Robin Warren

Helicobacter pylori and its Role in Gastritis and Peptic Ulcer Disease

Dr. Warren graduated M.B., B.S. from the University of Adelaide, Australia in 1961. After training at the Royal Melbourne Hospital, he was admitted to the Royal College of Pathologists of Australasia in 1967. Since then, he has been a Senior Consultant Pathologist at the Royal Perth Hospital in Western Australia, having become emeritus consultant pathologist in 1998.

Robin Warren.jpgIn 1979, Dr. Warren first observed the presence of small curved bacteria, resembling Campylobacter, on a biopsy of the gastric mucosa. During the next two years, Dr. Warren found many more examples of the bacteria on gastric biopsies, always on gastric-type epithelium and closely linked to a specific variety of gastritis. He submitted this work as a thesis to the Adelaide University in 2000 and was granted an M.D.

In 1981, Dr. Warren met Dr. Barry Marshall, Registrar in the Gastroenterology Department. A fruitful partnership developed between the two led to the demonstration of the clinical significance of the bacteria. They cultured the organisms and identified a new species, now called Helicobacter pylori. A clear association was found between H. pylori and peptic ulcers. Healed ulcers remained healed, without further medication after eradicating the bacteria.

Dr. Warren received the Distinguished Fellows Award of the Royal College of Pathologists of Australasia; the Honorary Fellowship of the Royal Australian College of Physicians; the gold medal of the Australian Medical Association; and was elected a Fellow of the Australian Academy of Science. Jointly with Dr. Marshall, he was awarded the Nobel Prize for Physiology or Medicine in 2005.

Robin Warren won the Nobel Prize in Medicine or Physiology in 2005, due to his discovery of Helicobacter pylori in the pathogenesis of peptic disease. However, he was highly confronted with sentences like «Bacteria can’t live in the stomach».

In a time of progressive and intensive scientific evolution, Robin Warren was the man that saw what no one around him could see: the linkage between bacteria and disease in the gastric environment, prooving he was right.

FRONTAL: Since you were awarded the Nobel Prize in Medicine and Physiology due to the discovery of Helicobacter pylori, how do you think your discovery has changed clinical practice?

Robin Warren: Well, certainly it has much changed the treatment of peptic ulcers. Mostly because now it is possible to cure the inherent disease and not only the ulcer. 48 years ago there was virtually no specific drug for this. They told us to drink milk and a few more things and it was basically what was done. After that, antacids and proton pump inhibitors started appearing. They are used now and can, indeed, heal the ulcers. The only problem is: if you stop taking the medication, the ulcers will come back. But if the patients come free of bacteria, the ulcers won’t come back. Although there are now very good drugs, I would not like to have ulcer disease whenever I stopped taking medication. Certainly we did, with this discovery, the difference for a lot of people because, worldwide, lots of people have ulcers. Although most have the infection, only 10% actually have ulcers. Despite not having made as much difference as it would 40/50 years ago, our discovery turned out to be important to many people.

F: Early in the discovery, what were the main difficulties that you faced when you tried to alert the scientific community about the growth of bacteria in the gastric mucosa?

RW: The greatest difficulty was that nobody believed the bacteria was there, all due to standard teachings at the time: bacteria could not grow in the stomach because it is too acidic and the bacteria could not grow there. Nobody knew they grew there, it was a bit like in the Middle Ages when it was said that the Earth was flat, and people took it as an absolute truth.

F: Did you have to gather many cases to show that the bacteria actually grew in the stomach?

RW: I took many photos to my slides in the Department of Pathology, but the clinics kept saying they did not believe: “If they are there, Dr. Warren, why hasn’t anybody seen them before?”. But they had already been noted before. People did not know much about the subject, because they did not even know they had already been “noticed” before. I did not know. Some of them said: “Well, if they are in the stomach, maybe it’s just because they are secondary to inflammation” and this was difficult to prove until later, when we infected people: I’m sure you heard about the adventure of Dr. Marshall, of drinking the bacteria. That’s why I did it, to fill Cox’s postulates and to show that the bacteria were significant.

F: It is known that the Helicobacter pylori contributes to the pathogenesis of gastric carcinoma and lymphoma. Have you studied many cases of this nature during your years of research?

RW: Personally, I did not. These infections last a lifetime; most people, as we know, got them as babies. When you are infected, unless you take antibiotics, they stay there. If you have 70/80 years and have the Helicobacter pylori infection, you had for sure associated gastritis, moderate or severe. The type of bacteria that you have and how the body adjusts to the bacteria remains the same all the time. If you had a severe reaction as a child, you will have a severe reaction as an adult. And if you have a severe chronic gastritis that, somehow, does not cause any symptoms, people will not know if there is something wrong with your stomach. Therefore, they have this persistent infection and I noticed, in many cases of older people with infection and injury throughout the stomach, that the gastric mucosa atrophies and sometimes dysplasia can happen up to “leather bottle stomach”, a classic form of gastric carcinoma: the tumor infiltrates diffusely throughout the stomach, so it looks like a leather bag. And this type of cancer, often in the intact mucous portion, passes through the same changes of Helicobacter infection, with the presence of the bacteria. Of course this does not prove anything, but in almost every case of this type of cancer, the intact mucosa shows inflammatory damage, therefore I could immediately infer that it could be a cause. I said this to Barry Marshall at the time, but he was too busy proving his colleagues that he was not crazy, and told me to shut up. At that time I did not believe that the bacteria could cause ulcers, much less cancer. There were people, particularly elderly women after infection, that developed cancer later. This was demonstrated mainly in Japan, where the incidence of gastric cancer in people aged 80 years was quite high and the Japanese government was seriously thinking about treating everyone around 65 years without investigating and heading straight for treatment to try to decrease the rate of gastric cancer. So it’s clearly related, but there is nothing that proves it concretely.

F: We all know that you are a reference to the entire medical community. What advice would you give to a medical student?

RW: I think that to win a Nobel Prize you have to be lucky. Start by finding something unusual, do not be influenced by people telling you that you’re wrong, but in a way that it should not disconnect you from having to prove that you are right! There were people saying that these bacteria were not there, but I could see them so I did not care much about what they said. It reached a point where I managed to convince my colleagues that the bacteria were there, even though they continued to state that they were not important. If you have a theory, and you think that this theory is correct, you have to find some way to prove it. You must have strong evidence so that other people using your methods can prove that what you proved is right. I never thought to win a Nobel Prize, but if you are pointing in that direction, publish your work first, because the Nobel Prize is guided by the first published work about the topic. In our case, we published a short summary one year before the article was seriously published; it ensured that we were the first. And our award was based on this summary, they did not care about the article published a year later. It has to be something new, and something that people do not really believe. If you find something you think is right, and people are all saying that you’re crazy and that it is wrong, prove to them that they are the ones who are wrong.

F: Do you think it is more difficult to win a Nobel Prize now due to the immense amount of research and articles being published?

RW: It has always been that way, I mean, you’re looking at things from your point of view now. A few years ago people looked at it the same way but with a different point of view. As a medical student, I think you should know a little of Medicine history, it is very important to see what the past doctors did. I think this is very important because it tells you that you are not the world’s most important people and doctors now are “bright”. People think that the ancient physicians, for not doing what we all do now, must have been idiots, but they were not… They were stupidly brilliant. Therefore, the greatest advice I have to give you is: read books about the history of Medicine.

Interviewers: Ana Craciun, Maria Leonor Rebordão

Writers: Joana Paiva, Duarte Calado