MY NAME IS SUSAN WEISS, I WORK
AT THE NATIONAL INSTITUTE ON
DRUG ABUSE, BUT I ALSO SERVE AS
THE DESIGNATED FEDERAL OFFICIAL
FOR THE BRAIN MULTI-COUNCIL
WORKING GROUP.
TODAY WE JUST HAVE ONE NEW
MEMBER, AND SHE'S AN EX OFFICIO
MEMBER JOINING FROM US DARPA,
DR. KRISTIN JORDAN, AND DR. NGAI
WILL INTRODUCE HER IN A COUPLE
MINUTES.
I'LL TAKE A FEW MINUTES TO
REMIND EVERYONE WHY WE'RE HERE
TODAY.
THE MCWG IS NOT A FORMAL
ADVISORY GROUP, BUT SINCE BRAIN
WAS INITIATED IT WAS RECOGNIZED
THAT THE EXPERTISE NEEDED FOR
SUCH A DIVERSE AND FAR-RANGING
INITIATIVE WOULD GO BEYOND WHAT
MOST SINGLE I.C. COUNCILS WERE
ABLE TO PROVIDE.
SO, THERE ARE TEN
REPRESENTATIVES FROM EACH OF THE
PARTICIPATING INSTITUTES AND
CENTERS, MANY OF THEM ARE FROM
THE INSTITUTE'S ADVISORY COUNCIL
AND WE ALSO HAVE SEVERAL EX
OFFICIO MEMBERS FROM FDA,
NATIONAL SCIENCE FOUNDATION,
DARPA AND IARPA.
WE DEPEND ON THE GROUP FOR
ONGOING OVERSIGHT OF SCIENTIFIC
VISION AND PROGRESS OF THE BRAIN
INITIATIVE, MEETING ITS GOALS.
AND WHICH HAVE BEEN OUTLINED IN
THE TWO STRATEGIC PLANS
DEVELOPED FOR "BRAIN."
WE ALSO HAVE ASK FOR FEEDBACK ON
CONCEPT CLEARANCES WHERE WE HAVE
NEW INITIATIVES THAT WE'RE
PLANNING TO ISSUE FUNDING
OPPORTUNITY ANNOUNCEMENTS ON,
AND IN CLOSED SESSION WE DEPEND
UPON THE MCWG FOR INPUT ON
FUNDING PLANS.
WHEN WE TRANSITION TO THE CLOSED
SESSION, I WILL GO OVER SOME OF
OUR OPERATING PROCEDURES FOR
THAT, AND IT WILL BEGIN AFTER A
45-MINUTE BREAK FOLLOWING THE
OPEN SESSION AT AROUND 2:15.
NOTE THAT WE WILL HAVE DIFFERENT
ZOOM -- A DIFFERENT ZOOM LINK
FOR THE CLOSED SESSION WHICH IS
SOLELY FOR MEMBERS OF COUNCIL
AND FOR GOVERNMENT EMPLOYEES.
AS A REMINDER, THE OPEN SESSION
IS BEING VIDEOCAST AND IT WILL
BE ARCHIVED AND POSTED ON THE
NIH AND BRAIN WEBSITE.
A FEW HOUSEKEEPING ITEMS, MUTE
YOUR LINE AND TURN OFF YOUR
VIDEO WHEN NOT SPEAKING.
THIS IS HELPFUL FOR THE
VIDEOCAST.
PLEASE DO TURN ON YOUR VIDEO
DURING THE DISCUSSIONS AND USE
THE RAISE HAND OPTIONS IF YOU
HAVE QUESTIONS.
WE WILL CALL ON YOU TO UNMUTE
YOURSELF.
WE PREFER YOU NOT TO USE THE
CHAT FUNCTION BECAUSE THAT'S NOT
VISIBLE TO THOSE ON VIDEOCAST.
FINALLY, AS I MENTIONED AT EACH
MEETING, I'M EXTREMELY GRATEFUL
FOR THE WORK OF MY HIGHLY
COMPETENT COLLEAGUES THAT GOES
INTO PREPARATIONS FOR THOSE
MEETINGS.
THIS IS QUITE A SUBSTANTIAL
EFFORT, ESPECIALLY WITH THE
ROUND LIKE THE MAY ROUND, WITH
25 PAY PLANS UNDER
CONSIDERATION.
IN PARTICULAR, I WOULD LIKE TO
RECOGNIZE KRISTIN DUPRE, NINA
HSU, DEB FREENER AND MICHELE
PEARSON, THEIR ATTENTION TO
DETAIL ADD TO THE BIG PICTURE,
ALLOWING THE MEETING TO RUN
SMOOTHLY AND EFFICIENTLY.
WE'LL BEGIN TODAY WITH AN UPDATE
ON BRAIN, AS USUAL FROM DR. JOHN
NGAI, DIRECTORY OF THE BRAIN
INITIATIVE.
FOLLOWED BY UPDATE FROM HANK
GREELY ON NEUROETHICS WORKING
GROUP.
FINALLY WE'LL BE HEARING FROM
ONE OF OUR NEWER MULTI-COUNCIL
WORKING GROUP MEMBERS, DR. BRYAN
ROTH WHO IS ALSO A LONG-TERM
NIDA GRANTEE AND MERIT AWARD E.
I TURN IT OVER TO DR. NGAI.
>> THANKS, SUSAN.
THANK YOU ALL FOR BEING HERE.
I THINK WE HAVE MEMBERS ON
MULTIPLE CONTINENTS, SO I'LL
SAY GOOD DAY.
A PLEASURE TO BE HERE, ALWAYS.
LET'S SEE IF I CAN SHARE MY
SCREEN.
CAN YOU SEE THE APPROPRIATE
SCREEN?
YEAH?
ARE WE GOOD?
>> YES.
>> OKAY.
THANKS.
WELL, BECOME, EVERYBODY, TO THE
MAY MEETING OF THE BRAIN
MULTI-COUNCIL WORKING GROUP.
I JUST HAVE A FEW UPDATES TO
GIVE YOU BEFORE WE HEAR SOME
GREAT -- BEFORE WE HEAR AN
UPDATE FROM HANK GREELY ABOUT
NEW GOINGS-ON AND A SCIENTIFIC
TALK FROM MEMBER BRYAN ROTH.
FIRST OF ALL, I WANT TO THANK AL
MUNDY, OUR EX OFFICIO MEMBER
FROM DARPA AND WELCOME DR.
KRISTIN JORDAN, DEPUTILY
DIRECTOR OF BIOLOGY TECHNOLOGY
OFFICE, WE'RE LOOKING FORWARD TO
CONTINUING CONVERSATIONS AND
SETTING UP EXCITING
COLLABORATIONS.
THIS IS THE TEAM WITHIN THE MEET
OFFICE OF THE BRAIN DIRECTOR,
I'D LIKE TO HIGH LIGHT DR.
KRISTIN LANCE, AND REMISS IF I
DID NOT A GIVE A SHOUT OUT TO
THE STAFF ACROSS NIH, TEN ICs
AND BEYOND, WELL OVER 100 GREAT
SCIENTISTS, I HOPE THIS IS UP TO
DATE BUT SEEMS LIKE ANYTIME I
SHOW THIS WE'RE MISSING ONE OR
TWO PEOPLE SO APOLOGIES IN
ADVANCE IF THAT'S THE CASE.
OUR EFFORTS ARE ORGANIZED AMONG
NINE SCIENTIFIC TEAMS LISTED
HERE FOR ANYBODY WHO IS
INTERESTED IN OUR PROGRAMS,
THESE ARE THE GREAT POINTS OF
CONTACT WHO CAN STEER YOU TOWARD
PEOPLE THAT CAN GIVE YOU BEST
ADVICE ABOUT THE PROGRAMS AND
WHETHER YOU SHOULD BE APPLYING
TO ONE OF OUR RFAs.
JUST QUICKLY, I WANTED TO GIVE
YOU A BRIEF OVERVIEW OF THE
STATUS OF THE BRAIN BUDGET.
SO HERE WE ARE IN FISCAL YEAR
22, REMINDER THAT BRAIN FUNDING
COMES FROM BASE ALLOCATIONS IN
DARK BLUE, TOGETHER WITH
ADDITIONAL FUNDS FROM 21ST
CENTURY CURES ACT, VARIABLE FROM
YEAR TO YEAR.
AND IN THIS LAST YEAR CONGRESS
WAS VERY GENEROUS GIVING US AN
ADDITIONAL $8 MILLION TO OUR
BASE ALLOCATION, FOR A TOTAL OF
$620 MILLION TO INVEST IN FY 22
THIS YEAR INTO BRAIN-FUNDED
RESEARCH NEXT YEAR IN FY23, WE
REALLY ARE LOOKING FORWARD TO
TAKING ADVANTAGE OF THIS LARGE
INCREASE IN FUNDING THAT WILL
HELP US LAUNCH BIG PROJECTS AND
MAINTAIN.
STAY TUNED ON THAT.
I WANTED TO GIVE YOU A RECAP OF
EVENTS THAT HAPPENED OVER THE
PAST YEAR OR SO.
FOLLOWING THE CONCEPT CLEARANCE
WE PRESENTED LAST YEAR ON BBQS,
"BRAIN" HOSTED A MEETING TO
BRING TOGETHER EXPERTS ACROSS
DIFFERENT DISCIPLINES,
NEUROSCIENCE, ENGINEERING,
COMPUTER SCIENCE AND THE LIKE,
TO IDENTIFY GAPS AND
OPPORTUNITIES FOR MORE
COMPREHENSIVE UNDERSTANDING OF
BEHAVIOR, HOW TO SYNCHRONIZE
THAT UP WITH THE STUDY OF NEURAL
CIRCUIT ACTIVITY.
THERE ARE A NUMBER OF HIGHLIGHTS
THAT CAME OUT OF THIS MEETING
BUT ONE OF THEM WAS THE
IMPORTANCE OF STUDYING BEHAVIOR
AND NEURAL ACTIVITY IN
NATURALISTIC CONDITIONS, THAT
CAN REVEAL THE FULL RANGE OF
BEHAVIORS IN A VARIETY OF ANIMAL
SYSTEMS.
THERE ARE A NUMBER OF
TECHNOLOGICAL NEEDS IDENTIFIED
INCLUDING BUT NOT LIMITED TO
IMPORTANCE AND CHALLENGES OF
MINIATUREIZATION, CLOSED LOOP
SYSTEMS, POSSIBILITY TO INVENT
AND INCORPORATE NEW SENSORS FOR
ACQUIRING DATA AND THE
IMPORTANCE OF SYNCHRONIZING
THESE DATA ACROSS MODALITIES TO
GIVE COMPREHENSIVE PICTURE AND
ONGOING COMPUTATIONAL LEADS IN
THE DATA SCIENCE SPACE INCLUDING
MACHINE LEARNING APPROACHES.
SO, THIS IS QUITE EXCITING, AND
RIGHT NOW WE ARE LOOKING FORWARD
TO ISSUING THE FIRST SET OF
FOAs, IN THE BBQS STAYS, SO
STAY TUNED FOR FURTHER
DEVELOPMENTS.
WE ALSO HAVE THE PLEASURE OF
PARTICIPATING IN AN EVENT, IN A
MEETING ORGANIZED AND HOSTED BY
CHILD HEALTH AS WELL AS BILL AND
MELINDA GATES FOUNDATION, AND
HERE THE GOAL WAS TO LOOK AT
OPPORTUNITIES FOR DEVELOPING NEW
TOOLS AND METHODOLOGIES FOR
STUDYING THE BRAIN ACROSS THE
LIFESPAN.
SO FROM EMBRYOGENESIS THROUGH
AGING.
WE COVERED A RANGE OF TOPICS
WHICH ARE QUITE EXCITING
INCLUDING RECENT DEVELOPMENTS,
SOME EMERGING THEMES WERE THE
OPPORTUNITIES FOR COLLABORATION
ACROSS RESEARCH SILOS, THE
IMPORTANCE OF USING NON-HUMAN
MODELS AS TRUE COMPARATIVE
MODELS TOGETHER WITH HUMAN
RESEARCH, AND OF COURSE THE
FOCUS ON NOT JUST DEVELOPMENT
BUT ALSO ON THE FLIP SIDE, TO
LOOK AT MECHANISMS OF AGING.
WE REALLY ARE INTERESTED, THE
GROUP REALLY WAS INTERESTED IN
STUDYING HUMANS ACROSS THE
LIFESPAN.
SOME INTERESTING OTHER THEMES
CAME OUT, THAT ONE OF WHICH WAS
TO -- THE IMPORTANCE OF
DEVELOPING TECHNOLOGIES AND
COMPUTATIONAL APPROACHES,
MACHINE LEARNING ALGORITHMS, FOR
EXAMPLE.
WHICH REALLY WILL HELP INCREASE
THE RESOLUTION AND POWER OF
EXISTING MODALITIES.
ONE PLACE WHERE THIS DID COME UP
WAS IN THE DEPLOYMENT OF VARIOUS
HUMAN BRAIN IMAGING TECHNOLOGIES
IN THE FIELD.
THERE'S INTERESTING AND COOL LOW
FIELD IMAGING DEVICES THAT ARE
DEPLOYED IN THE FIELD BUT OF
COURSE THEY GIVE LOWER
RESOLUTION THAN HIGH FIELD
MAGNETS FOUND IN MAJOR RESEARCH
CENTERS, MAJOR MEDICAL CENTERS,
AND I THINK ONE THEME THAT CAME
UP WAS ABILITY OR POSSIBILITY OF
INCREASING THE PRACTICAL
RESOLUTION OF THESE MACHINES
THROUGH MACHINE LEARNING
TECHNIQUES THAT WILL ACTUALLY
GIVE BETTER -- GIVE DELIVERY OF
BETTER CARE IN THE FIELD.
SO THIS IS AN ONGOING EFFORT,
WE'RE LOOKING FORWARD TO
CONTINUING THESE CONVERSATIONS
WITH COLLEAGUES IN CHILD HEALTH
TO SEE HOW BRAIN CAN CONTRIBUTE
TO THIS AREA.
WE HAVE AN UPCOMING EVENT, NEW
WORKSHOP ON CONTINUING TRIAL
RESPONSIBILITIES, I THINK YOU
FOLKS HERE HAVE SEEN A LOT OF
WORK, EXCITING WORK, FUNDED IN
PART BY THE BRAIN INITIATIVE,
USING INVASIVE DEVICES
EARLY STAGE CLINICAL TRIALS FOR
TREATMENT OF A VARIETY OF HUMAN
CONDITIONS.
ONE ISSUE THAT'S COME UP IS HOW
DO WE CONTINUE TO CARE FOR THESE
PATIENTS AFTER THE TRIAL IS
FORMALLY OVER.
WE DO FEEL THE URGENT
RESPONSIBILITY FOR CARING FOR
THESE HUMAN RESEARCH
PARTICIPANTS, PARTNERS, BUT
THERE ARE A VARIETY OF LEGAL AND
OTHER ISSUES THAT NEED TO BE
DEALT WITH.
SO THIS WAS APPROACHED IN A
TWO-PHASE WORKSHOP.
WE'VE ALREADY HELD THREE
PRE-MEETINGS WITH VARIOUS
STAKEHOLDERS.
AND WE'RE LOOKING FORWARD TO A
PUBLIC WORKSHOP NEXT WEEK THAT
INCORPORATION THE PERSPECTIVES
FROM THESE DIFFERENT STAKEHOLDER
GROUPS SO I INVITE YOU TO
ATTEND.
THIS AGAIN WILL BE A VIRTUAL
WORKSHOP GIVEN THE CURRENT
SITUATION.
OKAY.
SO, WE HAVE A BIG EVENT COMING
IN JUNE, JUNE 21 AND 22 IS OUR
EIGHTH ANNUAL BRAIN INITIATIVE
MEETING, ALL ARE WELCOME TO
ATTEND.
IT WILL BE HYBRID, AS OF NOW.
OF COURSE, THIS IS NOT LIMITED
TO BRAIN-FUNDED INVESTIGATORS
BUT WE REALLY ARE OPENING THIS
UP TO ANYONE WHO IS INTERESTED.
THE LAST TWO YEARS, THE
PANDEMIC, WE HAD GREAT
REGISTRATION AND ATTENDANCE FROM
ACROSS THE WORLD.
WE'RE HOPING THAT WE WILL
CONTINUE THAT NEW TRADITION OF
WIDE INTERNATIONAL ATTENDANCE
VIRTUALLY, BUT ALSO LOOKING
FORWARD TO AN IN-PERSON
COMPONENT IF WE ARE ABLE.
WE ARE MONITORING THAT SITUATION
VERY CLOSELY.
I JUST WANT TO HIGHLIGHT WE'LL
HAVE SIX SCIENTIFIC SYMPOSIA,
POSTERS, THREE KEYNOTE PLENARY
LECTURES, I ENCOURAGE YOU TO
ATTEND.
ABSTRACTS ARE DUE TODAY IF YOU
HAVEN'T SUBMITTED ALREADY.
I HOPE TO SEE YOU IN TWO
DIMENSIONS OR IN THREE
DIMENSIONS.
FOLLOWING LAST YEAR'S SUCCESS
WITH THE BRAIN INITIATIVE
CHALLENGE WHERE WE ASKED UNITED
STATES HIGH SCHOOL STUDENTS TO
OFFER PERSPECTIVES ON ASPECTS OF
WHAT WE DO, WE FOUND A GREAT
TOPIC THAT DID ENGAGE SOME
CREATIVE IDEAS, WAS THE AREA OF
EMERGING BRAIN TECHNOLOGY, WE'RE
IN THE PROCESS OF EVALUATING, I
BELIEVE WE'LL BE ANNOUNCING
AWARDS SOON, INCLUDING AT THE
BRAIN INITIATIVE MEETING.
I THINK YOU'LL ALL AGREE THERE'S
GREAT BEAUTY IN THE BRAIN, AND
SO WE HAVE A CONTINUING PHOTO
AND VIDEO CONTEST, AND THESE,
WINNERS OF THESE AWARDS WILL BE
ANNOUNCED AT THE MEETING AS
WELL.
OKAY.
SO, IT IS MAY.
THIS IS THE TIME WHERE WE LIKE
TO DISCUSS OUR DEMOGRAPHICS, THE
DEMOGRAPHICS OF BRAIN-FUNDED
INVESTIGATORS, FROM THE PAST
YEAR FROM FISCAL YEAR 21.
THE INFORMATION FROM THIS
ANALYSIS WHICH WAS BEAUTIFULLY
COMPILED AND GENERATED BY
DOCTORS CRAWFORD, RICHARDSON AND
LANCE, APPEAR IN YOUR ELECTRONIC
COUNCIL BOOKS AS WELL AS POSTED
ONLINE RIGHT NOW AND LET'S SEE,
SO FOR THOSE WATCHING YOU CAN'T
SEE THIS, THE ACTUAL SLIDES, BUT
THEY ARE ON THE BRAIN WEBSITE.
THERE'S A LINK TO IT, WE'LL MAKE
IT VISIBLE SHORTLY.
IN THE INTEREST OF TIME, ALSO
TEDIUM, I'M NOT GOING THROUGH
THE ENTIRE DECK.
I WANT TO HIGHLIGHT SOME OF THE
MOST SALIENT FINDINGS, THESE ARE
THE 20,000-FOOT VIEW.
THE BOTTOM LINE IS THAT THE
NUMBERS HAVEN'T CHANGED A WHOLE
LOT YEAR TO YEAR.
SO, IN TERMS OF DISCIPLINES THAT
ARE ENGAGED IN BRAIN-FUNDED
RESEARCH, THERE ARE A NUMBER OF
DISCIPLINES REPRESENTED, BEYOND
JUST NEUROSCIENCE AS A PRIMARY
IDENTIFIER.
ENGINEERING IS THE MOST POPULAR
DISCIPLINE, WHEREABOUT A THIRD
OF INVESTIGATORS IDENTIFY AS
ENGINEERS, HAVE AN ENGINEERING
INTEREST.
IN TERMS OF DIVERSITY OF
BACKGROUND, WOMEN AND
UNDERREPRESENTED GROUPS ARE
STILL UNDERREPRESENTED, RELATIVE
TO NIH OVERALL.
THIS HAS NOT CHANGED A WHOLE LOT
BEYOND THE NOISE FROM YEAR TO
YEAR.
THE GOOD NEWS THOUGH IS IF YOU
LOOK AT THE BOTTOM PART OF THE
PANEL, THERE'S NO OBVIOUS OR
DISCERNIBLE DIFFERENCES IN
FUNDING DISPARITIES BETWEEN
WOMEN AND MEN OR
UNDERREPRESENTED MINORITIES OR
NON-UNDERREPRESENTED MINORITIES.
WE'RE WORKING ON THIS AND I'LL
GET TO WHAT WE'RE DOING IN A
MOMENT TO ADDRESS THIS ONGOING
DISPARITY.
IN TERMS OF CAREER STAGE, ABOUT
A THIRD OF BRAIN-FUNDED
INVESTIGATORS ARE EARLY CAREER.
EARLY CAREER IS DEFINED HERE AS
WITHIN 14 YEARS OF TERMINAL
DEGREE.
GOOD NEWS HERE IS THAT THE EARLY
CAREER AND MID-CAREER APPLICANTS
HAVE FAVORABLE FUNDING RATES, A
HAIR ABOVE 30%.
PERFORMANCE SITES ARE FOUND IN
MOST STATES AS WELL AS PUERTO
RICO BUT FAVORS THE COAST,
NOTHING HAS CHANGED MUCH OVER
THE LAST YEAR.
AND, AGAIN, THE R01 INSTITUTIONS
ALSO SHOW FAVORABLE -- WELL, IN
ADDITION, THE NON-MINORITY
SERVING OR NON-IDEA ELIGIBLE
FARE BETTER.
ALL THIS IS WORK IN PROGRESS.
I WANTED TO REPORT THIS TO YOU,
THE FULL ANALYSIS CAN BE FOUND
IN YOUR ECBMs ALSO POSTED
ONLINE.
HERE IS WHERE WE ARE.
WHAT WE DECIDED TO DO THIS YEAR
WAS ALSO IN ADDITION TO LOOKING
AT DEMOGRAPHICS OF INVESTIGATOR
POOL TO ALSO LOOK AT WHAT ARE
THE DEMOGRAPHICS OF OUR HUMAN
RESEARCH PARTICIPANT POOL.
WE'VE LONG HELD THAT THE RICHES
THAT WE GAIN THROUGH BRAIN
INITIATIVE RESEARCH REALLY NEED
TO SERVE, AND WE CANNOT DO THAT
IF ONLY A LIMITED SUBPOPULATION
OF SOCIETY IS REPRESENTED.
SO BRAIN HAS BEEN FUNDING HUMAN
RESEARCH, HUMAN-FOCUSED RESEARCH
SINCE ITS INCEPTION IN 2014.
THIS GRAPH JUST SHOWS THE NUMBER
OF AWARDS THAT INCLUDED HUMAN
RESEARCH PARTICIPANTS, LOW IN
THE BEGINNING, AND THEN SPIKING
UP IN 2016.
AND MAINTAINING A FAIRLY
CONSTANT LEVEL THROUGH 2021.
SO, THERE ARE ROUGHLY 13,000
RESEARCH PARTICIPANTS ENROLLED
OVER THIS TIME FROM 2014 THROUGH
2021, AND COMPARED TO ABOUT A
MILLION NIH-FUNDED NEUROSCIENCE
PROJECTS.
AND I THINK YOU CAN SEE HERE
THAT AT LEAST IN TERMS OF THE
GENERAL CATEGORIES OF RACE AND
ETHNICITY, IT'S NOT PERFECT.
WE HAVE ROOM FOR IMPROVEMENT,
BUT THE DEMOGRAPHICS OF OUR
RESEARCH PARTICIPANT POOL
ROUGHLY MIRROR WHAT'S GOING ON
ACROSS NIH-WIDE IN THE
NEUROSCIENCES, AND SOMEWHAT LESS
WELL BUT COMPARED TO THE U.S.
CENSUS DATA.
SO, THIS IS, AGAIN, REASON FOR
SOME ENCOURAGEMENT THAT WE STILL
HAVE A WAYS TO GO BUT IT'S
CERTAINLY IN LINE WITH THE
OVERALL U.S. POPULATION.
AND THEN IN TERMS OF GENDER, WE
HAVE A PRETTY GOOD BALANCE OF
MALES AND FEMALES REPRESENTED IN
OUR RESEARCH PARTICIPANT COHORT.
OKAY.
SO, AGAIN, WE HAVE A WAYS TO GO,
BUT WE ARE FOCUSED ON PROMOTING
SCIENTIFIC EXCELLENCE THROUGH
ENHANCING DIVERSITY, EQUITY,
INCLUSION, IN ALL THAT WE DO.
WE SEE A LOT OF BENEFITS TO A
DIVERSE SCIENTIFIC WORKFORCE.
WE'VE DISCUSSED THIS BEFORE.
WE HAVE A MULTI-PRONGED
STRATEGY, ONE IS TO DEVELOP A
MORE DIVERSE WORKFORCE THROUGH
VARIOUS BRAIN-FUNDING
MECHANISMS, INCLUDING GRADUATES,
TRAINING FOR GRADUATE AND EARLY
POSTDOCTORAL SUPPORT, LATE
POSTDOCTORAL SUPPORT, EARLY
INDEPENDENT INVESTIGATOR
SUPPORT, AS WELL AS THROUGH
VARIETY OF BRAIN DIVERSITY
SUPPLEMENTS.
WE'RE WORKING ON CAPACITY
BUILDING, AND WE HAVE ONE FOA
RIGHT NOW THAT FOCUSES ON
PARTNERSHIPS BETWEEN RESEARCH
INSTITUTIONS, MAJOR RESEARCH
INSTITUTIONS WITH MINORITY
SERVING INSTITUTIONS, IDeA
ELIGIBLE, WE HAVE THE FIRST PLAY
PLAN LOOKING AT THAT LATER TODAY
IN CLOSED SESSION.
AND OF COURSE WE HAVE THIS NEWLY
LAUNCHED PLAN FOR ENHANCING
DIVERSE PERSPECTIVES THAT
REQUIRES APPLICANTS TO INCLUDE A
SUMMARY, ARTICULATE STRATEGIES
FOR ADVANCING THEIR SCIENCE,
TECHNICAL MERIT, THROUGH DIVERSE
PERSPECTIVES IN THEIR RESEARCH
TEAMS.
SO, A LITTLE BIT MORE ON THE
PDP, BRAIN RIGHT NOW HAS 18
ACTIVE FOAs THAT REQUIRE PDP
IN APPLICATION PROCESS.
16 OTHER FOAS HAVE SIGNED ON,
AND IN THIS ROUND WE HAVE EIGHT
FOAs FOR CONSIDERATION,
INCLUDING THE PDP, WE'LL TALK
ABOUT THAT IN CLOSED SESSION.
THIS WAS A PILOT PROJECT THAT
HAS TAKEN HOLD ACROSS NIH.
I THINK EARLY INDICATORS, IT'S
WORKING QUITE WELL.
WE'RE ACTIVELY ASSESSING ALL
ASPECTS OF THE PEDP FROM THE
REVIEWER EXPERIENCE, THROUGH
PROGRAM AND LOOPING BACK IN WITH
THE P.I.s.
WE DO NEED TO CERTAINLY
CALIBRATE ON WHAT WE'RE DOING
VERY CLEARLY AND BE TRANSPARENT
ABOUT THE PROCESS, WITH ALL
STAKEHOLDERS, BUT WE'RE HOPEFUL
THIS WILL IN FACT MOVE THE
NEEDLE AND BRING IN MORE DIVERSE
PERSPECTIVES THAT WILL LEAD TO
MUCH BETTER SCIENCE.
SO, AGAIN, OUR VIEW IS TO
SUPPORT THE BEST SCIENCE, WE
REALLY DO NEED TO PROMOTE
DIVERSE PERSPECTIVES IN
RESEARCH.
AND WE'RE WORKING ALONG MULTIPLE
LINES IN THIS REGARD.
THE PEDP WAS JUST ONE STEP IN
THAT DIRECTION.
WE ARE CONDUCTING MARKET
RESEARCH TO BETTER UNDERSTAND
HOW WOMEN AND SCIENTISTS
PERCEIVE AND EXPERIENCE WHAT
WE'RE DOING IN BRAIN AND FUNDING
OPPORTUNITIES.
WE'VE HAD QUITE A BIT OF
DISCUSSION OVER THE LAST FEW
YEARS ABOUT WHY IS IT THAT OUR
POOL OF INVESTIGATORS SEEMS TO
BE SKEWED TOWARD
WELL-REPRESENTED MALES.
THE GOOD NEWS HERE IF THERE IS
GOOD NEWS IS THAT THE FUNDING
RATES SEEM TO BE PRETTY EVEN SO
WE ARE LOOKING AT IN TERMS OF
OUTREACH WHAT CAN WE DO TO
BETTER ENGAGE SCIENTISTS ACROSS
A WIDER SWATH OF THE COMMUNITY.
WE'RE INTEGRATING D.E.I. GOALS
TO ENSURE OUR APPROACHES ARE
INCLUSIVE OF THE RESEARCH IN
PATIENT COMMUNITIES.
FINALLY WE REALIZE WE NEED TO
MEET EVERYBODY WHERE THEY ARE.
SO, PEOPLE ARE FEELING
DISINCLINED TO APPLY FOR BRAIN
FUNDING, WE CAN ESPOUSE BRAIN
ALL WE WANT HERE BUT IF PEOPLE
AREN'T TUNING IN THAT'S NOT
GOING TO HELP US.
WE'RE LOOKING AT WAYS OF
BRINGING THE MESSAGE OUT INTO
THE COMMUNITY, HOPEFULLY WITH
THE PANDEMIC EASING A BIT, BUT
ALSO THROUGH VIRTUAL PLATFORMS
WE CAN REACH WIDER SWATH OF THE
COMMUNITY.
SO THIS IS ALL ONGOING.
WE WELCOME YOUR INPUT ON THIS.
WE'RE TAKING THIS ALL VERY
SERIOUSLY IN THE INTEREST OF
DOING BETTER SCIENCE THAT CAN
BENEFIT A WIDER CROSS-SECTION OF
THE COMMUNITY.
WE'VE TALKED ABOUT THE BRAIN 2.0
TRANSFORMATIVE PROJECTS OVER THE
LAST FEW YEARS, AND THEY ARE ALL
OFFICIALLY LAUNCHED WITH THE
GREAT HELP OF CONGRESSIONALLY
DIRECTED FUNDS THAT CONGRESS
DECIDED THE IMPORTANCE OF THESE
PROJECTS MERITED SPECIFIC
CARVEOUTS TO LAUNCH THESE
PROJECTS.
THE BRAIN CELL CENSUS PHASE 2 OR
ATLAS WORK NOW FOCUSING
PRIMARILY ON HUMANS AND BIG
BRAINS BUT ALSO CONTINUING WORK
IN OTHER SPECIES, THIS WAS BUILT
ON THE SUCCESS OF THE BICCN, IN
ITS FINAL YEAR, HARD TO BELIEVE.
FIRST SET OF RFAs ISSUES, THEY
WILL BE REVIEWED HERE TODAY IN
CLOSED SESSION FOR FUNDING LATER
THIS SUMMER.
THE SECOND IS THIS ORGANIZING
RESOURCES FOR PRECISION BRAIN
CELL TYPE ACCESS ACROSS SPECIES,
CELL TYPE-SPECIFIC
ARMAMENTARIUM.
THIS WAS LAUNCHED LAST YEAR,
FIRST AWARDS MADE LAST YEAR.
THE GOAL HERE IS TO DEVELOP
TOOLS FOR SOMATIC CELL ACCESS IN
RODENT AND NHP BRAINS, HUMAN
CELLS AND TISSUES.
WE WANT TO DEVELOP BETTER TOOLS
FOR INTERROGATING AND MODULATING
NEURAL CIRCUITS WITH A LONG-TERM
GOAL OF DEVELOPING NEW
STRATEGIES FOR PRECISION GENE
THERAPIES IN HUMANS.
AGAIN, THE FIRST AWARDS WERE
ISSUES LAST YEAR, REVIEWING A
SECOND ROUND TODAY IN CLOSED
SESSION AND CAPACITY BUILDING
FOR TOOL DISSEMINATION WITH
MINORITY SERVING INSTITUTES,
SECOND RECEIPT DATE LATER THIS
SUMMER.
FINALLY, THE THIRD PROJECT IS
BRAIN INITIATIVE CONNECTIVITY
ACROSS SCALES, BRAIN CONNECTS,
WITH EMPHASIS ON THE MOUSE,
THESE THREE RFAs WERE JUST
ISSUED WITH THE FIRST RECEIPT
DATE COMING UP IN JULY.
I WANT TO TOUCH ON THAT FOR A
MOMENT.
THE GOAL OF MAPPING ENTIRE
MAMMALIAN BRAINS AT ANY LEVEL OF
RESOLUTION IS A LARGE ONE.
IT'S I THINK ARGUABLY SOMEWHAT
ASPIRATIONAL.
WE DON'T HAVE THE TECHNOLOGIES
YET TO DO THESE PROJECTS AT THE
SCALE THAT WE WISH TO.
SO WE'RE LOOKING AT THIS AS A
TEN-YEAR EFFORT.
IN THE FIRST FIVE YEARS, PHASE
1, WE WILL HOPEFULLY FUND
PROJECTS THAT WILL ASSESS
DIFFERENT APPROACHES FOR THEIR
ABILITY TO ACHIEVE THE NECESSARY
RESOLUTION AT SCALE.
ALONG THE WAY WE WANT TO LEARN
SOME BIOLOGY.
SO WE ARE ASKING THAT THESE
PROJECTS DEVELOP THESE
TECHNOLOGIES ON USE CASES THAT
WILL BE OF INTEREST AND
IMPORTANCE TO THE SCIENTIFIC
COMMUNITY.
SO WE WANT TO LEARN SOME BIOLOGY
ALONG THE WAY WHILE WE INVENT
AND DEVELOP THESE NEW
TECHNOLOGIES.
WE IN THE PROCESS WILL NEED TO
EVALUATE WHICH OTHER
TECHNOLOGIES ARE GOING TO WORK.
WE'LL HAVE TO ASSESS AND DEVELOP
A PLAN FOR IMPLEMENTING PHASE 2,
SCALEUP TO VERY MANY SYNAPSE
RESOLUTION MAPS IN A MOUSE BRAIN
AS WELL AS AXON LEVEL MAPS IN
BIG BRAIN, NON-HUMAN PRIMATE AND
HUMAN BRAINS.
OUR APPROACH TO THIS FOR ISSUING
RFAs IS A MIX OF LARGE
INTEGRATED PROJECTS AND
ACHIEVING ALL COMPONENTS OF THE
PIPELINE, AS WELL AS SMALLER
AWARDS THAT WILL BE TARGETING
NEW AND PERHAPS LESS TESTED
METHODOLOGIES IF THEY CAN BE
VALIDATED COULD ACCELERATE THE
OVERALL EFFORT.
THIS WILL BE MANAGED AS A
CONSORTIUM, NOT UNLIKE THE WAY
WE'VE BEEN MANAGING WITH I THINK
GOOD SUCCESS, THE CELL CENSUS
PROJECT, WITH PRE-PUBLICATIONS
SHARING AND CONCRETE GO/NO-GO
DELIVERABLES.
THESE WERE JUST ISSUED.
TWO LARGE PIECES WILL BE
COMPREHENSIVE CENTERS, UM 1, TO
MAP HUMAN AND NON-HUMAN PRIMATE
BRAIN CONNECTIVITY, AND THEN AS
I JUST MENTIONED SMALLER SINGLE
COMPONENT PROJECTS THAT ARE
AIMED AT OPTIMIZING CURRENT
TECHNOLOGIES DEVELOPING NEW
ONES, POTENTIALLY MORE RISKY
THAT IF THEY WORK COULD
ACCELERATE THE OVERALL EFFORT.
OKAY.
SO, THAT'S WHERE WE ARE IN TERMS
OF THE MECHANICS OF WHAT WE'VE
BEEN DOING, WE'RE REALLY EXCITED
ABOUT THESE, ALL THESE THREE
PROJECTS.
I THINK THEY WILL REALLY GO A
LONG WAY TO SUPPORTING BRAIN'S
OVERALL GOAL OF UNDERSTANDING
NEURAL CIRCUIT BASIS OF
BEHAVIOR, BOTH IN HEALTH AND
DISEASE, SO THERE'S BEEN A LOT
OF GREAT SCIENCE HAPPENING OVER
THE LAST YEAR OR SO, CERTAINLY
SINCE THE LAST TIME WE MET.
I JUST WANTED TO GIVE A FEW
HIGHLIGHTS OF SOME RECENT
STUDIES.
JUST TO PUT THIS WORK IN
PERSPECTIVE, ONE QUESTION WE GET
ASKED INCLUDING FROM OUR FRIENDS
ON THE HILL WHAT IS THIS BASIC
FANCY RESEARCH DISCOVERY SCIENCE
DOING FOR US?
ONE THING I GOT ASKED, WHEN ARE
WE GOING TO SEE A PAYOFF FROM
THE CELL CENSUS PROJECT?
HERE'S A PAPER JUST PUBLISHED
FROM THE BROAD INSTITUTE WHERE
THEY USED SPATIAL
TRANSCRIPTOMICS TO MAP OUT CELL
TYPES IN HUMANS, LOOKING
SPECIFICALLY AT MID-BRAIN
DOPAMINE NEURONS, POSTMORTEM
TISSUE.
AND THROUGH THIS TRANSCRIPTIONAL
PROFILING THEY IDENTIFIED TEN
DISTINCT SUBPOPULATIONS OF
DOPAMINE NEURONS, AGAIN IN
HUMANS, AND USING THE TECHNIQUE
CALLED SLICE Seq, THEY MAPPED
A IS IS UP SET IN THE
SUBSTANTIA NIGRA, MORE
VULNERABILITY TO PARKINSON'S
DISEASE NEURODEGENERATION,
PROFILING OF TISSUE FROM
PARKINSON'S DISEASE PATIENTS
SUGGESTS SOME SUBTYPES INDEED
ARE DISEASE VULNERABLE, WHEREAS
OTHERS ARE PERHAPS MORE
PROTECTED.
I THINK WE HAVE QUITE A WAYS TO
GO BUT THE ABILITY TO USE THE
TECHNOLOGIES THAT HAVE BEEN
DEVELOPED IN PART WITHIN THE
LARGER BRAIN INITIATIVE CELL
CENSUS PROJECTS TO APPLY TO
HUMAN CONDITION, HUMAN DISEASE,
REALLY NOW GIVES US THE
POSSIBILITY OF LOOKING AT THIS
DISEASE WITH MUCH GREATER
PRECISION AND HOPEFULLY WITH EYE
TOWARD CURES THAT ARE FOCUSED ON
NOT JUST THE CELLULAR
GRANULARITY BUT ALSO WITHIN THE
CELLS, IDENTIFYING PATHWAYS THAT
WE CAN TARGET SPECIFICALLY,
PERHAPS SOME TOOLS WE'RE
DEVELOPING IN ADJACENT PROJECTS
INCLUDING THE ARMAMENTARIUM
PROJECT.
THIS IS ALL VERY EXCITING.
THE AC SEG RATION OF KNOWLEDGE
FROM THESE KINDS OF PROJECTS IS
TRULY BREATHTAKING.
I HOPE YOU'LL AGREE.
FROM A SYSTEMS POINT OF VIEW
THERE'S A NICE PAPER THAT CAME
OUT RECENTLY FROM HARVARD, USING
VOLTAGE IMAGING, TO IDENTIFY
SPINAL CIRCUITS THAT MODULATE
LOCOMOTION IN ZEBRAFISH,
IDENTIFYING NON-OSCILLATING
NEURONS, REVEALING A ROLE IN
REGULATIONING DURATION AND
STRENGTH OF SWIMMING BUT NOT
AFFECTING FREQUENCY.
THIS ENABLES IN VIVO
MEASUREMENT, ESSENTIAL FOR
IDENTIFYING NATURAL ISTIC FIRING
PATTERNS, OFFERING A WINDOW INTO
BEHAVIOR, HELPFUL TO TEASE APART
CIRCUITS, DIFFERENT ASPECTS OF
BEHAVIOR THEY REGULATE.
OKAY.
SO, WITH SOME TREPIDATION I'M
GOING TO PRESENT BRIEFLY A STUDY
LED BY OUR OWN SAMIR.
IF YOU'RE NOT IN THE O.R. FEEL
FREE TO CORRECT ME IF I GET
ANYTHING WRONG.
THE EXCITING THING IN THE STUDY
AND NEXT STUDY IS THE MOVE
TOWARD PERSONALIZED TREATMENTS
FOR MAJOR DEPRESSIVE DISORDERS,
THESE ARE DISORDERS THAT REALLY
IMPACT THE PATIENTS, FAMILIES,
SOCIETY IN GENERAL.
WE NEED NEW APPROACHES FOR
CURES.
HERE WHAT WE'RE SEEING IS THE
APPLICATION IN A VERY
INTERESTING AND NOVEL WAY OF
DEEP BRAIN STIMULATION TO TREAT
SYMPTOMS.
ONE OF THE CHALLENGES IS THAT
IT'S NOT ALWAYS CLEAR WHEN AND
WHERE TO STIMULATE.
HERE SAMIR AND COLLEAGUES USED
HOLOGRAPHIC AUGMENTED REALITY,
THERE'S A REPRESENTATION OF A
CONNECTIVITY WITHIN THE BRAIN.
THEY USE THIS AUGMENTED REALITY
TO PLAN THE IMPLANTATION OF DBS
LEADS AND STEREOEEG RECORDING
ELECTRODES AND USE RECORDINGS
OVER ABOUT A WEEK-AND-A-HALF TO
MONITOR ACTIVITY, CORRELATED
WITH OTHER BEHAVIORAL
MEASUREMENTS, OUTPUT
MEASUREMENTS TO OPTIMIZE DBS
STIMULATION PARAMETERS.
THE PATIENT'S SYMPTOMS IMPROVE
LEADING TO REMISSION, AS YOU CAN
SEE HERE, AND DISCONTINUATION,
AS YOU CAN SEE HERE, AND
DISCONTINUATION IN A DOUBLE
BLINDED STUDY SHOWED THAT IN
FACT THIS STIMULATION WAS
CAUSING AN IMPROVEMENT OF
SYMPTOMS, WHEREAS THE DEVICE LED
THE PATIENT BACK TO A BETTER
MENTAL STATE.
THIS IS ALL VERY EXCITING IN
TERMS OF TAILORING THERAPIES TO
INDIVIDUAL PATIENTS AND
HOPEFULLY THIS WILL BE A
TECHNIQUE THAT CAN BE SCALED UP
OVER TIME.
IN A ANOTHER STUDY THEY
PERFORMED A SIMILAR TYPE OF
EXPERIMENT, USING LONG-TERM
MULTI-SIDE STEREO EEG RECORDINGS
TO DETECT ACTIVITY MARKERS AND
IDENTIFY TREATMENT LOCATION, I
BELIEVE IN THE VENTRAL CAPSULE,
IMPLANTED A TWO-WAY SENSING
STIMULATION DBS DEVICE.
WHAT THEY HAVE DONE IS THEY USED
A BIOMARKER-DRIVEN CLOSED LOOP
THERAPY RESULTS IN RAPID AND
SUSTAINED IMPROVEMENT IN
DEPRESSION.
WE CAN TALK ABOUT WHETHER
THERE'S A VALUE IN DOING THIS ON
THE FLY, MOMENT TO MOMENT, BUT
IT'S EXCITING FROM BOTH
PERSPECTIVE OF TAILORING
TREATMENTS TO INDIVIDUAL
PATIENTS AND TAILORING THROUGH
TIME, THROUGH CLOSED LOOP
THERAPIES.
DBS IS SHOWING IT HAS A LOT MORE
TO GIVE US IN THE RIGHT HANDS
WITH CREATIVITY, I'M LOOKING
FORWARD TO SEEING BROADER
APPLICATION OF THIS APPROACH IN
THE YEARS TO COME.
WE HAVE SEVERAL NEW FUNDING
OPPORTUNITIES.
I MENTIONED THE BRAIN CONNECTS
RFAs, THREE RFAs.
BRAIN IN THE TRANSLATIONAL
DEVICE FIELD RECENTLY SIGNED ON
TO ALIGN WITH BLUEPRINT -- THE
BLUEPRINT MED TECH PROGRAM WHICH
SETS UP TECHNOLOGY INNOVATOR
HUBS, SO HERE WE ARE ENCOURAGING
FOLKS TO APPLY TO THE BRAIN
PROJECTS BUT HOPEFULLY WITH
ABILITY TO TAKE ADVANTAGE OF
THESE INNOVATOR HUBS THAT WILL
HELP EARLIER STAGE PROJECTS GET
THROUGH THE EARLY STAGE
DEVELOPMENT AND REGULATORY
PROCESS AND ON TO DEPLOYMENT IN
HUMANS.
WE'VE ALSO SIGNED ON TO THIS
SCIENCE EDUCATION PARTNER
PROJECT, R25 PROGRAM ACROSS NIH.
WE'RE TRYING TO EXPAND THE POOL
OF BRAIN RESEARCHERS.
THERE'S WAY TO STAY UP TO DATE
ON FUNDING OPPORTUNITIES AND
EVENTS.
THERE'S THE BRAIN BLOG, BRAIN
INITIATIVE WEBSITE, AS WELL AS
THE GUIDE.
OF COURSE, YOUR GREATEST REVERSE
WOULD BE WITHIN OUR POOL OF
TALENTED BRAIN PROGRAM OFFICERS
AND YOU CAN FIND MORE
INFORMATION ABOUT BRAIN AT OUR
WEBSITE.
I WILL STOP THERE AND OPEN THE
FLOOR FOR QUESTIONS AND
DISCUSSION.
>> I DON'T SEE ANY HANDS RAISED.
I THINK YOU DID A WONDERFUL,
CLEAR, EXCITING PRESENTATION.
I THINK MAYBE WE SHOULD MOVE ON,
UNLESS -- ONE MORE CHANCE,
ANYBODY WANT TO ASK JOHN ANY
QUESTIONS?
>> GOING, GOING, GONE.
>> THIS IS DAVID FROM IARPA.
CAN YOU HEAR ME?
>> YES.
>> MAYBE THERE IS NO ANSWER TO
THIS QUESTION BUT I'M JUST
CURIOUS, IF YOU HAVE A
PREDICTION FOR THE TIME SCALE
OVER WHICH THE DIVERSITY
TRAINING AWARDS WILL TRANSLATE
INTO HIGHER APPLICATION RATES,
BY WOMEN AND MINORITIES, SO THAT
THEY ARE BETTER REPRESENTED IN
THE P.I. PORTFOLIO.
>> THAT'S A GREAT QUESTION,
DAVID.
WELL, I CAN GIVE THE OPTIMISTIC
OR REALISTIC VIEW.
SOMEWHERE IN BETWEEN, K99 R 00
PROGRAM IS DIRECTED WORD WOMEN
AND UNDERREPRESENTED GROUPS.
THE PROGRAM HASN'T BEEN AROUND
THAT LONG BUT WE'RE ALREADY
SEEING I THINK CLOSE TO 20+
INVESTIGATORS WHO TRANSITIONED
TO THE R00 PHASE, SO THEY HAVE
BECOME INDEPENDENT FACULTY
MEMBERS.
SO WE'RE HOPEFUL THAT AT LEAST
SOME OF THESE JUNIOR INDEPENDENT
INVESTIGATORS WILL COME IN FROM
BRAIN FUNDING, THE IDEA IS TO
BRING THEM INTO OUR ECOSYSTEM
AND HOPEFULLY THEY WILL STICK
AROUND FOR A BIT.
SO, I'M HOPEFUL THAT WE'LL SEE
SOME INCREASE FROM THAT SEGMENT.
BACKING UP A LITTLE BIT WE'RE
ALSO FUNDING TOGETHER WITH
BLUEPRINT THE D SPAN PROGRAM,
THAT GIVES SUPPORT TO LATE STAGE
GRADUATE AND EARLY STAGE
POSTDOCAL TRAINING, TRYING TO
BRING IN MORE DIVERSE VOICES
INTO THE BRAIN ECOSYSTEM.
IT'S NOT JUST ABOUT MONEY.
MICHELE AND JOHN,Y CHURCHILL AND
COLLEAGUES AND TRAINING TEAM
HAVE DONE A GREAT JOB BUILDING
COMMUNITY.
THEY TALK TO EACH OTHER.
THERE'S PEER TO PEER SUPPORT,
MENTORING GOING ON.
I THINK THESE PROGRAMS WILL I
HOPE HELP.
IT COULD TAKE A SCIENTIFIC
GENERATION OR TWO TO SEE A
DIFFERENCE.
I MEAN, YOU KNOW, THIS IS A BIG
SHIP TO TURN.
SCIENCE GOES BY GENERATIONS.
AN IMPROVEMENT IN THE TREND. OF
AND IT'S NICE ALSO TO SEE THAT
WE HAVE ACCEPTED DIVERSITY OF
SUPPLEMENT REPORTS FROM OUR R00
GRANTEES, SO I THINK IT'S HAVING
A GENERATIVE EFFECT.
HOW WILL IT TAKE TO MOVE THE
NEEDLE?
I CAN'T TELL BUT WE'LL BE
WATCHING CLOSELY.
IF YOU DIG DOWN IN THE DATA IN
THE DEMOGRAPHICS ANALYSIS YOU'LL
SEE SOME YEARS ARE BETTER THAN
OTHERS BUT ARGUABLY IT'S ALL
IN -- I CAN'T SAY THAT ANY
CHANGE YEAR TO YEAR IS OUTSIDE
OF JUST NORMAL VARIABILITY.
I'M HOPING WE'LL START SEEING
THAT TREND MOVE UP.
SO REALISTICALLY IT MIGHT TAKE
ONE OR TWO SCIENTIFIC
GENERATIONS WHICH YOU MIGHT
COUNT AS BETWEEN FIVE AND TEN
YEARS.
I HOPE IT WILL BE ON THE SHORTER
RANGE BUT WE'RE DOING WHAT WE
CAN TO MAKE THAT TRAJECTORY GO
STEEPER.
JIM, YOU HAD YOUR FIRST UP AND
TED -- PHYSICAL HAND UP.
TED HAS A VIRTUAL HAND UP.
>> IT'S GREAT TO SEE THE
PROGRESS ON ALL THESE FRONTS.
MAYBE THIS WILL HAPPEN IN THE
CLOSED SESSION HEARING MORE
ABOUT THE PEDP PLANS PUT IN, AND
DEFICIENCIES THAT NEED TO BE
CORRECTED TO MAKE PLANS MORE
TENABLE.
MAYBE THAT WILL COME IN THE
CLOSED SESSION.
THE OTHER QUESTION I HAD THOUGH
RELATED TO SOMETHING YOU
MENTIONED DURING THE JANUARY
MEETING.
AND THAT'S WHETHER OR NOT
THERE'S BEEN MUCH PROGRESS ON
BRAIN WORKS INITIATIVE, THINKING
ABOUT SCIENCE, NEUROSCIENCE IN
GENERAL, AND I DON'T KNOW IF YOU
HAVE AN UPDATE ON THAT.
>> YEAH, SO THE BRAIN WORKS
PROJECT IS ONGOING.
DR. MOHAMMED GASSIMI IS WORKING
WITH US AGAIN.
HE FINISHED HIS ONE-YEAR DATA
SCHOLAR FELLOWSHIP WITH US AT
THE END OF LAST YEAR.
AND WE FIGURED OUT A WAY TO
CONTINUE COLLABORATING WITH HIM
ON THIS.
WE'RE LOOKING FORWARD TO USING
HIS NATURAL LANGUAGE PROCESSING
ALGORITHMS TO REALLY HELP US
ASSESS NOT JUST WHAT BRAIN HAS
DONE BUT WHERE WE MIGHT BE GOING
WITH IT.
WE'VE HAD A LOT OF CONVERSATIONS
HERE AND ALSO INTERNALLY ABOUT
WHAT CONSTITUTES SUCCESS, HOW DO
YOU EVEN MEASURE SUCCESS.
CAN WE EVEN AGREE ON WHAT
SUCCESS LOOKS LIKE AND FORGET
HOW TO MEASURE IT.
WE'RE HOPING THAT WITH SOME MORE
SOPHISTICATED TOOLS WE MIGHT BE
ABLE TO APPROACH THIS IN A
HYPOTHESIS-DRIVEN WAY TO
UNDERSTAND WHAT WE'RE DOING AND
WHAT IMPACT WE'RE HAVING, WHAT
DOES THIS MEAN FOR US.
STAY TUNED.
WE'RE WORKING ON THAT.
MAYBE I'LL HAVE AN UPDATE FOR
EVERYBODY IN THE SUMMER, LATER
IN THE SUMMER.
WE MEET IN AUGUST.
TED?
>> THANKS, JOHN.
IT'S GREAT TO SEE EVERYBODY.
GREAT TO SEE EVERYTHING
HAPPENING.
I HAVE A COUPLE QUESTIONS AND A
COMMENT.
I HOPE THAT'S OKAY.
MY FIRST QUESTION IS FOLLOWING
UP ON THE QUESTION ABOUT
TRAINING AND DIVERSITY AND, YOU
KNOW, WE HAD THE K99 AND R00s,
WENT BACK EARLIER IN CAREER TO
F99.
BUT I'M INCREASINGLY STRUCK BY
THE CHALLENGES, THE MORE
MID-CAREER CHALLENGES.
YOU KNOW, THE K TO R TRANSITION,
AND ALSO THEN R TO R TRANSITION
WHERE YOU FIND INDIVIDUALS THAT
ARE SORT OF FAILING WITH ONE R
01 AS THEY SEEK TO TRANSITION.
IN PARTICULAR I WONDER IN THE
CONTEXT OF COVID, I KNOW THERE
WERE SOME EXTENSIONS GRANTED BUT
WORTH NOTING THE IMPACT OF COVID
HAS CONTINUED.
AND IN ALL SORTS OF WAYS ONE WAY
IS WITH, FOR EXAMPLE, STAFFING.
THAT MAKES IT MORE DIFFICULT NOW
TO DO SOME EXPERIMENTS, EVEN
THOUGH WE CAN, WITH REDUCED
RESTRICTIONS.
I WONDER WHAT THOUGHTS ARE
THINKING BEYOND K99 AND BEYOND
Rs, REALLY, TO THINK MORE
ABOUT CAREER AWARDS OR OTHER
THINGS TO HELP INDIVIDUALS AS
THEY NAVIGATE RATHER THAN JUST
WAITING FOR THIS TO GO THROUGH
THE GENERATIONS.
IT SEEMS LIKE THERE ARE PLACE
WHERE IS WE MIGHT BE ABLE TO
HAVE AN IMPACT.
>> YEAH, THAT'S A GREAT POINT,
TED.
WE'LL CERTAINLY KEEP THAT IN
MIND.
WE'VE BEEN ISSUING MORE THAN A
FEW COVID-RELATED REASONS AND
DELAYS, I THINK ACROSS NIH THE
MODE HAS BEEN TO ERR ON THE SIDE
OF BEING GENEROUS.
ONE THING WE'RE VERY MUCH
KEEPING AN EYE ON, LET'S SEE
WHAT THE FY 22 DEMOGRAPHICS LOOK
LIKE, I'M REALLY CONCERNED THAT
WE'RE GOING TO SEE A DISPARITY
IN FUNDING SUCCESS RATES.
WE DIDN'T SEE THEM IN 2021 BUT
I'M NOT TAKING ANYTHING FOR
GRANTED HERE.
I THINK THE MID-CAREER PHASE, I
WENT THROUGH THIS MYSELF.
IT'S A TOUGH TIME, RIGHT?
SOMEWAY SAY THE HARDEST THING TO
DO IS GET YOUR FIRST R01 BUT
IT'S TO GET YOUR SECOND, OR DO
WE NEED A FIRST ONE, WHAT CARLA
REFERRED TO, LOOKING AT ME, AS
THE UGLY DUCKLING PHASE.
WE'RE LOOKING AT OTHER WAYS TO
RETAIN CERTAIN PROFESSIONALS IN
THE SPACE WHO MIGHT OTHERWISE BE
PULLED TO OTHER CAREER OPTIONS.
WE'RE PLOOKING -- LOOKING AT
ALL THIS.
IT'S ALL IN THE MIX.
>> THINKING ABOUT MAYBE
PARTICULAR KINDS OF K AWARDS,
THAT STRIKES ME AS SOMETHING TO
THINK ABOUT CREATIVELY.
>> RIGHT.
>> THE OTHER THING I JUST WANTED
TO RAISE AS WE THINK ABOUT
TREATMENTS WHICH IS ABSOLUTELY
TERRIFIC, SOME OF THE DBS YOU
WERE PRESENTING.
YOU KNOW, I'M STRUCK, THIS IS A
GENERAL COMMENT, BY HOW MUCH AS
WE THINK ABOUT THIS
CONCEPTUALLY, I THINK MANY
PEOPLE THINK ABOUT BRINGING
FUNCTION TO WHAT IT WAS
TYPICALLY.
AND I CERTAINLY HAVE SEEN THIS
IN THE AUTISM FIELD AND IN THE
NEURODEVELOPMENTAL FIELD WHERE
NOW WE FOR SOME OF THE, YOU
KNOW, THE MOTOR NEURON DISEASES
WE HAVE SOME AAV TREATMENTS.
EVEN THERE IT'S BEEN DIFFICULT
TO MEASURE FUNCTION.
WE'RE NOT JUST GOING TO RESTORE
FUNCTION.
I REMEMBER SOME WORK FROM HELEN
NEVILLE FROM DECADES AGO,
LOOKING AT SECOND LANGUAGE
LEARNING, AND AMERICAN SIGN
LANGUAGE LEARNING, WHERE THERE
WERE NEURAL CIRCUITS ON THE
OTHER SIDE OF THE BRAIN THAT
WIND UP BEING INVOLVED AND OTHER
PARTS OF THE BRAIN IN PLASTICITY
THAT ACTUALLY CAN DRIVE SOME
SECOND LANGUAGE LEARNING AND
FUNCTIONAL SECOND LANGUAGE BUT
ARE ACTUALLY DISTINCT FROM WHAT
WOULD BE THE PRIMARY LANGUAGE.
I THINK THINKING MORE CREATIVELY
ABOUT WHAT WE MIGHT EXPECT THESE
THERAPIES TO DO IS ACTUALLY
REALLY IMPORTANT.
I THINK WE HAVEN'T REALLY EVEN
THOUGHT ABOUT THAT BECAUSE WE'VE
BEEN SO FAR FROM ALL THIS.
IT'S KIND OF TIME TO THINK ABOUT
THAT.
IF WE DON'T THINK ABOUT IT, WE
MIGHT HAVE HAVE A THERAPY WE MAY
NOT KNOW IS EFFICACIOUS BECAUSE
WE CAN'T ACTUALLY SEE IT BECAUSE
WE DON'T HAVE THE RIGHT
MEASURES.
SO A LOT OF THE MEASURES WE
HAVE, PARTICULARLY IN THE
PSYCHIATRIC SPACE, ARE OFTEN
MEASURES THAT ARE BASED ON
DIAGNOSING SOMEBODY, NOT
ACTUALLY GETTING A SENSE OWH
R THEY ARE IMPROVING OR
NOT.
I THINK WE HAVE A LOT OF WORK TO
DO AS WE THINK ABOUT THE
OPPORTUNITY OF THERAPIES.
>> YEAH, THAT'S A GREAT POINT,
TED.
I AGREE WITH ALL OF THE ABOVE.
ALSO, TO APPRECIATE THAT THE
BRAIN ONCE WE'RE HATCHED IS NOT
STATIC, AS YOU'RE PERHAPS
GETTING TO THIS A BIT.
>> RIGHT.
>> THIS WAS A BIG MOTIVATION
BEHIND THE LIFESPAN WORKSHOP IS
TO REALLY UNDERSTAND HOW IS THE
BRAIN CHANGING OVER TIME.
WHEN WE DO THINK ABOUT
INTERVENTIONS, WHAT ARE WE
TRYING, AS YOU SAY, WHERE ARE WE
TRYING TO GET THE BRAIN BACK TO
AND WHAT IS IT CAPABLE OF DOING
AND HOW DO WE MEASURE IT?
THIS GOES AT ALL LEVELS OF
ANALYSIS, BEHAVIORAL ANALYSIS AS
WELL AS ON THE -- IN TERMS OF
CELLULAR BASIS.
IF WE LOOK, FOR EXAMPLE, AT THE
BLOOD-BRAIN BARRIER, CELLULAR
CONSTITUENTS CHANGE OVER THE
LIFETIME OF THE ANIMAL OR HUMAN.
IF WE'RE THINKING ABOUT, FOR
EXAMPLE, THERAPIES THAT DEAL
WITH CROSSING OR BREACHING THE
BLOOD-BRAIN BARRIER THIS WILL
LIKELY BE DIFFERENT FOR YOUNG
CHILD, YOUNG CHILD, VERSUS OLDER
ADULT.
I AGREE COMPLETELY.
AND THIS IS ONE OF THE
CHALLENGES THAT WE ARE FACING.
>> THANK YOU.
>> I JUST WANT TO MAKE A QUICK
COMMENT ON THAT ALSO.
I THINK THE OTHER THING THAT NIH
IN GENERAL IS STARTING TO PAY
MORE ATTENTION TO ARE PATIENT
OUTCOMES AND WHAT IS IT THAT'S
MEANINGFUL FOR A PATIENT.
SO IT MAY NOT NECESSARILY BE
FULL RESTORATION OF CERTAIN
FUNCTIONS BUT RESTORING
FUNCTIONS THAT REALLY CAN AFFECT
THE QUALITY OF THEIR LIVES.
SO I AGREE IT'S A REALLY GOOD
POINT.
JOHN, IF YOU'RE READY WE CAN
MOVE ON TO HANK.
>> IN THE INTEREST OF STAYING ON
TIME FOR ONCE, PROFESSOR GREELY?
>> WHY THANK YOU, DR. NGAI.
YOU WERE SO SUCCINCT IN YOUR
PRESENTATION I THOUGHT I WAS
GOING TO HAVE 23 MINUTES TO TALK
INSTEAD OF 10 MINUTES TO TALK.
I WASN'T PLANNING TO USE THE 23,
I'M NOT PLANNING TO USE THE
WHOLE 10.
GREETINGS FROM THE NEUROETHICS
WORKING GROUP.
WE TYPICALLY MEET TWICE A YEAR.
WE MEET BEFORE THE JANUARY
MEETING OF THE MULTI-COUNCIL
WORKING GROUP AND BEFORE THE
AUGUST MEETING.
OUR LAST MEETING WAS JANUARY 24.
I REPORTED ON THAT MEETING AT
THE JANUARY 25 MEETING OF THE
MULTI-COUNCIL WORKING GROUP, WE
HAVEN'T MET SINCE THEN SO I
DON'T HAVE MUCH IN THE WAY OF
NEW THINGS TO REPORT.
BUT I DO HAVE A LITTLE BIT.
OUR GROUP IS HOLDING A WORKSHOP
ON CLINICAL TRIAL
RESPONSIBILITIES THAT MAY
CONTINUE PAST THE END OF THE
TRIAL THAT WILL BE TUESDAY AND
WEDNESDAY OF NEXT WEEK.
IT'S BEEN AN ISSUE THAT'S BEEN
ON MANY PEOPLE'S MINDS WITH
RESPECT TO PARTICULARLY
IMPLANTED DEVICES, IN PEOPLE.
WE ARE ALSO CONTINUING TO BE
AVAILABLE FOR CONSULTS, FOR
PEOPLE WHO HAVE GRANTS FROM THE
BRAIN INITIATIVE AS WELL AS FROM
THE PROGRAM OFFICE, PROGRAM
STAFF, AND SO ON.
WE'RE DOING A CONSULT NEXT WEEK,
NEXT FRIDAY, ABOUT AN ETHICAL
ISSUE WITH RESPECT TO A GRANT
APPLICATION.
OTHER THAN THAT, WITH RESPECT TO
THE NEUROETHICS WORKING GROUP
ITSELF, THERE ARE TEN OF US.
I CO-CHAIR IT ALONG WITH
CHRISTINE GRADY, CHIEF OF THE
NIH DEPARTMENT OF MEDICINE,
DEPARTMENT OF BIOETHICS AT THE
CLINICAL MEDICAL CENTER.
BUT JOHN HAS BEEN CONTINUING TO
ROTATE THE MEMBERSHIP OF IT.
GOING OFF OUR COMMITTEE, AT THE
LAST MEETING, WAS THE MAN OF
MANY HATS, STEVE HYMAN, LOSING
ONE HIS HATS, I'M HAPPY TO SAY
THAT HE'S BEING REPLACED, WELL,
REPLACED, HIS HAT IS BEING TAKEN
UP BY HIS SUCCESSOR IN ANOTHER
HAT, NEW PRESIDENT OF THE DANA
FOUNDATION, DR. CAROLINA MONTOJO
JOINING AT OUR AUGUST MEETING.
THAT'S IT FOR SPECIFIC COMMENTS.
A COUPLE OTHER THINGS TO COMMENT
ON MORE BROADLY IN NEUROETHICS,
ON FEBRUARY 7, LED BY FRANCIS
SHEN, WHO IS A P.I. ON ONE OF
THE NEUROETHICS GRANTS, THE
NEUROETHICS P.I.s GOT TOGETHER
AND HELD A VIRTUAL MEETING,
INVITING MEMBERS OF THE --
MEMBERS AND STAFF MEMBERS FROM
THE NEUROETHICS WORKING GROUP,
IT WENT REALLY WELL.
THEY PLANNED TO CONTINUE TO HAVE
MEETINGS OF THE NEUROETHICS
P.I.s, AND TALK ABOUT WHERE
THE FIELD IS DOING AND WHAT CAN
BE DONE.
SECOND, EXACTLY ONE HOUR AND
FIVE MINUTES AGO, I GOT AN
E-MAIL FROM KHARA RAMOS, WHO IS
NOW WITH THE DANA FOUNDATION,
SAYING THE DANA FOUNDATION IS
SEEKING APPLICATIONS FOR
PLANNING GRANTS FOR FUTURE DANA
CENTERS FOR NEUROSCIENCE AND
SOCIETY.
DANA IS PLANNING TO FUND AT
APPROXIMATELY A MILLION DOLLARS
A YEAR FOR FIVE YEARS ONE OR
MORE CENTERS ON NEUROSCIENCE AND
SOCIETY WHICH I THINK IS ANOTHER
VERY GOOD SIGN ABOUT THE
IMPORTANCE WITH WHICH THE
ETHICAL, SOCIAL AND LEGAL ISSUES
RAISED BY NEUROSCIENTISTS ARE
BEING TAKEN.
THERE'S BEEN CONVERSATION IN THE
GENERAL FIELD AROUND THE NOOG
GUIDING PRINCIPLES FOR
NEUROETHICS, SIMILAR BUT MAYBE
DIFFERENT FROM OECD, NOTHING
SUBSTANTIVE TO REPORT OTHER THAN
OUR WORK CONTINUES TO BE
NOTICED.
IT CONTINUES TO BE NOTICED IN
LARGE PART, THANKS TO THE HUGE
HELP WE GET FROM DR. NINA HSU,
OUR STAFF CONTACT, WITH THE
BRAIN INITIATIVE AND DR.
HENDRICKS OF THE NIH CLINICAL
BIOETHICS CENTER WHO WORKS ON A
LOT OF ISSUES AROUND THE
NEUROETHICS WORKING GROUP.
I THINK THAT'S THE END OF MY
REPORT, JOHN, IN APPROXIMATELY
FOUR MINUTES AND SEVEN SECONDS.
>> THANK YOU, HANK.
>> YOU'RE WELCOME, JOHN.
>> WE HAVE TIME FOR QUESTIONS OR
COMMENTS.
>> THEY DID WITH WITH YOU TOO,
NOBODY ASKED A QUESTION FOR
SEVERAL SECONDS AND YOU GOT
DELUGED.
>> LET'S GIVE PEOPLE A BIT OF
TIME.
WE'RE VERY MUCH LOOKING FORWARD
TO THE CONTINUING
RESPONSIBILITIES OR WORKSHOP,
SOMETHING THAT'S BEEN FACING
US -- IT FACES THE WHOLE FIELD
OF BIOMEDICINE BUT I DO FEEL
ONCE WE ARE IMPLANTING DEVICES
INTO PEOPLE'S HEADS, THIS DOES
TAKE ON SOME ADDITIONAL AREAS OF
CONCERN.
I SEE TED HAS HIS HAND RAISED.
>> HANK, THANKS A LOT.
VERY INTERESTING HEARING THE
DISCUSSIONS.
I HAVE A KIND OF A GENERAL
COMMENT IN THIS SPACE, AND I'VE
MADE THIS COMMENT TO JOHN, AND I
JUST THOUGHT I WOULD MAKE IT TO
THIS GROUP.
LAST TIME I BELIEVE, MAYBE IT
WAS IN LAST NEW EGG MEETING, OR
IN THIS MEETING, I'M SORRY, I
CAN'T REMEMBER, A CLINICAL TRIAL
PARTICIPANT SPEAK WHICH WAS
REALLY, REALLY TERRIFIC.
AND I THINK AS WE THINK AND LOOK
TO THE FUTURE WHERE WE'RE ABLE
TO HAVE THERAPEUTIC IMPACT WITH
THE TECHNOLOGIES DEVELOPED BY
THE BRAIN INITIATIVE, I THINK
IT'S MORE AND MORE IMPORTANT TO
INCORPORATE INDIVIDUALS AND
FAMILIES THAT ARE IMPACTED BY
THESE DISORDERS.
I REALIZE EACH OF THE INDIVIDUAL
COUNCILS DO THAT IN THEIR OWN
WAY.
MENTAL HEALTH RECENTLY STEPPED
DOWN, BRANDON STAGLAND, A
PHENOMENAL ADVOCATE.
THIS IS DIFFERENT THAN A
CONVENTION ILL -- CONVENTIONAL
ADVISORY PANEL, I'M NOT IN THE
NIH SYSTEM BUT I WANT TO MAKE
THE POINT I THINK IT'S IMPORTANT
THAT WE REALLY FULLY INCORPORATE
THE PERSPECTIVE OF INDIVIDUALS
IMPACTED BY BRAIN DISORDERS.
AND THAT WE DO THAT, I THINK WE
SHOULD DO THAT AT THIS LEVEL.
BUT I JUST WANTED TO RAISE THAT
AS A COMMENT.
>> I THINK THAT'S A GOOD POINT.
THE NEUROETHICS WORKING GROUP
CURRENTLY HAS -- WE'RE ABOUT
EVENLY SPLIT BETWEEN
SCIENTISTS/CLINICIANS ON ONE
HAND AND ETHICISTS ON THE OTHER,
ALTHOUGH MANY PEOPLE ARE A
LITTLE BIT OF BOTH.
OF COURSE, ALL TEN OF US ON THE
GROUP ARE AFFECTED BY BRAIN
DISEASES, EITHER PERSONALLY OR
THROUGH OUR FAMILIES AND
FRIENDS.
THERE'S NO ONE IN THE COUNTRY OR
THE WORLD WHO IS NOT AFFECTED BY
BRAIN DISEASES.
THE IDEA OF INCREASING THE VOICE
AND PARTICIPATION OF PEOPLE WHO
ARE MUCH MORE DIRECTLY AFFECTED,
I THINK, IS ONE THE NOOG SHOULD
BE CONSIDERED.
>> YOU RAISE A GOOD POINT THE I.
C.S HAVE REPRESENTATION, THE
VOICES.
WHAT WE'VE BEEN LOOKING AT,
WE'VE BEEN LOOKING TOWARD
FINDING A VOICE OR VOICES THAT
REPRESENT NOT NECESSARILY
SPECIFIC DISEASE AREAS BUT
REALLY MORE FROM THE DOMAIN OF
HUMAN RESEARCH PARTICIPANTS.
THERE ARE SOME FOLKS OUT THERE,
WE'RE ACTUALLY MOVING ALONG ON
THAT.
ALBEIT SOMEWHAT GLACIALLY, BUT
POINT WELL TAKEN.
I HOPE TO HAVE A MORE POSITIVE
THING TO SAY ABOUT THAT IN THE
COMING MONTHS OR SO.
>> THANKS, TED.
>> ALSO IMPORTANT TO KNOW, I
HOPE YOU HAVE TIME TO TUNE IN TO
NEXT WEEK'S CONTINUING TRIALS
WORKSHOP, WE'LL HAVE
PARTICIPANTS THERE THAT ARE
ACTUAL PATIENTS OR CAREGIVERS IN
THESE CLINICAL TRIALS.
THIS IS A VIEWPOINT, THESE ARE
STAKEHOLDERS, RIGHT?
IT'S NOT JUST SOMEBODY GIVING US
OUTSIDE ADVICE.
THESE ARE ABSOLUTELY COMMITTED
STAKEHOLDERS SO WE DO NEED TO
KEEP THAT FRONT OF MIND.
OKAY.
OTHER QUESTIONS OR COMMENTS?
OKAY, SUSAN, IS BRYAN UP NEXT?
YES.
>> IS BRYAN WITH US?
>> YES, I SAW HIM EARLIER.
THERE HE IS.
>> OKAY, GREAT.
IT'S MY PLEASURE TO INTRODUCE
OUR SPEAKER, DR. BRYAN ROTH, ONE
OF NIMH'S COUNCIL
REPRESENTATIVES.
AND PRIOR TO THE PANDEMIC THERE
WAS A TRADITION HAVING NEW
MEMBERS GIVE SCIENCE TALKS AT
THESE MCWG MEETINGS.
FOR THE INTEREST OF TIME AND
ZOOM FATIGUE WE KIND OF USED
THIS SLOT MORE SPARINGLY.
I THINK WE MIGHT HAVE SKIPPED
OVER A FEW BUT WE'LL CIRCLE
AROUND TO YOU OTHER NEW MEMBERS.
DON'T FEEL LEFT OUT.
WE THOUGHT THIS WOULD BE A GREAT
TIME TO HAVE BRYAN TELL US ABOUT
SOME OF HIS RECENT RESEARCH.
HE'S THE MICHAEL HOOKER
PROFESSOR IN DEPARTMENT OF
PHARMACOLOGY AT UNIVERSITY OF
NORTH CAROLINA, CHAPEL HILL.
AND HE'S ALSO THE DIRECTOR OF
THE NIMH PSYCHOACTIVE DRUG
SCREENING PROGRAM.
BRYAN'S RESEARCH INTERESTS ARE
IN G-PROTEIN COUPLED RECEPTOR
STRUCTURE AND FUNCTION,
SYNTHETIC NEUROBIOLOGY AND DRUG
DISCOVERY, A PIONEER IN THE
FIELD OF CHEMOGENETICKICS AND
INVENTED DREADDS, DESIGNER
RECEPTORS EXCLUSIVELY ACTIVATED
BY DESIGNER DRUGS, THAT'S A
TECHNOLOGY THAT'S BEING USED BY
HUNDREDS OF LABS AROUND THE
WORLD TO PROBE NEURAL CIRCUIT
FUNCTION.
AMONG HIS MANY HONORS HE'S
ELECTED MEMBER OF THE NATIONAL
ACADEMY OF MEDICINE, AS WELL AS
AMERICAN ACADEMY OF ARTS AND
SCIENCES, HAS BEEN HIGHLY
PROLIFIC AS WELL AS GENEROUS
SHARING REAGENTS AND TODAY WILL
TELL US ABOUT RECENT WORK ON NEW
CHEMICAL AND SYNTHETIC BIOLOGY
TECHNIQUES.
SO BRYAN, ALL YOURS.
THANK YOU FOR BEING HERE AND
AGREEING TO GIVE THIS TALK.
>> THANKS.
GREETINGS FROM SPAIN.
CAN YOU HEAR ME ALL RIGHT?
>> YES, WE CAN.
>> GREAT.
BEFORE I START, I THOUGHT I
WOULD SAY I'M AT A SYMPOSIUM PUT
ON BY CELL PRESS ON THE
NEUROBIOLOGY OF NEUROPSYCHIATRIC
DISORDERS, AND THE THING THAT
MADE THE BIGGEST IMPRESSION ON
ME SO FAR IN THE FIRST DAY AND A
HALF OF PRESENTATIONS WAS HOW
MUCH PRESENTATIONS RELY ON
METHODOLOGY AND KNOWLEDGE FROM
THE BRAIN INITIATIVE.
EVERY PRESENTATION WOULD BE
DIFFERENT AND INEFFICIENT IN
MANY WAYS WITHOUT THE WORK DONE
BY THIS ASTOUNDING INITIATIVE.
SO KEEP UP THE GOOD WORK, FOLKS.
HOPEFULLY WE CAN CONTINUE IN THE
FUTURE.
WHAT I'M GOING TO TALK ABOUT
TODAY IS SOME WORK THAT HAS
EMERGED FROM MY LAB OVER THE
LAST FEW YEARS, I'LL GIVE YOU AT
THE VERY END SOME RECENT
UNPUBLISHED DATA ON OUR EFFORTS
TO COME UP WITH NEW WAYS, MORE
EFFECTIVE WAYS, OF MAKING
THERAPIES FOR SERIOUS
NEUROPSYCHIATRIC ILLNESSES.
AND IN PARTICULAR, DRUG
THERAPIES.
AND IN THE TALK TODAY I'M GOING
TO FOCUS ON A SINGLE FAMILY OF
DRUGGABLE TARGETS IN THE HUMAN
GENOME CALLED G-PROTEIN COUPLED
RECEPTORS.
AND THEY GET THEIR NAME BECAUSE
THEY COUPLE TO HETEROTRIMERIC,
THEY EXERT SIGNALING ACTION UPON
DRUG BINDING, AGONIST BINDING,
EXCHANGES, AND THE ASSOCIATION
OF HETEROTRIMERIC G-PROTEINS AND
ACTIVATION OF SIGNALING
PATHWAYS, THE ONE I'M SHOWING
HERE IS ONE SHARED BY SEVERAL OF
THE SEROTONIN RECEPTORS I'M
GOING TO BE TALKING ABOUT TOWARD
THE END OF THE TALK.
SO FOLLOWING THIS CONVENTIONAL
SIGNALING PROCESS, THE RECEPTORS
ARE TYPICALLY PHOSPHORYLATED,
AND THEN PROTEINS CALLED
ARRESTINS BIND.
BECAUSE OF THE BINDING, THEY
ABROGATE, ARREST SIGNALING,
SERVE AS SCAFFOLDS AND THE
SIGNALING HIS A DIFFERENT
TEXTURE IN SPACE AND TIME.
ONE OF THE THEMES IN DRUG
DEVELOPMENT AND DRUG DISCOVERY
AT G-PROTEIN COUPLED RECEPTORS
IS TO DISCOVER DRUGS THAT
SELECTIVELY MODULATE THESE
VARIOUS PATHWAYS WITH THE IDEA
THAT SUCH BIASED DRUGS MAY
REPRESENT NEW AND IMPROVED
THERAPIES FOR A LARGE NUMBER OF
HUMAN DISEASES.
NOW, AS I'M SURE MANY OF THE
SCIENTISTS HERE KNOW, ABOUT A
THIRD OF THE FDA-APPROVED DRUGS
THAT ARE CURRENTLY IN USE IN THE
U.S. TARGET G-PROTEIN COUPLED
RECEPTORS AS CANONICAL TARGET.
SOME YEARS AGO WE DECIDED TO TRY
TO MAP THE RECEPTOR TARGET FOR
THE VARIOUS APPROVED DRUGS, THAT
TARGET GPCRs ACROSS THE
SPECTRUM IN THE HUMAN GENOME,
THIS IS A PHYLOGENETIC TREE.
ONLY A SMALL NUMBER OF THE 400
OR SO DRUGGABLE GPCRs IN THE
HUMAN GENOME ARE TARGETED BY
APPROVED MEDICATIONS, AND THIS
IS RAISED THE POSSIBILITY WE
MIGHT BE ABLE TO IDENTIFY NEW
AND PROMISING THERAPEUTICS BY
STUDYING THESE UNDERSTUDIED AND
UNTARGETED G-PROTEIN COUPLED
RECEPTORS IN THE HUMAN GENOME.
THIS WAS A GOAL OF A LARGE
INITIATIVE THAT IS NOW WINDING
DOWN CALLED ILLUMINATING THE
DRUGGABLE GENOME INITIATIVE THAT
MY LAB IS PART OF.
AND OUR PARTICULAR PORTION OF
THIS WAS TO CREATE TOOL
MOLECULES SO THESE ARE DRUG-LIKE
MOLECULES FOR MANY OF THE
UNDERSTUDIED G-PROTEIN COUPLED
RECEPTORS INCLUDING WHAT ARE
CALLED THE ORPHANS.
AT -- AND THE APPROACH THAT
WE'VE USED AND PIONEERED RELIES
FIRST ON STRUCTURAL
DETERMINATION OF THE RECEPTORS
AND THEN WHAT'S CALLED
STRUCTURE-GUIDED OPTIMIZATION.
AND THEN ONCE WE HAVE THESE TOOL
MOLECULES IN HAND, TO VALIDATE
THEIR USE FOR NOVEL THERAPEUTIC
INDICATIONS.
HERE AGAIN IS THE PHYLO GRAM OF
G-PROTEIN COUPLED RECEPTORS.
OVER THE YEARS MY LAB AND THE
LABS OF MY COLLABORATORS, RAY
STEVENS AND VADIN AT USC, ERIC
XU LAB NOW AT CHINA, MY LAB,
HAVE COLLABORATED AND SOLVED
STRUCTURES OF A NUMBER OF VERY
IMPORTANT G-PROTEIN COUPLED
RECEPTORS AND RECALL THE FIRST
STEP OF OUR APPROACH FOR
CREATING DRUG-LIKE MOLECULES
THAT ULTIMATELY COULD BE USED AS
THERAPEUTICS IS TO SOLVE THE
STRUCTURE OF THE RECEPTOR.
AND SO A NUMBER OF STRUCTURES
WERE SOLVED, I'LL GO THROUGH
THESE QUICKLY.
VIRTUALLY ALL, THE OPIATE
RECEPTORS HAVE NOW BEEN SOLVED
IN VARIOUS STATES.
LISTING THE PUBLICATIONS THERE.
INTERESTING STRUCTURE OF THE
SMOOTH END RECEPTOR, WHICH IS A
DRUGGABLE TARGET THAT IS
TARGETED BY MANY DRUGS USED IN
TREATING SERIOUS CANCERS,
MELATONIN RECEPTORS WHICH ARE
TARGETS FOR DRUGS THAT AFFECT
CIRCADIAN RHYTHMS, AND MAY BE
USED FOR TREATING THINGS LIKE
JET LAG, VARIOUS SEROTONIN
RECEPTORS THAT ARE THE TARGETS
FOR MANY, MANY DRUGS THAT ARE
USED IN NEUROLOGY AND
PSYCHIATRY.
DOPAMINE RECEPTORS, AGAIN, THEY
ARE THE TARGETS FOR MANY DRUGS
THAT ARE USED IN TREATING
DISEASES AS DIVERSE AS
SCHIZOPHRENIA AND PARKINSON'S
DISEASE.
AND MORE RECENTLY, AN
INTERESTING FAMILY OF ORPHAN
GPCRs INVOLVED IN BOTH THE
SENSATIONS OF PAIN AND
SENSATIONS OF ITCH, AND THE IDEA
IS THAT ANOTHER STUDY AND
UNDERSTANDING OF UNDERSTUDIED
RECEPTORS MAY PROVIDE NEW
THERAPIES FOR PAIN AND ITCH.
SO, ONCE WE HAVE SOLVED THE
STRUCTURES, THEN WE USE THESE
STRUCTURES FOR EITHER
DISCOVERING NEW DRUG-LIKE
MOLECULES THAT CAN INTERACT WITH
THE RECEPTORS OR TO OPTIMIZE
THEM BY WHAT'S CALLED STRUCTURE
GUIDED OPTIMIZATION, OR
SOMETIMES BOTH.
I WANT TO DESCRIBE OUR EFFORTS
ON DOPAMINE RECEPTORS.
OF COURSE, THERE ARE A NUMBER OF
MEDICATIONS THAT ARE USED TO
TREAT VARIOUS NEUROPSYCHIATRIC
DISEASES THAT TARGET DOPAMINE
RECEPTORS.
UNFORTUNATELY MOST OF THESE
DRUGS ARE RELATIVELY
NON-SELECTIVE.
AND HAVE A NUMBER OF SERIOUS
SIDE EFFECTS DUE TO THEIR OFF
TARGET ACTIVITY.
AND SO WHAT WE DECIDED TO
ATTEMPT SOME YEARS AGO WAS TO
SEE IF WE COULD SOLVE THE
STRUCTURES OF THESE RECEPTORS
WHICH WE DID.
AND THEN TO USE THIS INFORMATION
TO DEVELOP DRUGS THAT ARE MORE
SELECTIVE IN INTERACTING WITH
DOPAMINE RECEPTORS WITH THE IDEA
THAT EVENTUALLY THEY WOULD BE
MORE EFFECTIVE TREATMENTS FOR A
NUMBER OF DISEASES.
WE SOLVED STRUCTURES, AND YOU
CAN SEE THE FINDING POCKETS
THERE.
ONCE WE HAD THE STRUCTURES WHAT
WE DID, WE BEING THE LAB OF MY
COLLABORATOR AT UCSF, USED A
POWERFUL COMPUTATIONAL APPROACH
WHICH IS CALLED AUTOMATED
DOCKING WHICH CAN PREDICT WHICH
COMPOUNDS CAN BIND TO A SPECIFIC
SITE THAT LOOKS LIKE THIS
TRIANGLE, AND HERE AT THE D 4
DOPAMINE RECEPTOR WE HAVE THE
TRIANGLE AND ANOTHER POCKET.
THE IDEA IS CAN WE SAMPLE
CHEMICAL SPACE IN A
COMPUTATIONAL WAY TO FIND
COMPOUNDS TO INTERACT
SELECTIVELY WITH ONE RECEPTOR,
AND NOT THE OTHER.
AND IN THIS CASE WE USED THE D4
RECEPTOR AS THE TEST AGENT.
AND ONE OF THE NICE THINGS ABOUT
THESE COMPUTATIONAL APPROACHES
IS THAT MILLIONS AND NOW
BILLIONS, LITERALLY BILLIONS OF
MOLECULES, CAN BE TESTED IN A
RELATIVELY RAPID FASHION.
SO WE RECENTLY COMPLETED A
SCREEN OF TWO BILLION MOLECULES,
AND THIS WAS COMPLETED IN ABOUT
A DAY AND A HALF WITH A VERY
LARGE CLUSTER OF SUPERCOMPUTERS.
IN OUR OFFICIAL STUDIES WE
DOCKED MILLIONS OF MOLECULES,
DOCKED IN SILICO.
YOU CAN IMAGINE EACH OF THE
SHAPES IS A DIFFERENT MOLECULE,
AND THE COMPUTATIONAL APPROACHES
ALLOW FOR PICKING OF COMPOUNDS
THAT WOULD HAVE A HIGH
PROBABILITY OF INTERACTING WITH
THE RECEPTOR.
TO GIVE A LITTLE MORE DETAIL ON
HOW THIS IS DONE WE NOW HAVE
VERY LARGE LIBRARIES OF
MOLECULES WHICH EXIST ONLY IN
THEORY.
THESE LIBRARIES ARE NOW IN THE
TENS OF BILLIONS OF COMPOUNDS,
BUT THE COMPOUNDS EVEN THOUGH
THEY DON'T EXIST IN THE PHYSICAL
UNIVERSE COULD IN THEORY BE
SYNTHESIZED BY A SKILLED
CHEMIST.
SO WHAT IS DONE IS THESE VERY
LARGE LIBRARIES ARE THEN
COMPUTATIONALLY INTERROGATED
AGAINST THE RECEPTOR TYPE.
ONE OF THE THINGS ABOUT THE
APPROACH IS THAT EACH OF THE
MOLECULES IS TESTED IN A LARGE
NUMBER OF DIFFERENT ORIENTATIONS
UP TO A MILLION ORIENTATIONS AND
CONFIRMATIONS.
YOU CAN IMAGINE IF YOU'RE
TESTING BILLIONS OF MOLECULES,
MILLIONS OF ORIENTATIONS, YOU'LL
HAVE VERY LARGE DATASETS.
THEY ARE SCORED.
AND THEN ULTIMATELY COMPOUNDS
ARE SYNTHESIZED FROM THOSE THAT
WERE TESTED.
AND OPTIMIZED.
AND THIS IS A LITTLE MOVIE ON
HOW THIS WAS DONE WITH THE D4
RECEPTOR.
HERE YOU HAVE OUR STRUCTURE OF
THE D4 RECEPTOR, IN COMPLEX WITH
ANTIPSYCHOTIC DRUG, A HIGH
RESOLUTION STRUCTURE, AROUND 1.9
ANGSTROMS, BECAUSE OF THIS WE'RE
ABLE TO SEE MANY FEATURES OF
DRUG INTERACTING WITH RECEPTOR
THAT WE WOULD NOT NORMALLY BE
ABLE TO SEE.
D4 RECEPTOR HAD THIS -- I'LL GO
BACK HERE A BIT -- HAS THIS
EXTENDED BINDING POCKET, UNIQUE
TO THE RECEPTOR.
SO WHAT WE DID WAS RE, AS WE
INTERROGATED OUR LIBRARY OF
INDIVIDUAL MOLECULES, WE MADE
SURE THAT THEY INTERACTED BOTH
WITH THE SORT OF REGULAR BINDING
SITE AS WELL AS WITH THIS
EXTENDED BINDING SITE.
AND THROUGH AN ITERATIVE SERIES
OF OPTIMIZING CHEMICAL
OPTIMIZATION OF SCAFFOLDS AND
ITERATIVE DOCKING, WE WERE
ULTIMATELY ABLE TO COME UP WITH
THIS COMPOUND UCS 924 WHICH
TURNED OUT TO BE A NANOMOLE OR
POTENCY, HIGHLY SELECTIVE D4
AGONIST, ANIMATION PREPARED BY
ANAAT.
OVER THE YEARS WE'VE CARRIED OUT
A NUMBER OF SIMILAR CAMPAIGNS,
MY LAB AND THE CHOIKET LAB HAVE
BEEN LEADING THIS EFFORT FOR
WELL STUDIED G-PROTEIN RECEPTORS
AND UNDERSTUDIED RECEPTORS, THIS
IS AN INTERESTING FINDING WITH
THE TWO ORPHAN RECEPTORS.
GPR 65 AND GPR 68, MORE RECENT
DATA WITH THE ITCH RECEPTORS,
RECENTLY PUBLISHED IN "NATURE."
DATA ON THE SMOOTH END RECEPTOR.
VERY INTERESTING PAPER CURRENTLY
IN PRESS ON A TARGET WHICH HAS
HISTORICALLY BEEN IMPOSSIBLE TO
DRUG.
WE NOW HAVE A HIGHLY SELECTIVE
TOOL COMPOUND FOR THAT.
AND THEN MELATONIN SELECTIVE
COMPOUNDS WHICH HAVE BEEN SHOWN
TO MODULATE CIRCADIAN RHYTHM,
ARE D4 SELECTED COMPOUNDS, AND
MOST RECENTLY, I'LL GO INTO THIS
IN SOME DETAIL SHORTLY, NOVEL
COMPOUNDS TARGETING CANNABINOID
RECEPTORS OVERCOMING A
LONGSTANDING DIFFICULTY IN
GETTING SUBTYPE SELECTIVE
AGENTS.
AND FOR THIS PROCESS, THIS WAS
JUST VERY RECENTLY PUBLISHED BY
-- COLLABORATION WITH MY LAB AND
SADYBEKOV'S LAB AT USC, NOT AS
SIMPLE AS I TRIED TO SHOW IN THE
INITIAL CARTOON, BUT THERE ARE
MANY HOLES AND CREVICES IN WHICH
DIFFERENT PARTS OF THE MOLECULE
MAY FIT.
AND SO THEY CAME UP WITH THIS
REALLY CLEVER IDEA THAT THEY MAY
BE ABLE TO ULTIMATELY
INTERROGATE REALLY HUGE CHEMICAL
SPACE BY DOING AN ITERATIVE
PROCESS WHERE AN INITIAL
BUILDING BLOCK OR BUILDING
BLOCK-LIKE COMPOUNDS WERE DOCKED
INTO THE RECEPTOR, AND THEN IN
SILICO THROUGH SIMPLE
THEORETICAL CHEMICAL REACTIONS
MOIETIES CAN BE ADDED ON TO THE
INITIAL HIT COMPOUND SO IT CAN
ENGAGE THE OTHER SITES OF THE
BINDING POCKET TO YIELD HIGHLY
SELECTIVE AND POTENT COMPOUND.
THIS IS WHAT'S CALLED A
SYNTHON-BASED APPROACH.
WE WERE ABLE TO INTERROGATE A
LARGE LIBRARY OF 11 BILLION
COMPOUNDS, THE LARGEST BASICALLY
THE LARGEST COMPUTATIONAL
PROJECT TO DATE.
THEY HAVE COME UP WITH AN
INTERESTING NAME FOR THIS
APPROACH, V-VYNTHES, THESE ARE
THE DETAILS.
THIS APPROACH HAS MANY
ADVANTAGES OVER CURRENT
COMPUTATIONAL APPROACHES WHICH
ARE LISTED HERE.
ULTIMATELY WE WERE ABLE TO
UTILIZE THIS APPROACH TO
IDENTIFY A HIGHLY SELECTIVE CB2
CANNABINOID RECEPTOR ANTAGONIST,
I KNOW DR. WEISS FROM NIDA
KNOWS, YOU KNOW, HOW MANY
MILLIONS OF DOLLARS HAVE BEEN
SPENT BY NIDA TRYING TO COME UP
WITH SELECTIVE COMPOUNDS FOR
CANNABINOID RECEPTORS.
THIS TURNS OUT TO BE A 600 PICO
MOLE POTENCY HIGHLY SELECTIVE
COMPOUND WITH EXCELLENT
DRUG-LIKE PROPERTIES.
THIS GIVES AN IDEA OF THE
OVERALL APPROACH.
THIS APPROACH CAN BE USED FOR
G-PROTEIN COUPLED RECEPTORS AND
ENZYMES, KINASES, ION CHANNELS
AND SO ON, VIRTUALLY ALL OF WHAT
ARE THOUGHT TO BE DRUGGABLE
TARGETS.
ULTIMATELY WHEN THE BRAIN
INITIATIVE HAS REALIZED ITS GOAL
OF IDENTIFYING EVERY -- THE
PHENOTYPE OF EVERY NEURON IN THE
BRAIN, LISTS OF DRUGGABLE
TARGETS WILL EMERGE FROM THAT.
ULTIMATELY DRUGS WILL NEED TO BE
MADE AGAINST THEM.
SO THIS IS A TECHNOLOGY THAT WE
HAVE DEVELOPED TO ACCELERATE
THAT.
AND THE REMAINING TIME I WANT TO
SHOW HOW WE'RE USING THIS
APPROACH TO VALIDATE NOVEL
THERAPEUTIC ACTIONS.
AS I MENTIONED, THE FIRST, A
YEAR OR SO AGO, WE SHOWED WE
COULD USE THIS APPROACH TO
OBTAIN DRUGS THAT ARE HIGHLY
SELECT SELECTIVE FOR MELATONIN
RECEPTORS, AND SHOWED IN
COLLABORATIVE STUDIES WITH THE
GROUP AT BUFFALO THAT WE COULD
HAVE ON-TARGET MODULATION OF
CIRCADIAN BIOLOGY IN EXPECTED AS
WELL AS UNEXPECTED WAYS AND WE
THINK THIS MAY LEAD TO BETTER
TREATMENTS FOR CONDITIONS LIKE
JET LAG AND CIRCADIAN RHYTHM
DISORDERS.
ONE OF THE COMMENTS AND THEMES
THAT COME UP TYPICALLY IN
DISCUSSIONS OF THE BRAIN
INITIATIVE IS THAT, YOU KNOW,
THIS IS ALL REALLY COOL SCIENCE,
BUT WHEN ARE WE GOING TO
ACTUALLY DELIVER SOMETHING FOR
HUMANS THAT WILL ULTIMATELY LEAD
TO BETTER TREATMENTS FOR SERIOUS
NEUROPSYCHIATRIC ILLNESSES?
I'M GOING TO TAKE YOU THROUGH A
SHORT CASE STUDY THAT SHOWS OUR
APPROACH FOR THIS.
AND IT'S BASED ON A FINDING,
REALLY ASTOUNDING AND
UNEXPECTED, NOW ABOUT FIVE YEARS
AGO FROM GRIFFITHS LAB AND
OTHERS SHOWING A SINGLE DOSE OF
PSILOCYBIN INDUCES RESPONSE IN
INDIVIDUALS REFRACTORY TO
TREATMENT.
AND NOT ONLY WAS THIS SINGLE
DOSE -- WAS THE EFFECT OF A
SINGLE DOSE HIGHLY SIGNIFICANT
BUT WAS LONG LASTING.
SO THEY DID A FOLLOW-UP STUDY AT
SIX MONTHS AND FOUND THAT THE
MAJORITY OF THE PATIENTS THAT
WERE TREATED WITH THE SINGLE
DOSE OF PSILOCYBIN NOT ONLY WAS
DEPRESSION AND ANXIETY AMILOR
RATED BUT MOST RETURNED TO A
LEVEL OF FUNCTION WHERE
DEPRESSION AND ANXIETY WERE NO
LONGER LIMITING TO THEIR DAILY
LIFE.
THERE'S UNIQUE PROPERTIES, THE
FIRST IS THEY IN PHASE 2 STUDIES
APPEAR TO HAVE A RAPID AND
SUSTAINED THERAPEUTIC ACTION.
GRIFFITH LAB PUBLISHED 12-MONTH
FOLLOW-UP.
YOU CAN SEE THAT EVEN 12 MONTHS
AFTER A SINGLE ADMINISTRATION OF
PSILOCYBIN THE RATING OF THE
PATIENTS ON A TYPICAL DEPRESSION
RATING SCALE WITH
INDISTINGUISHABLE FROM
INDIVIDUALS NOT DEPRESSED.
THE ACTIONS ARE ROBUST.
MOST PATIENTS ARE NO LONGER
DEPRESSED.
THE OTHER THING THAT'S
INTERESTING IS THE PSYCHEDELICS
INDUCE A MEMORABLE OR SALIENT
EXPERIENCE, AND IN RETROSPECTIVE
STUDIES WHEN INDIVIDUALS WERE
ASKED WHAT IS THE MOST MEMORABLE
EVENT THAT YOU'VE HAD IN YOUR
LIFE, TYPICALLY THE PSILOCYBIN
EXPERIENCE WAS LISTED AS ONE OF
THE TOP ONE OR TWO EXPERIENCES
IN THEIR LIFE.
MORE RECENTLY, THIS WAS JUST
PRESENTED AT A SYMPOSIUM THAT I
WAS AT IN LONDON LAST WEEK, BY
THE LICTHI LAB AT BASAL, TWO
DOSES OF LSD FOR TREATMENT OF
ANXIETY.
AGAIN, THERE'S THIS RAPID AND
VERY SUSTAINED EFFECT ON ANXIETY
IN PATIENTS THAT WERE PREVIOUSLY
REFRACTORY FOR TREATMENT.
YOU CAN SEE IN THE LSD-TREATED
GROUP 65% OF PATIENTS HAD
GREATER THAN A 30% REDUCTION IN
ANXIETY SCORE.
SO THESE ARE REALLY HUGE
EFFECTS.
AND SO WE, MY LAB, ALONG WITH
THE CHOYKET LAB AND OTHERS, IN A
GRANT FUNDED BY DARPA HAVE BEEN
GIVEN TASK TO COME UP WITH NEW
THERAPEUTIC AGENTS WHICH HAVE
THE THERAPEUTIC EFFICACY OF
DRUGS LIKE PSILOCYBIN AND LSD
WITHOUT THE PSYCHEDELIC
EXPERIENCE.
THE PROBLEM IS THAT DRUGS LIKE
LSD AND PSILOCYBIN HAVE AN
EXTREMELY COMPLEX PHARMACOLOGY,
SO YOU CAN SEE THEY INTERACT
WITH A NUMBER OF RECEPTORS HERE
IN THE GPCR-OME, AND IT'S
THOUGHT THAT OF ALL OF THE 30 OR
SO RECEPTORS THAT LSL INTERACTS
WITH ONLY ONE OF THESE IS
ACTUALLY RESPONSIBLE FOR
THERAPEUTIC ACTIONS.
THAT'S THE 5-HT 2A RECEPTOR,
EVIDENCE GOES BACK TO STUDIES IN
MICE SEVERAL DECADES AGO,
SHOWING THE PSYCHEDELIC ACTIONS
OF THESE DRUGS CORRELATE WITH
SEROTONIN RECEPTOR AFFINITY,
MUCH LATER STUDIES IN KNOCKOUT A
MICE IN WHICH SEROTONIN RECEPTOR
WAS GENETICALLY DELETED DO NOT
RESPOND TO PSYCHEDELICS, AND MY
LAB AND THE CHOYKET LAB, MOST
INTERESTING DATA FROM HUMAN
STUDIES WHERE EFFECTS OF BOTH
PSILOCYBIN AND LSD ARE BLOCKED
IN A DOSE DEPENDENT AND COMPLETE
FASHION BY THIS SORT OF
SEROTONIN F-HT2A ANTAGONIST.
THE FIRST STEP OF DESIGNING
DRUGS THAT INTERACT WITH THIS
RECEPTOR THAT MIGHT BE
THERAPEUTIC BUT NOT PSYCHEDELIC
WAS TO SOLVE THE STRUCTURE OF
THESE RECEPTORS.
AND SO THIS WAS DONE OVER
SEVERAL-YEAR PERIOD, AS YOU CAN
SEE FROM THE REFERENCES HERE,
I'M NOT GOING TO SHOW THE
STRUCTURES.
INSTEAD WHAT I'D LIKE TO SHOW IS
ANIMATION THAT WAS CREATED BY
ASHELMAN OF RIBOSOME STUDIO, WAS
ON THE TV SHOW HAMILTON'S
PHARMACOPEIA.
WE HAVE LSD, THE LSD MOLECULE.
YOU CAN IMAGINE IT'S FLOATING
THROUGH SPACE, FLOATING THROUGH
SOMEONE'S BLOODSTREAM.
IT'S NOW GETTING INTO THE BRAIN.
AND GETTING CLOSE TO A RECEPTOR.
AND IN THE BACKGROUND THERE YOU
CAN SEE THIS WHITE OBJECT SORT
OF DANCING AROUND.
THAT'S THE RECEPTOR, YOU CAN SEE
THE LSD WIGGLES ITS WAY IN THE
RECEPTOR THAT'S ACTUALLY
TECHNICALLY A MULTI-STEP BINDING
MODE.
A LITTLE LID FALLS OVER THE TOP
OF THE RECEPTOR AND TRAPS LSD IN
THE RECEPTOR.
THIS STABILIZES VARIOUS
CONFIRMATIONAL CHANGES, WHICH
ULTIMATELY LEAD TO SIGNALING
EVENTS.
NOW WE'RE GOING TO DIVE INSIDE
THE CELL, ULTIMATELY LEADING TO
THE DISASSOCIATION OF
HETEROTRIMERIC G-PROTEIN.
HERE GO BETA GAMMA
SUBOPPORTUNITIES.
SUBUNITS, IN THE BACKGROUND
CALCIUM SPIKES.
CAN WE CREATE A DRUG THAT
TARGETS ONLY THIS RECEPTOR?
AND ACTIVATES ONLY THIS
SIGNALING PATHWAY?
THAT WAS THE GOAL.
AND BEFORE WE COULD DO THIS WE
REALIZED WE NEEDED TO SOLVE
MANY, MANY ADDITIONAL
STRUCTURES.
I'M NOT GOING TO GO INTO HOW
THIS WAS DONE.
BUT ULTIMATELY WE'VE OBTAINED
STRUCTURES, ESSENTIALLY OF THIS
RECEPTOR WITH MOST OF THE SORT
OF PROTOTYPICAL PSYCHEDELIC
DRUGS AND NON-PSYCHEDELIC DRUGS
IN G-PROTEIN COUPLED FORM SHOWN
HERE AND IN COLLABORATION WITH
THIS TALENTED POSTDOC, ALVAREZ,
HAVE BEEN ABLE TO OBTAIN THE
STRUCTURE OF LSD IN THE ARRESTIN
COMPLEX.
NOW WE HAVE BASICALLY HIGH
RESOLUTION STRUCTURES OF
PSYCHEDELICS ALONE AT THE
RECEPTOR, COUPLING WITH
G-PROTEIN, AND COUPLING WITH
ARRESTIN, NOW WE CAN USE THIS
INFORMATION TO DESIGN DRUGS THAT
SELECTIVELY INTERACT WITH THE
RECEPTOR AND ACTIVATE A
SIGNALING PATHWAY AND SO WE'RE
ABLE TO DO THIS, AND THIS IS THE
COMPOUND THAT WE ULTIMATELY
IDENTIFIED, IT'S A COMPOUND
CALLED R-69, AND HERE IN MAGENTA
IS THE PREDICTED MODE, BY THE
THEY BIND TO RECEPTOR, IN GREEN
THE EXPERIMENTAL IDENTIFIED
MODE.
AND WHAT WE FOUND BASICALLY,
THESE ARE STUDIES DONE BY RAMONA
RODRIGUEZ IN BILL WETZEL'S LAB
AT DUKE, THE COMPOUND HAS ROBUST
RAPIDLY ACTING AND SUSTAINED
ANTI-DEPRESSANT AND ANXIOLYTIC
ACTIONS IN MICE, IN VIVO.
IT HAS NO PSYCHEDELIC DRUG-LIKE
ACTION IN VIVO, NO REINFORCING
ACTION IN VIVO, SO WE DON'T
THINK IT WOULD BE A DRUG OF
ABUSE, EFFECTS OF SINGLE DOINGS
ARE LONG LASTING UP TO SEVERAL
WEEKS AFTER A SINGLE DOSE WE'RE
SEEING SUSTAINED ANTI-DEPRESSANT
AND ANXIOLYTIC ACTIONS OF THESE
DRUGS IN MICE, THE TAKEHOME
MESSAGE IS THAT MY LAB AND
OTHERS HAVE CREATED MANY NEW
TECHNOLOGIES FOR ACCELERATING
DRUG DISCOVERY AT DRUGGABLE
TARGETS.
WE FOCUS ON G-PROTEIN COUPLED
RECEPTORS, SOME TECHNOLOGIES ARE
LISTED THERE.
ALONG WITH THE CHOIKET LAB WE'VE
DEVELOPED LARGE SCALE SCREENING
PLATFORMS FOR DISCOVERY FOR
VIRTUALLY ANY MOLECULAR TARGET,
AND IN PARALLEL WE HAVE
IDENTIFIED MANY NO STRUCTURES
THAT WE CAN USE AS TEMPLATES FOR
NEUROPSYCHIATRIC DRUG DISCOVERY.
AND THIS I THINK IS ULTIMATELY
WHERE THE BRAIN INITIATIVE IS
GOING TO HAVE TO GO.
THIS IS THE TEAM OF
INVESTIGATORS THAT IS INVOLVED
IN THIS AS I SAID, IT'S A HUGE
MULTI-CENTER INITIATIVE FUNDED
BY THE NIH AND DARPA.
THESE ARE THE FUNDING AGENCIES
HERE.
I WANT TO THANK THEM ALL.
IN PARTICULAR, NATIONAL
INSTITUTE OF DRUG ABUSE AND
NATIONAL INSTITUTE OF MENTAL
HEALTH THAT FOR MANY YEARS
FUNDED BASIC SCIENCE IN MY LAB,
AND WITH THAT I'M HAPPY TO
ANSWER ANY QUESTIONS YOU MAY
HAVE.
THANK YOU FOR YOUR ATTENTION.
>> WOW, THANKS, BRYAN.
TRULY AMAZING.
IT'S GREAT TO SEE HOW YOU AND
YOUR COLLEAGUES LEVERAGED THE
REVOLUTION IN STRUCTURAL BIOLOGY
OF MEMBRANE PROTEINS FACILITATED
BY CryoEM, TO INCORPORATE
POWERFUL COMPUTATIONAL
TECHNIQUES AND SHOWS NOT JUST
THE POWER OF SCALING THIS WAY
BUT WE NEED TO BE ABLE TO FOCUS
THESE TOOLS ON WELL-DESIGNED
STUDIES WITH IMPORTANT GOALS IN
MIND.
I THINK YOUR WORK EMBODIES THAT
WONDERFULLY.
I HAVE A ZILLION QUESTIONS BUT I
DON'T WANT TO HOPPING THE TIME.
DAVID MARKOWITZ, YOUR HAND IS
UP.
>> CAN YOU HEAR ME?
>> YES.
>> HI.
GREAT TALK.
THANK YOU.
I WAS STRUCK BY ONE OF YOUR
EARLIER SLIDES ON THE
COMPUTATIONAL LIGAND
PRE-DEDUCTION STUDIES WHERE YOU
SAID THE V-SYNTHES PACKAGE HAS
22% HIT RATE FOR PREDICTED
LIGAND TARGET INTERACTION, 22%
SUCCESS RATE.
THAT'S AMAZING.
THE BINDER TARGET PREDICTION
CAPABILITIES IN THE
PROTEIN-PROTEIN INTERACTION
FIELD NOW USING ROSETTA FOLDS,
FOR EXAMPLE.
>> RIGHT.
>> SO THAT'S A REALLY AMAZING
ADVANCE.
MY QUESTION FOR YOU IS WHAT THE
PROSPECTS ARE FOR COMPUTATIONAL
TOOL TO DEVELOP HIGHLY SPECIFIC
LIGANDS, RIGHT?
YOU HIGHLIGHTED A FAMILY OF 400
OR SO GPCRs, AND IF YOUR HIT
RATE IS 22%, FOR PREDICTING
INTERACTIONS WITH ANY ONE OF
THEM, THAT WOULD IMPLY YOUR
ABILITY FOR SPECIFIC LIGANDS IS
NOT GREAT ACROSS THAT FAMILY.
CAN YOU COMMENT ON WHAT'S
NECESSARY TO DEVELOP HIGHLY
SPECIFIC LIGANDS USING --
>> YEAH, SO, ALL OF THE ONES I
SHOWED YOU ARE HIGHLY SELECTIVE.
THEY ARE BOTH HIGH POTENCY AND
SELECTIVE FOR THAT GPCR.
IF YOU DIG, IF YOU'RE
INTERESTED, DIG INTO THE PAPERS,
WHEN WE HAVE
THE FINAL COMPOUNDS, WE PROFILE
THEM AGAINST ALL THE G-PROTEIN
COUPLED RECEPTORS IN THE HUMAN
GENOME AS WELL AS ALL THE
KINASES.
AND WHAT WE FIND IS THAT OUR
GOAL IS HIGHLY, HIGHLY SELECTIVE
COMPOUNDS, AND WE'VE SUCCEEDED
AT THAT.
I THINK THE REASON THAT WE'RE
SUCCESSFUL FOR G-PROTEIN COUPLED
RECEPTORS IN PARTICULAR TOO IN
NATURE FIRST THEY HAVE AMAZING
BINDING POCKETS AND THE BINDING
POCKET AT EVERY GPCR IS HIGHLY
UNIQUE.
SO, EVEN THOUGH SEROTONIN
RECEPTORS FOR INSTANCE HAVE --
THERE 15 RECEPTORS, THEY ALL
BIND SEROTONIN.
BINDING SITE FOR SPECIFIC SMALL
MOLECULE THAT'S SYNTHETIC IS
GOING TO BE VERY DIFFERENT FROM
ONE RECEPTOR TO ANOTHER.
SO, THAT'S THE FIRST THING.
BINDING SITES BASICALLY HAVE
EVOLVED TO BE USED AS DRUG
TARGETS ESSENTIALLY.
THE OTHER THING IS THAT WE FOCUS
ON NOVEL CHEMICAL MATTER.
SO, WE GET OUT OF STANDARD
CHEMICAL SPACE, SO AS I
MENTIONED IN THE BEGINNING MOST
OF THE DRUGS FOR INSTANCE THAT
ARE USED IN PSYCHIATRY ARE
HIGHLY POLY PHARMACOLOGIC, SO HE
THEY WILL INTERACT WITH 10 TO 50
DIFFERENT RECEPTORS BECAUSE THEY
USE A LIMITED CHEMICAL SPACE
DISCOVERED HISTORICALLY, OKAY?
BASICALLY WHAT WE -- WHAT MY
COLLABORATORS AND I HAVE DONE IS
WE'VE GONE INTO COMPLETELY NOVEL
CHEMICAL SPACE, WE'RE BASICALLY
IN CHEMICAL SPACE THAT DOESN'T
EXIST IN THE PHYSICAL UNIVERSE.
AND WHEN WE FILTER OUR
COMPOUNDS, WE FILTER THEM NOT
ONLY FOR CHEMICAL NOVELTY, SO
MAKING SURE THEY DON'T RESEMBLE
ANYTHING THAT'S KNOWN TO
INTERACT WITH THE RECEPTOR, BUT
ALSO FOR DRUG-LIKE PROPERTIES,
YOU KNOW, ABSENCE OF OFF-TARGET
ACTION AND SO ON.
IN TERMS OF THE HIT RATE, IT
VARIES AS YOU MIGHT GUESS FROM
TARGET TO TARGET.
SO, IT'S BEEN AS LOW AS ZERO.
SOOME RECEPTORS IT DOESN'T
SEEM TO WORK WELL FOR.
IT'S NOT ENTIRELY CLEAR WHY THAT
IS.
ALL THE WAY TO 50%.
WE RECENTLY DID A SCREEN OF 2
BILLION MOLECULES, 2 250 OR SO
THIGHED SYNTHESIZED, 50% HIT
RATE, BASICALLY EVERYTHING IN
BETWEEN.
>> GREAT, THANK YOU.
>> YEAH, YEAH, YEAH.
IT'S AMAZING THAT IT WORKS.
>> THANKS, BRYAN.
HOW ARE WE DOING ON TIME, SUSAN?
>> WE'RE A LITTLE BIT OVER TIME
BUT EVEN IF WE GO UNTIL 12:45 WE
STILL HAVE HALF AN HOUR FOR THE
BREAK.
SO IF THERE ARE OTHER QUESTIONS
WE'VE GOT NINE MINUTES TO TAKE
THEM.
>> YEAH, OTHER QUESTIONS?
BRUCE?
>> FANTASTIC TALK.
SUPER INFORMATIVE.
LIKE JOHN I'VE GOT A MILLION
QUESTIONS.
I'LL FOCUS ON ONE.
OBVIOUSLY FOR NEUROACTIVE DRUGS
GETTING PAST THE BLOOD-BRAIN
BARRIER IS ANOTHER CRITICAL
CONSIDERATION.
IS THERE A WAY TO BUILD MODELS
OF THAT INTO YOUR CONSTRAINT
SPACE SO THAT YOU TARGET ON
THOSE THAT NOT ONLY HAVE
FAVORABLE PK AND PD PROPERTIES
BUT WE KNOW ARE GOING TO GET
INTO THE BRAIN?
WHAT'S THAT STATUS?
>> YES.
SO, --
>> THAT WAS A STRAIGHTFORWARD
ANSWER, VERY GOOD.
>> YES, SO WE DO THOSE FOR WHAT
IT'S WORTH, I WOULD SAY.
SO THOSE ULTIMATELY YOU HAVE TO
DO PK STUDIES IN MICE.
WE'VE BEEN LUCKY SO FAR
ACTUALLY, I DON'T KNOW IF THIS
IS JUST DUMB LUCK OR IF THE
COMPUTATIONAL APPROACHES
ACTUALLY WORK THE WAY THEY ARE
SUPPOSED TO, THAT THE COMPOUNDS
HAVE HAD REALLY GOOD
BIOAVAILABILITY, AND BRAIN
PENETRATION.
THE COMPOUND THAT'S THIS NOVEL
NON-PSYCHEDELIC COMPOUNDS GET
INTO THE BRAIN THREE TIMES
BETTER THAN INTO THE PLASMA.
SO IT HAS A BRAIN TO PLASMA
RATIO OF 3:1, WHICH WAS NOT
SOMETHING WE HAD ANTICIPATED.
BUT OF COURSE WE HAVE OTHER
COMPOUNDS THAT DON'T GET INTO
THE BRAIN AT ALL.
I THINK THAT'S CERTAINLY A
CHALLENGE, IT CONTINUES TO BE A
CHALLENGE, BASICALLY COMING UP
WITH BETTER WAYS OF PREDICTING
PHARMACOKINETIC PROPERTIES,
PLASMA PROTEIN BINDING, ET
CETERA, SO IT'S A HUGE AREA FOR
INNOVATIVE ADVANCES.
>> THANKS, BRYAN.
OTHER QUESTIONS?
WALTER?
>> GUESSING ALSO MAYBE BRUCE
WOULD BE INTERESTED IN A
TECHNIQUE, GETTING GOOD
RADIOLIGANDS FOR ALL SORTS OF
CELL-SPECIFIC RECEPTORS?
>> THAT WAS MY SECOND QUESTION.
>> YEAH, WE'D LOVE TO
COLLABORATE WITH RADIOCHEMISTS.
SO IF YOU KNOW ANY RADIOCHEMISTS
THAT WANT TO COLLABORATE WE HAVE
MANY, MANY INTERESTING
MOLECULES.
WE'D LOVE TO DO THOSE
COLLABORATIONS.
>> I THINK WE MIGHT HAVE A FEW
THAT WOULD LINE UP TO GET
ACCESS.
>> ALL RIGHT.
SEND ME AN E-MAIL, YEAH.
>> BRYAN, SOME HAVE ARGUED
CALLING THESE G COUPLED
RECEPTORS DOESN'T CAPTURE ALL
THEY DO.
WHAT'S THE PERFORMANCE TONINGS
FOR LOOKING AT DOWN EXTREME
SIGNALING PATHWAYS, TRYING TO
FIND SELECTIVITY AWAY FROM
HALLUCINOGENIC COMPOUNDS?
>> YEAH, SO I THINK, YOU KNOW,
THE BIG QUESTION NOW IS CAN WE
MAKE NON-PSYCHEDELIC DRUGS THAT
ARE THERAPEUTIC?
AND, YOU KNOW, I WOULD SAY WE
JUST DON'T KNOW.
I WANT TO TIP MY HAT TO DARPA
BECAUSE THEY WERE WILLING TO
COME UP WITH BASICALLY A PROJECT
WHICH WE DON'T EVEN KNOW IF IT'S
POSSIBLE, RIGHT?
SO, IT'S THE SORT OF EPITOME OF
THE HIGH RISK, HIGH REWARD
PROJECT.
BECAUSE GOING INTO IT WE
DON'T -- WE DIDN'T KNOW, WE
STILL DON'T KNOW FANTASTIC
POSSIBLE DON'T IF IT'S POSSIBLE
TO SEPARATE THERAPEUTIC FROM
PSYCHEDELIC EFFECTS BUT THEY
GAVE SUFFICIENT RESOURCES WE'LL
ULTIMATELY BE ABLE TO HAVE TOOL
COMPOUNDS WE CAN TEST IN HUMANS.
I THINK IT'S FAIR TO SAY DESPITE
THE FACT THESE COMPOUNDS HAVE NO
PSYCHEDELIC DRUG-LIKE ACTION --
WE SHOULD KNOW WITHIN 20 OR 30
MINUTES ACTUALLY IF THE DRUGS
ARE PSYCHEDELIC.
>> OKAY.
IF THERE ARE NO OTHER QUESTIONS,
THANK YOU, BRYAN, FOR A REALLY
TERRIFIC TALK.
>> SURE.
>> VERY IMPRESSIVE AND
INSPIRING.
I WISH WE COULD JOIN YOU AT THE
BAR IN SPAIN WHERE YOU ARE.
IT'S ALMOST DINNER TIME, RIGHT?
PERHAPS NEXT TIME WE CAN GET
TOGETHER AND CONTINUE THIS
DISCUSSION.
>> SO, AGAIN, JUST A REMINDER
THERE'S A DIFFERENT ZOOM THAT
YOU NEED TO COME TO THE CLOSED
SESSION FOR.
AND WE WILL BE STARTING AT 2:15.
AND BRYAN, THANKS.
THAT WAS AN AMAZING
PRESENTATION.
VERY EXCITED TO HEAR ABOUT IT.
>> THANKS FOR FUNDING OUR WORK.
>> WELL WORTH OUR MONEY.
>> GREAT WORK.
WE'LL LEAVE THIS ZOOM MEETING,
MEMBERS WILL COME BACK TO CLOSED
SESSION