The Medscape Awards in Infectious Diseases: The Most Important Discovery of a New Bacterium (1980-2012)

The Most Important Discovery of a New Bacterium (1980-2012)

My choice for the greatest achievement in the discovery of a new bacterium is Helicobacter pylori. The story of this organism and its etiologic roles in peptic ulcer disease and gastric cancer is a prime example of a relationship that was long suspected but resisted bitterly by the medical establishment, with eventual victory and a Nobel Prize.
Early history relevant to the role of H pylori in peptic ulcer disease includes the 1868 recommendation by Kussmaul to use bismuth agents to treat peptic ulcer disease, although the antibacterial properties of bismuth were yet to be discovered.1 In 1939, A. Stone Freedberg reported H pylori in the human stomach but abandoned this research when he was ordered to move on to other subjects.2,3 Barry Marshall later speculated that Freedberg would have won the Nobel Prize for his discovery in 1951 if his mentor had allowed him to continue his work.4 In 1964, John Lykoudis5 recommended antibiotic treatment for peptic ulcer disease at a meeting of the Medico-Surgical Society of Greece, but the manuscript was rejected and Lykoudis was subsequently fined 4000 drachmas for administering this treatment.
The roles of Robin Warren and Barry Marshall in the discovery of H pylori began in 1981, when Dr. Marshall, a young gastroenterologist, joined Dr. Warren, a pathologist, in the Royal Perth Hospital in Australia.6
Dr. Warren had observed the bacterium in gastric biopsies and autopsies, and Dr. Marshall advocated antibiotic therapy, which proved successful.6 Despite the early successes of these 2 eventual Nobel laureates, the road they traveled was not always smooth. Marshall and Warren reported "unidentified curved bacilli on gastric epithelium in active chronic gastritis" in The Lancet in 19837 and a more comprehensive description of this association based on a review of 100 gastric biopsies in 1984.8 The field of gastroenterology, however, was not ready for this challenge to long-held beliefs about peptic ulcer disease and its treatment.
The backlash was brutal.1 Dr. Larry Altman, medical correspondent for The New York Times, who reported these results, later wrote, "I have never seen the medical community more defensive or critical of a story."9 I spoke with Dr. Altman about these events, and to this day, he recalls that "this was the review that got me the most heat for misleading the public" (Personal communication. May 16, 2012).
To defend his thesis, in 1984 Marshall intentionally drank cultured H pylori and developed gastric symptoms, which were relieved with antibiotics.10 Another health professional who was similarly frustrated by the rejection of the theory of an association between H pylori and gastritis leading to peptic ulcer disease also consumed the putative agent. Multiple gastric biopsies before and after ingestion nicely demonstrated the resulting disease; however, Marshall's colleague was less fortunate because antibiotics were unsuccessful in eradicating his disease, and he had debilitating symptoms for 3 years.11,12
My experience with this disease was brief but telling. In 1986, I was invited to present a summary of the science of a bacterial cause of peptic ulcer disease at the annual meeting of the American Gastroenterology Association in San Francisco. I reviewed the data and submitted my abstract, but was somewhat shocked by the response from those who had invited me because they insisted on an editorial rebuttal. Their concern was that some attendees listening to my talk "might actually believe a bacterial cause." The "Editor's Note" for the program read:
Dr. Bartlett has summarized results from a number of reports dealing with gastric campylobacter-like organisms (GCLO) and gastritis. While intriguing, these reports (most of which are letters or abstracts) have done no more than call attention to an association between gastritis and GCLO. What remains completely unsettled, in our opinion, is whether GCLO are the cause of gastritis or present as a result of gastritis (ie, organisms colonize only in the presence of inflamed mucosa of some other etiology).
Despite this relatively rude treatment of an invited guest, I braced for the encounter and showed slides of the gastric biopsies from before and after self-ingestion of H pylori by Arthur Morris.11 I then placed a glass of water (that I claimed to have seeded with H pylori but which was actually plain water) on the podium and invited skeptics to drink after my presentation. There were skeptical comments, but no one drank from the chalice.
It is not possible to identify a specific data set or a particular report that changed conventional teaching about peptic ulcer disease to a recognition that it was a bacterial infection rather than a consequence of gastric acidity. The period between 1987 and 1990 was particularly important because during this time, antibiotics to eradicate H pylori resulted in high rates of cure and prevention of relapses.13 Subsequent work implicated H pylori as a cause of gastric cancer14 and gastric lymphoma.15
The citation at the presentation of the Nobel Prize in 2005 is particularly important in terms of recognizing the importance of both the pathogen and the disease it causes:
Against prevailing dogmas, you [Drs. Warren and Marshall] discovered that one of the most common and important diseases of mankind, peptic ulcer disease, is caused by a bacterial infection of the stomach. Your discovery has meant that this frequently chronic and disabling condition can now be permanently cured by antibiotics, to the benefit of millions of patients. Your pioneering work has also stimulated research all around the world to better understand the link between chronic infections and diseases such as cancer.
The rationale for this selection as the most important discovery of a bacterium and its role in human disease is based on several observations that contribute to the weight of H pylori as an important and unusual pathogen.
• It is one of the most common infections, on the basis of serology studies that imply not simply colonization but an immune response to microbial infection. Most serologic studies show prevalence rates of 20%-90%; which vary substantially by age (with rates greater than 50% in persons older than 50 years) and by social class or national patterns of hygiene.16 In the United States, approximately 30% of people are colonized with H pylori, and colonization persists unless the person takes antibiotics directed against H pylori.
• H pylori is the major cause of peptic ulcer disease, which affects 15%-20% of those colonized or approximately 10% of the population at a cost of approximately $3.4 billion per year for healthcare in the United States.17
• H pylori is an unusual infection because it causes a chronic inflammatory response without the usual findings to suggest infection, such as elevation of C-reactive protein level, erythrocyte sedimentation rate, or procalcitonin level.18 As a traditional infectious disease model, H pylori violates all the rules.
• H pylori is a recognized carcinogen, presumably by its association with chronic inflammation (chronic gastritis).14 Thus, it is the only bacterium listed as a class 1 carcinogen,19 and it is also implicated in gastric lymphoma.15
The long battle to legitimize H pylori as a human pathogen was the classic example of the difficulty our profession has with unconventional theories. For this and the other reasons cited above, the discovery of H pylori receives my vote for the greatest achievement in discovery of a bacterium in the past 30 years.
Timeline: Historical Highlights -- Gastric Ulcer as a Chronic Bacterial Infection Caused by Helicobacter pylori Infection
1586: First report of gastric ulceration.1
1825: Classic description of gastric function based on observations in a patient with a war wound that resulted in a gastric-cutaneous fistula.2
1857: Symptoms of peptic ulcer disease reported in detail.3
1881: Billroth provides the first report of upper gastrointestinal endoscopy.4
1906: Spirochetes reported in gastric biopsy specimens.5
1910: Peptic ulcer was attributed to gastric acid,6 and antacids became standard treatment.
1915: The "Sippy diet" is reported, using milk and cream throughout the day and much of the night.7 This became a favored therapy for the next 6 decades.
1924: Urease activity reported in human stomachs.8 This was thought to be generated from gastric mucosal cells because the stomach was thought to be sterile.
1966: Report of the gastric histamine receptor,9 and the first report of H2-receptor therapy followed quickly.10
1973: The proton pump was described11; this was immediately followed by proton pump inhibitor treatment.12
1975: Spirochetes and chronic gastritis are shown on gastroscopy in 80% of patients with gastric ulcers.13
1979: Robin Warren detected bacteria growing in gastric biopsy specimens, but the findings were apparently uninteresting to fellow pathologists. Two years later he met Barry Marshall, a young gastroenterologist, and the men spent the next 7 years studying what is now known as H pylori.
1983: Warren and Marshall report on bacteria associated with gastritis and peptic ulcer disease from their initial collaboration.14
1984: The seminal report15 from the Warren/Marshall collaboration showed the association of curved bacteria in the lesions of patients with chronic antral gastritis and ulcers.
Some of the observations in the seminal report are interesting, convincing, and even compelling, because the investigators found typical spiral or curved bacteria in antral specimens from 58 of 100 patients who underwent endoscopy with gastric biopsy.
We found a close association between pyloric campylobacter and antral gastritis. When polymorphonucleocytes (PMNs) infiltrated the mucosa, the bacteria were almost always present (38/40). In the absence of inflammation they were rare (2/31), suggesting they are not commensals. We know of no other disease state where, in the absence of complicating factors such as ulceration, bacteria and PMNs are so intimately related without the bacteria being pathogenic.
Conventional wisdom at the time was that the stomach is normally sterile owing to the acid environment, but the investigators opined that the bacteria were not in gastric fluid but rather on gastric cells.
1985: Self-inoculation experiment by Dr. Marshall was reported.16 This was a failed attempt to satisfy the Koch postulates because the result was gastritis, but he never developed a gastric ulcer.
1987: Eradication of H pylori shown to be associated with long-term cure of duodenal ulcer.17,18
1987: Report of the urea breath test.19
1987: The antibacterial activity of bismuth against H pylori is reported.20
1989: Campylobacter pylori is renamed Helicobacter pylori. 21,22
1994: H pylori is named a grade 1 ("definite") carcinogen.23
1994: H pylori is implicated as the cause of gastric non-Hodgkin lymphoma.24
1994: A National Institutes of Health consensus report endorses antibacterial therapy for peptic ulcer disease.25
1997: Management guidelines for peptic ulcer disease recommend antibacterial treatment for the first time.26
2005: The Nobel Prize is awarded to Drs. Barry Marshal and Robin Warren.
References
1. Donati M. Demedica historia mirabilt. Mantuae per fr. Osanam, Lib. IV, Cap iii:1586;196.
2. Beaumont W. A case of wounded stomach. Med Record. 1825;8:14-9, 840.
3. Brinton W. On the Pathology, Symptoms, and Treatment of the Stomach. With an Appendix of Cases. London: Churchill Livingston; 1857.
4. Billroth CA. Offenes Schreiben an Herrn Dr. L. Wittelshöfer. Wien Med Wochenschr. 1881;31:161-165, 1427.
5. Krienitz U. Ueber das Auftreten von Spirochaeten verschiedener Form im Mageninhalt bei Carcinoma ventriculi. Dtsch Med Wochenschr. 1906;22:872.
6. Schwarz K. Ueber penetrierende Magen- und Jejunalgeschwure. Beitr Klin Chir. 1910;67:96-128.
7. Sippy BW. Gastric and duodenal ulcer. Medical cure by an efficient removal of gastric juice corrosion. JAMA. 1915;64:1625-1630.
8. Luck JM, Seth TN. The physiology of gastric unease. Biochem J. 1924;18:357-365.
9. Ash AS, Schild HO. Receptors mediating some actions of histamine. Br J Pharmacol Chemother 1966;27:427-439.
10. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H2-receptors. Nature. 1972;236:385-390. Abstract
11. Ganser AL, Forte JG. K+-stimulated ATPase in purified microsomes of bullfrog oxyntic cells. Biochim Biophys Acta. 1973;307:169-180. Abstract
12. Lindberg P, Brändström A, Wallmark B, et al. Omeprazole: the first proton pump inhibitor. Med Res Rev. 1990;10:1-54. Abstract
13. Steer HW. Ultrastructure of cell migration through the gastric epithelium and its relationship to bacteria. J Clin Pathol. 1975;28:639-646. Abstract
14. Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983;1:1273-1275. Abstract
15. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1:1311-1315. Abstract
16. Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfill Koch's postulates for pyloric Campylobacter. Med J Aust. 1985;142:436-439. Abstract
17. Rauws EA, Tytgat GN. Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet. 1990;335:1233-1235. Abstract
18. Coghlan JG, Gilligan D, Humphries H, et al. Campylobacter pylori and recurrence of duodenal ulcers -- a 12-month follow-up study. Lancet. 1987;2:109-111.
19. Bell GD, Weil J, Harrison G, et al. 14C-urea breath analysis; a non-invasive test for Campylobacter pylori in the stomach. Lancet. 1987;1:1367-1368.
20. Marshall BJ, Armstrong JA, Francis GJ, Nokes NT, Wee SH. Antibacterial action of bismuth in relation to Campylobacter pyloridis colonization and gastritis. Digestion. 1987;37 Suppl 2:16-30. Abstract
21. Luning G. Campylobacter pylori becomes Helicobacter pylori. Lancet 1989;2:1019-1020.
22. Goodwin CS, Armstrong JA, Chilvers T, et al. Transfer of Campylobacter pylori and Campylobacter mustelae to Helicobacter gen. nov. as Helicobacter pylori comb. nov., respectively. Int J Syst Bacteriol. 1989;39:397-405.
23. International Agency for Research on Cancer. Schistosomes, liver flukes and Helicobacter pylori. In: IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. vol 6. Lyon: IARC; 1994.
24. Parsonnet J, Friedman GD, Vandersteen DT, et al. Helicobacter pylori infection and risk for gastric cancer. N Engl J Med. 1991;325:1127-1131. Abstract
25. Thamer M, Ray NF, Henderson SC, Rinehart CS, Sherman CR, Ferguson JH. Influence of the NIH Consensus Conference on Helicobacter pylori on physician prescribing among a Medicaid population. Med Care. 1998:36:646-660. Abstract
26. Current European concepts in the management of Helicobacter pylori infection. The Maastricht Consensus Report. European Helicobacter pylori Study Group. Gut. 1997;41:8-13. Abstract