RETROSPECTIVE Donald Metcalf: The father of modern hematology Jerry M. Adams1 and Suzanne Cory Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia On December 15, 2014, the hematology and founded each colony and for the previously leukemia research communities lost one of unknown extracellular cytokines required for their greatest leaders to pancreatic cancer. their survival and proliferation, which Don Through a remarkable 60-year research ca- termed “colony-stimulating factors” (CSFs). reer, Donald Metcalf led the discovery and Over time, Don’s team and others devised characterization of the regulators of blood similarclonalassaysfortheprogenitorsof cell production. The legacy of his work is not other white blood cell types, eventually reveal- only that blood cells have become the best- ing the complete genealogical “tree” from the understood complex biological system, but multipotential blood stem cell to the diverse also that the clinical applications of its reg- mature cell types. Furthermore, Don’sper- ulators have already benefited over 20 million ceptive analysis revealed that their leukemic cancer patients. counterparts had acquired self-renewal hall- Metcalf—Dontoallwhoknewhim—was marks of stem cells while losing features of born in 1929 in Mittagong, a small Australian terminal differentiation. The insights gained countrytowninNewSouthWales.Hisfirst on the multifaceted blood cell system made it scientific work, on ectromelia virus, came du- a paradigm for the normal and neoplastic de- ring medical training at the University of Syd- velopment of many other tissue types. ney. In 1954, Don moved to Melbourne’s From the outset, Don had the bold vision Walter and Eliza Hall Institute of Medical that if the CSFs could be purified in sufficient Research (WEHI), which became his perma- amounts, they could become new medicines Donald Metcalf. Image courtesy of The Walter nent scientific home. Throughout his career, for augmenting blood cell production in pa- and Eliza Hall Institute of Medical Research. Don was supported by a unique fellowship tients receiving cancer chemotherapy or bone from the Cancer Council of Victoria. marrow transplants. In the 1970s, however, Don first worked on vaccinia virus this seemed a pipe dream. Early purification and Nick Gough in leading roles, to clone with the institute’s director, the eminent efforts had revealed that these proteins were GM-CSF cDNA (3). Large-scale production of the CSFs from virologist and later Nobel Prize-winning made in only trace amounts and that gran- ’ immunologist, Sir Macfarlane Burnet. Unfor- ulocyte and macrophage development was cloned genes finally permitted tests of Don s tunately, Don’s intent to pursue cancer re- stimulated by at least four different factors, vision for medical application, with clinical search, which was further whetted by a now denoted granulocyte (G)-CSF, macro- colleagues, such as George Morstyn, Glenn two-year postdoctoral fellowship at Harvard, phage (M)-CSF, granulocyte-macrophage (GM)- Begley, and Richard Fox, assuming vital roles. rankled the autocratic Burnet, who regarded CSF, and multi-CSF (IL-3). Excitingly, just as Don had predicted, clinical cancer as “an inevitable disease” and, there- Recognizing that achieving his goal would trials showed that G- or GM-CSF treatment fore, anyone who chose to study it as “either require intense application of biochemistry reduced the dangerous drop in white blood afoolorarogue.” Consequently, Don was and molecular biology, as well as cell and cells in cancer patients following chemother- “banished” for years to the smelly, allergy- animal biology, Don showed great leadership apy or radiotherapy (4). In an unexpected inducing, animal house, from which he was in inspiring younger colleagues with those bonus, Don and colleagues found that these only rescued when the directorship passed skills to share his vision. What Don’s autobi- CSFs mobilized hematopoietic stem cells to Gus Nossal, who greatly admired Don’s ography (2) termed the “dogged pursuit” of from the bone marrow into the blood (5). work, as did the subsequent WEHI Direc- the CSFs proved arduous, requiring up to The ease of harvesting the mobilized stem tors (Suzanne Cory and Doug Hilton). a million-fold enrichment and yielding only cells from blood and their rapid ability to In 1966 came the illuminating discovery microgram amounts. Key colleagues in replenish the blood cell system have trans- underpinning all of Don’ssubsequent this Herculean endeavor included Richard formed medical practice: their injection has research: he and Ray Bradley found that Stanley, Tony Burgess, and Nic Nicola. Fi- rendered bone marrow transplantation largely granulocytes and macrophages, essential nally, a decade of effort yielded the amino obsolete and greatly extended the range of components of the body’s immune system, acid sequence of GM-CSF fragments. In could be grown as colonies in soft agar (1). 1984, using the emerging genetic engineer- Author contributions: J.M.A. and S.C. wrote the paper. This seminal finding immediately provided ing technology, this information enabled 1To whom correspondence should be addressed. Email: adams@ an assay for the single progenitor cell that the team, which now included Ashley Dunn wehi.edu.au. 2628–2629 | PNAS | March 3, 2015 | vol. 112 | no. 9 www.pnas.org/cgi/doi/10.1073/pnas.1500346112 Downloaded by guest on September 24, 2021 cancer patients able to receive intensive of his life held at WEHI only three months data.” Don always resisted speculation and RETROSPECTIVE chemotherapy. before his death: reflecting their universal ad- derided those who built houses of cards from Don Metcalf ’s singular achievements have miration and respect for Don, almost the en- minimal data as “strutters” and “snake-oil “ been recognized by numerous major prizes tire WEHI staff formed a cheering Guard of salesmen.” ” and honors, including the Robert Koch Prize Honor to escort him into the institute, weak- Don himself should have the final words (1988), the Sloan Prize of the General Motors ened in body but never in mind or spirit. on his lifelong motivation (7): “Ican’twaitto Cancer Research Foundation (1989), the What characteristics allowed Donald get to work. ...It’s like Christmas, isn’tit? Albert Lasker Award for Clinical Medical Re- Metcalf to publish 739 scientific papers plus Opening the incubator door and getting out search (1993), the Gairdner Foundation In- nine books and remain at the apex of hema- tray loads of cultures and saying, ‘Well, ternational Award and US National Academy tology for over 50 years? All attest to Don’s what’s happened? ... Iwonderwhathap- of Sciences Kovalenko Medal (1994), the focus, tenacity, integrity, and diligence, per- ’ ... ’ Royal Medal of the Royal Society of London haps ingrained by his Scottish Presbyterian pened. [If it] hasn t worked again, well, ... ’ ” (1995), Harvard University’s Warren Alpert upbringing. As Nossal has noted (6), another day tomorrow, we ll try again. In Foundation Prize (1997), the Chiron Interna- “Don’s 10-hour days at the microscope keeping with that spirit, when his cancer pro- tional Award (1999), the Donnall Thomas (bad back notwithstanding) have become gressed, Don had his favorite microscope Prize of the American Society of Hematology, legendary....But perhaps the biggest single moved into his home and continued working the inaugural Salk Institute Medal for Re- factor was [his] devotion to the primary until a few weeks before his death. search Excellence (2005), and the Lifetime Achievement Award of the American Asso- ciation for Cancer Research and Grand Hamdan International Award (2007). Don 1 Bradley TR, Metcalf D (1966) The growth of mouse 5 Dührsen U, et al. (1988) Effects of recombinant human bone marrow cells in vitro. Aust J Exp Biol Med Sci 44(3): granulocyte colony-stimulating factor on hematopoietic progenitor was also elected to numerous learned societies, 287–299. cells in cancer patients. Blood 72(6):2074–2081. including the Australian Academy of Science, 2 Metcalf D (2000) Summon up the Blood: In Dogged Pursuit of 6 Nossal G (2009) in Celebrating the achievements of Professor Don the Blood Cell Regulators (AlphaMed Press, Dayton, OH). Metcalf on his 80th birthday. Available at www. the US National Academy of Sciences, the 3 Gough NM, et al. (1984) Molecular cloning of cDNA discoveriesneeddollars.org/uploads/pdf/donmetcalf.pdf. Accessed Royal Society, and the Academy of the Amer- encoding a murine haematopoietic growth regulator, granulocyte- January 22, 2015. ican Society for Cancer Research. Despite this macrophage colony stimulating factor. Nature 309(5971):763–767. 7 Metcalf D (2009) in Celebrating the achievements of Professor 4 Morstyn G, et al. (1988) Effect of granulocyte colony stimulating Don Metcalf on his 80th birthday. Available at www. wealth of international acclaim, we suspect factor on neutropenia induced by cytotoxic chemotherapy. Lancet discoveriesneeddollars.org/uploads/pdf/donmetcalf.pdf. Accessed that Don was equally moved by the celebration 1(8587):667–672. January 22, 2015. Adams and Cory PNAS | March 3, 2015 | vol. 112 | no. 9 | 2629 Downloaded by guest on September 24, 2021.