WHICH IS TO HONOR DR. CLAUDE
DESPLAN, IN THE FRONT OVER HERE.
AND DR. DESPLAN IS A SILVER
PROFESSOR OF BIOLOGY AND
NEUROSCIENCED A NEW YORK CENTER
AND AT THE NYU IN ABU DHABI.
DR. DESPLAN HAS A RICH
SCIENTIFIC BACKGROUND AND SET OF
EXPERIENCES, HAS DONE WHAT I'D
SAY IS REMARKABLE WORK THAT
INVOLVES THE GENERATION OF
NEURAL DIVERSITY ESPECIALLY
USING DROSOPHILA VISUAL SYSTEM,
AMONG MANY OTHER AREAS.
AND I KNOW YOU'RE GOING TO ENJOY
HIS LECTURE TODAY.
BUT FOR NOW WHAT I REALLY WANT
TO DO IS PASS THIS OFF TO STEVE
HOFFMAN, WHO IS THE VICE
PRESIDENT OF SCIENCE
PARTNERSHIPS AT THE FOUNDATION
OF THE NIH.
STEVE WILL SAY SOME WORDS ABOUT
THE FNIH.
WELCOME, STEVE, AND THANK YOU
AGAIN.
[APPLAUSE]
>> THANK YOU.
WELCOME TODAY.
THANKS, MIKE.
GOOD AFTERNOON.
WELCOME, I'M STEVE HOFFMAN, VICE
PRESIDENT OF SCIENCE
PARTNERSHIPS, AT THE FOUNDATION
FOR THE NIH.
I'VE BEEN THERE FOR 12 1/2
YEARS, SO IT'S BEEN PLEASING IN
A LOT OF PARTNERSHIPS WITH MANY
NIH I.C.s INCLUDING MIKE AND
NEI TO SUPPORT AND HELP BRING
FORWARD EDUCATION AND TRAINING
IN THIS TYPE OF AREA.
I'M DELIGHTED TO JOIN YOU TODAY
FOR THE 2025 JORAM PIATIGORSKY
BASIC SCIENCE LECTURE AND AWARD.
TODAY WE'RE PLEASED TO HONOR AS
MIKE SAID DR. CLAUDE DESPLAN WHO
WILL PARENTHESES THE LECTURE.
MANY OF YOU MAY KNOW, OR NOT,
THAT THE FNI H IS A 5013C
ORGANIZATION ESTABLISHED BY
CONGRESS TO SUPPORT THE MISSION
OF THE NIH.
WE RAISE FUNDS, CREATE AND
MANAGE PROGRAMS AND
PUBLIC/PRIVATE PARTNERSHIPS TO
SUPPORT BASIC SCIENCE, ADVANCE
BIOMEDICAL RESEARCH AND SUPPORT
EDUCATION AND TRAINING LIKE THE
LECTURE WE HAVE TODAY.
OUR FOCUS IS ON TEAM SCIENCE,
CONNECTING NIH WITH THE BEST
ACADEMICS, LIFE SCIENCES AND
NON-PROFIT AND PATIENT RESEARCH
ORGANIZATIONS TO REALLY SOLVE
PROBLEMS THAT NO ONE
ORGANIZATION CAN DO THEMSELVES.
MIKE AND HIS TEAM HAVE BEEN
TREMENDOUS COLLABORATORS WITH
FNIH.
WE WORK WITH THEM ACROSS
AUTOIMMUNITY, RARE DISEASES,
NEUROSCIENCE, OBVIOUSLY VARIOUS
EYE DISEASES, AND OTHER PROGRAMS
THAT WE HAVE IN DEVELOPMENT
THROUGH THEM.
THROUGH THEIR STEWARDSHIP AND
ALSO BASED AGAIN ON THE GENEROUS
SUPPORT OF DR. PIATIGORSKY AND
HIS WIFE LONA WERE ABLE AND
HONORED TO BRING THIS LECTURE
FORWARD IN SUPPORT OF SCIENCE
AND NEI TODAY.
WHAT WE'RE GOING TO HEAR ABOUT
IS THE FUNDAMENTAL MECHANISMS OF
NEUROGENESIS, THE DROSOPHILA,
SIGNALING PATHWAYS, MANY OF
THESE CONSERVED ACROSS SPECIES,
INCLUDING HUMANS.
DR. DESPLAN'S WORK IS AN
EXEMPLARY DEMONSTRATION OF THE
TYPE OF RESEARCH AND AWARDS THAT
THIS AWARD SEEKS TO SUPPORT.
SO PLEASE ENJOY THIS LECTURE.
AGAIN, THANK YOU FOR ALLOWING US
TO SHARE IN THIS VISION, THE
IMPACT EXEMPLIFIED AS WE SET OR
SIGHTS ON FUTURE ADVANCEMENTS.
I'LL TURN IT BACK TO MIKE, AND
THANK YOU AGAIN.
>> STEVE, THANK YOU VERY MUCH
FOR ALL THAT YOU DO WITH US AT
THE FNIH.
THIS GROUP HAS BEEN GREAT
ACADEMIC PARTNERS WITH US AND
ARE REALLY NICE PEOPLE TO WORK
WITH.
WITH WHAT I WANT TO INTRODUCE
DR. JEREMY NATHANS, SCIENTIST,
WHO IS REALLY WELL KNOWN TO ALL
OF US AT THE NATIONAL EYE
INSTITUTE.
JUST BY WAY OF A QUICK
INTRODUCTION, DR. NATHANS IS
PROFESSOR OF MOLECULAR BIOLOGY
AND GENETICS, NEUROSCIENCE AND
OPHTHALMOLOGY AT THE JOHNS
HOPKINS UNIVERSITY SCHOOL OF
MEDICINE.
HE'S DONE GROUNDBREAKING WORK IN
TERMS OF THE MECHANISMS THAT LET
US SEE COLORS.
HE IDENTIFIED GENES THAT CODE
FOR COLOR VISION, RECEPTORS, THE
CONES OF THE RETINA,
GROUND-BREAKING STUFF DECADES
AGO.
THAT WORK HAS LED TO DISCOVERIES
THAT HAVE CHANGED OUR
UNDERSTANDING OF HOW PEOPLE SEE
THE WORLD.
ANDBUT THE REAL REASON THAT
JEREMY IS HERE, HE'S ONE OF THE
MEMBERS OF THE SELECTION
COMMITTEE FOR THE PIATIGORSKY
LECTURE AND AWARD.
I'LL TURN THE MIC TO YOU, SO
WELCOME.
[APPLAUSE]
>> I'M GOING TO SAY A FEW WORDS
ABOUT JEROME.
FIRST LET ME SAY IT'S A GREAT
HONOR TO BE HERE FOR THIS JORAM
PIATIGORSKY BASIC SCIENCE
LECTURE AND AWARD.
THE LECTURE CELEBRATES CREATIVE
SCIENCE AND ALSO CELEBRATES A
CREATIVE SCIENTIST.
JORAM PIATIGORSKY.
JORAM WAS THE FOUNDING DIRECTOR
OF THE LABORATORY OF MOLECULAR
AND DEVELOPMENTAL BIOLOGY HERE
AT THE NATIONAL EYE INSTITUTE AT
NIH.
STARTING IN THE EARLY 198 0s
WHEN NOTHING WAS KNOWN ABOUT
GENE STRUCTURE AND
MULTI-CELLULARRING OR HE
EXPLORED LENS STRUCTURE AND
DEVELOPMENT AND ORGANISMS AS
DIVERSE AS JELLYFISH AND MICE.
THIS WORK LED TO INSIGHT THAT
ANATOMICALLY DIVERSE ORGANISMS
RETAIN EXTRAORDINARY MOLECULAR
SIMILARITIES AND ALSO LED TO HIS
DISCOVERY OF GENE SHARING,
EVOLUTIONARY MECHANISM IN WHICH
A SINGLE PROTEIN PLAYS DISTINCT
ROLES IN DIFFERENT CELL TYPES.
I'VE KNOWN JORAM FOR ALMOST 40
YEARS.
AND I ADMIRE BOTH HIS WORK AND
HIS APPROACH TO LIFE.
IN PARTICULAR, I ADMIRE HIS
SCIENTIFIC ORIGINALITY AND
DETERMINATION TO MARCH TO THE
BEAT OF HIS OWN DRUMMER IF THAT
MEANT FORGOING WHAT MIGHT HAVE
SEEMED TO BE TRENDIER
DIRECTIONS.
HIS INSIGHT YIELDED REWARDS,
MOST DRAMATICALLY IN HIS
DISCOVERY OF GENE SHARING, I
ALSO ADMIRED JORAM'S DRIVE TO
DEVELOP NON-SCIENTIFIC TALENTS,
IN PARTICULAR TALENTS AS A
WRITER, ENCOMINGS SCIENTIFIC
TREATISE, FICTION, COLLECTIONS
OF ESSAYS AND AN AUTOBIOGRAPHY.
JORAM HAS BECOME AN AUTHORITY ON
INUIT SCULPTURE, A CHAMPION OF
THAT KIND OF ART, BEFRIENDED AND
PROMOTED MANY INUIT ARTISTS.
I ADMIRE HIS KIND INSIDE AND
WISDOM.
HE AND LONA MADE A GIFT TO THE
INTELLECTUAL LIFE OF THE NIH
THAT WILL BRING CREATIVE
SCIENTISTS TO THE CAMPUS AND
INSPIRE THE NEXT GENERATION OF
RESEARCHERS.
NOW I'M PLEASED TO INTRODUCE
JORAM PIATIGORSKY.
[APPLAUSE]
>> WELL, THANK YOU ALL FOR
COMING.
EXCUSE ME.
THANK YOU TO THE FNIH AND NEI
FOR ALL THE HELP AND WORK AND
DELIVERANCE YOU'VE BEEN ABLE TO
DO.
I'LL BE A COUPLE MOMENTS HERE.
AND NOT DETRACT FROM THE MAIN
ATTRACTION, DR. DESPLAN.
THE REASON I CREATED THIS
LECTURE AWARD, TWO REASONS.
ONE OF THEM IS JUST I GUESS FOR
MYSELF THAT I WANTED SOME WAY TO
BE ABLE TO GIVE BACK SOMETHING
TO THE NIH, TO THE NEI, WHO HAVE
SUPPORTED MY WORK SO GENEROUSLY
FOR CLOSE TO 50 YEARS I THINK.
AND I THINK THAT THAT'S
ABSOLUTELY EXCEPTIONAL.
IT ALLOWED ME TO DO THINGS THAT
REALLY THINK WOULD BE VERY HARD
TO DO WITHOUT SUCH SUPPORT AND
ALLOWED THE ACADEMIC FREEDOM I
BELIEVE IS SO CRITICAL FOR
SCIENCE.
THEY NEVER TOLD ME WHAT TO DO,
JUST SET ME FREE AND FUNDED MY
WORK, WHICH IS A REASON I WOULD
LIKE TO DO THE SAME TO THEM IN
SOME WAY.
THE OTHER REASON IS MY DEEP
BELIEF IN BASIC RESEARCH.
OF COURSE, CLINICAL RESEARCH,
MEDICAL RESEARCH, APPLIED
RESEARCH IS ABSOLUTELY CRUCIAL,
IN NO WAY WOULD I LIKE TO SEE
THAT EVEN SLIGHTLY DECREASED.
WE'RE ALL DEPENDENT ON IT, AND
IT'S OF TREMENDOUS VALUE.
BUT IT'S ALSO I THINK IMPORTANT
TO REMEMBER THAT A LOT OF WHAT
WE CAN DO IN MEDICAL RESEARCH
COMES FROM THE WONDERFUL STUDIES
IN BASIC SCIENCE THAT HAS NO
GOAL BEYOND UNDERSTANDING.
IT'S IN A SENSE DESTINATION
FREE, SEEKING GREATER
UNDERSTANDING, FROM WHAT WHAT
YOU NEVER KNOW WHAT'S GOING TO
COME ACROSS AND IT'S A LONG
HISTORY OF EXTRAORDINARY
ADVANCES BECAUSE THERE WERE
PEOPLE BEFORE WHO STUDIED
GENERAL PHENOMENON AND THAT'S
TIED IN A LITTLE BIT WITH THE
EYE.
I WORKED ON THE EYE, ON THE
LENS, CORNEA, FOR MANY YEARS.
BUT IN GENERAL, THE EYE HAS BEEN
SUPPORTED I BELIEVE OR MAIN
INTEREST TO OPHTHALMOLOGISTS,
PEOPLE INTERESTED IN THE EYE,
WHEN DISCOVERIES ARE MADE SEEING
HOW IT APPLIES TO THE EYE AND I
THINK THAT'S BEEN CRUCIAL AND
IT'S TERRIBLY IMPORTANT.
BUT I THINK WHAT ALSO CAN
HAPPEN, AND IT DOES HAPPEN, AND
IS HAPPENING, IS THAT INSTEAD OF
GOING FROM THE WORLD TO THE EYE,
IT'S POSSIBLE WITH REALLY FINE
BASIC SCIENCE YOU CAN GO FROM
THE EYE TO THE WORLD AND WHAT'S
DISCOVERED BY RESEARCHERS IN
VISION AND COMPONENTS OF THE EYE
CAN BE FOUND APPLICABLE TO ALL
KINDS OF OTHER PHENOMENONN , IN
MY OWN STUDIES WITH RESPECT TO
GENE EVOLUTION.
BY SUPPORTING THE IDEA OF BASIC
RESEARCH IT WILL ALLOW IN SOME
WAY TO -- IF THIS LECTURE HELPS
IN SOME WAY TO ALLOW THAT TO
INCREASE AND AT LEAST NOT BE
FORGOTTEN AS THE MEDICAL
RESEARCH IS DEVELOPED, I THINK
IT WILL BE GREAT BENEFIT, NOT
ONLY TO SCIENCE BUT TO THE EYE
INSTITUTE ITSELF BECAUSE THEN
PEOPLE WHO MAYBE NOT HAVE LOOKED
AT THE EYE INSTITUTE BASIC
SCIENTISTS BECAUSE THEY SAID
THAT'S MORE FOR VISION THAN
MEDICINE THEY WILL RECOGNIZE THE
TREMENDOUS COMPLEXITY AND
TREMENDOUS OPPORTUNITIES IN EYE
RESEARCH FROM ALL SORTS OF
LEVELS MAYBE THAT WOULD BE A
GOOD IDEA FOR ME TO APPLY TO THE
EYE INSTITUTE AND I THINK THAT
WOULD ENRICH THE EYE INSTITUTE
WITH NEW GENERATIONS, NEW BLOOD,
AND I'VE SEEN IT WORK IN MY OWN
LAB IN THE SENSE THAT ALMOST
NOBODY WHO HAS COME TO MY LAB AS
A POSTDOC KNEW ANYTHING ABOUT
THE EYE WHEN THEY CAME AND
ALMOST ALL OF THEM HAVE
CONTINUED IN EYE RESEARCH.
SO I HOPE THAT THIS LECTURE WILL
PROMOTE THAT TO SOME EXTENT.
THANK YOU VERY MUCH.
[APPLAUSE]
>> THIS WAS A WELL CHOREOGRAPHED
SET OF INTRODUCTIONS, AND I
DIDN'T MEMORIZE THE SCHEDULE.
I'M BACK HERE.
I'M GOING TO SAY SOME THINGS
ABOUT CLAUDE DESPLAN, OUR
SPEAKER AND AWARDEE.
CLAUDE IS THE SILVER PROFESSOR
OF BIOLOGY NYU, DIRECTOR OF THE
CENTER FOR DEVELOPMENTAL
GENETICS.
HE WAS BORN IN ALGERIA, LIVED
THERE UNTIL HE WAS 9, HIS
PARENTS LEFT AS THE ALGERIAN WAR
FOR INDEPENDENCE FINISHED.
THEY LEFT AND WENT TO FRANCE.
HE WAS EDUCATED AT THE FRENCH
VERSION OF HARVARD, AND THEN AT
THE UNIVERSITY OF PARIS FOR HIS
Ph.D.
ONE OF HIS FIRST PAPERS WAS
DEVELOPING IMMUNOASSAY FOR
PARATHYROID HORMONE, PUBLISHED
IN "THE LANCET" IN 1977.
I MENTIONED THIS BECAUSE I WAS
ALSO WORKING ON PARATHYROID
HORMONE AS UNDERGRADUATE, WE
WERE ALMOST SYNCHRONIZED.
AND THEN CLAUDE DID SOMETHING
QUITE DIFFERENT.
HE WENT TO UCSF AS A
POSTDOCTORAL FELLOW, SWITCHED
INTO DEVELOPMENTAL GENETICS AT
THE MOST EXCITING MOMENT, AS THE
DISCOVERY OF THE HOMEOBOX GENES
HAD BEEN MADE, IT WASN'T CLEAR
WHAT THEY DID.
HE SHOWED THESE WERE
TRANSCRIPTION FACTORS USING GENE
IN DROSOPHILA AND DEFINED NOT
ONLY THE REGION OF THE PROTEIN
THAT BOUND DNA, ALSO DEFINED DNA
BINDING SITE AND THEN AS AN
INDEPENDENT INVESTIGATOR HE DID
A SERIES OF STUDIES OF
DROSOPHILA DEVELOPMENT INITIALLY
IN EMBRYO BUT IN MORE RECENT
YEARS IN THE VISUAL SYSTEM THAT
HAVE BUILT ON THIS MOLECULAR
GENETIC REDUCTIONIST APPROACH,
HOW DID GENES CONTROL
DEVELOPMENT.
THAT'S THE BIG PICTURE.
AND AMONG MANY THINGS CLAUDE HAS
úDOI
CAN'T CITE THEM ALL, BUT I'LL
SAY THAT HE WAS ONE OF THE
ORIGINAL PEOPLE WHO REALIZED THE
IMPORTANCE OF THE PAX FAMILIAR
OF TRANSCRIPTION FACTORED, PACKS
PROTEINS HAVE TWO DNA BINDING
DOMAINS, INTERACTING WITH TARGET
DNAs, IN COLLABORATION WITH
JOHN CORIAN AND CARL PAYBO
SOLVED CRYSTAL STRUCTURES OF
PROTEINS BOUND TO DNA TARGETS.
ONE OF THEM, THE MOST FAMOUS IS
PAX 6, THAT BINDS TO THE
RHODOPSIN PROMOTER IN
DROSOPHILA, KICKED OFF HIS
PASSION FOR THE VISUAL SYSTEM
AND SINCE THEN HAS DONE MANY
THINGS IN VISION, IN FLIES,
DEFINED AT A COMPLETE LEVEL THE
TRANSCRIPTOMES OF DEVELOPING FLY
OPTIC LOBE, HAS DEFINED
TRANSCRIPTIONAL CONTROL UNITS
AND CIRCUITS, HAS ALSO DEFINED
NEURAL CIRCUITS, FUNCTIONAL
NEURAL CIRCUITS THAT CONTROL
SENSATION OF MOVEMENT, MOVEMENT
OF OBJECTS IN THE OUTSIDE WORLD.
RECENTLY EXTENDED HIS INTEREST
TO ANTS, HE'S BEEN WORKING ON
ANT OLFACTION AND CONTROL OF
CAST IN ANTS.
ANTS ARE NOT THE ONLY
NON-DROSOPHILA INTEREST.
HE'S ALWAYS TAKEN THE DROSOPHILA
INSIGHTS AND EXTENDED THEM TO
OTHER INSECTS, FOR EXAMPLE
WORKED ON BUTTERFLIES AND
STOCHASTIC CONTROL OF
PHOTORECEPTOR SIGHT IN
DROSOPHILA AND SUBSEQUENTLY IN
BUTTERFLIES.
CLAUDE, I WANT TO SAY I'VE
WONDERED AT SOME POINTS HOW YOU
HAVE MANAGED TO DO ALL OF THIS
STUFF, WHAT I'VE REALIZED IS
ONLY RECENTLY CLAUDE HAS VERY
GOOD GENES.
HIS MOTHER WAS A YOGA INSTRUCTOR
INTO HER 90s.
YOU'VE GOT BOTH NATURE AND
NURTURE WORKING ON YOUR SIDE.
I'LL JUST CONCLUDE BY SAYING
CLAUDE HAS BEEN WIDELY
RECOGNIZED FOR HIS MANY
CONTRIBUTIONS, A MEMBER OF THE
NATIONAL ACADEMY OF SCIENCES,
WAS AWARDED EDWIN CONKLIN PRIZE
FOR SOCIETY OF DEVELOPMENTAL
BIOLOGY.
HE GOT ONE OF THE SORT OF BEST
TEACHER AWARDS FROM NYU
RECENTLY, AND HERE'S THE ONE I
LIKE THE BEST.
HE GOT THE COOLEST PROFESSOR
AWARD FROM NYU.
I'D LIKE TO HEAR MORE ABOUT THAT
ONE.
SO, CLAUDE, WE'RE LOOKING
FORWARD TO YOUR TALK.
THANK YOU SO MUCH.
[APPLAUSE]
>> IT'S VERY HUMBLING TO BE
HERE.
AS SCIENTISTS WE WORK VERY HARD.
WE GET AMAZING RESULTS
SOMETIMES.
WE SUFFER SOMETIMES ALSO.
ALSO STARTING TRYING TO MAKE
SURE PEOPLE UNDERSTAND WHAT
WE'RE DOING.
SO ACTUALLY I FIRST MET JORAM
WHEN MAYBE 25 YEARS AGO.
HE DESCRIBED THIS MOTION PROTEIN
CAN BE USED FOR TWO DIFFERENT
PURPOSES, FINE TUNING FUNCTIONS
ENZYME AND FUNCTION AS A LENS.
I WAS STRUCK.
I REMEMBER A NICE DISCUSSION AT
THE TIME.
BUT ANYWAY, I WANT TO THANK
JORAM AND LONA FOR BEING HERE
AND THE COMMITTEE AND RECOGNIZED
BY THE PEER SOMETHING WE DO
VALUE VERY MUCH.
WE LIKE TO KNOW PEOPLE RECOGNIZE
WHAT WE'RE DOING.
I WANT TO THANK NIH AND NEI
BECAUSE OVER THE LAST 25 YEARS,
NOT 50 BUT 25 YEARS MY LAB HAS
BEEN SUPPORTED BY SEVERAL NEI
GRANTS.
WITHOUT THAT NOTHING HAS BEEN
DONE, EVERYTHING I TALKED ABOUT
WAS SUPPORTED BY NEI.
OF COURSE, I WANT TO RECOGNIZE
MY LAB, HAS DONE SO MUCH.
I'VE BEEN ABLE TO ATTRACT
AMAZING PEOPLE.
SO AT MY LIFE, IN MY LAB, STILL
NOW, I HAVE A LOT OF GREAT
PEOPLE, AT EVERY LEVEL, MANY OF
THEM YOU'LL SEE NOW DEVELOPING
THEIR OWN LAB.
I SHOULD NOT FORGET MY OTHER
PERSON, MY WIFE IS NOT A
SCIENTIST, BUT SHE HELPS ME WITH
BEAUTIFUL PICTURES TO APPRECIATE
WHAT THE VALUE OF ART WOULD BE.
I WILL STOP BEFORE I BECOME TOO
EMOTIONAL AND TELL WHAT YOU
WE'RE DOING IN THE LAB AND WHAT
WE'RE DOING TO FIGURE OUT.
OKAY.
SO, THIS IS A FAMOUS PICTURE
FROM THE SPINAL CORD IN
VERTEBRATE, AND WHEREBY WE KNOW
HOW TO MAKE THE DIFFERENT TYPES
OF NEURONS THAT FORMS THE SPINAL
CORD, FROM THE MOTOR NEURONS TO
THE INTERNEURON TO THE SENSORY
NEURON AND HOW IT'S BEING DONE.
ALL THESE DIFFERENT TYPES OF
CELLS SOME FROM SIMPLE GRADIENT
OF SONIC HEDGEHOG, IN THE FLOOR
PLATE TO DIFFUSE ALONG THE
VENTRAL DORSAL PATH OF THE
SPINAL CORD AND CAN ACTUALLY
LEAD TO THE SPECIFICATION OF ALL
THOSE THINGS.
WE KNOW HOW IT'S HAPPENED AT
MOLECULAR LEVEL.
THE NOTION OF DIFFERENT LEVELS
OF THE TARGET OF THE SIGNALING
PATHWAY HERE ARE ABLE TO INDUCE
GENE EXPRESSION AND HOW
DIFFERENT GENE IN DIFFERENT
COLOR BASICALLY ALLOW THE SYSTEM
TO FUNCTION TO MAKE SPECIFIC
TYPE OF NEURON.
TO THE POINT PEOPLE SPECIAL
INFORMATION WHICH YOU SEE HERE
ALONG THIS AXIS ALMOST
EVERYTHING TO SPECIFY.
HOWEVER, WE KNOW IN FACT FROM
THE WORK OF ANOTHER GRANT,
AMAZING PERSON IN EYE VISION,
MANY YEARS AGO IN FACT THE
RETINA OF MOUSE IS NOT PATTERNED
SO MUCH BY SPECIAL INFORMATION
BUT PATTERNED BY TEMPORAL
INFORMATION.
WHAT I MEAN BY THAT THE FIRST
RETINA GANGLION CELLS BEING
PRODUCED EARLY DURING THE
RETINAL GENESIS, LATER ON ALL
THE CELL TYPE HAVE BEEN
PRODUCED, SO WE KNOW THE TIME IS
VERY IMPORTANT BUT THERE'S A BIG
PROBLEM HERE THAT WE HAVE NO
IDEA TO BE ABLE TO DRIVE
SPECIFICATIONS OF DIFFERENT
TYPES OF NEURONS.
SO MAYBE THIS IS MORE STRIKING
LOOKING AT THE CORTEX OF THE
VERTEBRATE CORTEX, WHEREBY AS
YOU KNOW THE CORTEX IS MADE OF
DIFFERENT LAYERS AND CORTEX MADE
FROM CELLS ORIGINATING FROM THE
BASE OF THE CORTEX AND AS THEY
DIVIDE PRODUCE NEURONS FROM
THESE AREAS AND THAT MEANS THESE
ARE DOING THAT IN A TIME-WISE
MANNER.
TIME IS VERY IMPORTANT HERE.
TO BE CONTROVERSIAL WE KNOW
COMING FROM ONE SINGLE, THAT CAN
DO SIX, FIVE, FOUR, THREE, TWO
IN INSIDE-OUT MANNER, BEAUTIFUL
CLONES SHOW IN THE TABLE YOU CAN
SHOW SINGLE PROGENITOR CAN
PRODUCE LAYER SIX, FIVE, FOUR,
THREE, TWO, BASICALLY YOU CAN
SEE FROM ONE PROGENITOR YOU CAN
MAKE SIX, FIVE DIFFERENT TYPES
OF NEURONS.
AGAIN HERE WE DON'T KNOW THE
MECHANISM WHICH HAS HAPPENED.
HOW DOES TIME TAKE INTO
CONSIDERATION?
TODAY I'LL TELL HOW WE CAN
CONTRIBUTE AND HOW TIME CAN BE
TAKEN INTO CONSIDERATION
INCLUDING SPACE AND HOW NEURONS
CAN BE SPECIFIED BY THE
MECHANISM.
SO THE SYSTEM THAT REVIEWS
VISUAL SYSTEM, FLIES CAN FLY
HIGH SPEED, ACROBATIC FLYING,
NEED VERY GOOD EYES TO DO THAT.
IN FACT DEDICATE MORE THAN 2/3
OF THE BRAIN TO THE VISUAL
SYSTEM.
OLFACTORY IS REDUCED, THE REST
OF THE BRAIN SERVES TO INTERPRET
THE INFORMATION COMING FROM THE
EYE.
SO WHAT YOU HAVE HERE IS
ACTUALLY BEAUTIFUL PICTURE FROM
THE FLY EYE.
YOU CAN SEE AT THE TOP THE
RETINA, ONLY CONTAINS 800 UNITS,
BASICALLY PIXELS.
THE EYE SEES 800 PIXELS YET TRY
TO CATCH A FLY, MUCH BETTER THAN
YOU ARE IN ORDER TO ESCAPE.
PHOTORECEPTOR IN FLIES ARE BOTH
PHOTORECEPTOR AND RETINA
GANGLION CELL, THEY DO PROJECT
LONG PROJECTION HERE TO THE
FIRST LAYER OF THE OPTIC LOBE,
OF COURSE THE LAMINA.
AND WHAT YOU HAVE HERE IS THE
STRONG PROJECTION AS PROJECTION
OF THE PHOTORECEPTOR BASICALLY
THE ROAD OF THE FLY, THE LAMINA
STRUCTURE IS THE FIRST STEP IN
MOTION DETECTION, A SIMPLE
STRUCTURE MADE OF FIVE TYPES OF
NEURONS, HERE COLLECTING
INFORMATION FROM PHOTORECEPTOR,
PROJECT THEM INTO THE NEXT STEP
IN THE VISUAL PATHWAY, CALLED
THE MEDULLA, RECEIVES
INFORMATION FROM THOSE GREEN
PHOTORECEPTORS HERE BASICALLY
THE CONES OF THE FLY, THE CONES
OF THE FLY DON'T STOP IN THE
MEDIA, THEY GO INTO THE MEDULLA,
PROCESS INFORMATION FOR COLOR
VISION.
THIS MEDULLA IS MUCH MORE
COMPLEX STRUCTURE IN THE WHOLE
SYSTEM, IN FACT CONTAINS MORE
THAN ALL THE INDIVIDUAL SYSTEM
WHICH MEANS ONE-THIRD OF ALL THE
NEURONS IN THE BRAIN OF THE
FLIES.
THIS INFORMATION IS BEING
PROCESSED IN MANY WAYS, AND IS
GOING TO LEAD TO THE PROJECTION
TO INTERPRETATION BY OUTPUT
NEURONS, TAKE INFORMATION FROM
THE VISUAL SYSTEM AND SEND IT TO
CENTRAL BRAIN AND BASICALLY
DRIVE THE CORRECT BEHAVIOR OF
THE FLY.
SO I'M GOING TO FOCUS MY
ATTENTION ON THIS MEDULLA
STRUCTURE BECAUSE IT'S ACTUALLY
THE MOST COMPLEX AND MOST
INTERESTING STRUCTURE, WE DO A
LOT OF WORK ON THE OTHER
STRUCTURE BUT AGAIN THINGS, THE
PICTURE MAY BE LESS APPLICABLE
TO THE SYSTEM.
SO, AGAIN WHAT YOU HAVE HERE,
40,000 NEURONS THAT BELONG TO
100 CELL TYPES.
WHICH MEANS INDEED YOU CAN SEE
THAT THERE IS NEED FOR
GENERATING A LOT TO PROCESS THAT
INFORMATION ABOUT MOTION, OBJECT
DETECTION, LOOMING OR COLOR
VISION, OKAY?
SO ABOUT SEVEN OR EIGHT YEARS
AGO, 2017, 2016 OR 2017, WERE
RESISTANT TO THE OMICS KINGDOM,
IN FACT AT THAT TIME HAD NEVER
DONE AN RNAseq OR ATAC-SEQ WAS
THE MOST STUPID THING TO DO,
WHAT DO WE GAIN?
I CHANGED MY MIND, DON'T WORRY.
AND THE FATHER OF THIS PROGRAM
THAT ALLOWS PEOPLE TO INTERPRET
SINGLE CELL, JOINED THE
DEPARTMENT, AMAZING.
BY KNEW YOU ARE TIRED OF SINGLE
SEQUENCING YOU'VE SEEN OF
OTHERS, BUT WE CAN MAKE VERY,
VERY GOOD USE OF IT AND TAKE
ADVANTAGE BECAUSE YOU CAN
PROVIDE A LOT OF INFORMATION
ABOUT WHAT WE WANT TO DO, OKAY?
SO, WHAT YOU HAVE ON THE NEXT
PICTURE IS ACTUALLY THE FIRST
INCLINATION OF A SINGLE CELL
SEQUENCING OF THE WHOLE OPTIC
LOBE OR 270 NEURONS AND YOU CAN
SEE SOMETHING STRIKING.
YOU'VE SEEN A LOT OF SINGLE CELL
SEQUENCING FROM MANY PEOPLE AND
USUALLY IT'S A BLOB WITH
DIFFERENT COLORS.
HERE YOU CAN SEE EVERYTHING IS
VERY WELL SEPARATED, ALL THE
CELL TYPES ARE VERY WELL
DEFINED.
YOU CAN SEE ALL DIFFERENT
COLORS, ALL VERY WELL SPECIFIED,
YOU CAN SEE CLUSTER OF CELLS AT
EACH WELL-CHARACTERIZED BY THEIR
SIZE.
THESE , YOU CAN GET A LOT OF
INFORMATION.
WE HAVE TRANSCRIPTOME OF ALL OF
THE CELLS THAT YOU HAVE IN THE
VISUAL SYSTEM OF THE FLY.
AND BY NOW YOU MIGHT KNOW THAT
ACTUALLY JANELIA RELEASED
CONNECTOME TO ALL OF THESE
NEURONS, THE WHOLE BRAIN OF THE
FLIES.
WE KNOW EXACTLY HOW THIS NEURON
IN BLUE CONNECTS TO THE NEURON
ORANGE, HOW THEY CONNECT TO EACH
OTHER, AND WE DON'T KNOW WHAT
THEY DO BUT WE KNOW THEY CONNECT
TO EACH OTHER AND OF COURSE
SINCE WE KNOW THE CONNECTOR,
TRANSCRIPTOME, YOU CAN FIGURE
OUT WHAT MIGHT BE INVOLVED IN
BOTH TO ALLOW THE TWO CELLS TO
CONNECT TO EACH OTHER.
SO I DON'T KNOW WHY WE GET SUCH
A GOOD SEPARATION OF THE
DIFFERENT CLUSTER.
IT MIGHT BE THEY ARE GOOD AT
DETERMINING CELL TYPE,
VERTEBRATES ARE MORE FLEXIBLE IN
TERMS OF MORE PLASTICITY AND A
CONTINUUM OF CELLS, I'M NOT SURE
WHAT HAPPENED BUT HERE THINGS
ARE GOOD.
NOW IN BLUE A LITTLE BLOB, BIG
BLOB ACTUALLY IN BLUE, WHICH IS
ACTUALLY HERE.
SO THIS BIG BLOB IS ACTUALLY
USUALLY WHEN YOU SEE A BIG BLOB
LIKE THAT IN SINGLE CELL
SEQUENCING YOU SEE SOME AMBIENTS
IN IT, WE KNOW THE MOST
IMPORTANT CELL TYPES T4 AND T 5
CELLS ARE FIRST CELL SENSITIVE
TO MOTION, T4 TO ON MOTION, T5
TO OFF MOTION, EIGHT CELL TIMES,
44 AND 45 THAT CELL GOES FRONT
TO BACK MOTION, BACK TO FRONT,
DOWN MOTION ON/OFF.
YET IN THIS SITUATION HERE WHAT
YOU CAN SEE ALL GROUPED INTO ONE
SINGLE CLUSTER, YOU CANNOT
DIFFERENTIATE FROM TRANSCRIPTION
POINT OF VIEW.
THEY DID INVOLVE IN DIFFERENT
WAYS.
WE THOUGHT BIT, INDEED MAYBE
THIS MAKES SENSE BECAUSE THOSE
CELLS DO ALL PERFORM THE SAME
COMPUTATION, COMPARE TWO POINTS
IN SPACE, MOTION ARRIVES HERE
BEFORE THAT ONE, OR THAT ONE, OR
THAT ONE, SO DOESN'T MATTER IN
THE ADULT, THEY DO EXACT SAME
THING.
WHAT MATTERS DURING DEVELOPMENT,
WHEN THEY FIND CONNECTION TO
CONNECT FRONT TO BACK, BACK TO
FRONT.
, UP AND DOWN.
WE SAID MAYBE WE SHOULD LOOK AT
THE SAME THING AND NOT DEFINE
NEURON DIVERSITY OF WHAT YOU SEE
HERE BUT BY VIRTUE OF WHAT YOU
SEE IN THE CONTEXT OF THE
DEVELOPMENT.
SO WE SAY, OKAY, LET'S DO THAT.
LET'S GO TO DEVELOPMENT AND
FIGURE OUT WHAT'S HAPPENED.
I WANT TO GO BACK, TO THE SITE
OF THE CLUSTER DOES MATTER.
ALL THOSE CELLS ARE CELLS WHICH
ARE ONE-TO-ONE TO THE BASICALLY
EXONAL PIXEL OF THE VISUAL
SYSTEM.
RUNNING IN PATTERN TO EACH
OTHER, ALL OCCUPIED BY ONE OF
THOSE CELLS, C3, MI9, WHATEVER.
CLUSTER MUCH LARGER RECEPTOR
FIELD, HAVE MUCH LOWER
STOCHIOMETRY.
WE HAVE A LOT OF INFORMATION
HERE, AND THIS IS GREAT.
AGAIN, ONE DAY WE HOPE TO
CONNECT TO THE CONNECT HOME BUT
SO FAR DIFFICULT BECAUSE WE
DON'T KNOW HOW TWO DIFFERENT
TYPES CAN ALLOW CONNECTION, HERE
IT DOESN'T ALWAYS WORK WELL.
SO WE SAY LET'S LOOK TO SEE IF
WE CAN FIND MORE RESOLUTION IN
TERMS OF SPECIFIC IDENTITY OF
THE DIFFERENT CELL TYPES.
WE DID A SINGLE CELL SEQUENCING
AT DIFFERENT TIME OF
DEVELOPMENT, 70% HERE OR 50 AND
BEFORE.
WHEN YOU GO TO THE BEGINNING,
CELL HAS BEEN JUST BORN, THE
NEURON JUST MADE IS A MATURING
AND ACTUALLY GOING TO BE -- IN
THE PROCESS OF BEING FINISHED.
NOW IF YOU LOOK AT THIS TIME OF
DEVELOPMENT HERE AROUND P50, THE
SYNAPSES ARE BEING MADE.
WE SHOULD LOOK TO CONNECT TO THE
DIFFERENT PART.
INDEED YOU CAN LOOK IN DETAIL,
YOU CAN SEE ACTUALLY INDEED
EIGHT CELL TYPES FORMING THIS
BIG BLOB IN THE ADULT FORMING
EIGHT SUBTYPES.
INDEED YOU CAN LOOK AT
RESOLUTION, CREATE RESOLUTION
DEPENDING WHEN YOU LOOK IN
DEVELOPMENT.
ANOTHER LAYER OF COMPLEXITY AND
RESOLUTION TO ADD ATAC-SEQ,
COMBINE WITH SINGLE SEQUENCING
TO FIND WHERE THE GENE NEEDS TO
BE BECAUSE CHROMATIN IS OPEN.
YOU CAN RECAPITULATE HOW EIGHT
CELL TYPES ARE BEING PLAYED
DURING THE DEVELOPMENT.
AMAZING TO ME, A SITUATION WHERE
TWO PROGENITORS HERE -- OKAY.
I'M GOING TO TRY TO USE THE
OTHER POINTER.
SO TWO OF THEM, THEY DIVIDE WITH
ASYMMETRY DIVISION, NOTCH ON,
NOTCH OFF, DIVIDE AGAIN NOTCH
ON, NOTCH OFF, YOU CAN SEE AS A
CONSEQUENCE EIGHT CELL TYPES, 44
AND 45 BEING MADE, SIMPLY BY
COMBINING TRANSCRIPTOMIC AND
ATTACK SEQUENCE, FOLLOW
TRAJECTORY AND KNOW WHICH GENE
EXPRESSED ALONG EACH ONE OF THE
TRAJECTORY, FIGURE OUT HOW THE
NETWORK IS BEING ABLE TO
FUNCTION.
OKAY.
THIS IS VERY NICE, COMPLETE
DESCRIPTION OF TRANSCRIPTOME BUT
THE QUESTION IS, OKAY, HOW DO WE
GET THERE?
HOW DO WE DEVELOP AND GET TO
DEVELOPMENT TO FIGURE OUT WHAT
HAPPENED?
HOW DO YOU GENERATE ALL THESE
MANY CELL TYPES, OKAY?
SO AGAIN FOCUSING ATTENTION TO
MEDULLA, MADE OF 40,000 NEURONS,
AND NEURONS ARE BLUE STUFF YOU
SEE HERE, ALL SEPARATED FROM THE
CONNECTION, AND 40,000 NEURONS,
BASICALLY INNERVATE THOSE 800 IN
GREEN HERE, 800 PIXEL OF THE
VISUAL SYSTEM.
IN MOUSE YOU CAN DIVIDE 40,000
BY 100, AND THEN STOCHIOMETRY,
100 NEURONS THAT PROCESS
INFORMATION.
YOU HAVE 800 REPEATED CIRCUITS
NEXT TO EACH OTHER, REPEAT OVER
AND OVER GENERAL, HELPFUL WHEN
IT COMES TO UNDERSTANDING HOW
THESE THINGS HAPPEN.
HOW DO YOU GENERATE ALL HUNDREDS
OF NEURONS THAT INNERVATE EACH
OF THE HUNDRED HERE.
HOW DO YOU MAKE HUNDRED NEURONS?
SIMPLISTIC VIEW WAS LET'S DO IT
THAT WAY.
YOU'RE GOING TO MAKE ONE NEURAL
STEM CELL, EACH WILL GENERATE
ALL HUNDRED NEURONS THAT OCCUPY
THIS.
YOU UNDERSTAND THIS MAY BE
DIFFICULT TO UNDERSTAND BECAUSE
YOU CAN MAKE HUNDRED CELLS FROM
STEM CELLS BUT NOT HUNDRED CELLS
FROM ONE GIVEN STEM CELL.
LET'S FIGURE OUT WE'RE NOT FAR
HERE.
LET ME GIVE SOME BACKGROUND IN
TERMS OF HOW THIS MEDULLA
STRUCTURE IS BEING MADE, HOW DO
YOU MAKE THIS MADE OF 800 TYPE
OF NEURON?
EVERYTHING START FROM PURPLE
HERE, AND THIS IS GOING TO BE
TRANSFORMING TO NEUROBLASTS, THE
NAME OF STEM CELLS IN FLIES,
NEUROBLASTS IN GREEN.
THERE'S A PROGRESSION OF
NEUROGENESIS, THE PURPLE CELL
WILL BECOME GREEN, GREEN-GREEN,
AFTER THREE OR FOUR DAYS PURPLE
CELLS WILL BE TRANSFORMED INTO
NEURAL CELLS.
OVER A PERIOD OF FOUR DAYS, AN
ADVANTAGE.
SO, IF YOU TAKE A PICTURE OF
THAT SCHEMATIC YOU CAN SEE YOU
HAVE THE NEUROEPITHELIUM IN
PURPLE HERE AND THEN AROUND THE
OUTER EDGE A SET OF NEURAL STEM
CELLS GET PRODUCED, THEN AN HOUR
LATER ANOTHER SET, ANOTHER SET,
ET CETERA, ET CETERA.
AND SO UNTIL ALL THE
NEUROEPITHELIUM HAS BEEN
CONSUMED.
I THOUGHT 800 NEURAL STEM CELLS
ONE FOR EACH ONE OF THE 800
RESPONDING TO 800 PIXEL.
IT'S NOT EXACTLY CORRECT BUT WE
CAN AMEND.
IF YOU MAKE A CROSS-SECTION,
FLIP 90-DEGREE, YOU SEE THE
NEUROEPITHELIUM HERE, THE
NEUROEPITHELIUM IS HERE, AND
THIS CELL OUTER EDGE OF THE
CRESCENT SHAPE WILL BECOME
NEUROBLAST, NEURAL STEM CELL.
NEUROBLAST IS A STEM CELL
DIVIDES BY RENEWING THEMSELVES
AND PRODUCING ONE CELL, OKAY,
DIVIDING ONCE MORE, ONLY ONCE
MORE, TWO NEURONS, OKAY?
SO BETWEEN EACH DIVISION OF THE
STEM CELL PRODUCE TWO NEURONS,
NOTCH ON AND NOTCH OFF NEURON,
BASICALLY NOTCH IS A POWERFUL
SYSTEM TO DISTINGUISH TWO CELL
TYPE, NOTCH ON, NOTCH ON.
TWO HOURS LATER THE NEXT
NEUROEPITHELIUM WILL DIVIDE, AND
SO ON AND SO ON.
AT THE END WHAT YOU HAVE, YOU
HAVE YOUNG NEUROBLASTS, THAT
JUST DIVIDE NOW, AND ALL
NEUROBLASTS DIVIDE A WHILE AGO,
AND FROM THIS ALL NEUROBLAST,
AND ALL NEURONS FROM THIS.
WHAT YOU CAN DO IS LABEL ONE OF
THOSE NEUROBLASTS HERE AND THEN
SEE WHAT HAPPENS.
YOU CAN SEE ON THE NEXT SLIDE,
SO IN FACT YOU HAVE EACH
NEUROBLAST MAKES LONG COLUMN OF
TWO NEXT TO EACH OTHER AND
PRODUCES MAYBE 40 OR 50 NEURONS
AT ONCE.
OKAY.
SO GOOD.
THIS IS VERY NICE.
BUT BIG QUESTION IS HOW CAN ONE
NEUROBLAST HERE PRODUCE MANY
DIFFERENT NEURONS AND EACH ONE
OF THEM SHOULD BE DIFFERENT
BECAUSE YOU NEED TO PRODUCE
HUNDRED TYPE OF NEURONS.
IT'S VERY HARD TO UNDERSTAND
EXCEPT ABOUT 25 YEARS AGO MY
COLLEAGUE AND FRIEND CAME OUT
WITH A BEAUTIFUL MODEL TO
EXPLAIN HOW AGAIN EACH
NEUROBLAST CAN PRODUCE MANY CELL
TYPES, HERE AN EXAMPLE, YOU CAN
GET MULTIPLE CELL TYPES BEING
MADE THERE, OKAY?
25 YEARS AGO WAS WORKING ON
VENTRAL NERVE CORD OF THE FLIES,
IDENTIFYING SAME TYPE OF
NEUROBLASTS, NOTICED SOMETHING
INTERESTING THAT EARLY BORN
NEUROBLAST EXPRESS TRANSCRIPTION
FACTOR CALLED HUNCHBACK, DIVIDE,
PRODUCE A NEURON WHICH EXPRESS
HUNCHBACK.
THE SAME NEUROBLAST TIRED OF
EXPRESSING HUNCHBACK WILL TURN
ON HUNCH BARK AND TURN OFF, SAME
THING FOR PDM, VERY NICE,
CONCEPT IS AMAZING.
THE CONCEPT IS THERE.
WE CAN TRY TO SEE WHO UNDERSTAND
HOW YOU CAN PRODUCE HUNDRED
NEURON THAT I DESCRIBED TO YOU
EARLIER.
WHEN THIS CAME OUT PEOPLE WORK
ON THE CORTEX, MOUSE RETINA SAY
IT'S WHAT WE NEED TO EXPLAIN, OR
WHY YOU PRODUCE LAYER SIX, FIVE,
FOUR, THREE, TWO, THIS EXPLAIN
BUT NOBODY CAN FIND SOMETHING
LIKE THAT.
NOT EXACTLY TRUE.
MICHELLE IN CANADA FINDS
SOMETHING THAT RESEMBLE SERIES
OF FOUR THREE GENES IN RETINA
WHICH KIND OF LOOK LIKE THAT BUT
I THINK IT'S SLIGHT DIFFERENT
MECHANISM.
WE SAY IN FLY, MUCH CLOSER IN
TERM OF MECHANISM, IMAGING
SYSTEM, WHAT YOU HAVE HERE IS
SYSTEM WHEREABOUTS BY IN ONE
SNAPSHOT EARLY BORN NEUROBLASTS,
THEN LATE BORN NEUROBLASTS, YOU
CAN EXPRESS THIS EXPRESSES
HUNCHBACK, AND IN ONE SNAPSHOT
YOU COULD SEE EVERYTHING.
WE FAILED COMPLETELY, NONE WOULD
EXPRESS HERE BUT WE FIND
SOMETHING A LOT NICER BECAUSE WE
FIND THE SAME THING, SAME
CONCEPT EXCEPT THE GENE WERE
DIFFERENT.
INSTEAD OF FOUR GENES WE GET SO
FAR SIX OR SEVEN AND THEN YOU
CAN SEE MORE LATER.
YOU CAN FIND EACH EXPRESSING
GENE CALLED HOMOTHORAX, ERMs,
AND THEN HOMEO BRAIN.
NOW POSSIBILITY OF MAKING SIX OR
SEVEN TEMPORAL WINDOWS THAT
COULD PRODUCE SIX OR SEVEN
DIFFERENT TYPE OF NEURON.
IT WAS VERY NICE.
THE PICTURE I SHOWED EARLIER IN
THE FIRST SLIDE IS EXACTLY THIS.
TOP VIEW OF THE NEUROREPEATER,
HERE, NOT CONSUMED, EARLY BORN
NEUROBLAST EXPRESSED GENE HOMEO
THORAX, I WANT TO SHOW YOU, YOU
CAN SEE WHAT HAPPENED IN REAL
LIFE, INDEED EACH ONE OF THE
CELL BECOME -- GOES THROUGH THE
SERIES WHEREBY IT EXPRESSES
HOMEOTHORAX, AND THE YOUNG
NEUROBLASTS LATER EXPRESS, NOW
USED TO BE YOUNG AND EXPRESS
HOMEOTHORAX.
SHORT OF THE HUNDRED WE WANT TO
GENERATE.
SO, THE RULE OF THE GAME HOW
DOES THIS FUNCTION?
HOW CAN SERIES OF TRANSCRIPTION
FACTOR EXPRESS IN VERY SAME
CELL?
THE SYSTEM WORKS QUITE WELL.
WHAT HAPPENED THERE, AGAIN,
NEUROBLAST IS BORN AND EXPRESS
THE TRANSCRIPTION FACTOR.
IF YOU DO MUTATION, YOU CAN SEE
WHAT'S GOING HAPPEN. IN FACT,
YOU KEEP GOING TO THE DIVISION
BUT YOU GET STUCK INTO THE ITEM
WORLD WINDOW SIMPLY BECAUSE GENE
X ACTIVATES GENE X PLUS ONE, X
MINUS ONE ISLET.
THERE WAS SLIGHT VARIATION BUT
THE RULE SEEMS TO APPLY, A WAY
THE SYSTEM PROGRESS IS SIMPLY
TRANSCRIPTION NETWORK ACTIVATES,
B,C,D, IN FACT YOU CAN -- THIS
IS WHAT HAPPENED HERE.
SORRY.
AND WHAT HAPPENED THIS SERIES IS
GOING TO HAPPEN AND BASICALLY BE
ABLE TO PRODUCE A NUMBER OF
NEURON.
SO AGAIN SHOW YOU SAME PICTURE
ALL OVER AGAIN TO POINT
SOMETHING HERE BASICALLY WHAT
GOES WRONG, THERE'S MANY
NEUROBLAST HERE, DON'T EXPRESS
ANY KNOWN TRANSCRIPTION FACTOR.
THE WAY WE GOT THE HUNCHBACK,
SIMPLY IN THE FRIDGE, ALSO DEEP
INSIGHT.
SO WE SAY LET'S TRY TO SEE
WHETHER WE CAN FIND A WAY TO GET
SOMETHING MORE SYSTEMATIC TO
EXPRESS, TO IDENTIFY ALL OF
THOSE TRANSCRIPTION FACTOR WHICH
EXPRESS IN THE NEURONS IN THE
PICTURE HERE.
LET'S TAKE THIS STRUCTURE HERE
AND YOU CAN SEE ONE SNAPSHOT
AGAIN, ALL NEUROBLASTS, ALL
STAGE OF DEVELOPMENT.
LET'S TAKE THIS AND SEQUENCE
THEM AS A SINGLE CELL LEVEL TO
SEE WHICH ONE EXPRESS WHICH
GENE, MAYBE TRY TO ORGANIZE INTO
A PATHWAY.
YOU'LL SEE IT WORKS BEAUTIFULLY
WELL.
WHAT YOU HAVE HERE AGAIN A
PICTURE NOT AS PRETTY WITH ALL
THE BEAUTIFUL YOU SEE BEFORE
BECAUSE NOW IT'S PROCESS OF
DEVELOPMENT, BASICALLY
EVERYTHING IN PROCESS OF
DEVELOPING.
WHAT YOU HAVE HERE, YOU HAVE
THE -- OKAY.
SO YOU HAVE THE NEUROBLAST HERE,
OKAY?
AND NEUROBLAST HERE.
THEN YOU HAVE THE NEURONS AND
NOW THE NEURONS THE BEAUTIFUL
BLOT ELONGATED STRUCTURE
CORRESPOND TO MATURATION OF THE
NEURONS, AND UNTIL THE
TRAJECTORY, AT THE OTHER
TRAJECTORY IF YOU LOOK AT THE
NEXT STEPS, ONE GROUP OF CELLS I
SHOWED YOU BEFORE, IF YOU ADD
THEM TO THE SYSTEM YOU CAN SEE
THAT ADDED TO THE TIP OF EACH
ONE OF THE DIRECTION, OKAY?
SO YOU CAN SEE NOW YOU CAN
RECONSTRUCT PRECISELY WHAT
HAPPENS BETWEEN THE -- SORRY.
I HAVE SOME PROBLEM WITH THE
POINTER.
SO YOU CAN SEE HERE THAT YOU CAN
GO FROM NEUROBLAST, SO
NEUROREPEATER, NEUROBLAST,
DEVELOPING NEURONS, MATURE
NEURONS, YOU CAN SEE AGAIN
TRAJECTORY COMPLETELY, YOU CAN
REALLY UNDERSTAND HOW YOU CAN
MATURE AND PRODUCE THOSE
NEURONS.
BUT LET'S LOOK AT THE
NEUROBLAST, YOU CAN SEE THERE'S
SOME STRUCTURE WHICH EXISTS HERE
IN THE SENSE THEY ARE NOT
JUST -- IT'S VERY STRUCTURE,
WHEN YOU CLOSE YOU GET SOMETHING
VERY SURPRISING BECAUSE YOU SEE
EXACTLY WHAT YOU EXPECT BECAUSE
THESE ARE PURE COMPUTER
RENDERING, JUST WHAT THE
COMPUTER SPITS OUT.
YOU CAN SEE AT THE BOTTOM WHAT
YOU HAVE.
EXACTLY WHAT YOU SEE ON THIS
PICTURE.
WE CAN REPRODUCE WITH COMPUTER
WHAT HAPPENED IN REAL LIFE.
EXCEPT ON THE MAP YOU CAN SEE A
LOT OF NEURAL BLASTS WHITE,
EXACTLY WHAT THE CONTENT IS
BECAUSE OF SINGLE CELL
SEQUENCING.
YOU HAVE ORGANIZATION DUE TO OUR
SERIES THAT WE KNEW, YOU CAN SEE
WHAT IS GOING TO BE ABLE TO
IDENTIFY ALL THE TRANSCRIPT
FACTOR IN BETWEEN, AND WHAT YOU
SEE HERE IS EXACTLY THAT.
YOU CAN RECOGNIZE ON THE X-AXIS
HERE, COMES BACK A SECOND TIME,
I WILL COME BACK THERE'S TWO
WINDOWS OF EXPRESSION, WE GO
BACK TO OUR FRIEND ISLET, THE
NEW ONE, NOW WE HAVE THE
COMPLETE SERIES OF TRANSCRIPTION
FACTOR FROM TIME WHEN THE
NEUROBLASTS WERE BORN TO THE
TIME BASICALLY THE NEUROBLASTS
ARE GOING TO DIVIDE AND FINISH
THEIR LIFE HERE.
YOU CAN SEE THE POWER OF SINGLE
CELL SEQUENCING AND SOFTWARE TO
BE ABLE TO PROCESS THE DATA IN
SUCH A WAY YOU CAN ORGANIZE INTO
VERY SPECIFIC WAYS.
YOU CAN DO THE SAME THING AS I
DESCRIBED.
MOST OF THE GENE, X PLUS ONE,
BASICALLY ARE OPEN.
INDEED FOR EXAMPLE HOMOTHORAX,
AT SOME POINT GOING TO OVERLAP
WITH EACH OTHER, AND TEMPORAL
WINDOW IS COMBINATION OF TWO OR
THREE OF THE TRANSCRIPTION
FACTOR WHICH ACTUALLY I SHOW IN
THE NEXT SLIDE.
AGAIN, NEUROBLAST HERE, WHEN
YOU'RE BORN EXPRESS HOMOTHORAX,
DITCHED TO -- DIVIDE TO PRODUCE
A CELL.
HOMOTHORAX IS STILL THERE.
THEN WE TURN OFF, TURN ON ERM,
SO ON.
I THINK YOU WILL SEE THIS IS NOT
SO EASY TO DEFINE, EXACTLY DON'T
KNOW WHEN THE TRANSITION OCCUR.
BUT NOW WE HAVE TWELVE TEMPORAL
WINDOWS, SPECIFY AT LEAST TWELVE
TYPE OF NEURON, SHORT OF THE
HUNDRED WE WANT TO DO.
BECAUSE EACH DIVISION HERE YOU
HAVE ANOTHER DIVISION DIVIDE
WITH NOTCH ON, NOTCH ON, GREEN
AND RED NEURON.
IN FACT CAN MULTIPLY TWELVE
WINDOW BY TWO, GET 24 CELL
TYPES.
WE'RE GETTING THERE.
WE CAN SPECIFY 24 CELL TYPES BY
THIS TEMPORAL SERIES OF
TRANSCRIPTION FACTOR.
NOW WE HAVE ACTUALLY SOLVED A
MAJOR ISSUE, WE'VE NOW -- HOW
TIME CAN BE INVOLVED IN PROCESS,
WHAT IS THE MECHANISM BY WHICH
TIME IS INVOLVED BY THE THEORY
OF TRANSCRIPTION FACTORS THAT
CONTROL EACH OTHER AND THEN
GENERATE NEURONS BELOW THEM AS A
CONSEQUENCE OF BEING SPECIFIC
TRANSCRIPTION FACTOR IN THE
GENOME.
SO BUT WHAT ABOUT THE OTHER 75
NEURONS WE NEED TO MAKE?
WE ONLY MAKE 24 YEARS.
WE OBSERVE WAY BEFORE THE
NEUROBLASTS ARE BORN, WHAT I
TOLD YOU IS TRUE FOR ALL THE
NEUROEPITHELIUM CELLS, HEMO
THORAX, IN SPITE OF THAT SHOW
DIFFERENT IN TERMS OF WHERE THEY
ARE.
WHICH MEANS TIP OF THE CRESCENT
EXPRESS RX, FAMOUS FOR ITS ROLE
IN EYE DEVELOPMENT IN MOUSE.
OPTIX, VSX, ALSO INVOLVED IN
DEVELOPMENT.
YOU CAN SEE DORSO PATH OR
VENTRAL PART OF THE PATHWAY, SIX
DOMAINS, RX, OPTIX, VSX VENTRAL.
DOMAIN DO PLAY A ROLE IN
SPECIFYING THE NEURON.
HERE YOU HAVE THIS ILLUSTRATION,
JUST THE FIRST TEMPORAL WINDOW.
NEUROBLAST JUST BORN, EXPRESS
HEMOTHORAX, PRODUCE MI-1, AND
NOW UNICHROME, ONE FOR EACH.
AND EACH OF THE NEUROBLASTS ARE
GOING TO PRODUCE MI-1, ALL
PRODUCE ONE.
BUT THEN YOU CAN DO MORE DETAIL
FOR SERIES, THERE'S ACTUALLY ALL
THE NEURONS BEING PRODUCED, FOR
EXAMPLE PM3 ONLY PRODUCED BY THE
VSX DOMAIN OR PM 2, OR PM 1
PRODUCED BY THE VENTRAL, WHICH
MEANS OF COURSE THEY ARE GOING
TO PRODUCE IN A SMALLER AMOUNT,
SMALLER STOICHIOMETRY.
NOW THINGS BECOME CLEAR.
SINCE YOU HAVE AT LEAST SIX
DOMAINS OF DIFFERENT, EACH
DOMAIN APPEAR TO PRODUCE
DIFFERENT NEURONS, WHAT IS SOME
OF THE NEURONS APPEAR TO CARE
WHERE THEY COME FROM, THEREFORE
WHAT YOU CAN SEE YOU CAN
MULTIPLY THE 24 TYPES OF NEURONS
YOU CAN PRODUCE, MULTIPLY SIX
SPECIAL DOMAINS, GET 144 NEURON
TYPES, LARGE ENOUGH TO EXPLAIN
HOW YOU CAN PRODUCE ALL THE
NEURONS.
SO I THINK WE HAVE NOW A DEEP
UNDERSTANDING OF HOW THOSE
DIFFERENT TYPES OF NEURONS CAN
BE BORN AND HOW THEY CAN BE
GENERATED BY COMBINATION OF
TEMPORAL SERIES, SPECIAL
INFORMATION, ALSO NOTCH ON/NOTCH
OFF THAT DOUBLES THE NEURONS.
SOMETHING TO BE SOLVED HERE, WHY
DO YOU HAVE NEURONS LIKE RED WE
KNOW WHERE IT COMES FROM, OR
BLUE DO CARE WHERE THEY COME
FROM, FROM VSX, DORSAL OR
VENTRAL.
WE TRIED TO IDENTIFY ALL THE
NEURONS THAT COME FROM EACH ONE
OF THE DOMAIN.
WHAT YOU CAN SEE AGAIN CRESCENT
SHAPE, HERE IN GREEN MARKER ONLY
LABELS NEURON THAT COME FROM
DORSAL OR VENTRAL, THE TIP.
YOU CAN IDENTIFY THE NEURONS
THAT COME FROM THAT.
I COULD LIST HUNDRED NEURONS,
THOSE NEURONS FOR EXAMPLE TM5
A-B FROM DORSAL OPTICS AND A BIT
OF THE VSX, SO ON, AND EXPLAIN
HOW THOSE DIFFERENT NEURONS ARE
BEING PLAYED FROM DIFFERENT
DOMAINS.
A NUMBER OF NEURONS STOCHIOMETRY
DEMEANT ON THE SIZE OF THE
NEUROREPEATER.
WELL ILLUSTRATED HERE FROM THE
WORK OF A POSTDOC IN THE LAB,
YOU CAN SEE CRESCENT SHAPE,
DIFFERENT DOMAIN, SOME OF THE
NEURON IS ACTUALLY INTERNAL
NEURON PRODUCED FOR EXAMPLE VERY
LARGE NUMBER, THE WHOLE
NEUROREPEATER WHEREBY NEURON
WHICH HAVE SMALLER STOCHIOMETRY
PRODUCE SMALLER DOMAIN, THIS
COMES FROM A VERY TINY DOMAIN.
YOU CAN ESTABLISH CORRELATION
BETWEEN THE SIZE OF DOMAIN WHERE
THEY COME FROM AND STOCHIOMETRY
OF THE NEURON.
YOU CAN IMAGINE YOU CAN KNOW HOW
YOU CAN COMBINE ALL THE FEATURES
TEMPORAL, SPATIAL, NOTCH, THE
SITE OF THE DOUGH DOMAIN TO PRE
ALL IN STOCHIOMETRY.
EVERYTHING WAS GOOD.
THERE WAS A PROBLEM WE CAME AT
SOME POINT, SOMETHING I DIDN'T
EXPECT VERY MUCH.
AGAIN, I TEND TO HAVE KIND OF
DOGMATIC VIEW OF THE WORLD.
EVERYTHING SHOULD BE GOOD MODEL
AND SHOULD FIT VERY WELL.
YOU WORK ON FLIES, THIS WORKS
QUITE WELL.
THE MODEL WOULD BE THAT YOU HAVE
800 NEUROBLASTS THAT PRODUCE ALL
THOSE NEURONS.
BUT IN FACT WHEN YOU REALIZE IN
DETAIL, THIS WASN'T THE CASE.
YOU HAVE ON THE LEFT SIDE
NEUROEPITHELIUM IN BLUE, AND
NEUROBLASTS FORMED AT THE OTHER
EDGE AS A WAVE FROM THE OUTER
EDGE OF THE NEUROEPITHELIUM TO
THE CENTER.
IN PURPLE, MI1, I SHOWED YOU,
THERE WAS DISCREPANCY HERE.
A NUMBER DID NOT CORRESPONDS TO
NUMBER OF NEUROBLASTS PRODUCED
HERE, MORE DRAMATIC WHEN THE
MORE NEUROEPITHELIUM HAS BEEN
PRODUCED, AND DIGESTED, EATEN BY
NEUROBLASTS, MANY FOR COMPARED
TO MI1.
2,000 FOR 800 MI1.
THERE'S SOMETHING WRONG HERE.
WHY DO YOU HAVE MORE NEURONS,
MORE NEUROBLASTS THAN NEURONS,
THE MODEL PRODUCED WAS GREAT, IF
YOU HAVE 2,000 YOU SHOULD SEE AT
LEAST 2,000 MI1s, WHICH WAS
NOT THE CASE.
WAY CAME UP WITH THE -- WE CAME
UP WITH THE FOLLOWING SITUATION.
FIRST TEMPORAL MI1, TM1, 4,
LATER ON 2, 6.
AND THE IDEA WILL BE THAT THIS
HAPPEN WHENEVER CELL CYCLE
DIVISION OCCURS IN THE MI1
WINDOW OR TM1, ET CETERA.
YOU THINK THERE'S NO REASON WHY
IT COULD BE COORDINATED CAN
TEMPORAL WINDOWS.
YOU NEED TO REGROW TO BE ABLE TO
DIVIDE AGAIN.
THERE'S NO REASON THIS SHOULD BE
SYNCHRONIZED WHICH DEPENDS ON
THE NETWORK WHERE HEMO THORAX
ACTIVATE ISLETS.
WHAT HAPPENS IF YOU DISCONNECT
CELL CYCLE FROM TEMPORAL WINDOW
PROGRESSION?
INDEED IN PARTICULAR CELL CYCLE,
THEN THE PROGRESSION OF THE
TEMPORAL WINDOW YOU COULD
IMAGINE IN FACT NOT EVERY
TEMPORAL WINDOW WILL BE HIT BY
CELL CYCLE BY DIVISION AND
THEREFORE FOR EXAMPLE IN THIS
CASE MI1 WINDOW WILL NOT BE HIT
BY A CELL CYCLE, NOT PRODUCED
HERE BUT TM 1 OR 4, MAYBE NO TM
6, AND SO ON.
LET'S TRY TO SEE THAT.
TO SOME EXTENT, TM 6 HERE, MAYBE
THE NEXT NEUROBLAST WILL
INTRODUCE A TM 6 AND NOT A TM 2.
IT WILL AVERAGE WHEN 2,000
NEUROBLASTS ONLY PRODUCE MI 1
EVERY 2 1/2 NEUROBLASTS
BASICALLY YOU WILL GET BASICALLY
THE CORRECT STOCHIOMETRY FOR
EACH OF THE NEURON.
VERY NICE BUT CAN WE TEST
WHETHER TRUE?
WE CAN DO THAT BECAUSE YOU CAN
TEST WHAT HAPPENED TO THE
LINEAGE EACH OF THE SINGLE
NEUROBLASTS.
YOU CAN SEE THE NEURON IS BORN,
PRODUCE MI 1 NOTCH ON, A FEW
CELL TYPES HERE.
TM 2 AND TM 6.
DO WE SEE EVERY NEUROBLAST
PRODUCE ALL THOSE EXPECT ALL
THESE?
AND IN FACT THE WAY WE DO THAT
WE LOOK ONLY ON THE NOTCH ON
LINEAGE, GREEN LINEAGE, BECAUSE
WE HAVE A MOCKUP FOR THAT AND
TRANSCRIPTION FACTOR WHICH
REMEMBER I TOLD YOU THERE WAS
THIS TEMPORAL TRANSCRIPTION
FACTOR WHICH EXPRESSED ONLY IN
TWO DIFFERENT WINDOWS OF THE
TEMPORAL SERIES, AND TURNS ON
ANOTHER GENE, SO FOUR CELL
TYPES, TM 1, TM 4, TM 2, TM 6,
WITH JUST ONE MARKING YOU CAN
IDENTIFY LINEAGE, NOT BECAUSE
IT'S GREEN AND SO FOUR CELLS YOU
EXPECT TO FIND.
NOW WE'RE GOING TO LOOK ONE BY
ONE AT MULTIPLE DIFFERENT
NEUROBLAST LINEAGE TO SEE
WHETHER THEY FOLLOW THIS FULLY
HERE, OKAY?
SO, YOU CAN GENERATE IN FLIES,
ANALYZE IN DETAIL.
HERE TWO EXAMPLE OF CLONES, THE
CLONES STARTED HERE, PRODUCED
THIS, AND NEUROBLAST WAS AT THE
END, IN FACTS JUST DISAPPEARED
BECAUSE IT DIED.
AND FOUR TYPE OF NEURONS,
BASICALLY LET ME TRY TO SHOW YOU
IN DETAIL THE RESULTS IN YOU
INTERPRET THEM.
AGAIN THE CLONE, YOU CAN SEE
THIS CLONE CONTAIN TM 1 AND TM 4
AS EXPECTED BUT CONTAIN NO TM 2,
NO TM 6.
THIS ONE CONTAINS 1 TM 2, NO 6,
AND SO ON AND SO ON WHICH IS
EXACTLY WHAT YOU EXPECT, EACH
NEUROBLAST LINEAGE DEFER FROM
NEXT BUT OVERALL THE WHOLE THING
DISCOVERED, THAT MEANS ALL THE
NEUROBLASTS TOGETHER WILL
PRODUCE ALL THE NEURONS YOU NEED
MAKE.
THE INTERPRETATION WILL BE THIS
WILL BE THE LINEAGE EVERY
NEURON, EVERY TEMPORAL WINDOW
WAS BEING USED BUT IN FACT YOU
CAN SEE DEEPENING EACH ONE OF
THE LINEAGE ONLY SOME SUBSETS
BEING USED?
WHY DO WE HAVE THE
STOCHASTICITY?
IT MIGHT BE FOR PLASTICITY,
ROBUSTNESS OF SYSTEM, MIGHT BE
BECAUSE IT'S DIFFICULT TO
COORDINATE THE NUMBER OF CELL
CYCLE WITH NUMBER OF CELL
DIVISION, AND OF COURSE THIS
WILL REQUIRE ADJUSTMENT AT THE
END, WHAT YOU CAN SEE YOU NEVER
PRODUCE MORE THAN THE NUMBER OF
NEURONS AND SEE YOU'RE GOING TO
ELIMINATE THEM.
SO, IT SEEMS WHAT WE'VE DONE
HERE IS GO INTO DETAIL, AND THE
ONLY THING WE DON'T KNOW REALLY
WHAT HAPPENS, WHY DO WE HAVE THE
TEMPORALS WE DESCRIBE HERE AND I
MADE THEM AS TEMPORAL WINDOWS,
YOU OPEN AND CLOSE BECAUSE IT'S
A TRANSCRIPTION NETWORK,
TRANSITION FROM ONE TO THE NEXT
IS NOT A SHARP WINDOW.
IT'S A DIFFUSE WINDOW AND WE
DON'T KNOW HOW YOU CONNECT
SYSTEM WITH POSITIVE FEEDBACK
WHERE YOU'RE GOING TO MAKE A
DECISION, THIS WINDOW, THAT
WINDOW, NOTHING IN BETWEEN.
WE DON'T KNOW WHAT HAPPENS AND
WE'RE STILL WORKING ON FIGURING
OUT WHAT'S GOING ON THERE.
SO, OOPS.
WHAT'S GOING ON?
I WANT TO GIVE CREDIT TO PEOPLE
THAT HAVE DONE THE WORK IN THE
LAB.
THIS WAS INITIATED BY NIKOS, NOW
A PROFESSOR IN PARIS.
ALL THE LATER WORK DONE BY
FELIX, A STUDENT IN THE LAB,
ALSO JOINED NIKOS IN PARIS, AND
TOOK A JOB, AND A CURRENT
Ph.D. STUDENT.
ONE DAY I TELL YOU EVERYTHING
ELSE WE DO ON THE FLIES,
DIFFERENT SYSTEM ON THE FLIES,
ALSO THE WORK IN COLLABORATION
ON THE ANTS.
I WANT TO THANK YOU VERY MUCH.
AGAIN, VERY PROUD TO BE HERE
TODAY AND TO BE ABLE TO TELL YOU
THIS STORY AND THANKS TO ALL OF
YOU.
[APPLAUSE]
>> ALL RIGHT.
CLAUDE, WONDERFUL, AND VERY
COMPLEX TALK.
I MEAN, I HAD QUESTIONS ALONG
THE WAY BUT YOU ANSWERED SOME OF
THEM, BUT SOME REMAINING.
LET ME BEGIN FROM THE BOTTOM UP.
ONE OF THE THINGS YOU SAID THERE
ARE A LOT OF NEUROBLASTS, 2,000
OR SO.
AND YOU EXPECTED ONLY 800, ONE
FOR EACH.
I'M NOT SO SURE WHY BECAUSE YOU
ANSWERED THAT QUESTION OBVIOUSLY
THAT NOT EVERY NEUROBLAST HAS TO
PRODUCE ALL THE CELL TYPES,
RIGHT?
ALONG THE SAME WAY, DID YOU
CONSIDER THE POSSIBILITY THAT
CELL CYCLE TIME CAN BE DIFFERENT
AT DIFFERENT TEMPORAL AND
SPATIAL REGIONS?
IT DOESN'T HAVE TO BE PRECISELY
IDENTICAL.
AND THAT ALSO CAN CREATE
DIFFERENT ISSUES, SIMILAR THERE
COULD BE SOME MIGRATION OF CELLS
AT DIFFERENT TIMES AS WELL,
WHICH COULD CHANGE THEIR NATURE.
AND THEN AGAIN THERE MAY BE
CELLS WHICH INTERACT WITH EACH
OTHER, THEY MAY BE GIVING
DIFFERENT SIGNALS, AND THAT
COULD CREATE FURTHER NEURONAL
DIVERSITY, SO MANY DIFFERENT
WAYS, SO I'M NOT SURE WHY SUCH A
MATHEMATICAL WAY WE HAVE TO SHOW
THIS, AND ON TOP OF ALL THAT
MOST OF THE TIME YOU TALKED
ABOUT QUALITATIVE STUFF, AMOUNT
OF TRANSCRIPTION FACTOR, BASED
ON IN SOME CASES ISC BUT SR RNA
YOU WERE TALKING ABOUT RNA.
BUT QUANTITATIVE ISSUES,
TRANSCRIPTION FACTORS IN
DIFFERENT QUANTITIES CAN HAVE
DIFFERENT FUNCTIONS.
SO THERE ARE LOTS OF THINGS, MY
FRIEND, WE STILL HAVE TO ANSWER.
A LONG WAYS TO GO.
>> YOU ASK FIVE OR TEN QUESTIONS
AT THE SAME TIME.
AND IT WOULD TAKE AN HOUR TO
ANSWER TO YOU, FIRST THING I CAN
ANSWER THAT CELL TYPE.
YOU SAY THERE MAY BE MODULATION
OF CELL TYPE OR PLASTICITY, AND
I THINK TO SOME EXTENT WE CAN
START IN FLIES BECAUSE FLIES
HAVE NO PLASTICITY.
THEY ARE BORN, LIVE FOR A FEW
DAYS OR WEEKS AND DIE.
THEY DON'T CARE ABOUT
PLASTICITY.
WHETHER THE CELL CYCLE CAN VARY
IN SPEED, WHETHER TEMPORAL
WINDOW CAN BE LONGER OR SHORTER
I AGREE.
WE SEE DIFFERENT IN CELL CYCLE.
IN FACT CELL CYCLE GETS LONGER
WITH TIME.
BUT, YOU KNOW, SIMPLY NATURE FOR
EXAMPLE MAKING LONGER TEMPORAL
WINDOW, CELL CYCLE SLOWS DOWN.
OR MAKING SMALLEST DOCUMENTARY
BECAUSE YOU CAN ALSO ADDRESS
DOCUMENTARY BY THE SPACE BY
WHICH THEY COME FROM BUT THE
FREQUENCY AT WHICH THEY ARE HIT
BY TEMPORAL WINDOW, WE CAN
DISCUSS MAYBE TONIGHT OR ANOTHER
DAY, WE SEE EACH OTHER.
THANK YOU.
>> SO IF THE SPATIAL WINDOWS FOR
THE MORE RARE CELL TYPES ARE SO
RESTRICTED, YOU WOULD THINK
THERE HAS TO BE A LOT OF
TANGENTIAL MIGRATION GOING ON.
>> THE CELLS ARE BEING MADE IN
THE SAME PLACE, I'M TALK BECOME
THE VERTICAL, LOWEST COMING FROM
THE SMALL DOMAIN.
ONE CLONE, THEY STAY THERE, THEY
SEND PROJECTION THAT COVER THE
WHOLE RETINA, THEN THEY DO WHAT
YOU SAY, DON'T MIGRATE.
I THINK THEY MOVE, I THINK,
BECAUSE SHORTEN AXONS TO BE
CLOSER TO PROJECTION.
THEY DO THE CELL MOVEMENT.
WE'RE INTERESTING TO FIGURE OUT
RETINOPATHY, WE'RE WORKING QUITE
HARD, MY NEXT GRANT FROM NEI
WILL BE ON THIS TOPIC, AND WE
IDENTIFY THE FACT THAT PCP
PATHWAY APPEARS TO BE INVOLVED
IN THE PROCESS OF FINDING OUT
WHERE PROJECT AXONS.
THERE'S EXAMPLE OF CELL
MIGRATION IN FLIES.
AGAIN ALSO TOPIC OF ANOTHER
GRANT, BUT IT'S ACTUALLY A
SPECIAL TYPE OF CELL THAT DOES
MIGRATES, THE WAY YOU EXPECT
CELL TO MIGRATES AND SENDS
PROJECTIONS.
>> THANKS.
>> THIS IS REALLY A FANTASTIC
LECTURE AND I HAVE TO
CONGRATULATE YOU ON YOUR COLOR
SELECTION.
BRILLIANT.
I'M MORE INTERESTED IN THE
PROCESS OF HOW NOTCH IS TURNING
ON AND OFF IN YOUR VERY FIRST
STEP.
WE KNOW A LITTLE MORE ABOUT
SEGMENTATION OF THE DORSAL CORD
AND VERTEBRAL DEVELOPMENT WHEN
THE NOTCHES TURN ON AND OFF,
ESPECIALLY ON THE EPIGENETICS OF
CHROMATIN MODELING.
IS THERE SIMILARITY OF THE NOTCH
ON AND OFF IN YOUR SYSTEM?
HAVE YOU LOOKED --
>> SO NOTCH HAS BEEN DISCOVERED
IN FLIES, MOSTLY WHAT'S CALLED
LATERAL INHIBITION, TWO CELLS
DIVIDE EXACTLY THE SAME, THIS
TUG OF WAR ONE WILL BE NOTCH ON,
ONE NOTCH OFF.
BECOME A NEURON, THE WAY TO
DESCRIBE WHAT I TEACH MY
STUDENTS.
WHAT HAPPENS TWO CELLS DIVIDE,
ONE BECOMES NOTCH ON, ONE NOTCH
OFF.
THIS IS A STRONG DECISION
BECAUSE BEING NOTCH ON IS
DIFFERENT FROM NOTCH OFF.
ALL NOTCH-ON NEURONS -- NOTCH --
VERY STRONG DECISION, INHIBITORY
PATHWAY, CRITICAL NOTCH PATHWAY,
I'M A, YOU MUST BE B.
I'M A, YOU'RE GOING TO BE B.
TUG OF WAR BETWEEN TWO CELLS.
ACTUALLY THE MOLECULAR NATURE OF
THE REGULATION, AUTOREGULATION,
NOTCH ACTIVATES ACTIVITY, NOTCH
RECEPTOR, LACK OF NOTCH ACTIVITY
INHIBITS NOTCH, ACTIVATES DELTA,
OKAY?
>> GREAT TALK.
I'M WORKING ON GENETICS, I KNOW
FLY IS GREAT MODEL FOR GENETICS
TOO.
I'M JUST WONDERING IS THERE ANY
STUDY WHERE PEOPLE HAVE LOOKED
AT THE MUTANTS, THE STUDY,
WHETHER A PARTICULAR TYPE OF
CELL --
>> YEAH, VERY COMPLEX QUESTION,
WE CAN MAKE MUTATION AT WILL,
CELL SPECIFIC NATURE OF THE
MUTATION, OVERALL I MEAN YOU CAN
SAY THINGS FOLLOW WHAT TRY TO
DESCRIBE SO SKIPPED A LOT OF
STEPS WHERE WE MADE SURE THIS
WAS ACTUALLY CORRECT SO, FOR
EXAMPLE, IF YOU INTERRUPT THE
TEMPORAL SERIES YOU CAN SEE THE
TEMPORAL SERIES BLOCKED BECAUSE
YOU CANNOT PROGRESS BUT CELL
CYCLE DIVIDE.
YOU CAN ALSO PREVENT CELL CYCLE
FROM OCCURRING, BLOCK CELL
CYCLE, TEMPORAL IS GOING.
OR YOU CAN ACTUALLY CHANGE THE
SPECIFIC NEURON, MAKE TWO
NEURONS OF THE SAME CELL TYPE,
ONE DIE, A LOT OF THINGS CAN
DESCRIBE WHICH I CANNOT DO IN
THIS TALK.
MOST OF THE WORK WE DO IS, YOU
KNOW, BESIDE SINGLE CELL
SEQUENCING IS DOING CROSS IN FLY
WITH MUTANTS, LOOKING AT
MICROSCOPE.
>> GREAT.
THANK YOU.
>> CLAUDE, THANK YOU SO MUCH.
ANY OTHER QUESTIONS HERE THAT
PEOPLE WANT TO ASK ABOUT OR TALK
ABOUT?
OKAY.
LET ME TRY TO SUM THINGS UP
HERE.
I THOUGHT THIS WAS A BEAUTIFUL
TALK.
JUST THANK YOU VERY MUCH, AND
CONGRATULATIONS FOR DOING THIS.
YOU KNOW, FOR US.
YOU KNOW, JORAM, YOU MENTIONED
AT THE BEGINNING HAD YOU A
PHRASE.
TAKING THE WORLD TO THE EYE.
AND TAKING THE EYE TO THE WORLD.
AND I REALLY LIKE THAT.
I'VE BEEN THINKING ABOUT THAT
FOR THE PAST HALF HOUR.
AND I THINK THERE WERE SOME
GREAT EXAMPLES, CLAUDE, THAT YOU
GAVE OF BOTH OF THOSE
DIRECTIONALITIES.
YOU KNOW, ANATOMY, PHYSIOLOGY,
DEVELOPMENTAL, NEUROSCIENCE.
STOCHASTIC PROCESSES, SEEMED
LIKE SORT OF MACHINE LEARNING.
I THOUGHT THIS WAS A BEAUTIFUL
EXAMPLE OF ALL THOSE THINGS,
WHAT I HOPE THIS IS REALLY ALL
ABOUT.
AND SO JUST A BIG WORD OF THANKS
TO YOU.
AND JORAM AND LONA, THANK YOU
FOR YOUR WORK IN MAKING THIS
POSSIBLE.
TO STEVE AND THE FNIH GROUP,
THANK YOU FOR WHAT YOU'VE DONE
WITH THIS.
BEHIND THIS IS A SELECTION
COMMITTEE.
AND JEREMY NATE ANSWER, KAPIL
AND OTHERS WHO AREN'T HERE.
CONNIE, BOB, CAROL, DAN, THEY
HAVE DONE A LOT OF WORK LEADING
UP TO THIS.
AND OF COURSE THERE ARE PEOPLE
FROM STEVE'S CREW AT THE FNIH
AND OUR CREW WHO WORKED ON THIS.
STEVE, I KNOW THAT THERE WAS
REGINA, MOLLY, ASHLEY IN THE
BACK THERE.
AND FROM THE NEI GROUP, FROM
KAPIL'S GROUP, DAVID, PRINCESS,
CHARLES, AND KATHERINE, YOU
KNOW, DEMOTT, GREAT WORK.
I HAVE TO SAY THAT, YOU KNOW,
THOSE OF YOU WHO ARE AT NEI KNOW
I'VE REALLY BEEN TRYING TO
COMMUNICATE THE REALLY NEED WORK
THAT HAPPENS IN THE VISION SPACE
TO PEOPLE OUT THERE.
AND SOMETIMES I SEE A PAPER THAT
IS REALLY NEAT, I'LL MAKE A FLAG
AND POST IT ON SOCIAL MEDIA.
SOMETIMES KATHERINE DEMOTT AND
MARIA WILL POST BIT.
A LOT OF PEOPLES HAVE BEEN FROM
CLAUDE DESPLAN'S GROUP TO THE
POINT A COUPLE TIMES I
INTERCEPTED AND SAID WE HAVE TO
POST ABOUT SOMEBODY ELSE.
AND KATHERINE WILL CONFIRM THIS
IS TRUE, THAT I'VE ACTUALLY
INTERCEPTED A COUPLE OF THESE.
BUT REALLY APPRECIATE YOUR
COMING HERE AND SHARING THAT
WITH US.
YOU KNOW, I THINK WHAT I'M GOING
TO SAY TO CLOSE THIS OUT AND SAY
THAT WE'RE GOING TO HAVE A
RECEPTION THAT'S OUTSIDE.
AND TO ALL OF YOU, ESPECIALLY
TRAINEES, PLEASE TAKE A MOMENT
AND INTRODUCE YOURSELF TO DR.
DESPLAN HERE.
THAT'S REALLY WHAT THIS IS ALL
ABOUT.
JUST EXCHANGING IDEAS, MEETING
PEOPLE.
TO THOSE ON THE COMMITTEE, WHICH
IS BASICALLY GOING TO BE CLAUDE
BEFORE YOU GO OUT THERE, PLEASE,
WITH JORAM AND LONA AND JEREMY,
STEPHEN, KAPIL, STAY HERE AND
WE'LL TAKE A FEW PICTURES.
WITH THAT, PLEASE ENJOY THE
RECEPTION.
THANK YOU FOR COMING.
CLAUDE, THANK YOU AGAIN.
[APPLAUSE]
[END OF PROGRAM]