>>WELCOME I'M CATHERINE LAW
AT NCCIH, NIH
WELCOME TO DAY 1
I WILL TURN OVER TO CO CHAIRS
TO ALLOW THEM TO WELCOME
YOU AND FOR THE EVENT.
I AM FROM NIH
AND I WOULD LIKE TO THANK YOU
ALL, THE NIH AND U.S. DA STAFF
AND ALL OF THE SPEAKERS WHO
HAVE GIVEN OF THEIR TIMES AND
EXPERTISE TO HELP US AND TO
ALL OF YOU FOR SHOWING YOUR
INTEREST.
WE WANT TO BEGIN THIS MORNING
WITH A FEW DEFINITIONS TO GET
EVERYONE ON THE SAME PAGE.
SO WE LOOK AT THE PROBLEM AND
MANY INCONSISTENT OUTCOMES
FROM PROBIOTIC INTERVENTIONS.
AS YOU KNOW --
[INDISCERNIBLE]
SO THEREFORE WE MUST BRIDGE
THIS GAP AND ALLOW PROBIOTIC
STRAINS WITH INDIVIDUAL
FACTORS INCLUDING MICROBIOME
AND ENVIRONMENT AND LIFESTYLE.
WE WILL HAVE QUESTIONS TO
SERVE AS FUTURE QUESTIONS FOR
RESEARCH SO I WILL STOP THERE
AND TURN IT OVER TO MY
COADVISOR, Dr. SORKIN.
>> GOOD MORNING, THANK YOU,
Dr. KIM.
I WOULD LIKE TO ADD MY THANKS
WITH DOCTOR KIM FOR ALL OF YOU
WHO HELPED PREPARE THIS
WORKSHOP AND ALL OF YOU
SHOWING YOUR INTEREST FOR
JOINING US FOR IT.
WHILE WE'RE DOING DEFINITIONS,
LET ME REVIEW THE DEFINITION
OF DIETARY SUPPLEMENTS.
THIS IS A DEFINITION OF
DIETARY SUPPLEMENTS DEVELOPED
IN 1994 AND IF YOU LOOK AT IT,
PROBIOTICS FIT INTO THE
CATEGORY OF OTHER DIETARY
SUPPLEMENTS.
THIS IS WHY THE OFFICE OF
DIETARY SUPPLEMENTS IS
INTERESTED IN THIS WORKSHOP
AND SHARE THE HOPE THAT BY THE
TIME WE FINISH THE WORKSHOP
TOMORROW WE WILL HAVE A BETTER
IDEA OF DEFINING
INTERVENTIONS, MEASUREMENTS TO
INCREASE THE EFFICACY OF
PROBIOTIC INTERVENTIONS, THE
RESEARCH AND REACH THE FULL
POTENTIAL OF THIS RESEARCH
AREA TO ACHIEVE FULL CLINICAL
UTILITY.
ODS IS HAPPY TO BE JOINING
WITH NIEHS AND OTHER MEMBERS
OF THE WORKSHOP SO I WILL HAND
IT BACK TO DOCTOR KIM FOR THE
OTHER INTRODUCTIONS.
>> OKAY, THANK YOU.
SO IT IS MY HONOR TO INTRODUCE
OUR NEXT SPEAKER WHO WILL GIVE
A FEW WORDS TO TIP OFF THIS
WORKSHOP.
SO PLEASE JOIN ME IN WELCOMING
Dr. LANGEVIN.
>> HELLO, THANK YOU FOR
WELCOMING ME AND I AM HAPPY TO
BE PARTICIPATING IN THIS
WORKSHOP THAT HAS SUCH A
DIVERSE FIELD.
IT IS REALLY EXPANDIC AND THE
LINE BETWEEN CONVENTIONAL AND
COMPLIMENTARY APPROACHES IS
WORRYING AND THEREFORE, AT
NIH, WE FIND A WAY TO THINK
ABOUT THE THINGS WE SUPPORT IN
NEW CATEGORIES BASED ON THEIR
PRIMARY THERAPEUTIC INPUT SO I
WILL SHOW YOU A LITTLE VIDEO
TO SHOW YOU HOW THE PROBIOTICS
WILL FIT INTO THIS BIG
PICTURE.
SO YOU CAN SEE THIS IS WHAT WE
CALL OUR BUBBLE DIAGRAM AND
YOU CAN SEE THE THREE BIG,
SORT OF LARGE TYPES OF THE
DIFFERENT -- WHAT WE CALL THE
THEIR PUTATIVE, NUTRITIONAL,
PSYCHOLOGICAL AND PHYSICAL.
AND YOU WILL SEE THESE BUBBLES
OVERLAP PARTIALLY TO INCLUDE
OTHER CATEGORIES, FOR EXAMPLE,
DRUGS AND DEVICES.
SO THIS ILLUSTRATES HOW THIS
PARTICULAR INSTANCE, HOW THE
CATEGORY OF NUTRITION INCLUDES
THINGS LIKE FOR EXAMPLE THE
DIET AND DIETARY PATTERN AND
IT ALSO INTERCEPTS WITH THE
PSYCHOLOGICAL CATEGORY, FOR
EXAMPLE, INTERVENTIONS THAT
PROMOTE MICROBES.
HERBS AND THINGS THAT ARE
PARTS OF A PERSON'S DIET AS
WELL AS OTHER PLANTS THAT ARE
NOT TAKEN AS PART OF DIET BUT
USED FOR MEDICINAL PURPOSES AS
WELL AS OTHER PRODUCTS SO YOU
SEE IT IS A DIVERSE FIELD AND
ALSO THE DIAGRAM SHOWS THE
SAME PRODUCT, FOR EXAMPLE,
NIACIN THAT CAN BE USED AS A
SUPPLEMENT BUT ALSO A
MEDICATION DEPENDING ON THE
DOSE THAT IS USED.
AND IT ALSO INCLUDES OF CORES
PROBIOTICS AND PREBIOTICS
WHICH ARE CRUCIAL FOR THE
MICROBIAL AND INCLUDE PLANTS
AND HERBS AND THE POTENTIAL
INTERACTION BETWEEN THE SIMPLE
OR MULTIPLE BIOLOGICAL
SYSTEMS.
THIS IS PARTICULARLY IMPORTANT
FOCUSING ON WHAT WE CALL WHOLE
PERSON HEALTH WHICH MEANS THE
WAY WE DEFINE WHOLE PERSON
HEALTH IS EMPOWER INDIVIDUALS
TO IMPROVE THEIR HEALTH IN
MULTIPLE DOMAINS, BEHAVIORAL,
BIOLOGICAL AND SOCIAL AND THE
WHOLE SYSTEM.
SO WE ARE PARTICULARLY
INTERESTED IN MULTISYSTEM
APPROACHES THAT TIE TOGETHER
VARIOUS AREAS THAT HELP WITH
HEALTH AND DISEASE PREVENTION.
THE WHOLE PERSON HEALTH
EMPHASIZES THE PATHWAY IS
BIODIRECTIONAL INCLUDING
APPROACHES TO LIFESTYLE AND
NUTRITION AND OTHER FACTORS
THAT CAN HELP AN INDIVIDUAL
RESTORE THEIR HEALTH.
SO I AM REALLY LOOKING FORWARD
TO THIS WORKSHOP WHICH WILL
INCLUDE MANY EXAMPLES OF THIS
TYPES OF RESEARCH INCLUDING
PATIENT SHALL AND TEMPORAL
DYNAMICS OF BIOLOGICAL
ACTIVITY, PROBIOTICS, GI
TRACT, ESPECIALLY PROBIOTICS
LINKING THE GASTRO INTESTINAL
TRACT WITH THE BRAIN AND OTHER
IMPORTANT TOPICS.
SO THERE ARE A LOT OF
CHALLENGES STANDING IN THE WAY
OF PROGRESS IN FILLING THESE
GAPS AND OF COURSE WE WANT TO
PROVIDE A CLINICAL FOUNDATION
FOR FUTURE EFFORTS TO HAVE A
PRECISION PRO BY YACHTIC
THERAPY.
AND NOW I WILL TURN THINGS
OVER TO Dr. GABRIELA RISCUTA
FROM THE NATIONAL CANCER
INSTITUTE AND Dr. LUNSFORD
FROM THE NATIONAL INSTITUTE OF
DIABETES AND DIGESTIVE AND
KIDNEY DISEASE.
THEY WILL INTRODUCE THE
SESSION SPEAKERS AND SHARE THE
SLIDES SO NOW I WILL TURN
THINGS OVER TO Dr. LUNSFORD,
THANK YOU SO MUCH.
TAKE IT AWAY.
>> GOOD MORNING, EVERYONE, I'M
DWAYNE LUNSFORD, LIKE TO
WELCOME YOU TO SESSION 1, AND
AS A REMINDER, YOU CAN FIND
FULL DETAILED SPEAKER
BIOGRAPHIES IN THE PROGRAM
BOOK.
OUR FIRST SPEAKER IS Dr.
RIMA WITH A SESSION CALLED
METABOLOME GENOME GUT
MICROBIOME DIET EXPOSOME
TOWARDS A PRECISION MEDICINE
APPROACH FOR PROBIOTIC
THERAPIES.
YOUR AUDIO IS NOT WORKING
Dr. LUNSFORD, WOULD YOU GO?
>>I APPRECIATE
BEING INVITED
I HAVE BEEN ASKED TO SPEAK
WITH CLINICAL TRIALS.
I HAVE CLINICAL TRIALS I HAVE
BEEN DOING FOR 15 YEARS NOW
AND ALSO A PHYSICIANS SO I
BRING THAT TO THE HOUSE, TOO.
I HAVE BEEN A PAID CONSULTANT
FOR HOWARU AND ANOTHER PAID
POSITION.
SO I WAS SPECIFICALLY ASKED TO
COVER THE CHALLENGES FACED
DURING PROBIOTIC CLINICAL
TRIALS DUE TO DIFFERENT
RESPONSES TO PROBIOTIC
INTERVENTIONS AND HOW TO
IMPROVE THE RESPONSIVENESS IN
THE CLINICAL SETTING.
I TRANSLATED THIS AS SUCH AND
SO MY OBJECTIVES WILL BE TO
REVIEW HOW CLINICAL TRIALS ARE
CARRIED OUT AND ANALYZED,
UNDERSTAND WHAT WE ARE
ACTUALLY REQUIRED TO DO IN
CLINICAL RESEARCH, HELP US TO
CONSIDER WHAT NEEDS TO BE DONE
TO GET TO CLINICAL TRIALS IN
PROBIOTICS.
MOST COMMON REASONS
INTERVENTION DOES NOT WORK IS
YOUR STRAIN HAS LIMITED TO NO
EFFICACY.
OR YOUR STRAIN DOESN'T WORK
FOR THAT INDIVIDUAL, FOR THAT
INDICATION OR AGE, SEX OR
DIET.
I WILL SAY IN SPECIFIC
PROBIOTIC TRIALS, TIMING SEEMS
TO BE ESPECIALLY IMPORTANT.
THIS IS A REALLY NICE STUDY BY
Dr. ALLEN THAT LOOKED AT
ANTIBIOTIC-ASSOCIATED
DIARRHEA, ONE OF THE FEW AND
IT STARTED ON PEOPLE AVERAGE
3-7 DAYS.
WE TRY TO START IT IMMEDIATELY
AND OTHERS HAVE DONE THE SAME
WITH A BETTER OUTCOME SO IT
HAS BEEN SEEN THAT WITH
CERTAIN ANTIBIOTICS, YOU DO
NEED TO TIME THE SUPPORT.
HOW DO WE LOOK AT THE DATA IN
CLINICAL FORM, AND HOW DOES
ONE DO THIS?
EXAMINING CLINICAL TRIALS IS
VERY DIFFERENT THAN BENCH
RESEARCH LOOKING FOR
SIGNIFICANT FINDINGS AND HERE
IS A STATEMENT BY THE STUDENT.
[ READING FROM SLIDE ]
WE TESTED DIFFERENT VARIABLES
ON A PROMOTER GENE THAT COULD
BE LOCKED ON TO DETERMINE IF
WE COULD REDUCE INFLAMMATION
IN PEOPLE WITH INFAMILIAR TORE
BOWEL DISEASE.
WE TESTED A VARIETY OF
DIFFERENT FACTORS ON THE GENE
THROUGHOUT THE SUMMER BUT NOT
SINGLE FACTOR SIGNIFICANTLY
ALTERED THE GENE.
ON THE FINAL DAY OF THE WEEK
8, I FINAL LIE FOUND A
VARIABLE THAT SIGNIFICANTLY
ALTERED IT.
SO THE ANALYSIS WAS TOTALLY
DIFFERENT THAN WHAT HE DID.
SO WE LOOK AT THE PRIMARY
OUTCOME MEASURES.
THIS IS THE STUDY I WILL TALK
TO YOU AND SHOW YOU SOME DATA
AND WHAT WE DID WAS TO LIST
THE PRIMARY OUTCOME AND
SECONDARY.
THIS IS THE PRIME CARE
OUTCOME, CHANGE FROM BASELINE
LEVELS OF FECAL SHORT-CHAIN
FATTY ACID WITH PARTICULAR
FOCUS ON ACETATE AND THEN
CHANGE FROM BASELINE LEVELS OF
FECAL SHORT-CHAIN FATTY ACID
WITH PARTICULAR FOCUS ON DAY
30.
SO WE LOOKED AT A NUMBER OF
MICROBIOTA PIECE SEES AND THIS
IS WHAT EVERYONE IN A CLINICAL
TRIAL IS REQUIRED TO DO, EVERY
REVIEWER OR EDITOR LOOKS TO
SEE THAT THIS IS DONE.
SO THAT IS OUR PRIMARY
OUTCOMES AND THERE ARE SOME
OTHERS ON THE LIST BUT WHAT
HAPPENS IF WE FOUND ACETATE
HAD NO CHANGE OR IF IT WAS
IMPACTED BY INTERVENTION OR IF
IT WAS CHANGED AT DAY 14 OR 21
BUT NOT DAY 7?
AND THEN THE OTHER OUTCOMES,
A CHANGE IN REPORTED SYMPTOMS
AND WHAT IF WE FOUND KIDS WHO
TOOK THE PROBIOTIC
SIGNIFICANTLY MISSED LESS
SCHOOL?
SO THIS IS VERY IMPORTANT ON
THE TRIALS WITH PRECISION
METRICS AND THE REASON WE DO
THAT OR ONE OF THE REASONS IS
WE NEED A LIST AHEAD OF TIME
SO WE CAN CHAIN TO DATA MINE.
SO WHERE WE REPORT THIS WHEN
WE REPORT OUR TRIALS IS THE
CHECKLIST.
SO PEOPLE WHO NOT DONE
CLINICAL TRIALS, THERE ARE
CHECK LISTS YOU HAVE TO SHOW
IN JOURNALS WHERE YOU SPEND
ANY TIME TALKING ABOUT IT.
WHICH IS THIS.
[ READING FROM SLIDE ]
SO THIS NEEDS TO BE LISTED AND
IF YOU HAD MAJOR CHANGES OR
DON'T LIST YOUR PRIMARY OR
SECONDARY OUTCOMES, A GOOD
JOURNAL WILL REJECT YOUR
RESEARCH.
SO WHAT HAVE WE DONE IN THE
PAST TO IDENTIFY RESPONDERS?
WELL, INCLUSION/EXCLUSION IS
USED FOR SAFETY BUT ALSO TO
HELP FIND WHO BENEFITS SO WE
HAVE EXCLUDED ELDERLY OR
INFANTS, PEOPLE WHO HAVE
CERTAIN DIETS, ONLY
HOSPITALIZED PATIENTS, WE HAVE
BEEN DOING THAT FOR YEAR.
SO CLINICAL RESEARCHERS HAVE
ALWAYS TRIED TO FIND
RESPONDERS, IN THE PAST CALLED
DATA MINING, NOW WE CALL IT
PREDICTIVE ANALYTICS, MACHINE
LEARNING, DATA ANALYTICS,
ALGORITHMS, ET CETERA.
BUT THE PROBLEM IS YOU ARE
LOOKING AT SOMETHING THAT
COULD DIFFER SIGNIFICANTLY BUT
DOESN'T ANSWER THE QUESTION.
THE MORE TESTS ONE RUNS, THEY
ARE LIKELY TO SEE AN EFFECT
AND ONE CAN EASILY MISTAKE
THAT FOR A TRUE FINDING.
THIS CAN RESULT IN A P VALUE
AT 0.05 LEVEL OF STATISTICAL
SIGNIFICANCE.
AND WHAT ONE CAN AND SHOULD DO
IS CHANGE THEIR P VALUE FOR
THIS BUT PAY ATTENTION TO HOW
THEY DO THAT.
HERE IS A CARTOON DOCUMENT
WHERE JELLY BEANS CAUSING
THAT, IT WORKS ALL THE WAY
THROUGH AND SAY GREEN JELLY
BEANS CAUSE ACNE AND WE SEE
THIS RESEARCH ALL THE TIME
ESPECIALLY LEAP IN THE LAY
TRANSFER TALKING ABOUT COPY
AND THINGS LIKE THAT, ALWAYS
GETS A LOT OF PRESS BUT REALLY
WHAT ONE NEEDS TO ASK IS, IS
THIS AN OUTCOME OR DATA
MINING?
SO MULTIPLE OUTCOMES IN
PERSONALIZED MEDICINE, A STUDY
REGISTERED AND THE PRIMARY
OUTCOME LIFTED ON MICROBIOME,
STOOL AND ORAL SAMPLES, TIME
FRAME ONE YEAR.
DOES THIS MEAN THERE IS ANY
CHANGE AT ALL ANY TIME OF THE
YEAR THAT IS A SUCCESS OR WHAT
CHANGES THE MICROBIOME?
WELL, IF PEOPLE ARE BETTER IN
DAY 7 BUT NOT BETTER IN DAY 3,
I HAD A NEGATIVE STUDY SO THIS
LOOKS LIKE SOMEONE WHO IS A
BENCH RESEARCHER TRYING TO DO
CLINICAL STUDIES AND
EVERYTHING IS FINE AT THE
BEGINNING BUT AS IT GOES
THROUGH, WITH DIFFERENT
EFFECTS.
SO THIS IS A STUDY WE TALKED
ABOUT BEFORE, AND YOU CAN SEE
PROBIOTICS, SOME PEOPLE GOT
THEM, SOME WHO GOT CONTROL
NEVER GOT UP TO THE ACETATE
BUT PEOPLE WHO GOT THE ACTIVE,
THEY GOT BACK TO DAY 1 SO WE
TRY TO LOOK AT THE MECHANISM
AND WE ALSO DID THE MICROBIOME
DATA BUT I WANTED TO TALK
ABOUT THIS BECAUSE IT IS A
NICE EXAMPLE.
YOU SEE THIS LOOKS REALLY
NICE.
REALLY HAPPY ABOUT THIS, GOING
FROM R-32 TO R-33, VERY
POSITIVE BUT THEN LOOK HERE.
THIS IS GROUP DATA BUT IF YOU
ACTUALLY LOOK AT THE RAW DATA,
SOME PEOPLE DID BETTER, SOME
PEOPLE DID WORSE BUT THAT IS
NOT HOW IT WAS REPORTED IN
CRITICAL MEDICINE.
WE WEREN'T TRYING TO HIDE IT,
THIS JUST LOOKS BETTER.
BUT AGAIN SOME PEOPLE DID
BETTER, SOME PEOPLE DID WORSE
BUT YOU CAN'T TELL HOW OR WHY
SOME PEOPLE DID BETTER THAN
OTHERS.
SO PERSONAL I.C.E.D MEDICINE
IN MY OPINION BY DEFINITION
WOULD MEAN INDIVIDUAL DATA BUT
AGAIN, HOW WE ARE REQUIRED TO
REPORT CLINICAL TRIALS IS BY
GROUP SO AGAIN, THIS IS THE
CONSORTYOU SEE HERE, THE
STATIVITY -- STATISTICAL
METHOD USED TO REPORT FOR EACH
GROUP BUT NO ONE LOOKS BACK
HERE AND SAYS LET'S FIGURE OUT
WHY THIS PERSON IS HERE, THIS
PERSON IS HERE.
IT IS NOT HOW THIS IS
REPORTED.
OKAY, ONE EXTRA CHALLENGE I
FIND IN DOING A STUDY FOR PRO
BY YACHT TICK TRIALS IS DIET.
DIET IS REALLY A HARD THING IN
PROBIOTIC TRIALS.
AGAIN, WE'RE NOT IN
LABORATORIES, CAN'T CONTROL
PEOPLE'S DIET AND EVERYONE
COMES TO US WITH DIFFERENT
DIETS AND MICROBIOMES.
AND IN HUMANS, THAT IS REALLY
COMPLEX.
THIS IS A REAL LIE NICE STUDY.
I LIKE THIS STUDY, YOU HAVE 36
PEOPLE TOTAL, 18 IN EACH
GROUP, SOME FED A HIGH FIBER
DIET, THE OTHERS A HIGH
FERMENTED FOOD DIET AND YOU
CAN SEE THIS INCREASED
MICROBIOME FUNCTION, THIS
INCREASED THE DIVERSITY AND
THE OUTCOME BUT AGAIN, A
36-PERSON RANDOM STUDY, THEY
WERE LOOKED AT FOR THREE DAYS
FOR NINE DIFFERENT TIME POINTS
AND 27 DAYS OUT OF 70 DAYS OF
INTERVENTION SO THINK IF YOU
HAVE BEEN A PART OF A TRIAL,
FOR 27 DAYS THEY LOGGED ALL
THEIR FOOD AND DRINK INTAKE
FOR THREE DAYS, TWO WEEKDAYS
AND ONE WEEKEND, EACH WEEK
DURING THE RAMP PHASE AND
EVERY WEEK FOR THE REST OF THE
STUDY USING HEALTHWATCH360
APP.
SO THE DIETICIAN REVIEWED THE
ENTRIES WITH PARTICIPANTS TO
ASSESS ACCURACY OF ENTRIES AND
PORTIONS.
ON AVERAGE OF THE THREE DAYS
USED FOR EACH TIME POINT,
ENTRIES FOR TIME POINTS
BASELINE WEEK 4, WEEK 10, WEEK
14 WERE REENTERED INTO THE
NUTRITION DATA SYSTEM FOR
RESEARCH DATABASE.
THIS WAS A GREAT STUDY BUT
THINK ABOUT HOW MUCH TIME WAS
SPENT.
THINK ABOUT THAT WHEN YOU ARE
DOING YOUR NIH STUDIES, IT
TAKES A LOT OF TIME BUT IT IS
REAL IMPORTANT WE HAVE THE
DIET DATA AND MOST OF THEM ARE
NOT GOING TO HAVE ANY LIKE
THIS KIND OF DATA.
SO A FEW POINTS, NUMBER NEEDED
TO TREAT, PROBABLY THE MOST
COMMON NUMBER WE USE, THE
AVERAGE NUMBER OF PATIENTS WHO
NEED TO RECEIVE THE TREATMENT
FOR ONE OF THEM TO GET THE
POSITIVE OUTCOME IN TIME
SPECIFIED.
>> YOU HAVE JUST A COUPLE
MINUTES LEFT, THANKS.
>> OKAY, NO PROBLEM.
SO THE PROBIOTIC A PREVENTS
COVID DEATH BY 75 PERCENT BUT
THE PLACEBO ALSO PREVENTS
DEATH BY 25 PERCENT, THAT
MEANS 25 PERCENT OF THE PEOPLE
DIDN'T NEED TO DIE AND THE
STUDY IS AMAZING.
SO STATINS, THE MEDICATION YOU
ARE ON, ONE IN 217 AVOIDED
NONFATAL MYOCARDIAL
INFARCTION, 1 IN 313 AVOIDED
NONNATAL STROKE.
PASSENGERSLY AT HIGH LEVELS
POSSIBLE FOR CROSSOVER TRIAL,
STILL ANALYZED AS A GROUP BUT
THE PARTICIPANTS ENVIRONMENT,
DIET, HOW IT WASHES OUT, SO WE
DID A SHORT-TERM STUDY OF A
DAILY INTAKE OF YOGURT
CONTAINING BF-6.
IF WE STOPPED THE TRIAL BEFORE
THE CROSSOVER, WE HAD A
POSITIVE STUDY SO SOMETHING
PROBABLY HAPPENED WITH THE
GROUPS THAT HAD THE CHANGE IN
THE MICROBIOME LONG-TERM, SO
YOU THINK ABOUT THAT OVER THE
TRIAL, HARD TO GET THE FULL
DATA.
HOPEFULLY I HAVE CONVINCED YOU
THAT ARE YOUR STANDARD WAY OF
DOING CLINICAL TRIALS CAN
REALLY LIMIT THE INFORMATION
WE GLEAN ABOUT INDIVIDUAL
RESPONSES, OUR ANALYSIS IS
BASED ON GROUP AGGREGATES AND
MASKS INDIVIDUAL RESPONSES,
AND REQUIREMENT FOR SETTING UP
THE TRIAL WITH A PRIORI
ESTABLISHMENT OF SUCCESS,
KEEPS THE CLINICAL TRIALIST
FROM FISHING THROUGH A TON OF
DATA.
THIS SHOULD BE DIFFICULT AND I
THINK I WILL SKIP THIS AND I
THINK WE NEED TO TALK ABOUT
HOW WE MOVE FORWARD WITH
LIMITATIONS, HOW WE INTERPRET
THE FINDINGS BEING REPORTED
AND RETHINK ABOUT HOW WE
ENROLL AND ANALYZE IN ORDER TO
DO PRECISION MEDICINE CLINICAL
TRIALS.
THANK YOU FOR YOUR TIME AND I
WILL CREDE TO THE NEXT
SPEAKER.
>> THANKS, DAN, THANKS FOR
STEPPING IN OUT OF ORDER AND I
AM SURE THERE WILL BE REALLY
GREAT QUESTIONS LATER ON.
WE HAVE RIMA BACK?
>> CAN YOU HEAR ME OKAY?
>> YOU SOUND GOOD, THANK YOU,
>> I THANK THE
ORGANIZERS FOR AN EXCELLENT
WORKSHOP AND A GREAT PRIVILEGE
TO SHARE TODAY EXPERIENCES WE
HAD WITH A LARGE PART OF
CONSORTIA FOR PRECISION
MEDICINE INVOLVED THE STUDY
AND TREATMENT.
SO THE STUDY WE TALK ABOUT
TODAY WAS FUNDID BY I GM F AS
WELL AS OTHERS.
ANOTHER CONSORTIUM WAS FUNDED
BY IMS WHERE WE WERE TRYING TO
UNDERSTAND THE VARIATION OF
RESPONSE AMONG PEOPLE WHO ARE
DEPRESSED AND PEOPLE WITH
DISORDERS.
AND TRANSLATING IDEAS FROM
CONSORTIUM TRYING TO
UNDERSTAND AND THINK ABOUT
METABIOMICS IN A MOREPRECISE
WAY.
ALSO NIH FUNDED THE STUDY YOU
SEE HERE.
BRIEFLY HOW WE VIEW THE WORD I
THINK IS THE FIRST THING AND
THAT IS WE ARE INFLUENCED BY
THE GENOME WHICH OF COURSE
TELLS US SOMETHING ABOUT
MORBIDITY, SUSCEPTIBILITY AND
INFORMS HOW WE RESPOND TO
MEDICATION -- IN SOME CASES,
NOT ALWAYS BUT THIS IS THE
INVOLVEMENT OF GENOMICS AND SO
THAT DATA IS IMPORTANT AND NOT
ONLY IS THAT IMPORTANT, WE ARE
REALIZING QUICKLY THAT THE
METHOD BY WHICH WE ARE EXPOSED
TO IT IS ALSO IMPORTANT AND
CAN BE USED FOR
SUSCEPTIBILITY.
AND ALSO GUT INFLUENCED BY THE
MICROBIOME.
THE GUT MICROBIOME AND STUDIES
EMERGING IS AT A CROSSROAD
WITH OUR DIET, OUR
ENVIRONMENT, SOCIAL NETWORKS,
ALL INTERCONNECTING THINGS
THAT DO DEFINE AT THE END WHO
WE ARE AS INDIVIDUALS AND WE
SHOW IN THE BACKGROUND THE
NETWORK THAT DESCRIBE
ULTIMATELY WHO WE ARE.
AND I WANT TO SCAMP GUY SCAMP
GUY WHAT I MEAN BY THIS.
EXEMPLIFY.
SO WE LOOK AT THE METABOLIC
PATHWAYS AND PROCESSES
IMPLICATED IN HUMAN DISEASE
AND HOW THEY ARE INFLUENCED BY
THE MICROBIOME AND MEASURED IN
THE BLOOD OR OTHER TISSUES
REVEAL SUSCEPTIBILITY ON AN
INDIVIDUAL BASE.
WE HAVE LEARNED THROUGH
PARTNERSHIP WITH THE WEILL
CORNELL INSTITUTE, AND HOW WE
LOOK AT ALL THESE AFFECTS IS
HIGHLY BASED ON OUR GENES.
SO THE STUDY FROM UNIVERSITY
OF CAMBRIDGE SHOWING HIGH
DENSITY FOR EACH, NOT ONLY CAN
THE AGAIN HOME IN IDENTIFY AN
IDENTITY BUT THE CHEMISTRY
SHOWS UNIQUE AMONG INDIVIDUALS
AND THIS CHANGES THE PARADIGM
OF HOW WE THINK ABOUT
PRECISION MEDICINE AND
PRECISION HEALTH.
NOT ONLY IS OUR METABOLISM
PLAYING A PART IN THE GENOME,
IT REALLY PUTS TOGETHER THE
INFLUENCES OF THE BACTERIA AND
METABOLITES MEASURED BY THE
PROFILE OF WHAT WE EAT.
SO THE GENOME AND MICROBIOME
BOTH GIVES US INFORMATION FOR
MEASUREMENT OF THE METABOLOME.
TO COMMENT ON THE SIN GEE, YOU
KNOW, WE KNOW THAT THE FIRST
METABOLITES WE INGEST, WHETHER
HIGH FIBER OR THE OTHER THINGS
WE TAKE IN, THROUGH OUR
GENETIC MAKEUP, AND BASED ON
WHAT WE INGEST, THERE IS A
WHOLE BUNCH OF ACTIVITY THAT
COMES FROM THIS AND THEY ALSO
PROVIDE FURTHER MATERIAL THAT
WE CONTINUE TO PRODUCE AS
HUMANS OF THE METABOLISM.
SO IT IS A TRUE PARTNERSHIP
BETWEEN BACTERIA AND THE HUMAN
AND GIVING US THE TARGETING
GUT MICROBIOME.
WE ARE TRYING TO UNDERSTAND
THE COMPLEXITY AND DIVERSITY
THE METABOLISM USES THE
BACTERIA, WE ARE ALSO SEE THAT
THE WORK CAN TEACH US ABOUT
THE BIOCHEMISTRY THAT IS
MODULATED BY THE MICROBIOME.
WE KNOW THERE IS A WHOLE LIST
OF BACTERIA IN THE MICROBIOME
THAT ARE EITHER PRODUCED BY
THE BACTERIA DIRECTLY OR
CORRELATED BY THE BACTERIA AND
I CAN GIVE YOU SPECIFIC
EXAMPLES.
FOR EXAMPLE, CHOLESTEROL, IT
IS METABOLIZED BY AN ENZYME
BUT THEN THERE IS A WHOLE
NUMBER OF ENZYMES THAT ARE
PRODUCED THAT COMPLETE THE
CHOLESTEROL THAT CAN IMPACT ON
HUMAN HEALTH.
SO I LOOK AT CHOLESTEROL AND
SAY THIS IS HUMAN AND THE REST
OF THIS IS THE BACTERIA,
RIGHT?
SO THERE ARE OTHER FACTORS,
CARBON, THE CHOLINE,.
[INDISCERNIBLE] MANY OF THESE
TURNED ON OR OFF.
SO IF WE ARE TALKING ABOUT
MICROBIOTICS, WE ARE TALKING
ABOUT THE END SILENCE AND
ACTIVITY THAT IT INFLUENCES
THAT SEEM TO BE THE RESULT OF
HUMAN HEALTH.
WE HAVE GROUPS WHO ARE DOING
THE SUBSCRIPTION TRYING TO
UNDERSTAND THE SYNERGY BETWEEN
THE HUMAN AND BACTERIA, TRYING
TO SEE HOW WE CAN MODULATE
THIS.
WE HAVE A PORTAL FOR BUILDING
ASPECTS OF BUILDING MICROBIAL
METABOLITES AND WHAT PROFESSOR
DAVID WISHART AND OTHERS HAVE
DONE IS DETERMINE THIS
BACTERIA WHERE WE CAN LOOK AT
THE ENVIRONMENT, THE DIET, AND
REVIEW THIS TO GIVE US MORE
RESOURCES, AND HOW THEY
NETWORK WITH THE BACTERIA.
WE KNOW THAT THE EXPOSOME DOES
INFLUENCE THE MICROBIOME AND
METABOLOME.
ALL ARE INTERCONNECTED AND ALL
INFLUENCE AND ARE MAJOR
DECISION MAKERS INCLUDING THE
METABOLOME.
I PULLED THIS STUDY LOOKING AT
THE VARIANCE OF BLOOD
METABOLOME, LOOKING AT THE
EXPOSOME OF BLOOD METABOLOME
AND ASK ABOUT THE RELATION OF
COGNITION ASSOCIATED
METABOLITES WITH GUT,
MEDICATION AND GENETICS, AND
CAN I CHANGE THE INFLUENCES OF
THE GUT MICROBIOME, AND WHAT
ARE THE INFLUENCES, WHICH
BACTERIA SCREENS AND WHICH ARE
IN THE MICROBIOME AND HOW THE
GENOME WILL INFLUENCE THE
INTERACTION OF GENOME GUT
MICROBIOME.
AND THE DRUGS WE ARE ON CAN
RESULT IN A VARIATION IN
QUALITY.
OR TO GIVE US THE OPPORTUNITY
TO TALK ABOUT THE QUALITY AND
INDOLES PRODUCED BY GUT
MICROBE.
WE KNOW THAT THEY CORRELATE
WITH ANXIETY AND DEPRESSION,
CERTAIN BACTERIA THAT IMPACTS
THE BRAIN IN PROFOUND WAYS AND
WITH REGULARITY.
IF YOU LOOK AT THE HUMAN
BACTERIAL METALISM, IT IS
REGULATED BY GENES AND IN PART
IS ALSO PREDICTED BY THE
IMMUNITY BUT THE TRYPTOPHAN IN
THE GUT WILL PRODUCE
INDOTOXINS AND A THIRD OF
HUMANS CAN COMPLETE THIS BY
MAKING BLOOD INDOXYL SULPHATE
LEVELS THAT CORAL LATER WITH
ANXIETY AND DEPRESSION.
SO THIS COMES WITH A
PARTNERSHIP BETWEEN THE HUMAN
AND BACTERIA, THE HUMAN AND
THE ENDS SAME, THE CHANGES IN
THE BRAIN AND HERE ARE THE MRI
CHANGES IN A VERY SENSITIVE
AREA WHICH CORRELATES ARE
ANXIETY AND DEPRESSION.
>> YOU HAVE THREE MINUTES.
>> OH, WE KNOW ALSO THESE
COMPOUNDS ARE IN THE BRAIN,
RIGHT?
SO IT GIVES US AN AVENUE TO
START TO THINK ABOUT
PROBIOTICS AND I HOPE THAT WE
CAN COMPLETE THE STORY HERE
AND SHOW THE COSMETIC APPROACH
OF HOW CAN WE IMPROVE THE
MICROBIOME.
SO THE EMERGING ROLE FOR GUT
MICROBIOME THROUGH BRAIN
IMAGING AND JUST A FEW WORDS
WHAT WE HAVE DONE AT NI GM S,
ONE SIZE DOES NOT FIT ALL.
THERE IS SYNERGY BETWEEN
GENETICS AND CONSORTIUM TO
HAVE NO RESPONSE OR COMPLETE
RESPONSE AND WITH SOME CLASSES
OF DRUGS, AFFECT THE GENOME OF
EACH INDIVIDUAL.
THIS LEADS TO BETTER
PREDICTION OF RESPONSE AND
VARIATION OF RESPONSE.
I DO NOT HAVE TIME TO GO
THROUGH ALL OF THIS BUT ONE
STUDY OF ESCITALOPRAM
INVESTIGATION WITH THE MAYO
CLINIC, TO LOOK AT THE PEOPLE
WHO RESPOND AND DO NOT
RESPOND, NOW TO GET TO THE
ENZYME AND SEE THE REDUCED
FUNCTION OR DEGRADATION THAT
IS NECESSARY TO SUPPORT AND
THE DRUGS THEY ARE TAKING, WE
SAW HOW IMPORTANT THEY ARE INY
FINING RESPONSE OR NO
RESPONSE.
THE BACTERIA THEREFORE DO PLAY
A ROLE IN HOW WE METABOLIZE
THE DRUG AND MUCH MORE.
SO NOW WE HAVE A RESPONSE, WE
CAN MAP THE GENETICS TO SEE
ETHNICITY AND HOW THAT
CONTRIBUTES TO VARIATION, WE
CAN LOOK AT WHAT IS THE
MECHANISM THAT IS DIFFERENT
BETWEEN THE RESPONDERS AND
OTHER RESPONDERS AND LOOK AT
MEN AND WOMEN WITH ASPIRIN AND
DETERMINE A RESPONSE.
THE RESULTS THAT WE FOUND IN
INDIA CAN BE APPLIED TO ANY
GROUP.
AND WHAT WE HAVE LEARNED IS
THE EXPOSURE OF THE MICROBIOME
AND CONTRIBUTION TO HUMAN
DISEASES, TO TEACH US
SOMETHING ABOUT THE RESPONSE,
THE VARIATION OF THE RESPONSE
AND IF YOU THINK OF
PROBIOTICS, HOW ARE WE GOING
TO CHANGE THE MICROBIOME, HOW
WILL WE MARKET IT AND THE
QUANTITATIVE MEASURES THAT CAN
TELL US DID WE MODERATE THE
END RESULT FOR THE INDIVIDUAL.
>> THANK YOU, RIMA, THAT IS
GREAT THOUGHT.
OUR NEXT SPEAKER WILL BE Dr.
MARK HAUPT, HIS TALK ENTITLED
IMPORTANCE OF INVESTIGATIONAL
PRODUCT MANUFACTURING FOR
PROBIOTIC INTERVENTION TRIALS.
TAKE IT AWAY, MARK.
THANK YOU FOR THIS OPPORTUNITY
TO JOIN YOU TODAY AND THANKS
TO THE ORGANIZERS WHO PUT THIS
TOGETHER.
I HAVE THE PRIVILEGE OF
FILLING IN FOR Dr. STAHL TO
SHARE WITH YOU THE IMPORTANCE
OF VET TKPWAEUGSAL PRODUCT
MANUFACTURING FOR PROBIOTIC
INTERVENTION TRIALS.
I SPENT MY CAREER IN PHARMA
WORKING ON VARIOUS ELEMENTS
INCLUDING PRECISION MEDICINE
THERAPYS AND APPROACHES AND
HOW TO IDENTIFY THE RIGHT
PATIENTS TO THE RIGHT DRUGS,
THE RIGHT PRODUCT AND SO WHAT
I HOPE TO PROVIDE TODAY IS THE
LOOK INTO THE PROBIOTIC
PROCESS AND HOW TO IDENTIFY
THE STRAIN, HOW TO PRODUCE IT,
WHICH FORMULATION.
THERE ARE THINGS TO REALLY
CONSIDER WHEN PUTTING A TRIAL
TOGETHER TO INSURE YOU HAVE
THE GREATEST LIKELIHOOD OF
SUCCESS.
FOR DISCLOSURE, I AM AN
EMPLOYEE OF IFF.
SO THE THINGS WE WILL WORK
THROUGH TODAY, WHAT ARE THE
OPPORTUNITY TO CONSIDER WHEN
CHOOSING WHICH PROBIOTIC FOR
HAVE VENGE, GETTING THE RIGHT
FORMATS AND FORMULATIONS AND
WHAT ARE THE CHALLENGES AND
OPPORTUNITIES WITH THE FINAL
FORMAT SOLUTION, YOU WANT A
SOLUTION TO GET THE FINAL
PRODUCTS THROUGH AND THAT
INCLUDES SHIPPING, STORAGE,
ALL OF THOSE.
AND AGAIN, THIS IS NOT
DEFINITIVE IN GREAT DETAIL FOR
THE MANUFACTURING PROCESS BUT
TO INSURE WE HAVE THE RIGHT
SOLUTIONS FOR YOUR TRIAL, TO
ANSWER THE QUESTIONS YOU ARE
LOOKING TO ANSWER.
THIS IS A VERY HIGH LEVEL
OVERVIEW INTO PROBIOTICS
PROCESSING STEPS.
YOU HAVE THE PREPARATION, THE
NATURAL FILTERING PROCESS,
SEPARATING THE PRODUCT AND
THIS IS MAYBE A LITTLE
OVERSIMPLIFICATION OF THE
POINT, THIS IS NOT THE END
PRODUCT OR END DECISION OF
WHAT COMES OUT AS PROBIOTIC
FORMULATION.
MANY DECISIONS WE COULD MAKE
AFTER THIS TO INSURE WE HAVE
THE RIGHT ELEMENTS.
SO WHAT ARE THE STEPS FOR
DEVELOPING INVESTIGATIONAL
PRODUCTS?
FIRST OBVIOUSLY IS WHAT ARE
THE STRAINS.
SECOND, WHAT ARE THE CELL
COUNTS YOU ARE TRYING TO
STUDY, WHAT IS THE RANGE OF
CELL COUNTS ACCEPTABLE, THE
CONDITION THE STUDY.
AND THE VIABLE AND ADEQUATE
DOSES DELIVERED THROUGH THE
STUDY, THE DENSITY, INSURING
YOU HAVE HIGH QUALITY STRAINS
FREE OF CONTAMINATES AND ALL
OF THIS TOGETHER ADDRESSES THE
QUALITY AND SAFETY.
SO WHAT ARE SOME OF THE THINGS
NEEDED FOR THE CLINICAL TRIAL
DESIGN?
WHAT IS THE CORRECT STRAIN?
IS IT A SINGLE STRAIN OR
MULTIPLE STRAIN OF CONSORTIUM
YOU NEED TO DEMONSTRATE THE
INTENSITY?
WHAT IS THE DOSE?
THE LENGTH OF INTERVENTION AND
AGE OF PARTICIPANTS WITH THE
MATERIAL WE PROVIDING.
THE AGE OF PARTICIPANTS, DO
THEY REPRESENT ADULTS AND THE
CHANGES IN THE LIVER TO THE
PROBIOTIC, THE ANALYSIS OF
METHODS TO INCLUDE DIVERSITY
AND THE POPULATIONS
DIFFERENCES, WHAT ARE THE
CRITERIA YOU LOOK AT IN THE
POPULATION TO EVALUATE AND
THIS MAY ULTIMATELY INFORM THE
STRAIN YOU BACTERIA USED IN
THE STUDIES.
THE OTHER THING TO CONSIDER IS
THE CHARACTERISTIC OF WHERE
THIS STUDY WILL BE CONDUCTED
BECAUSE THIS INFORMS WHAT IS
PROVIDED, THE SUPPLY CHAIN FED
TO THE LIVER OF OF PROBIOTIC,
TO MAKE SURE IT IS SAFE, TO
MAKE SURE THE THEY ARE STORY
AND STORAGE CONDITIONS ARE
SATS IF A ACCIDENT TREE AT THE
SITE.
LEVERAGING HISTORICAL TRIALS
WITH THE DESIGN DATA TO INFORM
NEW TRIAL DESIGNS CAN BE
INFORMATIVE BUT DIRECT
TRANSMISSION IS INDIVIDUAL.
SO WHAT ARE THE KEY QUESTIONS
WE EXPLORE PRIOR TO ENGAGING
WITH A SUPPLIER FOR A
PROBIOTIC SOLUTION?
FIRST OF ALL, WHAT STRAINS
WILL BE STUDIED AND WHAT TOES?
DOSE?
AND WE WILL GET INTO THAT.
THERE ARE DIFFERENT STRAINS
THAT HAVE THE POTENTIAL FOR
EFFICACY AT DIFFERENT DOSES.
IS IT GOING TO BE STUDIED AT
1B, 5B?
WOULD MULTIPLE STRAINS
INCREASE THE CHANCE FOR
SUCCESS?
WHAT ABOUT PREBIOTICS?
SO IF YOU ARE STUDYING
MULTIPLE STRAINS, YOU WILL
HAVE DIFFERENT OUTCOMES.
HOW WILL THE PRODUCT DELIVER?
AND IT IS NOT JUST TO THE
INDIVIDUAL BUT MAKING CERTAIN
YOU HAVE THE RIGHT FORMAT, A
WAY TO STORE AT THE DELIVERY
SYSTEM TO MAKE SURE YOU HAVE
PRODUCTIVITY AND STABILITY
REQUIRED TO DELIVER THE
PRODUCT.
SO WHEN SPEAKING ABOUT WHICH
STRAIN TO CHOOSE WHICH HAS
BEEN BROUGHT UP A NUMBER OF
TIMES, WE LOOK AT THE FUNCTION
OF THE VARIOUS STRAINS AND
CERTAINLY THIS IS A VERY HIGH
LEVEL OVERVIEW OF THE STRAIN
SELECTION.
SO AS YOU CAN SEE HERE, THE
VARIOUS STRAINS ARE OF
INTEREST, HEALTH CONDITIONS
CAN INFORM AREAS, DELIVERED
WITH FIBER DEPENDING ON THE
STRAIN BUT THE ADDITIONAL
NUANCES NEED TO BE COVERED IN
THE VARIOUS POPULATIONS TO PUT
TOGETHER AN OPPORTUNITY SO
LOOKING AT WHAT DATA ARE
NEEDED TO HELP YOU DESIGN
THIS.
WHEN WE TALK ABOUT EXTREMES,
WE THINK ABOUT PROTOCOL, WHAT
DOES IT TAKE TO BE A
PROBIOTIC, TO INSURE THE
STABILITY, MAKE SURE IT IS
SAFE.
THE OTHER ENVIRONMENTAL
CONDITIONS MAKING SURE THERE
ARE NO FOREIGN ELEMENTS IN IT,
INSURING APPROPRIATE QUALITY,
MAKING SURE THE STRAINS ARE
IDENTIFIED AND PUT TOGETHER,
YOU KNOW WHAT YOU ARE PUTTING
INTO YOUR PATIENT.
SURVIVABILITY, TO INSURE THAT
YOU HAVE LIVE PROBIOTICS AND
UNDERSTANDING THE CLINICAL
SURVIVABILITY.
THE KWROEFRPBLG HYPOTHESIS FOR
END OF SHELF-LIFE TARGET, THIS
IS AN EXAMINER SHOWING AS WE
PRODUCE A PROBIOTIC, WE START
THE UNIT AT THE TIME OF
MANUFACTURING ON THE
PRODUCTION LINE, AND WILL
REDUCE OVER TIME WITH
INVESTIGATIONAL PRODUCT
RELEASE AND THAT TRANSLATES TO
END OF SHELF-LIFE TARGETED
POTENCY SO WE NEED TO INSURE
THAT THE SPECIFIC ELEMENTS ARE
INTENDED FOR SHELF-LIFE.
AND ARE THE INGREDIENTS
SUITABLE FOR PROBIOTIC
SURVIVAL?
AND IF NOT, WE NEED TO EXCLUDE
THOSE PRODUCTS.
THIS IS AN EXAMPLE OF BI-26
STABILITY IN INFANTS FORMULA
STORED IN DIFFERENT
CONDITIONS.
SO IF YOU LOOK HERE AT THE
LABEL CLAIM OF 18 PER WILL
.3 GRAMS SERVING, THIS IS
GETTING INTO THE FORMAT OF THE
POWDER PROVIDED AND PACKAGING
IN DIFFERENT CLIMB ZONES BUT
WHAT YOU SEE HERE IS THE TIME
THE FORMULA WAS PRODUCED UNDER
DIFFERENT CONDITIONS, YOU CAN
SEE THE REDUCED EFFICACY.
SO THIS IS AN EXAMPLE, A
PICTURE OF ONE OF OUR
INVESTIGATIONAL PRODUCT
SUITES, AND KNEES ARE
QUESTIONS TO BE ASKED OF YOUR
SUPPLIER, WHAT DOES THE
FORMULATION LOOK LIKE, WHAT
ARE THE MEASURES TAKEN TO
INSURE COMPLIANCE, WHAT ARE
THE FORMATTING IMPLICATIONS
DESIGNED AND HOW CAN YOU
FORMULATE, THAT?
THIS IS AN EXAMPLE OF
INVESTIGATIONAL PRODUCT
TESTING AND LABELING, THE
LABELING THAT GOES ON THE
PRODUCT AND THE POINT TO KEEP
IN MIND HERE AND THIS IS
CRITICAL, THE CAPSULES ARE
VERY GOOD FOR STABILITY
ALTHOUGH IT MAY INTRODUCE
CHALLENGES IN SOME
POPULATIONS.
SACHETS ARE THE EASIEST FOR
STABILITY BUT NEED VERY
SPECIFIC INSTRUCTIONS ON HOW
TO TAKE THEM.
FOOD FORMATS CAN BE DIFFICULT
FOR STABILITY DUE TO SHELF
LIVELY AND READY-TO-DRINK
BEVERAGES HAVE OTHER
CHALLENGES WITH SHIPPING AND
SO ON.
>> YOU HAVE JUST A FEW MINUTES
LEFT.
>> NO PROBLEM, THANK YOU.
THIS IS APP EXAMPLE OF A
FORMAT TO BE DEVELOPED TO MEET
THE NEEDS OF A STUDY, THE
BI-26 IS SPRINKLED AS A METHOD
OF DELIVERY TO HELP HEALTHY
IMMUNE DEVELOPMENT IN INFANTS
AND CHILDREN.
SO REALLY WHEN IT ALL COMES
TOGETHER, PUTTING TOGETHER
PROBIOTIC SCIENCE, NEEDS GOOD
PARTNERSHIP AND DELIVERING
WITH THE EXPERTISE OF
MANUFACTURERS TO INSURE WE
HAVE THIS INTENDED OUTCOME
WITH THE POPULATION.
AND IT REALLY TAKES THE
PARTNERSHIP DISCUSSION
SPECIFICALLY TO TALK ABOUT THE
DETAILS AND SO I WILL END WITH
THAT AND IF YOU HAVE QUESTIONS
FURTHER ABOUT THIS, I WILL BE
HAPPY TO TALK TO YOU AS WELL
AND APPRECIATE YOUR
PARTICIPATION.
>> GREAT, MARK, THANKS AGAIN.
WE WILL TURN THIS OVER TO
KATHERINE FOR OUR FIRST BREAK
OF THE DAY.
>> WE ARE INDEED, THANK YOU,
Dr. LUNSFORD.
WE ARE GOING TO TAKE A
5-MINUTE BREAK, EVERYBODY,
DRINK WATER, STRETCH, WALK
AROUND, WILL COME BACK AT
11:45 EASTERN AND A REMINDER
TO PARTICIPANTS TO MUTE YOUR
AUDIO AND STOP SHARING YOUR
VIDEO AND WE WILL ALL BE BACK
HERE IN FIVE MINUTES.
AND I AM GOING TO BE SHARING A
BRIEF BREAK SLIDE WHILE THEY
ARE AWAY.
THANK YOU EVERYONE, SEE YOU IN
FIVE MINUTES.
>> OUR NEXT SPEAKER EVERYONE
IS SUSAN LYNCH FROM
THE UNIVERSITY OF
CALIFORNIA-SAN FRANCISCO AND
HER TALK IS PRY BIOTIC
CLINICAL TRIALS, OPPORTUNITY
TO UNDERSTAND HUMAN
MICROBIOLOGY.
>> THANK YOU SO MUCH AND
THANKS TO THE ORGANIZERS FOR
THE INVITATION TO BE HERE
TODAY.
BEFORE I START BY WAY OF
DISCLOSURE TO SAY I AM
COFOUNDERRER AND SERVE AS
BOARD OF DIRECTORS, CULT STAND
FOR SIOLTA THERAPEUTICS AND
WILL NOT BE TALKING ABOUT ANY
WORK GOING ON IN THOSE REALMS
TODAY.
SO HOW WE AS A GROUP TRY TO
PRAOEUFRB MICROBIOME RESEARCH
IS REALLY MOVING AT FULL SCALE
AND I THINK OF IT AS
MULTIDATA, HOW MANY
POPULATIONS, UNDERSTANDING
MICROBIOTA, MICROBIAL SPECIES
AND STRAINS AND THE CELLULAR
AND MOLECULAR AND HOW THAT
APPLIES TO CLINICAL OUTCOMES.
SO THIS REALLY SHOWS A
MULTIAPPROACH TO THE STUDIES
AND MOVING FROM HUMAN
POPULATIONS AND FILLING THESE
GAPS IN OUR KNOWLEDGE TO
UNDERSTAND WHO PROBIOTICS WORK
FOR AND HOW THEY MAY OPERATE
WITHIN THE COMPLEX OF THE GUT
MICROBIOME.
SO I WANT TO SHARE WITH YOU A
STUDY THAT WE PERFORMED A
NUMBER OF YEARS AGO IN
COLLABORATION WITH U.S. FF, A
CLINICAL TRIAL OF INFANT
PROBIOTIC SUPPLEMENTATION AND
FOR HIGH RISK FOR ASTHMA
INFANTS, DEFINED BASED ON THEY
HAD AT LEAST ONE PARENT WITH
DIAGNOSED ASTHMA.
THE BABIES WERE SIX TO TEN
MONTHS FOLLOWED BY A WASHOUT
PERIOD OF 12 MONTHS AND THEN
SEEN AT 3 YEARS OF AGE AND A
BIT OF SPOILER ALERT, THERE
WAS NO SIGNIFICANT DIFFERENCE
BETWEEN THE PREVIOUSLY
SUPPLEMENTED AND THE PLACEBO
GROUP IN THIS STUDY BUT
SUGGESTS THAT WE COULD
ACTUALLY UNDERSTAND A LITTLE
BIT MORE ABOUT HOW PROBIOTIC
SUPPLEMENTATION INFLUENCES THE
GUT MICROBIOME AND WHETHER
THERE ARE DIFFERENCES TO BE
LEARNED FROM THIS TRIAL.
IN PARALLEL TO HIGH RISK
INFANTS, MICHAEL ALSO HAD A
COHORT OF HC INFANTS AND
PURELY ON SUPPLEMENTATION HAD
THE FORESIGHT TO COLLECT
SAMPLES FROM THE INFANTS AND
THIS ALLOWED US TO USE MRNA
SEQUENCING AND TARGETED ON THE
LG AND HC ASPECT.
AND THE FIRST THING OBVIOUS TO
US WAS THAT COMPARED TO
INFANTS SHOWN HERE IN GREEN OR
THE HEALTHY CONTROL ARM,
BABIES BORN TO HIGH RISK FOR
ALLERGY AND ASTHMA BABIES
DEMONSTRATED A SIGNIFICANTLY
DIFFERENT TRAJECTORY OF GUT
MICROBIOMES, SIGNIFICANTLY
LOWER THAN THAT OF THE HEALTHY
CONTROLLED SUBJECTS.
BUT THOSE HIGH RISK INFANTS
WHO RECEIVED THE SUPPLEMENTS
FOR THE FIRST SIX MONTHS OF
LIFE NO LONGER DEMONSTRATED
THE SIGNIFICANT DIFFERENCE IN
SLOPE IN ACCUMULATION OF
DIVERSITY BUT AS YOU CAN SEE,
THEY STILL HAVE DEFICIENCIES
IN THE MICROBIOME AND LARGELY
DUE TO A HE COULD TPHR*EGS
LEGS OF RICHNESS, ACCUMULATION
OF DIFFERENT TYPES OF
MICROBIOME I WANTED INDICATING
THAT A SINGLE SPECIES WAS
INSUFFICIENT TO RECAPITULATE
THE RICHNESS ACCUMULATION, THE
NUMBER AND TYPES OF ORGANISMS
NECESSARY IN A HEALTHY GUT
MICROBIOME.
NONETHELESS, WHAT WE DID SHOW
WAS THE SUPPLEMENTED INFANTS,
AFTER THREE MONTHS OF DAILY
SUPPLEMENTATION DEMONSTRATES A
GUT MICROBIOME THAT WAS
SIGNIFICANTLY MORE LIKE THAT
OF THE HEALTHY CONTROL
POPULATION AND THAT WAS EVEN
MORE PRONOUNCED BY SIX MONTHS
OF AGE.
BUT BY NINE MONTHS OF AGE,
THIS SIMILARITY HAS BEEN LOST
AND BY 12 MONTHS OF AGE, WE
SEE THIS SNEAK BACK IN AND NOT
SURE WHY THIS OCCURRED.
WHEN WE LOOKED AT TARGETED
METABOLO MIC, THE HIGH RISK
GROUP HAD A MORE SIMILAR FECAL
METABOLOME COMPARED TO HEALTHY
INFANTS BUT AGAIN THIS WAS BY
12 MONTHS OF AGE, PERHAPS
EXPLAINING WHY WE SAW NO
SIGNIFICANT DINNERS IN COULD
YOU TELL COME AT THREE YEARS
OF AGE.
HERE I WILL WALK YOU THROUGH
SORT OF THE DETAILS OF THE
FEATURES OF THE FECAL META
BOLOME THAT CHARACTERIZED
THESE INFANTS WHO HAD BEEN
SUPPLEMENTED.
AND WHAT I AM SHOWING YOU HERE
IS IN THE WARMER COLORS, THE
METABOLITES WERE ENRICHED IN
THE HIGH RISK PLACEBO GROUP
COMPARED TO THE HEALTHY
CONTROL OR THE HIGH RISK
LACKED -- LACTOBACILLUS
SUPPLEMENTED BABIES.
SO WE CAN SEE THE GUT
MICROBIOME IN BOTH HIGH RISK
BABIES ASSOCIATED WITH A RANGE
OF INFLAMMATORY MONOHYDROXIDE
FATTY ACIDS BY CODES.
IN COMPARISON, INFANTS WHO
RECEIVED SIX MONTHS OF
SUPPLEMENTATION, AS YOU CAN
SEE CLEARLY, THERE IS QUITE A
LOT OF OVERLAP IN TERMS OF THE
LIPIDS AND HAD STEROIDS
PRODUCED IN THAT FECAL
METABOLOME -- OR PRESENT IN
THAT THAT OVERLAP THE HEALTHY
CONTROLLED CHILDREN.
WHICH MEANS THE PROBIOTIC
INTRODUCTION REALLY HAD A
PROFOUND EFFECT IN THE SPECIES
OF THESE INFANTS.
AND AMONG THOSE LIPIDS WERE A
LARGE NUMBER OF HIGHLY
INFLAMMATORY FATTY ACIDS.
SO BY INTRODUCING THIS DAILY
FOR THE FIRST SIX MONTHS OF
LIFE, IT COULD REALLY
REENGINEER METABOLISM IN THE
FECES OF THESE INFANTS.
BUT THESE ARE SIMPLY
CORRELATIONS, METABOLITES THAT
ARE ENRICHED IN THESE INFANTS.
SO WE MOVED ON TO DETERMINE
WHETHER THE PRODUCTS IN THESE
MICROBIOTICS REALLY HAD AN
EFFECT ON THE IMMUNE SYSTEM
RELATED TO ASTHMA.
SO HERE YOU HAVE THE ASTHMA IN
CHILDREN, ASSOCIATED WITH
REDUCED REGULATORY T SKRELS,
INCREASED TH2 CELLS AND IGE.
SO IF YOU LOOK AT THE CELLS
FROM HEALTHY ADULT OWNERS THAT
DICTATE THE T CELLS AND THEIR
PHENOTYPE BUT WE USE THE CELL
FREE PRODUCTS WITH INFANTS IN
THE TRIAL TO DETERMINE HOW
THEY WILL INFLUENCE THE
DENDRITIC AND T CELL IMMUNITY
IN VITRO.
AND WHAT WE COULD SEE IS AFTER
SIX MONTHS OF SUPPLEMENTATION
WHERE WE SAW THE TINY INCREASE
IN T CELLS AND LIPIDS, WE SAW
A BIG INCREASE IN FREQUENCY
COMPARED TO THE PLACEBO GROUP
AND THE HEALTHY GROUP.
BY 12 MONTHS, WE SAW NO
SIGNIFICANT DIFFERENCE IN
REGISTERED T CELLS FREQUENCY
IN THESE GROUPS AND THAT AGAIN
WAS ASSISTED WITH THE SHIFT
BACK TOWARDS FECAL METABOLOMES
THAT REALLY IS QUITE LIKE THAT
OF THE PREVIOUSLY
PLACEBO-SUPPLEMENTED INFANT
SUGGESTING WHILE THE
SUPPLEMENTATION IS OCCURRING,
THERE IS A REENGINEERING OF
THE METABOLOME THAT HAS AN
EFFECT ON THE IMMUNE FUNCTION.
AND HERE SUE CAN SEE THE
LACTOBACILLUS WEREN'T IN THESE
INFANTS AND TESTIMONIES
STRAIGHTS THAT LACK OF IT IN
INFANTS 6 AND 12 MONTHS OF AGE
SHOWS AS SIGNIFICANT.
SO A BIT LATER IN THE YEAR A
PAPER PRO SPRAYEDD US WITH A
BETTER VIEW OF HOW THE
PROBIOTIC STRAINS WORK ON
SUPPLEMENTATION OF
INDIVIDUALS.
THIS IS THE STUDY FROM THE LM
GROUP AND THEY SUPPLEMENTED
HEALTHY ADULTS WITH A COCKTAIL
OF 11 COMMONLY USED PROBIOTIC
SPECIES, FOLLOWED THESE
INDIVIDUALS OVER TIME AND
SEAMED THEM EXTENSIVELY.
AND WHAT YOU CAN SEE
CONSISTENT WITH THEIR OWN
OBSERVATIONS IS DURING THE
SUPPLEMENTATION PERIOD, MANY
OF THE PRO BIOTICS ARE IN THE
FECES BUT AFTER THE
SUPPLEMENTATION, THEY ARE NOT
FOUND WHICH SUGGESTS THERE ARE
REALLY POOR BIOTIC STRAINS IN
THE PASS GASTROINTESTINAL
TRACK.
THEY WENT ON TO SHOW THE
LOCATIONS OF THE PROBIOTIC
SPECIES THAT HAVE A PREVALENCE
ALONG THE GI TRACT THEY PREFER
TO COLONIZE.
YOU CAN SEE A HEIGHTENED
ABUNDANCE OF THEM AT SPECIFIC
SITES SO THE REGION OF STRAINS
FOR THESE ORGANISMS CONTRIBUTE
TO MUCOSA.
FOR THE STUDY, THE CAPACITY OF
REDUCED ORGANISMS TO COLONIZE
WERE REALLY LINKED TO WHETHER
THERE WERE RELATED COMPETITIVE
STRAINS AT THAT SITE.
SO IF THE ORGANISMS FOUND A
NICHE IN WHICH THEY WERE
COMPATIBLE WITH OTHER PIECE
SEES, THEY WERE LIKELY FOUND
IN THAT SITE.
THE PRESENCE OF THE ORGANISMS,
DID CHANGE THE
TRANSCRIPTAL MUCOSAL PATTERNS
AND THEY HAD THE EARLY
COLONIZATION AND THE
INTRODUCTION OF PRO BY YACHT
TICKS LED TO CHANGES IN T CELL
RESPONSES AND INFLAMMATORY
RESPONSES AND THOSE WITH THE
OTHER INTRODUCTION HAD A
CHANGE IN T CELLS AND RECEPTOR
PATHWAYS THAT PERHAPS, THE
INTRINSIC FACTORS PLAY A ROLE
FROM PREVENTING THE ORGANISMS
FROM COLONIZING THE NICHE.
AND IT MAY BE LIMITED IN
UNIVERSALITY AND PERSISTENTLY
IMPACT THE GUT MUCOSA AND SO
SUGGESTING PERHAPS WE SHOULD
BE THINKING BY DEVELOPING NEW
AND PERSONALIZED PROBIOTIC
APPROACHES FOR TREATMENT FOR A
NUMBER OF CONDITIONS.
>> YOU HAVE ABOUT TWO MINUTES.
>> PERFECT, THANK YOU.
AND JUST TO THINK ABOUT HOW WE
INTRODUCE AND INCORPORATE
THESE KINDS OF APPROACHES INTO
OUR PROBIOTIC TRIALS, THE KEY
IS TO HAVE STANDARDIZED
DEMOGRAPHIC, CLINICAL AND
BIOSPECIMEN COLLECTIONS, BOTH
IN THE PRE, PERI AND POST
SUPPLEMENTATION PERIODS AND I
AM NOT SUGGESTING BY THIS
THERE IS A EXAMINER IN EACH OF
THESE TIME LINES BUT THAT WE
DO LOOK ACROSS THESE THREE
TYPES.
HERE WOULD YOU HAVE THE
SPECIMEN, SKIN SAMPLES
CONDITIONING ON WHAT IS BEING
CONSIDERED AND PARALLEL WITH
BLOOD SAMPLES TO ALLOW
ASSESSMENT OF A RANGE OF STATE
OF MODALITY.
THESE SAMPLES NEED TO BE
PROCESSED AT THE TIME OF
COLLECTION AS PRESERVED AND
UNPRESERVED FRACTIONS TO ALLOW
THE AS SIT ANALYSIS, DNA AND
RNA BASED ANALYSIS TO
UNDERSTAND TRANSCRIPTAL
DIVERSITY BOTH OF THE HOST AND
MICROBIOME TO ALLOW US TO
FACILITATE THE APPROACHES AND
REALLY FUNCTIONAL ASSAYS, LIKE
THE IMMUNE ASSAYS, THE MASS
SPECTOMETRY ANALYSIS TO ALLOW
THE MICROBIOME ON PHYSICAL
LOGICAL FEATURES IN VITRO.
AND ULTIMATELY WHAT WOULD BE
IDEAL IS FOR ALL THIS DATA
FROM THESE TRIALS TO BE AS
MENTIONED, LOCATED IN A DATA
LIBRARY, TO BE A RESOURCE FOR
US TO CONTINUE TO UNDERSTAND
WHO RESPONDS, HOW THEY
RESPOND, THE FEATURES OF THOSE
WHO MAY BE RESPONSIVE TO
SPECIFIC PROBIOTIC
SUPPLEMENTATION AND THIS IS
KIND OF DATA THAT WILL BE
FACILITATED BY MACHINE
LEARNING APPROACHES AS HAS
BEEN MENTIONED.
SO I WILL LIKE TO THANK THOSE
WHOSE WORK I SHARED WITH YOU
TODAY, A NUMB OF INDIVIDUALS
IN OUR GROUP WHO MADE OUR
STUDIES POSSIB
THANKS TO THE ORGANIZERS I WILL
GIVE A LITTLE BIT OF AN
OVERVIEW WHERE THAT GOT
MICROBIOTA HAS TAUGHT ABOUT
THE GUT INTERACTIONS BETWEEN
THE BRAIN AND WE HAVE BEEN
ABLE TO HARNESS THAT
INFORMATION TO DROP THAT
INTERACTION SO VERY QUICKLY
THERE ARE CONDUITS SO THE
CHEMICAL COMMUNICATION THAT
ARE TRANSFORMED IN THE LIVER
AND IMPACT BEHAVIOR.
THE CONTEXT HERE IS SPECTERS
ON OUR SPECTRUM DISORDER.
AND THEN IS DIAGNOSED.
THERE ARE A NUMBER OF
COMORBIDITIES FOR AUTISM THAT
ALSO IMMUNE DYSFUNCTION WHERE
ALL OF THE VALLEYS THAT ARE
IMPACTED.
IT GETS ACROSS THE
EPITHELIUM AND THEN IS IN THE
LIVER.
THIS IS A RELATED COMPOUND AND
THEN TO BE ELEVATED IN HUMAN
AUTISM THAT IS IN THE COHORT
WITH THE SAME CHEMICAL
CATEGORY WE WILL COME BACK TO
THIS TREATMENT THAT
ESSENTIALLY NEUTRALIZES ALL OF
THE METABOLITES.
SO I MENTIONED AND TO PRODUCE
THAT AND OF COURSE YOU WANT TO
TRANSLATE THIS TO HUMANS AND
WE PUBLISH THE DATA SET PATH
FROM SAMPLES GIVEN TO US WHERE
THEY HAD COLLECTED PLASMA AND
FECES THAT ARE TYPICALLY
DEVELOPING INDIVIDUALS TO A
LARGE DATA SET AND THEN ONE
THIRD OF THE INDIVIDUALS AND
ABOUT ONE THIRD OF THESE WITH
AUTISM THOSE HAVE
GASTROINTESTINAL SYMPTOMS AND THEN
THEY ENGINEERED STRAINS TO
PRODUCE WITH THOSE BACTERIAL
STRAINS ARE IDENTICAL EXCEPT
THE EP POSITIVE BACTERIA TO
HAVE THESE GENES AND THEN THE
SAME BACTERIAL SPECIES THAT DO
NOT CONTAIN.
SO THAN THE COLONIZED TWO
GROUPS OF MICE WHETHER THE
NEGATIVE GROUP OR THE POSITIVE
GROUP THAT DISTINGUISHES THESE
TWO GROUPS OF MICE AND THEN WE
VALIDATED WE COULD ELEVATE FOR
EP IN THE FECES OF THESE
ANIMALS IN THE CIRCULATION
SHOWING HERE WITH LOSS OF
BLOOD THAT WE CAN DETECT AND
IF WE BLOCK EXPORTS WE WILL
SEE A BUILDUP OF EPS IN THE
BRAINS OF THESE ANIMALS.
WE DON'T DETECT MUCH FOR THE
CIRCULATION WITH A
QUANTITATIVE CONVERSION AND
OTHER LINES OF EVIDENCE.
SO WE SHOWED THE BRAIN
ACTIVITY AND ANYTHING IN RED
IS MORE ACTIVE FOR THOSE WHO
UNDERSTAND THE ANATOMY OF THE
BRAIN THIS IS A PART OF THE
LIMBIC SYSTEM WITH EMOTIONAL
BEHAVIOR AND REGULATION THERE
ARE A NUMBER THAT ARE LESS
ACTIVE WE DON'T HAVE TIME TO
SHOW IS THE CHANGE OF
CONDUCTIVITY WHICH HAS BEEN
SHOWN AND MOUSE MODELS.
>> WE WANT TO UNDERSTAND HOW
THE BRAIN REGIONS CHANGES AND
MANIFESTS REGULAR OR MOLECULAR
SO WITH SIX DIFFERENT BRAIN
REGIONS AND THE PIE CHART
SHOWS GENES IN SIX OF THESE
REGIONS THIS IS THE REGION
THAT IS MOST EFFECTIVE AND
THOSE THAT WERE IN THIS REGION
THAT IS PRETTY INTERESTING AND
THEN THE PANEL ON THE BOTTOM
BUT ALSO ON THE PRECURSORS AND
THAT'S WHAT YOU SEE IN THE OPC
IMAGE.
SO THEN WE WENT TO VALIDATE.
AND THEN SPECIFIC FOR THOSE
PRECURSOR CELLS.
AND THOSE THAT DO HAVE
PRECURSORS ARE ELEVATED AND ON
THE RIGHT SIDE YOU CAN SEE
WITH THAT EXPRESSION OF GENES
THAT ARE ASSOCIATED.
SO IT REALLY LOOKS LIKE IN ALL
THE MATURATION AND AFTER THEY
TOLD US.
AND THEN TO LOOK AT SURFACE
MARKERS TO DIFFERENTIATE AND
THEN YOU CAN SEE ON THE LEFT
BARS THAT QUOTIENT FOR EP
POSITIVE WHERE THIS INCREASED
TO THE NEGATIVE GROWTH SHOWING
THAT THERE ARE MANY LESS
MATURE SITES PER VOLUME TO
THAT THERE ARE NO DIFFERENCES
SO WE PROPOSE THAT THEY ARE
THERE BUT THOSE ARE
DIFFERENCES THAT THERE IS A
RESTRAINT IN THE MATURATION.
ALSO FOR THOSE WHERE WE LOOKED
AT ADDITIONAL MARKERS LOOKING
AT THOSE POPULATIONS OF CELLS
AND THEN AGAIN WITH A PROFILE
THAT THERE ARE LESS MATURE IN
THE POSITIVE GROUP VERSUS THE
NEGATIVE GROUP AND THIS IS THE
CASE AS WELL SO ALL THE SITES
HAVE A NUMBER OF DIFFERENT
FUNCTIONS THAT PRIMARILY THEY
HELP WITH SIGNALING ACROSS THE
AXONS.
AND WITH THAT ELECTRON
TOMOGRAPHY TO VISUALIZE THE
MYELIN WHICH IS THE SHEATH
THAT COVERS THE AXON LIKE THE
CODING ON A COPPER WIRE
HELPING TO TRANSMIT SIGNALS
LONG DISTANCES.
AND AGAIN WE SEE THE PANEL
BASED ON THE PROGRAMS THAT
THERE ARE MORE AXONS AND GROUP
A HIGHER G RATIO FOR CELL
STRUCTURE AND THEN WE SEE
THINNER MYELIN AND THAT IS IN
THE POSITIVE GROUP AND THEN
THAT WAS QUANTITATIVE AND THE
MYELIN IS THINNER IN THE
POSITIVES US ALL CONSISTENT
WITH MATURATION AND AND THEN
TO LOOK AT THE NUCLEUS OF THE
THALAMUS SPECIFICALLY AND THE
LOWER FA SCORE MEANS THERE'S
MORE DISORGANIZED MYELIN
CONSISTENT WITH THE PREDICTION
OF GENE EXPRESSION.
SO WITH THIS MATURATION WITH
THE MYELINATION DEFECTS.
SO WILL THIS PROMOTE ALTERED
BEHAVIOR QUICK SO USING TEST
FOR ANXIETY, WE CAN SHOW ON
THE LEFT SIDE IT ENTERS LESS
AS A MEASURE FOR ANXIETY AND
TO BE PLACED ON THE PLATFORM
THE MORE ANXIOUS MICE DO NOT
OPEN AS FREQUENTLY AS THOSE
THAT ARE IN THE PEANUT
NEGATIVE GROUP.
SO THERE'S A NUMBER OF OTHER
BEHAVIORS THAT ARE ALTERED
THAT ARE CONSISTENT WITH THE
FACT THE LIMBIC SYSTEM IS
INFECTED.
ALL OF THESE ARE EMOTIONAL
BEHAVIORS SO THERE IS NO
COGNITIVE BEHAVIOR OR CHANGE
IN MODAL BEHAVIOR.
I WILL FINISH IN A COUPLE OF
MINUTES.
SO ULTIMATELY THIS WORKING
HYPOTHESIS TOGETHER TO CHANGE
A NUMBER OF METABOLITES AND
THERE IS AN INCREASED WITH THE
PSYLLIUM AND FENNEL AND THEN
SULFATED AND WITH THE CELLULAR
AND MOLECULAR STRUCTURES AND
BEHAVIORS WITH WHAT WE BELIEVE
TO BE BRAIN SIGNALING.
SO WE SAID CAN WE INTERVENE
AND USE PROBIOTICS AS WELL TO
REPAIR THE EPITHELIUM AND THEN
TO ASK CAN WE IDENTIFY A SMALL
MOLECULE DRUG TO INTERFERE
WITH SIGNALING FROM THE BRAIN?
SO WE HAVE AST 120 AND THEN WE
SHOW TO ADMINISTER THIS DRUG
IMPROVES EMOTIONAL BEHAVIORS
THAT THEN IN A NUMBER OF
DIFFERENT PARADIGMS AND THEN
WE CAN SEE THAT CONTROL MICE
HAVE BEHAVIORAL CHANGES FROM
THE DRUG IMPROVING AND WE
SHOULDERS LEVELS.
THEN WE DESIGN SMALL CLINICAL
TRIAL WITH 26 ADOLESCENTS OF
AUTISM BETWEEN 12 AND 17 YEARS
OF AGE.
THE TRIAL INCLUDED EIGHT WEEKS
OF DOSING ADMINISTERING TWICE.
TO LOW-DOSE TO MEDIUM AND THEN
HIGH-DOSE AND THEN TOOK
BEHAVIORAL MEASUREMENTS AND
TISSUE SAMPLES THROUGHOUT THE
COURSE OF THE TRIAL AND IT'S
IMPORTANT TO MENTION.
AND INITIALLY WE SHALL
ENGAGEMENT AND THEY ARE ALL
VERY SIMILAR IN THE URINE AND
THE DATA AND THE PLASMA AS
WELL AND SO WE BELIEVE BY
HAVING THIS ORALLY AVAILABLE
BUT NOT OBSERVABLE IT DOES NOT
PENETRATE INTO THE CIRCULATION
AND IT SEQUESTERS THOSE
METABOLITES THEY ARE EXCRETED
AT THE CIRCULATORY LEVEL.
SO LOOKING AT CLINICAL SCORES
WE SEE A NUMBER OF DIFFERENT
BEHAVIORAL IMPROVEMENTS FOR
ANXIETY AND VULNERABILITY.
AND YOU CAN SEE MANY OF THE
INDIVIDUALS WITHIN A WEEK
PERIOD AND THEN TO SEE A VERY
NICE DECREASE WITH A TOTAL
POPULATION BUT ALSO THE RIGHT
HAND PANEL IN THOSE
INDIVIDUALS MANY IMPROVED IN
EIGHT WEEKS AND THERE WAS A
FOUR WEEK WASHOUT SO THAN TO
STOP THE DRUGS AND FOUR WEEKS
LATER MANY SYMPTOMS HAVE
REBOUNDED.
SO THIS IS A CONCEPT TO HAVE
IMPROVEMENTS HAVE BEHAVIORAL
OUTCOMES WHICH IS VERY MUCH A
CONCEPT AND THEN FINALLY THE
ACKNOWLEDGMENT SLIDE AND
HIGHLY COLLABORATIVE TO HELP
US ALONG THE WAY SORRY I WENT
A COUPLE MINUTES OVER.
>> JUST A REMINDER DON'T
FORGET TO SUBMIT YOUR
QUESTIONS FOR THE PANEL
DISCUSSION COMING UP.
THE FINAL SPEAKER SESSION ONE
WE WILL TALK ABOUT
OPPORTUNITIES AND CHALLENGES
FOR MEDICINES BASED ON
BACTERIAL CONSORTIUM.
>> THANK YOU VERY MUCH.
DR. MENON: THANK YOU VERY MUCH
FOR THE OPPORTUNITY TO SPEAK
HERE TODAY AND TO THE REST OF
THE SPEAKERS FOR THEIR
EXCELLENT INSIGHTS AND
RESEARCH PRESENTED SO FAR.
THE ASPECT OF PRECISION ARE
THE CHALLENGES HAS TO DO WITH
ONCE THE DRUG MEASURES
AFFECTED WHAT IS NEEDED TO
RATIONALIZE CHEMICAL SUCCESS
AND FEARS AND THEN A SHARE OF
THOSE STUDIES OF CONSORTIA.
I AM AN EMPLOYEE AND WHAT WE
SHARE TODAY'S BASED ON
ANYTHING THAT HAS NOT BEEN YET
APPROVED BY THE FDA BACK
TESTED.
>> TO MAKE AN ANALOGY THAT HAS
BEEN RAPIDLY ADVANCING SOME OF
THOSE BIOLOGICS AND THAT
EVOLUTION OVER THE PAST
CENTURY AND THOSE CHALLENGES
IN THE MICROBIOTA AND IN
ESSENCE SOLVING A SIMILAR
PROBLEM THE COMPLEX BIOLOGICAL
MATERIAL IS DIFFICULT TO
QUANTIFY THAT POPULATION IN
THE CONTEXT OF PLASMA AND
FINALLY THEN WITH ACTIVE
INGREDIENTS WITH THE
UNDERSTANDING OF THE FACTORS
DEFINED CONSORTIA TO PRECISELY
SCREEN AND CHARACTERIZE AND
MANUFACTURE AND TRACK THE DRUG
AND AMONG OTHER THINGS IT LETS
US ASK TARGETED QUESTIONS THAT
WE DO NEED TO ESTABLISH SOME
DEFINITIONS OF THE BIO
THERAPEUTIC PRODUCT.
HOW THE HOST AFFECTS THE DRUG
CAN BE THOUGHT OF OF THE
ABUNDANCE OF THE BACTERIA AND
THE AFFECTION AND HOW LONG
THEY STICK AROUND FOR SO THE
PERSISTENCE AND THAT HAS TO DO
WITH HOW THE DRUG AFFECTS THIS
IS ABOUT BIOCHEMICAL AND FOR
MICROBIOTA TREATMENTS IT HAS
TO INCLUDE THE MICROBIOTA AND
METABOLITES.
IT'S VERY DIFFICULT TO CAPTURE
THE REASONABLE QUANTITATIVE
WAYS IN THESE PROCEDURES
BECAUSE OF THE BATCH TO BATCH
VARIABILITY AND MAKES IT HARD
TO RATIONALIZE.
IT'S CHALLENGING EVEN IN THE
CONTEXT BUT IT IS FEASIBLE.
SO WHAT DO I MEAN ABOUT
COMPLEXITY WITH THE HUMAN
DEFENSE OF THE TRIFECTA AND
THE BIOCHEMICAL HABITAT AND
THE DISEASE CONTEXT AND SO ON.
SOME OF THE FACTORS I HAVE
HIGHLIGHTED THE IMPACT OF THE
DOSING SCHEDULE AND
IMPORTANTLY THE INTERACTION
WITH THE BROAD-SPECTRUM
ANTIBIOTICS AND WITH NO OTHER
BACTERIAL DEFEND CITY MINE --
DENSITY AND THEN TO CREATE A
CHANGE FOR ADVANCEMENT.
SO THE FOCUS OF MY TALK TODAY
WILL ADDRESS AS WHAT I VIEW AS
A KEY GAP IN THE CLINICALS ON
-- THE CLINICAL SPACE
PARTICULARLY WITH RESPECT WITH
ANTIBIOTICS.
BUT BEFORE WE GET THERE WITH
THE ISSUE OF DRAFTING THE
BACTERIA THAT HAVE BEEN
INTRODUCED AND TELLING THEM
APART FROM WHAT WAS ALREADY
THERE.
OUR APPROACHES SOLVING THIS
PROBLEM HAS TWO STEPS PUSHING
THAT UNIQUE SO ON THOSE
GENOMES AND THEN WE HAVE A
PROCESS IN EACH GENOME THAT IS
BASED ON COVERAGE ONE IS SHOWN
ON THE X AND THE OTHER THAT IS
THE INVESTIGATIONAL PRODUCT
AND EVERYTHING IN GREEN
REPRESENTS EXPECTED
RELATIONSHIP FROM THE META-
GENOMIC SAMPLE AND THOSE
DEVIATIONS IN RED FOR EXAMPLE
CAN INDICATE A HIGH DEPTH OR
PART OF THE GENOME THIS CAN BE
AN ARTIFACT AND WITH THIS
APPROACH AND THEN LOOKING AT
THOSE KINETICS.
AND THEN WITH THOSE
MODALITIES.
AND WITH THOSE LONG-DISTANCE
CASE.
AND THEN PLEASE STICK AROUND
TO UP TO A YEAR.
AND THESE QUANTITIES THE
OVERALL EXPOSURE AND ARE THEY
DOSE-DEPENDENT?
AND IF THE TREND EXIST IS THAT
PART OF THE CONSORTIUM THAT
NOW WE ARE STARTING TO COLLECT
THE DATA TO ANSWER THESE TYPES
OF QUESTIONS AND THIS IS A
SIDE THAT MAKES ME VERY
HAPPY.
THESE ARE STOOL SAMPLES
COLLECTED THROUGH PHASE I AND
PHASE II STUDIES IN DIFFERENT
PATIENT POPULATIONS.
AND WITH THOSE SAMPLE
COLLECTIONS DURING ANTIBIOTIC
TREATMENT AND DOSING.
AND OF THE HOST BIOME SYSTEM
WITHIN THE FRAMEWORK.
AND OF THOSE FEATURES MAY BE
GENERALIZED AND I WILL GIVE
YOU A COUPLE OF EXAMPLES AND
THEN THOSE VOLUNTEERS AND THAT
WAS RECENTLY PUBLISHED A
COUPLE OF WEEKS AGO AND THE
DETAILS GO CHECK IT OUT.
AND THEN WITH THOSE
FREQUENCIES.
AND THEN TO CONTROL THE ONLY
ONE THERE WAS AN ANTIBIOTIC
AND THEN SO THEN WE LOOKED AT
WHAT GOD IN.
AND THEN ON THE AXIS FROM THE
START OF DOSING FROM ONE YEAR
AFTER AND SO THOSE HIGH LEVELS
OF OBSERVATIONS CAN BE
DISTINGUISHED IN THE GROUP
WHICH IS ONE OF THOSE COHORTS
AND WE SEE THOSE SPECIFIC
DETECTIONS IS VERY DIFFERENT
FROM VERY MORE QUANTIFIABLE
WERE THIS IS MOSTLY
BACKGROUND.
AND THOSE ARE DETECTED IN MOST
REGIMENS AND THERE IS A
DISTINCT DOSE FROM SINGLE-DOSE
CORE FOR COHORTS HERE YOU CAN
SEE AN INCREASE THAT IS MORE
ROBUST AND FINALLY AND THEN
ENHANCES COLONIZATION AND THAT
HAS MUCH MORE COLONIZATION
FROM THESE COHORTS SO LOOKING
AT ABUNDANCE THAT YOU CAN SEE
EXPANDING THE ABUNDANCE AND
THAT WE REACH LEVELS THAT ARE
COMPARABLE BETWEEN ONE AND
10 PERCENT AND THEN THROUGHOUT
WEEK 12 AND STARTS TO DEFINE
AFTERWORDS AND IN TRADITION
USING TO QUANTIFY THAT
EXPOSURE OR TO GO BACK TO
CONSORTIUM THEN TO CALCULATE
THE AREA AND THEN WE CAN
CONSOLIDATE WOULD'VE TOLD HER
ON -- TOTAL EXPOSURE WITH THE
SINGLE INCREASING DOSES.
AND THEN TO EXPOSE THE TREND
IS EVIDENT AND WE CAN SEE THAT
AND THEN IT IS NECESSARY AT A
HIGH LEVEL FOR A LONGER PERIOD
OF TIME SPENT THESE
OBSERVATIONS ARE GENERALIZED
AGAINST THE CONSORTIA AND
LARGER STUDIES WITH THIS
EXPOSURE TO THE DOSE.
WITH THOSE COMBINATIONS WITH A
HIGH DOSE LEVEL AND THEN THIS
CONFIRMS THOSE OBSERVATIONS SO
FIRST IN THE LEFT COLUMN
NEITHER COHORTS SEIZED
COLONIZATION BUT IN THE MULTI-
DAY DOSING WE SEE THE
TRANSIENT COLONIZATION IT
DECLINES AFTER ACTIVE DOSING
IS COMPLETED.
WHERE AS IN THE RIGHTMOST
COLUMN YOU SEE CONDITIONING
ROBUST COLONIZATION AFTER SIX
MONTHS AND THE HIGH DOSE GROUP
BUT IT IS HIGHER.
SO THEN ON A SINGLE SLIDE, WE
SEE THE FINDING IT IS
IMPORTANT THROUGH THE
CONSORTIA WHILE THE DOSE LEVEL
HAS A LESSER AND LESS
CONSISTENT EFFECT.
AND THEN TO GET STRINGS INTO
THE SUBJECT AND THEN EIGHT
WEEKS AFTER STARTING DOSES OF
HOW LONG IT TAKES.
>> BUT BEFORE I WIND UP I WANT
TO GIVE YOU A BRIEF TASTE OF
THE COMPLEXITY.
BECAUSE THE DOSE AND THE
MICROBIOTA.
SO THAT TOP LEFT THIS IS THE
MEASURE ONCE AGAIN FROM LEFT
TO RIGHT AND THAT IS WHERE IT
STARTED OUT AND ONE WEEK AFTER.
BUT THE DIFFERENCE FROM LEFT
TO RIGHT INDICATES
DOSE-DEPENDENT RECOVERY SO
QUICKER IN A HIGHER DOSE
GROUPS.
AND WHILE THIS IS HAPPENING A
DIMINISHING OF FACTS.
AND IN THOSE COHORTS AND THE
OTHER MEASURE OF RECOVERY.
AND IM SHOWING ON THE LEFT
WITH THE PRIMARY AND SECONDARY
THAT ARE ELEVATED IN THE STATE
WITH SPECIFIC THEY ARE KNOWN
TO INSTIGATE WHERE THE
SECONDARY ARE SUPPRESSED OR
INHIBITS FORMATION AND THAT IS
WHY IT IS CLINICALLY RELEVANT
IF WE LOOK AT IT FROM THE
APPLICATION.
AND THOSE ASSETS ON THE LEFT
AND THE EXPEDITED RECOVERY AND
IN FACT THE CONVERSION PRIMARY
TO SECONDARY THE GET COMMUNITY
STARTS OF THE GROUPS OF
MICROBIOTA AND AND WITH THOSE
THERAPEUTICS IT HAS TO BE TIED
TO THE MICROBIOLOGY.
>> AND JUST WHAT I HAVE'S
SHOWN YOU TODAY THAT IS A LOT
OF ACRONYMS BUT IT IS CRITICAL
TO MAKE SENSE AND STEP ONE TO
FIGURE OUT WHY A STUDY WORKED
AND WHY IT DID NOT AND WITH
THOSE GENOMICS AND THE LIBRARY
COULD BE USED TO TELL APART
THE STRAINS INTRODUCED FROM
THOSE THAT ARE ALREADY IN
PEOPLE THAT KEEP IN MIND THAT
I MEASURE OVERALL DRUG
EXPOSURE THAT MAKES US DRUG
DEPENDENT.
AND THEN THE MICROBIOTA WITH
THOSE DEPENDENT AFFECTS SEEN
IN THE RECOVERY.
AND WITH THAT I WOULD JUST
LIKE TO ACKNOWLEDGE THE VERY
TALENTED TEAM FROM JANSSEN
PHARMACEUTICALS AND OUR KEY
COLLABORATORS THAT ALLOWED
THIS MAMMOTH WORK TO COME
TOGETHER.
THANK YOU VERY MUCH FOR YOUR
ATTENTION.
>> THANK YOU LIKE THAT
MECHANISTIC MICROBIAL.
THAT'S A TERM OF THE DAY SO
FOR THE PANEL DISCUSSION I
WILL TURN THAT OVER TO START
THE DISCUSSION WITH GABRIELLA.
>> THANK YOU FOR THE WONDERFUL
SPEAKERS AND IN MANY
CHALLENGES WITH DISCUSSION AND
WE HOPE WE CAN GO MORE IN
DEPTH TO SOME OF THE
CHALLENGES.
THAT THE INVESTIGATORS AND SO
THEN ACTUALLY SO WE HAVE THOSE
QUESTIONS AND THEN ASK IF HE
CAN ADDRESS WHAT ARE THE
CLINICAL GAPS FOR THE
KNOWLEDGE AND METHODOLOGY?
AND WHAT ARE THE NEW
RESOURCES?
AND THEN TO ADDRESS SOME OF
THE GAPS.
>> IT IS A VERY LONG QUESTION.
I WILL ALSO DEFER TO OTHERS.
THERE IS A LOT.
AS A SAID IN MY TALK WE HAVE
TO REMEMBER HOW BIG THE FIELD
THIS IS.
AND THEN WITH THE BENCH
RESEARCH AND HOW FAR WE HAVE
COME.
ALSO WE NEED TO REMEMBER HOW
FAR WE ARE FOR THOSE THAT HAVE
LESS DIET AND MICROBIOTA
INFLUENCE.
BUT WE HAVE LOTS OF EXCITING
THINGS THAT WILL HAPPEN OVER
THE NEXT 20 YEARS.
>> BUT CLINICALLY THE MOST
EXCITING IS WHAT JEFF IS
TALKING ABOUT.
AND OBVIOUSLY AND THAT IS
WHERE A LOT OF RESEARCH WILL
GO.
I DON'T THINK IT IS A CURE-ALL
AND THEN WITH DIABETES AND
HYPER TRIGLYCERIDES BUT.
>> BUT I HAVE ONE SPECIFIC
QUESTION.
AND THEN AND THEN HAD WE MAKE
IT WORK?
AND THEN WITH A COMPLIANCE FOR
THE DIET OR THE DATA
COLLECTION.
AND WITH THOSE CLINICAL
TRIALS.
AND THEN DAYS SEND OR
SOMETHING AND THEN WE COLLECT
THE PILLS AT THE END BUT THE
NICE THING IS YOU CAN TEST
WITH THE INTERVENTION
PROBABLY.
YOU CANNOT BE SURE BUT
COMPLIANCE AGAIN CLINICAL
MEDICINE IS SLOPPY.
IT'S PROBABLY HARDER EVEN IN
BETHESDA MARYLAND PATIENTS ARE
NOT ALWAYS IN COMPLIANCE SO WE
ALWAYS TRIED TO MEASURE AND
THEN THE SECOND PART I FORGOT.
>> IT IS THE EXPRESSION WHY
DID IT WORK?
SO THOSE THINGS TO PUT BACK
AND THEN TO SPECIALIZE IT'S AN
IMPORTANT OBSERVATION WE CAN
MAKE.
BECAUSE IT WORKED OR DID NOT
WORK.
AND THEN TO LESSEN SOMETHING
LIKE THAT.
WITH THAT EXPERIENCE WITH
SOMETHING TO SHARE.
>> THESE ARE 10000-FOOT
QUESTIONS.
[LAUGHTER]
>> I KNOW.
>> I AM WONDERING IF I CAN
THROW A QUESTION OUT THERE?
I AM WONDERING FOR OTHER
MEMBERS AND OTHER SPEAKERS IN
THE FIRST SESSION ARE THERE
APPROACHES THAT CAN BE ADOPTED
FOR INTERVENTIONS FROM GENETIC
RESEARCH WHERE PEOPLE ARE
RANDOMIZED ACCORDING TO A
RELEVANT GENOTYPE LIKE OMEGA-3
FATTY ACID SYNTHESIS ON
POLYMORPHISM TYPE ARE THERE
METHODS FOR OTHER INTEGRATED
MODALITIES WITH MEDICAL
APPROACHES OFTEN WITH
DIFFERENT PARTICIPANTS HAVE A
RANDOMIZED STRUCTURED APPROACH
TO DIFFERENT INTERVENTIONS
BASED ON THE CHARACTERISTICS
AT THE START OF THE TRIAL ARE
SOME OF THOSE APPROACHES
USEFUL FOR STUDYING PROBIOTICS
BASED ON DIET AND
CHARACTERISTICS HOW DO YOU GO
ABOUT USING THAT INSTRUCTION
QUICK.
>> I THANK YOU ARE ASKING AN
AWFUL LOT.
THAT'S A WONDERFUL QUESTION
BUT MICROBIAL COMMUNITY IN
DIFFERENT COMPONENTS ARE MANY
DIFFERENT THINGS TO HOST
BIOLOGY AND THOSE WOULD HAVE
DIFFERENT EFFECT SIZES AND
THEN YOU HAVE TO BEGIN BY THE
GIFT OF ATTENTION ONE
BIOLOGICAL QUESTION IN TERMS
OF THE RELATIONSHIP BETWEEN
MICROBIAL COMMUNITY AND THE
OPERATIONS.
AND THE TYPE OF STEPS THAT THE
SPEAKER TALKS ABOUT HER HIGHLY
RELEVANT AND TO DEFINE A
PARTICULAR TARGET TO
UNDERSTAND THE BIOLOGICAL
SIGNIFICANCE OF STRING LEVEL
VARIATION WHICH IS ENORMOUSLY
INSPIRING.
IF YOU DO IDENTIFY THE TARGETS
OF THE PRECLINICAL MODELS
REPRESENTATIVE OF A POPULATION
AS A WHOLE, STILL TASK WITH
THE EXPERIMENTAL MEDICINE
PARADIGM OF RANDOMIZED
CONTROLLED STUDY TO UNDERSTAND
WHAT THE INDIVIDUAL IS PRIOR
TO THE INTERVENTION IF YOU HIT
THE TARGET.
AND THEN THE EFFECT SIZE OF
THE POPULATION.
THAT WILL BE THE PREREQUISITE
FOR SUBSEQUENT TRIALS.
IF YOU DO SEE THAT EFFECT ON A
HOST SYSTEM THEN YOU HAVE TO
DETERMINE IF THAT INTERVENTION
IS A DIRECT RESULT OF THE
ORGANISM OF INTEREST AND IF IT
IS PRODUCING EFFECT VOICE
INTERACTION WITH OTHER
ELEMENTS.
AND THIS IS WHAT THE FIELD IS
ABOUT.
AND DIFFERENT COMPONENTS OF
DIFFERENT MICROBIAL
COMMUNITIES.
AND SO I'M WORRIED THIS IS
ABOUT SYSTEMS BIOLOGY SO THAT
IS MY PHILOSOPHICAL RESPONSE.
>> SO IS THIS A SYSTEM BIOLOGY
AND MICROBIOLOGY.
>> ONE ASPECT OF EXPERIMENTAL
MEDICINE JUST ONE TEAM
APPROACHING ALL DISEASES?
THE QUESTION ASKING ABOUT
COMPLEXITY AND BRAIN BIOLOGY
OF NEURODEVELOPMENT THERE IS
SO MANY DIMENSIONS TO THAT AND
SO MANY ASKED ABOUT THOSE IN
THE MICROBIOTA.
>> I JUST WANT TO ADD THE
FOLLOWING THAT WE UNDERSTAND
THE COMPLEXITY OF THE ACTIONS
OF THE SYSTEM TO BRING
RESOURCES AND DATABASES TO
MOVE FORWARD.
BUT THAT IS THE PRODUCTS OF
THE BACTERIA AND THEN TALK
ABOUT THOSE COMPOUNDS.
AND THAT IS CORRELATED WITH
ANXIETY.
AND THESE ARE MARKERS TO MOVE
FROM THIS COMPLEXITY.
AND THEN WE CAN MESH ON --
MEASURE AND METABOLIZE.
AND WITH THE STRATIFICATION
AND LOOK AT THOSE WHO ARE THE
MOST AFFLICTED WITH THAT
CHANGE OF THE MICROBIOTA SO
I'M SAYING THAT BIOCHEMISTRY
CAN EVEN MARK THAT
STRATIFICATION IF WE DON'T
UNDERSTAND THAT COMPLEXITY OF
THE INTERACTIONS TO SATISFY AM
UP FOR A RESPONSE.
SO IS THAT CORRELATED WITH THE
BENEFIT?
WE DO HAVE THE PROMISE WHILE
WE LOOK AT THE COMPLEXITY.
>> .
>> THANK YOU I JUST WANT TO
ECHO THAT THE TRIAL IS
DEPENDENT ON THE QUESTION.
SO DO YOU THINK IN THE SPACE
WITH THAT ADAPTIVE TRIAL FOR
STUDY POPULATIONS.
AND ALSO IT HAS A LARGE
PLACEBO THAT'S UNANTICIPATED
THAT'S ALLOW YOU TO GROW YOUR
SAMPLE SIZE.
SO THESE ARE TECHNIQUES THAT
CAN BE USED EITHER TO IDENTIFY
AND THEN IT IS A TOOL THAT CAN
BE USED.
>> THE QUESTION HAS TO BE WELL
THOUGHT OF AND PRECISE.
>> AND THAT IS VERY SPOT ON
AND THERE IS A NEED WITH NON-
MICROBIOTA AND THEN AND HOW TO
DO PATIENT ELECTION AND
STRATIFICATION.
AND THEN TO HAVE THAT
ECOLOGICAL OUTCOME AND THEN IF
YOU ARE TRYING TO MODULATE THE
ACCESS OR STIMULATE THE IMMUNE
SYSTEM.
YOU MAY HAVE VERY DIFFERENT
WAYS THE COMMUNITY RESPONSE
AND THE WAY YOU MIGHT THINK
ABOUT IDENTIFYING PATIENTS WHO
ARE MOST LIKELY TO BENEFIT
FROM THAT KIND OF INTERVENTION.
SO IT'S IMPORTANT WE ARE
STARTING TO DO THIS NOW TO
DEFINE THE DATA THAT IS NEEDED
THAT CAN THEN BE USED IN THE
SYNDICATIONS AND CATEGORIES SO
HOW DO WE SELECT A PATIENT AND
WHY IT IS THE SIGNATURE?
IT SIMPLER WHEN WE TRY TO SEE
ECOLOGICALLY WHAT TYPE OF
MATHEMATICAL METHODS THAT CAN
BE PREDICTED BASED ON THAT BUT
IT BECOMES MUCH HARDER WITH
THOSE RESPONSES.
AND THEN WE NEED DATA TO PUT
THE PRINCIPLES OF PRECISION
INTO A FIELD THAT IS HARD TO
GENERALIZ GENERALIZE.
>> IT'S THE SAME TYPE OF DATA.
>> I JUST WANT TO EXTEND THE
COMMENT BUT PHARMA STILL
STRUGGLES TO IDENTIFY PATIENT
POPULATIONS THAT ARE MOST
LIKELY TO RESPOND TO DISEASES
THAT HAS BEEN DRUGGED FOR
DECADES.
AND THE HOST OF OTHERS AND
IT'S VERY HARD TO KNOW WITH
THOSE THAT ARE CLINICAL
TRIALS.
TO UNDERSTAND IS THAT FOR THE
FIELD OF THE MICROBIOTA VERY
COMPLEX TO A PARTICULAR
DISORDER THAT IS BEEN FIGURED
OUT.
SO WE STILL NEED MORE DATA.
AND WITH THOSE GENETIC
DISORDERS COULD CONSTRAIN AND
INCREASE THE PART BUT WE'RE
NOT THERE YET FOR MICROBIOTA.
SO WE SELECT FOR CRITERIA IS
THAT HAD GASTROINTESTINAL
SYMPTOMS AND THEN THAT ARE
FUNDAMENTALLY ARE SECONDARILY
RELATED AND THAT HYPOTHESIS IN
THE FIELD OF CLINICAL TRIAL WE
DON'T KNOW.
AND OF THOSE PARTICULAR
VARIABLES SIDE-BY-SIDE.
>> BUT BECAUSE AS ACTIVE
RESPONSE OF ALL SITUATIONS IN
THAT.
>> THE MICROBIOTA IS NOT
EVERYTHING.
AND WITH THE ELECTRONIC HEALTH
RECORDS AND THEN TO HARMONIZE
AND THOSE TRUE FEATURES
PATIENCE TO RESPOND THOSE ARE
MICROBIOLOGICAL AND IN YOU AND
RELATED TO DEMOGRAPHIC DATA
FOR EXAMPLE.
AND JUST EXPECTING THE
MICROBIOTA AND WHO WOULD BE
RESPONSIVE TO TREATMENT.
WE NEED TO TAKE A FAR MORE
HOLISTIC VIEW OF HUMAN BIOLOGY
AND THOSE OF THOSE
INTERACTIONS.
>> .
>> AND THOSE STRATEGIES THAT
ARE INTERESTING BUT ONLY
USEFUL CLINICALLY AND THEN TO
BE VALIDATED.
AND HOW LONG WOULD THAT TAKE?
>> I CAN COMMENT.
SO THEN TO IDENTIFY CERTAINLY
WILL HELP US AND FOCUS
STRATEGIES SO WITH THOSE
COMPOUNDS.
AND THEN WE ARE WITHIN THOSE
COMPOUNDS WITH A HANDFUL OF
THOSE METABOLITES.
AND WITH THAT TARGETED
APPROACH SO THAN THE
FEASIBILITY AND THAT IS
DEFINITELY DOABLE.
>> IF THEY WANT TO COMMENT ON
THIS?
>> SO THE PART ABOUT FEATURE
SELECTION IS THE OTHER
CHALLENGES OF COURSE IF YOU DO
AND INTERVENTION OF WHATEVER
INTERVENTION AND THAT IS A
DEMANDING SET OF CHALLENGES.
AND WITH THAT CAPACITY TO DO
LONGITUDINAL STUDY ON --
LONGITUDINAL STUDIES.
AND THOSE EFFECTS COULD BE
QUITE PROFOUND.
AND THEN TO DETERMINE.
>> SO THE NEXT QUESTION IS IT
IS INCREASINGLY CLEAR THAT IN
THE MICROBIOTA TO AFFECT THAT
POSITION?
HOW IS THAT I'M TAKING INTO
ACCOUNT THE SAMPLE COLLECTION
AND IT IS IMPOSSIBLE FOR
RENOVATIONS TAKEN INTERVENTION
OR IS IT EASIER TO NOTICE THAT
TIME OF THE SAMPLE COLLECTION?
AND I WILL ADD ONE MORE THING.
AND THAT IS PART OF THE
TRANSLATION.
>> THANK YOU FOR ASKING THE
QUESTION.
WE CAN TALK ABOUT THAT A
LITTLE BIT LATER THIS
AFTERNOON.
SO WHERE LOOKING AT A MOVIE
WERE TRYING TO TAKE A SNAPSHOT
SO IN A NORMAL CHILD DIET SO
IS DIFFERENT THAN DURING THE
DAY WE ARE STARTING TO SEE
EVIDENCE THOSE MICROBIOTA
SAMPLES.
AND THAT JUST SHOWS WHAT
OCCURS IS JUST A PARENT IF YOU
LOOK AT LARGE POPULATIONS.
WE HAVE BEEN LOOKING AT IT
WITH THE LARGE CIRCADIAN
CHALLENGES AS WELL AS SEASONAL
CHANGES IN THE MICROBIOTA.
SO THE RULES THIS IS WHAT
WE'RE TRYING TO UNDERSTAND.
AND THEN MAY NOT TRANSLATE TO
HUMANS THAT CLEARLY BECAUSE
USUALLY WHEN PEOPLE SAMPLE
FROM MICE THEY ARE SAMPLING
DURING THE DAY WHICH MICE ARE
NOCTURNAL SO THEY ARE NORMALLY
EATING HAVE A DIFFERENT
MICROBIOTA DURING THE NIGHT.
SO WE NEED TO BE STUDYING THAT
MORE IN THE NIGHTTIME.
AND THAT BETTER CORRESPONDS TO
HUMANS DURING THE DAY BUT WE
NEED TO UNDERSTAND THE
IMPLICATION TO UNDERSTAND IF
THAT IS WHY SOME OF THE
CHANGES OF THE MICE DON'T
TRANSLATE INTO HUMANS OR IF WE
CAN CREATE MORE EFFECTIVE
MICROBIOTA MEDIA THERAPY.
>> .
>> SO THEN TO FAIL.
BUT THEN THE ONE THING THAT IS
A POTENTIAL SOLUTION, CAN YOU
SHARE YOUR SOURCE AROUND THE
TRIAL AND HOW YOU ARE WORKING
TO THAT PRECISION?
>> .
>> AND IS GENERALLY A
CROSSOVER.
WHAT THEY ARE GETTING AND THE
RESEARCH.
AND THAT IS.02 PERCENT OF
CLINICAL TRIALS.
AND THEY ARE DIFFICULT AND
TIME-CONSUMING AND THERE ARE
SOME OF THOSE STUDIES BUT I
THINK IT'S POSSIBLE BUT I
DON'T THINK IT'S THE ANSWER
AND THEN IT CAUSED A LOT OF
RESOURCES.
>> FOR THE SECOND QUESTION.
SO THROUGH TRANSLATION WE ARE
HERE TO TOUCH ON THAT SO HOW
OFTEN BUT MANY OF THESE GROUPS
SO IF WE ARE THINKING ABOUT
RESEARCH FROM THE CLINICAL
TRIAL.
AND THEN FOR THE NEXT PAPER
TRIAL FOR PRECISION?
>> AND I WORK A LOT WITH NIAID
AND WITH THEIR CLINICAL TRIALS
WITH ASTHMA AND ALLERGY AND
THE MECHANISTIC STUDIES WITH
THE OLDER CLINICAL TRIALS TO
PROVIDE FUNDING SO THAT WE CAN
MAXIMIZE OUR UNDERSTANDING OF
HOW TREATMENTS AND
INTERVENTIONS FROM THE
MICROBIOLOGICAL AND IMMUNE
PERSPECTIVE.
AND THAT IS JUST AN INCREDIBLE
INFRASTRUCTURE TO HAVE IN
PLACE AND THEN TO MAXIMIZE THE
UNDERSTANDING OF HUMAN
EXPERIMENTS AND WITH THAT
INFRASTRUCTURE TO UNDERSTAND
THAT BIOLOGICAL AND
MECHANISTIC INTERVENTION OF
POPULATIONS.
AND THAT'S AN INCREDIBLE
RESOURCE.
WITH ALLERGY AND ASTHMA.
>> .
>> AND THEN YOU CAN TELL WHAT
IT WAS AND YOU CAN SET AN
EXAMPLE DO YOU NEED A STREAM
TO BE THERE FOR A LONG PERIOD
OF TIME SO IS IT ENOUGH TO
HAVE A LOW ABUNDANT STREAM IN
THE BACKGROUND OR SOME OTHER
ASPECT?
AND THEN THINKING
SPECIFICALLY.
BUT WHAT WOULD BE REALLY BAD
AND BASED ON THE OBSERVATIONS
FOR A RESPONSE OF A PARTICULAR
INDICATION AND WITH TIMING AND
EXTENT OF CHANGES THE ECOLOGY
AND THEN FOR HOW LONG CERTAIN
STREAMS NEED TO BE PRESENT AND
THEN ANOTHER THING THAT IS
POSSIBLE IS USE THE CLINICAL
EXCESSES FROM PEOPLE THAT
RESPOND BETTER TO AN
INTERVENTION AND THEN TO SEE
YOU NEXT GENERATION DRUGS WITH
THAT ITERATIVE OPTIMIZATION OF
THE MONTH AND THEN BIT BY BIT
SO THE MORE YOU START TO
MEASURE THAT IS A SUCCESS OF
CLINICAL TRIALS BACK INTO THE
LAB AND THEN TO MEASURE WHAT
WAS DIFFERENT AND THAT IS A
KEY PIECE MISSING FROM THE
FORWARD TRANSLATION AND WITH
THOSE VARIABLES OF THE HUMAN
POPULATIONS AND THEN WITH THE
OPPORTUNITY TO RATIONALIZE
THEM BACKWARDS.
>> SOMEBODY WANT TO COMMENT?
>> .
>> I WANT TO MAKE THE POINT
AND THEN THE ADVANCE
UNDERSTANDING THE TO FOLLOW UP
ON THE NEXT GENERATION.
AND THEN THEN IF WE EXPERIENCE
TO BE VERY ATTENTIVE TO
INFORMED CONSENT AND THEN TO
BE THOUGHTFUL ABOUT THAT WITH
OF THE ANTI- GUN CULTURE
COMMUNITIES AND THEN THOSE
ORGANISMS.
AND THEN THE LAST PIECE ABOUT
IT AT THE TIME THAT THEY ARE
PRODUCED.
AND ALL OF THIS REQUIRES THE
PERSON THAT JUST SPOKE OF
ADVANCED THINKING OF
ORGANIZATION.
THAT IS AN INSTRUMENTAL PART
OF EXPERIMENTAL MEDICINE FOR
TRANSLATION.
DOES THAT PLAY INTO YOUR
PLANS.
THANK YOU.
>> .
>> I JUST WANT TO GO BACK TO
THE CONCEPT OF AN F1 BUT WITH
THAT STUDY BUT ACE ENORMOUS
POWER FOR TO LOOK AT THE
INDIVIDUAL AND THEN TO HAVE
THE GENOME.
AND IT IS EXTREMELY POWERFUL.
AND THEN WITH THE COMMUNITY OF
METABOLIC RESEARCHERS.
AND THOSE BECAUSE EVERY DEFECT
IN METABOLISM.
THAT HAS MADE A HUGE IMPACT
WITH THE TREATMENT OF CANCER.
AND THOSE IT HAS BECOME.
AND THEN TO BE GROUPED
TOGETHER AND THEN FROM THE
DATE DATA THAT IS GATHERED.
>> .
>> I JUST WANT TO GIVE MY
SUPPORT.
FOR THE MISSED OPPORTUNITY
FROM THE RESEARCH WITH THAT
CHARACTERIZATION ALL THE WAY
THROUGH CLINICAL TRIALS AND
THAT INFORMATION BACK FROM THE
CLINIC AND THEN TO COLLECT
THAT DATA.
AND THEN TO TRANSLATE.
SO THE VALUE DOESN'T GET
LOCKED INTO A SINGLE ONE SO
HAVING A COMMON PLATFORM THAT
IS A CRITICAL PIECE TO THAT.
>> INDEED YES.
AND THEN TO MOVE TO THE NEXT
QUESTION SO WHAT IS THE
BIOAVAILABILITY?
SO HOW IS THIS ASSESSED?
CAN IT BE ASSESSED?
AND THEN WHAT ABOUT THE GAP?
>> I CAN COMMENT ON THIS SINCE
I WAS ON THIS TOPIC BUT USING
MEASURES OF EXPOSURE THAT ARE
ECOLOGICAL IS PROBABLY THE
FIRST STEP THAT IS THE
APPROACH WE HAVE FOLLOWED SO
FAR.
IT DOES PRESUPPOSE THAT
EVENTUALLY BE EFFICACY IS
ABUNDANCE AND THIS MAY NOT BE
THE RIGHT ASSUMPTION BUT IT
SEEMS TO BE WORKING SO FAR
GIVEN WHAT EVERYONE HAS
COMMENTED ON THE COMPLEXITY
THAT COULD WELL BE THAT YOU
DON'T NEED A BUNCH OF BACTERIA
TO BE PRESENT.
THINK IS UNDER 20 PERCENT OF
THE MICROBIOTA.
AND THAT'S WHERE WE START SO
WHAT EXPOSURE CONSTITUTES.
AND WITH THAT MICROBIOTA.
AND THEN TO DO THAT
MATHEMATICAL BOOST THAT CAN
HELP YOU UNDERSTAND TO
INTRODUCING THE DRUG.
IN THIS HAS TO BE SUPPLEMENTED
AND AS WE CONTINUE IN THE
FUTURE OF CLINICAL TRIALS WITH
OTHER MEASURES THAT ARE NOT
SOLELY ABUNDANT SPACE BUT OF
COURSE CERTAIN CONCEPTS AND
THEN TO THINK ABOUT IT
FUNDAMENTALLY DIFFERENTLY.
>> SO ONE THING I WAS
WONDERING IS THAT MOST OF YOUR
ASSESSMENTS AND PRESENCE OF
MACRO ORGANISMS WE LOVE THAT
YOU ARE DOING SPECIFIC
SEQUENCE SO YOU CAN ASSESS IF
WHAT YOU PUT IN.
SO WE LOOKING AT WHAT'S COMING
OUT IN THE FECES OR WHAT IS IN
C TO?
AND FROM YOUR DOSE-RESPONSE A
FACT YOU CAN SEE A GOOD
RESPONSE AT LOW DOSES AS WELL
TO SUGGEST IT HAS TO BE LIVE
AND A WAY TO REPLICATE SO THAT
ANSWERS ONE OF THE OLD
QUESTIONS FROM THE FIELD
FIELD.
>> WHAT IF THAT IS ASSAY IN
WHAT'S GOING ON THE INSIDE?
YOU MAY THINK MORE AWAY, SO
WHAT YOU THINK QUICK.
>> THAT'S A GREAT QUESTION.
EVERYTHING THAT I SHOWED AND
WITH THE PRESENTATION TO BE
VERY INTERESTING LIKE SPEED
AND HABITAT AND THAT ABILITY
TO LATCH ONTO CERTAIN
HABITATS, THAT IS AN ASPECT
THAT WE HAVE NOT COVERED INTO
QUANTIFY THE AMOUNT OF THE BUG
AND TO YOUR OTHER QUESTION I
THINK WE NEED TO FIND A WAY TO
DISTINGUISH WASHOUT OF DRUG IN
AND DRUG OUT OF WHAT TO EXPECT
AND WHAT TYPE OF DYNAMICS IF
YOU SEE ACTIVE REPLICATION?
AND THEN WHAT YOU START TO
IMPLEMENT SO THAT IS MORE IN
LINE OF ACTIVE REPLICATION
FROM WHAT YOU WERE SUGGESTING.
>> AND THEN TO DISTINGUISH
WASHINGTON AND WASHOUT FROM
COLONIZATION PER SE.
>> YES.
>> .
>> AND SO WITH YOUR HUMAN
TRIALS AND JUST THINKING BACK
TO THE SMALL MOLECULE BASE DID
YOU DO ANYTHING THAT WAS
DIETARY OR STANDARDIZATION?
>> WITH THE PHASE ONE STUDIES
WE DO HAVE CONTROL DURING THE
DOSING BUT BEYOND THAT WHILE
YOU CAN PROVIDE GUIDELINES IT
IS ONE OF THE CHALLENGES WITH
THIS ENDEAVOR PEOPLE EAT WHAT
THEY WANT.
SO WE CAN MAKE RECOMMENDATIONS
AND COLLECT DATA, BUT THESE
HAVE ALL BEEN REALLY HARD FOR
US TO DO.
IN AN IDEAL WORLD WE COULD
AGAIN PRIME THE MICROBIOTA FOR
WITH PREBIOTIC CERTAIN DIET
RECOMMENDATIONS.
BUT IT HAS BEEN CHALLENGING TO
DO THAT GIVEN COMPLIANCE
ISSUES AND THE ABILITY TO
COLLECT DATA AT THAT LEVEL SO
SOME OF THE VERY PRACTICAL
THINGS WITH THIS KIND OF WORK
THAT WAS MENTIONED HAS GOTTEN
IN THE WAY TO ALLOW US TO
CONTROL FOR DIET.
>> AND A QUICK ONE TO MARK TO
COMPLETELY UNDERSTAND OF
PATIENT COMPLIANCE.
WHAT ABOUT PROPER DELIVERY TO
THE CORRECT BIO?
BIO?
AND THEN TO OPTIMIZE THAT?
>> IT'S A GREAT QUESTION AND
THE OPPORTUNITIES WITH THOSE
MECHANISMS AND GO BACK TO THE
STABILITY OF THE ORGANISMS
THOSE FROM WHICH THEY ARE
SEPARATED SO IT IS OF INTEREST
YOU DON'T JUST WANT TO TAKE IT
IN AND MEASURE WHAT'S COMING
OUT THOSE OPPORTUNITIES TO
PRIME THE ECOSYSTEM SO THERE
ARE DIFFERENT APPROACHES AND
TO BE EVALUATED AS WELL AS THE
MECHANISMS TO STUDY THAT AND
ALL THE TOOLS THAT ARE
INVESTIGATED WITH THAT
ENDOSCOPY IT'S A CHALLENGE BUT
A QUESTIONS OF HOW DO YOU GET
THAT PERSISTENCE QUICK.
>> .
SO, COMING BACK TO THE
DISCUSSION OF BIOAVAILABILITY
AS WE DANCE FROM ASSOCIATIONS
OF ORGANISMS TO CLINICAL
OUTCOME AND ACTION WE KNOW THE
MOLECULES THAT ARE SECRETED
AND WE CAN DO MORE TRADITIONAL
STUDIES WHERE THE MOLECULES
ENTER THE CIRCULATION.
THIS IS A RETRACTABLE PROBLEM
FOR THOSE THAT ARE CURRENTLY
STUDIED TO DEFINE THEMSELVES
AT THE MOLECULAR LEVEL SO I
PUSHED GOING BEYOND JUST
ORGANISMS TO UNDERSTAND WHAT
ARE THE CHEMICAL INTERACTIONS.
>> I HAVE A QUESTION FOR YOU
JUST FROM THE PERSPECTIVE OF
YOUR VANTAGE POINT WHAT IS THE
ROLE OF COMBINING CAPACITY AS
AN ADVANTAGE STRATEGICALLY TO
UNDERSTAND BETTER THROUGH YOUR
OREGON AS ONE -- ORGANISMS AND
ALSO TO UNDERSTAND METABOLIC
FUNCTIONS EXPRESSES THOSE
MICROBIAL COMMUNITIES?
>> SO I THINK THAT WE HAVE NOT
LEVERAGED AS MUCH AS I WOULD
LIKE IN THAT DIRECTION BUT ONE
THING WE'RE DOING RIGHT NOW
EVEN WITH MEADOW GENOMICS DATA
FROM WHAT IS IN OUR DATABASES
AND THEN THOSE THAT ARE IN THE
SESSION BUT THAT ALLOWS US TO
GET BEYOND THAT.
IF WE ARE ABLE TO INVESTIGATE
SIGNATURES ON FOR SPONSORING A
TALKED ABOUT TODAY IS EQUAL
BUT WE HAVE STUDIES AS WELL
AND THE QUESTION IS AND WITH
THAT POSITIVE OUTCOMES AND CAN
WE MAP THOSE BACK TO A
PARTICULAR FUNCTIONS OF THIS
IS THE ANALYSIS WE ARE
STARTING TO DO.
AND THE WORK THAT YOU SHARED
IS WHAT I LIKE TO DO IN THE
CLINICAL COHORTS TO
INVESTIGATE THE WAYS THROUGH
THE RESIDENT COMMUNITY AND
WHAT CAN BE ATTRIBUTED.
>> I GUESS THAT IS AN
OPPORTUNITY TO LOOK AT
EXPRESSION AND SMALL ARE AND A
METHODS ARE IMPROVED WITH
SEQUENCING TO DETERMINE WHAT
SIGNALING AND METABOLIC
PATHWAYS IN THAT COMMUNITY
CONTEXT SO I DO THINK IT
TECHNICAL ISSUE IS TO GET THAT
DEPLETION ACHIEVED EFFICIENTLY
SO YOU DON'T HAVE TO WASTE SO
MUCH OF YOUR INVESTMENT ON
THOSE SEQUENCES.
THANK YOU.
>> I WILL READ THIS QUESTION
AND IS THAT ON ANY OTHER
SPEAKERS THAT WANT TO COMMENT
IN DESIGNING SYNTHETIC PLASTIC
TECHNOLOGIES?
>> SYNTHETIC PLASMID
TECHNOLOGY?
>> THAT IS THE TECHNOLOGY ON
-- QUESTION, YES.
>> I DON'T KNOW IF I CAN MAKE
ANY EXPLICIT COMMENTS.
BUT FROM THE PERSPECTIVE OF
THE PUBLIC MOVING FORWARD WITH
THE FIRST CONSORTIA INCLUDING
GENETICALLY ENGINEERED
ORGANISMS.
I THINK IT WILL BE VERY
IMPORTANT TO HAVE THE PUBLIC
UNDERSTAND THAT NATURALLY
OCCURRING ORGANISMS CAN BE
ASSEMBLED TO SPECIFIC
FUNCTIONS TO PROVIDE FUNCTIONS
THAT ARE NOT EXPRESSED BY A
MICROBIAL COMMUNITY AND
ALTHOUGH FROM A RESEARCH
PERSPECTIVE THE SYNTHETIC
BIOLOGY AND WITH THAT IMPACT
ON PUBLIC ACCEPTANCE SO THE
FIELD HAS TO BE VERY MINDFUL
MINDFUL.
AND ALSO THE IDEA OF A KILL
SWITCH HOW DO YOU DOSE
SOMETHING THAT IS GENETICALLY
ENGINEERED?
AND NATURE HANDS TAUGHT US
THAT IS A FANTASY THAT IS MY
TWO CENTS.
>> IT'S VERY DIFFICULT SINCE
WE DON'T KNOW YET.
HOW THAT WORKS.
DOES ANYBODY ELSE WANT TO
COMMENT?
IF NOT THEN I'LL GO TO A
DIFFERENT TYPE OF QUESTION.
THOSE THAT ARE PREDICTING THE
OUTCOMES HAVE TO BE FULLY
DEFINED FOR THAT GUIDANCE THAT
IS TOO CONSTRICTING?
>> IT'S DEFINITELY
CONSTRICTING THERE ARE REASONS
FOR THAT BUYS SECONDARY OR THE
TERTIARY OUTCOMES SO I THINK
THERE IS A RATIONALE FOR THAT
BUT THEY ARE CONSTRICTING AND
HAVE AN ANSWER IF THEY ARE TOO
CONSTRICTING BUT IT DEFINITELY
HAS TO BE THOUGHT ABOUT AS
FIRST-LINE OF MEDICINE BUT
THERE ARE SOME GOOD EXAMPLES
FOR PERSONALIZED MEDICINE.
>> ANYONE TO STOP ANYTHING
THAT STANDARD CLINICAL TRIAL
WITHOUT PRIMARY OR SECONDARY
OUTCOMES AND THEN WHAT THEY
LOOKED AT?
IS THERE ANYTHING TO STOP THEM
THAT THIS IS SOMETHING WE
COULD FOLLOW UP IN THE NEXT
TRIAL?
>> THEY CAN DO THAT FOR SURE
BUT THEY CANNOT REPORTED AS
PRIMARY AND THAT'S IT THEY'VE
DONE IN THE PAST SO THEY CAN
DEFINITELY REPORTED THEY JUST
NEED TO BE HONEST ABOUT IT
IT'S IMPORTANT FOR NEW
APPLICATIONS AND RESEARCH IT
JUST NEEDS TO BE HONEST.
>> SO AFTER THE STUDIES WE
WANT PEOPLE TO COME BACK AND
USING THE DATA THERE IS SO
MUCH MORE TO LEARN AND WITH
THAT INVESTMENT COMING UP WITH
NIH AND THEN WE ADVOCATE AN
OPEN SCIENCE IS THE AREA WE
ARE LIVING IN AND THEN
RESEARCH IS MADE PUBLIC AND
THE WHOLE COMMUNITY AND THEN
TO REDISCOVER AND THE COMMENT
RESOURCES AND TO MAKE AN
IMPACT.
>> WE HAVE THREE HANDSET.
ONE -- HANDS UP.
>> I HAVE A QUESTION FOR YOU
BECAUSE IN DEALING WITH
MICROBIOTA BASED CLINICAL
TRIAL TRIALS, IT'S VERY TOUGH
TO GET A SINGLE PRIMARY
OUTCOME MEASURE WHEN YOU ARE
TRYING TO NOT ONLY
RECONFIGURATION OF THE
MICROBIOTA ITSELF SO YOU RUN
INTO A PROBLEM WITH
TRADITIONAL HIGH-IMPACT
CLINICAL JOURNALS DEALING WITH
THAT AND THEN OF COURSE THE
ISSUE OF FDR AND ACHIEVE
STATISTICAL SIGNIFICANCE.
I'M NOT SAYING THIS IS A VERY
CLEAR WAY BUT MICROBIOTA BASED
INTERVENTIONS TRYING TO
CONNECT THAT COMMUNITY CREATES
A DUALITY THAT MAKES THAT
INITIAL DESCRIPTION FOR
CLINICAL TRIALS SOMEWHAT
CHALLENGING.
I DON'T KNOW IF YOU HAVE ANY
VISUAL OR MICROBIAL OR
CEREBRAL RESPONSE?
>> I AGREE WITH YOU.
>> BUT AT THE SAME TIME IF YOU
JUST SAY WE WILL SEE CHANGES
THEN YOU PROBABLY WELL.
DID YOU THINK ABOUT THEM
BEFORE?
DOES THAT MAKE SENSE?
BUT I AGREE BUT A LOT OF THIS
IS BEGINNING AND THEN YOU HAVE
TO JUST PICK A TIME FRAME.
>> WE HAVE FIVE MORE MINUTES
SO IF ANYBODY ELSE HAS
SOMETHING THEY WANT TO SAY FOR
THE LAST TWO OR THREE MINUTES
QUICK.
>> I JUST WANT TO MAKE A BRIEF
COMMENT ON THE QUESTION OF THE
REQUIREMENT TO DECLARE PRIMARY
OUTCOMES OR SECONDARY
OUTCOMES?
>> IT IS RESTRICTED BUT
NECESSARY THAT WAS POINTED OUT
BECAUSE THE SHEER NUMBER OF
THINGS GIVEN THAT THIS FIELD
IS NEW WHEN IT COMES TO MANY
OF THESE TRANSLATIONS OR
APPLICATIONS CAN MEAN IF WE
ARE NOT CAREFUL WE COULD END
UP IN A SITUATION WHERE THIS
WE ARE CLEARLY DEFINING OUR
OUTCOMES AND THAT DOESN'T TAKE
AWAY FROM THE FACT THOSE
OUTCOMES THAT ARE
UNDERSTANDING ARE VERY LIMITED
SO THERE WILL BE THE
ADJUSTMENT PERIOD OR A PAIN
PERIOD WHY WE DEVELOPED AN
UNDERSTANDING TO GET TO THE
POINT AS MENTIONED THAT WHEN
WE KNOW IT IS A PARTICULAR
MOLECULE AND WHAT IS THE
MECHANISM?
ONCE YOU KNOW THE MECHANISM
YOU CAN DEFINE YOUR OUTCOME
PRIOR TO THE TRIAL WITH MUCH
MORE CONFIDENCE AND LESS FEAR
OF THE EFFICACY SO THEN TO
DEFINE THE OUTCOMES THERE
COULD BE A PERIOD WHAT TO LOOK
FOR AND NOT ENTIRELY
SUCCESSFUL.
>> WE ARE GOING TO ADD TO THAT
WITH THE REGULATORY
REQUIREMENTS BECAUSE IT'S IN
ITS INFANCY AND WITH THOSE
PROACTIVE CONVERSATIONS WITH
THOSE REGULATORY AND AGENCIES
THOSE KINDS OF THINGS CAN BE
HELPFUL AGAIN.
IS THAT ARE BIO TERRY
SUPPLEMENT HAVING THOSE
PROACTIVE CONVERSATIONS AND
THAT IS NOT NECESSARILY
MEANINGFUL BUT THAT DOES NEED
TO BE DEFINED IT DOESN'T MAKE
IT EASY FOR THOSE OF THE
REASONS.
>> WE HAVE TWO MORE MINUTES IF
ANYBODY WANTS TO SAY SOMETHING
BEFORE THEY BREAK FOR LUNCH?
AND NOW I SAID THE WORD
LUNCH.
[LAUGHTER]
THANK YOU SO MUCH THANK YOU
FOR CO- MODERATING THIS
SESSION WITH ME.
I HOPE YOU WILL KEEP IN TOUCH
WITH US LET US KNOW THE
PROGRESS AND LET US HELP YOU
AND TRY TO DO TOGETHER BETTER
RESEARCH AND MORE SPECIALIZED.
THANK YOU SO MUCH.
>> AND THANK YOU.
THAT WAS A GREAT DISCUSSION.
THAT DOES TAKE US INTO THE
LUNCH BREAK.
>> I WANT TO WELCOME
EVERYBODY BACK FROM LUNCH.
SO FOR OUR SECOND SESSION THIS
IS GOING TO BE LED OUR SESSION 2
IS HOST MICROBIOME DR. VARGAS IS
FROM THE NATIONAL INSTITUTE OF
CHILD HEALTH AND HUMAN
DEVELOPMENT AND DR. HAMILTON IS
FROM NIDDK.
QUICK SLIDE SHOWS ALL THE
SPEAKERS AND DR. HAMILTON IS
GOING TO BE INTRODUCING OUR
SESSION SPEAKERS AS EACH PERE
PREPARES TO SHARE THEIR SLIDES.
I'M GOING TO TURN IT OVER TO
DR. HAMILTON.
>> THANK YOU VERY MUCH KATHERINE
I WOULD LIKE TO THANK ALL THE
ORGANIZERS FOR THE HARD WORK
MAKING THE SUCH AN EXCITING
MEETING AND THANK THE PREVIOUS
SPEAKERS FOR THEIR OUTSTANDING
TALKS.
I WOULD LIKE TO REMIND THE
PARTICIPANTS THAT THE PROGRAM
BOOK IS AVAILABLE ONLINE AND
ALSO WITH THE SPEAKERS ABSTRACTS
AND BIO SO PLEASE TAKE ADVANTAGE
OF THAT.
I'M PLEASED TO COMODERATE THE
SESSION WITH MY COLLEAGUE
DR. ANGELA VARGAS.
WE START WITH DR. SONNENBURG
WITH THE ABUNDANCE OF NEXT
GENERATION PROBIOTIC THERAPIES.
DR. SONNENBURG THANK YOU VERY
MUCH FOR JOINING US.
>> RIGHT.
THANKS VERY MUCH FOR THAT
INTRODUCTION.
IT'S A PLEASURE TO BE HERE.
I WANT TO THANK THE ORGANIZERS
AS WELL, THE COLLECTED KNOWLEDGE
IN THIS MEETING IS SUPER
IMPRESSIVE.
I'M SORRY WE COULDN'T ALL BE
TOGETHER TO EAT AND CHAT AN
EXCHANGE MORE IDEAS BUT
WONDERFUL TO BE WITH YOU
VIRTUALLY.
SO THIS MORNING WE HEARD A LOT
ABOUT PROBIOTIC OR MICROBAL
THERAPIES AND THE INDIVIDUALITY
OF THE MICROBIOTA AND THINKING
ABOUT PROBIOTIC THERAPIES AND I
WANTING TO THROUGH OUR DATA
USING SIN THEYING BIOLOGY TO
ATTEMPT TO CONTROL ENGRAFTMENT
OF A SINGLE MICROBE WHEN
ENGRAFTED TO DIFFERENT
MICROBIOTAS.
MOST OF THE DATA I'LL PRESENT
TODAY WAS DEVELOPED GENERATED IN
MY LAB BUT LICENSED BY NOVEME.
I WANT TO START OFF WITH THEIR
WONDERFUL WORK BUT THEY'RE
INCREDIBLE SCIENTISTS THAT
STARTED THIS COMPANY.
I'M COFOUNDER THERE, ARE A FEW
COFOUNDERS, I'M MOSTLY DOING
WHAT I DID IN THE LAB WATCHING
THEM DO AMAZING THINGS SO
THEY'RE SYNTHETIC BIOLOGISTS AND
HAD THIS BEAUTIFUL VISION OF
USING GUT MICROBES IN A WAY
THAT'S DIFFERENT FROM THINKING
ABOUT THEM AS OUR COMPOSITE
BIOLOGY, USING THE SENSING
CAPABILITIES OF THESE MAY BE
ROBES THAT THEY'VE EVOLVED FOR
THEIR SURVIVAL AND REWIRING THE
SYSTEMS TO ALLOW THE MICROBES TO
MAKE DECISIONS, EXECUTE SPECIFIC
TASKS WITHIN THE GUT SO THINKING
ABOUT THE HUMAN MICROBIOTA IS A
TECHNOLOGY PLATFORM FOR
MANIPULATING HUMAN BIOLOGY.
SO JUST TO REVIEW I THINK THERE
ARE MANY DIFFERENT DEFINITIONS
OF SYNTHETIC BIOLOGY.
WE CAN THINK ABOUT NOTOBIOTIC
MICE.
SO WES HAMMERED HOME THIS IDEA
OF GENERATING A PARTS LIST OF
GENETIC PARTS THAT COULD BE
WIRED TOGETHER IN DEVICES THAT
WOULD GIVE PREDICTABLE OUTCOMES
SO WE WORKED ON THIS VERY HARD
FOR SEVERAL YEARS, FOCUSSED
MAINLY ON THE BACK DROIDZ
[PHONETIC SPELLING], AND I'LL
SKIP A LOT OF THE BACKGROUND OF
THIS.
THE IMPORTANT HURDLE I WANT TO
TALK ABOUT TODAY IS IS ISO GENIC
VISCOSITY IN THE GUT, PUBLISHED
2013 IN NATURE THEY SHOWED IN
YOU COLONIZE NOTBIOTIC MICE A
SECOND MARKED STRAIN DIFFERENT
FROM THE FIRST STRAIN CAN'T
ENGRAFT IN THE MICROBIOTA.
BIOTIC.
>> SO WE, THIS CONCEPT OF ISO
GENIC PRIORITY EXCLUSION IS ONE
THAT HASN'T BEEN CONFINED TO THE
BACK TROIDZ.
THERE'S A NICE STUDY OF WALTERS
LAB LOOKING AT BIFIDA BACTERIA
IN HUMANS AND THEY ADMINISTERED
THIS PROBIOTIC FOR TWO WEEKS
THAT SHOWS TYPE BY THE DENSITY
OF THE MICROBE SURVEYED IN THE
STOOL OF THESE INDIVIDUALS.
ALL SHOW B LONG EM OVER TWO
WEEKS AND ABOUT TWO THIRDS OF
THEM CLEARED BIFIDA LONG EM THAT
WASHES OUT AFTER THE END OF THE
TREATMENT BUT A THIRD OF THE
GROUP AFTER TAKING B LONG EM HAS
APPEARS PERMANENTLY ENGRAFTED IN
THEIR BBIOOME AND HARBOR A
SIMILAR STRAIN OF BASE LINE SO
THE SAME EXCLUSION HAS BEEN
SHOWN FOR A PATHOGEN FOR
SALMONELLA BY DENISE'S LAB IN
MICE MODEL SO THREE DIFFERENT
YLA OF GUT BACTERIA.
DOESN'T MEAN IT'S A UNIVERSAL
PHENOMENON BUT SOMETHING THAEKS
TENDS BEYOND THE BACK TROIDZ SO
YOU KNOW I THINK IN THINKING
ABOUT LAUNCHING A MICROBAL
THERAPEUTIC COMPANY HOW DO YOU
TAKE A STRAIN AND MAKE SURE IT
WILL GRAFT REPRODUCIBLEY.
WE HEARD TALKED ABOUT A KILL
SWITCH THAT CAN YOU GET RID OF
IT WHEN WANT TO SO THEY'VE BEEN
DEVELOPING A LOT OF TOOLS FOR
THIS BUT IT'S REALLY COMPLICATED
BY THE INDIVIDUALITY OF HUMAN
MICROBIOTAS, SOME MAY HARBOR ISO
JENIC STRAINS SOME NOT SO LIZ
LOOKED AT THREE DIFFERENT GROUPS
OF MICE ONE HARBORING A
CONVENTIONING A MOUSE
MICROBIOTA.
SHE ADMINISTERED A SURROGATE
THERAPEUTIC STRAIN A BACK TROIDZ
STRAIN THAT WAS LABELED IN
EXPRESS IN GFP THAT WE CAN TRACK
AND SHE SHOWED THAT THE DENSITY
OF THIS STRAIN OVER THE FIRST
WEEK IN THESE THREE DIFFERENT
GROUPS OF MICE VARIES WIDELY.
ONE GROUP THAT COLONIZES TO HIGH
LEVEL AND DWINDLES ANOTHER THAT
COLONIZES TO INTERMEDIATE LEVELS
AND APPEARS TO STAY CONSTANT THE
FIRST WEEK AND ANOTHER GROUP BY
DAY 7 THIS MICROBE IS DROPPED
BELOW THE LEVEL OF DETECTION.
WE THOUGHT FEEDING IMULIN SO
LET'S PROVIDE A SUPPORTING
CARBOHYDRATE TO HELP IT.
WHEN WE DISTRIBUTED IMULIN ONE
OF THE GROUPS WASN'T DURABLE IT
DIDN'T COME BACK FROM DETEST.
THIS STRAIN WE ORIGINALLY
ISOLATED FOR ABILITY TO UTILIZE
A SOMEWHAT UNIQUE POLY SACK RIDE
IN THE DIET KNOWN AS PORFORIN SO
FEEDING SEAWEED WE SEE HIGH AND
PRE-PRODUCIBLE LEVELS ACHIEVED
INDEPENDENT OF THE BACKGROUND
GUT MICROBIOTA SO THIS
PRIVILEGED ACCESS TO POLY AGO
RIDE WHERE THERE'S NO BACKGROUND
COMPETITION WE KNOW THERE'S
PROBABLY DIFFERENT LEVELS OF
COMPETITION FOR IMULIN BUT
PORFORIN ALLOWS THE THERAPEUTIC
STRAIN TO BLOOM PROCEED
PRODUCEABLELY.
THEY GAVE THE ABILITY TO ABILITY
TO POLY SACK RIDE OUT I WILL
SAYINGS AND THEY SHOW LOOKING AT
THE DENTIST OF THAT ENGINEERED
STRAIN THEY CAN TOGGLE THE
ABUNDANCE OF THE STRAIN, SO GO
FROM LOW TO HIGH LEVELS WHEN
THEY FEED PORFORIN IN COMPARISON
TO TOTAL CULTURE DENSITY HERE SO
THEY THINK THEY'RE ACHIEVING 10
PERCENT OF THE DENSITY OF THE
MICROBIOTA ON HIGH DOSE SEAWEED
EXTRACT.
THEY TAKE THE SEAWEED AWAY THE
STRAIN DROPS TO A LOWER LEVEL.
THEY ALSO SHOWED THAT THIS IS
DOSE RESPONSIVE SO AT 1 PERCENT
PORFORIN THEY ACHIEVED TEN TO
THE 10th CFU PER MILL.
SO NOT EXACTLY WHAT I WOULD HAVE
PREDICTED A DIRECT LYNN REGARD
RELATIONSHIP OF THE PORFORIN IN
THE DIET COMPARED TO THE DENSITY
OF MICROBE IN THE GUT.
WE CAN STAIN THOSE BACKGROUND
MICROBES IN PINK HERE AND OUR
STRAIN IN GREEN ON LOW DOSE HIGH
DOSE PORFORIN YOU CAN SEE MANY
OF THE BACK TROIDZ IN THE HIGH
DOSE PORFORIN.
ONE INTERESTING NOTE HERE IS
OTHER THINGS HAPPENING BESIDES
ENGRAFTMENT OF THE STRAIN.
TWO ISO GENIC STRAINS OF BACK
TROIDZ ONE.
>> THE FIRST STRAIN HAS BEEN
ELIMINATED FROM THE MICROBIOTA.
REALLY, ILLUMINATING EXPERIMENT
HERE WAS ONE THAT ACTUALLY WAS
CAUSED BY A SCHEDULING CONFLICT
WHERE LIZ HAD TO DO THE
PORPHORIN FEEDING FOR A SHORTER
PERIOD OF TIME.
LEAVE THESE LUCKY RESULTS WHERE
WHEN YOU FEED FOR A SHORTER TIME
YOU START TO SEE DISAPPEARANCE
OF THE FIRST COME -- COLONIZER.
WHEN YOU STOP THE PORPHORIN THE
FIRST STRAIN THAT CANNOT USE IT
BOUNCES BACK AND EXHIBITED EQUAL
ABUNDANCE IN THE ABSENCE TO A
I-ING STRAIN SO THERE APPEARS TO
BE AN EXCHANGE PROCESS THAT DOES
NOT GO TO COMPLETION ON THE
SHORTER DURATION PORPHORIN
FEEDING.
INTO IT APPEARS THIS HAS TO DO
WITH CRYPT LOCALIZATION SO BASED
ON FINDINGS FROM THE MASMANIAN
THAT INDICATED THAT CRYPT
LOCALIZATION WAS IMPORTANT, WE
LOOKED AT THE FIRST ARRIVING
STRAIN FIRST IN RECOMMENDED
SECOND IN GREEN IN THE SKIES OF
ISO GENIC EXCLUSION WE SEE
EXCHANGE BUT AS THE EXCHANGE
HAPPENS WE SEE THE SECOND
ARRIVING PORPHORIN GREEN STRAIN
INVADE THE CRYPTS.
SO NOW, NOVOME HAS TAKEN TO
CLINICAL TRIALS IN HUMANS AND
HERE WE SEE INDIVIDUALS THAT ARE
SEEING PORPHORIN UTILIZE'S
STRAIN RECEIVING EITHER NO
PORPHORIN OR INCREASING DOSES OF
PORPHORIN AND BASICALLY WE SEE
THE SAME AS IN THE MOUSE MODEL
INCREASING LEVELS MUCH DENSITY
OF THE PORPHORIN UTILIZING
STRAIN AND HIGHEST DENSITY
ACHIEVED IN THE HIGHEST DOSE
PORPHORIN AND THIS IS AN
ATTENUATED STRAIN WITH KILL
SWITCH SO YOU REMOVE THE
PORPHORIN THESE STRAINS CRASHED
OUT OF THE MICROBIOTA AND WASHED
OUT SO NOW THEY'RE MOVING ON TO
PHASE 2-A WITH HIGH DOSE A THAN
STRAIN THAT DEGENERATES TO DEAL
WITH HYPER OXILREA I WANT TO
FINISH WITH HUMAN STUDDISTS THAT
CHANGE HOST BIOLOGY PARAMETERS
WITH DIET INDUCED AL TRAIGSZ,
THIS IS THE RESULT OF A CENTER
FOR HUMAN MICROBIOME STUDIES,
CHRISTOPHER GARDNER HAS BEEN
PERFORMING DIETARY STUDIES WE
SEE THE FEE FFI-FO STUDY IN
COLLABORATION WITH CHRISTOPHER'S
GROUP FIBER AN FUR MEANTED AND
LOOKING AT KETOGENIC DIETARY
INTERVENTIONS BUT ALSO
PROBIOTICS AND PRO --
PRE-BIOTICS.
>> WE ARE LOOKING AT THE
PARAMETERS ASSOCIATED WITH
METABOLIC SYNDROME, THIS IS AN
PROBIOTIC WITH THREE STRAINS
THAT HAVE EVIDENCE FOR IMPACT OF
FEATURES OF METABOLIC SYNDROME.
WE HAVE A PLACEBO CONTROLLED
TRIAL BASELINE TEN WEEK
INTERVENTION AND WASHOUT PERIOD
WHERE WE TAKE STOOL AND BLOOD
AND MEASURING THINGS AS WELL AS
CONDUCTING FOOD SURVEYS.
QUICK SUMMARY RESULTS, NO COHORT
WIDE EFFECTS ON METABOLIC
SYNDROME OR NO ENGRAFTMENT OF
THESE METABOLIC STRAINS BUT
THERE APPEAR TO BE INTERACTION
WITH FACET OF DIET AND THERE'S A
SUBSET OF INTERVENTION GROUP
THAT RESPONDS BASED ON WHAT
THEY'RE EATING OR CORRESPONDING
TO THAT SO WE WILL REPORT THAT
SOON.
>> YOU HAVE ABOUT ONE MINUTE.
>> YOU HAVE ONE MINUTE.
>> PERFECT.
LAST SLIDE.
WE HAVE ALSO CONDUCTED A
PRE-BIOTIC STUDY FOR RE-JUVE
NATION OF THE AGING MICROBIOTA
AND LOOKING AT THE POSSIBILITY
OF A MILK SACK RIDE, TWO FUCOSYL
LACK TOE METABOLIC MARKERS
PLACEBO CONTROLLED WITH LOW DOSE
HIGH DOSE AND BASELINE PERIOD IN
THIS CASE I THINK WE HAVE A SIX
WEEK INTERVENTION AND A WASHOUT
AND WE DO SEE A DOSE CAN
DEPENDENT BLOOM IN BIFIDA TRIAL.
I WANT TO END BY ACKNOWLEDGEING
THE WONDERFUL PEOPLE IN MY
GROUP.
I THINK I MENTIONED THE MAIN
ONES DURING THE TALK, MANY
WONDERFUL COLLABORATORS, THANKS
TO OUR FUNDING SOURCES INCLUDING
NCCIH AND NIDDK AND THANKS VERY
MUCH.
I'M EAGER TO HEAR THE REST OF
THE TALKS.
>> THANK YOU VERY MUCH,
DR. SONNENBURG.
OUR NEXT SPEAKER IS DR. KASHYAP
FROM ROCHESTER CLINIC THE ROAD
TO MICROBIAL DRIVEN MEDICINE.
>> THANK YOU FOR INVITING ME.
I WANT TO TALK A LITTLE BIT
MICROBUY OL FITS IN SYSTEMS
BIOLOGY IN TERMS OF DRIVING THE
SELECTION OF PRECISION OF
PROBIOTICS.
SCLOESH SUR NOT RESULT OF THE
TOPIC TODAY.
I START WITH A CODE QUOTE FROM
WILLIAM . . . WE TRY TO THINK
ABOUT IT AS SCIENCE BUT IT'S
PRACTICED AS ART WAS TREATMENT
IS DEVELOPED AS ONE SIZE FITS
ALL AND PHYSICIANS ARE LEFT WITH
INDIVIDUALIZED TREATMENT BASED
ON EXPERIENCE WITH PATIENTS.
AS WE THINK ABOUT PRECISION
MEDICINE IS TRYING TO CHANGE
THAT A MODEL WHEREBY EACH
TREATMENT IS GOING TO BE
TAILORED TO AN INDIVIDUAL
PATIENT INSTEAD OF USING ONE
SIZE FITS ALL AND DONE BY
COMBINING DIFFERENT DATA.
OF COURSE, I THINK FAR OFF BEING
ABLE TO DEVELOP TREATMENTS FOR
INDIVIDUALS WE THINK ABOUT
PUTTING THEM INTO SMALLER
SUBGROUPS WHICH RIGHT NOW ARE
JUST RELYING ON CLINICAL
LABORATORY DATA BUT HOPEFULLY AS
WE MOVE FORWARD ESPECIALLY WITH
PRECISION BIOTICS WILL WILL BE
BASED ON SOME FORM OF
MICROBIOLOGIC
MICROBIOLOGICAL.
>> WE STARTED ADDING THE HOST
GENOME AND THOUGHT WE WILL BE
ABLE TO FIND THE ANSWER TO MOST
DISEASES.
WE ARE FAR FROM THAT HAND SLOWLY
REALIZING THERE MIGHT BE SOME
DISEASES WHICH ARE PREDOMINANTLY
MICROOBAMA.
>> IF YOU LOOK AT SUBGROUPS IN
EACH DISEASE THERE MIGHT BE A
STRONG COMPONENT AND THAT'S
WHERE PRECISION MEDICINE COMES
IN.
WHEN YOU THINK ABOUT DIFFERENT
COMPONENTS THEY DON'T LIVE IN A
VACUUM SO THEY NEED TO BE TAKEN
TOGETHER INTO ACCOUNT.
WHEN WE STUDY ONLY AN EXPOSED
BIOME OR THE HOST WE MAY BE
ATTRIBUTING A LOT MORE THAN THAT
ONE FACTOR AS OSTER MAN TAKING
ALL TOGETHER.
SO IF YOU WERE TO CONSIDER
COMBINING SOME OF THESE DATA
ADVANTAGE BY INTEGRATION USING
UNBIASED METHODS WE COULD
DEVELOP MODELS BASED ON A. I.
AND A GOOD EXAMPLE OF THIS IS
RESPONSE TO DIET IN CHANGES OF
BLOOD GLUCOSE OR LIP IDZ BUT
THESE STUDIES PROVIDE INSIGHT
CELL CULTURE AND TOGETHER THE
MECHANISMS IN IDENTIFICATION OF
NOVEL TARGETS AND IN FACT, THIS
CAN THEN BE VALIDATED BACK IN
HUMAN STUDIES TO SEE IF
MECHANISMS WHICH CAME OUT OF
PRE-CLINICAL MODELS HOLD TRUE IN
HUMAN STUDIES BUT MORE
IMPORTANTLY THIS WILL HOPEFULLY
PROVIDE A BETTER WAY FOR
PRECISION PROBIOTICS IN THE
FUTURE.
I WANT TO FOCUS ON A DEAL,
IRRITABLE BOWEL SYNDROME AND WE
KNOW THAT BOTH DIET AND MICROBES
ARE AN IMPORTANT PART OF THE
PHYSIOLOGY.
IT'S A SYMPTOM BASED DISEASE
CLASSIFIED BASED ON ABDOMINAL
PAIN WHICH COULD BE ASSOCIATED
WITH CHANGES IN DEFACATION IN
FREQUENCY OF STOOL OR APPEARANCE
OF STOOL AND DECLASSIFIED AS
CONSTIPATION, DIET PREDOMINANT
OR MIXED FORM.
THE FACTORS ASSOCIATED WITH IBS
ARE ALL FACTORS WHICH CAN AFFECT
THE MICROBIOME AND THE
UNDERLYING PATH OL OF IBS
INCLUDING CHANGES OF TRANSIT SO
WE DID A A STUDY OF THE DAD I'M
GOING TO SHARE TODAY.
I'M NOT GOING TO SHARE ALL THE
DATA FROM THE STUDY BUT I WANT
TO MAKE A FEW POINTS WITH THE
STUDY.
THIS WAS A STUDY IN OWN TWO
PHENOTYPES WHERE WE COLLECTED A
LOT OF THE HOST INFORMATION
INCLUDING CLINICAL META DATA AS
WELL AS ENVIRONMENTAL DATA DIE
FRIDAY DATA EVERY TIME POINT, WE
COLLECTED STOOL SAMPLES IN SIX
MONTHS, WE ALSO COLLECTED HOST
SAMPLES IN FORM OF COLON
BIOPSIES AND BLOOD AND THIS
PROVIDED US WITH OPPORTUNITY TO
LOOK AT EXTENSIVE LOOKS AT HOST
AN MICROBES.
I'VE OUTLINED EXCLUSION HERE WE
TRY TO MATCH FOR AGE.
WE LOOK AT THE DATA, FIRST
DECIDED AS I MENTIONED THAT THIS
KIND OF MODEL CAN SERVE TO
VALIDATE WHEN WE FOUND IN FETAL
STUDIES.
IF WE FOCUS ON SOME METHOD
PREVIOUSLY IDENTIFIED THE FIRST
TIME.
A LOT OF EARLY WORK IN A LAB ON
BACTERIAL FATTY ACID AND HOW
THEY INFLUENCE SEROTONIN IN THE
GUT WHAT WE FOUND IN OUR
PATIENTS WHEN WE LOOKED AT THE
STOOL SAMPLES DECREASED FROM
PATIENTS WITH CONSTIPATION
IRRITABLE BOWEL SYNDROME.
BUT, WE FOUND THIS IS NOT AN
INCIDENTAL FINDING.
THE CHANGE PERSISTS OVER THE 6
MONTHS THAT SAMPLED THESE
PATIENTS.
WE TOOK A STOOL SAMPLE TO SEE IF
THE TRANSITED PHENOTYPE CAN
BE -- AND HAD A LONGER TRANSIT
LINE.
WE LOOKED FOR THE APPEARANCE OF
THE DYE IN THE STOOL AND THAT
GIVES US THE TRANSIT TIME IN THE
G. I. ATTRACT AND WE FOUND IT
WAS SLOWER IN MICE AS COMPARED
TO THE HEALTHY CONTROLS AND WE
LOOKED AT THE FATTY ACID LEVELS
AS COMPARED TO CONTROL.
SO COMBINING WHAT WE HAD SEEN IN
PRE-CLINICAL MODELS IT PROVIDES
FAIRLY STRONG EVIDENCE.
THE NEXT QUESTION WHAT'S DRIVING
THE BU TRAIT PRODUCTION.
WE THINK IT'S LIKELY DRIVEN BY
THE MICROBE.
SO WE LOOKED AT SPECIFIC
BACTERIA GENOMIC REGIONS AND
IDENTIFIED TWO GENE REGIONS IN
OUR COHORT WHICH COORDINATED
WITH THE BU TRAIT PRODUCTION.
IF BU TRAIT IS A DRIVER IT
SHOULD BE REDUCED IN PEOPLE WHO
CONSUME A LOT OF FIBER BASELINE
AND THEN REDUCE THE FIBER
INTAKE.
WE COULD SEE A SIGNIFICANT
INCREASE IN THE FIBER WHICH
COLLECTED SAMPLES BEFORE AND
AFTER IN THE DIELT AS WELL AS
SYMPTOMS.
AS EXPECTED AS THE FIBER LEVELS
DROP, THE FATTY ACID DROPS IN
THE INTESTINE AND STOOL BUT
THERE WAS DECREASE IN
MICRODIVERSITY WHICH COORDINATED
WITH THE APPEARANCE OF SYMPTOMS
IN THESE PATIENCE ONE BLOATING
AFTER EATING COMMON IN IBS AND
PAIN IN BOWEL MOVEMENT WHICH IS
COMMON FROM CONSTANT TAKES IBS.
>> WHETHER BACTERIA WHICH CAN
CONVERT TRIP TOE FAN TO
ACTIVATES A HOST RESENATOR WHICH
IS PRESENT ON THE EPITHELIUM.
NEXT QUESTION IS WHERE IS THIS
COMING FROM BECAUSE ESTABLISH
THAT DIET IS THE SAME BUT IT CAN
CHANGE BASED ON THE MICROBES ARE
PRESENT.
IT'S LIKE AN INCREASE IN
MICROREPRODUCTION OF TRIP TOE
FAN AND TRIP MEAN WHICH CAN BE
DRIVEN BY THOSE MECHANISMS.
THE IDEA OF DOING THIS KIND OF
STUDY WAS TO IDENTIFY OR GET
KNOWLEDGE AND THAT'S WHAT WE
DID.
SO WE LOOKED AT UNTARGETED ME
TABLOIDS TO SEE IF THERE WOULD
SEE -- AS YOU CAN SEE IT WAS
FAIRLY CONSISTENT ACROSS SIX
MONTHS.
AGAIN, THE PROTEIN INTAKE . . .
WAS SIMILAR AMONG THE TWO
GROUPS.
TOGETHER THIS CHANGED
CORRELATED.
SO IT'S A HOST . . . WHICH IN
FACT IS NOT CHANGED IN OUR
COHORT OF CHANGES.
WE WENT BACK TO THE DRAWING
BOARD AND SAID THERE'S INCREASED
PRODUCTION OF . . . IN
CONSTIPATION PATIENTS AN
IDENTIFIED USING A SIMILAR
METHODOLOGY WHICH CORRELATES
CONSUMPTION OF HYPO ZAN TEEN.
WHEN WE DID THIS EXPERIMENT
LOOKING AT BOTH PRODUCERS AN
CONSUMERS YOU SEE INCREASED IN
THE PRODUCERS LOW LEVEL IN
CONSUMERS BUT WHAT SURPRISED US
MEASURE GUT TRANSIT TIME IT WAS
MUCH LONGER IN THE MICE WHICH
SUGGESTED WE HAVE A ROLE TO PLAY
IN G. I. TRANSIT.
>> YOU HAVE ABOUT TWO MINUTES.
>> MECHANISM CAN WHICH AFFECT
HYPER ZAN TEEN BU TRAIT LEVELS,
SO DEPENDING ON MECHANISMS IF
YOU THINK OF IT WE WENT FROM
MECHANISMS IN EACH INDIVIDUAL.
HOW DO WE CLASSIFY THEM, IF YOU
LOOK AT THE SUMMARY THE POINT I
WANTED TO MAKE THERE'S A CHANGE
IN BACTERIA METABOLITES CAN
CHANGE IN G. I. FUNCTION.
CONTEXT MATTERS BECAUSE WHICH I
SHOWED EXAMPLES OF FUNCTION IN
THE BIODISEASE BUT IT COULD
COULD . . . IBS SPAISHTS.
INDIVIDUAL METABOLITES MY SINNER
JIES OR METABOLIZE EACH OTHER.
THESE KIND OF LONGITUDAL STUDIES
CAN IDENTIFY MECHANISMS.
NOT ALL DISEASE IS DRIVEN BY
MICROBIOME AND MIKE OH THERAPIES
WILL NOT CURE THEM ALL.
LOOKING AT PROBIOTICS WE ARE
LOOKING IN THREE DIFFERENT
REGIONS AN THAT'S WHAT YOU ARE
GOING TO HEAR THROUGHOUT THIS
CONFERENCE.
I MENTIONED MICROBIOTIC
THERAPIES ARE IMPORTANT F. THIS
MECHANISM IS CRITICAL FOR THE
PHENOTYPE AND HOW TO FIND A
PROBIOTIC AND THERAPY AND HOW TO
DEFINE CLINICAL TRIALS OR
RETHINK CLINICAL TRIALS TO
TARG
TARGET.
ALL THIS WORK IS DONE WITH
STUDENTS IN MY LAB AND
COLLABORATOR LABS AND IBS STUDY
STORTD BY NIH IN COLLABORATION
WITH UNIVERSITY OF MINNESOTA AN
LOOK FORWARD TO GOOD DISCUSSION
ON THAT.
THANK YOU.
>> DR. KASHYAP THANKS FOR
SETTING LIGHT ON A DISEASE THAT
HAS BEEN SORT OF THOUGHT OF AS
PSYCHOLOGICAL ILLNESS.
YOU BROUGHT SOME VERY IMPORTANT
INFORMATION ABOUT THE PATHOGEN
ASSIST.
NEXT SPEAKER IS DR. DR. HAMMER
IN RESPONSE TO REGULATION
METABOLIC REWIRING LONG FETAL
DERIVED FETAL CELLS MANY
DR. HAMMER.
>> DR. HAMMER, YOU NEED TO
UNMUTE, PLEASE.
>> MY NAME IS GIANNA HAMMER.
I'M IN THE PROCESS OF MOVING TO
UNIVERSITY OF UTAH AT SALT LAKE
CITY THIS COMING JUNE.
SO, FOCUS WILL BE ON LONG LIVED
FEE AT ALL DERIVED CELLS AND
THEIR ZEAL FOR THE MICROBIOME
AND A QUESTION I'VE BEEN
THINKING IS WHAT HOST
MICRODYNAMICS ARE OPEN FOR
LEARNING N. MY LAB WE NEVER TAKE
FOR GRANTED THE RULES ARE GOING
TO BE THE SAME IN ALL CONTEXT
DEPENDING ON SMALL INTESTINE OR
COLON, TUMORS vs. NORMAL TISSUE
SO WE DON'T TAKE IT FOR GRANTED
THAT EVERYTHING WILL ACCULTURE
ALWAYS SO WE ARE LOOKING FOR
THINGS FLEXIBLE.
SO OUR FOCUS WILL BE ON GAMMA
DELTA T CELLS AND I NEVER EVEN
SAID THE WORDS DELTA GAMMA T
CELL UNTIL MY STUDENTS SHOW HOW
LONG THEY EXPAND IN COLON
TUMORS.
THEY'VE CONSUMED A LOT OF MY
THOUGHT NOW BECAUSE I REALIZE
AFTER MY STUDENT POINTED OUT
THERE'S A BIG GAP ABOUT HOW
THESE REACT WITH MICROBIOTA SO
GAMMA DELTA T CELLS COME IN TWO
TYPES.
BOTH THOSE MICROBES ARE
DIFFERENT FROM CONVENTIONAL T
CELLS SO THEY CAN SENSE MICROBES
EVEN DIRECTLY AND INDIRECTLY SO
ANOTHER CELL WILL SEE A SIGNAL
SIGHT KIND AND TURN ON
FUNCTIONS.
THE DELTA GAMMA ARE DEFINITELY T
CELLS.
THEY HAVE A T CELL RESENATOR BUT
IT'S DEBATABLE WHETHER THEY NEED
THE T CELL TO DO THEIR FUNCTION.
THE INTEREST TO ME HAS BEEN THE
FLAVOR THAT MAKES IL-17.
THE REASON IS THIS CLASS IS
GAMMA DELTA T CELLS IS ALMOST
CONCLUSIVELY MADE DURING FETAL
LIFE.
SO, DURING FETAL LIFE IT
DEVELOPS THESE CELLS AND THESE
ARE ENTERING THE BARRIER TISSUES
SO SINCE THERE'S A STRONG
PREFERENCE, DUST DON'T MAKE
THESE TYPES OF T CELLS.
THIS MEANS THESE CELLS ARE
SENSITIVE TO RADIATION AND NOT
HAVE OPPORTUNITIES TO COME BACK.
IF THERE'S PADS GENERAL INDUCED
OR REASON WHY THEY DIE AGAIN
THEY WILL NOT HAVE OPPORTUNITY
TO COME BACK.
THESE ARE FETAL DERIVED AND THEY
STAY IN THE BODY THROUGHOUT THE
LIFETIME.
THEY'RE PRIMARILY RESIDENT IN
BARRIER TISSUES WHERE MICROBIOTA
ARE DOMINANT.
IN THESE BARRIER TISSUES THEY
ARE IMPORTANT FOR PATHOGEN
DEFENSE.
IN SOME CASES THEY DEFINITELY
HAVE ROLES OR MISBEHAVIORS IN
DISEASE BUT THEY ALSO HAVE HAD
IMPORTANT TISSUE HOMEIO STAYSIES
AND SO FORTH.
THEY ALSO LIVE IN OTHER TISSUES
AND ONE THING I WON'T TOUCH UPON
IS THEY ALSO RESIDE IN THE MEAN
JEEZ OF THE BRAIN.
2019 HAVE BEEN INDICATED IN
SHORT TERM MEMORY ANXIETY AND
SOCIALABILITY.
SO FROM THESE DIFFERENT CONTEXT
BEING IN THE BRAIN, THEY CAN
INTERACT WITH MICROBIOTA OUR
QUESTION HAS BEEN HOW DO THESE
LONG LIVED FETAL DERIVED CELLS
INTERACT WITH PROBIOTICS AND HOW
THEY INTERACT WITH MIKE.
MAYBE THEY'RE CONTINUOUS
LEARNINGERS.
MAYBE THEY CONSTANTLY INTERACT
WITH MICROBES KEEPING WITH BEING
FLEXIBLE WHAT THEY DO AND BEHAVE
AND THEY COULD BE QUITE FIXED.
MAY THEY COME OUT OF THE FETAL
THYMUS AND ONCE THE BABY IS
COLONIZED WITH FULL SET OF
MICROBIOTA MAYBE YOU'RE ONE AND
DONE SO WE BASICALLY WE WANTED
TO MAKE HEAD WAY ON THESE QUITE
SIMPLE QUESTIONS.
WE HAVE TO ASK WHAT DOES
LEARNING LOOK LIKE, WHAT THE
KIND OF BEHAVIORS MIGHT BE
REGULATED BY THE MICROBIOME.
THE SCIENTIFIC SENSE WHAT DO WE
AS SAY.
SO FROM STUDNESS GERM FREE MICE
WE KNEW THAT CELL NUMBER AND
EVEN THE FORM OF PRODUCTION BY
THESE DEDICATED CELLS IS
ACTUALLY NOT SOMETHING VERY EASY
TO SEE IS GOING TO BE LINKED TO
THE MICROBIOTA.
SO IN ASKING ABOUT HOW WHAT WE
ACTUALLY LOOK FOR AND HOW THESE
ARE RESPONDING TO THE MICROBES
WE AGAIN REALIZE COMPARATIVE
ANALYSIS OF THE TWO FLAVORS,
THEY BOTH LIVE IN THE GUT AND WE
OF COURSE IF THIS WAS, IF WE HAD
LEVERAGE TO DO ANY KIND OF
TRANCE RICK TOMICS HAD A THAT IS
NOT BEEN INFORMS FOR THESE IN
THE GUT WITH THE TOOLS AND
KNOWLEDGE THAT WE CAN MAKE HEAD
WAY ON THAT.
PEOPLE TELL THE DIFFERENCE
BETWEEN THESE T CELLS THAT DON'T
WORK IN THE GUT HENCE WHY
THERE'S A GAP IN THE FIELD HOW
THEY'RE BEHAVING IN THE SATTIN.
SO TO ASK HOW THESE CELLS ARE
DIFFERENT AND INTERACTING WITH
MICROBIOTA WE DID A SAMPLE . . .
READING OF MARKERS ASSOCIATED
WITH ACTIVATION.
SO IF THE CELL IS GOING TO BE
BE . . . BY A MICROBE WE HAVE
MOLECULES THAT MIGHT BE CHANGING
CHANGING.
WE DIDN'T FIND A GREAT SET OF
MARKERS.
A GREAT SET THAT TOLD US THERE
WERE REMARK DIFFICULTIESES FOR
EVERYTHING WITH THE EXCEPTION OF
ONE MOLECULE.
THIS MOLECULE WAS HIGHLY
DISTINCT IN EXPRESSION.
WE PARTNER'S THIS TD-1
EXPRESSION WITH ANOTHER MODEL
THAT HAD BASICALLY A MESSY HIS
TOE GRAM BUT PUT THESE TWO
TOGETHER IT NICELY SEPARATED A
POPULATION THAT WAS PURRAGEOUS
DYNA D-1 POSITIVE AND POPULATION
PD-1 NEGATIVE AND ANOTHER
POPULATION THAT WAS A BUMP IN
THE ELBOW IF YOU WILL OF GAMMA
DELTA T CELLS.
IF WE FOCUS ON THE PD-1 THEY DID
NOT MAKE THE SIEPT KIND
INTERFERING GAMMA.
FOCUSSING ON THE NEGATIVE
POPULATION WILL MAKE THE SIGHT
KIND INTER FERN GAMMA DND MAINL
AISLE 17 AND THE MINOR BUMP IF
WE SIMULATE THOSE THEY WERE A
MIX OF BOTH TYPES OF GAMMA DELTA
T CELL AND WE BROUGHT THIS UP AS
WELL WITH GENE EXPRESSION
ANALYSIS SO LOOKING AT
POPULATION 1 THESE HAVE AISLE 17
A AND AISLE 17 F.
POPULATION 2 DOES HAVE
INTERFERON GAMMA.
SO ALSO WE DID THE ANALYSIS WITH
THE MASTER TRANSCRIPTION FACTOR
THAT IT ALLOWS CELLS TO MAKE
AISLE 17.
ALL THESE CELLS WERE POSITIVE
AND NEGATIVE AND LITTLE BUMP ON
OUR ELBOW WAS A MIX OF BOTH
POPULATIONS BUT IT WAS CLEAR
THEY'RE OF THE AISLE 17 FLAVOR
OR POPULATION.
SO WITH THIS SET OF RULES WHERE
WE KNEW PD-1 WE KNEW THAT THESE
WERE THE GAMMA DELTA 17'S AND
THE PD-1 NEGATIVES WERE THE
INTERFERON GAMMA PRODUCING
POPULATION.
WE COULD ATTENUATE WHAT THE
MICROBIOTA WERE DOING TO CHANGE
THESE.
SO WE COULD HAVE A CELEBRATION
SAYING IT'S IMPOSSIBLE FOR US TO
TELL THE DIFFERENCE WITH THESE
CELLS IN THE GUPT AND FIGURE OUT
WHAT THEY'RE DOING BUT THAT
WASN'T NECESSARILY THE PURPOSE
HERE.
OUR PURPOSE THEN ASKING AFTER WE
FOUND OUT PD-1 WAS A SUBSET OF
POPULATIONS WHY ASKED WHY PD-1,
IS MICROBIOTA AT FAULT AND WHAT
IS THE FUNCTION OF PD-1 AND WHAT
IS THE ROLE IF ANY ON HUMAN
HEALTH.
SO TO TEST THE INFLUENCE OF
MICROBIOTA WE DID THE ELBOW WITH
PEED B PEDIATRIC EXPRESSION AND
WE GIVE THE ANTIBIOTICS TO ADULT
MICE OVER FOUR WEEKS AND THIS
PD-1B EXPRESSION COLLAPSED
LOOKING MORE LIKE A SOCK THAN A
BOOT AND NOT BECAUSE THE FETAL
DERIVED CELLS ARE DYING.
HERE ARE THE POSITIVE FIELD
DERIVED CELLS AN ANTIBIOTIC
TREATMENT.
THE PD 1 IS BACKWARD BUT WE HAVE
THAT GAMMA T POPULATION.
THEY JUST DON'T HAVE PD-1
ANYMORE SO WE KNOW THE PD-1
EXPRESSION IS NOT A PERMANENT
MARKER ON THIS POPULATION.
WE ALSO DON'T NEED TO IT LIVE OR
EXIST OR ANYTHING BUT
IMPORTANTLY, PD-1 IS SUSTAINED.
IT'S GREAT EVIDENCE TO SAY THESE
CELLS ARE CONSTANTLY RECEIVING
STIMULUS FROM THOSE MICROBES.
SO OUR ONLY PATH TO LOOK AT THE
MICROBES THAT HAVE A DOMINANT
INFLUENCE IN THIS HERE IS A HIS
TOE GRAM EVERYTHING ELSE TESTED
DID HAVE SOME EFFECT.
THIS COMES DOWN TO ASKING DOES
PD-1 HAVE A FUNCTION.
AS CONTINUOUSLY EXPRESSED HAVE A
FUNCTION.
SO AS YOU MAY KNOW PD 1 IS
FAMOUS AS A T CELL INHIBITOR
INHIBITOR . . . FOR THEIR
DISCOVER BEFORE SO IS MICROBIOTA
INHIBITOR AND IF SO THIS COMES
DOWN TO WHAT DO WE AS SAY.
THERE'S CONFLICTING DATA ON
GAMMA DELTA T CELLS SO IN 2010 A
STUDY SUGGESTED IF YOU PUT
MICROBIOTA ON SO WHAT DO WE ARE
WE GOING TO ASSAY.
WE FOCUS ON AISLE 17 GFP
REPORTER.
SO, CERTAINLY THE PD-1 POSITIVES
ARE MAKING AISLE 17.
THIS IS THE CONTROL, THE DATA IS
BLACK AND WHITE THAT MICROBIOTA
ARE A NATURAL AISLE 17
PRODUCTION.
BUT ANOTHER THING I'LL JUST
QUICKLY TOUCH BEYOND, WE ALSO
FOUND SIMILARITIES IN GENITAL
TRACK AS WELL AS THE LUNGS.
MICROBIOTA ARE FOR IMPORTANT
MAKING THAT.
SO, NOW WE KNOW THAT MICROBIOTA
ARE CONSTANTLY STIMULATING OUR
GAMMA DELTAS.
WE IDENTIFIED PD-1 AS SOMETHING
THAT COMES OUT OF THIS
RELATIONSHIP BUT IMPORTANTLY
IT'S A BINARY THING.
WE JUST GAVE PD-1 ANTIBODIES AND
SURE ENOUGH THERE'S AN INCREASE
IN THE AMOUNT PRODUCED.
WE KNOW BOTH MOLECULES CAN BE
DYNAMICLY REGULATED.
SO, WE WANTED TO ASK ABOUT
UNIQUE EXPRESSION MODALITIES IN
SETTING UP MICROBIAL BIOSIS.
IN THE CUTE MODEL WE ACTUALLY
FOUND THAT YES, THE GAMMA DELTA
TURN UP AISLE 17 BUT ALSO PD-1.
AND FUNNY ENOUGH IF YOU LOOK AT
THE RESOLUTION PHASE SOMEHOW
THESE CHANGES ARE LONG LIVED
BECAUSE WELL AFTER THE
INFLAMMATION THEY HAVE AUGMENTED
RESPONSES.
DATA I SHOW, THIS IS A SUMMARY
ABOUT THE AUGMENTED BEHAVIOR
HERE BUT WE ALSO FIND THAT AFTER
AN INSULT THESE GAMMA DELTA'S
LEARN NEW BEHAVIORS WHERE THEY
DECIDE TO LIVE.
SO IN LOOKING FOR WHAT MIGHT BE
BEHIND THIS KIND OF LEARNING
EXPERIENCE, WE IDENTIFIED
INCREASED LIPID UP TAKE THAT
HAPPENED IN FECAL DERIVED IMMUNE
TELLS AND PUT TOGETHER DATA THAT
AISLE 17 AND PD 1 CAN GO AS WELL
AS INCREASED UP TAKE.
SO I'LL WRAP IT UP.
I JUST HAVE LISTED SOME
QUESTIONS THAT WE CAN THINK
ABOUT FOR OUR FUTURE DISCUSSION
DYNAMIC INTERPLAY WITH THESE
CELLS, WE ARE INTERESTED IN HOW
THIS CONTRIBUTES TO CELLS
INCLUDING THE GUT-BRAIN ACCESS
AND HOW SPECIFICALLY MAY ALTER
THE TIMELINE TO BASELINE.
THAT IS ALL FOR MY TALK.
THANK YOU SO MUCH.
>> THANK YOU DR. HAMMER.
THAT WAS AN OUTSTANDING TALK ON
IMMUNE DYSFUNCTION AN PD-1
EXPRESSION AND AISLE 17
THOUGHTFUL PRESENTATION.
THANK YOU AGAIN.
NEXT IS DR. JUN ON IMMUNE CELL
AND DISFUNCTION.
>> CAN YOU HEAR ME OKAY.
>> YES, SIR.
>> THANK YOU SO MUCH FOR GIVING
ME OPPORTUNITY TO PRESENT OUR
DATA HERE.
THIS IS A WONDERFUL WORKSHOP.
SO TODAY I'D LIKE TO TELL YOU
ABOUT THIS IDENTIFICATION OF
IMMUNE MODULETARY AND FOCUS ON T
CELLS.
ON T CELLS FOLLOWING TALKING I'M
GOING TO FOCUS ON-70 CELLS
INVOLVED IN HOSTING IMMUNE
RESPONSE AGAINST EXPRESS
BACTERIA BUT THOSE INVOLVED IN
DIFFERENT TYPES OF AUTO
INFLAMMATION.
THE UNIQUE FEATURE OF THE CELLS
IS IT'S PROGRAMMED KEY
TRANSCRIPTION PROGRAM IS
TRANSCRIPTION FACTOR WHICH
HAPPENS THROB A RO GAMMA T WHICH
HAS A CONTROL WITH LIGON.
MANY YEARS AGO WE WANTED TO
IDENTIFY AN INHIBITOR THAT CAN
BLOCK THE CELLS BY BINDING TO
GAMMA LIGON, FROM THIS APPROACH
WE ARE ABLE TO IDENTIFY PLANT
DERIVED CARDIAC TOXIN AS SHOWN
HERE THAT INTERACT WITH RA GAMMA
T AND SUPPRESSES TRANSCRIPTION
ACTIVITY.
WHEN WE ADD TO THE CULTURE WE
ARE ABLE TO FIND THAT INHIBITS
SUBL DIFFERENTIATION COMPARED TO
A CONTROL, WITHOUT AFFECTING T
CELL ABILITY TO BECOME ANOTHER T
AFFECTOR CELLS.
SIGNS THEIR PRESENTED IN THE GUT
AND WE THOUGHT PERHAPS
MICROBIOTA HAVE A ABILITY TO
CONTROL FUNCTION BY SECRETING
INTO THE METABOLITES THAT MAY
ACT ON RO GAMMA T JUST LIKE
INYOU BEHINDIVE FUNCTION SO
BASICALLY THE QUESTION IS CAN WE
IDENTIFY NATURAL BACTERIA
METABOLITES.
SO FIND THESE MOLECULES WE
DECIDED TO FOCUS ON BIO AS SAY
BIASES EVEN THOUGH HOSTED IN THE
LIVER WHEN BHE GOT THE BACTERIA
TRANSFORMATION SO BIOAS SAY CAN
BE METABOLITES AND HAVE A
STRUCTURE SIMILARITY TO THOSE OF
KNOWN LIGONS THAT INCLUDING THE
SPECIFIC INHIBITOR.
THESE ARE THE STRUCTURAL SO WE
WANTED TO TEST HER HIGH
HYPOTHESIS THAT THIS ACTS AT RO
GAMMA INHIBITOR.
SO, TO IDENTIFY SUCH A MOLECULE
WE COLLABORATED AND COLLECTED
VARIOUS PRIMARY BIOAS SAYS AND
RAN A VERY SMALL SCALE CHEMICAL
SCREEN IN THIS CASE INSTEAD OF
USING WE USE A PRIMARY T CELL SO
WE . . . AS CONTROL AND DURING
THIS PROCESS WE ADDED INDIVIDUAL
BOW AS SAY.
SO FROM THIS APPROACH WE WERE
ABLE TO IDENTIFY TWO DYNA DRIVE
WITHOUT AFFECTING
DIFFERENTIATION BUT WE FOUND
THAT ENHANCER SO IF I SHOW YOU
PRELIMINARY RAW DATA WE FOUND
THAT . . .
>> AND THEN WHEN WE ADD THIS
MOLECULE TO CULTURE, INDIVIDUAL
CULTURE DIFFERENTIATION NOT OWL
MOLECULE SUPPRESS
DIFFERENTIATION.
SO WHEN WE DID RNA ANALYSIS WITH
WIDE TYPE T CELLS IN THE CULTURE
AND COMPARED AND FOUND THAT IT'S
A GENE EXPRESSION CHANGES ARE
VERY SIMILAR TO THOSE CHANGES IN
TH
THIS, LIKELY TO BE A MAJOR
TARGET OF IT.
IN VIVO WHETHER WE INDUCED THE
DIFFERENTIATION BY FEEDING MICE
WITH-17 BACTERIA WE SUBJECT
THESE MICE TO DIET AND THEY'RE
LED TO LEVEL OF T CELL IN VIVO
WITH MICE AS WELL SO FROM THIS
APPROACH WE ARE ABLE TO ABLE TO
FIND DIFFERENT SHAKES WITH RO,
GAMMA 2 AND BASICALLY FUNCTION
INHIBITOR.
I DON'T HAVE A TIME TO ALL THE
DATA BUT THIS PUBLISHED WORK SO
JUST GIVE YOU THIS ONE DATA
THERE, SO THIS DATA INCREDIBLE
SPECIFICITY OF METABOLITE.
IN THIS CASE ALMOST ALL FOUR
ISOMARS WE USE AN EXPRESSION AS
A READ OUT AND FOUND THAT IT'S
ONLY RELATED MOLECULE CAN
INCREASE DIFFERENCES SHAKES
AGAIN HIGHLIGHTING THE
INCREDIBLE SPECIFICITY OF THIS
VIRUS.
SO, FROM H DATA WE ARE ABLE TO
FIND TRANSFORMED INTO TWO
DIFFERENT MOLECULES THAT GET TO
THE IMMUNE CELL T CELLS IN VIVO
AND EITHER BY SUPPRESSING BY
GAMMA 2 OR ENHANCING REGAILIA
FRIDAY T CELL BY STIMULATING OR
CHANGES AND BIAS BASICALLY
SUPPRESSING INFLAMMATION.
SO, AFTER WE GOT THIS DATA WE
WANTED TO FIND THE BACTERIA THAT
NEED YATES THIS PROCESS.
SO WE WORKED WITH HARVARD
MEDICAL SCHOOL AND SHE BASICALLY
ICE LATHE A THOUSAND BACTERIA
COLONIES FROM TWO SAMPLES OF
COLITIS PATIENTS AND ANDED . . .
ACID AND AMONG THE MANY BACTERIA
WAS ABLE TO IDENTIFY SEVERAL
BACTERIA AND THE ABILITY TO
GENERATE CELLS FROM LCA SO
THAT'S WHAT WE FOCUSED ON FOR
THE FOLLOWUP ANALYSIS TO HAVE AN
ENZYME AND WE THINK THIS ENGINE
NEED YATES THIS TRANSFORMATION.
HOWEVER, THERE'S NO GENETIC
MANIPULATION AVAILABLE, SO WE
COLLECT IT AS A HOW MANY --
HUMAN ISOLATE WHY THOSE ISOLATED
DO NOT HAVE THIS ENGINE CAN
GENERATE SO WE SHOW THAT THIS IS
EXPRESSING THIS ENGINE CAN
PRESENCE OF THERE ENZYME
CORRELATES WITH PRODUCTION OF
THE ENZYME INPUT AND FOR THE
INHIBITION OF CELLS
DIFFERENTIATION.
SO WE SHOW THAT THE COLONIZATION
IS SUFFICIENT TO PRODUCE T CELLS
HOWEVER WHEN WE COLONIZE I DOES
NOT HAVE THIS ENZYME, WE NO
LONGER ABLE TO DETECT THIS
PRODUCTION.
FUNCTIONLY WE SHOW THAT IT'S
FEEDING MICE WITH THE LCA THAT
DOESN'T AFFECT DIFFERENTIATION
SO THIS PARTICULAR CASE WE ARE
INDUCING THE CELL INJECTIONSING
MICE WITH CIPRO FAST FOR AND
CORRELATE THE . . . AND DON'T
SEE CORRELATION.
HOWEVER WHEN WE REPEAT THE SAME
EXPERIMENT COLONIZED WITH . . .
BACTERIA WE ARE ABLE TO PROTECT
THOSE MICE THAT WITH HIGHER
LEVEL OF . . . WHICH I DIDN'T
HAVE TIME TO TELL YOU ABOUT IT,
WE SAW THERE'S A LEVEL PRESENCE
OF THIS BACTERIA WHICH HAS THE
ABILITY TO GENERATE INHIBITOR
LCA IT CAN REGULATE
DIFFERENTIATION IN MOUSE IN
VIVO.
>> DR. HUH YOU HAVE A COME MORE
MINUTES.
>> WE COORDINATE WITH PUBLIC
HEALTH AND LOOK AT THE RELATIVE
LEVEL OF VARIOUS VIRUS AND HOW
THEY'RE CONTROLLED AND THIS IS A
VERY BUSY SLIDE BUT BASICALLY AS
YOU CAN SEE MOST OF THE BIOPSIES
WE LOOK AT THE LEVEL IS
COMPARABLE.
IT DOESN'T MATTER WHETHER
THEY'RE LIKE IV PATIENT OR
HEALTHY HOWEVER WE LOOK AT
BIO-ASSAY WE FOUND THEIR LEVELS
ARE DECREASED IN PATIENT WITH
IBD SO NEVER TO BE ASSOCIATED
WITH INFLAMMATORY CONDITION.
SO BASED ON FROM THESE DAD WE
ARE ABLE TO SHOW IDENTIFY THIS
EXAMPLE WHERE ONE . . . CAN BE
FURTHER MODIFIED THROUGH THE
INTRODUCTION OF BACTERIA . . .
AND THEN YOU KNOW, SO KIND OF
AROUND THE SAME TIME A SIMILAR
REPORT WAS KIND OF A PAPER
FINDING OR REPORTED FROM OTHER
GROUPS IN THAT THEY ALL FOUND
AND THE REAL YINTING FINDING IS
THAT ALL THIS VIRUS IS SEEM TO
WORK ON RECEPTORS SO SUGGESTING
THE COMPLEX NATURE OF THIS
REGULAR MECHANISM AND IS VERY
INTERESTING FINDING WAS MADE BY
HONDA GROUP IN JAPAN AND NOTICED
IDENTIFIED HIGHLY PRESENTING THE
CENTENARIAN PATIENT SO THE
IMPORTANCE OF INTRODUCTION IN
HUMAN HEALTH.
I STOP HERE, ALL THIS WORK IS
DONE BY HIGHLY TALENTED FELLOW
IN MY LAB, AND ALL THIS WORK IS
REALLY MADE POSSIBLE THROUGH A
WONDERFUL COLLABORATION WITH
MANY WONDERFUL SCIENTISTS AND
PARTICULARLY A BIG SHOUT TO THE
STAFF MS AND CONTRIBUTING TO
MAKE THESE FINDINGS SO I WANT TO
STOP HERE AND THANK YOU VERY
MUCH.
>> THANK YOU DR. HUH FOR YOUR
STIMULATING TALK.
IT'S REALLY A VERY STIMULATING
TALK.
WE MOVE ON TO DR. AMIR FROM
UNIVERSITY OF CALIFORNIA SAN
DIEGO, TALKING ABOUT THE
MICROBIOME AND TIME.
AND THIS WILL BE THE LAST PART
OF OUR AFTERNOON SESSION USING
ENGINEERED BACTERIA TO
UNDERSTAND THE MICROBIOME AND
CIRCADIAN RHYTHM AND
RELATIONSHIPS.
>> AMIR.
>> CAN YOU HEAR ME?
GREAT.
THANK YOU FOR THAT INTRODUCTION
AND ORGANIZING SUCH AN
OUTSTANDING CONFERENCE.
DEFINITELY VERY EXCITING TO HEAR
MY COLLEAGUES TALK.
AND I DO HAVE SOME DISCLOSURES.
IN PARTICULAR SOME OF THE
ENGINEERED BACTERIA WORK THAT
I'LL BE DESCRIBING HAVE BEEN
LICENSED THROUGH A COMPANY
CALLED
[NAME] BIOTHERAPEUTICS AN SINCE
THIS IS TALKING TO A
NON-CIRCADIAN BIOLOGY GROUP IT'S
WORTH BACKING UP TO DISCUSS HOW
THE ROTATION OF THE EARTH WHICH
CAUSES CHANGES IN TEMPERATURE IS
A VITAL ENVIRONMENTAL CUE.
ANIMALS FROM SIGN A BACTERIA TO
MAN ALWAYS HAVE EVOLVED
MECHANISMS TO TAKE ADVANTAGE OF
THESE CHANGES DURING THE DAY,
AND AS YOU CAN IMAGINE, AN
ANIMAL THAT IS ABLE TO PREDICT
WHEN IT'S GOING TO BE DARK OUT
OR WITH IT'S GOING TO BE COLD,
WILL HAVE AN ADVANTAGE OVER ONES
THAT DO NOT HAVE OR CANNOT MAKE
THOSE PREDICTIONS AND WILL NOT
KNOW WHEN IT'S GOOD TO GO OUT
AND WITH IT'S TIME TO GO HOME TO
THE NEST.
ABOUT 45 PERCENT OF ALL GENES
ACROSS ORGANS ON THE LATE IN A
24-HOUR PERIOD AN AS CAN YOU SEE
BY THE STUD BY
[NAME] ET AL THEY ARE INVOLVED
IN DISEASES AND WILL BE OFTEN
THE TARGET OF MEDICATIONS, IN
PARTICULARLY, METABOLISM IS A
IMPORTA
IMPORTANTER IS KADIAN SYSTEM AND
ABOUT 80 PERCENT OF GENES ON THE
LATE IN A 24 HOUR PERIOD.
WHEN WE TALK ABOUT CIRCADIAN
RUMSFELD PEOPLE GET IMAGES OF
JETLAG OR LACK OF SLEEP BUT WE
ARE TALKING ABOUT AUTONOMOUS
CIRCADIAN PROTEINS TO HELP EACH
SUBTLTIES PATE WHAT IT SHOULD BE
DOING OR MACHINERY UP OR DOWN
REGULATING BASED ON, EXTERNAL
EVENTS.
THE REASON WHY THESE SYSTEMS ARE
IMPORTANT IS THEY COORDINATE
DISTANCE IN TISSUES AND ACROSS
MULTIPLE SYSTEMS, FIZZ LOGICAL
PROPHECIES WITH EACH OTHER.
WHEN I STARTED BECOMING
INTERESTED IN CIRCADIAN BIOLOGY,
ONE OF THE MAIN QUESTIONS THAT
CIRCADIAN BIOLOGISTS HAD WAS HOW
DOES LIGHT PERCEPTION OR SIGNALS
THAT WE GET FROM OUR RETINA THAT
GOES TO OUR BRAIN LEAD TO
CIRCADIAN ON THE LEGISLATION IN
THE PERIPHERAL ORGANS AND THERE
WAS PURPORTED TO BE THIS NEURAL
HUMERAL MECHANISM THAT WE HAVE
NOT IDENTIFIED POSSIBLY INVOLVED
IN AUTONOMIC NERVOUS SYSTEM OR
HORMONES WE HAD NOT YET
IDENTIFIED THAT HELPED THE CNS
CONTROL PERIPHERAL RHYTHM IN
LUNGS KIDNEYS INTESTINES AND
LIVER, HOWEVER OVER THE LAST 6
YEARS WHAT IS CRYSTALIZING IS
THE MICROBIOME THAT'S REQUIRED
FOR LIGHT TO ENTRAIN THOSE
CLOCKS, AND THAT IT CAN ALSO
MODULATED OTHER PERIPHERAL
ORGANS SUCH AS THE KIDNEYS AND
THE SPLEEN FOR EXAMPLE, AND THAT
REALLY WHAT'S HAPPENING IS THAT
THE BRAIN IS INFLUENCING THE
TIMING OF THE OUR FEEDING AND
ENTRAINING THE CLOCK THROUGH
NEAT RENT INTAKE AN ALSO THE
PRODUCTION OF SECONDARY
METABOLITES.
SO THESE MICROBAL METABOLITES
ARE ENTRAINING AGENTS.
WE DON'T UNDERSTAND HOW YET.
WE HAVE CANDIDATES IN MODIFIED
BILE ACID IS AS BEING SECONDSARY
METABOLITES AND THIS IS AN AREA
OF ACTIVE INVESTIGATION.
GOING BACK TO SIR KADE YUM
RHYTHM AND METABOLISM THE
RELATIONSHIP BETWEEN THESE TWO
BECAME VERY SALIENT WHEN
MUTATIONS OF CIRCADIAN
REGULATORS HAVE LED TO THIS
METABOLIC MODEL SO BASICALLY
EVERY CLOCK EVERY MUTANT OF A
CLOCK PROTEIN THAT IS THIS
METABOLIC PHENOTYPE.
AND
[NAME] SHOWS THAT CLOCK
MUTATIONS IN HUMANS ARE
ASSOCIATED WITH DIABETES AND
OBESITY AND NOT SURE IF THERE'S
THERAPEUTIC POTENTIAL THUS FAR.
OTHER THING INTERESTING EVERY
MODEL OBESITY HAS SOME OTHER SIR
KADE YUM RHYTHM PROBLEM, BEST
EXAMPLE MICE MORE THAN DOUBLED
THE AMOUNT OF FOOD INTAKE AND
DURING THE PERIOD WHEN THEY'RE
SUPPOSED TO REST AND THEY
ESSENTIALLY SUPPRESS CALORIE
INTAKE AN THAT IS NOT A BIG PART
OF THIS.
WE HAVE DONE A STUDY TO SHOW SIR
KA
KADIAN FLUCTUATIONS IN THE GUT
BIOME BUT NICE EAT DURING THE
NOCTURNAL PERIOD SO THIS IS JUST
A TRACING OF A MOUSE FEEDING
PATTERN AND AS YOU CAN CAN SEE
DURING THE NOCTURNAL PERIOD THEY
EAT MORE AND WE SEED A CHANGE IN
THE GUT MICROBIOME THAT IS IN
LINE WITH THAT WHERE THERE'S AN
INCREASE AND DECREASE IN
BACTERIA EATING SPECIES BUT
DURING THE RELATIVE FAST WHEN
THEY'RE SLEEPING DURING THE
LIGHT PERIOD WE SEE AND
COMPLETELY ALTER FLUCTUATION.
DIET INDUCED OBESITY MICE ARE
CONSUMEING THE SAME AMOUNT OF
FOOD NIGHT AND DAY AND WE DON'T
SEE THESE FLUCTUATIONS AN HENCE
LOSE THIS IMPORTANT
ENVIRONMENTAL CUE FOR PERIPHERAL
RHYTHM.
WE CULTURED WITH THREE OTHER
GROUPS WHO SIMILAR RESULTS
WITHIN SIX MONTHS AN THIS IS ONE
OF THE MOST ROBUST RELATIONSHIPS
AND REPEATABLE RELATIONSHIPS TO
BE FOUND IN A GUT MICROBIOME.
YOU KNOW, WE TO THE THAT TO BE
HONEST WE THOUGHT THAT WHEN WE
PUBLISHED THAT WORK IT WOULD
CHANGE THE WAY PEOPLE WOULD VIEW
MICROBIOME RESEARCH.
MY COLLEAGUES IN THE OTHER LAB
THAT PUBLISHED THIS BUT FIVE
YEARS AFTER THE PUBLICATION OF
THIS DATA, WE DID A QUICK SEARCH
FOR NATURE PUBLISHING GROUP
SCIENCE PUBLISHING GROUPS CELL
CRAFT AND ALL THE JOURNALS
PUBLISHED BY ASM AND FOUND ABOUT
586 PUBLICATIONS IN THE YEAR
2019 THAT PRESENTED NEW DATA,
AND ONLY 5 REPORTED WHEN THEY
RECORDED THEIR SAMPLES.
33 HAD A RELATIVE REPORTING SUCH
AS THEY DID IT IN THE MORNING OR
BEFORE TREATMENT OR SOMETHING
LIKE THAT.
BUT THE VAST MAJORITY DO NOT
PRESENT OR DO NOT DISCUSS WHEN,
NOT EVEN LIKE HOW MANY WEEKS
AFTER THEY STARTED THEIR
INTERVENTION THAT THE MICROBIOME
WAS COLLECTED AND JUST TO GIVE
YOU AN IDEA HERE, AS YOU CAN
IMAGINE, WE LOOKED AT
DISSIMILARITIES ACROSS TIME
POINTS AND YOU CAN SEE THAT
WITHIN A SPAN OF FOUR HOURS
THERE IS A RADICAL CHANGE IN HOW
CLOSE OR SIMILAR THESE
MICROBIOMES ARE TO EACH OTHER.
SO IF SOME ONE WAS RECORDING,
LET'S SAY YOU HAD A HOST WHO
LIKED TO WORK LATE IN THE DAY
THEY WOULD GET COMPLETELY
DIFFERENT RESULTS IF THEY WENT
TO THE MICE JUST BEFORE THE
LIGHTS TURNED OFF IN YOUR MICE
AQUARIUM YOU COULD PRACTICALLY
SHOW ANY MICROBIOME RESULTS WANT
FROM YOUR STUDY SO THE TEMPLATE
TIME IS VERY IMPORTANT IN THESE
MEASURES.
IN PARTICULAR WE WERE INTERESTED
IN A CONCEPT OF TIME RESTRICTED
FEEDING, JUST TO REFRESH MEMORY,
MICE IN DIET INDUCED OBESITY
LEADS TO LOW CYCLING OF
METABOLIC RUMSFELD PER PHENOTYPE
BUT TIME RESTRICTED FEEDING
WHERE WE RESTRICT ACCESS TO FOOD
TO ONLY THE NOCTURNAL PERIOD
LEADS THESE MICE TO CONSUME THE
SAME AM OF FOOD SO SAME NUMBER
OF BLOCKS OF CHEESE BUT
RESTRICTED TO THE NOCTURNAL
PERIOD AND PRESERVE THESE HIGH
AMPLITUDES FLUCTUATIONS AND
PREVENT IN METABOLIC PHENOTYPE
ASSOCIATED WITH HIGH FAT DIET.
YOU KNOW WHEN WE DID MICROBIOME
STUDYIES ON THESE GROUPS WE WERE
SURPRISED THERE WERE LITTLE
DIFFERENCES THERE WAS
RESTORATION OF THE CYCLICALNESS
TO THE MICROBIOME BUT WE FOUND
THAT EVEN THOUGH THE MIKE WOE
BIOME DOESN'T SHIFT MUCH
FUNCTIONALLY WE DO SEE A LOT OF
SHIFT SO FOR EXAMPLE MY POST
DOCTOR SHOWED THAT BIOACID IN
THE ILIUM THERE'S A SWING FROM
BIOACED DIFFERENCE THAT ARE
RESTORED DEHIGH FAT DIET HAND
THIS CORRESPONDED CHANGES IN
BIOASIA I HAD SIGNALLING AS WELL
AS DOWNSTREAM TARGETS OF
RECEPTORS AND ONE OF MY STUDENTS
IS WORKING ON THE TRANSCRIPT OF
THESE MICE AND WHAT WE FOUND ONE
THING THAT WAS VERY DIFFERENT
BETWEEN WAS THE CYCLICAL
ACTIVITY, WHILE THE MOUSE EATS
YOU SEE RESTRICTED MICE DON'T
EXPRESS THE . . . AND THE BACK
PRACTICE ARE MORE EXPOSED TO
BACK ARE THE A IN THE LUMEN THEY
START . . . THIS GENE WE WERE
THINK DOES BIOLACK PARTICULAR
MODIFICATION AFFECT THE SIR KADE
YUN RHYTHM OF THE MOUSE OR THE
METABOLISM.
WE DECIDED TO TAKE A NEW
APPROACH WHERE WE ISOLATED
NEEDED BACTERIA, SPECIFICALLY IN
NATIVE E-COLI AND WE DECIDED TO
ADD BENEFICIAL FUNCTIONS AND
LABEL AND WHEN WE GAVE IT BACK
TO THE MOUSE AND WE FOUND THAT
BY DOING THIS WE CAN DO THESE
KNOCK IN FUNCTION STUDIES AND
FULLY CONVENTIONALIZE MICE
WITHOUT ANTIBIOTICS BECAUSE
ANTIBIOTICS AFFECT METABOLISM
AND WE ARE ABLE TO ISOLATE THE
FACT OF THE SINGLE FUNCTION.
WHAT WE SAW WITH ENGINEERED NATE
I HAVE BACTERIA IS THAT ONE OF
THINGS CAUSED BY COVID WAS IT
HELPED EXTEND THE STUDY FOR MORE
THAN TWO YEARS WHERE WE HAD
FOUND OUT NOT ONLY PERSISTENT
COLONIZATION BUT WE FOUND THE
BACTERIA MAINTAINS ITS FUNCTION
BETWEEN TWO YEARS OF THE STUDY.
>> YOU HAVE ABOUT TWO AND A HALF
MINUTES.
>> OKAY.
CAUSE OF WEIGHT LOSS AN IMPROVE
INSULIN SENSITIVITY BUT WE
DIDN'T NOTICE ANY WEIGHT WITH
OUR FULLY CONVENTIONALIZED MICE
BUT WE NOTICED A DIFFERENCE IN
MIXED MEAL GLUCOSE AN INSULIN
AND DID REVERSE THE PHENOTYPE IN
AN OBOB MOUSE THAT WAS ABLE TO
IMPROVE SENSITIVITY BUT IT
AFFECTS CIRCADIAN RHYTHM SO WE
DECIDED TO PURSUE THIS IN
ANOTHER MODEL.
THIS IS AN H MOUSE WHERE WE
NOTICED THAT H MICE WEIGH MORE
EVER BODY FAT EVER INSULIN
RESISTANCE AND EVER THAT DESPITE
CONSUMING LESS FOOD AND DO
SPREAD THEIR CALORIE INTAKE.
ONE OF MY POST DOCS FOUND
THAT . . . WAS DIFFERENT
BETWEEN YOUNG AGE MICE SO WE
DECIDED TO USE BACTERIA TO SEE
HOW IT AFFECTS THIS AGE
ASSOCIATED PHENOTYPE AND HE
FOUND THE . . . DID IMPROVE
APPROVE INSULIN SENSITIVITY BUT
IT RESTORED EATING PATTERNS AND
OTHER CIRCADIAN ASPECTS OF THE
MOUSE THAT WE HAD MEASURED.
SO OVERALL THE LUM INAL
ENVIRONMENT, WHAT DOES IT MEAN
TO SAY THE MICROBIOME IS
DIFFERENT BETWEEN EXPERIMENT AND
CONTROL WHEN THE DIFFERENCE
BETWEEN NIGHT AND DAY IS FAR
DIFFERENT?
SO, REALLY, THE IMPORTANCE OF
THIS DYNAMIC OF THE MICROBIOME
NEED TO BE FURTHER EXPLORED.
LACK OF ACCOUNTING TIME, LUM
INAL FLUKSZ ARE IMPORTANT AND
BEING INVESTIGATED BY LOTS OF
PEOPLE INCLUDING US.
SCIENCE IS NOT DONE IN
ISOLATION.
WE CERTAINLY COULD NOT HAVE DONE
ALL THIS WORK WITHOUT THE
SUPPORT OF OUR COLLABORATEDERS
AND OUR FUNDERS, PRIMARILY NIH
SO THANK YOU SO MUCH FOR THIS
OPPORTUNITY.
>> THANK YOU VERY MUCH FOR THAT
ASSIMILATING TALK ON THE
CIRCADIAN RHYTHM AND ITS IMPACT
ON THE MICROBIOME.
KATHERINE I'LL TURN IT OVER TO
YOU.
>> WELL, THANK YOU DR. HAMILTON.
WE ARE ACTUALLY MOVING NOW TO A
BREAK.
WE HAVE A BRIEF BREAK HERE.
WE ARE GOING TO BE COMING BACK I
BELIEVE AT 3:30 P.M. SHARP AND I
WANT TO THANK THE PRESENTERS WHO
SPOKE.
I'M LOOKING FORWARD TO HEARING
FROM THE REST OF THE SPEAKERS IN
SESSION TWO WHEN WE RETURN
PROMPTLY AT 3:30.
>> DR HAMILTON BACK TO YOU
>> THANK YOU MANY IT IS GIVES ME
GREAT PLEASURE TO WELCOME
DR. SHARON.
>> SO THANK YOU VERY MUCH FOR
THE INVITATION TO PRESENT AN I'M
VERY EXCITED TO SHARE SOME OF
OUR RESEARCH.
SO, I OFTENTIMES TALK ABOUT
RESEARCH LOOKING AT INTO A BLACK
BOX.
MY LAB CONDUCTS BASICS AN
TRANSLATIONAL RESEARCH FOCUSED
ON DIETARY COMPONENTS
PARTICULARLY HUMAN MILK
COMPONENTS.
WE HEARD A LOT ABOUT THE HUMAN
GLUK OH SOOK RIDES.
WE CAN FAIRLY EASILY GET STOOL
SAMPLES TO MEASURE METABOLITES
BUT WHAT HAS BEEN TRICKY IS
GETTING ACCESS TO HOST GENOME
AND EPI GENOME.
SO A NUMBER OF YEARS AGO I
APPROACHED A COLLEAGUE TWO GOOD
COLLEAGUES ABOUT A NON-INVASIVE
APPROACH SO DR. RAP CHAP KIN AND
LAURIE AT TEXAS A & M HAD
DEVELOPED A WAY TO EXFOLIATE A
CELL TRANSCRIPTO.
WE HAVE BEEN LIMITED BY LACK OF
INVASIVE WAY TO BUT WE LEARNED
THAT A 6TH OF EPITHELIAL CELLS
ARE SHEDDED THROUGH GUT
TURNOVER . . . AND OTHERS HAVE
SHOWN THAT THESE CELLS ARE MADE
VIABILITY CONNECTS TO CULTURED
AND YOU CAN MEASURE NUTRIENTS IN
THEM AS WELL.
SO DR. CHAP KINS FOCUS WAS ON I
SAID YOU THINK THIS CAN BE
APPLIED TO HUMAN INFANTS.
SO WE CONDUCTED A PROOF OF
CONCEPT STUDY WHERE WE COLLECTED
STOOL SAMPLES OF VAGINAL
DELIVERED MOTHERS AND ALL
INFANTS WERE FED THE SAME
FORMULA AS WELL.
SO, THE TECHNIQUE BASICALLY
STOOL SAMPLES ARE COLLECTED FROM
THE DIAPER PUT IMMEDIATELY INTO
A DENATUREATION SOLUTION AND
THEN THESE THIS MIXED BY HAND SO
THIS IS ACTUALLY DONE IN THE
HOME.
THE MOTHER OF THIS INFANT WHO IS
DOING THE SIMPLE COLLECTION AND
THEN, THE SAMPLES WERE TAKEN
INTO THE LAB AND AT THIS TIME WE
WERE DOING GENE MARKER AWAY, WE
ARE NOW DOING SEQUENCING BUT
DR. CHAP KIN HAS DEVELOPED A
TECHNIQUE TO ENENRICH THE
MAMMALIAN MRNA . . . SO IT
WORKED WELL, NOW WITH SEQUENCING
THERE'S A LOT OF MAY BE ROBAL
SIGNATURES IN THERE BUT ARE
SOMEWHAT ABLE TO ENRICH THE HOST
SO WE STARTED WITH 57,000 GENES.
AGAIN WE WERE TRYING TO BE
CONSERVATIVE BECAUSE OF SOME OF
THE ISSUES THAT WERE RAISED THIS
MORNING ABOUT MULTI-OMICS AND
FALSE DISCOVERY SO WE SELECTED
4200 GENES ON ALL THE ARRAYS SO
IF IT WAX ONLY IN THE BREASTFED
INFANT SIMPLE OR FORMULA FED IT
WASN'T INCLUDED.
AFTER THE CORRECTIONS FOR FALSE
DISCOVERY RATES WE FOUND ABOUT
1200 YEENS THAT WERE
SIGNIFICANTLY DIFFERENT AND FEW
L'S THAN .05.
AGAIN TO REDUCE THE POTENTIAL
FOR FALSE DISCOVERY WE HAD A
PRIORI DEVELOPED A LIST OF GENES
WE HIGH HYPOTHESIZEth MIGHT BY
DIFFERENT IN THE GUT VSZ FORMULA
OR BREASTFED INFANTS LISTED 529
YEARS.
WE WEATHER I HADDED THE 1200
GENES ON THAT AND ENDED UP WITH
146 GENES.
THOSE WERE SUBJECTED TO A NUMBER
OF STATISTICAL AND . . .
ANALYSES ONE BEING LINEAR
DISCRIMINATE ANALYSIS TO DECIDE
WHICH GENES PROVIDE THE BEST
CLASSIFIES OF BREAST vs. FORMULA
FED INFANTS AND UPLOADED TO
UNDERSTAND THEIR NETWORKS AND
RELATIONSHIPS.
WE LOOK AT ONE AND TWO AND THREE
GENE COMBINATIONS AND SEEING
SEPARATION OF OUR GROUPS.
ONE THING I NOTICED THE
BREASTFED WE SEE MORE
VARIABILITY THAN WITH THE
FORMULA FED INFANTS AND JUST TO
GIVE SOME IDEAS OF THE GENES,
E-PASS ONE WHICH IS H I FM 1
ALPHA WAS THE MOST
DISCRIMINATORY GENE BETWEEN
FORMULA AND BREASTFED INFANTS.
LDA DOES DEPENDENT ON WHOLE
CHANGES BUT WE ALSO WERE
INTERESTED IN WHOLE CHANGE
DIFFERENCES SO IT'S IMPORTANT TO
NOTE THAT THE GENES THAT ARE
MOST DISCRIMINATORY WERE ALL
UPGRADED IN BREASTFED AND WE
HAVE SEEN THAT THE GET EFFECT
SEEMS TO BE DOWN REGULATING GENE
EXPRESSION.
WE WERE SEEING A LOT OF
TRANSCRIPTION FACTORS BUT SEEING
A NUMBER OF IMPORTANT GENES I
SAID ONE ALPHA, IT'S TWO ALPHA,
AND I WORK AND CONTINUE TO WORK
WITH PRE-TERM INFANTS SO WHAT'S
INTERESTING IS WE KNOW THAT
BREASTFEEDING PROTECTS AGAINST A
DISEASE CALLED . . . AND WE
DON'T EVER AUNTHING OF THE MEDIC
NICHES BUT WE FOUND IN TERM
INFANTS WE FOUND THE MOST
CRIMINAL STORY TRANSCRIPT OME
LETS THE GENE CELLS BE MORE
TOLERANT TO HYPOXIA SO THAT IS
SOMETHING WE ARE FOLLOWING UP TO
SEE IF THAT PROTECTIVE EFFECT IS
PROTECTING THOSE CELLS FROM
GOING INTO NECROSIS.
THROUGH META CORPS WE WERE ABLE
TO SEE THE MAJOR GENE NETWORKS
AND PATH WAYS AND THEY WERE
HIGHLY SIGNIFICANT AN ALL THESE
REALLY SUPPORT THE SORT OF
CLINICAL EM DEEM LOGICAL
DIFFERENCES THAT WE'VE SEEN
BETWEEN BREASTFED AND FORMULA
FED INFANTS BUT I'LL HAVE TO
TELL YOU AT THIS, WHEN WE GOT
THIS DATA, I HAD BEEN STUDYING
BRESD AND FORMULA FEEDING 20
YEARS AND WAS SURPRISED WE ARE
CHANGING FUNDAMENTAL GENES
INVOLVED IN GUT DEVELOPMENT, YOU
KNOW, GUT PROLIFERATION AN NOTCH
DIFFERENTIATION SO THIS PROVIDE
US AN INSIDE INTO THIS BLACK BOX
IN TERMS OF WHAT IS THE
RELATIONSHIP BETWEEN DIET
POST-GENE EXPRESSION AND WE CAN
USE THESE GENE COMBINATIONS AND
BIOMARKERS TO DIMINNISH AND SO,
IT HELPS O' -- TO GIVE FORMULA
COMPOSITION.
WE DID A COMPARISON OF PRE-TERM
vs. TERM INFANTS AND IN THIS
CASE ABLE TO SHOW THE
DEVELOPMENTAL DIFFERENCE HIGHER
INFLAMMATORY GENE EXPRESSION AND
AN NIH GRANT SO WHEN WE SUBMIT
THESE PAPERS THE ONE QUESTION
ALWAYS COMES LIKE WHERE ARE
THREE CELLS COMING FROM AND WE
KNEW WE COULD SEE SMALL
INTESTINAL SIGNATURES BUT WHAT
WE DID WAS WENT BACK STARTED THE
REVERSE TRANSLATION, TALKING
ABOUT INTO THE PIGLET MODEL SO
THIS IS A GRAPHICAL ABSTRACT SO
WHAT WE ACTUALLY COLLECTED WERE
MUCOSAL SAMPLES FROM THE ILIUM A
SENDING AND DESCENDING COLON AND
LUM NATURAL CONTENTS FROM SAY
SENDING AND DESCENDING COLON SO
YOU SEE A VERY RIGHT OF CELL
TYPES AN LOOKED AT THE
TRANSCRIPTOME AND IF YOU LOOK AT
ILIUM A.C. AND D.C. MUCOSA WE
FOUND ABOUT 12,000 GOALS AND IN
THE EX-FOLIOME THERE DESCENDING
COLON EX-FOLIOME IS THE FOLD
ABOVE THE RECTUM SO WE COLLECT
THIS BECAUSE IT HASN'T BEEN SHED
AND YOU DON'T KNOW HOW LONG IT'S
BEEN OUT SO THIS WAY IT'S READY
TO BE VOIDED FECAL SIMPLE SO WE
THINK THIS IS CLOSE TO WHAT WE
ARE SEEING IN OUR HUMAN INFANTS
IN THE THIS CASE WE ARE SEEING
ABOUT 6,000 GENES AND 50 PERCENT
OVERLAP WITH THE GENES.
AND ABOUT 94 PERCENT OVERLAP
BETWEEN THE GENES AND THE A.C.
EX-FOLIOME SO JUST PAST THE I
WILL YAL JUNCTION AN D.C. SO
SEEMS ONCE THOSE CELLS GET
EX-POLL YAITD THEY'RE FAIRLY
STABLE.
SO WE THEN WENT AND WE HAD
GENERATED LISTS OF DIFFERENT
GENES REPRESENTATIVE OF
DIFFERENT REGIONS IN THE GUT SO
TO ORIENT YOU FOR THE NEXT FEW
SLIDES, YOU SEE ILIUM MUCOSA,
A.C. NEW COAST, A D.C. MUCOSA
AND THEN THE A.C. AND D.C.
EX-POLL GOME SO THE DARKER BLUE
SHOWS THE GENES.
SO IT'S CLEAR WE ARE SEEING IN
THE A.C. AND D.C. EX-FOLIOME
GENES THAT ARE EXPRESSED IN THE
ILIUM BUT TO LESSER DEGREE IN
THE COLON SO IT'S JUST
REPRESENTING THE MUCOSAL
UNDERLYING IT.
SO THESE WERE DIFFERENT AREAS OF
THE GUT.
THESE WERE AGAIN GENE MARKERS
FOR VARIOUS CELL TYPES SO YOU
COULD SEE STEM-CELLS, TRANSIT
AMPLIFYING CELLS AND YOU KNOW,
VERY GOOD SIGNATURES AND THEN,
LASTLY, WE COMPARED SO DONE A
NICE PAPER ON HUMAN INTESTINE
AND SO WE MAPPED OUR PIGLET
EX-FOL
EX-FOLIOME AND MUCOSAL CELLS ON
THIS.
SO LOOKING AT THIS AS FINDING
GENES IF YOU GO ACROSS THE
BOTTOM IN LIPID BIOSALT VITAMIN,
ALSO TRANSPORTER GENES AS WELL
AS HORMONES AND IMMUNE GENES AND
I THINK ONE THINGS REALLY
EXCITING TO US IF WE BLOW THIS
UP YOU'LL SEE THAT FOR SEVERAL
GENES PARTICULARLY FATTY ACED
BINDING 2 USED AS ANOTHER
SUPPORTER AND STRONG EXPRESSION
IN THE GRANT THAT WE'VE
SUBMITTED IS BASICALLY TO MAKE
THE POINT THAT WE THINK THAT WE
CAN USE THIS EX-FOLIOME TO GAIN
INSIGHT INTO SMALL INTESTINAL
FUNCTIONAL GENES.
>> YOU HAVE THREE MINUTES.
>> SO, I THINK PERTINENT TO THIS
WORKSHOP IS REALLY THEN CAN WE
USE THIS ALSO TO LOOK AT HOST
MICROBE INTERACTIONS.
SO USING THE ORIGINAL CHAP KIN
STUD WE'VE THE HOST GENE
EXPRESSION AND THEN WITHIN THE
SAME STOOL SAMPLES WE SEQUENCE
THE 16-A AND META GENOME AND YOU
CAN SEE THIS IS THE FINAL LEVEL
BETWEEN FORMULA AND BREASTFED
INFANTS.
YOU CAN SEE QUITE SIGNIFICANT
DIFFERENCES, HIGH LEVELS OF BACK
TROIDZ AND PROOF OF MICROBE DIA
SO WHEN YOU LOOKED AT
INDIVIDUALS WE CAN SEE DISTINCT
MICRO
MICROBAL SIGNATURES.
SO, KIND OF TWO POINTS, IF YOU
LOOK AGAIN AT THESE FORMULA FED
INFANTS JUST LIKE HOST GENE
EXPRESSION THE MICROBIOME HAS
BEEN PUSHED TO BE VERY SIMILAR
SO WE ASKED, CAN WE USE THESE
DIFFERENCES IN THE MICROBIOTA TO
PREDICT DIFFERENCES IN HOST GENE
EXPRESSION.
AGAIN, USING THE DATA FROM THE
CHAP KIN PAPER, WE HAD THE HOST
TRANSCRIPTOME AND DID SHOTGUN
SEQUENCINGS AT THIS TIME 4-5-4
AND DON'T NOVA SEEK AND OTHER
MORE SOPHISTICATED METHODS SO
WHEN WE DID THE MICROBIOME OR
META GENOME SEQUENCING WE LOOKED
AT GENE CATEGORIES AND WE
FOCUSED ON VIRULENCE GENES AND
THEN IN TERMS OF THE HOST
SIGNATURES, WE LOOKED AT RANDOM
GENES OR INTESTINAL BIOLOGY
GENES AND BE IMMUNITY AND
DEFENSE GENES AND THERE WAS A
VERY ROBUST RELATIONSHIP BETWEEN
THE MICROBAL GENES AN BABY
DEFENSE GENES AND KNOB
RELATIONSHIP WITH RAMP COME
GENES AND WEAK WITH INTESTINAL
BIOLOGY GENES AND FIRST TIME WE
COULD LOOK AT WHETHER SIGNATURES
IN THE MICROBES WERE POTENTIALLY
CROSS TALKING WITH THE BABY.
AND SO THESE ARE JUST 11 BABY
IMMUNITY DEFENSE MUCOSAL GENES
THAT WERE MOST HIGHLY RELATED
STATISTICALLY WITH MAY BE ROBAL
VIRULENCE GENES SO EVEN THOUGH
IT'S A RELATIONSHIP WITH
VIRULENCE GENES IT IMPACT
WHETHER THE BABIES WERE FORMULA
OR BREASTFED INFANTS SO
UPREGULATED WERE SOME OF THE
INTESTAL PEAR STAL ASSIST, ALSO
ACTIVE . . . MEDIATED MICROBEAL
DEFENSE.
YOU CAN SEE MANY OF THESE ARE IN
THERE'S A DOWN REGULATION OF
THAT INFLAMMATION.
SO CONCLUDING AN IMPLICATIONS
BELIEVE THAT THE EX-FOLIOS ME
REPRESENTS THE RESERVATION FROM
THE SMALL AND LARGE INTESTINE
AND YOU CAN PROBE HOST
INTERACTIONS SPRI A EX-FOLIOME.
THIS COULD BE USED FOR GROUP
COMPARISONS BUT THIS IS A
PERFECT SITUATION SO EACH
INDIVIDUAL COULD HAVE A
BASELINE.
YOU COULD DO YOUR INTERVENTION
AND LOOK AT A WASHOUT PERIOD, SO
YOU HAVE TO COLLECT THE SAMPLES
CORRECTLY.
THEY NEED TO BE COLLECTED INTO
THE SOLUTION.
THEY CAN'T BE FROZEN OR BUT ONCE
THEY'RE IN THE SOLUTION THEY'RE
STABLE BUT WE REALLY THINK THIS
HAS AN OPPORTUNITY TO BE USED
ACROSS THE LIFE SPAN SO JUST TO
THANK MY COLLABORATORS AT TEXAS
A & M, PEOPLE IN MY LABORATORY
AS WELL AS OUR FRIENDS.
THANK YOU.
>> THANK YOU DOCTOR FOR THAT
TALK COMPARING FORMULA AND
BREASTFED BABIES.
I WOULD ASK THE PARTICIPANTS IF
YOU HAVE QUESTIONS PLEASE SEND
THEM OUT FOR OUR PANEL
DISCUSSION.
WE ARE VERY HONORED FOR OUR NEXT
SPEAKER DR. STEVE ENTOWNSEND
FROM VANDERBILT.
HE'S GOING TO TALK ABOUT THE
APPLICATION OF TWO TIME FUCOSYL
LACTOSE IN PREVENTING INTESTINAL
INJURY.
>> THANK YOU FOR THE
INTRODUCTION AND I APPRECIATE
ALL OF THE GREAT PRESENTATIONS I
HEARD TODAY AND LOOK FORWARD.
I HAVE TO DISCLOSURES.
NEITHER DOES MY COLLABORATOR
DR. FONG, SO WE ARE GOING TO
TALK ABOUT SACK RIDES, I'VE BEEN
ON THE FACULTY OF VANDERBILT
EIGHT YEARS AND OUR GROUP HAS
HISTORICALLY BEEN INTERESTED IN
MILK SCIENCE TRYING TO TEASE
WHAT THE MOLECULES DO IN THE
CONTEXT OF PREVENTING ILLNESS IN
BABIES.
WE HAVE BEEN INTERESTED IN
EXTENDING THOSE PARADIGMS AND
RESEARCHING THE POWER OF HUMAN
MILK SACK RIDES TO REPAIR DAMAGE
FROM CHEMOTHERAPY AND OTHER
ISSUES.
SO WITH THAT I'LL GIVE A BRIEF
DISCUSSION ON SOME OF THE
MACROMOLECULES OF HUMAN MILK.
TERRENCE OUT THAT MY GROUP TOOK
AN INTEREST IN MACROMOLECULES IN
SACK RIDES BECAUSE THEY'RE NOT
PRESENT IN COW MILK SO WE
THOUGHT IF WE COULD CHARACTERIZE
SOME OF THE ACTIVITY OF THESE
SACK RIDES HMO'S WE WOULD HAVE A
KEY WAY TO DETERMINE WERE
BREASTFED BABIES ARE SO HELP
THEY.
TURNS OUT THAT HUMANS PRODUCE
ABOUT 8-20 GRAMS PER LITER OF
SACK RIDES IN MILK AND WE HAVE
T
THESE HAVE BEEN ON THE SCENE
ABOUT 40 YEARS AND IF YOU TALK
TO GREAT PEOPLE LIKE ART OR DAVE
THEY WOULD TELL YOU BACK IN THE
8 OLS AND 90s, PEOPLE IN THE
COMMUNITY WEREN'T REALLY
INTERESTED IN FIGURING OUT WHAT
THESE COMPOUNDS DO BUT FOLKS
LIKE DR. MURROW AND OTHERS TURNS
OUT DURING THAT TIME PERIOD,
EARLY 80S, 90s, WE DISCOVERED
THESE COMPOUNDS WERE PRE-BIOTICS
SO THEY . . . GROWTH ADVANTAGE
OVER PATHOGENS, THEY'RE
ANTI-ADHESIVE ABLE TO PREVENT A
PATHOGEN BIONING TO THE SYSTEM.
OUR GROUP AND OTHERS HAVE TEASED
HOW THEY'RE ANTI-MICROBAL
AGENTS.
EVERYTHING THAT WE DISCUSSED ON
THE LAST SLIDE LAST TO DO WITH
MICROORGANISMS.
SO IT TURNS OUT THESE COMPOUNDS
ACTUALLY HAVE SOME EFFECTS ON
HUMAN CELLS, SO IT'S KNOWN IN
THE LITERATURE THESE COMPOUNDS
ARE MODULATORS AND ASSISTING IN
BRAIN DEVELOPMENT AND HAVE AN
IMPORTANT ROLE IN THE
DEVELOPMENT OF THE EPITHELIAL
LAYER SO WITH THESE DIVERSE
ACTIVITIES IN MIND WE WANTED TO
START TRANCE LATING TO THE
BIOLOGY AND BASIC CHEMISTRY
THAT'S BEEN ABSORBED WITH THESE
COMPOUNDS TO SEE IF WE COULD
TRANSLATE TO HELP.
SO WE STARTED OUT WITH A REAL
YINTING TOOL COMPOUNDS WE
STARTED WORKING WITH LACTOSECHY
THINK FOR MOST PEOPLE THE HMO
YOU WOULD KNOW MOST ABOUT.
SO, WITHOUT QUESTION IS THE MOST
COMMON ILLEGAL SACK RIDE SEEN IN
HUMAN MILK.
THE TYPES WILL SACK RIDES IN OUR
BODY ARE CONSEQUENCE CONSEQUENCE
OF MACHINERY WE PROCESSES SO IF
YOU'RE A SECRETER YOU GENERATE
ENZYMES THAT WILL GENERATE
COMPOUNDS THAT HAVE SIMILAR
STRUCTURES TO TWO PRIME FL SO
THEY HAVE GLUCOSE CONNECTED TO
SUGARS IN THIS BOX AND SECRETER
TWO PRIME O IS THE MOST COMMON
HMO.
LOOK AT NON-SECRETER MILK TURNS
OUT THEY HAVE MILK THAT'S
DOMINATED . . . SO I PROVIDE
THIS AS A CLARIFYING.
I'M SORRY TO SEE COMMERCIALS
TALK ABOUT TWO PRIME FO IT'S THE
MAJORITY GLOBALLY.
NOW THIS POINT OF THE GAME WE
TURN INTO THE MORE CURRENT
RESEARCH SO I DRAW ATTENTION TO
THE CONCEPT OF ORAL MICHAEL
SIGHTIES.
IT REFERENCE TO I GUESS THE
DAMAGE ON THE MUCOSAL SURFACE
USUALLY IN THE ORAL CAVITY
USUALLY SIDE EFFECT OF
CHEMOTHERAPY, A WOMAN
APPROACHING TEN YEARS OF BUT
ORAL MIKE SIGHTIES WAS PAINFUL
AND THE WORSE PART OF HER
EXPERIENCE WITH CHEMOTHERAPY.
SO, FRONTIER TYPE OF TREATMENT
WHEN IT COMES TO PREVENTING OR
DEALING IS THE IDEA THAT WE CAN
I GUESS TARGETEN DETERMINE AL
GROWTH FACTOR RESETTER SO IT'S
BEEN SHOWN IF YOU TARGET THIS
RESETTER YOU CAN OFTEN INDUCE
DISEASE FORMATION DIRECTLY
TARGETING INTESTINAL MUCOSAL
HEALING.
BASED ON THE LITERATURE WHAT I
DESCRIBED EARLIER, WE
HYPOTHESIZE THEY COULD ACTIVATE
AND BE USED TO PREVENT MIKE US
SIGHTIES.
SO.
THIS VALIDATES THE PRINCIPLE OF
THAT THEORY THAT WE OBSERVE WE
CAN USE PRIME LACTOSE TO
SOMETIME LATE ACTIVATION OF THE
EG RESETTER.
WE WANTED TO STUDY WHAT THIS
COULD MEAN IN AN ANIMAL MODEL SO
WE DECIDED TO WORK WITH THE TNBS
ACID, A MODELED YOU CAN USE TO
REALLY I GUESS SIMULATE CRONOS
DISEASE IN MICE.
WE ARE GOING TO GIVE MICE FOUR
WEEKS FOR LACTOSE IN WATER AND
ZERO WE ARE GOING TO GIVE
THEM . . . ACID.
WHAT WAS COOL ABOUT THIS
EXPERIMENT WE CLEARLY SAW IN
COMPARISON TO OUR CONTROL IF WE
GAVE THESE MICE THIS CLIETIES
INDUCING AGENT IN THE PRESENCE
OF TWO PRIME LACTOSE WE CAN
SIGNIFICANTLY REDUCE THE AMOUNT
OF INTESTINAL INJURY.
WE CAN SEE WE HAVE A NEGATIVE
CONTROL.
NOW, MOVING FORWARD, YOU KNOW,
WE WENT IN TO GO AHEAD AND
VALIDATE WE WERE HITTING THE EGF
RESETTER SO WE PERFORMED THE
EXPERIMENT INVOLVING THE WILD
TYPE OF MICE, KNOCKOUT LACKING
THE GEFR INTESTINAL EPITHELIAL
CELLS MOST CLEARLY FROM THE DATA
TWO TIME LACTOSE IS ABLE TO
SOMETIME LATE THE RESETTER AND
THIS IS LIKELY KEY MECHANISM
PREVENTING CLIETIES.
ALTHOUGH WE KNOW EGF RESETTERS
ARE AT PLAY WE WANTED TO
EVALUATE WHAT EFFECTS THE
MICROBIOME AND FILMS MIGHT HAVE
ON THE PREVENTION OFITIS.
SO, WE NOTICED THAT WE FOUND
THAT TWO PLIEM IT HAS THE
ABILITY TO INCREASE THE COUNTS
OF MICROORGANISMS ASSOCIATED
WITH INFLATION GOING TO
ENCOURAGE CLIETIES AN OTHER
INFORMS OF INFLAMMATION.
NOW AT THIS STAGE OF THE GAME WE
KNOW A LITTLE BIT FROM OUR
RESEARCH FROM THE PRECEDENT
AVAILABLE IN LITERATURE, WE KNOW
THAT WE HAVE SPECIFIC PROTEIN
TARGETS BUT WE ALSO KNOW THAT WE
HAVE SORT OF A THINKING ABOUT
SOMETHING INITIATED BY TEAM THEY
ARE.
THIS IS A COOL EXPERIMENT.
WE USE TED MODEL OF
CHEMOTHERAPY.
THIS IS A NICE REPRESENTATION OF
HIGH DOSE CHEMOTHERAPY FOR
HUMANS.
WHEN HUMAN BEINGS GET CHEMO OR
RADIO THERAPY IN GENERAL WE SEE
U BIG TUESDAY DAMAGE INTESTINAL
LINING SO WE THOUGHT WE COULD
REPAIR OR PREVENT DAMAGE CAUSED
BY CHEMO.
SO, RIGHT OFF THE BAT, YOU KNOW
IT WAS PRETTY COOL WE OBSERVED
THAT LACTOSE IS ABLE TO PREVENT
CHEMOTHERAPY FROM INHIBITING THE
GROWTH OF HEALTHY CELLS WHEN
THEY'RE EXPOSED TO CHEMOTHERAPY
BUT INTERESTINGLY WHEN IT COMES
TO TRANSFORM CELLS THIS WAS OUR
FIRST REALLY COOL LEAD TO LET US
KNOW WE HAVE SOMETHING NICE
BREWING.
NOW MOVING FORWARD WE INITIATED
A STUDY WHERE WE EVALUATED THE
INFLAMMATION OF THE SMALL SATTIN
OF A MOUSE COHORT WITH
CHEMOTHERAPY EXPOSURE.
SO IN THIS CASE PRE-TREATMENT
WITH TWO PRIME FL RODRIGUEZED
INFLAMMATION SIGNIFICANTLY.
IT'S IMPORTANT TO NOTE THAT
COTREATMENT OCCURRED AFTER
CHEMOTHERAPY WAS INITIATED.
DID NOT HAVE A SIGNIFICANT
EFFECT IN REDUCING INFLAMMATION.
NOW COMPARED WITH THE
CHEMOTHERAPY FOR 5 FU TREATMENT
ALONE WE KNOW THAT TREATMENT IS
ABLE TO PROTECT AGAINST BODY
WEIGHT LOSS.
WE SHOW THAT IT'S ABLE TO
AMELIORATE INFLAMMATION SCORE.
SO YOU WOULD THINK IF WE EXPOSE
THE MOUSEN THEY'LL YUM TO AN
AGENT WE WOULD SEE US RAISE AND
INFLAMMATION IN THE SATTIN AND
ABNORMALITIES COULD BE DECREASED
SO LACTOSE AS PROPHYLAXIS.
NOW THE HOME STREP WITH THE LAST
TWO OR THREE STRIDES, IT TURNS
OUT THAT IT'S REALLY IMPORTANT I
GUESS THAT THE MUCOSAL LAYER FOR
THE TRAINEES IN THE AUDIENCE IF
YOU THINK ABOUT OUR MUCOSAL
LAYER IT'S SUPER IMPORTANT IN
PROTECTING SURFACES AGAINST
BACTERIAL INFECTIONS VIRAL
ASSAULTS AND MECHANICAL DAMAGE
TO G. I.TRACT SO THERE'S THE
CONCEPT OF THE GOBLET CELL.
WITH CHEMOTHERAPY THESE CELLS
GET DAMAGED.
BUT IF WE TREATED WITH TWO NAME
FL FOR 36-7 DAYS OR EXPERIMENT
WE WERE ABLE TO MAINTAIN THE
COUNT OF GOBLET
>> NOW IT TURNS OUT THAT AGAIN
GETTING BACK TO THE MICROBIOME
-- BASICALLY IT'S ABLE TO
DECREASE CHEMO THERAPEUTIC
INDUCED ALTERATIONS OF THE
INTESTINAL MICROBIOTA.
SO THIS IS SUPER IMPORTANT
BECAUSE IT IS DEFINITELY PRESENT
IN THE LITERATURE THAT
CHEMOTHERAPY IS ASSOCIATED WITH
THESE PATIENTS SO WE WANTED TO
EVALUATE OVER-ALL FECAL BACTERIA
COMPOSITION -- AND SO I'M
TALKING ABOUT -- SHANNON THERE
AND IT WAS OBSERVED THAT
PRETREATMENT -- WERE ABLE TO
ELICIT A NICE SHIFT BACK TO
NORMAL GIVEN THE CHEMO
THERAPEUTIC AGENT.
NOW WE CAN AGAIN HIT HOME THE
POINT THAT IF WE'RE EXPOSING
THESE MICE WHERE THEY GET THE
CHEMO WE SEE THAT WE CONTINUE TO
UP REGULATOR MAINTAIN SOME
ACCEPTS OF NORMALITY.
INCREASE THE COUNTS OF
ANTIINFLAMMATORY BAC -- BACTERIA IS
GOOD.
WITH THAT THAT WAS A RAPID FIRE
OF THIS RESEARCH PROGRAM IN 13
AND A HALF MINUTES.
I WANT TO THANK DR. -- FONG
YOUNG.
AND I APPRECIATE YOUR ATTENTION.
>> THANK YOU VERY MUCH.
THAT WAS A VERY IMPRESSIVE TALK
ON THE ROLE OF TWO PRIME FL AND
PREVENTING INTESTINAL INJURY.
WHICH HAS THE POTENTIAL FOR
PATIENTS THAT ARE ON
CHEMOTHERAPY.
THANK YOU VERY MUCH FOR YOUR
TALK.
OUR NEXT TALK IS FROM LIPING
ZHAO.
>> THANK YOU FOR YOUR
INTRODUCTION.
HIHI, EVERYONE.
I WOULD LIKE TO THANK THE
ORGANIZERS FOR THE OPPORTUNITY
TO SPEAK HERE.
I'M GOING TO DISCUSS HOW WE MAY
USE THE REFERENCE FREE AND THE
GUILT BASE MADE APPROACH TO
ANALYZE GENOME RESULT -- FOR
DISCOVERING PRO-BIOTIC BACTERIA
WITH ECOLOGICAL COMPETENCY.
THE COMPLEXITY AND DENSITY OF
MICROBES IN OUR GUTS IS SUCH
THAT IT CAN BE CALLED OUR --
JUNGLE.
TO UNDERSTAND THE ROLE OF SOME
COMPLEX -- EXISTENCE WE NEED TO
ADOPT THE REFERENCE OF THREE AND
THE APPROACH.
WHAT IS REFERENCE FREE.
IT MEANS THAT -- DATABASES TO
ANNOTATE.
BECAUSE A SUBSTANTIAL PART OF
OUR DATASET FROM NOVEL MEMBERS
-- AND THAT CANNOT BE PROPER
LEANN STATED.
VERY OFTEN WILL BE DISCARDED IN
THE DOWNSTREAM ANALYSIS.
IF YOU DO DATABASE -- YOU WILL
ONLY STUDY THE PART OF THE DATA
THAT HAS BEEN LOOKED AT BY OTHER
PEOPLE BEFORE.
TO OVERCOME THIS LIMITATION WE
SHOULD DO A NOVEL ASSEMBLY.
WHICH CAN THEM EXAMINE THE
BEHAVIOR AND ASSESS THEIR
CORRELATIONS.
WHAT IS GUILD?
MEMBERS FROM DIFFERENT SPECIES
WORK TOGETHER AS A COHERE
APARTMENT FUNCTION CALLED GUILD.
MEMBERS STRIVE OR DECLINE
TOGETHER.
BACK IN 2015 WE SHOWED THAT --
BACTERIA WAS RESPONSIBLE AS
GUILD AND NOT AS TEXTILE.
SOME VIEWED -- THE RESEARCH --
SOME ARE NEGATIVELY ASSOCIATE
AND OTHERS SHOWED NO
ASSOCIATIONS.
HOW CAN WE IDENTIFY GUILD WHICH
PLAICES IMPORTANT ROLES.
OUR WORKING HYPOTHESIS IS THAT A
DIFFERENT BACTERIA -- WHICH
PROVIDES ESSENTIAL FUNCTIONS TO
THE HOST ITS MEMBERS WILL NEED
TO KEEP A ROBUST ECOLOGICAL
RELATIONSHIP WITH EACH OTHER.
SO ONE STRATEGY FOR TESTING THIS
IS LOOKING FOR GENOME PAIRS
WHICH CAN KEEP STABLE ECOLOGICAL
ACCENT -- BY PROFOUND CHANGES.
WE DECIDE TO TEST THIS
HYPOTHESIS BY USING HIGH FIBER
-- -- AND IDENTIFY STABLE GENOME
PAIRS AS BACKBONE OF ESSENTIAL
GUILD.
IN THIS PUBLISHED CLINICAL TRIAL
ON TYPE II DIABETES THE
RANDOMIZED CONTROL DESIGN AND
THE TRANSPLANTATION -- FROM THE
SAME PATIENT DEMONSTRATED A
CAUSAL ROLE OF HIGH FIBER
ENRICHED -- PRODUCING BACTERIA
IN SUPPRESSING PATHOGENS -- --
SO WE DID ANOTHER LARGER SCALE
RANDOMIZED CONTROLLED TRIAL
WHICH HAD A ONE-YEAR --
FOLLOW-UP ON PATIENTS AFTER
THREE MONTHS HIGH FIBER
INTERVENTION.
BASELINE M0.
AND ONE YEAR FOLLOW-UP AFTER THE
HYPER INTERVENTION.
WE DID A MEDICAL CHECK UP.
WE ASSEMBLED 1845 HIGH QUALITY
-- BACTERIA GENOMES FROM THE
DATASET.
THESE GENOMES ACCOUNTED FOR 70%
OF THE TOTAL.
THIS MEANS THAT OUR -- ARE
DOMINATED BY BACTERIA.
ANONE YEAR AFTER THE -- STOPPED --
NO DIFFERENCE FROM THE CONTROL
AND DISEASE ALSO CAME BACK.
SO AMONG THE 1845 GENOMES WE
SELECTED 447 BECAUSE THEY WERE
SHARED BY MORE THAN 75%.
-- -- OUT OF MORE THAN 100,000
POSSIBLE GENOME PAIRS MORE THAN
92% HAD -- AT THE END OF THE
THREE TIME POINTS.
INDICATING THAT IT'S A RARE
EVENTS FOR TWO GENOMES TO
ESTABLISH THE ECOLOGICAL
RELATIONSHIP.
635 PAIRS INVOLVING 141 GENOMES
WAS SELECTED BECAUSE THEY
CAPTURED THE SAME ECOLOGICAL
INTERACTION EITHER ALWAYS -- OR
ALWAYS -- CORRELATED ACROSS ALL
THE THREE TIME POINTS.
THESE 141 GENOMES WERE CLUSTERED
INTO TWO CUBES.
BASED ON THE STABLE INJECTIONS.
THERE WERE ONLY -- CORRELATIONS
INDICATING A -- OF RELATIONSHIP.
INTERESTINGLY IN THE NETWORKS
THESE HAVE ONLY 8% OF THE TOTAL
GENOMES BUT MORE THAN 80% OF THE
TOTAL REACTIONS.
IF WE REMOVE THESE 141 GENOMES
THE WHOLE NETWORK WILL COLLAPSE.
THESE TWO GUILDS WORK AS THE
MOST IMPORTANT MODELS IN THE
NETWORK.
THEY ARE THE MOST STABLE
CONNECTED AND ALSO HIGHLY
CONNECTED.
THEY ARE THE BACKBONE OF THAT
ECOLOGICAL NETWORK.
FUNCTIONAL ANALYSIS SO THAT THE
50 GENOMES HARBORED -- -- -- AND
-- PRODUCTION.
8 THIS MEANS THAT -- MAY HAVE
ADAPTED -- TO HIGH FIBER
ENVIRONMENT.
INTERESTINGLY THE 91 GENOMES HAD
A MUCH MORE --ANT BUY ON THE
CALL RESISTANCE.
----- INCREASE ITS ABUNDANCE
FROM M0 TO M3 AND THEN DECREASED
FROM M3 TO M16.
THE TWO FORMED AND ACTED AS A
SEESAW LIKE STRUCTURE.
BASED ON THE ABUNDANCE OF THIS
141 GENOMES PREDICTED 41 OUT OF
43 -- -- -- INDICATING A
SIGNIFICANT ASSOCIATION OF AT
LEAST 141 GENOMES.
---NOW THE QUESTION IS IS THIS
SEESAW LIKE NETWORK UNIQUE TO
OUR STUDY COHORT AND -- OR IS IT
AN INHERENT ECOLOGICAL PATTERN.
WE FIRST TESTED -- THE NETWORK
THAT EXISTED IN AN INDEPENDENT
CASE CONTROL TYPE II DIABETES
STUDY.
WITH OUR 141 GENOMES AND
REFERENCES -- IN BOTH CASE AND
CONTROLLED GROUPS.
YOU CAN SEE A SIMILAR SEESAW
NETWORK WAS DETECTED IN BOTH
GROUPS.
MODERATE PREDICTION -- CASE
UNDER CONTROL.
THIS MEANS THAT THE TWO SEESAW
NETWORK ARE NOT INTRINSIC
STRUCTURE.
ALSO NOT THE DIET SPECIFIC.
WE THEN TESTED THE MODEL IN
OTHER DISEASES OTHER THAN TYPE
II DIABETES.
WE FOUND A SIMILAR NETWORK
STRUCTURE OF THREE DIFFERENT
TYPES OF DISEASES.
MACHINE LEARNING MODEL BASED ON
THE 141 GENOMES HAD AN
OUTSTANDING PREDICTION POWER.
SO FURTHER CONFIRM THE RELEVANCE
-- WE INCLUDED 8 MORE
INDEPENDENT METHODS FROM FIVE
OTHER DISEASES ACROSS DIFFERENT
ETHNICITIES AND GEOGRAPHIES.
THE MACHINE LEARNING MODEL HAD A
-- POWER FOR -- ---IN ALL OF
THESE CASES.
SO THESE RESULTS SUGGEST THAT
THE TWO COMPETING VIEWS
ORGANIZED AS THE SEESAW LIKE
NETWORK ARE POSSIBLE --
STRUCTURE OF THE -- HUMAN .
AS WE KNOW -- FIBER INTAKE WAS
MUCH HIGHER AND ONLY REDUCED
SIGNIFICANTLY IN THE PAST 160
YEARS.
HIGH FIBER INTAKE MAY HAVE
LATITUDE FORMATION OF THIS
SEESAW FORMATION.
GENOMES MAY HAVE BEEN
TRANSMITTED OVER MILLIONS OF
YEARS FROM OUR COMMON ANCESTORS.
THEY MAY WORK AS A HIGH FIBER
SELECTIVE AND EVOLUTIONARY --
SUCH A SEESAW NETWORK MAY
AGGRAVATE VARIOUS CONDITIONS
DEPENDING ON THE BALANCE.
FROM ECOLOGICAL PERSPECTIVE NOT
ALL MEMBERS ARE EQUALLY
IMPORTANT FOR THE EXISTENCE.
FOR EXAMPLE -- AT A -- FOR THE
RAINFOREST.
IF YOU LOSE THE -- YOU MAY LOSE
EVERYTHING.
SO FOUNDATION SPECIES IS
DIFFERENT FROM CASE STONE
SPECIES.
IT'S IMPORTANT TO THE EXISTENCE.
FOUNDATION SPECIES IS IMPORTANT
TO THE -- ECOSYSTEM.
SINCE -- ---FROM MANY DIFFERENT
SPECIES AND WORK TOGETHER AS A
GUILD WE PERMEATE AS FOUNDATION
GUILD.
ITS COMPETING GUILD MAY INDUCE
OR AGGRAVATE DISEASES SO IT CAN
BE TERMED THE -- ---FOUNDATION
GUILD BACTERIA ARE OUR NATURAL
PRO-BIOTICS.
YOU MAY NOT -- ---OF THE
BACTERIA.
YOU ONLY NEED A MUTATION OF
SUPPORT.
MAKE IT DOMINANT.
>> YOU HAVE TWO MINUTES.
>> OKAY.
THANK YOU.
>> OUR DATA SHOWS THAT SOME
PATIENTS SUCH AS THE -- COHORTS
ONE MAY STILL HAVE THEIR OWN
FOUNDATION GUILD BACTERIA BUT AT
A LOWER ABUNDANCE POSSIBLY DUE
TO LONG-TERM DEFICIENCY.
PRO VOWIN -- PROVIDING NUTRITIONAL
SUPPORT.
-- -- WE DEVELOPED THE FORMULA
WHICH HAS BEEN GIVEN -- ---BY
THE FDA FOR PATIENTS WHO HAVE
THEIR OWN FOUNDATION GUILD.
THIS FORMULA MAY HELP RECOVER --
---WE ARE CONDUCTING A TRIAL FOR
COVID-19 AND -- ---ON OTHER
PATIENTS INCLUDING MULTIPLE
SCLEROSIS AND PARKINSON DISEASES
AND CANCER CHEMOTHERAPY.
IN OUR RECENT CASE STUDY SHOWED
THAT -- -- BACTERIA -- -- --
SYMPTOMS IN LONG COVID OF
PATIENTS.
WHILE OTHER PATIENTS SUCH AS THE
SECOND -- COHORT HERE MAY HAVE
LOST MOST MEMBERS OF THEIR --
FOUNDATION GUILD THE SEESAW LIKE
NETWORK MAY NO LONGER HOLD THE
EFFECTS.
THE PATIENTS -- -- CANNOT
---RESTORE A HEALTHY STRUCTURE.
SO FOR PATIENTS WHO HAVE LOST
THEIR OWN -- GUILD WE CAN
IDENTIFY AND ISOLATE BACTERIA
FROM HEALTHY DONORS FOR
DEVELOPING PRECISION PRO-BIOTIC
THERAPY.
LIVE CULTURES WHICH ARE
CORRESPONDING TO THE GENOMES.
THE BACTERIA HAS THE ECOLOGICAL
-- FOR -- -- THEY ARE ALSO
ECOLOGICAL COMPATIBLE BECAUSE
THEY ARE -- SO IF YOU APPLY
THEM.
WE CAN ALSO PROVIDE APPROPRIATE
CARBOHYDRATES AS THE ENERGY
INPUT TO HELP FOUNDATION
BACTERIA RECOVER AND MAINTAIN
DOMINANCE.
SO WITH THAT I WOULD LIKE TO
FINISH WITH OF ACKNOWLEDGMENT
AND LOOKING FORWARD TO QUESTIONS
DURING OUR PANEL DISCUSSION.
THANK YOU.
>> THANK YOU VERY MUCH.
REALLY CONGRATULATE YOU ON
CLARIFYING THE CONCEPT OF
REFERENCE AND FREE AND GUILD
BASE APPROACHES FOR DISCOVERING
NOVEL PRO-BIOTIC BACTERIA.
WE'LL CONTINUE WITH DR. ANDREW
GOOD MAN TO WRAP UP THE
AFTERNOON.
THE MICROBIOME CONTRIBUTION TO
DRUG METABOLISM.
>> GREAT.
HI, EVERYONE.
THANK YOU FOR THE CHANCE TO
PARTICIPATE IN THIS WORKSHOP AND
TELL YOU A BIT ABOUT THE WORK
GOING ON IN MY LAB.
AND I'M GOING TO START AT THE
END WITH THE ACKNOWLEDGMENT.
I'M GOING TO TELL YOU ABOUT THE
WORK FROM A TEAM OF PEOPLE IN MY
LAB INITIALLY LED BY TWO
TALENTED FORMER POSTDOCS -- AND
NOW CURRENTLY BEING LED BY
ANDREW -- A GRADUATE STUDENT IN
THE LAB
>> YOU NEED TO GO TO
PRESENTATION MODE, PLEASE.
>> I'M IN PRESENTATION MODE.
>> JUST GO AHEAD -- GO AHEAD AND
HIT THE SLIDE SHOW ICON AT THE
BOTTOM OF YOUR SLIDES.
WE'RE SEEING YOUR SLIDES WITH
ALL OF THEM DOWN THE LEFT SLIDE.
>> I'M SORRY ABOUT THAT
>> NO WORRIES.
OR YOU MIGHT NEED TO SWAP
MONITORS.
WE'LL LET YOU BRING THAT BACK
UP.
>> DO YOU WANT TO TRY SHARING
AGAIN AND IF YOU HAVE ISSUES --
AND THEN COME DOWN TO THE BOTTOM
AND HIT YOUR SLIDE SHOW AND YOU
SHOULD BE FINE
>> WHAT DO YOU SEE NOW?
>> WE'RE NOT IN SLIDE SHOW MODE
YET.
CAN YOU ROLL YOUR CURSOR DOWN TO
THE BOTTOM AND HIT YOUR SLIDE
SHOW MODE?
>> I'M IN SLIDE SHOW ON MY
COMPUTER.
>> OKAY.
DAN IS GOING TO TAKE OVER AND
SHARE SLIDES ON YOUR BEHALF.
CAN YOU CUE DAN FOR DAN.
>> --
>> THIS IS DAN SHARING ON BEHALF
OF DR. GOOD MAN.
CAN YOU GO TO THE NEXT SLIDE,
PLEASE.
>> SO YOU CAN GO TO THE NEXT
SLIDE.
THANK YOU.
>> SO WE HAVE BEEN INTERESTED
FOR A LONG TIME IN USING MEDICAL
DRUGS AS CHEMICAL PROBES TO
UNDERSTAND THE MICROBIOME AND
THIS INTEREST WAS INSPIRED BY
THE HISTORY OF HOW WE LEARNED
ABOUT THE LIVER.
SO WE'VE KNOWN FOR APPRECIATED
THE THE POWER OF THE LIVER FOR
CENTURIES.
AND MUCH OF WHAT WE KNOW NOW
ABOUT LIVER COMES FROM OUR STUDY
OF HOW MEDICAL DRUGS ARE
METABOLIZED BY THIS ORGAN.
AND ALONG THE WAY WE'VE LEARNED
HOW TO IMPROVE THE SAFETY AND
EFFICACY OF MEDICAL DRUGS BUT
ALSO HAVE LEARNED THAT MANY OF
THE PROCESSES THAT DRUGS THAT
THE LIVER CARRIES OUT ON MEDICAL
DRUGS ALSO ARE PART OF THE
NORMAL PHYSIOLOGY OF THIS ORGAN
AND WE REASON THAT SAME
APPROACHES COULD TEACH US ABOUT
THE MICROBIOME.
SO NEXT SLIDE.
SO WHEN I WAS MENTIONING SAFETY
AND EFFICACY IT'S USEFUL TO
START WITH THE GUIDE ABS FROM
THE FDA WHICH IS NOT ONLY DRUGS
BUT ALSO THEIR METABOLITES CAN
PLAY A ROLE IN SAFETY OF DRUGS
AND THE CURRENT GUIDANCE IS IF A
DRUG METABOLITE EACHS 10% OF THE
TOTAL EXPOSER THAT IS ENOUGH TO
MONITOR FOR POTENTIAL SAFETY
CONCERNS.
SO WE'RE INTERESTED IN BOTH
DRUGS AND IN THEIR METABOLITES.
SO WE'VE LEARNED QUITE A BIT
TODAY ABOUT HUMAN AND ANIMAL
STUDIES OF THE MICROBIOME.
SO THIS STATEMENT AT THE TOP
WILL NOT BE CONTROVERSIAL TO
THIS AUDIENCE.
BUT WHAT I WOULD ARGUE IS THAT
AT THE VERY LEAST TYPICAL
PRECLINICAL ANIMAL STUDIES ARE
NOT DESIGNED TO MEASURE THE
MICROBIOME IMPACT.
AND ONE REASON IS HERE FROM THE
CONSORTIUM SHOWING THAT ALTHOUGH
AT THE BROAD LEVEL THE LEVEL
THAT IS CONSERVED BETWEEN HUMANS
AND PRECLINICAL MODEL SPECIES
ONCE YOU START LOOKING AT A GENE
CATALOG YOU CAN SEE THAT THE
OVERLAP IS -- GETS SMALLER AND
THAT IS HIGHLIGHTED IN THE
FIGURE ON THE RIGHT WHERE IN
PINK IS THE FRACTION OF THE
GENES IN THE META GENOME FROM
THESE DIFFERENT SPECIES THAT ARE
SHARED WITH HUMAN AND GRAY IS
THE FRACTION THAT IS NOT.
SO AGAIN WE'RE NOT CAPTURING THE
GENETIC REPERTOIRE BY LOOKING IN
TYPICAL PRECLINICAL ANIMAL
STUDIES OF DRUG METABOLISM.
7 SO OF COURSE DRUGS ARE ALSO
STUDIED IN HUMANS BEFORE THEY GO
TO MARKET AND ONE OF THE
IMPORTANT STAGES IS MASS BALANCE
STUDIES WHERE SMALL AMOUNTS OF
LABEL DRUGS ARE GIVEN TO A SET
OF USUALLY FOUR TO 8
INDIVIDUALS.
URINE AND FECES ARE COLLECTED
AND THEN THE LABEL IS QUANTIFIED
AND TYPICALLY AT LEAST 80% OF
THE LABELED COMPOUND IS
RECOVERED AND APPROACHES ARE
USED TO LOOK AT THE METABOLITES
THAT ARE PRODUCED.
BUT WHAT IS CLEAR IS THAT WHEN
WE ANY ABOUT THE MICROBIOME A
STUDY OF 4-6 INDIVIDUALS IS
UNLIKELY TO CAPTURE THE RANGE
THAT WE KNOW TO EXIST.
AND ALSO IN THIS DATA FROM AGAIN
FROM META HIT SHOWING THE
LARGEST CATEGORY OF GENES IN
THESE STUDIES ARE THOSE THAT ARE
FOUND IN LESS THAN ONE OUT OF
SIX INDIVIDUALS.
AND SO ALSO WHEN WE LOOK AT
URINE AND FECES THIS MAY NOT
TELL US WHERE IN THE BODY A DRUG
METABOLITE IS MADE.
SO DESPITE THE FACT THAT THESE
TYPICAL PRECLINICAL STUDIES ARE
DESIGNED TO ALMOST AVOID SEEING
MICRO BIOMEDIA DRUG METABOLISM
THE GUT IS STILL EMERGING AS A
SECOND ORGAN.
AND NEXT PANEL SHOWS SOME OF THE
MODIFICATIONS THAT HAVE BEEN
OBSERVED AND THE POINTS HERE IS
THAT THERE IS QUITE A DIVERSITY
OF METABOLIC REACTIONS THAT HAVE
BEEN ASSOCIATED WITH MICROBIAL
ACTIVITY.
THIS MAY BE BECAUSE THEY ARE
USING THESE DRUGS NOT JUST TO
ELIMINATE THEM FROM THE BODY AND
THEN ALSO THAT THE DRUGS THAT
HAVE BEEN ASSOCIATE WITH MICRO
BIOMEDIA AND METABOLISM SPAN
MANY DISEASE INDICATIONS
INCLUDING MOST OF THEM OUTSIDE
OF THE GUT.
SO I ALSO WANT TO COME BACK TO
THE THEME OF SHARED METABOLISM
BETWEEN THE GUT AND THE LIVER.
SO EVEN IF THE REACTION IS
IDENTICAL IT'S STILL IMPORTANT
TO UNDERSTAND WHERE IN THE BODY
THIS METABOLISM IS OCCURRING
BECAUSE ALL OF THE FACTORS ON
THIS SLIDE WILL HAVE A DIFFERENT
IMPACT ON DRUG METABOLISM.
DEPENDING ON WHETHER THE
MICROBIOME OR LIVE IS
RESPONSIBLE AND I'LL COME BACK
TO THIS.
THE QUESTIONS ARE BASIC.
MANY WOULD ARGUE THAT THESE
QUESTIONS * HAVE BEEN ADDRESSED
30-40 YEARS AGO AND WE STILL
DON'T HAVE THE ANSWERS WHEN WE
LOOK AT HOW THE MICROBIOME
METABOLIZES DRUGS SO WE SET OUT
TO GENERATE A PIPELINE THAT
WOULD ALLOW US TO MAP THE
CAPACITY OF HUMAN GUT MICROBES
TO METABOLIZE DRUGS WITH THE
GOAL OF ANSWERING THE QUESTIONS
ON THIS SLIDE AS WELL AS
IDENTIFYING KEY MICROBES THAT
MAY BE IMPORTANT FOR THESE
PROCESSES.
SO IN THE INTEREST OF TIME I
WON'T GO THROUGH THE DETAILS OF
THE METHOD BUT I'LL TELL YOU
THAT WE USED AN INVITRO POOLING
METHOD TO SURVEY THE CAPACITY OF
76 DIFFERENT GUT BACTERIA.
AND WE DID THIS BY COMBINING THE
DRUGS INTO POOLS AND THEN USING
MASS SPECTORMETRY TO QUAINT TIE
AND IDENTIFY THE METABOLITES IN
THE PRESENCE OF EACH OF THESE
GUT BACTERIA.
SO I'M SHOWING YOU HERE A HEAT
MAP OF THE DATA WHERE EACH
COLUMN IS ONE OF THE DRUGS THAT
WAS METABOLIZED BY ONE OF THE
SPECIES THAT WE HAD INCLUDED AND
EACH ROW REPRESENTS ONE OF THE
76 SPECIES.
THERE IS A FEW TAKE HOME HIGH
LEVEL MESSAGES THAT WE LEARNED
FROM THIS.
THE FIRST IS THAT FOR ABOUT
TWO-THIRDS OF THE DRUGS THAT WE
TESTED WE COULD FIND AT LEAST
ONE MICROBE THAT METABOLIZED THE
DRUG.
THE SECOND WAS THAT WHEN WE
CLUSTERED THE DATA RELATED
MICROBES CLUSTER TOGETHER
SUBJECTING THERE IS AN
UNDERLYING LOGIC AND THIRD,
THERE WERE EXAMPLES WHERE DRUGS
WITH CHEMICAL SIMILARITY WERE
METABOLIZED OR IGNORED BY THE
SAME MICROBES.
SUGGESTING A LANGUAGE OF WHAT WE
DON'T UNDERSTAND OF HOW FAR
THESE MICROBES ARE RECOGNIZING
THE DRUGS AND DECIDING WHAT TO
DO WITH THEM.
ALTHOUGH THESE PATTERNS AT THE
BROAD SENSE ONCE WE START
LOOKING AT MORE DETAIL THINGS
GET MORE COMPLICATED.
HERE IS ONE EXAMPLE -- IT IS
METABOLIZED MOST ACTIVELY.
YOU CAN SEE ALSO MANY OTHER
BACTERIA THAT DON'T METABOLIZE
THE DRUG.
SO WE AGAIN USE MASS
SPECTORMETRY TO DETERMINE WHICH
METABOLITE WAS BEING MADE.
AND NEXT -- WHAT WE FOUND IS BY
IDENTIFYING THE ACTUAL GENE
RESPONSIBLE FOR THIS ACTIVITY WE
HAD A BIOMARKER.
SO, IT'S NOT THE NAME OF THE
BACTERIA OR EVEN THE FUNCTIONAL
CLASS OF THE ENZYME THAT TELLS
US WHETHER OR NOT A -- DRUG --
IT REQUIRES FINDING THE
INDIVIDUAL ENZYME THAT IS
RESPONSIBLE.
ONCE WE KNOW WE THEN HAVE AN
INDICATOR THAT DISTINGUISHES THE
MOST ACTIVE STRAINS.
THIS GENE PREDICTS THE ACTIVITY
OF A COMPLETE HUMAN GUT
MICROBIOMES IN METABOLIZING THIS
DRUG.
SO IN MY LAST FEW MINUTES I WANT
TO TURN TO THIS SECOND POINT
WHICH IS THAT WHEN WE SAW THAT
THERE WERE SO MANY MICROBE
THAT'S COULD METABOLIZE THESE
DRUGS AND THAT TWO-THIRDS OF THE
DRUGS WERE METABOLIZED BY ONE
SPECIES WE STARTED TO THINK THAT
MAYBE SOME OF THE THAT HAD BEEN
ATTRIBUTED TO LIVER ACTIVITY MAY
BE DUE TO MICROBIOME ACTIVITY.
I'LL SHOW YOU ONE EXAMPLE WHICH
IS ANTI VIRAL DRUG.
IT'S METABOLIZED -- BY BOTH THE
LIVER AND THE THE MICROBIOME AND
THIS MATTERS BECAUSE THIS
METABOLITE CAN CONTRIBUTE TO A
DRUG DRUG INTERACTION THAT HASH
FATAL.
THE NATIVE SUB STRAIGHT AND THE
REASON IS THAT -- BVU INHIBITS
-- WHEN PEOPLE TAKE BRIVUDINE --
THEY SHOW ACCUMULATION.
BUT DRUGS THAT LOOK LIKE -- 80%
OF -- IS CLEARED.
SO INHIBITION CAUSES A FATAL
ACCUMULATION OF THIS CHEMO
THERAPEUTIC.
TO AGAIN IDENTIFY THE SPECIFIC
ENZYME THAT GUT MICROBES USE.
AND WHAT WAS USEFUL IS THAT WE
CAN COLONIZE GERMFREE MICE WITH
MUTANT STRAINS AND THEN MEASURE
THE TOXICITY OF THE DRUG AFTER
IN THE LIVER IN THE PRESENCE OF
THESE EYEWITNESSES O -- ISOGENIC STRAINS.
AND SO YOU CAN SEE THE
SIGNIFICANT DIFFERENCE IN THE
ACCUMULATION DUE TO JUST A
SINGLE ENZYME IN THE GUT
MICROBES OF THESE MICE.
SO TAKING CAREFUL MEASUREMENTS
OF THE LEVELS OF DRUGS AND
METABOLITES IN EACH SECTION OF
THE GUT AS WELL AS OVER TIME
ALLOWS US TO BUILD MATHEMATICAL
MODELS TO DESCRIBE THIS PROCESS.
THE REASON FOR BUILDING THESE
MODELS IS TO QUANTIFY HOW MUCH
THE MICROBIOME IS CONTRIBUTING
AND THEN SECOND TO PREDICT HOW
DIFFERENT FACTORS SUCH AS IF MY
MICROBIOME IS MORE ACTIVE THAN
YOURS OR A DRUG SHOWS DELAYED
ABSORBS HOW THESE DIFFERENT
FACTORS MAY IMPACT THE
CONTRIBUTION OF THE MICROBIOME.
I WON'T GET INTO THE DETAILS.
IT'S A COMPARTMENTAL MODEL WHERE
WE USE OUR MEASUREMENTS IN THESE
MICE THAT VARY IN A SINGLE DRUG
METABOLIZING ENZYME TO PREDICT
NOT ONLY THE LEVELS OF
METABOLITES THAT ARE APPEARING
IN THE GUT BUT ALSO HOW MUCH OF
THAT IS ENDING UP IN THE SERUM
AND THESE CAN GET MORE
COMPLICATED -- AS SHOWN HERE AS
WELL AS MULTIPLE METABOLITES
WHICH I'M NOT GOING TO GET INTO
NOW
>> YOU HAVE ABOUT TWO MINUTES.
>> GREAT.
JUST THE TAKE HOME MESSAGE THIS
ALLOWS US TO PUT A NUMBER ON HOW
MUCH OF THE TOXIC DRUG
METABOLITE IS BEING PRODUCED.
AND WHAT THE MODEL TELLS US IS
ABOUT 70% OF METABOLITE IS
COMING FROM WHAT THE BACTERIA
ARE DOING.
AND THE NEXT SLIDE POINTS OUT
THAT THIS IS A DRUG THAT IS
FAIRLY WELL ABSORBED.
WE KNOW THE LIVER IS ABLE TO
CARRY OUT THIS AND LITTLE IS
FOUND IN FECES BECAUSE IT'S SO
READILY ABSORBED.
EVEN DRUGS WITH CHARACTERISTICS
CAN STILL HAVE A LARGE
MICROBIOME CONTRIBUTION.
SO IN THE LAST FEW SLIDES I'LL
TELL YOU ABOUT SOME UNPUBLISHED
WORK THAT HAS BEEN VERY
EXCITING.
USING THE SAME PIPELINE BUT
APPLYING IT TO GUT COMMUNITIES
FROM UNRELATED HUMAN DONORS.
BRIEFLY SOME OF THE DATA
EMERGING WHERE WHAT WE SEE IS
THAT THERE ARE INDIVIDUALS WITH
HIGHLY VARYING RATES OF
METABOLISM OF THESE DRUGS.
IN RED AND BLUE -- IN RED IS THE
SAME INDIVIDUAL AFTER INCUBATION
WITH TWO DIFFERENT DRUGS AND THE
INDIVIDUALS THAT HERE MOST
ACTIVE ON ONE ARE NOT THE ONES
THAT ARE THE MOST ACTIVE ON THE
OTHER.
THIS IS ALLOWING US TO MOVE
FORWARD FROM REDUCTIONIST
STUDIES OF SINGLE MICROBES TO
PREDICTING THE ACTIVITY.
SO WITH THAT I'LL END BY
HIGHLIGHTING THAT A MEDICAL DRUG
CAN SERVE AS TOOLS TO UNDERSTAND
HOW MICROBES CAN TRANSFORM IN
THEIR ENVIRONMENT.
AND THEN FINALLY I THINK THAT IN
THE NEXT ANIMATION -- WE SHOULD
START TO THINK ABOUT HOW THESE
MICROBIOME VARIATION THAT WE'RE
SEEING SHOULD DRIVE HOW MEDICAL
DRUGS ARE BEING DEVELOPED HOW
WE'RE MAKING SURE THEY ARE BEING
TESTED IN THE APPROPRIATE
PATIENT COHORT AND THINKING
ABOUT PREBIOTIC AND PRO-BIOTIC
THERAPIES THAT CAN BE INCLUDED
IN THE ADMINISTRATION OF THE
DRUGS.
WITH THAT I'LL STOP AND THANK
YOU.
>> DR. GOOD MAN.
THANK YOU FOR THAT EXCELLENT
TALK.
IF YOU REMEMBER WE WOULD TALK
ABOUT DRUG TOXICITY.
WE NEVER THOUGHT ABOUT THE
IMPACT OF THE MICROBIOME AND YOU
DID A WONDERFUL JOB OF
EXPLAINING THAT.
THANK YOU VERY MUCH.
>> THANK YOU DR. HAMILTON AND
ALL OF THE SPEAKERS.
DO YOU HAVE A COUPLE OF
CONTINUES BEFORE DR. VARRICCHIO
GAS TAKES OVER.
*
>> I'M TURN IT OVER TO DR.
DR. VARGAS.
>> THEY REALLY FOCUSED ON
PRECISION PRO-BIOTIC RESEARCH.
AND I JUST WANT TO SAY A BIG
THANK TO ALL OF THE SPEAKERS AND
ORGANIZERS.
AND AS WE MOVE INTO THIS LATE
AFTERNOON PANEL I HOPE TO KEEP
UP THE ENERGY AND START THE
DISCUSSION.
I'M GOING TO ASK SPEAKERS TO
RAISE THEIR HAND IF THEY HAVE
QUESTIONS AND FOR SPEAKERS FOR
THIS SESSION TURN YOUR VIDEO ON
AND UNMUTE YOURSELF WHEN YOU'RE
READY TO ANSWER A QUESTION.
IF YOU HAVE ADDITIONAL QUESTIONS
YOU WANT TO PUT IN THE CHAT THAT
IS FINE TOO.
WE'LL START WITH A QUESTION I
HAVE AND THEN I'LL LOOK FORAYED
HANDS.
SO I'M GOING TO START WITH
SOMETHING THAT REALLY STRUCK ME
AS I WAS LISTENING TO THE
PRESENTATIONS THIS AFTERNOON.
DR. DONOVAN AND OTHERS PRESENTED
NEW TECHNIQUES THAT ARE COMING
OUT AND THAT ARE AVAILABLE.
AND I THINK I WORK IN EARLY LIFE
SO I THINK ABOUT INFANTS AND HOW
WE NEED TO BE NONINVASIVE THERE.
BUT THERE ARE MANY OTHER REASONS
WHY WE NEED NONINVASIVE MEASURES
ESPECIALLY AS WE MOVE INTO AREAS
OF PREVENTION WHERE WE'RE
LOOKING AT HEALTHY INDIVIDUALS.
ARE THERE OTHER OPPORTUNITIES
WITHIN INFANTS, ADULTS, OLDER
ADULTS WHERE WE REALLY NEEDED
ADVANCES IN NONINVASIVE
TECHNOLOGY TO MOVE PRECISION
PRO-BIOTICS INTO CLINICAL
TRIALS?
>> ASHLEY, YOU HAVE A SHY GROUP.
>> IT IS 4:30.
>> I CAN MAKE A QUICK COMMENT.
I THINK THAT BASED ON THE
EXCELLENT WORK OF INDIVIDUALS
WHO PRESENTED THIS AFTERNOON AS
WELL AS OUR OWN BIAS OF SEEING
HOW INCREDIBLY VARIABLE THE
MICROBIOME IS NOT ONLY BETWEEN
INDIVIDUALS BUT WITHIN THE
INDIVIDUAL AS WELL.
I THINK THAT A LOT OF THE FACT
THAT THAT INDIVIDUALS HAVE TAKEN
IS ONE OF TRYING TO IDENTIFY
FUNCTIONS THAT THE BACTERIA DO
OR SMALL MOLECULES OR THINGS OF
THAT SORT AND ULTIMATELY IF WE
WANT TO FIND BETTER
TRANSLATIONAL METHODS THAT WORK
AT A MORE POPULATION LEVEL IN A
CLINICAL TRIAL AS DESCRIBED
EARLIER TODAY THAT WE REALLY
HAVE TO FIND SOMETHING THAT
BYPASSES THE MICROBIOME ITSELF
AND ACTUALLY PULLS ON THE LEAVES
THAT THE MICROBIOME PReSS.
I THINK THAT THAT IS PROBABLY
LIKE THE THEME THAT THESE SMALL
MOLECULES ARE -- WE'RE
DISCOVERING THAT THE MICROBIOME
IS USING THESE TO AFFECT THE
ECOLOGY AND WE HAVE TO USE THEM
IN A SIMILAR WAY TO DO SO IF WE
WANT TO DO WHAT THE MICROBIOME
IS DOING IN TERMS OF AFFECTING
HEALTH.
THAT IS A CONTINUING CONJECTURE
AND I THINK THIS ISSUE OF
VARIABILITY IS ONE THAT IT'S
PRETTY -- DIFFICULT TO DEAL WITH
WITH.
I'LL STOP THERE BECAUSE NOW
THERE ARE OTHER PEOPLE.
>> THANK YOU FOR THE COMMENT.
WONDERFUL COMMENT.
DR. ZHAO.
>> I HAVE A HIGH LEVEL COMMENT
ON THIS QUESTION.
YES, I AGREE THAT NOT ONLY THE
NONINVASIVE MEASURES ARE WHAT WE
NEED PARTICULARLY WITH CLINICAL
TRIALS AND ALSO WITH BABIES WITH
OLDER PEOPLE.
BUT IN GENERAL TAKING THE STOOL
SAMPLE AND IDENTIFYING THE
MICROBIOME IS A NONINVASIVE
TECHNOLOGY AND YOU ARE RIP AND
METABOLITES ANALYSIS IS ANOTHER
EXAMPLE OF A NONINVASIVE
TECHNOLOGY.
SO IF YOU LOOK AT URINE AND
STOOL IF YOU ALSO COUNT BLOOD
SAMPLE THAT IS THE LEAST
INVASIVE WAY.
SO THIS ACTUALLY CAN BE WIDELY
SEND.
SO URINE, BLOOD AND A FECAL
SAMPLE IS THREE WINDOWS.
AND ANY BIOLOGICAL MOLECULE IN
THESE THREE REASONS HAS A
MECHANISM.
IT'S A -- -- HAS VERY RICH
INFORMATION WHICH ACTUALLY
REFLECTS OUR HEALTH OR OUR
DISEASES AND COMPOUNDED BY DIET,
AGE, GENDER AND ALL KIND OF
THINGS.
WE DEFINITELY SHOULD MOVE TOWARD
THIS DIRECTION.
BUT WE NEED VERY DIFFERENT WAY
OF ANALYZING THE DATA AND AGAIN
I WOULD COMMENT THAT DO NOT RELY
ON THE DATABASE BUT LET THE DATA
SPEAK FOR ITSELF.
THAT IS VERY, VERY IMPORTANT.
>> AND WE'RE GOING TO COME BACK
TO THAT SPECIFICALLY.
I'M CURIOUS ABOUT YOUR THOUGHTS
ON THAT.
DR. ZIMMERMAN GO AHEAD.
>> THE COMMENT ABOUT NONINVASIVE
SAMPLING.
I THINK THE POINTS THAT WERE
BROUGHT UP ARE GOOD ONES.
WE HAVE A LOT OF GOOD METHODS
THAT REPORT ON A WIDE VARIETY OF
BIOLOGY GOING ON IN THE GUT.
WHAT WAS EXCITING IS THE
PROSPECT OF TAKING STOOL SAMPLES
AND GETTING A READE OUT OF WHAT
IS HAPPENING TO THE EPITHELIUM
IN THE SMALL INTESTINE.
IT'S ONE OF THE AREAS THAT HAS
BEEN SUPER HARD TO ACCESS AND
THERE HAVE BEEN A FEW CUTTING
EDGE STUDIES THAT HAVE DONE --
WORK IN THIS AREA.
THERE IS ADDITIONAL WORK GOING
ON LOOKING AT THE SMALL
INTESTINAL COMMUNITY.
THERE ARE CAPSULES NOW BEING PUT
THROUGH THAT OPEN UP AND COLLECT
SAMPLES AND MICROBE THAT'S
DEMONSTRATE THERE IS A DIFFERENT
COMMUNITY IN THE SMALL
INTESTINE.
JUST A TON OF INTERESTING
BIOLOGY GOING ON.
THAT'S AN AREA TO THINK B. HOW
CAN WE DECONVOLUTE SYMBOLS -- OR
DEVELOP TECHNOLOGIES THAT AND IT
MAY BE STOOL TRANSCRIPT --
NOMICS AND IT MAY BE CAPSULES
BUT A PUSH AND I THINK FOR A LOT
OF THE DISEASES THAT WE'RE
SEEING TAKE THE IMPACT OF THE
MICROBIOME ON RESPONSE TO IMMUNO
THERAPY.
WE STILL DON'T KNOW WHAT WE
SHOULD BE MEASURING.
AND SO TAKING MORE MEASUREMENTS
AND ADDITIONAL MEASUREMENTS IS
SUPER IMPORTANT AND I JUST
WANTED TO COMMENT ABOUT THE
BUTTONS THAT THE MICROBIOME IS
PUSHING ON AND I BROADLY AGREE
WITH THE COMMENT THAT IF YOU'RE
THINKING ABOUT TREATING A
DISEASE OR SPECIFIC INDICATION
AND YOU KNOW WHAT IMMUNE CELL
YOU NEED TO INDUCE OR WHAT BILE
ACID OR WHAT RECEPTOR -- I AGREE
WITH THIS.
BUT THE WAY THE FIELD SHOULD BE
THINKING IS CREATING MICROIAL
ECOLOGY THAT PREVENTS DISEASE
RATHER THAN TREATING DISEASE.
AND CREATING A HEALTHY ECOSYSTEM
-- SO I THINK ON THE ONE HAND WE
NEED TO THINK SPECIFICALLY ABOUT
WHAT WE'RE TARGETING AND ON THE
OTHER HAND WE SHOULD BE MOVING
TOWARDS THINKING ABOUT HOW TO
PREVENT CHRONIC INFLAMMATORY
DISEASES.
IF WE DON'T FIGURE OUT HOW TO
PREVENT THEM.
>> GREAT.
THANK YOU.
>> ONE ASPECT OF NONINVASIVE
IMAGING WHICH IS STILL APPEALING
BECAUSE IT'S PART OF MOST
PEOPLE'S CLINICAL CARE IS THE
USE OF IMAGING TO EITHER FIGURE
OUT THE METABOLIC ACTIVITY.
THE VERY WHAT REALLY HAVE IS THE
ABILITY TO MEASURE INTESTINAL
GAS WITHOUT ANY --
DIFFERENTIATION OF WHAT TYPE OF
GAS IT IS.
BUT IF YOU CAN BUILD ON
REALITIES -- THAT'S AN AREA OF
NEED BECAUSE IT'S SOMETHING THAT
WE CAN IMPLY MEANT DIRECTLY IN
THE CLINIC WITHOUT HAVING TO
COME UP WITH AN ENTIRELY NEW
PARADIGM BUT CAN BE HUGELY
INFORMATIVE IN THAT REGARD.
>> GREAT POINTS.
>> I'LL JUST ADD THAT I THINK
EVEN IF WE'RE LOOKING AT URINE
OR BLOOD THERE IS STILL I WOULD
REALLY PUSH FOR THE FACT THAT WE
STILL NEED A LOT OF BASIC
STANDARDIZATION AND I THINK
AMIR'S PRESENTATION ABOUT
CIRCADIAN RHYTHMS.
DO YOU COLLECT A 24 HOUR URINE
SAMPLE AND ALL OF THIS AND THE
TIMING.
SO I THINK THAT WE'RE AT A
JUMPING TOUR NOW WHERE * STUDIES
SHOULD BE FUNDED.
WE NEED IT TO BE FIGURING OUT
WHAT IS THE BEST WAY TO SAMPLE
AND PRESERVE SAMPLES AND THEY
WOULD BE A GOOD INVESTMENT OF
NIH TO HELP TO IDENTIFY WHAT
WOULD BE THESE MARKERS AND WHAT
IS THE BEST AND CONSISTENT WAY
AND COME UP WITH SOME GUIDANCE
SO THAT WE CAN COMPARE DATA AND
WE CAN DO MACHINE LEARNING AND
COMPARE ACROSS TIME.
I WAS STRUCK WITH YOUR DATA AND
I'M GLAD WE COLLECTED ALL OF THE
FIRST DIAPERS FROM OUR BABIES IN
THE MORNING.
BUT BABIES EAT 24 HOURS A DAY.
EVEN THOUGH WE'RE SAYING
SOMETHING LIKE BLOOD SAMPLES IS
NONINVASIVE IT'S STILL HIGHLY
INVASIVE FOR A HEALTHY INFANT.
SO I THINK THAT THERE IS STILL
OTHER METHODS THAT WE NEED TO
CONSIDER WITH INFANTS.
>> THANK YOU, DR. DONOVAN.
>> THANK YOU DR. VARRICCHIO GAS.
>> HEALTHY GUT MICRO BUY ON THE
A. IS IT THE SAME REGARDLESS OF
THE DIET OR THE ENVIRONMENT.
>> I HAVE TWO MORE QUESTIONS BUT
I'M STOP THERE AND GIVE PEOPLE A
CHANCE TO BECAUSE THE OTHERS ARE
DIFFERENT.
>> IT WOULD BE USEFUL TO KNOW IS
THAT THE BASELINE MICRO BIOTA?
PROBABLY NOT.
IF THEY WERE SICK AT BASELINE.
>> NOBODY IS ANSWERING IT.
I WOULD SAY WHAT WE SAID AT A
RECENT CONFERENCE.
IT'S TOUGH.
TO DEFINE A HEALTHY MICROBIOTA
IS SOMETHING THAT COMES UP.
THEY WANT TO MOVE TOWARDS THAT.
AND THE ONLY ANSWER IS HEALTHY
PEOPLE HAVE HEALTHY MICROBIOTA.
HOW DO WE DIVERSE SOMETHING IN
SOMEBODY THAT HAS NO OVERT
SYMPTOMS OF DISEASE.
BECAUSE PREVENTION FIELD IS
TOUGH.
TO KEEP YOU HEALTHY THERE IS NO
WAY TO MEASURE HEALTH AND WE
HAVE NOT FIGURED OUT HOW TO
MEASURE HEALTH SO HOW DO WE SAY
THAT WE NEED TO DO XY AND Z TO
PREVENT THEM FROM GETTING SICK
IT'S A DIFFERENT PERSPECTIVE
BECAUSE WE SEE PEOPLE WHO ARE
SICK BUT WE DO GET PEOPLE WHO
ARE HEALTHY WHO WANT TO DO
SOMETHING WITH THE MICROBIOME
AND OFTEN TIMES IT'S MORE
HARMFUL.
>> GREAT POINTS.
>> YES.
SO AGAIN WHAT IS A HEALTHY
MICROBIOME?
THIS IS THE HOLY GRAIL AND THE
FUNDAMENTAL QUESTION FOR THE
WHOLE FIELD.
IT IS CHALLENGING TO ANSWER THAT
QUESTION.
HOWEVER IT IS DOABLE TO ANSWER A
DIFFERENT QUESTION.
IF YOU HAVE TWO MICROBIOME
SAMPLES FROM THE SAME PERSON --
AND COLLECTED WITH ALL OF THE
MEDICAL DATA.
WHICH ONE IS THE HEALTHIER.
THIS QUESTION IS POSSIBLE -- --
THIS IS WHY WE USE HIGH FIBER
DIETS TO DO THE INTERVENTION.
AND THEN WE SEE -- CHANGES OF
THE MEDICAL PARAMETERS AND THEN
WE ARE ABLE TO ANSWER THE
QUESTION.
OF AFTER HIGH FIBER INTERVENTION
THE HOST BECOMES HEALTHIER AND
THE ASSOCIATED NEW MICROBIOME
PROBABLY CAN BE CONSIDERED A
HEALTHIER MICROBIOME.
SO WORKING ON THIS QUESTION ALL
TOGETHER WITH DIFFERENT
APPROACHES DIFFERENT
INTERVENTIONS AND EVENTUALLY THE
WHOLE FIELD MAY BE ABLE TO
ANSWER THE QUESTION.
>> OPTIMISTIC.
I LIKE IT.
>> -- -- THERE ARE PARTS OF THE
WORLD WHICH EAT A HIGH FIBER
DIET AND WE KNOW THAT THE
WESTERN WORLD DOES NOT BUT IF
YOU LOOK AT THE LIFE EXPECTANCY
THERE ARE REASONS FOR THAT.
THE LIFE SPECK TACT SEE OF
PEOPLE IN THE WESTERN WORLD WHO
DO NOT CONSUME THAT STILL SEEMS
TO BE LONGER.
* HOW DO YOU DEFINE HEALTH IN
THIS INSTANCE?
>> THIS IS ACTUALLY A VERY
INTERESTING QUESTION.
I WOULD LIKE TO COMMENT AGAIN.
WHEN WE SAY HIGH FIBER DIET IT'S
NOT ANY FIBER.
AND SO IF YOU LOOK AT PEOPLE AT
A HIGH LEVEL, TALKING ABOUT THE
HIGH FIBER DIETS IN THOSE UNDER
DEVELOPED AREAS MOST MAY CONSUME
THE HIGH NONFERMENTABLE FIBER
AND ALSO THEY HAVE VERY LOW
PROTEIN INTAKE AND MANY OTHER
ISSUES.
SO ITS NOT ANY FIBER.
IT HAS TO BE THE COMBINES OF
FIBER WHICH CAN PROMOTE THE
BENEFICIAL PART OF YOUR
MICROBIOME AND THEN -- ---SO WE
FOR EXAMPLE IF YOU LOOK AT THE
-- THE DATA -- TOTAL INCREASE OF
TOTAL FIBER INTAKE ASSOCIATED
WITH THIS PREVENTION -- OF
COLLIN CANCER FOR EXAMPLE.
-- -- INTO VEGETABLE AND FOOT
FIBER AND GREEN BASED FIBER --
ACTUALLY HAS -- BECAUSE
VEGETABLE AND FRUIT FIBER ARE
MOSTLY NONPERFECTMENTABLE.
THEY HAVE PHYSICAL EFFECT -- --
BUT MOST OF THE FIBER IN THOSE
PLANTS THEY ARE NONFERMENTABLE
AND THEY DO NOT PRODUCE CERTAIN
ACIDS.
SO WE NEEDED TO BE MORE INTO THE
QUESTION -- AND NOT TO HAVE A
GENERAL HIGH FIBER AS AN
UMBRELLA.
>> SPECIFICS ARE IMPORTANT.
GOOD POINT.
I'M GOING TO MOVE TO DR. -- SON
ENSBERG.
>> I JUST WANTED TO COMMENT ON
THE HEALTHY MICROBIOME QUESTION
BECAUSE ALL OF THE COMMENTS ARE
RIGHT -- ON POINT.
THERE ARE THEY KINDS OF COMMON
FEATURES THAT APPEAR TO BE
ASSOCIATED WITH HEALTH.
LIKE -- PRODUCTION APPEARS TO BE
SOMETHING THAT MOST STUDIES ARE
FINDING MORE OF THAT IN THE
CONTEXT OF A WESTERN MICRO
BIOTAS HEALTHIER.
SAME WITH DIVERSITY.
NOT NECESSARILY THAT YOU WANT
MORE DIVERSITY BUT IN THE
CONTEXT OF THE MICROBIOTA MORE
DIVERSITY SEEMS TO BE BETTER.
OUTGROWTHS OF BACTERIA SEEMS TO
BE BAD AND ASSOCIATED WITH
INFLAMMATION.
BUT A BIGGER ISSUE -- ABOUT
FIRST OF ALL THE QUESTION OF
LIFE-SPAN.
THAT IS A GOOD ONE AND ONE THAT
WE HAVE TO GRAPPLE WITH.
COMPARING THE LIFE-SPAN WITH
THOSE THAT LIVE IN LOW AND
MIDDLE INCOME COUNTRIES IS NOT A
FAIR COMPARISON.
BECAUSE IF WE HAD A BETTER MICRO
BUY OAT AM WE MIGHT BE ABLE TO
LIVE LONGER.
*.
THE OTHER ISSUE IS HOW -- IF YOU
LOOK AT THE MICROBIOTA OF A
HEALTHY PERSON -- WHAT PLAGUES
US ARE THE CHRONIC DISEASES AND
THOSE USUALLY TAKE DECADES TO
DEVELOP.
THE QUESTION IS IF YOU LOOK AT A
HEALTHY PERSON DO THEY
NECESSARILY HAVE A HEALTHY
MICROBIOTA -- OR ONE THAT IS
PROMOTING THE VERY INFLAMMATION
A DECADE OR TWO DOWN THE ROAD IS
GOING TO CAUSE THEM TO HAVE SOME
TERRIBLE DISEASE.
SO IT'S HARD TO SAY THAT HEALTHY
PEOPLE HAVE HEALTHY MICRO
BIOTAS.
* SO IT'S A BIG CHALLENGE AND
THE WAY THAT WE'VE BEEN THINKING
ABOUT THIS ONE WAY IS TO TURN AN
EVOLUTIONARY FILTER ON THIS.
JUST THAT IT MAY REPRESENT A
STATE THAT OUR HUMAN GENOME
EVOLVED WITH AND THERE MAY BE
FEATURES THAT ARE HUMAN GENOME
HAS COME TO INSPECTOR MAYBE MORE
ACCUSTOMED TO.
A SIMPLE EXAMPLE IS - --
DEGRADATION.
AND WE ALSO KNOW THAT IF YOU
DON'T HAVE THAT SPECIES YOU'RE
MORE LIKELY TO DEVELOP KIDNEY
STONES.
AND SO, THAT IS JUST AN EXAMPLE
OF A FUNCTION THAT WE'RE LOSING
DURING IN DUST SITUATION THAT IS
LEADING TO ANOTHER * DISEASE
THAT IS A PROTOTYPIC WESTERN
DISEASE, KIDNEY STONES.
SO, THAT IS ONE EXAMPLE OF
BRINGING BACK A FUNCTION -- EVEN
THOUGH MOST OF US HAVE MAYBE
HEALTHY MICROBIOMES WE MAY BE
MISSING THAT AND AT INCREASED
RISK FOR THAT DISEASE.
SO ANY WAY JUST SOME THOUGHTS.
>> THANK YOU.
>> I AGREE.
THE PROBLEM IS THE FEAR OF THE
UNKNOWN.
IN TERMS OF MOST THINGS CAN BE
TOLD AS SAYING YOU CAN EAT THIS
TO STAY HEALTHY.
WE DON'T KNOW ABOUT THE CHANGE.
IF WE KNEW WHAT THAT CHANGE WAS
THAT 20 YEARS LATER IS GOING TO
TRIGGER A DISEASE WE CAN SAY
OKAY.
THAT IS SOMETHING TO BE
TARGETED.
BUT RIGHT NOW IT'S THE FAST
UNKNOWN.
PEOPLE WHO COME TO SEE YOU WANT
TO KNOW.
AND WE DON'T KNOW IT AND THEY
WANT YOU TO FIX IT WITHOUT US
KNOWING IT.
SO, ITS A MATTER OF PRACTICAL
VERSUS CONCEPTUAL.
SO I COMPLETELY AGREE THAT --
BUT IF WE DON'T KNOW IT IS THIS
THE RIGHT TIME TO GO AFTER IT.
I'M NOT SAYING WE SHOULD STOP
LOOKING FOR IT.
BUT IN REALTIME -- THAT IS WHERE
THE CHALLENGE IS.
>> I COMPLETELY APPRECIATE THAT.
>> WE'LL HAVE THE LAST COMMENT
FROM DR. -- ZHAO AND THEN MOVE
ON.
>> IT IS POSSIBLE TO APPLY
INTERVENTIONS THAT CAN CHANGE
THE MICROBIOME.
WHICH WILL BE IN THE TIME FRAME
OF A FEW MONTHS INSTEAD OF YOU
NEED TO WAIT MANY YEARS AND YOU
NEED TO HAVE PREVIOUS SAMPLES
AND WAIT UNTIL THE DISEASE
MANIFEST AND THEN YOU COMPARE
AFTER AND TRY TO IDENTIFY
SOMETHING WHICH CAN PREDICT THE
RISK.
I PREFER INTERVENTION TRIALS
WHICH CAN CHANGE THE MICROBIOME
NOW RATHER THAN WAIT MANY
DECADES TO SEE HOW THE AGE
RELATED CHANGE OF THE MICROBIOME
ACTUALLY DRIVES THE RISK.
>> CAN I JUST MAKE A QUICK
POINT.
I KNOW A COUPLE OF YEARS AGO
STEVEN O'KEEFE AND -- PUBLISHED
A NICE PAPER WHERE THEY WERE IN
AFRICA AND AFRICANS AND THEM
AFRICAN-AMERICANS IN
PHILADELPHIA AND THEY BASICALLY
SWAPPED THE DIETS.
THEY WENT TO AFTER AFFECTED THEM
HAMBURGERS AND AFRICAN-AMERICANS
SORT OF A TRADITIONAL DIET.
AND WITHIN DAYS THEY COULD SEE
THROUGH BIOPSIES -- CHANGES IN
GENE EXPRESSION AND CHANGES IN
PROLIFERATION.
SO IT'S NOT EVEN MONTHS.
AND THAT WAS A WHOLE SIGNATURE.
IT WAS INVASIVE BECAUSE THEY
TODAY DO A BIOPSY.
BUT I THINK THAT WE DON'T HAVE
TO WAIT DECADES NECESSARILY.
THERE COULD BE SOME QUICKER
TYPES OF ASSAYS THAT COULD BE
DONE AND YOU CAN SCREEN
DIFFERENT PRO-BIOTICS IF YOU
HAVE THE BIOMARKERS OF WHATEVER
OUTCOMES YOU'RE LOOKING FOR.
>> EXCELLENT.
AND ON A POSITIVE NOTE.
BARBARA, DO YOU HAVE ADDITIONAL
QUESTIONS THAT YOU WANTED TO ASK
AT THIS TIME?
>> SURE.
I'M HAPPY TO ASK MORE QUESTIONS.
AS WE THINK ABOUT LOOKING AT
THIS SMALL MOLECULE METABOLITES
GENERATED BY OUR MICRO GUT IN
PICK.
WHAT KIND OF SAMPLE SIZE YOU
WOULD NEED IF YOU ARE LOOKING AT
METABOLITES OR URINE OR FECES TO
UNDERSTAND -- TO BE ABLE TO MAKE
PREDICTIONS ABOUT WHO'S GOING TO
HAVE WHAT RESPONSE TO A GIVEN
INTERVENTION BECAUSE YOU'RE
LOOKING ACROSS ALL KINDS OF
BACKGROUND DIETS AND GENOTYPES.
ALL KINDS OF DRUG EXPOSER AND
OTHER ENVIRONMENTAL EXPOSURES.
AS WELL AS DIFFERENT BASELINE
MICROBIOTA.
SO I'M WONDERING WHAT KIND OF
SAMPLE SIZE WOULD YOU NEED TO BE
ABLE TO SEE AN EFFECT AGAINST
THAT BACKGROUND VARIABILITY.
THAT IS ONE OF THE CENTRAL
QUESTIONS FOR THIS WORKSHOP?
HOW DOES THAT HELP YOU BE ABLE
TO PREDICT --
>> YOU BROKE UP A LITTLE BIT
>> ARE YOU ASKING HUNDREDS,
THOUSANDS, TENS OF THOUSANDS.
A BALLPARK?
>> IT'S A GREAT QUESTION AND I'M
NOT GOING TO GIVE A VERY
SATISFYING ANSWER.
BUT WHAT WE'VE LEARNED WHERE
WE'VE LOOKED AT TENS TO
HUNDREDS' THOUSANDS OF
INTERACTIONS BETWEEN SMALL
MOLECULES AND MICROBES IS THAT
WE SEE THE ENTIRE SPECTRUM OF
SIGNAL.
SOME OF WHICH WE WOULD SEE WITH
FIVE INDIVIDUALS AND OTHERS
WHERE WE'RE ONLY SEEING IT
BECAUSE OF THE DEPTH THAT WE
HAVE.
SO I THINK IT'S GOING TO BE VERY
HARD TO SAY THAT THE NUMBER IS
235 PEOPLE OR SOMETHING LIKE
THAT BUT MAYBE WE SHOULD THINK
ABOUT WAVES OF STUDY THAT ALLOW
US TO TRY TO DO A POWER ANALYSIS
BECAUSE I THINK THERE IS NOT
GOING TO BE ONE ANSWER.
8 BUT IF THERE ARE PILOT STUDIES
THAT GIVE US A SENSE OF THE
DEPTH IT MAY HAVE TO BE
INDIVIDUALLY DETERMINED FOR EACH
STUDY.
>> THANK YOU.
DR. ZHAO.
>> I WOULD AGREE WITH THAT AND
IN OUR CLINICAL TRIALS WE ALWAYS
COLLECT SAMPLES OVER TIME.
AVENUE SOME TRIALS ARE WELL
FIVELY SMALL SAMPLE SIZE.
SOME ARE LARGE.
AND WHILE BASICALLY IT DEPENDS
ON WHAT KIND OF METABOLITES
YOU'RE TALKING ABOUT.
YOU WILL BE ABLE TO SEE
SIGNIFICANT CHANGES OVER TWO OR
THREE MONTHS TIME BUT IF YOU'RE
TALKING ABOUT OTHER METABOLITES
MAYBE A WEAK SIGNAL AND THE
PRODUCER IS A MINOR MEMBER OF
THE COMMUNITY THEN YOU MAY NEED
RATHER LARGE SAMPLE SIZE TO BE
ABLE TO DETECT THAT.
>> GOOD POINT.
>> THE ONE OTHER THING I WOULD
ADD IS THAT -- IT'S VERY EASY
FOR US WHO STUDY THE MICROBIOME
TO THINK ABOUT THE MICROBIOME AS
THE ACTOR ACTING ON THE HOST.
AND AND A LOT OF TIMES WHEN WE
WHEN I TALK TO THE CLINICAL
FELLOWS AND THEY ASK ME WHY ARE
MICROBIOMES IMPORTANT.
REALLY THE BACTERIA DON'T EVEN
KNOW THE HOST EXIST.
THEY JUST KNOW THAT THEIR --
EXIST.
AND IT'S THE HOST THAT IS
INTERPRETING THE SIGNALS OF
THESE BACTERIA.
SO WE'RE PRETTY CONVINCED THAT
FOR EXAMPLE BILE ACIDS -- ARE
BASICALLY SAYING SOMETHING ABOUT
THE NUTRITIONAL VALUE OF WHAT
THE HOST IS CONSUMING.
WHETHER THERE IS -- IN THIS CASE
PARTICULAR FATTY AS I FAT -- FATTY ACIDS I N
THE DIET.
WHY IS THE HOST EVEN CARE ABOUT
THESE SMALL METABOLITES BEING
PRESENT.
AND WHY WOULD IT HAVE SYSTEMS IN
PLACE TO DETECT THESE THINGS.
AND I THINK THAT THAT HAS REALLY
HELPED US UNDERSTAND OR FRAME
SOME OF THE EXPERIMENTS TO
BETTER UNDERSTAND THE
RELATIONSHIP.
BUT & ALSO HAS GIVEN US A NEW
APPRECIATION OF BILE ACIDS BUT
WHEN WE FIRST STARTED OFF IT WAS
LIKE SEARCHING FOR THE KEYS
UNDER THE LIGHT.
IT'S EASY TO KNOW.
IT'S EASY TO STUDY FATTY ACIDS
BECAUSE YOU KNOW THEY ARE FROM
THE BACTERIA RATHER THAN THE
HOST.
WE NEED TO TAKE A STEP BACK AND
THINK ABOUT WHY DO THEY CARE
THAT THESE SPECIFIC MOLECULES
ARE PRESENT.
>> EXCELLENT OBSERVATION.
>> SO I DON'T WANT TO -- GIVE --
ANSWER BUT OVER-ALL WE DON'T
KNOW ENOUGH.
IN ORDER TO DO THESE STUDIES TO
SAY WHICH METABOLITE PROVIDES A
HEALTH BENEFIT -- AND A GOOD
CORRELATION -- WE NEED TO DO
MORE STUDIES.
WE NOW KNOW THAT -- CAN CONTROL
-- -- -- ---BUT BY A LARGE AND
WE JUST -- HAVE SCRATCHED THE
SURFACE.
WE FIRST NEED TO KNOW -- --
IMPORTANT PLAYERS.
THEN WE CAN REALLY -- MEANINGFUL
COMPARISON.
JUST MY TWO CENTS.
BUT MORE STUDIES NEED TO BE
DONE.
>> THANK YOU.
>> BACK TO THE ORIGINAL
QUESTION.
IT'S DIFFICULT TO TELL THE
SAMPLE SIZE BECAUSE THE IDEA OF
DEVELOPING THE SAMPLE SIZE WE
KNOW ALL OF THE THINGS THAT
AFFECT THE METABOLITE AND THE
SMALL MOLECULE THAT THEY ARE
LOOKING AT BUT IT DEPENDS ON THE
COHORT CHARACTERISTICS.
A POPULATION FROM THE SAME AREA
THAT MIGHT BE YOU NEED A SMALLER
NUMBER BUT IF YOU INCREASE THE
GEOGRAPHIC REACH OF THE STUDY
AND THAT IS -- JUST LOOK AT --
STUDIES -- INCREASING THE NUMBER
SO YOU HAVE MORE VARIABILITY.
WE KNOW WHAT THE VARIABILITY OF
THE METABOLITE WAS THEN WE COULD
COME UP WITH A MORE REASONABLE
SAMPLE SIZE.
BUT IF YOU'RE DOING A DISCOVERY
STUDY I DON'T THINK YOU WOULD BE
ABLE TO DO THAT.
IN THE MIDWEST EVERYBODY PRETTY
MUCH EATS THE SAME THING.
IF WE DID THE SAME THING
COMPARED TO THE -- THE WEST
COAST THERE WOULD BE A HUGE
DIFFERENCE IN DIETARY FIBER AND
THAT IS WHAT DROVE US TO DO SOME
OF THESE STUDIES.
IF WE EXPANDED OUR GROUP WE
WOULD HAVE LOST SOME OF THE
SIGNALS WE WERE SEEING BECAUSE
THERE WAS SO MUCH BASE LINE
VARIABILITY.
THE TWO LARGE STUDIES THAT HAVE
LOOKED AT THIS -- WHICH IS THOSE
LOOKING AT THE GUY -- GLYCEMIC
RESPONSE.
AND THEY WERE DONE ACROSS TWO
CONTINENTS.
IT'S ALL PART OF THE DEVELOPED
WORLD.
NOT TAKING -- THE DEVELOPING
WORLD.
SO I IMAGINE IF YOU WANTED TO
LOOK AT THE SAME IN THE
DEVELOPING WORLD IT WOULD TAKE A
SIMILAR COHORT SIZE TO FIND THE
SAME INDICATORS.
>> ALL RIGHT.
AND I'LL JUST ADD THAT WHEN WE
WERE PUTTING TOGETHER OUR WORK
-- FOR OUR PROGRAM WE STRUGGLED
WITH THESE SAME ISSUES AND THE
SOLUTION IS SOMETHING LIKE AN --
TRIAL OR DO YOU DISCOVERY
SCIENCE AND THEN FIGURE OUT THE
VARIATION IS AND DO IT IN A
SMALLER COHORT.
IT'S A HUGE ISSUE THAT EVERYONE
IS TRYING TO TACKLE.
DR. ZHAO
>> -- THE SAMPLE SIZE QUESTION,
OF COURSE HOST IS THE RESPONSE.
AFFECTS THE RESPONSE.
IS ACTUALLY CRITICAL.
AND SO WE NEED TO KNOW HOW MUCH
OF THE MICRO -- PRODUCT -- AND
THAT CAN ACTUALLY INDUCE A
RESPONSE -- WHICH CAN BE
MEASURED.
WE WOULD LIKE TO SEE A
DIFFERENCE -- BETWEEN THE TWO
DIFFERENT GROUPS AND THAT IS
CRITICAL FOR ESTIMATING SAMPLE
SIZE.
AND I WOULD LIKE TO ADD A SHORT
COMMENT ON THE PREVIOUS
QUESTION.
OF VIABILITY OF PRO-BIOTIC
BACTERIA.
THE PRODUCT PUTTING BENEFICIAL
-- ARE HIGHLY AVAILABLE.
THEY ARE SO READILY -- ABSORBED.
HOWEVER THEY ARE PRODUCERS IF
NOT HAVING ECOLOGICAL DOMINANCE
IN THE GUT THEN THE ACTUAL
PRODUCTS PRODUCED IT WOULD BE
LIMITED SO THE HOST ACTUALLY
BECOMES DEFICIENT.
WE MAY NEED TO INTRODUCE ANOTHER
CONCEPT -- FOR PRO-BIOTIC
BACTERIA.
>> INTERESTING.
SO DR. -- I'M GOING TO MOVE TO A
QUESTION THAT HAS BEEN BURNING.
IT LOOKS LIKE FOUR PEOPLE HAVE
ASKED THIS.
THIS IS ABOUT TRANSIT TIME.
THIS IS FOR DR. KASHYAP.
HOW IMPORTANT IS TRANSIT TIME
KNOWING THAT HUMANS ARE ABLE TO
CONTROL THEIR TRANSIT TIME AND
CHOOSE WHEN TO DEFECATE.
AND HOW MUCH OVERLAP IS THERE
BETWEEN MICE TRANSIT TIME VERSUS
HUMAN KNOWING THEY ARE VERY
DIFFERENT.
>> I CAN TAKE THE SECOND ONE IF
YOU WANT TO TAKE THE FIRST ONE.
>> SO THE SECOND PART -- MICE
DEFECATE -- IT'S NOT HARD TO GET
24 HOUR STOOL --S FROM THEM
ESPECIALLY DURING THEIR FEEDING
TIME.
MORE PELLETS THAN WE KNOW WHAT
TO DO W THERE IS ALWAYS A
QUESTION OF WHETHER THESE
CIRCADIAN CHANGES THAT WE
OBSERVE IN MICE APPLY TO HUMANS.
WE KNOW THAT HUMAN ORAL SAMPLES
LIKE SALIVA AND SKIN DO HAVE
CIRCADIAN FLUCTUATION AND THERE
WAS A RECENT PAPER BY THE GROUP
IN GERMANY -- WHO SHOWED THAT
THERE IS CIRCADIAN TO THE
MICROBIOME WHEN LOOKED AT A
POPULATION LEVEL MEANING THAT
PEOPLE WHO TEND TO DEFECATE
LATER IN THE DAY HAVE A
DIFFERENT MICROBIOME COMPOSITION
THAN THOSE WHO DEFECATE EARLIER
IN THE DAY.
WE HAVE DONE SOME PRELIMINARY
LOOK AT THE AMERICAN GUT AND
OPEN BIOME SETS AND WHAT WE
FOUND IS WHEN YOU LOOK -- OPEN
BIOME HAS INDIVIDUALS WHO HAVE
PROVIDED HUNDREDS OF STOOL
SAMPLES AND COLLECTED USUALLY
BETWEEN 9 AND 5.
WHAT WE'VE FOUND IS THAT THERE
IS NO WAY TO PREDICT WHEN A
SAMPLE WAS COLLECTED BASED ON
THIS COMPOSITION.
EITHER WITHIN ONE INDIVIDUAL OR
CROSS INDIVIDUALS.
THESE CYCLICAL CHANGES SEEM TO
EXIST IN A MORE POPULATION LEVEL
AS OPPOSED TO AN INDIVIDUAL
LEVEL THAT YOU HAVE TO HAVE
THOUSANDS OF SAMPLINGS TO
ACTUALLY BE ABLE TO SEE THESE
FLUCTUATIONS.
SO THEN COMES THE IMPORTANT AND
ANOTHER IMPORTANT QUESTION.
USUALLY WE HAVE -- MOST PEOPLE
HAVE A RECTUM IN WHICH WE STORE
OUR POOP UNTIL IT IS SOCIALLY
APPROPRIATE TO DEFECATE.
AND THAT WHILE IT IS THERE WATER
IS BEING ABSORBED BY THE COLON
AND THE NATURE OF THE EVENTER IS
CHANGING AND PROMOTING CERTAIN
BACTERIA AND WHAT NOT.
THE ONE THING THAT WE STRUGGLE
WITH -- WITH HUMAN RESEARCH IS
WHETHER THE BIOME IS INDICATIVE
OF WHAT WAS GOING ON IN OTHER
REGIONS THAT ARE MORE
BIOLOGICALLY IMPORTANT.
IN THE ILEUM OR IN A PATIENT
WITH INFLAMMATORY BOWEL DISEASE
-- WHETHER THEY ARE INDICATIVE
OF SOME OF THE OTHER REGIONS AND
WE ARE STRUGGLING TO FIND THAT
IT IS.
AND SOME SAMPLES THAT WE'VE
LOOKED AT WE'RE NOT FINDING THAT
SORT OF SIGNATURE AND THAT IS
WHY THE STOOL HAS NOT BEEN THAT
GREAT OF A BIOMARKER.
SO I THINK THERE NEEDS TO BE
BETTER WAYS OF ASSESSING THE
MICROBIOME BESIDES STOOL.
AND AS WAS SUGGESTED EARLIER
MAYBE EARLIER METHODS SUCH AS
LOOKING AT BLOOD OR URINE OR
SOMETHING ELSE.
BUT I THINK THAT WE DEFINITELY
NEED TO BETTER UNDERSTAND WHAT
IS IT THAT WE'RE LOOKING AT WHEN
WE'RE LOOKING AT STOOL
MICROBIOME FROM HUMANS.
S IT STORAGE TIME.
IS IT A REFLECTION OF DIET?
OR -- WHAT I THINK IS GOING ON
IS ALL OF THOSE THINGS ARE
DROWNING OUT OF THE ORGANISMS
AND METABOLITES THAT ARE PERHAPS
MORE IN PARTICULARRIVE OF WHAT
IS GOING ON PHYSIOLOGICALLY AND
WE NEED TO FIGURE OUT HOW TO
SEPARATE THE NOISE FROM THE
SIGNAL.
>> THANK YOU.
>> I THINK ONE THING TO REMEMBER
IS THAT PEOPLE GO BACK AND FORTH
AND THERE ARE FUNDAMENTAL
DIFFERENCES AND WE CANNOT CROSS
COMPARE TRANSIT TIMES BETWEEN
THE TWO.
MICE WILL DEFECATE WHEN THEY --
-- AND HUMANS -- THAT IS NOT HOW
WE MEASURE TRANSIT TIME.
IT'S GOING TO BE A VERY
DIFFERENT STUDY IN HUMANS AS
COMPARED TO MICE.
WE DON'T COLLECT HUMAN SAMPLES
AND PUT THEM IN LIQUID NITROGEN
RIGHT AWAY AS WE DO FOR MOUSE
SAMPLES.
THAT IS WHY YOU NEED A LARGER
POPULATION OF HUMANS WHEN YOU'RE
STUDYING THESE DIFFERENT
CHANGES.
THERE IS BOTH HUMAN STUDIES AND
ANIMAL STUDIES WHICH SHOW THAT
THE TRANSIT TIME IMPACTS THE
MICROBIOME COMPOSITION AND
VISA-VERSA.
WE HAD DONE A STUDY -- TRYING TO
SEE IF THIS IS MUTUALLY
REINFORCING FORMULA WHERE IF IT
CHANGES IF YOU TAKE THAT
COMMUNITY AND PUT THEM INTO A
BRAND-NEW HEALTHY MOUSE WILL YOU
PERPETUATE THAT PHENOTYPE AND
YOU DO TO SOME EXTENT.
WHICH MEANS IF THE MICROBES ARE
DRIVING -- IT DOESN'T MATTER HOW
THEY CAME TO BE THERE.
WHETHER THEY WERE INITIALLY
SELECTED BECAUSE THE PATIENT WAS
CONSTIPATED OR BECAUSE THE MOUSE
WAS CONSTIPATED BUT IT'S GOING
TO TRY TO PERPETUATE THAT
PHENOTYPE IN THE HOST.
AND THAT WAS SORT OF ONE STUDY
THAT WE DID TO TRY TO UNDERSTAND
THIS DIFFERENCE BETWEEN CAUSE
AND EFFECT WHICH IS WHAT WE
FOCUS ON.
THE MINE CORRECTS DO THE CAUSE
AND EFFECT.
OR IS IT A MUTUALLY ENFORCING
MECHANISM AND THIS EXISTS IN
MOST PHENOTYPES.
CHRONIC INFLAMMATION, IT DOESN'T
HAVE TO BE THE -- EVENT.
BUT ONCE THE COMMUNITY IS
ESTABLISHED IN AN INFLAMED GUT
IT'S GOING TO TRY TO PERPETUATE
THAT PHENOTYPE.
I THINK YOU CAN ASSESS THE FACT
OF TRANSIT ON THE MICROBIOME.
THE OTHER DIFFERENCE -- IN TERMS
OF WHAT DOES THE STOOL
REPRESENT?
WHEN WE TAKE MOUSE SAMPLES -- IT
GIVES YOU ALL OF THE INFORMATION
FROM THE STOOL.
FROM HUMAN SCHOOLS -- ONE THE
CONSISTENCY VARIES.
-- ---THE FACT THAT IT'S NOT
UNIFORM ACROSS THE ENTIRE
SURFACE OF THE STOOL.
-- THEREOF HAVE BEEN STUDIES
EARLY ON LOOKING AT CORE SAMPLES
FROM A STOOL AS COMPARED -- TO
SEE IF THERE ARE DIFFERENCES.
THERE ARE DIFFERENCES IN THE
METABOLITES AND IN THE MICROBES.
HOW DOES THIS LEAD TO ACTUAL
BIAS IN THE FINDINGS AND IF IT
DOES LEAD TO A BIAS IN THE
FINDINGS.
TRANSIT TIME IS AN IMPORTANT
CONSIDERATION.
BECAUSE HUMANS TRANSIT TIME IS
UP TO 24 HOURS AS COMPARED TO
MICE YOU MIGHT NOT GET
EVERYTHING THAT YOU'RE LOOKING
FOR.
IF YOU LOOK AT A SAMPLE OF STOOL
THAT IS TAKEN AT ANY TIME AND
COMPARE IT TO A 48 HOUR SAMPLE
STOOL -- STORING THE FAT AND
CALCULATING -- IT'S SENSITIVE --
IT'S NOT PERFECT BUT IT'S NOT
TERRIBLE EITHER.
SO THERE IS DEFINITELY
ADVANTAGES AND THAT IS WHY WE
LOOK AT A 48 HOUR COLLECTION
WHEN WE LOOK AT SOME OF THE
MARKERS.
WE'RE NOT THERE IN MATERIALS OF
GETTING THERE FOR THE
MICROBIOME.
IT'S GOING TO TAKE TIME.
>> SURE.
THAT MAKES SENSE.
WE'RE GOING TO GO TO DR. KIM.
>> MY QUESTION IS VERY SPECIFIC
TO -- ---I HAVE A QUESTION
AROUND EXPANDING YOUR RESEARCH
CONCEPT ON THE -- FOR EXAMPLE
MANY OF THE PERSONS WHO --
CONSUME THE PRO-BIOTICS IN THE
HUMAN POPULATION.
THEY OFTEN TIMES HAVE DIFFERENT
MEDICATIONS AND DO WE -- CUFF
COMMENT ON WHETHER THE RESEARCH
HAS BEEN DONE TO UNDERSTAND WHAT
WOULD BE THE AFFECT OF THE
PRO-BIOTICS.
8 OR IS IT THE OTHER WAY AROUND.
HOW THIS DRUG CREATES -- EFFECTS
-- ---OR HOW WE ARE AFFECTED BY
THE PRO-BIOTIC INTAKE DURING THE
DIFFERENT MEDICATION.
DO WE KNOW ABOUT THIS AND WHAT
IS THE BEST WAY TO INTERROGATE
THESE QUESTIONS.
>> THIS IS A WONDERFUL REALLY
GREAT QUESTION.
AND I THINK THAT I'LL GIVE TWO
ANSWERS.
SO IN -- WE SIMPLY DON'T KNOW
ABOUT THE ROLE OF THE MICROBIOME
AND DRUG METABOLISM IN HUMANS.
I REPEAT THE ESTIMATE OF MAYBE
BEING 30-40 YEARS BEHIND OF OUR
UNDERSTANDING OF DRUG
METABOLISM.
WE'RE NOW POISED TO START TO
STUDY THESE QUESTIONS AND I'LL
COME BACK TO THE MODELING.
MATHEMATIC MODELING TO TRY TO
MAKE PREDICTIONS ABOUT THINGS
THAT ARE HARD TO MEASURE
DIRECTLY.
SO FOR EXAMPLE IT MAY BE
DIFFICULT TO SAY WHAT IS THE
IMPACT OF A CERTAIN PRO-BIOTIC
ON MICROBIOME MEDIATED DRUG
METABOLISM BUT WE COULD ASK
SOMETHING LIKE WHAT WOULD HAPPEN
IF THE NET ACTIVITY -- INCREASED
BY 20% OR 80%.
HOW MUCH WOULD THAT AFFECT THE
AMOUNT OF A TOXIC DRUG
METABOLITE EXPOSURE IN
CIRCULATION.
AND IF THE MODEL TELLS US THAT
EVEN A CHANGE OF 80% WOULD NOT
HAVE A VERY BIG EFFECT IN
CIRCULATION THEN WE FOCUS ON A
DIFFERENT TARGET.
SO I THINK IT'S GOING TO BE A
COMBINES OF USING MODELING TO
PREDICT WHAT THE MOST TRACTABLE
DRUGS AND MICROBES WILL BE AS
WELL AS DOING THE STUDIES.
THE REASON WE GOT INTERESTED IN
THE FIRST PLACE IS THIS IS A
PROTOBASE TO THE MICROBIOME THAT
YOU CAN PREDICT.
IT'S DIFFICULT TO PREDICT WHEN
SOMEONE WILL GET CANCER OR IDB.
BUT WE CAN PREDICT WHEN SOMEONE
WILL TAKE A DRUG.
THIS IS AN OPPORTUNITY TO LOOK
AND ASK HOW WELL WE CAN
UNDERSTAND WHAT ARE HAPPENS
AFTER THE DRUG IS CONSUMED.
SO THOSE ARE NOT VERY SATISFYING
ANSWERS BUT YOU RAISED SOME VERY
IMPORTANT QUESTIONS.
>> EXCELLENT.
KATHERINE IF YOU DON'T MIND
PUTTING UP THE SLIDE ON THE OVER
ARCHING QUESTIONS.
WHILE YOU ARE THINKING ABOUT THE
ANSWERS TO THESE LITTLE
QUESTIONS -- WHICH ARE HUGE I
JUST WANT TO REFLECT ON THE FACT
THAT I THINK GOING BACK TO
DR. DONOVAN'S COMMENTS HOW IT
WOULD BE NICE TO HAVE SOME
GUIDELINES FOR RESEARCH.
COMMON DATA ELEMENTS.
WAYS TO COLLECT SAMPLES.
ETC.
IT SOUNDS LIKE THIS GROUP AND
THE REST OF THE SPEAKERS IN THE
WORKSHOP MIGHT BE THE GROUP TO
HELP SET THAT.
I WANT TO PLANT THAT AS A SEED
THAT YOU GUYS ARE THE PEOPLE AND
THAT I'VE BEEN SO IMPRESSED WITH
EVERYTHING THAT YOU'VE TALKED
ABOUT.
THIS COULD BE A POTENTIAL
PRODUCT OF THE WORKSHOP.
I WILL BE QUIET AND LET YOU SEE
IF THERE IS ANYTHING YOU WANT TO
TALK ABOUT.
>> I THINK STANDARDIZATION IS
KEY FOR SUCCESS AND FOR US TO
COMPARE OUR NOTES AND INTEGRATE
OUR DATA AND CONFIRM THE
FINDINGS.
I HAVE BEEN WORKING WITH
INTERNATIONAL HUMAN MICROBIOME
CONSORTIUM.
AND ONE CONTINUOUS EFFORT TO IS
TO DEVELOP QUALITY CONTROL
STANDARDS
EVERYBODY MUST USE THE SAME --
-- THAT IS NOT THE RIGHT WAY TO
GO.
BUT HOWEVER WE NEED TO SET A
STANDARD.
WHAT KIND OF RECOVERY RATE AND
HOW TO ENSURE ALL OF THE CELLS
-- -- -- AND THAT KIND OF
STANDARD NEEDS TO BE DISCUSSED
AND ESTABLISHED AND AGREED BY
EVERYBODY IN THE FIELD SO THAT
WE CAN COMPARE OUR NOTES.
>> EXCELLENT POINT.
>> ONE -- WHICH HAS BEEN HELPFUL
IS THE IMMENSE EFFORT THAT WENT
INTO ALL OF US WHICH IS
COLLECTING EVERY SINGLE SAMPLE
-- AND THERE WAS A HUGE MISSED
OPPORTUNITY WHERE THAT IS THE
KIND OF STUDIES THAT COULD HAVE
HELPED.
STANDARDIZED AND IMPLEMENTED AND
-- AND I THINK -- TO SET UP
SOMETHING LIKE THAT AGAIN IS NOT
GOING TO BE FEASIBLE.
BUT -- WOULD COLLECT STOOL
SAMPLES -- FROM A LARGE PORTION.
AND IT WOULD BE HELPFUL AND
ESTABLISHING BASELINE
VARIABILITY IN A LOT OF THESE
FACTORS WHICH I THINK IS NEEDED.
THE QUESTION IS HOW IS THE DATA
GOING TO BE USED BEYOND AS
OPPOSED TO -- SEEDING ADDITIONAL
STUDIES.
EVERYBODY IS DOING CLINICAL
STUDIES AND DOING ANIMAL
STUDIES.
THERE IS VERY LITTLE CARRASCO
MOON INDICATION BETWEEN THE TWO
REGIONS AND SO EVERYBODY COMES
UP WITH DIFFERENT HYPOTHESIS BUT
THEY ARE NOT CROSS FEEDING AS
MUCH AS WOULD HELP ADVANCE THE
FIELD.
I PUT UP THE LAST SLIDE.
IF YOU WORK CONCURRENTLY IN
DIFFERENT AREAS.
8 THAT WOULD REALLY HELP.
>> EXCELLENT.
THANK YOU.
7 I'LL OFFER THE OPPORTUNITY FOR
ONE LAST COMMENT AND THEN TURN
IT OVER TO THE ORGANIZERS
>> I THINK I THROUGHOUT THE
TALKS I HEARD ABOUT HOW
IMPORTANT NUTRITION IS AND HOW
DIFFICULT IT IS TO MEASURE.
THE WEAKEST LINK BUT BUILDING ON
THE COMMENT I THINK WE'RE AT A
KEY TIME WITH NUTRITION FOR
PRECISION WHERE THERE IS SO MUCH
POTENTIAL OVERLAP.
A WHOLE CLINICAL CENTER THAT IS
GOING TO BE LOOKING AT COMPARING
THE ASA24 AND DEVELOPING NOVEL
METHODS.
GETTING THAT CROSS TALK BETWEEN
-- WITH THE NUTRITION FOR
PRECISION HEALTH.
ROB NIGHTS LAB -- GOT THE
SEQUENCING THE MICROBIOME CENTER
AND SO THEY CAN CERTAINLY BE IN
THOSE CONVERSATIONS OF HOW DO WE
STANDARDIZE AND COLLECT THE
SAMPLES AND GETTING INTO THE
OTHER SAMPLES WHICH ARE GOING TO
BE CRITICALLY IMPORTANT FOR
UNDERSTANDING THE METABOLISM.
WE REALLY NEED TO BRING THESE
TOGETHER.
>> SLEPT.
THANK YOU.
-- EXCELLENT.
THE MORE CONVERSATIONS WE CAN
HAVE THE CLOSER WE'LL GET TO
STANDARDIZATION.
>> IF PEOPLE KEEP THROWING UP
THEIR HANDS SAYING IT'S TOO
HARD.
WE DON'T KNOW HOW TO MEASURE:
WE'RE GOING TO FUND YOU GUYS TO
FIGURE OUT HOW TO DO THIS.
THAT IS TWO COMPLETELY DIFFERENT
APPROACHES AND WE NEED SERIOUS
FUNDING IF NUTRITION IS
IMPORTANT FOR THESE DISEASES AND
THE MICROBIOME.
WE NEED TO FIGURE THIS OUT.
IT SHOULD NOT BE ROCKET SCIENCE
>> GREAT POINT.
THANK YOU.
7 THANK YOU ALL FOR THE
WONDERFUL CONVERSATION.
THANK YOU ALL FOR YOUR WONDERFUL
TALKS.
YOU HAVE HIT ALL OF THE HIGH
POINTS.
ALL OF THE DIFFICULT TOPIC --S.
>> THANK YOU SO MUCH DR. VARGAS
AND HAMILTON AND ALL OF OUR
MODERATORS AND PRESENTERS TODAY.
THIS WAS A WONDERFUL DAY ONE.
I HAVE TH TASK OF DRAWING DAY ONE
TO A CONCLUSION.
I WANT TO REMIND OUR VIEWERS
THAT WE'RE HERE TOMORROW FOR DAY
TWO.
APRIL 27th AT 10:00 A.M.
EASTERN AND AGAIN WE'RE ON NIH
VIDEO CAST.
COME BACK AND JOIN US.
WE'RE SURE TO HAVE SOME
WONDERFUL TALKS AND SESSIONS
TOMORROW AND THEN DR. KIM AND
DR. -- WILL HAVE A FEW CLOSING
THOUGHTS AND WE LOOK FORWARD TO
HEARING FROM DR. GARY WOO AS OUR
KEYNOTE.
WITH THAT I'M GOING TO DRAW THIS
TO A CLOSE.
THANK YOU ALL.
I WISH EVERYBODY A LOVELY
EVENING AND WE'LL SEE YOU ALL
TOMORROW.
THANK YOU EVERYONE AND HAVE A
GREAT EVENING.