>>I'D LIKE TO INTRODUCE MY
VERY GOOD FRIEND AND COLLEAGUE,
DR. DAN KASTNER WHO OBTAINED HIS
A.B. SUMMA CUM LAUDE FROM
PRINCETON UNIVERSITY IN 1973 AND
Ph.D. AND M.D. FROM BAYLOR
COLLEGE OF MEDICINE IN 1982.
AFTER COMPLETING INTERNAL
MEDICINE RESIDENCY HE MOVED TO
THE NATIONAL INSTITUTES OF
HEALTH 1985 AND IS AN NIH
DISTINGUISHED INVESTIGATOR CHIEF
OF THE INFLAMMATORY DISEASE
SECTION AND SCIENTIFIC DIRECTOR
EMERITUS OF THE DIVISION OF
INTRAMURAL PROGRAM AT THE
NATIONAL INSTITUTE.
THAT IS VERY IMPORTANT TO ME
BECAUSE DAN MENTORED ME AND I'M
NOT DOING HIS FUNCTION AS A
SCIENTIFIC DIRECTOR AN
OPPORTUNITY TO THANK DAN FOR
MAKING THE HOUSE VERY STABLE FOR
ME TO STEP IN.
THANKS, DAN.
THROUGHOUT HIS CAREER AT THE NIH
DOING RESEARCH HAS FOCUSSED ON
GENOMIC STRATEGY TO UNDERSTAND
DISORDERS OF INFLAMMATION WITH
PATIENTS RELATIVELY RARE
DISORDERS SEEN AT THE NIH
CLINICAL CENTER HOSPITAL.
THIS WORK HAS PROVIDED DETAILED
MOLECULAR EXPLANATION FOR THE
ILLNESS AND HAS ESTABLISHED THE
CONCEPTUAL BASIS FOR HIGHLY
ELECTIVE TARGETED THERAPIES.
AND HAS INFORMED OUR
UNDERSTANDING OF MORE COMMON
ILLNESSES.
DAN'S GROUP PROPOSED THE NOW
WIDELY ACCEPTED CONCEPT OF
AUTOINFLAMMATORY DISEASE
DISORDERS OF THE EVOLUTIONARY
PATIENT OF THE IMMUNE SYSTEM.
DAN HAS WON A NUMBER OF AWARDS
AND HONORS.
THAT IS ABSOLUTELY CORRECT AND
THE LIST WOULD GO ON BUT I'M
GOING TO SUMMARIZE IT QUICKLY.
INCLUDING ELECTION TO THE
NATIONAL ACADEMY OF SCIENCE IN
2010, TO THE NATIONAL ACADEMY OF
MEDICINE IN 2012 AND RECOGNITION
AS THE FEDERAL EMPLOYEE OF THE
YEAR IN 2018 AND THE PRIZE IN
MOLECULAR MEDICINE IN 2019 AND
CRAWFORD PRIZE FROM THE ROYAL
SWEDISH ACADEMY OF SCIENCE AND
THE CRAWFORD FOUNDATION IN
202137 -- 2021.
I WELCOME DR. KASTNER.
>>THANK YOU FOR THE KIND
INTRODUCTION.
AND I WANT TO THANK YOU AND ALL
OF THE BOARD OF SCIENTIFIC
DIRECTORS FOR HAVING CHOSEN ME
FOR THIS VERY HIGH HONOR OF
GIVING THIS THE 2023 MIDER
LECTURE.
DR. MIDER ON THE SLIDE RIGHT
HERE THE OPENING SLIDE.
HE WAS THE FIRST HE WAS A
DIRECTOR OF LABORATORIES AND
CLINICS WHICH IS THE EQUIVALENT
OF THE DEPUTY DIRECTOR FOR
INTRAMURAL RESEARCH.
I HOPE DURING THE COURSE OF MY
TALK YOU'LL SEE HOW WE CAN BRING
TOGETHER WHAT GOES ON IN THE
LABORATORY AND WHAT GOES ON IN
THE CLINICS.
IN THIS PARTICULAR CASE LOOKING
AT AUTOINFLAMMATORY DISEASE AND
THE HUMAN CONDITION.
BUT BEFORE WE LAUNCH INTO THAT,
I MUST REMIND YOU THAT I HAVE NO
FINANCIAL RELATIONSHIPS TO
DISCLOSE.
IN ANY EVENT STARTING OUT FOR
THOSE NOT FAMILIAR WITH THE
SYSTE
SYSTEMIC AUTOINFLAMMATORY
DISEASE THESE ARE EPISODES OF
SEEMINGLY UNPROVOKED, LOCALIZED
OR SYSTEMIC INFLAMMATION WITHOUT
THE HIGH TITER ANTIBODIES OR T
CELLS ONE WOULD TYPICALLY SEE IN
THE AUTO IMMUNE DISEASE AND THEY
CAN HAVE DRAMATIC EVIDENCE OF
INFLAMMATION I'LL ILLUSTRATE
WITH A FEW PHOTOS ON THE SLIDE.
THIS HAPPENS TO BE THE FOREARM
OF A YOUNG MAN FROM KANSAS CITY
WITH A SYNDROME OF PYO GENIC
ARTHRITIS AND ACNE.
THIS PARTICULAR CASE THE SKIN
LESIONS ONE OF THE SKIN LESIONS
CAN HAVE.
THIS TOOK SEVERAL MONTHS FOR THE
PATIENT TO HEAL.
HERE WE HAVE AN MRI OF THE LEG
OF A PATIENT WITH THE TNF
RECEPTOR ASSOCIATED SYNDROME.
THESE PATIENTS CAN HAVE
INFLAMMATION GOING DOWN INTO THE
MUSCLE COMPARTMENT OF FASCIITIS
THAT MIGRATES DOWN THE LOW.
A RELATIVELY NEW INFLAMMATORY
DISEASE ROSEA THAT PRESENTS WITH
VISION LOSS AND THE PATIENTS
DEVELOP A POLY ARTICULAR
ARTHRITIS AND THE LAST EXAMPLE
IS DAD2 THE DEFICIENT WHICH IS A
DISEASE YOUNG CHILDREN CAN
PRESENT WITH UNEXPLAINED FEVERS
SOMETIMES STROKES OR SOMETIMES
INFLAMMATION OF THE BLOOD
VESSELS VASCULITIS.
THIS TURN OUT TO BE DISORDERS OF
THE PHYLOGENETICALLY ANCIENT
INNATE BRANCH OF THE IMMUNE
SYSTEM AND PROVIDED NEW INSIGHTS
INTO HUMAN BIOLOGY AND
OPPORTUNITIES FOR TARGETED
THERAPIES.
NOW TO PUT THIS IN HISTORICAL
PERSPECTIVE I PRESENT THE IMAGE
OF PAUL ERLIC.
AN IMMUNOLOGIST OF THE 20th
CENTURY AND WON THE NOBEL PRIZE
IN PHYSIOLOGY AND MEDICINE IN
AND PROPOSED OF HORROR
AUTOTOXICUS THAT IT WOULD BE
PERSON FOR THE NETWORK IT TURN
AGAINST THE HOME AND THE DOGMA
IN THE EARLY 20th CENTURY WAS
AUTO COMMUNITY WOULDN'T BE
POSSIBLE AND THERE WAS HASHI
MOTO'S DISEASE AND THE LATTER
HALF OF THE 20th CENTURY WAS THE
TIME WHEN AUTOIMMUNE DISEASES
SORT WE USUALLY THINK OF WERE
FIRST CHARACTERIZED.
IT WAS NOT UNTIL THE END OF THE
20th CENTURY ACTUALLY THAT THIS
CONCEPT OF AUTOINFLAMMATORY
DISEASE CAME TO THE FORE.
MY FIRST EXPOSURE TO A PATIENT
WHO TURNED OUT TO HAVE WHAT WE
NOW CALL AUTOINFLAMMATORY
DISEASE WAS ACTUALLY WHEN I WAS
A BEGINNING FELLOW IN
RHEUMATOLOGY HERE AT THE NIH.
HERE YOU SEE THIS WAS A
HAND-WRITTEN NOTE THAT I WROTE
ON NOVEMBER 14 OF 1985 AFTER I
HAD SEEN THIS PATIENT IN CLINIC.
A YOUNG MAN OF ARMENIAN ANCESTRY
WITH A LIFE LONG HISTORY OF
RECURRENT FEVERS AND ARTICULAR
ARTHRITIS AND TURNED OUT TO HAVE
FAMILIAL MET -- MEDITERRANEAN
DISEASE AND IT WAS THOUGHT TO BE
AN RECESSIVELY INHERITED DISEASE
BUT NO ONE KNEW WHAT THE GENE
WAS OR ANYTHING ABOUT THE
PATHOPHYSIOLOGY OF THE DISEASE
IN ANY SERIOUS WAY.
IN ANY CASE IT'S SEEN IN PEOPLE
OF ARMENIAN, ARAB, TURKISH,
ITALIAN AND JEWISH ANCESTRY.
IT'S CHARACTERIZED BY ONE TO
THREE DAY EPISODES OF FEVER WITH
STERILE PERI TINNITUS OR SOME
PATIENTS DEVELOP ARTHRITIS AND
AT LEAST IN SOME CASES THEY CAN
HAVE OTHER SYMPTOMS.
THIS IS A DRAMATIC DISEASE FOR
ME SEEING THE PATIENT.
THERE WAS A TREATMENT WHICH WAS
GREAT BUT IT DID DEF -- THIS WAS
AT THE MAGICAL TIME AT THE
BEGINNING OF THE GENOME PROJECT
AND THE POSSIBILITY OF DOING AT
SCALE SOME SCREENING THE WHOLE
GENOME TO DISCOVER THE CAUSE OF
THE SQUEEZE YOU DIDN'T HAVE A
CLUE AS TO WHAT WAS GOING ON.
THAT WAS FANTASTIC AND
EVENTUALLY TOOK TIME FOR ME TO
GET INVOLVED IN THIS BUT BY THE
SUMMER OF 1989 I WAS HARD AT IT
IN TERM OF TRYING TO FIND THE
NEED FAMILIAL MEDITERRANEAN
SYNDROME AND BECAUSE OF THE FACT
THERE WERE FEW MARKERS IN THE
HUMAN GENOME THAT WERE KNOWN AT
THAT TIME ONLY ABOUT 300 MARKERS
OF DNA MARKERS IN THE WHOLE
HUMAN GENOME YOU HAD TO HAVE
LOTS OF FAMILIES IN ORDER TO BE
ABLE TO ACTUALLY MAP A DISEASE
GENE.
HERE YOU SEE THE EXPEDITION I
WENT ON IN THE SUMMER OF 1989
AND HERE I'M VISITING A FAMILY
IN THIS AREA AND HERE'S MY
COLLABORATOR IN THESE ADVENTURES
AND THIS PARTICULAR FAMILY IS A
FAMILY WHERE THE PARENTS WERE
FIRST COUSINS OF ONE ANOTHER AND
YOU CAN SEE THE FAMILIAL
RESEMBLANCE BETWEEN THE TWO OF
THEM.
IT WAS A GREAT FAMILY FOR DOING
THE GENETIC LINKAGE ANALYSIS.
ALL TOGETHER WE DREW BLOOD ON
248 INDIVIDUALS AND MADE EVB
CELL LINES ON THESE PEOPLE AND
WHAT WE DID BACK IN THOSE DAY TO
MAP A DISEASE GENE.
AFTER A COUPLE YEARS WE WERE
SUCCESSFUL IN MAPPING THE GENE
TO THE CHROMOSOME 16 THEN WE
DEVELOPED GENOMIC AND
TRANSCRIPTAL MAPS AND SEQUENCING
ALL THE GENES WE FOUND IN 200KB
INTERVAL WE THEN HAD TO SCREEN
FOR MUTATIONS AND ULTIMATELY IT
WAS THE TENTH OF THE 10 GENES
THAT WERE ASSOCIATED WITH FMF
AND WE FOUND WHAT WE HAD BEEN
HOPING FOR THIS BRAND NEW GENE
NOBODY KNEW ANYTHING ABOUT IT
BEFORE AND WE NAMED THE ENCODED
PROTEIN PYRIN AFTER THE FEVER
AND THAT WAS EXCITING.
IT WE DIDN'T KNOW HOW IT WORKED
OR WHATEVER AND WERE FACED WITH
THE PUZZLE OF FIGURING OUT HOW
THAT WORKED WHICH HAS BEEN
SOMETHING THAT HAS TAKEN US A
BIT OF TIME TO FIGURE OUT.
ONE OF THE EARLY CLUES IS THE
END TERMAL 90 AMINO ACID OF THE
PROTEIN IS A PROTOTYPE FOR A
DOMAIN KNOWN AS THE PYRIN DOMAIN
AND FORMS SIX ALPHA HELICES YOU
CAN SEE HERE AND THAT ALLOWS FOR
THE FORM OF A CHARGE WITH
POSITIVE CHARGES IN BLUE AND
NEGATIVE IN RED AND BASICALLY
THAT ALLOWS FOR THE
SELF-SELF-INTERACTION, THE COG
NATE INTERACTION OF THE PYRIN
DOMAIN FROM ONE DOMAIN TO
ANOTHER PROTEIN.
THAT'S HOW A NUMBER OF THE
PROTEINS IN THE INNATE IMMUNE
SYSTEM INTERACT AND THERE'S 20
THAT HAVE PYRIN DOMAIN.
THAT'S ONE OF THE GREAT THINGS
WE LEARNED EARLY ON.
ONE THING THAT WAS GREAT TOO AND
KEEPING THE CONNECTION BETWEEN
THE LAB AND THE CLINIC IS SO
IMPORTANT IS THAT WE STARTED
SEEING PATIENTS THAT CAME TO THE
NIH WHO WERE REFERRED WITH THE
POSSIBILITY THEY MIGHT HAVE FMF
AND WE HAD A GENETIC TEST AND
COULD TELL IF THEY DID OR NOT
AND SOME DID BUT THEN THERE WERE
SOME THAT DID NOT.
WE IDENTIFIED A COHORT OF
INDIVIDUALS WITH DOMINANTLY
INHERITED RATHER THAN
RECESSIVELY INHER ITTED FEATURES
AND DIFFERENT TREATMENT FROM FMF
AND TURNED OUT A COUPLE YEARS
AFTER WE FOUND THE GENE FOR FMF
FOUND THOSE PATIENTS HAD
MUTATIONS IN THE P55 TNF
RECEPTOR AND WE CALL THAT
DISEASE TRAPS THE TNF RECEPTOR
ASSOCIATED PERIODIC SYNDROME AND
THOUGHT MAYBE WE WERE SEEING AN
EMERGING FAMILY OF NEW DISEASES
THAT WERE DIFFERENT FROM THE
AUTOIMMUNE DISEASES BECAUSE THEY
DIDN'T HAVE EVIDENCE OF T CELL
INVOLVEMENT.
AND THOUGHT TO CALL IT
AUTOINFLAMMATORY DISEASES
INSTEAD.
IT'S JUST A GUESS THAT MIGHT BE
THE CASE.
THE FOLLOWING YEAR ACTUALLY WE
PUBLISHED AN OPINION ARTICLE IN
WHICH WE SPECULATED ON ALL OF
THE DIFFERENT DISEASES THAT
THERE MIGHT BE THAT COULD BE
AUTOINFLAMMATORY BASED ON THE
IDEA THESE PATIENTS HAD
INFLAMMATION WITHOUT AUTO
ANTIBODIES AND WE HAVE THE
CLASSIFICATION SCHEME AND A
COUPLE FIT INTO THE SYNDROMES
WHERE YOU HAVE THE FAMILIAL
URTICARIA OR A SYNDROME WHERE
THEY DON'T NEED CODE TO BE
INDUCED TO DO THAT.
THEN IT WAS MAGICAL.
HAL HOFFMAN AT THE UNIVERSITY
SAN DIEGO IDENTIFIED THE GENE
MUTATING IN THE TWO CELL
DISEASES I JUST SHOWED ON THE
LAST SLIDE.
IT TURNED OUT THE GENE MUTATED
IN THOSE DISEASES HAS THE PI
PIRE -- PYRIN DOMAIN AND THAT
WAS GREAT FOR US AND THEN THE
OTHER THING THAT WAS HAPPENING
WAS IN SWITZERLAND THERE WAS
THIS GUY INTERESTED IN IL1 GETS
ACTIVATED.
THERE'S A PRO FORM OF IL1 AND IT
HAS TO GET CLEAVED TO BE
ACTIVATED AND HE FIGURED OUT
THERE WAS A MACRO MOLECULAR
COMPLEX CALLED THE INFLAMMASOME
AND GUESS WHAT WAS AT THE HUB?
NLRP3 THE SAME PROTEIN THAT IS
THE PROTEIN THAT HAL HOFFMAN
FOUND WITH THE PYRIN DOMAIN.
WE HAD AN IDEA OF OF
AUTOINFLAMMATION AND CLUE THREES
DISEASES HAD SOMETHING TO DO
WITH IL1.
THEN AS IF THE STORY IS NOT
MIRACULOUS ENOUGH THERE'S
ANOTHER PIECE TOO AND THAT IS
THAT IVONA AND OTHERS DISCOVERED
AN EVEN MORE SEVERE DISEASE THAN
THE ONES I TOLD YOU ABOUT IN
FACT ALSO ARE MUTATIONS AND
THOSE PATIENTS NOT ONLY GET
FEVERS AND HIVES BUT ALSO
DEVELOP ASEPTIC MENINGITIS
LEADING TO BLINDNESS, DEAFNESS
AND DISABILITY AND THIS IS
SHOWING THE MUTATIONS ARE ALL IN
THE SAME DOMAIN FOR THE THREE
DISEASES.
SO IN ANY CASE THAT LED THE GOOD
DOCTOR MANSKI TO ORGANIZE A
TRIAL HERE AT THE NIH CLINICAL
CENTER LOOKING AT AN IL1
INHIBITOR IN 18 CHILDREN THAT
HAVE THE INFLAMMATORY DISEASE.
THIS IS A DISEASE THE PROGNOSIS
IN THESE KIDS WOULD BE HORRIBLE
AND IF YOU LOOK AT THE BEFORE
AND AFTER OF WHAT HAPPENED SO
BEFORE TREATMENT YOU CAN SEE THE
HIVES-LIKE RASH AND
CONJUNCTIVITIS AND THE WHITE
INDICATES INFLAMMATION OF THE
MENINGES AND THE COCHLEA AND THE
HIVES-LIKE RASH AND CONJUNC
CONJUNCTIVITIS GOES AWAY AND THE
OTHER SYMPTOMS GO AWAY.
HAVE A COHORT OF CHILDREN WHO
HAD A HORRIBLE PROGNOSIS WHO NOW
ARE SKILL ON THE MEDICATION.
WE SAW ONE ON A MEETING AT
AUTOINFLAMMATORY DISEASES THREE
WEEKS AGO IS NOW A GRADUATE
STUDENT STUDYING
AUTOINFLAMMATORY DISEASES.
IT'S A WONDERFUL, WONDERFUL
OUTCOME OF THAT.
IN ANY CASE THE FIELD HAS TAKEN
OFF AT THIS POINT MIKE MCDERMOTT
SPECULATES THEY'RE TWO ENDS OF
THE CASE.
SETH MASTERS IN MY LAB PUBLISHED
AN ARTICLE THAT SORT OF
SUMMARIZES 10 YEARS AFTER THE
PROPOSAL OF THE CONCEPT OF
AUTOINFLAMMATION WHAT WAS THE
MOLECULAR CLASSIFICATION AT THAT
TIME AND SORT OF TONGUE AND
CHEEK HE CAME UP WITH THE TITER
HORROR IN FLAMATICA AND THE
CONCEPT HORROR AUTOTOXICUS AND
AUTOINFLAMMATION WAS IMPOSSIBLE
AND THIS ARTICLE INTRODUCES ALL
SORTS OF AUTOINFLAMMATORY
DISEASES BEING DESCRIBED AND
DISCUSSED IN TERMS OF THEIR
PATHOPHYSIOLOGY.
SHORTLY THEREAFTER RON LASKER
PUBLISHED A TEXTBOOK OF
AUTOINFLAMMATORY 800 PAGES LONG
AND THERE WAS A MEETING OF THE
INTERNATIONAL SOCIETY ON
SYSTEMIC AUTOINFLAMMATORY
DISEASES WITH LIKE 360 PEOPLE
THERE MORE THAN 50 DISEASES.
IT'S NOT GOING TO BE POSSIBLE
FOR THE ONE HOUR IN THE LECTURE
A LOTTED TO ME TO GO THROUGH THE
50 DISEASES WE COULD TALK ABOUT
SO I'LL TALK ABOUT ONE OF THEM
THAT'S IMPORTANT BECAUSE OF ITS
FREQUENCY AND BECAUSE OF ITS
SEVERITY AND BECAUSE THERE'S A
TREATMENT FOR IT AND ANOTHER
THAT'S A REAL RECENT ONE.
THE FIRST ONE IS THIS DISEASE
DADA EFFICIENT OF ADA2.
A DISEASE WE COVERED AND
COLLEAGUES DISCOVERED
INDEPENDENTLY AT ABOUT THE SAME
TIME AND THE TWO PUBLICATIONS
WERE PUBLISHED BACK TO BACK IN
THE NEW ENGLAND JOURNAL.
WE HAD SEEN A NUMBER OF KIDS
HERE THAT PRESENTED WITH FEVERS
AND STROKES.
PHIL HAD SEEN A GROUP OF
CHILDREN WITH FEVERS AND
SOMETIMES INFLAMMATION OF THE
BLOOD VESSELS BUT BOTH TURNED
OUT TO HAVE MUTATIONS IN THE
SAME GENE WHICH IS THIS GENE
ADA2.
YOU CAN SEE HERE ON THE SLIDE
THE ARROWS POINT THE STROKES IN
THE DEEP BRAIN NUCLEI AND THIS
IS VASCULITIS A NECROTIC AREA OF
THE EAR OF A PATIENT.
IN ANY CASE, A PROBLEM WITH THIS
WAS THAT THESE KIDS CONTINUED TO
HAVE STROKES NO MATTER WHAT THE
TREATMENT SEEMED TO BE.
AND SHOWN HERE IS DR. AMANDA
OMBRELLO SHOWING TNF INHIBITERS
IS EFFECTIVE UP THESE PATIENTS
AND IT'S BECOME STANDARD OF CARE
AT THIS POINT.
THE OTHER DISEASE I WANT TO
MENTION IS DISABLING PANS
SCLEROTIC MORPHIA.
THIS IS A DISEASE THAT'S NOT A
HOUSEHOLD NAME OR NOT IN MOST
HOUSEHOLDS.
IT'S A DISEASE IN WHICH PATIENT
HAVE THICKENING OF THE SKIN, A
FORM OF FIBROSIS THAT GOES DOWN
DEEP BELOW THE SKIN, SUB
CUTANEOUS AND MUSCLE TISSUE TO
THE BONE.
THESE PATIENTS ALSO CAN HAVE
PROBLEMS WITH POOR WOUND HEALING
AND CAN DEVELOP SQUAMOUS CELL
CARCINOMA AND THE DIAGNOSIS IS
TO LIVE 10 YEARS AFTER
DIAGNOSIS.
IT'S A SEVERE DISEASE.
IT SO HAPPENED I WAS GIVING A
VIRTUAL GRAND ROUNDS TO THE
UNIVERSITY OF CALIFORNIA SAN
DIEGO ABOUT A YEAR AGO FEBRUARY
OF 2022.
AT THE END OF MY TALK I WAS
MEETING WITH VARIOUS PEOPLE
VIRTUALLY EVERYTHING IS
IMAGINARY, WHATEVER.
IN ANY EVENT I WAS TALKING TO
LORI BRODERICK ON THE FACULTY
THERE AND TELLING US ABOUT THE
FAMILY SHE WAS CARING FOR THIS
DISEASE AND THE STORIES WITH YOU
HORRIFIC OF A YOUNG MAN ABOUT 20
OR SO WHO HAS THIS CONDITION
PANSCLEROTIC MORPHEA AND HAD
DOUBLE AMPUTATION OF BOTH ARMS
AND LEGS BECAUSE OF UNCONTROLLED
INFECTION AND SQUAMOUS CELL
CARCINOMAS.
AS IF THAT WASN'T TERRIBLE
ENOUGH HIS OLDER BROTHER STARTED
TO DEVELOP THE SAME KINDS OF
LESIONS.
SO AT THAT POINT THE PHYSICIANS
CARING FOR THAT FAMILY REFERRED
THE FAMILY TO DR. BRODERICK WHO
DID EXOME SEQUENCING AND FOUND A
GAIN OF FUNCTION OF WHAT LOOKED
TO BE A GAIN OF FUNCTION
MUTATION IN STAT 4.
THE PROBLEM WAS SHE ONLY HAD THE
ONE FAMILY AND SO SHE COULDN'T
REALLY PUBLISH BECAUSE USUALLY
YOU HAVE A CONFIRM TRY --
CONFIRMATORY FAMILY AND OUR
GROUP COLLABORATING WITH THE
UNIVERSITY OF PITTSBURGH HAD THE
MISSING LINK.
WE HAD ANOTHER FAMILY WHERE
THERE WAS A CHILD WITH A DE NOVO
MUTATION THAT ALSO HAD A SIMILAR
PHENOTYPE AND THEN ACTUALLY BILL
GAHL HAD A THIRD FAMILY.
ALL OF A SUDDEN IT BECAME A MORE
CONVINCING STORY.
JOHN O'SHEA WAS ALSO IMPORTANT
IN HELPING US THROUGH ALL THE
SIGNALLING WITH STAT 4 AND HIS
EXCELLENT POSTDOC RACHEL
PHILLIPS AND THE OUTSTANDING
Ph.D. STUDENT SARAH BLACKSTONE
DOES THE FUNCTIONAL STUDYING AND
HERE'S PHOTOS WITH PATIENT WITH
PANSCLEROTIC MORPHEA AND THE AND
THEN THE MUTATIONS.
THEY'RE ALL IN THE SH2 DOMAIN
WHICH IS AN IMPORTANT ACTIVATION
DOMAIN OF STAT 4.
IN ANY CASE, ONE OF THE FIRST
THINGS THAT WE NEEDED TO DO WAS
TO ACTUALLY DEMONSTRATE THESE
ARE GAIN OF FUNCTION MUTATIONS
AND THIS IMAGE JUST SHOWS
COMPARING STAT 4 PHOSPHORYLATION
BETWEEN THE WILD TYPE WHICH IS
IN BLUE AND THE OTHER COLORS YOU
CAN SEE THE OTHER COLORS ARE
SHIFTED TO THE RIGHT AND THERE'S
INCREASE PHOSPHORYLATION AUDIT
IN THIS WAY AND THEN IF THE
CELLS ARE STIMULATED THAT WAS
UNSTIMULATED.
IF THE CELLS ARE STIMULATED
THERE'S PERSISTENT
PHOSPHORYLATION COMPARED WITH
THE WILD TYPE.
LARRY BRODERICK ALSO DID AN
ASSAY LOOKING AT WOUND HEALING
IN VITRO AND IF YOU TAKE A
FIBROBLAST WITH THE PIPETTE IT
WILL GROW BACK AND YOU CAN
MEASURE HOW LONG THAT TAKES.
YOU CAN SEE FOR THE WILD TYPE
THEY FROZE UP THE CUT AND CLOSES
UP WITHIN ABOUT 24 HOURS FOR THE
MUTATION IT'S STILL OPEN AT 24
HOURS AND IF YOU LOOK AT THE
CULTURES THERE'S A LOT OF IL6
BEING RELEASED IN THE MUTATION
AND IN FACT IF YOU LOOK AT THE
WOUND HEALING IF YOU TAKE EITHER
COMPARING THE WILD TYPE WITH THE
MUTANT YOU CAN SEE THE MUTANT
DOESN'T CLOSE UP BUT IF YOU ADD
IL6 TO THE WILD TYPE IT GETS
ALSO HAVING A PROBLEM WITH
REGARD TO THE WOUND HEALING.
IT APPEARS IL6 IS PLAYING AT
LEAST SOME ROLE IN THAT.
IT SUGGESTS A POSSIBLE POSITIVE
FEEDBACK LOOP AND IL6 IS DOWN
STREAM OF STAT 4 AND IL6 CAN BE
PRODUCED AND FIBROBLASTS HAVE
RECEPTORS THAT SIGNAL THROUGH
STAT 4.
AND THE KINASES ARE INVOLVED.
USING A JACK INHIBITOR WOULD
MAKE A CERTAIN AMOUNT OF SENSE
AND ONE CAN SEE IN VITRO IT
REDUCE THE IL6 USING THE
RUXOLITINIB AND ONE CAN HELP THE
MUTANT CELLS WITH THE RUXO
RUXOLITNIB.
THIS WAS PUBLISHED IN THE NEW
ENGLAND JOURNAL OF MEDICINE
ONLINE ONE WEEK AGO TODAY.
IT'S NOT IN THE PRINT VERSION OF
THE JOURNAL YES.
IN ANY CASE THE TITLE OF THE
TALK IS HIGH SOUNDING TITLE.
AUTOINFLAMMATORY DISEASE AND THE
HUMAN CONDITION.
AND WHAT IN GENERAL CAN WE SAY
ABOUT AUTOINFLAMMATORY DISEASE
AND THE HUMAN CONDITION.
EITHER YOU FORGOT THE QUESTION
BY NOW OR JUST DYING TO KNOW.
THE FIRST THING I CAN SAY IS WE
LEARNED THAT MICROBIAL
INFECTION, INNATE IMMUNE AND
CELL BIOLOGY ARE INFERETRINSICA
RELATED.
ONE THING THAT CAME FROM THE
STUDY OF THE DISEASES IS WE'VE
SLOWLY BUT SURELY FIGURED OUT
THE MECHANISM OF THE DISEASE
MORE THAN JUST KNOWING SUCH AND
SUCH A GENE HAS MUTATED.
I'LL JUST SHOW YOU THIS ONE
EXAMPLE OF FMF AND IT TOOK
ALMOST 20 YEARS FROM THE TIME WE
FOUND THE GENE TO THE TIME WE
FIGURED OUT THE PATHWAY AND A
NUMBER OF OTHER PEOPLE WERE
INVOLVED IN THIS TOO.
IN ANY EVENT THE STORY -- YOU
MIGHT THINK THAT PYRIN, THE FMF
PROTEIN IS A SENSOR FOR
SOMETHING THAT'S A RECEPTOR FOR
SOME SORT OF MICROBIAL PATHOGEN
YOU'LL HAVE A DIAGRAM OR A
PATHOGEN THAT BINDS TO PYRIN.
THAT WAS THE MIND SET WE HAD AT
THE BEGINNING.
THAT WOULD BE THE WAY IT WOULD
WORK.
IT TURNED OUT THAT WAS WRONG.
SO IN THIS FIGURE YOU CAN SEE
JUST HERE THESE WILL TWO PYRIN
MOLECULES THAT ARE BEGINNING TO
FORM AN INFLAMMASOME AND THE
REGULATION OF IT OCCURS IT
STARTS HERE INSIDE THE MOLECULE
WITH ROW A.
IT'S THE GTP ACE THAT CAN
CONNECT KINASES WHICH LEADS TO
THE PHOSPHORYLATION OF PYRIN AND
IT'S BOUND BY THE INHIBITOR 1433
MOLECULES.
IN THE NORMAL SITUATION WHERE
YOU HAVE ALL THIS WORKING YOU
HAVE BASICALLY A TONIC
INHIBITION OF THE PYRIN
INFLAMESOME AND THEY ARE TOXIN
WILL DISRUPT ROW A AND WHEN THAT
HAPPENS YOU DON'T GET
PHOSPHORYLATION OF PYRIN AND CAN
GET ACTIVATION OF THE IN FLAM
-- INFLAMMASOME AND IT TURNS
OUT CERTAIN BACTERIA MAKE TOXINS
THAT INACTIVATE ROW A AND IS A
KEY MOLECULE FOR THE ACTIN CY
CYTOSKELETON AND IT'S IMPORTANT
FOR MITOSIS AND DEGRANULATION
AND THEY NEED A FUNCTIONING ROW
A AND HAVE TOXINS THAT
INACTIVATE ROW A AND THE PYRIN
INFLAMMASOME IS THE EVOLUTIONARY
RESPONSE TO THAT.
THIS IS AN EXAMPLE OF WHERE THE
INNATE IMMUNE SYSTEM WORKS
INDIRECTLY AND HOSOFTEN IT'S
SENSING CHANGES IN CELLULAR
MOMENT YO STAVES.
-- HOMEOSTASIS THAN BINDING TO A
BACTERIAL OR VIRAL PRODUCT.
IT'S AN INTERESTING THING.
THIS IS A PHOTO OF A PATIENT IN
THE PHOSPHORYLATION SITE AND
HAVE CONTINUOUS AND HAVE A
NEUTROPHILIC DERMATOSIS.
WE HAVE A CAT AND MOUT
RELATIONSHIP.
HERE THIS STRAIN MAKES BUBONIC
PLAGUE AND YOU SAY OKAY SO THE
PYRIN INFLAMMASOME IS A DEFENSE
AGAINST PLAGUE EXCEPT THAT
PLAGUE HAS EVOLVED ANOTHER TOXIN
GAP M THAT CAN PHOSPHORYLATE
PYRIN AND HIJACKS SO THAT BLOCKS
THE PYRIN INFLAMMASOME AND HAVE
A BACK AND FORTH AND THEN AND
YOU SEE THE PHOSPHORYLATION OF
PYRIN IN HEALTHY INDIVIDUALS ON
THE LEFT BUT IN INDIVIDUALS WITH
FMF THEY ACTUALLY DON'T SEE
INCREASED PHOSPHORYLATION OF
THEIR PYRIN.
THE CARRIER STATE FOR FMF IS A
DEFENSE AGAINST PLAGUE.
SO ONE WOULD THINK THEN THIS
LEADS TO SELECTION FOR FMF
MUTATIONS SO WE LOOKED IN THE
TURKISH POPULATION TO SEE IF
THERE WAS EVIDENCE FOR SELECTION
OF FMF MUTATIONS.
SO ONE OF THE TELLTALE SIGNS OF
SELECTION IS IF YOU HAVE A VERY
BIG HAPLOTYPE, A BIG DNA
FINGERPRINT ASSOCIATED WITH THE
MUTATION.
YOU CAN SEE THE WIDTH OF THE
BLUE PEAK HERE.
THAT'S THE WIDTH OF HAPLOTYPES
ASSOCIATED WITH THE FMF MUTATION
WHEREAS THE ORANGE SORT OF
NEEDLE POINT THERE IS THE WIDTH
OF THE WILD TYPE ALLELE.
THERE'S DEFINITELY A MUCH LARGER
HAPLOTYPE ASSOCIATED AND IT'S ON
THE TAIL OF THE BELL CURVE AND
ONE CAN CALCULATE A SELECTION
COEFFICIENT NOR MUTATION THAT
TURNS OUT TO BE 0.077 WHICH IS
HIGHER THAN THE SELECTION
COEFFICIENT FOR LACTASE
PERSISTENCE AND THE ABILITY TO
DIGEST COW'S MILK AS AN ADULT IS
THOUGHT TO BE IN SELECTION IN
THE EUROPEAN POPULATION.
TO SUM THIS UP AND MAYBE TO
THINK A LITTLE BIT THEN ABOUT
THE HUMAN CONDITION, WE HAVE
THIS ORGANISM THAT LEADS TO THE
PHOSPHORYLATION OF PYRIN AS A
WAY OF SABOTAGING THE IMMUNE
SYSTEM.
HAVE A DISEASE FAMILIAL
MEDITERRANEAN DISEASE AND
THEY'RE PROTECTED AND YOU HAVE
THE HUMANS AND PLAGUE WHEREBY WE
GET RESISTANCE TO PLAGUE IN A
LARGER PROPORTION OF THE
POPULATION IN EXCHANGE FOR
INDIVIDUALS DEVELOPING A
POTENTIALLY LETHAL ILLNESS
THAT'S LESS COMMON BECAUSE OF
THE FACT IT'S A RECESSIVELY
INHERE
INHERENTED -- INHERITED DISEASE.
ONE THING I THINK IS GROWING
OLD.
SO GROWING OLD AND THE RISK OF
AUTOINFLAMMATION.
THAT'S THE NEXT TOPIC HERE.
IT HAS TO DO WITH THE HUMAN
CONDITION.
YOU KNOW IT'S BETTER TO GROW OLD
THAN NOT TO GROW OLD.
YOU HAVE TO THINK OF IT IN THAT
WAY TOO.
THIS IS THE WORK OF DAVID BECK
WHO WAS AN EXCELLENT POSTDOC IN
LAB NOW A JUNIOR FACULTY MEMBER
AT NYU AND PETER GRAYSON A
TENURE TRACK INVESTIGATOR IN
NAIMS AND ANOTHER WHO IS A STAFF
CLINICIAN IN MY GROUP.
THEY FELT WE WERE NOT GOING FAST
ENOUGH IN TERMS OF FINDING
DISEASE GENES AND ONE SHOULD
TAKE ANOTHER APPROACH THAN THE
SORT OF STODGY OLD APPROACH OF
PHENOTYPE FIRST.
SO PHENOTYPE FIRST IS WHERE YOU
GROUP TOGETHER A BUNCH OF
PATIENTS THAT HAVE SOME
PHENOTYPE IN COMMON AND THEN TLI
TO FIND A GENE THAT EXPLAINS
THAT PHENOTYPE.
THAT'S TRIED AND TRUE WAY OF
DOING IT.
BUT THE GENOTYPE FIRST APPROACH
INSTEAD IS THAT YOU COME UP WITH
A LIST OF GENES THAT YOU'RE
INTERESTED IN AND IN DAVID'S
CASE HE WAS INTERESTED IN ALL OF
THE GENES THAT HAVE ANYTHING TO
DO WITH REGULATING YOU
UBIQUI
UBIQUITYLATION AND WE DISCOVERED
GENES CAUSED BY THIS AND HE
THOUGHT THIS WAS A GREAT LIST
AND USED THE LIST OF 841 GENES
TO INTERROGATE 477 EXOMES OR
GENOMES AND 1,083 FROM THE
UNDIAGNOSED DISEASES COHORT AND
THEY'RE SHARED AMONGST CASES AND
FOUND AFTER DOING THIS HERCULEAN
FEAT HE FOUND THREE MIDDLE AGED
MEN WHO SEEMED TO BE
HETEROZYGOUS AT RESIDUE 41 OF
THE UBA1 GENE.
THAT SEEMED PRETTY GOOD ON THE
FACE EXCEPT UBA1 IS LIKE THE
GENE THAT ENCODES THE PROTEIN
INVOLVED INITIATING ALL
UBIQUITYLATION SO HOW CAN YOU
LIVE WITH SERIOUS MUTATIONS IN
THE GENE.
THAT'S ONE PROBLEM.
THEN THE REAL PROBLEM CAME AND
THAT IS UBA1 IS ENCODED ON THE X
CHROMOSOME AND THESE PATIENTS
ARE MEN WHO ARE HETEROZYGOUS AND
MEN ONLY HAVE USUALLY ONE X
CHROMO
CHROMOSOME.
IS IT A SEQUENCING ERROR?
HE CHECKED AND IT WASN'T AND I
WON'T BE TELLING YOU IF IT WAS.
THIS IS AN EXTRA X CHROMOSOME.
WE CHECKED AND IT WASN'T THAT
EITHER.
COULD IT BE A SOMATIC MUTATION
WHERE THE DNA WAS DERIVED FROM
PERIPHERAL BLOOD LEUKOCYTES AND
RATHER THAN ALL HAVING THE WILD
TYPE AND MUTANT FORM, SOME WOULD
HAVE THE WILD TYPE FORM AND SOME
WOULD HAVE THE MUTANT FORM.
THAT WAS THE IDEA.
SO DAVID PROCEEDED TO TEST THAT
HYPOTHESIS AND SURE ENOUGH HE
WAS RIGHT.
IF YOU LOOK AT THE NEUTROPHILS
AND LEUKOCYTES AND THE MYELOID
CELLS HAVE THIS RESIDUE AND
LYMPHOCYTES AND T CELLS AND B
CELLS DO NOT.
THAT WAS NEAT WE FOUND EVIDENCE
OF A SOMATIC MUTATION OF THE
MIDDLE AGED MEN AND THEN COMES
THE FACT STRANGER THAN FICTION.
THAT IS THAT WE WASN'T TO SEE
THE HEMATOPATHOLOGY SUITE AND
BECAUSE HE'S THESE PATIENTS HAD
A HEMATOLOGIC CONDITION WE
LOOKED AT THE BONE MARROW AND
THEY ALL HAD FUNNY LOOKING MACK
-- MACULES AND WE CAME BACK
LATER AND SHE PRESENTED ME WITH
TWO REPORTS OF PATIENTS WITH THE
VACUUM -- VACUOLES AND THEY HAD
BONE MARROW FROM EIGHT YEARS
BEFORE AND THEY HAD MYELOID
RESTRICTIVE SOMATIC RESTRICTIONS
AS WELL.
THEY WERE MIDDLE-AGED MEN THAT
APPEARED TO BE HETEROZYGOUS FOR
IBA1 AND ONE HAD RELAPSE POLY
C
CONDRITIS AND BEFORE YOU KNOW IT
WE HAD A COHORT OF 25 PATIENTS
THAT ALL OF THEM WERE MEN WITH
SOMEWHAT EXPLAINED FEVERS AND
INFLAMMATION THAT HAD VARIOUS
DIAGNOSES AND RELAPSING POLY
CHONDRITIS AND BEING AFICIONADOS
OF NAMING THINGS WE THOUGHT IT
WAS A NAMING OPPORTUNITY AND WE
THOUGHT IT SHOULD CONVEY WHAT'S
GOING ON AND CALL IT VEXAS.
IT STANDS FOR VACUOLES BECAUSE
MOST HAVE VACUOLES AND
UBIQUITIN-ACTIVATING ENZYME AND
LINKED AND INFLAMMATORY AND
SOMATIC AND IT WAS PUBLISHED IN
THE CELEBRATORY NEW YEAR'S EVE
EDITION OF THE NEW ENGLAND
JOURNAL OF MEDICINE IN 2020.
THEN WHAT HAPPENED IS IT TURNS
OUT VEXAS IS MORE COMMON THAN
WHAT WE EVER THOUGHT.
SO DAVID IN COLLABORATION WITH
DOUG STEWART AND THE CANCER
INSTITUTE AND PEOPLE AT THE
GEISINGER CLINIC IN EASTERN
PENNSYLVANIA DID A
POPULATION-BASED STUDY LOOKING
AT THE FREQUENCY IN THEIR CLINIC
AND IT TURNED OUT THERE WERE 12
INDIVIDUALS WHO HAD BEEN GENOME
SEQUENCED POSITIVE OUT OF
163,000.
THAT WORKS OUT TO BE IF YOU LOOK
AT THE MAP 1 IN 4,000 MEN OVER
THE AGE OF 50 WHICH IS QUITE A
LOT.
AN ESTIMATED POPULATION
PREVALENCE OF 74 PER MILLION
ACROSS AGE GROUPS AND MORE
COMMON THAN A LOT OF THE
DIAGNOSIS THAT WERE THE
DIAGNOSES THESE PEOPLE HAD
BEFORE AND EXTENDED THE CLINICAL
PHENOTYPE TO OTHER THINGS AS
WELL.
IN ANY CASE WE'RE GETTING CLOSE
ON TIME.
FORTUNATELY WE'RE GETTING TO THE
END THOUGH WHICH IS UNUSUAL FOR
ME.
SO IN ANY CASE THE LAST LITTLE
VIGNETTE IS A STORY ABOUT COMMON
GENETIC VARIANTS IN THE SPECTRUM
OF DISEASE.
SO THIS LITTLE SEGMENT ON THIS
SLIDE WE LOOK AT IMAGES OF
PATIENTS WITH THIS DISEASE AND
THOSE NOT FAMILIAR IT'S ANOTHER
DISEASE THAT IS SEEN IN THE
MIDDLE EAST AND ACROSS ASIA AND
CHINA AND JAPAN AND IT'S
CHARACTERIZED BY THE TRIAD OF
PAINFUL ULCERATIONS OCULAR
INFLAMMATION AND GENITAL
ULCERATIONS AND SOME DEVELOP
POSTU LES IN THE SKIN.
WE FOUND AT LEAST ONE MONOGENIC
CONDITION THAT'S SORT OF LIKE
THIS DISEASE BUT WE ALSO DONE A
NUMBER OF GWAS STUDIES AND HAVE
IDENTIFIED BESIDES HLAB51 WELL
KNOWN AND 17 OTHER GENES WITH
SUSCEPTIBILITY TO BEHCET'S
DISEASE AND IT WAS CAREFULLY
PHENOTYPED 1,000 PATIENTS AND
CONTROLS.
IT WAS A HUGE JOB.
AND THEN AFTER WE HAD COMPLETED
THAT WORK THE DIRECT TO CONSUMER
COMPANY 23 AND ME CAME OUT WITH
A GENOME WIDE ASSOCIATION STU
STUDIES OF CANKER SOURCE AND
ASKED DO YOU GET FREQUENT CANKER
SORES YES OR SO AND DID A GOOD
WAS AND THE SAME GENES WE FOUND
IN BEHCET'S DISEASE ARE COMMON
WITH CANKER SORES AND SOME ARE
INTERESTING INTERLEUKIN 10 AND
ALPHA AND STAT 4 AND CCR3.
THEN WHAT HAPPENED IS A FELLOW
IN MY LAB WAS STUDYING A
CONDITION IN CHILDREN CALLED
FAPA STANDING FOR PERIODIC
FEVERS WITH PHARYNGITIS AND
CERVICAL ADENOITIS AND THEY GET
SORES IN THEIR MOUTH AND SORE
THROWS AND SWELLING OF THE LYMPH
GLANDS AND IT'S A GENETICALLY
COMPLEX DISEASE.
MOST KIDS GROW OUT OF IT AND
BECAUSE IT'S IN BETWEEN THEY
LOOKED TO SEE IF THE SAME GENES
ARE ASSOCIATED WITH
SUSCEPTIBILITY TO FABA AND THEY
ARE.
YOU HAVE THE SPECTRUM OF
DISEASES ON THE ONE END IS
SEVERE WITH BEHCET'S DISEASE AND
THE OTHERS WITH RECURRENT ULCERS
IN FABA AND SOME ARE PREDISPOSED
TO IMMUNE OR INFLAMMATORY TYPES.
THIS IS IT THE 30,000 FOOT VIEW
AND THESE HAVE TAUGHT US HOW
INNATE IMMUNITY WORKS AND
TARGETED THERAPIES HAVE BEEN
TRANSFORMATIVE WHILE VALIDATING
OUR UNDERSTANDING OF THE
UNDERLYING DISEASE AND THE
IMMUNE SYSTEM MAY PROTECT
AGAINST PATHOGENS BUT
PREDISPOSED TO AUTOINFLAMMATION
AND SOME ACCOUNT FOR EARLY ONSET
OF AUTOINFLAMMATORY DISEASES AND
THINK THERE'S MORE TO BE
DISCOVERED AND GENETIC VARIANTS
CONFER RISK FOR SOME
AUTOINFLAMMATORY CONDITIONS AND
PHENOTYPES.
IN ANY CASE AT THIS POINT I'M
WRAPPING UP.
I WANT TO THANK MY COLLEAGUES IN
THE LAB PICTURED HERE ARE
CURRENT COLLEAGUES IN THE LAB
AND IN PARTICULAR TWO
EXTRAORDINARILY COMPETENT STAFF
SCIENTISTS AND CERTAINLY A
NUMBER OF OTHERS TO BE MENTIONED
COLLEAGUES IN THE CLINIC AND
THIS IS VERY MUCH A PARTNERSHIP,
A COLLABORATION BETWEEN THE LAB
AND CLINIC, STAFF CLINICIANS AND
A NUMBER OF OTHER INDIVIDUALS AS
WELL.
QUITE A FEW COLLABORATORS AND
THESE ARE SOME OF THE MOST
RECENT ONES.
THEN OF COURSE OUR PATIENTS.
THIS HAPPENS TO BE THE
MEETING -- THE FIRST
INTERNATIONAL MEETING OF
PATIENTS OF ENDADA2 IN 2016 AND
THIS WORK WOULD NOT BE POSSIBLE
WITHOUT PATIENTS PLAYING A MAJOR
ROLE.
A NUMBER OF PEOPLE THATTED IN
VARIOUS WAYS TO MY CAREER VERY
BRIEFLY BOB RICH WHO WAS MY
GRADUATE SCHOOL ADVISER AND HALF
A CENTURY AGO NOW INTRODUCED ME
TO ALL THE FUN AND EXCITEMENT OF
IMMUNOLOGY SUCH AS IT WAS IN THE
1970s.
THE LATE FRED STEINBERG WHO
HIRED ME AS A CLINICAL FELLOW AT
THE NIH IN 1985.
PAUL PLOTS WHO WAS A ROLE MODEL
IN TERMS OF A PHYSICIAN
SCIENTIST AND THE LATE HARRY
METZKER AND I'LL NEVER FORGOT
THE WORDS HE SAID WHEN I STARTED
HE SAID, DAN, HERE'S SOME
RESOURCES.
JUST GO AND HAVE SOME FUN AND BE
SURE TO HAVE DATA READY IN 18
MONTHS WHEN YOU PRESENT TO THE
BOARD OF SCIENTIFIC COUNSELORS.
THAT WAS HENRY.
AND CERTAINLY I APPRECIATE THE
LATITUDE HE EXTENDED.
MY COLLABORATOR IN ISRAEL AND
MIKE DEAN OF THE CANCER
INSTITUTE WHO TAUGHT OUR GROUP
HOW TO DO OUR GENETICS AND
GENOMICS AT SCALE BEFORE THERE
WAS A GENOME INSTITUTE.
AND PAUL BUT WHO HAS BEEN A
SCIENTIFIC ADMINISTRATIVE
COLLABORATOR MANY YEARS.
THE LATE STEVE KAST THE DIRECTOR
OF NIAMS AND ERIC GREEN FOR
BEING A WONDERFUL BOSS AND
SCIENTIFIC AND PERSONAL
COLLABORATOR AS WELL AND THEN
MICHAEL GOTTESMAN HERE IN THE
FRONT ROW.
MICHAEL FOR THREE DECADES
CREATED A CULTURE HERE IN THE
INTRAMURAL PROGRAM.
WE TALK ABOUT HAVING A
SCIENTIFIC COMMUNITY IN WHICH WE
VALUE HIGH-RISK, HIGH-REWARD
VALUES AND HE INCULCATED THAT
INTO OUR COMMUNITY AND I THINK
WE OWE HIM ALL OF US OWE HIM A
DEBT OF GRATITUDE FOR THAT.
THEN FINALLY MY WIFE.
THIS IS OUR WEDDING BAY BACK IN
1985 WHEN WE WERE SETTING OUT ON
A BIG ADVENTURE IN BETHESDA AND
THEN IN SWEDEN WHEN I GOT THE
PRIZE.
SHE'S BEEN A SOURCE OF SUPPORT
AND STRENGTH AND A BEST FRIEND
OVER ALL THAT PERIOD OF TIME.
THEN FINALLY THE LAST SLIDE HERE
THE NIH CLINICAL CENTER WHICH
MADE THIS POSSIBLE, THREE
INSTITUTES THAT HAVE PLAYED A
MAJOR ROLE IN MY WORK AT THE
NIAMS I STARTED IN AND NGRI
WHERE I AM NOW AND THE NIAID
WHICH PROVIDED GREAT
COLLABORATION AND A NUMBER OF
CLINICAL TOPICS OVER THE LAST
COUPLE OF YEARS.
WITH THAT, I WILL CALL IT TO A
CLOSE.
I SEE WE HAVE ABOUT THREE AND A
HALF MINUTES FOR QUESTIONS.
I'LL TRY TO ANSWER YOUR
QUESTIONS.
>>HOW DO YOU EXPLAIN THE LATE
ONSET OF DISEASE IN THESE
PATIENTS IF THE MUTATION HAS
BEEN THERE FOR THE INDIVIDUAL'S
ENTIRE LIFE?
IS THERE A MISSING VARIABLE NOT
ACCOUNTED FOR?
>>FOR THOSE DISEASES WHERE
THERE ARE GERM LINE MUTATIONS
THAT'S A QUESTION THAT COMES UP.
CERTAINLY FOR A LOT OF THESE --
THE DISEASES THAT I WAS TALKING
ABOUT THAT ARE THE MONOGENIC
DISEASES, THEY PRESENT BY
ADULTHOOD ANYWAY.
IT'S NOT AS IF PEOPLE ARE GOING
FOR A LONG LONG TIME BUT IT'S
STILL A POINT WELL TAKEN THAT WE
DO NOT UNDERSTAND THE MECHANISMS
OF THESE DISEASES.
WE TRIED MAKING MOUSE MODELS AND
WITH FAMILIAL MEDITERRANEAN
FEVER WHICH WE DID MAKE AND THEY
HAVE CONTINUOUS INFLAMMATION
RATHER THAN EPISODIC.
THE PRECLUDED US LOOKING FOR
PROVOCATIVE FACTORS AND THE
INTERESTING THING WAS WE DID
THREE DIFFERENT MUTATIONS OF
DIFFERENT SEVERITY IN HUMANS.
THERE'S A DIFFERENT SEVERITY IN
MICE BUT OPPOSITE.
THE MOST SEVERE IN THE HUMAN IS
THE LEAST SEVERE IN THE MOUSE
WHICH IS I GUESS ANOTHER
DEMONSTRATION WE ARE NOT MICE.
>>GOOD TO CLARIFY THAT.
ANOTHER ONE, DR. KASTNER ALWAYS
A FASCINATING TALK!
.
COULD YOU SHARE THOUGHTS ON
SECONDARY GERM LINE DUE TO
UNCONTROLLED AUTOIMMUNE DISEASE.
MORE SPECIFICALLY CAN EPIGENETIC
CHANGES FROM CHRONIC
INFLAMMATION MAKE IT LOOK LIKE
THE NEW ONSET OF INFLAMMATORY
DISEASE.
ANY CONNECTION TO MITOCHONDRIAL
DYSFUNCTION IN THAT SENSE?
>>ALL EXCELLENT IDEAS.
WE HAVE NOT TESTED THOSE
HYPOTHESES BUT CERTAINLY THE
QUESTION IS CORRECT THAT THERE
IS VERY MUCH AN INTERACTION
BETWEEN THE ADAPTIVE AND THE
INNATE IMMUNE SYSTEM.
ONE WOULD EXPECT IF SOMEONE HAS
GERM LINE MUTATION OR
SUSCEPTIBLE VARIANTS FROM ONE
SIDE OR THE OTHER ONE COULD
IMAGINE OVER TIME ONE COULD GET
SECONDARY EFFECTS THAT WOULD
BLEED OVER TO THE OTHER DOMAIN
OF THE IMMUNE SYSTEM.
I'LL WRAP UP WITH THREE POINTS,
CME CODE I THINK WAS 44460.
THERE WILL BE A RECEPTION
OUTSIDE FOR PEOPLE HERE AND I'M
PRETTY SURE THE HISTORY OFFICE
WOULD LOVE A COPY OF THE HAND
WRITTEN LETTER SOME DAY SHOULD
YOU WANT TO GIVE IT TO THEM.
>>THANK YOU.