Professor Elspeth McLachlan, physiologist

Professor Elspeth McLachlan. Interview sponsored by 100 Years of Australian Science (National Council for the Centenary of Federation).

Elspeth McLachlan received a BSc Hons from the University of Sydney in 1963, then went to London where she worked as a test pharmacologist for Roche Products, screening anti-hypertensive drugs, before moving to the library of the British Museum. She began teaching at the University of Sydney in 1970. The University of Sydney awarded her a PhD in 1973. From 1974 to 1982, McLachlan worked at Monash University in the physiology department.

In 1984 McLachlan moved to the Baker Medical Research Institute in Melbourne where she remained until 1988. She then became professor and head of the department of physiology and pharmacology at the University of Queensland. In 1993 she moved to Sydney as Conjoint Professor, Prince of Wales Medical Research Institute. Since 1999 she has also been the director of the Centre for Research Management, National Health and Medical Research Council. McLachan was awarded a DSc by the University of Sydney in 1994.

Teachers' notes to accompany this transcript.
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Interviewed by Professor David Hirst in 2000.


A wake-up call: coming home to science

Just what made you want to be a scientist, Elspeth?

I don’t think I wanted to be a scientist, or that the concept of science as a career ever occurred to me until I was nearly 30. When I was young I thought – like everybody, I suppose – that I would just get married and have lots of children. Then I ended up not getting married and I wondered what would happen next, what sort of job I would get.

I’d had lots of jobs continuously from the day I left university – absolutely no problems about that. I did what everybody did in the ’60s, and went to England. First I got a job in London as a test pharmacologist for Roche Products, screening anti-hypertensive drugs. That was pretty horrifying, because they were even more archaic in their technology than the University of Sydney practical classes. I moved off as soon as I could, into a job in the library of the British Museum.

But you must have been interested in science, even to go into Roche pharmacology. There must have been some questions there that interested you.

No. I did my university course because I had decided at 16, when I was leaving school, that I didn’t want to do medicine after all. I didn’t really want to face a medical course and the responsibilities that being a practising clinician puts on you.

It’s funny, because for me it was quite the opposite. For no good reason I was determined to be a pharmacologist from about the age of 16, when I barely knew what the word meant. I had a career mapped out which I achieved by the time I was 32.

Did you want to be a pharmacologist because you thought you would get a job in a drug company and earn lots of money, or to do university work?

I thought it would be interesting to find out how body function was altered by chemicals. (This was way before the hippie era.) Actually, in those times we didn’t have to think of a career – there were opportunities everywhere to do anything we wanted to do in the ’60s.

That is true at any time. It’s a question of how much time and effort you put into preparing yourself for what you end up doing. And I think it’s bad to choose too early. Was your decision influenced by your experiences at school, perhaps with good biology teachers?

No, I had hopeless biology teachers. But the subject matter was interesting. Tell me, though: if you were enjoying life in England, why did you come back to Australia?

Oh, the Swinging ’60s was great but I didn’t want to live in Europe any more, doing the same thing for the rest of my life. Australia was my home and I was going to settle down. So I came back, and for a while I worked in industry in Australia. At that time I didn’t want to get my hands dirty, and the idea of having to go back to the sorts of experiments I had done – on anaesthetised animals, with lots of blood everywhere – was a bit threatening. I had quite enjoyed sitting at a nice big desk in the British Museum and talking to people, and I thought it would be nice to just keep doing that sort of thing. So I worked in Johnson & Johnson, again for only a few months, doing more or less clerical work associated with specifications, regulations – which turned out to be intensely boring.

After a very short time I realised that, in this country anyway, there were at that time no real jobs or careers for somebody with my biological science training except in laboratories. You could go into a drug company and sell drugs to doctors – which wasn’t quite my scene – or you could go and do research. I had enjoyed research quite a lot when I was doing Honours, so I went back to that as a thing to do.

But your PhD was a long step away from what you had done in Honours, wasn’t it?

Oh yes. I had had five years away from that, so I wasn’t interested in it. I had worked in various labs doing different kinds of things, and it was really more a question of meeting the right person to trigger me.

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A much-needed trigger

Who was the right person, then?

Max Bennett, believe it or not. He showed me what the world of doing professional science is like. Previously I had been working mostly in university and hospital laboratories as somebody’s research assistant, and although the questions were very important and the experiments we did were very good, we didn’t have much output. It wasn’t very well directed. Instead of answering very important questions or intermingling with the world, it was all done as if in a back room. Max gave me the view that you could actually become part of the science community, in which case you had to be professional and do things the way that real scientists did them.

What I said I wanted to do at that time was the thing that you ended up doing: looking at the control of the cardiac pacemaker by the vagus and the sympathetic nerves. I spent six months mucking about, with absolutely no skill, trying to do the dissection of the pacemaker with the vagus nerve and the sympathetic nerves and everything, and they always died. You know about that, don’t you?

Yes, I do. I was lucky, I had a very good trained hand – Graham Campbell used to do all the dissections for me.

Well, I’d never done a dissection. I could do that now, I’m sure, even without your people showing me, but I had no training in skills or experience at all in doing that kind of thing.

Max persuaded you to do experiments on ganglia. You were given a very good problem and you solved it incredibly well.

Max was very good, letting me muck about with these stupid dissections for a while, and then he said, ‘Okay, that’s enough of that. Now you’re going to start poking these ganglia.’ The first year was very difficult for me, I must admit, because I had no electrophysiological training either. He just showed me mechanically what to do, but I didn’t understand very much until I had been doing it for about a year and gradually things started to fall into place.

I don’t know if it was Max who put me onto the thing that most turned me on at that time. It might have been because I knew Steve Redman that I got very interested in trying to work out how sympathetic neurons integrated information along their dendritic trees (in the same way that Steve was working at that time on motor neurons in the spinal cord). It seemed to me we should be able to use the same principles, and, as it turns out, we can. But I’ve only just now, after 30 years, got to the stage where we have some model of how we might begin. One can do much more elegant things in motor neurons – simply because the neurons are much larger and you can do more with them than with sympathetic ones. So I never really solved that problem, and integration still has a number of very interesting questions for me.

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An attraction to the autonomic nervous system

I came to Australia because of its great strength in the autonomic nervous system in the early ’70s. That must have been about when you started work on it.

I started in 1970, but I had been working on cardiovascular innervation for some time. The cardiovascular control side of autonomic physiology was already in existence; it has been quite strong in this country for a long time. But you are referring to the burgeoning of Geoff Burnstock, Mollie Holman and Mike Rand in Melbourne, and the offshoot of their students – Max was one – who became the seeds of groups all over the country working in autonomic physiology.

I wanted to ask you about your PhD. Was it planned out that you were going to do your first degree, and you did that, and then you were going to do your second degree and so you did that? Is that the way it worked?

I was a spectacularly poor student. No-one wanted me as a PhD student. I was eventually taken on by the head of department in Leeds, Professor Wood, whose sole aim was to become the Dean of Medicine so he didn’t care what I did. On the basis that I’d not much clever thought, I decided I would learn a good technique. So I taught myself electrophysiology, making intracellular recordings from the skeletal neuromuscular junction. Professor Wood decided then that I should be supported, so he bought me all the equipment and I did the first intracellular recordings in a converted toilet in the basement. At the time I didn’t realise the virtue of that.

Yes – a concrete floor, nice and solid. No movement, absolutely perfect.

Funnily enough, the whole of my life has been characterised by good luck. For no intellectual reasons whatsoever but just to learn electrophysiology, I started working on how to block neuromuscular transmission with local anaesthetics. I had no idea of the ramifications of the project, but it worked out very well. It was the first demonstration that you could modify the kinetics of junctional currents, synaptic currents. And it was a complete fluke.

Did all your intellectual input, apart from the Dean of Medicine drifting in and out, come from reading?

Yes. And reading about two New Zealanders who were working in Australia was one reason I wanted to come here. Liley worked with Eccles and had at that time done the most work on mammalian neuromuscular junction. I found his papers very inspirational for their simplicity. The other person was John Hubbard. I’ve never actually met either of them.

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Tying new insights back into the body

Your success hasn’t depended on good luck as much as mine did, but some people have been big influences. Steve Redman must have been one of them.

He was. When I first met him – socially – he was an electrical engineering student.

The lowest of the low!

And a rather odd one because he was doing a PhD somewhere, and I didn’t know electrical engineers did PhDs. But he then turned out to be working in neurophysiology and that was fascinating to me. I was mainly in cardiovascular physiology and came into neurophysiology with Max – through the back door. Discovering that Steve was doing something that was related to what I doing was very interesting. He has been a major influence on me, and I think on you too.

Definitely. When I arrived at Monash, suddenly all these ridiculous little circuit diagrams that people drew came to life. I had thought this was an abstract mass of little value other than as entertainment for electrical engineers, but sitting in with Steve, seeing the experiments, seeing the data coming in, was a great revelation. One could see how they could be applied and how they mattered in body function. Actually, a lot of what he taught me about motor neurones I have subsequently used on smooth muscle, where arterioles behave like a branching tree – smooth muscles are interconnected so you need complex modelling to understand them.

The refinements that Steve brought were unbelievable, and I agree there was a big need for you to follow that pathway. But in another sense the information transfer that you described is what matters, and that is the thing we need nowadays to tie home, back into body physiology.

That’s what I was going to say. I think the thing that characterises you and me from a lot of other people who work in this area is that both of us, in our own different ways, are always trying to get things back into the body – working in a cellular sense and quite analytically on single cells and interpreting what ion channels do in membranes, but all the time trying to keep your eye on what those channels might do if still attached to a body. A lot of people in science don’t do that.

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The getting of experimental wisdom

You jumped over your work with Bernard Ginsburg in Edinburgh, before you came to Monash. I had a little time with Bernard Ginsburg too. I think your time with him was pretty formative for you.

It was very formative. In my PhD I had worked entirely by myself. But Bernard, although he had arthritis and so couldn’t dissect, insisted on sitting in at every experiment while the data was being collected – which means you have to talk. And by talking you become educated, you widen your mind. So now when young students come in, I try and work with them for a year. They might think my approach is somewhat archaic, but the emphasis one gives them, the educational values they absorb simply by talking to someone who’s been around, that is beyond price. And you’ve adopted this hands-on approach with your students.

Yes, I have certainly tried to do that. It’s not always easy to get them to sit still long enough, but that is the way to a depth of understanding. As an Honours student or beginning a PhD, your understanding of the literature is so superficial, really, that it’s difficult to get to know what it means, as opposed to merely trotting out, over and over again, phrases that you’ve picked up and read.

The biggest problem in collecting data is to know when you have done the experiment properly. The repetition is very important but so is the basic experimental design, and you can only gain that by sitting with people and watching them do it. When you’re a young person it’s pointless reading a paper and saying this, this and this. When you are of our antiquity, life becomes a bit easier. At the start one’s got to be shown what to do, to be educated in technical skills and taught to critically analyse data.

In our area that’s so true. I find it very frustrating talking with people who work with primarily biochemical types of techniques, which often are automated to the extent that they are done repetitively – you don’t know what the outcome will be until some considerable time later, so you do a sequence of steps according to a recipe book, like cooking. Then you put the cake in the oven and you’ve got to wait to bring out the cake and see whether it’s worked. Obviously you’ve got to be a good technician to be able to get the cake to work, but once you’ve worked out how to do that recipe you just do it again and again.

Our experiments don’t work like that. Because you’re interacting with living cells, quite often you see something which doesn’t fit the recipe and you have to do something different to respond to it. That’s so much harder for the young people to do: they can’t see when it has gone wrong as easily as we can. We can walk past an experiment, see something on the oscilloscope screen and say, ‘Hey, just a minute. That one’s different. There’s something going on here,’ when they’ve been worrying that they were doing the recording wrong or that the knob wasn’t turned the right way. In their neurophysiological experiments, they are expecting unusual technical things but not unusual biology.

In molecular biology, a lot of the techniques now are so standardised that people simply gather data. You build into the variance of your experiment the errors introduced by your technicians or the errors of your equipment, and you just keep on doing enough experiments to bring the variance down. We don’t do that. We throw out the experiments because they’re actually bad data and we can see that. But a young person often can’t see it. It’s very difficult to get them to understand the concept.

In our field as well it’s creeping in, with a lot of the sophisticated computer collection routines, that people are measuring data, seeing currents changing, and assuming it’s changing correctly. There is a detachment from the experiment. That is something we’ve got to guard against very, very strongly. Science is becoming more of a career than an interest and a number of powerful people don’t do any experiments. This is a major problem facing science – in Australia, certainly America and probably Europe.

Yes, and quite a lot of results come out that are probably not very useful because of that. They get published by big names but are delusive in their meaning. It is a concern but I don’t see how we’re going to get round it, because science is getting bigger and more of an industry.

We have to find a way around it, though, because the skills of the people leaving are experimental skills. Some of us can administrate efficiently in certain areas, but we’re not trained administrators; we are experienced scientists. It is something that I think you in your present position at the National Health and Medical Research Council are going to have to look at.

Very carefully.

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Broadening and grounding the experimental approach

When you arrived at Monash University and then we collaborated, that was a dream come true for me. You were the darling of the physiological society, a marvellous inspiration, and you brought the skills you had learned from Max Bennett. Then you picked up skills from Archie McIntyre and Bob Porter. They were magnificent leaders of a department.

They certainly were. It was a very exciting department to be in. It has been very interesting, moving around, to see what other people thought of it at that time. There was a great deal of jealousy within Australian physiology that the Monash department had so many people in it who all got on so well and were so productive and doing lots of different things. Although it was big in autonomic neurophysiology, there were also a lot of other groups in neurophysiology and other kinds of physiology, and we all knew what was going on in the department. It was terrific, a very broadening experience for me intellectually to be able to find out so much. People were willing to communicate about what they were doing and were excited about what they were doing, and about wanting to be the best at what they were doing.

That’s right. And we were the best.

We certainly were the best at the time, absolutely.

You have talked about the narrowness of approach of a number of scientists. Monash showed me, and you as well, I think, that one shouldn’t study just an area but a discipline. The things that I learned from Steve, Archie, Bob, were in fields where I never intended to work, and then the messages brought home were of great use within the area I studied.

True. And the other thing about that period was that we were involved in a lot of teaching, and it had to be broader than the areas each of us was researching – or sometimes, in my case, largely not in the areas I was researching. Having to learn the information from other people’s research in the department in these different areas and to be able to communicate to students about them was a very broadening experience. It really helped to give a perspective on how to design my own experiments, an ability to see the things that are relevant rather than little side-issues.

I completely agree with you. The things I learned from Bob about motor control were very important messages in looking at neuronal firing, which are applicable through the autonomic nervous system. You can go on to kidney and blood flow, neuronal control of blood flow, ionic balance in the CSF, ionic balance in the blood – all these things I knew nothing about before I arrived at Monash, yet they are key in understanding the functioning of any system, back in the body.

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Inspiration and support

How did you enjoy your time at Monash, especially with Mollie Holman?

It was terrific. It was wonderful for me because I met you.... We had a lot of things going for us because of Mollie’s influence on the group. There were six or seven people all more or less interested in the same kinds of things. It was probably a very unusual situation in a university department to have quite so many people with overlapping interests and with a nice ability to be independent people at the same time as being part of the group. The concept of a research group nowadays is a senior scientist and some various levels of other people, like a little pyramid, under them. It wasn’t really like that at all, was it?

No. I found Mollie quite inspirational. The freedom she gave us made a very big impression on me. We were all allowed to do what we wanted and she’d go off and battle for money for us. She didn’t expect much back from me; she just enjoyed interaction. And I think you became more anatomical during that unique time.

Well, I think that came rather later on. I’d always been rather interested in it, because I did it in Honours. The thing I did, by myself, when I got stuck on the physiology – which was in fact bordering on being too difficult to go any further with – was to say, ‘I don’t understand the system. I wonder how it’s made up, what are the building blocks.’ At about that time I started the combination of anatomy/physiology which I still do.

But I’d like to talk more about what we gained out of that system at Monash. We had people working on different bits of the gut, people working on the vas deferens and people working on ganglia, on all sorts of little different bits of the body, but we were all interested in the same general problems. And we had those amazing sessions when we used to sit round with glasses of sherry. They were very good times.

That’s right. But I remember there being bottles – no, flagons – of sherry.

I suppose you’d call those sessions ‘journal clubs’ now. But we didn’t talk about articles very often, did we? We mostly talked about problems.

Problems, and what we were actually doing. That was really very good, because someone would come in with a completely different approach. Sometimes it would be a technical support solution, sometimes an intellectual solution. And Mollie was there as a group leader, much like a cheer leader, providing drive and inspiration but not directing us.

She used to come and give answers, though. Because of her wide experience she could definitely help with the answers to the problems. She was able to give of her experience verbally and we all learned a lot: ‘Oh, I hadn’t thought of it that way. That’s a useful thing.’

I don’t know why that was. It could be just because of the youth of the university: we were all employed at the same time, we were all working at the same time in the lab.

The university had recently expanded quite a lot and then it was stable for a long period. We all came in and had to get our own grants, which were pretty small at first.

Yes! But we didn’t need them, in fact. The department was very supportive. That’s been a big change in the system. When I look through the universities now I see very, very little support for research. One absolutely has to get grants. But quite substantial pieces of equipment could be bought from departmental funds in those days.

Everything except the odd item. I remember my operating microscope – it was the first thing I ever got and it was very exciting – and my oscilloscope, that I still use. But all the other bits and pieces, the department provided. Some of them were old, somebody else had had them before, but you could always put together a rig. You didn’t have to get it all together yourself, chasing around as some people have to now to find money to buy all the little bits and pieces.

And the departments provided good solid support in the workshops. That was one of the things that Bob encouraged – the electronics workshop, the mechanical workshop.

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To teach or not to teach?

But then you left Monash to work at the Baker Institute. That must have been your first time in a research institute.

That was my first time in pure research. I was 40 years of age before I started any full-time research – all the way through I’d always worked, always had lecturing positions. Even as a PhD student I was a lecturer in the department, with a huge teaching load. For six months as an NHF fellow I didn’t have to teach, but that was fairly brief. So it was an amazing thing to me, when I was in a position to drive a research program, to be able to go and do it all the time. And the same thing happened to you: you went to the John Curtin School and suddenly left all the teaching behind you, and it was a terrific thing. Didn’t you notice that?

Oh, I noticed it. But neither of us stayed where we went to.

No. For various reasons those places aren’t always the same as we thought they were going to be. My period at the Baker was very successful, though, and I left there because I was leaving Melbourne. And I think the reason you left the John Curtin School was that Canberra was inconvenient for you. So it was more for personal reasons than because of the institution. I think you would have been able to get what you wanted, because the facilities were there.

The facilities were magnificent, but it still worries me that the institutes are separated from the teaching. You mentioned earlier that spending some time teaching was very beneficial for your research efforts. That’s a very big plus about doing research in a department rather than an institute.

It was very important. But I taught for 20 years and stopped, and I really would hate to go back and do that now. In the last five or six years since I’ve been at the Prince of Wales Medical Research Institute I have had an appointment at the University of New South Wales and so I’ve always been teaching. This year will be, probably, the first ever when I haven’t given some undergraduate lectures. They have been trivial – very few recently but I can still teach quite well and I think the experience of doing it for a long time was very important, whether or not you do it continuously forever. Don’t you think that’s what it is?

Actually, I disagree with you. I think that in the institutes one forgets the real world – the students. Undergraduates make one remember how little one knows, and that’s a very important facet of being a research scientist. I think in an institute there is a tendency to take on a view that problems are too small, the answers are known, when often they’re not.

I wouldn’t say that. The thing I like is that in the last few years I have been involved more in communicating with practising clinicians in a teaching role. Effectively, it’s a teaching role. I might be telling them about some of my recent research, but I have to present it just as I would an undergraduate lecture. They’ve been much more enjoyable to teach: rather than imagined problems or problems that come out of some textbook interpretation of the world, they actually come back with a real problem and ask you to try and solve it. That’s one thing we get quite a lot of at the institute.

Medical practitioners will ring up out of the blue and say, ‘I’ve had half a dozen cases of this. I don’t understand it. It’s something to do with autonomic function.’ It is fascinating to me that they hadn’t thought it was going to be something simple to explain, but only because they don’t think about the nervous system in the way that you or I think about the nervous system. They think about it in the way that they learned in their textbook 25 or 30 years ago and so they are not prepared to consider the other aspects that we now know a lot about and that are completely absorbed into our understanding of how the nervous system works. It would be nice to write that book that I’m probably not going to write until I retire!

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How and when to collaborate with clinicians

What do you think of the big move nowadays towards collaboration with clinicians?

I wish it would work. I think the demands on clinicians’ time are very hard to get over. Quite a lot of people 20 years ago would have an afternoon or two or a day off a week when they could interact with somebody in a research sense, and many of the professors of medicine in universities had research teams that they actively interacted with. Nowadays they don’t interact with them very much at all. They have a senior scientist who runs the lab, does the experiments and so on, and they come and discuss the data. They have some intellectual input, of course, and like Mollie they have the wise input into other people’s experiments, but they don’t have time to get the practical involvement. And I don’t know how to give them the time.

At the National Health and Medical Research Council we are looking at trying to buy some time for them, but to set it up to work is very difficult. You would know that from your experience with Meng Chong Ngu. As a practising clinician who wanted – and still wants – very much to do research, he found that, even though he had time set aside for him, his clinical job at the hospital involved being called away by telephone to a patient in the middle of his day off, and he had to go. It’s impossible to get over that psychological aspect of your work. Even though in theory somebody else can deal with it, in practice you do it.

Funnily enough, though, one of the most successful collaborations I had was with a clinician, Gerry Silverberg, a magnificent surgeon from Stanford. The questions he raised that would never have occurred to me were very, very exciting. The collaborations have to exist somehow. The thing about talking to a clinician is you know their opinions are correct: the person really does have a cerebral artery spasm, say. It’s a very important aspect that we need to bring into medical research, but I agree, I don’t know how we’re going to do it.

Well, that worked because he actually, physically went somewhere to do research. He went to the other end of the world for six months. So maybe we have to buy people periods like that. And maybe the Australian clinicians have to go overseas.

Probably, and we have to attract American and European clinicians to come here.

I have had the relationship with Germany for a long time. Ralf Baron is now Professor of Neurology, and although he had a year in San Francisco last year he’s also planning to come back for two to three months to do a small project with us. If they can engineer to get away physically, they can get immersed enough to do something very useful.

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Becoming internationalised

We have said that people coming to us is useful. How have your travels overseas helped? You touched briefly on Bernard Ginsburg.

That was a sabbatical year, the first time I’d ever been away as a scientist. We went to Edinburgh and I worked in Bernard’s lab. Bob Martin was there, and to have two great classical neuromuscular junction neurophysiologists in the lab at the same time was for me marvellous, a very exciting experience. Bernard was the intellectual and didn’t actually get his hands on, but Bob Martin was very much the hands-on person. He made a wonderful little voltage clamp out of a cigar box, with all the wires held together with little bits of matchstick. It was terrible, because the circuit used to oscillate all the time when a bit of match had moved. Eventually I went away and bought all these BNC plugs and rewired the whole thing, and it was wonderful – we never lost any experiments after that.

I would never have been able to build the cigar box clamp; he was the one with the skills in electronics that allowed him to do that. But in a practical sense I’m quite good at getting things to work professionally, and we got some very nice results out of that time of nearly a year. I enjoyed that very much. That was really my first 'post-doc', even before the Baker – the first time I had a period doing nothing but research. It was in somebody else’s lab and I had the great experience of having two very great scientists to interact with, and it was good fun.

Was that before or after Wilfrid Jänig's time?

That was where I met Wilfrid. He was passing through Edinburgh, I think to visit Alan Brown, who was the great spinal cord person at the Royal (Dick) School of Veterinary Studies, and to give a lecture. I went to his seminar, and knowing his work and his interest in sympathetic efferents I talked to him afterwards, and the next day he came over to the lab and we talked for seven hours, I think, continuously.

At that time he understood English but spoke it in very broken German. It was very noticeable to me over the next five years, as we communicated more and more, that his English advanced a long way. The manuscripts he used to write at that time were hysterically unreadable until he started sending them to me to translate from Ginglish into English. We still write three or four times a week to each other.

Wilfrid probably had the biggest influence on me over the longest time. He kept up the physiology side, whereas I’d been rather cellular for a long time when I was working with you and through the Monash systems. Although we knew it had to be important physiologically, he actually forced me much more to work in that direction. And he made sure I got invited to all sorts of meetings. I met people and became known, and therefore now get invited more – through him, not through anybody else. He more than anybody else internationalised me: previously, nobody ever knew who I was. I could never go to meetings because my lectures at Monash were always in the middle of the northern summer. Do you remember that wonderful meeting in Japan that you and Christopher (Bell), Graham Campbell and all went off to?

That was a tremendous meeting.

I was supposed to go as well – my first such invitation – but I couldn’t because of my lectures. I was very disappointed. When in 1979 I had the opportunity at last to meet all these people, Wilfrid said to me, ‘Oh yes, we didn’t invite you to that symposium last year because no-one had met you.’ I said, ‘Well, how could anybody meet me? I was on the other side of the world.’ This extraordinary European view was firmly embedded, that you couldn’t say hello to somebody or write them a letter because you hadn’t been introduced.

That’s when I realised how important it is to send people around the world just to say hello, because people know you exist but unless they have met you they won’t communicate with you. Mind you, I haven’t found it a restriction: I write to people I have never met about their work, and they always respond very warmly. But I think we have always done that from Australia because we lacked the opportunity to go.

I had a European childhood, and I still would be reluctant to write to someone I hadn’t spoken to. I realise it’s idiocy, but it is still a part of me. But I am interested to notice, as I get older, that I’m the person who is always approached for speakers to talk at the smooth muscle meetings. I think it is very important for you and for me that we retain those personal links so that we can ensure our young scientists get international exposure.

That’s right, and to be able to send them to the right people overseas.

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Communication and internationalisation

You say you are approached about smooth muscle, but I find it really sad that nobody who works in the central nervous system pays any attention to the work we do in the autonomic nervous system. I think the work I’ve done in the autonomic nervous system is better and more important than a lot of the work I have done in the areas where people think of me. A lot of international people think I work in pain. I have never worked in pain but I have done a lot of work that is applicable to neurophysiology in general. But people won't read it because it is 'autonomic'.

In fact, some of the experiments we did together were ground-breaking, such as the localisation of calcium channels on dendrites, which is now a common aspect of all CNS synapses, and changes in synaptic efficacy during development, which is a well-known phenomenon in the central nervous system.

But how many times do they quote you?

It doesn’t matter – we know we did it first! And the good ones in the CNS know we did it first. But our system is easier to analyse than the central nervous system, whose complexity makes it very difficult to analyse at a cellular level, and I do think sometimes the people in the central nervous system are losing sight of the big question, looking for micro-domains when the big questions are still about how the telephone directory is connected.

That’s largely a methodology problem, isn’t it? Everybody’s got a certain set of skills now which can be learnt – patch clamping you can go and learn to do, and pathway tracing, noise analysis and various things like that – and can just be applied to the system you’re working on. It is very much a micro approach. In the central nervous system, particularly. One synapse – one connection between one neuron and another – is not a very important connection really. Not many people are working on networks and how the networks integrate.

Actually, I find the work of the Japanese the most interesting. A lot of them are doing very impressive work on the central nervous system’s organisation – how the cortex responds to inputs and so on during behaviour. They’re very innovative with techniques to record local blood-flow changes in regions of the brain associated with particular functions. In particular, to record flow and to record electrically from nerve cells at the same time is fantastic. You go to Japan a lot, don’t you?

I go to Japan once or twice a year if I can. I find tremendous inspiration from there, but I find the Japanese an enigma: they will work very hard, and on a very complex problem, but they often don’t seem to worry about telling the world. I don’t know whether there’s a language problem, but many of them present their data only in Japanese meetings. I have said to them, ‘You’ve got to start giving the presentations in English, you’ve got to put the posters up in English, have English slides. You’ve got magnificent scientists but it’s absolutely no use being a big fish in a small pond,’ and the answer is, ‘Japan is what matters.’ I have had numerous arguments with the international secretary of the Japanese Physiological Society.

That’s really interesting, because the Japanese I work with are all acutely conscious of the need to communicate in English. I think the main reason they ask me there is to talk to them in English and make them talk in English, and correct their papers for them. (I’ve done a lot of that as an exercise both for the Germans and for the Japanese in internationalising their science.) But the general attitude might be a bit different. I haven’t been to many different places in Japan and I’ve never been to one of those Japanese meetings, although I know they conduct them in Japanese. That’s natural, though. The German physiological meeting is held in German, and why shouldn’t it be? I don’t see any harm in that. They just need to have some scheme in Japan – because the language problem is much worse for them – to have more regular interaction, to improve the English of the young ones coming through and give them more confidence and experience. Some of the students are fantastic.

My recommendation to them is to try and organise themselves to leave the country for, say, three months every second year as the Thais do, to go to live in an English-speaking lab to keep up their English. Most of them have had their year or two as post-docs in an English-speaking environment, but then they tend to slip back a bit.

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Inspiration, persistence and humour

But tell me: what about somebody like Tomita? Is he still active? He spent all that time at Oxford and in Melbourne, and he has no problem with the English language.

Tadao Tomita is magnificent. He was my inspiration and the only reason I did any work in smooth muscle, because he wrote the first paper analysing cable properties in smooth muscle. I was working with Bernard in an area of darkness and greyness, and suddenly there was light and inspiration. Shortly before he retired I spent some time with him which reinforced my idea of what a good research scientist is. Even though he had got cataracts and could barely see, every day he would do his own experiment. And every day he would look and say, ‘This response is odd,’ but he would get it over and over again so he knew it was correct and it had to be analysed.

It’s as if that lucky trip has set me up for my next few years research, I think, recording from interstitial cells, which I first started with Tadao. I went into the laboratory and he said, ‘There are two types of cells in this preparation.’ When I asked, ‘Why have you just discovered them? You’ve been working on it for 20 years,’ he said, ‘Yes, but there are two and I only get one, once a month, in 30 impalements.’

So you had to find out how to get them more often in order to keep the input up?

Exactly. So I used my methods of recording to gather multiple recording from a preparation on a daily basis. That was a tremendous help.

Is it because you managed to combine your – shh, dirty word – anatomy to identify where these cells were, that you could get a greater success rate with interstitial cells?

You know as well as I do that if you can see what you’re doing with a living system you can record from it. If you simply pin the preparations and look at them with a very good microscope, you can isolate different cell types and pick up small visual clues – although recently I’ve become more of an anatomist and now can see them alive with a c-kit stain.

That’s good. And then you can go straight for it.

That’s exactly right. I do go back and see Tomita, but he’s retired and is now in charge of the Red Cross in the Kansai area. He says that means he merely rubber-stamps things all the time, but I’m quite sure that’s not right. Tomita was definitely a big influence on me. He was a very analytical person, very clever, and he’d got a remarkably good sense of humour. Your sense of humour has always been magnificent too. Has it helped you out?

It makes me survive intact on bad days.

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The need for thinking-space

Although Tomita’s retired, you still go back to Japan. Are the other people there as inspirational, or are you doing this more as a kind of legacy of what he gave you?

They’re not as inspirational, because they didn’t have the good start that Tomita had. He worked with Edith Bülbring, who gave those Japanese incredible power within the system. She said, ‘These people are really very great.’ She taught them in the Oxford system, where they had time to sit down and think. Many of the present-day Japanese I visit have the same intellectual skills but they have spent a lot of time in Japan where they have simply had to work very, very hard. This is a problem still that the Japanese face.

I encourage them to come and work in my lab, and I insist that they work from 9 till 5 and then go home and think about the work in the evening. Then they will talk to me and to other people about the work. I’m talking about quite senior professors, and I think that gradually they are realising, perhaps like the whole of the Japanese nation, that the work ethic is good but it needs space for thinking. That’s one aspect of Australia that is magnificent. People talk about this as being an easy-going country, but Australians work very hard over short periods. They play hard, but they have plenty of time to think, and we should never get that out of our system.

That’s absolutely right. Encouraging the young people to think goes back to what you were saying: they think it’s a career and not an interest. They only think about it as a job that they do 9 to 5, perhaps with, ‘Oh, there’s a few papers I should be reading this evening,’ but not necessarily considering it as an interest they should ponder on in the evenings, thinking about what the data were like.

The sociable aspect of Australia is very good. We touched on it with Mollie and the sherry-drinking sessions. We may have behaved in a totally disgusting way, but it was a time to sit down and argue. If one’s science is a hobby, which it should be, then one does find it interesting, does talk about it. I believe a lot of young people are tainted by school and still think, ‘Well, we shouldn’t talk about that now. It’s like doing our exams.’ Our educational system has become too driven by examinations.

That’s true. People don’t realise during their doctoral studies that they’re actually developing as an individual person. They think they’re just ticking off the next step in the career path.

Well, were you a very successful undergraduate?

I was in the beginning, because my parents were very good at encouraging me to study. (I went home, quite a long way from university, every day.) I was also very lucky in that I could swot for exams at the last minute and pass them pretty easily. University was relatively easy but I did work hard in third term. You had to jam everything in for that one exam, and I suppose I was quite lucky that I could get it out again – but two months later it was all gone. In fact, I tell my students now that there’s no point in their swotting up for exams. When I went to start teaching after five years, I had to relearn things that I had passed exams with high marks in. I would read the book and think, ‘This is amazing. Isn’t it interesting, it works like that!’ It had completely disappeared from my brain that I’d ever known the details.

It is fascinating to me how your mind can dispose of things that you really understand quite well and that theoretically should be a building block for something that you carry with you. One reason why I’m a great believer in mature-age PhD students is that even if they’re not particularly bright, by that time they have got over that hump of shoving information in, letting it vomit out again and shoving more in. They’ve worked out better how to collect information and keep the bits that are necessary for a job or something that they’ve had to develop skills for, so when they come into the laboratory they want to learn the skills of the lab and of the science they’re working on. And they retain it. So even though they may not make great intellectual leaps, it is much easier to teach them and they seem to develop very easily. We usually get people for PhDs at an age of 21 or 22 or 26, when they’re only just learning that. The beginning of a PhD is usually very difficult, I find, not only in coming out of the university system of exams into lab work but also in maturing personally. Somebody who has had a job for five years is nearly always much more receptive to science.

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Can women expect to succeed in science?

While you’ve been working in science, have many problems been created because you are a woman? When I was first elected to the Academy, there were only three women. It was outrageous. It’s definitely still a male-dominated field, yet among the young people I am working with, it seems the women are the next generation.

It’s interesting that for me a lot of the problems have come from being a woman of my generation. My expectations that I would get married and have children didn’t mean I wouldn’t work, but they meant a career such as I have ended up having would never be the way to fill in my time. I think there is a problem for most women who have children to be able to do as much as I have, because there isn’t time. You have to be fantastically well organised and have lots of support systems, either financially or personally, to fit in as much science and teach and do the other things that I’ve had to do in my life.

It’s not that one is more important than the other, but I think it explains a lot why women are under-represented in the Academy. Most of the men who get into the Academy are tending towards 50 years of age. Things were not very well organised for women of that vintage, so when we were young we didn’t achieve as much as most of the men. We had to be very unusual people – perhaps people from academic backgrounds who had a lot of support in that way, or simply very dedicated. I hold in enormous awe the women in the Academy that I’ve met. They’re all far better than I am, and intellectually amazing – as are, in fact, nearly all the men. It is a group that I feel very honoured to be amongst, because they really are an amazing collection of people. You always meet interesting people who have done interesting things.

I was very lucky. People were very supportive. That was a period when women didn’t go in the direction of careers as much, but nothing would have stopped me if I had wanted a career in medicine. It wasn’t that any outside influences limited me; I opted out. There were plenty of women in the medical course, and I don’t remember anything as impeding me in getting jobs or whatever.

I think the hardest time was when I went to Queensland as head of department. That was the first time I struck such a situation in my actual job, but it probably happens to men, too: when you become a head of department, an authority figure, for the first time, you suddenly stand apart from the people you work with. I’ve never felt like that about them – I’ve always just felt they were somebody I happen to work with. But they regard you in a different way, and I was very conscious of them regarding me in a different way particularly because I was a woman: ‘Don’t pay any attention to her, she’s a silly old bag,’ or, ‘The old woman says this.’ I got the feeling from odd people, not everybody, when I went to that position, that you could be more dismissive of a woman in an authority position than you could of a man. That was a bit difficult to take. But I can’t say that being a woman impeded me in achieving.

I don’t agree with you at all. I still think there’s an immense prejudice against women succeeding. Partly it is because they actually bear the child. But then there is a definite feeling that women aren’t strong enough to lead. That is obviously totally and utterly wrong, but there is a strong feeling in the community which appears in business and in academia. I don’t know how we make steps forward to alter that.

In biological sciences and in medicine there have been a lot of women. And in the Academy we have powerful women leaders in biological sciences. In the other areas of science it’s much harder: in chemistry and physics there are very few women, and Dorothy Hill was unusual as a geologist.

I’ve often voiced the view – and been laughed out of court – that it would be a perfectly reasonable approach that a woman who takes time off and has a child has five papers added to her CV. Our society needs children, we depend upon children, biologically the women have to carry the child. And that’s all there is. Yet there seems to me to be no move in that direction whatsoever.

That’s true, but my feeling, looking at the younger women that I know now – many of them very successful – is that a lot of support systems are in place now that people can use, provided they can earn, to help them have the time in science much more easily. It’s not only having a child, it’s actually the time that you have to spend with the child afterwards that interferes with what might be a free-range thinking exercise in science. And I can see that there are a lot of people able now to juggle with this arrangement.

To get back to what you were saying, there’s no doubt that a lot of the brightest young ones are women, and it is interesting that even some of the bright ones quite often don’t see themselves as going necessarily on to the top. They don’t feel that’s particularly important. I must say I never thought it was particularly important. I only ended up in those jobs because they were there. It wasn’t because I had any ambition to become a head of department or anything like that; I just did it because it was the next thing that was offered.

The same thing applies to most men. But there is a natural tendency to look for a man to lead a department.

Probably there is. You have had a head of department who is female, haven’t you?

We have indeed. It is a major breakthrough for Melbourne. This is the first woman Professor of Zoology, and it seems to work well. I’m very happy about it, but probably my attitude is somewhat coloured because my wife, Christine, was quite a leader in industry and certainly found glass ceilings along the way.

She broke through them, though.

Yes, largely. She could only do that because I was an academic. Had I been a businessman, she would have failed. An academic can work erratic hours and can provide more at-home support, which gives her more freedom.

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Contributions to be proud of

I wanted to ask you two scientific questions. First, looking back on what you’ve achieved, which particular contribution do you feel proudest of? And that is not necessarily what other people think of.

The contributions I feel proudest of, without doubt, are being involved in work with you, with a number of collaborators, that showed that the autonomic nervous system was organised – structured. The little piece that I was involved with was how the nerves communicated with the target muscles. When I started I was told that the autonomic nervous system was simply a hormonal system: it went up and down with stress. What has become increasingly apparent is that the autonomic nervous system is organised, and perhaps even better than the somatic nervous system. Everything is tightly controlled. There is very little room for mistake. The nerves communicate with specific muscles, telling them what to do. One of the enjoyments of working with you has been in parallel: you have done the same with the central nervous system processing pathways. That makes me feel very proud, and I’m sure you feel proud of your part in the central nervous system.

Yes, but I was thinking slightly differently, about trying to take cellular things back into the body. The two sets of experiments that I think back on – although they weren’t particularly nice at the time – were the ones that we did together way back in the ’70s, getting beautiful recordings from the spinal cord which other people largely didn’t believe. There weren’t very many, but they showed the answer to a lot of questions. Now all the people working in that system are finding out in a very complicated way, using modern techniques in isolated preparations, that what we got in the whole animal was actually right. So I was very proud of that, which was taking cellular physiology back into the animal.

The other experiments – which also hardly anybody has paid any attention to – were those I did in ganglia, where we recorded in anaesthetised animals from intact ganglia and looked at the patterns of integration. I think there’s always a suspicion that we are dissecting out things that no longer are real, but we were really only able to interpret those patterns because of all the experience we had had in isolated preparations. Again we didn’t get very many recordings, but the ones we got revealed all sorts of things which we can now say about how the system is working in the body and how a lot of the things that we find out in isolated preparations do reflect what is happening in the body. Conceptually, what I like most is that I contributed at different levels.

The only thing I haven’t really done properly – and you haven’t either, yet – is to record from smooth muscle, a blood vessel in vivo. We did record some things, but not enough.

I spent three months in Tucson trying to do that, working in a very good circulation laboratory, but they couldn’t keep the preparations alive, which was absolutely amazing to me. It certainly is a big problem that needs answering.

Perhaps one of us will manage to do it before we go.

It is still a very interesting aspect. My present work is almost doing that in an organ bath. I’m managing to record from interstitial cells and seeing them communicating with muscle cells. Doing paired recording enables one to look at communication between different cell types, and it really is the future of physiology, especially cellular physiology. Getting to know all the little pieces and putting it back together, together, together is where the future is going to be.

We are quite lucky, really, because the systems we work in have big signals and we can do without these massive computers to handle all the signals that arise.

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‘Eureka!’ moments

Secondly, what exciting scientific moment in an experiment – it doesn’t have to be the most important – flashes through your mind as the one when you did a ‘Eureka!’?

I always forget these things. When they go, they go. But a magnificent moment was working with Narelle Bramich and suddenly discovering that Otto Loewe, who discovered chemical transmission, had found an antagonist that blocked a unique population of adreno receptors. It was the first conclusive pharmacological proof I’d had that sub-synaptic receptors differed from extrajunctional receptors. We had an agent which would block all the other putative transmitters – wouldn’t block the purines but would selectively block the novel sets of adreno receptors onto their nerve terminal.

And most recently it was putting one electrode into an interstitial cell and then another into smooth muscle cells and seeing the communication, seeing one cell driving another, putting current through one electrode, artificially communicating and showing that the lines of communication were fully open. That was my moment.

So they are largely technical things?

Yes. Science is dominated by technical findings. You don’t have to be clever, you just have to be able to measure well. If you can design the experiment and make a good measurement, then you get an insight. What was your moment of joy, then?

I’ve had a couple. One that I will always remember was when I looked down the microscope and saw sympathetic nerve terminals in dorsal-root ganglia. I didn’t believe it would be possible, so it was very exciting to see another one of Wilfrid’s predictions come true. He had said, ‘Somewhere we’ve got to have a situation where after nerve injury the sympathetic nerves somehow become associated with sensory nerves. Let’s have a look and see where this happens,’ and I had said, ‘Oh well, okay, I’ll do the dissection, I’ll do the histology for you, etc. etc.’ But then it was just amazing – and amazing that it worked at all, because you have to look at a particular time, and however it was that we guessed the right time, but the very first one I did provided some of the best pictures. It was so exciting. I thought it must be wrong, but when you do it again and again it’s always the same. I remember calling people in and saying, ‘Come and have a look at these,’ until everyone in the lab had actually seen them and been convinced that it was real.

A lot of people in other parts of the world didn’t think it was real, but they certainly do now, because other people have confirmed it. Ed Perl, with his particularly acerbic nature, said to me at a meeting in Kyoto, ‘I would never have believed it if your name hadn’t been on it.’ I was very flattered by that.

The other thing I really enjoyed, even though this is absolutely trivial and scientifically not important, was the experiments that James Brock and I did with ciguatoxin. That was a revelation too, to see what a nerve toxin can do to nerve terminals. When you actually see with the microelectrode how the nerves are releasing transmitter and changing the responses of blood vessels or ganglia, it just explains so obviously all of the clinical symptoms which had been a great mystery before. You know, when the symptoms of fish poisoning are diarrhoea, nobody gets very excited about it because they presume it’s due to some inflammatory process irritating the mucosa and producing the sorts of bacterial endotoxins that cause increases in gut contractions. But in practice in this case the toxin goes zap, straight through at incredibly low concentrations – we were down to 10 picomole. It zaps straight for the nerve terminal, spews out all this transmitter, and you can sit and watch it for hours – great fun, absolutely wonderful. Not a particularly important scientific finding, but such a nice way to see how something functions in the body so simply on just one or two systems, and having quite profound effects on the whole behaviour of a person. So a lot of science is quite fun.

Those experiments are the excuse I claim for not bothering to measure from a blood vessel in vivo. You did it, more or less, in the organ bath, inducing natural firing patterns in the nerve. They give completely different responses from the artificial ones we generate with stimulators, et cetera, but you did generate a natural firing pattern with your small doses of toxin.

Yes. If only that toxin was more available, we could have done a whole lot more. It’s too difficult to get quantities of it – and it’s a real nuisance, once you put it in your system. You’ve got to throw out everything from your organ bath and start all over again, because those molecules, so few of them, lurk around for a very long time.

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The making of new medicines

There seems to be a trend – it goes in waves – to look for toxins like this to make new medicines. Do you think it is a way forward in science?

I suppose it is, because if we know what the channels are and the receptors that are activated, if they are specific, then it is better than combinatorial chemistry to find a natural compound from whose chemistry you can actually identify the right part which activates the receptor. The problem with even the combinatorial chemistry and the way that drugs are developed now, including the genetic techniques, is they all seem to be even more blockbuster than they used to be. The idea that knocking out a particular receptor or activating a particular receptor for one particular symptom is not going to affect all the rest of the body is to me mind-blowing. It is amazing to me that even Viagra works without causing people to faint much more often than it does. It is a quite dangerous compound to release, yet it seems to be pretty effective with a lot of people without having problems.

A lot of that is fortuitous, in that the way the drug companies test things is not logical but rather random. They find a compound that they think might work in a system and whack it through behavioural tests in animals, and if the animals don’t fall over then it’s probably okay to try it in people. It all seems a bit haphazard. It gets things onto the market quicker, but it doesn’t seem very safe. I would like to know a little bit more about whether the receptors are different in different tissues, so that you can target the one which is only in the gut and not the one which is also in the heart or the brain, say, and get all these difficult side effects. One of the major problems of clinical medicine is drug interactions and side effects of particular compounds – which differ in different people. That is inevitable, I think.

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Vital implications of the autonomic nervous system

Which of your work do you think has been clinically most useful? I’ve enjoyed finding things about the body, but somewhere along the line we have to use the information to make people’s lives better. For example, your work on pain is going to be of profound clinical value in the future.

I’m not sure that my work on pain will be of profound value. The big amount of work that has been done in the last five years on nerve injury induced pain is very important, because what was happening used to be very mystical. People weren’t doing the right kinds of experiments, and now they are. I must say it’s nice to be still doing experiments in that area, where you can do lots of new things still. Because I come from the autonomic nervous system, I tend to look at it a completely different way from the people who come to it from sensory neurophysiology – that is most of those who work in the pain field. They are a particular type of person. I feel rather out of it.

I think the people I have helped have been the doctors or even the patients that I could talk to about their individual cases. I do get phone calls from patients with pain. I can’t care for them, but I can often give them a pretty plausible explanation of what has happened, which often is as much as they need. Since the autonomic nervous system is involved with so many bits of the body, if there is a symptom which seems unrelated to where they think the disease is, and either the medical people or the patients are confused, it can often help when you say, ‘Look, I’m sorry, there’s a reflex there. It’s an ordinary standard reflex. We can demonstrate it in any anaesthetised animal. This wiring is probably in your body anyway. We can’t just take it away. It’s going to do that response.’ That’s why we want to do work in spinal patients who have disconnected autonomic nervous systems with funny reflexes. A lot of these funny reflexes are really there, and it’s just because you have removed the control of the wiring diagram that it goes haywire in a lot of pathological states.

To drift off at this point: I’ve always been obsessed with being anti-teleological. I think that in the autonomic nervous system particularly there is a very strong push from the broader medical scientists, medical practitioners, to think of the autonomic nervous system or even the whole of the body as being perfectly evolved to control the body, otherwise why would we be here – everything must have come through evolution. But I have an absolute conviction that we have a long, long way to go before our bodies are perfectly evolved, and it is so arrogant to think that everything we are now is there for a purpose. I’m sure you would know that too, from your own work, and any pharmacologist must recognise that if you know where a receptor is, you can introduce a chemical into the body that activates that receptor, even though the receptor might never have been activated by that chemical or, probably, any other that we know of in the body.

That’s right, but I have a different view of evolution, that it is not to maximise design but to minimise danger. If parts of the body, receptors, are left, then providing they’re not activated and in the way, why bother to remove them? As you know, when you denervate a muscle it very rapidly changes and responds to a whole bevy of different pharmacological agents. As soon as the innervation comes in, if those receptor sites remain it will be disaster, so the body suppresses them. But if they weren’t dangerous, I am quite sure the body would leave them functioning.

Yes – but only if it doesn’t actually produce a problem which prevents you from reproducing. Evolutionarily, many things that we now see in the inefficiencies of our body are actually things which occur long after reproduction age, and they are not going to stop us.

Thank you, Elspeth. It has been nice to catch up with you again. I have missed our times together.

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