>> OKAY. WE'RE GOING TO GO
AHEAD AND GET STARTED HERE.
THANK YOU TO ALL OF YOU FOR
BEING HERE. I'M MICHAEL CHIANG
DIRECTOR OF THE NATIONAL EYE
INSTITUTE. I'M EXCITED ABOUT
WHAT THE NEXT FEW HOURS ARE
GOING TO BE FOR ALL OF US HERE
CH PLEASED TO WELCOME YOU TO THE
JORAM PIATIGORSKY BASIC SCIENCE
LECTURE. WE HAVE AN INCREDIBLE
AWARDEE, COMING FROM THE OTHER
WASHINGTON, SEATTLE. DR.
PIATIGORSKY WILL INTRODUCE IN
MORE DETAIL. REALLY EXCITED,
RACHEL, TO HAVE YOU HERE.
WELCOME TO BETHESDA AND THE NIH.
MY JOB IS TO TELL YOU ABOUT THIS
DAY, HOW IT GOT TO BE. BASICALLY
TELL YOU ABOUT DR. PIATIGORSKY
AND HIS LEGACY HERE. SO THIS IS
AN ENDOWMENT CREATED BASICALLY
TO HELP US RECOGNIZE WORK OF EYE
AND VISION SCIENTISTS AT THE
FOREFRONT OF BASIC EYE SCIENCE
RESEARCH . I'M REALLY PROUD THIS
AWARD IS NAMED FOR A SCIENTIST,
DR. PIATIGORSKY, WHO REALLY MADE
CRUCIAL CONTRIBUTIONS TO OUR
SCIENTIFIC LEGACY HERE AT THE
NATIONAL EYE INSTITUTE. HE CAME
FROM NICHD, NATIONAL INSTITUTE
OF CHILD HEALTH AND DEVELOPMENT
IN 1981 TO SET UP BASICALLY ONE
OF THE FIRST LABS THAT STUDIED
THE MOLECULAR AND DEVELOPMENTAL
BIOLOGY OF VISION. HIS LAB
REALLY OPENED UP THE PRACTICE OF
USING MOLECULAR BIOLOGY AND
GENETICS, LAB TECHNIQUES
INCLUDING GENE EXPRESSION AND
MECHANISMS OF THE EYE. JORAM'S
COLLEAGUES USED SQUID, SCALLOP,
OCTOPUS, JELLY FISH TO BASICALLY
LEARN MUCH OF WHAT IS KNOWN
TODAY ABOUT CHRISTALINES IN
INVERTEBRATES. THIS HAS HELPED
DIVERSIFY THE CRISTALLINES AND
HELP IN THE CONVERGENCE IN
EVOLUTION. HIS LAB HAS
ESTABLISHED THE CORNEA TOGETHER
WITH LENS ACCUMULATE
MULTI FUNCTIONAL SPECIFIC
CRYSTALINES. THIS LED TO THE
FIRST CORNEAL PROMOTER FOR
ALDEHYDE 3A1 AND EXTENDED THE
NOTION OF THE CORNEAL
CRYSTALINES AS THE REFRACTON
HYPOTHESIS AND THAT THESE HAVE A
LOT IN COMMON, THE USE OF CHRIS
THESE FOR OPTICAL PROPERTIES AND
THE PROPOSAL WAS THEY SHOULD
CONSIDER USING THE LENS AND
CORNEA AS A SINGLE UNIT HE
CALLED THE REFRACTON. HE
SUPPORTED THIS BY DEMONSTRATING
CATARACT IN MICE WHO LACKED THE
GENE FOR THIS MAJOR CORNEAL
ALDEHYDE 3A1. WHEN JORAM WAS
CHIEF OF HIS LAB AT THE NEI THE
DEVELOPMENT LAB OF BIOLOGY HE
RECEIVED THE HELEN KELLER AWARD
IN 2008, PRESENTED BY THE HELEN
KELLER FOUNDATION FOR RESEARCH
AND EDUCATION FOR SIGNIFICANT
CONTRIBUTIONS DURING THE COURSE
OF A CAREER OR SINGLE
CONTRIBUTION FOR EXCEPTIONAL
IMPORTANCE TO VISION SCIENCE. SO
THAT AWARD WON A NUMBER OF
AWARDS THAT REALLY MARKED THE
REMARKABLE CAREER THAT JORAM HAS
HERE AT THE NATIONAL EYE
INSTITUTE. WHEN HE RETIRED HE
BECAME A WRITER AND WROTE ABOUT
THINGS LIKE FICTION, ESSAYS, A
MEMOIR. A COUPLE ARE ON MY
BOOKSHELF NOW. SO YOU'LL BE
HEARING ABOUT JORAM, YOU KNOW,
SHORTLY. BUT I JUST WANT TO
CLOSE MY REMARKS BY JUST
EXPRESSING MY EXPRESSION TO YOU,
JORAM, TO YOUR WIFE LONA, WHO IS
IN THE BACK HERE, AND TO THE
FNIH FOR MAKING THIS LECTURE
POSSIBLE AND BRINGING PEOPLE
LIKE DR. RACHEL WONG HERE. NOWLY
TURN TO THE FNIH, THANK YOU.
>> SURE, NO PROBLEM. GOOD
AFTERNOON, EVERYONE. I'M SUSAN
CHILLINGLAW THE DIRECTOR OF GIFT
PLANNING FOR FOUNDATION FOR
NATIONAL INSTITUTES OF HEALTH,
WITH MY COLLEAGUE REGINA MERIT,
IN THE BACK THERE. SHE IS OUR
DONOR RELATIONS AND FUND
OFFICER. LOVE COLLINS, OUR BOSS
AND VICE PRESIDENT OF
ADVANCEMENT COULDN'T BE WITH US
BUT SENDS HIS SALUTATIONS AND
CONGRATULATIONS TO DR. WONG.
WHAT WE TRY TO DO AT THE
FOUNDATION IS WORK WITH
BENEFACTORS TO CREATE
INITIATIVES THAT SUPPORT
RESEARCH, EDUCATION AND
ILLUMINATE RESEARCH THAT COMES
OUT OF THESE PARTNERSHIPS, SO WE
ARE SO GRATEFUL TO LONNIE AND
JORAM PIATIGORSKY FOR THIS
INITIATIVE, WHICH WILL GO ON
WELL PAST YOUR LIFETIME. IT IS
QUITE A LEGACY, SO WE ARE SO
GRATEFUL TO YOU BOTH FOR THIS
INITIATIVE. NOW I'D LIKE TO TURN
IT OVER TO JEREMY NATHANS, THE
CHAIR OF THE SELECTION COMMITTEE
OF THE PIATIGORSKY AWARD. THANK
YOU SO MUCH.
[ APPLAUSE ]
>> I'M JEREMY NATHANS, A
PROFESSOR AT JOHNS HOPKINS AND
INVESTIGATOR AT HOWARD HUGHES
MEDICAL INSTITUTE. IT IS A
REALLY GREAT HONOR TO BE HERE TO
INTRODUCE JORAM, THEN
AFTER WARDS RACHEL WONG, OUR
HONOREE AND SPEAKER. WHAT
MICHAEL SAID IS THIS HONORS
CREATIVE SCIENCE AND CREATIVE
SCIENTIST JORAM PIATIGORSKY.
MIKE DESCRIBED JORAM WAS THE
FOUNDING DIRECTOR OF LABORATORY
OF MOLECULAR AND DEVELOPMENTAL
BIOLOGY AT THE NEI. STARTING 80s
WHEN ALMOST NOTHING WAS KNOWN OF
THIS JORAM EMBARK ON A QUEST TO
UNDERSTAND THE LEVEL OF THE
GENETIC BLUEPRINT. HE FOCUSED ON
THE LENS, MIRACLE OF ENGINEERING
AND EXPLORED THE STRUCTURE AND
DEVELOPMENT IN ORGANISMS, AS
MIKE SAID, IN ORGANISMS AS
DIVERSE AS JELLY FISH AND MICE.
LEADING TO INSIGHT THAT
ANATOMICALLY DIVERSE ORGANISMS
RETAIN REMARKABLE MOLECULAR
SIMILARITIES AND LED TO
DISCOVERY OF GENE-SHARING, A
MECHANISM IN WHICH A
SINGLE-PROTEIN PLAYS TWO ROLES
IN DIFFERENT CELL TYPES. I HAVE
KNOWN JORAM ABOUT 40 YEARS. I
ADMIRE MANY THINGS ABOUT HIM. I
ADMIRE HIS SCIENTIFIC
ORIGINALITY, HIS DETERMINATION
TO MARCH TO THE BEAT OF HIS OWN
DRUMMER. THE RESULT OF THAT
ORIGINALITY WAS THAT JORAM'S
COMBINATION OF INSIGHT HAS
YIELDED RICH REWARDS, MOST
DRAMATICALLY IN DISCOVERY OF
GENE SHARING BUT ALSO IN A WHOLE
SERIES OF THOTHER INSIGHTS AND
DEVELOPMENT. I ADMIRE JORAM'S
DRIVE TO DEVELOP HIS
NON-SCIENTIFIC TALENTS. IN
PARTICULAR HIS TALENT AS A
WRITER, WHICH HE HAS DONE WITH
EXTRAORDINARY SUCCESS. THE
GENRES OF JORAM'S PUBLISHED
BOOKS ENCOMPASS SCIENTIFIC
TREATISE, FICTION, AUTOBIOGRAPHY
AND ESSAYS. I JUST COMPLETED HIS
ESSAY COLLECTION A FEW MONTHS
AGO, IT IS FANTASTIC. I ADMIRE
JORAM'S KINDNESS AND WISDOM. SO
WITH THIS LECTURE AND AWARD
JORAM AND LONA HAVE MADE AN
ENDURING GIFT THAT WILL BRING
CREATIVE SCIENTISTS TO THIS
CAMPUS AND INSPIRE THE NEXT
GENERATION OF RESEARCHERS, THANK
YOU.
[ APPLAUSE ]
>> I DIDN'T REALIZE I WAS
SUPPOSED TO SPEAK. I WON'T SPEAK
LONGER THAN AN HOUR.
[ LAUGHTER ]
>> I'M REALLY HAPPY TO SEE
THIS LECTURE AWARD NOW GOING
INTO ITS SECOND YEAR. IT WILL BE
GOING ON FAR BEYOND THAT. TO
HAVE CONTINUED EXCELLENCE WITH
RACHEL WONG TO GIVE OUR SECOND
AWARDEE, THE TALK FOR TODAY. I
STARTED THIS AWARD FOR SEVERAL
DIFFERENT REASONS. ONE IS THAT
NIH AND NEI HAS BEEN SO
EXTRAORDINARY FAINEAR GOOD TO M
WANTED TO GIVE BACK. THEY HAVE
FUNDED MY WORK, MY LABORATORY, I
DON'T KNOW HOW MANY YEARS I WAS
AT NIEHS, 45 YEARS, AND NEVER AT
ANY POINT DID ANYONE COME TO ME
AND SAY WHAT I SHOULD BE WORKING
ON. I WAS GIVEN ACADEMIC
FREEDOM. THAT IS SO INVALUABLE
TO DO BASIC RESEARCH. I AM SO
GRATEFUL FOR THAT. WHICH BRINGS
ME TO THE SECOND REASON FOR
GIVING THE AWARD, IS THAT I
WANTED TO HELP IN SOME SMALL WAY
TO PERPETUATE THE IMPORTANCE OF
BASIC RESEARCH. WE STRESS THE
IMPORTANCE OF CLINICAL WORK. I
IN NO WAY MEAN TO DEROGATORY
STATEMENTS ABOUT THAT OR TO SAY
IT SHOULDN'T BE SUPPORTED EVEN
MORE. IT IS CRUCIAL. BUT IT ALSO
FOLLOWS ON THE FOOTSTEPS OF THE
BASIC RESEARCHER. PEOPLE OFTEN
SAY BASIC RESEARCH WHERE YOU ARE
STUDYING FUNDAMENTAL PROCESSES
IS CURIOSITY-DRIVEN. AND I
REALLY HAVE -- I DON'T AGREE
WITH THAT IN THE SENSE THAT I'M
NOT AWARE OF ANY KIND OF
RESEARCH IN ANY AREA THAT
DOESN'T INVOLVE CURIOSITY. WHAT
I THINK IS CRITICAL ABOUT BASIC
RESEARCH IS THAT IT IS
DESTINATION-FREE. THAT SEEMS TO
BE THE IMPORTANT POINT. THAT
EACH FINDING IS GOING TO
PROBA
PROBABLY GOING TO UPSET YOUR
PREVIOUS IDEAS AND EACH PAPER
WILL HAVE YOU CONSIDER THINGS
DIFFERENTLY AND THE OPEN MIND IS
THAT NOT " I WANT TO CURE THIS
DISEASE " BUT THE IDEA IS TO
REALLY UNDERSTAND, TO MY LAST
POINT BEFORE I GO, IS THAT I WAS
ON A PANEL MANY YEARS AGO ABOUT
PRIORITIES FOR FUNDING GRANTS.
IN THAT DISCUSSION AMONG THE
PANELISTS UP THERE WAS THE IDEA
THAT THE HUMAN CATARACT SHOULD
BE THE HIGHEST PRIORITY. ONE OF
THE THINGS THAT I THINK I HELPED
INFLUENCE, WHICH WAS REALLY
IMPORTANT TO ME, IS THAT
ULTIMATELY WHAT WAS NOW
CONSIDERED THE HIGHEST PRIORITY
FOR RESEARCHING THE LENS WAS THE
NORMAL LENS. NOT EVEN THE HUMAN
NORMAL LENS BUT THE NORMAL LENS
BECAUSE IN FACT, WHETHER YOU
LOOK AT A JELLY FISH, A SCALLOP
OR A COW OR YOUR ROOMMATE, THEY
ALL HAVE , IN FACT,
SIMILARITIES AND FANTASTICALLY
INTERESTING DIFFERENCES THAT ARE
RELEVANT TO THE ENVIRONMENT,
EVEN ANIMALS THAT ARE CALLED
PRIMITIVE ARE NOT PRIMITIVE BY
ANY MEANS AT ALL; WHAT THEY ARE
IS EXTREMELY WELL -- THAT IS THE
CRITICAL THING, HOW DID THEY DO
THAT, UNDERSTANDING NORMAL
TISSUES. I'M SURE DR. WONG WILL
HELP ME UNDERSTAND THAT QUEST
AND FEEL THIS AWARD WILL HELP IN
TERMS OF GIVING FROM INSTEAD OF
THE OUTSIDE WORLD TO HOW THE EYE
WORKS BUT HOW THE EYE WORKS. IT
IS FROM THE EYE TO THE WORLD,
NOT FROM THE WORLD TO THE EYE.
SO THANK YOU VERY MUCH.
[ APPLAUSE ]
>> OKAY. I'M GOING TO
INTRODUCE OUR SPEAKER TODAY,
RACHEL WONG. IT IS A PLEASURE,
RACHEL, TO INTRODUCE YOU AS THE
2024 PIATIGORSKY LECTURE AND
AWARD RECIPIENT. RACHEL IS A
NEUROBIOLOGIST WIDELY RECOGNIZED
FOR HER WORK ON DEVELOPMENTAL
MAKE NFLS OF THE ASSEMBLY OF
NEURONAL CIRCUITS, EXPLORING
ACTIVITY-DEPENDENT AND
INDEPENDENT CUES IN THE RETINAL
SYSTEM, PARTICULARLY IN
VERTEBRA. IN RACHEL'S PAPERS
IMAGES OF CELLS AND ISSUES AND
RETINA ARE BEAUTIFUL AND IS
READER IS AWARDED WITH A
SCIENTIFIC AND AESTHETIC TREAT.
SHE GREW UP IN MALAYSIA AND
RECEIVED A BACHELORS IN PHYSICS
AND OBTAINED A PHD IN VISUAL
NEUROSCIENCE FROM AUSTRALIA
NATIONAL UNIVERSITY. DID
POST-GRADUATE RESEARCH AT THE
VISION RESEARCH INSTITUTE IN
AUSTRALIA, STANFORD AND VISION,
TOUCH AND HEARING RESEARCH
CENTER IN AUSTRALIA. IN 1994 SHE
JOINED THE FACULTY AT WASHINGTON
SCHOOL OF MEDICINE IN ST. LOUIS
AND 2006 MOVED TO SEATTLE,
PROFESSOR AND CHAIR OF
DEPARTMENT OF BIOLOGICAL
STRUCTURE. HAS RECEIVED MANY
AWARDS INCLUDING THE FREEDOM
AWARD FOR RESEARCH IN VISION AND
OPT MOLL GI AND BRIAN BOYCOTT
PRIZE AND ELECTION TO THE
NATIONAL ACADEMY OF SCIENCES.
CONGRATULATIONS, RACHEL. WE LOOK
FORWARD TO YOUR LO LECTURE.
[ APPLAUSE ]
>> SO I'M ALMOST SPEECH LESS,
WHICH MEANS THAT WILL BE VERY
SHORT. THANK YOU SO MUCH FOR
THAT VERY KIND INTRODUCTION,
JEREMY. I HAVE KNOWN JEREMY FOR
A LONG TIME. I JUST MET JORAM
PIATIGORSKY. I'M EXTREMELY HO
HONORED. THIS REALLY JIVES WITH
ME. YOU WILL SEE THE NUMBER OF
SPECIES WE HAVE GONE THROUGH
THROUGH MY TIME AS AN
INVESTIGATOR IS QUITE EXTENSIVE.
MY FATHER USED TO ASK ME,
HAVEN'T YOU JUST FOUND ONE MODEL
YOU CAN USE. I WAS LIKE, NO.
EVERY EYE IN A DIFFERENT ANIMAL
OR EYE IN DIFFERENT ANIMAL USES
A DIFFERENT STRATEGY TO MAKE ITS
OWN RETINA SO IT CAN BASICALLY
PROCESS THE VISUAL WORLD FOR THE
IMPORTANT THINGS FOR THAT
ANIMAL. SO I THINK COMPARATIVE
NEUROBIOLOGY IS EXTREMELY
IMPORTANT BUT JUST WANTING TO
UNDERSTAND HOW THINGS WORK AND
HOW THE RETINA WORKS TO INFORM
US OF WHAT -- WHEN THINGS GO
WRONG, WHY DOES IT WORK AND HOW
YOU MIGHT PUT IT BACK TOGETHER.
THIS ISN'T MY TALK. I WILL TRY
TO GET TO MY TALK.
ALL RIGHT. BECAUSE WE HAVE
TWO SCREENS I HAVE DECIDED NOT
TO USE THE LASER POINTER SO I
HAVE A MOUSE THING MOVING
AROUND. IF YOU DON'T SEE IT THIS
WAY, THIS IS THE LOW CONTRAST
SCREEN, THAT IS THE HIGH
CONTRAST SCREEN. WHICHEVER WORKS
FOR YOU I THINK IS FINE WITH ME.
SO I THINK I HAVE LESS THAN AN
HOUR. I'M GOING TO GET GOING SO
YOU CAN ACTUALLY END UP WITH
RECEPTION. HOPE YOU HAD LUNCH
ALREADY SO CAN KIND OF PAY
ATTENTION. NOW AS JERRY
MENTIONED FOR MANY YEARS MY
LAB'S BEEN INTERESTED IN
DEVELOPMENT OF RETINA,
PARTICULARLY THE VERTEBRATE
RETINA. WE HAVE ALSO IN RECENT
YEARS BEEN INTERESTED IN REPAIR.
WE FIGURED WE COULD USE SOME OF
TECHNIQUES WE HAVE MUSTERED
TOGETHER TO STUDY THE
DEVELOPMENT OF THE RETINA
TOWARDS A BETTER UNDERSTANDING
NOT SO MUCH OF HOW TO REPAIR THE
RETINA, IN MY CASE, BUT REALLY
TO UNDERSTAND THE HURDLES THAT
THE ADULT RETINA MIGHT FACE IN
ORDER TO REPAIR ITS CIRCUITRY
EITHER IN DISEASE OR IN INJURY.
SO MOST OF THE TALK I WILL TELL
YOU ABOUT -- I WILL WALK YOU
THROUGH A JOURNEY OF OURS WHERE
WE HAVE TRIED TO UNDERSTAND
BASICALLY WHAT THE MECHANISMS
ARE, ESPECIALLY CELL
INTERACTIONS THAT ARE IMPORTANT
FOR SETTING UP PARTICULARLY THE
CIRCUITRY OF THE RETINA, SO THIS
WILL BE DEVELOPMENT. TOWARDS THE
END I WANT TO SHARE SOME OF OUR
REASON TO WORK AND TRYING TO
UNDERSTAND HOW CIRCUITS FALL
APART. MAYBE WHAT WE MIGHT NEED
TO THINK ABOUT IN TERMS OF HOW
WE MIGHT NEED TO PUT IT BACK
TOGETHER. SO THIS IS ALSO
ESPECIALLY FOR ANAN, WHO BROUGHT
ME HERE MANY YEARS AGO TO GIVE
THE WALLS LECTURE. ONE OF THE
PROGRAM OFFICERS ASKED ME, ARE
YOU GOING TO WORK ON DISEASE? I
SAID I GUESS I'M AT THE NIEHS SO
THE ANSWER WOULD BE YES. WE DID
GO BACK AND WE DID START
SOMETHING USING SOME OF THE
TECHNIQUES. THAT WAS VERY
INSTRUCTIVE. BUT TODAY LET ME
REMIND YOU -- AND I DON'T THINK
I NEED TO DO MUCH IN TERMS OF
GOING THROUGH THIS. WE ALL
APPRECIATE THE WONDERFUL AND
BEAUTIFUL STRUCTURE OF THE
VERTEBRATE RETINA. WE KNOW HOW
THE CELLS ARE LAYERED. WE KNOW
ITS CONNECTIVITY IS NOT HAPPEN
HAZARD. THAT IN FACT, THERE ARE
LOTS OF PATHWAYS THAT CHANNEL
VISUAL INFORMATION FROM
RECEPTORS TO RETINAL GANGLION
CELLS. WE KNOW ABOUT THE ROCK
PATHWAY, WHICH DEALS WITH DIM
LIGHT LEVELS AND KNOW ABOUT THE
CONE PATHWAY, IMPORTANT FOR
THINGS LIKE COLOR, WHERE YOU
WILL SEE MY SLIDES AND MAYBE
EVEN READ SOME OF THE LETTERS ON
THOSE SLIDES. PHOTO RECEPTORS,
THE RODS AND CONES HAVE CAUSED
CYNOTIC INFORMATION THROUGH
BIPOLAR CELLS, ROD AND COMBINE
CELLS CONNECT TO GANGION THAT
SEND THAT TO BRAIN. WITH E KNOW
ABOUT MODULAR CONNECTIONS
VERTICAL PATHWAY BY HORIZON
CELLS IN RETINA AND
NEUROSURGEONS WHICH ARE
INHIBITORY THAT SHAPE
CONNECTIONS THAT ARE CROSS
BETWEEN BI AND GANGLION CELLS.
FOR THOSE THAT STUDY CELLS IN
THE RETINA YOU WILL APPRECIATE
THEY ARE NOT ONLY ROD AND CONE
PATHWAYS BUT MANY YEARS AGO, I
WON'T SAY HOW MANY BECAUSE RALPH
IS HERE, WE KNOW THERE ARE
ON-AND-OFF PATHWAYS THAT CHANNEL
INFORMATION RESPONSES IN TWO
WAYS. SO WHEN YOU TURN ON THE
ROOM LIGHT THE ON WOULD BE
POLARIZED AND LIGHT UP. AT THE
SAME TIME THE OFF PATHWAY WILL
BE SUPPRESSED, POLARIZED, A
YINYANG INFORMATION HOW YOU
CONVEY PATHWAYS ACROSS THE
RETINA. THE WONDERFUL THING
ABOUT THE RETINA TOO IS YOU CAN
IMMEDIATELY GUESS WHAT SOME OF
THE FUNCTION MIGHT BE SIMPLY BY
LOOKING AT THE STRUCTURE
ORGANIZATION. WE KNOW, FOR
EXAMPLE, ON-AND-OFF CIRCUITS ARE
REALLY SEPARATED MOSTLY
INTERDISTINCTLY IN THE RETINA.
FOR A NEUROBIOLOGIST, INTERESTED
IN VISION, IF YOU WANT TO LOOK
WHERE ALL THE CIRCUITRY IN EYES
AND GUESS WHAT FUNCTION MIGHT BE
YOU CAN DO A LOT BASED ON THE
STRUCTURE OF ORGANIZATION. NOW
TO START AT THE -- JUST TO
FINISH OFF THIS PART, I SHOULD
REMIND YOU OF COURSE WITHIN EACH
OF THE MAJOR CLASSES OF NEURONS
IN THE RETINA, MANY TYPES -- AND
THAT IS TO REMIND YOU OF ITS
COMPLEXITY. EVEN OF GANGLION
CELLS, THE ON-AND-OFF, THERE ARE
NOT ONLY TWO TYPES BUT MANY
DISTINGUISHED BY THEIR
MORPHOLOGY AND DISTINCTION. THIS
IS ONLY TWO. WHAT ARE YOU DOING
HERE? MOST DEVELOPMENTAL
NEUROBIOLOGISTS, YOU NEED TO
UNDERSTAND HOW CELLS ARE MADE
AND THE RIGHT TYPES AND THE
RIGHT TIME. CAN Y'ALL SEE THIS
OKAY, THE LOW-CONTRAST SCREEN?
THEN YOU HAVE TO HAVE FACTORS
THAT CAUSE THESE CELL, THESE
NEURONS TO GROW IN DIFFERENT
COMPARTMENTS LIKE A A /* AXONS
AND DENDRITES. SO THINGS TAKE
PLACE DURING DEVELOPMENT. IT IS
NOT JUST STRUCTURALLY DIFFERENT
BUT FUNCTIONS WITH THESE
NEURONS. THEN THE NEXT STEP,
WHICH IS REALLY IMPORTANT, IT
MAKES THE RIGHT PARTNERS AND
RIGHT SYNAPSES. NOT JUST THE
RIGHT TYPE BUT THE RIGHT NUMBER
OF SYNAPSES AND THIS INFLUENCES
PROPERLY WITHIN THE CIRCUITRY SO
EVENTUALLY YOU END UP WITH
NEURONS THAT PAIR UP AND MAKE
CONNECTIONS WITH EACH OTHER.
IMAGINE FOR THE VERTEBRATE
RETINA YOU HAVE TO MAKE THESE
ALMOST THE SAME TIME SO THE
SEQUENCE IS MOSTLY IN PARALLEL
SO MANY PROCESSES HAVE TO TAKE
PLACE FOR CO -GENERATION OF
CIRCUITS TO MAKE SURE THEY ALL
WIRE PROPERLY. WE HAVE MOSTLY IN
THE LAST YEARS I THINK FOCUSED
ON THIS PART OF DEVELOPMENT,
WHICH IS TRY TO UNDERSTAND THE
MECHANISMS THAT SHAPE THE
CIRCUITRY BETWEEN CELLS IN THE
RETINA. TO DO SO WE HAVE USED A
VARIETY OF TECHNIQUES, WHICH
WILL BECOME OBVIOUS SOON.
IMPORTANTLY WE HAVE DONE THIS IN
A VARIETY OF SPECIES. THIS IS
ONLY A SMALL HANDFUL RELATED TO
THE SLIDES FOR TODAY. FROM CHICK
ALL THE WAY TO HUMAN SO WE CAN
THINK ABOUT HOW THE VERTEBRATE
RETINA, WHAT MECHANISMS ARE USED
AND ARE COMMON BUT ALSO
DISTINCT. LIKE JORAM SAYS,
BECAUSE EACH OF THESE EYES MAY
IN FACT, HAVE A DIFFERENT THING
THEY ARE REALLY, REALLY
INTERESTED IN AND THEY NEED TO
CREATE A CIRCUIT THAT IS USED,
FOR EXAMPLE, IN CLIMATES NOT
PRESENT IN ZEBRAFISH, FOR
EXAMPLE, AND VICE VERSA. LET'S
START IN THE BEGINNING. I START
AT MY LAB IN WASH U AND ONE OF
MY FIRST STUDENTS AT THE NIH
KNEW I WAS INTERESTED IN THE
PROCESS OF MAKING CONNECTIONS.
ONE OF THAT IS -- ONE IMPORTANT
QUESTION WAS TO ASK, WHAT ARE
THE FACTORS THAT SHAPE THE
DENDRYTIC UNIVERSE OF THE CELLS.
IMAGINE IF THEY ARE NOT GROWING
OR MAY NOT BE MAKING THE RIGHT
PARTNERSHIPS. SO MOST OF THE
TIME, OR AT LEAST RIGHT UP TO
THAT STAGE YOU LOOK AT DENDRITIC
DEVELOPMENT BY FIXING TISSUE AT
DIFFERENT TIME, LABELING THE
CELL, IF YOU COULD, AND SAY THIS
IS WHAT IT LOOKS LIKE NOW AND
FEW DAYS LATER AND FROM THAT
DEDUCE PERHAPS THE CELLULAR
INTERACTIONS THAT REGULATE THE
DENRITIC ORGANIZATION. BUT HAD
MUCH BETTER IDEA. I DON'T LIKE
LOOKING AT DEAD TISSUE VERY
LONG. IT IS ALL STATIC. IT IS
LIKE A SOCCER GAME. YOU DON'T
KNOW HOW THE GOAL HAPPENED.
LARRY CAME OUT WITH A GENE GUN,
A BALLISTIC DEVICE WHERE YOU CAN
COAT LITTLE PARTICLES AND SHOOT
IT GENTLY ON A PIECE OF RETINA
THAT'S BEEN ISOLATED, PUT IT IN
AN INCUBATOR, GET IT TO BED.
THEN THE NEXT DAY, IF YOU DO
YOUR COATING WITH D.N.A. THAT
ENCODES FOR THE JELLY FISH GREEN
PROTEIN, YOU CAN ACTUALLY GET
THE CELLS TO GLOW. YOU CAN DO
TIME-LAPSED. THE RETINA STAYS
HAPPY IN THE DISH FOR DAYS. THIS
IS JUST NOT TO EMPHASIZE
ANYTHING OTHER THAN FROM THESE
TYPES OF APPROACHES WE CAN LOOK
AT, FOR EXAMPLE, FORMATION OF A
NEW PROCESS OR ELIMINATION OF
SOME PROCESS OVER TIME. THE
BOTTOM LINE FROM THESE STUDIES
WE RELEASE OF GLUTAMATE WAS
IMPORTANT IN GETTING NEW
PROCESSES TO STABILIZE AND ALSO
FOR THE EYEBALL TO GROW. THAT
LED TO A NEW SERIES OF
EXPERIMENTS WHERE WE DECIDED TO
USE THE GENE GUN TO NOT ONLY
SHOOT THIS IN BUT MONITOR THE
ACTIVITY WITHIN THE CELL. OFTEN
WHAT WE NORMALLY DO IS WE USE
ELECTRODES AND YOU
PATCH-CLAMPING ONTO A CELL AND
YOU WOULD LISTEN. THIS IS A
CELL-ATTACHED PACK SO YOU DON'T
BREAK ANYTHING. WE KNEW IF WE
PUT A HOLE IN THE MEMBRANE THE
CELL WAS PROBABLY GOING TO DIE
AFTER SOME PERIOD OF TIME. WE
MAY DO THINGS LIKE WASH OUT
CONTENTS IN THE CELL BODY THAT
MIGHT ACTUALLY BE IMPORTANT FOR
SOME OF THE PROCESSES WE ARE
INTERESTED IN. SO CHRISTIAN HAD
THIS IDEA WITH PATRONELL AND BEN
VANGAN AT SOMETHING WE WERE ALL
AT. COATING THE PARTICLES NOT
WITH PARSE BUT CALCIUM INDICATED
DYES. IT WORKED. IN SOME CASES
THE BULLET WENT IN AND OVER TIME
IN THE TIME LAPSE YOU CAN DETECT
CHANGES IN FLOUR FLOURESCENCE
BUT THERE WERE LITTLE FLASHES
YOU MIGHT SEE IN THE DENDRITES.
AND YOU PROBABLY SEE BLINKIES
OVER TIME. SO WHEN YOU CORRELATE
THIS YOU CAN MONITOR THE VOLT
CHANGES SAME TIME AS CALCIUM
CHANGES. YOU SEE WHEN YOU HAVE
THE BIG FLASH YOU WILL HAVE A
BURST OF SPIKES, THESE ACTION
POTENTIALS BUT THE LITTLE LOCAL
EVENTS, THERE WAS NO CHANGE IN
VOLTAGE. SO THERE ARE DIFFERENT
CALCIUM EVENTS. WE FOUND WHEN
YOU PUT THE RETINA, THIS IS A
CHICK RETINA IN VITRO, THAT
STOPS THE CALCIUM-INDUCED,
RELEASE FROM THE CELLULAR CELLS,
THE GANGLION WOULD SHRINK OVER
TIME SO IT IS IMPORTANT FOR
ESSENTIALLY KEEPING THE
DENDRITES STABLE. WE COULD
RESCUE FROM SHRINKING BY PUTTING
BACK LOCALLY BY SHINING
ESSENTIALLY UV SPOT IN CELLS IN
WHICH WE HAVE LOADED NOT ONLY
WITH CALCIUM INDICATOR BUT WITH
SOMETHING CALLED KACHE CALCIUM
WHERE THIS CHEMICALLY RELEASES
UPON ABSORPTION OF UV LIGHT. SO
THIS REGION HERE WE FOUND VERY
LITTLE RETRACTION WHEN YOU PUT
THE LET THAT OUTSIDE REGION
WHERE THERE IS NO UNCAGING OF
CALCIUM, YOU SEE RETRACTION. SO
THAT TOGETHER SUGGESTS THESE
LOCAL EVENTS STABILIZE DENDRIT E
DEVELOPMENT. THERE WAS A LOT
GOING ON. I WON'T GO THROUGH
ALL. BUT THE CALCIUM EVENTS
OCCUR WHEN PRE-SYNAPTIC CONTACT
THE GANGLION CELLS AND IT IS
THAT CONTACT THAT TRIGGERS
CALCIUM AND KEEPS THAT
CONNECTION TOGETHER, OKAY? IF
YOU WANT TO READ MORE, IT IS IN
A PAPER IN 2002. WE ALSO
REALIZED THAT WHILE WE CAN WATCH
ACTIVITY AND EVEN MONITOR DEN
DRITIC CHANGES LIVE IN A DISH
THINGS COULD BE DIFFERENT IN THE
ANIMAL THEMSELVES. IT WAS
IMPORTANT TO WATCH DENDRITIC
GROWTH INVIVO. THIS IS WHERE YOU
RECOGNIZE THIS CHARACTER. JEFF
JOINED THE LAB. HE IS EXCITED
ABOUT USING ZEBRAFISH, SO HE
HELPED SET UP THE ZEBRAFISH. THE
TANKS HADN'T EVEN ARRIVED THEN
IN THE LAB. WE HAVE EXPERIMENTS
FROM ANIMALS FROM THE LAB AT
UCSF AND JEFF AND ERIC MADE LOTS
OF PLASMIDS SO MAKE TRANSGENIC
ANIMALS WHOSE EYES GLOW,
DEPENDING ON THE PROTEINS. YOU
CAN DO TIME LAPSE. HERE ARE
EMACRIN CELLS, MIGRATING,
GETTING TO THE FORMING IPL AND
FORMING ITS PROCESSES. AND NIGHT
I THINK IT WAS JEFF WHERE HE
MONITORED THE GROWTH AND SAW IT
DEVELOPED TWO EYEBALLS
SEQUENTIALLY OVER TIME SO THE
INVIVO EXPERIMENTS. FROM THE
GANGLION CELL, DEPENDS UP TO
THAT TIME MOST THOUGHT THESE
DENDRITIC EYEBALLS BECOME K
CALCIFIED FROM A WAY THAT IS
DIFFUSE. THIS IS EVERYWHERE THEN
SOMETHING COMES ALONG, SHAPES
IT, CUTS UP A THE BRANCHES AND
BECOMES STRATIFIED. JEFF AND HIS
COLLEAGUES DISCOVERED WAYS OF
THE DENDRITIC LAMINATION OF
THESE CELLS AND THE EXAMPLE I
GAVE YOU THAT YOU JUST SAW HERE,
WAS ONE AND YOU CANNOT REALLY
KNOW THIS HAPPENED BECAUSE YOU
CANNOT FOLLOW THE SAME CELL IN A
DISH OVER TIME. OR FIXED RETINA
AT DIFFERENT TIMES AND THEN
INFER WHAT HAPPENED BECAUSE IT
IS NOT THE SAME CELL ANYMORE. SO
THE INVIVO IMAGING WAS CRITICAL
IN TELLING US THERE ARE MORE
WAYS THAN ONE FOR DEN DRITES TO
ACQUIRE SHAPE AND LAMINATION TO
MAKE CONNECTIONS TO THE
PRE-SYNAPTIC CELLS. WE DECIDED
WHILE WE LOVE DENDRITES WE
WANTED TO THINK ABOUT
CONNECTIONS. YOU NEED TO MAP UP
THE CONNECTIVITY AT THE LEVEL OF
SYNAP
SYNAPSES. WE MOVED FROM ZEBRA
FISH -- STILL HAD ZEBRAFISH BUT
TO THE MOUSE RETINA WHERE WE CAN
MAKE TRANSGENIC ANIMALS TO LABEL
PARTICULAR TYPES OF CELLS OR USE
GENETIC TOOLS TO -- FOR EXAMPLE
NEUROTRANSMISSION IN CERTAIN
CELL TYPES. SO WE LOVE THE GENE
GUN AT THIS STAGE, YOU CAN TELL.
MORE MACHINE GUNNERS ON THE
RIGHT. JOSH AND DAN USED THE
MACHINE GUN TO LABEL NOT ONLY
THE DENDRITIC EYEBALLS OF THE
GANGLION CELLS BUT THOSE
REPRESENT POST-SEN NAP TICK 95
INFUSED THE YELLOW PROTEIN. IF
YOU SHOOT THAT IN A TRANSGENIC
ANIMAL WHERE SOME BIPOLAR CELLS
ARE LABEL EXPRESSING DIFFERENT
PROTEIN COLOR, THIS IS THE WHOLE
RANGE OF COLORS FROM THIS JELLY
FISH MUTATED. THIS IS CORAL. YOU
CAN IDENTIFY THE LOCATIONS WHERE
THEY ACTUALLY CONTACT. THE
LITTLE DOTS ARE PS95 SUGGESTIVE
OF AN ACTUAL SYNAPSE AT THIS
SITE. USING THESE MAPPING TOOLS,
FLOURESCENCE MAPPING, DANIEL DID
THE STUDY WHERE WE NOT ONLY
LABEL SOME OF THE NEURONS BUT
SILENCE THROUGH THE EXPRESSION
OF TETANUS TOXIN WHICH DIFFUSE
AND TRANSMITORS CAN'T GET
RELEASED. THESE EXPRESS THIS
TETANUS TOXIN ONLY ON BIPOLAR
EXPRESS THE TETANUS TOXIN. WITH
E LOOK AT A TYPE POST-SYNAPTIC
TO THE CELLS. YOU SAW THE ALPHA
GANGLION AND LOTS OF DOTS AT 25
AND IN THE MOUSE. BUT IN THE TNT
MOUSE WHERE THERE IS LITTLE NO
TRANSMISSION FROM THE BIPOLARS
TO THE GANGLION, FAR FEWER PS95
AND FEWER SYNAPSES. IF YOU
QUANTIFY, IT IS ABOUT THE SAME
BUT DON'T INCREASE -- TNT DOES
NOT INCREASE IN THE WILD TYPE.
SO THAT TELLS YOU BIPOLAR CELL
TRANSMISSION IS IMPORTANT FOR
GETTING THE SYNAPSES MEET WITH
THE RETINAL GANGLION CELLS.
HARVARD WENT UNSTEP FORWARD.
INSTEAD OF WIPING PEOPLE BY THE
WHOLE POPULATION, HE DID A FEW.
THIS IS EXPRESSING TETANUS
TOXIN, THIS ISN'T. HE ASKED THE
QUESTION, IF YOU HAVE TWO
NEIGHBORS WHO ARE SHARING A
POST-SYNAPTIC CELL HERE AND ONE
IS INACTIVE AND THE OTHER IS
NOT, IS THIS INACTIVE ONE LOSE
SYNAPSES, CONTACTING WITH
GANGLION CELL AND NEIGHBOR TAKE
ADVANTAGE OF THE SILENCE AND
GRAB THE SYNAPSE S? IS THERE A
COMPETITION? A WINNER AND LOSER,
AS YOU SEE IN A NEUROMUSCULAR
JUNCTION OF DEVELOPMENT. TURNS
OUT INACTIVE BIPOLAR CELL MAKES
FEWER SYNAPSES, JUST A NUMBER,
COMPARED TO AN ACTIVE NEIGHBOR
SHARING THE SAME PIECE OF
DENDRITE. BUT WHAT WE SEE IS
THIS. WE DON'T SEE TAKEOVER .
THE NEIGHBOR IS NOT
OPPORTUNE ISTIC. WHAT IT HAS, IT
WILL KEEP IT, WHILE SILENCED
NEIGHBOR IS LOSING SYNAPSES AND
ITS MORPHOLO DPV Y DOESN'T
CHANGE. IF YOU LOOK AT THE PF95,
SPOTS, THEY ARE LARGER,
DENDRITES WHEN CONTACTED BY UP
ACTIVE BIPOLAR CELL. THIS IS
TYPICAL, JEFF WILL TELL YOU,
COMOSTATIC RESPONSE. IS BETTER,
PUTTING MORE RECEPTORS, BUT OF
COURSE NOTHING GOING ON THERE.
SO YOU CAN SEE LOCAL CHANGES AT
THE LEVEL OF INDIVIDUAL
SYNAPSES. SO TRANSMISSION FROM
BIPOLAR CELL S IS IMPORTANT.
DANIEL PUT TOGETHER THIS
WONDERFUL SUMMARY SLIDE THAT I
BORROWED FROM HIM. IN WILD TYPE
YOU MIGHT GET X NUMBER WHEN YOU
ARE SILENCE THE BIPOLAR
INDIVIDUALLY OR AS A POPULATION,
YOU WILL STILL GET A DECREASE IN
NUMBER OF SYNAPSES MADE THOSE
SILENT BIPOLAR CELLS, OKAY.
DANIEL WENT ON USING THE CRX
NEWTON, WHERE FULL RECEPTORS ARE
NOT FUNCTIONING NORMALLY,
BIPOLAR ACTIVITY IS UP. AND IF
VIRUS HAS BECOME MORE ACTIVE,
THEY ACTUALLY MACK MORE
SYNAPSES. SO KIND OF LIKE A
DIAL. DEPENDING ON BIPOLAR
ACTIVITY, THE BIPOLAR CELL WILL
MAKE MORE OR LESS SYNAPSES WITH
GANGLION CELL. THIS IS GOOD TO
KNOW. ESPECIALLY IF YOU WANT TO
REWIRE SOMETHING YOU MIGHT WANT
TO ASK WHAT IMPORTANT IS
ACTIVITY OF PRE-SYNAPTIC TO
POST-SYNAPTIC CELL TO MAKE THE
RIGHT NUMBER OF SYNAPSES. WELL,
AFTER GOING THROUGH ALL THE " WE
MUST DO LIVE " STUFF TO FOLLOW
AND SEE HOW IT HAPPENS INVIVO,
MOST RECENTLY WENT TO LOOK AT
FIXED TISSUE. IT IS LIKE WHAT
HAPPENED HERE? WELL, TURNS OUT
THERE ARE CERTAIN THINGS THAT
EVEN WITH THE MOST WONDERFUL
FLORESCENTS YOU CAN'T BE CERTAIN
YOU ARE LOOKING AT A SYNAPSE.
YOU TYPE SOMETHING, EXPRESS IT,
GOES TO THE SITE. IT IS A GOOD
INDICATION BUT HOW DO YOU KNOW
THAT EVERYONE IS
SYNAPSE ED?ENTER THE BEST WAY IS
ELECTRO MICROSCOPY TO THE LEVEL
OF NAN NANOMETER. THAT WITH
SCANNING, THE THANKS GROUP
DEVELOPED. YOU KNOW KEVIN
BRICKMAN BECAUSE HE WAS HERE,
HAD INSTRMENTAL PART IN GETTING
THE ZERO BLOCK PHASE SCANNING EM
METHOD FOR US ALL TO USE. WE
HAVE BEEN DOING A LOT OF THIS.
PARTLY BECAUSE THERE ARE SOME
TISSUES WE CANNOT DO LIVE OR
INVIVO IMAGING, SUCH AS IN
HUMANS. SO WE DECIDED EM WAS
IMPORTANT. THIS IS ESSENTIALLY
HOW IT WORKS. YOU CAN DO ALL
THESE RECONSTRUCTIONS. MANUALLY
IN THIS CASE. AFTER YOU HAVE CUT
SECTIONS, SCANNED THE SURFACE,
THAT SECTION IS THROWN AWAY. GET
THE NEXT SECTION AND BUILD IT
OVER TIME. THE MOVIE YOU JUST
SAW WAS ESSENTIALLY SERIES OF
IMAGES BROUGHT TOGETHER WITH
THIS METHOD, RECONSTRUCTED BY
HAND. YOU SEE TWO BIPOLAR CELLS,
THE DENDRITES ARE THE BIPOLAR
CELLS AND RIBBONS HERE AND PHOTO
RECEPTORS AND MIDGET BIPOLAR
CELLS IN THE HUMAN. IT IS
POSSIBLE TO CORRELATE IMAGING
WITH ZERO EM. WE HAVE LABELED IN
THIS CONDITION THE GANGL ION
CELLS THESE BRIGHT PATCHES, TYPE
WITH YFP TRANSGENIC ANIMAL. TAKE
THE IMAGE, NOW WHERE THESE ARE.
YOU CAN TAKE THE BLOCK AND
RECONSTRUCT PROCESSES. WE KNOW
IT WAS IN CELL BODY OF A
GANGLION CELL. THESE ARE AMOCRON
MAKING GABA CYST AT THAT SITE.
WE STUDY TO STUDY DEVELOPMENT OF
SYNAPSES OF CELLS BUT I DON'T
HAVE TIME TO TALK ABOUT THAT
MUCH TODAY. SO WE WILL ALL TALK
ABOUT CHOOSING PARTNERS AND
MAKING APPROPRIATE SYNAPSES,
MOSTLY USING EM METHODS RIGHT
NOW. I WANT TO TALK ABOUT THE
CONNECTIVITY, WITH I IS REALLY
TO CONNECT IS HOW YOU FIND AND
CHOOSE RIGHT PARTNERS, THE
SELECTION HERE AND HOW DO YOU
MAKE RIGHT NUMBER OF CONNECTIONS
EVEN IF THE PARTNERS OF YOUR
CHOICE. THIS IS A GRADUATE
STUDENT SO M & Ms IN CASE YOU
ARE NOT SURE. THIS PARTICULAR
STUDENT LIKES RED AND BLUE M &
Ms. THAT IS ALL SHE PREFERS,
LEAVES THE REST AND YOU SAY WHAT
MOLECULE IS MAKING HER DO THAT?
SHE IS VERY HAPPY WITH. THE
OTHER PART IS WHAT PART OF THIS
SYNAPSE EXCITE, HOW DO YOU PUT
EACH OF THESE SYNAPSES TOGETHER?
THERE IS A SPECIALIZED ANATOMY.
FOR EXAMPLE, THE DIET SYNAPSE IN
THE RETINA. THEY ARE ALSO
GETTING THE RIGHT RECEPTORS AND
PRO TYPES AT SYNAPSES IN THE
RIGHT LOCATIONS, WHICH IN THIS
CASE WE CAN LABEL UP WITH AM
MEAN KNOW CHEMISTRY OR TYPE THEM
WITH TRANSGENIC ANIMALS. I WON'T
TALK ABOUT THESE SYNAPSES, A LOT
OF FOCUS ON WIRES. I WILL STUDY
ON THE OUTER RETINA, ASKING THE
QUESTION HOW DO YOU CHOOSE
PARTNER S? MAYBE I WON'T BE
ANSWERING HOW BUT THE FACT YOU
NEED TO CHOOSE PARTNERS OR MAYBE
SOME DON'T NEED PART NERS AND
TALK ABOUT THE INNER RETINA FOR
THIS PARTICULAR SYNAPSE, WHICH
WE WILL GET TO IN A MINUTE.
BECAUSE ANAN IS HERE, I DECIDED
TO PUT THIS LITTLE SNIP PET IN
TO TALK ABOUT ROD AND CONE
CONNECTIVITY. I THINK THIS IS
THE FIRST TIME YOU ARE SEEING
IT. ABOUT THE FIRST TIME I AM
TOO. SO WE WILL WORK ON THIS
TOGETHER. WE ALL KNOW ROD
BIPOLAR LOVE RODS. THEIR PRIMARY
CONNECTIONS ARE ROD. THEY IN
MOUSE RETINA CAN CONTACT SOME
CONES TOO BUT THEY REALLY LIKE
RODS. THE CONVERSE IS TRUE FOR
THE CONE BIPOLARS WHICH LOVES
CONES AND VERY FEW RODS. WELL,
WE KNOW ALSO THE ROD KIND
SYNAPSES DIFFER SOMEWHAT. THE
ROD SPHERE IS SMALLER, THE CONE
IS MORE TRIANGULAR, HAVE MORE
SITES THE CONE BIPOLAR CELLS.
BOTH ARE INVITING SYNAPSES IN
THAT THEY PUT LITTLE DENDRATIC
TIPS IN THE SPIR RI KAL OPPOSITE
THE RUB BO RIBBON SIDE WHERE
RELEASE OCCURS. THE MANY STUDIES
FOR EXAMPLE WHERE YOU DON'T HAVE
MANY CONE, LOSS OF CONES FOR
EXAMPLE, EITHER TO DEVELOPMENT
OR DISEASE, THE UN-BIPOLAR CELLS
CAN CONTACT THE RODS. THEY DO.
THEY DON'T EN DODGE NATE ALL THE
TIME. IN CASE YOU LOSE RODS THE
ROD BIPOLAR CELL NOT HAVING MY
RODS WILL CONTACT MORE CONES. SO
CHI IN MY LAB WAS NOT INTERESTED
SO MUCH IN RODS AND CONES BUT A
RETINA WITH CONE-FREE, NO RODS
AND LOTS OF CONES. THIS IS THE
RD7 RETINA, THE S CONE MUTANT,
FOR EXAMPLE. AND THE NRL
KNOCK-OUT. YOU ALL KNOW ABOUT
NRL BECAUSE ANON IS HERE AND
DISCOVERED HOW IMPORTANT THIS
GENE IS IN REGULATING ROD FATE.
THIS IS CONE FATE. IF THERE IS
ANYTHING WRONG, BASICALLY TELL
ME LATER. IF YOU GET RID OF NRL,
YOU DON'T MAKE RODS. IT IS
INCREDIBLE. THIS IS A REALLY
IMPORTANT GENE. AT THE SAME
TIME, YOU DON'T LOSE THOSE
CELLS, THEY ALL BECOME CONE-LIKE
CELLS. NOT JUST CONE-LIKE BUT S
CONE-LIKE CELLS. ASSOCIATED WITH
CONES RATHER THAN WITH RODS. IF
YOU COMPARE AND LOOK AT WHAT
THESE CONE TRENDS ARE COMPARED
TO CONES, WHAT DO THEY HAVE IN
COMMON, THEY HAVE IN COMMON SOME
HISTOLOGY, WAVELENGTH AT 360.
KNOW NR23 STANDS FOR NRL, IF YOU
LOOK AT THE MU TIGS, WH -- MUTA
YOU MAKE CONES. THINGS ARE A
LITTLE MORE COMPLICATED IN THE
RD7. YOU NOT ONLY MAKE THESE
CONE-LIKE CELLS BUT YOU ALSO
HAVE A HYBRID, A ROD/CONE HYBRID
WITH RODOPSIN IN IT AND MANY
THINGS. IT WILL BE MANY OF THOSE
THINGS ANON AND I WILL TALK
ABOUT LATER , THE GENE PROFILES
THAT MAKES THESE CELLS THE WAY
THEY ARE. BASICALLY SHE ASKED
WHAT HAPPENS TO BIPOLAR CELLS
WHEN FACED WITH JUST CONES AND
CONE TRENDS IN THE NRL KNOCK-OUT
OR THIS THREE PHOTO RECEPTOR
TYPES IN THE RD7? FIRST OF ALL
COULD WE FIND AND DIFFERENT
TYPES OF RECEPTORS. YOU CAN SEE
RODS AND CONES LOOK DIFFERENT.
CONES MULTIPLE RIBBONS, RODS
SINGLE, VARIOUS ARE TRIANGULAR,
THESE ARE BULBOUS. IN NRL CONE
LOOK MORE LIKE RODS BUT HAVE
MULTIPLE RIBBONS AND THEIR CONES
A LITTLE ALTERED SLIGHTLY MAYBE
NOT QUITE TRIANGULAR BECAUSE
THERE'S SO MANY OF THESE THAT
ARE PUSHING EVERYBODY AROUND.
YOU SEE THESE TWO TYPES. THESE
ARE 0EM RECONSTRUCTIONS AND IN
THE RD7 YOU SEE THE HYBRID. THE
CONE TRENDS, WHICH IS MORE LIKE
-- SO SOMETHING IN BETWEEN. THEN
THE NORMAL CONES BECAUSE THEY
COME -- THEY MEET FROM CONE PER
CURSOR LINEAGE INSTEAD OF THE
ROD. IF YOU LOOK AT THE
RECEPTORS, THIS IS THE NORMAL
TRID ARRANGEMENT. THEY MAKE LOTS
OF SYNAPSES BUT SOME ARE NOT
VERY NOVEL. THEY DON'T HAVE IN
THIS CASE BIPOLAR BUT NO HORIZON
CELLS COAT IN THAT SITE. SOME
THESE SYNAPSES ARE NOT NORMAL
BUT MAKE LOTS OF SYNAPSES WITH
CONE TRENDS. SHE MAPPED OUT THE
CONNECTIVITY. THE FIRST IS IF
YOU LOOK AT THE CONE PRECURSOR
DERIVED CELLS, SO IN RD7 AND THE
KNOCK-OUT AND NOT WILD TYPE THIS
IS WHAT LOOKS LIKE. YOU CAN SEE
ROD BIPOLAR DON'T LIKE CONE-LIKE
CELLS. WILD TYPE WE KNEW
ALREADY. MAYBE A LITTLE BIT IN
OUR KNOCK-OUT, THERE IS SOME,
BUT IN THE RD7 IT IS PRETTY MUCH
WILD TYPE LEVEL. BUT IN THE ROD
PRECURSOR DERIVED PATHWAY THAT
LINEAGE THAT REQUIRES THE NRL
AND 2E3 WE SEE A COMBINATION OF
EFFECTS. WE SEE THE ROD BIPOLAR
CENTS DON'T MIND CONE TRENDS BUT
IN RD7 THE ROD BIPOLAR PREFER
MORE THAN CONE TRENDS IN THE
KNOCK-OUT SO THIS SEEMS REALLY
CONFUSING BUT WE CAN THINK ABOUT
IT IN OTHER WAYS IN A WHILE. I
SAID TO GI, WHAT IS COMING AND
WHAT IS DIFFERENT IN THESE TWO
CONDITIONS THAT CAUSE THE ROD
BIPOLAR AND CONE BIPOLAR TO
SELECT PARTICULAR PARTNERS AND
NOT OTHERS? ROD IS GOING TO
CONNECT WITH BIPOLARS AND SAID
NO IT IS NOT THE MORPHOLOGY BUT
THERE ARE GENES EXPRESSED IN
TH
THIS CLUSTER THAT RODS RECOGNIZE
OR USE THIS THESE ARE MORE
PREFERRED PARTNERS AND THIS
ISN'T THERE. EITHER THE TWO CONE
TRENDS ARE DIFFERENT OR THERE IS
A CHOICE IN SENSE OF THE RD
WHERE THE BIPOLARS CAN GO FOR
MORE ROD-LIKE RECEPTORS COMPARED
TO A CONE-LIKE ONE. A CHOICE OR
SOMETHING DIFFERENT. SO ANON
HELP ME LATER AND FIGURE OUT
WHAT THE MOLECULAR DIFFERENCES
MIGHT BE. THE IMPORTANT THING IS
CONE BIPOLARS. THIS IS ONE TYPE,
CONE TYPE 6. NRL AND RD7 THESE
CONE BIPOLAR CELLS, HERE IS THE
WILD TYPE. THEY NORMALLY DON'T
WANT RODS BUT IN NRL THEY ARE
QUITE HAPPY WITH THE CONVERTED
CONES OR THE CONES THEMSELVES.
IN THE RD7 THEY PREFER THE
CONES, SOME CONE TRENDS BUT NOT
THE HYBRID. SO AGAIN I THINK WE
CAN USE THESE TWO ESSENTIALLY
MODEL SYSTEMS TO BEGIN TO TEASE
APART COLLECTION OF MOLECULES
THAT HAVE RODS TO ROD BIPOLARS
AND CONE BIPOLARS JUST PICKING
UP CONES. IF YOU KNEW WHAT THESE
MOLECULES ARE, NOT JUST SO MUCH
FOR UNDERSTANDING DEVELOPMENT
BUT MIGHT BE USEFUL IN TERMS OF
SETTING UP WHAT COULD BE
IMPORTANT DATA ON REPAIR.
LEAVING THE BIPOLARS JUST TO
TELL YOU THAT THE HORIZON CELLS
WHICH ALSO ARE PARTNERS AT THIS
SYNAPSE NORMALLY HAVE DENDRITES
AND AXONS AND DENDRITES NORMALLY
LIKE CONES AND AXONS LIKE RODSN.
A CONE FULL RETINA YOU HAVE THE
DENDRITE SEPARATED BUT
CONNECTIVITY ARE NO LONGER
SPECIFIC. THE AXONAL AND
DENDRITIC CONTRAST RODS AND
CONES IN NRL AND NO RODS LEFT.
SO QUICK SUMMARY, BASICALLY WHAT
WE FOUND IS THAT IN THE WILD
TYPE YOU HAVE KIND OF THIS
CONDITION. IN THE NRL KNOCKOUT I
DEMONSTRATED ROD BIPOLAR CONNECT
TO BOTH TYPE OF RECEPTORS SO
WILL THE CONE BIPOLAR CELL BUT
IN THE RD7 THE ROD BIPOLAR
PREFERS THE HYBRID OVER THE CONE
TRENDS AND THE CONE BIPOLAR
CELLS PREFER THE CONE-LIKE CELLS
COMPARED TO THE ROD HYBRID.
THERE IS SOME SELECTIVITY. WE
JUST DO NOT KNOW EXACTLY WHAT
THESE ARE. THAT IS WHAT I JUST
SAID. BUT I THINK IF YOU ARE
COMPLETELY CONFUSED AT THE
WIRING, DON'T WORRY ABOUT IT AT
ALL. I THINK THE KEY HERE FOR ME
WAS NOT WHO PICKED WHO BUT YOU
CAN EXPRESS IN FOUR RECEPTORS
ALONE THAT. WILL DICTATE
SYNAPTIC PARTNERSHIP WITH THE
BIPOLAR CELLS. THAT ALONE FOR
REPAIR, THAT WOULD BE REALLY
GOOD TO KNOW. YOU WON'T HAVE TO
AFFECT TWO SITES OF THE
PARTNERSHIP IN ORDER TO FORM
THAT HANDSHAKE. YOU JUST HAVE TO
DO SOMETHING WITH THE LEFT HAND
AND THEY WILL KNOW WHICH RIGHT
HAND TO GO FOR. MAKE SENSE? VERY
QUICKLY THE MOLECULAR
INTERACTIONS, FOR SURE, IS
IMPORTANT. AT LEAST LET'S LOOK
AT WHAT HAPPENED TO THE --
BASICALLY DEVELOPMENT OF THESE
SYNAPSES FOR RODS AND CONES FOR
EXPERIENCE AND WE FIND IF YOU
DOT REAR THE ANIMAL THE DOT
REARING DIMINISHES THE CONE BUT
NOT THE ROD. THESE ARE RAWLINGS
YOU ARE FAMILIAR WITH SO CONE
RESPONSE IS DOWN BUT NOT WITH
THE ROD. THAT IS BECAUSE IN THAT
AT THE FULL RECEPTOR SYNAPSE
APPEARS TO BE NORMAL. THESE ARE
JUST STAINING FOR THESE
RECEPTORS BUT MUCH LOWER IN
CONES THEMSELVES. SO THESE
RECEPTORS SEEM TO NOT CLUSTER OR
HANG AROUND IN DOT REARING IN
CONE PATHWAY BUT NOT IN THE ROD.
YOU DON'T NEED LIKE TO KEEP THAT
ROD SORT OF SYNAPSED TOGETHER.
SO LET'S SEE. I HAVE LITTLE MORE
TIME. SO LET'S TALK NOW, MOVE
FROM OUTER RETINA TO INNER
RETINA. I PROMISE WE CAN TALK A
LITTLE ABOUT THE OUTPUT OF THE
CELLS. HERELY STICK TO THE ROD
PATHWAY WHERE I WILL TALK A
LITTLE ABOUT ROD BIPOLAR
CONNECTING WITH ENOCRN CELL AND
PARTICULARLY THIS PICTURE, WHAT
THEY LOOK LIKE, WHAT WILL HAS
INJECTED. YOU WILL SEE CELLS
MAKE CONNECTIONS PRETTY MUCH
WITH THE ROD BIPOLAR CELL
FORMING SYNAPSE WITH TWO TYPES
OF AMMOCRYNS AND INTERESTING NOT
DRIVEN BY ROD BIPOLAR CELL BUT
DRIVES IT ALSO. RESIP ROW KAL
FEEDBACK FOR THIS INHIBITION.
THAT OCCURS AT THESE DOTS. I
WILL TALK ABOUT THIS SYNAPSE.
WITH E KNOW THE SELECTIVITY OF
THE A17 FOR ROD BIPOLAR CELLS IS
HERE. SO THIS IS A17 CELL. ALL
THESE -- SORRY, ALL THESE YELLOW
DOTS ARE WHERE BUTONS ARE WITH
THE ROD BIPOLAR CELLS, MAKE VERY
FEW CONE, BIPOLAR OR GANGLION
CELL SYNAPSES. THE FEW THEY MAKE
WITH THE BIPOLAR CELL, WHICH
THERE ARE MANY TYPES OF THESE.
SO WE KNOW THIS A17 REFERENCE
FOR ROD BIPOLAR CELLS APPEAR
EARLY IN DEVELOPMENT. YOU CAN
SEE POST 9 AND 10 ARE MUCH OF
THE SYNAPSES ARE HERE AND THEY
ARE YELLOW WITH THE ROD BIPOLAR
CELLS. OKAY. SO SELECTIVITY
EARLY. WHAT HAPPENS IF YOU KILL
OFF THESE ROD BIPOLAR CELLS? WE
USE A METHOD WHERE WE EXPRESS ON
BIPOLAR CELLS. NOT ONLY ROD BUT
SOME ON BUT NOT OFF BIPOLARS
USING LINE WHERE EXPRESSED
TOXIN. THEY EXPRESS YELLOW IN
PROTEIN BUT IF NOT REMOVED THERE
IS NO DTA EXPRESSION. SO THESE
FLUORESCENT AREAS ARE TERMINALS
WITH I ARE FINE AND DOT AREAS
WHERE THERE ARE BIPOLARS AND
EXPRESSING DTA. WE DO
FLUORESCENT IMAGING, USE THE
LASER TO MAKE MOUNTS TO FIND
EXACTLY THESE BUTONS AGAIN UNDER
EM. FROM ONE OF THEM TRACE BACK
A17AMACYN CELL. WHAT WE CAN SEE
IF YOU DO NOT HAVE MANY ROD
BIPOLAR CELLS DURING DEVELOPMENT
THE A17 MAKES MORE SYNAPSES WITH
THE COMBINED BIPOLAR CELLS.
THERE IS SOME QUANTIFICATION
HERE. MANY OF THESE COMBINED
BIPOLAR CELLS, THERE ARE LOTS OF
OFF, SOME ON BUT WE KILLED SOME
ON BIPOLAR CELLS. WITH THIS ONE
STUDY WE THINK A17 RECOGNIZES
THIS ROD BIPOLAR NOT BY CUES
BECAUSE THEY ACTUALLY MAKE
SYNAPSES TOO SO NOT RESTRICTED
TO THIS LAYER. BUT THEY SEEM TO
NEED SOME SELECTION CRITERIA
WHICH HELP THEM GO FOR ROD
BIPOLARS OVER CONE.
IF YOU DON'T HAVE ROD THEY WILL
GO FOR THE CONE BIPOLAR EVEN THE
OFF CELLS. THIS CAN EXTEND ON
AND OFF AND ROD AND CONE
PATHWAY S SO WE THINK THERE
MIGHT BE SOME SUPPRESSIVE SIGNAL
DISCOURAGING A17 FROM SYNAPSING
WITH CONE BIPOLAR WITH ROD WHEN
THEY MAKE CONTACT WITH ROD
BIPOLAR CELLS.ENTERTHIS
SUPPRESSIVE SIGNAL IS I FORM A
HANDSHAKE, I KNOW WHO MAKING
HANDSHAKE WITH, I DON'T NEED TO
REACH OUT TO THE NEXT PERSON OR
SOMETHING LIKE THAT. A STRONG
HANDSHAKE. IF THAT HANDSHAKE
ISN'T THERE, NEXT PERSON, GO
DOWN TO THE NEXT ROW AND MICHAEL
IS NOT HERE SO GO TO THE NEXT
PERSON FOR HANDSHAKE. MAY BE
THAT THE TYPE ALLERGY. IS THIS
SPECIAL A17 IN THE MOUSE OR LIKE
JORAM SAID COULD IT BE SOMEONE
IN CROSS SPECIES OR DIFFERENT.
SO IN ZEBRAFISH WE FOUND A
SIMILAR PHENOMENON. INSTEAD OF
BIPOLAR WE HAVE HORIZON CELL
THAT LOVES UV CONES, THESE GUYS,
OVER BLUE CONES. DURING EARLY
DEVELOPMENT THERE IS ALREADY A
BIAS AND THAT BIAS GROWS AS THE
ANIMAL GROWS UP AND MAKES MORE
CONNECTIONS. LOVES UV, A LITTLE
BLUE. BUT IN DEVELOPMENT IF YOU
USE MUTANTS IN WHICH THERE ARE
FEW UV CONES, NOW YOU ASK WHAT
HAPPENS. THIS IS A SUMMARY OF
THIS PAPER BY AKISHI. THIS
HORIZON CELL WILL MAKE LOTS OF
BLUE CONE INSTEAD. SO LIKES --
ALL NEURONS LIKE TO MAKE
SYNAPSES, PLEASE MAKE A SYNAPSE.
THEN LIKE WHICH TYPE. SO IN
ABSENCE OF PREFERRED PARTNER
THIS HORIZON CELLS GO FOR THE
SECONDARY ONE. IT DOESN'T GO FOR
RED GREEN, THOUGH. SO THERE IS
STILL SOME SELECTIVE ONES, MAKE
SELECTIVITY AS THEY MAKE THEIR
CIRCUITRY DURING DEVELOPMENT. WE
DO NOT KNOW WHAT THIS BRICK
MIGHT BE. IF THERE IS SUCH A
BRICK. WHEN FEW ARE HERE MAKE
PARTNERSHIP, DON'T DO BLUE. IT
IS A CONCEPT I THINK IS WORTHY
OF US THINKING MORE INDEPTH.
BECAUSE WHEN YOU ALSO REWIRE
SOMETHING WHAT ARE YOU
PRESENTING TO THE NEW NEURONS
THAT -- FROM THE NEW NEURON'S
POINT OF VIEW WOULD BE
ADVANTAGES FOR THE SURVIVING
NEURONS , THE ONES THEY CONNECT
TO IT. IF THEY NOW HAVE A
CHOICE, HOW DO YOU HELP THEM
MAKE THAT CHOICE? WE DIDN'T
EXPECT THIS. WE THOUGHT IF IT IS
A MOLECULAR MATCHING, YOU HAVE
MOLECULES A HERE, MOLECULES A
AND RECOGNIZE SO YOU HAVE
SELECTIVITY INDEED, A FANTASTIC
WAY OF SELECTIVITY. THERE'S LOTS
OF EXAMPLES, ESPECIALLY IN
INVERTEBRATE DEVELOPMENT AND IN
THE INNER RETINA, JOSH'S GROUP.
SO I JUST WANT TO EMPHASIZE
LOSING SOME PARTNERS DOESN'T
ALWAYS LEAD TO INCREASE
CONNECTIVITY. THE OTHER AMACRYN
MAKES CONNECTIVITY TO OFF
BIPOLAR CELLS. IF YOU NOW REMOVE
ALL THE BIPOLAR CELLS THE
PRIMARY PARTNER IS GONE. IT CAN
STILL MAKE CONNECTIONS WITH
GANGLION CELLS BUT VERY FEW.
WHAT HAPPENS? INCREASED
CONNECTIONS TO THE GANGLION CELL
OR NOT? SO CLAIR WHEN IN THE LAB
LOOKED AT THE STRUCTURES, THE
OUTPUT SITE OF THE CELL. WE CAN
IMAGE AND SEE WHAT THEY LOOK
LIKE. WE HAVE THIS BIPOLAR MOUSE
FROM MIKE'S GROUP, DSX2
KNOCK-OUT AND YOU CAN STILL SEE
LOBULES. THE NUMBER DO GO DOWN.
IN FACT, IF YOU MEASURED THE
NUMBER OF SYNAPSES THESE LOBULES
MAKE WE HAVE NOW OF COURSE
BIPOLAR CELLS DOESN'T INCREASE
WHICH MEANS A2AMOCYN CELL LIKES
BIPOLAR AS PRIMARY SYNAPTIC
PARTNER, TAKE AWAY, I WILL JUST
DO GANGLION CELL BECAUSE THE
ROLE FOR EXAMPLE THE BIPOLAR IN
THE GANGLION CELL MUST BE VERY
DIFFERENT. ALSO COULD BE THE
HIERARCHY OF CHOICES IS WITHIN A
CLASS OF CELLS. YOU KNOW WE GOT
RID OF ROD AND OTHER BIPOLARS
AND PICKED THE OFF-CONE BIPOLAR
BUT A17 DIDN'T GO CRAZY AND
SYNAPSE OTHER AMOCYN AND GANG
CELL S SO MIGHT BE WITHIN THE
PREOR POST SYNAPTIC CLASS THAT
IS THE PRIMARY CHOICE. I THINK I
HAVE A LITTLE MORE TIME. I
WANTED TO PICK SOME TOPICS I
FELT MY COLLEAGUES HERE MIGHT BE
INTERESTED IN. MANY OF THEM SO
MANY THINGS. SOMETHING THAT WILL
HELP PERHAPS FURTHER THE
DISCUSSION BECAUSE MIGHT BE
SOMETHING THAT THEY ARE
INTERESTED IN. UP TO THIS POINT
I HAVE BEEN EMPHASIZING MAKING
HANDSHAKING BETWEEN NEURONS IN
THE RETINA, MAKING S CIRCUITS
BETWEEN NEURONS SO THAT WIRING
SPECIFICITY IS IMPORTANT. HOW WE
THINK ABOUT GLIAL, HAVE NOT
THOUGHT ABOUT GLIAL CELLS UNTIL
RECENTLY BECAUSE WE ARE WATCHING
IN THE LAB, WORKING WITH DAVID
BURRSON. THIS IS NOT DAVID
BURRSON. SO I JUST HAVE TO BAKE
HIM LOTS OF CAKES. HE IS HAPPY,
STARING A THE SCREEN. VERY GOOD
MITOCHONDRIA PAINTING, BY THE
WAY. SO WHEN SHE'S BEEN LOOKING
AT IS ASSOCIATION OF CELLS WITH
THE BIPOLAR CELLS. FOR THAT HERE
IS AN EXAMPLE OF WHAT A MULE
CELL LOOKS LIKE OR PROCESSES IN
THE RETINA. 3D RECONSTRUCTION,
PAINFUL AND FINE PROCESSES,
MANUALLY OR ESSENTIALLY WE KNOW
THE MULE CELLS ASSOCIATE CLOSELY
WITH MEMBRANE OF MANY NEURON,
ESPECI
AXONS OF BIPOLAR AND WHERE THE
RIBBON IS. SHE ASKED ARE THESE
PROCESSES -- DO THEY JUST COME
UP RANDOMLY AND FILL UP SPACE?
WE KNOW WHAT MULE CELLS DO
FUNCTION FOR PRODUCTION OF
GLUTAMATE AND FUNCTIONS. GO SEE
OTHER REASONS AND OTHER ROWS,
FORMULA CELLS IN TERMS OF WHAT
THEY DO IN THE RETINA. WE WANTED
TO KNOW HOW THEY ASSOCIATE WITH
THE BIPOLARS. SO HERE ARE THE
MUELLER CELLS IN MAGENTA. SO
CONNECTIONS NEXT TO THE AXON
TYPES O F BIPOLAR CHEELLS, THISS
ONE ACROSS MANY. YOU CAN SEE THE
TYPE FIVE BIPOLAR CELL IS
PAINTED, ITS AXON AND PROCESSES
ARE PAINTED QUITE STRONGLY WITH
MUELLER PROCESSES, WHERE TYPE
SIX IS VERY LITTLE ASSOCIATION
HERE. SHE'S BEEN DOING THIS FOR
ALL TYPES OF BIPOLAR CELLS AGAIN
IN THE MASS, ROD BIPOLAR CELLS
ARE HEAVY PAINTED TYPE 5s
BIPOLAR CELLS WHICH ARE STILL
THIS CASE ON, SOME TYPE 3 MAYBE
BUT 6 IS NOT MUCH, SORRY, WHERE
TYPE 9 DOESN'T HAVE VERY MUCH.
IF YOU START QUANTIFYING, AND WE
WANTED TO START DOING THIS, BUT
TYPE 2 HAS VERY LITTLE, TYPE 6 A
LITTLE, TYPE 5 HAS A LOT MORE BY
COMPARISON. WHAT COULD THIS
DIFFERENCE MEAN? IT COULD MEAN
THAT, YOU KNOW, THEY PLAY SOME
ROLE IN RESPONSES OF GANGLION
CELLS. TYPE 6 PROVIDE MAJOR
INPUT ON SUSTAIN OR LIGHT STEP.
TYPE 5s I AND OTHERS PROVIDE
MAJOR INPUT TO GANGLION CELLS
AND SPIKE. IF YOU RECALL FROM
GANGLION CELLS THEY LOOK SIMILAR
IN THEIR RESPONSES, CURRENTLY
RESPONSES AND THE GANGLION
CELLS, HERE IS SUSTAINED AND
HERE IS THE TRANSIENT. I DON'T
KNOW IF THERE IS ANYTHING TO DO
WITH THIS, JEFF. YOU CAN TALK
AGAIN BECAUSE THIS EXPERIMENTS
OF GALTOM. THE, EXPRESS IN THESE
CELLS TO GET A READOUT OF
GLUTAMATE IN TISSUE BUT THE
EXPRESS IS ON DENDRITE OF CELL
SO WHATEVER NEAR THE CELLS YOU
CAN SEE A FLUORESCENT CHANGE.
HERE ARE REGIONS OF INTEREST IN
GANGLION CELL FOR EACH REASON
AND SEE SUSTAINED GLUTINATE
FLORES SENSE IN THE -- DENDRITES
FOR UNSUSTAINED AND YOU SEE
TRANSIENT FLUORESCENT CHANGES.
AS JEFF POINTED OUT THESE ARE
LONG GLUTAMATE, MILLISECONDS,
NOT JUST SECONDS, BUT WHY DO WE
SEE THIS. DUE TO ASSOCIATION HOW
MUCH MUELLER CELLS ARE NEAR
AXONS OR SYNAPTIC SITES. ONE OF
THE FUNCTION IS SOAK UP
GLUTIMATE THROUGH THEIR
TRANSPORTERS. WE ARE NOT THERE
YET BUT INTERESTING OBSERVATION
THAT EVEN GLIA IN RETINA HAS
SOME SPECIFICITY IN PART NERSHI
WE WANT TO MAKE. TEN MINUTES,
THEN WE CAN ALL GO. FINALLY
WHERE ARE WE NOW? WE TRYING TO
I.N.S. CIRCUITRY IN DISEASE AND
HOW WE THINK ABOUT THAT OF
THINKING ABOUT THE CIRCUITS,
WHAT HAPPENS IN TERMS OF REPAIR.
WE KNOW THIS BEAUTIFUL
ORGANIZATION CAN BE COMPLETELY
DISRUPTED BY MANY DISEASES. THIS
JUST ONE EXAMPLE, RETINITIS
WHERE RODS REACH TO INNER RETINA
TO GANGLIAL CELL. WE DON'T HAVE
A DISEASE MODEL BUT FIGURED IT
WOULD BE INTERESTED TO LOOK AT
THE FULL WHICH HASN'T BEEN
LOOKED AT IN FULL DETAIL WHEN
COMES TO CIRCUITRY OR IN SOME
DISEASE. IS CIRCUITRY ITSELF. WE
KNOW THERE'S SPECIALIZED
ORGANIZATION IN THE PRIMATE
PHOBIA INCLUDING OUR OWN WHERE
MIDGET PATHWAY SINGLE CONE
CONNECTS THROUGH A PAIR OF ON
AND OFF BIPOLAR CELL THAT
CONNECTS TO GANGLION CELLS, LIKE
PRIVATE LINE. THERE IS A LOT
MORE CONVERGENCE AND DIVERSE
AGAINST. THERE IS PRIVATE LINE
ALSO EXISTS IN THIS PHOBIA.
TYRO, AN OPHTHALMOLOGIST, BACK
IN JAPAN NOW, CAME OVER AND HAD
BROUGHT SOME EYES THAT HAD
RECEIVED LASER TREATMENT. THAT
SHOULD BE A CELL HERE. THIS WAS
IN BASICALLY WHERE THEY WERE
BURNING OFF AUTO RECEPTORS USING
A LASER CALLED AGULATION METHOD
TO SEE NEW PHOTO RECEPTORS AND
LOOK FOR REPAIR. THEY ARE DEPEND
RATING A -- THEY ARE GENERATING
A MODEL. SO THE ANIMALS, TISSUE,
EYES SENT TO US. BASICALLY MANY
REGIONS BUT THE LASER TREATMENT
STARTED EITHER AT TWO WEEKS
BEFORE FIXIATION OR TWO OR SIX.
WE COULD SEE THE CHANGE OVER
TIME. THIS IS AN EMA OF THIS
REGION THAT'S BEEN LASERED, SO
AROUND HERE. YOU CAN SEE ALL THE
FIBER HERE, MORE SPACE WITH
CONES ANYMORE. RPE IS STILL
INTACT. THESE ARE EDGE, FLOPPED
OVER A LITTLE BIT BUT ALL HAVE
ALL THEIR SEGMENTS. THIS
SCHEMATIC REALLY BROUGHT HOME TO
ME HOW DIFFERENT THE PHOBIA IS
IN TERMS FOR US TO THINK ABOUT
REPAIR. HERE WE LASERED AND
KILLED OFF BUT CONNECTIONS OF
PHOTO RECEPTORS WERE HERE
BECAUSE OF FIBER EXTEND HUNDREDS
OF MICRONS AND MAKE CONNECTIONS
WITH THE BIPOLARS HERE, OKAY. IF
YOU WERE TO TAKE THIS RE-JOHN
FOR EM, YOU WILL SEE THERE ARE
NO COMPARABLES BUT THE CONE CELL
BODIES WERE UP HERE. WHAT WE
FOUND IS FAR FROM THIS DEPRIVED
ZONE WHERE ALL THE CELLS HAVE
DISAPPEARED. SO IN THIS AREA YOU
SEE THE MIDGET CONNECTIVITY BOTH
ON AND OFF PRIVATE LINE. IN THE
PARTICLE MAKE HANDSHAKE AND SIX
MONTHS POST ABLATION SUGGESTING
YOU HAVE THIS ON-AND-OFF
ORGANIZATION. IN THIS BOUNDARY
YOU SEE WEIRD THINGS SOMETIMES.
YOU CAN SEE DIVERGENCE AND
CONVERGENCE IN MIDGET PATHWAY
THAT IS NOT NORMAL. I WON'T HAVE
TIME TO TALK ABOUT THE SCHETOM
BOUNDARY, WHICH YOU MAY BE
INTERESTED BUT WANT TO TALK
ABOUT DISCONNECTED MIDGET CELLS.
WHAT HAPPENS TO THEM? WHEN THERE
ARE NO MORE CONES FROM -- THIS
IS SIX MONTHS. IN GENERAL IT IS
HARD TO TELL WHETHER THERE IS A
CHANGE IN CONVERGENCE OR
DIVERGENCE AT ALL. THIS CASE
CONVERGENCE. SOMETIMES EVEN IN
THE NORMAL PHOBIA YOU MIGHT NOT
SEE A ONE-TO-ONE. THERE ARE
SOMETIMES TWO CELLS THAT ARE
CONNECTED. BUT WHAT CLEAR IS
NUMBER OF SYNAPSES IN THE OFF IN
THIS PARTICULAR CASE DEFINITELY
GOES DOWN, OKAY. THESE WILL BE
SYNAPSES HERE. THE SAME
DIVERGENCE, BY HOW MANY BIPOLAR
CELLS IS ONE-TO-ONE BUT WE NEED
30 CELLS TO BE CERTAIN. NOT
GOING TO MAKE TOO MUCH OF THE
DIVERGENCE OR CONVERGENCE BUT
DECREASED SYNAPSES IN THE OFF
CELLS. WHEN WE LOOKED A LOT MORE
-- THINK WILL SHOW HERE --
EVENTUALLY WE ALSO FOUND IF YOU
LOOK AT RIBBONS INSTEAD, SO ALL
SYNAPSES. YOU LOOK AT ON-AND-OFF
CELLS BASICALLY THE AMOUNT OF
AXONAL MATERIAL, TERMINAL
LENGTH, DOESN'T CHANGE ALL THAT
MUCH. BUT YOU SEE THIS DROP IN
SYNAPSES. THIS CASE REALLY BOTH
ARE ON AND FOR OFF. THE DECREASE
IN OUTPUT SYNAPSE, RIBBONS IN
THIS STAGE, OCCURS BETWEEN TWO
WEEKS AND TWO MONTHS
POST-ABLATION SO THIS
PROGRESSIVE LOSS OF CONNECTIONS
OR SYNAPTIC SITES BETWEEN CELLS
THAT MAKE THE HANDSHAKE. MOST OF
THE TIME IT IS A SINGLE MIDGET
BIPOLAR TO GANGLION CELL. SO IT
IS STILL KIND OF MARRIED TO THE
SAME WHATEVER, IT IS JUST
TALKING LESS. FEWER SITES OF
COMMUNICATION BECAUSE OF LOSS OF
SOME RIBBONS. WHATEVER REMAINS,
THOSE SYNAPSES SEEM TO MAINTAIN
NORMAL STRUCTURE ARRANGEMENT. WE
KNOW MOST OF THE SYNAPSES
NORMALLY ARE DIET, WHERE THE
WITH BIPOLAR MAKES CONNECTIONS
WITH TWO POST SYNAPTIC CELLS AND
FIND MOST SYNAPSES ARE STILL
DIED. SO WHAT IS HAPPENING IS
ESSENTIALLY POST-SYNAPSES ARE
DROPPING OFF, LOSING RIBBONS AND
SYNAPSES, LOSING CONNECTION WITH
GANGLION CELL AND NOT SOMETHING
ELSE. NOW SOME THESE
REARRANGEMENTS REMIND ME OF THE
HUMAN RETINA IN DEVELOPMENT
WHERE THERE IS A LOT OF
CONVERGENCE AND DIVERGENCE IN
RETINA BETWEEN MIDGET BIPOLAR
AND GANGLION CELLS. EVENTUALLY
THEY ARE ZOOMED AWAY, THOUGH WE
DON'T HAVE TIME POINTS EXACTLY
WHEN WHEN THESE CONNECTIONS
WHICH THE PRIVATE ORGANIZATION
WHICH IS DOWN HERE ONE-TO-ONE.
YOU CAN SEE BOTH CONVERGENCE AND
DIVERSE AGAINST, IT TAKES TIME
TO SHAPE THAT PRIVATE LINE
CONNECTIVITY IN DEVELOPMENT IN
HUMAN. BUT WHAT WE THINK IS
DIFFERENT IS THAT ALTHOUGH THERE
ARE CHANGES THIS PALACE TISTY
AND DEVELOPMENT BETWEEN THE
PATHWAY BETWEEN GANGLION AND
BIPOLAR, IN DEVELOPMENT THE
REFINE
REFINEMENT OF THIS NEED TO LET
GO. SO IF YOU READ PAPER WITH
PRIMARY PARTNER IS ESTABLISHED
VERY EARLY AND DOESN'T DECREASE
VERY MUCH AT ALL. SO IT SHAPES
ITSELF LASTLY BY DROPPING OFF
SOME OF THE PARTNERS AND KEEPING
PARTNERSHIP ONLY WITH ONE
GANGLION CELL. IN THE ADULT CONE
LOSS MODEL, SINGLE PARTNER IS
MAINTAINED. DOESN'T REACH OUT TO
MANY MORE PARTNERS, AS A GENERAL
RULE. BUT IT IS LOSING SYNAPSES
THOUGH IT IS MAINTAINING THE
SINGU
SINGULAR HANDSHAKE. MAKE SENSE,
EVERYBODY? GOOD. THERE IS A LOT
MORE WORE TO DO WITH THIS AND
WHAT THE CHANGES MIGHT BE
NEED ED THAT LEAD TO THIS
CIRCUIT REMODELLING IN THE
MIDGETS, WHAT ARE FUNCTIONAL
CHANGES THAT COULD BE REFLECTED
IN THE ANATOMICAL CHANGES AND
HOW FAST THIS OCCURS. SO YOU
HAVE TO DO PHYSIOLOGY. FOR ME
THERE IS ALWAYS GOING TO BE SOME
REMODELLING WE CANNOT RECTIFY.
HOW MUCH DO WE NEED TO IN ORDER
TO RESTORE VISION AT LEAST TO A
LEVEL WE MIGHT BE SATISFIED
WITH? MAYBE THE FINEST AND CAN
GET THAT ONE-TO-ONE IN FULL
GLORY BUT GET CLOSE TO IT AND
WHAT WOULD THOSE THINGS BE. I'M
GOING TO END WITH THIS SLIDE. I
THINK THIS IS GOING TO BE THE
SPECIAL CHALLENGE WHEN IT COMES
TO THE PHOBIA, OR ANY ANIMALS
THAT MEET THE PHOBIA. HOW YOU
BRING NEW PHOTO RECEPTORS,
WHETHER YOU PUT ORGANITES IN
CELLS AND RECEPTORS IN REGION
THAT'S LOST AND HAVE THEM
CONNECT TO PARTNERS THAT REMAIN
THAT ARE NOT IN THE SAME ROOM.
THEY ARE KIND OF IN THE NEXT
ROOM BUT THEY WERE CONNECTED
BEFORE BUT THEY HAVE TO FIND
EACH OTHER. YOU WILL SAY WELL
DEVELOPMENTAL NEUROBIOLOGIST,
GIVE THEM RIGHT FACTORS, HELP
THEM GROW PROCESSES AND DO ALL
THIS AXON GROWTH PATHWAY STUFF,
SHOULD BE ABLE TO GET THEM TO
FIND THEIR PARTNERS IN THE NEVER
ROOM, JUST NEVER GET THEM.
SLIGHT PROBLEM. THAT IS THE
HUMAN PHOBIA, THE PHOTO -- CONE
PHOTO RECEPTORS AND BIPOLAR
MIDGETS MAKE THEIR CONNECTIONS
VERY EARLY, PRETALNAPRENATALLY,E
BY MID-GESTATION. PHOTO
RECEPTORS LOOK LIKE THIS. THEY
DON'T EXTEND THESE FIBER OF
HANDS UNTIL THE PIT STARTS TO
FORM. IF THEY DON'T DO IT
THROUGH A GROWTH CONE BECAUSE
THEY HAVE ALREADY MADE THE
CONNECTION WITH THE BIPOLAR
CELL. IT IS TONS OF RIBBONS, THE
SYNAPSES ARE FORMED. SO THE
FIBER OF HAND IS PROBABLY
EXTENSION TO INTERSTITIAL GROWTH
SO YOU CAN USE AXON FINDING CUES
TO GET NEW FULL RECEPTORS TO
GROW AXONS TO REACH BIPOLARS IN
NEXT ROOM. WE HAVE TO THINK OF
OTHER WAYS IF YOU WANT TO REPAIR
PHOBIA CIRCUITRY TO GET THESE
TWO CELL TYPES TOGETHER USING
MECHANISMS THAT ARE PROBABLY
NOVEL TO THEM, THAT THEY HAVE
NOT USED DURING DEVELOPMENT. SO
REPAIR DOESN'T OFTEN MEAN
REVERSE ENGINEERING AS A
DEVELOPMENT. BECAUSE SOME OF THE
TOOLS USING DEVELOPMENT MAY NOT
EVEN BE THERE AND THERE MIGHT
NOT EVEN BE STRATEGIES YOU THINK
YOU JUST HAVE TO, YOU KNOW, TURN
THE GENE ON AND YOU ARE GOING TO
DO IT AGAIN BECAUSE IT JUST
NEVER USED TO DO IT. I THINK
THESE ARE THINGS WE HAVE TO
THINK ABOUT WHEN WE HAVE THE
CHALLENGE, THE SPECIAL CHALLENGE
I THINK FOR THE PHOBIA. SO WITH
THAT I WANT TO THANK MY LAB,
EVERYBODY, MORE OR LESS IN THE
LAST 30 YEARS OR SO. SOME YOUNG
ONES. YOU CAN SEE WE RECRUIT
THEY WILL YOUNG. THE WORK
LARGELY OF CHI, NOW AT THE ALLEN
INSTITUTE. HERE IS CHI. MANY
OTHER PEOPLE THAT I HAVE TO
THANK AND HAVE NOT TIME TO TALK
ABOUT THEIR WORK. MANY
COLLEAGUES I HAVE TO THANK ALSO.
YOU SEE SOME OF THEM HERE. WILL,
PICTURE NEW ONE, BUT
PARTICULARLY WANT TO THANK THE
NEI FOR THEIR SUPPORT THROUGH
THE 30 YEARS AS AN INVESTIGATOR,
MY PROGRAM OFFICES WHO HAVE BEEN
VERY SUPPORTIVE OF OUR LAB
PROGRAM. I HIGHLIGHT ANON
BECAUSE HE'S ALWAYS SUPPORTED ME
FROM WHEN I WAS VERY YOUNG TILL
NOW. HE'S BEEN A WONDERFUL
COLLEAGUE IN TERMS OF DISCUSSING
SCIENCE, BUT HE'S VERY
INSPIRATIONAL BUT ALSO ALWAYS
EXTREMELY SUPPORTIVE. EVEN
THOUGH I KNOW NOTHING ABOUT
GENES AND WE DON'T TALK EXACTLY
THE SAME JARGON BUT WE HAVE THIS
SAME UNDERSTANDING THAT WE ENJOY
EACH OTHER'S SCIENCE, HOPEFULLY.
THERE IS MORE TO TALK ABOUT
LATER. FINALLY I WANT TO THANK
DR. PIATIGORSKY AGAIN AND LONA
PIATIGORSKY. I WAS READ ING THIS
BOOK ON THE PLANE WAS GIVEN TO
ME. IT IS WONDERFUL BECAUSE I
LOVE ALL SORTS OF ANIMALS. I
THINK WHAT I'M LEARNING FROM HIM
APART FROM GREAT SCIENCE IS
MAYBE I SHOULD START LOOKING AT
INV
INVERTEB
INVERTEBRATES. THERE IS SO MUCH
ABOUT THEIR STRATEGIES IN HOW
THEY USE THEIR EYES, AND I THINK
THAT IS USED BY ANY SPECIES TO
CREATE AN IMAGE-GATHERING
PROCESSING EYE I SUPPOSE THAT IS
BEST SUITED FOR THAT SPECIES
NEEDS. HOPEFULLY I GAVE YOU A
FLAVOR OF WHAT WE ARE ABOUT. AND
I HAVE A LOT TO READ, I REAR.
THERE IS A TRILOGY AND MANY OF
HIS WORKS. SO THANKS DR.
PIATIGORSKY, FOR THIS LECTURE
AND THANK THE NIEHS, MICHAEL,
FOR THEIR SUPPORT, THANK YOU
[ APPLAUSE ]
[ OFF MIC ]
PU
>> ANAN.
>> THANK YOU FOR THIS
WONDERFUL TALK. I DON'T
UNDERSTAND ANYTHING ABOUT
INVERTEBRATES SO WE WILL TALK
ABOUT PHOTO RECEPTORS LATER. I
SOMEHOW GOT STUCK WITH RODS AND
CONES AND DON'T SEEM TO LEAVE
ME. BUT THE QUESTION I HAD IS
REALLY MORE FOR YOUR LAST. WHY
DID YOU -- WHY IS NOT A GOOD WAY
TO PUT IT. I WILL SAY IN MOST
RETINAL DISEASES, IN HUMANS AT
LEAST, PHOBIA CONES REMAIN
INTACT. THOUGH THEY ARE NOT
FUNCTIONAL THEY ARE THERE. I
THINK IT WILL BE FUN TO SEE WHAT
HAPPENS TO THEIR CONNECTIVITY
WITHOUT THE ACTIVITIES, RIGHT?
>> ABSOLUTELY.
>> SAME THING HAPPENS THAT
THE FIRST CELLS -- ACTUALLY ONE
OF THE UGLY CELLS THAT DIE IN
MACULAR DEGENERATION WILL BE
RODS.
>> YES. P
>> RODS I HAVE ALWAYS FELT
ARE THE SOLDIER BEES AND CONES
ARE LIKE QUEEN BEES. THERE ARE A
B
BUNCH INSIDE AND THE DENSITY,
THE RODS IS SORT OF PROTECTING
THEM. WHEN THEY BEGIN TO DIE AND
MACRO DEGENERATION YOU HAVE
SCOTOPIC VISION LOSS. SO I'M
CURIOUS TO SEE WHEN RODS DIE --
>> WHAT HAPPENS TO
CONNECTIVITY OVER TIME.
>> AND IN THE FOEB CORNEAL
REGION SO WHEN DYSFUNCTIONAL THE
STRUCTURE IS THERE, THE
CONNECTION.
>> THE SYNAPSE MAY BE
DIFFERENT.
>> SO THAT SORT OF --
>> ALL THAT CAN BE DONE. I
THINK IN THE PAST WHEN YOU WENT
TO LOOK AT CONNECTIVITY, THE EM
SLIDES IS A REAL PAIN AND NOT
CERTAIN WHAT THE FULL
RECONSTRUCTION LOOKS LIKE, THE
METHODS ALLOW YOU TO DO THAT. IT
IS VERY PAINFUL INDIVIDUALFUL TO
PAINT INDIVIDUAL CELLS SECTION
BY SECTION THOUGH IT IS ON A
TABLET. IF THE AI SYSTEM WORK
WITH SCALEABLE MINDS, COMPANY
THE ENTIRE EM VOLUME VERY
QUICKLY. BECAUSE THEY CAN DO
THAT, FOR EXAMPLE IF YOU HAVE
GOOD BLOCKS FOR DIFFERENT
STAGES, YOU CAN START LOOKING AT
CONNECTIVITY CHANGES. YOU CAN DO
THE FUNCTION. YOU HAVE TO DO THE
PHYSIOLOGY. THEN THE BEST THING
WOULD BE CORRELATE PHYSIOLOGY
WITH THE MOLECULAR CHANGES WITH
WHAT MIGHT BE TRIGGERING
SOMETHING, RIGHT. NOT JUST YOU
LOSE THIS AND THIS IS THE END
POINT. I HAVE TO SAY THAT
EVENTUALLY -- SORRY, I HAVE TO
SAY THAT THE SCOTOMA BOUNDARY,
WHICH I DIDN'T TALK ABOUT,
THINGS ARE NOT NORMAL THERE.
THAT WAS SURPRISING. WE THOUGHT
IS IT BECAUSE OF NEIGHBORS? I
DON'T THINK SO. I THINK WHAT WE
DID WITH LASER, IT IS A GOOD AS
CAN BE BUT NOT A STEP FUNCTION.
YOU PROBABLY DIDN'T KILL CELLS
AT BOUNDARY BUT PROBABLY MADE
THEM SICK, LIKE SUNBURNED OR
SOMETHING LIKE THAT. SO WE THINK
STRUCTURALLY WE HAVE THE OUTER
SEGMENTS BUT SOMETHING NEEDS TO
RECORD FROM SCLETOMA BOUNDARIES
AND HAVE TO SAY IF THIS PART
ISN'T FUNCTIONING PROPERLY THIS
COULD BE OUTCOME OF THE
REWIRING. YOU SEE MOSTLY THE
REWIRING IS ACTUALLY AT THE
SCLETOMA BOUNDARY.
>> IF I WAS GOING TO DO THAT
I WOULD PUT LASER IN SCONE SIDE
MORE THAN THE PHOBIA REGION.
>> YOU COULD DO THAT TOO. IN
FACT, IN THOSE ANIMALS THEY
PLACE THOSE LESIONS IN MANY,
MANY DIFFERENT REGIONS. HE WAS
THE COMPANY FOREVER BUT NOW HE
CAN GET TO THOSE QUESTIONS.
>> NOBODY ELSE, I CAN ASK ONE
MORE QUESTION.
>> SURE.
>> WHEN DOES REALLY THE PIT
FORMATION BEGIN?
>> IN HUMANS SOMETHING LIKE
25 DAYS FETAL.
>> 25 DAYS FETAL.
>> IT IS PRETTY EARLY. YOU
SEE A LITTLE INDENTATION. IT
CARRIES ON UNTIL AFTER BIRTH.
>> BUT AT 25 DAYS NO OPTIC
PIT. WHICH FIRST APPEARS AROUND
35 DAYS IN HUMAN FETUS. SO I
WOULD THOUGHT FORMATION IS
SOMEHOW RELATED. CONES AND
GANGLION WHEN TOMMY AND I WERE
DOING CLOSER TO 70, 80 DAYS. I'M
CURIOUS, PIT FORMATION IS TAKING
PLACE MOST EVEN BEFORE CELL
DEFERENCE TAKE PLACE.
>> THE PIT FORMATION -- THE
CONES DEVELOP VERY EARLY. SO DO
SURPRISINGLY THE BIPOLARS AND
GANGLION CELL AND
STRATIFICATION. BY MID-GESTATION
WHERE THERE IS NO PIT, AFTER THE
PIT STARTS FORMING, THE
CONNECTIONS BETWEEN THE CONES
AND BIPOLARS ARE ALREADY SET.
AND THE GANGLION CELL AND
BIPOLAR DEATH THAT OCCURS, THERE
IS A LOT OF CELL DEATH, IS DONE
BY MID-GESTATION.
>> BUT BASED ON WHAT --
SOLELY AT 80, TEN OR 11 WEEKS.
>> YEAH. SORRY, 25 WEEKS --
DID I SAY DAYS?
>> OKAY. THAT MAKES SENSE.
NOW I'M OKAY.
>> IT IS REALLY FAST, ANON.
>> ALL RIGHT.
>> I THINK WE ARE READY FOR
THE RECEPTION, THANK YOU ALL.
[ APPLAUSE ]
>> I WAS JUST ASKED TO MAKE A
COUPLE CLOSING REMARKS. I REALLY
DON'T ALMOST KNOW WHERE TO START
WITH HAVING HEARD ALL THIS. IN
YEARS OF MY CAREER, WORKING IN
PORTLAND, OREGON, FOR THOSE OF
YOU DON'T KNOW OREGON IS A STATE
IN THE NORTHWEST ABOUT THREE
HOURS FROM SEATTLE. BECAUSE OF
THAT I HAVE HEARD RACHEL TALK
MANY TIMES OVER THE YEARS. AWARD
LECTURES, MANY THINGS. ONE THING
THAT'S TRULY IMPRESSED ME ABOUT
RACHEL'S TALKS IS THAT THEY
DON'T ALL COME OUT THE SAME. I
THINK THAT IS REALLY
ILLUSTRATIVE OF THE BREADTH OF
AMAZING WORK YOU HAVE DONE. THAT
CREATIVITY AND BREADTH OF STUFF
YOU PRESENTED TODAY. ANOTHER
THING THAT REALLY STRUCK ME IS
YOU SUMMARIZED SEVERAL DECADES
OF WORK HERE OVER SUCH A BREADTH
OF -- YOU KNOW, YOU TALKED ABOUT
ANATOMY, IMAGING, PHYSIOLOGY,
L
RETINAL
RETINA BY BIOLOGY. THAT IS
IMPRESSIVE AND HOW YOU PLACED
YOUR WORK IN CONTEXT OF WHAT SO
MANY OTHER PEOPLE HAVE DONE IN
THAT AREA. BOTH IN YOUR NETWORK
AND ALSO A LITTLE BIT OUTSIDE
YOUR NETWORK. I THINK THOSE ARE
REALLY ALL MODELS OF HOW AMAZING
SCIENCE REALLY SHOULD BE DONE.
SO I WANT TO THANK YOU FOR
SHARING YOUR KNOWLEDGE AND
EXPERTISE WITH US. BOTH IN THE
LAST HOUR AND ALSO JUST OVER,
YOU KNOW, THE NEXT 24 HOURS THAT
YOU'LL BE IN BETHESDA. I WANT TO
THANK -- THERE IS A GROUP OF
PEOPLE WHO REALLY OVER SEES
THIS. OBVIOUSLY JORAM, YOU AND
LONA, THANK YOU AGAIN. THE GROUP
THAT DOES THE SELECTION FOR
THIS. THERE IS A GROUP, JEREMY,
BOB, CAPEL, CONNIE I DON'T
BELIEVE IS HERE. I'M NOT GOING
TO SAY TOO MANY BECAUSE I DON'T
WANT TO LEAVE SOMEBODY OUT. YOU
DID A GREAT JOB IN PICKING AND
THANKS TO THE FNIH FOR
OVERSEEING THIS. WE'VE GOT A
RECEPTION. RACHEL, JORAM AND ALL
STAY SO WE WILL TAKE
PHOTOGRAPHS. CAPEL, DON'T RUN
OFF ANYWHERE. FOR EVERYBODY
ELSE, THERE IS A RECEPTION AND
THANK YOU ALL FOR COMING.
[ APPLAUSE ]