Helicobacter pylori & Nobel Prize in medicine & physiology


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  • In spite of frequent variations of media, and temperatures of incubation, from these 34 specimens, however, spiral bacteria were notcultured, because incubation was limited to 48 hours.
  • Bacteriologist Robert Koch discovered the anthrax disease cycle (1876); and the bacteria responsible for tuberculosis (1882) and cholera (1883). Koch formulated rules for the control of epidemics of cholera. "Koch's Postulates" (Kochsche Postulate, refined in 1884) are still the basic procedures used by modern epidemiologists and medical researchers: (1) Identify a specific organism, (2) obtain a pure culture of that organism, (3) reproduce the disease in experimental animals using the pure culture, and (4) recover the organism from the infected animals. Robert Koch Robert Heinrich Hermann Koch Born:11-Dec-1843Birthplace:Clausthal-Zellerfeld, GermanyDied:27-May-1910Location of death:Baden-Baden, GermanyCause of death: Heart FailureRemains: Cremated, Robert Koch Institute, Berlin, GermanyGender: MaleRace or Ethnicity: WhiteSexual orientation: StraightOccupation:DoctorNationality: GermanyExecutive summary: Discovered bacteria that causes tuberculosis Wife: Emmy AdolfineFraats (m. 1866)Daughter: Gertrud (b. 1865)Wife: Hedwig Freiberg (m. 1893)University: University of Göttingen (1866)Professor: University of BerlinNobel Prize for Medicine 1905
  • Koch's postulates (or Henle-Koch postulates) are four criteria designed to establish a causal relationship between a causative microbe and a disease. The postulates were formulated by Robert Koch (German physician & bacteriologist ) and Friedrich Loeffler in 1884 and refined and published by Koch in 1890. Koch applied the postulates to establish the etiology of anthrax and tuberculosis, but they have been generalized to other diseases.However, Koch abandoned the second part of the first postulate altogether when he discovered asymptomatic carriers of cholera[1] and, later, Typhoid Mary. Asymptomatic carriers are now known to be a common feature of many infectious diseases, especially viruses such as polio, herpes simplex, HIV and hepatitis C. As a specific example, all doctors and virologists agree that poliovirus causes paralysis in just a few infected subjects, and the success of the polio vaccine in preventing disease supports the conviction that the poliovirus is the causative agent.The third postulate specifies "should", not "must", because as Koch himself proved in regard to both tuberculosis and cholera, not all organisms exposed to an infectious agent will acquire the infection. This may be due to chance, to acquired immunity, or to genetic immunity. An example of genetic immunity: human immunodeficiency virus (HIV) seems to be normally unable to infect persons who carry the deletion CCR5 Δ32.
  • A silver stain (Warthin Starry) of HP (black wiggly things) on gastric mucus-secreting epithelial cells (x1000). This picture is notorious because it is of Dr. Marshall's stomach biopsy taken 8 days after he drank a culture of H. pylori. The experiment was published in 1985 (Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfill Koch's postulates for pyloric Campylobacter. Med J Aust 1985; 142: 436-439).
  • Helicobacter pylori (3.5 × 0.6 μm) has a smooth wall and four to seven sheathed flagella arising from only one end of the cell.These features distinguish it from Campylobacter spp., which have rough cell walls and a single, thinner, unsheathed flagellum at each endof the cell. Other Helicobacter spp. have distinguishing features such as many flagella and axial filaments (H. felis from cats) or flagella sprouting from the sides of the organism (H. mustelae from ferrets). Mature organisms appear as spiral forms with 1.5 wavelengths.
  • Barry J. Marshall receiving his Nobel Prize from His Majesty the King Carl XVI Gustaf of Sweden at the Stockholm Concert Hall, 10 December 2005.
  • Helicobacter pylori & Nobel Prize in medicine & physiology

    1. 1. H. Pylori & Nobel Prize for Medicine Samir Haffar M.D. Assistant Professor of Gastroenterology
    2. 2. Giulio Bizzozero (1846 - 1901) Italian Pathologist • Desribed for the first time presence of helicobacters in the stomach of dogs • Communicated his discovery during meeting of the Turin Medial Academy on 18th of March 1892 • Spirilli described by Bizzozzero were presumably H. beilmannii or H. felis Figura N et al. In Marshall BJ, ed. Helicobacter pioneers. Victoria, Australia: Blackwell, 2002.
    3. 3. Bizzozero’s drawing Bacteria live in acid producing cells These bacteria must be acid tolerant or must turn off acid secretion Figura N et al. In Marshall BJ, ed. Helicobacter pioneers. Victoria, Australia: Blackwell, 2002.
    4. 4. Investigators who described H. Pylori in human & mammalian gastric mucosa Investigators from - France - Poland - Germany - United Kingdom - United States - Greece - China - Soviet Union
    5. 5. First detailed histological & ultrastructural on human H. Pylori • Done by Steer in Southampton in 1975 • Spiral bacteria closely apposed to mucus secreting cells Bacteria possessed at least one flagellum • Polymorphonuclear leucocytes migrated through gastric mucosa, presumably in response to bacteria • Culture of endoscopic biopsy yielded only Pseudomonas aeruginosa (not a spiral organism) Steer HW. J Clin Pathol 1975 ; 28 : 639 – 46.
    6. 6. Royal Perth Hospital, Perth, Western Australia • Histological & ultrastructural studies of the gastric mucosa had been published in 1979 * • Spiral bacteria were seen, but because they did not invade the mucosa were thought to be irrelevant * Fung WP et al. Am J Gastroenterol 1979 ; 71 : 269 – 79.
    7. 7. Robin Warren Histopathologist – Royal Perth Hospital • Expert in gastric pathology & bacterial staining in pathological specimens • He took notice of these bacteria & correlated them with presence of polymorphonuclear leucocytes • He emphasised that stomach must not be viewed as sterile organ Warren JR. Lancet 1983 ; I : 1273.
    8. 8. Barry Marshall Registrar in training – Royal Perth Hospital, 1981 • Learning gastroenterology for 6 months • He reviewed with Warren case notes of pts in whom large numbers of gastric spiral bacteria had been seen • One of the patients, with severe epigastric discomfort, treated fortuitously with tetracycline; symptoms resolved & subsequent endoscopic biopsy showed antral gastritis had also resolved Marshall BJ. In: Blaser MJ, ed. Campylobacter pylori in gastritis & peptic ulcer disease. New York: Igaku-Shoin, 1989: 7 – 23 .
    9. 9. J A Armstrong Head of electron microscopy unit – Royal Perth Hospital • Marshall asked him for assistance in 1981 • He & his assistant Wee obtained high magnification electronmicrographs of bacteria in endoscopic biopsy • When Warren & Marshall could not agree on wording of a joint letter to the Lancet in 1983, Armstrong advised them to write separate letters
    10. 10. C S Goodwin Head of microbiology department – Royal Perth Hospital • Marshall asked him for assistance in late 1981 • Agreement of a protocol Gastric biopsy from 100 consecutive patients Consultant gastroenterologists: Waters & Sanderson Gram stain & culture Supervisor: Pearman, microbiologist Technologists: Kosaras & Royce Goodwin C S. Gut l993 ; 34 : 293 – 294.
    11. 11. The Protocol Started in March 1982 The first 34 cultures Spiral bacteria seen in Gram stain in six Spiral bacteria were not cultured Incubation was limited to 48 hours The 35th culture Incubating during Easter holiday (5 days in Australia) Pure growth of 1 mm transparent colonies H. pylori had been finally cultured (14 April 1982) Goodwin C S. Gut l993 ; 34 : 293 – 294.
    12. 12. Results Among the 100 specimens • Spiral bacteria seen histologically 58 patients • Spiral bacteria seen in Gram stain 34 patients • Culture of the new organism 11 patients Goodwin C S. Gut l993 ; 34 : 293 – 294.
    13. 13. Follow-up • Gram stain of colonies showed only slightly curved organisms, not spirals & Marshall doubted whether they had grown the correct organism • Armstrong & Wee produced electron micrographs revealing that bacteria were spiral with 5 sheathed flagella which proving they were not Campylobacter spp • Annear achieved lyophylisation of several cultures Two earliest isolates: NCTC 11637 & NCTC 11638 Goodwin C S. Gut l993 ; 34 : 293 – 294.
    14. 14. Marshall – the catalyst of the team • Rushed not to publish • Went to library to read new articles & old books • Consulted experts in bacteriology & gastroenterology • Realized that gastritis had high association with DU & only slightly less so with GU • Devised selective media for primary isolation • Discovered HP sensitivity to bismuth & metronidazole Marshall BJ et al. Med J Aust 1985 ; 142 : 439 – 44.
    15. 15. First publications of Marshall & Warren • Letters - Warren JR. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983; i: 1273. - Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983; i: 1273-4. • Original article Marshall BJ, Warren JR. Unidentified curved bacilli in stomach of pts with gastritis & peptic ulceration. Lancet 1984; i: 1311-4.
    16. 16. Name of the bacteria • Skirrow (1993) 1 Suggested the name Campylobacter pyloridis • Marshall et all (1984) 2 Formally proposed the name C pyloridis Rules of Latin grammar required to change it to C pylori 1 Proceedings of Second International Workshop on Campylobacter infections. London: Public Health Laboratory Service, 1983 : 33 – 8. 2 Marshall BJ et al. Microbios Lett 1984 ; 25 : 83 – 88.
    17. 17. Robert Koch (1843 – 1910) Discovered Anthrax disease cycle - 1876 Bacteria of TB - 1882 Bacteria of cholera - 1883 Formulated Koch’s Postulate -refined in 1884) Award Nobel prize for medicine 1905
    18. 18. Koch's postulates Causal relationship between a microbe & a disease  Microorganism must be present in every case of disease  Microorganism must be isolated from diseased organism & grown in pure culture  Cultured microorganism should cause disease when introduced into a healthy organism  Microorganism must be recoverable from experimental infected host Koch R. J Hyg Inf 1893 ; 14 : 319 – 333.
    19. 19. Marshall's stomach biopsy Marshall BJ et al. Attempt to fulfill Koch's postulates for Campylobacter Pylori. Med J Aust 1985; 142 : 436 – 439. Silver stain of HP on gastric epithelial cells (x1000) Marshall's stomach biopsy taken 8 days after he drank culture of HP
    20. 20. New Name for Helicobacter Pylori Unlikely to change the name again • 1985 Goodwin studied cellular fatty acids of C Pylori Discover unique profile which indicated new genus 1 • 1989 Sufficient evidence to justify new genus Goodwin devised the name Helicobacter So we now have H. pylori 2 1 Goodwin CS et al. J Med Microbiol 1985 ; 19 : 257 – 67. 2 Goodwin CS et al. Int J Syst Bacteriol 1989 ; 39 : 397 – 405.
    21. 21. Helicobacter pylori HP Smooth wall 4–7 sheathed flagella arising from one end of cell Campylobacter Rough cell walls Single thinner flagellum at each end of cell
    22. 22. Electron micrograph of H. pylori Spiral morphology & sheathed unipolar flagella
    23. 23. Teamwork, between four departments, was the secret of the first successful culture, in Royal Perth Hospital, Western Australia, of human gastric spiral bacteria, now called Helicobacter pylori.
    24. 24. Was the culture of H. Pylori an accident? • Some said that it was an accident • They were fortunate in Perth that a five-day Australian holiday occurred during the project • This proved what Louis Pasteur said: “chance favors only the prepared mind”
    25. 25. Louis Pasteur (1822 – 1895) “Chance favors only the prepared mind ” “Dans les champs de l’observation, le hasard ne favorise que les esprits préparés”
    26. 26. Marshall BJ, ed. Helicobacter pioneers. Victoria, Australia: Blackwell, 2002.
    27. 27. Why previous investigators didn't recognize HP? • In his chapter in Helicobacter Pioneers, Warren says it would have been very difficult even one decade earlier to make observations that he & Marshall made • He mentions in particular the advent of: Fiberoptic endoscopy Gastric tissue obtained from autopsy or surgery Samples autolyzed before pathological examination Electron microscopy Define way in which HP attached to gastric epithelium Marshall BJ, ed. Helicobacter pioneers. Victoria, Australia: Blackwell, 2002.
    28. 28. H. pylori is one of the most studied organisms in medicine: More than 22,000 relevant articles have been listed in PubMed from 1983 to 2005 * Parsonnet J. N Eng l J Med 2005 ; 353 : 2421 – 2423.
    29. 29. Co-Winners of Nobel Prize in 2005 for their discovery of HP Barry Marshall & Robin Warren
    30. 30. Warren & Marshall receiving the Nobel Prize from the King Carl XVI Gustaf of Sweden Stockholm Concert Hall, 10 December 2005
    31. 31. Press release of the Nobel committee • Acknowledged the “prepared mind(s)” & tenacity” of the new laureates as keys to their success • Unlike Louis Pasteur, the committee neglected to mention luck Parsonnet J. N Eng l J Med 2005 ; 353 : 2421 – 2423.
    32. 32. Nobel Prize for clinicians At the time of Warren & Marshall’s discovery • They were physicians doing their daily jobs • They were not in laboratory chasing after Nobel Prize • They had no intention of being in the limelight • They had no research grants for studying ulcer disease • They happened upon something interesting, & driven by curiosity, they investigated & reported it Parsonnet J. N Eng l J Med 2005 ; 353 : 2421 – 2423.