Episode Summary

Dr. Robert Gaynes, distinguished physician and professor of infectious diseases at Emory University, joins Meet the Microbiologist for the 3rd, and final, episode in a unique 3-part segment, in which we share stories about the life and work of medical pioneers in infectious diseases. Here we discuss the career of Dr. Barry Marshall, the Australian physician who is best known for demonstrating, in a rather unorthodox way, that peptic ulcers are caused by the bacterium, Helicobacter pylori.

Gaynes is author of Germ Theory: Medical Pioneers in Infectious Diseases, the 2nd edition of which will publish in Spring 2023. All 3 scientists highlighted in this special MTM segment are also featured in the upcoming edition of the book.

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Ashley's Biggest Takeaways

  • By the 1880s, the germ theory of disease had been fully accepted, and for the next 100 years, medicine put diseases in 2 categories: infectious diseases or chronic diseases.
  • Barry Marshall and Robin Warren began to blur the line between these 2 disease categories.
  • Marshall was born in Western Australia in 1951.
  • He was the oldest of 4 children.
  • His father was a tradesman, and his mother, prior to having children, was a nurse.
  • Marshall chose to go to medical school and graduated in the mid 70s.
  • He did an internship again in Western Australia, and then decided that he wanted more of an academic career. So he moved to the Royal Perth Hospital to continue training in Internal Medicine.
  • As part of this training, individuals of the program were encouraged to perform an annual research project.
  • For his project, Marshall partnered with Robin Warren, a pathologist who had been looking at gastric biopsies from patients who had a variety of GI illnesses, including gastritis.
  • At the time, the stomach was believed to be a sterile environment, due to the high concentration of acid that is present, and gastritis was considered a chronic disease.
  • The cause of gastritis was unknown, however cigarette smoking and stress were correlated with the disease.
  • Despite encountering more than a decade of skepticism from the scientific community, Marshall was finally able to prove that H. pylori was not only associated with, but also the cause of peptic ulcer disease.   
  • Koch’s Postulates outline the 4 criteria that must be satisfied in order to establish a causal relationship between a microbe and disease.

Koch’s 4 Postulates:

  • The microorganism must be found in abundance in all organisms suffering from the disease but should not be found in healthy organisms.
  • The microorganism must be isolated from a diseased organism and grown in pure culture.
  • The cultured microorganism should cause disease when introduced into a healthy organism.
  • The microorganism must be re-isolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.

Featured Quotes:

Gaynes: “There were some major shifts in thinking with organisms that were discovered in the 20th century, and now the 21st century, and by adding those chapters [to the 2nd edition of Germ Theory], it allowed me to discuss some of the most important pathogens that humanity has had to deal with.”

“Barry Marshall did something in the 1980s, along with his colleague, Robin Warren, that really changed thinking as much about microorganisms and their effect on humans as the germ theory of disease itself.”

“The story of what Barry Marshall really did is a golden opportunity to examine one of the central reasons for studying the history of medicine, which is to understand how change occurs in medicine.”

“In my career, what I learned in medical school about peptic ulcer disease, was totally wrong, and I watched as Barry Marshall and Robin Warren tried to convince a very skeptical medical world that it had something to do with this funny shaped bacterium called Helicobacter pylori.

“[Marshall] was a very bright student and had a boundless curiosity. One of the other aspects that I saw in his background was that his curiosity was compounded with a certain tenacity. When he got on a subject, he was tenacious in learning about it.”

“He had chosen the specialty of internal medicine, which I think suited his personality. But he was still training, and part of that training was that all individuals in that program were encouraged to perform a research project each year. [That’s how] he got connected with a pathologist named Robin Warren.”

“One of the things that Warren noted was an unusual curved bacterium that really no one had much commented on, prior to that time. This was in a series of patients; it wasn't just an isolated event. And he became rather interested, but he was a pathologist. He didn't really see patients.”

“Marshall took this list [of patients] that Robin Warren had developed and began to look it over. He realized that one of the patients on the list was a woman he had actually taken care of, and no one knew exactly what was wrong with her, even though she had a variety of GI symptoms. And he became quite intrigued.”

“He began to look in the literature (going back 50 years) to see if anyone else had ever described this curved bacterium, and much to his surprise, he found that this had been described before, even though it never been fully cultured. So he said, ‘this isn't a completely new finding. There must be something going on with this.’”

“So what they eventually did was put together all of the patients that had had issues, and they decided to do a study of 100 patients (including the first few patients from list) where all the patients with gastrointestinal symptoms would be biopsied, the biopsy would be looked at and, importantly, the biopsy would be cultured.”

“They found that every single patient that had a duodenal ulcer had evidence of this bacterium, which we now know is H. pylori.”

“In 1983, Barry Marshall decides he's going to present this association between H. Pylori and peptic ulcer disease at the Royal Australian College of Physicians meeting in Perth, Australia, and I asked him about that experience.”

Marshall: “I did the presentation, and the gastroenterologists didn't believe a bit of it. Someone sort of stood up and said, ‘Barry, you know, people with duodenal ulcers don’t have gastritis—’ But I had done so much literature searching I knew that they were wrong. So it was difficult to tell your senior bosses, trained at the Mayo Clinic, that they were wrong.”

Gaynes: “He said in his Nobel speech that, to the gastroenterologists, the concept of a germ causing ulcers was like saying the earth is flat. And he realized after this meeting, that the data weren't going to be enough, and it was going to be difficult to get them to really rethink what they thought they knew.”

“In 1983, Barry Marshall did something that is familiar to all clinical microbiologists. He had the micro lab develop a lawn of H. pylori, and then he impregnated a disc with Bismuth. And he put the Bismuth disc directly on the culture plate to see what happened.”

Marshall: “Right at the end of the day before I went home, I went up to the micro lab, and, with the lab tech there, we opened the incubator and got that petri dish out. And there was this crisp zone about a 15 mm-20 mm radius around the Bismuth disc. And I knew that if you drink Pepto Bismol, you must have 1000s of μg per mL, that's pretty effective.”

Gaynes: “When you have a putative organism that causes a disease, we've known for over 100 years, that one of the ways to prove that this organism causes this disease is to prove Koch’s Postulates. Koch’s Postulates were developed by Robert Koch. He had the idea that 1) The putative organism must be constantly present in diseased tissue. 2) You can isolate the organism and pure culture from that disease tissue. 3) You take the organism from a pure culture, and you induce disease when you inject it into experimental animals. 4) From those experimental animals you must get back the same organism.”

“The problem was they could not develop an animal model for H. Pylori. He tried many different ways, many different animals, with any number of different types of inoculums. And he could not develop one. He was quite frustrated and doing this. And so with that frustration, he took, really, quite a brave step.”

“He mixed up a slurry of H. Pylori bacteria and drank it, knowing that he had a normal biopsy of his stomach before he did this, and then 10 days later, he got the same endoscopist to do a biopsy. And as he said, he had bacteria everywhere. He had done the self-experimentation.”

Marshall: “I went home and told my wife about it, and of course, she was like, ‘Oh, my God, you're gonna infect the whole family. That's why you've got such a bad breath. This is disaster.’”

“I think he was surprised that he got this acute illness. But it helped him develop the natural history of what happens when someone gets H. Pylori. Often, particularly in developing world, very young children will get this acute illness with some vomiting, and then things will die down for a while. [Marshall] was very sick, but he was able to treat and cure himself.”

“The major article that I saw on physician self-experimentation was published in 2012, in the journal called the Texas Heart Institute, by a Dr. Weiss, who found, in the last 2 centuries, about 465 examples of physician self-experimentation, about 2/3 of which were in the area of infectious diseases, which might include vaccine administration.”

“The conclusion from Dr. Weiss’s study showed that, despite the fact that a lot of these were pretty unwise decisions—including a few deaths—many of the self-experiments were invaluable to the medical community and actually helped in understanding disease.”

“In 1985, Procter & Gamble funded a fellowship and a laboratory at the University of Virginia in the United States for Marshall to further his research. And while he expected to be in the U.S. for maybe 2-3 years, he ended up staying in America for about 10 years, and his research at the University of Virginia, at this point, centered around diagnostic tests for H. Pylori.

“The main thing that that they worked on in in that time was a breath test that used a very minute amount of radioactive carbon-13 that was in a material called urea. And if H. pylori were in the stomach of a patient, the urea would be broken down by the bacteria’s urease enzyme, and it would produce very small amounts of radioactive CO2, which could be detected in a patient's exhaled breath within minutes.”

“Now this was a game changer. It eliminated the need to study H. Pylori, by using endoscopy by looking at slides of stomach or ulcer biopsies, and it eliminated the need to have to cultures to see if H. pylori was present in the stomach.”

“1994 was the real watershed year. In February of that year, the National Institutes of Health held a consensus meeting in Washington D.C., which, after a couple of days, had a statement to the effect that the key to treating duodenal gastric ulcers was detection and eradication of H. Pylori.”

“In his Nobel speech he said, ‘I had been waiting 10 years for this day. And I felt a combination of relief and satisfaction that I had achieved what I set out to do to do. Years before I had developed the hypothesis, tested and proved it, and now it had reached official acceptance.’ So it took him 10 years from when he personally was convinced that he was on the right track to really get this kind of consensus statement.”

“He had a lot of people that that simply would not accept it, particularly in the first 10 years of his efforts. And it was rather discouraging that, you know, it was almost like people were voting. So I asked him about his thinking on the process of getting people to accept his idea. And this is what he said.”

Marshall: “We couldn't knock down our own hypothesis. That's the thing, be critical of your own data, and then go with the data. And once you've got a pathway, and you're getting facts, then it doesn't matter how many people there are out there who don't believe you. Science is not a democracy.”

Links for the Episode:

From the ancient worlds of Hippocrates and Avicenna to the early 20th century hospitals of Paul Ehrlich and Lillian Wald to the modern-day laboratories of François Barré-Sinoussi and Barry Marshall, Germ Theory brings to life the inspiring stories of medical pioneers whose work helped change the very fabric of our understanding of how we think about and treat infectious diseases.
Germ Theory: Medical Pioneers in Infectious Diseases

The second edition of Germ Theory, which will include chapters on Françoise Barré-Sinoussi, Barry Marshall and Tony Fauci, will publish in Spring 2023. 

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Barry Marshall with the Nobel Medal