Nobel Prize, Stockholm Sweden
December 5 - 14, 2005
Barry J Marshall - Robin Warren co recipients, Medicine
Dagens Nytheter Newspaper December 11, 2005
He made himself a drink – and finally won
Yesterday Barry Marshall
got to drink champagne
with the king. 21 years
ago he drank a scary
mixture of beef tea and
bacteria to convince
stubborn doctors that
Helicobacter pylori
causes stomach ulcers.
Karin Bojs talked to the
Nobel laureate in
medicine.
It was years before
the discovery became
widely known and was
able to help patients
with stomach ulcers. In
June 1982, Barry
Marshall and Robin
Warren published their
first findings in The
Lancet. But it wasn't
until 1993 that
antibiotics became the
standard treatment in
Sweden, and it took
another year in the USA.
- An enormous number of people could have been treated in the eighties. I can forgive the researchers who were sceptical for scientific reasons, because they were waiting for the data. But I can't forgive those who were treating individual patients: people suffering terribly from stomach ulcers, who were bleeding and sometimes dying. Why didn't those doctors tell their patients about antibiotics and let them take part in trials!
It was easier to convince ordinary general practitioners than stomach specialists, says Barry Marshall. The stomach specialists, the gastroenterologists, were so full of all the dogmas they had had to learn about stomach ulcers being caused by stress and poor diet and genetic factors.
The big pharmaceutical companies were another powerful brake on progress, because they were investing so heavily in their gastric acid inhibiting medicines. In the eighties, acid inhibitors like Tagamet and Zantac were the most spectacular golden calves in the whole pharmaceuticals industry.
- Companies were totally focused on acid inhibitors. They drowned out research on Helicobacter by funding hundreds of clinical studies exclusively on acid inhibitors. They sucked almost all patients with stomach ulcers into these studies. This was initially the case with Astra, too, which in the late eighties introduced its all-time best seller, the acid inhibitor Losec.
- Astra could have included antibiotics in its Losec trials, but chose not to.
Barry Marshall thinks the explanation is simple.
- It wasn't in the companies' interest. Any economist can tell you that a share that is worth 20 dollars if patients have to take tablets all their lives will collapse to just a fraction of this value if they only need to take medicine for a couple of weeks.
The man who came to save both Astra's business fortunes and the world's stomach ulcer sufferers was doctor Peter Unge from Gävle, a small town north of Stockholm. He discovered that Losec and antibiotics taken together made an excellent combination. In 1993 he published a solid study showing this.
- It created a boom.
What's more, in 1994 the patent for the first H2 blocker expired. Glaxo no longer had any interest in combating knowledge about the use of antibiotics against stomach ulcers, and the world was no longer safe for Helicobacter pylori.
The fact that Robin Warren and Barry Marshall both lived in Perth in Australia - far from the power centres of the world of medicine and pharmaceutics - also contributed to the sluggish response to their work.
- as did the fact that neither of them was a gastroenterologist. Robin Warren was a placid and reserved pathologist, and at the time of the discovery Barry Marshall was a 31-year-old training to be a general practitioner.
- To begin with we had our hypothesis about the bacteria, and then we began to learn more about stomach ulcers. We entered the field from a quite different direction.
There were hundreds of facts that qualified gastroenterologists thought they knew, but which were completely off the mark. Robin Warren regards their view of medicine as religion rather than science.
- It's like Galileo trying to explain to the Pope: "Your Holiness, the planets revolve around the sun, I have seen it." But the Pope said: "No way, that's not what we were taught."
An example of this is when Warren and Marshall sent a short summary of their first findings to a meeting of the Australian association of gastroenterologists in 1983. They got back a refusal slip which stated that the meeting had received 67 summaries, but that they were unfortunately only able to accept 56. Thus the first ever paper on patients with stomach ulcers and gastritis having bacteria in their stomachs was among the eleven that were rejected.
- I reread that summary last night, and I can agree that it was not very well written. For instance, we hadn't included any figures. But the principal problem was that those people were not interested in research or anything new.
Robin Warren tried for over a year to get one of the clinics interested in the small curved bacteria he had discovered in stomach tissue samples.
Barry Marshall threw himself into the assignment in 1981. It was part of his final training as a general practitioner to conduct a small-scale scientific study, and it suited his obstinate character to study bacteria in the stomach, where everyone claimed no bacteria could survive due to the acid environment. In no time he had collected data and samples from 25 patients. He read vast quantities of literature on the subject and treated his first gastritis patient with antibiotics - an elderly Russian man. The following year, he succeeded in cultivating the bacterium in test tubes, and started a bigger trial, with 100 patients.
But then Barry Marshall, his wife Adrienne and their four children had to move almost two thousand kilometres north of Perth to Port Hedland, where he had to work for a term as a general practitioner in order to obtain his degree.
Back in Perth, he continued his research, alongside his day job as a doctor. Even though he and Warren got an article published in the internationally leading British medical journal The Lancet in 1983, things were still moving very slowly.
- This was the worst time of all. I had no proper research funding, we had to pay 16 per cent interest on our mortgage, and we had four small children. He maintains that he was "persona non grata", an undesirable, at the hospitals in Perth at this time.
- I was rushing around the place like a tornado and making a lot of extra work for people. "Why is it so chaotic here today? Well, Dr Marshall was on TV last night talking about stomach ulcers." The switchboard was overloaded, the staff received twice as many letters, phone calls and patients.
It was one thing that almost every patient with a stomach ulcer and gastritis had been shown to have the bacteria. That Marshall had succeeded in curing many patients using antibiotics was quite another. But for an infectious agent to be scientifically accepted as such you also have to be able to show that it infects laboratory animals.
Barry Marshall and a colleague tried using piglets. But the pigs just grew and grew and became bigger and more aggressive, without any Helicobacter infection or gastritis being recorded.
Then Barry Marshall made his decision, without informing either the hospital's ethics committee or his wife.
He swallowed the equivalent of two tablespoons of the cultivated bacterium.
One week later he woke up in the small hours of the morning and vomited. He continued to vomit every morning, he felt nauseous and his breath stank.
On the tenth the day he let one of his co-workers examine his stomach. No doubt about it, he had developed gastritis. Three days later the bacterial samples showed that he was also carrying Helicobacter pylori.
Then he confessed to his wife. She was naturally thoroughly alarmed, with the pressure of four small children, an uncertain financial situation, and two recently broken ribs from a car accident.
After a few more days of vomiting and stinking breath she demanded that he should take antibiotics. His stomach recovered rapidly, to the relief of his wife, but to the disappointment of Marshall himself, who had been hoping to obtain a lot more interesting data.
He doesn't regret what he did.
- It was a crucial experiment. I subsequently learnt that children sometimes have the same type of vomiting, and that this was common in the past. This is of course when they get the bacterium inside them. Their immune system suppresses it after a while, but they are colonised by these bacteria for the rest of their lives.
So what are the personal qualities that laid the foundation for his success? He has described himself as "pushy", with a touch of ADHD.
- You need self-confidence. I used to drive my mother crazy by always contradicting her. My wife usually says that I don't necessarily have a point of view, I just automatically have an opinion that is the opposite of everyone else's.
At school he was a terror to his teachers, as he constantly contradicted them.
- I want to do something different, I see no attraction in doing the same as everyone else.
So if his surroundings had been a little more supportive, given the young Barry Marshall abundant research funding and made him a professor?
- Then I would probably not have gone any further with Helicobacter pylori. I needed that resistance.
Barry Marshall denies with some vigour that he is a particularly effective worker because he sleeps less than other people.
- I like sleeping, I need eight hours a night. It's important to sleep, because sleep reinforces your memory.
What's more, he likes having a twenty minute siesta in the afternoon.
- I stretch out on the floor of my office with my mp3 player. First I listen a bit to a recorded lecture, then I fall asleep. Then I wake up and have a cup of strong coffee and can be 100% productive for the rest of the day.
- An enormous number of people could have been treated in the eighties. I can forgive the researchers who were sceptical for scientific reasons, because they were waiting for the data. But I can't forgive those who were treating individual patients: people suffering terribly from stomach ulcers, who were bleeding and sometimes dying. Why didn't those doctors tell their patients about antibiotics and let them take part in trials!
It was easier to convince ordinary general practitioners than stomach specialists, says Barry Marshall. The stomach specialists, the gastroenterologists, were so full of all the dogmas they had had to learn about stomach ulcers being caused by stress and poor diet and genetic factors.
The big pharmaceutical companies were another powerful brake on progress, because they were investing so heavily in their gastric acid inhibiting medicines. In the eighties, acid inhibitors like Tagamet and Zantac were the most spectacular golden calves in the whole pharmaceuticals industry.
- Companies were totally focused on acid inhibitors. They drowned out research on Helicobacter by funding hundreds of clinical studies exclusively on acid inhibitors. They sucked almost all patients with stomach ulcers into these studies. This was initially the case with Astra, too, which in the late eighties introduced its all-time best seller, the acid inhibitor Losec.
- Astra could have included antibiotics in its Losec trials, but chose not to.
Barry Marshall thinks the explanation is simple.
- It wasn't in the companies' interest. Any economist can tell you that a share that is worth 20 dollars if patients have to take tablets all their lives will collapse to just a fraction of this value if they only need to take medicine for a couple of weeks.
The man who came to save both Astra's business fortunes and the world's stomach ulcer sufferers was doctor Peter Unge from Gävle, a small town north of Stockholm. He discovered that Losec and antibiotics taken together made an excellent combination. In 1993 he published a solid study showing this.
- It created a boom.
What's more, in 1994 the patent for the first H2 blocker expired. Glaxo no longer had any interest in combating knowledge about the use of antibiotics against stomach ulcers, and the world was no longer safe for Helicobacter pylori.
The fact that Robin Warren and Barry Marshall both lived in Perth in Australia - far from the power centres of the world of medicine and pharmaceutics - also contributed to the sluggish response to their work.
- as did the fact that neither of them was a gastroenterologist. Robin Warren was a placid and reserved pathologist, and at the time of the discovery Barry Marshall was a 31-year-old training to be a general practitioner.
- To begin with we had our hypothesis about the bacteria, and then we began to learn more about stomach ulcers. We entered the field from a quite different direction.
There were hundreds of facts that qualified gastroenterologists thought they knew, but which were completely off the mark. Robin Warren regards their view of medicine as religion rather than science.
- It's like Galileo trying to explain to the Pope: "Your Holiness, the planets revolve around the sun, I have seen it." But the Pope said: "No way, that's not what we were taught."
An example of this is when Warren and Marshall sent a short summary of their first findings to a meeting of the Australian association of gastroenterologists in 1983. They got back a refusal slip which stated that the meeting had received 67 summaries, but that they were unfortunately only able to accept 56. Thus the first ever paper on patients with stomach ulcers and gastritis having bacteria in their stomachs was among the eleven that were rejected.
- I reread that summary last night, and I can agree that it was not very well written. For instance, we hadn't included any figures. But the principal problem was that those people were not interested in research or anything new.
Robin Warren tried for over a year to get one of the clinics interested in the small curved bacteria he had discovered in stomach tissue samples.
Barry Marshall threw himself into the assignment in 1981. It was part of his final training as a general practitioner to conduct a small-scale scientific study, and it suited his obstinate character to study bacteria in the stomach, where everyone claimed no bacteria could survive due to the acid environment. In no time he had collected data and samples from 25 patients. He read vast quantities of literature on the subject and treated his first gastritis patient with antibiotics - an elderly Russian man. The following year, he succeeded in cultivating the bacterium in test tubes, and started a bigger trial, with 100 patients.
But then Barry Marshall, his wife Adrienne and their four children had to move almost two thousand kilometres north of Perth to Port Hedland, where he had to work for a term as a general practitioner in order to obtain his degree.
Back in Perth, he continued his research, alongside his day job as a doctor. Even though he and Warren got an article published in the internationally leading British medical journal The Lancet in 1983, things were still moving very slowly.
- This was the worst time of all. I had no proper research funding, we had to pay 16 per cent interest on our mortgage, and we had four small children. He maintains that he was "persona non grata", an undesirable, at the hospitals in Perth at this time.
- I was rushing around the place like a tornado and making a lot of extra work for people. "Why is it so chaotic here today? Well, Dr Marshall was on TV last night talking about stomach ulcers." The switchboard was overloaded, the staff received twice as many letters, phone calls and patients.
It was one thing that almost every patient with a stomach ulcer and gastritis had been shown to have the bacteria. That Marshall had succeeded in curing many patients using antibiotics was quite another. But for an infectious agent to be scientifically accepted as such you also have to be able to show that it infects laboratory animals.
Barry Marshall and a colleague tried using piglets. But the pigs just grew and grew and became bigger and more aggressive, without any Helicobacter infection or gastritis being recorded.
Then Barry Marshall made his decision, without informing either the hospital's ethics committee or his wife.
He swallowed the equivalent of two tablespoons of the cultivated bacterium.
One week later he woke up in the small hours of the morning and vomited. He continued to vomit every morning, he felt nauseous and his breath stank.
On the tenth the day he let one of his co-workers examine his stomach. No doubt about it, he had developed gastritis. Three days later the bacterial samples showed that he was also carrying Helicobacter pylori.
Then he confessed to his wife. She was naturally thoroughly alarmed, with the pressure of four small children, an uncertain financial situation, and two recently broken ribs from a car accident.
After a few more days of vomiting and stinking breath she demanded that he should take antibiotics. His stomach recovered rapidly, to the relief of his wife, but to the disappointment of Marshall himself, who had been hoping to obtain a lot more interesting data.
He doesn't regret what he did.
- It was a crucial experiment. I subsequently learnt that children sometimes have the same type of vomiting, and that this was common in the past. This is of course when they get the bacterium inside them. Their immune system suppresses it after a while, but they are colonised by these bacteria for the rest of their lives.
So what are the personal qualities that laid the foundation for his success? He has described himself as "pushy", with a touch of ADHD.
- You need self-confidence. I used to drive my mother crazy by always contradicting her. My wife usually says that I don't necessarily have a point of view, I just automatically have an opinion that is the opposite of everyone else's.
At school he was a terror to his teachers, as he constantly contradicted them.
- I want to do something different, I see no attraction in doing the same as everyone else.
So if his surroundings had been a little more supportive, given the young Barry Marshall abundant research funding and made him a professor?
- Then I would probably not have gone any further with Helicobacter pylori. I needed that resistance.
Barry Marshall denies with some vigour that he is a particularly effective worker because he sleeps less than other people.
- I like sleeping, I need eight hours a night. It's important to sleep, because sleep reinforces your memory.
What's more, he likes having a twenty minute siesta in the afternoon.
- I stretch out on the floor of my office with my mp3 player. First I listen a bit to a recorded lecture, then I fall asleep. Then I wake up and have a cup of strong coffee and can be 100% productive for the rest of the day.