2005 Nobel Prize in Physiology or Medicine

Introduction

On his birthday in 1979, Robin Warren, a pathologist with an interest in gastric ulcers, noticed spiral-shaped bacteria wherever he saw signs of inflammation in biopsies from patients with gastritis and ulcers. When Barry Marshall, who had recently completed his medical training, decided to find a research project, he talked to Robin Warren about his unusual observations.

Working together at the Royal Perth Hospital, over the following years their research showed that bacteria, not stress or lifestyle, caused the majority of gastric ulcers. It defied accepted wisdom that the stomach was too acidic to allow bacteria to survive, grow and cause disease. Their work was to rewrite the text books and go on to earn the greatest scientific prize of all, the Nobel Prize.

The discovery has lead to a greater understanding of the link between chronic infection, inflammation and cancer. Doctors world-wide routinely treat patients who suffer from painful ulcers with a simple course of antibiotics.

Since then, Warren has retired, but Marshall continues his research at the University of Western Australia on the bacteria that causes gastric ulcers.

They traveled to Stockholm in December 2005 to receive the award from the Nobel Committee. And it all started as an interesting observation by Warren on his birthday.

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.

Glossary

antibiotic. A substance produced by bacteria or fungi that destroys or prevents the growth of other bacteria and fungi.

antibody. A protein produced by the body's immune system in response to a foreign substance (antigen). An antibody reacts specifically with the antigen that induced its formation and inactivates the antigen. Our bodies fight off an infection by producing antibodies.

bacterium (plural bacteria). A single-celled, microscopic organism without a distinct nucleus.

biopsy. A minor operation that removes cells or tissue for microscopic analysis.

cancer. One of the defining features of most cancer cells is that they grow when they should not. Ignoring signals from the rest of the body, they tend to multiply regardless, encouraging blood vessels to supply them with food and oxygen at the expense of normal tissue nearby. Once a mass of cancer cells (a tumour) has grown large enough, it will often invade other tissues. It will eventually push through the wall of a lymph vessel or blood vessel and clumps of cancer cells will break off and travel around the body. The cancer can then be very hard to cure. The clumps (called metastases) can settle almost anywhere and start to grow as a tumour. The whole body is soon seeded with tumours of the original cancer cell type. Usually, it is then only a matter of time before vital functions of the body are interfered with and the patient dies.

chronic inflammation. Used to describe a medical condition that continues for a long time, often with little change. A chronic disease, such as asthma, may have acute episodes, when the situation worsens for short periods of time.

endoscopy. A medical procedure used to observe the inside of the body without performing major surgery. An endoscope is a long flexible tube with a lens at one end and a magnifying eyepiece at the other. To view ulcers, the lens end is inserted into the stomach and duodenum via the mouth, and light passes down the tube to illuminate the area of interest.

enzyme. A protein that acts as a catalyst. Every chemical reaction in living organisms is facilitated by an enzyme.

epidemiology. The study of diseases or conditions in human populations and the factors that influence their incidence and prevalence.

epithelial cells. Layer of cells that lines cavities, tubes and exposed surfaces of the body. Epithelial cells are often secretory in function.

duodenum. The region of the small intestine of mammals that occurs after the stomach. It is about 25 centimetres long, lined with villi and is a site for the digestion of food and absorption of nutrients.

flagella (singular flagellum). One of the ways bacteria can move is by flagella, which consist of a hollow, rigid cylinder made from the protein flagellin. A protein filament is anchored to the cell by 'hook', 'bearing' and 'rotor' structures. About 50 genes are needed to assemble a complete flagellum and supply energy to drive motility.

The filament rotates at more than 1,000 revolutions per second, driving the anticlockwise rotation of the flagellum, moving the cell forward. To change direction, the flagella stop, and then rotate in the opposite direction for a short time, causing the cells to tumble randomly. The cells can move off in another direction when the flagella start to rotate in the anticlockwise direction again. For more detailed information see Cell motility (School of Biochemistry and Molecular Biology, University of Leeds, UK).

gastric mucosa. The epithelial lining of the stomach that produces mucus.

gastritis. Inflammation of the stomach.

gene. The basic unit of inheritance. A gene is a segment of DNA that specifies the structure of a protein or an RNA molecule.

genetic variation. The variety of different types of genes in a species or population.

immune system. The cells, tissues and organs that assist the body to resist infection and disease by producing antibodies and/or altered cells that inhibit the multiplication of the infectious agent.

immunisation. The process by which the body develops the capacity to combat a specific infection. Immunisation can be induced by introducing vaccines into the body. This is more correctly called vaccination or inoculation, but the word immunisation is used to mean the same thing.

inflammation. Inflammation is the process that makes living tissue swell, become painful and turn red. Inflamed tissue contains damaged cells and has a higher than normal blood flow through it — which is why it's red and warm. It is usually 'infiltrated' by many cells of the immune system. Compounds released from damaged cells cause fluid and more inflammatory cells to leak out of the blood vessels in the area; this fluid accumulates and may make the tissue swell or block tubes. Inflammation is often associated with infection but it can also be caused by allergic reactions.

pathogen. An organism capable of causing a disease.

protein. A large molecule composed of a linear sequence of amino acids. This linear sequence is a protein's primary structure. Short sequences within the protein molecule can interact to form regular folds (eg, alpha helix and beta pleated sheet) called the secondary structure. Further folding from interaction between sites in the secondary structure forms the tertiary structure of the protein.

Proteins are essential to the structure and function of cells. They account for more than 50 per cent of the dry weight of most cells, and are involved in most cell processes. Examples of proteins include enzymes, collagen in tendons and ligaments and some hormones. For more information see Protein structure and diversity (Molecular Biology Notebook, Rothamsted Research, UK).

toxin. A poison, usually a protein made by a pathogenic bacteria, which is highly toxic for other living organisms. An endotoxin is contained within the bacteria and is released when the cells die or a physically damaged. An exotoxin is secreted by the bacteria into its surroundings or injected directly into cells.

ulcer. A break in the tissue lining the stomach. For more information see Stomach ulcer (Better Health Channel, Australia).

vaccine. A preparation consisting of antigens of a disease-causing organism which, when introduced into the body, stimulates the production of specific antibodies or altered cells. This produces immunity to the disease-causing organism. The antigen in the preparation can be whole disease-causing organisms (killed or weakened) or parts of these organisms.

virulent. The degree to which a disease-causing organism can affect the organism it attacks.

white blood cells. (Also known as leucocytes.) A colourless white blood cell involved in helping the body against toxins, and viral and bacterial infections. White blood cells are the immune system cells. They can be divided into many different categories on the basis of their function and appearance. There are good photographs of the different types of white blood cells at White blood cells (Puget Sound Blood Center, Washington).

Activities

Ulcer bug breakthrough (Science upd8, UK)

Students learn that peptic ulcers are caused by bacteria and can usually be cured by antibiotics. Access to activities is free to registered users.

Puzzle page (BrightSparks, Australia)

Links to an Australian Nobel laureates crossword puzzle, 'find-a-word' puzzle and teachers notes.

Further reading

Australasian Science

November/December 2005, pages 44-45
A bug that Australians have controlled (by Peter Pockley)
Describes Barry Marshall's life, the first time H. pylori was cultured and the self-experiment.

October 2005, pages 44-45
The curved bug that caused tummy ulcers (by Peter Pockley)
An interview with Robin Warren about his life and the work that won him the Nobel Prize.

September 2005, pages 40-42
How to win a Nobel Prize (by Peter Doherty)
Supplies some helpful hints on what to do to increase your chances of winning a Nobel Prize.

Journal of Clinical Pathology

October 2002, volume 55, pages 284-285.
Helicobacter pylori (by H Eguchi and S F Moss)
This technical article looks at the role of H. pylori in the initiation of programmed cell death and the development of cancer.

New Scientist

11 August 2001, pages 30-33
Dead man walking (by Garry Hamilton)
Raises some questions that still need to be answered about H. pylori and ulcers.

Scientific American

February 2005, pages 24-31
An endangered species in the stomach (by Martin Blaser)
Asks whether eradication of H. pylori is good or bad for public health.

Skeptical Inquirer

November 2004
Bacteria, ulcers, and ostracism? (by Kimball Atwood IV)
Argues that the ten year lag between the discovery and acceptance of H. pylori as the cause of ulcers was normal.

Useful sites

Helicobacter pylori (Centre for Digestive Diseases, Australia)

Provides background information, symptoms, diagnosis and treatment of ulcers.
http://www.cdd.com.au/html/expertise/diseaseinfo/helicobacter.html

Provides links to images, information and other material about H. pylori.
http://www.hpylori.com.au/index.html

Describes the work of pioneer researchers towards the discovery of the role of H. pylori in causing ulcers.
http://www.abc.net.au/rn/science/ss/stories/s782213.htm

Provides information about H. pylori, its diagnosis, treatment and clinical information.
http://www.helico.com/

The official website of the Nobel Foundation which provides links to the press release, career information on the prize winners, the Nobel lecture and other resources.
http://nobelprize.org/medicine/laureates/2005/index.html

• Barry Marshall

  Provides some biographical information and a summary of his work.
  http://www.tallpoppies.net.au/cavalcade/marshall.htm

• J. Robin Warren

  Provides some biographical information and a summary of his work.
  http://www.tallpoppies.net.au/cavalcade/warren.htm