>> OKAY, THANKS FOR COMING.
LET'S GET STARTED.
I AM MIA SUN.
IT'S MY PLEASURE TO INTRODUCED
TO'S SPEAKER.
BUT BEFORE I FORGET, TODAY'S
CME CODE IS 5016.
-- 50116.
AND THE PEOPLE WATCHING THE
TALK ON VIDEOCAST CAN SUBMIT
YOUR QUESTIONS ON THE BUTTON
SEND LIVE FEEDBACK.
YOU CAN ASK THE SPEAKER
QUESTIONS THAT WAY.
OKAY, SO LET ME TRY TO GIVE A
GOOD INTRODUCTION.
BECAUSE IT'S REALLY NOT AN EASY
JOB TO CONDENSE WENDELL LIM'S
ACCOMPLISHMENT INTO A SHORT
INTRODUCTION BUT I WILL DO MY
BEST.
SO WENDELL LIM, DR. WENDELL LIM
IS BUYER'S DISTINGUISHED
PROFESSOR AT U.C. SAN
FRANCISCO, SCIENTIST OF
MOLECULAR, HE GOT BACHELOR'S
HARVARD IN CHEMISTRY.
POSTDOC AT YALE.
ALSO IN BIO PHYSICS AND
BIOCHEMISTRY.
HE JOINED U.C. SAN FRANCISCO IN
1996.
SINCE THEN HE HAS TAKEN
NUMEROUS LEADERSHIP POSITIONS
INCLUDING THE DIRECTOR OF U.C.
SAN FRANCISCO CENTER FOR
SYSTEMS AND SYNTHETIC BIOLOGY,
ONE OF THE NIH CENTERS IN
SYSTEMS BIOLOGY UNTIL 2019.
SINCE 2020 HE HAS BEEN THE
DIRECTOR OF CELL DESIGN
INSTITUTE, AND ALSO DIRECTOR OF
CENTER FOR SYNTHETIC
IMMUNOLOGY, BOTH AT U.C. SAN
FRANCISCO.
AND BEYOND U.C. SAN FRANCISCO
HE HAS BEEN REALLY SERVING THE
ENTIRE COMMUNITY OF PEOPLE WHO
ARE DOING QUANTITATIVE SYSTEMS
BIOLOGY AND SYNTHETIC BIOLOGY
IN THIS ANNUAL CONCERT SERIES
WE CALL WINTER Q BIO.
A LONG TIME CO-ORGANIZER IN
THAT CONFERENCE SERIES.
WENDELL IS REALLY A PIONEER IN
SYNTHETIC BIOLOGY APPROACHES
AND HE HAS OPENED MANY MULTIPLE
DIFFERENT RESEARCH AVENUES.
SO I WILL JUST TRY TO COVER A
LITTLE BIT HERE.
SO HIS APPROACHES TO
ENGINEERING CELLS IS REALLY
COOL IN THE SENSE YOU BASICALLY
TELL LYMPHOCYTES TO TELL
INSTRUCTIONS LIKE IF YOU SEE A
AND B, DO, C AND D.
SUCH AS KILLING THE TARGET
CELLS OR ACTIVATE SOME GENES.
SO THESE ARE REALLY HIGH
PRECISION THERAPEUTIC
APPROACHES HE HAS PIONEERED.
AND IN 2016 HE PUBLISHED NOT
ONE, BUT THREE CELL PAPERS THAT
REALLY DEMONSTRATE THAT THIS
WORKS WITH THE SYSTEM THAT HE
TERMS SYNTHETIC NOTCH
RECEPTORS, ALSO CALLED SYN
NOTCH SYSTEMS.
AND IN 2022 HE PUBLISHED TWO
PAPERS IN SCIENCE.
ABOUT HOW CAR T-CELL PHENOTYPES
CAN BE MANIPULATED BY MIXING
AND MATCHING OF DIFFERENT
MOTIFS OR DOMAINS.
REALLY BEAUTIFUL WORK.
HE SO FAR PUBLISHED MORE THAN
150 PEER-REVIEWED PAPERS IN HIS
OVER 60 PATENTS.
AND I WAS CURIOUS TO SEE WHAT
IS THE TOP-SIDED PAPER OUT OF
ALL OF THIS.
SO I FOUND IT'S ACTUALLY THIS
CELL PAPER PUBLISHED IN 2013.
TOGETHER WITH ACTUALLY ANOTHER
WALS SPEAKER NEXT MONTH,
JENNIFER DOUDNA, SHOWING CRISPR
CAN BE MADE TO BE REVERSIBLE.
HE DEVELOPED THIS CRISPR EYE
METHOD IN THE PAPER.
FOR ALL HIS ACCOMPLISHMENTS HE
HAS RECEIVED NUMEROUS HONORS
AND AWARDS, MANY DISTINGUISHED
LECTURES.
HE HAS BEEN EDITORIAL BOARD OF
CELL AND SCIENCE.
HOWARD HUGHES MEDICAL INSTITUTE
INVESTIGATOR.
AND EVEN BACK IN 2012, HE WAS
NAMED ONE OF THE 50 PEOPLE WHO
WILL CHANGE THE WORLD BY U.K.
MAGAZINE WIRED.
AND TODAY'S LECTURE, WE WILL
SEE HOW HE CONTINUES TO REALLY
PUSH THE BOUNDARIES, BOTH
TECHNOLOGICALLY AND
CONCEPTUALLY AT THE FOREFRONT
OF SYNTHETIC BIOLOGY.
THANK YOU SO MUCH FOR VISITING
NIH.
WENDELL, I WOULD LIKE TO
WELCOME YOU.
[ APPLAUSE ]
>> WENDELL LIM: THANK YOU.
CAN EVERYONE HEAR ME OKAY?
SO THANK YOU VERY MUCH, MIA,
FOR THAT KIND INTRODUCTION AND
FOR INVITING ME.
AND HELLO TO EVERYONE BOTH HERE
IN PERSON AND ONLINE.
SO WHAT I WOULD LIKE TO TALK
ABOUT IS OUR EFFORTS OVER THE
LAST SEVERAL YEARS TO TRY TO
ASK WHETHER WE CAN ACTUALLY
CREATE NEW BIOLOGY.
WHAT DOES IT TAKE TO ACTUALLY
LEARN HOW TO PROGRAM CELLS AND
CELLS IN THEIR FUNCTION AND HOW
CAN WE APPLY THIS TO VARIOUS
IMPORTANT THERAPEUTIC PROBLEMS.
HERE ARE MY DISCLOSURES.
AND THEN WHAT I WOULD LIKE TO
DO IS START BY TALKING ABOUT
THIS GENERAL FIELD OF SYNTHETIC
BIOLOGY AND HOW I THINK ABOUT
IT.
AND IT'S REALLY THIS IDEA OF
LEARNING BY BUILDING.
I THINK THAT OVER THE LAST MANY
DECADES WITH THE ADVENT OF
MOLECULAR BIOLOGY AND
UNDERSTANDING THE GENE, WE HAVE
COME TO REALIZE THAT BIOLOGY IN
THE HIGH-LEVEL FUNCTIONS WE SEE
IN VARIOUS ORGANISMS ARE THE
RESULT OF A HIERARCHY OF LEVELS
WHERE GENETIC PROGRAMS LEAD TO
ENCODE MOLECULAR NETWORKS LEAD
TO CELLULAR NETWORKS AND IT'S
REALLY THE ENSEMBLE OF THESE
THAT LEAD TO THE FUNCTIONS WE
ARE SOEN NAM ORED OF THAT WE
SEE IN LIVING SYSTEMS.
RIGHT NOW IN GENERAL, THE WAY
WE LOOK AT THESE SORTS OF
SYSTEMS WE ARE INTERESTED IN
PARTICULAR FUNCTION AT A HIGH
LEVEL AND WE TEND TO TRY TO
DECONSTRUCT AND MAP OUT THE
GENES AND HOW DO THEY INTERACT
WITH ONE ANOTHER.
THIS IS FOCUSED ON TAKING THOSE
BIOLOGICAL BEHAVIORS THAT EXIST
AND TRYING TO UNDERSTAND THEM.
IN A WAY, WHAT WE ARE
INTERESTED IN SYNTHETIC
BIOLOGY, WE ARE INTERESTED IN
THAT PROBLEM BUT REALLY IN A
BIGGER CONTEXT.
MAYBE ANOTHER WAY OF PHRASING
WHAT ARE POSSIBLE.
WHAT ARE THINGS YOU COULD BUILD
WITH BIOLOGICAL SYSTEMS?
AND THAT IS IMPORTANT FROM
SEVERAL DIFFERENT PERSPECTIVES.
ONE IS THAT REALLY, YOU KNOW,
IF YOU LOOK AT A BROADER SET OF
SYSTEMS AND UNDERSTAND WHAT CAN
ACHIEVE A CERTAIN FUNCTION,
WHAT ARE THE GENERACIES,
PAERNTS, YOU CAN GET A BETTER
UNDERSTANDING OF THE RULES THAT
GOVERN THE BEHAVIOR.
IF YOU EXPLORE THIS SPACE OF
USING BIOLOGIC COMPONENTS TO
CREATE NEW SYSTEMS PROBABLY
THERE ARE INTERESTING NEW
BEHAVIOR S OUT THERE SOME WHICH
COULD BE THERAPEUTICALLY USEFUL.
WE ARE INTERESTED IN BOTH
QUESTIONS AND EXPLORING THEM
REALLY IN CONJUNCTION.
ONE WAY OF THINKING ABOUT THAT,
THE TRADITIONAL WAY, PERHAPS
THINKING ABOUT PROBLEMS IN
IMMUNOLOGY OR DEVELOPMENT,
THESE ARE BOTH CASES WHERE
SYSTEMS OF CELLS DO AMAZINGLY
COMPLEX AND PRECISE ACTIONS.
PERHAPS TRYING TO REPHRASE THIS
IN A MORE GENERATIVE WAY IN
TERMS OF HOW YOU CREATE
FUNCTION FROM THE BOTTOM UP.
WE COULD ASK IF WE UNDERSTAND
THE DESIGN LOGIC OF THESE
SYSTEMS HOW MIGHT WE BE ABLE TO
FOR INSTANCE IN IMMUNOLOGY
CREATE IMMUNE CELLS THAT KILL
FOREIGN CELLS THAT NATURALLY
INVADE.
OR SYNTHETIC DEVELOPMENT HOW
CAN WE PROGRAM CELLS SO THEY
SELF ORGANIZE IN CUSTOM TISSUES
FOR REGENERATION OR REPAIR.
BY TAKING ON THESE SORTS OF
PROBLEMS WE ARE TRYING TO DO
THING THAT'S ARE USEFUL AND
ONLY CELLS COULD DO BUT ALSO
COULD HELP US GIVE US BIGGER
CONTEXT FOR UNDERSTANDING THE
PRINCIPLES AND RULES AND LOGIC
OF BIOLOGICAL REGULATION.
THE OTHER THING IS RIGHT NOW WE
ARE VERY FOCUSED ON THE NOTION
OF TRYING TO CHANGE CELLULAR
CONVERSATIONS.
HOW CELLS INTERACT WITH ONE
ANOTHER AS NETWORKS.
OF COURSE BIOLOGY OCCURS AT
MANY DIFFERENT LEVELS.
ONE OF THE POINTS I WANT TO
MAKE, WE HAVE MADE AMAZING
ADVANCES AT THE ATOMIC AND
MOLECULAR SCALE UNDERSTANDING
THE INTERACTIONS BETWEEN
DIFFERENT MODULES.
FOR EXAMPLE, THE FIELD OF
CHEMISTRY USED TO BE ABOUT
STUDYING INDIVIDUAL MOLECULES.
BUT REALLY NOW WE HAVE THIS
GREAT FUNDAMENTAL UNDERSTANDING
HOW ORBITALS AND BONDS WORK.
AND REALLY CHEMISTRY IS MUCH
MORE BASED ON PRINCIPLES AND
NOT ABOUT WHAT MOLECULES DON'T
AND DO EXIST BUT WHAT CAN EXIST.
LIKE THAT WE UNDERSTAND
MOLECULES AT A BETTER LEVEL.
BUT I THINK A LOT OF BIOLOGY WE
LOOK AT THE HIGHER LEVEL BOILS
DOWN TO MOLECULES ENGAGING AT
THE CELLULAR LEVEL.
WE ARE INTERESTED IN TRYING TO
FOCUS ON THAT.
WHAT WE WOULD LIKE TO BE ABLE
TO DO IS TO DEVELOP THE FIELD
OF CELL ENGINEERING AND CELL
DESIGN TO BE AS FACILE WHAT WE
CAN DO WITH TODAY'S SYNTHETIC
CHEMISTRY OR PROTEIN
ENGINEERING.
THEY HAVE AMAZING CAPABILITIES
I THINK MOLECULES BY THEMSELVES
CAN'T HAVE, WHETHER SMALL
MOLECULES OR BIOLOGICS.
MOLECULES COULD HAVE PRECISE
SPECIFICITY.
BECAUSE THESE ARE MOLECULES
THEY WILL GO EVERYWHERE, AND
THE SAME GENES ARE EXPRESSED IN
DIFFERENT CELLS YOU WILL HAVE
SYSTEMIC CROSS REACTIONS AND
TOXICITIES.
CELLS, HOWEVER, THIS HAPPENS OF
COURSE NATURALLY IN THE BODY,
CELLS HAVE THE ABILITY TO SENSE
AND INTEGRATE ENVIRONMENTAL
INFORMATION TO CONTROL WHERE
THEY GO AND WHEN THEY EXECUTE
CERTAIN FUNCTIONS.
CELLS CAN MIGRATE.
THEY CAN ADHERE OR BE RETAINED
IN CERTAIN PLACES.
INTERACT SPECIFICALLY AND
LOCALLY INDUCE ACTIVITIES,
PROLIFERATION, PAYLOADS OR
COMMUNICATION WITH OTHER CELLS.
I WOULD ARGUE MANIPULATING
CELLULAR AGENTS MAY BE A FAR
MORE POWERFUL WAY TO INTERACT
WITH DISEASES SPECIFICALLY
COMPLEX DISEASES THAT INVOLVE
CELLULAR ECOSYSTEMS LIKE
CANCER, AUTOIMMUNE ORFEI BREAUX
SIS.
WHAT I WOULD LIKE TO TALK ABOUT
TODAY QUICKLY IS THREE THINGS.
ONE I WANT TO GIVE YOU AN
INTRODUCTION TO THE TYPE OF
SYNTHETIC BIOLOGY TOOLKIT TO
REWIRE CELLS.
WHAT ARE THE FUNDAMENTAL UNITS
IF YOU WERE GOING TO ENGINEER
CELLS WHAT ARE THE MODULES YOU
NEED THAT WOULD GIVE YOU THE
MOST CAPABILITIES.
I WILL TELL YOU ABOUT SOME
THINGS WE HAVE BEEN WORKING ON
AND REWIRE HOW CELLS INTERACT
WITH THEMSELVES AND THEIR
ENVIRONMENT.
AND THEN I WANT TO TALK ABOUT
HOW WE CAN THEN APPLY THIS
TOOLKIT TO TWO DIFFERENT
PROBLEMS.
MOSTLY I WILL TALK ABOUT
DEVELOPING NEXT GENERATION
IMMUNE CELL THERAPIES FOR SOLID
TUMORS BUT BEYOND CANCER,
INCREASED RECOGNITION, THIS
DEVELOPMENT OF A TISSUE GPS
SYSTEM THAT ALLOWS US TO TELL
CELLS TO GO TO AND ONLY ACT IN
A CERTAIN ANATOMIC ISSUE AND
PROGRAMMING CELLS TO TREAT
DISEASES LIKE CANCER LIKE
AUTOIMMUNITY OR
NEUROINFORMATION.
AND A SHORTER PART TO TALK
ABOUT EFFORT TO APPLY SAME TOOL
WITH DIFFERENT PROBLEM THAT OF
DEVELOPMENT TRYING TO
UNDERSTAND HOW WE CAN WIRE
CELLS TO SELF-ORGANIZE AND SELF
PATTERN INTO VARIOUS
ARCHITECTURES AND HOW THIS
MIGHT BE USED TO HELP GUIDE
STEM CELLS TO DEVELOP INTO
SPECIFIC TISSUES OR SHAPES.
SO LET ME FIRST TALK ABOUT THIS
TOOLKIT FOR REWIRING CELLULAR
NETWORKS.
LET'S SAY WE HAVE A PROBLEM OF
A CAR-T CELL AND WE WANT TO
ENGINEER TO TREAT A SOLID TUMOR.
WE NEED IT TO BE ABLE TO TALK
TO THE TUMOR, RECOGNIZE IT,
HAVE A CONVERSATION, TALK TO
THE STROMA, AS WELL AS OTHER
IMMUNE CELLS IN THE ENDOGENOUS
IMMUNE SYSTEM BUT ALSO AMONGST
THEMSELVES IN AUTOCRATIC SORT
OF WAYS.
IF WE WANT TO DO THAT WHAT ARE
THE WORDS WE NEED TO WRITE NEW
CELLULAR PROGRAMS TO CHANGE THE
RELATIONSHIPS AND CONVERSATIONS
THESE CELLS HAVE, IDEALLY WE
WOULD LIKE TO, LIKE WITH THIS
DRY ERASE MARKER PENCIL IN NEW
THINGS AND ASK HOW DOES THAT
CHANGE THE BEHAVIOR OF THE NEW
SYSTEM.
WE WANT TO BE ABLE TO DO THAT
AND WE WANT TO HAVE GENETICALLY
ENCODED COMMANDS THAT COULD
PROGRAM NEW CELLULAR
INPUT/OUTPUT RELATIONSHIPS.
THIS IS STILL DIFFICULT BUT
FINITE QUESTION, WE WOULD LIKE
A CELLULAR NODE TO ENGINEER TO
DETECT A NEW INPUT LIKE XYZ,
SOMETHING OUTSIDE ITS
ENVIRONMENT, HAVE THAT TURN ON
A NUMBER OF CANONICAL
RESPONSES, PRODUCING SECRETED
SIGNAL OR RECEPTOR TO SEND
SOMETHING OR CHANGE SHAPE OR
DIVIDE AND GROW.
CLASSICAL RESPONSES WE WOULD
LIKE TO BE ABLE TO HAVE AS
OUTPUTS.
SO WHAT ARE SOME OF THESE
GENETIC COMMANDS?
MANY OF YOU ARE PROBABLY
FAMILIAR WITH CHIMERIC -- CAR.
BASICALLY IT TAKES THE
INTRACELLULAR PARTS OF THE TCR
COMBINED WITH SIGNATORY
RECEPTORS BUT PUTS ON THE
OUTSIDE NEW ANTIBODY FOR A
PARTICULAR ANTIGEN.
THAT ALLOWS US TO REDIRECT TO A
CELL THAT HAS THIS NEW ANTIGEN.
SO IT SHOWS HOW YOU CAN
REPROGRAM THAT OUTPUT TO LINK
IT TO ENDOGENOUS OUTPUT.
HERE ARE THINGS WE HAVE
DEVELOPED AND ARE WORKING ON,
ONE I WILL GO INTO MORE DETAIL,
SYNTHETIC NOTCH SYSTEM.
THAT'S THE WAY WE COULD CHANGE
THE OUTSIDE WITH SINGLE CHAIN
ANTIBODY, WHAT IT DOES, IT
RELEASES TRANSCRIPTION ALDO
MAIN THAT GOES INTO THE NUCLEAL
DOMAIN.
SO IT'S A NEW WAY TO PUT A NEW
INPUT BUT HAVE ALMOST ANYTHING
AS AN OUTPUT THAT WE CAN ENCODE
GENETICALLY.
IT'S VERY, VERY FLEXIBLE AS AN
INFORMATION TRANSMISSION
MODALITY.
AND THEN SOME OTHER THINGS,
WHAT I WILL CALL SYNTHETIC CELL
ADHESION MOLECULES, SYNCAMS.
WHAT KIND OF INTERFACE BY
CHANGING THE INTRACELLULAR
DOMAINS AND CHANGE THE
CYTOSKELETON.
ENGINEERED CHEMOKINE SYSTEM.
GIVE YOU LONG-TERM MEMORY AND
FATE BIFURCATION.
I WON'T TALK ABOUT TODAY.
LET'S GO OVER THE SYN NOTCH
SYSTEM.
THE NATURAL NOTCH RECEPTOR
DETECTS SIGNAL DELTA ON A
NEIGHBORING CELL, THIS
MECHANICAL FORCE LEADS TO
CLEAVAGE AND INTRACELLULAR KETS
CUT OFF AND REGULATES
TRANSCRIPTION OF VARIOUS GENES.
WE COULD RECOGNIZE ARBITRARY
MOLECULE X ON THE OUTSIDE WORLD.
PUT TRANSCRIPTION FACTOR ON THE
INSIDE.
THIS COULD TURN ON WHATEVER
GENES, WHY WE PUT BEYOND THAT
RESPONSIVE PROMOTER.
SO THIS ALLOWS US TO CHANGE
WHAT WE DETECT IN THE
ENVIRONMENT AND CONTROL ALSO
WHAT THE CELLULAR RESPONSE IS.
MOREOVER, WE HAVE SHOWN THAT WE
CAN CHANGE THE OUTSIDES, HAVE
DIFFERENT KIND OF RECOGNITION
HEADS AND BY THE SAME TOKEN WE
CAN ALSO CHANGE THE
INTRACELLULAR PART AND PUT ON
DIFFERENT TRAN DESCRIPTION ALDO
MAIN THAT'S RECOGNIZE DIFFERENT
PROMOTERS SO WE COULD HAVE A
WHOLE SET, ORTHOGONAL TO EACH
OTHER.
THESE CAN ALL FUNCTION IN THE
SAME CELL.
THAT'S AN INCREDIBLY FLEXIBLE
WAY TO CHANGE RELATIONSHIPS
BETWEEN CELLS AND INDUCE NEW
RESPONSES.
VERY QUICKLY ABOUT SYNTHETIC
ADHESION MOLECULES.
THEY HAVE THIS, THEY HAVE TO
BIND TO EACH OTHER TO FORM
TISSUE, TO THE EXTRA CELLULAR
MATRIX AND TO MIGRATE OR
TRANSMIGRATE THROUGH THE
ENDOTHELIUM AND IMPORTANT FOR T
CELL SYNAPSE OR NEURONAL
SYNAPSES.
THERE ARE A LOT OF COMPLEX
ADHESION MOL KEWELLS.
WE COULD ENGINEER SYNTHETIC WE
REPLACE THESE EXTRA CELLULAR
DOMAINS WITH ANTIGEN
INTERACTIONS OR GFP BUT
DEPENDING ON WHAT KIND OF
INTRACELLULAR DOMAIN WE PUT ON
THE INSIDE AND HOW IT ENGAGES
THE INTRACELLULAR, CYTOSKELETON
WE COULD GET DIFFERENT STRENGTH
AND MORPHOLOGICAL DEPEN DEN SY.
WHAT IS SHOWN HERE IS AN
EXAMPLE, IF WE TAKE GFP
INTERACTION BUT HAVE IT TIED TO
THE INTRACELLULAR, WE GET
SOMETHING THAT REPLICATES BROAD
AND TIGHT INTERFACE WITH
CADHERIN.
THIS ALLOWS US TO TUNE STRENGTH
AND SYNAPSE PROPERTIES FOR
SORTING AND ASSEMBLY.
I WILL SHOW YOU MOVIES THESE
ARE THINGS WE ENGINEERED THE
BLUE CELLS WITH DIFFERENT
ADHESIONS THEY COULD EITHER
FORM A NODE OR FORM THIS SHELL
AROUND THE CLUSTER SO WE COULD
START PROGRAMMING THOSE
BEHAVIORS AND WE HAVE USED THAT
IN A LOT OF DIFFERENT WAYS.
LET ME GO TO THE MAIN PART OF
THE TALK HOW WE CAN APPLY THIS
TO NEXT GEN CELL THERAPIES.
EVERYONE KNOWS ABOUT CAR T
THERAPIES ONE OF THE FIRST CELL
THERAPIES FDA A PROVED, THANKS
TO PIONEERING WORK BY JIM --
WE KNOW WE CAN MAKE THESE
ARTIFICIAL RECEPTORS THAT
RECOGNIZE ANTIGENS ON CANCER
AND KILL THEM AND THIS HAS BEEN
REMARKABLE ADVANCE FOR
HEMOPOETIC CANCERS.
WE HAVEN'T HAD AS MUCH SUCCESS
IN TARGETING SOLID TUMORS WITH
CAR T'S.
BECAUSE IT'S NOT REALLY THAT
SIMPLE AS RECOGNIZING THE
CANCER CELLS.
RECOGNIZING CD 19 KILLS ALL T
CELLS IS TOLERABLE AND THAT'S
HOW IT CAN WORK.
WE NEED A CELL THAT CAN
RECOGNIZE THE ANTIGENS ON THE
CANCER.
BUT EQUALLY IMPORTANT, MANY
ANTIGENS ESPECIALLY FOR SOLID
TUMOR ARE ALSO EXPRESSED ON
NORMAL TISSUE.
WE HAVE TO FIND WAYS TO AVOID
TOXIC CROSS REACTION.
IN ADDITION MANY TUMOR SPECIFIC
ARE ALSO HETEROGENEOUS.
CERTAIN CELLS CAN ESCAPE.
IF YOU GET TOO SPECIFIC YOU
HAVE PROBLEM OF MORE CELLS
MIGHT ESCAPE.
ALSO SOLID TUMORS TEND TO BE
SUPPRESSIVE, SO YOU HAVE TO
OVERCOME THE SUPPRESSIVE TUMOR
MICRO ENVIRONMENT.
THERE ARE MULTIPLE CHALLENGE
THAT'S HAVE TO BE SOLVED IN
CONCERT TO GET THIS THERAPY.
PART OF OUR GOAL IS DEPLOY SOME
OF THE DIFFERENT MODULAR TOOLS
WE HAVE TO IMPROVE EACH OF
THESE DIFFERENT ISSUES AND TRY
TO DO IT IN CONCERT.
LET ME TELL YOU ABOUT ONE
SOLUTION WE HAVE BEEN WORKING
ON FOR QUITE SOME TIME.
FIRST FOCUSED ON INCREASING
RECOGNITION SPECIFICITY OF SAY
SOLID TUMORS BUT HAS OTHER
IMPLICATIONS ON SOME OTHER
PROBLEMS.
CAN WE PROGRAM FOR EXAMPLE A T
CELL TO RECOGNIZE A
MULTI-ANTIGEN SIGNATURE USING A
TWO RECEPTOR CIRCUIT WHERE WE
COMBINE SYN NOTCH AND A CAR
INTO A KIR SET.
KIR SET.
-- CIRCUIT.
IN NORMAL TISSUES COULD YOU GET
THIS CROSS REACTION THAT COULD
BE TOXIC.
THIS IS WHAT I WAS TALKING
ABOUT, WE COULD MAKE A CELL
THAT HAS A SYN NOTCH RECEPTOR
THAT WOULD RECOGNIZE ANTIGEN A
THAT WOULD BE IN THE TUMOR.
IT WOULD BE LINKED TO THE
EXPRESSION OF A CAR GENE, SO
THAT CAR IS NOT GOING TO BE
EXPRESS BUD ONLY -- EXPRESSED.
IF WE MAKE THIS TWO RECEPTOR
CIRCUIT, BASICALLY IT'S OFF SO
IT WOULD SPARE THAT HAD AND
GENT B BUT TISSUE THAT HAS
ANTIGEN A ON A CANCER CELL OR
PART OF THE CANCER MICRO
ENVIRONMENT IT WOULD TURN ON
THE SYN NOTCH AND THIS WOULD
TURN ON THE CAR, AND THE CAR
WOULD BE ABLE TO INDUCE
EXPRESSION OF THE CAR AND KILL
THE CELLS THAT HAD ANTIGEN B.
BUT ONLY IN THE CASE WHERE THE
A AND B WERE TOGETHER LOCALLY
IN SPACE, OKAY.
AND WHAT IS SHOWN HERE IS AN
ANIMATION OF WHAT WE HOPED
WOULD HAPPEN.
AS WE TAKE THESE SORT OF CAR
SYN NOTCH T-CELLS AND PUT THEM
IN A MOUSE WITH TWO TUMORS, ONE
WITH THE KILLING ANTIGEN, THEY
WOULDN'T BE ACTIVATED AND BE
NEUTRAL BUT WITH THE PRIMARY
ANTIGEN IN GREEN THEY WOULD GET
TURNED ON AND KILL THAT IN THAT
CASE ON THAT SIDE.
WE SHOW WE TAKE MODEL TUMORS
PUT IN ONE THAT HAS THE
KILLING, KILLING AND PRIMING,
WE SEE THIS AMAZING DIFFERENCE
IN THE SAME ANIMAL WHERE THE
SYN CAR T CELLS ONLY KILL THAT
ONE SIDE.
THIS SHOWS THESE ARE THE
CONTROL T-CELLS AREN'T KILLED
IF YOU PUT IN THE NORMAL CAR T
CELLS IT WILL KILL BOTH TUMORS
BUT THE SYN NOTCH CAN DETERMINE
BETWEEN THE SINGLE AND DUAL
ANTIGEN.
SO WE HAVE NOW MOVED FROM THE
SIMPLE MODEL ENGINEERED TUMORS
TO SEVERAL DIFFERENT THINGS.
WE AND OUR COLLEAGUES HAVE
WORKED ON DEPLOYING THIS IN
GLIOBLASTOMA.
THEY ONLY KILL WHERE THEY ARE
IN PROXIMITY.
CAR EXPRESSION SHUTS OFF ONCE
THE CELLS LEAVE THE REGION OF
PRIMING WITH A HALF-LIFE OF A
FEW HOURS.
SO THEY DON'T HAVE TIME TO
MOUNT THIS MULTI-DAY RESPONSE
YOU NEED TO CLEAR A TUMOR.
IN ADDITION, IT'S IMPORTANT TO
NOTE THAT THE PRIMING ANTIGEN
IS NOW ONLY USED FOR
RECOGNITION AND NOT FOR KILLING.
SO IT'S REALLY JUST AN
INFORMATIONAL MOLECULE THAT
LOCALIZES WHERE THE KILLING
WILL TAKE PLACE.
IT DOESN'T NEED TO BE
HOMOGENOUS.
IT CREATES BLAST RADIUS THE
CELLS PRIMED CAN NOW KILL ANY
CELL THAT HAS THE KILLING
ANTIGEN OVER A BLAST RADIUS.
WE CAN HARNESS NEOANTIGENS THAT
ARE SPECIFIC BUT HOMOGENOUS.
THE KILLING ANTIGEN NEED NOT BE
PERFECTLY SPECIFIC AS LONG AS
DUAL ANTIGEN COMBINATION IS
ONLY FOUND ON THE TUMOR.
THAT'S IMPORTANT, IF WE PRIME
AT A VERY LOCALIZED WAY WE
COULD START KILLING BASED ON
BROADER SET OF ANTIGENS
INCLUDING ONE THAT'S MIGHT HAVE
CROSS REACTION IN OTHER
TISSUES, AS LONG AS THOSE DON'T
OCCUR WITH THE PRIMING ANTIGEN.
AND THEN IMPORTANTLY,
CONDITIONAL INDUCTION OF THE
CAR, GREATLY DECREASES THE
DEGREE OF CAR T CELL EXHAUSTION.
MANY CIRCUIT ARE MUCH BETTER
CLEARING THE TUMORS IN THE
CIRCUIT CONTEXT RATHER THAN
CONSTITUENT OF CAR.
ALSO IMPORTANTLY, I WON'T TALK
ABOUT THIS BUT VERY IMPORTANT
PART, SYN NOTCH COULD BE USED
TO INDUCE INFLAMMATORY PAYLOADS
WE HAVE DONE THIS WITH IL2 AND
HAS POWERFUL EFFECT OVERCOMING
THE MICRO ENVIRONMENT IN
PANCREATIC AND MELANOMA TUMORS
AND MORE EFFECTIVE THAN ARMORED
FORMS OF CAR THAT ARE
CONSTITUTIVE.
I WANT TO TALK B WE HAVE DONE A
LOT OF THIS WORK IN
COLLABORATION WITH MY COLLEAGUE
IN NEUROSURGERY AN EXPERT IN
GLIOBLASTOMA, THERE ARE TWO WE
HAVE BEEN DEVELOPING, ONE
E-SYNC.
A CIRCUIT THAT PRIMES WITH A
TUMOR NEOANTIGEN, EGFRVIII.
SPLICE VARIANT PART OF THE
EXTRA CELLULAR DOMAIN.
THIS IS TUMOR SPECIFIC.
BUT WHEN THEY DID A TRIAL USING
A CAR OF RECOGNIZING IT, IT
WENT TO THE TUMOR AND KILLED
THE EGFRVIII CELLS BUT IT
ESCAPED AND SURVIVED WITH
EDITING OF THAT ANTIGEN.
SO IT'S VERY POWERFUL BUT WE
WANT TO USE IT FOR KILLING IN A
SELECTIVE WAY BUT INFORMATION
PRIMING ANTIGEN, WE HAVE USED
IT AS A SYN NOTCH RECEPTOR TO
PRIME EXPRESSION OF A
TWO-HEADED CAR.
THESE ARE MORE HOMOGENOUS BUT
IMPERFECTLY SPECIFIC BUT BY
COMBINING IN THIS PARTICULAR
WAY, ONE GIVES MORE COMPLETE
KILLING AND ONE GIVES MORE
LOCALIZED SPECIFICITY IT WORKS
QUITE WELL.
THIS HAS BEEN PUBLISHED.
WE HAVE A 90-YEAR APPROVAL AND
IN PHASE TWO OF CLINICAL TRIAL,
WE ARE EXCITED ABOUT THAT.
THIS OTHER ONE B-SYNC PRIME
ONCOA NORMAL BRAIN-SPECIFIC
ANTIGEN.
BCAN ONLY FOUND IN THE BRAIN.
WE COULD MAKE A SYN NOTCH THAT
RECOGNIZE THAT'S MOLECULE IN
THE BRAIN AND INDUCES THIS
TWO-HEADED CAR, THE SAME ONE.
AND THESE ANTIGENS ARE NOT
EXPRESSED IN THE NORMAL BRAIN.
IT ENDS UP BEING REALLY VERY
SPECIFIC AND WE ARE VERY
EXCITED ABOUT IT AND I WILL
TELL YOU ABOUT THAT.
ONE OF THE KEY CONCEPTS HERE IS
THAT WE WOULD LIKE TO ACTUALLY
BE ABLE TO RESTRICT A
THERAPEUTIC, NOT TO JUST
RECOGNIZE IT'S MOLECULAR TARGET
BUT RESTRICT ANATOMICALLY IN A
TISSUE WHERE IT ACTS.
IT'S HARD TO DO THAT WITH A
MOLECULAR DRUG.
OFTEN BIND WITH MULTIPLE
TISSUES BECAUSE OF THE SAME OR
RELATED TARGETS ARE IN
DIFFERENT TISSUES.
LET'S SAY WE WANTED TO HAVE
THIS ATTACK SOMETHING IN THE
BRAIN.
THEN ONE IT MIGHT HAVE TROUBLE
GETTING INTO THE BRAIN BUT ALSO
CROSS REACT WITH OTHER CITES.
-- SITES.
IF WE COULD INSTRUCT THE DRUG
TO ONLY GO TO THE BRAIN IT
WOULD SOLVE A LOT OF PROBLEMS,
IT MIGHT BE MORE EFFECTIVE IN
THE BRAIN WHERE THE DISEASE IS.
BUT ALSO WE WOULD DROP OUT ALL
THE CROSS REACTION THAT
OCCURRED OUTSIDE THAT TISSUE.
OF COURSE THIS IS HOW A LOT OF
BIOLOGY WORKS.
THINGS GO AND OCCUR IN THE
SPECIFIC TISSUES AND THAT'S WHY
THE SAME MOLECULES COULD BE
USED IN DIFFERENT CONTEXT.
HOW MIGHT WE DESIGN A CELL TO
RESTRICT ITS ACTIVITY TO A
SPECIFIC TISSUE LIKE THE BRAIN?
WE HAVE TRIED TO IDENTIFY BRAIN
OR CNS SPECIFIC EXTRA CELLULAR
ANTIGEN AND DESIGN SYN NOTCH TO
RECOGNIZE THESE, AND USE TO
INDUCE EXPRESSION OF A
THERAPEUTIC PAYLOAD.
IN THE CASE OF A CANCER LIKE
GLIOBLASTOMA WE COULD INDUCE
EXPRESSION OF A CAR, ONLY KILL
WITHIN THOSE ANTIGENS IN THE
BRAIN CONTEXT.
BUT AS I WILL TELL YOU LATER WE
ARE ALSO INTERESTED IN
EXPRESSING OTHER PAYLOADS FOR
NEUROINFLAMMATION COULD BE
EXPRESSED SUPPRESSIVE PAYLOADS.
SO WE DID WITH MILOS SIMIC LAB
RESEARCH, THERE ARE CERTAIN
MOLECULES IN THE BRAIN THAT ARE
EXTRA CELLULAR THAT ARE QUITE
SPECIFIC THAT INCLUDES CERTAIN
SURFACE MOLECULES ON NEURONS OR
ON OLIGO DEN SITES.
EXTRA CELLULAR NETWORK, IT HAS
HYLAURONIC, BUT THEN BCAN.
WE RAISE ANTIBODIES AGAINST
THIS AND MADE ELEVATED BCAN SYN
NOTCH RECEPTORS.
AS IT INTERACTS WITH THE P
REGION AROUND THE ASTROCYTE IN
GREEN.
HOW DO WE APPLY THIS TO
SOMETHING LIKE GLIOBLASTOMA, I
WANT TO REVIEW, THE ANTIGENS WE
CHOOSE TO USE FOR KILLING, WELL
KNOWN GLIOBLASTOMA.
BOTH OF THESE ARE WELL
EXPRESSED ON MOST GLIOBLASTOMAS.
BUT ONE OF THE PROBLEMS IS THAT
THESE ARE ALSO EXPRESSED IN
OTHER NORMAL TISSUES BUT NOT IN
THE BRAIN.
NOT IN THE NORMAL BRAIN.
SO WHAT WE DECIDED TO DO, FROM
MILOS SIMIC LEADING THIS WORK,
TO MAKE A SYN NOTCH AGAINST
BCAN AND HAVE THAT SO IF WE
DETECT THE BRAIN, THAT WILL
TURN ON THE CAR THAT WILL KILL
THESE GLIOMA ASSOCIATED
ANTIGENS EVEN THOUGH THEY
AREN'T ABSOLUTELY SPECIFIC BUT
THE ONLY ONES IN THE BRAIN, SO
THE IDEA IS THE INTERSECTION OF
THESE TWO VENN DIAGRAMS WOULD
BE THE GLIOBLASTOMA.
SO THEIR LAB MADE THESE CELLS,
TESTED IN VITRO AND NOW INVIVO
WITH A GBM TEW MORE, PBK MODEL
IMPLANTED IN THE BRAIN.
THIS ROBUSTLY CLEARED THESE
TUMORS FROM THESE, INCREASED
SURVIVAL, NEARLY ALL THE MICE
SURVIVED.
THIS SOMEONE OF THE STRONGEST
RESPONSES WE HAVE SEEN OF ALL
OUR GLIOBLASTOMA THERAPIES.
IT WAS ACTING VERY EFFECTIVELY
AND WE ARE GETTING A LOT OF
PRIMING.
WE TAKE THE TISSUE EARLY MID
TREATMENT AND WE LOOK AT THE
CD3 T CELLS THERE'S ONLY
SIGNIFICANT ACTIVATION OF THE
SYN NOTCH IN THE BRAIN SAMPLE.
SO WE ARE VERY EXCITED ABOUT
THAT, SEEMS TO BE VERY STRONG
AND BRAIN SPECIFIC INDUCTION OF
THE SYN NOTCH.
ONE OF THE THINGS WE ARE MOST
EXCITED IS THIS COULD BE A PAN
GBM THERAPY, IT'S NOT THAT WE
HAVE TO FIND PATIENTS THAT HAVE
THAT SPECIFICKING THIS SHOULD
WORK FOR ALL PATIENTS, THAT'S A
BIG DEAL THINKING ABOUT HOW TO
SCREEN AND HOW HARD IT IS FOR
FINDING THE RIGHT PATIENTS.
WHAT ABOUT OUTSIDE OF THE BRAIN?
WHAT WE DID IS TOOK THE SAME
TUMOR CELLS AND PLANTED ONE IN
THE BRAIN AND ONE IN THE FLANK.
NECESSITY -- THEY BOTH HAVE
THE KILLING ANTIGEN BUT ONLY
THE ONE IN THE BRAIN.
IN THE SAME MICE, BRAIN TUMORS
ARE CLEARED BUT THE FLANK
IMPLANTED TUMORS ARE NOT
CLEARED IN THE SAME ANIMALS.
IT REALLY INDICATES THAT THIS
IS BRAIN RESTRICTED ACTIVITY.
OKAY, SO WE NOW ACTUALLY ARE
REALLY EXCITED THAT WE HAVE
THIS KIND OF GPS SYSTEM THAT
CELLS COULD KNOW THEY ARE IN
THE BRAIN.
WE HAVE INTERESTED RESULTS
ABOUT THINGS IN LUNG AND
PANCREAS ALSO.
BUT WHAT WE REALIZE THIS COULD
BE USED FOR OTHER DISEASES TO
DELIVER TO THE BRAIN.
THERE'S BEEN A LOT OF WORK IN
THE PAST PEOPLE TRYING TO FIND
DIFFERENT CYTOKINES OR FACTOR
THAT'S COULD HAVE DIFFERENT
IMPACT ON NEUROINFLAMMATION, EA
MODELS, SOME WORK WAS SHOWN TEN
YEARS AGO, SOMETHING LIKE
IL-10, SUPPRESSIVE CYTOKINE
WHEN EXPRESSED IN THE BRAIN,
WHEN YOU INJECT AAV IN THE
BRAIN, THE HIGH LEVEL
EXPRESSION CAN BLOCK EAE BUT
SYSTEMICALLY INJECTED IL 10 IS
INEFFECTIVE, EITHER NOT ABLE TO
GET TO THE BRAIN OR HIGH ENOUGH
LEVEL.
MILOS WORKING WITH COLLEAGUES,
INCLUDING SCOTT ZANVILLE IN THE
NEUROLOGY DEPARTMENT ASKED CAN
WE MAKE A T-CELL WITH SYN NOTCH
DELIVER IL 10 AND HOW WOULD
THIS WORK WITH MULTIPLE
SCLEROSIS.
LET ME TELL YOU ABOUT THE
ANIMALS, MOG, ANTIGEN FROM
MYELIN SHEATH CELLS.
TH 17 AND ADOPTIVELY TRANSFER
THAT INTO A MOUSE AND THAT
MOUSE WILL DEVELOP
NEURODEGENERATION AND
NEUROINFLAMMATION.
IN THIS CASE WE WOULD ASK COULD
WE TRANSFER THE SYN NOTCH,
THERAPEUTIC CELLS INTO THOSE
CELLS AND WOULD THOSE HAVE
EFFECTS ON THE EAE?
WE LOOK AT DIFFERENT EFFECTS,
NEUROLOGICAL SCORES, PARALYSIS,
ET CETERA, WHAT WE SEE IN FACT
WHEN WE GIVE THESE CELLS WE
COULD SEE SIGNIFICANT
AMELIORATION.
BY DAY 12 THEY ADOPTED EAE BUT
THE MICE TREATED WITH THOSE
SUPPRESSORS CELLS MAINTAINED
GOOD MOBILITY.
WE ARE ABLE TO SEE AN EFFECT.
WE ARE EXCITED THESE ARE EARLY
DAYS BUT IDEA WE CAN TARGET
CELLS TO TISSUE.
WE ENGINEERED T-CELLS THAT USE
MULTI-RECEPTOR CIRCUIT,
MULTIPLE COMPONENTS LINKED
TOGETHER.
TO MAKE PRECISE
DISEASE-SPECIFIC DECISIONS AS
AN EXAMPLE IN THE CASE OF
GLIOBLASTOMA WE ARE ABLE TO
ENGINEER PRECISE BRAIN CANCER
CELL THERAPIES BY PROGRAM CELLS
THAT ONE CAN SENSE THEY ARE IN
THE BRAIN AND INDUCE EXPRESSION
OF A CAR.
THIS IS AN EXAMPLE OF A
POWERFUL EXPRESSION OF
ANATOMICAL AND MOLECULAR
SPECIFICITIES THAT REALLY ONLY
A CELL CAN DO EFFECTIVELY.
WE ARE EXCITED THAT WE HAVE
DEVELOPED A WAY TO HAVE BRAIN
SENSING CELLS THAT COULD BE
USED IN A DISEASE-AGNOSTIC
MANNER TO DELIVER EITHER IMMUNE
SUPPRESSIVE BUT ALSO
REGENERATIVE PIE LOADS OR ONES
FOR NEODEGENERATION.
WE ARE TRYING TO IMPROVE CELL
MIGRATION, TRANSMIGRATION
ACROSS THE BBB BUT ALSO IT'S
POSSIBLE WE COULD TARGET OTHER
TISSUES IN AN ANALOGOUS KIND OF
GPS, CELL GPS MECHANISM.
I WANT TO REMIND EVERYONE WE
ARE REALLY EXCITED WE ARE
STARTING THIS EGRB3 WITH THIS
TEAM AT UCSF AS WELL AS MID
STREAM IN TERMS OF PREPARING
OUR IND FOR THE BRAIN-PRIMED
BCAN ONE, HOPEFULLY WE WILL BE
ABLE TO REPORT ON THAT SOON.
SO THE LAST PART OF MY TALK, I
WANT TO TALK ABOUT TRYING TO
APPLY THESE SAME FUNDAMENTAL
TOOLS TO A DIFFERENT PROBLEMS
FACED IN BIOLOGY.
BUT ONE THAT STILL REQUIRES
CELLS TO TALK TO EACH OTHER IN
VERY PRECISE PROGRAMS IN THE
CASE OF DEVELOPMENT.
HOW CELLS INTERACT WITH ONE
ANOTHER TO CHANGE AND ORGANIZE
IN SPACE.
THAT COMPLEX BEHAVIOR COULD BE
PRE-PROGRAMMED INTO A SET OF
DNA.
SO THIS, I WILL SHOW YOU IN
THIS MOVIE, ACTUALLY SOME
SIMPLE CASES WE TOOK, GOT THEM
TO ORGANIZE IN DIFFERENT THINGS.
SPONTANEOUS WAY.
SO WHY GENE DEVELOPMENT, WE ARE
INTERESTED FROM A BOTTOM-UP
VIEW.
ARE THEY UTILIZED IN DIFFERENT
DEVELOPMENTAL PROGRAMS AND HOW
THEY ARE PUT TOGETHER TO
CONSTRUCT THE DIFFERENT
MORPHOLOGIES WE SEE IN METZOANS.
FOR TRANSPLANT, MIGHT IT BE
BETTER TO HAVE CERTAIN
PROPERTIES UNIQUE TO THAT.
THE FUNDAMENTAL QUESTION, PART
OF WHAT WE ARE TRYING TO DO AT
A MORE BASIC LEVEL IS, TO ASK,
CAN WE USE THE SAME SORT OF
TOOLKIT WE HAVE BEEN USING FOR
ENGINEERING THE T-CELLS TO ALSO
ENGINEER DEVELOPMENT?
ARE THOSE REALLY THE
FUNDAMENTAL RELATIONSHIPS THAT
ARE POWERFUL FOR CREATING THESE
NEW PROGRAMS?
AND SO SEVERAL YEARS AGO, TODA
AND MARSUIT WHEN POST DOCS THEY
ASKED CAN WE TAKE CELL LINES
LIKE IL 19 OR LESS THAT DON'T
SELF ORGANIZATION AND PUT IN
PROGRAMS THAT WOULD.
WHAT IS THE BASIC LOGIC OF
DEVELOPMENTAL PROGRAMS, ONE
HYPOTHESIS, MOST PATHWAYS IN
DEVELOPMENT HAVE CELL THAT'S
TALK TO ONE ANOTHER AND THOSE
INDUCE SELECTIVE CHANGES IN
MORPH FOLG.
SO CAN WE USE SYN NOTCH TO
ENGINEER TO RECOGNIZE EACH
OTHER BUT LINK THOSE TO THE
INDUCTION OF VARIOUS
MORPHOLOGICAL, THINGS LIKE
ADHESION, COULD WE INDUCE
ADHESION MOLECULES THAT CHANGE
HOW THE CELLS SORT, AS STANDARD
FOR DIFFERENTIATION, COULD WE
INTRODUCE FLUORESCENT PROTEINS
BUT ALSO INTRODUCE NEW SIGNALS
LIKE SYN NOTCH LIGANDS THAT
WOULD CARRY ON THIS
CONVERSATION FURTHER.
SO THEY DID THAT, THIS JUST
SHOWS SOME OF THE THINGS THEY
WERE ABLE TO DO, THIS WAS A
CELL POPULATION ABLE TO
INTERACT WITH ONE ANOTHER AND
YOU GET THIS DIFFERENTIATION
INTO GREEN AND RED POPULATION,
IN THIS CASE, THEY ORGANIZE IN
THIS POLARIZED FASHION.
THE NEXT EXAMPLE IS ONE WHERE
WE HAVE SIMILAR SET OF CELLS WE
PUT TOGETHER, THEY START
INTERACTING, WHAT YOU WILL SEE
IS FORMATION OF A GREEN-COLORED
CORE AND THAT LEADS TO
FORMATION OF AN INTERMEDIATE
RED OR M-CHERRY INTERMEDIATE
SHELL.
JUST TO EXPLAIN HOW THIS WORKS,
IN THIS LAST CASE THIS IS
RECIPROCAL CONVERSATION BETWEEN
TWO CELLS.
TWO CELLS, A AND B SHOWN AT THE
TOP.
THE A CELL HAS A SIGNAL THAT
WILL TURN ON A SYN NOTCH AND B
WILL TURN ON GFP AND HIGH LEVEL
OF KADHERON.
TURNS OUT THAT WAS AN EXTRA
CELLULAR, THAT TURNS ON M
SHARING AND INTERMEDIATE LEVEL.
THOSE CELLS TURN RED AND FORM
THIS SHELL.
THIS HAPPENS IN A VERY
SPONTANEOUS AND STEREOTYPED WAY
CONSISTENTLY.
WE CAN CUT THEM AND THEY WILL
STILL REGENERATE THAT
STRUCTURE, ET CETERA.
WE COULD GET SIMPLE SELF
ORGANIZATION.
THIS IS ANOTHER EXAMPLE OF A
LOT OF DEVELOPMENT HAS LARGER
SCALE INGREDIENTS THAT LEAD TO
PATTERNING.
TODA SHOWED HE COULD MAKE A SYN
NOTCH, BY MAKING SECRETOR CELLS
THAT WOULD PRODUCE A GFP IN
THIS CASE, WHAT WE CALL A BODY,
BOTH ANCHOR CELLS THAT WOULD
TRAP THE GFP AND THEN COULD
ALLOW IT TO BE DETECTED BY A
TELL WITH AN ANTIGFP SYN NOTCH.
SENDERS AND BODY OF CELLS, FOUR
MILLILITER SO FAIRLY LARGE
SCALE.
WHAT WE SEE WE ARE ABLE TO
GENERATE A GRADIENT OF RESPONSE
THAT EMANATES FROM THAT SOURCE.
AND IF WE NOW ELABORATE THAT
WITH VARIOUS POSITIVE AND
NEGATIVE FEEDBACK LOOPS THAT
OCCUR IN THE BODY, THIS
ARTIFICIAL BODY OF CELLS WE ARE
ABLE TO GET THE SAME BODY TO
RESPOND IN DIFFERENT WAYS TO
THE GRADIENTS AND WE GET
DIFFERENT KINDS OF PATTERNS
LIKE SHOWN ON THE RIGHT SIDE.
A FRENCH FLAG PATTERN, THE
CLASSIC RESPONSES THAT HAVE
BEEN THEORIZED IN DEVELOPMENTAL
BIOLOGY.
I WON'T TALK, MUCH OF THAT HAS
BEEN PUBLISHED AND THERE'S A
LOT OF INTERESTING STUFF THERE.
BUT THAT'S KIND OF TAKING CELLS
THAT DON'T DEVELOP AND TRY TO
MAKE SIMPLE THINGS FROM SCRATCH.
WHAT ABOUT TRYING TO GUIDE LIKE
STEM CELLS.
ONE THING WE HAVE BEEN
INTERESTED IN MORE RECENTLY,
ASKING IF WE CAN TAKE ES CELLS
AND ENGINEER CELLS THAT WILL
TALK TO THEM AND SPATIALLY
DEFINED WAYS.
THESE ARE WHAT WE ARE CALLING
SYNTHETIC ORGANIZER CELLS THAT
COULD PROVIDE MORPH GENIC
INSTRUCTION.
WE CAN GET PRETTY INTERESTING
THINGS TO COME OUT OF THAT.
YOU KNOW, THE IDEA IS WHEN WE
LOOK AT DEVELOPMENT AND TRY TO
DRIVE DIFFERENTIATION IN VITRO,
MOST OF THE TIME WE ARE TAKING
ES CELLS AND ADDING MORPHOGENS,
MAYBE CHANGING THE TIME AND
DOSE BUT DOING THIS IN THIS
ISOTROPIC WAY.
VERY DIFFERENT FROM WHAT
HAPPENS IN VIVO, THERE ARE
CELLS IN SPECIFIC LOCATIONS
PRODUCING SPECIFIC MORPHOGENS.
SOME EXCITING WORK ON EMBRYOS
WORK FROM VARIOUS LAB THAT'S
SHOW EXTRA EMBRYONIC CELLS CAN
SELF ORGANIZE AROUND ES CELLS
THAT LEAD TO QUITE ADVANCED IN
VITRO EMBRYO GENESIS.
CAN WE TRY TO RECAPITULATE THAT.
REENGINEER SYNTHETIC CELL
THAT'S WOULD ORGANIZE IN SPACE
AROUND THE ES CELLS AND BE NOW
THE SOURCES OF THESE MORPHOGENS.
WE NEED TO PROGRAM SPATIAL CELL
ASSEMBLY.
NATURAL ADHESION AND ENGINEERED
ONES WE COULD PROGRAM WITH
SYNTHETIC ADHESION MOLECULES.
AS I SHOWED BEFORE THESE MOVIES
ARE FIBROBLAST CELL LINES
ENGINEERED, THE SAME ONES BUT
ENGINEERED IN DIFFERENT WAYS TO
ORGANIZE AROUND THESE RED ES
CELLS IN EITHER FORMING A NODE
OR A SHELL.
WHAT WE CAN DO WITH THESE IS
NOW COMBINE IN DIFFERENT WAYS
AND GET DIFFERENT
ARCHITECTURES, SINGLE NODE,
SHELLS COMBINED TO GET
DIFFERENT PATTERNS AND TRY TO
EXPRESS MORPHOGENS FROM THESE
ANISOTROPIC WAYS.
THE FIRST THING, THIS IS WORK
FROM TOSHI, POST DOC IN THE
LAB, IS TO ASK CAN WE DELIVER
THIS KEY EARLY EMBRYONIC
MORPHOGEN WITH 3A FROM SPECIFIC
ORGANIZER CELLS AND WHAT WE
FIND IS WE CAN GENERATE VERY
TUNABLE AND DIRECTIONAL
GRADIENTS.
THESE ARE ES CELLS WITH PTCF
MCHERRY, THAT'S WHY IT WILL
TURN ON.
IF WE GIVE A WNT AGONIST, IT
TURNS ON, IN THE MEDIA IT TURNS
EVERYTHING ON IN THIS ISOTROPIC
SPHERICAL WAY.
IF WE PROVIDE WNT EXPRESS FROM
SHELL, WE SEE SOMETHING VERY
SIMILAR.
BUT IF WE EXPRESS WNT FROM THIS
NODE WE SEE POLARIZED
ACTIVATION, GRADIENT THAT GOES
ACROSS THAT AND ELON GAIGS OF
THE BODY ALONG WHAT LOOKS LIKE
A PRIMITIVE ANTERIOR, POS
STEEROR AXIS.
IF WE MAKE A SECOND NODE AND
PUT IT 180° AWAY AND MAKE A WNT
INHIBITOR DKK1 WE CAN GET
STEEPER, ACROSS THE SPAN OF
THAT BODY, IF YOU WILL.
SO WHAT HAPPENS AS WE TUNE
THESE GRADIENTS? WHAT HAPPENS
TO THE MORPHOLOGICAL OUTPUTS?
WHAT IS SHOWN HERE AFTER EIGHT
DAYS SOME OF THE THINGS WE SEE.
I WANT TO START WITH THE MIDDLE
ONE.
WHICH IS WHERE WE HAVE BOTH THE
WNT AND DKK NODES, THE
INHIBITOR, THIS LEADS TO STEEP
GRADIENT WITH HIGH DYNAMIC
RANGE ACROSS THE WHOLE BODY.
WE SEE SPECIFIC TISSUES
ARRANGED IN MORE OR LESS THE
CORRECT ANTERIOR, POS STEEROR
ARRANGEMENT.
WE SEE THINGS LIKE OTX2 NEURAL
MARKERS AROUND THE DKK1 NODE
AND THEN VARIOUS MARKERS FOR
EXAMPLE, THIS IS CARDIAC
TISSUE, VERY LOCALIZED IN THE
MIDDLE.
WE THINK THIS IS THE ANTERIOR
AND POS STEEROR IN THIS DUAL
NODE STRUCTURE.
INTERESTINGLY THOUGH, IF WE USE
SINGLE NODE WITH DKK1 WE GET
ALMOST ALL NEURAL FATES.
WE SEE POSTERIOR AND THE
CARDIAC TISSUE AT THE MOST
ANTERIOR THERE.
AND SO WHAT WE SEE, WE CAN SEE
SPECIFIC LINEAGES ARISING AND
ORGANIZED IN THE APPROPRIATE
ANTERIOR POSTERIOR TOPOLOGY BUT
THE RANGE AND SHAPE AND
STEEPNESS DETERMINE THE
SPECTRUM OF LINEAGES WE
OBSERVED IN THE RESULTING
EMBRYOID.
DUAL HEAD WITH THE MOST RANGE
OF FATES.
ONE THING I HOPE YOU CAN SEE IN
THE MOVIE, THE BEATING CARDIAC
TISSUE, IT'S LOCALIZED.
THESE ARE SELF ORGANIZING
ORGANIZED SUB TISSUES IN THIS
ANTERIOR, POSTERIOR AXIS.
IF WE LOOK MORE CAREFULLY IN
THE CASE IF WE HAVE SINGLE WNT
NODE, THAT HAPPENS THERE, THIS
GRADIENT IS LESS STEEP AND YOU
DON'T GET ALL THE TISSUES BUT
IT'S SHALLOWER, WE FIND WE
ACTUALLY GET INTERESTING
MORPHOLOGY SUGGESTING HIGHER
RESOLUTION SPATIAL OR
MORPHOLOGICAL INFORMATION.
ONE THING WE SEE PROBABLY ABOUT
15% OF THOSE EMBRYOIDS.
WE SEE A CAVITY, AND HEART BY
IMAGING HAS A REGULAR BEAT,
WHICH IS QUITE UNEXPECTED AND
REALLY DIFFICULT TO SEE IN A
SPONTANEOUS SELF ORGANIZING
WAY, THIS KIND OF STRUCTURE.
MOST OTHER EFFORTS AT
RECONSTRUCTING HEARTS HAVE
INVOLVED TAKING MULTIPLE
LINEAGES AND COMBINING THEM.
NOT ONLY TO WE SEE THIS
HEART-LIKE CAVITY.
IT HAS MARKERS LIKE CARDIAC TRA
CONE IN, OR TX2K5 LOCALIZED
AROUND THE REGION, BUT WE SEE
BY STAINING FOR ENDOTHELIAL
MARKERS, IT LOOKS IT'S LINKED
TO THE EXTENDED VASCULAR
NETWORK MARKED IN GREEN.
(NKX2.5) REALLY THIS IS AN
AMAZING CASE OF SELF
ORGANIZATION OF A MULTI-CELL
TYPE HEART-LIKE STRUCTURE IN A
SPONTANEOUS WAY.
SO ONE OF THE THINGS WE ARE
THINKING, THERE ARE KIND OF
DIFFERENT WAYS OF LOOKING HOW
TO DRIVE DEVELOPMENT IN VITRO
OR RECONSTITUTING.
SOME WORK IN THE PAST HAS BEEN
TAKING ES CELLS AND USING
COMBINATIONS OF PROTOCOLS OF
DIFFERENTIATION FACTORS TO
DRIVE DIFFERENTIATION OF
SPECIFIC LINEAGES AND MAYBE YOU
COMBINE THOSE IF YOU ARE
INTERESTED IN TISSUES.
ON THE SYNTHETIC EMBRYO SIDE
USING FAIRLY NATURAL CELLS, CAN
YOU PUSH ALL THE LINEAGES AND
GET SELF ORGANIZATION OF THE
WHOLE BODY.
WE THINK WITH SOME SYNTHETIC
ORGANIZERS WE CAN TUNE
SOMEWHERE BETWEEN THAT TO DRIVE
CERTAIN REGIONS OR RANGES OF
LINEAGES AND STILL GET SOME
SELF ORGANIZATION OR DRIVE
THINGS TO NON NATURAL NON
NATIVE FATES IN SOME CONTROLLED
WAYS.
THIS IS EARLY DAYS BUT WE ARE
VERY EXCITED ABOUT THAT.
WHAT WE HAVE SHOWN WITH THE
SYNTHETIC DEVELOPMENT WORK, WE
CAN COMBINE COMPONENTS THAT
CONTROL CELL-CELL SIGNALING,
DIFFERENTIATING CELL ADHESION
AND MORPHOLOGICAL PRODUCTION
FOR EXTRA CELLULAR MORPHOLOGIES.
THEY CAN PROVIDE PROGRAMABLE
CELLS WITH INFORMATION RICH
SPATIAL THAT CAN GENERATE
DISTINCT TISSUE, ASSOCIATED
VASCULAR NETWORK, WE CAN CUSTOM
TUNE THE GRADIENT RANGE AND
STEEPNESS TO ALTER THE RANGE
AND RESOLUTION OF THE
MORPHOLOGICAL OUTCOMES.
AND THIS APPROACH, WE THINK
COULD BE APPLIED TO MANY
DIFFERENT TYPES OF MORPHOGENS
AS PROGENITOR CELLS.
COULD WE USE THIS APPROACH IN
VIVO TO GENERATE OR RECONSTRUCT
AROUND SITES OF INJURY TO DRIVE
REGENERATION IN SITU.
A LONG WAYS AWAY BUT REALLY
EXCITING.
TO CONCLUDE THE WHOLE TALK I
HOPE I HAVE BEEN ABLE TO SHOW
YOU LIVING CELLS ARE THESE
AMAZING MACHINES UNLIKE OTHER
SCALES LIKE MOLECULES HAVE THIS
MUCH HIGHER LEVEL TO INTEGRATE
INFORMATION OVER A HIERARCHY OF
SCALES, ANATOMICAL OR
MOLECULAR, AND THEY CAN
SPATIALLY COORDINATE BY SENSING
AND INTERACTING WITH THEIR
ENVIRONMENT OR NEIGHBORING
CELLS.
IF WE TAKE ADVANTAGE OF THIS,
THERE ARE MANY THINGS WE CAN DO
AND BUILD TOOLS AND SENSORS
THAT ALLOW US TO PRECISELY
CONTROL AND CHANGE THE CELLULAR
INTERACTIONS AND BUILD
DIFFERENT CELLULAR PROGRAMS AND
CIRCUIT, INCLUDING USING THESE
TWO OPERATING, MANY DIFFERENT
CELLS INCLUDING IMMUNE CELLS
THAT COULD SEARCH FOR CANCER OR
TARGET TISSUE FOR SUPPRESSING
INFLAMMATION OR PUTTING IN CELL
THAT'S COULD PROVIDE SPATIAL
INSTRUCTION THAT COULD GUIDE
DEVELOPMENT.
AND JUST WANT TO LEAVE YOU WITH
THE THOUGHT THAT UNDERSTANDING
HOW TO MANIPULATE THE LOGIC
WILL ANSWER I THINK MANY
QUESTIONS IN BIOLOGY WE DON'T
UNDERSTAND.
WE KNOW A LOT ABOUT THE
COMPONENTS OF BIOLOGY, WE KNOW
LESS HOW THEY ARE PUT TOGETHER,
THE LOGIC.
POWERFUL WAYS TO GENERATE NEW
THERAPEUTIC PLATFORM THAT'S
COULD INTERFACE WITH COMPLEX
DISEASES LIKE CANCER OR
FIBROSIS OR AUTOIMMUNITY.
WE CAN DIRECT THE CONVERSATIONS
THAT HAPPEN IN THESE ECOSYSTEMS.
WITH THAT LET ME THANK ALL THE
PEOPLE IN MY LAB AND
COLLABORATORS.
I WANT TO FOCUS, MILO SIMIC THE
FELLOW LEADING THAT, WATCHMAKER.
SCOTT ZAMVIL.
ALSO BIO INFORMATICS DONE WITH
MY COLLEAGUE AT PRINCETON.
THE SYNTHETIC ORGANIZE ERICCA
ALSTEAD WORK DONE BY SOSHI
YAMADA IN COLLABORATION WITH
OPHIR KLEIN.
SO THANK YOU VERY MUCH.
[ APPLAUSE ]
>> ANYONE WITH QUESTIONS PLEASE
USE THE MICKS.
WE HAD A QUESTION THAT CAME IN,
IF YOU ARE READY FOR IT.
>> OKAY.
>> SO HOW DO BRAIN TARGETED CAR
T CELLS PENETRATE THE
BLOOD-BRAIN BARRIER?
>> WE KNOW THERE IS ALWAYS, I
MEAN T-CELLS CAN GET IN THE
BRAIN, THEY END UP CAUSING
M.S., THEY CAN GET IN EARLY GBM
TRIALS THAT EGFR CAR THEY DID
GET INTO THE BRAIN.
IT'S PRETTY CLEAR IN DISEASES
LIKE BRAIN TUMORS AND M.S.,
THERE ARE SOME ALSO SOME DAMAGE
TO THE BBB THAT ALLOWS CELLS TO
GET IN EARLIER, MORE
EFFECTIVELY.
SO IT'S UNCLEAR, OUR CELLS ARE
GETTING IN THERE, WE DO SEE
THEM, THEY ARE PROLIFERATING.
SO THEY DO GET IN.
TO SOME DEGREE, WE THINK IT'S
AMPLIFIED IN THESE PARTICULAR
DISEASE CASES BUT WE ARE
WORKING ON TRYING TO IMPROVE
WAYS TO GET THEM THROUGH THE
BBB.
>> VERY BRILLIANT, AS USUAL.
MY QUESTION IS ABOUT THE
SPECIFICITY OF YOUR GBM
TARGETING T-CELLS.
YOU SHOWED BACKGROUND
INFORMATION IN THE SPLEEN.
DO YOU UNDERSTAND IT, IS THERE
ENOUGH LIGANDS IN THE SPLEEN?
WHAT IS HAPPENING THERE?
IS THERE LEAKINESS.
>> YOU ARE SEEING THE GLASS
HALF EMPTY.
>> VERY CONCERNED ABOUT
BACKGROUND.
>> IT'S MUCH, MUCH LOWER.
THERE'S A LITTLE BIT, I WOULD
SAY, WE, I GUESS, WE HAVE DONE
EXTENSIVE NON-BRAIN TUMOR
KILLING AND WE DON'T SEE
ANYTHING THERE.
WE DON'T SEE PROLIFERATION OF
CELLS THERE.
WE THINK WE ARE BELOW THE
THRESHOLD FOR ANY SORT OF
EFFECTS.
>> I GUESS MORE GENERAL
QUESTION, MOVING FROM THE MOUSE
MODEL TO PATIENT, DO YOU HAVE A
WAY TO TEST THE DIFFERENT
TISSUES TO SEE --
>> WELL, I MEAN, WE'VE GONE
THROUGH THE R&D PROCESS ON THIS
AND WE ARE USING MOUSE CROSS
REACTIVE ANTIBODIES.
WE ARE DOING TOX IN THE MOUSE.
ALSO RECHECKING EVERYTHING
AGAINST HUMAN TISSUE LIBRARIES
AND SO FAR THAT'S ALL CHECKED
OUT.
YOU KNOW, THIS IS WHAT A DOSE
ESCALATION IS FOR.
I WOULD SAY, A LOT OF THESE,
THE EGFR 3, THAT CAR HAS BEEN
IN TRIALS AND THERE WASN'T A
PROBLEM.
SO YOU KNOW, COMBINATION OF
THINGS.
BUT THERE ARE UNKNOWNS.
YES?
>> WHEN YOU WERE SHOWING US THE
EXPRESSION OF THE WNT, AND YOU
SHOWED US THE GRADIENT WHEN YOU
INDUCED THE NODES AND
INHIBITORS WHAT WERE YOU USING
TO DIRECT THE NODES AND
INHIBITORS?
>> TO THE SECOND NODE?
>> YES.
>> THE SECOND NODE HAS MORE --
ELEMENT TO IT AND WE ARE
TRYING TO IMPROVE THAT.
>> OKAY, AND THE ON THE CARDIAC
EXPRESSING CELLS, WHAT WERE
THEY, SO THEY INDUCED THE
VESSEL EXPRESSION IN THE NEARBY
CELLS.
DID THOSE VESSEL, WHAT DID
THOSE VESSEL EXPRESSING DO TO
THE NEIGHBORING CELLS?
>> WENDELL LIM: YEAH, WE ARE
JUST KICK-STARTING THE EVENT.
THIS IS ONE SIGNAL.
AND CLEARLY, THERE'S A LOT OF
WNT PNB4, A LOT OF THINGS THAT
GO ON IN REGIONS THERE.
SO WE ARE TRYING TO TRACK BY
SCOPE AND OTHER THINGS WHAT ARE
THE SEQUEL LA OF EVENT THAT'S
HAPPEN.
THIS IS THE TRICKY THING.
ONE TRIGGERING THE NEXT THING
AND SO FORTH.
SO THAT'S ALL TO BE WORKED OUT.
>> THANK YOU.
>> GREAT TALK.
I HAVE A QUESTION ABOUT YOUR
BRAIN-SPECIFIC SYN NOTCH CAR.
AND YOU ARE USING TANDEM CAR?
AND I'M WONDERING IF THERE'S
ANY DIFFERENCE WHEN YOU HAVE
ONLY SINGLE TARGET VERSUS TWO
TARGETS, ANY RATIONALE BETWEEN
USING TANDEM CAR?
>> WENDELL LIM: YEAH, THE
RATIONALE BEHIND USING THE
TANDEM CAR HAS TO DO WITH THE
FACT THAT EVERY PATIENT IS
DIFFERENT, BUT THE NUMBER OF
PATIENTS THAT HAVE HIGH
RELATIVELY HOMOGENOUS
EXPRESSION.
IF YOU ARE LOOKING AT TANDEM,
THAT'S AN ORGATE, KILLING
ACROSS BOTH CIRCLES, RIGHT?
WE WANT TO MAKE THE DECISION
SWITCH OF SPECIFICITY TO BE
VERY SPECIFIC AND WE WANT THE
KILLING TO BE BROADER.
>> ALL RIGHT, THANKS.
>> I WANT TO BUILD OFF THE
QUESTION ON THE SYNTHETIC
ORGANIZER CELLS IN THE ASSEMBLY.
IT'S INCREDIBLE YOU COULD SEE
THE DEVELOPMENT OF THE CARDIAC
TISSUE, BUT COULD YOU COMBINE
THAT WITH YOUR SYN NOTCH TO
FURTHER DEVELOP --
>> WENDELL LIM: THAT WAS REALLY
OUR INTENT AT FIRST.
THEN WE REALIZED WE HAVE TO DO
FIRST THINGS FIRST.
EVEN JUST LOCALIZING THEM WOULD
BE VERY IMPORTANT.
BUT YES, WE HAVE NOW THE
ABILITY TO KILL NODES AND
REPLACE THEM WITH NEW NODES AND
WHAT WOULD BE REALLY POWERFUL,
WHEN YOU TRY TO STRING TOGETHER
THESE DIFFERENT EVENTS, AS IN
DEVELOPMENT, IS TO BE ABLE TO
NOW HAVE AN ORGANIZER THAT
WOULD DETECT A MARKER OF THE
NEXT STAGE OF DEVELOPMENT IN A
LOCALIZED WAY.
WE ARE TOTALLY INTO THAT.
>> THANK YOU.
>> HI, PROFESSOR, REALLY
FANTASTIC WORK.
I HAVE A KIND OF NAIVE QUESTION.
THE OTHER LAB GOING TO USE SYN
NOTCH FOR CUSTOMIZED INVIVO
EXPERIENCE.
HOW COULD WE UTILIZE THAT?
ARE THOSE SYN NOTCH BUNCH OF
PLASMA WITH MULTI-CODING OR ARE
THERE COMPANIES WE CAN WORK
TOGETHER OR PAY FOR SERVICE?
>> WENDELL LIM: THAT'S A GREAT
QUESTION.
I WOULD SAY THERE ARE NOW
SEVERAL VERSIONS OF SYN NOTCH
AND WHEN WE TAKE A NEW
ANTIBODY, AN ANTIGEN THERE'S
SOME DEGREE OF OPTIMIZATION WE
NEED TO DO.
IT ALSO DEPENDS ON SOME
VERSIONS PRODUCE MORE PAYLOAD
BUT MORE LEAKAGE, SOME ARE
TIGHTER BUT HAVE LESS AND ALSO
CELL-TYPE SPECIFIC THINGS.
WE ARE TRYING TO COME UP, TO
MAKE OUR LIVES EASIER BUT
EVERYONE'S LIFE EASIER IS COME
UP WITH A SMALL LIBRARY OF
DIFFERENT TEMPLATES WHERE ONE
COULD POP IN YOUR ANTIBODY,
SCSV OF INTEREST, AND GUIDE
THOSE INTO THINKING WHAT THE
APPLICATION IS AND WHAT
BEHAVIORS WOULD BE THE BEST.
>> SO IF THIS IS LIKE A MINI
LIBRARY AVAILABLE --
>> WENDELL LIM: NOT YET.
A LOT OF THESE THINGS ARE
AVAILABLE ON ADD GENE, BUT WE
ARE CHANGING HEIGHTS OF EXTRA
CELLULAR DOMAIN AND DIFFERENT
SCAFFOLDS FOR THE RECEPTOR.
WE ARE EXPANDING THAT FOR OUR
OWN CASE.
BUT WE WILL MAKE THAT AVAILABLE.
>> OKAY, THANK YOU.
>> ONE MORE?
>> THANK YOU FOR THE TALK.
I HAVE A VERY GENERAL QUESTION.
I'M THINKING WHETHER THERE ARE
ANY EMERGING PHENOMENA IN THE
WORK YOU PRESENTED.
UNEXPECTED CELL STATE OR
UNEXPECTED CELL FUNCTIONS?
>> WENDELL LIM: IN THE T-CELLS
OR DEVELOPMENTAL SYSTEMS?
>> IN BOTH.
>> WENDELL LIM: YEAH.
WELL, THAT RAISES OBVIOUSLY A
GREAT QUESTION OF ARE THERE
POSSIBLE CELL STATES THAT YOU
COULD DRIVE CELLS INTO, BE THEY
IMMUNE CELLS OR STEM CELLS
ALONG SOME TRAJECTORY.
AND I SUSPECT THAT THERE ARE.
I THINK IT'S A VERY FUNDAMENTAL
QUESTION.
YOU SEE A CERTAIN REALM OF
SIMULATIONS DURING LIFE AND
EVOLUTION.
AND ARE THE CELL FATES OF THE
T-CELLS AND STEM CELLS SO
CANONIZED THEY STAY ON TRACK.
THEY COULD GO OFF SOME.
THERE ARE CELL THAT'S ARE HARD
TO CLASSIFY.
TO WHAT DEGREE, I DON'T KNOW.
BUT THAT'S A VERY, SORT OF
IMPORTANT AND FUNDAMENTAL
QUESTION.
>> THANK YOU.
>> OKAY, THANK YOU VERY MUCH,
EVERYONE, FOR COMING TO THE
LECTURE.
AND THIS HAS BEEN A REALLY, YOU
KNOW, LIVELY QUESTIONS AND
ANSWERS.
BUT YOU CAN CONTINUE CHATTING
WITH THE SPEAKER IF YOU WANT.
WE HAVE A RECEPTION JUST
OUTSIDE THE AUDITORIUM.
AND WITH THIS, THIS WRAPS UP
THE LECTURE.
THANK YOU.
[ APPLAUSE ]
>> WENDELL LIM: THANK YOU.