The news that Don Metcalf has left us marks a turning point in experimental Haematology. For myself, Ton and Geoff, members of the DECIDE consortium, Don was the father of experimental hematology and we are his humble disciples. Without doubt, he was one of the most accomplished cell biologists of the 20th century and we feel privileged having known and discussed science with him. Not only did Don have boundless passion for his science, namely understanding the process of leukemia development, but also he was a devoted family man, extraordinarily well read and a wonderful raconteur with a sharp, critical sense of humor. Homage to his life has already been posted and I would encourage all our ESR’s to read this article.

I would like to take this opportunity of adding some personal anecdotes. I was lucky enough to have carried out my PhD studies in Don’s research group at the Walter and Eliza Hall Institute. My encounters with him at this time have affected my career profoundly. Before embarking on his career as an experimental hematologists working with bone marrow cells, Don had already established himself as an outstanding thymologist. In the early sixties, his Institute director had told him to stop working on the thymus and find another avenue of research. His 1966 monograph entitled “The Thymus: Its role in Immune Responses, Leukaemia Development and Carcinogenesis” was my thymus “Bible” and still occupies a prominent place in my book collection.

His experiments had established that the thymus was an organ in which significant cell proliferation occurred but that when thymus cells were placed in culture, they survived poorly. In addition, Don had grafted multiple thymuses subcutaneously into adult mice observing no change in peripheral lymphocyte numbers-probably the first demonstration of what we now call lymphocyte homeostasis.

Professor Donald Metcalf

Therefore, in 1977 when I began presenting at his laboratory meetings my own experiments attempting to clone T cells from in vitro mixed lymphocyte cultures using thymus cells as responders, Don reacted to these with considerable skepticism. His remarks were typically rather caustic including “you’re wasting your time-the best thing thymocytes do in vitro is die!” Naturally as a naïve PhD student, such remarks from the laboratory head were upsetting and challenging but they taught me to be extremely self-critical, and to set up experiments in such a way as to try and disprove any hypothesis, that is to adopt the “null hypothesis”. Luckily, in this case, we were both right as I managed to show that the frequency of clonable T cells among thymocytes was indeed extremely low.

Prior to completion of my PhD, one afternoon I went to visit Don in his office to ask his advice on what I should do next. As usual in those days, Don was at his microscope smoking a cigar, surrounded by mountains of Petrie dishes and counting colonies. All experiments in his laboratory went under his microscope. However, in that interview, Don gave me what turned out to be three crucial pieces of advice. Firstly, he suggested I go and do my post-doctoral studies in Lausanne, Switzerland. Don had done a short sabbatical there and had worked and published with my future supervisor whom he regarded with high esteem. In many ways, these were my most productive years. Secondly, he advised me “not to be a butterfly”.  By this, Don meant that to be a successful scientist, it’s best to stick to an area of work even if the going gets tough, rather than to frequently change subjects. Sometimes, I wish I had followed his advice. Lastly, he said that when writing papers, never discuss topics outside the realm of the results presented. This is sound advice given that reviewers frequently look for any weaknesses in authors’ arguments and such diversions provide them with easy ammunition.

In the context of the DECIDE network, one of our scientific aims is to address the question of how cell lineage choice is occurring in the bone marrow. Some of the published work from our network, Tsapogas et al. Haematologica  99(4): 638-46 (2014) and unpublished single cell RT-PCR analysis of various highly purified bone marrow progenitors tend to support the notion that cytokines may play an instructive role in hematopoietic development. Indeed, that cytokines play an instructive role in lineage commitment is an idea that Don had been instrumental in championing. This began following the publication of Don’s single author 1991 Proc. Natl. Acad. Sci. USA 88:11310-11314 paper entitled “Lineage commitment of hemopoietic progenitor cells in developing blast cell colonies: Influence of colony-stimulating factors”. In this technological tour-de-force, often affectionately referred to by us as “doing the Don experiment”, he micro-manipulated cells from individual colonies and placed them in different cytokine cocktails observing corresponding differences in lineage outcome. The conclusions of this work flew in the face of competing models of the time that favored a more stochastic model of cell lineage commitment. This debate came to boiling point in a series of commissioned articles entitled “Controversies in Hematology” published in Blood 92: 345-352 (1998). In this debate, Australian Don, confronted three UK-based researchers and in a rebuttal to his UK colleagues, Don stated in typical humorous tongue-in-cheek fashion that “This prearranged controversy has ended up with three English authors versus one Australian; the odds seem about right, regardless of whether it is dice, cricket, or hematopoiesis.” Such wry remarks merely reflect Don’s passion for his science.

To bring us up to date, it is worth quoting from a much more recent Metcalf publication entitled “Hemopoietic cytokines” from Blood 111:485-491 (2008), an issue marking the 50th anniversary of the American Society for Hematology. In this review, Don summarizes the roles on hematopoiesis of three cytokines, namely erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage stimulating factor (GM-CSF).  In conclusion, he states: “However, certain facts stand out clearly. The administration of single agents can have predictable and dramatic effects on hematopoiesis despite all the potentially interacting and buffering networks. We need to keep these simple facts in mind. Every member of this network of regulators is likely to prove to have a unique role in a particular situation, and our future task is now to establish precisely what roles are played by each of these candidate regulators and in what clinical situations the application of these regulators may prove to be of value.”

As Don had previously stated, “If paradise exists for experimental biologists, then hematopoiesis has surely got to be it”! We can hope that some of our ESR’s will in future be able to contribute to the tree of knowledge growing in Don’s paradise.

Rhodri Ceredig.