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A Humble Bacterium Sweeps This Year’s Nobel Prize

Francis Mégraud1,* 1INSERM ERI-10, Laboratoire de Bactériologie, Université Victor Segalen Bordeaux 2, Bordeaux, France *Contact: [email protected] DOI: 10.1016/j.cell.2005.11.032

Earlier this month, the Nobel Prize in Physiology or Medicine was awarded to the Austra- lians Barry Marshall and Robin Warren for their discovery of the bacterium Helicobacter pylori and its role in peptic ulcer disease and gastric cancer. It is the first time since 1928 that the Nobel Prize has been awarded for the discovery of a bacterium, and H. pylori is the first bacterium to be associated with cancer.

It was Robin Warren, a pathologist almost all individuals with gastritis, Convincing the Skeptics working in Perth, who, 25 years ago, peptic ulcers, and duodenal ulcers. The implication that an infectious agent first noted that spiral bacteria colonized Indeed, more than 80% of stomach could be the cause of peptic ulcer dis- the lower part of the stomach (antrum) ulcers and 90% of duodenal ulcers ease was a revolutionary idea in the in about half of the patients from which are known to be caused by H. pylori. 1980s, and one that was greeted with he had taken biopsies. Crucially, he Furthermore, it became clear that skepticism by the medical community. noted that inflammation of the mucosal stomach cancer can result in infected At that time, there were numerous the- lining of the stomach (gastritis) always individuals where H. pylori causes ories to explain the etiology of peptic appeared close to the location of the widespread inflammation of the stom- and duodenal ulcers, including the link- spiral bacteria. Intrigued by these find- ach lining (IARC Working Group, ing of ulcers to lifestyle and stress. The ings, Barry Marshall, a young clinical 1994). Inflammation is also associ- most popular theory was that ulcers fellow, teamed up with Warren (see ated with a rare stomach tumor called developed in response to excess acid Figure 1), and together they assayed MALT (mucosa-associated lymphoid in the stomach. This resulted in the stomach biopsies from 100 patients. tissue) lymphoma. About 50% of indi- development of drugs that blocked

Researchers working on Helico- viduals worldwide are infected with H. H2 receptors expressed by stomach bacter look back on the date of Easter pylori (usually passed from mother to parietal cells, which when activated, 1982 as the “birthday” of H. pylori. This child) and develop gastritis, but many induced the cells to produce acid. It is the date that Marshall was first able remain asymptomatic. Peptic ulcer is ironic that Sir James W. Black was to culture H. pylori from biopsy material disease arises in 10% of infected peo- awarded the 1988 Nobel Prize in Phys-

in the laboratory. Thinking that H. pylori ple, gastric adenocarcinoma in 1%, iology or Medicine for discovering H2 was related to another gram-negative and gastric MALT lymphoma in less receptors. His work paved the way for

bacterium called Campylobacter, Mar- than 0.1%. the development of H2 receptor-block- shall decided to try growing H. pylori ing drugs to treat peptic ulcer disease. on agar plates usually used for cul- Such drugs changed the management turing Campylobacter. Although such of this disease because gastric sur- plates are normally discarded after 2 or gery became limited to cases of stom- 3 days, there was the fortuitous inter- ach perforation or gastric malignancy.

vention of the Easter holiday. Arriving However, the H2 receptor-blocking back from a 4-day break, Marshall dis- drugs and their successors, the pro- covered colonies of H. pylori thanks to ton-pump inhibitors, only treated the the extended incubation period (War- symptoms of peptic ulcer disease, and ren and Marshall, 1983). the frequent relapses necessitated There followed a frenzy of research lifelong maintenance treatment. that began to unravel the mysteries The first time that Marshall and War- of H. pylori, with data appearing on ren presented their work at a national Figure 1. Barry Marshall and Robin the characteristics of the bacterium, Warren with the Author meeting in Australia, it was rejected methods to diagnose it, and the host Barry Marshall (left) and Robin Warren (center) outright. Whereas Warren was too immune response (Marshall and War- with the author (right), who presented the award shy to push their remarkable findings, of the European Helicobacter pylori Study ren, 1984). Marshall and Warren went Group to Marshall and Warren at their Lisbon Marshall had a missionary’s zeal and on to show that H. pylori is found in meeting in 1997. vigorously defended their research. In

Cell 123, December 16, 2005 ©2005 Elsevier Inc. 975 order to convince the reluctant medical et al., 2005; see Cell Biology Select, Marshall and Warren’s seminal dis- community of the robustness of their page 963 of this issue). In addition, covery that a humble bacterium, H. discovery, Marshall did the ultimate molecules comprising the H. pylori cell pylori, causes gastritis, peptic and experiment. He drank a culture of H. wall, especially muramyl dipeptides, duodenal ulcers, and in some cases, pylori, developed acute gastritis and are recognized by host epithelial cell gastric cancer, merits the 2005 Nobel then successfully treated the illness NOD receptors leading to activation of Prize in Physiology or Medicine for its with antibiotics (Marshall et al., 1985). the NF-κB signaling pathway and pro- remarkable impact on public health Thanks to the discovery of Marshall duction of interleukin 8, a proinflam- and for opening up new avenues and Warren and Marshall’s definitive matory cytokine (Viala et al., 2004). of research. This low-tech discov- experiment, a lifelong treatment was Within the last 5 years, it has become ery in the final decades of the 20th suddenly replaced by a short course clear that host factors are involved in century—which saw the explosion of antibiotics (NIH Consensus Confer- the pathogenesis of H. pylori. Gastric of technology and the emphasis on ence, 1994). In addition, MALT lym- carcinoma has been linked to a poly- mechanistic approaches to research— phoma could be successfully treated morphism in the interleukin-1β (IL-1β) demonstrates that not all discoveries by eradicating H. pylori infection, mak- gene. Certain IL-1β/IL-1β receptor gen- require a high-tech laboratory and the ing it the first human cancer to be cured otypes are associated with atrophy of latest equipment. The tenacity of Mar- by antibiotics. These developments did the gastric mucosa due to the ability of shall and Warren illustrates that impor- not please the pharmaceutical indus- this cytokine to block acid production. tant discoveries can still be made by try, although it was still necessary to Indeed, when IL-1β is produced in large doggedly pursuing unexpected results prescribe antisecretory drugs in order amounts, the risk of gastric carcinoma with an open mind. to increase the stomach’s pH, thus increases (El Omar et al., 2000). allowing the antibiotics to do their job. Another important discovery reveals References that the gastric mucosa cells that H. pylori: Opening up New become tumorigenic are mesenchy- Bagnoli, F., Buti, L., Tompkins, L., Covacci, A., and Amieva, M.R. (2005). Proc. Natl. Acad. Sci. Avenues of Research mal stem cells originating in the bone USA 102, 16339. Among the more than 20,000 articles marrow. An elegant study using mice about H. pylori published since 1983, repopulated by stem cells harboring El-Omar, E.M., Carrington, M., Chow, W.H., Mc- Coll, K.E., Bream, J.H., Young, H.A., Herrera, J., many have been devoted to the study different markers showed that in ani- Lissowska, J., Yuan, C.C., Rothman, N., et al. of the bacterium and understanding mals with a long-term Helicobacter (2000). Nature 404, 398–402. its secrets. We now know that Helico- felis infection, stem cells homed to Falush, D., Wirth, T., Linz, B., Pritchard, J.K., bacter is very heterogeneous. Not only gastric tissue and, because of the Stephens, M., Kidd, M., Blaser, M.J., Graham, mammals but many other vertebrates inflammatory environment, became D.Y., Vacher, S., Perez-Perez, G.I., et al. (2003). carry their own specific Helicobacter tumorigenic (Houghton et al., 2004). Science 299, 1582–1585. species, most of which are harmless We await confirmation of this intrigu- Houghton, J., Stoicov, C., Nomura, S., Rogers, commensals. In contrast, H. pylori ing finding in other carcinomas where A.B., Carlson, J., Li, H., Cai, X., Fox, J.G., Gold- induces inflammation in its human host inflammation is present. enring, J.R., and Wang, T.C. (2004). Science 306, 1568–1571. and cannot be considered a commen- There are other domains beyond sal. In 1997, H. pylori became the third pathogenicity where the discovery of H. IARC Working Group on the Evaluation of Carci- bacterium to have its genome totally pylori has opened up new avenues of nogenic Risks to Humans (1994). Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum. sequenced (Tomb et al. 1997), and in research. One such example is phylo- 61, 177–241. 1999, it became the first bacterium for geography, given that H. pylori has been which the genome sequences for two associated with humans for thousands Marshall, B.J., and Warren, J.R. (1984). Lancet 1, 1311–1315. strains were obtained. The discovery of of years. By comparing sequences of the so-called cag pathogenicity island housekeeping genes of H. pylori from Marshall, B.J., Armstrong, J.A., McGechie, D.B., and Glancy, R.J. (1985). Med. J. Aust. in H. pylori reveals how commensal human populations in different geo- 142, 436–439. bacteria acquire beneficial proper- graphical areas, it is possible to identify ties that give them the upper hand in strain genotypes. Models can then be NIH Consensus Conference. (1994). Helico- bacter pylori in peptic ulcer disease. JAMA 272, the bacteria-host relationship. Genes developed to infer the ancient geno- 65–69. contained within the cag pathogenic- types of this bacterium. Such studies ity island encode proteins that enable reveal ancient human migrations, such Tomb, J.F., White, O., Kerlavage, A.R., Clay- ton, R.A., Sutton, G.G., Fleischmann, R.D., H. pylori to transfer molecules to the as the migration of Amerindians from Ketchum, K.A., Klenk, H.P., Gill, S., Dougherty, cytosol of host gastric epithelial cells Asia, the Maori from Southeast Asian B.A., et al. (1997). Nature 388, 539–547. and to interfere with host cell signaling islands, and the Bantu from Cen- Viala, J., Chaput, C., Boneca, I.G., Cardona, A., pathways. Recently, the CagA protein tral Africa (Falush et al., 2003). Such Girardin, S.E., Moran, A.P., Athman, R., Memet, has been shown to disrupt the organi- microbial studies complement data on S., Huerre, M.R., Coyle, A.J., et al. (2004). Nat. zation and assembly of apical junctions ancient human migrations derived from Immunol. 11, 1166–1174. in epithelial cells and also to perturb genetics, mitochondrial DNA analyses, Warren, J.R., and Marshall, B. (1983). Lancet 1, epithelial cell differentiation (Bagnoli and language studies. 1273–1275.

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