The Nobel Prize in Medicine or

Physiology 2005Barry James Marshall (Australian Gastroenterologist)

John Robin Warren (Australian Pathologist)

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Barry James Marshall

• Born in 30 September 1951 in Kalgoorlie• Attended high school in

Newman College• Graduate from University of

Western Australia MBBS program in 1975• Married with Adrienne in 1972

when he was in Year 5• Began training as a

specialised physician in 1978 • Moved to Royal Perth Hospital

in 1979.• Meet J. Robin Warren in 1981

and started on gastroenterology project with him.

http://blogs.bmj.com/fg/files/2014/12/Prof-Barry-Marshall-acknowledge-Adrienne-Marshall-photographer.jpg

John Robin Warren AC• Born on the 11th of June 1937 in North

Adelaide, SA.• Attended Westbourne Park School and

St. Peter’s College before receiving his M.B.B.S. degree from the University of Adelaide in 1961.

• Married Winifred Theresa Warren in the early 1960s and had five children.

• Elected to the Royal College of Pathologists of Australasia in 1967

• Met with Dr. Barry Marshall in 1981 and undertook research into H. pylori.

• After receiving the Nobel Prize, he was elected a Fellow of the Australian Academy of Science in 2006.

• Made a Companion of the Order of Australia in 2007.

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Helicobacter pylori Its Role in Gastritis and Peptic Ulcer Disease

What is Helicobacter pylori?• Spiral-shaped, gram-negative,

microaerophilic (need low level of O2) bacterium

• Class 1 carcinogen (induce cancer)

• Invades the mucosal lining and cause 95% DU and 75% GU

• Associated with gastric cancer and lymphoma

• Patients infected with H.pylori has been found to have higher levels of gastrin and pepsinogen and reduced level of somatostatin and impaired duodenal bicarbonate secretion

• Increase pH in stomach, promote colonization, promoting development of gastric metaplasia and making it more susceptible to acid injury

https://wellnessbysilvia.files.wordpress.com/2014/09/helicobacter.jpg

Timeline of H. pylori Discovery

• 16th century BC – first description of gastric symptoms, and relation of gastric symptoms and meal times• 16th century – findings and description of

gastric and duodenal ulcers on autopsies• 1893 – first well-known of gastric

helicobacters; description of ‘spirochetes’ inhabiting gastric gland and canaliculi of parietal cells

H pylori in 20th century• 1924 – discover urease in stomach, thought that is naturally

occurring • 1940 – Freedburg observes spiral-like bacteria in 40% of

specimens• 1950s – 1960s – Ito observed spirilli in gastric mucosa

appearance under electron microscope• 1954 – ‘There is no bacteria in human stomach – presence of

bacteria is contamination’• 1964 – First treatment of PUD using anti-bacterial agent;

rejected due to lack of clinical trials• 1970s – study presence of bacteria and inflammation during

gastric ulcer. Found that carbonexolone treated gastric ulcers

Discovery of H. pylori by Marshall and Warren• 1979, Warren discovered the bacteria on a chronic gastritis biopsy using

Warthin-Starry silver stain—small curved, spiral bacteria were observed!

• 1982, Marshall and Warren studied to determine the relationship between H. pylori and PUD and a new genus of helicobacter was successfully cultured.

• 1984, Marshall intentionally consumed H. pylori after failing to infect pigs. Then he used antibiotics to relieve his symptoms.

• 1985, Marshall published the results of self-induced infection in MJA.

• 1987, NEJM published a study on H. pylori which agrees on their discovery

• 1989, Warren developed the 14C-urea breath test for the detection of gastric Campylobacter pylori infection, and was published in MJA.

• 1994, WHO accepted that H. pylori as a causative factor in stomach cancer.

Problems with researching H. pylori• Skepticism• Lack of good quality biopsies • Use of surgical or post mortem specimens• Inadequate clinical specimens and technology to

culture bacteria

Why Worth a Nobel Prize Award?Before the discovery• in era of 1980s

• the cause of peptic ulcer was “assumed” to be due to excess gastric acid secretion from:• lifestyle, diet, alcohol and drugs, or is genetically determined

• accepted that bacteria could not survive in acidic environment of normal human stomach – stomach is sterile!!!

• H2 receptor antagonist drugs to lower stomach acid secretion were found effective to treat peptic ulcer• ranitidine (Zantac) • cimetidine (Tagamet)

• helicobacter in gastric lining was never linked to be the causative• was seen as a non-pathogenic commensal flora following

peptic ulcers

Why Worth a Nobel Prize Award?Treatments before Discovery

• lifelong treatment of acid-blocking drugs• Only ease symptoms – not treat underlying disease• almost always recurring as soon as the drug stopped

• removal surgery of the lower third of the stomach• Cause difficulty in maintaining weight – reduce ghrelin

secreting cell• Sometimes cause ‘gastric cripple’

• Took long time treatment• cost were expensive

Why Worth a Nobel Prize Award?After Discovery• The first to prove the association of H. pylori as pathogen for

peptic ulcer disease• Dramatic change over the medical perspective and understanding

• Prove some bacteria can survive stomach acid• Urease in H. pylori produces ammonia to neutralise stomach

acid• NH2CONH2 + H+ + 2H2O → 2NH4+ + HCO3

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• Flagella which allows motility in viscous mucus• Adhesins which facilitate adherence to stomach wall• Provides a suitable environment for survival and colonisation

• Prove H. pylori is not a commensal but a cause of PUD and stomach cancer• H. pylori attack stomach lining, causes acid to get through the lining• Enhanced production of free radicals and causes increased rate of host cell

mutation

Impact of discovery towards current medical practice• Treatment and management of peptic ulcers – decline in

PUD and gastric cancer in late 20th century• Provide simple, much cheaper antibiotic cure for PUD

• Reduce usage of stomach surgery• Reduce medical cost burden• Faster treatment• Effective recovery• Reduces ulcer relapse

http://www.faseb.org/portals/2/pdfs/opa/pylori.pdf

Impact of discovery towards current research•Made H. pylori infection one of the most studied

paradigms of pathogen biology1. Listed as carcinogen – associated with gastric

carcinoma and MALT lymphoma2. Association with other conditions3. Further research; genomic diversity, pathogenicity,

mechanism, development of urea breath test

What’s next?

• Antibiotic resistanceMetronidazoleIn U.S., Clarithromycin resistance is found in 20% of H.

pylori positive patients

• Association of lifestyle, H. pylori, and development of gastric cancer

Why does certain population have higher risk of developing gastric cancer than others despite similar infection rates?

Possible Future Development• Changing epidemiology of upper gastrointestinal diseases

(peptic ulceration, oesophageal and gastric adenocarcinoma, gastro-oesophageal reflux disease and sequelae) with changing prevalence of colonisation with Helicobacter pylori

• Recognition of host factors that predispose to diseases induced by H pylori

• Definition of genetic characteristics of H pylori that are associated with significant variance in risk of disease

• Vaccinations against certain diseases based on specific interactions between H pylori and host

• Colonisation of some hosts with strains of H pylori with low virulence to reduce risk of particular diseases

Possible Future Development• In 1989, Strachan proposed the “hygiene hypothesis”,

stating that the exposure to infectious agents and living in an unhygienic environment might “educate” the immune system and thus protect against the development of allergic diseases.• Ondek™ has created and patented a derivative of H.

pylori that has retained its immune regulatory properties to combat the escalating problem of allergy.• Current targets are eczema, food allergies and allergic

asthma. • Further research to target more allergic reactions.

References:• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047919/• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1113159/• http://ondek.com/our-approach/• http://www.nobelprize.org/nobel_prizes/medicine/laureates/2

005/

• http://www.ncbi.nlm.nih.gov/books/NBK2432/.• http://

www.nobelprize.org/nobel_prizes/medicine/laureates/2005/marshall-lecture.pdf

• http://www.ncbi.nlm.nih.gov/pubmed/2593958• http://www.ncbi.nlm.nih.gov/pubmed/3335917• https://www.science.org.au/teacher-notes-dr-robin-warren• http://www.faseb.org/portals/2/pdfs/opa/pylori.pdf