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In Memoriam: Prof. Makio Ogawa

2024; Elsevier BV; Volume: 134; Linguagem: Inglês

10.1016/j.exphem.2024.104229

1873-2399

Keisuke Ito, Richard Stanley, Toshio Suda,

Acute Myeloid Leukemia Research

Dr. Makio Ogawa, a pioneer and trailblazer in stem cell research, passed away on February 6, 2024, at his home in New Hampshire, just after celebrating his 84th birthday with a spirited online game of Go (a game much like checkers); his wife Mary-Jane found him peacefully at rest after he did not respond to a routine lunchtime call. Makio always worked with great energy, striving for scientific advancement and endeavoring to provide chances for the next generation of scientists. Over the course of his career, he influenced so many researchers and physicians that his absence will be keenly felt. Makio's contributions to experimental hematology, and his dedication to the protegees whom he directly or indirectly mentored, trained, or influenced, within the International Society of Experimental Hematology (ISEH), are truly remarkable. Makio was renowned for his groundbreaking work in both experimental hematology and hematopoietic stem cell (HSC) research, and his contributions were widely recognized, earning him the William Dameshek Prize (1991) from the American Society of Hematology (ASH). His impact was international, as he served as a mentor to over 40 postdoctoral trainees in the Ogawa Laboratory at the Medical University of South Carolina, Charleston, SC, where he was critical to the integration of Japanese and American research efforts. Additionally, he served as a regional editor for the International Journal of Hematology (IJH), the official journal of the Japanese Society of Hematology (JSH), and a president of International Society of Experimental Hematology (ISEH, 1990). His article "Be Ambitious" (RinshoKetsueki, 59:244-249, 2018) has been widely influential in the scientific community, and is often cited for its insights. Toshio Suda, one of Makio's earliest trainees, had the privilege of meeting Makio almost half a century ago at a symposium on aplastic anemia held on Mount Hiei, a mountain located on the border of Shiga and Kyoto Prefectures in Japan, renowned as a center for Buddhist ascetic practices and training. At that time, stem cell research was in its infancy, and faced significant challenges in the establishment of myeloid colonies, let alone the formation of erythroid colonies. Makio identified the issues as stemming from defective culture incubators and/or bovine fetal serum used in the culture process, and successfully addressed them. As a result, he became one of the pioneering PIs to successfully grow massive erythroblast colonies from peripheral blood. His pioneering work in erythroid colony formation from cord blood and peripheral blood, which showcased the existence of HSCs in circulating blood, soon drew widespread attention. His subsequent status as a rising scientific star inspired many young Japanese hematologists to follow in his footsteps. Makio's journey began at Osaka University Medical School. Despite his deep respect for his mentor, Professor Yuichi Yamamura, he decided to further his pursuit of a practical, clinically-oriented approach by undergoing clinical training in English at Yokosuka Naval Hospital. Subsequently, he moved to the United States and became a clinical fellow at Dartmouth College under the guidance of Dr. Ross McIntyre. A poignant encounter with a patient suffering from IgE myeloma on Christmas Eve proved pivotal to his professional future. Makio reached out to the well-known immunologist Dr. Kimishige Ishizaka, who at that time was working in Denver, regarding a possible career in "serious" stem cell research, and soon found himself working under the mentorship of Professor Ernest McClulloch. Professor McClulloch proposed the concept of stem cell biology in 1961 at the University of Toronto, which was a mecca for stem cell research then (and now). Toronto housed brilliant minds like Drs. Norman Iscove and Connie Eaves, an exceptional researcher the ISEH community also recently lost (Kent D & Purton LE, Exp Hem, 2024). However, despite a growing sense of new scientific horizons, Makio still felt that direct involvement in stem cell research was not technically feasible at the time. Nonetheless, he established his independent research lab at the Medical University of South Carolina (MUSC) in Charleston, where he faced challenges with limited resources but found joy in forging a unique scientific path. His collaborations with Dr. Hiroshi Hara, Dr. Kinichi Kidoguchi, and Dr. Takashi Terasawa from 1976-1982 resulted in a new level of analysis of erythroid colonies, revealing the expression of fetal hemoglobin (HbF) in adult bone marrow erythroblast colonies and establishing the scientific theme of hemoglobin switching. This research deepened Makio's connections with prominent molecular biologists such as Dr. Arthur Nienhuis (NIH)and Dr. George Dover John Hopkins). In 1980, Dr. Tatsutoshi Nakahata introduced the concept of colonies consisting of multiple cell lineages (GMM colonies) at the Ogawa Lab. An amusing incident occurred during this study when a reviewer doubted whether erythroblasts were present in those colonies. Upon replating, erythroblast colonies indeed appeared, leading to the realization that colonies comprising undifferentiated cells should also exist, which ultimately led to the identification of "blast colonies". Ironically, the reviewer's skepticism ultimately propelled the progress of the research. The research was subsequently pursued by Toshio and Junko Suda and involved tracking the differentiation of daughter cells using blast colonies. This work, detailed in Makio's NIH grant application, progressed exactly as outlined in their proposal. When Toshio raised questions and concerns, Makio would calmly respond with, "I have already considered that," revealing the calm foresight characteristic of a skilled player of Go or Shogi (Japanese chess). Using Toshio's findings as a basis, Makio eventually proposed a stochastic model of differentiation that opposed the prevailing model that cytokines like erythropoietin induce differentiation. According to Makio's model, these cytokines merely act as proliferative signals, and cellular differentiation occurs autonomously and randomly. This study demonstrated that it was possible to manipulate hematopoietic stem and progenitor cells at the single-cell level and revealed the possibility of asymmetric cell division (although the mechanisms of this process still required clarification). Makio preferred to submit this groundbreaking paper to the Journal of Cellular Physiology1,2, where Professor McCulloch was editor-in-chief (no one cared much about "impact factor" back then). Professor McCulloch's restrained comment was unforgettable: "The results match the Stochastic Model of differentiation, but it cannot be claimed to be proven." During Toshio's overseas studies in the early 1980s, Makio received visits from many notable researchers, including Professor McCulloch, David Golde (Professor at UCLA), Curt Civin (Professor at Johns Hopkins), Yuichi Yamamura (President of Osaka University), Tadamitsu Kishimoto (Professor at Osaka University and a former classmate), FumimaroTakaku (Professor at the University of Tokyo), and Teruko Ishizaka (Immunologist at the University of Colorado). These visits exemplify Makio's robust connections within the research network. Many postdocs, including Toshio himself, received guidance from Makio that was almost philosophical in tone, in comments such as "The choice of what to do and what not to do is important," "Focus is crucial," "Even if it is minor at first, conduct original research," and "To achieve, read the data carefully and repeatedly." Character often gets passed down from leaders to their team members, and similarly, there were anecdotes told by Makio about Professor McCulloch being so lost in thought that he didn't realized he had started chewing on his chalk. Makio's attitude of tackling the challenging and fundamental questions in science led to a reverence for his research that is being passed down from one generation to the next. Keisuke Ito (2nd generation), a former trainee of Toshio (1st generation), was inspired by the pioneering work of Toshio and Makio3,4, especially their single-cell approach utilizing a micromanipulator to compare the differentiation capacity of corresponding daughter cells, a breakthrough achieved some forty years ago, when techniques like -omics, intravital imaging, lineage-tracing, and advanced sorting machines did not exist. Despite never having the privilege of being mentored directly by Makio, Keisuke considers himself a direct disciple of this scientific master, and his own research has been dedicated to expanding our understanding of the regulatory pathways controlling the equilibrium of healthy and malignant HSCs, with an emphasis on cellular metabolism and mitochondrial physiology, now hot topics in the field of experimental hematology (see Editorial by Ito K, Vol 128, Exp Hematol, 2023)5-9. Using the classical cell biology methods pioneered by Makio and Toshio, Keisuke has illuminated how mitochondrial metabolism precisely governs HSC fate, highlighting the deterministic nature of HSC fate determination. The paired daughter cell (PDC) assay can retrospectively determine the division patterns of HSCs by assessing the reconstitution capacity of each daughter cell, which has enabled Keisuke's team to demonstrate how mitochondrial metabolism influences the "fate decisions" made by HSCs, namely, whether to self-renew or differentiate into specialized blood cells. Regrettably, the paper by Keisuke and his trainees (3rd generation) in Cell Stem Cell10 did not reach Makio's eyes, as it was published one month after his passing. One of Makio's favorite pastimes was boating, and he had a particular penchant for indulging in Engawa—a delicacy derived from the base of a flounder's fin—while aboard. Conversely, sailing holds a special place in Keisuke's heart. Amid the serene expanse of either sea or lake, Keisuke and his team hoped someday to personally engage Makio in deep discussions regarding their discoveries. Regrettably, this dream never came to fruition; nevertheless, it remains a testament to the legend of Makio's unwavering commitment to scientific inquiry, a legacy perpetuated by those he inspired. Richard Stanley, Professor Emeritus of Developmental & Molecular Biology and Renée E. and Robert A. Belfer Chair in Developmental Biology, Albert Einstein College of Medicine, reminisce about the days half a century ago, speaking in the following manner:I first met Makio in 1972, shortly after I arrived to take up my first faculty position at the Ontario Cancer Institute (OCI) in the Biology Division of the Department of Medical Physics of the University of Toronto. He had completed his clinical fellowship with Dr. Ross McIntyre at Dartmouth and was pursuing his PhD at OCI under the guidance of Dr. D.E. Bergsagel and in close collaboration with E.A. "Bun" McCullough. His thesis work focused on the chemotherapy of mouse myeloma and the effects of chemotherapeutic agents on cultured mouse and human hematopoietic cells. During our overlap, we would meet regularly at Bun's Leukemia Group Meetings, also attended by the late Connie Eaves. Makio graduated in 1973 and moved to the Medical University of South Carolina as an Assistant Professor where he carried out seminal work in hematopoiesis, receiving the William Dameshek Prize of the American Society of Hematology (ASH) in 1991. Over the years, we would catch up at ASH meetings. A real friend, it was always a pleasure to see him and to discuss his science. I miss those meetings with him. The setting of our tribute, is Charlestone, a picturesque coastal city shadowed by its history in the Civil War. Makio continued his groundbreaking hematopoietic research here until the age of 70, but then departed to spend the final, remarkable chapter of his life in a peaceful little town near Hanover, New Hampshire. Surrounded by cherished memories with his wife in a splendid home nestled in the woods, he embraced a serene and contemplative existence. Two years ago, Toshio had the privilege of engaging in a leisurely conversation with him as he relaxed in the rustic landscape of New England. We sincerely offer our heartfelt prayers for Professor Ogawa's peaceful rest. Photo of Drs. Ogawa and Suda during Suda's visit to Dr. Ogawa's home in New Hampshire in June 2022 (left). Makio enjoyed the beauty of nature in his garden (right), observing hummingbirds and other wildlife. Reference1.Suda, T., Suda, J., Ogawa, M. & Ihle, J.N. Permissive role of interleukin 3 (IL-3) in proliferation and differentiation of multipotential hemopoietic progenitors in culture. J Cell Physiol124, 182-190 (1985).2.Suda, T., Suda, J., Spicer, S.S. & Ogawa, M. Proliferation and differentiation in culture of mast cell progenitors derived from mast cell-deficient mice of genotype W/Wv. J Cell Physiol122, 187-192 (1985).3.Suda, T., Suda, J. & Ogawa, M. Disparate differentiation in mouse hemopoietic colonies derived from paired progenitors. Proc Natl Acad Sci U S A81, 2520-2524 (1984).4.Sun, J., et al. Clonal dynamics of native haematopoiesis. Nature514, 322-327 (2014).5.Karimnia, N., Harris, J., Heazlewood, S.Y., Cao, B. & Nilsson, S.K. Metabolic regulation of aged hematopoietic stem cells: key players and mechanisms. Exp Hematol (2023).6.Li, J., et al. Chronic inflammation can transform the fate of normal and mutant hematopoietic stem cells. Exp Hematol127, 8-13 (2023).7.Schonberger, K. & Cabezas-Wallscheid, N. How nutrition regulates hematopoietic stem cell features. Exp Hematol (2023).8.Ussishkin, N. & Nachmani, D. A Bloody Feast-Nutritional Regulation of Hematopoiesis. Exp Hematol127, 1-7 (2023).9.Ma, W., et al. Metabolic regulation in erythroid differentiation by systemic ketogenesis in fasted mice. Exp Hematol (2023).10.Bonora, M., et al. A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate. Cell Stem Cell31, 359-377 e310 (2024). * * * * * * * "Life is stochastic" Fumihiko Ishikawa1, Momoko Yoshimoto2, and Tatsutoshi Nakahata3 1Riken Center for Integrative Medical Sciences, Yokohama, Japan 2WMU Homer Stryker MD School of Medicine, Kalamazoo, MI, USA 3Central Institute for Experimental Animals, Kawasaki, Japan Dr. Ogawa graduated from Osaka University Faculty of Medicine in 1964 and chose a unique path of taking clinical training at US Naval Hospital (USNH) Yokosuka in Japan. USNH Yokosuka is located within the American Naval base and provides health service to American Naval families in Yokosuka. It has offered 1-year fellowship program to Japanese resident doctors since 1952. At that time, Dr. Ogawa was one of only 16 Japanese residents while all others including doctors, nurses, and patients were American. The clinical practice of evidence-based medicine that was performed in USNH (which was not established in Japan at that time) fascinated Dr. Ogawa and led him to decide to get residency training in the US. As such, contrasting his enormous contribution to basic research in stem cell biology, not many people knew that Dr. Ogawa initially pursued clinical medicine rather than working on basic research. After the residency training in Japan, Dr. Ogawa joined the residency program at the Dartmouth School of Medicine in 1966, followed by the fellowship program. Having his initial motivation in Hematology and Oncology, seeing the second patient of IgE myeloma in the world and meeting Dr. Kimishige (Kimi) Ishizaka, who first discovered IgE, pushed him into medical basic research. This was the timing when WHO announced in 1968 the presence of the 5th immunoglobulin, IgE based on the studies by Dr. Ishizaka's group at Children's Asthma Research Institute, Denver, and Drs. Bennich and Johansson in Sweden. Dr. Ogawa reported the second IgE myeloma patient in NEJM 1969 by extracting and purifying IgE at Dr. Ishizaka's lab. With a great appreciation for Dr. Ogawa's treatment, the patient with IgE myeloma generously donated his serum and contributed to IgE research all over the world. Through this experience, Dr. Ogawa came across the excitement of finding novelty and how to conduct research. Also, he started thinking that only clinical practice cannot develop a new therapy. When Dr. Ogawa was finishing the fellowship, Dr. Kimi Ishizaka did not advise him to continue working on IgE or Ig production by normal and diseased plasma cells. He suggested that Dr. Ogawa should jump into a field of cellular biology, especially "stem cell biology". As per the advice, Dr. Ogawa joined the PhD program at the University of Toronto, Ontario Cancer Institute in 1970 and learned stem cell biology at Dr. McCulloch's lab. For young scientists reading this article, Drs. McCulloch and James Till first discovered stem cells in the blood and reported it in Radiation Research in 1961 and Nature in 1963. In Dr. McCulloch's lab, Dr. Ogawa met Drs. Connie Eaves, Norman Iscove, Richard Stanley, TakMak, and others. Gathering of these international scientists in Toronto became a unique and essential power of stem cell biology and biomedical research. After obtaining Ph.D., Dr. Ogawa was recruited to Medical University of South Carolina (MUSC), Charleston in 1973, and started up his lab. He was fortunate to have talented Japanese postdocs in his lab, including Dr. TatsutoshiNakahata, a leading scientist in Pediatric Hematology, Dr. Toshio Suda, a leading stem cell biologist and an Editor-in-Chief at Experimental Hematology, and others, most of them became Professors and leading scientists in Japan and established basic and translational stem cell research and medicine. Dr. Ogawaput a lot of effort into measuring the "stemness" and "multilineage differentiation capacity" of hematopoietic stem/progenitors (HSPCs) using colony-forming assays. Dr. Ogawa identified a blast cell colony, which consists of only immature hematopoietic stem/progenitors. These blast colonies are capable of self-renewal (producing secondary blast colonies) and multi-lineage differentiation (producing GEMM colonies after replating). He intensively engaged in replating colony-forming assays and paired daughter experiments and examined the cell types in the daughter colonies. These studies led him to propose the stochastic model in which the differentiation process from HSCs to each lineage happens stochastically. This experimental system is now well accepted as an asymmetric cell division by hematopoietic stem cells. In addition, Dr. Ogawa found blast colony-forming cells are present at a higher frequency in the umbilical cord blood compared to adult bone marrow, built a basis of the current cord blood transplantation therapy. Indeed, based on Dr. Ogawa's report, Dr. Hal Broxmeyer at Indiana University extended the experiments and performed the first cord blood transplantation therapy. Ogawa's lab also set out to perform in vivo CD45.1/CD45.2 syngeneic mouse transplantation to assess the in vivo fate of purified stem and progenitor cells and found changes in CD34 expression in HSCs with age (from CD34 positive in juvenile mice to CD34 negative in adult mice) and upregulation of CD34 expression in activated adult HSCs. In the 2000s, the lab's effort was made to understand the contribution of HSCs to generating tissue fibroblasts and adipocytes and how HSCs are plastic in relevance with regenerative medicine. The lab has established a fibroblast colony-forming assay in the context of stem cell plasticity. Dr. Ogawa encouraged lab members to take strategies for making a good transition from in vitro to in vivo experiments and to keep asking themselves what is novel and what is original. As such, Dr. Ogawa is known as a dedicated, enthusiastic mentor for anyone who loves science. He accepted many postdocs internationally (more than 40 mentees from Japan) and helped their career development (. While Dr. Ogawa had fostered physician scientists from Japan at his lab, he encouraged us to find ways to become international and be exposed to US culture appreciating diversity. Right before I (Fumihiko) left Charleston for Japan, Dr. Ogawa invited Dr. Leonard Shultz to MUSC for a talk. Since his introduction of Dr. Shultz to me, I got a chance to collaborate with the Jackson Laboratory and Lenny's lab for more than 20 years. Dr. Ogawa gave different opportunities to each person in a way he or she can make contribution or enjoy science globally. To make sure that ex-fellows do those, Dr. Ogawa visited Japan every couple of years. Throughout his life, Dr. Ogawa also dedicated himself to Kendo, a traditional Japanese martial art that cultivates not only physical prowess but also one's spiritual fortitude. Kendo requires concentration, endurance, swift decision-making, humility, and consistency. Dr. Ogawa embodied the principles of Kendo in his character and actions. In the morning he passed away, according to the story found at www.legacy.com/us/obituaries/vnews/name/makio-ogawa-obituary?id=54512743, he was looking forward to playing Go online with his friend and teacher. Go, or Igo (pronounced E-Gou) (囲碁) is a Chinese/Japanese traditional board game, which requires prospective and analytic thinking, strategic approaches, and patience, like conducting research. It seems natural that Go attracted him. I still remember his big smile, joking "Life is stochastic". Dr. Ogawa was a great figure for us, not only as a scientist but also as a human being and a pioneer who opened up paths in life. Our heartfelt condolences on the passing of Professor Ogawa. At the ASH meeting (San Antonio).Drs Nakahara (left), Makio Ogawa (center), and . Makoto Kawakita (right) A man at peace with dignity Mervin C. Yoder 1 and David A. Williams 2 1University of Pittsburgh/MIRM, Pittsburg 2Harvard Medical School, Boston Children's Hospital, Boston I fondly recall the first International Society for Experimental Hematology (ISEH) meeting that I attended in Providence, RI in 1992 with my colleague David Williams. As David predicted, the meeting was energetic, talks were exciting with new ideas and theories about stem and progenitor cell origins and assays, and the international mix of senior and junior scientists and students attending the sessions were engaged and enthusiastic. Makio made a marked first impression on me when we met in the poster presentation session, as he introduced himself with his broad smile and series of probing questions about the work I was presenting. I was well aware of Makio's published interests in clonal studies of hematopoietic stem and progenitor cells, use of hematopoietic growth factors to probe cell potency, theories of stochastic differentiation, and the significance of these contributions and their impact on the field at that time. I was not prepared for how kind, thoughtful, and congenial he was or how his kind of collaborative sharing of ideas with a colleague you had never met before, could make science so much fun. That ISEH meeting was a tremendous initiation into the field of experimental hematology and Makio was one of the key luminaries in the field that were so welcoming and encouraging that helped develop the careers of so many young scientists. Through the years, I enjoyed meeting Makio in his laboratory or hosting him at my institution for seminars. I always looked forward to seeing him and catching up on his new insights about unresolved questions. He did not disappoint! He was such a gentleman, a man at peace with dignity, while navigating the often-turbulent seas of scientific discourse on the way to discovery. * * * * * * * HSC fate and highlights Karl Welte,1.Lothar Kanz,1 WillemFibbe,2 1Senior professor of the University Tuebingen, Germany 2Professor of Leiden University Our friend and colleague Makio Ogawa passed away on February 6, 2024. Makio, who has had a significant impact on research of hematopoiesis for more than four decades, is mourned by the scientific community. Indeed, he was one of the heroes of hematopoetic research. Makio joined James Till and Ernest McCulloch at the University of Toronto where he received a PhD. Under their mentorship, he began conducting research on a model of stem cell functions in which the decision of hematopoietic stem cells to self-renew and differentiate is a stochastic process. Makio became a faculty member at the Medical University of South Carolina in Charleston in 1973. He continued his research on the stochastic role of hematopoiesis, which led to major contributions in the field of hematopoietic stem cell biology. He became an excellent and well-recognized scientist, having authoredhundreds of manuscripts. Two seminal papers on models of hematopoietic stem cell renewal and commitment, one published in 1983 in Blood1 and the other published in 1993 in Blood2, were the standard reading for thousands of hematologists. He was not only an exceptional teacher, but also a mentor to hundreds of young scientists, generously sharing his wealth of knowledge and experience. Throughout his career, he trained over thirty students and postdoctoral fellows for careers in academic or industrial settings. He always maintained a close relationship with his former fellows. He became Professor Emeritus of Pathology and Laboratory Medicine in 2011. I personally met Makio for the first time at Experimental Hematology meetings in the 1980s when I was Head of the of the Cytokine Laboratory at the Memorial Sloan-Kettering Cancer Center New York. We engaged in intensive discussions for hours with Malcolm A.S. Moore and Donald Metcalf on the role of the newly identified G-CSF in stochastic versus determined hematopoiesis. Makio and myself met later many times at meetings in the US and Germany and became close friends. The scientific community is deeply affected and saddened by the loss of a remarkable scientist with his immense knowledge and an always friendly and helpful colleague. He leaves behind a profound legacy and will be missed by all of us. Rest in peace, my friend! ◇Reference1Ogawa M, Porter PN, Nakahata T. Renewal and Commitment to Differentiation of hematopoietic stem cells. Blood 61, 1983; 823-8292Ogawa M. Differentiation and Proliferation of hematopoietic stem cells. Blood 81, 1993; 2844-2853 Recommendation of Dr. Ogawa Toru Nakano1 1Osaka University Dr. Makio Ogawa was a senior colleague at Osaka University Medical School and, to me, a figure akin to a deity. I began my research in hematology in 1984 and around that time, Dr. Ogawa and his postdoc, Dr. Toshio Suda proposed a stochastic model of hematopoietic cell differentiation. I came to respect Dr. Ogawa from the bottom of my heart due to the hypothesis that overturned the conventional view. Several years later, at the ISEH meeting held in Tokyo, I had the chance to sit next to Dr. Ogawa on the bus to a recreational event. I vividly remember how delighted I was and the various conversations we had. Dr. YukihikoKitamura, who was my supervisor, had a close relationship with Dr. Ogawa, so when I was looking for a place to study abroad, I turned to Dr. Ogawa for help. Ultimately, I became a postdoc in Dr. Thomas Graf's laboratory, one of the laboratories he recommended. If it were not for Dr. Ogawa's introduction, my subsequent career as a researcher would have been significantly different. Even after that, he always warmly encouraged me whenever we met at conferences. I still treasure the congratulatory letter he sent me when I became a professor in 1995. Despite his repeated invitations to come and visit South Carolina, unfortunately, I never had the chance to go. My heartfelt condolences go out to him. * * * * * * * Memory of Dr. Makiko Ogawa Sam Shimosaka1 1Chairperson Asian Cellular Therapy Organization It was a shocking news for me when I was informed from Charleston Group member that Dr. Makio Ogawa suddenly passed away. I had appointment to have a dinner in Tokyo when he will visit Japan in March. Dr. Makio Ogawa and I have been working together for the research in stem cell biology. He was the philosopher in stem cell biology. Early 1980's we started working together. Single cell assay is one his key achievement in hematology research. I was helped by his work because I have been involved in the research and development of hematopoietic growth factors. We joined stem cell biology meeting in Tuebingen, Germany together which was organized by Profs. Lothar Kanz and Willem Fibbe and their friends. After his retirement, I visited his home in New Hampshire and enjoyed time together with him and his wife, Mary Jane. His smile was so attractive. Many lady scientists were enchanted with his smile. We used to have nice time for dinner with friends at the AHS annual meetings. He trained so many young hematologists and many of them became leaders in the hematology. He was the excellent teacher and researcher. We lost most important stem cell biologist. With his wife, Mary Jane. in New Hampshire * * * * * * * In memoriam by TPO researchers Takashi Kato, D.Sc.1 1Molecular Physiology, Department of Biology,Faculty of Education and Integrated Arts and Sciences, Waseda University In 1987, I joined the laboratory of Dr. Takaji Miyake, who was trying to purify thrombopoietin (TPO) from the urine of patients with aplastic anemia at the University of California Santa Barbara. Dr. Miyake was a brilliant scientist who successfully purified erythropoietin with Dr. Goldwasser at the University of Chicago. However, Dr. Miyake was not a sociable scientist or a person who praised others excessively. One day, however, Dr. Miyake introduced me at his home to Dr. Makio Ogawa, saying that of all the researchers he had met, Dr. Ogawa was the most trustworthy. Since then, Dr. Makio Ogawa has become a respected scientist for me. The purification of TPO in California was unsuccessful. Later, at the ISEH symposium in Minneapolis in 1994, my colleague at Kirin