Donald Metcalf: The father of modern hematology

On December 15, 2014, the hematology and leukemia research communities lost one of their greatest leaders to pancreatic cancer. Through a remarkable 60-year research career, Donald Metcalf led the discovery and characterization of the regulators of blood cell production. The legacy of his work is not only that blood cells have become the best-understood complex biological system, but also that the clinical applications of its regulators have already benefited over 20 million cancer patients.

Donald Metcalf. Image courtesy of The Walter and Eliza Hall Institute of Medical Research.

Metcalf—Don to all who knew him—was born in 1929 in Mittagong, a small Australian country town in New South Wales. His first scientific work, on ectromelia virus, came during medical training at the University of Sydney. In 1954, Don moved to Melbourne’s Walter and Eliza Hall Institute of Medical Research (WEHI), which became his permanent scientific home. Throughout his career, Don was supported by a unique fellowship from the Cancer Council of Victoria.

Don first worked on vaccinia virus with the institute’s director, the eminent virologist and later Nobel Prize-winning immunologist, Sir Macfarlane Burnet. Unfortunately, Don’s intent to pursue cancer research, which was further whetted by a two-year postdoctoral fellowship at Harvard, rankled the autocratic Burnet, who regarded cancer as “an inevitable disease” and, therefore, anyone who chose to study it as “either a fool or a rogue.” Consequently, Don was “banished” for years to the smelly, allergy-inducing, animal house, from which he was only rescued when the directorship passed to Gus Nossal, who greatly admired Don’s work, as did the subsequent WEHI Directors (Suzanne Cory and Doug Hilton).

In 1966 came the illuminating discovery underpinning all of Don’s subsequent research: he and Ray Bradley found that granulocytes and macrophages, essential components of the body’s immune system, could be grown as colonies in soft agar (1). This seminal finding immediately provided an assay for the single progenitor cell that founded each colony and for the previously unknown extracellular cytokines required for their survival and proliferation, which Don termed “colony-stimulating factors” (CSFs).

Over time, Don’s team and others devised similar clonal assays for the progenitors of other white blood cell types, eventually revealing the complete genealogical “tree” from the multipotential blood stem cell to the diverse mature cell types. Furthermore, Don’s perceptive analysis revealed that their leukemic counterparts had acquired self-renewal hallmarks of stem cells while losing features of terminal differentiation. The insights gained on the multifaceted blood cell system made it a paradigm for the normal and neoplastic development of many other tissue types.

From the outset, Don had the bold vision that if the CSFs could be purified in sufficient amounts, they could become new medicines for augmenting blood cell production in patients receiving cancer chemotherapy or bone marrow transplants. In the 1970s, however, this seemed a pipe dream. Early purification efforts had revealed that these proteins were made in only trace amounts and that granulocyte and macrophage development was stimulated by at least four different factors, now denoted granulocyte (G)-CSF, macrophage (M)-CSF, granulocyte-macrophage (GM)-CSF, and multi-CSF (IL-3).

Recognizing that achieving his goal would require intense application of biochemistry and molecular biology, as well as cell and animal biology, Don showed great leadership in inspiring younger colleagues with those skills to share his vision. What Don’s autobiography (2) termed the “dogged pursuit” of the CSFs proved arduous, requiring up to a million-fold enrichment and yielding only microgram amounts. Key colleagues in this Herculean endeavor included Richard Stanley, Tony Burgess, and Nic Nicola. Finally, a decade of effort yielded the amino acid sequence of GM-CSF fragments. In 1984, using the emerging genetic engineering technology, this information enabled the team, which now included Ashley Dunn and Nick Gough in leading roles, to clone GM-CSF cDNA (3).

Large-scale production of the CSFs from cloned genes finally permitted tests of Don’s vision for medical application, with clinical colleagues, such as George Morstyn, Glenn Begley, and Richard Fox, assuming vital roles. Excitingly, just as Don had predicted, clinical trials showed that G- or GM-CSF treatment reduced the dangerous drop in white blood cells in cancer patients following chemotherapy or radiotherapy (4). In an unexpected bonus, Don and colleagues found that these CSFs mobilized hematopoietic stem cells from the bone marrow into the blood (5). The ease of harvesting the mobilized stem cells from blood and their rapid ability to replenish the blood cell system have transformed medical practice: their injection has rendered bone marrow transplantation largely obsolete and greatly extended the range of cancer patients able to receive intensive chemotherapy.

Don Metcalf ’s singular achievements have been recognized by numerous major prizes and honors, including the Robert Koch Prize (1988), the Sloan Prize of the General Motors Cancer Research Foundation (1989), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award and US National Academy of Sciences Kovalenko Medal (1994), the Royal Medal of the Royal Society of London (1995), Harvard University’s Warren Alpert Foundation Prize (1997), the Chiron International Award (1999), the Donnall Thomas Prize of the American Society of Hematology, the inaugural Salk Institute Medal for Research Excellence (2005), and the Lifetime Achievement Award of the American Association for Cancer Research and Grand Hamdan International Award (2007). Don was also elected to numerous learned societies, including the Australian Academy of Science, the US National Academy of Sciences, the Royal Society, and the Academy of the American Society for Cancer Research. Despite this wealth of international acclaim, we suspect that Don was equally moved by the celebration of his life held at WEHI only three months before his death: reflecting their universal admiration and respect for Don, almost the entire WEHI staff formed a cheering “Guard of Honor” to escort him into the institute, weakened in body but never in mind or spirit.

What characteristics allowed Donald Metcalf to publish 739 scientific papers plus nine books and remain at the apex of hematology for over 50 years? All attest to Don’s focus, tenacity, integrity, and diligence, perhaps ingrained by his Scottish Presbyterian upbringing. As Nossal has noted (6), “Don’s 10-hour days at the microscope (bad back notwithstanding) have become legendary….But perhaps the biggest single factor was [his] devotion to the primary data.” Don always resisted speculation and derided those who built houses of cards from minimal data as “strutters” and “snake-oil salesmen.”

Don himself should have the final words on his lifelong motivation (7): “I can’t wait to get to work. …It’s like Christmas, isn’t it? Opening the incubator door and getting out tray loads of cultures and saying, ‘Well, what’s happened? … I wonder what happened.’ … [If it] hasn’t worked again, well, another day … tomorrow, we’ll try again.” In keeping with that spirit, when his cancer progressed, Don had his favorite microscope moved into his home and continued working until a few weeks before his death.