ESSAY | TOWARD JES 100TH ANNIVERSARY
My career in endocrinology and outstanding neuroendocrinologists we collaborated
2024 Volume 71 Issue 2 Pages 83-88
Details
2024 Volume 71 Issue 2 Pages 83-88
The Japan Endocrine Society (JES) was founded in 1927 and will celebrate its 100th anniversary in 2026. It was 1968 when I first became a member of the JES. I started my research into endocrinology the next year. Since then, my fellows and I have been very much indebted to many members of the JES. I continued clinical and basic research mainly on the hypothalamic-pituitary-adrenal (HPA) axis as a physician scientist with many collaborators for nearly 40 years. I was principally interested in the neuroendocrine response to stresses. Acute and persistent stress evokes HPA axis changes. Persistent stress has been shown to cause sleep and anxiety disorders, depression, as well as metabolic and cardiovascular disorders. We investigated adaptive and maladaptive neuroendocrine responses to such stresses.
In 1982, Professor Jiro Takahara (Fig. 1), supervisor of the endocrine research group in the Third Department of Okayama University Medical School, moved to Kagawa Medical School, and consequently I became the chief of the endocrine group. I supervised 10 fellows in this group, conducting neuroendocrine research in the department, and 12 others after moving to Kochi (Kochi Medical School (1991–2003) and Kochi University Medical School (2003–2008)). I encouraged them to present their research results not only at the meetings of the JES, but also at the meetings of the American Endocrine Society (ENDO) and International Society of Endocrinology. ENDO is the oldest endocrine society in the world. It was founded in 1922, five years before the start of the JES. The results of our research were published in the Endocrine Journal of JES (originally Endocrinologia Japonica) as well as in overseas journals. I also encouraged my fellows to go abroad and experience working with outstanding researchers. Ten of them were accepted by leading endocrinologists in the United States and they continued research in those neuroendocrinologists’ laboratories. They received excellent instruction and learned a considerable amount, including about innovative research methods. In this essay, I would like to briefly describe my career in endocrinology and introduce some of the outstanding and leading neuroendocrinologists under whose supervision my fellows worked and learned greatly.
Prof. T. Ofuji (left) and Prof. J. Takahara (right)
In 1968, I joined the Third Department of Internal Medicine of Okayama University Medical School. Professor Tadashi Ofuji (Fig. 1) was the founder of the department. The main research fields of the department were clinical immunology, nephrology, and endocrinology and metabolism. The first patient I was in charge of in the department suffered with intractable Cushing’s disease. That led me to be interested in basic and clinical research into HPA axis regulation, and to join the endocrine research group.
In 1947, shortly after the end of the Second World War, when Japanese researchers had very little access to information from overseas, Dr. Ofuji used mice to inject a double dye into their hearts. He made a Sparteholz-type transparent specimen, and found pituitary portal veins which flow from the median eminence to the anterior pituitary gland. He confirmed this for the first time in Japan. Later, he reported that similar pituitary portal veins exist in rats and humans.
My research started in 1969, when the structure of TRH was determined by Dr. Roger Guillemin’s and Dr. Andrew Schally’s groups. In 1971, the structure of LHRH was determined by Dr. Schally’s group. Dr. Guillemin and Dr. Schally were awarded the Nobel Prize in 1977. Regarding corticotropin releasing factor (CRF), Safran et al. reported in 1955 that CRF was present in hypothalamic extracts, but its structure and secretory mechanism were not sufficiently clarified. That is why I became interested in CRF and the regulatory mechanism of ACTH secretion. At that time, Dr. Takahara was struggling to measure CRF activity in the pituitary portal vein of dogs. CRF activity was measured by bioassay, a very time-consuming job. He anesthetized a dog, and operated on it to visualize the pituitary portal vein, which he then cut and collected a small amount of blood every 30 minutes. A trace amount of the serum from the collected blood was injected into the carotid artery of a rat, which was anesthetized and treated with low dose of dexamethasone. Ten minutes later, the adrenal gland of the rat was removed by laparotomy and the corticosterone in the adrenal gland was measured for CRF activity using the fluorescence method. ACTH activity was also measured by bioassay by injecting the sample into the carotid artery of hypophysectomized rats and by measuring the corticosterone in the adrenal glands in a manner similar to CRF assay. This series of experiments required a great deal of time and patience. As a beginner in endocrine research, I learned that obtaining experimental data required tremendous effort.
We set up a radioimmunoassay for ACTH in 1973 and conducted research into the regulation of CRH and ACTH secretion. I sent application letters to some neuroendocrinologists in the United States, who were doing research on CRH and ACTH regulation. In 1975, Professor Alvin Brodish accepted me into his laboratory in the Department of Physiology and Pharmacology at the Bowman Gray School of Medicine in Winston-Salem, North Carolina. He had moved from Cincinnati to Winston-Salem and started his career as the chairman of the department one month before I arrived in Winston-Salem. I was the first and only endocrinologist in his laboratory, so I had to set it up with the help of technicians. When Professor Brodish was in Cincinnati, he proposed that CRF exists not only in the hypothalamus but also in the periphery organs, and he named it tissue CRF which is also involved in ACTH secretion under strong stresses. He performed experiments by measuring serum corticosterone using the fluorescence method. In his laboratory, I learned the method for destroying a rat’s mediobasal hypothalamus. I used the ACTH RIA in detecting tissue CRF in these rats’ plasma with anti-ACTH antibodies I had brought with me from Japan.
In 1976, one year after I started my research in Dr. Brodish’s laboratory, I attended the ENDO annual meeting held in San Francisco for the first time. In June 1977, I attended the ENDO annual meeting in Chicago and made a presentation at a poster session. The results of much cutting-edge research were presented at the ENDO annual meeting. It was a very exciting meeting giving me access to the latest research and information. I met many outstanding endocrinologists there. In August 1977, I returned to Japan and went back to my work on clinical and basic research in the Third Department of Internal Medicine at Okayama University. Since then, I had attended the ENDO annual meeting almost every year until I retired from the medical school. Dr. Brodish and his wife visited us in Okayama in 1988 when the International Congress of Endocrinology was held in Kyoto (Fig. 2).
With Prof. T. Hiroshige (left) and Prof. A. Brodish (center) in Kyoto (1988). They were friends at Yale University.
In 1991, I was appointed as a professor of the Second Department of Internal Medicine of Kochi Medical School. I divided the members of my department into three groups; endocrine, diabetes and metabolic disorders, and nephrology. Members of each group worked hard to attain the optimal research results. I mainly guided the members of the endocrine group, and continued research with them. Our clinical and basic research was into HPA axis disorders and thyroid gland disorders. Many of my neuroendocrine research fellows went to the United States and collaborated with famous neuroendocrinologists.
Dr. Norihito Ohno of my research group in Okayama University was accepted by Professor Samuel M. McCann (1925–2007), the chairman of the Department of Physiology at Southwestern Medical School in Dallas, Texas. Dr. McCann was one of the pioneers of neuroendocrinology, and had already accomplished great work regarding the presence of LH-releasing factor, GH-releasing factor, GH-inhibiting factor in the hypothalamus, and the role of vasopressin in ACTH secretion. He was also an excellent mentor and was very enthusiastic about training young researchers. While Dr. Ohno was working in his laboratory, he was able to publish some papers on the CRF/ACTH system under Dr. McCann’s research guidance. Dr. McCann stood out as a dynamic researcher at every academic meeting.
Dr. Mariana Morris and her husband Dr. David Sundberg received their PhD degree under Dr. McCann’s supervision in Dallas. They joined Dr. Brodish’s laboratory one year after me where they were assigned as associate professors. Later, Dr. Teruhiko Hattori, a fellow member of our research group in Okayama University was accepted to Dr. Morris’ laboratory and continued research in the same department where I worked for Dr. Brodish in Winston-Salem. Dr. Morris had a high-titer anti-vasopressin antibody created in Dr. McCann’s laboratory, and Dr. Hattori used it for his research. Dr. Tatsuya Nishioka from my group in Kochi Medical School also worked for Dr. Morris in her laboratory. He was given an anti-oxytocin antibody from Dr. Morris for his research. Dr. Morris and Dr. Sundberg visited us in Okayama during a meeting of the International Society of Neuroendocrinology held in Kitakyushu in Japan. Unfortunately, Dr. Sundberg died of cancer while still young a few years after visiting us.
Dr. Kazuharu Murakami was supervised by Professor William F Ganong (1924–2007; Fig. 3), who was the chairman of the Department of Physiology at the University of California San Francisco, one of the top physiology departments in the world. He is a world-famous physiologist, one of the pioneers of neuroendocrinology, and the author of the famous textbook The Review of Medical Physiology. The book has been translated into at least 18 languages and studied by many medical students. Dr. Ganong identified the renin-angiotensin axis in the regulation of aldosterone, and accomplished great work in the role of electrolytes and the central nervous system in hypertension. He was also excellent in guiding many young researchers. Dr. Murakami was impressed by his guidance on how medical research should be conducted.
Prof. W.F. Ganong (center) and Dr. K. Murakami (right) (1985)
Dr. Murakami was also supervised by Professor Mary F. Dallman (1935–2021) when she served as a vice chairman of Dr. Ganong’s department and he engaged in research into the area of neuroendocrinology. Dr. Dallman accomplished outstanding achievements in elucidating the feedback mechanism of glucocorticoids and neuroendocrinological responses to stress. She was called a true giant in neuroendocrinology. I remember that she asked very sharp and perceptive questions at every ENDO meeting. Following Dr. Murakami, Dr. Shuso Suemaru from our group joined Dr. Dallman’s research group and was supervised by her on the feedback mechanism of glucocorticoid. After returning to Japan, he became interested in psychoneuroendocrinology, and he published several papers on HPA axis disorders in patients with senile dementia and neurodegenerative disorders. When the International Neuroendocrine Congress was held in San Francisco in 1986, Dr. Dallman invited us to her home while we attended the congress. When the International Congress of Endocrinology was held in Kyoto in 1988, she visited Okayama and enjoyed a Seto Inland Sea cruise with us (Fig. 4).
With Prof. M. Dallman (left) and Dr. S. Suemaru (right) on a boat in the Seto Inland Sea (1988)
Dr. Toshihiro Takao went to America twice to do research under the supervision of Dr. Errol De Souza. Dr. De Souza had accomplished much work in a wide range of fields within neuroscience and neuroendocrinology. When Dr. Takao joined Dr. De Souza’s research group, the latter’s interest was in the role of cytokines on endocrine regulation and immune system regulation. Dr. Takao was also very interested in this, and after returning to our research group in Kochi, he published many research papers on the role of interleukin 1 (IL1) and its receptor on HPA axis regulation. In 1998, when the ENDO meeting was held in New Orleans, some members of our group and I met Dr. De Souza and enjoyed having dinner with him (Fig. 5). He and his wife visited Kurashiki (Dr. Takao’s hometown) when he came to Japan to attend an international academic meeting in Japan.
With Dr. E. De Souza (right end) and Dr. T. Takao (center) in New Orleans (1998)
Dr. Shinya Makino worked under supervision from Dr. Philip W. Gold at the National Institute of Mental Health (NIMH). Dr. Gold made great achievements in the area of psychiatry, the neurology of depression, the stress response and the role of CRH in depression. Dr. Makino mastered the technique of in situ hybridization in Dr. Gold’s laboratory, and after returning to Japan, he used this technique in our department to measure the mRNAs of CRH, CRH receptors, proopiomelanocortin, vasopressin, neuropeptide Y, glucocorticoid and mineral corticoid receptors, and published many research papers on the mechanisms of neuroendocrine responses to stresses. He also co-worked with Professor Miklos Palkovits in NIMH, who was a great Hungarian neuroanatomist and neuroendocrinologist (Fig. 6). Prof Palkovits clarified the distribution of many kinds of neuropeptides in the central nervous system. He spent half a year at Semmelweis University, Budapest and half a year in NIH at that time. He also visited us in Okayama, when he was invited to Japan to give a special lecture.
With Dr. S. Makino (left) and Prof. M. Palkovits (center) at NIMH (1995)
Dr. Mitsuru Nishiyama was supervised by Dr. Mary Stenzel-Poore at Oregon Health Science University (Fig. 7). Dr. Nishiyama came back with CRH transgenic mice that Dr. Stenzel-Poore had developed, as a model of Cushing’s syndrome, and investigated the mechanism of hyperphagia caused by glucocorticoid. After attending the ENDO meeting in San Francisco in 2002, my wife and I visited Dr. Nishiyama in Dr. Stenzel-Poore’s laboratory in Oregon. She invited us to dinner. The following year, we invited her to deliver a lecture at the CRH/ACTH meeting being held in Osaka. She also delivered a lecture in Kochi.
Dr. M. Nishiyama (left) and Prof. M. Stenzel-Poore (right) at Oregon Health Science University (2002)
Dr. Joseph Majzoub is a friend and a co-worker of Dr. Yasumasa Iwasaki, who came to join our group from Nagoya University four years before I retired from Kochi University. Dr. Iwasaki had accomplished many achievements before he came to Kochi and he advanced his research further there. Dr. Majzoub’s research focused on the behavioral and neuroendocrine roles of vasopressin and CRH, and the regulation of CRH transcription by silencing factors. When the ENDO meeting was held in New Orleans in 1998, several members of our research group and I enjoyed dinner with him. The following year, he visited us in Kochi after attending the International Neuroendocrine Congress held in Kitakyushu (Fig. 8). He gave a lecture on CRH knockout mice in Kochi. He also enjoyed sightseeing in both Okayama and Kurashiki.
With Prof. J. Majzoub (second from left in front) and members of our research group in Kochi (1998)
Another great neuroendocrinologist I cannot forget is Professor Wylie W. Vale (1942–2011) of the Salk Institute. He helped Dr. Guillemin (Nobel laureate) to determine the structure of TRH and LH-RH. He and his group also discovered many neuropeptides and their receptors while publishing many excellent and leading papers. At that time I was performing CRF bioassays in my research that combined monolayer cultures of rat anterior pituitary cells and RIA of ACTH. When I attended the Lake Biwa International Conference held in 1980, I learned from Dr. Stephan Zimmerman of Germany, that Dr. Vale had elucidated the structure of ovine CRH. I wrote to Dr. Vale and asked if I could have small amount of it. Dr. Vale willingly sent me several mg of ovine CRH. I used it to make an anti-CRH antibody and established a CRH RIA. I was able to further advance my research on CRH by using this antibody. Later, when he succeeded in elucidating the structure of urocortins, CRH-related peptides, he kindly sent me a small amount of urocortins, which we then used in our research. With gratitude, I invited him as a special lecturer on CRH research to the meeting of the Japan Neuroendocrine Society held in Kochi in 2002 (Fig. 9). In addition to being a hard-worker and brilliant scientist, he also had an excellent sense of humanity, as well as being an inquisitive, broad-minded, and witty person. Sadly, he died suddenly during a vacation in Hawaii. Innumerable words of condolence from all over the world appeared on the Internet showing just how highly he was respected as a researcher and how much he was loved by many people.
With Prof. W. W. Vale at The 29th Annual Meeting of Japan Neuroendocrine Society in Kochi (2002)
As I have already described, members of our research group were greatly helped and enlightened by many excellent neuroendocrinologists of the United States. We were very happy to be friends with them. Their friendship is so precious and an irreplaceable memory to me. The number of young Japanese doctors studying endocrinology who participate in the meetings of ENDO and the International Society of Endocrinology has recently decreased considerably. I would like to advise young Japanese doctors to participate in overseas academic conferences, meet other excellent researchers and make friends with them, and if possible to conduct research overseas while still young.
Kozo Hashimoto
Honorary Member
Professor Emeritus, Kochi University
Mabi Memorial Hospital
E-mail: hashiko@hyper.ocn.ne.jp
Careers in JES
2012– Honorary Member
2008– Senior Councilor
2002–2005 President for Shikoku Regional Branch
1979– Councilor
1968– Member
Activities in JES
2008 Chair, 18th JES Clinical Update on Endocrinology & Metabolism
2003 Chair, 3rd Annual Meeting of JES Shikoku Regional Branch
