given both pancreas and kidney transplants (4). Animal data on pancreas transplantation at the University of Minnesota and other centers provided encouraging information on the potential value of such an approach, despite many potential challenges with dual transplantation, including management of pancreatic duct drainage, a concern over pancreatic auto-digestion, the need to limit organ ischemic time, and the very limited knowledge of immunosuppression. To be considered for this study, patients had to have advanced renal disease and marked difficulty with glycemic control. Thus, only patients with the worst prognosis were subjected to the risks of the procedure in spite of almost certain increased risk of adverse outcomes.
In this seminal work, the team performed 10 pancreas and 9 simultaneous kidney transplants between December 1966 and March 1970. Their report on these 10 patients in the Annals of Surgery (4) contains extensive and insightful details about the background animal and bench research that preceded the procedure in patients. The following comments highlight the reasons for going forward with pancreas transplantation: “The patients on whom such a procedure is done must be suffering a risk greater than that entailed by such an experiment. They must have reached a point where conventional therapy had nothing to offer them” (4). This statement reflects some of Fred’s concern not only for the project but also for the impact on individual patients. He always exemplified this empathy and individual concern as he made his regular rounds.
Due to the limited success of pancreas transplantation—only 1 in 10 of the early recipients maintained insulin independence for any sustained period—this procedure was discontinued until being restarted at the University of Minnesota in 1978. However, renal transplantation continued for those with diabetes. In those years, most patients with diabetes were excluded from renal replacement therapy (dialysis, transplantation) and those who did start dialysis generally died within the first year. However, working with the world-class renal transplant group at the University of Minnesota under the direction of the chairman of surgery, Dr. John Najarian, Fred was able to extend the program to include diabetes patients based both on the absence of data that supported exclusion of such patients and due to the high rates of end-stage renal disease in this group. In 1973, Fred and colleagues published the experience on renal transplants in 40 patients with diabetes, including 37 with “juvenile onset diabetes” (5). Although formal criteria for candidate patient selection had not been established, they excluded two patients for advanced age and four due to “overwhelming complications of diabetes” (5). At the time of this publication in 1973, 31 patients (78%) were alive 4 months to 4 years after transplantation, and of the 29 who had functioning grafts, 20 were considered “fully rehabilitated” (5). For unexplained reasons, mortality was higher in the patients who received related donor grafts compared with those with cadaveric grafts. Consistent with later experience however, outcomes for renal transplantation were consistently, albeit modestly, better in nondiabetes patients than in those with diabetes.
In the late 1980s, Fred discussed the outcomes of the early renal transplant program in a grand rounds presentation at the Cleveland Clinic (with B.J.H. in attendance), where he noted that several patients from the early transplant series were alive with functioning kidney grafts more than 15 years after their transplant procedures. Few times in the history of medicine have the efforts of a single individual with a small group of collaborators transformed the treatment of a disease with 100% mortality into one that now carried the potential for long-term survival. A key additional question remained from the earlier experience with combined renal–pancreas transplantation. What benefit might be accrued if the metabolic abnormalities of type 1 diabetes could be eliminated with the addition of simultaneous pancreas transplantation in an effort to restore normoglycemia?
Pancreas Transplantation in Diabetes Mellitus
Following the discontinuation of clinical pancreas transplants at the University of Minnesota in the late 1960s, significant investigation was devoted to improving the technique in animal models. By the late 1970s, the pancreas transplant program at the University of Minnesota was restarted under the direction of transplant surgeon Dr. David E.R. Sutherland with the support of Fred and Najarian. From the very beginning, the procedure itself faced surgical challenges as well as significant skepticism from members of the university’s endocrinology group and other global colleagues. The first patient to receive a pancreas graft in this “era” had a remarkable clinical response; her graft functioned until her accidental death more than a decade after transplant. Despite the success of the index case, the next nine recipients of pancreas transplantation experienced multiple problems, including complications resulting from the management of exocrine drainage, liponecrosis, graft ischemia/infarction, and immunosuppression. During his postdoctoral training, one of the authors (B.J.H.) approached Fred to inquire: “If the first graft had not been so successful, would the pancreas program be continuing?” Fred’s response was testament to his equanimity—providing gentle admonition and the matter-of-fact manner in which he approached problems: “You were not here when we started kidney transplantation.” Fred’s conviction was that it was worthwhile to tackle difficult problems in a thoughtful way, learn from past experience, and continue to apply learnings from laboratory, clinical, and nonclinical data, while always keeping the interest of the patient with diabetes in mind.
Fred led the involvement of the diabetes and endocrine team that collaborated with the surgical transplant program; during this time, he worked closely with many collaborators, including Drs. Michael Mauer, Michael Steffes, Jose Barbosa, John Bantle, Elizabeth “Betsy” Seaquist, David Kendall, and others, who were necessary to support the program and address important scientific and clinical questions. Under Fred’s early guidance, this group undertook increasingly detailed studies of the metabolic effects of successful pancreas transplantation (6–9). These studies were expanded when Dr. R. Paul Robertson joined the endocrine faculty with additional studies of pancreatic function; longitudinal studies of both living related (hemipancreas) donors and information on small numbers of islet and autologous islet transplant recipients were undertaken (10–13). In addition, Fred and Sutherland advocated establishing an international registry of pancreas transplantation, thus allowing procedures performed from a variety of large and small programs to be collected and analyzed. Registry data not only provided documentation of temporal improvement in outcomes from pancreas transplantation but also permitted assessment of the success of various surgical approaches. Under Fred’s leadership, the University of Minnesota program regularly reported on both lessons learned in the field of pancreas transplantation and contributed to the sustained success of many pancreas transplant procedures (12,14–17). Other major scientific contributions supported, mentored, and guided by Fred, Sutherland, and Robertson during the 1980s and 1990s included important studies of the effects of hemipancreas graft donation on glucose tolerance, assessment of the impact of persistent diabetes on renal transplant grafts, early evidence of the familial clustering of renal disease risk in diabetes that predated years of analysis of genetic linkage in diabetic nephropathy, and evidence of no adverse effects/possible benefits of pancreas transplantation on diabetic retinopathy (11–13,18–21).
Other Contributions
Fred is also remembered for his role in other areas of scientific and academic pursuit. His mentoring of young scientists was characterized by support and collaboration as well as modeling his humble, but unwavering, support of other areas of interest including the prevention of renal disease in diabetes (18,19), studies of the natural history of β-cell function in type 2 diabetes (22), studies of nutrient and glucocorticoid effects on β-cell response (23–29), and unending interests in seemingly simple (30) but clinically important areas of research. Many who worked with Fred over the years were touched both by his thoughtful scientific curiosity and his warm, compassionate, and perpetual focus on the individual affected by diabetes. Recognition for these attributes was acknowledged nationally in 1978 when he was the recipient of the American Diabetes Association’s (ADA’s) Outstanding Physician Educator award. His easygoing nature, combined with this scientific interest, was evidenced in many very human ways. While he advocated and implemented the use of one of the first computer-based data management systems in the General Clinical Research Center (GCRC), he often reverted to use of hand-drawn slide materials, pencil-and-paper statistical calculations, and his quirky, old Royal typewriter. With these simple tools he was always willing to step forward to educate and support his colleagues. Never was this more evident than during an ADA-sponsored symposium when the scheduled speaker, his colleague Sutherland, was stranded in Minnesota by one of the region’s well-known heavy snowfalls. Fred simply stepped in—with little preparation—and gave a masterful presentation of data and his perspective on the current status of pancreas transplantation. This very human side of Fred as colleague and mentor lives on in the memory of those who were fortunate enough to work with him.
Early Work With George Thorn
Early in his academic career, Fred was provided the opportunity to work with Dr. George Thorn. Their collective work contributed greatly to our understanding of glucocorticoid physiology (30–34), and this work set the stage for Fred’s willingness to continually reevaluate challenging clinical and scientific problems. As an example, the need for appropriate glucocorticoid adjustment during acute illness in a patient with primary adrenal insufficiency was raised during Fred’s attending rounds. Fred addressed the conundrum of how to insure adequate glucocorticoid replacement and yet minimize hyperglycemia risk using his experience from almost 30 years earlier. He provided historical perspective and clinical insight noting: “Before glucocorticoid replacement was available, patients with adrenal insufficiency lived near Mass General, so they could get venous or hypodermal clysis when they went into adrenal crisis. When oral glucocorticoid preparations became available, adrenal crisis essentially disappeared as long as patients could take their usual daily doses of oral meds” (B.J.H., personal communication).
Career-Long Contributions to Understanding β-Cell Function
Many years before the formal National Diabetes Data Group and ADA definitions of diabetes were commonplace, students, fellows, and faculty alike heard Fred comment about the key observations suggesting that diabetes was a heterogeneous disorder with some diabetes characterized by evidence of insulin insufficiency and other forms of diabetes characterized by a diminished effect of circulating insulin or the impact of counterregulatory substances from the pituitary and adrenal glands (31–36). In an effort to begin to understand this problem, Fred was one of the first investigators to develop insulin assays that could be applied to animal and human studies (37). When proinsulin and C-peptide were characterized by Steiner and colleagues (38–43), Fred engaged in dialogues with Dr. Arthur Rubenstein, other members of The University of Chicago group, and colleagues interested in β-cell function. Based on these discussions, Fred embraced the concept of using C-peptide as a biomarker to study β-cell function. He was particularly interested in understanding whether urinary C-peptide, collected over periods of 4 to 24 h, could be used as an integrated measure of β-cell function (28,29,44). His interest in β-cell function not only was applied to the ever-increasing number of pancreas transplant recipients but also, later in his career, was key in designing the “Wadena” (Minnesota) community study—a rural community in which β-cell function and aging could be studied serially in a relatively stable population of healthy aging individuals with diabetes (22,45,46).
University Group Diabetes Program
Fred played an important centrists’ role in the landmark University Group Diabetes Program (UGDP) (47,48). The final historical commentary on the UGDP has not yet been written (and may never be) and the acrimonious dialogue that characterized the early 1970s is a distant memory. At the time of the study, Fred was one of a small number of introspective and thoughtful investigators who not only helped conceive the project but also served to carefully assess the potential implications of both the study design and reported outcomes. Randomized controlled clinical trials were still novel when the UGDP was designed in the late 1960s, and issues of power calculations, adjustments for baseline risk and confounders, and the need for data safety monitoring were not yet fully developed. Fred was instrumental in bringing Genell Knatterud (who became a long-standing director of the Maryland Medical Research Institute) and her group to work with the other UGDP investigators to both design and implement the trial. In an era where both the potential benefits and risks of more intensive treatment of type 2 diabetes were essentially unexplored, Fred made a concerted effort to stay above the fray and criticism that ensued when it was reported that sulfonylurea (tolbutamide) treatment as compared with placebo was associated with no significant reduction in markers of eye or renal disease, yet was associated with an apparent increase in cardiovascular risk. To the critics who felt the conclusion had been reached with haste and the tolbutamide study arm should be allowed to continue, Fred’s approach was simple and clearly stated: “As investigators, we did not feel that we could in good conscience go forward with the trial” (B.J.H., personal communication). Historians will note that it was nearly two decades before the results of the UK Prospective Diabetes Study (UKPDS) data reported additional cardiovascular outcome data in a study of glycemic control in type 2 diabetes (49,50). This example exemplifies how Fred maintained both his scientific perspective and never lost sight of the potential that other valuable data would be derived from the UGDP. Fred and his colleagues had renal biopsy specimens available from UGDP participants. By using the best glucose measures available to them, these data provided compelling early data that there was indeed a potential relationship between levels of glycemia and histologic evidence of renal damage. In this case, Fred strove for the highest quality scientific and clinical data possible. In short he was the consummate perfectionist, so in spite of much encouragement to publish these data with Dr. Anna Mary Carpenter (a pathology colleague at the University of Minnesota) in the early 1980s, he did not see fit to do so until 1993 (51) when additional data, including the findings of Diabetes Control and Complications Trial (DCCT) (52), could both corroborate the findings and provide a more complete scientific story.
Scientific Leadership and the University of Minnesota General Clinical Research
When the concept of core research facilities became a reality through the National Institutes of Health General Clinical Research Program, Fred was one of the initial and successful applicants and served as the first director of the GCRC at the University of Minnesota. Even in this leadership role, Fred always held the strong conviction that trainees, colleagues, and collaborators should understand not only the disease states under study but also the basic, yet critical, core of statistics and study design. One of the authors (B.J.H.) had weekly lunches with Fred discussing the book Statistics at Square One (53) and still has his signed copy from Fred with the inscription that also reflects his ongoing interest in literature: “To Byron Hoogwerf FCG 3/15/79 (Ides of March).” When there was a need for clarity on a topic, Fred encouraged regular meetings and discussions with staff from across the study team—including the biostatisticians. With the introduction of one of the earliest clinical information systems (Clinfo), Fred and his colleagues assured that this system was broadly available to GCRC scientists and encouraged its use by all investigators. (Two of the authors [B.J.H. and D.M.K.] first met sitting in front of Clinfo terminals working away on separate projects with Fred and collaborators.) This prescient work with clinical information and the capacity to see the critical interdependence of those with varying scientific expertise are additional testament to but two of Fred’s incredibly valuable contributions to the field of diabetes mellitus.
Fred Goetz was one of the quiet giants of diabetes care and research during the second half of the 20th century. Throughout his career, he consistently engaged in critical thought, tackled challenging scientific questions, and effortlessly synthesized key elements of scientific learning over time, all while maintaining a consistent focus on the well-being of patients. He leaves behind a loving family, a grateful professional community, and a legacy of mentorship, collaboration, and community service. Always the scholar, he used his love of the arts to address a seemingly intractable problem in diabetes with Holmes’ memorable poem (1).
