>> WELCOME TO THE SECOND SESSION
OF THE 20TH YEAR OF DEMYSTIFYING
MEDICINE.
FOR THOSE WHO ARE TUNING IN
PERHAPS FOR THE FIRST TIME,
PERHAPS A WORD OF EXPLANATION IS
TO FIRST POWERPOINT HERE.
THIS IS THE BROOKLYN BRIDGE
WHICH IS THE LOGO FOR THIS
COURSE, IT IS BASICALLY A COURSE
IN BRIDGE BUILDING, CONNECTING
DIFFERENT DISCIPLINES IN SCIENCE
BIOLOGY ENGINEERING AND
MEDICINE.
WE ARE LIKE THE TWO INDIVIDUALS
ON THE CAT WALK, WHO TODAY ARE
DISCUSSING THE SPLIT PERSONALITY
THAT TWO IMAGES OF HELICOBACTER
PYLORI.
PRIOR TO ABOUT 1990, GASTRITIS
AND PEPTIC ULCER DISEASE WERE
MOST COMMON MEDICAL ILLNESSES.
IT WAS GENERALLY BELIEVED THEIR
ETIOLOGY WAS RELATED TO
SECRETION OF HYDRO COLORRIC ACID
BY THE STOMACH PLUS ADDITIONAL
FACTORS TERM STRESS.
THE STRESS A DRUG, IT COULD
BE ALCOHOL, DIET, OR SO CALLED
TYPE A PERSONALITY.
THE TREATMENT INVOLVED ANTACID
AND FOR COMPLICATIONS SURGERY.
TREATMENT ALSO SOMETIMES
INVOLVED COUNSELING AND OTHER
THERAPIES BASED ON THE PREMISE
OF THIS BEING A COMBINATION OF
PSYCHOLOGIC AND PHYSIOLOGIC
DISEASE.
THE COMPLICATIONS WERE SERIOUS.
THERE WERE PERFORATION,
HEMORRHAGE, AND RELATIONSHIP OF
GASTRIC CANCER PARTICULARLY TO
GASTRIC ULCERS.
THE SURGERY WAS IDENTIFIED BY A
WIDE VARIETY OF NAMES OF
INDIVIDUAL SURGEONS WHO PUT
THEIR OWN NAME ON THEIR
PARTICULAR PROCEDURE.
BUT ALMOST ALL INVOLVED SOME
TOTAL GAS TREKTOMY WITH OR
WITHOUT SEGREGATION OF THE VAGUS
NERVE WHICH HOPED TO REGULATE
HYDRO COLORRIC ACID SECRETION.
UNTIL 1990 THINGS BEGAN TO
CHANGE IN UNEXPECTED DRAMATIC
IMPORTANT WAY.
SUDDENLY THE CONCEPT THAT PEPTIC
ULCER DISEASE AND GASTRITIS
COULD BE A BACTERIAL DISEASE WAS
EARTH SHAKING.
THE TREATMENT BEGAN TO CHANGE,
THE PROTON PUMP INHIBITORS TO
BLOCK ACIDS SECRETION AND
ANTIBIOTICS TO AFFECT BACTERIA
FOUND.
THE RATE OF COMPLICATIONS
DECREASED TREMENDOUSLY AND SOME
TOTAL GASTRECTOMY IS NOWHERE
NEAR WHAT IT WAS LIKE IN
PRE-1990 ERA.
HOW DID ALL THIS COME ABOUT?
HOW DID THIS AMAZING CHANGE
OCCUR?
IT BEGAN ABOUT 1981 WHEN IN
PERT, AUSTRALIA, IF YOU WANTED
TO FIND A CITY FURTHER FROM THE
EAST COAST OF THE UNITED STATES,
YOU GO TO PERT.
A BEAUTIFUL CITY ON THE WEST
COAST OF AUSTRALIA, SURROUNDED
BY GORGEOUS BEACHES, WILD LIFE
AND A GREAT UNIVERSITY, THE
UNIVERSITY OF WESTERN AUSTRALIA,
WHICH IS WHERE OUR FIRST SPEAKER
BARRY MARSHALL RECEIVED HIS
MEDICAL TRAINING.
WHILE A REGISTRAR RESIDENT AT
THE ROYAL SCHOOL BARE REMET AND
COLLABORATED WITH A PATHOLOGIST,
ROBIN WARREN WHO HAD BEEN
OBSERVING SPIRAL BACTERIA IN
SPECIMENS OF HUMANS WHO HAD
PATIENT GASTRITIS.
THIS WAS LATER IDENTIFIED AS
HELICOBACTER PYLORI.
A VARIETY OF STUDIES LED TO THE
IDEA THAT MAYBE PEPTIC ULCER
DISEASE WAS THE RESULT OF
INFECTION.
THIS WAS MET WITH GREAT
SKEPTICISM FROM CLINICIANS,
SOCIETIES PUBLICATIONS, FUNDING
SOURCES.
HOWEVER, MARSHALL AND WARREN DID
SOMETHING THAT ALL GOOD
INVESTIGATORS DO WHO BELIEVE
THEY ARE FOLLOWING SOMETHING OF
INTEREST AND CHALLENGE, THEY
PERSEVERED IN A SERIES OF
REMARKABLE STUDIES, THEY
ESTABLISH A LINK BETWEEN
HELICOBACTER INFECTION AND
PEPTIC ULCER DISEASE.
FOR THIS WORK IN 2005, HAY
SHARED THE NOBEL PRIZE IN
PHYSIOLOGY AND MEDICINE.
DR. MARSHALL HAD RECEIVED AFTER
RECEIVING THE NOBEL PRIZE AS
RECEIVED A HUGE NUMBER OF
SPECIAL PRIZES AND AWARDS, THE
LASKER AWARD, THE GARDENER
FOUNDATION AWARD, THE ERLICH
AWARD, GOLDEN PRIZE OF THE
AMERICAN ACADEMY OF ACHIEVEMENT,
BUCHANAN MEDAL OF ELECTED
SOCIETY, ELECTED O THE FELLOW OF
ROYAL SOCIETY, ALL BASED UPON
THESE EXTRAORDINARY STUDIES THAT
WERE PERFORMED.
IN ADDITION IS WORK WHICH
PERSISTED AND HAS CONTINUED IS
ALSO RAISED THE QUESTION
HELICOBACTER INFECTION IS A
DOUBLE BARREL EVENT HAVING SOME
BENEFICIAL EFFECT PERHAPS AND
CERTAINLY IN THE CASE OF THEIR
STUDIES DELETERIOUS ONE.
ONE OF THE INDIVIDUALS WHO
PROFOUNDLY DISAGREED IN THE
BEGINNING WITH HYPOTHESIS THAT
ULCERS WERE INFECTIOUS DISEASE
WERE OUR SECOND SPEAKER, MARTY
GLASER.
MARTIN IS A PHYSICIAN
MICROBIOLOGIST, HE GRADUATED
FROM NEW YORK UNIVERSITY, TOOK
HIS RAINING IN COLORADO THEN WAS
CHAIRMAN OF MEDICINE AT NEW YORK
UNIVERSITY.
ACTUALLY MOVED TO RUTGERS
UNIVERSITY WHERE HE IS AT THE
ROBERT WOOD JOHNSON MEDICAL
SCHOOL PROFESSOR OF MEDICINE AND
PATHOLOGY AND LABORATORY
MEDICINE.
HE HOLDS THE HENRY RUTGERS CHAIR
OF THE HUMAN MICROBIOME AND IS
DIRECTOR OF THE CENTER FOR
ADVANCED BIOTECHNOLOGY AND
MEDICINE.
HIS WORK THE PAST 30 OR MORE
YEARS HAS RELATED HUMAN
MICROBIOME TO DISEASES, TO
HEALTH AS WELL AS TO DISEASES.
IN PARTICULAR HE FOCUSED ON
CAMPILOBACTER AND HELICOBACTER
PYLORI.
IMPOSED THE QUESTION OF WHETHER
IT HAS ACTUALLY A PROTECTIVE
ROLE.
DURING THIS WORK HE DEVELOPED
THE HYPOTHESIS H PYLORI IS AN
ANCIENT UNIVERSAL INHABITANT OF
THE HUMAN STOMACH AND THAT IT'S
BEEN DISAPPEARING AS A RESULT OF
20TH CENTURY CHANGES IN
SOCIOECONOMIC STATUS INCLUDING
THE USE OF ANTIBIOTICS AND THIS
LOSS OF HEALTH CONSEQUENCE IS
NOT ONLY GOOD IN THE SENSE THAT
IT IS REDUCING SOME DISEASES OF
THE STOMACH INCLUDING GASTRIC
CANCER BUT BAD AS WELL, HE'S
DONE EXTENSIVE WORK ON THE
RELATIONSHIP OF THE MICROBIOME
THROUGH ASTHMA, DIABETES,
OBESITY AND NEOPLASTIC DISEASE.
HE IS HIGHLY RECOGNIZED BY ALL
THE PROFESSIONAL SOCIETIES THAT
HE HAS BEEN A MEMBER OF,
PRESIDENT OF THE SOCIETY OF
INFECTIOUS DISEASE, MEMBER OF
THE NATIONAL ACADEMY OF MEDICINE
ARTS AND SCIENCES, HE GAVE THE
KUNYON LECTURE AT THE NIH
SEVERAL YEARS AGO, HE RECEIVED
AWARDS, THE FLEMING MEDAL AND IN
2015 TIME MAGAZINE ANNOUNCED
THAT HE WAS AMONG THE 100 MOST
SIGNIFICANT INFLUENTIAL PEOPLE
IN THE WORLD SO TODAY WE ARE
EXTREMELY FORTUNATE THAT TWO
HIGHLY ACCOMPLISHED EXPERIENCED
INDIVIDUALS DISCUSSED THIS VERY
IMPORTANT QUESTION AND A
CHALLENGING ONE FROM THE
CLINICAL AND THE BASIC SCIENCE
PERSPECTIVE SUMMARIZED AS THE
SPLIT PERSONALITY OF
HELICOBACTER.
OUR FIRST SPEAKER WILL BE BARRY
MARSHALL.
AND AS I MENTIONED PLEASE SUBMIT
YOUR QUESTIONS DURING HIS TALK
AND WE WILL HAVE A QUESTION AND
ANSWER SESSION AT ITS
CONCLUSION.
BARRY YOU ARE ON.
THANKS VERY MUCH FOR THAT IRWIN
THIS IS A LOGO AND WE HAD THIS
ON T SHIRTS AT A CONFERENCE IN
PERTH IN 2002 BECAUSE THAT WAS
20 YEARS AFTER THE ORIGINAL
CULTURE HELICOBACTER PYLORI.
IT IS AMAZING THAT THIS
DISCUSSION AND PRESENCE IS STILL
IN HELICOBACTER SO THANK YOU FOR
SAVING ME FROM HAVING TO GET
INVOLVED WITH THIS BECAUSE
USUALLY WHEN -- IF I DISCUSSED
THIS IN A LATE YEAR I'M
PRESENTING A LOT OF IDEAS THAT
COME FROM MARTIN BLAZER'S WORK
OVER THE YEARS -- BLASERS WORK
OVER THE YEAR SO IT IS GREAT TO
HAVE HIM ON THE FACULTY THERE.
SO THERE'S THE GOOD AND THE BAD
HELICOBACTER.
THE ONE ON THE RIGHT PRODUCES A
TOXIN AND THE ONE ON THE LEFT
PROBABLY DOESN'T.
OF COURSE WE CAN THEN FIGURE OUT
WHICH WE BELIEVE AND IN
DIFFERENT AGE GROUPS PROBABLY
GOING TO BE DIFFERENT.
SO I WILL SHOW A FEW MORE OF
THESE OVER THE SLIDE AS WE GO
ALONG.
SO NOW I'M GOING TO ADVANCE THE
SLIDES THERE.
SO MY FINANCIAL DISCLOSURE, I AM
PARTNERING A COMPANY THAT
EFFECTIVELY MAKES A BUSINESS OUT
OF SELLING THINGS RELATED TO
HELICOBACTER PYLORI TREATMENT
DIAGNOSIS.
NOT ALL THAT I TALK ABOUT NOT
REALLY TREATMENT STUDY LECTURE
BUT WE WILL TALK ABOUT THINGS
PROBABLY NOT AVAILABLE IN THE
UNITED STATES BUT NOT HAVE ANY
BENEFIT FROM THAT.
SO APPROVED OFF LABEL DRUGS.
LEARNING OBJECTIVES, IN THE
ENVIRONMENT AND HOW HELICOBACTER
PYLORI WAS PEPTIC ULCER AND
GASTRIC CANCER.
THE RESEARCH PATHWAY IS GETTING
HYPOTHESIS TO TESTING IT AND
MOVING ON GETTING ANOTHER
HYPOTHESIS AND TESTING IT SO
THAT'S A GOING TO APPLY TO EVERY
RESEARCH EFFORT.
THE CLINICAL THING IS YOU MUST
SEE THE IMPORTANCE OF THE
PROSPECT OF RANDOMIZED DOUBLE
BLIND STUDY WHICH IF IT WASN'T
FOR THE FDA BEING SO DIFFICULT
WITH THE PHARMACEUTICAL
COMPANIES IN THE UNITED STATES
IT WOULD HAVE BEEN MANY, MANY
YEARS BEFORE THE WORLD STARTED
DOING THAT.
I ALWAYS HAVE RESPECT FOR --
THEY GET A BAD RAP SOMETIMES.
WE CAN TALK ABOUT HOSE SEATS AND
HOW WE CHANGE THINKING OVER
TIME.
THEN THINK HOW MANY YEARS IT
TOOK FOR OUT ALL TO HAPPEN FOR
IMPORTANT THINGS TO CHANGE IN
MEDICINE.
SO YES GO HERE TO WAR -- WE GO
TO WAR REASON'S FIRST CASE, 1979
ON HIS BIRTHDAY SO IT IS THE
11TH OF JUNE 1949 AND HE WAS 40
AT THIS POINT.
THERE HE IS IN THAT OFFICE A
COUPLE OF YEARS LATER.
ON THE LEFT-HAND SIDE YOU CAN
SEE THAT SMALL PRINTING, THAT'S
THE REPORT, FIRST CASE OF
HELICOBACTER PYLORI AND HE MAKES
THE POINT THERE IS A
SUPERFICIAL, JUST GOING TO SET
MY POINTER OPTIONS, HOLD ON, I'M
GOING TO CHANGE TO LASER
POINTER.
SO YOU CAN SEE DESCRIBE PLASMA
CELLS AND THEN DIFFERENT THINGS,
THESE BACTERIA SHOW MORPHOLOGY
OF CAM LOWBACTER, THEY ARE
GROWING AND NOT A CONTAMINANT.
NOT SURE SIGNIFICANCE OF THESE
FINDINGS BUT FURTHER
INVESTIGATION OF EATING FUNCTION
CASTRO FUNCTION AND MICROBIOLOGY
MIGHT BE WORTHWHILE.
I WENT TO WORK WITH HIM ON THIS.
SO HE'S -- I HAPPEN TO BE IN THE
RIGHT PLACE RIGHT TIME LOOKING
FOR A RESEARCH PROJECT WHICH IN
YOUR TRAINING IN TO BE PHYSICIAN
IN WESTERN AUSTRALIA, YOU ARE
SUPPOSED TO DO CLINICAL ANY KIND
OF RESEARCH PROJECT EACH YEAR SO
DO THAT AS NORMAL ACTIVITIES.
VERY INTERESTED IN WARREN'S
BACTERIA.
JUST TRYING TO FIGURE OUT HOW
COULD BACTERIA LIVE IN THE
STOMACH, IT WAS EXCITING TO FIND
OUT THAT THE ALL THE TEXTBOOKS
WERE WRONG THERE WERE THINGS
LIVING IN THE STOMACH NOT
REPORTED THE THE TEXTBOOK.
I THOUGHT GREAT I'LL GET A
PUBLICATION OUT OF THIS AND THEN
GO ON WITH MY CAREER.
SO DIDN'T START OFF TRYING TO
FIND THE ULCERS, IT IS A CASE OF
CURIOSITY DRIVEN RESEARCH, HOW
BACTERIA SURVIVE IN THE STOMACH
WHEN THERE'S ACID THERE.
SO MOVING ON THIS IS WARREN'S
FIRST CASE.
SO THIS IS -- ON THE LEFT-HAND
SIDE IS ONE OF THESE COMMENTS
FROM AN ARTICLE THAT HE DID
SOMEWHERE A FEW YEARS LATER.
HE SAYS THEY WERE CLOSELY
RELATED TO THE ACTIVE GASTRITIS
SO HISTOLOGY BUT NOT THE
BACTERIA BEFORE.
THE PRESENCE OF NEUTROPHILS IN
THE STOMACH WAS ALMOST PA KNOW
PNEUMONIC OF HELICOBACTER, YOU
CAN SEE MANY CURVE SPIRAL
BACTERIA PARTICULARLY AROUND THE
TIGHT JUNCTIONS, THAT'S WHERE
THEY LIKE TO LIVE, HAY ALSO ON
THE 3-D STRUCTURE IF YOU CAN
IMAGINE.
THESE YELLOW PARTS HERE IS THE
YELLOW STAIN AND SILVER STAIN
AND EPITHELIAL CELLS SECRETING
MUCOUS AND THERE WAS
HELICOBACTER SO NORMAL CULTURES
OF THE MOUTH IF YOU LIKE WOULD
BE GRAHAM POSITIVE, GRAHAM
NEGATIVE COCCI FUNGI NOT
HOMOGENOUS CURVE BACTERIA LIKE
THIS.
AT THAT TIME CAMPYLOBACTER WAS
CULTURED THE FIRST FEW YEARS,
AND THAT WAS WHERE THE
MICROBIOLOGY WAS VERY EXCITING
AND ACTUALLY MARTY BLASER AT THE
CAMPYLOBACTER MEETING IN BROS
SELLS IN 1983 I GUESS.
THAT WAS WARREN'S FIRST CASE.
THE QUESTION WAS HOW DID BACK
TIER WHERE SURVIVE IN THE
STOMACH BECAUSE THEY ARE KILLED
WITH PH LESS THAN THREE.
GASTRIC SECRETION ACID IN THE
STOMACH OR PH LESS THAN TWO
OFTEN NEAR 1.5 SO DEFINITELY YOU
CAN SHOW IT KILLS BACTERIA.
ALMOST EVERYTHING SO NOBODY WAS
LOOKING FOR BACTERIA IN THE
STOMACH SO THAT WAS POSITIVE.
WE STARTED THIS COLLABORATION IN
1981.
THERE'S ME AND ROBIN IN HIS LAB
STUDYING PATHOLOGY BOOKS ET
CETERA, THAT WAS ABOUT '84 I
THINK.
SOME YEARS LATER I -- I'M MOVING
MY SCREEN, FIX THE SCREEN
AROUND, I DID AN INTERVIEW WITH
READERS DIGEST IN '88.
SCIENTISTS FOUND IT HARD TO
ACCEPT TEACHING TO AUSTRALIANS
NOT ONLY WITH THE INVESTIGATORS,
SEEM SUPREMELY CONFIDENT THEIR
HYPOTHESIS WAS CORRECT.
SO AFTER PRESENTING YOUR ONE
INTERNATIONAL MEETING AND
MEETING SOME PRETTY GOOD
SCIENTIFIC THOUGHTFUL GASTRO
ENTEROLOGISTS AND INFECTIOUS
DISEASE PEOPLE IN EUROPE, NOTICE
NOTICING THAT THESE BACTERIA
WERE IN EVERY COUNTRY AND
REPORTED BEFORE, SO WE BECAME
CONFIDENT YOU SEE BY THE TIME IT
WAS PUBLISHED WE HAD BEEN
TESTING THIS FOR THREE YEARS SO
MADE IT DIFFICULT FOR US BECAUSE
PEOPLE SAID THEY ONLY GOT ONE
PAPER AND THEY THINK -- THERE
WAS REASON TO SKIP I SUPPOSE.
SO THE PREVIOUS DISCOVERIES WERE
THAT MANY PEOPLE HAD SEEN THESE
BACTERIA AND LATER PUBLISHED A
BOOK ON THIS OF COURSE.
AND THE EARLY DISCOVERIES IS
ALSO IN ITALY AND -- FREEBURG,
FITZGERALD THESE PEOPLE WERE
STILL ALIVE, I THINK WHEN WE
MADE OUT A DISCOVERY, SONNENBURG
CO-AUTHORED SOMETHING THERE.
I THINK IT WAS -- SO A LOT OF
PEOPLE SAW THE BACTERIA BUT
COULDN'T GET ANY TRACTION
TOWARDS RESEARCH PROJECT OR
ANYTHING.
AND MOVED ON.
SO THEY PRODUCED ONE PAPER ON IT
BUT REALLY DIDN'T THINK THAT WAS
SOMETHING CONNECTED WITH ULCERS.
SO FREEBURG WAS FAMOUS ONE FROM
1939, '40 IN BOSTON HE PUBLISHED
HIS PAPER SPY ROQUETTES IN
GASTRIC MUCOSA.
THAT IS HIM IN 1940 WHEN I MET
HIM AND 2005 IN NEW YORK TIMES
HE GOT A BIG TIME WRITE UP
DISCOVERY.
HE LATER CAME UP HEAD OF
CARDIOLOGY ISRAEL IN BOSTON BUT
ALWAYS HAD NOSTALGIC IDEAS ABOUT
HIS FOR RAYS INTO MICROBIOLOGY
OF THE STOMACH.
AND HERE IS ILLUSTRATION FROM
HIS PAPER.
YOU CAN SEE THE SPATIAL
BACTERIA, HE WAS DOING SILVER
STAINS SAME STAIN Z AS ROBERT
WARREN, HE WAS REMOVING STOMACHS
AND FEW POSTMORTEM SPECIMENS SO
HE IDENTIFIED THE BACTERIA AND
NOBODY BELIEVED THAT BACTERIA
COULD LIVE IN THE ACID STOMACH
AND P CONTAMINATIONS.
A FEW YEARS LATER THE TOP
PATHOLOGIST IN THE UNITED STATES
AT WALTER REED HOSPITAL IS EDDIE
PALMER AND HE HAD ONE OF HIS
FELLOWS LOOK AT THOUSAND
SPECIMENS IN THE COLLECTION.
HE SAYS NONE OF THE ELIMINATING
SPECIMENS WAS FOUNDED TO CONTAIN
SPY ROQUETTES, TO BE SPY ROW
CHEAT NATURE.
SO HE WAS UPSET WHEN THEY DIDN'T
CONFIRM BECAUSE IT IMPLIED THE
FINDINGS WERE WRONG SO THEY
CARRIED A GRUDGE ON HIS SHOULDER
AND MOVED TO CARDIOLOGY AND WAS
SUCCESSFUL THERE.
PEOPLE ASK ME, IF IT WASN'T FOR
THIS PAPER BEING INCOMPETENTLY
DONE, I DON'T KNOW WHY.
THEN THIS MIGHT HAVE BEEN WORKED
OUT IN THE '50s AND STUDIES
OUT BEFORE.
THE -- HE WAS AN ECZEMA VENEREAN
IN THE JAPANESE REGIMENT IN
WORLD WAR II AND THEY WOULD SEND
JAPANESE REGIMENT, IT WAS IN
ITALY AND GERMANY AND PLACES
WHERE JAPANESE -- WITH HIS PALS
AND MADE IT THROUGH AND WENT TO
MEDICAL SCHOOL AT HARVARD AND
BECAME ONE OF THE FIRST AGNAT
MISTS WITH A GOOD ELECTRON
MICROSCOPE AND HERE HE IS
PUBLISHING A BIOPSY HE TOOK OF
HIS OWN STOMACH BECAUSE HE HAD
DONE ANATOMY OF CAT SO STOMACH
AND WONDERED WHETHER PEOPLE HAD
THESE BACTERIA SO HE SWALLOWED
HIS OWN SUCTION BIOPSY CHEW, IT
WAS A LITTLE BIT DANGEROUS AND
TOOK A BIOPSY OF HIS OWN STOMACH
AND GOT BEAUTIFUL FRESH
MICROSCOPY AND HERE YOU SEE ONE
OF THE MAJOR TEXTBOOKS OF
PHYSIOLOGY HE PUBLISHED A
BEAUTIFUL PICTURE OF
HELICOBACTER PYLORI WITH
MULTIPLE FLAGELLULA ON THE END
STUCK TO EPITHELIAL CELLS BUT
HIS TEACHING WAS LOTS OF ANIMALS
HAVE THEM, EVERYBODY HAS THEM
AND NOBODY IN BOSTON SHOWED ANY
INTEREST IN HELICOBACTER UNTIL
MANY, MANY YEARS LATER.
PERHAPS BECAUSE THEY HAD SEEN A
PICTURE IN MEDICAL SCHOOL AND
MOVED ON.
SO WARREN AND I GOT TOGETHER WE
STUDIED A HUNDRED PATIENTS AND
THIS IS A STUDY DONE IN 1982 SO
I THINK ABOUT APRIL, FINISHED IN
JUNE.
TO SEE HOW MANY HAD BACTERIA, IT
WAS PROSPECTIVE AND BLINDED IN
THAT WE WERE JUST DOING A STUDY
IF YOU LIKE AND WE WANT TO SEE
WHO HAD IT.
SO I WAS SENDING THE BIOPSIES
WITHOUT MUCH CLINICAL
INFORMATION TO WARREN AND ALSO
THE ENDOSCOPY CULTURE THEM AND
STATISTICIAN RECEIVED THE
AMALGAMATED DATA EVENTUALLY SO
HUNDRED PATIENTS FROM ENDOSCOPY,
I HAD A NICE QUESTIONNAIRE ABOUT
THE PEOPLE AND I MUST HAVE BEEN
CONVINCING BECAUSE OUT OF 1 O 01
PATIENTS INVITED TO PARTICIPATE
I HAD A HUNDRED, SO ALMOST NO
DROP OUTS OF REFUSALS.
58% HAD THE BACTERIA.
BUT WHEN WE LOOK AT THIS TABLE
YOU SEE OF THE PATIENTS WITH
ULCER, 13 OF 100% HAD THE
BACTERIA SO P VALUE .3, NOW .4
AND GASTRIC BYPASS IS 77% AND
HELD UP IN OTHER STUDIES SO THAT
WAS PRETTY INTERESTING AND OTHER
THINGS ON VARIOUS PUNCH CARDS
CALLED KALAMAZOO CARDS.
WE PUBLISHED THIS EVENTUALLY, A
YEAR LATER IN THE LANSETT.
ONE THING ABOUT NO MATTER WHAT
YOUR P VALUE IS, IF THE PEER
REVIEWERS DON'T BELIEVE IT, JUST
ASSUME THAT YOU SAVE THE DATA
AND ALWAYS TELL OR WASN'T
BLINDED IN THE PROPER WAY,
PEOPLE JUST IN THEIR HEARTS
COULDN'T BELIEVE IT.
AND SO THERE WERE VARIOUS
REASONS WHY WE MIGHT HAVE
SELECTED GROUP, ET CETERA, ET
CETERA.
SO WE WENT OFF AND TRIED TO
PROVE US WRONG AFTER WE
ANNOUNCED IT.
BY THE TIME THIS WAS PUBLISH WED
FOUND ASSOCIATION WITH
ALLOTTERS, STARTED TO TREAT A
FEW PEOPLE, GETTING PRETTY
EXCITED ABOUT IT.
SO IT WAS HARD TO KEEP US UNDER
WRAPS NOT SURE WHAT THE NEXT
SLIDE IS.
THE ACID BLOCKER TREATMENT WAS A
BILLION DOLLAR BUSINESS, 3
BILLION IN 1993, '84.
WOULD THE WORLD ACCEPT A NEW
COURSE OF ULCERS ON THE BATE OF
DATA FROM 13 PATIENTS?
THE ANSWER IS NO WAY.
SO I JUST WARN THE YOUNG
INVESTIGATORS NEVER PUBLISH A
PAPER WITH 100% OF ANYTHING, IN
BIG MEDICINE.
NO ONE BELIEVES IT, NOTHING IS
100%, FIND AN EXCEPTION AND PUT
IT IN IF YOU CAN SO THIS IS
WHERE I WAS TELLING MARTIN I
ACTUALLY DISCOVERED THE GOOD AND
BAD HELICOBACTER SITUATION
BECAUSE THERE WAS I WASN'T GREAT
STATISTICIAN BUT LOOK AT THIS
TABLE AND THIS LINE HERE,
ESOPHAGUS ABNORMAL.
SO WHEREAS THE AVERAGE WAS 58%
INFECTED, 41% ESOPHAGUS.
SO PEOPLE WITH ACID REFLUX WOULD
HAVE BEEN IN THAT GROUP.
HAD LESS THAN NORMAL
HELICOBACTER.
SO IF YOU WOULD LOOK AT THIS P
VALUE NON-SIGNIFICANT BUT OF
COURSE IT IS THE OTHER TAIL OF
THE NORMAL DISTRIBUTION AND IT
SHOWS THERE'S SOME PROTECTION OF
THE ESOPHAGUS BY HELICOBACTER
PYLORI.
I DIDN'T PICK UP THIS UNTIL THE
'90s WHEN OTHER PEOPLE STARTED
MAKING A CAREER OUT OF IT SAYING
HELICOBACTER MAY BE SHOULDN'T BE
TREATED IF YOU HAVE ESOPHAGITIS
BECAUSE IT COULD BE ACID A BIT
LOWER AND YOU WOULD BE HARMING
PEOPLE IF YOU RETURN ACID TO
NORMAL.
SO THIS IS WHERE I DISCOVERED
THE GOOD AND BAD HELICOBACTER,
DIDN'T REALIZE I HAD DISCOVERED
IT UNTIL FIVE OR SIX YEARS LATER
IN MY DATA TABLE IN THE LANSETT.
SO LET'S PRESS ON WE TRIED TO
PRESENT THAT, THIS IS THE
REJECTION LETTER I STILL HAVE
THAT FRAMED IN MY OFFICE FROM
THE GASTRO ENTEROLOGY SOCIETY
AUSTRALIA.
WE REGRET YOUR RESEARCH PAPER
WAS NOT ACCEPTED, NUMBER OF
ABSTRACTS FROM THIS MEETING, 67
SUBMITTED, WE GO 56 SO IN THE
BOTTOM 20%, THEY WOULDN'T GIVE
ME A POSTER.
NOT ONLY DIDN'T I GET AN ORAL
BUT I DIDN'T GET A POSTER EITHER
SO THAT POINT IT WAS SHAMEFUL TO
BE INTERESTED IN CAMPYLOBACTER
IN THE STOMACH BECAUSE IT
COULDN'T BE TRUE, IT CAME FROM
NOWHERE.
SO FOUND IT INTERESTING, IT MADE
MORE CHALLENGING AND MORE FUN
FOR US I SUPPOSE.
TO PROVE EVERYONE ELSE IS WRONG.
HOW DO YOU PROVE GERMS ARE
HARMFUL, A HARMFUL PATHOGEN, WE
TRIED TO INFECT MICE RATS GINNY
PIGS PIGS AND ULTIMATELY HAD
SOME SUCCESS WITH HUMAN.
THESE BEFORE INFORMAL
ADMINISTRATION TO RARE VARIOUS
ANIMALS ONE OR TWO USUALLY AND
NOTHING -- EVERYTHING WAS
RESISTANT AND I DID A FORMAL
EXPERIMENT ON SOME PIG LETS
WHICH GREW AND ULTIMATELY AFTER
SIX MONTHS THEN DISCOVERED IT
WAS NOT LONG ENOUGH TO PERFORM
ENDOSCOPY ON THIS PIECE SO
NEARLY FULL SIZE AND THE
BACTERIA COULDN'T BE INFECTED SO
THE EXPERIMENT FAIL SOD THE END
EXASPERATED I SAID THE CRUCIAL
QUESTION IS WHAT COMES FIRST
BACTERIA OR THE ULCERS.
SO THE HUMAN VOLUNTEER
EXPERIMENT.
THIS WAS PUBLISHED MANY YEARS
LATER BY THE ABBOTT COMPANY YOU
MAYBE ERYTHROMYOSIN, THAT WAS A
FIRST GOOD ANTIBIOTICS FOR
HELICOBACTER AND THEY PRODUCED A
ULCER TALES AND GAVE IT TO EVERY
DOCTOR IN AMERICA.
HERE I AM DRINKING THE BACTERIA
SO I DRANK TWO FRESH PETRI
DISHES OF STRAIN OF HELICOBACTER
WE ISOLATED FROM A PATIENT AND I
WAS BEING CAREFUL, IT WAS
SENSITIVE TO IN VITRO AND WE HAD
CURED THE PATIENT BY GIVING HIM
METRANITIS, THE WORST CASE
SCENARIO ARE GOOD BLEEDING ULCER
BUT I CAN TAKE THE TREATMENT AND
GET RID OF THE GERM SO THAT'S
HAPPENED.
I DRANK IT, VARIOUS THINGS
HAPPENED, I HAD ENDOSCOPY
BASELINE, STOMACH WAS NORMAL,
BIOPSIES NORMAL, I DRANK THAT
BACTERIA AND THEN I DEVELOPED
HISTOLOGICAL GASTRITIS WHICH WAS
BIOPSIED ON DAY 10 SO SHOW AD
HEALTHY PERSON CAN PICK UP AND
CARRY THE BACTERIA, WE DIDN'T
HAVE TO HAVE THE YOU WILLER
FIRST WHICH WAS ALWAYS THE
ARGUMENT PEOPLE HAD.
THIS IS MY GASTRIC MUCOSA
SIMILAR TO THE CASE THAT WARREN
SOUGHT FIRST TIME AROUND AND
MANY HELICOBACTERS.
SO INTERESTING I HAD A
HELATOSIS, VOMITING AND THERE
WAS NO ACID IN THE VOMIT SO A
LOT OF THINGS HAPPENED THAT
SHOOK MY MEMORY ABOUT THE THINGS
I READ IN THE MEDICAL BOOKS.
IT REMIGHT BED ME OF TEXAS
EPIDEMIC WHERE THEY STUDIED A
ACID SECRETION AND BLOCKING IN
1978 AND THE PERSON WAS PETE
PETERSON AND JERRY RAMSEY, A FEW
FAMOUS NAMES IN GASTRO
ENTEROLOGY.
HE HAD COME FROM BOSTON THEY HAD
A EPIDEMIC OF SUDDEN GASTRITIS
IN 30 VOLUNTEERS BECAUSE PASSING
GASTRIC NIACIN TUBES AND CHAIN
KNOW HOW TO STERILIZE THEE, THEY
INCLUDED THEY WERE BE STERILE IN
STOMACH ACID SO THEY MADE THAT
MISTAKE.
THEY INFECTED EVERYBODY AND THEY
WERE SOME OF THE BIGGEST
SKEPTICS OF THIS GROUP IN DALLAS
PARTICULARLY CALLED THE ACID
MAFIA FOR MANY YEARS BECAUSE
THEY WERE U STILL ON THE ACID
BOAT RATHER THAN MOVING TO THE
HELICOBACTER TREATMENT.
THEY WERE QUITE PROKOFIEV IN THE
HELICOBACTER AREA.
THE OTHER THING ABOUT BUSINESS
MUT, THEY THOUGHT IT WAS SOME
KIND OF A COATING PRODUCT AND
HAD BEEN USED AS AN ANT ACID
SUPPLEMENT FOR MANY YEARS IN
GERMANY, 200 YEARS IN FACT, IT
WAS AROUND OVER COUNTER MEDICINE
AND I HEAR YOU SEE THIS IS
ACTUALLY BISMUTH ON A DISC OF
HELICOBACTER PYLORI PROVIDED IN
1983.
I PREDICTED THAT ANY DRUG WHICH
HAD A LOW RELAPSE RATE OF PEPTIC
ULCER YOU TREAT A PATIENT FOR
THREE MONTHS AND STOP THE
TREATMENT, THE ULCER WOULD COME
BACK SO VERDICTLY EVERYONE WAS
ON ACID BLOCKERS THE REST OF
THEIR LIME BUT WHEN PATIENTS
WERE TAKING BISMUTH TREATMENT IT
WAS NOT AN ACID BLOCKER 30%
PEOPLE NEVER HAD RECURRENCE OF
ULCER SO THIS WAS NOTED IN
ENGLAND AND EUROPE.
SO PEOPLE WERE EXCITED ABOUT IT
IN THE YEARS JUST BEFORE --
ARRIVED SO I PREDICTED MUST BE
AN ANTIBIOTIC AND METALS LIKE
ARSENIC WERE USED AS
ANTIBACTERIALS BEFORE ADVENT OF
PENT SILL LYNN.
PEOPLE HAD FORGOTTEN ABOUT THAT,
IT IS AN ANTI-BACK EARIAL AND
U.S. PEOPLE WERE TAKING IT AS A
WELL KNOWN DRUG.
SO 30 MINUTES AFTER SWALLOWING
THE MISDEMEANOR SIN, YOU SEE
BACTERIA ARE DECOME POSING AND
DETACHED, ET CETERA.
SO IT IS STILL GOOD TREATMENT
FOR HELICOBACTER, ONE OF THE
HINGES THE BUG CANNOT WELCOME
RESISTANT TOO.
THAT POINT I CONNECTED UP WITH
PROCTER & GAMBLE WHO MAKE PEPTO
BUSINESS MALL AND THEY HAD THESE
DREAMS OF GETTING BILLION DOLLAR
SALES WITH PEPTO BISMAL, GAVE ME
A FELLOWSHIP AND THERE'S MY BOSS
RICHARD GRANT AT THE UVA
GEOGRAPHIC MEDICINE, I WAS IN
GASTROP ENTEROLOGY DOING
CLINICAL TRIALS FUNDED BY
PROCTER & GAMBLE.
IT WAS A FANTASTIC TIME TO TURN
UP IN THE UNITED STATES AND
CARRY ON THE RESEARCH.
I HAD A DOUBLE BLIND STUDY IN
AUSTRALIA NEARLY FINISHED THAT
POINT.
THAT'S WHEN I STARTED MEETING
EVERYBODY IN THE UNITED STATES
AND MARTIN BLASER AND I HAD
MEETINGS WITH PROCTER & GAMBLE
AND TRYING TO GET RID OF
HELICOBACTER IN THOSE DAYS.
HERE YOU SEE THE HIS HISTORY OF
PEPTO BISMAL AROUND A HUNDRED
YEARS, IN THE LITERATURE, IN
CONJUNCTION WITH REMEDIES IT IS
SERVICE TREATING GASTRIC ULCERS
AS WELL AS RELIEF OF ACUTE
GASTRITIS U.S. LITERATURE FROM
1900 WAS USING IT ANYTHING GUT
RELATED THOUGH TRIED PEPTO
BISMMAL AND TWEET A FEW TOOK IT
FOR EXACERBATION.
THAT WAS DISCOVERED ALREADY.
SEW LATER ON THIS IS A PICTURE
OF A MOUSE PAD I GOT FROM ASTRA
ZENECA AND NOW THAT ASTRA ZENECA
AND GLAXO WELCOME SO THAT WAS
THE FIRST TREATMENT FOR
HELICOBACTER AND THEY KIN LIKE
THAT THEY WERE COMPETING AGAINST
BISMUTH AT THAT STAGE SO THEY
WERE ADVERTISING NO BISMUTH
IMPLYING -- THEY HAD THE
TREATMENT AMOXICILLIN.
SO IT WAS FAKE NEWS THAT IT WAS
DANGEROUS AND THEY WERE CLAIMING
THEY DIDN'T USE BISMUTH AND PPI
AMOXICILLIN AND BISMUTH IS STILL
AROUND TODAY ONE OF THE GOOD
TREATMENTS.
SO HERE IS A I THINK I'M GOING
ALL RIGHT.
ANOTHER TEN MINUTES OR SO.
THIS IS OUR UNDERSTANDING OF THE
EPIDEMIOLOGY EARLY ON YOU SEE
THE WHOLE POPULATION OF
AUSTRALIA, UNITED STATES IS IN
THE GREEN AND THEN ABOUT A THIRD
TO 30 TO 50% OF THE POPULATION
IS GOING SO HAVE HELICOBACTER
PYLORI AND THEN IT IS VERY
INTERESTING THAT NEARLY ALL
PEPTIC ULCER DISEASES IN THE RED
GROUP ARE THE DUE DENUMB ULCER
SO IT LOOKS LIKE IT IS
IMPOSSIBLE TO GET A ULCER IN THE
GREEN BECAUSE SURELY PEOPLE
WOULD LOSE THESE BACTERIA,
ACCIDENTLY TAKING ANTIBIOTICS.
SO THEY WOULD BE IN THE GREEN
ROOM, YET THERE WAS HARDLY
ANYBODY IN THE GREEN GROUP
GETTING A DUODINAL ULCER SO THE
PREDICTION WOULD BE IF YOU COULD
GET RID OF THE HELICOBACTER AND
MOVE THE PATIENT IN THE GREEN
GROUP YOU WOULD CURE PEPTIC
ULCERS.
SO THAT IS WHAT WE WANTED TO DO,
PROSPECTIVE STUDY WE ARE
EVENTUAL -- I GOT FUNDED BY
AUSTRALIA AND NIH STARTING IN
'85 WE START AD THREE YEAR STUDY
OF THAT.
THIS IS THE OUTCOME PUBLISHED IN
LANSETT IN 1988.
SO WHAT WE GAVE WE GAVE PEOPLE
BISMUTH UNTIL THE ULCER WAS
HEALED SO EIGHT WEEKS OF
TREATMENT.
IF THEY DIDN'T HEAL THEY WOULD
DISCARD AUTO OF THE STUDY AND
SAY YOU HAVE TO BE HEALED OF
ULCER TO GET STARTED ON THIS
FOLLOW UP.
WE STOPPED EVERYTHING.
JUST KEPT OUR FINGERS CROSSED
AND FOLLOWED PEOPLE UP.
YOU SEE IF THE PATIENT HAD JUST
RECEIVED SEMETADINE ACID CLOCKER
AND PLACEBO ANTIBIOTICS, THE
PATIENTS QUICKLY RELAPSED.
THEY HAD THREE MONTHS FOLLOW-UP
ENDOSCOPY AND WE REMOVED SOME OF
THEM RELAPSED STRAIGHT AWAY, WE
REMOVED LOTS AT THREE MONTHS,
HAD RECURRENCE AT ENDOSCOPY AND
CONTINUED TO RELAPSE THERE.
AND AT SIX MONTHS WE DID ANOTHER
ENDOSCOPY AND TOOK MORE OUT.
AT 12 MONTHS WE DID A FINAL
ENDOSCOPY AND TOOK MORE OUT SO
IN THE PLACEBO GROUP A LOT
RELAPSED.
WHEREAS IN THE ANTIBIOTIC GROUP
IF WE HAD ERADICATED THE
HELICOBACTER VERY FEW RELAPSED.
IN FACT THEY HAD REFLUX
ESOPHAGITIS SYMPTOMS SO THEY
WERE TAKEN OUT A STUDY AS
RELAPSE BUT THEY DIDN'T HAVE A
DUODENAL ULCER SO QUITE A
REMARKABLE DIFFERENCE, I DON'T
KNOW WHY I'M NOT SEEING ANY LOSS
THE TRANSITION THERE BUT 80%
CURE IN THE TOP GROUP VERSUS 20%
BOTTOM GROUP.
PEOPLE DIDN'T LIKE THE FACT YOU
USE BISMUTH BECAUSE YOU CAN'T
BLIND IT, NOT GOOD ENOUGH SO WE
PUBLISHED IN THE LANSETT, NOT
THE NEW ENGLAND JOURNAL BECAUSE
MEDICATIONS ARE NOT AVAILABLE IN
THE U.S. AND WOULD HAVE CAUSED
CHAOS TO PUBLISH THIS IF THERE
WAS NO TREATMENT AVAILABLE.
THAT WAS ALL RIGHT AND
EVENTUALLY IT WAS THE STATE
STUDY WAS -- SAME STUDY WAS DONE
IN AUSTRALIA AND THEY USE R
AMOXICILLIN AND METRA ZYNOL, WE
HAD A GOOD CURE RATE, YOU SEE
THIS GROUP THE RELAPSE WAS 10%
AND 90% THIS THIS GROUP SO SAME
RESULT BUT REALLY NO ONE ARGUES
WITH BLINDING OF THAT STUDY
PUBLISHED IN NEW HE CAN LAND
JOURNAL 1993.
SO THERE WERE OTHER STUDIES THAT
DID IT, THERE WAS DOUBLE BLIND
STUDY, THIS CONFIRMATION BY ROSS
IN AMSTERDAM USING A BISMUTH
COMBINATION.
DAVID GRAHAM USED PEPTO BISMAL
AND TETRA ZYCLEAN, 90%
HELICOBACTER GREAT STUDIES
PUBLISHED THERE IN GASTRO
ENTEROLOGY AND HENSHELL IN VIE
YEAHNA SO THAT CHANGED THINKING
SO NOW IT WAS RESPECTFUL TO TALK
ABOUT HELICOBACTER, IT WAS
PUBLISHED BY THE CONSENSUS
MEETING AT THE NIH.
TO END OF IT LIMITED TREATMENT
INDICATION, PATIENTS WITH
ULCERS, IF THE PATIENT HAD
HELICOBACTER WHICH WAS WHICH WAS
80% THAT DIDN'T HAVE ULCERS SO
THEY WEREN'T SURE ABOUT THAT
ONE.
THERE IS NO PROVEN TREATMENT BUT
AMOXICILLIN WAS TOUTED AT THAT
POINT, NO LONGER EMBARRASSING TO
TALK ABOUT HELICOBACTER SO
PEOPLE WITH BAD ULCERS AT THAT
POINT.
BACK TO THE ORIGINAL QUESTION WE
HAD ALPHA BACTERIA LIVE MANAGE
THE STOMACH.
HOLLAND NOTICED UREASE AND WE
LOOKED AT THAT, ONE DAY ON A
PLANE WE WERE DISCUSSING IT AND
FIGURED OUT IT WAS THE UREASE OF
H PYLORI WITH SPOONING UREA,
CONSUMING A HYDROGEN AND
GENERATING AMMONIA AND BY
CARBONATE SO H PYLORI PROTECT
ITSELF FROM ACID SO WE RAISED
BACK TO LAB AND DID SOME NICE
EXPERIMENTS.
SO IN THIS STUDY IF YOU LOOK
HERE WE HAVE GOT AN ACCESS OF PH
SO THIS IS NEUTRAL IN THE LEFT
GOING THROUGH ACID SOLUTION ON
THE RIGHT AND THEN LOG OF
SURVIVING BACTERIA AFTER 30
MINUTES, THE DOTTED LINE IS C
JUJUNI IS THE CROSSES AND IF YOU
PUT C JUJUNI IN DIFFERENT PH,
AFTER 3.5 IT IS GETTING KILLED
AND IS NEARLY ALL KILLED AT PH
3.
THEN PROTEASE WHICH IS A
MODERATE UREASE PRODUCER BUT NOT
AS STRONG H PYLORI.
YOU CAN SEE 19TH TO THE 9TH.
AND 3.5 YOU HANDLE IT AND THIS
IS ACTUALLY SOLUTIONS OF GASTRIC
SOME UREA PRESENT IN THE ACID,
YOU SEE IT IS KILLED AT BELOW
2.5, NO PROTEASE SURVIVING BUT
HELICOBACTER YOU PUT IT IN ANT
ACID WITH UREA PRESENT SO UREA
IS GASTRIC JUICE GASTRICLY ONE
MILLIONLY MOLAR AND HELICOBACTER
IS SURVIVING.
NOTHING ELSE SURVIVES
HELICOBACTER DOESN'T NEED
SPECIAL TRICKS, IT IS THE ONLY
THING THAT'S GROWING THERE IN
ANY NUMBERS IN YOUR GASTRIC
MUCOSA.
I OFTEN ARGUE WHETHER THERE IS A
GASTRIC MICROBIOME, I WOULD SAY
IT IS NOT, IT IS WHAT YOU
SWALLOW IN YOUR SPIT AND SOON
KILLED BY THE ACID.
SO THIS IS THE IDEA, THE UREA IS
COMING THERE AND IT SPLITS AND
MAINTAINS INTERNAL PH OF 5 TO 6
UNDER FAIRLY UNDER CONDITION
WHERE IS IT CAN COLONIZE IN
GASTRIC MUCOSA.
IT IS SO STRONG IN FACT YOU TAKE
BIOPSY FROM THE STOMACH AND PUT
IN KRISTIN UREASE BACTERIA, WE
CAN SEE PINK AFTER FEW HOURS IN
SO WE MADE A STRONG ONE AND THAT
IS A COMMON HELICOBACTER AND
THAT IS A BIOPSY FROM THE
PATIENT WITH A DUODENAL ULCER SO
THAT WAS RAPID DIAGNOSTIC TEST
WITH FIRST RAPID TEST WHERE THE
FIRST TEST ON THE MARKET FOR
HELICOBACTER AND IT WAS CALLED
THE CLO TEST.
THAT IS THE TEST THAT MY COMPANY
STILL SELLS ALL OVER THE WORLD
KIMBERLY CLARK, SO PATENT IS
EXPIRED SO I CAN'T SHOW IT ON MY
-- WE RECOMMEND 30 MILLION AT
LEASTUREASE TESTS DONE AROUND
WORLD TO SHOW YOU I'M NOT BIASED
I SHOW YOU THE BILLIONS OF KNOCK
YOU HAVE A TESTS AROUND THE
WORLD IN EVERY COUNTRY YOU CAN
MAKE IT FOR ABOUT A CENT SO
THERE'S STILL VERY, VERY USEFUL
TESTS.
SO THEN THERE WAS ANOTHER BIT OF
INTERESTING RESEARCH WE HAD
DONE.
WE MEASURED UREA IN GASTRIC USE
OF PATIENTS WITH AND WITHOUT
HELICOBACTER PYLORI, THIS WAS A
STUDY I HAD DONE IN 1983 AT FREE
METAL HOSPITAL ABOUT UREA
HYDROLYSIS.
WE NOTICED IF YOU WERE NORMAL
PERSON YOU HAD UREA IN YOUR GAY
STRICT JUICE SIMILAR TO BLOOD
UREA.
IF YOU HAD H PYLORI ALL THE UREA
WAS GONE, LESS THAN ONE
MILLIONLY MOLAR PER --
MILLIMOLAR.
INSTEAD OF BIOPSY WHAT ABOUT A
BETH TEST SO THE ONE I CHOSE WAS
CARBON 14 UREA, ALMOST
SIMULTANEOUSLY DAVID GRAHAM AND
COMPANY STARTED USING CARBON 13
UREA, THEY STABILIZED THE
TECHNOLOGY IN HOUSTON AND DOING
METABOLIC STATES.
IN C 14 WE PUT UREA IN A
CAPSULE, IF H PYLORI IS PRESENT
IT'S SPLIT TO AMMONIA AND CO 2
YOU CAN SEE THE SIGNAL OF THE CO
2 CARBON ISOTOPE COMING OUT IN
THREE OR FOUR MINUTES.
IF YOU DIDN'T HAVE H PYLORI IT
WAS EXTREAT CRETEED UNCHANGED IN
THE URINE, -- EXCRETED IN THE
URINE, TURNED IN TO BICARBONATE
WHICH YOU CHECKED IN A BREATH IN
A BALLOON SO ULTIMATELY THIS
TEST WAS APPROVED BY THE FDA IN
ABOUT 1896.
IT IS ALSO ABOUT 30 MILLION
TESTS A YEAR, I THINK MOSTLY IN
CHINA SO IT IS IN MANY
COUNTRIES: SOMEONE DOING THE
BREAST TEST THERE, SWALLOWING
THE CAPSULE BALLOON AND ONE
BREATH ISOTOPE TO MEASURE IN A
ISOLATION COUNTER OR SOMETHING.
MILLIONS -- THOUSANDS OF
VERSIONS OF THIS TEST AROUND THE
WORLD IN USE USE.
SO I'LL GET BACK TO FINAL
SLIDES, ORIGINS OF GOOD BUG BAD
BUG SAGA SO BECAME EXCITING
ABOUT 1999 AS I SAID IN EARLY
STUDY IF YOU HAD ESOPHAGEAL
DISEASE LIKE ESOPHAGITIS THERE
WAS A CASE AGAINST TREATING
HELICOBACTER PYLORI BECAUSE A
LOT OF PEOPLE LOWERS ACID
SECRETION MAYBE NOT IN SO MUCH
IN DUODENAL PATIENTS BUT OTHER
PEOPLE.
SO THIS ONE IS ESOPHAGEAL REFLUX
AS RISK FACTOR FOR CARCINOMA,
THIS IS A BIG STUDY DONE OUT OF
SWY DEAN WITH FANTASTIC LONG
TERM RECORDS OF ALL PEOPLE WITH
REFLUX DISEASE, ACID REFLUX AND
WHAT HAPPENED TONEME IN THE LONG
TERM.
SO HERE IS THE THIS
RETROSPECTIVE COHORT STUDIES.
820 CONTROLS AND THEY HAD PEOPLE
THAT DEVELOPED ESOPHAGEAL
CARCINOMA, AS KNOW CARCINOMA OF
THE STOMACH.
AND ESOPHAGEAL SQUAMOUS
CARCINOMA.
YOU SEE BOTH AT LEAST JUAN WEEK
TEN YEARS BEFORE THE CANCER,
THAT WAS -- LOOK BACK TEN YEARS
AND SELECTED OUT THESE PEOPLE,
SO HEART BURN REFLUX BOTH AT
NIGHT AT LEAST ONCE PER WEEK SO
THEY DIDN'T HAVE IT IN THEIR
CONTROLS, 8%, IF THEY HAD
ESOPHAGEAL ADENOCARCINOMA, TEN
TIMES MORE LIKELY TO HAVE HAVE
HAD REFLUX DISEASE TEN YEARS
BEFORE.
BUT THAT ASSOCIATION WASN'T
PRESENT FOR GASTRIC CARCINOMA OR
SQUAMOUS CARCINOMA OF THE
ESOPHAGUS SO THIS IS MAJOR AND
IT TOLD EVERYBODY OKAY ACID
CAUSES ADENOCARCINOMA OF THE
ESOPHAGUS, YOU DON'T JUST WALK
AROUND SIPPING ANTI-ACID FROM
TIME TO TIME, YOU NEED TO TREAT
PROPERLY WITH PPI AND MAYBE
THINGS WHICH MAKE ESOPHAGITIS
WORSE ARE GOING TO BE RISK
FACTORS FOR THE ESOPHAGUS
ADENOCARCINOMA, ONE OF THE FEW
CANCERS INCREASING IN THE UNITED
STATES, I THINK LEVELED OFF BUT
WAS INCREASENING THE UNITED
STATES WHEREAS MOST OTHERS WERE
DECREASING.
SO THAT LEADS INTO MARTY'S
DISCUSSION.
I WILL KEEP OUT OF OF HIS
TERRITORY.
LET'S SEE IF WE CAN GO FURTHER.
I WILL JUST ACKNOWLEDGE THAT
THIS -- ONE OF THE IMPORTANT
PEOPLE IN MY LIFE ADRIENNE, DR.
WARREN, HIS WIFE HAS PASSED AWAY
SADLY.
AT THE MOMENT I'M STILL
UNIVERSITY OF WEST AUSTRALIA AND
I HAVE A LAB MARSHALL LABNA NICE
GRANT AT MARSHALL LAB OF
BIOENGINEERING SO WE ARE DOING
POINT OF CARE GADGETS AS OUR
AIMS.
AND YOU WILL SEE MORE OF THAT IF
PEOPLE WANT TO PHOTOGRAPH THIS
AND GET A WE CHAT LINK.
ONE MORE SLIDE.
SO THE TWO DECADES OF HIGH
CO-BACTER PYLORI WITH THE NICE
AND NAUGHTY HELICOBACTER WE CAN
TALK ABOUT THAT ANOTHER 20
YEARS, WE MAY GET ANOTHER
CONFERENCE IN PERTH IN 2024.
WE CAN PUT A BID IN THAT I
THINK.
THAT'S THE END OF MY TALK.
THANK YOU.
>> THANK YOU VERY MUCH.
I THINK IT MIGHT BE USEFUL TO
NOW HAVE MARTY BLAZER GIVE
MISTALK AND AT THE END HAVE
QUESTIONS FOR BOTH.
MARTY BLASER.
BECAUSE MOST QUESTIONS ACTUALLY
FALL INTO EITHER/OR CATEGORY OR
BOTH.
SO MARTY WOULD YOU BEGIN PLEASE.
THANK YOU FOR THE INVITATION TO
GIVE THIS TALK, IT IS ALWAYS
VERY INTERESTING TO HEAR BARRY.
HE TELLS US ABOUT THE PAST.
GOING TO TRY TO MOVE INTO THE
FUTURE.
THIS IS CALLED THE SPLIT
PERSONALITY OF H PYLORI.
SO MY FINANCIAL DISCLOSURE, I
HAVE NOTHING TO DISCLOSE.
THE OBJECTIVES ARE TO UNDERSTAND
THE BIOLOGY OF HELICOBACTER
PYLORI TO UNDERSTAND THE BASE OF
INTERACTIONS WITH HOSTS, TO
BETTER UNDERSTAND THE
PATHOPHYSIOLOGY ASSOCIATE WITH
THE INTERACTIONS.
AND TO CONSIDER THE COST AND
BENEFITS OF CARRYING H PYLORI.
THIS SLIDE SHOWED THE GEOGRAPHIC
STRUCTURE THE WORLDWIDE H PYLORI
POPULATION FOR STUDY OF MORE
THAN 700 HELICOBACTER ISOLATES
FROM AROUND THE WORLD USING
MULTI-LOCUST TYPE SEQUENCING AND
THE ISOLATES WERE ORGANIZED
ACCORDING TO THEIR SEQUENCE
TYPE.
THEY ARE SHOWN IN COLORS.
AND YOU CAN SEE THAT THE COLORS
AREN'T RANDOM.
THEY ARE QUITE ORDER.
THIS ORDINATION IS CONSISTENT
WITH THE IDEA THAT HUMANS HAVE
BEEN CARRYING HELICOBACTER SINCE
BEFORE THE OUT OF AFRICA EVENT
WHICH WAS 58,000 YEARS AGO.
AS HUMANS DIVERGED AROUND THE
WORLD, SO DID THEIR
HELICOBACTERS.
THIS IS EVIDENCE FOR THE
VERTICAL TRANSMISSION OF
HELICOBACTER AND ONE OF THE
PIECES OF EVIDENCE THAT
HELICOBACTER IS QUITE ANCIENT,
THIS TOOK IT BACK ABOUT 58,000
YEARS AGO, THERE'S NOW STRONG
WORK TAKING IT BACK MORE THAN
100,000 YEARS IN HUMANS.
AND BY INFERENCE IT IS PROBABLY
IN HUMANS AND ANCESTORS SINCE
BEFORE WE WERE HUMANS.
SO THIS IS CLEARLY AN ANCIENT
ORGANISM.
SECOND SHOWN HERE IS A SCHEMATIC
OF THE INTERACTIONS BETWEEN A
CO-EVOLVED COLONIZING MICROBE OF
THE HOST.
THIS IS WORK WITH DENISE A MATT
PETITION.
HER IDEA OF CO-EVOLVED ORGANISMS
IS KNOWING HOW TO TALK TO THE
HOST THROUGH PHYSICAL AND
CHEMICAL SIGNALS AND THEY
RECEIVE SIGNALS AND NUTRIENTS
BACK.
DENISE MODELED THIS A DYNAMIC
EQUILIBRIUM, ROBUST, RESILIENCE,
INVOLVES NEGATIVE FEEDBACK LOOPS
AND THE REAL QUESTION IS WHAT
HAPPENS WHEN A CO-EVOLVED
PERSISTENT ORGANISM IS LOST?
WHAT HAPPENS TO THE PHYSIOLOGY
OF THE HOST?
THAT IS WHAT I WILL BE TALKING
ABOUT.
SO LET ME VERY -- BARRY SPOKE
ABOUT PEPTIC ULCER DISEASE, I'M
ONLY GOING TO MENTION IT
BRIEFLY, STARTING WITH GASTRIC
CANCER, 50 YEARS AGO A P
PATHOLOGIST FROM COLUMBIA
DEVELOPED A SEQUENCE BEGINNING
WITH THE NORMAL GASTRIC MUCOSA
GOING TO GASTRITIS TO ATROPHY
METAPLASIA TO DYSPLASIA TO
CANCER.
OVER THE YEARS EACH STEPS WERE
CONFIRM BUD NO ONE UNDERSTOOD
WHY THERE WAS TRANSITION FROM
WHAT WAS CALLED NORMAL TO WHAT
WAS CALLED GASTRITIS UNTIL H
PYLORI WAS IDENTIFY.
WITH THE IDENTIFICATION OF H
PYLORI AND ITS STRONG
ASSOCIATION WITH GASTRITIS AS
BARRY AND ROBIN SHOWED NOW WE
CAN SAY IS HELICOBACTER REALLY
RELATED TO GASTRIC CANCER SO WE
AND OTHERS DID PROSPECTIVE
STUDIES LOOKING AT ASSOCIATION
OF HELICOBACTER WITH DEVELOPMENT
OF CANCER.
THREE STUDIES, I WAS INVOLVED IN
THIS STUDY INVOLVING HAWAII,
STUDY JAPANESE AMERICAN MEN
ENROLLED IN A COHORT IN THE
1950s, THEY WERE FOLLOWED FOR
THE NEXT 21 YEARS, OVER THAT
TIME 109 MEN DEVELOPED STOMACH
CANCER, WE MATCHED THEM WITH 109
CONTROLS WHO DIDN'T HAVE STOMACH
CANCER, WE WENT BACK TO THE
FREEZER AND TOOK OUT THEIR SERUM
TO SEE IF THEY -- WE COULD
DETECT ANTIBODIES TO
HELICOBACTER MEANING THEY WERE
INFECTED.
WE FOUND THOSE MEN WHO CARRIED
HELICOBACTER WERE SIX TIMES MORE
LIKELY TO DEVELOP GASTRIC CANCER
IN ENSUING 21 YEARS THAN THE MEN
WHO DIDN'T.
ALL THE STUDIES WERE POSITIVE,
META ANALYSIS ODDS RATIO ABOUT 4
AND WE ADJUSTED FOR CONFOUNDERS
GIVES AN ODDS RATIO OF 9.
HELICOBACTER PYLORI BECAME CLEAR
THAT HELICOBACTER PYLORI ARE WAS
THE MAJOR CAUSE OF GASTRIC
CANCER AROUND THE WORLD, AS WARY
INDICATED THIS IS A VERY
IMPORTANT DISEASE.
ONE OF THE QUESTIONS THOUGH IS
THAT MOST PEOPLE WHO HAVE
HELICOBACTER DON'T DEVELOP
GASTRIC CANCER AND THEY DON'T
DEVELOP ULCERS EITHER.
SO THE QUESTION IS WHAT IS GOING
ON.
WE AND OTHERS HAVE FOR GASTRIC
CANCER HAVE BEEN FOLLOWING THE
PATHWAY OF ATROPIC GASTRITIS
EFFECTS ON EPITHELIAL CELLS
LEADING TO CANCER, WHAT CAN
CAUSE THE DIFFERENCES AMONG
PEOPLE MAYBE STRAIN DIFFERENCES
OF BACTERIA OR HOST DIFFERENCES
OR CO-FACTOR DIFFERENCES, WE
WORK IN THESE DIFFERENT AREAS
BUT I WILL SHOW YOU ONE AREA
THAT WE WORKED ON LIKE BARRY'S
EXPERIMENT, WE WERE FISHING FOR
GENES IN HELICOBACTER, AND WE
MADE IT A LIBRARY IN
HELICOBACTER GENES IN 1989 AND
WE PROBED IT WITH SERUM FROM
SOMEBODY WHO HAD ANTIBODIES
POSITIVE TO HELICOBACTER, I
REMEMBER THIS EXPERIMENT VERY
WELL BECAUSE IT WAS MY SERUM.
MY SERUM PICKED UP A PROTEIN IN
A LAMBDA GT 11 BANK THAT WASN'T
IN BACKGROUND.
THAT IS A PROTEIN THAT
EVENTUALLY WE CALLED CAGA.
WE DISCOVERED A YEAR BEFORE
RENAL BUT TOGETHER WE CALLED IT
THE SAME.
NOW WE KNOW A LOT ABOUT CAGA.
IT IS A PROTEIN THAT
HELICOBACTER PYLORI INJECTS INTO
EPITHELIAL CELLS, A HIGH
MOLECULAR WEIGH PROTEIN,
HELICOBACTER HAS A TYPE 4
SECRETION SYSTEM INJECTING IT,
PROTEIN UNDERGOES TYROSINE
PHOSPHORYLATION.
IT INTERACTS WITH MULTIPLE HOST
CELL PATHWAYS AND ALTERS MANY
PHENOTYPES IN EPITHELIAL CELLS,
THAT'S LINKED TO INCREASE RISK
FOR ULCER DISEASE AND IN MANY
STUDIES INCREASE RISK OF STOMACH
CANCER.
SO WE HAVE BEEN BEGINNING TO
UNDERSTAND WHAT MAKES THE
DIFFERENCE BETWEEN PEOPLE WHO
HAVE HELICOBACTER.
BUT WHILE ALL THIS WAS
HAPPENING, HELICOBACTER PYLORI
WAS DISAPPEARING.
HERE ARE DATA FROM STUDIES WE
DID LOOKING AT THE N HAYNES
SURVEYS IN THE UNITED STATES
LOOKING AT HELICOBACTER
PREVALENCE BY AGE AND YEAR OF
BIRTH IN BOTH MALES AND FEMALES
AND WHAT WE FOUND IS THAT PEOPLE
BORN EARLY IN THE 20TH CENTURY
HAD HIGH RATES OF THE ORGANISM
AND LATER IN THE 20TH CENTURY
HAD LOW RATES.
THIS WAS CONSISTENT WITH THE
IDEA THAT THIS ANCIENT ORGANISM
OF HUMANS WAS DISAPPEARS FROM
HUMANS OVER A FEW GENERATIONS.
THERE HAVE BEEN MANY STUDIES
THAT CONFIRMED THIS, I WANT TO
SHOW YOU THIS CLEARLY, THIS
DISAPPEARANCE OF HELICOBACTER IN
JAPANESE FAMILIES STUDIED BY
URUTA ET AL WHO LOOKED AT GRAND
MOTHERS MOTHERS AND CHILDREN AND
YOU CAN SEE THE STEP DOWN.
IN FACT THIS IS WHAT HELPED ME
UNDERSTAND THERE IS -- THAT
THERE ARE DISAPPEARING ORGANISMS
THAT SOME OF OUR ANCIENT
ORGANISMS WE CARRY MAY
DISAPPEAR.
SO THE GOOD NEWS IS THAT STOMACH
CANCER IS DISAPPEARING AS YOU
MIGHT EXPECT SINCE HELICOBACTER
IS THE MAJOR CAUSE.
NO MATTER HOW YOU COUNT IT,
STOMACH CANCER IS DISAPPEARING.
HERE IN 1982 HERE IS A DISCOVERY
OF HELICOBACTER, ACTUALLY
STOMACH CANCER LARGELY
DISAPPEARED BEFORE THE DISCOVERY
DISCOVERY.
BUT SO THIS HAS BEEN GOING ON
SINCE THE EARLY 20TH CENTURY.
SO ALL THIS IS VERY GOOD NEWS.
MANY GASTROENTEROLOGISTS THINK
THE ONLY GOOD HELICOBACTER IS A
DEAD HELICOBACTER, WHY NOT GET
RID OF IT FOR EVERYBODY, CAUSES
ULCERS CAUSES STOMACH CANCER,
AND IN FACT GASTRO ENTEROLOGISTS
ALL OVER THE WORLD ARE SEARCHING
AND DESTROYING.
GETTING RID OF HELICOBACTER FROM
EVERYBODY.
BUT UNFORTUNATELY THAT IS NOT
THE WHOLE STORY.
BECAUSE AS BARRY SAID THE OTHER
DISEASES ARE RISING AND ONE IS
ADENOCARCINOMA OF THE ESOPHAGUS,
THE FASTEST RIDING CANCER IN THE
UNITED STATES AND IN FACT ALL
DEVELOPED COUNTRIES THIS CANCER
IS GOING UP BETWEEN SIX AND 16%
A YEAR ACROSS THE DEVELOPED
WORLD.
AS BARRY MENTIONED, THIS CANCER
IS STRONGLY LINKED TO REFLUX
ESOPHAGITIS FIRST DESCRIBED IN
THE MEDICAL LITERATURE IN
1930s AND HAS BEEN INCREASING.
INTERMEDIATE STEP IS BARRETTES
ESOPHAGUS FIRST DESCRIBED IN
1950 AND THEN CANCER DESCRIBED
AROUND 1970 SO THESE ARE NESTED
CURVES ALL INCREASING AT A TIME
THAT HELICOBACTER IS GOING AWAY.
SO THE QUESTION IS ARE THEY
RELATED?
THERE HAVE BEEN MANY STUDIES
BARRY SHOWED UP AN INTERESTING
ILLUSTRATION OF THAT, WE DID A
MORE FORMAL STUDY, THIS WAS A
STUDY WITH COLLEAGUES AT THAT
TIME NATIONAL CANCER INSTITUTE,
LED BY FERRIN AND BILL BLOT.
HERE WE LOOK AT THE ATBC STUDY
IN FINLAND, COHORT OF 29,000 MEN
MIDDLE AGE FOLLOWED FOR SIX
YEARS, DURING THAT TIME 234 MEN
DEVELOPED CANCER, 173 WERE
TRADITIONAL STOMACH CANCER, THEN
61 WERE CANCERS -- THIS IS THE
JUNCTION CANCERS THAT ARE LIKE
ADENOCARCINOMA OF ESOPHAGUS SO
LOOK AT THE TRAY US THAL CANCER
THE ODDS RATIO ABOUT 8 AS WE
HAVE COME TO EXPECT BUT FOR THE
PROXIMAL CANCER, THE ODDS RATIO
IS LESS THAN ONE, IT IS INVERSE,
ASSOCIATED WITH PROTECTION.
SO THIS IS ONE OF MANY STUDIES
THAT HAVE SHOWN THE SAME EFFECT,
THEY SHOW THIS BECAUSE WE HAVE
BOTH DATA IN THE SAME STUDY, IT
WAS ALL LARGE STUDY BLINDED AND
THERE'S MANY INDEPENDENT STUDIES
SHOWING THE SAME THING.
SO ABOUT 20 YEARS AGO I PROPOSED
A RECIPROCAL RELATIONSHIP
BETWEEN THE ADENOCARCINOMA OF
THE LOWER STOMACH AND THOSE OF
THE ESOPHAGUS IN UPPER STOMACH.
THE IDEA WENT IF YOU HAD
HELICOBACTER ESPECIALLY CAG
POSITIVE STRAIN YOU WOULD HAVE A
LOT OF INFLAMMATION IN YOUR
STOMACH LEADING TO ATROPIC
GASTRITIS AND GAINS IN THE LOWER
STOMACH, A PROCESS THAT TAKES
DECADES N CONTRAST IF YOU DON'T
HAVE HELICOBACTER AND YOU DON'T
HAVE A CAGA POSITIVE THAT I CALL
A CAG WHICH UNFORTUNATELY STILL
HASN'T CAUGHT ON THEN YOU ARE
HIGH RISK FOR REFLUX BARRETT'S
AND CANCER ALL SHOWN, A PROCESS
THAT ALSO TAKES MULTIPLE DECADES
SO BOTTOM LINE IS YOU CAN'T WIN.
IT'S BAD TO HAVE HELICOBACTER
AND GOOD TO HAVE HELICOBACTER.
MOST DON'T DEVELOP EITHER CANCER
SO THE REAL QUESTION IS WHAT IS
GOING ON, CAN WE UNDERSTAND THE
PROCESS A LITTLE BETTER.
SO ABOUT TEN YEARS AGO A GROUP
FROM THE NATIONAL CANCER
INSTITUTE LED BY BILL ANDERSON
PUBLISHED SOME VERY INTERESTING
DATA LOOKING AT GASTRIC CANCER
RATES BY SUBSET OF CAUCASIANS IN
THE UNITED STATES IN ABOUT 30
YEARS.
MOST RATES ARE GOING DOWN
CARDIAC CANCERS WERE GOING UP AS
WE NOW KNOW.
THEY FOUND ANOTHER CANCER OF THE
CORPUS THAT WAS DEFINED --
DEFYING THE TREND WHEREAS OTHERS
GOING DOWN IT WAS GOING UP
SLIGHTLY.
AND WHEN THEY LOOK AT THE DATA
BY AGE, THEY FOUND THAT CANCER
IN OLDER PEOPLE WERE GOING DOWN
AT A FAST RATE, NOT SO OLD
PEOPLE GOING DOWN AT SLOW RATE
BUT YOUNG PEOPLE THE GASTRIC
CANCER WERE GOING UP.
THIS WAS BIRTH COMORTALITY BORN
SINCE 1952 WHICH INTERESTINGLY
IS AROUND THE TIME ANTIBIOTICS
CAME INTO WIDE PRACTICE.
SINCE THEN THE GROUP HAS
CONTINUED THESE STUDIES HERE
THEY ARE LOOKING AT THE RATES OF
NON-CARDIAC CANCER IN MEN AND
WOMEN, BY AGE IN OLDER PEOPLE IT
IS GOING DOWN NOT SO OLD, IT IS
FLAT AND IN YOUNGER PEOPLE IT IS
GOING UP.
AND IN FACT WE WERE ASKED TO
WRITE AN EDITORIAL ABOUT THIS
AND WE BELIEVE THIS WAS -- THEIR
WORK HAS SHOWN US THAT THERE'S A
NEW CANCER AMONG US.
WE CALL THE SIF CANCERS, CORPUS
DOMINANT YOUNG FEMALE DOMINANT
BECAUSE THE RATES WERE HIGHER IN
FEMALES HAHN MALES AND IN FACT
THE ANNUAL INCREASE IN WOMEN IS
TWICE THE RATE IN MEN.
THESE ARE GOING RAPIDLY.
SO MUCH RAPIDLY THAT THE NCI HAS
ESTIMATED BY 2050 THE SEX
DISTRIBUTION OF GASTRIC CANCER
WILL FLIP, FROM MALE PREDOMINANT
TO FEMALE PREDOMINANT.
VERY RECENTLY LAST MONTH ANOTHER
GROUP FROM THE METASTASIS
INCLUDING SOFT SAME
INVESTIGATORS LED BY MINKO SUNG
LED ANTI-INFLAMMATION PARIETAL
CELLS AND GASTRIC CANCER RISK
THEY WEREN'T USING THE FINISHED
MATERNITY COHORT OF A MILLION
PREGNANT WOMEN BORN OVER 50 YEAR
PERIOD, 529 CASES OF GASTRIC
CANCER, THEY MATCH WITH THAT
SAME NUMBER OF CONTROLS.
THEY HAD SERUM FROM PREGNANCIES,
17 YEARS BEFORE THEY DEVELOPED
CANCER SO HERE THEY ARE LOOKING
AT A THE ASSOCIATION OF
AUTOANTIBODIES, WITH THE CANCER
DEVELOPMENT ALL TOLD ALL
PARTICIPANTS THEY HAD
HELICOBACTER, HAIRPIN CREASE
RISK FOR STOMACH CANCER AS
CONFIRMING WHAT WE ALREADY KNOW
BUT IF THEY HAD ANTI-PARIETAL
CELL ANTIBODIES THEY WERE ALSO
INCREASE RISK.
THE RISK WAS PARTICULARLY HIGH
IF H HIGH LORI NEGATIVE, ODDS
RATIO IS FIVE AND A HALF NOT
REALLY SIGNIFICANT H PYLORI
NEGATIVE.
WHAT IS INTERESTING WHEN THEY
LOOK AT THE CANCER OF THE CORPUS
AND THE FUNGUS IN THOSE THAT HAD
ANTI-PARIETAL CELLS ANTIBODIES
THE ODDS RATIO WAS 25.
IT IS A REALLY STRIKING
ASSOCIATION WITH THESE NEW
CANCERS OF THE CORPUS.
I WAS IMPRESSED BY THIS AND
WROTE HER AND ASKED HER IF SHE
WOULD EXAMINE THE RELATIONSHIP
BETWEEN THESE ANTIBODIES AND H
PYLORI SERO NEGATIVITY.
SHE SENT ME THE DATA AND I'M
APPRECIATIVE OF HER SENDING IT
AND LETTING ME SHARE THIS
BECAUSE SERO NEGATIVE PEOPLE IN
GENERAL WERE TWICE AS LIKELY TO
HAVE ANTIBODIES AS THE SERO
POSITIVE PEOPLE BUT PEOPLE THE
WOMEN WHO HAD GASTRIC CANCER IF
THEY WERE SERO NEGATIVE THEY
WERE SIX TIMES MORE LIKELY TO
DEVELOP GASTRIC CANCER THAN IF
THEY DID NOT HAVE THESE
ANTIBODIES.
SO THIS IS A VERY STRONG RISK
FACTOR IN PEOPLE WHO DON'T HAVE
H PYLORI.
IN FACT THEIR POPULATION
ATTRIBUTABLE RISK FOR GASTRIC
CANCER FROM THESE AUTOANTIBODIES
IS ABOUT A THIRD.
SO THEY IDENTIFIED WITH
POTENTIALLY A VERY IMPORTANT
CAUSE.
SO THE QUESTION IS WHY DO PEOPLE
WHO DON'T HAVE HELICOBACTER HAVE
ALL THESE AUTOANTIBODIES TO
THEIR STOMACH.
THIS IS A SUMMARY OF THE
CHANGING EPIDEMIOLOGY OF GASTRIC
AND ESOPHAGEAL ADENOCARCINOMA.
THE ANCIENT GASTRIC CANCER
THAT'S THE ONE ASSOCIATED WITH
HELICOBACTER PYLORI, ASSOCIATED
WITH ATROPIC GASTRITIS, OLDER
PEOPLE MALE PREDOMINANT, THE
MODERN IS GE JUNCTION CANCER,
RELATED TO BARRETT'S ESOPHAGUS
AND NOW THE POST MODERN ONE
CORPUS SEEMS TO BE RELATESSED TO
AUTOIMMUNE GASTRITIS, IT IS IN
THE YOUNGEST PEOPLE WITH THIS
STRIKING DIFFERENCE IN SEX
RATIO.
SO WHAT IS GOING ON?
LAUREN AND MICHAEL AWE DESCRIBED
HELICOBACTER IN CELLULAR
INFILTRATION IN THE STOMACH
WHICH WARREN CALLED GASTRITIS,
THEY ARE INFLAMMATORY CELLS IN
THE STOMACH.
I WONDER MAYBE THERE IS AN
ALTERNATIVE NAME, RATHER THAN
CALL IT GASTRITIS IT IS THE
RESPONSE TO THE ANCIENT
MICROBIOTA.
IN OTHER WORDS THIS IS NORMAL
AND THE STOMACHS THAT DON'T HAVE
CELLS ARE HISTORICALLY ABNORMAL.
SO WHAT COULD THOSE CELLS BE
DOING?
WHY MIGHT WE HAVE CO-EVOLVE WITH
HELICOBACTER?
ONE IDEA IS THESE IMMUNOSITES
ARE IMMUNE ADJUVANT AND HELPING
US DEAL WITH INFECTION.
I WILL SHOW YOU THREE EXAMPLES.
HERE IS A STUDY LOOKING AT THE
RELATIONSHIP BETWEEN
HELICOBACTER AND DIARRHEA, THOSE
KIDS WITH HELICOBACTER HAD LESS
DIARRHEA THAN THE KIDS WHO DID
NOT.
HERE WE ARE LOOKING AT IMMUNE
RESPONSES TO LIVE ORAL TYPHOID
VACCINES IN VOLUNTEERS PEOPLE
WHO HAD HELICOBACTER HAD
STRONGER RESPONSES, THAN PEOPLE
WHO DID NOT.
HERE IS A STUDY, IN WHICH 41
MACAQUES WERE GIVEN
MICROBACTERIUM TUBERCULOSIS AND
AS WHO WOULD DEVELOP ACTIVE
DISEASE OVER THE NEXT SIX TO
EIGHT MONTHS.
THE PEOPLE HELICOBACTER POSITIVE
WERE PROTECTED FROM ACTIVE TB
ODDS RATIO .31 SO THESE ARE SOME
EXAMPLES OF POTENTIAL BENEFIT
HISTORICALLY THAT MIGHT EXPLAIN
WHY SO MANY PEOPLE HAD
HELICOBACTER.
WHAT ARE THESE CELLS DOING?
IN ADDITION TO TH 1 CELLS
THERE'S T REGULATORY CELLS,
CELLS THAT MAKE IL 10, FOX P 3
TGF BETA.
SO THE QUESTION IS WHAT IS THE
BIOLOGICAL SIGNIFICANCE OF
GASTRIC IMMUNE POPULATIONS?
JUST FIGHTING INFECTION OR
PERHAPS HAS TO DO WITH
REGULATION OF ALLERGIC RESPONSE?
AS YOU ALL KNOW ASTHMA AS GONE
UP DRAMATICALLY IN THE POST WAR
PERIOD.
THERE'S RELATIONSHIP BETWEEN
ASTHMA AND GERD SO WE BEGAN TO
STUDY COULD HELICOBACTER
PROTECTING FROM GERD PROTECT
FROM ASTHMA?
THE FIRST STUDY WAS A STUDY IN
NEW YORK LOOKING AT 318 ASTHMA
PATIENTS AND 208 NON-ASTHMA
CONTROLS AND WE ORGANIZED THE
DATA, OUR REFERENCE GROUP FOR
PEOPLE WHO DON'T HAVE
HELICOBACTER AND DON'T HAVE A
CAGA POSITIVE STRAIN, THAT IS A
REFERENCE GROUP ODDS RATIO ONE.
PEOPLE INFECTED WITH IT CAG
NEGATIVE ODDS RATIO OF 3.4 BUT
C, AG POSITIVE ODDS RATIO .63
INVERSE ASSOCIATION CONSISTENT
WITH THE IDEA THAT HELICOBACTER
MIGHT PROTECT AGAINST ASTHMA.
IN THIS STUDY WE ALSO LOOK AT
ACID FREE SURVIVAL AMONG ADULTS
IN THIS STUDY SO EVERYBODY IN
THIS SURVIVAL CURVE, EVERYONE
BEGAN LIFE FREE OF ASTHMA AND
EVERYONE DEVELOPED ASTHMA
BECAUSE THAT IS WHO WE CHOSE.
IF WE LOOK AT THE AIDS THAT
DEVELOPED ASTHMA THEY DEVELOPED
ON AVERAGE IN THEIR 20s, THOSE
WHO DEVELOPED -- WHO HAVE -- WHO
DID NOT HAVE HELICOBACTER
DEVELOPED IT WHEN THEY WERE
ABOUT 11.
VERY STRONG DIFFERENCE.
SO WE THEN DID A STUDY, AGAIN
LOOKING AT THE N HAYNES, THIS IS
WORK THAT U CHEN AND I DID.
WE LOOKED PAT ODDS RATIO FOR
ASTHMA, THE REFERENCE GROUP WAS
NO HELICOBACTER.
IF WE LOOK AT ADULT ONSET ASTHMA
THERE'S NO RELATIONSHIP WITH
HELICOBACTER.
THE CHILDHOOD ONSET ASTHMA AGAIN
CAG POSITIVE STRAIN STRONG
INVERSE ASSOCIATION.
WE HAVE NOW DONE THREE LARGE
INDEPENDENT STUDIES ALL BLINDED
WITH THOUSANDS OF PEOPLE WE
CONTINUE TO FIND THIS
EPIDEMIOLOGIC ASSOCIATION.
WE KNOW THIS IS ASSOCIATION
CORRELATION IS NOT CAUSE.
SO IN FACT THERE HAVE BEEN
EXPERIMENTAL STUDIES AND I WANT
TO POINT TO THE WORK OF ANN
MUELLER'S LAB TO DEVELOP A MOUSE
MODEL IN WHICH MICE WERE
SENSITIZED WITH ALLERGEN, HOUSE
MICE DUST ANTIGEN AND CHALLENGE
THEY DEVELOP ASTHMA LIKE
FINDINGS.
THEIR STUDIES INCLUDING STUDY BY
ISABELLE ARNOLD HAD THREE GROUPS
OF MICE, MICE WITHOUT
HELICOBACTER OR MICE GIVEN
HELICOBACTER WHEN THEY WERE
INFANTS OR ADULTS.
SO THIS SLIDE SHOWS THE MAIN
RESULT OF THE STUDY, THEY DID A
METHYL CHOLINE CHALLENGE, USED
IN MICE AND HUMANS, IF YOU
INGEST METHYL CHOLINE YOU'LL
START TO WHEEZE SO HERE WE ARE
LOOKING AT MICE THAT DIDN'T GET
THE DUST MITE ANTIGEN WITH MORE
METHYL CHOLINE BUT NOT BY MUCH.
IF THEY GOT HOUSE DUST MITE
ANTIGEN AND DIDN'T GET ANY
INFECTION THEY ARE WISING A LOT.
WHEN THEY GOT HELICOBACTER IN
ADULTS, IT DIDN'T MAKE A
DIFFERENCE BUT IF THEY GOT IT AS
A CHILD IT MADE A BIG
DIFFERENCE.
WE CAN SEE BACK TO BASELINE.
WE CAN SEE INFLAMMATORY SCORE
PAS POSITIVE CELLS WE CAN SEE IT
IN HISTOLOGY.
IN FURTHER WORK I DON'T HAVE
TIME TO SHOW YOU, IN ANN
MUELLER'S LAB SHOWED
HELICOBACTER PROGRAMS DENDRITIC
CELLS TO MAKEICSL 18 WHICH
INCLUDES T REGULATORY CELLS, WE
HAVE DONE FURTHER WORK THAT
EXTENDED THIS WORK.
ONE OTHER FUNCTION OF THE
STOMACH IS THAT IT PRODUCES
HORMONES.
IT PRODUCES LEPTON AND PRODUCES
DCALIN.
IT IS IMPORTANT BECAUSE WHEN YOU
WAKE UP MANY THE MORNING AND YOU
ARE HUNGRY, GHREHLIN IS TELLING
YOU IT IS TIME TO EAT.
SO DID AN HELICOBACTER ON
FASTING POST MEAL SERUM
GHREHLIN.
HAIR FASTING IS HIGH, AFTER THEY
EAT IT GOES DOWN AS EXPECTED.
AFTER HELICOBACTER ERADICATION
PRE-MEAL IS HIGH, AND POST MEAL
DOESN'T GO DOWN.
THIS IS ONE OF MANY PIESES OF
EVIDENCE THAT HELICOBACTER IS
AFFECTING HORMONAL PHYSIOLOGY IN
THE STOMACH.
SO DEVELOPED A MOUSE MODEL WHICH
WE WERE LOOKING AT EFFECTS OF
HELICOBACTER IN THE STOMACH AND
SYSTEMICALLY.
WE SAW INFECTING MICE
HELICOBACTER AFFECTED
COLONIZATION AND ANTIBODIES AND
PRODUCED HISTOPATHOLOGY,
AFFECTED HORMONES, IT CHANGED
THE MICROBIOTA IN THE STOMACH
AND ELSEWHERE AND CHANGED TO
GENE EXPRESSION IN STOMACH AND
IN THE LUNG.
AND PULMONARY T-CELL RESPONSES
AS WELL.
HELICOBACTER IS NOT JUST LIMITED
TO AFFECT ON THE STOMACH.
SO JUST TO SUMMARIZE, AS THE
WORLD HAS CHANGED FROM
HELICOBACTER DOMINATED STOMACH
TO A STOMACH FREE OF
HELICOBACTER, THERE'S BIG
CHANGES IN CANCER THAT I TOLD
YOU ABOUT AND THERE ARE CHANGES
IN OTHER ASPECT OF PHYSIOLOGY
INVOLVING GASTRIC OF META
STATIN, ACIDITY LEPTON AND T
REGULATORY CELLS HAVE BEEN SHOWN
AND THERE ARE CONSEQUENCES
ASSOCIATED WITH THIS, THE
DECREASE IN ULCERS AND GASTRIC
CANCER THAT'S GOOD NEWS.
ALSO THE RISE IN GERD AND THE
CANCER THAT FOLLOW, ASTHMA,
INFECTION AND SILL YAK DISEASE
SO THE LAST QUESTION I'M GOING
TO ADDRESS IS HELICOBACTER GOOD
FOR US OR BAD FOR US.
SO U CHEN AND I DID ANOTHER
STUDY WE LOOKED AT N HAYNES HAD
DATA ON PEOPLE WE HAD
HELICOBACTER STATUS IN 1988 AND
WE FOLLOWED THEM TO DEATH IN
2006.
WE HAD 100,000 ADULT PERSON
YEARS, 2,000 PEOPLE DIED DURING
THOSE 18 YEARS IN THE N HAYNES
STUDIES, MOST FROM
CARDIOVASCULAR DISEASE OR CANCER
AND OUR QUESTION IS, WAS
HELICOBACTER GOOD FOR THEM OTHER
BAD FOR THEM.
SO FIRST WE JUST LOOK AT GI
CANCER.
WHEN WE LOOK AT GASTRIC CANCER
THE ODDS RATIO WAS 40.
IF YOU HAD HELICOBACTER YOU ARE
40 TIME MORRIS LIKELY TO DIE OF
GASTRIC CANCER THAN IF YOU
DIDN'T.
SO BASICALLY HELICOBACTER IS
RESPONSIBLE FOR ALL GASTRIC
CANCER IN THE UNITED STATES OF
THE CLASSIC KIND BUT THERE WERE
ONLY 16 EVENTS LESS THAN 1
PERCENT OF THE POPULATION DIED
FROM GASTRIC CANCER.
FOR THE OTHER CANCERS THERE
WASN'T SIGNIFICANCE THOUGH
INVERSE SIGNIFICANCE OF KAG
NEGATIVE STRAINS WITH PANCREATIC
CANCER.
THERE'S MORE CASES WITH CAG
NEGATIVE THAN ALL GASTRIC
CANCER.
BUT WE WANTED TO LOOK AT THE
BOTTOM LINE, ALL CAUSE
MORTALITY.
SO WHEN WE COMPARED THE PEOPLE
WHO WERE HELICOBACTER NEGATIVE
AS THE REFERENCE GROUP, THOSE
WERE HELICOBACTER POSITIVE THE
ODDS RATIO WAS 1.00.
IT COULDN'T HAVE BEEN CLOSER IF
WE TRIED.
THERE WAS NO NET EFFECT ON
MORTALITY.
IT DIDN'T MATTER WHETHER C AG
POSITIVE OR NEGATIVE STRAIN,
ESSENTIALLY THE SAME.
BUT SOMETHING MUST BE MAKING UP
FOR THOSE CASES OF GASTRIC
CANCER SO WHEN WE LOOK AT CARDIO
VASCULAR MORTALITY WE SEE
TENDING TOWARD NEGATIVE BUT IN
PARTICULAR WE LOOK AT STROKE
THERE WAS STRONG INVERSE
ASSOCIATION, WE DIDN'T SUSPECT
IT IN THE LEAST BUT THAT IS WHY
WE DO RESEARCH, TURNS OUT THIS
WAS THE SECOND STUDY SHOWING
INVERSE ASSOCIATION OF
HELICOBACTER WITH STROKE.
THERE'S SOME EVIDENCE THAT T
REGULATORY CELLS PROTECT AGAINST
STROKE AS WELL.
SO POTENTIALLY A MECHANISM.
SO IF I HAVE TO SUMMARIZE THERE
IS A BIPHASIC NATURE OF
HELICOBACTER PYLORI IN
INTERACTIONS WITH HUMANS.
THERE IS COST AND BENEFIT, THE
COST ARE MOSTLY LATER IN LIFE
ULCER DISEASE METABOLIC
SYNDROME, WHICH I HAVEN'T TALKED
ABOUT IN CLASSICAL GASTRIC
CANCER AND PERHAPS THERE'S
BENEFIT EARLY IN LIFE INFECTIONS
ASTHMA, THERE'S EVIDENCE ON SILL
YAK DISEASE STROKE AS I SHOWED
YOU REFLUX EOSINOPHILIC
ASPHAGITIS AND OTHER CANCERS I
TALKED ABOUT.
SO JUST TO FINISH THE ONLY GOOD
HELICOBACTER PYLORI A DEAD
HELICOBACTER?
I DON'T THINK.
WHAT I WOULD SAY IS HELICOBACTER
PYLORI IS A HUMAN MICROBIOTA,
ISOR ITS DISAPPEARANCE HAS
CONSEQUENCE GOOD AND BAD, THAT
IS FUTURE OF MEDICINE.
MANY PEOPLE HAVE HELPED ME, HAVE
TRIED TO ACKNOWLEDGE SOME OF
THEM BUT IS A GREAT TEAM EFFORT
OVER THE YEARS.
WITH THAT I WILL STOP.
>> THANK YOU, VERY MUCH, MARTY
AND AND DARRELL FOR THIS
STIMULATING CONVERSATION.
THERE'S SEVERAL QUESTIONS THAT
COME UP, PERHAPS EITHER ONE CAN
VOLUNTEER OR BOTH OF YOU TO
RESPOND TO IT.
WHAT DO YOU THINK IS THE ORIGIN
OF H PYLORI?
SEEMS TO ME I READ SOMEWHERE
EVEN IN THE ORGANISMS IN THE
DEEP SEA EVENTS, FAMILY MEMBERS
OF THE CAMPYLOBACTER
HELICOBACTER FAMILY ARE PRESENT.
>> LET ME TAKE THIS ONE IRWIN.
SO CAMPYLOBACTER HELICOBACTER,
THEY COLONIZE THE DIGESTIVE
TRACKS OF MANY ANIMALS, IT IS A
BIG FAMILY OF ORGANISMS AND IF
YOU LOOK AT MOUNTAINS THAT HAVE
(INAUDIBLE) WHICH IS IN THEIR
ACID SECRETION, THEY ALL HAVE
ORGANISMS THAT ARE HELICOBACTERS
OR ARE SIMILAR TO HELICOBACTERS.
THIS IS ANCESTRAL TO ACID
SECRETING STOMACHS.
OF COURSE IF YOU LOOK AT
NON-HUMAN PRIMATES THEY ALL HAVE
HELICOBACTER THAT LOOK VERY
SIMILAR TO H PYLORI.
SO THIS IS ANCESTRAL JUST LIKE
WE HAVE MANY OTHER ANCESTRAL
BACTERIA.
>> WHAT DO YOU THINK IS THERE
ANY SIGNIFICANCE TO THEIR
PRESENCE IN THE DEEP SEA VENTS
THOUGHT BY EVOLUTIONARY
BIOLOGISTS THAT HAVE SOMETHING
TO DO WITH THE ORIGIN OF LIFE?
>> WELL THESE ARE SOME OF THE
EARLIEST PLACES THAT BACTERIA
ROSE AND AS YOU KNOW BACTERIA
THE OLDER FORM OF LIFE ON EARTH
THEY PRECEDE ALL OTHER FORMS OF
LIFE ON EARTH BY 2 BILLION
YEARS.
I'M NOT AWARE THAT THERE ARE
TRULY CAMPYLOBACTERS IN THE DC
VENTS BUT WORK OF CARL LOUIS AND
NORMAN PACE HAVE SHOWN US A
GREAT PHYLOGENY OF BACTERIA IN
THE WORLD.
>> I'LL MAKE A FEW COMMENTS, WE
HAVE SEEN LOOK AT THE ECOLOGY IN
THE ROOM MICROFLUIDIC FLORA THAT
TAKES THE LAST VESTIGE OF OXYGEN
OUT OF THE ROOM AND ALLOWS THE
INTERNAL PART OF THE ROOM TO BE
AN AEROBIC, THERE ARE SOME
INTERESTING EMs SHOWING
SIMILAR LOOKING BACTERIA,
SOMETIMES COLONIZING THE ACID
SECRETING STOMACH OF REMNANTS SO
MY OPINION IS HUMANS PICKED THEM
UP FROM RHEUM FANTASTICS IN
AFRICA JUST EATING THE GUTS.
AND 30,000 YEARS AGO IT PICKED
UP THE HELICOBACTER PICKED UP
THE CAG TOXIN WHICH STARTED
PRODUCING THESE DISEASES LIKE
PEPTIC ULCERS AND MAYBE MAKING
GASTRIC CANCER MORE LIKELY.
THAT HAPPENED IN THE JOURNEY OF
HUMANS FROM AFRICA OVER TO ASIA.
SO IT IS A BIT OF A STORY.
WE FOUND SIMILAR HELICOBACTER IN
DOLPHINS.
ALSO IN MARSUPIAL MICE OF
DIFFERENT KINDS, IN AUSTRALIA.
SO AT THE MOMENT WE DON'T KNOW
BUT I WOULD SAY HUMANS ATE
SOMETHING AT SOME POINT.
>> THE ALTERNATIVE IS IF THESE
ARE ANCESTRAL IN ALL MAMMALS AND
THERE IS A LOT OF EVIDENCE FOR
THAT.
>> IN VIRGINIA WE LOOK AT A
COUPLE OF POSSUMS AND COULDN'T
FIND ANY HELICOBACTER IN THEIR
STOMACH.
SO --
>> DEPENDS HOW YOU LOOK.
DEPENDS HOW YOU LOOK.
>> THERE'S QUESTIONS ABOUT HOW
REALLY DOES H PYLORI, LIVE IN
THE STOMACH, DOES IT FORM
BIOFILMS?
IS THAT ONE OF THE MECHANISMS
THAT MANY HOPE TO PROTECT IT?
DO WE KNOW ANYTHING ABOUT BARRY
YOU MENTIONED ABOUT ITS
ASSOCIATION AT LEAST IN EARLY
OBSERVATIONS AND LOCALIZATION
AIRTIGHT JUNCTIONS, ARE THERE
ANY CLUES AS TO WHAT IT IS AT
THE LEVEL OF CELLS PARTICULARLY
THE PARIETAL CELL HOW THE
ORGANISM EXISTS.
AREN'T BIOFILMS AN IMPORTANT
PART OF H PYLORI?
>> I'M NOT SURE -- IF YOU SAY
BIOFILMS THEN YOU -- I'M
THINKING QUORUM SENSING, IT CAN
REACH PRETTY ANY CONCENTRATIONS
AND ARE BEING SHAREED FROM THE
STOMACH IN REPLENISHED WITHIN
THE GLANDS AND ALTHOUGH ET
COLONIZES THE STOMACH IT IS
USUALLY IN RATHER LOW NUMBERS IN
ACID SECRETING TOP END OF THE
STOMACH IN THE CORPUS.
SO SUPERFICIAL.
IT IS PRETTY CONCENTRATED IN THE
DEEP PARTS, DEEP GLANDS IN THE
INTERIM IN DUODENA ULCER
PATIENTS AND THOSE PEOPLE HAVE
LITTLE ECTOPIC AREAS OF GASTRIC
MUCOSA IN THE DUODENUM, WHERE
THE INFLAMMATION IS REALLY
SEVERE, H PYLORI GROW IN DENSE
CONCENTRATIONS.
SO BIOFILM, IT IS A BIOFILM AND
JUST THE SHEER NUMBERS ACTUALLY
BECAUSE THE AMMONIA IN THE
INTERLEUKINS YOU DO FIND H
PYLORI IF THE ACID SECRETING
GLANDS AND INSIDE THE PARIETAL
CELLS WHICH ARE PROBABLY MY
OPINION TURNED OFF THAT STAGE.
THAT'S ONE REASON IT IS HARD TO
ERADICATE.
BUT NOT SURE WHERE THE RELEVANCE
OF BIOFILM IS, MAYBE YOU ARE
THINKING THAT MAYBE YOU COULD
STOP IT FROM STICKING.
GET RID OF IT THAT WAY CUT DOWN
THE NUMBERS.
>> H PYLORI IS SUPERBLY ADAPTED
FOR HUMAN STOMACH JUST AS
BACTERIA LIVE IN VOLCANOS THEY
CAN LIVE IN DEEP SEA VENTS, IN
GRANITE.
NEW F YOU GIVE BACTERIA
NUTRIENTS THEY WILL MULTIPLY, H
PYLORI IS WELL ADAPTED,
HELICOBACTER ARE ACTIVELY
MULTIPLYING MANY THE PRESENCE OF
80 YEARS OF LIFE SOMEBODY HAS
BECAUSE IF THEY DIDN'T THEY
WOULD BE ELIMINATED BY
PERISTALLSIS BUT THEY ARE
MULTIPLYING SO THERE IS AN
EQUILIBRIUM BETWEEN RATE OF LOSS
AND RATE OF GAIN AND THEY HAVE
DONE WELL BUT NOTHING PREPARED
THEM FOR 20TH CENTURY LIFE WITH
CHLORINATED WATER AND
ANTIBIOTICS.
>> INTERESTING IMMUNOLOGIC H
PYLORI WE STILL GOT TO TEST THIS
IN SOME HUMAN MODELS TO SEE IF
WE CAN GET CLINICAL EFFECT AND I
KNOW MARTY HAD DISCUSSIONS ON
IT.
ONE OF THE PROJECTS I HAVE ON
THE BACK BURNER AT THE MOMENT
LIMITED FUNDING, ET CETERA,
WOULD BE TO CREATE A PRODUCT
CONTAINING LIKE A ACTIVE PYLORI,
ORIGIN MALI WE RIDE TO FIND IT
HARMLESS LIVE HELICOBACTER
PERHAPS GENERATE SOME OF THESE
BENEFICIAL IMMUNOLOGIC FIX BUT
WE COULD NOT FIND A HARMLESS
HELICOBACTER PYLORI EVEN ONES
WITHOUT TOXIN SOMETIMES PRODUCE
ULCERS OR EROSIONS IN THE ACUTE
STATE SO NOT SUITABLE AT THE
MOMENT TO CREATE A VACCINE OR
PROBIOTIC TREATMENT BUT
INTERESTING IN THIS
INVESTIGATING KILLED H PYLORI,
HAVING THE ANGIOGENIC STRUCTURE
AND ALL THE COMPONENTS OF
HELICOBACTER PYLORI PRESENT IN
SOME KIND OF A PRODUCT WHICH YOU
COULD TAKE ORALLY, IF IT WERE --
WE CAN SOLVE TECHNICAL ISSUES
WITH IT, THEN THREE YEARS FROM
NOW, WE MIGHT GET TO STAGE OF
DOING A CLINICAL TRIAL WHERE WE
LOOK AT THE IMMUNE EFFECT OF
TAKING HELICOBACTER AND THE
ULTIMATE WOULD BE AS A
SUPPLEMENT TO PROTECT OUR
CHILDREN FROM ASTHMA IN ALLERGIC
FAMILIES, IF EVERYONE IN
FAMILIES GOT ALLERGIES AND
ASTHMA IS PARTICULARLY COMMON,
IT MIGHT BE POSSIBLE TO SOMEHOW
MODULATE THIS EFFECT BY
INTRODUCING HELICOBACTER TYPE OF
ANTIGEN MANY THE DIET AT THE
VERY EARLY AGE.
SO WE DON'T KNOW.
>> ALONG THOSE LINES MARTY,
FRANCESCA ASKS BASED ON YOUR
PRESENTATION WOULD IT MAKE SENSE
TO ENCOURAGE H PYLORI IN YOUNGER
PEOPLE, AND TO TREAT THE
BACTERIA LATER IN LIFE?
>> YEAH SO IN 1998 I WROTE IN
THE BRITISH MEDICAL JOURNAL THAT
WE WILL BE GIVING HELICOBACTER
BACK TO PEOPLE IN THE FUTURE.
AND I THINK THAT'S WHERE THE
LOGIC LEADS, THAT MOTHERS PASS
HELICOBACTER TO THEIR KIDS SINCE
TIME IN MEMORIAL AND HAD EARLY
LIFE BENEFITS, NOW BECAUSE WE
ARE LIVING LONGER AND MAYBE
BECAUSE WE CHANGED THE ECOLOGY
OF THE STOMACH, WE ARE SEEING
SOME EFFECTS, GASTRIC CANCER IS
A DISEASE FROM ANTIQUITY, PEPTIC
ULCER DISEASE IS A DISEASE THAT
ERODES IN 19TH CENTURY.
IT IS A RELATIVELY NEW DISEASE,
SOMETHING CHANGED IN GASTRIC
ECOLOGY IN 19TH CENTURY WE DON'T
-- NOBODY KNOWS WHAT IT WAS.
I THINK FRANCESCA IS ON TO
SOMETHING THAT WE SHOULD
REPOPULATE PEOPLE WITH
HELICOBACTER WHEN THEY ARE
YOUNG, GET THE BENEFIT WHEN
YOUNG AND AT SOME AGE MAYBE 30
OR 40 AFTER GIVING BIRTH TO THE
NEXT GENERATION SO THEY CAN PASS
IT ON, AGAIN THIS ORGANISM HAS
BEEN IN HUMANS FOR COUNTLESS
HUMAN GENERATIONS.
THAT'S SOMETHING THAT SHOULD NOT
BE DISCOUNTED.
>> I WILL GET ALONG WITH THAT
POINT, THAT IS RADICAL BUT OF
COURSE THAT IS A GOOD IDEA --
>> JUST AS RADICAL AS YOU WERE
IN 1980.
>> OBVIOUSLY I WAS THINKING OF
AN IMMUNE MODULATION IN TRYING
TO FIND A HARMLESS HELICOBACTER
AND AFTER WE DID ABOUT 30
VOLUNTEERS.
WE HAD THE MOST BENIGN
HELICOBACTER WE COULD FIND AND
IT -- WE STILL HAD A COUPLE OF
PATIENTS WHO HAD TO BE TAKEN OFF
TREATMENT BECAUSE THEY HAD
EROSION.
AS WE UNDERSTAND IT MORE THESE
THINGS PROBABLY GOING TO BE
POSSIBLE.
>> THE INTERESTING THING IS THAT
THE CAGA POSITIVE STRAINS ARE
THE MOST PATHOGENIC AND MOST
BENEFICIAL BECAUSE THEY ARE THE
ONES THAT ARE THE MOST
INTERACTIVE AS A HOST.
THEY ARE -- THERE'S LIKE THE LOW
INTERACTIVE STRAIN, THE CAG
NEGATIVE AND POSITIVES, PROBABLY
IN THE OLD DAYS, MOST PEOPLE
HAVE MULTIPLE STRAINS IN THEIR
STOMACH, THEY HAD A KIND OF
ECOLOGICAL COMMUNITY MET WITH
BUFFERING AND MAYBE RISE OF
ULCER DISEASE IS WHEN
MULTIPLICITY OF HELICOBACTER OF
THE STOMACH WHEN COUNT SO INNED
THE OF FIVE STRAINS YOU ONLY HAD
ONE AND IT WAS A CAG POSITIVE
STRAIN.
>> THE OTHER THING IS, THE
PARADOX WITH H PYLORI IS IT WAS
ALWAYS ULCERS ARE CAUSED BY
STRESS WHICH IS CAUSED BY THE
20TH CENTURY BUT IN THE 19TH AND
20TH CENTURY, HUMANS HAD NEVER
BEEN SO HEALTHY IN THAT THE
AMOUNT OF PROTEIN AND THE ACID
SECRETION IN 20TH CENTURY HUMANS
PARTICULARLY PEOPLE IN CHICAGO,
NEW YORK WHERE THE DUODENAL
ULCER EPIDEMIC STARTED TO BE
NOTED ESPECIALLY SO PEOPLE WHO
ATE PLENTY OF PROTEIN WERE
BIGGER IN THIS RECENT
GENERATIONS AND HAD HIGHER ACID
SECRETION SO THEY GOT INTO THIS
-- THEY EXCEEDED THIS THRESHOLD
WITH MUCOSAL DAMAGE AND ACIDITY
LED TO DUODENAL ULCER.
THE PARADOX WAS VISIBLE MANY THE
AIDS EPIDEMICK, I DON'T THINK I
EVER SAW HIV PATIENT WITH PEPTIC
ULCER AND NEVER A PROBLEM WITH
PATIENTS WITH CHEMOTHERAPY.
YOU KNOCK OUT MOST OF THE IMMUNE
SYSTEM YOU CANNOT GET PEPTIC
ULCER SO IT IS THE REACTION
AGAINST THE HELICOBACTER THAT
CAUSED THE DUODENAL ULCER AND IT
IS A SIGN OF ROBUST HEALTH.
IN A PERSON WITH HELICOBACTER.
>> WE HAVE AN INTERESTING
QUESTION ON THE SCORE MAYBE BOTH
WILL COMMENT ON, DOES
HELICOBACTER ACTUALLY INDUCE AN
IMMUNE TOLERANCE?
THAT IS INFLAMMATION THAT
PERSISTS DESPITE THE ACTIVATION
OF A WHOLE RANGE OF IMMUNE
MEDIATED MECHANISMS.
>> WHAT WE KNOW IS SUCCESSFUL
MICROBES ALL HAVE SECRETS, THEY
ALL HAVE THEIR TRICKS THAT
ENABLE THEM TO BE SUCCESSFUL,
HELICOBACTER HAS FOUND A NICHE
THAT OTHER ORGANISMS CAN'T
COLONIZE VERY WELL.
AND IT IS ACTUALLY TO
HELICOBACTER BENEFIT TO KEEP AN
ACID STOMACH BECAUSE NOW THEY
DON'T HAVE TO COMPETE WITH STREP
AND E. COLI.
WHEN ACIDITY GOES DOWN LATER IN
LIFE HELICOBACTER IS LOST AND
THE OTHER GUYS COME IN.
SO THEY ARE MANIPULATING ACID.
THEY INCREASE -- FOR EXAMPLE
HELICOBACTER RECRUITS T
REGULATORY CELLS TO SUPPRESS THE
IMMUNE RESPONSE.
THERE'S LOTS OF EVIDENCE THAT
HELICOBACTER IS UNDER IMMUNE
SELECTION.
THEREFORE IT IS BENEFICIAL.
THAT IS THE SYMBIOSIS, NOT ONLY
BENEFICIAL HELICOBACTER BUT TO
THE HOST BECAUSE IT CUTS DOWN
CERTAIN ALLERGIC RESPONSES.
>> DO YOU WANT TO COMMENT ABOUT
THAT BARRY?
>> I PRETTY GO ALONG WITH THAT.
IT IS FOUND -- WE DID A STUDY
WHERE WE INFECTED A COUPLE OF
PEOPLE WITH HELICOBACTER AND DID
FORGE SEQUENCING ON THE
ORGANISMS BEFORE THEY TOOK IT
AND THEN THINK COUPLE OF WEEKS
LATER, THREE MONTHS LATER.
WE JUST SEE AN AMAZING NUMBER OF
SNPS, LIKE 70 SNPS IN THE FIRST
ISOLATE WE GOT FROM THE PERSON.
THIS WAS THE MUTATION RATE MANY
THE HELICOBACTER WAS SIMILAR UP
THERE WITH SOME OF THE VIRUSES
SO WHEN YOU THINK ABOUT IT
HELICOBACTER ONE OF ITS TWIN
BROTHERS, IT DOESN'T CARE ABOUT,
CHECKING THE ACCURACY OF THE
SECOND GENOME COPYING, IF IT
MAKES AN ARROW, OKAY LET'S TRY
THAT, LET'S GO AHEAD WITH IT.
THE WORST CASE SCENARIOS ONE
TWIN BROTHERS DIES OFF AND THE
OTHER ONE POPULATES, AND
SUCCEEDS, THIS WAS CARBOHYDRATE
ANTIGENS AND ADHESINS THAT
HELICOBACTER HAD.
IF YOU TALK SAY SOMETHING --
TOOK SAY SOMETHING CARBOHYDRATE
SOME KIND OF SUGAR, IT'S INTO H
PYLORI, FUCOSE.
IS THAT RIGHT?
>> FUCOSE.
>> YEAH.
T THERE'S LADY IN CANADA WHO HAD
DONE THOSE STUDIES, IN CALGARY.
BUT ALL THAT HAPPENED WAS H
PYLORI TURNED OFF THOSE GENES OR
TURNED THEM BACK ON, THEY HAD A
LOT OF POLYAs IN IT, RANDOMLY
TURNING ON AND OFF THESE SURFACE
ANTIGENS OR ADHESINS.
IT WOULD ADAPT TO YOUR STOMACH
OR MY STOMACH DIFFERENT WAYS
DEPENDING WHAT OUR BLOOD GROUP
WAS.
AND EVENTUALLY EXACTLY LIKE A
LOCK AND KEY ON TO YOUR PERSONAL
GASTRIC MUCOSA.
SO THAT IS ONE OF THE TRICKS.
>> BARRY REMINDS ME THAT STOMACH
HAD FOUR MAJOR BLOOD GROUP
ANTIGENS, LOUIS A, B, X AND Y
AND HELICOBACTER HAS ALL THE
GENES TO MAKE LOUIS A B X AND Y.
SO YOU CAN IMAGINE THAT IF THE
STOMACH IS GREEN AND YOU INGEST
HELICOBACTER THAT'S RED OVER
TIME DUE TO THIS MUTAGENESIS
THAT STRAIN WILL CONVERGE TO
LOOK LIKE STOMACH OF THE HOST.
WE -- HELICOBACTER IS A
CHAMELEON, TRYING TO MERGE WITH
THE HOST SO THAT IT WON'T BE
DETECTED.
>> IS HELICOBACTER FOUND IN
OTHER INTESTINAL ORGANS?
>> HELICOBACTER PYLORI ONLY
LIVES IN GASTRIC MUCOSA, PEOPLE
WITH ECTOPIC MUCOSA IN THEIR
DUODENUM OR METHYL DI VEER TICK
LAM, IT WON'T COMPETE WITH THE
ORGANISMS IN THE COLON.
>> WE PUBLISHED A CASE OF
ECTOPIC GASTRIC MUCOSA IN THE
RECTUM AND IN SPITE THE FACT IT
WAS COVERED IN FECES IS THE ONLY
THING GROWING ON THAT MUCOSA
WHICH WAS ACID SECRETING MUCOSA
THE SIZE OF ONE PIECE WAS
HELICOBACTER PYLORI, SO NO
PROBLEM COMPETING, PROVIDED THAT
IT HAS GASTRIC MUCOSA AND ACID
BEING SECRETED SO WHENEVER THAT
HAPPENS --
>> AGAIN VERY GOOD EVIDENCE FOR
TERRIFIC ADAPTATION TO HUMAN
BIOLOGY.
ONE OTHER POINT THE INTEREST
THING ABOUT HELICOBACTER YOU DO
DEVELOP AN IMMUNE RESPONSE TO IT
WITH IGG IGA IGM ALL THE USUAL
THING, ABOUT 80% O PEOPLE WILL
PRODUCE SECRETE IGA.
THAT HAS ABSOLUTELY NO
CORRELATION WITH THE PERSISTENCE
OR ERADICATION OF THE ORGANISM.
SO PARADOXICAL IN A WAY.
>> WHAT YOU SAY IS GENERALLY
TRUE THOUGH WHEN YOU ERADICATE
HELICOBACTER OVER TIME THE
ANTIBODIES GO AWAY.
BUT IT TAKES A LONG TIME.
IT MAY TAKE UP TO A YEAR IN SOME
CASES TWO YEARS FOR THE
ANTIBODIES TO GO AWAY BUT THEY
GO AWAY.
>> SO WE GAVE -- HAD AN
EXPERIMENT WE REINFECTED PEOPLE
WITH THEIR OWN STRAIN AFTER
CURING THEM OF HELICOBACTER AND
ANTIBODIES WERE SKY HIGH, WE
GAVE THEIR OWN STRAIN OF
HELICOBACTER BACK AND EACH TIME
WE DID THAT ON TWO OCCASIONS, IT
COLONIZED AGAIN AND JAY IN
RHESUS MONKEYS DID THE SAME
THING.
>> IT MAKES YOU ANY IN SOME WAYS
HELICOBACTER HAS -- HAS
HITCHHIKED AND THE ANTIBODY
RESPONSES ARE IN SOME WAYS
ADAPTIVE.
FOR HELICOBACTER.
BUT WE DON'T KNOW.
JUST LIKE YOU CAN HAVE HIV WITH
PLENTY OF ANTIBODIES BUT IT IS
NOT SUFFICIENT TO ERADICATE THE
ORGANISM.
>> SO JORDAN ASKS WHETHER IS
GENE EDITING BEING EXPLORED AT
PRESENT WITH THE IDEA OF
MODIFYING H PYLORI SO THAT IT
WOULD BE BENEFICIAL?
>> I THINK THAT IS A GREAT IDEA
BUT FIRST WE HAVE TO GET OVER
THE DOGMA THAT THE ONLY GOOD
HELICOBACTER IS A DEAD ONE
BECAUSE IF YOU JUST WANT TO
ELIMINATE ALL HELICOBACTER
THERE'S NO POINT DOING GENETIC
ENGINEERING.
BUT IF YOU THINK THERE MAYBE
SOME BENEFITS TO HELICOBACTER
THEN WE CAN START APPLYING
SCIENCE TO IMPROVE THE STRAIN.
>> IT WILL HAPPEN.
QUITE SURE IT WILL HAPPEN AND WE
WILL HAVE DIFFERENT FLAVORS,
PEOPLE ACTUALLY OFTEN ASK ME
WHAT IT TASTES LIKE AND THE GOOD
NEWS IS THAT IT DOESN'T HAVE ANY
FLAVOR, IT IS TASTELESS SO BIG
OPPORTUNITY FOR PRODUCTS WITH
HELICOBACTER IN THE MIDDLE OF
THEM,
>> IT WILL TAKE A LOT OF
MARKETING.
>> THERE'S A LOT OF INTEREST THE
LAST FEW YEARS OF INFLAMMATION
AS A CAUSE OF CANCER AND IT HELD
UP IN HEPATITIS AND CERVICAL
CANCER, LIVER CANCER GASTRIC
CANCER I SUPPOSE SO THAT YOU
HAVE TO FIGURE OUT -- YOU HAVE
TO KNOW MORE ABOUT IMMUNE
RESPONSE CREATING INFLAMMATION
IN THE STOMACH YOU ARE GOING TO
HAVE TO HAVE A LOT OF DATA ON
THE OUTCOME OF THAT BEFORE THE
FDA WILL GIVE YOU A TICK.
>> BARRY MENTIONS AFTER CANCER,
I MENTION THIS ABOUT GASTRIC
CANCER RISING IN YOUNG PEOPLE,
THAT'S NOT THE ONLY CANCER THAT
IS RISING IN YOUNG PEOPLE,
THERE'S'S COLON CANCER RIDING,
KIDNEY CANCER RISING, SOMETHING
IS HAPPENING.
BEING A MICROBIOLOGIST I THINK
IS BECAUSE OF THE CHANGE IN THE
MICROBIOME AND THAT OBVIOUSLY
THAT LEADS TO NUMBER OF TESTABLE
HYPOTHESES.
BUT SOMETHING VERY STRIKING IS
HAPPENING WITH CANCER IN
DEVELOPING COUNTRIES.
>> KEEP AN EYE ON THAT.
>> HERE IS A MORE PERSONAL
QUESTION FOR YOU.
VAL ASKS HOW DIFFICULT WAS IT TO
TRUST YOURSELF AND YOUR RESULTS
DESPITE THE OBVIOUS PUSH BACK
FROM THE SCIENTIFIC COMMUNITY?
YOUR ONLY ALLOWED ONE HOUR TO
ANSWER THAT QUESTION.
>> SO I DIDN'T TRUST MYSELF.
IN FACT ALL THE TIME I WAS
SAYING COULD IT REALLY BE TRUE
HOW CAN I TEST THIS HYPOTHESIS,
IF YOU -- I'M NOT SAYING I WAS A
GOOD SCIENTIST NECESSARILY,
OBVIOUSLY AN EXPERIMENT WITH THE
N OF 1 IS NOT SCIENTIFICALLY
VALID PEOPLE HAVE MADE SOME BIG
MISTAKES OVER THE YEARS BY
TESTING THINGS ON THEMSELVES BUT
WHAT YOU CAN SAY IS THAT I LOST
MY TRAIN OF THOUGHT, IT IS FIVE
O'CLOCK IN THE MORNING HERE.
SO WHAT WAS -- YES SO WHAT YOU
HAVE TO DO IS BE OWN MAJOR
CRITIC.
SO INITIALLY IT WAS OKAY IF IT
IS TRUE THAT THESE BACTERIA ARE
CAUSING GASTRITIS IF WE TREAT
THEM ERADICATE THEM WE SHOULD BE
ABLE TO SEW A CHANGE IN THE
GASTRITIS SO THAT'S WHERE I
STARTED OFF WITH ANTIBIOTICS AND
ADDITIONAL TREATMENTS.
LET'S TEST IT ON OTHER PEOPLE
WITH SEVERE RECURRENT ULCERS AND
SEE WHAT HAPPENS WITH AN OPEN
MIND.
WE HAD ABOUT NINE OUT 11
PATIENTS IN 1985 AND PRESENTED
THAT IN OTTAWA AND THEN SO THEN
THE NEXT THING IS THERE MUST BE
SOME WAY, A WAY THAT SOMEHOW I'M
SELECTING THE PATIENTS, IT IS
NOT BLINDED OR WHATEVER SO LET'S
DO A PROSPECTIVE DOUBLE BLIND
STUDY.
AND SEE.
SO THAT WE WENT THROUGH ALL
KINDS OF HOOPS AND SO IN FACT IN
OUR STUDY, EVERYBODY ON PLACEBO
THOUGHT ABOUT GETTING THE REAL
DRUG SO THE PATIENTS WE BLINDED
THE PATIENTS AND THE CRITICS
WOULD SAY THAT IS THE STOOL WENT
BLACK BUT THE PATIENTS WERE NOT
TOLD THAT.
YOU MAY NOTICE DISCOLORATION, SO
IT WAS A PROSPECTIVE STUDY WHEN
WE HAD RESULT WE LOOK AT
GRADATION OF CURE RATE OF THE
PEPTIC ULCER WAS PROPORTIONAL NO
TO NUMBER OF PATIENTS IN EACH OF
FOUR GROUPS THAT HAD COMPLETE
ERADICATION OF HELICOBACTER.
HAVING SUPPRESSION AND THEN NOT
TOTAL ERADICATION DIDN'T MAKE
MUCH DIFFERENCE IN 12 MONTH
FOLLOW-UP.
IF YOU HAD ERADICATION LIKELY
DIDN'T CATCH IT BACK AGAIN, THEN
YOU HAVE THIS REMARKABLE
DIFFERENCE WHICH HELD UP.
BUT BY THE TIME I CAME TO THE
UNITED STATES WHICH ALREADY HAD
THAT STUDY HALF FINISHED.
AT THAT POINT I WAS CONFIDENT WE
TESTED IT SEVERAL DIFFERENT
WAYS.
THE ANSWER FOR SCIENTISTS,
ANYBODY DOING ANY
EXPERIMENTATION WHENEVER YOU GET
A GOOD RESULT, HOW CAN YOU
ACCIDENTLY FAKED IT, HOW CAN IT
BE JUST BIT OF LUCK?
HOW COULD YOU HAVE SELECTED THE
SAMPLES THAT YOU WERE TESTING.
MAYBE THAT ONE THAT YOU HAD
REMOVED THAT WAS OUTLIER, MAYBE
THAT SHOULD HAVE BEEN KEPT IN,
THAT'S THE SORT OF THING, I LOT
OF THESE FORENSIC ANALYSES THAT
ELIZABETH DOES ALL THE TIME
LOOKING AT PEOPLE WHO ERASED THE
OUTLIERS OUT OF THE EFFECTS
RESULT OR SOME KIND OF
ILLUSTRATIONS JUST COPIED A FEW
BANDS INTO THEIR GEL.
I'M GOING TO LOOK AT YOUR GEL
CAREFULLY, LOOKS LIKE IT IS TOO
GOOD TO BE TRUE.
>> WHEN WE FOUND CAGA WE FOUND
THAT CAG -- PEOPLE HAD ULCERS
WAS 100% OF PEOPLE WITH ULCERS
AND 63% OF PEOPLE WITH
GASTRITIS.
>> REMEMBER THOSE NUMBERS.
>> ONE YEAR LATER, ONE AND A
HALF YEARS LATER, GENE CRAB TREE
PUBLISHED RESULTS ACROSS THE
OCEAN, 100% ULCER, 62%
GASTRITIS.
AT THAT POINT WE KNEW IT WAS
TRUE.
INDEPENDENT CONFIRMATION SHOWING
EXACTLY THE SAME THING.
SO -- CONFIRMATION.
>> SO THE PEOPLE WHO REALLY
HATED HELICOBACTER WERE THE
GASTROENTEROLOGISTS IN MELBOURNE
AND JOHN LAMBERT REPEATED OUR
STUDY IN MELBOURNE THE FOLLOWING
YEAR, WE HAD 92% OF ULCERS WERE
POSITIVE WHEN WE DID A LARGE
STUDY OF 70 ULCERS.
HE GOT 92 OR 93% INDEPENDENTLY
IN MELBOURNE.
SO CONFIRMATION IS SO IMPORTANT.
>> SO THE OTHER QUESTION IS WHEN
YOU GOT SOMETHING EXCITING AND
HOW DO YOU GET SOMEBODY TO
SUPPORT YOUR RESEARCH, IT IS
MUCH -- SO BEAUTIFUL IF YOU CAN
GET A COMPANY LIKE PROCTER &
GAMBLE BANK ROLLING YOU FOR A
FEW YEARS, THINGS TO MOVE ALONG,
YOU MIGHT BE TO CUSSED ON THE
PRODUCTS A LITTLE BIT.
I ALWAYS SAY WELL THE FIRST
THING YOU DO IS FIND THE COMPANY
THAT'S THE BIGGEST IN THAT
INDUSTRY, AND TRY TO ASK THEM TO
SUPPORT YOU, BECAUSE THEN YOU
ARE ON EASY STREET.
IF THEY DON'T SUPPORT YOU THEN
YOU GO COMPETITION.
AND SAY YOU CAN BE THE KINGS IF
YOU CAN SUCCEED IN OUR -- SO
GLAXO WELCOME AND GOT NOWHERE
AND THEN SO THE NEXT THING I
WENT TO THE BISMUTH COMPANIES
AND THE BOSTON IT WAS QUITE
HOSTILE WITH THE RESEARCH
PEOPLE, YOU HAVE TESTED THESE IN
PRODUCTS IN EVERY POSSIBLE WAY,
YOU NEVER DID THE MIC OF COMMON
BACTERIA WITH THEM.
AND THEY HADN'T DONE THAT SO
THEY WERE IN TOTAL DISGRACE.
LUCKILY A FELLOW MIKE AT PROCTER
& GAMBLE HAD BEEN LOOKING AT
TRAVELERS DIARRHEA WITH PEPTO
BISMOL AND ALL OF A SUDDEN HAD
THE IDEA THAT BISMUTH COMES BACK
AS A ULCER TREATMENT, IT WAS
TESTED IN EARLY JOHNNY, NOT A
GOOD CURE BY ITSELF, ANTIBIOTIC
AS WELL.
SO IT WAS EXCITING THERE FOR A
WHILE.
SO YOU TRY TO PROVE IT I DON'T
THINK AND IF YOU CAN'T PROVE IT
WRONG MAYBE IT IS RIGHT.
THE THING TO DO IS TRY AND DO IN
YOUR OWN LAB WITH YOUR OWN
RESEARCH WHAT EVERYONE ELSE IS
GOING TO TRY TO DO AS PART OF
THE SCIENTIFIC PROCESS.
THAT'S WHAT I -- IN THE UNITED
STATES IS THAT ONCE IF THERE WAS
THE SLIGHTEST CHINK IN THE
ARMOR, EVERYONE WHO WOULD GO FOR
IT AND TRY TO PREVIEW A WRONG,
SO -- PROVE YOU WRONG SO IT IS
DIFFICULT FOR A YOUNG
INVESTIGATOR TO HANDLE THAT.
JUST SO VERY UNFAIR THAT YOU
LOSE ALL YOUR FRIENDS SOON AS
YOU HAVE A NEW IDEA.
THAT IS THE WAY SCIENCE GOES AND
MAYBE SOME PLACES IN THE WORLD
NOT HAVING SO MUCH SUCCESS AS
THE UNITED STATES IS BECAUSE
THEY AREN'T PUTTING ALL THEIR
CARDS OUT.
REALLY BITING THE BULLET AND
TAKING CRITICAL LOOK AT THEIR
OWN EXPERIENCE.
>> SURE YOU WOULD AGREE THAT
THERE IS A LOT OF FOLLOW THE
LEADER IN BOTH MEDICINE AND
SCIENCE.
THE PAIR OF DOGMA IS ASTOUNDING.
>> I LOOK AT MY EARLY -- LOOKING
AT LATEST FROM THE LANSETT,
THERE'S THOUSANDS OF PAPERS LIKE
THAT THAT ARE OUT THERE,
HELICOBACTER THAT ARE WELL CITED
PAPERS, SO IF YOU SEARCH FOR
HELICOBACTER YOU DON'T FIND
THOSE EARLY REFERENCES.
IT'S A LITTLE BIT SAD.
I WAS COMPLAINING LIKE ANYTHING
YES THAT I WENT I WAS FILLING
OUT THE JOHNS HOPKINS CONFLICT
OF INTEREST DOCUMENTS AND DOING
THOSE ONLINE FORMS.
THE DEFINITION OF -- THIS SORT
OF ETHICS OF PRESENTATIONS IN
THE JOHN HOPKINS CME PROGRAM ET
CETERA.
YOU WERE NOT PRESENT ANY
INFORMATION THAT'S ANECDOTAL OR
NOT PROVEN, YOU WANT TO PROMOTE
UNPROVEN PRODUCTS THAT HAVE NOT
BEEN TESTED IN A PROPER DOUBLE
BLIND WAY, ALL KINDS OF GOOD
SCIENTIFIC CLINICAL RESEARCH
RULES IN THERE ABOUT WHAT YOU
CAN PRESENT AT THE JOHNS HOPKINS
CME.
SO I PRINTED THAT OUT, I WILL
TALK ABOUT IT TO MY BLOOD PEOPLE
AND CLINICS BECAUSE THIS IS THE
PROBLEM AROUND THE WORLD.
PARTICULARLY IN CHINA THERE'S
PEOPLE WHO EASILY FUNDED ON
NATURAL MEDICINE AND TRADITIONAL
MEDICINE.
IT IS REALLY GOT NO SCIENTIFIC
BASIS.
IN CHINA I KNOW
>> THERE ARE GREAT SCIENTISTS IN
THE INSTITUTION, THE TOP
INSTITUTIONS JUST LIKE
EVERYWHERE ELSE IN THE WORLD
WHERE THERE IS EUROPE, UNITED
STATES OR AUSTRALIA, THEY ARE --
THEY HAVE REALLY HARD CORE
SCIENCE GOING ON THERE AND THE
CHINESE FDA HAS GOT HARD CORE
RULES EMULATING THE U.S. FDA.
BUT A LOT OF PEOPLE STILL
BELIEVE THAT THERE IS MORE THAN
SCIENCE OR -- HARD TO EXPLAIN,
TRADITIONAL STUFF I GUESS, IN
EVERY COUNTRY AND A LITTLE BIT
HORRIFIED WHEN THE CHINESE
WHATEVER NATURAL MEDICINES AND
TCM WAS ACCEPTED OR ADDED ON TO
THE WORLD HEALTH ORGANIZATION
ACCEPTED MEDICINES LIST.
SO NOT SURE WHAT THE DEAL IS
WITH THAT.
IT REALLY BROUGHT WHO DOWN A FEW
WRUNGS IN MY VIEW AS WELL.
IT IS SOMETHING THAT IS A BIT OF
A DICHOTOMY IN MANY PLACES.
>> SO WE HAVE A SORT OF MOST
RECENT QUESTION, MAYBE YOU WANT
TO COMMENT ABOUT.
IS THERE A GENETIC
PRE-DISPOSITION TO CANCER
RELATIONSHIP TO H PYLORI?
>> YEAH, IT'S BEEN SHOWN LMR AND
RAPKIN AND COLLEAGUES SHOWED 20
YEARS AGO THAT PEOPLE WHO HAD
CERTAIN POLYMORPHISMS IN THEIR
CYTOKINE GENES WERE MORE LIKELY
TO GET GASTRIC CANCER, OBVIOUSLY
NOT A STRONG HELICOBACTER IS SO
IMPORTANT IN HELICOBACTER
GASTRIC CANCER YOU CAN HAVE ANY
GENOTYPE, IF YOU DON'T HAVE
HELICOBACTER YOU ARE NOT GOING
TO GET TRADITIONAL CANCER BUT IT
INCREASES RISK.
THERE'S IN QUESTION.
>> THAT SOMETHING THAT IS OFTEN
IGNORED BECAUSE PEOPLE WITHIN
EARLY GASTRIC CANCER MIGHT GO
THROUGH PARTIAL GASTRICTOMY AND
HAVE A CURE THAT IS A LEAD TO
FAMILY BECAUSE IMMEDIATE
RELATIVES IF THEY HAD
HELICOBACTER THEY HAVE SAME
STRAIN AND GENES AND RELATIVE
RISK IS FOUR TIMES NORMAL IF
YOUR BROTHER HAD GASTRIC CANCER
YOU NEED TO BE IMMEDIATELY
TESTED FOR HELICOBACTER AND GET
TREATED.
THAT WILL CUT THE RISK DOWN BY
ABOUT 50% BUT YOU ARE STILL --
YOU COULD HAVE STEM CELLS
FLOATING AROUND IN GASTRIC
MUCOSA.
THIS IS WHY I THINK AS PEOPLE
HAVE LOOKED AT HELICOBACTER OVER
LONG TERM IF YOU NEVER HAD YOU
HARDLY GET GASTRIC CANCER.
IF YOU LOOK AT PEOPLE WITH
GASTRIC CANCER HALF OF THEM WITH
HELICOBACTER AND HALF DON'T SO
YOU MIGHT SAY THERE IS ANOTHER
50% WHO DIDN'T HAVE HELICOBACTER
SO MUST BE ANOTHER COURSE BUT
JANE CRABTREE I THINK IT WAS,
THEY CULTURED GASTRIC MUCOSA
FROM GASTRIC CANCER PATIENTS WHO
HAD NO HELICOBACTER AT THE TIME
OF THEIR SURGERY.
HEADACHE SHOW TISSUE FROM THE
STOMACH WAS GENERATING
ANTIBODIES AGAINST HELICOBACTER
THOUGH THERE IS NO MORE ORGANISM
THERE.
>> YOU SEE WHAT HAPPENS IS WITH
THE DEVELOPMENT OF ATROPIC
GASTRITIS THAT LEADS THE GASTRIC
CANCER, TAKES DECADES BUT DURING
THAT TIME THE HELICOBACTER WHICH
INITIATED THE PROO SYCES IS
GONE. IT CAN'T SHRIVER IN
ATROPIC GASTRITIS ENVIRONMENT SO
THAT'S WHY SO MANY PEOPLE ARE
NEGATIVE, THAT'S WHY THE
STRONGEST RESULTS WERE STUDIES
PROSPECTIVE WHEN AS CERTAINMENT
OF HELICOBACTER STATUS WAS A
DECADE OR MORE PRIOR TO THE
CANCER.
>> THE OTHER THING IS THOUGH
PEOPLE SAY HELICOBACTER IS A
CARCINOGEN, I THINK IT RUNS THE
LINING OF THE STOMACH, LOWERS
ACIDITY, YOU GET OTHER BACTERIA
THAT CONTINUE THE CANCER RISK.
HOE THE HELICOBACTER IS GONE.
THE EXAMPLE FOR THIS IS THAT
PEOPLE WITH DUODEN ABOUTL ULCER
NEVER GET CANCER.
NEVER GET GASTRIC CANCER UNTIL
MANY YEARS LATER WHEN THE ULCER
IS LONG GONE SO
GASTROENTEROLOGIST NEVER BIOPSY
PATIENTS WITH DUODENAL ULCER,
WHAT IS THE POINT?
WE NEVER FIND CANCER.
SO THEY ARE ONLY BIOPSY GASTRIC
ULCERS AS ONE OF THE REASONS IT
WAS FAMOUSLY MISTED HELICOBACTER
FOR SO LONG.
>> THERE'S PARADOXES WITH
HELICOBACTER THAT STILL EXIST
FOR EXAMPLE, HELICOBACTER
ASSOCIATED WITH BOTH GASTRIC AND
DUODENAL ULCER BUT ONE IS LOW
ACID STATE, OTHER IS HIGH ACID
STATE AND AS BARRY SAID DUODENAL
ULCERS PROTECT AGAINST GAY VIC
CANCER IN EPIDEMIOLOGIC STUDIES.
SO WHY SOMEONE GETS A GU, WHY
SOMEONE GETS DU, WE DON'T
UNDERSTAND.
>> YOU DO SEE PEOPLE WHO HAD
DUODENAL ULCER IN THE PAST NOW
GASTRIC YOU WILL CERTAIN MANY
YEARS LATER GOT NEITHER.
SO I THINK THAT GOES ON BUT HARD
TO --
>> HAVE GU ON THE PATHWAY.
>> WELL, I WANT TO -- WE HAVE
COME TO THE END OF OUR TIME
ALTHOUGH I SUSPECT WE COULD HAVE
GONE ON CONSIDERABLY LONGER.
BUT ON BEHALF OF EVERYONE I
REALLY WANT TO THANK BOTH OF YOU
VERY MUCH PARTICULARLY BARRY FOR
BEING SO VIBRANT AT FIVE O'CLOCK
IN THE MORNING, THAT IS
ADMIRABLE AND MARTY, THANK YOU
AGAIN, YOU HAVE GIVEN EVERYONE
MUCH TO THINK ABOUT AND MY
SUSPICION IS THAT THE VAST
MAJORITY OF PEOPLE AROUND THE
WORLD WHO ARE LISTENING TO THIS
PROGRAM ARE NOT AWARE OF THE
BASIC PROPOSITION THAT YOUR
PRESENTATIONS OFFERED UNDER THE
IDEA OF THE SPLIT PERSONALITY.
IT IS MORE COMPLICATED.
MORE CHALLENGING AND MORE
OPPORTUNITIES FOR YOUNG PEOPLE
PARTICULARLY USING ADVANCE
TECHNOLOGY AND CONCEPTS TO LOOK
AT THESE PROBLEMS, THEY AREN'T
GOING AWAY BY THEMSELVES.
AND WITH ALL GOOD SCIENCE IT
RAISES GOOD QUESTIONS.
THANK YOU BOTH FOR RAISING THE
GOOD QUESTIONS, AS WELL AS
RELATING VERY GOOD SCIENCE.
THANK YOU VERY, VERY MUCH WE ALL
APPRECIATE IT.
WERE YOU WELL.
>> THANK YOU.
>> THANK YOU VERY MUCH.
>> GOOD TO SEE YOU.
>> THANK YOU.