Nobel prize is awarded to doctors who discovered H pylori

BMJ 2005; 331 doi: http://dx.doi.org/10.1136/bmj.331.7520.795 (Published 6 October 2005)
Cite this as: BMJ 2005;331:795.1

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29 October 2005

SIR - Although retired now, I was Head of the Microbiology Department in Royal Perth Hospital where Helicobacter pylori bacteria were first cultured in April 1982. In October 1981 Marshall was a junior doctor working in the Histopathology Department with Warren, and they asked me to culture stomach specimens (without any research money!). Longer times of incubation were about to be attempted when the 35th culture was left (not “overlooked”) during the Australian Easter holiday of five days; and that culture revealed a pure growth of "Campylobacter pyloridis" (the first name). In 1983-84 Marshall and Warren published their letters and paper.

I was on sabbatical leave, while Marshall moved to Fremantle Hospital Microbiology Department for six months, and worked only on H pylori; from there he wrote the first description of the culture(1) stating “We have cultured the bacteria…” and this has been repeated by him and nearly all other writers subsequently. So perhaps it is not strange that after his 1995 Lasker award, Marshall wrote that Warren and he “together embarked on an attempt to culture the organisms”… “We tried many different culture media”.(2) Marshall wrote two good papers in 1985; and then in 1986 went to the USA for 8 years, and without "Australian co-operation" wrote a few reviews. However, from 1984 it provided me with a wonderful opportunity, often with the eminent electronmicroscopist Armstrong, for 22 research papers (50 in all) on “Campylobacter pyloridis” that led to its first culture in liquid medium, the first reliable serology test for infection, and the first evidence of genomic variation in H pylori, etc. It should also be recorded that the genus name Helicobacter was not introduced by Marshall or Warren. In 1989, I published the new genus name Helicobacter(3)-in the required technical journal, which is not found on Medline - with contributions from colleagues in Queensland and England.

This was against a background of Microbiology service for the 1000-bed hospital, keeping MRSA out of the hospital, and treating many post- infection syndrome patients. I left Western Australia at the end of 1989 for family reasons, and helped start a Medical School in the Middle East.

From 1994 Marshall and Warren have been recognised by various Australian and other awards, and I congratulate them on the Nobel Prize. Certainly, Marshall was the first to challenge clinicians to accept H pylori as the cause of peptic ulcer, but Microbiology expertise and research were essential from the beginning.

C Stewart Goodwin FRCPath, FRCPA
Wimbledon

1. Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983; i: 1273-4.

2. Marshall BJ. The Albert Lasker Medical research Award. Helicobacter pylori. The etiologic agent for peptic ulcer. J Am Med Ass 1995; 274: 1064 -6.

3. Goodwin CS, Armstrong JA, Chilvers T, et al. Transfer of Campylobacter pylori and Campylobacter mustelae to Helicobacter gen. nov. as Helicobacter pylori comb. nov. and Helicobacter mustelae comb. nov. respectively. Int J Syst Bacteriol 1989; 39: 397-405.

Competing interests: None declared

Competing interests: None declared

Charles S Goodwin, retired

past professor

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26 October 2005

I was under the impression that peptic ulcers can be treated by targeting H. pylori. If this is the case, doesn't it suggest that this bacterium is the cause?

Competing interests: None declared

Competing interests: None declared

Onisillos Sekkides, Medical Editor

London, NW1

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26 October 2005

The fulfillment of Koch's postulates in humans has been discussed by Marshall himself in 1995, when he came to the conclusion, that "that only one of the many steps required for the development of peptic ulceration has so far been fulfilled, i.e. the ability of H. pylori to produce histological gastritis in a susceptible host." (1).

Since then, the Helicobacter researchers came up with the mongolian gerbil as an animal model that allowed observation of H.pylori induced pathogenesis. In the gerbil model, a direct connection between experimental H.pylori infection and induction of chronic active gastritis (2), intestinal metaplasia, gastric and duodenal ulcer (3,4) and even gastric carcinomas could be established (5,6).

One can still argue that what is true for gerbils isn't necessarily true for man, of course, but these data clearly indicate the pathogenic potential of H.pylori alone. Undisputed are the facts that additional factors like high salt, low vitamin c diets or smoking can influence the outcome of disease as well as genetic predispositions of the infected host.

So, by what we know now, Helicobacter pylori really is the causative agent of gastric inflammation, and -at least in the animal model- of carcinomas of the upper digestive tract.

This knowledge gave rise to studies like (7), which found that "Anti- H. pylori therapy may be considered as one of the treatment options for early-stage H. pylori-positive gastric DLBCL(MALT)[=diffuse large B-cell lymphoma with features of MALT]", and though this has to be validated in larger studies yet to come, it is a very promising result.

This would not have been possible without the detailed knowledge we now have due to the discovery of Warren and Marshall (8).

1. Helicobacter pylori in peptic ulcer: have Koch's postulates been fulfilled? Marshall BJ., Ann Med. 1995 Oct;27(5):565-8.

2. Helicobacter pylori-induced chronic active gastritis, intestinal metaplasia, and gastric ulcer in Mongolian gerbils. Ikeno T, Ota H, Sugiyama A, Ishida K, Katsuyama T, Genta RM, Kawasaki S., Am J Pathol. 1999 Mar;154(3):951-60.

3. Helicobacter pylori infection induces duodenitis and superficial duodenal ulcer in Mongolian gerbils. Ohkusa T, Okayasu I, Miwa H, Ohtaka K, Endo S, Sato N., Gut. 2003 Jun;52(6):797-803.

4. Characteristics of a clinical isolate of urease-negative Helicobacter pylori and its ability to induce gastric ulcers in Mongolian gerbils. Mine T, Muraoka H, Saika T, Kobayashi I., Helicobacter. 2005 Apr;10(2):125-31

5. Development of Helicobacter pylori-induced gastric carcinoma in Mongolian gerbils. Honda S, Fujioka T, Tokieda M, Satoh R, Nishizono A, Nasu M., Cancer Res. 1998 Oct 1;58(19):4255-9

6. Development of gastric adenocarcinoma in Mongolian gerbils after long-term infection with Helicobacter pylori. Zheng Q, Chen XY, Shi Y, Xiao SD., J Gastroenterol Hepatol. 2004 Oct;19(10):1192-8.

7. Long-term results of anti-Helicobacter pylori therapy in early- stage gastric high-grade transformed MALT lymphoma. Chen LT, Lin JT, Tai JJ, Chen GH, Yeh HZ, Yang SS, Wang HP, Kuo SH, Sheu BS, Jan CM, Wang WM, Wang TE, Wu CW, Chen CL, Su IJ, Whang-Peng J, Cheng AL., J Natl Cancer Inst. 2005 Sep 21;97(18):1345-53.

8. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Marshall BJ, Warren JR., Lancet. 1984 Jun 16;1(8390):1311-5.

Competing interests: None declared

Competing interests: None declared

Michael A Aigner, PhD

None

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If an abnormally elevated intraluminal pCO2 is required for H pylori to thrive, as proposed, then the fact that the organism did thrive in Marshall was an indication that he had an abnormally elevated intralumuinal pCO2 and possibly an abnormally low intramural pH either intermittently or even continuously when he swallowed the innoculate. If in addition an abnormally low intramural pH is a cause or harbinger of chronic diseases in later life, as proposed (1), he might have developed one or more of these since then. Has or will he?

The issue is important for if H pylori infestation is a marker of an abnormally elevated intraluminal pCO2 then it is insufficient to eradiate the gastritis and ulcers with which it might be associated. The ultimate therapeutic aim should be to restore the intraluminal pCO2 and intramural pH to normality. This is possibly most easily achieved by withdrawing pharmacological/chemical causes and/or reversing any metabolically significant and possibly clinically occult occlusive vascular disease.

1. Iatrogenic diseases with a common cause? Richard G Fiddian-Green (25 October 2002) eLetter re: Edward H Wagner and Trish Groves Care for chronic diseases BMJ 2002; 325: 913-

Competing interests: None declared

Competing interests: None declared

Richard G Fiddian-Green, None

None

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"But did the organism cause the inflammation—or was it the inflammation that allowed H pylori to flourish? This chicken and egg uncertainty was resolved in the time honoured manner: through self experimentation. Marshall swallowed a culture of the bacteria, developed gastritis, and then under-went endoscopy and stomach biopsy. H pylori was present in the tissue samples; the requirements of Koch's third and fourth postulates had been met in triumphant fashion"(1).

Koch's postulates were fulfilled for gastritis but not peptic ulceration. As all gastroenterologists and GI surgeons have known for generations gastritis is not the same as peptic ulceration neither is it the cause of the ulcers. H pylori infection would seem rather to be a secondary factor in the pathogenesis of peptic ulceration one clearly contributing to its recurrences(2). To prove his case Marshall or his proxy needs first to demonstrate that he has a normal intraluminal pCO2 and then to show that swallowing the bacteria can cause a bone fide ulcer without having to smoke.

1. Geoff Watts. Nobel prize is awarded to doctors who discovered H pylori BMJ 2005;331:795 (8 October), doi:10.1136/bmj.331.7520.795

1. Richard G Fiddian-Green H Pylori: cause or effect? http://www.gutjnl.com/cgi/eletters/35/8/1033#385, 8 Apr 2004

Competing interests: None declared

Competing interests: None declared

Richard G Fiddian-Green, None

None

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9 October 2005

"Gastric Ulcers are associated with H.Pylori."

It is simply amazing how small bits of information that we learned at medical school have big stories behind them. It never occured to me that that piece of knowledge written above that we as students considered so simple was actually the result of extensive efforts and hard work. It is considered so valuable to the extent that it was awarded a nobel prize in Medicine. So i guess from now on we should remember that any medical problem we consider so simple was once battled with it and feared.

Competing interests: None declared

Competing interests: None declared

Ala Farah, House Officer

Academy C. Teaching Hospital

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9 October 2005

Unlike religion, hypotheses in science are never settled, even with a Nobel Prize. Marshall's hypothesis of ulcer disease causation is simply one in a long line of hypotheses for the etiology of gastric and duodenal ulcer disease which have been tested and found wanting in explanatory and predictive power. The incidence of ulcer disease, in the U.S. at least, has been declining for over 50 years, decades before Marshall discovered H. pylori in many ulcer craters, and even longer before therapy directed at eradicating this organism became widespread. Koch's postulates -- the logical method to determine whether a microorganism's presence is a cause or an effect of a disease process -- have never been fulfilled for Helicobactor pylori causing ulcer disease in either humans or experimental animals, to my knowledge. Much is made of Marshall's drinking a stew of H. pylori and suffering a rip-roaring, biopsy diagnosed gastritis, which yielded -- amazingly -- H. pylori, but this experiment is repeated, unwillingly, milions of times a year throughout the world when people ingest improperly handled food and drink (I suspect that I myself have contributed to this experiment genre once at a church picnic, eating an egg salad which had sat long and unrefrigerated). By his efforts (a partial fulfilling of the Postulates) Marshall simply added one more pathogen to a long list of bacteria which when ingested in large quantities (certainly in much higher concentrations than would ever be occur endogenously) cause a nasty gastritis, from which the organism can be isolated. As an aside, did Marshall do a control experiment with the H pylori culture medium to see if that caused gastric inflammation on its own?

Groups with higher incidences of H. pylori colonization (e.g. African Americans and Hispanic populations in the United States) have lower incidences of ulcers than those with lower incidences of H. pylori. Many third world countries have virtually 100% colonization by the age of 25 without demonstrating an expected glut of ulcer complaints. Having more of something which causes a disease and having less of the disease is not a good causal argument.

Finally, while there is good evidence that antibiotics and bismuth therapy can heal gastrointestinal ulcers, this therapy is equally effective against experimental ulcers in germ-free animals, indicating that their anti-ulcer effects do not depend on antibacterial actions.

Competing interests: None declared

Competing interests: None declared

Robert A. Da Prato, M.D., Physician

Portland, Oregon USA

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