WELCOME TO THE CLINICAL CENTER GRAND ROUNDS,
A WEEKLY SERIES OF EDUCATIONAL LECTURES FOR PHYSICIANS AND
HEALTH CARE PROFESSIONALS BROADCAST FROM THE CLINICAL
CENTER AT THE NATIONAL INSTITUTES OF HEALTH IN
BETHESDA, MD.
THE NIH CLINICAL CENTER IS THE WORLD'S LARGEST HOSPITAL TOTALLY
DEDICATED TO INVESTIGATIONAL RESEARCH AND LEADS THE GLOBAL
EFFORT IN TRAINING TODAY'S INVESTIGATORS AND DISCOVERING
TOMORROW'S CURES.
LEARN MORE BY VISITING US ONLINE AT HTTP://CLINICALCENTER.NIH.GOV
GET STARTED.
ABSOLUTELY DELIGHTED TO THRILLED
TO INTRODUCE OUR SPEAKER TODAY
AND I WANT TOED WELCOME ALL OF
YOU TO THE CLINICAL CENTER GRAND
ROUNDS DISTINGUISHED CLINICAL
RESEARCH SCHOLAR AND EDUCATOR IN
RESIDENCE PRESENTATION.
AND THIS PRESENTATION IS PART OF
THE GREAT TEACHERS SERIES.
THE CONTEMPORARY CLINICAL
MEDICINE GREAT TEACHER GRAND
ROUNDS IS A SPECIAL SERIES
WITHIN THE CLINICAL CENTER GRAND
ROUNDS PROGRAM.
AND THIS WAS FIRST CONCEIVED BY
DR. PAUL PLOTTS WHO WAS A
DISTINGUISHED SCIENTIST OF THE
NIAMS ASK UNFORT MATILY RECENTLY
PASSED AWAY BUT HE WAS THE 1 WHO
REALLY GOT THIS STARTED.
THE PURPOSE OF THIS IS TO INVITE
TO THE CLINICAL CENTER TOP
LEADERS IN MEDICINE AND SCIENCE
TO PRESENT ON TOPICS AND IDEAS
ABOUT WHICH THEY ARE PASSIONATE
TO SHARE THEIR REFLECTIONS WITH
US AND TO INSPIRE YOUNG
INVESTIGATORS IN THE PURSUIT OF
CAREERS IN BIOMEDICAL RESEARCH.
I ALSO WANT TO REMIND ABOUT THE
CME.
SO THOSE OF YOU WHO WANT CME,
THE NUMBER IS 50552.
AND SO, YOU WOULD JUST TEXT
THAT--YEAH, THERE IT IS UP
THERE.
OKAY, GOOD.
AND ALSO, WE INVITE TO YOU
PROVIDE FEEDBACK ON TODAY'S
LECTURE BY SCANNING THE QR CODE,
NOW THESE DAYS IT'S ALL ABOUT QR
CODES.
SO YOU NEED YOUR CELL PHONE IN
ORDER TO DO IT.
FOR APPLYING FOR--FOR THOSE
APPLYING FOR CME, YOU WILL APPLY
VIA SURVEY FEEDBACK AND THE
SURVEY WILL BE USED TO PROVIDE
IMPORTANT INFORMATION ABOUT THIS
PRESENTATION THAT ALLOWS TO YOU
SUBMIT ANY QUESTIONS FOR FUTURE
GRAND ROUND TOPICS.
AND THEN FOLLOWING THE
PRESENTATION, QUESTIONS FOR THE
SPEAKER WILL BE TAKEN FROM THE
MICROPHONES IN THE AISLES OVER
HERE--OOPS SORRY.
AND ADDITIONALLY, THE VIDEOCAST
VIEWERS CAN SUBMIT QUESTIONS AT
ANY TIME DURING THE LECTURE, YOU
HAVE TO DO A SCROLL DOWN AND
CLICK ON THE LIVE FEEDBACK
BUTTON ON THE WEBSITE.
AND THOSE QUESTIONS WILL BE
ANSWERED AT THE END OF THE
PRESENTATION.
SO TODAY, WE ARE ABSOLUTELY
HONORED TO HAVE OUR SPEAKER
DR. DANIEL GERSHWIN AND IS A
PIONEER SCIENTIST RECOGNIZED BY
HIS GROUND BREAKING WORK ON
ACCURACYATISM, GENETICS AND
FUNCTIONAL DENATIONAL LIBRARY OF
MEDICINICS.
HE IS 1 OF THE HIGHEST CITED
NEUROLOGISTS IN THE WORLD.
AND I WILL TELL YOU ON A
PERSONAL NOTE, I WAS TALKING TO
HIM YESTERDAY AND I KNEW HIS
UNCLE NORM GESHWIN, WHO WAS A
WORLD FAMOUS BEHAVIORIAL
NEUROLOGIST AND ALSO HIS COUSIN
WHO IS ALSO A WORLD FAMOUS
NEUROLOGIST AT UCSF, AND
SPECIALIZED IN RAPIDLY
PROGRESSIVE DEMENTIAS AND THEY
HAVE INFLUENCED NEUROLOGY AND
NEUROSCIENCE IN MANY WAYS AND SO
IT IS REALLY A GREAT HONOR TO BE
ABLE TO INTRODUCE YOU.
DR. GESHWIN SERVES AS THE GORDON
AND VIRGINIA MCDONALD PROCESSOR
IN NEUROLOGY, PSYCHIATRY AND
HUMAN GENETICS AT CRUCIATE
LIGAMENT CLA.
IN HIS CAPACITY AS A SENIOR
ASSOCIATE DEAN AND ASSOCIATE
VICE CHANCELLOR FOR PRECISION
HELT, HE LEADS THE INSTITUTE FOR
PRECISION HEALTH AT UCLA.
HE EARNED HIS BACHELOR'S DEBRIS
IN CHEMIST RADIOY AND PSYCHOLOGY
IN DARTMOUTH IN 1982 AND AN
MD-Ph.D. AT YALE SCHOOL OF
MEDICINE IN 1991.
HE COMPLETED INTERNSHIP IN
INTERNAL MEDICINE AND RESIDENCY
INEUROLOGY, AND AS WELL AS POST
DOCTORAL IN GENETICS AT UCLA,
AND HE HAS RISEN UP THROUGH THE
RANKS AT UCLA, AND STARTED THE
NEUROGENETICS PROGRAM WITHIN THE
DEPARTMENT OF NEUROLOGY THERE.
AND HE ALSO CO-FOUNDED THE
CENTER FOR ACCURACYATISM
RESEARCH AND TREATMENT WHICH HE
CONTINUES TO LEAD.
AS A RESEARCHER DR. IMRKS ESHWIN
PILOT PROJECT OR NEARED SYSTEMS
BIOLOGY METHODS IN NEUROLOGIC
AND PSYCHIATRIC DEC WITH A FOCUS
ON AUTISM SPECTRUM DISORDERS AND
NEURODEGENERATIVE CONDITIONS.
HIS LAB HAS MADE PRAIJOR
CONTRIBUTIONS TO ADENTIFYING
GENETIC CAUSINGS OF AUTISM
SPECTRUM DISORDER, DEFINING THE
MOLECULAR PATHOLOGY OF AUTISM
AND ALLIED PSYCHIATRIC DISORDERS
AND WORKED TO INCREASE DEMENTIA
RECOGNITION EMPLOY HE SITS ON
THE EDITORIAL BOARDS OF CELL,
SCIENCE AND NEURON.
HE'S A RECIPIENT OF NUMEROUS
GRANTS FOR HIS RESEARCH AND
RESERVED A CERT ON THE ADVISELY
BOARDS OF THE ALLEN INSTITUTE
AND NIMH.
AS A TEACHER HE MENTORED MORE
THAN A HUNDRED POST DOCTORAL AND
GRADUATE STUDENTS.
IN 2011 HE WAS ELECTED TO THE
NATIONAL ACADEMY OF MEDICINE,
AND IN 2022 HE WAS AWARDED THE
SARNAC PRIZE FOR HIS
CONTRIBUTIONS TO UNDERSTANDING
OF THE GENETICS OF AUTISM NOTING
HE ESTABLISHED THE MODERN ERA OF
RESEARCH IN AUTISM GENETICS.
BY MAKING BIOMEDICALS AND
PHENOTYPE DATA EASILY ACCESSIBLE
TO RESEARCHERS WORLD WIDE, HE'S
OPENED THE FIELD TO COUNTLESS
SCIENTISTS, SPURRING DISCOVERY
AND CREATING NEW PARADIGM FOR
RESEARCH IN PSYCHIATRY GENETICS.
SO PLEASE JOIN ME IN WELCOMING
TODAY'S GRAND ROUNDS SPEAKER
DR. DANIEL GESHWIN WHO WILL
PRESENT HIS TALK ON GENETICS AND
GENOMICS OF NEUROPSYCHIATRIC
DISORDERS.
[ APPLAUSE ]
>> THANK YOU DOCTOR FOR THAT
EXTREMELY OVERLY KIND
INTRODUCTION AND THANK YOU
ALL--THANKS FOR HAVING ME HERE.
IT'S REALLY BEEN A GREAT, YOU
KNOW GREAT NOW DAY AND A HALF,
I'LL CALL IT, FEELS ALMOST LIKE
2 DAYS BUT WE'LL CALL IT 2 DAYS.
IT'S BEEN WONDERFUL TO MEET ALL
THE TRAINEES AND STUDENTS AND
THEN MEET WITH SOME OF MY OLD
COLLEAGUES AND FRIENDS AND SOME
I HABIT MET BEFORE BUT WHOSE
WORK I REALLY ADMIRE.
I WAS TRYING TO FIGURE OUT HOW
TO KIND OF FRAME TODAY AND I
DECIDED THERE WERE A LOT OF
DIFFERENT WAYS I COULD GO.
BEFORE I GET INTO IT AND IT
STARTS ROLLING I WOULD SAY 3
THINGS THEY WOULD LIKE TO GET
ACROSS.
ONE IS THAT THAT DESPITE HAVING
KIND OF NO OVERT PATHOLOGY,
THESE DISORDERS, THESE
PSYCHIATRIC DISORDERS THAT ARE
DIFFERENTIATED FROM NEUROLOGIC
DISORDERS HAVE QUITE
SUBSTANTIALLY MOLECULAR
PATHOLOGY AND THAT CAN BE USED
TO DEMONSTRATE AND DEVELOP
TREATMENT.
I ALSO WANT TO SAY THAT I THINK
IT'S ESSENTIAL, 2 THINGS ARE
ESSENTIAL MOVING FORWARD.
ONE OF THEM IS TO DO DISCOVERY
BASED RESEARCH.
IT'S JUST, WE DON'T HAVE A MODEL
FOR HOW THE BRAIN WORKS, WE
DON'T KNOW HOW IT WORKS AND WE
REALLY HAVE TO PUSH DISCOVERY
FORWARD AND THAT'S ALWAYS HAD A
BAD NAME BUT THAT'S WHAT WE DO,
AND THEN THIRDLY, I THINK WE'RE
ON THE PRECIPICE OR ON THE LIP
OF AMAZING DISCOVERIES BECAUSE
OF ALL THE TECHNOLOGY THAT WE
HAVE AND I REALLY WANT TO MAKE A
PLUG FOR KIND OF HIGH THROUGH
PUT BIOLOGY.
SO RATHER THAN TESTING
HYPOTHESIS 1 AT A TIME TESTING
MANY IN PARALLEL.
SO I HAVE NO DISCLOSURES.
THERE'S MY LEARNING OBJECTIVES
AND I ALSO WANT TO SAY
ESPECIALLY THAT I USE MEDICAL
TERMINOLOGY, EPARTIALLY FOR
SOMETHING AS UNIVERSAL AS
AUTISM, WHERE PEOPLE MIGHT HAVE
A WIDE SUSCEPTIBILITY FOR A VERY
WIDE RAINCHL OF FEATURES BUT I
OFTEN FALL INTO THE USING THE
MEDICAL TERMINOLOGY SUCH AS
RISK.
SO THE THING THAT DRIVES THIS
WORK IN NEUROPSYCHIATRIC
DISORDERS IS THAT HAVING A PATH
OF PHYSIOLOGIC MODEL OF DEC IS A
STARTING POINT FOR TREATMENT TO
DEVELOPMENT.
SO CANCER IS A DISORDER,
PROLIFERATION AND INVASION,
CAUSED BY MANY DIFFERENT THINGS,
ASTHMA IS A DISEASE OF HYPER
REACTIVE WEAR WAVES THAT IS DUE
TO VIERPTAL CHALLENGE DUE TO
GENETIC BACKGROUNDS.
STROKE IS A DISORDER OF ACUTE
BRAIN HYPOOX GENERATEDDATION, I
KNOW THAT SOUNDS LIKE A TWIST
BUT BECAUSE THAT'S ESSENTIALLY
THE BASIS.
IT HAS A NUMBER OF VASCULAR AND
CARDIAC AND OTHER ETIOLOGIES AND
SO THE QUESTION IS, WHAT DEFINES
THE PATH OF PHYSIOLOGY OF
NEUROPSYCHIATRIC DISORDERS,
THAT'S ALWAYS A GREAT STARTING
POINT IN WHICH TO PUT GENETIC
FINDINGS, AND SO ANOTHER POINT
THAT I'M GOING TO MAKE WITH
REGARD TO THIS JUST AS A KIND OF
FOUNDATIONAL POINT JUST TO PAVE,
TO PUT THE PAVEMENT DOWN SO TO
SPEAK FOR THE TALK IS WHAT I
CONSIDER THE FALLACY OF EXPERT
HYPOTHESIS, UNLIKE PHYSICS OR
MATH, BIOLOGY IS STILL HIGHLY
DESCRIPTIVE, PROVING WHAT IS
IMPORTANT IS THEREFORE VERY
HARD, OF COURSE IF I TELL THE
STUDENTS IN MY LAB, IF YOU ARE
WORKING ON SOMEBODY'S DISEASE OR
DISORDER, THAT IS BY ITSELF VERY
IMPORTANT BUT HYPOTHESIS DRIVEN
RESEARCH LED TO DECADES OF
STUDY, THIS IS JUST 1 LITTLE
EXAMPLE FOCUSING ON NEURONS AND
NEURODEGENERATIVE DISEASE AND
CERTAINLY WE LOSE NEURONS AND
THEY'RE IMPORTANT BUT IT IGNORED
HALF THE CELLS IN THE BRAIN AND
I WILL NOT GO INTO THIS IN GORY
DETAIL, BUT THE POINT IS NOW
THAT WE CAN COLLECT RELATIVELY
COMPLETE UNBIASED DATA SETS, WHY
NOT LET THE DATA DRIVE THE
QUESTIONS OR LET THE DATA ORDER
THE HYPOTHESIS FOR US AND PUT
THEM IN AN ORDER FOR US TO TEST
THEM.
GENETIC DATA PROVIDES A CAUSAL
ANCHOR FOR THIS.
SO IF YOU HAVE A GENETIC
MUTATION OR A VARIANT, THE
DISEASE DOESN'T CAUSE THAT IN
THE VAST MAJORITY OF CASES WHERE
YOU CAN GO FROM GENE ALL THE WAY
THROUGH TO FUNCTION.
SO ANOTHER KIND OF GUIDING
FRAMEWORK IS THE FOLLOWING:
THAT GENES INTERACT WITH THE
ENVIRONMENT DURING DEVELOPMENT
TO CREATE A STRUCTURE THAT HAS
MANY DIFFERENT LEVELS FROM GLOSS
ANATOMY ALL THE WAY THROUGH
MOLECULAR.
IT'S NOT A STATIC STRUCTURE,
IT'S A VERY DYNAMIC STRUCTURE
AND THAT IS WHAT UNDERLIES
COGNITION AND BEHAVIOR AND OF
COURSE COGNITION AND BEHAVIOR
IMPACTING THE STRUCTURE AND
THE--YOU KNOW WHAT I LOOSELY USE
THE TERM STRUCTURE.
SO EVERYTHING THAT WE ARE DOING
IS KIND OF IN THIS CONTEXT OF
TRYING TO UNDERSTAND HOW GENES
ACT THROUGH DEVELOPMENT, NOW 1
OF THE THINGS ABOUT THE
ENVIRONMENT, IT'S SUPER
IMPORTANT IN BRAIN DEVELOPMENT
BUT GENETIC SYSTEM VERY
CONSTRAINED, EACH THOUGH THE
GENOME IS BIG, IT'S STILL
TRACTABLE, AND SO I VIEW THE
GENETICS AS A TARTING POINT FOR
BEGINNING TO UNDERSTAND EVEN
GENE ENVIRONMENT INTERACTIONS,
SO WE FOCUSED ON GENETICS RATHER
THAN THE ENVIRONMENT FOR THAT
REASON BECAUSE WE THINK IT'S
VERY TRACTABLE.
SO THEN THE QUESTION IS, HOW
MUCH IS THERE GENETIC INFLUENCE
ON NEUROPSYCHIATRIC DISORDERS,
SO THIS IS JUST A REVIEW WE
WROTE A NUMBER OF YEARS AGO, I
SHOW THE PREVALENCE, ON THE
LEFT, FROM ANXIETY DISORDERS ALL
THE WAY DOWN TO TERRETS
SYNDROME, SCHIZOPHRENIA A LITTLE
BIT UNDER 1%.
ACCURACYATISM NOW CLOSE TO 2%,
HIGH HERITABILITY IN A VARIETY
OF STUDIES, YOU LOOK AT
MONOZYGOTIC, VERSUS DIOZYGOTTIC
TWINS, YOU LOOK AT DATA IN
FAMILY HERITABILITY, THERE WAS A
BIG CONFIDENCE BOUND, A LARGE
STUDY RECENTLY IN TWINS SUGGEST
LARGE INHERITABILITY.
IF YOU MEASURE THE SNP, THE
COMMON CONTRIBUTION IT'S USUALLY
LESS THAN THE TOTAL HERITABILITY
FOR A LOT OF REAPS BUT IT'S JUST
ANOTHER WAY OF MEASURING
HERITABILITY, THERE IS
SUBSTANTIAL HERITABILITY ACROSS
THESE DISORDERS THAT VARIES AND
THAT MEANS THAT THERE ARE
GENETIC ARCHITECTURES AS WELL,
THE CONTRIBUTION OF COMMON
VARIANTS IS MORE IN SOME OF THE
ADULT ONSET DISORDERS AND THE
CONTRIBUTION OF RARE PROTEIN
DISRUPTING DISORDERS IS AND DE
NOVO MUTATIONS IS HIGHER IN THE
EARLIER ONSET, LIKE DOWNS
SYNDROME FOR EXAMPLE AND WHAT
THIS LITTLE SIMPLE GRAF SHOWS
HERE IS SOMETHING I THINK IS
KIND OF PROFOUND, THAT THIS IS
THE GENOME WIDE, YOU KNOW AT
THAT TIME IN 2015, AT THE TIME I
WROTE THIS, THIS IS THE NUMBER
OF LOCI IDENTIFIED,
SCHIZOPHRENIA BEING AT THE
BOTTOM AND AS 1 CAN SEE 2
THINGS.
ONE CAN FIND LOCI FOR THESE
DISORDERS THAT ARE NOT DEFINED
BASED ON SOME BIOCHEMICAL
MEASUREMENT, BUT ON OBSERVATION
OF BEHAVIOR AND COGNITION.
SO THERE IS SOME--I DON'T WANT
TO SAY TOTAL, SOME BIOLOGICAL
COHERENCE, BUT AS THE SAMPLE
SIZE INCREASE, 1 IDENTIFIES MORE
AND MORE LOCI, AND THAT'S SHOWN
HERE AGAIN IN A SLIGHTLY LATER
PAPER WITH PAT SULLIVAN, WE JUST
KIND OF LOOK AND YOU CAN SEE
THAT THERE'S ALMOST AN
INFLECTION POINT WHERE ONCE YOU
REACH IN THE 30-50,000, THE
NUMBER OF GENOME WIDE
SIGNIFICANT LOCI GOES UP
EXPONENTIALLY, WHAT'S
INTERESTING THERE IS IN AUTISM
IT REALLY HASN'T HIT THAT YET SO
WE ONLY HAVE A HANDFUL OR SO OF
GENOME WIDE SIGNIFICANT LOCI BUT
STILL GENE DISCOVERY HAS BEEN
VERY ACTIVE AND PRODUCTIVE AS I
WILL TELL YOU IN A
SECURITIZATION.
--IN A SECOND.
ANOTHER THING THAT'S KIND OF
REMARKABLE IS IF YOU TAKE THE
SNP HERITABILITY AND CONTRAST IT
ACROSS THESE DISORDERS THAT
THERE IS SUBSTANTIAL GENETIC
CORRELATION AND THIS EXISTS FOR
MANY REASONS WHICH I WON'T GO
INTO LIKELY BUT BIPOLAR AND SITS
FRENNIA, THE HIGHEST AND EVEN
AUTISM WHICH ARE VASTLY
DIFFERENT TRAJECTORIES AND SIGNS
AND SYMPTOMS HAVE A POINT TO
GENETIC CORRELATION AT THE LEVEL
OF COMMON VARIANCE WHICH IS
QUITE SUBSTANTIAL WHICH IS
TELLING US THAT THERE ARE SHARED
AND DISTINCT COMPONENTS OF RISK.
SO WITH THAT KIND OF AS A
FOUNDATION, I WILL NOW JUMP INTO
AUTISM WHICH I'VE BEEN WORKING
ON SINCE AROUND 1999 OR SO.
SO AUTISM IS NOT DEFINED BY
ANYTHING OTHER THAN COGNITION
AND BEHAVIOR.
IT'S A SYNDROME, NOT A DOZE, IT
OVERLAPS A LOT WITH A LOT OF
DEVELOPMENTAL DISORDERS AND WHAT
MAKES IT AND WHAT STANDS OUT IS
THESE DIFFICULTIES IN SOCIAL
COGNITION AND WHAT I SHORT HAND
AS MENTAL FLEXIBILITY WHICH IS
REALLY, YOU COULD SAY,
REPETITIVE, RESTRICTIVE
BEHAVIORS, ABOUT 30% HAVE
INTELLECTUAL DISABILITY.
INTELLECTUAL DISABILITY DOES
NOT--DOES NOT NECESSARILY TRAVEL
WITH AUTISM ALL THE TIME, IT'S
NOT A CORE COMPONENT, ABOUT 10
OR 15% HAVE DIFFERENT SEIZURES
AT DIFFERENT TIMES.
SO 1 WAY I KIND OF LOOK AT THIS,
AND YOU MIGHT ASK, THERE'S A LOT
OF--THIS SUGGESTS A LOT OF
PLEOTROPY, YOU COULD HAVE
ACCURACYATISM, YOU CAN HAVE
AUTISM WITH INTELLECTUAL
DISABILITY, WITH MOTOR
DYSFUNCTION OR SEIZURES, ET
CETERA AND AS IT TURNS OUT, 1
WAY TO THINK ABOUT THIS IS THIS
NOTION OF WADDING TON'S
EPIGENETIC LANDSCAPE THAT THE
BRAIN DEVELOPMENT IS OCCURRING
IN KIND OF, YOU KNOW, ALONG A
TRACK LET'S SAY AND GENETICS IF
YOU HAVE CERTAIN VARIANTS OR
CERTAIN LARGE EFFECT MUTATIONS
IT KIND OF KNOCKS YOU OFF THAT
TRACK, PREDISPOSING YOU TO THESE
THINGS BUT THERE'S NOT A 1 TO 1
CORRELATION BETWEEN A SPECIFIC
GENE AND A SPECIFIC CLINICAL
SYNDROME REALLY YET THAT WE CAN
POINT TO.
AUTISM AFFECTS ABOUT 1 IN 40
CHILDREN TODAY, THERE'S A 4-1
RATIO OF MALES TO FEMALES.
IT'S MORE COMMON THAN MANY OTHER
CHILDHOOD DISORDERS WHICH MAKES
IT IMPORTANT FROM PUBLIC HEALTH
STANDPOINT, NOT THAT THESE OTHER
DISORDERS AREN'T IMPORTANT,
NORMAL LIFE EXPECTANCY, PRETTY
MUCH, ALTHOUGH AGAIN, DEPENDING
ON HOW COMPLEX IT IS, IF
SOMEBODY HAS, YOU KNOW RECURRENT
SEIZURES AND STUFF LIKE THAT,
THAT'S GOING TO HAVE AN IMPACT
BUT AUTISM SIZE, NORMAL LIFE
EXPECTANCY, ABOUT 10-15% WILL
DEVELOP EPILEPSY.
SO THAT'S KIND OF MY BRIEF
CLINICAL INTRODUCTION.
AND IT'S INTERESTING BECAUSE IF
I HAD BEEN GIVING THIS TALK A
DECADE AGO, IT WOULD BE MENTAL
DYSFUNCTION, AND LANGUAGE
DYSFUNCTION AND COGNITIVE
ABILITY BUT AS PART OF THE
EVOLUTION, THEY TOOK LANGUAGE
OUT OF DISCUSSION WHICH I'M
HAPPY TO DISCUSS.
ABOUT A THIRD WILL HAVE
INLECTUAL DISABILITY, BUT AGAIN,
INLECTUAL DISABILITY IS NOT A
CORE COMPONENT OF AUTISM.
ONE OF THE REASONS WHY IT WAS
FIRST DRIEBED NOT TOO LONG AGO
AND THIS DESCRIPTION BY LEO
CANNER IS UNCANNY IN A LOT OF
WAYS BECAUSE IT NAILED A LOT OF
THINGS.
BUT HE REALLY POINTS TO THE
POINT THAT THESE CHILDREN ARE
BORN LIKE THIS, IT'S INNATE,
DIDN'T SAY IT'S GENETIC BUT
SHOWS THAT THERE'S A FAMILIAL
AGGREGATION OF AUTISM LIKE
FEATURES, BUT THEN YOU KNOW SO
YOU MIGHT ASK WHY DIDN'T THINGS
MOVE AHEAD THAT FAST AND THIS IS
1 OF THE REASONS THIS IS THIS
PSYCHODYNAMIC THEORY THAT AUTISM
WAS PSYCHOGENIC THAT IT WAS
CAUSED BY PARENT, MY COLD
PARENTING AND THE CHILD WAS
PROTECTING THEMSELVES FROM THIS
KIND OF LACK OF EMOTION IN COLD
PARENTING WHICH OF COURSE WAS
WRONG BUT WAS WIDELY ACCEPTED
BECAUSE OF THE KIND OF
PREVALENCE OF ANALYSIS AT THAT
TIME AND THAT'S WEENK REASON WHY
GENETICS HAS BEEN SO IMPORTANT
IS BECAUSE STARTING WITH THE
PAPER BY [INDISCERNIBLE] IT
NAILED THE FACT THAL IS A
GENETIC DISORRER AND IT WAS A
SMALL SAMPLE SIZE AND ALL OF
THAT BUT NOW, YOU KNOW THAT'S
TURNED OUT TO OF COURSE BE TRUE
AND ONCE THAT WAS OF COURSE
PROVEN BEYOND A REASONABLE
DOUBT, WE ALREADY KNEW THAT
THERE WERE MEDICAL GENETIC
DISORDERS ASSOCIATED WITH AUTISM
BUT THIS NAIL THAD IT WAS A
BIOLOGIC DISORDER AND THAT'S WHY
GENETICS HAS BEEN SO IMPORTANT
IN PUSHING THIS FORWARD, SO
INDEED, IF WE LOOK THERE'S A
HUGE GROWTH IN ACCURACYATISM
RISK GENES AND ALMOST ALL OF
THESE THAT ARE LISTED HERE ARE
GENES THAT ARE HAPPEN LO
INSUFFICIENT, THAT MEANS THERE'S
A MUTATION THAT DISRUPTS THE
PROTEIN ON 1 CHROMOSOME, THE
OTHER BEING OKAY.
THESE ARE USUALLY DE NOVO.
OCCASIONALLY INHERITED BUT MOST
OF THESE ARE LIKE DOWNS
SYNDROME, PARENTS DON'T HAVE
THEM, THEY OCCURRED IN THE GERM
LINE.
AND 1 THING THAT'S JUST BEEN
DRIVING THIS IS THE ENDLESS
INNOVATION AND TECHNOLOGY WHICH
HAS ALLOWED US TO GET TO A POINT
WHERE 1 CAN PERFORM WHOLE
EXOHM OR GENOME SEQUENCING IN
10S OF THOUSANDS OF PEOPLE AT
REASONABLE COST IT'S WAY CHEAPER
TO SEQUENCE PEOPLE THAN TO
PHENOTYPE THEM SO THIS HAS LED
TO AN EXPLOSION IN IDENTIFYING
RISK GENES THERE ARE MORE THAN A
HUNDRED SYNDROMIC YEENS,
TOTALLY, YOU COULD SAY 200 HIGH
CONFIDENCE RISK YEENS THAT ARE
YOU ARE IN THE SAN FRANCISCO
PFAFFY DATA BISE BY SIMONS.
IF YOU KIND OF BROADEN IT TO SAY
IT COULD CAUSE AUTISM OR
DEVELOPMENTAL DISABILITY SO YOU
COULD GET MORE POWER IN LARGE
SAMPLES, THERE ARE MORE GENES
AFFILIATED WITH AUTISM, YOU
COULD SAY, AND ALL THIS GENETICS
HAS SHOWN EVIDENT FOR A FEMALE
PROTECTIVE EFFECT, THAT IS
FEMALES HAVE TO HAVE A GENETIC
LOAD TO HAVE AUTISM, THAT'S WHAT
IT LOOKS LIKE AT THIS POINT AND
IN TERMS OF DE NOVO EVENTS,
THEY'RE MORE LIKELY TO OCCUR IN
SPERM THAN IN THE EGG, SO OLDER
DATS ARE ASSOCIATED WITH MORE DE
NOVO CNVs ALTHOUGH AGE IS NOT
TOTALLY ACCOUNTING FOR WHAT'S
GOING ON IN AUTISM.
SO ALL IN ALL, IF I WILL
SUMMARIZE THE GENETIC
DISCOVERIES, MANY FORMS OF
GENETIC VARIATION AND MOTES OF
INHERITANCE AND THIS HAS SHOWN
HERE WHAT WE SAW IN 2016 AND THE
WAY WE SUMMARIZE IT STANDS TRUE
TODAY, THAT THERE ARE MORE AND
MORE OF THESE RARE CONDITIONS,
NONE OF WHICH ACCOUNT FOR MORE
THAN 1% OF AUTISM, EITHER SINGLE
YEEN MUTATIONS OR TRUCTURAL
CHROMOSOMAL VARIATION, THAT IS
GAIN OR LOSS OF A COPY OF A
CHROMOSOME THAT INVOLVES USUALLY
MORE THAN 1 GENE AND THESE ARE
SHOWN HERE, AND THEN THE
SYNDROMIC FORMS LIKE FRAGILE X,
ET CETERA.
BUT IN 2016 IF WOE COLLAPSE THIS
IT ACCOUNTED FOR ABOUT 10% OF
THE PATIENTS, WE COULD PREDICT
THAT THE DE NOVO SINGLE GENE
MUTATIONS WOULD ACCOUNT FOR
ABOUT 15% OR SO, AND THAT'S BORN
OUT.
BUT THERE'S PREDICTED COMMON
INHERENT, INHERITED IT IS ABOUT
49% AND THERE'S ABOUT 40%
UNACCOUNTED FOR WHICH IS LIKELY
UNINHERITTED FORMS OF VARIATION
AND OTHER FORMS OF VARIATION
THAT HAVEN'T BEEN PICKED UP YET.
SO THERE'S STILL A LOT OF GENE
DISCOVERIES TO HAPPEN BECAUSE
WHAT'S BEEN IDENTIFIED ARE
MUTATIONS IN THE HIGHLY
CONSTRAINED DEVELOPMENTAL JEEPS,
THEY'RE REALLY BIG EFFECT ON
MUTATIONS THAT KNOCK OUT YEENS
OR IN A COPY NUMBER VARIANT
KNOCK OUT 22 YEENS OR 3 GENES
AND SO THERE'S AN ENORM AUSNEED
TO IDENTIFY THE COMMON GENETIC
VARIATION AND AS I MENTIONED
THERE ARE ONLY ABOUT 5 OR MAYBE
NOW 12 UNPUBLISHED LOCI, SO WE
MEDE TO, YOU KNOW REALLY MOVE
FORWARD AND PART OF THIS HAS TO
DO, I WILL MAKE A QUICK
DEVIATION IN A WAY, WITH THE
FACT THAT THE WAY FAMILIES AND
AUTISTIC PRO BANDS, THE WAY
PATIENTS ARE RECRUITED AFFECTS
WHAT YOU WILL FIND AND THERE
HAVEN'T BEEN ENOUGH LARGE FAMILY
STUDIES BUT THE CURRENT YIELD IN
CLINICAL TESTING IS SOMEWHERE
BETWEEN 10 AND 15%, YOU DO A
CLINAL MICROARRAY, IF IT'S A
WHOLE YOU DO WHOLE PRAJ ILLEGALS
X SEQUENCING AND IF NOT YOU DO
WHOLE IME NOAM CHROMOSOME
SEQUENCING AND THERE'S TONS OF
PLEOTROPY.
SO AGAIN, I COULD SPEND THE
WHOLE TALK JUST TALKING ABOUT
THE RELATIONSHIP, THE PHENOTYPES
TO GENO TYPES AND ALL OF THAT
AND I DON'T WANT TO DO THAT BUT
I DO WANT TO JUST MAKE 1 POINT,
THAT JUST LIKE ALMOST EVERY
OTHER HUMAN CONDITION, IT
FOLLOWS A COMPLEX GENETIC MODEL
THAT I WILL CALL LIABILITY
THRESHOLD MODEL DEVELOPED BY
FALCONER AND BEHAVIORIAL
GENETICS LIKE 70 YEARS AGO.
BUT IF YOU KIND OF THINK OF
THESE REPETITIVE RESTRICTIVE
BEHAVIORS, SOCIAL BEHAVIORS,
LANGUAGE WHICH I DO BELIEVE IS
PART OF AUTISM, THERE'S A
CONTOUR, A FUNCTION AND
DYSFUNCTION AND THE GENETICS
JUST PULLS YOU OVER ON 1 SIDE,
AND IT COULD BE A BUNCH OF LARGE
EFFECT 1 SINGLE LARGE EFFECT
MUTATION OR IT COULD BE A BUNCH
OF ADAATIVE POLYGENIC RISK WHICH
WE KNOW LESS ABOUT AND I WILL
SHOW YOU 2 GRAPHS THAT MAKE THAT
POINT.
THIS IS FROM OUR OWN WORK IN
INHERITED AND FAMILIES WITH 2 OR
MORE CHILDREN, AND WHAT WE
FOUND, WE FOUND REALLY THE FIRST
STRONG STATISTICAL EVIDENT, THAT
THERE ARE RARE INHERITED
VARIANTS THAT COME PRACTICES
PARENTS TO CHILDREN, THE
REQUESTY IS, WHY ISN'T THE
PARENT AFFECTED IF THIS RARE
INHERITED VARIANT.
WELL, IT'S NOT SUFFICIENT TO
CAUSE THE AUTISM.
WHAT HAPPENS IS THE KIELD IS
GETTING THE RARE INHERITED
VARIANT PLUS POLYGENIC RISK AND
THAT'S WHAT'S SHOWN ON THE
Y-AXIS IS THE POLYGENIC RISK AND
SO, THIS PERSON WHO HAS--IS
ASHINGED, WHO'S CARRYING A RARE
INHERITED VARIANT IN THE BLUE,
THEY HAVE INCREASED TRANSMISSION
FROM THE PARENTS OFPOLOGYY GENIC
RISK, SO IT'S A MIX OF RARE
VARIANT AND POLYGENIC RISK.
AND THAT'S ALSO BEEN SEEN IN
OTHER STUDIES, THIS IS 1 FROM
JONATHAN'S [INDISCERNIBLE] LAB
WHICH IS NOT A FAMILIARIAL STUDY
BUT THOSE WHO HAVE DAMAGING DE
NOVO MUTATIONS ARE NOT GETTING
THE TRANSMISSION OF POLYGENIC
RISK AGAIN ON THE Y-AXIS.
AND WHAT WE SHOW IS THAT THOSE
WITHOUT IT ARE GETTING THAT.
SO IF YOU HAVE A LARGE DAMAGING
MUTATION, YOU DON'T NEED TO
INHERIT POLYGENIC RISK.
YOU MIGHT BUT YOU DON'T NEED TO
BUT IF YOU HAVE A RARE INHERITED
VARIANT FROM THE PARENT IT'S
LIKELY TO BE LESS BECAUSE OF THE
PARENT SO YOU NEED A COMBINATION
OF FACTORS.
SO THIS GIVES YOU 1 LITTLE WAY
THAT 1 CAN BEGIN TO PARSE OUT
AND PEOPLE HAVE STARTED TO DO
THIS, THE GENO TYPE, PHENOTYPE
RELATIONSHIPS AND THAT'S A VERY
INTERESTING AREA OF AUTISM BUT I
WILL FOCUS ON MORE ON THE
THERAPEUTIC DEVELOPMENT AND
MOVING TO MECHANISTIC
UNDERSTANDING EMPLOY SO GENETICS
HAS BEEN AMAZINGLY SUCCESSFUL IN
IDENTIFYING CAUSES OF AUTISM.
SO MANY, AND ACROSS
NEUROPSYCHIATRIC DISORDERS,
ESPECIALLY SCHIZOPHRENIA AS
WELL, AND THESE GENES PROVIDE
TARGETS FOR UNDERSTANDING
THERAPEUTIC DEVELOPMENT BUT THEY
HIGHLIGHT EXTREME HETEROGENETIC
DISORDERS, AND WE CAN SEE THAT
IN 10-15% OF CASES AND THE
QUESTION IS DO WE HAVE TO
DEVELOP A TREATMENT FOR EACH
DISORDER WILL WILL THERE BE 1
VERGE ENSEL IN SPECIFIC
BIOLOGICAL PATHWAYS, DEVELOPMENT
STAGES, PROCESSES OR BRAIN
CIRCUITRY THAT WE CAN THEN
CAPITALIZE ON.
AND I THOUGHT ABOUT THIS FOR
ALMOST 20 YEARS AS A VERY HARD
PROBLEM AND IT'S GOING TO
REQUIRE US ASKING AT WHAT LEVEL
IS THEIR CONVERGENCE, OBVIOUSLY
THERE'S CONVERGENCE AT SOME
LEVEL IN THE PHENOTYPES AGAIN
BUT IS THERE MOLECULAR
CONVERGENCE, AND THIS WILL
REQUIRE REALLY INTEGRATING DATA
ACROSS MANY LEVELS, SO 1 OF THE
QUESTIONS IS HOW DO YOU TAKE
DATA THAT HAS MANY DIFFERENT
KINDS OF MEASUREMENTS RIGHT IF
YOU'RE MEASURING GENE EXPRESSION
VERSUS SOME OTHER QUANTITATIVE
PHENOTYPE OR EPIGENETIC DATA HOW
DO YOU PUT ALL THAT TOGETHER,
AND THE WAY THAT WE'VE
CONCEPTUALIZED IT IS THAT NO
SINGLE YEEN ORANTITY IS ACTING
ALONE, JUST LIKE WE DON'T ACT
ALONE, WE'RE PART OF SOCIAL
NETWORKS AND OTHER TYPES OF
NETWORKS, YEENS ARE PART OF
NETWORKS, AND SO WE SPENT A LOT
OF TIME IDENTIFYING WHO ARE THE
NETWORKS OF GENES AND SO YOU CAN
THINK HERE, WE HAVE EXPRESSION
LEVEL, THIS IS JUST A CARTOON
OVER A BUNCH OF DIFFERENT BRAIN
SAMPLES.
AND THE GENES NATURALLY BECAUSE
OF THE WAY THEY'RE REGULATED
WILL BE GROUPED INTO DIFFERENT
FUNCTIONAL CATEGORIES.
SO, THE YEENS --GENES IN GROUP P
AND DOWN, I AM NOLL TELLING YOU
WHAT THE SAMPLES, ARE, IT
DOESN'T MATTER AND THEN THERE'S
GROUP B AND C.
ET CETERA.
SO WE CAN IDENTIFY THE NATURAL
CO VARIANTS THAT'S GOING ON THAT
WE THINK IS RELATED TO THE
UNDERLYING REGULATORY
ARCHITECTURE OF TURNING YEENS ON
AND--GENES ON AND OFF.
EACH OF THESE GROUPS YOU CAN
CALL THEM CLUSTERS, WE CALL THEM
NETWORK MODULES.
THEY'RE CONNECTED IN SUCH A WAY
THAT THE NETWORK IS MORE LIKE AN
AIRLINE MAP NOT LIKE A HUB MAT,
SO THERE ARE HUBS AND SPOKES SO
THE HUBS ARE PARTICULARLY
VULNERABLE TO DISRUPTION OF THE
NETWORK AND THEN YOU CAN
DECOMPOSE LEAVES OR LEAVE A LOT
OF DIFFERENT WAYS TO UNDERSTAND
WHAT MODULTIMATELYS MEAN SO THEY
ALMOST ALWAYS CORRESPOND TO SOME
ELEMENTAL BIOLOGICAL FUNCTION
EMPLOY SO IF WE PROFILES A
HUNDRED DIFFERENT PIECES OF
CEREBRAL CORTEX FROM A HUNDRED
DIFFERENT INDIVIDUALS, THE MAIN
SOURCE OF VARIANCE WELL IS THE
CELL TYPE COMPOSITION AND SO
WHAT WE END UP PULLING OUT IS
MODULES RELATED TO DIFFERENT
CELL TYPES KIND OF A
DISCIPLINARY SILIC O DISSECTION
SO TO SPEAK.
AND WHEN WE DO THAT WITH BULK
TISSUE WE PULL OUT
TRANSCRIPTIONAL PATTERNS THAT
RELATE TO EACH OF THE INDIVIDUAL
CELL TYPES TO SOME EXTENT IF YOU
HAVE ENOUGH SAMPLES.
AND WE AND MANY OTHER PEOPLE
HAVE SHOWN THIS IS ROBUST AND
REPRODUCIBLE.
IF YOU TAKE A HUNDRED HUMANS AND
GET A PIECE OF CORTEX YOU GET A
ROBUST NETWORK AND YOU CAN USE
THAT FOR A LOT OF DIFFERENT
THINGS, THE NETWORK IS ALSO
BIOLODGEICALLY MEANINGFUL, IF
YOU'RE A HUB VERSUS PERIPHERAL
IN THAT NETWORK OR MODULE.
BUT THE STRUCTURE SERVES AS A
CRITICAL BASIS, THE TRANSCRIPT
OHM HAS AN ORGANIZATION AND YOU
CAN ASK ARE THE MODULES CHANGING
IN DISEASE, IS THE GENE
CONNECTIVITY WHERE IT IS IN THE
MODULE CHANGING OR IF I DON'T
KNOW WHAT A GENE DOES, IF IT
SITS IN A RIBOSOMAL MODULE, IT'S
DOING THAT FUNCTION.
SO IT CAN HELP WITH FUNCTIONAL
ANNOTATION FOR THINGS THAT
AREN'T WELL KNOWN.
SO, IF WE TAKE THIS KIND OF
MODEL AND BEGIN TO THINK ABOUT
THE CONSEQUENCES OF GENETIC
VARIATION IN THE BRAIN MOVING
FROM DNA ALL THE WAY UP TO
BEHAVIOR, WE'RE LOOKING AT AN
INTERMEDIATE PENE O TYPE, MRNA,
NOT BECAUSE IT'S THE MOST
MEANINGFUL PHENOTYPE, IT IS BUT
IT'S TRACTABLE.
WE CAN LOOK AT HIGH RESOLUTION
AT VERY HIGH DYNAMIC RANGE.
WE CAN MEASURE HUNDREDS OR
THOUSANDS OF SAMPLES AND
THEREFORE, WE CAN GET DATA THAT
ALLOWS US TO MAKE INFERENCES
ABOUT THESE OTHER THINGS IN
THESE OTHER LEVELS AND CONNECT
TO THEM.
SO FIRST I'M GOING TO TALK ABOUT
WORK THAT WE'VE DONE TO ASK
QUESTIONS IN THE BRAIN,
POSTMORTEM BRAIN, USING MRNA
MEASUREMENTS.
SO NEUROLOGIC DISORDERS, I
MENTIONED THIS AT THE BEGINNING,
I MENTIONED THIS LIKE
PARKINSON'S AND, ALS, I HAVE
NEUROPATHOLOGY BUT PSYCHIATRIC
DISORDERS ARE CONSIDERED
DIFFERENTLY BECAUSE OF THEIR
LACK OF DEFINING PATHOLOGY.
SO WE LOOKED AT THIS YEARS AGO
WHEN MICRO,A RAYS WERE BECOMING
ACCESSIBLE THAT WE COULD LOOK
BEYOND MICROSCOPIC EVOLUTION TO
IDENTIFY AND FIND MOLECULAR
PATHOLOGY AND ACROSS
NEUROPSYCHIATRIC DISORDERS BUT
FIRST IN AUTISM, AGAIN IT'S LIKE
THE METAPHOR IS, BEFORE WE HAD
THE MICROSCOPE, WE COULD NEVER
SEE AMYLOID OR NUCLEAN BEFORE WE
HAD ANTIBODIES AND OTHER THINGS
SO AS OUR RESOLUTION GETS BETTER
AND BETTER WE GET A DIFFERENT
VIEW OF THESE DISORDERS AND WHAT
REALLY DEFERENTIATES THE
PSYCHIATRIC DISORRERS FROM
NEUROLOGIC DISORRERS IS THE LACK
OF PHYSICAL PATHOLOGY.
SO FIRST STUDY WAS DONE IN
AROUND 20 CASES AND CONTROLS,
LED BY A POST DOCTORAL FELLOW AT
THE TIME [INDISCERNIBLE] WHO
RUNS A VERY SUCCESSFUL LAB IN
SYDNEY OFF THE RAILIA, AND
BASICALLY WITH THE SMALL SAMPLE
SIZE, SHE FOUND IN ABOUT 2/3RDS
OF PATIENTS THERE WAS A
REPRODOUSIBLE PATHOLOGY
INVOLVING DOWN REGULATION OF A
BUNCH OF GENES INVOLVED IN
NEURAL TRANSMISSION AND SYNAPSE
FUNCTION AND AN UPREGULATION OF
YEENS EXPRESSED IN ASTRO CITES
AND MICROGLIA.
AND SO WHAT WAS INTERESTING IS
NOW, REMEMBER, THIS IS A
PHENOTYPE, EVEN THOUGH IT'S
MOLECULAR, IT'S JUST SOMETHING
WE'RE VISUALIZING, WE'RE SEEING
IT.
WE DON'T KNOW IF IT'S A CAUSE OR
CONSEQUENCE OF HAVING THE DISORD
BUT 1 THING WE CAN DO IS WE ASK
ASK TO THE EXTENT THAT WE
UNDERSTAND OR CAN MEASURE
GENETIC VARIATION, RARE OR
COMMON GENETIC VARIATION THAT
CONTRIBUTES TO AUTISM, WHERE
DOES THAT SIT WITHIN THESE
MODULES AND IT SAT 100 PERCENT
IN M12 THE SINATTIC NEURONAL
YEENS SO OUR CAUSAL MODEL IS
THAT THE GENETIC VARIATION IS
SITTING THERE, SOMEHOW CAUSING
DYSFUNCTION IN NEURONS AND WELL
IS A CHANGE IN MICROGLIA AND
ASTRO SIGHTS THAT'S CALLED
NEUROINFLAMMATORY EMPLOY NOW
SINCE THEM WE MASSIVELY
INCREASED THE SAMPLE SIZE, THIS
IS LED BY AN MD-Ph.D. STUDENTS
WHO WERE 2 POST DOCS,
[INDISCERNIBLE], AND HERE
INSTEAD OF HAVING 2 MODULES WE
NOW IDENTIFY BECAUSE WE HAVE
MORE SAMPLES WE GET MORE REFINED
VIEW OF CO EXPRESSION, WE CAN
DISENTANGLE THE
NEUROINFLAMMATORY AND THE
NEURONAL PIECE, THERE WERE 3
DOWN REGULATED MODULES SHOWN
THERE, AND THEY CONTAIN
DIFFERENT ASPECTS OF SYNAPTIC
AND MIEWRONAL FUNCTION, AND THEN
THERE ARE 2 UPREGULATED, 1 OF
THEM IS AN ASTRO SIGHT MODULE
AND THE OTHER CONTAINS MICROGLIA
MARKERS, IN OTHER WORDS, THE
HUBS ARE KNOWN MARKERS OF THOSE
CELLS, SO AS WE GO ALONG, WE'RE
REFINING THIS PATTERN MORE AND
MORE AND REPLICATING IS QUITE
SURPRISINGLY, THIS IS IN 113
SAMPLES, WE ALSO HAD SAIT
SAMPLES OF PATIENTS WITH
DUPLICATIONS WHICH IS THE
MONOGENIC FORMS OF WHICH 90% OF
THE PATIENTS HAVE AUTISM AND
THAT PATTERN WAS MORE HOMOGENIUS
AND A LITTLE BIT STRONGER BUT
MATCHED THIS AUTISM PATTERN,
IDIO PATHIC AUTISM EXACTLY.
SO OVER THE YEARS IN A NUMBER OF
STUDIES, WE AND OTHER PEOPLE
HAVE NOW SHOWN THERE WERE KIND
OF 3 MAJOR FEATURES OF THE
CONVERGENT MOLECULAR PATHOLOGY,
IMEAN THIS IS JUST A STARTING
POINT.
THIS IS NOT A REFINED CELLS FIN.
ONE THING WOE SAW IN ALL OF OUR
STUDIES WAS THAT IF YOU LOOK AT
THE DIFFERENCE BETWEEN TEMPORAL
LOBE AND FRONTAL LOBE YOU SAW A
LOT OF GENES AND CONTROLS AND
THAT PATTERN WAS ATTENUATE IN
AUTISM.
SO THERE WAS AN ATTENUATE
CORTICALE PATTERNING EMPLOY AND
ANOTHER THING WE SAW IS THAT
CEREBELLUM DOESN'T REALLY HAVE
MUCH MOLECULAR PATHOLOGY AT ALL.
THERE WERE NO DIFFERENTIALLY
EXPRESSED YEENS IN CEREBELLUM.
AND WE SEE THIS CHARACTERISTIC
MOLECULAR DISREGULATION
INVOLVING INCREASE IN THE NEURAL
IMMUNE INFLAMMATORY AND
DECREASED SYNAPTIC YEEN
EXPRESSION AND IT'S SHARED BY
THE 15 KEY DUPLICATION.
SO NOW, IF WE GO BACK TO THIS
MODEL CITIZEN LEAKULAR
NEUROPATHOLOGY IN A CAUSAL
MODEL, THIS IS VERY HAND WAVING,
BUT WE HAVE TO START THINKING
THIS WAY, WE HAVE CAUSAL GENETIC
VARIATION THAT'S SOMEHOW LEADING
TO ALTERED DEVELOPMENT, NEURONAL
GENE EXPRESSION, ET CETERA,
SYNAPTIC DYSFUNCTION AND THEN
THERE'S ASTROCYTE, MICROTBLIA
AND INFLAMMA ARE TOY.
IS IT ADAPTIVE?
IS IT MALTAXER DATA
PROTECTIONIVE?
WE DO NOT KNOW.
MY GUT FEELING IS THAT IT CAN BE
THAT ARK DATA PROTECTIONIVE.
SO EVEN THOUGH IT'S NOT CAUSAL,
THAT MICRODPLIA ASTRO SIGHT
PICTURE STILL MIGHT BE A
THERAPEUTIC TARGET, SO I'M NOT
SAYING YOU CAN ONLY TARGET BUT
YOU HAVE TO UNDERSTAND WHERE
THINGS BEGENERATED AND HOW THEY
PROGRESS TO BEGIN TO UNDERSTAND
WHERE WE ARE.
AND SO, THIS IS A KIND OF MODEL,
RIGHT IN AND OBVIOUSLY THERE'S A
TON MORE WORK BUT IF YOU THINK
BACK TO 75 YEARS AGO, LOOKING AT
CANCER TISSUE OR A HUNDRED YEARS
OKAY WHEN YOU COULD SAY, CANCER
IS A DISORDER OF PROLIFERATION
AND INVASION, WE'RE AT LEAST
TARTING TO HIT WHAT THE
POTENTIAL CELL TYPES MIGHT BE
THAT ARE INVOLVED IN WHAT'S
GOING ON.
SO 1 OF THE MAJOR QUESTIONS THAT
WAS ANYTHING --GOING ON IN OUR T
MIKE ASKED WHEN HE WAS A POST
DOC IN THE LAB, HE WAS A
RESIDENT IN PSYCHIATRY WHEN HE
DID THIS WORK BEFORE BECOMING A
POST DOC WITH AN UNDERGRADUATE
STUDENT JILL HANEY WHO BECAME A
GRADUATE STUDENT LATER.
SO HERE'S THE THING, HAVE YOU
ALL THE GENETIC ETIOLOGY, YOU
HAVE ALL THESE THINGS YOU COULD
MEASURE, EEGs, IMAGING, WE'RE
MEASURING ALTERED GENE BRAIN
EXPRESSION POSTMORTEM ACROSS
THESE DISORDERS.
WHAT MIKE DID IS HE BASICALLY,
WE REASONED--WE WENT LOOKING ON
THE WEB FOR AS MANY DATA SETS AS
WE COULD FIND ASK IT WAS MOSTLY
MICROARRAY DATA SETS AT THE TIME
SO THERE WAS ALMOST 900
DIFFERENT MICROARRAYS FROM
DOZENS OF DIFFERENT TODAYS, IT
WAS A HUGE TASK, TOOK MORE THAN
AIER TO INTEGRATE THEM AND
NORMALIZE THEM TOGETHER, AND
WHAT WE COULD SEE ACROSS ALL OF
THESE STUDIES WAS THAT THERE WAS
A TRANSCRIPTOMICY RELATIONSHIP
BETWEEN THEM, THAT
IS--DEPRESSION WAS CORRELATE
WIDE BIPOLAR AND SCHIZOPHRENIA
ABOUT THE SAME.
BIPOLAR AND SCHIZOPHRENIA WAS
HIGHLY CORRELATE WIDE EACH
OTHER, AS WELL AS AUTISM MORE SO
AND THEN THERE WAS THIS
CORRELATION WITH INFLAMMATORY
BOWEL DISEASE THAT WAS VEXING,
BECAUSE IT TURNS OUT THAT'S A
SMALL PART OF THE
NEUROINFLAMMATORY CYTOKINE
UPREGULATION.
ANOTHER BRAIN DISORDER LIKE
ALCOHOLISM WASN'T CONNECTED TO
ANY OF THESE, IT REALLY DIDN'T
SHOW ANY, ANY FEATURES THAT
REALLY CONNECTED IT.
SO I WAS WONDERING THIS LOOKED A
LOT LIKE THE RISK OF POLYGENIC
RISK SCORES I SHOW YOU IN THE
BEGINNING SO WE ASK THE
QUESTION, SO THE FIRST THING WE
ASKED IS, WHAT CELLS ARE BEING
IMPACTED?
ARE THESE DISORDERS THE SAME?
AND WE COULD SEE MUCH MORE
PROPOUND SYNAPTIC REGULATION IN
AWSHATISM BUT IT WAS PARTIALLY
SHARED BY SCHIZOPHRENIA, WE SAW
INCREASED ASTRO CITE
UPREGULATION ACROSS THESE
DISORDERS BUT THE MICROGLIA
ACTIVATION WAS SPECIFIC TO
AUTISM.
NOW I'M NOT SAYING THAT THAT
MEANS THAT IT IS, BUT AT LEAST,
WITH ALL THESE DATA THAT'S WHAT
WE SAW.
YOU CAN ALSO SEE THERE'S NO
OLIGIO DENDRITIC CELLROCYTE,
PATHOLOGY, AGAIN, THIS IS BULK
TISSUE PROFILING.
SO I HAD THIS IDEA THAT HOW ARE
THESE TRANSCRIPT OM CORRELATIONS
RELATED TO THE GENETIC OVERLAM
AND WHAT REALLY STRUCK US AND
THIS IS SURPRISING, I HAVE TO
ADMIT THAT ALMOST 50% OF THE
VARIANTS IN TRANSCRIPT OHM OVER
LAP IN RELATED TO VARIATIONS SO
IF WE PLOT TRANSCRIPT OHM AND
GENETIC SNP CORRELATION, THE ROW
WAS .7.
AND THE GREEN STUFF IS PART OF
RNA SEQ TO REPLICATE THIS USING
A DIFFERENT MODEL AND METHOD.
SO THIS WAS KIND OF STRIKING.
IT DOESN'T MEAN THAT THE GENETIC
SYSTEM DIRECTLY INFLUENCING
THESE BUT THERE'S SOME
RELATIONSHIP WITH THIS
TRANSCRIPT OHM PATTERN IT TO THE
KIND OF EPPED STATE THAT WE'RE
SEEING IN THE BRAIN THAT'S
REPRESENTED BY THE
TRANSCRIPTOME, SO ON THE BACK OF
THIS, ALL THIS WORK AT THE SAME
TIME WE WERE PART OF A
CONSORTIUM CALLED THE PSYCHE END
CONSORTIUM WHICH HAS BEEN
IMPORTANT AND INFLUENTIAL IN THE
FIELD BECAUSE WE'RE WORKING
TOGETHER AS A CONSORTIUM, WE
WERE ABLE TO HAVE ENORM
AUSNUMBER OF SAMPLES EMPLOY SO I
WENT FROM 113 TO 936 CONTROLS.
AND AGAIN, ALL THE DATA WAS
PROCESSED BY DATA CORE MARKER
AND GP WANG WHO WERE PART OF
ENCODE AND NORMALIZED AND THIS
GAVE US EVEN A WAY MORE REFINED
VIEW OF WHAT MIGHT BE GOING ON
WITH USING BULK TISSUE,
MASSIVELY PRIME NETWORK WHICH I
WILL SHOW IN A SEC.
NEXT THING WE SAW WAS ISOFORMS,
YEENS ARE SPLICED AND DIFFERENT
FORMS OF THEM AND THE BIGGEST
SIGNAL IN TERMS OF CELL TYPE
SPECIFICITY AND DEC WAS ISOFORM
DISREGULATION.
WE SAW VERY SPECIFIC MUCH MORE
REFINED NEURAL IMMUNE PATHWAY
ANDS TRAJECTORIES AND I WILL PUT
THIS UP HERE FOR THOSE WHO
HAVEN'T SEEN THE PAPER, THESE
ARE ALL THE MODULES THAT ARE
ASSOCIATE WIDE DEC THAT WE
IDENTIFIED THERE WERE NIX OF
THEM.
SOME OF THEM WERE GENE WHICH
MEAN ITS WAS A TRANSCRIPT AND
OTHERS OF THE ISOFORM MODULES
AND THE NICE THING IS THAT THE
ISOFORM AND YEEN CLUSTERED
TOGETHER.
AND WE LOOK HERE AT THEIR DEC
ASSOCIATION THE CELL TYPE THAT
THEY'RE LIKELY REPRESENTING WITH
COMMON GENETIC VARIATION AND HAD
IS JUST A SMALL PEAK AT SOME OF
THE DEC ASSOCIATED MODULES, BLUE
BEING GENES THAT ARE DOWN
REGULATED, RED UPREGULATED AND
YOU THE COLOR, THE MORE DARK IT
IS THE MORE PROFOUND IT IS AND
WE CAN SEE THERE ARE THINGS THAT
ARE MORE SEVERE IN AUTISM,
THINGS MORE SEVERE IN
SCHIZOPHRENIA AND BIPOLAR, ET
CETERA, IT BASICALLY PARALLELS
THE MAJOR FINDINGS WE HAD BEFORE
BUT IT REFINE TODAY
EXTRAORDINARILY INTO VERY
SPECIFIC PATHWAYS, VESICLE
RECYCLING AND SYNAPTIC SIGNALING
ALSO GAVE US A HINT THAT THE
BLOOD BRAIN BANIER AND THE EPPED
O THELLIAL CELLS AND THE
INFLAMMATORY RESPONSE WENT
BEYOND GLIAL CELLS.
I WILL GIVE YOU A SENSE OF THIS
SO WE WERE ABLE TO HAVE INSTEAD
OF AN ASTRO CITE AND MODULE, WE
NOW HAVE ASTRO GLIAL MODEL,
EXPRESSED THERE, WE HAVE AN NF
CAPPA B MODULE AND THE ISHT
FERON RESPONSE MODULE CONTAINED
59 OF 63 KNOWN RESPONSE
INTERFERENCE YEENS.
SO THESE ARE VERY, VERY TIGHT
BIOLOGICAL PROCESSES THAT WE'RE
IDENTIFYING AND NOW THAT WE'RE
IRS DENTIFYING THE 2011 STUDY,
AND THE 2016 ASTRO CITE
MICROGLIA TO PULLING THESE APART
AND SHOWING THERE IS DIFFERENCE
HERE AND AGAIN THE MICROGLIA
BEING UPREGULATED IN AUTISM AND
NOT THE OTHER DISORDERS AS WELL
AS A VERY, VERY STRIKING
INTERFERON RESPONSE WHICH AGAIN
IS QUITE INTERESTING.
AND AGAIN, 1 CAN LOOK AT THE
TRAJECTORY AS WELL, NOW OF
COURSE, THE PATIENTS WITH
SCHIZOPHRENIA AND BIPOLAR, WE
ONLY HAVE A FEW FOLKS IN THEIR
TEENS OR SO, BUT 1 CAN SEE
REALLY MASSIVELY DIFFERENT
TRAJECTORIES, 1 IS THAT
SCHIZOPHRENIA AND BIPOLAR LOOK
SIMILAR AND THEY LOOK DIFFERENT
IN AUTISM AND AGAIN THIS FFCAPA
B MODULE WAS INTERESTING TO ME
BECAUSE IT'S GOING DOWN IN
AUTISM, BUT IT'S STAYING UP IN
SCHIZOPHRENIA AND BIPOLAR
DISORDER SO AGAIN, THEY'RE
UNIQUE SIGNALING PATHWAYS GOING
ON AND SO IN THE NEXT ITERATION
OF PSYCHE ENCODE WE BESTARTED TO
BEGIN TO PULL THIS APART USING
SINGLE CELL WORK WHICH I WILL
GET TO IN A SECOND, HOPEFULLY.
SO 1 OF THE QUESTIONS WE ALSO
ASKED AND WE'RE ASKING HOW WIDE
SPREAD.
THE STUDIES I'VE SHOWN YOU SO
FAR USE FRONTAL LOBE OR FRONTAL
TEMPORAL LOBE OR COMPARE THEM TO
CEREBELLUM.
WE WERE INTERESTED AND MY
HYPOTHESIS WAS AUTISM INVOLVES
SOCIAL COGNITION AND MENTAL
FLEXIBILITY SO IT'S A FRONTAL
LOBE AND ANTERIOR TEMPORAL LOBE,
MAYBE POSTERIOR TEMPORAL
DISORDER SO WE PROFILES ALL
THESE REGIONS ACROSS A LOT OF
SUBJECTS, THIS TOOK YEARS JUST
TO DO THE DISSECTIONS SO THE
ANALYSIS WAS LED BY MIKE AND
JILL AND MIKE, BUT--I'M SHOWING
DIFFERENTIAL GENE EXPRESSION UP
AND DOWN OVER THE REGIONS AND SO
IF YOU AVERAGE THE WHOLE CORTEXT
EFFECT HA'SOT X-AXIS AND THE
REGIONAL EFFECT IS ON THE Y, SO
A STEEP, STEEPER SLOPE THAN 1 IS
SHOWING THAT THAT AREA'S MORE
AFFECTED.
AND YOU CAN SEE MANAGE REALLY
STANDS OUT, BA 7 AND 17, BUT BA
17 IS PRIMARY VISUAL CORTEX, IT
SHOWED BY FAR THE MOST PROFOUND
DISREGULATION.
AND IT WASN'T DUE TO A CHANGE IN
CELL TYPE OR ANYTHING LIKE THAT,
WE DID SINGLE CELL ANALYSIS, SO
THIS WAS REALLY QUITE SHOCKING.
AND WE WERE ALSO ABLE TO SHOW
AGAIN, I WANT TO EMPHASIZE THIS,
THAT WHEN WE LOOKED FOR
ENRICHMENT HAD COMMON GENETIC
VARIATION AND RARE GENETIC
VARIATION, REMEMBER THIS IS
2022, SO SINCE THE INITIAL 2011
PAPER, THERE'S BEEN A TON OF
GENE DISCOVERY AND WHAT WE'RE
ABLE TO SHOW IS THAT THERE'S
THIS MODULE AGAIN, MOST
PROMINENT POSTERIORLY IN THE
BRAIN, IN OCCIPITAL LOBE AND
TEMPORAL LOBE AND SUPERIOR
PARIETAL LOBE, BUT THAT IS
DISREGULATED ACROSS THE WHOLE
BRAIN THAT INVOLVES CHEMICAL
SYNAPTIC TRAN MISSION, SYNAPSE,
COGNITION AND SOME OF THE MOST
HIGHLY CONNECTED YEEN NASAA.COM
THAT SHOWN HERE.
SO AGAIN, THIS--1 OF THE THREADS
GOING THROUGH HERE IS THAT
GENETIC VARIATION IS SITTING AND
RISK ASSESSMENTS RUPTING
SOMETHING ABOUT NEURONAL
DYSFUNCTION, SO NOW OF COURSE WE
CAN DO SINGLE CELL ANALYSIS.
SO WE STARTED THIS LITERALLY 6
OR 7 YEARS -ING AND WE VERY,
VERY PAIN STAKING AND CAREFULLY,
THIS IS LED BY A POST DOC CANNED
WHAT, AND WE HAD A ABOUT 30,000
CEILS, WE DO THE USUAL QUALITY
CONTROL, WE DO 2 WAYS OF
IDENTIFYING CELL TYPES, 1 OF
THEM USING REFERENCE ATLAS LIKE
ASMA, AND THE OTHER WITH THE
ATLAS WAS IN MOTOR CORTEX, SO IT
DOESN'T HAVE ALL THE CELLS AND
NUMBER 2 IT DOESN'T HAVE DISEASE
INFLAMMATORY AND MICRO DPLIA AND
ALL THAT AND WE COULD SO THAT
OUR ANNOTATIONS PRETTY MUCH
CORRESPONDED WITH THE KNOWN
ANNOTATIONS AND WHETHER WE DID
IT IN A SUPER VIED OR UNSUPER
VISED WAY AND I'M JUST GOING
TO--IT IS UP ON BIOARCHIVE AND
SLEEP APNEA AND OBESITY KNOW TO
BE PUBLISHED AND I WANT TO
HIGHLIGHT A FEW THINGS ABOUT
SINGLE CELL ANALYSIS THAT WERE
QUITE REMARKABLE.
SO 1 THING THAT WE SEE, IS THAT
THERE'S DOWN REGULATION IN LAYER
2, 3, AND LAYER 5, CLOSESALLY
PROYECTING EXCITATORY NEURONS
AND SOMATIC STATIC NEURONS.
IT'S NOT ALL EXCITATORY NEURONS,
IT'S MOSTLY BIGGEST CHANGES ARE
IN LAYER TO 3.
IT'S INTERESTING TO US BECAUSE
THESE ARE THE REGIONS THAT ARE
CONNECKING DIFFERENT HEMISPHERES
AND LONG RANGE CONNECTIONS IN
THE CORTEX BUT WE ALSO SEE A
PROFOUND DISREGULATION IN OLIGO
DENDRITIC CELLROCYTES WHICH WE
HAVEN'T BEEN ABLE TO SEE IN THE
TISSUE.
IT WAS MASKED BY THE CHANGING IN
THE ASTRO FLI COLSISSA AND THAT
WAS INTERESTING AS WELL.
AND IF WE LOOK FOR ENRICHMENT IN
THE ASD ENRICHED YEENS IT'S ALL
IN THE DOWN REGULATED YEENS,
COLOSESLY PROECTOMYOSIN ARED SO
NOT CORTICALE NEURONS BUT
NEURONS THAT PROJECTING ACROSS
THE CORPUS COLOSES ORDER OF
MICRONS.
SO WE SEE THESE REACTIVE STATES,
NOT JUST IN MICROTBLIA BUT NOW
IN OLIGO DENDRITIC CELLROCYTES.
SO IT'S GIVING US AGAIN A MORE
REFINED PICTURE, WE ALSO DID
SPATIAL TRANSCRIPTOMICS WHICH I
DON'T HAVE TIME TO SHOW YOU
WHICH SHOWED THAT THE MICROGLIA
AND ASTRO CITE REGULATION
EXTENDED THROUGHOUT THE GRAY
MATTER BUT AGAIN WAS MOST
PROFOUND IN THE UPPER LAYERS.
BUT 1 THING CAN YOU DO THAT YOU
CANNOT DO WITH BULK TISSUE IS
IDENTIFY THE REGULATORY DRIVERS
WITH I THINK HIGH ACCURACY AND
PRECISION EMPLOY SO YOU CREATE
SINGLE CELL CO EXPRESSION
NETWORKS, WE USED A PROGRAM
CALLED SCENIC HERE, IT'S BEEN
REVISED TO BE SCENIC +, WE FOUND
THAT IT'S PREDICTIONS ARE QUITE
ACCURATE WHEN YOU--WHEN THE
DAILY BASIS THEA IS GOOD.
IT PRINTS THE DATA INTO REGUE
LONS, AND THE YEEPS THAT HAVE
THE BINDING SITES IN THE 5 PRIME
REGION AND AUTOCO REGULATED
WITH, SO THE NOTION THAT IT'S
COMBINED THERE AND IN YOUR DAT
IT'S CO REGULATED.
WE CORE THEM, AND RANK THEM.
SO 1 OF THE QUESTIONS WAS, IF WE
COULD IDENTIFY REGULATORY
DRIVERS WHICH WE COULD DO, AND
THIS WAS LED BY LUCY A POST DOC
IN THE LAB, HOW MUCH ARE THE
EXPRESSION DID IT ACCOUNT FOR
AND ACCOUNTED FOR ENORMOUS
AMOUNT.
JUST THE YEENS DOWN STREM WAS 6
TRANSCRIPTION FACTORS ACCOUNTED
FOR MORE THAN HALF OF THE
TRANSCRIPTION ALGORITHMS
DISREGGULES, AT LEAST PREDICTED
TO ACCOUNT FOR THEM.
SO THIS IS A BIOINFORMATIC
PREDICTION.
IT'S REALLY REMARKABLE.
NOW YOU MAY NOTICE IF YOU'RE A
OFFICKIANAD O, THESE DRIVERS,
HALF THE YEENS HERE ARE KNOWN
AUTISM RISK YEERNS IN WHICH MEAS
MONOGENIC DE NOVO MUTATIONS
MUTATIONS
OCCUR, SO THAT WAS PRETTY
INTERESTING.
SO WE ASKED IF WE LOOK AT WHAT
WAS CHANGE NOTHING AUTISM, WAS
IT ENRICH INDEED ACCURACYATISM
RISK YEENS SO 72 OF THE 1S
IDENTIFIED ARE ASD SAFARI HIGH
CONFIDENCE GENES ADENTIFIED NOW.
A REMARKABLE ENRICHMENT.
SO THIS PATTERN THAT'S
CONSIDERING AT A CELL TYPE
LEVEL, AT SOME LEVEL, IS BEING
DRIVEN BY RISK GENES AT LEAST,
THAT'S THE MODEL AND WHETHER
THAT'S A DEVELOPMENTAL
PHENOMENON THAT'S PERSISTING OR
AN UNGOING DENATIONAL LIBRARY OF
MEDICINE NONE IS CLEAR, SO YOU
MAY SAY HOW DO YOU KNOW THIS?
SO WE WENT FURTHER AND TRIED TO
VALIDATE THIS.
SO THE EXPERIMENTAL VALIDATION
USING PUBLICLY AVAILABLE DATA,
THE CONNECTIVITY MAP WHERE
PEOPLE AT ON BROAD AND
COLLABORATORS HAVE NOT JUST
GIVEN, THEY'VE GIVEN THOUSANDS
OF FDA DRUGS TO CELLS AND
MEASURED THE TRANSCRIPTIONAL
PATTERN BUT THEY ALSO KNOCKED
OUT ABOUT 10,000 YEENS AND
MEASURED THE TRANSCRIPTIONAL
PATTERN SO WE CAN ASK, IF YOU
KNOCK OUT THESE TRANSCRIPTION
FACTORS THAT THEY'VE KNOCKED
OUT, DOES IT CAUSE THE GENE
EXPRESSION CHANGES THAT WE
PREDICT OCCUR AND THE ANSWER IS
A RESOUNDING YES.
SO IF WE TAKE ALL REGUE LON
TRANSCRIPTION FACTORS IT'S NOT
REALLY SIGNIFICANT BUT IF WE
TAKE THOSE THAT ARE IN CNS CELL
TYPES FROM CNS DATA IT'S HIGHLY
SIGNIFICANT, WE'RE ONLY ABLE TO
ELECTRIC AT 31 OUT OF THE 70, IF
THEY DID CRSPR OF ALL CELL TYPES
THAT'S STRONGER AND THAT'S ALSO
SIGNIFICANT AND SO BOTH SH KNOCK
OUT AND CRSPR KNOCK OUT SHOWS
REALLY PROFOUND OVERLAP OF THE
YEEPS THAT WE WOULD--OF THE
REGUE LONS THAT WE IDENTIFIED SO
WE THINK THIS IS A NICE WAY TO
USE EXTERNAL DATA SO WE
DEPARTMENT HAVE TO DO THE CRSPR
EXPERIMENTS IN OUR LAB, SOMEONE
HAD ALREADY DONE THEM AND IT'S A
GREAT EXAMPLE OF THE UTILITY OF
PUBLIC DATA AND THESE KINDS OF
RESOURCES SO OUR MODEL FOR
WHAT'S GOING ON POSTMORTEM BRAIN
IS THAT THE CORTEX IS IMPACTED
BY A GENETICALLY DRIVEN NEURONAL
FUNCTION AND SHIFTED TO A MORE
REACTIVE HOMEOSTASIS BROADLY BUT
MORE STRONGLY CONVERGES ON
LAYERS OF THE CORTEX.
SO NOW THE BIG DEAL IS TO
UNDERSTAND HOW DID THIS ARRIVE
IN MOW DID IT HAPPEN IN WE KNOW
THAT IS THE STATE OF THE BRAIN
WHEN THESE PEOPLE DIED BUT
LIKELY RELATED TO THEIR
UNDERLYING DISORDER BECAUSE IT'S
SEEN OVER AND OVER AND OVER
AGAIN EMPLOY BUT HOW DOES IT
OCCUR?
SO IF WE GO BACK TO THE MODEL
AGAIN, WE COULD ALSO ASK IN A
FORWARD GENETIC WAY, WE'VE BEEN
KIND OF GOING IN A VERMEN
INFECTED VERSE GENETIC WAY, HOW
DOES KNOWN AUTISM RISK IMPACT
THESE MODEL CITIZEN LICKULAR
PHENOTYPES GOING FORWARD IN THAT
DIRECTION AND OF COURSE WE CAN'T
DO THAT IN ADULT HUMAN BRAIN BUT
THERE ARE--ARE WAYS TO LOOK AT
THAT.
ONE OF THE WAYS WE DID EARLY ON
IN 2013, WITH NEIL WIDE WHO WAS
A MD-PHEAR D IN THE LAB, IS WE
TOOK THAT DATA AND BASICALLY HAD
FETAL CORTEX ALL THE WAY THROUGH
ADULTHOOD, WE WENT FROM 8 WEEKS
GUESTATION TO 3 YEARS BECAUSE
AUTISM IS DIAGNOSED BEFORE 3
YEARS, OR STARTS OFTEN NOT
DIAGNOSED UNFORTUNATELY.
AND ASKED IF WE CRETE
MODULTIMATELYS THAT CORRESPOND
TO BASIC ASPECTS OF DEVELOPMENT
AND WE SHOW CELL BIRTH,
MIGRATION, OUTBIRTH, ALL THIS
HAPPENING WAS THERE ANY
CONVERGENCE AND WHAT WE FOUND
AND THIS HAS BEEN PUBLISHED SO
I'M SUMMARIZING IT IS THAT
INDEED THE AUTISM RISK GENES WE
KNEW THIS 2012 ARE HIGH
LIKELIHOOD CONVERGED DURING
FETAL DEVELOPMENT AND THEY
CONVERGED IN KIND OF 2 MAIN
PATTERNS, 1 WAS GENES THAT
DISRUPT CHROMATIN AND
TRANSCRIPTIONAL REGULATION THAT
WAS ENRICH INDEED THESE DE NOVO
MUSEUM THAIGZS AND THEN LOWER
IMPACT VARIANTS THAT IMPACTED
SYNAPTIC DEVELOPMENT BUT ALL
EXPRESSED KIND OF MIDGUESTATION
IN FEEDAL BRAIN.
AND WE LOOK TO SEE WHERE
THESE--WE HAD A MACAQUE ATLAS AT
THE TIME ASK WE COULD SEE THEY
WERE IN SUPERFICIAL LAYERS.
THIS IS A PREMONITION OF WHAT WE
FOUND 10 YEARS LATER IN THE
CORTEX THAT THE SUPERFICIAL
LAYERS ARE MORE IMPACTED SO THIS
REALLY BEGAN TO TELL US THAT WE
NEEDED, WE HAVE HIGH IMPACT
GENES AFFECTING TRANSCRIPTIONAL
REGULATION AND THE KIND OF LOWER
IMPACT AFFECTING SYNAPTIC
DEVELOPMENT NEURONAL FUNCTION
AND FIT WITH THE MODEL THAT
ENCODES HAD KIND OF PUT OUT
THERE FOR KIND OF
TRANSCRIPTIONAL REGULATION.
THAT THE GENETIC ARCHITECTURE
WE'RE SEEING, THAT THESE DE NOVO
LARGE MUTATIONS ARE OCCUR
NOTHING IN TRANSCRIPTIONAL
REGULATION, THIS TOP TIER
REGULATORS THAT WE REALLY NEED
TO UNDERSTAND NEURODEVELOPMENT
MUCH BETTER AND HIGHLIGHT THE
NEED FOR REFINED UNDERSTANDING
OF REGULATORY NETWORKS AND MOST
REGULATORY NETWORKS, MOST OF THE
REGULATORY ELEMENTS IN THE HUMAN
GENOME ARE IN NONCODING REGIONS
AND IT LED US TO SPENDING YEARS
WHICH WE STILL ARE DOING TO MAKE
MAPS OF THESE NONCODING REGIONS
AND WHAT THEY DO, SO YOU NEED TO
UNDERSTAND ARE THEY ACTIVE
REGIONS OR OPEN IN THAT TISSUES
AND 1 CAN DO THAT BY LOOKING AT
THE HISTONE MODIIVES, DNA
METHYLATION, TRANSCRIPTION
FACTOR BINDING.
THE KEY IS THAT THIS OCCURS IN A
CELL TYPE AND TISSUE DEVELOPMENT
IN A SPECIFIC WAY SO YOU NEED TO
MAKE MAPS FOR ALMOST EVERY
TISSUE IN CELL TYPE THAT YOU'RE
INTERESTED IN LOOKING AT TO
REALLY UNDERSTAND THAT.
SO WE WERE INTERESTED IN BRAIN
DEVELOPMENT AND WE HAD SEEN THAT
AUTISM GENETIC RISK IS SUPER
RICH IN FETAL BRAIN DEVELOPMENT
SO WE SPENT YEARS MAKING MAPS,
BUILDING REFERENCE MAPS OF YEEN
REGULATION AND CO EXPRESSION
BOTH USING ININATE NUR 2016
WHICH CONNECTED ENHANCERS TO
YEENS, LOOKING AT OPEN CHROMATIN
AND CONNECT THAGOREAN TO THE
HIGH C, CANNED WHAT, A NUMBER OF
THE PSYCHE ENCODE PAPERS MAKING
A FETAL SINGLE CELL MAP OF HUMAN
BRAIN, MAKING A EQTL MAP OF
HUMAN BRAIN, ET CETERA.
SO ONCE WE HAVE THESE MAPS
THERE'S A LOT WE CAN WITH IT
NOW, WE CAN ANNOTATE NONCODING
VARIATION AND THERE'S A LOT WE
HAVE DONE THERE AND I WILL SHOW
YOU 1 SLIDE TO GIVE YOU AN IDEA,
SO THIS WAS WORK THAT
[INDISCERNIBLE] DID IN THE LAB
AND WE MADE OUR FIRST GENERATION
MAPS AND SO THERE WAS AN AUTISM
GWAS, COMMON GENETIC VARIATION.
NINETY-FIVE% OF THE YEEPS SAT
IN THE NONENCODING REGION.
WE COULD USE THE MAPS TO
UNDERSTAND THAT AND AGAIN IT
SHOWED THAT NOT JUST RARE
GENETIC VARIATION BUT COMMON
GENETIC VARIATION WAS
PARTITIONED INTO THIS VERY, VERY
EARLY FETAL DEVELOPMENTAL
TRAJECTORY.
AND WHEN WE LOOKED ACROSS BRAIN
REGIONS WE ALSO SAW AGAIN IT WAS
FETAL MORE EXPRESSED IN ADULT
BUT CORMORE IN OTHERS ESPECIALLY
DURING FETAL SO AGAIN WEB
CONNECTED REPLICATED THIS AND
VALIDATED IT BUT THISSIVE GOES
YOU 1 IDEA FOR HOW THESE MAPS
WITH BE USED AND I WILL SHOW YOU
ANOTHER.
I KNOW I'M RUNNING SHORT SO I'M
GOING TO SKIP THIS AND JUST SAY
THAT IF WE LOOK AT GWAS, NOT
JUST FOR AUTISM OR SCETS FRENNIA
BUT IF YOU HAVE ANY 1 OF 6
DEFINED PSYCHIATRIC DISORDERS
AND CALL YOU AFFECTED AND IF YOU
DON'T HAVE 1 YOU'RE UNINFECTED
SO THIS IS EYE SIGHT WITH THOMAS
AND ANDREW, WE IDENTIFIED
MULTIPLE LOKREBS CYCLE I, GENOME
WIDE SIGNIFICANT THAT GIVE RISK
FOR ALL THESE DISORDERS IN THE
SAME KIND OF DIRECTION AND WHEN
WE AGAIN MAP THOSE AND FOLLOW UP
WITH THE PGC GROUP AND A MUCH
LARGER SAMPLE, WE MAP THEM AND
THEY'RE IMPACTING RISK, AND
REGISTER DURING FETAL BRAIN
DEVELOPMENT AND IT'S NOT
EXCLUSIVE AND THE SAME THING
WITH AUTISM.
SO THE QUESTION IS WHAT'S NEXT,
HOW DO THESE MOLECULAR CHANGES
OCCUR OVERTIME AND HOW DO
GENETICS IMPACT DEVELOPMENT.
SO HOW DO WE CONNECT THESE TO
THE PATTERNS IN THE BRAIN, SO
WE'VE BEEN USING INVITRO IPSC
MODELS TO UNDERSTAND HOW GENETIC
RISK KIND OF PERCOLATES TO LEAD
TO DEVELOPMENT TO THESE PATTERNS
AND THE QUESTION IS HOW DO WE
USE THESE TO DEVELOP TREATMENT.
SO AGAIN I WILL TRY TO ZIP
THROUGH THIS IN 5 MINUTES, IF
YOU'LL STICK WITH ME BECAUSE I
THINK THIS IS--I REALLY WANTED
TO SHOW SOME NEW THINGS WE'VE
BEEN DOING.
INITIALLY THE FIRST QUESTION IS
HOW WELL DO THESE IPSC MODELS,
MODEL DEVELOPMENT AND WHICH
PARTS OF HUMAN CORTICALE
DEVELOPMENT DO THEY MODEL.
SO WE DEVELOPED A TRANSCRIPTOMIC
FRAMEWORK TO EVALUATE MODELS OF
NEUR-AL DEVELOPMENT BY STEM
CELLS. THIS IS JASON STEIN AND
LUIS WHEN THEY WERE POST DOCS IN
THE LAB.
SO WE DEVELOP A NUMBER OF TOOLS
TO ASK WHAT DO I HAVE IN MY
DISH?
AND THEN WE ASK, IF WE TAKE
THESE YEENS IN THE M2 CHROMATIN
MODIFIER IS IT PRESERVED AND
EXPRESSED, IT IS INVITRO, EVEN
FOR PRIMARY IN 2 D IN A DISH,
GOING FORWARD WITH WORK WITH THE
LAB, WE'VE BEEN ABLE TO SHOW
THAT IF YOU GROW THESE IN 3D
INSTEAD OF 2 D, AT 2 D, THEY
KIND OF STOP AT 26 WEEKS, YOU
NEVER GET THAT WELL
DEFERENTIATED.
BUT THEY GROW THESE AND WE'VE
BEEN GROWING THEM FOR 2ER YOAN
MONCADAS IN THE LAB NOW AND AT
THIS POINT SURGEIO HAD IT HAS
WELL, AND YOU CAN SEE THAT THE
OCCURS IN VIVO, MATCH WHAT'S
HAPPENING IN VIVO EACH PAST
POSTNATAL BIRTH.
THIS IS WITH THE TRANSCRIPT OHM,
WE SHOWED THIS
ELECTROPHYSIOLOGICALLY, WE SHOW
IT WITH HISTONE MARKS AND OTHER
TOOLS AS WELL, SO WE THINK WE
HAVE A GOOD TOOL FOR ESPECIALLY
MODELING EARLY DEVELOPMENT IN A
DISH.
HOW ABOUT TREATMENT DEVELOPMENT
IN SO WE'RE USING THESE TO
UNDERSTAND THE IMPACT OF
SPECIFIC YEENS BUT THERE ARE 2
WAYS TO THINK ABOUT THIS.
TARGETING RARE FORMS OF AUTISM 1
GENE AT A TIME OR TARGETING
CONVERGE EPT PATHWAYS, THESE BIG
NETWORKS THAT I'VE BEEN TALKING
ABOUT, SO HOW CAN WE DO THAT,
WELL, THE AUTISM RISK JEERNS
THAT I TOLD YOU ABOUT, VAST
MAJORITY OF THEM ACT BY HAPLO
INSUFFICIENCY, THERE'S A DE NOVO
MUTATION THAT KNOCKS OUT 1 COPY
AND THAT'S SHOWN HERE.
SO YOU ONLY GET AN EXPRESSION
OFF 1 ALLELE AND THERE'S A
MUTATION, A LOT OF DIFFERENT
REGIONS, STOPS THE EXPRESSION,
USUALLY MEDIATED TO K, AND IT
TURNS OUT THAT THESE HAPLO
DEFICIENT GENES HAVE MUCH LOWER
EXPRESSION AND PART OF THAT IS
BECAUSE THEY'RE DOSE SENSITIVE
GENES, THEY'RE NOT JUST
SENSITIVE TO THESE
INSUFFICIENCIES, THEY ACTUALLY
OVER EXPRESSION OF THESE YEENS
AND QUITE DETRIMENTAL SO HOW DO
WE RESCUE THESE, LIKE IF--HOW DO
YOU GET THE RIGHT LEVEL OF
EXPRESSION, KIND OF--YOU KNOW
YOU HAVE TO BE CONCERNED ABOUT
THAT SO WE REASONED WITH ALL OF
OUR ENHANCER MAPS IF WE HIT THE
RIGHT ENHANCERS WE COULD GET
SMALL AMOUNTS OF INCREASED
EXPRESSION, THAT WOULDN'T BE
TOXIC, WE WOULD BE HITTING THE
ENDOGENOUS REGULATORY ELEMENTS.
AND SO THIS IS WORK LED BY
GEORGE 10, A POST DOC IN THE
LAB, SO THE IDEA WE USE CRSPR,
TO BASIC LYE TARGET THE
REMAINING NONMUTANT ALLELE TO
TURN JEEP EXPRESSION BACK UP.
AND THERE'S A LOT OF WORK
INVOLVED IN THAT, 1 OF THE
THINGS YOU HAVE TO DO IS YOU
HAVE TO IDENTIFY ENHANCERS AND
TEST THEM AND MAKE SURE THEY
WORK SO AGAIN WE TOOK ALL THOSE
MAPS THAT WE AND OTHER PEOPLE
HAD MADE EMPLOY COMBINED THEM,
DESIGNED MULTIPLE GUIDES TO EACH
ENHANCER, HAD 3 OR 4 OR 5
ENHANCERS PER YEEN AND WE
TARGETED THEM IN CELL CULTURE
AND WE IDENTIFIED A HANDFUL OF
GUIDE RNAs THAT WORKED AND WE
HAVE A WHOLE FLOW WHERE WE DO IT
FIRST IN PRIMARY NEURAL
PROGENITORS AND NEURAL
DEMENTIONS WHICH IS AN EASIER
THING AND THEN ALSO IN HUMAN, 3
DIMENSIONAL ORGANOIDS BI PSC
ORGANOIDS AND THIS IS SHOWING
FOR 2 MUTATIONS WE GOT FROM
[INDISCERNIBLE] LAB, THAT
INDEED, THEY'RE KNOCKED OUT AND
WHEN WE CRSPR A THEM WE CAN
RESCUE THE LEVELS BUT THE KEY IS
PHENOTYPE RESCUE.
THE REASON WE CHOSE THESE 2 IS
BECAUSE THEY HAVE WELL
CHARACTERIZED PHENOTYPES BY
OTHER PEOPLE.
ONE MUCH THEM IS DECREASED
FIRING RATE IN SCN 2 A, AND
THAT'S WHAT IT LOOKS LIKE
COMPARED TO CONTROL.
WHEN WE CHRIS RSPR A AND
CONTROL, WE'RE ABLE TO RESCUE
THE YEEN.
SO THERE'S PROLIFERATION
PHENOTYPE AND A CELL FEIGNEE
TYPE SO WE LOOKED AT THOSE WE'RE
ALSO ABLE TO MEASURE GENE
EXPRESSION AND SAY ARE WE
PUSSING GENE EXPRESSION BACK
TOWARDS WILD-TYPE AND YOU CAN
SEE THERE THE MUTANT IS ON TOP
IN YELLOW AND THE CRSPRA AND
WILD-TYPE ARE TOGETHER.
MAYBE NOT SURPRISING BAH WE'RE
ONLY GETTING A 30% INCREASE IN
THE CHDA ISSUE BUT WE ARE ABLE
TO RESCUE THE SIZE AND
PHENOTYPE.
SO THERE ARE A LOT OF HURDLES A
LOT OF OBSTACLES FOR IN VIVO
HUMAN USE AND ET CETERA BUT WE
THINK THIS IS A PROMISING WAY TO
THINK ABOUT IT.
THELING THING WAS TO TALK ABOUT
AND I APOLOGIZE FOR GOING OVER
BUT I WAS TOO EXCITED IS HOW
ABOUT TARGETING THESE CONVERGENT
PATHWAYS AND A LOT OF THIS HAS
TO DO WITH FOLKS I SPOKE WITH
YESTERDAY, PUTTING THIS IN REAR,
THOSE WITH POLYGENIC RISK OR
COPY NUMBER VALID AND RELIABLE
YABTS THAT AFFECT MANY YEENS SO
WITH SURGERY WE'VE BEEN DOING
THIS MASSIVE STUDY THAT WAS JUST
PUT UP ON BIOARCHIVE WITH ALL
THESE DIFFERENT MONO, KIND OF
LARGE GENE MOSTLY COPY NUMBER
VARIANT FORMS OF ACCURACYATISM
AND ABOUT 10 CASES OF IDIO
PATHIC AUTISM AND CONTROLS AND
WE DIFFERENTIATE THEM AT 25, 50,
75 AND A HUNDRED DAYS, MEASURE
THEIR TRANSCRIPT OHM, SHOWN ON
THE LEFT IS EXTREMELY HIGH
REPRODUCIBILITY, BETWEEN
DIFFERENT LINEUPS AND DIFFERENT
INDIVIDUALS WITH THE SAME
MUTATION, ET CETERA.
SO WE FOUND SOMETHING
FASCINATING.
AT DAY 25 THERE IS EXPRESSION
BETWEEN MUTANTS AND THERE'S
CORRELATION BETWEEN MANY OF THEM
BUT IT'S NOT MASSIVE, BUT AT DAY
100 THIS IS LAWEDDER DALE IT
LOOKS LIKE.
THERE'S KIND OF A MASSIVE--WE
CALL IT CONVERGENT OR WHAT'S
OCCURRED SO DEEPT KNOW WHY IT'S
OCCURRED SO WE STARTED TO ASK
COULD THERE BE SOMETHING DRIVING
THIS.
SO WE LOOKED UPSTREAM OF ALL
THESE GENES, WE DID A GENE CO
EXPRESSION ANALYSIS AND WE
IDENTIFIED A BUNCH OF MODULES
THAT ARE CHANGING AND WE FOUND 1
CALLED M5 THAT WAS ENRICHED IN
TRANSCRIPTION FACTORS AND IN
FACT THE BINDING SITES OF THOSE
TRANSCRIPTION FACTORS WERE
ENRICHED IN THE OTHER MODULES.
SO WE REASONED THAT MAYBE THIS
MODULE IS DRIVING THE OTHERS AND
SO, AGAIN THIS WORK WAS DONE BY
AARON GORDON AND SE-GIN YOON AND
LUCY AND THIS IS FASCINATING
THIS IS SHOWING THE M5 MODULE AT
THE BEGINNING, I'M SORRY IN THE
MITTED AND THE OTHERS ARE ON THE
OUTSIDE, THESE ARE ALL
ACCURACYATISM RISK GENES, BEING
DRIVEN BY THE M5 SET OF
TRANSCRIPTIONAL REG IEWLGTORS,
MASSIVELY AGAIN ENRICHED AND
AUTISM RISK GENES.
AND IN FACT IF YOU THINK ABOUT
IT FOR THIS TO BE THE DRIVER IT
WOULD HAVE TO BE EXPRESSED
EARLIER THAN THE OTHERS AND
THAT'S WHAT WE SEE, WE SEE THAT
M5 IS IF YOU LOOK AT THE LIGHT
BLUE, THAT'S SHOWING EXPRESSION
AT DWIF AT AS, SO M5 IS A VERY
EARLY EXPRESSED MODULE.
MOST YEENS EXPRESSED EARLIER
THAN THE YEENS IN THE OTHER
MODULE, SO THIS BECOMES
PLAUSIBLE THAT BIO-INFORMATICS
IS TELLING US THAT HE'S MIGHT BE
REGULATING THOSE YEENS SO WE
AGAIN, HERE WE HAD TO DO THE
CRISPR EXPERIMENT IN OUR LAB.
WE TOO NEUROPROGENITTORS AND
THIS WAS LED BY JACQUELINE
MARTIN AND LUCY BICKS, SO WE CUT
THE GENES AND APPROXIMATELY THEM
TO THE DIFFERENT GENES, IT WAS
26 OF THEM AND YOU DO THE
EXPERIMENT ONCE AND THEN YOU DO
SINGLE SECURITIES LAWQUENCING
AND YOU IDENTIFY WHICH CELLS
HAVE WHICH GUIDE AND WHAT THEIR
GENE EXPRESSION IS.
AND 1 THING WE CAN SEE IS THIS
IS THE EXTENT OF DOWN
REGULATION.
WE'RE ABLE TO KNOCK DOWN 80% OF
THE GENES, AT LEAST 50%, BUT NOT
ALL OF THEM, SOME OF THEM WERE
KNOCKED DOWN ABOUT PIRT MORES
BUT 80% HAD REALLY STRIKING
KNOCK DOWN SO THIS WORKED,
THERE'S A WIDE VARIATION IN THE
AMOUNT OF DOWN STREAM GENES FROM
EACH OF THESE, SOME OF THESE
HAVE MINOR EFFECTS, OTHERS HAVE
HUGE EFFECTS BUT WHAT WE COULD
SEE WHEN WE ASKED IF THERE WAS
AN ENRICHMENT IN THE PREDICTED
TARGET YEENS IN THIS VERY SIMPLE
NEURONAL SYSTEM, WE GOT VERY
SIGNIFICANT ENRICHMENT IN 11 OF
THE 26.
THIS IS A SIMPLE VALIDATION IN A
SIMPLE SYSTEM THAT THE
PREDICTIONS WE'RE MAKING ABOUT
TRANSCRIPTIONAL REGULATION ARE
LIKELY TO BE ACTUALLY TRUE.
SO NOW WE HAVE A NETWORK OF
GENES THAT ARE DIFFERENT AND SO
HOW DO WE TARGET IT.
THIS IS WHERE I WILL END.
ONE OF THE WAYS TO MATCH THE
TARGET, IS MATCHING THE GENE
COMEGZ TO THE CONNECTIVITY MAP,
THEY HAVE THOUSANDS OF PROFILES
OF F, DIDA APPROVED DRUGS, SO
YOU LOOK AT GENE COMEGZ FROM
YOUR DISEASE MODEL AND YOU MATCH
IT TO LINETWORK CSCLOUD, AND YOU
MODIFY THE PATTERN, AND I GET A
LOT OF PUSH BACK FROM IT BUT I
THINK IT'S AN INCREDIBLE
LOAMACYY POWERFUL METHOD.
YOU IDENTIFY GENE MODULE, YOU
SCREEN CLUE AND THEN YOU RESCUE
THE PHENOTYPE.
WE'VE DONE IN THIS CNS
REGENERATION WITH CLIFFORD
WOLF'S LAB IN HARVARD, WE'VE
DONE IN THIS MOUSE AND INVITRO
IN NEURODEGENERATIVE TAU-OP A
THY MODELS AND WE'VE DONE THIS
MORE RECENTLY TO MODULATE
MICRODPLIA FUNCTION ASK WE CAN
MODULATE PHAGOCYTOSIS AS
PREDICTED BY THE TRANSCRIPT OHM
NETWORK, DECREASING FATOSTATIN
INCREASING SO THE KEY HERE IS
YOU CHARACTERIZE THE NETWORK
MODULES.
YOU IDENTIFY DRUGS OR GENES
PREDICTED TO CHANGE EXPRESSION.
YOU TEST IF THE PERTURBED
PROTURBATION DRIVES THE CHANGES
AND HERE'S THE PROBLEM, IN THE
TEST IT HAS THE DESIRED
PHENOTYPE EFFECT, IN
NEURODEGENERATION, DECREASE
INFLAMMATION IN CNS
DEGENERATION, I WANT THEAXON TO
GROW LONGER AND IN THE
NEUROPSYCHIATRIC DISEASES, I
DON'T KNOW WHAT THE PHENOTYPES
ARE SO THERE'S A HUGE NEED TO DO
INVITRO TYPE DISCOVERY WHICH WE
AND OTHER PEOPLE ARE INVOLVED IN
BUT THAT'S THE MISSING LINK IN
NEUROPSYCHIATRIC DISORDERS NOW.
SO HIGH THROUGH PUT METHODS, THE
BIOLOGY CENTER, STEM CELLS
MAKING OVER 200 LINES AND WE
WILL TEST THEM USING HIGH
THROUGH PUT PHYSIOLOGY DEVELOPED
BY MY COLLEAGUES AND HIGH
THROUGH PUT NEUROPHYSIOLOGY AND
WE THINK WE WILL BE ABLE TO
IDENTIFY REPRODUCIBLE PHENOTYPES
THAT COULD BE USED FOR DRUG
SCREENING.
SO IN SUMMARY, GENOMIC AND GENE
NETWORK APPROACHES FOR DEFINING
POINTS IN THE BRAIN, THEY DEFINE
BIOLODGE CONVERGENCE, I TOLD YOU
WHERE THAT CONVERGENCE OCCURS IN
AUTISM AND THIS OVERLAPS IN THE
DRIVERS OF THE CHANGES AS WELL
IN TERMS OF THE GENETIC DRIVERS
AND I THINK THIS PROVIOLATIONS A
STARTING POINT, IT'S A BASIC
FOUNDATION FOR UNDERSTANDING HOW
GENETIC RISK PROPAGATES ACROSS
DEVELOPMENT AS WELL AS FOR
DISEASE MODEL ANDS THERAPEUTIC
DEVELOPMENT.
SO I HAVE TO THANK A HUGE LAB.
I MENTIONED PRETTY MUCH
EVERYBODY INVOLVED IN THIS.
PEOPLE WITH THE STARS HAVE GONE
ON TO SET UP THEIR OWN LABS OR
NEXT THING.
AND I HAVE LONG-TERM
COLLABORATIONS WITH SURGE ROW P
A SCA'S LAB IN TAN FORD, THOMAS
WERGE AND HICOLLEAGUES AT
iPSYCHE IN DENMARK, CLIFFORD
WOOLF, AND ALL OF THIS, KIND OF
KREENS WORK IN NEUROAL REPAIR.
SO AGAIN, AND OUR FUNDING
SOURCES ARE LISTED THERE, THANKS
FOR YOUR ATTENTION.
I REALIZE I'VE GONE QUITE OVER,
I APOLOGIZE.
[ APPLAUSE ]
I GUESS THERE ISN'T TIME FOR ANY
QUESTIONS
QUESTIONS BUT I'M HAPPY TO TAKE
SOME.
I DON'T WANT ANY DIFFICULT
QUESTIONS.
>> THANK YOU.
ONE QUICK QUESTION.
I WAS STRUCK BY THE FACT THAT
THE PRIMARY VISUAL CON'RE CORTEX
HAD THAT HIGHER CORRELATION SO I
WAS CURIOUS, DO YOU SEE SIMILAR
THING FIST YOU LOOK IN DIFFERENT
CORTICALE REGIONS AND OTHER
DISEASES, LIKE SCHIZOPHRENIA
WHICH IS PREDOMINANTLY THOUGHT
TO BE A FRONTAL LOBE ISSUE, AND
THEN, TOO, IN THE SCIENCE PAPER,
MAYBE YOU MENTIONED AND I MISSED
IT BUT DID YOU COLLECT TISSUE
FROM THE PRIMARY VISUAL CORTEX
THERE, AND WAS IT--DO YOU SEE
THAT SIMILAR EFFECT OR
CONSISTENT EFFECT WHERE IT HAD
THE STRONGEST DIFFERENCE IN GENE
REGULATION.
>> YEAH, I MEAN I WOULD LO OF TO
DO THAT STUDY.
WE'RE NOT FUNDED TO DO THE
SINGLE CELL ANALYSIS BEYOND WHAT
WE LOOKED AT IN EVERY STUDY,
EVEN THE NEW PSYCHE ENCODE
PACKAGE IS FOCUSING ON
PREFRONTAL CORTEX.
THAT'S BEEN THE FOCUS.
WE'VE LOOKED IN SOME
NEURODEGENERATIVE DISEASE, PSP,
PROGRESSIVE SUPERIOR NUCLEAR
POLICY, ALZHEIMERS AND TEMPORAL
FRONTAL DEMENTIA, THERE WE SEE
VISUAL CORTEX EVEN THOUGH
THERE'S NO TAU PATHOLOGY.
SO IT IS INTERESTING HOW THESE
CHANGES ARE PROPAGATING THROUGH
THE CORTEX ASK WHAT THEY
ACTUALLY MEAN, THEY'RE GIVING US
A MA LECULAR PICTURE OF THE
STATE OF THE TISSUE AND WHY IT'S
IN THAT STATE, STILL, I THINK IS
HARD TO UNDERSTAND.
BUT WE ARE DOING SPATIAL
TRANSCRIPTOMICS NOW LOOKING AT
AREA 17-18 BECAUSE THERE ARE A
LOT OF HYPOTHESIS HAS TO WHY IT
BEING BE THE EXPANSION OF AREA 4
OR 3-4 IN PRIMARY VISUAL CORTEX,
SO WE'RE LOOKING AT 17, 18,
THALAMUS, VISUAL THALAMUS, WE'RE
LOOKING AT OTHER SENSORY REGIONS
TO SEE IF WHAT'S HAPPENING IS
PRIMARY SENSORY DYSFUNCTION
WHICH OF COURSE SENSORY MOTOR
DYSFUNCTION HAS BEEN VERY
RECOGNIZED BY PATIENTS AND
FAMILIES BUT VERY
UNDERRECOGNIZED IN THE
DIAGNOSTIC RUBRIC RELATED TO
AUTISM.
SO THERE ARE A BUNCH OF
POSSIBILITIES THERE.
YEAH BUT WE PROFILED VISUAL
CORTEX BECAUSE WE THOUGHT IT
WOULD BE UNAFFECTED SO NOT TRUE.
>> JUST A TERRIFIC TALK.
REALLY ENJOYED IT.
SO VOWRSLY THIS IS A
NEUROLOGICAL DISORDER WHEN YOU
ARE LOOKING AT THE BRAIN, YOU
KNOW A LOT OF THESE YEENS ARE
EXPRESSED ELSEWHERE AT THE SAME
TIME SO I WAS WONDERING WHETHER
THERE'S BEEN ANY ATTEMPT TO LOCK
AT SAY PERIPHERAL BLOOD,
LEUKOCYTES OR SPINAL FLUID TO
SEE IF THERE ARE SIMILAR GENE
DISREGULATIONS OR TRANSCRIPTS
THAT CAN BE DISEASE SPECIFIC?
>> YEAH, WE'VE DONE BLOOD.
I DON'T--AND THE STUDENT IN MY
LAB WAS HIGHER BY AMAZON TO DO
MACHINE LEARNING SO WE NEVER
ENDED UP PUB LIRIM HAJRULLAHUING
THE PAPER BUT WE'VE DONE
HUNDREDS OF BLOOD SAMPLES FROM
SIBLINGS, MATCH SIBLINGS THERE'S
REALLY NO SUBSTANTIAL SIGNATURE
THERE, WHAT WE'RE SEEING IS A
REALLY A MOLECULAR PATHOLOGY.
IT'S NOT CAUSAL SO IF WE LOOK IN
BLOOD AT 16 P DELETION OR ANY OF
THESE CMDs, WE CAN SEE
UPEAGULATION OF THE CMV IN
ALMOST ANY TISSUE SO WE CAN
CAPTURE THAT, THE PRIMARY
GENETIC LESION, LET'S CALL IT,
BUT YOU DON'T CAPTURE THE LATER
KIND OF PATHOPHYSIOLOGY IN THE
BLOOD YET, WE CERTAINLY HAVEN'T
SEEN IT WITH TRANSCRIPTOMICS AND
WE'VE DONE A LOT AND WE SHOULD
PROBABLY PUT IT SOMEWHERE AT
SOME POINT.
IT'S PRETTY OLD NOW.
BUT WE REALLY DIDN'T FIND
ANYTHING OF ANY INTEREST, WHAT
WE DO FIND IS WHEN YOU LOOK AT
MONOGENIC DISORDERS THAT HAVE
VERY BIG IMPACTS CAN YOU BEGIN
TO SEE SOME OF IT PLAYING OUT IN
THE PERIPHERAL BLOOD.
>> WHAT ABOUT SPINAL FLUID?
>> NEVER LOOKED.
IT'S HARD ENOUGH TO GET CONSENT
TO TAKE BLOOD OR EVEN SALIVA
FROM AN AUTISTIC CHILD OR
ADOLESCENT, AND THE PARENTS AND
GETTING SPINAL FLUID WOULD BE
HARD.
IF IT'S NOT IN THE
COURSE--ESPECIALLY WITH--RIBs
AND STUFF, IF THEY'RE IN REGULAR
CLINICAL CARE.
IT WOULD CERTAINLY BE
INTERESTING.
NOBODY'S LOOKED AT EXOSTUDIES OF
MULTIPLE ENDOCRINES, THERE ARE A
LOT OF INTERESTING THINGS 1
COULD DO.
I THINK LOOKING AT PROTEOMICS
MIGHT BE MORE INTERESTING THAN
THE TRANSCRIPT OHM.
YEAH?
>> QUICK QUESTION REGARDING BY O
INFORMATICS PIPELINE.
SO THE MODULES YOU'RE REFERRING
TO THEY'RE DERIVE FRIDAY BULK
TRANSCRIPTOMIC DATA OR WELL IS A
SINGLE CELL IMPLEMENTATION FOR
THAT AS WELL?
>> YEAH, SO WHAT I'VE SHOWED
HERE IS VAST MAJORITY OF BULK
WGCNA, BUT THE HGWGCNA CAN ALSO
BE AMRIED TO THE SINGLE CELL
DATA AS WELL.
YEAH.
YEAH, SO IT'S ALL JUST--IT'S
ROBUST RWGCNA.
>> THANKS.
NI WANT TO SAY THANK YOU VERY
MUCH FOR GIVING THE DISTIN
WISHED SCHOLARRED LEDGE'RE
LECTOR PREC, WE HAVE SOMETHING
WE WOULD LIKE TO PRESENT TO YOU
SO DR. [INDISCERNIBLE] FOR THE
GREAT TEACHERS,.
>> OH GREAT.
>> SO.
>> SOMETHING ELSE FOR YOU TO
TAKE HOME, RIGHT IN [LAUGHTER]
NAS THE NIH MEDICAL EXAMINER
COMMITTEE CHAIR, I HAVE THE
HONOR AMONGST ALL THE CLINICAL
DIRECTORS YOU MET DURING YOUR
VISIT TO PRESENT YOU WITH THIS,
THIS IS THE 2024 DISTINGUISHED
CLINICAL SCHOLAR ASK EDUCATOR IN
RESIDENCE SO CONGRATULATIONS AND
THANK YOU FOR YOUR VISITING AND
IT THANK YOU FOR A WONDERFUL
TALK.
NTHANK YOU VERY MUCH.
IT'S BEAUTIFUL.
THANK YOU. 2250 01:19:31,900 [ APPLAUSE ]