To move forward you needed solid experimental proof. What obstacles did you encounter?
We had been trying to infect animals to see if they would develop ulcers. It all failed; we could not infect pigs or mice or rats. Until we could do these experiments, we would be open to criticism. So I had a plan to do the experiments in humans. It was desperate: I saw people who were almost dying from bleeding ulcers, and I knew all they needed was some antibiotics, but they weren’t my patients. So a patient would sit there bleeding away, taking the acid blockers, and the next morning the bed would be empty. I would ask, “Where did he go?” He’s in the surgical ward; he’s had his stomach removed.
What led up to your most famous and most dangerous experiment, testing your theory on yourself?
I had a patient with gastritis. I got the bacteria and cultured them, then worked out which antibiotics could kill his infection in the lab—in this case, bismuth plus metronidazole. I treated the patient and did an endoscopy to make sure his infection was gone. After that I swizzled the organisms around in a cloudy broth and drank it the next morning. My stomach gurgled, and after five days I started waking up in the morning saying, “Oh, I don’t feel good,” and I’d run in the bathroom and vomit. Once I got it off my stomach, I would be good enough to go to work, although I was feeling tired and not sleeping so well. After 10 days I had an endoscopy that showed the bacteria were everywhere. There was all this inflammation, and gastritis had developed. That’s when I told my wife.
How did she react?
I should have recorded it, but the meaning was that I had to stop the experiment and take some antibiotics. She was paranoid that she would catch it and the kids would catch it and chaos—we’d all have ulcers and cancer. So I said, “Just give me till the weekend,” and she said, “Fair enough.”
Your personal experience convinced you that Helicobacter infection starts in childhood. Can you explain?
At first I thought it must have been a silent infection, but after I had it, I said, “No, it’s actually an infection that causes vomiting.” And when do you catch such infections? When you’re toddling around, eating dirty things and playing with your dirty little brothers and sisters. The reason you didn’t remember catching Helicobacter is that you caught it before you could talk.
You published a synthesis of this work in The Medical Journal of Australia in 1985. Then did people change their thinking?
No, it sat there as a hypothesis for another 10 years. Some patients heard about it, but gastroenterologists still would not treat them with antibiotics. Instead, they would focus on the possible complications of antibiotics. By 1985 I could cure just about everybody, and patients were coming to me in secret—for instance, airline pilots who didn’t want to let anyone know that they had an ulcer.
So how did you finally convince the medical community?
I didn’t understand it at the time, but Procter & Gamble [the maker of Pepto-Bismol] was the largest client of Hill & Knowlton, the public relations company. After I came to work in the States, publicity would come out. Stories had titles like “Guinea-Pig Doctor Experiments on Self and Cures Ulcer,” and Reader’s Digest and the National Enquirer covered it. Our credibility might have dropped a bit, but interest in our work built. Whenever someone said, “Oh, Dr. Marshall, it’s not proven,” I’d say: “Well, there’s a lot at stake here. People are dying from peptic ulcers. We need to accelerate the process.” And ultimately, the NIH and FDA did that. They fast-tracked a lot of this knowledge into the United States and said to the journals: “We can’t wait for you guys to conduct these wonderful, perfect studies. We’re going to move forward and get the news out.” That happened quite quickly in the end. Between 1993 and 1996, the whole country changed color.
You have since devised tests for H. pylori. How do they work?
The first diagnostic test, done after a biopsy, detected Helicobacter that broke down urea to form ammonia. More recently I developed a breath test for Helicobacter based on the same principle. That test was bought by Kimberly-Clark, and they sell it all over the world. That one little discovery set me up for the rest of my career.
Is it possible to create a vaccine against Helicobacter?
After 20 years and a lot of hard work by companies spending millions, we have still been unable to make a vaccine. The reason is that once it’s in you, Helicobacter has control of your immune system. Once I realized this, I said, well, if it’s too difficult to make a vaccine against H. pylori, what about loading a vaccine against something else onto the Helicobacter and using it as a delivery system? So that is my vaccine project, and it is my life at the moment. I’m making a vaccine against influenza. We’ll find a strain of Helicobacter that doesn’t cause any symptoms. Then we’ll take the influenza surface protein and clone that into Helicobacter and figure out how to put it in a little yogurt-type product. You just take one sip and three days later the whole surface of your stomach is covered with the modified Helicobacter. Over a few weeks, your immune system starts reacting against it and also sees the influenza proteins stuck on the surface, so it starts creating antibodies against influenza as well.
How would this be better than current flu vaccines?
Right now it takes a year to make 50 million doses of flu vaccine, so you only get vaccinated against last year’s flu. Whereas we are building swine flu vaccine as we speak. We know the sequence of the swine flu virus. You can make the DNA. You can put it in Helicobacter—with a home brew kit, I can make 100,000 doses in my bathtub. Using the same method, a Helicobacter vaccine against malaria would be dirt cheap. You could make 100 million doses in the middle of Africa without a refrigerator. You could distribute it at the airport through something like a Coke machine.
Based on this experience, should we be taking a fresh look at other diseases that do not have well-understood causes?
Helicobacter made us realize that we can’t confidently rule out infectious causes for most diseases that are still unexplained. By the 1980s, infectious disease was considered a has-been specialty, and experts were saying everyone with an infectious disease could be cured by antibiotics. But what about when your kids were 2 years old? Every week they’d come home with a different virus. You didn’t know what the infections were. The kids had a fever for two days, they didn’t sleep, they were irritable, and then it was over. Well, you think it is over. It might be gone, but it has put a scar on their immune system. And when they grow up, they’ve developed colitis or Crohn’s disease or maybe eczema. There are hundreds of diseases like this, and no one knows the cause. It might be a germ, just one you can’t find.
How can we track down these mystery pathogens?
What we would like to do, hopefully with funding from NIH, is launch big, long-term programs. You would enter your baby into a trial the day he is born. We would have his genome decoded. We’d survey your microbiome [all the microorganisms in the body and their DNA] and maybe your husband’s microbiome, and all that would go in a database. Then we would come along and take a feces culture from your baby each month. And if ever he got a fever, we would swab his cheek and save that. We would do 10,000 kids like this. Then, in 20 years’ time, we would find that 30 of them developed colitis, and we would go back. If we could get all of that material out of the deep freeze and run it through the sequencing machine, we would find the answer. In the last 20 years, people have been so focused on linking disease with environmental factors like chemicals and pollution. But the environmental factor could be an infectious agent that you had in your body at some time in your life. Just because somebody ruled out an infectious cause in the 1980s or ’90s doesn’t mean this was correct. Technology has moved forward a long way.
Even now, though, isn’t it hard for new ideas to be heard when medical journals are gatekeepers of the status quo?
It’s true, but they have their ears pricked up now because every time a paper comes to them, they say: “Hang on a minute, I had better make sure that this is not a Barry Marshall paper. I don’t want to have my name on that rejection letter he shows in his lectures.” Now they might say, “It’s so off-the-wall....Is it true?”