Abstract
RAI, radioactive iodine; TH, thyroid hormone; TRH, thyrotropin releasing hormone; TRH-R, TRH receptor; TSH, thyrotropin; TSH-R, TSH receptor.
During the initial two decades, a number of studies that used radioactive iodine (RAI), which was at the time newly available, were performed by CEB scientists. Dr. Joseph Edward (Ed) Rall, the founding Chief of CEB, and Dr. Jacob (Jack) Robbins, who later became CEB Chief, performed a series of studies, which they had been begun with Dr. Rulon Rawson at Memorial-Sloan Kettering Cancer Center in New York, on the use of RAI in the diagnosis and treatment of thyroid diseases, in particular of thyroid cancer. Drs. Rall and Robbins established the safety and efficacy of RAI usage and in collaboration with computational biologists, in particular Dr. Mones Berman of another NIDDK laboratory, developed a kinetic model of iodine metabolism that was used to optimize the effective RAI dose administered, while reducing its suppressive effects on the bone marrow (1). Simultaneously, Drs. Rall and Robbins began their studies of serum thyroid hormone (TH) binding proteins that led to the breakthrough “free” TH hypothesis in which they elucidated the role of free (or unbound) TH, as opposed to total TH in blood, as the biologically relevant TH component (2). These studies were part of one of the most successful collaborations in the history of thyroid research.
Another early recruit to CEB was Dr. Jan Wolff. While in the laboratory of Dr. I.L. Chaikoff at the University of California, Berkeley, Dr. Wolff discovered the inhibitory effect of high concentrations of iodide on iodine organification in the thyroid, a major regulator of thyroid gland function (“Wolff-Chaikoff effect”). Dr. Wolff, in some studies in collaboration with Drs. Rall and Robbins, made a number of seminal contributions to our understanding of the transport of iodide and other anions in the thyroid gland that predicted the discovery of the sodium-iodide symporter (3). A related finding by Drs. Wolff and Robbins was that lithium ion was an inhibitor of iodide release by the thyroid. This finding, as with so many basic discoveries by NIDDK investigators, was translated into clinical use of lithium in the treatment of hyperthyroidism and as an adjunct in the RAI treatment of thyroid cancer (4).
The initial studies of TH binding proteins were extended by a collaboration within CEB between Dr. Robbins and Dr. Harold Edelhoch. In these experiments, the structure and binding properties of thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (transthyretin) were elucidated. For example, the single polypeptide chain functional unit of TBG, which binds a single molecule of TH, was shown to be different than the oligomeric transthyretin, which binds two molecules of TH in a negatively cooperative manner and binds retinol-binding protein. Another important area of collaboration amongst Drs. Rall, Robbins, and Edelhoch involved studies of thyroidal iodoproteins, in particular thyroglobulin. For example, in a series of elegant studies, they delineated the structure of thyroglobulin and its role as a substrate for iodination as the precursor of THs (5). Studies of thyroglobulin and other iodoproteins were joined by Dr. Hans Cahnmann who delineated the coupling mechanism within thyroglobulin that led to TH synthesis and also synthesized many TH analogs that were used to study TH metabolism (6).
At the same time the structural studies of TBG were being performed, experiments to elucidate the site and regulation of the biosynthesis of TBG were ongoing. For example, Dr. Robbins' laboratory showed conclusively that TBG is synthesized in the liver and both the synthesis and secretion of TBG are enhanced by estrogen (7).
Clinical research collaborations that included Drs. Rall, Robbins, and Wolff involved their participation in studies of RAI fallout after hydrogen bomb testing in the Pacific Ocean near the Marshall Islands and after the Chernobyl accident, and of reactor protection measures in the United States (8).
Initially in collaboration with Dr. Rall, Dr. Vera M. Nikodem and then Dr. Sheue-yann Cheng performed studies of TH nuclear receptors. Their research, in which they used triiodothyronine (T3) derivatives to covalently label the receptor, provided early insights into the structure and function of the nuclear receptor by showing that it was a single polypeptide chain that binds either T3 or thyroxine (9). More recently, Dr. Douglas Forrest continued studies of the molecular biology of THs. His continuing research focuses on the roles of THs, TH deiodinases, and TH receptors in development of mammalian sensory systems. In particular, Dr. Forrest has described the critical role of local generation of T3 in the development and homeostasis of the mammalian retina (10).
Dr. Bruce D. Weintraub performed research on several aspects of the biology of the pituitary–thyroid axis. He studied the regulation of thyrotropin (TSH) gene transcription and cloned the complementary DNA (cDNA) for the TSH beta-subunit. He produced biologically active, dimeric TSH in cells in tissue culture that led to a series of collaborations in which recombinant human TSH was developed for use in patients. Dr. Weintraub studied the structure–function relationships of TSH and created novel TSH mutants that exhibited increased activities (11). His translational and clinical research also included studies of pituitary (12) and TH resistance syndromes and TSH-secreting pituitary tumors in collaboration with many extramural investigators (13).
Upon returning to the CEB, I continued my studies of the thyrotropin releasing hormone (TRH)/TRH receptor (TRH-R) and the TSH/TSH receptor (TSH-R) systems. Our studies focus on understanding how the TRH-R and the TSH-R function at the molecular level and on the development of small molecule ligands (SMLs) for these receptors. Our studies involve collaborations with computational chemists, organic chemists, molecular pharmacologists, and neuroscientists. For the TRH-R and the TSH-R, we characterized molecular details of their signaling and regulation in in vitro models, of their biology in intact animal models (14 –16), and developed SMLs as probes of extra-pituitary functions of the TRH-R (17) and extra-thyroidal functions of the TSH-R (18). We think that SMLs for the TRH-R may be used in the future as treatment for several nervous system disorders, SML agonists for the TSH-R may be used in clinical practice to stimulate radioiodine uptake by residual thyroid cancer cells in the diagnosis and treatment of patients with thyroid cancer, and SML antagonists for the TSH-R to treat Graves' disease, especially ophthalmopathy.
In summary, there have been wide-ranging studies of the hypothalamic–pituitary–thyroid axis conducted by CEB investigators,3 which have impacted our understanding and treatment of diseases of the thyroid gland. The success of these collaborations amongst multidisciplinary teams of scientists, which began in CEB more than 50 years ago, is still a model for biomedical research into the future.
Footnotes
Acknowledgment
The author thanks Dr. Jan Wolff for his thoughtful comments regarding this commentary.
1
The CEB was disbanded as part of a re-organization of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Intramural Research Program in 2010.
2
Although investigators in the CEB performed research in other areas of endocrinology, this commentary is limited to research performed in thyroid-related areas.
3
In addition, thyroid researchers from around the world spent time as trainees or visiting scientists at CEB. These scientists made important contributions to the research performed in CEB and were among the many scientists who collaborated with CEB investigators when at their home institutions. The trainees subsequently filled many senior medical school and research institute positions throughout the world.