WELCOME BACK TO DAY TWO OF THE
PRECISION PROBIOTICS THERAPIES
AND CHALLENGES AND WORK SHOPS.
AND ON BEHALF OF THE NIH
PLANNING COMMITTEE FOR THE
WORKSHOP WE WANT TO WELCOME
EVERYONE BACK FOR DAY TWO.
BEFORE WE BEGIN I WOULD LIKE TO
REVIEW A FEW LOGISTICS.
A REMINDER TO MUTE YOURSELVES
WHEN NOT SPEAKING AND DO MAKE
SURE YOUR VIDEO IS ON DURING
YOUR SESSION OR PARTICULARLY
WHEN SPEAKING OR IF YOU HAVE
COMMENTS DURING THE PANEL
DISCUSSION.
FOR OUR NIH VIDEO CAST VIEWERS
YOU ARE WELCOME TO SUBMIT A
QUESTION AT ANY TIME USING THE
FORM.
THE LINK IS GOING TO BE RIGHT
BELOW THE SCREEN WHERE YOU'RE
VIEWING THE LIVE STREAM.
WE WILL TRY TO GET TO AT LEAST A
FEW OF THE QUESTIONS FROM THE
AUDIENCE DURING OUR PANEL
DISCUSSION TIMES BUT WE'RE
UNLIKELY TO GET TO ALL OF YOUR
QUESTIONS.
HOWEVER ALL QUESTIONS SUBMITTED
WILL BE COLLECTED AND SHARED
WITH THE PLANNING TEAM.
FINALLY THE BULK OF THE MEETING
IS BEING RECORDED AND WILL BE
ARE SO, I HAVE HAD FOR FUTURE
VIEWING.
WE ASK THAT YOU BE RESPECTFUL BY
THE FACT THAT SOME OF OUR FOLKS
MIGHT BE SHARING EARLY DATA
REFRAIN FROM TAKING SCREEN
SHOTS.
I'M NOW PLEASED TO TURN IT OVER
TO OUR COCHAIRS DR. HYE-SOOK KIM
AND DR. BARBARA SORKIN.
WELCOME YOU TODAY AND WILL TURN
IT OVER TO OUR SPEAKERS.
TAKE IT AWAY
>> THANK YOU, KATHERINE AND
THANK YOU EVERYONE AND WELCOME
TO EVERYONE.
I WOULD LIKE TO START WITH THANK
YOU TO ALL OF THE SPEAKERS
YESTERDAY AND THE MODERATORS OF
THE BOTH SESSIONS ONE AND TWO
FOR THE FABULOUS TALK AND VERY
EXCITING DISCUSSIONS.
DURING THE SESSIONS WE ACTUALLY
HAD IDENTIFIED CHALLENGES AND
GAPS IN OUR CURRENT TECHNOLOGY
IN PRECISION PROBIOTICS.
FOR INSTANCE DEFINING
CLARIFICATIONS OF MECHANISMS
ACTIONS.
AND WE ALSO FOUND A NONINVASIVE
METHOD IS VERY CHALLENGING AND
VERY IMPORTANT.
SO FOR CONTINUE OUR JOURNEY
TODAY WE'LL HEAR MORE ABOUT THE
TECHNOLOGY.
AND WE'LL HAVE THE DISCUSSION
AROUND WHERE THIS TECHNOLOGIES
SHOULD BE ADVANCED AND WHAT
HURDLES ARE THERE.
BARBARA.
7
>> THANK YOU SO MUCH HYE-SOOK
FOR THAT QUICK SUMMARY OF
YESTERDAY.
MY THANKS AS WELL TO THE
SPEAKERS AND ORGANIZERS AND ALL
OF THE PEOPLE WHO SUBMITTED
GREAT QUESTIONS.
IT WAS VIGOROUS AND INFORMATIVE
AND THOUGHT PROVOKING DISCUSSION
AND LET'S KEEP UP THE MOMENTUM
TODAY.
BUT BEFORE WE MOVE TO THE
SCIENCE TALKS PER SAY IT IS MY
GREAT PLEASURE TO INTRODUCE THE
ACTING DIRECTOR DR. JOSEPH
BETTS.
JOE BRINGS TO THE DIRECTOR SHIP
OF ODS IN ADDITION TO HIS GREAT
INTERPERSONAL SKILLS A WEALTH OF
EXPERIENCE.
HE WAS THE VICE PRESIDENT FOR
SCIENTIFIC AND TECHNICAL AFFAIRS
-- AND WORKED AFTER THAT FOR
MANY YEARS AS THE FOOD AND DRUG
ADMINISTRATION AND THEN AS A
RESEARCH COUNCIL.
HE BRINGS A WEALTH OF
INFORMATION AND IT IS -- I'M
VERY, VERY GLAD TO INTRODUCE
HIM.
JOE, TAKE IT AWAY.
THANKS FOR THE GREAT SESSION
YESTERDAY.
IT WAS WONDER SON.
AND I LOOK FORWARD TO MORE
SAME.
WHAT I BRING TO THIS VERY QUICK
HOPEFULLY TALK IS KIND OF MY
PERSONAL PERSPECTIVE FROM HAVING
BEEN A REGULATOR IN INDUSTRY AND
ALSO DIRECTOR OF ODS AND WHY
THIS WORK IS SO IMPORTANT.
SO I JUST START OFF QUICKLY --
WITH A LITTLE BIT BOILERPLATE
ABOUT THE DIETARY SUPPLEMENT
ACT.
A COUPLE OF THINGS.
DEFINE DIETARY SUPPLEMENTS AS A
CATEGORY OF GOODS AS HAS NOT
BEEN THE CASE IN THE PAST.
IT CREATED THE DIETARY SUB
ELEMENTS BY AMENDIN AMEND AMENDING.
WHY IS THIS IMPORTANT?
* I'M GOING TO READ THIS WHOLE
SLIDE BUT I WILL SAY THAT THE
REGULATORY PROVISIONS OF FOOD
AND DRUG -- ACT DEFINE THE
PRODUCTS PLACED IN THE
MARKETPLACE BY THE INTENDED USE.
DRUGS ARE INTENDED TO CURE,
TREAT, MITIGATE DISEASE IN MAN
OR ANIMALS.
SUPPLEMENTS ARE INTENDED TO
SUPPLEMENT THE DIET.
THAT IS THE WHOLE DEFINITION.
THERE IS SOME OTHER STUFF AROUND
IT ABOUT WHAT CAN GO INTO THE
MANUFACTURING OF A DIETARY
SUPPLEMENT BUT THAT IS THE GIST
OF IT.
ANYTHING THAT WE CAN INGEST TO
SUPPLEMENT THE DIET IS A DIETARY
SUPPLEMENT.
SUPPLEMENTS ARE CONSIDERED FOODS
AND FOODS ARE SAFE BY DEFINITION
UNLESS THEY ARE DIETARY
INGREDIENTS.
SO, THAT IS ALSO AN IMPORTANT
INGREDIENT.
SOME OTHER STUFF INTENDED TO BE
TAKEN BY MOUTH.
IT CONTAINS ONE OF SEVERAL
INGREDIENTS WHICH IF YOU HAVE
GONE INTO A WHOLE FOODS OR CBS
YOU'LL RECOGNIZE VITAMINS AND
MINERALS AND AMINO ACIDS BUT
ALSO PRO-BIOTICS.
ALSO DIETARY SUPPLEMENTS HAS A
DATABASE -- LABELED DATABASE.
THERE IS OVER 136,000 INDIVIDUAL
LABELS OR PRODUCTS FOR DIETARY
SUPPLEMENTS.
THAT IS A LOT OF PRODUCTS.
IT'S SEARCH ARTICLE.
-- SEARCHABLE.
AND THERE IS NOT QUITE 6,000
LABELS USING THE BROAD TERM
PRO-BIOTIC.
THAT IS 4.5% OF THE DATABASE AND
JUST BY WAY OF COMPARISON THE
NUMBER OF FDA APPROVED
PRO-BIOTIC DRUGS WHICH ARE
REGULATED BY THE CENTER OF
BIOLOGICALS IS ZERO.
SO, THAT IS WHY ALL OF THIS
WONDERFUL SCIENTIFIC EXPLORATION
IS NECESSARY.
WHY IS THAT THE CASE?
ONE CAN MAKE THE ARGUMENT
ECONOMICALLY THAT IT'S CHEAP TO
BRING A DIETARY SUPPLEMENT TO
THE MARKET OR SOMETHING LIKE
THAT.
REALLY ASIDE FROM MAINTAINING
GUT HEALTH WHY ARE WE LOOKING AT
PRO-BIOTICS IN THE FIRST PLACE?
IT'S -- SOME OF THE TALKS WE
HEARD YESTERDAY WERE TALKING
ABOUT ULCER -- COLITIS.
IT'S NOT A DRUG CLAIM.
SO ODS PROVIDES A FACT SHEET
AMONG OUR MANY FACT SHEETS
DEALING WITH THE SUBJECT OF
PRO-BIOTICS.
WE HAVE FACT SHEETS FOR
CONSUMERS FOR PROFESSIONAL
PRACTITIONERS AND ALSO A SPANISH
LANGUAGE FACT SHEET.
AND IT'S ABOUT PRO-BIOTICS IS
DIETARY SUPPLEMENTS.
AN ATTEMPT TO SUMMARIZE THE
USES.
ODS DOES HAVE IT'S NOT AN
ENORMOUS A AMOUNT OF MONEY IN
OUR PORTFOLIO BUT WE DO HAVE
SOME INVESTMENT IN PREBIOTICS
AND PRO-BIOTICS RESEARCH.
IN 2020 THAT WAS NORTH OF HALF A
MILLION DOLLARS.
WE CO-FOUND DRAFT APPLICATIONS.
I DO WANT TO GIVE AN
INTRODUCTION BY WAY OF PROVIDING
MY OWN REASON THAT WE NEED TO DO
THIS RESEARCH AND ALSO TO
PROVIDE A A LITTLE BIT OF
BACKGROUND IN ADS's STAKE IN
THIS AREA.
SO I WILL END THAT THERE.
* SO THAT WE CAN MOVE ON TO OUR
NEXT SPEAKER.
WE HAVE WONDERFUL SPEAKERS WHO
ARE WAY MORE EXPERT IN THIS AREA
THAN I AM AND I WOULD RATHER
DEVOTE OUR TIME TO THEM RATHER
THAN TO ME.
SO THANK YOU.
AND WE'LL MOVE ON TO OUR KEYNOTE
FOR THE DAY.
SO WE'LL MOVE ON TO OUR KEYNOTE.
AND THAT IS DR. GARY WU.
HE IS FROM THE UNIVERSITY OF
PENNSYLVANIA.
HE IS THE FORWARD INNOCENT --
PROFESSOR GASTROINTESTINAL.
DIRECTOR OF THE PAN CENTER FOR
NUTRITIONAL SCIENTISTS AND
MEDICINE AND CO-DIRECTOR -- GO
MOLECULAR STUDIES AND CHILDREN'S
HOSPITAL IN PENNSYLVANIA
MICROBIOME PROGRAM.
HE WAS THE INAUGURAL DIRECTOR
AND CHAIR OF THE BOARD FOR THE
AMERICAN GASTRO INTEREST LOGICAL
ASSOCIATION * AND EDUCATION.
AND IS AN ELECTED MEMBER OF BOTH
THE AMERICAN SOCIETY FOR
CLINICAL INVESTIGATION AND THE
ASSOCIATION OF AMERICAN
PHYSICIANS.
RESEARCH IN THE WU LAB -- AND
THE RELATIONSHIP OF SEVERAL
ASPECTS OF METABOLISM -- -- --
HIS TALK TODAY IS THE GUT
MICROBIOME AS A PROTOTYPE FOR
THE OPPORTUNITIES THAT
CHALLENGES IN THE DEVELOPMENT OF
PRO-BIOTICS.
THE NEXT STEP.
DR. WU.
TAKE IT AWAY
>> GREAT.
THANK YOU SO MUCH FOR THAT
INTRODUCTION.
LET ME SHARE MY SCREEN HERE.
AM I ALL GOOD HERE?
>> YOU ARE INDEED.
>> ALL RIGHT.
AWESOME.
THANK YOU VERY MUCH FOR INVITING
ME TO PARTICIPATE IN THIS
SYMPOSIUM.
WHEN I SORT OF REFLECTED ABOUT
WHAT I WOULD SPEAK ABOUT OVER
THE NEXT 35 MINUTES OR SO I
THOUGHT INSTEAD OF SPEAKING WITH
GRANULARITY ABOUT ONE OR TWO
PROJECTS THAT I WOULD GIVE YOU
AN OVER-ALL PERSPECTIVE
CONCEPTUAL FRAMEWORK FROM THE
VIEWPOINT OF A PHYSICIAN
SCIENTISTS AND WHAT IT MEANS TO
HAVE A PHYSICIAN PRO-BIOTIC FOR
THE TREATMENT OF DISEASE.
AND I WILL USE INFLAMMATORY
BOWEL DISEASE AS THAT CONCEPTUAL
FRAMEWORK.
AND WITHIN THAT NOTION I WANTED
TO HIGHLIGHT BOTH THE
OPPORTUNITIES AND CHALLENGES IN
THE FIELD BUT JUST AS
IMPORTANTLY HIGHLIGHT THE
SPEAKERS AND SESSIONS 3 AND 4.
THE TOPICS AND THEIR EXPERTISE
TO GIVE YOU A FLAVOR OF HOW THIS
IS INTEGRATED TOGETHER WHEN
THINKING ABOUT THE DEVELOPMENT
OF NEW TYPES OF THERAPEUTIC
MODALITIES.
SO THESE ARE MY DISCLOSURES NONE
OF WHICH ARE RELEVANT TO MY TALK
TODAY.
WHEN THINKING ABOUT PRECISION
PROBIOTICS THERAPY I WANT TO
HIGHLIGHT THE PRECISION MEDICINE
INITIATIVE THAT WAS STARTED BY
BARACK OBAMA.
IT WAS FUNDAMENTAL IN LAUNCHING
THE PROGRAM HERE AND THE
STATEMENT -- BELOW IS ACTUALLY
GERMAIN TO THE NOTION OF
PRECIPITATION THERAPIES.
UNTIL NOW MOST MEDICAL THERAPIES
HAVE BEEN DESIGNED FOR THE
AVERAGE PATIENT.
AS A RESULT OF THIS ONE SIZE
FITS ALL APPROACH TREATMENTS CAN
BE SUCCESSFUL FOR SOME PATIENTS
BUT NOT FOR OTHERS.
PRECISION MEDICINE IS AN IN
VACATE I'VE APPROACH THAT TAKES
INTO ACCOUNT INDIVIDUAL
DIFFERENCES IN PEOPLE'S GENES,
ENVIRONMENTS AND LIFESTYLES.
SO THIS IS THE PROGRESSION OF
SCIENCE AND REDUCTION OF
PRACTICE THINKING ABOUT NEW
TYPES OF PRODUCTS THAT WOULD
TREAT PATIENTS WITH DISEASE.
THERE ARE PROCESS -- FECAL
PRODUCTS AND DEFINED MICROBIAL
CONSORTIA.
WE KNOW THAT RECURRENT CDI IS
EFFECTIVELY TREATED BY FMT AND
WE'RE HOPEFUL THAT THESE OTHER
MODALITIES CAN BE SUCCESSFUL.
FOR OTHER DISEASES IT'S POSSIBLE
THAT FMT MIGHT HAVE A ROLE.
BUT CERTAINLY IS THE FOCUS OF
TECHNOLOGY DEVELOPMENT
ESPECIALLY WHEN THINKING ABOUT
MICROBIAL CONSORTIA DEVELOPMENT.
WE BETTER DEFINE WHAT WE'RE IN
ACCUMULATING PATIENTS WITH THE
SAFER IT'S GOING TO BE.
WE BEGIN WITH FMT.
THAT IS WHERE WE ARE NOW BUT
WE'RE HOPEFUL THAT FOR
SUSTAINABILITY WE'LL BE MOVING
ON TO BETTER TYPES OF
TECHNOLOGIES BASED ON WONDERFUL
SCIENCE IN THE FIELD.
SO THESE ARE THE VARIOUS
SESSIONS OBVIOUSLY IN THE
SYMPOSIUM.
I'M GOING TO HIGHLIGHT SECTION
THREE AND SECTION FOUR.
SO WHERE VERY BE BEEN AND WHERE
ARE WE CURRENTLY?
THE MOTION OF PRO-BIOTICS WHICH
ARE DEFINED AS LIVE MICRO
ORGANISMS -- CONFER A HEALTH
BENEFIT TO THE HOST.
AND JUST PULL OUT ONE PARTICULAR
QUOTE FROM THIS.
WHERE THE AUTHOR STATES ALL-PRO ALL-PRO
BIOTICS HAVE BECOME AN INTEGRAL
PART.
SO I THINK WE'VE LEARNED A LOT
ABOUT THE PROCESSING AND
DEVELOPMENT OF PRO-BIOTICS
KEEPING ORGANIZ -- ORGANISMS LIVE AT
SCALE.
FROM THE FDA STANDPOINT LIVE
PRODUCTS WHICH ARE DEFINED AS
LIVE ORGANISMS THAT FOR EXAMPLE
BACTERIA THAT TREAT, PREVENT OR
CARRY DISEASE CONDITION IN
HUMANS AND IS NOT A VACCINE.
THESE ARE THE FOUR LARGE AREAS
THAT I WANT TO COVER.
IN MY TALK.
WHAT IS THE ACTIVE COMPONENT?
DOES IT NEED TO BE ALIVE.
CAN IT BE DEAD?
DOES IT INVOLVE DRUG METABOLISM.
DOES IT INVOLVE METABOLITE
PRODUCTION AND MAYBE FUNGI AND
VIRUSES ARE ACTUALLY IMPORTANT.
IN A LIVE ORGANISM IS NECESSARY
-- WE HEARD A LOT ABOUT THAT.
YESTERDAY.
I WILL REPEAT SOME OF THIS MAYBE
FROM A SLIGHTLY DIFFERENT
PERSPECTIVE TODAY.
THE IMPORTANCE OF THE
ENVIRONMENT OF THE CONTEXT OF
THE MICRO BIOTA.
AND THEN IS THERE A NEED FOR
COMPANION DIAGNOSTIC RESEARCH.
WHAT IS THE ACTIVE COMPONENT?
OBVIOUSLY NOVEMBER ALE BACTERIAL
STRAINS ARE IMPORTANT AND ERWIN
IS GOING TO BE SPEAKING ABOUT
NOVEL PRO-BIOTICS.
DRUG METABOLISM.
ANDY GOOD MAN GAVE A GREAT TALK.
EMILY WILL BE TALKING ABOUT
DECIPHERING THE HUMAN MICROBIOME
WITH CHEMISTRY.
WE HEARD A BIT ABOUT THIS
YESTERDAY.
A NICE ARTICLE IN CELL.
TO IDENTIFY SMALL MOLECULES THAT
HAVE AN IMPACT.
I'M GOING TO COME BACK TO THE
TOPIC THAT WHICH IS GOING TO BE
DIFFERENT BUT THIS IS A
MARVELOUS ARTICLE.
ENGINEERED FUNCTION.
TO DELIVER THERAPEUTICS.
MAYBE IT'S NOT JUST BACTERIA.
MIC ROW -- AND FUNGI AND YEAST
ARE IMPORTANT.
AND JUNE HAS DONE SOME REALLY
IMPORTANT WORK IN THIS AREA AND
SHE IS GOING TO BE TALKING ABOUT
THE IMMUNE SYSTEM TO IDENTIFY
RELEVANT MICROBES AND I SUSPECT
THAT SHE WILL BE TOUCHING UPON
FUNGI.
BUT NOBODY IS TALKING ABOUT
VIRUSES THAT I KNOW OF FOR
EXAMPLE BACTERIA AGE BUT I WANT
TO HIGHLIGHT THIS WORK ABOUT
TARGETING BACTERIA TO ATTENUATE
ALCOHOLIC LIVER DISEASE AND THEN
THE NOTION OF WHETHER OR NOT IT
COULD BE A POST BIOTIC.
THE ORGANISM DOESN'T NECESSARILY
NEED TO BE VIABLE AND THIS IS
INTERESTING.
SHOWING PAST OUR RISED --
READING * TO A BIGGER EFFECT
THAN THE LIVE ORGANISMS ITSELF.
SO IT'S A WIDE RANGE OF TOPICS
THAT WE CAN TALK ABOUT IN
TERMING WHAT IS THE ACTIVE
COMPONENT THAT CAN BE UTILIZED
OR TREAT DISEASE.
THIS BI-DIRECTION ALL THE OF
MICROBIOME INVESTIGATION.
BASIBASIC RESEARCHERS DEFINE -- AND
FOR THAT REASON THERE IS A HIGH
SIGNAL TO NOISE RATIO.
FOR THOSE PURPOSES WE CAN DEFINE
PROOF OF CONCEPT CAUSE AND
EFFECT RELATIONSHIPS IN A MODEST
SIDE COHORT.
ON THE OTHER HAND ULTIMATELY WE
WANT TO BE DOING THINGS THAT ARE
RELEVANT TO HUMANS BUT THE
CHALLENGE IS THAT HUMANS LIVE IN
A FREE LIVING AND I HIGHLY
VARIABLE ENVIRONMENT.
HIGH LEVEL GENETIC DIVERSITY AND
VARIABLE DIET.
AND FOR THAT REASON THERE IS A
LOWER SIGNAL TO NOISE RATIO.
BUT WE DO HAVE TO KEEP IN MIND
THAT SMALL EFFECT SIZE OVER
LARGE POPULATIONS CAN BE
IMPACTFUL.
ALSO IT EMPHASIZES THE NEED FOR
THE APPROACH TO THERAPEUTICS.
SO AS AN EXAMPLE OF THIS THIS IS
JUST WORK WE PUBLISHED A NUMBER
OF YEARS AGO LOOKING AT THE
IMPACT OF DIET.
THIS WAS A CONTROLLED FEEDING
EXPERIMENT.
10 HEALTHY VOLUNTEERS.
RANDOMIZED TO HIGH FIBER VERSUS
LOW FIBER DIET.
WE COLLECTED FECAL SAMPLES.
EACH BALL IS A DIFFERENT
COMPOSITION OF A MICR MICRO BOTA.
EACH INDIVIDUAL OR EACH COLOR IS
VERY DIFFERENT FROM THE OTHER
COLORS.
SO, THAT IS HOW DIFFERENT WE ARE
FROM EACH OTHER.
THE ARROWS POINT TO DAY ONE OF
THE STUDY.
FOR EACH ONE OF THE -- FOR A
NUMBER OF DIFFERENT COLORS AND
YOU CAN SEE THAT DAY ONE OF THE
STUDY IS DIFFERENT FROM ALL THE
OTHER DAYS OF THAT PARTICULAR
COLOR MEANING THAT YES DIET DOES
HAVE AN IMPACT ON THE -- ON THE
-- COMPOSITION.
THE OTHER POINT IS THAT THE
VECTOR FROM DAY ONE TO ALL OF
THE OTHER DAYS SEEMS TO BE --
STOCASTIC.
NOT CONSISTENT.
EVEN THOUGH PEOPLE WERE EATING
SIMILAR THINGS.
PEOPLE DIDN'T CONVERGE IN TERMS
OF THEIR COMPOSITION OF MICRO
GOT A WITHIN 10 DAYS.
* SO ONE COULD SAYS THERE IS A
LOT OF NOISE.
BUT IT'S INFORMATION THAT CAN BE
MINED AND HAS UTILITY FOR THE
PURPOSES OF PERSONALIZATION.
SO THIS IS SOME OF THE WORK THAT
YOU ALL KNOW OF BY AARON AND
OTHERS AT THE WEISMAN INSTITUTE
WHO TOOK ADVANTAGE OF THAT
INTEREST SUBJECT VARIABILITY IN
THE MICROBIOME TO COME UP WITH A
PERSONALIZED NUTRITION PREDICTOR
THAT WOULD IMPROVE GLYCEMIC
RESPONSES.
THIS IS EARLY DAYS BUT IT'S AN
INTERESTING CONCEPT AND IN TOTAL
THAT WHOLE NOTION OF
PERSONALIZATION AND PRECISION IS
REALLY THE CORNERSTONE FOR THE
PRECISION FOR NUTRITION HEALTH
INITIATIVE THAT WAS JUST
LAUNCHED BY THE ALL OF US
PROGRAM AT NIH WHERE THE GUT
MICROBIOME IS A VERY IMPORTANT
COMPONENT OF THAT.
SO WHAT ACTUALLY IS RESPONSIBLE
FOR THAT INTER-SUBJECT
VARIABILITY?
THERE IS EVIDENCE THAT THIS IS
AT THE STRAIN LEVEL OF MICROBES.
SO I'M SHOWING YOU SOME WORK
FROM NICOLE AND CURTIS --
SHOWING YOU DOMINANT FREQUENCY A
CONGRESS ALL SITES -- AND
MICROBIAL SPECIES AND BIOMARKERS
AND THE POINT IS THAT SINGLE
STRAINS FROM A SEQUENCING
STANDPOINT TEND TO DOMINATE MOST
SPECIES.
BUT THAT GENETIC DIVERSITY IS
SOMEWHAT DIFFERENT BETWEEN
DIFFERENT TYPES OF SPECIES WHERE
STRAIN DOMINANCE IS SOMEWHAT
DIFFERENT.
NEVERTHELESS THE MICROBIAL
STABILITY AND UNIQUENESS THAT WE
SEE EXTEND DOWN TO THE STRAIN
LEVEL.
SO WE HEARD A LOT ABOUT
DIFFERENT STRAINS YESTERDAY.
WE'LL BE HEARING MORE ABOUT THAT
TODAY.
THIS IS JUST A REVIEW BY CURTIS
EXAMINING DIFFERENT MODALITIES
BY WHICH YOU CAN LOOK AT STRAIN
LEVEL EPIDEMIOLOGY.
I WANT TO HIGHLIGHT THIS CORNER
HERE.
ALTHOUGH THERE IS A DOMINANT
STRAIN AND SOMETIMES VERY
DOMINANT IN A PARTICULAR SPECIES
WHEN YOU ACTUALLY ISOLATE
ORGANISMS AND CULTURE THEM YOU
CAN PICK OUT MANY DIFFERENT
TYPES OF STRAINS FOR PARTICULAR
SPECIES IN MOST CASES.
SO WHAT THAT MEANS IS THAT
SEQUENCING TELLS US PART OF THE
PICTURE.
YOU CAN PICK UP THE DOMINANCE OF
ONE PARTICULAR ORGANISM BUT
THERE MAY BE LESS DOMINANT
STRAINS THAT CAN BE EQUALLY
IMPORTANT IF NOT MORE IMPORTANT
THAN PHYSIOLOGY.
WE DO NEED TO BE DOING BASIC
MICROBIOLOGY AND CULTIVATION
GROWING ORGANISMS TO LOOK AT
PHYSIOLOGY.
ANOTHER THING THAT WE HAVE TO BE
COGNIZANT OF IS LATERAL GENE
TRANSFER.
MAKING THE POINT THAT ON HUMAN
BODY SURFACE THAT'S THERE COULD
BE SUBSTANTIAL -- IN TRANSFER.
THEY ARE NOT ENTIRELY STABLE
OVER TIME.
THIS IS WORK THAT WAS
HIGHLIGHTED BY JUSTIN --
YESTERDAY.
JUST BEARS REPEATING.
LOOKING AT A PRO-BIOTIC DELIVERY
TO INDIVIDUALS WHERE SOME
INDIVIDUALS ACTUALLY SHOWED
ENGRAPHMENT VERSUS INDIVIDUALS
THAT DID NOT SHOW ENGRAPHMENT
AND THIS WAS OR LATE WITH UNDER
REPRESENTATION OF CARBO HIGH
RATE UTILIZATION.
THE NICHE IS OPEN FOR THE
ENGRAPHMENT OF A PRO-BIOTIC
BACTERIA BECAUSE OF HIGHER
RESOURCE AVAILABILITY.
THE BIOLOGICAL BASES FOR THIS
HAS BEEN SHOWN BY A NUMBER OF
INVESTIGATORS FIRST OF ALL BY --
-- JUSTIN SHOWED THIS YESTERDAY
AND ENGRAPHMENT AND PERSISTENCE
OF -- IS SOMEWHAT DEPENDENT UPON
THE -- WHICH IS INVOLVED IN --
METABOLISM.
SO WHEN MUTATED IT CAN NO LONGER
OUTCOMPETE THE WILD TYPE.
THIS IS A LOSS OF FUNCTION --
BUT -- THIS IS A GAIN OF
FUNCTION -- WHERE THE STRAIN CAN
ACTUALLY PERSIST IN THE NEW
NICHE DEVELOPED.
SO WORK BY ALLEN AND OTHERS AT
THE WEISMAN INSTITUTE UTILIZED A
PRO-BIOTIC CONSORTIUM TO REALLY
LOOK AT THIS IN BOTH ANIMAL
MODELS AND HUMANS.
AND IT'S A VERY IMPORTANT
OBSERVATION FOR THE FIELD HERE.
THE FIRST POINT IS THAT STOOL
DOESN'T NECESSARILY REPRESENT
THE MUCOSAL SURFACE.
WE KNOW THAT.
KNOWING THAT -- AND CERTAIN
CIRCUMSTANCES OCCURS AT THE
MUCOSAL SURFACE.
WHEN THINKING ABOUT TRANSLATION
OF MICE TO HUMANS IS MICE HAVE
RESISTANCE TO PRO-BIOTICS.
SO HIGHLIGHTING THE ADVANTAGES
AND SOME OF THE OPPORTUNITIES
YET CHALLENGES IN THE FIELD.
SO THERE ARE A NUMBER OF
INVESTIGATORS THAT ARE GOING TO
BE TALKING ABOUT I THINK TOPIC
THAT'S ARE RELEVANT TO
INTER-SUBJECT VARIABILITY.
I'VE LISTED THEM HERE.
I WANT TO MENTION THAT --
TALKING ABOUT SMALL INTESTINAL
MICROBIOTA WHICH IS NOT SO MUCH
IN THE LITERATURE BECAUSE OF
TECHNOLOGIC ISSUES.
I DO WANT TO MENTION JULIA OH.
FACTORS THAT ARE RELEVANT TO THE
GUT SO WE'VE GOT TO BE COGNIZANT
THAT THE SKIN IS ALSO VERY
IMPORTANT AND WE CAN LEARN A LOT
FROM LESSONS THAT JULIA IS GOING
TO BE TALKING ABOUT ALSO.
SO THAT COLONIZATION RESISTANCE
COULD BE A RELATIVELY SMALL
NICHE BUT THERE ARE OBVIOUSLY
OPPORTUNITIES TO OPEN UP THE
NICHE TO ALLOW ENGRAPHMENT OF
PRECISION PRO-BIOTICS AT A
LARGER SCALE AND WE HEARD ABOUT
THIS YESTERDAY.
ESSENTIALLY HIGHLIGHTING THE
FACT THAT PRETREATMENT WITH MICE
AND ALLOWS ENGRAPHMENT OF
ORGANISMS AND THERE IS A DOSE
DEPENDENT RESPONSE MULTI-DAY
DOSING WOULD LEAD TO MORE
PERSISTENT ENGRAVE WANT OVER
TIME * IF TREATED WITH AN
ANTIBIOTIC TO FACILITATE
ENGRAFTMENT.
SO IS THE ENVIRONMENT
GUT IMPORTANT WHEN THINKING
ABOUT THE MICROBIOTA.
AND HERE I'M GOING TO PUT ON
MORE OF MY PHYSICIAN HAT.
SO INFLAMMATORY BOWEL DISEASE
CAN BE GUIDED INTO TWO DISEASES.
REASONS DISEASE WHICH IS CHRONIC
INFLAMMATION INVOLVING ANY
REGION OF THE ENTRUSTAL TRACT.
THESE ARE CHRONIC DISEASES THAT
REQUIRE LIFELONG IMMUNO
SUPPRESSION.
IT'S COMPLEX.
A GENETIC PREDICTION AND WE
THINK THE MOST IMPORTANT
ENVIRONMENTAL TRIGGERS IS
PROBABLY THE GUT MICROBIOTA
WHICH LEAD TO A REGULATORY
DEFECT RESPONSIBLE FOR THAT
CONNICK INFLAMMATORY RESPONSE.
IF WE WERE TO ASK HOW MUCH IS US
VERSES THE ENVIRONMENT WE THINK
THAT THE GENETIC CONTRIBUTION TO
THE DEVELOPMENT OF REASONS
DISEASE IS 30% TO 40%.
AND THIS IS BASED ON THE STUDY
IN IDENTICAL TWINS.
ENVIRONMENTAL FACTORS ARE THE
LARGEST CONTRIBUTOR.
AND THAT IS WHY I WANTED TO
HIGHLIGHT THIS AS A PARADIGM.
AND EVIDENCE FOR THIS -- IS THE
INCREASING IN DENSE ASSOCIATED WITH
WESTERNIZATION.
WE'RE SEEING A RAPID RISE IN
ASIA AND THIS IS PRIMARILY IN
INDIA AND IN CHINA AND OTHER
COUNTRIES.
SO THIS IS A VERY, VERY POWERFUL
ENVIRONMENTAL EFFECT THAT
EXTENDS WELL BEYOND INFLAMMATORY
BOWEL DISEASE.
OTHER TYPES OF DISEASES THAT ARE
VERY IMPORTANT IN THE HEALTH OF
THE HUMAN POPULATIONS ARE SEEING
A RAPID INCREASE BECAUSE OF
ENVIRONMENTAL INFLUENCES.
SO WE'RE FOCUSED ON THE
MICROBIAL ENVIRONMENT.
WE DO KNOW THAT THE ENVIRONMENT
IT IS VERY, VERY DIFFERENT WHEN
COMPARED WITH HEALTH.
SO WHAT IS RESPONSIBLE FOR THIS?
I USE DYSBIOSIS US AS A GENERAL
TERM -- ASSOCIATED WITH DISEASE.
THIS IS NOT NECESSARILY A
COMPLETELY POPULAR TERM BUT I
USE THIS AS A WAY TO EXPRESS
THIS IDEA ABOUT AN ALTERNATIVE
CONFIGURATION.
WORK ABOUT ANDREA AND OTHERS
HAVE HELPED TO DEFINE REASON WHY
THE MICROBIAL COMMUNITY IS
DIFFERENT AND IT'S LARGELY
BECAUSE OF HOST DERIVED FACTORS.
INFLAMMATION IS AN OXIDATIVE
PROCESS THAT CAN LEAD TO AN
OXIDATIVE ENVIRONMENT IN THE GUT
AND A LOT OF THESE ORGANISMS ARE
MORE -- TOLERANT.
THE HOST CAN PRODUCE SMALL
MOLECULES THAT PROMOTE AN ROBE
ARREST PERFORATION.
* TOGETHER IT REALLY MEANS THAT
IT'S THE HOST ITSELF.
THE INFLAMMATORY PROCESS THAT IS
LEADING TO AN ENVIRONMENTAL
PRESSURE OTICON PLEX MICROBIAL
COMMUNITY THAT FAVORS THE
OUTGROWTH OF PARTICULAR
ORGANISMS.
SO WE CAUSED THIS DISBOSE US.
-- WE HEARD A LOT ABOUT FROM A
NUMBER OF INVESTIGATORS
YESTERDAY.
SO YOU HAVE A MOUSE THAT
SPONTANEOUSLY DEVELOPED COLITIS
-- A HEALTHY MOUSE CAN LEAD TO
DEVELOPMENT OF DISEASE.
SO THAT TRANSFERABILITY OF THAT
MICROBIOTA COMMUNITY AND THE
RECAPITULATION -- PROVIDES CAUSE
AND EFFECT INFORMATION.
PROVING THAT IN FACT THE --
PATHOGENESIS.
THAT IS IN ANIMALS.
WHAT ABOUT IN HUMANS.
LET ME GIVE YOU ONE POTENTIAL
EXAMPLE.
HERE ARE THREE CLINICAL TRIALS
SHOWING BENEFIT FOR FECAL
TRANSFER.
I'M NOT SAYING AND I'M NOT
ADVOCATING FOR STANDARD F MT AS
THE TREATMENT FOR THIS.
IT'S A WINDOW INTO THE
OPPORTUNITIES THAT MIGHT BE
AVAILABLE FOR CHANGE IN THE
MICROBIOTA IN HUMANS WITH
INFLAMMATORY BOWEL DISEASE.
THERE IS A CAUSE AND EFFECT
RELATIONSHIP AND THE DISEASE
PATHOGENESIS SPECIFICALLY IN
HUMANS.
SO GETTING BACK TO THE BASIS OF
THE DYSBIOSIS US I WANT TO MAKE
A POINT.
ONE OF THE MECHANISMS IS
AEROBIC.
THE LOSS OF MITOCHONDRIAL -- AND
ALLOW THE DYNAMIC FLOW OF OXYGEN
THAT WOULD FAVOR THE OUTGROWTH
OF ORGANISMS SUCH AS -- -- SO,
THAT IS ONE PARTICULAR
MECHANISM.
THE OTHER IS ANAEROBIC.
IN THE ABSENCE OF OXYGEN
INFLAMMATION IN THE GUT COULD
PRODUCE ALTERNATIVE RECEPTORS
THAT WOULD FACILITATE ANAEROBIC
REST PERFECT RAISING AND THAT
WOULD LEAD TO THE DYSBIOSIS US
ALSO.
ONE IS OXYGEN AND THE OTHER IS
AN ALTERNATIVE ELECTRONIC
RECEPTOR TO OXYGEN.
HOW CAN THAT HAPPEN?
THIS IS JUST A THOUGHT
EXPERIMENT ON MY OWN PART SO I
CAN TAKE THE BLAME BUT LET ME
TELL YOU THE THOUGHT AND THAT IS
THE IMPORTANCE OF SPATIAL
DISCRIMINATION OR SPATIAL
CHARACTERIZATION WHEN THINKING
ABOUT BIOLOGY IN THE GUT.
BUT WHAT I PUT ALONG THE Y AXIS
IS A RATE AND THIS IS THE
SPATIAL RESOLUTION INCREASING
DISTANCE.
SO MAYBE ORGANISMS THAT ARE
CLOSER TO THE SURFACE THAT ARE
IN A MORE MICRO AEROBIC
ENVIRONMENT THAT IS THE
OPPORTUNITY TO HAVE A MORE
AEROBIC RESPONSE THAT PLAYS A
ROLE IN THE DEVELOPMENT OF
DYSBIOSIS US BUT AS YOU MOVE
AWAY MORE IN ANN AEROBIC
ENVIRONMENT THAT IS PERHAPS
WHERE MORE RECEPTORS PLAY A
GREATER ROLE IN THE DEVELOPMENT
OF DYSBIOSIS US.
AND * JUST A CONCEPT -- OF THE
MICRMICROBIOTA IN ITS ENVIRONMENT IN
THE GUT MAY BE IMPORTANT.
WE HAVE A HINT THIS MAY BE THE
CASE IN HOOP ANS.
-- IN HUMANS.
-- -- BASED ON A SWAB OR
BIOPSIES ARE DIFFERENT IN
COMPOSITION.
AND THE ORGANISMS THAT ARE
ADHERENT TO THE MUCOS A IN PART
ARE MORE ARROW TOLERANT.
WE HAD DEVELOPED A TECHNOLOGY
WITH THE NOTION THAT THE HOST
ACTUALLY PROVIDES OXYGEN IN TO
THE GUT ENVIRONMENT.
WE DEVELOPED A TECHNOLOGY USING
-- AND NANO PROBES THAT WOULD
ALLOW US TO QUANTIFY --
NONINVASIVELY AND IN REALTIME.
WE COULD SHOW THAT IF YOU
QUANTIFY OXYGEN IN HUMAN -- IN
MOUSE TISSUE IN THE LIVER THAT
-- IT IS ABOUT 40TOR.
BUT IF YOU NOW SWITCH THE MOUSE
INSPIRING AMBIENT AIR TO 100%
OXYGEN THERE IS AN IMMEDIATE
RISE AND WHEN YOU TURN BACK ON
THE AMBIENT AIR REDUCES.
AS YOU HYPER OXYGENATE -- YOU
CAN NOW SEE A DYNAMIC RESPONSE.
IF YOU REDUCE OXYGEN BACK DOWN
JUST LIKE IN TISSUE THE OXYGEN
LEVELS BEGIN TO DROP.
HOWEVER THEY DON'T REDUCE DOWN
TO THE BASELINE AND YOU CAN DO
THE SUCCESSIVELY BUT THERE IS
ALWAYS A LITTLE BIT OF OXYGEN
LEFT IN THE ENVIRONMENT.
THIS SHOWS THAT IN FACT WE
PROVIDE OXYGEN INTO THE -- GUT
THAT IS CONSUMED BY -- MICROBES.
THERE IS IS COMPLEXITY IN TERMS
OF THE CHEMISTRY THAT MAY BE
RELEVANT TO THE OXYGEN DYNAMICS
BETWEEN THE HOST AND THE LUMEN
OF THE GUT.
WE DEMONSTRATED THIS BOOK
LOOKING ATROPHIESES.
-- AT -- FECES.
7 * EVEN GERMFREE FECES -- WILL
CONSUME OXYGEN DOWNTOWN AN --
AEROBIC STATE IN A COUPLE OF
AREAS.
STRESSING THAT FECAL MATERIAL IS
A VERY COMPLEX AND BIOLOGICALLY
ACTIVE MATRIX AND WE KNOW THAT
FECAL MATERIALS VERY GOOD
INSULATOR AGAINST OXYGEN.
SO WHY IS THAT RELEVANT?
I JUST SHOWED YOU ONE RESULT
FROM CHRIS .
WE SHOWED THAT -- AS IT MOVES
TOWARD THE MUCOSAL SURFACE WILL
ACTUALLY ACTIVATE A TYPE THREE
SECRETION SYSTEM THAT PROMOTES
PATHO AGAIN US TEE.
* MEANING THAT THE OXYGEN
GRADIENT IS NOT ONLY IMPORTANT
FOR WHAT IS ACTUALLY LIVING IN
THESE VARIOUS TYPES OF
ENVIRONMENTS BUT IT'S IMPORTANT
FOR THE BIOLOGICAL FUNCTION.
IT WILL CHANGE GENE
REPRESENTATION, ACTIVITY -- AND
VARIOUS LI -- BIOLOGICAL FUNCTIONS.
THERE ARE GROWING TECHNOLOGIES
TO LOOK AT SPATIAL RESOLUTION OF
THE MICROBIOTA SO THIS IS WORK
USING FLUORESCE ANC -- * ALONG
WITH I THINK A VERY SPECIALIZED
OPTICS AND MACHINE LEARNING
ALGORITHMS THAT ALLOW THESE
INVESTIGATORS TO CHARACTERIZE AT
HIGH LEVEL OF COMPLEXITY THE
COMPOSITION OF THE MICROBIOTA AT
BODY SURFACES.
SO, THAT IS THE COMPOSITION OF
MICROBIOTA BUT WE HEARD ABOUT
METABOLITES AND THEY CAN BE
SPATIALLY RESOLVED USING ALL OF
THE MASS SPECTORMETRY IMAGING.
THEY DID -- MSI ON CONTROLLED
SECUM.
YOU CAN SEE THE COLORS ARE VERY
DIFFERENT FOR THESE THREE SMALL
MONTHLY SCHOOLS AND IT'S NOT
JUST THE GUT.
NOT * JUST THE FECES BUT THE
TISSUE ITSELF.
SO THIS IS VERY INTERESTING
INFORMATION.
THERE ARE HUNDREDS OF DIFFERENT
FEATURES THAT CAN BE SPATIALLY
RESOLVED IN TERMS OF
METABOLITES.
SPATIAL RESOLUTION OF THE
MICROBIOTA TOGETHER WITH THE
METABOLITES ARE PRODUCING AND
COULD BE IMPORTANT FOR THING
ABOUT FUNCTIONALITY OF THE MICRO
BUY OAT A. TALKING ABOUT THINGS
* THAT ARE RELEVANT.
SOME ARE TALKING ABOUT LAB ON A
PILL FOR SPATIALLY TARGETED --
THINKING ABOUT SPATIAL
RESOLUTION.
AND DR. KIM HAS DEVELOPED A
DISEASE ON A CHIP TYPE MODALITY
THAT WOULD BE ACTUALLY VERY WELL
SUITED TO LOOK AT
CHARACTERIZATION AT SPATIAL
RESOLUTION.
SO I USE OXYGEN.
WE DO HAVE TO THINK ABOUT HOW
ADDITIONAL WAYS BY WHICH THE
HOST AND MICROBE ACTUALLY
INTERACT IN THINKING ABOUT
THERAPEUTIC PRODUCTS AND WEARING
MY HAT AS A PHYSICIAN I NEED TO
EMPHASIZE AND GIVE YOU A LITTLE
BIT OF PRIMER HOW WE CURRENTLY
TREAT INFLAMMATORY BOWEL
DISEASE.
THE FIRST APPROACH IS INDUCE
REMISSION.
TREAT THE DISEASE TO TURN OFF
THE INFLAMMATION SO PATIENTS
FEEL WELL AND YOU NORMALIZE
LABORATORY VALUES.
ONCE YOU INDUCE REMISSION THE
NEXT STEP IS TO PREVENT THE
DISEASE FROM COMING BACK OVER
TIME.
AND SADLY INFLAMMATORY BOWEL
DISEASE PROBABLY REQUIRES
LIFELONG IMMUNO SUPPRESSION.
HOWEVER THERE IS A NOTION THAT
YOU CAN CHANGE THE DISEASE.
WE HAVE A HINT OF THIS AND THE
NOTION OF CHANGING THE
ENVIRONMENT OF THE GUT MAY
ACTUALLY PROVIDE AN OPPORTUNITY
TO CHANGE THE COURSE OF DISEASE
AND WE HAVE TO MONITOR THESE
PATIENTS LONG-TERM FOR POTENTIAL
SERIOUS OUTCOMES LIKE
DEVELOPMENT OF CANCER AS WELL AS
MONITORING OUTCOMES WITH IN
TERMS OF THERAPY.
SO IN TREATING WE HAVE --
DIFFERENT TYPES OF DRUGS
BEGINNING FROM THE SIMPLE TO
MUCH MORE ADVANCED TREATMENTS
AND THESE ARE LARGELY TARGETED
BIOLOGICS.
AND IF YOU DON'T RESPOND
UNFORTUNATELY YOU MAY NEED TO
HAVE SURGERY.
BUT THERE IS A WHOLE APPROACH
THAT WE USED TO TREAT AND WE
HAVE TO BE COGNIZANT OF THIS
WHEN WE THINK ABOUT COMING ONE
NEW THERAPEUTICS FROM THE
MICROBIOTA STANDPOINT.
THE HOST EXERTS AN ENVIRONMENTAL
PRESSURE ON THE MICROBIOTA AND
OUR HOPE IS THAT WE WILL COME UP
WITH BETTER STRATEGIES TO CHANGE
THE CONFIGURATION THAT WILL HELP
THE HOST.
BUT THAT ACTUALLY BRINGS UP A
COUPLE OF VERY IMPORTANT POINTS.
WHAT ARE YOU TRYING TO DO WHEN
YOU TARGET A PRECISION
PRO-BIOTIC.
ARE YOU TRYING TO ACTUALLY TREAT
ACTIVE DISEASE UP HERE OR ARE
YOU GOING TO PREVENT
REOCCURRENCE.
BUT IT IS VERY DIFFICULT TO
DEMONSTRATE PREVENTION OF
RECURRENCE.
MAYBE THAT'S AN OPPORTUNITY TO
BE THINKING B. THE OTHER IS DO
YOU WANT TO HAVE A STAND ALONE
THERAPEUTIC OR MAYBE A
COMBINATION THERAPY.
MAYBE YOU NEED TO BE TREATING
THE HOST USING SOME LEVEL OF
IMMUNO SUPPRESSION FOR CHANGING
THE GUT.
MIGHT MAKE THE DRUGS THAT WE
CURRENTLY USE BETTER.
>> DR. WU, YOU HAVE ABOUT FIVE
MINUTES
>> OKAY.
>> SO WE HAVE A NUMBER OF
INVESTIGATORS TALKING ABOUT
HOSTESS, MICROBIOTA REACTIONS.
I WON'T GET INTO DETAILS.
IT'S GOING TO BE VERY IMPORTANT.
BARBARA HAS A VERY NICE MODEL
SYSTEM ABOUT THE WILD MICROBIOTA
THAT IS GOING TO BE VERY
IMPORTANT.
SO WE DO HAVE AN EXAMPLE WHERE
TARGETED THERAPEUTIC IN THIS
CASE -- WERE ATTEMPTED TO BE
USED AS A TREATMENT FOR US
CERTIFY COLITIS.
*.
THE INDIVIDUALS THAT WERE
ENROLLED WERE REFRACTORY TO
STANDARD THERAPEUTICS.
THIS TRIAL WAS TERMINATED FOR
LACK OF CLINICAL EFFICACY.
NEVERTHELESS I THINK WE'LL LEARN
A LOT FROM THIS AND THIS IS JUST
THE START OF MANY DIFFERENT
TYPES OF OPPORTUNITIES.
THE FINAL THING IS COME PANS
DIAGNOSTICS.
CAN YOU COME UP WITH A
DIAGNOSTIC TO FIND OUT WHO WOULD
RESPOND TO THE TREATMENT.
SO IF YOU TANG ALL -- PATIENTS
WHO ACHIEVE REMISSION THERE IS
NO RESPONSE COMPARED TO PLACEBO.
HOWEVER YOU STRATIFY INDIVIDUALS
USING A COME PANS DIAGNOSTIC --
BASICALLY A BLOOD TEST.
YOU CAN SEE THERE IS A DOSE
DEPENDENT RESPONSE IN RESPONSE
TO THE ANTITMF DRUG.
TRYING TO DEFINE WHO'S GOING TO
RESPOND IS GOING TO BE IMPORTANT
AND THERE IS ARE OTHER EXAMPLES
IN ONCOLOGY AND THIS IS BREAST
CANCER -- TREATING WITH
INHIBITORS.
AS A MODALITY FOR A COME PANS
DIAGNOSTIC.
WE HAVE EVIDENCE FOR THIS.
THIS IS A PHASE II CLINICAL
TRIAL LOOKING AT TREATMENT ON
PREVENTION OF RECURRENCE OF --
INFECTION.
THIS CLINICAL TRIAL DID NOT SHOW
A SIGNIFICANT BENEFIT.
DID NOT REACH STATISTICAL
SIGNIFICANCE BUT THESE
INVESTIGATORS DID THE FIELD A
FAVOR BY DOING A POST HOCK
ANALYSIS SHOWING THEY USED PCR
TESTING TO DETERMINE ELIGIBILITY
IN THE STUDY AND THAT CANNOT
DIFFERENTIATE.
TOXIN TESTING CAN MAKE THAT
DISTINCTION BETWEEN INFECTION
VERSUS COLONIZATION.
THEY ALSO DETERMINED THAT THE
DOSE MAY NOT HAVE BEEN OPTIMAL.
SO THIS SAME APPROACH WAS
UTILIZED AND WAS PUBLISHED IN
THE NEW ENGLAND JOURNAL OF
MEDICINE.
THEY USED THE COME PANS
DIAGNOSING -- *.
AGAIN EMPHASIZING THE IMPORTANCE
OF A COMPANION DIAGNOSIS.
AND WE KNOW FROM THE HOST
STANDPOINT -- DEFINING -- HOST
IMMUNE PATTERNS THAT PREDICT
OUTCOME TO THE TREATMENT OF
ANTITMF.
WE'RE SEEING INFORMATION THAT
MINING THE MICROBIOTA CAN BE
USED AS A PROGNOSTIC FACTOR.
AND MAYBE THINKING FORWARD
MICROBES THEMSELVES PRECISION
PROBIOTICS COULD BE PART OF A
CELL-BASED BIOSENSOR -- AGAIN AS
ANOTHER MICROBIOLOGICAL
PREDICTIVE MARKER.
HERE IS MY LAST SLIDE.
IN THE FIELD RIGHT NOW WE HAVE
ANIMAL MODEL STATUS SHOWING
CAUSE AND EFFECT.
AND WE HAVE HUMAN ASSOCIATION
STUDIES.
WE WANT TO GET DOWN TO A LIVE
THERAPEUTIC PRODUCTS.
AND WHAT WE'RE CURRENTLY DOING
IS FMT -- -- AND WE DO NEED TO
BE MOVING DOWN THIS AXIS HERE
AND WE'RE SEEING THIS EVOLUTION.
AND THAT INCLUDES HUMAN
INTERVENTION STUDIES TO
DETERMINE WHETHER OR NOT WHAT WE
OBSERVE IN ANIMAL MODELS IS
RELEVANT TO HUMAN PHYSIOLOGY.
THERE IS NO GOOD MODEL FOR
INFLAMATORY BOWEL DISEASE THAT
ACTUALLY RECAPITULATES THE HUMAN
RESPONSE TO OUR THERAPEUTIC
INTERVENTIONS.
SO IT'S A TALL TASK BUT VERY
IMPORTANT.
ALSO IMPORTANT TO KNOW THAT ONLY
ABOUT 30% OF INDIVIDUALS RESPOND
TO CURRENT THERAPIES AND 30% OF
INDIVIDUALS LOSE RESPONSIVENESS.
SO THERE IS AN IMPORTANT NEED
FOR BETTER AND ALTERNATIVE
THERAPEUTICS.
A QUOTE -- PERFECT IS THE ENEMY
OF GOOD SO WE TALKED ABOUT A LOT
OF GRANULAR CONCEPTS.
WOULD IT BE GREAT IF WE KNEW ALL
OF THESE THINGS ABOUT THE
MICROBIOTA.
A LOT OF INTERACTIONS.
BUT THE NOTION IS THAT MAYBE WE
DON'T NEED TO KNOW EVERYTHING TO
MAKE FORWARD PROGRESS IN THE
FIELD.
SO IT'S IMPORTANT TO BE
HYPOTHESIS DRIVEN BUT THE
COMPLEXITY MEANS THAT WE MAY NOT
KNOW EVERYTHING.
AND I USE AN EXAMPLE -- WHICH IS
THE STANDARD DRUG USED.
VERY SAFE.
VERY EFFECTIVE.
HOWEVER, WE DON'T KNOW HOW IT
WORKS.
THE LIST OF THINGS THAT IT
INHIBITS OR INDUCES IS RELONG
BUT WE KNOW THAT IT WORKS.
SO THERE ARE OPPORTUNITIES I
THINK TO MOVE FORWARD.
AND THINK ABOUT HUMAN
INTERVENTION STUDIES.
THAT WILL TEACH US A LOT OF
IMPORTANT THINGS.
EVEN WHEN WE DON'T KNOW
PRECISELY EVERYTHING ABOUT THE
SYSTEM.
SO WITH THAT I TOLD YOU ABOUT
THE OXYGEN DYNAMICS.
HIGHLIGHTING THE GROUP OF
INDIVIDUALS IN RED THAT DID THAT
WORK AND I THANK YOU AGAIN VERY
MUCH FOR THE OPPORTUNITY TO GIVE
YOU THIS PRESENTATION TODAY AND
I LOOK FORWARD TO THE PANEL
DISCUSSION.
THANK YOU.
>> THANK YOU SO MUCH, DR. WU.
A GREAT TALK AND ALSO THANK YOU
TO DR. BETZ FOR HIS OPENING
REMARKS.
NOW I'M PLEASED TO TURN THINGS
OVER TO DR. PADMA MARUVADA.
AND DR. RYAN RANALLO.
NEXT GENERATION PRO-BIOTICS, NEW
TRAIN IDENTIFICATION AND
DEVELOPMENT.
THEY WILL ALTERNATE AND
INTRODUCING THEIR SPEAKERS AND
I'M GOING TO BRING UP A QUICK
SLIDE THAT SHARES WITH YOU WHO
THE SPEAKERS WILL BE.
DR. RANALLO IS GOING TO LEAD OFF
IN INTRODUCING THE SPEAKERS.
AND SO I WILL TURN IT OVER TO
DR. RANALLO WHO WILL INTRODUCE
THE FIRST SPEAKER OF SECTION 3.
THANK YOU.
TAKE IT AWAY.
>> THANK YOU, KATHERINE.
I ALSO WANT TO THANK GARY FOR AN
INCREDIBLY THOUGHTFUL KEYNOTE
AND THE WAY IN WHICH HE
ARTICULATED TODAY'S SESSIONS AND
PUT THEM INTO CONTEXT.
IT'S JUST GOING TO MAKE OUR JOBS
SO MUCH EASIER.
SO WITH THAT GOOD MORNING,
EVERYBODY AND WELCOME TO THE
THIRD SESSION OF OUR WORKSHOP.
AND AS KATHERINE SAID IT'S NEXT
GENERATION PRO-BIOTICS STRAIN,
NEW DEVELOPMENT.
ALONG WITH MY COLLEAGUE PADMA
MARUVADA.
WE WILL BE YOUR MODERATORS.
AND WE WILL BE HOSTING YOUR
PANEL DISCUSSION.
AS A REMINDER SPEAKERS, -- THE
LIST OF SPEAKERS FOR THE SECTION
IS IN YOUR PROGRAM GUIDE ALONG
WITH THE BIOS AND ABSTRACTS.
FOR THOSE OF YOU WATCHING PLEASE
REMEMBER TO SUBMIT QUESTIONS FOR
THE PANEL DISCUSSION AS I SAID
WE'LL TRY TO GET TO SOME OF
THOSE.
AND WITH THAT I WOULD LIKE TO
INTRODUCE DR. JULIA OH.
JULIA.
IT'S ALL YOURS.
>> ALL RIGHT.
>> SO JUST BY WAY OF CONTEXT --
A LOT ABOUT HEALTHY VERSUS
DISEASE MICROBIOMES AND HOW WE
MIGHT TARGET THESE DIFFERENCES
TO DEVELOP THERAPEUTICS.
THE SKIN MICROBIOME.
WE'VE DEFINED SOME OF THE
CHARACTERISTICS.
THERE MIGHT BE HEALTHY
CONFIGURATIONS THAT DIFFER
BETWEEN INDIVIDUALS BUT WHOSE
OVER-ALL PARAMETERS ARE DEFINED
BY THE SKIN SITE.
AND THESE DEFINE.
IN TERMS OF DIVERSITY AND
STABILITY OVER TIME.
WHEN YOU HAVE A -- TO THE SYSTEM
WHETHER IT'S IN THINKSIC -- OR *
EXTRINSIC -- IT CAN BE DRIVEN
INTO A DISEASE MINIMUM THAT IS
CHARACTERIZED -- AS PATHOGENS
TAKE OVER.
AND I SHOW THIS TO YOU BECAUSE
-- IT SHOWS THE TARGETS.
THERE ARE SOME KEY UNRESOLVED
KNOWLEDGE GAPS.
AND ONE THAT I'LL TALK ABOUT IS
STRAIN DIVERSITY.
DIFFERENT STRAINS HAVE DRAMATIC
PHENOTYPIC DIFFERENCES.
AND FROM A MICROBIAL PERSPECTIVE
WE NEED TO CARE ABOUT STRAINS.
SO FOR EXAMPLE THE SINGLE TOXIN
-- E. COLI CAN TURN OUR CLONING
FRIEND INTO A PATHOGEN THAT
CAUSES KIDNEY FAILURE.
AND DEPENDING ON WHICH STRAIN
YOU HAVE GREEN OR RED YOUR
DISEASE SUSCEPTIBILITY OR
TREATMENT RESPONSE CAN BE
DIFFERENT.
BUT IT GETS MORE COMPLICATED.
DO WE ACQUIRE AND MAINTAIN JUST
ONE STRAIN WITHIN AN INDIVIDUAL
SO ALL RED OR ALL GREEN?
OR DO WE HARBOR MIXTURES WHICH
CHANGESES THE PICTURE.
SO EVEN HEALTHY PEOPLE MIGHT BE
RESERVOIRS.
DIFFERENT STRAINS MIGHT COMPETE
AGAINST EACH OTHER.
PREVENT COLONIZATION.
THE LOCATION MIGHT BE IMPORTANT.
LARGELY UNANSWERED QUESTION WAS
CRITICAL.
WHETHER WE HAVE ONE OR MANY
STRAINS OF THE GIVEN SPECIES AND
THEN ASSOCIATED QUESTIONS.
HOW DO WE ACQUIRE THEM AND WHAT
HAPPENS TO THEM OVER THEIR
TENURE IN OUR BODIES.
SO WE USE METRO GENOMIC
SEQUENCES.
AND A LIMITATION -- WHICH IS FAR
MORE COMPREHENSIVE IN TERMS OF
RECOVERING DIVERSITY.
A LIMITATION IS THAT IT HAS
LIMITED ACCURACY.
AND ALGORITHMS TEND TO
UNDERESTIMATE STRAIN DIVERSITY.
AS WE SEQUENCE INDIVIDUAL
GENOMES AND THIS PROVIDES US THE
RESOLUTION THAT WE NEED TO
UNDERSTAND SOME OF OUR BASIC
QUESTIONS.
-- LOOKING AT WITHIN AN
INDIVIDUAL STRAIN DIVERSITY WE
LOOKED AT STAPH -- WE ALL HAVE
IT AND IT'S PRETTY MUCH
EVERYWHERE ON OUR SKIN.
AND WHILE IT'S ESSENTIAL -- IT'S
LOW IN ABUNDANCE.
NOW THE FLIP SIDE IS ALSO THE
COMMON CAUSE OF BLOOD INFECTION.
SO UNDERSTANDING HOW CERTAIN
TRAINS ARE ASSOCIATED WITH
DISEASE WILL PROVIDE INSIGHTS
INTO THE TRANSITION.
8 AND SO IN OUR FIRST PASS WE
CULTIVATED AND SEQUENCED 1500
ISOLATES FROM FIVE HEALTHY
INDIVIDUALS AND THEN COMPARED
THEIR GENOMES TO ANSWER BASIC
QUESTIONS.
JUST RECAPPING THEM HERE.
SO TO ANSWER THE FIRST QUESTION
OUR FIRST EXTRAORDINARY RESULT
WITH THAT BASICALLY -- EVERY
ISOLATE WAS A DIFFERENT
GENETICALLY STRAIN.
SO THE HEAT MAP OF GENE
PREVALENCES WERE REPRESENTATIVE.
THIS IS GENE CONTENT DIFFERENCES
WITH SKIN SITE ON THE X AXIS.
7 SO FIRST OFF THE HETEROGENEITY
-- CAN HAVE DIFFERENT
COMPILATION OF GENES.
IT CAN BE UNIQUE TO THE SKIN
SITE.
SUGGESTING A STRONG SKIN SITE
SPECIALIZATION.
BUT AGAIN THE OVER-ALL
HETEROGENEITY SUGGEST THAT THERE
ARE ADDITIONAL FACTORS CAUSING
THIS.
WHAT COULD BE SOME OF THE
FACTORS?
FOR EXAMPLE MAYBE WHERE THESE
DIFFERENT STRAINS COME FROM.
THESE STRAINS ARE SO DIVERSE
THAT IT'S UNLIKELY FOR ALL OF
THESE DIVERSE STRAINS TO DIVERGE
FROM A SINGLE PARENT STRAIN.
IT'S THOUGHT THAT WE GET OUR
MICROBIOME FROM OUR MOMS AND
THEN TRANSMISSION EVENTS, THESE
MIGHT BRING NEW STRAINS IN OR
EVOLUTION.
AS WE -- -- TO INFER THE SOURCE
OF THE STRAIN -- BECAUSE SNIPS
CAN ACT LIKE A MOLECULAR CLOCK
AND THAT IS REFLECTED BY THE
CLOSESTHE --CLOSENESS.
-- -- THIS WAS SURPRISING
BECAUSE THE ONLY OTHER STUDY
LOOKING AT FRAGILIS -- DIVERGES
OVER TIME.
BUT THEN WHAT OTHER OTHER
FACTORS?
TRANSMISSION BETWEEN BODY SITES
WITHIN AN INDIVIDUAL.
SO BY TRACKING SNIPS WE CAN
MOUNT THE MOST COMMON WAYS FOR
STRAINS TO TRAVEL WHICH IS BY
TOUCH.
THE LINES SHOW THE PREVALENT
TRANSMISSION ROUTES FROM THE
HANDS TO THE FACE.
THE GENES AS WELL IN A MECHANISM
CALLED MORE ZONE TAN GENE
TRANSFER.
* SO A FICK EXAMPLE -- AND ALSO
*.
THE
WHICH CAN MAKE PATHOGENS
RESISTANT TO TREATMENT.
AND THEN WE LOOK FOR EVIDENCE OF
DISSEMINATION OF THESE GENETIC
ELEMENTS.
ON THE LEFT IS AN EXAMPLE.
ON THE RIGHT WE SEE A MAP OF
DISSEMINATION WITHIN AN
INDIVIDUAL.
THE DARKNESS OF THE BLUE DOTS
REFLECT IS PREVALENCE.
WE SEE THE RESISTANCE GAMES HAVE
DISSEMINATED TO DIFFERENT SITES.
HORIZONTAL GENE TRANSFER -- AND
SO NOW WE HAVE AN EMERGING
PORTRAIT.
IT STARTS WITH OUR COLONIZATION
OF A GENETICALLY DIVERSE
STRAINS.
AND BEING REALLY SURPRISED BY
THE DEGREE WITHIN AN INDIVIDUAL
STRAIN DIVERSITY THAT WE FOUND
WE WONDERED IF THIS DIVERSITY
WAS A NECESSARY CONSEQUENCE.
AND TO EXPLAIN ONE CONSEQUENCE
OF STRAIN DIVERSITY -- QUORUM
SENSING ENDED UP BEING RELEVANT
HERE.
SOME BACTERIA PRODUCES A
CHEMICAL.
AND TURN ON A SPECIAL SET OF
GENES.
AND THERE IS MORE AUTO INDUCER
AND THESE CAN BE TURNED ON AND
ALL OF THE CELLS IN THE
POPULATION.
SO WHAT HAPPENS WITH THE
DIFFERENT MIXTURES.
BASED ON THE LITERATURE WE
THOUGHT THAT IT MIGHT CAUSE
INTERFERENCE IN THE POPULATION.
AND THAT IS EXACTLY WHAT WE
OBSERVED ENVY TOE.
-- *.
AND WE MADE THEM IN DIFFERENT
PROPORTIONS.
TRANSCRIPTION AS MEASURED WAS
VERY STRONGLY REPRESSED COMPARED
TO WHEN YOU GIVE IT TO -- THAT
IS STRONGLY INDUCED.
AS A COROLLARY STRAIN DIVERSITY
CAN BE AN IMPORTANT DETERMINANT.
AND NOW WE'RE TESTING THIS IN
MOUSE MODELS.
SO ADDING VERY PLANTS.
*.
NOW DIGGING DEEPER -- IT BEGS
FOR QUESTIONS LIKE WHICH STRAINS
IS WITHIN AN INFECTION AND WHICH
STRAINS DO WE USE FOR AN
ANTIBIOTIC.
WOULD IT BE BETTER TO USE A
GENETICALLY SIMILAR OR MORE
DISTANT STRAIN.
AND THEN YOU HAVE WHAT ARE THE
FUNCTION, CONSEQUENCES OF STRAIN
DIVERSITY IN THE SKIN?
WE'VE BEEN TAKING A FEW
APPROACHES.
SO FOR EXAMPLE TAKING IN MIND TO
ALL OF THE UNKNOWN FUNCTIONS OF
ALL OF THE STRAIN SPECIFIC GENES
-- WE DEVELOP GENOME WIDE CRISPR
INTERFERENCE -- TO PROBE --
PLASTICITY IN DIFFERENT
ENVIRONMENTAL CONDITIONS
RELEVANT TO THE SKIN.
WE DEVELOPED A PLATFORM
PROFILING THE RESPONSE OF SKIN
ORGANOIDS TO COLONIZATION BY
DIFFERENT STRAINS WITH DIFFERENT
HOST READOUTS.
AND TO SHOWING A SNAPSHOT.
SO HERE WE'RE LOOKING AT A FEW
OF THE DIFFERENTIALLY EXPRESSED
GENES.
AND THEY ARE BOXED IN RED WITH A
TIME SERIES.
AND YOU CAN SEE CLEARLY THERE IS
TIME EFFECTS.
AND SECOND YOU CAN SEE THE
EFFECTS OF THE CATHETER
ASSOCIATED STRAIN.
SO A STRAIN SPECIFIC EFFECT IN
THESE ORGANOIDS.
AND WE'RE ALSO SEEKING TO
UNDERSTAND HOW GENETIC DIVERSITY
LINK CANS TO THE ME LA -- METABOLITES.
WE'RE USING COME FEW
INDICATIONAL PREDICTIONS -- -- SO HERE
WE'RE LOOKING AT THE SCORES.
AND IN CATEGORIES OF INTEREST.
METABOLITES THAT ACTIVATE AGE
SIGNALING THAT MEDIATES SKIN
BARRIER REPAIR AS WELL AS
DIFFERENT FACETS OF THE IMMUNE
SYSTEM.
MAJOR DIFFERENCES BETWEEN THE
TWO STRAINS IN SOME OF THESE
PATHWAYS.
AND THAT IS MY TWO BIG TAKE
AWAYS HERE.
THIS IS GOING TO BE HIGHLY
SPECIES SPECIFIC.
WE SEE EXTENSIVE WITHIN AND
INDIVIDUAL STRAIN DIVERSITY.
SO DESIGNING THERAPEUTICS WE
NEED TO THINK NOT ONLY AT THE
SPECIES LEVEL BUT AT THE STRAIN
LEVEL.
NOW WITH THAT JUST THANKING MY
FANTASTIC GROUP AT THE JACKSON
LABORATORY AND MY WONDERFUL
COLLABORATORS AS WELL.
>> THANK YOU.
THANK YOU, JULIA.
THAT WAS A WONDERFUL
PRESENTATION.
OUR NEXT SPEAKER IS DR. JUNE
ROUND FROM THE UNIVERSITY OF
UTAH.
>> GOOD MORNING, EVERYONE.
AND CAN YOU SEE THIS?
>> YES.
>> RIGHT IN THE MIDDLE OF THE
PRESENTATION.
WHICH IS ALWAYS GOOD.
>> YOU ARE IN SPEAKER
PRESENTATION MODE SO MAYBE IF
YOU CAN SWAP MONITORS.
THAT IS WHAT WE SEE.
PERFECT.
>> THANK YOU SO MUCH FOR PUTTING
TOGETHER THIS MEETING.
IT'S BEEN A WONDERFUL AND
INVITING -- ME TO PRESENT SOME
OF OUR WORK.
I'M GOING TO TALK ABOUT
ORGANISMS THAT WE HAVE NOT
MENTIONED IN THIS MEETING YET.
BUT ARE STILL AN IMPORTANT
ALBEIT SMALL PROPORTION OF OUR
MICROBIOTA.
IN KEEPING WITH THE FOCUS OF
THIS MEETING I THOUGHT I WOULD
TELL YOU A STORY THAT WE
PUBLISHED LAST YEAR REGARDING
HOW THE FUNGI REACTS TO PROMOTE
COLONIZATION AND ALSO PROMOTING
INTESTINAL HEALTH AND EXPLORING
THAT IN AN THERAPEUTIC WAY.
IGA HAS BEEN WELL APPRECIATED.
IGA CAN NEUTRA -- NEUTRALIZE TOXINS.
IT'S ALSO REALLY IMPORTANT IN
STRUCTURING THE MICROBIOTA
COMPOSITION.
AND IN A VARIETY OF WAYS BUT
MOST OF THE STUDIES EVER LARGELY
FOCUS ENDS AGAIN ON THE
BACTERIAL COMPONENT.
78 SO AS I'VE MENTIONED THE
MICROBIOTA IS COMPLEX.
A LOT OF BACTERIAL DIVERSITY BUT
ALSO HOME TO VIRAL AS WELL AS
FUNGAL ORGANISMS.
WE WONDERED WHETHER OR NOT IGA
WAS IMPORTANT.
SO WE STARTED WITH SOME VERY
SIMPLE QUESTIONS REGARDING IGA
AND ITS INTERACTION WITH FUNGAL
SPECIES.
BUT WE GOT INTERESTED IN FUNGI
APPROXIMATELY 10 YEARS AGO
BECAUSE THERE WAS A CLINICAL
TEST THAT WAS ABLE TO
DISTINGUISH BETWEEN REASONS
DISEASE AND YOU WILLER RATE I
HAVE COLITIS.
AT THE TIME THIS HINTED TO US
THAT FUNGAL SPECIES AND THE
IMMUNE RESPONSE MIGHT BE
RELEVANT IN DISEASES SUCH AS
INFLAMMATORY BOWEL DISEASE.
SO TO ASK THE SIMPLE QUESTION OF
WHETHER OR NOT FUNGAL SPECIES
WERE EVEN RECOGNIZED BY IGA WE
COLLABORATED WITH -- WHO
PROVIDED US SOME FECAL SAMPLES
FROM HEALTHY INDIVIDUALS AND
ALSO FROM THOSE WITH DISEASE.
WE INCUBATED THEM WITH KNOWN
FUNGAL STRAINS THAT ARE
PREVALENT IN THE HUMAN GUT
MICROBIOTA.
-- WE DID SEE IGA SEEMS TO HAVE
SOME SORT OF SPECIFICITY.
BUT WE SAW LITTLE REACTIVE
AGAINST ORGANISMS.
SO THIS DATA DEMONSTRATED THAT
INDEED IGA DOES BIND AND
RECOGNIZE FUNGAL -- ORGANISMS IN
THE GUT BUT IT DOES SEEM TO HAVE
SOME SELECTIVITY.
WE SEE VERY SIMILAR RESULTS.
SO HERE WE'VE TAKEN GERMFREE
ANIMALS AND WE'VE MONO
ASSOCIATED THEM WITH -- THAT
WE'VE ENGINEERED.
AND WE LOOK AT THE RESPONSE AS
MEASURED.
AND WE SEE SIMILAR RESULTS.
WHERE CALBICANS IS HIGHLY
TARGETED.
DESPITE BEING THE ONLY THING
PRESENT IN THE GERMFREE ANIMAL.
I WANT TO MAKE SURE YOU CAN
STILL HEAR ME BECAUSE MY
COMPUTER JUST BLIPPED OUT.
>> YOU'RE STILL LOOKING AND
SOUNDING VERY GOOD.
>> GREAT.
I'M SORRY.
IT JUST FREAKED OUT AND I DON'T
KNOW WHAT HAPPENED.
SO IT SEEMS LIKE IGA ROBUSTLY
TARGETS -- BUT NOT NECESSARILY
-- -- -- SO WE WONDERED WHAT IGA
WAS DOING TO THE -- FUNGI.
AND IN ORDER TO ANSWER THE
QUESTION WE EXPLORED THE FIRM
FREE MOUSE SYSTEM.
THEY DO NOT HAVE AN ADAPTIVE
RESPONSE AND WE ASSOCIATED AGAIN
ENGINEERED WITH GFP.
WE PULLED THOSE SPECIES OUT OF
THE ANIMALS AND WE PERFORMED AN
RNA SEEK ON THE FUNGI ITSELF.
IT LOOKED VERY DIFFERENT
TRANSCRIPTIONALLY WHEN COMPARED
TO YEAST PULLED OUT OF WILD TYPE
ANIMAL AND ONE OF THE MAJOR
PATHWAYS THAT WAS CHANGED OR UP
REGULATED IN YEAST THAT CAME
FROM AN ANIMAL THAT LACKED
ADAPTIVE IMMUNITY WERE GENES
THAT WERE ASSOCIATED WITH HYPO
TRANSITION.
IF YOU'RE UNFAMILIAR WITH THE
BIOLOGY THIS YEAST IS ABLE TO
EXIST IN MULTIPLE FORMS.
THE DOMINANT FORMS THAT ARE
FOUND WITHIN THE GUT ARE THE
YEAST FORM WHICH IT LOOKS MUCH
LIKE A BUDDING YEAST.
BUT UNDER CERTAIN ENVIRONMENTAL
CONDITIONS -- THEY CAN UNDERGO A
PROCESS AND IT CAN FORM THESE
VERY ELONGATED -- NOW -- STUDIED
IN DEPTH BY MANY INVESTIGATORS
FOR VAGINAL INFECTIONS AS WELL
AS SYSTEMATIC INFECTIONS AND THE
HYPHAE ARE ASSOCIATED WITH
INVASIVENESS.
ASSOCIATED WITH GREATER DISEASE.
SO SINCE WE SAW THAT THE
TRANSCRIPTIONAL PROGRAM WAS UP
REGULATED IN -- THAT WERE COMING
FROM MICE THAT LACKED ADAPTIVE
IMMUNITY WE WANTED TO
COLLABORATE WHAT THESE YEAST
LOOK LIKE IN THE GUTS OF
ANIMALS.
SO AGAIN WE COLONIZED IN THIS
CASE WE COLONIZED AND WE ALSO
INCORPORATED A B CELL
DEFIBRILLATORS ANIMAL SO WE
COULD PINPOINT THIS RESPONSE TO
POTENTIALLY ANTIBODIES.
AND WHEN WE PERFORM FISH ON THE
CANADAAL BY CANS WE SEE A PRETTY
STRIKING PHENOTYPE.
WE SEE THAT CANADA ALBICANS
EXIST MORE IN THE YEAST FORM.
WE SEE THAT MOST OF THE CANADA
EXIST IN THE ELONGATED HYPHAEA.
MORE OVER IF YOU USE IMAGE
STREAM ANALYSIS CLASS A --
COMBINATION THIS IS AN VIDEOS
CELL WHERE WE STAINED IT -- --
ALSO COME IN WITH ANTI IGA THAT
IS PHYSICALLY BINDING TO THE
YEAST AND WHAT WE CONSISTENTLY
FIND IS THAT IGA IS TARGETING
THE HYPHAL FORM OF THE YEAST AS
OPPOSED TO THE YEAST FORM OF THE
FUNGI AND THIS CAN BE
QUANTITATIVE BECAUSE -- THIS IS
AN APPROACH WHERE WE SEE MORE OF
THE POSITIVE FRACTION IS BINDING
TO THE HYHH AL FORM
THE IGA RESPONSE IS SUPPRESSING
THE TRANSITIONAL PROGRAM.
AND THAT IGA IS PHYSICALLY
BINDING TO THINGS THAT ARE
ASSOCIATED WITH HYPHAL WITHIN
THE GUT OF ANIMALS.
SO WE WANTED TO UNDERSTAND WHAT
ARE THESE THAT ARE BEING BOUND
BY IGA.
SO WE TOOK A BIOCHEMICAL
APPROACH.
WE TRIED A LOT OF THINGS.
BUT WE TOOK A BIOCHEMICAL
APPROACH.
7 SO THE WAY THAT THIS WAS DONE
WE GREW UP -- CABLICANS IN MEDIA
THAT PROMOTES YEAST FORMATION --
AND THEN TAKE THOSE AND RUN THEM
ON A GEL AND WE PROBE THAT GEL
WITH IGA THAT IS ISOLATED FROM
GERMFREE MICE AND WHEN DO YOU
THIS AGAIN WHAT YOU FIND IS THAT
THE IGA ACTIVITY TENDS TO BIND
TO PROTEINS THAT ARE ASSOCIATED
WITH HY PHI.
AND WHAT WE IDENTIFIED IS THAT
IGA TENDS TO BIND ADD MOTIONS
SUCH AS ALS3 AS WELL AS HYR1.
7 SO THIS HELPED US TO IDENTIFY
WHAT EPITOPES WERE BEING
RECOGNIZED.
SO AS I SHOWED YOU EARLIER IN
THE TALK -- IT DOES NOT SEEM TO
BE TARGETED BY IGA.
SO WE WONDERED IF THESE
ADHESIONS WERE SUFFICIENT FOR AN
ORGANISM TO NOW BE TARGETED BY
IGA.
SO WE ENGINEERED -- TO EXPRESS
SOME OF THESE ADD -- ADHESIONS.
AND INDEED -- YOU CAN NOW SEE
THE EMERGENCE OF IGA REACTIVITY.
THIS IS JUST TO SHOW YOU THAT
WHEN YOU LOOK AT REACTIVITY IN
HUMANS WHEN YOU ISOLATE THAT
FECAL WASH AND ASK WHETHER OR
NOT THERE IS IGA IN THE GUTS OF
HUMAN THAT'S REACTS AGAINST
THESE SPECIFIC ISOTOPES WE FIND
HUMANS ALSO POSSESS REACTIVITY
TO MANY OF THESE ADHESION
INCLUDING ALS1 AND ALS3 IN
PARTICULAR.
SO IT IDENTIFIES THAT THESE
EPITOPES ARE RELEVANT IN HUMANS
AS WELL.
SO THE MORE IMPORTANT QUESTION
IS DOES THIS MATTER FOR INTEST
NATURAL HEALTH AND INTESTINAL
DISEASE.
WE WANTED TO ASK THE QUESTION OF
WHETHER OR NOT THIS FILL MEN
TAKES PROCESS WAS IMPORTANT FOR
* INTESTINAL DISEASE.
A LOT OF COOL GENETIC TOOLS THAT
WE EXPLOITED AND ONE IS THAT YOU
CAN FORCE YEAST TO STAY THE
FUNGI TO STAY IN THEIR YEAST
FORM BY FORCING EXPRESSION OF A
TRANSCRIPTION FACTOR CALLED
NRG1.
WHEN YOU FORCE THE TRANSCRIPTION
FACTOR TO BE OFF THE YEAST WILL
THEN FORMER LONG GATED --
>> YOU HAVE ABOUT TWO AND A HALF
MINUTES.
>> PERFECT.
THANK YOU.
YOU THEN TAKE THESE ORGANISMS --
AND WE INDUCED -- AS A MODEL OF
INFLAMMATORY BOWEL DISEASE.
WHEN WE DID THIS WE SEE THAT
THIS ENHANCES AND WHEN YOU FORCE
THOSE ORGANISMS TO STAY IN THEIR
YEAST FORM IT REDUCES THEIR
DISEASE.
HOWEVER WHEN YOU PAUSE THOSE
ORGANISMS THAT EXACERBATES THE
INTESTINAL DISEASE.
SO THIS SAYS THAT THE FORM OF
THE FUNGI IS REALLY PROMOTING
DISEASE IN THIS ANIMAL MODEL.
SO THE FINAL DATA SLIDE THAT
I'LL SHARE WITH YOU IS THAT WE
WONDERED IF WE CAN EXPLOIT THIS
NATURAL PRUNING THAT THE IMMUNE
SYSTEM DOES TO THE GUN GAS TO
PREVENT * OR PROTECT FROM
INTESTINAL DISEASE IN MICE.
AND WE COLLABORATE CO-LAB -- COLLABORATED --
AND WE WERE PROVIDED WITH THE
VACCINE AGAINST ALS3 AND WE
IMMUNIZED ANIMALS WITH -- --
ALUM AND WE INDUCED AS PER MY
PREVIOUS SLIDE.
NOW WHEN CANDICE NOT AROUND THIS
VACCINATION PROTOCOL THIS IS
LITTLE AS ONE WOULD PREDICT.
AGAIN WE SEE THAT THE PRESENCE
OF CANADA -- WORSENS DISEASE BUT
IN ANIMALS THAT WERE GIVEN THE
VACCINE AGAINST ALS3 TO PROMOTE
THIS IGA RESPONSE THESE ANIMALS
DIDN'T DEVELOP DSS COLITIS.
SO REALLY THIS IS AN EXAMPLE OF
WHEN WE'RE STUDYING THE
INTERACTION BETWEEN MIKE ROBES
AND THE IMMUNE * SYSTEM WE CAN
EXEMPLOYED WHAT NATURE HAS
EVOLVED.
AND IN THIS PARTICULAR INSTANCE
WE'VE IDENTIFIED EPITOPES ON THE
ORGANISMS THAT CAN BE USED IN
VACCINATION STRATEGIES TO
PREVENT THE DISEASE CAPABILITIES
OF THESE PARTICULAR ORGANISMS.
AND ONE CAN IMAGINE USING IGA
JUST AS ONE EXAMPLE TO IDENTIFY
A RELEVANT BACTERIA, FUNGI EVEN
VIRUSES AND THEIR MOLECULES AND
USE THIS TO DESIGN THERAPEUTIC.
SO WITH THAT I'LL END AND I'LL
ACKNOWLEDGE ALL OF THE WONDERFUL
COLLABORATORS.
WE HAVE GREAT COLLABORATORS AND
THEN ALL OF THE WONDERFUL WORK
WAS DONE BY A TALENTED POSTDOC
WHO'S GOING TO START HER OWN LAB
HERE IN JULY.
AND THE FUNDING TO SUPPORT THIS
WORK.
THANK YOU VERY MUCH AND I LOOK
FORWARD TO THE PANEL DISCUSSION
>> THAT WAS A REALLY GREAT TALK
AND IT MAKES ME WONDER IF
SIMILAR THINGS ARE HAPPENING
WITH BACTERIA SPORE FARMERS BUT
WE'LL SAVE THAT FOR THE PANEL.
THE NEXT SPEAKER IS FROM JANUARY
PETER VAN PIJKEREN.
TAKE IT AWAY JP.
>> SO SCREEN IS THERE AND YOU
CAN HEAR ME OKAY.
SUPER.
THANK YOU VERY MUCH FOR THE
INTRODUCTION AND THANK YOU TO
THE ORGANIZERS FOR PUTTING
TOGETHER A NICE WORKSHOP AND I'M
DELIGHTED TO SHARE SOME OF THE
WORK THAT WE'VE BEEN DOING.
SO OUR LAB IS INTERESTED TO
UNDERSTAND PRO-BIOTIC MECHANISMS
AS IT PERTAINS TO GUT FITNESS
AND THE ABILITY OF PRO-BIOTIC TO
INTERACT WITH THE HOST AND
LEVERAGE THE KNOWLEDGE TO THE
DEVELOPMENT OF MICROBIAL
THERAPEUTICS.
MOST OF THE WORK THAT WE DO WE
USE THE GUT SYMBIONT.
A SPECIES THAT CAN BE FOUND IN
THE GUT OF A LARGE NUMBER OF
VERTEBRATES INCLUDING IN HUMANS.
IT'S NOT A DOMINANT SPECIES IN
HUMANS BUT IT CAN BE FOUND AND
IT IS AN ORGANISM THAT HAS
EVOLVED TO THRIVE WITHIN THE GUT
ECOSYSTEM.
WITHIN THE LAST 10 YEARS WE'VE
INVESTED HEAVILY IN THE USE OF
TOOLS.
WORK STARTED WHEN I WAS A
POSTDOC.
OUR LAB LATER DEVELOPED CRISPR
-- -- -- I WILL NOT GO INTO THE
DETAILS TALKING ABOUT 10 MINUTES
IS ENOUGH TO PUT EVERYBODY TO
SLEEP BUT THE TAKE AWAY MESSAGE
IS WE HAVE A CART BRANCH FOR OUR
ABILITY AND THESE TOOLS ARE
ESSENTIAL AND CRITICAL TO
UNDERSTAND GENE FUNCTION AND
SPECIFICALLY WITH THE WORK IN
RELATION TO GUT FITNESS.
IT HAS PROVEN FRUITFUL.
SO -- IT IS NOT UNIQUE IN THE
FACT THAT IT IS ACTUALLY IN THE
GENOME -- EMBEDDED BACTERIAL
DNA.
MOST HAVE THAT.
AND WHAT WE FOUND IS THAT WHEN
ACTUALLY -- PASSES THROUGH THE
GI TRACT AND WE USE MICE FOR
THIS WHAT WE SEE IS THAT THIS
VIRAL DNA IS NOW BECOMING
ACTIVATED LEADING TO THE --
VIRAL DNA.
ULTIMATELY LEADING TO THE
RELEASE OF THESE VIRUS PARTICLES
IN THE GUT ECOSYSTEM.
AND WHILE THIS IS A BURDEN
BECAUSE PART OF THE POPULATION
IS BEING KILLED -- AT THE SAME
TIME WE FOUND THAT IN THE
VARIETY -- THAT THESE PROVIDE A
COMPETITIVE ADVANTAGE.
BECAUSE STRAINS THAT ARE IN THE
SAME NICHE AND COMPETING FOR THE
SAME NUTRIENTS CAN BE KILLED BY
THESE VIRUSES GIVING THE STRAIN
A COMPETITIVE ADVANTAGE.
AND FURTHER STUDIES TRY TO
UNDERSTAND WHAT THE TRIGGERS IN
THE GUT ARE THAT ACTUALLY LEAD
TO THE ACTIVATION OF THESE VIEW
VIRUSES.
WE FOUND THAT ACTUALLY DIETARY
-- FRUCTOSE AND ALSO FATTY ACIDS
PRESENT IN THE GUT ARE TRIGGERS
THAT ACTIVATE THESE VIRUSES.
LEADING TO THE -- -- -- WHAT WE
SEE IS THAT WHEN THIS HAPPENS
AND WHEN -- IT PASSES THROUGH
THE GI TRACT THAT APPROXIMATELY
80% OF THE BACTERIA ARE BEING --
LYSED BY THESE VIRUSES.
AND THAT WAS TO US INTRIGUING
SPECIFICALLY IN THE LIGHT THAT
THIS PROVIDES AN OPPORTUNITY TO
LEVERAGE VIRUSES.
WE HAVE A BACTERIAL STRAIN THAT
IS ENGINEERED VIRUSES ARE BEING
PRODUCED THEREBY RELEASING THE
THEY AR-- THERAPEUTIC PROTEIN.
WHEN WE USE A CHEMICAL WE SEE
THAT VIRUSES ARE PRODUCED AND
THE MORE CELLS THAT ARE LYSED
LEAD TO AN INCREASE IN THE
RELEASE OF THE PROTEIN AND THIS
IS DRIVEN BY VIRUSES BECAUSE IF
WE DO THIS SAME EXPERIMENT IN
BACTERIA THAT LACK THE VIRUSES
THAT DO PRODUCE THE PROTEINS
NOTHING HAPPENS.
SO TO USE VIRUSES NOW AND TO USE
THIS CONCEPT OF LYSIS HAS AN
ADVANTAGE OVER USING THE
CONVENTIONAL PATHWAY.
SO SINCE THE PATHWAY IS
ESSENTIAL TO THE BACTERIA CELL
YOU CAN IMAGINE NOW IF YOU ASK
THE CELL TO PRODUCE A LOT OF
PROTEIN THIS BECOMES A METABOLIC
BURDEN.
ANOTHER ADVANTAGE IS THAT THE
DESIGN IS SIMPLIFIED.
HAVING THE RIGHT PEPTIDE AND
HAVE THE DESIGN SUCH LEADING TO
EFFICIENCY CORRECTIOSUFFICIENT -- SECRETIO N.
WHAT THEY'VE SHOWN AND WE SEE
SIMILAR THINGS WITH OTHER CITO
KINDS.
THIS APPROACH WILL AVOID THAT
AND ALTHOUGH WE'RE QUITE A FEW
STEPS REMOVED FROM ALL
CONTAINMENT -- IT'S A STEP
TOWARDS CONTAINMENT.
8 SO WE HAVE THE LUXURY TO WORK
WITH SEVERAL -- COLLABORATORS
WHO ARE KNOWLEDGEABLE AND ONE OF
THESE COLLABORATORS IS FROM THE
UNIVERSITY OF CALIFORNIA SAN
DIEGO AND ONE OF THE EXPERTISE
WAS LIVER DISEASE.
IN THIS PARTICULAR MODEL WHAT
THEY ARE DOING IS THAT THEY HAVE
MICE THAT THEY FIELD A DIET THAT
IS ENRICHED IN ETHANOL.
THIS CONTINUOUS ETHANOL
CONSUMPTION LEADS TO THE --
DAMAGE TO THE LIVER CELLS AND A
PROXY FOR DAMAGED LIVER IS TO
MEASURE THE PRESENCE IN THE
BLOOD SCREAM.
THE MORE YOU HAVE IN THE
BLOODSTREAM THE MORE LIVER
DAMAGE THAT CAN BE LINKED TO
THAT.
IF YOU LOOK AT MICE THAT ARE
BEING FED WE SEE THAT THE LEVELS
ARE COMPARABLE BUT WHEN THEY ARE
PROVIDED WITH AN ENGINEERED --
WE SEE A SIGNIFICANT REDUCTION
IN THE AMOUNT OF ALT HERE.
THIS IS BASED ON LOCAL DELIVERY.
THIS IS LOCAL DELIVERY.
THEY WENT ON AND -- I'LL GO OVER
THAT HERE.
BUT OUR APPROACH HERE IS
FUNCTIONAL.
-- -- -- AS RADIATION ONCOLOGY
-- THEY HAVE A MODEL FOR TOTAL
BODIY RADIATION.
THIS IS THE SECOND EXAMPLE WHERE
THE ENGINEERED PRO-BIOTIC HAS
PROVEN FRUITFUL HERE AND IN THIS
PARTICULAR MODEL WHAT THEY DO IS
THEY EXPOSE MICE TO RADIATION,
THE RADIATION IS TO TISSUE
DAMAGE AND IF YOU DON'T DO
ANYTHING THIS TISSUE DAMAGE IS
EXPECTED TO REDUCE THE LIFE
EXPECTANCY OF THE ANIMAL.
RADIATION CAN BE ONE OF THE
TREATMENTS IN CANCER AND TO HAVE
MEANS TO REDUCE THE 6 -- THE
IMPACTS OF TISSUE DAMAGE ON
HEALTHY CELLS AND SPECIFICALLY
ON HEALTHY CELLS MEASURES ARE
NEEDED TO BASICALLY REDUCE THAT.
SO TO THE EXTENT IF YOU LOOK AT
THE DATA FROM THIS YOU SEE THAT
MICE LEFT UNTREATED AFTER 30
DAYS NEARLY ALL OF THE MICE
SUCCUMB TO THE RADIATION.
THE CONTROL HERE DOES NOT DO
MUCH TO THE SURVIVAL OF THE
ANIMALS BUT THE ENGINEERED
PRO-BIOTIC WE SEE HERE THERE IS
A SIGNIFICANT INCREASE IN THE
SURVIVAL.
AS A THIRD EXAMPLE -- WE HAVE
DONE THIS IN HOUSE.
AND WE SEE HERE THAT -- 22 IN A
MODEL OF DIET AND OH DEESE TEE
THE RELEASE -- LEADS TO THE
REDUCTION OF LIVER
TRIGLYCERIDES.
SO OVER-ALL I THINK IT'S PRETTY
EVIDENT THAT MAKING USE OF THE
MATERIAL VIRUSES TO -- PROTEIN
AND THE ENVIRONMENT IS
EFFICACIOUS IN THESE PRECLINICAL
MODELS.
HOWEVER FOR MOST OF THE
EXPERIMENTS THAT I'VE SHOWN YOU
HERE WE'RE RELYING ON THE
ENVIRONMENTAL TRIGGERS IN THE
GUT TO RELEASE THE THERAPEUTIC.
AND REALLY WE WOULD LIKE TO BE
IN A SITUATION THAT WE WOULD BE
IN CONTROL OF THE DETONATORS AND
ARE NOT RELIANT ON THE DIET OF
SUGAR OR FATTY ACIDS IN THE GUT
OR OTHER COMPONENTS IN THE GUT
ECOSYSTEM.
WE HAVE IDENTIFIED WHAT WE REFER
TO AS A -- AND THIS IS A SINGLE
GENE WHOSE ACTIVATION IS ENOUGH
TO ACTIVATE THE VIRUSES.
AND LEADING TO LYSIS.
AND THIS IS INDEPENDENT OF ANY
ENVIRONMENTAL TRIGGER OR
ACTIVATE OR BUT THIS EXPRESSION
OF THE SINGLE GENE AND TO SHOW
YOU A PROOF OF CONCEPT HOW WE'VE
LEVERAGED THAT WHAT WE'VE DONE
IS THAT WE HAVE CREATED A TRAINS
DESCRIPTIONAL INFUSION -- AND *
THIS IS A GENE OF INTEREST
LOOKED UP TO THE -- AND THIS IS
IN THE OFF STATUS.
WHAT WE SEE IS THAT IT NICELY
GROWS UP OVER TIME INCREASING
CELL DENSITY AND IF YOU LOOK AT
THE AMOUNT OF THE PROTEIN --
BARELY ANY LIE SIS AND THEREFORE
BARELY ANY RELEASE.
-- THE NICE THING ABOUT THIS IS
THAT IT TAKES ABOUT THREE HOURS
UPON THE ACTIVATION TO LEAD TO
LICE US OF THE CELLS AND THIS
THREE HOUR TIME WINDOW IS ENOUGH
PROTEIN BEING PRODUCED INSIDE
THE CELL.
AND WHAT WE SEE IS THAT AFTER
THREE HOURS THE CELL DENSITY
GREATLY DECREASES.
7 AND WHAT WE NOW SEE IS THAT WE
HAVE MICRO GRAM LEVELS OF
PROTEIN BEING RELEASED.
AND I THINK THIS IS ACTUALLY
EXCITING BECAUSE THIS PROVIDES
OPPORTUNITIES AND NOT ONLY TO
CONTROL THE RELEASE OF A
THERAPEUTIC UPON SENSING
ENVIRONMENTAL FACTOR WHETHER
THAT IS INFLAMMATION IN THE GUT
OR IN THE PRESENCE OF A TOXIN
FOR EXAMPLE THAT CAN ACTIVATE A
PROMOTER LEADING TO THE RELEASE
OF A PROTEIN AND I THINK THIS
MAY PROVIDE OPPORTUNITIES IF YOU
THINK OF DIAGNOSTICS THAT
PROMOTE OR LOOK FOR A PARTICULAR
DISEASE STATE IF YOU LIKE.
>> YOU HAVE ABOUT THREE MINUTES.
>> OKAY.
GREAT.
THANK YOU.
THESE ARE OPPORTUNITIES HERE
THAT WE'RE LOOKING FORWARD TO
LEVERAGE.
IN TERMS OF EFFICACY AND SAFETY
WE ARE WORKING WITH A GMO AND
ONE OF THE APPROACHES THAT WE
TAKE IS THAT WE'VE NOW DEVELOPED
A LINE -- WHICH DELETED 10 GAMES
AND THIS SO-CALLED -- IS
EXPECTED TO HAVE REDUCED
COLONIZATION POTENTIAL AND THIS
IS A PLATFORM WE WANT TO PREFER
TO DEVELOP TO DELIVER A
THERAPEUTIC MOLECULES.
AND I CAN SHARE THAT THIS --
MUTE ANNUAL AT LEAST IN A MODEL
OF IRRADIATION FOR OVARIAN
CANCER IN MICE HAS PROVEN
SUCCESSFUL AND IS COMPARABLE TO
THE EFFICACY OF THE WILD TYPES
SO THIS IS VERY EXCITING.
I ALREADY TOUCHED A BIT ON
BIOSENSORS SO I WILL NOT GO OVER
THAT IN DETAIL.
AND I ALSO WANT TO MENTION THAT
IN THE NEAR FUTURE BECAUSE WE
HAVE BEEN USING MICE FOR MOST OF
THE STUDIES WE HOPE TO LEVERAGE
THIS TO USE SOME LARGER ANIMALS
TO LOOK FOR PROOF OF CONCEPT AND
TO BETTER UNDERSTAND PHYSIOLOGY
AND THERAPEUTIC OF THE
PRO-BIOTIC AND FOR THAT WE WILL
BE USING A MINIATURE SWINE THAT
WE HAVE AVAILABLE ON CAMPUS.
VERY EXCITED TO SEE ONE OF OUR
PARTNERS -- WHO IS USING SOME OF
THE STRAINS THAT WE'VE DEVELOPED
AND THESE WILL BE TESTED SOON IN
NONHUMAN PRIMATES.
AND I'M REALLY LOOKING FORWARD
TO SEE WHAT WILL BE HAPPENING
WITH THESE EFFECTS AND LASTLY
BECAUSE I'VE BEEN BLOWING THE
HORN.
I THINK ONCE WE START TO LEARN
MORE ABOUT THE IMPACT OF
SPECIFIC ORGANISMS IN HEALTH AND
DISEASE ULTIMATELY THERE WILL BE
THE NEED TO INNER.
>> BACTERIA AND THERE WILL BE --
A GAP TO OVERCOME THERE IN TERMS
OF LACK OF TOOLS THAT ARE
AVAILABLE TO DO SO.
SO WITH THAT I AM FIRST OF ALL
GRATEFUL TO A GREAT TEAM OF
PEOPLE THAT I HAVE IN THE LAB
BECAUSE WITHOUT THEM I WOULD NOT
BE GIVEN THE OPPORTUNITY TO TELL
YOU THE STORY HERE.
I'M ALSO GRATEFUL FORth
ACADEMIC COLLABORATORS THAT I
MENTIONED EARLIER IN MY TIME
HERE.
FUNDING FROM INDUSTRY AND
GRATEFUL TO BE IN THE POSITION
TO DO WHAT WE LIKE TO DO AND
HOPEFULLY TO PUSH THINGS FORWARD
AND I'M THE OWNER AND FOUNDER OF
A CONSULTING COMPANY.
NONE OF THE WORK DISCLOSED HERE
TODAY IS RELATED TO THAT.
I THANK YOU VERY MUCH FOR YOUR
ATTENTION.
7
>> THANK YOU SO MUCH, J.P.
THAT WAS A GREAT TALK.
I'M GOING TO HAND IT OVER TO
KATHERINE AS WE HEAD INTO A
SHORT BREAK.
7
>> YES.
WE'RE GOING TO TAKE A QUICK
BREAK AND WE'RE GOING TO HEAD
OUT FOR A FIVE MINUTE BREAK.
AND SO WE'RE GOING TO COME BACK
VERY SPECIFICALLY AT
11:46
>> WELCOME BACK.
WE'RE READY TO START THE SECOND
HALF OF SESSION THREE AND I'M
GOING TO TURN IT OVER TO
DR. PADMA MARUVADA.
DR. MARUVADA, PLEASE TAKE IT
AWAY.
>> THANK YOU.
AND GOOD MORNING.
IT'S MY PLEASURE TO CO-LEAD THIS
SESSION WITH MY COLLEAGUE --
RYAN RANALLO AND I'M PLEASED AND
EXCITED ABOUT ALL OF THIS TALK
THAT WE'VE IN THE LAST -- --
YESTERDAY AND ALSO THIS MORNING.
SO WE ARE NOW CONTINUING WITH
THE CURRENT SESSION.
AND WE HAVE THE FIRST SPEAKER
TAMI LIEBERMAN FROM
MASSACHUSETTS AND SHE WILL BE
TALKING ABOUT INFERRING INHUMANE
BIOLOGY BY RECONSTRUCTING WITHIN
PERSON BACTERIAL EVOLUTION.
>> THANK YOU ALL.
AND THANK YOU TO THE ORGANIZERS
FOR HAVING ME HERE.
I ENJOYED THE TALKS.
MY LAB STARTED IN 2018 AND WE
FOCUSED ON HOW BACTERIA EVOLVE
AND I'M NOT TALKING ABOUT HOW
COMMUNITY COMPOSITION IS
CHANGING OVER TIME BUT HOW
INDIVIDUAL MICROBES ARE EVOLVING
AND MUTATING.
I DON'T HAVE ANY CONFLICTS TO
DECLARE.
AND THERE IS A LOT OF POTENTIAL
WITH EVOLUTION.
EACH OF US HAS ABOUT 10 TRILLION
BACTERIA IN AND ON US.
EACH HAS ABOUT A MILLION BASE
PAIRS AND EACH TIME ONE
REPLICATES THERE IS ABOUT A ONE
IN A BILL CHANCE OF CREATING A
MUTATION.
EVERY TIME THEY REPLICATE WHICH
IS MAYBE ONCE A DAY THERE ARE
BILLIONS OF MUTATIONS UPON WHICH
SELECTION CAN ACT AND IN MY LAB
WE USE THIS TO UNDERSTAND THIS
ADAPTATION BUT ALSO AS A GENERAL
LENS TO UNDERSTANDING
MICROBIOLOGY IN VIVO.
AND WE DO THIS BECAUSE LIKE A
LOT OF FOLKS HERE TODAY WE'RE
INTERESTED IN THIS BIG GOAL OF
HOW CAN WE ADD A MICROBE TO AN
ESTABLISHED MICROBIOME WITHOUT
BOMBING IT WITH -- ANTIBIOTICS.
.
AND IT COULD BE GENETICALLY
ENGINEERED OR NATURALLY
OCCURRING BUT THE BIG CHALLENGE
IS BEYOND AFTER IDENTIFICATION
WOULD BE UNDERSTANDING MY
COMMUNITY -- ECOLOGY TO PREDICT
THESE MICRO BIOMES.
WE'RE IN THE EARLY DAYS AND NOW
IS THE THIRD TIME YOU'VE SEEN
THIS GREAT EXPERIMENT WHERE --
IT IS GIVEN TO HEALTHY HUMANS
AND AFTER REMOVAL THIS BACTERIA
WAS NOT DETECTED IN MORE THAN
HALF OF THE PARTICIPANTS.
AND WHILE POST TALK THE AUTHORS
ARE ABLE TO SHOW SOME POSSIBLE
REASONS WHY THESE STRAINS --
WERE GRAFTED IN THESE
INDIVIDUALS AND NOT THESE IT'S
GOING TO BE IMPORTANT.
7 AND UNDERSTANDING WHEN SINGLE
STRAINS VERSUS MULTIPLE STRAINS
CO-EXIST IS ALSO GOING TO BE
IMPORTANT.
FOR SOME SPECIES EVERYBODY IS
COLONIZED BY A SINGLE STRAIN OF
THAT SPECIES BUT FOR A LOT OF
THE SPECIES IT'S MORE OFTEN THE
CASE THAT MULTIPLE STRAINS ARE
QUITE COMMON AND ON THE SKIN --
FOR THE TWO MOST DOMINANT
BACTERIA ON THE SKIN MULTIPLE IT
WILL STRAIN COLONIZATION IS THE
NORM.
AND ONE COULD SAY WHY ARE THERE
NOT INFINITE STRAINS ON THE
SKIN?
BEYOND THAT THERE IS A NUMBER OF
BASIC QUESTIONS WE STILL NEED TO
UNDERSTAND TO MANIPULATE MICRO
BIOMES.
WE NEED TO KNOW WHAT THE NICHE
RANGE IS.
DOES A BACTERIA HAVE ANY CHANCE
OF LIVING ON ME THAT LIVES ON
YOU.
WE KNOW THAT THE BIG PLAYERS ARE
GOING TO BE DIET AND IMMUNE
SYSTEM ARE GOING TO PLAY ROLES.
AND LASTLY IS WE DON'T KNOW WHAT
THE ROLE IS WITHIN EVOLUTION.
THEY ARE ALREADY ADAPTED TO SOME
UNIQUE SET OF FORCES WITHIN ME
AND SO MICROBE FROM THE OUTSIDE
ENVIRONMENT IS NOT GOING TO
STAND A CHANCE AGAINST THE
PREADAPTED MICROBE.
AND THE UPSIDE IS BY TRACKING IT
NOT ONLY DO WE LEARN ABOUT THIS
IMPORTANT FORCE BUT WE LEARN
SOME OF THE ANSWERS TO OTHER
QUESTIONS AS WELL.
AND IN PARTICULAR BY
RECONSTRUCTING WITHIN PERSON
EVOLUTION WE CAN RECONSTRUCT HAS
BACTERIA SPREADS WITHIN
INDIVIDUALS OR WITHIN A PERSON
AS JULIA MENTIONED AND ALSO BY
LOOKING AT WHAT GENES THEMSELVES
ARE CHANGING WE CAN UNDERSTAND
THE CHALLENGES TO BACTERIA
SURVIVORRAL IN VIVO.
GIVEN THIS GREAT POTENTIAL AND
MAYBE WHAT I'M SELLING IS THIS
GREAT TOOL YOU MIGHT BE ASKING
WHY YOU HAVE NOT HEARD ABOUT
MORE STUDIES ABOUT IN PERSON
EVOLUTION.
IF WE WANT TO STUDY EVOLUTION WE
MIGHT NEED TO GET DIFFERENT TIME
POINT SAMPLES.
AND WHILE LONGITUDINAL DATASETS
ARE GREAT WHAT WE'VE LEARNED
OVER TIME IS THAT CROSS SAMPLING
-- FROM A SINGLE PERSON CAN HELP
US PROJECT BACK INTO THE RECENT
PAST.
AND THE REASON THIS HAPPENS AS
-- BASED ON LESSONS WE'VE
LEARNED FROM FINISH FISHES
DISEASE WHEN ADAPTIVE MUTATIONS
ARISE WITHIN INDIVIDUALS THEY
OFTEN RISE IN FREQUENCY AND
REMOVE THEIR AN SEVENS FOR BUT
THEY COEXIST WITH OTHER ADAPTIVE
MUTANTS AND THIS COEXISTENCE
ALLOWS US TO PROJECT BACK INTO
THE PAST AND FOR RECENT WITHIN
PERSON EVOLUTION.
THERE IS A SECOND REASON AS WELL
WHICH IS TECHNICAL.
USING SEQUENCING WE'RE NOT GOING
TO GET THE WHOLE GENOME
RESOLUTION THAT WE NEED FOR
STUDYING EVOLUTION.
BUT ALSO METAGENOMICS IS QUITE
DIFFICULT AND I WANT TO
HIGHLIGHT THAT MORE.
WHEN WE'RE LOOKING FOR MUTATIONS
IN EVOLUTION WE WANT TO FIND
THESE VARIANTS THAT HAVE EMERGED
WITHIN A PERSON DUE TO DENOVO
MUTATIONS.
.
BECAUSE TWO DIFFERENT STRAINS
HAPPEN TO COLONIZE ON THE SAME
PERSON OR TWO DIFFERENT STRAINS
OF DIFFERENT SPECIES SHARE THE
SAME MOBILE ELEMENT.
AND THEN ONCE WE IDENTIFIED THE
MUTATIONS WE WANT TO KNOW WHICH
ONES IN THEIR THE SAME CELL AND
THIS CAN BE A HARD COMPUTATIONAL
PROBLEM.
SO WE DO OLD SCHOOL STUFF -- OF
SEQUENCING THEM INDIVIDUALLY.
WE PERFORM EVE LOSING NARY
RECONSTRUCTION.
THEY ARE INFERRED TO HAVE HAD
HAPPENED RECENTLY.
WE'VE GOTTEN THE LAB PROCESSES
DOWN PRETTY WELL AND IT'S LESS
THAN $20 FOR SEQUENCES AND
SAMPLE SET PERFECT ISOLETTE.
AND IN MY POSTDOC WE SET OUT TO
ANSWER ANY OF THESE MUTATIONS
THAT PROVIDE A SIGNIFICANT
BENEFIT AND WHEN WE LOOKED AT
THE COMMON GUT BUGS WE DEFINED
IN VIVO -- AND WITHIN THESE 12
PEOPLE WE IDENTIFIED MANY CASES
WHERE THERE WAS IN PERSON
EVOLUTION.
WITHIN PERSON -- SO ALL OF THESE
TIPS ARE ISOLETTES FROM THE SAME
PERSON.
WE IDENTIFIED GENES THAT WERE
MUTE INDICATED MULTIPLE TIMES ON
INDEPENDENT BRANCHES OF THESE
TREES AND THIS IS A STRONG
SIGNATURE OF ADAPTATION.
AND SO WE IDENTIFIED A BUNCH OF
GENES THAT HAD THE SIGNATURE OF
PARALLEL EVOLUTION AND IT TOLD
US THAT OURER MEMBRANE SYNTHESIS
GENES ARE GETTING DENOVO POINT
MUTATIONS THAT ARE PROVIDING
STRONG -- AND THIS WORK TELLS US
THAT IT'S IMPORTANT -- A PATHWAY
NOW WHERE WE CAN IDENTIFY GENES
THAT ARE IMPORTANT FOR SURVIVAL
IN VIVO BUT THESE BACTERIA MUST
BE EXPERIENCING SOME NEW
SELECTIVE FORCES.
AND THERE IS REALLY STRONG
SELECTIVE PRESSURES.
AND WHAT THIS MEANS THAT IS FOR
BACTERIA THAT HAS THIS PATTERN
WE MIGHT NEED TO HAVE
PERSONALIZED APPROACHES TO DRIVE
ENGRAPHMENT.
FOR EXAMPLE -- DRIVING THE
CHANGES MAYBE BEFORE WE GET
SOMEBODY A PRO-BIOTIC WE WANT TO
FIRST PROFILE WHICH ARE IN THEIR
GUT MICROBIOME.
IN THE COURSE OF THE STORY WE
WERE FORTUNATE YOU HAVE TO BEGIN
WITH EVERY DAY METRO GENOMICS TO
GET THIS DIAGRAM.
THERE ARE TWO COEXISTING SUB
LINEAGES -- WHICH COEXIST
THROUGHOUT THIS WHOLE TWO-YEAR
TIME PERIOD DESPITE THE FACT
THAT ONE HAS A LOT OF
COMPETITIVE DYNAMICS WITHIN IT.
SO THIS BLUE GENOTYPE IS ABLE TO
OUT PERFORM THE PURPLE WITHOUT
AFFECTING THE ORANGE.
HOWEVER BECAUSE WE'RE SAMPLING
FROM STOOL WE CANNOT TELL IF
THESE ARE NOT COMPETING BECAUSE
THEY ARE SEPARATING IN SPACE.
WE WERE FOCUSING ON THE SKIN
MICROBIOME.
AND WE'RE INTERESTED IN THE SKIN
BECAUSE IT ALLOWS US TO ANSWER
THESE QUESTIONS BUT ALSO A LOT
OF DISEASES WITHOUT GOOD ANIMAL
MODELS.
WE'VE BEEN FOCUSING ON THE OILY
SKIN OF YOUR FACE AND BACK AND
CHEST BECAUSE IT'S EASY TO
SAMPLE.
IT'S RELATIVELY LOW DIVERSITY.
WHERE WE CAN SEE -- A COUPLE OF
GENE US US DOMINATING.
AND IT'S REALLY A STABLE
MICROBIOME.
NOT JUST SOME SAMPLING FROM THE
ENVIRONMENT.
AND WE'VE BEEN FOCUSING ON -- A
DOMINANT BACTERIA IN SKIN WHICH
LIVES IN YOUR PORES.
IT'S ON EVERYONE.
AND IT'S ANAEROBIC.
SO IT PREFERS TO GROW ON THE
BOTTOM OF THE PORES WHERE THERE
IS A LOT OF NUTRIENTS.
AND WE PERFORMED A STUDY W WHERE
SET OUT TO ASK IF DIFFERENT
STRAINS ARE COEXISTING BECAUSE
OF ADAPTIVE OR NEUTRAL FORCES.
WE PERFORMED LARGE SAMPLING AND
FINE FACIAL SCALES.
AND USING THIS APPROACH WE WERE
ABLE TO SHOW AGAIN -- WHAT IS
ALREADY KNOWN IS THERE ARE MANY
C ACNES EXISTING.
YOU CAN SEE THERE ARE SIX
DIFFERENT STRAINS COEXISTING ON
THIS PERSON.
AND SHARE SIMILAR GENE CONTENT.
>> YOU HAVE ABOUT TWO AND A HALF
MINUTES
>> OKAY.
I'M GOING TO GO FAST.
THIS IS COMMON ACROSS ALL OF OUR
SUBJECTS.
WHEN WE SEE WHERE THESE LINEAGES
ARE -- WE DON'T SEE ANY SIG
GOINGS OR STRONG SEGREGATION FOR
THE SURFACE OR DEEPER WITHIN
PORES BUT WHEN WE ZOOM IN AND
LOOK AT THE LEVEL OF INDIVIDUAL
PORES WE SEE SOMETHING MORE
STRIKING.
-- -- WE EXPECT TWO RANDOM
COLONIES FROM THE SAME FOR TO BE
FROM THE SAME LINEAGE OR SAME
STRAIN ABOUT HALF OF THE TIME
BUT IN FACT WHAT WE FIND IS THAT
WE PICKED TWO COLONIES FROM THE
SAME POOR THEY ARE ALMOST FROM
THE SAME STRAIN.
SUGGESTING THAT THERE ARE
DIFFERENT MICROBIAL COMMUNITIES
ON EACH OF THESE ISLANDS ON OUR
FACE AND WHEN WE LOOK -- IF
NEARBY ISLANDS HAVE SAME
LINEAGE'S THEY DON'T.
SO MAYBE THIS IS SUGGESTING THAT
EACH CORE IS SELECTING THROUGH A
DIFFERENT TYPE OF STRAIN.
AND TO UNDERSTAND THIS WE CAN
ZOOM IN MORE TO LOOK WITHIN
STRAIN DIVERSITY AND THIS IS TO
A SCALE BAR THAT IS VERY SMALL.
DOZENS OF MUTATIONS AND WE CAN
SEE THAT EACH FOR IS QUITE
SEGREGATED ON THE TREE.
SUGGESTING THAT IT'S NOT JUST
FILTERING BUT THERE IS A VERY
RECENT ANCESTOR WITHIN EACH FOR.
AND WHERE ACROSS LINEAGES -- WE
SEE LOTS OF DIVERSITY AT THE
LINEAGE LEVEL WITHIN THE LINEAGE
LEVEL BUT A SMALL SEGMENT OF
THAT DIVERSITY WITHIN EACH FOR.
AND SO THIS TELLS US THAT THERE
IS SOME RECENT BOTTLENECK WITHIN
EACH FOR AND WE DETERMINE THAT
THIS IS NOT ADAPTIVE.
WE DO NOT SEE ANY SIGNATURES OF
ADAPTIVE EVOLUTION WHICH WE
WOULD EXPECT TO SEE.
SO THERE HAS GOT TO BE SOME
NEUTRAL DRIVER AND IT'S NOT JUST
TRIVIAL.
SO WE THINK WHAT WAS GOING ON --
PORES ARE CREATING STRONG
PRIORITY EFFECTS AND STRONG
BOTTLENECKS BECAUSE PERHAPS OF
THEIR PHYSIOLOGY.
AND BY THE TIME THE SECOND CELL
CAN COME IN THE FIRST CELL IS
ALREADY OCCLUDED THE SPACE.
WHAT THIS MEANS IS THAT THE
BACTERIA YOU GROWING FASTER EACH
OF THESE STRAINS AND EACH
GENOTYPE HAS ITS OWN LITTLE TEST
TUBE TO WORK IN AND DOESN'T
REALLY COMPETE WITH OTHER
STRAINS WHICH MIGHT BE MORE
ADVANTAGEOUS AND WHAT THIS MEANS
IN TERMS OF IMPLICATION FOR
POTENTIAL THERAPY IS THAT -- MAY
NOT MATTER SO MUCH AND WHAT WE
WANT TO DO -- IS FOCUS ON
REMOVAL OF THE STRAINS.
WE DON'T KNOW YET -- WE SEE
DIFFERENCES AND WHAT WE'RE
PROTECTS POSING IS THAT FACIAL
STRUCTURE IS ONE COMPONENTS BUT
THERE ARE OTHERS TOO AND
DETERMINING WHICH OF THESE
FACTORS IS IMPORTANT FOR HOW
MUCH ADAPTATION IS GOING ON WILL
HELP US UNDERSTAND WHEN WE MIGHT
USE PERSONALIZED APPROACHES IN
THE MICROBIOME.
I TRIED TO THANK THE KEY PLAYERS
BUT THIS WORK WAS HIGHLY
COLLABORATIVE AND THERE ARE MANY
INVOLVED.
AND I'M HAPPY TO TAKE QUESTIONS
DURING THE PANEL DISCUSSION.
THANK YOU.
>> THANK YOU, TAMI.
THAT WAS A POWERFUL TALK.
NOW WE'LL GO ON TO THE NEXT
SPEAKER DR. ERWIN ZOE ZANIDAKIS.
>> THANK YOU VERY MUCH.
.
>> THANK YOU VERY MUCH.
AND I WOULD LIKE TO THANK THE
ORGANIZERS FOR A FANTASTIC
PROGRAM THAT THEY ASSEMBLED AND
INVITED ME TO GIVE THE TALK AND
I WOULD LIKE TO FOCUS ON THE
NOVEL MICROBIOME.
YOU HAVE TO LOOK AT THE STRAINS
AND UNDERSTAND THEM AND SEE IF
THEY HAVE A POTENTIAL TO BE USED
IN THE FUTURE.
THIS IS WHAT WE'VE HEARD THESE
DAYS THAT GUT MICROBIOME IS VERY
IMPORTANT FOR US.
WE CREATE ABOUT 500 GRAMS OF GUT
MICROBIOTA WITH US.
EACH INDIVIDUAL HAS A UNIQUE
COMPOSITION AND THAT IS
RELATIVELY STABLE OVER TIME BUT
OF COURSE -- -- ISN' ---ANTIBIOTICS CAN
HAVE A HUGE EFFECT AND OF COURSE
DIETS.
BUT ALSO -- ---THAT -- YOU SEE
DISTANT MICR -- ---THERE ARE MANY
DEFINITIONS.
BUT IT COMES BACK TO THAT YOU
INGEST LIVE MICROBES AND THEY
HAVE ACTIVITY IN YOUR INTESTINE
THAT IS SUPPOSED TO BE
BENEFICIAL AND SOME STUDIES HAVE
SHOWN THE RESTRAINTS.
BUT IF YOU LOOK AT THE CURRENT
STRAIN COLLECTIONS THE MAJORITY
IS DERIVED FROM FOOD AND FOOD
COMPONENTS BECAUSE OF THE --
THAT WE CAN SAFELY USE THEM.
BUT THEY ARE SELECTED ON
SCALABILITY.
BECAUSE WHERE YOU HAVE TO MARKET
THEM YOU HAVE TO DELIVER THEM IN
BIG AMOUNTS.
SO THEY HAVE TO BE CULTURED AND
THEREFORE MANY OF THEM ARE --
TOLERANT.
OR SOMETIMES EVEN -- -- ---OR
EVEN SOME YEAST.
BUT WE'VE ALSO SEEN THAT THAT
THE EFFICACY IN TRIALS IT IS NOT
CONSISTENT AND ALSO -- --
DISEASES YOU SEE THE PRO-BIOTICS
ARE NOT REALLY HELPFUL OR CANNOT
DO -- -- THE ACTIVITY THAT'S YOU
HOPE FOR.
BUT WE ALSO KNOW THAT -- THERE
ARE MANY MICROBIOMES THAT HAVE
BEEN ASSOCIATED.
SO THERE IS A NEED FOR WHAT WE
CALL NEXT GENERATION PRO-BIOTICS
AND THAT IS WHY IN 2019 WE
ASSEMBLED A CONSORTIUM THAT WE
FOCUSED ON.
THE RESTRAINTS OF THE
MICROBIOMES IN THAT WE HAVE IN
THE GUT.
AND THE CONSORTIUM IS BASED ON
THE NUMBER OF ENTERPRISES -- --
AND -- WE STUDY DIFFERENT
ASPECTS OF THIS FOR EXAMPLE
GENERATION OF PRO-BIOTICS
CANDIDATES.
7 AND NEXT GENERATION
PRO-BIOTICS THAT ARE -- HUMAN
DERIVED BACTERIA THEY'VE BEEN
ASSOCIATED WITH A VARIETY OF
BENEFICIAL HEALTH EFFECTS.
AND THE SAME IS FOR -- WHICH WAS
MENTIONED BEFORE.
BUT YOU CAN LOOK AT -- EQOUL
PRODUCERS.
AND THE SAME OF THIS PROJECT IS
THAT WE ISOLATE AND CORRECT --
FROM THE HUMAN INTESTINE THAT
CAN BE USED IN THE NEXT
GENERATION OF PRO-BIOTIC.
THERE ARE SOME THINGS THAT YOU
HAVE TO KEEP IN MIND AND I'LL
BRIEFLY DISCUSS THEM AND THE
FIRST THING IS THAT YOU -- DEAL
WITH ANAEROBIC MICROORGANISMS.
YOU HAVE TO ISOLATE THEM.
AND THEN YOU WANT TO KNOW THEIR
ACTIVITY IN THE INTESTINE.
SAFETY ISSUES IN ORDER TO MARKET
THEM AND THEN PRODUCE THEM IN
LARGE SCALE AND WHAT MAKES ITS
COMPLEX IS THAT YOU NEED WAYS OF
STORING AND PACKAGING THEM AND
THAT IS SOME CHALLENGES.
-- FORGETTING THE ISOLATES THIS
IS THE WORK OF THE -- -- THE
APPROACH WHICH IS REALLY NICE
APPROACH WHERE YOU TRY TO
ISOLATE AS MANY AS POSSIBLE IN
THE -- HIGH THROUGH PUTNAMER AND
IT STARTS WITH USING -- A MEDIAN
THAT ALLOWSES MANY DIFFERENT
MICROBES TO GROW AND PICK UP THE
COLONIES AND IDENTIFY THEM --
BUT ALSO FOLLOWED BY -- --
SEQUENCE WHICH ENABLE YOU TO GET
AN IDEA -- AND IN THAT GROUP
THEY'VE MORE THAN A THOUSAND
ISOLATES FROM FECAL SAMPLES WITH
A LOT OF BACTERIA.
A HUGE DIVERSE COLLECTION.
THEY HAVE A LARGE COLLECTION OF
-- THE STRAINS WHICH WE SEE AS A
MODEL ORGANISMS FOR OUR PROJECT.
7 WELL IN OUR GROUP WE HAVE
ANOTHER WAY OF -- ISOLATING
MICROBES AND THAT IS A TARGETED
APPROACH.
WE TRY TO ENRICH MICROBES BASED
ON A FUNCTION.
8 AND SOME PREVIOUS WORK THAT
WE'VE DONE WAS FIRST WHEN I WAS
A STUDENT I WAS ABLE TO ISOLATE
AN ORGANISM -- WHICH -- ENDED UP
BEING AN ISOLATE FROM A PHYLUM
THAT WAS NOT KNOWN YET.
BUT WE HAVE 96 SAMPLES WHICH WAS
ISOLATED FROM TARGETING FROM
MUCUS -- IT WAS BEEN FREQUENTLY
STUDIED.
TRIALS HAVE BEEN ONGOING AND
IT'S TOWARDS LET'S SAY ONE OF
THE NEXT GENERATION OF
PRO-BIOTICS.
IT WAS RECENTLY ISOLATED -- LICE LICE
IN.
-- AND TO SEE THEIR POTENTIAL
FOR THIS NOVEL NEXT GENERATION
PRO-BIOTICS.
IN THIS PROJECT WE ALSO LOOKED
AT -- CAPACITY AND WHAT WE DID
HERE WAS WE USED ONE TYPE OF
MEDIUM AND WE ADDED A SINGLE OR
A MIX OF -- CARBON AND ENERGY
SOURCES THAT I BELIEVED WERE
ABLE TO -- IN THE BEAUT RATE
PRODUCTION.
AND ALSO PH CAN HAVE AN EFFECT.
WHEN YOU LOOK AT BUTYRATE
PRODUCTION, IT WAS REPORTED --
THAT YOU HAVE LOWER PH BUT WE
DID NOT SEE THAT.
WE SAW -- AN -- EFFECT ON THE PH
AND ALSO THE -- YOU SEE
DIFFERENCE THIS IS SOMETHING
THAT WE'RE WORKING ON AND WE'RE
TRYING TO ISOLATE SOME OF THESE
THAT WERE ENRICHED HERE.
AND NOW I WANT TO COME BACK TO
THE STRAIN COLLECTION THAT WE
HAVE IN OUR CONSORTIUM AND FOCUS
ON THIS.
AND -- I FIND IT NICE TO SHOW
SOME MICROSCOPIC PICTURES.
YOU SEE TWO STRAINS IN THE TWO
PICTURES AND YOU CAN SEE HOW
COMPLETELY DIFFERENT THEY LOOK.
IF YOU WOULD HAVE SAID THESE
WERE TWO DIFFERENT SPECIES
PEOPLE WOULD HAVE BELIEVED ME
BUT THESE ARE TWO STRAINS OF THE
SAME SPECIES.
SO I BELIEVE THAT THE STRAIN
DIVERSITY IS VERY IMPORTANT AND
WHEN YOU CULTIVATE THEM -- AND
HARVEST THEM AFTER 24 HOURS YOU
SEE THE METABOLIC PATHWAYS ARE
DIFFERENT.
WITH THE SECOND STRAIN PRODUCING
MUCH MORE BUTYRATE THAN THE
FIRST STRAIN.
INDICATING THE HUGE DIFFERENCE
IN THE CAPACITY OF JUST THE SAME
SPECIES BUT TWO DIFFERENT
STRAINS.
ONE EXPERIMENT THAT WE PERFORMED
IS THAT WE LOOKED AT WHAT
HAPPENS IF THE -- WE ADD THEM TO
THE FECAL -- CAN THEY ADAPT TO A
NEW ECOSYSTEM OR ARE THEY UNABLE
TO -- IN THESE COMMUNITIES.
WE -- THE SAME CONDITIONS.
WE MIMIX EDIT.
AND AND YOU CAN SEE THE PICTURES
-- YOU CLEARLY SEE THE
INDIVIDUALITY ON THE --
PRODUCTION BUT YOU SEE COMPARED
TO CONTROLS YOU DO NOT SEE A LOT
OF DIFFERENCES.
THAT IS SOMETHING THAT YOU DON'T
EXPECT -- BUT WHAT WE'RE NOW
TRYING TO SEE IS THE FOLLOWING
-- AND THAT IS BASED ON LET'S
SAY IN THE NICE PAPER FROM THE
GROUP THAT WAS PUBLISHED
RECENTLY.
YOU CAN CLASSIFY THEM IN THE
INTESTINE IN FOUR GROUPS.
BASED ON WHETHER THEY OCCUPY THE
NICHE OR IF THEY ARE ACTIVE.
WHICH IS SHOWN IN THIS PICTURE
-- WITH THE ORGANISMS -- -- AND
THE METABOLIC CAPACITY OR THEY
CAN BE -- -- AND HARDLY DO
ANYTHING.
8 CLEARLY FROM THE -- AT TH ---METABOLIC
LEVEL THEY ARE ON THE LOW LEVEL
BUT WE DON'T KNOW IF THEY ARE IN
HIGH NUMBERS OR LOW NUMBERS AND
THAT IS SOMETHING THAT WE STILL
HAVE TO FIND OUT BECAUSE MAYBE
THIS STRAINS TAKE OVER IN AN
EXISTING -- BACTERIA THAT IS IN
THE INTESTINE OF THE ORIGINAL
SAMPLE.
BUT THAT IS SOMETHING THINGS
THAT WE DON'T KNOW AND WE HAVE
TO STILL STUDY.
OTHER THINGS THAT WE ARE
STUDYING IS OF COURSE WHAT IS
THE IMPACT OF THE STRAINS AND
THE METABOLITES ON WHOLE CELL
VIABILITY AND ACTIVITY.
THAT IS DONE BY FECAL CELL --
AND WE WANT TO KNOW WHAT IS THE
ANTIBIOTIC RESISTANCE PROFILE.
SO THESE ARE ALL MORE TYPE OF
SAFETY THINGS THAT YOU HAVE TO
CONSIDER WHEN YOU WANT TO
GENERATE THE NEXT GENERATION
PRO-BIOTICS.
OTHER THINGS TO CONSIDER IS OF
COURSE THE PRODUCTION -- THAT
YOU NORMALLY WHEN WE STUDY THESE
MICROBES WE HAVE A MAXIMUM OF
50.
AND THE QUESTION IS OF COURSE DO
THE STRAINS BEHAVE THE SAME.
BECAUSE -- ANAEROBIC MICROBES
DON'T LIKE TO BE SHAKEN.
AND THIS IS SOMETHING THAT WE
WILL STUDY OF COURSE.
WHEN -- LONG TIME FOR HUMAN
CONSUMPTION YOU CANNOT USE AN
UNDEFINED MEDIUM SO YOU NEED TO
DEFINE A MEDIUM WITH SAFE
COMPONENTS AND THAT IS SOMETIMES
NOT EASY TO DO WHERE YOU HAVE
ISOLATES BECAUSE YOU HAVE NO
KNOW WHAT THEY NEED FOR THE
GROWTH ENVIRONMENT AND THAT IS
QUITE A LOT OF TESTING.
AND THEN OF COURSE IF YOU WANT
TO PUT THEM ON THE MARKET THERE
ARE STRICT -- HOW CAN WE PACKAGE
THEM AND HOW CAN THEY SURVIVE ON
THE SHELF OR EVEN WHEN THEY PASS
THE INTESTINE SO THESE ARE ALL
QUESTIONS THAT WE ARE STILL
BRAINSTORMING ABOUT AND DOING
THE FIRST EXPERIMENTS ABOUT WHAT
WE CAN DO HERE.
IN SUMMARY I THINK I SHOW THAT
-- A NICE SUCCESSFUL COLLECTION
OF MICROBES AND APPROACHES TO
HAVE SOME -- THAT ARE PROMISING
IN THE NexGenATION
PRO-BIOTICS.
THE PATH TO GET FROM AN ISOLATE
-- -- HAS SOME CHALLENGES.
78 ESPECIALLY SINCE THEY ARE
OFTEN ANAEROBIC.
AND THE FIRST SELECTION -- IS
NOW TAKEN AND VERY EXCITED ABOUT
IT AND ALSO IT'S NICE ALSO FROM
THE EXPERIENCE TO LEARN ABOUT
MICROBES ITSELF BECAUSE I FEELY
AGREE THAT IN ORDER TO
UNDERSTAND THE GUT MICROBIOME UM
WE NEED TO UNDERSTAND WHY WE
HAVE CERTAIN STRAINS PRESENT IN
SOME AND NOT OTHERS AND DIVE
INTO THIS TO UNDERSTAND WHAT IS
HAPPENING IN OUR GUT.
AND MY LAST SLIDE I WANT TO
THANK ALL OF THE PEOPLE WHO WERE
INVOLVED IN THE STUDY.
I WOULD LIKE TO THANK YOU FOR
YOUR ATTENTION AND WILL BE HAPPY
TO ADDRESS QUESTIONS.
>> THANK YOU, THAT WAS A VERY
NICE TALK.
SO NOW WE'LL MOVE ON TO THE LAST
BUT NOT THE LEAST TALK FROM
DR. RUSTEM ISMAGILOV AND HE WILL
BE TALKING ABOUT SMALL INTESTINE
AND MICROBES THAT ARE ESSENTIAL
FOR HUMAN HEALTH.
>> THANK YOU VERY MUCH.
CAN YOU CONFIRM THAT YOU CAN
HEAR ME AND SEE THE SCREEN?
>> YES.
VERY WELL.
>> WONDERFUL.
I'M ABSOLUTELY DELIGHTED TO BE
HERE AND HONORED TO BE HERE.
AND EVERYTHING I'M GOING TO SAY
IS ONLY POSSIBLE BECAUSE OF THE
GROUP OF TALENTED COLLABORATORS
IN THE LAB WHO REALLY DO ALL OF
THIS WORK AND ALSO FABULOUS
COLLABORATORS THAT WE'VE BEEN
FORTUNATE TO WORK WITH OVER THE
YEARS AND I'M EXTREMELY GRATEFUL
TO ALL OF THEM.
I WANT TO START OUT BY POINTING
OUT THE SIMPLE HYPE CYCLE THAT
APPLIES TO ANY NEW IDEA AND
TECHNOLOGY.
IT STARTS OUT AND GETS TO THE
EXPECTATIONS -- WHERE IT WAS
GOING TO CURE EVERY POSSIBLE
DISEASE AND SOLVE ALL KINDS OF
PROBLEMS AND THEN THE TROUGH OF
DISALLUSIONMENT.
AND SO, THAT IS ALL NORMAL AND
THEN THE REALLY INTERESTING
USEFUL PART HAPPENS HERE.
THE SLOPE WHERE YOU START --
WHAT IS POSSIBLE AND NOT
POSSIBLE AND HOW TO GET THERE.
AND I WOULD LIKE TO ARGUE THAT
THERE ARE SIX THINGS OR ADD TO
THIS LIST -- OF THE SIX THINGS
THAT I THINK ARE REALLY
IMPORTANT TO KEEP IN MIND AS
WE'RE CLIMBING UP THE SLOPE AND
MAKING PROGRESS.
JUST TO HIGHLIGHT DIFFERENT
PARTS OF IT AND THE FIRST POINT
IS IT'S REALLY SMALL INTESTINE
AND THE GUT MUCOSAL INTERFACE
THAT WE HAVE TO THINK ABOUT IN
ADDITION TO POOP.
IT'S REALLY A SIMPLE ARGUMENT.
ALL OF THE FOOD AND NUTRITION
THAT IS PROCESSED IN THE SMALL
INTESTINE.
THE FOOD IS ABSORBED HERE.
THE IMMUNE SYSTEM -- IS HERE AS
WELL.
AND IF YOU THINK ABOUT THE
SURFACE AREA IT'S OF THE SMALL
ENTRUSTMENT.
ABOUT 30 SQUARE METERS.
ABOUT THE SURFACE AREA OF A
TENNIS COURT.
IT'S ABSOLUTELY CRITICAL.
TO BE THINKING ABOUT THIS PART
OF THE SYSTEM NOT ONLY WHAT
COMES OUT HERE.
ALONG THESE LINES IF YOU WANT TO
THINK ABOUT HUMAN SMALL
INTESTINE YOU HAVE TO BE CAREFUL
WITH INTERPRETING MOUSE MODEL
RESULTS.
BECAUSE THEY EAT THEIR OWN POOP.
IT'S BEEN KNOWN FOR VERY LONG
TIME 50 YEARS OR MORE THAT THERE
ARE OLD PAPERS THAT DESCRIBE
THIS THAT EVEN IN THE STROMS OF
RODENTS THEY HAVE A VERY HIGH
LOAD AND IT DOESN'T DROP VERY
MUCH AND HUMANS -- YOUNG HEALTHY
HUMANS ARE DIFFERENT.
VERY LOW LOAD.
7 THAT IS KEY FOR US TO KEEP IN
MIND AS YOU CAN IMAGINE.
AND I ALSO WANT TO EMPHASIZE --
ONE POINT HERE IS OF COURSE THIS
CAN BE -- OLD LITERATURE OF HOW
TO DO IT.
IT'S NOT WHAT WE DO NOW --
DEVELOPED REALLY IMPORTANT WAY
OF TESTING THESE HYPOTHESIS BY
DEVELOPING THESE MECHANICAL TAIL
CUPS THAT PREVENT THE MICE FROM
EATING THEIR POOP.
AND WHAT IS NOT SHOWN HERE BUT
SHOWN IN THE PAPER -- WHICH I
ENCOURAGE TO YOU READ IS THAT
THE MICROBIOTA LOOKS VERY MUCH
MORE LIKE HUMAN.
RATHER THAN FECAL MICR MICROBIOTA IN
THE MOUSE.
WHAT IS REALLY IMPORTANT IS THAT
THE -- PROFILES COMPLETELY
DIFFERENT IN THESE MICE.
AND THE STANDARD APPROACH IS
SINGLE HOUSING OR WIRE FLOORS
ARE QUITE INEFFECTIVE AT LEAST
IN OUR HANDS.
THAT IS NOT A GLAMOROUS BUT
IMPORTANT RESULT.
ONE MORE POINT IS IF YOU ARE
DEALING WITH SYMPTOMS LIKE THIS
-- WHERE THE LOADS CHANGE BY
ORDERS OF MAGNITUDE YOU HAVE TO
BE QUANTITATIVE.
IT'S NOT ENOUGH TO SAY THAT
SOMETHING CHANGES FROM 2% TO
35%.
WE NEED TO KNOW HOW MUCH.
LET ME ILLUSTRATE BY A SIMPLE
POINT.
WE'RE DOING A STUDY WHERE IN A
HEALTHY COHORT -- IT'S 50/50 AND
THEN IN DISEASE IT'S 80/20.
THIS COULD MEAN LOTS OF THINGS.
AND IN FACT IT COULD MEAN THAT
TAX ON A WENT UP AND B DIDN'T
CHANGE.
OR IT COULD MEAN THAT BOTH OF
THEM WENT DOWN.
JUST THAT B WENT DOWN MORE THAN
A.
SO, THAT IS IMPORTANT WHEN
YOU'RE TRYING TO FORMULATE
HYPOTHESIS FROM YOUR ANALYSIS.
SO JUST TO SOLVE THIS PROBLEM --
THEY DEVELOPED A NICE METHOD
THAT ALLOWS YOU TO GET
QUANTITATIVE SEQUENCING DATA AT
LOW COST AND LOW EFFORT AND IS
PRACTICAL.
THEY'VE CHARACTERIZE EDIT VERY
WELL.
IT WORKS IN ORDERS OF MAGNITUDE
QUANTITATIVELY WITH HIGH
PRECISION OF ACCURACY AND WHAT
WAS IMPORTANT * TO KEEP IN MIND
THAT IT'S NOT A PROBLEM BECAUSE
HUMAN MITOCHONDRIAL DNA
OVERLAPS.
SO THERE IS INTERFERENCE MAKING
IT DIFFICULT.
I ENCOURAGE YOU IF YOU'RE
WORKING WITH SAMPLES TO USE THIS
METHOD TO LEARN MORE.
AND OF COURSE I WANT TO
ILLUSTRATE THIS WITH A COUPLE OF
EXAMPLES WHEN THINKING ABOUT THE
HUMAN.
ANOTHER REALLY NICE ASPECT IS
BECAUSE WE -- KNOW THE ASPECTS
OF THE HUMAN MITOCHONDRIAL DNA
-- -- QUITE LOW MASS CULTURAL
SAMPLES AND ONE EXAMPLE OF THIS
WAS -- A COLLABORATION -- IN THE
LAB -- AND HELPING TO GET
QUANTITATIVE HIGH QUALITY DATA.
FROM BIOPSIES FROM THESE
PATIENTS AND FOUND INTERESTING
ASSOCIATIONS BETWEEN -- ACTIVE
BASILLE AS -- * AND CELIAC
DISEASE.
THIS IS ALL PUBLICLY AVAILABLE
AND THERE IS AN PRINTOUT THERE.
FORTUNATE TO BE ABLE TO WORK
WITH THEM AND AS YOU PROBABLY
KNOW THEY HAVE THIS INCREDIBLE
STUDY WHERE THEY ARE ANALYZING
MICROBIOTA AND MANY OTHER --
THAN HUMANS.
THIS IS A STUDY OF 250
MICROBIOMES -- WITH QUANTITATIVE
MEASUREMENTS WHICH FOUND THERE
IS A SPREAD OF BACTERIAL LOADS
IN HUMANS AND YOU AS YOU MAY BE
WOULD EXPECT.
8 AND OF COURSE KNOWING THESE
NUMBERS ARE REALLY IMPORTANT
BECAUSE WE OFTEN THINK ABOUT A
REALLY PAY A LOT OF ATTENTION --
AND HOW CAN WE NOT PAY ATTENTION
TO -- SITES REALLY IMPORTANT TO
THINK ABOUT QUANTITATIVE
MEASUREMENTS IN THESE CONTEXT.
THERE IS HUGE DISTRIBUTION OF
LOADS OF INDIVIDUAL TAX OM.
AND THAT MANY OF THEM APPEAR TO
BE ORALLY THRIVED AND IT'S NOT
CONTAMINATION.
GONE TO GREAT PAINS TOGETHER TO
MAKE SURE IT'S NOT THE MODEL OF
CONTAMINATION.
8 AND THIS IS DESCRIBED IN THE
PAPER.
WE FOUND THIS QUANTITATIVE
MEASUREMENTS ALLOWED US TO LOOK
AT NEW TYPES OF ANALYSIS.
SO-CALLED DISRUPT OR ORGANISMS
THAT OVER GROW SIGNIFICANTLY --
-- AND DISRUPT THE REST OF THE
MICRMICRO BUYMIKE-- MICROBIOTA.
AND THERE WAS ANOTHER GROUP OF
DISRUPTORS THAT ARE RARE BUT
WHEN THEY HAPPEN THEY HAPPEN AT
HIGH LEVELS AND ALMOST ALL OF
THEM WERE -- -- SO REALLY NOT
SOMETHING THAT WAS -- HOPING TO
FIND IN THE HUMANS THAT WERE
WALKING AROUND BUT THAT IS WHAT
IT IS AND WE HAVE TO TO BE
THINKING ABOUT HOW THESE KINDS
OF LIKELY PATHOGENIC ORGANISMS
AFFECT HUMAN HEALTH.
AND JUST ONE GLIMPSE OF THESE
RESULTS WERE WE SHOW THAT AGAIN
THESE DISRUPT OR O I WILLS BOTH
DRIVE THE GI SYMPTOMS AND THE
DETAILS ARE DESCRIBED IN THE
PAPER.
AND THAT WAS IN COLLABORATION
AND -- WONDERFUL STUDY.
I WANT TO COME BACK TO THE POINT
THAT GARY WAS MAKING EARLIER
ABOUT -- BALANCE AND TALK ABOUT
THIS FOR A SECOND.
WE DO FIND THAT IN THESE SYSTEMS
THERE IS A VERY GOOD CONCORDANCE
BETWEEN AEROBE -- AND THESE ARE
MIXED COMMUNITIES.
THIS GETS ME TO THE FOURTH POINT
THAT IS THE CONTROL OF THESE
SYSTEMS CAN BE REALLY DIFFICULT
BECAUSE THEY CAN SHOW BIZARRE
BEHAVIORS THAT DEFY OUR LOGIC
AND SCIENTIFIC APPROACH.
TAMI -- WORKING WITH MANY OTHER
-- PEOPLE -- DEMONSTRATED THAT
EVEN SIMPLE COMMUNITIES CAN SHOW
THIS WEIRD BEHAVIOR -- AND THESE
SYSTEMS ESSENTIALLY REALLY GET
STUCK AT HIGH OR LOW LEVEL AND
THERE IS ALMOST NOTHING THAT YOU
CAN DO TO PUSH IT BETWEEN THESE
TWO STATES AND I DON'T HAVE TIME
TO DESCRIBE IT IN DETAIL BUT
IT'S PUBLISHED IN THIS PAPER.
BUT IT HAS IMPORTANT
IMPLICATIONS ABOUT THINKING
ABOUT CONTROL AND STUDY OF HUMAN
MICRMICROBIOTA BECAUSE CONTROL IS
DIFFICULT.
THERE IS ALMOST NOTHING THAT CAN
GET YOU TO PUSH THE SYSTEM
BETWEEN THESE TWO STATES UNLESS
YOU TAKE IT WAY OUTSIDE AND THE
SCIENTIFIC STUDY BECOMES VERY
DIFFICULT BECAUSE SMALL
PROHIBITIONS IN A WE DOO-DOO
NOTHING AND WE'LL MISS THE
IMPORTANT FACTORS THAT CONTROL
THE SYSTEMS FOR THIS REASON.
*.
DEMONSTRATED THAT -- THAT THESE
ARISE FROM CARBON/OXYGEN
BALANCE.
NEED TO UNDERSTAND WHAT WAS
HAPPENING AND IT'S NOT ENOUGH TO
HAVE NAMES OF MICROBES.
WE NEED TO HAVE GENOMES AND HAVE
MORE MUCH INFORMATION.
AND THAT IS CHALLENGING.
THERE IS GREAT WORK THAT HAS
BEEN DUNGEONING TO GET METRO
GENOMES OUT OF POOP AND 90% --
HOWEVER IF IT'S SOMETHING THAT A
BIOPSY THAT THE LAB CAN OBTAIN
FROM A PATIENT -- AND IT'S
MOSTLY HOST AND THIS IS
TECHNICALLY VERY CHALLENGING BUT
EXCITED TO SAY THAT -- THEY'VE
BEEN ABLE TO SOLVE THESE
PROBLEMS.
THEY ARE NOW BEGINNING TO GET
SHOTGUN DATA FROM THESE BIOPSIES
THAT ARE ECONOMICAL AND WE CAN
DO LODGE TIED NATURAL STUDIES
ALONG THE GI TRACT AND WE CAN
SEE -- A LOT ABOUT STRAINS AND
HOW STRAINS VARY ACROSS
PATIENTS.
AND THIS IS JUST A QUICK
ANALYSIS.
WE CAN ALSO GET TO THESE VERY
EXCITING RESULTS WHERE WE START
RECONSTRUCTING GENOMES.
8 BUT JEFF WAS TALKING YESTERDAY
-- AND IT'S A COLLABORATION --
VERY EXCITING AT MANY LEVELS.
THIS IS SHOWING THAT THE
RECONSTRUCTION -- -- META
GENOMES FROM HUMAN BIOPSIES THAT
ALLOW US TO LOOK AT THE STRAINS.
AND WHAT IS GOING TO BE REALLY
EXCITING IS GOING BACK TO THE
CELIAC DATA AND SAYING WE KNOW
THERE IS ACTING BASILLE ARIAS.
-- HOW DO WE REALLY BEGIN TO
FORM MAK -- A MAKE USIC -- -- *.
THIS BRINGS ME TO MY LAST POINT
-- ABOUT SPATIAL STRUCTURE AND
IMAGING.
.
AND AGAIN VERY CHALLENGING --
PROBLEMS THAT WE'VE BEEN
THINKING ABOUT THIS AND IT TOOK
A LONG TIME BUT IT'S MOVING
FORWARD.
THEY'VE DEVELOPED APPROACHES
THAT ALLOW US TO DO 3-D --
IMAGING WHILE PRESERVING THE
MICROBIAL GOLD THAT IS ATTACHED
TO THE SURFACE.
THE LAYERS -- AND UNDERSTAND THE
SPATIAL GRADING THAT GARY WAS
TALKING ABOUT.
THAT PAPER JUST CAME OUT AND I
ENCOURAGE TO YOU LOOK AT IT.
WE ALSO OF COURSE THESE METHODS
ALLOW TO YOU LOOK AT THE HOST
CELLS
THE IMMUNE CELLS AND THE ANATOMY
DAMAGE AND THE INFRASTRUCTURE
AND THE MICROBES AS WELL.
AND I'M EXTREMELY GRATEFUL FOR
THEIR WORK.
MY LAST SLIDE.
THE POINTS THAT WE NEED TO KEEP
IN MIND.
THINK ABOUT THE SMALL INTESTINE.
THE GUT MUCOSAL INTERFACE.
IF THE TOTAL LOAD CHANGES YOU
MUST USE QUANTITATIVE TOOLS.
CONTROL IS DIFFICULT BECAUSE
THERE ARE ALL KIND OF CRAZY
BEHAVIORS THAT WE WILL SEE.
WE HAVE TO THINK ABOUT THEM WHEN
WE DESIGN PRO-BIOTICS.
WE NEED TO LOOK AT STRAINS AND
GENOMES.
AND OF COURSE 3-D STRUCTURE IS
GOING TO GIVE US AN INCREDIBLE
VIEW OF HOW THE INTERACTION IS
TAKING PLACE.
I APPRECIATE YOUR ATTENTION AND
THE CHANCE TO SPEAK.
>> A FANTASTIC TALK.
I REALLY GIVE A BIG SHOUT OUT TO
THE SPEAKERS IN THIS SESSION AND
NOW WE WOULD LIKE TO MOVE TO THE
DISCUSSION PART.
THAT IS THE MOST EXCITING PART
OF THE WHOLE THING.
SO RYAN WILL LEAD THE --
DISCUSSION
>> THANK YOU EVERYONE.
THAT WAS REALLY GREAT.
PADMA AND I ARE GOING TO GO BACK
AND FORTH AND ASK QUESTIONS.
AND AGAIN I'LL ENCOURAGE THE
VIDEO CAST FOLKS TO SUBMIT
QUESTIONS.
THEY'VE BEEN ENTERED INTO THE
CHAT.
I'M GOING TO START OFF WITH A
REALLY A GENERAL QUESTION THAT I
THINK ENCAPSULATES THIS
WORKSHOP.
AND WHAT I'M GOING TO DO IS I'M
GOING TO ENCOURAGE OUR PANELISTS
AND I WON'T CALL ON YOU IF YOU
DON'T FEEL LIKE SAYING ANYTHING
BUT THEY ALL HAVE DIFFERENT
PERSPECTIVES OR SIMILAR
PERSPECTIVES AND IT'S THE
QUESTION THAT ONE OF OUR
PREVIOUS SPEAKERS HAD TALKED
ABOUT.
AND HIS QUESTION IS AND MY
QUESTION TO EVERYBODY AND YOU
CAN RAISE YOUR HAND OR JUMP
RIGHT IN -- HOW DO WE DEFINE
NEXT GENERATION PRO-BIOTICS?
AND THERE HAS BEEN SOME UNIQUE
PERSPECTIVES IN THE CHAT AND I'M
GOING TO OPEN IT UP WITH THIS
QUESTION.
>> MAYBE I CAN JUMP IN BECAUSE I
THINK IT WAS MENTIONED IN MY
TALK -- I SEE NEXT GENERATION
PRO-BIOTICS IS THAT -- IT'S
STRAIN DERIVED FROM THE HUMAN
INTESTINE OR THE HUMAN SKIN AND
THAT YOU FOCUS ON TARGETING MORE
OF THE FUNCTION OF HEALTH OR
RELATED TO HEALTH.
CLASSICALLY IT WAS MORE FOOD
DERIVED ORGANISMS THAT MIGHT
HAVE AN IMPACT AND NOW IT'S MORE
I THINK TARGETED FOCUSED ON THE
FUNCTION AND THAT THEY ARE FROM
THE ECOSYSTEM.
BUT YOU WANT THEM TO HAVE A
FUNCTION.
>> THAT IS GREAT.
GO AHEAD, GARY.
PLEASE.
>> SO SO MY COMMENTS ACTUALLY A
LITTLE BIT MORE SIMPLE.
I WOULD LIKE TO SEE PROOF OF
CONCEPT THAT THIS ACTUALLY IS
GOOD FOR HEALTH.
THAT IT ACTUALLY IMPROVES
HEALTH.
JUST THE NOTION OF A PRO-BIOTIC
WHETHER ALIVE OR DEAD OR
METABOLITE.
I THINK WE AGAIN I TRY TO
EMPHASIZE THE FACT -- WONDERFUL
SCIENCE AND WE'VE LEARNED A LOT
AS A FIELD LARGELY IN ANIMAL
MODEL SYSTEMS BUT EXAMPLES IN
HUMAN PHYSIOLOGY WHERE CHANGING
THE MICROBIOTA IS BENEFICIAL ARE
LARGELY LACKING SO MY MOTIONS
THAT THE CORNER STONE OF A
DEFINITION FOR NEXT GENERATION
ROW BIOTIC IS SOMETHING THAT
ACTUALLY IMPROVES HUMAN HEALTH.
TREATS OR PREVENTS THE DISEASE
IN A WAY THAT THE CURRENT
GENERATION OF PRO-BIOTICS ARE
NOT ABLE TO DO.
>> THANK YOU, GARY.
TAMI.
>> MAYBE I'M THINKING THIRD A
GENERATION AFTER THAT.
SO I TOTALLY AGREE WITH WHAT HAS
BEEN SAID SO FAR.
BUT GOING FORWARD I THINK THERE
ARE A BUNCH OF MICROBE THAT'S
WERE DISCUSSED YESTERDAY THAT
ARE NOT GOING TO CURE DISEASES
BUT WOULD MAYBE PROMOTE HEALTH
AND PREVENTS DISEASES.
BACTERIAS THAT CAN PREVENT
KIDNEY STONES.
THERE IS A LARGE NUMBER OF THESE
OUT THERE THAT IF WE HAVE A
LITTLE BIT OF EACH OF THESE
DIFFERENT MICROBES MAYBE THEY
WOULD PROMOTE HEALTH.
A SYSTEM IN WHICH WE TAKE EACH
OF THOSE LARGE COCKTAILS EVERY
DAY TO PREVENT DISEASES THAT IS
PROBABLY NOT GOING TO HAPPEN OR
AT LEAST WOULD BE VERY
EXPENSIVE.
SO DRIVING ENGRAPHMENT AND
HAVING MIKE JOBS THAT LIVE
LONG-TERM IS GOING TO BE
IMPORTANT.
IT'S GOING TO INVOLVE SCIENCE
AND POLICY AND HOW TO ENCOURAGE
THE DEVELOPMENT OF DRUGS THAT
ARE NOT TAKEN ON A DAILY BASES
BUT I THINK THAT CAN HAPPEN.
7
>> THAT'S GREAT.
THANKS, TAMI.
J.P.
>> SO I THINK WHEN I THINK ABOUT
THE TERM NexGen ROW BIOTICS
MY NEXT THOUGHT WOULD BE WHAT IS
A PRO-BIOTIC.
THE HEALTH BENEFITS.
IT SHOULD HAVE BEEN ESTABLISHED
AND WHEN I THINK OF THE NEXT
GENERATION THIS IS ACTUALLY
STARTING FROM THE ORIGINAL
PRO-BIOTIC WHEREBY THE ORGANISM
EATER IS ENGINEERED TO HAVE A
MORE BENEFICIAL EFFECT OR TAKING
SOME OF THE ECOLOGICAL
PRINCIPLES AND TAKING IT INTO
CONSIDERATION FOR THE EFFECT OF
THE PRO-BIOTIC.
BRIEFLY COMMENTING ON WHAT --
WAS SAYING IN TERMS OF
ENGRAPHMENT AND IT DEPENDS ON
WHO YOU ASK.
ENGRAPHMENT IS NOT A REQUIREMENT
FOR PRO-BIOTIC EFFICACY.
LOOKING AT THE PRECLINICAL
MODELS WHEREBY MOST PRO-BIOTICS
THAT YOU FEED THE ANIMAL WILL
PASS THROUGH AND DO NOT
COLONIZE.
YET THERE ARE THESE FUNCTIONS
THAT YOU SEE IN RELATION TO
LIVER DISEASE ETC.
SO ENGRAPHMENT WOULD NOT BE A
REQUIREMENT FOR BEING A
PRO-BIOTIC.
BUT THAT IS JUST MY TWO CENTS.
>> EVERYBODY IS GOING TO COME AT
THIS DIFFERENTLY SO THIS IS A
GREAT QUESTION.
GO AHEAD, JUNE.
PLEASE.
>> AS THE I'M
>> JUST OF THE GROUP I THINK --
* NexGen PRO-BIOTICS IT
SHOULD CONSIDER THE IMMUNE
EFFECT.
ONE OF THE MAJOR THINGS THAT IGA
DOES TO CANADA IS THAT IT HELPS
CANADA STICK AROUND IN THE GUT
SO YOU NEED THE APPROPRIATE IGA
RESPONSE TO STAY THERE AND IT
DOESN'T NECESSARILY AFFECT
CANADA LOADS BUT IT EFFECTS THE
LOADS OF CANADA.
SO WHEN THERE IS A CERTAIN IGA
RESPONSE THAT KEEPS CANADA AWAY
FROM THE MUCOS A BUT IT CAN
STILL COLONIZE -- MOST PEOPLE
ARE FAMILIAR WITH -- THE WORK --
IT REQUIRES AN IGA RESPONSE.
8 IN MY OPINION I THINK THAT WE
REALLY NEED TO THINK ABOUT HOW
THE IMMUNE SYSTEM IS GOING TO
PRUNE THAT PARTICULAR PRO-BIOTIC
THAT WE'RE GOING TO GIVE AND IN
FACT WE MIGHT BE ABLE TO NOT
ONLY USE VACCINATION STRATEGIES
TO GET RID OF MICROBES THAT WE
DON'T WANT BUT WE MIGHT BE ABLE
TO USE VACCINATION STRATEGIES TO
ENHANCE COLONIZATION OF MICRO
THAT'S WE WANT TO STAY IN THE
GUT.
>> THAT IS WONDERFUL.
WE HAVE AN IGA QUESTION CUED UP.
>> LET'S FINISH UP WITH JULIA.
>> BEING PURE MICROBIOLIGIST I
HAD A POINT SIMILAR TO JUNE'S
THAT I THINK THERE IS A LOT MORE
THAT NEEDS TO GO INTO THE MODEL
INSTEAD OF JUST THINKING ABOUT
THE SKIN STATUS OF SKIN BARRIER
THE RESIDENT IMMUNE CELLS.
I THINK OF PRO-BIOTICS AS EVEN
MORE DIFFICULT IN MANY WAYS THAN
THE HUMAN PRECISION MEDICINE
TARGETING OF THE CLASSICAL
GWINNETT CALL VARIANCE.
THERE SHOULD BE A * DIAGNOSTIC
PANEL OF SOME OF KIND TBD THAT
ALLOWS BETTER SELECTION OF A
PRO-BIOTIC STRAIN -- I'M A GAIN
OF SOME OF THESE EMERGING
TRANSPLANTS.
ENGINEERING MICROBES OBTAINED
FROM AN INDIVIDUAL TO RESTORE
MISSING FUNCTIONS BUT AN
IMPLANT.
SO YOU'RE NOT PERFECT TUBING A
LOT OF THE ASPECTS OF THE
SYSTEM.
BUT GIVING SOMETHING THAT IS
SIMILAR TO WHAT THE ECOSYSTEM
HARD HAS.
-- ALREADY HAS.
8 I AGREE WITH GARY'S POINT.
SOMETHING THAT WORKS PLEASE.
THAT IS THE FIRST -- THAT I HAVE
TO AGREE WITH TOO BEFORE WE GET
INTO THE SCIENCE PROJECT
>> YOU THANK YOU.
I APPRECIATE THAT.
TAKING THE MODERATOR ROLE A
LITTLE TOO FAR.
HOW THEY ARE USED.
TO YOUR LAST POINT.
HOW ARE THEY USED?
AND I'LL HAVE A PREAMBLE TO A
QUESTION ABOUT SEQUENTIAL
ADMINISTRATION OF PRO-BIOTICS.
RIGHT IN THAT REALM OF WHAT A
NEXT GENERATION PRO BUY OATIC
MAY OR MAY NOT BE
*.
>> SO -- -- ---A FEW POTENTIAL
PRO-BIOTIC IN THE MAKING.
-- -- CAN WE EXPECT THIS TO BE
THE -- THE LOW HANGING FRUIT.
PRO-BIOTICS THAN -- IN THE NEAR
FUTURE.
OR ARE THERE OTHER PRO-BIOTICS
IN THE WORKS.
-- ANYBODY WANT TO CHIME IN
THERE?
--
>> I CAN START OFF WITH JUST MY
VIEW.
IN GENERAL THIS FIELD IS NOT
REALLY LOW HANGING FRUIT EXCEPT
FOR OUR FOR EXAMPLE JUST --
INFECTION WHERE WE HAVE A ROAD
MAP BECAUSE WE KNOW IT'S A
PROBLEM.
FMT WORKS.
YOU WANT TO REDUCE IT TO
SOMETHING THAT CAN BE
MANUFACTURED FOR THE REVENGE OF
THE INFECTION.
I ALSO THINK THERE ARE OTHER
EXAMPLES IN HUMAN DISEASE.
SMALL INTESTINAL BACTERIAL OVER
GROWTH.
COLONIZATION WITH ANTIBIOTIC
RESISTANT ORGANISMS.
WE KNOW THAT THESE ARE PROBLEMS
AND THERE ARE SOME EXAMPLES FOR
TREATMENT OF THESE DISORDERS BUT
MAYBE A POSITION PRO-BIOTIC
WOULD BE BETTER.
SO WE USE THEM TO TREAT SMALL
BACTERIAL INTESTINAL OVER
GROWTH.
COLONIZING INDIVIDUALS THAT HAVE
ORGANISMS.
SO, THAT IS SORT OF LOW HANGING
FRUIT BUT NOT BECAUSE WE DON'T
HAVE THE POSITION PRO-BIOTIC TO
TREAT THAT BUT WE KNOW THAT IS A
MICROBIAL PROBLEM AND WE KNOW
THAT CHANGING THE MICROBIOTA IN
SOME WAY CAN BE BENEFICIAL.
SO I THINK LIKE THE NEXT
GENERATION BEYOND THE TREATMENT
OF -- WOULD BE ALONG THAT TIER.
THINGS THAT ARE MORE DIFFICULT
-- AND I USED IT BECAUSE IT'S
MUCH MORE COMPLEX AND PROBABLY
MUCH MORE CHALLENGING .
IT DOESN'T MEAN THAT IT'S NOT --
-- AND THAT IS MY COMMENT.
WE CAN PROBABLY MOVE FORWARD
WITHOUT KNOWING EVERYTHING ABOUT
THE SYSTEM.
YOU JUST HAVE TO KNOW ENOUGH TO
MAKE AN EDUCATED HYPOTHESIS
ABOUT WHAT THE NEXT STEP WOULD
BE.
>> I AGREE WITH WHAT GARY WAS
JUST SAYING.
THAT IT'S -- I ALSO DON'T SEE IT
AS A LOW HANGING FRUIT.
ALSO BECAUSE OF THE POINTS HE
MENTIONED BUT IN ADDITION TO WE
ARE DEALING WITH 8 SOME TIME
STRICT -- ANAEROBIC MICROBES.
7 THE CLASSICAL PRO-BIOTICS IF
YOU WANT TO PRODUCE THEM AND
KEEP THEM ALIVE IT'S MUCH EASIER
AND ALSO THE SCALABILITY.
BUT THAT IS REALLY A CHALLENGE.
7 A CLASSICAL WAY OF -- TURN
THEM KNEEPADERS THAT YOU CAN
USE.
SO THERE ARE REALLY A LOT OF
CHALLENGES SO KEEPING THEM ALIVE
IF THAT IS NEEDED.
ALSO ONE OF THE THINGS THAT WE
SHOULD LOOK AT THIS FOR EXAMPLE
THAT WAS ALSO GARY SAYING THAT
FOR INSTANCE -- PASTEURIZED THAT
WORKED VERY WELL.
THERE IS STILL A LOT -- IT'S
PROMISING AND WE'RE ON THE WAY
BUT THERE IS A LONG ROAD TO GO
TO COME TO REALLY SOMETHING THAT
YOU CAN APPLY TO LET'S SAY A
LARGE HUMAN POPULATION.
THE HOLY GRAIL TO PREVENT OR
CURE SOMETHING.
>> IT MIGHT BE TAKING SOME OF
THE PRO-BIOTICS THAT HAVE NOT
WORKED SO FAR IN IBD AND START
ADMINISTERING THEM DURING
REMISSION.
GARY WOULD MENTIONED THIS THIS
MORNING DURING HIS TALK IN
TRYING TO CHANGE THE MICROBIOTA
WHEN THE HOST IS ACTIVELY
SCULPTING THE ENVIRONMENT
AGAINST PRO-BIOTIC THAT YOU'RE
TRYING TO ADMINISTER.
IS NOT SURPRISING BUT THAT HAS
NOT WORKED.
TRYING TO CHANGE THE PARADIGM
AND DO THE HARD CLINICAL TRIALS
OF ADMINISTERING PRO-BIOTICS
DURING REMISSION SOUNDS TO ME I
DON'T KNOW IF ANYONE IS DOING
IT.
I'M NOT AWARE IF THAT IS BEING
DONE YET AND I WANT TO ECHO WHAT
GARY MENTIONED THIS MORNING.
>> THANK YOU.
>> I ALSO WANTED TO JUST REMIND
EVERYONE OF THE SLIDE THAT GARY
HAD IN HIS MARVELOUS KEYNOTE.
I UNDERSTAND STANDARD WHAT
KEYNOTE MEANS ONCE I HEARD HIS
TALK.
SO THIS WAS PERFECT.
THE POINT ABOUT COME PANS
DIAGNOSTICS AND MATCHING THE
RIGHT PERSON WITH THE RIGHT
PRO-BIOTIC COULD BE EXTREMELY
POWERFUL.
FINDING THE MATCH.
SO, ITS JUST LIKE IN CANCER ON
AVERAGE THINGS DON'T WORK BUT
FOR SPECIFIC PEOPLE THAT YOU CAN
IDENTIFY THEY WORK PRETTY WELL.
SO ONE OF THE SCIENTIFIC
QUESTIONS IS TO ME IS ARE WE IN
THAT SITUATION OF PRO-BIOTICS.
IS THERE SOMETHING OUT THERE.
WE JUST DON'T KNOW HOW TO MAKE
THE MATCH.
AND OPTIMISTICALLY THAT WOULD BE
GREAT BECAUSE MEASURING THINGS
IS EASIER THAN DOING MEDICINE
FROM SCRATCH AND FINDING MATCHES
IS EASIER THAN DEVELOPING
THERAPEUTICS.
IT'S AN OPEN QUESTION THAT
SHOULD BE ANSWERED.
>> RYAN.
7
>> I WANT TO GO BACK TO WHAT
GARY SAID AS WELL IN A DIFFERENT
WAY.
BUT TO THINK ABOUT WHAT WE'RE
TALKING ABOUT -- I MENTIONED THE
WAY IN WHICH WE USE THEM IN AND
THE IDEA OF STAGING THE
INTERVENTION IF YOU WILL FOR
ACTIVE DISEASE AND TO WHAT TAMI
SAID DISEASE REMISSION.
SO AGAIN THINKING ABOUT IT'S NOT
LOW HANGING FRUIT.
I TOTALLY AGREE BUT IT WAS
REALLY STIMULATING TO HEAR THAT
BECAUSE WE DO HAVE SITUATIONS
WHERE THERE IS ACTIVE DISEASE
AND CLEAR PRESSURE FROM THE HOST
TO EITHER REJECT OR ACCEPT
DEPENDING ON THE ECOLOGY OF THE
STRAIN BUT THAT ECOLOGY IS NOT
GOING TO BE THE SAME OVER TIME.
DO WE THINK AND CHECK-IN WITH
DIAGNOSTICS OR POINT OF CARE TO
CHANGE THE REGIMEN TO EITHER --
SO I DON'T KNOW IF ANYONE HAS
THOUGHTS ON THAT.
BUT IT DOES --
>> LET'S HEAR FROM GARY.
HE HAS HIS HAND UP.
7 THE CLOSING COMMENT ON THIS
QUESTION.
MAYBE I USED THE LOW HANGING
FRUIT AS A MISNOMER BUT I
THOUGHT MAYBE WHAT KIND OF A
NexGen PRO-BIOTIC COULD BE
EXPECT IN THE NEXT FIVE OR 10
YEARS.
GARY.
>> I ACTUALLY JUST HAD A COMMENT
-- TO RUSTEM'S -- IN ONE OF MY
FIRST SLIDES I SAID PRO-BIOTICS
ARE NOT -- DON'T HAVE AN
INDICATION FOR MEDICAL
TREATMENT.
IN CLINIC WHEN WE SEE OUR
PATIENTS THAT HAVE GI SYMPTOMS
THERE ARE PATIENTS THAT SWEAR BY
CERTAIN TYPES OF PRO-BIOTICS.
THEY SAY THIS DEFINITELY MAKES
ME FEEL BETTER AND I HAVE NO
REASON NOT TO BELIEVE THEM.
IN GENERAL ON AVERAGE WE CANNOT
REALLY SHOW THAT THERE IS A
DEMONSTRATED EFFECT.
I THINK THAT MAYBE AN
OPPORTUNITY IS TO ACTUALLY
LISTEN TO OUR PATIENTS.
PATIENTS WHO REALLY DO DERIVE
SOME TYPE OF BENEFIT FROM EVEN
THE CURRENT PRO-BIOTICS THAT WE
USE.
WHAT MAKES THEM DIFFERENT IN
TERMS OF THEIR MICRO BUY OAT
COME.
THEIR LIFESTYLES AND THEIR DIET
AND THAT MAKES THEM HAVE A
BENEFIT THAT IN GENERAL WE
CANNOT SEE ACROSS EVERYBODY.
THAT IS A DIFFERENT WAY OF
THINKING ABOUT PERSONALIZATION.
BUT I THINK AT THE END OF THE
DAY WE'RE TRYING TO MAKE OUR
PATIENTS BETTER AND WHEN OUR
PATIENTS ARE TELLING US I
DEFINITELY FEEL BETTER IF I USE
THIS PRO-BIOTIC.
WE MIGHT WANT TO PAY MORE
ATTENTION TO THAT.
>> THANK YOU.
THAT IS VERY HELPFUL.
>> RYAN WILL YOU TAKE THE NEXT
QUESTION?
>> I HAVE A LOT OF QUESTIONS BUT
I WANT TO KEEP THE MOMENTUM
GOING AND PICK OUT SOME A ASPECTS.
THE ASPECTS OF THE HOST THAT PUT
PRECIOUS ON THE MICRO ROW BUY
OAT UM AS WE INTRODUCE STRAINS
OR TRYING TO MODIFY THE * THE
COMMUNITY IN GENERAL.
THIS COMES FROM A QUESTION FROM
THE VIDEO CAST AND IT'S SIMPLE
AND THEN I'LL MAYBE ELABORATE.
IGA HOST IMMUNITY.
AND THINK ABOUT HOW IGA IS AND
JUNE CORRECT ME IF I'M WRONG BUT
IS DESIGNED TO BE SHORT-LIVED
AND NOT HAVE LONG-TERM MEMORY IN
THAT SENSE.
AND THE QUESTION REALLY IS IN
TERMS OF THE HOST IMMUNE
RESPONSE ARE THERE WAYS IN WHICH
YOU CAN ENVISION --
CO-ADMINISTERING ASPECTS OF THE
HOST TO EITHER ACCEPT OR TO
MODIFY THE MIKE ROPIAL COMMUNITY
AND -- AND WHETHER OR NOT THAT
IS A FEATURE WE SHOULD BE
BUILDING INTO THE DESIGN'
NexGen PRO-BIOTICS.
AND I * I CALLED OUT JUNE BUT
OTHERS WITH ANSWER AS WELL.
>> I'LL COMMENT ON IT SINCE YOU
CALLED ME OUT.
BUT SO I THINK I ELUDED TO THIS
WHEN I JUST SPOKE.
AND THAT IS I GUESS THE WAY I
ENVISION ONE WAY IN WHICH YOU
COULD THINK ABOUT INCORPORATING
HOW THE HOST INFLUENCES THAT
PRO-BIOTIC IS IS THERE HAVE BEEN
A FEW STUDIES INCLUDING THE
FUNGI STUDY THAT I JUST TALKED
ABOUT THAT DO ATTEST TO A ROLE
FOR IGA IN PARTICULAR IN HELPING
AN ORGANISM COLONIZE AND STAY
WITHIN THE GUT.
SO THERE HAVE NOT BEEN ANY
EXPERIMENTS TO DO THIS BUT I
ENVISION AND I HOPE WE'LL TEST
ONE DAY THAT YOU COULD VACCINATE
YOU COULD ELICIT SOME SORT OF
IMMUNE RESPONSE RIGHT BEFORE OR
AS YOU'RE GIVING A PRO-BIOTIC TO
HELP IT TO COLONIZE OR MAYBE GET
TO THE APPROPRIATE LOCATION.
WE'VE TALKED ABOUT LOCATION
ESPECIALLY IN THE SI AND THEN
THE S II G IS VERY PREVALENT.
SO I CAN IMAGINE THAT IT IS
BOOSTING AN IGA RESPONSE AS
YOU'RE GIVING THAT PRO-BIOTIC
MIGHT HELP IT STICK WHERE YOU
WANT IT TO BE.
SO, THAT IS MY THOUGHTS ON THAT.
7
>> I SAW YOU NODDING A LITTLE
BIT.
ANYTHING TO ADD MORE ON THAT?
>> I ABSOLUTELY AGREE WITH WHAT
JUNE SAID.
THAT IS -- REALLY INTERESTING.
AND -- THE TOOLBOX THAT WE HAVE
AND I ALSO WANTED TO ECHO WHAT
YOU SAID ABOUT MORE COMPLEX
APPROACHES.
7 COMING BACK TO THE POINT ABOUT
SIMPLE SYSTEMS AND STRONG
BEHAVIORS.
IF YOU YOU'RE TRYING TO LAND A
PLANE YOU JUST DON'T POINT IT
DOWNWARDS.
8 THERE IS TURBULENCE AND ALL
KINDS OF STUFF AND WE DON'T
UNDERSTAND THE PHYSICS TO FIND
SIGNIFICANT DIGITS.
BUT WE CAN STILL LAND THE PLANE
AND THAT IS DONE BY A SERIES OF
STEPS.
THIS QUESTION IF YOU HAVE A
SYSTEM THAT IS STUCK LET'S SAY
IN AN UNFAVORABLE STATE.
WHAT WAS THE NUMBER OF STEPS
THAT YOU NEED TO TAKE.
THE SIMPLEST STEPS THAT YOU NEED
TO TAKE.
AND IF THE ANSWER IS IT'S 20
IT'S PROBABLY GOING TO BE
IMPRACTICAL BUT IF THE ANSWER IS
TWO THAT COULD BE ACTIONABLE.
7 SO A APPRECIATE YOU RAISING
THE QUESTION.
THAT IS GOING TO BE AN IMPORTANT
POINT TO THINK THROUGH.
>> THANK YOU.
7 JULIA.
7
>> SO BUILDING ON BOTH OF THOSE
COMMENTS.
AGAIN THINKING ABOUT THE SKIN
SPECIFICALLY SO THE STRAT YUM --
IS DESIGNED TO KEEP STUFF OUT SO
THAT INHERENTLY IS A BARRIER TO
ANY PRO-BIOTIC COLONIZATION.
AND NONCOLONIZING PRO-BIOTICS
THE DISSEMINATION -- -- AND SO
AS YOU KNOW THINGS I'VE BEEN
THINKING ABOUT THAT.
VARYING IN PRACTICALITY.
IF YOU BRIEF THE SKIN BARRIER
WHEN YOU GET A WOUND THAT IS THE
MOST POWERFUL DRIVER FOR STAPH.
THAT IS ONE WAY I'VE BEEN
THINKING THAT ONE COULD INTEREST
MORE STABLY OR MAKE MORE
ACCESSIBLE THE IMMUNE CELLS.
TO ASSIST THE COLONIZATION AND
THAT IS A COMBINATION.
TO TARGET THE COLONIZATION.
BUT THEN AGAIN YOU HAVE TO
CHANGE THE WAY THAT YOU THINK
ABOUT THE DELIVERY -- OF YOUR
PRO-BIOTIC OF CHOICE BECAUSE
THEN YOU ALTER THE ENVIRONMENT
AND THAT IS A WHOLE DIFFERENT
SET OF CRITERIA FOR JUDGING A
STRAIN TO BE PRO-BIOTIC.
IS HOW DOES IT BEHAVE IN BREACH
SKIN BARRIER VERSUS -- SKIN
BARRIER VERSUS A BARON CONTACT
WITH THE EPITHELIAL CELLS.
ANTIBIOTIC CLEARANCE IS ANOTHER
THOUGHT.
AN AGGRESSIVE WAY TO REDUCE THE
COLONIZATION RESISTANCE OF A
COMMUNITY.
2 WHAT HAS BEEN PUBLISHED IT HAS
VARYING EFFICACY IN SKIN BUT
THOSE KINDS OF I WOULD SAY
DISTURBANCES OF THE ECOSYSTEM --
THEY SHOULD NOT BE DISCOUNTED
BUT IT DOES ADD ANOTHER LAYER OF
COMPLEXITY IN UNDERSTANDING THE
6 EFFICACY.
>> ONE QUESTION I HAVE FOR YOU
AS YOU WERE -- SPEAKING AND IT
RELATES TO THE TOPIC OF YOUR
TALK AND IT STRUCK ME THAT
MULTIPLE FOUNDERS MIGHT BE THE
STARTING POINT.
FOR PARTICULARLY FOR SKIN
MICROBIOMES.
THE WAY IN WHICH YOU WATCH THE
DISTRIBUTION AND HOW YOU MIGHT
DELIVER THAT IT SEEMS TO ME THAT
IT'S SLIGHTLY DIFFERENT THAN
PERHAPS WHAT WE SEE IN THE GUT.
AND AS A STARTING POINT FOR
CONSORT WHY OF MULTIPLE GENRE
WHERE I GET THE SENSE FROM YOUR
TALK IN PARTICULAR THAT IT WOULD
NOT BE REALLY THAT COMPLEX AT
THE GENRE LEVEL BUT AT THE
STRAIN LEVEL.
JUST THROWING THAT OUT THERE
>> I WOULD LOVE TO TALK ABOUT
HOW EVERY DIFFERENT SKIN SITE
YOU'LL NEED A DIFFERENT SET OF
ORGANISMS AND TARGETS.
VERY NAIVE ABOUT THE GUT
ECOSYSTEM.
THE CRIBS AT THE MICRO LEVEL AND
THERE ARE INTESTINAL CRIPS.
I SUSPECT IT WOULD BE TRUE IN
THE GUT AS WELL.
YOU CAN SEE IT MORE READILY IN
THE SKIN.
>> THANK YOU SO MUCH.
7
>> I JUST WONDERED -- AND I
UNDERSTAND -- -- ----- -- --
SOME OF THE ASPECTS -- CAN WE --
EYE OF ---THAT WE CAN IDENTIFY
TO DETERMINE WHETHER OR NOT
BACTERIA -- CAN -- IS IT
SOMETHING THAT WHEN YOU SEE LIKE
THE CONDITIONS OR THE BACTERIA
-- THIS MAY OR MAY NOT.
>> I'M HAPPY TO JUMP NCATS I
THINK WE'RE QUITE FAR FROM THAT.
*.
THERE ARE PRINCIPLES THAT WERE
BROUGHT UP YESTERDAY THAT HAVE
SHOWN TO BE SOMEWHAT TRUE WHICH
IS THAT IF THERE IS A NICHE THAT
IS NOT YET OCCUPIED THAT IS NOT
YET BEING USED THEN ADDING
SOMETHING IN MIGHT BE TRIVIAL.
BUT BEYOND THAT -- WE'RE REALLY
IN EARLY STAGES.
7
>> YEAH.
CAN WE HAVE STRAINS TO HAVE THEM
ADAPT BETTER OR TO ADHERE BETTER
AND TO DO BETTER AND WHAT I
STRONGLY AGREE WITH WHAT WITH
WHAT CARE GARY WAS SAYING WE DO
NOT NEED TO KNOW EVERYTHING TO
MAKE USE OF THESE STRAINS AND TO
IMPLEMENT THEM AND TO HAVE AND
EFFECT.
UNDERSTANDING MECHANISM FROM
PRO-BIOTICS WILL GREATLY HELP TO
ANSWER THE QUESTION THAT YOU
WERE ASKING AND IF WE BETTER
UNDERSTAND THE UNDERLYING
MECHANISMS -- ULTIMATELY AND
THESE STUDIES ARE HARD AND THAT
TAKES A LOT OF TIME AND ENERGY
AND A LOT OF RESTRICTIONS IN
ORDER TO IMPLEMENT THAT.
IF YOU THINK ABOUT WE TALKED
ABOUT STRAIN -- -- AND IT'S
RESTRICTIVE.
AND IF YOU THINK ABOUT ISOLATING
MICROBES FROM THE GUT THESE ARE
NOT GENETICALLY AMENABLE.
SO THERE ARE BARRIERS TO
OVERCOME BUT ONCE WE HAVE A
BETTER MECHANISTIC UNDERSTANDING
WE WILL BE IN A BETTER ABLE.
7
>> SO WHEN I'M THINKING ABOUT
ENGRAPHMENT OR PERSISTENCE AND
THE NICHE THERE IS SOME THINGS
THAT WE NEED TO KNOW.
WE HAVE AN IN TUITION ABOUT IT.
FOR EXAMPLE IN THE GUT THE
MICROBIOTA THAT IS ADHERENT TO
THE MUCOUS OR IS IN AFFIX WITH
THE HOST.
BECAUSE THINGS THAT DON'T --
BASICALLY FLOW THROUGH AND GIVEN
WINDOWS THEY WILL DISAPPEAR
AFTER A CERTAIN PERIOD OF TIME.
THAT IS A CURRENT NOTION.
I DON'T KNOW IF IT'S ABSOLUTELY
PROVEN BUT THERE ARE HUMAN
OBSERVATIONS THAT WOULD SUGGEST
THAT IS TRUE.
SINCE I'M A GASTROENTEROLOGIST
WE KNOW THAT PEOPLE GET
COLONOSCOPIES THEY FLUSH OUT
EVERYTHING AND WITHIN A SHORT
AMOUNT OF TIME THEIR MICROBIOTA
RECONSTITUTES.
BECAUSE OF THE ORGANISMS THAT
HAVE BEEN GRAFTED OR ARE
PERSISTENT IN THE MUCUS AND ARE
ASSOCIATED WITH THE HUMAN HOST
AND THEY'VE REGENERATED.
THAT GIVES US THE PRINCIPLE THAT
THOSE ORGANISMS THAT ARE
ASSOCIATED WITH US MAY BE THE
MOST IMPORTANT WHEN WE THINK
ABOUT PERSISTENCE AND
ENGRAPHMENT.
ONE THING THAT WE DID NOT TALK
ABOUT SO FAR IS THE NOTION OF "A
BIOFILM."
ONE CAN THINK ABOUT IT AT A
COMPLEX COMMUNITY JUST AS IS
TOOTH ENAMEL OR CONSORTIUM THAT
EXIST WITH EACH OTHER AND THIS
GETS TO A LEAPING NOTION OF A
COMMUNITIES THAT COEXIST BECAUSE
OF MUTUAL INTERACTIONS.
>> A QUESTION BUILT ON SOMETHING
GARY JUST SAID BUT TO START WITH
ONE OF THE THINGS -- THROUGHOUT
THE SESSION FOCUSED OFF STRAINS
AND EVEN YESTERDAY TO SOME
EXTENT TO THINKING ABOUT STRAIN
PHENOTYPE AND METABOLIC OUTPUT
PATHWAYS.
THIS IDEA OF NexGen BEING
ASSOCIATED WITH SOME SORT OF
MECHANISM OF ACTION OR
THERAPEUTIC BENEFIT.
AND WE HEARD A COUPLE OF
EXAMPLES OF WHERE A PHENOTYPE IS
IDENTIFIED AND VERIFIED AND
MAYBE EITHER AN ANIMAL SYSTEM OR
OTHER WAYS AND THAT MY QUESTION
TO THE ENTIRE PANEL IS HOW
IMPORTANT IS IT TO UNDERSTAND
THE PHENOTYPES AND HOW
PHENOTYPES CHANGE DEPENDING ON
THE SYSTEM THEY ARE IN.
A PHENOTYPE FOR BUTYRATE IS
OUTPUT AS ONE IN ISOLATION
VERSUS A FECAL SLURRY.
THAT TYPE OF CHANGE SO I'M
THINKING OF SYSTEMS FOR EXAMPLE
JUST LOOKING AT IT IN THE
CONTEXT OF A COMPLEX MICROBIAL
ECOSYSTEM OR BIOREACT OR IN THAT
WAY OR ANOTHER SYSTEM THAT I
HEARD MENTIONED OR ORGANOIDS AND
THIS IDEA OF INTESTINAL
ORGANOIDS AND HOW THEY CAN BE
USED TO STUDY -- GARY MENTIONED
O2 AND GEOGRAPHY -- WITHIN THE
MUCOS A AND ALSO BIOFILMS.
AS WE UNPACK AND SELECT AND WE
THINK WE'VE LOCKED DOWN THE
PHENOTYPE HOW IMPORTANT IS IT
FOR EACH INDIVIDUAL PROGRAM AS
THEY ADVANCE TO TEST THE
DURABILITY WITHIN THE DIFFERENT
CONTEXT.
MAYBE --
>> ARE YOU LOOKING FOR MODELS?
>> YES.
EXACTLY AND AGAIN IT DOESN'T
HAVE TO BE JUST THE GUT BUT IT
CAN BE OTHERWISE.
FOCUSING ON PHENOTYPES THAT ARE
IMPORTANT AND METABOLIC OUTPUT
AND HOW THAT MIGHT CHANGE
DEPENDING ON THE SYSTEM THAT
YOU'RE LOOKING AT.
AND I'LL STOP THERE.
>> ANY RESPONSES FROM THE PANEL?
>> IT WOULD MAKE PERFECT SENSE
THAT THE PHENOTYPE WOULD BE
DIFFERENT.
THERE IS IG AND ALL KINDS OF
OTHER STUFF.
OXYGEN.
PERHAPS FOOD.
THAT IS VERY DIFFERENT
ENVIRONMENT THAN EVEN THE LARGE
ENTRUST ON OR COLON.
SO YOU COULD EXPECT DIFFERENT
PHENOTYPES ACROSS THE GUT AND
IT'S IMPORTANT TO FIGURE OUT HOW
TO ACTUALLY PROFILE THAT.
CAN WE DO -- IN THESE
COMMUNITIES OR CAN WE JUST TO
UNDERSTAND THE ISSUE -- DYNAMICS
AND GENE EXPRESSION -- WOULD BE
INTERESTING AND IMPORTANT TO
KNOW.
I MEAN I'M 99.9% THEY WILL BE
DIFFERENT.
JUST DON'T KNOW WHAT KIND OF
DIFFERENCES THERE WOULD BE.
7
>> RYAN -- LOOKS LIKE SOMEBODY
ELSE RAISED THEIR HAND SO I'LL
WAIT.
>> OKAY.
MY QUESTION IS FOR GARY.
THAT IN PANKY YACHTIC CANCER WE
-- ARE LOOKING FOR SOME MARKERS
* THAT CAN DETECT PANCREATIC
CANCER EARLY AND WHAT ARE
MICROBIOMES AND THEIR -- RELATED
TO CANCER.
THE QUESTION IS DO YOU SEE WHAT
ARE MICR MICROBIOTA IN COLITIS OR
CHRON'S DISEASE.
HAVE YOU SEEN THAT?
>> YES.
IT'S ACTUALLY INTERESTING.
-- IT SEEMS TO BE ASSOCIATED
WITH A NUMBER OF DIFFERENT
DISEASES AS YOU POINTED OUT.
IN PANCREATIC CANCER.
BUT IN INFLAMMATORY BOWEL
DISEASE AND EVEN IN COLON CANCER
-- -- SO YOU CAN THINK OF IT AS
ONE LONG TUBE AND THE THINGS
THAT YOU SWALLOW IN YOUR MOUTH
COULD EASILY END UP THROUGHOUT
YOUR I INTESTINAL TRACT.
THERE ARE A NUMBER OF EXAMPLES
INCLUDING INFLAMMATORY BOWEL
DISEASE.
I'M SURE THERE ARE STUDIES THAT
I'M NOT AWARE OF LOOKING AT
STRAIN ASSOCIATIONS BETWEEN WHAT
IS IN THE MOUTH AND WHAT IS IN
THE INTESTINAL TRACT.
AND ASSOCIATED WITH INFLAMMATORY
CONTEXT LIKE THE -- TAMI MIGHT
HAVE A BETTER NOTION OF THAT
THAN ME.
I CAN'T PULL OUT LITERATURE ON
THAT.
BUT I DID WANT TO ACTUALLY
RESPOND TO RYAN'S QUESTION ABOUT
MODEL SYSTEMS.
SO WHEN I THINK ABOUT IT THESE
MODEL SYSTEMS ARE BASICALLY IF
YOUR GOAL IS TO TREAT AND
UNDERSTAND HUMAN PHYSIOLOGY
THESE MODEL SYSTEMS ARE BASED ON
FENO COPY WHAT WE ACTUALLY SEE
IN HUMAN BIOLOGY BUT WE CANNOT
STUDY HUMAN BIOLOGY BECAUSE IT'S
TOO COMPLEX.
TO FIGURE OUT CAUSE AND EFFECT
MECHANISMS BUS JUST BECAUSE WE
TRY TO FENO COPY WHAT WE SEE IN
HUMANS DOESN'T MEAN THAT THAT IS
ACTUALLY THE COMPLETE ANSWER TO
THE BIOLOGICAL MECHANISM.
THE WAY I WOULD THINK ABOUT IT
IS IF YOU CAN COME AT IT FROM
SEVERAL SYSTEMS AND COME UP WITH
A CONSISTENT ANSWER THEN YOU'RE
FENO COPYING HUMAN BIOLOGY
WHETHER YOU'RE USING ORGANOIDS
OR WHATEVER OR A MOUSE MODEL
SYSTEM IF THEY POINT IN THE SAME
DIRECTION IT'S LIKELY TO BE MORE
TRUE THAN JUST ONE PARTICULAR
MODEL SYSTEM.
7
>> I WAS THINKING -- FROM A
DEVELOPMENT STANDPOINT.
AS WE PULL THESE OUT OF THE LAB
AND START TO DEVELOP AND TRY TO
UNDERSTAND HOW THEY WORK MORE
HOW VALUABLE IS THIS TYPE OF
CHARACTERIZATION.
TO ME IT SEEMS IMPORTANT BUT NOT
ESSENTIAL.
AND GOING ALONG WITH THAT HOW --
DOES ONE TAKE A MODEL SYSTEM AND
TRY TO UNDERSTAND FRIENDS STRAIN
EVOLUTION.
WHERE PERHAPS A STRAIN EVOLVES
BASED ON THE PRESSURE FROM THE
HOST TO ENGRAFT OR PERSIST
VERSUS SOMETHING WHERE J.P. WAS
TALKING ABOUT THAT IS NOT THE
GOAL AT ALL.
ENGRAFT MEANT MAY NOT BE THE
GOAL.
* AND THAT SYSTEM THERE IS
DIFFERENT THERE ARE DIFFERENT
REQUIREMENTS FOR
CHARACTERIZATION.
THAT IS ALL I'M THINKING.
THE KIND OF DICHOTOMY.
I DON'T KNOW IF YOU OR J.P. WANT
TO PINE ON THAT AT ALL.
>> AND I AGREE.
IT DEPENDS ON WHAT YOU'RE
STUDYING AND WHICH CONTEXT
YOU'RE STUDYING IT IS AND DON'T
GET ME WRONG I'M NOT SAYING THAT
COLONIZATION IS NEVER A
REQUIREMENT.
IT MAY CERTAIN BEING SITUATIONS
WHERE ENGRAPHMENT OF
COLONIZATION DOES CONTRIBUTE TO
THE MICROBIAL EFFECT BUT IN MY
HUMBLE EFFECT THAT COLONIZATION
IS NOT A REQUIREMENT.
BUT I AGREE WITH WHAT YOU WERE
SAYING EARLIER.
JUST MY TWO CENTS.
>> INTERESTED IN METABOLITE
PRODUCTION MAYBE YOU DON'T
NECESSARILY NEED TO HAVE THE
ORGANIZE I WILL ENGRAPH.
YOU CAN TAKE IT ON A REGULAR
BASES.
IT'S GOING TO PRODUCE THE
METABOLITE OF INTEREST.
>> I AGREE BUT IT DEPENDS ON HOW
MANY METABOLITES YOU WANT TO
PRODUCE.
ACTIVE TREATMENT OF DISEASE AND
I AGREE.
WE CAN PROBABLY DESIGN SOME
BACTERIA THAT HAS SOME
THERAPEUTIC EFFECT WHILE THEY
ARE -- PASSING THROUGH.
YOU WANT TO HAVE ENGRAPHMENT AND
ALSO FOR MAYBE I'M TOO
FUTURISTIC -- WHERE WE HAVE MANY
MICROBE THAT'S WE ADD TO OUR
MICROBIOMES DURING HEALTH AND
THE FUTURE OF MEDICINE IS ABOUT
PROLONGING HEALTH AND NOT JUST
TREATING DISEASE AND IN THAT
CASE I THINK ENGRAPHMENT SHOULD
BE A GOAL.
>> YOU HAVE YOUR HAND UP --
>> CAN YOU HEAR ME?
>> GREAT.
I'M ON MY BIKE AND I'VE BEEN
LISTENING IN AND A GREAT MORNING
SESSION.
JUST -- TO ADD A BRIEF COMMENT
ABOUT THE CONCEPT OF ENGRAPHMENT
I THINK -- THE NexGen
PRO-BIOTICS IDEA IS SUCH A BROAD
ONE.
AND WE'RE BUILDING OFF OF THIS
WELL SEND DEFINITION OF
PRO-BIOTICS BUT WE'RE TALKING
ABOUT A HUGE RANGE OF POTENTIAL
APPLICATIONS, PRODUCTS,
INDICATIONS AND I THINK WE DON'T
WANT TO BE TOO ENCUMBERED BY THE
TRADITIONAL ARE DIGS -- CONCEPT
*.
MAKING SURE WE FRAME THE
CONVERSATION AROUND NOTHING
BEING MUTUALLY EXCLUSIVE.
THERE ARE SO MANY POSSIBILITIES
THAT ENGRAPHMENT MAYBE PARTIAL
ENGRAPH MEANT.
MAYBE TEMPORARY.
ALL OF THESE THINGS ARE SUPER
EXCITING SO I JUST WANTED TO ADD
THAT.
THANK YOU.
>> THANK YOU.
>> I HAVE ANOTHER QUESTION -- --
REPORTED MANY TIMES WITH MANY
MICROORGANISMS AND WE KNOW THAT
THIS IS -- -- ---SO HOW MUCH --
REGENERATION DO YOU HAVE -- AND
ALSO IN COLON ESPECIALLY LEFT
AND RIGHT COLON THEY HAVE -- --
THAT -- PHENOTYPE -- AND -- ---
---SO HOW MUCH EPPI -- EPIGENETICS --
>> ANYBODY?
>> BUTYRATE IS AN INHIBITOR --
SO IT REALLY IS A VERY, VERY
BROAD LANDSCAPER OF THE
EPIGENOME.
AND I THINK THERE IS A LITTLE
BIT OF EVIDENCE THAT MAYBE IT
PLAYS A ROLE.
HOW MUCH EVIDENCE ACTUALLY IS
THAT IT WOULD SIGNIFICANTLY
ALTER THE EPIGENOME --
INHIBITION THE WAY THAT WE WOULD
SEE IT IN CELL CULTURE IS -- --
NORMALLY CELLS WOULD ACTUALLY
OXIDIZE QUICKLY AND MAY OR MAY
NOT ALLOW BUTYRATE TO REACH
CONCENTRATION THAT'S WOULD IN
HIP STATE THE ACTIVITY AND * AND
CHANGE THE NUCLEUS.
CELLS THAT ARE NOT -- MAY BE
MORE AVAILABLE TO LANDSCAPE THE
EPIGENOME THAT WOULD THEN
INHIBIT PROLIFERATION.
SO IT DEPENDS ON THE METABOLIC
CAPABILITIES OF THE CELL WHEN
YOU'RE JUST TALKING ABOUT
BUTYRATE.
THERE IS A BODY OF LITERATURE
THAT THE MICROBIOTA IS
ASSOCIATED WITH THE EPIGENOME.
HOW MUCH IS BIOLOGICALLY
RELEVANT IN HUMANS WE DON'T KNOW
THAT.
UNLESS I'M NOT -- I'M NOT AWARE
OF THE MOST RELEVANT LITERATURE
RIGHT NOW.
>> -- AND THE APPROVED -- IN
COMBINATION -- -- ---THEY WORK
VERY WELL.
8
>> SO GARY, YOU HAVE A QUESTION.
>> I THINK YOU DID ANSWER THE
QUESTION BUT THEY APPRECIATE IF
YOU CAN ANSWER ON THE ZOOM
CALLS.
SO HER QUESTION IS HOW JUST --
LIFESTYLE INTERVENTION AND
STRESS MANAGEMENT CAN BE HELPFUL
-- COMBINE LIFESTYLE AND MICRO
BIOME INTERACTIONS -- THAT IS
THE QUESTION.
>> YEAH.
SO I THINK THAT IS A VERY
FORWARD THINKING QUESTION.
THERE IS A LOT MORE INTEREST NOW
ABOUT STRESS AND INFLAMMATORY
DISEASES AND INFLAMMATORY BOWEL
DISEASE IS ONE OF THE PARADIGMS.
THERE IS A LOT OF THOUGHT -- BUT
IT IS REFLECTED IN INFLAMMATORY
BOWEL DISEASE.
HOW MUCH IS ACTUALLY AN EFFECT
TO DISEASE MANAGEMENT WE DON'T
HAVE EXACT NOTION OF THAT IN
HUMANS.
CERTAINLY ANIMAL MODELS STRESS
IS IMPORTANT IN REGULATING THE
IMMUNE RESPONSE BUT THINKING
FORWARD IT MAY ACTUALLY BE MORE
IN A MAINTENANCE PHASE OF
TREATMENT.
IN OTHER WORDS MAYBE IT'S GOING
TO BE VERY DIFFICULT IN TERMS OF
JUST LIFESTYLE MODIFICATIONS OR
EVEN THE NEXT GENERATION OF
PRO-BIOTICS TO TREAT ACTIVE
DISEASE FOR MANY REASONS THAT WE
HIGHLIGHTED THIS MORNING.
HOWEVER ONCE YOU INDUCE
REMISSION THE OPPORTUNITY THEN
IS CAN YOU CHANGE THE
ENVIRONMENT?
AND THAT WOULD BE YOUR LIFESTYLE
TOO.
LIFESTYLE, REDUCE STRESS.
EAT A HEALTHIER DIET.
TAKE THE RIGHT PRO-BIOTIC.
AND CHANGE THE ENVIRONMENT SO
YOU CAN REDUCE IMMUNO
SUPPRESSION.
THERE IS A NOTION THAT AND THIS
IS EVEN GOES TO THE TRANSPLANT
PHYSIOLOGY THAT YOU MIGHT BE
ABLE TO REDUCE OR ELIMINATE IT
BUT YOU MIGHT NEED TO CHANGE THE
ENVIRONMENT.
THAT IS WHERE COMPANION
DIAGNOSTIC WOULD BE IMPORTANT.
YOU DON'T WANT TO HAVE
SOMEBODY'S DISEASE GO
UNCONTROLLED.
YOU WANT TO IDENTIFY IN ADVANCE
WHO YOU MIGHT BE ABLE TO SAFELY
REDUCE IMMUNO SUPPRESSION.
SO IT'S A VERY FORWARD THINKING
AND IT WOULD BE THE ULTIMATE
GOAL.
>> THANK YOU.
ANYTHING TO ADD TO THAT?
>> I WAS GOING TO ECHO WHAT --
GARY SAID.
I THINK STRESS IS A COMPLICATED
FEATURE.
STRESS MAY BE INVOLVED IN THE
EARLY PATHOGENESIS OR
COMORBIDITY.
BUT IN IBD IT MAY COME AFTER THE
ONSET OF DISEASE AS BEING MORE
ANNEX AGE RATING FACTOR -- *.
WHEN IT SHOULD BE ADDRESSED AND
HOW WOULD DEPEND ON DIFFERENT
DISEASES BECAUSE IT PLAYS A PART
IN MOST DISEASES.
THEY CAN ALTER THE MUCOS A BY
ALTERING THE GUT.
THERE ARE DIFFERENCES BETWEEN
ACUTE AN -- AND CHRONIC STRESS.
IT'S RELEVANT TO MOST OF THESE
CHRONIC DISEASES.
>> MAYBE CAN I ADD A COMMENT TO
THIS.
I APPRECIATE THESE COMMENTS.
78 IT'S VERY IMPORTANT -- THAT
WE'RE INTERESTED IN WHAT WE CALL
MULTI-MODEL INTERVENTIONS THAT
ACT ON MULTIPLE ASPECTS.
SO THIS IS AN INTERESTING
THOUGHT.
THAT YOU COULD HAVE AND
MULTI-COMPONENT INTERVENTION
THAT COULD ADDRESS MANY FACTORS
INCLUDING THE DIET.
INCLUDING THE MICROBIOME AND
LIFESTYLE.
AND IT WOULD BRING TOGETHER A
LOT OF THE AREAS THAT THEY ARE
INTERESTED IN INCLUDING MIND AND
BODY THERAPIES THAT WE HAVE
ROBUST INTERVENTIONS NOW AND WE
CAN REDUCE NOT ONLY
PSYCHOLOGICAL STRESS BUT THE
INDEXES THAT INDUCE STRESS.
THIS MIGHT BE SOMETHING THAT
WOULD REALLY FIT WELL INTO THIS
FIELD OF WORK.
7
>> THANK YOU.
7
>> JUST TO ADD.
I THINK ALSO THAT LIFESTYLE AND
ALSO THAT IS IMPORTANT ALSO.
FOR HEALTH.
7 YOU CAN SIMPLY -- BY
INTRODUCING -- THE STRAIN
WITHOUT CHANGING ANYTHING ELSE
THAT IS PROBABLY NOT THE HOLY
GRAIL.
YOU ALSO NEED TO FOR EXAMPLE
FROM A MICROBIAL POINT OF VIEW
YOU CAN PRODUCE BUTYRATE -- THAT
YOU MIGHT BE MISSING BUT THEY
ALSO NEED TO PROVIDE THE SOURCE
FOR WHICH IT CAN PRODUCE
BUTYRATE BECAUSE MANY OF THE
MICROBES THAT ARE REVERSIBLE.
THE BUTYRATE PRODUCER MIGHT
PRODUCE -- BUTYRATE THAT IS
DEGRADING THE FIBERS.
SO I THINK THIS APPROACH THAT
YOU NEED ALSO PROBABLY LIFESTYLE
MODIFICATIONS.
I THINK THAT'S AN IMPORTANT ONE.
>> GARY.
>> I JUST WANTED TO ADD THAT THE
MULTI-MODALITY TREATMENT AND
LIFESTYLE ALTERATIONS IF THAT
INCLUDES QUALITY OF LIFE THAT'S
AN IMPORTANT END POINT FOR
PATIENCES.
QUALITY OF LIFE IS JUST AS
IMPORTANT AND WE HAVE DIFFERENT
TYPES OF MATRIXES AND WAYS TO
EVALUATE THAT.
THAT IS A VERY RELEVANT END
POINT FOR TREATMENT OF PATIENTS.
>> THANK YOU.
SO WE JUST HAVE A COUPLE OF
MINUTES TO GO BACK TO THE
GENERAL QUESTIONS THAT OUR
ORGANIZERS HAVE POSED TO US.
IF YOU HAVE ANY FINAL COMMENTS
ON THESE TWO QUESTIONS.
WHAT ARE CRITICAL GAPS IN OUR
KNOWLEDGE AND METHODOLOGIES FOR
THE RESEARCH AREAS PRESENTED?
AND WHAT NEW RESOURCES OR
METHODS -- ARE NEEDED TO FILL
THE GAPS IN THE SHORT-TERM OR IN
THE LONG-TERM?
IF YOU HAVE ANY FINAL CONTINUES
ON THESE TWO QUESTIONS WE'LL
SPEND A COUPLE OF MINUTES TO GO
OVER THEM.
WHO WANTS TO GO FIRST?
JULIE.
>> MY FAVORITE NEW TECHNOLOGY IS
THE NC2 TRANSCRIPT OMICS BECAUSE
WE NEED TO UNDERSTAND WHERE THE
MICROBES ARE WITH RESPECT TO THE
RELEVANT HOST CELLS.
BECAUSE IT LOOKS LIKE THEY ARE
SPECIFIC POPULATIONS.
THAT ARE RESPONDING TO MICROBIAL
COLONIZATION.
AND OUR -- THAT DON'T CAPTURE
THAT NUISANCE.
RIGHT NOW -- I DON'T THINK THE
-- HAS BEEN REALLY SOLVED FOR
MICROBES GIVEN HOW DIFFICULT THE
TECHNOLOGY IS.
7 BUT THERE ARE A LOT OF
PROMISING WORK IN THE MAMMALIAN
FIELD THAT I THINK WILL AT LEAST
BE RELATIVELY AND IMMEDIATELY
APPLICABLE TO LOOKING AT THESE
INTERACTIONS
>> THANK YOU.
8
>> I ALSO THINK -- ONE OF THE
GAPS IS -- AND THAT HAS BEEN
DISCUSSED THAT IS WE NEED TO
KNOW THE STRAIN VARIATION AND --
KNOWING WHAT THEY ARE DOING.
BECAUSE WE ALSO LOOK AT THE NAME
AND -- ---THE SMALL INTESTINE --
THAT DIDN'T LIKE TO SEE.
AND THERE IS ALSO THE IDEA THAT
WE SAY THAT -- -- -- AND STAPH
IS ALSO ASSOCIATED WITH
SOMETHING THAT IS NOT SO HEALTHY
BUT ON THE OTHER HAND -- IT'S
ALSO IN THE YOGURT THAT WE
CONSUME DAILY.
WE NEED TO GO INTO A NOT BASED
ON THE NAME JUST ASSUME THAT
THEY ARE IN -- OR THE OTHER AND
TO TAKE E. COLI AS AN EXAMPLE.
IT CAN BE A NASTY PATHOGEN THAT
CILICES YOU BUT IN ANOTHER
STRAIN IT CAN HELP YOU.
>> THANK YOU.
>> WE NEED TO GO BEYOND NAMES
AND GET TO GENOMES AND
FUNCTIONS.
AND I'M THE FIRST TO ARGUE FOR
THREE OTHER COMPONENTS.
UNDERSTANDING THINGS
QUANTITATIVELY IS REALLY
IMPORTANT BECAUSE THE RANGE OF
POSSIBILITY IS SO HUGE THAT IT'S
NOT ABOUT PERCENT ANY MORE.
IT'S ABOUT ABSOLUTELY
QUANTITIES.
AND ALSO SPATIAL INTERACTIONS --
AND NUMBER OF PEOPLE -- --
ABSOLUTELY CRITICAL IN
UNDERSTANDING -- THAT WOULD BE
REALLY IMPORTANT AND THE THIRD
POINT IS WE REALLY SHOULD FIND A
WAY TO DO THIS GREAT HUMAN AND
NOT MODEL SYMPTOMS.
IF YOU THINK BY THE WE DON'T
KNOW WHAT WE'RE TRYING TO MODEL.
AND IF YOU DON'T KNOW WHAT
YOU'RE TRYING TO MODEL YOU'RE
JUST TOE -- TRYING TO STUDY WHATEVER
IS IN THE DISH.
WE CAN BE MUCH MORE DELIBERATE
ABOUT BUILDING THE MODELS THAT
REFLECT THE HUMAN MODEL.
SO TO ME GETTING HUMAN DATA EVEN
THOUGH IT'S GOING TO BE HARD AND
IT'S NOT GOING TO BE POSSIBLE TO
DO IT IN HUGE NUMBERS BUT
GETTING HUMAN DATA SO WE CAN
ANCHOR THE OTHER WORK IS SO
CRITICAL THAT WE CANNOT WAIT TO
DO THAT.
THANK YOU.
>> GARY.
>> SO I WOULD SAY AN
ASPIRATIONAL GOALS WE BEGIN TO
DO MORE AND MORE HUMAN SUBJECT
STUDIES.
HUMAN INTERVENTION STUDIES.
IT WOULD BE GREAT AND I KNOW
PEOPLE HAVE TAKEN APPROACHES TO
THIS BUT IT COULD BE DONE
BETTER.
ACTUALLY TO SHARE DATA AND SHARE
INFORMATION.
SHARE BIOSPECIMENS BECAUSE HUMAN
SUBJECT STUDIES ARE EXPENSIVE
AND TAKE A LONG TIME TO DO AND
THERE IS A GREAT OPPORTUNITY TO
LEARN FROM EACH OTHER.
I KNOW THAT IN CERTAIN
CIRCUMSTANCES THAT MIGHT BE
NAIVE BUT THE MORE THAT WE DO
THIS WITH ALL OF THE DIFFERENT
TYPES OF EXPERTISE WE CAN LEARN
A A LOT.
EVEN WHEN THE END POINTS NOT MET
WE CAN STILL LEARN A LOT BY
SHARING THE INFORMATION
TOGETHER.
>> THANK YOU.
TAMI.
>> I -- IT WAS LARGELY SAID.
AS GARY WAS JUST TALKING I WAS
TRYING TO THINK ABOUT WHAT ARE
WAYS THAT WE COULD REALLY
LEVERAGE THESE TRIALS.
IN A MORE POWERFUL WAY AND TO
HAVE OPEN CALLS FOR
COLLABORATION WHEN YOU DO A BIG
TRIAL.
A WAY OF INVITING LARGER
COMMUNITIES TO HELP.
AND REALLY THINKING ABOUT THAT
AT THE GET-GO IN TERMS OF SAMPLE
COLLECTION.
WHEN SAMPLES ARE COLLECTED A LOT
OF THE TRIALS THEY ARE COLLECTED
IN WAYS IN -- A BUT THEY ARE
PRESERVES IT BUT MAKES IT
IMPOSSIBLE TO CULTURE THE
ORGANISMS FROM.
MAKING SURE THAT WE'RE
COLLECTING SAMPLES IN A WAY THAT
WE CAN ANALYZE.
CULTURALLING ORGANISMS IS SO
IMPORTANT
>> THANK YOU SO UP IN.
WE'RE COMING TO THE END OF THE
HOUR.
WE HAVE TO STOP AT THIS POINT.
FIRST OF ALL I THANK YOU ALL FOR
YOUR EXCELLENT TALKS AND ALSO
YOUR INSIGHTFUL COMMENTS AND
KNOWLEDGE AND ANSWERS TO THE
QUESTIONS POSED.
AND AT THIS POINT I JOIN MY
COLLEAGUE -- IN THANKING YOU ALL
AND HANDING IT OVER TO DIANE.
DO YOU HAVE ANY FINAL CONTINUES?
>> I DON'T SEE -- RYAN.
YOU'RE ON MUTE
>> SORRY.
I DON'T.
APPRECIATE IT.
HANDS IT OVER TO KATHERINE.
>> THANK YOU.
THAT WAS A GREAT SESSION AND
WONDERFUL DISCUSSION AND THANK
YOU TO OUR SPEAKERS FOR PUTTING
FORWARD SOME FASCINATING TALKS.
NOW I'M GOING TO TAKE US TO
LUNCH.
WELCOME BACK FROM LUNCH, IT IS
2:00 P.M. AND TIME TO START
SESSION 4 FOR THE PROBIOTICS
ME WANTING.
THIS SESSION WILL BE MONITORED
BY MUKESH VERMA AND Dr.
DONAHUE FROM NIDDK.
THIS SESSION WILL BE EMERGING
TECHNOLOGIES FOR PRECISION
PROBIOTICS AND Dr. VERMA
WILL BE PRODUCING THE SESSION
SPEAKERS.
AND SO WITH THAT SAID, I WILL
TURN IT OVER TO Dr. VERMA TO
TAKE IT AWAY TO INTRODUCE OUR
FIRST SPEAKER.
>> THANKS, WELCOME, EARN, TO
ANOTHER EXCITING SESSION OF
PROBIOTICS AND WITH THAT, I
WOULD LIKE TO INVITE Dr. KIM
TO DISCUSS AND HE IS FROM THE
UNIVERSITY OF TEXAS AUSTIN.
>> THANK YOU FOR YOUR
ATTENTION.
I AM IN PRESENTATION MODE, CAN
YOU SEE THE SLIDES?
>> WE CAN SEE THE SLIDES,
YEAH.
>> LET ME RESCALE THAT.
>> HERE YOU GO.
>> DID THAT WORK?
>> IT IS NOT CONVERTING OVER
TO PRESENTATION MODE.
>> HMM.
>> DAN OR DIANE, DOES EITHER
OF YOU HAVE Dr -- YES, HERE
WE GO, DAN HAS THAT UP FOR
YOU.
THANK YOU, DAN.
>> THANK YOU SO MUCH AND I
REALLY APPRECIATE FOR THIS
OPPORTUNITY.
NEXT SLIDE, PLEASE.
SO I AM GOING TO GIVE YOU SOME
IDEA ON HOW THE CHIP ALLOWS
YOU TO GET THE MICROBIOME
ENVIRONMENT AND MAKE IT
POSSIBLE FOR CROSSOVER SITE.
IN ANY EVENT, YOU WANT TO
BUILD UP THE PATIENT'S SLOWLY.
NEXT SLIDE, PLEASE.
I AM SORRY, WOULD YOU GO BACK?
THANK YOU.
SO WHAT WE ARE TRYING TO MAKE
HERE IS A TISSUE INTERFACE OF
OUR TEST SO HAVING THE CORE
MEMBRANE AND THEN EVENTUALLY
ONCE THESE ARE PATHEN S, YOU
CAN DETERMINE THE PATHO CELLS
AND EVENTUALLY YOU ARE JUST
MAKING THEMICROBIOME THAT
ALLOWS THEM TO INTERACT.
NEXT SLIDE, PLEASE.
SO WE ARE USING SILICON
POLYMER TO MAKE THE CHIP AND
ONCE WE HAVE THE PATTERN ON
THE SURFACE WITH PUNCHING,
CUTTING AND ALIGNING, THEN WE
CAN ALSO INTRODUCE SOME CHIPS
THAT CONTAIN THE CELLS AND
THEN YOU ARE GROWING THE CELLS
IN THE DATA AND THEN YOU CAN
TAKE IT OUT AND COLLECT THE
SAMPLE FROM THE DERMA SITE AND
YOU CAN LAUNCH ANY ASSAYS OR
EXTINGUISH OR AFFIX THE CELLS
FOR STAINING AND MICROSCOPY.
NEXT SLIDE, PLEASE.
SO YOU ARE LOOKING AT THE
CHIP, THE SILICON POLYMER IS
CRYSTAL CLEAR AND YOU HAVE A
MICROCHANNEL AS MENTIONED
INSIDE THAT AND HOPEFULLY YOU
CAN SEE THERE IS A VACUUM
CHAMBER CONNECTED TO THE
VACUUM CONTROLLER ESSENTIALLY
MAKING THE FUNCTION SITE HAVE
NEGATIVE PRESSURE.
NEXT SLIDE, PLEASE.
SO HERE YOU SEE EVERYTHING
HERE WITH THE TKPWEUZ LOGICAL
FLOW IN FUNCTION AND NEXT
SLIDE, PLEASE.
AND THIS IS A DIFFERENT TYPE
IT HAVE EPITHELIAL CELLS HERE.
YOU CAN USE SEVERAL MODELS AND
HERE USING THIS
MICROARCHITECTURE IN VITRO,
YOU CAN USE THIS AND
REPRODUCIBLY FILL THIS MODEL
WITH DIFFERENT TYPES OF FILM.
NEXT SLIDE, PLEASE.
SO HERE YOU CAN SEE WE CAN USE
THE MO RPHODENISIS, STARTING
WITH THE BOTTOM LAYER.
NEXT SLIDE.
AND THAT WAY YOU ARE NOT ONLY
MAKING THIS MIMICRY OF THE
CULTURE, YOU CAN ALSO
DEMONSTRATE THE ACTUAL
BEHAVIOR OF THE PROLIFIC CELLS
HIGHLIGHTED IN RED, THEY ARE
MIGRATING AND ALSO YESTERDAY,
ANOTHER SPEAKER MENTIONED THE
HOST CELL IS IMPORTANT FOR THE
MICROBIOME SIDE BUT WE CAN USE
THE CELLS FOR THE LAYER.
NEXT SLIDE, PLEASE.
AND THERE ARE A COUPLE OF BASE
THAT USE INVIVO OR INVITRO
MODELS AND AS WE DISCUSSED A
COUPLE OF TIMES, THE HUMAN
MICROBIOME IS NOT NECESSARILY
REFLECTING THE ANIMAL
MICROBIOME.
AND ALSO WHEN YOU THINK ABOUT
THE IN VITRO MODELS, IT IS
VERY DIFFICULT TO REGULATE THE
OVERGROWTH OF THE BACTERIA AND
SOMETIMES PEOPLE ARE JUST
TRYING TO USE PART OF IT BUT
YOU NEED TO PUNCTURE IT TO
INTRODUCE THE LIVING CELLS
INTO THE BACTERIA SLIDE.
NEXT SLIDE, PLEASE.
SO THESE ARE LIMITATIONS THAT
WE ACTUALLY HAVE OVERCOME WHEN
YOU CONSIDER FOR THE NEXT
GENERATION MODELS OF TESTING.
NEXT SLIDE, PLEASE.
SO THE COURSE YOU ARE TAKING
HERE IS ONCE WE HAVE ONE
LAYER, WE CAN STRUCTURE THE
EPITHELIAL CELLS, LOOKING AT
THE LEFT BOTTOM, THE
SCHEMATIC, WE PICTURE THE
CELLS AND ACTUALLY YOU CAN
STOP THE FLOW, ALLOW THEM TO
BE CIRCUITUOUS AND THEN RESUME
THE INFUSION USING FRESH
MEDIUM AND SUPPLY OXYGEN.
ALSO WE ARE MOVING ALL THE
WEIGHT AND EVENTUALLY YOU CAN
CHIP OFF THE MICROCELLS TO BE
HAPPY SO YOU ARE LOOKING AT
THE LIVE IMAGES OF THE
PROBIOTICS CHAIN, OR YOU CAN
LOOK AT THE COLI, NEXT SLIDE,
PLEASE.
AND AT THE BOTTOM, YOU CAN SEE
IT WILL SPREAD AND CAN BE
STUDIED OUTANY COMPROMISE TO
THE BARRIER.
NEXT SLIDE, PLEASE.
THE NEXT CHALLENGE, WE REALLY
NEED TO OVERCOME SOME AEROBIC
BACTERIA, SOME OF THEM ARE
LIVING IN THE CULTURE BUT WE
HAVE TO PUNCTURE THE CELLS.
NEXT SLIDE.
FOR THIS, WE INTRODUCE THE
MULTICULTURE MEDIUM ON THE
CHIP.
SO THERE IS A SHARP RADIUS ON
THE SIDE AND ON THE RIGHTHAND
SIDE, CO-CULTURE IT
WITHINTERIM BAGUETTE TEAR YUM,
THEY COMMUNICATE TO EACH OTHER
VITRALLY SO WE CAN
SUCCESSFULLY CULTURE THEM FOR
UP TO A WEEK WITHOUT ANY
COMPROMISE OF THE BACTERIA.
NEXT SLIDE.
SO BY LEVERAGING THIS
APPROACH, WE ARE ALSO TAKING
FECAL SAMPLES AND PROCESS THEM
AND INTRODUCE THEM ON A CHIP
AND YOU CAN LOOK AT ON THE
LEFTHAND SIDE, THIS IS THE
LIVE CULTURE AND YOU CAN
COMPARE BEFORE AND AFTER THE
INOCULATION AND ON THE BOTTOM
LEFT YOU CAN SEE THE PATH OF
MIGRATION.
NETWORKS SLIDE.
AND ALSO YOU CAN SEE IN THIS
CASE LIKE FOR CHIP 1 THROUGH
3, THEY JUST REPLICATE THE
CHIP WITH FECAL MICROBIOTA AND
IN THE LABORATORY, YOU CAN SEE
THE FECAL SAMPLE, THE SEQUENCE
RESULTS OF THE BUILDUP IN THE
CHIP ALLOWS YOU TO MAKE THE
BEST OF THE CHIP CULTURALLY.
HOWEVER IN THE LIQUID CULTURE,
YOU ONLY SEE ONE IN VITRO
WHICH YOU CAN SEE HERE.
SO WE CAN LOOK AT THE MICROBE
DIVERSITY AND ALSO THE BIOME
FROM THE FECAL SAMPLE.
NEXT SLIDE.
SO WE ARE TRYING TO LEVERAGE
OUR SYSTEM TO UNDERSTAND THE
MECHANISTIC BACKGROUND HOW AND
WHICH COMPLEX FACTORS CAN
ACTUALLY BE USED IN THE ONSET
OF INFLAMMATION.
NEXT SLIDE.
WE STARTED TO USE DSF -- DSS
AND YOU HAVE TO USE A LOT OF
TIME FOR THE CULT CHOW AND
WITH THE INFLAMMATION IN
ANIMAL MODELS, WE CAN
INTRODUCE THE BARRIER CENTER
AND YOU CAN SEE WE DON'T SEE
ANY BUILDUP HERE.
SO WE THOUGHT THIS WAS A GREAT
OPPORTUNITY TO MANIPULATE
PHYSICALLY TOWARDS THE BARRIER
FUNCTION.
NEXT SLIDE, PLEASE.
SO WE CAN UNCOUPLE OF
CONSTRUCT OF FACTORS IN THIS
AND RECOUPLE THEM ONE AT A
TIME TO UNDERSTAND WHICH
FACTOR ACTUALLY INDUCED THE
INFLAMMATION.
SO WE STARTED BY USING THE
VITREOUS ONLY COUPLED WITH
IMMUNE CELLS.
SO WE STARTED THAT ON THE LEFT
AND YOU CAN SEE WITH THE
CELLS, IT INCREASED BUT WE
DON'T SEE ANY FUNCTION TO
INFLAME SO THAT MEANS WE DON'T
HAVE IT YET.
SO NEXT SLIDE, PLEASE.
SO HERE YOU CAN SEE THE
VITREOUS AND THE LEVEL HAS
BEEN AMPLIFIED.
NEXT SLIDE, PLEASE.
AND THE BARRIER FUNCTION IS
VERY IMPORTANT.
WE ALREADY HAVE THE MICROBIAL
CELLS AND BACTERIA WITH THE
PREMISE OF THE CELLS
THEMSELVES BUT DON'T
NECESSARILY HAVE INFLAMMATION
AND MAINLY BECAUSE WE
DEMONSTRATE THE FUNCTION
LITERALLY MAINTAINS THE
EPITHILEAL FUNCTION.
NEXT SLIDE, PLEASE.
SO SOMETIMES IT WORKS,
SOMETIMES IT DOES NOT AND THAT
IS ONE OF THE KEY ISSUES WE
WANT TO SHOW HERE.
SO HERE WE TESTED WITH THE
EPITHILEAL BARRIER AND
THEN-PROVING THE BARRIER
FUNCTION.
>> YOU HAVE THREE MINUTES.
>> SO WE DEMONSTRATE IF WE
JUST INTRODUCE THE PROBIOTIC
STRAIN BEFORE WE DISRUPT THE
BARRIER, THEN WE CAN ACHIEVE
THE BARRIERS.
BUT IF THE BARRIER IS ALREADY
COMPROMISED, THE PROBIOTIC
STRAIN DOES NOT WORK.
NEXT SLIDE, PLEASE.
AND ALSO WE USE SIMILAR
APPROACHES FOR INTRODUCING THE
BARRIER OPTIONS, ONE MORE
SLIDE, PLEASE.
AND DEMONSTRATE THAT WITH THE
CO-CULTURE WHICH YOU SEE HERE.
ALSO THE DISORGANIZED
BARRIERS.
NEXT SLIDE PLEASE.
SO THE NEXT THREE MINUTES I
WILL GIVE YOU SOME APPROACHES
FOR CREATING A PATIENT AVATAR
TO VALIDATE THE SAMPLE.
NEXT SLIDE, PLEASE.
SO WE CAN WAIT A MINUTE FOR
THE APPROACH TO BUILD THE
INDIVIDUAL SITUATION WITH THE
PATIENT, NEXT SLIDE, PLEASE.
SO YOU CAN SEE HERE WE CAN
RECREATE THE CELLS AND ON
CHIPS, WE CAN ALSO DEMONSTRATE
THE MUTANT SESSIONS.
NEXT SLIDE, PLEASE.
SO WE HAVE A LOT OF APPROACHES
WITH OUR CLIPIANS FOR SHOWING
CANCER ON THE CHIPS AND ONE OF
THE THINGS WE'RE FOCUSING ON
HERE IS THE MICROBIOME
CONTROLS ON IMMUNOTHERAPY,
METASTASIS AND METABOLISM.
SO HERE WE TAKE THE PATIENT'S
MATERIAL AND PUT IT ON A CHIP
ON A BAGUETTE TERM BASIS AND
FOCUSING ON HOW IT CAN MOT
LAID WITH EXPRESS TUMOR CELLS.
NEXT SLIDE, PLEASE.
SO HERE WE FOCUS ON PD1 AND
YOU CAN SEE HERE THE POTENTIAL
EXPRESSION IS PARTICULARLY
HIGH BUT WHEN YOU CULTURE WITH
LIVING BACTERIA CELLS, YOU
DON'T REALLY SEE THAT.
NEXT SLIDE, PLEASE.
SO HERE WE TESTED WITH THE
BACTERIA ALONE OR THE LIVE
BACTERIA ALONE AND YOU CAN SEE
HERE WITH THE T CELLS, THEY DO
INDUCE A POTENTIAL IMMUNE
RESPONSE ON THE TUMOR HERE.
NEXT SLIDE, PLEASE.
SO WRAPPING UP HERE THEN, IT
IS TRYING TO PAINT VARIOUS
PATIENT SAMPLES THAT HAVE
CHANGES, BIOCHANGES OR RACE OR
ETHNICITY GROUP AND YOU CAN
TAKE DIFFERENT TYPES OF
PROBIOTICS OR SMT AND
UNDERSTAND THE COMBINATION OF
THE FACTORS FOR INDUCING AND
PRODUCING OUTCOMES IN HUMAN
MICROBIOME.
NEXT SLIDE, PLEASE.
SO I WANT TO THANK ALL THE
COLLABORATORS, THANK YOU VERY
MUCH.
>> THANK YOU AND WE INTRODUCE
THE NEXT SPEAKER.
THANK YOU.
>> OKAY, I THANK THE NIH FOR
ALLOWING ME TO GIVE MY TALK SO
HERE WE SHOW THE SRT LEVELS
IMPORTANT FOR MICROBIOME
HEALTH.
THESE PROPOSALS SHOW THE
PROPOSAL TO SHIFT TO A
STRATEGY FOR RESPONDERS AND
NONRESPONDERS AND THAT IS
BASED ON HUMAN GENOMIC
MATERIAL FOR EXAMPLE AND ALSO
MICROBIAL INFORMATION FOR
STRATIFIED PATIENTS AND MAKE A
PREDICTION BASED ON THEIR
RESPONDER STATUS AND THEN
SPECIFICALLY TAILORED THERAPY
OF THE INDIVIDUAL.
AND THAT IS DONE ON NOT ONLY A
GROUP LEVEL BUT INDIVIDUALLY.
SO THIS IS THE MECHANIC CAN
FIFTHIC APPROACH AND BASED ON
A NUMBER OF HUMAN STUDIES AND
ANIMAL MODELS.
THE TRANSLATION FOR HUMAN
CONDITIONS IS NOT ALWAYS TRUE,
IT CERTAINLY HOLDS TRUE FOR
PRECISION PROBIOTICS AND IS
ALSO DRIVEN BY THE ORGANISM
ITSELF.
SO HERE IN VITRO TECHNOLOGIES
ARE COMING, LOOKING AROUND THE
CORNER, MULTIPLE STAGES OF THE
ENVIRONMENT OF MUCOSA OR
INTEGRATION OF THE HOST FROM
THE SWITCH WE JUST HEARD ABOUT
IN THE TALK FROM Dr. KIM.
SO IT IS IMPORTANT TO
APPRECIATE WHAT THE IN VITRO
MODELS CAN OFFER.
SO DUE TO THE FACT THERE IS A
MULTILEVEL CONTROL YOU CAN
PROVIDE IMPORTANT INFORMATION
FOR EXPLAINING THESE
OBSERVATIONS.
SO THIS TAKES INTO ACCOUNT
THERE ARE LONGITUDINAL
GRADIENTS, SECTIONAL GRADIENTS
AND TAKE INTO CONSIDERATION
THE ENVIRONMENT AND THEN WE
ALSO NEED TO BETTER LOOK AT
THE INTEGRATION FROM THE DATA
SETS, LOOKING FOR EXAMPLE, AT
TIMELY ANALYSIS TO TRACK
MICROPRECISIONS AND ENDPOINTS.
I THINK IT IS CLEAR TO
APPROACH -- AS MENTIONED IN
ONE OF THE PREVIOUS TALKS --
TO APPROACH IT IN A MICROBIAL
MANNER.
SO WHAT WE ARE WORKING WITH IS
CALLED SHINE IN THE HUMAN IN
VITRO SYSTEM AND JUST LIKE
OTHER SAMPLES WORLDWIDE, IT
CAN BE INOCULATED WITH DONOR
MATERIALS FROM AN INDIVIDUAL
AND THEN THE MODEL MIMICS THE
AVERAGE HUMAN BEING SO IN THAT
SENSE, MANY OF THE PARAMETERS
ARE ACTUALLY STANDARDIZED.
HOWEVER, IF WE REALLY WANT TO
UNDERSTAND THE VALUE OF
PERSONAL EVALUATION, WE
CONTINUE TO MOVE TOWARDS
PERSONALIZATION CELL.
I WOULD LIKE TO POINT OUT ONE
EXTREMELY IMPORTANT MICROBE
ACQUIRED.
THE DATA OBTAINED AND COMPARED
WITH DATA AND THIS IS KNOWN TO
BE VALUABLE IN SEVERAL HEALTH
EFFECTS.
FOR EXAMPLE, THE MICROBE
QUANTITY IN EXTREME OF SLIDE 1
OR 2 LANDSCAPE, SHOWN TO HIGH
LIFE OR THE QUANTITYIZATION
AND MAY IMPACT THE SUCCESS OF
PRECISION BIOTICS AND
PATHOGENS.
SO MANY FACTORS UNDER LIE THE
MICROBIAL DATA BUT MOST
IMPORTANTLY, IT APPEARS TO BE
A VERY DOMINANT FORM SHAPING
BOTH THE COEFFICIENTS AND
QUANTITY.
SO AN EXAMPLE OF WHAT WE TOOK
IN OUR CONTROLLED MODEL
SYSTEM, WE STARTED OFF WITH
INDIVIDUALS WITH EITHER A
SHORT, LONG OR MEDIUM TRANSIT
TIME, LUCKILY GO INTO THE
SYSTEM, STABILIZE THE SYSTEM
INTO A MODEL AND THEN INDUCE
THREE DIFFERENT TRANSIT TIMES.
THE FULL SCALE IS RELATED WITH
THE TRANSIT TIME.
SHORT TRAFFIC TIMES, THEY
CORRESPOND WITH LOWER
MICROBIAL QUANTITIES.
AND ON THE LEFT PART OF THE
SLIDE, YOU CAN SEE WE WERE
ABLE TO CAP PIT LATE THE
EFFECT AND FOUND TRANSIT TIME
TO DETERMINE THE DIFFERENCES
IN MICROBIAL COMPOSITION.
SO I WOULD LIKE TO ZOOM IN ON
TWO OF THESE AND THE
DIFFERENCES IN TRANSIT TIME WE
HAVE TALKED ABOUT IN THIS
WORKSHOP HAVE A HUGE
DIFFERENCE ON THE MICROBIAL
SUCCESS AND ON THE LEFT SIDE
YOU CAN SEE IT PREFERS THE
RESIDENT COLON BUT ALSO OCCURS
LONGER TRANSITION TIMES.
THEN ON THE RIGHT YOU HAVE
OTHER STREAMS WITH A SHORTER
TIME SO MAYBE THIS IS FOR
SPECIFIC PROGRAM APPLICATIONS.
PERMIZATION ALSO PLAYS AT THE
LEVEL OF A SPECIFIC METABOLIC
CONVERSION.
SO THIS IS AN EXAMPLE FROM THE
FIELD AND I CONVERTED IT WITH
HUMAN MICROBES THAT MIGHT BE
IMPORTANT FOR INDIVIDUALS WITH
SUDDEN CHANGES IN HORMONE
LEVEL.
SO WE'RE DOING FECAL
VACCINATIONS SAMPLES FROM THE
INDIVIDUAL AND YOU CAN SEE IT
IS GOING FROM ZERO TO
100 PERCENT.
SO WHAT WE DID WAS SELECT A
LOW TO MODERATE AND HIGH
MICROBIAL SAMPLE FROM
INDIVIDUALS AND SO WE HAVE
STUDIES WHERE WE SEE
INDIVIDUALS INGESTING THE
SAMPLE, YOU CAN SEE THE
EXCRETION PROFILES ARE
REFLECTED OF THEIR HIGH,
MODERATE OR LOW SE CRETER
STATUS AND ALSO THIS IS
SIMULATED WHERE THE SAME
MATERIAL FROM THE INDIVIDUALS
IS ABLE TO CONSERVE THAT
STATUS AND SHOW IT IN
PROFILES.
THE PERSONALIZATION IS NOT
ONLY ABOUT THESE GENOTYPES BUT
SOMETIMES WE NEED TO ALSO LOOK
INTO THE PATIENT SHALL
ORGANIZATION AND THIS IS A
SLIDE I OFTEN USE IN MY
PRESENTATION BUT I THINK YOU
WOULD ALL AGREE WITH ME THERE
IS NO SUCH THING AS A TRAINING
MICROBIAL LEVEL WITH ALL THESE
ENVIRONMENTS BUT A PLATFORM
IMPORTANT TO CONSIDER AND IN
THE LAB, WE HAVE SEVEN
DIFFERENT ONES FOR THESE
MICROBIOMES.
SO HERE WE ARE LOOKING AT THE
FIBER, WHEAT BRAND FOR EXAMPLE
ENRICHED WITH A VERY COMPLEX
STRUGGLE SURE WHICH CAN BE
TAKEN FROM ONE VESSEL TO
ANOTHER IN THE SHINE SYSTEMS
AND JUST LET THE SYSTEM
STABILIZE AND WE LOOK AT THE
GRAPH EFFECT ON THESE WHEAT
BRAND PARTICLES AND WHAT YOU
SEE IS WHEAT BRAND IS ALSO A
DRIVER OF COMPLICATION, YOU
SEE THERE IS A NICE FIXATION
BETWEEN THE BRAN ASSOCIATED
WITH ENRICHED WITH BIOIC
INDUCING ABILITIES.
SO YOU CAN TAKE THESE TAILS
FOR A VERY TIMED RESULT,
SEVERAL MINUTES OR OVER
SEVERAL HOURS AND LOOK HOW IT
TAKES PLACE AND AGAIN WE CAN
SEE HERE FOR THE INDIVIDUALS
HERE, THEY HAVE NIGHT DYNAMICS
OF THIS PROCESS, EVENTUALLY
ENDING UP WITH THE EXECUTION
AND FUNCTION BEING SUPPORTED
BY THESE PARTICLES.
SO WE HAVE THE FUNCTIONAL
NICHE AND SHOW IN VITRO IT
INCREASED IN PRODUCTION AND
ALSO ENHANCED THE INTEGRITY
AND THEN IN THOSE GROUPS, LIKE
TO DEMONSTRATE SEVERAL OF
THESE ARE ABLE TO INDUCE
REGULATORY T-CELLS.
SO THIS DEMONSTRATES VARIOUS
INDIVIDUALS, IN THIS CASE,
CONE'S DISEASE IN TERMS OF
HEALTH STATUS AND IN TERMS OF
THE DISEASE AND YOU SEE THIS
IS CORRESPONDING IN
FUNCTIONALITY, 35 PERCENT, IN
THIS CASE, ACTIVE CROHN'S
DISEASE COMPARED TO PATIENTS
IN REMISSION AND HERE YOU SEE
THIS IS ALL CORRESPONDED WITH
ABILITIES.
A LOT OF DOWN REGULATED
MATERIAL HERE FOR CROHN'S
DISEASE AND DIVERTICULITIS,
YOU SEE IT IS SLIGHTLY
OXYGENIZING AND WE CAN STUDY
THAT OVER THIS MEMBRANE AND
DEMONSTRATE IT IS ABLE TO DO
SO TO COPE WITH THIS OXIDATIVE
STRESS.
>> YOU HAVE THREE MINUTES.
>> THAT'S GREAT.
SO TO FINISH OFF, I WOULD LIKE
TO HAVE A COUPLE SLIDES MORE
ON THE UNRAFFLING OF HOW WE
CAN USE THIS IN VITRO
TECHNOLOGY TO UNRAFFLE THE
INTEGRATION OF THE PROBIOTICS
SHOWN ON THE PROMINENT SIDE.
SO WE HAVE CAPTURED THE
BACTERIA BUT ALSO SOMETIMES
THE STRESSORS.
THERE IS A CERTAIN COLIZATION
THAT IS PRESENT IN INDIVIDUALS
AND THIS MAY COMPROMISE THE
GRAPHIC SUCCESS.
THERE IS ANOTHER PROCESS
TAKING PLACE AND THAT IS
LINOLEIC ACID.
BASICALLY YOU ARE SEPARATING
THIS ACID AND ALLEVIATING
TOXICITY.
AND THIS IS SOMETHING THAT IS
DONE THIS IS TAKING PLACE IN
THE MICROBIOME SO WHEN YOU
COMPARE THE FATTY ACID
PROFILES BETWEEN THE AREAS,
YOU SEE THERE IS AN ENRICHMENT
OF THE MUCOSAL AREAS.
SO WHEN WE DO FURTHER STUDIES
WITH THE SHINE SYSTEM AND LOOK
AT THE SEQUENCING DATA AND
THEN DRAFT THESE CORE CURRENT
NETWORKS, IT IS INTERESTING TO
SEE THE CORE CURRENT NETWORKS
ARE MADE AUTOMATICALLY BY THE
PATIENT, FOR EXAMPLE, BASED ON
MUCOSAL BUT BROADER LINOLEIC
DUCTS.
AND THE MOMENT WE ADD LINOLEIC
ACID, SOMETHING ELSE HAPPENS.
YOU CAN SEE HERE THE EFFECT
AND THIS TELLS US MAYBE THESE
ARE AN IMPORTANT STABILIZING
EFFECT FOR THE SYSTEM AND THEN
THE QUESTION IS CAN EACH
SPECIES CONTROL THE STRESS.
SO WE CAN SEE IN THE CASES OF
LINOLEIC ACID, THERE IS
TOXICITY FOR BOTH BACTERIA AND
WE HAD A COMPLETE LOSS OF
BUTRATE PRODUCING
FUNCTIONALITY.
BUT IN THE PRESENCE OF IT, YOU
CAN SEE THE WE HAVE PROTECTION
OF THE LEVELS AND PROTECTION
OF PRODUCING FUNCTION.
SO THIS COULD RESULT
EVENTUALLY IN INFORMATION ON
HOW TO GUIDE US TOWARDS
PRECISION BIOTICS, MAKING
COCKTAILS FROM LINOLEIC ACID,
HYDROGEN PRODUCING CELLS --
[INDISCERNIBLE]
SO TO END, I WOULD LIKE TO
JUST GIVE A COUPLE OF
OPPORTUNITIES AND CHALLENGES.
SO IN VITRO TECHNOLOGY, I HOPE
YOU AGREE WITH ME THAT
PERSONALIZATION IS ACHIEVABLE
AND VALIDATION IS CRUCIAL.
I THINK AN IMPORTANT CHALLENGE
IS WE NEED TO EXPAND THIS TO
THE SITE OF ACTION AND THE
INTRODUCTION OF MEDIUM SUCH AS
LINOLEICS.
AND EVENTUALLY PROVIDE MORE
INSIGHT ON THE PRECISION
MICROBIOTICS IMPORTANCE AND
THEN COMBINATION OF THE
STUDIES IS VERY VALUABLE BUT I
WOULD GO ALSO FROM AVERAGE
DATA TO INDIVIDUAL DATA SO WE
UNDERSTAND IT ON A PERSONAL
LEVEL AND WITH THAT I WOULD
LIKE TO THANK YOU FOR YOUR
ATTENTION.
>> THANKS A LOT, DOCTOR AND
NOW WE MOVE ON TO
MICROBIOACTIVITY
>> OKAY, SO I AM SURE EVERYONE
WOULD AGREE WITH THE STATEMENT
THAT EVEN THOUGH WE HAVE MADE
HUGE AMOUNT OF PROGRESS IN THE
FIELD OVER THE PAST FEW YEARS,
IDENTIFYING CAUSAL OR
MECHANISTIC THINGS IN THE
MICROBIOME IS STILL A
CHALLENGE AND THIS IS AFTER WE
HAVE BEEN ABLE TO PRODUCE
CATALOGS OF GENES AND THE
MICROBES THEY PRODUCE AND THAT
IS TO MY POINT TODAY THAT EVEN
THOUGH WE HAVE THESE, THE
ANALOGIES ARE POOR AT
ANALYZING THE GENES AND STILL
LACK FUNCTIONAL IMPLEMENTATION
SO I THINK THIS IS REALLY ONE
OF THE KEY BARRIERS WE HAVE.
SO ONE OF THE QUESTIONS THAT
HALF OF MY LAB WORKS ON IS
ESSENTIALLY THE TIERS AND
FUNCTION PARTICULARLY IN THIS
RELEVANT NOISE.
SO OUR SOMEWHAT UNIQUE
APPROACH OR FOCUS TO
APPROACHING THIS PROBLEM IS TO
DEVELOP NEW TECHNOLOGIES THAT
WE REFER TO AS FUNCTIONAL
APPROACHES TO DISTINGUISH THEM
FROM BIOGENETIC APPROACHES AND
THEY ARE ALL BASED AROUND THE
SAME FUNDAMENTAL PRINCIPLE
WHEN WE SOMETIMES
CONCEPTUALIZE AS USING THE
HOST AS A LENS TO ILLUMINATE
THE MICRO BIOTICS THAT SHAPE
OUR OWN BIOLOGY AS WELL AS THE
MACROBIOTIC ACTION.
AND THIS IS AROUND THE IDEA
THAT THE MICROBES THAT ARE
LIKELY TO DO INTERESTING
THINGS WITH US ARE THOSE
PRODUCTS THAT CAN INTERACT
WITH OUR OWN BIOLOGY IN SOME
SPECIFIC WAY AT A MOLECULAR
LEVEL.
SO IF WE PRODUCE TOOLS LIKE
FISHING HOOKS THAT FISH OUT
MICROBES DIRECTLY INTERACTING
WITH THE HOST OR BETTER YET,
TO PROFILE POTENTIAL
INTERACTIONS BETWEEN MICROBES
AND VARIOUS HOST PROTEINS THAT
MAY BE SENSING THOSE MICROBES,
THAT MAY SHOW WHAT IS
AFFECTING THEIR SUCCESS.
SO WE HAVE SCHOOL DISTRICT
SOME SUCCESS IN THE PAST WITH
MICROBES AND THINGS YOU HAVE
HEARD ABOUT ALREADY CALLED IGA
AS WELL AS RECENTLY STUDIED
PUBLISHED STUDIES STILL IN
REVIEW THROUGH ULTRA HIGH
INPUT BIOASSAYS AND SO WE CAN
ENGAGE THIS IMPORTANT FAMILY
OF HOST RECEPTORS.
BUT TODAY I WANT TO FOCUS ON A
THIRD AREA OF INTEREST WHICH
IS COMPLETELY UNPICK
ACCOMPLISHED BASED ON THE IDEA
OF PROFILING DIRECT PHYSICAL
INTERACTION BETWEEN IMPACT
MICROBES AND EXTRA CELLULAR
PROTEIN.
SO THIS STORY I WILL TELL YOU
VERY BRIEFLY TODAY STARTED
ALMOST SEVEN YEARS AGO,
ACTUALLY, WITH A CONVERSATION
WITH MY COLLEAGUE ERIN RING AS
WELL AS BOTH OF OUR FIRST
GRADUATE STUDENTS WHO, ONE OF
WHOM HAS TAKEN OVER IN MY LAB
AND ANOTHER WHO WILL COME
LATER TO UNDERSTAND THE
STRUCTURE AND FUNCTION OF THIS
DATA.
BUT THE BASIC IDEA AS I
ELABORATED THAT BACTERIAL
INTERACTION WITH DEXO PROTEINS
MAY REVEAL THE MICROBIOTA AND
THEIR INTERACTIONS.
ANYONE WHO STUDIES THESE WOULD
KNOW WHY THEY ARE INTERESTING
BUT NOT ONLY ARE THERE
INTERESTING OPPORTUNITIES FOR
MICROBES TO INTERACT WITH POST
BARRIER SERVICES BUT SINCE WE
STARTED THIS PROJECT SEVEN
YEARS AGO, A HUGE AMOUNT OF
EMERGING EVIDENCE TO SUGGEST
THAT MICROBES MAY ACTUALLY
HAVE THE OPPORTUNITY TO
INTERACT WITH DIVERSE CELL
TYPES AND THEREFORE THERE ARE
EXTRA CELLULAR AND SEEK CRETED
PROTEINS EVEN IN AREAS WE
PREVIOUSLY THOUGHT WERE
STERILE.
SO DESPITE THE POTENTIAL
IMPORTANCE OF THESE
INTERACTIONS, IF YOU GO TO THE
LITERATURE, YOU WILL FIND
ACTUALLY THIS INTERACTION WITH
THE MICROBIOTA IS ALMOST
COMPLETELY UNMATCHED.
SO ASIDE FROM A FEW REALLY
NOTABLE EXAMPLES, ONE
DESCRIBED BY WENDY HERE AND
OTHER POST SERVICE RECEPTORS,
PARTICULARLY IN THE CONTEXT OF
MODULATION IN COLORECTAL
CANCER, ASIDE FROM A FEW
ANTIDOTES, THESE ARE
COMPLETELY UNMATCHED.
SO WHAT WE SET OUT TO DO IS
DEVELOP A TECHNOLOGY THAT
WOULD SYSTEMATICALLY ALLOW US
TO EXPLORE THIS SPACE AND
SPECIFIC AREAS OF INTERACTION.
SO THE DREAM WAS IN A WAY TO
DEVELOP WHAT YOU CAN KIND OF
CONCEPTUALIZE IN THE MOLECULAR
SEARCH ENGINE THAT WOULD ALLOW
US TO SPONTANEOUSLY OCCUR
ACTIONS BETWEEN THE MICROBES
AND THE BINDING PARTNER.
SO THESE WOULD ALL BE THE
PROTEINS OR WHAT MY COLLEAGUE
REFERS TO AS THE XEXOPROTEUM,
IN A SINGLE TUBE.
AND WITHIN THE INTERACTUM
WOULD BE INTEREST THAT WOULD
ALLOW US TO ASSIGN WHAT WE
THINK OF AS POST DENDRIC
MICROBE FUNCTION AND USE THE
RECEPTORS OF THE MICROBES
ENGAGING, AGAIN TO REITERATE
THE IDEA OF USING A HOST AS A
LENS, USING THE DEEPOLOGY OF
BIOLOGY RECEPTORS TO EXPLORE
THE HYPOTHESIS OF WHAT
RECEPTORS ARE BINDING AND THE
PHYSICIAN LODGIC OUTCOMES THAT
MAY RESULT FROM THOSE
INTERACTIONS.
SO THIS IS A CLASSIC SLIDE,
TECHNOLOGY SLIDE THAT SUMS UP
FIVE OR SIX YEARS OF WORK IN A
SINGLE CARTOON AND I WILL GO
OVER IT QUICKLY BECAUSE OF
TIME.
SO IN ESSENCE, WHAT WE MANAGED
TO DO WAS TO DEVELOP THIS
YEAST SYSTEM IN ERIN'S LAB TO
DEVELOP A LIBRARY OF BAR CODED
YEAST AND HE DID THIS BY
CURATING AND CLONING THESE
INDIVIDUALLY INTO YEAST
SECTORS AND TRANSFORMING THESE
INTO YEAST CLONES SUCH THAT
YOU HAVE A DISPLAY OF PRETTY
TEENS LINKED TO THIS BAR CODE.
THEN WE CAN TAKE THAT LIBRARY
OF YEAST CLONES, MIX IT WITH A
BACTERIA THAT IS LABELED, FISH
OUT THE YEAST AND BECAUSE
THESE ARE BAR CODED YEAST, YOU
CAN THEN USE SIMPLE SEQUENCING
TO DECONVOLUTE THE ENRICHMENT
INTO THE HOST MICROBIOTA
INTERACTOME.
SO WHAT WE HAVE IS THE
INTERACTION AND I ALLUDED TO
WE DIDN'T WANT TO DO THAT JUST
FOR ONE BIOME BUT LOOK ACROSS
MULTIPLE BIOMES TO LOOK FOR
PATTERNS AND UNDERSTAND THE
EXTENSIVE PATTERN INTERACTION
AND WHETHER WE CAN MAKE ANY
PREDICTIONS OF BIOLOGY BASED
ON THAT.
SO WHAT WE DID WAS HAVE OUR
FIRST FORUM ON WHETHER WE CAN
USE THIS FOR INTERACTOMES
ACROSS DIVERSE PH YLOGENIES
AND TISSUE OF ORIGINAL.
SO THIS IS WHAT WE FOUND WHICH
WAS REALLY REMARKABLE.
WE LOOKED ACROSS 519 STRAINS,
MORE THAN OF 0 PERCENT OF ALL
HUMAN EX EXOPROTEINS,
IDENTIFIED THOUSANDS OF
INTERACTIONS INVOLVING
HUNDREDS OF STRAINS AND
PROTEINS.
AND THIS STAIN IS OF TISSUES
AS WELL AS PATTERNS OF
INTERACTIONS.
AND WE WERE ABLE TO VALIDATE
THE INTERACTION WITH OUR
APPROACHES WITH PROTEINS IN
THE CELLS SO THIS IS OUR YEAST
DISPLAY AND THEY ACTUALLY SHOW
OVER ARCHING BINDING PATTERNS
WITH A BIOLOGICAL LOGIC, VERY
INTERESTING TO US BECAUSE KIND
OF A GUT CHECK ON WHETHER THIS
IS WORKING OR NOT.
SO I CAN'T HAVE TIME TO GO
THROUGH ALL OF THIS HERE BUT
ONE OF THE THINGS WE LOOKED AT
IS STRAINS FROM SIMILAR GENRE
ACTUALLY INTERACT WITH
PROTEINS THAT ARE PART OF THE
SAME PATHWAY.
YOU SEE TISSUE EXPRESS
PROTEINS IN SKIN AND MICROBES
IN OTHER SITES DO NOT INTERACT
WITH THOSE PROTEINS.
NOT SURPRISINGLY, A SHARED
INTERACTION AND ESPECIALLY AS
A SPECIES IN GENUS LEVEL, AT
LEAST PARTIALLY EXPLAINED BY
GENE TRANSFERS AND INTERACTION
IN HAVING AN INDIVIDUAL NIB
BUT ALSO ON THE FLIP SIDE AS
YOU HAVE HEARD A LOT ABOUT, WE
HAVE SEEN A LOT OF VARIATION
BETWEEN STRAINS WHICH IMPLIES
FUNCTIONAL RELATION.
WE HAVE ALSO SEEN A MYRIAD OF
INTERACTIONS WHICH WE THINK
APPLY CRITICAL ROLES IN
BACTERIAL LIFE IN THE COMPLEX
OF A HOST INCLUDING NICHE
COLONIZATION, TISSUE
REMODELING AND
IMMUNOMODULATION.
AND I WILL TELL YOU IN THE
LAST COUPLE OF MINUTES A
REALLY FASCINATING ONE WE
THINK EXISTS AND USING THE T
CELL PRODUCED IN MAMALIAN
CELLS.
THIS WAS REALLY FASCINATING TO
US BECAUSE CD7 IS HIGHLY
EXPRESSED IN THE EPITHELIAL
LIMPOCYTES IN THE INTESTINE
AND THE SPECIES DIRECTLY
ENGAGING THESE CELLS DON'T
REQUIRE T CELL SIMULATION FOR
ACTIVATION AND THERE BY
RELIEVING THE PHENOTYPES IN
CROHN'S.
SO WE WERE INTERESTED IN
KNOWING WHETHER THIS WAS HOST
SPECIES SPECIFIC AND FOR BOTH
REVOLUTIONARY AND PRACTICAL
REASONS, WE WERE INTERESTED IN
UNDERSTANDING WHETHER THIS
INTERACTION WAS SPECIFIC TO
HUMAN HOSTS OR WHETHER IT
COULD BE FOUND IN OTHER HOSTS.
AND WE FOUND IN THIS CASE IT
COULD ONLY BIND TO HUMAN CD7
AND COMPLETELY FAILED TO BIND
TO MOUSE CD7.
>> YOU HAVE THREE MINUTES.
>> PARDON?
>> THREE MINUTES.
>> PERFECT, I AM ALMOST DONE.
SO JUST TO SUM UP, WE THINK
THAT TECHNOLOGY REALLY OFFERS
THE FIRST EVER GLIMPSE OF A
COMPREHENSIVE POST MICROBIOTIC
INTERACTOME, IT ALLOWS US TO
GET A GLIMPSE OF COMPREHENSIVE
HOST MARC CROWBEEN IOTA
INTERACTOME, USING A HOST AS A
LENS TO DECONVOLUTE THE
COMPLEXITY OF THE HUMAN
MICROBIOTA AND ALSO TO GAIN
ANS UNDERSTANDING HOW
APPROPRIATE MOUSE MODELS ARE
IN STUDYING EFFECTS OF HUMAN
DISEASE.
SO JUST KIND OF LAST SIDE,
FUTURE OUTLOOK, HOPEFULLY I
HAVE INTRODUCED THIS TO YOU IN
AN INTERESTING WAY ON THE
FUNCTIONAL PROFILING OF THE
MICROBEEN IOME.
AND WHILE I DISPARAGED THESE
IDEAS IN THE BEGINNING, THIS
IS REALLY INTERESTING WHEN WE
COMBINE THE EXPERIMENTAL
PLATFORMS WITH THE DATA, WE
GET THE RESULT FROM THE GBC
WORK I DIDN'T HAVE TIME TO
TELL YOU ABOUT.
WE ALSO FIND THAT THERE ARE
PATIENT SUBSETS THAT HAVE A
SHARED MICROBIAL PICTURE OF
THE DISEASE AND THIS WOULD
ACTUALLY MOVE AWAY FROM
TARGETING MERE MICROBES AND
TOWARDS POTENTIAL HOST TARGET
ZONES COMPUTED WITH PATHOGENIC
MICROBES.
SO WITH THAT, WE WILL THANK
EVERYONE WHO DID THE WORK AS
WELL AS THE NOTABLE FUNDING
FROM NIH AND THANK EVERYONE
FOR THEIR ATTENTION.
>> THANK YOU, THIS WAS REALLY
EXCITING.
SO NOW WE MOVE ON TO THE NEXT
SPEAKER FROM HARVARD
UNIVERSITY WHO WILL TALK ON
MICROBIOME CHEMISTRY.
>> ALL RIGHT, I WOULD LIKE TO
THANK THE ORGANIZERS FOR
INVITING ME TO BE A PART OF
THIS VERY INTERESTING
WORKSHOP.
MY TRAINING IS ORIGINALLY IN
CHEMISTRY AND WHAT INITIALLY
IN MY LABS, MICROBES WAS THE
AMAZING METABOLISM PRODUCED
WITH THESE ORGANISMS.
SO THIS HAS PROVIDED RICH
OPPORTUNITIES TO DISCOVER
ENZYME AND ANA BOLIC
ACTIVITIES BUT I HAVE ALSO
BECOME REALLY PASS IT NEIGHED
BY THE ROLES THESE METABOLITES
PLAY IN COMMUNITIES LIKE
MICROBIOMES.
IT EXPANDS THE TISSUE BODY AND
IMMEDIATE UNITED STATES
REPORTED INTERACTIONS WITH THE
HOST.
WE HAVE SEEN ACTUALLY MANY
EXAMPLES OF THIS THROUGHOUT
THE WORKSHOP, THAT MICROBIAL
METABOLISM CAN BE STRONGLY
CORRELATED WITH HEALTH
OUTCOMES.
HOWEVER OUR UNDERSTANDING OF
THE BIOLOGICAL CONSEQUENCES IS
STILL QUITE LIMITED.
WAS A WAS HIGHLIGHTED IN THE
LAST TALK, MOST ACTIVITIES
HAVE IN THE BEEN LINKED TO
REGIMES OR INSCIENCE AND A
HUGE FRACTION OF THESE GENES
OR MOLECULES ASSOCIATED WITH
THIS COMMUNITY ARE STILL
UNRACQUET RISED AND --
UNCHARACTERIZED.
SO THESE ARE THE TYPES OF
QUESTIONS.
WE USE THESE STUDIES TO GAIN A
MOLECULAR UNDERSTANDING OF
METABOLISM WILL REVEAL NEW
FUNDAMENTAL INSIGHTS INTO THE
BIOLOGY OF THIS COMMUNITY BUT
ALSO PERHAPS ENABLE
THERAPEUTIC INTERVENTIONS
INCLUDING THE SELECTION AND
ENGINEERING OF PROBIOTIC
THERAPIES.
SO FOR TODAY'S PRESENTATION, I
WANTED TO PROVIDE ON WHAT IS
HOPEFULLY A FORWARD-LOOKING
UNDERSTANDING OF THE GUT
BACTERIAL FUNCTION AND THE
ROLE I SEE CHEMISTRY PLAYING
NOW AND IN THE FUTURE.
SO THERE ARE EXAMPLES OF
ENZYME METABOLITE DISCOVERIES
FROM MY LAB BUT I WANT TO
BEGIN BY REEMPHASIZING THIS
PROBLEM.
WE HAVE AN EXTREMELY POOR
UNDERSTANDING OF MICROBIOMES
FROM A FUNCTIONAL PERSPECTIVE.
SO HERE I AM SHOWING YOU DATA
FROM A PERSPECTIVE, THIS DATA
FROM THE HUMAN MICROBIOME
PROJECT AND REALLY SHOWS HOW
ANNOTATIONS OF GENES IN GUT
MICROBIOME SAMPLES IS
PROBLEMATIC.
THERE IS A HUGE GAP IN OUR
ABILITY TO LINK THESE GENES TO
FUNCTIONS CONFIDENTLY.
AND THIS IS OF COURSE A
PROBLEM THAT EXISTS FOR OTHER
MICROBIAL COMMUNES, OTHER BODY
SITES.
SO IF WE WANT TO UNDERSTAND
WHAT THE HUMAN MICROBIOME IS
DOING, WE NEED TO CONNECT
THESE REGIMES TO FUNCTION AND
MY LAB IN PARTICULAR HAS BEEN
TRYING TO MATCH METABOLIC
ACTIVITIES WITH GENES AND
ENZYMES SO AGAIN WE REALLY
THINK UNDERSTANDING BACTERIAL
ENZYMES WILL BE CRITICAL FOR
THE UNDERSTANDING OF
MICROBIOMES, DISCOVERING AND
STUDYING ENZYMES APPROVES OUR
ABILITY TO ANALYZE MICROBIAL
AGAIN HOME IN AND MICROBIOME
SEQUENCING DATA AND MAKE MORE
ACCURATE PREDICTIONS ABOUT THE
CAPABILITIES.
AND ENZYMES THEMSELVES CAN
PROVIDE KEY INSIGHTS IN
ENVIRONMENTAL FACTORS SUCH AS
PH.
FINALLY UNDERSTANDING ENZYMES
CAN HELP US MANIPULATE
MICROBIAL FUNCTION EITHER
THROUGH DEVELOPING SMALL
INHIBITORS OF ENZYME ACTIVITY
OR HELPING US ENGINEER A
PROBIOTIC STRAIN WITH SPECIFIC
FUNCTIONAL CAPABILITIES.
THESE SOMETIMES OF STRATEGIES
CAN BE USEFUL TOOLS TO APPLY
TO ACTUALLY STUDY THE
FUNDAMENTAL ROLES OF METABOLIC
ACTIVITY IN COMPLEX
COMMUNITIES BUT OF COURSE CAN
ALSO BE THE POTENTIAL FOR
THERAPEUTIC INTERVENTION.
SO MUCH OF MY LAB'S WORK IN
THIS SPACE HAS INVOLVED
LINKING KNOWN GUT METABOLIC
ACTIVITIES TO SPECIFIC MIKE
MICROBIAL GENES AND PROJECTS.
AND ONE OF MY FIRST PROJECTS
ILLUSTRATED HOW A CHEMICAL
UNDERSTANDING OF ENZYMES AND
METABOLISM CAN BE VERY
POWERFUL IN THIS COMPLEX
PROBLEM SO THIS ACTIVITY WAS
OF INTEREST TO US BECAUSE IT
GENERATES THIS MOLECULE, TMA
WHICH IS A PRECURSOR TO TMAO
WHICH HAS BEEN LINKED TO
CARDIO METABOLIC DISEASE.
WHEN WE BEGAN OUR STUDIES, THE
GENE THAT ENZYMES ARE
RESPONSIBLE FOR THE CHOL INE
METABOLISM WERE NOT KNOWN.
WE BEGAN OUR STUDY BY THINKING
ABOUT THE ENZYME IN THE
PATHWAY WHICH INVOLVES A VERY
COMPLEX CLEAVE LADIES AND
GENTLEMEN REACTION AND THIS
BIOCHEMICAL LOGIC REMINDED US
OF A BETTER CHARACTERIZED
PATHWAY.
THIS HELPS US ASSIGN THE TWO
ENZYMES IN THE PATHWAY THAT
WERE SHARED TO RESEARCH THE CH
OL INE GENE CLUSTER.
THIS ALSO LED US TO IDENTIFY
EVEN IN THAT CLUSTER, THE GENE
INCLUDING THE KEY ENZYME
RESPONSIBLE FOR METHYLENE
PRODUCTION.
THIS TURNS AUDIT TO BE A
ENZYME IN A MUCH LARGER FAMILY
AND WE COULD GO ON TO
CHARACTERIZE THE ENZYME AND
GAIN A DEEPER UNDERSTANDING OF
HOW IT WORKS AND HOW IT IS
DIFFERENT FROM THE LARGER
ENZYME FAMILY AND THAT
KNOWLEDGE IS CRITICAL FOR
ALLOWING US AND OTHERS TO
BETTER UNDERSTAND THIS
ACTIVITY IN GUT MICROBIOMES.
SO WE COULD MORE ACTIVELY
IDENTIFY THE CHOL INE BACTERIA
AND IDENTIFY THIS GENE IN
SEQUENCING DATA.
WE WERE ABLE TO GENETICALLY
MANIPULATE THE CHOLINE
BACTERIA AND USE THESE IN
ANIMAL MODELS TO STUDY THE
EFFECTS ON VARIOUS PHENOTYPES.
AND WE ALSO WERE ABLE TO
LEVERAGE THE UNDERSTANDING TO
START DEVELOPING SMALL
MOLECULE INHIBITORS WHICH MAY
BE CANDIDATES FOR
THERAPEUTICS.
SO THIS EARLY WORK I THINK
ILLUSTRATES THE VALUE OF BEING
ABLE TO LINK METABOLISM TO
GENES BUT IT ALSO TOOK US IN
AN OPPOSITE DIRECTION,
STARTING OFF BY CONTRACTIZING
A GENE TO A HOST PHENOTYPE AND
TRYING TO UNDERSTAND THEIR
FUNCTIONS.
A LOT OF OUR WORK IN THIS
SPACE HAS INVOLVED A GUT
BACTERIAL GINO TOXIN AND THESE
GENES WERE IDENTIFIED IN E.
COLI STRAINS.
THEY ALSO TURN OUT TO BE
PREVALENT IN A PROBIOTIC
STRAIN.
THESE GENES WERE INITIALLY
IDENTIFIED BECAUSE THEY CAUSED
THE BACTERIA CARRYING THEM TO
BE GINO TOPIC TOWARDS HUMAN
CELL LINES AND OVER THE YEARS,
BACTERIA CARRYING THESE GENES
HAVE BEEN STRONGLY CORRELATED
TO THE DEVELOPMENT OF
COLORECTAL CANCER.
THE ENZYMES INVOLVED IN MAKING
A NATURAL PRODUCT, THE ACTUAL
MOLECULE PRODUCED BY THE GENE
WAS HARD TO ISOLATE AND
CHARACTERIZE EVEN USING
TRADITIONAL METHODS.
SO I DECIDED TO TAKE A
CONVENTIONAL APPROACH TO LEARN
MORE ABOUT THIS MOLECULE.
USING THIS STRATEGY AS WELL AS
ISOLATING METABOL ITES FROM
THE STAIN, WE WERE ABLE TO
COMPOSE A FINAL STRUCTURE OF
THIS GINO TOXIN.
THIS IS A COMPLEX MOLECULE BUT
I WOULD LIKE TO EMPHASIZE ONE
IMPORTANT AND UNEXPECTANT
FEATURE, THESE TWO STRAINS
HAVE A POTENTIALLY REACTIVE
DISPLAY AND THIS UNDERSTANDING
OF THE CHEMICAL STRUCTURE AND
ACTIVITY HAS BEEN NOW REALLY
CRITICAL IN EFFORTS TO BETTER
UNDERSTAND CANCER DEVELOPMENT
AND THE RISK IT MAY POSE NOT
AGENT.
SO THESE ARE EXAMPLES OF
DETRIMENTAL ACTIVITIES THAT
ONE MAY NOT WANT IN A
POTENTIAL BIOTIC BUT WHAT
ABOUT BENEFICIAL ACTIVITIES?
WELL, WE HAVE BEEN RECENT LOO
HE INVESTIGATING ONE SUCH
ACTIVITY AND THIS IS
CHOLESTEROL METABOLISM.
CHOLESTEROL HAS BEEN LONG
HYPOTHESIZED IT IS SPECIFIC TO
THE HOST BUT AGAIN IT IS
DIFFICULT TO CORRELATE BECAUSE
IT IS POORLY UNDERSTOOD.
SO WE USE THIS INFORMATION TO
SEARCH FOR POTENTIAL KLESKO
TROT METABOLIZING ENZYMES IN
GUT MICROBIOMES AND WHAT IS
PARTICULARLY NEAT ABOUT THE
SEARCH WE DID WAS WE WERE ABLE
TO LEVERAGE DATA AND MATCHED
STOOL ENZYMES.
SO WE WERE ABLE TO LOOK FOR
CANDIDATE ENZYMES THAT
CORRELATED WITH THE PRESENCE
OF THIS AND THE TWO STEPS IN
THIS PATHWAY.
SO THE ENZYME IS ACTUALLY
FOUND IN UNCULTURED GUT
BACTERIA, HIGHLIGHTING THOSE
ORGANISMS HAVE AN IMPORTANCE
AND AN UNDER EXPLORED SOURCE
OF METABOLISM.
FINALLY WE ALSO OBSERVED A
CORRELATION BETWEEN HAVING
CHOLESTEROL METABOLIZING
BACTERIA IN ONE'S MICROBIOME
AND HAVING LOWER SERUN
CHOLESTEROL LEVELS SO THAT
CORRELATION IS SUBJECTIVE THIS
ACTIVITY MAY BE BENEFICIAL FOR
THE HOST AND PLAY A ROLE IN
LOWERING CHOLESTEROL.
SO WITH THE IDENTIFICATION OF
REGIMES INVOLVED IN THIS
PATHWAY, THIS HIGHLIGHTS THE
POSSIBILITY OF PERHAPS
ENGINEERING PROBIOTICS TO BE
ABLE TO PERFORM THIS
METABOLISM.
SO I HOPE THE POWER OF
CHEMICAL KNOWLEDGE CAN BE USED
TO GUIDE METABOLISM BUT I WANT
TO TALK ABOUT HOW TO
ACCELERATE THESE AS WELL.
LIKE THE REASON REVOLUTION IN
DNA SEQUENCING, I WOULD ARGUE
WE HAVEN'T YET HAD AFFECTED
OUR ABILITY TO PERFORM
FUNCTIONAL CONTRACT FUNCTION
AND SO WE HAVE THIS --
>> YOU ARE JUST OVER THREE
MINUTES.
>> OKAY, I THINK IT IS
CRITICAL TO PRIORITIZE
FUNCTIONS AND GENES FOR
INTEREST FOR FURTHER STUDY AND
ONE WAY THIS CAN BE DONE IS
FOCUS ON UNCHARACTERIZED
MEMBERS OF LARGE PROTEIN SUPER
FAMILIES AND HERE IS A
SEQUENCE NETWORK BEING
SELECTED, SO WE CLUSTER
PROTEINS BASED ON THEIR
SHARED, POTENTIAL SHARED
FUNCTIONS AND YOU ACTUALLY SEE
WITHIN THIS NETWORK, THERE ARE
MANY CLUSTERS OF ENZYMES WHICH
ARE NOT PROPOSED INACTIVITY.
BECAUSE WE KNOW ABOUT HOW THIS
BROADER ENZYME FAMILY DOES
CATALYSIS, WE MIGHT HAVE A
BETTER STARTING PLACE TO
CHARACTERIZE NEW ENZYME FAMILY
MEMBERS.
ANOTHER STRATEGY MY LAB HAS
BEEN USING IS REALLY ASSESS
THE ABUNDANCE AND DISTRIBUTION
OF PROTEIN FAMILY MICROBIOMES.
SO HERE IS DATA AND USING THIS
WE CAN ACTUALLY IDENTIFY
ENZYME FUNCTION THAT ARE
PARTICULARLY PROMINENT IN
ENVIRONMENTS LIKE THE GUT
MICROBIOME.
SO FOR EXAMPLE, WE ACTUALLY
FOUND THE MOST ABUNDANT PLACE
FOR THE ENZYME WAS
UNCHARACTERIZED AND WE WERE
ABLE TO ACTUALLY CHARACTERIZE
THE FUNCTION OF THIS ENZYME
AND DISCOVER THAT IT IS
INVOLVED IN METABOLIZING THE
HOST AND DIETARY ABUNDANCE OF
OBJECTION SEEPROLINE.
SO WE ARE NOW USING THIS
APPROACH TO ANALYZE OTHER
TYPES OF DATA SETS AND WE
THINK BY APPLYING IT IN A
COMPARATIVE MANNER TO BE
PARTICULARLY HELPFUL IN
ALLOWING US TO FIND UNKNOWN
ENZYMES THAT MAY BE CONNECTED
TO THE DISEASE.
SO FINALLY WE ALSO THINK THERE
ARE OPPORTUNITIES TO
CHARACTERIZE MEMBERS OF LARGE
ENZYME FAMILIES IN PARALLEL
AND WE STARTED DOING THIS
THROUGH CATAPULTING ENZYMES
AND THE FAMILY OF
UNDERSTANDING THE NEURAL
TRANSMITTER DOPAMINE.
BECAUSE THIS TYPE OF ACTIVITY
IS INDUCED BY THE SUBSTRATE,
WE RECOGNIZED WE COULD USE RNA
SEQUENCING TO RAPIDLY CONNECT
OTHER DEHYDROXYLATION EVENTS
RESPONSIBLE FOR THAT
CHEMISTRY.
WE CAN UNDERSTAND THE
CORRELATION BETWEEN GENE
PARENT AND ARE METABOLISM AND
THAT WORKFLOW IS EX SAINTING
AND A WAY TO SCALE THE
FUNCTION TO MANY ENZYMES
SIMULTANEOUSLY.
SO I WOULD LIKE TO NOW END BY
HIGHLIGHTING I THINK THERE HAS
BEEN VERY ENCOURAGING PROGRESS
IN THE LAST TEN YEARS AND IN
CHARACTERIZING FUNCTION OF
MICROBIOMES BUT WE NEED TO DO
MORE, TRULY ANALYZING THE
FUNCTIONAL REVOLUTION NEEDS TO
BE DONE BUT WE KNOW THEY PLAY
A ROLE SO I WOULD LIKE TO END
BY THANKING MY COLLABORATORS,
SOURCES OF FUNDING AND YOU ALL
AGAIN FOR THE OPPORTUNITY TO
PARTICIPATE IN THE WORKSHOP.
>> VERY EXCITING, VERY NICE
TALK..
VERY INTERESTING.
NOW WE WILL MOVE ON TO OUR
NEXT SPEAKER TALKING ABOUT
PROBIOTICS IN HUMAN
MICROBIOME.
>> OKAY, GREAT, THANKS SO MUCH
EVERYONE.
THIS IS REALLY A DELIGHT TO
WATCH AND PARTICIPATE IN THE
WORKSHOP THE PAST COUPLE OF
DAYS.
I WANT TO START BY EMPHASIZING
A POINT ABOUT THE WORKSHOP
THAT GARY ALLUDED TO THIS
MORNING, THAT I THINK
SOMETHING THAT REALLY MAKES IT
STRONG IS THE DIVERSITY OF
DEFINITIONS OF PROBIOTICS THAT
WE HAVE ESPECIALLY COUNTERED
IN THE PAST COUPLE OF DAYS
WHERE WE ALL KIND OF AGREE
THAT IT HAS SOMETHING TO DO
WITH INFLUENCING MICROBIAL
COMMUNITY BY ADDING LIVE
MICROBES, BUT WE HAVE HEARD
ABOUT PROBIOTICS FROM THE
PERSPECTIVE OF DIET DERIVED,
WE HAVE HEARD ABOUT PRODUCTS
THAT CAN BE ORALLY DELIVERED
OR OTHERWISE AND I RECOGNIZE
AFTER JULIA'S TALK USING SKIN
BIOTICS AS A EXAMINER.
WE HAVE HEARD ABOUT PROBIOTICS
THAT CAN BE LITERALLY THE
ADDITION OF WHOLE LIVE
MICROBAL CELLS OR THOSE THAT
ARE TRANSIENT OR HAVE A
BENEFICIAL EFFECT ON THE
COMMUNITY BASED ON THE
PRODUCTS THEY MAKE SO I THINK
IT IS IMPORTANT TO REMEMBER IN
CONTEXT OF THE SCIENCE WITH
REGARD TO WHICH PROJECT, PART
OF WHAT HAS MADE THE WORKSHOP
SO GREAT IS THE SCIENCE AROUND
THE PROBIOTICS CAN BE USED TO
HELP EACH OTHER, TO GET AN
UNDERSTANDING OF WHY THEY WORK
AND HOW TO MAKE THEM WORK
BETTER.
SO WITH THAT IN MIND, I WANT
TO SPEND SOME TIME TODAY ON
RESULTS WE HAVE FROM THE HUMAN
MICROBIOME BIOACTIVE RESOURCE
OR HMBR AND TO POTENTIALLY
IDENTIFY AND CHARACTERIZE AS A
FOLKS ON THE GUT MICROBIOME.
AND HERE WE HAVE WHOLE
MICROBIAL CELLS THAT CAN BE
BENEFICIAL OR PRO INFLAMMATORY
IN THE GUT.
ALSO BIOACTIVE IN THE SENSE OF
MICROBIAL PROTEINS PRODUCTS OR
SMALL MOLECULE MODIFICATIONS
THAT INDUCE SOME PHENOTYPE ON
THE HOST.
AGAIN IN HMBR, WE ARE FOCUSING
ON INFLAMMATORY BOWEL DISEASE
AND GUT INFLAMMATION BUT A LOT
OF THE RESOURCES THAT COME OUT
OF THIS ARE GENERALIZED TO
OTHER SETTINGS OF
MICROBIOTICS.
SO THERE IS A WHOLE LOT OF
INFORMATION I WON'T HAVE TIME
TO TALK ABOUT TODAY BUT HMBR
DOES EVERYTHING FROM SCALING,
FINDING, MICROBIOME
COMPUTATIONAL METHODS, DATA
RESOURCES SPECIFICALLY FOR
IBP, METHODS I WILL FOCUS ON
TODAY FOR ACTUALLY WHAT EMILY
WAS ALLUDING TO AT THE END OF
HER TALK, PRIORITIZATION OF
THE MOST INTERESTING POTENTIAL
BIOACTIVE DEVELOPMENTS, BE
THEY WHOLE SPECIES OR OTHER
PRODUCTS AND I WILL TALK A
LITTLE ABOUT THIS TODAY.
IT WILL BLEED A LITTLE INTO IN
VITRO AND SCREENING METHODS
AND KUDOS TO THE TEAM FOR
PUTTING ALL OF THIS ONLINE
THROUGH THE PORTAL THAT YOU
ARE WELCOME TO TAKE A LOOK AT
FOR MORE INFORMATION.
SO MANY OF THE EXAMPLES I WILL
FOCUS ON TODAY COME FROM THE
DATA RESOURCES THAT HMBR
PROVIDES WHICH IS A UNIFORMLY
PROCESSED SET OF JUST OVER
7500IBD MICROBIOME PROFILES.
AND THESE THEN HARMONIZE WITH
EACH OTHER FOR ABOUT 15 TOTAL
STUDIES USING A PACKAGE THAT
IS NOW GENERALLY AVAILABLE
WITH METADATA SO THE SCORES
AND MEDICATION USAGE MEAN
ROUGHLY THE SAME THING FROM
DATA SET TO DATA SET.
SO IN THE DATA HERE, WE
UNIFORMLY PROCESS THESE DATA
SETS.
MUFFIN PROVIDES A BATCHED
CORRECT ADJUSTMENT AND WE CAN
IDENTIFY WHICH MICROBES OR
PRODUCTS ARE ASSOCIATED WITH
THE GINO TYPE TOPICS AND
WHETHER THERE ARE MULTIPLE
MICROBIAL SUBTYPES FOR BOWEL
DISEASE FOR EXAMPLE, OR
WHETHER THERE ARE CONSISTENT
PATTERNS FOR MICROBIOME
PROFILES WITHIN THE
POPULATION.
SO THIS RESULTS IN JUST OVER
516 SAMPLES FROM SEVERAL DATA
SETS WHICH ARE LONGITUDINAL
AND YOU CAN SEE FROM THE QUICK
BREAK DOWN HERE, A FOURTH WITH
CROHN'S DISEASE, A QUARTER
FROM A VARIETY OF DIFFERENT
POPULATIONS, BACKGROUNDS,
SAMPLING METHODOLOGIES, ET
CETERA, ET CETERA.
A QUICK ASIDE ABOUT ANOTHER
PLATFORM THAT HAS REALLY
HELPED IN THE UNIFORM
PROCESSING OF THESE DATA IS
THAT WE JUST RECENTLY UPDATED
THE BIOBAKERY WHICH IS OUR
SUITE OF MOSELEY SHOTGUN
COLLABORATIVE METHODS AND NICK
IS WORKING HARD ON A FOURTH
VERSION THAT INCORPORATES
INFORMATION FROM SHOTGUN
METADATA ASSEMBLIES SO KEEP AN
EYE OUT FOR ANOTHER VERSION IN
THE NEXT FEW WEEKS THAT
PROVIDE A UNIFORM WAY TO
PROCESS SHOTGUN METAGENOMES
WHILE TAKING INTO ACCOUNT FROM
RECENT METAGENOMIC ASSEMBLIES
AND THIS LETS US DO THINGS
LIKE PROFILE MORE DIFFICULT,
MORE CHALLENGING ENVIRONMENTS
A LITTLE BETTER AND I ALSO
WANTED TO CALL OUTLY VIE'S
GROUP ON THE METADATA PACKAGE
THAT REPRESENTS TENS OF
THOUSANDS METAGENOMES IN A
SIMILARLY PROCESSED MANNER FOR
IBE AND OTHERWISE.
SO THEN ONE THING THE HMBR
MAKES VERY EASY IS TO QUICKLY
COMPARE FOR A SIMPLE MICROBIAL
PROFILE ASSOCIATED WITH IBD
INFLAMMATION ACROSS THE
DIFFERENT STUDIES AND FIND
CONSISTENCY THAT MATCHED VERY
CLOSELY WHAT HAS BEEN
PUBLISHED BEFORE.
SO GARY MENTIONED THIS EARLIER
THIS MORNING WHERE THERE IS
THIS WELL APPROACHED AND
ESTABLISHED PRO INFLAMMATORY
MICROBES IN CD/UC, DEPLETED IN
ERRANT ORGANIZATIONS AND ARE
MANY TYPICAL MICROBES THAT
LIKE IN COLORECTAL CANCER TEND
TO BE ENRICHED IN IBD.
MANY OF THESE HAVE BEEN SEEN
IN STUDIES WITH DATA SETS AND
DIFFERENTIATE WHICH ONES ARE
SPECIFICALLY ASSOCIATED WITH
INFLAMMATION VERSUS USED IN
MEDICATIONS, STEROIDS AND
SUCH.
WHAT GETS MORE INTERESTING IS
DIGGING INTO THE HOW AND WHY
OF THIS AND WE CAN EXPLAIN
SOME OF THESE IN TERMS OF THE
FUNCTIONAL DATA THAT COMES
ALONG WITH THEM.
SO THE SETS THAT ARE UNIQUE
SNEAK TO FUNCTIONALLY ENRICHED
IN THE SHOTGUN METAGENOMES,
THINGS LIKE IRON SEQUESTRATION
WHICH TENDS TO BE A UNIQUE
TIPPING POINT OR RESOURCE
DURING INFLAMMATION AND THEN
LOST IN INFLAMMATION MORE
BROADLY ASSOCIATED
POLYSACCHARIDE MEMORIMENTATION
THAT ARE LOST.
AND REALLY THERE WAS JUST ONE
PATTERN OF THIS ANALYSIS OR
ONE SET OF MICROBIAL CHANGES
THAT GOT MORE AND MORE EXTREME
IN CONJUNCTION WITH GREATER
INFLAMMATION.
EVEN WHEN WE LOOKED FOR
MULTIPLE DIFFERENT TYPES OF
MICROBIAL CONFIGURATIONS OR
MULTIPLE DIFFERENT WAYS IN
WHICH INFORMATION MIGHT
DISRUPT THE MICROBIOME.
THERE WAS REALLY JUST ONE
DIRECTION OF CHANGE HERE WE
COULD SEE VERY CLEARLY WITH
THE INFLAMMATION INGREDIENT IN
A CROHN'S DISEASE POPULATION.
THIS SAME GRADIENT EXISTED IN
OUR NONIBD ROLES WHICH ALLOWS
TO US PICK OUT THE NONIBD BUT
NOT TRULY HEALTHY INDIVIDUALS
AND THEN THE ONE EXTREME THAT
IS GENERALLY PREVALENT IN OUR
HEALTHY CONTROLS.
SO WE EXPECTED THERE WOULD BE
THESE MORE EXTREME TYPES OF
IBD BUT WHAT WE FOUND IS THERE
IS A GRADIENT OF CHANGE THAT
OCCURS ACROSS THE POPULATION
OF SUBJECTS.
AS ANOTHER QUICK ASSIGNMENT ON
THE METHODOLOGY, ONE OF THE
THINGS THAT WE HAVE BEEN
INTERESTING IN BREAKING OUT A
LITTLE MORE IN MICROBES
ASSOCIATED WITH ACTIVITIES
HERE AND WITH COLORECTAL
CANCER, WHAT THE STRAINS OF
THESE ARE OR WHAT CASSETTES OR
ENRICHMENT MIGHT BE IN A
SPECIFIC SPECIES IN
ASSOCIATION WITH IBD OR OTHER
PHENOTYPES.
SO A VERY EARLY PACKAGE WE'RE
WORKING ON THAT ESSENTIALLY
LOOKS AT FOUR STREAMS.
AS WAS MENTIONED EARLIER, IT
WILL BE VERY DIFFICULT WITH
SHOTGUN GENOMES BUT IT SAYS
OKAY HERE ARE THE SAMPLES
WHERE I DON'T JUST DETECT THE
ORGANISM BUT I CAN TELL WHICH
STRAIN IT IS IN THE SAMPLE,
WHETHER THEY ARE STRAINS OF
THE SAME SPECIES IN AND
OUTSIDE OF A PHENOTYPE SO THIS
IS A COLORECTAL CANCER EXAMPLE
RATHER THAN A IBD EXAMPLE.
OR ENRICHMENT SO MAYBE THERE
IS NOT SOMETHING THAT
IDENTIFIES A PARTICULAR STRAIN
BUT SUBSETS OF THOSE STRAINS
ENRICHED IN A PHENOTYPE.
SO THIS IS A VERY EARLY STAGE
BUT FEEL FREE TO LOOK AT THIS
AS A UPCOMING METHOD OF
DEVELOPMENT.
FINISHING UP THOUGH, JUMPING
BACK TO OUR IBD SAMPLES AGAIN,
UP WITH OF THE THINGS WE
WANTED TO USE THE DATA
RESOURCES OF THE HB MR FOR IS
HAVE A BETTER UNDERSTANDING
WHY PRO AND ANTIINFLAMMATORY
MICROBES MIGHT DO THE THINGS
THEY DO, ESPECIALLY IN THE
CONTEXT OF POTENTIAL
PROBIOTICS.
SO ERIC AND OTHERS IN THE
GROUP PUT TOGETHER A SYSTEM
FOR TAKING THIS GIANT MASS, AS
EMILY MENTIONED IN THE
PREVIOUS SLIDE, DISEASE
ASSOCIATED BUT UNCHARACTERIZED
MICROBIAL PRODUCTS AND TRYING
TO PRIORITIZE AND AN NOTATE
THOSE BASED ON INTEGRATION OF
DIFFERENT INFORMATION ACROSS
MICROBIOME POPULATIONS.
SO THE SYSTEM OF METADATA
STARTS WITH A COLLECTION OF
METAGENOMES, IDENTIFIES THE
GENE FAMILIES AND TAXOMIC
ASSOCIATION AND THEN
INTEGRATES A SET OF
INFORMATION FROM METAGENOMIC
SEQUENCES, THEIR HOMOLOGY TO
KNOWN ISOLATES AND THEN
NONHOMOLOGY INFORMATION FROM
THINGS LIKE THEIR CARRIAGE OR
ECOLOGICAL DISTRIBUTION TO
THEN PRIORITIZE --
>> YOU HAVE THREE MINUTES.
>> TIME WARNING, GREAT, THANK
YOU.
TO THEN PRIORITIZE BASED ON
ECOLOGICAL PHENOTYPIC AND
SEQUENCE BASED INFORMATION
WHICH OUT OF THE MANY MILLIONS
OF UNCHARACTERIZED PROTEINS
MIGHT BE THE ONES THAT BEST
EXPLAIN HEALTH OR DISEASE
ASSOCIATED MICROBES AND THESE
WE WILL REFER TO AGAIN AS KIND
OF SHORTHANDED BIOGENE
PRODUCTS.
SO USING A SUBSET OF THE DATA
FOCUSING ON THE HUMAN
MICROBIOME PROJECT IBG SHOTGUN
GENOMES, THE DATA WAS ABLE TO
CLUSTER GENES RESULTING IN A
BIT UNDER 45 MILLION
INDIVIDUAL MICROBIAL READING
STRAINS, CLUSTERING DOWN TO
JUST OVER TWO MILLION UNIQUE
NUCLEOTIDES AND A MILLION AND
A HALF PROTEIN FAMILIES THAT
ARE MORE GENEROUS WITH AMINO
ACID IDENTITY.
SO THESE CORRESPOND ROUGHLY
WHERE YOU WOULD EXPECT A
SEQUENCE TO HAVE A UNIQUE
BIOCHEMICAL FUNCTION AND AS
EMILY ALSO MENTIONED IN THE
TALK, ONLY A THIRD OR A
QUARTER OF THEM HAVE
REASONABLE CHARACTERIZATION.
EITHER THEY ARE TOO DIVERTED
TO BE CONFIDENT ABOUT
TRANSFERRING BIOHOMOLOGY IN
THE REMAINING OR
UNCHARACTERIZED.
SO I WAS ABLE TO CATALOG THESE
SEVERAL MILLION BREATHE TEEN
FAMILIES FROM THE MMV2 AND
PRIORITIZE THEM AND FOR THE
SAKE OF TIME, I WILL SKIP OVER
THE PROCESS OF THAT
METHODOLOGY.
A COUPLE OF EXAMPLES THAT END
UP GETTING SNIPPED OFF THE TOP
ARE A COUPLE THOUSAND PROTEINS
THAT ARE PRIORITIZED MOST IBD
RELEVANT OVER THE POTENTIAL
MILLION PROTEINS, A FEW WE
HAVE BEEN ABLE TO VALIDATE.
ONE IS A COLLECTION OF PILL
VARIANTS ENRICHED WHERE
SURPRISINGLY EVEN THOUGH WE
DIDN'T LOOK AT TRANSCRIPT
GENOMIC INFORMATION, ALMOST
ALL THE ENTIRE SET OF THE
VARIANTS WERE OVEREXPRESSED IN
ACCOMPANYING METATRANSCRIPT
INFORMATION DURING
INFLAMMATION AND THESE TURNED
OUT TO BE IMMUNOGENIC WHEN
TESTED IN CELL LINES
AFTERWARDS AND AGAIN FOR THE
SAKE OF TIME, I WON'T GET INTO
IT BUT THE SAME WAS TRUE FOR A
HIGHLY PRIORITIZED FAMILY OF
OTHER SAMPLES SPECIFICALLY
WITH MUCOUS.
AND WAS UNABLE TO FORM PROPER
BIOFILMS.
AND SO I WILL THANK THOSE IN
MY LAB AND THE FUNDERS AND
THANK YOU FOR THE OPPORTUNITY.
>> OKAY, NEXT WE HAVE THE NEXT
SPEAKER TALKING ABOUT
MICROBIOT A PATHOGENS.
IT IS NOW ESTABLISHED THAT ALL
MATTER OF ORGANISMS AND
MICROBIOTA THAT LIVE ON US AND
IN US AND INVOLVED IN OUR BODY
SIN SIS MAY BE DIFFERENT IN
THE MICE AND REGIONS WE STUDY
BUT POTENTIALLY SERVE SIMILAR
FUNCTIONS, CONTRIBUTE TO ALL
HEALTH AND THE SEVERITY OF
OUTCOME OF DISEASES WE
ENCOUNTER DURING LIFE.
SO IF WE LOOK AT ANIMALS,
HOWEVER, THE SITUATION IS
DIFFERENT.
IN LABORATORY MICE WHICH WE
HAVE NOT BEEN ABLE TO KNOW THE
PATHOGENICS OF DISEASES,
POPULATED WITH MICROBIOTA
WHICH IS NOT VERY SIMILAR TO
WHAT THEY HAVE IN THE WILD.
AND TO PROVE THAT MICROBIOTA
CONTRIBUTES TO SPECIFIC
DISEASE PATHWAYS, THESE MICE
HAVE BEEN PREPARED FOR
MICROBIOMES.
SO THIS IS AN ASPECT OF THE
STUDY THEN THAT MODELS WHAT IS
FOUND IN THE NATURAL WORLD.
AND THE QUESTION IS WHAT CAN
WE LEARN FROM THE MICROBIOME
ABOUT INFLAMMATION IMMUNE
RESPONSES.
SO THIS STUDY STARTED WHEN
STEFAN JOINED THE LABORATORY
SEVERAL YEARS AGO.
HE IS NOW AN INDEPENDENT
INVESTIGATOR IN GERMANY.
HE ESSENTIALLY WENT OUT AND
TRAPPED WHITE MICE, EUTHANIZED
THEM AND STUDIES THEIR
MICROBIOME.
IN THE ANALYSIS, THE WHITE
MOUSE BIOME WAS VERY MUCH LIKE
THE MOUSE READINGS --
[INDISCERNIBLE]
SO WHAT CAN WE DO TO.
SO WE LOOK AT CLEAN LABORATORY
MICE AND THIS IS DONE
BASICALLY EVERY TEN
GENERATIONS.
SO IN CONTRAST HERE, WE TOOK
CRYO PRESERVED EMBRYOS AND
TRANSFERRED THEM INTO LIVE
MICE.
THE OFFSPRING THEN HAD THE
GENETICS OF THE INFLAMMATORY
MOUSE STRAIN BUT ALSO THE
WHITE MICROBIOME.
AND THIS WILL NOT MAKE THEM AN
IDEAL MODEL BUT AT LEAST
POINTING IN THE RIGHT
DIRECTION AS REPRESENTED BY
THIS ARROW AND MAY INCREASE
THE PRESENTATION OF BIOME
INFORMATION WITH THESE MOUSE
MODELS.
THE HUMAN MICROBIOME IN THE
GUT, NOT IDENTICAL IN THESE
MICE, NOW DOWN TO GENERATION
6, 7 OF THESE MICE AND WITH
EACH GENERATION, THE
MICROBIOME IS TRANSPOLICE
DEPARTMENT TO THE OFFSPRING.
SO IN THE GUT, THE INSTANCE IS
NOT EXACTLY THE SAME AS THE
WHITE MICE BUT ALSO INCLUDED
THE OTHER DATA SETS FROM THE
WHITE MICE.
SO YOU LOOK AT THE COLONY, YOU
HAVE ALSO MORE VIRAL AND
SPATIAL BIOME IN THESE MICE.
SO WE LOOK AT IMMUNE WITH THE
GENES AND BLOOD TO SEE THE
WHITE MOUSE TRANSCRIPTOME.
SO HOW DOES THIS TRANSLATE TO
IMMUNE RESPONSES?
SO TO BE ABLE TO TEST THIS, WE
ENGAGED THIS STUDY TO LOOK AT
THE BASICALLY WE FIND TWO
MODELS THAT WERE DOCUMENTED
AND ONE OF THEM I WILL SHOW
FROM THIS STUDY, THE
LABORATORY MICE ININJECTION OF
THIS AND WHAT WAS SUPPOSED TO
BE DEVELOPED IN THE TREATMENT
FOR ANY DISEASE SO WITH THE
INDUCTION OF INFORDHAM TORE
CCYTOKINES WITH THESE MICE,
YOU SEE THE HIGHER CYTOKINES
IN THE LAB MICE THAN THE
WILDLING MICE.
THE ONE EXCEPTION WAS I10 WHEN
ANTIINFLAMMATORY OCCURS IN
GREATER LEVELS IN THE LAB MICE
THAN THE WILDLING MICE.
SO THE IN LOOKING AT THE
METABOLISM, THIS STUDY SHOWS
THE MICROBIOME HAS TWO
EFFECTS.
IN THE LAB MICE, AND THE
WILD-TYPE, IT PROTECTED THEM
FROM THE HIGH FAT DIET.
SO IF YOU LOOK AT THE CONTENT
TO SEE THE LAB MICE LIVER
ENZYMES ARE MUCH HIGHER IN THE
LAB MICE THAN IN THE WILDLING
MICE.
THIS WAS DUE TO THE HIGH FAT
DIET BECAUSE INITIALLY WE WERE
INTERESTED IN OBSERVING THAT
BUT THE WILDLING MICE NEVER
DEVELOPED ANY SIGNIFICANT
OBESITY.
WE TRIED TO TREAT THE OBESE
MICE BUT UNFORTUNATELY THIS
DID NOT WORK.
THE LAB MICE DIET AND THE
WILDLING MICE AND TRANSFER THE
MICROBIOME, THE LAB MICE DO
NOT BECOME PROTECTED FROM HIGH
FAT DIET AND OBESITY.
AND AT THE SAME TIME WHEN WE
TRIED TO ELIMINATE THE
WILDLING MICROBIOME AND THESE
ACCUMULATE IN THE WILDLING
MICE, THEY DO NOT HAVE THE
SAME NET EFFECT.
THE EXPERIMENT ITSELF, YOU SEE
HERE THE MICROBIOME OF THE LAB
MICE IS MOVED TO THE LEFT ON
AXIS1 AND DID NOT MATCH THAT
CLOSELY TO THE WILDLING MICE
AND THEN TREATED WITH
ANTIBIOTICS, YOU SEE THE SAME
SHIFT FOR BOTH THE LAB MICE
MICROBIOME AND THE WILDLING
MICROBIOME.
SO BOTH WERE AFFECTED BUT THE
EFFECT ON THE WILDLING MICE
WAS NOT REPLICATED.
SO WHEN YOU TAKE LAB MICE AND
FOSTER THEM, THEN YOU CAN
TRANSFER THE PROTECTIVE
EFFECTS OF THE WILD MICE
MICROBIOME TO THE LAB MICE IN
RESPONSE TO HIGH FAT DIET.
THE WEIGHT GAIN IN THE COHORT
MICE WAS NOT FOUND IN THE WILD
MICE.
AND THIS IS INTERESTING
BECAUSE THEY USE THE SAME
AMOUNT OF ENERGY SO WHAT WE
LOOKED AT WAS THE ENERGY
EXPENDITURE.
THERE WAS A HIGHER BODY
TEMPERATURE IN THE WILDLING
MICE COMPARED TO THE LAB MICE
AND YOU SEE THAT IT IS GREATER
IN WILDLING MICE, THE
TEMPERATURE AND THE SAME FOR
MALES AND FEMALES ON ANY OF
THE DATA I SHOWED.
THIS IS INTERESTING THAT THE
WILDLING MICE HAVE A HIGHER
BODY TEMPERATURE THAN LAB
MICE.
WHAT DOES THIS TELL US ABOUT
HUMANS?
WE KNOW WITH HUMANS, THE
NORMAL BODY TEMPERATURE IS SET
TO 37 DEGREES CELSIUS AND THIS
WAS ESTABLISHED BY A GERMAN
PHYSICIANS IN LEIPZIG IN 1851
AND HE MEASURED THE
TEMPERATURE IN 25,000 PATIENTS
THAT PROVIDED IN TEMPERATURE
BEING SET TO CERTAIN -- OR
98.6 DEGREES FAHRENHEIT.
AT THAT TIME THE STANDARD LIFE
EXPECT TAPS SEE WAS ONLY 38
YEARS AND IT IS BECAUSE THERE
WERE MANY INFECTIONS THAT
BASICALLY KILLED PEOPLE EARLY
IN LIFE.
SO WHAT HAPPENED AFTER THIS?
VERY INTERESTING TO SEE WHAT
HAPPENED.
THERE WAS A RECENT PAPER
PUBLISHED THAT BASICALLY USED
TEMPERATURE MEASUREMENT AS A
PUBLISHED IN HUMANS, AND WAS
USED TO SEE ABOUT TEMPERATURE
CHANGE OVER TIME.
WHAT YOU CAN SEE IS THERE IS A
SIGNIFICANT DECREASE IN BODY
TEMPERATURE FROM THE 19TH
CENTURY TO TODAY.
AND 1.6 PERCENT IN BODY
TEMPERATURE OVER THIS PERIOD
OF TIME AND AND DECREASE IN
MEN AND FEMALES.
SO THIS MEANS WE MAY HAVE LOST
SOME OF THE PROTECTION EFFECTS
THAT THE WILD MICE MICROBIOTA
HAS GIVEN US WITH EXPANDED
LIFE THAT MAY HAVE ROBBED US
OF POTENTIAL MICROBES.
SO THIS IS WHAT I SHOWED.
THE PROTECTION AGAINST
DIET-INDUCED OBESITY
THROUGHOUT ADULT LIFE AND
ANIMAL MODELS WITH NATURAL
MICROBIOTA MAY INCREASE THE
USEFULNESS OF LABORATORY MICE
AS MODELS FOR HUMAN IMMUNE
RESPONSES IN PRECLINICAL
STUDIES AND ALLOW
MECHANISTICALLY, RESEARCH ON
THE ROLE OF ALL KINGDOMS OF
COMPLEX MICROBIOTA IN HEALTH
AND DISEASE.
SO I WOULD LIKE TO THANK THOSE
WHO HELPED ME IN THIS WORK, MY
LAB AND COLLABORATORS, ALL
INTRAMURALLY AND EXTRAMURALLY
AND LIKE TO MENTION THESE --
[INDISCERNIBLE]
THANK YOU.
I WILL TURN IT OVER TO THE
NEXT SPEAKER.
>> THANK YOU VERY MUCH BARBARA
REHEMANN.
OUR NEXT TALK IS SAMEER
SONKUSALE.
>> CAN YOU SEE MY SCREEN?
>> YES BUT NOT -- OKAY NOW IT
IS RIGHT.
>> OKAY, SO FIRST I WILL THANK
THE ORGANIZERS FOR INVITING ME
TO PRESENT HERE.
I BRING A DIFFERENT
PERSPECTIVE TO THIS
CONVERSATION.
I REALLY ENJOY LISTENING AND
LEARNING FROM ALL OF YOU IN
THE LAST TWO DAYS AND I BRING
A PERSPECTIVE AS I AM TRAINED
AS A ELECTRICAL AND
BIOENGINEER AND AM TRAINED IN
SOME OF THE CHALLENGES THAT
YOU ALL ARE LOOKING AT AND
MADE SOME PROGRESS TO SHOW WE
CAN DO SPATIAL MAPPING OF THE
MICROBIOME USING ENGINEERING
INNOVATIONS SO THIS IS MORE OF
AN ENGINEERING TALK RATHER
THAN A MICROBIOME DISCUSSION.
LET'S SEE IF I CAN ADVANCE MY
SLIDES.
SO I HAVE SOME CON FLICKS.
ONE OF THE KEY MESSAGES THAT
CAME THROUGH DURING THE TWO
DAYS OF DISCUSSIONS IS THAT
THE MICROBIAL
BIOEMPLOYEOGRAPHY OF THE GUT
IS REALLY IMPORTANT AND THIS
IS A PICTURE I BORROWED FROM
ONE OF THE REVIEW ARTICLES AND
IT SHOWS THAT DIFFERENT ORGANS
IN DIFFERENT AREAS OF OUR GI
TRACT HARBOR DIFFERENT
MICROBIAL SPECIES.
SO UNDERSTANDING WHERE AND HOW
THEY INTERACT WITH THE HOST IS
REALLY IMPORTANT.
SO I ACTUALLY TRIED TO COME UP
WITH AN ANALOGY TRYING TO
UNDERSTAND, AND I DON'T HAVE A
SLIDE FOR THAT BUT THESE ARE
THE KEY OBSERVATIONS OF ALL
THE TALKS I HEARD OVER THE
LAST TWO DAYS AND IT WAS
MENTIONED THE MICROBIIOTA IN
SMALL INTESTINE IS QUITE
DISTINCT FROM THE MICROBIOTA
IN THE STOOL AND REALLY DOES
NOT CAPTURE THE DIVERSITY OR
CON SHORTIUM SEEN IN THE SMALL
INTESTINE.
ALSO AS I JUST ALLUDED TO
EARLIER, THE MICROBIOME
VARIOUS LONGITUDINALLY ACROSS
THE GI TRACT FROM THE STOMACH
TO THE COLON AND ACTUALLY THE
MUCOSAAL MICROBIOTA IS QUITE
DISTINCT FROM THE LUMINAL
MICROBIOTA SO THE SPATIAL
MAPPING IS REALLY IMPORTANT
WHERE YOU ARE TRYING TO
UNDERSTAND THE MICROBIOME HOST
CONDITION FOR UNDERSTANDING A
CONDITION.
FINALLY, WE RECOGNIZE IT IS A
LIVING, DYNAMIC ECOSYSTEM AND
WE HEARD CIRCADIAN RHYTHM
INFLUENCES THE MICROBIAL
COMPOSITION SO IN SOME WAY
ANALYZING A STOOL SAMPLE DOES
NOT WIDELY REPRESENT THE
SPATIAL AND TEMPORAL
DISTRIBUTION.
WHEN YOU ARE TRYING TO CAPTURE
THE MICROBIOTA FROM THE STOOL,
IT IS EX EXTREMELY HARD TO I
HAVE AN UNDERSTANDING THE
COMMUNITY IS FACING AND
ESSENTIALLY THE FECAL MATTER
ANALYSIS IS INADEQUATE.
SO I FAIL TO RECALL WHO
INTRODUCED ME TO THIS BUT THIS
POINT THAT IT IS A VERY
COMPLEX ECOSYSTEM, YOU HAVE
LOTS OF DIFFERENT ORGANISMS IN
DIFFERENT AREAS, THERE ARE
MICROCLIMATES AND
MICROENVIRONMENTS THAT ARE
VERY IMPORTANT, SUPPORTING
DIFFERENT ORGANISMS ALL THE
WAY TO SMALL INSECTS,
BUTTERFLIES, TO LARGE ANIMALS
AND ANIMALS THAT LIVE AT THE
BOTTOM IN THE SO I WILL AND
THEN THERE ARE SOME SPECIES
THAT LIVE ON THE CANOPY ON THE
ROOFTOP AND THESE SPECIES, YOU
KNOW, EVEN DURING THE DAY, YOU
HAVE DIFFERENT SPECIES
POPULATING THAT ARE COMING OUT
AND THE LIFETIME OF DIFFERENT
SPECIES THAT ACTUALLY SPENT
TIME IN THE FOREST.
AND THE WAY WE ARE TRYING TO
UNDERSTAND THE RAIN FOREST OR
THE WAY I SEE IT, THE ANALOGY
HERE, ESSENTIALLY ALL YOU ARE
DOING IS BLENDING ALL THE
INFORMATION IN A BLENDER AND
THEN ANALYZING THE STOOL
SAMPLE AND HOSTING THE STOOL
SAMPLE SOMEHOW PRESENTS OR
WILL CAPTURE THE EXTREME
SPATIAL AND TEMPORAL DIVERSITY
THAT THE RAIN FOREST HAVE.
SO I BELIEVE THE FIRST PROBLEM
TO SOLVE HERE IS LOOK AT WAYS
THAT GEOGRAPHY MAPPING CAN
HELP TO REPRODUCE THE
DIVERSITY OF THE MICROBIOME
THAT WILL GIVE US MORE
SOLUTION SO ESSENTIALLY THIS
IDEA IS USED TO LOOK AT THE
BACTERIA AND OBJECTIVES AS
WELL.
SO I WAS RECRUITED WHEN I WAS
LOOKING TO WORK ON DEVELOPING
DIAGNOSTIC PLATFORMS, THE
PROGRAM MANAGER APPROACHED ME
AND SAID CAN YOU DEVELOP TOOLS
OR DEVICES TO SOLVE THIS
PROBLEM AND AN ENGINEER LIKES
RESOLVING CHALLENGES AND
CHALLENGES SO IT WAS AN
INTERESTING PROJECT OVER THE
LAST FIVE OR SIX YEARS AND I
WILL SHOW YOU SOME PLATFORMS
DEVELOPED OVER TIME THAT WILL
TAKE US IN THAT DIRECTION.
SO THIS IS THE FIRST BUILD, IT
IS CALLED AN OSMOTIC PILL THAT
ALLOWS YOU TO TAKE A SPATIALLY
SAMPLING FROM THE GI TRACT.
IT IS EXTREMELY SAFE.
THERE IS NO ELECTRONICS IN
THIS PILL.
IT IS A FACETED PILL, HAS FOUR
HELICAL CHANNELS DRIVEN BY A
MICROPUMP AND THE MICROPUMP
USES THE PRINCIPLE OF
RESPONSES ON ONE SIDE AND THEN
BASICALLY PULLS THE FLUID
THROUGH THE ECOCHANNELS WHERE
YOU ESSENTIALLY HAVE A
MICROPUMP PULLING A EXAMINER
IN.
THERE IS A MAGNET INSIDE AND I
WILL EXPLAIN THE PURPOSE OF
THE MAGNET AND THEN BASICALLY
SOME DYE FOR EASY SPOTTING.
SO THE DESIGN OF ALL THE
INLETS AND EXIT NOZZLE IS VERY
WELL CONTROLLED SO YOU HAVE
THE BEST POSSIBLE SAMPLING
SCENARIO.
SO THIS IS HOW THE PILL LOOKS,
THIS PICTURE HERE JUST A
COLLECTION OF DIFFERENT PILLS.
THE GOOD NEWS HERE IS THE PILL
DESIGN IS VERY SIMPLE, IT CAN
BE TREATED, IT NOT EXPENSIVE
SO THIS BOWEDS WELL FOR THE
COMMUNITY.
IF YOU ARE TRYING TO USE THE
PILL FOR LARGE STUDIES, THESE
PILLS ARE STRAIGHTFORWARD FOR
US TO MAKE AND HAPPY TO SHARE
THESE WITH YOU FOR YOUR OWN
INVESTIGATION.
THIS PICTURE SHOWS YOU THE
DESIGN OF THE SEMI PERMEA --
SEMIPERMEABLE ACTION AND THE
WAY IT WORKS, YOU INGEST THE
PILL WITH AN ENTERIC COATING,
PH DEPEND ENT AND PROTECTS THE
PILL IN IT THE ACIDIC
ENVIRONMENT OF THE STOMACH.
AFTER IT REACHES THE SMALL
INTESTINE, THE ENTERIC COATING
WILL BE DISSOLVED AND WILL
START THE SAMPLING PROCESS.
YOU CAN CONTROL THE SAMPLING
PROCESS BY CONTROLLING THE PH
OF THE SOLUTION SO YOU CAN
EITHER START SOONER OR LATER
BASED ON HOW YOU FORM THIS
COMPOSITION.
IMAGINE IT HAS A VERY
IMPORTANT ROLE.
THE PILL MOVES ON ITS OWN DUE
TO NATURAL PERISTALTIC
FUNCTION SO YOU HOLD THE
MAGNET CLOSE TO THE LOCATION
YOU WANT AND THIS ESSENTIALLY
CAPTURED MORE SAMPLING FROM
THAT AREA.
SO THE PILL IS ESSENTIALLY A
PROPORTIONAL SAMPLING PILL AND
KEEPS SAMPLING UNTILL ALL THE
CHANNELS IN THE PILL ARE FULL
AND THEN WHEN IT EXITS ON THE
OTHER SIDE, YOU CAN ANALYZE
THE CONTENTS OF THE PILL, DO
ALL YOUR OMIC STUDIES ON THE
CONTENT.
SO IT IS NOT JUST SAMPLING THE
MICROBIOME BUT THE BILUMEN AND
ESSENTIALLY ALL THE OTHER
CONTENTS IN THE AREA OF THE GI
TRACT.
SO WE MAKE VERY DIFFERENT
VERSIONS OF OSMOTIC PILLS.
THE ONES INJECTED IN ANIMALS
ARE THE ONES ON THE LEFT BUT
WE ALSO MAKE A PILL THAT CAN
BE TESTED WITH LARGE AND SMALL
ANIMAL USE, SHOWING YOU
DIFFERENT SAMPLING CAPACITY
FOR DIFFERENT PILLS THAT WE
MADE WITH DIFFERENT FUNCTIONS.
SO YOU CAN TEST ALL THE WAY
FROM MICE TO LARGE ANIMALS.
SO THE PUMPING ACTION IN THE
PILL IS USING PRINCIPLE0s
MOST SIS, LOOKING AT THE
PERMEABLE MEMBRANE ON ONE SIDE
AND OVER TIME, CREATES0s MOT
TICK PRESSURE DIFFERENCE AND
THAT IS BASICALLY WHAT IS
DRIVING.
WHAT IS SHOWING HERE IS IT
CONTINUES TO OPERATE UP TO 48
HOURS SO SAMPLING FOR A VERY
LONG TIME IN THE PILL.
SO THIS IS POTENTIALLY A VERY
SIMPLE WAY OF GETTING THE
AQUEOUS SAMPLE FROM THE
ENVIRONMENT.
SO THE FIRST TIME I WAS TRYING
TO WORK ON THIS, WE HAD COULD
COME UP WITH OUR OWN CUSTOM
SETUP FOR THE FUNCTION OF THE
PILL, JUST MAKING SURE THE
PILL WORKS AS WE INTENDED.
SO HOW THE PILL IS INSERTED,
IS THERE ANY LEAKAGE AND ONCE
YOU SAMPLE THE CONTENT, DOES
ANY OF IT LEAK OUT DOWNSTREAM
OF THE COLON AND THEN YOU HAVE
TO MAKE SURE THE ACTIVATION
PORTION IS WORKING, WHEN YOU
BRING THE MAGNET TO THE PILL,
DOES IT EXAMINER MORE IN THE
AREA YOU WANT AS OPPOSED TO
ANOTHER.
SO WE BASICALLY MADE A SET OF
EX VIVO GI TRACT AND
ESSENTIALLY MONITOR THE
PERISTALTIC MOTION WITH THE
PUMP AND TRYING TO UNDERSTAND
HOW THE GI TRACT MOVES.
TO COME UP WITH A CLEAR
UNDERSTANDING OF THE ASPECTS
OF THE PILL THAT CONTRIBUTE TO
THE SAMPLING PROCESS MORE THAN
ANYTHING.
SO WE REALIZED THE PILL DID
WORK WELL, THE CONTENTS OF THE
PILL AND THE SAMPLING ACTION
IS QUITE RELIABLE.
>> YOU ARE JUST UNDER THREE
MINUTES.
>> OKAY, THANK YOU.
SO WE DID A LOT OF LEAKAGE AND
CONTAMINATION STUDIES AND IN
THE INTEREST OF TIME, I WILL
NOT GO OVER THE DETAILS OF
THIS BUT BASICALLY A SETUP
THAT EXPOSES THE PILL TO
CERTAIN CONTENTS AND MAKE SURE
THE SAMPLE YOU ACQUIRED IS
POTENTIALLY THE SAMPLE YOU
INTENDED TO THIS SHOWS HERE IT
IS CAPABLE OF SAMPLING THREE
DIFFERENT DYES WITHOUT ANY
LEAKAGE OR CONTAMINATION.
SO THE PILLS ARE TESTED IN
VIVO, IN THE ANIMAL.
SO THIS IS THE PCO A PLOT OF
WHAT WE FIND IN THE PILL
THROUGH THE DIFFERENT FEATURES
OF THE GI TRACT.
THIS IS JUST A VERY SMALL
STUDY ON A PIG AND THEN THERE
ARE TWO IN VIVO STUDIES WITH A
MOUSE AND CAT AND THE STUDIES
HERE SHOW WE ARE CAPABLE OF
SAMPLING FROM THE REGION OF
THE GI TRACT WHERE WE
INTENDED.
SO WE ALSO DID ANOTHER STUDY
IN MONKEYS WHERE WE ALSO -- SO
THIS STUDY WAS NOT TO DO
TARGETED SAMPLING BUT TO FIND
OUT WHETHER IT IS DIFFERENT
THAN OTHER SPECIES AND WE
FOUND THAT YES WHAT WE SEE IN
THE PILL IS A PRESENTATION OF
THE ENTIRE GI TRACT, NOT JUST
WHAT YOU FIND IN THE FECES.
SO THERE ARE SOME CHALLENGES
WITH THE0s MOT TICK PILL.
WE ARE WORKING ON NEW VERSIONS
OF THE PILL AND ONE OF THE
THINGS WE OBSERVED IS THERE IS
SOME CONTAMINATION OF THE PILL
CONTENT DOWNSTREAM AND YOU
HAVE TO BE ABLE TO SAMPLE
HIGHLY VISCOUS GI CONTENT.
SO WE MADE SOME NEW PILLS AS I
DISCUSSED, AND THESE ARE PILLS
THAT ACTUALLY WORK BY SAMPLING
FROM THE LIPS ON THE SIDE AND
WITH THE ACTION OF THE GI
TRACT WILL ACTUALLY PUSH THE
SAMPLE INTO THE PILL.
AS IT GET IN THE PILL, THERE
ARE THESE TINY BEADS, WATER
ABSORBING BEADS AND OVER TIME
ONCE IT IS FULL, THEY LOCK.
SO BECAUSE OF THIS CLOSING
MECHANISM, YOU HAVE ALMOST NO
LEAKAGE OR CONTAMINATION AND
ARRIVED AT THE SAME CONCLUSION
THAT THE PILL HAS LITTLE
LEAKAGE OR CONTAMINATION.
WE HAVE A VERSION 3 OF THE
PILL CALLED THE ARCHIMEDES
SCREW.
IT IS A TINY BIOPSY DEVICE,
VERY GENTLE AND ESSENTIALLY
ALLOWS SAMPLING OF THE MUCOSA.
SO I WILL SHOW YOU THIS IS HOW
IT WORKS, HAS TINY MOTOR AND
WITH AN ON/OFF CONTROL,
TRIGGERS THE PILL TO TURN ON
AND OFF BASED ON WHERE YOU
WANT THE SAMPLE.
SO ONCE YOU KNOW WHERE THE
PILL IS, YOU CAN ACTIVATE IT
USING A MAGNET WITH THE MOTOR
INSIDE THAT WILL POTENTIALLY
ALLOW YOU TO SAMPLE THE
CONTENT.
SO DESIGNED CAREFULLY, THIS
WILL ALSO ALLOW YOU TO SAMPLE
THE MUCOSAL MICROBIOME.
SO THIS IS SHOWING THE VIDEO
FROM THE TOP VIEW AND SOME
EXPERIMENTAL STUDIES, NEXT
SHIED, WE WILL MOVE FORWARD
AND THIS IS THE SAME SET SHOWN
EARLIER FOR CHARACTERIZING THE
FUNCTIONALITY.
BEFORE I END, I JUST WANT TO
GIVE YOU AN OVERVIEW, THERE IS
A LOT OF OPPORTUNITIES FOR
ENGINEERS TO CONTRIBUTE TO
THIS AREA OF PROBIOTICS.
OVER THE YEARS, WE HAVE
DEVELOPED A LOT OF DEVICES AND
THIS IS JUST SHOWING YOU A
LANDSCAPE OF WHAT HAS HAPPENED
SO FAR.
A PIN CAM IS VERY WELL-KNOWN
FOR ENDOSCOPY AND I SHOWED YOU
A PILL THAT CAN DO NONINVASIVE
BIOPSY, THERE ARE DEVICES THAT
CAN TRACK WHERE THE PILL IS
INSIDE THE GI TRACT.
THERE WAS RECENT WORK ON
TRACKING, YOU KNOW, ALL THE
GASSES IN THE SMALL INTESTINE
SO THIS ALLOWS US TO CAPTURE
THE FATTY ACIDS IN THE SMALL
INTESTINE.
JUST VERY EXCITING WORK
HAPPENING IN THE AREA OF
INGESTIBLE DEVICES AND I THINK
THE COMMUNITY WILL BE VERY
INTERESTED IN CONTRIBUTING AND
WITH THAT, I WILL STOP, THANK
YOU.
>> OKAY, THANK YOU, OKAY,
GREAT.
Dr. VERMA?
>> OUR NEXT DISCUSSION WILL BE
HELD BY MY COMODERATOR BUT
FIRST AN ANNOUNCEMENT?
>> YES, I KNOW WE ARE A LITTLE
OVER FOLKS BY TEN MINUTES BUT
I STILL WANT TO GIVE EVERYBODY
A FIVE MINUTE BREAK
>>> AND WELCOME BACK,
EVERYBODY, AFTER A SHORT BREAK
BEFORE WE BEGIN OUR QUESTION
AND ANSWERS SO TAKE IT AWAY.
>> THIS IS A GREAT WAY TO END
THE WORKSHOP.
I FELT THESE TALKS EMPHASIZED
THE NEED FOR MECHANISTIC DATA
AND CURRENT CONVENTIONALITY OF
THE MICROBIOME HOST AND HOW IT
RELATES TO DISEASE AND I GUESS
I WOULD START BY SAYING HOW
CAN WE LEVERAGE THESE
TECHNOLOGIES, KIND OF MODEL
THIS FOR THE DYNAMIC NATURE OF
THE THESE INTERACTIONS?
OR CAN YOU DO IT, OR IS IT
JUST ONE MORE DIFFICULTY IN A
VERY COMPLEX MODELING SYSTEM?
>> MAYBE I CAN START
ANSWERING.
WITH RESPECT TO THE
LONGITUDINAL MODEL, YES, OF
COURSE BUT WITH REGARD TO THE
INTRUSIONS IN THE MOUSE MODELS
COULD IMPAIR THE FUNCTIONING
MICROBIAL CONDITION.
>> OKAY, WHAT ABOUT IN TERMS
OF THIS, YOU KNOW, THIS TALK
HAS BEEN A LOT ON THE
MICROBIOME BUT REALLY
INVOLVING PROBIOTICS.
SO WHERE DOES PRECISION
PROBIOTICS FIT INTO YOUR
SYSTEM IN TERMS OF HOW THEY
MIGHT BE USED TO DEVELOP THE
PRECISION PROBIOTICS?
>> WELL, IF I LOOK AT OUR
SITUATION, I WOULD SAY WE
STARTED FROM IN VIVO WITH THE
PATIENT, SEE IN THE COMMUNITY
OTHER FUNCTIONALITIES AND
TRYING TO CHASE WHAT IS GOING
ON IN THE ENVIRONMENTS AND
THAT IS ACTUALLY LEADING US TO
IDENTIFICATION OF CERTAIN BUGS
OR CERTAIN FUNCTIONS THAT SEEM
TO BE MISSING AND WE CAN
ALLOCATE THESE TO THE SPECIFIC
SITES OF INFECTION.
AND I THINK WITH MY TALK, I
TRIED TO INDICATE HOW WE COULD
ACTUALLY COMBINE THIS
INFORMATION TO SEE, OKAY, WHAT
MIGHT FIT WITH ONE ANOTHER,
WHAT ARE FUNCTIONAL
COMPLIMENTARY TO EACH OTHER
AND THEN TO START COMPOSING
THESE COCKTAILS.
SO THAT IS ONE OF THE WAYS
THAT ARE BEING DEVELOPED AND
THAT ARE DONE IN VERY SIMPLE
STRAIGHTFORWARD SYSTEMS BUT
NEED TO BE DONE IN QUICK
CLINICAL IN VIVO STUDIES
BEFORE MEDICAL TRIALS.
>> AND YOU ALL HAVE QUESTIONS
FOR EACH OTHER.
I SEE KURT HAS HIS HAND
RAISED.
>> GEMMA IS BEFORE ME.
>> OKAY, GO AHEAD.
>> RIGHT, SO AS THE
PERSPECTIVE OF ENGINEERING I
SHARED WITH YOU, JUNG, WITH
PROBIOTICS, WE CAN UNDERSTAND
HOW THEY TRAIN IN RELATION TO
THE EPITHELIAL SAMPLES AND
TRACING THOSE FROM DIFFERENT
LOCATIONS OF THE PATIENT,
EITHER SMALL OR LARGE
INTESTINE AND ALSO YOU CAN
MATCH THE DIFFERENT TYPE OF
MICROORGANISMS AS WELL.
SO THAT IS ONE POSSIBLE
APPROACH THAT OUR SYSTEM CAN
CONTRIBUTE FROM IN STUDY AS IT
IS NOW.
>> THANK YOU, CURTIS?
>> SOMETHING TOM SAID
RESONATED WITH ME IN RESPONSE
TO BOTH OF QUESTIONS IN
THAT FROM A BIOPERSPECTIVE,
SOMETHING WE FOUND HELPFUL AND
MANY OF US HIGHLIGHTED THIS
AFTERNOON, THE IMPORTANCE OF
SLIDING BACK AND FORTH ALONG
THAT SCALE BETWEEN BIG
POPULATION STUDIES AND THEN
IMMUNOLOGICAL BIOLOGICAL
MECHANISTIC STUDIES AND IT IS
EASY FOR ONE PROJECT TO GET
STUCK AT ONE END OF THAT
STRICT TRUM BUT IN ORDER TO
FIND AND TRANSLATE PROBIOTICS
DEFINED BROADLY, BEING ABLE TO
MOVE FROM ONE INTO THE OTHER
AND BACK IS PARTICULARLY
HELPFUL.
>> ONE. QUESTIONS WE HAD
COMING IN JUST DURING THE
CHAT, I THINK IT WAS TO TOM
AND ABOUT THE CHEMICAL
COMPOSITION OF THE MEDIUM SO I
THINK YOU MAY HAVE SAID
SOMETHING IN THE CHAT BUT OUR
AUDIENCE AT LARGE MAY BE
INTERESTED SO WHAT IS THE
EXPECTED LOOMAL FACTORS ON ALL
YOUR OUTCOMES?
>> WELL, IT IS HUGE.
WE WORK IN A CONVENTIONAL
BASIS BUT IF YOU ARE TRYING TO
TAKE FECAL SAMPLES FROM
DONORS, OF COURSE YOU HAVE TO
CONSIDER THE FIBER INTAKE
OTHER OTHER THINGS THAT MIGHT
HAVE AN IMPACT ON NOT ONLY
UPPER DIGESTION BUT ALSO
MICROBIAL.
AND IT HAS A TREMENDOUS
DIFFERENCE AND YOU CAN SEE
FROM THE BIOGRAPH CALL GROWTH
ON ONE HAND AND THEN ON THE
OTHER HAND, TOTALLY DIFFERENT
SO YES, THAT IS ONE THING YOU
HAVE TO TAKE INTO THE
EQUATION.
>> ANOTHER QUESTION COMING IN
THROUGH THE CHAT WAS ABOUT THE
WILDLING MICE IN TERMS OF HOW
LONG, HOW MANY GENERATIONS
THEY RETAIN THEIR MICROBIOME
AS WILDLING MICE?
>> YEAH, WE DON'T KNOW.
I ASSUME EVENTUALLY SOMETHING
WILL GET LOST.
WE ARE CURRENTLY AT GENERATION
6-7 AND IT IS THE SAME
PHENOTYPE AND WE HAVE KNOCKOUT
WILD MICE AND WE ASSUME THAT
THE PATHOGENS MAY ALSO NOT BE
THAT COMMON SO I THINK
EVENTUALLY WE WILL HAVE TO
EXPOSE THEM AGAIN BUT SO FAR
IT HAS BEEN STABLE.
>> OKAY, A QUESTION COMING IN
FROM THE AUDIENCE AT LARGE AND
THAT IS TO Dr. VALKAS WHICH
IS THE E. COLI USED TO TREAT
PATIENTS, BENEFICIAL PATIENTS
WITH IBD, YOU SAID IT WAS
PHENO TOXIC AND SO THE
QUESTION IS, IS THAT INVENTED
OR DOES THIS STRAIN HAVE
PREVENTIVE OR LOW-LYING
PROTECTION AS WELL?
>> YEAH, KIND OF THE DEBATE
ABOUT WHAT THESE GENES ARE
DOING IN THE MUCOSAL HAS BEEN
GOING BACK AND FORTH NOW WITH
TWO GROUPS REPORTING DIFFERENT
GENOTYPES AND THERE IS ALSO
INTERESTINGLY SOME CROSS TALK
WITH PROTEINS INVOLVED AND
MAKING THIS UNITOXIN AND
TRANSPORT SOME OF THE PRODUCTS
THAT ARE SUPPOSED TO BE
INVOLVED IN THE BENEFICIAL
EFFECTS OF THE MUCOSAL.
SO THERE IS KIND OF, YEAH, BIG
QUESTIONS REGARDING YOU CAN --
IF THIS STRAIN HAS BEEN USED
FOR SO LONG, YOU KNOW, IS THAT
MAYBE AN INDICATION THAT, YOU
KNOW, IT IS NOT LIKELY TO
REALLY BE INVOLVED IN CANCER
IN HUMANS?
THERE IS STILL A LOT OF
QUESTIONS ABOUT WHETHER THE
ACTIVITY IS ACTUALLY OCCURRING
IN PATIENTS WHO ARE TAKING
THIS STRAIN.
CERTAINLY I THINK IT MAY
DEPEND ON WHERE THE STRAIN IS
IN THE GUT AND PARTICULARLY
WHETHER IT CAN CONTACT THE GUT
EPITHELIUM BECAUSE THE RESULT
FROM EXPOSURE IS CONTACT
DEPENDENT SO IF THE ORGANS ARE
NOT CONTACTING THE FECAL
CELLS, THERE SHOULDN'T BE
GINO -- GENOTOXICITY SO A LOT
OF QUESTIONS STILL COMING.
>> SO WE WOULD ALL LOVE TO
HEAR YOUR THOUGHTS ON WHAT ARE
THE CRITICAL THOUGHTS IN OUR
KNOWLEDGE, SOME OF THE
METHODOLOGY, GAPS IN THE
METHODOLOGY FOR THE RESEARCH
AREAS OR, YOU KNOW, WHAT NEW
RESOURCES OR METHODS ARE
NEEDED TO FILL THESE GAPS IN
EITHER THE SHORT OR LONG-TERM.
SO WE WOULD LOVE TO HAVE A
LITTLE BIT OF YOUR INSIGHTS
INTO THESE AREAS.
THESE ARE THE QUESTIONS FROM
EACH SESSION.
>> YOU WANT TO GO FIRST?
>> YES, WHAT CONFUSES ME IS
THIS SINGLE CELL SORTING SO
BASED ON THE SORTER, YOU CAN
ACTUALLY LOOK AT FUNCTIONAL
MICROBES AND ALSO SPECIFIC
LABELING OF THESE.
ONE CAN ALSO LOOK AT SPECIFIC
METABOLIC INTERACTIONS SUCH AS
METABOLISM AND SEE TO WHAT
EXTENT THE MICROBES ARE
DIRECTED IN METABOLISM.
AND I THINK NEXT STEP WOULD
BE, OKAY, HOW CAN WE FURTHER
ADVANCE THAT INSIGHT.
SO IF YOU CAN SEPARATE THEM,
CAN YOU ALSO STUDY THEM IN
MORE DETAIL JUST FROM AN ANA
TOMIC PERSPECTIVE AND AN
INTERESTING QUESTION FOR
ISOLATION PURPOSES SO THAT IS
SOMETHING I AM VERY
INTERESTED.
IN.
>> OKAY, YOU ALSO HAD YOUR
HAND UP?
>> YES FROM, A SIMILAR
PERSPECTIVE WITH MY PREVIOUS
COMMENTS THAT THE GLASS HALF
EMPTY ANSWER MIGHT BE THAT
THERE IS OF COURSE NO SILVER
BULLET BUT THE GLASS HALF FULL
ANSWER FROM SOMEBODY WHO WORKS
IN THE ENVIRONMENT THAT IS
ENRICHED FOR HUMAN POPULATION
GENETICISTS FOR EXAMPLE AND
OTHER TYPES OF MOLECULAR
ETIOLOGY, HUMAN SEQUENCING
DIDN'T SOLVE EVERYTHING 20
YEARS AGO AND EVERYTHING BUILT
ON THAT TO ADDRESS THESE
QUESTIONS IN HUMAN GENETICS
HAVE BEEN BETTER IN THE THODZ
FOR POPULATION STUDIES, BETTER
TECHNOLOGIES AND ANALYTIC
METHODS FOR WIN KNOWING OUT
SIGNAL VERSUS NOISE,
COLLECTING FROM MORE DIVERSE
POPULATIONS AND THEN JUST
ELBOW GREASE ON FOLLOWING UP
ON THE ESPECIALLY TEAM LOGICAL
PART IN DETAIL.
SO WE HAVE SEEN THAT PLAY OUT
IN TERMS OF HUMAN GENETICS THE
LAST FEW YEARS.
AND I FORGOT TO SHOW THE CURVE
IN THE PRESENTATION EARLIER
BUT WE'RE STILL AT THE
BEGINNING OF THAT PROCESS FOR
MICROBIOTIC DEVELOPMENT.
WE NEED BIGGER, MORE DIVERSE
POPULATIONS WITH MORE CAREFUL
METHODOLOGIES AND THEN JUST
PLAIN FOLLOWING UP ON WHAT THE
MECHANISMS AND PROMISING HITS
OF THE BEST COUPLE OF THOUSAND
OUT OF THE TOTAL POSSIBLE
MILLIONS OF HITS WE GET FROM
THOSE.
>> ANY OTHER TAKERS ON THIS
QUESTION?
ONE OF THE THINGS --
>> I GUESS I WILL JUST FILL
OUT WHAT TOM SAID.
ALSO I THINK GENERALLY INSIGHT
TO TRANSFER, GOING TO BE VERY
BORING, VERY TECHNICAL ANSWER
BUT WE STILL DON'T HAVE A GOOD
WAY TO LOOK AT WHAT MICROBES
ARE DOING WHERE THEY ARE DOING
IT IN AN UNBIASED, BROADER
WAY.
AND WE CAN DO THIS MAYBE A
LITTLE BIT ONE GENE AT A TIME
BUT I THINK IT WOULD BE --
YEAH, IT WOULD BE PRETTY
REVOLUTIONARY TO BE ABLE TO DO
THAT ON A GENOME SCALE AND
RIGHT NOW I GUESS MAYBE CURTIS
OR OTHERS COULD COMMENT BUT I
THINK JUST MICROBIAL
TRANSCRIPTOMICS GENERALLY IS
STILL RELATIVELY UNDER
UTILIZED AND I DON'T KNOW IF
THAT IS BECAUSE EVERYONE HAS
CONVERGED ON THE IDEA IN A IF
YOU ARE GETTING RNA FROM
STOOL, IT IS NOT MEANINGFUL
ANY WAY BECAUSE THAT IS NOT
WHERE THE MEANINGFUL THING IS
HAPPENING OR IF THERE ARE
OTHER TECHNICAL REASONS THAT
THIS IS STILL -- YEAH, FEW AND
FAR BETWEEN, THESE KINDS OF
STUDIES.
>> IN OUR HANDS, THERE ARE
DEFINITELY TECHNICAL HURDLES
STILL, WHERE IT IS JUST PLAIN
HARD TO GET GOOD UNBIASED
OSAMA RNA FROM THE STOOL SO
THE COMBINATION OF EXTRACTION
AND DEPLETION OF RNA AND
SEQUENCING OF A SUFFICIENT
AMOUNT OF MATERIAL FROM THE
RESULTING EXTRACT, IT IS JUST
PLAIN TOUGH TO PUT ALL THOSE
STEPS TOGETHER.
SO I HAVE LEAN IS BE REALLY A
TECHNICAL CHALLENGE.
IN THE FEW CASES WHERE WE HAVE
BEEN ABLE TO GET MICROBIAL
TRANSCRIPTO ME DATA, IT IS NOT
THE END YOU WILL BE ALL, YOU
HAVE TO GET IT IN THE RIGHT
PLACE AT THE RIGHT TIME BUT
DEFINITELY INFORMATIVE WHEN
YOU CAN GET IT.
[LAUGHTER]
>> GREAT.
I WAS GOING TO SAY ONE OF THE
THINGS TO KIND OF ANNOUNCE TO
EVERYBODY WHO MAY NOT ALREADY
KNOW IT, THERE IS AN
ANNOUNCEMENT OF FUNDING,
OPPORTUNITY ANNOUNCEMENT
IDENTIFYING MICROBIAL
M ETABOLITES AND THE NUMBER IS
PAR-21-253 AND YOU CAN E-MAIL
ANY OF US TO GET IT.
THE INSTITUTE HAS A NUMBER OF
THEM.
[INDISCERNIBLE]
SO PLEASE LOOK AT THAT FOR A
FUNDING OPPORTUNITY.
ANYTHING ELSE THAT YOU WOULD
LIKE TO ASK EACH OTHER?
SAMEER?
>> YES, I JUST DIDN'T GET A
CHANCE TO TALK ABOUT ONE OF
THE ASPECTS THAT WAS POSSIBLE
WITH THE INGESTIBLE DEVICES
AND I KNOW WE TALKED ABOUT
GRAFTING TO PROVIDE THE EXACT
LOCATION WHERE YOU WANT IN
VIVO.
THE PILL CAN ALSO BE USED AS A
TARGETED DEVICE TO DELIVER
PROBIOTICS FOR WHAT YOU WANT
FOR A TARGETED LOCATION BASED
ON WHERE YOU IMMOBILIZE THE
PILL AND RELEASE.
SO THIS WILL ALSO TAKE FROM
THE IMPOSITION FROM THE
APPROACH IS ALSO DELIVERY.
SO THERE IS A LOT OF CONTROL
OVER THE SPATIAL AND TEMPORAL
ASPECT NOT JUST FOR SAMPLING
BUT ALSO TO TARGET BI
DIRECTIONAL.
YOU CAN SAMPLE AND WHILE YOU
ARE DOING THAT, THERE IS A
POTENTIAL THERE TO HAVE BI
DIRECTIONAL CAPABILITIES THAT
WE HAVEN'T EVEN EXPLORED.
I AM SURE I AM GOING TO GET A
LOT OF FEEDBACK FROM ALL OF
YOU AND LOVE TO HEAR FROM ALL
OF YOU BUT THERE IS A LOT OF
POSSIBILITY WE HAVEN'T
EXPLORED FROM THE
TECHNOLOGICAL SIDE.
SO I WOULD SAY JUST BRING YOUR
VISION OUT, PUT IT OUT THERE
AND LET US FIGURE IT OUT.
AND YOU KNOW IT MAY BE HARD
BUT WE WILL START SOMEWHERE
AND I THINK THERE IS A BIT OF
FAST-FORWARD TO GETTING THERE.
SO JUST COUPLE OF RESPONSES
HERE.
THANKS.
>> THANK YOU.
>> I KNOW THAT IT IS KIND OF
TOWARDS THE END OF THE DAY,
THAT EVERYBODY IS QUITE TIRED
AS THIS HAS BEEN A WONDERFUL
PRODUCTIVE MEETING --
>> SORRY, DID YOU SEE TOM HAS
HIS HAND RAISED?
>> NO, I DID NOT, TOM?
>> YEAH, THANKS FOR THAT.
MAYBE I HAVE A QUESTION FOR
Dr. KIM THAT RELATES TO THE
DIMENSIONS OF THE MOUSE AND
THE IMPORTANCE ON THE
MICROBIOME, JUST WONDERING
WHAT IS THE DIMENSION OF THE
MUCOSAL LAYER THAT WE CAN
GENERATE INTO THE TIPS YOU ARE
GENERATING AND DOES IT ALSO
COME, AS YOU DEMONSTRATED
THERE IS OXYGEN GRADIENT BUT
YOU HAVE THAT FURTHER
EXTENDING INTO A MUCOUS LAYER
IN THE SYSTEM AS WELL AND IF
SO, IS THERE A DIFFERENCE
BETWEEN LOWER AND UPPER GI
WITH DIFFERENT THICKNESSES OF
THE MUCOSAL CELLS?
>> SO I WILL GIVE YOU A COUPLE
OF DIFFERENT ANSWERS.
FIRST QUESTION, IN TERMS OF
THE LOCATIONS FOR CREATING THE
MUCOUS LAYER AND IT DEPENDS ON
HOW YOU STRUCTURE IT.
SO IN THIS CASE, WE ARE
PREPARING THE PATIENTS AHEAD
OF TIME, YOU CAN GIVE THEM A
PILL FOR GENERATING MORE
MUCOUS AND THEN MAYBE GREATER
OXYGEN, POTENTIALLY CHANGE THE
FILTRATION BUT WE DON'T
NORMALLY INCREASE MUCOUS BUT
THERE IS A PROCESS FOR THAT.
AND THEN TAKING THE CELLS AND
BASICALLY SAYING THAT THERE'S
A MANIPULATING OF THE MUCOSAL
ECOSYSTEM.
SO IT IS NOT NECESSARILY
COLLECTING FOR THE MICROBIOME
BUT BASICALLY THOSE ARE
SOMETHING THAT ONCE THEY HAVE
THE FULLY ESTABLISHED MUCOUS
LAYER, THE OUTR AREA,
DEPENDING ON OXYGEN GRADIENT
AND PROBABLY MAKE THEM
DEPENDENT WITH SOME BODIES AND
OTHER TYPE OF BUILD THAT CAN
POTENTIALLY MAKE ANTIMICROBE
CHIPS.
WE HOPE WE CAN SEE MORE
BIOLOGICAL BRILLIANCE,
MECHANICAL INSIGHT AND
CONTRIBUTION FOR THE MACHINE.
>> OKAY, SO DO YOU HAVE A SORT
OF A WISH LIST OF THINGS THAT
YOU WOULD WANT IN ORDER TO
MAKE, YOU KNOW, SOME KEY
ADVANCES IN THIS AREA?
AS A GROUP?
>> I THINK ANY OF US CAN HOP
IN HERE TOO.
>> YEAH, THIS IS JUST A PANEL
DISCUSSION.
>> ANY TIME THAT GETS ASKED IN
A NIH WORKSHOP, IT IS SO HARD
NOT TO ANSWER MORE FUNDING
OPPORTUNITIES.
[LAUGHTER]
>> YEAH, MORE FUNDING
OPPORTUNITIES BUT SOME OF IT
COULD BE WHAT WOULD YOU ASK
FOR IN TERMS OF -- IS IT
RESOURCES, IS IT, YOU KNOW,
TECHNOLOGY?
IS IT, YOU KNOW --
>> I SEE THAT Dr. -- RUSTEM
HAS COME ON.
>> I THINK SOME OF US SAY IT
IS EASY TO ASK FOR HELP BUT
WHAT IS CHALLENGE IS GETTING
THE ORIGINAL DATA AND SORT --
JUST HAVE ENOUGH DATA TO START
ASKING QUESTIONS.
IN OTHER WORDS WE AS A
COMMUNITY VALUE MECHANISTIC
STUDIES BUT YOU CAN'T DO THEM
IF YOU DON'T KNOW WHAT IS OUT
THERE OR KNOW WHAT QUESTIONS
TO ASK, ESPECIALLY WHEN YOU
DON'T KNOW THE SIDE AND
EFFECTS.
SO THAT IS CRITICAL AS A
COMMUNITY TO BE THINKING
ABOUT, SORT OF LIKE THE PIP
EFFORTS, WHAT ARE THE THINGS
THAT PIP CAN DO AND ALLOW A
LOT OF HUMAN DATA TO MOVE
FORWARD AND WHAT GARY
MENTIONED THIS MORNING, VERY
MUCH ALONG THESE LINES.
SO FIGURING THAT OUT AND HOW
TO GET A LOT OF HUMAN DATA AND
HOW TO SHARE IT IN A
MEANINGFUL WAY SO LOTS OF
PEOPLE CAN BUILD STUDIES AND
ASK BEAUTIFUL MECHANISTIC
QUESTIONS, TO ME THAT IS ONE
CHALLENGE NO PI COULD EVER
SOLVE AND KIND OF REQUIRES NIH
TO TACKLE IT TOP-DOWN.
>> CURTIS, YOU ARE NEXT.
>> THERE WE GO.
RUSTEM'S ANSWER WAS VERY
SIMILAR TO WHAT I WAS GOING TO
SAY, THERE IS NO MORE SERIOUS
THAN THE FUNDING MECHANISMS,
BECAUSE THIS IS SUCH A BROAD
COLLABORATIVE FIELD,
MECHANISMS THAT HIP BETWEEN OR
ON THE ONE AND BIG CONSORTIUM
PROJECTS LIKE HRP ARE
PASSENGERSLY BENEFICIAL.
SOMETHING HRP-1 LAUNCHED VERY
WELL IS SORT OF A NETWORK OF
COLLABORATORS, GROUPS OF
PEOPLE THAT ARE INTERESTED IN
WORKING ON MICROBIOME PROBLEMS
TOGETHER AND SADLY I DON'T
KNOW IF WE WILL EVER SEE THAT
BIG OF A PLATFORM AGAIN BUT
GROUPS THAT ARE MID-SIZED OF
GETTING COLLABORATORS TOGETHER
ON THIS PROBLEM WOULD BE VERY
HELPFUL, I WOULD AGREE.
>> CURTIS JUST ANSWERED MY
QUESTION.
BECAUSE I HAVE BEEN HEARING
ABOUT SO MUCH
INTERDISCIPLINARY RESEARCH AND
THE IMPORTANCE OF DIFFERENT
APPROACHES AND MODES OF
RESEARCH FROM THE MOLECULAR
AND CHEMICAL TO THE ECOLOGICAL
AND POPULATION INFORMING EACH
OTHER SO YOU ANSWERED MY
QUESTION, THANK YOU.
>> I HAVE QUESTIONS FOR Dr.
SAMEER.
SO THAT IS QUITE A FILE THAT
YOU HAVE IN THE HRP AND I KNOW
IT TOOK A LOT OF YEARS JUST
FOR THE RESEARCH TO ACQUIRE
BUT WHAT WOULD YOU HIGHLIGHT
IN A SINGLE CASE?
>> THAT IS A GREAT QUESTION
AND I THINK CORRESPONDING
ISSUE GET TO CLINICAL TRIALS,
I ACTUALLY SPECIFICALLY SHOULD
MENTION THAT AND IN VIVO IF IT
GOES WELL, WE WILL BE ON TRACK
TO DO SOME HUMAN TRIALS AND
THAT IS SOMETHING IMPENDING IN
THE PIPELINE.
SO HOW DOES THE DEVICE MEET
THE FDA IS THE QUESTION AND
THERE IS NO CLEAR ANSWER AT
THE MOMENT.
THE REASON I AM SAYING THIS IS
THIS STILL DOES NOT DIAGNOSE
OR TREAT ANYTHING SO AS A
MEDICAL DEVICE, IT IS
SOMETHING YOU ARE USING TO
STUDY AND UNDERSTAND WHAT IS
GOING ON.
AND AS LONG AS WE STAY SAFE
WITH THE MATERIALS AND THE
DEVICES THAT I SHOWED WHICH
DOES NOT HAVE ANY ELECTRONICS,
NO BATTERY, NOTHING TOXIC, WE
STAY CLOSE TO THAT.
WE HEARD WE EXPECT IT TO BE
MINIMAL TO GET.
SO WE SHOWED THE NEXT ONE WITH
THE DEVICES AND ELECTRONICS IN
IT AND I BELIEVE THAT WILL BE
DIFFICULT TO GET APPROVAL.
SO WE SHOWED ANOTHER VERSION
OF THE PILL THAT WOULD GATHER
A EXAMINER OF THE MICROBIOME
AND I THINK THAT IS SOMETHING
THAT CAN BE DISSEMINATED
BROADLY FOR HUMAN STUDIES.
THEY ARE VERY EASY FOR US TO
MAKE AND I ENVISION THE HURDLE
TO BE LOWER FOR THAT BUT IT IS
A GOOD QUESTION AND OF COURSE
IT STARTS WITH GETTING THE
REGULATORY APPROVAL FIRST AND
THEN SOME FUNDING TO GO THERE.
>> SO YOU HAVE THAT PENDING --
PARDON ME.
>> SO HOW DOES THE SAMPLING
CONTRIBUTE?
IS IT ENOUGH QUANTITY AND
QUALITY FOR THE MICROBIOME
STUDIES?
>> RIGHT NOW WE ARE JUST DOING
THE 16S, TRYING TO LOOK AT THE
MICROBIAL POPULATION AND OF
COURSE IF YOU ARE LOOKING AT
POPULATIONS, TWO, 300
MILILITERS IS SOMETHING YOU
CAN DO AND OF COURSE IT IS
JUST A PILL BUT YOU AT LEAST
HAVE A STATISTICALLY USEFUL
DATA SET HERE WHEN YOU ARE
TRYING TO DO STUDIES WITH
HUMANS WITH MORE PILLS.
SO YOU GET MORE SAMPLES AND
THERE WILL BE MORE RIGOR IN
THE DATA YOU GENERATE USING
THESE PILLS.
>> SO DID YOU HAVE A QUESTION,
MAY NOT BE DIRECTLY RELATED TO
WHAT WE JUST COVERED BUT
SOMETHING WE TALKED ABOUT IN
THE SESSION, RIMA?
>> NO, NOT SO MUCH, I WANTED
TO ECHO SOME OF THE
SUGGESTIONS IN THE LAST 20
MINUTES.
THERE IS SO MUCH HERE,
MULTILINES, MULTIDEPENDENCIES
AND ALSO THE IMPORTANCE OF
CREATING PROJECTS AND OPEN
TIMES WHICH CAN BE USED AND
LEVERAGED BUT THE COMMUNITY AT
LARGE IS TRULY MOST IMPORTANT
AND ALL POWERFUL.
YOU ARE CREATING SOME TOOLS
FOR MICROBIOME METABOLITES AND
JUST ONE THAT CAME OUT OF A
POPULATION OF OVER 600
RESOURCES.
THANK YOU.
>> GARY?
>> I JUST WANTED TO TALK ON
THE IBF OPPORTUNITIES.
I THINK ONE OF THE BIG AREAS
THAT NIH AND OTHER PLACES
COULD BE PUSHING FORWARD OR
THINKING ABOUT GENE
ENVIRONMENTAL INTERACTION.
YOU KNOW WE HAVE DONE A LOT IN
HUMAN GENETICS AND GENOMICS,
BEGINNING TO EXPLORE THE
ENVIRONMENT WHICH IS VERY,
VERY DIFFICULT.
BUT I SORT OF FEEL LIKE DIET
AND ENVIRONMENTAL ARE TWO VERY
BIG FACTORS AND FROM A
CONCRETE STANDPOINT, THE
PHYSICIANS NUTRITION HOUSE IS
JUST BEING LAUNCHED AND THEY
ARE SORT OF IN THE PLANNING
PHASE RIGHT NOW.
SO I THINK THERE MAYBE IS AN
OPPORTUNITY FOR GETTING SOME
FEEDBACK FROM THE PEOPLE HERE
THE LAST FEW DAYS TO THE
NUTRITION PHYSICIANS HOUSE
BECAUSE THAT PROGRAM IS
DESIGNED TO LOOK FOR
BIOMARKERS TO STRAT GUY FROM
THE STANDPOINT OF PRECISION
HEALTH BUT THIS GROUP IS
THINKING MORE ABOUT
THERAPEUTICS AND MAYBE THAT IS
AN OPPORTUNITY TO LEVERAGE AND
DESIGN THE STUDY IN A WAY THAT
YOU COULD DUAL-PURPOSE OR
LEVERAGE SOMETHING OR AT LEAST
START THE CONVERSATION.
BECAUSE THERE HAS BEEN A BIG
INVESTMENT INTO THAT
PARTICULAR PROGRAM AND IT IS A
BIG, BIG PROJECT.
SO IF YOU -- YOU DON'T WANT
TO REALLY MISS ANY
OPPORTUNITIES.
>> AND THE MICROBIOME
COMPONENT, INDEED IT IS A
GREAT OPPORTUNITY TO CONNECT
WITH.
>> I ALSO HAVE A COUPLE OF
QUESTIONS COMING IN THROUGH
THE CHAT AND ONE IS ABOUT THE
WILD SITE MICE, DID YOU TRY TO
TRANSFER THE MICROBIOTICS AND
DOES IT WORK OR DO THE LAB
MICE GET RESISTANCE TO THE
WILDLING GUT MICROBIOTA?
>> WE FOUND THAT IN THE STUDY
IT DOES NOT TRANSFER ACROSS.
SO IN THIS NATURE, METABOLISM,
THERE ARE MANY MORE THINGS TO
STUDY.
>> AND THEN THIS IS A QUESTION
FOR NOAH, THE DISCOVERY OF THE
MICROBIOME INTERACTIONS, HOW
MANY OF THE IDENTIFIED
MICROBIAL PROTEINS ARE KIND OF
UNKNOWN PROTEINS?
AND THIS IS RELEVANT TO THE
GRAPH AND PROPORTION OF
MICROBIAL GENES THAT ARE
INDICATED?
>> YEAH, SO THANKS FOR THAT
QUESTION BECAUSE IT ALLOWS ME
TO MAKE A VERY IMPORTANT POINT
WHICH I THINK I PROBABLY
FAILED TO MAKE CLEARLY WHICH
ARE THERE ARE TWO SIDES TO
THIS INTERACTION EQUATION.
THERE IS THE MICROBIAL SIDE
AND HOST SIDE AND OUR
TECHNOLOGY, IT TELLS YOU IS
ACTUALLY WHICH HOST PROTEIN IS
BOUND BY THE BACTERIA OR WHAT
HOST IS TARGETED BY THE
PROTEIN.
IT DOES NOT TELL US ANYTHING
ABOUT THE MICROBIALS THAT THE
PROTEIN IS TRYING TO ADDRESS
AND THAT IS REALLY WHERE WE
WANT TO GO TO THE OTHER SIDE
OF THE EQUATION AND WORKING
WITH CURTIS TO THINK ABOUT
THAT.
AS I HAVE TRIED TO DESCRIBE,
WE HOPE THAT WITH THE RIGHT
SCALE OF INTERACTOMES PLUS
GENOMES, FOR EXAMPLE, WE WILL
BE ABLE TO MAKE THOSE
PREDICTIONS OF THE PROTEINS
INVOLVED IN THESE
INTERACTIONS.
AND MY STRONG FEELING IS, AND
CURTIS CAN JUMP IN AND EITHER
SUPPORT OR CONTRADICT ME, BUT
MY STRONG FEELING IS THE VAST
MAJORITY OF THOSE GENES WILL
BE UNANNOTATED BECAUSE I THINK
A LOT OF ANNOTATED GENES TO BE
HONEST AT THIS POINT ARE
ANNOTATED BECAUSE THEY ARE
CORE PARTS OF BEING A
BACTERIUM, CORE PARTS OF BEING
A BACTERIAL METABOLISM AND
EXIST IN ALL BACTERIA.
SO I THINK ONE THING WE HAVE
TO REMEMBER AND I AM GETTING
OFF ON A RANT ABOUT IT BUT ONE
THING WE HAVE TO REMEMBER IS
THE ONLY WAY TO AN NOTATE A
GENE THAT HAS NEVER BEEN
STUDIES AND NO HOMOLOGY TO THE
GENE THAT HAS NEVER BEEN
STUDIED IS TO CONDUCT A
EXPERIMENT.
A HUNDRED YEARS AGO, WE COULD
SEQUENTIALLY AND CHEAPLY
CONVENIENCE HUMAN GENOMES AND
THERE ARE PEOPLE SAYING IF WE
JUST CONVENIENCE ANOTHER
HUNDRED THOUSAND GENOMES, WE
CAN FIGURE OUT WHAT THESE
GENES DO AND THAT IS JUST NOT
HOW IT WORKS.
SO OBVIOUSLY I ADVOCATE WITH
COUPLING THESE POWERFUL
APPROACHES WITH THE
EXPERIMENTAL APPROACHES BUT
NOW I THINK WITH THE TOOLS WE
HAVE IN SYNTHETIC BIOLOGY AND
COMMENTORY BIOLOGY, WE CAN
MATCH THE SCALE OF OUR
EXPERIMENT POWER WITH THE
PROBLEM WE HAVE WITH THE
MICROBIOME AND THAT IS KIND OF
MY 2 CENTS ON THAT.
>> I CAN SECOND THAT.
I ALSO STRONGLY SUSPECT THERE
IS NOT JUST A MAJORITY BUT
ENRICHMENT FOR CHARACTERIZED
PROTEINS AMONG INTERACTORS
BECAUSE THEY ARE ENRICHED FOR
THINGS THAT WORK IN A DISH FOR
THE MOST PART.
EVEN HUMAN MICROBIOME
INTERACTORS HAVE NOT BEEN
STUDIED BEFORE AND IT MIGHT BE
ABLE TO INTEGRATE SOME KIND OF
SEQUENCING ACTIVITY WITH
FOLLOW UP.
AND WE DO THIS WITH YOU, WITH
WENDY, A LOT OF OUR PROJECTS,
TAKE SOMETHING THAT SHOWS UP
IN A MOUSE WHERE YOU SAY HUH,
THAT IS PRETTY COOL, GO BACK
TO A HUMAN DATA SET AND SEE IF
IT WORKS IN HUMAN POPULATIONS
TOO SO BOTH WORK REALLY WELL.
>> GARY, YOU HAVE A HAND UP, I
DON'T KNOW IF IT IS A NEW HAND
OR OLD HAND.
>> OH, ME?
IT IS AN OLD HAND, SORRY.
>> OKAY, SO I DON'T HAVE
ANYMORE QUESTIONS TO ALL THE
SPEAKERS.
I DO HAVE -- THE SESSIONS
WE'RE COVERING LIKE ON PILLS,
FUNGUS, VIRUSES, WHAT IS THE
PANEL'S OPINION ON USING
BACTERIAL SPORES AS PART OF
MICROBIOTA WHERE THE SPORES
SHOW CORRELATION, WHY NOT USE
THEM AS PROBES?
OKAY, HELP MEAN OUT HERE.
>> THANK YOU.
WELL, IT IS A DIFFERENT
QUESTION.
>> YEAH, I DON'T HAVE AN
ANSWER TO THAT ONE BUT IF YOU
HAVE AN ANSWER TO ANOTHER ONE,
THAT IS GREAT.
[LAUGHTER]
>> THANK YOU.
I HAVE A ANSWER.
THE META BOLITE, I WOULD LIKE
TO COMMENT THAT ANALYZING THE
META BOLITES IS VERY IMPORTANT
AND WE SHOULD DO THAT BUT WE
ALSO NEED TO KEEP IN MIND THAT
THE PRODUCER, THEIR PRODUCER
ACTUALLY EVEN MORE IMPORTANT,
THERE IS BECAUSE OF FUNCTIONAL
REDUNDANCY ON EVERY
BIOMETABOLITE WILL BE PRODUCED
BY MANY ACTIONS, NOT JUST ONE
EXPERIENCE.
AND THE HUMAN BACTERIA
ACTUALLY HAVE DIFFERENT IMPACT
ON THE HOST.
FOR EXAMPLE, SOME BACTERIA
PRODUCE PEUTRIDS WHICH IS
GOOD NOT ONLY FOR BACTERIA BUT
ALSO FOR THE HOST.
SO IF YOU ONLY FOCUS ON THE
METABOLIZE, IT WILL ACTUALLY
NOT HELP THE FIELD VERY MUCH.
SO NO MATTER WHAT WE DO, WE
MUST KEEP IN MIND THIS IS AN
ON ECOSYSTEM AND SINGLE
APPROACH, SINGLE METABOLITE
PROBABLY WILL NOT HELP.
THIS IS REALLY VERY, VERY
IMPORTANT BACK TO MORE OF THE
QUESTION, YOU MEAN THE
PERFORMANCE OF THE MICROBE
BACTERIA AND BECAUSE THEY ARE
THE DOMINANT FORM, MYSELF I
WOULD NOT FOCUS ON THEM,
UNLESS THEY ARE GERMINATING IN
THE GUT.
OTHERWISE MORE PROPERLY GO
PAST THE GUT AND I WOULD NOT
WORRY TOO MUCH ABOUT THAT.
>> OKAY, ANY OTHER QUESTIONS?
YOU CAN TAKE YOUR HAND DOWN
AND I WILL CALL YOU AGAIN.
>> AND I HAVE PUSHBACK ON WHAT
HE JUST SAID AND ACTUALLY
AGREE THAT -- I MEAN MY
FEELING IS THAT THERE MAY BE
MICROBES THAT ARE LIVING IN
SOME SORT OF DORMANT STATE AT
VERY, VERY, VERY LOW LEVELS,
QUITE LONG-TERM, THAT ARE
WAITING FOR OPPORTUNITIES TO
HAVE THEIR NICHE REAPPEAR.
I MEAN, JUSTIN, I DON'T KNOW
IF HE IS STILL ON THE CALL
HERE, I THINK HIS WORK SHOWED
THIS REALLY REALLY ELEGANTLY.
SO I WILL PUSH BACK ON THAT
IDEA ALTHOUGH I AGREE WITH
MANY OTHER THINGS THAT LIFENG
JUST SAID.
>> ANYBODY ELSE HAVE A TIE
BREAKER OPINION IN TERMS OF
WHERE THEY WANT TO GO?
[LAUGHTER]
YOU GOT THIS?
>> YEAH, JUST TO CHIME IN, IT
I AGREE WITH BOTH OF THOSE
POINTS.
I MEAN, I THINK THEY ARE
TOTALLY COMPATIBLE.
I THINK BOTH OF THOSE OPINIONS
ARE TOTALLY COMPATIBLE AND WE
KNOW THE MICROBIOME IS
COMPLEX, WE KNOW THAT THERE
ARE DEFINITELY LOW LEVEL
COMMUNITIES AND ORGANIZED KIND
OF SECLUDED SPACES THAT ARE
PROBABLY NOT SO METABOLICALLY
ACTIVE, AND MAYBE WE COULD
EXPAND BUT I THINK, YEAH,
THOSE ARE TOTALLY IN LINE WITH
THE WAY I THINK ABOUT THE
ECOSYSTEM.
>> CURTIS?
>> I WAS GOING TO RELATE THIS
BACK TO A POINT THAT TAMMY
RAISED EARLIER AND I THINK WE
LOST TAMMY BUT I THINK THIS
HELPS TO EXPLAIN SOME OF THE
DISPARITY BETWEEN LIKE PLACES
LIKE THE SKIN WHERE WE SEE
LOTS OF LOCAL HYPERGENEITY
WHERE AT THE MACRO LEVEL OF
THE GUT, THERE IS A LOT LESS
HYPERGENEITY.
SO THE IMPORTANCE OF DORMANT
BUGS AND LIPIDITY OF SUITES
HELPS TO EXPLAIN THAT.
IF YOU HAVE RARE BUGS, YOU
WILL HAVE A LOT OF TROUBLE
SEEING THEM BY SEQUENCING OR
CULTURE.
BUT IF THEY ARE ABLE TO BE
MIXED UP IN ENVIRONMENTS LIKE
THE GUT AS OPPOSED TO THE
SKIN, IT WILL LOOK LIKE THERE
WILL ONLY BE ONE DOMINANT
STRAIN THERE.
SO I THINK THAT IS WHERE
THINGS LIKE SPORES OR LOW
ABUNDANT STRAINS INTERSECT
SOME OF THE POPULATION
GENOMICS THAT CAME UP IN
TAMMY'S TALK.
>> GREAT.
ANY OTHER COMMENTS?
WELL, IT LOOKS AS THOUGH THERE
IS A CONSENSUS IN TERMS OF A
GAP AND SHOULD BE MORE
OPPORTUNITIES FOR LARGER
GROUPS WORKING TOGETHER.
AGAIN, IT ALWAYS SEEMS LIKE
ONE OF THE OUTCOMES COMMONLY
EXPRESSED BY THE PANELS HERE
AND SOMETHING THAT SEEMS AS
THOUGH THE NATURE OF THE WORK
NEEDS TO HAVE SOMETHING THAT
IS ON A LARGER SCALE THAN
INDIVIDUAL OPPORTUNITIES.
ANY OTHER COMMENT, BARBARA?
>> YEAH, I THINK SPECIFICALLY
LARGER IN THE SENSE OF BEING
MORE VALUABLE, MORE CANCER,
MULTIDISCIPLINARY.
>> OKAY, SO LARGER GROUPS,
MORE INTERDISCIPLINARY.
ANYBODY ELSE WANT TO REITERATE
ANY OF THE MAJOR POINTS THAT
MIGHT HAVE BEEN MADE?
I FEEL LIKE I AM SUMMARIZING
THE GRANT REVIEW HERE.
[LAUGHTER]
>> YOU WANT ME TO BRING BACK
UP THE QUESTIONS?
>> YEAH, IF WE COULD TAKE ONE
LAST LOOK AT THE QUESTIONS
BECAUSE WE ARE GETTING CLOSE
TO THE END HERE AND I KNOW IT
HAS BEEN A VERY LONG DAY BUT I
THOUGHT IT WAS INCREDIBLY
INFORMATIVE AND INTERESTING.
SO AGAIN, CRITICAL GAPS IN
KNOWLEDGE AND METHODOLOGIES
FOR THE RESEARCH AREAS
PRESENTED.
ANY RESOURCES OR METHODS
NEEDED TO FILL THE GAB IN BOTH
SHORT TERM AND LONG-TERM, SO
THINK ABOUT THE DIFFERENCE
THAT MIGHT BE SHORT OR LONG.
THIS IS YOUR LAST CHANCE FOR
INTERACTION.
STATE YOUR CASE.
IF NOT, I AM GOING TO -- I SEE
CURTIS AND JUSTIN, IT COULD
HAVE BEEN A TIE SO I WILL LET
YOU TALK.
>> MINE IS VERY SHORT THIS
TIME AND IN TERMS OF FILLING
THAT LONG-TERM GAP THAT CAME
UP MORE YESTERDAY THAN TODAY
IS HOW THESE INTERSECT WITH
REGULATORY FRAME WORKS.
WE HAVE A WHOLE ADDITIONAL
WORKSHOP ON HOW THE DIVERSITY
OF PROBIOTIC RESEARCH FOR THE
MANY DIFFERENT POSSIBLE
DEFINITIONS OF PROBIOTICS
FALLS UNDER DIFFERENT
REGULATORY FRAME WORKS AND
WHAT IS BEING DONE FOR
SAMPLING PRODUCTS LIKE WE JUST
SAW RECENTLY VERSUS LIFE
THERAPEUTIC PRODUCTS VERSUS
DIETARY SUPPLEMENTS AND
ASPECTS OF PROBIOTICS THAT WE
HAVE HEARD ABOUT TODAY SO I
WILL PUT THAT OUT THERE AS A
LONGER-TERM NEED.
>> THANK YOU, JUSTIN?
>> YOU KNOW, I LOVE THE IDEA
THAT IT IS A BIG COLLABORATIVE
PROJECT.
I THINK THIS IS WHERE EXCITING
THINGS ARE HAPPENING IN THE
FIELD RIGHT NOW BUT THE OTHER
THING THAT STRUCK ME ABOUT THE
SPEAKERS HERE AND WHAT I RUN
INTO THE FIELD OVER AND OVER
AGAIN IS THE EXPANSION OF
YOUNG INVESTIGATORS DOING
REALLY EXCITING THINGS IN THE
FIELD AND QUITE OFTEN IT IS
HARD TORE FOR THEM TO FIT IN
TO BIG ESTABLISHED CONSORTIA
SO THINKING ABOUT BACK WHEN I
WAS STARTING MY LAB, THE NEW
INNOVATER WAS MASSIVE FOR
ALLOWING US TO DO SOME THINGS
BUT THE FUNDING LEVEL, I WAS
VERY LUCKY TO GET IT.
SO THINKING ABOUT OTHER
MECHANISMS LIKE THAT WHERE IT
COULD BE A SINGLE PI KIND OF
OUT OF THE BOX THINKING, MAYBE
SMALLER THAN THE INNOVATOR BUT
GIVING THESE NEW INNOVATIVE
IDEAS ROOM TO -- LIKE IF YOU
LOOK AT WHAT NOAH PRESENTED
TODAY, THIS ENTIRELY NEW
METHOD, TOTALLY
GROUNDBREAKING, MASSIVE
EFFORT, WOULD BE VERY HARD FOR
A NEW INVESTIGATOR TO DO AS
THEY WERE GETTING ESTABLISHED
BECAUSE, YOU KNOW, IT IS SUCH
A -- IT TAKES DEVELOPMENT, IT
TAKES LIKE YOU KNOW HAVING A
COMMITTED TEAM TO HAVE FUNDING
FOR A NUMBER OF YEARS.
TO THINKING ABOUT WAYS FOR
INVESTIGATORS TO EXPLORE COOL
NEW APPROACHES COULD BE REALLY
VALUABLE TOWARDS THE FIELD,
YEAH.
>> THANK YOU.
>> I THINK THE GAP COULD BE
CONVERTED TO QUESTIONS.
YOU KNOW, WE NEED TO ASK A FEW
VERY IMPORTANT QUESTIONS AND
THEN ANSWER THOSE QUESTIONS
BASED ON IS THERE A COMMON
BIOLOGICAL BASIS FOR HUMAN
BEHAVIOR.
AND THERE SEEMS TO BE, YOU
KNOW, ALL KIND OF THINGS THAT
SEEM TO BE CONNECTED TO
DIFFERENT DISEASES, LIKE OBESE
PATIENTS MAY HAVE HIGHER RISK
OF DEVELOPING MORE SEVERE FORM
OF COVID-19, ALL OF THESE
QUESTIONS BUT TALKING ABOUT
THE BIOLOGICAL BASIS
UNDERNEATH ALL THESE RISKS, IS
PART OF THAT COMMON BIOLOGICAL
BASIS.
AND ANOTHER YOU KNOW MORE
TECHNICAL ISSUE, YOU KNOW WITH
THE IMPACT AND MANY STUDIES
USE MICROBIOTICS AND PREDICT
RESPONSE BUT MANY OTHER
STUDIES SHOW THAT SOME MEMBER
OR EVEN NONDETECTABLE, WHEN
THEY BECOME DOMINANT, THEY
BECOME VERY IMPORTANT.
SO YOU CANNOT PREDICT BASED
JUST ON MICROBIOTICS.
SO MAYBE MORE LIKE THIS, THANK
YOU.
>> THANK YOU.
>> I WANTED TO ENTER A POINT
OR SEVERAL POINTS.
I THINK ANOTHER OPPORTUNITY
ALONG THIS LINE IS TO IDENTIFY
WHAT IS ACTUALLY NEED HE
NEEDED TO DO VERSUS EASY TO
DO.
SO WE CAN WORK TOGETHER TO DO
MEANINGFUL SITE STUDIES AND
THAT IS WHAT WEEK DO.
NOT THAT THE SMALL INTESTINE
IS NOT EVENTUALLY IMPORTANT,
IT IS JUST DIFFICULT TO DO
THAT.
SO THE POINT OF HAVING ALL
THESE CLEAR ROLES FOR
ENGINEERS, ALIGNING WITH THAT
AND WE WANT THESE TYPES OF
CAPABILITIES, JUST PAUSING AND
SPENDING ENOUGH TIME AND
RESOURCES TO MAKE THAT HAPPEN
BECAUSE THAT RESULTS IN
STUDIES THAT COULDN'T BE DONE
EITHER -- OTHERWISE AND MOVE
THAT FORWARD.
JUST FIGURE OUT HOW TO ASK THE
QUESTION AND ENGAGE THE
BROADER COMMUNITY.
THERE ARE VERY TALENTED
ENGINEERS OUT THERE THAT COULD
HELP IF WE JUST ASK THE RIGHT
QUESTIONS.
>> YES, THANK YOU, VERY
IMPORTANT WORK IS NEEDED.
ANY OTHER QUESTIONS BEFORE WE
PASS THIS MEETING PACK TO OUR
ORGANIZERS?
IF NOT, I WILL TAKE ONE LAST
LOOK HERE.
SO I AM GOING TO HAND IT BACK
OVER TO MARVA.
>> DO YOU HAVE ANYTHING ELSE
BEFORE WE MOVE ON?
>> NO, IT IS TIME TO GO TO
OUR CLOSING WITH YOU AND MARVA
SO HYE SOOK, I WILL TAKE IT
AWAY AND SHARE SOME THOUGHTS
IN CLOSING, LOOKING AT THE
HIGHLIGHTS FOR THE PAST TWO
DAYS, JUST FANTASTIC.
BARBARA?
>> OH, WELL, I LOOKED AT SOME
OF THE POINTS AND TRYING TO
ADDRESS REMARKS BUT FOUND IT
WAS ALREADY DONE IN THE
SESSION OF DISCUSSION.
SO I STRUGGLE HOW WE CAN
CLOSE, SO HOW ARE WE GOING TO
THINK ABOUT GOING THIS
DIRECTION BECAUSE WE HAVE THE
BEST CHALLENGES AND
OPPORTUNITIES AND KEEP TALKING
ABOUT IMPORTANCE OF THE
COLLABORATION, IMPORTANCE OF
THE VERIFIER, THAT IS VERY
IMPORTANT BUT IT CLOSE IT, WE
LIKE TO DISCUSS HERE AND THIS
IS IMPORTANT FOR THE CLINICAL
OUTCOME MEASUREMENTS, WORKING
FOR THE PROCEDURE, HOW CAN I
IDENTIFY THE TARGETED
INFORMATION THAT MOST LIKELY
IS MORE RESPONSIVE.
SO WE SCORE LONGITUDINAL
STUDIES ARE IMPORTANT AND ALSO
PROBABLY THE STRUCTURE IN THE
PERSPECTIVE OF TRANSCRIPTOME,
VERY IMPORTANT.
AND WE ALSO THINK ABOUT THE
SAMPLING AND THE METHOD TO
COLLECT THE DATA AND FORMAT IT
WELL.
SO NOW WE ARE TALKING ABOUT
SAMPLES FROM EVERYWHERE,
MICROBIOME SAMPLES FROM HUMANS
AND FROM ANIMALS SO THAT IS
FANTASTIC WE HAVE THAT ECODATA
AS WELL SO THERE MUST BE
SYSTEM STANDARDIZED FORMAT
THAT WE CAN USE FOR THIS STUDY
COLLABORATIVELY AS IT WOULD BE
EXPENSIVE WITH JUST ONE
PERSON.
SO THAT IS THE CHALLENGE AND
OPPORTUNITY.
>> YEAH, I THINK THERE IS
NEED FOR DEVELOPING COMMUNITY
CONSENSUS ABOUT WHAT MET IT
DATA ARE NEEDED, WHETHER IT IS
IN CHARACTERIZING THE
INTRODUCTION ITSELF, OR HOW
YOU ARE DOING THE STUDY, HOW
YOU ARE SAMPLING THE STUDY.
I THINK ONE OF THE ISSUES THAT
I WANT TO GO BACK TO THAT CAME
UP DURING THE WORKSHOP WAS THE
QUESTION. CIRCADIAN TIME AND
SEASONALI ITY AND WHAT A
DIFFERENCE THOSE MAKE AND HOW
WE CAN THINK ABOUT AT LEAST
PRESCRIBING IF NOT CONTROLLING
FOR THEM.
BEGINNING TO THINK MORE NOT
JUST ABOUT THE BACTERIAL
COMPONENT OF THE MICROBIOME,
MICROBIOTA BUT ALSO THE
ENVIRONMENT BECAUSE THOSE
CLEARLY HAVE IMPORTANT ROLES
BUT ARE MAYBE A LITTLE HARDER
TO STUDY THAN THE BACTERIAL
COMPONENT.
ONE OF THE THINGS THAT CAME UP
WAS THE IMPORTANCE OF THINKING
ABOUT HOW YOU CHARACTERIZE
NORMAL.
YOU KNOW, WHAT IS -- PERHAPS
NOT NORMAL BUT HEALTHY, WHAT
DOES HEALTHY LOOK LIKE, HOW
DOES IT VARY WITHIN AN
INDIVIDUAL AND FROM INDIVIDUAL
TO INDIVIDUAL BY THEIR, YOU
KNOW, DIFFERENT WAYS TO
DESCRIBE THAT.
AND I THINK THE OTHER THING WE
HEARD A LOT ABOUT THE
IMPORTANCE OF IS THE
IMPORTANCE OF DOING PILOT
CLINICAL TRIALS BEFORE YOU GO
TO A LARGER CLINICAL TRIAL
BECAUSE THE PILOT CLINICAL
TRIAL CAN HELP YOU FIGURE OUT
WHAT YOUR EFFECT SIZE IS AND
WHAT YOUR SAMPLE SIZE SHOULD
BE, WHAT OUTCOME SHOULD BE,
WHEN YOU LOOK AT IT, WHAT DOSE
IT SHOULD BE AND WHEN YOU ARE
EXPOSED TO IT AND FOR HOW
LONG, WHO SHOULD BE INCLUDED
IN YOUR TRIAL, WHO WILL HAVE
AN EFFECT, WHO CAN IT HAVE AN
EFFECT ON?
YOU KNOW ARE THERE SOME PEOPLE
WHO ARE ABLE TO BE COLONIZED
BY THE INTRODUCTION OF PEOPLE
FOR THE BIOME EFFECT.
>> YES, AND ALSO THE
IMPORTANCE OF COMBINING ANIMAL
ACTION BECAUSE WE CAN DEVELOP
CLEAR INTERACTION OF THE
MICROBIOME JUST TO KNOW WHAT
AND WHERE WE CAN SEE THIS
NATURE.
SO I THINK IT IS VERY
IMPORTANT AND VERY CHALLENGING
AND WHILE WE LOOK AT THIS
TODAY OR ANOTHER DAY, IT IS
ABOUT THE CHALLENGE GOING
FORWARD AND HOW WE CAN SEE THE
EFFECT OF THE MICROBIOME, THAT
IS THE MOST KEY PART AND VERY
CHALLENGING PART BUT I THINK
THE FEEL, I BEEN THINKING
ABOUT IT LONG TIME NOW, JUST
PUT BACK TOGETHER AND OPEN THE
DOOR AND WE CAN START FORMING
THE ROW SEARCH OF TEAMS TO
FIGURE OUT HOW WE CAN TACKLE
NEW TYPES OF ACTIVITY.
I THINK THAT IS IMPORTANT
POINT EVERYONE IS MAKING OVER
TWO DAYS.
>> AND WIDER ON THAT, Dr.
KIM, JUST FIGURING OUT
MECHANISM IS SOMETHING YOU CAN
GET OUT OF THE PILOT CLINICAL
TRIAL, ESPECIALLY IF YOU HAVE
THE INFRASTRUCTURE TO ARCHIVE
LOT SPECIMENS, WHEN DRIVES
THOSE SPECIMENS, A COMMUNITY
CONSENSUS STANDARD FOR HOW
THEY ARE COLLECTED AND MADE
AVAILABLE FOR OTHER
RESEARCHERS PR-PS TO ALSO
ACCESS AT AN APPROPRIATE TIME.
>> YEAH, I ACTUALLY WILL
MENTION SOME OF THE NIH
SAMPLES FOR US AND --
[OVERLAPPING SPEAKERS]
>> YEAH, AND THEY HAD THE LAST
PHENO CODING AND NOT SURE THE
MICROBIOME BUT THEY HAVE THE
RECORD AS WELL AS THE METADATA
AND IT IS REGULARLY AVAILABLE.
>> I WAS CHECKING TO SEE
WHETHER PODMA WAS HERE SINCE
SHE WAS ONE OF THE PROGRAM
MANAGERS ON THAT.
THERE IS A RECENTLY MICROBIOME
COMPONENT BUT IT IS RECENTLY
PRODUCED AND IT WILL BE A
WHILE BEFORE IT IS AVAILABLE
AND I AM A PART OF THAT
PROJECT, PRODUCING MICROBIOME
SAMPLES AND PART OF THE WORK
THAT WILL BE AVAILABLE BUT AS
CURT SAID, IT WILL BE A LITTLE
WHILE BEFORE IT IS AVAILABLE.
>> AND ALSO IN TERMS OF THE
METADATA, WE HAVE BEEN NEEDING
TO STANDARDIZE SO WE CAN GET
ACCESS TO THE DATA AND ANALYZE
THE CLINICAL OUTCOME.
ALSO THE NIH IS ONE OF THE
LEAST --
[INDISCERNIBLE]
CALLED BRIDGES FOR AI AND IT
IS NOT ABOUT THE DATA FOR AI
BUT ABOUT HOW TO GENERATE THE
MACHINE LEARNING AND AI DATA
SETS.
THEY ALSO HAVE SOME
OPPORTUNITY FOR METRO BIOME
GROUP TO PARTICIPATE IN THAT
KIND OF ACTIVITY SO THAT WE
CAN USE THAT TO GENERATE THE
ASSEMBLY OF HUMAN DATA.
WE HAVE A RAISED HAND?
>> MICROBIOME DATA IN SOURCES,
YOU WEIGH OUTCOME AND SO
BEFORE PREGNANCY AND AFTER
PREGNANCY, FOR SEVEN YEARS,
THEY ARE FOLLOWED AND APPROVE
ONE MONTH, SIX MONTHS, THEY
COLLECT MICROBIOME SPECIMEN
THAT WE CAN USE FOR THIS SO
THAT IS IMPROVED BY NIH SO
MICROBIOME AND OUTCOME.
>> OKAY, THANK YOU.
ANYTHING ELSE?
>> WELL, IF I COULD SHARE, I
HAD A QUICK SLIDE.
I WANTED TO GET TO SOME OF THE
CAVEATS AND CHALLENGES, YEAH,
JUST SOME OF THE CHALLENGES WE
TALKED ABOUT OVER THE COURSE
OF THE TWO DAYS, STRAIN
INSTABILITY, PART OF
CHARACTERIZING INTERVENTION,
ONE IN PARTICULAR, TALKED
ABOUT OUR KNOWLEDGE OF
BEHAVIOR OF MICROBIAL SYSTEMS.
THE IDEA THAT A SINGLE
MOLECULE MAY BE MULTIPLE
MECHANISMS AND MECHANISMS CAN
ENERGIZE OR CHEMICALLIZE AND
WE NEED TO KNOW ABOUT THAT
BECAUSE IT MAY REPRESENT AT SO
MANY DIFFERENT LEVELS AND THEN
THE IMPORTANCE OF TOGGLING
BACK AND FORTH BETWEEN
DIFFERENT SYSTEMS, BETWEEN
CHIPS WHERE EACH SYSTEM HAS
ITS OWN ADVANTAGES AND
DISADVANTAGES, WHETHER YOU ARE
DOING LARGE SCALE
TRANSCRIPTOME OR LOOKING AT IN
VIVO BUT IT IS A FIERCELY
COMPLEX THING TO STUDY BECAUSE
IT IS DYNAMIC, INTERACTIVE,
THE OUTCOME INTEGRATES MANY
DYNAMICALLY INTERACTIVE
INPUTS.
BUT I THINK WE CAME OUT OF
THIS MEETING WITH A LOT OF
EXCITING EMERGENT TOOLS,
WHETHER IT'S THE CURRENTLY --
[INDISCERNIBLE]
, USING -- USING THINGS LIKE
SHINE, MBHR, I CAN SEE WE HAVE
A LOT OF NEW TOOLS TO TACKLE
THESE CHALLENGES AND I AM
HOPING WE ARE ON THE
ENLIGHTENMENT UPLOPE OF
RUSTEM'S CURVE THERE.
>> YEAH, AND I ALSO LIKE TO
COMMENT ABOUT THE CONTINUED
IMPORTANCE OF DIAGNOSTICS.
SO THE TECHNOLOGY DISCUSSED
TODAY IS -- COULD BE THE
PROTOTYPE FOR THE LONG-TERM
AND SOLVE THAT ISSUE IN THE
DIAGNOSTIC.
BUT I SEE THIS IS A GOOD
OPPORTUNITY FOR THE FIELD AS
WELL.
>> FABULOUS DISCUSSIONS.
I THINK MANY, MANY THINGS, MY
THANKS TO EVERYBODY, KUDOS TO
EARN EVERYONE.
>> AND I LIKE TO SAY
MICROBIOTICS, IT IS VERY NEW
SO I THINK WE WILL GET THERE.
>> AND ONE OF THE THINGS THIS
WAS SORT OF SAID TODAY BUT
PERHAPS NOT THAT EXPLICITLY IS
ONE OF THE LEVELS WE NEED TO
BE THINKING ABOUT THIS ALL IN
IS THE CONTEXT OF EVOLUTION,
WHETHER IT IS THE
MICROORGANISM OF EVOLUTION OUR
HUMAN EVOLUTION BECAUSE IF IT
DOESN'T MAKE SENSE IN THAT
CONTEXT, IT MAY NOT MAKE
SENSE.
>> MM-HMM, YES, AND I LIKE TO
ECHO ABOUT THE -- I LIKE THE
FACT THAT RESURFACING
MICROBIOTIC AS PREVENTIVE
METHOD AS WELL AS TREATMENT.
SO THE WHOLE QUESTION OF THE
RESEARCH AND I THINK IT IS
NEAT MICROBIOME IS APPEARING
IN THE PREVENTIVE METHOD.
ANYTHING ELSE BARBARA?
>> JUST A FINAL THANK YOU AND
I WILL LET YOU HAND IT OFF.
>> OH, ALL RIGHT.
SO ALL THE TALKS WERE VERY
EXCITING, VERY INFORMATIVE AND
ALSO --
[INDISCERNIBLE]
AND WE MADE A LOT OF
CONDITIONS ON HOW THE
PROCEDURES OF THERAPY HAVE
BEEN CHALLENGING AND THE
DISCUSSION WAS VERY EXCITING
AS TO LIKE THE TALKS AND
STIMULATING OUR THOUGHTS ON
WHERE THE FIELD SHOULD MOVE
FORWARD.
SO THANK YOU ALL FOR CREATING
THESE OUTCOMES AND SENDING US
OFF IN THE DIRECTION FOR THE
COMMUNITY.
AND I LIKE TO TAKE THIS MOMENT
TO SAY THANK YOU ALL, OUR
SPEAKERS, MODERATORS AND YOU
WHO JOINED AS WELL.
AND SPECIAL THANKS TO OUR
COMMUNICATIONS, THE MODERATOR
OF THE WHOLE WORKSHOP AND WE
HAD THE IT TEAM WHO WORKED
REALLY HARD.
AND LAST BUT NOT LEAST I LIKE
TO THANK THE NIH AND ODF FOR
THEIR SUPPORT TO THESE
WORKSHOPS AS WELL AS PROPOSING
THE MICROBIOME TOPIC.
THAT IS ALL.
ANYTHING ELSE I NEED TO
DISCUSS?
>> NO, I THINK IT HAS BEEN A
LONG TWO DAYS, FABULOUS BUT
LONG.
DO WE HAND BACK TO KATHERINE?
>> YEP.
>> WELL, I JUST WANT TO SAY
THANK YOU EVERYBODY AND I
REALLY ENJOYED THAT FINAL
DISCUSSION SESSION.
I ALWAYS LIKE TO BE THE
CHEERLEADER FOR DISCUSSION IN
THE FINAL DAY BECAUSE I KNOW
THAT IT IS SUCH A LONG MEETING
AND SUCH A FASCINATING TALK
THAT CAN ALMOST BE
OVERWHELMING TO TAKE IN OVER A
TWO DAY PERIOD SO I THANK
EVERYONE FOR THEIR STICKING
WITH US TILL THE VERY END.
THANK YOU TO BARBARA AND JOE
AND -- THE REST