John Robin Warren was born in Adelaide in 1937. Despite an equal love for photography Warren entered medical school at the University of Adelaide, graduating with an MB and BS in 1961. A chance turn of fate led Warren to pathology and after training at the Royal Melbourne Hospital in 1967 he was admitted to the Royal College of Pathologists of Australasia. Warren then moved to Perth to take up a position as staff specialist in pathology at the Royal Perth Hospital (1968–98). It was during this time that Warren first observed bacteria in stomach sections associated with peptic ulcers (1979). Warren began to work with Barry Marshall in 1981 and together they were able to demonstrate that the bacteria Warren observed (now called Helicobacter pylori) was the causative agent in peptic ulcers. This revolutionary discovery was at first rejected by the medical fraternity but finally led to a cure for peptic ulcers.
Interviewed by Norman Swan in 2008.
Contents
Early observations of Helicobacter
I see you have a book with you there, Robin. Would you explain it to me?
It is called Helicobacter Pioneers, and is quite a fascinating book to look at. Years after Barry and I did our work, he collected, as far as possible, everyone he could find that had written about Helicobacter in some form or other before us. When we did our work, nobody knew that anyone had ever seen them before. It was a bit hard to believe, and to tell you the truth, I didn’t believe it. But Barry collected the names of these people and either got their original articles or got the people themselves to write a chapter for this book, which he edited.
So when was the first time that somebody noticed Helicobacter bugs in the gut?
Well, the first one that we’ve got was 120 years ago – a man in Italy called Bizzozero.
What did he think they were?
He just described them in dogs, and drew them. He could get decent sections of stomach from dogs; you can actually cut sections out and put them straight in fixative, which we never did from humans. (In fact, one of the reasons why they weren’t seen in humans was that there were no good specimens to see them in.) And so the book shows some quite nice pictures of these bacteria in dogs, drawn in 1892.
Did any of those early people get close to thinking that it was related to gastritis?
No, not as far as I know. There was a Greek doctor, though, who didn’t discover the bacteria but did discover, by chance, that people with peptic ulcer disease seemed to be cured by antibiotics. When he tried to patent this as a treatment for peptic ulcer disease, everyone thought he was mad. But, you know, he was right. [laugh]
Were you ever accused of being mad?
I wasn’t personally, although I was ‘accused’ of a few things when I first started. It’s too far back to remember exactly what was said, but basically no-one believed the work that I was doing. I could show them beautiful pictures of the bacteria and they simply didn’t want to see them. People have asked me how I kept going, but it didn’t really worry me because I could see the bacteria and I could photograph them, and I could show them to you. And if someone else wanted to say they weren’t there, well, good on them. (But they’re just crackers!)
So how does this bug work?
I don’t know how it works, but I can show you a model – one of Barry’s little pieces of fun – in which the bacterium is magnified something like 10,000 times. It has flagella at one end and it’s a helical shape. That spiral shape is how it got the ‘helico’ part of its name. It’s not really green as in this model; that’s simply imagination.
Is this an indolent bug or does it move around a lot?
It does seem to move around. Particularly in specimens taken from the stomach, and just in culture fluid, in electron microscopy you can see that it seems to move around quite a lot. I don’t think it moves around much in the stomach itself, but grows on the epithelial surface of the stomach. I could show you a picture of that in the book.
This is a picture taken by me when I first found these things actually on the specimens. This is a very high magnification of the top of the epithelial cells lining the stomach, showing two epithelial cells bulging out into the lumen, as they do when they are affected by these bacteria: they become abnormal and are no longer flat. And in many places on the surface of those cells you can see bacteria. The cells are covered with masses of bacteria, stuck on all over the surface of the epithelium.
They seem to stick onto little things called microvilli. You can see cross-sections of some microvilli here, and you can also see several little ones with the bacteria stuck on them. So the bacteria seem to stick onto the remains of those microvilli.
The microvilli are very important structural things for these cells, because each microvillus contains a bundle of filaments which branch down through the cells and attach to the base of the cells. But when the bacteria attach to them, the microvilli seem to disappear. (You can see that in most of the area here there are no microvilli.) As soon as that happens, the filaments detach from the surface and suddenly the surface has no structure left. It just bulges out into the lumen.
And becomes very vulnerable, hence the ulceration?
It could do, I don’t know. I’m not sure if that’s why it becomes vulnerable or not. But the whole cell loses its structure and becomes amoeboid.
Seeing the bacterium for what it is
Robin, when did you take the photograph you have been showing me?
In June 1979. I first saw the bacteria on my birthday, and that photograph would have been taken the day after my birthday.
So this is one of the first photographs you ever took of the bug?
Yes. The tissue for this is from a wax block, whereas a few days later I took a piece of tissue from a special plastic block which is processed for electron microscopy. The earlier one is at a lower power, being taken just from the top of some cells.
Tell me what you thought, how you reacted, when you first saw that.
I thought they were interesting. I have with me here my first report on the original case I had, and I can show you the ordinary microscope view of the original case. And you can have a close-up view yourself. This shows cells bulging out into the lumen, and stuck on the surface of the epithelium are masses of little bacteria which are staining quite nicely with a silver stain – they stain black.
You can see masses of bacteria in the views from that original case, but I didn’t know what they were. The teaching at the time was that bacteria can’t grow in the stomach. (I eventually worked out my own theories as to why they did grow there.)
All we’d ever hear from the clinicians was something like, ‘Peptic ulcer, query carcinoma.’ But I thought these bacteria were interesting. We’re always finding interesting things in pathology. When you look down the microscope at pieces of tissue, though, it’s not unusual to find something unexpected, because there are so many unusual things. And if there are 10,000 unusual things, you find one of them every now and again.
That is exactly right. But not everybody pursues the one interesting thing in the 10,000 that you might see.
Well, you don’t usually try and see them again. But with this one I actually had my own colleagues challenging me: ‘Really, Robin, if you think they are interesting, why don’t you try and find some more?’ So I thought, ‘Okay, there’s no harm in trying to find some more,’ and I started actively looking for these bacteria. They weren’t hard to find once I’d seen them.
It was like opening your eyes in front of you?
Yes. I’d never seen them before that – I ‘knew’ they weren’t there, because everyone said they weren’t there.
In the particular case here, the mucosa in the section are shown at the usual fairly low power, because most of the diagnostic pathology is done using a fairly low-power magnification.
Usually you’re looking at cells and their reaction?
You’re looking at the tissues more than the cells, and with the low power you can see most things. But all I could see of the bacteria was a funny-looking thin blue line stuck on the surface of the cells in some areas. Wondering what that might be, I had a quick look with high power, and it seemed that there might be little organisms there.
So then I had a look with the oil immersion lens, at the highest power we can use for light-microscopy. And to me it seemed obvious that there were little organisms growing around, stuck on the surface of the epithelial cells, but not as clear with the ordinary H&E-stained section. [Hematoxylin and Eosin stain is a popular method for staining cellular proteins and nucleic acids and is one of the stains most widely used in medical diagnosis].
Did you ever find out anything much about that person whose case changed your life?
No.
So what did you do next?
Well, I took the slides around and showed them to my colleagues. I eventually convinced the boss that there probably was something there, although he thought it was just some sort of peculiar artefact. I got a bit angry then. I’d been playing around with silver stain, staining bacteria in tissues – where they are hard to see. The ordinary stains that you use in microbiology, as a rule, are not all that effective in tissue sections, firstly because you don’t know if there are any bacteria there at all. Even if there are, in tissues they are usually in pretty small numbers. Secondly, the stains tend to stain the same for both bacteria and tissues anyway, so it’s hard to see the bacteria against the background.
If you’ve got Staph aureus you can see them, because those organisms are Gram-positive and they stain, whereas the tissues don’t stain with a Gram stain. And acid-fast bacilli like tuberculosis stain, and the tissues are more or less acid-negative; they are not acid-fast. So if you look hard in the right places, even though they’re not easy to see you can find them pretty definitely.
But most bacteria stain pretty much the same as the tissues, and they are very hard to see – and usually they are not there in very good numbers anyway. It’s not like in a micro lab, where you can use these stains perfectly because you just get a culture, take it off the plate and stick it on a glass slide for inspection.
So you were crossing the line here?
[laugh] Anyway, I’d been playing around trying to find a stain for organisms in tissues.
Just by chance I’d had a few cases of Granuloma inguinale, a disease caused by Gram-negative bacilli, which normally you wouldn’t be able to see very well: if you just stain them with a Gram stain, the background stain for the Gram stain stains all tissues as well. But they stain with the silver stain. They’re intracellular bodies called Donovan bodies, seen as little pairs of black dots with the silver stain inside the cells. If you use a silver stain to stain the lymph nodes or whatever you suspect of having the disease, you find these cells with a whole group of double dots in them, the Donovan bodies. I had a few cases of those, and they were very clear-cut and obvious.
Also, you use the silver stain for spirochaetes in syphilis, and they’re pretty obvious too. Although the spirochaetes are very fine little spiral organisms which you wouldn’t expect to be able to see clearly, they show up quite well. With those two things I thought, ‘Right, I’ll try this on other Gram-negative organisms.’ And I had some success – not overall success by any means, but some Gram-negative organisms did stain quite well with a silver stain.
So on this day I thought, ‘Right, I’ll see if my silver stain works on these bacteria.’ As you can see in this photograph it did work, very well.
It’s a gobsmacking picture.
Yes. [laugh] I took that in and showed it to my superiors, who finally agreed that those were bacteria and they were probably were growing there and not merely an artefact of some sort. Their response was, ‘Robin, if you really think they are of any significance why don’t you look for some more?’ So, although I had been just a bit disappointed that no-one was particularly interested in the bacteria – and actually they never did get particularly interested in them – at least they did agree with me after a while.
Once I started looking for the bacteria I found them quite often. And the more I saw them, the easier it was to see them. We got a lot of gastric biopsies at that time, and suddenly, after looking for the bacteria for a few days, I was finding them in about a third of the biopsies.
Linking the bacteria with stomach inflammation
When did you start linking all this to the pathology?
That gradually occurred over, probably, the next few months and year or so. It soon became fairly obvious that in all the cases where I was finding these bacteria, the mucosa was inflamed.
Wasn’t that the reason for the biopsy in the first place?
No. Actually, I was working in the pathology laboratory, and you’ve got to understand that, as far as the clinicians are concerned, the pathologist is there as a service man: he does what they ask and that’s the end of it. They just send down biopsies from what they want looked at. Usually, I suppose, the most common biopsies from the stomach were from peptic ulcers, gastric ulcers – because gastric ulcers are fairly often malignant.
So they’d come down, ‘Gastric ulcer, query carcinoma.’ And that’s all we saw on the request form, of course. The tissue was often affected by the ulcer, and it was difficult for me to see what the bacteria were causing when there was a nearby ulceration causing surrounding inflammation anyway.
And, of course, the bacteria can be secondary to that rather than the primary cause?
Well, that’s what the clinicians used to tell me: ‘They’re either secondary to the ulcer or they’re secondary to the inflammation – if they are there at all, Dr Warren.’ No-one believed they were there. Remember that the standard medical teaching, regardless of Barry’s book about all the previous people who had seen them and had been forgotten about, was that bacteria couldn’t grow in the stomach.
Were you getting irritated by all this?
Oh, mildly. But I didn’t care all that much, because I was doing my own work down in my own room. By the time I finished, I had hundreds of them. And they were all the same, really. Basically, they were all showing bacteria there with inflammation in the adjacent mucosa, so that it looked to me as if the inflammation was being caused by the bacteria.
So you were, in effect, a ‘lonesome cowboy’ trying to work on these little bacteria, trying to make a strong enough case for cause and effect?
Yes. It was just my own opinion at that time.
No research associate yet in view
What made you look for somebody to help you out?
Well, I didn’t particularly look for anybody else, except once.
The electron microscopist in our department was John Papadimitriou, one of the most prolific publishers in Western Australia – he had hundreds of papers. He had taken part in a study by my superior officer in the department, Dr Len Matz, and they’d written a paper, a few years before our paper came out, describing the histology of gastric biopsies. The study, actually, was set up with them by the clinician in the gastroenterology department, who wanted a paper on a series of biopsies showing the histology related to whatever it was related to, and he himself did the clinical side. (They each wrote their own stuff for the paper.)
It was the first time, in our department anyway, that such a study had been done showing electron microscopy of a series of gastric biopsies. John Papadimitriou found the bacteria in about a third of his biopsies, and he did mention that in his report in the paper. But the person I showed these things to, even though he co-authored the paper, never realised that there were bacteria. He never saw them himself, and he didn’t connect with John Papadimitriou’s report in his paper. [laugh] Neither did the clinician catch on to this until some years later.
What has this taught you about how people perceive things?
I think you see what you want to see. But it wasn’t any problem for John Papadimitriou, the same as it wasn’t any problem for me, because he had his pictures of them. In fact, that picture I showed you is probably one of his. He had plenty like that for this paper which had been written before I started.
Some months later, I took the electron microscopy picture of my original case down and showed it to the chief technologist in the electron microscopy department. I was trying to find out if the people in his department had looked at pictures of any previous gastric biopsies. I thought maybe they would have better pictures than I had made of that one, for instance: if they had been processed properly in plastic they’d be decent pictures, whereas although that one of mine is not bad, considering it’s not meant for electron microscopy, the standard is not as good as the real ones.
Anyway, I was discussing this with the chief technologist and asking, ‘Do you think there could possibly be any other gastric biopsies that have been looked at here in previous years?’ But he said, ‘Oh, I don’t think so, Dr Warren. We really don’t get gastric biopsies down here – kidneys and things like that, but not gastric biopsies.’ And then his junior, a young Chinese bloke, walked past the table, glanced at the table with all my pictures laid out on it and said, ‘Hey, they look just like those pictures that Papadimitriou was taking a couple of years ago.’ He walked on [laugh] and the chief technologist looked again at them and looked at me, ‘Hey, they do, don’t they? That’s right, he did.’ So he got out all the pictures that John Papadimitriou had taken a couple of years before, and in almost half the cases they showed the bacteria all over the place.
I tried to bring in Papadimitriou then, because I needed somebody to back me up and help me, and I thought someone with his reputation would be perfect.
Was he happy to work with you?
Well, no. When he saw my stuff and realised it was the same as he’d seen before, I don’t think he was particularly interested. And he had plenty of work to do anyway. All he said was, ‘Keep doing your stuff, Robin, and you’ll get there.’
This is like a story of someone passing up on a famous novelist or the next big thing in opera: somebody had just passed up a Nobel Prize!
What led you to bring in another person after all?
I was feeling a bit disappointed. I had no-one working with me and no-one believing me, and I didn’t know quite where to go from there.
Then, in the middle of 1981, Barry Marshall turned up in my room. He was the new gastroenterology registrar, and he was expected to have a research subject to write a paper on before he left. I think he was offered a topic on the statistical basis of something that was going on in gastro. But he wasn’t particularly interested, so someone got cranky with him and said, ‘Look, if you’re really not interested in the subject we suggest you go down to see what Dr Warren’s doing with bacteria in the stomach, and find out what it’s all about.’ So Barry knocked on my door, came in and asked to see the work I was doing.
By that time I was in the process of writing a paper myself on the work that I had done. For my paper I’d collected a whole lot of cases of biopsies with the bacteria, and related information, and I had some nice pictures and my own theories. So I showed Barry all my slides and so on of bacteria growing in the stomach, and we spent the whole afternoon discussing my work. To tell you the truth, though, he did not seem particularly interested.
Really?
No. Anyway, I asked him if he could send me down some biopsies that had not been taken near any local lesion such as a gastric ulcer, and in particular some taken from down at the bottom of the stomach, the antrum, because that seemed to be where they showed best. And he agreed to send me a series of biopsies during the rest of that year showing apparently normal stomachs – no obvious abnormality, taken from normal intact mucosa. For some reason he fairly quickly became quite interested, and by the time the year was out he was very interested. So he went from there to setting up a full study of a whole series of 100 biopsies from outpatients who were sent in for gastroscopy.
So what did you think of Barry, this youngster who walked through the door?
Oh, I quite enjoyed working with him. I think I can honestly say that he was the first person who actually was interested in what I was doing. I’d been working on these for a couple of years, but I couldn’t really prove anything till he and I worked together, till our combined work was done.
So this was a team effort?
It was a team effort, basically, except that by then Barry’s period of working in the gastro department was finished. He actually set up the study, giving every patient a huge questionnaire to fill in on all the symptoms – he had every symptom he could think of. He really did a good job of it, in the circumstances. The patients filled in the questionnaire and then they had their gastroscopy done and a biopsy. And apart from the ordinary biopsies for whatever was wanted, a couple of biopsies were taken from the antrum and sent down to me. I then looked at them and worked out what degree of gastritis there was, and how many bacteria were present on each one, and we got together afterwards and tried to correlate all this stuff.
It was quite obvious from the work I did on these very nice biopsies that the bacteria were clearly related to a special sort of gastritis which had been called by Richard Whitehead ‘active gastritis’. (He came from England but by then, actually, was working at Flinders University in Adelaide.) These bacteria seemed to be present whenever there was active gastritis, and if there wasn’t active gastritis there weren’t any bacteria. There was an almost 100 per cent relationship both ways – although the activity, so-called, was often very mild and was only found by nuts like me who looked at some patients terribly carefully with electron microscopy! It was always there to some degree.
I got the people in my department to describe these bacteria so that I had a bank of cases. Every gastric biopsy that came would be seen anyway by one of about four pathologists – the work was spread around – and those pathologists were actually describing them and, basically, coding each biopsy for the bacteria, if they saw them.
Did it become part of routine practice?
It became part of routine practice. But they didn’t care about it; they were only doing it because I wanted them to. As far as they or the clinicians or anyone else was concerned, it was nothing but a waste of time. They were just doing it to shut me up. Nevertheless, I could then go to our records and analyse what had been found.
What sort of person does it take to stick with this, to sit down at a microscope and hunt through all these cases?
Well, really, to a large extent I wasn’t doing anything particularly special with these cases. It was just a slight extra on my ordinary day-to-day work. And whereas Barry, when he started his study, needed money to set it up, I didn’t need to have any extra money or anything like that. I was being paid by the hospital for my ordinary work and this was just a bit extra.
How did ethics committees take to it?
The ethics committee didn’t come into it while I was working on it. I was only reporting what I saw, that’s all, and it had nothing to do with ethical considerations. I myself was never involved with ethics committees. But I think our study in 1982 did have to be okayed to some extent by the ethics committee, or whatever it was then, because there were 100 patients who had extra biopsies taken and sent down to me, when these were not particularly ‘necessary’ biopsies.
Childhood and family background
What sort of childhood did you have?
I think I had a fairly happy childhood. I didn’t know much about what was going on, mind you: this was straight after the Depression and during the Second World War, and apparently things were fairly tough. I don’t think it was easy for my parents. But for me things weren’t all that bad.
What did your parents do?
Dad is a wine expert, so-called, and made Hardy’s wines. He was their technical director. And my mother was a housewife.
Did you grow up in Adelaide or in the Barossa, where the grapes were being grown?
I grew up in Adelaide. That was home to me.
And where did you sit in the family – any siblings?
I was the eldest of three sons.
Are they still alive?
One is.
What’s your dominant memory from childhood?
I don’t know if I’m kidding myself, but the incident that has often come back as the first thing I can remember from my childhood is going with my mother to a movie in Adelaide at the Metro Theatre, where they showed MGM films. I can’t remember ever seeing a film before that. Apparently this was a black-and-white film about Nelson, but all I remember is that there were sails floating around all over the place and smoke everywhere, and then this bloke was collapsing on the deck of the ship.
Perhaps you could remember it because of the line ‘Kiss me Hardy,’ when the Hardy company paid the bills in your home!
[laugh] Well, I don’t know. But that’s the first thing I can consciously remember, back in the early ’40s.
I suppose you went to school in Adelaide. Which school did you go to?
Actually, I do remember going up the street to Mrs Luck’s school when I was about four or five. (I used to ride up there on my trike.) I can remember being in grade 1 and grade 2, but I was a year younger than normal. Mrs Luck didn’t mind taking younger people. It was quite interesting, also, that she was teaching a year ahead of what they did at the primary school.
After grade 2 I went to the Westbourne Park Primary School. Other people with me at Mrs Luck’s school went there as well, but whereas they went up to grade 3, I had to do grade 2 again because, it was said, I was too young to go into grade 3. I’d already been doing grade 2 in Mrs Luck’s school, writing in cursive writing with a pen and ink – and suddenly at the primary school I had to do writing all over again, this time with just a pencil, and printing!
Did you start misbehaving at school because of that?
I don’t think I misbehaved. I’m not that sort of person. I think I was pretty boring, really.
It was probably just as well that they did put me down a grade, actually. I would have been all right doing the grade 3 work but I’d have been too young in other respects and would probably not have mixed in very well with the society levels. I’ve never been much of a society person – and I guess that’s why, later, I fitted in quite nicely in the pathology laboratory.
What were your best subjects at high school? What did you enjoy? Or was it all just a chore?
I enjoyed science subjects. I think the one I enjoyed most was maths, which I always found interesting – maybe it’s a bit silly that a doctor enjoyed maths, but still. Actually, most of my mother’s Verco family were a sort of dynasty of doctors in Adelaide. She wanted to be a doctor, like her father. But he died and so my grandmother brought up their four kids, during the Depression, with a great deal of difficulty. To find yourself a single mother with four kids in those days was not much fun, even if they had extended families and that sort of thing. Anyway, my grandmother could only get enough money to send her son to the university, and my mother was not too happy that her younger brother went off doing medicine and she couldn’t. (She did nursing instead.) Whether that background had much to do with it, I don’t know, but from my childhood I always wanted to be a doctor. I don’t really know why. I don’t think my mother ever tried to push me into becoming one.
Do you think your mother felt thwarted?
Oh yes, but I don’t think she passed it on to me particularly. I just did want to do that. I read about doctors – actually, I read lots of science subjects and so on. There was no such thing as television in those days, but I had wireless and books, although we didn’t have a lot to read apart from things like Biggles books. [laugh] I don’t think I missed out on much by not being able to sit down playing games as my grandchildren do these days. It might make them skilled at playing games, but I don’t know what else it does for them.
A happy marriage and a love of photography
I have seen some of your photographs. What fascinates you about photography?
I always wanted to be a photographer, maybe because my father used to take a few pictures. He was never all that mad keen on it, but he had an old Voigtländer camera from the pre-war days and used to take quite nice pictures.
So this has been your major hobby?
Yes. When I was a little kid I was always nagging him to give me a camera, so when I was about 10 he finally gave me a nice Box Brownie with a few extra filters and things on it that opened and shut. Then I got hold of books about photography and read up all the stuff about that, and the next Christmas I got him to get me a developing and printing set.
I can remember, back in those days, getting the old 120 films and developing them in a dish down in our cellar, and fixing them and so on. They were orthochrome films, so you could use a red light while you were doing that.
I think there’s more to these photographs than meets the eye. Would you say your life was changed by photography, in a sense?
Well, I have here probably the worst picture I took, but it shows my wife soon after we first met – actually, when we got engaged. (A year later we got married.) It’s a very poor quality enlargement, made by me, from a film, but considering it’s been stuck for 40 years in this wallet or other wallets that I’ve been sitting on for that time, it’s really not in bad condition.
Where did you meet your wife?
We met when I was doing final year medicine. I was doing obstetrics, during which we had to live-in, and she was there doing obstetrics too. She was in another unit with a whole lot of girls doing obstetrics at the same time, but in a different year from me. We met and gradually got more and more serious, and suddenly realised that we were very serious and decided to get married. We were married a year after I graduated.
Children?
Yes, five – well, six, but the last one died.
I’m sorry to hear that. Was your wife your best friend, in a sense? In other words, did you have many friends apart from your wife?
Not a lot. I knew people from the rifle club – rifle shooting was the only sport that I was really ever any good at – and some colleagues, of course.
You have suggested that you are not very sociable.
I’m not very good at that sort of thing. I never remember anybody’s name, to start with. It’s always quite embarrassing. My wife was wonderful: she could remember everybody’s name and would say to me, ‘Here’s Mr So-and-So. Don’t forget his name.’ [laugh]
Would you tell me what happened to your wife?
She died 10 years ago. She got carcinoma of the pancreas and that fairly quickly killed her. I retired then, actually. After having spent a few months looking after her I thought, ‘Now, will I go back to work or retire?’ I decided to be done with it, and just retire. I haven’t really done any active research work or anything since then.
How did life change for you?
Well, it enabled me to do more of my photography for a while. And then I found that some people, for example the Australian National University, wanted copies of all my papers. By that time I was interested in computers and I thought I would download and scan all these papers into the computer, and set them up and so on. I didn’t know how difficult that was going to be! It’s one thing scanning a paper into the computer; it’s another thing scanning it in with word recognition software and then getting the thing all worked out so that it has no errors in it and is the same as the original, and ensuring that people really can use the text.
What made you do pathology?
That’s another story. I wasn’t intending to do pathology. After I’d done what is called now the intern year – it was a junior resident year in those days – I suppose I must have been fairly simple but I thought it would be the normal thing to apply for the job I wanted. It seemed reasonable to me. I mean, I wouldn’t be too happy if I was advertising jobs and I got a whole lot of applications from thousands of people who weren’t in the least bit interested.
What was the job you wanted?
I wanted to do psychiatry, actually. I didn’t even know that it was hard to get jobs in that, but I thought it would be interesting. So I applied for a job doing psychiatry. Didn’t get it. And suddenly found that I had nothing, because all the other jobs around the place had been taken. I eventually found a job doing pathology, which was about the only thing left. Nobody else wanted it.
Do you think you would have been any good as a psychiatrist?
Probably not, I don’t know. Who knows. In medicine I didn’t really mind all that much because, as I was going through doing medicine, I never found anything that I wasn’t interested in. I liked it all. So I could have done anything, as far as I was concerned. But once I started doing pathology I found it was very interesting, and I stuck with it.
What is it you liked about pathology?
Oh, it was just fascinating looking down the microscope at the slides – most of which, in those days, we’d made ourselves. I started off doing haematology, actually. We’d go and take samples of bone marrow from patients in the hospital, smear the samples out on the slides ourselves and look at them to see what was wrong with them. Quite fascinating. And the haematology was quite good from the point of view that you had a bit of patient contact there.
But you don’t get much human contact, patient contact, in pathology?
Well, for haematology you certainly do, but not for tissue pathology, which is what I ended up doing.
Did you miss that patient contact?
I never gave myself time to miss it, so I never consciously did.
Leaving Adelaide for Melbourne and then Perth
You did your junior resident year in Adelaide, but for pathology you trained in Melbourne, I think.
Yes, I trained finally in Melbourne when I actually decided to do pathology. I got a good job. By that time I’d learnt that what you do is to apply for every job available, so you go through the Medical Journal of Australia and you find everyone in Australia that wants an ‘anything’. I applied for everything in pathology, because I was interested in pathology, but also I applied for everything I could. I got a job at the Royal Melbourne Hospital and went there, and I never looked back, really.
Did you have good mentors there?
Yes, I did. In Melbourne I started off doing haematology. I did general pathology, actually, not just specialising in tissue pathology. That meant I had to do haematology, biochemistry, microbiology – it was a help for me later on that I had done microbiology – and tissue pathology. It took five years, and I ended up doing a couple of years of tissue pathology.
Did you do any research in those days?
I had to write a couple of papers, which were interesting but never got published.
It’s interesting that neither you nor Barry, two Nobel Laureates, had a strong track record in research.
I had no record in research, really. I did write a paper on using cane toads for pregnancy testing. In those days the only pregnancy test we had required the use of cane toads that were sent down from Queensland. You’d inject the cane toad with the patient’s urine and see whether the toad would ovulate. But by the time I had written my paper on the pregnancy test with cane toads, biochemical test kits were available and suddenly the whole lot was out of date.
Why the move to Western Australia?
After I got my membership of the College of Pathologists, a strange-looking character came into the office next door to my room and began talking to Dr [J Douglas] Hicks, who was my boss then. (Doug Hicks was a very good pathologist, and if you insist that I must have had a mentor I guess I’d have to call him my mentor.) Suddenly the two of them came round to my room and the visitor said, ‘You’re coming to Western Australia next year as my consultant’ – or junior consultant or something, I don’t know. ‘What? Am I? First I’ve heard of it!’ [laugh] Apparently it was Professor ten Seldam, the original Professor of Pathology at the University of Western Australia, and he knew Doug Hicks. So Hicks must have told him about me.
And you dutifully went along?
Actually, I wanted to get a job in New Guinea. Robin Cook was the major pathologist in New Guinea at that time, when that country was changing over from being an Australian territory to being independent.
It was also around the time of the research done by Carlton Gadjusek on kuru. New Guinea was quite a hotbed of pathology.
Well, Alpers I think was particularly involved with that. But I wasn’t expecting to be working particularly in that sort of thing. It would’ve just been doing pathology in the general hospital in Port Moresby and probably picking up some knowledge of tropical diseases and so on, and getting a bit more experience of hands-on pathology.
But you’ve no idea what it was like trying to get that job, because it had to go through the Department of Foreign Affairs and everything had to be done with red tape and by the book. And I had a limited period of time, because I had a job sort of offered to me here but I wanted the job in New Guinea – and, apparently, the people there wanted me to go. But I’d write to the Department of Foreign Affairs and then hear nothing more about it. I’d write to them again, saying, ‘Look, please can you do something?’ and they’d write back and say, ‘Don’t do anything yet. We’ll fix it up in the next couple of days.’ A couple of days later, still nothing’s happened. I’d write to them again, or even phone them, but it kept on going like that: ‘Don’t do anything, we will fix it.’ They never could fix it, though, so in the end I just had to tell them, ‘I’m not going to New Guinea. I’ve got to go over to Perth.’ And we came here.
Eventual acceptance of Helicobacter’s significance
So you had made observations over an extended period, from an extended number of patients, and Barry had come in and was doing more research with you. What was your reaction, then, when Barry told you he had swallowed a dose of Helicobacter?
Oh well, I knew he was going to do it. He wanted me to do it too, but I thought it was a daft idea and I told him I wasn’t particularly interested. As it turned out, apparently I wouldn’t have been able to do it anyway because I was already infected. I was an example of the majority of the patients with the infection, who have no symptoms and don’t know they’ve got it.
That, in fact, was one of the difficulties we had. Our critics used to say, ‘Look, if all these people have got this infection yet they have no symptoms at all, how can you tell us that this bacterium is actually causing any trouble?’ The fact that every duodenal ulcer patient had the infection didn’t seem to mean anything. (If 100 patients are infected, maybe 90 of them have no symptoms, but in the remaining 10 you’ve got all of the duodenal ulcer patients.)
It’s extraordinary. But I think the fight against you and Barry got pretty vicious at times.
It never got particularly vicious as far as I was concerned. I think I was just regarded as a daft pathologist. It was a bit annoying at times when I’d show people a picture and they’d try to tell me there was nothing there, but the way I describe it is that it would be like your trying to tell me that our cameraman today is not there with a camera, when plainly he is there with a camera – I can see him there with a camera. I don’t have to argue about it. [laugh]
It must have felt a bit ironic when, after years of people fighting against your idea, you then had the world almost claiming it as their own, jumping on the bandwagon?
It took a while for that to happen. I just couldn’t understand the response, though, after we published our work in 1983 and 1984. Suddenly people in laboratories around the world repeated the work that we did, trying to prove we were wrong. Basically, they looked at a series of patients to see what they could find. I suppose that they were all intending to prove that we were lying, that it was a lot of waffle. Yet not one paper actually did that. They all, to some greater or lesser degree, said the same thing we did.
You’d opened your eyes, and they saw?
Yes. Suddenly, over the next two years, there were hundreds of papers published which merely repeated the work we’d done. They did nothing more than that!
Apparently, over the next decade our paper was the most quoted paper in the whole medical literature – because, in effect, it was the only one. There have some related discoveries, of course; there are some in this book. But usually, when someone publishes something new like this, other people have done a bit of work here and a bit of work there and another bit of work here, so that eventually all these things come together. If there’s some momentous discovery, it has all of them behind it. It’s very rare that you just get something that, boom, comes out of nowhere; someone publishes it without there being anything behind it.
So everybody who wrote about it for the next few years quoted our work, because it was the only work to quote.
Wasn’t the bacterium called Campylobacter to begin with?
Well, I said it was Campylobacter-like, so we called them CLOs, Campylobacter-like organisms. Recognition that it was not quite the same, however, took some time; for a while, actually, everyone more or less agreed with me that it was very similar to the usual varieties. Most Helicobacters have about four flagella – or even six in some instances – whereas Campylobacters don’t have multiple flagella. Neither do they have the funny little knobs which Helicobacter has on the end of the flagella, and the structure of its flagella is a little bit different too from the usual Campylobacters.
But certainly to me, just looking at these with the light microscopy and not doing any microbiology work on them, they looked like a variety of Campylobacter. And they were close enough for the microbiologists to be reasonably happy, although they seemed to think that they were not precisely the same.
Who gave it the name Helicobacter?
Eventually it was decided that this must be a separate genus. The two were just too different to be called one genus. So someone suggested, at a meeting, that this spiral organism should be called Helicobacter – and the name stuck. Previously we ourselves had called it Campylobacter pylori. (Actually, we started off by calling it Campylobacter pyloridis, but apparently that was naughty: pyloridis, it seems, is a Greek term but a Latin term should have been used. So it was ‘Latinised’ to pylori.)
In all those years when you were fighting for recognition of the argument that this was causative, does any moment stick in your mind as particularly memorable, either positively or negatively?
I think one of the most memorable moments for me in the whole story occurred one day immediately after the Easter holiday when, just as I was starting work, Barry came into my room and said, ‘Hey, they’ve got a positive culture this morning!’ We had been thinking by then that they were all going to be negative – half the series had gone already and there was nothing positive.
I think this was the occasion when your biopsies had been allowed to culture for longer than usual.
Yes. The people in the microbiology laboratory, being busy, had been treating our research plates as if they were just ordinary, routine plates, which they keep for about 48 hours. Then, if the cultures are negative, they are chucked out. When I found out that our plates had been getting chucked out after 48 hours I was furious; I went around and stripped the skin off the microbiologists for that. And so they started leaving them until they’d overgrown or dried out or become useless or whatever. But we got a few more positive cultures.
Actually, a year later the senior microbiologist started getting interested in these and wanted to do some work on culturing them, trying to prove that the microbiologists’ work was better than mine. In the end I think we had to call it a draw.
For our main series with Barry we got only a few positive cultures. Most of the ones I could see the bacteria in were negative. But it was found, apparently, that the incubator being used for our cultures had been leaking. We were trying to culture them as if they were Campylobacter, and apparently they do in fact culture like Campylobacters – in hypoxic conditions, with low oxygen but not no oxygen and not too much oxygen. Well, there was too much oxygen, so most of them were negative.
But once they started to be done in a new incubator they were 100 per cent positive: if I saw them, the microbiologists saw them, always. Cultures became a really excellent tool for saying whether the bacteria were there or not.
The award of a Nobel Prize, and its aftermath
Did you ever think this was Nobel Prize winning stuff?
Oh, I didn’t. Barry did, actually. [laugh] One day, after a year or two, when we were going over some of the work he said, ‘ I think we’ve got something really going here, Robin. I reckon we could probably get a Nobel Prize for this.’ My response was, ‘Don’t be stupid. We’re only growing a few bacteria in the stomach. Who the hell gets a Nobel Prize for that?’ But I have to admit he was right.
What was it like when you got the call?
I didn’t believe it at first. For a start, everyone used to phone Barry – he was the big front man for the team – and I don’t know why they didn’t call him. But Barry and I used to go and have dinner each year at the restaurant in the old Swan Brewery. Barry liked playing around with the Internet and he would know exactly when the Nobel announcement was going to be made, so usually we would be having dinner then.
(Although the whole process is supposed to be very secret, we did think we had probably been nominated, because at least two lots of people had asked me for my CV so that they could nominate us for the Nobel Prize.)
This had been going on for about five years. Whether or not we got a prize didn’t worry me particularly, but Barry wanted to go and have dinner every year. Usually Barry would be on his email-telephone thing – he loves playing around with these super electronic gadgets – and he’d get all the news when it was going through and say, ‘Oh, no, we’re not there this time.’
Anyway, in 2005 my phone rang while we were sitting down there having dinner. My plate of fish and chips had just been put in front of me, but of course I had to take out the phone and answer it. So then a strange voice said, ‘This is Stockholm calling.’ My reaction was, ‘Oh, yes, I’ll bet it is.’ But the voice continued, ‘We’re ringing to announce that you’ve won the Nobel Prize for Medicine or Physiology this year.’
I was stunned. I said, ‘Can I tell Dr Marshall?’ ‘No, no,’ was the reply. ‘It’s not being officially announced for 25 or 35 minutes. You can’t tell anybody till then.’ Meanwhile I was trying to let Barry know by sign-language what was going on, and eventually I asked, ‘Well, can I give the phone to Dr Marshall?’ ‘Ah, yes, I suppose so.’ And so this person told Barry. What could be the difference between that and my telling him, I don’t know!
And since then?
Well, since then things have got busy. The award was announced 25 or 30 minutes later, and from that second the phone started buzzing. In fact, I’ve got some pictures at home that Barry took at the time, I suppose with the camera on his phone. He says he doesn’t remember the pictures, but I’m pretty certain they were actually taken at the time – my beard was big and bushy, and the phones looked right for that time. Later on, a TV crew got us to do a mock-up of what happened, but for these pictures Barry must have photographed me as I was taking the original call.
You’re retired now. Is the Nobel Prize still influencing your life?
Well yes, to some extent, but although I try to get out a bit whenever possible, I’m not young and mad like Barry. He likes racing all over the place and a lot of the time he’s overseas, because to run all the laboratory business and so on he needs money. And I think he needs to be constantly seen to be actually doing something, where I don’t. [laugh] I don’t particularly want to travel so much. I must admit that a lot of the overseas trips have been fun, but overseas trips for work are not the same as overseas trips for a holiday.
Certainly, you are given some money, and I’m not sorry about that. But, for me, even if you are given a business class seat without charge, it’s still torture to sit for hours and hours in a plane. The way I put it, really, is that if anyone found out that a person at Casuarina Prison was being stuck in solitary confinement with a great noise booming out and their bed moving about under them – having to sleep on something like a plane’s chair – there’d be hell to pay. But because someone is going overseas in a Qantas plane that’s considered to be great. Everyone thinks you’re so damn lucky. Well, I don’t think it’s all that lucky!
Overall I’m not sorry about missing that side of it. And the actual events in Stockholm are not entirely enjoyable. Apart from the major ceremonies there are receptions, usually two sessions a day or even three – morning, afternoon and evening receptions. You see, every body in Stockholm has to have its reception, even if the same people get asked to all of them. So you get into a crowded room and you have to stand there for two or three hours. That wrecked my foot, actually: I think I’m suffering from fallen arches or something. I suppose I’m just getting old and dropping to pieces.
And you, a person who doesn’t particularly like socialising, have to socialise?
Yes, to socialise and to stand there. And half the time you can’t even nibble things, ’cause everyone wants to talk to you. Since then I’ve tried to get out of every reception I can!
Robin, thank you very much for taking the time to talk to us.
© 2024 Australian Academy of Science
