Australian Biography

Donald Metcalf - full interview transcript

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You said that your wife was in the next ward. Were you married at that time?

No, no. No she was a ... I think she was a third or fourth year nurse at Prince Alfred.

So how did you meet her?

In the ward, when I became a ... I think the two wards shared their residents at times, anyway, she was working with me as a nurse. And I rather fancied the look of her. So that ... that's what happened ... [interruption] ...

And had you just ... just now as we're on this subject, when you were a boy at high school and so on and growing up as an adolescent, what part did girls play in your life?

Not much. Not much, actually, although you thought about them an awful lot. You had your fancies. I can't remember now, but I'm sure there were some good-looking women medical students. We were in with the physiotherapy students too ... were a much better looking lot than the medical students.

And at that time, from ...

But we didn't have steady girlfriends, one didn't then, I mean, I can't think of anyone who had a steady live-in girlfriend as happens now. That just didn't happen.

What did you do when you wanted to take a girl out, where did you go?

Well, you went to the pictures or there were dances often or sometimes you'd go to concerts, down at the Town Hall in Sydney, or ... yeah, mainly in the Town Hall, remember the Youth Series concerts, they ... they were on then. What else did you go to? You might visit friends' houses if you knew somebody who lived in Sydney. Went to the beach, went for rides on the Manly ferry. There was no end of things. All pretty simple.

And so what was it about your wife that made you decide that she was special?

Um, I liked the look of her, I liked her bright eyes and her wit and liveliness and ... we seemed to be on the same wavelength. We differ in almost every aspect, that became apparent with the passing years, but we managed to survive nonetheless. We don't agree on any subject, virtually. But the ... there you go. We appeal to each other.

Do you have different politics?

Yes, we don't discuss politics, because she's rabid and I'm not rabid but, no, there are lots of things you don't discuss, we have different religions and we don't discuss that either and we don't agree on many things. But we agree on a few things.

And what do you think made her decide that she wanted to marry you?

Goodness knows. Same sort of thing, I suspect. It's interesting, I lived in an institute full of 600 people, most of whom are under the age of 30, so they're about of an age that we're talking about. And you can go along and look at eyes and say, you know, you're a bright spark, no, you're dull, da-da-da-da. Now they're all formally quite intelligent people but a few of them immediately strike your attention and I think that's what you look for in people. Now, fortunately, everyone has a different idea of who looks interesting or else we'd all be trying to marry the same person. It's ... it's a bit of magic, isn't it?

So it wasn't long after you met her that you got married?

Um, it was ... it was about a year later, about a year later. She wasn't finished and she wanted to spend some time with her widowed mother in the country and so we were engaged and then got married about nine months later.

And what was happening with your career, you were doing a ... you were a clinical residency but you still had this hankering after research, so what did you do?

Well, about half, not, about two-thirds of the way through my first year I didn't know what I was going to be doing the next year and thought maybe I would do haematology. There was a special type of resident who looked after the haematology in the hospital and of all the different disciplines, now that I was beginning to see them, that was the one that had the most interest, blood disease. Right. So I thought, if the worst comes to the worst, I will try and get taken on, appointed as a ... as the haematology resident. But an advertisement had come to my attention for a cancer fellowship in Melbourne, didn't sound right. Sounded, they were looking — and in fact they were — for a professor to start a cancer research unit in Melbourne for the Anti-Cancer Council of Victoria. Now, being a small world as it was then, the head of the Anti-Cancer Council was an old wartime friend of Professor Ward, so he went to him and said, ‘Do you have any young people around Sydney who you think might be fitted for this job?’ And he said, ‘Well, go and see Metcalf or bring him down to Melbourne, look at him and decide.’ Which they did. So I twigged to the fact that they were really after somebody a lot more experienced and important than me and I said I'd ... I'd take the fellowship if it was offered to me but I'd take it at half-salary. Now, I can't remember being equally stupid again. But that appealed to them I think. So I was brought down to Melbourne and examined by a bunch of luminaries here and what I didn't know is that they'd been searching for this fellow, Carden Fellow, for some years and just approaching ex-patriot Australians and saying, ‘Will you come back to Melbourne and run this cancer research group?’ And they weren't interested, that it's a small hick town and they didn't want their career to suffer by going to Melbourne, and they didn't want it. So it came to me. I'm still the same fellow 50 years later because the terms of the fellowship did not have a termination clause in it, so they don't have any way to fire me. And as long as I keep producing scientific papers, they're stuck with me.

Are you still on half-salary, Don?

No, no — am I on half-salary? I took a voluntary cut after I stopped being assistant director and just an ordinary professor's salary. But my current boss thinks I only work half-time and only gives me a half-aliquot of research funds, which I think's a bit stiff since I start work at seven every morning. However we don't go into that. We don't talk about the war.

So way back, starting out, how old were you when you became Carden Fellow for the first time? And did they only give you half-pay by the way?

I don't know. I think they started me off on a lower salary. Um, how old was I? I was 26, I was 26. 26. 26. Yeah, 26.

And so you were quite young and you went down ...

Quite young, quite unexperienced and I knew that the Hall Institute was the best medical research place in the country and I'd been to visit it when I was doing my Bachelor of Medical Science studentship, that was the carrot you got. If you worked hard, you could have one week in Melbourne visiting. So I was headed for Melbourne, and the Anti-Cancer Council with some difficulty had persuaded the director, [Frank Macfarlane] Burnet, to accept me as a fellow, you didn't have to pay my salary or my working expenses. What he didn't like was the notion of anyone in his institute doing cancer research because ... and he told me this at our first interview, he said, ‘Come in, Metcalf, sit down. You want to do cancer research? I have to tell you, cancer is an inevitable disease, people get it, there's no way to prevent it and there's no treatment. And as far as I'm concerned, anyone who wants to do cancer research is either a fool or a rogue. Now, if you're serious, go out there into the lab and for the first two years, work on virology.’ So for the first two years I worked on vaccinia virus. As a virologist. And then I started to get a bit toey and say, ‘I really am hired to work on cancer research and I want to work on leukaemia because it's cancer of blood cells.’ And so I used to go down to Werribee where there was a state farm and collect all the chooks that had leukaemia. Now you can tell a chook's got leukaemia because it has paralysed wings and paralysed legs, so you walked around and if there was a chook walking around with paralysed wings, it had leukaemia and leukaemia in chickens is caused by a virus. It's infectious. So I was still being a virologist but I was now working on leukaemia so I brought ... used to drive a little car down and come back with a carload of sick leukemic chooks and starting to work on them. That's how I got back into leukaemia research. But Burnet was never very fussed with what I was doing because he didn't ... he honestly believed that cancer research was a waste of time.

Now, Sir Macfarlane Burnet believed that cancer research was a waste of time and yet you were housed there but paid by the Anti-Cancer ... what did the Anti-Cancer Council think of you not working on it?

Oh, they were tolerant. They were very tolerant and that was the good fortune I had right through my professional career, that they tolerated me and what I was doing, so for 15 years when I was trying to purify colony-stimulating factors and so year after year I'm still trying, I'm still trying, they ... they put up with me. Whereas the rest of the scientists around the country every three years have to justify what they've done or they get sacked. No more money. So, that first period they understood that there was trouble with Burnet and that I was going to be working on viruses for two years.

So, knowing that Sir Macfarlane Burnet felt this way about cancer research, why had they particularly wanted you to be housed there?

It was ... it was both. The choice was the Peter McCallum Clinic or the university, they didn't want me, and so Burnet grudgingly took me on as a research worker. So I had no training, no formal training in cancer research until I went to work in Harvard Medical School in Boston.

How did that come about?

It came about because I was interested in the thymus gland. Why was I interested in the thymus? Well, a Hungarian working in Boston had discovered that mice develop leukaemia very commonly but he discovered that if you take out the thymus gland in the chest they don't get leukaemia. Alright. Now, I had been working not on viruses that caused leukaemia but on the possibility that the reason why you get leukaemia is because the white blood cells in the body are being overstimulated by the hormones that control their growth. And this same man, Jacob Furth, the same Hungarian, had discovered that you could get cancer of organs like the thyroid or the pituitary or the ovary by overstimulating them. So if you had too much prolactin and you overstimulated the breast, you developed a breast cancer. If you were a mouse. And so there was this whole body of knowledge that said, look, you can get cancers by having out of balance the things that are controlling the growth of different tissues and I thought, okay, well, that could be what leukaemia's all about. At that time, in the early 1950s, nobody knew leukaemia was a cancer. Nobody knew. Nobody knew until a few years later.

What did they think it was?

Could have been like pernicious anaemia, because the bone marrow looks exactly the same and that's just a vitamin deficiency. So there were people, admittedly out in left field, who believed that leukaemia might be a deficiency disease. But I thought, no, okay, it's a cancer. But everyone believed that leukaemia is caused by viruses, because there are viruses that caused leukaemia in chickens, in mice they'd just been discovered, in cattle. And so why not humans? Now, years later, billions of dollars later, they find that one sort of human leukaemia is caused by a virus but that was later. But I thought, no, no, no.

Not a major one.

No, well, it is if you live in Japan because it's quite common in the southern islands of Japan. But I liked this other story better, that the over ... imbalance of growth factors controlling things ... so that was the tack I wanted to take. So I had to discover what controlled white blood cells and I had to have a model to work with so ... chickens had leukaemia so I started to ask ... what controls chicken white blood cells? I was in lots of bother there. But it was at that time that this Jacob Furth wrote his papers saying, okay, this virus disease in mice that causes leukaemia, actually you can prevent it by taking the thymus gland out. So my first research was to find out what the thymus gland did. And I was the one who discovered that if you take out the thymus you influence all the other lymphoid tissues in the body. So I was working on the thymus. So I got the chance to go and work in Boston and I went to work with him because he was Mr Thymus and besides he was the originator of this whole piece of cancer biology that said you can get cancers by imbalance of growth factors. So it was there I learnt my trade. He was an experimental pathologist, I sort of learnt what diseases were in the mouse and all about tumour viruses, leukaemia-causing viruses and did my own stuff on the thymus. While I was there, I pretty much wasted my time but I had to be trained ... I got to meet all the people ... there were probably 50 people in the world that worked on leukaemia research then. And I knew them all because I'd met them all at meetings and so it was good from that point of view and I came back to Melbourne with some expert knowledge. And then you learnt on the hoof then, by mistakes.

What was your own stuff on the thymus? What were you doing with it?

I was ... I was taking it out and showing that, when you took it out, the other organs that have lymphoid cells in them were smaller and less active. Possibly that was the reason why taking out the thymus stopped leukaemia development. I thought this was great and I found that maybe the thymus was making something that controlled these blood cells, which it is, but that took another 40, 50 years for other people to come up with. So you start with a notion that's a bit off-centre that you try to follow and you go to the person who has done work on an organ that nobody in the world had ever worked on before. Because it shrivels up in adults, the thymus, just a little shred. So people said, ‘Oh, it shrivels up, it's got no function.’ And it doesn't. I could take your thymus out and nothing bad would happen to you. But if I took it out from you when you were a baby you ... your immune defence system would be shot, would be no good and you'd have no protection against infections. That came later. But it was one of those organs that nobody knew what it did because it didn't seem to matter whether you had it or not. Couldn't say the same about the pancreas, if you took the pancreas out you'd get diabetes. So that's what the pancreas did. Take the thymus out, nothing seemed to happen, so it had no function; that was wrong.

How is it that an organ that's so crucial when you're young, ceases to be relevant when you get older?

Well, if you believe the immunologists they will tell you the following story. The thymus makes one sort of white cell called the T lymphocyte, T for thymus. And T lymphocytes protect you against viruses and foreign tissue grafts and possibly against some sorts of cancer. Now, most of the cells that get made in the thymus die there, within a couple of days. Why do they die? Because they are attacking their own tissues and so they have to be assassinated ... The few that are not, the few that are really interested in looking at strange things like viruses, get out into the body but once they're out there they become long lived memory cells and they live for the lifespan of the person. So you don't have to keep making new ones, after a certain age, so you and I at our age probably don't need to make any brand new T cells because we are running on the memory ones we had as children. And so it didn't matter if you took the thymus out, when you're old. No, that's not my work, but I did some of the early work in that field. So I spent the first 10 years working on the thymus and that sort of leukaemia, lymphoid leukaemia, and it wasn't until we accidentally found how to grow white blood cells in culture, and they were a different sort of white blood cell, that I had to switch to one of the other families of blood cells and learn all about them. So I'm no longer a thymus person but years ago I used to be known as Mr Thymus; that was a very long time ago.

Now, back there in Harvard, did you take your ... did you take your new wife with you?

I took my new wife and I had one daughter and we had two new daughters in Boston, we had two true-blue Boston children ... and in a famous obstetrics hospital there called the Boston Lying-In Hospital, which years later got sold to a drug company that actually mass produced the hormone that I discovered later on. So, I like to say, probably incorrectly, in the same room that my child was born, the first recombinant GM-CSF was produced. It's probably not true but in the same building.

And how did you take your fatherhood?

It was fine. I was a good, good father until the children were about 10 and then I was not a very good father, I was strict and uncompromising. But it ... I was a good father for young kids.

How many children have you got?

Four. Four daughters.

So you were a strict father to teenage daughters?

No, I was just a terrified father sitting at home waiting for them to come back, while they were waiting on the corner until it got late enough to be respectable to come back. You know, 2 am. The joys of parenthood. I ended up with four daughters and none of them are doctors or scientists, they're two lawyers, one artist, one teacher. They said they didn't want to compete with me and they are best-suited doing what they're doing I think.

When you came back to Melbourne, after this stint in one of the great centres of the world, did your stocks with Mac Burnet rise at all?

Well, he was one of the world's great virologists working with viruses when I left to go to Boston. And he'd had a seachange in the two years I was away and he became interested in white cells and immunology. That's the biology of the cells that I'd been working with before I left. So I came back still being an expert on T cells and ... but not as an immunologist, so I wasn't interested in what the T cells were doing protecting a body against infections, I was interested in the cells and how they came to be leukemic when they did. So you can work on the same organ but from a different point of view. I'm still saying, ‘Why are you getting leukaemia?’ And he's now prepared to discuss, ‘Why are you initiating an immune response?’ So we could talk now. We didn't talk often and I was banned to the animal house for seven years so I had to go down, tunnel under the hospital and work in the animal house in some small laboratories there and that's where I did my cancer research, on the thymus. While all of the people in the main institute were now immunologists. And some of them were now working on the thymus but we're still different. I'm still working on cancer of the thymus, all the others are working on other aspects. So I was never on the staff at the institute. if you look at the old annual reports, I'm listed as visiting and attached. And I was visiting and attached for eight years.

Don, why did he put you in the animal house?

Because that had spare labs that were empty, they'd been occupied by Frank Fenner who'd moved to Canberra and ...

But he was a virologist?

He was a virologist so they were virus labs, they ... that's where myxomatosis was developed, in these labs and the insectary there, still had the mosquitos that they were using to infect the rabbits and give them myxomatosis. So I took over those labs, nobody wanted them so I slowly got an assistant and a couple of post-docs and so on and we got up to a team of about 10 there. But we were outsiders, I mean, the tunnel from the hospital is pretty noisesome and you go under it and you go through the laundry, where there were 5,000 Greek women doing the laundry for all the city hospitals, and then you went past the rubbish dump and then you came to the animal house. Now, I'm allergic to animals so I had hayfever every one of those eight years. Just a running nose, sneezing all the time. But it was home, that was our little ...

Now the administration knew you were allergic to, what, mainly mice then?

Oh, look, yeah, if you're allergic that's too bad, a third of the staff are allergic to animals. And that's one of the joys of being a research worker yet you ... that's one of the dangers. You get allergic to animals.

Does it just make you sneeze or ... ?

It does except I get a bit wheezy after a while, but I'm allergic to everything, pollens, there are no flowers in this room because I would be coughing and wheezing.

But you can touch them alright, it doesn't create problems?

If I've got gloves on. Animals ... I wouldn't touch flowers, I mean, you get pollen and you're allergic, the pollen is what makes you allergic. So you can't get downwind of a flower or you'll start sneezing. That's alright.

So, you're down in the animal house sneezing away and how did your work progress?

Ah, it ... what I was trying to do, probably couldn't be done. A whole animal is too difficult to work with, you ... you can ask the questions what ... what makes your white cells this level but how do you go about it? Do you take organs out and see what difference that makes, da, da, da, and you can get a certain amount of information, but you're not really getting the truth of the matter, getting to the bones of it. So, those 10 years, although I discovered a lot of things about the thymus that are still true today, it was ... it was a dead end. I was very glad when the chance came to switch fields because I'd taken it as far as it could go and it hasn't actually been taken any further in some respects. Until the last year or two, was a tough problem that couldn't be solved. How the thymus works. But the ...

So, do people who work on it now, come to see you to ask you about what you did?

Not often, sometimes, if they're old enough. No, no. What I ... what I discovered is now sort of given knowledge in textbooks and that's that, you don't ask who discovered that. Listen, if you discover something more than two years ago, it's not recorded anywhere, you're not credited with it. The young don't read anything that's older than two years. So unless you keep working on the same subject, you have no currency whatsoever. If I stop working today, two years’ time, ‘Who's he?’ He's gone. It's a hard life, it's very competitive, medical research. And the young are quite unrelenting in their passion for newness and it's got to be done in the last two years or it's probably wrong and stupid, old-fashioned.

Is that why you won't stop working?

Probably. Probably, too scared. But it's an interesting phenomenon, you ... you actually can be very offended if you are no longer quoted, if you don't realise this phenomenon that unless you're actually still producing information on that subject, you drop out of ... out of recognition ... you're no longer quoted. Now, if you put my name into a computer, you would get the information, it is there, but it's not used by today's workers. So all the marvellous things that got discovered, 30, 40 years ago and some of them were marvellous, are sort of lost.

Lost or just in consolidated revenue?

I would say lost. I found that if you put, for example, a thymus as a graft under the skin, so a mouse had two thymuses — it had its own thymus, had a thymus under its skin which was exactly the same ... exactly the same. And then if the mouse got pregnant, you with me? Mouse is pregnant now, it's got two thymuses. During pregnancy, the mouse's own thymus gets very, very small, withers away. This one, doesn't change. Now, I wrote that up, I described it in Nature, top science journal in the world, has anyone ever quoted that? No. It's true. But it's not relevant, is it? You're not running around being pregnant and with two thymuses. So what's the point of it? Well, the point is we don't understand why that thymus graft didn't change the same way as your own thymus.

In a normal pregnancy with one thymus, does the thymus shrivel up?

I presume it does, in women. It certainly does in a mouse and I assume that women are the same.

And so ...

And then it'll regrow again once you've delivered. It ... it's not permanently shrivelled as it would be in middle age or old age.

Was the thymus under the skin acting in the body in the same way as the ... ?

As far as you could see it was making its T cells exactly the same way. Smelled the same, looked the same. Did the same things.

Did it have any noticeable affect on the mouse?

No, the thymus is one organ that the body has no knowledge how big it is. The body knows how big the liver should be and if you cut out half your liver, it will grow again in about 48 hours to the same size as a liver. But the body has no idea how big the thymus should be so there's no cut off ... so I put as many as 50 thymuses into a mouse and the mouse was just walking around solid thymus tissue but the body can't tell that. It's one of the curious things about thymus. It's a strange organ.

So if some bright young spark wanted to get some good ideas for research ... ?

They read an old paper and say, ‘Gee, let's put 50 thymuses into a mouse.’ And the thing is that the editor and the referees wouldn't realise that they were repeating something that had been done. Can be done. Can be done.

Plagiarism is alright if it's from ... from someone old?

Can ... can be done. It can be done. Oh it's done all the time.

So, going back to the fact that you were working on a whole animal and you began to realise that this wasn't getting you where you wanted to go, what did you do?

I didn't sort of think that way, I was still working and writing papers and trying to make discoveries, making discoveries, but by accident a colleague of mine in a university had been trying to grow bone marrow cells. Now he'd been trying to grow leukaemia cells from a mouse and I had the mice that got leukaemia so I used to supply him with the leukemic cells. So we were sort of collaborating on this study and he couldn't get the leukemic cells to grow anyway. And he tried a trick that an American had discovered in working in Denver, that if you had an underlayer of cells as a feeder layer then you could make cells grow. So he tried that. And the feeder layer that he used was bone marrow cells. So now he's got a culture dish with two layers. He's got bone marrow cells in the bottom, and he's got the leukemic cells on top. And whoops, colonies of cells grew but they weren't in the layer that had the leukemic cells. He wasn't growing colonies of leukemic cells, he was growing colonies from bone marrow. Nobody in the world had ever been able to grow bone marrow before, ever. There were books written saying it couldn't be done. And so what had happened was that the leukemic cells were making something that was making the bone marrow cells make colonies. So he turned the system upside-down and he had the leukemic cells as a feeder layer and the bone marrow cells as colonies. I thought, that's great. That's the system I'm going to use. Because you had to add things to the cultures before they would grow. And the colonies were colonies of white cells. So I had ... we had a way of growing white blood cells but we had to add something to them, to make them grow. Maybe that was the hormone that normally controls the way those white cells grow. Let's purify it, let's find out what it is. So 20 years later, we'd done just that. We didn't know it was going to be a 20-year job but we had the technique. Now it's by accident. And things in science often — not always — happen by accidents like that, so here was a complete accident and it happened at the same time in Israel in the Weizmann Institute in Rehovot, and they were also trying to grow leukemic cells and they saw this happen. So two groups didn't know each other, no contact, same year discovered the same phenomenon. Now the Israelis always said we stole their technique but we knew we didn't steal it. We'd tell them to get lost. Ah, but things happen by chance and they often happen simultaneously and that often leads to a lot of bad blood in science. It's ... I suspect this happened to a degree with HIV, the AIDS virus. People are working with the same sort of technology, whoops, they discover the same thing at the same time. And then there's bad blood. You stole ours. No, we stole yours.

Now you ... it was Ray Bradley who was ...

He was working in the University of Melbourne.

Yes, and so when you went into his laboratory or you saw this ...

He brought the cultures over to us in the animal house. And it was raining as I remember, him carrying them in, out of the rain. Look at these. It was great.

And did you see the significance straight away?

Yeah, I thought, this is marvellous. God, these things are like galaxies looking at them under the microscope, just star clouds coming at you, like a spaceship. I thought, I'm going to work with that. It's too bad I know nothing about granulocytes or macrophages, the two white cells, I'll just have to start. And it's interesting when you start working in this field, even though you've got a brand new technique that's obviously going to wipe the existing world out, you're not regarded as anyone of consequence because you haven't worked on that field before. They will accept anything I say about the thymus because I've been working in it for 10 years, but about granulocytes? ‘No, he's not a granulocyte man.’ So for about five years, you are nobody, didn't matter what meeting you went to and what results you talked about, ‘He's a novice.’ It happens. So you don't, you shouldn't change your field too often or you ... you're a novice all your life. Anyway, so that's how it happened, by accident.

So you did the right thing in deciding to spend the next 20 years looking at this?

I've ... it's the next 40 years now.

So are you the kind ... [interruption] ...

[end of tape]

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