1. H. Pylori & Nobel Prize for Medicine
Samir Haffar M.D.
Assistant Professor of Gastroenterology

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. 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. Investigators who described H. Pylori in
human & mammalian gastric mucosa
Investigators from
- France
- Poland
- Germany
- United Kingdom
- United States
- Greece
- China
- Soviet Union

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Electron micrograph of H. pylori
Spiral morphology & sheathed unipolar flagella

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. 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. Louis Pasteur (1822 – 1895)
“Chance favors only the prepared mind ”
“Dans les champs de l’observation, le hasard
ne favorise que les esprits préparés”

29. Marshall BJ, ed. Helicobacter pioneers.
Victoria, Australia: Blackwell, 2002.

30. 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.

31. 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.

32. Co-Winners of Nobel Prize in 2005
for their discovery of HP
Barry Marshall & Robin Warren

33. Warren & Marshall receiving the Nobel Prize
from the King Carl XVI Gustaf of Sweden
Stockholm Concert Hall, 10 December 2005

34. 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.

35. 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.