Nearly Twenty Years after Barry Marshall's Big Gulp

Helicobacter pylori: Physiology and Genetics Edited by Harry L.T. Mobley, George L. Mendz, and Stuart L. Hazell Washington, DC: ASM Press (2001). 608 pp. $125.95You've probably heard this story. It is not apocryphal. The whole episode evokes the zeitgeist of an earlier era of investigator-initiated, hypothesis-driven experimentation where the subjects were the scientists themselves. Almost 20 years ago, stomach biopsies from patients were being cultured in an attempt to retrieve a spiral-shaped microbe that had been associated with gastritis and ulcers. The hospital microbiology lab was dealing with an outbreak of antibiotic-resistant Staphylococcus aureus, putting these “experimental” biopsy cultures low on the queue of things that needed to be examined. A set of plates was left in the incubator over a long holiday weekend and not inspected until six days had elapsed, instead of the customary two-day interval. The six-day time frame was just right for Helicobacter pylori, the slow-growing, gram-negative, microaerophilic bacterium, to make its presence first known. Two years later, in the tradition of self-experimenters like Daniel Carrion, Max von Pettenkofer, David A. Robinson, and Walter Reed's brave colleagues Jesse Lazear, Aristides Agramonte, and James Carroll (L.K. Altman, Who Goes First: The Story of Self-Experimentation in Medicine, University of California Press, 1998), a young investigator swallowed 109 colony forming units of this microbe. Barry Marshall's “big gulp” produced gastritis, which is the precursor to peptic ulcer disease. His symptoms subsided with antibiotic treatment, Koch's postulates for gastritis were fulfilled, the treatment for peptic ulcers was revolutionized, and we were provided with a vivid demonstration that a chronic disease had a heretofore unappreciated infectious basis. The story inspired others to search for cryptic microbes that may cause diseases such as multiple sclerosis, atherosclerosis, and rheumatoid arthritis.Fast forward 20 years, past a mountain of 10,624 published papers with Helicobacter pylori (or its earlier nom de plumes Campylobacter pyloridis and C. pylori) in their titles, past complete annotated genome sequences from two different H. pylori strains, and we come to the present. We find ourselves with a great deal of knowledge, but still needing enlightenment about how this bacterium has learned to insinuate itself in the stomachs of approximately one half of our fellow humans.To paraphrase a prominent American politician, H. pylori is a “uniter not a divider.” It has attracted a diverse, multidisciplinary consortium of microbiologists, cell biologists, cancer biologists, epidemiologists, and others who are seeking to understand how this organism is able to adapt to, and persist within, its specialized gastric niche for decades at a time. They have asked why the host-bacterial relationship in most cases is relatively innocent while in others, the destiny of infection is skewed toward development of severe pathology. Martin Blaser, a prominent worker and conceptualizer in this field, suggests we consider H. pylori as having an “amphibiotic relationship” with its hosts, where pathogenic significance is determined by context (In Helicobacter pylori: basic mechanisms to clinical cure 1998, pp. 43–48, R.H. Hunt and G.N.J. Tytgat, eds., Dordrecht, The Netherlands: Kluwer Academic Publishers, 1998). On the one hand, we know that the presence of the organism is associated with increased risk for peptic ulcer disease and gastric adenocarcinoma. On the other hand, the absence of H. pylori appears to be associated with a greater risk of developing gastroesophageal reflux disease (GERD for acronym lovers), as well as its ominous potential consequences (esophageal cancer). Colonization may also protect from pathogens that cause diarrheal illnesses in childhood. The general view is that disease risk stems from a hard-to-pin-down confluence of microbial, host, and environmental factors. The challenge has been to identify these factors.Drs. Mobley, Mendz, and Hazell have assembled a comprehensive, highly informative textbook that will be invaluable for those who are just entering the field, as well as for the cognoscenti. Assembling 46 chapters written by 95 authors into a cohesive whole is a daunting task for even the most intrepid editors. In this case, they have done an admirable job of organizing a vast amount of information into seven sections. The reader is able to easily move from a concise, well-balanced discussion of the epidemiology of infection at the beginning of the volume, to helpful reconstructions of bacterial physiology and metabolic regulation (aided by knowledge gleaned from its, and other microbial genome sequences), to detailed discussions of H. pylori genetics, to overviews of the determinants of virulence and descriptions of elicited host responses (from inflammation to cancer), and finally to summaries of how host-microbial relationships are being modeled and dissected in animals. The chapters are well referenced and remarkably up to date. From its first entry (ABC transporters) to its last (zoonosis), the index serves as a user-friendly guide for retrieving specific bits of information from the bundle of facts presented in this exceptional reference source.A certain degree of redundancy is inevitable in compilations such as this. Nonetheless, all the central “themes and melodies” of this bug and its infection are well represented. For example, there is an excellent review of what is known and not known about transmission. Acquisition typically occurs in childhood, with studies emphasizing intrafamilial spread, yet the exact mode of transmission remains controversial. Features of H. pylori that help support a sustained host-bacterial relationship are explored in depth throughout the text—from the outer membrane LPS and its lipid A component that help reduce immunologic responses, to the organism's amazingly plastic genome.The enormous value of knowing the complete genome sequence of two H. pylori strains is emphasized in numerous chapters. H. pylori has a relatively small genome, like many highly host-adapted bacterial species. There is a paucity of encoded global regulatory proteins and “two component regulatory systems” that so many other bacterial species use for modulating adaptations to changing physiologic conditions. Instead, this organism appears to lean heavily on its capacity for genetic variation to achieve and maintain fitness in host niches that evolve over the course (and as a consequence) of prolonged infection.Genetic diversity among H. pylori populations is manifested by variations in gene order, gene content, and gene sequence. Recombination appears to be a more prominent driver of diversification than in other bacterial species (formally stated, this organism has a “recombinational or panmictic population structure”). H. pylori strains, in turn, contain a multitude of genes with homology to components of restriction-modification (R-M) systems. The full significance of these diverse strain-specific ensembles of complete and seemingly incomplete R-M systems remains to be deciphered. They may serve many functions: as a type of “immune system” that protects the genome from invasion by large fragments of “foreign” DNA while still allowing for incorporation of smaller pieces of DNA via recombination, or as modulators of gene expression through methylation of cis-acting transcriptional regulatory elements. Like some other infamous mucosal pathogens (H. influenzae and Neisseria spp), H. pylori uses slipped-strand mispairing to spur its adaptive evolution within its host niche: the resulting frame-shift mutations act as switches to turn production of proteins on or off. There is extensive discussion of how variation in gene content in the organism's cag pathogenicity island (and the PAI's type IV secretion system) are intimately linked to host responses.The editors note in their preface that they wanted to create a book that “would summarize and review the accumulated knowledge on this important human pathogen.” They have succeeded. In 2004, exactly twenty years will have elapsed since the “big gulp.” The chances of making major advances in our understanding the biology of this microorganism and the determinants of its host relationships could not be brighter. DNA microarrays containing more than 98% of the known ORFs of the two sequenced strains are now available for whole genome genotyping of clinical isolates (Salama et al., Proc. Natl. Acad. Sci. USA 97, 14668–14673, 2000). Undertaking a comprehensive screen for the presence or absence of bacterial genes in strains taken from defined patient populations, or from individuals over the course of their infection, provides an opportunity to build a knowledge base for correlating microbial and host phenotypes with H. pylori genotypes. Genetically manipulatable and environmentally defined animal models are becoming available to model host traits thought to function as risk factors for development of severe pathology. Methods are emerging for monitoring bacterial gene expression in vivo (Rokbi et al., Infect. Immunol. 69, 4759–4766, 2001), raising the hope that both host and microbial gene expression can be monitored simultaneously during the course of infection. The feasibility of conducting screens for essential H. pylori genes has been demonstrated (Chalker et al., J. Bacteriol. 183, 1259–1268, 2001). The first reported large-scale prokaryotic protein-protein interaction map has been produced using information from the sequenced H. pylori genome and a version of the yeast two-hybrid system (Rain et al., Nature 409, 211–215, 2001). Amidst all of this emerging technology, this book should serve as an invaluable guide for placing new results into the broadest possible context.