The Nobel laureate whom no one believed
This article is part of an ongoing series in which we interview some of inkl’s incredible readers around the world, to learn from their experiences, and to help share their wisdom with the world.
Last week we sat down with Professor Barry Marshall, the 2005 Nobel Prize recipient for his and Dr. Robin Warren’s discovery that Helicobacter pylori bacteria causes duodenal stomach ulcers. Dr Warren and Professor Marshall’s pioneering research upended the erstwhile consensuses that bacteria could not survive in the stomach, and that duodenal ulcers were either stress-related or hereditary. When they first started looking into Helicobacter pylori, they thought it might be limited to patients in Australia. They eventually realised that it affects at least 50% of the world’s population.
We spoke with Professor Marshall about making a momentous discovery, having nobody believe you, what it feels like to win a Nobel Prize, and the future of superbugs.
We now know that there are far more bacterial cells than human cells in the human body; up to 1,000 different types of bacteria live in your gut alone. And while a raft of recent studies have linked gut health to weight gain, endurance and depression (and contributed to the burgeoning popularity of kombucha and kimchi), scientists only started taking the gut seriously about three decades ago.
Throughout most of the 20th century, scientists assumed that bacteria couldn’t survive in the stomach because of its high acidity levels – PH 1 and 2. As Professor Marshall explains, “It is the same as sucking the acid from your car battery and diluting it tenfold. If you put bacteria into it, it becomes sterile after ten seconds. That’s strong stuff.”
So in 1979, when Marshall’s co-Nobel-laureate Dr. Robin Warren first showed his colleagues the bacteria he discovered in stomach ulcer patients, they dismissed it. “They told him that it was just contamination,” Marshall says. But Warren couldn’t ignore the bacteria. By 1982 he had found over 100 cases of it, and asked Marshall to help him with his research. “We thought this bacteria might only be in Australia, that maybe people got it from kangaroos of chickens,” Marshall recalls. The chicken hypothesis was enough to get Marshall on board (“My Dad was running a chicken factory, so I was interested.”)
The duo ran a study in Perth with 100 patients who were experiencing epigastric (or upper abdomen) pain. They would take a biopsy and an endoscopy, and send specimens to labs for testing. They soon found a causal link between this bacteria, Helicobacter pylori (HP), and duodenal stomach ulcers – the most common type of stomach ulcers. “We found that if a patient didn’t have the bacteria, it was almost impossible for them to get [duodenal] ulcers,” Marshall explains.
“We realised there was a chance that these bacteria were causing irritation in the stomach, and the reason nobody had picked it up is because they had never looked at stomach bacteria.”
Having not only established that bacteria could live in the gut, but that there was some correlation between the presence of HP and ulcers, Marshall and Warren needed to see if they could cultivate HP. In the tradition of many great scientific discoveries (think Alexander Fleming’s discovery of penicillin), this is where an accident (read: good luck) helped.
It was Easter in 1982. “We took a biopsy on the Thursday. Friday was a holiday, and on Saturday the lab tester was busy, so he left the cultures in the incubator. By Tuesday he came back and saw these new bacteria growing,” Marshall says. “Until then, scientists thought you couldn’t culture anything from the stomach because there was no bacteria, due to the stomach acid killing it. It turns out they just hadn’t worked out how to culture anything.”
By 1983, Warren and Marshall were curing HP-bearing patients’ of their stomach ulcers with antibiotics, and were ready to share their findings. “We wrote a paper for the Lancet Medical Journal, and after that we received letters from all over the world. We knew it was a momentous discovery. Half of the global population were infected with HP, and 10% of people in the western world would get an ulcer sometime in their life,” Marshall says.
It seemed that their findings were finally shifting from the fringes of scientific research to mainstream application. But while support was flooding in from around the world, one entity was noticeably silent: big pharma.
During the 1970s, pharmaceutical companies built a multi-billion dollar industry based on maintaining, rather than curing, stomach ulcers. Their success is best epitomised by Tagamet – the antacid that became the world’s first “blockbuster drug” (generating $1b annually in revenue) in 1986. Patients would have to take 5 Tagamets per day, costing around US$5. Many patients had to take it over their lifetime to avoid chronic relapsing. That lifetime reliance was a pretty exciting prospect for drug companies, Marshall says.
But by 1983, these two Australian scientists were threatening to overturn an entire industry with their discovery that duodenal ulcers could be fixed with antibiotics. Naturally, drug companies were tight-lipped about HP’s existence for over a decade. “They were pushing hundreds of annual publications about stomach acid blockers, while we had one or two publications about HP,” Marshall says. That was enough to convince many sceptics that Warren and Marshall were wrong. Another part of the reason that nobody believed them is that it was difficult for other scientists to replicate their tests. “It’s quite technical to look inside stomachs and run tests for bacteria and ulcers. Not many people had the tools to do that.”
Warren and Marshall continued researching and spreading the word. “I was becoming increasingly frustrated,” Marshall admits. “Every time I would give a lecture about the bacteria some professor would stand up and say: ‘How can you prove this? People get stomach ulcers, then their immune system is so mixed up that they catch this bacteria because of the ulcer.’” Warren and Marshall needed to prove which was the chicken, and which was the egg – they needed to experiment on humans.
The problem, of course, was getting approval for human testing. This is partly why the history of medical and scientific breakthroughs is littered with stories of self-experimentation. For example, Walter Reed and his research team infected themselves with Yellow Fever to prove that the disease was mosquito-borne. “One of the men died. You can’t always get away with self-experimentation, but they did prove it,” Marshall says.
Marshall and Warren were among many scientists who tried to infect animals with HP – including mice, rats, guinea pigs and pigs. But it was harmless. “I had said from the beginning that if we couldn’t infect animals we would do a human experiment. So in 1985, I decided to infect myself,” he says. “I drank [the bacteria] with some beef broth. For the first few days I was ok. By day five I was bloated, I wasn’t sleeping and I was breaking out into sweats. The next morning I started vomiting, and I vomited for days. We then did a biopsy and saw that I was infected.”
Marshall’s audacious self-experimentation led him to discover that children pick up HP bacteria at a young age. They might later develop ulcers depending on other factors, such as their health. “I learned a lot from that experiment and published it in the Medical Journal of Australia, but nobody really believed it. Ten years went by and other people started experimenting with HP in their own labs and catching it. Then they started to believe us, and trying to figure out the best treatment.”
Warren and Marshall’s discoveries were not only a feat of tireless experimentation and research; but of great endurance and patience. “You have to keep fighting the battles to convince other people that you’re right until everyone believes you,” he says.
Indeed, it can take decades to gain global recognition. It was 23 years between Warren and Marshall’s first experiment, and winning the Nobel Prize. “In the 1990s people started telling us we might win,” he says. “Each year we would get excited, and then be disappointed. By 2003 we had given up. But every year we would go and have a beer together on announcement day.”
“That day in 2005 we were at the brewery having a drink when Robin’s phone rang. It was someone from the Karolinska Institute and they said: ‘You and Dr. Marshall have won the Nobel Prize!’ Robin was pretty deadpan,” Marshall laughs. ”He thanked them and they said: ‘But we have to tell the winners in person and we can’t find Dr Marshall anywhere. We’ve called his office, the university and his home.’ It was hilarious. He passed the phone across the table to me and they told me: “Dr. Marshall, you’ve won the Nobel Prize”, and I just thought: Oh that’s great!”
“Winning [the Nobel prize] changes your life. But...discover[ing] a fundamental principle concerning a disease, or a chemical that will make a product that betters peoples’ lives, that’s far more exciting than winning the Nobel Prize.”
We tend to think of the Nobel Prize as the ne plus ultra of one’s career. It’s easy to imagine that after such an honour the recipient would consider their work done. This has not been the case for Marshall. It’s been forty years since Dr. Warren first noticed HP bacteria, and Marshall continues to focus on eradicating it. His current challenge is treating patients with multiple strains. “When I see patients in China, often they have had five different treatments and they still have HP, so you have to use strong combinations of antibiotics.”
He estimates that 500 million people in China, 500 million in Africa, and 400 million in South America are infected with HP. Giving each person an individual set of antibiotics would be a monolithic feat, and Marshall says it is not the answer for a global cure. “A higher standard of living, clean water and clean toilets will make it harder for Helicobacter to spread,” he says. “If the global economy improves, it will decline, but it will be at least 50 years before it’s gone.”
Marshall has also broadened his focus to superbugs. “Superbugs – or bacteria that grow in plug holes where people take lots of antibiotics – are ordinary bacteria,” he says. “For a healthy person it wouldn't make a difference. But if you get leukaemia it might be the last bacteria that doctors can’t kill. As we become more sophisticated with cancer treatments, for example, these superbugs become more important to us.”
He believes that continued scientific experimentation will herald in an era of better diagnosis and more targeted antibiotics. “In 20 years the doctor will stick a dipstick down your throat that will tell you what you’ve got: strep throat, or virus. Then they can prescribe the exact antibiotic you need. So the amount of antibiotics consumed will drop, but people will be taking the right one. Personalised treatment, [immunotherapy] and precision medicine are going to save us from drug-resistant bacteria.”
As we think about the worsening effects of climate change, and food and water insecurity, superbugs are less visible global risks that we need to address. Marshall believes that research into the microbiome, DNA and the genome will help to solve superbugs. But the most sustainable solution is to prevent bacteria from spreading in the first place. Improving living standards will prevent the spread of bacteria and bugs, and help to shift the focus from cure to prevention.
Image: Frances Andrijich