The interview

Shortly after the announcement of the 2005 Nobel Prize winners, The Australian Academy of Science (AAS) spoke to Robin Warren (RW) and Barry Marshall (BM) about their prize-winning research.

AAS: How did you start on the road to the Nobel Prize.

RW: Back in 1979, I was interested in gastritis, microscopy and different ways of staining samples for observation. I initially observed spiral-shaped bacteria in samples from patients with gastritis and ulcers. The presence of bacteria always coincided with signs of inflammation of the gastric mucosa (Diagram 1: The gastrointestinal tract).

When I first saw the bacteria there in the stomach, living in conditions nobody believed possible, I preferred to believe my eyes and not medical text books. As far as I was concerned, the bacteria were there in the stomach and their presence was an important part of the inflammation response.

AAS: How did you and Barry Marshall start working together?

RW: One day this strange character burst into my room and demanded to see my research work. That was Barry Marshall looking for a research project. We began working together in 1981.

AAS: What did you think of the idea that bacteria lived in the stomach and caused disease?

BM: Of course it went completely against what we were taught from text books, but when Robin shows you these samples and you can see them there for yourself, you believe it.

There was never any doubt in my mind that these bacteria did live in the stomach and all the medical books were wrong. That was from the first afternoon I met Robin.

We didn't have any big agenda in those days about discovering the cause of ulcers, we were just, wow, new bacteria in the stomach, isn't that interesting?

AAS: So, what was the discovery that you and Barry Marshall reported in 1984 that eventually lead to you receiving the Nobel Prize?

RW: We did a study on 100 of Barry's patients who were suffering from gastritis or ulcers and he convinced them to come back again and again for endoscopies etc. We took samples from the patients and eventually we were able to grow Helicobacter pylori from them (Diagram 2: Features of H. pylori). That caused a lot of excitement, because we'd been trying to grow them for a while without much luck.

After about three years of work we were convinced that the H. pylori were important in the formation of ulcers. We had treated patients with ulcers with antibiotics and the ulcers did not come back.

AAS: Your theory had some critics though...

BM: A controversial part of the research was the ability of H. pylori — any bacteria really — to live in the acidic environment of the stomach. Even those who accepted that the bacteria were there in the stomach didn't believe that it caused gastritis and ulcers.

Although there were a few objections to the theory, it intrigued and encouraged other researchers to repeat the studies and investigate the theory further.

AAS: You were so convinced that the bacteria caused ulcers, you decided to experiment on yourself.

BM: Yes, I did. We didn't have an animal model to study the disease then, so I decided to infect myself to prove that a healthy person could develop the disease after being infected with the bacteria. We believed the bacteria came first, causing inflammation, then ulcers.

AAS: What did you do?

BM: Robin did an endoscopy and showed that everything was normal and that I didn't have an infection to begin with. Then I drank the bacterial brew, down in one gulp. I started to feel ill after a couple of days, started feeling nauseous and vomiting. My wife wasn't very happy when she found out what I had done. I developed gastritis, which is inflammation of the stomach, but I didn't get an ulcer. Robin did another endoscopy and checked to see what was happening. I also noticed that the vomit was watery, not acidic like normal vomit. I recovered without any treatment. After that, people started to pay a bit more attention.

AAS: So how do bacteria live in such an acidic place as the stomach?

BM: It turns out that the shape of the H. pylori allows them to sort of cork screw through the thick mucus that the cells lining the stomach produce to protect themselves from the acids and enzymes that digest the food you eat (Diagram 3: The protective mucus layer of the stomach).

The body's immune system responds to the invasion and causes inflammation. H. pylori evades the body's defense mechanisms that usually protect us from disease. If this goes on for a while the patients suffer chronic inflammation which can be quite painful (Diagram 4: H. pylori invades epithelial cells). If this continues, then an ulcer can form, which can lead to bleeding and a hole in the stomach wall.

AAS: How were patients treated before your discovery?

RW: Drugs to stop the acid, a bland diet and sometimes surgery. But it wasn't really effective. The ulcers returned and kept causing problems for patients for many years. It used to make life unbearable for people who suffered from ulcers. It made them completely different people.

Once we started treating patients with antibiotics and could cure them once and for all, they were so pleased with the outcome, word got around and we had other patients coming to us asking for the new treatment.

It took about ten years from the publication of the initial discovery before it became accepted practice to treat patients suffering from gastric ulcers with antibiotics.

AAS: How common is it for people to have H. pylori?

RW: Well, that depends on where you live and how old you are. Around 60 per cent of people world-wide, but in some developing countries it can be up to 90 per cent, and a lot of those are children. In Australia and other developed countries it's around 30 per cent, mostly in people over the age of 40.

AAS: Does everyone with H. pylori get ulcers?

BM: No, it's interesting. One or two people out of every ten who have the bacteria will develop gastritis and ulcers, and about one in a hundred will develop cancer. We don't yet know why. We don't know what triggers the H. pylori to start causing disease.

But we do know about the genes that H. pylori uses to invade cells and what makes particular types of H. pylori more virulent than others. We know how it adheres to cells, causes an immune response and inflammation. H. pylori also changes the cells normal cycle of growth and division, which can lead to uncontrolled cell multiplication and cancers (Diagram 5: The immune system responds to the invasion).

It may be that H. pylori is what's called a commensal bacteria. One that's often found in the body, without having any harmful effect, and it may even be of some benefit.

AAS: You make it sound so simple. Was any one else working on ulcers back then?

BM: Yes, there were others who had observed different pieces to the puzzle. A Greek doctor in the 1950's had even treated patients with antibiotics, but nobody believed him, except of course the patients he cured. Our study was at the right place and time, and we managed to convince enough people to do their own studies, so that eventually they had to change their minds. It took a while, but eventually it was accepted.

AAS: Why is this discovery so significant?

BM: Because it changed accepted dogma. Bacteria do live in extreme environments, they can cause chronic inflammation and that can lead to cancer. The only cancer to kill more people is lung cancer. It's a huge problem in many Asian and developing countries.

It's also significant because it made other researchers think about their work in a different way, to start looking for bacteria where-ever long-term inflammation is part of a disease. Things like ulcerative colitis, Crohn's disease and irritable bowel syndrome.

Of course, it also means that thousands of people can get a simple, effective treatment once and expect results to last.

The discovery of the role of H. pylori in the formation of gastritis and ulcers — and their treatment with antibiotics — is just the beginning. It can certainly be said to have 'conferred the greatest benefit on mankind', which is one of the requirements of the work to win a Nobel Prize.

Immediate outcomes of Marshall and Warren's work include advances in the diagnosis of gastritis and ulcers, including antibody tests, identifying H. pylori from biopsies and urea breath tests.

Researchers are currently investigating the finer details of the pathogenic mechanism of H. pylori, including what makes some isolates more virulent than others and adaptation of the bacteria to changes in stomach conditions. Also of interest is the genetic variation in humans which leads to differences in susceptibility to infection by H. pylori.

Other researchers are investigating how colonisation of epithelial cells by H. pylori and long term inflammation can lead to cancer. An interesting twist to the story is that infection by H. pylori may play a protective role against other forms of cancer.

Researchers are wary of widespread indiscriminate use of antibiotics against H. pylori that could lead to bacterial resistance. One possible answer to increasing bacterial resistance to antibiotics is to develop a vaccine against H. pylori.

Click on pictures to
enlarge an artists impression of the human body, H. pylori and the infection process.
(will open in a new window)


Diagram 1: The gastrointestinal tract

Diagram 2: Features of
H. pylori

Diagram 3: The protective mucus layer of the stomach

Diagram 4: H. pylori invades epithelial cells

Diagram 5: The immune system responds to the invasion