>>I'M FROM
THE MALIGNANCY BRANCH AND I HAVE
THE HONOR AND PRIVILEGE TO
INTRODUCE TODAY'S SPEAKER.
AND THE REASON IS THAT I HAVE
KNOWN AMIRAN DZUTSEV FOR QUITE
SOME TIME BECAUSE WE'VE BEEN
DISCUSSING ALF SCIENCE AND
DIFFERENT RESEARCH PROJECTS AND
WE WERE KIND OF IN SIMILAR YEARS
SO I'M HAPPY TO INTRODUCE HIM.
AMIRAN DZUTSEV GOT HIS TRAINING
AS AN MD AT THE NORTH STATE
MEDICAL ACADEMIA IN RUSSIA
RUSSIA AND HAD A PH.D IN RUSSIA
AND HE CAME TO THE NCI, I
BELIEVE IN 2003 AS A POSTDOC.
HE SPENT A COUPLE OF YEARS WITH
2009 WHERE HE WAS WORKING ON
QUESTIONS IN MUCOSAL IMMUNOLOGY
AND THEN HE MOVED ON AND WENT TO
THE GROUP OF GEORGIA THAT
CHANGED THE NAME SEVERAL TIMES
AND I ALWAYS FORGET THE NAME
THAT IT'S RIGHT NOW.
IN THE END, HE REALLY LED SOME
PIVOTAL STUDIES AND INVOLVED
STUDYING THE GUT MICROBIOME AND
HOW THE GUT MICROBIOME MAY
AFFECT OUTCOME OF CHEMOTHERAPY,
IMMUNOTHERAPY, AND NOT ONLY IN
ANIMAL STUDIES BUT ALSO IN
CLINICAL TRIALS.
PART OF THEM BEING CONDUCTED
HERE AND THEN A LOT OF THEM ALSO
IN COLLABORATION WITH OUTSIDE
INVESTIGATORS IN THE CONTEXT OF
MAINLY MELANOMA AND IMMUNE
CHECKPOINT INHIBITOR THEORY.
HE HAS A GREAT EXPERTISE IN THIS
CHILD FIELD.
HE IS ONE OF THE PRIVILEGED
INDIVIDUALS WHO DO NOT ONLY KNOW
THE MEDICINE BUT BASED ON HIS
TRAINING AND IMMUNOLOGY BUT
TOWARDS A VERY GOOD IN
MATHEMATICS AND BIO INFORMATICS
WHICH IS OBVIOUSLY KEY WHEN YOU
WORK WITH ALL THAT DATA.
I DON'T WANT TO TAKE MORE OF HIS
TIME.
WITHOUT FURTHER ADIEU, AMIRAN
DZUTSEV WE'RE LOOKING FORWARD TO
YOUR TALK.
>>Dr. Dzutsev: THANK YOU VERY
MUCH.
IT'S A VERY KIND INTRODUCTION
AND THANK YOU TO OUR DIRECTORS,
THOMAS, FOR GIVING ME THE
OPPORTUNITY TO PRESENT OUR WORK
IN FRONT OF YOU.
THAT IS A PRIVILEGE.
SO I STILL ALREADY I'M GOING TO
BE TALKING ABOUT THE MICROBIOME.
SO WHAT IS MICROBIOME IN
GENERAL?
SO MICROBIOME IS A COLLECTION OF
DIFFERENT MICROBES THAT OCCUPY
THE SAME NICHE IN THE ORGANISM.
THIS MICROS BUILDING TO MULTIPLE
DIFFERENT MEMBERS OF THE TREE OF
LIFE.
SO THEY CAN COME FROM BACTERIA
SPECIES, FROM FUNGI, BACTERIA,
FROM THE VIRUSES, PROTOZOA AND
OF COURSE THE MOST ABUNDANT OF
THEM ALL IS BACTERIA AND HOW
DIVERSE HUMAN BACTERIA
MICROBIOME AND EXTREMELY
DIVERSE.
THERE ARE THOUSANDS OF SPECIES
OF DIFFERENT -- HUNDREDS OF
THOUSANDS OF STRAINS THAT
CONTAINS HUNDREDS OF THOUSANDS
OF DIFFERENT GENES THAT HAVE
VARIETY OF DIFFERENT FUNCTIONS
THAT OCCUPY OUR BODIES AND THE
SIDE THAT IS THE MOST IN THIS
BACTERIA IN TERMS OF THE SPECIES
AND THE DIVERSITIES AND THE
NUMBERS, IS THE G.I. TRACT.
AS YOU CAN SEE HERE, THE STOOL
MICROBIOME IS REPRESENTED THE
MOST.
SO WHAT IS THE EFFECT OF
SPECIFICALLY GUT MICROBIOME ON
HUMAN HEALING AND DISEASE AND
IT'S EXTREMELY DEPENDENT ON THE
HEALTH OF THE G.I. TRACT
MICROBIOTA.
WE KNOW ALREADY THAT MICROBIOME
EFFECTS MANY ASPECTS OF THE
SYSTEMIC DISEASES.
IT EFFECTS DEVELOPMENT OF THE
COLITIS.
IT EFFECTS EVEN THE BRAIN
DISORDERS SUCH AS ATTENTION
DEFICITS, THE ALZHEIMER'S,
PARKINSON'S DISEASE,
DEPRESSIONS, ALSO IT HAS AN
EFFECT ON CARDIOVASCULAR
DISEASES.
BUT THE THINGS THAT IT EFFECTS
THE MOST IS THE IMMUNE SYSTEM.
AND MICROBIOME HAS EFFECTS ON
BOTH LOCAL LEON IMMUNE SYSTEMS
AND GLOBALLY.
LOCALLY, IT'S MORE OBVIOUS THING
TO EXPECT FROM MICROBIOME AFTER
ALL IT'S A BACTERIA THAT IS A
FOREIGN BODY TO OURSELVES AND
THE FACT THAT WE'RE OBSERVED
GLOBALLY CONCERNS NOT ONLY IN
THE LIMP NODES THAT DRAIN ALL
THESE PERIPHERAL SITES SUCH AS
RESPIRATORY SYSTEM G.I., TRACT,
ET CETERA BUT ALSO THINGS LIKE
BONE MARROW AND INTERNAL ORGANS
INCLUDING ALSO THE TUMOR THAT IS
A FOREIGN BODY BUT NEVERTHELESS
ORIGINATES FROM INTERNAL ORGANS.
SO FOCUSING ON THE LARGEST SIDE
OF THE INTERACTION OF MICROBIOTA
WITH THE HOST THE G.I. TRACT,
THE G.I. TRACT BOTH SMALL
INTESTINE AND THE LARGE
INTESTINE HAVE A LARGE NUMBER OF
MICK ROW ORGANISMS THAT INHABIT
IT AND THEY EFFECT IMMUNE
SYSTEMS, NOT JUST BY SOMETHING
THAT WE WOULD EXPECT WHICH IS
BACTERIAL PRODUCTS, AND THINGS
LIKE THAT BUT ALSO BY THE
METABOLITES WHICH WE VERY WELL
KNOW ALREADY HAVE AN EFFECT,
SUCH AS SHORT CHAIN FATTY ACIDS
AND DIFFERENT TYPES OF
METABOLITES AND IT EFFECTS THE
SYSTEM IN MULTIPLE DIFFERENT
WAYS.
I'M GOING TO ACTUALLY START
TALKING ABOUT THE INTERACTION OF
THE MICROBIOTA WITH THE HOST,
SPEAKING ABOUT THE COLON.
COLON HAS, AS I JUST MENTIONED,
THE LARGEST NUMBER OF BACTERIAL
SPECIES IN THE BODY.
IT HAS ABOUT 1,000 TIMES MORE
MICROBES THAN SMALL INTESTINE
AND YET SURPRISINGLY, THE VAST
MAJORITY OF THE G.I. TRUTH
IMMUNE SYSTEM IS IN THE SMALL AT
THE SCENE TIN.
COLON ON THE OTHER HAND, HAS
VERY VIEW FORWARD STRUCTURES
THAT ARE RANDOMLY DISBURSED THAT
ARE CALLED COLON I CAN PATCH.
THEY LOOK LIKE AND THE FUNCTION
LOOK LIKE VERY SMALL NODULES HE
EMBEDDED IN THE TISSUE OF THE
G.I. TRACT.
AND THEY DO HAVE ALL THE
FEATURES OF THE LYMPH NODES.
THEY HAVE B. CELLS, SPECIALIZED
TYPE OF STROM OWE CELLS AND IN
THE COLON, THIS ORGAN, THIS
PATCH IS SEPARATED FROM THE WITH
A THIN LAYER OF ONE OVER THE OVP
A THEELY YUM.
IF THEY LOOK FLAT IN THE COLON
IT'S CALLED DOME.
THIS IS THE SINGLE EPITHELIAL.
IT'S SURROUNDED BY CRYPTS.
IN CONTRAST, DOME DOESN'T HAVE
THE MUCUS SO IT ACTUALLY IS MORE
EXPOSED TO THE CONTENT COMPARED
TO THE OTHER PLACES IN THE G.I.
TRACT.
SO WE WANTED TO STUDY THE
INTERACTION OF THE MICROBIOME
HOST IN THE COLON AND AS A MODEL
WE CHOSE TO REPLACE MICROBIOTA
WITH DIFFERENT SIZES OF
NANOPARTICLES.
THESE WERE VERY DENSE SIZE FROM
20 TO 1,000 NANOMETERS.
FOR REFERENCE, THE SIZE OF THE
BACTERIA IS TYPICALLY LARGER
THAN 200 NANOMETERS SO THESE ARE
MUCH SMALLER IN THE SIZE OF THE
VIRUSES.
BUT WHEN WE LOOKED AT THE COLON
I COLICWE SAW THE BEADS WHICH WS
THAN NANOMETERS OF SIZE, THE
SMALLER END OF OUR TESTED SAMPLE
SIZES OF THE BEATS WERE ABLE TO
TRUST INTO THE COLON I CAN PATCH
TISSUE.
IT WAS THE ONLY PLACE WHERE WE
FOUND THE BEATS.
NOWHERE ELSE WERE THESE TRANCE
LOCATED INSIDE.
IF YOU LOOK CAREFULLY ON THIS
IMAGE, RIGHT UNDER, THERE ARE
DEN DRY DICK CELLS IN RED AND
THE BEATS ARE IN GREEN.
WHAT IS INTERESTED IS THESE ARE
LOCALIZED AS A STRAINS THAT
FOLLOWS SOME INVISIBLE PATH.
IF YOU LOOK CLOSER UNDER THIS
IMAGE, IT HAS MULTIPLE ELEMENTS
HERE THAT I WANT TO CONVEY.
YOU WILL SEE THAT SOME OF THESE
CONTINUE WITH A RED COLOR OF THE
CDC WHICH IS A DAN CRADDOCK CELL
AND SOMETIMES YOU HAVE THE
ENTIRETY OF THE CHAIN BEING
TRANSMITTED ALL THE WAY THROUGH
INSIDE AND TO NOTE THAT THE
RESULTS ARE VERY STRONG VERY
THAT IS BASED ON MEMBRANE THAT
LIES ON THE THESE DEN DIRECT
CELLS PENETRATE FOR THESE SMALL
PARTICLES TO GO THROUGH AND ON
THIS IMAGE, FOR EXAMPLE, YOU SEE
THAT THESE TINY CHANNELS
ACTUALLY MADE BY DENDRITES FROM
THE CELL AND I'M NOT SHOWING IT
HERE BECAUSE OF THE LACK OF THE
TIME, BUT WE DID DEMONSTRATE
THAT THIS PROCESS IS DEPENDENT
AND WHILE WE DEPLETE THE CELLS
THESE CHANNELS STAY OPEN FOR
ALMOST TWO HOURS.
AND AGAIN THIS PROCESS IS THAT
EXTENDED BASED ON MEMBRANE INTO
THE SPACE AND ONLY FOUND
ASSOCIATED WITH THE DOME OF THE
COLONIC PATCH, AS YOU CAN SEE,
GREEN CELLS AND THEY PENETRATE
THE MEMBRANE TOWARDS THE LIEU
MIN WHICH IS RIGHT HERE.
THIS IS A SIMPLIFIED VERSION.
WHAT WE SEE ON THE LEFT, YOU
HAVE PROCESSES THAT PENETRATE TO
FORM THIS PORES AND THE SMALL
PARTICLES IS 20 NANOMETERS IN
SIZE, PENETRATE INTO THE COLONIC
PATCH.
SO HOW QUICKLY THIS PARTICLE CAN
ACTUALLY REACH THE AREAS,
DIFFERENT AREAS OF THE COLONIC
PATCH THAT ACTUALLY MATTER FOR
THE RESPONSE AND IT'S ABOUT FOUR
HOURS.
THESE PARTICLES ALREADY FOUND
DEEP WITHIN THIS PATCH AND BEING
PRESENTED TO THE B-CELL BY THESE
DENDRIC CELLS THAT YOU CAN SEE
IN GREEN.
INTERESTINGLY, THE TRANSPORT OF
THESE PARTICLES WAS INDEPENDENT
OF DENDRIDIC CELLS.
YOU CAN SEE ON THIS GRAPH AND
THIS IS THE INTENSITY OF THE Y
AXIS AND IS ABOUT HALF OF THESE
PARTICLES ACTUALLY DO NOT GET
ASSOCIATED WITH THE CELLS AND
THEY'VE BEEN TRANSPORTED TO SOME
OTHER WAY PROBABLY IN THE
PASSIVE MANNER.
SO, WE ALSO LOOKED AT THE OTHER
TYPES OF THE ANTIGEN SAMPLEING
AND THIS IS DIFFERENT TYPES OF
CELL THAT HAS A DIFFERENT
PHENOTYPE.
THIS WAS POSITIVE DENDRITIC
CELLS AND THEY HAVE A VERY
DIFFERENT BEHAVIOR FROM THE ONES
THAT I JUST SHOWED A SECOND AGO.
THEY DO NOT EXTEND DENDRITES.
INSTEAD THEY EXHIBIT ACTIVE
PATROL AND BEHAVIOR AND ON THE
LEFT SIDE, YOU HAVE THE LAYER
AND THE LINE IN THE MIDDLE IS
ACTUALLY A LUME IN FROM THE
COLLAPSED SIDE OF THE INTESTINE
AND YOU SEE THIS C POSITIVE CELL
PENETRATES BASED ON MEMBRANE,
GOES UP TO THE LUMEN AND SAMPLES
IT.
THE SAME CAN BE SAID ABOUT THE
CRYPT ON THE RIGHT.
THE CRYPTS NEXT TO THE ARE
PATROL BY DENDRITIC CELLS AND
CAN THESE CELLS TAKE UP THE
BACTERIA.
YES, THEY CAN.
AND THIS IS A RED FLUORESCENT
SALMONELLA THAT HAS TAKEN OUT BY
THIS HIGHLY DENDRITIC CELL AND
TAKES IT TO PRESENT TO IMMUNE
CELLS AND THESE CELLS LOCALIZE
MOSTLY IN THE T-CELL AREAS
PROBABLY MEANING THE MOST IMPACT
THESE ANTIGENS WOULD HAVE ON THE
T-CELL IS CLOSEST.
WE WOULD REALLY WONDER HOW THIS
INTERACTIONS BETWEEN THE CELLS.
HOW DO THEY MANAGE TO MANIPULATE
THE CELLS TO EXHIBIT SUCH A
STRANGE BEHAVIOR AND ONE WAVE
DOING IT IS SO DO THE SINGLE
CELL SEQUENCES AND LOOK FOR THE
CELLS OF THE CHEMOKINES AND
CHEMOKINES RECEPTORS SO HERE WE
LOOK AT THE CHEMOKINES AND THE
RECEPTORS ON THE CELLS THAT WE
RECOGNIZE IN THOSE CHEMOKINES
AND WE FOUND CCL20, CCL6 AS A
PAIR AND WE FOUND CCL6 AND CCL1.
I'M GOING TO FOCUS ON CCL20 FOR
A BIT.
SO THE COLONIC PATCH WITH THE
GREEN CCL20 AND RED CD11 CELLS
YIELDS US THE INFORMATION THAT
SHOWS THAT THESE CELLS ARE
COLOCALIZED QUITE WELL.
IN THIS CASE, FOUR LOCALIZE
AROUND THE CRYPT SURROUNDING THE
COLONIC PATCH AND THIS IS TRUE
FOR BOTH OF THEM.
ANOTHER INTERESTING FEATURE OF
THIS CHEMOKINES THAT WHEN WE USE
THE SPECIALIZED TYPE OF FIX TIVE
THAT PRESERVES THE MUCUS TO LOOK
AT INTERACTION OF THE MUCUS WE
SAW IN THIS IMAGE, SEEN VERY
WELL, THAT THE KEEP CHEMOKINES
IS BEING SECRETED INTO THE LUMEN
BECAUSE YOU HAVE A CELL THAT
SAMPLES NOT ONLY THE CONTENT BUT
THE LUMEN THAT CONTAINS AND AND
ANOTHER FEATURE OF THESE TYPE OF
CELLS ARE VERY SPECIFICALLY WERE
PRODUCING CCL20s ONLY WHEN IN
THE CLOSE CONTACT WITH THE
COLONIC PATCHES.
YOU CAN SEE THESE SEMI CIRCLES
OF THE GREEN SURROUNDING THE
COLONIC PATCH ON THE RIGHT.
SO THIS IS OUR VERY SIMPLIFIED
MODEL.
YOU HAVE EPITHELIUM THAT
SEPARATES BACTERIA FROM THE
COLONIC PATCH AND YOU HAVE CELLS
THAT CREATE THIS NANO PORES THAT
WILL ACTUALLY FIRST IDENTIFIED
AND THIS THEY ALLOW PASSIVE
SMALL FRAGMENTS OF THE
MICROBIOTA AND THIS PROBABLY
PIECES OF THE DEAD BACTERIA AND
MIGHT BE SOME FAGES AND VIRUSES
AND DIFFERENT TYPE OF
METABOLITES AND WE HAVE TO
RECOGNIZE THERE'S NO MECHANISM
IN THE COLON TO TRANSPORT ANY
TYPE OF METABOLITES INSIDE THE
BODY EXCEPT FOR THIS TYPE OF
MECHANISM.
BECAUSE MOST OF THE COLON CELLS
ABSORB WATER AND SALTS.
AND OF COURSE, WE HAVE ANOTHER
TYPE OF CELL THAT SAMPLES THE
LUMEN CONTENT AND TAKES UP
ANTIGEN INSIDE OF THE COLONIC
PATCH TO PRESENT THIS TO THE
CELLS.
THE FIRST MECHANISM MOSTLILY
EFFECTS THE B CELLS FROM THE T
CELLS AS WELL AND THE DENDRITIC
CELLS THAT PATROL MOST LIKELY
PRESENT ANTIGEN TO THE T-CELLS
AND OF COURSE, THIS IS BY THE
CHEMOKINES AND PRESUMABLY THIS
WOULD BE A GOOD POTENTIAL FOR A
TARGET FOR VARIETY OF DISEASES
THAT ACTUALLY USES THIS
MECHANISM TO SAMPLE MICROBES.
NOW HOW DOES THIS WHOLE
INTERACTION OF THE MICROBIOTA
WITH THE HOST EFFECT THE
RESPONSES TO THE CANCER, FOR
EXAMPLE?
IT'S AN EXAMPLE OF INTERACTION
OF THE MIC MICROBIOME AND THE PT
SEVERAL YEARS IT'S BEEN PROVEN
QUITE WELL THAT THERE IS VERY
STRONG CONNECTIONS BETWEEN THE
COMPOSITION OF MICROBIOTA AND
THE DEVELOPMENT OF CANCER.
THE INITIATION OF THE CANCER.
AND OBVIOUSLY THE RESPONSE TO
THE THERAPY.
AND I ACTUALLY THINK THAT IN
PART THIS IS NOT BECAUSE OF THE
WORK THAT WE DID ALONG WITH WORK
THAT THAT WAS DONE AND PARALLEL
AND PUBLISHED WITH US
BACK-TO-BACK.
SO WHAT WE'RE OBSERVING QUITE A
WHILE AGO, ALMOST 10 YEARS AGO
AND THE REASON I'M SHOWING THIS
OLD DATA BECAUSE IT WILL FEED
INTO THE NEXT THING THAT I'M
GOING TO TALK ABOUT SPECIFICALLY
ABOUT PATIENT STUDIES.
SO, MICE WERE TREATED WITH
ANTIBODY COCKTAILS THAT WAS
DEPLETING THE BUT THE MICROBIOTA
TWO WEEKS.
TUMORS WERE IMPLANTED INTO THE
MICE AND WE HAD TWO TYPES OF
THERAPIES THAT WERE GIVEN TO THE
MICE.
IMMUNOTHERAPY AND THE
CHEMOTHERAPY.
AS YOU CAN SEE, AND THESE TWO
PANELS, ABSENCE OF THE THIS WAS
REPEATED BY MANY OTHER GROUPS
AND THIS IS VERY PRODUCING
PHENOMENON BECAUSE NOW, IT'S
ESTABLISHED VERY WELL AND THEN
IF YOU DO THE SAME TRICK, BUT
WITH THE CHEMOTHERAPY YOU WILL
SEE EXACTLY THE SAME FEE ONLY
ON.
THE MICE STILL RESPONDING TO
THE.
THE DIFFERENCE HERE IS STARK FOR
SURVIVAL AS YOU CAN SEE.
SO WE ACTUALLY TRIED TO ANSWER
THE QUESTION EXACTLY HOW THIS IS
HAPPENING AND WE DID CRIP TOM I
CAN STUDIES AND FULL STUDIES AND
THE CONCLUSION THAT WE CAME UP
WITH IS THAT THE ANTIBODY OF
TREATMENT OR JUST THE DEPRESSION
WITH LIKE JOHN FREEMA RESULTS IN
REDUCTION OF BOTH NUMBERS OF
IMMUNE CELLS AND ACTIVITY.
AS YOU CAN SEE HERE ON THE LEFT
PANEL THAT SHOWS THE DIFFERENT
PATHWAYS, YOU HAVE REDUCTION IN
TOXICITY, YOU HAVE INCUBATION OF
THE PROLIFERATION OF DIFFERENT
CELL TYPES AND THIS IS MIRRORED
BY THE FLOW SEM TOM TREE DATA SO
IN GENERAL, BACTERIA IS CRITICAL
FOR MAINTAINING PROPER IMMUNE
CELL HOMEOSTASIS IN THE TUMOR
FOR SUCCESSFUL TREATMENT OVER
THESE CANCERS.
FOLLOWING OUR AND OTHER SIMILAR
TYPE OF PAPERS, MAINLY
INVESTIGATORS RUSHED INTO
LOOKING AT THE FACTS OF THE GUT
MICROBIOTA INSIDE THE PATIENTS
AND IN THIS PARTICULAR STUDY ALF
THEM DID IMMUNOTHERAPY WITH
CONTACT PD1 AND THEY LOOPED THE
EFFECTS OF TREATMENT IN
PATIENTS.
THE PROBLEM AROSE WHEN, AS WE
SPEAK, DUST SETTLED AND WE
STARTED LOOKING SPECIFICALLY AT
THE TYPE OF MICROBES THAT WERE
SPECIFIC FOR EACH ONE OF THESE
STUDIES AND UNFORTUNATELY, WHAT
EVERYBODY REALIZED VERY QUICKLY
THAT THE RESULTS WERE VERY
DIFFERENT BETWEEN THE DIFFERENT
STUDIES AND THAT PRESENTED A
HUGE PROBLEM BECAUSE HOW CAN WE
TRUST THIS TYPE OF DATA?
OBVIOUSLY IN ANY KIND OF
CLINICAL STUDY, IF YOU ANSWER
THE QUESTION TO THIS
CONTROVERSIAL DATA, WITH TWO
THINGS.
ONE IS OBVIOUSLY THE META
ANALYSIS BUT THE OTHER THING IS
GOING WITH THE MUCH LARGER
SAMPLE SIZE.
THIS IS WHAT OUR CLINICAL
COLLABORATORS IN PITTSBURG,
HASSAN AND DIWAKAR DID, THEY
DECIDED, TOGETHER WITH US, A
LARGER CLINICAL STUDY.
AT THE TIME IT WAS THE LARGEST
ONE THAT WERE TREATING MELANOMA
PATIENTS WITH ANTI PD1 THERAPY
AND FOLLOWED THE RADIO GRAPHIC
RESPONSES TO THE TREATMENT FOR
SOME TIME.
THIS IS THE FIRST R THE FIRST RE
RESULTS WE GOT.
ON THE LEFT SIDE, THIS IS A MAP
AND BLUE AND RESPONDERS AND RED
NOTE RESPONDERS AND YOU CAN SEE
THAT THE CENTRAL SEPARATION IS
QUITE SIGNIFICANT AND THIS IS
REFLECTED IN THE VERY GOOD P
VALUE AND ALSO WE GOT VERY GOOD
LIST OF THE TOXONEME THAT WERE
DIFFERENT BETWEEN THE RESPONDERS
AND NOTE RESPONDERS ACTUALLY.
THERE WAS MUCH LARGER LIST THE
ANSWER WAS IN THE META ANALYSIS.
SO WE DOWNLOADED THE DATA FROM
THESE DIFFERENT STUDIES AND WE
PUT THEM TOGETHER AND FOR
PIPELINE AND IN ORDER TO SEE
RESPONDERS AND VERY QUICKLY AND
IT'S ALL THE DIFFERENT STUDIES
IN DIFFERENT COLORS AND DID NOT
LINEUP WITH EACH OTHER SO THEY
WERE VERY QUITE DIFFERENT.
OF COURSE, THERE ARE STATISTICAL
TOOLS TO DEAL WITH THIS AND YOU
CAN ALSO DO IT AS WELL META
ANALYSIS WITH MULTIPLE DIFFERENT
TECHNIQUES AND GET YOUR TAXONOMY
LIST.
THE CORRECTED DATA YIELDED US
ACTUALLY IMPROVED P VALUE STUDY
AND IT WAS INSTEAD OF .006,
..002 WHICH WAS GOOD.
WE WERE CONFIDENT THAT WE SHOULD
BE NOW LOOKING AT THE DATA AND
THIS IS WHAT IT LOOKS LIKE.
THIS IS A CLY DRO GRAM.
IT'S A SIMPLIFIED WAY.
IT'S CIRCLIZED TREE OF LIFE.
IN THE CIRCLES, ARE HIGHER
LEVELS SUCH AS CLASS AND PHYLUM
AND THE OUTER SURGERIES,
SPECIES, GENUS, ET CETERA.
ONE OF THE REASONS WHY THIS IS
ACTUALLY USEFUL WAY OF LOOKING
AT IT BECAUSE IT LOOKS AT HIGHER
LEVEL TOXIC AND IT'S EFFECTED.
FROM ANALYZING MULTIPLE
DIFFERENT DAY SETS THIS WAY I
CAN TELL YOU THAT THIS IS A VERY
RARE TYPE OF VISUALIZATION OF
THE ANALYSIS.
WHAT I MEAN IS, TYPICALLY WE
DON'T SEE THE TIGHTLY CLUSTERED
BACTERIA THAT SIGNIFIES THE
WHOLE TREE EFFECTED IN YOUR
COMPARISON.
SO BLUE HERE, AND TALKING ABOUT
HERE AND NO RESPONDERS WILL
MOSTLY RELATED TO BACTERIA AND
THAT WAS MOSTLY COMPRISED OF
DIFFERENT SPECIES THAT GO ON TO.
AND MOST AND SEVERAL TRAINS
BACTERIA AND SOME STUDIES
REPORTED EARLIER.
SO, OF COURSE THE PROBLEM WAS
MAY WERE NOT HAPPY ABOUT BAN
MUCH CORRECTION BECAUSE WHAT IF
IT CONTAINED INFORMATION WE'RE
MISSING.
ONE WAY IS TO GET MORE DATA.
HOW DO WE GET MORE DATA?
IT DOESN'T EXIST ANYMORE.
WE TRY THE TECHNIQUES AND IF YOU
MANAGED TO ALIGN YOUR DATA WITH
A LARGER DATA, YOU CAN IMPUTE
YOUR LARGER DATA WITH
INFORMATION THAT CONTAINS THE
SMALLER DATA.
IT HAS A LOT OF LIMITATIONS AND
THIS OBVIOUSLY IT'S NOT A
REPLACEMENT FOR THE REAL THING
OF THE LARGER ANALYSIS.
FOR THE TIME BEING, FOR CURIOUS
MICE, WHICH WERE AT THE MOMENT,
IT WAS A GOOD THING TO DO.
FORTUNATELY FOR US IT WAS A
PROJECT THAT AMERICAN GUT
PROJECT THAT MANAGED TO COLLECT
ABOUT 10,000 STOOL SAMPLES AT A
TIME OF ANALYSIS AND FORTUNATELY
THIS DATASET WAS DONE WITH THE
SAME TECHNIQUES AS WAS DONE WITH
THIS DATASETS THAT WE HAD IN OUR
HANDS.
SO WE ANALYZED IT WITH OUR OWN
TOOLS PRIOR TO VENTURING OFF AND
TRYING TO ALIGN OUR DATA AND
IMPUTE IT AND SO ON.
WHAT WE SAW FROM THIS DATA
ANALYSIS WAS DIFFERENT FROM WHAT
WAS REPORTED BEFORE BECAUSE WE
USED OUR OWN TOOLS THAT WERE
QUITE IMPROVED COMPUTATIONAL
TOOLS WERE IMPROVED SINCE THE
TIME OF THE PUBLICATIONS OF THIS
DATASETS.
BECAUSE OF THE SINGLE CELL
SEQUENCE AND TECHNOLOGY THERE
WERE MANY TOOLS DEVELOPED FOR
THESE TYPE OF DATA.
SO WHAT YOU CAN SEE HERE ON THE
LEFT SIDE IS THE UMAP AND EVERY
DOT IS A STOOL SAMPLE.
WHAT YOU CAN SEE IS IN COLOR A
DIFFERENT CLUSTER THAT WE USE
SOFTWARE AND TO PREDICT WHAT
TYPE OF CLUSTERS IT CONTAINS AND
THEN WE LOOKED AT THE TOX
SPECIFIC FOR THESE CLUSTERS ON
THE RIGHT X WHAT WE SAW IS THAT
EVERY SINGLE CLUSTER THAT YOU
CAN SEE ON THE LEFT, HAD ITS OWN
SIGNATURE THAT WAS BUILT OUT OF
DIFFERENT UNITS.
ALL THESE CLUSTERS WERE
DIFFERENT.
SO YOU TRUST ME WITH THESE TYPE
OF INFORMATION, I'M SHOWING YOU
SOME OF THE DATA HERE.
THIS IS THE SAME.
L AS I JUST SHOWED BEFORE.
THEY JUST CALL IT A BIT
DIFFERENTLY.
>>THIS IS VERY ANNOYING.
I APOLOGIZE FOR THAT.
SO, RED MEANS HIGH AND BLUE
MEANS LOW.
SO SOME OF THE SPECIES, IS
ENRICHED IN ONE CLUSTER.
THE SAME GOES FOR PEP TON FILL
US AND THEY'RE ONE TYPE OF
CLUSTER FOR A PERSON LIKE ME WHO
IS DOING MICROBIOME FOR MANY
YEARS, GOD KNOWS FOR HOW LONG,
THIS IS A VERY STRANGE BECAUSE
IN MY PRIMITIVE MIND I ALWAYS
CONSIDERED MICROBIOME AS SOME
SORT OF A CONTINUOUS SPACE THAT
THERE ARE NO TYPES THAT WE
CLAIMED BEFORE.
IT JUST ONE SPACE THAT WE MAY
HAVE HAVE AND IT MAY GO OR IT
MAY NOT GROW.
YES WE DID KNOW THAT THERE ARE
SOME RELATIONSHIPS IN THE
INTESTINE AND SOME BUGS TRY TO
KILL ANOTHER BUG OR COMPETE FOR
THE FOOD, ET CETERA BUT TO SEE
THEM AS COMPRISING SOME SORT OF
ENTITIES LIKE THIS TO BEHAVE
LIKE A CELL TYPES IN THE HUMAN
BODY, THAT WAS QUITE AMAZING.
AND WE STILL DON'T UNDERSTAND
HOW THIS SO-CALLED THERE ARE
SOME SPOTS OF MAGENTA, GREEN,
RED, ET CETERA AND YOU CAN
ACTUALLY VISUALIZE THIS A BIT
BETTER AND USING THEY OCCUPIED
DIFFERENT PLACES AND WHY IS THIS
IS IMPORTANT BECAUSE IT EXPLAINS
OF THE NATURE THAT THEY'RE REAL
AND NOT IN THE SENSE THAT
THEY'RE TECHNICALLY PROBLEMATIC
AND THEY'RE JUST -- THESE
STUDIES SAMPLED THE DATASETS
FROM DIFFERENT SPACES FROM
DIFFERENT LOCATIONS OF THIS
MICROBIOME HYPER SPACE.
SO, THIS STUDY WERE COLLECTED IN
DIFFERENT PLACES IN THE UNITED
STATES SO NATURALLY LET'S LOOK
IF THERE'S ANY DISTRIBUTION
DIFFERENCES OF THE MICROBIOME
ACROSS THE UNITED STATES.
THIS IS WHAT WE HAVE.
FORTUNATELY FOR US ONCE AGAIN,
THIS DATASET IS VERY RICH.
IT CONTAINED THE DATA OF
GEOGRAPHICAL COR DIN AT FOR
EVERY SINGLE SIMPLE AND WE
STARTED FOR EVERY SINGLE MICROBE
TYPE A MAP WHERE THEY
DISTRIBUTED ACROSS THE UNITED
STATES.
IT TURNED OUT THEY DISTRIBUTED
QUITE DIFFERENTLY FROM EACH
OTHER.
SOME OF THEM DISTRIBUTED EVENLY
ACROSS THE U.S. WHERE IT'S THE
MICRO TYPE 8 AND EAST COAST SO
VERY DIFFERENT AND IF YOU LOOK
AT THIS DATASETS THAT WE WERE
DISCUSSING, THEY HAD A VERY,
VERY DIFFERENT COMPOSITION OF
THE MICRO BIO TYPE.
CONTRIBUTING TO THE PROBLEMS
THAT PEOPLE SEE BETWEEN THE
STUDIES.
SO GOING TO THE MORE IMPORTANT
QUESTION HOW THIS ACTUALLY
EFFECTS THE RESPONDERS AND NOTE
RESPONDERS.
WHAT DOES THIS MAP GIVE US THAT
WE DIDN'T HAVE BEFORE IS THE
MIKE KOBE TYPES FOR EVERY SINGLE
CLUSTER OF MICROBE YO TYPE WE
CALCULATE THE PREPORTION OF
RESPONDERS AND NOT RESPONDERS
AND MAP THIS AND THIS IS WHAT WE
HAVE GOT.
INSTEAD OF GETTING PATCHES OF
BLUE AND RED, WE'RE GETTING A
SUPER PATCH, A HUGE GROUP OF
BLUE AND HUGE GROUP OF RED.
SOME SORT OF A BELT OF EVILS IF
YOU MIGHT THINK ABOUT IT BECAUSE
THIS RED SIGNIFIES ENRICHMENT IN
NON RESPONDERS SO NATURALLY
THEY'RE SEPARATED INTO GOOD ONES
AND WE SEPARATE THIS BIG BELT
INTO TWO CLASSES AS WELL AND
THIS IS WHAT HAPPENED.
SO YOU HAVE THE TWO GOOD AND TWO
BAD TYPES AND THESE ARE THE ON
THE RIGHT SIDE THAT ARE
SIGNIFICANT.
OBVIOUSLY WE IDENTIFIED WAY MORE
WITH THIS TYPE OF ANALYSIS
BECAUSE THE SHEAR NUMBERS MANY
OF IT'S THE WHOLE POINT OF
IMPUTING THE DATA.
WE DID IDENTIFY NEW BACTERIA,
FOR EXAMPLE, THAT WAS NOT
IDENTIFIED PREVIOUSLY NOW META
ANALYSIS BUT IN THE BACK-TO-BACK
PAPER THAT WE HAD PUBLISHED,
WITH NICOLAS GROUP, THEY FOUND
THAT IT'S A GOOD BACK AND THE
SAME GOES WITH THE THINGS LIKE
THAT. THE BAD BACTERIA WERE
MOSTLY SIGNIFIED BY BAD AND
MICROBIOME TYPE ONE AND TWO WAS
MARKED BY BACTERIAS.
AND I THINK TO MENTION FROM THIS
SLIDE IS THAT BACTERIA THAT HAS
BEEN A TOPIC OF MANY CLINICAL
ACTUALLY STUDIES AND MANY
BIOTECH STARTUPS IS A PART OF
THE GOOD MICROBIOME TOOL.
SO WE REALLY WANTED TO SEE IF
THIS IS ALL TRUE AND HOW DO YOU
GET TO THAT?
HOW DO WE TEST THE IN SOME OTHER
WAY AND THEY'RE NOW DATASETS
THAT WE HAD AND THEN WE
REMEMBERED THAT THERE WERE
STUDIES A WHILE AGO THAT SHOWED
THAT ANTI-BUY OT I CAN THERAPY
PRIOR TO PD1 AND RESULTS IN THE
LOSS OF THE EXPOS TO THE PD1 SO
WE'RE TALKING ABOUT THE PRIOR
ALL THE WAY TO SIX MONTHS BUT
NOT AT THE TIME AND OF THE
TREATMENT SO, AS YOU CAN SEE
HERE, THE NO ANTIBIOTIC HAS
PREVIOUS SURVIVAL WITH ANTIBODY
BAD.
AND AGAIN, THIS AGP PROJECT
THANK GOD, EXISTS PROVIDED THE
TREATMENT AND THIS IS THE RESULT
OF THE DENSITY PLOTS THAT WE
PROD.
WITHOUT ANTIBIOTICS, THIS IS
WHAT WE SEE ON THE LEFT SIDE.
WITH ANTIBIOTIC THIS LOOKS VERY
DIFFERENT AND IF YOU OVER LAY
THESE TWO DENSITY PLOTS, YOU GET
THE RED SPACES THAT SHOW WHICH
ONE IS ACTUALLY THE MOST
PROBLEMATIC INDUCED BY
ANTIBIOTIC TREATMENT SO WE
DEFINED THIS AS A MICROBE TYPE
AND THIS IS AGAIN.
LET'S LOOK AT OUR MAP AND THEY
LOST THE GOOD PORTION AND GAINED
THE WHOLE DIVERSITY OF THE BAD
TYPE.
APPROXIMATE VERY BRIEFLY I'M
GOING TO TOUCH ON THE STUDY THAT
WE WERE VERY LUCKY TO BE PART
OF.
WHICH IS TRANSFER OF MICROBIAL
MATTER FROM RESPONDING PATIENTS
TO NOT RESPONDING PATIENTS AND
LOCKING AT THE REVERSAL OF THE
PHENOTYPE OF LACK OF RESPONSE TO
ANTI HD PD-1 TREATMENT.
AGAIN TOGETHER WITH PITTSBURG,
WE OBSERVED THAT THE RECIPIENTS
THAT RECEIVED FECAL MICROBIAL
TRANSPLANT ACTUALLY REVERSED THE
NON RESPOND EGG PHENOTYPE AND
WERE RESPONDERS TO TREATMENT
AFTER THEY RECEIVED.
LET'S LOOK AT THE BACTERIA THAT
IS DIFFERENT BETWEEN RESPONDERS
AND NOT RESPONDERS.
THIS IS A COMPLETELY DIFFERENT
STUDY DONE WITH DIFFERENT
PROTOCOLS, DIFFERENT TIMES AND
EVERYTHING.
AND YET THE BACTERIA THAT WE SEE
ALREADY FAMILIAR TO US, LET'S
PUT TOGETHER THE STUDY I JUST
SHOWED BEFORE AND WE'LL SEE,
BECAUSE OF THE NUMBER SIZE OF
THE PATIENTS, OF COURSE WE HAVE
MORE IN THE META ANALYSIS
HOWEVER, THESE TWO LOOK PRETTY
IDENTICAL TO ME.
SO THIS IS A VERY BRIEF
CONCLUSION.
SO WE HAVE ALREADY MULTIPLE
LINES OF EVIDENCE THAT INDICATE
THAT THE BENEFICIAL NATURE OF
MULTIPLE SUCH AS BACTERIA AND
WHILE HIGHLIGHTS THE ROLE
NEGATIVE ROLE OF BACTERIAITIS
AND THE DIFFERENCES THAT
INITIALLY WERE KIND OF CONFUSING
TO ALL OF US, ACTUALLY RESULT IN
THE DIFFERENT SUB SAMPLE
INTERESTING DIFFERENT STUDIES
FROM MICRO HYPER SPACE AND THIS
MAYBE ROW TYPES ARE TWO LARGE
GROUPS, TWO BENEFICIAL AND TWO
DETRIMENTAL AND ONE OF THESE BAD
GROUPS CAN BE INDUCED BY
TREATMENT AND ALSO WE OBSERVED
THEY CAN REVERSE THE PHENOTYPE
OF NON RESPONDERS AND PATIENTS
TO MAKE THEM RESPONDERS AND THAT
WAS QUITE IMPRESSIVE.
SO YOU WOULD ASK WHAT EXACTLY IS
HAPPENING WITH THESE TYPE OF
RESPONDERS AND NOT RESPONDERS
AND THE FUNCTIONAL SPACE.
GENES FROM BACTERIA ARE DOING
ALL THAT AND YOU ARE RIGHT.
THE PROBLEM IS THAT IT'S VERY
INDICTMENT TO ANSWER.
AND THE REASON IS BECAUSE THE
DIFFERENCES ARE SO BIG THAT VAST
MAJORITY OF THESE GENES
IDENTIFIED THEY WERE DIFFERENT
BETWEEN RESPONDERS AND NON
RESPONDERS WHICH WERE 1,000
SOMETHING GENES, THEY WORE
MARKERS OF THE BACK TER TEE AS
WHAT WE DISCUSSED IN THE MAIN
DRIVERS OF THIS TWO PHENOTYPES.
SO THERE ARE WAYS OF THINKING
ABOUT IT IS IF WE COULD COMPARE
BENEFICIAL SPECIES ON THE LEFT
AND THE SPECIES ON THE RIGHT,
HUNTING DOWN THESE VERY TINY
SPECKS GREENS.
THOSE ARE THE GENES THAT DRIVE
OUR PHENOTYPE OF RESPONSE IN
GROWN AND NO RESPONSE IN RED.
YOU ALSO IDENTIFY A LOT OF PATH
GENES THESE BLUE CIRCLES ON THE
LEFT OR ORANGE CIRCLES ON THE
RIGHT SO HOW DO WE SEG ROW GATE
PASSENGER GENES FROM THE DRIVER
GENES OR FUNCTIONAL GENES AND
THERE ARE MULTIPLE TOOLS ONE CAN
USE AND ONE OF THE WAYS OF DOING
IT IS TO DO THE ANALYSIS WITHIN
THE TOX SO WE CAN TAKE A
SIGNIFICANT TOX THAT WE'RE JUST
SHOWING YOU AND SPLIT IT EVEN
FURTHER USING DIFFERENT TYPE OF
TECHNIQUES INTO THE STRAINS AND
THESE ARE SHOWN IN THESE CIRCLES
AND WITH A DASHED LINE.
WITHIN THE CIRCLE, WE HAVE THESE
GROWN GENES THAT PRESENTED HERE
AND THE GENES OF INTEREST AND IF
WE DO THIS BETWEEN THE MULTIPLE
DIFFERENT SIGNIFICANT TAX
SEPARATELY FOR BENEFICIAL AND
SEPARATELY FOR DETRIMENTAL AND
THEN WE'LL HAVE THIS TYPE OF
DIAGRAM THAT WILL SAY, YES, YOU
FIND THESE GENES IN MORE THAN
ONE TAXA SO THERE'S A HIGH
PROBABILITY THAT THIS IS A GREN
THAT DRIVES IT.
SO THIS APPROACH HAS ITS OWN
LIMITATIONS BECAUSE IT HAS TO BE
PART OF THE GENOME WHICH IS
COMPRISED UP TO 20% OF THE
BACTERIAL GENOME AND HOWEVER
IT'S NOT ALWAYS THAT HIGH.
NEVERTHELESS, WE FOUND THAT THIS
IS A REALLY GOOD WAVE US TRYING
TO NARROW IT DOWN THESE HUGE
NUMBER OF GENES AND THIS IS WHAT
WOVE GOT.
WHAT YOU WANT TO LOCK AT IS THE
SPECIES IN RED AND THEY WERE
INITIALLY FOUND TO BE
SIGNIFICANT AND THE BLUE GOWNS
THAT ARE COMMONLY DIFFERENT
BETWEEN THE RESPONDERS AND
RESPONDERS IN FAVOR OF THE
RESPONDERS IN THIS SLIDE AND
WHAT WE SEE HERE IS THAT THE
BACTERIA THAT HAVE HIGH LEVELS
OF THE OF DEGRADING ENZYMES ARE
BENEFICIAL SO OUR CYCLIC DI-GMP
STING AGONIST ELSE WHAT MAKES
METABOLIZE RATED TO RIBOFLAVIN
PATHWAY AND WE DID THE SAME
THING WITH THE LPS NON
RESPONDING BACTERIA AND WE
OPENED THERE WAS A LOT OF GENES
THAT WERE RESPONSIBLE FOR
SYNTHESIS WERE DIFFERENT BETWEEN
THE RESPONDERS AND NOT
RESPONDERS AND THIS IS A HEAT
LAMP OF ALL THE LPS GENES AND
NOW DATASETS THAT WERE FOUND
THAT HAVE AND COMPARE RESPONDER
AND NOT RESPONDERS PATIENTS SO
THERE'S A VAST MAJORITY OF LPS
RELATED GENES CONNECTED TO THE
RESPONDERS.
>>HOW THE HOST RESPOND TO THIS
BEHAVIOR OF THE MICROBIOME AND
WE DID SOMETHING THAT IS NOT
TYPICALLY DONE IN THE FIELD
WHICH IS ANALYZING IN THE STOOL
SIM TOSAMPLE.
SO BEFORE I THROW ME OUT OF THIS
PODIUM FOR DOING THAT I WANT TO
CONVINCE YOU THIS IS A GOOD
IDEA.
SO YOU HAVE A LOT OF CELLS SHED
INTO THE GUT, RIGHT.
THESE ARE NOT JUST EPITHELIAL
CELLS.
THESE ARE IMMUNE CELLS THAT WE
JUST SAW EARLIER OCCUPIED.
WHEN THEY SHED, THEY OCCUPY A
HEFTY PREPORTION FROM .5 ALL THE
WAY TO 1% OF THE SCHOOL RNA WITH
THE HOST RNA.
YES, IT'S VERY DEGRADED BUT IT'S
VERY PRECIOUS INFORMATION
BECAUSE YOU HAVE THE EXACT TIME
OF STOOL SAMPLE.
CALL IT LICK SIMILAR TO LIQUID
BIOPSY THAT WE USE FOR HUMAN
BLOOD.
THESE ARE RESULTS.
ON THE LEFT SIDE WE HAVE GENES
WITH NONRESPONSERS AND THE RIGHT
SIDE WE SEE RESPONDERS SO IT'S A
GOOD NUMBER.
IF YOU DO THE PATH 1 ANALYSIS,
YOU SEE MOST OF THE GENES IN NOT
RESPONDER SIDE ACTUALLY HAVE
UPSTREAM IN THE PATHWAYS LPS
THAT WE JUST TALKED ABOUT.
SO WHAT ELSE CAN YOU DO WITH
THIS DATA?
IMPUTE THE CELLS THAT EXIST IN
THE EXFOLIOME.
ALSO TRUST COMPRISES OF
DIFFERENT RNA SPECIES THAT
RESIDE IN DIFFERENT CELL TYPES
SO CAN DIFFERENT TECH NECKS AND
IN THIS CASE CALLED GCA WE CAN
RECORRECT THESE AND COMPARE
RESPONDERS WITH NON RESPONDERS
EX WHAT YOU SEE HERE IS A LOT OF
INNATE IMMUNE CELLS WERE
INCREASED IN THE KNOWN
RESPONDERS COMPARED TO THE
RESPONDERS THAT HAD A VERY
REGULAR IS TYPE OF CELL TYPES
SUCH AS GOBLET CELLS AND ET
CETERA.
SO LET'S SUMMARIZE THESE
FINDINGS TOGETHER AND BRING THIS
IN ONE PIECE.
THIS IS OUR WORKING HYPOTHESIS.
SO WE HAVE BACTERIA SPECIES.
WE ALSO IDENTIFIED AND THEY
PRODUCED LPS AND THEN THERE ARE
SOME 'EM UNION CELLS IN THE GUT
THAT MAKE THEY TRAVEL DIRECT LOW
TO THE TUMOR AND THIS EFFECTS
THE RESPONSE TO THE PD1 THERAPY
IN A NEGATIVE WAY.
YOU CAN BLOCK THIS LPS WITH
ENZYMES THAT HAVE BEEN
INTERESTEPRODUCEDBY THE GOOD BLS
BLOCKING THIS PATHWAY.
WE ALSO FOUND THAT THEY HAVE
PATHWAY AND INSIDE OF THEM AND
JUST WANT TO REMIND YOU THAT
METABOLITES THAT SURROUND THIS
PATHWAY TALLLY PRIME MATE CELLS
AND FINALLY, WE SAW THAT
BACTERIA SUCH AS THESE FROM THE
GENOUS PRODUCE DJMP.
PREDICTED TO PRODUCE DJMP AND
THIS IS STING THAT HAS BEEN
REPORTED TO MODULATE MONOCYTE
DIFFERENTIZATION AND FOR THE
PROOF OF IT, FROM OUR OWN
INSTITUTE FROM NCI PUBLISHED A
VERY NICE PAPER IN CELL THAT
DEMONSTRATED THAT HUAWEI MP
WHICH IS RELATIVE TO JMP
PRODUCTS EFFECTS MONOCYTE
TRANSITION AND EVENT EFFECTS THE
RESPONSE OF THE TUMOR THERAPY
AND THERE'S A GROWING BODY OF
EVIDENCE THAT MAKE CELLS
IMPORTANT FOR THE RESPONSE TO
THE THERAPY SO, WITH THAT, I
WANT TO CONCLUDE MY TALK AND
THANK MOSTLY GEORGIA WHO IS THE
BRAIN BEHIND MOST OF OUR
OPERATIONS FOR HIS INSIDE FULL
COMMENTS AND IDEAS AND
PIONEERING THESE MICROBIOME
STUDIES IN THE FIELD IN GENERAL.
I WANT TO THANK HASSAN AND
DIWAKAR AND OUR CLINICAL
COLLABORATORS WITH WHOM NONE OF
THIS WORK WOULD HAVE DID NOT
POSSIBLE AND THE STAFF OF THE
MICROBIOME CORE.
HUNDREDS OF SAMPLES.
I ALSO WANT TO THANK MEMBERS OF
OUR LAB JOE MAKALIK AND POONAM
AND MIRIAM WHO WERE INSTRUMENT
IN THIS WORK AND ALSO ROMINA FOR
HER EARLIER WORK ON THIS TOPICS
FOR US AND FOR ALWAYS USEFUL
ADVICES AS WELL AS ANDRE AND
OTHERS WHO PLAYED INSTRUMENTAL
ROLES IN THESE PROJECTS AND THE
FACILITY AND OF COURSE, JAY WHO
PLAYED A IMPORTANT ROLE IN OUR
DENDRITIC CELL STORY AND I WANT
TO THANK JASMINE WHO ALWAYS
PROVIDES USEFUL INSIGHTS AND THE
STORIES THAT ARE PRESENTED SO
THANK YOU FOR YOUR TIME.
>>THAT WAS SUCH A GREAT TALK.
SO I HAD A QUESTION, BASED ON
THE FACT THAT THERE COULD BE
GEOGRAPHICAL OR REGIONAL OR
DIETARY CHANGES, DO YOU SEE THE
FUTURE FOR BIOMARKERS OF
RESPONSE AND NONRESPONSE AT THE
LEVEL OF BACTERIA OR AT THE
FUNCTION DIFFERENCE THE LPS OR
THE HUMAN RESPONSE, LIKE WHAT
YOU ARE SEWING IN THE HUMAN RNA
SO THAT'S LIKE PART ONE AND PART
TWO, I WAS CURIOUS ABOUT IN THE
NON RESPONDERS, BECAUSE YOU SAY
THAT THERE'S LIKE 1% OF HUMAN
NUCLEIC CONTENT IN YOUR STOOL
SAMPLE, DO YOU SEE HIGHER LEVELS
IN THE NON RESPONDERS, DO THEY
HAVE A LEAKY GUT IF THERE'S MORE
INFLAMMATION AND THERE'S JUST
MORE CELLS LEAKING INTO THE
STOOL?
>>Dr. Dzutsev: IF I MAY START
FROM THE SECOND QUESTION.
NO.
WE DID NOT LOOK AT THE HIGH
NUMBER.
IN FACT, OUT OF THE PRESENT VERY
HIGH PREPORTION OF THE SPECIES
RNA SPECIES IN THE GUT AND IN
THE STOOL AND IT'S VERY
DIFFICULT, ACTUALLY TO GET
ENOUGH PROPER RATES BECAUSE OF
THE LEVEL OF DEGRADATION AND SO
WE DIDN'T REALLY DO THESE TYPE
OF A CORRELATION BUT I THINK
IT'S A VERY GOOD IDEA,
ESPECIALLY GIVEN THE FACT THAT
YES, WE SAW THE NUMBER OF
VOLUNTARY CELLS GO UP.
SO VERY REASONABLE IDEA.
REGARDING THE DIFFERENT
PREDICTIVE POWER OF DIFFERENT
TYPES AND IN GENERAL WE RESPOND
AND NOT RESPOND SIGNATURE YOU
ARE ASKING EXACTLY THE SAME
QUESTION AS MANY COMPANIES
ALREADY TRIED TO DO SO THERE ARE
A MULTI MILLION BUSINESS AT THE
MOMENT WHERE PEOPLE TRIED TO PRO
DICTIONARY DIFFERENT RESPONSES
IN ORDER TO MODIFY THE TREATMENT
AND TO CHANGE THE GUT MICROBIOME
WITH A DIET.
THEY HUNT FOR GOOD DONORS THAT
SO LET'S SAY YOU DEFINE A GOOD
DONOR FROM THIS TYPE OF STUDY
AND THEN YOU CAN TAKE THIS GOOD
DONOR FROM THE POOL OF PATIENTS
BUT JUST FROM PEOPLE WHO ARE
AROUND YOU FROM YOUR RELATIVES
OR JUST FROM PEOPLE ON THE
STREET BY THE FECAL SAMPLES AND
SO IT'S VERY ACCEPTS OF
BUSINESS.
IT SOUNDS LIKE LIKE A VERY CHEAP
THING TO DO, RIGHT.
BUT IN FACT, IT COST UPWARDS UP
TO $2,000 TO PRO A SINGLE FMT
TRANSPLANT RIGHT NOW.
YEAH.
THAT IS THE BIG MONEY AND A LOT
OF PEOPLE DOING THIS TYPE OF
STUFF RIGHT NOW.
>>THANK YOU.
>>THAT WAS A LOVELY TALK AND
THIS IS WHAT OUT OF MY STRONG
SUIT SINCE I'M A CELL SIGNALER.
THE QUESTION I HAD, WHEN YOU
LOOK AT THE GEOGRAPHIC
DISTRIBUTION OF THE DIFFERENT
BACTERIA AND YOU THINK ABOUT
CLINICAL TRIALS, DO YOU FIND
THAT IF YOU DO YOUR CLINICAL
TRIAL IN HOUSTON YOU WILL BE
SUCCESSFUL AND IN BETHESDA DON'T
DO THE TRIAL.
THE BETTER WAY IS TO CHANGE THE
BACTERIA.
>>NO, BECAUSE ALTHOUGH I DID
PRESENT THIS AS A FACT, THE
FIELD IS YET TO ACCEPT OUR
INTERPRETATION OF THE EVENTS
HERE.
AND SECOND OF ALL, PEOPLE REALLY
DON'T WANT TO LIMIT THEIR
CLINICAL TRIALS BECAUSE OF SOME
PETTINESS LIKE GOUGH OWE GRAPH I
CAN LOCATIONS.
BECAUSE THEY HAVE OTHER THINGS
TO WORRY ABOUT LIKE PATHOGENS OR
WHATEVER OR OTHER TYPE OF
METADATA THAT THEY'RE LIMITED TO
DO ANYWAY ALREADY.
N GENERAL, IF WE'RE ACTUALLY
USING UPS THIS TYPE OF APPROACH,
AND WE'RE ACTUALLY SCALING THIS
UP MUCH MORE RIGHT NOW, WE HAVE,
INSTEAD OF JUST DOING THIS
MICROBIOME ON SPACE WE'RE DOING
THIS ALSO ON THE FUNCTIONAL
SPACE AND USING THOUSANDS OF
PEOPLE AND TO RECONDUCT ALL
THESE DIVE TYPE OF GENOMES AND
HAVING THE DIFFERENT TYPE OF
LAYOUTS SO WE WANT TO EXPAND
THIS IDEA EVEN FURTHER.
WHEN WE HAVE THAT, PEOPLE CAN
JUST SIMPLY ADJUST THEIR RESULT
BASED ON THIS TYPE OF DATA AND
THAT WILL BE WAY MORE'S YEAR
THAN CHANGING THE OF CLINICAL
TRIALS.
BECAUSE PEOPLE ALSO TRAVEL FROM
OUTSIDE.
ESPECIALLY TO NIH.
EVEN IN THE PLACES LIKE
PITTSBURG.
THAT IS WHY IT'S VERY.
>>IF YOU GO BACK AND LOOK AND
SEE WHOSE TRIALS WERE SUCCESSFUL
AND WHOSE WEREN'T?
>>WE DEFINITELY PLAN TO DO THAT
BECAUSE WE SPECIFICALLY GO BACK
TO THE OTHER PEOPLE'S DATA.
THAT'S OUR -- THAT'S OUR
PIPELINE RIGHT NOW.
THAT'S WHAT WE DO THIS NOW EVERY
TIME.
>>THANK YOU.
>>YEAH.
>>SO LET ME ASK YOU JUST ONE
QUESTION.
WHICH YOU HAVEN'T TOUCHED UPON
THIS.
THE MICROBIOME ARE IN THE TUMOR
CELLS.
OBVIOUSLY, THAT IS A WHOLE
DIFFERENT STORY AND THERE'S A
LOT OF DISCUSSION WHETHER YOU
KNOW, ABOUT THE BIOMARKERS, ET
CETERA, HOW THIS IS EFFECTED.
WHAT I WAS WONDERING IS IF YOU
CAN JUST BASICALLY PROVIDE SOME
COMMENTS THERE?
>>Dr. Dzutsev: YEAH, SO, I'M
GOING TO -- I HAVE ACTUALLY
SLIDES READY.
I SEE WHAT HE IS GOING TO SHOW.
>>WE'RE NOT -- SO ACTUALLY
THERE'S A STUDY THAT WAS DONE BY
IN COLLABORATION WITH POONAM IN
THE LAB AND WE LOOKED AT THE
DIFFERENCES IN MICRO BIO TOM AND
IN THIS SLIDE YOU HAVE
MICROBIOME.
WE DEVELOPED OUR OWN PROTOCOLS
TO HAVE A HIGH SENSITIVITY
BECAUSE IT'S A VERY DIFFICULT
THINGS TO DO TO ACTUALLY
SEQUENCE VERY TINY NUMBER OF
MICROBES WITHIN THE TUMOR.
NEVERTHELESS, THIS IS A VERY,
VERY GROWING FIELD AND IT MAKES
SENSE.
WE FOUND BACTERIA REPORTED TO BE
INVOLVED IN THE LIVER CANCER
DEVELOPMENT AND IT'S ALMOST
UNIVERSALLY ACCEPTED AND ON ONE
SIDE AND WE ALSO FOUND A WHOLE
BUNCH OF OTHER THAT ARE JUST
INCREASINGLY CONSIDERED TO BE
PART OF THE DEVELOPMENTS
SPECIFICALLY FOR CCA AND ONE OF
MY FAVORITE SLIDES ACTUALLY IN
THESE TOPICS IS ACTUALLY SEEN
HERE ON THE RIGHT.
THESE ARE THE SLIDES THAT POONAM
DID BY SUSTAINING THE TUMORS,
LIVER TUMORS THAT WERE PROVIDED
BY TIM HERE.
THANK YOU, VERY MUCH.
AND HIS COLLABORATORS WITH THE
16S PROBE IN GREEN.
AS YOU CAN SEE, THE BACTERIA
ACTUALLY LOCALIZES INTRA CELL IN
LARGE QUANTITIES.
INTER TUMORAL BEHAVIOR BEHAVES
AS IF IT'S EFFECTING THE TUMOR
SAMPLES SO THERE ARE MULTIPLE
EXAMPLES FROM THE SLIDES
COLLECTED TO CLAIM THAT THIS IS
CORRECT MANY OF ALTHOUGH I'M
SHOWING YOU AS IF IT'S A
UNIVERSAL HIGHLY DISPUTED
PHENOMENON BUT THOSE CELLS ARE
VERY REAR SO THEY'RE LESS THAN
1/5,000 CELLS THAT ARE
INFECTIONED PER SLIDE.
NEVERTHELESS, THEY EXIST AND
THEY DO HAVE A PHENOTYPE.
PEOPLE DID REPORT IT ALREADY
THAT IN SOME CANCERS, MICROBIOME
CONTROLS THE RESPONSE TO A
DIFFERENT TYPE OF THERAPY.
THIS IS A VERY EXCITING, VERY
NOBLE FIELD OF STUDY THAT MY
TEAM ACTUALLY STUDIED A WHILE
AGO IN THE LIVER CANCER MODELS
AND IT'S BEEN GAINING A LOT OF
STEAM.
>>SO IT'S 1:00.
I WOULD LIKE TO THANK YOU AGAIN.
THAT WAS A SUPER EXCITING TALK
AND I HOPE THERE'S WAY MORE TO
COME.
THANK YOU.
>>Dr. Dzutsev: THANK YOU, TIM.
[APPLAUSE]