Professor Geoffrey Burnstock, neurobiologist

Professor Geoffrey BurnstockNeurobiologist

Geoffrey Burnstock was born in London, England, in 1929. He finished his secondary education at Greenford County Grammar School in 1946 and then spent 1947 doing National Service with the Air Force. Burnstock then enrolled in science courses at the Kingston Technical Institute and worked weekends in the graveyard. In 1950, he was accepted into King’s College, University of London. Here he completed a BSc degree (1953), majoring in mathematics and physics. He then went on to complete a PhD (1957) at King’s College and University College London, University of London. Burnstock’s PhD research was in the field of zoology, where he examined gut motility in fish. In 1956, he was invited to join the Physiology Department at the National Institute for Medical Research in Mill Hill, London (1956-57). Whilst there, he developed the ‘sucrose gap technique’ for recording from smooth muscle. This led to a position in the Department of Pharmacology at Oxford University (1957-59). After spending a year at the University of Illinois on a Rockefeller Travelling Fellowship (1959), Burnstock took the leap to Australia.

Burnstock took up a senior lecturer position at the University of Melbourne in the Department of Zoology (1959). He was then promoted to reader (1962) and finally Professor and Chairman of Department (1964-75). During his time in Melbourne, Burnstock made radical discoveries about the role of ATP (adenosine triphosphate) in neurotransmission. He returned to England and University College London in 1975 to take up a post as head of the Department of Anatomy and Developmental Biology. He held this position until he stepped down as Head of Department in 1997, whereupon he was made Emeritus Professor. In the same period, Burnstock served as President of the International Society for Autonomic Neuroscience (1995-2000) and Director (1997-2004) and then President (2004-today) of the Autonomic Neuroscience Institute (now Centre) at the Royal Free and University College Medical School. Professor Burnstock continues his research in the field of purinergic signalling, with links to both basic and applied research. He has supervised more than 100 PhD and MD students.

Burnstock has received many awards and honours throughout his career for his contributions to autonomic neurobiology, physiology and gastroenterology including a Silver Medal from the Royal Society of Victoria (1970), and a Gold Medal from the Royal Society (2000). His research has led to the publication of more than 1200 original papers, which have been cited over 80,000 times.


Interviewed by Professor Robyn Williams in July 2008.

Contents


Smooth Muscle Man

I am Robyn Williams. My guest today is Professor Geoffrey Burnstock, who is a Fellow of the Australian Academy of Science and a Fellow of the Royal Society of London.

I have also known Geoffrey Burnstock as The Smooth Muscle Man – that is the name of a film that we made back in the mid­seventies. It was fascinating. The ‘smooth muscle man’ was someone who did so many different things, he played the guitar, he was a sculptor and he did research. I remember filming in a graveyard. Do you remember that?

Yes. I used to walk in the graveyard. It seemed to be a good place to sort out my thoughts. It was peaceful and nice.

Absolutely. You also liked to be reflective and quiet.

Yes, I think that is true. Another hobby I have is carving wood and I find that very restful. I also do jigsaw puzzles the last thing at night and then I sleep like a baby.

Do you still sometimes play the guitar?

No. I was never very good. I wanted to be a flamenco guitar player. I went to Spain and learned there. Then they said, ‘Go down and play and, if they like it, they will dance’, and nobody danced. Then I knew I was hopeless. But, philosophically, that was important, everybody has strengths and weaknesses, and I realised that you have to go for your strengths and not flog your weaknesses. So I packed up. I sang songs and wooed a few women, but that is all I did on the guitar.

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Working-class roots

How well did you know right from the beginning that science was going to be so important to you?

I have to say that I had no idea. After reading romantic novels, I wanted to do medicine, but I couldn’t get into med school. I had the wrong background for that.

What did science mean to you as a little boy?

The only memory I have is absurd. I can remember when I was about six lying down with my eyes half closed and seeing globules in the air, probably dust. I thought I had discovered oxygen, and that excited me at the time.

You had heard of oxygen?

Yes.

Tell us about your family.

Well, I had a father, who had run away to sea when he was 14 and was wounded in the battle of the Somme – he had had a lung blown out. So he was completely uneducated, but an intelligent man and a family man. I had a modest mother and a glamorous sister. We had a happy life but a very frugal one. We remember how we had chicken only once a year, at Christmas-time. This was during the war as well.

Was it a big family in the East End?

I had lots of uncles and aunties – something like 12 – one or two didn’t survive. But I wasn’t brought up in the East End. I was brought up initially in Portobello Road and then in Ealing.

More in the Notting Hill area?

Just for a while, when I was young. Then we went to Ealing and, during the war, I was at Greenford County Grammar School.

Was it any good?

I don’t think it was a great school, but it was okay.

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Theology, philosophy and ‘sliding doors’

Most scientists who have been interviewed say that, at some stage, there was a special mentor or a teacher, who made all the difference. Was that the case with you as well?

No. I have never had a mentor or a special teacher at school. The only teacher that liked me was the religious teacher. I became atheist at the age of 13 and I made the religious sessions more exciting for people by challenging them.

So there were no mentors, but presumably your school course involved science as a matter of routine.

Yes. But then, not being able to get into medical school, I had to do national service. When I came out, I went to Kingston tech and did a couple of additional science subjects. But still I couldn’t get into medical school. The only place that would take me was Kings College, London – to do a course (AKC) in theology. I was allowed to do a degree in pure maths and physics simultaneously, which I was good at.

An atheist did theology?

Yes, exactly. It was pretty absurd, but at least it gave me a start. It wasn’t easy. The class system was pretty powerful at that time.

So you wanted to get into tertiary education at all costs.

Of course. It wasn’t easy. My father had died at that stage and I had to look after my mother. I worked every weekend in a graveyard – weeding, digging and so forth, to keep going. I had no contacts with influence. I missed out by one day in getting an ex-army grant to go to the university. Whereas, years later in Melbourne, I did have contacts. If I had been in Melbourne, somebody would have helped me – but at the time it was not possible.

By one day! You were late or they were late?

I don’t know what it was, in looking back. But I didn’t have any support, so I had to work for a living and make some money.

This is ‘sliding door’ stuff, isn’t it? Where an opportunity could come or not come within a terribly short time and could make a whole difference to the course of your life.

I was never unhappy about it. I don’t think I even realised that there were challenges.

Some people say that you can tell only at the end of someone’s life whether they have had a happy time. But you strike me as being happy constantly. Is that true?

My philosophy is ‘if you can’t do it one way, you find another’.

Exactly. So you do theology or maths and later put them together.

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Fishy PhD

Was that first degree okay?

Yes. Then I switched to biology and I was on my way.

You managed to do zoology at London?

Yes. At London. But the PhD was quite extraordinary. These days I advise young people that finding the right supervisor is terribly important. You should find out whether they are active in science, whether they are getting grants and whether they are publishing papers. But when I started my PhD I didn’t know anything about this. And although the head of department wanted me to do a PhD with him, I went with the one person in the department who was nicest to me. She took me out to dinner. But she didn’t have a research record at all. On the first day I went there, I said, ‘I’m passionate to start doing research. Just tell me what to do’. She said, ‘I guess you’d better go away for six months and find the gaps in the literature’. That was brutal and idiotic: how can you find the gaps unless you read everything? So, in effect, I tossed a coin. I said, ‘shall I work on the brain or the gut? The gut. Shall I work on the biochemistry of the gut or shall I work on motility? Motility’. Then I started reading.

Then I did some weird things, because I had no proper supervision. I looked at the literature about motility and discovered that all the studies were using isolated bits of intestine put in an organ bath. I thought, ‘really, one wants to see motility in vivo’, and I thought, ‘fish are interesting because the goldfish eats continuously, whereas the pike eats only once every two months. So why don’t I compare the in vivo motility in these two fish?’

By ‘motility’ do you mean the movement of the food in the gut?

Yes. My first paper was in Nature in 1957 and it was of a fish with a condom on it. It had a condom because you had to cut a gap in the fish and then have something transparent in order to see the gut. It was an absurd paper. It wouldn’t get into Nature today.

Where did you get the condom?

That was absurd too. I wrote to Durex, and they sent me a mixture of condoms of different sizes with the ends cut off. In later years when I went to Oxford and then to America on a fellowship, they kept sending these things and the secretaries would open them up and think, ‘what on earth is this guy doing with huge condoms with the ends cut off?’ It was very embarrassing. Anyway, that’s another story’.

And you answered them and then they didn’t believe you.

Actually the condom didn’t work. It had to be a piece of plastic, because eventually a condom would shoot off the fish. I had to screw a piece of transparent plastic into the dorsal musculature of the fish.

Professor in the Royal Society says, ‘condoms don’t work’. Just imagine how far that would go.

I probably shouldn’t mention this, but I have another condom story which is funny. After my national service I was a medical orderly in Hamburg, Germany and one of my jobs was to dish out condoms. When they let me out to go to university early, I thought I might need some of these and I put several hundred in a box. When I got to Customs, the Customs man started taking these hundreds of condoms out of the box. People were watching and it was deadly silent and I was bright red – an 18-year-old boy. Then he put them all back and, without a word, just saluted me. I went on my way and everybody in the room cheered. I will never forget that. That was absurd but very interesting.

Anyway, you published in the journal Nature. That was the kick­off. Then in the end you obviously got your PhD.

The original female supervisor dropped out and JZ Young in anatomy at UCL was interested in fish physiology. He was a great man who worked with squid axons and so on. So I asked him if he would be my supervisor and he, in fact, finished me off for my PhD.

JZ Young is a legend and his textbooks were used for generations. In fact, I used two of them.

He was my final supervisor in the last six months or so, and I got my PhD.

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Paving the way to Oxford with the sucrose gap technique

At the end of my PhD I wanted to learn physiology. I wanted to do this because I was the world expert on defecation in the brown trout – not exactly a highly competitive area. So I needed to learn more sophisticated techniques than organ bath pharmacology.

There weren’t world conferences on the defecation of the brown trout.

No, there were not. Feldberg, one of the founders of pharmacology and a great man, was at the National Institute for Medical Research. He didn’t mind oddballs like me. So I went to Mill Hill and Feldberg welcomed me into his physiology department. There I developed a technique called the ‘sucrose gap technique’ for recording correlated electrical and mechanical changes in smooth muscle. It was a wonderful technique that I developed with Ralph Straub, a guy from Switzerland.

The leading lab in smooth muscle at that time was Edith Bülbring’s in Oxford pharmacology. When she saw the result, she invited me to go to Oxford. They had been using microelectrodes in spontaneously active muscle and they got about a three per cent success rate during the year – and I can’t stand that level of failure. This new technique we developed appealed to her. So I went to Oxford pharmacology and developed the method there. That was a big break.

But smooth muscle itself: what is the difference between that and the kind of muscle that you have in your leg?

The muscles that you use for walking, moving and so forth are striated muscles. Smooth muscles are the muscles which control the movement of the gut, the uterus and the bladder. They don’t have striated biofilaments in them and they have a different physiology.

They are under remote control.

Right. Mostly they are automatically controlled through the

autonomic nervous system.

So there you are, in the great elite confines of Oxford, having kind of got into science by the skin of your teeth and escaping a working class family. Did you settle in all right?

Yes. I had just got married. Nomi and I lived in Park Town and it was delightful. I would walk across the park to work and I had good colleagues. It was a good department. I didn’t want to belong to the colleges though. I don’t like elitist systems very much.

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Great mates in Australia

Then I got a Rockefeller Fellowship to go to America for a year. After that I had to decide whether to come back to Oxford or to stay in America. But the people I liked in Oxford were all Australians – people like Mollie Holman and Mike Rand.

They were great mates of mine. I liked them so much that I thought I would try to get a job in Australia, and that’s when I moved there in 1959. I had a senior lectureship in zoology at Melbourne University.

And were you right? Was it a good move?

It was a great move. In general, in England, if you want to do something new, the first response is, ‘it can’t be done. Don’t you know there’s a war on?’ Whereas, in Australia, the first thing they say is, ‘give it a go, mate’. They don’t necessarily help you, but somehow I felt at home immediately. I got the breaks, and it wasn’t long before I got the chair of zoology there.

It’s a great department, isn’t it?

It was not a great department in a way. It’s a good department now. It was an exciting time. I brought in lots of amazing PhD students who are now leading figures in Australia – Max Bennett, Julie Chamley and John Furness – these are all outstanding scientists.

But the weird thing is that you weren’t really a zoologist at all.

I was interested in mechanisms but not really in animals much. I liked marine biology because that was beautiful.

How did you get on in a department whose mere existence was dedicated to animals?

I supported everybody who was good and filled in the gaps that I couldn’t cover. I gave lectures in cell biology but not in other things in neuroscience. But that has always been the case with me. After all, then I went to anatomy and developmental biology in London and I hardly knew the difference between an arm and a leg. I have also been offered chairs in pharmacology. I have been No. 1 in the world for 12 years for citations in pharmacology. So what am I? Mostly I am interested in physiology and pathophysiology these days. You can’t label scientists so easily these days.

Not at all.

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Purinergic story

Was it in Melbourne that the purinergic story took off?

Indeed. That was terribly exciting. The first conceptual step was in the sixties. At that time there were two established neurotransmitters in the autonomic system – acetylcholine and noradrenaline. We had an innervated smooth muscle preparation and my students, Max Bennett and Graeme Campbell, and I set up the sucrose gap. We stimulated in the presence of atropine and guanethidine. They are drugs that block classical adrenergic and cholinergic transmission. And, to our amazement, we saw hyperpolarisations. What we expected was to stimulate the muscle directly and to get depolarisation and contraction, but we got hyperpolarisation and inhibition. This was debated internationally.

Then I was very lucky. I had a Japanese postdoc and they had just discovered tetrodotoxin from the puffer fish. This is a marvellous tool because it blocks nerve transmission but not the action of smooth muscle. So we put tetrodotoxin on the preparation and this completely blocked the hyperpolarisation of the muscle. So we knew that the hyperpolarisations were inhibitory junction potentials in response to non-adrenergic non-cholinergic neurotransmission. That was a huge conceptual breakthrough. Obviously the next step was: if we had non-adrenergic, non-cholinergic nerves, what was the transmitter?

Exactly. Let’s put this into context. Various parts of the body may have five different functions. Look at the genitals: they do about four things, if you are lucky. Is it the case here? That maybe the neurotransmitter, the purinergic stuff, happens to have more than one function?

Well, we had criteria, which Jack Eccles had named, for proving that something was a neurotransmitter. We tried everything – neuropeptides, excitatory amino acids and monoamines – but none of them worked. Then I read a classical paper that Szent-Györgyi had published in 1929. He was a brilliant man, a Nobel Prize man. He described, for the first time, excitatory effects of extracellular purines – not ATP – on the heart and blood vessels. Up until then, ATP was owned by the biochemists. It was an intracellular energy source and nobody had thought of it as an extracellular signalling molecule as well. But by then we had found non-adrenergic non-cholinergic nerves in the bladder and ATP fitted exactly as this transmitter.

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Controversial ATP signalling

But, with such a ubiquitous molecule involved in energy transfers, could it not just be there anyway rather than having a nervous function?

Well, you are quite right. First of all we published a paper in 1970 suggesting that ATP was the transmitter in the non-adrenergic, non-cholinergic nerves. Then I published a big review in 1972 called Purinergic Signalling. ATP is a purine nucleotide, so I invented the word ‘purinergic’. This was very controversial. For the next 20 years nobody believed in this story at all. The main reason they didn’t believe was exactly what you have implied – people felt it was very unlikely that if ATP was such a ubiquitous molecule, it would also be an extracellular signalling molecule. In fact, it is now quite clear that it is an early molecule in biological evolution. ATP was utilised both as an intracellular energy source and as an extracellular signalling molecule.

In the last year there have been some very exciting papers in which they have cloned and characterised the ATP receptor in amoeba, Schistosoma, and even green algae. And they found it is almost identical to that found in mammals and humans (the P2X ion channel receptor), which is astonishing. That means that it is perhaps the most primitive signalling molecule in the body. And that is why it is so important now and why the field is absolutely exploding in every direction.

So this became known as the ‘third nervous system’.

It was called the third nervous system, but this was misleading.

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One nerve, multiple transmitters

Another thing happened, and it was disturbing at the time. I was on sabbatical leave in California and we discovered that ATP was released not only from these non-adrenergic, non-cholinergic nerves in the gut and bladder but also with sympathetic nerve stimulation. I was deeply shocked and I stayed up all night thinking that I had to reject my hypothesis. But, when the sun rose in the morning, I suddenly thought, ‘could it be that ATP is a co-transmitter with noradrenaline?’ This was another huge conceptual breakthrough.

When I came to England, I published a paper, a commentary, in Neuroscience: ‘Do some nerve cells release more than one transmitter?’ There was Dale’s principle: one nerve contains only one transmitter. Sir Henry Dale didn’t invent it, it was Eccles, but everybody accepted it. To come to England and challenge Dale’s principle – a cocky Aussie – was too much for most people. So I had a bad start again in England.

Before we get into your return to England, there is a fourth nervous system transmitter: nitric oxide. Does that fit into your story?

Yes. You can talk about adrenergic, cholinergic, peptidergic and purinergic transmission. But you can’t talk about adrenergic or cholinergic nerves, when there is more than one transmitter in there. Those original non-adrenergic non-cholinergic nerves in the gut turned out to release not only ATP but also nitric oxide. Some of them even release vasoactive intestinal polypeptide. But the amazing thing is that now we know that there is not a single nerve known in either the periphery or the central nervous system that doesn’t utilise ATP as a co-transmitter. The proportions vary in different physiological and developmental conditions, but all of them have both. It has taken the brain people longer than the peripheral people to realise this, but it is extremely important. Often these transmitters, ATP and glutamate or ATP and GABA, work synergistically. They enhance each other’s effect. This increases the peripheral manipulative possibilities.

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New messenger, new receptor

An inevitable question that everyone asks is ‘applications?’ Knowing what you do about the basic science of transmission, can you apply it? Can it be used?

Well, this is evolution, and different transmitters and combinations of transmitters have been utilised depending on the physiology of survival. This is how evolution works. It is complicated. For example, the hippocampus scientists, who are interested in memory and learning, always stimulate a slice at 100 hertz, so they get glutamate out. But, if they stimulate at five hertz, they get ATP coming out. ATP affects memory because it affects the glutamate. Also, ATP breaks down very quickly with ectoenzymes to adenosine, and adenosine acts as a presynaptic modulator of release of excitatory transmitter. That is why caffeine works through this system – it blocks the adenosine receptor.

I see. So, knowing this, you can apply it. You can change the body in various ways, improving health and so on.

Yes, but this was only the start. If you have a new messenger, you have to have receptors for that messenger. So that was the next challenge. Soon after I got to London, I came up with another major hypothesis. This hypothesis was that there were two families of receptors, one for ATP and one for adenosine. Remember adenosine is the breakdown product. That overcame a lot of the confusion in the field because, if you put ATP on and it breaks down very quickly to adenosine, are you acting on an ATP receptor or an adenosine receptor? So that was the first step.

Then the turning point in people accepting the purinergic hypothesis was in the early nineties. We started cloning and characterising the receptors and the subtypes. I met with Eric Barnard, who was an expert in cloning nicotinic receptors, and tried to persuade him to work with me to clone the receptors for ATP. I couldn’t do it. Eric was a student with Lewis Wolpert and me at Kings College. We did work together and discovered and published in 1993 the first G protein-coupled P2Y receptor. A year later the ion channel P2X receptors were cloned and characterised. Then people started taking it very seriously.

Also, at about that time, the early nineties, it was discovered that there is purinergic synaptic transmission. That is, nerve­nerve transmission and not neuromuscular, which is what we’d focused on earlier. That awakened the neuroscientists for the first time.

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Scientists as artists at UCL

And here you are back in the very department run by JZ Young, the person who looked after you at the end of your PhD. How did you transform this department at UCL?

To any new staff that I employed I said, ‘I think scientists are creative people exactly like artists. I am going to treat you like an artist. You can do anything you like – anything short of anarchy. If you interfere with other people, I’ll stop it immediately. But otherwise I want to let you express your creative spirit in whatever way suits you best. My main job is to keep the bureaucrats off your back. If you need anything, come and see me and I’ll try and get it for you’. I have a terrific sympathy for creative people, and it is the passionate people who are the ones who really succeed in the end. Slowly the department developed very well. By the time I stepped down in 1997, there were 26 full professors and seven Fellows of the Royal Society. It was a five­star research department – very exciting.

The other part of the philosophy is that I felt that a head of department shouldn’t just be an administrator, even if he is a good one. He should set the example by being passionately involved himself. I had a group of 35 people working with me – PhD students and postdocs. That meant that I had to delegate some of the jobs of running a department – major teaching things. I kept a hold on the department, but I felt that I had to set an example in terms of being creative as well. So I was still very active in research, as well as supporting everybody else who wanted to be active. It seemed to be a good environment. People stayed and it was a happy, good department, full of life and passion and excitement. You don’t always see this when you visit labs, and it disappoints me when it’s flat.

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Fabulous family of artists

One of the secrets of your success and happiness is the fact that you had not simply this hinterland of guitar, sculpting and the arts but also a fabulous family. How important has that been to your life?

Yes, a great family. Now, with seven grandchildren, it is an equally exciting and wonderful life. Next to work or equal to work is family. Social things are not so important to me any more.

Back to Nomi.

Yes. She has been wonderfully supportive all my life. But she is very tough. Recently I said to her, ‘you know I am well over 80 now and a lot of professors, when they get over 80, they go a bit funny. Will you let me know if this is the case?’ She said, ‘I’ll let you know, but you won’t believe me,’ which I thought was very clever, actually.

I like it. Nomi is an artist, but what kind of art?

In the last few years she has been a ceramic sculptor doing very interesting things. The oldest daughter is now head of art restoration at the Courtauld. The middle daughter is in Sydney. She went to the Sydney Film School and she writes and directs children’s movies. The third one did postgraduate sculpture at the Slade School of Fine Art at UCL. They are all in the arts, and that’s fine with me. And I carve wood. I love carving wood.

And the wood that you carve isn’t simply an exuberant expression of the positive side of life. You often have grim views as well, don’t you?

Well, I suppose so. I can’t draw, so I have to see a shape in a piece of wood. I look at it, look at the grain and feel it. Nearly always it turned out to be a mother and daughter. That seems to be a fundamental motif that I must see. Many of them are mothers and daughters. Also, there are abstracts which, looking back, look more like women and embracing figures than abstracts. But it is not a profession. It is an amateur thing. If I feel bad and can express it in the wood, I do that.


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Retirement pains

I have to show you the one that I did when they closed my labs when I was 75. I still felt at the height of my creative power and I had to stop.

Why would they do that? Was it because of retirement age?

I don’t know. They were kind to me at UCL. Most people had to be retired at 65. I stayed on as head of department until they found somebody else, which was when I was 67. Then they set me up with a fine institute at the Royal Free, which is part of UCL. But, when I got to 75, they decided that was enough. If they had looked at what I was doing, I think they might have let me go on. People from all over the world still wanted to come to be postdocs or PhD students and I had to say no. They still do it to this day.

But the nice thing is that there are labs all over the world that still find me useful. So, in effect, I have postdocs and PhD students to work with in lots of different labs. I am still pretty active and publishing lots of papers. Also one of the roles of an old man like me is to try to help everybody else coming into the field. So I spend quite a lot of time advising and helping people – drug companies as well.

So you don’t think that being over 80 is the time to retire?

No. I jokingly say, ‘I think I’m coming up to my peak’.

It certainly is your peak, I must say.

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Therapeutic potential

Perhaps I should mention that the first 30 years was mostly basic science, but now there is a huge interest in the pathophysiology of purinergic signalling and the therapeutic potential. Lots of drug companies are going to make money out of it. The first drug to come out of our work is called clopidogrel. It is used against stroke and thrombosis and it made $8.6 billion last year in America alone – very exciting.

We have been working with Roche and other companies and we are very close to getting a totally new approach to pain. One of the P2X receptors is involved in the initiation of pain, and we are developing antagonists which are going to make a huge difference to the pain field. In addition, there are drug companies interested in cystic fibrosis, dry eye, bladder incontinence, diabetes, the CNS and cancer. I have just written a Nature paper on neurodegenerative diseases and cancer, and there is lots of interest. So the exciting thing is that maybe, after all those years of just expressing my basic creative spirit, I might even do something useful before I’m finished. I would like that. That would be good.

You gave a fantastic list of diseases and of drug company development. Could you give me a few examples of the specific sorts of applications that have resulted from your kind of research?

Coming back to clopidogrel, it is one that is used very widely throughout the world against stroke and thrombosis. The platelets have a P2Y G protein-coupled purinergic receptor, P2Y12, which, when occupied, leads to platelet aggregation – clotting. Clopidogrel is an antagonist of the P2Y12 receptor, so it stops the clotting and it is better than aspirin. It is very successful.

For pain, morphine mostly acts by interrupting the pain pathways at the spinal cord level and it doesn’t work for all kinds of pain. We discovered that there is a P2X3 ion channel receptor on nociceptive pain fibres. For instance, when you get a stone in the ureter, it is incredibly painful and that is because the ureter is distending and releasing ATP. The ATP then acts on these pain fibres and sends the message up to the cortex that it hurts ‘down there’. It is the same with colic gut and the bladder when you need to pee badly. So this is going to be a big breakthrough in treatment. There are now drugs in clinical trials. The drugs are really good because they are small molecules, they are orally bioavailable and they are stable in vivo. This is what we have been waiting for. Many of the other antagonists are of no use clinically. You have to have ones which can be given by mouth and which are stable in vivo, and this is happening now.

You also mentioned cystic fibrosis, I think?

Yes. That involves a P2Y2 receptor which mediates the release of mucin. They have made a drug that lasts longer. The drug is also used against dry eye, where there were no other drugs for it.

The P2X7 receptor is a particularly interesting one, because not only does it open cation channels when it’s occupied but it also opens a huge pore which leads to cell death – apoptotic cell death. This is involved in inflammatory conditions in the brain, like all these neurodegenerative diseases: Alzheimer’s, Parkinson’s, MS, Huntington’s, ALS, epilepsy and migraine. P2X7 antagonists are being explored by a number of companies against inflammatory disorders. Against cancer however, an agonist to P2X7 receptors kills cancer cells. This is a very interesting approach to it.

The field is exploding. For me, it is wonderful. Imagine the pleasure I have. It is out of my hands now. Thousands of people are working on this system. I keep up with the literature. I have about 450,000 reprints in my office of every paper ever published on any part of the system of purinergic signalling. I can help people very quickly. I am often asked to assess papers and grant applications in the field. I can’t do them all, but I can quickly give them the names of people who can probably do a better job than me. So it is more active than it has ever been.

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Despite the doubters the truth comes out

Tell me about those 20 years when things weren’t progressing and when you were held up to doubt. What happened?

First of all, when I left Melbourne to go to London, the professor of medicine at that time – a caustic figure whom I won’t name – at my farewell, said, ‘This is Geoff Burnstock, the inventor of the pure imagine hypothesis’. It was pretty tough. He also said, ‘he’s the only rat that I know who’s going to a sinking ship’, meaning England.

Charming.

He was a tough guy. He is not alive any more. I liked him. He was a good doctor.

How did you respond to that awful barb?

I laughed. But there was another thing that happened. People like to see blood so, at top international meetings – like IUPHAR – they put me in a workshop with three other people, who didn’t believe in the purinergic story. We had 10 minutes each, and the audience was entirely behind the three opponents. It was pretty unpleasant. I had already published about 100 papers on it and the others published nothing at all, but they felt that the audience was with them. But I stopped doing those meetings. I don’t mind being competitive, but one of the guys on the other side had a heart attack and died on the spot. So I decided not to do workshops any more. It was not easy. People used to come up, trembling, and say, ‘I’m going to devote my life to destroying the purinergic hypothesis'. It excited a lot of negative passion, and I have never understood this.

I did have a very painful experience at the Royal Society, as a matter of fact, before I was elected. I had only been in London for a few years and they had a meeting in which one of my students presented the purinergic case. They didn’t ask me to do it as they were asking young people. I think my student gave a fair presentation. Afterwards, there was a five­minute discussion time. The chairman had obviously agreed that somebody else could show some slides. I had never heard of the person and they showed four incomprehensible slides which, he said, destroyed the purinergic hypothesis. People looked at me – there were 15 seconds left – and I said, ‘I have never seen this work, it has not been published and I need to study it carefully and take it into consideration, but it doesn’t look to me like a major thing’. But, for years after, people would come up to me and say, ‘wasn’t the purinergic hypothesis destroyed at that Royal Society meeting 10 years ago?’ It was so painful and so unfair.

You were ambushed.

I don’t know why it happened, but it did. Maybe it wasn’t deliberate. The person never published their result. I never heard of them again and they didn’t exist. It was just awful. That was one of the painful things for me, I have to say.

Most of the public would imagine that science is a kind of saintly pursuit of the truth and all you scientists work together very happily. Once you have had your very nice arguments everyone says, ‘yes, well, that was wrong and this was right and on we go’. But it’s not like that, is it?

Science stumbles along. It can be led astray by strong personalities in the wrong or the right direction. But, in the end the truth comes out, which is what is wonderful about science: it’s cumulative and eventually one does find out what is true.

After a few years, that kind of byplay eventually leads to a higher understanding.

Yes. Well, it did.

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Purine clubs and journals

Now the situation is that the purinergic story is established and you got into journals.

There are Purine Clubs being setup. I have started a journal myself called Purinergic Signalling, which is extremely successful. It is going to have a high impact factor in no time at all.

What do the clubs do?

The clubs bring together all of the people in, let’s say, Germany or Italy or Japan who are working on purinergic mechanisms of one kind or another. It might be diabetes, it might be Alzheimer’s disease, and they bring these people together. I have just been in Brazil where 240 young people are working on purinergic signalling. And, being the grandfather, I had to give the opening talk, which is very nice. They have just set up a club in England as well. It’s great. It has not happened in Australia yet, but maybe it will happen.

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Recognition but not a ‘club man’

Now we are looking at the last phase of a tremendous career. You have been elected to the Royal Society and here we are in this august place. What does it really mean to you?

It is a nice feeling to be recognised by your colleagues and friends for the work that you have tried to do through the years. It was even nicer when they gave me the Royal Gold Medal. It is awarded once a year in biology, in physics and in applied science. I got the biology one about eight years ago. That was very exciting. I think we all need a pat on the head, whether we are young and starting or an old man that’s trying to do his best through the years. It is very nice to be recognised.

When you come to the Royal Society, with all its various activities, do you enjoy that?

I don’t come as much as I used to. One always meets very interesting and exciting people here, because it is a home for gifted people. I have been on a few committees and so forth. But I have never been a club man. I like to be an individual who can have their own views. If you make loyalty to a club there can be a conflict of interest if you don’t agree with the philosophy of the club. I like to keep my personal integrity, so I am not great at clubs. I am very proud to be a member of the Royal Society, but I don’t use it like some people perhaps would.

Is it the same with nations and nationalism and politics? You don’t get embroiled in that at all?

For right or wrong, this is the way it is.

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Still call Australia ‘home’

What about Australia? You remember that very fondly.

I do.

Do you go back occasionally?

I go back every single year. First of all we have inherited a beach house in New Zealand and we spend time there. Then I have two daughters and four grandchildren living in Sydney and we have our best friends all living in Melbourne. My wife would like to spend six months there, but I am still working hard. So I only spend two months. After 54 years of marriage, I have had to learn to cook, because Nomi doesn’t come back for another couple of months.

Fifty four years of marriage! And the secret is?

I don’t know that there is a secret. I think we respect the areas of excitement and development that each of us has. We are not critical of each other’s interests and excitements. We have a nice open marriage in that respect.

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Advice: intelligence, imagination, resilience, courage and passion

Geoffrey Burnstock, here we are in slightly difficult times. Having yourself experienced coming up with very little background, little money and having to take a theology degree, what advice would you give to a young person with no idea of what a science career is like? What would you say about persevering in science?

It is very interesting. Since I have had over 100 PhD students and many postdocs, I was asked recently in Japan ‘what do you look for in a good scientist?’ It was an interesting question. I said the obvious things: intelligence, manipulative skills, imagination and resilience. Resilience because it is tough at times doing research and you don’t give in. Judgement is an interesting one. That is an intuitive thing – when to leave something alone that is not working and not to persist. Knowing that is an intuitive thing.

I have a lovely anecdote about that. I remember all my PhD students by one anecdote or another. It was in Melbourne. Von Euler, the Nobel Prize winner for noradrenaline, was visiting his daughter there, but he knew me and he said, ‘let’s have lunch’. I said, ‘can I bring a student?’ He said, ‘fine’. I went to the student and said, ‘you’re in luck. The best man in the whole world in the field of your PhD is here. Would you like to join us for lunch?’ He said, ‘impossible. I’ve bought my sandwiches already’. I knew that he would never succeed, and he never did.

Courage: if you find something that doesn’t fit established doctrines, you don’t hide it under the carpet. You make sure that that is right. That is the thing that is more important. In general, I find that Aussies are more prepared to have that kind of courage. The English tend to think, ‘it’s too big. There must have been something wrong with the drug’. But the one thing that is more important than anything else, and that’s what I look for, is passion. If you really don’t want to do it, it doesn’t work. It was very interesting in Japan. Because of the culture there, the women who were asking me about this were very gentle and modest but they tried to look passionate after I had told them this. People in Brazil or Italy are passionate and they show it. But it is vital. I always look for something in their lives – whether they were the captain of the hockey team, a collector of stamps or whatever – as passion is vital to succeeding in research.

There is one problem with that – the passion and the courage. You have shown that, after 20 years, you were proved right and the people who said that they were going to destroy your idea were proved wrong. What if you came to know after 20 years that you were wrong? How many people do not budge? What would you say to them?

That again is a very interesting point. I was standing next to von Euler once when one of these people came up and said, ‘I’m going to destroy you. I’m devoting my life to destroying your hypothesis’, and von Euler gave me some wonderful advice. He said two things. First of all, he said, ‘negative people vanish. Don’t worry about them. But look very carefully at the criticism’. He said, ‘you must be particularly careful, if you are being attacked on a hypothesis, to be objective. You mustn’t try to fit all the data to support your hypothesis. You must think of other possibilities. If it’s an emotional criticism, discard it. But, if it’s a real experiment, you have to do it yourself or at least take it very seriously. You have got to be objective. You have got to be the first one to give up your hypothesis, if the facts say that’. It was tremendously good advice for me. I was very careful, after that, not to get defensive but to always look very carefully at new data.

Going back to the rest of the story – which, in your case, was quite glorious – can I still think of you as the ‘smooth muscle man’?

I am still interested. But, again, I am not a club man, so I have never belonged to the ‘smooth muscle club’.

But you are smooth.

Yes, I suppose so! I still have a soft spot for the gut and for smooth muscle but mostly the nervous system.

And you remember putting condoms on fish, fondly. Thank you very much, Geoffrey Burnstock.

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© 2017 Australian Academy of Science

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