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GERALD DONALD AURBACH March 24, 1927–November 4, 1991 By IRA PASTAN G erald d. a urbach r evolutionized o ur understanding of bone metabolism and calcium homeostasis. Gerald D. Aurbach was born in Cleveland, Ohio, on March 24, 1927, but grew up in Washington, D.C. After spending one year in the U.S. Army-Air Force at the end of World War II, he entered the University of Virginia, where he received his bachelor’s degree in 1950 and his M.D. in 1954. These years at the University of Virginia were some of the happiest days of Gerry’s life and he remained devoted to the University of Virginia for the remainder of his life. He received the singular honor of being named the Centennial Alumnus of the university in 1988. Ironically it was during a visit to the university on November 4, 1991, that he was fatally injured in a senseless act of violence. Gerry began his studies on parathyroid hormone early in his career while a medical student at the University of Virginia in the laboratory of Dr. William Parson. Dr. Parson was chief of medicine and a professor of medicine at the University of Virginia. A renowned endocrinologist, Parson had worked with Dr. Fuller Albright, a leader in the field of endocrinology and metabolism, while training at the Mas- sachusetts General Hospital. After graduation from medical school, Gerry took an internship at the New England Medical 3

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4 BIOGRAPHICAL MEMOIRS Center and a residency at the Boston City Hospital. In 1956 he joined the laboratory of Ted Astwood as a research fel- low at Tufts Medical School, where he was able to continue his studies on parathyroid hormone. This area of research occupied most of his research career. At that time only a few polypeptide hormones had been characterized. It was known that injection of an extract of parathyroid glands into test animals raised calcium levels in the blood, but the nature of the active substance was not known. Many investi- gators had already tried to purify this factor without success. Gerry thought of the novel idea of using phenol extraction to remove the hormone from proteins with which it was as- sociated and to inactivate proteases causing its degradation. This approach was very successful and a paper published in 1959 established Gerry as the leader in the field. Despite his early success Gerry felt he needed further training in research and applied to a new, prestigious train- ing program at the National Institutes of Health in Bethesda, Maryland. Gerry was selected for the Research Associate Training Program and in 1959 joined the laboratory of William Jakoby, where he received training in enzyme bio- chemistry. In 1961 he accepted a research associate position in the Metabolic Diseases Branch of the National Institute of Arthritis and Metabolic Diseases and established his own research group. He spent his entire career in the branch, eventually becoming its chief in 1973. When Gerry started his own laboratory, he returned to the parathyroid hormone field. His first goal was to obtain sufficient amounts of highly purified protein to determine its sequence. This was a challenging problem because the amount of hormone in each parathyroid is very low; para- thyroid glands are small and protein purification techniques were in their infancy. Aurbach and colleagues were able to overcome these obstacles and they obtained sufficient

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5 GERALD DONALD AURBACH amounts of highly purified bovine and human hormone to fully characterize the protein. In addition, they were able to chemically synthesize a biologically active form of the protein. These studies opened up the field of parathyroid hormone research, eventually leading to the understand- ing and treatment of several important diseases, including osteoporosis. The availability of purified parathyroid hormone enabled Gerry to investigate several new areas of research. One of these was to develop a radioimmunoassay that could measure parathyroid hormone levels in the blood and other body fluids. This assay became a valuable tool in the diagnosis of hyperparathyroidism. A second was to radiolabel parathyroid hormone and determine its pharmacokinetic behavior. And a third was to investigate the mechanism of parathyroid hor- mone action. Influenced by the classic studies of Earl Suther- land, Gerry reasoned that parathyroid hormone acted on its target tissues, kidney and bone, by raising cyclic adenosine monophosphate (AMP) levels. To study this process in ani- mals and humans he and his fellow, Lew Chase, developed a highly sensitive assay for cyclic AMP. They then used this assay to show that parathyroid hormone activated adenylate cyclase and elevated cyclic AMP levels in target cells and in the urine. The cyclic AMP in the urine could be used to as- sess the parathyroid hormone status of patients, an invaluable clinical tool. He was also in the position to investigate some hereditary diseases of calcium metabolism. Fuller Albright had described pseudohypoparathyroidism as the first example of a disease of hormone resistance rather than hormone deficiency. Gerry and Lew Chase discovered that patients with pseudohypoparathyroidism failed to elevate cyclic AMP levels in the urine in response to parathyroid hormone and showed that the biochemical basis of this was a defect in the ability of parathyroid hormone to activate renal adenylate

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6 BIOGRAPHICAL MEMOIRS cyclase. And later, with Allen Spiegel, Gerry showed that the specific defect in adenylate cyclase was a deficiency in the guanine nucleotide binding protein Gs. Gerry’s contributions extended outside the parathyroid hormone field and had broad implications for the entire field of hormone action. One very important contribution was the design and synthesis of radiolabeled iodohydroxy- benzylpindol. This compound was used as a marker of spe- cific binding to the beta-adrenergic receptor, and enabled Aurbach and colleagues to study in detail a critical initial step in hormone action. Gerry was a fine physician and his groundbreaking re- search in the parathyroid hormone field resulted in many patients being referred to the National Institutes of Health from community hospitals as well as large medical centers in the United States and abroad. Gerry being a compassionate person and physician kept in close touch with his patients over the years. In collaboration with John Doppman, a radiologist from the Clinical Center, and many endocrine surgeons, including Sam Wells, Murray Brennan, and Jeff Norton, Gerry’s team achieved an extraordinary success rate in treating patients with hyperparathyroidism who had previously had unsuccessful neck exploration; thus, making the NIH Clinical Center the leading referral center for the treatment of hyperparathyroidism. Additionally, studies by his group, and particularly with Steve Marx, led to the characterization of several hereditary forms of hyperparathyroidism (multiple endocrine neoplasia Type 1, familial hypocalciuric hypercalcemia, hyperparathy- roidism-jaw tumor syndrome) and the eventual identification of the genetic basis for each of these diseases. One striking example of Gerry’s impact on clinical medicine is the cur- rent excitement about using parathyroid hormone to treat osteoporosis.

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7 GERALD DONALD AURBACH Gerry’s reputation as an outstanding researcher and a superb mentor and clinician encouraged young physicians to come to NIH to work and train in his laboratory. Many are now leaders in the endocrinology and biomedical com- munities; these include Lew Chase (chief of medical service, Veterans Affairs Medical Center, Washington University, St. Louis), Allen Spiegel (director of the National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]), Steve Marx (chief of the Metabolic Diseases Branch at NIDDK), Ed Brown (Endocrine/Hypertension Division at Brigham and Women’s Hospital in Boston), Maria Luisa Brandi (professor in the Endocrine Section at the University of Florence in Italy), and John Bilezikian (chief of the Endocrine Division at Columbia University Medical Center in New york). Gerry’s contributions were recognized by many awards, some of which included the John Horsely Memorial Award from the University of Virginia in 1960, the Andre Lichiwitz Prize from France in 1968, the William F. Neuman Award of the American Society for Bone and Mineral Research in 1981, the Gairdner Foundation International Award in 1983, the Edwin B. Astwood Award from the Endocrine Society in 1985; and the Distinguished Service Medal of the Public Health Service in 1988. Perhaps one of the most meaningful awards was the Ed- win B. Astwood Award of the Endocrine Society. This was because Gerry began his research career in Dr. Astwood’s laboratory and was very active in the Endocrine Society, holding positions on various committees and serving as its president from 1998 to 1999. Since his death, both the Endocrine Society and the American Society for Bone and Mineral Research have established memorial lectures in his honor. The University of Virginia Medical School established the Gerald D. Aurbach Professorship in Endocrinology in 1998 in recognition of his scientific contributions and his

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8 BIOGRAPHICAL MEMOIRS service, and in 2002 the university named their new medical research building “The Gerald D. Aurbach Medical Research Building” in his honor. Gerry was a member of many prestigious medical societ- ies, including the American Society for Clinical Investiga- tion, the American Society for Biochemistry and Molecular Biology, and the Association of American Physicians. He was a founding member of the American Society for Bone and Mineral Research. He served as president of the Endocrine Society. In 1986 he was elected into the National Academy of Sciences. Gerry was a fourth generation Washingtonian. His moth- er’s family arrived in Washington in 1859. He attended the Lafayette Elementary School and graduated from Wilson High School in 1945. Part of his reason for joining the NIH staff was to return to the city he loved. Gerry was a devoted husband to Hannah, whom he married in 1960, and he was a wonderful father who set a fine example for their daughters, Elissa and Pamela. yearly family vacations at North Shores in Rehoboth Beach, Delaware, and in Virginia Beach, Virginia, were always looked forward to. Winter trips to Colonial Williamsburg, Virginia, through New year’s Eve were also a favorite, especially since Hannah was from the Tidewater area. A lover of classical music, Gerry was also an accomplished pianist who enjoyed sitting down at his Steinway Grand (which he had played since age 6) upon returning home from work no matter what the hour. He could often be seen jogging in Great Falls Park close to his home in Potomac, Maryland. He was an avid Redskins fan through both the good and bad times. He and his dad seldom missed attending the Sena- tors baseball games. He was a collector of old maps, and any John Wayne movie was his favorite. He and Hannah visited all new art exhibitions in Washington and found local art

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9 GERALD DONALD AURBACH museums when traveling; the Smithsonian National Air and Space Museum was Gerry’s favorite because of his love of flying. Gerry also enjoyed traveling. Trips to Asia (especially Singapore), Israel, and Europe, often combined with meet- ings and speaking engagements, were always very special to both Gerry and Hannah. I met Gerry in Boston when he was a fellow in the labora- tory of Ted Astwood and I was a medical student. We came to the National Institutes of Health the same year and were both interested in the mechanism of action of polypeptide hormones. Because we lived in the same general area, we often drove home from work together. He was a wonderful friend and colleague, as well as a gentle, wise, and supportive person loved and respected by his colleagues and family.

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10 BIOGRAPHICAL MEMOIRS SELECTED BIBLIOGRAPHy 1959 Extraction of parathyroid hormone with phenol. Arch. Biochem. Bio- phys. 80:467-468. Isolation of parathyroid hormone after extraction with phenol. J. Biol. Chem. 234:3179-3181. 1962 With W. B. Jakoby. The multiple functions of thiooxidase. J. Biol. Chem. 237:565-568. 1963 With S. A. Berson, R. S. yalow, and J. T. Potts Jr. Immunoassay of bovine and human parathyroid hormone. Proc. Natl. Acad. Sci. U. S. A. 49:613-617. 1965 With R. A. Melick and J. T. Potts Jr. Distribution and half-life of 131I-labeled parathyroid hormone (bovine) in the rat. Endocrinol- ogy 77:198-202. With J. T. Potts Jr., L. M. Sherwood, and A. Sandoval. Structural basis for biological and immunological activities of parathyroid hormone. Proc. Natl. Acad. Sci. U. S. A. 54:1743-1751. 1966 With L. M. Sherwood, A. D. Care, G. P. Mayer, and J. T. Potts Jr. Evaluation by radioimmunoassay of factors controlling the secre- tion of parathyroid hormone. I. Intravenous infusions of calcium and EDTA in the cow and goat. Nature 209:52-55. With A. D. Care, L. M. Sherwood, and J. T. Potts Jr. Evaluation by radioimmunoassay of factors controlling the secretion of parathy- roid hormone. II. Perfusion of the isolated parathyroid glands of the goat and sheep. Nature 209:55-57. With J. L. H. O’Riordan, A. H. Tashjian Jr., P. L. Munson, and P. G. Condliffe. Thyrocalcitonin: Ultracentrifugation in gradients of sucrose. Science 154:885-886.

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11 GERALD DONALD AURBACH 1967 With R. A. Melick, J. R. Gill, S. A. Berson, R. S. yalow, F. C. Bartter, and J. T. Potts Jr. Antibodies and clinical resistance to parathyroid hormone. N. Engl. J. Med. 276:144-147. With J. T. Potts Jr. Parathyroid hormone. Am. J. Med. 42:1-8. With L. R. Chase. Parathyroid function and the renal excretion of 3’,5’-adenylic acid. Proc. Natl. Acad. Sci. U. S. A. 58:518-25. 1968 With L. R. Chase. Renal adenyl cyclase: Anatomical separation of sites sensitive to parathyroid hormone and vasopressin. Science 159:545-547. With L. J. Deftos, A. S. Rabson, R. M. Buckle, and J. T. Potts Jr. Para- thyroid hormone production in vitro by human parathyroid cells transformed by Simian virus 40. Science 159:435-436. 1969 With R. Marcus. Bioassay of parathyroid hormone in vitro with a stable preparation of adenyl cyclase from rat kidney. Endocrinol- ogy 85:801-810. With J. L. H. O’Riordan and J. T. Potts Jr. Immunological reactivity of purified human parathyroid hormone. Proc. Natl. Acad. Sci. U. S. A. 63:692-698. 1970 With G. L. Melson and L. R. Chase. Parathyroid hormone-sensitive ad- enyl cyclase in isolated renal tubules. Endocrinology 86:511-518. 1971 With J. T. Potts Jr., G. W. Tregear, H. T. Keutmann, H. D. Niall, R. Sauer, L. J. Deftos, B. F. Dawson, and M. L. Hogan. Synthesis of a biologically active N-terminal tetratriacontapeptide of parathyroid hormone. Proc. Natl. Acad. Sci. U. S. A. 68:63-67. With J. L. H. O’Riordan and J. T. Potts Jr. The isolation of human parathyroid hormone. Endocrinology 89:234-239. With D. Desbuquois. Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radio-immunoassays. J. Clin. Endocrinol. 33:732-738.

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12 BIOGRAPHICAL MEMOIRS 1972 With D. Powell, P. M. Shimkin, J. L. Doppman, S. Wells, S. J. Marx, A. S. Ketcham, and J. T. Potts Jr. Primary hyperpara-thyroidism: Pre-operative localization and differentiation between adenoma and hyperplasia. N. Engl. J. Med. 286:1169-1175. With S. J. Marx and S. A. Fedak. Preparation and characterization of a hormone-responsive renal plasma membrane fraction. J. Biol. Chem. 247:6913-6918. With S. J. Marx and C. J. Woodard. Calcitonin receptors of kidney and bone. Science 178:999-1001. 1973 With J. P. Bilezikian. A beta-adrenergic receptor of the avian turkey erythrocyte. I. Binding of catecholamine and relationship to ad- enylate cyclase activity. J. Biol. Chem. 248:5577-5583. With S. J. Marx, D. Powell, P. M. Shimkin, and S. A. Wells. Familial hyperparathyroidism. Mild hypercalcemia in at least nine members of a kindred. Ann. Intern. Med. 78:371-377. With J. L. Doppman, S. A. Wells, P. M. Shimkin, K. D. Pearson, J. P. Bilezikian, D. A. Heath, D. Powell, and A. S. Ketcham. Parathyroid localization by angiographic techniques in patients with previous neck surgery. Brit. J. Radiol. 46:403-418. With J. P. Bilezikian, J. L. Doppman, P. M. Shimkin, D. Powell, S. A. Wells, D. A. Heath, A. S. Ketcham, J. Monchik, L. E. Mallette, and J. T. Potts Jr. Preoperative localization of abnormal parathyroid tissues: Cumulative experience with venous sampling and arteri- ography. Am. J. Med. 55:505-514. With S. J. Marx, D. Powell, P. Shimkin, S. A. Wells, A. S. Ketcham, J. E. McGuigan, and J. P. Bilezikian. Familial hyperparathyroidism. Ann. Int. Med. 78:371-377.

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13 GERALD DONALD AURBACH 1974 With H. D. Niall, R. T. Sauer, J. W. Jacobs, H. T. Keutmann, G. V. Segre, J. L. H. O’Riordan and J. T. Potts Jr. The amino-acid se- quence of the amino terminal 37 residues of human parathyroid hormone. Proc. Natl. Acad. Sci. U. S. A. 71:384-388. With A. M. Spiegel. Binding of 5’-guanylyl-imidodiphosphate to turkey erythrocyte membranes and effects on beta-adrenergic-activated adenylate cyclase. J. Biol. Chem. 249:7630-7636. With S. A. Fedak, C. J. Woodard, J. S. Palmer, D. Hauser, and F. Troxler. Beta-adrenergic receptor: Stereospecific interaction of iodinated beta-blocking agent with high affinity site. Science 186:1223-1224. 1976 With E. M. Brown, D. Hauser, and F. Troxler. Beta-adrenergic recep- tor interactions: Characterization of iodohydroxybenzylpindolol as a specific ligand. J. Biol. Chem. 251:1232-1238. 1977 With A. M. Spiegel, H. E. Harrison, S. J. Marx, and E. M. Brown. Neonatal primary hyperparathyroidism with autosomal dominant inheritance. J. Pediatr. 90:269-272. With S. J. Marx, A. M. Spiegel, and E. M. Brown. Family studies in patients with primary parathyroid hyperplasia. Am. J. Med. 62:698- 706. 1980 With A. M. Spiegel, S. T. Eastman, M. F. Attie, R. W. Downs Jr., M. A. Levine, S. J. Marx, J. L. Stock, A. Saxe, and M. F. Brennan. In- traoperative measurements of urinary cyclic AMP to guide surgery for primary hyperparathyroidism. N. Engl. J. Med. 303:1457-1460. With S. J. Marx and A. M. Spiegel. Incidence of primary hyperpara- thyroidism. N. Engl. J. Med. 302:1313.

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14 BIOGRAPHICAL MEMOIRS 1982 With S. J. Marx, A. M. Spiegel, M. A. Levine, R. E. Rizzoli, R. D. Lasker, A. C. Santora, and R. W. Downs Jr. Familial hypocalciuric hypercalcemia: The relation to primary parathyroid hyperplasia. N. Engl. J. Med. 307:416-426. With A. M. Spiegel, M. A. Levine, and S. J. Marx. Pseudo-hypo- parathyroidism: The molecular basis for hormone resistance—a retrospective. N. Engl. J. Med. 307:679-681. 1983 With R. E. Rizzoli, M. Somerman, and T. M. Murray. Binding of radioiodinated parathyroid hormone to cloned bone cells. Endo- crinology 113:1832-1838. 1986 With M. L. Brandi and H. G. Coon. Bovine parathyroid cells: Cultures maintained for more than 140 population doublings in serum-free medium. Proc. Natl. Acad. Sci. U. S. A. 83:1709-1713. With M. L. Brandi, L. A. Fitzpatrick, R. Quarto, A. M. Spiegel, M. M. Bliziotes, J. A. Norton, J. L. Doppman, and S. J. Marx. Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type I. N. Engl. J. Med. 314:1287-1293. 1989 With S. J. Bale, A. E. Bale, K. Stewart, L. Dachowski, O. W. McBride, T. Glaser, J. E. Green III, J. J. Mulvihill, M. L. Brandi, K. Sakaguchi, and S. J. Marx. Linkage analysis of multiple endocrine neoplasia type 1 with INT2 and other markers on chromosome 11. Genom- ics 4:320-322. With E. Friedman, K. Sakaguchi, A. E. Bale, A. Falchetti, E. Streeten, M. B. Zimering, L. S. Weinstein, W. O. McBride, y. Naamura, M. L. Brandi, J. A. Norton, A. M. Spiegel, and S. J. Marx. Clonality of parathyroid tumors in familial multiple endocrine neoplasia type I. N. Engl. J. Med. 321:213-218.

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15 GERALD DONALD AURBACH