Kevin J. Catt, of Chevy Chase Md., a member of the Endocrine Society since 1970, died October 1, 2017 at age 85, after a long illness.
Catt was a powerhouse in endocrinology who participated actively in the Endocrine Society as member of the Council, and as member of the editorial boards of The Journal of Clinical Endocrinology & Metabolism and Endocrine Reviews, as well as numerous other endocrine journals. He was editor-in-chief of Trends in Endocrinology & Metabolism from 1995-2010. Catt was a member of the American Society for Clinical Investigation and the Association of American Physicians, American Society of Biological Chemistry, The Royal Society of Medicine and the Royal Australasian College of Physicians.
During his highly productive career, Catt has been an inspiring and exemplary mentor to more than 150 post-doctoral fellows and visiting scientists, many of whom successfully established research groups of their own to pursue ideas that in many cases were initiated in his laboratory.
Kevin Catt was born in Richmond, Victoria, Australia, received his MD degree from the University of Melbourne, and PhD in biochemistry from Monash University, Melbourne, Australia. After completion of his residency and his term as Registrar in Medicine at the Royal Melbourne Hospital, Catt moved to the Department of Medicine, Prince Henry’s Hospital, Monash University, initially as lecturer, and then as senior lecturer and reader in medicine where he initiated his stellar scientific career and made major contributions to several areas of endocrine research.
Catt’s early scientific contribution – his invention of the solid-phase radioimmunoassay – has enormously impacted science, technology, and clinical chemistry to the present day. His initial work led to the discovery that proteins, such as antibodies, simply adsorbed to various polymers in tubes, particles and discs and could be employed for sensitive and rapid radioligand assays of several protein hormones, including growth hormone. This technique and its derivatives have been widely applied to the measurement of protein and non-protein antigens such as steroids and cardiac glycosides.
Catt’s discovery was also the precursor of solid plate ELISA assays. Its principle was generally recognized as revolutionary and was welcomed by the immunological field and industry for its wide application and its utility in assay kits. For this advance Catt received several awards, including the Pharmacia Award for Science and Technology. While in Australia, he also developed other new analytical methods for research studies and clinical investigation. His studies to assay plasma levels of estrogens and gonadotropins in women during the menstrual cycle, in collaboration with Drs. Maria Dufau and Henry Burger, published in The Lancet in 1970, provided the first clear indication that estradiol is responsible for triggering the mid-cycle surge of LH. Catt also performed pioneering work on the isolation and sequencing of a major pregnancy hormone, human placental lactogen, and the demonstration of its structural similarity to growth human growth hormone.
These collective areas of Catt’s research revealed new aspects of calcium signaling that mediated the actions of many peptide hormones and defined the structures and structure-function relationships of the angiotensin II and GnRH receptors, which are crucial regulators of cardiovascular function and reproduction.
Catt moved to the U.S. in 1969, initially as a visiting scientist in the Department of Medicine, New York Hospital, Cornell University. During his short stay in that Institution he wrote “The ABC of Endocrinology,” published initially as individual chapters in The Lancet in 1970. Due to its success, this series was subsequently published as a book that was translated into several languages, including Spanish, Italian, and Japanese.
From 1970 until his retirement in 2012, Catt worked at the National Institute of Child Health and Human Development, National Institutes of Health in Bethesda, Md. He served as chief of the Endocrinology & Reproduction Research Branch, where he led an internationally recognized group working on hormone receptors, signaling, and actions.
During his career, Catt published more than 700 scientific papers and book chapters and was among the most highly cited scientists. He had patents on his invention of solid-phase radioimmunoassay for estimation of peptides and polypeptide hormones in human plasma, including growth hormone. Catt received numerous national and international awards, including the “Public Health Service Superior Service Award,” “Presidential Meritorious Executive Rank Award,” the “Dale Medal” of the British Society for Endocrinology, and many major lectureships, including the “Geoffrey Harris Memorial Lecture” of the International Society of Neuroendocrinology and the “Hisaw Lecture” at the 7th International Congress of Endocrinology.
A major research direction of Catt and his group was the identification and characterization of cellular receptors for peptide and polypeptide hormones in their target cells. His work led to the characterization of receptors for angiotensin II in adrenal and smooth muscle and of gonadal receptors for luteinizing hormone (LH) and follicle stimulating hormone (FSH). In the pituitary gland, he focused on the analysis of receptors for hypothalamic neuropeptides, such as gonadotropin releasing hormone (GnRH) and corticotropin-releasing hormone (CRH). Angiotensin II, GnRH and CRH receptors also were found in specific regions of the brain, consistent with the roles of these neuropeptides within the central nervous system, their regulation of pituitary function and underlying mechanisms for stress-related disorders.
Another aspect of Catt’s work has been in the area of homeostatic receptor regulation. Together with Maria Dufau, it was observed that receptors for LH in the testis and ovary were maintained by physiological concentrations of hormone. However, they found that increased levels of circulating LH and activation of gonadal function caused LH receptor downregulation and cellular desensitization to the hormonal stimulus. These changes were found to be due to a loss of cell surface LH receptors and defects in the steroidogenic pathway that caused the cells to become refractory to further hormonal stimulation. From these studies, the concept of spare receptors for LH emerged. Their studies led to the understanding that excess cell surface LH receptors in gonadal cells maximized the efficacy of small physiological circulating concentrations of LH to ensure sensitivity to the hormone.
Catt’s group further observed similar regulation of the GnRH receptor by its cognate hormone. The process by which receptors for GnRH were lost from the cell surface during hormone action was shown by morphological studies to be due to internalization of the hormone receptor complexes by the stimulated target cells. Of note, this process was dependent on the agonist properties of the hormone. Another notable finding about the GnRH receptor was its ability to interact with the structurally related peptide responsible for sexual conjugation in yeast (alpha mating factor), indicating the evolutionary conservation of function by GnRH as a dominant reproductive hormone.
Catt also has made outstanding contributions to our understanding of the functions of the renin-angiotensin system. This work began with his early studies in Melbourne, Australia to develop antibodies to angiotensin II. These antibodies, which were utilized to measure circulating angiotensin levels in health and disease, provided a major breakthrough regarding elevation of circulating angiotensin levels in hypertension. Catt’s subsequent research at the NIH on angiotensin II receptors has yielded important insight into their properties and roles in cardiovascular function.
Research of the Catt laboratory on the hypothalamus and pituitary included cloning of the GnRH receptor and revealed that hypothalamic GnRH-producing neurons exhibited an intrinsic rhythmicity that mimics the pulsatile mode of GnRH secretion in vivo.
Catt and his colleagues also made major contributions to our understanding of the signaling mechanisms through which receptor activation on target cells by peptide hormones is translated into a cellular response. His early studies on the actions of LH in the testis and ovary, and of ACTH in adrenal fasciculata cells, demonstrated that these hormones act primarily via stimulation of cAMP formation and activation of protein kinase A. In contrast, the actions of angiotensin II stimulation of aldosterone synthesis in adrenal glomerulosa cells were found to involve calcium-dependent mechanisms. This finding led to expanded investigations into the control of aldosterone secretion and to the discovery that calcium signaling was key to angiotensin II action. Catt’s group characterized phosphoinositide and inositol triphosphate changes that followed angiotensin II receptor activation. They discovered new metabolic pathways impacting inositol phosphates and identified a specific intracellular receptor for the calcium-mobilizing messenger inositol triphosphate in the adrenal and pituitary glands. Similar studies on the control of pituitary function by GnRH also revealed the importance of calcium- and phospholipid-dependent pathways, as well as roles of arachidonic acid and its metabolites.
Research of the Catt laboratory on the hypothalamus and pituitary included cloning of the GnRH receptor and revealed that hypothalamic GnRH-producing neurons exhibited an intrinsic rhythmicity that mimics the pulsatile mode of GnRH secretion in vivo. Also, hypothalamic neurons were shown to possess receptors for endothelin, which induced GnRH secretion. In gonadotrophs, they observed that GnRH, acting via calcium signaling, induced synchronized interdependent activation of cytoplasmic/plasma membrane oscillators. This, in turn, generated a bursting pattern of membrane potential through activation of K+ channels to maintain intracellular calcium signaling during sustained agonist stimulation. These collective areas of Catt’s research revealed new aspects of calcium signaling that mediated the actions of many peptide hormones and defined the structures and structure-function relationships of the angiotensin II and GnRH receptors, which are crucial regulators of cardiovascular function and reproduction.
During his highly productive career, Catt has been an inspiring and exemplary mentor to more than 150 post-doctoral fellows and visiting scientists, many of whom successfully established research groups of their own to pursue ideas that in many cases were initiated in his laboratory. His legacy is therefore carried on in laboratories all over the world, including the U.S., Canada, Latin America, as well as in Europe, Australia, New Zealand, and Asia.
On a personal note, Kevin was a modest and caring person with a great sense of humor. He was quietly tough and demanding, but never expected more of his coworkers than he did of himself. He was an outstanding scientific writer, and the clarity and completeness of his research papers is exemplary. Moreover, he was a true Renaissance man with an extensive knowledge of history, literature, music, and art. He loved opera – Turandot being his absolute favorite – and would travel great distances throughout the world to see it performed with different casts and venues. His scientific acumen, quick wit, extensive knowledge of the arts and science, mentorship, and friendship will be greatly missed.
He is survived by his wife Dr. Maria Dufau, two sons, Nicholas and Matthew, and two grandsons.