Milestones in European Thyroidology (MET)

Jacob Robbins (1922-2008)

For many thyroidologists, Jack Robbins was not only a great scientist but also an excellent clinician, a friendly, gentle person, always encouraging everyone. It is also because he developed so many links with European investigators that he was made Honorary member of the European Thyroid Association in 2001. Until his sudden death at age 85, he kept active in many fields of thyroid research, and most particularly in the last years in the follow-up of pediatric thyroid cancer resulting from radioactive fallout after the Chernobyl nuclear reactor disaster in 1986.

He was born in Yonkers (N.Y., USA) in 1922. Benefiting of a scholarship awarded by Cornell University, he started at Cornell (Ithaca, NY) in 1940, studying chemistry and obtained an undergraduate degree in 1944. He then continued at Cornell Medical College in New York City. His studies were interrupted by World War II when he had to join the US army and he finally graduated as MD in 1947. After his internship in Medicine, he moved to the Memorial Hospital as resident and as research fellow at the Sloan-Kettering Cancer Center in New York, joining the team of Rulon Rawson. In 1950, Ed Rall came from the Mayo Clinic, where he had been working with Raymond Keating and Alexander Albert, then leaders in radioiodine (131I) kinetic research, to the Sloan-Kettering. From then on, the team "Robbins & Rall " developed a constant and exploding interest in thyroid metabolism. Jack Robbins left New York in 1954 to join the recently created NIH Clinical Center in Bethesda. In 1955, Ed Rall was invited to Bethesda in order to develop and to lead the Clinical Endocrinology Branch (CEB) at the National Institute of Arthritis and Metabolic Diseases (NIDDK). In 1963, Rall became scientific director of the NIDDK and Jack Robbins became Chief of the Clinical Endocrinology Branch (CEB) from then through 1991. Scientists having a great variety of competences, such as Hans Cahnman (an organic chemist), Harold Edelhoch (a physical chemist), Jan Wolff (an MD with a Ph.D. in Biochemistry), Ira Pastan, Jesse Roth and Philip Gorden (three clinical associates of the CEB) and several others constituted an almost permanent core of the CEB for many years. The charisma of Ed Rall first and then of Jack Robbins allowed to maintain a remarkable stability within the group and thus a constant scientific productivity. Many fellows came to work at the CEB in exchange programs, particularly from Italy, Belgium and Japan.

Involved in the use of radioiodine (131I) for the treatment of thyroid cancer, Jack had become interested in the study of the circulating radioiodinated compounds of patients treated with radioiodine for thyroid cancer. Using paper chromatography, he concluded on the presence of labeled thyroxine and thyroglobulin in the blood. Then, by the recently developed paper electrophoresis, he observed that the circulating thyroxine was bound to an inter-alpha globulin. Robbins and Rall developed a series of experiments to understand the role of the thyroxine-binding globulin (TBG). Together with Ed Rall, Jack Robbins put forward the hypothesis that thyroxine had to be «free thyroxine», or not bound to any plasma proteins to be active at the peripheral level. The free thyroxine hypothesis was progressively expanded and investigated in a series of clinical situations. The T4 bound to TBG was considered as acting as a buffering system to store the circulating thyroid hormones in equilibrium with minute amounts of unbound or free thyroxine effective at the cellular level.

Jack published more than 260 papers over the course of his career and was active in a number of exchange programs that brought thyroid specialists not only from the States but also from Europe, (particularly from Italy and Belgium), from Japan and other parts of the world to NIH. The list of visiting scientists and young postdoctoral fellows who were associated directly with Jack Robbins while he was Chief of the CEB is impressive (see Table). In fact, the list of all foreign scientists working at the CEB in those years is much longer. Particularly continuous was the flow of European scientists and especially so of Italian scientists, the first of whom, Mario Andreoli, from Rome, joined the lab of Jack Robbins in 1959. Nino Salvatore started the Neapolitan flow in 1962. Giancarlo Vecchio first met Jack in 1963, when working in his lab for two years as a postdoctoral fellow. Soon started not only a very fruitful collaboration, which was also shared with Nino and Marisa Salvatore, but also a very strong, friendly relationship with both Jack and his wife, Jean and with the entire family, which still lasts now.

At the beginning of the 1960's, another protein was receiving great attention and this was thyroglobulin (TG), the main thyroid store of thyroid hormones. Studies on the molecular structure of thyroglobulin strongly benefited from the presence at the CEB of Hans Cahnman and Harold Edelhoch. In fact, together with Nino and Marisa Salvatore, Cahnman, Edelhoch and Vecchio, Robbins worked on the purification, isolation and the physico-chemical characterization of an as yet undiscovered iodoprotein, the 27S iodoprotein, which constitutes about 5% of the total thyroid iodoproteins in the gland.

But several other subjects of investigation were carried on in the following years in Jack's lab by other European and non European investigators, such as abnormal TG, iodoproteins in experimental rat thyroid tumors ( a model developed by another eminent scientist, not directly associated with the CEB, namely Sy Wollman), thyroid polyribosomes, T-3 uptake in rat skeletal muscle and many others. However, the problem of thyroid hormone-binding proteins in blood continuously attracted the research interest of Jack, who has continued to make fundamental discoveries in this field. Robbins kept pursuing his researches on the thyroxine-binding proteins in different pathophysiological states, during pregnancy and in early human fetuses and newborns. As a model, TBG biosynthesis was studied in vitro in isolated monkeys' hepatocytes and in cultured human hepatoma cells. The effects of estrogens on TBG metabolism in Rhesus monkeys were also studied. Besides studying TBG, Jack focused his attention on another important serum hormone-binding protein, called prealbumin. Thyroxine-binding prealbumin (TBPA), now known as transthyretin (TTR), was studied extensively by Jack and his co-workers. It may have a possible role in the delivery of thyroid hormones to parts of the central nervous system. Considering the general thyroid economy, TBG-T4 acts as the " saving account " and the TBPA-T4 as the " checking account " responsible for the peripheral distribution of thyroid hormones. The CEB group largely contributed to the understanding of the molecular, the physicochemical properties and the binding characteristics of the human T4 and T3 transport proteins allowing understanding of the storage function and the buffering role of these carriers. More recently, the lipoprotein-thyroid hormones interaction were investigated in collaboration with Salvatore Benvenga, coming from another Italian town, Messina, in Sicily.

Jack Robbins was also a leading authority on the effects of radioactive fallout. In further fruitful collaboration with Ed Rall, he had studied incidences of thyroid cancer in patients exposed to radioactive fallout from nuclear testing. Jack Robbins has helped direct long term studies on the survivors of nuclear tests and accidents in the inhabitants of Nagasaki and Hiroshima and of the Marshall Islands from the 1940's to the 1980's. His research on preventing and treating radiation-related problems helped save lives and prevent illness during the near-meltdown at Three Mile Island in the U.S. He continued his research, after retirement, following the health effects of iodine fallout after the Chernobyl reactor meltdown in Ukraine in 1986. Earlier, in the 1950's, he had examined the therapeutic properties of radioactive iodine when used to pinpoint and treat cancer in the thyroid, a treatment of choice nowadays for differentiated thyroid cancer.

Besides leading the CEB, Robbins fulfilled several offices as Editor-in-Chief of Endocrinology (1968-1972) and as President of the American Thyroid Association (1974-75). In 2001, he received the "Laurea" (M.D. degree) Honoris causa from the University of Messina. He was Honorary member of the European Thyroid Association, the Italian Endocrine Society and the Japanese Endocrine Society. He became Scientist emeritus (NIDDK, NIH, PHS) in 1995 but continued directing the Foundation for Advanced Education in the Sciences at NIH (2000-05) as President. He was awarded many prizes and honours.

Jack was a regular attendee of most of the ETA meetings. He maintained a strong scientific relationship with several European scientists who had been working at the CEB and always nurturing his old fellows. In particular, his relationship with the Naples laboratory was strengthened by his frequent trips to Naples and his continued collaboration with Nino Salvatore, Giancarlo Vecchio and other members of the Naples lab. Our scientific interests, which had begun with thyroglobulin in 1963, shifted to another mutual interest, this time thyroid cancer, another field where Jack Robbins has made outstanding contributions.

Jack was a gentle and a soft spoken man with an acute sense of humor. His way of welcoming everyone with Jean, his wife, not only at the NIH but also at home and at the cattle farm are among the many souvenirs we keep of him in our heart. The memory of Robbins' New Year's Eve with 4 different quartets playing in different parts of the house will always remind us of the quality of life that the Robbins constantly preserved.

Giancarlo Vecchio (1) and Christian Beckers(2)
(1) Universita degli Studi di Napoli Federico II (Italy)
(2) University of Louvain Medical School (Belgium)