The First Tomoh Masaki Award (2011)

Life Sciences 91 (2012) 466–469

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Life Sciences

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The First Tomoh Masaki Award (2011)

Matthias Barton a,⁎,1, Noriaki Emoto b,c,2,3, Takashi Miyauchi d,⁎,2,3 a Molecular Internal Medicine, University of Zurich, 8057 Zurich, Switzerland b Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan c Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan d Department of Cardiovascular Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

abstract

Professor Tomoh Masaki, a Japanese physician-scientist born in 1934, is particularly known for the discovery of endothelium-derived peptide endothelin and its receptors, among many other scientific achievements. In recognition of his work, the Tomoh Masaki Award was established in 2011 by the Endothelin International Ad- visory Board of The International Conferences on Endothelin as a biannual scientific prize in recognition of Masaki's innovative and ground-breaking work that has led to new clinical applications. The inaugural Tomoh Masaki Award was presented at The Twelfth International Conference on Endothelin held in Cambridge, UK, to one his former graduate students, Professor Masashi Yanagisawa as the first recipient of this award, who played an instrumental role in the discovery of endothelin at the University of Tsukuba, Japan. The article summarizes the scientific achievements of Masaki and the awardee, Masashi Yanagisawa, also including personal reflections of two of Masaki's former graduate students on their teacher as well as on the awardee of The First Tomoh Masaki Award 2011 and their work as scientists and their role as mentors. © 2012 Elsevier Inc. All rights reserved.

The Tomoh Masaki Award who is currently at the University of Texas Southwestern, Dallas, and the University of Tsukuba, Japan. Also presented are personal reflections In early 2011 the Guest Editor proposed to the Endothelin International of two of Professor Masaki's former graduate students at the Universityof Advisory Board to establish a new award in the name of Tomoh Masaki in Tsukuba, Takashi Miyauchi (now Professor of Cardiovascular Medicine at recognition of his innovative and ground-breaking research work in the University of Tsukuba), and Noriaki Emoto (now Professor of Cardiovas- field of endothelin science and vascular biology which has led to the cular Medicine at Kobe University and Kobe Pharmaceutical University). development of endothelin receptor antagonists as a new therapeutic principle in medicine. It was agreed to establish The Tomoh Masaki Tomoh Masaki: an extraordinary physician-scientist Award which was to be presented biannually – after a careful selection process – on the occasion of the International Conferences on Endothelin Born in 1934, Tomoh Masaki obtained his M.D. from the Faculty of to individuals for their extraordinary contribution in the field of Medicine of the University of Tokyo in the late 1950s and completed endothelin research in basic or clinical science. The design of the his internship training (Masaki and Sawamura, 2006). In 1963, he hand-crafted award plate depicts the amino acid sequence of the started to work in research at the University of Tokyo with Professor endothelin-1 peptide as well as an artistic impression of Professor Setsuro Ebashi (Fig. 2) as a graduate student to eventually obtain a Tomoh Masaki (Fig. 1). This article summarizes the life and work of Ph.D. degree. His work lead to the discovery of α-actinin and Professor Masaki as a scientist and presents the inaugural recipient of M-protein (Ebashi et al., 1974; Kuroda et al., 1981; Masaki and Takaiti, The First Tomoh Masaki Award (2011), Professor Masashi Yanagisawa 1974), as new proteins involved in muscle structural biology. His research also contributed to the identification of discovery of other mus- cular proteins, including different types of myosin and troponin (Otsuki et al., 1967) as well as describing their role in muscle cell differ- ⁎ Correspondence to: M. Barton, Molecular Internal Medicine, University of Zurich, LTK entiation, which also included identification of the gene sequence of Y44 G22, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Tel.: +41 77 439 5554; fax: +41 44 635 6875, or T. Miyauchi, Department of Cardiovascular Medicine, Department these muscle proteins (Masaki and Sawamura, 2006; Masaki, 2003). of Internal Medicine, Division of Clinical Medicine, Faculty of Medicine, University of In 1975, Masaki was promoted to Professor of Pharmacology at the Tsukuba, Tsukuba, Ibaraki 305‐8575, Japan. Tel.: +81 29 853 3210; fax: +81 29 853 3143. Institute of Basic Medical Sciences at the University of Tsukuba E-mail addresses: [email protected] (M. Barton), [email protected] (Figs. 3 and 4), where most of ground-breaking work was done that (T. Miyauchi). fi 1 Guest Editor, Endothelin XII. led to the identi cation of endothelin and its ETB receptor in the 2 Guest Associate Editor, Endothelin XII. late 1980s (Inoue et al., 1989; Sakurai et al., 1990; Yanagisawa et al., 3 Chair-Elect, The Thirteenth International Conference on Endothelin, Tokyo 2013. 1988). Professor Masaki moved to the Faculty of Medicine at Kyoto

Personal reﬂections on a teacher and mentor

In April of 1986, Takashi Miyauchi joined Masaki's laboratory as a graduate student at the University of Tsukuba. There were two major projects, one on the molecular analysis of myosin chains (Supervisor and Head: Professor Masaki), the other on pharmacological characterization of vasoactive peptides (Project Head, Professor Katsutoshi Goto; Supervisor Professor Masaki; Takashi Miyauchi was part of this team). After Professor Masaki's team had completed cloning of smooth muscle myosin heavy chain and sequencing of its cDNA (Yanagisawa et al., 1987), his laboratory began to work on the identification of an endothelium-derived vasoconstricting factor (EDCF) in May 1987 (Masaki, 1998). Only a few months later, Professor Louis Ignarro published a paper (Ignarro et al., 1987) identifying NO as the endothelium-dependent relaxing factor discovered seven years earlier by Furchgott and Zawadzki (1980). In early 1987, the cardiology resident Hiroki Kurihara had presented a paper by Professor Robert Highsmith's group in one of Professor Masaki's journal clubs describing as a novel endothelial cell-derived Fig. 1. The hand-crafted award plate of the Tomoh Masaki Award, showing the amino acid sequence of the endothelin-1 peptide published in 1988 and an impression of Pro- peptidergic vasoconstrictor (Hickey et al., 1985). Graduate student fessor Tomoh Masaki. The award was presented to Professor Masashi Yanagisawa at Masashi Yanagisawa proposed to Professor Masaki to identify this the Twelfth International Conference on Endothelin in Cambridge, United Kingdom peptide as his Ph.D. thesis project (Vane, 1991). Yanagisawa and (Award design by the Guest Editor). Kurihara – supervised by Professor Masaki – started their work in May 1987 (Masaki, 1998, 2004). They were joined in their efforts by the pharmacologist Katsutoshi Goto who supervised and the protein chemist Sadao Kimura, both were from the Faculty of Basic Medical University in 1991, where his work led to the identification of a Sciences of the University of Tsukuba. Because Professor Masaki's receptor for oxidized low-density lipoproteins expressed in vascular laboratory had great experience with cloning, molecular biochemistry, endothelial cells (Masaki and Sawamura, 2006; Sawamura et al., and pharmacology, the works of purification, identification, and 1997). Following his professorship at Kyoto University, Professor sequencing cDNA of the EDCF endothelin was completed within seven Masaki was appointed Director of the Research Institute of the months and a manuscript was sent to Nature in December 1987 National Cardiovascular Center in Osaka in 1997, and President of (Masaki, 1998; Yanagisawa et al., 1988). Professor Masaki, being a med- Osaka Seikei University in 2003. In 2007, Masaki was appointed ical doctor by training, soon developed an interest to study the role of Professor at Tokyo Women's Medical University from where he re- endothelin in pathophysiology and disease and already before publish- tired in 2009. He currently lives in Tokyo, where the Thirteenth ing the report in Nature further proposed to explore the role of International Conference on Endothelin will be held in 2013 celebrating endothelin in animal models and patients with cardiovascular disease, the 25th anniversary of the discovery of endothelin (ET-13 Tokyo). particularly to study changes in endothelin plasma levels. In January of 1990, Noriaki Emoto joined Professor Masaki's laboratory as a graduate student. The first encounter left a great impression on Emoto and was important for his own research and his later life as a scientist. Professor Masaki said:

“Dr. Emoto, there are so many papers published in a year” (spreading his arms to indicate the amount of publications) “but there are only a few meaningful theses published every year” (showing a half an inch of a gap with two of his ﬁngers). “Most of them are junk. You should work on what you believe in, that is important. Never engage in a meaningless study and waste your time with that.”

Professor Masaki made sure that Emoto could do his research and provided his support. He did not insist to be informed about every- thing, arguing that it did not matter so much what everyone was studying in his laboratory as long as it was unique and interesting. Professor Masaki's attitude towards research is also evident from another episode. In February 1992, Professor Masaki's former graduate student Yanagisawa was about to leave for his new position at the University of Texas Southwestern Medical School in Dallas, ac- companied by Emoto, and one day Professor Masaki stopped by the laboratory and said:

Fig. 2. Three generations of scientific mentoring: Professors Tomoh Masaki (middle), “I really would like to start some new research. We don't have to work Masashi Yanagisawa (right) and Masaki's mentor Setsuro Ebashi (left) with his wife on endothelin anymore since Dr. Yanagisawa is going to be gone soon. at the Okazaki National Research Institute, Okazaki, Japan. The photograph was taken We should start researching something more attractive.” on April 17, 1988 at a time when Ebashi was Professor at the Okazaki National Research Institute, Japan, just weeks after the report on the discovery of endothelin had been fi published in Nature on March 31, 1988. At a time when the rst endothelin receptor antagonists were (Photographs by Hiromi Yanagisawa). published, work on the identification of endothelin-converting 468 M. Barton et al. / Life Sciences 91 (2012) 466–469

Fig. 5. Photographs of Professor Tomoh Masaki taken in 1991 at the University of Tsukuba at the farewell party prior to his transition to the University of Kyoto (left), and taken in Fig. 3. Photograph of Professor Tomoh Masaki taken in the summer of 1985 at his lab in 2008 at a celebration with his former students and research fellows (right) after he had the University of Tsukuba with his student, Yoko Tomobe, ten years after he had joined received the First Setsuro Ebashi Award of the Japanese Pharmacological Society for his the faculty of the University of Tsukuba in 1975. contributions to vascular biology. (Photograph by Yoko-Irukayama Tomobe). (Photographs by Yoshitoshi Kasuya and Takashi Miyauchi). enzyme molecule was in progress, and the role of endothelin in Masaki and his colleagues were awarded The Second Tsukuba Prize, pathophysiology became unveiled, it seemed that Professor Masaki which included a huge silver medal and a research award of ¥ 5 million had already lost his interest to intensify his studies on endothelin (Vane, 1991) which at the time was around 150,000 USD. In 1991, but rather was looking to start research on something completely Professor Masaki moved to the University of Kyoto (Fig. 5). different and new. The above personal encounters give some reflection of Professor Masashi Yanagisawa: visionary and researcher Masaki's attitude as a scientist, mentor, and teacher and his approach to science. He has been a great mentor to numerous students and Professor Masashi Yanagisawa is without doubt one of the most fellows with the ability to pick highly important areas for his research successful scientists among many researchers who studied under and is always asking the essential question for science, namely “what Professor Masaki. His first year of graduate school after finishing is new?”. He trained, motivated, and encouraged young researches to medical school, Yanagisawa spent to learn molecular biological tech- think freely and independently, and supported them in their niques at the National Institute for Physiological Sciences in Okazaki. individual research goals. This work resulted in his first thesis on the molecular structure of myo- Professor Masaki frequently gave parties for his laboratory staff – sin (Yanagisawa et al., 1987). For his PhD project he was looking for a sometimes held under cherry blossoms – where he used to sing tradi- novel (as opposed to an already known molecule), and he convinced tional Japanese folk songs. Soon after the discovery of endothelin Professor Masaki to identify a peptide that had been described in a re- Professor Masaki became Vice Dean of the University of Tsukuba cent paper (Hickey et al., 1985) that had been presented and discussed Medical School and dedicated much of his time to research and in the journal club. Professor Masaki accepted this proposal to identify education of medical students. On December 11, 1990, Professor this peptide and did so by integrating specialists from pharmacology, protein chemistry, biochemistry, and molecular biology (Masaki, 1998). Being scientifically highly gifted and dedicated, Yanagisawa, fo- cusing on his new research project, quickly obtained results and put together his first thesis on endothelin within only in a few months. The whole project and integrating different disciplines to ensure ultimately fast results was owed to the oversight and organization of his mentor, Professor Masaki. At the farewell party at Tsukuba University held for Professors Masaki and Yanagisawa in 1991, Yanagisawa said that he was not quite sure if he was deserving to receive accolades from many of the attendees, but that there was one thing he said he was proud of, which he put in the following words: “I made the right decision to choose Professor Masaki as my mentor among many outstanding professors in Tsukuba University. I chose to study with Professor Masaki and that was the best choice I could make. I would not be able to challenge a new task had I not been with Professor Masaki, and there would have been no discovery of endothelin and the further progress in endothelin research without him”. Fig. 4. Photograph of Professor Tomoh Masaki in the summer of 1985 at his laboratory at the University of Tsukuba with his graduate students Yoshitoshi Kasuya, Tomohisa Following his work on the discovery on endothelin with Professor Ishikawa, and Youichi Miyamoto. These students were involved in two of Professor Masaki, Professor Yanagisawa continued his research in the Masaki's major projects, one being the molecular analysis of myosin chains, the other fi being the pharmacological characterization of vasoactive peptides. endothelin eld and made many seminal contributions, including iso- (Photograph by Yoshitoshi Kasuya). lation and sequencing of endothelin-2 and endothelin-3, as well as M. Barton et al. / Life Sciences 91 (2012) 466–469 469 the identification of endothelin receptors. He moved to the University an Order of Culture from the Emperor and Empress of Japan (1999 of Texas Southwestern Medical School in Dallas in 1992 to set up his International Prize for Biology). own laboratory where he identified the two known endothelin The purpose of The Tomoh Masaki Award will continue to be the rec- converting enzymes (ECE-1 and ECE-2), and since has fundamentally ognition of individuals for their outstanding scientificachievementsto contributed to the understanding of the role of endothelin in advance science and medicine, the ability to motivate and mentor physiology and disease by generating animal models using others, and for continuous scientific excellence in the endothelin field. gene-targeting of components of the endothelin system in specific Such a purpose is likely to also please the award's name holder. In July tissues and cells. 2011 Professor Masaki, who now is 78 years old, accepted the invitation to serve as Honorary Guest Editor of the Endothelin XII Proceedings, and The recipient of The First Tomoh Masaki Award (2011) in an e-mail to the Guest Editor expressed his emotions related to his main discovery as follows: The inaugural Tomoh Masaki Award (Fig. 1) was presented at The “… I can not follow the recent advances in ET research. I only enjoy it.” Twelfth International Conference on Endothelin in Cambridge, UK, in September 2011 (Barton and Davenport, 2012). Not only in discover- ing endothelin and contributing key observations to this area of re- Conflict of interest search, Professor Masashi Yanagisawa has been always challenging new fields and contributed to the progress in biomedical science and None. leaving footsteps with the same scientific discipline that Professor Masaki had taught him. Among those nominated, the Endothelin Acknowledgment International Advisory Board unanimously elected Masashi Yanagisawa as the inaugural recipient of The First Tomoh Masaki Award (2011). The authors are indebted to Hiromi Yanagisawa, Soichi Miwa, The award was presented to Professor Yanagisawa at the gala dinner Yoshitoshi Kasuya, and Suzette Sandin for providing information and of The Twelfth International Conference on Endothelin at Clare's College photographs and making it possible to use them in this article. of the University Cambridge (Fig. 6); he was deeply moved about the recognition he received for his work and for having been chosen as References the inaugural recipient of an award that bears his mentor's name. When the Tomoh Masaki Award was established in 2011 none of Barton M, Davenport AP. The Twelfth International Conference on Endothelin (ET-12), the members of the Endothelin International Advisory Board was Cambridge 2011. Life Sci 2012;91:460–3. aware that only a few years before – in 2008 – Professor Masaki Ebashi S, Masaki T, Tsukui R. Cardiac contractile proteins. Adv Cardiol 1974;12:59–69. – himself had been the recipient of the inaugural Setsuro Ebashi Award Endo M. Obituary: Setsuro Ebashi (1922 2006). Nature 2006;442:996. ET-13 Tokyo. http//www.endothelin-conferences.org/Conferences/Tokyo2013/. [accessed (Masaki, 2008) which the Japanese Pharmacological Society had May 30, 2012]. created bearing the name of Masaki's mentor Professor Setsuro Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of – Ebashi (Fig. 2), who had died only the year before (Endo, 2006; arterial smooth muscle by acetylcholine. Nature 1980;288(5789):373 6. Godfraind T. Setsuro Ebashi, Ph.D. J Cardiovasc Pharmacol 2007;49:64–5. Godfraind, 2007; Otsuka, 2007). It comes to no surprise that Professor HickeyKA,RubanyiG,PaulRJ,HighsmithRF.Characterizationofacoronaryvaso- Ebashi, who has importantly contributed to the understanding of the constrictor produced by cultured endothelial cells. Am J Physiol 1985;248(5 physiological role of intracellular calcium (Endo, 2006; Otsuka, 2007), Pt 1):C550–6. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing had been a good friend of Professor Robert F. Furchgott since the factor produced and released from artery and vein is nitric oxide. Proc Natl Acad 1960s (Godfraind, 2007). Furchgott was the one who in the late Sci U S A 1987;84(24):9265–9. 1970s discovered the importance of endothelial cells as source of va- Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, et al. The human endothelin family: three structurally and pharmacologically distinct soactive factors (Furchgott and Zawadzki, 1980). Ten years earlier, isopeptides predicted by three separate genes. 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Professor Masashi Yanagisawa, recipient of The First Tomoh Masaki Award 2011, its complementary DNA sequence. Implications on topography and function of during his award speech at the gala dinner of the Twelfth International Conference on myosin. J Mol Biol 1987;198(2):143–57. Endothelin held on September 13, 2011 in the Great Hall of Old Court, Clare College, Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel University of Cambridge. potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332(6163):411–5. (Photograph by Suzete Sandin).