Australian Biography

Donald Metcalf - full interview transcript

Tape of 11

Tape 1 2 3 4 5 6 7 8 9 10 11

How did you get out of the animal house?

I got away from the animal house when a new director was appointed to the institute, Gus Nossal. And his first act was to ask me to be the assistant director and to come into the main building, and we had a sixth floor there that was not complete so we purpose completed it as a set of labs and we had marvellous new expanded quarters that were purpose built, it was great. So that was 1966, I think. '66. Yeah.

How did that make your work different, being in the new environment?

Didn't make a lot of difference except that you could look out and see the city below you. It was a great view, better labs and so you could put equipment in and increase the number of people in the group. And the mice were in proper animal rooms so I wasn't sneezing all the time, so it was great. And you were with other people so you could collaborate with them, because it's very hard with a colleague who's 50 yards away or a hundred yards away to do an experiment together, whereas, if they're on the floor below you it's quite easy. So more of the experiments were done using additional people with the skills from other groups. So it really surged ahead because if you're given extra space, more people, more opportunities to do the job a different way, it helps.

What was the connection between the move from the animal house and the opera Fidelio that you ... ?

Opera, Fidelio, now that's a good question. The opera ... in the Fidelio all the prisoners come out from the underground prison, isn't it? By pushing open the grates in some productions. Maybe that's what it was. It felt like escaping out of prison. And joining the rest of the world. Were we rescued by a faithful wife? No, I don't think so. A new director.

What other things did the new director mean for you? Was there any other element that changed for you as a result of Gus coming in to replace Mac Burnet?

Well, he was 100 percent for the program we were doing, he wanted to work on leukaemia, he wanted to work on regulators of cell growth, so it was precisely the area that he wanted in his institute and it made it complete for him because he had people working on autoimmune disease, people working on infections and then he had people working on cancer of the same blood cells. So it was a nice match. I think we added some intellectual power but it made the ... it made his grouping balanced and you could see that.

Now, in describing the way in which things developed you've taken us already through the various stages, from the first idea to what inspired, and you're eventually getting clinical trials that worked on human patients, but what happens once you prove that something can be done to make it actually happen in a way that will get it out to a lot of people?

Well, first of all, you need people like Tony Burgess, who was originally my first assistant and while this was going on became director of the Ludwig Institute next door, to go round knocking on company doors and saying, ‘Look these are interesting molecules, they probably have some clinical use, take an interest.’ And eventually slowly, very slowly, companies agree, yes, maybe it is. So he had to line up companies that would possibly have an interest. Once you've done that and, of course, what you must remember at exactly this time, biotechnology companies were starting in California so quite independent of all the academics like us, they were saying, let's develop these agents to make money. Which they did. So Amgen, the most successful one, said, ‘Let's find the gene for CSFs.’ Which they did. And let's make a billion dollars a year. Which they do. And from their little group there are now 16,000 people in a small town all based on the money they earn from CSF and from Erythropoietin, the two similar drugs. So, they're doing it the commercial route with a view to applying it and so they have built up a set of people out advertising, getting clinical trials done and going to doctors, saying, this is the stuff to use. And we're doing the science and, you know, this is what it can do and this is how they should be used. And so on. So, we had to do a lot of sort of leg work trying to interest companies and actually the existing companies never played a part in the development of those agents.

The ... their mental thinking is surprisingly inflexible, enormous companies like Merck Sharp and Dohme or Bayer, have programs that are set in concrete years ahead and even if they wanted to, even if you convinced them, ‘This is the new agent, you should be in it,’ they can't do it. So we learnt that bitterly over the years. They were not the people you approached and in fact the people who successfully introduced things into clinics were these new companies that had no background, weren't in the pharmaceutical industry, and had to develop everything from nothing: their sales people, their medical reps. But in general, through one route or another, mainly through this commercial route, more and more clinical trials are done, all the data ... rooms fulls of data are sent to Washington to be gone through. Yes, it's done all these tests. You've done this, you've done that and then they agree that it can be used. For certain purposes. And they never license anything for any use, so you're allowed to use one CSF for one particular use and nothing else. And it doesn't make sense to me but that's the way it works.

You've talked earlier about the FDA and their incredible power in getting these things to happen. How ... I mean, what actually has to happen with the FDA and a development like this? Do you deal with them or does the biotech or pharmaceutical company deal with them?

Yeah. We deal with them once removed so the company, let's say Amgen, comes to Melbourne, collects all the doctors in the Royal Melbourne together and said, ‘We're prepared to fund a clinical trial. Are you prepared to do it? This is what you have to do. This is all the paperwork you've got to do. You need extra nurses, you need stacks and stacks of clerical people.’ And you produce this room full of data from studies on maybe 30 patients and that's collected and similar sets of data from maybe three or four other hospitals are then all sent to Washington, and they sit in judgement on it and say, well, you know, ‘Does it fulfil the rules? Is it efficacious? Is it safe? Is it da-da-da? And will it be less costly to patients than existing treatment?’ And if the answer to that is yes, then slowly they will approve it for certain uses. If the answer's no, it's back to the starting blocks. Now, why that should cost ... I think it's a thousand million dollars Australian, now, I do not know. There are hundreds of people involved. So we don't have anything to do with it. We've passed our baton on to a patent holding company in America and they've dealt with the company. So it's the company that then comes to us as academics and says, ‘Test the thing and we'll make use of the data, have it licensed and you guys get nothing out of it except that money that supported the trial and the fame and honour of having made money for us. No, the fame of having introduced a new treatment.’ It's a funny business so scientists never are the ones that deal with the government, to get something licensed, so if for example one day stem cell products are used clinically, it won't be the group at Monash who worked with the stem cells and maybe not the group that showed the application, but it'll be by proxy some company that's developed to, you know, expand the subject, get the material all certified, clean and usable.

To create it into a commercial product?

Yeah, it's a very ... there should be a cheaper way of getting new drugs tested because there are a lot of young people out there discovering new things that could be used on somebody, that will never be used. Because the process of doing it ethically and legally is too expensive. So an enormous German company like Bayer can only develop one product a year. Can't afford any more. So if you're a young guy and you've just discovered the hormone that controls, da, da, da, too bad. The company can't afford to test it and develop it.

The reason they can't afford to test and develop it has to do with the whole weight of government and regulatory conservatism ... ?

And the possibility that Mrs Jones may have bravely volunteered to test this but whoops it killed her, or whoops she became desperately ill, as happened in a clinical trial in England a few months ago. And so there are lawsuits, but that's part of it, now what fraction of the cost is covering that, I don't know but, you know, there are multiple issues at stake and sometimes ... sometimes it takes years to prove that what you're doing is actually better than the existing way. For example, we discovered when we were testing CSFs in the first lot of patients, because we were carefully monitoring everything, that all the stem cells in the bone marrow were coming out into the blood. So the clinician said, ‘Hey, why don't we use blood for a transplant instead of bone marrow?’ Because to take bone marrow, you need an anaesthetic, you need a team of doctors sucking ... trying to suck one litre of bone marrow out of all your bones, everywhere they can find one, it's not a pleasant job. And it's not very efficient. This way, you give a patient an injection of CSF and then just collect their blood, so you're giving a blood transfusion, read a book, watch a television movie, it's over, finished. And it's better, it ... it works faster, you don't have to spend weeks in hospital, and it's less dangerous, right? But proving all that, the step between us finding the stem cells, the clinicians trying the first test and saying, ‘Hey this is working well,’ to having all the clinicians in the country and every other country saying, ‘No more bone marrow transplants, it's all peripheral blood stem cells,’ takes a decade.

So, hardly anyone now uses bone marrow for transplants and yet the original observation was made in 1988. So it takes time. And it's nobody dragging their feet, it's just ... just takes time to accumulate the clinical practice and results.

And a lot of money?

Ah, I suspect for that one, not a lot of money, because you didn't have to change the setup of a hospital. I mean, it is true now that you can have a transplant almost as an outpatient, so you don't need an elaborate ward with barrier nursing and germ-free containment, that's gone because you don't need it. But that's simplifying a hospital, that's saying, ‘Okay we can do it in the ward instead of having a special ward.’ So that wasn't an expense but that might have happened. So the fact that you can come back now and say, ‘Listen, it only costs a third of the money to do a transplant this way than the old way,’ is part of the story but you also didn't have to build a special hospital to do it. So it all adds up and it ... sometimes new developments do require new capital works, so it's not just that the technique's better, it's ... I've got to change the building and do something else. Train new people.

Now in this whole chain of development of a new drug, when you as the scientists really basically pass on to a commercial enterprise to develop and exploit it, where does the intellectual property go?

Good question. I don't think we made a penny out of that observation. Could be wrong, I don't think so. It happened ... it happened by accident, right, the discovery that stem cells go into the blood was an accident, it wasn't figured on in the original protocol and ... but it was happening, it happened while the company was still applying to the FDA, so it could add that use into the application for licensing. So it didn't need any separate patents, it didn't need any separate official approval, so it's all one packet. It's not that Amgen pays any royalties to us, but if it had been the other way around, I think it would have all been included in the one packet.

Now, in relation to the CSFs, you know, what ... how does that work from the point of view of returns in royalties for the intellectual property in that?

Well, we don't have the intellectual property for the most commonly used CSF, G-CSF, we discovered it, we purified it first, but we didn't clone the gene first. And patents are issued on processes, so if you discover a new method for growing wheat, that's a patent, but if you discover a new form of wheat, that's not a process, that's just discovering what's out there in nature. So CSFs exist in our body, so if we discover them, and say, ‘Hey there's such a thing as CSFs, we've purified it, here it is in a bottle,’ that's not an invention. The invention is to discover a way of making that by getting the gene in this case and making that. So that's what you can patent. Now, we do have the patent for one of the CSFs and it's not used very often because the company is not as aggressive as the other company. But I think it's a more versatile product and it ought to be used more often. Now, turns out that it is being tested now in bowel disease, in Crohn's Disease, and it seems to be working. So, I was discussing earlier this week, what happens now to the patents that we hold if we say, ‘Oh and by the way, you can use it in Crohn's Disease,’ if that turns out to work. And the answer is, that you can't really change the original patent, you have to ... but you can take out a patent called a user patent, which says, I am now describing an invention for making CSF for Crohn's Disease. And maybe you get that, maybe you don't.

So it's funny, to an outsider it must seem ridiculous and cumbersome and it is. I think it is. But it's bureaucracy and that's the way it goes. There ought to be a way of testing drugs more cheaply. I come to you and I say, ‘Look, I've discovered something, I think it's good for you, I think it's going to work, are you willing to have me try it?’ And you say, ‘Ah, yes, and I'm willing not to sue you if it goes wrong.’ And the government says, ‘You get 10 people like that and I think you've made a fair case and we'll license it somehow.’ That shouldn't take a thousand million dollars. There ought to be a simpler way but nobody's found one yet.

So [with] the Walter and Eliza Hall Institute, as an institute, you personally as a scientist have not benefited financially from the work you did on CSFs, which are now used all over the world?

No, that's not quite true. We get royalties from one CSF and in a good year it's about a million dollars a year. Maybe more, maybe two, three million, and I think the patents are beginning to run out in Europe but they are still alive in America, where most of the money comes from. And there's a complex formula that's been developed by the Board at the institute where the institute gets most of the money and the inventors, the people named in the original patent, get portion of the rest. So I, myself, do get some royalties and the institute gets some royalties, they're not mega bucks, they're millions not billions. Um, different institutes do it different ways but it usually works out something like that. It's ... the government and various granting agencies are trying to do something to ... which to them sounds logical but will be a disaster, and they're saying the following, ‘I gave you the money for that research, I want a percent of the royalties.’ And he says, ‘I gave you some of the money for that research.’ Because usually the research money comes from several places. Each one wants a cut of the action. And if it adds up to 100 percent then the institute and the scientists get nothing, because all the research is paid for by somebody else. Right? So unless we do something, unless the rest of the country does something, we're at risk of having everyone who ever contributed any money saying, ‘I want a portion of that royalty.’ Whatever it is, now it's not often much, but sometimes it is.

So the principle is that money can earn money but labour, however skilled, can't.

I'm not ... I'm not sure how it'll end up, we are complaining bitterly to Canberra and anyone who'll listen, but they all say, ‘I'm sorry but it's my money, I gave it and I deserve a piece of the action.’ Now I have to pay money to the Anti-Cancer Council so they get royalties from CSFs and that's the only one but if the federal governments, through NHMRC [National Health and Medical Research Council], said, ‘hey, but we gave (as they did) five million dollars this year’ I think to our group, ‘we want five million dollars worth of the action.’ We're cooked. As an institute, we get nothing. There has to be a way around that one, that's a new twist this year, but it's happening around the world simultaneously, every agency. It started in America with NIH [National Institutes of Health] in Washington — some of our money comes from America — saying, ‘We want part of the royalties.’ And the Anti-Cancer Council saying, ‘We want part of the royalties.’ Canberra saying, ‘We want part.’ Where does it stop? Then 100 percent is reached and we get zip. And we're saying, ‘What is the point of us doing anything if there's no reward at the end?’ Not that you do it to make money but it's sort of nice if you get a bit of credit for what you do. How would you solve it? It's not easy.

Yes, well I was ... I was just thinking it is part of a trend that labour, however skilled, isn't valued the way capital is.

It may ... may be that it's happening, it's ... yes. It's essentially that, it's the money and it's quotes, my money, it's the taxpayer's money usually. There it goes. We have an interesting way to spread our royalty in our institute; everyone on the staff gets a cut. So they each get a cheque about this time of the year, and it's the same sum for everyone: wash-up ladies, animal girls, scientists, director, everyone gets the same percent. And it’s a couple of thousand but it's nice.

That sounds almost socialist, Don.

It does, doesn't it? I try to treat everyone equally and it's quite interesting, in the days when I was assistant director, when you had to sign pay cheques, when there were such things as pay cheques, literally cheques that you signed, to notice that there really wasn't much difference in the pay cheque of an animal technician versus a unit head, a professor. By the time the taxation difference is taken into account that, yeah, it's within spitting distance. So, the fact that you were always just called by first name, never Doctor Metcalf, never Professor Metcalf, just Don, is something you live with and you ... everyone treats everyone else with respect, but as equal. It is a bit socialistic. But then we're all in the same boat. I mean, if an animal technician makes a mistake with the mice, you are screwed, you are in complete disaster, you'll get the wrong answer, you won't know what's happened, it's chaos. So the lowest person in the team can torpedo the whole thing by accident, just as much as the ... one of the leaders goes astray.

What sort of a mistake would he make with the mice?

Oh, some mice, there are more than one sort of mouse that's white-coloured. Mix them up in the breeding boxes, I mean, they're dealing with a quarter of a ... half a million mice a year. They're all inbred mice with maybe 30, 50 different types and if you make a mistake, and it's happened, it's very hard to detect but you get completely different answers. Um, ... you just can't afford it. I mean, if you were to go into our animal house, which is a great performance because it's all automated, each mouse box has its own air supply, you've got to go through air showers and everything's on computer. Our ... every mouse doesn't have a computer chip on its ear but it's getting to that point. It's a lot of high-tech stuff and you can make a mistake entering up mice and mix them up, yes, you can. It's scary. So you have to make sure they know exactly what the project is, what's at issue, what ... why things have to be this way. So there's a lot of ... you don't issue orders any way, this ... like you used to in the old days, now it's ‘sit down, we discuss this. Everyone clear what's happening? Why it has to happen? You know your job, we'll check this when it ...’ So it ends up everyone perhaps being worth much the same sum of money. Anyway, we digress.

Now the whole institute has this relationship with Melbourne University, how does that work? What is the relationship?

It is a fairly loose relationship. We're a university department, which allows us to have postgraduate students, masters and PhD students. So they're students in the university. Each student by law is supposed to be, or the institution that has a student is supposed to get, I don't know, let's say, $15,000 a student from federal government. I think we get about a few hundred so we are chiselled by the university and they don't regard us as part of the university until the day comes they have to describe their research work, then of course we're part of the university. We don't sit on any of the committees and we don't ... we're not allowed to teach any of their undergraduates, they don't like us teaching undergraduates because we might steal them. The brightest, we ... we might well. But ... so it's a ...

Maybe they find their way to you, anyway, Don?

Oh they do. We take our ... the best from all over the whole country but it's not a close relationship you ... you might have a close working relationship with a particular person in a particular department, and there are some departments that are more closely related to us than others, but by and large it's just a place across the road. I shouldn't say that because we're all professors in the university but I don't think the university can have it both ways. They don't really treat us properly and we are a jewel in their crown but they don't wear that crown too often.

Would you like to be teaching undergraduates?

No, I would hate it. I have stood in, taught medical students and that is a frightening experience, to have them sitting there reading the newspaper or eating their lunch, or throwing things at each other. Oh, I would hate that.

Do you think you're a good teacher of the undergraduates or the postgraduates?

Probably. As a formal teacher, yeah, I think probably. I write good books that I intend to be teaching books. Ah, and I'm a good undergraduate lecturer, I just wouldn't like to do it because I find that to give one lecture in a day absolutely wipes you out for the rest of the day, emotionally you just don't feel like working. I really feel sorry for university people who try to do research and teach, it's hopeless.

So, but it's useful to the institute to have postgraduate students?

Absolutely. We have about 90, I think 90 PhD students, at any one time, that's a lot.

So what specifically would you like from the university that you don't get?

Nothing. I'm ... I'm happy, I'm happy. Um, what would we like from the university we don't get? No, I ... no I ... the interaction's fine, really. It ... there are a number ... particularly Melbourne University has a number of institutes that are physically around it, like the [Howard] Florey Institute, like the ones down Royal Parade, and you couldn't really conceive of a university embracing the lot. It's ... it's very like Cambridge and Oxford, there are research institutes there that are often considered part of the university of Oxford or Cambridge but really have little to do with it. I worked in one in Cambridge. Ah, and that's probably how it should be. The needs are different, the way you do things are very different.

You were talking earlier about royalties and intellectual property. You've done quite a lot of collaboration in your own work with the Ludwig Institute, how does it work out when something emerges from that work that has commercial potential?

Well, we share the patents, as we do with GM-CSF, so Ludwig and the institute have half each. And in fact, we passed our rights over completely to the Ludwig, and they worked through their head office in Zurich to interact with the company, so it's a very indirect thing. That's the way you have to do it, you have to ... practicalities, so you need one research institute to handle ... to interact with the next level of development. Or it's chaos, you couldn't expect the drug company to interact simultaneously with some places, it's silly. That's my understanding anyway.

So the CSF on which you have the patent is called a GM?

GM, yeah.

GM-CSF?

Yeah, that's because it stimulates granulocytes and macrophages, the two main families of white cells that handle bacteria and fungi.

And you have that patent because you actually cloned the ...

The gene first.

The gene. How do you do that?

I'm not a molecular biologist.

But therefore you're probably better positioned to explain it than if you were?

How we did it was to painfully purify the protein and you chop the protein up into its building blocks, they're called amino acids, and you work out the sequence of those amino acids along the length of the protein. And once you've got a stretch of about 30 in the right order, you can work out by a formula what gene would have coded for that. So you can artificially make that gene and you make it radioactive by putting radioactive parts in it and you can then use that as a fishing hook to go and say, ‘Where is the gene in this cell that codes for that?’ Now, there's one property, the fishing hook you've made will only bind strongly to the real gene. So you've got 30,000 genes and you've got a little radioactive fishing hook that's part of one of those 30,000. So you just put all the genes like a big stew at random, one into each bacteria, and you grow bacterial colonies. So you've got this plate with bacterial colonies all over it and you put blotting paper on it very carefully and you pull it off very carefully and it takes away part of each one of those bacterial colonies. Then you pour on this radioactive little gene fishing hook and then you develop the x-ray and there's one little black spot and, you say, that's the CSF gene. It's all done in one day, the way I describe it. It actually takes a few months and there it is. It might not be a complete gene and you might have to go back and do it all over again to find another part of the gene, but that's how you do it. That's called ‘cloning the gene’. Because each gene is in a colony or a clone and you've got to find the one that you want. And that's all based on the property that ... the little artificial gene you made and he really sticks hard to the same gene.

You're doing this with your hands in space?

All that happens in the lab is just pouring, people pouring ... pouring what looks like clear water onto clear water and going away and saying, ‘It's there, it's there.’ See. It's boring, molecular biology.

What strikes me when you look ... when you look at that, when you do that, and when you talk about what you're doing with your colonies and so on, and you're explaining what you're looking at like this, it ... the concept of how ...

Visual, the things are there, I'm trying to describe the plate and there it is. There, right there, one spot, you see that one black boy, that's the day that was, that's winning the Melbourne Cup. There! That's it!

The thing is, how small is this?

These colonies, you can see them with your naked eye, they're pin-size. Millions of bacteria but all with the same little gene bit in them, growing in a big plate of nutrient jelly. It's pretty macro, it's a mystery. Mystery is putting that in a machine and saying, ‘That's the sequence.’ And that's what machines do nowadays so that's ... it's stuff I don't understand. That's hard stuff.

But what you're talking about is only pinhead size and without the microscope?

Yes. But you can see a black spot on an x-ray film. It's an x-ray film you put on top of this and you develop it and there's one little black spot and ... and you fit that back onto your original plate, which has all the colonies on, you say, ‘That's the one there that made the black spot.’ And you pick that off and you can grow it. You can grow a big vat of it, you can make a million gallons of that bacteria. And you do. And you make a billion dollars with it. Now, as I say, the techniques for doing that are much, much simpler these days and you really could take a smart student, third-year science student, and say, ‘Please clone the gene for this, this is part of the sequence and bring it back in by February.’ They could do it. If they couldn't do it, you'd wonder how smart they were. Things change.

You said you're quite careful in picking the bright-eyed and bushy-tailed ones to be the people who work with you because you ... you like ... you think, you know, it's good to get the best and the brightest into your lab..

No, I wouldn't take the brightest, no way.

Why not?

Ah, I distrust anyone who tops the year. Why? Because they've got a photographic memory and they will believe anything they read and can regurgitate it; that's why they topped the year. Now what you read in a text book is 90 percent wrong, everyone realises that. So they're learning complete rubbish. And they're not saying, ‘Hang on a minute, I don't believe that. That, I'm disbelieving.’ So what you're looking for, are people that are smart enough, but not this sort of person. So what I look for are the people in the top third, alright? They're usually troublesome rebel rousers but they know enough and then if they've got bright eyes, I'll pick them. But I've learnt that the ... now people will strangle me, who happen to have topped the year in something, but I can think of some doozies — who I wouldn't trust to treat my cat — who topped the year. It's a difference in [that] people who are very, very good at passing exams usually have a very retentive memory and to me, by definition, that means that they don't doubt or question things. They haven't got time, they ... they're trying to actually soak up the written knowledge and the written knowledge isn't reliable; even my written knowledge is not reliable. Nobody's is. Come on.

Well, it's an interesting prejudice to encounter, Don. The idea that the very best ...

It's not prejudice, it's ... the best in the land, or I'm sure they're good for something.

This is the boy who came dux.

Yes, well. Probably it wasn't a good year.

So I'm just wondering, among your students that you've had come and work with you, are there any — and I know that it's like picking a favourite child — but are there any that have gone on to do things that really amazed you and ... [interruption] ...

[end of tape]

Proceed to Tape 7