Australian Biography

Donald Metcalf - full interview transcript

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Ray Bradley had found these ... this way of culturing bone marrow cells, which had suggested ideas to you about what you could do. How does that work? You were talking about the competition with the Israelis — when you have a colleague like that who makes such a fundamental change to the way you're working, how do acknowledgements and credit and all of that, how does that work out in that case?

It can be very awkward. For the first couple of years we worked as a team, doing one part of the technique in his laboratory over the road from us and one part in ours and we were quite careful not to develop the whole technique ourselves. Now it wouldn't happen these days but in the '60s I was quite careful that we wouldn't be seen to be treading on his heels or taking his discovery. Ah, so we waited two years before solo experiments of ours were done and we learnt the technique and an American post-doc came and together we did it. Then by natural instinct the waves parted because he was more interested in the nature of the cells that were growing and I was more interested in what was stimulating those cells to grow. So all of my efforts went down that track, I didn't care whether my cultures were the world's best or biggest as long as they could read out the concentration of what I was putting in. Because the number of colonies you got equals the number ... the concentration. So with time, the two pathways diverged quite a lot and so he has a stream of publications about the nature of those cells and I have a stream of publications on colony-stimulating factors. Um, where it gets awkward is in later life when people start to give you prizes and they're just given to one person. And you have to say, ‘Well this is a very nice prize to win and I'm grateful for that but it was a joint discovery’ and da-da-da-da-da. And you have to say all this. Or when you're writing about it, you're certainly careful to say exactly how it happened. Now a lot of people wouldn't do that but it seemed right to me. What does Ray Bradley think about it all? I don't know, we've never discussed it. But in different institutions with groups that are about the same size and being fairly careful not to work on the same area, [it’s] about all you can do.

And the work that you then went on to do, based on that initial finding, was off on a different path?

Yep.

And what path was that? What was the next thing?

Well, in principle it was quite simple: bone marrow cells will not grow and make colonies unless you add things to them. What were those things that you added? Well, they were extracts of tissue, so you could grind up lung tissue and add the juice from that to the culture, maybe that would make colonies grow, maybe it wouldn't. So you went around testing all the different tissues in the body to see which ones had activity. Turned out they all did, because these hormones are made all over the body. And then a period of about two or three years elapsed during which we had to get indirect evidence that the whole idea was correct. Now, if we were really detecting what controlled white cells, then the level, the concentration of that thing which we called CSF, should change if you had an infection because you suddenly need a lot of white cells and you need them to work hard so let's go fellas, let's have a high concentration. Did that happen? So we went and studied thousands of patients, some of whom had infections — and were the levels higher of CSF as we could detect in their serum or in their urine? And the answer was yes. So that sort of indirect evidence said, ‘Yep, you're on the right track,’ what you're picking up, what you're calling colony-stimulating factors, does seem to make sense as a regulator of those protective white cells. So then you take a decision: I wonder what the nature of this CSF is. And the chances were quite good that it might have been a virus. Now, you might think it's very easy to tell the difference or not, how to tell the difference between a virus and a protein molecule but in fact, it's quite hard. And some of the most nasty viruses are in fact called prions, that are protein molecules, so you can't tell the difference. Anyway, we finally said, no, this is a protein, let's try and purify it and find out exactly what it is. Well, that was a straightforward question to ask, we put a PhD student to work doing that, Richard Stanley, and he tried to purify it. Well, none of us realised that in 1968 it was absolutely impossible to purify that sort of protein because only one molecule in a million was CSF, and the techniques for separating all the other proteins based on their size or their electrical charge or stickiness just didn't exist. They hadn't been invented yet. So it took a decade for biochemical colleagues around the world to invent the techniques that you needed to do the job of separating CSFs from other proteins. So, we didn't know that at the time. So we had to look around for what's a good source of CSF? What's the cheapest source? Didn't have much money. Turned out that you could detect it in urine, so great. Ah, let's purify CSF from human urine.

So buckets were put in our toilets, women's toilets and men's toilets, everyone on the staff had to use the bucket and not drop cigarette butts in it, and then we had to as the first step ... put this urine into a big sausage bag ... skins and dialyse it against water, and so our lab had an enormous stainless steel tank with evil smelling urine in it and ... being purified for the first step, getting rid of all the things that were soluble and rubbish. And we spent, I suppose we spent, about five years purifying CSF from human urine. And at that stage, Richard Stanley left and went to Toronto to work as a post-doc and that project sort of stopped because CSF in urine is pretty lousy stuff, actually. A much better looking, in terms of what it could do, was CSF out of mouse lung tissue. And that seemed to be a rich source so we started to make mouse lung CSF. Which means injecting a mouse with a bacterial extract and that increases the amount of CSF in the lung and then three hours later, taking the lungs out of a mouse and putting them in a test tube and culturing them for 48 hours and then harvesting the fluid from that little culture. And we had to do that for a quarter of a million mice and that gave us enough CSF to purify. So when it's one molecule in a million it's tough going. And so what with the delays in technology allowing this, it took 15 years to actually end up with a little tube of purified CSF. Which was too small an amount to put into a mouse so you could never prove that it would actually work if you injected it into a mouse. So now we're up to the mid 1980s and we're smart because first of all we found that there wasn't one CSF but there were four of them, four different ones. We'd purified all of them, we were the only people in the world who had pure CSFs, but the amounts we had were too small to do anything but use it carefully in cultures.

So we knew the properties of these molecules but we couldn't actually prove that we hadn't wasted the last 15 years. That's where it becomes important that the Anti-Cancer Council is tolerant and is still happy to support this project, based on no proof of anything other than that you have been busy but maybe wasting your time. So, how to get round this logistical bottleneck? How to mass produce CSF. The molecules are too big and complicated to synthesise, it's impossible. You can't get enough by extracting the richest source, so that's out, and the only way is to find the gene in the body that codes for the production of that CSF and get it out. Now that's easy to say now, it's the sort of job you'd get a student to do. But in 1983, there were only about six genes that had ever been isolated out of the body. So this was very early days and tough going finding these genes, but in a period of three years, genes for all of the four CSFs were isolated, some by us, some by Americans, Japanese. And the other job was to find out: now you've got the gene, how do you mass produce protein from it? The product — well that's dead easy now too. You call up your supplier and they give you a bacterium that you can put the gene in and it will mass produce it. They didn't exist then so it was a tough job for a Swiss company to figure out how to mass produce CSF from our gene in bacteria. It probably cost them about two million dollars to make us a little bit in a bottle. But it was enough then to inject into mice and say, ‘Well does it work? Does it elevate the levels of white blood cells?’ And the answer is, it did. That was a big relief. And a year's work, 15 of purification, not good. But it worked and what was scary was how quickly the corresponding genes in humans were isolated in this same three-year period. Sort of a golden period. And so you suddenly had mass produced human CSF and why not test it in patients? See how it worked. So the tests in patients were actually being done within two years of the tests in mice.

And that ... I never expected that to happen, I just ... it was scary, I thought you'd be testing this stuff in monkeys for a decade before it was safe to test in humans but, no, it was tested and the Royal Melbourne Hospital was one of the hospitals testing it and it worked fine, it wasn't toxic. And you know, within a couple of years the FDA [US Food and Drug Administration] had said, ‘Yep, it works, it's safe, go for it, it's licensed.’ And that was one of the fastest drugs ever licensed by the FDA. And after that, about five million plus patients have had CSF. So it's a funny sort of progression from an accidental discovery, a couple of people working on it, tackling a job that's impossible technically. Getting more and more people to help, of course — by the end of the whole set of experiments there were 300 plus people who'd done various bits of that study, in our labs. And you have to drag in more and more experts, biochemists, the molecular biologists and the clinicians and the nurses and so on and the little ... the whole job was finished. Now, that sort of project is pretty typical of the way medical science goes ... you don't sit down with a blank sheet of paper and say, ‘I am going to discover this and this is the way we will do it this is what we'll need. Give us the money.’ It doesn't happen that way. By accident.

It's much more chaotic in that sense.

You hope it's ordered chaos but it's ... the progress is zigzag. I mean, it used to be infuriating to have students doing their PhD on that project, getting to a certain level of expertise and then, whoops, they've gone. Gone for a post-doc overseas. And you start all over again with another raw student and you're almost back where you started and then you go a bit further and rip, it's like the teeth of a saw, you’re just going up. I feel ... I was a bit on a treadmill at times.

During that very long period that you were trying unsuccessfully to purify it and ...

We were doing lots of other things as well ...

What?

... fortunately, because remember our job was to find out what caused leukaemia and one of the interesting things about these CSFs is that some of them on some leukaemias will turn the leukemic cells back into normal cells. So the whole idea that started this ... is that an imbalance between these great factors, is in fact correct. And for a long time we thought, well, we're really working on a cure for leukaemia, by using these things to make the cells behave. That hasn't worked out that way at all. It ... the CSFs when they're used in the clinic are used for patients with any sort of cancer. They're just used to stimulate blood cell formation. But of necessity we were making all sorts of discoveries about the nature of these white cells and their ancestors and how leukemic cells behaved, and looked at hundreds of patients who had leukaemia and studied their cells, using this culture technique. So there were hundreds of papers being written that are all, in their way, important papers about the biology of blood cells and leukemic cells. But the mainline project was pretty tortuous and it did not bear fruit until 15 years later.

Who thought of the name, colony-stimulating factor, for it and why?

It's a descriptive name, it's the fact that you drop it in the dish to make colonies develop so why not, colony-stimulating factor? Did I think of it, or did Bill Robinson, the American? I don't know, it's in the first paper we wrote together and that's where it came from.

And ...

It's unfortunate because it's also the abbreviation of cerebrospinal fluid and a few people get confused and of course nowadays, a little faceless bureaucrat in Washington decides, ‘No, that's not the correct biochemical name, I will rename this molecule, filgrastim.’ Which you can't pronounce and then the company says, ‘Sorry, we have a product that we're selling as Neupogen. And so all the patients ever see is, Neupogen, but if they look at the fine print on the bottle they'll find it's G-CSF [granulocyte colony-stimulating factor]. What's in a name?

The four different kinds of CSFs that you've found, do they have different functions? Do they ...

I'm sure they do. They ... in a sense they all work on the same ancestral population. It's a dopey system where multiple regulators are controlling the same cells and each cell has ... can be spoken to by each one of these regulators but one of them concentrates on one sort of white cell, the granulocyte [while] one concentrates on another, the macrophages, and each one does different jobs, and you realise this when you build mice that have that gene missing and you can do that. It's another two million dollar project but you can build a mouse that looks normal except it has no gene that codes for one of the CSFs and you say, ‘Okay, what's wrong with you?’ And, that'll be wrong and that'll be wrong and that'll be wrong. And you take another mouse and knock out one of the other CSFs and say, ‘What's wrong?’ Nothing, nothing. Oh they've got lung tissue with ... with terrible lesions in it. So it turns out, when you do the knockout studies, you prove that each one, in part, does the same job and in part is separate so none of them are redundant, they're not just duplicating each other for no reason.

So when you come to use it, in an actual clinical form, to give to patients to regenerate bone marrow which one do you use?

The one that is most aggressively sold by the pharmaceutical company. And that is Neupogen, which is an agent that stimulates granulocytes so it's good for infections but not all infections. But you would think that out there in the marketplace there would be pharmaceutical companies desperate to sell any one of these, they're all good agents. But no, the one that has the patent for another one, is pretty lackadaisical and they're not pushing their product. And the patients don't like it, it actually makes them feel a bit achy and so on. The fact that it does them good and saves their life is different; if you don't feel good when they've given it to you, it's no good. And if this company is saying, ‘My stuff's fantastic.’ And advertising it in the New York Times, ‘demand from your doctor that he treats you with Neupogen.’ Ah, that's what you use.

So all four of them would be appropriate for use, you're saying?

On certain occasions, and if you ask how many patients in the world have ever had two of these CSFs together, it's about five. Five patients in the whole world. Why? Because the companies don't talk to each other.

Right, but they would be better off if they ... ?

Well, I believe so, because they're designed to work as collaborators and enhance each other. So you know the biology. And you know what makes sense. But the difference between that and arranging for a patient to have what's sensible is just an impossible hurdle at the moment.

So different companies have got patents on each of the four?

Yep.

Four different companies?

One company has two and the company that has one of them has never set foot in the clinic and so it's ... it's one-and-a-half companies if you like.

Because it sounds like a cocktail of them all would do more good than anything?

Would probably work. What you have to realise ...

But no-one seems to do that.

Ah, no, because the Federal Drug Administration, the FDA, rules the world in a way that the president of the US can't possibly. And what the FDA says, goes. And the FDA was set up in the late '20s or the '30s to eliminate the problem of kidney disease from taking APC tablets, remember APC tablets? Aspirin phenacetin codeine [caffeine]. They damage your kidney. And so this government agency was set up to stop the sale of medicines that were mixtures of things. So you have to prove that one drug alone will work. Never mind coming along and saying ... but two are better. Don't ... you can't test like that. So that's how companies end up with the patent for one, because it costs a hundred million dollars to test and get approval for any one drug. And nobody's rich enough to try all the different combinations. Truth of the matter is, we're being over simple, if we're talking about these two white blood cells, we now know that there are about, well, let's say 10 to 20 different regulators that can control them to a degree, so you're really saying, ‘Why don't you try all 20 together?’ Now there are a million ways of trying a combination of 20 drugs, literally a million, and it's impossible. So out there somewhere is the perfect cure for Mrs Smith — will Mrs Smith ever get it? No. It's hard bridging the gap between the laboratory, where you can test not a million mice, but a thousand mice, and going to the clinic and testing one patient — now the gap may only be 50 yards down the corridor but it's a big gap.

Do you remember the day that you actually got enough of these cloned to be able to inject into a mouse and seeing that it worked? Do you remember the day that ... ?

I do. I do very well because the end of a glass pipette broke off and dropped into my shoe and stuck into the end of my toe just as we were harvesting the fluid and I was too anxious to stop and pull this bit of glass embedded in my toe out. I do remember it, can take you to the exact room, I think. It was an important day when it came out milky with extra white cells, I thought, ‘Good, we haven't wasted 20 years.’

So apart from the fact that you had a very severe pain in your toe ... ?

It wasn't painful. I was too happy.

But how ... what does that sort of moment actually ... I know it's impossible to describe feelings, but could you have a go for us?

Yeah, I thought ... I felt great. That I hadn't wasted my time. Did I shout Eureka? No, I don't think so. But I certainly breathed a sigh of relief, I thought, bloody hell that's good. There's somebody somewhere who's going to get that stuff.

And that was what it was really about for you?

Yeah.

It wasn't beating the people in the laboratory across the world?

Oh, that too. That ... that's normal everyday interchange, competition. But I can ... after years of thinking about it in terms of leukaemia, and what could it do for a leukemic population, suddenly — and you might think we were a bit stupid and naive ... not to think of this possible use earlier — I could ... if you can change the number of white cells, there's got to be a patient somewhere with some disease where that matters. And if it works in a mouse it's going to work with a human. That's what should happen. Now if you got a splitting headache because you had that drug, that hormone, you couldn't use it. And a lot of perfectly good reagents can't be used because they are toxic. People discovered a similar sort of agent that would control these famous T cells that we were talking about coming from the thymus. But they can't use that stuff because it is ... gives fearful side reactions. So we were lucky in a sense.

Does this give any ... does this give us any ... ?

Oh, it gives a few and now people have the luxury of saying, ‘Hey, I wonder whether there are some patients, like with rheumatoid arthritis, whose condition is made worse by this particular CSF. What would happen if we developed antibodies to the CSF? Could we try them in patients with rheumatoid arthritis?’ And that ... those tests are about to start next year. So that's another turn of the wheel, you knock yourself out for a quarter of a century getting something to work to be used and now you're busy saying, ‘Ooh, I think there are patients I could stop this working in.’

So what was the first major group of patients for whom this was seen to be pretty suitable, and therefore the first that you trialled it all on?

The easiest ones for everyone to try it on ... was pretty much the same in Boston and certainly in Melbourne, were patients who were having bone marrow transplants, because if you've got leukaemia or you've got a bad cancer and you're getting massive doses of chemotherapy, you totally destroy the bone marrow in the patient ... you've killed the patient. The only way you can resuscitate that patient is to give them an injection of bone marrow cells. And they've got to learn to settle down in the bone marrow and grow again because without that you'll have no blood cells. So there are a captive set of patients, that they have had a serious sequence of treatments and it was known that you're going to be in hospital for weeks afterwards while this transplant grew, carefully being nursed; very expensive, difficult technique. Let's try it on those patients and they were the first patients being tried on. That's why José Carreras was one of the first patients ever to get treated with CSF because he had leukaemia, had a marrow transplant, it wouldn't grow, and in Seattle he was one of the first patients. So, the answer to the question is, cancer patients were the most convenient group to try this treatment on. Because they have a common problem that they've had their bone marrow destroyed and they're trying to regrow their cells. It's not touching the cancer at all but it's sort of like a blood transfusion helping the patient. And then there are patients who actually have diseases because they have no ... not enough of these white cells. Curious diseases like cyclic neutropenia. Every 18 days, your white cell levels fall to nothing, every 18 days you get an infection. Might just be a cold, might be a middle-ear infection, might be pneumonia. Every 18 days of your life, you get an infection? These kids' life is a misery, the family can never go on holidays, they can't go to school. There are not very many of these around the world.

This kid in Geelong I met, now has everyday shots of CSF, like you give yourself insulin, and perfectly normal, big strapping kid. So there are uncommon patients who this is the perfect sort of treatment for and then there are the millions who ... whose treatment is helped by it. But it actually isn't anything to do with the treatment. So it's a mixed bag and all those CSFs have been in use clinically for about 15 years, it's still early days. I mean, people are realising, oh my god, one of the things they should be doing: every patient who is badly burnt, you know they're going to get infections, you should start treating them straightaway with CSFs, before they ever get their infections. Does anyone ever do that? Never. You know, people, you just want to knock their heads together and say, ‘For god's sake, use your common sense.’

So if ... sometimes when people are being exposed to infection they're given gamma globulin and so on, that was very common at one stage, did you find?

Oh yeah.

Would it be possible with ... if CSF was very freely and readily available, to prevent infections with it?

Yeah, I think so. I think so. I mean, let's face it, CSFs aren't all that expensive, I think I'm right, they're only about 100 dollars a day, the treatment, and all I know is if I was badly burnt, I'd want to have a CSF treatment right now, thanks very much. If I had to have an abdominal operation, tomorrow, let's start the CSF treatment because the chances are your wound is going to get infected and da-da-da. And antibiotics are only good so far and they need help from the body's defences. Um, that's me nagging on and somebody I find to give it to me but the average patient doesn't know that and they're not getting it. And doctors are conservative and because, you know, if something goes wrong people will sue and so they're ... there's a real reason for caution. It's just that time goes by, you get a bit impatient.

You're a scientist, stuck away in a laboratory, do you ever get to meet the patients who've benefited from your work?

Not often but sometimes I do. Sometimes you meet them in the supermarket. Um, they did collect together a whole lot of patients at Government House a couple of years ago, just for a big get-together, that was sort of fun.

Sort of fun?

It was fun. It was a stinking hot day, actually. No, it was fun, it was nice.

And you mentioned José Carreras, the opera singer, one of the great tenors of the world. Your association with him was fruitful in other ways for research, wasn't it? How did that work out?

Um, not really. He now has a leukaemia research foundation of his own and a lot of his royalties he pays into the foundation and it supports young people, training and doing research. We've never taken money from it, but it does exist. And we've met him a few times here, when he's been in Australia. He's a nice, nice man.

The association with him gave a lot of publicity to the work, do you find that slightly ironic?

I found it slightly distasteful I think you shouldn't pick on people and use them as a fundraising manoeuvre, I think I'd be quite cranky if I was that patient.

You participated though in one of those fundraisers and were sung Happy Birthday.

I did. But I wasn't fearfully happy about it, I just felt that, yeah, that's being opportunistic, a little bit — anyway, it was for a good cause.

You made the point at that, that he was a patient, was part of what you considered to be the research team. What did you mean by that?

Well look, if I come along to you with a bottle of new juice and say, ‘I don't know whether this is poisonous or not, are you prepared to volunteer to have it?’ That makes you part of the team. And if you can say, ‘Well this is okay but I'm sorry but I'm getting a ringing in my ear.’ Then nobody else can tell me that, you really are part of this ... this person ... of this, the study ... in figuring out what's going on. So I regard the patients as part of the team, yeah, for sure. Ah, would I volunteer myself? Don't know. If I trusted the scientist, maybe. No, I think, well, if you're in desperate straits and there's nothing else, why not try ... a lot of these things are pretty double-edged. Progress isn't always upwards, progress is a little bit snaggletooth.

Not everybody would be as ambivalent about having José Carreras sing them Happy Birthday, either.

Um, I don't ... I think it's a bit naive to think that it's me that did all this discovering and all this creativity, it really was several hundred people. And so I didn't isolate the genes, I didn't mass produce them, I didn't make that bottle of stuff that he was given, so why parade around saying, ‘It was me. It wasn't hard, it was me.’ You work at every step of the way but, you know, it was a team.

The hero version ...

So, I think if the whole 300 were there, we ... Yeah, yeah! Go. But the Americans believe truly that they discovered it. So if you read an account of CSFs now, it starts with the work done in Amgen in Los ... in Los Angeles, yeah. Sorry about that. It started in 1983. And you think, well, that's not quite true. Yeah, but that's ... that's the way history gets revised.

And there is a sort of what they call ‘hero version’ of history, which really requires a single individual hero, and in relation to CSFs in Australia at any rate, you're the hero, but you seem quite uncomfortable with that. Is that a concept ... ?

No, no, I'm comfortable but I'm just a realist and said, ‘Listen, I didn't do that alone.’ Anyone who claims that's a nitwit. And readily demonstrable as just being a blow-hard. Ah, would it have all happened if I'd never set foot on the earth? Yeah, probably, probably. Things tend to happen as the discovery of how the culture cells happened. Yeah, somebody would have twigged to it, somebody would have persisted, somebody would have done it, I suspect. Ah, you're the one that did it, so you can say, you're identified with that and that's what you did.

In respect of this, with all these different people coming in, and increasing numbers of both different disciplines, and increasing numbers of people coming to work on the team, what is the role of the team leader?

Well, it's quite complicated, everything from raising enough money to support them — and remember each research worker costs about half a million dollars a year, not in salary but in costs. Somebody's got to organise that money to be gouged out of somebody. Ah, somebody's got to recruit bright young students, young post-docs, somebody's got to have a game plan and says, ‘This is what we'll do — what we'll try and do.’ And if they're like me, somebody who is prepared to go out there and do it too, because I like to do everything myself as well as everyone else, so we're all working together. Much more fun. And then someone who's put it all together and go and do it all over again, so a team leader is many things. Father, confessor sometimes. Ah, an exemplar, hopefully. A bully sometimes, a ... you know, many parts. What makes a good leader? There ... it's funny if you look around our building, it's got 600 scientists in and say, ‘Who are the good leaders?’ I would pick four or five. And it's interesting, everyone else would pick the same four or five. They're all totally different in characteristics, one's aggressive, one's a flamboyant excessive, one's scholarly, you know, but each in their own way is a good leader. What's interesting is if you say: where'd you grow up? And nearly always 80 percent of the time it's in the country. Where'd you go to school? State school or one of the ...

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