WANTED TO START WITH A FEW
HOUSEKEEPING ITEMS. I'M JANICE
LEE AND CLINICAL DIRECTOR FOR
NIDCR. MAKING NOTE THERE WILL
BE A 15 MINUTE COFFEE BREAK AND
VISUAL HISTORY WITH POSTERS ON
FAES TERRACE AND NOTE THERE WERE
NO NIDCR APPROPRIATED FUNDS USED
FOR RECEPTION. I HAD TO SAY
THAT. BREAK IS AT 10:45.
WELCOME TO THE NIDCR CELEBRATION
OF 25 YEARS OF RESEARCH HERE AT
THE NIH THAT COINCIDES WITH 75TH
ANNIVERSARY WITH NIDCR AS AN
INSTITUTE AND THE SYMPOSIUM IS
ONE OF SPECIAL EVENTS FOR OUR
YEAR-LONG CELEBRATION AND IS
SEPTEMBER ELEVENTH AND
ACKNOWLEDGING THE TRAGEDY OF
THAT DAY NOW 22 YEARS AGO. WE
WILL NOT FORGET. MUCH HAS
CHANGED SINCE THAT TIME. TODAY,
MUCH HAS CHANGED IN
UNDERSTANDING OF FIBRO DYSPLASIA
AND [INDISCERNIBLE] BECAUSE OF
THE TREMENDOUS RESEARCH AND
DISCOVERIES THAT OCCURRED HERE
AT NIH THAT YOU WILL HEAR ABOUT
THROUGH THE LINEUP OF SPEAKERS
TODAY. THE INDIVIDUALS
PERSONIFY JOURNEY OF EARLY
DISCOVERIES OF GENETIC MUTATIONS
AND MECHANISTIC UNDERSTANDING OF
THIS DISEASE AND TREATMENTS
BEING STUDIED.
IT IS THROUGH A COLLABORATIVE
EFFORT AND SPIRIT THAT A COMMON
THEME IS WOVEN INTO OUR STORY
YOU WILL HEAR FROM NIDCR
INVESTIGATORS AND OTHER IC
INVESTIGATORS AS WELL AS
INTERNATIONAL COLLEAGUES WHO
CONTINUE TO TACKLE THIS DISEASE.
MOST IMPORTANTLY YOU WILL HEAR
FROM PATIENTS WHO ARE AT THE
CENTER OF OUR RESEARCH AND
ADVOCACY GROUPS BRINGING
AWARENESS TO THIS DISEASE.
AND TO THE RESEARCH THAT IS
HELPING US TREAT AND CURE FOR
PATIENTS.
FIRST SPEAKER TODAY, DR. ALLEN
SPIEGEL WHO IS DEAN AND
PROFESSOR AT ALBERT EINSTEIN
COLLEGE OF MEDICINE IN NEW YORK
AND IS ACTUALLY THE DEAN
EMERITUS AND PLEASED TO WELCOME
HIM BACK AT NIH. HE BEGAN HIS
CAREER AT NIH IN 1973 AS A
CLINICAL ASSOCIATE IN THE
ENDOCRINOLOGY PROGRAM AND WORKED
WAY THROUGH RANKS OF NIH AS
SENIOR INVESTIGATOR, BRANCH
CHIEF AND SCIENTIFIC DIRECTOR OF
NIDD INTRA MURAL PROGRAM AND
BECAME DIRECTOR OF NIDDK IN
1999. PROGRESSION SEEMS NATURAL
BUT DOESN'T HAPPEN TO ALL OF US.
HE BECAME THE DEAN OF ALBERT
EINSTEIN COLLEGE OF MEDICINE IN
2006. DR. SPOOEG ELIS A WORLD
RENOWNED SCIENTIST WHOSE WORK ON
DISCOVERY OF GS VARIANTS AND
SYNDROME WAS PUBLISHED IN NEW
ENGLAND JOURNAL IN 1991. DR.
SPIEGEL, PLEASE DO US THE HONOR
TO START OUR JOURNEY.
>> AUDIENCE: [APPLAUSE].
>> DR. LEE, COLLEAGUES,
DISTINGUISHED GUESTS, PATIENTS,
MEMBERS OF PATIENT ADVOCACY
ORGANIZATION. IT IS A PRIVILEGE
TO SPEAK IN THIS SYMPOSIUM. I'M
ASKED TO DESCRIBE THE HISTORY OF
THE DISCOVERY OF GS ALFALFA
VARIANTS AS CAUSE OF FIBROUS
DYSPLASIA WE WILL REFER TO
FIBROUS DISPLACE YUSH/ACUTE
SYNDROME. YOU WILL SEE WHY. I
WILL DESCRIBING THAT HISTORY
PROVIDE A HISTORICAL PERSPECTIVE
AND ANCIENT HISTORY IN SOME
SENSE.
I HOPE YOU WILL BEAR WITH ME. I
WILL BE SOMEWHAT SELF-INDULGENT
IN DESCRIBING MY PERSONAL
TRAJECTORY AS AN INVESTIGATOR
INTERESTED IN MECHANISM OF
HORMONE ACTION REALLY SINCE
WORKING AS AN UNDERGRADUATE IN
THE LABORATORY OF THE LATE MARK
BOTENSKY WHO EMERGED AS A
RESEARCH ASSOCIATE FROM NIH
INTRAMURAL PROGRAM SETTING UP
HIS LAB AT NYU. HE INTRODUCED
ME TO THE SECOND MESSENGER
SYSTEM ABOUT HORMONES AS FIRST
MESSENGERS. IN THIS CASE ADENO
CYCLASE GENERATING FROM ATP AND
SO-CALLED SECOND MESSENGER AND
WORKING ON THIS SYSTEM AS AN
UNDERGRADUATE THIS WAS AN AREA
PYRON EARED BY EARL SUJERLAND
WHOSE GROUP RECEIVED THE NOBLE
PRIZE IN 1991. HE CAME TO GIVE
A SEMINAR AND ATTENDED BUT
NUMBER OF NIH INTRAMURAL
INVESTIGATORS. ONE, MARTY
RODBELL WAS THE PERSON
RESPONSIBLE FOR SHOWING ABSOLUTE
DEPENDENCE ON HORMONE
STIMULATION ON CYCLIC AMP ON
GUANINE NUCLEOTIDES SOMETHING
THAT UNTIL HIS DISCOVERY ELUDED
-- RODBELL AND HIS ASSOCIATES
THEREFORE PUT G-PROTEINS AND
EVENTUALLY WE WILL SEE
G-PROTEIN-COUPLED-RECEPTORS ON
THE MAP AND FOR THIS WORK
RODBELL SHARED THE NOBLE PRIZE
IN 1994.
I WAS FORTUNATE TO COME TO THE
LAB OF R BACH IN 1973 AT NIH.
THIS WAS MY OPPORTUNITY TO
BECOME AN ENDOCRINOLOGIST THAT
IS PARADIGMATIC BENCH TO BEDSIDE
AND BACK MEDICAL SUBSPECIALTY.
I HAD TO TESTIFY IN CONGRESS ON
BEHALF OF NIH APROPRIATION.
RALPH REPUBLICAN OF OHIO WAS
CHAIR OF THE ANIH APROBE RATION
COMMITTEE WE HAD THEME BENCH TO
BEDSIDE HE MISREAD AND SAID
BEACH TO BEDSIDE. THAT VAGUE
ARY IS TESTIFYING IN CONFR
GREYS. R BACH HAD NUMBER OF
ACCOMPLISHMENTS IN NIH
INTRAMURAL PROGRAM AND GAVE
FURTHER OPPORTUNITIES TO PURSUE
HORMONE MECHANISM TRANSLATION IN
A TRANSLATIONAL WAY AND FROM
THIS WORK WE EVOLVED CONCEPT OF
INBORN ERRORS OF SIGNAL
TRANSDUCTION. WE ARE STEALING
THE TERMINOLOGY OF
[INDISCERNIBLE] WHERE A GENETIC
DEFECT LEADING TO ENZYME
DEFICIENCY CAUSES DISEASE
THROUGH BUILDUP OF SUBSTRATE
FETAL KINNURIA OR -- LOSS OF
FUNCTION MUTATION IN SOME
SIGNALING COMPONENT AND THIS
WOULD LEAD TO HORMONE RESISTANCE
BECAUSE OF THE HOMEO STATIC
FEEDBACK STIMULATING HORMONE
WOULD BE HIGH DETECTED BY RADIO
ASSAY AND HORMONE WAS DEFICIENT
IN HORMONE RESPONSE. INBORN
ERRORS OF METABOLISMIN BORN
ERRORS OF SIGNAL TRANSDUCTION
COULD HAVE OPPOSITE TYPE GAIN OF
A SINGLE COMPONENT HYPERWHATEVER
THE ENDOCRINE FUNCTION IS AND
FEEDBACK A DEPRESSION OF
STIMULUS HORMONE AND ELUDED TO A
COLLEAGUE THAT IS FROM HARVARD
MEDICAL SCHOOL TO THE FACT I
WOULD SHOW A SLIDE PICTURING IN
THIS CASE ANCIENT BULL FINCH
BUILDING AT MASS GENERAL
HOSPITAL SPENDING MANY SLEEPLESS
NIGHTS AS AN INTERN AND
RESIDENT. BULL FINCH BUILDING
WAS THE SITE OF WORK OF FULLER
ALBRIGHT ONE OF THE GIANTS OF
ENDOCRINOLOGY BY NOT TOTAL
COINCIDENCE HAD OPPORTUNITY TO
DESCRIBE GENETIC BASIS OF TWO
DISEASES THAT CARRY HIS EPIN
EMIC NAME
PSEUDOHYPOPARATHYROIDISM AND
SUBJECT OF TODAY'S SYMPOSIUM THE
MCKUHN ALBRIGHT SCUNE ALB-ALBRI
IS THE WORK OF LEE WEINSTEIN A
POST DOC IN THE LAB AND BRANCH
CHIEF OF MY FORMER BRANCH
METABOLIC DISEASES BRANCH AND WE
WILL SEE SUBJECT OF TODAY'S
SYMPOSIUM GAIN -- THE G-PROTEIN
COUPLED RECEPTORS COULD BE THE
SITE OF LESIONS AND SHOWED
NEPHRO GENIC DIABETES INSIPIDUS
WAS LOSS OF MUTATIONS IN VASO
RECEPTOR SUPPRESSOR AND POST DOC
IN LABORATORY WORKING
INDEPENDENTLY SHOWING GAIN OF
FUNCTION MUTATION IN LUTEINIZING
HORMONE RECEPTOR COULD BE
GENETIC CAUSE OF FAMILIAL MAIL
PREKOESHS PUBERTY. THIS IS
GTPACE SCHEMA AND 7
TRANSMEMBRANE RECEPTOR COUPLED
TO THIS THAT CAUSES CYCLIC AMP
PRODUCTION AND BETA GAMMA
TIGHTLY BOUND SUBUNITS. GDP
TIGHTLY BOUND AND WHEN AGONIST
BINDS TO RECEPTOR ACTIVATING
G-PROTEIN SO GTP EXCHANGES FOR
GDP BUT ALLOWS EFFECTOR
STIMULATION CYCLIC AMP
STIMULATION -- AND PHYSIOLOGIC
RESPONSES.
THE INTRINSIC GTPACE HALTS
STIMULATION BUT THAT INTRINSIC
GTPACE COULD BE BLOCKED BY ALPHA
ACTIVATING MUTATION WE WILL SEE
AND BY EXTERIOR TOXIN WHERE
MARTHA VAUGHN IN PROGRAM OF
HEART AND LUNG SHOWED PARTICULAR
ARJINNINE RESIDENT DUE THAT WE
WILL SOON BE FAMILIAR WITH IS
SITE OF ADP -- COVALENT
MODIFICATION BLOCKING GTPACE
LEADING TO UNREGULATED
STIMULATION OF CYCLIC AMP
FORMATION AND -- WE WERE
FORTUNATE TO HAVE COLLEAGUES IN
CHILD HEALTH INSTITUTE AT THE
TIME STUDYING TREATMENT OF
PREKROERGS PUBERTY LYNNE AND
GLORIA AND OTHER COLLEAGUES AND
ONE DISEASE THEY STUDIED WAS
MCKUHN ALBRIGHT SYNDROME THAT
PREKOESHS PUBERTY IS A SYNDROME.
STAGE 2 BREAST DEVELOPMENT IS
FEATURED IN A YOUNG GIRL OBVIOUS
CAFE OLAY PIGMENTATION. THIS IS
A BODY CAST BECAUSE OF FRACTURES
DUE TO FIBROUS DYSPLASIA THAT
ARE CARDINAL FEATURES OF A
TRIIAD THAT CHARACTERIZES MCKUHN
ALBRIGHT SYNDROME. NOW, IT IS
VERY INTERESTING TO LOOK BACK AT
ORIGINAL PUBLICATIONSCARDINAL F
THAT CHARACTERIZES MCKUHN
ALBRIGHT SYNDROME. NOW, IT IS
VERY INTERESTING TO LOOK BACK AT
ORIGINAL PUBLICATIONS -- THAT
HAS PRECOCIOUS PUBERTY AND
HYPERTHYROIDISM AND SAYS BASIC
PROBLEMS IN NORMAL AND
PATHOLOGIC PHYSIOLOGY IN THIS
CHILD PRESENTS REMAINS UNSOLVED
AND WOULD REMAIN UNSOLVED FOR
ANOTHER 54 OR SO YEARS.
REASON IT IS MCKUHN ALBRIGHT
SYNDROME SIMULTANEOUSLY IN 1937
IN NEW ENGLAND JOURNAL PAPER
ALBRIGHT DESCRIBES ANOTHER
DISORDER OSTEOFIBROSIS DISSEMIN
ATA THAT IS NOW FIBROUS -- IF
PATHOLOGIC MANIFESTATIONS THAT
AT FIRST SEEM TO BE TOTALLY
DISCONNECTED ARE FOUND TO OCCUR
TOGETHER IN SUFFICIENT SERIES OF
PATIENTS SOME RELATION BETWEEN
THEM IS APPARENT AND SUCH IS THE
CASE IN THE BIZARRE SYNDROME
WHICH IS THE SUBJECT OF THIS
PAPER AND ELUDES TO MCKUHN CASE
AT PRESBYTERIAN HOSPITAL IN NEW
YORK AND POINT THAT PEEKED MY
INTEREST IS DISPARATE
MANIFESTATIONS WHAT UNIFYING
HYPOTHESIS COULD BRING THEM ALL
TOGETHER. CAN'T BE OCCURRING BY
CHA
CHANCE. A GERMAN DERMATOLOGIST
HOPLY SPECULATED THAT MCCUNE
ALBRIGHT SYNDROME HAD A LETHAL
GENE SURVIVING BY MOEZ AISSAMOS
AT FIRST AS A DERMATOLOGIST HE
LOOKED AT PIGMENTATION THEY
DIDN'T FOLLOW DETERMINE ATOID
LINES BUT LINES OF BLASH CO A
DEVELOPMENTAL MORPHOLOGY. WHAT
HE THOUGHT IS THAT THE DISEASE
WAS CAUSED BY AUTOSOMAL DOMINANT
LETHAL GENE THAT COULDN'T
SURVIVE IN THE ZYGOTE. IF THERE
WAS A LATER SOMATIC MUTATION,
THAT LATER SOMATIC MUTATION
COULD SURVIVE AND LEAD TO AN IS
SO-CALLED MOSAIC DISTRIBUTION
THAT WE WERE ENCOURAGED BY THAT
HYPOTHESIS AND FURTHER
ENCOURAGED BY THIS PAPER
PUBLISHED IN 1989 IN NATURE FROM
HENRY BORNE'S LAB AT UCSF AND
GROUP OF ITALIAN INVESTIGATORS.
THEY EXAMINED THE PITUITARY
TUMORS SO-CALLEDSOME ATTOTROVE
TUM
TUMORS.
SOME ATTO
FOCAL SOMATIC MUTATION CAUSING
ISOLATED ENDOCRINE HYPOMALFUFRJS
THAT INVOLVED ARGININE 201 THAT
HAPPENS TO BE SITE OF ATPRB
OSCILLATION AND THAT
MODIFICATION BECAUSE THAT
RESIDENT DUE IS IN APPROXIMATE
TO GDP TIGHTLY BOUND BY WHAT YOU
CAN SEE HERE IS ALPHA SUBUNIT
THAT IS BETA AND TIGHTLY BOUND
GAMMA AND WILL SEE ELEGANT
STRUCTURAL PICTURES BY
PIONEERING WORK IN SEMINAR AND
RECEPTOR CRUMB WILLING TO
G-PROTEIN ALLOWING EXCHANGE OF
GTP AND CRUCIAL ROLE FOR THIS IS
YOU WILL NOTICE A GLUTAMINE 227
IN APPROXIMATE CAUSE THAT RARELY
YOU COULD HAVE MUTATIONS IN THAT
GLUTAMINE. PRIMARILY THIS
ARGININE 201 WAS THE SITE OF THE
MUTATIONS.
NOW, THIS IS THE PAPER
ULTIMATELY PUBLISHED IN 1991
ELUDED TO ALREADY BY DR. LEE LEE
WEINSTEIN AND ANDY SHANKER AND
COLLEAGUES AT NIH SHOWED
MUTATIONS OF AXON NIH INCREASED
ACTIVITY OF GS PROTEIN AND
INCREASED CYCLIC AMP FORMATION
AND PRESENT IN VARIOUS TISSUES
OF PATIENTS WITH MCCUNE ALBRIGHT
SYNDROME THIS IS SOMATIC
MUTATION LEADING TO THIS MOSAIC
DISTRIBUTION.
HERE IS SOME OF THE ACTUAL DATA.
AGAIN, ANCIENT HISTORY AND THIS
IS BY NOW OUTMODE TECHNIQUE
NATURE GRADIENT GEL
ELECTROPHORESIS NEGATIVE AND
POSITIVE CONTROL AND TISSUE
SAMPLES FROM A REPRESENTATIVE
PATIENT AND IDEA IS ON THIS
DENATURE GELL -- SOME SEGMENTS
WILL MIGRATE DIFFERENTLY AND A
MORE FOCAL TEST IS ALLELE
SPECIFIC OLIGONUCLEOTIDE --
NEGATIVE AND POSITIVE CONTROL
AND TISSUE SAMPLES ONLY IN THE
POSITIVE CONTROL AND TO VARYING
DEGREES IN TISSUE SAMPLES DOES
ONE SEE MUTANT INSTEAD OF
ARGININE 201 CYSTINE MUTATION
AND CG DINUCLEOTIDE FROM CODON
BEING A HOTSPOT AND THIS
MUTATION COULD OCCUR IN PATIENTS
WITH MCCUNE ALBRIGHT AND FURTHER
ANATOMIC DATA YOU FROM PAPER
SUBJECT WITH PROKOESHS PUBERTY
AND HAD OVARY REMOVED AND NORMAL
APPEARING OVARY WITH NORMAL
FOLLICLES NO DETECTION OF R201C
MUTATION AND DNA ABNORMAL
INAPPROPRIATE DEVELOPED FOLLICLE
AND FROM THIS ABNORMAL AREA
THERE WAS COPIOUS AMOUNTS OF
R201C MUTATION AND IN SUMMARY
FIBROUS DYSPLASIA MCCUNE
ALBRIGHT SYNDROME DUE TO
SPORADIC PLEAO TROEBIC PHENOTYPE
CAFE OLAY SKIN PIGMENTATION
GONADSOME ATTOTROVE ADRENAL --
STIMULATOR ENDOCRINE AND
MELANOCYTE GROW IN FUNCTION AND
FACT YOU HAVE UNREGULATED
HORMONE STIMULATION OF CYCLIC
AMP COULD EXPLAIN PATHOGENESIS
AND IN CASE OF BONE A
COMPLICATED SITUATION THAT WE
WILL HEAR ABOUT LATER IN THE
SYMPOSIUM FROM PAM AND MARA THE
SOMATIC MUTATION OF GS ALPHA
ARGININE 201 AND RARELY IF AT
ALL GLUTAMINE 227 SPECULATIVELY
GERM LINE LETHAL AND MOSAIC
PHENOTYPE -- ANDY DESCRIBED
PATIENTS WITH EARLY SOMATIC
MUTATIONS THAT HAD SEVERE
WIDESPREAD DISEASE VERSUS LATE
FOCAL SOMATIC MUTATION
TIPPIVEFIED BY ISOLATEDSOME
ATTOTROVE PITUITARY TUMOR. WE
WILL HEAR IN DETAIL FROM MICHAEL
COLLINS ALLISON BOYCE ABOUT
CLINICAL STUDIES INVOLVING
PATHOGENESIS AND TREATMENT OF
LINKED SYNDROMES. THANKS FOR
YOUR ATTENTION.
>> AUDIENCE: [APPLAUSE].
>> >> THANK YOU DR. SPIEGEL.
NEXT SPEAKER IS PAM ROBEY WHO
STARTED POST DOCTORAL WORK AT
NIAMS AND NAEI AND YOU WILL
NOTICE A THEME WHERE THERE IS
INTERDISCIPLINARY COLLABORATION
AND INTER-IC COLLABORATION AND
SHE JOINED NIDCR IN 1983 AND IS
CURRENTLY SENIOR INVESTIGATOR
AND CHIEF OF SKELETAL BIOLOGY
SECTION AND CRANIOFACIAL
DISEASES BRANCH AND MIKE COLLINS
AND I CUT TEETH ON BONE BIOLOGY
TO UNDERSTAND BONE DISORDERS AND
IN 1993 DR. ROBEY RECEIVED FULL
BOX OF BONE SPECIMENS FROM
ENDOCRINOLOGIST AT NIH AND HE
ASKED HER TO IDENTIFY WHAT THE
MUTATION AND HOW THE
ABNORMALITIES OF THIS PARTICULAR
GENE WOULD THEN RESULT IN THE
BONE PHENOTYPE AND BEGAN HER
QUEST ITALIAN COLLEAGUES PAULO
AND MARA WHO ARE HERE TODAY TO
UNDERSTAND IMPACT OF MUTATION ON
BONES OF PATIENTS WITH FD AND
MAS A SKELETAL DISEASE. DR.
ROBEY?
>> AUDIENCE: [APPLAUSE].
>> I'M FINE, THANKS.
>> THANK YOU, JANICE. I
APPRECIATE THE INTRODUCTION.
THANK YOU ALL FOR COMING TO HEAR
ABOUT OUR JOURNEY DURING THE
LAST 25 YEARS.
SO, I WILL START OFF WITH A
LITTLE BIT ABOUT WHAT SKELETAL
STEM CELLS ARE. A LITTLE OF THE
HISTORY OF FD/MAS AT NIDCR AND
ROLE OF SKELETAL STEM CELLS AND
DISEASE AND WHY FD/MAS IS A STEM
CELL DISEASE.
SO, FIRST, A LITTLE BIT OF
REFRESHER WHAT A STEM CELL IS.
DEFINING FEATURES OF A STEM CELL
ARE TWO. ONE, IT HAS THE
ABILITY TO SELF-RENEW. THE
SECOND IS THAT A SINGLE CELL IS
ABLE TO REPLENISH AND REFORM AN
ENTIRE TISSUE. THE SO-CALLED
POTENCY OF THE CELL. THE WAY
THAT A STEM CELL REFRESHES
ITSELF IS BY A SELF-RENEWING
DIVISION WHERE STEM CELL DIVIDES
ASYMMETRICALLY AND ONE IS A MORE
COMMITTED CELL GOING ON TO
TRANSIENTLY AMPLIFY AND THEN
AFTER A CERTAIN AMOUNT OF
PROLIFERATION GOES ON TO
DIFFERENTIATE THAT IS THROUGH
SYMMETRIC DIVISION AND SECOND
DAUGHTER OF THE STEM CELL
REMAINS STEM CELL SO-CALLED
ASYMMETRIC DIVISION THAT IS NOT
THAT SIMPLE AND MAY ACTUALLY
TOGGLE BACK AND FORTH BETWEEN
SYMMETRIC AND ASYMMETRIC
DEPENDING ON THE SITUATION.
THIS IS A WORKING PARADIGM AND
TWO PROPERTIES THAT DEFINE A
STEM CELL THAT THE DEFINITION OF
STEM CELLS IS OFTEN KIND OF
DISREGARDED AND MANY CELLS ARE
CALLED STEM CELLS WITHOUT BEING
TRUE STEM CELLS WITHOUT RIGOROUS
CRITERIA AND DURING DEVELOPMENT
WE HAVE WHAT SOME WOULD CALL THE
MOTHER OF ALL STEM CELLS, THE
FERTILIZED EGG THAT ISTODY
POTENT WITH ABILITY TO FORM NOT
ONLY CELLS IN BODY BUT PLACENTAL
AND OTHER MEMBRANES.
THIS GOES ON TO DIVIDE TO FORM
THE BLASTOCYST WHERE YOU HAVE
TRIFEKTO DETERMINE ON OUTER
SURFACE AND CLUMP OF CELLS IN
MIDDLE INNER CELL MA S THAT IS
PLURIPOTENT MEANING THEY WILL
MAKE CELLS OF EMBRYO BUT NOT
PLACENTAL MEMBRANES AND INNER
CELL MATH GIVES RISE TO ESL
CELLS WE USE IN THE LABORATORY
AND BLASTOCYSTS DEVELOP AND WE
HAVE GASTROFORMATION AND GERM
LAYERS ECTOGERM NEED AZ
DETERMINE AND ENDODETERMINE AND
COMMITTED TO LINEAGES THAT LOST
POTENCY AND WE CALL THEM
MULTIPOTENT AND AFTER BIRTH WE
HAVE MATURE DIFFERENTIATED CELLS
AND MAINTAIN A CERTAIN
POPULATION OF STEM CELLS AND
PROBABLY ALL TISSUES IN THE
BODY. ADULT STEM CELLS ARE
ABSOLUTELY NECESSARY FOR TISSUE
SELF-RENEWAL AND REFRESHMENT.
SO, IN THE BONE MARROW,
ALEXANDER FREEDEN STEIN I'M
SORRY WORKING WITH MAUREEN OWEN
FIRST DEFINED BONE MARROW
STROMAL CELLS A SUBSET WHICH
WERE MULTIPOTENT STEM CELLS.
WHAT HE DID WAS TAKE A SINGLE
CELL SUSPENSION OF BONE MARROW
AND PLAYED IT AT VERY LOW
DENSITY AND RAPIDLY ADHERIENT
FIBRO BLAST CELL THAT CELL PROL
COLONY TAKING CELLS TO PUT ON
APPROPRIATE SCAFFOLD AND TRANCE
PLANT INTO MICE AND GET
FORMATION OF ECTOPICOSICLE WITH
BONE AND STROMA AND MARROW DIPPO
CITES OF DONOR ORIGIN AND STROMA
SUPPORTS FORMATION OF HEM
ATTOPOEESIS THAT IS RECIPIENT
ORIGIN THAT IS A DEFINING
FEATURE OF BONE SKELETAL STEM
CELL. THESE CELLS ARE ALSO VERY
IMPORTANT IN TERMS OF SUPPORTING
FORMATION OF OSTEOCLASTS.
THESE CELLS ARE IMPORTANT REALLY
IN SKELETAL HOMEOSTASIS AND WE
FOUND BY DOING TRANSPLANTATION
ASSAY IS ONLY 1 OUT OF 5 OF CFUF
ARE IN FACT MULTIPOTIENT AND
SKELETAL STEM CELLS ARE CFUFS
AND NOT ALL ARE SKELETAL STEM
CELLS AND PROVED BY DOING SERIAL
TRANSPLANTATION THAT CELLS DO IN
FACT SELF-RENEW AND ARE
BONIVEFIED ADULT STEM CELLS AND
YOU HEARD FROM JANICE AND ALLEN
WE BEGAN TO TO STUDY -- HE SAID
IDEA WHY THEY HAVE FIBROUS
DYSPLASIA THAT BEGAN OUR JOURNEY
AND AT TIME MARA RIMINUCCI WAS A
FELLOW IN THE LAB AND THEY
STARTED TO LOOK AT PARAFIN
BLOCKS DISCOVERING THIS WAS AN
INTERESTING DISEASE AND HAVING
HARD TIME GETTING LIVE TISSUE.
THAT WAS REALLY A CHALLENGE.
SHLOMA SUGGESTED WHY NOT START A
CLINICAL STUDY TISSUE
PROCUREMENT STUDY AND AT THAT
TIME [INDISCERNIBLE] WAS
INENDOCRINE FELLOW WHO DECIDE
TODAY LEARN ABOUT BONES AND CAME
TO THE LAB. WE GOT TOGETHER AND
PUT TOGETHER A SERIES OF
CLINICAL PROTOCOLS. ONE WAS
NATURAL HISTORY. ONE WAS
TREATMENT OF THE DISEASE WITH
ADRONATE -- ALLEN DROENNDRODRO
WITH US DURING 25 YEARS AND
BASICALLY THE BOTTOM LINE WAS WE
HAVE -- WE KNOW WHAT THE
MUTATION IS. ACTIVATING
MUTATION OF GS ALPHA CAUSING
EXCESS CYCLIC AMP PRODUCTION AND
WHAT DOES IT MEAN TO BONE?
THAT WAS REALLY OUR GOAL
THROUGHOUT ALL OF THE STUDIES.
THEN I WAS WORKING ON BONE
SKELETAL STEM CELLS AT SAME
TIME. I THOUGHT, GEEZ. MAYBE
THERE IS A LINK BETWEEN THE
SKELETAL STEM CELL AND FIBROUS
DYSPLASIA OF BONE. THIS WAS A
THOUGHT THAT OCCURRED TO US
BECAUSE WE THOUGHT, OKAY.
SKELETAL STEM CELLS ARE
IMPORTANT IN CONTROLLING BONE
FORMATION AND BONE DESTRUCTION.
THEY CONTROL FORMATION OF
OSTEOMRAFTS AND REASONED THAT
ANY GENETIC MUTATION OR DMAFRNG
ACTIVITY CAUSED BY CHANGES IN
SURROUNDINGS WILL RESULT IN A
SKELETAL DISEASE OR DISORDER.
WE CHOSE TO WORK ON FIBROUS
DYSPLASIA TO SEE IF THIS
HYPOTHESIS WAS CORRECT.
WE HAVE TISSUES REPRESENTATIVE
OF THREE GERM LAYERS -- WE HAVE
AXIAL AND APPENDICULAR CRANIAL
FIBROUS DYSPLASIA AND WE HAVE
PERKOESHS PUBERTY THAT COMES
ENDODERM AND PATTERN IN MCCUNE
ALBRIGHT SYNDROME REASONED THAT
MUTATION MUST BE OCCURRING IN
INNER CELL MAST OF DEVELOPING
BLASTOCYSTS. WE GET CYST
MUTATIONS OR HISTADEAN MUTATIONS
DEPENDENT ON METHYLATION AND
DEAMINATION THAT OCCURS DURING
EPIGENETIC RE-PROGRAMMING OF THE
INNER CELL MASS DURING DEVELOP
ME
DEVELOP
DEVELOPMENT.
LOOKING AT LESIONAL BONE THIS IS
ALKALPHATASE -- THEY
WEREN'T ON STEROIDS BUT HAD
SOMETHING RELATED TO STEROIDS.
THAT WAS OUR WORKING
HYPOTHESIS.
WHAT WE NOTICE IS THAT IT ALSO
HAS A LOT OF VARIATION, THAT
DEPENDING ON LOCATION OF LESIONS
WE COULD HAVE CHINESE WRITING
KIND OF PATTERN AND HAVE
SCLEROTIC AND PATH ETTOID
PATTERNS PRIMARILY IN BASE OF
THE SKULL AND HAD HYPERCELLULAR
PATTERN THAT IS PRIMARILY IN THE
NATHIC BONES IT IS A
HETEROGENOUS DISEASE DEPENDING
ON THE LOCATION AND LOOKED
FURTHER AND PAOLO AND MARA FOUND
THAT THIS DISPLASTIC BONE IS
ABNORMAL AND WOVEN BONE YOU CAN
SEE IN POLARIZED LIGHT MIKE ROSS
COPY AND IS UNDERMINERALIZED NOT
NORMAL MINERAL CONTENT AND
LOOKING BY STANDARD H & E YOU
SEE THAT NORMAL MARROW IS
REPLACED BY FIBROTIC MARROW WITH
NO BLOOD FORMATION AND NO
ADIPOCYTES YOU CAN SEE CELLS
RETRACTING AWAY FROM SURFACE OF
THE BONE MAKING SHARPIE FIBRO
BONE THAT IS DUE TO
OVERPRODUCTION OF CYCLIC AMP
CAUSING FIBRO BLASTIC CELLS TO
RETRACT THAT IS DEFINING FEATURE
OF FIBROUS DYSPLASIA AND WE
NOTICED TAKING FIBROTIC MARROW
AND DO THE STANDARD COLONY
FORMING EFFICIENCY WHICH IS
FIRST THING WE DO WITH A BONE
DISEASE LOOKING AT NUMBER OF
COLONIES FORMED BECAUSE IT IS
APPROXIMATION OF NUMBER OF STEM
AND PROGENITOR CELLS AND WE SAW
THAT THESE CELLS WERE VERY
IMMATURE AND COLONY FORMING
EFFICIENCY WAS SKY HIGH COMPARED
TO THE NORMAL MARROW.
THEN WE THOUGHT, OKAY. WE HAVE
GOT THESE LARGE NUMBER OF COLONY
FORMING UNITS AND HOW DOES IT
CAUSE THE DISEASE?
WHAT WE DID WAS WE DID CLONAL
ANALYSIS AND PLATED THE CELLS AT
CLONAL DENSITY AND GATHERING UP
ALL CLONES AND PUT THEM INTO OUR
TRANSPLANT, WHAT WE GOT WAS A
COMPLETE REPLICA OF FIBROUS
DISPLASTIC TISSUE REMINISCIENT
OF TISSUE WE GOT FROM THE
PATIENT THEMSELVES AND WAS PROOF
OF PRINCIPLE THAT WE ACTUALLY
COULD USE SKELETAL STEM CELLS TO
RECAPITULATE A SKELETAL DISEASE
BY USING AN IN VIVO
TRANSPLANTATION MODEL IN A
MOUSE.
IF WE TOOK NORMAL CELLS AND
NORMAL CLONES AND GOT A
NORMALOSICLELE AS WE EXPECTED
AND WHAT WE GOT WHEN WE
TRANSPLANTED MUTANT CELLS IS WE
HAD NONNOSICLE AND CELLS
BASICALLY DIED AND DID NOT FORM
BONES.
THIS, AGAIN, WAS PROOF OF
HAPPENLES HYPOTHESIS THAT THIS
MUTATION ONLY SURVIVES WHEN YOU
HAVE NORMAL AND MUTANT CELLS
TOGETHER THAT MUTANT CELLS BY
THEMSELVES WILL NOT SURVIVE.
SO, ANOTHER THING WE NOTICED AS
WE LOOKED AT COLONY FORMING
EFFICIENCY ASSAYS IS WE HAD HUGE
NUMBERS IN YOUNG PATIENTS UNDER
THE AGE OF 30. I THINK WE CAN
REDEFINE YOUNG MAYBE UNDER THE
AGE OF 50. I DON'T KNOW.
IN OLDER PATIENTS, THERE WAS A
DRAMATIC DECREASE IN THE NUMBER
OF COLONY FORMING UNITS THAT
THIS CORRELATED VERY, VERY
TIGHTLY WITH AGE THAT OLDER THE
PATIENT, FEWER THE CFUFS.
THE QUESTION IS WHY?
SO, WE STARTED TO LOOK AT THIS
MORE CAREFULLY LOOKING AT X-RAYS
HERE YOU CAN SEE THERE IS AN
OBVIOUS LESION AND BASICALLY WE
COULD SEE THESE LESIONS AT 10,
21 AND 41 YEARS OLD. LOOKING AT
THEM HISTOLOGICALLY THEY WERE
QUITE DIFFERENT. IN YOUNG
LESIONS WE SAW POORLY
MINERALIZED MATRIX THIS IS
OSTEOID THAT IS NOT MINERALIZED
AND THIS IS FIBROUS DISPLASTIC
MARROW AND IN OLDER PATIENT WE
SAW ALMOST A NORMAL STRUCTURE
THAT ONLY HAD VERY LIMITED AREAS
OF UNMINERALIZED OSTEOID AND IN
OLDER PATIENT THIS WAS A
COMPLETELY NORMAL SAMPLE TAKEN
FROM ILLIAC CREST THAT IS
NORMALLY YELLOW MARROW AT THIS
AGE. YOU WILL -- AS YOU WILL
HEAR, THIS IS ALL DUE TO THE
OSTEOID IS ALL DUE TO EXCESS
FIBRO BLAST GROWTH FACTOR 23
THAT YOU WILL HEAR MORE ABOUT
THAT LATER. WHEN WE LOOKED AT
SAMPLES AGAIN AND DID THE TUNNEL
ASSAY WE NOTICED IN YOUNG
PATIENTS THERE WAS A HUGE AMOUNT
OF CELL DEATHS AS SHOWN HERE BY
THE TUNNEL ASSAY. YOU CAN SEE
APOPTOTIC BODIES THAT ARE
IMBEDDED IN THE BONE AND IN THE
STROMA. THE CELLS WERE DYING.
SO, THIS LED US TO KIND OF PUT
TOGETHER OUR HYPOTHESIS ABOUT
WHAT IS HAPPENING WITH AGING, A
PROCESS WE CALL NORMALIZATION.
IN THE LESION, WE HAVE A MIXTURE
OF NORMAL AND MUTANT STROMAL
PROGENITOR CELLS AND MUTATION
CAUSES INITIALLY HUGE INCREASE
IN PROLIFERATION AND STROMAL
CELLS BEING ON STEROIDS THAT
THEY TAKE OVER THE WHOLE MARROW
AND IS INCREASE, OF COURSE, IN
CYCLIC AMP AND GS ALPHA ITSELF
THAT CAUSES ABNORMAL FORMATION
OF BONE WITH THESE RETRACTED
CELLS THAT UNDERGO APOPTOSIS AND
WITH AGING AS APOPTOSIS IS
OCCURRING, WE LOSE THE MUTANT
SKELETAL STEM CELLS AND NORMAL
SKELETAL STEM CELLS SURVIVE AND
THOSE CELLS GO ON TO FORM NORMAL
BONE AND SUPPORT NORMAL
HEMATOPOEESIS AND FORMATION OF
MARROW ADIPOCYTES AND WHY WAS
THE X-RAY ABNORMAL? NORMAL
MUTANT CELL REMODELED ON AN
ABNORMAL SCAFFOLD AND ABNORMAL
ARCHITECTURE WAS MAINTAINED EVEN
THOUGH THE BONE WAS PRETTY MUCH
NORMAL AND SUPPORTED NORMAL HEM
ATTOPOEESIS.
SO, WHAT DOES THIS MEAN TO THE
SKELETAL STEM CELL?
WHAT WE HYPOTHESIZE IS WHEN THE
MUTANT STEM CELL DIVIDES IT
DIVIDES SYMMETRICALLY SO BOTH
DAUGHTERS ARE SOMEWHAT COMMITTED
TO OSTEOGENIC LINEAGE AND
PROLIFERATING LIKE BATS OUT OF
HELL AND REPLACING THE NORMAL
MARROW WITH FIBROTIC MARROW AND
AT A CERTAIN POINT CELLS START
TO APOP TOES AND BASICALLY KILL
THEMSELVES OFF SO THAT THE
NORMAL CELLS SURVIVE.
SO, THIS TELLS US THAT CYCLIC
AMP IS VERY IMPORTANT TO CONTROL
DURING THE ASYMMETRIC
SELF-RENEWING DIVISION OF A
SKELETAL STEM CELL.
IN SUMMARY, BASICALLY I HAVE
TOLD YOU THAT BONE MARROW
CONTAINS MULTIPOTENT STROMAL
CELLS THAT ARE SUBSETS OF BONE
MARROW STROMAL CELL POPULATION
FORMING BONE STROMA SUPPORTING
BLOOD FORMATION AND MARROW
ADIPOCYTES CONTROLLING
OSTEOCLASTS KREN TLAL MEDIATORS
OF HOMEOSTASIS AND ARISE IN
MULTIPOTENT EPIBLASTS IN INNER
CELL MASTS AND DERIVATIVES OF
MUTANT EPIBLASTS GIVE RISE TO
TISSUES IN ALL THREE GERM LAYER
AND MUTATIONS DISRUPT FUNCTION
OF THE STEM CELL LEADING TO
ABNORMAL BONE AND ABNORMAL
SULFATE CHOICES LEADING TO
FIBROUS TISSUE AND MUTANT CELLS
DON'T SELF-RENEW AND APOP TOES
AND NORMAL CELLS BEGIN TO RESUME
NORMAL BONE FORMATION AND
QUALITIES DO CHARACTERIZE
FIBROUS DYSPLASIA AS A STEM CELL
DISEASE.
SO, AT THIS POINT, IF I WERE TO
MAKE A LIST OF ALL PEOPLE TO
ACKNOWLEDGE WE WOULD BE HERE
FOREVER. I WILL GET EMOTIONAL.
I ALWAYS DO. I WOULD LIKE TO
THANK KENNY -- HENNING BURKE ED
ALL HANSEN FOR THEY HAS PASS AD
WAY I'M GETTING EMOTIONAL AND
LARRY TABAK THAT ALSO THIS CRAZY
LADY THAT WANTED TO DO THESE
STUDIES AND HAVE THEIR SUPPORT
WAS REALLY GREAT AND ALLEN YOU
WERE ONE OF MY BIGGEST STARS
THANK YOU SO MUCH. I HAD THE
BEST COLLEAGUES EVER WITH LARRY
FISCHER MAIRIAN YOUNG MIKE, AVA
AND MY FORMER BRANCH AND
SKELETAL BIOLOGY SECTION AND
FORMER CELL FELLOWS SERR GAY AND
NATASHA AND MAH ESHGS SH HAS
PASSED AWAY UNFORTUNATELY AND
MARA AND HER GROUP AT SAPIENZA
AND PENNY WHO WE HIRED JANICE TO
WORK WITH PENNY AND GOT ONE OF
THE FIRST BENCH TO BEDSIDE
AWARDS AT NIH RESEARCH NURSES IN
INSTITUTE AND ENDOCRINE TRAINING
PROGRAM AND EVERYBODY. THANKS
SO MUCH. I APPRECIATE IT. HERE
IS TO BETTER TREATMENT AND CURE
DURING THE NEXT 25 YEARS PRAFR
YOU WILL HEAR ABOUT THAT.
>> AUDIENCE: [APPLAUSE].
>> >> LET ME THINK OF SOMETHING
FUNNY. SHE SHOWED THAT OUR
BONES CAN GET BETTER.
DR. RIM UNUCHI STUDIES BONE
MARROW -- FIBROUS DYSPLASIA AND
RECEIVED MEDICAL DEGREE AND PHD
AT SAPIENZA UNIVERSITY AS IS
BOARD CERTIFIED PATHOLOGIST AND
SPENT 2 YEARS IN CSDB WORKING IN
PAM'S LAG AT FOGARTY
INTERNATIONAL FELLOW USING A
MOUSE MODEL IDENTIFIED ANTIRANK
LIGAN ANTIBODY.
SHE HAS WORKED CLOSELY WITH
CLINICAL COLLEAGUES AT NIDCR TO
LEAD THE WAY INTO POTENTIAL
THERAPEUTICS OF LESIONS AND
TODAY WILL DESCRIBE MODELS AND
HER WORK ADVANCING OUR
UNDERSTANDING OF THE BIOLOGY OF
FIBROUS DYSPLASIA.
>> AUDIENCE: [APPLAUSE].
>> THANK YOU, JANICE. THANK YOU
TO ALL OF THE ORGANIZERS FOR
HAVING ME HERE TODAY TO TALK
ABOUT FIBRO DYSPLASIA AND MODELS
THAT HELP US TO CLARIFY IT.
ALSO, ABOUT THE QUESTIONS THAT
THESE EXPERIMENTAL MODELS ARE
NOW RAISING THAT WE HAVE TO
ADDRESS IN THE NEXT FUTURE.
BEFORE STARTING MY PRESENTATION,
I WOULD LIKE TO MENTION ONCE
AGAIN MENTOR PAULO AND HIS
CONTRIBUTION TO THE
UNDERSTANDING OF THIS DISEASE.
WHEN WE FIRST STARTED STUDIES
FIBROUS DYSPLASIA WAS COMMONLY
REFERRED TO AS A DISEASE WITH
FIBROUS OSTEOMETAMRASHIA AND
DISEASE WITH COLLAGEN FIBROUSING
TO BONE AND EXAMPLE OF
OSTEOBLASTS IN THE EXAMPLE HERE
AND THINK THAT THIS FIRM
REJECTION OF THIS VIEW AND
METAPLASTIC BONE AT LARGE IS
IMPORTANT TO SET DIRECTION OF
FOLLOWING STUDIES WE HAVE THEN
PERFORMED WITH DR. COLLINS AND
MANY COLLEAGUES HERE AT NIH AND
TO WHICH INDEED WE HAVE
UNDERSTOOD THAT AS WE HAVE JUST
HEARD THAT FIBROUS BONE
FORMATION NORMAL BONE FORMATION
IN FIBROUS DYSPLASIA MEANING
POSITION OF WOVEN BONE WITH
FIBERS HYPERMINERALIZED MATRIX
AND FEATURES OF [INDISCERNIBLE]
THAT IS [INDISCERNIBLE] MAY BE
ASCRIBED TO ABNORMAL
DIFFERENTIATION AND/OR EXPANSION
OF CELLS OSTEOGENERALICALLY
BROUGHT ABOUT BY MUTATIONS AND
IDENTIFY MOLECULAR BASIS OF THIS
FUNCTION.
ALL IN SIZE TO WHICH WE GAIN AT
THE BEGINNING OF THE NATURE OF
THIS DISEASE BY STUDYING HUMAN
SAMPLES HAVE BEEN CONFIRMED BY
MULTIPLE TRANSGENIC MOUSE MODELS
THAT HAVE BEEN DEVELOPED OVER
THE YEARS CLEARLY SHOWING THAT
FIBROUS DYSPLASIA LIKE PHENOTYPE
IS REPRODUCED WHEN THE MUTATION
IS EXPRESSED IN IN WHOLE
OSTEOGENERALICALLY BY USING
EITHER UBIQUITOUSLY OR
CONSTITTIVELY EXPRESSED
PROMOTORS SUCH AS EXOGENOUS
PROMOTORS PGK OR [INDISCERNIBLE]
BY OUR GROUP OR EARLY
[INDISCERNIBLE] SUCH AS PRX1
THAT IS USED BY ZAO AND
COLLEAGUE AND CANYON AND
COLLEAGUES AND [INDISCERNIBLE]
WHICH IS EXPRESSED BY BONE
MARROW STROMAL CELLS OR USING
[INDISCERNIBLE] THAT MARKS EARLY
OSTEOGENERAL CAL [INDISCERNIBLE]
SHOWED BY CANYON A COLLEAGUE Z *
AND COLLEAGUES. AND WHEN
EXPRESSION IS DRIVEN BY
PROMOTORS SPECIFICALLY DEFINING
BONE FORMING CELLS SUCH AS 2.3
COLLAGEN FRAGMENT OF COLLAGEN
TYPE 1 PROMOTOR MEANING MUTATION
IS RESTRICTED TO OSTEOBLASTIC
CELLS MIGHT DEVELOP DIFFERENT
HIGH BONE MASS PHENOTYPE AND ALL
TOGETHER THIS DATA AND
TRANSGENIC MODELS HAVE LED US TO
RECLASSIFY FIBROUS DISSIA --
DYSPLASIA AND CRITICAL ROLE OF
STEM CELL IN ITS BIOLOGY.
HOWEVER, AS FOR MANY OTHER
ORGANS REASON OF DEVELOPMENT AND
APPLICATION OF NEW TECHNOLOGIES
TO STUDY OF BONE AND BONE MARROW
BIOLOGY IS RAISING MANY
QUESTIONS IN FIBROUS DYSPLASIA
FOR EXAMPLE USING TECHNIQUES
SUCH AS MOUSE LINEAGE TRACING
AND WE HAVE RECENTLY LEARNED
THAT IN BOTH HUMAN AND MICE
THERE ARE MULTIPLE POPULATIONS
OF SKELETALS THEMSELVES WITH
DIFFERENT DISTRIBUTION IN TIME
AND SPACE BONE MARROW STROMA
LONG KNOWN AS GENUS COMPARTMENT
IS MORE COMPLEX THAN WE
PREVIOUSLY THOUGHT SUCH AS STEM
CELLS AND SKELETAL FIBROBLASTS
FUNCTIONAL WHICH IS STILL
UNKNOWN AND KEEPING IN MIND THAT
FIBROUS DYSPLASIA IS A MOSAIC
DISEASE AND AT THIS POINT THERE
ARE SOME IMPORTANT QUESTIONS WE
NEED TO ADDRESS. FOR EXAMPLE,
DO ALL THESE DIFFERENT CELL
POPULATIONS GENERATE FIBROUS
DYSPLASIA EXPRESSING CAUSATIVE
MUTATIONS OR WHAT IS THE ROLE OF
THESE DIFFERENT STROMAL CELL
SUBSET OTHERS THAN SKELETAL STEM
CELLS IN DEVELOPMENT OF THE
DISEASE?
THERE IS OBVIOUSLY A SUBSTANTIAL
AMOUNT OF WORK TO CLARIFY POINTS
AND SOME PRELIMINARY IN SIZE
HAVE BEEN RECENTLY PROVIDED BY
THESE TRANSGENIC MOUSE MODELS WE
GENERATED IN OUR LAB IN WHICH
THE FUNCTION OF MUTATION OF GS
ALPHA IS RESTRICTED TO A
POPULATION OF STROMAL CELLS
MARKED BY EXPRESSION OF MOUSE
AND PROMOTER AND CONNECTING
POSITIVE STROMAL CELLS HAVE BEEN
ORIGINALLY REPORTED AS
POPULATION OF VASCULAR MARROW
STROMAL CELLS ACTING AS MAJOR
SOURCE OF LYINGAND IN BONE AND
BONE MARROW MIGRAINE ENVIRONMENT
AND POPULATION OF COMMITTED
CELLS WITH NO OSTEOGENIC
ACTIVITY THAT IS REASON WHY
DEVELOPING MOUSE MOD HEELS
INTERESTED IN UNDERSTANDING
EFFECT OF MUTATION OF BONE
MARROW SITES AND HOWEVER WHEN WE
CROSSED THE LINE WITH MTMG
REPORTER LINE SO THAT IN
[INDISCERNIBLE] CONNECTING CELLS
ARE GREEN ON RED BACKGROUND WE
OBSERVED THAT FIRST THESE CELLS
COULD BE FOUND AROUND BLOOD
VESSELS AND AROUND BLOOD VESSELS
THAT RUN ACROSS -- DURING MOUSE
GROWTH CELLS CONTRIBUTE TO
[INDISCERNIBLE] BONE FORMATION
AT HEMATOPOETIC SITES SUCH AS
[INDISCERNIBLE] AND LONG BONES
WE ASSUME THEY ACT OR HAVE
MULTIPOTENT SKELETAL STEM CELLS
WHEREAS [INDISCERNIBLE] SUCH AS
DETAIL, SORRY.
OKAY. SUCH AS DETAIL THEY
GENERATE SITES THAT ARE BEHAVING
AS COMMITTED PROGENITORS AND
WHEN THE MUTATION IN SPECIFIC
CASE IS RESTRICTED TO CELL
POPULATION, MICE TRANSGENIC MICE
FIRST DEVELOP OSTEOPEENIC
PHENOTYPE WITH LOW BONE MASS
GENERALIZE [INDISCERNIBLE]
INTRACORTICAL LESIONS AND THIS
IS CONSISTENT AND IN AGREEMENT
WITH STIMULATION OF RANK LIGAND
SECRETION BY MUTATION AND
HOWEVER DURING MOUSE GROWTH AT
SIZE AT HEMATOPOETIC SITES AND
SITES THAT THESE CELLS HAVE
OSTEOGENIC ACTIVITY THIS
PHENOTYPE IS CONVERTED TO BONE
MASS PHENOTYPE AND SUSTAIN IT BY
CONNECTING POSITIVE CELLS THAT
THESE CELLS IN FEMALE MICE
PRODUCE ALSO ECTOPIC
PERIVASCULAR INTRAMODULEARY BONE
AND IMPORTANT TO NOTE IS IN BOTH
CASES THIS BONE IS NORMAL BONE
AND LARGELY [INDISCERNIBLE] AND
IS MINERALIZED AND THERE IS NO
MICRO FIBROSIS EXCEPT FOR VERY
FEW FIBROTIC FIBRO BLAST CELLS
THAT ARE AT VERY RAPID BONE
POSITION. AT THESE SITES IN
WHICH SITES ARE OSTEOGENIC
LESIONS DURING MOUSE GROWTH AS
OUR FIELD WITH EITHER NEWLY
FORMED BONE OR HEMATOPOEESIS
THAT IS ANOTHER INTERESTING
FINDING THAT IS CONSISTENT WITH
WHAT WE HAVE OBSERVED A FEW
YEARS AGO BY USING IN VITRO
MODEL EXPERIMENTAL MODEL OF THE
DISEASE OBTAINED BY TRANCE
DEUCING HUMAN BONE STEM CELLS
WITH [INDISCERNIBLE] AND WE HAVE
OBSERVED THAT MUTATION
UPREGULATES OSTEOGENIC GENES AND
GENES INVOLVED IN HEMATOPOE
EATIC FUNCTIONS AND SUGGESTS
THAT WE DO NOT FIND HEMATOPOETIC
CELLS IN LESIONS AND
[INDISCERNIBLE] ITSELF DOESN'T
APPEAR ABILITY OF PROGENITOR
CELLS TO SUPPORT HEMATOPOEESIS.
IN CONTRAST AT SITES THAT CELLS
DO NO THE HAVE OSTEOGENIC
ACTIVITY LYTIC LESIONS OF MOUSE
GROUJ ARE CONVERTED TO FIBROUS
LESIONS OR [INDISCERNIBLE] OF
FIBROUS DYSPLASIA AND WHAT IS
IMPORTANTLY INTERESTING TO NOTE
HERE IS FIBROTIC TISSUE IS
LARGELY MADE BY TOMATO POSITIVE
CELLS CONNECTING NEGATIVE CELLS
NONMUTED CELLS THAT IS IN
AGREEMENT WITH WHAT REPORTED AND
HAS BEEN PREVIOUSLY REPORTED BY
CANON COLLEAGUES AND
[INDISCERNIBLE] MOUSE MODEL THAT
THEY HAVE SHOWN THAT FIBROSIS IS
A NONCELLULAR EFFECT OF EXTREME
EXPRESSION OF [INDISCERNIBLE]
AND SO ALTHOUGH THE EXISTENCE --
THIS MAY DEPEND ON SPECIFIC
NATURE OF STEM CELL POPULATION
OR ON MICRO ENVIRONMENT WHICH
THIS POPULATION IS WORKING AND
THEY ALSO SHOW AND HAVE SHOWN
THAT STROMAL CELLS SUBSET OTHER
THAN SKELETAL STEM CELLS MAY
TRIGGER OR CONTRIBUTE TO THE
DEVELOPMENT OF THE DISEASE AND
FOR EXAMPLE THEY MAY TRIGGER
DEVELOPMENT OF DELETIONS.
AND I THINK THAT BOTH THESE
POINTS ACTUALLY LEAD TO ONE
SINGLE HYPOTHESIS THAT IS MAYBE
WHAT IS VERY CRITICAL TO FIBROUS
DYSPLASIA BIOLOGY IS A LOCAL
PERSISTENT UNBALANCED
STIMULATION OF BONE FORMATION
MEANING EXCESS STIMULATION OF
BONE [INDISCERNIBLE] COMPARED TO
BONE FORMATION THAT WE HAVE SEEN
IN DETAIL OF THESE MICE.
DUE FOR EXAMPLE TO NATURE OF
CELLS WITH DIFFERENT COMBINATION
OF CELLS.
THIS BRINGS US TO THE OTHER SIDE
OF FIBROUS DYSPLASIA BIOLOGY AND
BONE ABSORPTION AND WE KNOW
ALREADY THAT BONE ABSORPTION
PLAYS A MAJOR ROLE IN
PATHOGENESIS OF THIS DISEASE
SHOWN BY EFFECT OF RANK LIGAND
AND [INDISCERNIBLE] IN BOTH MICE
AND HUMANS.
WE KNOW THAT IN MICE TREATMENT
WITH MOUSE RANK LIGAND AND
[INDISCERNIBLE] LEADS TO
REPLACEMENT OF FIBROTIC TISSUE
WITH HYPERMINERALIZED BONE AND
PREVENTS DEVELOPMENT OF NEW
LESIONS AS SHOWN BY OUR GROUP A
FEW YEARS AING THAT HAS SHOWN
RECENTLY BY OTHER GROUPS.
WE ALSO KNOW THAT IN PATIENTS
TREATMENT WITH KNOW ASSUME AB
CAUSES REDUCTION WITH
IMPROVEMENT RECENTLY SHOWN BY
CLINICAL TRIAL GOING HERE AT
NIH.
WE ALSO KNOW THAT THERE IS A
MAJOR DRAWBACK WITH THE
TREATMENT. SO, THE TREATMENT
CAN BE AN EFFICIENT TREATMENT
FOR FIBROUS DYSPLASIA AND KNOW
THERE IS A MAJOR DRAWBACK THAT
IS SEVERE REBOUND OF THE DISEASE
AT TREATMENT DISCONTINUATION.
IT MEANS HERE THERE ARE NEW
QUESTIONS WE NEED TO ADDRESS IF
IN THE NEXT FUTURE TO NOT ONLY
BETTER UNDERSTAND BIOLOGY OF THE
DISEASE BUT ALSO TO REFINE THESE
THERAPEUTIC APPROACH.
FOR EXAMPLE, I THINK WE NEED TO
BETTER UNDERSTAND THE MECHANISMS
THAT ARE LEADING TO OSTEOBLAST
FORMATION IN FIBROUS DYSPLASIA.
FOR EXAMPLE, WE NEED TO
UNDERSTAND HOW WE CAN STIMULATE
OSTEOGENIC DIFFERENTIATION
WITHIN FIBROTIC TISSUE WITHOUT
INCREASING OSTEOBLAST FORMATION
AND SHOWING HERE THIS WORK BY
CANON COLLEAGUES THAT THEY HAVE
CROSSED [INDISCERNIBLE] WITH
MOUSE LINE WITH GENETIC
DOWNREGULATION OF WIND PATHWAY
SHOWING THAT PROGENY MICRO
FIBROSIS IS RESCUED AND
OSTEOBLAST [INDISCERNIBLE] IS
INCREASED COMPARED TO WILD TYPE
MICE AND ANOTHER QUESTION THAT I
THINK IS INTERESTING IS THAT
AREN'T THERE OTHER SOURCES OF
RANK LIGAND AND OTHER SORTS THAT
MAY CONTRIBUTE TO NORMAL
OSTEOBLASTOGENESIS AND KNOW THAT
MUTATED STROMAL CELLS ARE MAJOR
PLAYER WE AGREE ON THIS AND
CAN'T EXCLUDE CONTRIBUTION OF
OTHER CELL TYPES AND AT THIS
TIME I CAN TELL YOU IMMUNE CELLS
THAT ARE MAJOR PRODUCERS OF RANK
LIGAND IN BODY THAT WE FIND IN
SKELETON NOT INVOLVED IN THE
PROCESS. WITH WE CROSSED OUR FD
MICE WITH KID MICE TO EXPRESS
MUTATION ON IMMUNOCOMPROMISED
BACKGROUND WE HAVE SEEN
DEVELOPMENT OF NOT TYPICAL FDA
PHENOTYPE AND CAN'T EXCLUDE
CONTRIBUTION OF OTHER CELL TYPES
FOR EXAMPLE VASCULAR ENDOTHELIAL
CELLS AND BLOOD CELLS BASED ON
FREQUENT OBSERVATION OF ATOPIC
-- THIS IS VERY RARE FIND. I
THINK THAT FIBROUS DYSPLASIA IS
PROBABLY UNIQUE DISEASE IN WHICH
WE CAN FIENTD OSTEOBLAST
FORMATION WITHIN BLOOD VESSELS
AND NEITHER CAN WE EXCLUDE A
CELL AUTONOMOUS EFFECT OF
FORMATION AND SHOWING THIS
SECTION APPROACHING WHICH WE
COLLECTED MANY OSTEOBLASTS FROM
SAME PATIENTS BY THIS SECTION
AND WE HAVE OBSERVED THAT
OSTEOBLASTS IN HUMAN FIBROUS
DYSPLASIA MUTATED ALLELE AND
WOULD LIKE YOU TO NOTE THAT THIS
PATIENT IN WHICH WE HAVE FOUND
MUTATED SEQUENCE IN OSTEOBLASTS
AND NOT IN THE SURROUNDING
FIBROTIC TISSUE NEITHER IN BONE
THAT IS KWON FIRMING VALIDITY OF
OUR APPROACH.
SO, AGAIN, THIS IS SOMETHING
THAT WE NEED TO FURTHER EXPLORE
IN THE FUTURE.
I THINK THAT THE MOST
INTERESTING QUESTION AT THIS
TIME RELAETDED TO OSTEOBLASTS
AND OSTEOBLAST INHIBITION IN
FIBROUS DYSPLASIA IS HOW -- WHAT
IS MECHANISM THROUGH INHIBITION
OF RANK LIGAND AND OSTEOBLASTS
LEADS TO BONE FORMATION MEANING
LEADS TO REPLACEMENT OF FIBROUS
TISSUE WITH MINERALIZED BONE IN
MICE AND LEADING TO BONE
IMPROVEMENT IN HUMANS AND SO
DOES IT STIMULATE OSTEOGENIC
DIFFERENTIATION OF FIBROTIC
TISSUE OR OTHER MECHANISMS WE
HAVE TO CLARIFY?
SO, IN AN ATTEMPT TO START TO
CLARIFY THIS POINT, WE RECENTLY
HAVE PERFORMED THESE TYPES OF
EXPERIMENTS WE TREATED OUR FD
MICE WITH FOUR DOSES OF
[INDISCERNIBLE] AND TWO DOSES OF
CALCIUM AND WE HAVE IN 17 DAYS
AND COMPARED TREATED MICE WITH
UNTREATED FD MICE AND WILD TYPE
MICE USING NANOSTREAM
[INDISCERNIBLE] ALLOWING
MOLECULAR ANALYSIS ON CALCIFIED
AND TISSUES THAT WE HAVE BEEN
ABLE TO COMPARE MOLECULAR AND
HISTLOGICAL CHANGES ON SAME
SAMPLES AND ON THE SAME SAMPLES
AND MOLECULAR CHANGES WE USED A
PANEL OF SELECTED GENES AND
GENES INVOLVING
OSTEOBLASTOGENESIS AND
[INDISCERNIBLE] BIOLOGY AT LARGE
LAND SHOW YOU MOST SIGNIFICANT
RESULTS.
WE OBSERVED DOWNREGULATION OF
MOST GENES.
THIS IS NOT BREATHTAKING RESULTS
OR EXPECTED RESULTS.
STILL, I THINK THAT THERE ARE
SOME POINTS THAT ARE
CONSIDERATION FOR EXAMPLE WE
HAVE SEEN THAT CSF1 CYTOKINE
THAT IS INVOLVED IN EARLY STAGES
OF OSTEOBLASTS PROLIFERATION AND
DIFFERENTIATION THAT IS
UPREGULATED IN FD LESIONS
COMPARED TO NORMAL BONE IS NOT
EFFECTED BY TREATMENT. IN THIS
SUGGESTS THAT DURING ANTI-RANK
LIGAND TREATMENT WE DON'T SEE
DIFFERENTIATED OSTEOBLASTS OR
OSTEOBLASTS OR [INDISCERNIBLE]
PROGENITORS STILL FORM AND
ACCUMULATE MAYBE GETTING READY
FOR REBOUND EFFECT AT END OF THE
TREATMENT.
OBVIOUSLY, REDUCTION OF DOWN
REGULATION OF THIS MARKER
ASSOCIATES WITH REDUCTION IN
NUMBER OF OSTEOBLASTS AND
CON10SATION OF COLLAGEN FIBERS
AND SURPRISING, HOWEVER, WE HAVE
OBSERVED ALSO THAT TREATMENT
CAUSES A GENERAL REDUCTION IN
THE OSTEOGENIC ACTIVITY OF
TREATED FD LESIONS AND SHOWN BY
DOWNREGULATION OF OSTEOGENIC
GENES ALL OSTEOGENIC GENES BY
PATTERN OF EXPRESSION OF THE
CRITICAL OSTEOGENIC MARKERS THAT
IS ABSOLUTELY SIMILAR IN TREATED
COMPARED TO TREATED MICE THAT IS
ALWAYS RESTRICTED IN MICE TO
BONE SURFACE AND AS SHOWN BY
CALCIUM LABELING SHOWING CLEAR
REDUCTION IN NUMBER OF BONE
METRICS POSITION SIZE IN TREATED
MICE COMPARED TO UNTREATED MICE
AND, AGAIN, THESE SIDES OF BONE
METRIC DEPOSITION ARE OBSERVED
CLOSE TO BONE SURFACE IN MICE AT
LEAST. TO CONCLUDE, I THINK
THESE SUGGEST A VERY SIMPLE
MECHANISM THROUGH WHICH DURING
BASED ON WHICH DURING INHIBITION
OF BONE ABSORPTION AND BONE
REMODELING, OSTEOBLASTIC CELLS,
CELLS ARE MORE DIFFERENTIATED
ALONG BONE SURFACE MAY SIMPLY
CONTINUE TO PRODUCE BONE TO
REVEAL ABSORPTION AND MAYBE THEY
CONTINUE TO PRODUCE BONE ON
SCAFFOLD PROVIDED BY COLLAGEN
FIBERS IN FIBROTIC TISSUE. IF
THIS IS CORRECT, OBVIOUSLY, THIS
IS PRELIMINARY DATA ON MICE. IF
THIS IS CORRECT, THIS SUGGESTS
THAT MAYBE WE REALLY DON'T NEED
TO STIMULATE THE OSTEOGENIC
ACTIVITY OF FD CELLS BUT WE NEED
SIMPLY TO GIVE THEM TIME TO DO
BONE AND DO WHAT THEY KNOW HOW
TO DO.
I THINK THAT MAYBE THIS WAS MY
LAST SLIDE. I THANK YOU VERY
MUCH FOR YOUR ATTENTION.
>> AUDIENCE: [APPLAUSE].
>> THANK YOU, MARA. OUR NEXT
SPEAKER NEEDS NO INTRODUCTION.
HE IS PRACTICALLY SYNONYMOUS
WITH FIBROUS -- IS
ENDOCRINOLOGIST AND SENIOR
INVESTIGATOR OF CHIEF OF
SKELETAL DISEASES AND MINERAL
HOMEOSTASIS SECTION AT NIDCR AND
RECEIVES MEDICAL DEGREE AND
COMPLETED ENDOCRINOLOGY
FELLOWSHIP AT NIH AND DR.
COLLINS STARTED WITH DR. PENNIES
AND PAM TO TAKE A DEEP DIVE INTO
FIBROUS DYSPLASIA MCCUNE
ALBRIGHT SYNDROME AND
PROTOENROLLED 300 PATIENT AND
PATIENT ADVOCACY IS LEGENDARY.
HE WILL DESCRIBE PARADIGM OF
RARE DISEASE INFORMING BONE
BIOLOGY AND BONE TREATMENT.
THANK YOU, MIKE.
>> THANK YOU JANICE FOR THAT
NICE INTRODUCTION.
SO, THIS IS THE TITLE OF MY
TALK.
THIS IS FIBROUS DYSPLASIA. WE
HAVE BEEN HEARING ABOUT THIS.
THIS IS WHAT PATIENTS LOOK LIKE.
IT CAN EFFECT ANY PART OF THE
SKELETON CRANIAL AXIAL
APPENDICULAR SKELETON AND HAS
MANY CONSEQUENCES YOU CAN SEE
HERE SURGERIES SCOLIOSIS
DEFORMITY FRACTURES AND PAIN AND
PROETEE OE AN DISEASE WITH MANY
COMPLICATIONS THAT OFTEN RUNS
TOGETHER WITH EXTRA SKELETAL
MANIFESTATIONS WHEN YOU HAVE
EXTRA SKELETAL MANIFESTATIONS WE
CALL THIS MCCUNE ALBRIGHT
SYNDROME ANY COMBINATION YOU CAN
HAVE ONE ORE 2 OR MANY.
IT IS AN INCREDIBLY COMPLICATED
DISORDER. YOU CAN HAVE GROWTH
HORMONE ACCESS OSTEOMALACIA AND
NUMBER OF NEOPLASMS AND IS TRULY
I THINK ONE OF THE MOST
COMPLICATED MEDICAL DISORDERS
THERE IS. AS I SAW EARLIER PART
OF THE COMPLICATEDNESS OF THE
DISORDER IS DUE TO SOMATIC
EXPRESSION OF MUTATED VARIANT OF
G ALPHA S THAT IS UBIQUITOUSLY
EXPRESSED PROTEIN TO
THEORETICALLY INVOLVE TISSUE.
IT CAN THEORETICALLY INVOLVE ANY
TISSUE. THIS IS FURTHER
COMPLICATED AND DEPENDING ON
TISSUE IF MELANO -- THERE IS
LIGAND INDEPENDENT ACTIVATION
MELANIN IS PRODUCED OVARIES AND
ESTROE DIAL -- RESPONSIBLE FOR
RETRIEVING SPECIMENS AND DOING
WORK TO FIND THE VARIANT.
THIS IS FURTHER COMPLICATED
THOUGH AS WE GET INVOLVED WITH
TREATMENT AND TRYING TO FIGURE
THIS OUT. THERE IS 10
ADENOCYCLASES EXPRESSED IN BONE
AND PHOSPHO DIESTERACES IN
PATHWAY THAT ARE ALSO INVOLVED
IN THIS PHENOTYPE AND
POTENTIALLY THERAPEUTIC TARGET
AS WELL.
INCREDIBLY COMPLICATED DISEASE.
SO, AS THIS IS SHOWN GRAPHICALLY
IN DIFFERENT WAY WHAT PAM
DESCRIBED EARLIER WAY THIS
HAPPENS AND DATA THAT SUPPORTS
THIS SO FAR IS STEM CELL
SOMEWHERE EARLIER IN DEVELOPMENT
DEVELOPS THIS BY CHANCE VARIANT
IN GNAS THIS DISEASE-CAUSING
VARIANT DURING GASTROLATION AND
VARIANT SPREADS OUT TO INVOLVE
GERM LAYERS PROPAGATED OUT
THROUGH EMBREEO GENESIS.
WE THINK THAT THE MAP OF ECTED
DISEASE IS ESTABLISHED IN UTERO.
DEPENDING TEMPORALLY WHEN
MUTATION OCCURS AND ANATOMICALLY
WHERE MUTATION OCCURS WILL
DEFINE FINAL PHENOTYPE THAT WE
SEE IN THE PATIENTS.
THIS IS MY ORIGIN STORY HOW THE
STUDIES STARTED. I WAS A FELLOW
IN INTERINENDOCRINE TRAINING
PROGRAM THAT IS MAJOR SUPPORT OF
THIS DISORDER FROM VERY
BEGINNING. 1997 FIRST YEAR
DURING FELLOWSHIP WORKED WITH
ALLEN SPIEGEL AND STEVE MARKS I
WAS HAPPY ABOUT IT AND FIRED UP
ABOUT NOTION OF TRANSLATIONAL
RESEARCH THAT IS A NEW CONCEPT
AT THE TIME. I WENT TO ALLEN
FOR A CAREER TALK. I SAID,
ALLEN, I'M INTERESTED IN STAYING
AT NIH TO DO TRANSLATIONAL
RESEARCH. ALLEN AND HIS
[INDISCERNIBLE] STRAIGHT FORWARD
AND MUCH APPRECIATED WAY SAID
WELL THAT IS FINE MIKE THERE IS
NO PLACE RIGHT NOW FOR YOU IN
NIDDK. YOU COULD ALWAYS GET A
STRAIGHT ANSWER FROM ALLEN AND
STILL CAN. I WAS UNDAUNTED AND
INTERESTED IN BONE MARROW
HOMOOSTASIS AND WENT TO BEST LAB
ON CAMPUS WHERE THEY DID THAT
PAM ROBEY CELL BIOLOGIST I
TALKED TO PAM AND I'M REALLY
INTERESTED IN BONE AND SHE DREW
A CARTOON I HAVE TO THIS DAY
STILL HAVE ON WALL IN MY OFFICE
AND NO THE THAT MUCH HAS REALLY
CHANGED ABOUT IT.
ANYWAY, SO, AS YOU CAN SEE SHE
HIGHLIGHTED GS ALPHA HERE THAT
WAS INVOLVED IN THIS AT THAT
TIME WE ARE WORKING ON CLINICAL
STUDY IN FIBROUS DYSPLASIA YOU
ARE A DOCTOR WANT TO HELP? I
WAS HESITANT AT FIRST. I WILL
TELL YOU WHY. ANYWAY, WAY I
REMEMBER SHE CREATE THE FIRST
DRAFT OF PROTOCOL AND IN CHILD
HEALTH WE WERE STUDYING AND
TREATED PRECOCIOUS PUBERTY OF
PATIENTS LARGELY IGNORING
FIBROUS DYSPLASIA AND CLEAR TO
ME IN MOST PATIENTS THIS WAS
BIGGEST PROBLEM. I LOOKED UP
NOT MUCH ON FIBROUS DYSPLASIA
COMPLICATED DISEASE AND THINKING
NOT SURE, PAM. SHOWING FIRST
DRAFT OF PROTOCOL. FD IS A
DIFFICULT DISEASE. CAN I SEE
PROTOCOL?
I LOOKED AT IT. 20 PAGES OF
BACKGROUND THAT WAS ELOQUENT BUT
NOTHING WHAT WOULD WE MEASURE
HOW WOULD WE DO THAT HUGE
PROTOCOL TURNED INTO THREE
PROTOCOLS THAT PAM DESCRIBED
EARLIER AND SETTLED ON THIS
STUDY THAT IS BACKBONE WHAT WE
DID IN ANALYSIS AND CONTINUES TO
GENERATE MASSIVE AMOUNT OF DATA
DEFINING NATURAL HISTORY OF
SPECTRUM AND EFFECTIVE
TREATMENTS OF THIS DISORDER AND
DON'T THINK THERE IS ANY PLACE
IN WORLD YOU COULD DO A STUDY
LIKE THIS ESPECIALLY AS LONG AS
WE HAVE DONE IT AT NIH AND FOR
THAT WE SUPPORT LEADERSHIP AND
INSTITUTES THAT HAVE BEEN
PARTNERS ENDOCRINE TRAINING
PROGRAM THAT ENABLED A
TREMENDOUS AMOUNT OF RESEARCH TO
BE DONE. COHORT STUDY
PROSPECTIVE STANDARDIZED
COLLECTION OF DATA AND SPECIMENS
THAT WE PERFORM RETROSPECTIVE
ANALYSIS AND ARE NICELY ABLE TO
DEFINE SPECTRUM NATURAL HISTORY
OF DISORDER THAT IS CRITICAL FOR
DEVELOPMENT OF THERAPIES FOR
THESE PATIENTS HAS BEEN
INCREDIBLY SUCCESSFUL. HAVE
SEEN OVER 300 SUBJECTS AND PAM
SAID FROM ONE-TO-ONE 02 AND 25
YEARS OF FOLLOW UP AND 150
PUBLICATIONS ON IT AND 6
INTERVENTIONAL TRIALS.
SO, I WANTED TO TALK ABOUT THREE
AREAS OF THIS EARLY WORK THAT I
THINK ARE PARTICULARLY
IMPORTANT.
THIS IS WORK DONE BY ELIZABETH
HEART THAT IS A MEDICAL STUDENT
AT THE TIME AND ELIZABETH IS A
BRANCH CHIEF AT FDA OVERSEES
STUDIES OF RARE DISORDERS AND
CAN'T HELP BUT THINK SHE GOT
TURNED ON TO IT DOING THIS WORK
AND ONE THING ABOUT THE STUDY
LIKE THIS YOU BEGIN TO SEE
PATTERNS YOU THINK YOU NEED THEM
AND IF PATTERNS EXIST GOING BACK
QUERYING DATA AND WHAT WE DID
AND SEEMED TO US PATIENTS IF
THEY DEVELOP NEW LESIONS IT WAS
QUITE EARLY IN THEIR LIFE AND
RELATIVELY EARLY AGE THAT ALL
DISEASE THAT THEY WILL GET WAS
ESTABLISHED AND IS IMPORTANT FOR
PATIENTS ESPECIALLY. THEY CAN
KNOW THESE PARENTS THAT SUFFER
SO MUCH WITH CHILDREN IN THE
BEGINNING THAT THIS WON'T
CONTINUE ENTIRE LIFE AND WILL
SLOW DOWN AT SOME POINT IN TIME.
WE FOUND REALLY QUITE SURPRISING
AND BEFORE AGE OF 5 AND 90% OF
CRANIO FASHIAL LESIONS ARE
PRESENT AND APPENDICULAR LESIONS
AND AXIAL LESIONS ARE PRESENT AS
WELL. THIS CONFIRMED THIS DATA
AND HYPOTHESIS THAT THIS
IDENTIFIED THE PERIOD OF
ACQUISITION VERY EARLY AND IS
CRITICAL DEVELOP AGO I DRUG AND
TREATMENT FOR THIS YOU THINK YOU
WILL PREVENT LESIONS. IF YOU
TREAT HERE NO WAY ALREADY OVER
YOU HAVE TO START HERE EARLY.
ALLISON WILL TALK ABOUT THAT
LATER.
NEXT, I THINK IT WAS A VERY
IMPORTANT FINDING THAT IS ONE
THING THAT WE LEARNED EARLY ON
THAT THINGS NOT TO DO BY
OBSERVING PATIENTS.
SO, WHEN WE FIRST STARTED, ONE
COMMON PROCEDURES PERFORMED WITH
PATIENTS WITH FIBROUS DYSPLASIA
IS CURE ATAUJ AND GRAFTING AND
DIGS OUT FIBROUS DYSPLASIA
PUTTING BONE COMMENT AND TISSUE
REPLACEMENTS IN BONE COMMENT OR
WHATE
WHATEVER.
PASH YERPTS COULD COME TO US
HAVING HAD THESE PROCEDURES OVER
AND OVER. WE LOOKED AT 23
PATIENTS AND 20 YEARS OF FOLLOW
UP AND 52 GRAFTS. NO MATTER
WHAT GRAFT WAS IT WAS READILY
AND RAPIDLY REABSORBED IN YOUNG
PATIENTS. THIS WAS A FUTILE
PROCEDURE AND SOMETHING THAT
SHOULD BE AVOIDED IN PATIENTS
ABLE TO SHOW WITH THIS CURETTAGE
GRAFTING AND LIMITED VALUE IN
FIBROUS DYSPLASIA. I WANTED TO
GO TO NEXT ANOTHER ISSUE THAT
ALLISON AND ENCOUNTERED
FREQUENTLY AND ONCE A WEEK OR
MORE OFTEN GET INQUIRIES FROM
AROUND COUNTRY AND WORLD HOW WE
TAKE CARE OF THESE PATIENTS
COMPLICATED PATIENTS YOU WOULD
IMAGINE AND PUT TOGETHER A LIST
OF THINGS SEND OUT OVER AND OVER
AND OVER AGAIN AND WRITE A PAPER
ABOUT THIS. THIS IS WHAT WE
DID. WHAT THIS REPRESENTED WAS
TREATMENT ALGORITHMS FOR FIBROUS
DYSPLASIA THAT IS EVIDENCE-BASED
AND EXPERT OPINION AND DEVELOPED
SIMPLE USER FRIENDLY ALGORITHMS
THAT WAS INITIALLY DISTILLATION
OF 57 PUBLICATIONS ON THIS
EXPANDED IN 2019 TO 85
PUBLICATIONS AND PUBLISHING IN
2015 AND 2019 AND USEFUL TOOL
FOR CLINICIANS AND ADVOCACY
GROUPS LEARN TODAY GIVE THIS
PUBLICATION TO THEIR PATIENTS.
GENE REVIEWS AS OPEN ACCESS TO
TAKE PUBLICATIONS AND ALGORITHMS
TO CLINICIANS THAT HAS BEEN MOST
HELPFUL ASPECT OF DISSEMINATING
INFORMATION AND DEVELOPING
TREATMENTS FOR PATIENTS.
OKAY.
ONE OF THE BIG THINGS THAT
ESPECIALLY TO ME AS AN
ENDOCRINOLOGIST THAT WAS
INTERESTING ABOUT THIS DISORDER
IS PHENOMENON OF LOW BLOOD
PHOSPHATE IN FIBROUS DISMRASHIO
HYPOPHOSPHO TEEMIA IT IS
CRITICAL TO MINERALIZE BONE AND
SAW HISTLOGIC SECTIONS OF
UNMINERALIZED -- LEADING TO
SCOLIOSIS AND OTHER PROBLEMS AS
WELL AND STARTED OUR ASSUMPTION
WAS THIS WAS DUE TO MUTANT
VARIANT IN THE KIDNEY AND MADE
SENSE. PARATHYROID HORMONE
THROUGH GS ALPHA LEADS TO CYCLIC
AMP IN URINE AND IF THIS IS CASE
RENAL TUBE YOU'LL MUTANT GS
ALPHA ONE SHOULD SEE INCREASED
PHOSPHATE AND [INDISCERNIBLE]
AND THERE WAS NEWLY DISCOVERED
HORMONE FGF23 THAT WAS CAPABLE
OF STIMULATING ELEVATED
PHOSPHATE IN URINE AND IN CASE
OF FG23 CYCLIC AMP IS NORMAL AND
ANOTHER DIFFERENCE BETWEEN TWO
HYPOTHESIS IS APPROXIMATE MA'AM
TUBE YOU'LL CELLS EXPRESSED 1
ALPHA HYDROXYLACE THAT ACTIVATED
VITAMIN 125D AND IF MUTANT GSA
MEDIATED WE WOULD SEE INVERSE
RELATIONSHIP AND IF IT WERE FG23
MEDIATED EXPECTED TO SEE
POSITIVE CORRELATION BETWEEN THE
TWO. NOW HAVING LARGE BODY
RETROSPECTIVE DATA TO GO BACK TO
WE HAD BEEN PRESSING ENOUGH TO
COLLECT APPROPRIATE INFORMATION
IN STUDY IN BEGINNING AND LOOKED
BACK AND QUERIED RETROSPECTIVE
DATA AND WHAT WE SAW WAS CLEAR
AND PATIENT SEEN WITH
HYPERPARATHYROIDISM AND SURE
ENOUGH AS EXPECTED THEY ELEVATED
NEF ROTH NOWS CYCLIC AMP AND IT
WAS NORMAL AND FURTHER MORE
CORRELATION BETWEEN 125D AND
PHOSPHORUS WAS CONSISTENT FDF23
RATHER THAN MUTANT GS IN KIDNEY
AND BONE TURNOVER SKELETAL
DISEASE BURDEN CORRELATED
PHOSPHATE LO S THAT POINTED TO
FD BONE AS POTENTIALLY SOURCE OF
FGF23 AND LED TO MOST IMPORTANT
STUDY THAT WE HAVE BEEN ABLE TO
DO IN THIS CONDITION.
THAT IS SHOWN HERE.
THAT IS WHERE WE WERE ABLE TO
SHOW THAT DEGREE OF ELEVATION OF
FDF23 CORRELATED WITH AMOUNT OF
FIBROUS DYSPLASIA AND IN SITU
HYBRIDIZATION THAT FGF23 WAS
EXPRESSED HIGHLY IN WOVEN BONE
DYSPLASIA AND WE WERE
IMPORTANTLY ABLE TO SHOW THAT
FGF23 WAS PRESENT IN NORMAL BONE
AND THIS REALLY IDENTIFIED
NORMAL BONE AS SOURCE OF FGF23
AND IS A MAJOR FINDING IN THE
FIELD AND ONE OF THE REASONS AS
YOU POINTED OUT ALLEN THAT WE
STUDY RARE DISEASES BECAUSE THEY
FORM COMMON BIOLOGY.
THIS REALLY LEAD TO AND OPENED
DOOR TO LIST OF DISORDERS WE
STUDIED AND FIBROUS DISMRASHIO
TUMOR INDUCED OSTEOMALACIA AND
HYPOPARATHYROIDISM -- PHYSIOLOGY
OF MINERAL HOMEOSTASIS AND LOOK
AT DISORDER OF FGF23 DEFICIENCY
AND THESE DISORDERS ALLOW US
WINDOWS INTO UNDERSTANDING
BIOLOGY AND PHYSIOLOGY OF
PATIENTS.
I'M COMING DOWN TO A CLOSE HERE.
THERE IS ONE MORE CONDITION THAT
I WANT TO FOCUS ON A LITTLE BIT
THAT IS CUTANEOUS SKELETAL
HYPOPHOSFATEMIA SYNDROME. IT IS
INTERESTING. IT REMINDED ME OF
A PATIENT WE SAW THAT WAS
SIMILAR TO WHAT WE DID THIS WEEK
WITH PATIENTS WITH PATIENT
COMMITTEE AND AT FD/MAS
COMMITTEE MEETING IN 2013 I
ENCOUNTERED THIS MOTHER HERE
CAME TO THE MEETING WITH BIG
BINDER FULL OF RECORDS AND J
X-RAYS AND THEY WERE REFERRED TO
AS BINDER MOMS MOST OF TIMES IT
WAS MOMS AND THEY BROUGHT
COMPUTERS TO THE MEETING
YESTERDAY.
HER SON HAD A SKIN LESION LIKE
THIS.
PIGMENTED MAC YULE FOR SURE AND
MOSAIC DISTRIBUTION OF SKELETAL
DISEASE RIGHT HAND EFFECTED LEFT
NOT LEFT ILLI AT CREST WAS
EFFECTED BUT NOT RIGHT. SHE WAS
A REMARKABLE WOMAN AS HIS PARENT
AND AS MANY OF THESE. SHE SAID
HIS DOCTOR TOLD ME THIS WAS
FIBROUS DYSPLASIA MCCUNE
ALBRIGHT SYNDROME I DON'T THINK
IT IS I SAID I THINK YOU ARE
RIGHT I DON'T KNOW WHAT IT IS
BUT BET WE CAN FIGURE IT OUT.
THIS IS AN INCREDIBLE THING WE
CAN DO HERE. WHEN PATIENTS COME
TO US AT NIH AND DON'T KNOW WHAT
THEY HAVE WE CAN HAVE LEVEL OF
CONFIDENCE WE WILL BE ABLE TO
FIGURE IT OUT. WE WERE ABLE TO
SURE ENOUGH. SHORTLY AFTER THAT
SAW A COUPLE PASHGENTS ONE HAD
BEEN SEEN BY KEITH AT YALE
UNIVERSITY AND TOGETHER WE PUT
TOGETHER A COLLECTION OF FIVE
PATIENTS ALL OF THE PATIENTS WE
FOUND SOMATIC VARIANCE IN DTPACE
HRAS AND CALLED IT CUTANEOUS
SKELETAL HYPOPHOSPHATEMIA
SYNDROME.
ANOTHER IMPORTANT FEATURE THOUGH
ASPECTS WERE IN [INDISCERNIBLE]
AND GOT INTO LITERATURE WAY TO
TREAT THIS DOING LARGE EXCISIONS
OF SKIN LESIONS AND THOUGHT THAT
IT WAS COMING FROM BONE, FGF23.
NEVERTHELESS PATIENTS GOING
THROUGH LARGE PAINFUL EXCISIONS
OF LESIONS TO NO AVAIL. WE
DEVELOPED A MOUSE MODEL THAT WAS
DONE INITIALLY STARTED BY
[INDISCERNIBLE] WHO WAS A FELLOW
WHO CAME HERE FROM SPAIN TO WORK
WITH US.
DEANNA HAD NEVER TOUCHED A
PIPETTE WHEN SHE GOT HERE AND
GOT INITIAL STEPS TO DEVELOP
MOUSE MODEL THAT LUIZ HAS TAKEN
FORWARD AND DONE WORKING WITH IN
DOING INTERESTING WORK WITH THAT
YOU WILL SEE AS WELL. ANYWAY,
WHAT IS INTERESTING IS THIS IS
THE EXACT SAME MODEL WE USE FOR
FIBROUS DYSPLASIA A MODEL THAT
MARA TALKED ABOUT AND PUT IN PRX
MOUSE AND PUT IN ALPHA GS
MUTATION WE GET PROLIFERATION OF
SKELETAL CELLS IN END OSTE OM IN
THE MARROW AND USING THIS
MUTATION SAME MODEL GET THIS
PROLIFERATION THAT RISES FROM
PERIOSTEUM AND IN TACT FGF23
LEVELS ARE HIGH IN THIS ANIMAL
AND THESE MICE HAVE
HYPOPHOSFATEMIA AND SURE ENOUGH
IN THE MICE WE SEE LARGE LESIONS
ARISING FROM PERIOSTEUM AND
QUESTION SEE FGF23 EXPRESSION IN
NORMAL BONE AND WHAT LUIS
OBSERVED THAT IS A CRITICAL
OBSERVATION FIRST OF ALL WHEN
YOU PUT AN RAS MUTATION YOU GET
PERIOSTAL DISEASE AND WHAT HE
OBSERVED ALSO IS THIS. VERY,
VERY ROUTINELY FGF23 EXPRESSING
CELLS IN MICE REALLY ARE CLOSE
TO THE PERIOSTEAL SURFACE NOT
INDEOSTAL SURFACE AND LEAD TO
WORKING HYPOTHESIS THAT IT
APPEARS TO BE CONFINED TO WILD
TYPE ANIMALS AND THAT IS POINT
THAT MARA MADE EARLIER ABOUT
DIFFERENT TYPES OF SKIN CELLS WE
HAVE BEEN DISAPPOINTED THAT
MOUSE MODEL OF FIBROUS DYSPLASIA
HAVE NOT HELPED WITH FGF23 AND
DIDN'T FIGURE IT OUT SO WELL AND
THINK IT WILL HELP US FIGURE
SOME OF THIS OUT.
IN FACT, I WANT TO MAKE THIS
OBSERVATION IN THE 2023 PAPER
SHOWING LOTS OF FGF23 EXPRESSION
IN NORMAL BONE THIS IS -- IN
RETROSPECT IT TIES THIS TOGETHER
AND IS VERY INTERESTING.
SO, I WILL CLOSE NOW. THERE IS
A MILLION PEOPLE TO THANK. I
HOPE I AM ABLE TO KEEP IT
TOGETHER BETTER THAN PAM DID.
THERE IS A TON OF PEOPLE AND
LOTS OF PEOPLE WHO ARE VERY
CRITICAL AND MY MENTORS OF
COURSE PAM AND STEVE AND MARK
AND LEE WEINSTEIN INCREDIBLY
HELPFUL AND MY CURRENT GROUP
RACHEL GAV ANY WHO I HAVE WORKED
WITH WHOLE TIME I HAVE BEEN HERE
WE WERE FELLOWS TOGETHER AND
GREAT FELLOWS DEANNA AND I WANT
TO THANK INTERINSTITUTE
ENDOCRINE TRAINING PROGRAM
INCREDIBLE SUPPORTERS OF OUR
WORK THE WHOLE TIME.
UNFORTUNATELY NICHD PEDIATRIC
ENDOCRINE TRAINING PROGRAM THAT
RAINED RACHEL AND
[INDISCERNIBLE] IS NO LONGER
HERE AND LOSS INSTITUTE AND HOPE
IT COMES BACK AND PROVIDED
INCREDIBLE NUMBER OF VERY
TALENTED MEDICAL STUDENTS THAT
HAVE GONE ON TO INVESTIGATORS AS
WELL AND PEOPLE FROM OUTSIDE
THAT I HAVE WORKED WITH AND NOW
FOR A BIG SLIDE THAT IN 2024
AFTER 25 YEARS, I WILL BE
LEAVING NIH FOR HORIZONS YET TO
BE DETERMINED. THAT IS IT.
>> AUDIENCE: [APPLAUSE].
>> >> THANK YOU, MIKE.
BEFORE WE GO ON BREAK, I WANT TO
SPEND A LITTLE TIME THANKING THE
ORGANIZING COMMITTEE AND MIKE,
ALLISON AND PAM HAVE PLAYED A
HUGE ROLE GETTING THIS TOGETHER
AND PULLING TOGETHER A WONDERFUL
LINEUP OF AMAZING SPEAKERS AND
PEOPLE THAT HAVE MADE A
DIFFERENCE IN THIS DISEASE AND
THANKING MY STAFF IN OFFICE OF
CLINICAL DIRECTOR FOR ALL THEIR
BEHIND THE SCENES WORK AND STAFF
OF DR. DESOOUZA WHO ALSO HELPED
AND COMMUNICATIONS TEAM THAT
PLAYED A BIG ROLE MAKING SURE
INFORMATION WAS OUT THERE AND
WILL INVITE EVERYONE TO THE
COFFEE BREAK. I WOULD LIKE TO
ASK THE PATIENTS AND PATIENT
ADVOCACY GROUPS TO COME FORWARD
SOON AS YOU HAVE HAD COFFEE AND
COOKIES TO COME FORWARD. WE
WILL START THE NEXT SESSION IN
10 OR 15 MINUTES.
I WOULD LIKE TO START THE FINAL
HALF AND FIRST SPEAKER IS
ALLISON BOYCE HAVING TRAINED AND
COMPLETED PEDIATRIC --
PRESTIGIOUS AND COMPETITIVE
TENURE TRACK AWARD FOR
EXCEPTIONAL CLINICAL
INVESTIGATORS SHE RECEIVED IN
2020.
SHE TOOK THE LEAD ON THE FD/MAS
STUDY AT NIH IN 2016 AND
INTERNATIONAL REPUTATION IS WELL
BISHED AND WILL SHARE CURRENT
STATUS OF PROGRAM AND NEXT PHASE
OF THE JOURNEY INCLUDING FOCUS
ON TREATMENT AND HOPEFULLY SOME
DAY A CURE. THANKS.
>> THANK YOU VERY MUCH DR. LEE
FOR THAT INTRODUCTION. IT IS AN
HONOR AND PRIVILEGE TO BE HERE I
JOINED THE INTRAMURAL PROGRAM 13
YEARS AGO TO WORK IN MIKE
COLLIN'S LAB AND COULDN'T HAVE
ASKED FOR A BETTER ENVIRONMENT
TO GROW AND DEVELOP AS A
SCIENTIST. INTRA MURAL PROGRAM
HAS BEEN SUPPORTIVE AND RIGOROUS
AND MY PLEASURE TO SHARE WORK
THAT HAS BEEN ONGOING IN FD/MAS
AND SHOW YOU HOW WE WILL TAKE IT
INTO THE FUTURE.
SO, AS DR. COLLINS SHARES
NATURAL HISTORY STUDY WAS
FOUNDED IN 1998 AND SINCE THEN
SERVED AS BACKBONE OF RESEARCH
OVER PAST 25 YEARS CAPITALIZING
ON UNIQUE RESOURCES OF NIH
CLINICAL CENTER THIS RECRUITED A
COHORT OF PATIENTS UNPARALLEL
INNED IN THE FIELD RESEARCH IN
FIELD HAS BEEN PRODUCTIVE
GREATER THAN 50 PUBLICATIONS
GENERATED AND 6 CLINICAL TRIALS
AND TOGETHER HAS FORMED BULK OF
DEFINITIVE CLINICAL LITERATURE
IN FD/MAS.
I WANTED TO SHARE AN EXAMPLE HOW
RESEARCH ON NATURAL HISTORY
STUDY HAS TRANSFORMED CARE FOR
PASH YERPTS OPTIC CANAL IS A
BEAU ENE STRUCTURE LOCATED AT
BACK OF ORITY SERVING THROUGH
TUNNEL OPTIC NERVE CHANNELS
CONNECTING EYE AND BRAIN IF THIS
IS SQUEEZED OR STRETCHED IT CAN
DAMAGE THE NERVE AND CAUSE
BLINDNESS AND AT TIME THAT
NATURAL HISTORY STUDY STARTED
STANDARD OF CARE WAS TO PERFORM
A SURGERY CALLED OPTIC CANAL
DECOMPRESSION TO WIDEN CANAL AND
PREVENT THE NERVE FROM CAUSING
-- PREVENTING BONE FROM CAUSING
VISION LOSS IN PATIENTS WITH
NORMAL VISION AND CLINICIANS
THOUGHT THIS WAS NECESSARY TO
PREVENT FD FROM CAUSING
BLINDNESS AND ONE OF THE
EARLIEST OBSERVATIONS AFTER
NATURAL HISTORY STUDY STARTED
WAS FAIRLY LARGE PROPORTION OF
PATIENTS HAD VISION LOSS WHEN
INVESTIGATORS COMPARED PATIENTS
ACROSS COHORT THEY NOTED LARGEST
RISK FACTOR FOR VISION LOSS WAS
HISTORY OF HAVING HAD OPTIC
NERVE DECOMPRESSION SURGERY AND
THIS DATA SUGGESTS STANDARD OF
CARE SURGERY INCREASED VISION
LOSS AND NERVE DAMAGE
INTEROPERATIVELY AND OVER NEXT
SEVERAL YEARS WE STUDIED THIS
TOPIC MUCH MORE CLOSELY
INVESTIGATORS PERFORMED
METAANALYSIS SHOWING WATCHFUL
WAITING CLOSE VISION MONITORING
LED TO SUPERIOR OUTCOMES
COMPARED TO OPTIC NERVE
DECOMPRESSION AND COHORT GREW
LARGER IDENTIFIED GROWTH HORMONE
EXCESS WAS FACTOR FOR VISION
LOSS AND EARLY TREATMENT COULD
PREVENT THIS MORBIDITY AND
RECENTLY DEFINED STANDARDS
MEASURING THICKNESS OF FIBER
LAYER SURROUNDING OPTIC NERVE TO
ALLOW TO IDENTIFY EARLY SIGNS OF
NERVE COMPRESSION BEFORE
PATIENTS DEVELOP VISION LOSS AND
TAKING TOGETHER THIS LINE OF
RESEARCH TRANSFORMED CARE OF
OPTIC CANAL FD FROM INVASIVE
MORBID SURGERIES TO REFINED
APPROACH BASED PRIMARILY ON
MONITORING AND MEDICAL
MANAGEMENT.
RELATIONSHIP BETWEEN GROWTH
HORMONE EXCESS IS WORTH
EMPHASIZING EARLY EVIDENCE THAT
EARLY INTERVENTION COULD HAVE
MORBIDITY PATIENTS WITH EQUAL
VOLUMEMENT AND SEVERITY OF
GROWTH HORMONE ACCESS PATIENT ON
TOP WASN'T DIAGNOSED OR STARTED
ON TREATMENT UNTIL AGE 8 TA
ENAND DEVELOPED MA SSIVE
OVERGROWTH OF SKULL AND JAWS AND
ORBITS OCCOLLUSION OF OPTIC
CANALS THAT IS UNFORTUNATELY
BLIND AND DEVELOPED HEARING LOSS
AND PATIENT ON BOTTOM SCREENED
EARLY AND YOU CAN SEE THAT SKULL
IS GENERALLY OVERALL SYMMETRIC
AND HAS NORMAL VISION AND NORMAL
HEARING AND THINK IT IS AN
ENCOURAGING SIGN THAT EARLY
INTERVENTION CAN TRANSFORM
OUTCOMES.
SO, I WILL SWITCH GEARS A LITTLE
BIT AND TALK ABOUT RESEARCH
IDENTIFYING THERAPEUTIC TARGETS
AND FIBROUS DYSPLASIA AND LINE
OF RESEARCH ARISEN OUT OF
OBSERVATION THAT FD LESIONS ARE
IN STATE OF HIGH BONE REMODELING
SEEING CLINICALLY DR. COLLINS
SHARED DURING CHILDHOOD LESIONS
EXPAND AND INVADE AREAS OF --
FORMATION AND REABSORPTION IN
PATIENTS LEVELS CORRELATE WITH
OVERALL AMOUNT OF SKELETAL
DISEASE BURDEN.
HISTLOGICALLY WE SEE LARGE
AREAS OF ABNORMAL BONE FORMATION
AND PROMINENT OSTEOCLAST GENESIS
AND LED TO ASK QUESTION COULD
TARGETING -- BE EFFECTIVE
TREATMENT STRATEGY FOR FD?
SO, BIPHOSFENATE ARE SYNTHETIC
ANALOGS INCORPORATED INTO
SKELETAL MATRIXES INACTIVATING
OSTEOCLASTS INCORPORATED INTO
BONE LONG HALF LIFE OF GREATER
THAN 10 YEARS WITH GREAT
SUSTAINED EFFECT OF BONE DENSITY
AND TREATMENTS OF OSTEOPOROSIS
AND BONE TUMORS.
YOU HEARD EARLIER TO INVESTIGATE
ROLE OF BIPHOSFENATE AND FD
PLACEBO CONTROLLED TRIAL USING
ORAL FORMULATION AWILL ENDROE
LITE AND STUDY IN TWO YEAR
ENROLLING 36 PATIENTS AND HAD NO
EFFECT ON BONE FORMATION
MARKERS.
WE SAW INCREASE IN DENSITY OF FD
LESIONS ON DECHLA SCANNINGS ON
CHILDREN AND WERE NO EFFECT ON
ADULTS.
THERE WAS NO EFFECT ON BONE
PAIN AND DISAPPOINTINGLY NO
CHANGE IN CLINICALLY RELEVANT
OUTCOMES MEASURES SUCH AS
FRACTURES AND PHYSICAL
PERFORMANCE MEASURES OR IN RADIO
GRAPHIC APPEARANCE OF FD
LESIONS. HOWEVER, THERE IS A
MECHANISM FOR TARGETING
OSTEOCLASTS THROUGH PROTEIN
RANKLE RECENTO ACTIVATOR AND
PROTEIN IS MEMBER OF TUMOR
NECROSIS FACTOR SUPER FAMILY
HIGHLY EXPRESSED BY OWE OF THEO
BLASTS AND PROGENITOR CELLS AND
ALL OF WHICH PARTICIPATE IN OST
EO CLAST GENESIS AND BINDING TO
OSTEOCLASS PRECURSORS ACTIVATES
DIFFERENTIATION AND INFUSION OF
OSTEOCLASTS AND NUMBER OF YEARS
HAD GROWING EVIDENCE THAT
MICHAEL SEEMS TO PLAY A ROPE IN
FD PATHOGENESIS AND LEVELS IN
PATIENTS BLOOD AND CORRELATES
WITH OVERALL AMOUNT OF SKELETAL
DISEASE BURDEN AND HIGH LEVELS
OF EXPRESSION IN FD TISSUE AND
CORRELATES ALSO WITH HIGH AREAS
OF OSTEOGENIC CELL PROLIFERATION
AND SERIAL -- THIS IS CLINICALLY
RELEVANT RANKL -- SO, WE
HYPOTHESIZED THAT RANKL
INHIBITION WITH DENNO ASSUME AB
WOULD BE A STRATEGY TO DECREASE
LESION ACTIVITY AND INCREASE
MINERALIZATION IN FD LESIONS --
WHEN MEDICATION IS STOPPED BONE
TURNOVER CAN REBOUND INCREASE
TEMPORARILY TO LEVELS HIGHER
THAN PRE-TREATMENT AND BECAUSE
OF THAT WAS IMPORTANT TO US IN
THE STUDY TO INVESTIGATE SAFETY
OF STOPPING DENOSUMAB AND
INCLUDED EXTENSIVE INTENSIVE
POST-TREATMENT MONITORING
PERIOD. PRIMARY ENDPOINT OF
STUDY WAS BONE TURNOVER MARKERS
SECONDARY ENDPOINTS HAD PAIN AND
FUNCTION AND EFFECTS IN FD
LESION BONE BIOPSIES.
SO, DENOSUMAB HAD A PROFOUND AND
SUSTAINED EFFECT ON BONE
TURNOVER MARKERS SEEING DECLINES
IN P1 AND P3 AND BONE FORMATION
MARKER AND BONE ABSORPTION
MARKER AND CONTRAST TO STUDY IN
AWILL ENDROE LATE DON'T SEE
EFFECT ON MARKERS AND SODIUM
FLUORIDE PET CT IS ANATOMICAL
IMAGING TECHNIQUE MEASURING
AMOUNT OF TRACER TAKEN UP INTO
LESIONS THAT YOU CAN SEE AFTER 6
MONTHS OF DENOSUMAB WE SEE A
PROFOUND DECREASE AND LESIONAL
ACTIVITY TO PHYSIOLOGIC LEVELS
IN SOME PATIENTS AND WHAT
ENCOURAGING THIS IS A COMPANY BY
PROFOUND IMPROVEMENTS IN
CLINICAL OUTCOMES.
FOR EXAMPLE, THIS PATIENT HERE
AND THIS ONE THAT HAS REALLY
SEVERE THORACIC FD INVOLVEMENT
HAD SUCH RIB EXPANSION SHE HAD
PULMONARY RESTRICTION REQUIRING
CONTINUOUS OXYGEN THERAPY AND IN
A MONTH OF STARTING DENOSUMAB
HER PULMONARY FUNCTION IMPROVED
AND SHE WAS ABLE TO DISCONTINUE
OXYGEN. THIS WAS ENCOURAGING
EFFECTS SAW WERE PERFORMED IN
SAME SITE BEFORE AND AFTER
DENOSUMAB TREATMENT INCREASE IN
BONE CONTENT AND REDUCTION IN
EXPRESSION IN CELL PROLIFERATION
MARKER AND INCREASE IN THE
EXPRESSION OF THE MATURE
MINERALIZATION MARKER. SO, WHEN
WE PUT THIS TOGETHER IT SEEMS TO
SUGGEST A PATTERN WHERE
ANTI-RANKL INHIBITION -- ALLOWS
THEM TO ADOPT A MATURE PATTERN
OF DIFFER ENTI
DIFFERENTIATION THAT COULD MAKE
MORE BONE.
IN THIS MOUSE MODEL IT EXPRESSES
HUMAN G ALPHA S VARIANT. MICE
DEVELOP EXPANSILE FIBROUS
LESIONS THAT MIMIC FD RADIO
GRAPHICALLY AND HISTLOGICALLY
AND TREATMENT OF ANTI-RANKL YOU
CAN SEE THAT THE LESIONS DEVELOP
SUBSTANTIAL INCREASE IN
MINERALIZATION AS EVIDENCE ON
MICRO CT. HISTLOGICALLY WE SEE
SIMILAR FINDINGS TO HUMAN TISSUE
AND REDUCTION IN CELLULARITY AND
REDUCTION IN CELL PROLIFERATION
MARKERS AND DECREASE IN
EXPRESSION OF EARLY OSTEOGENIC
MARKER AND INCREASE IN MATURE
OSTEOGENIC MARKER SCLER OSTEN.
TO INVESTIGATE INTERACTIONS
BETWEEN CELL TYPES AND FD
LESIONS WE DEVELOPED AN FD
EX-VIVO CELL CULTURE MODEL AND
BONE MARROW CELLS FROM FD MOUSE
WERE ISOLATED AND CULTURED AND
THEN G ALPHA S VARIANT
EXPRESSION WAS INDUCED
SPECIFICALLY IN OSTEOPROGENITOR
CELLS VIA DEOXY CYCLING AND THEY
PRODUCE OSTEOCLASTIC SIGNALING
FACTORS THAT INCREASE PRODUCTION
AND ACTIVITY OF OSTEOCLASTS AND
SIMILAR TO EFFECTS IN HUMAN AND
MOUSE TISSH RANKLLE INHIBITION -
DEOXY CYCLEAN WE SAW INCREASE IN
OSTEOGENERALITIOR CELLS AND WHEN
WE TREAT WITH ANTI-RANKL WE SEE
DECLINE IN EXPRESSION OF THE
LEVELS AND HIGH LEVELS OF
PROLIFERATION ARE NO LONGER
SEEN.
SO, PUTTING THIS LINE TOGETHER,
WE CONCLUDE THAT RANKL
INHIBITION DECREASES
PROLIFERATION AND INCREASES
MATURATION OF FD CELLS.
THIS IS EVEN BEYOND EXPECTED
ANTI-ABSORPTIVE EFFECTS
HIGHLIGHTING ROLE OF OSTEOBLAST
SIGNALING IN FD PATHOPHYSIOLOGY.
AGAIN, THIS IS QUITE EXCITING
HOWEVER WE RANNISH AUTO YOUS
WITH BONE TURNOVER REBOUND AND
ALL PATIENTS IN STUDY WERE
TREATED WITH [INDISCERNIBLE] AT
TIME -- FOUR PATIENTS CTX BONE
ABSORPTION MARKER RETREATED TO
ABOVE PATIENT LEVELS EXTREMELY
SEVERE INCREASING 600% OF
BASELINE LEVEL ASSOCIATED WITH
SEVERE HYPERCALCEMIA TO 23
MILLIGRAMS PER DECILITER.
PATIENT HOSPITALIZED AND SHE
RECOVERED WITHOUT ANY SEC WELLA
AND CLEARLY HIGHLIGHTS IMPORTANT
ADVERSE EVENT THAT WE NEED TO BE
AWARE OF.
DENOSUMAB FOR FD WHERE ARE WE NO
YOU? EXCITING POTENTIAL TO HAVE
EFFECT ON FD LESION ACTIVITY AND
COMPOSITION AND SEVERE POST
DISCONTINUATION HYPERKALGSEMIA
OCCURS IN SUBSET OF PATIENTS IN
IMPORTANT ADVERSE EVENT AND
QUESTIONS WE NEED TO STILL
ANSWER. WHO SHOULD WE TREAT?
DOESN'T NEED TO MEET MEDICATION
FOR EVERYONE WITH FD AND COULD
BE POWERFUL TOOL FOR PATIENTS
WITH SEVERE MORBIDITY AND HOW
LONG WE SHOULD TREAT PATIENTS
IMPORTANT CONCLUSION FROM ADULT
STUDY TO MAINTAIN BENEFITS OF
DENOSUMAB WE HAVE TO CONTINUE.
WE SAW DRAMATIC EFFECTS 6 MONTHS
OF TREATMENT IMPORTANT AMOUNT OF
TIME IN SKELETAL PHYSIOLOGY AND
COULD GET AWAY WITH TREATING AT
MUCH LOWER DOSE AND MAINTAIN
BENEFITS .
FURTHER STUDIES NEEDED TO
DETERMINE CLINICAL UTILITY OF
DENOSUMAB THAT IS PARTICULARLY
THE CASE IN CHILDREN.
SO, AS DR. COLLINS SHARED AN
IMPORTANT OBSERVATION FROM
NATURAL HISTORY STUDY IS FD
LESIONS PROGRESS IN CHILDHOOD --
THIS CREATES WINDOW OF
OPPORTUNITY WHERE IF WE CAN FIND
INTERVENTION THAT WILL PREVENT
FD LESIONS FROM FORMING AND
EXPANDING THAT IS HOW WE CAN
HAVE A TRANSFORMATIONAL EFFECT
ON THE DISEASE AND CURRENTLY
CONDUCTING A PHASE 2 STUDY OF
DENOSUMAB WITH PRIMARY GOAL OF
FD LESION PROGRESSION IN KIDS
AND EXPANSION AND COMPARING TO
UNTREATED PATIENTS FROM NATURAL
HISTORY STUDY FURTHER
CAPITALIZING ON THAT UNIQUE DATA
WE HAVE BEEN ABLE TO GATHER OVER
THE PAST 25 YEARS.
ANOTHER -- SO, BASED ON WHAT WE
HAVE LEARNED FROM THE ADULT
STUDY WE WILL USE A VERY, VERY
LOW DOSE OF DENOSUMAB ABOUT
12-FOLD LOIER AND WILL GIVE THIS
MEDICATION MONTHLY AND THIS
STUDY IS CURRENTLY ENROLLING AND
WOULD LIKE TO CLOSE BY SHARING
ABOUT ANOTHER ONE OF OUR
EXCITING STUDIES THAT IS
STARTING THAT RELATES TO
TREATMENT OF FGF23 EXCESS AND
DR. COLLINS SHARED -- LEADING TO
LOW BLOOD PHOSPHORUS LEVELS
LEADING TO CLINICAL
COMPLICATIONS RICK ETS AND
OSTEOMALACIA AND INCREASES RISK
OF FD RELATED COMPLICATIONS
FRACTURES AND DEFORMITIES YEARS
ON NATURAL THRIFT STUDY PATIENT
AS PEAR TO BE PARTICULARLY
VULNERABLE TO EFFECTS OF PHOSPHO
TEEMIA AND REVIEW OF 240
PATIENTS NUND PHOSPHORUS LEVELS
AT LOWER PART OF THE NORMAL
RANGE ARE ASSOCIATED WITH HIGHER
RATES OF FRACTURES AND
ORTHOPEDIC SURGERIES AND
SUGGESTS THAT PATIENTS WITH FD
MAY BENEFIT MAINTAINING
PHOSPHORUS LEVELS IN HIGH RANGE
TO PROTECT THEIR BONES. TESTING
THIS PROVIDING PHASE 2 TRIAL --
THIS TREATMENT ALLOWS US TO FINE
TUNE PHOSPHORUS LEAVELES. SO,
OUR PRIMARY ENDPOINT WILL AIM TO
ACHIEVE A HIGH NORMAL PHOSPHORUS
LEVEL AT TOP OF THE RANGE AND IF
FIND FRGZ STUDY ARE SUPPORTIVE
HAS POTENTIAL TO TRANSFORM
MANAGEMENT OF FGF23 EXCESS AND
FD AND THANKING GROUP METABOLIC
BONE DISORDERS UNIT THAT ARE
WONDERFUL AND MAKE COMING TO
WORK A PLEASURE EVERY DAY AND SO
MANY COLLABORATORS OFFICE OF THE
CLINICAL DIRECTOR AND
INTERNATIONALLY AS WELL. OF
COURSE, NONE OF THIS WITH BE
POSSIBLE WITHOUT CLOSE
PARTNERSHIP WITH PATIENT
COMMUNITY AND IS QUITE UNIQUE
ABOUT HOW THE RESEARCH AND NIDCR
HAS PAIRED WITH PATIENT
COMMUNITY FROM DAY 1 THAT REALLY
ACCELERATED BOTH THE AMOUNT AND
QUALITY OF RESEARCH WE HAVE BEEN
ABLE TO DO. THANKS VERY MUCH.
>> AUDIENCE: [APPLAUSE].
>> THAT WAS THE PERFECT SEGUE.
ALLISON OR DR. BOYCE HAS
MENTIONED WE COULDN'T BE HERE
DOING RESEARCH AND BEING AS
SUCCESSFUL WITHOUT OUR PATIENT
PARTNERS AND WITHOUT ADVOCACY
GROUPS THAT HAVE BEEN SUCH
LEADERS IN THE FIELD AS WELL.
I WOULD LIKE TO INVITE
MRS. MCBRIDE WHO IS EXECUTIVE
DIRECTOR OF FD/MAS ALLIANCE WITH
OVER 15 YEARS EXPERIENCE IN
NON-PROFIT SECTOR LEADERSHIP
ROLES.
IT IS HARD TO MENTION THE
ALLIANCE WITHOUT RECOGNIZING IT
WAS ORIGINALLY THE FD FOUNDATION
AND WITHOUT ACKNOWLEDGING
CHARLIE HARLOUS WHO FOUNDED THE
GROUP AND WHOSE PRESENCE IS FELT
STILL TODAY. I'M PLEASED TO
HAVE MRS. MCBRIDE HERE TODAY TO
TELL US A LITTLE ABOUT THE WORK
OF FD/MAS ALLIANCE AND RECENT
CONFERENCE THAT JUST HAPPENED
OVERTHE WEEKEND. THANK YOU.
>> GOOD MORNING. IT IS A
PRIVILEGE TO BE HERE AND
PRIVILEGE FOR ME TO REPRESENT
FD/MAS ALLIANCE. FD/MAS
ALLIANCE HAS A PRETTY SIMPLE
MISSION, NEWLY DIAGNOSED NEED A
PLACE TO TURN AND ACCESS TO
WORLD CLASS RESEARCHERS AND
ACCURATE INFORMATION IS CRITICAL
AT EVERY STEP AND STAGE OF THIS
CHRONIC DISEASE AND WE WORK AS
ORGANIZING PRESENCE ENCOURAGING
RESEARCHERS TO ADVANCE AND
MAKING SURE PATIENT PRIORITIES
REMAIN AT THE FOREFRONT.
I ALSO WANT TO SAY THAT FD/MAS
ALLIANCE IS A MEMBER OF NIDCR,
PATIENT ADVOCACY COUNCIL
ADVOCATING ON BEHALF OF NIDCR
AND NIH ON CAPITOL HILL AND
JOINT LETTERS AND VISITING
MEMBERS OF CONGRESS AND PROUD TO
SAY WE WORK CLOSELY WITH ALLISON
BOYCE WHO IS CHAIR OF MEDICAL
ADVISORY COUNCIL AND MEMBER OF
STEERING COMMITTEE AND DR.
MICHAEL COLLIN WHO'S IS KIND AND
GENEROUS WITH ME SERVES AS CHAIR
OF FD/MAS SCIENCE ADVISORY --
AND MY COLLEAGUES WILL SPEAK
MORE ABOUT THAT FD/MAS ALLIANCE
IS A FOUNDING MEMBER AND REASON
I LOOK TIRED IS WE HAD A
THREE-DAY CONFERENCE THAT WAS A
WONDERFUL WONDERFUL EXPERIENCE
WITH COLLABORATION, COOPERATION
AND COME RAD REAND COLLEAGUE
WILL SPEAK MORE ABOUT THAT.
I WANT TO SHARE ABOUT THE FDMA
ALLIANCE AND ACCOMPLISHMENTS IF
IN RESEARCH.
WE RAISED OVER $160,000 IN
RESEARCH FUNDING PARTNERING WITH
U PEN MILLION DOLLAR BIKE RIDE
THIS SPRING AND NO. 1
FUNDRAISING TEAM FOR SECOND YEAR
IN A ROW.
THIS MEANS WE ARE NO. 1 OF 30
RARE DISEASE PATIENT ADVOCACY
ORGANIZATIONS. WE ARE NO. 1
BECAUSE OUR GROUP IS SO
PASSIONATE.
THIS YEAR WE WILL BE ABLE TO
OFFER AT LEAST FOUR GROUPS.
BETWEEN 2 AND 4 GRANTS.
WE HAVE BEEN DOING THIS SINCE
2014 AND SUPPORTED OVER 17
RESEARCH PROJECTS FUNDING OVER A
MILLION DOLLARS IN RESEARCH.
I WENT THE WRONG WAY.
NO. WHAT DID I DO?
>> AUDIENCE: [APPLAUSE].
>> OKAY. ALSO PROUD TO SAY
BECAUSE OUR ADVOCATES WE HAVE
BEEN INCLUDED IN PEER REVIEWED
MEDICAL RESEARCH PROGRAM PARTNER
OF DEFENSE PROGRAM RESEARCH
INITIATIVE 4TH YEAR IN A ROW AND
2023 FIRST FD PROPOSAL TO
RECEIVE FULL FUNDING THIS YEAR
AND DR.S YANG AND WEIN WERE
AWARDED OVER $3.4 MILLION TO
STUDY FD/MAS AND NIH RECENTLY
AWARDED R01 GRANT TO THREE
FORMER MILLION DOLLAR BIKE RIDE
WINNERS AWARDEES. DR. CHAO, DR.
FERERRO AND DR.UENT WORTH AND IS
REMARKABLE FOR A SMALL GROUP
LIKE US.
THIS YEAR WE DID LOTS WITH
COMMUNITY SUPPORT AND MOST
IMPORTANT THING WE HAVE DONE IS
LAUNCHED A PATIENT ADVISORY
COUNCIL TO MAKE SURE WE ARE
TRULY TRULY REFLECTING VOICE OF
THE PATIENTS POSTING SOCIALS AND
CONTESTS AND PROVIDE SUPPORT
SERVICES.
THANK YOU TO GLOBAL GENES
FINANCIAL LITERACY GRANTED WE
HOSTED 2 WEBINARS HELPING
PATIENT NAVIGATE DISABILITY
BENEFITS FEDERAL DISABILITY
BENEFITS AND CREATED A PAGE ON
OUR WEBSITE FOR THAT.
IN 2024 WE ARE LOOKING FOR
UPDATES FOR NEW MILLION DOLLAR
AWARDEES AND ARE GETTING A NEW
PLATFORM FOR PATIENT REGISTRY.
WE WANT TO CONTINUE TO SUPPORT
FEDERAL RESEARCH FUNDING AND
COMMUNITY INITIATIVES.
BUT, WHAT I WANT TO REALLY SHOW
IS THIS VIDEO A TESTAMENT AND
RESILIENCE AND STRENGTH TO
COMMUNITY MEMBERS WHICH IS WHY
I'M HERE.
>> AUDIENCE: [APPLAUSE].
>> LEA WAS BORN CLOSE TO FULL
TERM. RIGHT AWAY WE NOTICED
SOMETHING WASN'T RIGHT. HE WAS
HAVING SEVERE VOMITING AND
DEVELOPED CAFE OE AU LAIT SPOTS
>> HER ENDOCRINOLOGIST SUGGESTED
IT WAS OUTLIAR COULD BE MCCUNE
ALBRIGHT SYNDROME.
>> I THOUGHT IT WAS
DISREGULATION AND PERIODS WHEN I
WAS 16 I WENT BLIND IN RIGHT EYE
AND FOUND OUT I HAD IRIS
DYSPLASIA.
>> -- A RARE DISEASE AND BY
DEFINITION THEREFORE EFFECTS
LESS THAN 200,000 PEOPLE IN THE
UNITED STATES.
>> FD/MAS ARISES DUE TO
MUTATIONS IN GNAS GENE THAT
INCLUDES A RECEPTOR THAT IS
IMPORTANT FOR SIGNALING IN
MULTIPLE DIFFERENT TYPES OF
TISSUES AND ESPECIALLY BONE AND
ENDOCRINE SYSTEM. WHEN MUTATION
-- IN BONE EXCESS RECEPTOR
SIGNALING LEADS TO FORMATION OF
FIBEROSOUS BONE LESIONS CAUSING
PROBLEMS FACIALLY SYMMETRY
BLINDNESS DEAFNESS FRACTURES AND
PHYSICAL DISABILITY.
>> WE WENT TO A THEME PARK.
HE WAS STANDING ON A STROLLER
TYPE OF THING AND I MOVED IT OUT
OF THE WAY.
HE FELL OFF IT AND BROKE A LEG.
>> DURING THE SCHOOL YEAR,
TEACHERS WATCH HER LIKE HAWKS
AND KNOW SHE IS LED ON THE
SWINGS DON'T LET HER CLIMB
ANYTHING.
>> CONSIDER WHAT IT IS LIKE TO
GO TO THE PLAYGROUND AND NOT DO
WHAT YOU WANT TO DO.
>> I WANT TO [INDISCERNIBLE] MOM
SAID NO, NO, NO, NO.
>> FIRST TIME I HAD PLEASURE
SEEING GIANA WE COULD SEE EARLY
EVIDENCE OF FIBROUS DYSPLASIA
SINKING FEELING KNOWING LESIONS
ARE THERE AND NOTHING WE CAN DO
ABOUT IT.
>> I'M CURRENT PRESIDENT OF
FD/MAS ALLIANCE AND MISSION AT
ALLIANCE IS TO DEVELOP THIS
COMMUNITY FOR PATIENTS, PARENTS
AND FAMILIES TO DRIVE THE
RESEARCH THAT IS REQUIRED TO
FIND THAT TREATMENT OR CURE.
>> FD/MAS ALLIANCE PLAYS
CRITICAL CUTTING EDGE ROLE IN
PRESENT AND FUTURE RESEARCH OF
FD/MAS.
>> THE FUTURE OF THE ALLIANCE IS
KEY TO SUCCESSFUL RECRUITMENT TO
NIH. THIS IS EXTREMELY RARE
DISEASE AND WE HAVE OVER 300
PATIENTS ON NATURAL HISTORY
STUDY THAT ARE EXTENSIVELY
PHENOTYPED WHEN WE HAVE A
MEDICATION WE CAN COMPARE
OUTCOMES TO EXTENSIVE HISTORICAL
CONTROL DATA.
>> PATIENT ARE EDGETRY HAS
INFORMATION ON OVER 1,000
PATIENTS AND WE HAVE INFORMATION
ON ALL ASPECTS OF LIVES OF
PATIENTS. IRB APPROVED AND
PARTNERED WITH NORD TO HELP US
MAKE THIS AVAILABLE TO MORE
RESEARCHERS THAT CAN ASK US TO
ADD QUESTIONS SPECIFICALLY FOR
THEIR RESEARCH PROJECTS.
>> FD/MAS ALLIANCE HELPS FOCUS
RESEARCH ON TRYING TO SOLVE
PROBLEMS MOST IMPACTING PATIENTS
AND WE HAVE EXTENSIVE EXPERIENCE
CONDUCTING INTERVENTIONAL
STUDIES THAT ESTABLISH STANDARD
OF CARE FOR ENDOCRINE TREATMENTS
AND CHALLENGE IS IDENTIFYING
EFFECTIVE TREATMENT FOR BONE
DISEASE AND WHAT WE ARE MOTIVATE
TODAY DO NEXT.
>> HEADWAY MADE IN FD/MAS AND
TARGETING ALPHA GS WILL HAVE
BROADER EFFECTS AND OTHER
CONDITIONS INCLUDING CERTAIN
TYPES OF CANCERS AND GOOD DRIVER
FOR PEOPLE TO BE INTERESTED AND
BE INVESTED AND TO WORK IN THIS
AREA.
>> FD/MAS ALLIANCE IS COMMIT
TODAY SUPPORTING RESEARCH AND
REACHED MILLIONTH DOLLAR RAISE
IN 2022 AND HAVE ABILITY TO FUND
MULTIPLE RESEARCH GRANTS EVERY
YEAR SDMR GROUP INVESTIGATORS
BENEFITING FROM RESEARCH MONEY
ARE COLLABORATIVE AND REAL
PROGRESS MADE AND NEW TRIALS ON
THE WAY AND NEW THERAPIES IN
LABORATORY NOW MIGHT BE
TREATMENTS FOR FD/MAS IN THE
FUTURE.
>> HAVING SOMETHING TO TAKE THE
EDGE OFF WOULD MAKE GREATEST
DIFFERENCE LIVING WITH CHRONIC
PAIN OR EPISODIC SEVERE PAIN
THAT COULD BE DEBILITATING IS
EXHAUSTING.
>> MY HOPE IS FOR HER TO SET HER
SIGHTS ON ANYTHING AND
ACCOMPLISH THAT AND KNOW WITH A
CURE AND THE RIGHT MEDICINE THAT
IS POSSIBLE FOR HER.
>> I WANT FOR HIM TO BE ABLE TO
SEE AND FOR HIM TO BE ABLE TO
WALK AND TO BE ABLE TO BE SEEN
IN PUBLIC WITHOUT THAT FACIAL
DEFORMITY WHERE YOU CAN'T WALK
DOWN THE STREET WITHOUT
[INDISCERNIBLE] LOOKING AT YOU.
>> FD/MAS ALLIANCE HAS DONE
GROUNDWORK ALREADY.
>> CREATING SITUATION WHERE.
>> THE ALLIANCE IS READY AND
PATIENTS THERE AND ARE ON CUSP
ADVANCING TREATMENTS IN FIBROUS
DYSPLASIA MCCUNE ALBRIGHT
SYNDROME.
>> THANK YOU. THANK YOU TO
EVERYBODY IN THE VIDEO.
>> AS YOU CAN SEE, WHILE WE CAN
DO RESEARCH HERE AT THE NIH,
PATIENT COMMUNITY REALLY NEEDS
THE ADVOCACY.
WHAT THEY DO IS AMAZING.
PATIENTS HAVE DAY-TO-DAY ISSUES
AND HAVE ADVOCACY GROUPS WORKING
TO MAKE SURE THAT OUR PATIENTS
ARE CARED FOR AND FOR ALL LITTLE
THINGS THEY REALLY DO NEED TO
LEAD NORMAL LIVES. THANK YOU
VERY MUCH.
THE NEXT ADVOCACY GROUP HERE
REPRESENTED BY MAR TEEN DECKER
IS INTERNATIONAL CONSORTIUM FOR
FD/MAS THAT STARTED IN 2014
GROUP OF CLINICIANS PATIENTS AND
RESEARCHERS FROM AROUND THE
WORLD PASSIONATE ABOUT ADVANCING
CLINICAL CARE RESEARCH FOR
INDIVIDUALS WITH FIBROUS
DYSPLASIA MCCUNE ALBRIGHT
SYNDROME. IT LAUNCHED LAST YEAR
CONGRATULATIONS MREENDZED TO
HAVE MRS. MAR TEEN DECKER HERE
AS A MEMBER OF INTERNATIONAL
CONSORTIUM SHARE A FEW WORDS
ABOUT THE CONSORTIUM AND IMPACT
IT IS HAVING ON ALL OUR PATIENTS
WORLDWIDE. THANK YOU
[APPLAUSE].
>> THANK YOU. GOOD MORNING,
EVERYONE. I'M MARTINA DECKER
AND PATIENT MONOSTATIC FIBROUS
DYSPLASIA. AFTER DIAGNOSIS I
INITIATED DUTCH PATIENT
ASSOCIATION AND NOW INVOLVED
WITH INTERNATIONAL CONSORTIUM
FOR FIBROUS DYSPLASIA MCCUNE
ALBRIGHT SYNDROME. YES. LET'S
GO. BASICALLY, THE BASIC
INTERNATIONAL CONSORTIUM
ORIGINATES FROM SIMPLY A COUPLE
PEOPLE COMING TOGETHER IN 2015
AS WAS ALREADY SAID.
SHARING IDEAS AND SHARING
UPDATES ON RESEARCH.
EVER SINCE IT WAS I THINK A
BIANNUAL MEETING COMING TOGETHER
ON AN INFORMAL BASIS.
VERY QUICKLY DURING MEETINGS,
THE INITIATIVE WAS TAKEN TO
DEVELOP INTERNATIONAL GUIDELINES
FOR PATIENT HEALTHCARE AND
PATIENTS WITH FD/MAS THAT WAS
BASICALLY START OF MORE AND MORE
COLLABORATION WITH VARIOUS
STAKEHOLDERS AND ESPECIALLY
RESEARCHERS AND PATIENT
ASSOCIATIONS AND AT SOME POINT
BECAME NEED FOR MORE STRUCTURAL
AND ORGANIZED INTERNATIONAL
CORPORATION AND WRITING GROUP
WAS SET UP TO RIGHT TO TERMS OF
REFERENCE TO START THIS FORMAL
CONSORTIUM.
INDEED AT THE END LAST YEAR IN
FEBRUARY DURING CELEBRATION OF
FD/MAS GLOBAL AWARENESS WEEK WE
HAVE BEEN ABLE TO LAUNCH
OFFICIALLY INTERNATIONAL
CONSORTIUM FIBROUS DYSPLASIA
MCCUNE ALBRIGHT SYNDROME
INTRODUCE BOARD OF DIRECTORS TO
YOU HERE. INTENTION IS TO HAVE
ALWAYS REPRESENTED IN THE BOARD
OF THE CONSORTIUM BOTH VARIOUS
STAKEHOLDERS SO BOTH
RESEARCHERS, SCIENTISTS AND
PATIENT REPRESENTATION AND
PREFERABLY FROM DIFFERENT
COUNTRIES.
WHAT DO WE WANT TO ACHIEVE WITH
CONSORTIUM?
ALSO ON WEBSITE WE IDENTIFIED
MISSION WITH FOUR MAIN POINTS TO
IMPROVE CARE AND FINE SOLUTIONS
FOR UNMET NEEDS OF PATIENTS AND
CARE PROVIDERS ENCOURAGING
TESTING AND DEVELOPMENT OF
POTENTIAL ENCOURAGING TREATMENT
TO IMPROVE ACCESS TO INFORMATION
WORLDWIDE AND SUPPORT DEVELOP
COOPERATIVE SCIENTIFIC STUDIES
AND INITIATIVES AND BEING A
CONTACT PLATFORM SO PATIENTS AND
SPECIALISTS ARE ABLE TO FIND US
AND REACH US AND WEBSITE AND
SOCIALS WE ARE ON LINKEDIN AND
PLAY A CENTRAL ROLE IN THIS.
DEFINITELY ALSO LIKE LIVE
MEETINGS LIKE WE HAD YESTERDAY.
IN A SHORT PERIOD OF TIME WHAT
HAS BEEN ACHIEVED SO FAR.
WELL, IT IS TREMENDOUS THAT
FD/MAS COMMUNITY IS GROWING SO
FAST.
THE LAST YEAR OR SO, A LOT OF
NEW COUNTRIES HAVE JOINED ALSO
THE INTERNATIONAL PATIENT
ASSOCIATION MEETINGS.
THEY DO NOT ONLY BRING EXTRA
PATIENTS BUT EXTRA RESEARCHERS
AND SPECIALISTS TO FD/MAS
COMMUNITY.
THAT IS VERY GOOD.
EVERY MONTH THE INTERNATIONAL
PATIENT ASSOCIATIONS MEET ONLINE
THAT IS QUITE CHALLENGING
CONSIDERING ALL DIFFERENT TIME
ZONES INVOLVED THAT WE TRY TO
MANAGE.
IT IS REALLY GREAT TO HAVE ALL
THESE DIFFERENT NATIONALITIES
WORKING TOGETHER AND WE SPEAK
ABOUT COMMON GOALS AND
CHALLENGES AND HELP EACH OTHER
OUT WHEREVER WE CAN.
AND WELL WE QUITE ACHIEVED
WORKING ON PROJECTS TOGETHER AND
ACHIEVING QUITE A BIT OF THINGS
AMONGST THINGS FROM LAST YEAR
HAVE BEEN ABLE TO DEFINE AND
PRESENT PRIORITIES IN PATIENT
CARE FOR PATIENTS WITH FD/MAS
AND CAN ALSO BE FOUND ON ONE OF
THE POSTERS YOU WILL FIND IN THE
COFFEE AREA IN MORE DETAIL.
WE OFTEN HAVE COORDINATED
AWARENESS CAMPAIGNS DURING
FD/MAS AWARENESS WEEK THAT IS
ALWAYS ON THE 20TH OF FEBRUARY.
OUR SPANISH COLLEAGUES HAVE
DEVELOPED A CHILDREN'S BOOK, A
GIFT CALLED MATEO AVAILABLE IN
VARIOUS LANGUAGES AND WIDELY
AVAILABLE ON AMAZON AND THIS
WEEK LAUNCHED CHILDREN'S
INFORMATION FLYER ABOUT FD/MAS
GIVING CHILDREN ABILITY TO
EXPLAIN THEIR DISEASE TO THEIR
FRIENDS OR TEACHERS IN A
CLASSROOM AND MADE ANIMATION
VIDEO ON FD/MAS.
NOT ONLY PATIENT ASSOCIATION
HAVE BEEN WORKING TOGETHER.
OTHER STAKEHOLDERS BEING
RESEARCHERS AND OTHER
SPECIALISTS HAVE BEEN WORKING
TOGETHER MORE AND MORE AND LED
TO WIDE VARIETY OF PUBLICATIONS.
AS I ALREADY INDICATED, ONE MAIN
ACHIEVEMENT IN THIS IS
INTERNATIONAL GUIDELINES FOR
HEALTHCARE PATIENTS FOR FD/MAS
CLINICAL PATHWAY AND FROM THAT
MADE TRANSLATION INTO PATIENT
GUIDE THAT IS BASICALLY USED AS
A TOOL FOR PATIENTS TO HELP THEM
WITH DOCTORS APPOINTMENTS AND
ENHANCES ALSO COMMUNICATION
BETWEEN PATIENT AND DOCTOR AND
ENHANCES ALSO UNDERSTANDING
ABOUT THE DISEASE.
THESE BOTH GUIDELINES AND
PATIENTS GUIDE HAVE BEEN
REVIEWED YESTERDAY IN
YESTERDAY'S MEETING AND WILL
UPDATE IT IN THE COMING TIME.
SO, THIS WAS YESTERDAY.
I THINK THAT ONE OF THE
CONCLUSIONS WE HAD IN
YESTERDAY'S MEETING IS IN RECENT
YEARS LOTS OF PROGRESS HAS BEEN
MADE ON RESEARCH AND ON HEALTH
CARE AND ALSO ON INCLUSION OF
PATIENT INVOLVEMENT IN ALL THIS.
I THINK CELEBRATING 25 YEARS OF
RESEARCH SHOWS COMMITMENT AND
ALSO THE CLINICAL RESEARCHERS
INVOLVEMENT OF NIH AND FD/MAS
COMMUNITY AND DR. ALLISON BOYCE
AND MIKE COLLINS HAVE BEEN
INVOLVED FROM THE BEGINNING AND
WITH SETUP OF INTERNATIONAL
CONSORTIUM AND ARE GREAT
INTERNATIONAL CORPORATION HAS
BEEN, WELL, GREAT VALUE TO
INTERNATIONAL FD/MAS COMMUNITY.
WE ARE REALLY GRATEFUL FOR THAT.
BIG HAIRY GOAL AS I ALWAYS CALL
IT, I HOPE TODAY I HAVE BEEN
ABLE TO SHOW YOU WE HAVE VERY
MUCH GROWING COMMUNITY AND ALSO
VERY ACTIVE ONE. I HOPE THIS
ENCOURAGES ALL RESEARCHERS TO
CONTINUE THEIR GREAT WORK WITH
AIM OF REACHING BIG AND HAIRY
GOAL AND UNRAVELING SECRETS AND
MYSTERIES ON FD/MAS AND POSSIBLE
SOLUTIONS.
GO FOR IT.
THANK YOU.
>> AUDIENCE: [APPLAUSE].
>> I LOVE WHAT YOU SAID ABOUT
PATIENTS LEADING RESEARCHERS AND
CLINICIANS AND REALLY TAKING A
LEAD BECAUSE SOMETIMES IT IS THE
PATIENT WHO EDUCATES US.
WE WILL SHAKE IT UP A LITTLE
BIT. I SEE TWO PEOPLE AND TWO
BOUNCING BEANS BACK THERE. WE
WILL HAVE A PATIENT AND
PROFESSIONAL PANEL. I WOULD
LIKE TO INVITE OUR PATIENT
GUESTS AND DR. BOYCE AND DR.
COLLINS TO COME TO THE FRONT.
YOU WILL HEAR FROM THOSE WHO
LIVE WITH THIS CONDITION.
>> AUDIENCE: [APPLAUSE].
>> I THINK I'M SUPPOSED TO SH S
THERE.
>> THANK YOU VERY MUCH.
SHOUTOUT TO PATIENT SUPPOSED TO
ATTEND TODAY. TIFFANY MYER AND
HOPE SHE IS WATCHING FROM
ONLINE. SHE UNEXPECTEDLY HAD A
HOSPITALIZATION. SHE WON'T BE
ABLE TO JOIN US. SHE HAS BEEN
PART OF NATURAL HISTORY STUDY
FROM BEGINNING AND SENT A BRIEF
STATEMENT I WILL READ. I WOULD
TELL EVERYONE I KEEP COMING TO
NIH. I RECEIVE CARE FROM
FOREMOST RESEARCH CENTER IN
COUNTRY AND DOCTORS AND NURSES
THERE ARE LIKE FAMILY. YOU AND
ALL DOCTORS THERE CARE SO MUCH
ABOUT THEIR PATIENTS.
I TELL PEOPLE ALL THE TIME ARE
YOU FAMILIAR WITH THE NATIONAL
INSTITUTES OF HEALTH? I'M LUCKY
ENOUGH TO GO THERE FOR MEDICAL
CARE I CAN HELP OTHERS THERE IN
THE PROCESS IF I CAN CHANGE THE
FACT I HAVE MY CONDITION I
WOULDN'T. I HAVE MET SO MANY
WONDERFUL PEOPLE BECAUSE OF IT
AND IT MAKES ME A COMPASSIONATE
AND POSITIVE PERSON AND THANK
YOU FOR ALL YOU DO FOR ME AND MY
PARENTS AND MY HUSBAND.
>> AUDIENCE: [APPLAUSE].
>> WE HAVE CLEARLY MANY
WONDERFUL PATIENTS.
DO YOU WANT TO INTRODUCE
YOURSELVES?
>> WE ARE FANCY AND HAVE -- WE
ARE MICCED UP. I'M IVONNE AND
MOTHER OF GIANA. WE HAVE WORKED
WITH DR. BOYCE FOR THE LAST FIVE
YEARS SINCE GIANA'S DIAGNOSIS
AND PLEASURE TO BE HERE TODAY.
THANK YOU.
>> HI. I'M GIANA.
I AM 7 YEARS OLD. YES.
>> WOULD YOU LIKE ME TO
INTRODUCE YOU? WE HAVE HERE
LUCY WHO IS 7 YEARS OLD.
>> 8.
>> SORRY SHE IS 8 YEARS OLD.
LUCY AND GIANA ARE PATIENTS ON
NIH STUDIES AND THEY GOT TO
ACTUALLY MEET RECENTLY AT NIH
WHEN THEY CAME TO THE CLINICAL
CENTER.
MAYBE WANT TO SHARE A LITTLE BIT
ABOUT WHAT IT WAS LIKE TO MEET
SOMEONE WITHIN NIH EITHER MOM OR
GIRLS OR WHOEVER WOULD LIKE TO
SHARE? WANT TO GO?
>> IT WAS REALLY DIFFERENT
BECAUSE EVER SINCE HAVING TO GO
THERE, I ALWAYS JUST HAVE TO BE
BY MYSELF AND NO ONE THERE.
THAT IS IT.
>> YEAH. IT WAS -- IT IS A
POTENTIALLY LONELY JOURNEY.
LIKE THE WAY YOU HAVE ALL
DESCRIBED HOW THIS IS A REALLY
INCREDIBLY RARE CONDITION AND
LEARNING TO TALK ABOUT IT AND
LEARNING HOW TO ADVOCATE IS
LONELY WHEN YOU DON'T HAVE
ANYBODY ELSE YOU COULD SAY LIKE
SLOW DOWN AND LIKE I GET IT. I
GET IT. SO, WHEN THE GIRLS
STARTED THEIR DENOSUMAB
TREATMENT IT WAS FIRST TIME I
MET ANOTHER PARENT, LAURA, WHO
JUST UNDERSTOOD EVERYTHING I WAS
GOING THROUGH. TO HAVE GIANA
NOT HAVE TO EXPLAIN TO KIDS LIKE
WHAT? WHY CAN'T YOU JUST RUN
WITH ME? WHY CAN'T YOU -- AND
FOR IT TO BE LUCY WHO IS LIKE
YEAH. LET'S SLOW DOWN. WE ARE
CHILLING. WE ARE FINE AND TO
LOOK AT EACH OTHER AND KNOW AND
SHARE THE STORY WITHOUT HAVING
TO HAVE WEIRD LOOKS OR HAVE THE
QUESTIONS WAS REALLY POWERFUL.
SO, DR. BOYCE HAS BEEN TRYING TO
GET US TO MEET FOR LITERALLY THE
LAST FIVE YEARS.
WE HAVE BEEN IN THE NIH TOGETHER
AND JUST MISSED EACH OTHER. FOR
THEM TO GO THROUGH ONE FULL WEEK
STAYING AT NIH WHICH COULD BE
AREALLY SCARY AS A KID TO BE IN
THE HOSPITAL OVERNIGHT. THEY
HAD PLAY DATES ON A DAILY BASIS.
ENTIRE NURSING STAFF IN ONE END.
>> 1 NORTHWEST, YES.
>> THEY WERE INCREDIBLE AND
HELPING US SET UP PLAY DATES
TOGETHER AND GIVING GIRLS SPACE
TO WATCH MOVIES AND GO ON
PLAYGROUNDS AT CHILDREN'S IN AND
IT WAS SOMETHING THAT COULD BE
REALLY SCARY TURNED INTO
SOMETHING THAT WAS A POWERFUL
OPPORTUNITY TO BUILD
RELATIONSHIP AND FIND SOMEBODY
THAT EXPERIENCED THE SAME THING.
NOT A LOT ARE THIS YOUNG BUT
THREE THERE AT SAME TIME AND ARE
BESTIES TO THIS DAY AND GET TO
TALK AND CONNECT WITH EACH OTHER
AND HAVE SOMEBODY WHO GETS THEM.
I HAVE A PARENT THAT GETS ME.
IT IS REALLY BEAUTIFUL.
>> I REALLY APPRECIATE YOU
BRINGING UP ONE NORTHWEST
NURSING UNIT. AS HIGHLIGHTED AS
WELL, NONE OF THIS WOULD BE
POSSIBLE WITHOUT SUPPORT FROM NI
HAD. AND NIH CLINICAL CENTER IN
PARTICULAR. WE ARE GRATEFUL FOR
THAT. CAN YOU THINK OF ANYTHING
THAT WAS NICE ABOUT COMING TO
THE CLINICAL CENTER? I'M TRYING
TO PRY SOMETHING OUT OF YOU. I
KNOW YOU HAVE FUN WITH SOME
GUINEA PIGS.
WANT TO SHARE ABOUT THAT?
>> YES. THERE IS A GUINEA PIG.
SHE WAS LIKE I THINK 7 YEARS
OLD. SHE WAS REALLY CUTE AND
REALLY WAL M. AND JUST LIKE
VERY, VERY NICE TO BE WITH.
>> DON'T URNL WILL I GET TO PLAY
WITH A GUINEA PIG WHEN IN THE
HOSPITAL.
>> CAN I SAY SOMETHING?
>> OF COURSE.
>> IT WAS MY FIRST TIME ACTUALLY
SEEING A GUINEA PIG IN REAL
LIFE. IT WAS SCARY AND FUN AT
THE SAME TIME.
I JUST LOVED IT.
THAT IS IT.
>> [LAUGHING].
>> GREAT. DR. COLLINS DID YOU
WANT TO ASK ANY QUESTION SNZ I'M
HOGGING THE MIC HERE.
>> I WONDER IF YOU COULD TELL
MORE ABOUT THE PHENOMENON OF THE
FIRST TIME MEETING ANOTHER
PATIENT.
THIS IS SUCH A UNIVERSAL FEATURE
OF PATIENTS WITH RARE DISEASES
AND NEVER REALIZED WHAT IT WAS
JUST A UNIVERSAL FINDING AND
WHAT IT MEANS AND BEING INVOLVED
WITH THE FOUNDATION.
>> YEAH.
YEAH. ONE THING I WILL SAY IS
ORIGINALLY WITH DR. BOYCE, SHE
WHO LET ME TELL YOU I'M ONE OF
THOSE PARENTS I HAVE NO MEDICAL
BACKGROUND BUT I'M A LEARNER AND
I'M SO CURIOUS AND LIKE TO BE
ABLE TO TALK. IT IS A UNIQUE
CONDITION THAT I WANT TO BE ABLE
TO TALK ABOUT IT. I ASKED MAYBE
UP TO THIS POINT 5 MILLION
QUESTIONS TO DR. BOYCE ABOUT ALL
THESE THINGS AND REASON FOR IT,
I WANTED TO HAVE LANGUAGE TO
TALK WITH HER AND TEACHERS AND
OTHER DOCTORS AND DAYCARES ABOUT
WHAT THIS CONDITION IS AND WHAT
IS TRICKY, SHE IS 7 AND TO HAVE
LANGUAGE TO TALK ABOUT HER
CONDITION TO OTHER KIDS IS
TOUGH.
>> I HAVE DONE IT 5 MILLION
TIMES.
>> YOU HAVE DONE IT 5 MILLION
TIMES, RIGHT.
>> I HAVE TO SAY TO COUSINS TO
AND EVERYONE AND SO TIMELY ONE
TIME DO I HAVE TO.
>> YEAH.
>> WHAT WAS IT LIKE FOR YOU TO
HAVE LUCY TO -- TO -- YEAH. TO
HAVE LUCY WHEN YOU FIRST MET HER
AND TALKING ABOUT WHAT WAS GOING
ON WITH YOU AND HOW WAS THAT?
>> IT WAS ACTUALLY REALLY FUN
AND FIRST TIME I WANTED TO GO TO
NIH BECAUSE YEAH. SHE MADE ME
HAVE A GOOD TIME AND WE ALWAYS
PLAY.
YEAH.
>> YEAH.
>> SO, I THINK JUST HAVING FOR
ME HAVING HER AND HAVING THEM
TALK ABOUT AND HEARING ABOUT HOW
THEY TALKED ABOUT IT TO EACH
OTHER WAS USEFUL. SHE GOT TO GO
BACK TO THE SCHOOL AND HAVE
DIFFERENT WAYS TO TALK ABOUT IT
AND HAVING A PARENT EVEN TALK
ABOUT WELL WHAT DO YOU ALL DO
FOR RECESS AND WHAT ARE
ACCOMMODATIONS MADE FOR YOU AND
WHAT DO YOU DO DURING PE?
THINGS WHERE I EXPLAIN THE
CONDITION AND COOL. I STILL
DON'T KNOW WHAT WE SHOULD AND
SHOULDN'T LET HER DO. TO HEAR
DIFFERENT APPROACHES I LEARNED
INSTEAD OF HAVING HER GO OUT TO
RESEARCH AND LIKE, YOU KNOW, SIT
HERE AND HAVE DIFFERENT THINGS
YOU CAN DO WHILE YOU WATCH
FRIENDS PLAY WHY DON'T YOU BE A
TEACHER'S AID?
HEARING WHAT LUCY DOES IN HER
SCHOOL AND GIANA NOW HAS HER
FIRST JOB YA'LL AT 7 YEARS OLD.
SHE IS A TEACHER'S AID DURING
RECESS IN A PRE-K CLASSROOM CAN
TELL YOU WHAT IT IS ABOUT IT WAS
INSPIRED BY LUCY'S JOURNEY AND
WE CAN IMPROVE THE QUALITY OF
LIFE IN SCHOOL BECAUSE OF
CONNECTIONS WE MADE THROUGH THE
STUDY AND THROUGH OUR STAY HERE.
DO YOU WANT TO TALK ABOUT THAT
AT ALL?
>> YES. MY FIRST DAY ON THE JOB
WAS REALLY CRAZY AND I HAD TO
TAKE CARE OF A LOT OF KIDS.
I ACTUALLY FELT LIKE A REAL
TEACHER BECAUSE I DIDN'T HAVE TO
JUST STAY OUTSIDE LOOKING AT
KIDS DOING NOTHING.
I ACTUALLY CAN LIKE DO STUFF AND
IT ACTUALLY FELT REALLY HAPPY
AND AT THE SAME TIME IT FELT
LIKE OH, MY GOSH. SO, YEAH.
THAT IS IT.
>> YEAH. MAYBE JUST ONE MORE
QUESTION. I HAVE KNOWN BOTH
THESE GIRLS FOR A LONG TIME AND
GIANA IN PARTICULAR I THINK WAS
REALLY NICE.
AS SOON AS THE PUZZLE WAS PUT
TOGETHER SHE HAD MCCUNE ALBRIGHT
SYNDROME WE WERE ABLE TO SWOOP
IN RIGHT AWAY. COULD YOU SHARE
WHAT IT WAS LIKE TO COME TO NIH
AND WORK THROUGH THAT DIAGNOSIS?
>> YOU WOULD LIKE TOO. DO YOU
REMEMBER?
I KNOW.
>> SO, MY FIRST TIME EVER THERE
WAS REALLY SCARY BECAUSE I WAS
ONLY TWO AT THE TIME. I DIDN'T
KNOW WHAT TO DO AND BLAH, BLAH,
BLAH.
FIVE YEARS LATER I FEEL LIKE IT
IS REALLY FUN. NOW I HAVE A
FRIEND, LUCY.
AND NOW I'M JUST USED TO THIS
STUFF.
>> YEAH. YEAH. I WILL TELL A
LITTLE ABOUT OUR JOURNEY.
SHE HAS THIS BEAUTIFUL DRESS ON
AND SHE WRAPS HER LEGS MOST OF
THE TIME LEGS OUT AND IN THE
VIDEO YOU SEE SHE WAS BORN WITH
A SIGNIFICANT AMOUNT OF CAFE AU
LAIT SPOTS AND THAT IS DIFFERENT
AND WENT TO SEVERAL
DERMATOLOGISTS TO TRY TO FIGURE
OUT.
>> TEACHERS YOU MEAN DOCTORS?
>> YES. A SPECIALIST. A SKIN
DOCTOR. JUST TRYING TO FIGURE
OUT WHAT DOES THIS MEAN OR WHAT
IS THIS HAPPENING NO ONE KNEW IT
WAS MOW SDACISM AND AS LONG AS
NOT CANCEROUS WE ARE OKAY NOBODY
KNEW ANYTHING BEYOND THAT.
>> SORRY ME AND MY MOM -- WELL,
ME JUST THOUGHT IT WAS BIRTH
MARKS.
>> YEAH. BIRTH MARKS; RIGHT?
THAT IS ONE PIECE OF THE PUZZLE.
NO DERMATOLOGIST PUT ANYTHING
TOGETHER. WHEN SHE WAS A BABY
SHE STARTED TO BLEED. THAT IS
DEFINITELY DIFFERENT. WE WENT
TO SEVERAL GYNECOLOGISTS AND
PEDIATRIC GYNECOLOGISTS AND NO
ONE COULD STILL FIGURE OUT WHAT
WAS HAPPENING UNTIL DR. GOMEZ
LOBO WAS LIKE WAIT A MINUTE.
THE SPOTS, THE BLEEDING, SHE HAS
THIS INCREDIBLY RARE CONDITION
AND THAT IS WHEN SHE INTRODUCED
US TO DR. BOYCE. SOMEBODY
FINALLY PUT IT TOGETHER. YA'LL
WE HAD BEEN TO MAYBE 8 OR 9
DOCTORS AT THAT POINT. A
GAZILLION DOCTORS AND NO ONE PUT
PIECES TOGETHER UNTIL DR. LOBOS
SAID I GOT IT AND HIT THE GROUND
RUNNING AND 5 YEARS LATER YOU
STILL KNOW HER.
WHAT WAS INTERESTING IS THERE IS
A CONFERENCE THAT ADRIAN TOLD
YOU ABOUT WITH FD/MAS ALLIANCE
HAPPENED A FEW WEEKS AFTER WE
WERE DIAGNOSED. DR. BOYCE WAS
LIKE YOU HAVE TO COME TO IT. IT
WAS VERY LONELY AND LOOKED IT UP
ONLINE AND WHAT? EXTREMES WHAT
IT COULD BE COULD BE EITHER
NOTHING OR SHE COULD BE BLIND.
OKAY. ABSOLUTELY NOTHING OR SHE
MIGHT LOSE ALL HER HEARING.
WHAT? THERE WERE ALL THESE
QUESTIONS. GOING TO THAT FIRST
CONFERENCE AND DR. BOYCE JUST
SAT AND MAYBE JUST THE FIRST
MEETING W WAS HOURS WHERE I
LITERALLY I'M AN ACADEMIC NOT A
DOCTOR BUT CAME IN WITH MAYBE 50
QUESTIONS. THERE IS NO WAY THIS
WOMAN WILL SIT WITH ME. WE
MIGHT HAVE SAT A COUPLE OF HOURS
THE VERY FIRST TIME.
>> A BILLION HOURS.
>> SHE MET AND ANSWERED EVERY
SINGLE QUESTION. AT THE END SHE
ASKED, IS THERE MORE? ANYTHING
ELSE? I HAVE NEVER FELT SO
CARED FOR THAN I DO WITH ANY
DOCTOR THAT I SEE AT THE NIH OR
EVEN I DON'T KNOW IF DR. TOSEY
IS HERE BUT SHE IS OUR
ORTHOPEDIC SURGEON. YES.
PLEASE GIVE IT UP FOR DR. TOSEY.
>> AUDIENCE: [APPLAUSE].
>> SITTING THROUGH WITH US AND
ANSWERING ALL OUR QUESTIONS IS
THE PART THAT MAKES ME KNOW SHE
WILL BE OKAY. DR. BOYCE SAID WE
HAVE A TEAM FOR HER AND WILL BE
HER TEAM FOR LIFE.
>> FOR LIFE?
>> AUDIENCE: [LAUGHING].
>> WELL, THANK YOU GUYS SO MUCH.
THIS HAS BEEN WONDERFUL TO GET
YOUR PERSPECTIVE.
>> THANK YOU.
>> BIG ROUND AFTER MOF APPLAUS
THESE GIRLS.
>> AUDIENCE: [APPLAUSE].
>> I HOPE YOU GATHERED FROM THE
PANEL THIS CONCEPT OF BUILDING
BELONGING IS IN LINE WITH WHAT
NIDCR HAS BEEN WORKING TO
ACHIEVE AND IS WONDERFUL TO HAVE
PATIENTS HERE AND PATIENT
ADVOCATES AND FINAL PRESENTATION
FOR THE DAY IS A VERY SPECIAL
GUEST. I WILL ASK DR. MIKE
COLLINS TO INTRODUCE KELLY COHEN
WHO IS A MOM OF ONE OF OUR
PATIENTS. KELLY WILL BE THE ONE
TO INTRODUCE OUR FINAL SPEAKER.
>> PLEASURE TO INTRODUCE KELLY
COHEN WHO YOU SAW IN THE VIDEO
FROM FD/MAS ALLIANCE AND ASKED
HER TO INTRODUCE DR. KAB ILL KA.
SHE INTRODUCE MD HE TO DR.
KABIKKA. IT IS AN INSPIRING
STORY. ALL THESE PARENTS ARE
INSPIRING STORIES.
>> AUDIENCE: [APPLAUSE].
>> THANK YOU, MIKE.
THANK YOU ALL FOR TAKING THE NIH
AND NIDCR AND PATH OF DOING
RESEARCH ON MCCUNE-ALBRIGHT
SYNDROME FOR THE LAST 25 YEARS.
BECAUSE OF WHAT YOU STARTED HAD
HERE AND THE NETWORK OF AMAZING
DOCTORS AND RESEARCHERS YOU HAVE
PUT TOGETHER MY SON LIAM HAS
ENJOYED A MUCH IMPROVED QUALITY
OF LIFE THAN WE COULD HAVE
IMAGINED.
HE ALSO HAS THE MOST IMPORTANT
THING. HE HAS HOPE. HOPE FOR A
BETTER FUTURE.
ON A VERY PERSONAL NOTE, DR.
COLLINS AND DR. BOYCE, YOUR
TIRELESS EFFORTS FROM EVERY
PATIENT IN THE UNITED STATES AND
EVERY FAMILY AND FAMILIES
ABROAD, WE THANK YOU.
>> AUDIENCE: [APPLAUSE].
>> NOW, I HAVE THE DISTINCT
HONOR OF INTRODUCING YOU TO DR.
BRIAN KAB ILL KA, THE KEYNOTE
SPEAKER TODAY AND WILL DO THIS
BY WAY OF TELLING YOU THE STORY
HOW DR. KABILKA BECAME INVOLVED
WITH THE TEAM HERE. MY SON LIAM
HAS MCCUNE ALBRIGHT SYNDROME AND
SYMPTOMATIC SINCE BIRTH HE HAS
SEVERE PRESENCE OF DISEASE HIS
INFANCY WASN'T A TYPICAL
PRESENTATION. THROUGHOUT HIS
FIRST YEAR OF LIFE LIAM WAS BY
MY SIDE 247 REQUIRING CONSTANT
FEEDING. HE WAS ALWAYS IN PAIN.
GOING FROM DOCTOR TO DOCTOR AND
GETTING FREQUENTLY MISDIAGNOSED
OR BRUSHED OFF AND FRACTURED
EASILY AND FREQUENTLY INCLUDING
FRACTURING HIS FEMUR MULTIPLE
TIMES BEFORE HIS FIFTH BIRTHDAY
EACH TIME REQUIRING COMPLETE
MOBILIZATIONS FOR WEEKS AT A
TIME. HAD THYROID REMOVED AT
AGE 4 THAT IS MUCH EARLIER THAN
THAT SURGERY IS TYPICALLY
PERFORMED INCREASING THE RISK OF
PERMANENT NERVE INJURY. EVERY
VACATION WE TOOK AS A FAMILY,
WHICH IS WHERE MY HUSBAND AND I
WERE INTERVIEWED WAS ALWAYS
AROUND SURGERY OR GOING TO JAIL
TO GET HIS THYROID REMOVED. IF
YOU ASK LIAM ABOUT HIS SUMMER HE
WILL TALK ABOUT VACATION GOING
DOWN EARLY OR TO DISNEY OR SEE
ALLIGATORS. IT IS A WAY OF LIFE
AS A FAMILY.
THOSE FIRST YEARS WERE UTTERLY
EXHAUSTING. I WAS COMPLETELY
GRIEF-STRICKEN. EVERY NIGHT I
WOULD HOLD MY BABY IN MY ARMS
HOPING I COULD DRIP ENOUGH FEEDS
INTO HIM TO HAVE ENOUGH ENERGY
FOR THE NEXT DAY. THEY WERE
DIFFICULT TIMES AND SOMETIMES
DESPERATE TIMES CREATE DESPERATE
PEOPLE DOING UNCHARACTERISTIC
THINGS TO ACCOMPLISH THEIR GOAL.
MARCH 15TH, 2016 I WAS DOWN A
RABBIT HOLE SEARCHING
INFORMATION ON MCCUNE ALBRIGHT
TRYING TO LEARN MORE ABOUT GENE
PROTEINS DR. KABILKA'S RESEARCH
START TODAY POP UP. I WAS
IMPRESSED AND I SENT AN
UNSOLICITED E-MAIL TO A NOBLE
PRIZE WINNER WHY NOT SWING FOR
THE FENCES?
AFTER INTRODUCING MYSELF AND SON
LIAM I WROTE I'M HOPEFUL THERE
ARE RESEARCHERS LIKE YOURSELF
WHO MIGHT BE ABLE TO SHED SOME
INSIGHT INTO THIS VERY
DEBILITATING SYNDROME IF MCCUNE
ALBRIGHT AT ALL PEAKS YOUR
INTEREST LET ME KNOW AND I WILL
CONNECT YOU WITH THE WORLD'S
EXPERTS AT NIDCR'S NIH.
TO MY WONDERMENT JUST A FEW
SHORT HOURS LATER I RECEIVED A
REPLY FROM DR. KABILKA THAT I'M
SURE YOU DON'T KNOW THIS. YOU
GET THOUSANDS OF E-MAILS AND
VERY IMPORTANT E-MAILS.
YOU PROBABLY DON'T REMEMBER THIS
ONE, BUT IT MEANT MORE THAN
ANYTHING TO ME.
THANK YOU.
DEAR KELLY, THANK YOU FOR YOUR
E-MAIL OUR RESEARCH INVOLVES
STUDYING RECEPTORS THAT ACTIVATE
GS ALPHA. THIS IS OF INTEREST
TO ME. I WOULD BE INTERESTED IN
LEARNING MORE ABOUT ONGOING
NIH-FUNDED RESEARCH EFFORTS.
BEST WISHES, BRIAN. REALLY?
[LAUGHING].
WOW!
HOPE!
AFTER THAT, THE FD/MAS TEAM FROM
THE NIDCR NOW HAD A NOBLE
LAUREATE CONTRIBUTING WITH THEM.
DR. BRIAN KABILKA IS CHAIR IN
CARDIOLOGY AND PROFESSOR OF
MOLECULAR AND CELLULAR
PHYSIOLOGY AT STANFORD
UNIVERSITY SHARING 2012 NOBLE
PRIZE IN CHEMISTRY FOR STUDYING
-- SUCCESSFULLY IDENTIFIED GENE
THAT REGULATES FORMATION OF THE
RECEPTOR FOR HORMONE ADRENALINE.
IT WAS LATER DISCOVERED THERE IS
AN ENTIRE FAMILY OF RECEPTORS
THAT LOOK AND ACT IN SIMILAR
WAYS.
G-PROTEIN COUPLED RECEPTORS
APPROXIMATELY HALF OF ALL OF OUR
MEDICATIONS USED TODAY MAKE USE
OF THIS KIND OF RECEPTOR. IT IS
MY DISTINCT HONOR AND PRIVILEGE
TO INTRODUCE YOU TO DR. BRIAN
KOBILKA.
>> AUDIENCE: [APPLAUSE].
>> THANK YOU.
>> SO, THANK YOU FOR THAT
WONDERFUL INTRODUCTION. I'M
VERY GRATEFUL THAT YOU CAUGHT ME
ON A GOOD DAY RESPONDING TO MY
E-MAIL.
>> AUDIENCE: [LAUGHING].
>> I HATE TO ADMIT I'M NOT SO
GOOD AT RETURNING E-MAILS AND
ALSO WANT TO THANK MICHAEL AND
HIS COLLEAGUES FOR INVITING ME
TO THE CELEBRATION.
I'M HONORED TO BE HERE. IT HAS
BEEN A LEARNING EXPERIENCE FOR
ME.
SO, IT IS -- IT IS AMAZING TO
SEE HOW THIS SPECIAL UNIT WAS
PUT TOGETHER AND HOW THEY
LEARNED SO MUCH ABOUT THIS
DISEASE JUST BY CAREFUL
HISTORIES OF PATIENTS OVER MANY
YEARS. SO, ANYWAY,
UNFORTUNATELY, MY RESEARCH
DOESN'T DIRECTLY CONTRIBUTE TO
THIS. THERE IS A RELATIONSHIP
IN THAT I HAVE BEEN VERY
INTERESTED IN UNDERSTANDING HOW
G-PROTEIN-COUPLED-RECEPTORS WORK
AND THESE ARE RECEPTORS THAT
HAVE ACTUALLY THE PHYSIOLOGICAL
ROLE OF ACTIVATING G-PROTEINS
AND I WOULD LIKE TO TELL YOU
ABOUT TODAY IS OUR INTEREST IN
USING WHAT WE LEARNED TO DEVELOP
DRUGS FOR THESE RECEPTORS.
SO, I WANT TO TALK ABOUT THE
CHALLENGES OF DRUG DISCOVERY AND
FIRST WILL GIVE A BRIEF OVERVIEW
WHAT G COUPLED PROTEIN RECEPTORS
ARE AND DISCUSS MAJOR CHALLENGES
IN DRUG DISCOVERY AND TALK A
LITTLE ABOUT HOW STRUCTURAL
BIOLOGY AND WORK THAT WE DO
MIGHT BEGIN TO ADDRESS SOME OF
THE CHALLENGES IN DISCOVERING
DRUGS FOR RECEPTORS.
I WILL USE PRIMARILY THE MIU
OPEN YET RECEPTOR AS A MODEL
SYSTEM FOR THIS. YOU WILL
PROBABLY UNDERSTAND WHY IN A
LITTLE BIT. G-PROTEINED COUPLED
RECEPTORS AND MAJORITY OF
HORMONES IN NEUROTRANSMIT IRS
AND PARADIGM FOR HOW THEY WORK,
THIS WAS WORKED OUT MANY YEARS
AGO SHOWN IN BOTTOM WHERE
RECEPTORS ARE ACTIVATED BY
HORMONE OR NEUROTRANSMITTER AND
BETA RECEPTOR IS ACTIVATED IN
ADRENALINE AND G-PROTEINS
CONSIST OF THREE COMPONENTS
ALPHA, BETA AND GAMMA SUBUNIT.
ALPHA IS ONE MUTATED IN MCCUNE
ALBRIGHT SYNDROME AND UPON
ACTIVATION G-PROTEIN RELEASES
GDP AND BINDS GTP AND GOES ON TO
SPLIT INTO TWO COMPONENTS ALPHA
SUBUNIT AND BETA GAMMA SUBUNIT
THAT MODIFY VARIOUS ENZYMES AND
CHANNELS IN CELL SHOWN IN GS
ACTIVATING A DENDENO -- AND SUBS
REASSEMBLE AND CYCLE CAN BEGIN
AGAIN.
SO, IN ADDITION TO BEING
IMPORTANT FOR MEDIATED RESPONSE
HORMONES AND NEUROTRANSMITTERS
THEY MEDIATE SENSE OF SIGHT,
SMELL AND SOME TASTE. THIS IS
FAMILY TREE AND OVER 800 MEMBERS
AND 800 G-PROTEIN COUPLED
RECEPTORS IN THE FAMILY TREE.
THE MAJORITY OF THESE, THE
LARGEST FRACTION OF THESE ARE
FOR SENSE OF SMELL AND ROUGHLY
400 OLFACTORY RECEPTORS THAT
THERE ARE FOUR RECEPTORS
INVOLVED IN VISION.
SO, THE LARGEST SUBFAMILY AND
THERE IS FIVE SUBFAMILIES AND
LARGEST IS WHAT WE CALL FAMILY A
THAT INCLUDES RECEPTORS FOR
WHICH MY LAB IS REALLY FOCUSED
ON ANURGIC RECEPTORS DOPAMINE
AND CER TONIN AND THEY ARE SOME
OF THE HORMONES AND
NEUROTRANSMITTERS YOU MIGHT BE
FAMILIAR WITH AND ALSO RESPOND
TO OPIATES AND CAN ABINNOIDS AND
OPIATE RECEPTOR FAMILY CONSISTS
OF FOUR MEMBERS AND I WILL
BRIEFLY MENTION INTERESTING
MEMBER OF THIS FAMILY THAT
INCLUDES R--EE CREPTORS FOR
GLUCAGON GLP THAT YOU MIGHT HAVE
HEARD OF ALL OF THE RECENT NEWS
ABOUT DRUGS TARGETING THIS
RECEPTOR BEING EFFECTIVE IN
TREATING OBESITY AND PARA
THYROID HORMONE IMPORTANT IN
BONE METABOLISM AS WELL.
BECAUSE THEY PLAY SUCH AN
IMPORTANT ROLE IN MEDIATING
CELLULAR RESPONSES TO
NEUROTRANSMITTERS LARGER CLASS
OF TARGETS FOR PHARMACEUTICAL
INDUSTRY AND ROUGHLY TLAE 3% OF
DRUGS ON MARKET TARGET G COUPLED
PROTEIN RECEPTORS. HOWEVER,
SUCCESS RATE FOR CONSIDERING HOW
MANY RECEPTORS THERE ARE HAS
BEEN SOMEWHAT DISAPPOINTING. I
WILL TALK ABOUT THAT A LITTLE
BIT.
MY LAB HAS BEEN VERY INTERESTED
IN UNDERSTANDING STRUCTURAL
BASIS FOR RECEPTOR FUNCTION.
WE HAVE USED A VARIETY OF
DIFFERENT APPROACHES TO ELUS
DATE THE STRUCTURES TO TRY TO
UNDERSTAND HOW STRUCTURE
DICTATES FUNCTION AND THESE ARE
SOME LANDMARKS IN MY LAB IN
TERMS OF BEGINNING TO UNDERSTAND
HOW RECEPTORS WORK AND THEY ARE
FIRST STRUCTURE OF RECEPTOR THAT
IS ABSTAINED BY X-RAY
CYSTOGRAPHY AND THE RECEPTOR
THAT IS GAMMA RECEPTOR FOR
ADRENALINE.
AND WE SUBSEQUENTLY WERE ABLE TO
GET A STRUCTURE OF AN ACTIVE
STATE STABILIZED BY AN ANTIBODY
AND IN 2011 A STRUCTURE OF
RECEPTOR CAUGHT IN ACT OF
ACTIVATING G-PROTEIN GS.
SO TO UNDERSTAND HOW THIS WORKS,
WE SORT OF LOOK ATTACKTIVE AND
INACTIVE STATES TO TRY TO
UNDERSTAND MAJOR CHANGES OF
STRUCTURE OF RECEPTOR AND HOW IT
LEADS TO CHANGE OFS IN STRUCTURE
OF G-PROTEIN AND WHAT I WILL DO
IN THE NEXT FEW MINUTES IS JUST
DISCUSS THE RECEPTOR THAT IS
GOING FROM INACTIVE STATE TO
ACTIVE STATE.
MAJOR STRUCTURAL CHANGES THAT
TAKE PLACE.
FIRST OF ALL, G-PROTEIN COUPLED
RECEPTORS CONSIST OF SEVERAL
MEMBRANE SPANNING DOMAINS THAT
ARE ALPHA HEELISIES.
THE MEMBRANE SPANNING DOMAINS ON
EXTRA CELLULAR SIDE FORM A
POCKET BINDING HORMONE
ADRENALINE.
UPON BINDING HORMONE YOU CAN SEE
THERE ARE RELATIVELY SMALL
STRUCTURAL CHANGES THAT TAKE
PLACE AS A RESULT OF HORMONE
BINDING THAT PROPAGATE TO MUCH
LARGER STRUCTURAL CHANGES ON
INSIDE OF THE CELL.
THEY CREATE A CAVITY FOR BINDING
OF THIS LAST COMPONENT OF THE
ALPHA -- THE RAFT AMEAN OF GS
ALPHA OR ALPHA SUBUNIT.
SO, I WANT YOU TO NOTE THAT OF
ALL OF THE STRUCTURAL CHANGES
THAT TAKE PLACE, LARGEST THAT IS
OCCURRING IN THIS TRANSMEMBRANE
THAT WE CALL TRANSMEMBRANE 6
THAT MOVES OUT. THIS HELIX FROM
THE G-PROTEIN MOVES IN. THIS
ALLOWS THE GDP TO BE RELEASED IN
GDP DIVIDE.
SO, AT THE TIME WE OBTAINED
STRUCTURE OF BETA TWO RECEPTOR,
IT WAS ONE RECEPTOR OF THE 800
COUPLING TO ONE SUBTYPE OF
G-PROTEIN AND THERE ARE MULTIPLE
G-PROTEIN SUBTYPES.
WE WANTED TO KNOW WHETHER WHAT
WE LEARNED ABOUT BETA TWO
RECEPTOR APPLIED TO LARGER
FAMILY OF BETA 2 COUPLED
RECEPTORS AND WANTED TO LEARN
ABOUT WHY BETA TWO RECEPTOR
ACTIVATED SPECIFICALLY THIS
PROTEIN GS AS TO MANY OTHER
G-PROTEIN SUBTYPES.
SO, WE STARTED OBTAINING
STRUCTURES OF OTHER G-PROTEIN
COUPLED RECEPTORS COUPLED TO
OTHER G-PROTEINS AND INITIAL
STRUCTURE BY CRYSTALO GRAPHY AND
NEVER ABLE TO DO ANY OF THESE
OTHER COMPLEXES AND DOO YOU TO
ADVANCES IN CRYOELECTRICAL MIKE
ROSS COPY IN 2017 ABLE TO USE
CRYO-EM TO OBTAIN STRUCTURES OF
RECEPTORS AND G-PROTEIN COMPLEX
STRUCTURES AND ARE PROBABLY
LITERALLY OVER 100 NOW SOLVED BY
CRYOELECTRON MICROSCOPY AND
POINTING OUT ROGER WHO IS AN
EXPERT IN G-PROTEINS KNOWING
ABOUT GS MUTATIONS THAN I DO WAS
A CRITICAL COLLEAGUE IN
OBTAINING RECEPTORS OF COMPLEXES
AT STANFORD WHO HELPED US TO GET
ALL STRUCTURES BY CRYOELECTRON
MICROSCOPY AND WHAT DO WE LEARN
FROM THESE STRUCTURES?
SO, FIRST OF ALL, NUCLEOTIDE
FREE. ALL THESE STRUCTURES WERE
OBTAINED IN AN UNUSUAL STATE
THAT WE HAD TO GET RID OF
NUCLEOTIDES TO MAKE SURE ONCE
GDP WAS RELEASED THAT GTP DIDN'T
PINED AND COMPLEXES ARE
NUCLEOTIDE FREE AND ARE VERY
SIMILAR FOR FAMILY AGING PROTEIN
COUPLE THE RECEPTORS THAT REALLY
DIDN'T DEPEND ON G-PROTEIN AND
STRUCTURAL CHANGES OF G-PROTEIN
WERE SAME AND STRUCTURAL CHANGES
IN RECEPTOR WERE THE SAME.
WHAT I MENTIONED EARLIER ON THAT
THERE IS ANOTHER FAMILY, FAMILY
B. THIS FAMILY PLAYS A ROLE AS
I MENTIONED MINERAL METABOLISM.
AND THE STRUCTURAL CHANGES IN
FAMILY B ARE SIMILAR BUT
ACTUALLY MORE DRAMATIC AND I
WANTED TO BRIEFLY SHOW AN
EXAMPLE.
SO, OUR FAMILY B RECEPTOR WE
STUDY IS GLUCAGON RECEPTOR THAT
IS TRURLLY VERY SIMILAR TO
PARATHYROID HORMONE RECEPTOR
THAT WE KNOW IS IMPORTANT IN
MINERAL METABOLISM AND I WANT TO
COMPARE THE ACTIVATION OF THE
BETA TWO RECEPTOR THAT YOU CAN
SEE TRANSMEMBRANE 6 FOR BETA TWO
RECEPTOR WITH A GRADUAL OUTWARD
BENDING AS CONSEQUENCE OF
HORMONE BINDING.
IN CONTRAST FAMILY B RECEPTORS
PARATHYROID RECEPTOR AND
GLUCAGON RECEPTOR HAVE A
DRAMATIC DISRUPTION IN
TRANSMEMBRANE 6 AND UNFAVORABLE
VERY -- THERE IS HIGH ENERGY
BARRIER TO BE ABLE TO ACCOMPLISH
THIS. IT IS ASSOCIATED WITH
VERY DIFFERENT KINETICS BETWEEN
FAMILY A AND B RECEPTORS
INCLUDING VERY PROLONGED
ACTIVATION AND VERY INEFFICIENT
ACTIVATION AND PROLONGED
ACTIVATION. NOT ONLY DOES IT
TAKEN EARTH JI TO CAUSE THE
STRUCTURAL CHANGE BUT ALSO MAKES
IT MORE DIFFICULT TO RETURN TO
INACTIVE STATE.
SO, WE THINK THAT THIS MAY PLAY
A ROLE PARTICULARLY IN FAMILY B
RECEPTORS FOR ROLE IN
MAINTAINING CARBOHYDRATE AND
MINERAL BALANCE.
SO, THE STRUCTURAL CHANGES IN
G-PROTEINS AND THREE MAJOR
CLASSES OF G-PROTEINS GS AND
GQ11 AND GI FAMILY UPON
ACTIVATION ARE SIMILAR AND ALPHA
HELICAL DOMAIN OF G-PROTEINS AND
ALPHA SUBUNIT SHOWN HERE AS TWO
COMPONENTS AN RAS COMPONENT AND
ALPHA HELICAL DOMAIN THAT IS
VERY FLEXIBLE ONCE RECEPTOR IS
ACTIVATED IT BECOMES VERY
DYNAMIC.
WHAT WAS A LITTLE DISAPPOINTING
IS AFTER GETTING ALL OF THE
COMPLEXES WE STILL DON'T
UNDERSTAND COUPLING SPECIFICITY
AND UNDERSTAND WHY A PARTICULAR
GCPR WILL PREFER COUPLING TO
SPECIFIC G-PROTEIN AND WILL BE
DETERMINED BY A SORT OF
INTERMEDIATE STATE AND WE HAVE
OTHER KINDS OF DATA I WON'T HAVE
TIME TO TELL BUT WHERE WE HAVE
ACTUALLY EVIDENCE FOR TWO
INTERMEDIATE STATES THAT WE
BELIEVE INTERMEDIATE STATES ARE
PROBABLY DETERMINING WHICH
G-PROTEIN IT PREFERS AND BY TIME
IT GETS TO NUCLEOTIDE FREE STATE
THAT DETERMINATION HAS ALREADY
OCCURRED.
SO, NOW I WOULD LIKE TO MOVE ON
AND TALK ABOUT CHALLENGES IN
DRUG DISCOVERY AND WONDERFUL
RECEPTORS AND TARGETS AND TURNS
OUT THAT THEY HAVE A VERY
COMPLEX SIGNALING PATHWAYS.
WHAT I SHOWED YOU IN THE FIRST
FEW SLIDES WERE SINGLE RECEPTOR
COUPLING TO SINGLE G2 PROTEIN
THAT DOESN'T APPLY TO ME WITH
MANY RECEPTORS [INDISCERNIBLE]
RECEPTOR IS TARGET FOR MOST
OPIATE ANALGESICS AND DRUGS FOR
ABUSE AROUND MIU RECEPTOR
COUPLES TO 6 NOT 1 DIFFERENT
ISOFORMS.
AS WELL AS INTERACTING WITH
NONG-PROTEIN SIGNALING AND
REGULATORY PROTEINS.
SO, THE QUESTION IS WHICH OF THE
PATHWAYS ARE RESPONSIBLE FOR
THERAPEUTIC EFFECT THAT IS ANAL
GEEZIA REALLY AND ARE
RESPONSIBLE FOR ADVERSE EFFECTS
IF WE COULD LEARN THIS AND MORE
ABOUT IT AND IF WE COULD CONTROL
SIGNALING BEHAVIOR IN THEORY WE
WOULD HAVE SAFER MORE EFFECTIVE
ANALGESICS AND PHARMACOLOGY IS
ALSO COMPLEX AND ARE NOT SIMPLY
ACTIVATORS AND INHIBITORS AND
HAVE SPECTRUM OF ACTIVITY THAT
WE REFER TO AS EFFICACY FROM
FULL AGONIST TO PARTIAL AGONISTS
THEY SUPPRESS -- HAVE SOME LEVEL
OF ACTIVITY IN ABSENCE OF DRUG
OR HORMONE AND INVERSE AGONISTS
SUPPRESS THAT ACTIVITY AND
EXAMPLES OF THIS YOU MIGHT HAVE
HEARD OF ARE FEN TANNAL AND
MORPHINE AND HEROIN AND MORPHO
DON'T ARE PARTIAL AGONISTS AND
[INDISCERNIBLE] IS A WEAK
PARTIAL AGONIST AND NAL OXONE IS
INVERSE AGONIST. IN ADDITION TO
EFFICACY ISSUES OF AFFINITY AND
BU PREN OR FEPRENORPHINE IS --
IT ILLUMINATED DOES IT CROSS
BLOOD/BRAIN BARRIER? ALL THESE
HAVE TO HAVE PROPERTIES TO BE AN
EFFECTOR DRUG.
THERE IS TISSUE SPECIFIC
SIGNALING.
THERE ARE EXAMPLES ANY DON'T
HAVE A EXAMPLE FOR OPIATE
RECEPTOR AND FOR EXAMPLE BETA
RECEPTORS IN THE HEART HAVE VERY
SPECIFIC SIGNALING DOMAINS THEY
RESIDE IN AND EXPRESSING BETA 1
AND BETA 2 RECEPTOR ON IT
UNDIFFERENTIATED CELL THEY
BEHAVE SIMILAR AND CARDIAC
MYOCITES THEY BEHAVE DIFFERENTLY
AND RESIDE IN SPECIFIC SIGNALING
DEPARTMENTS.
PERHAPS MOST CHALLENGING IS HIGH
DEGREE OF SEQUENCE SIMILARITY IN
WHAT WE CALL ORTHOSTATIC BINDING
POCKET THAT IS THE SITE WHERE
HORMONES AND NEUROTRANSMITTERS
NORMALLY BIND AND GIVING YOU AN
EXAMPLE, AGAIN, NOW, THIS IS
JUST A FAMILY A TREE THAT I WILL
FOCUS ON A SUBBRANCH.
HIGHLIGHTED HERE ARE ADENO
NURJIC RECEPTORS AND DOPAMINE 5.
JUST FOCUS IN ON CLUSTER ADENO
URGIC STRUCTURES ARE SIMILAR TO
DOPAMINE RECEPTORS AND SEROTONIN
RECEPTORS AND TRYING TO DEVELOP
A DRUG FOR CERTIFY TONIN
RECEPTOR IS DIFFICULT TO DEVELOP
A SUBTYPE SELECTOR DRUG AND MANY
CASES THIS TARGETED DRUG COULD
HAVE EFFECTS ON ADENO NURJIC
RECEPTORS AND CONSEQUENTLY
SELECTIVITY IS LOST.
FINALLY, THERE IS POLYMORPHISMS
WITH RESPECT TO DRUGS COULD BE
VARIANCE IN RECEPTORS THEMSELVES
AND IN MET ABOLIST DRUGS THAT IS
EXAMPLE OF POLYMORPHISM IN HUMAN
OPIATE RECEPTORS AT METHIONINE
BELOW BINDING POCKETS AND IT IS
SIMILAR TO ENDOGENOUS MET ANO
KEF LYNNE AND PATIENTS WITH
METHIONINE TO VAILINE MUTATION
WITH MARKED REDUCTION IN
RESPONSE TO OPIATES PARTICULARLY
MORPH
MORPHINE.
SO, HOW MIGHT WE DO A BETTER JOB
AT IDENTIFYING DRUGS?
FIRST, CAN WE USE STRUCTURES TO
HELP IDENTIFY NOVEL DRUGS?
CONVENTIONAL DRUG DISCOVERY IS
DONE BY SCREENING EXPERIMENTALLY
RELATIVELY LARGE LIBRARIES OF
COMPOUNDS AND LARGE LIBRARY FOR
DRUG COMPANY TO SCREEN A MILLION
COMPANY COMPOUNDS AND SCAFFOLD
DIVERSITY IS SOMEWHAT LIMITED IN
THAT THERE ARE A MILLION
COMPOUNDS THAT ARE VERY SIMILAR
TO EACH OTHER HAVING TO BE
EXPERIMENTALLY TESTED ON CELLS
AND RECEPTOR AND PROCESS IS SLOW
AND EXPENSIVE AND DEVELOPMENTS
OVER PAST TWO DECADES OR SO
PARTICULARLY FROM LAB BRANCH
[INDISCERNIBLE] HAVE DEVELOPED
DOCKING ALGORITHMS THAT YOU CAN
DO SCREENING COMPUTATION ALLEY
AND COMPOUND LIBRARIES COULD BE
LARGER AND THIS IS A SLIDE THAT
IS COMPOUND LIBRARIES ARE NOW UP
TO A BILLION PRO S ES AND
LIBRARIES HAVE HIGHER SCAFFOLD
DIVERSITY AND PROCESS IS FAST
AND ALL DONE ON COMPUTER AND
EACH COMPOUND IS TESTED IN
THOUSANDS OF ORIENTATIONS AND IF
FITS WELL IT IS A HIT AND IF IT
DOESN'T IT IS DISCARDED AND
PROCESS IS FAST AND LESS
EXPENSIVE AND TRIED TO DO WITH
RECEPTOR THAT IS A NUMBER OF
YEARS OLD AND I USE IT AS A
EXAMPLE.
OUR INITIAL GOAL IN FINDING
NOVEL DRUG FOR RECEPTOR WAS TO
TRY TO FIND A DRUG THAT ONLY
COUPLED G-PROTEINS AND NOT
SUFFICIENT TO ARESIDENTENCE THAT
ARE IMPORTANT FOR TOLERANCE
PEOPLE DESENSITIZE.
WE WORKED WITH BRIAN AND
SCREENED LIBRARY OF 5 MILLION
COMPOUNDS.
WE SELECTED COMPOUNDS THAT LOOK
NOTHING LIKE KNOWN OPIATES AND
IDEA IF WE HAVE NOVEL CHEMISTRY
MIGHT SEE NOVEL BIOLOGY.
WE PICKED 20 TOP CANDIDATES THAT
DID BINDING AND SIGNALING ASSAYS
AND CHEMICAL OPTIMIZATION AND
ULTIMATELY WE HAD NOVEL
COMPOUNDS WE COULD TRY IN
ANIMALS AND THIS JUST IS A
COLLECTION OF TOP-SCORING
COMPOUNDS BINDING TO MANY
DIFFERENT PLACES IN OPIATE
BINDING POCKET.
WHAT WE DID WAS A SIMPLE BINDING
TEST IDENTIFYING COMPOUNDS THAT
COULD INHIBIT BINDING TO
ORTHOSTATIC POCKET.
INITIAL COMPOUND WAS RELATIVELY
LOW AFFINITY AND THROUGH A
SERIES OF CHEMICAL OPTIMIZATIONS
RELATIVELY MINOR OPTIMIZATIONS
WE WERE ABLE TO GET
1,000-INCREASE IN POTENCY OF
THIS COMPOUND.
THIS IS SOME FUNCTIONAL DATA.
FIRST WANT TO LOOK AT EFFECT ON
G-PROTEINS AND DAMGO IS AS I
MENTIONED ANALOG OF
[INDISCERNIBLE] ENDOGENOUS
OPIATE THAT IS A STANDARD FOR
MEASUREMENTS THAT IS A FULL
AGONIST.
YOU CAN SEE MORPHINE IS A STRONG
PARTIAL AGONIST AND DRUG THAT IS
PEZIUM21 IS NOT AS EFFICACIOUS
BUT SIGNIFICANTLY MORE POTENT
ACTIVATING G-PROTEIN AND
MORPHINE AND WANTED TO AVOID
INTERACTION WITH ARRESTIN AND
YOU SEE ARREST AND RECRUITMENT
MEASURE HOW RECEPTORS CAN ENGAGE
ARRESTIN AND DAMGO IS HIGHLY
EFFECTIVE ARRESTIN RECRUITER AND
MORPHINE IS MODERATE TO WEAK
PARTIAL AGONIST FOR ARRESTIN.
HOW DID IT BEHAVE IN TERMS OF
ABILITY TO ACT AS ANALGESIC?
THIS IS A HOT PLATE ASSAY.
WE MEASURE HOW OFTEN THEY LICK
PAWS AS INDICATION OF PAIN AND
MORPHINE IS A VERY EFFECTIVE
ANALGESIC AND [INDISCERNIBLE] IS
NOT AS EFFECTIVE AS MORPHINE HAS
PROLONGED ACTIVITY POSSIBLY DUE
TO FACT IT DOESN'T RECRUIT
ARRESTIN.
WHAT ABOUT ADVERSE EFFECTS?
MAJOR ADVERSE EFFECTS FOR
OPIATES ARE THAT IT CAUSES ONE
STOP BREATHING AND SUPPRESSES
RESPIRATION AND YOU SEE PZM21 IS
PRETTY SIMILAR TO VEHICLE
CONTROL WHEREAS MORPHINE CAUSES
A PRETTY SEVERE DECREASE IN
RESPIRATION RELATIVE TO THE
VEHICLE CONTROL.
NEXT QUESTION, HOW ABOUT
ADDICTION?
THERE IS NOT REALLY GREAT ASSAYS
FOR ADDICTION IN MICE.
ONE OF THE ASSAYS THAT SEEMS TO
COORDINATE OR CORRELATE QUITE
WELL IS ACTIVITY.
WHEN YOU GIVE A MOUSE OPIATE IT
INCREASES ACTIVITY PROBABLY
BECAUSE IT STIMULATES
DOPAMINERGIC SYSTEM MORPHINE
ANIMAL ACTIVE INCREASES
DRAMATICALLY. FINALLY, ASSAY
CALLED CONDITION PLACED
PREFERENCE.
MOUSE IS PUT INTO A CAGE WITH
TWO COMPARTMENTS VISUALLY
DISTINCT HORIZONTAL OR VERTICAL
STRIPES.
WHEN OR IN THIS CHAMBER IS GIVEN
MORPHINE AFTER SEVERAL DAYS OF
TRIALS AND COME BACK A WEEK
LATER PUTTING MOUSE INTO THE
CAGE HE WILL GRAVITATE TOWARDS
THE COMPARTMENT WHERE HE
RECEIVED MORPHINE.
THIS IS A PRETEST SHOWING THAT
THE MOUSE DOESN'T CARE INITIALLY
WHICH SIDE OF THE CAGE HE IS ON.
HOWEVER, AFTER RECEIVING
MORPHINE YOU CAN SEE MOUSE NOW
PREFERS MORPHINE CHAMBER AND
THIS IS NOT THE CASE WITH PZM21
AND RESULTS SUGGEST THAT IT IS
POSSIBLE TO DEVELOP A DRUG USING
UNCONVENTIONAL METHODS AND USING
CRYSTAL AND CRYO STRUCTURES AND
WANT TO EXTEND THIS A LITTLE BIT
TO SAY IT IS POSSIBLE TO IMPROVE
THAT DRUG WHEN YOU HAVE A
STRUCTURE.
SO, ALL OF THE CHEMISTRY IS DONE
BY PETER'S LAB.
AFTER GETTING THE STRUCTURE OF
PZM21 BOUND TO THE OPIATE
RECEPTOR WE NOTICE THIS RING OWE
K PIED THIS SPACE.
WAS A BIT MORE ROOM AND PETER
DESIGNED NEW COMPOUND THAT FIT
THIS SPACE BETTER AND ABLE TO
GET A COMPOUND AND STRUCTURE DID
WHAT YOU EXPECTED IT TO DO AND
RESULT OF THIS MODEST CHANGE
EFFECT OF STIMULATING G-PROTEINS
IS UNCHANGED BUT HAS A 10-FOLD
LOWER POTENCY FOR ARRESTIN AND
IS MORE RESISTANT TO ARRESTIN
RECRUIT
RECRUITMENT.
NEXT TOPIC I WANT TO TALK ABOUT
IS STRUCTURE GUIDED EVOLUTION OF
EXISTING OPIATES AND CAN WE TAKE
A OPIN OPIATE AND MAKE IT BETTE
ADDING THINGS TO IT OR TAKING
THINGS AWAY.
I WA TOPT REMIND YOU THAT ONE OF
OUR GOALS IS TO SEE IF WE CAN
NOW DEVELOP. WE HAVE ARRESTIN
OR G-PROTEIN BIASED DRUGGED AND
NOW WANT TO SEE IF WE CAN START
TO ACTUALLY DEVELOP DRUGS THAT
ARE SELECTED FOR SPECIFIC
G-PROTEINS AND MAYBE ADVERSE
EFFECTS WILL DISAPPEAR WHEN WE
CAN NARROW DOWN TO G-PROTEINS
RESPONSIBLE FOR ANAL GEEZIA.
THESE STUDIES WERE DONE IN
COLLABORATION WITH
[INDISCERNIBLE] AND CHEMIST
[INDISCERNIBLE] FROM WASHINGTON
UNIVERSITY IN ST. LOUIS AND WANT
TO TALK A LITTLE ABOUT THE
BINDING POCKET BEFORE THE OPIATE
RECEPTORS AND UNLIKE MANY
RECEPTORS INCLUDING ADENO URGIC
RECEPTOR THIS IS LARGE BINDING
POCKET THAT BINDS A WIDE VARIETY
OF COMPOUNDS INCLUDING PEPTIDES
LIKE METAKEF LYNNE AND DAMGO AND
IT CAN ALSO BIND TO ANOTHER TYPE
OF ALKALOID WHICH IS AN OPIATE
AGONIST AND THERE ARE SYNTHETIC
AGONISTS THAT ARE SMALLER
INCLUDING METHO DON'T.
NOW, THE MOST LETHAL DRUG IS NOT
FENTANYL THAT IS 100 FOLD MORE
POTENT THAN FENTANYL AND SAFEST
DRUG IS [INDISCERNIBLE] AND WE
WANTED TO SEE FIRST OF ALL HOW
DO THESE DRUGS FIT IN THIS
POCKET?
CAN WE LEARN SOMETHING ABOUT HOW
TO CHANGE DRUGS TO MAKE THEM
SAFER OR MORE EFFICACIOUS?
FIRST OF ALL, WE ARE INTERESTED
IN UNDERSTANDING WHICH G-PROTEIN
SUBTYPES THESE DRUGS MIGHT
PREFERENTIALLY ACTIVATE.
THIS IS A BUSY SLIDE THAT I
WON'T GO THROUGH ALL THESE.
EACH COLOR REPRESENTS ACTIVATION
OF DIFFERENT G-PROTEIN OR A
AARRARRE
ARRESTIN. IN CONTRAST
[INDISCERNIBLE] IS RELATIVELY
WEAK. AT MANY OF THESE YOU CAN
PARTICULARLY SEE GZ HAS HIGHEST
POTENCY FOR GZ FENTANYL AND
LOWEST FOR [INDISCERNIBLE] AND
THIS IS INTERESTING HAS HAS
DIFFERENT G-PROTEIN SIGNALING
PROFILE AND ABLE TO GET
STRUCTURES BOUND TO BOTH OF THE
COMPOUNDS.
YOU WILL NOTICE THERE IS A
POCKET THAT IS DIFFERENT AND IS
OCCUPIED IN MET WRATH NEEN
STRUCTURE BUT NOT
[INDISCERNIBLE] STRUCTURE. WE
CAN SEE THAT BECAUSE METRAGENINE
INSERTED INTO POCKET PREVENTED
INTERACTIONS OF AMINOS IN POCKET
SHOWN IN [INDISCERNIBLE]
STRUCTURE AND INTERACTIONS WE
CALL HYDROGEN BONDS THAT AS A
RESULT OF INTERACTIONS THERE ARE
CHANGES THAT OCCUR IN
CYTOPLASMIC DOMAINS WHERE
G-PROTEINS COUPLE AND WE BEGIN
TO SEE HOW OCCUPYING DIFFERENT
PARTS OF THIS POCKET MIGHT ALLOW
US TO CHANGE BEHAVIOR OF SOME OF
THESE EXISTING OPIATES.
I WILL PASS ON THIS ONE.
SO, THE FOLLOWING IS A EXAMPLE
OF A STRUCTURE GUIDED EVOLUTION
OF [INDISCERNIBLE].
WE HAVE A COMPOUND THAT IS SAFE.
CAN WE MAKE IT SAFER OR MORE
SELECTIVE?
WITH [INDISCERNIBLE] DID IS HE
NOTICED SPACE ABOVE THE COMPOUND
AND MAYBE HE COULD START TO ADD
THINGS THAT WOULD EXTEND INTO
THE SPACE. LOOK WHAT HAPPENS.
IT IS A TRIAL AND ERROR.
HE DEVELOPED ONE OF THESE
COMPOUNDS THAT WE CALL SC103.
AT FIRST, I WANT TO TAKE YOU
BACK TO METRAGENINE -- NOW, YOU
CAN SEE JUST BY ADDING AEROMATIC
RING ON OUTER SIDE OF PROK ET HE
CHANGED G-PROTEIN SIGNALING
PROFILE.
NOW, GZ IS THE MOST EFFICACIOUS
HERE. GZ IS LEAST EFFICACIOUS.
WHAT IS MORE IMPORTANT, IT
ACTIVATES ONLY THREE PROTEINS
GZ, GOA, AND GB. HOW DOES IT
BEHAVE? ANIMALS IN ANAL GEEZIA
ASSAY IS AS GOOD AS MORPHINE.
NOT QUITE AS GOOD AS METRAGENINE
AS POTENCY AND POTENT AND
EFFICACIOUS AS MORPHINE AND HAS
NO EFFECT ON RESPIRATORY
SUPPRESSION AND SUGGESTS THAT WE
CAN IN FACT BEGIN TO EVOLVE
DRUGS PERHAPS WITH SIGNALING
PROFILES.
WHAT HAVE WE LEARNED FROM
STUDIES SO FAR?
WE ARE BEGINNING TO UNDERSTAND
ROLE OF DIFFERENT G-PROTEINS AND
BELIEF ALGEEZIA REQUIRES GOA
AND/OR GOB AND POSSIBLY GOZ AND
POSSIBLE RESPIRATORY ADDICTION
THAT IS POSSIBLY A COMBINATION
OF GZ, GI1 AND GI2 OR GI3 AND
TOLERANCE IS MEDIATED BY
ARRESTIN.
SO, I DON'T KNOW HOW MUCH TIME I
HAVE.
OKAY. I HAVE A FIVE-MINUTE
STO
STORY.
I WANT TO MENTION LAST AREA OF
DRUG DISCOVERY MADE POSSIBLE BY
[INDISCERN
[INDISCERNIBLE].
SHOWN HERE IS MET AN KEF LYNNE
SHOWN IN BLUE AND REST OF
RECEPTOR IS SHOWN IN GREEN.
THIS REPRESENTS POTENTIAL
BINDING SITES FOR ALOSTERIC
MODULATORS THAT ARE OUTSIDE OF
THE ORTHOSTERIC POCKET AND
MODULATE OR AUGMENT OR INHIBIT
RESPONSES TO NATIVE HORMONE OR
NEUROTRANSMITTER MINIMIZING
ADVERSE EFFECTS OF
[INDISCERNIBLE] AND CAN HAVE
GREATER ACTIVITY SINCE MOST
HIGHLY CONSERVED PART OF
RECREPTOR IS A BINDING POCKET
THAT WE USE DNA ENCODED CHEMICAL
LIBRARIES TO IDENTIFY NOVEL
COMPOUNDS THAT ARE HUGE
LIBRARIES OF COMPOUNDS UP TO
TRILLION COMPOUND LIBRARIES
AVAILABLE WHERE EACH COMPOUND
INCLUDES A DNA BARCODE THAT YOU
CAN IDENTIFY WHICH COMPOUND
STICKS TO RECEPTOR BY SEQUENCING
AND THESE LIBRARIES ARE COVE
AILIENTLY ATTACHED TO SMALL
MOLECULES BINDING TO DNA STRANDS
AND BAR CODES AND LARGER NUMBER
OF CYCLES THAT YOU ADD MORE
FRAGMENTS TO LARGER THE LIBRARY.
JUST BRIEFLY YOU MIX YOUR
RECEPTOR ACTIVE OR INACTIVE
STATE WITH LIBRARY AND WASH AWAY
THINGS THAT DON'T BIND AND ELUDE
THINGS THAT DON'T BIND AND MIGHT
DO IT A COUPLE TIMES AND AT END
YOU SEQUENCE WHAT BOUND AND
DETERMINE WHICH COMPOUNDS YOU
FIND.
YOU CAN USE ACTIVE OPIATE
RECEPTOR COUPLED TO GI TO
IDENTIFY POSITIVE ALOSTERIC
MODULATORS IN INACTIVE STATES TO
IDENTIFY NEGATIVE MODULATORS
THAT WE DID THIS WITH A
RELATIVELY SMALL LIBRARY OF 4
BILLION COMPOUNDS AND FROM THESE
WHAT IS REALLY REMARKABLE IS WE
SELECTED 5 AND HAD LIMITED
ABILITY TO PAY FOR MORE
COMPOUNDS AND SAID WE WILL
SELECT 5. OF THESE WE
IDENTIFIED 1 PAM AND 1NAM THAT
IS A VERY HIGH EFFICIENCY RATE
AND WERE ABLE TO GET STRUCTURES
OF -- THE RECEPTORS THAT WERE
BOUND TO THESE.
I WANT TO SHOW YOU. THEY ARE
INTERESTING IN WHERE THEY BIND.
SO, THIS IS A NEGATIVE ALOSTERIC
MODULATOR THAT BINDS BETWEEN TM7
AND TM1 AND FORMS OVER NAL OXONE
[INDISCERNIBLE] ONE PROBLEM WITH
NAL OXONE TREATING OVERDOSE IS
HAS A SHORT LIFE AND HOPING THAT
PERHAPS SOMETHING LIKE THIS NAM
MIGHT EXTEND NALOXONE'S HALF
LIFE MAKING IT MORE EFFECTIVE AT
PREVENTING OVERDOSE DEATHS AND
PERHAPS STRANGEST COMPOUND IS A
POSITIVE ALOSTERIC MODULATOR
THAT BINDS AS SHOWN HERE ON THE
OUTSIDE OF THE RECEPTOR THAT
TURNS TRANS MEMBRANES 6 AND 7
THAT IS IMPORTANT FOR ACTIVATION
THAT HAS ACTIVE AND INACTIVE
STATE THAT YOU LOSE BINDING
POCKET FOR THIS POSITIVE
ALOSTERIC MODULATOR. I WILL END
HERE. THIS IS AN ONGOING
PROCESS AND WE CONTINUE TO LOOK
FOR BETTER DRUGS AND IMPROVE
DRUGS WE HAVE AND WE ARE
INTERESTED IN SUBTYPE SELECTIVE
DRUGS AS WELL AS DRUGS THAT WORK
AS ALOSTERIC MODULATORS.
THESE ARE PEOPLE THAT HAVE DONE
THE WORK AND PARTICULARLY
CALLING OUT EVAN THAT DID OPIOID
RECEPTOR WORK I TALKED ABOUT AND
THIS IS DONE IN COLLABORATION
WITH [INDISCERNIBLE] AT
WASHINGTON UNIVERSITY AND
APPRECIATE YOUR ATTENTION AND
APPRECIATE FUNDING FROM NIH.
THANK YOU.
>> AUDIENCE: [APPLAUSE].
>> THANK YOU, DR. KOBILKA. THIS
ROOM IS FULL OF YOUNG
SCIENTISTS.
YOUR DISCOVERIES ARE
INSPIRATIONAL. I HOPE THAT
PEOPLE ARE THINKING ABOUT THE
APPLICATION AND TARGETED
THERAPIES AND ALL DISEASES THAT
WE REALLY CAN ADDRESS AND CURE
AND TREAT.
AND AS OUR YOUNGEST GUEST SAID
JUST EARLIER, GO FOR IT!
>> AUDIENCE: [LAUGHING].
>> I WOULD LIKE TO TAKE THIS
MOMENT TO INVITE THE DIRECTOR OF
NIDCR, DR. RENA D'SOUZA TO THE
PODIUM FOR HER CLOSING REMARKS.
DR. D'SOUZA PROVIDED TREMENDOUS
SUPPORT AND IS AN ADVOCATE FOR
OUR RESEARCH TO APPLY AND
IMPROVE HEALTH OF OUR PATIENTS.
DR. D'SOUZA, THANK YOU.
>> THANK YOU.
>> AUDIENCE: [APPLAUSE].
>> THANK YOU DR. KOBILKA. IT
WAS JUST FASCINATING TO SEE THE
JOURNEY FROM TASTE AND SMELL AND
TOUCH TO GO INTO STRUCTURED
BIOLOGIES AND TACKLE A PROBLEM
NATIONWIDE AND DEVASTATING TO
OUR SOCIETY. THANK YOU FOR
THAT. IT HAS BEEN
INSPIRATIONAL. FOR ME, HUMBLING
AND EQUALLY PROUD OF ALL WE HAVE
HEARD TODAY.
FROM TIME I ARRIVED IN OCTOBER
OF 2020, I HAD THIS THROUGH THE
IMPORTANCE OF REALIZING PROMISE
OF SCIENCE AND FOR BENEFIT OF
OUR PATIENTS AND IN ORAL HEALTH
THAT IS SO TRUE TODAY. DESPITE
TECHNOLOGY AND SCIENCE COMING
TOGETHER UNPRECEDENTEDLY TO MAKE
IT ACTUALLY POSSIBLE FOR THE
FIRST TIME IN OUR HISTORY TO
MAKE THE LIVES OF PATIENTS
BETTER IS TRULY AN OPPORTUNITY
THAT WE CAN'T MISS.
SO, FOR ME, THIS IS TRULY REALLY
A REVELATION AND MUST SAY THAT
EVERY TIME I TALK TO ALLISON OR
KELLY OR RACHEL, THEY SPEAK OF
YOU, MIKE. FOR YOU, LEGACY YOU
LEAVE AT NIH IS WONDERFULLY
BRIGHT AND TALENTED MOTHERS AND
WOMEN. THANK YOU FOR THAT. LE
IT IS A LEGACY. WE MISS YOU BUT
IT WILL LIVE ON AND I KNOW THAT
YOU WILL STAY CONNECTED WITH NIH
AND OUTSIDE WORLD.
JEANNA AND LUCY I'M AN ADVOCATE
FOR IPHONES FOR YOU. I KNOW YOU
ASKED ME TO SAY THAT.
[LAUGHING].
EVEN THOUGH YOU HAVE TO USE IT
IN A CAREFUL WAY I THINK YOU CAN
COMMUNICATE WITH EACH OTHER AND
PROBABLY ALL OF THE YOUNG
INDIVIDUALS LIKE YOU WHO SUFFER
FROM THIS CONDITION AND MANY
GOOD WAYS TO CONNECT AND MAKE
SCIENCE ACTUALLY SO PUBLICIZED
OR ALL GOOD ASPECTS OF SCIENCE
TO BE PUBLICIZED IN THIS WORLD
THAT MISINFORMATION AND
DISINFORMATION THRIVE; RIGHT?
SPECIAL THANKS FOR THOSE THAT
PIONEERED FOUNDATIONAL DISCOVERY
ENNIGMATIC AND COMPLEX CONDITION
FOR ALL THAT YOU DID TO UNRAVEL
THE COMPOUND NATURE OF G-PROTEIN
COMPLEXES AND RECEPTORS AND FOR
JANICE AND FOR MAKING THE
INFRASTRUCTURE AVAILABLE FOR
ALLISON AND KELLY AND MIKE AND
OTHERS TO GET DONE WORK THAT IS
IMPORTANT, THANK YOU FOR WHAT
YOU DID TO CLINICAL RESEARCH AT
N IC
NIDCR, THANK YOU AND PAM AND
SPIEGEL AND MARA AND MICHAEL AND
ALLISON AND ALL OF YOU
EMPHASIZED IMPORTANCE OF THE
FOUNDATIONAL SCIENCES IN
CREATING AND MAKING POSSIBLE,
ACTUALLY, TRANSLATIONAL
CONTINUUM. IT IS IN FACT A
CONTINUUM AND NOT BASIC ON ONE
END AND CLINICAL ON THE OTHER AS
WE ARE PART GROWING UP IN THE
NIH WORLD WHERE WE HAD TO BE
HYPOTHESIS DRIVEN AND
MECHANISTIC THAT IN FACT THAT
CONTINUUM IN THE END WITH
PATIENT IN THE CENTER THAT
ACTUALLY MAKES A DIFFERENCE AND
FIBROUS DYSPLASIA AND MCCUNE
ALBRIGHTS -- UNPREDICTABLE
CLINICAL PRESENTATIONS QUITE
BURIED CONFOUNDED MEDICAL
PROFESSIONALS GENERATIONS
READING FROM NOTES I DON'T WANT
TO MISS ANYTHING IMPORTANT I
TEND TO BE MORE EMOTIONAL THAN
PAM AND MIKE.
SO, PURSUIT OF KNOWLEDGE IN
FIELD BEGAN WITH A SIMPLE
QUESTION THAT WE KEEP AND SHOULD
BE ASKING OURSELVES EVERY DAY
HOW CAN WE UNRAVEL THE MYSTERIES
OF THE SYNDROME AND ANYTHING
COMPLEX IN LIFE AND IMPROVE
LIVES OF THOSE EFFECTED?
ANSWER LIES IN COLLABORATIVE
SYNERGY BASIC TRANSLATIONAL AND
CLINICAL RESEARCH THAT I DEFINE
AS CONTINUUM AND BASIC RESEARCH
IS BEDROCK OF SCIENTIFIC
DISCOVERY AND NIH STAYED TRUE TO
COURSE AND UNRAVEL GENETIC
MUTATIONS FOR THIS CONDITION
SHEDDING LIGHT HOW BONE TISSUE
IS REPLACED WITH ABNORMAL
FIBROUS MATERIAL AND HOW
[INDISCERNIBLE] GOES AWRY AND
WONDER HOW FIBROBLASTS ARE
IGNORED IN THIS AND PERHAPS NEED
TO BE LOOKED AT THEY ARE TEEP
WHOSE PHENOTYPE IN FUNCTION
HASN'T BEEN EXPLORED THAT IS
JUST ME AND HELPING US
UNDERSTAND MOLECULAR BASIS OF
DISORDERS CAUSED BY DEFECTS IN
G-PROTEINS MUTATIONS ARE
RESPONSIBLE FOR SYNDROMES
DIVERSE PHENOTYPE OR
MANIFESTATIONS AND TRANSLATION
RESEARCH BRIDGED GAP BETWEEN LAB
DISCOVERIES AND CLINICAL
APPLICATION AND THIS CRUCIAL
STEP TRANSFORMS GENETIC INSIGHTS
INTO POTENTIAL THERAPEUTIC
STRATEGIES INFORMING HOW
EXPERIMENTAL TREATMENTS CAN
TRANSITION FROM BENCH TO BEDSIDE
AND BACK OFFERING MUCH HOPE AND
PROMISE TO PATIENTS.
OUR WORK HAS SHOWN OR YOUR WORK
HAS SHOWN THAT THE PATH TO
HARNESSING BODY'S OWN HEALING
POTENTIAL IS GROUNDBREAKING WORK
AND WHETHER STEM CELL THERAPIES
OPENING NEW ORRIZONS OPENING AND
MANAGING PROBLEM REVERSING
DEVASTATING EFFECTS IT COMES AND
REFLECTING ON 25 YEARS OF
TIRELESS DEDICATION AND
COLLABORATION I CAN SEE A BETTER
WAY TO CELEBRATE 75 YEARS FOR
EXISTENCE AT NIH FOR NIDCR AND
SEE FRUITS OF LABOR MOVING FROM
PLACE OF UNCERTAINTY TO ONE OF
HOPE AND TREATMENT OPTION AND
PERSONALIZED THERAPIES IN REACH
AND FIBROUS DYSPLASIA MCCUNE
ALBRIGHT IS NOT INSURMOUNTABLE
CHALLENGE BUT FIELD RIPE WITH
PROMISES AND IS PROMISE TO YOU
GIANA AND LUCY AND IN CLOSING WE
REMAIN COMMITTED TO ADVANCING
INTEGRATION OF BASIC TRANSLATION
AND CLINICAL RESEARCH NOT ONLY
FOR FIBROUS DYSPLASIA AND MCCUNE
ALBRIGHT SYNDROME BUT ALL RARE
DISEASES TOGETHER WE ARE TORCH
BEARERS OF HOPE, ARCHITECTS OF
PROGRESS AND GUARDIANS OF
BRIGHTER FUTURE FOR ALL THOSE
THAT DEPEND ON OUR COLLECTIVE
EFFORTS.
THANK YOU ALL FOR COMING FOR
YOUR UNWAIVERING DEDICATION TO
THE SCIENTISTS THAT MADE THIS
JOURNEY TRULY INSPIRING FOR
GENERATIONS TO COME. I THANK
YOU FROM THE BOTTOM OF MY HEART.
>> AUDIENCE: [APPLAUSE].
>> NOW I WOULD LIKE TO INVITE
EVERYONE TO FAES TERRACE FOR
REFRESHMENTS AND VISUAL HISTORY
OF FDA JOURNEY AND HISTORY OF
SPEAKERS AND PATIENTS AND
LEADERS IF YOU CAN STAY BACK FOR
A FEW MINUTES FOR PHOTOS.