Haematology and Blood Transfusion Vol. 31 Modern Trends in Human Leukemia VII Edited by Neth, Gallo, Greaves, and Kabisch © Springer-Verlag Berlin Heidelberg 1987 Introduction for Donald Metcalf M. Moore 1 It is a personal pleasure to introduce my understand the environment, the man, and friend and former colleague, Donald Met­ the interplay of chance and the prepared calf. He is best recognized as one of the mind. In 1965 the Nobel Laureate, Sir Mac­ founding fathers of modern experimental farlane Burnet, retired as Director of the hematology, but we should not forget his Walter and Eliza Hall Institute for Medical pioneering work on the thymus. From 1956 Research (WEHI), appointing as his suc­ and the decade thereafter, Don undertook a cessors his two proteges, Gus Nossal as Di­ series of elegant studies on thymic cell kin­ rector and Don Metcalf as Assistant Direc­ etics and was one of the first to analyze the tor and Head of the Cancer Research Unit. impact of thymectomy and thymic grafting This was a wise decision, since Don re­ on lymphopoiesis. Indeed, he should be con­ mained relatively unburdened by adminis­ sidered the first to demonstrate the effects of trative responsibilities, which he naturally thymectomy on lymphoid tissue and the au­ finds irksome, and was able to pursue his sci­ tonomous control of lymphocyte prolifer­ entific interests. The "golden age of immu­ ation within the thymus. In addition, his nology" can be considered to have begun in analysis of leukemogenesis in AKR mice is the mid-1960s and the Hall Institute was still considered definitive, revealing his abil­ very much at the forefront. Don has always ity to compare and contrast the cellular biol­ disliked the "bandwagon" concept of re­ ogy of the normal and neoplastic to gain in­ search, choosing instead to move in his own sight into the etiology and pathogenesis of directions and as much as possible into un­ leukemia. The same consummate skills as an charted territory. experimentalist, and the same insight and in­ At this time, experimental hematology terest, were to mark his subsequent investi­ was emerging from its lowly status as a de­ gations into myelopoiesis and myeloid leu­ scriptive morphological discipline, helped by kemia that have occupied the last two de­ radioisotope labeling kinetics and the first cades. stem cell assay (CFU-S), as well as some I had known and admired Don's work knowledge about erythropoietin and regula­ during his "thymic phase," since I also be­ tion of erythropoiesis. While vision and con­ gan my research career on thymic develop­ cepts are necessary to move a field, there is ment, and it was this area that led me to a third essential, the catalyst of methodol­ move from England to Australia in 1967 to ogy. Hematology lacked in vitro systems for begin what was to be a 7-year collaboration quantitation of hematopoietic cell prolifer­ with Don. Why, you may ask, did Don move ation and differentiation, and so an impor­ out of the thymus area at the very time that tant milestone was reached in 1965 when it became a major preoccupation of immun­ Don, with Dr. Ray Bradley, developed a ologists? To understand this you must semisolid culture technique, permitting the clonal growth and maturation of granulo­ 1 Memorial Sloan-Kettering Cancer Center, 1275 cytes and macrophages, from committed York Avenue, New York, N.Y. 10021, USA precursors in the bone marrow. This tech- 14 nique was subsequently modified by him pendent for cell proliferation, but one CSF, and his colleagues to permit the clonal cul­ G-CSF, also had the property of suppressing ture of eosinophils, megakaryocytes, B-lym­ myeloid leukemic cells by enforced differ­ phocytes and multipotential cells. With the entiation. While showing that myeloid leu­ use of these clonal culture techniques and kemia development need not involve auto­ cell separation procedures, he and his col­ crine mechanisms, Don and his group have laborators succeeded in characterizing he­ recently shown that the genes for GM-CSF matopoietic stem cells and progenitor cells. and interleukin-3 (IL-3) can function as His analysis of the growth requirements of proto-oncogenes. It is exceedingly unlikely granulocytes and macrophages led to the that WEHI-3 would have been analyzed to discovery of a group of specific glycoprotein the extent it was if it had developed else­ regulators, the colony stimulating factors where and one wonders without it how long (CSFs). All four murine CSFs have been it would have taken to "discover," purify, purified by his group, and work by his group and clone IL-3 and G-CSF, since both and others has now led to the cloning of growth factors were discovered as a direct cDNAs for all four murine and human result of the use of the WEHI-3 cell lines as CSFs. His recent work, using bacterially constitutive sources of IL-3 and as specific synthesized recombinant CSFs, has shown responders to G-CSF. that the CSFs' function in vivo is to control Early in 1986 I had the pleasure of attend­ the production and function of granulo­ ing a Birthday Party Symposium at the Hall cytes, monocytes, and related blood cells. In Institute to celebrate the 21st anniversary of this era of mega buck science, it is instructive the discovery of the in vitro hematopoietic to remember that much of the pioneering colony assay. It was very much a coming-of­ work and the seminal observations were age party for experimental hematology, her­ made in agar cultures using tools no more alding its own golden age, which Don was so sophisticated than a microscope, a handheld instrumental in creating. For those who at­ micropipette, glass slides, and orcein stain. tended the final party, the image of Don To the requirements of vision, technical Metcalf, Ray Bradley, Leo Sachs, and Bun expertise, and powers of observation, there McCulloch, festooned with colored balloons must be added "Chance, Fortune, Luck, of varying sizes representing the cellular and Destiny, Fate, Providence which determine regulatory aspects of their respective con­ whether you walk to the right or left of a par­ tributions to hematology, was a vision better ticular tree ... " I think this is best illustrated seen than described. What was also evident by recalling the circumstances surrounding was the contribution that Don has made in the murine myelomonocytic leukemia inspiring the second, and what is now the WEHI-3. This tumor arose very early in a third generation of "new wave" experimen­ very large experiment on mineral oil induc­ tal hematologists. tion of plasmacytomas in BALBjc mice, be­ Don's contributions were recognized by ing carried out by Noel Warner and myself. his recent award of the Wellcome Prize of Not only was this tumor unique among all the Royal Society which is, I am sure, just the hundreds of tumors that subsequently the beginning of a succession of recognitions developed, it was exactly the right tumor for his pioneering role in the modern era of (myelomonocytic leukemia), with the right hematology and leukemia research. Your properties (responded to CSFs by prolifer­ work has not only led to the discovery and ation or differentiation, produced CSFs, characterization of hematopoietic growth cloned in agar), in the right place (Cancer factors, but as a former clinician (1953, Research Unit, WEHI), at the right time Royal Prince Alfred Hospital, Sydney), the (1968-1969), when our interests were ex­ initiation of clinical trials with recombinant tending from the role of growth factors in growth factors must be a source of satisfac­ normal myelopoiesis to regulatory aberra­ tion to you - ("Only if they are done right," tions in myeloid leukemia. I hear you say). With these words, ladies and Studies on WEHI-3 led to subsequent gentlemen, it is my distinct personal pleasure studies in which human myeloid leukemic to present to you an extraordinary scientist, populations were shown to remain CSF -de- Dr. Donald Metcalf. 15 .