Barry Marshall likes quotes. Over a bacon and eggs breakfast at the Nittany Lion Inn on a frigid December morning, he peppers the conversation with passages that have inspired him. Not surprisingly (Marshall is, after all, a down-to-earth Aussie) his favorites seem to be those that cut through pomp and pretension. "The greatest obstacle to discovery," says Marshall, quoting social historian Daniel J. Boorstin, "is not ignorance—it is the illusion of knowledge."
Marshall can lay fair claim to an impressive depth of knowledge, particularly about Helicobacter pylori, a tiny spiral-shaped bacterium covered with whip-like hairs that serve both as its 'legs' and as a high-powered drill.
It was a "research project on the side, something I just fell into" says Marshall, describing how, in 1981 as a young clinical fellow at the Royal Perth Hospital in Western Australia, he had first joined senior pathologist Robin Warren in investigating the link between bacterial infection and peptic ulcers. Neither scientist could have imagined that their collaborative research efforts would span two decades and eventually lead them to share the 2005 Nobel Prize in Medicine.
New doors opening
Putting down his coffee cup, Marshall (still slightly jet-lagged after flying from Perth to Penn State) reflects with some amazement on the road that led to the award, as well as the changes in his life since his "Nobel luck" as he self-effacingly calls it.
Though he admits that laureates "owe supporters a lot of favors in the form of lectures and commencement speeches," he also notes that many new doors have opened to him. His recent part-time appointment at Penn State as the Francis R. and Helen M. Pentz Professor of Science is one such example. "I get a lot of value from the association," says Marshall, "largely because of the genomics and infectious disease expertise here." At the Huck Institutes of the Life Sciences, in particular, "researchers are interested not just in outcome-driven science,but also in curiosity-driven science," he adds.
It was Marshall's own innate curiosity that paved the way for the revolutionary discoveries he made with Robin Warren.
In 1979, Warren first observed that in half his patients undergoing gastric biopsies, colonies of corkscrew-shaped bacteria were present in the antrum, or lowermost part of the stomach. More crucially, he noticed that the presence of these bacteria almost always coincided with evidence of gastric inflammation.
Together Marshall and Warren studied the biopsies of 100 patients, and—after several attempts—Marshall was able to cultivate the previously unknown bacterium, later named Helicobacter pylori.
Marshall and Warren began to suspect that gastritis and peptic ulcers—painful conditions that plague countless people worldwide—were, in fact, caused by H. pylori infections, not by stress, spicy food, and other lifestyle factors which were then commonly believed to be the culprits.
The bacterial theory of ulcers was nothing new. First proposed in 1899 by Polish gastroenterologist Walery Jaworski—and periodically advanced by other researchers in the decades that followed—the idea had been routinely rejected based on the entrenched belief that microorganisms could not survive in the stomach's acidic environment.
Marshall and Warren were the first to correctly identify the bacteria and to propose that H. pylori survive by hiding under the stomach's Ph-neutral mucous layer. For the first time, here was a theory that could not be casually dismissed.
Challenging the status quo
To say the duo's dogma-defying H. pylori hypothesis was poorly received would be an understatement. "We fought for ten years," Marshall says. Tagamet and Zantac are among the world's biggest-selling prescription drugs, he adds. Both these drugs are given to patients on the premise that too much stomach acid—created by stress and poor diet choices—is the cause of their ulcers. (Notes Marshall, while inhibiting acid can allow ulcers to temporarily heal, they frequently recur since the H. pylori infection is still present.)
As Marshall puts it, the "Acid Mafia"—pharmaceutical companies heavily invested in the old paradigm—was not enthusiastic about the researchers' assertion that ulcers were infections that could be cured by a short, relatively low-cost regimen of antibiotics.
In the face of sustained opposition from the medical establishment, "I knew I had to do an animal model of some sort," Marshall explains. "We started with a piglet experiment, but we ended up with pigs that were about a hundred pounds," he recalls with a chuckle. "Chaos!" What's more, says Marshall, "to make the bacteria 'take' in the pigs, they had to eat a human diet. So three times a day the hospital meal was brought in for the pigs...Mashed potatoes and everything else! It was a funny experiment, but we were dead serious about it at the time and I didn't see any humor in it."
Our waitress glides by, filling coffee cups and clearing plates.
Marshall continues, "The thing about pigs is they're born in such filth, they're covered with bacteria and have very strong immunity. So we couldn't get the bacteria to take! At the end of that experiment, it had gotten nowhere and I'd wasted six months."
Adds Marshall, "There's such impatience and frustration when you can see the pathway you need to follow, but it's just not happening."
A very personal risk
The solution? "The short-cut through that problem was just to do a human experiment," Marshall says. "But if I had put in a proposal, everybody would have said 'Here's this junior guy doing eccentric research in our hospital. Are we going to let him give these bacteria to medical students or other people?' I would have gotten nowhere."
To Marshall, his next move was clear. Without informing his family—"It's a lot easier to obtain forgiveness than permission," he quips—Marshall drank a Petri dish full of H. pylori extracted from a patient suffering from gastric ulceration. "Well, here it goes, down the hatch," is what he recalls saying before drinking. His lab technicians were horrified.
As he had hoped and expected, Marshall soon developed painful gastritis. He endured two weeks of vomiting, appetite loss, and halitosis (bad breath can be a marker of H. pylori infection), during which time two endoscopies confirmed both his infection and the ulcerative damage to his stomach mucosa. "So, great experiment!" exclaims Marshall, with his trademark devil-may-care exuberance.
A confession to his wife—and a course of antibiotics—eventually set everything right.
Barry Marshall
Longtime colleagues and co-Nobelists Marshall and Warren pose at a favorite haunt in hometown Perth, Australia.
Pluck and luck
"Everyone was against me, but I knew I was right," declared Marshall in 1998, after being honored by the American Academy of Achievement.
"What gives some people the ability to challenge a prevailing dogma and hold tight to their beliefs?" I ask him.
"I think I've always just gone my own way," he responds. "As I often say, in science, you've got to be pretty thick-skinned and ready to take the blows."
You also have to be open to new ideas, he suggests. "In my case, I wasn't great at sports and was always the last kid picked for the football team," recalls Marshall of his childhood in the small Outback town of Kalgoorie. "From an early age, I was looking for my niche. But I was unfocused and went off in many directions."
"Anything that was interesting, I'd have a go at!" he adds, smiling. " I always had some kind of project I was building in my garage. But in school, once I'd convinced myself I could do a particular subject, the excitement would go out of it. I like the excitement of new things—boredom is the worst thing."
These days, Marshall is still game to 'have a go' at new things. "Since the Nobel," he comments, "people have said to me that it's very difficult to do more than one important thing in your lifetime. But I sat down and thought 'I'm 56. I was successful at understanding a disease. I was successful in diagnostics and treatment.' And I asked myself 'What is the most important thing I could do with my H. pylori knowledge in the next few years?"
Productive collaborations
Marshall's new focus is the development of innovative approaches to vaccine development, specifically the potential insertion of viral antigens into bacteria such as H. pylori. He believes that collaborations with colleagues in Penn State's Center for Infectious Disease Dynamics, the Eberly College of Science, and the College of Medicine, among others, will prove fruitful for all parties. "There are world experts here," notes Marshall, "And whenever I come here and talk to faculty, I learn a lot."
What's more, notes Marshall, Penn State has the latest equipment. "Some of these instruments I've seen are still in evolution—but because of the connection with the University, you can see the latest model coming out six months before anyone can get hold of it."
While his principal appointment will remain at the University of Western Australia (in fact, the school is building The Marshall Centre for Infectious Diseases Research and Training, to be completed in March of 2008), Marshall plans to spend time on the University Park campus during annual spring and fall visits, overseeing research and giving lectures.
In time, he hopes that "there can be an easier exchange of Penn State professors on sabbatical or interested students spending a semester studying in Western Australia, perhaps at the Marshall Centre."
During a University Park lecture in December 2007, the "unfocused kid from Kalgoorie" had some words of advice for aspiring laureates in the audience: "Remember that if you're on a good research and discovery track, you should be on it a couple years before people start thinking about it," said Marshall. "People might think you're crazy, but..."—and then the quote-loving maverick reached for some words of wisdom from Louis Pasteur—"Chance favors the prepared mind.
Barry J. Marshall, M.D., is a physician, Nobel Prize laureate in Medicine, Professor of Clinical Microbiology at the University of Western Australia, and most recently the Francis R. and Helen M. Pentz Professor in Penn State's Eberly College of Science. He can be reached at bmarshall@hpylori.com.au.