How many institutions have the courage to construct a brand new center with an elevator shaft that ascends like an overgrown chimney, three stories above the roof, visible to its neighboring medical centers for over a decade as its leaders plan for expansion? Joslin Diabetes Center did, thanks to the faith that its former Chairman of the Board, Arthur O. Choate Jr., had in the fast-growing world-class diabetes center founded by Elliott P. Joslin, M.D. (1869-1962). And the risk paid off. The building we see today, surrounded by its small park and entered on one level through an inviting skylit atrium, has those three extra floors and more. Within its walls the vision continues. “While the Joslin represents many things to many people, what it should represent in everyone’s mind is the world leader in diabetes research,” says C. Ronald Kahn, M.D., President of Joslin Diabetes Center and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.

In 1898 Dr. Joslin (EPJ to his colleagues) opened a medical office on Bay State Road and joined the staff of the just-opened New England Deaconess Hospital (NEDH). He decided to study diabetes, then an obscure and poorly understood disease, after his mother was diagnosed with it and an aunt died from the disease several years later. The pancreas had just been identified as the relevant organ in control of metabolism, but its exact role was still unknown, since at this time hormones had yet to be discovered. Undaunted by these mysteries, EPJ established the world’s first diabetes registry and, in 1900, his “magnificent obsession” with diabetes led to a life-changing meeting in Germany with Adolph Magnus Levy (1865-1955), then considered a world leader in metabolic investigation. For twenty years EPJ tackled the “fatal” disease with every available treatment. Banting and Best’s discovery of insulin in 1921 revolutionized diabetic care and positioned EPJ as a natural leader in its clinical treatment. In 1924 he recruited Dr. Priscilla White (1900-1989) to work in his diabetic clinic and take charge of the clinic’s pregnant women and children. In addition to teaching medicine at HMS and Tufts University School of Medicine and directing the Joslin Clinic’s youth division, Dr. White also held medical positions at Faulkner Hospital and the Boston Hospital for Women, was consultant to the Boston Floating Hospital and Boston Children’s Hospital, and helped to found the Clara Barton Birthplace Camp for Diabetic Girls. Author of the textbook, Diabetes in childhood and adolescence (1932), and frequent co-editor with EPJ, Dr. White is best known for devising “White’s classification of diabetes in pregnant women,” which predicted fetal survival based on maternal age at disease onset, duration, and the presence of complications.

The Brigham and Women's Hospital Department of Medicine has had a research affiliation with Joslin for many years. Your Medicine Online met recently with Dr. Kahn and George L. King, M.D., Professor of Medicine at Harvard Medical School and Research Director at Joslin Diabetes Center, to learn more about these collaborations.

Your Medicine Online: Dr. Kahn, tell us about the Joslin Diabetes Center, and its relationship with the BWH Department of Medicine.
C. Ronald Kahn : I will start off by saying that the Joslin is truly a unique organization. While there are other excellent diabetes programs, with great people, the Joslin is much more comprehensive in its vision of the problem. Joslin has not only a huge number of type 1 diabetes initiatives in research and clinical care, but also has large initiatives around type 2 diabetes, and diabetic complications, all brought together in a single institution. In this context, we bring everything we can to bear on the problem, from basic research, to clinical research, to clinical care, education, and in many cases to outreach efforts. Because we are large and comprehensive, there is the ability to interact with the “best of the best” across a variety of diabetes disciplines, whether immunology, islet transplant, or vascular complications, or my specialty, type 2 diabetes research.

Copyright 2005 Joslin Diabetes Center

The relationship with the BWH Department of Medicine is another unique aspect of Joslin. Historically, Joslin has had what I’ll call a ‘bivalent’ position, associated in two different directions at the same time, which among Harvard institutions has become –unfortunately—increasingly rare. For the first fifty years of the existence of this institution, and more correctly, Dr. Joslin was tightly linked in several directions. His clinical practice was part of the NEDH, although he also did some metabolic research with collaborators in the Department of Physiology at the Medical School. However, there was always a relationship with the Lying-In, related to its maternity and delivery unit. In the 1920s, when insulin became available and type 1 diabetes was no longer a rapidly fatal disease, it became clear that women with diabetes could actually go through pregnancy. Priscilla White joined the staff, and strengthened the relationship with the Lying-In hospital, both from a clinical and clinical research perspective.

The real link with the Brigham came in the early 1950s, when George Thorn was chairman of Medicine at the Peter Bent Brigham Hospital (PBBH). Around the mid-1950s, when Elliott Joslin decided to add an element of more basic research, the first person he recruited as a basic science research director at the Joslin was one of Dr. Thorn’s protégés, a French-Swiss physician named Albert Renold (1923-1988). George Cahill, another Thorn protégé, stepped into the position several years later when Renold returned to Switzerland. Prior to that, Alexander Marble was named Director of Research at Joslin, but his research was very much part of the clinical practice. So Renold and Cahill were the initiators of what became known as the Elliott P. Joslin Research Laboratories, with its focus on basic research. George Cahill served as Research Director while also, I believe, serving as head of the Endocrine-Metabolic Division for the Peter Bent Brigham Hospital. Thus there was this very unusual relationship, with the Clinic tightly affiliated with NEDH—which became BIDMC—and the Research division became more closely linked to the PBBH, which became the BWH. In fact when I was recruited, in 1981, it was as head of research for Joslin Diabetes Center and also head of diabetes at BWH. I did this for 10 years. There was some ambivalence even then about how you could be in two institutions, but I never saw it as a problem. My philosophy was that we don’t need to compete over patients with diabetes; there are plenty of them. What we do need is to make sure they get excellent care, and to establish the best possible paradigms for care and research. The diabetes service at BWH was part of the division of Endocrinology, but the division really had three leaders. Gordon Williams was the head of Endocrinology; Reed Larson was the head of the Thyroid unit, and I was head of Diabetes and Metabolism.

So we have a 53-year relationship with the Brigham, much longer if we go back to Dr. White’s relationship to the Lying-In. It has been characterized by very strong, positive relationships. Gene Braunwald, who recruited me to Boston and whom I consider a true mentor, had both the energy and the vision to create a truly great department of medicine, but also built strong bonds between institutions in the Longwood area, including between BWH and Joslin.

Today these interactions continue, especially at the level of research. My research focuses on type 2 diabetes and aspects of insulin resistance, where we have had a number of important collaborations. We had strong research interactions with Andrea Dunaif, a specialist in polycystic ovarian (PCO) disease, while she was Chief of the Division of Women’s Health at Brigham and Women’s Hospital and Director of Harvard Medical School’s Center of Excellence in Women’s Health several years ago. We currently interact closely with Dennis Selkoe’s laboratory in Neurology, which is studying the relationship between insulin resistance and neurodegenerative diseases, and I have also collaborated with members of the Joe Loscalzo’s group, when he was still at Boston University. This is because insulin resistance is central to the pathophysiology of so many disorders, including obesity, the metabolic syndrome, hyperlipidemias, hypertension, accelerated atherosclerosis. It’s also linked to other medical problems like non-alcoholic fatty liver disease, PCO disease, and even neurodegenerative diseases like Alzheimer’s disease. Insulin resistance syndrome is a collection of related diseases, of which diabetes is the most obvious metabolic disorder and obesity probably second.

Our immunologists also interact with the immunology groups at the Brigham and other area Harvard institutions. So we have great people on both sides of the street and we take advantage of that. Fortunately, research is slightly less encumbered by the boundaries of the hospital systems. This has been a major strength of the Harvard environment.

YMO: Dr. King, tell us a little about your background and some of your team’s most exciting research projects.
George L. King: I trained as a diabetes and endocrinology person and was at the NIH as a fellow when Ron Kahn was hired as Research Director here. He brought me on as a junior faculty. At that time, and still today, the research division at Joslin received most of our appointments through the Department of Medicine at the Brigham, while Joslin Clinic receives most appointments through Beth Israel. This tradition has been going on for ages. We are one of three divisions at the Joslin Diabetes Center. One is the Clinic, with its affiliation with BIDMC. One is the Research division, with many active affiliations with the BWH. And the third is our Strategic Initiative (SI), which includes publications, professional medical education, disease management, the Joslin Vision Network and affiliated centers across the country and internationally. In the Research Division we have 11 sections and about 300 people and about 120-140 fellows at any one time. We have about 40 full-time faculty in research.

With 11 sections, there are many exciting projects, so I’ll give you just a few examples. Among the researchers studying type 1 (insulin-dependent or juvenile) diabetes, we have an outstanding immunology section headed by Drs. Diane Mathis and Christophe Benoist, who jointly hold the William T. Young Chair in Diabetes Research at Joslin. They are both on the BWH Department of Medicine faculty, and are also both elected members of the National Academy of Science. They work on what goes wrong in the T cells that induce the autoimmune process that cause the destruction of islets that cause type 1 diabetes. They also head up the Juvenile Diabetes Research Foundation (JDRF) Center on Immunological Tolerance in Type 1 Diabetes at Harvard Medical School. Their project has two aspects. The first is understanding how the body tolerates itself. Type 1 diabetes occurs when the body begins to destroy its own islet cells, which produce insulin. If you could fix that, you could prevent type 1 diabetes. The Mathis/Benoist lab has done an incredible amount of work to understand that process. The second aspect is the question: how can you induce people to accept transplanted islets? How can you induce “tolerance” so the body will accept the transplanted islets? It’s actually very difficult. Transplant patients currently are on high doses of immunosuppressive agents, increasing the risk of many other problems. So this is one very, very exciting study.

Another important initiative in diabetes research is stem cell research. In the Developmental and Stem Cell Biology Section at Joslin, headed by Dr. T. Keith Blackwell, our number one goal is basic science—learning how stem cells develop into specialized cells—and then taking this information into clinical medicine. Joslin is also an active participant in the Harvard Stem Cell Institute, which includes representatives from every Harvard institution. We have several faculty involved in the program, including Dr. Mathis, who is on the HSCI Executive Committee. Dr. Gordon Weir, head of the Joslin Section on Islet Transplantation and Cell Biology, heads the HSCI diabetes program. Dr. Weir, who holds the Diabetes Research and Wellness Foundation Chair at Joslin, oversees the Human Islet Core Facility at Joslin which isolates islet cells for human transplantation and provides them to multiple transplant groups around New England. The group looks not only at transplant from a clinical point of view, but also explores how the islet grows and ways to identify alternate sources of insulin-producing cells. I should also mention the work of Dr. Steve Shoelson on insulin resistance and type 2 diabetes. Dr. Shoelson was trained at BWH Dept of Medicine as a resident. This

included research time at the Joslin with Dr. Kahn. He then did his fellowship in the joint Longwood area program, spent more time in research with Ron and finally joined the staff at Joslin with his appointment in the Department of Medicine at the BWH. This past year, he was named Professor of Medicine at Harvard Medical School– which is a testament to the joint efforts of Joslin and BWH to mentor and train new faculty. He also holds the Helen and Morton Adler Chair in Structural Biology at Joslin. His February 2005 publication in Nature Medicine catapulted Steve to national prominence.

YMO: What’s your opinion, Dr. King, about the current media focus on a “diabetes epidemic”? How do you measure this problem, and how is it related to obesity?
Dr. King: I don’t use the word “epidemic” lightly, but there is clearly a huge increase in obesity. Obesity has almost doubled in the past ten years. And whenever you have a higher prevalence of obesity, you have a huge increase in diabetes.

For example, twenty years ago the prevalence of diabetes in adults was 4%; now the national average is 6.3%, but the rate is as high as 8-10% in some states, according to CDC statistics. The highest increase comes from minority populations. About 12% of Hispanics over age 20 have diabetes, and the rate is slightly higher for African-Americans; one out of every five African-American females over age 55 has diabetes. Among Asian-Americans, 10% over age 20 have diabetes. And Asians are not, for the most part, obese. We know both environment and genetics play a role, but the gene can’t have changed so quickly in the last twenty years. It has to be partly genetic because we know certain groups have higher rates of obesity, and certain groups have more diabetes, even without obesity. For example, in rural Asia there is only 2% diabetes. The rate is 10% for Asian-Americans in the U.S. In Hong Kong it’s 12%. A hundred miles north of Hong Kong, it’s only 2%, in a population that is genetically the same. But if you take a Caucasian and move them to Hong Kong, the rate is still 4-5%.

YMO: Finally, are there new directions or changes you would like to see in the ongoing development of this rich research relationship between the Joslin and the BWH Department of Medicine?
Dr. Kahn: We have seen many great interactions and still have opportunities for many more. Fortunately physicians and scientists are often very collegial at a personal level, and this allows important research collaborations. Unfortunately, it is more difficult on the clinical side, since hospitals, even Harvard teaching hospitals, often feel competitive with one another. In endocrinology and metabolism, we have overcome this by creating a joint Longwood Area Endocrine Fellowship, a training program involving fellows from the BWH, BIDMC, and the Joslin. Fellows are recruited by one of the three institutions, and share the same clinical rotations. They go back to their parent institution for their research. As a joint program, it has benefited everyone, and in my opinion provides a much stronger fellowship training experience. The fellows love it. They experience different kinds of hospital environments. At Joslin, we also have a joint fellowship with the Children’s Hospital that been very successful in recruiting some of the strongest pediatric endocrine fellows to their program.

Dr. King: In fact, when I first established my vascular cell biology lab here, I learned how to grow endothelial cells from Mike Gimbrone, head of the Pathology department at the BWH. And when Ron and I came to Joslin, in 1981, we began the joint lectureship with the BWH Department of Medicine, the Priscilla White Lectureship. Dr. White was a Radcliffe undergraduate who was not allowed to enter HMS since they didn’t accept women. We actually have her rejection letter from Harvard. But Dr. Joslin thought very highly of her, and wanted someone to work with children and pregnant women. Dr. White was able to reduce mortality rates from approximately 80% to the mother or the children, to less than 40%, a huge change. We wanted to honor her, and Dr. Braunwald was very supportive. We have had some of the best people in the world as Priscilla White lecturers, including four Nobel Prize winners.

Other collaborations include, for example, complications of diabetes, which is my area. We work on answering the question, why does the diabetic patient develop eye disease, kidney disease, and heart disease? My lab collaborates with several members of BWH’s cardiology division. For example, we collaborate with Drs. Rich Lee and Jim Liao, to understand how high glucose levels, oxidative stress and insulin resistance may play a role in causing diabetic heart and vascular complications. Allison Goldfine, one of the key members in our clinical research section here, works very closely with Mark Creager at the BWH, and uses the BWH CRC. The BWH Department of Medicine and other departments have great scientists and this has helped both sides to form collaborations. More speaker exchanges would be very good. The more we know about the other scientists, the more interaction there will be.

Dr. Kahn: I think one of the things that’s particularly important in the area of diabetes research is that we’re not just doing endocrine research. We’re doing cardiovascular research. We’re doing eye research. We’re doing various kinds of physiology, lipid metabolism research, liver research. And so one of the things that I think is really a very strong plus is our interaction, and the interactions we have with all Harvard institutions.

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For more information:

Joslin Diabetes Center website
Joslin Diabetes Center Research Laboratories website
Centers for Disease Control (CDC), statistics on diabetes
World Health Organization, “The Cost of Diabetes”

On the History of the Joslin Diabetes Center:
Barnett DM. “Dr. Joslin’s Magnificent Obsession.” Joslin Magazine. 2005 (Spring issue):22-25.
Dunn PM. “Dr. Priscilla White (1900-1989) of Boston and pregnancy diabetes.”
Arch. Dis. Child. Fetal Neonatal Ed. 2004;89:276-278. Available online at http://fn.bmjjournals.com/cgi/content/full/89/3/F276


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