HERE IS DR. BOB DATTA,HE
COMES FROM LONG BEACH,
CALIFORNIA.
BUT THEN COMPLETED MUCH OF HIS
TRAINING IN THE NORTHEAST.
HE RECEIVED A B.S. IN MOLECULAR
BIO PHYSICS AND HISTORY FROM
YALE.
PRIOR TO MATRICULATING TO
HARVARD'S MEDICAL SCHOOL WHERE
HE COMPLETED HIS M.D. AND Ph.D.
IN NEUROBIOLOGY.
FOLLOWING THAT HE RELOCATED TO
COLUMBIA UNIVERSITY WHERE HE
WAS ABLE TO WORK WITH NOBLE
LAUREATE RICHARD AXLE, BOB, I
ASSUME AROUND THE SAME TIME YOU
WERE TRAINING.
SO AN INTERESTING TIME TO BE
PART OF THE LAB.
FOLLOWING THAT HE JOINED
HARVARD AS FACULTY.
THIS WAS IN 2009.
AND PROCEEDED THROUGH THE RANKS
QUITE QUICKLY, REACHING THE
RANK OF PROFESSOR JUST 12 YEARS
LATER IN 2021.
BOB IS A SCIENTIFIC ADVISOR,
MEMBER OF ADVISORY BOARDS
THROUGHOUT THE COUNTRY AND
WORLD.
HE SUPPORTS INDUSTRY, ACADEMIA,
AS WELL AS HERE AT HOME WHERE
HE IS AN ADVISORY BOARD MEMBER
OF OUR NATIONAL SMELL AND TASTE
CENTER.
BOB HAS CONTRIBUTED TO PEER
REVIEW, THE NIH, NSF, MULTIPLE
OTHER PLACES AND IS TRULY A
RESOURCE.
A LEADING VOICE WITHIN THE
OLFACTION AND SENSATION
COMMUNITIES.
BOB STUDIES HOW THE BRAIN
ORGANIZES AND INTEGRATES
INFORMATION ABOUT SENSATION TO
DRIVE MEANINGFUL INTERACTIONS.
HOW WE TAKE SIGNALS FROM THE
WORLD AROUND US AND INTEGRATE
THAT INTO BRAIN FUNCTION AND
INTERACTIONS.
THIS HAS SPANNED FROM DETECTION
TO CNS INTEGRATION, ALL THE WAY
FORWARD TO ACTION.
AND I'M INCREDIBLY EXCITED TO
HEAR SOME OF HIS NEWER FINDINGS
AND WORK I BELIEVE HAS THE
POTENTIAL TO TRULY PUSH OUR
FIELD FORWARD.
SO WITH THAT, AND NO PRESSURE,
BOB?
[ APPLAUSE ]
I HAD TWO TASKS AND BOB, JUST
ONE SECOND.
FOR EVERYONE JOINING US, IF YOU
WOULD LIKE TO RECEIVE CME
CREDIT FOR THIS EVENT, PLEASE
ENTER THE CODE 57691 IN THE
JOHNS HOPKINS CME PORTAL.
THANK YOU.
>> Sandeep Datta: GREAT, THANKS
SO MUCH, JOSH FOR THAT REALLY
KIND INTRODUCTION.
AND THANKS TO ALL OF YOU HERE
AT THE NIH.
THIS IS REALLY AN HONOR FOR ME
AND MY LAB, THIS IS THE
NATION'S PREEMINENT BIO
INSTITUTE.
I'M GRATEFUL TO CATCH UP WITH
OLD FRIENDS, ALL OF YOU AND
SHARE SOME OF OUR SCIENCE.
AS JOSH MENTIONED MY LAB'S MAIN
INTEREST IS THINKING ABOUT HOW
THE BRAIN TAKES SENSORY
INFORMATION AND GENERATES
NATURAL BEHAVIORS IN THE REAL
WORLD.
TODAY I'M NOT GOING TO TALK AT
ALL ABOUT THE WORK MY LAB DOES,
INSTEAD I WANT TO TALK ABOUT
SOME WORK WE HAVE BEEN DOING,
EXPLORING THE SENSE THAT IS
MOST IMPORTANT FOR MOST ANIMALS.
WE THINK OF SMELL BEING PRIMAL
TO ANIMALS, IT ALLOWS THEM TO
SMELL FOOD, ANIMALS AND THREATS.
FOR HUMANS WE THINK OF SMELL AS
BEING KIND OF AESTHETIC,
ALTHOUGH OF COURSE SMELLS ARE
CAPABLE OF ELICITING DEEP
MEMORIES AND EMOTION.
PEOPLE WHO ACUTELY LOSE THEIR
SENSE OF SMELL FEEL BEREFT AND
INCREASED RISK OF PSYCHIATRIC
DISORDERS LIKE DEPRESSION.
BECAUSE OF SMELL AND MEMORY,
RISK OF NEURODEGENERATION.
IT'S IMPORTANT WE UNDERSTAND
SMELL NOT JUST BECAUSE IT HELPS
US MAKE SENSE OF THE WORLD BUT
IMPORTANT FOR HUMAN HEALTH AND
WELLNESS.
TODAY I WILL TELL YOU ABOUT THE
CANONICAL OF SMELL AND WHY WE
THINK A LOT OF IT IS WRONG.
I WANT TO TALK ABOUT MAPS.
WHAT IS A MAP?
A SYMBOLIC REPRESENTATION THAT
CAPTURES SOME FEATURE ABOUT THE
WORLD, WHICH MAINTAINS
RELATIONSHIPS.
SO A GREAT EXAMPLE OF A MAP IS
THIS MAP OF THE UNITED STATES.
SO HERE, THE FEATURE THAT IS
BEING CAPTURED IS ELEVATION.
AND THE RELATIONSHIPS THAT ARE
BEING MAINTAINED ARE SPATIAL.
SO ARMED WITH THIS KIND OF MAP,
YOU CAN MAKE PREDICTIONS HOW
HARD IT WILL BE TO BICYCLE FROM
POINT A TO POINT B.
MAPS DON'T JUST HAVE TO CAPTURE
PHYSICAL FEATURES ABOUT THE
WORLD.
THEY OBVIOUSLY CAN CAPTURE MORE
ABSTRACT THINGS LIKE POLITICAL
BOUNDARIES.
ONE OF THE GREAT THINGS ABOUT
MAPS THEY ARE EASILY REPRODUCED
AND TRANSFORMED IN THIS FAMOUS
PAINTING CALLED MAP CALLED
JASPER JOHN.
THE POLITICAL BORDER THAT'S
SEPARATE THE STATES AND REMIND
US WE ALLBEE LONG TO THE SAME
COUNTRY.
MAPS ARE PERVASIVE IN THE
NERVOUS SYSTEM.
THE MAPS WE UNDERSTAND THE BEST
CREATE EXTERNAL WORLD FOR OUR
SENSES.
WE PARTICULARLY UNDERSTAND
THOSE FOR TOUCH, FOR SIGHT AND
FOR HEARING.
SO FOR EXAMPLE, WE KNOW THE
RETINA CONTAINS A RETINA
TOPICAL MAP OF THE VISUAL WORLD.
THERE ARE NEURONS THAT TEND TO
REPRESENT OBJECTS THAT MIRROR
EACH OTHER IN VISUAL SPACE.
THE COCHLEA HAS NEURONS NEAR
EACH OTHER IN PHYSICAL SPACE
TEND TO RESPOND TO SOUNDS OF
SIMILAR FREQUENCIES CHBLT
MAPPED OUT IN A PHYSICAL SPACE
ARE KEY CHARACTERISTICS IN
THESE MAPS.
AND IMPORTANTLY, THE STRUCTURES
OF THESE MAPS ARE MAINTAINED AS
INFORMATION PROGRESSES FROM
PERIPHERAL SENSE ORGANS FROM
THE THALAMUS AND CORTEX, WHICH
ITSELF CONTAINS TOPIC MAPS.
WE KNOW HOW THESE MAPS ARE
BUILT AND PROPAGATED FROM ONE
BRAIN AREA TO THE NEXT.
THE MAIN THEME IS GRADIENTS,
CHEMICAL GRADIENTS PLAY AN
IMPORTANT ROLE IN THE
DEVELOPMENT AND MAINTENANCE OF
THESE MAPS.
A MOLECULE FAA AND THALAMUS
CONTAINS EPHRIN-A.
THEY HELP GUIDE AXONS IN A
GUIDE TO GUIDE MANNER ALONG
THIS.
THESE ARE EXPRESSED IN THE
CILIOSENSORY NEURONS THAT LIVE
HERE IN THE OLFACTORY
ESPECIALLY THEME YUM IN YOUR
NOSE.
THROUGH MECHANISMS WE DON'T
FULLY UNDERSTAND THAT MATURAL
OLFACTORY SENSORY NEURONS
CHOOSE TO EXPRESS ONE AND ONLY
ONE OF SAY THOUSAND POSSIBLE
ODOR RECEPTORS THAT COULD BE
EXPRESSED IN THE MOUSE.
THERE ARE THOUSANDS OF
OLFACTORY SUBTYPES, EACH ONE OF
WHICH IS DEFINED BY WHICH
RECEPTOR IT EXPRESSES.
WE HAVE A THOUSAND DIFFERENT
TYPES OF RECEPTORS HOW ARE THEY
ORGANIZED IN SPACE IN THE
EPITHELIUM?
IS THERE A SENSORY MAP HERE IN
THE NOSE?
WHAT ARE YOU LOOKING AT HERE ON
THE RIGHT IS A WHOLE MOUNT OF A
MOUSE GENETICALLY MODIFIED,
THEY EXPRESS THE SAME ODOR
RECEPTOR, ONE CHANNEL OUT OF A
THOUSAND.
THESE NEURONS ARE ARRAYED ALONG
A STRIPE WHICH IN THE FIELD IS
REFERRED TO AS A ZONE AND ZONE
TRAVERSES THE EXTENT OF THE
EPITHELIUM AND OCCUPIES ABOUT A
QUARTER OF THE EPITHELIUM.
IT'S THOUGHT THERE ARE FOUR OF
THESE SO-CALLED ZONES.
EACH RECEPTOR IS SOMEHOW
THOUGHT DURING DEVELOPMENT TO
BE A SIGN-IN A STEREOTYPE
MANNER ONE OF THESE FOUR ZONES
AND LIVE IN ONE OF THESE FOUR
STRIPES.
HOWEVER, WITHIN EACH IT IS
THOUGHT CELLS PICKED RANDOMLY
FROM ONE IN 150 RECEPTORS.
TO THE EXTENT THERE'S A MAP IN
THE ZONE, THE VIBE OF THE NOSE
BASICALLY NEURONS DEVELOP AND
RANDOMLY PICK A RECEPTOR.
OKAY?
IT'S IMPORTANT TO NOTE THIS
PROCESS OF ODOR RECEPTOR CHOICE
DOESN'T JUST HAPPEN DURING
DEVELOPMENT BUT CONTINUOUSLY
THROUGHOUT THE LIFE SPAN.
JUST UNDERNEATH A LAYER OF
OLFACTORY SENSORY NEURONS IS
STEM CELLS CONTINUOUSLY
SPITTING OUT NEURAL PRECURSORS
AND GENERATING A WHOLE NEW SET
OF MATURE OLFACTORY SENSORY
NEURONS THAT HAVE TO CHOOSE NEW
RECEPTORS AND CONTINUOUSLY
BEING INTEGRATED INTO THIS
CIRCUIT.
HOW DOES INFORMATION GET FROM
THE NOSE TO BRAIN?
ALL THOSE NEURONS, THEY
ELABORATE AXONS AND PUNCTURE
THIS PLATE AT THE BASE OF THE
SKULL.
THEY ALL CONVERGE ON A SINGLE
INSULAR STRUCTURE WITHIN THE
OLFACTORY BULB IN THE BASAL
FOREBRAIN AND IT'S CALLED A
GLOMERULUS.
THERE ARE A THOUSAND GLOMERULI
IN THE OLFACTORY BULB.
TURNS OUT THE SPATIAL POSITION
IS INVARIANT FROM MOUSE TO
MOUSE TO MOUSE.
AND HUMAN, TO HUMAN, TO HUMAN.
THAT HAS AN IMPORTANT
CONSEQUENCE.
DIFFERENT ODORS WILL ACTIVATE
DIFFERENT RECEPTORS TO ACTIVATE
DIFFERENT PATTERNS OF GLOMERULI.
YOU COULD SEE THE SPATIAL
PATTERN FOR JASMINE IS
DIFFERENT OF ROSE.
AND BECAUSE IT'S INVARIANT
ACROSS ANIMALS, LOOKED AT ONE
OF THESE PATTERNS AND TELL YOU
WHAT SMELL THE MOUSE IS
SMELLING AT ANY MOMENT IN TIME.
THERE'S A PRECISE MAP OF ODOR
IDENTITY BUILT BY THE PRECISION
LOCALIZATION OF GLOMERULI IN
THE OLFACTORY BULB.
WHERE DOES IT GO FROM HERE?
SENT TO MULTIPLE HIGHER BRAIN
REGIONS RESPONSIBLE FOR ODOR
IDENTIFICATION AND MEMORY AND
EMOTION.
SOMEHOW THEY COLLABORATE IN
ORDER TO BUILD ODOR PERCEPTION.
WHAT HAVE I TOLD YOU?
I TOLD YOU THAT BASICALLY,
UNLIKE THE OTHER SENSES, THE
NOSE BARELY HAS A MAP.
RIGHT?
THERE ARE THESE FOUR WEIRD
ZONES.
BASICALLY EACH NEURON IN THE
OLFACTORY EPITHELIUM RANDOMLY
CHOOSES WHICH RECEPTOR TO
EXPRESS.
SO THE NOSE IS DISORDERED.
SOMEHOW THROUGH MECHANISMS WE
STILL DON'T UNDERSTAND AXONS
FROM THE NOSE GET TO THE BULB
WHERE THEY BUILD AN INCREDIBLY
PRECISE MAP OF GLOMERULAR
IDENTITY.
THE BRAIN READ THAT'S CODE TO
GENERATE PERCEPTION.
I WANT TO TALKED TO ABOUT THIS
IDEA OF DISORDER IN THE ZONES
IN THE NOSE.
I WANT TO EXPLAIN ABOUT THESE
ZONES.
THIS IS THE IMAGE I SHOWED YOU
BEFORE.
THIS IS THE WHOLE MOUNT.
CARTOON DEPICTING ZONES FROM
DORSAL TO VENTRAL.
WE TEND TO NOT DO THESE WHOLE
MOUNTS, INSTEAD WE TEND TO CUT
CORONAL SECTIONS.
THIS DORSAL TO CENTRAL ANATOMY
MAPS IN THIS KERNEL SECTION,
SUCH THAT THE DORSAL IN THIS
VIEW IS KIND OF MEDIAL OR
PROXIMAL HERE IN THE EPITHELIUM
AND VENTRAL IS LATERAL OR
DISTAL.
THIS STUFF IS MEDIAL.
MEDIAL OR DORSAL AND THIS IS
LATERAL OR VENTRAL.
THIS VENTRAL, OLFACTORY SENSORY
NEURON, ONE OF THESE VENTRAL
ZONES, IF YOU LOOK AT THAT
EXACT RECEPTOR IN THE CORONAL
SECTION THAT IS TO ORIENT YOU
TO THE DATA THAT IS COMING.
A QUESTION YOU MIGHT ASK, HOW
ARE THESE ZONES SHOWN HERE IN
THE EPITHELIUM RELATED TO WHERE
OLFACTORY SENSORY NEURONS
PROJECT THEIR AXONS IN THE BULB?
IT TURNS OUT THERE ARE FOUR
ZONES IN THE EPITHELIUM, THEY
ROUGHLY CORRESPOND TO FOUR
ZONES IN THE BULB RUNNING
DORSAL TO VENTRAL.
WE THINK THERE'S SOME MAPPING
FROM HERE TO HERE, KIND OF VERY
CRUDELY.
WE KNOW ABOUT THE MOLECULAR
MECHANISMS THAT SUPPORT THAT.
WE KNOW THERE'S A MARKER
PROTEIN THAT MARKS THE
OLFACTORY BULB DORSAL ROOT.
A COUPLE AXONS THAT SEEM LIKE
THEY MIGHT PLAY A ROLE IN
CONVERTING THIS ZONAL
ORGANIZATION IN THE EPITHELIUM
TO AN APPROPRIATE DORSAL
VENTRAL ORGANIZATION OF
GLOMERULI IN THE BULB.
I WANT TO REMIND YOU THE
OLFACTORY BULB IS INCREDIBLY
PRECISE.
ALL 1,000 GLOMERULI ARE
PRECISELY LOCATED.
THIS POSSIBLE ZONE TO ZONE
MECHANISM CANNOT EXPLAIN HOW IT
IS THAT WE HAVE SUCH A PRECISE
CODE FOR ODOR IDENTITY IN THE
BULB.
SO NOW LET'S TALK ABOUT SCIENCE
INSTEAD OF BACKGROUND.
THE QUESTION WE WANTED TO ASK
IS, COULD WE IDENTIFY SOMEHOW
MOLECULAR MARKERS THAT IDENTIFY
ALL THE DIFFERENT ZONES IN THE
NOSE?
THERE'S FOUR ZONES.
WE WANTED TO KNOW IF WE COULD
IDENTIFY A MARKER FOR ZONE TWO
OR THREE.
REASONING IF WE COULD IDENTIFY
SUCH A MARKER WE WOULD BE ABLE
TO UNDERSTAND HOW ODOR AND
RECEPTORS ARE LIMITED TO ONE OF
THESE FOUR ZONES.
THAT WAS OUR GOAL.
HOW DID WE DO THIS?
WE DID WHAT YOU WOULD EXPECT US
TO DO, A TON OF CELL SEQUENCING.
WE TOOK EPITHELIUM OUT OF MOUSE
CELL ZONE.
DEVELOP TRANSCRIPTOMES.
YOU ARE LOOKING AT A U-MAP PLOT.
PROXIMITY OF POIBTS IN THE PLOT
REPRESENT SIMILARITY IN THE
TRANSCRIPTOMES.
WE GET BOTH PRECURSOR AND
MATURE CELLS.
IN THIS PLOT MATURE CELLS ARE
HIGHLIGHTED BY THE MARKER OMP
WHICH IS SHOWN HERE IN YELLOW.
I WANT TO EMPHASIZE A COUPLE
POINTS ABOUT THESE DATA.
FIRST IN ORDER TO DO THE
EXPERIMENTS I'M ABOUT TO
DESCRIBE WE GENERATED THE
LARGEST SINGLE CELL SEQUENCING
SET EVER FOR NEURAL TISSUE,
ABOUT 5.5 MILLION INTEGRATED
CELLS INCLUDING 2.5 MATURE
NEURAL OLFACTORY SENSORY AND
PRECURSORS.
ANALYZING DATA AT SCALE LIKE
THIS REQUIRES SOPHISTICATED
COMPUTATIONAL METHODS.
I PROMISE NOT TO SHOW YOU MATH
BUT UNDERSTAND IT'S A BIG
ENGINE.
USING THAT ENGINE WE CAREFULLY
SEARCHED FOR GENES THAT MIGHT
MARK THESE DIFFERENT ZONES AND
WE FOUND NONE.
EVEN THOUGH WE BELIEVE THE
ZONES ARE REAL, OR HAD BELIEVED
TURNS OUT TO BE WRONG.
WE DECIDED TO ASK A MUCH HARDER
QUESTION.
CAN WE IDENTIFY GENES THAT
SYSTEMATICALLY VARY ACROSS
OLFACTORY SUBTYPES.
WE TOOK A THOUSAND CELLS THAT
EXPRESS ORA AND ORB.
WE DEVELOPED A THOUSAND SUCH
BINS AND ASKED CAN WE IDENTIFY
ANY HIGHLY VARIABLE CHAINS THAT
VARY ACROSS THE OLFACTORY
SENSORY SUBTYPES.
THE CANONICAL VIEW AND SUBTYPES
EACH IS THE SAME EXCEPT THE
RECEPTOR THAT EXPRESSES SO WE
EXPECTED TO FIND NOTHING.
INSTEAD WE WERE ABLE TO
IDENTIFY 1200 HIGHLY VARIABLE
GENES.
THIS VARIATION IS SUCH IF YOU
JUST TELL ME 100 OF THESE
HIGHLY VARIABLE GENES AND HOW
MUCH THEY ARE EXPRESSED I COULD
WITH 100% ACCURACY TELL YOU
WHICH ODOR RECEPTOR IS IN THAT
CELL.
SO RESPONDS TO OMP SUBTYPE.
THE REASON THESE 1200 GENES
WERE ORGANIZED INTO COHERENT
GENE PROGRAMS, GROUPS THAT CO
VARY THEIR EXPRESSION UP OR
DOWN.
WE USED CONSENSUS NINE MATRIX
TO IDENTIFY SEVEN SUCH PROGRAMS.
TODAY I WILL ONLY FOCUS ON TWO,
WHICH ARE SHOWN HERE.
THIS AGAIN IS A U-MAP PLOT.
MATURE OLFACTORY SENSORY NEURON.
THERE'S 150 GENES THAT BELONG
TO GEP DORSAL AND 150 TO GEP
VENTRAL.
I WILL HEAT MAP THAT OVER EACH
CELL, I WILL CALL THAT GEP
USAGE.
SOME CELLS USE GEP DORSAL AND
SOME USE GEP VENTRAL BUT NO
CELLS USE BOTH.
YOU MIGHT ASK WHY DID WE NAME
THESE THIS.
ONE OF THE 150 GENES IN THE GEP
IS FOR THE DORSAL DOMAIN.
WE THOUGHT MAYBE THIS GEP
REPRESENTS SOMETHING ABOUT
BEING IN THE DORSAL PART OF THE
EPITHELIUM.
WE KNEW SOME OF THE AXON
GUIDANCE GENES WHICH HELP GUIDE
AXONS FROM THE NOSE TO THE BULB
WE KNOW A COUPLE ARE EXPRESSED
VENTRALLY.
WE KIND OF PROVISIONALLY MADE
THESE BASED ON THE HYPOTHESIS
THEY MAY CONVEY INFORMATION
WHETHER THE NEURON RESIDES IN
THE DORSAL OR VENTRAL PART OF
THE EPITHELIUM.
WE WANTED TO LOOK AT THEM MORE,
SO WE DECIDED TO LOOK AT
OLFACTORY SENSORY NEURON
SUBTYPE.
ALL THOSE NEURON THAT'S EXPRESS
THE SAME RECEPTOR.
SO THERE'S A THOUSAND DOTS IN
THIS PLOT.
YOU SEE EACH OLFACTORY SENSORY
NEURON EITHER EXPRESSES GEP
DORSAL OR VENTRAL BUT NOT BOTH,
GENERALLY.
IF YOU EXPRESS GEP VENTRAL YOU
CAN USE IT MORE OR LESS, YOU
CAN KIND OF USE IT MORE OR LESS.
THE COMPLEMENTARY MEANS WE CAN
SUMMARIZE THE USE OF ALL 300
GENE THAT'S BELONG TO GEP
DORSAL AND VENTRAL AND TRACKING
AND CREATING A DORSAL VENTRAL
SCORE.
OR DV SCORE.
CELLS THAT HAVE LOW USE A LOT.
THAT HAVE HIGH DV SCORES USE IT
A LOT.
IT'S SUMMARIZING THESE 300
GENES.
WHAT WE SEE IS THAT EACH
OLFACTORY SENSORY NEURON
SUBTYPE IS ASSOCIATED WITH A
UNIQUE MEAN D.V. SCORE.
EACH OLFACTORY SENSORY NEURON
SUBTYPE IS USING THIS SET OF
300 GENES IN A UNIQUE WAY.
HERE YOU SEE UNIQUE EXAMPLES
AND DISTRIBUTIONS AND HERE YOU
SEE ALL THE OLFACTORY SENSORY
NEURON SUBTYPES ORDERED BY
THEIR MEAN D.V. SCORE.
EACH HAS A DISTRIBUTION.
IT'S NOT EVERY CELL THAT
BELONGS TO EACH SUBTYPE HAS THE
SAME EXACT D.V. SCORE BUT THEY
ALL HAVE A MEAN AND THIS PLOT
TILES THE POSSIBLE D.V. SCORES.
WHAT ARE THE INDIVIDUAL GENES
THAT MAKE UP A D.V. SCORE
ACTUALLY LOOK LIKE?
AND WHAT ARE THEY?
HERE ON THE Y AXIS YOU ARE
LOOKING AT THE MEAN 300 GENES.
WE ARE LOOKING AT SUBTYPES AND
ORDER WHETHER THEY HAVE LOW OR
HIGH D.V. SCORES.
WHAT YOU SEE QUITE CLEARLY IS
ALL OF THE D.V. GENES WE
IDENTIFY VIA THIS METHOD SEEM
TO BE ORGANIZED INTO GRADIENTS.
THERE'S A GRADING OF EXPRESSION
OF GEP VENTRAL AND DORSAL THAT
VARIES DEPENDING ON WHAT YOUR
CELLS D.V. SCORE IS.
IF YOU LOOK AT GENES IN A MAKE
UP THESE GEP'S WE FIND THEY
INCLUDE A TON OF GENES THAT ARE
ABOUT THE FUNCTION OF OLFACTORY
SENSORY NEURONS AND TWO
PARTICULAR TYPES OF GENES WE
WERE REALLY INTERESTED IN,
INCLUDING TRANSCRIPTION FACTORS.
WE WERE INTERESTED IN
TRANSCRIPTION THEY HELPED
.CELL IDENTIFY.
AND AXON IDENTITY THEY CAN HELP
IN PRINCIPLE HELP AXONS GET
FROM THE OLFACTORY EPITHELIUM
TO THE APPROPRIATE LOCATION IN
THE OLFACTORY BULB.
LET ME GIVE YOU A FEW EXAMPLES
OF THE GENES WE IDENTIFIED TO
GIVE YOU A FLAVOR OF WHAT THE
ACTUAL DATA LOOK LIKE.
HERE WE ARE GOING TO LOOK IN
THIS QUADRANT AT THE EXPRESSION
OF THREE TRANSCRIPTION FACTOR
THAT'S BELONG TO THE N.F.I.
FAMILY, I WILL BRING UP LATER,
IMPORTANT FOR OLFACTORY SENSORY
DEVELOPMENT.
ALL THREE ARE EXPRESSED AS
GRADIENTS THAT VARY AS A
FUNCTION OF THE D.V. SCORE.
NQO1 THOUGHT TO MARK THE DORSAL
DOMAIN OF THE EPITHELIUM.
THIS MARKER IS NOT EXPRESSED IN
SCORES THAT HAVE A VENTRAL D.V.
SCORE.
IT'S NOT EXPRESSED UNIFORMLY
BUT IN A GRADIENT.
HERE ARE THE TWO AXON HAD HELP
GUIDE THE ZONE IN THE NOSE TO
THE BULB.
THESE ARE BOTH THEMSELVES
ORGANIZED AS GRADIENTS,
FUNCTION OF THE D.V. SCORE.
THE PRESENCE OF ALL THESE
GRADIENTS, TOGETHER WITH THE
IDEA THAT MAYBE THE GEP DORSAL
AND VENTRAL ARE CONVEYING ABOUT
DORSALITY OR VENTRALITY
SUGGESTED THERE MAYBE AREN'T
FOUR ZONES.
MAYBE INSTEAD EACH NEURON HAS A
UNIQUE D.V. SCORE AND THAT
REPRESENTS WHERE IN THE
EPITHELIUM GOING DORSAL TO
VENTRAL.
IF THAT'S TRUE, INSTEAD OF
HAVING FOUR ZONES, BECAUSE EACH
OLFACTORY SENSORY NEURON, ON
AVERAGE, HAS A UNIQUE D.V.
SCORE ASSOCIATED WITH THE
PARTICULAR RECEPTOR CHOSEN YOU
WOULD IMAGINE A THOUSAND ZONES
OR THOUSAND PEEKS OF EXPRESS
GOING FROM DORSAL TO VENTRAL.
IS THAT TRUE?
WE DECIDED TO EXPLORE THAT
POSSIBILITY VIA THE USE OF THE
TECHNIQUE WHICH ALLOWS US TO DO
IN-SITU TO DO ALL AT ONCE IN
PARALLEL.
HERE IS A KERNEL SECTION.
YOU CAN SEE THEM SUPPORT CELLS
IN RED.
AND CELL THAT'S BELONG TO THE
LAMINA PROPRIA I WILL GET BACK
TO.
THE TECHNIQUE WORKS.
YOU ARE LOOKING MERFISH.
I WANT TO MENTION OF COURSE THE
ACTUAL CELLS ARE VERY SMALL SO
WE HAVE BLOWN UP THESE DOTS 100
TIMES.
YOU COULD SEE A SPATIAL
DISTRIBUTION FOR THIS
PARTICULAR VENTRAL RECEPTOR
THAT COULD BE EASILY DETECTED
BY MERFISH.
WE HAVE NC2 DATA FOR THE DV
SCORE.
DOES IT IN FACT DESCRIBE AXIS
THAT RUNS FROM DORSAL TO
VENTRAL?
AND ARE ODOR RECEPTORS BUILDING
A MAP RUNNING FROM DORSAL TO
VENTRAL?
THIS IS WHAT WE SEE.
ON THE LEFT WE WILL COLOR IT BY
ITS D.V. SCORE.
YOU SEE THIS BEAUTIFUL GRADIENT
RUNNING MEDIAL TO DISTAL,
DORSAL TO VENTRAL GOING FROM
HERE TO HERE, FROM RED TO BLUE.
ALONG EACH ONE OF THESE LITTLE
TERMINATES.
THAT TELLS YOU EACH CELL IN THE
NOSE HAS A UNIQUE D.V. SCORE
THAT CORRESPONDS DIRECTLY TO
THE CELL SPATIAL POSITION
DORSAL TO VENTRAL TOP TO BOTTOM
IN THE EPITHELIUM.
IS THERE A MAP BUILT OF ODOR
RECEPTORS?
HERE WE HAVE TAKEN OUT CURLY
Q'S AND ZOOMED IN SO YOU COULD
SEE THE SPATIAL GRADIENTS.
IS THERE ACTUALLY A MAP OF ODOR
RECEPTORS?
HERE WE IDENTIFIED THE ODOR
EXPRESSED BY EACH NEURON AND
LOOKED UP THE D.V. SCORE, AGAIN
WE SEE THIS BEAUTIFUL GRADIENT
GOING DORSAL TO VENTRAL ALONG
THE CURLY Q'S.
THE FACT WE SEE CONTINUOUS
GRADIENTS GIVEN THAT EVERY OSM
SUBTYPE MEANS THERE ARE 1,000
DIFFERENT PEEKS OF ODOR
RECEPTOR ON AVERAGE ORGANIZED
INTO A MAP.
THERE'S A MAP OF ODOR RECEPTOR
EXPRESSION IN THE NOSE.
THERE AREN'T FOUR STONES.
ZONES.
THERE ARE A THOUSAND ZONES
WHERE THE POSITION OF EACH ODOR
RECEPTOR VARIES CONTINUOUSLY
FROM RECEPTOR ZERO HERE TO
RECEPTOR 1,000 OVER HERE.
IF YOU JUST WANT TO SEE
DISTRIBUTIONS A LITTLE MORE TO
CONVINCE YOURSELVES HERE YOU
ARE LOOKING AT CUMULATIVE
EXPRESSION IN SPACE.
IF YOU LOOK AT TWOE RECEPTORS
WITH SIMILAR D.V. SCORES AND
ASK WHAT ARE THEIR SPATIAL
POSITIONS THEY HAVE HIGHLY
OVERLAPPING DISTRIBUTIONS,
WHICH IS TO BE EX PECKED BUT
THE MEANS ARE CLEARLY
DISTINGUISHABLE.
THAT MEANS WE CAN MAKE ACCURATE
PREDICTIONS BASED UPON
INDIVIDUAL CELLS D.V. SCORE
WHERE IT WILL BE IN THE
EPITHELIUM.
IF YOU GIVE ME A SPOT I CAN
GIVE A PREDICTION, CONSISTENT
WITH THE IDEA THERE'S SOME
UNDERLYING MAP.
I SHOWED IN-SITUS PREVIOUSLY,
THE VALUE OF EACH RECEPTOR IS
BROAD.
HOW COULD THERE BE A MAP OF
1,000 THINGS IF THEY ARE SO
OVERLAPPING.
HERE WE ARE LOOKING AT
DISTRIBUTION OF D.V. SCORES FOR
EACH OSM SUBTYPE IN SCRNA-SEQ
AND MERFISH.
THE THERE'S THE SHARP PEEK OF
EXPRESSION IN THE ESPECIALLY
THEME YUM BUT THERE'S A
DISTRIBUTION.
I THINK IT DESCRIBES WHY
PREVIOUSLY RESEARCHERS BELIEVED
THERE WERE ZONES.
ONE THING WE CAN DO BECAUSE WE
HAVE SO MUCH DATA WE CAN ASK IF
THE RANK ORDER IS SHARED ACROSS
INDIVIDUALS.
IF THIS IS REALLY A MAP, THE
MAP IN MY NOSE SHOULD BE THE
SAME AS THE MAP IN YOUR NOSE.
WHAT WE FIND FROM THESE DATA
THERE'S A 0.9 9 CORRELATION IN
THE RANK ORDER OF ODOR
RECEPTORS VENTRAL TO DORSAL.
THE MAP IS INCREDIBLY PRECISE
AND CONSERVED ACROSS
INDIVIDUALS MAKING IT A REAL
MAP.
SO THIS RAISES THE BROAD SET OF
QUESTIONS.
WHAT IS THE RELATIONSHIP
BETWEEN SPACE, THE D.V. SCORE
AND O.R. EXPRESSION?
EVERYTHING I HAVE SHOWN YOU
SUGGESTS ALL THREE ARE RELATED.
ALMOST CERTAINLY TO THE D.V.
SCORE REPRESENTS POSITION IN
SPACE.
BUT THERE MUST BE SOME
RELATIONSHIP BETWEEN THE SPACE
IN D.V. SCORE AND O.R.
EXPRESSION IN SOME WAY, IT'S
CLEAR O.R.'S ARE ORGANIZED IN
THIS PATTERN A THOUSAND
DIFFERENT STRIPES FROM DORSAL
TO VENTRAL.
WHAT MIGHT ESTABLISH THESE
RELATIONSHIPS? ONE NAIVE IDEA
IS MAYBE ACTIVITY DOWNSTREAM OF
EACH RECEPTOR WHICH WOULD BE
EXPECTED TO BE UNIQUE IN EACH
ODOR ENVIRONMENT IS DETERMINING
WHERE IT IS IN SPACE OR
DETERMINING THE D.V. SCORE.
THAT TURNS OUT TO BE NOT TO BE
TRUE.
IF YOU CLOSE ONE NOSTRIL YOU
DENY ONE HALF OF THE NOSE ANY
ODOR STIMULATION, WE CAN
SEQUENCE OUTSIDE OF THE NOSE
AND COMPARE TO THE NOSTRIL OPEN
AND WE SEE D.V. SCORES DON'T
CHANGE AT ALL.
WE CAN GENERATE A MOUSE WITH A
MONOCLONAL NOSE THAT LARGELY
EXPRESSS IN 95 PERCENT OF
NEURONS ONE ODOR RECEPTOR AND
IT IS SPRAYED OUT OVER THE
ENTIRE EPITHELIUM.
IF THE O.R. OR O.R. ACTIVITY IS
DETERMINING D.V. SCORES YOU
WOULD EXPECTING ALL TO HAVE THE
SAME D.V. SCORE.
INSTEAD THEY HAVE A COMPLETE
DIVERSITY OF D.V. SCORES
SUGGESTING THEY REPRESENT WHERE
YOU ARE IN SPACE AND THEY
AREN'T DETERMINED IN ANY WAY BY
THE ODOR RECEPTOR BEING
EXPRESSED.
OR NEURAL ACTIVITY.
OKAY, SO IF THAT'S TRUE, WHAT
YOU MIGHT IMAGINE A MODEL YOU
MIGHT BUILD IN YOUR HEAD IS
MAYBE SPACE DETERMINES THE D.V.
SCORES.
MAYBE SOME WAY D.V. SCORES
DETERMINE WHICH WAY O.R. IS
EXPRESSED, IF THAT MODEL IS
TRUE FROM SPACE TO D.V. SCORE
TO O.R.'S YOU WOULD EXPECT THE
D.V. SCORE GENES, SOME 300
GENES SHOULD NOT JUST BE
EXPRESSED IN MATURE OLFACTORY
SENSORY NEURONS BUT PRECURSORS
BEFORE O.R.'S ARE CHOSEN.
MAYBE THE D.V. SCORES GUIDE THE
CHOICE BASED UPON SPACE.
SO WE CAN BEGIN TO THINK ABOUT
THIS.
AGAIN, IN OUR DATASET WE HAVE
400,000 OLFACTORY STEM CELLS
AND PRECURSORS.
HERE WE WILL ISOLATE JUST THE
400,000 CELLS AND EXCLUDE ALL
THE MATURE OLFACTORY SENSORY
NEURONS AND HERE YOU COULD SEE
A CARTOON OF THE DIFFERENT
INTERMEDIATE STAGES.
AND WE WILL EMBED ALL TO A
U-MAP PLOT.
EACH IS A CELL.
WE WILL COLOR EACH CELL BY
WHAT'S CALLED PSEUDO TIME, THE
TRAJECTORY THEY TAKE FROM STEM
CELLS TO NEAR FULLY DEVELOPED
OLFACTORY SENSORY NEURONS.
MARKER GENES KNOWN TO BE
ASSOCIATED WITH THE STAGES THEY
ARE RELIABLY EXPRESSED ALONG
THIS AXIS.
THIS AXIS REALLY DOES REFLECT
DEVELOPMENTAL TIME.
THESE STEM CELLS ARE ABOUT TO
BE MATURE AND THEY ARE JUST
ABOUT TO EXPRESS ODOR RECEPTORS.
DO THEY EXPRESS D.V. GENES?
THE ANSWER TURNS OUT TO BE YES.
HERE WE WILL ILLUSTRATE
EXPRESSION ON D.V. ON THE MAP
PLOT.
SOME STEM CELLS HAVE HIGH D.V.
SCORES AND SOME HAVE LOW.
HERE THERE ARE CELLS WITH HIGH
D.V. SCORES AND INTERMEDIATE
AND LOW.
LONG BEFORE CHOSEN, CELLS KNOW
WHAT THEIR D.V. SCORES ARE,
THEREFORE THEY MUST KNOW WHERE
THEY ARE IN SPACE.
IF WE LOOK AT OUR MERFISH DATA
AND LOOK AT THE STEM CELL LAYER
UNDER THE OLFACTORY SENSORY
NEURON LAYER WE SEE NICE
GRADIENTS CONSISTENT WITH THE
IDEA THAT STEM CELLS KNOW WHERE
THEY ARE IN SPACE.
WE KNOW SPACE IS DETERMINING
D.V. SCORES SOMEHOW INFLUENCING
ODOR RECEPTOR CHOICE.
YOU MIGHT HAVE THE IDEA THE
RECEPTORS KNOW WHERE THEY ARE
IN SPACE AND SOMEHOW FADED TO
GENERATE A PARTICULAR ODOR
RECEPTOR.
LIKE A FATE RELATIONSHIP.
LIKE EACH STEM CELL IS ASSIGNED
TO EACH RECEPTOR AND THAT'S HOW
YOU GET THEM ORDERED FROM
DORSAL TO VENTRAL.
WE DID THE FIRST COMPREHENSIVE
FATE MAPPING EVER PERFORMED IN
THE OLFACTORY SYSTEM.
WE TOOK AN ANIMAL WITH ITS NOSE
AND GAVE IT A DRUG THAT KILLED
ALL OF THE MATURE SENSORY
NEURONS LEAVING ONLY THE STEM
CELLS BELOW.
WE THEN INFECTED THE NOSE WITH
A BAR CODED LENTI VIRUS.
LABELED THOEM.
WE WAITED A MONTH OR SO THESE
STEM CELLS DIVIDED AND REBUILT
THE EPITHELIUM FROM SCRATCH.
NEW MATURE OLFACTORY SENSORY
NEURONS.
WE CAN TAKE THESE RECOVERED
NOSES BR*NG BREAK THEM UP AND
DO SINGLE CELL SEQUENCING AND
ASK ABOUT THE PROGENY IT
GENERATED.
ONE THING YOU MIGHT IMAGINE
MAYBE EACH STEM CELL ONLY GIVES
RISE TO ONE TYPE OF O.S.N.
MAYBE EACH STEM CELL IS FATED
TO PICK A PARTICULAR RECEPTOR.
THAT TURNS OUT NOT TO BE TRUE.
INSTEAD EACH STEM CELL SEEMS TO
PICK A VERY RESTRICTED SET OF
RECEPTORS THAT HOVER AROUND THE
MEAN D.V. SCORE ASSOCIATED WITH
THAT STEM CELL.
HERE YOU SEE THE D.V. SCORES OF
ALL OF THE PROGENY ELICITED BY,
ASSOCIATED BY THE DIFFERENT
CLONES WE HAVE.
THEY ALL HAVE A MEAN D.V. SCORE
THAT HAS A VERY NARROW BAND.
IF WE LOOK AT THE DISTRIBUTION
THERE'S A VERY SHARP PEEK WITH
A LITTLE DISTRIBUTION AROUND IT.
WHAT THIS MEANS PRACTICALLY,
EACH OLFACTORY STEM CELL HAS AN
IDEAL FAVORITE TYPE OF RECEPTOR
IT WANTS TO PICK.
AND IT VERY FREQUENTLY PICKS
THAT RECEPTOR, BUT OFTEN IT
MAKES MISTAKES BECAUSE OF
BIOLOGY WHICH EXPLAINS THIS
DISTRIBUTION AND EXPLAINS WHY
THERE'S A SPATIAL DISTRIBUTION
ALONG THE DORSAL VENTRAL AXIS.
HERE I'M DESCRIBING HOW IT IS
SPACE MIGHT INFLUENCE ODORANT
RECEPTOR CHOICE.
BUT WHAT I HAVEN'T TOLD YOU
ABOUT IS HOW IT IS THE STEM
CELLS KNOW ANYTHING ABOUT SPACE.
HOW DO THEY KNOW?
WE WERE GUIDED BY WORK OTHERS
HAD DONE AND BY SOME
INTERESTING PROPERTIES OF OUR
DATASET WHICH SUGGESTED MAYBE
THE WAY SPACE IS ENCODED IN THE
EPITHELIUM IS GRADIENT OF
RETINOIC ACID.
EXPRESSED IN THE LAMINA PROPRIA
UNDERNEATH THE OLFACTORY
EPITHELIUM.
THIS ENZYME, AS YOU CAN SEE
HERE IN OUR MERFISH DATA IS
FROM A DORSAL TO VENTRAL
GRADIENT.
SUGGESTING THERE'S A GRADIENT
OF RETINOIC ACID.
INTERESTINGLY, IF WE LOOK AT
THE GENES THAT BELONG TO THE
D.V. SCORE WE SEE A TON OF
GENES THAT ARE ALL ORGANIZED IN
DORSAL VENTRAL GRADIENTS THAT
SEEM TO BE INVOLVED IN RETINO
ACID METABOLISM, OR BINDING TO,
SUGGESTING IT MIGHT BE A MASTER
CONTROLLER THAT TELLS STEM
CELLS AND PROGENY WHERE THEY
ARE.
WE CAN TEST THIS BY ADDING TO
THE NOSE RETINO ACID INHIBITOR
OR ADDING TO THE EPITHELIUM.
IF WE DO THAT, WE CAN FIND WE
CAN SHIFT THE POSITION OF
RECEPTORS ALONG THE DORSAL
VENTRAL AXIS.
IF WE INHIBIT RETINO ACID, IT
TENDS TO GENERATE CELLS WITH
MORE DORSAL D.V. SCORES AND
TENDS TO PICK MORE DORSAL AND
FEWER VENTRAL CELLS AND
RECEPTORS.
CONVERSELY IF WE ADD MORE
RETINOIC ACID WE SEE THE
OPPOSITE PATTERN.
IT TENDS TO PICK MORE VENTRAL
RECEPTORS AND EXPRESS MORE
VENTRAL D.V. SCORES AND
DEEXPRESS DORSAL RECEPTORS AND
TENDS TO HAVE FEWER DORSAL D.V.
SCORES AMONGST ITSELFS.
IN OTHER WORDS BY MANIPULATING
RETINOIC ACID UP OR DOWN I CAN
SHIFT THIS UP OR DOWN IN SPACE.
THE SHIFT WE ARE SEEING UP AND
DOWN IN SPACE IS NOT ONLY
APPARENT IN MATURE OLFACTORY
SENSORY NEURONS BUT IN STEM
CELLS.
IT SEEMS RETINOIC ACID IS A KEY
SIGNALING MOLECULE THAT TELLS
STEM CELLS WHERE THEY ARE IN
SPACE AND KICKS OFF CASCADE
THAT ENSURES THE CORRECT
RECEPTOR IS CHOSEN IN THE RIGHT
PLACE IN THE EPITHELIUM.
HOW MIGHT THAT PROCESS ACTUALLY
OCCUR?
WE HYPOTHESIZE MAYBE THE
PROMOTERS OF EACH O.R. GENE
CONTAIN COMBINING SITES.
HERE WE ARE DOING AN ANALYSIS
OF NUMBER OF BINDING SITES FOR
PARTICULAR TRANSCRIPTION
FACTORS.
I WON'T DISCUSS THESE TWO FOR
NOW THOUGH THEY ARE IMPORTANT
BUT NOTICE THESE TRANSCRIPTION
FACTORS.
YOU COULD SEE RAR HAS AN
INCREASING NUMBER OF BINDING
SITES AS CELLS BECOME MORE AND
MORE VENTRAL.
I TOLD YOU RETINOIC, THE LIGAND
IS ALSO EXPRESSED.
YOU MIGHT IMAGINE THIS PATTERN
WOULD ALLOW INDIVIDUAL ODORANT
RECEPTORS TO BE ORGANIZED ALONG
THE DORSAL VENTRAL AXIS.
THE FACTORS I SHOWED YOU AT THE
BEGINNING, FOR NFI ARE ALSO
ENRICHED IN MORE VENTRAL
RECEPTORS COMPARED TO MORE
DORSAL.
COMBINED YOU CAN IMAGINE THE
DIFFERENCES IN FRONT OF ODORANT
RECEPTORS TAKEN WITH THE
GRADIENTS COULD BUILD THE
THOUSAND DIFFERENT STRIPES.
I WILL TELL YOU BUT I WON'T
SHOW YOU WE HAVE PROVEN IN A
NUMBER OF WAYS.
ONE SIMPLE WAY IS MAKING A
GENETICALLY MODIFIED MOUSE AND
TAKING PROMOTER OF ONE AND
PUTTING IN FRONT OF ANOTHER,
THAT MOVES THE RECEPTOR IN A
PREDICTABLE WAY IN SPACE,
CONSISTENT WITH THE IDEA THE
GENOME ITSELF DETERMINES WHERE
IN THE EPITHELIUM EACH WILL BE
EXPRESSED.
THIS DESCRIBES A LITTLE WHAT WE
THINK IS GOING ON WITH THE
TRANSCRIPTION FACTORS PART OF
THE D.V. SCORE.
REMEMBER THERE'S THAT OTHER
CLASS OF GENES I TOLD YOU ABOUT?
I TOLD YOU 30 AXON GUIDANCE
GENES ALL EXPRESSED IN
GRADIENTS IN THE OLFACTORY
EPITHELIUM.
YOU MIGHT IMAGINE BECAUSE
THERE'S SO MANY THEY MIGHT BE
SUFFICIENT TO ENABLE AN
OLFACTORY SENSORY NEURON IN THE
EPITHELIUM BASED ON ITS
POSITION TO FIND IT'S CORRECT
GLOMERULAR POSITION.
THE POSITION IN THE NOSE MIGHT
ENTAIL THE EXISTENCE OF A MAP
IN THE BULB.
WE WANTED TO TEST THAT IDEA, WE
TOOK ADVANTAGE OF A DATA SET MY
COLLEAGUE AXLE FLEISCHMANN AT
BROWN USED TRANSCRIPTOMICS.
WE KNOW WITH THE MOUSE THE
MOLECULAR IDENTITY THAT
INNERVATES EVERY OLFACTORY
RECEPTOR IN THE BULB.
WE COULD ASK IN THE OLFACTORY
BULB ITSELF WHETHER OR NOT THE
LEVEL OF D.V. SCORE GENE
EXPRESSION BY THE INNERVATING
SENSORY NEURONS HAS ANY PATTERN
IN THE BULB.
ONE THING I WANT TO MENTION
THAT I GLOSSED OVER AT THE
BEGINNING, EACH BULB IS MIRROR
SYMMETRIC AND CONTAINS TWO
HEMIBULBS.
IF YOU COLOR GLOMERULUS BY THE
D.V. SCORE OF INNERVATING OSN'S
IT CREATES BEAUTIFUL GRADIENTS,
SUGGESTING THAT THE GENES THAT
CONTAIN THE D.V. SCORE CONTAIN
INFORMATION TO GUIDE AXON TO
ITS EVENTUAL DORSAL LOCATION IN
THE OLFACTORY BULB.
THEY DO A GREAT JOB PREDICTING
THE D.V. SCORE IMPUTED BY
SPATIAL POSITIONING IN THE
OLFACTORY BULB.
IMPORTANTLY IF WE USE THE D.V.
SCORE TO PREDICT THE ACTUAL 3D
POSITION OF GLOMERULI WE COULD
DO ACCURATELY WITH A 400 MICRON
ERROR.
EACH GLOMERULUS IS ABOUT 150
MICRONS BIG.
WITH THE SINGLE NUMBER I COULD
PREDICT THE THREE LOCATION OF
GLOMERULI WITH A ONE TO TWO
GLOMERULUS STRUCTURE, SEVERAL
MILLION METERS BIG.
SUGGESTING THAT THE MAP IN THE
NOSE REALLY CAN ENTAIL THE MAP
IN THE BULB.
OKAY, LAST SLIDE.
I TOLD YOU KEY SENSORY FEATURES
WERE ORGANIZED IN MAPS IN THE
RETINA AND IN THE COCHLEA.
SO YOU MIGHT IMAGINE THAT KEY
CHEMICAL FEATURES ARE SPATIALLY
ORGANIZED IN THE NOSE.
THIS IS AN OLD IDEA CALLED
KHEMOTOPY.
MAYBE THE REASON WHILE THERE'S
THIS HIGHLY PRECISE MAP IS TO
SUPPORT THE GENERATION OF THE
CHEMICAL MAP IN YOUR NOSE.
IS THAT TRUE?
MY LAB HAS DEVELOPED A
TECHNIQUE CALLED AK SEEK TO
FIND ALL THAT RESPOND TO THAT
ODOR.
JUST KNOW FOR A BUNCH OF ODORS,
22, 50, MAYBE 100 ODORS A
COMPLETE SET OF RECEPTORS THAT
RESPOND TO THOSE ODORS.
I COULD GO TO THE OLFACTORY
EPITHELIUM MERFISH AND COLOR IN
THE NEURONS IN THEIR POSITION
IN SPACE THAT ARE RESPONSIVE TO
ANY GIVEN ODOR.
YOU SEE BASICALLY TWO THINGS IN
THESE DATA.
THE FIRST IS THAT ACIDS LIKE
OCTANOIC TEND TO ACTIVATE ONLY
DORSAL CELLS.
THAT'S SOMETHING WELL KNOWN IN
THE OLFACTORY LITERATURE.
THERE'S ENRICHMENT FOR SOME
REASON FOR ACID RESPONSIVE
RECEPTORS IN THE DORSAL DOMAIN.
I WILL SAY FOR THOSE INTERESTED
IN OLFACTION WE THINK IT'S THE
ONE REAL ZONE IN THE BULB SEEMS
TO BE SPECIAL AND ENRICHED FOR
A PARTICULAR TYPE OF RECEPTOR.
BUT P FOR ALL THESE OTHER
GENERIC ODORANTS ESSENTIALLY
THEY ACTIVATE ALL THE DOMAIN.
INTERMINGLED.
IF YOU LOOK THERE'S NO WAY TO
DETERMINE AN ANIMAL SMELLING
OCTANOIC OR PENTYL ACETATE.
IF YOU TELL ME THE IDENTITY
WITH 100% ACCURACY I COULD TELL
THE ODORS APART.
ODOR RECEPTORS IN THE NOSE BUT
IT DOES NOT ORGANIZE CHEMISTRY.
LET ME SUMMARIZE WHAT I TOLD
YOU, WE STARTED WITH DISCUSSION
WHERE WE WERE WITH OLFACTION
AND DESCRIBED BASIC IDEA ODOR
CHOICE IS RANDOM, THERE'S
DISORDER IN THE NOSE AND
APPEARS IN THE OLFACTORY BULB.
WHAT I HAVE SHOWN YOU TODAY THE
NOSE IS JUST LIKE THE OTHER
PERIPHERAL SENSORY ORGANS.
AT LONG LAST WE HAVE DISCOVERED
MAP FOR OLFACTION.
THIS MAP ORGANIZES ALONG THE
DORSAL VENTRAL AXIS ALL 1,000
PEEKS RUN FROM TOP TO BOTTOM IN
A PRESCRIBED ORDER CONSERVED
ANIMAL TO ANIMAL TO ANIMAL.
THAT, I WOULD ARGUE MEANS THE
NOSE IS THE MOST PATTERNED
NERVOUS TISSUE IN YOUR ENTIRE
BODY.
WHICH I THINK IS RATHER
REMARKABLE.
I WILL SAY THAT PART OF THE
REASON, IF YOU READ THE
LITERATURE THAT PEOPLE FOR SO
LONG HAD THE IDEA THAT
RECEPTORS MUST BE CHOSEN
RANDOMLY BECAUSE NO ONE COULD
IMAGINE THAT DEVELOPMENT COULD
SOLVE THE PROBLEM OF PUTTING
1,000 THINGS IN PRECISE PLACES.
WHAT I SHOW HERE IN FACT IS IT
CAN.
WHY BUILD THIS MAP?
AS I STRIEBED IT'S NOT TO
ORGANIZE CHEMICAL SPACE.
WE THINK TWO LIKELY REASON, ONE
IS FOR ROBUSTNESS.
CHEMICAL TUNING OF INDIVIDUAL
RECEPTORS ARE BROAD AND
REDUNDANT.
BY TILING THE NOSE WITH ALL
THESE DIFFERENT RECEPTORS IF
YOU INJURY ONE PART OF THE NOSE
YOU WILL STILL SMELL ODOR SPACE
WITH THE REMAINDER PART OF THE
NOSE, SOMETHING NOT POSSIBLE IF
THEY WERE ORGANIZED IN CHEMICAL
SPACE.
WE THINK THIS IS A MECHANISM
FOR ROBUSTNESS.
WE ALSO THINK THIS IS PROBABLY
IMPORTANT BECAUSE IT ALLOWS
SPATIAL POSITION IN THE NOSE TO
DETERMINE THE SPATIAL POSITION
OF GLOMERULI IN THE BULB.
IN OTHER WORDS THROUGH ONE
PROGRAM IN WHICH RETINOIC ACID
DETERMINES T.D.V. GENES YOU
SOLVE TWO REALLY HARD PROBLEMS
JUST ONCE.
I WILL MENTION I THINK THIS
WORK HAS SUBSTANTIAL
IMPLICATIONS FOR THERAPEUTICS,
THERE ARE MILLIONS OF AMERICANS
WHO HAVE LOST THEIR SENSE OF
SMELL.
WE ARE REALLY INTERESTED IN
BUILDING PROSTHESIS OR USING
STEM CELLS AND UNDERSTANDING
BASIC PHYSIOLOGY IS ESSENTIAL
IF WE FIX PEOPLE WITH BROKEN
NOSES.
PRECISION OF MECHANISMS REALLY
SUGGEST THAT ACROSS THE ENTIRE
BRAIN WOULD HAVE PROFOUND
FUNCTIONAL CONSEQUENCES.
THINK IT CHANGES THE WAY WE
THINK A LITTLE BIT ABOUT NEURAL
DEVELOPMENT.
ALL OF THE WORK I'VE SHOWN YOU
TODAY WAS DONE BY THIS GUY,
DAVID BRAND.
A GRAD STUDENT IN MY LAB.
BRILLIANT GRADUATE STUDENT,
ALONG WITH WORK BY SUI AND TOM
BOSE'S LAB AT NORTHWESTERN.
NOW IS THE TIME I THANK NIH AND
I'M TRULY FWRAITFUL GRATEFUL.
IT'S TAUGHT US A LOT AND I'M
PROUD OF WHAT WE HAVE
ACCOMPLISHED.
I THINK AS YOU KNOW FUNDING AT
HARVARD HAS BEEN TERMINATED.
WE DON'T HAVE FUNDING ANY MORE
TO FUND THIS WORK.
I THINK THERE ARE PERVASIVELY
CHALLENGING THINGS ABOUT THAT.
I WANT TO FOCUS ABOUT THE
CONSEQUENCES FOR THE TRAINEES
WE ARE FACING UNPRECEDENTED
AMOUNT OF UNCERTAINTY.
TAIF
DAVID IS A GENIUS, IF YOU ASK
WHY HE DOES SCIENCE, HE IS
CURIOUS, HE DOES IT BECAUSE HE
FEELS IT'S A WAY HE CAN
CONTRIBUTE TO THIS COUNTRY.
HE FEELS IN DOING SCIENCE AND
ADDING TO THE LITERATURE HE IS
HELPING US BE THE BEST
AMERICANS WE CAN BE AND VIEWS
SCIENCE FUNDAMENTALLY AS A
SERVICE, A VIEW I VERY MUCH
SHARE.
ALL OF YOU HERE AT NIH YOU ARE
INVOLVED IN CUTTING EDGE
RESEARCH IN MEDICAL CARE.
BUT TRULY I THINK ALL OF US
APPRECIATE THAT ALL OF YOU ARE
DOING SCIENCE AS A SERVICE.
SPEAKING FROM MY SEAT AT
HARVARD WE KNOW THERE'S A LOT
OF STUFF GOING ON AT HARVARD
AND HERE, I WANT YOU ALL TO
KNOW WE SEE YOU AND WE ARE
SUPER GRATEFUL FOR EVERYTHING
YOU HAVE DONE, BOTH ON THE
INTRAMURAL AND EXTRA MURAL
SIDE, WE SEE YOUR SERVICE AND
WE APPRECIATE IT.
THANK YOU FOR EVERYTHING YOU
ARE ALL DOING.
THANK YOU FOR YOUR ATTENTION
AND I WILL TAKE ANY QUESTIONS
YOU MIGHT HAVE.
[ APPLAUSE ]
>> THANK YOU, PEOPLE HERE
CERTAINLY KNOW WHERE THE MICS
ARE.
WE HAVE SOME QUESTIONS COMING?
NO WE DON'T.
OKAY, BUT I DO HAVE A FEW
ONLINE.
I CAN'T QUITE SEE BEHIND ME.
OKAY, WE WILL START IN HERE.
>> THANK YOU VERY MUCH,
WONDERFUL TALK.
RETINOIC ACID LOOKS LIKE MUSTER
REGULATOR OF MANY SCENES.
DO YOU HAVE A MAP OF LAMINA
PROPRIA CELLS, WHAT TYPE OF
CELLS ARE MAKING IT?
>> Sandeep Datta: YEAH, SO WE
THINK THAT LAMINA PROPRIA,
THAT'S AS FAR CONTAIN A MET
BOLEIC ENZYME THAT CONVERTS.
WHAT WILL BE AMAZING IF WE CAN
VISUALIZE THE RETINOIC ACID
GRADIENT.
THERE ARE TOOLS.
THAT'S WHAT WE ARE DOING NOW.
LET'S TALK ABOUT IT FOR A
SECOND, THIS IS AN EXAMPLE THE
CARTILAGE IS PATTERNING THE
NERVOUS SYSTEM.
LET'S THINK ABOUT THAT FOR A
SECOND.
NOT USED TO HOW WE THINK ABOUT
IT.
IT'S VERY UNUSUAL AND
INTERESTING AND OBVIOUSLY A
THING WE ARE INTERESTED IN
WORKING ON.
THANK YOU FOR YOUR QUESTION.
>> THANK YOU.
>> THANK YOU FOR YOUR TALK, IT
WAS BEAUTIFUL.
I HAVE TWO QUESTIONS, YOU CAN
PICK SO WE CAN KEEP THE LINE
GOING.
I WAS WONDERING FIRST, I
UNDERSTAND THAT YOU HAVE
DEVELOPMENTAL TIME EVEN IN THE
ADULT HERE BECAUSE YOU HAVE
THIS CONTINUOUSLY REGENERATING.
I'M WONDERING IF YOU KNOW ABOUT
HOW THIS MAP IS ESTABLISHED IN
DEVELOPMENT IN TERMS OF THE
ANIMAL'S AGE.
MY OTHER QUESTION WHETHER THERE
MIGHT BE, THERE DON'T HAVE TO
BE FUNCTIONAL MAPS BUT WHETHER
EITHER VALENCE OR ACTION
SELECTION OR SOURCE MIGHT BE
OTHER KINDS OF MAPS THAT MIGHT
BE THERE.
>> Sandeep Datta: I WILL ANSWER
BOTH, IF IT'S OKAY.
THE FIRST QUESTION WAS, I KEEP
TALKING ABOUT THE ADULT AS IF
IT'S DEVELOPMENT, BUT IT'S NOT
DEVELOPMENT, THE MAP ORIGINALLY
DEVELOPS IN AN EMBRYO AND
REGENERATED IN THE ADULT.
I LEVERAGE THE ADULTS TO THINK
ABOUT THE ONTOGENY OF THE MAP.
WE THINK OF HOW THINGS ARE
ORGANIZED IN THE EMBRYO, I
THINK IT'S HIGHLY UNLIKELY THE
DETERMINANTS ORIGINALLY BUILT
THE MAP.
THIS RETINOIC ACID MECHANISM
DESCRIBING PROBABLY ISN'T
SUFFICIENT TO EXPLAIN THE
EMBRYO GENESIS OF THIS
STRUCTURE.
THERE'S PROBABLY OTHER
GRADIENTS INVOLVED BUT PROBABLY
SUFFICIENT TO MAINTAIN THE
ADULT TISSUE.
THE SECOND QUESTION YOU ASKED,
I HAVE LOOKED AT CHEMICAL
SPACE, RIGHT, I SEE THIS WEAK
DORSAL TO VENTRAL
DIFFERENTIATION.
BUT THERE'S MANY OTHER AXIS
THEY COULD BE ORGANIZED IS IT
POSSIBLE THOSE ARE ORGANIZED IN
SPACE.
MY ANSWER IS YES THAT IS
ABSOLUTELY POSSIBLE, WE ARE
LOOKING AT THAT NOW.
WE ARE CONTINUALLY GENERATING
THIS FOR DIFFERENT CATEGORIES
OF ODORANTS.
YOU MIGHT IMAGINE THERE'S
SPATIAL ORGANIZATION WHERE THEY
ARE IN THE ESPECIALLY THEME YUM.
ONE THING I WANT TO SAY FULL
DISCLOSURE SO WE ARE ON THE
SAME PAGE, THE SET OF RECEPTORS
WE IDENTIFY AS BEING ACTIVE
DEPENDSES ON THE CONCENTRATION
OF THE ODOR WE USE.
IT MAY NOT DEPEND ON THE ACTUAL
CONCENTRATIONS WE ARE TESTING.
WE ARE DOING IT ACROSS A RANGE
OF CONCENTRATIONS.
WE ARE AWARE THAT'S A
LIMITATION OF WHAT I SHOWED YOU
AND WE ARE THINKING ABOUT IT
CAREFULLY, THANK YOU FOR YOUR
QUESTION.
>> THANK YOU, BOB, THIS WAS AN
INSPIRING TALK AND I'M REALLY
PLEASED TO SHARE THE TIME WITH
YOU.
FOLLOW-UP, SIMILAR QUESTION BUT
MORE OF A CLINICAL BENZED.
-- BEND.
I'M CURIOUS AND HOPEFUL I WILL
SHARE HYPOTHESIS BUT CURIOUS
WHAT IT IS, IN THE ESTABLISHED
MODEL AND FOLLOWING INJURY,
THINKING OUR PATIENTS WITH PROZ
MIA OTHER QUALITATIVE OLFACTORY
DISORDERS DO YOU THINK THERE
MAY BE ASSOCIATION WITH
DISRUPTION OF THIS MAP RELATED
TO THEIR SYMPTOMS?
>> Sandeep Datta: YEAH, I THINK
THAT'S A REALLY WONDERFUL
QUESTION.
I THINK THE ANSWER IS YES.
MANY QUESTIONS, STEM CELL
BIOLOGY GETS CHANGED HERE A
LITTLE BIT.
IT COULD RECENTER OUR ATTENTION
WITH UNDERSTANDING AND
RESTORING THAT STEM CELL
BIOLOGY TO BUILD AN APPROPRIATE
MAP.
AS I TOLD YOU, IT'S ALMOST
CERTAIN THAT OVERALL PERCEPTION
DEPENDSES ON PATTERNS OF
ACTIVITY IN THE BULB.
AS I TOLD YOU, THIS ONE GENE
EXPRESSION PROGRAM COORDINATES
SPACE IN THE NOSE AND TARGETING
IN THE BULB.
SO THE STEM CELL BIOLOGY IS
CRITICAL AND IMPORTANT TO FOCUS
ON FOR THERAPEUTICS.
THANK YOU FOR YOUR QUESTION.
>> THANK YOU.
>> I WONDER WHETHER THE
CAUSATION MIGHT WORK A LITTLE
DIFFERENTLY FROM THE WAY YOU
ARE ENVISIONING IT.
IS IT POSSIBLE THE GLOMERULUS
THAT THE CELL LEACHES IS NOT
PRECISELY DETERMINED BUT WHICH
ONE IT REACHES DETERMINES, TO
SOME EXTENT, WHICH ODORANT
RECEPTOR WILL EXPRESS IN OTHER
FEATURES OF THE CELL?
>> Sandeep Datta: THAT'S A
GREAT QUESTION.
ONE MIGHT IMAGINE YOU BUILD
THIS TARGETING AND RETROGRADE
THAT TELLS YOU WHICH TO EXPRESS.
SORRY I WASN'T CLEAR, TURNS OUT
THEY ARE EXPRESSED WAY BEFORE
THE AXONS REACH THEIR TARGET
AND PEOPLE HAVE LONG THEORIZED
IT GOVERNS THE EXPRESSION OF
AXON GUIDANCE CHAINS OR GOVERNS
IN SOME WAY TO GET AXONS TO THE
RIGHT TARGET.
WE SHOW IT'S LARGELY NOT TRUE
IN THESE DATA.
THAT IDEA DERIVED FROM THE FACT
THE RECEPTOR IS CHOSEN EARLY
BEFORE THE AXON IS ELABORATED.
I THINK THAT QUESTION IS A GOOD
QUESTION.
>> I HAVE A LOT OF QUESTIONS,
SO I WILL ASK TWO.
SO ONE IS, THE PROGRAM THAT YOU
ARE SUGGESTING, PARTICULARLY
THE DEPENDENCE ON RETINOIC ACID
FOR DORSAL VENTRAL PATTERNING,
IS VERY SIMILAR, IT SOUNDS TO
PATTERNING FOR EXAMPLE OF THE
INNER EAR PRECURSOR.
I WAS WONDERING TO WHAT EXTENT
HAVE YOU LOOKED ACROSS OTHER
SYSTEMS IN THE BODY THAT HAVE
DORSAL VENTRAL PATTERNING AND
HAVE YOU LOOKED FOR
COMMONALITIES VERSUS
DIFFERENCES?
>> Sandeep Datta: THAT IS A
WONDERFUL QUESTION.
MY FRIEND AND COLLEAGUE LISA
GOOD RIDGE HAS A LARGE SINGLE
CELL SEQUENCING SET OF MANY
CELL TYPES IN THE EAR.
WE ARE BEGINNING TO THINK OF
THAT.
THE OTHER PLACE THERE ARE
INTERESTING SIMILARITIES IN
TERMS OF OVERALL ARE IN
D.R.G.NEURONS.
I DON'T HAVE ANYTHING TO SAY
ABOUT THAT BUT THEY ARE COMMON
PRINCIPLES THAT I THINK REALLY
MATTER.
WE ARE THINKING ABOUT THE
COMPARATIVE NARRATIVES AS WELL.
>> MY SECOND QUESTION, I'M AN
E.N.T. AND TRADITIONAL TEACHING
IS THAT THE OLFACTORY SENSORY
EPITHELIUM IS REALLY, IN HUMAN
LOCATED MORE IN THE -- AREA
OF THE NOSE.
HOW DOES THIS MAP CORRELATE
WITH THE HUMAN SENSORY
EPITHELIUM?
>> Sandeep Datta: WE HAVE BEEN
COLLABORATING WITH BRET
GOLDSTEIN AT DUKE TO DO
EXPERIMENTS WHICH ARE FUN.
MANY OTHERS ARE DOING IT, WE
ARE ASSEMBLING AN ATLAS, WE
HAVE THOUSANDS OF NEURONS IN
THAT ATLAS.
YOU WOULD EXPECT TO SEE
GRADIENTS OF DORSAL VENTRAL IN
THE HUMAN OR NOT DEPENDING THE
WAY THE ANATOMY IS ORGANIZED
AND WE ARE JUST GETTING INTO
THAT ANALYSIS NOW.
I WILL TELL YOU ABOUT A FUN
EXPERIMENT I'M SUPER EXCITED,
IT'S FUN, I THINK YOU WILL LIKE
IT.
WE ARE DOING THE FIRST
MOLECULAR BIOLOGY OF THE
NERVOUS SYSTEM IN HUMANS.
IN THE MOUTH WE HAVE METHOD AK
SEEK WHICH LET'S US KNOW WHICH
NEURONS ARE ACTIVATED FOR A
GIVEN SMELL.
YOU TAKE A MOUSE, GIVE IT AN
ODOR, KILL IT, AND SEQUENCE ITS
NOSE AND 200-GENE THAT TARGETS
ACUTE SENSORY NEURON THAT LET'S
US IDENTIFY ALL THE RECEPTORS
ACTIVATED AND HOW MUCH THEY ARE
ACTIVATED.
TURNS OUT THAT WORKS IN HUMANS.
WE HAVE BEEN GIVING SMELLS TO
PATIENTS, LEMON, ORANGE, PIZZA,
LET THEM SMELL FOR 30 MINUTES,
WE TAKE A BIOPSY OF THE NOSE
AND SEQUENCE THE SMELLS AND GET
THE SAME MOLECULAR SIGNATURES
BACK.
THIS PROVES THE IMMEDIATE FOSS
PROPOSED UBIQUITOUS MARKER OF
ACTIVITY BY GREENBERG IN 1984
IS BY NEURAL ACTIVITY IN HUMAN,
WE SEE A RESPONSE TO A REAL
CUE, WE THINK THIS COULD BE
HELPFUL AS USING THE NOSE AS
BIOMARKER, AFFECTED IN
PSYCHIATRIC DISORDERS AND
NEURODEGENERATIVE DISORDERS.
SENSITIVE TO IMMUNITY.
IT COULD BE A NEAT WAY OF
GETTING AT THE UNDERLYING
MOLECULAR VARIATION AT
DIFFERENT DISEASE STATES.
WE ARE BEGINNING TO THINK ABOUT
THAT AS WELL.
>> THANK YOU.
>> HI, GREAT TALK.
I WAS THINKING ABOUT YOUR
TRANSCRIPTION FACTOR BINDING
DATA, YOU ONLY LOOKED AT 1,000,
I WAS WONDERING IF YOU HAVE
CHROMATIN LOOPING DATA?
>> Sandeep Datta: YEAH, MY
FRIEND AND COLLEAGUE VARTIS AT
COLUMBIA IS EXPERT LOOKING AT
WITH RESPECT TO ODORANT
RECEPTOR GENES IN MATURE
OLFACTORY SENSORY NEURONS.
STAVROS THINKS THEY HAPPEN IN
WINDOW, PERHAPS UPSTREAM BUT
HIS DATA GUIDED BY HIS WORK, WE
THINK PRET WHY MUCH THINGS ARE
CLOSE BY THE O.R.
THESE ARE THE FASTEST EVOLVING
GENES IN YOUR GENOME, ALMOST AS
FAST EVOLVING AS THE IMMUNE
SYSTEM, THEY EVOLVE THROUGH
DUPLICATION AND THEN VARIATION.
YOU KIND OF WANT, IF YOU
DUPLICATE GENE FAMILY RAPIDLY
YOU WANT THINGS CLOSE BY TO
COPY THEM N SO THINGS AREN'T
BROKEN FREQUENTLY BY EVOLUTION.
THAT'S THE PRESSURE THAT GUIDES
THIS PARTICULAR ARCHITECTURE.
>> THANKS.
>> CAN I ASK A COUPLE QUESTIONS
FROM ONLINE?
IT'S BEEN BUILDING UP.
THERE'S A QUESTION ABOUT THE
ALZHEIMER'S DISEASE AND COVID
CONNECTION TO ANSOMIA.
WHAT CAN YOU SAY ABOUT THAT?
>> Sandeep Datta: WE WERE
ACCUMULATING LARGE DATASET OF
5.5 MILLION CELLS WHEN COVID
BROKE OUT.
WE HAD THE HALF MILLION AND
HUMAN DATA WE WERE ABLE TO LOOK
THROUGH THOSE DATA AND COME UP
WITH A HYPOTHESIS HOW COVID
MIGHT AFFECT THE SMELL.
WE BELIEVE BECAUSE THE VIRUS
ATTACKS THE SUPPORT CELLS BUT
NOT NEURONS DIRECTLY.
IN PART EXPLAINS WHY PEOPLE
TEND TO RECOVER THEIR SENSE OF
SMELL, THE NERVE CELLS ARE A
FEKTD BUT WHEN THE WHOLE SYSTEM
IS CLEAR IT CAN RECOVER.
FOR ALZHEIMER'S, WE STILL DON'T
UNDERSTAND THE LEVEL WHICH
ALZHEIMER'S AFFECTS THE
OLFACTORY SYSTEM.
IT'S A HARBINGER, IF YOU LOSE
YOUR SENSE OF SMELL IT'S
HARBINGER FOR FUTURE
DEGENERATIVE DISEASE, RELATIVE
RISK IS TEN TIMES.
IF YOU HAVE M.C.I. AND LOSE
YOUR SENSE OF SMELL.
MY DAD HAS PARKINSON'S, HE WAS
ANOSMIC TEN YEARS BEFORE HE
DEVELOPED P FULL BLOWN
PARKINSON'S.
IT HAS SOMETHING TO DO WITH THE
FACT THE SMELL CENTERS ARE IN
THE TEMPORAL LOBE.
I WOULD SAY WE DON'T FULLY
UNDERSTAND IT.
>> OKAY, ONE MORE UP THERE AND
ONE MORE BACK ONLINE.
>> HI.
>> Sandeep Datta: HI.
>> I WAS JUST THINKING THAT
THERE'S SOME NEURODEVELOPMENTAL
DISORDERS CHARACTERIZED BY
FAULTY MIGRATION OF STEM CELLS
AND I THINK IT WOULD BE REALLY
INTERESTING TO LOOK AT IF
THAT'S SOMETHING THAT OCCURS
WHEN EVEN ADULTHOOD AND THOSE
INDIVIDUALS WITH
NEURODEVELOPMENTAL DISORDERS IF
THAT IMPACTS THE MIGRATION AND
OLFACTORY ABILITIES AND
RECEPTOR EXPRESSION ON THAT
DORSAL VENTRAL AXIS.
>> Sandeep Datta: I THINK WE
DON'T UNDERSTAND THERE'S THESE
STEM CELLS THAT GENERATE
NEURONS AND WE DON'T UNDERSTAND
HOW FAR THEY MIGRATE, THE WAYS
IN WHICH MAYBE A RECEPTOR
GENERATED BY THE STEM CELL
MIGHT CHANGE THE WAY IT IS SOME
SPACE AND HOW MUCH THAT
INTRODUCES NOISE IN THE SYSTEM
AND HOW MUCH THE MIGRATION IS
PRECISE.
YOUR SUGGESTION IS VERY
INTERESTING.
I WILL MENTION ONE OTHER THING
YOU MIGHT FIND INTERESTING.
I TOLD YOU THERE WERE SEVEN
GENE EXPRESSION PROGRAMS.
TURNS OUT TWO WE PUBLISHED ON A
PAPER TWO YEARS AGO ACTUALLY
ENCODE A PROGRAM THAT ADAPTS
THE CELL TO LEVELS OF ONGOING
NEURAL ACTIVITY.
I DON'T WANT TO EXPLAIN IN ANY
DETAIL BUT ONE IMPORTANT THING
ABOUT IT, IF YOU LOOK AT A.D..
S.D. MODELS GENES INVOLVED IN
A.S.D. ARE MUTATED WE KNOW
THOSE ANIMALS AND PATIENTS ARE
HYPE SENSITIVE, TURNS OUT THAT
BROKE OLFACTORY SENSORY NEURONS.
WE THINK HOW THESE GENE
EXPRESSION PROGRAMS MIGHT SERVE
DIFFERENT FUNCTIONS IN THE CELL
AND RELATE TO DISEASE.
THIS IS ONE EXAMPLE OF THAT.
>> THAT'S AWESOME.
THANK YOU.
>> MAYBE CLOSE WITH THIS ONE
QUESTION, GENERALLY SPEAKING,
THE IMPORTANCE OF THE KIND OF
ANIMAL STUDIES YOU DO, AND
WHAT'S POSSIBLE AND NOT
POSSIBLE WITH NON-ANIMAL MODELS
THAT PEOPLE WANT TO TRANSITION
TO?
>> Sandeep Datta: THANK YOU FOR
THAT QUESTION.
MY LAB DOES A LOT OF
COMPUTATIONAL WORK AND MODELING
OF THE NERVOUS SYSTEM.
THAT'S A MAIN STAY OF WHAT WE
DO.
AT LEAST FOR THE NERVOUS SYSTEM
I WOULD ARGUE WE ARE NOT AT A
PLACE WE CAN SUBSTITUTE ANIMAL
RESEARCH.
NONE OF THE THINGS I TALKED
ABOUT TODAY, NONE OF THESE
INSIGHTS WOULD BE POSSIBLE
WITHOUT ACCESS TO INVIVO MODELS.
WE DON'T HAVE THE TRAINING DATA
YET TO BUILD SOPHISTICATED
MODELS OF NERVOUS SYSTEM.
EVERYONE WORKING WITH THAT
WOULD AGREE.
I THINK BRAINS ARE EMBODIED.
I MENTIONED AT THE BEGINNING I
THINK OF THE RELATIONSHIP
BETWEEN BRAEN AND NATURAL
BEHAVIOR IN THE WORLD.
IT'S HELPING YOU NAVIGATE A
WORLD WHICH YOU HAVE A BODY
THAT'S REAL.
SEPARATING THAT BODY AWAY FROM
THE BRAIN, I THINK, FROM A
RESEARCH PERSPECTIVE IS A BIG
MISTAKE.
I WOULD ARGUE WHILE IT'S A AN
IDEAL GOAL SILICON, TOXICITY
MAY BE CANCEROUS YOU COULD DO
THAT, FOR NEUROSCIENCE WE
SHOULD INVEST HEAVILY IN ANIMAL
RESEARCH WHILE ENCOURAGING
PEOPLE TO THINK OF ANSILICAL.
>> THANK YOU.
THERE'S A RECEPTION OUT THERE.
LET'S THANK THE SPEAKER.
>> Sandeep Datta: THANK YOU ALL
FOR YOUR TIME.
[ APPLAUSE ]