Barry Marshall and Robin Warren
Two of the nicest Nobel Prize winners I have met. Port Hedland connection. Helicobacter pylori colonizes half of the global population and causes Gastritis, Peptic Ulcer disease or Gastric Cancer.
Famous cartoon characters from Real Life!
Barry Marshall gets most mentions for their 2005 Nobel Prize because he was the one who swallowed a brew of Helicobacter pylori Bacteria to prove that it causes Stomach Ulcers. His dream was to eradicate the species discovered by Robin Warren.
In an article1 published in 2008, he recounts his decision to swallow.
I was aware of famous self-experiments because I read the history of John Hunter’s self-infection with gonorrhea and syphilis (which may have caused his death years later). However, I had been arguing with the skeptics for two years and had no animal model that could prove H pylori was a pathogen.
If I was right, then anyone was susceptible to the bug and would develop gastritis and maybe an ulcer years later. So I expected to develop an asymptomatic infection. The experiment was planned with a culture from a patient with dyspepsia and confirmation that it was sensitive to metronidazole. Then I underwent endoscopy in early July 1984 to confirm that I was negative for H pylori.
Three weeks later, I drank the ‘brew’ which was a suspension of two culture plates of the organism.
If only I knew that people would be so interested, I would have taken a photograph!
After five days, I started to have bloating and fullness after the evening meal, and my appetite decreased. My breath was bad and I vomited clear watery liquid, without acid, each morning at approximately 06:00.
Then, a follow-up endoscopy showed severe active gastritis with polymorphonuclear infiltrate and epithelial damage.
Evidently, H pylori was a pathogen for normal people. The ulcer did not merely set you up for catching the infection. People with asymptomatic H pylori were ‘carriers’ and most people did not have ulcers from the bacterium. Gastritis was explained.
Robin Warren discovery of Helicobacter pylori Bacteria
Here he was delivering his Nobel Lecture.2 He died in 2024.3
In his Nobel Lecture4, Robin Warren starts with:
This is the story of my discovery of Helicobacter.
At various times I have been asked: did I steal the discovery; did I find it by accident; did it follow some brilliant research work; or was it serendipity.
My answer to most of these is a definite “No.”
Obviously, as with any new discovery, there is an element of luck, but I think my main luck was in finding something so important.
I think the best term is serendipity; I was in the right place at the right time and I had the right interests and skills to do more than just pass it by.
Lack of Qualified Reviewers
Robin Warren had his paper submitted to The Lancet on his discovery delayed because the journal could not find suitable reviewers.
I sent a letter to the Lancet in 1983, a summary of the work I had done before I met Barry (ref 1). Barry sent an accompanying letter describing our joint work.
He also presented our findings at the Brussels Campylobacter conference.
Martin Skirrow, who chaired the conference, was very impressed with our work.
We sent our definitive paper to the Lancet in 1984 (ref 2).
Although the editors wanted to publish, they were unable to find any reviewers who believed our findings.
Our contact with Skirrow became crucial here. We told him of our trouble, and he had our work repeated in his laboratory, with similar results. He informed the Lancet and shortly afterwards they published our paper, unaltered.
Marital Bliss
Helicobacter patients show considerable variation.
I was involved with these early examples.
• Barry gave himself a severe active gastritis, to the disgust of his wife, in an attempt to fulfil Koch’s postulates.
• Morris, in New Zealand, gave himself chronic gastritis and took years to cure it.
• My wife developed arthritis and as soon as she took NSAIDs she developed severe epigastric pain. Stopping the NSAIDs reversed this. And again. I sent her to Barry, who found Helicobacter, treated it and she was able to take the NSAIDs. Do not take it for granted that NSAIDs are the only guilty party.
• Most patients are symptomless. This was actually one of our major difficulties. I was an example. After she was treated, my wife complained that I had bad breath.
I was positive for H pylori and after treatment marital bliss returned.
Experiments with Bismuth
In his Nobel Lecture, Barry Marshall recounted his excitement:
Q8. Was bismuth an antibacterial?
A. Yes. My laboratory colleagues at Fremantle Hospital helped me carry out the simple experiment described below. 10 mm filter papers were dipped into De-Nol liquid and allowed to dry. Helicobacter pylori were then heavily inoculated onto individual blood agar culture plates. The discs were placed in the center of the plates which were cultured from Friday until Tuesday.
When examined on the fourth day, a clear zone of bacterial inhibition was present around each of the discs (as shown in Figure 5).
I had discovered that Helicobacter was exquisitely sensitive to bismuth.
It was probably the most exciting day of my life when I saw that bismuth had killed the Helicobacter. It all fitted too perfectly to be a coincidence.
Everyone had forgotten that, in the days before penicillin, bismuth was an important antibacterial therapeutic agent.
I think that was the first time it crossed my mind that we might win the Nobel Prize.
My keen intern, Vinod Ganju, of Indian descent, then agreed to take some bismuth and undergo a gastroscopy. As shown in Figure 5, the numerous Helicobacter organisms could be seen practically exploding with dense bismuth precipitates all around them.
Barry Marshall Port Hedland connection
Barry Marshall was a busy man and arranged collaboration before the days of internet.5
The 100 patient study was completed at the end of May 1982. Perhaps because of my enthusiasm, I had recruited 100 patients rather quickly, with only two declining to take part.
In the School of Medicine Statistics division I found Norm Stenhouse who agreed to supervise the data analysis. This involved asking Robin and John Pearman to send their data tables separately to his student Rose Rendell.
I did the same with my demographic data and clinical questionnaire.
I completed the process immediately before my family of six departed for Port Hedland, a mining town 1,900 km from Perth, in the North of Western Australia.
In a frenzied weekend while my wife Adrienne was packing for the trip, I ducked out and spent all Saturday morning at the gastroenterology department photocopying the 100 endoscopy reports.
Several weeks later, now the acting physician at Port Hedland, I scored patients for the presence or absence of the main visible endoscopic lesions and mailed that final datatable to Rose.
No mention of the Endotoxin in 1980s
Looking at the Nobel Lectures of Marshall and Warren, I was struck by absence of any mention of the toxins exuded by Helicobacter pylori Bacteria. Despite having good quality electron microscope images showing Flagella, the duo were more interested in killing the bacteria than the toxicology.
Helicobacter pylori Endotoxin is less toxic than E. coli Endotoxin
Searching PubMed for “Helicobacter pylori Endotoxin” I found 494 papers.6
Searching PubMed for “Helicobacter pylori lipopolysaccharide” finds 743 papers.7
Note that after 4 decades Barry Marshall and others continue to publish the details of Helicobacter pylori Endotoxin structural variants.
The top listed 2022 paper was from Australian researchers.8
The next 2023 paper9 by Barry Marshall was a collaboration with researchers in China and concluded:
We demonstrated that the LPS lipid A and core-oligosaccharide domains are conserved among H. pylori strains of different phylogeographic origin, while the LPS O-antigen heptan moiety (commonly present in European strains) appeared to be absent in the clinical isolates.
Progression to Cancer
There are many researchers investigating Helicobacter pylori induced Cancer, and many papers looking at the detailed interactions of Lipid A.10
Close to the email length limit, so I might add references later.
Barry Marshall, Paul C Adams. 2008. Helicobacter pylori: A Nobel pursuit? Canadian Journal of Gastroenterology and Hpatology. https://onlinelibrary.wiley.com/doi/10.1155/2008/459810
https://www.nobelprize.org/prizes/medicine/2005/warren/photo-gallery/
https://www.nobelprize.org/prizes/medicine/2005/warren/facts/
https://www.nobelprize.org/prizes/medicine/2005/warren/lecture/
https://www.nobelprize.org/prizes/medicine/2005/marshall/lecture/
https://pubmed.ncbi.nlm.nih.gov/?term=Helicobacter%20pylori%20Endotoxin
https://pubmed.ncbi.nlm.nih.gov/?term=Helicobacter+pylori+lipopolysaccharide
Daniel Sijmons, Andrew J Guy, Anna K Walduck, Paul A Ramsland. 2021. Helicobacter pylori and the Role of Lipopolysaccharide Variation in Innate Immune Evasion. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.868225/full
Xiaoqiong Tang, Peng Wang, Yalin Shen, Xiaona Song, Mohammed Benghezal, Barry J Marshall, Hong Tang, Hong Li. 2023. Lipopolysaccharide O-antigen profiles of Helicobacter pylori strains from Southwest China. https://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866-023-03116-0
Barbara Schmidinger, Kristina Petri, Clara Lettl, Hong Li, Sukumar Namineni, Hellen Ishikawa-Ankerhold, Luisa Fernanda Jiménez-Soto, Rainer Haas. 2022. Helicobacter pylori binds human Annexins via Lipopolysaccharide to interfere with Toll-like Receptor 4 signaling. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010326