ANY CASE, I THINK I CAN JUST
START BY SAYING, THIS MORNING A
PLEASURE TO BE HERE.
I'M FROM CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH.
ALSO KNOWN AS CBER.
I ALSO WANT TO APOLOGIZE
BECAUSE I'M STILL STRUGGLING
WITH A COUGH [OFF MIC]
EARLIER INFECTION WITH COVID.
SO ANYHOW, IN REGULATING THE
PHARMACEUTICAL MANUFACTURING
SECTOR, AND ALSO MORE RECENTLY
WITH THE RAPID DEVELOPMENT,
ACCELERATED DEVELOPMENT,
COMMERCIALLY VIABLE GENE
THERAPIES.
BUT ALSO IN COORDINATING A
RAPID RESPONSE DURING THE
COVID-19 PANDEMIC, CBER
REALIZES THE NEED FOR MAXIMALLY
FLEXIBLE AND EFFICIENT AND
AGILE BIO PHARMACEUTICAL
MANUFACTURING SECTOR.
TO RELIABLY AND ALSO TIMELY
SUPPLY AND PRODUCE HIGH-QUALITY
BIOLOGICS.
TO ACHIEVE THIS VISION, CBER IS
WORKING ACTIVELY TO ENCOURAGE
THE DEVELOPMENT OF TECHNOLOGIES
TO MODERNIZE A WAY WE
MANUFACTURE QUALITY BIOLOGICS.
AND SO IN TODAY'S PRESENTATION,
WHEN MY SLIDES COME UP, I WILL
TALK ABOUT SOME OF THE
INITIATIVES UNDER OUR PROGRAM,
CBER, ADVANCED TECHNOLOGIES
PROGRAM TO REALLY PROMOTE THE
DEVELOP MENT AND ALSO ADOPTION
OF ADVANCED MANUFACTURING
TECHNOLOGIES TO REALLY, FOR THE
CBER REGULATED PRODUCTS.
I DON'T KNOW, SHOULD I WAIT FOR
THE SLIDES?
ALSO YESTERDAY, DR. SALLOW
SALOMON IN HER TALK, SHOULD
ENGINEER WITH THE END IN MIND.
[OFF MIC]
OH, SORRY.
I WAS JUST SAYING, I THINK
YESTERDAY, DR. SALOMON IN HER
PRESENTATION, SHE MENTIONED
THAT DEVELOPMENT SHOULD
ENGINEER WITH THE END IN MIND.
I THOUGHT THAT WAS A GREAT
POINT.
BECAUSE ESPECIALLY IN OUR
EXPERIENCE EVALUATING
BIOLOGICAL PRODUCTS WE SEE THE
DIFFERENT PHASES HOW THE
MANUFACTURERS STRUGGLE, RIGHT?
WHEN THEY REALIZE, SO INTENT,
FOCUSED ON CURRENT STAGE OF
DEVELOPMENT, SOMETIMES --
THERE'S ALSO MANY FACTORS TO
PUSH YOU TO ACCELERATE AND
ACCELERATE AND SPEED UP.
SO YOU DON'T ALWAYS THINK AHEAD
ABOUT THE COMMERCIAL NEEDS, OR
COMMERCIAL VIABILITY OF YOUR
DEVELOPMENT APPROACH.
AND VERY OFTEN IT ALSO COMES IN
MANUFACTURING.
SO THAT, WHEN YOU SHIFT YOUR
STRATEGY LATER ON, IN THE LATER
PHASE OF DEVELOPMENT, THAT JUST
CREATES A TREMENDOUS AMOUNT OF
CHALLENGES, SOMETIMES EVEN AT
THE COST OF REPEATING SOME OF
YOUR NON-CLINICAL OR CLINICAL
STUDIES.
THAT COULD ACTUALLY INTRODUCE
SIGNIFICANT DELAY IN YOUR
PROCESS AND PRODUCT DEVELOPMENT
TIMELINE, RIGHT?
AND SOMETIMES IT COULD BE AS
SMALL AS, OH, YOU KNOW,
SOMETHING WORKS MAYBE WITH
MICROFLUIDICS.
IF I HAVE TO SCALE UP, WHAT
KIND OF SCALE DO I NEED TO HAVE
FOR PILOT AND FOR PRODUCTION.
AND WHAT KIND OF PATIENT
DEMANDS DO I HAVE THERE TO MAKE
THAT HAPPEN?
AND MY CURRENT APPROACH THAT
WORKS FOR THE LABORATORY, FOR
EXAMPLE, CENTRIFICATION OR
FLUIDICS.
LIKE GENE THERAPIES, BECAUSE WE
DON'T HAVE A LOT OF PRODUCT
KNOWLEDGE OR MANUFACTURING
EXPERIENCE.
HOWEVER, THE CLINICAL
DEVELOPMENT IS ACTUALLY
ACCELERATED COMPARED TO
CONVENTIONAL PRODUCTS.
SO VERY OFTEN, YOU KNOW, THE
PROCESS DEVELOPMENT AND ALSO
ANALYTICAL DEVELOPMENT ACTUALLY
LAGS BEHIND.
AND THEN YOU HAVE THIS PUSH AT
THE END THAT DOESN'T ALWAYS
WORK OUT AS SMOOTHLY AS IT
SHOULD BE.
DO YOU THINK I SHOULD GIVE A
-- VERSION OF MY TALK?
[OFF MIC]
I WILL TRY MY BEST TO ANSWER
ANY QUESTIONS.
[OFF MIC]
>> ALL RIGHT, SO THIS WAS JUST
A TEST.
IT DIDN'T WORK OUT.
SO WE WILL HAVE LIGHTNING TALK
INSTEAD OF --
WE HAVE VLAHOS COMING FROM
STANFORD UNIVERSITY.
HE WILL BE TELLING US ABOUT
"COMPACT PROGRAMABLE CONTROL OF
PROTEIN SECRETION IN MAMMALIAN
CELLS".
SO, PLEASE.
>> Alexander Vlahos: PERFECT,
THANK YOU SO MUCH FOR THE KIND
INTRODUCTION.
I SEE MY SLIDES.
SWITCH?
HE IS SWITCHING.
OKAY, I WILL HAVE A BRIEF
15-MINUTE CHAT HERE ABOUT A
SLIDE WE HAVE BEEN WORKING ON
LABELED "COMPACT PROGRAMABLE
CONTROL OF PROTEIN SECRETION IN
MAMMALIAN CELLS".
SO WHEN WE THINK ABOUT ANY SORT
OF CELL THERAPIES OR IN
GENERAL, CELLS IN THE HUMAN
BODY ARE REALLY GOVERNED BY
INTRACELLULAR SIGNALS.
IT'S REALLY A CAREFUL
HOMEOSTATIC RELATIONSHIP, THAT
GOVERN THE IMMUNE CELL.
SO WHEN IT COMES TO THE
COMMUNICATION, THESE ARE ALL
GOVERNED BY INTERCELLULAR
SIGNALS AND ANY KIND OF CELL
THERAPY WE PLAN TO DELIVERY,
EITHER SOMETHING FOR PILOT
TRANSPORTATION, YOU ARE
ESSENTIALLY DISRUPTING THAT
HOMEOSTASIS.
THE FIELD OF SYNTHETIC BIOLOGY
HAS REALLY BEEN FOCUSING ON
USING THESE ENGINEERED CELLS
THAT CAN SENSE PROCESS AND
RESPOND TO ENDOGENOUS INPUTS
AND HAVE VARIOUS RESPONSE.
THE FIELD MAMMALIAN SYN-BIO,
ONLY IN THE PAST FIVE YEARS
THERE'S BEEN A PUSH TO USING
PROTEIN-BASED CIRCUIT.
SO SYNTHETIC PROTEIN BASED
CIRCUIT HAVE SOME ADVANTAGES,
THEY FUNCTION A ENTIRELY AT THE
POST TRANSLATIONAL LEVEL.
THEY ARE RELATIVELY COMPACT.
BEING ABLE TO BE ENCODED ALSO
UNDER THE CONTROL OF A SINGLE
PROMOTER.
AND MORE IMPORTANTLY, THEY
ACTUALLY CAN BE DELIVERED VIA
mRNA.
WHICH NOWADAYS IS A PRETTY
STANDARD THING WITH ALL THE
COVID VACCINE.
WHEN IT COMES TO THE CIRCUIT,
THE PROTEASE HAS BEEN THE
COMMON CURRENCY THAT'S ALLOWED
US TO DESIGN THESE COMPLEX
BEHAVIORS.
SO WHEN WE THINK OF THE INPUT
PROCESS AND OUTPUT SCHEME, THE
INPUTS REALLY CAN BE ANY SORT
OF DIMERIZATION EVENT THAT CAN
CONSTITUTE A PROTEASE AND
FUNCTIONAL.
CHOMP SOMETHING DEVELOPED IN
OUR GROUP IS THE PROCESSING
MODULE THAT ALLOWS US TO DO
ORTHOGONAL PROTEASE FOR THESE
COMPLEX BEHAVIORS AND ONLY
RECENTLY WE PUBLISHED A
PLATFORM CALLED RELEASE TO
CONTROL INTERCELLULAR SIGNALS.
BEFORE ANY ENGINEERING THAT
WOULD BE DONE WOULD BE DONE IN
THE CELL ITSELF AND WOULDN'T BE
ABLE TO COMMUNICATE WITH ANY
CELLS ON THE EXTERIOR.
SO JUST BRIEFLY THE WAY RELEASE
WORKS, IT REALLY HARNESSES
NATIVE ENDOGENOUS SIGNALING
MOTIFS, WE CAN TAG A PROTEIN OF
INTEREST, SHOWN HERE, WITH THIS
ER RETENTION MOTIF.
WHAT HAPPENS IS WHEN YOU TAG
THIS ER RETENTION MOTIF, IT'S
ACTIVELY TRANSPORTED BACK TO
THE ER.
AND THEY ARE IN THE CYTOSOL.
BECAUSE YOU HAVE SECRETION OF
THE PROTEINS VIA THE ER, THIS
SORT OF ALLOWS US TO CONTROL
THE SECRETION IN RESPONSE TO
PROTEASE ACTIVITY.
SO WHEN THERE'S NO PROTEASE
ACTIVITY OR YOU HAVE NO INPUT
ON, YOU END UP GETTING A
RETROGRADE TRANSPORT OF THE
PROTEIN OF INTEREST.
ONLY WHEN YOU HAVE ACTIVATION
OF THE PROTEASE YOU GET REMOVAL
OF THE MOTIF, IT GETS
TRANSPORTED THROUGH THE
SECONDARY PATHWAY.
AND OUR CASE WE ATTACHED A CURE
CUT CYTOMEMBRANE BOUND AND
PROCESS IT IN ITS SOLUBLE FORM.
THAT WAS AN EXAMPLE OF
ACTIVATING PROTEIN SECRETION IN
RESPONSE TO PROTEASE ACTIVITY.
SOMETHING IS TO TURN OFF
PROTEIN SECRETION IN RESPONSE.
THINK OF IT IS AS AN OFF-SWITCH.
INITIALLY WHEN WE WERE LOOKING
TO USE THE RELEASE PLATFORM FOR
THIS PROTEOLYTIC REPRESSION,
WE WOULD HAVE SOMETHING TO TURN
ON THE THING, YOU REQUIRE
MULTIPLE PROTEASES TO HAVE THIS
BEHAVIOR.
.
SO WHAT ENDS UP HAPPENING IS
YOU CAN HAVE AN INTERMEDIATE
THAT ACTS AS A PROCESSING SO
THE INPUT SUPPRESSES THAT,
EFFECTIVELY TURNING OFF THE
RELEASE SYSTEM.
BUT WHAT I WOULD LIKE TO SORT
OF SHOW IS THE FACT THAT EVEN
IN THIS TWO-PROTEASE SYSTEM, AS
YOU INCREASE THE AMOUNT OF
INPUT PROTEAS, YOU DON'T GET
A TURN OFF OF THE SYSTEM.
WE ARE LOWERING THE AMOUNT OF
PROTEASE FOR MORE COMPLEX
BEHAVIORS.
THE COMPONENTS NEED TO BE
REALLY FINALLY TUNED.
EVEN IN THIS IN VITRO SET UP WE
DON'T TURN OFF PROTEIN
SECRETION.
MORE IMPORTANTLY, AND AT THE
END OF THE DAY WE ACTUALLY
INCREASE THE OVERALL SIZE OF
THE TRANSCRIPT.
WHEN WE ARE THINKING OF
STREAMLINING THESE PROTEIN
CIRCUIT AND HARNESSES THE
ADVANTAGE OF COMPACTNESS, WE
WANT TO REDUCE THE SIZE OF OUR
TRANSCRIPT AS MUCH AS POSSIBLE.
SO WE REALIZE THAT SINCE WE ARE
FUNCTIONING ALL AT THE
POST-TRANSLATIONAL LEVEL, THERE
ARE ALSO ADDITIONAL OTHER
POST-TRANSLATIONAL THAT CELLS
USE TO CONTROL SURFACE
EXPRESSION NORMALLY.
SO ONE REALLY INTERESTING ONE
IS ACTUALLY THE INTERACTION
BETWEEN PHOSPHOROLATED PEP
TIDES AND THEIR ABILITY TO
RECRUIT IN THESE 14-3-3
SCAFFOLDING PROTEINS.
THEY CAN BLOCK THE MOTIFS BY
BLOCKING REACTIONS WITH THE
RETROGRADE MACHINERY.
EFFECTIVELY IN RESPONSE TO
PHOSPHORYLATION THERE ARE
RECEPTOR PROTEINS THAT ARE
EXPRESSED ON THE SURFACE.
THAT'S HOW THEY CONTROL THEIR
SURFACE EXPRESSION.
WE HAD A HYPOTHESIS WHAT IF WE
COULD HARNESS THESE 14-3-3
INTERACTIONS TO TUNE PROTEIN
SECRETION.
SO WHAT WE USED IS, INSTEAD OF
FOCUSING ON PHOSPHORYLATION WE
SIMPLY ATTACHED A 14-3-3
ANTAGONIST TO THE RELEASE
CONSTRUCT AND WE HAD ANOTHER
MUTANT VERSION IN WHICH THE
PEPTIDES INVOLVED WITH
RECRUITMENT WERE MUTATED OUT.
WHAT I'M SHOWING YOU HERE IS
EXAMPLE OF A PROTEIN THAT IS
NORMALLY SECRETED BUT WHEN IT'S
TAGGED WITH THE RELEASE COME
PRINCE GEORGE-VALEMOUNT --
COMPOUND THAT HAS A MUTANT
14-3-3, IT'S NOT SECRETED.
YOU GET BLOCK OF THE RETENTION
CAPABILITIES OF THE RELEASE AND
SECRETION OF YOUR PROTEIN OF
INTEREST.
WE CAN NOW DEVELOP A STRATEGY
WE CAN TURN OFF PROTEIN
SECRETION IN RESPONSE TO
PROTEASE ACTIVITY.
WITHOUT THE IMMEDIATE --
NEED OF AN INTERMEDIATE.
YOU HAVE ACTIVATION OF INPUT
PROTEASE.
IT'S RESTORED.
THIS IS AN EXAMPLE OF THE
CURVES WE HAVE BEEN SEEING.
WE ARE EFFECTIVELY GETTING
PROTEIN SECRETION COMPLETELY
TURNED OFF.
SO NOW WITH THE ABILITY TO DO
ON AND OFF, WE HAVE PREVIOUSLY
SHOWED YOU CAN DO AND OROGATE,
SINCE THIS IS A SYNTHETIC
CONSORTIUM IT WOULD BE WRONG IF
I DIDN'T SHOW ALL WE CAN DO.
SOME ARE MORE USEFUL THAN
OTHERS.
WE DON'T REQUIRE INTERMEDIATE
PROCESSING PROTEASES.
ONE THAT I REALLY ACTUALLY
THINK IS USEFUL, AT LEAST FOR
OUR CASE AND LONG-TERM GOALS IS
THIS NIMPLY GATE.
YOU HAVE AN ENGINEER CELL YOU
CO DELIVERED WITH THE
THERAPEUTIC CELL AND YOU
ESSENTIALLY WANT TO BE ABLE TO
ONLY SENSE A SPECIFIC CELL TYPE.
AN INPUT FROM A SPECIFIC CELL
TYPE.
SO IN THE TOP CASE THERE'S A
PRO-INFLAMMATORY MACROPHAGE.
YOU WANT TO TURN ON AN
ANTIINFLAMMATORY CYTOKINE IN
THAT SITUATION, BUT THERE MIGHT
BE ANOTHER SITUATION YOU HAVE
AN ADDITIONAL CELL AND
ADDITIONAL INPUT.
IN THAT SITUATION YOU WANT IT
TO TURN OFF.
THIS IS A PERFECT EXAMPLE OF
THE NIMPLY GATE ACTIVATION.
WHAT I WILL DO IS QUICKLY TAKE
THROUGH HOW THIS WHOLE GATE
WORKS.
IN THE FIRST CASE WE HAVE NO
INPUTS.
WHAT WE HAVE IS THE PROTEIN
RETAINED, AT THE END TERMINUS
WE HAVE AN ADDITIONAL MOTIF
FUNCTIONAL.
THE C-TERMINUS IS INHIBITED BY
THE PEPTIDE.
WHEN YOU HAVE INPUT OF INTEREST
YOU WANT TO TURN OFF, BY
REMOVING THE END TERMINAL
RETENTION MOTIF, THE SECOND IS
BLOCK YOU HAVE PROTEIN OF
INTEREST BEING SECRETED.
IN THE OTHER CASE REPRESENTED
BY THE OTHER PROTEASE, YOU ARE
REMOVING THE INHIBITOR, SO THE
PROTEIN OF INTEREST IS RETAINED.
FINALLY WHEN BOTH INPUTS ARE
PRESENT, EVEN THOUGH YOU REMOVE
THIS END TERMINAL MOTIF, YOU
HAVE A RESTORATION OF ACTIVITY
IN THAT SECOND MOTIF.
SO THE PROTEIN OF INTEREST IS
RETAINED.
HERE IS JUST AN EXAMPLE OF SORT
OF WHAT WE END UP SEEING WITH
THIS NIMPLY GATE.
IT'S FOR THIS RESPONSE TO
SPECIFIC INPUTS.
IN ADDITION TO BEING ABLE TO
SORT OF SENSE MULTIPLE INPUTS,
ANOTHER USEFUL POTENTIAL
ABILITY WOULD BE TO HAVE THIS
QUANTITATIVE PROCESSING OF
INPUTS.
WHAT I MEAN HERE IS THE ABILITY
TO SENSE CONCENTRATION OF A
GIVEN INPUT AND CONTROL PROTEIN
SECRETION IN RESPONSE TO THAT.
ONE NICE THING ABOUT PROTEASES
YOU CAN ACTUALLY TUNE THE
CUTTING EFFICIENCY OF A
PROTEASE BY SIMPLY CHANGING THE
AMINO ACID SEQUENCE, COMPONENTS
OF THE AMINO ACID SEQUENCES.
WHAT I'M SEEING HERE IN BOTH
THE ON AND OFF CASE OF THE
RELEASE AND RELEASE-NOT BY
CHANGING THE TUFT SITE, YOU CAN
CHANGE THE EFFICIENCIES AND
CONCENTRATIONS AT WHICH YOU
WILL GET A SUFFICIENT CUTTING
AND RELEASE OF YOUR PROTEIN OF
INTEREST.
AND SO, ONE EXAMPLE OF THIS
SORT OF CONDITIONAL PROTEIN
SECRETION IS EXAMPLE OF THE
ANALOG OR BAND PASS FILTER.
WHAT THIS MEANS IS ONLY WITHIN
A GIVEN RANG OF A CONCENTRATION
OF A GIVEN INPUT WOULD YOU GET
YOUR RELEASE CONSTRUCT BEING
RELEASED AND THEN FROM THERE
YOU WOULD BE ABLE TO HAVE YOUR
PROTEIN OF INTEREST BEING
SECRETED.
WHAT WE HAVE DONE IS MODIFIED
THE NIMPLY GATE, TO HAVE TWO OF
THE SAME PROTEASE CUT SITES BUT
WE MADE IT SO THE SECOND CUT
SITE SHOWN HERE IS LESS
EFFICIENT THAN THE FIRST CUT
SITE.
WHAT THIS MEANS IS AS YOU
INCREASE THE AMOUNT OF INPUT
CONCENTRATIONS, WHAT WILL
HAPPEN IS YOU WILL FIRST GET
REMOVAL OF THIS FIRST CUT SITE
TURNING ON PROTEIN SECRETION.
AND ONLY ONCE YOU HAVE REACHED,
THEN AS YOU INCREASE THE AMOUNT
OF PROTEASE, YOU WILL GET
REMOVAL OF BOTH AND THEN
TURNING OFF OF PROTEIN
SECRETION.
INDEED, WHAT WE HAVE SHOWN IS
WE HAVE THIS BAND PASS ACTIVITY
IN RESPONSE TO INCREASING THE
AMOUNT OF PROTEASE INPUT.
AND FINALLY, ONE THING THAT WE
HAVE ALSO REALLY SORT OF
FOCUSED ON IS, OKAY, SO WE
REALLY WANT TO LEVERAGE THE
FACT THAT WE ARE USING
POST-TRANSLATIONAL CIRCUIT.
AND SO ONE THING WE ARE REALLY
INTERESTED IN IS POTENTIALLY
USING mRNA TO DELIVER
PROTEIN-TAGGED PAYLOADS WITH
RELEASE.
SO THE IDEA HERE IS, LET'S SAY
YOU TRANSPLANT CO-DELIVER ANT
ENGINEERED CELL WITH YOUR
THERAPEUTIC CELL AND FOUR
MONTHS DOWN THE LINE YOU WANT
TO CHANGE THE OUTPUT OF WHAT
YOUR ENGINEERED CELLS ARE
CONTROLLING.
ONE THING WE ENVISIONED IS YOU
CAN ACTUALLY ENCODE A PROTEIN
TAG TO RELEASE.
IN THIS CASE WE ARE USING AN
IGG PROTEIN.
ALL UNDER THE CONTROL OF AN
mRNA.
AND IF WE WERE TO DELIVER IT
INDISCRIMINATELY TO THE SITE IT
WOULD GO EVERYWHERE.
BUT THE NICE THING ABOUT THE
RELEASE PLATFORM, IN THE HOST
CELLS OR WILD TYPE CELLS THEY
WOULD TAKE UP THE mRNA BUT THE
PROTEIN OF INTEREST WOULD BE
CONTAINED IN THE ER BECAUSE
THEY LACK MACHINERY TO RELEASE
THE CONSTRUCT.
COMPARISON THE CELLS THAT HAVE
THE PROTEASE CIRCUIT, THIS CASE
SMALL MOLECULE INDUCIBLE
PROTEASE SHOWN HERE, YOU WOULD
HAVE THE ABILITY TO ACTUALLY
USE THAT PAYLOAD.
WHAT WE DID, THIS HAS ALL BEEN
DONE IN VITRO BUT WE HAD A
MIXTURE OF THESE WILD TYPE AND
ENGINEERED CELLS AND WE
DELIVERED THE IGG CONSTRUCT VIA
mRNA.
WHAT I'M SHOWING HERE IN THIS
MIXTURE OF CELLS WHEN WE
SUSTAINED AND RAN FLOW
CYTOMETRY, THEY WERE ABLE TO
USE THE PAYLOADS AS EXPECTED.
THERE WAS NO EXPRESSION ON THE
SURFACE.
COMPARISON THE ENGINEERED CELLS
WERE ABLE TO NICELY PROCESS THE
CONSTRUCT AND EXPRESS IT ON THE
SURFACE.
AND SO TO SORT OF SUMMARIZE, WE
REALLY TRIED TO EXPAND THE
WHOLE RELEASE PLATFORM AND
THINK OF IT MORE AS A
PROCESSING OUTPUT AND OUTPUT
MODULE IN THESE PROTEASE-BASED
CIRCUIT.
WE HAVE SHOWN WE CAN IMPLEMENT
NEGATIVE REGULATION OF PROTEIN
SECRETION BY HARNESSING THE
ENDOGENOUS INTERACTIONS.
AND SHOWN THE DIFFERENT LOGIC
GATES AND QUANTITATIVE
PROCESSING WITHOUT REQUIRING
INTERMEDIATE PROTEASES, COMPACT
FYING AND STREAMLINING THE
ENTIRE CIRCUIT.
FINALLY WE SHOWED POTENTIAL OF
USING mRNA FOR THESE PROTEIN
CIRCUIT FOR FUTURE THERAPEUTICS.
AND WITH THAT I WOULD LIKE TO
THANK THE GAO LAB AS WELL AS
OUR FUNDING AGENCIES.
AND I'M HAPPY TO TAKE ANY
QUESTIONS.
THANK YOU SO MUCH.
[ APPLAUSE ]
>> HI.
I WAS WONDERING ABOUT HOW YOU
ARE TUNING THE PROTEASE
ACTIVITY.
IT SEEMED LIKE BASICALLY,
WHENEVER YOU MADE IT A LITTLE
BIT WORSE THAT'S THE MAIN WAY
OF TUNING IT, SO THAT IT
DOESN'T WORK.
DO YOU HAVE FINER CONTROL OVER
THAT?
>> Alexander Vlahos: IF I
UNDERSTAND CORRECTLY, ARE YOU
REFERRING TO THE PROTEASE CUT
SITE OR THE PROTEASE ITSELF?
>> IF YOU GO BACK ON THE SLIDE,
YOU HAVE THAT SLIDE THAT HAS
--
>> Alexander Vlahos: THIS ONE?
>> NO, FURTHER BACK.
THAT'S THE ONE.
YES.
I'M REFERRING TO THE CUT SITE.
>> Alexander Vlahos: YEAH, SO
WE ARE, WE CAN TUNE IT TO BE
WORSE.
I DON'T, WE HAVEN'T TRIED TO
MAKE IT BETTER.
WHAT WE HAVE DONE ON THE BETTER
END IS ACTUALLY TRYING TO USE
DIFFERENT TYPES OF MUTATED TEVS
OR OTHER PROTEASES WHICH ARE
MORE CATALYTICKLY ACTIVE.
THAT'S HOW WE HAVE GONE IN THE
OPPOSITE DIRECTION.
BUT FOR US TO TUNE THESE
CAPABILITIES WE ESSENTIALLY
FOCUS ON THE PROTEASE CUT SITE.
>> OKAY.
ALL RIGHT.
THANKS.
>> I WAS WONDERING IF YOU
LOOKED INTO ANY KIND OF SYSTEM
WHERE YOU COULD HAVE MORE THAN
TWO INPUTS TO FACILITATE GATES?
SO LIKE A THREE INPUT END GATE
OR FOUR INPUT END GATE OR
SOMETHING ALONG THOSE LINES?
>> Alexander Vlahos: WE HAVEN'T
LOOKED INTO THE THREE OR FOUR
INPUT GATES.
I THINK, BECAUSE THE MOD
LAIRITY OF SORT OF PROTEINS IN
GENERAL, I THINK IT COULD BE
FEASIBLE, BUT I HAVE TO DRAW IT
OUT AND SEE IF WE CAN FIND
ENOUGH RETENTION MOTIFS.
ONE NICE THING ABOUT -- SO
THE INITIAL RETENTION MOTIF WE
USED AND PUBLISHED ON IS A
DELEISING MOTIF BUT HAS TO BE
PRESENT AT THE C-TERMINUS, BUT
IT COULD BE FOUND IN LOOPS.
IN THEORY, YOU COULD, IN A WAY,
DESIGN AN END GATE WHERE YOU
HAVE MULTIPLE RXR MOTIFS WITH
PROTEASE CUT SITES IN BETWEEN
THEM TO HAVE THIS MULTI-END PUT.
>> AND A QUESTION ABOUT THE
LOGIC CIRCUIT BIOLOGY
ENGINEERING IN GENERAL.
FIRST END BIO.
I WAS WONDERING, DO YOU KNOW, I
THINK MARTIN FOSENEGER?
(?) LAB HAS DONE THIS.
DO YOU KNOW MORE COMPLICATED
CIRCUIT BUILT.
STARTING WITH GATES AND MAYBE
MOVING TO HALF ATERS OR FULL
ATERS OR ANYTHING LIKE THAT.
IF SO, HOW FAR PEOPLE ARE
TAKING IT.
AND WHAT YOUR PERSPECTIVE IS
ON, COULD WE HAVE LIKE A
BIOLOGICAL MICRO PROCESSOR AT
SOME POINT?
>> Alexander Vlahos: I THINK
THAT'S A REALLY GOOD POINT.
I THINK ONE THING THAT IS A BIT
TRICKY, AT LEAST IN OUR HANDS
THAT WE HAVE SEEN, IS WHEN YOU
TRY TO COMPLEX, OR MAKE THE
CIRCUIT MORE COMPLEX, THERE'S
ALWAYS A CHANCE THAT MORE
THINGS CAN GO WRONG.
LIKE IF A COMPONENT OF YOUR
CIRCUIT, LET'S SAY USING
TRADITIONAL TRANSCRIPTIONAL
CIRCUIT, THE ENTIRE THING COULD
GET MESSED UP.
OUR FOCUS HAS BEEN ON
SIMPLIFYING IT AS MUCH AS
POSSIBLE.
AT LEAST, YOU KNOW, INSTEAD OF
HAVING A SINGLE INPUT, SINGLE
OUTPUT.
BUT I THINK DEPENDING ON HOW
YOU ARE GOING TO ENGINEER YOUR
SYSTEM, YOU CAN ALSO THINK OF
DELIVERING MULTIPLE CELLS WITH
DIFFERENT OUTPUTS AND DIFFERENT
BEHAVIORS RATHER THAN HAVING A
SINGLE CELL THAT CAN DO
EVERYTHING.
I DON'T KNOW WHICH ONE IS THE
BETTER WAY TO GO.
I THINK BOTH HAVE THE POTENTIAL
TO WORK.
BUT YEAH, THAT'S SORT OF MY
VISION.
SOMETIMES SIMPLER IS BETTER
WITH THESE TYPES OF THINGS.
ESPECIALLY IF YOUR GOAL IS TO
EVENTUALLY TRANSLATE IT.
>> SURE, SURE.
THAT TOTALLY MAKES SENSE.
THANK YOU.
>> SURE, REALLY COOL EXTENSION
OF CHOMP, I LIKE ALL THE THINGS
YOU ARE DOING WITH SECRETION.
REAL QUICK, ONE OF THE
ADVANTAGES FOR THESE
PROTEIN-BASED CIRCUIT IS SPEED.
I DIDN'T SEE SPEED UP THERE TOO
TERRIBLY MUCH.
YOU ARE ADDING A LOT TO THE
SYSTEM.
IS IT STILL FAST?
>> Alexander Vlahos: IN THIS
CASE WE HAVEN'T SPECIFICALLY
LOOKED AT THE DYNAMICS OF THE
SYSTEM.
OTHERS HAVE LOOKED.
THEY ARE ABLE TO GET MEASURABLE
PROTEIN SECRETION WITHIN AN
HOUR TO TWO HOURS.
IN OUR HANDS IT'S BEEN ABOUT
TWO HOURS YOU CAN BEGIN TO SEE
PROTEIN SECRETION FROM THE
CELLS.
I THINK THERE ARE WAYS TO MAKE
IT FASTER.
THERE ARE SOME ER EXPORT MOTIFS
THAT MIGHT BE ABLE TO
FACILITATE TRANSPORT THROUGH
THE SECOND PATHWAY.
CAN WE HAVE THIS THING WORK?
BUT IT'S DEFINITELY SOMETHING
WE ARE INTERESTED IN DOING.
>> COOL, THANK YOU.
>> Alexander Vlahos: THANK YOU.
[ APPLAUSE ]
>> NOW WE WILL SWITCH GEARS.
WE HAVE TWO SPEAKERS COMING
FROM DARPA, DR. SHANNON GREENE
AND DR. MICHAEL.
DR.
DR. FEASEL, BIOCHEMIST AT
UNIVERSITY OF TEXAS, AUSTIN.
SO PLEASE, WITHOUT ANY FURTHER
ADO, I BELIEVE DR. GREENE WILL
GO FIRST, FEASEL AND THEN THERE
WILL BE A DANCE BETWEEN THE TWO
OF THEM.
THANK YOU.
>> Shannon Greene: GOOD
MORNING, EVERYONE.
THANK YOU FOR THE INTRODUCTION.
THIS TALK WILL PIVOT FROM THE
PREVIOUS PRESENTATION, I WILL
TALK ABOUT PLATFORM DEVELOPMENT
THAT WILL ENABLE THESE
SYNTHETIC BIOLOGY APPLICATIONS.
I'M A PROGRAM MANAGER IN
DARPA'S TECHNOLOGY OFFICE.
I WILL TALK ABOUT THE NUCLEIC
ACIDS WORLDWIDE OR NAW PROGRAM.
AT ITS BROAD LEVEL, NAW AIMS TO
DEVELOP INTEGRATED PLATFORM
THAT'S CAN SIN THEY SYNTHESIZE.
WE RELY ON OUTDATED CENTRALIZED
AND MOST CRITICALLY CELL-BASED
MANUFACTURING AND PRODUCTION
PARADIGM THAT RAPIDLY LIMITS
OUR ACCESS TO mRNA.
IF YOU WERE TO ORDER A HIGH
QUALITY DNA SEQUENCE FOR
EXPERIMENT THIS MIGHT TAKE
POTENTIALLY WEEKS.
IF WE ARE TALKING ABOUT
CLINICAL GRADE MATERIAL THAT GO
INTO HUMANS YOU ARE GETTING
DELAYS ON THE ORDER OF MONTHS.
AND MOST CRITICALLY ONE OF OUR
KEY LIMITATIONS IN GETTING
ACCESS TO HIGH QUALITY DNA AND
RNA THEY ARE PRODUCED USING
CELL-BASED METHODS.
CELLS ARE MESSY.
IF WE PURIFY FROM THE CELLULAR
MATERIAL, THIS IS A VERY
RESOURCE-INTENSIVE AND VERY
SKILL-INTENSIVE PROCESS, WHICH
DOES NOT LEND ITSELF TO
DISTRIBUTED MANUFACTURING.
SO TO REDUCE THESE BURDENS AND
GET AWAY FROM THE MESSY
CELL-BASED PROCESSES N.O.W. HAS
DIFFERENT MODALITIES FOR THE
DISTRIBUTED MANUFACTURING OF
BOTH RNA AND DNA.
THE MANUFACTURING PLATFORMS
WILL GO ALL THE WAY FROM
INSILKO SEQUENCE THROUGH THE
NUCLEOTIDE SYNTHESIS, STITCHING
TOGETHER INTO FULL LENGTH GENE
TEMPLATE PURIFYING THEM ALSO
WITH REAL-TIME ANALYTICS AND
QUALITY CONTROL CHECKS.
WHEN THE N.O.W. PROGRAM WAS
FIRST CONCEIVED IN 2019, AS I
MENTIONED, OUR CURRENT
CAPABILITIES FOR ACCESSING HIGH
QUALITY NUCLEIC ACIDS WERE
LIMITED TO THESE FACILITIES.
HOWEVER, DOD IS WORLDWIDE AND
WAR FIGHTERS ARE OFTEN EXPOSED
TO DISEASES WHERE THEY ARE
DEPLOY.
THEY CAN DEPLOY FOR
HUMANITARIAN ASSISTANCE,
DISASTER RELIEF MISSIONS WHERE
THEY ARE PROVIDING MEDICAL CARE
FOR LOCAL POPULATIONS.
IN THESE CASES, BEING ABLE TO
HAVE ACCESS TO RNA AND DNA
BASED MEDICAL COUNTERMEASURES
AT POINT OF NEED WHICH SHORTEN
THE LOGISTICAL SUPPLY CHAIN.
SO THE SOLUTION WE NEED IS
SOMETHING THAT IS VERY FAST.
SOMETHING THAT IS DISTRIBUTED.
IT'S FLEXIBLE AND ADAPTABLE TO
PIVOT TO RAPIDLY MAKING NEW
SEQUENCES OF NEED AND MAKE A
SYSTEM FULLY DEPLOYABLE.
THE CONCEPT IS THAT IF WE CAN
BEGIN TO RESPOND TO INFECTIOUS
DISEASE OUTBREAKS AT A VERY
EARLY SCALE AT THE POINT OF
NEED WE MIGHT HOPEFULLY OBVIATE
THE NEED TO MAKE MILLIONS OF
DOSES OF AN OUTBREAK IF WE CAN
NIP IT IN THE BUD VERY QUICKLY.
SO IN ADDITION TO RNA AND DNA
BASED MODALITYITIES FOR
COUNTERMEASURES THEMSELVES
OBVIOUSLY RNA AND DNA ARE
CRITICAL FOR A LOT OF DOD NEEDS.
THE MEDICAL COUNTERMEASURES
THEMSELVES.
PRECLINICAL TESTING.
DNA AND RNA ARE NEEDED FOR
BIOMANUFACTURING.
THE COVID-19 PANDEMIC
HIGHLIGHTED THE CRITICAL
RESOURCE AND OUR LACK OF EASY
ACCESS, AS MANUFACTURING SITES
WERE OVERWHELMED AND TIMELINES
WERE ORDERING THIS CRITICAL
RESOURCE WERE EXTENDED.
SO NOW, HOW DOES THE N.O.W.
PROGRAM AIM TO SOLVE THIS
PROGRAM.
THEY HAVE TWO TECHNICAL AREAS
ON THE LEFT.
TECHNICAL AREA ONE, ADVANCING
THE STATE-OF-THE-ART FOR
UPSTREAM, THIS IS ENZYMATIC, WE
ARE CHALLENGING OUR PERFORMERS
TO SYNTHESIZE GENE LENGTH
CONSTRUCTS UP TO FOUR KILOBASES.
AND SYNTHESIZE HIGH QUALITY DNA
OR RNA THAT IS ERROR-FREE.
HIGHLY CRITICAL TO HAVE A
MEDICAL COUNTERMEASURE GOING
INTO HUMANS AND USE SIMPLIFIED
STARTING MATERIALS.
SO WE WANTED THIS TO BE AN
ENZYMATIC PROCESS AND IDEALLY
CHALLENGE THE COMMUNITY TO
DEVELOP SOLUTIONS THAT COULD BE
EASILY FREEZE DRIED SO YOU
COULD HAVE REACTION WHERE YOU
COULD ALMOST HAVE A "JUST ADD
WATER" SOLUTION.
ON THE RIGHT-HAND SIDE,
TECHNICAL AREA 2, THIS IS WHERE
WE PUT OUR ENGINEERS TO WORK
WITH THE DOWNSTREAM PROCESS.
SO AS I MENTIONED WE ARE MOVING
AWAY FROM CELL-BASED
MANUFACTURING IN THIS PROGRAM
TOWARD ENZYMATIC SYNTHESIS OF
DNA AND RNA BUT THERE ARE OTHER
COMPONENTS OF THE THAT WOULD
NEED TO BE PURIFIED AND NEED TO
BE ABLE TO EMPLOY -- BEFORE
IT COULD BE DEPLOYED AS A
COUNTERMEASURE.
WE SET CHALLENGING METRICS THEY
HAD TO PRODUCE 500 DOSES IN A
FULLY AUTOMATED AND INTEGRATED
FASHION IN UNDER THREE DAYS.
NOW WE DON'T EXPECT OUR
PERFORMERS IN THESE PROGRAMS TO
GET TO THESE FINAL METRICS
OVERNIGHT, IT'S SET UP AS A
FIVE-YEAR EFFORT, EACH YEAR
THEY WOULD BE CHALLENGED WITH
CAPABILITY DEMONSTRATIONS THAT
WOULD FORCE THEM TO BE ABLE TO
SYNTHESIZE NUCLEIC ACIDS AT
GREATER LENGTH.
INCREASING THE QUALITY OF
SEQUENCE IDENTITY.
INCREASING PURITY.
DECREASING THE AMOUNT OF TIME
THEY WOULD NEED TO SYNTHESIZE
THESE MOLECULES.
WE ALSO SET METRICS FOR
INTEGRATION AND AUTOMATION.
WHERE IN THE BEGINNING OF THE
PROGRAM THE TEAMS WERE ABLE TO
USE VERY AIR-GAPED MODULES BUT
HAD TO MODULATE TOGETHER
THROUGH PURIFICATION AND
FORMULATION AT THE END.
SO RIGHT NOW I WILL SPEAK TO
THE FACT WE ARE ABOUT MIDWAY
THROUGH THIS PROGRAM.
THE A FIVE-YEAR EFFORT AND WE
ARE IN YEAR THREE.
THE N.O.W. PROGRAM HAS TWO
TEAMS, NG, MONTH MODERNA MAKING
MEDICAL COUNTERMEASURES AND GE
HEALTHCARE IS OUR DNA TEAM.
THE GE TEAM IS MAKING TWO
DEVICES.
ONE SYSTEM THAT WOULD MAKE A
SINGLE SEQUENCE OF DNA FOR
MEDICAL COUNTERMEASURE.
BUT IN PARALLEL THEY ARE MAKING
ANOTHER DEVICE THAT WOULD MAKE
LOWER QUANTITIES OF THAT
NUCLEIC MATERIAL FOR DNA
CAPABILITIES.
MY LAST MINUTES I WILL WALK
THROUGH HIGHLIGHTS FROM THE
PERFORMER TEAMS THE LAST COUPLE
YEARS.
END OF YEAR TWO MODERNA WAS
CHALLENGED WITH DEMONSTRATION
TO MANUFACTURE AND FORMULATE
DOSES OF RNA-BASED VACCINE.
THEY WERE ABLE TO MAKE OVER
800 DOSES USING MOSTLY
AUTOMATED PROCESSES.
ABOUT TWO OF THE 41 STEPS IN
THEIR PROCESS REQUIRE SOME
MANUAL INPUT.
BUT THEY MET OR EXCEEDED THE
DIFFERENT QUALITY METRICS THAT
WERE REQUIRED FOR THIS
CAPABILITY DEMONSTRATION.
AND IN THE FINAL YEARS OF THE
PROGRAM THEY WILL WORK TO
CONTINUE TO PHASE OUT ANY OF
THOSE MANUAL INTERVENTION STEPS
AND CONTINUE AUTOMATION OF THE
PLATFORM.
ON THE DNA SIDE OF THE HOUSE,
THE GE TEAM HAS A UNIQUE
CHALLENGE, THE DNA THAT COMES
OUT OF THE SYSTEM IS NOT WHAT
IS TRADITIONALLY USED FOR
COUNTERMEASURES.
NORMALLY DURING CELL-BASED
PROCESSES CELLS ARE MODIFYING
GENE BASE AND THIS HAS GONE
INTO HUMANS FOR CLINICAL TRIALS
FOR DNA-BASED VACCINES.
HOWEVER, GE ARE USING ROLLING
CIRCLE AMPLIFICATION TO
MODIFIED THE NUMBER OF DOSES.
AND IT'S A VERY HIGHLY BRANCHED
HIGHLY CAT M&R RISED STRUCTURE
AND RESULTS IN MATERIAL THAT IS
ALSO VERY VISCOUS.
SO THIS ROLLING CIRCLE
AMPLIFIED DNA HAS NOT YET BEEN
IN HUMANS SO THE QUESTION THE
GE TEAM HAS POSED NOT ONLY DO
WE MAKE THIS IN AN AUTOMATED
FASHION BUT WILL IT PERFORM THE
SAME IN ANIMAL MODELS.
WHAT I'M SHOWING ON THIS SLIDE
IS GE SYNTHESIZED INFLUENZA
VACCINE USING THE PROCESS ON
THE LEFTMENT TAKING OUR INPUT,
AND ENZYMES USING NUCLEOTIDES,
LIE GATING THEM TOGETHER INTO
BLOCKS, USING ENZYMATIC ERROR
CORRECTION TO REMOVE ERRORS
INTO THE SEQUENCE AND
SIMULATING IN THE FULL-LENGTH
SEQUENCE.
THEY WERE ABLE TO DO THE
IDENTITY WE CHALLENGED THE TEAM
WITH AND MADE IT IN ONLY FIVE
DAYS WHEN TECHNICALLY THEY HAD
A TIME PERIOD OF THREE WEEKS.
THE TECHNOLOGY TO PIGS AND WE
WERE ABLE TO DEMONSTRATE
COMPARABLE IMMUNE RESPONSE
ROLLING CIRCLE AMPLIFIED DNA
VERSUS THE N.O.W. PROCESS, AS
OPPOSED TO PLASMA
STATE-OF-THE-ART KERL.
THIS IS ONE VACCINE IN ONE
ANIMAL MODEL.
WE WILL TEST DIFFERENT TYPES OF
DNA VACCINES OR MEDICAL
COUNTERMEASURES THROUGHOUT THE
REST OF THE PROGRAM.
BUT THESE RESULTS ARE REALLY
ENCOURAGING AND POINT TO A
FUTURE FOR FULLY AUTOMATED
SYNTHESIS FOR MEDICAL
COUNTERMEASURES.
I WILL PIVOT TO MY COLLEAGUE
MIKE FEASEL, WHO WILL TALK
ABOUT SYNTHESIS OF PROTEINS.
HOW DO I GET OUT?
NEVER MIND, I WON'T TOUCH
ANYTHING THEN.
>> Michael Feasel: AWESOME,
THANK YOU VERY MUCH.
AN SHANNON SAID, I'M MIKE
FEASEL IN DARPA OFFICE.
I'M HAPPY TO SHOW YOU THE
PROTEIN MANUFACTURING PROGRAM.
QUITE A BIT YOU WILL NOTICE
LOOKS SIMILAR TO THE PROBLEM
SET SHANNON POSED FOR HER
PROGRAM NOW.
WE RELY ON VERY MUCH A HUB AND
SPOKE MODEL FOR DISTRIBUTION OF
PROTEIN PRODUCTS ACROSS THE
WORLD.
THAT MEANS PROTEIN PRODUCTION
IS HIGHLY CENTRALIZED, RELIANT
ON COLD CHAIN LOGISTICS AND
RELY HEAVILY ON
FOREIGN-SUPPLIED CELL SYSTEMS.
AND IN THE BIGGEST CHALLENGE WE
HAVE, I THINK IN PROTEIN
PRODUCTION IS THE AMOUNT OF
LEAD TIME REQUIRED.
ONCE YOU KNOW WHAT YOU WANT TO
MAKE, TO SOURCE THE CELLS TO
MAKE IT, TO ENGINEER THEM TO
MAKE THE THING YOU WANT AND
BRING THAT TO THE SCALE NEEDED
IN THIS HUB AND SPOKE MODEL IN
YOUR 20,000 LITER REACTORS,
THAT IS NOT A RAPID RESPONSE
WAY TO GO ABOUT RAPID
DISTRIBUTION.
WHAT WE ARE AIMING FOR OF
COURSE LIKE N.O.W. IS
DISTRIBUTED CAPABILITY THAT'S
COULD BE MORE TACTICAL PLACE TO
SUPPORT MORE DoD OPERATIONS TO
PROVIDE FOR BIOLOGIC SOLUTIONS,
WHETHER PRODUCTION ENZYMES FOR
THINGS LIKE N.O.W., BIOLOGIC
PRODUCTS THEMSELVES LIKE
INSULIN, CLOTTING FACTORS OR
OTHER PRODUCTION OR THERAPEUTIC
PROTEINS AS DoD NEEDS.
SO THE GOAL OF THE PROGRAM IS
TO -- LET ME TAKE A STEP BACK.
UNLIKE N.O.W. RPM IS NOT TRYING
TO BUILD A BIG BOX THAT DOES
ALL THE MANUFACTURING FOR US.
WHAT WE ARE TRYING TO DO IS
DE-RISK AND DEVELOP THE
TECHNOLOGIES THAT UNDER LIE
SUCH A BOX THAT COULD BE USED
IN THE FUTURE.
WE ARE FOCUSING ON INCREASING
PRODUCTION YIELD AND DECREASING
THE TIME REQUIRED.
UNDERSTANDING WHAT YOU WANT TO
MAKE TO ACTUALLY MAKING THE
STUFF.
WE WANT TO GET THAT FROM MONTHS
AND YEARS DOWN TO DAYS.
THE SECOND TECHNICAL AREA IS
THE FUNCTIONALITY OF THE
PROTEINS WE ARE PRODUCING.
SO THAT MEANS, APPROPRIATE
FOLDING OF THE PEPTIDES AND
PROTEINS.
AS WELL AS POST TRANSLATIONAL
MODIFICATIONS THAT OUR FIRST
SPEAKER TOUCHED ON QUITE A BIT
WHICH WAS A REALLY GOOD SEGUE
INTO THIS.
WE ARE LOOKING AT PRIMARILY N
AND O-LINKED GLYCOSYLATION.
THE PERFORMERS FOR TA-1, FOR
THE PROTEIN SIDE PRODUCTION,
PURITY AND LEAD TIME FOCUS, WE
ARE LOOKING AT OPTIMIZING OF
COURSE REACTION CONDITIONS.
WE ARE LOOKING AT MODIFYING DNA
AND RNA TEMPLATES.
DESIGNING BIO REACTORS AND
SUPPLEMENTING WITH ORGANELLES
FOR THINGS THAT CELL-PHORESIS
STEMS DON'T DO CURRENTLY.
THE SECOND AREA, WE ARE LOOKING
AT ADDING ENDOGENOUS ENZYMES.
WHAT IF YOUR SYSTEM DOESN'T
HAVE THE THING YOU NEED FOR THE
POST TRANSLATIONAL
MODIFICATION, FOR THE CHAPERON
FOLDING OF YOUR PEPTIDE OR
PROTEIN OF INTEREST, WE ARE
ADDING EXOGENOUS WHERE THEY CAN
AUGMENT THE PRODUCTIVE PROCESS.
OF COURSE ITEMS TWO AND THREE
ARE CHEMICAL MODIFICATIONS AND
LEVERAGING AND ENCODING FOR
THOSE EXOGENOUS PROTEINS IN THE
CELL SYSTEMS WE ARE TALKING
ABOUT TAKING LYSATES FROM.
THE LAST SLIDE, I PROMISE,
OVERVIEW OF PROGRAM SCHEDULE
AND METRICS.
THIS IS A FOUR-YEAR PROGRAM.
WE ARE COMING UP ON 11 MONTHS.
SO WE ARE ALMOST TO OUR FIRST
CAPABILITY DEMONSTRATION WHERE
THE PERFORMERS WILL HAVE TO
DEMONSTRATE THEY CAN MAKE A
PROTEIN OF SIZE GREATER THAN 5
KILODALTONS.
TALKING ABOUT LEAD TIME LESS
THAN TWO WEEKS.
PURITY GREATER THAN 80% AND
REACTOR SIZE GREATER THAN ONE
MIL.
O-LINKED GLYCANSES AT THIS
POINT.
AS YOU MOVE ACROSS THE TIMELINE
ALL THESE METRICS GET MORE
DIFFICULT AND MOVE TOWARD THE
END GOAL OF BEING ABLE TO
RAPIDLY PRODUCE LARGE PROTEINS
COMPLEX IN NATURE.
THEY ARE FOLDED APPROPRIATELY
AS GLYCOSOLATED.
PERFORMERS SHOW THEY ARE ABLE
TO OPTIMIZE THE ENHANCER
SEQUENCE FOR LARGER PRODUCTION
AMOUNTS OF THE PROTEIN.
IN THIS BLOT YOU CAN SEE
COMPARED TO THE BASELINE ON THE
FAR LEFT SIDE, A COUPLE
ENHANCER ELEMENTS THAT ARE MORE
OPTIMAL FOR THE PRODUCTION OF
THIS PROTEIN.
AND IT'S THE SARS-COV-2 BINDER
RECEPTOR DOMAIN.
BOTH HAVE ABOVE BASELINE LEVELS
OF PRODUCTION OF THIS PROTEIN.
ON THE RIGHT SIDE, THE
PERFORMERS IS DEMONSTRATING HOW
SELL PRODUCTION USING HOLLOW
FIBER BIO REACTOR IS NOT ONLY
MORE ADVANTAGEOUS HOW MUCH
STUFF IT COULD MAKE IN A GIVEN
TIME, IT'S SCALABLE.
THEY WENT FROM 20 MILLIONS TO
40 AND SIGNIFICANT INCREASES
OVER BATCH-STYLE REACTION WHICH
IS REALLY ENCOURAGING.
THE METRIC FOR THE FIRST
CAPABILITY DEMONSTRATION IS 100
MILLIGRAMS OF PROTEIN A WEEK.
IN THE 40 MIL HOLLOW FIBER
REACTOR THEY DEMONSTRATED THEY
HAVE REASONABLY IF THEY RUN
THIS THING FOR MORE THAN THE
TWO HOUR SINGLE BATCH IT CAN
CURRENTLY DO, IF THEY RUN IT
LONGER THEY CAN EASILY ACHIEVE
THAT GOAL.
WHAT WE ARE DEMONSTRATING HERE,
WHAT THE PERFORMERS ARE
DEMONSTRATING HERE AND WHAT I'M
TELLING YOU ABOUT BECAUSE I
DIDN'T DO THIS WORK PERSONALLY,
THEY ARE RIGHT ON TRACK TO
ACHIEVE PURITY METRICS
PRODUCING IN THIS CASE, T7 RNA
POLYMERASE.
IT ACHIEVES GREATER THAN 80%
PURITY.
ON THE RIGHT SIDE WHEN WE TALK
ABOUT FUNCTIONALITY, THIS IS AN
INDICATION THE SELF-REPRODUCED,
T7 RNA POLYMERASE IT IS
PRODUCIBLE IN THOSE GOLD
STANDARD SYSTEMS.
THAT'S ENCOURAGING AS WELL.
MY LAST DATA SLIDE, THIS IS THE
HEAVIEST WORK AND VERY RECENT
WORK DONE ON POST TRANSLATIONAL
MODIFICATION SIDE OF THE
PROGRAM.
WHERE LOOKING AT THE PERFORMERS
LOOKING AT SOLUBILIZING OR
GENERATING SOLUBILIZED
GLYCOSYLTRANSFERASES.
IN HUMANS THEY ARE ALL
MEMBRANE-BOUND PROTEINS.
ON THE RIGHT SIDE YOU CAN SEE
GLIOKOS LATED INCREASE IN
PRODUCTION CONCENTRATION AS YOU
INCREASE THE AMOUNT OF
GLYCOSILATED.
THEY ARE WORK AT INCREASING THE
AMOUNT OF GLYCOSYLATED.
WITH THAT, THAT ENDS MY
PRESENTATION AND I WILL INVITE
SHANNON BACK UP ON STAGE TO
ANSWER ANY QUESTIONS FOR EITHER
OF US.
[ APPLAUSE ]
>> SHANNON, IT WAS PRETTY
IMPRESSIVE, THEY ALREADY
KNOCKED OUT 3 OF THE 41 STEPS,
STUFF LIKE THAT.
WHAT ARE THE REMAINING
CHALLENGES, REMAINING
OPERATIONS, THAT TAKE A LITTLE
BIT MORE TO GET RID OF?
>> Shannon Greene: GREAT
QUESTION.
A COUPLE MANUAL STEPS THAT ARE
STILL WORKING ON BEING
AUTOMATED ARE INTEGRATING OX
-- SEQUENCING.
THAT COULD BE DONE AUTOMATED
BUT THEY DID STILL DO OFFLINE
SINGER SEQUENCING AS
INTERMEDIATE COMPARISON SO THE
REACTION WAS PAUSED AND THEN
RESUMED AUTOMATION DOWNSTREAM
OF THAT.
AND ONE OF THE OTHER TRICKY
STEPS IS STILL SOME OF THE
LIQUID HANDLING AT VERY, VERY
LOW VOLUMES FOR DOING THE
INITIAL BLOCK ASSEMBLY PRIOR TO
GOING TO FULL GENE LENGTH
ASSEMBLY AND THAT'S SOMETHING
WE ARE WORKING ONTO DE-RISK.
>> COOL, THANKS.
>> [OFF MIC]
YOU MENTIONED, MIKE, ALL GLYNIC
(?) ENZYMES BUT ARE YOU GOING
TO EXPAND TO OTHER
GLYCOLIZATIONS?
>> Michael Feasel: YES, END OF
PROGRAM GOALS, IF YOU GO BACK,
I THOUGHT THEY WERE INCLUDED IN
THIS SLIDE.
WE DO TALK ABOUT O AND N,
PHOSPHORYLATION IS ANOTHER ONE
MENTIONED EARLIER TODAY.
I THINK THOSE ARE THE MAJOR
ONES WE ARE LOOKING AT.
LIPIDATION OPTIONS BUT REALLY
THE OTHER POST TRANSLATIONAL
MODIFICATIONS ARE VERY MUCH
GOING TO BE PERFORMER DIRECTED.
SO AS WE NEED THEM, BASED ON
THE PROTEIN WE ARE TRYING TO
MAKE, THAT'S WHEN THEY WILL BE
INTRODUCED IN THE PROCESS THIS
YEAR.
I IMAGINE BY THE END OF THIS
PROGRAM THERE WILL BE MUCH MORE
THAN IS ACTUALLY DEPICTED HERE,
MORE SPECIFIC ONES, RATHER.
>> SURE, SURE.
LOOKS IMPRESSIVE.
THANK YOU.
>> Michael Feasel: THANK YOU.
>> ANY OTHER QUESTIONS?
IF NOT, THANK YOU VERY MUCH,
AND THANK YOU FOR KEEPING US ON
TIME.
THIS IS REALLY GREAT.
THANK YOU.
[ APPLAUSE ]
>> Miljan Simonovic: ALL RIGHT,
NOW WE ARE BACK TO THE FIRST
PRESENTER.
DR. KOO WILL NOW PRESENT HER
WORK FROM FDA.
PLEASE, DR. KOO, IF YOU COULD
COME UP.
THANK YOU.
AND I APOLOGIZE FOR THE GLITCH.
YEAH, THANK YOU.
>> Lily Koo: HI, WELL, THANK
YOU VERY MUCH.
THANK YOU, MILJAN AND JAMAL FOR
FINDING MY SLIDES AGAIN.
AGAIN, AS I SAID, IT'S A
PLEASURE TO BE HERE THIS
MORNING.
JUST TO TELL YOU A LITTLE BIT
MORE ABOUT CBER, AS I MENTIONED
EARLIER, AT CBER WE REVIEW AND
EVALUATE THE SAFETY AND
EFFECTIVENESS OF A LARGE
VARIETY OF BIOLOGICAL PRODUCTS
I WILL MENTION A LITTLE BIT ON
A LATER SLIDE.
AND YOU KNOW, AFTER GOING
THROUGH THE PANDEMIC AND
SUPPORTING THE COMMERCIAL
LAUNCH OF NOW QUITE A NUMBER OF
GENE PRODUCTS WITNESSING THE
EFFECTIVE TREATMENT IT BROUGHT
TO OUR PATIENTS, IT'S EXCITING.
BUT WE ALSO REALIZE OUR
LIMITATIONS ESPECIALLY IN THE
AREA OF BIOMANUFACTURING.
AND THERE ARE WAYS TO IMPROVE
EFFICIENCY.
AND ALSO AGILITY SO THAT WE CAN
BRING THE MEDICINE TO PATIENTS
FASTER.
AND CAN ALSO RESPOND MORE
RAPIDLY TO A HEALTHCARE
EMERGENCY.
AND SO THIS IS WHERE TODAY I
WOULD LIKE TO IN MY
PRESENTATION TODAY I WOULD LIKE
TO TELL YOU A LITTLE BIT MORE
ABOUT WHAT CBER IS DOING, JUST
TO PROMOTE DEVELOPMENT AND ALSO
ADOPTION OF ADVANCED
MANUFACTURING TECHNOLOGIES.
AND THAT IS UNDER SOME OF THE
INITIATIVE UNDER THE CBER
ADVANCED TECHNOLOGIES PROGRAM.
[COUGH]
SORRY.
I UNDERSTAND, IT DOESN'T
ADVANCE ON THIS SCREEN.
OKAY.
I JUST NEED TO GET A THING FOR
THIS.
YEAH, SO, CBER, WE HAVE A LARGE
PORTFOLIO OF BIOLOGICAL
PRODUCTS.
AND YOU MAY NOT BE AWARE OF.
WE REGULATE GENICS FOR
DIAGNOSIS OF DISEASES.
WE REGULATE BLOOD AND BLOOD
COMPONENTS FOR BLOOD
TRANSFUSION, BLOOD DERIVED
THERAPEUTIC PROTEINS, GENE
THERAPIES, MANY OF YOU ARE VERY
MUCH AWARE WHAT WE CAN DO
THERE, BOTH ANTOLOGIST.
INVIVO OR EX VIVO.
PREVENTIVE AND THERAPEUTIC.
LIVE BIO THERAPEUTIC PRODUCTS
INCLUDING FECAL BOWEL MICRO
BIOTA.
XENOTRANSPLANTATIONAL PRODUCTS.
TWO PATIENTS RECEIVE TWO PIG
HEART TRANSPLANTS GENETICALLY
MODIFIED TO REDUCE REJECTION BY
THE BODY.
AND EVEN THOUGH I THINK THEY
LASTED ABOUT 30-40 DAYS BUT
THAT'S A REALLY A CRAZY BREAK
THROUGH.
AND WE ARE CONTINUING TO WORK
ON THAT TO IMPROVE THIS KIND OF
PRODUCTS TO ADDRESS SHORTAGE OF
TRANSPLANTS.
WE ACTUALLY ALSO REGULATE
DEVICES.
ESPECIALLY THOSE DEVICES USED
FOR SCREENING, TESTING,
ISOLATION PROCESSING AND ALSO
DELIVERY OF BIOLOGICAL PRODUCTS.
AND CERTAIN COMBINATION
PRODUCTS THAT THE PRIMARY MODE
OF ACTION WOULD BE ATTRIBUTABLE
TO THE BIOLOGICAL COMPONENT.
AS YOU CAN SEE, MANY OF THESE
PRODUCTS REALLY ARE ENABLED AND
BENEFITED FROM SYNTHETIC
BIOLOGY TECHNOLOGIES AND TOOLS.
AND I BELIEVE THE WORK WE ARE
DOING HERE IS REALLY IMPORTANT
BECAUSE WHAT THAT DOES, WE ARE
PROVIDING BETTER QUALITY
PRODUCTS THAT ARE MORE POTENT.
THEY ARE MORE PRECISE AND THEY
ARE SAFER FOR THE PATIENTS.
SO PLEASE CONTINUE THE GREAT
WORK YOU ARE DOING.
AND THE REST OF THE SLIDES I'M
GOING TO TELL YOU A LITTLE BIT
MORE WHAT CBER IS DOING TO
SUPPORT THESE ADVANCED
TECHNOLOGIES, ESPECIALLY IN THE
BIOMANUFACTURING SECTOR, SINCE
THIS IS THE TOPIC OF THIS
WEEK'S MEETING.
I THOUGHT THE FOCUS ABOUT
MANUFACTURING FOR THIS YEAR'S
MEETING IS ACTUALLY REALLY
TIMELY.
BECAUSE WE ARE FACING MANY
CHALLENGES IN THIS SPACE.
THE REASON, THIS RE OBVIOUS
SOMETIMES AND NOT SO OBVIOUS.
PART IS BECAUSE BIOLOGICAL
PRODUCTS ARE JUST VERY COMPLEX.
THEY HAVE VERY COMPLEX
STRUCTURES, COMPLEX MODE OF
ACTIONS.
THEY ARE NOT EASY TO
CHARACTERIZE.
SO IT IS DIFFICULT TO ESTABLISH
YOUR CRITICAL QUALITY
ATTRIBUTES OR THE IMPURITY
PROFILE.
AND ALSO DIFFICULT TO IDENTIFY,
YOU KNOW, OR DEVELOP THE
RELEASE SPECIFICATIONS AND ALSO
THE ASSAYS USED TO SUPPORT THEM.
AND ALL THESE ARE VERY CRITICAL
ASPECTS OF FORMING A VERY
ROBUST CONTROL STRATEGY FOR A
MANUFACTURING PROCESS.
AND OF COURSE, MOST OF OUR
PRODUCTS ARE DERIVED FROM
LIVING CELLS, TISSUES AND
ORGANIZISMS WITH VERY VARIABLE,
VERY VARIABLE STARTING
MATERIALS.
SO THAT INTRODUCES ADDITIONAL
VARIABILITY TO OUR FINAL
PRODUCT.
IN ADDITION TO THE PROCESS OR
MANUFACTURING VARIABILITIES.
AND OF COURSE, BECAUSE THEY ARE
LIVING, WE HAVE TO ALWAYS
CONSIDER THEIR VIABILITY AND
HOW TO MAINTAIN THE DESIRED
PHENOTYPE THROUGH OUR
PROCESSING AND DURING STORAGE.
SO THAT'S ALWAYS A CONCERN.
AND MANY OF OUR PRODUCTS,
DEPENDING HOW THEY ARE SOURCED
AND SOME OF THE RAW MATERIAL
INTRODUCED IN THE MANUFACTURING
STREAM ARE SUBJECT TO
CONTAMINATION, WITH
ADVANTAGEOUS REAGENTS.
AND THERE NEEDS TO BE A CONTROL
TO PREVENT, DETECT AND ALSO
REMOVE THESE HARMFUL AGENTS
FROM THE FINAL PRODUCT.
THAT'S ALSO ANOTHER THING TO
CONSIDER.
THERE WILL BE RELIABILITY ON
PROCESSING, THE GMP
REQUIREMENTS THAT COMES WITH
ASEPTIC PROCESSING AND
OPERATORS AND ALL THESE
COMPONENTS INCREASE PRODUCTION
COST AND COMPLEXITY.
VERY OFTEN WHEN WE INTRODUCE A
NOVEL THERAPEUTIC MODALITY, FOR
EXAMPLE, SOME OF OUR GENE
THERAPY PRODUCTS, THE NOVELTY
OF IT PRESENTS UNIQUE
CHALLENGES AS WELL, RIGHT?
BECAUSE WE DON'T HAVE A LOT OF
PRODUCT UNDERSTANDING AND WE
DON'T HAVE A LOT OF
MANUFACTURING EXPERIENCE.
SOMETIMES THESE PRODUCTS
ESPECIALLY FOR ENTOLOGOUS
PRODUCTS -- DEVELOP
APPROPRIATE CONTROL STRATEGY.
SO THESE ARE VERY UNIQUE
CHALLENGES ASSOCIATED WITH
COMPLEX BIOLOGICS.
AND ALSO IN TERMS OF SCALING,
CURRENTLY THERE ARE TWO
DIFFERENT APPROACHES.
THEY ARE NOT COMMONLY EMPLOYED
TO INCREASE MANUFACTURING
SCALING.
ONE IS SCALE UP, WHICH WE ARE
ALL VERY FAMILIAR WHEN WE ARE
MOVING OUR PRODUCT DEVELOPMENT
PHASE FROM LABORATORY SCALE TO
INTERMEDIATE SCALE AND THEN TO
COMMERCIAL SCALE.
THAT IS JUST SIMPLY INCREASE
THE PROCESS VOLUME, RIGHT?
IT'S EASIER SAID THAN DONE.
MORE RECENTLY THERE'S ANOTHER
MODALITY AND APPROACH WHICH IS
TO SCALE OUT.
ESPECIALLY RELEVANT FOR
ANTOLOGIST.
WE SEE THAT TODAY WITH A LOT OF
THE TEAM MANUFACTURING, WE CAN
DO TO BIG COMPANIES, THEY HAVE
REALLY GREAT FACILITIES, YOU
KNOW, GMP COMPLIANT, BUT WHEN
YOU WALK IN IT REMINDS YOU OF
GOING BACK TO GRADUATE SCHOOL.
YOU SEE UNITS AND UNITS OF BIO
SAFETY CABINETS.
THERE'S A LOT OF CONSIDERATION
WHEN IT COMES TO SCALE OUT,
BECAUSE YOU WANT TO MAKE SURE
THERE IS CONSISTENCY IN EACH
LOT.
BECAUSE VERY OFTEN THEY ARE
VERY MANUAL, RIGHT?
HOW DO YOU BRING CONSISTENCY TO
HUMAN INTERVENTIONS AND HUMAN
MANIPULATIONS, THERE'S A LOT OF
TRAINING INVOLVED AND RETAIN
THE ASEPTIC CONDITIONS.
ALSO, IF YOU WANT TO INCREASE
PRODUCTION, ENCOURAGE
CONCURRENT MANUFACTURING, THERE
YOU HAVE TO WORRY ABOUT THE
RISK OF CROSS CONTAMINATION
WHEN YOU WORK IN THAT SPACE.
SO THIS IS UNIQUE.
BUT ON TOP OF THAT, I ALSO WANT
TO THINK ABOUT THE DIFFERENT
VARIETIES OF BIOLOGICAL
PRODUCTS THAT WE HAVE.
SO THE TWO APPROACHES I JUST
MENTIONED, THEY HAVE THEIR OWN
UNIQUE LIMITATIONS.
AND LOGISTICAL COMPLEXITIES AS
I MENTIONED EARLIER, BUT
NEITHER OF THEM REALLY FULLY
ADDRESS THE POTENTIAL
MANUFACTURING CAPACITY
BOTTLENECK THAT ARISES DURING A
SICH FOR DEMAND.
SO SEARCH FOR DEMAND.
SO FOR EXAMPLE, DURING COVID-19
WE REQUIRE LARGE QUANTITY OF
VACCINES TO BE MANUFACTURED
VERY RAPIDLY.
AND FACE MANY CAPACITY
BOTTLENECK THAT WE ARE VERY
WELL AWARE OF.
AND ON THE OTHER END OF THE
SPECTRUM, WE ALSO HAVE
BIOLOGICS INDICATOR FOR VERY
SMALL PATIENT POPULATION.
AS IN THE CASE OF RARE DISEASES.
AND ALSO FOR PERSONALIZED
MEDICINE WHERE, YOU MAY NEED TO
HAVE JUST A FEW LOTS, OR SMALL
LOT SIZE.
AND I HAVE TO ADDRESS MORE
INTERMEDIATE FREQUENCY.
SO I THINK, HOW DID THAT HAPPEN?
DID I PRESS IT BY MISTAKE?
I'M PRETTY SURE I DIDN'T PRESS
ANYTHING.
SO, ADDING FLEXIBILITY TO
SCALABILITY, I THINK THAT'S A
VERY CRITICAL CONSIDERATION IN
HOW WE CAN MAKE OUR PROCESS
MORE EFFICIENT.
SO HOW TO ADDRESS THESE
CHALLENGES?
AND CBER BELIEVE ONE CRITICAL
SOLUTION IS APPLICATION OF
EVENTS MANUFACTURING.
WHAT ADVANCED MANUFACTURING?
THAT'S COLLECTIVELY TERM FOR
INNOVATIVELY APPLIED AND NEW
MEDICINE MANUFACTURING
APPROACHES.
AND THE INTENT IS THAT BY USING
ADVANCED MANUFACTURING
TECHNOLOGIES, WE CAN PRODUCE
BETTER PRODUCT.
WE CAN SPEED TIME TO MARKET.
SORRY, I'M REALLY STRUGGLING
WITH THIS.
AND THERE ARE SEVERAL
CHARACTERISTICS THAT CAN
DESCRIBE A.M. OR HOW IT'S BEING
APPLIED.
THAT INCLUDES INTEGRATING NOVEL
TECHNOLOGICAL APPROACHES TO A
PROCESS.
ALSO USING ESTABLISHED
TECHNIQUE BUT IN A VERY
INNOVATIVE WAY, OR A NEW WAY.
AND ALSO APPLYING PRODUCTION
METHODS IN A NEW DOMAIN WHERE
WE JUST DON'T HAVE A LOT OF
EXPERIENCE OR DEFINED BEST
PRACTICE.
SO I THINK YOU CAN SEE NOVEL
IS A THEME THAT RUNS THROUGH
A.M.
AND EXAMPLES OF ADVANCED
MANUFACTURING, I CAN START WITH
SMART MANUFACTURING.
SO THIS IS A TERM THAT IS USED,
APPLIED TO THE USE OR
UTILIZATION OF ADVANCED
TECHNOLOGY SUCH AS AUTOMATION,
INTERNET OF THINGS.
ARTIFICIAL INTELLIGENCE, BIG
DATA ANALYTICS, TO OPTIMIZE
PROCESS CONTROL.
AND THAT IS THROUGH DIGITAL
CONNECTION AND DIGITAL
COMMUNICATION AMONG
MANUFACTURING SYSTEMS THAT USED
TO WORK IN SILO.
SO ANOTHER EXAMPLE OF SMART
MANUFACTURING I CAN GIVE YOU IS
THE CREATION OF A DIGITAL TWIN.
WHICH IS A MODEL BASED VIRTUAL
REPRESENTATION OF THE PHYSICAL
PROCESS, RIGHT?
AND THAT IS, AS A CLOSED LOOP
PROCESS CONTROL.
AND IT HAS INTERACTIVE
COMMUNICATION WITH THE PHYSICAL
PROCESS THROUGH DATA LINK.
THAT'S A REAL-TIME
COMMUNICATION THROUGH THE USE
OF ONLINE AND INLINE SENSORS,
PROCESS ANALYTICAL TECHNOLOGIES.
AND THAT ENABLE THAT TWING TO
MAKE REAL-TIME PREDICTIONS OR
DECISIONS FOR THE PROCESS.
AND THROUGH THAT WE CAN MAKE
OPTIMIZATION, ONLINE
OPTIMIZATION.
CONTINUOUS OR SEMI-CONTINUOUS
MANUFACTURING IS ANOTHER NEW
MANUFACTURING PARADIGM.
AND THAT IS, WHAT IT DOES, THAT
INTEGRATES THE UNIT OPERATIONS,
RIGHT?
AND IT HAS CONTINUOUS INPUT OF
THE RAW MATERIALS AND
CONTINUOUS OUTPUT OF THE DRUG
SUBSTANCE OR DRUG PRODUCT.
WHEN IT IS APPROPRIATELY
APPLIED, CONTINUOUS
MANUFACTURING COULD BE VERY
EFFICIENT.
BECAUSE IT HAS LITTLE DOWN TIME.
AND IT PRODUCES BETTER QUALITY
BIOLOGICS OR PRODUCTS BECAUSE
PRODUCTION IS ALWAYS HAPPENING
AT A STEADY STATE.
THE DYNAMIC FOR STARTING UP THE
SYSTEM IS NOT THERE.
AND IT'S CONTINUOUS, SO THAT'S
REALLY IMPORTANT FOR THE
CONSISTENCY OF THE QUALITY OF A
PRODUCT THAT MANUFACTURES.
AND ALSO HAS REAL-TIME PROCESS
CORRECTION AND OPTIMIZATION.
THAT ALSO MAKES THE PRODUCT
MORE ROBUST AND CONTROLS THE
FINAL DRUG PRODUCT QUALITY.
ADDITIVE MANUFACTURING, ALSO
KNOWN TO MANY OF US AS 3D
PRINTING, THAT'S ANOTHER MOVEL
MANUFACTURING MODALITY THAT
PROVIDES PERSONALIZATION AND
FLEXIBILITY TO THE WAY WE
MANUFACTURE BIOLOGICS.
AND MENTIONED QUITE OFTEN AT
YESTERDAY'S AND TODAY'S
MEETING, IT WAS A GREAT
PRESENTATION, VERY EXCITING IS
DISTRIBUTED OR POINT-OF-CARE
MANUFACTURING.
AND THIS IS, THE GOAL IS REALLY
TO BRING THE MEDICINE CLOSER TO
THE PATIENTS.
SO THAT CAN ENSURE SUPPLY,
RIGHT?
AS OUR PREVIOUS SPEAKER
MENTIONED.
AND ALSO TO REDUCE TIME TO
ADMINISTRATION, MANY BIOLOGICAL
PRODUCTS HAVE LIMITED SHELF
LIFE.
SOME OF THEM REALLY HAVE TO BE
DELIVERED TO THE PATIENT FOR
IMPLANTATION OR USE QUITE
SHORTLY AFTER PRODUCT RELEASE.
AND SOME OF THEM REQUIRE ULTRA
COLD STORAGE WHICH CREATES A
LOT OF LOGISTICAL CHALLENGES.
SO WHAT WE ARE REALLY LOOKING
FOR, FOR THESE POINT-OF-CARE OR
DISTRIBUTED MANUFACTURING IS
REALLY AVAILABILITY,
ACCESSIBILITY AND ALSO
AFFORDABILITY, RIGHT?
NOT MOVING.
OKAY.
IT'S MOVING HERE, BUT NOT THERE.
SORRY, I'M A LITTLE CONFUSED
WHICH DIRECTION I SHOULD BE
POINTING.
MUST BE ME, I'M HAVING A LOT OF
I.T. PROBLEMS THIS MORNING.
WHAT ARE SOME OF THE BENEFITS?
SOME ARE ALREADY MENTIONED.
ADVANCED MANUFACTURING WE THINK
IT WILL PRODUCE BETTER-QUALITY
MEDICINE.
BECAUSE THE MANUFACTURING IS
MORE CONTROLLED AND LESS
ERROR-PRONE.
WE KNOW WHEN YOU HAVE A LOT OF
HUMAN INTERACTIONS OR
INTERVENTIONS, WE ARE HUMAN, WE
MAKE MISTAKES AND CAN INTRODUCE
A LOT OF ERROR ALONG THE WAY.
AND WE ALSO EXPECT THAT THE
MANUFACTURING COSTS WILL BE
REDUCED SIGNIFICANTLY, DUE TO
SMALLER FOOTPRINT,
MANUFACTURING FOOTPRINT.
AND ALSO MORE EFFICIENT PROCESS.
AND ALL THESE THINGS.
AND ALSO MORE ROBUST PROCESS
MONITORING AND CONTROL.
THIS WILL LEAD TO LESS
DEFECTIVE PRODUCTS AND LESS
REJECTED BATCHES, RIGHT.
IT WILL HELP TO DEVELOP AND
ALSO MANUFACTURE MEDICINE MORE
RAPIDLY.
AND IT WOULD PREVENT OR REDUCE
AT LEAST SHORTAGES OF NEEDED
MEDICINE BECAUSE THE PROCESS IS
MORE CONTROLLED, IS MORE ROBUST.
AND TODAY, I THINK, MORE THAN
50% OF OUR DRUG SHORTAGES ARE
ACTUALLY DUE TO QUALITY-RELATED
MANUFACTURING ISSUES.
WE REALIZE THIS IS AN AREA,
THERE'S A LOT OF ROOM TO
IMPROVE TO MAKE IT MORE
EFFICIENT AND MAKE IT MORE
ROBUST.
AND IT WOULD IMPROVE EMERGENCY
PREPAREDNESS, AS IT PROVIDES
ADDITIONAL FLEXIBILITY AND
AGILITY TO THE WAY WE PIVOT AND
RESPOND TO PUBLIC HEALTH
EMERGENCIES.
BUT DESPITE ALL THESE BENEFITS,
INNOVATION, UP TAKE OF
INNOVATIVE APPROACHES
ESPECIALLY IN A REGULATED
SETTING COULD BE SLOW.
AND CBER RECOGNIZES THAT AND WE
UNDERSTAND IMPLEMENTATION OF
EMERGING TECHNOLOGIES TO
MANUFACTURE HIGH-QUALITY
COMPLEX BIOLOGICS PRESENTS A
LARGE VARIETY OF, A BIG VARIETY
OF CHALLENGES.
NOT ONLY TO THE INDUSTRY BUT TO
CBER AS WELL.
SO TO RESPOND TO THAT, WE
ESTABLISHED THE CBER ADVANCED
TECHNOLOGIES PROGRAM.
AND THE PROGRAM HAS THREE
PILLARS.
WE FUND RESEARCH AND
DEVELOPMENT PROJECTS TO SUPPORT
OUR REGULATORY SCIENCE BUT ALSO
INNOVATION.
WE BUILD INTERNAL SCIENTIFIC
AND REGULATORY EXPERTISE
BECAUSE WE REALIZE WE HAVE TO
KEEP PACE.
WE HAVE TO HAVE OUR OWN
SCIENTIFIC KNOWLEDGE AND
EXPERTISE IN-HOUSE IN ORDER TO
EVALUATE THE EFFECTIVENESS AND
SAFETY OF THESE PRODUCTS.
AND ALSO TO UNDERSTAND THE MORE
INNOVATIVE WAY OF ENGINEERING
AND DOING, TO MODERNIZE THE WAY
WE ENGINEER OUR PRODUCTS.
AND WE ALSO CREATED THE CBER
ADVANCED TECHNOLOGIES TEAM,
WHICH I WILL DESCRIBE A LITTLE
LATER ON A LATER SLIDE.
SO, FIRST, TALKING ABOUT THE
EXTRAMURAL RESEARCH THAT WE
SUPPORT.
SINCE 2018, CBER HAS ALREADY
AWARDED OVER 20 GRANTS AND
CONTRACTS TO SUPPORT RESEARCH
PROJECTS ADDRESS KNOWLEDGE AND
EXPERIENCE GAPS THAT WE HAVE
IDENTIFIED FOR EMERGING
MANUFACTURING AND TESTING
TECHNOLOGIES.
TO SUPPORT THE DEVELOPMENT AND
ADOPTION OF THESE ADVANCED
TECHNOLOGIES.
SO EACH YEAR WE IDENTIFY AREAS
OF NEEDS IN THE ADVANCED
MANUFACTURING TECHNOLOGY AREA
AND SOLICIT APPLICATIONS
THROUGH FDA BROAD AGENCY
ANNOUNCEMENT AND ALSO THROUGH
THE NIH GRANT AND FUNDING
PORTAL.
SO I REALLY ENCOURAGE EVERYONE
TO CHECK IT OUT AND SEE IF
THERE ARE AREAS OF INTEREST AND
TO YOU AND TO THE FDA TO CBER
AND PLEASE SUBMIT YOUR
APPLICATIONS.
WE REALLY WOULD BE VERY HAPPY
TO SEE MORE WORK-RELATED TO
SYNTHETIC BIOLOGY AND HOW THAT
CAN IMPROVE OUR
BIOMANUFACTURING STRATEGIES.
OKAY, THAT IS TOO FAR.
MAYBE I JUST NEED TO BE PATIENT.
GOOD.
SOME EXAMPLES OF THE PROJECTS
WE SUPPORT, WE SUPPORT 3D
PRINTING PROJECTS, INCLUDING
BIO PRINTING OF TISSUE AND
VACCINE FORMULATIONS.
WE HAVE SOME REALLY COOL
PROJECTS.
NOVEL MANUFACTURING MODALITIES
AND APPROACHES FOR CELL AND
GENE THERAPY PRODUCTS.
SOME INCLUDE USE OF AUTOMATION
AND ALSO DOWNSTREAM
PURIFICATION PROCESS.
AND ALSO RELATED TO CRITICAL
QUALITY ATTRIBUTIONS, DISCOVERY
AND IDENTIFICATION USING
MULTI-NOMIC ANALYSIS APPROACHES.
WE HAVE SEVERAL PRODUCTS,
CONTINUOUS MANUFACTURING OF
DIFFERENT TYPES OF PRODUCTS.
AND IN FACT, LAST YEAR, WE
AWARDED A VERY LARGE SUM
CONTRACT TO A TEAM LED BY
M.I.T. TO WORK OUT A REALLY
G.M.P. PILOT SCALE
DEMONSTRATION UNIT THAT CAN
MANUFACTURE VACCINE, mRNA-BASED
VACCINES IN A CONTINUOUS
FASHION.
WE HAVE SUPPORTED ADVANCED
MANUFACTURING OF SYNTHETIC
SCAFFOLDS THAT WILL MIMIC CELL
OR EXTRA CELLULAR MATRIX
PROPERTIES.
WORK PROCESS
MODELING/SIMULATION AND ALSO
ANALYTICAL TECHNOLOGIES.
HE
ESPECIALLY INTERESTING ARE NON
DESTRUCTIVE TECHNOLOGIES OR
REAL-TIME SENSORS THAT CAN HELP
WITH THE ADVANCEMENT OF
BIOMANUFACTURING.
THERE IS A WEBSITE YOU CAN
CHECK IT OUT.
IN SUPPORTING THESE EXTRAMURAL
PROJECTS CBER IS LEARNING ABOUT
THESE CUTTING EDGE RESEARCH AND
TECHNOLOGIES AS WELL BECAUSE WE
DON'T HOLD A MINI SYMPOSIUM, WE
INVITE OUR RECIPIENTS OF OUR
FUNDING.
AND WE ALSO ORGANIZE
EDUCATIONAL SEMINAR SERIES AND
VERY, MOST RECENTLY, THIS FALL,
WE LAUNCHED OUR NEW CBER
ADVANCED MANUFACTURING SEMINAR
SERIES.
THAT INCLUDES, FEATURES
SPEAKERS FROM OUR PAST AND
PRESENT RECIPIENTS FROM OUR
FUNDING.
AND ALSO LEADING EXPERTS FROM
ACADEMIA AND INDUSTRY AND ALSO
GOVERNMENT SECTORS.
IF YOU ARE INTERESTED, YOU CAN
DEFINITELY LET ME KNOW, THIS IS
A PUBLIC MEETING, SEMINAR AND
WE CAN INCLUDE SOME OF THE
FOLKS WHO ARE INTERESTED HERE.
SO NOW I WILL MOVE TO THE CBER
ADVANCED TECHNOLOGIES TEAM,
ALSO KNOWN AS CATT.
CATT WAS ESTABLISHD IN 2019,
THAT IS TO PROMOTE THE
DIALOGUE, EDUCATION AND INPUT
AMONGST CBER AND ALSO BETWEEN
CBER AND TECHNOLOGY DEVELOPERS
FOR ADVANCED MANUFACTURING
TECHNOLOGIES.
THAT IS REALLY TO ENCOURAGE
THEIR ADOPTION, THEIR
IMPLEMENTATION.
AND PEOPLE WHO PARTICIPATE IN
THE CATT TEAM IS A CROSS
FUNCTIONAL GROUP CBER
LEADERSHIP AND SUBJECT MATTER
EXPERTS COMING FROM OUR REVIEW
OFFICES.
SO THE OFFICE REPRESENTED
INCLUDING OFFICE OF DIRECTOR,
OFFICE OF VACCINE, OFFICE OF
BLOOD AND ALSO OFFICE OF
THERAPEUTIC PRODUCTS, AS WELL
AS OFFICE OF COMPLIANT AND
BIOLOGICAL QUALITY GROUP.
AND THE CATT IS REALLY INTENT
TO PROVIDE ACCESS TO EARLY
INTERACTION.
I WILL LET YOU IN A MOMENT HOW
EARLY WITH CBER, THAT'S IN THE
PRE-SUBMISSION SPACE AND
DISCUSS TECHNICAL AND
REGULATORY ISSUES.
SOMETIMES IT COULD BE PERCEIVED
REGULATORY ISSUES RELATED TO
THE IMPLEMENTATION OF THESE
INNOVATIVE TECHNOLOGIES.
SO WHEN SHOULD YOU COME IN WITH
A CATT MEETING?
WHEN IS A CATT MEETING
APPROPRIATE?
I'M TRYING TO FOCUS ON THIS
AREA.
YES.
SO HERE IS SOMETHING YOU ARE
PROBABLY ALL VERY FAMILIAR WITH.
THAT IS DRUG EVALUATION PROCESS
USED BY FDA.
TO EVALUATE THE SAFETY AND
EFFECTIVENESS OF A DRUG IN
BIOLOGICS.
AS YOU CAN SEE FDA OFFERS
PHASE-APPROPRIATE MEETINGS TO
PROVIDE BINDING REGULATORY
ADVICE.
TO HELP THE MANUFACTURER TO
MOVE ALONG THE PIPELINE.
UP TO THE POINT WHERE YOU ARE
READY TO SUBMIT A COMMERCIAL
APPLICATION.
[COUGHS]
SORRY.
BUT DURING THAT PROCESS, FDA
AND ESPECIALLY CBER RECOGNIZE
THAT FOR SOME INNOVATIVE CLASS
OF PRODUCTS, THEY REPRESENT
VERY UNIQUE CHALLENGES, RIGHT?
SO FOR EXAMPLE, THEY MAY BE
ASSOCIATED WITH UNKNOWN SAFETY
PROFILES.
THEY HAVE VERY COMPLEX
MANUFACTURING PROCESS AND THEY
HAVE THE NEED TO USE INNOVATIVE
MANUFACTURING OR TESTING
TECHNOLOGIES.
SO EARLY INPUT AT A PHASE
BEFORE, PHASE 1 COULD BE VERY
BENEFICIAL FOR THE
MANUFACTURERS.
PRODUCT DEVELOPERS.
SO THIS IS WHEN CBER INTRODUCED
INTERACT INITIAL TARGETED
REGULATORY ADVICE FOR CBER
PRODUCTS.
AND THAT MEETING IS DISCUSSED
IN THE CONTEXT OF A SPECIFIC
INVESTIGATIVE PRODUCT.
AND THE TIMING IS USUALLY
BEFORE YOU HAVE DEVELOPED A
MANUFACTURING PROCESS FOR YOUR
CLINICAL STUDIES.
AND BEFORE YOU HAVE DEVELOPED
ALSO LET'S SAY A PRELIMINARY
RELEASE, NOT RELEASE CRITERIA.
AND ASSAYS.
RIGHT, THIS IS QUITE EARLY BUT
YOU SHOULD HAVE PRELIMINARY
CRITICAL PILOT DATA FOR
DISCUSSION WITH THE AGENCY.
SO THIS IS INTERACT MEETING.
AND THEN WE INTRODUCE A CATT
MEETING THAT ACTUALLY COMES
EVEN EARLIER THAN THE INTERACT
MEETING IN TERMS OF PRODUCT
DEVELOPMENT PHASE.
SO THE CATT MEETING IS REALLY A
WAY TO ENCOURAGE EARLY
ENGAGEMENT FOR TECHNOLOGY
DEVELOPERS, OKAY.
AND ALSO FOR APPLICANTS LOOKING
TO IMPLEMENT NOVEL TECHNOLOGY
IN THEIR DEVELOPMENT PROGRAM.
TO SPEAK TO CBER EARLY AND TO
DISCUSS THE DIFFERENT POTENTIAL
TECHNICAL AND ALSO REGULATORY
CHALLENGES OR HURDLES THAT YOU
MAY THINK THAT WILL BE DOWN THE
LINE IN THE IMPLEMENTATION OF
THE TECHNOLOGY.
THE PURPOSE OF CATT IS ALSO TO
BRING AWARENESS TO CBER TO
UNDERSTAND THE TYPE OF
INNOVATIVE PRODUCTS OR
TECHNOLOGY THAT IS COMING OUR
WAY.
BUT BECAUSE THE ENGAGEMENT IS
IN AN EARLY PHASE OF
DEVELOPMENT, THE REGULATORY
ADVICE PROVIDED BY CATT AND
INTERACT ARE CONSIDERED
NON-BINDING.
SO WHAT IS THE SCOPE OF CATT
MEETING, I THINK SOME WE
MENTIONED EARLIER.
THE TECHNOLOGY SHOULD BE NOVEL
AND THEY SHOULD HAVE
SIGNIFICANT IMPACT ON PRODUCT
DEVELOPMENT, MANUFACTURING
PROCESS AND ALSO IN THE
MANUFACTURING CONTROL
STRATEGIES.
THERE CAN BE MANUFACTURING AND
TESTING METHODS WHICH CBER
DOESN'T HAVE A LOT OF
EXPERIENCE.
SO WE WOULD LIKE TO BE AWARE
AND UNDERSTAND.
AS I MENTIONED EARLIER THEY ARE
NOT FOR PRODUCT-SPECIFIC
DISCUSSIONS.
WHEN YOU WANT TO BRING
DISCUSSION IN THE CONTEXT OF A
PRODUCT, THEN INTERACT OR
PRE-IND SUBMISSION MEETINGS MAY
BE MORE APPROPRIATE.
THEY ARE NOT MEANT FOR HIGHLY
TECHNICAL DISCUSSIONS BECAUSE
OF HOW EARLY THE DEVELOPMENT
PHASE IS.
THIS IS WHAT WE REQUEST IN
TERMS OF WHAT SHOULD BE PART OF
YOUR MEETING REQUEST PACKAGE.
WE USUALLY ASK FOR A TWO-PAGER.
THAT IS TO INCLUDE BACKGROUND
INFORMATION TO DESCRIBE THE
TECHNOLOGY AND TO TELL US WHY
THE TECHNOLOGY AND PRODUCT IS
NOVEL AND UNIQUE AND WHAT'S THE
IMPACT ON TECHNOLOGY OR ON A
PARTICULAR PRODUCT CLASS.
WE WOULD LIKE A SUMMARY OF
MANUFACTURING OR DEVELOPMENT
PLAN, BECAUSE IF YOU DON'T HAVE
A PLAN THEN MAYBE IT'S NOT
READY FOR A CATT MEETING
DISCUSSION YET.
BUT IF YOUR PLAN IS TO ADVANCE
YOU MAY WANT TO CONSIDER
INTERACT OR PRE-SUBMISSION
MEETING.
WE ALSO ASK FOR YOU TO INCLUDE
THE QUESTION REGARDING THE
REGULATORY, TECHNICAL OR OTHER
ISSUES THAT YOU SEE POTENTIALLY
COULD IMPACT THE IMPLEMENTATION
IN THE FUTURE.
SO BRIEFLY, THE REVIEW PROCESS.
THE EVALUATION INITIALLY IS
TRIAGED BY OUR CATT
COORDINATORS.
THEY WILL LOOK AT WHERE THE
TECHNOLOGY BELONGS TO, OR
SOMETIMES CROSS DISCIPLINARY
AND WE WILL ASSIGN TO THE
DEVELOP -- RELEVANT REVIEW
OFFICES.
THEY WILL REVIEW IT AND
RECOMMEND THE CATT COORDINATOR
IF THE MEETING SHOULD BE
GRANTED OR DECLINED.
AND THEY CAN ALSO SAY, HEY, WE
ARE REALLY INTERESTED IN THE
TECHNOLOGY, WE WOULD LIKE TO
LEARN MORE ABOUT IT.
SO WE WANT TO HAVE A
DISCUSSION, WANT TO SEE MORE
INFORMATION, WE MAY ASK FOR
ADDITIONAL INFORMATION AND ASK
FOR THE MEETING SLIDES.
BUT SOMETIMES THEY MAY SAY HEY,
THIS IS SOMETHING THAT WE HAVE
ALREADY SEEN IN A PREVIOUS CATT
MEETING SO WRITTEN RESPONSE IN
THIS CASE SHOULD BE SUFFICIENT.
SOMETIMES WE ALSO RECOMMEND
THAT MAYBE THERE'S ANOTHER MORE
APPROPRIATE REGULATORY FORMAT
OR MEETING TO SUPPORT A
DISCUSSION.
SOME EXAMPLES OF TECHNOLOGIES
DISCUSSED INCLUDE CONTINUOUS
MANUFACTURING.
IT'S A RECURRING THEME.
WE ALSO HAVE SEEN THE
DEVELOPMENT AND SOME ARE REALLY
NEAT, OF SOME FULLY-ENCLOSED
AUTOMATED AND SCALABLE SYSTEMS
FOR THE MANUFACTURING OF CELL
THERAPY PRODUCTS.
AND REALLY IN THE FASHION YOU
CAN IMAGINE, CONCURRENT
MANUFACTURING AND HOW THEY CAN
ENABLE MAYBE DISTRIBUTED
MANUFACTURING OR POINT-OF-CARE
MANUFACTURING.
WE ALSO HAVE PROJECTS WORKED
OUT, OR MEETING REQUESTS THAT
WORK ON IMPROVE CELL LINE FOR
BOTH AAV VECTOR MANUFACTURING
AND VACCINE DEVELOPMENT.
WE HAVE SEEN A LOT OF USE OF
A.I. ESPECIALLY IN THE AREA OF
ADVANCED IMAGING TECHNOLOGIES.
AND THAT IS FOR EXAMPLE, VISUAL
INSPECTION FOR REAL-TIME
QUALITY ASSESSMENT.
AND WE ACTUALLY ALSO SEE A LOT
OF FACILITY DESIGN,
MULTI-PRODUCT MANUFACTURING TO
MAKE IT MORE EFFICIENT, THAT WE
CAN ALLOW CONCURRENT
MANUFACTURING AND A LOT OF
TIMES THEY USE MODULAR-TYPE OF
TECHNOLOGIES.
WE HAVE SEEN TECHNOLOGY
SUPPORTING GENE EDITING AND
ALSO INFORMATIC MENTIONED
EARLIER IN THE TALK AND
SCALABLE OF OTHER CELLULAR
VESSELS ANOTHER INTERESTING
MODALITY.
AND HERE I JUST WANT TO MENTION
THAT CBER ALSO PARTICIPATED IN
THE DEVELOPMENT AND PUBLICATION
OF ISHQ13 WHICH IS CONTINUOUS
MANUFACTURING OF DRUG SUBSTANCE
AND DRUG PRODUCT.
AND UNDER THE PURPOSE OF ICHQ13
IS TO PROVIDE HARMONIZED
GUIDANCE OF IMPLEMENTATION HOW
WE ARE USING CONTINUOUS
MANUFACTURING TECHNOLOGIES TO
MAKE OUR DRUG SUBSTANCES AND
DRUG PRODUCTS.
AND THE SCOPE AT THE MOMENT, I
THINK THEY APPLY TO CHEMICAL
ENTITIES AND THERAPEUTIC
PROTEINS.
AND ALSO, YOU KNOW, THE
CONVERSION FROM BATCH
MANUFACTURING PART OF EXISTING
TECHNOLOGY OR EXISTING WAY OF
MANUFACTURING AND CONVERTING
THAT TO C.M.
IN OUR EXPERIENCE WE HAVEN'T
SEEN A CONTINUOUS MANUFACTURING
APPLIED TO THE PRODUCT THAT
CBER REGULATES BUT WE BELIEVE,
YOU KNOW, THE PRINCIPLES SHOULD
APPLY.
AND THIS IS WHERE WE ARE HOPING
ALSO TO LEARN VERY MUCH ABOUT
C.M. THROUGH A CONTRACT THAT WE
AWARDED TO M.I.T. THAT I
MENTIONED EARLIER.
SO IN SUMMARY WE ARE WORKING
ACTIVELY TO ACCELERATE THE
DEVELOPMENT, ALSO ADOPTION OF
ADVANCED MANUFACTURING
TECHNOLOGIES.
AND WE WE ENCOURAGE THE
DEVELOPMENT OF INNOVATION AND
WE WANT TO HAVE PEOPLE TO COME
TO US AND ENGAGE IN DIALOGUE
EARLY ON.
I KNOW A LOT OF PEOPLE, I
JOINED FDA ALMOST 10 YEARS AGO.
I REALIZE THAT A LOT OF THE
MANUFACTURERS OUT THERE AND
TECHNOLOGY DEVELOPER, THEY ARE
ACTUALLY SCARED OF COMING TO
FDA AND TALKING TO US.
BUT WE ARE ACTUALLY, WE ARE
VERY REASONABLE, I THINK.
I THINK.
AND IN A WAY, FLEXIBLE.
AND THERE'S A REASON WHY VERY
OFTEN WE SAY OH SOME
CONSIDERATIONS ARE CASE-BY-CASE.
BECAUSE WE DO CONSIDER YOUR
PRODUCT AND HOW YOU MANUFACTURE
THEM AND PROVIDE TAILORED
RESPONSE TO HELP YOU TO MOVE
ALONG THIS PROCESS FROM
DEVELOPMENT ALL THE WAY TO
COMMERCIALIZATION.
AND WE ARE ACTUALLY DOING A LOT
OF WORK TO COLLABORATE
INTERNALLY WITH OUR SISTER
AGENCY, CDER, THEY HAVE
EMERGING TECHNOLOGY PROGRAM
THAT WE WORK CLOSELY WITH THEM
TO DEVELOP A LOT OF REGULATORY
APPROACHES AND FRAMEWORKS.
AND WE ALSO ARE WORKING
COORDINATING WITH OUR
INTERNATIONAL REGULATORY
PARTNERS TO PROMOTE GLOBAL
ADOPTION OF ADVANCED
TECHNOLOGIES.
BUT ALSO TO TRY TO LOOK FOR
WAYS TO HARMONIZE THE
REGULATORY APPROACHES FOR THESE
FUTURE PRODUCTS AND
TECHNOLOGIES.
BEFORE I END MY PRESENTATION, I
WANT TO TELL YOU A LITTLE BIT
ABOUT TWO ACTIVITIES, OR TWO
OUTREACH ACTIVITIES AT CBER
THAT IS CURRENTLY ONGOING.
THE FIRST ONE IS WE ACTUALLY
PUSHED OUT A PILOT CROWD
SOURCING ACTIVITY.
IT JUST STARTED THIS WEEK, I
BELIEVE.
IT IS CALLED ENVISIONING THE
FUTURE FOR BIOLOGICAL PRODUCTS.
AND THIS IS PART OF CBER'S GOAL
TO KEEP PACE WITH THE RAPID
ADVANCEMENT IN MANY OF OUR
PRODUCT AREAS IN
BIOMANUFACTURING.
BUT ALSO TO KEEP PACE WITH THE
TECHNICAL AND SCIENTIFIC ISSUES
THAT IMPACTS THE PRODUCTS THAT
WE REGULATE.
SO WE WANT TO INVITE OUR
STAKEHOLDERS AND YOU ARE AMONG
THEM TO BRING YOUR INSIGHTS AND
TO GIVE YOUR IDEA AND VISION
FOR THE FUTURE OF BIOLOGICS.
WHERE IS THIS GOING?
WHERE IS THE LANDSCAPE OF
BIOMANUFACTURING IN THE NEXT
TEN YEARS.
SO PLEASE, CHECK IT OUT.
AND SUBMIT IDEAS.
BECAUSE IDEAS YOU SUBMIT WILL
HELP INFORM CBER FOR OUR FUTURE
PLANNING ACTIVITIES.
AND IT COULD BE THE PLANNING OF
WORKSHOPS, HOW TO BUILD UP AND
CREATING MAYBE MORE INTRA CBER
INTERNAL RESEARCH INITIATIVES.
AND OTHER STRATEGIC PLANNING
ACTIVITIES.
SO THAT ENDS IN TWO WEEKS.
SO IF YOU HAVE A GREAT IDEA,
PLEASE SHARE WITH US.
ANOTHER ONE IS A REQUEST FOR
INFORMATION POSTED BY OUR
OFFICE OF THERAPEUTIC PRODUCT.
AND THERE, THEY WOULD LIKE TO
LEARN WHAT YOU THINK ARE THE
SCIENTIFIC CHALLENGES.
AND ALSO OPPORTUNITIES TO
ADVANCE THE DEVELOPMENT OF
INDIVIDUALIZED CELLULAR AND
GENE THERAPY PRODUCTS.
IT COULD INCLUDE MANUFACTURING,
NON-CLINICAL AND CLINICAL
DEVELOPMENT.
HERE IS A LINK, CHECK IT OUT
AND JUST PROVIDE YOUR PUBLIC
COMMENTS.
AND IF THERE IS A FOLLOW-UP
WORKSHOP, JUST FOLLOW THE
ANNOUNCEMENTS AND WE WOULD LOVE
TO HEAR YOUR INPUT.
SO WITH THAT, I WILL CONCLUDE
MY PRESENTATION THIS MORNING.
THANK YOU VERY MUCH FOR YOUR
ATTENTION AND IF THERE'S ANY
QUESTION ABOUT THE PROGRAM I
TALKED ABOUT, JUST FEEL FREE TO
SEND ME AN EMAIL.
THANK YOU VERY MUCH.
ALRIGHT WE ARE
BACK, BACK IN POWER.
NOW WE WILL DO SOMETHING A
LITTLE DIFFERENT.
WE WILL HAVE A PANEL.
I THINK IT'S ACTUALLY TOP-NOTCH
PANEL THAT IS HERE.
STARTING WITH DAVID BORHANI,
LILY KOO, SUZIE PUN, RACHELLE
SALOMON, PAUL SHEEHAN AND ARIEL
WEINBERGER.
I WILL ASK THE PANEL TO
INTRODUCE THEMSELVES.
PLEASE, YOU CAN START FROM
DAVID, LET'S GO.
>> David Borhani: OKAY, DAVID
BORHANI AT GINGKO BIO WORKS.
THANKS FOR INVITING US TO THIS
PANEL.
SO I AM ON THE BUSINESS
DEVELOPMENT SIDE, FOCUSED ON
GOVERNMENT IN THE PHARMA AREA.
MY TRAINING IS IN DRUG
DISCOVERY, CHEMISTRY,
STRUCTURAL BIOLOGY.
BEFORE JOINING GINGKO ABOUT
FIVE YEARS AGO, I WAS AT DEHR
RESEARCH DOING COMPUTATIONAL
DRUG DISCOVERY ABOUT TEN YEARS,
BEFORE THAT STRUCTURAL AT
ABBOTT IN WESTERN MASS, WORKED
ON IMMUNOLOGY, ONCOLOGY, SMALL
AND LARGE MOLECULE.
WAY BACK IN ANCIENT HISTORY, I
RAN MY OWN LAB, STRUCTURE-BASED
DRUG DESIGN, TRAINED AT HARVARD
IN STRUCTURAL BIOLOGY AND IN
CHEMISTRY AT M.I.T.
>> Lily Koo: HI, MY NAME IS
LILY KOO, THE PAST TEN YEARS
WORKING AT FDA, STARTED AS LEAD
REVIEWING OF RESPIRATORY
DEVICES IN THE CENTER FOR
DEVICES.
AN THEN I MOVED OVER TO CBER
AND THERE I WAS WORKING AS A
REVIEWER, ALSO AS G.M.P.
INSPECTOR FOR A LOT OF THE
BIOLOGICAL PRODUCTS.
MORE RECENTLY I BECOME INVOLVED
WITH THE PROGRAM CBER PROGRAM
FOR ADVANCED TECHNOLOGIES.
BECAUSE I THINK JUST DURING ALL
THE REVIEW AND INSPECTION I
STARTED TO SEE THE NEED BUT
ALSO THE ACTUAL IMPLEMENTATION
AND GROWTH IN MORE OF THE
APPLICATION IN ADVANCED
TECHNOLOGY AND I THINK THIS IS
THE FUTURE TO COME TO REALLY
MOVE THE SECTOR, THE
BIOMANUFACTURING SPACE AND ALSO
DEVELOPMENT, PRODUCT
DEVELOPMENT FORWARD IN GIANT
LEAPS IN THE FUTURE.
AND PRIOR TO THAT, I WAS
ACTUALLY AT THE N.I.H. FOR
ALMOST TEN YEARS.
I DID MY POST DOC WITH DR.
ROGER JERMAINE, LOOKING AT CELL
TRAFFICKING AND DEVELOPING
TECHNIQUES FOR IMAGING
TECHNIQUES AND NIAD, WORKED
WITH RESEARCH TECHNOLOGY AND
PROGRAM.
ANYHOW, THIS IS MY BACKGROUND
AND I HAVE AN ENGINEERING
BACKGROUND.
YEP, THIS IS IT.
THANK YOU.
>> MY NAME IS SUZIE PUN, DRUG
DELIVERY APPLICATIONS AND IN
THE LAST, I GUESS EIGHT YEARS
OR SO, WE HAVE BEEN DEVELOPING
MATERIALS FOR CELL
MANUFACTURING.
>> GOOD MORNING, MY NAME IS
RACHELLE SALOMON, PROGRAM
DIRECTOR AT NCI IN THE DIVISION
OF CANCER TREATMENT AND
DIAGNOSIS.
DCTD.
WE OVERSEE A CONTRACT AT THE
FREDERICK NATIONAL LABS, WHICH
IS FOR THE BIO PHARMACEUTICAL
DEVELOPMENT PROGRAM.
AND AT THIS FACILITY WE DO
G.M.P. MANUFACTURING OF
BIOLOGICS FOR PHASE I AND PHASE
II CLINICAL TRIALS.
I'M EXCITED TO BE HERE TODAY.
MY BACKGROUND IS AS AN
IMMUNOLOGIST I'VE BEEN AT NCI
FOR MANY YEARS.
BEFORE THAT I WAS AT NIAID AS A
PROGRAM DIRECTOR FOR INFLUENZA
VACCINE RESEARCH AND
DEVELOPMENT.
AND THAT REALLY CAME OUT OF MY
LOVE FOR LOOKING AT IMMUNE
RESPONSES AND THE INTERACTIONS
WITH VIRUSES.
I WAS A FELLOW WITH ROBERT
WEBSTER AT SAINT JUDE
CHILDREN'S RESEARCH HOSPITAL IN
MEMPHIS, TENNESSEE.
AND BEFORE THAT, WHAT SPARKED
MY INTEREST IN IMMUNOLOGY AND
UNDERSTANDING THE HOST RESPONSE
TO DISEASES AND PATHOGENS WAS
WORKING IN THE LABORATORY OF
CHRISTINE BYRON AT BROWN
UNIVERSITY WHERE I DID MY Ph.D..
SO I'M REALLY EXCITED TO BE
HERE AND SHARE SOME THOUGHTS
WITH THIS PANEL.
THANK YOU.
>> Paul Sheehan: HELLO,
EVERYONE, PAUL SHEEHAN, ARPA-H,
WE ARE NOW UP TO 12 FOLKS
TRYING TO COVER EVERYTHING THE
NIH IS TRYING TO DO, IT'S QUITE
A STRETCH.
BEFORE COMING TO DARPA-H, I WAS
DARPA IN THE BIOTECHNOLOGY
OFFICE, BTO.
I'M INTERESTED IN THE
INTERSECTION OF BIO
ELECTRONICS, SYNTHETIC BIOLOGY
AND SYNTHETIC ECOLOGY ALL
PULLED TOGETHER TO CREATE
CONTROL SYSTEMS FOR BIOLOGICAL
NETWORKS.
>> I'M ARIEL WEINBERGER, CEO
FOR -- WHAT WE FOCUS ON AS A
COMPANY IS DEVELOPING NEW
CLASSES OF RNA NOVEL MOLECULAR
CIRCUIT, IF YOU WOULD LIKE.
OR USING SYNTHETIC BIOLOGY TO
BUILD NUCLEIC ACIDS TO BUILD
WHERE AND WHEN THERAPEUTIC
PROTEINS ARE TRANSLATED.
WE ARE INTERESTED IN PRECISION
MEDICINES, WHAT WE CALL
AUTONOMOUS MEDICINES THAT CAN
DECIDE WHETHER TO MAKE PROTEIN,
WHETHER IT'S A DISEASE CELL AND
CONTROL THE OUTPUTS OF OUR
NUCLEIC ACID TECHNOLOGIES.
BEFORE THAT, BACKGROUND IS
EVOLUTIONARY BIOLOGIES BUT
THESE DAYS SYNTHETIC BIOLOGIES
AND MUCH OF WHAT YOU GUYS WORK
ON.
>> Miljan Simonovic: THAT'S
GREAT.
HOW WE WERE THINKING ABOUT
THIS, I WILL START OFF WITH A
FEW QUESTIONS.
I WOULD ENCOURAGE THE AUDIENCE
TO PARTICIPATE.
BUT ALSO AS THE DISCUSSION
GOES, WE WILL SEE HOW IT WILL
FLOW AND MAYBE ADDITIONAL
QUESTIONS WILL POP.
I WILL ASK TWO QUESTIONS, YOU
CAN PICK WHETHER YOU WANT TO
ANSWER BOTH OR JUST ONE.
WHAT ARE THE MAJOR CHALLENGES
IN BIOMANUFACTURING IN YOUR
AREA OF RESEARCH, OR WHATEVER
YOU ARE DOING AS MAYBE A
PROGRAM MANAGER, WHAT YOU ARE
COVERING WITHIN YOUR PORTFOLIO,
AS SOMEBODY RUNNING COMPANY,
WHAT WOULD BE THE MAIN
CHALLENGES.
AND THE SECOND WOULD BE, MAYBE
THIS IS PERTAINING TO
RESEARCHERS.
WHEN DO THEY HAVE TO START
THINKING ABOUT BIOMANUFACTURING.
AND WHAT WOULD BE THE
CONSIDERATIONS AND ISSUES THEY
HAVE TO TAKE INTO ACCOUNT?
BECAUSE IT IS DIFFERENT FROM,
AS I WAS CHATTING WITH DARPA
PEOPLE, DIFFERENT TO MAKE
POLYMERASE FOR TRANSCRIBING RNA
THAN FOR A LARGE SCALE
BIOMANUFACTURING PROGRAM.
SO, IF WE CAN START FROM ARIEL,
AND THE OTHER WAY AROUND.
THANK YOU.
>> ARIEL WEINBERGER: ABSOLUTELY.
THOSE QUESTIONS ARE KIND OF
INTERTWINED.
I WILL TRY TO ANSWER BOTH
TOGETHER, TO YOUR SECOND
QUESTION, CERTAINLY RUNNING A
COMPANY, THE GOAL IS TO MAKE
PRODUCTS, THAT MEANS TO GO
THROUGH FDA, THE FULL MONTY,
THE FULL GAMUT ON THAT.
IF WE RR ARE NOT ABLE TO
MANUFACTURE, OR THAT PRODUCT
SND AMENABLE TO SCAPABILITY,
IT'S PROBABLY A POOR INVESTMENT
FOR US.
AS A COMPANY IT'S PART AND
PARCEL WHAT YOU START WITH AT
THE OUTSET, AT LEAST A
PRINCIPLE VIEW WHETHER OR NOT
SOMETHING IS MANUFACTURERABLE
IN A WAY THAT IS AMENABLE TO
CLINICAL STUDIES AND ULTIMATELY
TO COMMERCIAL USE.
IN TERMS OF YOUR FIRST
QUESTION, OUR PARTICULAR AREA,
THE CHALLENGES THAT EMERGE IN
THE AREA WE WORK IN, OUR
COMPANY FOCUSES REALLY ON
NUCLEIC ACID THERAPEUTICS, THEY
ARE PROTEIN COATING.
WHEN YOU GET INTO THE DOMAIN OF
THERAPEUTICS AS OPPOSED TO
VACCINES, OBVIOUSLY THERE'S
BEEN A LOT OF WORK AND SUCCESS
IN VACCINES AND NUCLEIC
VACCINES.
THE SUCCESS IN THE DOSES OF
HUNDREDS OF MILLIONS OF
PATIENTS.
THERE ARE NO APPROVED mRNA
THERAPEUTICS.
THERE ARE A LOT OF INNATE OR
INTRINSIC CHALLENGES THAT
EMERGE IN THE THERAPEUTIC SPACE
THAT AREN'T OF THE SAME
MAGNITUDE IN TERMS OF THE
PROBLEM IN THE VACCINE SPACE.
A FEW OF THEM, AS MENTIONED
YESTERDAY YOU HAVE TO GIVE A
MUCH HIGHER DOSE WHEN GIVING
THERAPEUTICS, IT'S ABOUT 1,000
X HIGHER IN DOSE FOR
THERAPEUTIC VERSUS VACCINE.
IF YOU ARE JUST LOOKING AT A
META REVIEW OF THE LITERATURE.
THE IMMUNE SYSTEM FOR VACCINE
IS DOSE AMPLIFIER.
ANTIGEN YOU GET A LOT OF IMMUNE
CELLS BEING MADE.
YOU DON'T HAVE THAT FOR A
THERAPEUTIC WHERE YOU MAY HAVE
TO TREAT EVERY DISEASED CELL.
YOU HAVE ISSUES OF STABILITY,
YOU NEED THE THERAPEUTIC TO
STICK AROUND, WITH SNEENG
VACCINE YOU HAVE IMMUNE MEMORY.
IF YOU ARE TAKING LMP TO A
CELL, YOU CAN IMAGINE THE
DANGER SIGNAL THAT SENDS TO A
CELL.
THE CELL KNOWS WHAT THAT LOOKS
LIKE.
TO AN EXTENT IT'S REACTIVEGENIC.
FOR VACCINE THAT 12-HOUR EFFECT
WE FEEL AFTER WE GET VACCINES
IS A SIGN YOUR IMMUNE SYSTEM IS
KICKING IN.
YOU ARE KICKING OUT THE
THERAPEUTIC PAYLOAD AND YOU
AREN'T HAVING THE DESIRED
EFFECT BECAUSE DELIVERY IS CUT
OFF.
YOU HAVE THESE INTRINSIC
CHALLENGES IN THE THERAPEUTIC
SPACE YOU DON'T HAVE?
-- IN THE VACCINE SPACE.
YOU COULD EASILY MODIFY OR WE
NOW SCIENCE FICTIONFULLY,
THERE'S SCIENTIFICALLY, YOU
CAN'T DO WITH mRNAS WHERE
CHEMICALLY MANUFACTURING A
MULTI-KB mRNA OR PROTEIN-CODING
SEQUENCE IS A REAL CHALLENGE.
WE'RE NOT THERE.
SO NOW YOU HAVE TO RELY ON T7
PROTEASE, IT COULD INCORPORATE,
AND EVEN IF YOU COULD FIND A
WAY TO CHEMICALLY MODIFY THESE
LONG RNA'S, IT'S NOT CLEAR YOU
COULD TRANSCRIBE.
IT COULD BE LESS DEGRADABLE AND
IT WOULD BE LESS TRANSLATABLE.
SO THERE ARE A LOT OF PROBLEMS.
>> Miljan Simonovic: OKAY.
YOU SHOULD FOLLOW-UP ON THIS.
>> I THINK THAT'S EXHAUSTIVE.
OUR RESPONSE TO RPH THEY SHOULD
COME TO US AND WHEN THEY SHOULD
THINK ABOUT MANUFACTURING, MY
RESPONSE IS YOU HAVEN'T ALREADY
THOUGHT OF MANUFACTURING.
WE ARE HIGHLY FOCUSED ON
TRANSLATION.
WE AREN'T REALLY THERE FOR
DISCOVERY YOU NEED AN INITIAL
STRATEGY, EVEN EFFORT THAT'S
ARE A LITTLE BIT MORE
EXPLORATORY.
I WILL MENTION, THEY ARE TRYING
TO PRINT A HUMAN HEART IN UNDER
AN HOUR, THAT REQUIRES BILLIONS
OF CELLS, MASSIVE
DIFFERENTIATION AND SCALE-UP.
I THINK ALWAYS SCALE UP, HOW IS
THIS GOING TO MAKE ITS WAY
THROUGH, HOW IS IT GOING TO BE
MUTUALLY VIABLE.
WE HAVE LOTS OF DIFFERENT NEEDS.
IMMEDIATE NEED RIGHT NOW FOR
SOME PROGRAMS, HOW DO WE
EFFICIENTLY GENERATE CELLS WITH
THE MINIMUM OF ENGINEERING.
COULD RESPOND TO EXTERNAL STIM
LIE STIMULI.
WHAT SIGNALS CAN WE PUT IN TO
GENERATE EFFECTIVE PRODUCTION
IN VIVO, AS I WILL EXPLAIN
LATER.
>> I THINK PAUL'S RESPONSE WAS
EXCELLENT.
IT'S NEVER TOO EARLY TO START
THINKING ABOUT THE TRANSLATION
TO BIOMANUFACTURING.
I THINK LILY SHOWED THERE'S
EARLY, THE FDA UNDERSTANDS THIS
AND THERE'S EARLIER WAYS TO
INTERACT AND START HAVING THOSE
DISCUSSIONS WITH THEM.
BUT AGAIN, YOU KNOW, THIS IS A
SPACE WHERE YOU ARE WORKING
WITH THE END IN MIND.
THIS IS AN ENGINEERING TYPE OF
PARADIGM SO IT'S VERY DIFFERENT
THAN MAYBE ACADEMIC RESEARCHERS
ARE DOING AT THE BENCH.
WE PUT HIS TAGS ON A PROTEIN TO
HELP EASE WITH PURIFICATION.
BUT YOU CAN'T DO THAT, YOU'RE
NOT GOING TO PUT A PROTEIN THAT
DOESN'T NEED TO BE IN A PATIENT
IN A PATIENT.
SO START WITH THE END IN MIND.
ALWAYS THINK HOW DO I GET THIS
TO THE CLINIC.
AND THAT'S VERY IMPORTANT.
SOME CHALLENGES THAT OCCUR WITH
CELL MANUFACTURING, WE HAVE HAD
TO REALLY CHANGE OUR
UNDERSTANDING OF HOW TO OPERATE
AS A BIO MANUFACTURER.
WHEN THE DRUG GOES OFF IN
CLINICAL TRIALS FOR YEARS.
BUT IN THE PARADIGM YOU ARE
MANUFACTURING, GENETICALLY
ENGINEERING PATIENT CELL TO
GIVE BACK TO THAT PATIENT, IT'S
COMPLEX.
THERE ARE SO MANY MANY
LOGISTICAL CHALLENGES BEYOND
THE SCIENTIFIC AND SYNTHETIC
BIOLOGY CHALLENGES.
THERE'S THINGS THAT WE DIDN'T
FULLY APPRECIATE.
WHERE THE PATIENTS THEMSELVES
MAY NOT BE IN THE BEST OF
HEALTH AND THEY ARE JOINING
THIS CLINICAL TRIAL.
SO THEY NEED THIS THERAPY AS
SOON AS POSSIBLE.
SO YOU ARE SCHEDULING YOUR
MANUFACTURING TO FIT IN WITH
ALSO THE CLINICAL LOGISTICS.
WHEN CAN THEY GET THE PATIENT
THERE?
WHEN CAN THEY GET THE BLOOD AND
TRANSPORTATION LOGISTICS, BUT
ALSO IN ORDER TO ACCEPT THE
CELL THERAPY, MANY OF THE
PATIENTS HAVE TO BE LYMPHO
DEPLETED OR SOMETHING LIKE THAT.
BUT THEN THAT'S ANOTHER RISK.
WE DON'T WANT AN ALREADY-SICK
PATIENT TO BE LYMPHO DEPLETED
IF WE AREN'T ABLE TO
SUCCESSFULLY DELIVER THE
PRODUCT.
THERE ARE A LOT OF COMPLEXITIES
WE ARE DEALING WITH.
BUT THESE ARE CHALLENGES WE CAN
DEAL WITH.
LIKE HOW CAN WE GET ASSAYS THAT
CAN GIVE US THE RESULTS MORE
QUICKLY FOR STER RILLITY.
OTHER THINGS THAT CAN HELP WITH
RAPID RELEASE, WE WERE IN
PARADIGMS WE DIDN'T HAVE TO
RESPOND SO QUICKLY.
HOW DOES THAT WORK OUT.
I THINK THAT WENT WELL WITH THE
DISCUSSION THIS MORNING FROM
THE DoD.
IT'S JUST A DIFFERENT PARADIGM
OF MANUFACTURING TO CONSIDER.
SO, THANK YOU.
>> I WILL FOLLOW-UP ON RACHELLE.
ESPECIALLY COMPLEXITY OF
MANUFACTURING.
TWO THINGS WE THINK A LOT
ABOUT, IS FIRST HOW CAN WE TRY
TO TRANSFORM CELL MANUFACTURING
INTO A CLOSED SYSTEM.
SO THAT'S A LOT OF WHAT, I
THINK THE DARPA PEOPLE WERE
TALKING ABOUT FOR THE NUCLEIC
ACID AND PROTEINOTHERAPIES SO
CAN WE DO THAT ALSO FOR
CELL-BASED THERAPIES.
REDUCING THE RISK OF
CONTAMINATION.
AND THEN THE OTHER ONE IS CAN
WE SWITCH TO NOT HAVING TO USE
BIOLOGICS TO MAKE THIS BIOLOGIC.
AS YOU KNOW WITH CELL THERAPIES
IT RELIES A LOT OF ANTIBODIES,
VIRUSES, IT'S A VERY COSTLY
PROJECT BECAUSE YOU ARE USING
COSTLY REAGENTS JUST TO
MANUFACTURE.
WE ARE TRYING TO THINK OF WAYS
TO ELIMINATE OR REPLACE
BIOLOGICS WITH SYNTHETIC,
CHEAPER MATERIALS.
>> Lily Koo: GREAT POINTS AS
ALREADY MENTIONED BY PREVIOUS
PANELISTS.
I JUST WANT TO ADD, I THINK, I
COMPLETELY AGREE THAT WHEN YOU
START DEVELOPING A PRODUCT --
>> Miljan Simonovic: CLOSER TO
THE MIC.
>> Mike
>> Lily Koo: SORRY, IS THAT
BETTER?
RACHELLE MENTIONED YOU SHOULD
HAVE THE END IN MIND.
CONSIDERATION AS MENTIONED
EARLIER IN THE TALK AS WELL,
SCALING UP AND ALSO YOUR CELL
BANK, HOW DO YOU RENEW A CELL
BANK?
WHEN IT'S DEPLETED IT'S GOING
TO BE, IF YOU DON'T HAVE
SOMETHING AS A BACK UP OR
RENEWABLE SOURCE THAT WILL
PROVIDE CHALLENGES WHEN THERE
ARE COMPARABILITY STUDIES AS
YOU MOVE FORWARD IN A CLINICAL
BASIS.
THINK OF ANALYTICAL DEVELOPMENT
THAT IS IN PACE WITH YOUR
PRODUCT UNDERSTANDING.
AS YOU MOVE FORWARD IN A
PROCESS YOU MAY REALIZE SOME OF
THE ASSAYS AREN'T THE BEST
SUITABLE, RIGHT?
AND SOME OTHER CONSIDERATION IS
REALLY HOW TO MINIMIZE THE NEED
TO CHANGE YOUR MANUFACTURING
PROCESS FROM EARLY ONTO THE
LATER PHASES.
EVERY CHANGE YOU HAVE TO
DEMONSTRATE THAT A PROCESS
CHANGE HAS NO IMPACT ON PRODUCT
QUALITY AND EFFECTIVENESS.
ANOTHER CONSIDERATION IS
ESTABLISHING IMPURITY PROFILE.
WHICH CAN BE RELATED TO THE
PRODUCT AS WELL AS PROCESS
ITSELF.
WHEN YOU CHANGE THE PROCESS TOO
MUCH YOU MAY HAVE TO RECONSIDER
WHAT KIND OF IMPURITY PROFILE
YOU HAVE.
I THINK FROM THE FDA
PERSPECTIVE AND LOOKING FORWARD
INTO THE FUTURE, I THINK THE
CHALLENGE IS REALLY IN THE
IMPLEMENTATION OF MANY ADVANCED
TECHNOLOGIES.
AS I MENTIONED EARLIER, WE ARE
SEEING THE INCORPORATION OF
A.I., LET'S SAY.
OR DATA-DRIVEN MODELS.
IN BOTH THE DEVELOPMENT
OPTIMIZATION, BUT ALSO IN THE
CONTROL OF THE PROCESS ITSELF,
RIGHT?
SO THIS IS A DIFFERENT WAY TO
THINK ABOUT CONTROL STRATEGY.
AND WE NEED TO UNDERSTAND HOW
THIS IS DONE.
AND WE ALSO HAVE TO UNDERSTAND
IF OUR EXISTING REGULATION
COULD ACCOMMODATE SOME OF THESE
ADVANCED TECHNOLOGIES OR
DIFFERENT MODALITIES FOR
MANUFACTURING, FOR EXAMPLE,
DISTRIBUTED MANUFACTURING OR
POINT-OF-CARE MANUFACTURING.
I THINK THE EARLIER TALK ABOUT
THE CENTRALIZED HUB AND
SATELLITE SITES.
WHAT DO WE DO WITH
ESTABLISHMENT, REGISTRATION,
RIGHT?
WHAT DO WE DO WITH INSPECTION?
AND HOW DO WE STREAMLINE FOR
EACH UNIT ASSUMING THEY ARE
REALLY EQUIVALENT?
SO THESE ARE THE THINGS WE HAVE
TO CONSIDER AS AN AGENCY.
SO I WILL STOP HERE OTHERWISE
THE LIST CAN GO ON.
>> David Borhani: THIS IS GREAT.
IN BROAD AGREEMENT WITH
EVERYTHING SAID.
BECAUSE GINGKO DOESN'T
MANUFACTURE ANYTHING, WE HAVE
MAYBE SLIGHTLY A DIFFERENT
VIEWPOINT WE CAN BRING TO THIS.
WE ARE HELPING OUR PARTNERS TO
ADDRESS ALL OF THESE ISSUES,
HOPEFULLY BEFORE THEY GET
THERE, OR WHEN THEY ARE
ACTUALLY IN MANUFACTURING TO
IMPROVE THINGS.
SO AGAIN, ECHOING THE THEME,
START WITH WHAT YOUR END IS IN
MIND.
DESIGN THE THERAPEUTIC, NEW
BIOLOGICAL ENTITY SO IT
INCREASES THE EFFICACY AND
SAFETY YOU NEED BUT ALSO
DESIGNED WITH THE VIEW, IT MUST
BE MANUFACTURERABLE.
AS YOU ARE WORKING WITH
SOMEBODY LIKE GINGKO OR ANOTHER
PARTNER OR INTERNALLY, REALLY
BRING THOSE SORTS OF PROCESSES
AND DESIGN STEPS TO WHAT YOU
ARE ULTIMATELY DELIVERING AS
THE THERAPEUTIC CANDIDATE.
MAYBE TO BRING SOME REALLY
PROZEIC EXAMPLES TO MIND, WITH
COVID-19 WE WORKED WITH RRN AND
DNA VACCINE MANUFACTURERS TO
INCREASE THE YIELD OF PLASMA
DNA NEEDED FOR THESE PRODUCTS
AND PROCESSES.
AND THAT EFFECTIVELY DOUBLES
THE NUMBER OF DOSES OR
QUADRUPLES THE NUMBER OF DOSES.
IF YOU CAN BRING THOSE KIND OF
MANUFACTURING IMPROVEMENTS,
SOMETHING THAT WAS PERHAPS A
DIFFICULT PROCESS TO EXECUTE
SUDDENLY BECAME MAYBE FOUR
TIMES EASIER BECAUSE YOU DON'T
HAVE TO MAKE AS MUCH.
IT KIND OF ECHOES WHAT ARIEL
HAS BEEN SAYING AS WELL.
AND JUST ONE OTHER TRIVIAL
EXAMPLE FROM THE SAME TIME, WE
WERE ABLE TO IMPROVE PRODUCTION
OF VACCINE BY TEN FOLD IN WEEKS.
THAT ADDRESSED KEY REAGENT
ISSUE.
THERE MAY BE BIAS IN THE FIELD
SOME OF THESE THINGS HAVE BEEN
WORKED ON FOR SO LONG LIKE
PLASMA DNA.
WHO WOULD HAVE THOUGHT YOU
COULD JUST QUADRUPLE DNA IN
JUST TEN WEEKS.
THE OTHER THING THAT MAYBE IS
OUTSIDE OF WHAT HAS BEEN SAID
HERE IS CAN WE DO QUALITY BY
DESIGN?
SO SOMETHING THAT I HAVE
CHATTED WITH A FEW FOLKS ABOUT,
ESPECIALLY IN REGARDS TO CELL
THERAPIES IS HOW CAN WE I GUESS
MODIFY OR BREAK THIS PROCESS
WHERE WE HAVE ONE SET OF PEOPLE
DOING THE WORK, ANOTHER SET
CHECKING THE QUALITY OF WHAT
WAS DONE.
WAS EVERY STEP OF THIS COMPLEX
PROCESS DONE CORRECTLY?
WE WANT TO KNOW IT WAS DONE
CORRECTLY.
CAN WE DESIGN THE CELLS SO THAT
THEY TELL US THEMSELVES, YEP,
I'M CORRECT.
IF I'M NOT CORRECT, I DIE.
SO THIS IS LIKE PAINTING A
VISION, SCIENCE FICTION, BUT
MAYBE IN TEN YEARS WITH A
LITTLE BIT OF HELP FROM
DARPA-H, WE CAN BE THERE.
>> Miljan Simonovic: ALMOST
LIKE SELF-REPORTING TOOL OR
PLATFORM.
>> David Borhani: EXACTLY.
>> Miljan Simonovic: THIS IS
NICE.
YOU KIND OF SEGUE, I WANTED TO
FOLLOW-UP WITH A QUESTION AND I
HOPE THE CROWD WILL START
ASKING.
WE CAN GO TO YOU, DAVID, NOW.
IN YOUR EXPERIENCE IS THERE A
DIFFICULT PATH IN
BIOMANUFACTURING, FROM LET'S
SAY DISCOVERING LAB AT
UNIVERSITY TO FULL SCALE
PRODUCTION.
IS THERE A TYPICAL STANDARD
OPERATING PROCEDURE?
OR EVERY, WE USED TO SAY IN THE
LAB EVERY PROTEIN IS ITS OWN
TALE.
EVERY PROTEIN IS CRYSTALLIZED
DIFFERENTLY, YOU KNOW WHAT I
MEAN?
IS IT ALWAYS UNIQUE OR IS THERE
SOMETHING THAT STANDS OUT AS A
COMMON THREAD?
>> David Borhani: I WOULD SAY
UNIQUENESS IS UNFORTUNATELY THE
PROBLEM.
WHAT IS THE OPENING LINE OF ANA
CARINDARA?
(?) EVERY PROTEIN IS DIFFERENT
IN ITS OWN UNFORTUNATE WAY.
THAT'S THE PROMISE OF NUCLEIC
ACID THERAPIES, IN THEORY THEY
ARE ALL GOING TO BE THE SAME.
I WAS CHATTING WITH SHANNON
ABOUT THIS, AS DARPA NOW
EXPANDS INTO BROADER TYPES OF
DNA AND RNA THAT IT WANTS TO
MAKE AND THIS IS SHANNON'S,
WHAT SHE SHARED WITH ME, THAT'S
WHERE THEY ARE KIND OF HEADED,
WHAT KINDS OF CHALLENGES ARE
GOING TO ARISE?
ESPECIALLY WITH RNA.
IS YOUR MANUFACTURING PROCESS
ROBUST TO THE SECONDARY
STRUCTURE?
WITH PROTEINS, JUST TAKE THAT
AND PUT IT ON STEROIDS AND IS
THERE A SOLUTION TO THAT?
I'M NOT SURE.
OTHER THAN GETTING INVOLVED
VERY EARLY.
>> Lily Koo: I GUESS ONE THING
I CAN THINK OF, SOME OF OUR
THERAPEUTIC MODALITIES AND THE
WAY THE MATERIAL, THERAPEUTIC
MATERIAL IS DELIVERED REALLY
CREATE OPPORTUNITY FOR PLATFORM
TECHNOLOGIES, RIGHT?
AND I THINK THAT COULD BE ONE
WAY TO SPEED UP THE TRANSLATION
FROM LABORATORY TO
COMMERCIALIZATION.
THERE IS NO NEED TO REINVENT
THE WHEEL, RIGHT?
FOR EXAMPLE, DEVELOPMENT OF AAV
VECTORS FOR GENE THERAPY AND
ESPECIALLY WITH mRNA-BASED
THERAPEUTICS OR VACCINE
MANUFACTURING, WE CAN REALLY
LOOK AT SOME OF THE COMMON
OPERATIONS AND UNDERSTAND HOW
THEY CAN BE OPTIMIZED.
AND WITH YOU GUYS WORKING ON
SYNTHETIC BIOLOGY CAN DO YOUR
TWEAK FOR WHAT IS NEEDED AS AN
INPUT.
AND THEN WE CAN JUST RUN
THROUGH A PLATFORM TECHNOLOGY
AND TURN OUT THE DESIRED
THERAPEUTIC, IN AN IDEAL SCENE
NAIR YO.
SCENARIO.
ANOTHER THING I THINK OF, IS
WHEN I WAS A GRADUATE STUDENT
WORKING THE LAP, THERE IS
S.O.P. IN THE LAB, YOU DO YOUR
PIPETTING UNDER THE HOOD.
THERE IS NOT AS MUCH AWARENESS
OF BIOTECHNOLOGY AND
BIOMANUFACTURING.
I THINK WHEN WE CAN INTRODUCE
EARLY ON IN OUR EDUCATION ABOUT
REGULATORY SCIENCE, ABOUT
G.M.P. COMPLIANCE AND ABOUT
WHAT'S REQUIRED FOR A
COMMERCIALLY-VIABLE PRODUCT,
AND I THINK THEN WE COULD START
OUR RESEARCH WITH THESE THINGS,
REQUIREMENTS IN MIND AND I
THINK THAT WILL HELP AS WELL.
>> Miljan Simonovic: THAT IS
GOOD, I SPECIALIZE IN -- TOO,
MAYBE I SHOULD INVITE YOU TO
SEE WHAT NEEDS TO BE DONE ON
THAT FRONT.
>> Lily Koo: START EARLY.
YOU DON'T HAVE TO GET YOUR
FIRST JOB IN A PHARMACEUTICAL
COMPANY AND LEARN THE --
>> I'M HERE LEARNING THE SAME
THINGS, SO I DON'T HAVE
ANYTHING TO COMMENT ON.
>> Miljan Simonovic: OKAY, GOOD.
>> I DON'T HAVE ANYTHING
ADDITIONAL TO ADD.
>> I COULD ALWAYS TALK.
THERE'S ALWAYS A TENSION FOR
THINGS WE WANT TO FUND.
OFTEN WE JUST WANT TO SHOW IT
CAN BE DONE.
MANY TIMES IT COULD BE DONE BY
HOOK OR CROOK.
AND THEN YOU HAVE TO WORRY
ABOUT MANUFACTURING.
THIS IS COMMON.
HAVING WORKED ANOTHER LAB, A
SCIENTIST COMES UP WITH BIT OF
ELECTRONICS, RIGHT, THEY GO TO
THE E.E. AND THE DOUBLE-E IS
LIKE YEAH I KNOW WHAT YOU ARE
TALKING ABOUT, JUST STORE YOUR
VERSION THERE IN THE CORNER, ON
THE TRASH CAN.
RIGHT NEXT TO IT, YOU DON'T
HAVE TO ACTUALLY PUT IT IN, I
WILL DO IT LATER.
IT'S POORLY ENGINEERED SO
THERE'S ALWAYS THAT TENSION.
YOU WANT PEOPLE TO WORK HARD ON
SHOWING ITS POSSIBLE.
AT THE EARLIEST MOMENT START
BOTHERING WITH HOW ARE YOU
GOING TO ACTUALLY START
MANUFACTURING THIS?
THAT'S SOMETHING, IN THE DARPA
PROGRAM START MOVING IN, I WANT
YOU TO PROVE SOMETHING IS
POSSIBLE BUT AFTER YEAR ONE
ONCE YOU GET GOING, WE START
DOING THINGS, WHAT IS THE
DESIGN MODULAR, THIS CONSTRUCT,
EVERYTHING HAS TO WORK SO, OR
RUGGEDNESS THAT, YOU DO NEED TO
START THINKING ABOUT IT, MAYBE
NOT DAY ONE BUT AS SOON AS
THINGS START WORKING, LET'S
START ENSURING THAT IT HAS A
MANUFACTURING FUTURE.
>> I THINK I STRONGLY AGREE
WITH THAT POINT.
TO ANSWER YOUR QUESTION, I
WOULD SAY THAT, YOU KNOW, IF
YOU ARE DEVELOPING A NOVEL
TECHNOLOGY, THERE'S OBVIOUSLY,
I THINK BY CONSTRUCTION, BY
NECESSITY THERE ISN'T A TRIED
AND TRUE PATH BECAUSE YOU ARE
TRYING TO PAVE A NEW PATH.
THERE WILL BE KIND OF
DEVELOPING NEW APPROACHES TO
MAKE IT WORK, TO MANUFACTURE
IT, BUT AS PAUL SAID, EARLY ON,
AS THEY SAY IN COMPUTER
SCIENCE, PRE-OPTIMIZATION ISN'T
A GOOD IDEA.
YOU HAVE TO CHOOSE YOUR BATTLE
AND THE FIRST IS TO SHOW
FEASIBILITY BEFORE
MANUFACTURING.
AND TO ADD ONCE A TECHNOLOGY
mRNA EXAMPLE, WELL DEVELOPED
AND WELL SCALED YOU MIGHT MAKE
THE ARGUMENT THAT POST-MATURE
OPTIMIZATION IS JUST A WASTE OF
TIME AND MONEY.
IT SOUNDS TERRIBLE BUT IF YOU
ARE A COMPANY AND ACTUALLY
DEVELOPING THINGS AND THINKING
ABOUT GOING BACK THROUGH FDA ON
SOMETHING THAT IS ALREADY GOOD
ENOUGH, IT'S NOT ALWAYS CLEAR
THE PAY OFF IS THERE.
ON THE EARLY END YOU HAVE TO
SOMETIMES PURSUE AN APPROACH
THAT ISN'T SCALABLE ON THE
LATE-STAGE END IF SOMETHING HAS
ALREADY BEEN VALIDATED EVEN IF
THERE MAY BE A BETTER APPROACH,
BECAUSE THERE'S ALWAYS A WAY TO
OPTIMIZE SOMETHING, IT MAY NOT
BE THE BEST USE OF RESOURCES.
>> Miljan Simonovic: THANKS.
>> IF I COULD ADD ONE THOUGHT,
MAYBE TAKING A HISTORICAL
PERSPECTIVE, BECAUSE I'M MAYBE
OLDER THAN I LOOK.
WHEN I STARTED IN THIS
BUSINESS, IN 1990, IT WAS
REALLY COMMON IN THE SMALL
MOLECULE ARENA TO HAVE SMALL
GROUP FROM DEVELOPMENT,
DEVELOPMENT THOSE WHO WORKED ON
THINGS, LIKE FORMULATION AND
TOXICITY ASSESSMENT AND SO
FORTH.
I'M NOT EVEN TALKING CLINICAL
DEVELOPMENT.
AND CHEMISTS WOULD THROW
MOLECULES OVER THE VERITIABLE
WALL.
AND IT'S LIKE WE DID OUR JOB.
IT'S NOT OUR PROBLEM THE
COMPOUND IS BRICK DUST.
THAT HAS CHANGED DRAMATICALLY.
AND ALL OF THESE SORT OF
DEVELOPMENTAL ATTRIBUTES HAVE
BEEN BROUGHT EARLIER AND
EARLIER IN THE DISCOVERY
PROCESS.
AND SIMILARLY, FOR SYNTHESIS,
THOUGH PERHAPS A LITTLE LESS
SO, THE INTERNATIONAL ACTIONS
WITH THE PROCESS CHEMISTS HAVE
BEEN HAPPENING EARLIER AND
EARLIER.
OH YOU THINK YOU HAVE ONE IN
FIVE CANDIDATES LET'S GET
INVOLVED.
WE HAVE TO MAKE A TON OF IT.
YOU ONLY HAD TO MAKE 50
MILLIGRAMS ASAP BECAUSE YOU ARE
IN A DISCOVERY PROGRAM, WE ARE
OPERATING UNDER DIFFERENT
CONSTRAINTS.
I DON'T THINK THIS KIND OF MIND
SET IS REALLY THAT OPERATIVE IN
THE BIOLOGICAL REALM , SURE.
THERE'S DEVELOPMENTAL ASSAYS,
IS THERE A GOOD ANTIBODY OR NOT?
WILL IT CRASH OUT A SOLUTION OR
NOT?
BUT WHEN YOU GET TO THE MORE
AND MORE COMPLEX AND POWERFUL
TECHNOLOGIES, IT'S HARD TO
BRING THIS KIND OF END THINKING
EARLIER AND EARLIER.
BUT I THINK WE NEED TO TRY.
>> Miljan Simonovic: SO MORE
SYNERGY, MORE INTEGRATION EARLY
ON?
>> David Borhani: ABSOLUTELY.
AND TO BRING ON PLATFORMS AS
MUCH AS POSSIBLE.
>> Miljan Simonovic: HM.
ARE THERE ANY QUESTIONS FROM
THE AUDIENCE?
WE CAN OPEN TO THE FLOOR IF YOU
GUYS HAVE ANY QUESTIONS.
DON'T BE SHY.
OR MAYBE YOU ARE AFRAID BECAUSE
FDA IS HERE.
>> David Borhani: LILY IS
ABSOLUTELY TERRIFYING.
>> WHAT IS AUTOMATION DOING IN
BIOMANUFACTURING?
THAT IS SOMETHING I'VE BEEN
THINKING ABOUT.
SO THOSE OF YOU THAT HAVE A
COMMENT.
>> Miljan Simonovic: GINGKO'S
LAB IS ALL ROBOT.
>> WE USE AUTOMATION TO
DRAMATICALLY EXPAND THE SEARCH
SPACE SO WE CAN FIND THE BEST
ANSWER FOR MANUFACTURING.
BUT THAT'S, I DON'T THINK
THAT'S WHAT YOU ARE REALLY
ASKING.
I THINK THIS IS COMING TO WHAT
LILY WAS TALKING ABOUT.
REALLY BRINGING IN PROCESS
CONTROLS.
AND I MEAN, THIS IS NOT AN AREA
I KNOW ABOUT, SO THIS IS A WILD
GUESS, SOME COMBINATION OF
MECHANICAL COMPUTER AUTOMATION.
BUT CAN WE GET THE MATERIAL
ITSELF TO BE SOMEWHAT
SELF-AUTOMATING, BUT MAYBE LILY
CAN JUMP IN.
>> Lily Koo: I THINK
AUTOMATION, I THINK IT'S ALWAYS
INTERESTING, RIGHT?
WHEN WE LOOK AT A DOSSIER AND
WE LOOK AT PROCESS VALIDATION.
WE ALWAYS SAY YOU CAN ALWAYS
VALIDATE A PROCESS BUT YOU
CAN'T VALIDATE A HUMAN BEING,
YOU CAN QUALIFY A HUMAN BEING
BASED ON THEIR TRAINING AND
SORT OF THEIR PERFORMANCE.
AND I THINK THAT'S WHERE
AUTOMATION IS TRYING TO NOT
ONLY MAKE THE PROCESS EFFICIENT
BECAUSE THE MACHINE CAN RUN
MAYBE 24/7.
BUT ALSO TO MAKE IT MORE
CONSISTENT, RIGHT?
TO MAKE IT MORE ROBUST.
AND THERE ARE ALSO AREAS FOR
EXAMPLE, WHEN YOU THINK OF
ASEPTIC PROCESSES, A HUMAN IS
REALLY THE MAJOR SOURCE OF
CONTAMINATION.
YOU WALK IN AND START SHEDDING
EVERYWHERE.
YOU WALK INTO A G.M.P.
ENVIRONMENT YOU DON'T SEE
HUMANS STANDING IN ISO5
ENVIRONMENT.
YOU WILL HAVE YOUR BIOLOGICAL
SAFETY CABINET.
YOUR ISOLATOR AND HUMAN WORKS
AROUND IT.
WHEN I FIRST JOINED CBER, FIRST
THING I LEARNED IS THE CONCEPT
OF FIRST AIR.
WHICH IS THAT HEPA FILTERED
CLEAN AIR THAT HAS TO REACH THE
PRODUCT.
YOU CANNOT STICK YOUR HAND OR
ANYTHING IN THAT PATH.
SO I THINK AUTOMATION ALSO
INTRODUCE POSSIBILITY FOR THAT,
AND THAT'S I THINK SUZIE TALK
ABOUT HOW TO MAKE EVERYTHING
CLOSED SYSTEM.
CLOSED SYSTEM IS TO PREVENT,
REALLY TO SEGREGATE THE PRODUCT
AND THE PROCESS STREAM FROM THE
EXTERNAL ENVIRONMENT.
AND THAT INCLUDES US.
I THINK THIS IS, YEAH, SOME OF
THE MAIN POINTS WITH AUTOMATION.
THANK YOU.
>> I WILL ADD, IT'S A POINT OF
AUTOMATION WITH US, WANT TO
TALK WITH LILY HOW TO ENSURE
CONSTRUCTS, HOW DO YOU PULL
PEOPLE OUT OF THE MANIPULATION
BUT STILL ALLOW THE FLEXIBILITY
TO DO NEW THINGS, INSTEAD OF
HAVING SET UP ONCE AND
VALIDATE, HOW DO YOU HAVE THE
AUTOMATION BUT IN A FLEXIBLE
WAY.
USING A.I. AND THESE OTHER
SYSTEMS THAT DEAL WITH DIE
DIMENSIONAL.
VERY INTERESTED IN HE MERGING
ARTIFICIAL INTELLIGENCE WITH
THESE SELF-DRIVEN LABS PEOPLE
HAVE BUILT.
>> Miljan Simonovic: NOTHING
ELSE?
I MEAN, IT'S NICE THAT YOU
MENTIONED ARTIFICIAL
INTELLIGENCE.
HOW MUCH DO YOU SEE OUT THERE
BEING USED?
I'VE SEEN IT, OBVIOUSLY IN
PROJECTS THAT RELY ON
ENGINEERING ENZYMES,
ENGINEERING PROTEINS.
A LOT OF PEOPLE RELY ON A.I.
MACHINE LEARNING.
BUT WHAT OTHER AREAS DO YOU SEE
WITHIN THE BRANCH THAT YOU ARE
WORKING IN, THAT A.I. IS
POWERING UP OR FACILITATING OR
DO YOU FORESEE MAYBE BEING MORE
USED?
I DON'T KNOW IF YOU USE --
BIOLOGICS OR YOU ARE STILL
WAITING TO SEE?
>> Ariel Weinberger: THAT'S A
FAIR QUESTION.
I MAY BE AN OUTLIER ON THIS ONE.
THERE ARE THOSE WHO ARE VERY,
VERY ENTHUSIASTIC ABOUT USING
A.I. TO DEVELOP NOVEL DRUGS AND
THERE ARE THOSE WHO ARE A BIT
MORE SKEPTICAL, FOR ME, TO BE
FRANK, MAY BE SKEPTICAL ON A.I.
BUT BRING UP PROTEIN DESIGN AND
SUCH, ONE BUT CAN'T ACKNOWLEDGE
INCREDIBLE SUCCESSES THERE.
THERE ARE DEFINITELY PEOPLE
USING A.I. IN THE SPACE I'M IN.
WHETHER SORT OF PREDICTING
NOVEL ANTIGENS IF YOU ARE
MAKING VACCINES.
AND THERE ARE MANY AREAS, WHAT
PAUL WAS TALKING ABOUT
OBVIOUSLY IS INTEREST, YOU CAN
THINK ABOUT IT, GREAT USES FOR
IT IN MANUFACTURING, IN CLOSED
LOOP MANUFACTURING, AS WE
MENTIONED EARLIER.
YOU CAN THINK OF NOVEL WAYS FOR
ERROR CHECKING AND HIGH
DIMENSIONAL BIO ANALYSIS.
THERE ARE CERTAIN CASES, YOU
MENTION PROTEIN DESIGN, BUT
GENOTYPE TO PHENOTYPE, WHETHER
IT'S AMENABLE TO A.I., THE
TRAINING DATA AND WHETHER WE
HAVE THE RELIABILITY TO KIND OF
PUT THAT ALGORITHM INTO USING
BUILDING NOVEL DRUGS.
>> Miljan Simonovic: HM.
FAIR POINT.
>> David Borhani: YOU ASKED HOW
OFTEN I HEAR A.I.?
ALL THE TIME.
>> Miljan Simonovic: IS IT TO
USE?
YOU KNOW WHAT I MEAN, I CAN SAY
IT, BUT IS IT SOMETHING THAT
--
>> Paul Sheehan: I WOULD SAY IT
DEPENDS WHAT PEOPLE WANT TO USE
IT FOR.
GLORIFIED FITTING AND MAGIC.
DEPENDS ON WHO IS DOING IT AND
WHY.
-- PEOPLE DO HAVE CLEAR IDEAS
HOW THEY ARE USING A.I., THE
WAY THEY ARE USING IT, I WILL
GO BACK TO TALK A LITTLE BIT.
NOT TALK ABOUT NOT RUNNING
THESE PROGRAMS BUT THINGS DO
POP OUT.
WE HAD THIS EFFORT FOR CLOSED
LOOP COWN TROLL OVER WOUND
HEALING.
WE WERE BUILDING THIS SUPER
SMART BANDAGE, COULD PUT
INFORMATION BACK ON AND PART OF
THAT IS BUILDING WHAT IS GOING
ON IN WOUND HEALING.
ALL THE DIFFERENT COMPONENTS OF
THE CELLS IN THE WOUNDS AND PUT
DEEPER INFIRSTMENT LEARNING AND
IT PLAYED THE GAME OF WOUND
HEALING.
THE OUTCOME, NEW MARKERS, NEW
PATHWAYS THAT STARTED POPPING
UP AS IMPORTANT AND WOUND
HEALING WITHOUT SCARRING, RIGHT?
SO ULTIMATELY THAT CHANGED
CLINICAL STUDIES AT WALTER REED.
A SIDE EFFECT.
I THINK THAT'S A VERY
COMPLICATED SYSTEM.
EACH ONE OF THESE SIMULATIONS
TOOK 6-8 HOURS, MILLIONS OF
CELLS, 30-50 CELL TYPES.
SOMETHING A HUMAN, IT WAS VERY
CHALLENGING TO RUN DIFFERENT
EXPERIMENTS LIKE THAT.
BUT THAT A.I. WAS PATIENT,
COULD RUN THROUGH ALL THOSE
THINGS AND IDENTIFY THINGS LIKE
THAT.
I DO THINK CLEVER APPROACHES,
USING A.I. CAN SOLVE REAL
PROBLEMS IN BIOLOGY THAT IT'S
HARD FOR THE HUMAN BRAIN TO
COMPREHEND.
I WANT TO GO BACK TO SOMETHING
YOU MENTIONED, THE TRAINING
DATA.
FOR PEOPLE WHO COME TO ME, I
DON'T ACTUALLY ASK SO MUCH
ABOUT WHAT YOUR A.I. SOLUTION
IS, BECAUSE HONESTLY BY THE
TIME YOU START IN SIX WEEKS
SOMEONE WILL PUBLISH A PAPER
AND SAY NO, I'M GOING TO DO
THIS.
LOTS OF HIGH QUALITY DATA, LOTS
OF REPRODUCIBLE DATA AND WHERE
IT'S COMING FROM.
IF YOU HAVE NOVEL SET OF DATA,
THEN WE CAN TALK ABOUT A.I.
>> Miljan Simonovic: FAIR
POINT, FAIR POINT.
>> IF I CAN JUMP IN TOO, DATA.
DATA IS WHAT IT'S ALL ABOUT.
THE ALGORITHMS AND CAPABILITIES
ARE JUST MOVING SO FAST.
ONE OF THE, ACTUALLY A COUPLE
IDEAS WE HAVE BEEN TALKING
ABOUT AT GINGKO, HOW WOULD YOU
DO THIS.
IF YOU THINK ABOUT SMALL
MOLECULES THAT ARE COMPLEX
NATURAL PRODUCTS, HOW DO THEY
GET MADE?
THERE ARE MASSIVE ENZYMES THE
SPOKE CREATE THESE THINGS.
WE DON'T UNDERSTAND, IF YOU
WILL, THE LANGUAGE THEY ARE
SPEAKING, WE KNOW THEY ARE
AMINO ACID SEQUENCES BUT IT
DOESN'T TELL US WHAT MOLECULE
THEY WILL MAKE.
CAN WE USE A.I. TO UNDERSTAND
THAT AND USE A.I. TO UNDERSTAND
THE REVERSE PROCESS, I HAVE
THIS MOLECULE, WHAT SEQUENCE OF
AMINO ACIDS DO I NEED TO MAKE
IT?
SO I THINK WE WILL GET THERE,
THIS IS A TACKLABLE PROBLEM.
BUT IN THIS ONE IN PARTICULAR,
WE ARE THINKING, OKAY, HOW MANY
NRPS'S DO WE NEED TO MAKE OF
WHAT KIND OF MUTATION ALCOVE
RAJ TO EVEN COLLECT THE DATA
THAT WILL TRAIN THOSE MODELS.
IT'S A HUGE ISSUE.
>> Miljan Simonovic: I BELIEVE
WE HAVE A QUESTION.
>> JUST A QUICK QUESTION.
WE HAVE A PRETTY DIVERSE PANEL,
REGULATORY AGENCIES, FUNDING
AGENCIES, THESE TEND TO CLASH.
MY QUESTION IS, DO YOU THINK
THERE ARE REDUNDANCIES IN PLACE
INHIBITING BIOMANUFACTURING OR
ARE THERE PITFALL THAT'S NEED
TO BE ADDRESSED?
MAYBE COMBINATION OF BOTH.
SUCH A MIX OF PEOPLE HERE.
SO VERY OPEN-ENDED QUESTION.
>> Miljan Simonovic: I CAN SAY
YOU'RE NOT CLASHING.
>> WE ARE PARTNERS.
REDUNDANCY SOMETIMES IS GOOD.
I APPRECIATE FOR EXAMPLE, WE
HAVE AN FDA THAT IS TRYING TO
MAKE SURE WE HAVE THE SAFEST
AND BEST MEDICINES AVAILABLE.
BUT I LOOK AT IT IS EARLY AND
OFTEN ENGAGEMENT THAT IS THE
KEY.
>> Lily Koo: I WOULD ALSO LIKE
TO ADD, I DO SEE IT AS A VERY
COLLABORATIVE PROCESS.
AND I TOTALLY UNDERSTAND WHERE
YOU ARE COMING FROM, YOU AREN'T
THE ONLY ONE WHO THINKS THAT
FDA IS RESPONSIBLE FOR
DETERRING IMPLEMENTATION OF
ANYTHING NEW.
MAYBE THERE WAS A TIME IT WAS
LIKE THAT.
I THINK RIGHT NOW, THE AGENCY
IS, WE ARE VERY OPEN TO,
BECAUSE WE REALIZE THE FIELD IS
MOVING QUICKLY AND THERE ARE A
LOT OF THINGS WE DON'T
UNDERSTAND.
IN MANY WAYS WE ARE ALSO
LEARNING FROM YOU, AND THIS IS
WHY WE ARE INTRODUCING
ENGAGEMENT WITH THE PEOPLE
INVOLVED, EVEN TECHNOLOGY
DEVELOPER AT AN EARLIER AND
EARLIER PHASE.
I THINK IT WOULD BE A MISTAKE
TO BE HESITANT TO TAKE
ADVANTAGE OF THE MEETINGS WE
OFFER.
THERE ARE DESIGNATIONS FOR
CERTAIN PRODUCTS WHETHER THEY
ARE BREAK THROUGH.
IF THE PRODUCT IS APPROPRIATE
FOR THAT DESIGNATION, YOU
SHOULD APPLY.
PART OF THE ADVANTAGE IS THERE
IS ADDITIONAL INTERACTION
IMPLEMENTED IN THAT PROCESS,
YOU CAN INTERACT WITH AGENCY
AND ACQUIRE ADDITIONAL FEEDBACK.
I THINK THAT BACK AND FORTH
THROUGHOUT DEVELOPMENT PHASE IS
ACTUALLY VERY, VERY IMPORTANT.
SO BEFORE YOU GO TOO FAR IN THE
WRONG DIRECTION, WE CAN, YOU
KNOW, ASK FOR CORRECTION AND WE
CAN POINT OUT TO YOU, HEY,
LOOK, THIS IS A CONCERN.
BEFORE, IF YOU ARE TOO FAR IN
THE OTHER DIRECTION.
SO THIS IS WHERE SOMETIMES
CLASHES IS INEVITABLE BUT WE
ALSO HAVE TO LEARN TO AGREE TO
DISAGREE.
BUT OF COURSE IN THE END WHAT
SHOWS IS DOES YOUR PRODUCT GET
IMPROVED OR NOT BASED ON THE
PRODUCT YOU DEMONSTRATE.
BUT OVERALL, I THINK IT'S A
VERY COLLABORATIVE PROCESS.
>> THAT CLASH WAS A HARSH WORD
TO SEE.
>> Lily Koo: CLASH ISN'T ALWAYS
A BAD THING, IT BRINGS OUT
DIFFERENT OPINIONS WE HAVE TO
LEARN TO RESPECT EACH OTHER AND
WORK TOGETHER, OUR GOAL IS THE
SAME THING, PATIENT SAFETY AND
PATIENT BENEFIT.
>> I ACTUALLY WANT TO THANK YOU
FOR THAT BRAVE QUESTION.
BECAUSE SOMETIMES WE DON'T
DISCUSS THE ELEPHANT IN THE
ROOM OR THINGS LIKE THAT.
BUT IT IS VERY IMPORTANT.
AND I THINK MEETINGS LIKE THIS
ARE SO IMPORTANT WHERE WE ALL
GET TO INTERACT AND HEAR WHAT'S
GOING ON IN THE DIFFERENT
GROUPS AND EXCHANGE INFORMATION.
AND I THINK THAT ALWAYS IS
HELPFUL, TRANSPARENCY AND
ABILITY TO EXCHANGE IDEAS AND
INFORMATION.
WE ARE ALL STAKEHOLDERS BUT YOU
ARE RIGHT, WE HAVE DIFFERENT
GOALS.
A LITTLE BIT DIFFERENT.
AND SO IT IS HELPFUL TO HELP
EACH OTHER UNDERSTAND WHAT IS
IMPORTANT, OR THE EXPERTISE OR
FOCUS.
IT'S HELPFUL.
SO THANK YOU FOR YOUR QUESTION.
>> SORRY, I KIND OF WANT TO
BUILD ON WHAT YOU ARE SAYING.
FROM ONE VIEW IT COULD BE
CLASH, RIGHT?
I WOULD SAY ANOTHER WAY TO
THINK, EVERYONE IS PAID TO LOOK
AT A PROBLEM IN A DIFFERENT
WAY, RIGHT?
SO THERE ARE JUST DIFFERENT
LENSES.
IT'S A CHALLENGE BACK WHEN YOU
ARE RESEARCH AND SAY THIS
TECHNOLOGY IS COOL, RIGHT?
LOOK WHAT IS HAPPENING AND THE
DATA, RIGHT?
ALL THE WAY TO YOU MAKING A
DIFFERENCE IN A PATIENCE'S LIFE.
ONE STEP IS YOU WANT TO MAKE A
COMPANY, RIGHT?
THEY DON'T CARE AS MUCH ABOUT
THE COOL TECHNOLOGY, CAN WE
MAKE MONEY, RIGHT?
ULTIMATELY BECAUSE IT DOESN'T
EXIST.
THE FDA, THEY ARE PAID, IS IT
SAFE, RIGHT?
IT'S SAFE AND EFFICACIOUS BUT
IF I HAVE TO INJECT MYSELF FIVE
TIMES A DAY, MY LIFE ISN'T
BETTER, RIGHT?
SO ALL OF THESE ARE VALID
VIEWPOINTS ON LOOKING AT A
TECHNOLOGY.
WHERE YOU RUN INTO TROUBLE,
RUNNING FULL STEAM AND YOU
NEVER CONSIDER THAT THE OTHER
PEOPLE GATE KEEPERS ALL ALONG
THE WAY THAT DON'T LOOK AT IT
FROM A DIFFERENT VIEWPOINT OR
YOU DIDN'T LOOK AT THE LANGUAGE
OR THE EXPERIMENT TO TALK TO
THEM.
SO THE EARLIER YOU CAN START TO
TALK TO THEM TO THINK ABOUT
THEIR FRAMEWORK, THE BETTER OFF
YOU ARE.
>> I AGREE WITH THAT, IF YOU
HAVE A NOVEL TECHNOLOGY AND YOU
WERE TO EARLY ON PITCH IT TO A
QUALITY PERSON OR REGULATORY,
FDA ESPECIALLY CBER HAS BEEN
WELCOMING TECHNOLOGIES AT THEIR
INCEPTION POINTS.
BUT TRADITIONALLY IF YOU DO
THAT, YOU MIGHT GET A LOT OF
CONCERN, IT'S HELPFUL.
THE CLASH IS GREAT JUST AN
EARLY WARNING OF WHAT YOU WILL
FACE DOWN THE ROAD.
>> THANK YOU.
>> Miljan Simonovic: THANK YOU.
>> Lily Koo: ONE POINT ON A.I.?
I WANT YOU TO BE AWARE LAST
MONTH FDA ACTUALLY HAD A
WORKSHOP DISCUSSING THE
APPLICATION OF A.I. AND MACHINE
LEARNING IN MANUFACTURING,
RIGHT?
SO THIS IS SOMETHING I THINK
MAYBE IS COLLABORATIVE EFFORT
BETWEEN PQRA AND CBER.
I THINK IT'S VERY INTERESTING
WITH APPLICATION OF A.I., THIS
IS SOMETHING WE DON'T HAVE A
LOT OF EXPERIENCE YET,
ESPECIALLY IN MANUFACTURING.
BUT BASED ON PUBLIC COMMENT WE
HAVE IDENTIFIED SOME AREAS
WHERE AT LEAST THE INDUSTRY IS
THINKING HOW A.I. CAN BE
APPLIED.
YES, PEOPLE ARE THINKING ABOUT
USING A.I. AND MACHINE LEARNING
OR HYBRID MODEL TO APPLY FOR
PROCESS CONTROL POTENTIALLY OR
SOMETIMES JUST PROCESS
MONITORING, RIGHT?
TO INFORM YOU IF SOMETHING IS
DEVIATING.
A.I. COULD BE VERY COMPLICATED,
WHAT DO WE NEED TO TELL YOU,
FDA, RITE?
-- RIGHT?
THIS IS SOMETHING WE ARE STILL
WORKING OUT.
BUT WE THINK IT SHOULD BE A
RISK-BASED ASSESSMENT, RIGHT?
HOW YOUR ALGORITHM IS BUILT,
WHAT IT IS INTENDED FOR AND
WHAT KIND OF DECISION IT COULD
MAKE.
BUT MAYBE LOWER RISK, MAYBE WE
DON'T NEED AS MUCH INFORMATION.
WHEN IF YOU ARE A.I. AND
MACHINE LEARNING MODEL IS PUT
IN A PROCESS CONTROL AND IT
COULD ACTUALLY ACTIVELY MAKE
MANUFACTURING DECISIONS THIS IS
WHERE THERE WILL BE GREATER
SCRUTINY.
DATA IS SO CRITICAL, RIGHT?
OTHERWISE PEOPLE SAY GARBAGE
IN, GARBAGE OUT.
WE WANT TO MAKE SURE THE DATA
IS GOOD AND THE MODEL DOESN'T
SHIFT OVER TIME.
HE IS SPSHLLY A.I. MACHINE
LEARNING, THE MODEL IS BEG
CONTINUOUSLY UPDATED.
HOW ARE WE GOING TO MONITOR ITS
PERFORMANCE AND WHAT KIND OF
POST APPROVAL CHANGE WILL BE
REQUIRED FOR FDA TO CONSIDER.
THESE ARE THINGS WE DON'T HAVE
ANSWERS YET BUT WE ARE THINKING
ABOUT IT AND BASED ON A LOT OF
FEEDBACK FROM THE PUBLIC.
IF YOU DIDN'T ATTEND A
WORKSHOP, I DEFINITELY WELCOME
YOU TO CHECK IT OUT.
>> Miljan Simonovic: THAT'S
GREAT, YEAH.
>> IF I CAN JUST JUMP ONTO THAT
AS WELL.
SOMETHING THAT GINGKO HAS BEEN
THINKING ABOUT THROUGH OUR
CONCENTRIC BIO SECURITY ARM IS
USE AND MISUSE OF A.I. MODELS
LIKE CHATGPT.
CAN SOMEBODY REQUEST IN SOME
SEEMINGLY BENIGN WAY FOR
CHATGPT TO GIVE THEM
INFORMATION THAT IS ACTUALLY
NOT BENIGN INFORMATION.
WE NEED TO KNOW THE DATA THAT
GOES IN, BUT THE DATA THAT
COMES OUT, IS INSCRUTABLE.
HOW DO YOU VALIDATE THAT.
SOMETHING ELSE IS CALLED RED
TEAMING.
SO PRESENT THE MODEL WITH ALL
KINDS OF SCENARIOS AND SEE HOW
IT RESPONDS.
SO LIKE HOW WOULD YOU READ TEAM
TO DEATH A MANUFACTURING
ALGORITHM SO THAT EVEN THOUGH
YOU DON'T UNDERSTAND REALLY
WHAT THAT ALGORITHM IS, YOU
KNOW HOW IT WILL RESPOND UNDER
ALL THE SITUATIONS YOU CARE
ABOUT.
>> Miljan Simonovic: SO TRUST,
BUT VALIDATE.
>> David Borhani: YEAH.
>> Miljan Simonovic: THAT'S
VERY GOOD.
I THINK WE CAN GO ON AND ON AND
ON.
THERE IS A LIST OF QUESTIONS I
MAY BE ASKING, BUT LILY
ACTUALLY BROUGHT A VERY GOOD
POINT TO ALL OF YOU, IS TO GO
OUT ON THE WEBSITES AND SEEK
INFORMATION.
FEDERAL AGENCIES HAVE ALWAYS
ANNOUNCEMENTS ABOUT FUNDING
MECHANISMS, OPPORTUNITIES.
SO YOU CAN ACTUALLY SEEK
INFORMATION, GO TO WORKSHOPS
AND EDUCATE YOURSELF.
WHAT FUNDING AGENCIES, WITHIN
NIH THERE IS A GAZILLION
INSTITUTES, ACTUALLY IT'S A
LIMITED NUMBER OF INSTITUTES.
NIBIB IS DIFFERENT.
GOOGLE MAY BE YOUR FRIEND IN
THAT CASE.
AT ANY RATE, AT THIS POINT, I
THINK MANY OF YOU ARE PROBABLY
HUNGRY AT THIS POINT.
I WOULD LIKE TO THANK THE
PANELISTS FOR AN AMAZING
DISCUSSION.
AND I WOULD LIKE TO THANK YOU
FOR YOUR PATIENCE AND ATTENTION.
THANK YOU.
[ APPLAUSE ]
WELCOME, THIS IS THE FRIDAY AFTERNOON SESSION
FOR THIS WONDERFUL SYNTHETIC
BIOLOGY MEETING HOSTED BY NIBIB.
MY NAME IS RAHUL THAKAR.
I WILL BE THE MODERATOR THIS
AFTERNOON.
THE CHALLENGE FOR THE SESSIONS
IN THE AFTERNOON WILL BE
GETTING EVERYBODY EXCITED BUT
AS EVERYBODY IS THINKING ABOUT
THE WEEKEND.
BUT I THINK THIS WILL BE
DIFFERENT.
WE HAVE A LOT OF GOOD SPEAKERS
AND THESE SORTS OF
COLLABORATIONS.
OUR FIRST SPEAKER IS DR. SUZIE
PUN AT UNIVERSITY OF
WASHINGTON, DIRECTOR OF
MOLECULAR ENGINEERING AND
SCIENCE INSTITUTE.
AND SHE IS THE ASSOCIATE
DIRECTOR OF THE RESUSCITATION
ENGINEERING SCIENCE UNIT, OR
RESCU.
BEFORE SHE GOT TO WASHINGTON,
SHE RECEIVED HER Ph.D. AT CAL
TECH AND SHE DID OUR
UNDERGRADUATE WORK IN CHEMICAL
ENGINEERING AT STANFORD.
SHE HAS AN INCREDIBLE BODY OF
RESEARCH, INCREDIBLE
DISCOVERIES, DEVELOPMENTS AND
AN INCREDIBLE FOCUS ON
MENTORSHIP AS WELL.
HER TALK WILL COVER WHAT SHE
HAS DEVELOPED WITH RESPECT TO
POLYMERIC DRUG DELIVERY AND
COMBINING WITH DRUG DELIVERY
FOR CELL AND GENE THERAPY AND
REGENERATIVE THERAPY IN GENERAL.
DR. PUN?
>> Suzie Pun: HI, EVERYONE.
IT'S A PLEASURE TO SPEAK TO YOU
ABOUT THE RESEARCH WE ARE DOING
AT UNIVERSITY OF WASHINGTON.
LET ME JUST GET MY SLIDES UP.
IT'S STRANGE TO SEE MY GIANT
FACE UP THERE.
OKAY, ALL RIGHT.
SO TODAY I WILL TELL YOU ABOUT
WHAT WE ARE DEVELOPING FOR CELL
DELIVERING MANUFACTURING.
SO JUST A QUICK OVERVIEW OF THE
CONCEPT OF CAR T-CELL THERAPY.
THE BASIC PREMISE IS THAT WE
HARVEST THE WHITE BLOOD CELLS
FROM THE PATIENT, ISOLATE
T-CELLS AND ENGINEER THE
T-CELLS SO THEY CAN RECOGNIZE
AND FIGHT THE TUMOR AND
REINTRODUCE THESE INTO THE
PATIENTS.
THERE HAVE BEEN GREAT SUCCESSES
IN CERTAIN TYPES OF CANCERS
USING CAR T-CELL THERAPIES AND
CURRENTLY THERE ARE SIX FDA
APPROVED CAR T-CELL THERAPY
PRODUCTS ON THE MARKET.
TODAY I WILL TELL YOU ABOUT THE
MANUFACTURING PROCESS FOR
BREYANZI, WHICH IS THE BRISTOL
MYERS.
FOR BREYANZI, THE PATIENT UNDER
GOES A LEUKO PARESIS PROCESS
WHICH SEPARATES THE WHITE BLOOD
CELLS.
AMONG THE APPROVED T-CELL
PRODUCTS, BREYANZI USES DEFINED
RATIO OF CD4 AND T-CELLS IN THE
FINAL PRODUCT.
THE FINAL STEP AFTER THIS IS TO
ACTIVATE THE T-CELLS SO THEY
ARE PROLIFERATING WHICH ALLOWS
THEM TO BE TRANSDEUCED USING
RETRO VIRAL VECTORS.
AND THE ENGINEER CELLS
TRANSDUCED TO RECEPTORS, THESE
T CELLS ARE REINJECTED BACK
INTO THE PATIENT.
NOW ALL OF THE SIX FDA-APPROVED
T CELL PRODUCTS COST SOMEWHERE
BETWEEN $350,000 AND $500,000
PER PATIENT.
IT IS QUITE A TIME INTENSIVE
MANUFACTURING PROCESS AS WELL.
SO IT'S HIGH COST AND ALSO AN
EXPENSIVE PROCESS.
SO WHEN WE CAME INTO THIS FIELD
WE WANTED TO SEE IF THERE WERE
WAYS WE COULD IMPROVE
MANUFACTURING AND MAKE THE
PRODUCT MORE ACCESSIBLE FOR
MORE PEOPLE.
THE STATUS QUO IS THE FIRST TWO
STEPS FOR ISOLATION, AS WELL AS
FOR ACTIVATION, BOTH USE
ANTIBODIES.
SO YOU USE ANTIBODIES TO SELECT
THE CELLS AND ANTIBODIES TO
ACTIVATE THE CELLS AND THIRD
PROCESS USES VIRAL VECTORS.
ALL ARE EXPENSIVE REAGENTS.
TODAY I WILL FOCUS ON THIS VERY
FIRST STEP, WHICH IS THE
ISOLATION STEP.
IT USES ANTIBODIES MOBILIZED ON
MAGNETIC BEADS AND MAGNET IS
INTRODUCED TO SELECT THE CELLS
OF INTEREST.
WHEN THE MAGNET IS REMOVED,
THEY ARE STILL ASSOCIATED WITH
THE CELLS.
THEY HAVE MAGNETIC IRON OXIDE
BEADS.
THEY ARE ALREADY MARK WITH THE
MAGNETIC BEADS.
WE SAW THERE WAS A NEED FOR A
LOW-COST, TRACELESS AND
POTENTIALLY FASTER METHOD OF
SELECTION.
SO THAT'S WHAT I WANT TO TALK
TO YOU ABOUT TODAY.
THIS IS IN THE CONTEXT OF SOME
OF THE WORK WE HAVE BEEN DOING
IN MY LAB.
AS YOU WILL SEE THIS IS THE
THREE DIFFERENT PROCESSES,
ISOLATION, SELECTION, AND
GENETIC MODIFICATION.
WE PUT A REVIEW ARTICLE ON THE
DIFFERENT SYNTHETIC MATERIALS
MY LAB HAS BEEN DEVELOPING FOR
EACH STEP.
FOR TODAY'S PURPOSES WE WILL
JUST TALK ABOUT THE ISOLATION
STEP.
I WILL TALK ABOUT AN APTEMER
PROCESS AND DERIVATIVE TO USE
APTAMER BASED TRACELESS T-CELL
FOR SELECTION OF THE PRODUCT.
I WILL TELL YOU ABOUT
MULTIPLEXED METHOD, WE BELIEVE
WE CAN IMPROVE EFFICACY.
AND I WILL TALK A LITTLE ABOUT
OUR EYE TOWARD MANUFACTURING
AND ADAPTING THIS METHOD FOR
MANUFACTURING PROCESS.
WHAT ARE APTAMERS?
HOW MANY IN THE AUDIENCE KNOW
WHAT APTAMERS ARE?
IF YOU COULD RAISE YOUR HAND.
IT'S A LARGE PERCENTAGE.
I'M SO PLEASED.
SO APTAMERS ARE BASICALLY
SEQUENCE OF OLIGO NUCLEOTIDE
THAT CAN FOLD THEMSELVES ON A
SECONDARY STRUCTURE.
WHAT REALLY CAUGHT OUR
INTEREST, THEY HAVE HIGH
AFFINITY FOR THEIR TARGET.
THEY HAVE NANO MOW LAR BINDING,
SIMILAR TO ANTIBODIES BUT
CONTRAST TO ANTIBODIES WHICH
ARE NATURALLY MADE, APTAMERS
ARE SYNTHETIC.
ON A MOLAR THEY ARE HALF THE
COST, THEY CAN BE HIGHLY STABLE
AND ALSO VERY, VERY UNIFORM.
THEY AREN'T GOING TO VARY
BETWEEN BATCHES.
SO OUR HYPOTHESIS IS WE CAN
REPLACE ANTIBODIES USED IN THE
MANUFACTURING PROCESS WITH
THESE SYNTHETIC MOLECULES
CALLED APTAMERS.
NOW IN ORDER TO DO THIS WE HAVE
TO FIND APTAMERS THAT WILL BE
RELEVANT FOR T CELL
MANUFACTURING.
SO WHEN WE STARTED THIS PROJECT
WE STARTED TO IDENTIFY APTAMERS
THAT WOULD BIND TO HUMAN T
CELLS.
THE WAY TO IDENTIFY IS USUALLY
THROUGH A LIBRARY SELECTION
APPROACH.
SO WE ADAPTED AN APPROACH
DIRECTED BY WAYWARD TAN CALLED
HOME SELECTS.
WE TAKE LIBRARIES OF 10 TO THE
16th DIVERSITY.
AND THEN WE LOOK FOR APTAMERS
THAT BIND TO OUR CELLS OF
INTEREST.
AND WE REMOVE APTAMERS THAT
BIND NON-SPECIFICALLY.
WE DO THIS AS AN ITERATIVE
PROCESS.
OVER AND OVER.
SO IN OUR CASE, WE DID FIVE
ROUNDS.
I WILL TELL YOU THAT WE
ACTUALLY HAD TO DO THIS
MULTIPLE TIMES.
OUR FIRST ROUNDS OF SELECTIONS
WERE UNSUCCESSFUL.
AND WHAT ACTUALLY MADE THE
SELECTION SUCCESSFUL WAS A KEY
CHANGE IN THIS STEP RIGHT HERE
FOR OUR POSITIVE SELECTION.
WE HAD TO DO COMPETITIVE
BINDING WHERE WE PUT OUR WHOLE
LIBRARY WITH ALL WHITE BLOOD
CELLS SO THERE WAS COMPETITION
FOR BINDING.
AND THEN WE REMOVED ONLY THE T
CELLS AND FOUND APTAMERS THAT
BOUND TO THOSE T CELLS.
ALL RIGHT, SO WHAT YOU CAN SEE
HERE OUR LIBRARY IS
FLUORESCENTLY LABELED SO WE CAN
TRACK THE SELECTION PROCESS.
THIS IS OUR DIFFERENT ROUNDS OF
SELECTION.
WE ARE LOOKING AT BINDING TO
OUR T CELLS.
YOU CAN SEE BY ROUND 3 AND 4 WE
START TO GET A POPULATION
BINDING TO THE APTAMER LIBRARY.
WHEN WE GET TO ROUND 5, IF WE
LOOK IN OUR CONTROL CELLS THESE
DON'T EXPRESS A LOT OF T-CELL
RECEPTORS.
WE SEE BINDING TO OUR CONTROL
CELLS.
THIS TELLS US FIVE ROUNDS OF
SELECTION WE ARE GETTING
AMPLIFIED NON-SPECIFIC BINDERS.
INDEED WHEN WE DID SEQUENCING
AND TESTED SEQUENCERS THAT'S
WHAT WE FOUND.
ROUND FOUR SEQUENCE HAD QUITE A
FEW SPECIFIC.
AND THEN NON SPECIFIC.
I WILL SKIP OVER SOME OF THE
APTAMERS WE TESTED BUT ONE
ENDED UP BEING INTERESTING,
WHEN WE SYNTHESIZED AND LOOKED
FOR BINDING WE FOUND THIS
APTAMER FOUND ALL OF THE CD8
POPULATION.
THIS IS CD8 LABELING ON THE Y
AXIS, CD4 AND IT FOUND NONE OF
THE CD4 CELLS.
IT FOUND CD8 CELLS.
IF WE LOOK AT BINDING, 2
NANOMOLAR.
WE CAN FIND IT INDEED BINDS, WE
ELIMINATE THE APTAMER BINDING.
IF WE TAKE OUR CONTROL CELL
LINE THAT DOESN'T EXPRESS CD8
AND TRANSDUCE IT WITH CAN
INTRODUCE APTAMER BINDING.
IF WE COME WITH ANTIBODY
AGAINST CDLE WE CAN COMPETE
WITH THE APTAMER FOR BINDING.
BUT MOST CONVINCINGLY FOR ME,
IF WE TAKE THE RECOMBINANT CD8
WE CAN INTRODUCE BINDING TO
THIS PROTEIN, WE CAN CONFIRM
THIS IS HIGH AFFINITY NANO
MOLAR.
THEY ARE SWITCHABLE, UNLIKE
ANTIBODIES.
THEY BIND WITH ANTIBODY
AFFINITY BUT YOU CAN SWITCH THE
BINDING ON AND OFF BECAUSE THE
BINDING IS DEPENDENT ON THE
SECONDARY STRUCTURE OF THE
APTAMER.
WHAT I'M SHOWING IS THE
PREDICTED SECONDARY STRUCTURE.
THE APTAMER HAS CERTAIN
STRUCTURE WHICH FORMS THESE
SECONDARY STRUCTURES.
WHAT WE DID IS WE TOOK OUR
APTAMER AND WE EXTENDED THE
BOTTOM LOOP HERE, THOSE OF YOU
IN SYNTHETIC BIOLOGY ARE
FAMILIAR, THIS IS A TOE HOLD
SEQUENCE.
THAT ALLOWS US TO COME IN WITH
A SEQUENCE THAT IS COMPLETELY
COMPLIMENTARY SO IT WILL HAVE
HIGHER AFFINITY THAN THE
APTAMER ITSELF.
IF WE HAVE A REVERSAL AGENT
THAT WILL CHANGE THE SECONDARY
STRUCTURE OF THE APTAMER AND
SWITCH OFF ITS BINDING.
THIS HAPPENS VERY FAST.
SO WE JUST ADDED IN, LOOKED A
COUPLE SECONDS LATER, APTAMER
COMPLETELY LOSES ITS BINDING.
NOW YOU CAN IMAGINE FOR A
SELECTION AGENT, WE CAN HAVE
SOMETHING THAT BINDS TO OUR
CELLS OF INTEREST, BUT THEN WE
CAN ALSO SWITCH OFF BINDING AND
RELEASE THE CELLS WITHOUT
HAVING ANY SELECTION AGENT.
SO THIS IS A SCHEMATIC OF HOW
WE EMPLOY THESE APTAMERS.
WE IMMOBILIZE THEM ON MAGNETIC
BEADS.
THIS IS AN EXAMPLE OF THE LEUKO
PARESIS PRODUCT.
WE APPLY TO MAGNET, WE RETAIN
THE CD8 CELLS, ALL OF THIS IS
BEING DONE NOW.
THE DIFFERENCE IS NOW WE CAN
COME IN WITH A REVERSAL AGENT
THAT CHANGES THE CONFIRMATION
OF THE APTAMER AND THEN THE
CELLS ARE RELEASED TRACELESSLY,
WITHOUT ANY SELECTION AGENT.
SO WE ARE REALLY EXCITED ABOUT
THIS BECAUSE, NUMBER ONE WE
COULD POTENTIALLY MOVE TO A
COMPLETE LY SYNTHETIC SYSTEM.
WE HAVE NO CONTAMINATION, THESE
ARE COMING OFF UNTOUCHED THE
REASON THIS IS IMPORTANT YOU
CAN THEN DO SUBSEQUENT
SELECTION WITH THE CELLS.
WE CAN DO SERIAL SELECTIONS A.
THE END OF MY TALK I WILL GIVE
YOU AN EXAMPLE HOW WE HAVE DONE
THAT.
SO THE NEXT COUPLE OF SLIDES
ARE JUST TO SHOW YOU THAT THE
APTAMER SELECTED PRODUCT IS THE
SAME AS THE ANTIBODY-SELECTED
PRODUCT.
OKAY?
THIS IS FOR EXAMPLE, PB & M
FROM A HUMAN DONOR, ANTIBODY
SELECTION FOR CD8, A HIGH
POPULATION OF PURE CELLS SAME
AS WHEN WE DO APTAMER-BASED
SELECTION.
IF WE LOOK AT PURITY, WE HAVE
ABOUT 99% PURITY USING THIS
METHOD JUST LIKE WITH ANTIBODY
BASED SELECTION.
THE CELLS WE HAVE ANALYZED
EXTENSIVELY AND THEY ARE
INDISTINGUISHABLE FROM
ANTIBODY-BASED SELECTION.
IF WE LOOK AT PHENOTYPE THE
DISTRIBUTION IS THE SAME.
WE DID NANO STRING ANALYSIS ON
ALMOST 300 DIFFERENT RNA
TRANSCRIPTS AND WE SEE NO
DIFFERENCE AT ALL IN ANY OF THE
GENE EXPRESSION PROFILES.
AS FAR AS WE KNOW, THESE CELLS
FROM EITHER ANTIBODY OR
APTAMER-BASED SELECTION, THEY
ARE THE SAME.
AND WE FURTHER VALIDATED THIS
BY GENERATING CAR T CELLS FROM
BOTH ANTIBODY AND APTAMER
SELECTED CELLS AND TESTED IT IN
AN ANIMAL MODEL THAT WAS
NON-CURATED.
WE PICKED A NON-CURATED MODEL
TO SEE IF THERE WERE ANY
DIFFERENCES IN TUMOR GROWTH
RATE AS WELL AS SURVIVAL.
THE ANSWER IS, NOT
SURPRISINGLY, NONE.
SO THE ORANGE LINES ARE
TRIPLICATE HUMAN DONORS WITH
CAR T CELLS THAT WERE ISOLATED
EITHER ORIGINALLY BY APTAMER OR
ANTIBODY.
ANTIBODY IN ORANGE, APTAMER IN
BLUE.
WHAT YOU ARE SEEING IS THEY
BEHAVE ALMOST THE SAME.
AND IF WE LOOK IN THE MOUSE
MODEL, THE EFFICACY OF THESE
GENERATED CAR T CELLS IS ALSO
THE SAME.
SO OUR CONCLUSION FROM THIS
FIRST SECTION IS THAT WE CAN
NOW EMPLOY APTAMER-BASED
SELECTION.
THIS GIVES US A TRACELESS
PRODUCT AND ENGINEER CAR T
CELLS USING THIS APTAMER-BASED
APPROACH.
OKAY, I WILL MOVE ONTO ANOTHER
EXAMPLE USING APTAMERS, IN THIS
CASE TRYING TO IMPROVE THE
SAFETY OF THE FINAL CAR T CELL
PRODUCT.
I MENTIONED, VERY BRIEFLY, THAT
WE TRIED SEVERAL TIMES TO GET
THAT CD8 T CELL APTAMER WITHOUT
SUCCESS BEFORE WE FINALLY
FIGURED THE BEST METHOD FOR
SELECTION.
IN THE PROCESS OF DOING THAT WE
INITIALLY USED CULTURE CELLS WE
HAD JURKAT CELLS AND MUTANT
JURKAT MUTANT CELL LINE WHICH
IS NEGATIVE FOR MOST OF THE
T-CELL RECEPTORS.
WE ACTUALLY THOUGHT THIS WAS AN
UNSUCCESSFUL SELECTION.
BECAUSE AS WE MOVED ALONG THE
SELECTION PROCESS WE GOTTEN
RICHMENT IN BINDING TO BOTH
CELL TYPES.
WE DISGUARDED THIS AND MOVED ON
THE CD8 STUDY.
WE CAME BACK BECAUSE HE WITH
WERE GETTING BINDING APTAMERS
HERE.
WE WANTED TO SEE WHAT ACTUALLY
WAS BINDING?
WE TOOK OUT THE TOP APTAMERS
FROM SEQUENCING AND LOOKED AT
BINDING AND SAW THEY WERE
BINDING TO BOTH OUR POSITIVE
AND NEGATIVE CELL LINE.
AND IT BINDS WITH VERY HIGH
AFFINITY.
SO THE AFFINITY AGAIN HERE IS
ON THE ORDER OF SINGLE
NANOMOLAR.
WE ACTUALLY TRUNCATED TO 91
NUCLEOTIDES, IT DISPLAYS THE
SAME BINDING A FINITE BUT
SMALLER APTAMER TO WORK WITH.
SO WE ENDED UP IDENTIFYING THE
RECEPTOR USING A PULL-DOWN
ASSAY, WE REMOBILIZED THE
APTAMER, EXPOSED IT TO CELL,
AND RAN IT BY MASS SPEC.
THE RESULTS SHOWED WE WERE
ENRICHING TRANSCRIPTOR 1, ALSO
KNOWN AS CD71.
AGAIN WE WENT THROUGH THE
VALIDATION.
I WILL GO THROUGH THIS QUICKLY.
THIS IS VERY CHARACTERISTIC
WHEN WE KNOW OUR RECEPTOR THAT
THE STAINING OF THE RECEPTOR,
VERSUS STAINING OF THE ANTIBODY
ON CELLS WILL CORRELATE WITH
DIAGONAL, THE HIGHER THE
RECEPTOR THE HIGHER THE BINDING
OF THE APTAMER.
WE CAN SEE IF WE KNOCK DOWN THE
RECEPTOR, WE KNOCK DOWN APTAMER
BINDING AND WE CAN DIRECTLY
MEASURE BINDING USING
RECOMBINANT PROTEIN.
I LOVE TO SHOW THIS SLIDE
BECAUSE I THINK THIS IS THE
VERY FIRST CRYOIAIN IMAGE OF
APTAMER BOUND TO ITS TARGET.
THIS WAS DONE BY UNIVERSITY OF
NEW YORK, TONG WANG IS THE LEAD
OF THE TEAM.
THIS IS THE RECEPTOR AND
APTAMER IS SHOWN IN YELLOW.
AND THE COOLEST THING WAS HARSH
BANSIA A POST DOC WAS ABLE TO
MODEL THE APTAMER AND DETERMINE
EXACTLY WHICH NUCLEOTIDES IN
THE APTAMER ARE BINDING TO
WHICH AMINO ACID RESIDUES.
WE LOVE THIS BECAUSE IT ALLOWS
US TO BETTER ENGINEER THESE
APTAMERS.
WE HAVE BEEN DOING THIS WITH
ALMOST ALL THE APTAMERS WE
DISCOVER.
I JUST WANTED TO PUT THAT AS AN
ASIDE.
GOING BACK TO CELL THERAPY.
TURNS OUT CD71 IS OVER
EXPRESSED IN ALMOST ALL TYPES
OF CANCER CELLS.
IT'S RESPONSIBLE FOR BRINGING
IRON IN THE CELLS.
THESE CELLS RAPIDLY DIVIDING
NEED MORE RESOURCES SO THEY UP
REGULATE THIS TO GET MORE IRON.
YOU CAN SEE ACROSS THESE CELL
TYPES THAT CD71 IS OVER
EXPRESSED.
THIS IS RELEVANT BECAUSE IN
REIMAGINING OF CAR T CELLS IT'S
CRITICAL THERE ARE NO BLOOD
CANCER CELLS THAT MAKE IT IN
THE MANUFACTURING PROCESS.
THIS IS AN EXAMPLE REPORTED IN
NATURE MEDICINE OF ONE CAR T
CELL PATIENT WHO ENDED UP
HAVING A RELAPSE BECAUSE HE HAD
A LEUKEMIA CELL THAT MADE IT
INTO THE MANUFACTURING PROCESS.
AND THAT LEUKEMIA CELL WAS
TRANSDUCED WITH A CAR RECEPTOR.
THE CAR RECEPTOR MASKED THE CD
17 EPITOPE.
THE PATIENT UNDERGOS REMISSION
AND MANY DAYS LATER, ALMOST A
DAY LATER HE GETS LEUKEMIA
AGAIN AND THE CAUSE OF A
LEUKEMIA WAS A LEUKEMIA CELL
THAT MADE IT IN THIS T-CELL
MANUFACTURING PROCESS AND
TRANCE TRANSDUCED WITH THE CAR
T-CELL RECEPTOR.
IT'S QUITE AN ISSUE, THESE MUST
BE REMOVED DURING THE CAR
T-CELL MANUFACTURING PROCESS.
TURNS OUT THOSE HAVE HIGH
EXPRESSION OF THIS RECEPTOR.
SO WHAT WE PROPOSE, WE CAN
INCLUDE A STEP IN THE ISOLATION
PROCESS TO SPECIFICALLY REMOVE
LEUKEMIA CELLS BEFORE ENTERING
THE CAR T CELL PROCESS.
SO AS PROOF OF CONCEPT WE
SIMPLY APPLIED MAGNETIC BEADS
WITH OUR CD71 APTAMER, AND WE
SHOWED THAT WE CAN TAKE
MIXTURES OF CELLS, SO WE DOPED
IN LIEU -- LEUKEMIA CELLS
HERE AT 10%, IF WE MOVE IT
THROUGH THE COLUMN WITH CAN
REMOVE ALMOST ALL CELLS, THIS
SIGNIFICANTLY REDUCES ANY RISK
OF CONTAMINATION.
THIS WE CAN DO WITHOUT
IMPACTING AT ALL THE
LYMPHOCYTES THAT ARE NEEDED FOR
CAR T CELL MANUFACTURING.
YOU MAY WONDERING CAN WE
DEPLETE EVEN SMALL AMOUNTS OF
CONTAMINATION, THE ANSWER IS
YES.
WE TESTED DIFFERENT PERCENTAGES
AND WE CAN GET VERY HIGH
DEPLETION AT ALL THE
PERCENTAGES WE TESTED.
I TOLD YOU ABOUT THE CONCEPT OF
USING APTAMERS TO SELECT T
CELLS USING APTAMERS TO DEPLETE
T CELLS TO IMPROVE SAFETY.
AND NEXT EXAMPLE, THIS IS
SOMETHING NEW FROM OUR LAB, WE
ARE TRYING TO IMPROVE THE
EFFICACY OF SOME OF THESE CAR T
CELL THERAPIES.
SO IT IS NOW KNOWN THAT CERTAIN
SUBSETS OF T CELLS CAN ACTUALLY
GENERATE BETTER PERFORMING CAR
T CELL PRODUCTS.
BUT ONE OF THE CHALLENGES HAS
BEEN IN THE MANUFACTURING.
THAT'S BECAUSE IN TRYING TO
SELECT FOR MULTIPLE MARKERS, IF
YOU USE THE MAGNETIC APPROACH,
AGAINST ONCE THE CELLS ARE
MARKED WITH THE BEADS YOU CAN'T
DO ANY SUBSEQUENT SELECTIONS.
SO WHAT NORMALLY HAS TO BE DONE
IS A COMBINATION OF NEGATIVE
SELECTION, WHERE YOU REMOVE ALL
THE CELLS THAT YOU DON'T WANT
AND THEN POSITIVE SECTION.
AND THIS IS EVEN HIGHER IN COST
BECAUSE THE NEGATIVE SELECTION
STEP COMBINES A MIXTURE OF
ANTIBODIES NOW AND ALSO THE
EFFICIENCY AND YIELD IS LOWER.
SO WE THINK APTAMERS CAN
ADDRESS A LOT OF THESE ISSUES
WITH THE NEED FOR SERIAL
SELECTION.
I WILL MENTION THIS BRIEFLY, WE
HAVE BEEN ABLE TO TAKE TWO CELL
TYPE THAT'S HAVE COMPLETELY
ORTHOGONAL RECEPTORS AND APPLY
APTAMER AGAINST BOTH OF THESE
RECEPTORS.
WE CAN ISOLATE THE CELLS
TOGETHER ONTO A COLUMN.
AND THEN WE CAN SPECIFICALLY
ELUTE ONE CELL VERSUS THE
SECOND CELL BY APPLYING THE
REVERSAL AGENT SPECIFIC TO THAT
APTAMER.
IN ONE SECTION WE CAN ISOLATE
TWO DIFFERENT POPULATIONS OF
CELLS.
THAT'S ONE POSSIBLE
CONFIGURATION.
BUT THE ONE I WILL TALK TO YOU
ABOUT TODAY IS GETTING INTO
SUBSETS OF CELLS WHERE WE WANT
TO ISOLATE CELLS THAT HAVE
EXPRESSED TWO RECEPTORS ON THE
SAME CELL.
OUR INTEREST IN THIS IS DUE TO
ANI NAIVE AND MEMORY T CELLS
WHICH HAVE SHOWN TO BE MORE
POTENT IN TERMS OF CAR T CELL
EFFICACY.
THESE T-CELLS START OFF NAIVE
AND THEN THEY WILL START TO
DIFFERENTIATE.
OVER TIME INTO BECOMING
EFFECTOR CELLS.
THESE EFFECTOR CELLS ARE GOOD
AT KILLING BUT ALSO GENERATE
HIGHER CYTOKINE RESPONSE AND
THEY DON'T PROLIFERATE AS MUCH,
THEY HAVE LESS MEMORY.
WHAT I WILL SHOW YOU NEXT, THE
CELLS INTERMEDIATE HERE TURN
OUT TO BE BETTER FOR CAR T CELL
PRODUCTS.
THESE CELLS HERE, IF YOU LOOK
AT THEIR MARKERS ARE GOING TO
BE POSITIVE FOR CD4 AND CD8 BUT
THEN ALSO FOR CD62L, WHICH IS L
SELECTED.
SO WHAT WE REALLY WANT IS TO
HAVE T-CELLS CD8 POSITIVE BUT
ALSO CD62L POSITIVE.
THIS IS SOME EXAMPLE.
THIS WAS ACTUALLY A STUDY THAT
ENTERED INTO HUMAN STUDIES.
WHAT YOU CAN SEE HERE IS IF YOU
TAKE THE BULK T-CELL
POPULATION, SHOWN IN BLUE,
VERSUS THE T CELL POPULATION
GENERATED FROM NAIVE AND MEMORY
STEM CELLS, THAT'S SHOWN IN
RED, THAT THE RED POPULATION
WILL HAVE BETTER EFFICACY,
BETTER SURVIVAL AND MORE SAFETY
PROFILE, LESS CYTOKINE SYNDROME
THAT IS OBSERVED.
THIS WAS CARRIED OUT IN HUMAN
CLINICAL TRIALS.
I WILL JUST SUMMARIZE THE
FINDING HERE.
THEY SAID IT'S VERY EFFICACIOUS
BUT THE DEVELOPMENT OF CELL
ISOLATION TECHNOLOGIES THAT
UTILIZE CELL SORTING OR CELL
SERIAL COLUMN BASED SELECTIONS
WITH REVERSALLY BINDING AGENTS
MAY FURTHER REFINE THE
SELECTION OF T-CELLS.
SO I SPOKE WITH THE FIRST
AUTHOR OF THIS PAPER.
WHAT HE TOLD ME WAS THEY HAD A
SIGNIFICANT FRACTION OF
PATIENTS THEY COULDN'T TREAT AT
ALL BECAUSE THE YIELD WAS TOO
LOW.
THEY HAVE TO DO DOUBLE
SELECTION OF NEGATIVE AND
POSITIVE SELECTION.
WHILE THIS COULD BE MORE
EFFICACIOUS, THEY COULDN'T
GENERATE ENOUGH PRODUCT FOR A
SIGNIFICANT PERCENTAGE OF THE
PATIENTS.
I HAVE SHOWN IDENTIFICATION OF
TWO DIFFERENT APTAMERS.
I WILL SKIP THAT AND SAY WE
IDENTIFIED THE CD62 APTAMER
THAT HAS HIGH-BINDING AFFINITY.
HOPEFULLY THESE CURVES LOOK
VERY FAMILIAR TO YOU.
THIS ONE IS REALLY HIGH BINDING
AFFINITY.
LESS THAN ONE NM BINDING
AFFINITY.
WE CAN DEFINE BY CHARACTERISTIC
DIAGONAL OF APTAMER BINDING
VERSUS CD62L.
AND CONFIRM USING RECOMBINANT
PROTEIN.
WHAT WE CAN DO SINCE WE HAVE
THE TWO APTAMERS WE CAN USE
THEM TOGETHER.
WE CAN TAKE OUR PBMC'S, WE CAN
ADD IN BOTH APTAMERS.
WE CAN ADD IN, SORRY, APTAMER
FOR CD8 AND THEN ISOLATE OUR
CD8 POSITIVE CELLS.
SO THAT'S ISOLATION OF OUR CD8
POSITIVE CELLS AND TAKE THE CD8
POSITIVE CELLS SINCE THEY ARE
TRACELESSLY SELECTED, THEY
DON'T COME OFF WITH MAGNETIC
BEADS, AND PUT THEM BACK FOR
SECOND SELECTION, SERIAL
SELECTION.
WE INCUBATE WITH CD62 APTAMERS
AND WE CAN CAPTURE THE CELLS
ALSO USING TRACELESS SELECTION.
WE GET DOUBLE TRACELESS
SELECTION.
AND WE GET OUR PURE POPULATION
HERE.
THIS IS NOW CD8 POSITIVE AND
CD62 POSITIVE CELLS.
THE PURITY OF THE CELLS, USING
OUR DOUBLE APTAMER VERSUS
ANTIBODY SELECTION IS THE SAME.
BUT THE BIG DIFFERENCE IS IN
YIELD.
SO WE DOUBLE THE YIELD OF OUR
PRODUCT BY USING THIS TRACELESS
APTAMER-BASED SELECTION
APPROACH.
AND SO YOU CAN SEE HERE IF WE
ANALYZE THE PHENOTYPE OF THE
CD8 CELLS COMING OUT, WE START
OUT WITH ONLY THREE AND A HALF
PERCENT OF NAIVE T-CELLS.
IF WE ONLY DO CD8 SELECTION,
THE RELEVANT CELLS HERE ARE
JUST ABOUT A LITTLE BIT UNDER
HALF.
IF WE DO A COMBINATION OF CD8
AND CD62L SELECTION, THEN WE
ARE GETTING 70-80% OF OUR CELLS
BEING THESE NAIVE AND MEMORY
STEM CELL PHENOTYPES.
OKAY.
SO I'VE BEEN ABLE TO TELL YOU
ABOUT DIFFERENT APPLICATIONS OF
APTAMERS.
I JUST WANTED TO END WITH ONE
THING.
WE REALLY WANTED TO MOVE TO
MANUFACTURERABLE SYSTEMS.
AS I MENTIONED DURING THE PANEL
DISCUSSION, WE WANTED TO MOVE
TO SYNTHETIC REAGENTS.
SO HOPEFULLY I HAVE TOLD YOU
ABOUT APTAMERS WHICH ARE
SYNTHETIC ANTIBODIES FOR THIS
APPLICATION.
AND SECONDLY WE ARE INTERESTED
IN MOVING TO CLOSED SYSTEM.
INSTEAD OF USING MAGNETIC BEADS
AND REMOVAL OF MAGNETIC BEADS
WE WANTED TO SEE IF WE COULD
USE RESIN SO WE COULD HAVE
CHROMOTOGRAPHY-LIKE RECEPTION
OF CELLS.
THE ANSWER TO THAT IS YES.
WE HAVE BEEN ABLE TO COUPLE
THESE APTAMERS TO RESIN BEADS,
WE USE POLYSTYRENE BECAUSE IT
COULD BE EASILY STERILIZED.
WE HAVE BEEN ABLE TO USE THIS
FOR CELL DEPLETION.
I DIDN'T TALK ABOUT IT BUT WE
HAVE A HUMAN MONOCYTE BINDING
APTAMER.
WE CAN USE THIS FOR DEPLETION
OF CELLS THAT YOU DON'T WANT.
WE HAVE ALSO BEEN ABLE TO DO
THIS TYPE OF COLUMN-BASED
SELECTION FOR CD8 POSITIVE T
CELLS SO THIS WAS REPORTED IN
ACA BIO MATERIALS SCIENCE AND
ENGINEERING.
WE ARE EXCITED ABOUT THIS
APTAMER-BASED TECHNOLOGY.
THE ONE THING I DIDN'T MENTION
WAS THE PRICE.
SO FOR US, THE COST TO DO THE
MAGNETIC BASED SELECTION WITH
ANTIBODIES IS ABOUT $5,000 IN
THE REAGENTS.
THE APTAMERS WE USE FOR THE
APTAMER AND REVERSAL AGENT IS
LESS THAN $10.
THE APTAMERS BECAUSE WE USE LOW
CONCENTRATION AND BECAUSE
APTAMERS ARE SO CHEAP TO
PRODUCE.
WE ARE EXCITED ABOUT IT BECAUSE
WE THINK THE ABILITY TO REVERSE
THE SWITCHING OF THE APTAMER
MAKE IT'S VERY POWERFUL FOR
DOING ADVANCED SELECTION AND
COMBINED WITH THE CHEAPLESS OF
THIS APTAMER-BASED APPROACH WE
THINK IT COULD MAKE AN IMPACT
IN TERMS OF THE COST OF
MANUFACTURING.
ALL RIGHT, SO JUST TO SUMMARIZE
FOR THESE SECTIONS, IF THE
FIRST SECTION I TALKED ABOUT
CONCEPT OF USING APTAMERS.
THE MAIN POINT IS THE APTAMERS
ARE SWITCHABLE AND WE CAN GET
TRACELESS SELECTED CELLS.
THE SECOND SECTION I SHOWED WE
CAN ALSO USE THIS TO IMPROVE
SAFETY BY REMOVING CANCER CELLS.
THE THIRD SECTION I SHOWED WE
CAN ACTUALLY POTENTIALLY MAKE A
METHOD THAT WAS NOT
TRANSLATABLE BECAUSE OF POOR
YIELD INTO A POTENTIALLY
TRANSLATABLE PRODUCT.
WITH APTAMERS WE CAN GET ABOUT
DOUBLE THE YIELD FOR THE SERIAL
SELECTIONS.
FINALLY WE HAVE BEEN ABLE TO
SHOW WE CAN CHEMICALLY MODIFY
RESINS, AND USE CHROMATOGRAPHIC.
FOR THOSE WHO ARE GRADUATE
STUDENTS, SOMETIMES FAILED
EXPERIMENTS CAN STILL BE USEFUL.
THIS WORK WAS DONE IN CLOSE
COLLABORATION WITH MICHAEL
JENSEN AT SEATTLE CHILDREN'S,
HE IS THE FIZZ IKS I PHYSICIAN
I HAVE THE GREAT PRIVILEGE OF
WORKING.
THE CD8 WORK, BY NATALY
KACHEROVSKY.
EMMELINE CHENG.
MELISSA YANG DID HARD WORK.
ABE WU HAS BEEN PIONEERING THE
MEMORY STEM CELL POPULATION
ISOLATION.
THIS IS OUR LAB IN SUNNY
SEATTLE IN THE SUMMER.
WE ARE VERY GRATEFUL FOR OUR
FUNDING.
THIS WORK WAS STARTED BY
FUNDING FROM JUNE NO
THERAPEUTICS AND NOW NIH NIBIB.
VERY GRATEFUL.
I WOULD BE HAPPY TO ANSWER ANY
QUESTIONS THAT YOU MIGHT HAVE.
>> Rahul Thakar: SUZIE, THAT
WAS BEAUTIFUL WORK.
ONE QUESTION ABOUT THE TRANSFER
AND RECEPTOR, WHICH IS NEAR AND
DEAR TO MY HEART.
I WAS UNDER THE IMPRESSION
EVERY CELL HAS TRANSFER AND
RECEPTOR, HOW DO YOU GET NOT
LOSING THE CELLS YOU WANT WHEN
USING THAT COUNTER SELECTION?
>> Suzie Pun: YES, BECAUSE
TRANSFER AND RECEPTOR IS UP
REGULATED SO MUCH MORE, AND
BUEZ BECAUSE WE ARE USING
MAGNETIC, WE CAN'T RECOVER THE
CELLS WELL BECAUSE YOU DON'T
HAVE ENOUGH BEAD, SO IT TURNS
OUT TO BE A VERY SIMPLE
SELECTION.
IT'S BECAUSE OF THE LEVEL OF
DIFFERENCE.
>> COOL, THANK YOU.
>> VERY NICE WORK.
VERY BEAUTIFUL DATA.
I'M JUST CURIOUS WHEN YOU SAY
TEMPERATURE DEPENDENCE, SORTING
DEFICIENCIES, I'M CURIOUS ABOUT
THE SECONDARY STRUCTURE OF THE
APTAMERS AND IF YOU NEED TO
ANIL (?) AT DIFFERENT
TEMPERATURES?
>> Suzie Pun: THAT'S A GOOD
QUESTION, SOME APTAMERS CAN BE
TEMPERATURE SENSITIVE.
IN THIS CASE WE DIDN'T HAVE ANY
TROUBLE WITH THAT, WE DO OUR
SELECTIONS AT ROOM TEMPERATURE.
WE DO HAVE AN APTAMER THAT I
DIDN'T TALK ABOUT HERE THAT WE
WANTED TO USE IN VIVO AND THAT
APTAMER WHEN WE GET TO 37°
LOSES ABOUT HALF OFITY BINDING.
YOU ARE RIGHT THAT TEMPERATURE
SENSITIVITY CAN BE AN ISSUE.
SOME APTAMERS ARE STABLE ENOUGH.
I THINK THE OTHER THING WE CAN
DO IS TO INCREASE THE STEM
REGION OR SWITCH IN FOR
EXAMPLE, CG COMPLEXES TO TRY TO
INCREASE THE THERMAL STABILITY
AND ALSO DO THE SELECTION AT
THE TEMPERATURE THAT WOULD BE
RELEVANT, THE SELECTION OF THE
APTAMER.
IF YOU DO THE SELECTS PROCEDURE
AT A HIGHER TEMPERATURE, YOU
WILL SELECT APTAMERS THAT ARE
MORE STABLE AT THAT TEMPERATURE.
>> MAYBE A FOLLOW-UP QUESTION,
THE PRESENCE OF THE CELLS WITH
POTENTIAL RELEASE OF DNA OR
THINGS LIKE THAT, HAVE YOU SEEN
ANY EFFECT ON THE CELL SORTING
EFFICIENCY, BASED OFF HOW
CLEAN, FOR EXAMPLE, THE
STARTING PRODUCT IS?
>> Suzie Pun: WE HAVE IN A
SENSE, IF WE HAVE A LOT OF DEAD
CELLS THEY WILL SOMETIMES STICK
NON SPECIFICALLY TO THE RESIN
AND IT WILL GUM UP THE RESIN.
THAT WAS A PROBLEM WITH OUR
CHROMOTOGRAPHY ONES WITH WERE
RELYING ON GRAVITY FLOW.
IN THAT CASE WE HAD TO HAVE A
PRE-COLUMN TO REMOVE STICKY AND
DEAD CELLS IN THE
CHROMOTOGRAPHY METHOD.
WE HAVE TRIED FRESH CELLS AND
THAWED CELLS AND CELLS FROM
DIFFERENT DONORS AND HAVEN'T
SEEN A HUGE ISSUE WITH THAT.
>> REALLY GREAT TALK.
I ESPECIALLY REALLY ENJOYED
SEEING THE CHROMOTOGRAPHY WORK
WITH THE RESIN YOU HAVE DONE.
ONE QUESTION I THINK COMES UP
WITH RESIN REUSE, IT'S MAYBE
FINANCIALLY INCENTIVE TO REUSE.
THE APTAMERS YOU ARE USING TO
RELEASE EITHER THE CD8 CELLS OR
WHATEVER CELLS YOU ARE
SELECTING FOR.
IS REUSABILITY STILL POSSIBLE
WITH IT?
ONE THOUGHT IS HOW DO YOU
SEPARATE THAT CHANGED STRUCTURE
AFTER YOU ADD THE SECOND PIECE.
>> Suzie Pun: GREAT QUESTION.
THEE ARE THICALLY IT WOULD BE
TOTALLY REUSABLE BECAUSE WHEN
YOU REHEAT YOU CAN SEPARATE
THAT REVERSAL STRAND.
LIKE GABE WAS ELUDING TO, WHEN
IT COOLS IT WILL FOLD BACK IN
ITS SECONDARY STRUCTURE.
WE HAVEN'T EXPLORED THAT
BECAUSE THE APTAMERS ARE JUST
SO CHEAP.
THE $5 WORTH OF APTAMERS.
IS IT WORTH IT TO RESTERILIZE
IF THE COST OF YOUR REAGENT IS
SO LOW.
I CAN'T ANSWER THAT.
OKAY, THANK YOU.
ALL RIGHT, THANK
YOU.
[ APPLAUSE ]
Rahul Thakar: HELLO, AGAIN.
IT'S MY PRIVILEGE TO INTRODUCE
OUR NEXT SPEAKER, DR. PAUL
SHEEHAN FROM ARPA-H.
HE IS GOING TO GIVE YOU A
LITTLE BIT OF AN IDEA OF WHAT'S
GOING ON BETWEEN THE
INTERSECTION BETWEEN BIO
ELECTRONICS AND SYNTHETIC
BIOLOGY.
BEFORE HE WAS AT ARPA-H HE
RECEIVED A Ph.D. IN CHEMICAL
PHYSICS FROM HARVARD AND USED
THAT KNOWLEDGE AS A BASIS TO
PUSH FORWARD NANO SCALE
MECHANICS AND WHAT NOT AT
N.R.L. AND DARPA.
TAKING THOSE INFLUENCES AND
PIECES OF KNOWLEDGE HE HAS COME
TO ARPA-H IN FEBRUARY.
AND HE HAS ALREADY INITIATED
FOUR PROGRAMS.
ONE OF WHICH HE WILL TELL US
ABOUT.
THANK YOU.
>> Paul Sheehan: THANK YOU SO
MUCH JERMONT AND COMPANY, FOR
THE INVITATION.
GREAT.
AS RAHUL NOTED TODAY MY PLAN IS
TO TALK A LITTLE ABOUT THE
AGENCY, TO LET PEOPLE KNOW, I
HAVE AN IDEA.
IS IT A RIGHT FIT, A GOOD FIT
FOR ARPA-H.
AT THE END I WILL TALK ABOUT
SOME OF THE PROGRAMS WE HAVE
ANNOUNCED.
SOME OF WHICH TAKE ADVANTAGE OF
SYNTHETIC BIOLOGY SO YOU GET A
FEEL FOR THE KINDS OF THINGS WE
ARE LOOKING FOR.
FOR THOSE OF YOU WHO ARE
UNFAMILIAR, ARPA-H WAS SET UP A
YEAR AND A HALF AGO IN MARCH OF
2022.
THE INSPIRATION FOR IT WAS FROM
DARPA, THE AGENCY I CAME FROM
BEFORE ARPA-H.
IS EVERYONE FAMILIAR WITH DARPA?
SHOW OF HANDS?
GREAT.
THE CONCEPT BEHIND DARPA IS IT
IS AN AGENCY THAT UNDERTAKES
HIGH-RISK, HIGH-REWARD EFFORTS.
WE ARE A RISK MITIGATION
AGENCIMENT WE TAKE YOUR CRAZY
IDEA.
WE MEET WITH YOU MONTHLY, THINK
OF ANYWAY IT CAN GO WRONG, COME
UP WITH A BACK UP PLAN, TRY TO
FUND PEOPLE AS FULLY AS
POSSIBLE, EACH AND EVERY MONTH,
I HAVE TALKED TO SOME PEOPLE ON
THE PHONE CALLS EACH AND EVERY
MONTH TRYING TO TRACK WHAT'S
GOING ON.
THAT'S THE GLOBAL CONCEPT.
AND THAT IS A SOLUTION,
PROBABLY ONE OF THE BETTER
SOLUTIONS FOR ADDRESSING THESE
SORT OF WILD IDEAS.
IS IT EVEN POSSIBLE.
WE ARE REPRESENTING THE
COMMENTS FROM PRESIDENT BIDEN
WHEN HE ANNOUNCED IT.
SOME IDEAS ARE SO AUDACIOUS
SOME SAY IT WILL WORK ONLY IF
WE CAN TRY IT IN A BIG WAY,
RIGHT?
SO THE OTHER THING ABOUT
ARPA-H, THE WAY IT
DIFFERENTIATES FROM DARPA IS
THAT WE ARE REALLY, REALLY
FOCUSED ON ACCELERATING BETH
-- BETTER HEALTH OUT COMES FOR
EVERYONE.
FOR ME THE A UNIQUE OPPORTUNITY.
WE WERE TALKING ABOUT LUNCH
ABOUT ONE OF THE DIFFERENCES.
ONE OF THE DIFFERENCES FOR
DARPA WHEN I'M TRYING TO DO
BIOMEDICAL RESEARCH AT DARPA
IT'S FOR YOUNG HEALTHY WAR
FIGHTERS WHO GO THROUGH TRAUMA.
IT TENDS TO BE A SUBSET.
OFTEN THOSE APPLICATIONS ARE
FAIRLY NARROW.
SO I'M ALWAYS SEARCHING FOR
SOMETHING RELATED THAT COULD BE
SUFFICIENTLY, YOU KNOW,
REMUENER TIVE, PROFITABLE.
THERE IS BLAST INJURIES BUT
THAT'S ADJACENT TO DIABETIC --
WHICH IS A $20 BILLION A YEAR
PROBLEM.
I WOULD DEVELOP THIS
TECHNOLOGY, HIGH-TECH BANDAGE
FOR BURN AND BLAST INJURY, THE
COMPANY WOULD TAKE IT THROUGH
FDA FOR DIABETIC -- WE WOULD
TRY TO BRING IT BACK FOR BLAST
INJURIES.
HERE I DON'T HAVE TO DO THAT, I
CAN GO DIRECTLY AFTER THESE
PROBLEMS.
HOWEVER, THERE'S ALSO A WEIGHT
ON ME.
I HAVE TO TAKE INTO
CONSIDERATION ALL THE OTHER
THINGS AT THE BEGINNING, WHAT
IS THE PATIENT GOING TO
EXPERIENCE, HOW IS THEIR LIFE
GOING TO BE BETTER WITH THIS
TECHNOLOGY.
THE WAY IT'S SET UP,
GOVERNMENTLY, WE ARE WITH NIH
BUT THE ARPA-H DIRECTOR REPORTS
DIRECTLY TO SECRETARY BECERRA.
THE VAST EXPERTISE IS
INCREDIBLY VIABLE TO US AT
ARPA-H.
BE ABLE TO HIT YOU UP WITH
DIFFERENT INSIGHTS, DIFFERENT
THOUGHTS, HELP US IMPROVE
PROGRAMS.
BUT WE ARE INDEPENDENT SO WE
CAN GO OUR OWN WAY, PROPOSE OUR
OWN RULES, WORK IN THE SORT OF
FAST AND FLEXIBLE WAY THAT
ENABLES OUR PROGRAMS.
THE OTHER THING TO NOTE, WHEN I
WAS AT DARPA AND HAVEN'T
RECEIVED YET, HEY I WOULD LIKE
TO WORK IN YOUR RESEARCH LABS.
WE DON'T HAVE ANY LABS.
WE TAKE THE MONEY AND HAND IT
TO OTHER PEOPLE TO DO THE GOOD
RESEARCH.
SO FAR WE HAVE $2.5 BILLION FOR
INITIAL APPROPRIATION.
THESE ARE GENERALLY CONTRACTS,
NOT GRANTS.
THAT GOES BACK TO THE CONSTANT
INTERACTION WITH THE PERFORMER.
WE DON'T HAND YOU MONEY AND ASK
YOU TO REPORT BACK IN A YEAR OR
TWO.
WE ARE THERE EVERY STEP OF THE
WAY, HOW ARE THINGS
PROGRESSING, RIGHT.
THE OTHER THING WE HAVE WHAT WE
CALL A SUPER POWER, WE CAN PAY
OTHER AGENCIES, SUCH AS THE FDA
TO ENGAGE ON CERTAIN PROBLEMS.
WE ARE STILL FIGURING OUT HOW
THAT WORKS IN PRACTICE, BUT WE
ARE EXCITED TO PURSUE THAT
CAPABILITY, FLEXIBILITY.
ONE OF THE KEY FEATURES OF
ARPA-H.
ONE IS THAT THE AGENCY REVOLVES
AROUND PROGRAM MANAGERS, SUCH
AS MYSELF.
OFTEN PEOPLE GO WHAT IS ARPA-H
INTERESTED IN.
WHAT ARPA-H IS INTERESTED IS
WHATEVER THE PROGRAM MANAGERS
AT THIS TIME ARE INTERESTED IN.
I COMPARE IT TO THE PACIFIC
OCEAN.
WE CAN GO ANYWHERE, MOST OF THE
SPACE IS EMPTY, WE HAVE
VOLCANOS HERE AND THERE WE ARE
TRYING TO GENERATE A NEW ISLAND.
TRYING TO FIND IN THE GIGANTIC
SPACE, FOCUS INVESTMENT WILL
REALLY MAKE A DIFFERENCE.
WE HAVE HUGE AUTO --
AUTONOMY IN THIS TO DO WHATEVER
WE WANT.
I COME UP WITH AN IDEA, THERE'S
FEEDBACK IN THE OFFICE, I GO
STRAIGHT TO THE DIRECTOR, THE
DIRECTOR SAYS YES OR NO I CAN
PURSUE THIS PROGRAM.
THEY CHECK ON ME TWICE A YEAR,
BUT THEN I CAN HIRE, FIRE,
WHATEVER TO REPORT BACK TO THE
DIRECTOR.
WE WANT TO BE FAST, SO WE HAVE
VERY FAST CONTRACTING
MECHANISMS.
I CAN SAY WE, IN MARCH THIS
YEAR, THAT WE PUT OUT THIS OPEN
B.A., BEFORE THE END OF THE
FISCAL YEAR WE USED UP OUR
FIRST YEAR APPROPRIATION WHICH
WAS $1 BILLION.
WE MOVED A LOT OF RESEARCH IN
THE FIRST YEAR BECAUSE WE MOVE
QUICKLY AND NIMBLY.
FLEXIBILITY IN HIRING.
WE LOOK FOR PROGRAM MANAGERS
AND THAT'S ONE OF THE CALLS FOR
EVERYONE HERE, IF YOU OR
SOMEONE YOU KNOW WOULD BE
INTERESTED IN A PROJECT MANAGER
WE ARE ALWAYS LOOKING FOR
PEOPLE.
WE HIRE FROM GOVERNMENT,
ACADEMIA, FROM HMO'S,
CLINICIANS, ACROSS-THE-BOARD.
ANYONE WHO HAS AN IDEA AND
WANTS TO MAKE IT A REALITY IS
WELCOME.
PART OF THE JOB AND I THINK
THIS CAME OUT EARLIER IN THE
DISCUSSION, IS ADDRESSING ALL
OF THESE DIFFERENT CUSTOMERS,
EACH ONE OF THESE GROUPS HAS
THEIR OWN LENSES AND WE ARE
TRYING TO ADDRESS ALL THOSE
LENSES TO SOLVE A PROBLEM FOR
THIS ENTIRE COMMUNITY, RIGHT?
CUSTOMERS.
PATIENT GROUPS.
WE ENGAGE WITH THEM.
WHAT DO THEY WANT TO SEE IN
THEIR LIVES.
HOW CAN WE IMPROVE THEIR
DAY-TO-DAY EXPERIENCE.
HEALTHCARE PROVIDERS, IT WON'T
GET TO THE PATIENTS IF THE
CLINICIANS DON'T BUY INTO USING
T. THE PUBLIC AT LARGE WANT TO
SEE VALUE OUT OF THE MONEY THEY
ARE GIVING TO ARPA-H.
NIH, WE TRY TO PLUG IN.
THE TECHNOLOGY IS, YOU COME TO
US, IT'S AMAZING TECHNOLOGY, IT
NEEDS A LITTLE OOMPH BEHIND IT,
USE THE FLEXIBILITY TO GET THAT
OUT THERE.
LOTS OF OTHER FEDERAL PARTNERS,
FDA, CMS.
ACADEMIA, INDUSTRY, NGO'S, ALSO
PRIVATE INVESTORS TRYING TO
PULL ALL THESE COMMUNITIES IN.
THAT'S THE LABOR BUT THE
EXCITEMENT.
YOU HAVE A NEW TECHNOLOGY AND
YOU ARE TRYING TO GET IT ALL
THE WAY FROM SOMEONE'S GLIMMER
IN THE EYE, ALL THE WAY TO CMS
GIVING A CODE SO SOMEONE CAN
GET PAID FOR PROVIDING THIS
CAPABILITY.
SO SOME OF THE ORGANIZATIONAL
ATTRIBUTE THAT'S CAN SUPPORT
THE MISSION.
PROBLEM-FOCUSED PROGRAM
MANAGERS.
I DO NOT HAVE, I'M NOT DOING
RESEARCH IN GENERAL AND CANCER.
I HAVE A PARTICULAR PROBLEM
THAT I'M TRYING TO SOLVE AND I
WORK BACK TO A SET OF SOLUTIONS
AND THEY PUSH ALL THE WAY
THROUGH THOSE, RIGHT?
SO IT'S REALLY THAT FOCUS ON
THE PROBLEM AND I THINK OF
MYSELF AS A CONCIERGE FOR THE
PERFORMERS.
THE OTHER WAY TO DESCRIBE IT TO
PEOPLE, IT'S LIKE THE CANADIAN
GAME CURLING.
SO WE ARE BACK THERE WITH THE
PERFORMERS, WE THROW THE ROCK
AND I AND MY WHOLE TIME JUMP
OUT IN FRONT OF THE STONE AND
WE ARE THERE WITH THE BROOM,
RIGHT?
TRYING TO MAKE SURE IT GETS ON
TARGET.
THAT MEANS ANYTHING THEY MIGHT
NEED, IF THEY NEED TO TALK TO
THE FDA, TRYING TO FACILITATE
THAT IF NEEDED.
IF THEY NEED TO TALK TO
INVESTORS WE LINE THAT UP.
IF THEY NEED AN EXPERT IN
RESIDENCE TO COME UP WITH AN IP
FOR THE COMPANY.
ANY CONNECTION THEY MIGHT NEED
WE TRY TO FACILITATE THOSE
INTERACTIONS, RIGHT?
SO DEEP SUPPORT FROM ACROSS THE
AGENCY FOR ME.
WE LOOK FOR RADICAL CHANGE.
IF SOMEONE COMES TO US AND IT'S
SOMETHING ELSE SOMEONE ELSE
COULD OR SHOULD FUND THAT ISN'T
THAT RISKY, I SAY 4-5 TIMES A
DAY, YOUR IDEA IS GREAT, IT
SHOULD BE DONE, IT DOESN'T
REALLY FIT WITH US.
OTHER PEOPLE CAN DO THIS, IT'S
NOT A REALLY RISKY PROPOSITION.
YOU ARE DOING SOMETHING SMART
AND GOOD.
SO WE ARE REALLY LOOKING FOR
THESE HIGH-RISK, HIGH IMPACT
PROPOSALS THAT CAN REALLY WORK
ONLY AT SCALE.
LOTS OF AUTONOMY, AS NOTED.
I'M REALLY ONLY RESPONSIBLE TO
THE DIRECTOR.
ULTIMATELY AT THE END OF THE
DAY, THE AGENCIES, WHEN WE
FULLY STAFF WILL HAVE MAYBE
100-120 PROGRAM MANAGERS.
I IMAGINE THE SAME AT DARPA,
THE DIRECTOR KNOWS EVERY SINGLE
PROGRAM MANAGER BY NAME, ANY
TIME I CAN GO AND TALK TO THE
DIRECTOR ABOUT WHAT I WANT TO
GET DONE, RIGHT?
SO HIGHLY EMPOWER ERRED.
ER -- EMPOWERED.
THEN TERM LIMITS.
I HAVE TO SAY, I THINK IT'S ONE
OF THE BEST JOBS IN THE
GOVERNMENT, THEY GIVE YOU A LOT
OF AUTONOMY, MONEY, SUPPORT,
YOU GET TO WORK WITH AMAZING
PEOPLE AND THEN THEY KICK YOU
OUT.
YOU ONLY HAVE A SHORT AMOUNT OF
TIME TO GET THINGS DONE.
THEY CALL IT THE FLYWHEEL.
FEELS LIKE A TORE TORNADO WHEN
ARE YOU GOING THROUGH IT.
YOU GET THREE YEARS AND MAYBE
CAN GET AN ADDITIONAL THREE
YEARS.
IF SOMEONE GIVES YOU TEN YEARS,
YOU ARE LIKELY TO TAKE TEN
YEARS TO GET IT DONE.
IF YOU KNOW YOU HAVE THREE
YEARS YOU WILL PUSH DAY AND
NIGHT AND ON WEEKENDS TRYING TO
SEE SOME CHANGE WHILE YOU ARE
STILL THERE, RIGHT?
THIS MEANS PEOPLE COME AND GO.
THAT MEANS WE ARE ALWAYS
LOOKING FOR PROGRAM MANAGERS.
AGAIN, YOU WILL HEAR THIS
MULTIPLE TIMES, IF YOU KNOW
ANYBODY, IF YOU WANT TO BE A
PROGRAM MANAGER WE ARE ALWAYS
LOOKING FOR NEW CANDIDATES TO
COME IN AND TAKE IT OVER.
THE OTHER IMPACTS OF THIS, I'M
NOT THERE AT THE END OF MY
PROGRAM, RIGHT?
I COME AND PITCH A PROGRAM.
I MAY HAVE A FIVE-YEAR PROGRAM
AND I'M UNLIKELY TO BE THERE AT
THE VERY END.
YOU HAVE TO HAVE MULTIPLE EYES
ON IT, IT HAS TO BE CONVINCING
TO A LOT OF PEOPLE, NOT JUST MY
BUDDIES, MY PALS, NOT ACCUSING
ANYONE OF THAT, BUT IT HAS TO
BE CONVINCING TO LOTS OF FOLKS
TO MAKE THAT HAPPEN.
THERE ARE LOTS OF PHENOTYPES.
DO I HAVE TO COME FROM NIH OR
BE AN ACADEMIC.
THERE ARE LOTS OF FOLKS THAT
COME ALL OVER, THE RESEARCH
COMMUNITY, THE HEALTHCARE
COMMUNITY.
WHAT WE ARE REALLY LOOKING FOR
IS SOMEONE WHO WANTS TO TAKE
OWNERSHIP, THEY THINK LIKE A
CEO FOR EACH OF THESE EFFORTS.
YOU NEED NOT ONLY TO HAVE THAT
EXPERTISE, YOU NEED THE
CURIOSITY.
YOU NEED TO HEAR WHEN PEOPLE
COME IN, YOU ACTUALLY TALK TO
ME MORE ABOUT THAT, THAT SOUNDS
CRAZY BUT MAYBE THAT'S A THING,
I KNOW SOMEBODY WHO CAN MAYBE
SOLVE THAT PROBLEM.
YOU NEED TO BE ABLE TO LISTEN
ACROSS FIELDS.
OFTEN TIMES YOU WILL NEED TO
DEVELOP A TECHNOLOGY ACROSS
MULTIPLE DIFFERENT AREAS.
AS MENTIONED EARLIER, SOMETIMES
IT'S BIOELECTRONICS, SYNBIO.
YOU NEED TO BE OPEN TO MULTIPLE
FIELDS.
I WILL PUT IN A POINT ONE OF
THE NICE THINGS THEY DO FOR US,
THEY PROVIDE SCIENCE ENGINEER
TECHNICAL ADVISORS, SMART
PEOPLE Ph.D.'S WHO HELP US
THINK ABOUT PROBLEMS.
I OCCUR NTLY HAVE SEVEN PEOPLE
ON MY TEAM TO THINK OF
BIOMANUFACTURING TO CANCER, TO
CELL PRINTING, TO HELP ME THINK
ABOUT AND RUN ALL THESE
EFFORTS, RIGHT?
YOU AT LEAST HAVE TO BE OPEN TO
CONCEPTS OUTSIDE OF YOUR NARROW
LANE.
DECISIVE.
YOU CUT PEOPLE, RIGHT?
SOMETIMES THINGS DON'T WORK.
SO YOU HAVE TO MAKE SURE THAT
IF IT'S NOT WORKING, YOU CUT
THEM AND TAKE THOSE RESOURCES
AND YOU PUT THEM WHERE THEY ARE
GOING TO WORK.
DRIVE.
NO FEAR OF FAILURE.
THINGS CAN BLOWUP.
I GENERALLY, THE NEW PROGRAM
MANAGERS WHO ARE COMING IN,
LIKE HOW DO I KNOW?
WELL, IF YOU ARE WORRIED IT
WILL BLOW UP IN YOUR FACE YOU
ARE PROBABLY ON THE RIGHT TRACK.
THAT'S WHY WE ARE HERE, IT'S A
HIGH-RISK, HIGH-REWARD EFFORT.
YOU ARE HERE TO MAKE SURE IT
WILL WORK, IF NOT THAT'S OKAY.
I HAVE CUT EFFORTS BUT I HAVE
LEARNED FROM WHAT MOTHER NATURE
SAID YOU COULDN'T DO, SO THAT'S
USEFUL IN ITS OWN SELF-.
BE HONEST AND CUSTOMER CENTRIC.
I NEED TO KNOW WHO MY
STAKEHOLDERS ARE.
WHO I'M GOING TO DELIVER
TECHNOLOGY TO AND I NEED TO
MAKE SURE I CAN HAND THAT OFF
AT THE END OF THE PROGRAM.
FOR THE SIMPLE REASON THAT
AGAIN, THE PROGRAM STARTS, YOU
HAVE FOUR OR FIVE YEARS, RIGHT?
AND THEN IT HAS TO LIVE
SOMEWHERE ELSE.
WE ARE GONE.
WE ARE A VOLCANO, WE START, WE
STOP AND SOMEONE HAS TO PICK IT
UP AND SAY THIS IS WORTHWHILE.
ROSS WAS A NAVY SURGEON,
DARSHACK WAS THE CMO FOR UNITED
HEALTH.
ANDY WAS PART OF OPERATION WARP
SPEED.
YOU GET THE FEEL, FROM ALL OVER
FROM GOVERNMENT, FROM ACADEMIA,
ALANNA WAS IN ACADEMIA A BIT.
ALL ACROSS-THE-BOARD.
OKAY, SO ONE OF THE THINGS WE
ALWAYS PUSH IS SOMETHING CALLED
THE HEILMEIER QUESTIONS.
STOLEN FROM DARPA.
YOU KIND OF READ THE QUESTION.
NEVER QUITE GOT IT MYSELF.
THESE ARE PRETTY BASIC
QUESTIONS.
MOST PEOPLE WOPT KNOW THE
ANSWERS IF YOU LOOK AT IT.
HONESTLY I THINK A HIGH SCHOOL
DEBATE TEAM COULD COME UP WITH
THE QUESTIONS, BUT AT DARPA
THEY SAY IT'S MAGICAL.
I WILL SAY WITH EXPERIENCE THEY
ARE USEFUL, RIGHT?
MANY PEOPLE COME TO US AND THEY
ARE EXCITED ABOUT THE
CAPABILITY.
AND YOU START STEPPING INTO THE
QUESTION.
BEFORE YOU COME TALK TO US,
TAKE A LOOK, RIGHT?
THESE ARE SIMPLE QUESTIONS.
CAN YOU ANSWER THEM SUPER
QUICKLY?
WHAT ARE YOU TRYING TO DO, TELL
ME IN 30 SECONDS, NO JARGON,
HOW DO I CONVINCE OTHER PEOPLE,
GOOD IDEAS DON'T NEED A LOT OF
SALES MAN SHIP OR ADD VERTISING.
I WILL PRINT HUMAN HEARTS IN AN
HOUR BECAUSE PEOPLE ARE DYING
WAITING FOR HUMAN HEARTS.
AND THEN YOU EXPLAIN THE REST
OF YOUR TIME EXPLAINING HOW IT
COULD BE POSSIBLE.
WHAT'S HAPPENING RIGHT NOW.
NOT JUST WHAT'S IN THE CLINIC.
BUT WHAT'S ON THE RESEARCH
BENCH THAT IS NOT MAKING IT?
HOW IS YOUR TECHNOLOGY ANY
DIFFERENT?
WHAT'S NEW?
WHAT IS YOUR SECRET SAUCE,
RIGHT?
IF I HEAR ANOTHER ONE, I WILL
DO OMICS AND APPLY AI, AS IS
EVERYONE.
TELL ME HOW, PARTICULAR
APPROACH IS GOING TO MAKE A
DIFFERENCE.
NUMBER FOUR IS AMAZING.
MANY PEOPLE CAN'T ANSWER THIS,
IT'S STUNNING.
IT'S REALLY NEAT.
IT IS REALLY NEAT, BUT WHO
CARES.
I AGREE.
THIS IS ALL GOING TO WORK.
BUT AT THE END OF THE DAY, HOW
DOES THIS CHANGE THE WORLD?
AND A LOT OF PEOPLE DON'T HAVE
AN ANSWER TO IT, RIGHT?
I WOULD SAY THAT'S THE HEART OF
IT, RIGHT?
IF YOU CAN GET THROUGH THREE
AND FOUR, WHAT DOES IT MATTER,
WHO CARES?
HOW WILL THIS CHANGE THE WORLD,
YOU ARE OVER THE HUMP, RIGHT.
THE REST OF THE QUESTIONS, WHAT
ARE THE RISKS?
WE ARE THE RISK MANAGEMENT
AGENCY.
CAN WE MITIGATE THESE RISKS?
WHAT KEEPS YOU UP AT NIGHT.
WHEN WE FORM OUR PROGRAMS THIS
IS WHAT WE CALL TECHNICAL AREAS.
WE FIND THE HARDEST THINGS WE
HAVE TO DO AND WE FOCUS ON
THOSE.
SO WE KNOW SPECIFICALLY WHAT'S
GOING TO HAPPEN.
AND THE REST IS LIKE, HOW LONG
IS THIS GOING TO TAKE?
CAN WE GET THIS DONE IN 3-4
YEARS?
HOW MUCH WILL IT COST?
WHAT ARE MIDTERM AND FINAL
CHECKS?
JUST MILESTONES, WE ARE
MILESTONE DRIVEN, WHERE WILL
YOU BE IN ONE YEAR, TWO YEARS
AND FIVE YEARS, THAT KEEPS
PEOPLE HONEST.
TO KEEP THINGS ON TRACK.
THE LAST TWO THINGS, I THINK
DARPA YOU WOULD CONSIDER THIS
SACRILEGE TO ADD IN QUESTIONS
BUT I THINK IT'S APPROPRIATE
FOR OUR PAGE.
TO ENSURE EQUITABLE ACCESS TO
ALL PEOPLE.
HOW IS THE COST, ACCESSIBILITY,
USER EXPERIENCE GOING TO BE
ADDRESSED.
I WILL SAY FOR MYSELF, IF CAR T
THERAPIES ARE AMAZING, A
MIRACLE BUT ALSO A HALF MILLION.
I'M SURE YOU WILL BRING COSTS
DOWN.
I FEEL IF WE COME UP WITH
ANOTHER MILLION-DOLLAR SOLUTION
WE HAVE KIND OF FAILED.
THAT'S REALLY LIMITING ACCESS
TO THE PUBLIC.
HOW CAN WE MANUFACTURE THIS TO
BE CHEAP AND SUCCESSFUL.
HOW MIGHT THIS PROGRAM BE
MISPERCEIVED AND MISUSED.
WE WANT TO CREATE TRUST
PARTICULARLY WHERE PEOPLE DON'T
TRUST THE MEDICAL SYSTEM, WE
WANT TO BRING THEM INTO THE
HEALTHCARE SYSTEM.
SO HOW DOES IT WORK.
I AM STILL TRYING TO CONVINCE
PEOPLE TO APPLY TO BE A PROGRAM
MANAGER.
HOW DOES IT WORK?
A PROGRAM MANAGER COMES IN, YOU
PITCH THIS IDEA, WE ALL BEAT
YOU UP IN A NICE WAYMENT.
SAY YOU GET THE JOB.
YOU COME IN, HELP TO FIND THIS
CHALLENGE WITH YOUR CDA'S.
IT SHOULDN'T BE EASILY SOLVABLE
BY OTHER METHODS.
THE PROGRAM LAUNCH.
OFTEN TIMES YOU HAVE 2-3
PERFORMERS, SOMETIMES PEOPLE
PICK UP A FEW MORE PERFORMERS
AND THEY GO, RIGHT?
SO THIS, YOU KNOW, TYPICALLY
YOU SELL YOUR PROGRAM IN THE
FIRST COUPLE MONTHS.
THE B.A. GOES OUT.
WITHIN YOUR FIRST YEAR OR LESS,
NINE TO TEN MONTHS YOU WILL
HAVE KICKED OFF YOUR PROGRAM
AND THINGS WILL BE UNDER WAY.
FROM THEN, YOU HAVE YOUR
MULTIPLE PERFORMERS, LIKE I
SAID YOU WILL MEET WITH THEM
EVERY MONTH, NOT EVERYONE MAKES
IT, THAT'S OKAY, YOU TRY CRAZY
THINGS, OFTEN TIMES THERE WILL
BE SPIN OFFS BUT ONE WILL MAKE
IT TO THE END STATE.
AT THAT POINT YOU HAVE A
TRANSITION AND THAT TRANSITION
GOES OUT BROADLY ACROSS THE
U.S. PUBLIC.
AND I WILL TALK, I THINK THE
NEXT SLIDE SHOULD BE GREAT.
AS NOTED WE ARE HERE TO MAKE A
DIFFERENCE FOR THE U.S. PUBLIC,
FOR THE HEALTHCARE SYSTEM,
RIGHT?
ONE OF THE COOL THINGS THAT
ARPA-H HAS DONE IS SET UP THIS
PATIO OFFICE, THE PROJECT
SELLER TRANSITION INNOVATION
OFFICE.
HELP FOR YOUR NEW P.M., YOU
NEED TO COME WITH IDEA,
LANDSCAPE ANALYSIS, THOSE BITS
OF SUPPORT, THAT'S HELPFUL.
I THINK THE LATTER HALF OF THIS
IS WHAT'S REALLY AMAZING.
I HAVE SOME PERFORMERS, THEY
ARE DOING SOME COOL TECHNOLOGY.
PATIO IS THERE TO PROVIDE
BASICALLY THE MENU OF ALL THE
OTHER CAPABILITIES I CAN ORDER
FOR THEM.
THESE INCLUDE, OKAY I'VE GOT A
COMPANY, I NEED TO HAVE
SOMEBODY WHO KNOWS THE
LANDSCAPE SO I CAN COME UP WITH
AN APPROPRIATE IP STRATEGY.
OR THERE'S ELSIE, ETHICAL LEGAL
SCIENTIFIC IMPLICATIONS.
HELP ME WORK THROUGH OR WE WILL
BRING THAT RESOURCE.
ALSO CONNECTING TO VENTURE
CAPITALISTS WHO MAY WANT TO
INVEST IN THE TECHNOLOGY.
PEOPLE WHO ARE FAMILIAR WITH
REGULATORY ENGAGEMENT.
HELP ME THINK HOW I MIGHT
ENGAGE MOST EFFECTIVELY WITH
THE FDA, WE PROVIDE THAT
CAPABILITY.
THIS GOES BACK TO THE ROLE,
IT'S NOT JUST HANDING OUT THE
BRIEF CASE WITH THE CASH, BUT
DOING WHATEVER IS POSSIBLE TO
MAKE THOSE PERFORMERS
SUCCESSFUL.
SO AT THE END OF THE DAY, IF
THEY FAILED THAT'S BECAUSE THEY
DIDN'T WORK HARD ENOUGH, WHICH
SHOULDN'T HAPPEN, BECAUSE YOU
ARE THERE EVERY MONTH AND PICK
MOTIVATED PEOPLE.
OR MOTHER NATURE SAID NO.
OR YOU ARE TRYING TO LAY THIS
GROUNDWORK.
FANTASTIC ADDITIONAL CAPABILITY
FROM THE PATIO OFFICE.
ALL RIGHT.
SO THERE ARE LOTS OF DIFFERENT
WAYS TO PARTNER, AS NOTED.
BECOME A PROGRAM MANAGER.
WE ARE ALWAYS LOOKING FOR NEW
PEOPLE.
THE OPEN B.A. FOR PEOPLE, FOR
PEOPLE WHO WANT TO SEND IN
THEIR CRAZY IDEAS.
THE OPEN BAA IS ALWAYS OPEN.
HENCE THE NAME.
THIS ONE CLOSES IN MARCH, A NEW
ONE WILL OPEN THE NEXT DAY.
A THING TO KNOW FOR THE FIRST
COUPLE YEARS A LOT OF MONEY IS
GOING OUT THROUGH THE OPEN BAA,
YOU COME IN WITH YOUR CRAZY
IDEA, YOU SEND IN YOUR
ABSTRACT, WE EITHER SAY EH, OR
YEAH THAT'S INTERESTING, SEND
US A FULL PROPOSAL.
YOU SEND US A FULL PROPOSAL AND
WE WILL SEND OUT A NOTICE TO
FUND OR NOT FUND.
QUITE A FEW HAVE BEEN FUNDED
THIS YEAR.
NEXT YEAR IT WILL GO DOWN, THE
NUMBER OF PROPOSALS WE FUND OUT
OF THE OPEN BAA, THE REASON IS
NUMBER OF PROGRAMS WILL GO UP,
SO THE MONEY WILL SHIFT OVER.
THIS WILL ALWAYS BE AN OPEN
BAA, YOU CAN STILL DREAM REALLY
BIG FOR THE OPEN BAA.
BECOME A PROGRAM MANAGER.
THE OTHERS, FOR FOLKS WHO ARE
IN INDUSTRY WE HAVE A COOL
SYSTEM CALLED HUB AND SPOKE.
WE HAVE TWO HUBS, ONE IN BOSTON
AND DALLAS.
BOSTON IS ABOUT THE INVESTMENT
COMMUNITY TRYING TO BRING THEIR
TECHNICAL EXPERTISE TO
ACCELERATE PROGRAMS.
THE DALLAS THEY ARE USING THE
USER EXPERIENCE, RIGHT.
SO THERE ARE NO REQUIREMENTS IF
YOU RUN A TRIAL, FDA, IT HAS TO
REPLICATE THE POPULATION OF THE
UNITED STATES WHO SUFFERS FROM
THAT DISEASE, RIGHT?
THAT COULD BE A CHALLENGE.
THAT HUB IS THERE TO NORMALLY
EXPEDITE THE CLINICAL TRIALS
BUT ALSO DISTRIBUTE CLINICAL
TRIALS PEOPLE LIVING IN REMOTE
LOCATIONS CAN PARTICIPATE.
ALSO WORK ON USER ENGAGEMENT.
AGAIN HERE IS USER TECHNOLOGY,
HOW IS A PATIENT GOING TO LIVE
WITH THIS TECHNOLOGY.
CAN WE PROVIDE FEEDBACK AS
EARLY AS POSSIBLE TO SHAKE THAT
TECHNOLOGY.
IF YOU ARE ON THE COMMERCIAL
SIDE AND INTERESTING THERE IS
AN APPLICATION PROCESS.
WHAT HAPPENS WITH THE HUB AND
SPOKE, IF I NEED A CAPABILITY,
I CAN TAB INTO THE HUB AND
SPOKE.
I WOULD LIKE TO TALK TO
SOMEBODY IN THIS PARTICULAR
AREA WHO KNOWS THIS PARTICULAR
THING SO THAT THEY CAN HELP ME
WITH THE EFFORT AND LINEUP THE
PERFORMER.
OKAY, SO RIGHT NOW THERE ARE
FOUR INITIAL FOCUS AREAS.
HEALTH SCIENCE FUTURES, THEY
TEND TO DO THE MORE FAR OUT
THERE CONCEPTS.
LIKE WHAT MIGHT BE POSSIBLE.
STILL TRYING TO DELIVER
THERAPIES BUT THEY DO TRY TO
PUSH FOR IT.
SCALABLE SOLUTIONS IS TRYING TO
REACH EVERYONE QUICKLY.
WE HAVE TALKED A LOT ABOUT
MANUFACTURING TODAY.
THIS IS REALLY ONE THAT IS
TRYING TO PUSH ON MANUFACTURING
DISTRIBUTION OF BOTH THE
THERAPY ITSELF BUT ALSO DATA,
PUSHES AS BROADLY AS POSSIBLE.
PROACTIVE HEALTH.
LET'S TRY TO KEEP PEOPLE FROM
BECOMING PATIENTS.
LET'S GET THE U.S. POPULATION
TO BE AS HEALTHY AS POSSIBLE.
RESILIENT SYSTEMS TRYING TO
BUILD AN INTEGRATED HEALTHCARE
SYSTEM, WE HAVE A LOT OF
INFORMATION FLOATING AROUND
ELECTRONIC HEALTHCARE RECORDS.
HOW DO WE GIVE PEOPLE ACCESS IN
A USABLE FORM AND GET THE MOST
UTILITY OUT OF IT.
LOOK AT OUR HEALTHCARE SYSTEM
AND MAKE SURE IT'S RESILIENT
AGAINST ANY SORT OF
DISRUPTIONS, SUCH AS A PANDEMIC.
OKAY, SO THAT GIVES YOU AN
OVERVIEW OF THE OFFICE.
I WAS GOING TO TAKE A FEW MORE
MINUTES TO TALK ABOUT THE
PROJECTS I'VE FUNDED TO DATE.
HAPPY TO ANSWER ANY QUESTIONS
ABOUT THEM.
AND ALSO ABOUT A RECENT
ANNOUNCEMENT FOR A FIRST FULL
PROGRAM.
THIS IS TO GIVE YOU A FEEL FOR
THE SCOPE, I WILL TRY TO LEAVE
TEN MINUTES FOR QUESTIONS, IF
THAT'S ALL RIGHT.
HERE ARE SOME FUNDED PROJECTS.
THE FIRST ONE IS CALLED HEART.
THIS IS THE ONE I MIGHT HAVE
MENTIONED A FEW TIMES.
THIS IS TRYING TO PRINT A HUMAN
HEART IN UNDER ONE HOUR.
THIS IS TAKING A SAMPLE,
MASSIVE STEM CELLS.
YOU NEED BILLIONS OF
APPROPRIATE CELLS.
TAKE THE CELLS, STEM CELLS,
DIFFERENTIATING THEM IN THE
RIGHT QUANTITIES AND RIGHT
VOLUMES.
YOU HAVE MASSIVE QUANTITIES OF
CELLS AND YOU DON'T DO IT
QUICKLY THEY ARE ALL GOING TO
DIE, RIGHT?
YOU HAVE ONE HOUR, ROUGHLY, TO
PRINT ALL OF THESE CELLS SO
COME UP WITH VERY HIGH-SPEED
PRINTERS THAT BASICALLY NEEDLES
COMING IN FROM ALL SIDES AT THE
SAME TIME PRINTING THE HUMAN
HEART.
IT'S A VERY SCI-FI-LOOKING WAY.
AMAZING TEAM OUT THERE.
YOU CAN IMAGINE, THANKS TO THE
NEED, CELL ENGINEERING, MASSIVE
SCALABILITY, THESE 3D PRINTING
TECHNOLOGIES THEY HAVE WORLD
LEADERS ON THAT.
VASCULAR PRINTING, THE CELLS
WILL DIE IF YOU DON'T HAVE THE
VASCULATURE IS THERE AND
OPERATIONAL QUICKLY.
AND LASTLY ORGAN MATURATION.
YOU PRINT THIS IN AN HOUR, IT
DOESN'T MEAN IT'S READY TO GO,
YOU HAVE TO TAKE TIME TO MATURE
THE CELLS SO IT OPERATES AS AN
ORGAN.
SO THOR, HE NAMES EVERY PROGRAM
AFTER SOMETHING FROM MARVEL.
ANYWAY, FANTASTICALLY A CLEVER
GUY.
THIS IS A TARGETED HYBRID
ONCOTHERAPEUTIC REGULATION.
HE IS TRYING TO IMPLANT DEVICE
FOR CANCER.
A CONTROL SYSTEM THAT CAN
MODULATE THE LOCAL AND SYSTEMIC
IMMUNE SYSTEM OF A PATIENT,
EXTERNALLY, SO YOU CAN TUNE IT
UP AND TUNE DOWN AND A WEARABLE
THAT TRACKS THE PATIENT.
GOING AFTER REAL BIOLOGICAL
INFORMATION, USING A VARIETY OF
TECHNIQUES TO TRACK THE STATUS
OF THE IMMUNE SYSTEM.
CONCEPT IS NOT ONLY TO PROVIDE
BETTER THERAPY FOR CANCERS OF
THE PERITONEUM.
BUT ALSO PATIENTS WHO LIVE IN
LOWER SOCIOECONOMIC STATUS, OR
RURAL AREA, THEY CAN'T GO IN AS
EASILY, THEY CAN GO HOME, THE
CLINICIAN CAN ADJUST IT UP OR
TOWN, TRACKED WITH A WEARABLE
AND GIVE A WARNING.
IF THEY ARE STARTING TO
INITIATE, EXPERIENCE A CYTOKINE
RELEASE SYNDROME, A FLAG CAN GO
UP, THEY CAN GET IN THE CAR,
GET ON I A PLANE TO GET BACK TO
THE CLINIC.
A LOT OF FOCUSING ON HOW THE
BEST SITE OF CYTOKINES TO GO
AFTER SOLID TUMORS.
CELL FACTOR THAT'S ARE STABLE
AND HIGHLY PRODUCTIVE.
BIOCHEMICAL SENSORS.
DART.
THIS IS A LARGE ANNOUNCEMENT WE
RELEASED OUT OF HARVARD MEDICAL
SCHOOL.
DEFEATING ANTIBIOTIC RESISTANCE
THROUGH TRANSFORMATIVE
SOLUTIONS.
BASED ON A WEATHER MACHINE.
THIS IS GOING AFTER ANTIBIOTIC
RESISTANT.
EVERYONE IS FAMILIAR WITH PETRI
DISHES.
HE HAS A SYSTEM WITH TWO
MILLION KHAL -- CHANNELS AND
HE CAN CAPTURE A DIFFERENT
BACTERIUM IN EVERYONE, HE CAN
FISH OR HYPERSPECTRAL IMAGING
WITHOUT 96-98% ACCURACY.
EACH DAY HE LOOKS AT BILLIONS
OF CELLS WHICH PROVIDES
INCREDIBLE THROUGHPUT OF DATA.
AND WITH THIS, THEY CAN DO
THINGS LIKE UNDERSTAND THE
BASIS FOR ANTIBIOTIC
SUSCEPTIBILITY.
WHAT ARE THE PERSISTORS?
WHAT ARE THE SURVIVORS?
ONLY ONE IN 50,000, ONE IN
100,000.
HE HAS ENOUGH TRENCHES TO
IDENTIFY, NOT TO BUILDING TO A
COLONY AND LOSE THE PHENOTYPE,
BUT WHAT MAKES IT A SURVIVE R
YO.
EVEN IN THE PAST FEW WEEKS HE
HAS COME UP, IDENTIFIED NEW
GENES THAT MAY BE RESPONSIBLE
FOR THE PERSISTENCE.
HE IS ALSO COMING UP WITH A
SYSTEM TO MASSIVELY SCREEN FOR
NEW ANTIBIOTIC PEPTIDES.
HE CAN SCREEN, PRODUCER CELLS
NEXT TO THE TARGET PATHOGENS
AND LOOK AT WHICH ONES KILL OFF
THE PATHOGENS, SCREENING
MILLIONS OF DIFFERENT STRAINS
AT THE SAME TIME.
ONCE THAT IS DONE HE IS
OPTIMIZE IT.
THIS IS SOMETHING HE DID BEFORE
WITH SYNTHETIC BIOLOGY CIRCUIT
BUT YOU CAN CHANGE EVERYTHING.
YOU CAN SCREEN MASSIVE
LIBRARIES AT THE SAME TIME.
MILLIONS OF VARIANTS ALL RUN AT
THE SAME TIME TO LOOK FOR AN
OPTIMAL SOLUTION.
LASTLY, ANTIBIOTIC
SUSCEPTIBILITY TESTING.
THIS SYSTEM IS SO PRECISE IT
CAN LOOK AT DOUBLING TIMES, IT
CAN PREDICT DOUBLING TIMES EVEN
BEFORE THE BACTERIUM HAS
FINISHED DOUBLING.
IT HAS PRECISION IN DOUBLING
TIMES IN MILLISECONDS.
HOW THIS IS BEING IMPACTED,
AGAIN ALL SCREENED AT THE SAME
TIME.
THE CONCEPT YOU MAY HAVE SEPSIS
UTI, IN LESS THAN AN HOUR IT
WILL TELL YOU WHICH ANTIBIOTIC
YOU SHOULD BE GETTING.
THESE ARE PROGRAMS THAT HAVE
ALREADY BEEN FUNDED.
RECENTLY WE ANNOUNCED REACT,
RESILIENT EXTENDED AND
AUTOMATED CELLULAR THERAPIES.
A CARRIER THAT CAN CONTROL THE
RELEASE OF THERAPIES FROM
ENGINEERED CELLS, RIGHT?
YOU ARE FAMILIAR -- DID SOME
WORK, BOB LINGER RECENTLY, THE
CONCEPT YOU HAVE A DEVICE, IT'S
IMPLANTED FROM YOUR SMARTPHONE.
YOU CAN SEND A SIGNAL, THAT
SIGNAL TELLS THE BIO ELECTRONIC
DEVICE TO SHINE A LIGHT ON OR A
MAGNETIC FIELD OR ELECTRICALLY
STIMULATE CELLS.
ONCE STIMULATED THEY ARE
ENGINEERED TO RELEASE A THERAPY.
THAT'S CALLED A LIVING PHARMACY.
YOU CAN ALSO THINK OF THE
REVERSE.
I KNOW WENDELL LIM WAS HERE.
MANY HAVE BUILT TRANCE DEUSSERS.
WHEN IT DETECTS A HORMONE OR
CYTOKINE, IT GENERATES A
RESPONSE, BUBBLES, CHANGE IN
THE MEMBRANE POTENTIAL THEN
PICKED UP BY THE BIO ELECTRONIC
DEVICE AND REPORTED TO THE
SMARTPHONE.
THE CONCEPT IS YOU HAVE A NEW
INTERFACE INTO THE BODY.
YOU CAN ARBITRARILY CONTROL
CYTOKINES OR HORMONES OR TRACK
THE SAME COMING OUT OF THE
SYSTEM.
PROPOSERS DAY IS IN A FEW WEEKS
OUT IN DENVER AND ABSTRACTS ARE
DUE AT THE END OF THE MONTH.
LOOKING FOR ANY AND ALL TAKERS
FOR THE REACT PROGRAM.
ALL RIGHT, SO, I THINK THIS IS,
SHOULD BE MY LAST SLIDE.
TECHNICAL AREAS IN HERE.
ALMOST ALL OF THESE HINGE ON
SYNTHETIC BIOLOGY.
LONG-TERM MAINTENANCE OF CELLS
IN VIVO, RIGHT?
YOU ARE TAKING SOME CELLS AND
MAYBE THEY ARE NOT FROM THAT
AREA OF THE BODY.
MAYBE THEY ARE PLANTED SUB
CUTANEOUSLY, HOW DO YOU
MAINTAIN THE VIABILITY IN THAT
NEW ENVIRONMENT.
SOME MAY BE MODIFICATIONS TO
THE CARRIER.
SOME MAY BE INCLUSION OF HELPER
CELLS BUT ALSO SYNBIO HAS A
ROLE.
MANUFACTURER OF STANDARDIZED
CELL LINES.
WE NEED HOME HOMOGENEIC CELL
LINES.
HOW DO WE MAKE THAT MODULAR.
IF I SPEND MILLIONS AND
MILLIONS TO PRODUCE A CELL LINE
THAT WHEN ELECTRICALLY
STIMULATED WILL RELEASE ONE
PEPTIDE HORMONE AND NOW I WANT
TO MAKE THE NEXT, DO I HAVE TO
GO BACK TO SUB ZERO?
I THINK I HAVE A ROBUST CHASSI,
CAN I JUST WALK IN THE GENE TO
GENERATE THE DIFFERENT PEPTIDE.
IMPLANTABLE DEVICE THAT'S
COMMUNICATES WITH THE PATIENT,
THIS IS PROBABLY MORE FOR
DOUBLE E'S BUT ROBUST POWER
MANAGEMENT.
TWO MAIN TRACKS, LIVING THERAPY.
WHAT IS THE BEST WAY TO
STIMULATE A CELL TO RELEASE THE
THERAPY, RIGHT?
ELECTRICAL?
MAKE THE CHOICE, JUSTIFY IT,
AND ENGINEERING FOR THE CELL
AND DEVICE WORK BACK FROM THERE.
SIMILARLY FOR THE LIVING
SENTINEL.
ALL RIGHT.
AND I JUST WANT TO GIVE OUT A
QUICK SHOUT.
I KNOW THERE'S TALK ABOUT
VIRUSES EARLIER.
ANOTHER PROGRAM PROPOSERS DAY,
WE ARE TAG TEAMING IN DENVER,
THIS IS ANDY KILLIANSKI NEW
TECHNIQUES A.I. COMING UP WITH
BETTER VACCINES FOR PATHOGENS,
INSTEAD OF ONESIES, TWOSIES,
GOING AFTER MULTIPLE AT ONE
TIME.
THIS USED TO BE THE
UNIMAGINABLE FUTURE, WE ARE
HOPING FOR YOU TO BRING US YOUR
IDEAS, WHAT IS THE UNIMAGINABLE
FUTURE.
COME WORK WITH US AS A PROGRAM
MANAGER AND HELP US BUILD THAT
FUTURE.
THANK YOU.
[ APPLAUSE ]
>> THANK YOU, VERY ENGAGING
PRESENTATION.
I WAS WONDERING ABOUT THE TYPES
OF PROJECTS FUNDED BY ARPA-H,
DOES IT HAVE TO BE DIRECTLY
SOMETHING WITH A DIRECT
CLINICAL ENDPOINT OR TECHNOLOGY
THAT ENABLES THE BASIC SCIENCES
TO STUDY SOMETHING WITH PO --
POTENTIAL CLINICAL USE, HUMAN
CELL TYPE ATLAS.
I'M NOT SAYING I DID THAT, BUT.
>> Paul Sheehan: YOU ZIGGED AT
THE END THERE.
I WAS ABOUT TO SAY NO.
BECAUSE WE COME AND GO, WE WILL
NEVER BE AN AGENCY TO BUILD A
DATABASE.
BECAUSE WHO IS GOING TO RUN
THAT IN FIVE YEARS WHEN WE ARE
GONE.
HOWEVER, IF THERE IS SOME NEW
TECHNOLOGY THAT CAN INFORM
THOSE DATABASES WE ARE HAPPY TO
BUILD THAT.
IN THIS CASE PEOPLE BUILDUP
PATHOGEN DATABASES, SO THESE
TOOLS WE ARE BUILDING WILL
VASTLY HELP POPULATE THOSE
DATABASES, RIGHT?
THAT SAID, IN GENERAL WE DON'T,
WE'RE NOT REALLY A DISCOVERY
AGENCY, WE ARE A CAPABILITY.
NIH AND OTHERS DO A FANTASTIC
JOB WITH DISCOVERY, NEW
INSIGHTS.
WE WANT TO TAKE THAT AND PUSH
TO A CAPABILITY.
THAT CAPABILITY THEN OPENS UP
NEW FRONTIERS, DOES THAT MAKE
SENSE?
>> I THINK SO, IT STILL SOUNDS
IT'S A LITTLE ON THE EDGE WITH
REGARDS TO WHAT I'M ASKING.
TECHNOLOGIES TO ENABLE
DISCOVERY ARE STILL --
>> Paul Sheehan: IF AT THE END
OF THIS, YOU ARE LIKE OH THIS
IS A GREAT TOOL FOR LEARNING
MORE, NO.
THAT'S NOT REALLY US.
IF THIS TOOL IS OKAY, THIS TOOL
SOLVES THE PROBLEM OF SEPSIS
AND ALSO GENERATES INFORMATION
THAT WOULD BE GOING INTO A
DATABASE, SURE.
>> I SEE, I SEE.
THANK YOU.
I DID HAVE ONE MORE QUESTION
WHICH WAS, MY APOLOGIES, MAYBE
I MISSED THIS BECAUSE I WAS IN
THE RESTROOM AT THE BEGINNING
OF YOUR TALK.
DO YOU TAKE PROPOSALS FROM
ACADEMIC LABS?
>> Paul Sheehan: YEAH.
ABSOLUTELY.
ACADEMIC LABS.
BUSINESSES, INTERNATIONAL.
IF YOU ARE FROM NORTH KOREA, I
DON'T THINK SO, THAT WILL
PROBABLY BE A CHALLENGE.
BUT YEAH, FROM MOST PLACES AND
MOST PEOPLE.
>> GOT IT.
THANK YOU VERY MUCH.
>> SO ONE OF THE FOCUS AREAS
YOU SAID WILL BE PROACTIVE
HEALTH.
SO I'M CURIOUS HOW MUCH YOU SEE
PUBLIC HEALTH AS BEING A
COMPONENT OF THE ARPA-H
PROGRAMS?
>> Paul Sheehan: ALSO, I'M A
PROGRAM MANAGER, I DO MY THING.
THE HEAD OF PROACTIVE HEALTH
HASN'T BEEN ANNOUNCED, THEY
HAVE BEEN HIRED.
THAT IS, I MEAN, WE ARE TRYING
TO THINK OF THE HEALTHCARE
SYSTEM AT LARGE.
IN MANY WAYS.
SO TECHNOLOGIES AND
CAPABILITIES THAT WOULD IMPROVE
HOW THAT FUNCTION ARE ALWAYS
WELCOME.
AND ALSO, WE OFTEN THINK,
ESPECIALLY WITH DARPA LIKE THE
TECHNOLOGY, SO WOULD THE P.M.'S
THAT SHOWED UP LIKE DARSHUNK
AND BARPU, THEY ARE AT THE END,
TRYING TO THINK OF NEW MODELS
FOR PEOPLE TO GET REIMBURSED
FOR RURAL HEALTH.
OR HOW DO WE DO MATERNAL
HEALTH, HOW DO WE BRING
CAPABILITIES TO A RURAL SETTING
TO DO MATERNAL HEALTH WELL.
NOT JUST HERE IS SOME CRAZY
TECHNOLOGY WE AREN'T SURE THAT
WILL WORK.
WE'RE NOT SURE IF THIS POLICY
WILL WORK, WE ARE TRYING TO
FIGURE OUT FAR DOWN THE FIELD.
THEY MAY STILL HAVE WEIRD A.I.
OR OTHER COMPONENTS BUT IT'S
REALLY FARTHER DOWNSTREAM.
TO YOUR APPOINT, I HOPE
IMADDRESSING, IF YOU ARE
THINKING OF THE PUBLIC HEALTH
SYSTEM AND HOW TO DO BETTER AND
REARRANGE SOME THINGS THEY ARE
THINKING THROUGH THAT.
NONE OF THAT HAS BEEN ANNOUNCED.
>> GOOD TO KNOW, THANK YOU.
>> HELLO, THE CONTRAST WITH THE
DARPA PRESENTERS EARLIER WHEN
THEY WERE MAKING NUCLEIC ACIDS
OR PROTEINS FOR MILITARY
PURPOSE.
YOU HAVE THIS MAYBE BUYER,-END
USER READY TO GO WITH THE
MILITARY DEFENSE.
SO HOW EARLY, AND WHAT HAPPENS
WITH THE DOWNSTREAM USERS AND
INVESTMENTS, ARE THERE
MILESTONES IN THEIR PROJECTS TO
ENSURE YOU ARE GETTING BUY-IN
TO TAKE THIS TO THE NEXT STEP.
IT'S SO COMPLICATED IN THE
SPACE.
>> Paul Sheehan: IT'S SO
COMPLICATED.
HONESTLY THIS IS WHAT WE ARE
WORKING OUT RIGHT NOW.
YOU PUT YOUR FINGER RIGHT ON IT.
THE NICE THING ABOUT WORKING
FOR DARPA IS IF YOU ARE
BUILDING A HYPER SONIC MISSILE,
YOU KNOW WHO WILL BUILD IT AND
WHO WILL BUY IT.
NOT SO IN THE AMERICAN
HEALTHCARE SYSTEM.
YOU HAVE TO FIGURE ALL THAT OUT.
I CAN ANSWER FOR MYSELF,
THERE'S A NATURAL TENSION
THERE, IN THAT IF I'M TRYING TO
DO SOMETHING CRAZY ON THE
TECHNOLOGY SIDE I DON'T
NECESSARILY WANT TO BOTHER THE
PERFORMERS DO YOU HAVE A CMS
CODE IN THE FIRST YEAR?
HOW DO I INTRODUCE THAT?
AT THE SAME TIME WE CAN'T GET
TO YEAR FIVE AND SAY, HEY, DO
YOU THINK PATIENTS WILL WANT
THIS?
I TRY TO MAINTAIN A COGNITIVE
LOAD, AT THE RIGHT TIME, LET'S
START THINKING ABOUT IT.
AND SOME THINGS, IF YOU ARE
GOING TO ENGAGE WITH THE FDA,
RIGHT, YOU HAVE TO THINK ABOUT
IN YEAR ONE, THAT'S NOT A YEAR
TWO OR THREE.
SO PART OF MY JOB IS, YOU KNOW,
BRINGING UP THOSE ISSUES,
MAKING SURE THEY ARE TALKED
THROUGH AT THE RIGHT TIME.
>> ONE QUICK QUESTION, MICHELLE
TOOK THE FIRST PART OF IT FOR
ME, SO IT SAVES US SOME TIME.
IT HAD TO DO WITH THE DIAGRAM
OR THE FIGURE YOU SHOWED.
IT HAD THREE OF THE PERFORMERS.
TWO OF THEM NOT SUCCEEDING OR
WASHING OUT AT DIFFERENT POINTS
AND ONE MAKING IT TO THE FINISH
LINE.
DOES A MECHANISM EXIST FOR A
PERFORMER WHO DOES WASH OUT,
DOESN'T MAKE IT TO THE FINISH
LINE FOR WHATEVER REASON, DOES
A MECHANISM EXIST FOR YOU TO
FILTER THAT, SAY TO ONE OF THE
IC'S HERE AT NIH, THEY AREN'T
GOING TO MEET YOUR TIMELINES
BUT SAY UNDER AN EXTENDED
TIMELINE, FURTHER FUNDING, MORE
FLEXIBILITY?
>> Paul Sheehan: I HAVE
CERTAINLY SENT PEOPLE OVER.
ESPECIALLY IF THERE'S LIKE A
SUBSET.
HEY YOU REALLY SHOULD GO TALK
TO NIBIB, THEY WILL LIKE THIS
PART OF IT.
THERE HAVE ALSO BEEN ONES WHERE
THIS DOESN'T WORK, BUT THIS
PART OF YOUR EFFORT, WE ARE
GOING TO FORM A COMPANY.
WE ACTUALLY WILL PAY FOR AN
ENTREPRENEUR TO PAY FOR THAT
$250K, WE WILL PAY FOR THAT
ENTREPRENEUR TO PICK UP THAT
TECHNOLOGY AND DOING THE SAME
HERE.
EVEN THOUGH WE CUT PEOPLE, WE
TAKE CARE OF THE STUDENTS.
WE DON'T WANT ANYBODY TO GET
BURNED.
IF WE CUT THEM, THE STUDENTS
ARE STILL TAKEN CARE OF, WE
NEGOTIATE HOW LONG.
I HAVE CERTAINLY CUT PEOPLE,
BUT I DON'T THINK ANYONE HAS
EVER BEEN SURPRISED.
I THOUGHT IT WAS A GOOD IDEA,
YOU THOUGHT IT WAS A GOOD IDEA,
BUT IT'S NOT WORKING.
WE WILL END IT, OFFRAMP.
BUT IF THEY WORKED HARD, THEY
CAN COME TO ME THE NEXT DAY AND
CONSIDER THEIR IDEAS.
I THOUGHT IT WAS A GOOD IDEA
TOO, IT'S JUST NOT WORKING.
>> THAT WAS THE INTERESTING
PART FOR RISK MITIGATION, YOU
AREN'T SACRIFICING THEIR
FUTURES FOR WHATEVER IS NEEDED
IN THE FUTURE.
>> Paul Sheehan: WE TRY TO GET
TO AT LEAST THE NEXT PAPER, THE
NEXT SEMESTER, WHATEVER MAKES
SENSE.
HAVE I ANSWERED ALL QUESTIONS?
ALL RIGHT.
THANK YOU.
[ APPLAUSE ]
LET'S GET IT GOING.
OUR LAST SESSION HERE, IT
STARTS OFF WITH A WONDERFUL
TALK ABOUT DR. MANU PLATT.
CURRENTLY DIRECTOR FOR THE BETA
CENTER.
HE COMES TO US BY WAY OF
BACHELOR'S IN BIOLOGY FROM MORE
HOUSE AND POST DOC, HE IS A
REALLY COOL GUY AND NATIONALLY
RECOGNIZED LETTER IN DEIA AND
IMPLEMENTING IT IN STEM.
I WILL STOP AND LET MANU TALK
ABOUT THE BETA CENTER.
>> Manu Platt: THANKS FOR
HAVING ME AT THE END OF YOUR
SYNTHETIC BIOLOGY MEETING.
I WAS UP IN 2023 THEN HERE.
WHEN WE TALK ABOUT NIH WE THINK
ABOUT THE MONEY WE GIGANTE --
GIVE TO THE OUTSIDE WORLD BUT
THERE ARE MANY -- I'M HERE TO
TALK ABOUT THE BETA CENTER,
CENTER FOR BIO ENGINEERING
TECHNICAL ASSOCIATION.
-- TECHNOLOGY ACCELERATOR.
THERE ARE GREAT OPPORTUNITIES
HERE WITH THE INTRAMURAL
RESEARCH PROGRAM AND ONE OF MY
COLLEAGUES HAVE JOINED US IN
THE AUDIENCE WE WILL USE HIM
FOR RADIO LABELING.
THE I IN NIH IS PLURAL, THE
NATIONAL INSTITUTES OF HEALTH.
MOST OF THOSE CENTERS DO HAVE
INTRAMURAL RESEARCHERS HERE ON
THE BETH BETHESDA CAMPUS.
WE TRAIN POST DOCS, POST
BACCALAUREATE AND POST GRAD
STUDENTS AS WELL.
I AM IN NIBIB, A LITTLE MORE
THAN 20 YEARS.
WE ARE THE NATIONAL INSTITUTE
OF BIOMEDICAL ENGINEERING AND
BIO ENGINEERING.
UNDER BRUCE TROMBERG.
BEFORE I GOT HERE, HE SAID WE
SHOULD BRING TOGETHER ON CAMPUS
TO CREATE A COMMUNITY OF
BIOMEDICAL ENGINEERS.
FIRST THERE'S GREAT WORK WE CAN
DO TO CROSS COLLABORATE AND
CONNECT WITH EACH OTHER.
BUT ALSO THE NIH HAS A
WONDERFUL CLINICAL CENTER ON
THE CUTTING EDGE OF MEDICAL
TECHNOLOGY AND MEDICAL BREAK
THROUGHS AND ALSO DEVELOPING
EQUIPMENT, ASSAYS ET CETERA BUT
IN THE INTRAMURAL WE ARE NOT
LIKE YOUR UNIVERSITIES.
I'M SURE YOU DON'T HAVE SILOED.
WE ARE TRYING TO BUILD CROSS
CONNECTIONS AMONG THE DIFFERENT
INSTITUTES ON CAMPUS.
TO BUILD THIS MODEL FOR
DISCIPLINE ENGINEERING RESEARCH
AND CLINICAL TRANSLATION.
THERE'S A NUMBER OF DIFFERENT
TOPICS THAT ARE HAPPENING ON
CAMPUS THAT WE LIKE TO BRING
TOGETHER.
PLUS SOME NEW ENGINEERING
TOPICS BY BRINGING NEW HIRES
AND BRINGING FROM THE OUTSIDE.
CENTRAL TO THE BETA COMMISSION,
IS EXPANDING DIVERSITY, EQUITY
AND INCLUSION IN THE NIH'S
INTRAMURAL PROGRAM.
WE ARE TRYING TO BUILD A
COMMUNITY OF ENGINEERS AND
BIOMEDICAL ENGINEERS ON CAMPUS.
SO FAR WE HAVE GOTTEN 80
INTERESTED.
WE ARE CUTTING ACROSS 16
DIFFERENT INSTITUTES SO FAR.
WE ARE GETTING EVERYBODY
TOGETHER.
SO WE HAVE BEEN HAVING A SERIES
OF MEET AND GREETS AND OTHER
THINGS.
WHEN WE ASK WHAT ARE THE CORE
CAPABILITIES THEY PROVIDE IN
THEIR LAB THEY WOULD BE WILLING
TO SHARE OR WORK WITH OTHER
INVESTIGATORS I WAS SURPRISED
BY THE AMOUNT OF DIFFERENT
TOOLS THEY WERE WILLING TO
SHARE AND ALREADY BEEN
GENERATING AND USING.
BEYOND THAT I LEARNED ABOUT THE
NUMBER OF INVESTIGATORS WORKING
IN SIMILAR SPACES WHO HAVE NOT
YET MET EACH OTHER.
AGAIN, IT'S ALL ABOUT MEETING
INVESTIGATORS TO COLLABORATE.
THESE ARE THE MORE TRADITIONAL
TOOLS, PEOPLE ARE DEVELOPING 3*
D ORGANOTYPEIC TUMOR.
ENERGY METABOLISM.
AIR THEY BREATHE, CO THEY CAN
DO ALL THAT OVER A 24-48 HOUR
PERIOD AND EVEN LONGER IF NEED
BE.
WHO DOESN'T WANT ACCESS IF YOU
DO METABOLIC STUDIES.
THERE'S STRONG NEURO
CAPABILITIES ON THE OUTSIDE WE
HAVE THOSE IN HERE.
THERE ARE PEOPLE DEVELOPING AND
IMPROVING THEIR MACHINE
LEARNING, COMPUTER VISION AND
DEEP LEARNING.
BUT THERE'S A STRONG POOL TO
BRING MORE OF THESE INDIVIDUALS
TO CAMPUS.
TO THE TRAINEES LISTENING OR IN
THE AUDIENCE IF YOU ARE
INTERESTED IN COMING TO AN
EXCITING PLACE TO DO YOUR POST
DOC, THE NIH IS A GREAT PLACE
AND COMPLETELY COVER YOUR
HEALTHCARE WHILE A FELLOW AND
TRAINEE.
SELF-PITCH.
WE ARE IN THE IMAGING INSTITUTE.
THERE ARE A NUMBER OF DIFFERENT
IMAGING MODALITIS.
MR PET, PT CT SCANS.
OTHER WAYS TO TRACK THEM
THROUGH SMALL ANIMALS AND
PEOPLE ARE GETTING HUMAN
PROTOCOLS AS WELL.
I THINK THAT'S THE BIGGEST DRAW
AND MOST EXCITING THING IS THE
CLINICAL CENTER AT NIH.
IT'S LARGE, BUILDING 10, YOU
WILL BUMP INTO IT ON THE WAY
OUT.
THERE ARE LOTS OF CLINICAL
TRIALS AND WAYS TO TRANSLATE
YOUR WORK HERE ON CAMPUS.
WE ALSO NEED TO BE RECRUITING
AND TRAINING STUDENTS, WE WANT
YOUR STUDENTS.
THERE'S THESE WONDERFUL SUMMER
INTERN PROGRAMS IF YOU WOULD
LIKE TO SEND TO MEET A
PROFESSOR AND ESTABLISH
COLLABORATION WHEN THEY GO
BACK, WE HAVE OUR SUMMER
INTERNSHIP PROGRAM.
NIBIB SPECIFICALLY SPONSORS THE
BIOMEDICAL ENGINEERING SUMMER
INTERNSHIP UNDER THE BETA
CENTER.
FOR THOSE STUDENTS WHO
GRADUATED WHO WANT MORE
TRAINING BEFORE THEY DO AN
Ph.D., MD OR MD Ph.D..
ONE OR TWO YEARS, HEALTHCARE IS
COVERED WHILE WORKING HERE ON
CAMPUS.
THESE ARE GREAT OPPORTUNITIES
NIH'S OFFICE OF INTRAMURAL
TRAINING HELP STUDENTS PREPARE
APPLICATION, PREPARE M-CAT,
PREPARE AS LIFE AS A STUDENT
THOSE ARE ALL FREE TO STUDENTS.
NSF IS A GOOD FRIEND OF OURS,
AS YOU CAN IMAGINE.
THEY HAVE A WONDERFUL INTERN
PROGRAM.
FOR THOSE INTERESTED
PARTICULARLY IN BIO ENGINEERING
WORK, IF YOU ARE A GRAD STUDENT
FINISHING, OR NOT EVEN
FINISHING, BUT THERE'S A PLACE
IN YOUR PROJECT YOU CAN SPEND
3-6 WEEKS WORKING IN A LAB ON
THE NIH CAMPUS, IT'S A GREAT
WAY TO UNDERSTAND WHAT THE
INTRAMURAL PROGRAM HERE.
WE HAVE INVESTIGATORS HERE
LOOKING FOR PEOPLE WITH THE
SKILL SETS THAT YOU HAVE, OKAY?
WE ARE ALSO LOOKING, I'M HIRING
POST DOC FELLOWS FOR OTHERS AND
LOOKING FOR WAYS FACULTY
INTERESTED IN DOING SABBATICALS
TO ALSO COME ALONG ON CAMPUS,
MAKE FRIENDS, ESTABLISH
COLLABORATIONS.
WE ARE GREAT TO WORK WITH YOU,
WE CAN COLLABORATE WITH YOU ON
YOUR GRANT BUT WE DON'T TAKE
MONEY FROM YOU FROM YOUR GRANT,
AREN'T WE GREAT PEOPLE?
I CARE A LOT ABOUT DEIA.
STARTED IN LATE FEBRUARY BUT WE
STILL PUT TOGETHER A SUMMER
RESEARCH PROGRAM, WE HAD SIX
STUDENTS FROM HBCU'S, DEAF
SERVING INSTITUTION AT
GALLAUDET.
WE ARE ABOUT EXPANDING
BIOMEDICAL ENGINEERING.
BRING OTHERS TO IT FROM ALL THE
OTHER DISCIPLINES THEY COULD BE
BIOMEDICAL ENGINEERS AS WELL.
AND THEY PLAYED WITH THE LONG
RUNNING BCIP PROGRAM.
THERE'S A PICTURE OF OUR
FEARLESS LEADER, BRUCE
TROMBERG, TALLER THAN ME, STILL
HUMBLING MYSELF OVER THAT EVERY
DAY WE HAVE A MEETING.
AND OUR WONDERFUL DIRECTOR,
NICHOLE MORE BEGAN.
-- MORGAN.
I'VE BEEN BUSY ALL OF OCTOBER
AS YOU CAN SEE, I'M IN TOWN FOR
A WEEK.
WE ARE RECRUITING FROM DIVERSE
POPULATIONS, THE LAST ONE IS
SBRCMS IN NOVEMBER.
I'M TELLING YOU ALL TO TELL
YOUR FRIENDS THAT WE ARE HERE.
BUT IN THE FUTURE, WE ALSO
AGAIN, TRYING TO GET THE IRP,
INTRAMURAL RESEARCH PROGRAM TO
BIO ENGINEERS IN THE COMMUNITY.
NEXT YEAR THE ANNUAL MEETING IS
HELD IN BALTIMORE, MARYLAND
RIGHT UP THE WAY.
BEFORE THAT MEETING WE WILL
HAVE ON THE TUESDAY BEFORE THE
CONFERENCE STARTS, PEOPLE
BROUGHT TO CAMPUS AND WE WILL
HAVE SESSIONS ON THE NIH CAMPUS
FOR PROFESSORS AND GRAD
STUDENTS AND POST DOCS, COME
TO CAMPUS, SEE WHAT WE ARE
DOING, ESTABLISH CONNECTIONS,
WE WILL HAVE TALKS AND
INTERACTIONS.
COME ONE DAY EARLY AND YOU CAN
COME ON CAMPUS.
WE WILL ALSO BRING OTHER AGENCY
PARTNERS, FDA, I KNOW, IS
INTERESTED AND OTHER PEOPLE.
GETTING THE WORD OUT NOW, IN A
YEAR.
SEVERAL INSTITUTES ARE LOOKING
TO BE INVOLVED.
PLEASE, THINK ABOUT THAT FOR
YOU AND ALSO FOR YOUR TRAINEES.
BUT WHAT ELSE WE ARE OFFERING
TO OUR INTRAMURAL RESEARCH
PROGRAM, WE WANT TO LOWER THE
BARRIER TO ENTRY INTO USING
ENGINEERING PRINCIPLES AND
PRACTICES IN THEIR RESEARCH.
THEY CAN READ A PAPER AND SEE
SOMEONE MADE THIS NANO PARTICLE
WITH THE DELIVERY THING, I
DON'T KNOW, I DON'T KNOW HOW TO
MAKE THAT.
WE WILL OFFER CONCIERGE SERVICE
FOR BETA SERVICE AFFILIATES TO
MEET WITH THE TEAM WHERE THE
INVESTIGATOR WILL SAY WHAT
THEIR NEEDS MIGHT BE AND WE CAN
HELP THEM NARROW THE PROBLEM TO
A WORKABLE PLACE AND HELP THEM
GET STARTED GOING DOWN THOSE
DIRECTIONS.
NIBIB ALSO HAS THREE NIH-SHARED
RESOURCES.
IDEAS GROUP.
THEY CAN MAKE BOXES THAT WATCH
YOUR MOUTH AND CONTROL --
FANTASTIC.
ADVANCED IMAGING AND MICROSCOPY
RESOURCE.
THEY ARE AMAZING, AS WELL AS
WITH THE PROCESSING OF YOUR
SAMPLES AND THE A.I. AND DATA
GENERATION.
MY DEPUTY DIRECTOR NICHOLE
MORGAN RUNS THE BIOMEDICAL AND
ENGINEERING PHYSICAL SCIENCE.
SOME SOFTER MATERIALS AND HELP
WITH ALL OF THOSE THINGS AND
AGAIN MY GOOD BUDDY DALE IS
RADIO CHEMIST, YOU CAN RUN
MODELS LIVE IN STUDIES.
WE HIRED COMPUTATIONAL
BIOLOGIST.
WE ARE TRYING TO PROVIDE TOOLS
AND SKILL SETS TO LOWER THOSE
BARS TO MAKE EVERYBODY HERE
LOVE BIOMEDICAL ENGINEERING AND
BRING YOUR FRIENDS AS WELL.
M COULDING IN -- COMING IN
THE FUTURE WE WILL HAVE A MAKER
SPACE ON CAMPUS, THE FIRST EVER.
WE HAVE A FEW SPACES THAT
ALREADY HAVE THE MACHINERY AND
OTHER PLACES APPLY.
THE DIFFERENCE WITH THE MAKER
SPACE, WE WOULD TRAIN THE
RESEARCHERS IN YOUR GROUP ON
HOW TO USE A PIECE OF EQUIPMENT
AND THEY WOULD COME IN AND
CONTINUE TO MAKE THE
MODIFICATIONS AND DEVELOP THE
TECHNOLOGY.
SO REALLY EXCITED ABOUT THIS.
THIS IS ALL THE THINGS
HAPPENING IN THE BETA CENTER.
A MENU TO CLOSE OUT WITH WHAT I
TALKED ABOUT.
FIRST AND FOREMOST BUILDING
THIS IMAGING AND ENGINEERING
COMMUNITY ON CAMPUS.
IF ENGE ENGINEERS ARE OUT
THERE AND WANT TO COME, YOU
WILL NOT BE ALONE.
RELYING ON OUR EXTRAMURAL
PARTNERS, SEND YOUR STUDENTS,
POST DOCS, PROFESSORS.
BUILDING COLLABORATION, SOON WE
WILL HAVE OUR MAKER SPACE.
YOU CAN DO THAT HERE.
THANK YOU VERY MUCH FOR THIS
TIME TO SHARE.
IF THERE'S TIME FOR QUESTIONS I
WILL TAKE ONE OR TWO OTHERWISE
YOU CAN CATCH ME WHEN THIS IS
ALL OVER.
THANK YOU.
[ APPLAUSE ]
>> ONE QUICK ADMINISTRATIVE
NOTE, I WAS TOLD ANY POSTERS
THAT ARE STILL UP, THEY SHOULD
PROBABLY BE TAKEN DOWN,
PROBABLY AFTER THE NEXT COUPLE
OF TALKS.
SO PLEASE DON'T LEAVE THEM
HERE, TAKE THEM HOME WITH YOU.
WHAT WE HAVE ON DOCKET HERE IS
TWO FINAL LIGHTNING TALKS.
THE FIRST IS BY DR. SARA
MOLINARI, ASSISTANT PROFESSOR
AT UNIVERSITY OF MARYLAND,
COLLEGE PARK.
WILL TALK ABOUT "DE NOVO
ENGINEERED LIVING MATERIALS
FROM BACTERIA"
SARA?
[ APPLAUSE ]
>> Sara Molinari: HI, EVERYONE.
THANK YOU FOR STICKING AROUND,
YOU ARE THE BRAVE FOR STAYING
FOR THE LAST TALKS.
I JUST STARTED IN MY LAB AT
UNIVERSITY OF MARYLAND IN JULY.
MY RESEARCH IS BRAND NEW.
MOST OF WHAT I WILL TALK ABOUT
IS PART OF POSTDOCTORAL WORK, I
WILL GIVE YOU INSIGHT WHAT I
WILL DO NEXT.
THIS IS PROBABLY A LITTLE
DIFFERENT OF THE TALK THAT YOU
HEARD UNTIL NOW, BECAUSE WE ARE
MOSTLY GOING TO TALK ABOUT
BACTERIA.
AND I HOPE THAT BY THE END OF
THIS PRESENTATION, YOU ARE AS
CONVINCED AS I AM BACTERIA IS
SUPER COOL THAT HAS LOTS OF
POTENTIAL FOR BIOMEDICAL
APPLICATION.
OF COURSE THIS AUDIENCE NEEDS
NO INTRODUCTION WHY BIO
MATERIAL ARE SO INCREDIBLY
USEFUL FOR BIO MEDICINE, THEY
COVER A VAST ARRAY OF
APPLICATION.
BECAUSE OF THIS NEW MATERIAL
THAT WE CAN ACTUALLY DELIVER A
LOT OF NEW AND NOVEL
THERAPEUTICS LIKE DRUG
DELIVERY, MEDICAL IMPLANTS.
WOUND HEALING, BUT ALSO NEW
SURFACES THAT PREVENT THE
FORMATION OF BIO FILM TISSUE,
SCAFFOLD THAT WILL ALLOW THE
FORMATION OF ORGANOIDS AND SO
FORTH.
DESPITE THE GREAT ADVANCES IN
THIS FIELD, IN THE LAST DECADE
REALLY EXPLODED, THERE'S STILL
ONE THING WE ARE NOT REALLY
GOOD AT.
HAVING A MATERIAL THAT DOES A
LOT OF THINGS AT THE SAME TIME.
USUALLY BIO MATERIAL ARE
ENGINEERED FOR ONE PURPOSE AND
THEY ARE REALLY GOOD AT THAT
ONE THING.
THEY HAVE EXCELLENT MECHANICAL
PROPERTIES, BIO COMPATIBILITY
BUT IT'S VERY DIFFICULT THAT
ONE MATERIAL CAN COVER A BUNCH
OF DIFFERENT FUNCTIONS.
TO GIVE YOU AN EXAMPLE OF HOW
REALLY TRICKY THIS PROPERTY IS,
THINK ABOUT WOUND DRESSING.
THIS AN ACTIVE FIELD.
IMAGINE IF YOU HAVE WOUND
DRESSING THAT DOESN'T ONLY
MECHANICALLY PROTECT THE WOUND
BUT PREVENTS FORMATION OF
BIOGENIC BIO FILM, PREVENTING
SCARRING.
THIS IS EXTREMELY ACTIVE
RESEARCH AND THERE'S STILL NOT
A FINAL SOLUTION FOR THIS
PROBLEM.
IN THE SAME LINE OF THOUGHT
IMAGINE YOU COULD HAVE
PACKAGING THAT TELLS IF THERE'S
TOXIN IN THE FOOD OR CLOTHES IN
THE PHYSIOLOGY OF THE HUMAN
BEING.
MULTI-FUNCTIONALITY CAN OPEN A
LOT OF DIFFERENT POSSIBILITY, A
LOT OF DIFFERENT APPLICATION IN
THE FIELD OF BIO MEDICINE.
OF COURSE THE REASON WE STILL
DON'T HAVE A LOT OF
MULTI-FUNCTIONAL MATERIAL, IT'S
REALLY NOT EASY TO ENGINEER.
WE ARE LOOKING FOR A NEW
METHOD, NEW IDEAS TO ACTUALLY
ENGINEER MULTIPLE FUNCTION IN
BIO MATERIAL.
IF YOU ARE LOOKING AROUND,
MATERIAL THAT ARE ALREADY
MULTI-FUNCTIONAL YOU REALLY
DON'T NEED TO LOOK FAR BECAUSE
LIVING MATERIAL ARE ALREADY
HAVE A VAST ARRAY OF BIOLOGICAL
FUNCTION.
THEY CAN PROCESS MULTIPLE
INPUTS WITH MULTIPLE OUTPUTS AT
THE SAME TIME.
AND THEY ALSO HAVE A
COMBINATION OF PHYSICAL AND
MECHANICAL PROPERTIES THAT
SUPPORT THEIR FINAL PURPOSE.
MORE OF THAT, LIVING MATERIAL
THEY GROW WITH MINIMAL ENERGY
INPUT.
THEY JUST GROW FROM CELLULAR
CELLS, THEY DON'T NEED HARSH
CHEMICAL OR SPECIALIZED
FACILITY OR PRESSURE, NOTHING
LIKE THAT.
AND ALSO BECAUSE OF THEIR
ABILITY OF SELF-ASSEMBLING THEY
ALSO SELF-REPAIR, HIGH
LONGEVITY AND VERY LOW
MAINTENANCE COSTS.
SO DESPITE THE BROAD VARIETY OF
LIVING MATERIAL, LIKE FOR
EXAMPLE, THE HUMAN BODY,
ORGANS, PLANTS, SOIL, THEY ALL
SHARE A VERY SIMILAR STRUCTURE.
THEY ARE SELF-AMENDED IN BIO
LOGICAL MATRIX.
THE SELF-PRODUCED BIO MOLECULAR
MATRIX CONTROLS THE FINAL
PHYSICAL AND MECHANICAL
PROPERTIES.
SO WHAT I'VE DONE, I'M TRYING
TO REENGINEER THIS PROCESS.
LIKE FROM SCRATCH IN A CELL,
WHERE THE CELL HAS A
GENETICALLY ENCODED SYNTHETIC
MATRIX, BUT AT THE SAME TIME
ALLOWS THE CELLS TO REACH THE
MARKER CELL, SO ORGANIZE
HIERARCHICAL AGGREGATION OF
CELLS AND ALSO CONTROL THE
FINAL PROPERTIES OF THIS
MICROSCOPIC AGGREGATE.
SO I STARTED FROM A VERY
PECULIAR BACTERIA, THE PRESENCE
OF A SURFACE LAYER THAT
SURROUNDS THE ENTIRE OUTER
SURFACE OF THE CELL.
THIS SURFACE LAYER IS MADE OF
ONE SINGLE CALLED THE RSA.
(CAULOBACTER CRESCENTUS)
IT MAKES SURE IT DOESN'T FLY
AWAY.
DOMAIN THAT GIVES THE FINAL
THREE DIMENSIONAL SHAPE AND
SECRETION TAG.
SO THE SECRETION TAG WAS
PREVIOUSLY IDENTIFIED AS
SELF-AGGREGATING DOMAIN.
IN ORDER FOR THIS AGGREGATION
TO HAPPEN, IT HAS TO BE FREE
FROM THE SECONDARY STRUCTURE
THAT IT REACHES AT THE END.
WHAT WE DID WITH A SINGLE
GENETIC MODIFICATION, WE INSERT
NON STRUCTURAL DOMAIN, THIS IS
AN ELASTIC POLY PEPTIDE DOMAIN.
WE COMPLETELY UNFOLDED ON THE
PROCESS OF THE CELL.
WE EXPOSE, WE COVER EVERY CELL
WITH A STICKY LAYER, RIGHT?
THE CELLS BECOME STICKY.
SO THE RESULTS OF THE
STICKINESS IS THAT WHEN WE GROW
THE CELL, THE STATE OF GROWING
ITSELF AGGREGATES INTO
MICROSCOPIC MATERIALS.
THIS IS A TYPICAL FLASK, EVEN
BOWL IS ABOUT HALF A CENTIMETER.
THIS IS THE BIGGEST AGGREGATION
OF BACTERIA EVER ACHIEVED.
AND WE ACTUALLY IMAGE ALL THE
STRUCTURE OF THIS MATERIAL,
LIKE IN BLUE YOU SEE THE POLY
CELLULAR MATRIX, IN YELLOW YOU
SEE THE CELL, THIS MATRIX
PERMEATES THE ENTIRE STRUCTURE
OF THE LIVING MATERIAL THAT
GOES FROM SURROUNDING EVERY
SINGLE CELL TO PERMEATING THE
ENTIRE MICROSCOPIC STRUCTURE.
WE ALSO OBSERVE VERY PECULIAR
HOMOGENEITY AND INTERMEDIARY
MICROFICATION LEVEL.
I WILL BE HAPPY TO COMMENT MORE.
A SINGLE GENETIC MODIFICATION
IS ABLE TO ORGANIZE CELLS OVER
FOUR ORDERS OF MAGNITUDE SO WE
REACH THE -- OF SCALE.
VERY INTERESTINGLY BECAUSE THIS
IS EVERYWHERE IN THE STRUCTURE
LIKE WE SEE HERE, WHAT WE
HYPOTHESIZE BY CHANGING WE
SHOULD BE ABLE TO SIGNIFICANTLY
EFFECT THE FINAL PROPERTY OF
THE MATERIAL.
AND IN FACT, IF YOU LOOK AT
HERE, WE CREATED THREE
DIFFERENT VERSION OF THIS
MATRIX.
I DON'T KNOW IF IT'S OBVIOUS
FROM THIS PICTURE, BELIEVE ME
THIS PICTURE, THEY LOOK VERY
DIFFERENT FROM EACH OTHER.
YOU CAN TELL THERE'S A
DIFFERENCE.
ONE OF THE MAJOR DIFFERENCE FOR
EXAMPLE, IF YOU REMOVE THE
ANCHOR AND THE PROTEIN GETS
SECRETED FROM THE CELL, YOU
DON'T SEE HIGH DENSITY OF THE
CELLS YOU SEE IN OTHER TWO
MATERIALS.
SO WE UNDER UNDERSTOOD MUCH
BETTER WAY THAN SECRETION TO
CREATE MATERIAL THAT HAVE A
HIGH DENSITY OF CELLS.
MORE IMPORTANTLY, WHEN YOU
MEASURE THE MECHANICAL PROPERTY
OF THIS MATERIAL, WE SHOW THAT
THE MODULATION IS PRETTY
SIGNIFICANT.
WE HAVE OVER 25 FOLD DIFFERENCE.
THAT IS THE BIGGEST DIFFERENCE
THAT HAVEN'T BEEN ACHIEVED IN
THE FIELD.
ONLY ACHIEVED THROUGH GENETIC
MODIFICATION, THERE'S NO
MANIPULATION OF THE MATERIAL
WHATSOEVER.
ONCE WE WERE DONE, WE PLAYED
QUITE A BIT WITH THEM TO SHOW
WHAT THEIR POTENTIAL REALLY IS.
WE SHOW THAT WE COULD ACTUALLY
TAKE THEM OUT FROM THE LIQUID,
LIVE WITH NO ANTIBIOTIC AND PUT
IT BACK IN MEDIA AND GROW NEW
MATERIAL.
THIS IS VERY SIGNIFICANT ONLY
BECAUSE WE HAD FUN DOING THAT,
BUT BECAUSE IMAGINE IF YOU CAN
TURN THIS MATERIAL INTO
THERAPEUTICS, THE
TRANSPORTATION AND STORAGE OF
THE MATERIAL WILL NOT REQUIRE
ANY REFRIGERATION WHATSOEVER OR
ANY PARTICULAR FACILITY.
SO THEY CAN BE STORED AT ROOM
TEMPERATURE AND THIS MATRIX
PROTECTS THE CELL FROM
DESICCATION SO WHEN YOU
REINKNOCK IO RANCHO --
RE-INOCULATE AND SELF-ASSEMBLE.
THIS COULD BE SOMETHING LIKE
TOOTHPASTE, JUST TO GIVE YOU AN
IDEA.
AND ONE OF THE THINGS THAT WE
HAVE SEEN IS THAT WE CAN
ACTUALLY INCORPORATE INORGANIC
POWDER, GLASS POWDER IN THE
FORM OF A VERY STRONG STRUCTURE.
OF COURSE AFTER A MONTH THE
CELLS ARE WELL DEAD INSIDE THE
MATERIAL, SO THE MATERIAL ISN'T
LIVING ANY MORE, BUT THIS IS
LIKE A SELF-PRODUCING CEMENTING
AGENT THAT CAN REPRODUCE
ANYWHERE WITH NO NEED FOR
SPECIALIZED EQUIPMENT.
THERE ARE TWO THINGS THAT CAN
BE ACHIEVED.
WHEN WE TALK ABOUT BIOLOGIC
PROPERTY, WE AREN'T JUST
TALKING ABOUT WHAT WE CAN
ENGINEERING BUT WE CAN CHOOSE
BACTERIA THAT ALREADY DO
SOMETHING WE ARE INTERESTED IN,
FOR EXAMPLE, IN BIO MEDICINE WE
CAN THINK ABOUT PROBIOTICKS.
OR USE TO ENCODE NATURAL
FUNCTION THAT WOULD ALLOW TO
POTENTIATE.
WE CAN MODULATE THE PHYSICAL
AND MECHANICAL PROPERTY, NOT
ONLY WHAT WE ALREADY SHOW SO WE
CAN MODULATE VISCOSITY BUT
SURFACE ADHESION OR -- AND
ELECTRICAL CONDUCK TIVITY.
SO WHY, IN SUMMARY, ARE THE
NOVEL ELM'S SO TRANSFORMATIVE
AND WHICH ARE THE APPLICATION
WHERE THEY COULD BE MORE
RELEVANT.
FOR ONCE THEY INCREASE THE
LOCAL CONCENTRATION OF CELLS
BECAUSE THIS MATERIAL ARE
EXTREMELY CELL-DENSE.
THEY ALSO INCREASE THE PER SIS
STEN PERSISTENCY.
THEY CAN ADHERE TO TISSUE, THEY
SELF-REGENERATE AND SELF-REPAIR.
SOME IS FOR EXAMPLE TO USE THEM
AS PROBIOTICS WE KNOW ONE
OBSTACLE USING PROBIOTICS IS
THEY HAVE SCARCE AND
UNPREDICTABLE -- OF THE
INTESTINE.
IF YOU CAN ENGINEER BETTER
PERSISTENCY AND HIGHER -- OF
CELLS IT COULD BE POTENTIATED.
IT'S ALSO DIFFICULT TO STUDY
WHAT THESE PROBUY OTICS DO.
WE ARE AVERAGING PEOPLE TO HAVE
A MASSIVELY-DIFFERENT
COLONIZATION LEVEL.
SO WHAT WE SEE IS ON AVERAGE
WITH HIGH STANDARD DEVIATION.
SO THIS COULD ALSO BECOME A
TOOL TO STUDY WHAT ACTUALLY
PROBIOTICS DO IN THE HUMAN BODY.
IN THE SAME WAY, THESE TOOLS
CAN BE USED IN AGRICULTURE TO
FAVOR THE INTERACTION WITH
ENGINEERED CELLS AND PLANTS
WHICH IS CURRENTLY A MAJOR
LIMITATION IN THE APPLICATION
OF SYNTHETIC BIOLOGY IN
AGRICULTURE.
EVEN IF WE ENGINEER SYMBIOTIC
RELATIONSHIP IT'S PHYSICALLY
HARD TO KEEP THE BACTERIA NEXT
TO THE PLANT.
WITH THOSE IDEAS IN MIND, I
THANK YOU FOR YOUR ATTENTION
AND I WELCOME ANY QUESTIONS.
[ APPLAUSE ]
>> FOR THE PROBIOTIC
APPLICATION, I'M CURIOUS, DO
YOU KNOW WHETHER THE AGOCATION
OF THESE BACTERIA COULD, OR
DOES ENHANCE BACTERIAL
CONJUGATION DELIVERY METHODS?
>> Sara Molinari: THERE'S NONE,
THAT I KNOW OF.
THIS HAS NOT EVER BEEN OBSERVED.
IT IS KNOWN THAT BACTERIA
AGGREGATION ENHANCE THE
PROBIOTIC POTENTIAL.
THEY ARE USUALLY BETTER BECAUSE
THEY STICK LONGER IN THE
INTESTINE AND BY AGGREGATING
THEY CAN BE PERSISTENT IN THE
INTESTINAL TRACK.
>> I WAS WONDERING WHEN
CAULOBACTER --
>> Sara Molinari: THEY DIE
QUICKLY BUT IN THE MASS SPEC WE
HAVE SEEN THEY CAN SURVIVE UP
TO THREE WEEKS.
>> WOW.
THANKS.
>> VERY INTERESTING TALK, YOU
CAN SEE ME ENJOYING IT.
QUESTION, IS THIS MATRIX IS
SUSCEPTIBLE.
DO YOU KNOW WHICH COULD BREAK
IT DOWN?
>> Sara Molinari: NO, I WOULD
BE HAVE INTERESTED TO FIND THAT
OUT.
WHAT MY LAB WILL DO IS
IDENTIFYING THE DESIGN RULE FOR
THE APPLICATION OF THE
MATRIXES, SO WE WILL TEST
VARIETY OF DIFFERENT GENETIC
PARTS THAT CAN CONTRIBUTE TO
GIVE DIFFERENT FUNCTION.
THIS IS A VERY NICE SPACE TO
LOOK INTO.
>> JUST A QUICK QUESTION.
WHAT IS THE MINIMUM DIAMETER
THAT YOU CAN EXTRUDE THIS
MATERIAL THROUGH?
>> Sara Molinari: SORRY, THE
MINIMUM DIAMETER?
>> YEAH, I THINK YOU SAW
EXTRUSION THROUGH SYRINGE, WHAT
IS THE MINIMUM DIAMETER YOU ARE
USING, OR CAN YOU GO TO?
>> Sara Molinari: UNFORTUNATELY
I DON'T HAVE A QUANTITATIVE
ANSWER.
WE ALSO EXTRUDE SYRINGE WITH A
NEEDLE, I WOULD SAY A
MILLIMETER.
WE CAN CENTRIFUGE THIS MATERIAL
TO EXTRUDE SOME OF THE LIQUID
SO THAT CHANGES HOW VISCOUS IS
THE MATERIAL AND WHAT IS THE
EXTRUDABILITY LOOK LIKE.
>> THANK YOU.
>> THANK YOU FOR A GREAT TALK.
I HAVE A QUICK QUESTION TOO, DO
THE PROPERTIES OF THE MATERIAL
CHANGE MUCH LIVING IN DEAD
CELLS?
>> Sara Molinari: WE DIDN'T
LOOK A LOT INTO OCOLINGA?
(?) CELLS, THE STRENGTH IS IT
CONTAINS LIVING CELLS, THEY DO.
THE MASS IS STRONGLY REDUCED IF
YOU KILL THE CELL.
>> THANK YOU.
[ APPLAUSE ]
>> Rahul Thakar: NOW OUR FINAL
TALK OF THE DAY BY XINLING LI.
"MATHEMATICAL MODEL OF AND
GATED SYNTHETIC BIOMARKERS
PREDICTS TUNABLE SIGNAL TO
NOISE AND COOPERATIVE BEHAVIOR."
>> Xinling Li: HI, EVERYONE,
THANK YOU FOR STAYING UNTIL THE
END.
I'M XINLING LI.
WE THOUGHT TO SWITCH IT UP A
LITTLE BIT TODAY AND IN THIS
HIGHLY COLLABORATIVE MEETING WE
ARE GOING TO EXPLORE THE FLOOR
(AMRUDT)
AS EVERYONE KNOW THEY ARE A
LARGE IMPORTANT ENZYMES
INVOLVED IN A LOT OF
PHYSIOLOGICAL PROCESSES WHEN
THEY GET DYSREGULATED THEY CAN
BE PROGRESSORS OF DISEASE.
WE ARE STARTING TO SCRATCH THE
SURFACE AND LEARN MORE ABOUT
PROTEASES.
IN THE FIELD OF DIAGNOSTICS WE
KNOW THERE ARE DIFFERENT
PROTEASE DISEASE PROFILES
ACROSS DISEASE STAGES.
AS WELL AS DURING DRUG
RESPONSES TO THERAPY.
SHOWN HERE WITH CANCER IMMUNO
THERAPY.
AS SUCH PROTEASES ARE BEING
INCREASINGLY UTILIZED AS
ACTIVATION MECHANISM SUCH AS
MASS CYTOKINES, ACTIVATABLE
ENGINE PROBES.
AND SYNTHETIC BIOMARKERSING
SOMETHING OUR LABS HAVE
EXPERTISE, BIO ENGINEER SENSORS
THAT CAN CREATE DISEASE AND
RELEASE SYNTHETIC -- IN THE
URINE.
AS BIO ENGINEERS WE ARE DEEPLY
INTERESTED IN HOW CAN WE
GENERATE A QUANTITATIVE
UNDERSTANDING HOW THESE SYSTEMS
WORK.
AND HOW CAN WE USE THIS TO
DERIVE DESIGN GUIDELINES.
OUR LABS ARE USING ON THE
INTERFACE MATHEMATICAL MODELS
TO PREDICT THE BEHAVIOR OF
PROTEASE-ACTIVATABLE SYSTEMS.
HOW CAN WE MAP THE INSIGHTS WE
GAIN THROUGH EXPERIMENTS INTO
DIFFERENT MODEL SYSTEMS, MODEL
ORGANISMS AND POTENTIALLY
THINKING TOWARD TRANSLATION
INTO HUMANS.
SO ONE WAY WE FOUND WE CAN DO
THIS IS BY EXTRACTING
DIMENSIONS FROM MATHEMATICAL
MODELS.
THE SECOND TOPIC IS RELATED TO
TACKLING THE ISSUE OF SUBSTRATE
SELECTION.
JUST TO GIVE YOU A LITTLE
PERSPECTIVE, TYPICALLY WHEN WE
LOOK AT PROTEASES WE ARE
LOOKING AT 4-6 AMINO ACID
SEQUENCES.
DESIGN SPACE OF MILLIONS OF
SUBSTRATE WE CAN CHOOSE FROM.
CAN WE DESIGN COMPUTATIONAL
TOOLS TO SELECT THE BEST
SUBSTRATES FOR THE JOB AT HAND?
WHAT WE LEARNED IS TYPICALLY
THE PROMISCUOUS SUBSTRATES WE
THROW OUT BUT THEY MIGHT
CONTAIN A LOT OF USEFUL
INFORMATION.
FINALLY, CAN WE APPLY A
COMPUTATIONAL TOOLKIT FOR MORE
SENSITIVE AND EFFECTIVE
DIAGNOSTICS.
ONE WAY IS BY TAKING PRINCIPLES
OF COOPERATIVITY WE HAVE
LEARNED AND APPLY TO BETTER
DESIGN SENSORS.
WE ARE ASKING HERE CAN WE
DEVELOP MATHEMATICAL MODEL
THAT'S CAN HELP US DESIGN
BETTER COOPERATIVE SENSORS?
FOR THE FIRST TOPIC, HOW CAN WE
PREDICT SCALE.
WHAT I MEAN BY THIS, FROM IN
VITRO TO INVIVO OR FROM TUMOR
TYPE TO TUMOR TYPE OR FROM MICE
TO HUMANS.
THEY ARE DIFFICULT TO PREDICT
THE EFFECTS ON THESE SYSTEMS.
WE TOOK EXAMPLES FROM REYNOLDS
NUMBER CAN STRATIFY FLOW
REGIMES.
IT'S AGO NOTIC TO THE
CONDITIONS, IT SCALES WELL WITH
GEOMETRY, TEMPERATURE, FLUID.
WE WANTED TO APPLY THIS SIMILAR
PRINCIPLE TO A BIOLOGICAL
SYSTEM.
HERE IS AN EXAMPLE WITH A
MICROBIAL PROJECT ACTIVATED BY
MICROBIAL PROTEASE AND LEADS
TO CELL DEATH.
WE PERFORMED AND, BACTERIAL
ADVANTAGE, WHAT IS HELPFUL IS
THIS COULD PREDICT PROJECT
SUCCESS VERSUS ESCAPE WITH THIS
CLEAN STEP FUNCTION BASED ON
OUR MODEL.
WE WERE EXCITED AND WE STRESS
TESTED AGAINST NINE MODELS.
YOU CAN SEE WHAT IT PREDICTS
AND WHEN WE PERFORM AN
EXPERIMENT IT AGREES VERY WELL
SHOWING THE MODEL IS PREDICTIVE.
THIS IS POWERFUL AND SHOWS WE
CAN USE MATHEMATICAL MODELING
TO EXTRACT -- FOR SCALING.
I WILL TALK ABOUT SUBSTRATE
SELECTION.
THE WAY THE FIELD THINKS OF
THIS CHALLENGE IS THROUGH LONG
PIPELINE, GENERATING A LIST OF
CANDIDATE SUBSTRATES FOR
LITERATURE FOR THESE PROTEASES
AND SYNTHESIZING SUBSTRATES, A
SCREEN, AND THEN PERFORMING
WINNER SELECTION.
WE WILL FOCUS ON THE LAST
ARROW, THE WINNER SELECTION
ARROW.
TYPICALLY WHAT THE FIELD DOES,
WE LOOK FOR THE MOST ORTHOGONAL
SET OF SUBSTRATES POSSIBLE.
IDEALLY ONE SUBSTRATE FOR A
GIVEN PROTEASE.
BUT THIS IS AGAINST THE BIOLOGY
OR EVOLUTION OF PROTEASE WHICH
ARE EVOLVED TO BE VERY
PROMISCUOUS.
THERE ARE ADVANTAGES, IT
PROVIDES ALTERNATIVE
EVOLUTIONARY MECHANISMS AND
MORE BIOLOGICAL PROCESSES WHERE
IT COULD PERFORM MULTIPLE
FUNCTIONS.
WE ASKED CAN WE USE
MATHEMATICAL MODELS TO USE
PROMISCUOUS SUBSTRATES TO OUR
ADVANTAGE.
WE DERIVED THIS COMPRESSION
SCORE, THE NUMBER OF PROTEASES
BEING COVERED.
WE HYPOTHESIZED IT COULD LEAD
TO A MORE PROMISCUOUS SMALLER
LIBRARY THAT COULD PERFORM
DIAGNOSTIC ACCURACY.
WE TESTED USING TWO COMPRESSION
SCORES.
COMPLEX MIXTURE WITH PLASMA
FROM MICE.
IN THIS MIXTURE IT CAN'T
DIFFERENTIATE THE DOTS, BUT NOW
WITH HIGH COMPRESSION.
WITH MATHEMATICAL MODELING WE
CAN TAKE ADVANTAGE OF THE
PROPERTIES TO PERFORM
DIAGNOSTICS.
LASTLY, WE WILL TALK ABOUT HOW
WE CAN APPLY COOPERATIVITY TO
THE SITE OF EARLY DETECTION.
WHEN WE THINK OF EARLY CANCER
DETECTION IT'S A NEEDLE IN A
HEY STACK CHALLENGE.
TUMORS ON THE ORDER OF
MILLIMETERS TO CENTIMETERS,
THERE IS NOISE THAT CAN
COMPOUND ACCURACY.
WE COULD HAVE OFF TARGET NOISE
FROM CIRCULATING PROTEASES IN
BLOOD.
BLOOD VOLUME IS 4-5 ORDERS OF
MAGNITUDE LARGER THAN THE EXTRA
CELLULAR SPACE.
THIS COULD CONTRIBUTE.
AND THIS IDEA OF OFF TARGET ON
TUMOR NOISE, THERE AREN'T
TUMOR-SPECIFIC PROTEASES.
WHAT WE USE AS ACTIVATION
MECHANISMS ARE ALSO EXPRESSED
IN PROCESSES LIKE WOUND HEALING.
THERE ARE SEVERAL WAYS TO GO
ABOUT ADDRESSING THESE ISSUES.
ONE WAY IS TO DESIGN SENSORS
THAT REQUIRE CLEAVAGE BY TWO
PROTEASES.
WE HAVE A LARGE BODY OF WORK,
BUT I WILL HAND IT OVER TO
XINLING HERE TO TALK.
>> Xinling Li: WE STARTED
MODELING TWO ARMS WERE
IDENTICAL.
THE TWO ARMS COULD BE CUT
SEQUENTIALLY BY THE TARGET
PROTEASE TO FORM PRODUCT.
AT THE SAME TIME NOISE IS
COMBINED AND -- 2-ARM.
CONTRAST, WORK HAS CONTROL ONLY
HAS ONE ARM EITHER BY TARGET OR
NOISE PROTEASE.
THE 2-ARM AND GATED SENSOR AND
IT WILL BE MORE COMPLEX.
WE TAKE THE DIFFERENCES ACROSS
BIOLOGICAL COMPARTMENTS INTO
CONSIDERATION.
TUMOR PROTEASES EXIST WITH
LOWER CONCENTRATION OF THE
TUMOR.
PROTEASES IN TUMOR HAVE HIGH
REACTIVITY.
BLOOD HAS LARGE CIRCLE
PROTEASES OFF TARGET NOISE,
SINCE MOST ARE INACTIVE BY
INHIBITORS THEIR NOISE IS LOW.
THE MODEL WITH THE BIOLOGICAL
REACTION.
IN THIS CASE, THE PROJECT
PROTEASE IS TUMOR, AND NOISE IS
BLOOD, AND KM TARGET PROTEASE
IS 1-10.
TO COMPARE AND GATE SENSOR WE
USE THIS.
YOU CAN SEE, ON THE RIGHT SHOWS
SENSOR AND ON THE LEFT --
SIGNAL INPUT.
BECAUSE WE KNOW RESULTS CAN BE
NON INTUITIVE WE NEED
EXPERIMENTAL DATA TO MAKE SURE
OR MODEL IS DOING SOMETHING
RIGHT.
WE DESIGNED EXPERIMENT WE USE
--
FOR BOTH INPUT SINGLE SENSOR ON
THE LEFT AND 2-ARM AND GATED
SENSOR ON THE RIGHT.
WE CAN SEE FOR AND-GATED
SENSOR, THE NOISE IS HIGHER
THAN THE SINGLE INPUT AND THE
DIFFERENCE IS SIGNIFICANT.
THEREFORE THIS VALIDATES OUR
RESULTS FOR THE COMPUTATION
PART ON THE LEFT, INDICATING
OUR COMPUTATION PART IS RIGHT.
AND NEXT WE PICK A CONDITION
WHICH HIGH NOISE TO INTERROGATE
WHETHER MORE ARMS PROVIDE
CAPABILITY TO DISTINGUISH
SIGNAL TO NOISE.
WE CAN SEE THAT AS THE NUMBER
OF ARM INCREASES THE SENSOR
BECOMES MORE COOPERATIVE.
THE NEXT COULD BE RELATED TO
SPECIFICITY.
IT INCREASES MONATOMICKLY.
HOWEVER FROM OUR MODELING
RESULTS THAT'S NOT THE CASE.
WHEN WE FIX THE TIME POINT TO
30 MINUTES AND 90 MINUTES AND
SIGNALING MINUS NOISE WE CAN
SEE FOR 30 MINUTES ON THE TOP,
THE THREE-ARM SENSOR PERFORMED
BEST, WHICH HAS THE HIGHEST
SIGNAL AMOUNT OF NOISE.
WHERE AS FOR 90 MINUTES, THE
7-ARM SENSOR HAS THE HIGHEST
SIGNAL.
-- CAN INCREASE SPECIFICITY OF
THE SENSOR.
AND THEN NEXT WE START WITH OUR
TWO-ARM AND GATED SENSOR, THE
QUESTION WE WILL ASK ARE THEY
SENSITIVE TO CONCENTRATION IN
TUMORS.
BECAUSE WE KNOW THAT TUMOR
PROTEASE CONCENTRATION CAN BE
2-10 FOLD HIGHER THAN THE
HOUSING ORGAN.
ON THE LEFT, ONE AXIS IS SINGLE
INPUT SENSOR, THE Y AXIS IS
PARAMETER PROTEASE
CONCENTRATION DIVIDED BY --
AND THE DASH LINE IN THE PLOT
SHOWING TWO-ARM THE SAME AS ONE
ARM.
BUT WE CAN SEE THAT SINCE THE
BLUE CURVE IS ALWAYS ABOVE THE
DASH LINE, INDICATING THAT OUR
AND GATED SENSOR CAN ALWAYS
DETECT THE TUMOR WITH MUCH
HIGHER SPECIFICITY THAN THE
SINGLE INPUT SENSOR.
THEREFORE THEY ARE SENSITIVE TO
PROTEASES CONCENTRATION IN
TUMORS.
THE OTHER QUESTION, WE KNOW FOR
CANCER PATIENTS MANY ARE IN
HYPER COAGULATABLE STATE.
OUR SENSOR CAN STILL DETECT
TUMOR IN THOSE PATIENTS THAN
WITH SINGLE SENSOR.
LAST BUT NOT LEAST WE WANT TO
ASK HOW DO PROTEASE SUBSTRATE
-- WE ASK BETWEEN THE TARGET
PROTEASE AND SUBSTRATE
INCREASES THE SPECIFICITY OF
THE T2-ARM SENSE SORE INCREASES
MORE THAN SINGLE SENSOR, WE
WANT TO SELECT SUBSTRATE THAT
HAS HIGHER BINDING AFFINITY
WITH THE TARGET PROTEASE, TO
MAXIMIZE THE SPECIFICITY OF THE
SENSOR FOR TUMOR DETECTION.
AND ALSO IN SUMMARY, WE CAN USE
DIMENSIONAL SUSPECTER FOR
SCALING AND CONTAINS USEFUL
INFORMATION AND THIRD
INCREASING THE NUMBER OF ARMS
INCREASES CONNECTIVITY AND
SPECIFICITY OF THE SENSOR AND
LAST BUT NOT LEAST WE CAN
OPTIMIZE PARAMETERS TO INCREASE
SENSITIVITY FOR DETECTION OF
TUMOR.
WE CAN APPLY FOR
DIFFERENTIATING ANTI-TUMOR
RESPONSE FROM VIRAL INFECTION
AND DIFFERENTIATING METASTASIS
FROM LONG METASTASIS.
THANK YOU FOR LISTENING AND WE
ARE HAPPY TO TAKE QUESTIONS.
) ANIRUDH SIVAKUMAR)
THIS IS MORE OF A NITTY-GRITTY
QUESTION BUT I'M CURIOUS AS
SOMEONE WHO WOULD LIKE TO
IMPROVE MY OWN COMPUTATIONAL
MODELING SKILLS, I WONDER WHAT
SOFTWARE YOU USED FOR MAKING
THE MODELS OR WHAT PROGRAM.
>> Xinling Li: WE WERE USING MY
LAB, MAX ACTION MODELS.
>> VERY NICE, VERY NICE, THANK
YOU, THAT'S GREAT.
MUCH APPRECIATED.
ANY MORE QUESTIONS?
>> I LOVE PROTEASE QUESTIONS.
I DIDN'T WANT TO ASK TOO HARD
CORE OF A QUESTION.
QUESTION, ARE YOU THINKING OF
INCORPORATING WAYS SO DIFFERENT
PROTEASES WORK IN DIFFERENT
ENVIRONMENTS, ARE YOU THINKING
OF INCORPORATING DIFFERENT PH.
I LOVE THE IDEA OF THE NOISE,
BUT ARE YOU THINKING OF
CHANGING THE ENVIRONMENT.
>> YOU MEAN IN CONTEXT OF
COMPUTATIONAL MODEL.
OF COURSE THE REAL THING TOO.
BUT IT MIGHT AFFECT THE SYSTEM
THAT IS GIVING YOU THE
READ-OUTS.
>> YEAH, I WOULD ANSWER THAT IN
TWO DIFFERENT WAYS.
FOR THE MATHEMATICAL MODEL NOW
WE ARE THINKING OF THIS AS A
SINGLE COMPARTMENT.
TREATING IT IT WOULD BE TOUGH
IN THE CURRENT INSTANCE TO
THINK OF DIFFERENT
ENVIRONMENTAL CONDITIONS BUT
THAT IS CERTAINLY SOMETHING WE
ARE THINKING ABOUT, DIFFERENT
COMPARTMENTS WITH DIFFERENT
CONDITIONS, TUMOR COMPARTMENTS
AND BLOOD COMPARTMENTS.
THE OTHER WAY TO ANSWER THAT
QUESTION, WE ARE REALLY
INTERESTED HOW CAN WE FIND
SUBSTRATE THAT'S PERFORM BETTER
IN DIFFERENT PHYSIOLOGICAL
ENVIRONMENTS, SO WE ARE WORKING
ON DIFFERENT SCREENING
PLATFORMS, WITH MICE, WHAT
SUBSTRATES WILL PERFORM BETTER.
HOPEFULLY WE CAN CAPTURE THE
REAL PH CHANGES IN DIFFERENT
ENVIRONMENTAL CONDITIONS.
Xinling Li: THANKS.
[ APPLAUSE ]
>> Rahul Thakar: JUST TO ADD
MORE INFORMATION ABOUT THE
BALCONY POSTERS, THERE IS MORE
IN C.
I THINK I HAVE HEARD SO MANY
GOOD CONVERSATIONS.
WHAT I WOULD LIKE TO DO IS
THANK ALL THE PARTICIPANTS, THE
MODERATORS, THE SPEAKERS, THE
POSTER SESSION FOLKS, SYNTHETIC
BIOLOGY CONSORTIUM AND ALL THE
PEOPLE WHO SUPPORTED THIS EVENT.
I WISH YOU A SAFE TRIP BACK
HOME AND LOOK FORWARD TO SEEING
YOU HERE NEXT YEAR FOR THE
FIFTH ANNUAL SYNTHETIC BIOLOGY CONSORTIUM.
THANK YOU VERY MUCH. AND TAKE CARE CH.
[ APPLAUSE ]