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Professor Donald Metcalf was interviewed in 1998 for the Interviews with Australian scientists series. By viewing the interviews in this series, or reading the transcripts and extracts, your students can begin to appreciate Australia's contribution to the growth of scientific knowledge.
The following summary of Metcalf's career sets the context for the extract chosen for these teachers notes. The extract covers the discovery that blood cells could be grown in tissue culture by the addition of a colony stimulating factor (CSF) and how CSFs were then identified and analysed. Use the focus questions that accompany the extract to promote discussion among your students.
Donald Metcalf was born in 1929 in Mittagong, New South Wales and was educated at the University of Sydney. In 1951 he received a BSc (Med). He earned an MB BS in 1953 for his work on the ectromelia virus; this research was the beginning of his interest in haematology. He received an MD in 1961.
Metcalf was a resident medical officer at the Royal Prince Alfred Hospital in Sydney when in 1954 he accepted a Carden Fellowship in cancer research at Melbourne's Walter and Eliza Hall Institute of Medical Research (the Hall Institute), where he studied vaccinia virus. He was a postdoctoral student at Harvard Medical School between 1956 and 1958, returning to the Hall Institute as Head of the Cancer Research Laboratory in 1958.
Metcalf remained at the Hall Institute for the rest of his career, and he is still actively engaged in research. From 1965 to 1996 he was Head of the Cancer Research Unit and Assistant Director of the Hall Institute, and was also Research Professor of Cancer Biology at the University of Melbourne (1986-1996). In 1996 he became Professor Emeritus of the University of Melbourne.
Metcalf’s research focused on understanding how the body generates blood cells. His move from thymus research using whole animals to using tissue culture achieved a breakthrough in 1965. He and Ray Bradley found that they could grow blood-forming cells as colonies if they added something to the medium – colony stimulating factor (CSF). His subsequent work on CSFs led to the discovery that they are the hormones that control white blood cell formation and therefore are responsible for the body’s resistance to infection. CSFs are now used to help patients regenerate blood cells after cancer treatment.
Metcalf was elected a Fellow of the Australian Academy of Science in 1969, and was made an Officer of the Order of Australia in 1976 and a Companion of the Order of Australia in 1993. He was elected Fellow of the Royal Society (1983) and a Foreign Associate of the US National Academy of Sciences (1987).
One of Australia’s most eminent scientists, Metcalf has written eight books and more than 600 scientific articles. He has been awarded 36 of the most prestigious international and national research prizes. These include the Wellcome Prize (1986) and the Royal Medal of the Royal Society (1995), the Victoria Prize (2000) and the Prime Minister’s Prize for Science (2001). He has served for many years on the Cancer Advisory Panel of the World Health Organization.
The great watershed year was 1965, wasn’t it? Something quite dramatic changed it for all of you.
Yes. It arose from the phenomenon that individual cells in a culture of bone marrow cells growing in semi-solid medium, agar, could generate enormous colonies. Now, that technique was discovered by accident by Ray Bradley, a scientist working in the University of Melbourne with whom I had collaborated over the years. Two things became pretty obvious. For the first time in history, people could grow blood-forming cells as colonies. It turned out that (as had seemed likely) they were clones, each one coming from a single cell – and they made a colony of daughter cells during a week of incubation. But unless you added something to the medium in the culture, colonies would not grow. That something we called colony stimulating factor, CSF.
The point about the cultures was that they gave you a technique for measuring CSF concentrations, because the number of colonies that develop reflects the concentration of CSF. So we had a way of doing three things: working in tissue culture, which I knew we needed; detecting some factor that, hopefully, was a regulator of the sort we had been seeking for a decade; and measuring it. So yes, almost overnight all work on the thymus stopped.
It wasn’t that we immediately rushed over to Ray Bradley and taught ourselves how to culture colonies. We worked for the next year as a team, in which I continued to do the formal haematology and general cell biology, but eventually we did teach ourselves how to do the technique and take the next logical steps. Every so often there is an accidental occurrence like that, when you would have to be blind not to realise that here is something astonishing that warranted a few decades’ work – and so it proved.
So what to do about that watershed in the mid-’60s? It’s no good simply believing that you have a technique for discovering your favourite unknown hormone-regulating blood cells. You’re working with cells in a culture dish, artefacts abound, maybe colony formation was all just an artefact. To get further forward, several things were needed. The first was to be able to show that CSF was detectable in the serum and hopefully in the urine. Why? Because it would make sense if it’s a regulator that detectable levels of CSF should be present in the serum and urine. It would be nice also if you found that there were CSFs to be detected in tissues. It would make sense if you had an infection and needed to make extra protective white cells (granulocytes and macrophages) that CSF levels should go up, otherwise it would not be a good candidate for a regulator.
We spent about three years surveying patients with infections, looking at CSF levels in their urine and serum and looking at different tissues to see which had the greatest content of CSF – assaying all the time by the culture method, which was the only one available to us. And by, perhaps, late 1968 it was obvious that there was enough indirect evidence to support the notion, ‘Yes, CSF is a good candidate for a regulator. Let’s spend some time purifying it and putting a biochemical basis to it.’
I put a poor unfortunate PhD student, Richard Stanley, onto this 'simple' job of purifying CSF. (He is now a distinguished professor in New York; his photograph was on last month’s issue of Cancer Research.) We started with human urine because it was a good, cheap starting material. We had buckets for collection of urine in the Institute. First you had to take the cigarette butts out of it – these were the days when you could smoke in a research institute – and then you had to dialyse it in great evil-smelling tanks in 50 litre batches. Great stuff! It took nine years to purify CSF from human urine. Richard did not complete the job until he was in Toronto working as a post-doc.
This must have been getting into the early 1970s, was it?
Yes. Meanwhile, the situation was becoming a little bit murky and uncomfortable. The CSF from urine did not stimulate colony formation all that well. In particular, mostly we got only small macrophage colonies, not the large beautiful granulocytic macrophage colonies seen with the original Bradley technique. Clearly things were a bit more complicated than we had thought. There must be more than one type of CSF. When we began to analyse what type of CSF was being made by different tissues, it became appallingly obvious that lung tissue was making a CSF that had no chemical relationship whatsoever with urine CSF (which was now being called M-CSF because it pretty much only stimulated macrophage colony formation). Lung CSF was a much smaller molecule and it stimulated the formation of beautiful granulocyte macrophage colonies, so we called it GM-CSF.
It also became obvious that if you took lymphocytes and stimulated them with mitogens they produced another type of CSF with some remarkable properties. While all this had been going on, we and others had developed culture techniques that would grow colonies of other types of blood cell. (There are eight major families of blood cells.) CSF made by activated T lymphocytes could stimulate the formation of red cell or megakaryocyte colonies. Urine CSF or lung CSF could not do this. So there appeared to be yet another CSF.
It took us quite a while to realise there was yet another, fourth CSF. This turned out to be the most famous CSF of all – G-CSF. For two years I had missed the fact that there were miserable little colonies developing in certain culture dishes. I thought they were merely dead colonies! But the CSF causing the formation of these small granulocytic colonies came to be known as G-CSF, and it’s the one that is making mega-millions for drug companies.
So everything was happening simultaneously. You might say we were very slow to purify the CSFs, but the project had become four times more complicated. This is partly why the project took fifteen years to complete. Other sorts of assays were being developed all the time, we had to figure out all the novel biology behind why one type of colony was being made and why another, and we ended up with a project that needed four different purifications (for four different CSFs) and a much broader range of assays to be done.
Select activities that are most appropriate for your lesson plan or add your own. You can also encourage students to identify key issues in the preceding extract and devise their own questions or topics for discussion.
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