Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
The NIH Clinical Center is the world's largest hospital totally
dedicated to investigational research and leads the global
effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
SO ON BEHALF OF THE NIH GREAT
TEACHER SELECTION COMMITTEE IT
IS MY GREAT HONOR TO INTRODUCE
TODAY'S SPEAKER DAN KASTNER.
DR. KASTNER EARNED HIS MD AND
PhD FROM BAYLOR COLLEGE OF
MEDICINE AFTER COMPLETING HIS
BACHELOR OF ARTS DEGREE IN
PHILOSOPHY.
THROUGHOUT HIS NIH CAREER
DR. KASTNER'S RESEARCH HAS
FOCUSED ON THE GENETIC AND
GENOMIC STRATEGIES.
AS YOU WILL SEE HIS WORK HAS LED
TO THE DISCOVERY OF THE
MOLECULAR BASES FOR MANY OF
THESE CONDITIONS.
AND THIS HAS INFORMED OUR
UNDERSTANDING OF MORE COMMON IN
FLAM FERRY ILLNESSES.
ALSO PROPOSED THE CONCEPT OF
AUTO INFLAMMATION.
DR. KASTNER HAS WON NUMEROUS
AWARDS AND HONORS.
* THE FEDERAL EMPLOYEE OF THE
YEAR IN 2018 AND THE ROSS PRIZE
AND MOLECULAR MEDICINE IN 2019.
IN 2021 HE E RECEIVED THE
CRAWFORD PRIZE FROM THE ROYAL
SWEETERS ACADEMY OF SCIENCES.
HE IS PERSONABLE AND SELF-A
FACING.
YOU ARE IN FOR A TREAT.
HELPING TO ADVANCE THE CARE OF
OUR PATIENTS AND THAT WILL
QUICKLY BECOME SELF-EVIDENCE.
I WOULD LIKE TO WELCOME OUR
SPEAKER DR. DAN KASTNER.
THANK YOU SO, SO MUCH FOR THAT
VERY KIND INTRODUCTION.
I HOPE THAT I CAN MEASURE UP TO
THIS HIGH BAR THAT HAS BEEN
ESTABLISHED FOR ME BUT I WILL
GIVE IT MY BEST ANY WAY.
IT IS JUST MY ENORMOUS PLEASURE
TO BE HERE TODAY AND IT IS SUCH
A GREAT HONOR TO BE SELECTED TO
GIVE THIS TALK IN THE GREAT
TEACHER'S LECTURE SERIES.
AS ED HAS SAID THE TITLE OF THIS
TALK IS FACT STRANGER THAN
FICTION: ADVENTURES IN THE
GENOMICS OF INFLAMMATION AND I
HOPE OVER THE COURSE OF THE NEXT
HOUR THAT YOU TOO WILL SEE JUST
HOW MUCH FUN IT IS DOING THIS
KIND OF WORK AND WHAT ADVENTURE
IT HAS BEEN FOLLOWING SOME OF
THE LEADS OVER COURSE OF THE
LAST 37 YEARS ACTUALLY HERE AT
THE NIH CLINICAL CENTER.
SO TO GET ON WITH IT FIRST OF
ALL WE HAVE THE OH LICK P -- OBY
SLIDE I HAVE NOTHING TO
DISCLOSE.
AT THE END OF THE LECTURE THE
PARTICIPANT OUGHT TO BE ABLE TO
DO THIS, EXPLAIN THE DIFFERENCE
BETWEEN AUTOIMMUNE AND AUTO
INFLAMMATORY DISEASE.
SECOND, RECOGNIZE THE CLINICAL
FEATURES.
AND THIRD, DISCUSS THE EVOLVING
ROLE OF GENOMICS IN THE
DISCOVERY OF NEW AUTO
INFLAMMATORY DISEASES IN PATIENT
DIAGNOSIS.
BEFORE WE GET STARTED MAYBE WE
SHOULD PUT THIS IN AN HISTORICAL
PERSPECTIVE.
THIS IS IN SOME WAYS REALLY HARD
TO BELIEVE.
BACK AT THE BEGINNING OF THE
20th CENTURY THIS GUY PAUL
EHRLICH.
HE WAS A PROMINENT I'M OLOGIST.
* WHAT THAT MEANT WAS THAT THE
IMMUNE SYSTEM IS SO POTENT SO
FORMIDABLE THAT IT WOULD BE
UNIMAGINABLE FOR THE IMMUNE
SYSTEM TO TURN AGAINST ITS HOST.
SO THE PREVAILING DOCTRINE WHICH
LASTED FOR THE FIRST HALF OF THE
20th CENTURY WAS THAT
AUTOIMMUNITY WAS CONCEPTUALLY
IMPOSSIBLE TO HAPPEN.
AND SO THAT WAS THE PREVAILING
VIEW UP TO AROUND 1950 AND AT
THAT TIME -- THEY DISCOVERED
AUTO ANTIBODIES IN DISEASE OF
THE THYROID AND THAT WAS THE
BEGINNING OF THE DOCUMENTATION
OF AUTOIMMUNITY.
SO FOR THE FIRST HALF OF THE
20th CENTURY IT WAS DEEM TO BE
IMPOSSIBLE AND THEN AROUND 1950
AUTOIMMUNITY WAS DISCOVERED.
IT WAS THEN UNTIL THE END OF THE
20th CENTURY BEFORE THIS
CONCEPT OF AUTO INFLAMMATORY
DISEASE CAME ABOUT.
SO WE'LL TALK ABOUT HOW THAT
HAPPENED OVER THE COURSE OF THE
LAST FEW YEARS.
SO THE STORY STARTS WITH A
PATIENT AND THAT OF COURSE IS
REALLY THE NAME OF THE GAME.
REALLY, PATIENTS ARE THE CENTER
OF OUR EXISTENCE AT THE CLINICAL
CENTER AS THEY SHOULD BE THE
CENTER OF OUR EXISTENCE AS
CLINICAL INVESTIGATORS,
PHYSICIAN SCIENTISTS,
INDIVIDUALS WHO WANT TO ADVANCE
OUR UNDERSTANDING OF MEDICINE SO
WHEN I CAME HERE IN 1985 SHORTLY
AFTER I ARRIVED IN NOVEMBER OF
1985 I HAPPENED TO SEE A NEW
PATIENT IN RHEUMATOLOGY CLINIC.
A YOUNG MAN WHO HAD A LIFELONG
HISTORY OF EPISODES OF FEVER
OFTEN TIMES WITH MONO OR ARCTIC
EULAR ARTHRITIS.
*.
ESSENTIALLY HE WAS REFERRED TO
US WITH THE IDEA OF MAYBE WE
COULD FIGURE OUT WHAT HE HAD.
AT FIRST I DIDN'T RECOGNIZE WHAT
HE HAD FOR WHAT IT WAS.
FORTUNATELY THERE WAS A FELLA
FROM ISRAEL FROM THE LAB I WAS
WORKING IN AND WE CAME UP WITH
THE HYPOTHESIS THAT HE MIGHT
HAVE THIS CONDITION CALLED
FAMILIAL MEDICINE FEVER.
SO IS THAT?
IT'S A DISEASE FIRST RECOGNIZED
BACK IN 1945 BY A DIFFERENT
NAME.
AND BASICALLY THERE WERE 10
CASES DESCRIBED IN THE ANNALS OF
INTERNAL MEDICINE.
THESE WERE CASES OF INDIVIDUALS
WHO HAD STERILE PERFECT TOE
NIGHT US.
*.
LATER WITH THE IMMIGRATION OF
MANY JEWISH PEOPLE TO ISRAEL IT
WAS RECOGNIZED THIS IS A DISEASE
OF THE JEWISH POPULATION.
HERE ARE SOME OF THE KEY
FEATURES.
IT WAS RECOGNIZED AT THE TIME
THAT WE FIRST SAW OUR PATIENT
THAT IT WAS A GENETIC DISORDER.
CHARACTERIZED BY EPISODES OF
FEVER THAT MIGHT LAST ON THE
ORDER OF ONE TO THREE DAYS.
AND PATIENTS COULD ALSO HAVE
STERILE -- ARTHRITIS AS WAS THE
CASE FOR THE PATIENT THAT I SAW.
SOME OF THE PATIENTS CAN HAVE A
RASH ON THE ANKLE OR FOOT OR
LOWER LEG.
AND SOME PATIENTS COULD ALSO
HAVE THE DEPOSITION OF A
CLEAVAGE PRODUCT OF ONE OF THE
ACUTE FACE REACT ANTS AND IT WAS
A MAJOR CAUSE OF KIDNEY FAILURE
AND DEATH BACK BEFORE THE ADVENT
OF CULTURE TREATMENT.
FORTUNATELY IT WAS AVAILABLE.
WE PUT HIM ON IT AS A
THERAPEUTIC TRIAL.
HE RESPONDED BEAUTIFULLY AND
THAT WAS CERTAINLY PART OF THE
CONFIRMATION OF THE DIAGNOSIS AT
THE TIME.
BUT IN ANY CASE AT THAT TIME IT
WAS THE DAWN OF THE GENOME
PROJECT.
SO WHEN I WAS THINKING ABOUT
WHAT SORT OF A PROJECT COULD I
DO IN MY FELLOWSHIP ONE IDEA
THAT CAME TO MIND WAS POSSIBLY
THE IDEA OF FINDING THE GENE
THAT IS MU INDICATED.
-- MUTATED.
IT WAS WORKING ON THE SHOULDERS
OF GIANTS.
SO THE FIRST PERSON THAT
RECOGNIZED THAT POLLY MORE
OFISMS IN * DNA WAS THIS GUY
HERE.
YW -- KHAN.
AND HE SHOWED THAT -- IT
CO-SEGREGATED WITH SICKLE-CELL
ANEMIA IN A FAMILY.
SHORTLY THEREAFTER DAVID
BOBSTEIN -- MAYBE WE COULD MAKE
A MAP OF THE HUMAN GENOME BASED
ON DNA POLLY MORPHISMS.
* AND THEN WE HAVE OF COURSE THE
GOOD DR. COLLINS OUR FORMER NIH
DIRECTOR WHO EARLIER IN HIS
CAREER WAS VERY INVOLVED IN AND
A PIONEER IN THIS FIELD OF USING
THE APPROACH OF POSITIONAL
CLONING AS IT WAS CALLED TO
IDENTIFY HUMAN DISEASE GENES AND
THE FIRST TARGET WAS CYSTIC
FIBROSIS WHICH IS A DISORDER
THAT IS ALSO RECESSIVELY
INHERITED.
SO IN ORDER TO EMULATE I MADE A
FIELD TRIP TO ISRAEL AND YOU SEE
ME WITH MY COLLABORATOR VISITING
A FAMILY IN A CITY IN NORTHERN
ISRAEL AND YOU CAN SEE THIS
PHOTO HAS BEEN ALTERED TO MEET
HIPAA REQUIREMENTS SO EVERYBODY
HAS MY FACE THERE.
BUT ANY WAY IT'S A FAMILY IN
WHICH IT WAS SEGREGATING.
THE FATHER AND MOTHER IN THE
FAMILY WERE FIRST COUSINS TO ONE
ANOTHER AND THEN MULTIPLE
MEMBERS OF THE FAMILY.
ALL TOGETHER IN THE SUMMER OF
1989 WE WERE ABLE TO COLLECT
BLOOD SAMPLES FROM 62 FAMILIES
WITH MULTIPLE MEMBERS AND OVER
THE COURSE OF THE NEXT COUPLE OF
YEARS CULMINATING IN A PAPER
PUBLISHED IN THE NEW ENGLAND
JOURNAL OF MEDICINE WE
IDENTIFIED THE CHROMOSOMAL
LOCATION OF THE GENE.
THEN WE BECAME A GENOME PROJECT
FOR THAT AREA OF CHROMOSOME 16
AND WITH COLLABORATORS AROUND
THE WORLD WE WERE ABLE TO
DEVELOP GENETIC MAPS AND THEN
PHYSICAL MAPS AND
TRANSCRIPTIONAL MAPS AND
SEQUENCE DATA FROM THIS REGION
OF CHROMOSOME 16 NARROWING THE
AREA OF INTEREST UNTIL WE GOT
DOWN SYNDROME TO THE DNA.
AND EVENTUALLY WE FOUND THAT IT
WAS THE 10 THE THAT THE WE
LOOKED AT THAT TURNED OUT TO BE
THE GENE HARBORING MUTATIONS
THAT CO-SEGREGATED.
AND WE PROPOSED THE NAME PYRON.
IT WAS A DREAM COME TRUE FOR US
IN THE SENSE THAT IT TURNED OUT
TO BE A GENE THAT HAD NOT BEEN
RECOGNIZED BEFORE.
NOBODY KNEW ANYTHING ABOUT WHAT
IT WAS OR WHAT IT ENCODED BUT
ONCE WE GOT OVER THE ELATION OF
ALL OF THAT WE REALIZED WE HAD
TO FIGURE THAT OUT WHICH WAS NOT
A TRIVIAL MATTER TO SAY THE
LEAST.
ONE OF THE INITIAL CLUES THAT
CAME UP SOON WITHIN A COUPLE OF
YEARS WAS THAT THE END TERMINAL
90 OR SO AMINO ACIDS -- THE
PYRIN DOMAIN.
IT ALLOWS FOR THE FORMATION OF A
CHARGED DIPOL.
AND BASICALLY THROUGH
ELECTROSTATIC INTERACTIONS THE
DOMAIN CAN INTERACT AND THERE
ARE SOME 20 HUMAN PROTEINS.
THAT IN ONE WAY OR ANOTHER HAVE
A PYRIN DOMAIN.
THAT WAS GOOD.
THAT WAS HAPPENING WHILE AT THE
SAME TIME WE WERE CONTINUING TO
SEE PATIENTS BECAUSE AS I SAID
THAT IS ONE OF THE PARAMOUNT
THINGS IS TO CONTINUE TO SEE
PATIENTS.
SO WE WERE REFERRED PATIENTS.
SOME OF THEM WERE SENT TO US
WITH THE QUESTION DO THEY HAVE
FMF.
AND THE ANSWER WAS YES.
BUT THEN WE STARTED TO SEE OTHER
PATIENTS.
THEY DID NOT.
THERE WERE VARIOUS THINGS THAT
DIDN'T FIT.
THEY MAY NOT HAVE HAD MUTATION
IN THE CAUSATIVE GENE.
THEY WERE NOT FROM THE
MIDDLE-EAST OR THE MEDITERRANEAN
AREA.
THE ATTACKS WERE TOO LONG.
NOT RESPONSIVE.
SO IN ANY EVENT OVER THE COURSE
OF A COUPLE OF YEARS -- THEY
WERE ABLE TO TRACK DOWN THE NEXT
PERIODIC FEVER GENE WHICH ENCODE
THE RECEPTOR.
SO AT THAT POINT WE HAD WITHIN A
COUPLE OF YEARS A PERIOD OF TIME
IDENTIFIED A COUPLE OF GENES
THAT WHEN MUTATED LED TO
RECURRENT FAVORS AND
INFLAMMATION BUT IN WHICH THE
PATIENTS DID NOT HAVE AUTO.
BODIES AS ONE WOULD SEE IN THE
CHAT CALL AUTOIMMUNE DISEASES.
MAYBE THIS IS AN EMERGING NEWS
SET OF DISEASES AND WE PROPOSED
THE TERM AUTO INFLAMMATORY.
WHICH WAS TONGUE IN CHEEK BUT
PERHAPS WE THOUGHT THERE WAS
SOMETHING TO IT.
WE PUB LEARNED A PAPER IN WHICH
WE HYPOTHESIZED ON WHAT OTHER
DISEASES MIGHT POSSIBLY BE AUTO
INFLAMMATORY BASED ON CLINICAL
FINDINGS.
AND SO WE CAME ONE THIS
CLASSIFICATION SCHEME THIS
TENTATIVE CLASSIFICATION SCHEME
AND A COUPLE OF DISEASES THAT WE
PROPOSED AS POSSIBLY BEING AUTO
INFLAMMATORY FELL INTO THIS
CATEGORY.
THESE WERE DISEASES IN WHICH
PATIENTS WOULD HAVE AN INHERITED
CONDITION IN THESE TWO CASES
WHERE ON VARIOUS EXPOSURES OR
SOMETIMES NOT WITH EXPOSURES
THEY COULD DEVELOP FEVERS AND
BREAK OUT IN HIVES.
AND WITHIN A YEAR OF THAT AND
THIS IS WHERE IT'S FACT STRANGER
THAN FICTION INDEED THERE
APPEARED IN NATURE GENETICS THIS
PAPER AND THEY HAD IDENTIFIED
THE GENE THAT IS M MUTATED.
AND THE GENE TURNS OUT TO HAVE A
PYRIN DOMAIN.
WE HAD SOMETHING THAT GAVE US A
CLUE.
A COMMON THEME THAT WAS TYING
TOGETHER SOME OF THE DISEASES
THAT WE HAD PROPOSED AS BEING
AUTO INFLAMMATORY.
IN ANY CASE AT THE SAME TIME
THAT THAT WAS GOING ON AS IF
THIS WAS NOT ALREADY INCREDIBLE
ENOUGH THERE WAS THIS GUY OVER
IN SWITZERLAND WHO HAS PASSED
AWAY.
WHO WAS STUDYING THE ACTIVATION.
AND HE HAD IDENTIFIED THIS MACRO
MOLECULAR COMPLEX -- IT WAS
RESPONSIBLE FOR ACTIVATION.
A MAJOR MEDIATOR OF FAVOR AND
INFLAMMATION * AND THE THING
THAT WAS INTERESTING IS THAT ONE
OF THE HALL COOLS TURNED OUT TO
BE NRLP3 WHICH IS THE SAME
MOLECULE THAT WAS FOUND MUTATED.
WE HAD THE CONNECTION WITH
PYRIN.
THE INFLAMMASOME CONNECTION AS
WELL.
THAT COULD GIVE US AN IDEA AS TO
WHAT WAS GOING ON BIOLOGICALLY.
AND JUST FOR YOUR EDUCATION WHY
DON'T WE LOOK AT WHAT COULD BE *
HAPPENING AND THIS WAS A MOVIE
MADE THAT ILLUSTRATES THE NL --
NLRP3 INFLAMMASOME.
IT CAN INTERACT.
HERE YOU SEE IT GETTING
ACTIVATED.
VARIOUS BACTERIAL TOXINS OR
STRESS FACTORS CAN ACTIVATE IT
AND NOW YOU SEE THAT IT'S
ACTIVATED.
WE ARE HAVING INTERACTIONS AMONG
THE DOMAINS AND YOU SEE A DISK
FORMING AS A RESULT.
AND WE'RE LOOKING AT IT FIRST
FROM A TOP VIEW AND THEN WE'LL
LOOK AT IT FROM A SIDE VIEW AND
YOU'LL SEE NOW THAT ANOTHER
MOLECULE THAT IS CALLED ASC THAT
ALSO HAS A DOMAIN.
AND YOU SEE THAT WE'RE FORMING
FILAMENTS HERE BASICALLY CAUSED
BY THE DOMAIN INTERACTIONS.
AND THEN INTERACTIONS OF DOMAINS
AMONG THE ASC MOLECULES AND THEN
STICKING OUT ARE THESE BROWN
DOMAINS WHICH ARE CALLED CARD
DOMAINS WHICH HAVE A SIMILAR
STRUCTURE.
AND AND ALLOW FOR
SELF-INTERACTIONS THAT ARE NOW
DECORATING THESE FILLMEANT.
YOU HAVE MOLECULES WHICH ARE
THEN ABLE TO ACTIVATE INTEREST
LUC IN ONE AND 18 TWO MAJOR
INFLAMMATORY CYTOKINES.
AND THEN THE FRAGMENTS GOING OFF
AND NOW WE HAVE ANOTHER MOLECULE
AND YOU SEE THE FRAGMENTS
FLOATING OFF AND WE'LL SEE THEM
IN A COUPLE OF MINUTES DOING
WHAT THEY DO WELL WHICH IS TO
BLOW UP THE CELL.
SO NOW WE'RE GOING TO SEE THE
INFLAMMASOME FADE OFF INTO THE
SUN SET AND WE'LL FOCUS US ON
THE D MOLECULES.
THEY WILL FORM RINGS ESSENTIALLY
WHICH CAN BE INSERTED IN THE
CELL MEMBRANE FORMING PORES THAT
DISRUPT THE GRADIENT IN THESE
WHITE BLOOD CELLS AND LEAD TO
THE -- OF THE WHITE BLOOD CELL
AND THE RELEASE AND BASICALLY
LEADING TO INFLAMMATION.
SO, THAT IS THE CONCEPT OF HOW
THIS WORKS.
NOW SINCE WE KNEW THIS AT THAT
POINT THEN ONE COULD SAY WELL
ONE OUGHT TO BE ABLE TO TREAT
PATIENTS WITH THIS MUTATION WITH
AN INHIBITOR AND RAFAEL CAME UP
WITH THE IDEA OF TREATING A
COHORT OF 18 PATIENTS THAT WE
HAD WITH THE MOST SEVERE FORM OF
DISEASE CAUSED BY MUTATIONS.
A DISEASE CALLED NOMAD.
AND THIS IS A DISORDER WHERE NOT
ONLY DO THE PATIENTS HAVE FAVORS
AND-S BUT THEY HAVE A SEPTIC
MENINGITIS.
AND SO THIS IS A PAPER THAT WAS
PUBLISHED BACK IN 2006 THE
BEFORE AND AFTER.
YOU CAN SEE THE-S AND RASH, THE
WHITE REPRESENTS THE MENINGITIS.
ON DAILY INJECTIONS YOU CAN SEE
THAT THE-S GO AWAY.
CONJUNCTIVITIS GOES AWAY WITHIN
TWO OR THREE MONTHS.
THE MEN E-- MENINGITIS GOES AWA.
SOME OF THEM ARE NOW GRADUATING
FROM COLLEGE WHEREAS THE
PROGNOSIS WOULD HAD BEEN BLEAK
HAD THEY NOT BE TREATED.
SO WE HAVE THEN THIS CONCEPT OF
AUTO INFLAMMATION WITH TWO
FLAVORS OF IMMUNITY.
ADAPTIVE IMMUNITY AND AUTOIMMUNE
DISEASES.
THE INNATE IMMUNE SYSTEM IS A
MORE PRIMITIVE BRANCH -- THE
RECEPTORS ARE HARDWIRED AND THE
AUTO INFLAMMATORY DISEASES ARE
CHARACTERIZED BY UNPROVOKED
INFLAMMATION.
SO LET'S GO BACK FOR A BRIEF
MOMENT TO TALK ABOUT THE PYRIN
INFLAMMASOME.
IT ALSO ACTIVATES AISLE 1 AND
I'LL 18.
BUT IT'S REGULATED IN A VERY
INTERESTING WAY.
IT IS REGULATED BY A MOLECULE
CALLED ROW A WHICH LIVES ON THE
INSIDE OF THE CELL MEMBRANE.
AND ORDINARILY IT CAN TRIGGER
THE ACTIVATION OF PKN.
THAT LEADS TO INHIBITORY
PROTEINS BINDING TO PIE RING.
HOWEVER CERTAIN BACTERIA MAYBE
TO BE INS.
THEY DO THAT BECAUSE ROW A
ACTUALLY IS VERY IMPORTANT IN
THE ORGANIZATION OF THE
CYTOSKELETON.
AND SO, ITS A STRATEGY THAT
BACTERIA USE TO IN ACTIVATE
WHITE BLOOD CELLS.
TO IN ACTIVATE ROW A BUT THAT
THEN LEADS TO LESS INFORMATION
FOR LACKS OF PYRIN AND * AND
ACTIVATION.
SO THE PYRIN INFLAMMASOME DOES
NOT BIND TO THOSE TO BE INS.
IT'S RESPONDING TO PHYSIOLOGICAL
CHANGES IN THE CELL THAT ARE
INDUCED BY BACTERIAL TOXINS.
AND THE PYRIN INFLAMMASOME WAS
ONE OF THE EARLY EXAMPLES OF HOW
WE HUMANS ARE LIKE PLANTS.
IF YOU LOOK AT THESE SITES IF
YOU HAVE MUTATIONS BASICALLY YOU
GET A DISEASE CALLED PAAND.
WHICH LEADS TO A CONTINUOUS FORM
OF DETERMINES TO US.
*.
WE WERE ALSO INTERESTED IN WHY
THERE WAS SUCH A HIGH CARRIER
FREQUENCY OF FMF MUTATIONS IN
MIDDLE EASTERN POPULATIONS.
SO LOOKING AT THE SIZE OF THE
DNA FINGERPRINT ASSOCIATED
EITHER WITH THE MUTANT VERSION
OF THE GENE THAT IS SHOWN IN
BLUE HERE OR THE WILD TYPE SHOWN
IN ORANGE.
WHAT YOU CAN SEE IS THE EXTENT
OF THAT DNA FINGERPRINT IS MUCH
BROADER.
THAT IS SOMETHING THAT YOU SEE
WHEN A MUTATION IS UNDER
SELECTION AND WHAT YOU WOULD
EXPECT THEN WOULD BE THAT THE
SIZE OF THE ASSOCIATED
FINGERPRINT WOULD BE AT THE END
OF THE BELL CURVE FOR OTHER
GENES THAT HAVE A SIMILAR
FREQUENCY.
OTHER MUTATIONS THAT HAVE A
SIMILAR FREQUENCY AND SURE
ENOUGH IT IS.
WITH THAT ONE CAN CALCULATE WHAT
WOULD BE THE SELECTION CO-E
FISHES.
* * IT'S QUITE HIGH.
HIGHER THAN THE SELECTION
COEFFICIENT.
SO THIS IS DEFINITELY SOMETHING
THAT HAS BEEN UNDER SELECTION IN
THE MIDDLE-EAST AND ONE CAN USE
THESE ANALYSIS TO ESTIMATE THE
AGE OF THE MUTATION AND THAT IS
SOMETHING WHERE BETWEEN TWO AND
FIVE THOUSAND YEARS THAT THIS
PARTICULAR MUTATION AROSE IN THE
MIDDLE-EAST.
BIBLICAL TIMES.
WHAT COULD HAD BEEN SELECTING
FOR THESE HIGH CARRIER
FREQUENCIES.
ONE OF THE POSSIBILITIES IS YOUR
-- THE ORGANISM THAT CAUSES
BUBONIC PLAGUE.
IT MAKES A TOXIN THAT LEADS TO
THE INFORMATION FOR LACKS OF
PYRIN.
BLOCKING.
IT IS RELATIVELY RESISTANT TO
THAT.
BUT EVEN THE CARRIERS ARE ALSO
RESISTANT TO IT WHICH THEN
EXPLAINS THE SELECTION.
WELL, IN ANY CASE WHY DON'T WE
MOVE ON TO SOME OF THE OTHER
DISEASES THAT WE'VE BEEN
INTERESTED IN OVER THE YEARS AND
THIS GRAPH SIMPLY TELLS US
AROUND 2007 THE COST OF DNA
SEQUENCING DROPPED WITH THE
NexGen SEQUENCING
REVOLUTION.
YOU CAN SEE THE COST RELATIVE TO
THE COST OF COMPUTING.
AND THEY WERE IN PARALLEL UP TO
ROUND 2007 AND THEN SEQUENCING
BECAME MUCH LESS EXPENSIVE.
SO IT ALLOWED FOR DNA SEQUENCING
TO BE USED IN MANY RESEARCH
SETTINGS AND ONE THAT I WILL
TELL YOU ABOUT IS THE STORY OF A
LITTLE GIRL FROM NEW JERSEY WHO
WAS REFERRED TO US AT THE SAGE
OF 2.
AT THAT POINT SHE HAD ALREADY
HAD RECURRENT FEVERS AND THEN A
CATASTROPHIC NEUROLOGICAL EVENT
MAYBE THIS WAS NOMAD AND CAUSED
MEMENINGITIS.
TURNED OUT THE PATIENT DID NOT
HAVE THIS.
INSTEAD HAD MULTIPLE SMALL
STROKES IN THE DEEP BRAIN NUCLEI
FOR WHICH WE DID NOT HAVE AN
EXPLANATION.
THEN ABOUT 10 YEARS LATER
ACTUALLY THROUGH THE UNDIAGNOSED
DISEASES PROGRAM WE HEARD ABOUT
A LITTLE GIRL FROM TEXAS WHO WAS
SIX YEARS OLD AND OVER THE
COURSE OF HER SIX YEARS OF LIFE
SHE HAD NOT ONLY RECURRENT
FEVERS BUT SIX STROKES.
IN THE SAME DISTRIBUTION AS THE
LITTLE GIRL FROM NEW JERSEY.
MAYBE IF WE DID SEQUENCING THAT
MAYBE WE COULD FIND SOMETHING IN
COMMON AND I WOULDN'T BE TELLING
YOU THIS STORY IF WE HADN'T.
WE DEFINED SOMETHING IN COMMON
BASED ON RECESSIVE MODEL OF
INHERITANCE.
THERE WAS A GENE CALLED CECR1.
NOW WE CALL IT -- TYPE 2 WHICH
WAS MU INDICATED IN BOTH OF
THESE CHILDREN AND THEN WE FOUND
OTHER CHILDREN AS WELL WHO HAD
EITHER THE SAME OR OTHER
MUTATIONS IN THIS GENE.
AND SO WE PROPOSED THE NAME
DEFICIENCY -- IT IS MUTATED IN
SEVERE DISEASE.
ADA2 ALSO DOES HAVE SOME
ACTIVITY IN TERMS OF CATALYZING
AVERSION.
BUT IT IS AN EXTRA CELLULAR
PROTEIN AND HAS A ROLE IN BOTH
AS A GROWTH FACTOR AS WELL AS
FOR -- ENDOTHELIAL CELLS.
THIS IS THE PAPER IN WHICH WE
REPORTED AND YOU CAN SEE THE
SMALL STROKES THAT SOME OF THESE
PATIENTS HAD.
THIS WAS A HEMORRHAGIC STROKE.
THIS IS WHAT THE PATIENTS CAN
HAVE AND IT SHOULD RAISE THE
QUESTION OF WHETHER IT'S
DEFICIENCY OF ADA2 AND SOME
PATIENTS CAN ALSO DEVELOP -- A
LESION OF THE EXTERNAL EAR.
THIS GRAPH JUST SHOWS THE VERY
LOW LEVELS IN THE BLOOD IN
PATIENTS COMPARED WITH THEIR
UNAFFECTED PARENTS, CARRIER
PARENTS.
THIS PRESENTED US WITH A SIMILAR
KIND OF PROBLEM TO WHAT WE HAD
WITH NOMAD AND THAT WAS A COHORT
OF PATIENTS WITH THIS NEWLY
DISCOVERED DISEASE BUT NOT A
GOOD WAY OF TREATING IT BECAUSE
IT TURNED OUT THAT THE PATIENTS
THAT WERE REFERRED TO US WERE
CONTINUING TO HAVE STROKES AT
ABOUT A FREQUENCY OF MAYBE ONCE
EVERY THREE YEARS OR SO ON THE
AVERAGE.
AND THESE PATIENTS HAD BEEN
TREATED WITH MANY DIFFERENT
IMMUNE KNOW SUPPRESSANT AGENTS
WITHOUT AVAIL.
ONE WAS THE FACT THAT WE SAW TNF
ON SKIN BIOPSIES IN THE PERRY
VASCULAR AREAS AND * AND A
COLLEAGUE IN ISRAEL WHO HAD A
PATIENT HAD TREATED THE PATIENT
WITH BENEFICIAL RESULTS.
SO WE STARTED TREATING OUR
PATIENTS WITH TNF INHIBITORS IN
THE HOPES THAT MAYBE WE COULD DO
SOMETHING FOR THEM.
AND THESE ARE THE RESULTS.
THEY DID MARKETLY IMPROVE ON TNF
INHIBITORS.
BEFORE THEY HAD HAD 55 STROKES.
AFTER GOING ON THE INHIBITORS WE
HAD 700 PATIENT OBSERVATIONS AND
THE NUMBER OF STROKES WAS ZERO.
SO TNF INHIBITION IS VERY
BENEFICIAL IN PREVENTING THE
STROKES.
IT HAS BEEN DRAMATIC IN ITS
EFFECT ON THE PROGNOSIS OF THIS
CONDITION.
JUST A FEW OTHER HAVE I NETS OF
MONOGENIC * DISEASES THAT WE'VE
WORKED ON OVER THE LAST SEVERAL
YEARS.
BEING THE BENEFICIARIES OF THIS
NexGen SEQUENCING
REVOLUTION.
ONE OF THE DISEASES IS A
DISORDER IN WHICH PATIENTS HAVE
MU MUTATIONS IN A SIGNALING
MOLECULE CALLED RIP K1.
AGAIN WE'RE -- YOU CAN ACCUSE US
OF BEING SLOW OR VERY PERSISTENT
BUT IN ANY CASE WE DID FIND
DOMINANT INHERITANCE OF A
MUTATION IN THIS THREE
GENERATION FAMILY AND THEN A
COUPLE OF -- MUTATIONS IN THESE
OTHER TWO FAMILIES.
AND THESE PATIENTS CLINICALLY
HAVE DIFFUSED PAINFUL -- AND
ORGAN MEGALY.
324 OF THIS MOLECULE THAT IS A
PRO INFLAMMATORY MOLECULE THAT
IS CALLED RIP K1.
IT WOULD ORDINARILY BE CLEVED.
AND THIS IS ONE WAY THAT THE
SIGNALING IS TURNED OFF.
ONE OF THE FAMILIES -- THIS IS A
HIGHLY CONSERVED RESIDUE ACROSS
EVOLUTION AND ONE CAN SEE THAT
IN FACT -- THE MUTATIONS DO
RENDER THE PROTEIN RESISTANT TO
CLEAVAGE AND THROUGH A SERIES OF
FUNCTIONAL STUDIES INVOLVING THE
DEVELOPMENT OF MOUSE MODELS WITH
COLLEAGUES IN AUSTRALIA WE FOUND
THAT IT'S A MOLECULAR SWITCH.
AND THIS ACTUALLY WAS SOMETHING
THAT WAS AN IMPORTANT ENOUGH
PRINCIPLE THAT IT WAS PUBLISHED
IN NATURE.
ANOTHER DISEASE THAT WE HAVE NOT
YET PUBLISHED IS A DISEASE
CALLED SHARPENIA.
A YOUNG MAN FROM INDIA -- WHO
HAD EARLY ON SET RECURRENT
FEVERS, ARTHRITIS AND COLITIS
AND HE TURNED OUT TO BE A FRAME
SHIFT MUTATION IN THIS PROTEIN
SHARPEN WHICH IS INVOLVED IN THE
REGULATION OF A VERY IMPORTANT
POST TRANSLATIONAL MODIFICATION
OF PROTEINS PARTICULARLY IN
IMMUNE CELLS.
WE INVITED HIM TO COME TO THE
NIH AND ARE HERE ARE SOME
IMAGING VIEWS.
IT'S POTENTIALLY
LIFE-THREATENING.
BECAUSE IT CAN CAUSE INSTABILITY
OF THE NECK AND HERE COLITIS.
INFLAMMATION IN THE COLON.
SO IN ANY EVENT THROUGH A SERIES
OF FUNCTIONAL STUDIES AND
COMPARISONS WITH MOUSE MODELS WE
HYPOTHESIZED THAT TNF WAS
PROBABLY LEADING TO A FORM OF
CELL DEATH THAT LED TO
INFLAMMATION IN THIS PATIENT.
AND THAT TREATING HIM WITH AN
INHIBITOR WOULD WORK.
WHEN HE CAME TO US HE WAS NOT
TOTALLY WHEELCHAIR BOUND BUT
CERTAINLY NEEDED A WHEELCHAIR IN
ORDER TO GET AROUND.
AND OVER THE COURSE OF A YEAR WE
TREATED HIM FIRST WITH -- AN
INHIBITOR AND THEN ADDED AN
ANTIBODY AND IT DID HAVE A
DRAMATIC EFFECT.
AND HERE HE IS ABOUT A YEAR
AFTER WE STARTED SEEING HIM.
WE'RE SEEING HIM IN THE CLINIC.
HE IS STANDING BUT NOT ONLY
STANDING BUT HE WAS ABLE TO
DANCE.
AND THIS IS SOMETHING THAT WAS
INCREDIBLY GRATIFYING FOR US.
A THIRD DISEASE ANOTHER AUTO
INFLAMMATORY DISORDER THAT
CHRISTINA -- IS WORKING ON A
DISEASE THAT IS CALLED ROSA
WHICH STANDS FOR RETINAL
DYSTROPHY ...
ROSAH.
IT TURNS OUT TO BE A MOLECULE
THAT IS A SENSOR FOR SEVEN
CARBON SUGARS.
WHEN THEY ARE WITHIN THE CELL
THEY TRIGGER THE ACTIVATION OF
RK1 WHICH LEADS TO INFLAMMATION.
WHY WOULD THIS HAPPEN?
IT TURNS OUT THAT BACTERIA SOME
BACTERIA CAN MAKE SEVEN CARBON
SUGARS AND WE CANNOT.
SO TO HAVE AMOLE COOL THAT GETS
TURNED ON AND LEADS TO
INFLAMMATION IS A MECHANISM A AN
INNATE MECHANISM FOR THIS
BACTERIA.
AND THIS IS IN AN OBSCURE
BRANCH.
WE'RE STILL TRYING TO FIGURE OUT
HOW IT WORKS.
THE CLINICAL FEATURES OF ROSAH
ARE SHOWN ON THIS SLIDE AND YOU
CAN SEE THE OPTIC -- AND CALLS
CASE OF THE BASAL GANGLY YA.
THE ARTHRITIS IN THE HANDS.
THESE *.
THESE PATIENTS OVER TIME MANY
DEVELOP VISION LOSS AND GO ON TO
BLINDNESS.
HERE ONE CAN SEE -- VESSEL
LEAKAGE.
YOU CAN ALSO SEE D SEE -- EDEMAE
MACULAR OF THE EYE.
IN THREE PATIENTS THAT ARE IN
THE PROGRESSION OF VISION LOSS
WHERE THEY ARE ON THE ASCENDING
LOOM OF LOSING THEIR VISION AND
ACTUALLY THEY HAVE AT LEAST SO
FAR DONE FAIRLY WELL WITH THE
ANGIE OH GRAMS * IMPROVING.
WELL IN ANY CASE THERE IS LOTS
OF EXAMPLES.
THIS IS JUST THE GALLIES OF A
CHAPTER THAT LISTS MANY OF THE
AUTO INFLAMMATORY SYNDROMES.
IT'S NOT EVEN ALL OF THEM.
THE NUMBER OF THEM IS REMARKABLE
AND CONTINUES TO GROW.
BUT I THINK THAT AT THIS POINT
WHY DON'T WE FINISH UP BY
TALKING NOT ABOUT GERMLINE
MUTATIONS BUT INSTEAD SOMATIC
MUTATIONS AND WE'RE INTERESTED
IN ASKING THE QUESTION HOW DO
OLD PEOPLE GET AUTO INFLAMMATORY
DISEASE?
THIS IS A VEXING PROBLEM FOR ME
AND MY COLLEAGUES IN THE AUTO
INFLAMMATORY DISEASES CLINIC.
FOR CASES WHERE WE HAVE CHILDREN
THAT GREAT TO US WITH SEVERE
AUTO INFLAMMATION ONE CAN
REASONABLY HYPOTHESIZE THAT A
GERMLINE MUTATION CAN BE
RESPONSIBLE.
WHEN SOMEONE WHO'S 50 YEARS OLD
PRESENTING TO THE AUTO
INFLAMMATORY CLINIC FOR THE
FIRST TIME YOU HAVE TO THINK
ABOUT A NUMBER OF OTHER
POSSIBILITIES.
MAYBE THE PERSON HAS AN
INFECTION.
TRAVELED SOMEWHERE AND PICKED
SOMETHING UP.
MAYBE THEY HAVE CANCER AND THIS
IS JUST THE SYNDROME THAT WILL
DECLARE ITSELF AS CANCER LATER
ON.
IT'S A HARD NUT TO CRACK.
BUT CERTAINLY AN IMPORTANT ONE
AND WE SEE A NUMBER OF CASES
LIKE THIS IN THE CLINIC.
SO THIS WAS THE SETTING FOR NOW
MY FORMER FELLOW DAVID BECK AND
HIS COLLEAGUES WHO WERE
INTERESTED IN THIS ISSUE.
AND THEY DECIDED AND IT WAS
DAVID WHO DID THE WORK IN THE
LAB DECIDED TO TAKE A DIFFERENT
APPROACH TO DISCOVERY.
SO THE USUAL APPROACH THAT WE
MIGHT TAKE IS CALLED PHENOTYPE
APPROACH IN WHICH WE GROUP
TOGETHER PATIENTS THAT HAVE
SIMILAR MANIFESTATIONS AND THEN
USING GENETIC TECHNIQUES WE TRY
TO FIND SOME GENE A VARIANT OR
SET OF VARIANTS THAT COULD
EXPLAIN THE PHENOTYPE.
THAT IS THE USUAL MISSION THAT
WE GO ON IN GENETICS.
BUT DAVID HAD THIS IDEA THAT
RATHER THAN GOING PHENOTYPE
FIRST HE WOULD LIKE TO GO
GENOTYPE FIRST.
SO HE MADE A LIST OF ALL OF THE
GENES THAT HAVE NOTHING TO DO
WITH THIS.
OVER THE PREVIOUS COUPLE OF
YEARS WE DISCOVERED A COUPLE OF
DISEASES BY A PHENOTYPE APPROACH
THAT CAUSED TO BE BY
UBIQUITYLATION.
* THE PROGRAM WAS KIND ENOUGH TO
CONTRIBUTE 1083 GENOMES SO ABOUT
2500 GENOMIC SEQUENCES INTERGET
WITH 841 GENES.
FILTERING CRITERIA INCLUDED THAT
THE GENES WOULD NEED TO BE
RELATIVELY INTOLERANT OF
VARIANTS.
HAVE A PLI SCORCH GREATER THAN
0.9 AND THAT THEY WOULD BE
SHARED.
AND DOING ALL OF THIS WITH THE
2500 OR SO PATIENTS AND THE 841
GENES DAVID FOUND THREE MIDDLE
AGE MEN WHO HAPPENED TO BE
HETERO ZAIRE GUS FOR THIS GENE
UBA1.
*.
AT FIRST BLUSH THAT WOULD SEEM
GREAT BECAUSE UBA1 IS AN
IMPORTANT GENE IN REGULATING.
BUT IT'S SO IMPORTANT THAT ONE
COULD MAYBE SAY HOW IN THE WORLD
COULD SOMEONE HAVE A MUTATION IN
THAT GENE AND STILL BE ALIVE?
WHAT IS MORE IT TURNS OUT THAT
UBA1 IS ENCODED ON THE X
CHROMOSOME.
MEN ONLY HAVE USUALLY ONE X
CHROMOSOME.
SO IT COULD BE A SEQUENCING
ERROR.
WE RULED THAT OUT.
IT COULD BE AN EXTRA X
CHROMOSOME.
WE RULED THAT OUT.
SO INSTEAD IT COULD BE A SOMATIC
MUTATION IN WHICH RATHER THAN
THE DNA WHICH COMES FROM WHITE
BLOOD CELLS.
BASICALLY REPRESENTING THAT IN
ALL OF THE WHITE BLOOD CELLS
THERE IS A MUTANT AND WILD TYPE
VERSION OF THE GENE THAT THERE
MIGHT BE TWO POPULATIONS OF
WHITE BLOOD CELLS.
ONE THAT HAS THE MUTATION.
THE OTHER THAT DOESN'T HAVE THE
MUTATION.
SO HE SET ABOUT TO TEST THAT
HYPOTHESIS.
IN THE BLOOD THE DNA SHOWS TWO
PEAKS.
A MUTE ANNUAL AND A WILD PEAK.
THE BONE MARROW.
HOWEVER, IF YOU FRACTIONATE THE
BLOOD YOU SEE THAT THE MUTANT
PEAK PREDOMINATES STRONGLY
WHEREAS IN THE WILD TYPE PEAK IS
THE PREDOMINANT PEAK.
IT IS NOT THAT ALL OF THE CELLS
HAVE BOTH VERSIONS OF THE GENE.
IT'S THAT SOME OF THE DRILLS
CELLS HAVE THE MUTANT VERSION
AND SOME HAVE THE WILD VERSION
AND IF ONE DOES DIGITAL DROPIC
YOU CAN SEE THAT THE FRACTION
AND FIBROBLAST IS ZERO AND IT'S
ACTUALLY QUITE HIGH IN MYELOID
CELLS.
HERE IS ANOTHER FACT STRANGER
THAN FICTION MOMENT AND THAT IS
THAT WE THEN WENT TO VISIT THE
GOOD DR. KATHY CALVO TO LOOKING
AT THE BONE MARROWS.
AND SHE NOTICED THAT IN FACT THE
MYELOID -- HAD THESE FUNNY
LOOKING VACUOLES.
WE CAME BACK A FEW DAYS LATER
AND SHE TOLD ME EFFICIENTLY TO
MY SHE GRIN THAT WHERE SHE HAD *
SEEN IT BEFORE WAS IN A COUPLE
OF MY PATIENTS FROM 8 YEARS
BEFORE.
SO WE WENT BACK AND CHECKED
THOSE INDIVIDUALS.
THEY WERE MIDDLE AGED MENACE
WELL FOR MUTATIONS IN UBA1.
AND IN FACT WE FOUND EVIDENCE
FOR SOMATIC MUTATION IN THEM.
ONE OF THEM TURNED OUT TO BE
RELAPSING POLLY -- CHONDRITIS.
* AND WE SOON HAD 15 PATIENTS
WITH INFLAMMATION AND UBA1
MUTATIONS.
MIDDLE AGE MEN AT POSITION 41
AND THEN BY NOTING OUR NOSES
WITH OTHER PATIENTS WE FOUND
THAT THERE WERE PATIENTS WITH
SWEET SYNDROME, MGUS AND -- ALL
OF THEM WITH MUTATIONS IN UBA1.
SOME OF THE PATIENTS CARRIED
MORE THAN ONE DIAGNOSES WHICH IS
WHY THE PERCENTAGES ADD UP TO
MORE THAN 100%.
SINCE THEY HAVE MUTATIONS IN
UBA1 WE THOUGHT THAT WE SHOULD
SAY THEY HAVE THE SAME DISEASE
WHICH DAVID CAME UP WITH THE
NEXT VEXAS.
AND HERE YOU CAN SEE ON A SCAN
THE PYOU CAN SEE ...
AND IF YOU LOOKING LOOK YOU CANT
THEY LOOK AWFUL.
SO, IT'S NOT THAT THESE ARE
CELLS THAT ARE ALMOST CANCEROUS
THAT ARE PROLIFERATING BUT
RATHER THEY CAN TOLERATE THE
MUTATION AND IF ONE LOOKS AT
GENE EXPRESSION PROFILING THE
MYELOID CELLS HAVE AN
INFLAMMATORY PROFILE THAT THE
LYMPHOCYTES DO NOT.
USING A GENOTYPE FIRST STRATEGY
ONE CAN DEFINE NEW ILLNESSES.
THIS MAY GIVE RISE TO A NEW
MOLECULAR TAXONOMY.
WE'RE SUSPECTING THAT AND
FOLLOWING UP ON THAT IN GENETIC
STUDIES.
SO WE PUBLISHED THIS NEW DISEASE
IN THE NEW YEAR'S EVE EDITION OF
THE NEW ENGLAND JOURNAL OF
MEDICINE AT THE END OF 2020 AND
MUCH TO OUR SURPRISE ANOTHER
FACT STRANGER THAN FICTION.
IT TURNED OUT ABOUT THREE MONTHS
LATER THAT VEXAS HAD ALREADY
MADE IT TO PRIME TIME TV.
>> SO IN OTHER WORDS WE STILL
DON'T KNOW ANYTHING
>> YOU MIGHT WANT TO GET
INFECTIOUS DISEASE ON THIS.
>> THANKS, DOCTOR.
>> ETHAN, BASED ON SYMPTOMS I
THINK IT MIGHT BE VEXAS.
A GENETIC MUTATION.
IF ONLY DIAGNOSED 25 CASES.
>> IT WOULD CERTAINLY EXPLAIN
THE CRAZY CONSTELLATION OF
SYMPTOMS BUT I'M STILL NOT
LOOKING FOR ZEBRAS YET.
HEY, YOU WERE RIGHT.
GENETIC SEQUENCING FOUND THAT
MUTATION.
>> HOT DAMN.
>> I'VE STARTED TREATMENT.
AMAZING CATCH MAN.
>> THANKS.
THANK YOU.
>> WELL JUST TO MAYBE PUT A
LITTLE AIR OF REALITY IN THIS,
VEXAS IS A VERY DIFFICULT
CONDITION TO TREAT AND IT WOULD
NOT BE SO TRIVIAL AS SAYING I
JUST STARTED TREATMENT NOW BUT
IN ANY CASE THAT IS WORK FOR
DAVID BECK BECK.
DAVID PUBLISHED A PAPER IN THE
JOURNAL OF THE AMERICAN MEDICAL
ASSOCIATION LOOKING AT THE
CLINIC POPULATION.
163,000 INDIVIDUALS AND FOUND 12
INDIVIDUALS ACTUALLY WITH UBA1
MUTATIONS AND THE FREQUENCY OF
UBA1 MUTATIONS THESE MUTATIONS
IN MEN OVER THE AGE OF 50 IS
ABOUT ONE IN 4,000.
SO, IT'S NOT SUCH A RARE DISEASE
AFTER ALL.
CERTAINLY GIVEN THE DISPARATE
CLINICAL FEATURES OF PATIENTS IT
HAS GIVEN RISE TO THE THINKING
THAT MAYBE CLINICAL DIAGNOSIS
ARE TH -- THE LEAVES OF THE TREE
BUT THERE MAY BE RELATIONSHIPS
AT THE LEVEL OF THE ROOTS THAT
ARE NOT APPRECIATING WHEN WE
JUST LOOK AT THE CLINICAL
PICTURE SO IT DOES GIVE RISE TO
THE THOUGHT THAT MAYBE THERE IS
A NEW TAXONOMY OF DECEA DI -- D.
SO WITH THAT I'LL CALL IT TO A
CLOSE.
THERE WERE MANY, MANY PEOPLE
THAT CONTRIBUTED MIGHTILY TO THE
WORK.
SOME OF THEM ARE SHOWN ON THIS
SLIDE.
PEOPLE AT LEAST AT ONE TIME
MEMBERS OF MY LAB.
SOME OF THEM STILL ARE.
A NUMBER OF COLLABORATORS.
BOTH AT THE NIH AND ELSEWHERE.
BUT OF COURSE COMING BACK TO THE
CENTRAL THEME THIS IS ALL ABOUT
THE PATIENTS.
HERE IS A GROUP OF PATIENTS AT
THE FIRST INTERNATIONAL CONGRESS
THAT HELPED IN BETHESDA.
AND I CANNOT END WITHOUT
MENTIONING THE CLINICAL CENTER
WHICH AFTER ALL IS WHAT HAS MADE
ALL OF THIS POSSIBLE.
SO WITH THAT I WILL CALL IT TO A
CLOSE.
THANK YOU VERY MUCH FOR
LISTENING.
AVENUE I'M HAPPY TO TRY TO
ENTERTAIN ANY QUESTIONS YOU MAY
HAVE.
>> THANK YOU, DAN.
ABSOLUTE TOUR DEFOURS AND AUDIO
VISUAL SPECTACLE AS WELL.
WE HAVE TIME FOR ONE QUESTION.
AND SOMEONE HAD SUBMITTED A
QUESTION WHICH MAY DOVETAIL
NICELY TO THE ILLUSION OF THE
TREE AND ROOT TAXONOMY.
THEY COULD ACTUALLY HAVE AN AUTO
INFLAMMATORY COMPONENT AND COULD
THERE BE OVERLAP BETWEEN THE
DISEASES?
>> THAT IS A GREAT QUESTION, ED.
AND THE IDEA OF AUTO
INFLAMMATORY DISEASE THAT WE HAD
PROPOSED CERTAINLY IT'S A
CONCEPT TOILE SCHEMA BUT I DON'T
WANT ANYONE TO THINK IT HAS TO
BE MUTUALLY EXCLUSIVE.
IT'S A SPECTRUM AND CERTAINLY
THERE ARE SOME CONDITIONS IN
WHICH THERE SEEM TO BE
COMPONENTS OF BOTH.
I THINK IT'S MORE THAT IT HELPS
US IN THINKING ABOUT DISEASES
AND AT LEAST INITIALLY AND STILL
NOW WHEN YOU FIND GENES THAT ARE
MUTATED IN THESE MONOGENIC
DISEASES SOMETIMES IT TURNS OUT
IF THEY ARE AUTO INFLAMMATORY
THAT THOSE ARE SOME OF THE
BUILDING BLOCKS OR REGULATORS OF
THE INNATE IMMUNE SYSTEM
>> THANK YOU AGAIN FOR AN
OUTSTANDING TALK.
WE REALLY DO APPRECIATE IT.
>> THANK YOU, ED AND THANK
EVERYONE FOR WATCHING AS WELL.