SO GOOD MORNING
EVERYONE.
WELCOME TO THE 2024 SYMPOSIUM OF
THE NIH DISTINGUISHED SCHOLARS
PROGRAM.
I'M THE DIRECTOR FROM THE OFFICE
OF INTRAMURAL RESEARCH AND IT'S
MY PLEASURE TO INTRODUCE
DR. SHORE.
>> THANK YOU, DR. HASHIMOTO FOR
COMING AND LISTENING ONLINE.
I'M THE NIH DEPUTY DIRECTOR FOR
INTRAMURAL RESEARCH AND HAVE THE
HONOR AND PLEASURE EVERY SINGLE
YEAR OF OPENING THE NIH RESEARCH
FESTIVAL.
I WELCOME ALL OF YOU BOTH ONLINE
AND IN PERSON TO WHAT I TRULY
KNOW WILL BE THREE FANTASTIC
DAYS OF NIH SCIENCE.
THE NIH RED SOX BEGAN IN 1986 AS
NIH RESEARCH DAY.
AND THE FESTIVAL HAS BEEN HELD
ANNUALLY SINCE THEN WITH THE
EXCEPTION OF 1987 WHEN THEY
DECIDED TO CELEBRATE THE
CENTENNIAL OF NIH INSTEAD.
IN 2000 AS YOU LIKELY KNOW, THE
FESTIVAL WENT VIRTUAL AND
PRESENTED THE SAME CUTTING EDGE
SCIENCE BUT IN A DIGITAL ONLY
FORMAT.
LAST YEAR IT CAME BACK IN PERSON
WITH A VIRTUAL OPTION FOR MANY
OF ITS OFFERINGS AND WAS SO
SUCCESSFUL THAT WE DECIDED TO DO
MUCH OF SAME THING THIS YEAR BUT
WITH THE HOPE MORE AND MORE OF
OUR AUDIENCES WILL BE RIGHT
THERE IN THE SAME ROOM WITH THE
SPEAKERS.
IN ADDITION TO OUR SYMPOSIA AND
LECTURES THERE'S RESOURCE TABLES
I HOPE YOU'LL FREQUENT.
NEW THIS YEAR ARE THE INCLUSION
IN THE FESTIVAL ON WEDNESDAY OF
THE DR. PHILLIP CHEN JR. LECTURE
ON INNOVATION AND TECHNOLOGY
TRANSFER.
THE LECTURE ON NIH HISTORY AND
THIS WEEK'S WALS LECTURE.
WHAT A LINEUP WE HAVE.
WELL, THE FESTIVAL SHOWCASES THE
BREADTH AND DEPTH OF NIH
INTRAMURAL SCIENCE, THE
DIVERSITY OF VIEW POINTS,
APPROACHES AND SCIENTIFIC
BACKGROUND OF THE NIH INTRAMURAL
SCIENTIST AND THE JOY AND
CHALLENGE OF FINDING ANSWERS TO
QUESTIONS THAT NO ONE ELSE EVEN
THOUGHT TO ASK.
I HOPE OVER THE NEXT THREE DAYS
EVERY NIH INTRAMURAL SCIENTIST
WILL GET TO TAKE PART IN SOME
WAY IN THE PRESENTATIONS,
FESTIVITIES AND THE
COLLABORATIVE SPIRIT OF THE NIH
RESEARCH FESTIVAL.
IT'S NO ACCIDENT THE
DISTINGUISHED SCHOLARS SYMPOSIUM
IS THE OPENING EVENT OF THE 2024
RESEARCH FESTIVAL.
INDEED, DEDICATION OF THE DSP TO
WELCOMING, NURTURING AND
SUPPORTING A SCIENTIFIC
WORKFORCE THAT REPRESENTS THE
FULL BREADTH BOTH OF HUMAN KIND
AND OF INTELLECTUAL PURSUIT
MIRRORS PRECISELY WHAT NIH SEES
AS THE BEST FUTURE FOR SCIENCE
AND MEDICINE.
THE SYMPOSIUM WILL SHOWCASE THE
WORK OF INTRAMURAL INVESTIGATORS
AT DIFFERENT STAGES OF THEIR
CAREERS ENGAGED IN STUDIES OF
DIFFERENT KINDS OF BIOMEDICAL
AND BEHAVIORAL SCIENCE.
TOGETHER MAKING IT MORE
QUESTIONING OF THE SCIENTIFIC
STATUS QUO.
IT'S A PLEASURE TO OPEN THE
DISTINGUISHED SCHOLARS PROGRAM
SYMPOSIUM AND TO APPROACH THE
DAY WHEN ANYONE WHO ASPIRES TO
AND WORK TOWARDS A CAREER IN
SCIENCE OR MEDICINE CAN HONESTLY
SAY I BELONG.
NOW I'M GOING TO TURN THE PODIUM
OVER TO OUR DISTINGUISHED
SCHOLAR MASTER OF CEREMONIES.
>> THANK YOU VERY MUCH,
DR. SHORE AND DR. HASHIMOTO AND
THE DSP.
WE HAD A CONVERSATION THAT
MEETING IN PERSON IS SO MUCH
MORE CONDUCIVE TO INNOVATION AND
NICE TO SEE YOU IN THE AUDIENCE
AND THOSE ONLINE AS WELL.
FOR THE FIRST SPEAKER IS
DR. ANGELA BALLESTEROS ON
INSIGHTS IN THE TRANSDUCTION
CHANNEL ESSENTIAL FOR HEARING.
>> HI, EVERYBODY THANK YOU FOR
JOINING US.
ALLOW ME TO START THE AMAZING
SYMPOSIUM BY GIVING FUNCTIONAL
INSIGHTS INTO THE TRANSDUCTION
CHANNEL FOR HEARING.
WHEN I STARTED MY POSTDOC I
WANTED TO CONTRIBUTE TO ANSWER
THE QUESTION SHOWN IN PINK.
WE KNOW THE MOLECULES FOR
SENSING THE OTHER SENSES WE THEN
KNOW THE MOLECULAR IDENTITY OF
THE TRANSDUCTION CHANNEL
RESPONSIBLE FOR HEARING AND
BALANCE.
I WAS STRUCK BY THIS BECAUSE
HEARING LOSS IS THE MOST COMMON
SENSORY DISORDER AND AFFECTS
PEOPLE DRAMATICALLY INCREASING
LONGER AND MOVING TO
INDUSTRIALIZED CITIES.
WE CAN NOW SAY THE MC1 AND MC2
ARE RESPONSIBLE FOR HEARING AND
BALANCE.
LET ME TELL YOU ABOUT THE SYSTEM
WE WORK WITH.
THE SOUND WAVES TRAVEL FROM THE
OUTER EAR TO THE MIDDLE EAR TO
THE INNER EAR TO THE COCHLEA.
THAT'S WHERE WE HAVE THE
AUDITORY SENSOR AND IT'S A
SPECIFIC REGION IS WHERE WE HAVE
THE AUDITORY SENSORY CELLS WE
CALL THE HAIR CELLS.
AND THEY'RE CALLED THE HAIR
CELLS OF THE INNER EAR BECAUSE
THEY HAVE HAIR-LIKE BUNDLES.
SO EVERY HAIR CELL HAS ONE
BUNDLE THAT IS LOCATED AT THE
REGION OF THE SENSORY HAIR CELLS
AND THIS IS THE MECHANO SENSORY
OF SOUND AND THUS TRANSFORMING
THE STIMULI INTO ELECTRICAL
SIGNALS TO BE TRANSFERRED TO THE
BRAIN.
SO LET ME TELL YOU A LITTLE BIT
HOW THE MECHANO SENSORY
ORGANELLE DOES THIS.
WE HAVE A PROTEIN FILAMENT THAT
CONNECTS THE CILIA AND WHEN THE
SOUND WAVES GO INTO OUR INNER
EAR AND BEND THE BUNDLE IT WILL
PULL FROM THE MEMBRANE OF THE
CILIA LEADING TO THE OPENING OF
THE MECHANO SENSITIVE CHANNEL
THAT IS GOING TO ALLOW FOR THE
PERMEATION OF THE IONS IN THE
HAIR CELLS.
WE KNOW IT MAKES THE MECHANO
COMPLEX AND ONE OF THE BIG
QUESTIONS THAT REMAIN IN THE
FIELD IS WHICH ONE OF THESE
TRANS MEMBRANE PROTEINS WERE THE
ION CHANNEL AND HAVE THE MECHANO
ELECTRICAL TRANSACTION COMPLEX.
ING THE THE IDENTITY OF THESE
PROTEINS WAS NOT ONLY IMPORTANT
TO IDENTIFY THE MOLECULE
RESPONSIBLE FOR HEARING AND
DRUGS BUT WITH HAVE DRUGS USED
IN CLINIC LIKE ANTIBIOTICS THAT
CAN ALSO PERMEATE THROUGH THIS
CHANNEL AND ACCUMULATE INTO HAIR
CELLS AND KILL THE HAIR CELLS
LEADING TO PERMANENT HEARING
LOSS AND BY GETTING FUNCTIONAL
INFORMATION WE CAN MOTIVATE THE
DESIGN OF STUDIES TO REDUCE
TOXICITY OF THESE MOLECULES.
WE HAVE A LOT OF EXPERIMENTAL
EVIDENCE POINTING TO THE
PROTEINS SHOWN IN GRAY AS BEING
THIS IONIC CHANNEL.
WE TRIED TO GENERATE STRUCTURAL
MODELS FOR THE PROTEINS TO SEE
WHAT THEY ARE LOOK LIKE.
WE LOOKED FOR A DISTANT RELATED
PROTEIN THAT WE ALREADY HAVE
STRUCTURE WE CAN USE AS A
TEMPLATE TO MODEL THE STRUCTURE
AND WE FOUND OUT THERE ARE TWO
OTHER FAMILY OF PROTEINS AND THE
TMEM 16 PROGRAMS HAVE CONSERVED
PROTEINS WITH THE TMC PROTEINS.
AND THE OTHER FAMILY OF PROTEINS
ARE ACTUALLY PART OF THE TMCs OF
THE SAME SUPER FAMILY OF
PROTEINS AND IT WAS SO IN THE
EVOLUTIONARY STUDY.
SO WE HAVE MORE INFORMATION
ABOUT THESE TWO OTHER PROTEINS.
WE HAVE A STRUCTURAL INFORMATION
AND KNOW HOW THE PROTEINS LOOK
LIKE AND ALSO KNOW WHAT IS THEIR
FUNCTION.
THE PROTEINS ARE BOTH FAMILIES
THAT CAN FUNCTION AS IONIC
CHANNELS AND SUGGEST THE TMCs
MAY ALSO FUNCTION AS A CHANNEL
BUT INTERESTINGLY THE TMC
PROTEINS CAN HAVE MEMBRANE
REGULATORY FUNCTION IN A COUPLE
SLIDES.
THIS IS HOW THE STRUCTURAL MODEL
OF THE TMC LOOKS LIKE.
THIS IS THE FIRST STRUCTURAL
INFORMATION WE GOT ON THE TMC
PROTEINS.
THEY HAVE 10,000 MEMBRANE
DOMAINS.
MORE IMPORTANTLY THE GENERATION
WILL ALLOW US TO LOCATE 22
MUTATIONS.
THIS IS GOING TO HELP US
UNDERSTAND HOW THE POINT
MUTATIONS ALTER THE FUNCTION OF
THESE PROTEINS AND LEAD TO
HEARING LOSS.
WHEN WE LOOK FROM THE SIDE, WE
CAN SEE THE PRESENT OF A CAVITY
AT THE PROTEIN MEMBRANE
INTERFACE AND IT FUNCTIONS AS
THE ION PERMEATION PATHWAY OR
PORE RELATED TO THE PROTEINS AND
WE THOUGHT IT COULD ALSO
FUNCTION AS A PORT IN THE TMC
PROTEINS THE PORT OF THE
ELECTRICAL TRANSACTION CHANNEL.
WE LOOK AT THESE MORE IN DETAIL.
I'LL SHOW YOU A PICTURE LOOKING
FROM THE SIDES AND SEE THE
CAVITY AND THESE ARE ALL
HIGHLIGHTS THE IONS OR THE DRUGS
WILL HAVE TO FOLLOW TO ENTER THE
HAIR CELLS.
THIS MODEL NOT ONLY SUPPORT
FUNCTIONAL DATA FROM AN
ELECTRICO PHYSIOLOGY MODEL BUT
SUPPORTS THE PROTEINS AND THE
CHANNELS FOR HEARING AND
BALANCE.
ONE OF THE COOL THINGS I KEPT
WONDERING WHEN I LOOK AT THESE
STRUCTURAL MODELS WAS THESE
PARTIALLY OPEN TO THE PLASMA
MEMBRANE AND KEPT LOOKING AT HOW
THE IONS GO TO THE PLASMA
MEMBRANE AND LOOK AT HOW THE TMC
PROTEINS FUNCTION NOT ONLY AS
THE CHANNEL BUT THEY WORK.
SO IN THE TMC PROTEIN HAVE DUAL
FUNCTION AND IT ALLOWS FOR THE
PERMUTATION OF THE PHOSPHO LIPID
GROUP IS THOUGHT TO PARTICIPATE
IN THE SEALING OF THOSE IONS
FROM THE PLASMA MEMBRANE.
SO I HYPOTHESIZE MAYBE THE
PROTEINS CANNOT ONLY FUNCTION AS
IONIC CHANNELS BUT CAN ALSO HAVE
A LIPID FUNCTION AND REGULATE
THE HAIR CELL MEMBRANE.
BEFORE I SHOW YOU A BIT OF DATA
I NEED TO TELL YOU HOW THE
LIPIDS WORK.
SO THE PLASMA MEMBRANE THE CELL
MEMBRANE IS ASYMMETRIC AND
THEY'RE ALWAYS LOCATED IN THE
INSIDE OF THE CELLS.
AND WHEN WE HAVE AN ACTIVATED
LIPID SCRAMBLASE TO WHAT IS NOT
ACCESSIBLE AND LOST INTERACTIONS
BETWEEN THE PLASMA MEMBRANE AND
CANNOT SHOW WHAT IS BEING
GENERATED.
WE CAN USE PROOF TRADITIONALLY
LABELLED TO TO DETECT THE
PHOSPHO LIPIDS BY DOING THESE
KINDS OF ASSAYS WE CANNOT ONLY
TEST THE HAIR CELL BUNDLE BUT TO
TEST THE HYPOTHESIS OF THE TMCs
PLAYING A ROLE IN THESE NEW
FUNCTION.
I DON'T HAVE TIME TO SHOW YOU
HERE ALL THE DIFFERENT
EXPERIMENTS WE PERFORM USING
KNOCKOUT MODELS FOR THE TMC
PROTEINS AND DIFFERENT
MANIPULATIONS AND EVEN THE PLANS
FOR A MOUSE MODEL HAVING POINT
MUTATIONS.
BUT WHAT WE SAW IS THERE IS THIS
TMC1 DEPENDENT EXTERNALIZATION
AT THE BUNDLE DEMONSTRATING THEY
CANNOT FUNCTION WITH
DYSREGULATED MEMBRANE.
WE THINK WHEN THE ION CHANNEL OF
THE TMC PROTEINS IS WORKING THE
MEMBRANE IS PRESERVED BUT WHEN
WE HAVE MUTATIONS AT TMC1 THIS
FUNCTION GETS ACTIVATED AND IT
GETS EXTERNALIZED AND OBSERVE
THESE THAT ARE NOT ONLY ALTERING
THE PROTEINS BUT AFFECT
TRANSDUCTION.
WE THINK WHEN THIS IS HAPPENING
IN AN UNREGULATED WAY IT MAY BE
A MECHANISM THE HAIR CELLS ARE
USING TO RECYCLE NOT FUNCTIONAL
COMPLICE BUT WHEN IN AN
UNREGULATED WAY MAY BE TO HAIR
CELL DEATH AND HEARING LOSS.
OUR LAB IS NOT ONLY INTERESTED
IN THE CATHETERIZATION OF THE
TMC PROTEINS BUT ALSO IN
UNDERSTANDING HOW THE MEMBRANE
REGULATORY FUNCTIONALITIERS HAIR
CELL PHYSIOLOGY.
SO WITH THAT I WOULD LIKE TO
THANK MY FORMER LAB AND MENTORS
AND COLLABORATORS FOR ALL THEIR
SUPPORT, THE DSP PROGRAM FOR
THIS AMAZING OPPORTUNITY AND
WITH THAT I'LL BE HAPPY TO TAKE
ANY QUESTIONS IF I HAVE TIME.
>> THANK YOU, DR. BALLESTEROS.
IF YOU HAVE QUESTIONS COME UP TO
THE MIKE AND INTRODUCE YOURSELF
AND POSE ANY QUESTIONS.
DO WE HAVE SOMEONE MONITORING
QUESTIONS ONLINE?
THIS IS GREAT.
I HAVE A LOT OF QUESTIONS.
FANTASTIC.
BY BACKGROUND I'M A VASCULAR
CARDIOLOGIST SO THIS IS VERY
INTERESTING WE THINK OF THESE
SCRAMBLASES PROTEINS AS BEING
IMPORTANT IN REGULATING
ENDOTHELIAL HEALTH BECAUSE THE
PHOSPHO LIPIDS GET EXPOSED AND
GET CLOTS AND YOU NOTICE THE
FLIP BASES HAVE A SIMILAR
PHENOTYPE MODULATED BY TMC1 OR
THIS RESTRICTED TO THE
SCRAMBLASE FAMILY?
>> GOOD QUESTION.
WE KNOW MUTATIONS ALSO CAUSE
HEARING LOSS AND DEAFNESS SO
MEMBRANE RESOLUTION IS IMPORTANT
FOR PROPER HEARING AND BALANCE.
FOR NOW WE THINK -- AND THIS IS
NEW AND WE NEED TO DO MORE WORK,
WE THINK THE TMC FUNCTIONS
BECAUSE OF THE DATA GENERATED IN
OUR LAB WE KNOW THEY'RE NOT
LIPID SPECIFIC LIKE OTHER
SCRAMBLASES SUGGESTING THEY
DON'T NEED ENERGY LIKE OTHERS
AND SO THEY'RE A LITTLE BIT
DIFFERENT.
THEY'RE ALSO NOT REGULATED AS
THE TME16 SO THEY HAVE THINGS IN
COMMON WITH OTHER LIPIDS BUT
DIFFERENT IN SOME WAYS.
>> THAT'S WONDERFUL, THANK YOU.
DO THE HAIR CELLS REGENERATE?
>> THEY DO NOT.
I FORGOT TO MENTION THAT, THANK
YOU.
>> SO IF THEY DON'T REGENERATE I
THINK THERE'S IMPORTANCE IN
PRESERVING THEM.
>> YES.
THANK YOU SO MUCH.
>> ARE THERE OTHER QUESTIONS
FROM THE AUDIENCE?
OKAY, WONDERFUL.
THANK YOU VERY MUCH, DR
DR. BALLESTEROS.
I TRIED TO TAKE EVERY SEMINAR
FLA CARDIOVASCULAR.
THE NEXT SPEAKER IS
DR. JACQUELINE HAVE TO TALKING
ABOUT TREATMENT RELATED
CARDIOVASCULAR DISEASE AND
HEALTH INEQUITIES AMONG BREAST
CANCER SURVIVORS AND WILL BE
PRESENTING VIRTUALLY.
WELCOME, DR. HAVE TO.
-- WELCOME DR. VO.
>> THANK YOU FOR THE
INTRODUCTION AND GOOD MORNING
FROM LOS ANGELES, CALIFORNIA.
THANK YOU FOR THE ORGANIZATION.
I'M AT A CONFERENCE THIS WEEK A
JUNIOR INVESTIGATOR AND
DELIGHTED TO SHARE A BRIEF
DESCRIPTION OF ANY RESEARCH
PORTFOLIO.
THERE ARE OVER 4 MILLION BREAST
CANCER SURVIVORS IN THE UNITED
STATES.
THEY'RE LIVING LONGER DUE TO
ADVANCES IN SCREENING AND
TREATMENT AND SURVIVAL.
BECAUSE THEY'RE LIVING LONGER
DOESN'T NECESSARILY MEAN THEY'RE
LIVING BETTER.
MANY CANCER TREATMENTS CAN
UNFORTUNATELY CAUSE ADVERSE
HEALTH EFFECTS.
BREAST CANCER SURVIVORS FACE
RISK OF CARDIOVASCULAR COMPARED
TO WOMEN WITHOUT BREAST CANCER
DUE TO CHEMOTHERAPY.
WE REPORTED AN INTERESTING TREND
IN HEART DISEASE MORTALITY AMONG
WOMEN TREATED WITH CHEMOTHERAPY
FROM 1975 TO 2016 THE RISK WAS
DRIVEN BY CHEMOTHERAPY BUT IT
DOES NOT HAVE CHEMOTHERAPY
TYPES.
AND THERE'S A LACK OF DATA
DRIVEN STUDIES AND DON'T HAVE
AGE SPECIFIC RECOMMENDATIONS.
THE FINDINGS OF ONE OF MY
STUDIES AND THE AIM WAS TO
EVALUATE THE LONG-TERM RISK OF
INCIDENT OF CARDIOVASCULAR
DISEASE AFTER TREATMENT AMONG
APPROXIMATELY 10,000, ONE-YEAR
BREAST CANCER SURVIVORS.
WE HAVE A BREAST CANCER
SURVIVORS COHORT WITH
PROSPECTIVE FOLLOW-UP USING DATA
FROM CANCER REGISTRIES AND
ELECTRONIC HEALTH RECORDS AND
DEATH DATA.
THE CO-P.I. ALONGSIDE HERE AND
THE TEAM IS HIGHLIGHTED TO THE
RIGHT AND OUR COLLABORATORS
BELOW.
THE PRESENT STUDY LEVERAGED DATA
FROM KAISER PERMANENTEs.
THE PRIMARY EXPOSURE IS REGIMENT
TYPE BASED ON TOXICITY AND
OTHERS IN THE REFERENCE GROUP.
FOR OUTCOME OF INTEREST WE
INCLUDED CAUSE SPECIFIC
CARDIOVASCULAR DISEASE AND HEART
FAILURE AND ISCHEMIC HEART
DISEASE AND STROKE.
I'LL ONLY PRESENT THE CAR
CARDIOPATHY RESULTS.
WE HAD INCIDENTS ACCOUNTING FOR
COMPETING EVENT AND USED A
REGRESSION MODEL TO ACCOUNT OR
THE CARDIOVASCULAR RISK WITH AGE
AND CHARACTERISTICS AND OTHER
BREAST CANCER TREATMENTS AND
OTHER RISKS.
THESE ARE THE PATIENT AND BREAST
CANCER CHARACTERISTICS.
AND DIAGNOSED AT YOUNGER AGES
AND MORE ADVANCED STAGE AND MORE
AGGRESSIVE TYPES COMPARED TO
WOMEN WHO RECEIVE OTHER
CHEMOTHERAPIES OR NO
CHEMOTHERAPY.
THIS IS TYPE STRATIFIED BY AGE
AND THESE ARE WOMEN LESS THAN'
55 YEARS OF AGE AND THE RIGHT IS
WOMEN 65 YEARS AND OLDER.
ON THE X AXIS IS YEARS SINCE
BREAST CANCER DIAGNOSIS.
AT 10 YEARS AFTER BREAST CANCER
DIAGNOSIS THE RISK DIFFERENCES
FOR CARDIO MIOPANELY.
YOU CAN SEE THE WOMEN TREATED
WITH THESE SPECIFICALLY THE 10
YEAR INCIDENT WAS 1 IN 29 FOR
WOMEN LESS THAN 55 YEARS AND
LESS THAN 1 IN 10 FOR WOMEN 55
TO 64 YEARS.
NO DIFFERENCES FOR WOMEN TREATED
OLDER THAN 65.
WE LOOKED AT WOMEN WHO DID NOT
RECEIVE CHEMOTHERAPY AND A
BREAST CANCER DIAGNOSIS.
WOMEN TREATED THIS HAD HIRE
INSTANCES.
THESE RISKS PERSIST LONG TERM
FROM FIVE TO NINE YEARS AFTER
DIAGNOSIS AND 10 PLUS YEARS
AFTER AND WE FOUND RESULTS FOR
BREAST CANCER SURVIVORS LESS
THAN 65 YEARS.
THE HIGHEST RISKS WERE OBSERVED
AMONG THE YOUNGEST GROUP AGE 20
TO 64 YEARS RECEIVING THIS HAD A
THREE TIMES HIGHER RISK OF
DEVELOPING CARDIOMYOPATHY
COMPARED TO THOSE WHO DID NOT
RECEIVE ANY THERAPY.
ACROSS 24 YEARS OF FOLLOW-UP
BREAST CANCER SURVIVORS TREATED
WITH THESE WERE AT INCREASED
RISK OF HEART FAILURE AND THE
RISKS PERSISTED EVEN AFTER 10
YEARS AFTER BREAST CANCER
TREATMENT AND AMONG WOMEN
DIAGNOSED WITH BREAST CANCER
BEFORE AGE 65.
NOT EVERY PATIENT WHO RECEIVED
THESE WILL GO ON TO DEVELOP A
CARDIOVASCULAR DISEASE.
WHO ARE THE PATIENTS AT HIGHEST
RISK FOR DEVELOPING A TREATMENT
IMPLICATED DISEASE AND WANT TO
HIGHLIGHT THE NEED TO LOOK AT
HIGH RISK PATIENTS ESPECIALLY
YOUNGER WOMEN SURVIVING MANY
DECADES AFTER TREATMENT.
AND I LOOKED AT DIFFERENT
POPULATIONS AND THOSE IN THE
LOWEST ECONOMIC STRATS.
STATUS.
ONE AREA OF HEALTH DISPARITY
RESEARCH I'M PARTICULARLY
INTERESTED IN IS ASIAN AMERICANS
WHO COMPRISE DIFFERENT AND
DISTINCT RACIAL GROUPS AND IN
THE STUDY WE LOOKED AT ASIAN
AMERICAN AND PACIFIC ISLANDER
POPULATION.
AND I'VE HIGHLIGHT THE FEMALE
POPULATION.
CANCER MORTALITY WAS TWO TIMES
HIGHER FOR SOME GROUPS AND
LOOKED AT DISPARITIES WHO
RESPONSE A SMALL PERCENT OF THE
GROUP.
TO ACCOMPLISH ANY GOAL I
INCREASED THE RACIAL DIVERSITY
WITHIN THE COHORT WITH THE THE
SUPPORT OF THE NIH DISTINGUISHED
SCHOLAR PROGRAM AND I LOOKED IF
AND HOW IT IMPACTED MINORITIZED
CANCER SURVIVORS AND LOOKED AT
CARDIOVASCULAR DISEASE AND
MORTALITY AND RACE AND ETHNICITY
AND ACCOUNTING FOR SOCIO
ECONOMIC STATUS.
WITH THAT I'D LIKE TO
ACKNOWLEDGE AND THANK MY MENTORS
AND COLLEAGUES AND COLLABORATORS
AND MY MENTEE IN THE NIH
DISTINGUISHED SCHOLARS PROGRAM
AND IT'S BEEN A WONDERFUL YEAR
IN THE DSP AND I LOOK FORWARD TO
THE YEARS TO COME.
THANK YOU.
>> THANK YOU.
LEAVE IT TO THE DSP SCHOLARS TO
STAY ON TIME.
IT'S INTERESTING WORK AND
CONGRATULATIONS ON SEEING DIRECT
AND IMMEDIATE OUTCOMES OF YOUR
WORK CHANGING THE WAY DATA IS
COLLECTED TO THEN THINK ABOUT
WHAT COMES AFTER THAT.
THERE'S QUESTIONS IN THE
AUDIENCE, DR. PLATT.
>> THIS IS NICE.
I'M CURIOUS ABOUT DIABETES.
IT KEPT SHOWING UP AND KNOW IT'S
INCREASED IN CERTAIN
MINORITIZED.
WHAT'S THE SUGGESTION FOR BREAST
CANCER DOCTORS IN DEALING WITH
PATIENTS WITH DIABETES AND WHERE
IT MAY BE A COMPLICATION OF
BREAST CANCER.
I'M CURIOUS FOR ANY ADVICE ON
THAT.
>> THAT'S A GOOD QUESTION AND
CONSIDERING WE HAVE
COMORBIDITIES SO COMMON AND
CO-OCCURRING.
I DON'T HAVE PARTICULAR ADVICE
FOR CLINICIANS AT THE MOMENT FOR
DIABETES BUT IT NEEDS TO BE
RESEARCHED FURTHER AND LOOKING
AT CARDIOVASCULAR IN OUR STUDY
WE DIDN'T ACCOUNT FOR DIABETES
BUT IT'S SOMETHING WE'RE
CONSIDERING IN THE FUTURE FOR
PATIENT WHO'S PRESENT WITH
CO-MORBIDITIES HOW THEIR RISK OF
CARDIOVASCULAR DISEASE MAY CARE
IN PARTICULAR TO THEIR CANCER
TREATMENT.
THANK YOU.
>> I WAS INTRIGUED BY THE FACT
THAT WOMEN OLDER THAN 65 WERE
KIND OF PROTECTED.
I WAS WONDERING IF YOU HAVE ANY
HYPOTHESES IN TERMS OF MECHANISM
WHETHER THAT WAS MAYBE IN
THEY'RE IN SENESCENCE TO SOME
DEGREE AND THEY'RE HEART CELLS
ARE NOT AS VULNERABLE TO THE
ANTHRACYCLINE TREATMENT AND
WHETHER YOU'RE PLANNING STUDIES
IN THE FUTURE TO ELUCIDATE THAT.
>> THAT'S A GREAT QUESTION.
AMONG OLDER WOMEN THEIR HEART
WOULDN'T NECESSARILY BE
PROTECTED FROM THE CARDIO
TOXICITY I THINK WE'RE
HIGHLIGHTING A POTENTIAL
DIFFERENCE IN MAYBE HEALTH CARE
AND TREATMENT ACCESS FOR OLDER
PATIENT.
AS YOU GET OLDER THE RISK OF
CARDIOVASCULAR DISEASE INCREASES
SO CLINICIANS MAY BE MORE
CAUTIOUS WHETHER TO GIVE THEM A
CARDIO TOXIC DRUG WHEN THEY KNOW
THEIR RISK IS HIGHER THAN FOR A
YOUNGER WOMEN WHO ARE MUCH
HEALTHIER AND HAVE LESS
COMORBIDITY.
I DON'T KNOW IF THAT'S PER SE
THE CONSIDERATION AND BIOMARKERS
ARE AN IMPORTANT CONTEXT.
WE COLLECTED SOME INFORMATION
BUT IT'S ON BASED ON THE
ELECTRONIC HEALTH RECORDS BUT
SOMETHING WE'RE TRYING TO
ELUCIDATE FURTHER.
>> THANK YOU VERY MUCH.
THAT WAS INTERESTING WORK.
YOU SHOWED YOUR DATA IN
LONG-TERM CARDIOVASCULAR DISEASE
AFTER SOME INHIBITOR?
>> GREAT QUESTION.
THE STUDY WE HAVE IS ONGOING AND
HOPEFULLY WE CAN PRESENT THAT
MAYBE NEXT YEAR.
>> THE TREATMENT WITH
NON-CHEMOTHERAPY MAKES WE WONDER
WHETHER THERE'S AN INCREASE IN
CARDIOVASCULAR DISEASE COMPARED
WITH THE NORMAL OR NON-CANCER
POPULATION.
>> GOOD POINT.
I THINK ONE OF THE MAIN ASPECTS
HERE IS THAT CARDIOVASCULAR
DISEASE AND BREAST CANCER ARE
DISEASES THAT HAVE SOME RARE
RISK FACTORS AND SOMETIMES
BREAST CANCER SURVIVORS ARE AT
AN INCREASED RISK COMPARED TO
WOMEN NAON-CANCER AND LIKELY TO
DIE OF CARDIOVASCULAR DISEASE
AND WE TOOK THAT INTO PLAY.
>> THE DATA YOU SHOWED THAT LAGS
OF TENDS TO LAG A COUPLE YEARS
BEHIND WITH THE INCREASED USE OF
IMMUNOTHERAPY DO YOU KNOW IF
THERE'S A SIGNAL THERE THAT
MIGHT POINT IN THE SAME
DIRECTION OR NO COMPARISON WITH
CHEMOTHERAPY?
>> I THINK WITH AMONG THE BREAST
CANCER POPULATION IMMUNOTHERAPY
IS MORE RECENT AND TO ELUCIDATE
LONG-TERM RISK WILL TAKE MORE
TIME AND HOPE THAT'S SOMETHING
WE CAN CAPTURE IN THE FOLLOW-UP.
WE'RE EXCITED TO BE ABLE TO
ELUCIDATE THESE QUESTIONS IN THE
FUT
FUTURE.
>> IT MAY APPLY TO OTHER DISEASE
STATES LIKE CARDIOVASCULAR
DISEASE AND ATHEROSCLEROSIS AND
OTHERS AS WELL.
THIS IS AN INTERESTING AREA AND
WE'LL STAY TUNED FOR WHAT YOU
PRESENT.
THANK YOU, DR. VO.
WE'LL STAY ON THE FEMALE
IMMUNOTHERAPY, DR. ROSEA NYUYEN
FROM THE 2023 COHORT ON
IMMUNOTHERAPIES FOR PEDIATRIC
NEUROBLASTOMA FROM BENCH TO THE
BED SIDE.
>> I'M EXCITED TO BE HERE AND
WANT TO USE MY 10 MINUTES TO
TALK WITH YOU ABOUT
IMMUNOTHERAPIES FOR PEDIATRIC
NEUROBLASTOMA AND START WITH A
PICTURE OF MY LAB.
THE SOLID TUMOR AND IMMUNOLOGY
SECTION.
A DIVERSE GROUP OF PEOPLE FROM
SEVEN DIFFERENT NATIONS AND FUN
BUT DEDICATED COME TO THE LAB
EVERY DAY TO WORK ON DEVELOPING
NEW IMMUNOTHERAPIES WITH FOR
CHILDREN WITH SOLID TUMORS WITH
THE FOCUS ON NEUROBLASTOMA.
ONE OF THE APPROACHES I'LL SHARE
IS INTEGRATING THE GAMMA C
CYTOKINES AND AMONG THE GROUP
WE'RE PARTICULARLY INTERESTED IN
INTERLEUKIN 15 AND 21 TO IMPROVE
ANTIBODY THERAPY AND CAR T CELL
THERAPY.
NEURO BLASTOMA IS A SOLID TUMOR
THAT ORIGINATES FROM THE NEURAL
CREST AND YOUNG CHILDREN AND
TODDLERS ARE PREDOMINANTLY
AFFECTED.
PEDIATRIC ONCOLOGY AND CANCERS
IN GENERAL ARE VERY RARE AND
AMONG THIS GROUP OF PATIENTS WE
ONLY HAVE 650 NEW CASES A YEAR
BUT PUTS US AT THIS PART IN
CHILDREN AND THEY'RE AT HIGH
RISK FOR RELAPSE OR REFRACTORY
DISEASE OR DEATH.
IT'S NOT SURPRISING WHEN I TELL
YOU 15% OF ALL CANCER RELATED
DEATHS IN CHILDREN ARE CAUSED BY
NEURO BLASTOMA.
NOT BECAUSE WE DON'T TREAT THEM
THEY GET THE KITCHEN SINK AND
30% WITHIN THE POPULATION OF
HIGH-RISK PATIENTS CAN ACHIEVE
LONG-TERM REMISSIONS.
A BIG BREAKTHROUGH IN THE FIELD
WAS ACTUALLY THE FDA APPROVAL OF
THE ANTI-GD2 ANTIBODY THE FIRST
IMMUNOTHERAPY IN SOLID TUMOR AND
THE PHASE 3 TRIAL, CHILDREN WITH
NEURO BLASTOMA THAT ATTAINED A
STATE OF MINIMUM RESIDUAL
DISEASE WERE RANDOMIZED TO
RECEIVE STANDARD OF CARE OR THE
ANTIBODY WITH CYTOKINES AND A
TRIAL BENEFIT AND THIS BECAME
THE STANDARD OF CARE.
THE ANTIBODY WORKS -- IT'S QUITE
FASCINATING THERAPY IN MY MIND.
IT BRINGS TOGETHER EFFECTER
CELLS OF THE IMMUNE SYSTEM AND
TUMOR CELLS BY RECOGNIZING HIGH
LEVELS OF AN ANTIGEN IN THIS
CASE GD2 AND LEADS TO THE
KILLING OF THE TUMOR CELLS BY
THESE EFFECTER CELLS AND YOU CAN
MODULATE THE REACTION FOR
EXAMPLE BY ADDING CYTOKINES THAT
EITHER ENHANCE OR SUPPRESS THE
TUMOR CELLS AND CAN TAKE THE
CYTOKINES AND TETHER THEM TO THE
ANTIBODY SO YOU ONLY HAVE LOCAL
EXPOSURE OF THESE VERY POTENT
YET TOXIC MOLECULES.
AND THAT'S WHAT WE DID.
WE CREATED THESE IMMUNOCYTOKINES
BY USING THE ANTIBODY AND
TETHERING IL15 OR 21 TO THEM AND
COMPARED THEM TO AN EXISTING
IMMUNOCYTOKINE FROM THE GAMMA C
FAMILY.
AND WE TESTED THIS IN VITRO AND
IN VIVO.
I'M SHOWING DATA FROM AN IN VIVO
EXPERIMENT FROM ANIMALS.
THESE WERE IMMUNOCOMPETENT MICE
ENGRAFTED AND RANDOMIZED TO
RECEIVE ONE OF THE FOUR
TREATMENTS.
WE THEN PERFORMED BIO ILLUME
NE
ESSENCE AND BY DAY 30 THE ONES
THAT RECEIVED NO TREATMENT OR
THE CYTOKINE WITH IL2 HAD
SUBSTANTIALLY HIGHER TUMOR
BURDEN AND IN A SEPARATE COHORT
WE LET THE ANIMALS AGE OUT UNTIL
DAY 100 AND THERE WAS A CLEAR
WINNER.
THE ONES THAT RECEIVE HE HAD --
RECEIVED THE IL15 RECEIVED THE
GOOD MACROPHAGES AND A LOWER
LEVEL OF IMMUNE EXPRESSIVE T
REGULATORY IN THE ANIMALS THAT
RECEIVE THE TWO NEW CYTOKINES
COMPARED TO THOSE WITH 2.
THIS IS THE PRECLINICAL
RATIONALE TO GO IN THE CLINIC.
NOW WE'RE TRANSLATING THIS TO A
CLINICAL STUDY USING THE
ANTIBODY AND IL15 FIRST
SEPARATELY.
AND LOOKING FOR TOLERABILITY AND
BIOLOGIC SIGNAL AND HOPEFULLY
THIS WILL BE THE FOUND TO PAVE
THE WAY FOR THE CLINICAL
TRANSLATION OF THE
IMMUNOCYTOKINE WITH IL15.
I'LL USE THE SECOND HALF OF THE
TALK TO TALK ABOUT CAR T CELLS.
I'M SURE YOU KNOW THEY HAVE
TRANSFORMED THE TREATMENT OF
PATIENTS WITH LEUKEMIA AND
LYMPHOMA BUT IN SOLID TUMORS OUR
RESPONSES WERE NOT THAT GREAT AS
YOU CAN SEE HERE IN THE TABLE
THAT SUMMARIZES ALL THE
PEDIATRIC SOLID TUMOR CAR T CELL
TRIALS DONE THUS FAR.
FOCUSSING ON THE BLUE COLUMN YOU
CAN SEE WE ACHIEVED COMPLETE
REMISSION IN ONLY A FEW PATIENTS
AND LOOKING CLOSER THEY HAD
LIMITED DISEASE BURDEN.
THERE'S A LOT OF DIFFERENCES
BETWEEN LEUKEMIA AND SOLID
TUMORS.
CELLS HAVE I -- A HARDER TIME
GETTING IN THE TUMOR AND HAVE
LESS REPERTOIRE TO TARGET AND
THE T CELLS WHEN THEY GET IN THE
TME THEY ENCOUNTER A HOSTILE
ENVIRONMENT THAT PROHIBITS THEIR
FUNCTION AND HOW CAN WE OVERCOME
THE CHALLENGES?
WE TURN TO THE IL15 AND 21.
THIS IS WORK DONE BY ONE OF THE
POSTDOCS IN THE LAB.
WE USED GPC2 CAR T CELLS IN THE
TARGET AND THE TARGET WAS
DISCOVERED HERE AT THE NCI.
HE MADE A CAR AND GAVE IT TO US
AND WE OPTIMIZE IT FOR CLINICAL
TRANSLATION BUT ALREADY THINKING
ABOUT THE NEXT GENERATION TO
MAKE IT MORE POTENT PARTICULARLY
FOR PATIENTS FOR EXAMPLE WITH
LARGE TUMOR BURDEN.
AND USED THIS AND ENGINEERED A
VECTOR TO TETHER THEM TO THE
CELL MEMBRANE.
HE USED TWO NEUROBLASTOMA CELL
LINES AND IT'S AN IN VITRO CELL
CULTURE ASSAY WHERE YOU ADD
EVERY TWO TO THREE DAYS TUMOR
CELLS TO CAR T CELLS AND SEE HOW
WELL THEY ARE PERFORM WITH THE
CONSECUTIVE TUMOR RE-CHALLENGE.
AS THE GRAPH INCREASES HERE IT
MEANS THE TUMORS GROW THROUGH
AND POPULATE THE WELL.
YOU SEE VERY NICELY OVER TIME
INITIALLY THE BLUE AND RED LINE
REALLY RUN TOGETHER.
THE BLUE REPRESENTING THE CARS
ALONE AS THE RED IL15 AND 21.
AFTER TWO TO THREE RECHALLENGES
THE GRADUALLY DEMONSTRATE THE
CAR T CELLS PERFORM BETTER IN
CULTURE.
HE WAS ALSO ABLE TO SHOW THIS IN
VIVO IN AN ORTHOTOPIC XENO GRAPH
MODEL TO INJECT THE ML5 CELLS IN
THE PERIDROMAL FAT PAD AND THEN
TREAT THEM AND IT'S NOT
SURPRISING WITH A LARGE TUMOR
THE CARS ALONE DO NOT DO DAMAGE
BECAUSE THE TUMOR LINES JUST
PERSIST UP HERE AND YOU CAN SEE
WHEN THE TUMOR BURDEN DECREASES
BY WEEK THREE AND FOUR.
WITH THIS EFFORT WE'RE LOOKING
TO UNDERSTAND THE MECHANISMS
BETTER IN THE TUMOR ENVIRONMENT
AND WHAT IL15 AND 21 DOES OR DO
TO THE IMMUNE CELLS AND WE
LIMITED THE CONSITUTIVE PORTION
AND THIS IS THE END OF THE TALK.
I'D LIKE AGAIN TO THANK MY LAB
AS WELL AS ALL THE COLLABORATE
ERS AND INDUSTRY PARTNERS AND
OUR FUNDING SOURCES AND THE NIH
DSP PROGRAM AND PATIENTS AND
FAMILIES AND THIS TALK CAME AT
AN OPPORTUNITY TIME BECAUSE THIS
MONTH IS CHILDHOOD CANCER
AWARENESS MONTH AND I'M HAPPY TO
TAKE ANY QUESTIONS.
THANK YOU.
>> THANK YOU.
FASCINATING WORK.
WE HAVE A QUESTION ON THE LEFT
SIDE OF THE AUDITORIUM.
>> BEAUTIFUL WORK.
I'M LUIS FRANCO SCHOLAR FROM
2020 I THINK.
SAME CLASS.
SO TWO QUESTIONS ON THE ADCC
APPROACH WITH THE IL15
CONJUGATES IS IT THE MACROPHAGES
MATTER COMPARED TO ACTIVATION OF
THE NK CELLS?
>> WE DID THAT AND LOOKED AT IT
AND THE NK CELL MODELS WERE NOT
EXPANDED.
AND AT LEAST AT THE TIME POINT
WHEN WE DID OUR SINGLE CELL RNA
SEQ AND FLOW CYTOMETRY BUT IL15
IS THE JUICE FOR NK CELLS AND T
CELLS AND THERE'S CLINICAL
STUDIES WHEN YOU INFUSE IT AS A
FREE FLOATING AGENT YOU GET
MASSIVE EXPANSION OF NK CELLS OR
T CELLS AND I SUSPECT HAD IT
GONE LONGER WE WOULD HAVE SEEN
THAT PLUS THIS IS ONE OF THE
STUDIES IN THE CLINICAL TRIAL.
>> THE OTHER QUESTION WHAT'S THE
RELATIONSHIP BETWEEN THESE
TUMORS AND THE BLOOD BRAIN
BARRIER?
DO THEY NEED TO CROSS THE BLOOD
BRAIN BARRIER OR NOT?
>> IT'S A NON-CNS SO MOST THE
TUMOR BURDEN IS PERIPHERAL BUT
THE MOLECULAR OF THE MOLECULES
IS TOO BIG TO CROSS SO YOU WOULD
PROBABLY HAVE TO RE-ENGINEER IT
INTO A DYE BODY OR SOMETHING
SMALLER TO MAKE IT GO THROUGH.
>> I WAS WONDERING ABOUT NANO
BODIES AND SINGLE DOMAIN
ANTIBODIES WHICH SUPPOSEDLY HAVE
BETTER PENETRATION OF TISSUES.
>> I THINK IT'S A GREAT THOUGHT.
WE'RE PLAYING AROUND WITH THIS A
LITTLE BIT NOT WITH THE GD2
ANTIBODY BECAUSE THAT'S HIGHLY
EXPRESSED ON NERVES IN THE CNS.
WE HAVE TO BE A LITTLE CAREFUL
WITH TEXOXICITIES BUT IT'S A GRT
THOUGHT.
>> TO BUILD ON THAT I WAS ALSO
THINKING OF THIS FROM THE
STANDPOINT OF BLOOD BRAIN
BARRIER TRANSMISSION AND
WONDERING WHAT CYTOTOXICITY
WOULD YOU EXPECT TO SEE AND WHAT
SYSTEMIC TOXICITIES MIGHT YOU
EXPECT FROM THE UNRESTRAINED
SIGNALLING?
>> IT CAN CAUSE SERIOUS
NEUROTOXICITY IN TERMS OF PAIN
AND WE GIVE MORPHINE AND TRY TO
TITRATE IT UP AND THERE'S FORMS
OF ANTIBODIES WITH MUTATIONS
THAT DON'T ENGAGE THE COMPLEMENT
SYSTEM THAT MADE IT BETTER.
FOR THIS COMBINATION I THINK
THERE WILL STILL BE PAIN.
WE'RE GIVING THE TITRATION
SLOWLY BECAUSE THE OVERLAPPING
TOXICITY WOULD BE YOUR
INFLAMMATORY RESPONSE.
YOU HAVE TO BE CAREFUL.
IT CAN CAUSE BASICALLY
HYPERTENSION, RESPIRATORY
PROBLEMS DUE TO PULMONARY EDEMA
AND SLOW TRITATION OVER TIME IS
IMPORTANT AND PLUS THE WAY I
DESIGN THE TRIAL WAS NOT AS A
BOLUS BUT LONG-TERM INFUSION AND
THEY'RE TRULY WARRIORS AND I
DON'T THINK NONE OF US IN THE
ROOM WOULD BE ABLE TO TOLERATE A
TENTH OF THIS TREATMENT.
>> THANK YOU.
TRULY INSPIRING WORK.
THANK YOU, DR. NGUYEN.
OUR NEXT SPEAKER IS DR. DIANA
MONTEIRO TALKING ABOUT PROTEIN
CRYSTALLOGRAPHY AS A GATEWAY FOR
DRUG DISCOVERY.
THE TOPICS TRANSITION
BEAUTIFULLY.
>> THIS IS THE POINT WHERE I
SHOULD HAVE TURNED MY COMPUTER
ON WHEN I WAS STILL SITTING
THERE.
MIN
I THINK THIS IS GOING TO BE
DIFFERENT FROM EVERYTHING WE
HEARD SO FAR AND I'M A PROTEIN
CRYSTALLOGRAPHY AND STARTED AS A
CHEMIST AND I TOOK A BIG DETOUR
TO PROTEIN CRYSTALLOGRAPHY AND
COMING TO NCI MEANS I GET TO GO
BACK TO MY ROOTS IN DRUG
DISCOVERY WHICH IS WONDERFUL AND
INTERACT WITH BIOLOGISTS BECAUSE
I'M NOT A BIOLOGIST.
MY GROUP IS TECHNOLOGY AND
TECHNIQUE DRIVEN AND BRINGING
THIS AND I THINK IF YOU ALL JUST
TUNE OUT OF MY TALK JUST LOOK AT
THE LAST SLIDE MOSTLY AND THINK
ABOUT THE TECHNOLOGY THAT WE'RE
BRINGING IN BECAUSE I WOULD LOVE
TO HEAR ABOUT TARGETS AND THINGS
OF IMPORTANCE FROM THE PEOPLE
WHO UNDERSTAND CANCER FROM THIS
POINT OF VIEW OF ORGANS AND
SCALES WHICH IS DIFFERENT FROM I
WORK.
AND AND HAVING SPENT TIME IN
DYNAMIC CRYSTALLOGRAPHY I'M OF
THE OPINION THAT THEY'RE
MOLECULAR MEASURES AND FOR ME
AND MY GROUP WE DETERMINE HIGH
RESOLUTION STRUCTURES IN THIS
CASE NOW ONCOPROTEINS.
IT'S MY FIRST RODEO IN THE REALM
OF CANCER BUT ALL THE
TECHNOLOGY'S TRANSLATABLE.
WE ALSO LOOK AT PROTEIN LIGAND
COMPLEXES.
THIS MEANS WE DETERMINE
MECHANISMS.
AT THE POINT OF VIEW OF AU
TOMMIC MECHANISMS WE DEFINE THE
PROTEIN-PROTEIN INTERACTIONS
IMPORTANT FOR DEVELOPING OF
DRUGS AND GET STRUCTURED
ACTIVITY RELATIONSHIPS AND ALL
THIS IN AS HIGH THROUGHPUT TO
ACCELERATE EVERYTHING AND
MINIMIZE SAMPLE CONSUMPTION
BECAUSE AS IT TURNS OUT THE MORE
COMPLEX PROTEINS THE HARDER THEY
ARE TO MAKE AND MORE
APPRECIATION THEY BECOME AND
NEED TO TAKE THAT INTO ACCOUNT.
I HAVE A SOFT SPOT FOR THE
DYNAMIC.
AND THE DYNAMICS ARE OVERLOOKED.
I'LL SHOW A QUICK EXAMPLE OF A
PROJECT WE STARTED BACK IN MARCH
WHERE DYNAMICS WERE CLEARLY
HAVING AN INFLUENCE ON HOW THE
SMALL MOLECULES THAT WERE BEING
DESIGN WERE EFFECTIVELY
CORRECTED AT THE BEGINNING.
SMALL MOLECULES WE JUST LEARNED
ABOUT IMMUNOTHERAPIES.
AND THIS IS STILL THE HIGHEST
PERCENTAGE OF FDA APPROVED
DRUGS.
THERE'S SO MUCH HAPPENING IN
PROTEIN IMMUNOTHERAPY AND SMALL
MOLECULES STILL REPRESENTS A BIG
PART AND FROM ONE OF THE
PROJECTS I'LL TOUCH ON THE LAST
SLIDE IS LIKE COTHERAPIES TO
IMPROVE THE ABILITY OF DRUGS TO
WORK.
SO FOR US MAKING SMARTER DRUGS
AND SMARTER DESIGN WE'RE TRYING
TO TARGET THE RELEVANT BIOLOGY
AND HAVE TARGETED THERAPIES AND
LOWER OFF TARGET EFFECTS.
THESE ARE THINGS WE CAN TRY TO
MODULATE LOOKING AT SMALL
MOLECULES AND LOOK AT THE
STRUCTURES AND DYNAMICS.
SO BASICALLY HERE'S WHERE WE
ARE.
I DISCOVERED THE ONCOGENIC
PROTEIN AND WANT TO UNDERSTAND
THE MECHANISM AND CREATE A DRUG
TO TARGET OR I HAVE A DRUG FOR
THE PROTEINS BUT IT DOESN'T WORK
VERY WELL SO WHAT CAN I DO?
THIS IS REALLY WHERE THE
STRUCTURE ACTIVITY RELATIONSHIPS
COME IN FOR DRUG DESIGN.
I MOVED TO NCI LAST YEAR AND MY
LAB BECAME OPERATIONAL IN
FEBRUARY AND THIS IS THE FIRST
PROJECT WE TOOK ON.
OUR LITTLE PAC-MAN IS A PROTEASE
AND I WAS APPROACHED ABOUT THIS
PRE TEEN.
AND OUR COLLABORATOR WAS MAKING
INHIBITORS IT'S A SERINE
PROTEASE AND IT CLEAVES
PEPTIDES.
IT'S INVOLVED IN THE MATURATION
AND DEGRADATION OF NEUROPEPTIDES
AND INVOLVED IN DISEASES OF THE
BRAIN EFFECTIVELY AND PEPTIDE
HORMONES AND IT'S EFFECTIVELY
SOMEHOW -- NO ONE FULLY
UNDERSTANDS THIS COMPLETELY BUT
IT'S CONNECTED TO
NEURODEGENERATIVE DISEASES.
THEY FIRST STARTED BY TAKING
WHAT IS A PREVIOUS STRUCTURE OF
PREP AND DOTTING MOLECULES.
THIS IS THE MOLECULE THEY WERE
LOOKING AT.
YOU CAN'T REALLY SEE IT HERE
VERY WELL BUT I'LL SHOW A
DIFFERENT VIEW IN A SECOND.
IT'S LINKED.
SO THEY BUILT NEW MOLECULES THEY
THOUGHT WOULD MIMIC THIS WELL
AND DIDN'T WORK AS WELL AS
EXPECTED.
THE STRUCTURES POSED SOME ISSUES
TO GET GOOD STRUCTURES OUT AND
TOOK THE COMPOUND AND SOLVED THE
STRUCTURE AND IT LOOKS VERY
DIFFERENT.
I CAN SHOW THE OVERLAY.
IT'S NOT THE SAME MOLECULE BUT
THE ORANGE MOLECULE BASED ON THE
GREEN AND YOU CAN SEE IT SITS IN
A DIFFERENT POSITION AND IF THAT
WASN'T ENOUGH I'LL GIVE YOU THE
90 DEGREE VIEW.
IT'S A COMPLETELY DIFFERENT
POSITION.
TO SAY THE DOCKING IS VERY
USEFUL BUT IF YOU HAVE A SITE
THAT IS HUGE AND DYNAMIC AND
START WITH A STATIC CRYSTAL
STRUCTURE AND DESIGN FROM THAT
YOU RUN INTO PROBLEMS.
SO NOW THEY'RE STARTING TO
REDESIGN TO MAKE MORE POTENT
INHIBITORS.
WARE ALSO LOOKING INTO GETTING
THE STRUCTURES AT ROOM
TEMPERATURE.
THIS DID DONE AT CRYO
TEMPERATURES AND THAT'S ALSO
GOING TO CHANGE.
HOW WILL WE EXPAND ON THIS?
IT'S A HUGE SITE AND THE IN
SILICO IS A PROBLEM.
THOUGH THEY STARTED BECAUSE WE
FOND SOME INTERACTIONS THAT WERE
SUITABLE TO GUIDE THE STRUCTURAL
DESIGN AND MAKING NEW COMPOUNDS
WE'RE COMING IN WITH WHAT WE
CALL FRAGMENT BASED DISCOVERY.
FOR THOSE WHO KNOW WHAT THIS IS,
YOU CAN TUNE OUT BUT FOR THOSE
THAT DON'T IT'S COOL.
IT'S THE BACKBONE OF THE
MOLECULES AND THE INDUSTRY HAS
TAKEN HOLD OF THIS FROM MANY
YEARS.
FROM THE TECHNOLOGY PERSPECTIVE
ONE OF THE FIRST JOBS I HAD
COMING HERE WAS TO ESTABLISH THE
PIPELINE.
SO THE WAY IT WORKS IS THAT THIS
IS WHAT WE USED TO CRYSTALIZE
OUR PROTEINS AND EFFECTIVELY PUT
THESE LITTLE 200 DROPS OF
PROTEINS AND THERE'S REAL
CRYSTAL FROM PREP AND WE COLLECT
DATA AND TAKE A FRAGMENT
LIBRARY.
THESE ARE TINY MOLECULES AND
SOAK THEM IN AND HAVE
EFFECTIVELY NOT JUST 96 BUT
ABOUT 1,000 OF THEM AND THEN
THIS IS THE HARD PART.
WE MANUALLY MOUNT THEM AND SO MY
GROUP WITHIN THE FIVE PEOPLE
HAVE BEEN TOLD EVEN IF IT'S NOT
YOUR PROJECT WHEN WE HAVE THIS
YOU'LL SIT DOWN WITH THE
MICROSCOPE AND HELP WITH THE
CRYSTALS.
AND THEY'RE OKAY WITH THAT.
I HOPE.
LEAD
I EXAMPLE EVERY TIME.
SO WHEN WE HAVE THIS THE OTHER
IMPORTANT PART IS WE DO THE
INITIAL DATA COLLECTION IS JUST
A FEW CRYSTALS AND WE'RE TRYING
TO SOLVE A STRUCTURE WE DO IT
MANUALLY AND EVENTUALLY WE
AUTOMATE THIS AND HAVE CLOSE
RELATIONSHIPS WHERE WE RUN THIS
AND GET THE AUTOMATION TO WORK
WELL.
THERE'S A ROBOT IF ANYONE WANTS
TO COME AND WATCH DATA
COLLECTION IT'S PRETTY FUN.
COME AND LET ME KNOW.
THEY SHOOT X-RAYS AND COLLECT
THE DATA AND DO THE PROCESSING
AND GET THOUSANDS OF STRUCTURES
OUT AND THERE'S OTHER SOFTWARE
THAT WAS DEVELOPED BY A FRIEND
OF MINE IN SWEDEN THAT IS
FILTERING AND WE GET ABOUT 10%
OF HITS AND HAVE SOMEBODY BOUND
AND NEW AND NOVEL AND NEW
CHEMISTRY AND SOMETHING WE
HAVEN'T SEEN BEFORE AND THEN DO
THE MANUAL INSPECTION AND
CORRELATE IT TO THE LIBRARY.
OF COURSE WHAT I'M ABOUT TO SHOW
YOU IS THEORETICAL BECAUSE WE
STARTED IN FEBRUARY.
THIS IS OUR FIRST CAMPAIGN.
WE DON'T YET HAVE DATA TO SHOW
YOU BUT THE WAY IT WORKS IN THE
CASE OF PREP WE HAVE A HUGE
ACTIVE SITE.
WE'LL LOAD THE PROTEIN WITH A
SHORTER VERSION OF THE WAR HEADS
WE KNOW WORKS AND WE WANT TO
KNOW HOW WE EXPAND IT AND LOAD
IT WITH FRAGMENTS AND YOU
BASICALLY GET OTHER FRAGMENTS IN
YOUR ACTIVE SITES AND TRY TO
LINK THEM TO MAKE A MOLECULE
THAT IS TITER BINDING.
THIS IS OUR PIPELINE.
WE TYPICALLY START WITH PROTEIN
EXPRESSION PURIFICATION THAT'S
THE BIGGEST TIME WE SPEND TRYING
TO MAKE THE PROTEINS.
WE HAVE A LOT OF INFRASTRUCTURE.
THINGS THAT HELP ONE IN HIGH
THROUGHPUT AND ROBOTS AND DO
THIS WITH HIGH ACCURACY AND
REPRODUCIBILITY AND WE COLLECT
THE DATA.
THIS IS A MASSIVE ACCELERATOR
THAT PRODUCES VERY BRIGHT
X-RAYS.
MOST IS REMOTE NOW BUT I TRY TO
GO A COUPLE TIMES A YEAR THERE.
ONCE WE HAVE INITIAL STRUCTURES
AND READY TO GO HIGH THROUGHPUT
WE HAVE AN ACOUSTIC DROPLET
GENERATOR AND THE CRYSTALS ARE
SENSITIVE AND WE DO EVERYTHING
ACOUSTICALLY AND HAVE A SET THAT
HELPS MOUNT THE CRYSTALS.
AND WHAT WE'RE DOING IS BRINGING
THIS INFRASTRUCTURE IN.
RIGHT NOW WE ARE FINALIZING THE
INSTRUMENTATION IN THE LAB AND
THE PIPELINES AND IT IS UNIQUE
AND SIMILAR TO ONE OTHER
INSTITUTE THAT HAS IT BACK IN
CAMBRIDGE THE FIRST THAT BROUGHT
THIS TO ACADEMIC SCIENCE.
WE HAVE OTHER PROJECTS.
I WON'T HAVE TIME TO TALK ABOUT
THIS BUT HAVE PROJECTS REGULATED
TO THIS QUANTITATIVE CARBOXYLASE
INVOLVED IN METABOLISM AND SHOWN
TO BE HIGHLY EXPRESSED IN TUMORS
WHEN PEOPLE HAVE BAD OUTCOMES
WITH THEIR THERAPY.
WE'RE LOOKING INTO POTENTIALLY
MAKING DRUGS TOWARDS THIS.
THIS WAS THE ONE PROJECT FROM MY
PREVIOUS LIFE ANTIMICROBIALS
AGAINST PATHOGENS AND 60%
MORTALITY IF PEOPLE ARE IN
LONG-TERM CARE.
WE HAVE SOMETHING CALLED PROTAX
MOLECULES THAT NOT JUST
BYPRODUCT TO THE PROTEIN BUT
TRIGGER THE DEGRADATION AND
EFFECTIVELY TAKE THE PROTEIN OUT
OF THE EQUATION AND THIS IS THE
HOLY GRAIL DEALING WITH
ONCOGENIC FUSION PROTEINS.
THESE ARE DIFFICULT.
THEY'RE VERY SPAGHETTI LIKE.
THE FIRST POINT IS TO TRY TO DO
COMPUTATION TO FIND BINDING PARD
OF PARTNERS OR REGIONS TO LOOK
AT AND DISRUPT.
WITH THAT I WANT TO SAY THANK
YOU TO MY GROUP AS.
MOST THE PEOPLE WORKING HAVE
STARTED IN APRIL, MAY.
ALL THE WORK HAS BEEN DONE AND
THEY'VE BEEN PUSHING IT.
I HOPE YOU KEEP THIS IN MIND.
IF YOU HAVE A TARGET PROTEIN
YOU'RE INTERESTED IN AND MAKING
NEW DRUGS, COME AND TALK TO US
AND MAKE USE OF THIS TECHNOLOGY
WE HAVE AVAILABLE.
AND THANK YOU.
>> THANK YOU.
THAT WAS FANTASTIC.
I WANT TO COME MAKE A FIELD TRIP
TO SEE THIS IN ACTION.
DO WE HAVE QUESTIONS FROM THE
AUDIENCE AT ALL?
>> GREAT TALK.
I HAVE A PUBLIC HEALTH I'D LIKE
TO COLLABORATE WITH YOU.
MAYBE WE CAN CONNECT LATER.
>> SOUNDS GREAT.
>> THAT'S ALL I WANT TO SAY.
>> FANTASTIC.
THAT'S WHAT WE'RE HERE FOR.
>> YOU STARTED WITH CARBOXYLASE
AND WONDER ON ONE OF YOUR FINAL
SLIDES YOU MENTIONED AN
ONCOTARGET PROTEINS AND WHAT'S
THE DIFFERENCE BETWEEN TRYING TO
DESIGN MOLECULES THAT WILL BIND
TO AND ACTIVE ENZYMES VERSUS
NON-ENZYMATIC.
>> THEY'RE THE TYPICAL TARGETS.
THEY'RE PRETTY CONSTRAINED.
YOU HAVE VERY CLEAR INTERACTIONS
THAT HAPPEN BETWEEN YOUR PROTEIN
AND SUBSTRATE SO THIS IS
TYPICALLY WHAT YOU TARGET.
YOU HAVE THE PROBLEM IF YOU'RE
TARGETING SOMETHING THAT HAS A
SUBSTRATE THAT IS SIMILAR TO
WHAT HAPPENS IN THE CELL YOU MAY
HAVE OFF TARGET EFFECTS.
THE OTHER PROBLEM IS TYPICALLY
YOU START GAINING RESISTANCE.
SINGLE POINT MUTATIONS IN YOUR
SITE AND MOLECULE.
IN TERMS OF OTHER THINGS THAT
ARE NOT ENZYMES, TYPICALLY THEY
WORK BY THE MAJORITY OF CASES I
KNOW THEY WORK BY CONTACTING
WITH OTHER PROTEINS OR OTHER
LARGER ENTITIES IN THE CELLS.
SO NOW WE'RE LOOKING AT
PROTEIN-PROTEIN INTERACTIONS.
IF WE LOOK HERE AT THE
SIMULATION THERE'S LARGER AREAS
THAT BINDS AND FOR LESS
MUTATIONAL BURDEN IT KILLS
THERAPIES AND IT DISRUPTS
SPECIFIC INTERACTIONS.
FOR US WE'LL LIKELY TRY
DIFFERENT COMPOUNDS.
SO THAT'S FROM THIS WON'T WE CAN
CO BY CRYSTALLOGRAPHY BUT IT
WORKS IN THE SAME WAY.
>> QUICK QUESTION.
I'M FROM THE 2023 COHORT AND THE
LATEST ALLITERATIONS ARE
PROMISING.
>> THAT IS ALPHA FOLD.
IT HELPS BUT I DON'T KNOW IF
ANYONE HAS ALPHA FOLD.
IT HAS A TENDENCY TO PICK THINGS
THAT MAY NOT BE REAL.
WE USE IT ESPECIALLY FOR THINGS
LIKE THE ONCOGENIC FUSION
PROTEINS WHERE WE ARE TRYING TO
SEE -- BY QUICK BACKGROUND, THE
THING YOU SEE HERE STARTED WITH
A LIST OF HITS FROM BIO-I.D.
ASSAYS.
THINGS CLOSE TOGETHER IN THE
CELLS AND NOW EFFECTIVELY GOING
THROUGH 400 PAIRS AND SEEING IF
WE CAN SEE INDCATIONS ARE REAL
AND WE'LL HAVE TO SEE IF THEY
FIND AND IF THEY DO WE FOLLOW
THROUGH WITH A DRUG DISCOVERY
ASSAY.
IT'S COMPLETELY A HYPOTHESIS.
YOU CAN'T TAKE IT AT POINT VALUE
AND WE'VE SEEP THAT.
-- SEEN THAT.
>> WONDERFUL, THANK YOU VERY
MUCH.
THIS IS WONDERFUL.
WE'LL TAKE A SIX MINUTE BREAK
AND RESUME AT 11:15.
THANK YOU.
THE STRUCTURE SYMPOSIUM IS THREE
GROUPS OF DSP SCHOLARS
PRESENTING WORK AND THE SECOND
HALF OF THE FIRST COHORT IS WHAT
WE'LL NEED TO HEAR FROM IN FIVE
MINUTES.
GOOD MORNING.
WELCOME BACK.
FLEX YOUR ANKLES AND GET SOME
BLOOD CIRCULATION.
EXCITED ABOUT OUR NEXT SPEAKER.
THIS IS DR. MINKYO SONG ABOUT
THE IMMUNOEPIDEMIOLOGY OF AUTO
IMMUNITY AND AGING.
>> I LEAD THE LABORATORY OF
EPIDEMIOLOGY AND POPULATION
SCIENCES.
I'D LIKE TO THANK THE DSP FOR
SUPPORTING MY RESEARCH AND WOULD
LIKE TO TALK ABOUT
IMMUNOEPIDEMIOLOGY.
IT'S A TWO DISCIPLINES AND IT
CAN BE DEFINED AS A FIELD OF
STUDY THAT ADDRESSES HOW
DIFFERENCES AFFECT THE
EPIDEMIOLOGY OF INFECTIOUS
DISEASES, CANCER AND AUTO
IMMUNITY.
IT AFFECTS LIFE IN VARIOUS WAYS
IN AGING.
WHEN A PERSON GETS BORN THE
IMMUNE MATURES WITH THE AGING
PROCESS AND EVENTUALLY IMMUNITY
GET OLD IN IMMUNOSENESCENCE AND
T CELLS GO DOWN AND RESPONSES
ARE REDUCED AND THE INFECTION
RATE AND CANCER AND AUTO IMMUNE
DISEASES GO UP.
IN ORDER TO ANSWER THIS OVER
ARCHING RESEARCH QUESTION AND WE
FACE ALTERED IMMUNITY AND I'M
LOOKING AT AUTO IMMUNITY.
YOU CAN SEE ON THE SCIENCE COVER
IN 2022 -- I DON'T NO FEZ TOO
SMALL BUT AUTO IMMUNITY SAYS IS
THE DARK SIDE OF THE HOST
DEFENSE MEANING IMMUNITY THAT'S
SUPPOSED TO PROTECT THE HOST
GOES WRONG AND IS ATTACKING
ITSELF.
THAT'S THE DEFINITION IN SHORT.
I'D LIKE TO SAY THIS IS AN
EXCITING AND TIMELY OPPORTUNITY
TO CONDUCT RESEARCH IN AUTO
IMMUNITY AND AGING.
NUMBER ONE IT'S IN INCREASED
BURDEN OF DISEASES.
IT'S ESTIMATED AROUND 10% OF THE
WORLD'S POPULATION IS AFFECTED
BY AUTO IMMUNE DISEASE.
AUTO IMMUNE PATIENTS ARE LIVING
LONGER THANKS TO TREATMENT BUT
ANOTHER THING IS WOMEN ARE MORE
AFFECTED BY THE DISEASE MEANING
THESE ARE THE MAIN CARE TAKERS
OF THE FAMILY AND WILL AFFECT
THE HOUSEHOLD AND COMMUNITY
MORE.
THERE'S STILL LIMITED
UNDERSTANDING OF AUTO IMMUNE
DISEASE EPIDEMIOLOGY.
WE DON'T KNOW THE GEOGRAPHICAL
DIFFERENCES AND LACK SPECIFIC
DESIGNS AND NOT OF THE STUDIES
TAKE INTO CONSIDERING THE
EMERGING RISK FACTORS SUCH AS
NEW DRUGS AND INFECTIONS OR
CLIMATE CHANGE.
BUT WE ARE IN GOOD HANDS.
THERE'S IMMUNOLOGY AND THERE'S
MORE DATA VALUABLE NOW AND NOT
JUST THE CLASSIC DESIGN STUDIES
BUT SECONDARY STUDIES WE CAN
UTILIZE.
AND THE NATIONAL ACADEMIES OF
SCIENCE AND ENGINEERING THOUGHT
THIS WAS ALSO A GREAT NEED.
THEY PRODUCED THIS STUDY REPORT
IN 2022 FOR ENHANCING NIH
RESEARCH ON AUTO IMMUNE
DISEASES.
IN RESPONSE TO CONGRESS THE
OFFICE OF AUTOIMMUNE RESEARCH
WAS CREATED IN THE OFFICE ON
WOMEN'S HEALTH AND THE
INITIATIVE ON WOMEN'S HEALTH
RESEARCH ALSO EMPHASIZED AUTO
IMMUNE DISEASE IS ONE OF THEIR
PRIORITY AREAS AND LOOKING AT
AGE-ED DISEASES ONE OF THE
BIGGEST CHALLENGE IS TO
DISENTANGLE THE DIRECTIONALITY
OF AGING.
AS I SAID, WITH AGING AUTO
IMMUNE DISEASES INCREASE BUT
IT'S ALSO TRUE WITH AUTO IMMUNE
DISEASES AGE-RELATED DISEASE
SUCH AS CARDIOVASCULAR DISEASE
AND CANCER CELLS ALSO INCREASE.
AND WE'RE NOT SO SURE ABOUT THE
ASSOCIATIONS IN DIFFERENT RISK
GROUPS.
THERE'S TWO AIMS OF MY RESEARCH.
ONE IS TO UNRAVEL THE
ASSOCIATION BETWEEN AUTO IMMUNE
AND AIMING.
I'M LOOKING AT THE EFFECT OF
AGING ON THE RISK OF AUTO IMMUNE
DISEASES AND THE EFFECT OF AUTO
IMMUNE DISEASES ON THE AGING
PROCESS.
I'M INCORPORATING LONGITUDINAL
STUDY DESIGNS AND LIFE TIME
COURSE AND RISK FACTORS SUCH AS
INFECTION, MEDICATIONS OR
CLIMATE CHANGE.
A SECOND AREA IS TO DEVELOP
METHODS TO BETTER ASCERTAIN AUTO
IMMUNE DISEASE.
THEY'RE OFTEN UNDER DIAGNOSED
AND A LOT OF AUTO IMMUNE
PATIENTS ARE ASYMPTOMATIC.
YOU'LL SEE THE TIP OF THE
ICEBERG IN THIS FIELD.
TO BETTER QUANTIFY AUTO IMMUNE
DISEASE AND IMMUNITY I'M
UTILIZING THE CLINICAL
BIOMARKERS AND DEVELOPING NEW
BIOMARKERS FOR DETECTING THESE
AUTO IMMUNE DISEASES.
TODAY I WOULD LIKE TO INTRODUCE
YOU TO MY THREE EXCITING
PROJECTS I'VE LAUNCHED SINCE
ONBOARDING LAST YEAR INVOLVING
THE LONGITUDINAL AND LIFE COURSE
DESIGNS AND QUANTIFICATION OF
AUTO IMMUNE DISEASES AND ALSO
INCORPORATION OF CLIMATE CHANGE.
SO I DID TELL YOU AUTO IMMUNITY
INCREASES WITH AGE BUT THERE'S
NOT SO MANY DATA OUT THERE THAT
HAS DOCUMENTED THE AUTO ANTIBODY
CHANGE WITHIN AN INDIVIDUAL OR
WHETHER THE TRAJECTORIES DIFFER
BY SEX.
SO I AM UTILIZING THIS BALTIMORE
LONGITUDINAL STUDY OF AGING
SINCE 1958 WITH MORE THAN 3,000
VOLUNTEERS WITH LONGITUDINAL
DATA AND THERE'S CLINICAL AND
BIOMEDICAL AND FUNCTIONAL
MEASUREMENTS AND BIO SPECIMEN.
AND I AM INCORPORATING THE CASE
COHORT STUDY SELECTING 250
AUTOIMMUNE DISEASE AND COMPARING
THAT TO THE COHORT OF RANDOMLY
SELECTED INDIVIDUALS.
AND THEN I'M MEASURING THE
ANTI-NUCLEAR ANTIBODIES WHICH IS
ONE OF THE MOST COMMON
ANTIBODIES FOUND IN THE AUTO
IMMUNE DISEASE AND INCORPORATE
THE NOVEL TECHNOLOGY THE PROTEIN
ARRAY AND I'LL BE SELECTING 300
AUTOANTIBODY TO SEE IF THERE'S
ANY ANTIBODIES DOCUMENTABLE
WITHIN THE POMP.
SO WE'LL LOOK AT AGE-RELATED
CHANGINGS OF THE ANTIBODIES AND
THE RELATIONSHIP TO THE AUTO
IMMUNE DISEASES AND OTHER TYPES
OF AGE-RELATED DISEASE OTHER
THAN AUTOIMMUNE DISEASE.
I HAVE A LOT OF COLLABORATORS
THERE AND THIS HAS BEEN
CO-FUNDED BY THE OFFICE OF AUTO
IMMUNE DISEASE RESEARCH I
MENTIONED EARLIER IN THE
PRESENTATION.
THOUGH BLSA IS A UNIQUE DATA SET
IT'S VERY SMALL AND I NEEDED A
BIG DATA SET.
SO I WENT TO THIS HISPANIC
COMMUNITY HEALTH STUDIES THAT IS
AN NIH FUNDED COHORT WITH 16,000
HISPANICS WITH A WIDE AGE RANGE
THAT COVERS THE YOUNGER YEARS
MORE PRONE TO AGE-RELATED
AUTOIMMUNE DISEASES.
THERE'S A RICH COLLECT OF
LIFESTYLE FACTORS AND SOCIAL
DETERMINATES AND NEIGHBORHOOD
AND ENVIRONMENTAL FACTORS AND
YOU CAN SEE ON THE FIGURE ON THE
RIGHT THERE'S JUST SO MANY
THINGS WE CAN UTILIZE HERE.
HERE I'M ALSO DEFINING AUTO
IMMUNITY USING ANTIBODIES AND
USING ANTIGENS FROM THE AG ATLAS
THE LITERATURE-BASED
ACCUMULATION OF DIFFERENT
ANTIBODIES AND THEN TESTING
AROUND 1700 ANTIBODIES WITHIN
THE 10% OF THE POPULATION TO
SELECT THE MOST IMPORTANT WHICH
WILL BE AROUND 300
AUTO-ANTIBODIES WITHIN THE
16,000 POPULATION.
AND COMPARING THOSE ANTIBODY
LEVELS WITH RISK FACTORS
SURVEYED OR MEASURED WITHIN THE
COHORT AND LOOKING AT THE
ASSOCIATION WITH INFECTION AGENT
BECAUSE IT'S SUPPOSED TO BE A
TRIGGER FOR AUTOIMMUNE DISEASE
AND LOOK AT LATER RISK OF
DIFFERENT PHENOTYPES.
AND THEN ONE IMPORTANT THING IS
THAT SINCE THE COHORT IS
DISTRIBUTED ACROSS DIFFERENT
AREAS OF THE U.S., THEY HAVE
MEASUREMENTS AND THERE'S A
WORKING GROUP FOR CLIMATE CHANGE
AND I PLAN TO COLLABORATE WITH
THIS GROUP TO LOOK AT THE
CLIMATE CHANGE I'M INTERESTED UP
AND THE LAST PROJECT IS THE
CLIMATE CHANGE CONSEQUENCES AND
BIOMARKERS IN THAT SENSE.
AMONGST MANY CLIMATE CHANGES I
LOOKED AT HURRICANES AND IT'S
SUPPOSED TO HAVE INTERDIRECT OR
DIRECT EFFECT ON HUMAN HEALTH
THROUGH SOCIO AND PSYCHO
ENVIRONMENTAL STRESS AND FINALLY
TO THE CHRONIC OR STRUCTURAL
EFFECTS.
I'M UTILIZING THE ACTION TO
CONTROL CARDIOVASCULAR RISK IN
DIABETES WHICH IS AN
INTERVENTION TRIAL OF CONTROL
10,000 PEOPLE WITH LONGITUDINAL
SPECIMENS.
THIS IS UNIQUE BECAUSE IT'S BEEN
AFFECTED BY HURRICANE KATRINA IN
THE SOUTHEAST NETWORK AS YOU CAN
SEE ON THE MAP.
I'M COMPARING THE TULANE CITY
WITHIN THE LOUISIANA CLINICS AND
COMPARED TO OTHERS IN YELLOW
USING THE DIFFERENCE METHODS
TRYING TO FIGURE OUT THE
ADDITIONAL EFFECT OF HURRICANE
ON THE BIOMARKERS.
AND I'M USING OLINK UP WITH OF
THE MOST FAMOUS PROTEOMIC
PLATFORM AND WE'RE LOOKING AT
THE CHANGES OF SIGNATURES PRE
AND POST HURRICANE KATRINA AND
TO FIND OUT WHICH PROTEIN
MARKERS ARE PREDICTIVE OF THE
DIFFERENCES AND THOSE OF
COGNITIVE FUNCTION INCLUDED IN
OUR STUDY.
THIS WAS AWARD BY THE INTRAMURAL
CLIMATE CHANGE AND HEALTH
PROGRAM 2023.
THE TAKE HOME MESSAGE IS AUTO
IMMUNITY IS AN APPROACH TO THE
ROLE IN AGING.
THERE'S PROSPECTS IN CONDUCTING
RESEARCH IN THE AUTO IMMUNITY
AND IN ACCORD ANGST WITH THE
PHYSIOLOGICAL CHANGE IMMUNITY IS
CRITICAL AND DEVELOPING NEW
BIOMARKERS MAY HELP UNDERSTAND
THE AGING PROCESS AND HOPEFULLY
THE IDENTIFICATION OF HIGH RISK
INDIVIDUALS MAY LOOK AT
INTERVENTION AT EARLY STAGE.
I CAN'T DO THIS BY MYSELF AND
HERE'S MY SEAM THAT'S SUPPORTING
ME.
-- TEAM THAT IS SUPPORTING ME.
THANK YOU.
>> THANK YOU, DR. SONG.
IT SOUNDS LIKE INTERESTING AND
IMPORTANT WORK.
WE HAVE TIME FOR ONE QUESTION.
I LOVE IT.
I'LL ASK A QUESTION.
IT'S GOOD TO MODERATE BECAUSE I
CAN USE THE TIME HOW I WANT.
I KEEP LOOKING AT THE DATA OF
THE INCREASED INCIDENTS OF
CARDIOVASCULAR DISEASE, CANCER,
NEURODEGENERATIVE DISEASE AND
AUTO IMMUNITY WITH AGING AND
KEEP ASKING MYSELF IS THERE
ANYTHING GOOD ABOUT GETTING OLD?
>> I HAVEN'T GIVEN THAT THOUGHT
PHYSIOLOGICALLY.
ONE PART IS YOU'RE GETTING
WISER.
MORE TOLERABLE AND DON'T GET SO
MUCH STRESS IN SESSIONS LIKE
THESE.
>> WONDERFUL.
WE'LL LEAVE IT AT THAT THEN.
THANK YOU VERY MUCH, DR. SONG.
>> THANK YOU.
OUR NEXT SPEAKER IS DR. MANNU
PLATT FROM NIBIB TALKING ABOUT
DYNAMIC INTERPLAY BETWEENIO
MECHANICS AND BIOCHEMISTRY IN
SICKLE CELL DISEASE DISEASE
LARGE ARTERY DAMAGE.
>> LET'S DO IT.
IS THERE A LASER POINTER?
OKAY.
ALL RIGHT.
GREAT, THANK YOU ALL FOR HAVING
ME.
IT'S GREAT TO HEAR FROM MY OTHER
DISTINGUISHED SCHOLARS AND THOSE
IN MY SMALL MENTOR GROUP.
I FOUND OUT I'M A SENIOR
DISTINGUISHED SCHOLAR WHICH GOOD
THINGS ABOUT AGING.
I'M AT THE NATIONAL INSTITUTE OF
BIO MEDICAL ENGINEERING AND TALK
ABOUT
I WORK IN SICKLE CELL DISEASE
AND I'M AN INTRAMURAL
INVESTIGATOR AND THE DIRECTOR
NEWLY FORMED DATA CENTER FOR THE
CENTER FOR BIOMEDICAL ENGIN
ENGINEERING ACCELERATION.
OUR GOAL IS TO HELP BRING
PRINCIPLE TO THE NIH IRP AND
HELP ACCESS THE TECHNOLOGIES AND
BUILD COMMUNITY ON CAMPUS AROUND
BIOMEDICAL ENGINEERING AND USING
DIVERSITY, EQUITY AND INCLUSION
AS DRIVING PRINCIPLES FOR WHAT
WE DO.
WITH THAT WE WANT TO OFFER OUR
SCIENCE CONCIERGE SERVICE TO YOU
ALL AND HAVE BEEN PARTNERING
WITH THE RESOURCES AT NIBIB AND
BRINGING ONLINE NEW CAPABILITIES
SUCH AS SYSTEMS IN COMPUTATIONAL
BIOLOGY AND SOFT BIO MATERIALS
AND BUILDING NIH'S FIRST MAKER
SPACE TO COME IN AND MODIFY AND
MAKE YOUR OWN TOOLS AND RESEARCH
FOR YOUR ACTIVITIES COMING
ONLINE SOON.
WE BUILT OUR STAFF AND OUR
MANAGER AND TWO OF OUR STAFF
RESEARCHERS THAT WILL HELP GET
YOUR WORK DONE.
SO THERE'S OUR E-MAIL ADDRESS.
IF YOU'RE NOT ON OUR LIST SERVE
AND WANT ACCESS SEND US AN
E-MAIL WE'RE HAPPY TO HAVE YOU
AND MEET AND GREETS TO GET TO
KNOW YOU AND WE RUN TRAINING
PROGRAMS TO RECRUIT NEW BIO
ENGINEERS AND HELP SHOW THEM
WHAT THE NIH IRB CAN DO AND MANY
DON'T REALIZE THE EXCITING THING
HAPPENING HERE AND WE HAVE THE
LONG RUNNING PROGRAM AND
INTERNSHIP PROGRAM AND NIBIB
FUNDS THE STUDENTS BUT
DISTRIBUTE THEM TO INVESTIGATORS
AND WOULD LOVE TO SEE NEW
SCHOLARS AND YOU CAN MENTOR ONE
OF THESE STUDENTS AT NIBIB'S
COST AND IF OTHERS WOULD LIKE TO
CONTRIBUTE FUNDS WE'RE EXCITED
TO HAVE YOU JOIN US.
AND WE'VE OPENED IT UP TO NOT
JUST BIOMEDICAL BUT S.T.E.M.
MAJORS.
ALSO, ANOTHER OPPORTUNITY
OCTOBER 22 WE'RE HOSTING A BIG
BIO ENGINEERING DAY ON THE NIH
CAMPUS.
IF YOU HAVEN'T HEARD I'M
PITCHING IT.
YOU CAN STILL APPLY.
FREE REGISTRATION AND WE'RE
TRYING TO BRIDGE EXTRAMURAL AND
INTRAMURAL AND WE'RE HAVING
EVERYONE IN BETHESDA MEET US AND
BLEND OF POSTERS AND PITCHING
OUR WARES HOME TO AND GETTING
THEM TO WANT TO WORK WITH US.
TWO KEY NOTES FROM A COLLISION
GROUNDBREAKING ON SECOND HALF
AND ANOTHER ON DIAGNOSTICS.
OKAY.
NOW I GET TO TALK ABOUT ME.
I HAVE TO PLUG MY DATA CENTER
WORK SO IT CUTS MY TIME SHORT.
I RUN THE MATRICES LAB AND
MECHANICS AND TISSUE REMODELLING
AND COMPUTATIONAL EXPERIMENTAL
SYSTEMS.
I HOPE TO SHOW YOU A LITTLE BIT
ABOUT MY WORK AND SHOW HOW
ENGINEERING PRINCIPLES CAN BE
USED TO ASK BIOLOGICAL AND
CLINICAL QUESTIONS.
AND I LOVE PROTEASES MORE THAN
ANYTHING.
THIS IS ME AT THE GIC ON BE ON
THIS AND SS HAS SICKLE CELL AND
IT'S A HEALTH DISPARITY ONE IN
12 HAS SICKLE CELL TRAITOR
CARRIERS AND IT'S A GLOBAL
DISEASE.
I GOT INTO IT WITH THE
CARDIOVASCULAR COMPONENTS.
A LOT OF WORK IN THE MICRO
CIRCULATION AND I WAS TOLD
CHILDREN WITH SICKLE CELLS ARE
HAVING STROKE.
Ph.D. TRAINING WAS TALKING ABOUT
CARDIOVASCULAR DISEASE THAT
DEVELOP OVER 60, 70 YEARS AND
THE CELLS SICKLE UNDER THE
CONDITIONS AND 11% OF CHILDREN
WITH SICKLE CELL HAVE A STROKE
BY 16 AND GREATEST RISK IS 2 AND
6 YEARS OLD AND THERE'S A
COGNITIVE RESULT WHERE THEY LOOK
AT THE MRI AND REALIZE THE
CHALLENGES.
THERE'S AN AMAZING CLINICAL
TRIAL IN THE '90s SHOWING
INCREASED VELOCITIES ARE AT
GREATER RISK OF STROKE.
ONE CLINICAL TRIAL STOPPED EARLY
BECAUSE THOSE NOT RECEIVING
TRANSFUSIONS WERE RECEIVING
STROKES OR DIAG.
THIS IS STILL THE CURRENT STATE
OF CARE.
WHY ARE THE VELOCITIES INCREASED
IN WHEN YOU GET STENOSIS YOU CAN
GET INCREASED VELOCITY AND POST
STENOSIS YOU GET DECREASED FLOW
IN THE VASCULATURE AND THOSE ARE
SITES WHERE ATHEROSCLEROTIC
PLAQUES WERE FORMING.
YOU CAN SEE A PATHOLOGIST
STARTED TO SEE THESE AND TALKED
TO HIS BUDDY WHO SAID WE KNOW
WITH A BIFURCATION YOU GET FLOW
REVERSAL OVER THE CARDIAC CYCLE
AND WHERE YOU GET THE REGIONS IS
WHERE WE'RE SEEING THE PLAQUE
AND INCREASED DISEASE.
I SAID WHY ARE WE NOT LOOKING AT
THIS IN SECOND HALF.
SO WE -- SICKLE CELL AND WE
RECREATED THIS IN THE COMPUTER
TO USE COMPUTATIONAL FLUID
DYNAMICS TO SEE HOW IT CAN LEAD
TO DISTURBED FLOW THAT MIGHT BE
SUSCEPTIBLE TO THE REMODELLING
OF CHILDREN WITH SICKLE CELL AND
THEY HAD REGIONS OF FLOW
RECIRCULATION IN HUMANS.
NOW AS AN ENGINEER WE CAN
RECREATE THE FLUID PROFILES IN
VITRO AND HAVE A REACTOR AND NOW
YOU CAN PUT IN VASO PROTECTIVE
PROFILES OR ONE LIKE SEEN ON THE
OUTSIDE OF THE CAROTID ARTERY
WALL AND THE ENDOTHELIAL CELLS
THAT ELONGATE FLOW SHOW IT'S
WORKING AND THE THERE'S BIO M
MECHANICS AND THERE'S DIFFERENT
FLOW PROFILES AND BIO CHEMISTRY
RESPONSES.
THERE'S A MOUSE MODEL AND WE
KNOCKED OUT THE MOUSE HEME
SFLOEB -- HEMOGLOBINS AND WE
LOOKED AT THE MICE ACTIVATED WAS
ELEVATED IN THE CAROTID ARTERIES
OF THE MOUSE AND IN WHY HIBTING
CAN STOP IT FROM BEING TURNED UP
AND THEN LOOKED AT 5-MONTH-OLD
MICE AND THIS SHOCKED US.
WE WERE FOCUSSED ON THE
DEGRADATION BUT BY FIVE MONTHS
WE SAW THIS INCREDIBLE LOSS OF
COLLAGEN IN THE ARTERY WALL AND
CONFIRMED STIFFNESS AND YOU SEE
THE BLOWN OUT ARTERY.
ONCE THE CHILDREN GET PAST THE
OF STROKE THEY'RE AT RISK OF
HEMORRHAGIC STROKE AND LOSS OF
THE ARTERY WALL THAT PREDISPOSED
THEM TO THAT BUT THERE'S A
VARIABILITY.
THE SAME VARIABILITY GOES TO OUR
MASS MODEL.
MY SENIOR STAFF AND STAFF
SCIENTISTS IDENTIFIED A PROTOCOL
WE COULD MONITOR THE SAME MOUSE
AS THEY AGE TO REDUCE THAT
SUBJECT TO SUBJECT VARIABILITY.
SO WE'VE BEEN DOING THAT AND
OVER TIME FROM ONE TO FIVE MONTH
MONITORING THE CHANGES IN THE
DIAMETERS OFF THE ARTERIES OF
THE MICE AND HETEROGOUS AND WITH
LIVING MICE WE'RE ABLE TO SEE
THIS LUMINAL EXPANSION AS THE
MICE AGE WHICH MATCHES WHAT WE
WERE SEEING BEFORE BUT THEN THE
QUESTION IS HOW DOES THAT CHANGE
THE BIO MECHANICS OR BLOOD FLOW
PROFILES.
HERE I HAVE TALENTED POST-BACS
AND ALONG THE LENGTH OF THE
ARTERY THE FLUID PROFILE
CHANGING AND WE CAN LOOK AT THE
DISTRIBUTION VERSUS THE OTHERS.
AND WHAT'S INTERESTING IS YOU
SEE GREATER AREAS IN THE SS AND
IN THE STRAIGHT PARTS OF THE
ARTERY AND THAT BECOMES THE
DISTINCTION BETWEEN
CARDIOVASCULAR DISEASE AND
OTHERS AND NOW TRYING TO
REGISTER WHERE WE SEE THOSE WITH
THE BIOLOGICAL CHANGES WITH
HISTOLOGY AND IMMUNOHISTORIC
CHEMISTRY AND FINALLY THE GENE
THERAPY WORKED BUT STILL
REQUIRES A BONE MARROW
TRANSPLANT.
EVEN PATIENTS WITH TRANSPLANT
STILL ARE AT RISK SO WE WANT TO
UNDERSTAND IF THERE'S ADJUVANT
THERAPIES OR TIMING COULD BE
HELPFUL.
WE TRANSPLANTED AND THE EARLIER
WE DID THE TRANSPLANT WE COULD
PROTECT THE VASCULATURE FROM THE
INSULT AND WORKS OUT FOR THE
MICE LATER.
SO, ANATOMICAL CHANGES ARE
IMPORTANT AND THINKING ABOUT THE
MECHANICS OF THE BLOOD FLOW AND
BIOLOGY AND PATIENT TO PATIENT
BIOLOGY AND LOOK AT ADJUVANT
THERAPIES TO PROTECT THE
VASCULATURE AFTERWARDS IF THAT'S
NOT SUFFICIENT.
THANK YOU.
LOVE MY TEAM AND I WANT TO THANK
THE PROGRAM AND DR. MARIE
BERNARD VERY SUPPORTIVE AND I
WANT TO THANK DR. TROMBERG.
IT'S BEEN WONDERFUL TO BE HERE
AT NIH.
THANK YOU ALL.
COME SEE US SOON.
>> THANK YOU, DR. PLATT.
THAT WAS A TOUR DEFORCE AND
THANK YOU FOR THE ADVERTISING
FOR THE BETA CENTER.
WE HAVE TO CONNECT.
ARE THERE ANY QUESTIONS?
>> THANK YOU FOR THE WONDERFUL
TALK.
I'M AN ENDOCRINOLOGIST AND
LOOKING IF THE WORK YOU DO IS
APPLICABLE TO TO DIABETES WITH
CARDIOVASCULAR COMPLICATIONS.
YOU KNOW YOU FOCUS ON THE BIGGER
BLOOD VESSELS BUT IF WHAT YOU DO
CAN APPLY TO SMALLER VESSELS AND
COMPLICATIONS IN DIABETES.
>> ABSOLUTELY.
WE DO MRAs AND CAN EUTHANIZE
THEM AND GET THE VOLUME AND
ANATOMY OF THE MICROVESSELS AND
HAPPY TO TALK AFTER.
>> YOU'RE OPEN TO STUDYING
PEOPLE WITH DIABETES IN ADDITION
TO SICKLE CELL?
>> YES.
AND THE BETA CENTER CAN HELP
YOUR TEAM.
>> I CUT MY TEETH AS A POSTDOC
IN THE SAME LAB YOU DID YOUR
STUDY.
I WONDER WHEN WE THINK OF BLOOD
VESSELS WE THINK OF THEM MOSTLY
IN TERMS OF THE FLOW GOING
THROUGH IN ONE DIRECTION BUT YOU
DESCRIBE THERE'S AN AXIAL
STRETCH.
DO YOU THINK THERE ARE WAYS TO
POTENTIALLY REVERSE THIS
PHENOTYPE ONES IT SETS IN.
GETTING BACK TO THE AGING THING
BECAUSE AS YOU GET OLDER THEY
GET STIFFER.
>> WE LOOK AT ARTERIAL
STIFFNESS.
WE CANNOT CORRECT DAMAGE TO THE
ARTERIES AND PROVIDE THE
ELASTICITY BUT YOU CAN MODULATE
SOME COLLAGEN SO IT'S NOT TOO
STIFF BUT IF YOU REDUCE IT TOO
MUCH YOU'RE AT RISK OF BLOWING
IT OUT BUT I THINK THERE'S
REGENERATIVE PRINCIPLES AND
WE'RE TRYING TO FIND NEW WAYS
BUT I THINK THE NATIVE BODY
DOESN'T REPAIR ON ITS OWN.
>> AND SICKLE CELL DISEASE BEING
A HEMOGLOBINOPATHY TO YOU THINK
IT APPLIES TO OTHERS?
>> WE THINK THERE'S THINGS
HAPPENING IN THE ALPHA TAU AND
BETA TAU AND WE'RE FOCUSSING ON
SICKLE CELL BUT NOW GETTING INTO
SD AND THERE'S INTERESTING
THINGS AND TO THE ENCRINOLOGIST
I WAS HOPING YOU'D SAY
OSTEOPOROSIS BECAUSE THERE'S
BONE COMPLICATIONS BY LAB IS
ALSO LOOKING AT SO IT'S A
MULTI-FACTORIAL EFFECT AND
MULTI-ORGAN SYSTEMS.
>> THANK YOU.
OUR NEXT SPEAKER IS
DR. FLORENCIA PRATTO TALKING
ABOUT MULTI-LAYERED CON FREE
THROW LINE OF THE RECOMBINATION
AND DIVERSITY IN THE MAMMALIAL
GERM LINE.
>> SO I'M GOING TO TRY TO FOLLOW
AND TALK ABOUT THE MULTIPLE LAY
YEARS OF CONTROL IN THE
MAMMALIAN GERM LINE AND WE LOOK
AT REPLICATION.
AND ONE GOAL OF RECOMBINATION IS
TO LINK THE CHROMOSOMES TO
ORIENT AND SECOND IT CREATES NEW
ALLELE COMBINATIONS THEREFORE
HAS GENETIC DIVERSITY.
THE DOUBLE STRAND BREAKS ARE
IMPORTANT FOR SUCCESSFUL MIOS
IS.
THE CELL HAS TO MAKE THE RIGHT
AMOUNT IN THE RIGHT TIME AT THE
RIGHT PLACE AND THOUGH THERE'S
GOOD CONTROL IT'S BEEN ESTIMATED
UP TO 60% OF HUMAN HAVE THE
CHROMOSOMAL ABNORMALITY TO THE
ERRORS DUE TO MANY CASES ARE A
LEADING CAUSE OF MISCARRIAGES
INFERTILITY.
THERE'S BEEN TIME TRYING TO
UNDERSTAND HOW THE EVENTS ARE
MADE AND HOW TO CONTROL THE
OUTCOMES.
THESE ARE MADE BY CONSERVED
PROTEIN THAT MAKES THE DOUBLE
STRAND BREAK AND WE LOOK AT THE
BACTERIA AND COVERS THE FILAMENT
AND CELL MYOSIS AND ONCE IT'S
ENGAGED THE BREAKS ARE REPAIRED
AND IN MAMMALIANS THERE'S A
SHORT OUTCOME BUT DOESN'T HAVE
THE HAPLOTYPE SWITCH.
SO THE DOUBLE STRAND BREAKS
OCCUR AT HOT SPOTS.
AND THEN IT WAS DISCOVERED IT'S
A VERY INTERESTING PROTEIN AND
DERMINATE OF THE LOCATION AND
MYOTIC TRANSFERASE AND IT BINDS
TO THE GENOME AND THEREFORE
CHANGES THE LANDSCAPE AMONG
INDIVIDUALS.
IT IS THE FASTEST IN MAMMALS AND
WE FOUND HUNDREDS FROM HUMANS
AND MICE.
SO THERE WERE HOT SPOTS AND
LOOKED AT WHERE THEY WERE
LOCATED IN MAMMALS.
WE DEVELOPED A TECHNIQUE WHICH
IS WHERE WE PULL THIS DOWN AND
LOOK AT THE DNA ASSOCIATED WITH
IT.
WE KEEP THE FORMATION.
WE HAVE A STEREOTYPICAL PATTERN
OF STRAND TO THE BREAK AND TO
THE RIGHT OF THE BREAK.
THIS GIVES US A LOT OF
SENSITIVITY AND SPECIFICITY SO
WE WERE ABLE TO DO THIS FROM
HUMAN INDIVIDUALS.
THIS IS A SNAPSHOT FROM HUMAN
INDIVIDUALS.
THE POSITIONS OF THE HOT SPOTS
ARE DETERMINED BY THE TYPE OF
ALLELES THE INDIVIDUAL CARRIES
AND THERE'S A HUGE RECOMBINATION
AT THE CHROMOSOME.
THIS IS THE PART AND THERE'S
MORE HOT SPOTS AND THEY'RE MORE
FREQUENT.
THE PAST WORK UNCOVERED TWO
PROCESSES THAT OPERATE ON BROAD
SCALES.
ONE WHAT IS ILLUSTRATED HERE AND
TWO THE CONCENTRATION OF THE
RECOMBINATION.
SO WE THOUGHT TO UNDERSTAND WHAT
IS UNDERLYING THIS BROAD SCALE
CONTROL OF RECOMBINATION AND
THOUGHT TO LOOK TO THE
REPLICATION AND THIS IS LINKED
FOR REPLICATION MECHANISTICALLY
AND WE CANNOT STUDY MAMMALIAN
MYOSIS IN VIVO.
THIS IS HAPPENING IN THE MALES
IN THE TISSUE WHERE 1% OF THE
CELLS ARE UNDERGOING MYOTIC
REPLICATION.
THIS POSES MANY CHALLENGES AND
WE CAME UP WITH THIS METHOD TO
CHARACTERIZE FOR REPLICATION IN
MEIOSIS AND LOOK AT DOUBLE
STRAND DNA TO THE ORIGIN
DETECTION AND ISOLATED
REPLICATING THE NUCLEI AND HAVE
A MODEL TO UNDERSTAND WHAT'S
GOING ON IN MEIOSIS.
WE LEARNED MOUSE REPLICATION IS
SLOWER THAN THAT OF THE CELLS IN
THE TESTES AND ANY OTHER CELL
TYPE WE LOOKED.
THIS WAS NOT SURPRISING.
.
EVERYWHERE PEOPLE LOOKED THE
REPLICATION WAS SLOWER AND TAKES
TWICE THE TIME AND WHAT WE
LEARNED FROM OUR MODEL IS THE
SLOWER REPLICATION IS DUE TO
LOWER RATES.
THERE'S FEWER WHEN CELLS DO
MYOTIC REPLICATION AND TRYING TO
UNDERSTAND WHY AND WHAT'S THE
CONSEQUENCES OF HAVING SLIGHTLY
FASTER REPLICATION IN MEIOSIS.
WE LOOKED AT METRIC OF
RECOMBINATION WE HAD IN THE LAB
AND CAN FIND THE HOT SPOTS ARE
HIGHLY ENRICHED IN THE GENOME
THEREFORE CORRELATING THIS TO
THE PROCESS.
BUT WHEN WE LOOKED AT THE HUMAN
TIMING WE SEE THERE'S A VERY
DISTINCT PATTERN AND IT'S GERM
LINE SPECIFIC SEEING REPLICATION
AT THE ENDS OF THE CHROMOSOMES
EARLY.
THIS HIGHLY DIFFERENT PATTERN
MIRRORS THE DISTRIBUTION OF THE
BROAD SCALE OF DOUBLE-STRAND
BREAKS SUGGESTING THE EARLY
REPLICATION UNDERLYING THE
PATTERNS WE SEE IN BREAKS.
SO SINCE THEN WE HAVE APPLIED
THE METHOD TO STUDY REPLICATION
TO HUMAN TESTES.
WE HAD DETECTED ORIGINS AND HAVE
A NICE REPLICATION.
SO I TOLD YOU THE RELATION
BETWEEN BREAKS AND EARLY
REPLICATION AND NOW WITH THE
VERY FINE RESOLUTION WE CAN
START ASKING DIFFERENT
QUESTIONS.
AND WHEN WE LOOK AT DIFFERENT
REGIONS OF THE GENOME OR
INTERSTITIAL PARTS SEPARATELY WE
SEE A DIFFERENT STORY.
IN THE INTERSTITIAL PART THERE'S
MORE BREAKS AND THIS SUGGESTS
THE CHROMOSOMAL CONTEXT MODIFIES
THE PATHWAY USED TO RESOLVE THE
DOUBLE STRAND BREAKS.
AND THIS IS VERY IMPORTANT
BECAUSE WHEN WE HAVE HUNDREDS OF
BREAKS AND ONLY 10% RESULT AS A
CROSSOVER AND HOW THEY'RE
DETERMINED IS A FUNDAMENTAL
QUESTION ON MEIOSIS AND WE HAVE
TO START UNDERSTANDING THE
THINGS AND TO FINISH AND I
DIDN'T TELL YOU THIS IN HUMANS
REMEMBER I TOLD YOU THERE'S A
FEMALE MEIOSIS IS DIMORPHIC AND
ONE OF RISK FOR CHROMOSOME 21
AND DOWN SYNDROME IS HAVING THE
CROSSOVER TO THIS IN THE
CHROMOSOME.
THE SYSTEM IS ALLOWING US TO TRY
TO UNDERSTAND HOW THE PROCESSES
ARE CONTROLLED AND WILL HAVE
MORE ANSWERS IN A LITTLE WHILE.
SO JUST TO FINISH, I'D LIKE TO
THANK THE CURRENT MEMBERS OF MY
LAB AND MY LAB AT NIDDK AND ALL
THE COLLABORATORS PAST AND
PARENT AND THE DISTINGUISHED
SCHOLAR PROGRAM.
THANK YOU.
>> THANK YOU VERY MUCH.
THAT'S A FASCINATING TALK.
>>
>> THIS IS ROSE AGAIN.
I THOUGHT IT WAS ALSO A
FASCINATING TALK.
I HAVE A QUESTION ABOUT THE PRD
AND 9 REGIONS.
IN CHILDHOOD CANCER THERE ARE
RECURRENT FUSIONS AND THAT
PRECISELY RECUR IN DIFFERENT
PATIENTS.
SO AT THE REGIONS THAT LEAD TO
DOUBLE STRAND BREAKAGE DO THEY
CONTRIBUTE TO THAT PATHOGENESIS.
>> PEOPLE HAVE BEEN LOOKING INTO
THAT BECAUSE THERE'S A FIELD OF
ANTIGEN THAT IS MEIOTIC GENES IN
CANCER AND ONE STUDY LOOKED AT
CHILDREN WITH LEUKEMIA AND HAVE
EXCESS OF SOME OF THESE AND HAVE
THE TARGET BUT IT COULD
DEFINITELY MAKE AN IMPACT.
IT DOES NOT SO WE HAVE DIFFERENT
REPLICATION SIZE AND FUSIONS WE
DON'T SEE EXACT SAME POSITION
BUT IN CANCERS THEY'RE OVER
EXPRESSED AND UNREGULATED.
>> I LOVE THAT YOUR TALK STARTED
WITH PHYSIOLOGICAL PRINCIPLES
AND THEN MOVED TO DISEASE
STATES.
DURING MEIOSIS IS THE
SEGREGATION OF CHROMOSOMES
RANDOM ERR OR DO YOU HAVE HOT SS
THAT SEGREGATE TOGETHER?
>> THE MAJOR ASSORTMENT IS DUE
TO THE INDEPENDENT ASSORTMENT OF
CHROMOSOMES AND THEN WITH
CROSSOVERS YOU DO THE
INTERACTION.
IT'S NOT ONLY FEMALES THAT ARE
RECOMBINANT CHROMOSOME TENDS TO
STAY SO THERE'S SOMETHING THAT
SENSES RECOMBINANT IS BETTER AND
ONE HAS A RECOMBINATION EVENT
AND IF THERE'S SMALLER BIASSED
IN FEMALES.
>> IS THERE A THOUGHT ON WHAT
THE MECHANISM MIGHT BE?
>> NO, IT MUST BE A PROTEASE
THAT MARKS THE CROSSOVERS.
>> LOUIS.
>> GREAT TALK.
WHY DO YOU THINK SUCH AN
ERROR-PRONE MECHANISM WOULD HAVE
SURVIVED EVOLUTION?
THE CLASSIC GENETIC TEXTBOOKS
SAY YOU KEEP ACCUMULATING
VARIANTS AND YOU NEED SOMETHING
TO CLUSTER THE GOOD OR BAD ONCE
TOGETHER.
I'M NOT SURE THE EXPLANATION IS
SATISFACTORY BUT WHAT DO YOU
THINK?
>> THE FEMALE HORSES ARE JUST
LIKE HUMANS.
MANY ORGANISMS HAVE THE ERROR
RATE HIGH BUT NOT ALL.
WHAT PEOPLE HAVE PROPOSED IS YOU
DON'T WANT TO HAVE TOO MANY ONE
AFTER THE OTHER.
THAT'S ONE OF THE IDEA WHY IT'S
BEEN KEPT.
MAYBE WE'RE AT THE EVOLUTIONARY
TIME WHERE THIS IS A GLITCH THAT
IS GOING TO BE FIXED.
THAT'S NOT AN ANSWER.
THERE'S HUGE ATTRITION.
SO ABOUT 10% SURVIVE TO BIRTH.
SO THERE'S A LOT OF IN THERE.
>> THANK YOU.
>> WONDERFUL.
THANK YOU VERY MUCH.
THIS IS TO ERROR IS HUMAN.
>> CAN I USE IT?
>> WELL, THANK YOU.
WE'LL CLOSE THE MORNING SESSION
HERE AND BREAK FOR LUNCH.
I'LL REMIND YOU THERE ARE
POSTERS STILL ON THE TERRACE
UNTIL 12:30 SO IF YOU HAVE A FEW
MOMENTS GANDER OVER THERE AND
TAKE A LOOK AND PROVIDE SUPPORT
TO OUR TRAINEES PRESENTING
RESEARCH OTHER WISE TAKE A LUNCH
BREAK AND STRETCH YOUR LEGS AND
NO DBTs EVERYONE AND WE'LL SEE
YOU BACK.
THANK YOU.