>> WELCOME TO THE THIRD SESSION
OF THE 20th YEAR OF THE NIH
COURSE ENTITLED DEMYSTIFYING
MEDICINE.
THE LOGO AS SHOWN ON THE SLIDE
IS THE BROOKLYN BRIDGE.
WE ARE LIKE THE INDIVIDUALS ON
THE BRIDGE WHO ARE DISCUSSING OR
LEARNING FROM ONE ANOTHER ABOUT
IMPORTANT BIOMEDICAL AND
ENGINEERING PROGRESS AS IT CAN
INFLUENCE MEDICINE.
THINGS ARE NEVER THE SAME AFTER
A BRIDGE HAS BEEN SUCCESSFULLY
BUILT AND IN COURT MAY BE
THOUGHT OF AS YOU A COURSE IN
BRIDGE BUILDING.
TODAY'S TOPIC IS THE INTESTINAL
MICROBIOME.
I THINK THAT -- IN THE 17th
CENTURY WAS THE FIRST TO EVER
SEE THE MICROBIOME BY EXAMINING
CONTENTS OF FECAL MATERIAL ON
HIS MINIATURE MICROSCOPE.
IN THE 19th CENTURY -- IS
PROBABLY THE FIRST TO RELATE IT
TO DISEASE.
AND IN THAT SENSE TODAY WE WOULD
CALL TOXIC SHOCK.
BUT HE ALSO RELATED IT TO THE
POSSIBILITY OF HEALTH AND THAT
BY MODIFYING THE MICROBIOME
THERE MAY BE INFLUENCES ON HUMAN
HEALTH.
BUT IT WASN'T UNTIL 1977 WHEN
CARL WOESE INTRODUCED 16S
SEQUENCING WHICH REVOLUTIONIZED
MICROBIOLOGY
NOW THE DISCOVERY OF THESE
METHODS LED TO THE
QUANTIFICATION OF MICROBIOME
SPECIES AND THEN THE STUDY OF
THE COMPOSITION, REGULATION AND
ROLE IN PHYSIOLOGY AND DISEASE.
HOWEVER FOR MUCH OF THE WORK WE
ARE IN A DESCRIPTIVE STAGE.
THAT IS DESCRIBING THE
MICROBIOME IN DIFFERENT AGES,
SOCIOECONOMIC GROUPS AND
COMPARISONS AND CONTROL PATIENTS
AND THOSE WITH VARIOUS DIETS,
WEIGHT AND DISEASE.
THE HUGE CHALLENGE IS TO
DETERMINE WHETHER THE OBSERVED
MICROBIOME DIFFERENCES REPRESENT
CAUSE OR EFFECT.
NOW THE AVAILABILITY OF GERMFREE
AND ANIMALS IS AIDED.
HOWEVER THE QUESTIONS CONCERNING
HUMANS IN WHOM CLINICAL STUDIES
OF CAUSE AND EFFECT AND
MECHANISM ARE DIFFICULT IF NOT
AT TIMES SEEMINGLY IMPOSSIBLE TO
PERFORM.
AND THIS IS THE BRIDGE THAT WE
WILL BE DISCUSSING TODAY.
TODAY WE'RE VERY FORTUNATE TO
HAVE TWO OUTSTANDING SCIENTIST
DISCUSS THEIR EXCITING WORK IN
BRIDGING THE MICROBIOME WITH TWO
MAJOR CLINICAL PROBLEMS.
MALNUTRITION AND CANCER.
OUR FIRST SPEAKER WILL BE JEFFE
GORDON.
WHO GRADUATED FROM THE
UNIVERSITY OF CHICAGO SCHOOL OF
MEDICINE TRAINED IN MEDICINE AT
WASHINGTON UNIVERSITY IN ST.
LOUIS AND IN GASTROINTESTINAL.
AND AT THE NATIONAL INSTITUTE OF
HEALTH AND RETURNED TO
WASHINGTON UNIVERSITY WHERE HE
HAS SPENT HIS ENTIRE CAREER.
HE STARTED TO USE GENOMIC
SEQUENCES -- KNOW OBEY ON THEIC
ANIMALS AND THEIR RESPONSE TO
DIET IN PRECLINICAL AND CLINICAL
STUDIES.
* IN ONE OF HIS PAPERS HE SAID I
WANT TO CONFESS I'M MORE
MICROBIAL THAN I AM HUMAN
BECAUSE THE CONTENTS OF THE
MICROBIOME NUMBERING IN THE
TRILLIONS FAR EXCEEDS THE SUM
TOTAL AFTER ALL OF THE CELLS IN
THE HUMAN BODY.
JEFF IS A DISTINGUISHED
UNIVERSITY PROFESSOR AT
WASHINGTON UNIVERSITY.
AND PROFESSOR OF PATHOLOGY AND
IMMUNOLOGY ALSO OF DEVELOPMENTAL
BIOLOGY AND OF MOLECULAR MICRO
BIOLOGY.
HE HAS RECEIVED AN EXTRAORDINARY
NUMBER OF THE HIGHEST HONORS
THAT CAN BE BESTOWED UPON EYE
SCIENTISTS.
HE IS * A MEMBER OF THE
ASSOCIATION OF AMERICAN
PHYSICIANS.
A MEMBER OF THE NATIONAL ACADEMY
OF SCIENCES, OF ARTS AND
SCIENCES.
THE NATIONAL INSTITUTE OF
SCIENCE.
THE INSTITUTE OF MEDICINE.
THE AMERICAN PHILOSOPHICAL
SOCIETY.
AND HE HAS BEEN A RECIPIENT OF
VIRTUALLY EVERY MAJOR PRIZE AND
AWARD GIVEN FOR BIOMEDICAL
RESEARCH.
ONE OF THOSE AWARDS IN 2018 WAS
FROM THE ROYAL SOCIETY WHICH
BESTOWED ITS MEDAL WHICH IS THE
OLDEST SCIENTIFIC PRIZE IN THE
WORLD.
AND I WOULD JUST READ AS PUT ON
THE SLIDE THE REASONS FOR THAT
AWARD.
IT'S BECAUSE HIS WORK LED TO A
FUNDAMENTAL SHIFT IN THE WAY
SCIENTIST UNDERSTAND THE
RELATIONSHIP BETWEEN MICROBES,
HEALTH AND DISEASE AND HE LED TO
DISCOVERIES WHICH SHED NEW LIGHT
ON AMONG OTHER THINGS THE ORIGIN
OF TWO PRESSING GLOBAL HEALTH
PROBLEMS.
OBESITY AND CHILDHOOD
MALNUTRITION.
TODAY DR. GORDON IS GOING TO
SPEAK TO US ABOUT THE ROLE OF
THE MICROBIOME IN MALNUTRITION.
NEXT PLEASE.
OUR SECOND SPEAKER IS TIM GRETEN
WHO GRADUATED IN MEDICINE IN
GERMANY.
WAS A POSTDOCTORAL FELLOW IN
JOHNS HOPKINS.
RETURNED TO GERMANY AND IN 2010
WAS RECRUITED TO THE NATIONAL
CANCER INSTITUTE WHERE HE IS THE
DEPUTY BRANCH CHIEF FOR THE
THORACIC AND GI MA MALIGNANCY
BRANCH.
HE IS COCHAIR FOR THE CENTER OF
EXCELLENCE OF IMMUNOLOGY.
AND ALSO OF THE LARGE PROGRAM
INTERDISCIPLINARY AT THE NIH
DIRECTOR OFFED HEPATOCELLULAR
CANCER.
HE FOCUSES ON HEPATOCELLULAR
CANCER AND DURING THIS WORK EVEN
THE PAST SEVERAL YEARS HE HAS
BECOME INVOLVED IN THE
RELATIONSHIP BETWEEN LIVER
TUMORS PARTICULARLY CANCERS AND
THE GUT MICROBIOME.
AND THE TOPIC OF TIM'S TALK IS
HOW THE GUT MICROSOFT CONTROLS
GROWTH OF LIVER TUMORS.
NOW WE WILL CONSIDER QUESTIONS
AND ANSWERS AND DISCUSSION AT
THE CONCLUSION OF DR. GRETEN'S
TALK BUT PLEASE SUBMIT YOUR
QUESTIONS DURING THE ENTIRE
PROGRAM AND THEY WILL BE
PRESENTED AT THE END.
SO NOW I WANT TO THANK BOTH OF
OUR SPEAKERS FOR TAKING THE TIME
AND INTEREST TO PARTICIPATE IN
THIS PROGRAM.
AND JEFF IF YOU WOULD PLEASE
BEGIN.
>> THANK YOU VERY MUCH.
IT'S A PRIVILEGE AND PLEASURE TO
BE ABLE TO PARTICIPATE IN THIS
WONDERFUL PROGRAM.
>> THIS IS ADVENTURE.
TWO GROUPS OF INDIVIDUALS.
ON THE LEFT YOU CAN SEE A GROUP
OF VERY TALENTED STUDENTS AND
POSTDOCTORAL FELLOWS IN THE LAB
WHICH IS LOCATED AT THE CENTER
FOR GENOME SCIENCES AT
WASHINGTON UNIVERSITY IN ST.
LOUIS.
AND OUR LONG-STANDING
COLLABORATORS -- AT THE
INTERNATIONAL CENTER FOR
RESEARCH.
THIS IS FUNDED BUT THE BILL AND
MELINDA FOUNDATION AT THE NIH.
I HAVE NO CONFLICTS TO REPORT.
IT'S WORK DIRECTED AT THE
DEVELOPMENT OF COMPLIMENTARY
FOOD FOR CHILDHOOD.
THIS IS A GLOBAL HEALTH
CHALLENGE MADE WORSE BY THE
CURRENT PANDEMIC.
IT'S THE LEADING CAUSE OF DEATH
OF CHILDREN UNDER THE AGE OF
FIVE.
THERE HAVE BEEN MANY ESPECIALLY
DEEM LOGICAL SKUD EASE THAT HAVE
DEMONSTRATED THAT CHILD UNDER
NUTRITION IS NOT DUE TO FOOD IN
SECURITY ALONE.
*.
CURRENT THERAPIES HAVE EVOLVED
TO REDUCE MORTALITY.
BUT THEY'VE HAD VERY LIMITED
UNFORTUNATELY SUCCESS IN
OVERCOMING THE LONG-TERM
CONSEQUENCES OF UNDER NUTRITION
WHICH INCLUDES IMPAIRED LINEAR
GROWTH.
DEFECTS IN IMMUNE RESPONSES
INCLUDING VACCINATION AND NEURAL
DEVELOPMENTAL ABNORMALITIES.
SO THERE IS SOMETHING ABOUT
PATHOGENESIS THAT WE'RE MISSING
AND WHAT IS THAT?
WE'RE ALSO MISSING A
COMPREHENSIVE DEFINITION OF THE
BIOLOGICAL STATE OR STATES OF
UNDER NUTRITION.
THE TYPICAL WAY OF DEFINING
UNDER NUTRITION IS THROUGH THE
USE OF ANTHROPOMETRY.
THE MEASUREMENT AND THE
REFERENCING OF THOSE VALUES FOR
AN INDIVIDUAL TO A MULTI-NATURAL
BIRTH COHORT ASSEMBLED BY THE
WORLD HEALTH ORGANIZATION.
AND THE DEFINITION OF DEVIANTS
FROM NORMAL BASED ON THE NUMBER
OF NORMAL DEVIATIONS AN
INDIVIDUAL IS FROM HEALTHY
INDIVIDUALS IN THIS COHORT.
SO WE CAN DEFINE STUNTING AS A
LENGTH FOR AGE SCORE THAT IS A
CERTAIN NUMBER OF STANDARD
DEVIATIONS.
MODERATE STUNTING TO THE
DEVIATIONS BELOW THE MEDIAN FOR
THIS HEALTHY COHORT.
WASTING OR IMPAIRED GROWTH AS A
DEVIATION FROM NORMAL OF WEIGHT
FOR LENGTH OR HEIGHT.
MODERATE WASTING TWO TO THREE
STANDARD DEVIATIONS BELOW.
SEVERE WASTING A WLZ SCORE THAT
IS MORE THAN THREE STANDARD
DEVIATIONS AWAY FROM NORMAL.
BUT WHO WOULD DEFINE DISEASES
LIKE CANCER OR CARDIOVASCULAR
IMPAIRMENT AS MODERATOR SEVERE?
WE NEED A MUCH MORE
COMPREHENSIVE DEFINITION OF THIS
STATE OF IMPAIRED GROWTH.
AND YOU'LL SEE WHY THIS IS
PARTICULARLY IMPORTANT WHEN IT
COMES TO CONNECTING THE
MICROBIOME TO THE DISEASE
PATHOGENESIS.
SO WHAT ARE THE HYPOTHESIS THAT
OUR GROUP -- IS PURSUING?
THE HYPOTHESIS IS THERE IS A
DEFINAL NORMAL.
IT HAS A CHARACTERISTIC PROGRAM
OF ASSEMBLY THAT BEGINS AT
BIRTH.
AND THE DISRUPTION OF THIS
DEVELOPMENTAL PROCESS AFFECTING
AN ORGAN -- IS CAUSALLY RELATED
TO UNDER NUTRITION.
NOW A COROLLARY IS THAT HEALTHY
GROWTH OF INFANTS AND CHILDREN
IS LINKED TO HEALTHY DEVELOPMENT
OF THE GUT MICROBIOME.
THERE HAS TO BE A CO-DEVELOPMENT
OF THIS COMMUNITY AND THE HOST.
SO I'M GOING TO TAKE YOU ON A
MULTI-STEP JOURNEY THAT
DR. ARIAS HAS ELUDED TO IN HIS
IN INTRODUCTORY COMMENTS.
A JOURNEY THAT IS 'EM EMBLEMATIC.
THE FIRST IS TO DEFINE THE
DEFINITION OF NORMAL.
THE SECOND STEP IS DEVELOP A
METRIC FOR QUANTIFYING
DEVIATIONS FROM NORMAL AND
DETERMINING WHETHER THOSE
DEVIATIONS CORRELATE IN A
STATISTICALLY SIGNIFICANT
FASHION WITH DISEASE AND DISEASE
SEVERITY.
THE THIRD STEP IS TO DETERMINE
IF DEVIATION FROM NORMAL DO
CORRELATE WHETHER THEY ARE
SIMPLY AN EFFECT OR PERHAPS A
CAUSE OF DISEASE.
THE NEXT STEP IS IDENTIFYING
THERAPEUTIC TARGETS WITHIN A MY -- A
MICROBIAL COMMUNITY AND THEN
DEVELOPING THERAPEUTIC
INTERVENTIONS THAT ARE NOT
ORIGINAL EFFICACIOUS IN A GIVEN
POPULATION BUT THAT ARE SAFE,
DURABLE AND GENERALIZABLE.
AND CULTURALLY ACCEPTABLE AND
AFFORDABLE.
SO I'M GOING TO TAKE YOU ON THIS
JOURNEY THAT WE HAVE BEEN
PURSUING AND WE WILL BEGIN IN AN
URBAN SLUM LOCATED IN THE
CAPITAL OF BANGLADESH.
THE POPULATION DENSITY IS
REMARKABLE.
A HALF A MILLION PEOPLE LIVING
WITHIN TWO AND A HALF SQUARE
MILE AREA.
POPULATION DENSITY OF 77,000 PER
SQUARE KILOMETER AND THE
DEFINITION OF NORMAL WAS PURSUED
IN A BIRTH COHORT WHERE
INDIVIDUALS WERE ENROLLED AT
BIRTH REFLECTING THE DEEP TRUST
AND COMMITMENT OF MOTHERS AND
FAMILIES FOR THE HEALTH OF THEIR
OFFSPRING AS WELL AS THE DEEP
TRUST AND RESPECT THAT THEY HAD
FOR THE HEALTH CARE PROVIDERS
THAT THEY'VE BEEN INTERACTING
WITH SO THAT LONGITUDINAL
STUDIES CAN BE PERFORMED.
THEY'VE FORGED THAT LEVEL OF
TRUST, RESPECT AND DEVOTION OVER
THE COURSE OF THE LAST FOUR
DECADES.
MEMBERS OF THIS BIRTH COHORT
WERE FOLLOWED MONTHLY INITIALLY
FOR THE FIRST 24 MONTHS OF
POSTNATAL LIFE AND THROUGH THE
FIRST 60 MONTHS WITH MONTHLY
SAMPLING OF THE FECAL MICRO
BIOTA.
DATA WAS ACCUMULATED AND THE
INITIAL FOCUS WAS ON THE INFANTS
AND CHILDREN THAT HAVE NORMAL
SNTHROPOMY.
* AND THEN THE APPLICATION OF
CULTURE INDEPENDENT METHODS THAT
DR. ARIAS HAD DESCRIBED USING
THE BACTERIAL 16S GENE AS A BAR
CODE OF LIFE OF BACTERIAL LIFE
AND CLASSIFYING ORGANISM BASED
ON THE 16S SEQUENCE.
FROM HEALTHY MEMBERS LIVING IN
THIS URBAN SLUM A MICROBIAL
PICTURE OF NORMAL COMMUNITY
DEVELOPMENT EMERGED AND IN ONE
ITERATION OF THIS PICTURE SHOWN
HERE YOU CAN SEE THE COLUMNS AS
AGE BINS.
THE ROWS AT DIFFERENT BACTERIAL
-- AND THE COLORS INDICATING THE
RELATIVE ABUNDANCES OF THESE AT
A TIME AFTERBIRTH AND YOU CAN
SEE IN THE LEFT LOWER QUADRANT
AND GROUP OF ORGANISMS THAT ARE
PROMINENTLY REPRESENTED IN THE
FIRST SEVERAL MONTHS OF
POSTNATAL LIFE AND THOSE THAT
BECOME MORE PROMINENT LATER ON.
THIS IS THE RESULT OF THE
FIVE-YEAR ANALYSIS.
AND THIS GIVES YOU AN IDEA OF
WHAT PARTS OF THERE AND WHAT
PARTS MIGHT BE SHARED BY MEMBERS
OF THE MICROBIAL COMMUNITY.
BUT THEY FAILED TO ADDRESS A
FUNDAMENTAL ASPECT THAT WE NEED
TO UNDERSTAND ABOUT THE GUT.
AND THAT HAS TO DO WITH THE
ORGANIZATION AND ITS DYNAMISM.
WE NEED FOR GO BEYOND A SIMPLE
LIST OF PARTS.
-- SO WE NEED TO IDENTIFY A
SMALLER NUMBER OF INTERACTING
COMPONENTS THAT DESCRIBE NORMAL
MICROBIAL COMMUNITY DEVELOPMENT
IN HEALTHY INDIVIDUALS.
WHY JEFF ARE YOU DESCRIBING
THIS NEED FOR LOOKING AT
INTERACTIONS?
I'LL TRY TO PAINT A PICTURE.
BY GOING TO MACRO ECOSYSTEMS AND
EVEN HUMAN BEHAVIORS.
IMAGINE IF YOU ONLY FOCUSED ON
INDIVIDUAL FISH AND DISCARDED
ANY CONSIDERATION OF
INTERACTIONS YOU WOULD NEVER
APPRECIATE THE CONCEPT OF FISH
SCHOOLING.
SIMILARLY YOU WOULD NEVER BE
ABLE TO APPRECIATE THE DYNAMISM
OF BIRTH AND FLIGHTS OR ANTS
FORAGING.
SO HOW DO WE DO FEATURE
SELECTION AND IDENTIFY A SMALLER
NUMBER OF PARTS INTERACTING
PARTS IN THE GUT MICRO BIOTA.
NOR THAT PURPOSE WE TURN TO THE
STOCK MARKET AND A FIELD KNOWN
AS ECONO PHYSICS WHERE
INDIVIDUALS STARTED TO USE
STATISTICAL METHODS TO LOOK AT
VARYING PRICES OF STOCKS TO
UNDER THE DIFFERENT ECONOMIC
SECTORS AND THE BEHAVIOR OF THE
STOCK MARKET.
AND A VERY TALENTED POSTDOC IN
THE LAB APPLIED THE PRINCIPLES
AND METHODS OF ECONO PHYSICS TO
IDENTIFY A SMALL GROUP OF 15
CO-VARYING GUT BACTERIAL STRAINS
THAT DESCRIBED IN THIS HEALTHY
COHORT OF INFANTS AND CHILDREN
LIVING IN THE URBAN SLUM, NORMAL
COMMUNITY DEVELOPMENT.
AND THIS NETWORK OF CO-VARYING
-- ARE DESCRIBED HERE IN THIS
DIAGRAM HERE AND THE GREEN
MEMBERS ARE COMPONENTS OF THIS
NETWORK WHICH ARE TERMED AN ECO
GROUP.
FROM THIS ANALYSIS AS WELL AS
FROM OTHER TYPES OF ANALYSIS WE
WERE ABLE TO DETERMINE THIS
PROGRAM OF COMMUNITY ASSEMBLY IN
HEALTHY INDIVIDUALS IS LARGELY
COMPLETE BY THE END OF THE
SECOND POSTNATAL YEAR.
WE ALSO DISCOVERED -- IN THE
INITIAL ANALYSIS THAT THESE ARE
ALSO REPRESENTED IN THE
DEVELOPING GUT MY CREEPIAL
COMMUNITIES OF BIRTH * COHORTS
LIVING IN OTHER LOW-INCOME
COUNTRIES.
SO THERE IS SOMETHING ABOUT A
SHARED FEATURE OF THIS
DEFINITION OF NORMAL
>> WE WERE ABLE TO DISCERN THAT
CHILDREN HAD COMMUNITIES THAT
LOOKED YOUNGER THAT THAN YOU
WOULD EXPECT BASED ON THEIR
CHRONOLOGICAL AGE.
THIS CAN BE VIEWED AS MIKE CROW
BIOTA IN MATURITY.
AND CRITICALLY THIS IMMATURITY
WAS NOT REPAIRED WITH CURRENT
THERAPEUTIC FOODS.
THAT IS THE RESULT OF SEVERAL
HUMAN STUDIES DONE WITH OUR
COLLEAGUES.
BUT PERHAPS THIS IS NOT
SURPRISING BECAUSE CURRENT FOOD
BASED INTERVENTIONS FOR
CHILDHOOD UNDER NUTRITION HAVE
NOT BEEN DEVELOPED WITH
KNOWLEDGE OF OR CONSIDERATION OF
THE DEVELOPMENTAL BIOLOGY OF THE
MICROBIOTA.
THESE THEY WERE LEFT WITH AN
ABNORMALITY.
AND WE WONDERED WHETHER THERE IS
SOMETHING THAT WE COULD DO ABOUT
THIS BUT BEFORE WE PROCEEDED WE
LISTENED TO THE WORDS OF
DR. ARIAS AND TRIED TO CAPTURE
THIS CONCEPT OF CAN WE PERFORM A
TEST THAT DISTINGUISHES BETWEEN
EFFECT OR CAUSE.
THERE IS A STUDENT -- TOGETHER
WITH MARIA CARLSON AND DAVE
O'DONALD WHO ESTABLISHED OUR
FACILITY HERE AT WASHINGTON
UNIVERSITY IN 1996.
DID A SERIES OF MICROBIOTA
TRANSPLANT EXPERIMENTS.
A GROUP OF HEALTHY INDIVIDUALS
AND THOSE THAT HAD UNDER
NUTRITION AS DEFINED PROVIDED
FECAL SAMPLES.
THOSE SAMPLES WERE PRESERVED
IMMEDIATELY AFTER THEY WERE
PROVIDED AND THEY REPRESENTED A
SNAPSHOT OF THE MICROBIAL .
THEY WERE INTRODUCED INTO THE
INTESTINES OF YOUNG GERMFREE
ANIMALS.
SO BASICALLY SEVERAL ANIMALS
RECEIVED MICR MICRO BUY ON MIKE -- MICRO B IOTA AND
THE TEST CONSIST OF TAKING THE
SNAPSHOT AND REPLICATING THE
SNAPSHOT OF MICROBIAL LIFE AND
CONVERTING IT TO A MOVIE SO WE
COULD FOLLOW OVER TIME THE
EFFECTS OF THE COMMUNITIES ON
THE BIOLOGICAL PROPERTIES,
PHYSIOLOGY, METABOLISM AND
IMMUNE SYSTEM OF THE ANIMALS.
THE ANIMALS WERE GIVEN DIETS
THAT REPRESENTED THE DIETS OF
THE HUMAN DONOR.
IT WAS TYPICAL OF CHILDREN
LIVING IN THE SLUM.
SO WE COUL -- SO WE COULD ASK THE
QUESTION.
HOW MANY OF THE PHENOTYPES COULD
BE TRANSPLANT TO RECIPIENT
ANIMALS AND THE ANSWER WAS MANY.
SO USING QUANTITATIVE MAGNETIC
RESONANCE TO DEFINE BODY
COMPOSITION.
USING MICRO COMPUTED TOPOGRAPHY,
USING TARGETED MASS SPECTORMETRY
AND USING A VARIETY OF
APPROACHES INCLUDING FLOW TO
CHARACTERIZE IMMUNE FUNCTION.
IT WAS DETERMINED BY LAURA AND
IN THIS FIRST SET OF EXPERIMENTS
AND BY OF OTHERS IN THE
LABORATORY THAT MANY FEATURES OF
UNDER NUTRITION COULD BE
TRANSPLANT TO THESE ANIMALS.
LAURA TOOK ALL RECIPIENTS AND
APPLIED MACHINE LEARNING
ALGORITHMS TO IDENTIFY ORGANISMS
WHO REPRESENTATION WAS
SIGNIFICANTLY ASSOCIATED WITH
DIFFERENT FACETS OF GROWTH SO
SHE IDENTIFIED A SUBSET OF
GROWTH DISCRIMINATORY STRAINS
FROM THESE EXPERIMENTS AND THESE
STRAINS INCLUDED STRAINS THAT
WERE UNDER REPRESENTED AND UNDER
PERFORMING IN MATURE MICRO BIOTA
AND THEY BECAME OUR THERAPEUTIC
TARGETS AND WE WERE FUNDED BY
THE MELINDA AND BILL GATES
FOUNDATION.
USING THESE ANIMAL MODELS THAT
PORTRAYED THE MICROBES OF THE
VERY POPULATION THAT WE WANT TO
CHEETAHS WELL AS THEIR DIETS BUT
WE HAD TO DEVELOP AN
INTERVENTION THAT WAS CULTURALLY
ACCEPTABLE AND AFFORDABLE AND
SCALABLE.
SO WE SHALL NOT START BY
BASICALLY CREATING A NEXT
GENERATION CONSORTIUM OF AN A
AEROBIC CULTURED BACTERIA WHICH
WOULD BE DIFFICULT TO PRESERVE
IN A COLD CHAIN AND THERE IS NOT
A LOT OF TECHNOLOGY ABOUT HOW TO
DO SO AND THIS WOULD BE
EXTREMELY EXPENSIVE AS WELL AS
FACING A VARIETY OF REGULATORY
HURDLES THAT WOULD NOT BE FACED
IF WE WERE TO TURN TO FOOD AS A
PRINCIPLE AND FIRST CHOICE FOR
REPAIRING THE GUT MICROBIAL
COMMUNITIES OF THESE UNDER
NOURISHED CHILDREN.
SO A SECOND SERIES OF
HYPOTHESIS.
PERHAPS THE FOODS THAT ARE
CONSUMED BETWEEN THE PERIOD OF
EXCLUSIVE MILK CEASES AND THE
CHILD IS FULLY WEANED.
SOME OF THE FOODS MAY CONTAIN
KEY NUTRIENTS THAT ARE COVETED
BY THESE ORGANISMS.
THESE FOODS BY DEFINITION ARE
AVAILABLE AND CULTURALLY
ACCEPTABLE BECAUSE THEY ARE THE
FOODS THAT ARE GIVEN TO CHILDREN
IN THIS AREA OF THE WORLD BUT
THESE TYPES OF FOODS ALSO EMBODY
THE CHOICE THAT EVERY FAMILY
AROUND THE PLANET HAS TO MAKE.
WHAT FOODS SHOULD I SELECT TO
ENSURE THE HEALTHY GROWTH OF MY
INFANT OR CHILD?
SO IN APPROACHING THIS MINING
EXPEDITION WE'RE APPROACHING
THIS SET OF DECISIONS ABOUT HOW
TO FEED OUR INFANTS AND
CHILDREN.
DECISIONS THAT ARE CURRENTLY
BASED ON POLICIES THAT ARE NOT
PREDICATED ON KNOWLEDGE OR
CONSIDERATION OF THE
DEVELOPMENTAL BIOLOGY OF THE
MICROBIOTA.
THE APPROACH IN CONCERT WITH A
TALENTED POSTDOC A TALENTED
PhD STUDENT, MIKE BARRETT A
PERSON WHO OVERSAW OUR CLINICAL
WORK HERE IN THE LABS AT
WASHINGTON UNIVERSITY.
-- CONDUCTED A SCREEN FOR THESE
COMPLETE TREE FOOD INGREDIENTS.
* AND TO INCORPORATE THESE INTO
WHAT WE CALL PROTOTYPES THAT WE
WOULD TEST.
HERE IS OUR STRATEGY FOR
TESTING.
WE CULTURED ORGANISMS AND THE
FECAL MICROBIOTA AND THESE WERE
AGE AND GROWTH DISCRIMINATORY
ORGANISMS.
THEY WERE INTRODUCE INTO
GERMFREE MICE.
THEY WERE FED COMPLIMENTARY
FOODS AVAILABLE TO CHILDREN
LIVING THERE.
AND THESE FOODS WERE TESTED
INDIVIDUALLY AND IN VARIOUS
COMBINATIONS TO IDENTIFY THOSE
THAT WOULD INCREASE THE FITNESS
OF OUR TARGET -- ORGANISMS.
IF WE GOT A HIT WE WOULD
PRIORITIZE THE HIT BASED ON THE
SUSTAINABILITY, AFFORDABILITY
AND THE TASTE AND TEXTURE AND
SMELL.
-- NOW AFTER THIS SCREEN WAS
INITIATED AND THE LEADS WERE
IDENTIFIED DEEPER ANALYSIS OF
THE EFFECTS OF THE FORMULATIONS
ON GENE EXPRESSION AMONG MEMBERS
OF THE CONSORTIUM OF SEQUENCE
GENOME SEQUENCE BACTERIA WAS
AFFECTED.
AND THEN PROMISING LEADS WERE
ADVANCED TO A SECOND ROUND OF
ANALYSIS AND THIS INVOLVED NOT A
COLLECTION OF CULTURE SEQUENCE
BACTERIAL STRAINS FROM THE
CHILDREN BUT RATHER THE INTACT
UNCULTURED BACTERIA OF CHILDREN
WHO HAD BEEN TREATED WITHSTAND
THERAPY BUT WHOSE MICRO BIOTA
HAD NOT BEEN REPAIRED.
SO COULD THESE REPAIR THE MICRO
BIOTA THAT HAD BEEN INTRODUCED
INTO THESE ANIMALS AND FOR THOSE
COMBINATIONS THAT DID ADDITIONAL
STUDIES WERE PERFORMED ABOUT HOW
THE COMMUNITY RESPONDED AND HOW
THE HOST RESPONDED AND A
DECISION WAS MADE THAT I THINK
EMBODIES SOME OF THE CHALLENGES
IN THE FIELD.
DO YOU DIRECTLY GO FROM MICE
THAT EVEN THOUGH THEY PORTRAYAL
THE MICROBES DON'T HAVE THE
PROPERTIES THAT ARE AS CLOSE TO
HUMANS AS CERTAIN OTHER ANIMALS.
AND DO YOU CHOOSE A SECOND
ANIMAL SPECIES AND THAT IS
SOMETHING THAT WE DID.
WE DEVELOPED METHODS FOR
REDERIVING PIGS AT BIRTH AS
GERMFREE AND MAINTAINING THEM IN
A GERMFREE STATE AND INTRODUCED
THESE CONSORTIA OF ORGANISMS AND
LOOKED AT THE EFFECTS OF OUR
LEADING CANDIDATES.
SO THOSE CANDIDATES WERE THEN
ADVANCED TO OUR FIRST PREPROOF
OF CONCEPT STUDY.
IT INVOLVED CHILDREN AGE 12-18
MONTHS WITH WLZ SCORES OF MINUS
2 TO MINUS 3.
A SCORE ASSIGNED TO CHILDREN WHO
HAVE MODERATOR ACUTE
MALNUTRITION.
THESE CHILDREN IN THIS SMALL
STUDY OF 15 PER ARM RECEIVED ONE
OF FOUR DIFFERENT FOODS.
FOOD SUPPLEMENTS.
A READY TO USE SUPPLEMENTAL
FOOD, RICE AND LENTIL BASED.
AND THEN WE HAD THE VARIOUS
MBCF.
ONE, TWO, AND THREE.
THERE WAS A RUN IN PHASE FOR TWO
WEEKS IN WHICH DATA WAS
COLLECTED.
FECAL SAMPLES WERE OBTAINED AND
A BLOOD -- DRAW AT THE END OF
THE SECOND WEEK.
WE WANTED A MORE COMPREHENSIVE
DEFINITION.
AND WE COULD DO SO BECAUSE THERE
IS A TECHNOLOGY WHICH ALLOWED
MORE THAN 1300 DIFFERENT
PROTEINS WHICH ARE BOTH
BIOMARKERS AND MEDIATORS OF MANY
ASPECTS OF HOST BIOLOGY TO BE
QUANTIFIED.
THE INTERVENTION -- EXCUSE ME.
WE'RE ALMOST THERE.
WE'RE GOING BACK IN TIME.
THE INTERVENTION CONSIST OF TWO
FEEDINGS EACH DAY UNDER
SUPERVISION AND IN A UNIT
ESTABLISHED BY OUR COLLEAGUES
RIGHT IN THE MIDDLE OF THE URBAN
SLUM AND THE DEVOTION TO THE
MOTHERS OF THE CHILDREN IS
EMBODIED BY THE FACT THAT THEY
BROUGHT THE CHILDREN TWICE A DAY
FOR THESE INTERVENTIONS.
WHICH WERE PERFORMED UNDER
SUPERVISION.
THERE WAS A TWO WEEK FOLLOW-UP
PERIOD OF OBSERVATION AFTER THE
INTERVENTION AND THE OUTCOMES
WERE WHAT ARE THE EFFECTS.
WE DID NOT EXPECT GIVEN ONE
MONTH AND SMALL NUMBER OF
CHILDREN FOR US TO ACHIEVE A
STATISTICALLY SIGNIFICANT EFFECT
ON EITHER -- PONDERAL GROWTH OR
LINEAR GROWTH.
YOU CAN LOOK TO THE LOWER LEFT
AND SEE THE DIFFERENT
CONFIGURATIONS OF THE DIFFERENT
GROUPS.
AND THIS LOWER PORTION ARE
CHILDREN WITH SEVERE ACUTE
MALNUTRITION WHO ARE UNTREATED.
THEY ARE 12-18 MONTHS OF AGE.
HERE WE SEE FAR AWAY THE
CONFIGURATION OF 12-18-MONTH-OLD
HEALTHY CHILDREN.
THESE CONFIGURATIONS ARE DEFINED
BY THE REPRESENTATION OF THESE
15 ECO GROUP TAXA THAT HAD BEEN
IDENTIFIED AS CO-VARYING AND AS
A WAY OF DEFINING THE MICRO
BIOLOGY.
THE CHILDREN THAT ARE UNTREATED
ARE CLOSER TO HEALTHY THAN THOSE
WHO HAD -- THAT WERE UNTREATED
BUT OF ALL OF THE INTERVENTION
-- THAT AFTER ONE MONTH THEIR
EFFECTS ON THE CONFIGURATION
WERE SIGNIFICANTLY LESS
IMPRESSIVE THAN THE EFFECTS OF
MCDF2.
WHICH WAS THE BEST PERFORMING IN
THE MOUSE AND THE PIGLET.
NOT ONLY WAS THERE REPAIR BUT
ALSO A DRAMATIC EFFECT ON THE
PLASMA PROCEED YUM.
*.
YOU SEE A GROUP OF 50 PROTEINS
THAT WERE IDENTIFIED FROM THIS
-- ANALYSIS OF THE PLASMA --
PROCEED YUM OF HEALTHY CHILDREN
AND UNTREATED CHILDREN AS MOST
DISCRIMINATORY FOR A HEALTHY
STATE AND THE COLORS INDICATE
THE CHANGE IN THE LEVELS OF THE
PROTEIN AS A FUNCTION OF
DIFFERENT TREATMENT.
SO THE LEVELS, THE TREATMENT
EFFECTS IS NORMALIZED AND
MOVEMENT TOWARD RED INDICATES
MOVEMENT TOWARDS A MORE HEALTHY
LEVEL OF THIS PROTEIN.
M DCF 2 ASSUMING YOU'RE NOT RED
GREEN COLOR-BLIND IS ASSOCIATED
WITH THIS DRAMATIC CHANGE.
THAT HELTHATREPRESENT.
THEY ARE MEDIATORS OF BONE
GROWTH, METABOLISM, IMMUNE
FUNCTION AND NEURO DEVELOPMENT.
SO WITH THIS STUDY IN HAND A
SECOND PROOF OF CONCEPT STUDY
WAS PERFORMED WITH M DCF 2 AND
RUSF.
YOU CAN SEE THE COMPLIMENTARY
FOODS -- AND YOU CAN ALSO SEE
THAT THERE IS NUTRIENT
MICRONUTRIENTS IN BOTH THAT THE
PROTEIN ENERGY AND FAT ENERGY
RATIO AND THE AMOUNT OF CORE BOW
HYDRANTS ARE -- AND THE CALORIC
DENSITY IS 15% LESS.
SO AS IN THE * STUDY THE POC
STUDY WAS PERFORMED WHERE UNDER
SUPERVISION TWO SERVINGS
25 GRAMS EACH WAS GIVEN PER DAY.
NOW HERE IS THE DESIGN OF THE
STUDY.
A LONGER STUDY.
THREE MONTHS.
INITIALLY TWICE A DAY
ADMINISTRATION OF EITHER M DCF 2
OR RUSF.
AND THE THIRD MONTH TWICE A DAY
AT HOME UNDER SUPERVISION.
12-18-MONTH-OLD CHILDREN WITH
MODERATE ACUTE MALNUTRITION.
THE OUTCOME MEASURES IS A CHANGE
IN WLZ AND A SECOND OUTCOME
MEASURE IS THE REPAIR OF THE
MICRO BIOTA AND ALTERATIONS IN
THE PLASMA -- AND WE'LL PRESENT
THE RESULTS IN THE NEXT SLIDE.
ROBERT CHEN ANALYZED THE
RESULTS.
AND YOU CAN SEE THAT M DCF 2
PRODUCED A SIGNIFICANTLY GREATER
RATE IN CHANGE IN WLZ SCORE.
A GREAT RATE OF PONDERAL GROWTH.
SO WE NOW SHOULD THINK ABOUT
THERAPEUTIC FOODS NOT JUST BASED
ON THEIR CALORIC CONSENT.
WE DID AN ANALYSIS, ROBERT CHEN
DID AN ANALYSIS WHERE HE TOOK
THE DATASET FROM ALL
PARTICIPANTS IN BOTH ARMS.
AND THEN CORRELATED CHANGES IN
WLZ WITH A CHANGE IN EACH OF
5,000 DIFFERENT PLASMA PRO TEAMS
WHOSE LEVELS WERE MEASURED PRIOR
TO AND AT THE CONCLUSION OF THE
INTERVENTION.
SO SHOWN HERE IN THE LOWER LEFT
IS AN EXAMPLE OF THE TYPES OF
TESTS OF CORRELATION BETWEEN THE
RATE OF CHANGE IN WLZ OVER TIME.
AND THE RATE OF CHANGE OF A
PARTICULAR PROTEIN IGF1 AND
THOSE PLOTS ARE SHOWN AS DOTS
AND FROM THIS ANALYSIS A GROUP
OF 70WLZ CORRELATED PROTEINS
WERE IDENTIFIED.
THEY ARE INVOLVED IN MANY
ASPECTS OF POSTNATAL GROWTH,
MUSCULAR SKELETAL DEVELOPMENT
AND CNS DEVELOPMENT.
WE'RE LOOKING AT ON THE Y AXIS
THE FULL CHANGE OF EACH OF THESE
70 PROTEINS PRODUCED BY MCDF2
COMPARED TO RUSF.
SO NOW WE HAVE A GROUP OF 70
PROTEINS THAT ARE IMPACTED MORE
BY M DCF 2 THAN BY RUSF.
SIMILARLY MATT HIBBERD LOOKED TO
THE MICRO BIOTA TO IDENTIFY TAXA
AND TO DETERMINE IF IT WAS MORE
IMPACTED.
AGAIN FOR EACH INDIVIDUAL TAKING
THE DATA ABOUT THE CHANGE IN WLZ
OVER TIME AND CORRELATE WITH THE
CHANGE IN ABUNDANCE OF 700 --
USING THESE MODELS.
AND THOSE RESULTS SHOWN HERE
DISCLOSED 23 DIFFERENT TAXA
DEFINED AS STATISTICALLY
SIGNIFICANT IN TERMS OF THEIR
ASSOCIATIONS WITH WLZ.
AND 21 OF THEM ARE POSSIBLY
CORRELATED.
TWO ARE NEGATIVELY CORRELATED.
THIS ANALYSIS SHOWN IN THE LOWER
PORTION LOWER HALF OF THE SLIDE
DESCRIBES A COEFFICIENT BETA 1
FROM THESE LINEAR MIXED MODELS
THAT REPRESENTS THE CHANGE IN WL
WLZ.
THE TAXA ARE DESCRIBED BY
AMPLIFIED SEQUENCE VARIANTS.
AND YOU CAN SEE -- IT HAS
GREATEST IMPACT ON WLZ FOR UNIT
CHANGE IN IT'S BURNED ANNES BUT
THERE ARE A * --
[ INDISCERNIBLE ]
BUT GOING BACK TO THE ORIGINAL
QUESTION.
IT HAS A SIGNIFICANTLY GREATER
EFFECT PRODUCES SIGNIFICANTLY
INCREASED AMOUNTS OF THESE
POSSIBLY CORRELATED TAXA THAN
DOES RUSF AND HAS THE GREATEST
EFFECT ON REDUCING THE ABUNDANCE
OF THE PRINCIPLE NEGATIVELY
CORRELATED.
SO THIS TYPE OF ANALYSIS STARTS
TO CONNECT THE DOTS.
OUR CHANGES IN PONDERAL GROWTH
RELATED TO CHANGES IN AFFECTERS
OF DIFFERENT ASPECTS OF GROWTH
AS WELL AS CHANGES IN THE
REPRESENTATION OF DIFFERENT
COMPONENTS OF THE MICRO BIOTA.
THE NEXT TASK OF COURSE IS TO
GET DEEPER INTO THE MYSTERIES OF
THE MICRO BIOTA AND TO
UNDERSTAND HOW THESE DIFFERENT
-- CHANGED THEIR PATTERNS OF
GENE EXPRESSION SO HOW TO
EXPRESS GENOMIC FEATURES
CORRELATE WITH GROWTH RESPONSES?
THAT QUESTION AND THE ANSWERS
ARE CRITICAL FOR MORE DETAILED
MECHANISTIC INSIGHTS ABOUT HOW
MCDF2 AND OTHER INTERVENTIONS
WOULD BE AFFECTING THE HOST
GROWTH.
KEY FOR DEVELOPING MCDF AS WELL
AS THE DISCOVERY AND USE OF --
COMBINATIONS OF PRO-BIOTICS.
SO THE TASK ARE TO RECONSTRUCT
THE GENOMES OF ASSOCIATED
STRAINS PRESENT IN THE FECAL
SAMPLES.
IDENTIFY FUNCTION, FEATURES
ENRICHED IN THESE ASSEMBLED
GENOMES.
AND THEN TO DETERMINE WHICH
BACTERIAL PATHWAYS ARE IN THESE
WLZ CORRELATED MAGS.
AND TO CORRELATE THESE GENE
EXPRESSION DATA WITH RUTS OF
ANALYSIS OF THE COMPOSITION AND
THE METABOLISM.
SO IDENTIFYING THE BACTERIAL WLZ
CORRELATED STRAINS ARE IMPORTANT
TASKS AHEAD.
THOSE TYPES OF QUESTIONS THOSE
TYPES OF APPROACHES THE SEARCH
FOR BAGS.
AND THE USE AND TO GO BEYOND THE
DNA BASED DESCRIPTION OF THE
RESPONSE.
ALSO OPENED A DOOR FOR A NEXT
LEVEL OF MCDF DISCOVERY.
AND LYNN IS PERFORMING THESE
SORTS OF ANALYSIS WHERE
DIFFERENT FOODS CONSUMED BY
POPULATIONS IN DIFFERENT PARTS
OF THE WORLD ARE SCREENED FOR
THEIR EFFECTS ON MICROBIAL
POPULATIONS WHERE THESE ARE
CULTURALLY ACCEPTABLE AND HAVE
SATISFACTORY PROPERTIES AND COME
FROM SUSTAINABLE SOURCES.
THIS IS A REVERSE TRANSLATION
EXPERIMENT WHERE COMMUNITIES
CAPTURED PRIOR TO DURING OR
AFTER ONE OF THESE POC TRIALS
CAN BE REENROLLED IN THE TRIAL
IN THE FORM OF THEIR
TRANSPLANTATION AND THE TRIAL
CONDITIONS -- APPLY TO THE
ANIMALS SO THAT WE CAN TAKE A
MUCH DEEPER MORE REFINED VIEW OF
THE SIGNALING PATHWAYS THAT
CONNECT FOOD, FOOD METABOLISM
AND THE RESPONSE OF DIFFERENT
CELL LINEAGES AND DIFFERENT
ORGANS OF THE ANIMAL.
SO LET ME CONCLUDE.
WHAT ARE THE IMPLICATIONS?
I HOPE I PRESENTED SOME
INFORMATION THAT MIGHT PERSUADE
YOU TO THINK THAT HEALTHY GROWTH
MIGHT BE LINKED TO HEALTHY
GROWTH OF THE GUT.
ONE THAT INCLUDES A
CONSIDERATION OF THE ORGANISMS
IN GUT COMMUNITY.
THE MICRO BIOTA AND THE VAST
REPERTOIRE OF GENES.
THE MICROBIOME.
A POSSIBILITY OF A BETTER
DEFINITION OF WELLNESS FOR
INFANTS AND CHILDREN.
WE HAVE AT LEAST A TWO-YEAR
WINDOW IN POSTNATAL DEVELOPMENT
TO INTERVENE IF THERE IS
ALTERATION IN THE DEVELOPMENTAL
PROGRAM OF THIS MICROBIAL
COMMUNITY.
THE IMPLICATIONS ALSO OF HOW TO
FEED OUR INFANTS AND CHILDREN.
WHAT KIND OF COMPLIMENTARY FOODS
INFORMED BY KNOWLEDGE OF GUT
COMMUNITY DEVELOPMENT SO WE CAN
BE MUCH MORE EFFECTIVE STEWARDS.
AND THE NEED TO DETERMINE THE
EFFECTS OF INTERVENTIONS AT
DIFFERENT AGES, EARLIER.
THE DURATION OF THE
INTERVENTION.
THE DURABILITY OF THE EFFECTS OF
THE INTERVENTION ONCE IT IS
STOPPED.
SO GENERALIZABILITY, DURABILITY
AND SAFETY.
ALTERING HUMAN BIOLOGY BY TRYING
TO -- HAVE CATCH UP GROWTH AND
THIS IS SOMETHING THAT WE'RE
PURSUING AT SEVERAL DIFFERENT
SITES AROUND THE WORLD WHERE THE
BURDEN OF UNDER NUTRITION IS
GREAT SO I THANK YOU FOR YOUR
ATTENTION.
>> THANK YOU VERY MUCH JEFF FOR
THIS REALLY VERY EXCITING
PRESENTATION.
AND ILLUSTRATING VERY POWERFULLY
HOW THE PROBLEMS OF FINDING
CAUSE AND EFFECT BETWEEN A
CLINICAL PHENOMENA IN THIS CASE
MALNUTRITION AND THE MICROBIOME
IS A VERY DIFFICULT CHALLENGING
PROBLEM.
AND IS REALLY WHERE THE ACTION
IS AT AND IT'S VERY I THINK
AMAZING TO READ OF YOUR STUDIES
AND HEAR OF THEM.
AND REALIZE THAT IT'S MUCH MORE
COMPLICATED THAN JUST PRESENTING
A PATTERN OF DISTRIBUTION OF THE
MICROBIOME IN A GIVEN POPULATION
GROUP OR A GIVEN DISEASE GROUP
AND COMPARING IT.
THE MECHANICS, THE MECHANISMS
ARE CHALLENGING.
NOW WE'LL TURN TO TIM GRETEN AND
TIM, WOULD YOU PLEASE PROCEED.
>> THIS IS GOING TO BE VERY,
VERY DIFFICULT AFTER THIS
PRESENTATION.
BUT I WILL TRY MY BEST AND WE
ARE CHANGING GEARS QUITE
SIGNIFICANTLY.
WE'RE GOING TO TALK ABOUT HOW
THE GUT MICROBIOME CONTROLS
GROWTH OF LIVER TUMORS.
THESE ARE JUST A
DISCLOSURE.
I WANT TO SHOW YOU SOME CLINICAL
DATA IN THE BEGINNING HOW WE GOT
INVOLVED IN THIS.
SO AS A GENERAL INTRODUCTION YOU
HEARD ALREADY THE QUESTION IS
HOW DOES THE HUMAN CELLS AND THE
HUMAN GENOME INTERACT WITH THE
MICROBIAL CELLS AND GENES.
NOW WHAT WE'RE SPECIFICALLY
STUDYING HERE IS THE MICROBIOME
AND HUMAN CANCER.
AND THERE ARE CERTAIN ASPECTS.
WE KNOW THAT WE CAN USE THIS
ACTUALLY FOR DIAGNOSIS.
WE CAN IDENTIFY DNA IN BLOOD.
WE CAN USE AS A PROGNOSTIC
MARKER.
THERE ARE DIFFERENT WAYS HOW WE
CAN UTILIZE MICRO BIOTA
THERAPEUTICALLY.
AND HOW WE CAN USE THE
MICROBIOME TO UNDERSTAND
METASTASIS.
NOW WHAT I'M GOING TO TALK ABOUT
IS NOT CANCER IN GENERAL BUT I
WOULD LIKE TO FOCUS ON LIVER
TUMORS AND LIVER TUMORS CAN BE
DIVIDED INTO MAJORITY OF TUMORS
ARE LIVER METASTASISES AND
PRIMARY LIVER CANCER.
THE NUMBER ONE IS HELP WELL
EULAR AND CHOLANGIOCARCINOMA.
-- NOW WHY IS THERE THIS
INTEREST IN THE GUT MICROBIOME
AND THE LIVER?
THAT IS SIMPLE.
IT'S JUST ANATOMY.
YOU KNOW THAT THE MAJORITY OF
THE BLOOD THAT GOES INTO THE
LIVER AND FEEDS THE LIVER WITH
BLOOD SUPPLY IS ACTUALLY DRAINED
FRAT LARGE AND SMALL INTESTINE.
THAT DRAINS IN THE VEIN AND THEN
GOES INTO THE LIVER.
EVERYTHING THAT IS IN THE GUT
CAN POTENTIALLY MIGRATE HERE AND
BE DRAINED THROUGH THE DIFFERENT
BRANCHES INTO THE LIVER.
NOW LET ME GIVE YOU BECAUSE I
WANT TO TELL YOU A LITTLE BIT
ABOUT A SMALL CASE ABOUT BILL
ARI CANCER.
-- *.
THERE ARE LIMITED TREATMENT
OPTIONS.
AND WE DID A STUDY AND I'M NOT
GOING TO GO INTO THE DETAILS.
I WANT TO SHOW YOU WHAT DRIVES
OUR RESEARCH.
WE USED TREATMENT FOR PATIENTS
WITH DIFFERENT TYPES OF LIVER
CANCER.
WE TREATED THEM WITH INHIBITORS
THAT ACTIVATE THE IMMUNE
RESPONSE.
YOU CAN SEE THAT THE TREATMENT
WAS NOT EFFECTIVE.
THE MAJORITY OF PATIENTS WERE
ONLY TREATED FOR A SHORT PERIOD
OF TIME.
TUMORS GREW BUT THERE IS THIS
ONE OUTLIER.
YOU CAN SEE THIS PATIENTLY
SHOWED A CLEAR REDUCTION IN
TUMOR AND IT'S LONG LASTING.
SO IF YOU LOOK AT THIS
PARTICULAR CASE YOU CAN SEE HERE
NOW THE CLINICAL COURSE OF THE
PATIENT.
SO WE STARTED THE TREATMENT IN
2016 AND I CAN TELL YOU WE'VE
SEEN THIS PATIENT A COUPLE OF
WEEKS IN THE CLINIC AND SHE IS
STILL TUMOR FREE AND SHE WAS
TREATED WITH THE SAME TREATMENT
WITH THE REST OF THE POPULATION
THAT WE HAVE IN THIS TRIAL.
BUT SOMEHOW SOMETHING MUST HAD
BEEN VERY DIFFERENT.
THE PATIENT DEVELOPED AN
ABSCESS.
AND WE TREATED THE PATIENT WITH
ANTIBIOTICS.
THE PATIENT DEVELOPED COLITIS
AND WE PERFORMED A LOT OF
STUDIES.
WE LOOKED AT GENETIC -- AND WE
WERE NEVER SURE WHY THIS PATIENT
RESPONDED IN SUCH AN OUTLIER AND
I STILL DON'T KNOW THIS.
SO WHAT I WANT TO TELL YOU IS
IMMUNO THERAPY MAY ACTUALLY WORK
IN LIVER CANCERS.
BUT THERE ARE SO MANY UNANSWERED
QUESTIONS AND IN OUR INTEREST
HERE IS TO STUDY THE IMMUNE
MICRO ENVIRONMENT OF THE LEVE LIVER
AND HOW THE GUT MICROBIOME CAN
CHANGE THIS AND HOW IT DOES IT
IN THE CONTEXT AND EFFECT IMMUNE
RESPONSES.
HOW DO WE DO THIS?
WE BASICALLY TOOK USE OF A VERY
SIMPLE MODEL.
WHERE WE CAN USE TUMORS IN THE
LIVERS OF THE MICE AND THEY
DEVELOP TUMORS OVER A PERIOD OF
TIME AND THEN A NUMBER OF YEARS
AGO THIS WAS ONE OF THE FIRST
STUDIES -- WHERE ANTIBIOTIC WAS
ADDED TO THEIR DRINKING WATER.
THEY DEVELOPED WAY FEWER TUMORS.
I TREAT A LOT OF PATIENTS WITH
CANCER.
THIS WAS VERY HARD FOR ME TO
BELIEVE THAT JUST ANTIBIOTIC
TREATMENT WOULD ACTUALLY REDUCE
TUMOR NOODLES.
WE REPEATED THIS EXPERIMENT AND
USED OTHER MICE MODELS.
THE RESULT WAS ALWAYS THE SAME.
SO WE DID WHAT WE USUALLY DO
WHEN WE GO INTO IMMUNO THERAPY
STUDIES.
WE LOOKED AT DIFFERENT IMMUNE
CELLS.
THERE IS ONE CELL POPULATION
WHERE WE NOTICED AN INCREASE IN
MICE THAT WERE TREATED WITH THE
ANTIBIOTICS AND WE OBSERVED THIS
ACCUMULATION OF MKT CELLS.
SO THEY SHARE THE PROPERTIES OF
T CELLS.
THEY REPS CD1 MOLECULE.
IT ACTUALLY RECOGNIZES FOREIGN
LIPIDS.
IT'S A RATHER ABUNDANT IN THE
MOUSE LIVER.
IT EXPRESSES CXCR6. WE LOOKED
IN MORE DETAIL.
AND ANALYSIS WAS PERFORMED.
WE CAN IDENTIFY THEM AND IF WE
LOOK IN THE LIVER OF THE MICE WE
FIND MORE CXC6 POSITIVE CELLS.
THE IMPORTANT THING IS TO REALLY
LOOK AND REMEMBER THE LIVER
ANATOMY WITH THE PORTER VEIN
DRAINING THE BLOOD FROM THE GUT
BUT WHERE DOES THE BLOOD GO?
ONCE IT GOES INTO THE LIVER --
IT GOES INTO THE -- CENTRAL
VEIN.
THIS IS A MAGAZIN A -- MAGNIFICATION.
THEY ARE SO-CALLED LIVER SINUS
OIDAL AND ENDOTHELIAL CELLS.
HOW CAN THE GUT MICROBIOME
AFFECT MKT CELLS?
MKT CELLS EXPRESS CXC6.
AND IT TURNS OUT THAT INDEED --
MICE TREATED WITH ANTIBIOTICS
WERE THE MICE THAT HAD MORE NKT
CELLS AND FEWER TUMORS EXPRESSED
MORE CXCL16.
WE CONFIRMED THIS.
BASICALLY USING ANTIBIOTICS TO
DEPLETE THE MICROBIOME.
WE USED DIFFERENT MIKE -- MIKE
ANTIBIOTICS.
*
I DIDN'T SHOW YOU ALL OF THE
DETAILS.
THERE WERE MORE DETAILED STUDIES
STUDIES.
AND THE QUESTION IS AND REMAINS
HOW CAN THE GUT MICROBIOME
CONTROL -- EXPRESSION IN THE
LIVERMORE SPECIFICALLY IN THE
LIVER SINUS OUT AND ENDOTHELIAL
CELLS.
IT TURNED OUT THAT THE BILE
METABOLISM PLAYS A SIGNIFICANT
ROLE.
SO ONE OF THE -- IMPORTANT
FUNCTIONS OF THE LIVER IS TO
PRODUCE BIOSALTS WHICH ARE
RELEASED THROUGH THE COMMON DIAL
DUCT AND THE IMPORTANT THING TO
REMEMBER IS 95% ARE ACTUALLY
REABSORBED BY THE SMALL
INTESTINE AND GO BACK THROUGH
THE PORTER VEIN INTO THE LIVER.
NOW THE SECOND PART IS THAT THE
BIOSALTS ARE ACTUALLY
METABOLIZED BY BACTERIA.
CONGREGATED -- ARE RELEASED.
-- THEY ARE METABOLIZED BY A
SPECIFIC STEP.
AND THIS IS DONE BY CO BACTERIA.
THAT IS RESPONSIBLE FOR THIS
STEP OF METABOLIZING BILE ACIDS
TO SECONDARY BILE AS I -- BILE ACIDS.
WE LOOKED IN THE LIVER AND THE
SECONDARY BILE ACIDS AND THERE
IS AN INCREASE OF PRIMARY BILE
ACIDS AND REDUCTION OF SECONDARY
BILE ACIDS.
SO WE TREATED MICE WITH BILE
ACIDS AND ASKED CAN WE USE BILE
ACIDS TO CONTROL TUMOR GROWTH?
YOU CAN SEE THE RESULT OF THIS
EXPERIMENT
THIS IS OUR CONTROL.
MOUSE TREATED WITH ANTIBIOTIC
HAS FEWER TUMORS AND THEN IF WE
BRING BACK THE SECONDARY BILE
ACIDS WE CAN BASICALLY RESCUE
THIS -- OR MICE WOULD DEVELOP
MORE TUMORS.
YOU CAN SEE THE CUMULATIVE DATA.
NOW THIS IS INTERESTING BUT THIS
ONLY TELLS YOU THAT BILE ACIDS
CAN CONTROL TUMOR GROWTH.
WHAT YOU'RE INTERESTED IN IS THE
BACTERIA.
A NUMBER HAVE STUDIES I'M GOING
TO SHOW YOU A FEW OF THEM WHERE
WE ACTUALLY LOOKED NOW AT THE
SPECIFIC BACTERIA IN THE MICE
AND I TOLD YOU THERE IS A
SPECIES -- THAT WAS KNOWN TO BE
ABLE TO METABOLIZE BILE ACIDS SO
WE SET UP A MODEL WHERE WE CAN
NOW TREAT MICE FIRST WITH
ANTIBIOTICS.
AND THEN BRING BACK THE
CLOSTRIDIUM IN AND LOOK AT NKT
CELLS AND YOU CAN SEE THEY
BASICALLY START TO METABOLIZE.
NOW THIS IS AGAIN INTERESTING.
WE CAN NOW SHOW THAT THESE
BACTERIA CAN CONTROL THE NUMBER
OF NKT CELLS IN THE LIVER BUT IT
DOES NOT ADDRESS IS IF BACTERIA
CAN CONTROL TUMOR GROWTH AND
THAT IS NOW SHOWN HERE.
YOU ALREADY KNOW THE MODEL SO WE
HAVE MICE.
WE TREAT THEM WITH ANTIBIOTICS.
WE CHALLENGE THEM WITH A TUMOR
THAT GROWS IN THE LIVER AND THEN
WE BRING BACK THE -- INTO THE
MICE AND LOOK FOR TUMOR GROWTH
AND YOU CAN SEE ANTIBIOTIC
TREATMENT LEADS TO FEWER TUMORS
BUT IF WE ACTUALLY INFECT THE
MUSIC SEE A HIGHER NUMBER OF
METASTASIS OR TUMORS AND WHAT I
DON'T SHOW YOU -- THIS IS ALSO
TO A CHANGE IN THE NKT CELLS.
THE NUMBER GOES DOWN AS WELL AS
THE METABOLISM.
SO I THINK HERE THIS IS
CLASSICAL AND ONE OF THE FIRST
EXAMPLES WHERE WE NOW CAN
ACTUALLY IN POINT AT LEAST IN A
MODEL SYSTEM IN MICE CHANGES TO
A SPECIFIC IMMUNE FUNCTION BY
COMMENSURATE BACTERIA.
WE KNOW UNDER NORMAL CONDITIONS
THEY ARE RELEASED AND THEN WE
HAVE THE -- IN THE FECAL POOL
AND WHAT TYPE DO WE HAVE?
ARE THEY ABLE TO METABOLIZE
PRIMARY ISOLATES INTO SECONDARY
BILE ACIDS AND IF NOT THIS
BALANCE ACTUALLY CAN CONTROL THE
RELEASE OF -- -- IN THE LIVER.
THESE BILING BILE ACIDS GO INTO THE
LIVER WHICH LEADS TO THE
ACCUMULATION OF CXCR6 POSITIVE
NKT CELLS AND THESE NKT CELLS
CAN CONTROL TUMOR GROWTH.
THIS IS AN IDEAL MOUSE MODEL
WHERE WE CAN STUDY THIS AND THE
QUESTION OBVIOUSLY NOW IS DOES
THIS APPLY TO HUMAN AND PATIENTS
WITH LIVER TUMORS.
WE DON'T KNOW YET.
WE'RE GOING TO STUDY THIS.
WE KNOW FROM LARGE PATIENT
COHORTS THAT THERE APPEARS TO BE
A CORRELATION BETWEEN THE BILE
ACIDS CONCENTRATION PRIMARY TO
SECONDARY -- AND THE EXPRESSION
OF THE CXCL16.
AND A STUDY HAS SHOWN THAT THE
SAME ANTIBIOTICS THAT WE USE IN
OUR MOUSE MODEL CAN ACTUALLY
ALSO CHANGE THE BILE ACID
COMPOSITION IN BLOOD FROM
PATIENTS THAT WERE ENROLLED IN A
SMALL CLINICAL TRIAL.
SO THERE IS CERTAINLY SOME DATA
SUGGESTING THAT THIS MECHANISM
MAY ALSO APPLY TO HUMAN.
SO WE'RE TESTING IT WHERE WE
TREAT PATIENTS TO TARGET THE
SPECIFIC -- SPECIES AND
HOPEFULLY IN A YEAR OR SO I WILL
BE ABLE TO SHOW YOU THIS DATA.
NOW I WOULD LIKE TO CHANGE GEARS
AGAIN AND GO AND TELL YOU ABOUT
BAILY CANCER.
A SECOND MECHANISM HOW GUT
BACTERIA CAN CONTROL BILIARY
CANCER.
IT IS RELATIVELY RARE.
PRIMARY CANCER OF THE LIVER --
BUT IT IS SOMEWHAT INTERESTING
BECAUSE THERE ARE CERTAIN RISK
FACTORS INCLUDING A DISEASE
WHICH IS CALLED PRIMARY -- AND
INFLAMMATORY BOWEL DISEASE WHICH
IS ASSOCIATED WITH BILIARY
CANCER.
NOW IT HAD ALREADY BEEN SHOWN
THAT THERE IS WHAT WE CALL
INTESTINAL -- IN PATIENTS.
YOU CAN SEE ON THIS ANALYSIS THE
HEALTHY CONTROLS AND THEN HERE
PATIENTS WITH PSC -- AND HERE
YOU CAN SEE THE MORE DETAILED
DESCRIPTION OF THE BACTERIA IN
THESE INDIVIDUALS.
THE IMPORTANT THING TO REMEMBER
IS THAT APPARENTLY A DISEASE IN
THE LIVER CAN CAUSE DISBIOS US
AND CHANGES IN THE COMPOSITION
OF THE GUT BACTERIA.
WE USED TWO DIFFERENT MODELS.
AND THE WAY WE DO THIS AND WAY
WE USE THIS IS BY A TECHNIQUE --
SO WE CAN ACTUALLY INJECT PLASMA
OF INTEREST INTO THE MICE AND
BECAUSE WE USE A RELATIVELY
LARGE AMOUNT OF VOLUME THAT WE
INJECT IN A SHORT AMOUNT OF TIME
WE CAN GET EFFICIENCY IN THE
LIVER AND THESE MICE WILL
EXPRESS THE GENE OF INTEREST.
WE COMBINE THESE MODELS WITH
DIFFERENT PSC MODELS WHICH ONE
IS A GENETIC MODEL.
KNOCKOUT MODEL.
YOU CAN SEE HOW THE MICE DEVELOP
THE INFLAMMATION AND SCARS
AROUND THE BILE DUCTS AND THE
MODEL ON THE RIGHT IS WHERE WE
CONDUCT BILE -- IN THESE MICE.
SO IF WE INDUCE PSC IN THESE
MICE AND YOU CAN SEE HERE THE
RESULT WHERE WE INDUCE THE PSC
AND THE SAME APPLIES WITH MICE
-- THE KNOCKOUT MICE.
IT WAS INTERESTING TO SEE IF WE
LOOK AT THE -- THERE ARE CLEAR
SIGNS OF COLITIS.
YOU DON'T HAVE THE NICE
STRUCTURE AND THE MICE AFTER
BILE DUCT LOCATION AND IF YOU
LOOK AT PROTEINS IN THIS CASE --
YOU CAN SEE THAT THEY ARE
REDUCED IN MICE THAT HAVE
UNDERGONE BILE .
WE LOOKED AT THE NUMBER OF --
[ INDISCERNIBLE ]
WE LOOKED AT THE PORTER VEIN OF
THESE MICE AND WE CAN IDENTIFY
16SRNA.
WHICH A FUNCTIONAL EXAMPLE
PEOPLE--EXPERIMENT.
AND THEN WE CAN FIND THIS AND
YOU CAN SEE AN INCREASED UP TAKE
IN MICE AS A READ OUT FOR LEAKY
GUT AND COLITIS.
AND IF WE LOOK AT PATIENT
SAMPLES WE CAN FIND SIGNS OF A
BACTERIA IN LPS.
NOW IF YOU FYWE LOOK AT THE --
MICE IN WHICH WE INDUCE PSC WE
NOTICE AN ACCUMULATION OF
MYELOID OR DEpReS OR CELLS.
WHICH WE HAVE STUDIED * AND THEY
ARE VERY IMPORTANT IMMUNE
SUPPRESSORS.
YOU CAN SEE AN INCREASE OF THIS
CELL IN MICE WITH PSC.
WE CAN FURTHER SUBDIVIDE AND I'M
NOT GOING TO GO INTO THE DETAILS
-- ---THIS DOESN'T ONLY APPLY TO
ONE MODEL BUT WE CAN FIND THIS
IN THE SECOND MODEL.
NOW IF WE TREAT THESE MILES
SPECIFICALLY WITH NEOMYCIN YOU
CAN SEE THE ACCUMULATION -- THE
CELLS ARE NO LONGER PRESENT AND
IF WE PERFORM FMT STUDIES.
STUDIES WHERE WE TAKE REGULAR
MICE KEPT UNDER SPF CONDITIONS
AND WE TREAT THEM -- TO TARGET
GRAM POSITIVE OR GRAM NEGATIVE
BACTERIA.
HARVEST STOOL SAMPLES AND THEN
TRANSFER THESE INTO GERMFREE
MUSIC SEE THIS HAS A SIGNIFICANT
IMPACT ON THE NUMBER OF CELLS
AND YOU CAN SEE ON THE LOWER
RIGHT CORNER IF WE TREAT THESE
MICE WITH STOOL -- THERE IS A
SIGNIFICANT INCREASE.
DOES THIS ALSO LEAD TO AN
ACCUMULATION AS SHOWN ON THIS
SLIDE.
THE WHOLE MECHANISM -- ---
---APPEARS TO BE DEPENDENT ON
AGAIN A MECHANISM OR TLR4 AND
CXCL1.
MICE TREATED WITH -- TO INDUCE
COLITIS HAVE INCREASED NUMBERS.
WE CAN CLOCK OR OVER EXPRESS IT
AND THIS IS DEPENDENT ON
EXPRESSION OF TLR4.
YOU CAN SEE IN MICE WHERE THE
RECEPTOR IS KNOCKED OUT AND WE
DON'T FIND THESE CELLS.
SO WHAT I'VE SHOWN YOU IN THE
CONTEXT OF LIVER -- MICE THAT
DEVELOP A LEAKY GUT.
IT PLAYS A SIGNIFICANT ROLE.
AND THIS MECHANISM APPEARS TO BE
DEPENDENT TO GRAM NEGATIVE
BACTERIA.
NOW I HAVE NOT SHOWN YOU
ANYTHING ABOUT TUMORS AT THIS
POINT.
THIS IS ONLY LIVER CIRRHOSIS.
LEAKY GUT.
SO WHAT I WOULD LIKE TO SHOW YOU
NOW IS IF WE COMBINE THE MODELS
WHERE WE INDUCE TUMORS BY
INJECTION OF -- AND IN THIS CASE
-- WE SEE THAT THESE MICE
DEVELOP MORE AND LARGER TUMORS.
THE SAME APPLIES TO A SECOND
MODEL WHERE WE USE MDR2.
OR IF WE INDUCE COLITIS.
BUT ANYTHING THAT I'VE SHOWN YOU
SO FAR THAT LOCALS CONTROLS THE
MDSCS IT CONTROLS TUMORS.
IF WE OVER EXPRESS IN THE LIST
WE FIND MORE TUMORS.
WE CAN CONTROL AGAIN TUMOR
GROWTH IN THE MICE DEPENDENT ON
WHETHER WE COLONIZE MICE WITH
STOOL FROM THE INITIAL MICE
TREATED WITH NEO MICE SIN.
AND THE * THE MECHANISM IS
DEPENDENT ON THE RECEPTOR.
YOU CAN SEE THE BACTERIA OR THE
LPS DERIVED FROM A THE MICE WITH
COLITIS GO INTO THE LIVER AND
THEY DO NOT EXPRESS THE
RECEPTOR.
WE HAVE FEWER TUMORS AND WE CAN
OVERCOME THIS AGAIN BY OVER
EXPRESSION.
THERE IS SHOWN HERE UNDER NORMAL
CONDITIONS.
A NORMA NORM --
THIS WOULD BASICALLY CHANGE BILE
ACIDS AND CAUSE OTHER CHANGES
THAT WILL LEAD TO DISPIES ON US
AND A CHANGE * IN THE
COMPOSITION.
AND THEN WHAT I'VE SHOWN YOU
HERE THAT THROUGH A TLR4 -- THEY
EXPRESS CXCL1.
SO I BELIEVE I'VE SHOWN YOU HERE
TWO DIFFERENT MODELS HOW THE
MICROBIOME CAN CONTRIBUTOR
CHANGE THE TUMOR MICRO
ENVIRONMENT.
I'VE SHOWN YOU HOW THE LEAKY GUT
CAN LEAD TO AN ACCUMULATION OF
-- ---WHICH CAN CAUSE
INFLAMMATION BUT THERE IS OTHER
MECHANISMS THAT I DIDN'T SHOW
YOU OUT OF TIME BECAUSE I WANTED
TO SPECIFICALLY FOCUS ON IMMUNE
RESPONSES.
WE KNOW THERE ARE ALSO EFFECTS
THAT ARE MEDIATED BY STELATE
CELLS.
WE KNOW THAT THE -- THAT ARE
AFFECTED IN THE SYSTEM CAN ALSO
HAVE DIRECT EFFECT ON
HEPATOCYTES.
WHICH HAVE BEEN DESCRIBED TO
CONTROLLED TUMOR GROWTH.
SO WHAT I WOULD LIKE TO
SUMMARIZE AND LEAVE YOU WITH IS
THERE ARE MICRO BIOTA DEPENDENT
OF REGULATION OF CANCER
DEVELOPMENT AND PROGRESSION AND
TREATMENT.
IN THIS TALK I TOLD YOU ABOUT
THE MICRO BIOTA IN THE GUT AND
HOW THEY TALK TO THE LIVER.
WE KNOW THAT THESE MICRO BIOTA
CAN BE CHANGED TO A DIFFERENT
MECHANISM AS YOU HEARD IN THE
FIRST TALK HOW DIET CAN CHANGE
THIS.
WE CAN POTENTIALLY CHANGE THIS
BY ANTIBIOTICS.
WE CAN PERFORM FEELINGAL TRANS
TRANSPLANTATION.
THIS HAS AN EFFECT ON DIFFERENT
IMMUNE CELLS IN DIFFERENT PARTS
OF THE BODY.
I SPECIFICALLY FOCUSED ON THE
IMMUNE CELLS IN THE SPECIFIC
ENVIRONMENT OF THE LIVER AND I
SHOWED YOU IN THE FIRST PART
CHANGES ON NKT CELLS AND HOW IT
EFFECTS MYELOID CELLS AND THEN
THIS WILL LEAD TO CHANGES IN
CANCER INITIATION AND
PROGRESSION.
BUT THERE ARE ALSO VERY GOOD AND
INTERESTING DATA HOW THE GUT
MICROBIOME CAN ACTUALLY
POTENTIALLY ENHANCE THE EFFICACY
OR IMPAIR THE EFFICACY OF TYPES
OF CANCER TREATMENTS AND THERE
IS ACCUMULATING DATA ON
COMORBIDITY AND POTENTIAL SIDE
EFFECTS AND WITH THIS I WOULD
LIKE TO CLOSE AND THANK THE
PEOPLE IN MY LAB.
THE FIRST STUDY WAS LED BY THE
GROUP.
THE SECOND ONE BY -- AND NONE OF
THIS WORK WOULD BE POSSIBLE
WITHOUT COLLABORATORS IN THE
NIH.
WITH THIS I WOULD LIKE TO CLOSE
AND I'M HAPPY TO TAKE ANY
QUESTIONS.
>> THANK YOU.
THANK YOU VERY MUCH, TIM.
NOW WE HAVE A WHOLE SERIES OF
QUESTIONS AND I'VE TRIED TO PUT
SOME OF THEM TOGETHER SO THAT
FOLKS WHO -- NOT EVERYONE WHO
HAS SUBMITTED A QUESTION -- WILL
BE ABLE TO PRESENT.
LET ME POSE A FEW OF THEM HERE.
SO JEFF THE INTESTINAL
MICROBIOME CONSIST OF MORE THAN
JUST BACTERIA.
AND THERE IS AN INTERESTING
QUESTION ABOUT THE POSSIBLE ROLE
OR IF WE KNOW ANYTHING ABOUT THE
ROLE OF FACH AS THE MAJOR VIRUS
PRESENT IN THE INTESTINAL
MICROBIOME.
IS VIRUS LIKELY TO BE THE NEXT
AREA OF CONCERN IN TERMS OF ITS
INFLUENCING MICROBIOME ACTIVITY
OR WOULD YOU COMMENT ABOUT THAT?
IT'S AN INTERESTING QUESTION.
>> WELL, I THINK THAT IS A VERY
APPROPRIATE QUESTION TO ASK
CONSIDERING THAT FACH INFLUENCE
-- THAT MANY BACTERIA HAVE PRO
FAGUE WITHIN THEIR GENOME.
THE PARTS OF THE MICROBIOTA ARE
INTERCONNECTED.
THERE IS ROBUSTNESS.
AND THE ABILITY TO EXPRESS
CRITICAL FUNCTIONS DESPITE A
NUMBER OF PROTO BASES AND THE
ABILITY TO RECOVER.
*.
THERE IS A LITTLE QUESTION THAT
IT'S PLAYING ITSELF OUT WITHIN
THE GUT MICRO BIOTA BUT IT'S A
DIFFICULT SYSTEM TO DISSECT.
SO THERE IS AN EFFORT TO
CHARACTERIZE THE FHAGE THAT ARE
REPRESENTED IN MICROBIAL
COMMUNITIES.
MANY OF THE GENES IN BACTERIA
PHAGE -- WE HAVE LITTLE
UNDERSTANDING OF THEIR FUNCTION
WHICH LIMITS OUR ABILITY TO
GREATLY APPRECIATE THEIR
INFLUENCE ON THEIR HOST BACTERIA
CELLS.
THEY'VE BEEN VIEWED FOR SOME
TIME AS THERAPEUTIC AGENTS SO
ONE COULD DELIBERATELY STAGE AN
ATTACK OR TARGET PARTICULAR
ORGANISMS.
I WOULD ASK THE PERSON WHO POSED
THE QUESTION TO CONSIDER THE
FACT THAT PHAGE ARE A COMPONENT
ARE INSTRUMENTAL IN PROPELLING
THE DYNAMISM BUT WE HAVE A LOT
TO LEARN.
ONE SCHOOL COULD BE THE VERY
MODELS WE TALKED B. DEFINED
COMMUNITIES CAN BE INTRODUCED
INTO THE ENTRUSTMENTS OF THE
ANIMALS.
DEFINED COMMUNITIES CREATED AND
DELIBERATE ATTACKS BY PHAGE.
RECOVERED FROM HEALTHY OR
DISEASED INDIVIDUALS.
BUT THE DEVELOPMENT OF
RESISTANCE -- IS A FORM OF
BACTERIAL IMMUNITY.
WHETHER THE PHAGE DYNAMIC IS
MORE TELL RAT -- TELL RANT OR NOT.
>> ANOTHER QUESTION IS IN SOME
OF YOUR EARLIEST WORK I RECALL
THAT YOU WERE INTERESTED IN THE
QUESTION OF HOW THE INTESTINE
ACTUALLY DEVELOPS?
HOW THE INDIVIDUAL CELLS
CARRYING OUT DIFFERENT FUNCTIONS
ALONG THE LENGTH OF THE
INTESTINE COMPARTMENTALIZE THOSE
AREAS OF THE GUT.
SO THERE IS A QUESTION AS TO
WHAT DETERMINES -- WELL IT'S A
DOUBLE QUESTION.
WHAT DETERMINES THE MICROBIOME
DEVELOPMENT WITH AGE?
AND THE OTHER SIDE OF IT IS DOES
THE MICROBIOME IN THE NEWBORN
PLAY A ROLE IN THIS DEVELOPMENT
OF THE INTESTINE AND ITS VARIOUS
SEGMENT TALL FUNCTIONS AND
DISTRIBUTIONS.
*.
>> BIOGEOGRAPHY, THE FACT THAT
WE HAVE TO LOOK AT THE INTESTINE
AS CHANGING NOT ONLY WITH AGE
DURING THE FIRST SEVERAL YEARS
OF LIFE BUT ALSO THE FACT THAT
THERE ARE DIFFERENT COMMUNITY
CONFIGURATIONS ALONG THE LENGTH
OF THE GUT.
THAT THE SMALL INTESTINAL MICRO
BIOTA HAS BEEN A -- IN DOING
NITA BECAUSE OF THE DIFFICULTY
OF SAMPLING.
WE HAVE TO THINK ABOUT THE AGE
OF THE HOST.
THE CO-DEVELOPMENT AND WHAT
REGIONS OF THE INTESTINE WE WANT
TO SEEK TO REPAIR.
AND I'LL JUST SAY TO THE PERSON
WHO ASKED THE QUESTION.
NUMBER ONE, THERE IS AN ONGOING
EFFORT TO DETERMINE THE DEGREE
TO WHICH THE SMALL ENTRUS IN --
INTESTINE IS CONTRIBUTING TO THE
DISORDER.
IT WAS FIRST IDENTIFIED IN PEACE
CORPS WORKERS RETURNING TO THE
UNITED STATES AFTER LIVING FOR
SEVERAL YEARS IN AREAS OF POOR
SANITATION.
WHERE THEY HAD DEVELOPED MALL
ABSORBS, WEIGHT LOSS, DIARRHEA
AND THEY WERE ENDOSCOPED AND
WHAT WAS SEEN WAS THE SMALL
INTESTINAL VILLA HAD COLLAPSED.
THE SURFACE AREA HAD BEEN
REDUCED.
THE BARRIER DISRUPTED.
THERE WAS INFLAMMATORY DISORDER
IN THE SMALL INTESTINE.
THE BILL AND MELINDA GATES
FOUNDATION HAS BEEN WONDERING
WHETHER THE SMALL INTESTINAL
MICROBIOTA IS -- IN UNDER
NOURISHED CHILDREN.
OF CHILDREN WHO FAILED STANDARD
INTERVENTIONS AND WHERE IN
HIGHLY SPECIALIZED CENTERS WITH
ETHICAL APPROVAL THESE CHILDREN
UNDERWENT IN DO IS CO-PEOPLE TO
DETERMINE IF THEIR SMALL
INTESTINES -- --
AS WE MOVE FORWARD TO LOOK AT
THE DEVELOPMENTAL BIOLOGY AND
REPAIR AND STATES OF DISEASE
THAT WE'RE GOING TO HAVE TO HAVE
A POSITIONAL PERSPECTIVE.
ONE LAST COMMENT.
THE PERSON WHO QUESTIONED OR
RAISEDDED THIS QUESTION MUST
HAVE SPENT SOME TIME IN THE LAB
UNDER STEALTH TECHNOLOGY.
IS THE REPAIR OF THE MICRO BUY
AT ON ASSOCIATED WITH THE
EFFECTS ON EPITHELIAL BIOLOGY *.
CAN ONE CONNECT THE DOTS TO SEE
HOW REPAIR OF THE MICRO BIOTA
READS OUT IN TERMS OF THE
EXPRESSION OF GENES IN DIFFERENT
EPITHELIAL LINEAGES AS THEY
DIFFERENTIATE -- -- -- AND THERE
IS A LOT OF REASON TO BELIEVE
THAT IS ONE MANIFESTATION OF THE
IMPACT OF THE MICRO BIOTA JUST
LIKE WE BELIEVE THAT THE SHAPES
IN HEALTHY INDIVIDUALS THE
DEVELOPMENT OF EPITHELIUM -- --
-- --
>> IT'S BEEN ASKED IF THERE IS A
CORRELATION BETWEEN THE GUT
MICROBIOME AND THE SKIN
MICROBIOME IN TERMS OF CHANGES
PERHAPS DURING DEVELOPMENT I
GUESS IS WHAT THE QUESTION THAT
HAS BEEN ASKED IN THE NEWBORN.
AND IF SO AND STUDIES OF THE
SKIN MICROBIOME PROVIDE CLUES AS
TO WHAT IS GOING ON IN THE
INTESTINE.
AND MAYBE MAKE THINGS EASIER IN
TERMS OF ASSESSING SOME OF THE
CLINICAL STUDIES.
>> WELL I THINK THAT THE
STATEMENT IS A VERY GOOD ONE.
THERE IS MATERNAL TRANSFER OF
MICROBES TO NEONATE.
SOME OF THAT TRANSFER INVOLVES
ORGANISMS ASSOCIATED WITH SKIN.
THE SKIN IS A VERY
BIOGEOGRAPHICALLY COMPLEX ORGAN
WITH MANY DIFFERENT AND VARIED
METABOLIC FEATURES.
AND THAT IS REFLECTED BY
DIFFERENCES IN COMMUNITY
COMPOSITION AND FUNCTION.
THE OFTEN CITED EXAMPLE OF THE
ROLE OF THE SKIN IN MATERNAL
TRANSFER OF MICROBES TO THE
INFANT IS THE DIFFERENCES IN THE
INITIAL GUT COMMUNITY IN
VAGINALLY DELIVERED INFANTS
VERSUS C-SECTION.
I THINK THAT THE PRECISE ROLE OF
THE SKIN MICRO BIOTA IN DEFINING
THE LATER TRAJECTORY IS NOT AS
WELL UNDERSTOOD.
BUT TO THE EXTENT THAT THERE IS
CO-DEVELOPMENT OF MICROBIAL IN
THE IMMUNE SYSTEM AND SINCE THE
IMMUNE SYSTEM IS IMPORTANT AS A
FACTOR AS A DETERMINANT OF
COMMUNITY CONFIGURATION ONE
COULD IMAGINE THAT THERE ARE
MANY WAYS IN WHICH THESE
COMMUNITIES MIGHT BE CONNECTED.
>> SEVERAL PEOPLE ASKED WHAT ARE
THE PLANS FOR FOLLOWING UP THE
PARTICIPANTS IN THE BANGLADESH
STUDY IN TERMS OF FOLLOWING THEM
THROUGH MANY YEARS TO FIND OUT
WHETHER THERE ARE THINGS IN
THEIR COGNITIVE ABILITY OR ANY
OTHER MEASURABLE EVENT.
IS THAT PART OF YOUR PLAN?
>> WELL I LOVE THE QUESTION FOR
MANY REASONS BECAUSE IT
EMPHASIZES THE IMPORTANCE OF
LONGITUDINAL STUDIES AND
UNDERSTANDING HOW THE MICRO
BIOTA AFFECTS HOST BIOLOGY
RATHER THAN CROSS SECTIONAL
STUDIES.
I LOVE THE QUESTION BECAUSE IT
SPEAKS TO THE POINT OF WHAT ARE
THE EFFECTS OF REPAIR OF A
MICROBIAL COMMUNITY ON HOST
SYSTEMS BIOLOGY.
AND HOW LONG IS THE REPAIR?
EVIDENCEVIDENT IN TERMS OF CELLULAR AND
MOLECULAR AND WHETHER THE
EFFECTS ON DIFFERENT ORGANISMS
ARE ALSO DURABLE.
WE FEEL IT'S CRITICAL TO DO
FOLLOW-UP STUDIES IN POPULATIONS
WHERE THE LEVEL OF TRUST AND
DEVOTION BETWEEN THE HEALTH CARE
PROVIDERS AND THE FAMILIES IS
ENORMOUS AND THAT IS ONE OF THE
REASONS WHY WE'RE SO FORTUNATE
TO BE ABLE TO INTERACT WITH OUR
COLLEAGUES AND THE PROOF OF
CONCEPT STUDY OF CHILDREN WITH
PRIMARY MAM IS BEING EXTENDED
FOR FOUR YEARS WE EVERY SIX
MONTH SAMPLING.
EVEN THOUGH IT'S A THREE MONTH
INTERVENTION WE FEEL THAT THOSE
SORTS OF ANALYSIS -- ARE
CRITICAL.
WE WOULD LOVE TO LOOK AT MUCH
MORE DETAILED PHENOTYPING
INCLUDING AS THE PERSON ASKED
THE QUESTION -- IMPLIED.
NEURO DEVELOPMENT, LONG-TERM
EFFECTS ON BODY COMPOSITION ON
IMMUNITY.
THOSE TYPES OF STUDIES ARE VERY
DIFFICULT TO ACTUALLY EXECUTE
AND ARE QUITE COSTLY.
WE FEEL THEY ARE CRITICAL AND
THEY HAVE TO BE SUFFICIENTLY
POWERED.
ONE OTHER THING -- THE
IMPORTANCE OF DETERMINING
WHETHER A MORE EXTENDED PERIOD
OF INTERVENTION IS NECESSARY TO
HAVE A MORE DURABLE EFFECT AND
WHAT THE EFFECTS OF INTERVENTION
INTERVENTIONS ARE.
WOULD AN INTERVENTION FOR THREE
MONTHS IN A CHILD WHO'S SIX
MONTHS OLD HAVE A GREATER IMPACT
THAN LATER ON.
ON THE OTHER HAND YOU CAN SAY
THE MICRO BIOTA HAS MANY
DIFFERENT FUNCTIONAL STATES AND
THERE ARE MANY DIFFERENT
BIOLOGICAL STATES TO BEING UNDER
NOURISHED AND ONE OF THE
IMPORTANT LESSONS THAT WE WANT
TO LEARN IS HOW REPAIR OF THE
MICRO BIOTA IS LINKED TO THE
RESPONSES OF DIFFERENT ORGAN
SYSTEMS.
I THINK THOSE SORTS OF
CONNECTIONS WILL GIVE US DEEPER
INSIGHTS INTO THE PATHOGENESIS
OF UNDER NUTRITION.
BECAUSE WE WILL DEFINE DISREPAIR
MUCH MORE CO-GENTLY.
*.
INCLUDING THEIR AGE AS ONE
FACTOR.
>> YOUR STUDIES ARE IN
MALNOURISHED VERY YOUNG
CHILDREN.
DO YOU THINK THAT A SIMILAR
MECHANISM MAY BE A FOOT IN MUCH
OLDER INDIVIDUALS WHO HAVE
DISEASES WHICH ARE CHARACTERIZED
BY WEIGHT LOSS AND MAYBE EVEN
MAINTAINING A DIET BUT THEY ARE
STILL LOSING WEIGHT.
I'M THINKING OF PATIENTS WITH
LIVER DISEASE IN PARTICULAR BUT
TO TRY TO BRING IN -- PERHAPS
TIM WOULD WANT TO COMMENT.
IS IT POSSIBLE THAT ONE OF THE
-- WHAT YOU HAVE OBSERVED JEFF
IN YOUNG CHILDREN IS ALSO
OCCURRING IN MUCH OLDER
INDIVIDUALS PERHAPS EVEN IN
AGING LET ALONE WITH -- MAJOR
ORGAN DISEASE.
WHAT DO YOU THINK OF THAT?
>> DO YOU WANT TIM TO ANSWER OR
ME TO ANSWER.
>> MAYBE YOU BOTH CAN ANSWER IF
THERE IS AN ANSWER.
TIM, WHAT IS YOUR VIEW?
>> SO OBVIOUSLY THERE MAY BE
SIMILARITIES.
I'M SURE THERE ARE SIMILARITIES.
BUT IT'S VERY DIFFICULT TO
PREDICT THIS WITHOUT DOING THE
STUDY BUT I HAVE A QUESTION AND
JEFF WILL GIVE HIS ANSWER WHICH
IS IN THE SAME DIRECTION THAT
WAS JUST ASKED ABOUT THE
LONG-TERM FOLLOW-UP.
WE KNOW THAT ANY -- OF THE BIOME
IS VERY RAPID BUT USUALLY NOT
LONG LASTING.
AND I SAW IT ON YOUR SLIDES THAT
YOU ACTUALLY FOLLOW THE CHILDREN
FOR I BELIEVE IT WAS ONE OR
THREE MONTHS AFTER YOU STOPPED
THE INTERVENTION.
SO DO YOU THINK YOU'RE GOING TO
HAVE LONG LASTING EFFECTS IN THE
CHILDREN?
>> ONE OF THE REASONS THAT WE
WANTED TO BEGIN THESE TYPE OF
STUDIES IN THE DEVELOPING PHASE
IS THAT YOU BELIEVE IN THE
HYPOTHESIS -- IT HAS A PROFOUND
EFFECT ON SETTING PHYSIOLOGICAL
TRAJECTORY IS IT'S POSSIBLE THAT
AS THESE MECHANISMS EXIST ARE
FIRST ESTABLISHED -- THAT YOU
COULD HAVE A DURABLE EFFECT.
SO I DO THINK THAT IT WILL BE --
INTERESTING TO SEE THAT THE
DURATION OF AN EFFECT OF MICRO
BIOTA REPAIR DURING ITS
FORMATION AS OPPOSED TO THE
EFFECTS OF REPAIR ONCE THE ORGAN
SYSTEM AND THE HOST HAS FULLY
MATURED AND DEVELOPED.
WHAT IS THE EFFECT OF THE REPAIR
TO THE MICRO BIOTA IN A
60-YEAR-OLD AS OPPOSED TO A
SIX-MONTH-OLD?
>> IF THAT IS THE CASE THE
ANSWER TO THE QUESTION IF YOU
WILL SEE THE SAME EFFECT IN AN
ADULT THAT YOU SEE IN THE SMALL
CHILDREN IS PROBABLY NO.
>> MAYBE YES OR MAYBE NO.
IF ONE GOES BEYOND THE TYPES OF
STUDIES I JUST DESCRIBED.
TO A DEEP AND INSPIRING BUT
NONETHELESS DIFFICULT TASK OF
IDENTIFYING SIGNALING PATHWAYS
BY WHICH DIFFERENT COMPONENT
INFLUENCE HOST BIOLOGY.
SO IF YOU'RE ABLE AS A DURABLE
LEGACY TO ULTIMATELY BE ABLE TO
IDENTIFY THESE SIGNALING
PATHWAYS THEY BECOME YOUR
THERAPEUTIC TARGETS AND THERE IS
REASON TO CONJECTURE THAT THOSE
PATHWAYS STILL OPERATE DURING
THE INDIVIDUAL'S LIFE-SPAN.
SO I THINK THESE ARE I THINK ONE
OF THE AGENDA ITEMS IF WE'RE
FORTUNATE ENOUGH TO BE ABLE TO
SUPPORTED IN THESE TYPES OF
TRANSLATIONAL STUDIES AND
REVERSE TRANSLATIONAL STUDIES TO
BE ABLE TO DISCERN THE SIGNALING
PATHWAYS AND THEIR COMPONENTS.
THAT IS MY HOPE AND EXPECTATION.
BUT I ALSO AGREE WITH YOU
SOBRIETY IS VERY IMPORTANT IN
THE FIELD AND TO TEST THE
GENERALIZABILITY OF AN
INTERVENTION.
CHILDREN OF A PARTICULAR AGE
LIVING IN DIFFERENT REGIONS OF
THE WORLD.
TO BE ABLE TO DETERMINE THE
DURABILITY OF THE EFFECTS.
THAT IS ABSOLUTELY CRITICAL.
AND I HOPE THAT IS DONE IN A
VERY CAUTIOUS AND METHODICAL
KAY.
>> TIM, THERE IS AN INTERESTING
QUESTION WHERE SOMEONE HAS
POINTED OUT THAT THE VAST
MAJORITY OF PATIENTS WITH
HEPATOCELLULAR CANCER HAVE SOME
UNDERLYING CHRONIC LIVER DISEASE
ASSOCIATED WITH A LOT OF
REGENERATION, CIRRHOSIS AND ALL
SORTS OF THINGS.
THE QUESTION IS DOES DISBIOUS
AND THE INTESTINE -- * IS A
MAJOR ROUTE LEADING TO FIBROSIS
THE ALTERED HEPATOCELLULAR
REGENERATION AND NOT DIRECTLY TO
CANCER ITSELF?
CAN YOU VISUALIZE A WAY IN WHICH
ONE CAN DIFFERENTIATE THESE
VARIOUS ASSOCIATED EVENTS WITH
THE FACT THAT THE CANCER IS
OCCURRING IN PATIENTS WITH
CHRONIC ACTIVE FORMS OF LIVER
DISEASE, FIBROSIS AND A LOT ELSE
GOING ON
>> OBVIOUSLY THAT'S AN VERY
INTERESTING QUESTION.
AND THERE ARE MODELS WHERE WE
CAN DO THIS.
WE HAVE WAYS TO INDUCE DYSB
IOS IS.
THE MICE WITH LIVER DISEASE BUT
THERE ARE MANY WAYS.
SIMPLE ANTIBIOTIC TREATMENT IS
ONE.
AND IF YOU GO INTO THE ANIMAL
SYSTEM THAT ALLOWS YOU TO DO FMT
STUDIES YOU CAN INDUCE THE FMT
IN GERMFREE MICE AND THEN LOOK
AT THE EFFECT ON MECHANISMS THAT
WILL AUTOMATICALLY LEAD TO
FIBROID BROSIU AND CIRRHOSIS IN MICE.
IT IS NOT AS STRAIGHTFORWARD AS
ONE WOULD THINK BECAUSE GERMFREE
MICE ACTUALLY HAVE SIGNIFICANT
CHANGES IN THEIR GI TRACT BY
ITSELF.
SO JUST THE ABSENCE OF BACTERIAS
CAUSING SIGNIFICANT CHANGES BUT
YES WE DO KNOW THAT DYSB iOS
IS HAS SIGNIFICANT CHANGES.
* THAT CAN UP INTRODUCE OR
AMPLIFY CHANGES IN THE LIVER AND
NOT ONLY IN THE CONTEXT OF VIRAL
INFECTION.
WE KNOW THAT COMING BACK TO THE
IDEA OF NUTRITION THAT OBVIOUSLY
NOT ONLY WITH MALNUTRITION BUT
ALSO WITH OBESITY THERE IS
SIGNIFICANT CHANGES AND THE GUT
MICROBIOME IS SIGNIFICANTLY
DIFFERENT.
SO THE IDEA THAT THE GUT
MICROBIOME PLAYS A SIGNIFICANT
ROLE HERE IS CLEAR.
AND THEN LAST BUT NOT LEAST
THERE IS VERY GOOD DATA THAT THE
GUT MICROBIOME CAN ACTUALLY
CONTROL ALCOHOLIC LIVER DISEASE.
THIS IS DONE WITH WORK FROM OUR
COLLABORATOR WHO HAS DONE THIS
WORK.
AND THE REASON WHY I MENTIONED
THIS IS BECAUSE YOU TALKED ABOUT
THE PHAGES.
YOU CAN USE THIS TO DISRUPT
MECHANISMS AND THEREBY TREAT
ALCOHOLIC LIVER DISEASE.
IT'S A LONG ANSWER BUT BASICALLY
THEY ARE ALL INTERCONNECTED WITH
EACH OTHER AND IT'S VERY
DIFFICULT TO SAY IN THE END
WHICH IS THE --
[ INDISCERNIBLE ]
>> DO WE UNDERSTAND HOW ANY
INTESTINAL MICROBE YET A --
DYSBIOSIS US CAUSES.
>> IF YOU KILL ONE ANOTHER ONE
WILL GROW OUT.
THAT WOULD BE MY SIMPLISTIC
ANSWER
>> ONE OF THE LESSONS IS HOW
ELABORATE THE INTERACTION OF
MICROBES ARE AND THEY DON'T
FUNCTION IN ISOLATION AND THERE
HAS BEEN A LOT OF WORK SPEAKING
OF -- METABOLISM -- WITH -- AND
HAVE COMPLEX METABOLIC
INTERACTIONS THAT OCCUR THAT
CAUSES SEVERE -- WE CAN THINK
ABOUT MICROBIAL ACTIVITIES AS
HEALTH PROMOTING OR DISEASE
PROMOTING DEPENDING ON -- WHICH
THEY EXIST.
JUST LIKE THE NUTRITIONAL VALUE
OF FOOD MAY BE INFLUENCED TO A
SIGNIFICANT DEGREE BY THE
CHEMICAL COMPOSITION OF FOOD.
THE MICROBES DON'T SEE FOOD AS
BROCCOLI.
THEY SEE IT AS A COMPLEX -- OF
STRUCTURES.
AND DIFFERENT ORGANISMS ARE
CAPABLE OF HAVING DIFFERENT
ROLES IN THE PROCESSING OF THESE
THINGS.
ALTHOUGH IN GENERAL THESE
COMMUNITIES HAVE A LOT OF
DIVERSITY AND REDUNDANCY THAT
ALLOWS THEM TO WITHSTAND.
THE NUMBER OF GENES IN THE
MICROBIOME VASTLY EXCEED THE
NUMBER OF GAMES IN THE HUMAN
GENOME BECAUSE THEY ARE ABLE TO
PROVIDE US WITH BIOCHEMICAL
CAPABILITIES THAT WE HAVE NOT
EVOLVED ON OUR OWN.
THAT IS ONE OF THE WAYS THAT WE
CONSTRUE THIS.
BRINGING TOGETHER DIFFERENT
ORGANISMS THAT HAVE DIFFERENT
JOBS SO THE ENTIRE -- BIOME IS
FITTER.
>> THAT IS THE MIRACLE.
HOW DO THESE SYSTEMS ASSEMBLE?
HOW ARE THEY MAINTAINED AS WE
PERTURB THEM.
HOW DO THEY RECOVER?
IT'S STUNNING.
AND INSPIRING.
BUT TRYING TO FIGURE OUT THE
UNDERLYING MECHANISMS REALLY
REQUIRES A LOT OF TOOLS AND
LUCKILY WE LIVE IN AN ERA WHERE
WE HAVE THE CAPACITY TO DO DEEP
SEQUENCING NOT ONLY OF DNA BUT
RNA AND DO A LOT OF METABALOMICS
TO START LEARNING BASIC
PRINCIPLES THAT GLUE ORGANISMS
TOGETHER AND CONNECT THEM WITH
OURSELVES.
THAT IS THE HOPE.
BUT HUMILITY GIVEN THE FACE OF
THIS AND LACK OF HOW ABOUT ROUSE
AND SOBRIETY IS * IS REALLY
IMPORTANT.
>> THANK YOU.
TIM YOU MENTIONED THAT IN
GERMFREE ANIMALS THE INTESTINE
IS NOT LIKE IT IS IN INFECTED OR
NORMAL.
DO YOU WANT TO COMMENT BRIEFLY
ABOUT THAT?
WHAT ARE THE DIFFERENCES?
>> ANY POSTDOC OR GRADUATE
STUDENT AT THE LAB WHO'S WORKING
ON THIS ONLY HAS TO OPEN THE
ABDOMINAL CAVITY OF A MOUSE AND
YOU WOULD IMMEDIATELY SEE GROSS
CHANGES.
YOU WILL SEE A LARGE -- AND THE
GALLBLADDER IS DIFFERENT.
YOU CAN SEE THIS WITH YOUR BARE
EYE.
ONCE YOU START LOOKING CLOSER
YOU'LL SEE MORE CHANGES BUT IT'S
VERY OBVIOUS AND STUNNING WHEN
YOU SEE IT FOR THE FIRST TIME.
>> VERY EXCITING.
WELL WE'RE OUT OF TIME AND I'M
SURE ON BEHALF OF THE MANY, MANY
PEOPLE AROUND THE WORLD WHO HAVE
BEEN TAKING PART IN THIS, THEY
WOULD JOIN ME IN THANKING BOTH
OF YOU FOR TAKING THE TIME, THE
INTEREST AND PRESENTING SUCH
REALLY PROVOCATIVE AND
CHALLENGING, EXCITING
OPPORTUNITIES TO BUILD BRIDGES
AND IT SEEMS AS IF THERE ARE
GREAT OPPORTUNITIES IN THESE
FIELDS FOR BRIGHT YOUNG PEOPLE
WHO ARE LOOKING FOR NEW WORLDS
TO CONQUER.
THANK YOU VERY MUCH AND GOOD
LUCK
>> THANK YOU VERY MUCH.