Professor Don Metcalf
Professor Don Metcalf: a legend in his own time
Professor Don Metcalf is at the heart of one of the most famous scientific stories to emerge from the Walter and Eliza Hall Institute.
For almost 30 years, Professor Metcalf doggedly and painstakingly pursued one task: identifying and purifying the hormones that stimulate blood cells to produce the white blood cells needed by the body to fight infection.
Professor Metcalf is regarded as the ‘father of modern haematology’ for his pioneering research, which saw him identify colony stimulating factors (CSFs) – critical molecules that tell stem cells to multiply and mature to boost the immune system.
CSFs are now widely used in clinical medicine, predominantly in the treatment of cancer patients who have undergone chemotherapy. To date, Professor Metcalf’s discovery has benefited more than 10 million cancer patients worldwide.
CSFs also revolutionised transplant medicine, leading to new techniques to perform bone marrow transplants for patients with blood diseases such as leukaemia.
Professor Metcalf’s research has been supported by the Cancer Council Victoria for more than 50 years. The Cancer Council awarded him the Carden Fellowship in 1954, that fellowship has funded his work at the institute ever since.
Although Professor Metcalf officially retired in 1996, he is still an active researcher at the institute. A favourite anecdote at the institute about Professor Metcalf is that, the day after he retired, he came back to work as though nothing had changed. He has continued to do so.
Listen to Professor Metcalf recall his research career
- Early career at the institute
- Searching for CSFs: a 15 year struggle
- From bench to bedside
- Changing cancer and transplant medicine
- More growth factors discovered
- Awards
- External links
Early career at the institute
Professor Don Metcalf began his research at the Walter and Eliza Hall Institute in 1954, as the Carden fellow in Cancer Research of the then Anti-Cancer Council of Victoria.
He spent his early years studying vaccinia virus at the institute, at the behest of Sir Macfarlane Burnet. Following international sabbaticals, Professor Metcalf returned to the institute where, for 10 years, he studied the development of T cells in the thymus. His work on the high turnover of T cells in the thymus preceded the discovery that it is the organ where T cells are ‘educated’ to recognise self and non-self.
In 1965, under the new directorship of Professor Gus Nossal, Professor Metcalf was finally free to follow his passion – studying blood cell formation and, by association, leukaemia. In 1966 he became deputy director of the institute and the head of its Cancer Research Unit.
Searching for CSFs: a 15 year struggle
At the Walter and Eliza Hall Institute in the early 1960s, Professor Don Metcalf speculated that there must be a biological mechanism – one or more hormones – that controlled white blood cell production.
The existence of this unknown mechanism was suggested by the fact that patients suffering from infections experienced rapid increases in white blood cell production. Further, cancer patients whose bone marrow had been damaged by chemotherapy experienced a drop in white blood cell numbers but these numbers increased as the bone marrow recovered.
In 1965, a new technique opened up the possibility of identifying this mechanism.
“An accidental discovery of how to grow bone marrow cells in dishes led us to realise that there were things that you had to add to the bone marrow cells to make them grow,” Professor Metcalf said. “We wondered whether these were the hormones that we knew the body must use to control the production of blood cells, because you make enormous numbers of them each day, and you have to control this very carefully.”
The factors were dubbed ‘colony stimulating factors’ (CSFs) because they were the biological products, or growth factors, that stimulated the production of groups (or colonies) of white blood cells and other blood cells.
“None of us realised that 15 years of painful labour were only just beginning,” Professor Metcalf said. “The purification project was to require technology yet to be developed, the development of CSF sources yet to be discovered and the purification of four distinct CSFs, not the single form originally envisaged.”
The group started by seeking to show that CSF was detectable in blood serum and urine, and soon found that CSF could be detected in humans in all organs, the serum, and the urine, and was produced in increased amounts following infection.
Professor Metcalf said that it became evident CSFs were likely to be a genuine regulator of granulocytes and macrophages (which are both types of immune cells).
“It became a matter of some importance to achieve the purification of CSFs,” Professor Metcalf said. “Serious efforts to purify CSF began in 1968 with Richard Stanley using, as the starting material, human urine collected in the institute’s toilets. Initial purification involved removal of cigarette butts and an elaborate dialysis system in an evil-smelling tank in the corner of the laboratory.”
The factors they found in different tissues had variable effects on the white blood cell colonies that were being grown on agar plates, suggesting that multiple factors must exist.
“When we began to analyse what type of CSF was being made by different tissues, it became appallingly obvious,” Professor Metcalf said. “Clearly things were a bit more complicated than we had thought. There must be more than one type of CSF.* (*Australian Academy of Science)
In the end, four different CSFs were identified and purified by the team. These were:
- G-CSF (granulocyte CSF)
- GM-CSF (granulocyte-macrophage CSF)
- M-CSF (macrophage CSF)
- Multi-CSF (now called interleukin-3)
The road to this discovery was a long and laborious one.
“These were projects requiring grim persistence and not a little black humour to sustain,” Professor Metcalf said. “When the world’s supply of purified M-CSF was accidentally thrown out on two occasions in clearing up the laboratory mess of Richard Stanley and when purified G-CSF was repeatedly lost because of its appalling stickiness to plastic, the only response possible was black humour.”
From bench to bedside
In the early 1980s the group was in despair. Having identified and purified the CSFs, they came to the recognition that they would never be able to extract enough pure CSFs from tissues to use clinically.
“To get enough material for one patient we would have had to work for 250 years,” Professor Metcalf said. “We had purified CSF, we had done elegant tissue culture experiments, but now we’re into logistics and were facing a big black hole.”* (*Australian Academy of Science)
The team decided to try to use genetic cloning to produce CSFs for use in the lab.
“Looking back, we were probably pretty innovative to go for the CSF genes,” Professor Metcalf said. “But we were desperate.”* (*Australian Academy of Science)
In two years, from 1984 to 1986, they (and other groups) had cloned all four CSF genes from the mouse and human genomes, and had started producing them en masse. After 20 years of research, the hormone was finally ready to trial in animals. And it worked.
“In 1986, it was all over. I clearly remember, after getting a positive answer in mice, saying “OK, there is going to be a human with a disease where CSFs will be used,” Professor Metcalf said.* (*Australian Academy of Science)
Today G-CSF and GM-CSF are most often used to stimulate white blood cell production of cancer patients undergoing chemotherapy.
To date, more than 10 million cancer patients have benefited from the therapy that began more than 30 years ago in Professor Metcalf’s lab at the Walter and Eliza Hall Institute.
Colony Stimulating Factor (CSF) (Drew Berry & Etsuko Uno, 2009)
Changing cancer and transplant medicine
Why are CSFs so useful in cancer? It is all to do with the side-effects of chemotherapy.
Chemotherapy drugs search for rapidly dividing cells, which are typical of cancer tumours and attempt to destroy them. Unfortunately these drugs are unable to distinguish the rapidly dividing cells of cancer tumours from the rapidly dividing blood cells of the bone marrow.
Consequently, an undesirable side effect of chemotherapy is the progressive destruction of the bone marrow, leading to a rapid decline in the production of all blood cell types. With severely diminished numbers of white blood cells, cancer patients can become easy prey to serious and sometimes fatal opportunistic infections.
If the naturally occurring hormones for blood cell production could be found, then perhaps they could be artificially mass-produced and administered to cancer patients to rapidly restore normal blood cell production. In the case of white blood cells, this quick restoration would enable cancer patients to effectively fight off otherwise potentially fatal infections while their chemotherapy programs continued at full pace.
One of the first cancer patients to benefit from Professor Metcalf’s work was famed Spanish tenor Senor Jose Carreras. After being diagnosed with acute myeloid leukaemia, which did not respond to initial treatment, Senor Carreras received a treatment regime that included CSF therapy in 1987. He responded positively and recovered.
Senor Carreras visited the institute in 1991 to meet Professor Metcalf and thank him for his role in developing the treatment. He also attended Professor Metcalf’s seventieth birthday in February 1997 to sing him Happy Birthday.
The CSFs are also widely used in blood stem cell transplants, for the treatment of blood disorders such as leukaemia.
One of the side-effects of the use of CSFs is that it causes blood stem cells to mobilise out of the bone marrow into the circulatory system. This has been exploited for bone marrow transplants, allowing doctors to use G-CSF to mobilise blood stem cells for collection from the blood, rather than by the very painful extraction of bone marrow directly from the bone.
More growth factors discovered
Though Professor Metcalf’s discovery of the CSFs has defined his career and made him an Australian legend, it is not where his work, or his discoveries, ended.
In the late 1980s, Professor Metcalf was involved in the discovery of another mysterious multiple-action growth factor, leukaemia inhibitory factor (LIF), with Professor Nick Nicola and then-PhD student (now institute director) Professor Doug Hilton.
“What’s outstanding about it is that it was discovered and developed because it was a hormone that could make leukaemic cells suppress themselves,” Professor Metcalf said. “It turned out to be a most mysterious molecule – a major player in regulating brain function, how the pituitary produces hormones, how fat cells take in lipids, and how muscle cells regenerate.* (*Australian Academy of Science)
“It illustrates a problem we are finding more and more, that the body is using control chemicals that don’t make sense to us, because they are able to influence too many tissues. There are no diseases where you have something wrong with your brain, and your bones, and your blood cell formation, and your liver… and there’s no stage in development where it would make any sense at all for the same agent to control all four. Yet that’s what the body is doing. That tells us, I think, that we don’t understand too much about the body,” he said.* (*Australian Academy of Science)
LIF is now used, amongst other things, for maintaining mouse embryonic stem cells in their undifferentiated state (i.e. preventing them ‘maturing’ to make other blood or immune cells).
A great deal of Professor Metcalf’s time has been, and continues to be, spent identifying the numerous and varied hormone receptors on immune cells, and the genes that encode them.
Professor Metcalf has garnered almost every major international science prize, including the Bristol-Myer Prize for Distinguished Cancer Research (1987); Robert Koch Prize (1988); Alfred P Sloan Prize of the General Motors Cancer Research Foundation (1989); Albert Lasker Award for Clinical Medical Research (1993); Gairdner Foundation International Award (1994); Royal Medal of the Royal Society (1995); and American Association of Cancer Research Lifetime Achievement Award (2007).
Nationally, he has received the Victoria Prize (2000) and Prime Minister’s Prize for Science (2001). His peers have elected him a Fellow of the Australian Academy of Science (1969), Fellow of the Royal Society of London (1983), Foreign Associate of the US National Academy of Sciences (1988) and Companion of the Order of Australia (1993).