A Nobel discovery

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ONCE upon a time, there was a bacteria called Helicobacter pylori. Despite being one of the tenants in Homo sapiens, humans were unaware that such a creature had taken up residence in their body.

Aside from the fact that until the 17th century, mankind had no tools able to visualise microscopic organisms such asH. pylori, it had also very cleverly made its home in one of the most inhospitable environments in the human body – the stomach.

This highly acidic environment was so hostile that long after mankind became aware that there were such things as these mostly invisible-to-the-naked-eye, unicellular creatures, no one believed that anything, including bacteria, could survive there.

Now, while H. pylori was mostly a good tenant – keeping to itself and not causing any trouble – there were times when its bad side came out.

When this happened, its poor host would suffer from burning or gnawing stomach pains – usually if they had not eaten or during digestion after a meal – which would come and go for days or weeks at a time. Strangely enough, a drink of milk or eating often seemed to stop the pain, for a while at least.

Many causes were suspected of causing this condition, often called gastritis or dyspepsia, but no one suspected little old H. pylori.

For even though the elusive organism had been spotted on and off since the 19th century, and various scientists suspected that a bacteria might be the cause of gastritis, no one definitively put the two and two together until the fateful day when an obsessional pathologist met a contrarian medical registrar in the Land Down Under.

Little did the two doctors know that their meeting would not only lead to a permanent cure for a common disease, but also one of the most prestigious scientific prizes in the world, as well as immortalising one of them for a very bold move.

Two doctors meet

It was 1981, and that time of the year again for medical registrar Dr Barry Marshall to go around looking for a research project as part of his physician training at the Royal Perth Hospital in Australia.

As he was then doing his six-month rotation in gastroenterology, he asked his boss, Dr Tom Waters, if there were any relevant projects available.

Dr Waters then passed him a letter by pathologist Dr Robin Warren asking if there were any clinicians interested in working with him to find out more about a mysterious bacteria growing on the gastric biopsies of patients with chronic gastritis.

“That particular year, Dr Warren had already been looking at these bacteria for more than one year,” says the now honorary clinical professor and head of the Helicobacter pylori Research Laboratory at the University of Western Australia (UWA).

“He first saw them in 1979, and he looked at a few biopsies and mentioned them to his boss; but I think the attitude was, ‘Warren, you have a lot of real work to do, don’t worry about this silly bacteria’.”

The problem faced by Dr Warren was two-fold: firstly, it was an established “fact” that nothing could live in the hostile environment of the stomach; and secondly, even when his colleagues accepted his observations, they were not convinced of his hypothesis that the gastritis was due to the bacteria, preferring to believe that the bacteria came after the gastritis instead.

But, as Prof Marshall describes: “Dr Warren is quite obsessional; he’s not happy with an explanation like that. As he said, ‘I must find out what these bacteria are’.”

However, as a pathologist, he was dependent on clinicians to obtain biopsy samples, which was where Dr Marshall came in.

What drew Dr Marshall to the project was that he was convinced by Dr Warren that there was no other explanation for the bacteria from the biopsies other than that they were indeed living in the stomach, despite the fact that this went against conventional wisdom at the time.

“For some reason, this is my personality, I would always try to find the opposite point of view. Whatever you tell me, I would be attracted to the opposite (side),” he told this writer with a laugh, during a recent interview in Kuala Lumpur.

He adds: “My mother always said I was very argumentative.

“The other thing she would say was that I was a know-all, because from an early age, I used to read everything, particularly science and anything technical. And if something didn’t make scientific sense, I could never really believe it.”

And the thing that nailed it for him was that if the bacteria on the biopsies Dr Warren had examined indeed came from being swallowed, there would be all sorts of different bacteria in the biopsies. However, there was just the one type – the spiral-shaped bacteria that would come to be known as H. pylori, and therefore, they had to be from the stomach itself.

Accidents and obervations

As a clinician, Dr Marshall was curious to see if the patients from whom the biopsies had come from had any illness that could be caused by the bacteria.

“In our first six months, we didn’t find any proper connection. And we couldn’t grow the bacteria. So, really, for about nine months, the research was very negative,” he recalls.

But finally, a breakthrough came by accident.

According to Prof Marshal’s Nobel Prize lecture given in 2005, the laboratory technicians who were monitoring the biopsy samples Drs Warren and Marshall were trying to culture, had been reporting them as negative and throwing them out after only two days.

However, due to an especially busy holiday weekend, one sample was not looked at until five days later, when it was discovered to have grown the first lab culture of H. pylori.

Once the time factor had been discovered, the duo were able to progress with finding out which antibiotics killed the bacteria, and trying to establish its effects on patients.

“We studied 100 people – this was about April 1982 – and out of 37 people, we cultured the bacteria.

“Then after six months, we were analysing the data, and I noticed that people with ulcers had the bacteria much more commonly than anybody else, because normal people have it as well. And I said, it looks like the cause of ulcers.”

At that time, ulcers were thought to be due to a variety of causes, including stress and spicy food,

With such a potentially important discovery at stake, Drs Marshall and Warren continued gathering more patient data and samples for about another year.

“By 1983, we had tested it out on a whole lot of other ulcer patients, and it seemed to be holding out. And we started practising with different treatments,” says Prof Marshall.

While it was very hard trying to convince the medical and pharmaceutical communities of their discovery, their conviction and belief in their observations and scientific methodology never wavered.

“I was having this problem that whenever I presented the story about the bacteria possibly causing ulcers, everybody would say, ‘We don’t believe it. We think the ulcers come first, and then people with the ulcers just catch the bacteria from their food or something’,” he shares.

Other doctors were highly skeptical that there could still be an unidentified bacteria lurking within the human body and potentially causing such a common disease in the late 20th century.

But the fact is, Dr Warren was not the first person to spot H. pylori, nor was Dr Marshall the first to suggest its link to peptic ulcers and gastric cancer. (See Seeing isn’t always believing)

They were, however, the first to conclude that H. pylori lives in the stomach, prove the connection between the bacteria, gastritis and peptic ulcers, and find a cure, as well as convince the rest of the world of their findings.

And all it took was for Dr Marshall to drink about 50ml of a mixture teeming with H. pylori.

The human guinea-pig

By 1984, Dr Marshall had successfully treated several gastritis patients with a combination of bismuth and the antibiotic metronidazole.

At that stage, it looked like his resources for research were rapidly running out, and no one had been successful in finding an animal that could incubate the human H. pylori.

Convinced that he had a cure for gastritis in hand, Dr Marshall decided to use himself as a human guinea-pig to prove that H. pylori was indeed a harmful bacteria and was the cause of gastritis.

“With a human volunteer, you can then fulfil Koch’s postulates, which is, infect a person and possibly see the disease develop in that person.”

As he did not want to take the risk of the hospital’s ethics committee turning down this crucial experiment, he decided to adopt a “don’t ask, don’t tell” strategy.

“It would be much better if I did it and told them about it afterwards, And if it wasn’t successful, I wouldn’t have to tell them.

“So, it was a good strategy. I don’t recommend necessarily that that is always the way to go, but at that particular time, it solved this problem,” he says.

The self-experimentation was “80% successful”, as Prof Marshall describes it.

While he did not develop an ulcer, he did develop the illness that characterises infection by H. pylori, which he later discovered had previously been described primarily in children (although it was not ascribed to H. pylori).

And although he recovered spontaneously from the infection after a couple of weeks, he had proven that H. pylori could infect a healthy person and cause inflammation in the stomach, as well as live in the stomach of a healthy person.

There was still a long way to go before full acceptance by the medical community, but in the meantime, Dr Marshall was able to obtain enough funding for his research to continue, and he was able to help many patients who were either being referred to him or seeking him out themselves.

Prof Marshall has continued his groundbreaking work in H. pylori since then, having researched further into the bacteria, as well as coming up with two diagnostic tests to detect it.

Currently, he is working on developing H. pylori as a cheaper, faster and more convenient way of delivering vaccines to the general population.

He and Prof Warren, now an emeritus professor with UWA, jointly received the Nobel Prize in Physiology or Medicine in 2005 for their discovery of H. pylori and its link to gastritis and peptic ulcer disease.

Prof Marshall was in town recently for the signing of a letter of intent between Universiti Malaya and UWA to set up a research laboratory dedicated to the study of H. pylori.

The lab is to be named the University of Malaya Marshall Centre after him.

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