>> WELCOME.
I'M WIN ARIAS AT THE NATIONAL
INSTITUTES OF HEALTH IN
BETHESDA, MARYLAND.
AND IT'S A PLEASURE TO WELCOME
YOU TO ANOTHER EXCITING
PRESENTATION IN A COURSE IN
BRIDGE BUILDING.
THE NAME OF THE COURSE IS
DEMYSTIFYING MEDICINE.
AND IT HAS BEEN IN EXISTENCE AT
THE NIH FOR APPROXIMATELY 22
YEARS.
THE PURPOSE IS TO BRIDGE THE
EXCITING DEVELOPMENTS IN
BIOLOGY, ENGINEERING AND
COMPUTER SCIENCES WITH MEDICINE
AND GLOBAL HEALTH.
AND THE BRIDGE, AS EXEMPLIFIED
IN THE UPPER RIGHT PORTION OF
THIS SLIDE, THE BROOKLYN BRIDGE,
EACH WEEK FEATURES SOMETIMES
ONLY ONE BUT USUALLY TWO, AND
THOSE TWO ARE OFTEN JOINED BY A
PATIENT ON THE CATWALK OF THE
BRIDGE.
CONNECTING THEIR KNOWLEDGE AND
EXPERIENCE BOTH FROM A CLINICAL
PERSPECTIVE AND ALSO FROM A MORE
BASIC SCIENCE PERSPECTIVE.
THE GOAL IS TO CONVERT WHAT ARE
SILOS OF INFORMATION, NAMELY THE
IDEA THAT MUCH OF SCIENCE HAS
BECOME SO SPECIALIZED THAT THERE
ARE ALMOST LANGUAGES ASSOCIATED
WITH EACH DISCIPLINE.
AND LITTLE COMMUNICATION.
BUT PROGRESS IN HEALTH AND
MEDICINE HAS CERTAINLY
FACILITATED WHEN PEOPLE
COMMUNICATE, SHARE IDEAS, AND
BRING TOGETHER TO FORM ALMOST
LIKE NEW DISCIPLINES, AND NEW
APPROACHES TO COMBAT AND
UNDERSTAND HUMAN DISEASE.
SO DEMYSTIFYING MEDICINE MEETS
EVERY TUESDAY FROM 3:00 TO 5:00.
EASTERN STANDARD TIME FROM
JANUARY UNTIL THE END OF MAY.
YOU'RE WATCHING IT ON THE
VIDEOCAST FOR THE NIH.
AS SEEP IN SEEN IN THE EARLIER,
THERE ARE CME CREDITS FOR
PHYSICIANS WHO SEEK THIS.
THE CODE NUMBER FOR TODAY'S
SESSION IS 58786.
NOW, OF GREAT IMPORTANCE IS WE
ENCOURAGE YOU TO PLEASE ASK
QUESTIONS AND SUBMIT THEM VIA
THE "SEND LIVE FEEDBACK," WHICH
IS ON YOUR VIDEOCAST DISPLAY.
AND THOSE QUESTIONS WILL BE
SORTED AND AT THE END OF THE
PRESENTATIONS, THERE WILL BE
ABUNDANT TIME FOR DISCUSSION,
QUESTIONS, AND WE ENCOURAGE YOU
TO PLEASE DO THIS EVEN DURING
THE COURSE OF THE PRESENTATIONS.
NOW, ALL OF THE PREVIOUS
SESSIONS FOR THE PAST 20-ODD
YEARS ARE ARCHIVED, AND YOU CAN
ACCESS THEM IN THE WEB SITE
INDICATED ON THIS SLIDE, AND IF
YOU WANT ANY ADDITIONAL
INFORMATION, YOU CAN GET IN
TOUCH WITH US AT
DEMYSTIFYINGMED@NIH.GOV.
NOW TODAY'S TOPIC, NEXT SLIDE,
PLEASE, TODAY'S SESSION IS
REALLY ENTITLED SCRATCHING THE
HISTORICAL SURFACE OF PRURITIS,
WHICH IS LATIN FOR ITCHING.
NOW, WE ALL KNOW THE ITCHING
THAT'S ASSOCIATED WITH A MINOR,
SAY, MOSQUITO BITE, BUT THERE
ARE A HUGE NUMBER OF CLINICAL
ASPECTS OF PRURITIS, SOME OF
WHICH ARE MILD, AND MANY OF
WHICH ARE PROLONGED, COMPLEX AND
CAUSE REALLY GRAVE SUFFERING,
LARGELY IN THE FORM OF
UNCONTROLLABLE PRURITIS
PERIODICALLY, DISTURBING SLEEP,
CHANGING LIGHT PATTERNS, AND
OFTEN ASSOCIATED WITH OTHER
DISEASES, PARTICULARLY OF THE
LIVER, THE KIDNEY, CANCER,
DRUGS.
IT'S A COMPLEX FIELD.
IN LOOKING AROUND, I DISCOVERED
THE FIRST REFERENCE THAT I CAME
TO ITCHING IS ACTUALLY FROM THE
OLD TESTAMENT IN THE BOOK OF
DEUTERONOMY, WHERE WHEN THE LORD
DISPENSED MANY PLAGUES, THE LAST
ONE WAS THE ITCH.
AND THE QUOTE IS "THE LORD WILL
AFFLICT YOU WITH THE ITCH FROM
WHICH YOU CANNOT RECOVER."
NOW, HI HIPPOCRATES AND OTHERS
DESCRIBED DIFFERENT FORMS OF
PRURITIS, GAVE IT ITS NAME LATER
ON, AND ALSO VARIOUS TREATMENTS
WHICH WERE EMPIRIC.
IN THE 17TH CENTURY, A GERMAN
PHYSICIAN, HAFFENREFFER, OFTEN
BEGAN THE CLINICAL DESCRIPTION
OF VARIOUS FORMS OF PRURITIS.
AND OVER THE NEXT 200 YEARS, IT
SEEMS AS IF MOST OF THE EMPHASIS
WAS ON THE DESCRIPTION OF THE
CLINICAL PHENOTYPES, AND NOT
MUCH WAS KNOWN OR DISCOVERED
ABOUT ACTUALLY MECHANISMS.
AND IN FACT, IN A 1994 REVIEW,
THERE ARE ACTUALLY TWO EXTENSIVE
REVIEWS, AND THEY BOTH MAKE THE
SAME CONCLUSION, THAT NO
MECHANISMS ARE DEFINITIVELY
KNOWN.
THAT'S 1994.
NOW, IN THE NEXT COUPLE OF
DECADES, ADVANCES IN
NEUROBIOLOGY, IMMUNOLOGY AND IN
PARTICULAR THE RECEPTOR BIOLOGY,
HAVE DOMINATED THE FIELD AND
HAVE BROUGHT ABOUT THE
OPPORTUNITY TO STUDY AND LEARN
MORE ABOUT MECHANISMS WHICH
UNDERLIE EVENTUALLY THE DESIGN
OF EFFECTIVE TREATMENTS.
SO THE CHALLENGE IS TO BRIDGE
THESE GREAT ADVANCES IN
BIOLOGICAL SCIENCE WITH THE
CLINICAL DISEASE.
AND WE'RE VERY FORTUNATE TO HAVE
TWO OUTSTANDING SCIENTISTS HERE
AT THE NATIONAL INSTITUTES OF
HEALTH WHO WORK IN THIS LARGE
AREA AND HAVE M HAVE MADE VERY
SIGNIFICANT CONTRIBUTIONS.
OUR FIRST SPEAKER IS MARK HOON,
WHO'S A PRINCIPAL SENIOR
INVESTIGATOR IN THE NATIONAL --
SORRY, I'VE GOT THE WRONG THING
HERE.
HE'S IN THE CRANIO -- THE
NATIONAL INSTITUTE --
>> NICDR --
>> CDR, RIGHT, CRANIOFACIAL
RESEARCH.
>> DENTAL.
>> RIGHT.
MARK RECEIVED HIS PH.D. IN THE
UNITED KINGDOM AT THE UNIVERSITY
OF LEEDS, AND THEN WAS A
POSTDOCTORAL NATO FELLOW AT THE
UNIVERSITY OF FREIBURG.
HE CAME TO THE UNITED STATES,
WHERE HE SPENT SEVERAL YEARS,
VERY IMPORTANT YEARS, IN THE
LABORATORY OF CHARLES ZUCKER AT
COLUMBIA, WHERE RECEPTORS WERE
DISCOVERED FOR SWEAT, TASTE,
TOUCH, AND HE WAS THERE AT THAT
TIME AND MADE SIGNIFICANT
CONTRIBUTIONS TO UNDERSTANDING
THE NATURE AND MECHANISM
INVOLVED IN THIS INCREASING
FAMILY OF RECEPTORS.
IN 2006, HE CAME TO THE NIH AS A
PRINCIPAL INVESTIGATOR.
MARK HAS RECEIVED MANY AWARDS
AND VARIOUS INVITATIONS.
HIS RESEARCH CONCERNS THE
SOMATOSENSORY RECEPTORS, THEIR
MECHANISMS, INCLUDING THEIR
RELATIONSHIP TO PRURITIS.
AND HIS WORK HAS REALLY OPENED
UP THE DOOR TO A LOT OF VERY
EXCITING CHALLENGES AND
POSSIBILITIES TO BETTER
UNDERSTAND THIS SERIOUS AND
DIVERSE PHENOTYPE OF SEVERE
ITCHING.
NOW, OUR SECOND SPEAKER, IAN
MYLES, GRADUATED FROM COLORADO
STATE UNIVERSITY AND RECEIVED
HIS MEDICAL DEGREE FROM THE
UNIVERSITY OF COLORADO.
HE HAD A RESIDENCY AT OHIO
STATE, AND AN NIH FELLOWSHIP IN
ALLERGY AND IMMUNOLOGY.
IN 2011, HE JOINED THE U.S.
PUBLIC HEALTH SERVICE, WHERE HE
IS AN OFFICER, AND HE
PARTICIPATED EXTENSIVELY IN THE
EBOLA VACCINE STUDY, WHICH WAS
CONDUCTED IN AFRICA DURING THE
BEAEBOLA OUTBREAK IN THAT DECAD.
IN 2016, HE RECEIVED HIS MASTER
OF PUBLIC HEALTH FROM GEORGE
WASHINGTON UNIVERSITY, AND TWO
YEARS LATER, CAME TO THE NIH AS
A LASKER CLINICAL RESEARCH
SCHOLAR.
HE HEADS THE UNIT ON
EXPERIMENTAL THERAPEUTICS, IN
THE NATIONAL INSTITUTE OF
ALLERGY AND INFECTIOUS DISEASES.
HIS RESEARCH ORIGINALLY
CONCERNED THE MICROBIOME AND ITS
RELATIONSHIP TO SKIN DISEASE,
AND HE'S BECOME INCREASINGLY
INTERESTED AND WORKED ON
IMMUNOLOGIC MECHANISMS AND IS HS
SET UP THIS NEW UNIT ON
EPITHELIAL THERAPEUTICS.
SO WE WELCOME BOTH OF YOU, LOOK
FORWARD TO YOUR TALKS.
WE ENCOURAGE THE AUDIENCE TO
PLEASE SUBMIT QUESTIONS AT ANY
TIME DURING THE PRESENTATIONS.
AND SO OUR FIRST SPEAKER IS MARK
HOON.
SO MARK, CARRY ON.
>> THANK YOU, WIN, WITH THAT
INTRODUCTION.
SO WHAT I'M BASICALLY GOING TO
TALK TO YOU TODAY ABOUT IS THE
BASIC MECHANISMS, THE MECHANISMS
PART OF THE TITLE TODAY, AND
TELL YOU ABOUT HOW SIGNALS
TRANSMITTED FROM THE SKIN TO THE
BRAIN AND TO PRODUCE THE
SENSATION THAT'S CALLED ITCH OR
PRURITIS.
AND WITH THAT, I HAVE TO FIRST
OF ALL ACKNOWLEDGE THAT ALTHOUGH
THE MAJORITY OF ITCH IS ON THIS
MECHANISM FROM THE SKIN TO THE
BRAIN, THERE ARE SOME TYPES OF
ITCH AS WIN ALLUDED TO THAT
DON'T INVOLVE EITHER THE SKIN --
DON'T INVOLVE THE SKIN, SO FOR
INSTANCE, KIDNEY DISEASES.
BUT I'VE REALLY RESTRICTED MY
TALK TO THIS ONE PATHWAY, AND
THAT'S FOR THE SAKE OF TIME.
OKAY.
SO I ALSO WANT TO POINT OUT THAT
I'VE TRIED TO BREAK MY
PRESENTATION INTO TWO DIFFERENT
PARTS.
THE FIRST PART IS MAINLY
CONCERNING THE MECHANISMS
INVOLVED IN ACUTE ITCH, SO THE
SORT OF ITCH THAT WILL HAPPEN,
FOR INSTANCE, WHEN YOU HAVE AN
INSECT BITE.
THE SECOND PART OF THE TALK, I'M
GOING TO TALK ABOUT CHRONIC
ITCH, AND THIS IS THE TYPE OF
ITCH THAT'S ACTUALLY CLINICALLY
IMPORTANT.
THE DISEASES LIKE ATOPIC
DERMATITIS, VIE C PSORIASIS ANDS
WHICH LEAD TO ITCH.
THE LAST IS I'M GOING TO --
WHILE GIVING THIS TALK, GIVE AN
OVERVIEW, BUT WHAT I'VE TRIED TO
DO IS TO INTRODUCE SOME KEY
EXPERIMENTS THAT WE PERFORMED
AND OTHERS HAVE PERFORMED FROM
OTHER GROUPS THAT ACTUALLY POINT
TO THE EVIDENCE FOR THE PATHWAYS
THAT I'M GOING TO BE DESCRIBING.
WITH THAT, I'M GOING TO BEGIN
WITH THE FIRST SLIDE HERE THAT I
STARTED OUT WITH, WHICH IS AN
IMAGE THROUGH THE SKIN OF A
MOUSE --
>> EXCUSE ME, DR. HOON, YOU'RE
NOT SHARING THE SCREEN JUST YET.
>> OH, OKAY.
I'M SORRY.
LET ME TRY DO THAT.
SO AM I SHARING NOW?
>> YES, IT'S COMING UP.
>> GREAT.
SORRY ABOUT THAT.
SO THIS FIRST IMAGE THAT YOU
HOPEFULLY CAN SEE NOW IS A
PICTURE THROUGH THE SKIN OF A
MOUSE, AS I JUST TALKED TO YOU
ABOUT, AND IN MAGENTA, YOU CAN
SEE THE CELLS OF THE SKIN.
AND YOU CAN SEE THAT IT'S A
LAYERED STRUCTURE, SO DOWN AT
THE VERY BOTTOM HERE IS THE
DERMIS AND THE EP DEM EPIDERMISE
TOP OF THIS IMAGE AND THIS IS
THE OUTSIDE OF THE SKIN.
WHAT YOU CAN SEE IN THIS IMAGE
IS A GREEN FIBER THAT SNAKES ITS
WAY UP TO THE VERY TOP PART OF
THE SKIN.
SO THIS IS THE STRUCTURE OF THE
NERVE FIBER THAT'S ACTUALLY
RECEIVING INFORMATION THAT'S THE
FIRST PART OF THE ITCH PATHWAY.
SO IF WE GO TO MY SECOND SLIDE,
WE SEE A CARTOON OF THIS AT THE
TOP HERE.
AND YOU CAN SEE THAT I'VE GOT
HERE A MOSQUITO THAT'S ABOUT TO
BITE A FINGER, AND YOU CAN SEE
THE NERVES GO FROM THE SKIN,
THEY GO BACK, IT'S A VERY LONG
AXON THAT THEN TERMINATES IN THE
SPINAL CORD.
BUT IMPORTANTLY, THE CELL BODIES
OF THE NERVES THAT HAVE THESE
FIBERS ARE PRESENT IN THIS
STRUCTURE CALLED THE DORSAL ROOT
GANGLION.
AND THESE ARE FOUND CLOSE TO THE
SPINAL CORD AND INNERVATES
SPECIFIC AREAS OF THE SKIN.
AND IN THE HEAD, THE GANGLION,
IS CALLED THE TRIGEMINAL
GANGLION.
OKAY.
YOU CAN ALSO SEE ON THIS SLIDE
THAT I'VE ILLUSTRATED THAT
THERE'S DIFFERENT TYPES OF
SIGNAL THAT'S ACTUALLY COLLECTED
BY THIS GROUP OF NEURONS, AND
COLLECTIVELY THIS IS CALLED
SOMATOSENSATION.
SO SIGNALS FROM THE SKIN AND THE
NERVES THAT INNERVATE IT
COLLECTED FOR, FOR INSTANCE, HOT
AND COLD, THE PAINFUL STIMULI,
AND ALSO FOR ALL KINDS OF
DIFFERENT TYPES OF TOUCH.
AND IT'S GENERALLY NOW KNOWN
THAT THESE ARE ACTUALLY DETECTED
BY DIFFERENT CLASSES OF NEURONS,
AND I'M GOING TO BE GOING INTO
THIS A LITTLE BIT LATER.
SO THESE ARE JUST COLOR-CODED
HERE.
SO WHAT DOES THIS ACTUALLY LOOK
LIKE IN REAL LIFE?
THIS NOW SLIDE I'M ACTUALLY
ILLUSTRATING THIS IN A MOUSE
TISSUE.
SO OVER HERE YOU CAN SEE THE
TISSUE FROM A MOUSE WHERE WE'VE
INJECTED A VIRUS JUST INTO THE
PORE OF THE MOUSE, AND THIS
ILLUMINATES WITH A FLUORESCENT
PROTEIN THE FIBERS THAT ARE
COMING FROM THAT PAW, FROM THE
HIND PAW.
HERE ARE THE DORSAL ROOT
GANGLION, THE CELL BODIES, AND
THE FIBERS ARE GOING IN HERE
INTO THE SPINAL CORD.
I'VE ALSO SHOWN HERE ON THIS
SLIDE AN IN SITU HYBRIDIZATION
OF TWO GENES THAT IDENTIFY TWO
DIFFERENT CLASSES OF SENSORY
NEURONS.
SO THIS ILLUSTRATES THAT THERE
IS DIFFERENT CLASSES OF NEURONS,
AND NOW THROUGH SEQUENCING
INFORMATION, SINGLE CELL
SEQUENCING INFORMATION, WE KNOW
THERE'S AT LEAST 15 DIFFERENT
DISTINCT CLASSES OF SENSORY
NEURONS.
AND SOME OF THOSE, IN FACT, A
PAIR OF THOSE, TWO CLASSES, ARE
DEDICATED FOR ITCH.
SO THIS IS THE FUNDAMENTAL FIRST
PART OF THE ITCH PATHWAY.
THE NEXT PART OF THE PATHWAY
TAKES PLACE BOTH IN THE SPINAL
CORD AND THEN FURTHER IN THE
CNS.
I'M NOT GOING TO DESCRIBE THOSE
TODAY BECAUSE, AGAIN, WE HAVE
LIMITED TIME, AND I WANT TO
REALLY CONCENTRATE ON WHAT'S
REALLY HAPPENING AT THE VERY
PERIPHERY.
BUT THOSE ARE CLEARLY VERY
IMPORTANT FOR THE SENSATION AND,
IN FACT, THIS PART HERE IS
CALLED PRERECEPTION FOR A GOOD
IN FACT, IT'S NOT THE SPINAL SPL
CORD THAT ACTUALLY TELLS YOU,
THE ITCH IS IN YOUR BRAIN.
I ALSO WANT TO ACKNOWLEDGE THAT
ITCH ISN'T JUST THE SENSORY
NERVES.
WHAT THIS SLIDE HERE IS HERE TO
TRY AND REMIND ME TO TELL YOU IS
THAT AS WELL AS THE SENSORY
NEURONS THAT ARE SHOWN OVER
HERE, THE DIFFERENT CLASSES,
THERE'S ALSO CLEARLY CELLS IN
THE SKIN THAT WERE INVOLVED IN
THE DEVELOPMENT OF ITCH.
AND ALSO IMMUNE CELLS.
I'LL BE COMING BACK TO THIS IN
THE SECOND PART OF MY TALK WHERE
I START TO TALK ABOUT CHRONIC
ITCH.
SO I WANT TO NOW GO BACK TO THE
SENSORY NEURONS AND TELL YOU
WHERE MY GROUP STARTED WORK ON
PRERECEPTION.
WE TRIED TO IDENTIFY SPECIFIC
GENES NA WERE PRESENT IN
DISTINCT POPULATION OF NEURONS
IN THE HOPE THAT THIS WOULD
ACTUALLY ALLOW US TO ACTUALLY
START TO DISSECT THE MOLECULAR
BASIS OF ITCH.
THE KEY MOLECULE WE UNCOVERED IN
THAT SEARCH WAS THIS ONE.
IT'S NOT REALLY IMPORTANT, THE
NAME.
IT'S CALLED NPPB.
WHAT'S IMPORTANT ABOUT THIS
MOLECULE IS, FIRST OF ALL, YOU
CAN SEE HERE IT'S EXPRESSED IN A
VERY DISTINCT CLASS OF NEURONS.
THESE ARE SMALL DIAMETER
NEURONS.
WE SEE THAT THEY'RE ALL ABOUT
THE SAME SIZE, AND THIS IS
DIFFERENT FROM OTHER CLASSES OF
NEURONS.
THE SECOND FEATURE OF THIS GENE
IS THAT IT'S ACTUALLY A
POLYPEPTIDE THAT'S RELEASED FROM
THE NEURONS AND ACTS AS A
TRANSMITTER.
SO IN ORDER TO TRY TO UNDERSTAND
WHAT THIS MOLECULE MIGHT BE
DOING AND HOW THIS RELATES TO
ITCH, WE OF COURSE -- AND THIS
IS A VERY OLD SLIDE BECAUSE THIS
IS WORK THAT WAS DONE MORE THAN
10 YEARS AGO, WE MADE A
KNOCKOUT.
AGAIN I'M NOT GOING TO GO INTO
ANY DETAIL ABOUT THAT, THIS IS
REALLY OLD TECHNOLOGY.
NOW WE MAKE KNOCKOUTS IN MUCH
MORE SOPHISTICATED WAYS.
WHAT'S IMPORTANT IS, IS WHAT
THAT MOUSE TOLD US ABOUT THIS
PARTICULAR MOLECULE, NPPB.
AND WHAT IT TOLD US IS THAT
COMPARED TO WHEN WE KNOCK IT
OUT, IT DRAMATICALLY AFFECTS
ITCH.
AND SO I'M GOING TO GO THROUGH
QUICKLY HERE THIS EXPERIMENT.
WHAT WE DID IN THIS EXPERIMENT
IS WE INJECTED INTO THE SKIN OF
MICE DIFFERENT COMPOUNDS THAT
CAUSE ITCH IN THOSE ANIMALS.
THIS IS REFLECTED IN THE FACT
THAT THE ANIMALS SCRATCH.
AND AS YOU CAN SEE IN THE GREY
BARS, THIS IS WHAT HAPPENS WHEN
THESE COMPOUNDS ARE INJECTED,
AND THERE'S A DRAMATIC DECREASE
IN THE AMOUNT OF SCRATCHING THE
ANIMALS THAT HAVE A KNOCKOUT OF
NPPB DISPLAY.
BUT IMPORTANTLY, THOSE SAME
KNOCKOUT ANIMALS HAVE ALMOST
NORMAL RESPONSES TO OTHER
SOMATOSENSORY STIMULI.
SO THIS IS A VERY SPECIFIC
EFFECT ON THIS ONE TYPE OF
MODALITY WITHIN SOMATOSENSATION,
IT'S ONLY AFFECTING ITCH.
AND THIS CAN BE NOW AS SHOWN
HERE IN THIS SCHEMATIC, CAN SHOW
YOU EXACTLY WHAT'S HAPPENING
WITH THIS TRANSMITTER.
WHAT'S HAPPENING IS, WHEN THESE
NEURONS, THE PRIMARY ITCH
NEURONS ARE ACTIVATED, THEY
RELEASE THIS NEUROTRANSMITTER
TOGETHER WITH -- THAT HAVE THE
RECEPTOR FOR THIS PARTICULAR
NEUROTRANSMITTER.
AND IN TURN, THESE NEURONS THEN
SIGNAL FURTHER IN THE SPINAL
CORD AND EVENTUALLY SIGNALS GO
ON TO HIGHER CENTERS IN THE
BRAIN.
OKAY.
SO WHAT I'VE BEEN TELLING YOU SO
FAR ARE EXPERIMENTS THAT WE
PERFORMED IN THE LAB QUITE A FEW
YEARS AGO.
THESE ARE ALL EXPERIMENTS THAT
WERE PERFORMED IN MICE.
SO WE WERE VERY KEEN TO SEE
WHETHER OR NOT IN WAS THE CASE
ALSO IN HUMANS, AND SO MORE
RECENTLY, WE EXAMINED THIS IN
TWO DIFFERENT WAYS.
WHAT I'M SHOWING YOU HERE AGAIN
IS IMAGES THROUGH THE DORSAL
ROOT GANGLIA WHICH I TOLD YOU
ABOUT IN THE VERY BEGINNING,
WHICH SHOW THAT NPPB IS
EXPRESSED IN SENSORY NEURONS AND
IS A VERY SPECIFIC CLASS AND IS
EXPRESSED ALONG WITH OTHER
TRANSCRIPTS THAT HAVE IMPORTED
AND DEFINED SPECIFIC POPULATIONS
OF NEURONS.
THIS WE DID IN HUMAN NEURONS AND
THEN OTHER GROUPS, THIS IS
ACTUALLY DATA FROM A GROUP HERE
AT THE NIH, THE RYBA GROUP IN MY
INSTITUTE HAVE PERFORMED SINK EL
CELL SEQUENCING OF HUMAN DRG
NEURONS.
WHAT YOU CAN SEE IS THERE'S
ACTUALLY TWO CLASSES OF SENSORY
NEURONS THAT ARE
TRANSCRIPTIONALLY DISTINCT FROM
EACH OTHER THAT EXPRESS NPPB.
AND IF WE INTERROGATE THAT DATA
EVEN FURTHER AND PERFORM OTHER
LOCALIZATIONS, AGAIN, WHAT I'M
SHOWING YOU HERE IS IN SITU
HYBRIDIZATION DATA, AND BELOW
HERE, THE SINGLE CELL SEQUENCING
INFORMATION AND WHAT I'M SHOWING
YOU HERE IS THAT THESE NEURONS
EXPRESS NOW THE RECEPTORS THAT
WOULD EXPECT FOR H NEURONS.
IN PARTICULAR YOU CAN SEE A
HISTAMINE RECEPTOR, AGAIN IN THE
SINGLE CELL SEQUENCING
INFORMATION, IT'S PRESENT IN
THESE TWO POPULATIONS OF NPPB
NEURONS, AND THEN ALSO ANOTHER
RECEPTOR, THIS RECEPTOR WAS
FIRST IDENTIFIED BY THE GROUP AT
JOHNS HOPKINS, AND HE SHOWED --
I THINK THIS IS PROBABLY THE
REFERENCE THAT WIN TALKED ABOUT
IN 2001, THAT THERE'S THIS LARGE
FAMILY OF G PROTEIN COVERED
REACCRECEPTORS, AND THEY SHOWED
THEY'RE ACTUALLY ITCH RECEPTORS.
SO I WANT TO NOTE FROM XINZHONG
DONG'S GROUP THAT THESE CLASS OF
RECEPTORS THAT ARE ACTIVATED BY
QUITE DISTINCT PRURITOGENS THAT
ARE ACTUALLY RELEASED PROBABLY
WITHIN THE SKIN WHEN THE SKIN IS
DAMAGED, IN MOUSE, AT LEAST,
THIS IS A SEPARATE POPULATION
FROM THE NEURONS THAT EXPRESS
NPPB, AND THINGS ARE ACTUALLY A
LITTLE BIT DIFFERENT BETWEEN THE
MOUSE AND THE HUMAN IN THAT THE
RECEPTORS ARE -- THE RECEPTOR
FAMILY IS MUCH SMALLER AND THE
RECEPTORS ARE FOUND IN BOTH
POPULATIONS OF THE HUMAN ITCH
NEURONS.
OKAY.
SO LE LET'S GO BACK TO THIS MAPF
THE PATHWAY FOR ITCH.
WHAT YOU'LL SEE HERE IS I'VE
ADDED AN EXTRA DIMENSION OVER
HERE, WHAT ARE THE AGENTS THAT
ARE RELEASED POTENTIALLY IN THE
SKIN THAT ACTIVATE THE NEURONS?
SO WHAT ARE THE NPPB NEURONS
DETECTORS FOR?
AND SO IN ORDER TO DO THIS, MY
GROUP HAS USED A VARIETY OF
DIFFERENT METHODS TO TRY TO
IDENTIFY RECEPTORS THAT ARE
SPECIFIC TO THE NPPB NEURONS
THAT MIGHT BE INVOLVED IN ITCH.
AND WHAT WE IDENTIFIED WAS THREE
DIFFERENT RECEPTORS.
NAMES ARE NOT IMPORTANT AGAIN.
HERE ARE THE THREE NAMES OF THE
RECEPTORS.
BUT WHAT I CAN TELL YOU IS THAT
THIS RECEPTOR AND THIS RECEPTOR
ARE RECEPTORS FOR SMALL LIPIDS,
AND THIS IS THE RECEPTOR FOR
SEROTONIN.
IT'S A SPECIFIC SEROTONIN
RECEPTOR.
AND IN ORDER TO ACTUALLY
DETERMINE WHETHER OR NOT THESE
RECEPTORS AND THE AGONISTS THAT
ACTIVATE THOSE RECEPTORS ARE
ACTUALLY PRURITOGENS, WE MADE
USE OF THIS BEHAVIORAL ASSAY IN
MOUSE SO I'M GOING TO GO THROUGH
THAT VERY QUICKLY.
WHAT THIS ASSAY INVOLVES IS
INJECTING DIFFERENT AGENTS INTO
THE CHEEK OF MICE, AND WHEN
SOMETHING THAT'S PAINFUL TO
INJECT IT INTO THE CHEEK OF THE
MICE, THEY HAVE THIS REACTION AS
SHOWN HERE IN A AND B.
THEY WIPE THEIR FACES.
IN CONTRAST, IF AN AGENT THAT IS
ITCHY IS INJECTED INTO THE
CHEEK, THEY SCRATCH.
AND SO WE TESTED THE LIGANDS FOR
THESE THREE RECEPTORS IN THIS
ASSAY.
AND WHAT YOU'LL SEE IS THAT
THESE THREE AGENTS DO NOT CAUSE
WIPING.
WHAT THEY DO IS THEY CAUSE
SCRATCHING.
OKAY.
SO THIS IS ONE OF THE PIECES OF
EVIDENCE THAT WE HAD TO SHOW
THAT THE NPPB NEURONS ARE ITCH
NEURONS, AND THAT THEY HAVE AS
THIS SLIDE SUMMARIZES HAVE
SELECT RECEPTORS.
AND IT'S THE FACT THAT THERE'S
INCREASED LEVELS OF THESE
AGONISTS THAT LEADS TO THE
SCRATCHING RESPONSE.
AND IT'S NOT BY ACCIDENT THAT,
IN FACT, THESE THREE COMPOUNDS
ARE RULE TEULLY RELEASED FROM
MAST CELLS.
SO WHEN MAST CELLS ARE
ACTIVATED, FOR INSTANCE, MANY
DIFFERENT INSECTS, WHAT THEY
INJECT INTO WILL CAUSE A
DEGRAITDEGRADATION OF MAST CELLD
THEY THEN RELEASE AND ACTIVATE
SENSORY NEURONS AND IN TURN THIS
CAUSES AN ITCH PATHWAY.
SO THIS IS THE END OF THE PART
OF MY TALK ABOUT ACUTE ITCH.
I WANT TO NOW MOVE ON TO CHRONIC
ITCH.
ONE OF THE BIG CENTRAL CORE --
OF CHRONIC ITCH IS WHAT'S CALLED
THE ITCH-SCRATCH CYCLE.
SO THE ITCH-SCRATCH CYCLE IS
DEPICTED HERE IN THIS DIAGRAM
THAT WHEN YOU FEEL VERY ITCHY,
THIS LEADS TO YOU WANTING TO
SCRATCH AND SCRATCHING.
AND IN TURN, SCRATCHING CAUSES
DISRUPTION OF THE SKIN.
THE NOW DISTURBED, BROKEN SKIN,
ALLOWS PENETRATION OF VARIOUS
ALLERGENS AND IRRITANTS.
THIS IN TURN CAUSES INPLA NATION
INFLAMMATIONAND RECRUITMENT OF S
TO THE SITE, AND IN FACT, THIS
INFLAMMATION, THE IMMUNE CELLS
AND THE COMPOUNDS THAT ARE
RELEASED FROM THEM, CAUSES MORE
ITCHING.
WE ALL KNOW IF WE CAN STOP THAT
SCRATCHING, VERY OFTEN, THE ITCH
WILL GO AWAY, AND THE REASON FOR
THIS IS THIS CYCLE.
BUT IF YOU WERE TO TELL A
PATIENT WHO HAS CHRONIC ITCH,
OH, YOU SIMPLY NEED TO STOP
SCRATCHING, THEY WILL PROBABLY
GET PRETTY ANGRY WITH YOU,
BECAUSE CHRONIC ITCH IS
SOMETHING THAT YOU REALLY CAN'T
STOP YOURSELF FROM SCRATCHING.
SO BECAUSE OF THAT, WE NOW ARE
STARTING TO HAVE SOME
TREATMENTS.
SO SOME OF THE TREATMENTS MIGHT
BE TRYING TO REDUCE INFLAMMATION
AND ONE OF THE VERY OLD
TREATMENTS IS VARIOUS CORTISONES
TO ACTUALLY TRY TO REDUCE THE
INFLAMMATION, AND OFTEN THAT THE
REASONABLY EFFECTIVE.
BUT IF THEY COULD BE COMBINED
WITH ACTUALLY STOPPING TWO PARTS
OF THIS PATHWAY, AS INDICATED
HERE, THEN THE NET EFFECT MIGHT
BE EVEN GREATER.
SO IF WE CAN ACTUALLY, FOR
INSTANCE, STOP THIS -- WHAT'S
RELEASED FROM THE IMMUNE CELLS
FROM ACTIVATING THE NERVES THAT
I TALKED ABOUT IN THE FIRST PART
OF MY TALK, THEN PERHAPS YOU CAN
ACTUALLY GET A BETTER CESSATION
OF THIS ITCH-SCRATCH CYCLE.
AND THE FIRST INDICATION OF WHAT
MIGHT BE HAPPENING IN CHRONIC
ITCH CAME FROM A NUMBER OF
DIFFERENT GROUPS, NOT MY GROUP.
THE FIRST IS A GROUP, MARTIN
STEINHOF, THE SECOND, BRIAN KIM,
WHERE THEY IDENTIFIED THAT, IN
FACT, THE SENSORY NEURONS
EXPRESS A DIFFERENT CLASS OF
RECEPTOR.
THESE ARE CYTOKINE RECEPTOR.
SO ONE OF THE RECEPTORS IS A
RECEPTOR FOR INTERLEUKIN 31, AND
IN THIS PAPER, IT WAS SHOWN THAT
INTERLEUKIN 4 RECEPTOR WAS
IMPORTANT.
THE FEATURE OF THE CYTOKINE
RECEPTORS IS THEY WORK IN QUITE
A DIFFERENT WAY FROM THE
RECEPTORRINGS RECEPTORS I TALKEE
ACUTE PART OF MY TALK.
THOSE RECEPTORS CLASSICALLY LEAD
TO INCREASE IN CALCIUM AND THEN
DIRECT ACTION POTENTIAL FIRING.
THESE RECEPTORS IS KNOWN TO
OPERATE IN A VERY DIFFERENT WAY.
CLASSICALLY, THEY WERE
IDENTIFIED IN IMMUNE CELLS AND
NOT IN NEURONS.
AND THESE DISCOVERIES WERE SORT
OF GROUNDBREAKING BECAUSE THEY
ACTUALLY START TO EXPLAIN WHY A
NUMBER OF BIOLOGICS WHICH ARE
NOW VERY, VERY HOT AND BEING
USED IN SEVERE SKIN CONDITIONS
CAUSING CHRONIC ITCH.
SO FIRST OF ALL, I WANT TO --
AGAINST INTERLEUKIN 31,
INTERLEUKIN 4 RECEPTOR.
SO BOTH OF THOSE HAVE BEEN SHOWN
TO BE CLINICALLY EXTREMELY
EFFECTIVE TO REDUCING CHRONIC
ITCH.
SO OUR QUELL QUESTION A NUMBER F
YEARS AGO WAS ARE THERE ANY
OTHER CYTOKINE RECEPTORS BEYOND
THE INTERLEUKIN 31 AND
INTERLEUKIN 4 RECEPTORS.
AND INDEED, THERE IS.
AND THE RECEPTOR THAT WE
IDENTIFIED IS SHOWN ON THIS NEXT
SLIDE.
THIS IS THE INTERLEUKIN -- THIS
IS THE ONCOSTATIN M RECEPTOR,
AND WHAT I'M SHOWING YOU HERE
AGAIN IS IN SITU HYBRIDIZATION,
AND BY NOW YOU S YOU SHOULD KNOT
I'M SHOWING.
THIS IS ONE OF THE RECEPTORS
AGAINST NPPB, THE MOLECULE I
TALKED ABOUT IN THE FIRST PART
OF MY TALK, AND IF WE THEN LOOK
AT WHAT'S PRESENT IN THE HUMAN,
AGAIN, THE ONCOSTATIN M RECEPTOR
IS FOUND IN HUMAN AND THE NPPB
NEURONS AND THIS IS CONFIRMED BY
SINGLE CELL SEQUENCING.
SO THIS IS ANOTHER CYTOKINE
RECEPTOR, DOESN'T MEAN IT'S
INVOLVED IN ITCH.
SO THE FIRST THING WE TURNED TO
WAS TO ACTUALLY SEE IS
ONCOSTATIN M, ARE ONCOSTATIN M
LEVELS INCREASED IN CONDITIONS
OF CHRONIC ITCH?
SO WE TURNED TO SEQUENCING
INFORMATION THAT'S FROM -- THAT
ARE PUBLICLY AVAILABLE, AND AS
YOU CAN SEE HERE IN PATIENTS
WITH PSORIASIS, WHEN THEIR SKIN
HAS BEEN SEQUENCED, THEY HAVE
ELEVATED LEVELS OF ONCOSTATIN M.
COMPARED TO NORMALS, SHOWN HERE
IN BLACK.
THIS IS ALSO THE CASE FOR OTHER
SKIN CONDITIONS, FOR INSTANCE,
ATOPIC DERMATITIS, ALSO ANOTHER
CONDITION WHICH IS MUCH RARER,
CUTANEOUS T-CELL LYMPHOMA.
YOU CAN ALSO SEE THAT LEVELS OF
IL4 AND 13 ARE ALSO ELEVATED IN
ATOPIC DERMATITIS AND CTCL.
BUT NOT IN PSORIASIS.
AND IMPORTANTLY, FOR US, BECAUSE
WE ARE A BASIC RESEARCH LAB, WE
WANTED TO SEE WHETHER OR NOT THE
MODELS THAT ARE COMMONLY USED
FOR PSORIASIS AND ATOPIC
DERMATITIS ALSO HAVE ELEVATED
LEVELS OF ONCOSTATIN M, AND
INDEED THAT'S THE CASE THAT YOU
CAN SEE HERE IN THIS BOX,
THERE'S ELEVATED ONCOSTATIN M IN
A MODEL OF PSORIASIS, AND ALSO
IN THE MODEL OF ATOPIC
DERMATITIS.
SO THESE ARE ALL INSILICO
RESULTS.
WE ALWAYS LIKE TO LOOK DIRECTLY
IF THESE ARE SUPPORTED IN TISSUE
SO WE TOOK TISSUE FROM THESE
ANIMALS THAT HAVE A MODEL OF
PSORIASIS, AND WE LOOKED AT --
AGAIN, THIS IS IN SITU
HYBRIDIZATION, THE ONCOSTATIN M
IN THE TISSUE.
YOU CAN SEE HERE THIS IS SKIN
FROM THE EAR OF A MOUSE, AND
THERE'S VERY LITTLE OF
ONCOSTATIN M.
THIS IS VERY MUCH INCREASED IN
THIS MODEL, IN THIS MOUSE MODEL
OF PSORIASIS.
SO WE WANT TO, AGAIN, CHECK THIS
IN THE HUMAN TISSUE, AND IN
PARTICULAR, TO TRY TO UNDERSTAND
WHAT ARE THE CELLS HERE IN THE
SKIN THAT ARE ACTUALLY RELEASING
THE ONCOSTATIN M.
THE ANSWER IS SHOWN HERE.
WHEN WE LOOK AT THE LEVEL OF
ONCOSTATIN M, AND THIS IS NOW A
PLOT OF THE DIFFERENT CELLS THAT
ARE EXPRESSING ONCOSTATIN M, SO
THE KERATINOCYTES, ENDOTHELIAL
CELLS AND FIBROBLASTS DON'T
EXPRESS ONCOSTATIN M, WHAT
EXPRESSES -- THIS IS
DRAMATICALLY INCREASED IN
CUTANEOUS T-CELL LYMPHOMA, SO
THIS IS ONE OF THE MOST PRURITIC
CONDITIONS THAT IS KNOWN.
AND YOU CAN SEE THAT THE
ONCOSTATIN M IS EXPRESSED IN THE
T CELLS, AND THIS IS ALSO THE
CASE IN PSORIASIS, WHERE, IN
FACT, THERE'S THIS ELEVATED
ONCOSTATIN M IN BOTH THE T CELLS
AND THE MACROPHAGES.
OKAY.
SO THIS IS ALL DESCRIPTIVE, IT'S
TELLING US THAT THERE'S HIGH
LEVELS OF ONCOSTATIN M IN THE
SKIN FOR PATIENTS THAT HAVE
THESE CHRONIC ITCH SKIN
CONDITIONS.
WE KNOW THE RECEPTORS ARE IN THE
APPROPRIATE CELLS.
SO WHAT MIGHT BE THE MECHANISMS
BY WHICH ONCOSTATIN M MIGHT BE
DOING SOMETHING IN THOSE
NEURONS?
SO THE TWO MECHANISMS THAT WE
IDENTIFIED ARE THAT FIRST OF ALL
IN AN ACUTE SETTING, THEY CAN
POTENTIATE THE EFFECTS OF ITCH
INDUCING AGENTS.
SO IN OTHER WORDS, THEY ADD AN
EXTRA BOOST TO THE EFFECTS OF
THINGS LIKE SEROTONIN OR THOSE
SMALL LIPIDS.
AND THEN THE MORE INTERESTING
EFFECT OF ONCOSTATIN M AND ALSO
THE OTHER CYTOKINES WE ALSO
STUDIED IS THAT THEY HAVE VERY
MUCH LONG-TERM EFFECTS ON THE
EXCITABILITY OF NEURONS.
I WANT TO GO INTO SOME
EXPERIMENTS WHERE WE ACTUALLY
SHOW THIS.
THE FIRST -- SO THEY BOTH MAKE
USE OF ELECTROPHYSIOLOGY.
SO FIRST OF ALL, I WANT TO SHOW
YOU A PICTURE OF THESE NEURONS.
THESE ARE THE NEURONS SHOWN HERE
WITH THE FLUORESCENT MARKER, AND
IN HERE IN THIS GHOST IS
ACTUALLY AN ELECTRODE THAT'S
BE -- WE CAN RECORD THE CURRENTS
THAT ARE GOING INTO THAT NEURON.
THE CURRENTS I WANT TO REMIND
YOU ARE THE WAY IN WHICH NEURONS
TALK.
SO WHEN THERE'S AN INCREASED
CURRENT, OR AN ACTION POTENTIAL
FIRING, THIS IS THE WAY THAT
NEURONS TALK AND RELEASE
TRANSMITTERS DOWNSTREAM.
SO WHAT HAPPENS WHEN WE RECORD
FROM THESE NEURONS?
SO IF WE GIVE A PREU RIT GENERAL
LIKE HIS TA HISTAMINE TO THESE,
THEY HAVE A SMALL CURRENT.
WHAT'S IMPORTANT IS, THOUGH, IF
AFTER GIVING ONCOSTATIN M YOU
GIVE THE STATE Y SAME STIMULUS,T
CURRENT IS A LOT LARGER.
AND FOR COMPARISON, THIS IS THE
EFFECT IF YOU WERE TO GIVE TWO
BOUTS OF HISTAMINE.
THERE'S ACTUALLY REVERSAL OF THE
DESENSITIZATION THAT OCCURS.
SO AGAIN I WANT TO SHOW YOU DATA
FROM WHAT HAPPENS ACTUALLY IN A
MOUSE.
AND IF YOU INJECT ONCOSTATIN M
INTO A MOUSE ON ITS OWN, THE
ANIMAL SCRATCHES BUT NOT A LOT
MORE THAN IF YOU WERE TO INJECT
SASALINE CONTROL.
HOWEVER, IF YOU GO ONCOSTATIN M
WITH A PRURITOGEN, THERE IS THIS
BOOSTING OF THE EFFECTS OF
HISTAMINE, AS I SAID.
THIS IS A POTENTIATION THAT'S
DERIVED FROM THE ONCOSTATIN M.
SO I WANT TO GO ON TO THE SECOND
EFFECT OF ONCOSTATIN M, AND TO
DO THIS, I WANT TO TO A
DIFFERENT TYPE OF
ELECTROPHYSIOLOGY MEASUREMENT.
WHAT WE'RE DOING IN THIS
EXPERIMENT IS WE'RE EXCITING THE
CELLS WITH DIFFERENT TYPES OF
STIMULUS, THE STRONGEST ONE IS
SHOWN HERE IN RED.
AS YOU CAN SEE IN THE NORMAL
CONDITION, THESE NEURONS NEED TO
HAVE A LOT OF EXCITABILITY IN
ORDER TO WHAT'S SHOWN HERE AS
FIRE AND ACTION POTENTIAL.
WHAT HAPPENS NOW IS IF YOU GIVE
ONCOSTATIN M, THIS COMPLETELY
CHANGES.
SO NOW EVEN AT THE LOWEST
EXCITABILITY, WE NOW GET ACTION
POTENTIAL FIRING.
SO THIS SHOWS THAT THERE'S A
LONG TERM EFFECT THAT'S BOOSTING
THE EFFECT ON THE NEURONS, AND
THIS IS SOMETHING THAT OCCURS
OVER TWO DAYS THAT YOU NEED
THIS, BUT THIS DOESN'T GO AWAY
QUICKLY.
SO FOR THIS SECOND EFFECT,
AGAIN, I WANT TO SHOW YOU DATA
THAT IS CONFIRMATORY IN AN
ANIMAL MODEL, AND FOR THIS
EXPERIMENT, WHAT WE USE IS WE
USED AN ANTAGONIST, A GP130, A
BLOCKER, SO THIS IS THE
RECEPTOR, ONCOSTA TIPSTATIN M, E
NOT TOLD YOU THIS ACTUALLY FORMS
A DIMER.
THERE ISN'T A BLOCKER FOR THE
ONCOSTATIN M BUT THERE IS FOR
ITS EXCLUSIVE PARTNER, GP130.
SO WHAT WE WANTED TO DO WAS TO
EXAMINE WHETHER OR NOT IF WE
BLOCKED THIS RECEPTOR, COULD WE
RELIEVE PSORIASIS AND IN A MOUSE
MODEL.
INDEED WE COULD.
SO THIS IS THE EFFECT OF JUST
VEHICLE CONTROL, THE ANIMALS
CONTINUE TO CARRY ON SCRATCHING
AND IF WE GIVE THE BLOCKER, WE
CAN ACTUALLY RELIEVE ALMOST
COMPLETELY THE SCRATCH RESPONSES
IN THE MOUSE.
SO THIS SHOWS THAT THE
ONCOSTATIN M RECEPTOR, NOT ONLY
IN ELECTROPHYSIOLOGICAL
EXPERIMENTS BUT ACTUALLY IN A
MOUSE, IF WE CAN BLOCK IT, WE
CAN PREVENT THIS MODEL.
IN THIS MODEL.
SO THIS IS SHOWN HERE, THIS PAIR
OF SCHEMATICS WHERE IN NORMAL
CONDITIONS, IF THERE'S A
PRURITOGEN, FOR INSTANCE, HIS TA
MEAN OR SOME OTHER MOLECULE THAT
GETS IN CONTACT WITH THOSE NERVE
FIBERS, THERE IS THIS CURRENT
AND THEN ACTION POTENTIAL FIRING
AND SIGNALING INTO THE SPINAL
CORD.
AND WHEN WE GO TO -- NOW WE HAVE
AN INFLAMMATORY CONDITIONS WHERE
THERE'S ELEVATED ONCOSTATIN M,
THE SAME PRURITOGEN CAUSES A
GREATER CURRENT, A MORE ACTION
POTENTIAL FIRING AND, HENCE,
MORE ITCH.
I WANT TO GO BACK TO A SLIDE I
HAD IN THE BEGINNING THAT
DESCRIBES THE FACT THAT THERE'S
THIS INTERACTION BETWEEN NOT
ONLY THE NEURONS BUT THE IMMUNE
CELLS, WHICH I'VE BEEN TALKING
ABOUT A LOT, THIS IS THE SOURCE
OF THE INTERLEUKINS INCLUDING
ONCOSTATIN M INTO INTERLEUKIN 3T
THERE'S ALSO CROSSTALK BACK FROM
THE NEURONS TO THE IMMUNE CELLS,
SO THIS IS MORE RECENT DATA
SHOWING THERE'S THIS NEUROIMMUNE
EPITHELIAL TRIAD THAT IS
INVOLVED IN SKIN HOMEOSTASIS.
NOT ONLY IS THERE INTERACTION
BETWEEN THE NERVES AND THE
IMMUNE CELLS AND IMMUNE CELLS
AND THE NERVES, BUT THIS IS ALSO
THE CASE WITH THE STROMAL CELLS
AND THE STROMAL CELLS INTERACT
WITH THE IMMUNE CELLS.
SO THIS IS A VERY COMPLICATED
SET OF INTERACTIONS, BUT AT ITS
CORE, YOU CAN SEE THERE'S
INTERLEUKINS THAT -- CYTOKINES
THAT ARE INVOLVED IN
POTENTIATING BOTH THIS
INTERACTION AND ALSO THIS
INTERACTION.
AND I WANT TO FINALLY NOTE,
ALTHOUGH I'VE TALKED ABOUT
HISTAMINE A GREAT DEAL IN THE
CASE OF THE CHRONIC ITCH WITH
THE EXCEPTION OF UTE C UTICARIA,
HISTAMINE IS NOT REQUIRED FOR
THE MAINTENANCE OF ITCH AND THIS
IS SOMETHING THAT -- THE ANSWER
TO THIS, THAT THE MAST CELLS ARE
PROBABLY NOT THAT IMPORTANT.
IN CHRONIC ITCH, IT'S ACTUALLY
THESE OTHER TYPES OF IMMUNE
KRELTS, THE T CELLS FOR INSTANCE
THAT ARE VERY IMPORTANT IN THAT.
AND MY LAST SLIDE, I'M GOING TO
COME UP HERE, PROBABLY MY MOST
IMPORTANT SLIDE, IS
ACKNOWLEDGING THE PEOPLE THAT
DID ALL THIS WORK.
SANTOSH, JUERGEN AND
HISPANIC-YEN, WHO HAVE ALL GONE
ON TO SUCCESSFUL CAREERS OUTSIDE
OF NIH.
AND WITH THAT, I'M GOING TO
FINISH.
>> THANK YOU VERY MUCH, MARK.
SO IAN, WILL YOU CARRY ON,
PLEASE.
>> IT'S NOT LETTING ME START MY
VIDEO.
IT SAID DISABLED.
>> WE SEE IT ON OUR SIDE.
>> OH, THERE WE GO.
OKAY.
ALL RIGHT.
SO I'M GOING TO I'M IAN MYLES, I
WORK WITH NIAID AND I'M GOING TO
TALK ABOUT SOME OF OUR WORK,
WHICH IS FOCUSED ON KIND OF
WHAT'S DRIVING THE DISEASE FROM
AN ENVIRONMENTAL STANDPOINT.
SO AS CONFLICT OF INTEREST,
NIAID DOES HAVE A DEAL WITH A
COMPANY CALLED SKINESA TO SELL
THE PROBIOTIC THAT I WILL
MENTION AND SPRAYING PEOPLE WITH
BACTERIA IS NOT FDA-APPROVED,
MAYBE ONE DAY BUT NOT TODAY.
JUST AS A BASELINE FOR A CASE
PRESENTATION, IN 2016 WHEN WE
OPENED THE BEGINNING OF THE
TRIAL, 19-YEAR-OLD MALE HAD COME
IN, HE SUFFERED WITH ATOPIC DERM
FOR MOST OF HIS LIFE, HE TRIED
STEROIDS AND SOME OF THE OTHER
TREATMENTS THAT WERE AVAILABLE
IN 2016 WHICH AD ADMITTEDLY WERE
FAR FEWER THAN TODAY.
HE WAS ON THE WAIT LIST FOR
DUPIXON, HE WASN'T ABLE TO GET
IT.
SO HE WENT -- AS SOON AS HE
CLICKED ENROLL, HE SAID HE
STARTED SEARCHING FOR
EXPERIMENTAL TREATMENTS AND KIND
OF CAME TO US.
SO I'LL COME BACK TO HIM.
HE'S CERTAINLY NOT ALONE IN
TODAY'S WORLD IN TERMS OF THE
RATES OF ATOPIC DERMATITIS.
DRTHE VERY FIRST DESCRIPTION OF
WHAT IS ALMOST CERTAINLY ATOPIC
DERM CAME OUT OF THE EBERS PA
PAPYRUS, THAT WAS DEFINITELY
ECZEMA LOOKING BACK.
HIPPOCRATES AS HE MENTIONED
SPOKE ABOUT IT FREQUENTLY,
AUGUSTUS WAS KNOWN TO HAVE THE
ALLERGIC TRIAD.
SO THESE DIAGNOSES HAVE BEEN
KNOWN FOR BASICALLY ALL OF
CIVILIZATIONS BUT THEIR RATES
HAVEN'T COME CLOSE TO WHAT WE
HAVE TODAY.
YOU SEE GRAPHED ON THIS
TIMELINE, THIS INSANE HOCKEY
STICK GRAPHED FORMAT THERE WITH
THE INFLECTION POINT OF THE
UNITED STATES BEING IN AND
AROUND 1970.
SO IN THE 50s OR SO, THE RATES
OF ATOPIC DERMATITIS WOULD HAVE
BEEN IN THE 1 OR 2%, AND TODAY
WE'RE LOOKING AT 15 TO 20% OVER
A VERY SHORT PERIOD OF TIME.
SO THERE HAS TO BE SOME KIND OF
ENVIRONMENTAL FACTOR THAT WAS
INTRODUCED IN THE 1970s TO
GENERATE ANYTHING CLOSE TO THAT.
AND YET YOU CAN PLAY THIS GAME
FOR YOURSELF IF YOU RESEARCH
ATOPIC DERM PATHOGENESIS OR
EX-PA PATHOGENESIS, ECZEMA
MECHANISM, WHATEVER WORDS YOU
WANT, YOU'RE GOING TO GET A
GRAPH THAT LOOKS SOMETHING LIKE
THIS.
THESE ARE VALUABLE INFORMATION
IN TERMS OF WHAT'S GOING ON
INSIDE THE SKIN BECAUSE OF THE
FACT THAT YOU CAN USE SOME OF
THESE MONOCLONAL ANTIBODIES AS
BLOCKERS IN PEOPLE WHO WERE
PREVIOUSLY SUFFERING FROM
DISEASE ARE SUFFERING A LOT LESS
BECAUSE OF THESE MEDICATIONS.
BUT YOU'LL NOTICE ALL OF THESE
HAVE ONE THING IN COMMON, WHICH
IS IT'S GOING TO START AT THE
SKIP.
AND IT'S SKIN.
IT'S GOING TO MAKE THIS
INSINUATION WHATEVER IS GOING ON
IN THE SKIN IS SOMEHOW BELOW THE
SURFACE OF THE SKIN.
THERE WILL BE SOME COMMENTS
ABOUT THE MICROBIOME OR SOME
IRRITANT BUT REALLY NOT MUCH
ELSE GOING ON.
SO WE KIND OF REALIZE FROM
EPIDEMIOLOGY THAT SOMETHING
OUTSIDE OF THE BODY HAS TO BE
THE INCITING EVENT, AND YET MOST
OF THE WORK IS ON EVERYTHING
THAT HAPPENS INSIDE OF THE BODY.
SO IF YOU GO THROUGH THE
LITERATURE AND ASK, ALL RIGHT,
WELL, WHAT HAVE PEOPLE ESTABL
ESTABLISHED AS EXPOSURES THAT
PUT SOMEBODY AT RISK FOR ATOPIC
DERMATITIS?
I WOULD PUT THEM INTO FOUR BIG
CATEGORIES, THE FIRST OF WHICH
IS LIVING IN AN INDUSTRIAL
SOCIETY, SO PROCESSED FOODS,
PARTICULARLY HIGH CONSUMPTIONS
OF PROCESSED FOODS.
YOU SEE HERE THE DOTTED LINE
WOULD MEAN IT HAS NO EFFECT AT
ALL, SO THIS MEANS THAT THERE'S
A HIGHER RISK FOR PROCESSED
FOODS.
ANTIBIOTICS EXPOSURE, THERE'S
SOME RISK.
IF YOUR MOM HAS ALLERGIES, YOUR
CHANCES FOR ATOPIC DERM IS
HIGHER.
DAD DOESN'T SEEM TO BE RELEVANT
IN THIS PARTICULAR CALCULATION.
SIBLINGS ARE ACTUALLY
PROTECTIVE, WHICH IS INTRIGUING.
LIKE THE MORTGAGE OLDER SIBLINGS
MORE OLDER SIBLINGS YOUV THE LEG
TO HAVE ATOPIC D.
MOVING FROM A NON-INDUSTRIALIZED
COUNTRY TO THE UNITED STATES OR
EUROPE PRIOR TO TWO YEARS OF AGE
GREATLY INCREASES YOUR RISK AND
THEN THERE'S A COMPOUNDED RISK
ON TOP OF THAT IF YOU MOVE TO AN
URBAN ENVIRONMENT WITHIN THE
UNITED STATES.
AFTER SIX YEARS OF AGE YOU CAN
MOVE ANYWHERE YOU WANT IN THE
GLOBE AND YOUR RISK IS NOT GOING
TO CHANGE WHATSOEVER.
SO THAT KIND OF SPEAKS TO THE
CHANCE THAT THERE IS A
DEVELOPMENTAL WIN DOLE THAT IF
YOU EXPOSE SOMEBODY TO SOMETHING
THAT IS AMERICA OR EUROPE LEVEL
INDUSTRIALIZATION, THEY'RE GOING
TO BE AT RISK IF THEY GET PAST
THAT WINDOW, THEN IT DOESN'T
REALLY MATTER.
SO NORMALLY WHEN YOU TALK ABOUT
URBAN ENVIRONMENTS, WE TEND TO
ASSUME THAT'S FROM AUTOMOBILE
EXHAUST, WHICH WOULD BE THE
SECOND CATEGORY, BUT IF YOU LOOK
AT THE SPECIFIC COMPONENTS OF
AUTOMOBILE EXHAUST.
YOU CAN SEE SOME ARE RIGHT ON
THIS LINE OR NOT REALLY ALL THAT
RELEVANT AT ALL.
DESPIECT THE FACT THAT LIVING
NEAR A HIGHWAY PARTICULARLY
WHILE YOU ARE PREGNANT CAN HAVE
A PRETTY PROFOUND EFFECT.
SO THIS MEANS EITHER THESE
FACTORS FROM AN AUTOMOBILE ARE
SYNERGIZING WITH EACH OTHER OR
THAT THERE'S SOMETHING IN A CAR
EXHAUST THAT ISN'T BEING
MEASURED BY THE TRADITIONAL AIR
QUALITY INDEX.
SO WHEN YOU SEE THE AIR QUALITY
INDEX, THOSE ARE JUST SIX
CHEMICALS THAT TYPICALLY COME
OUT OF THE BACK OF AN
AUTOMOBILE, BUT THOSE SIX
CHEMICALS ARE NOT REALLY
ASSOCIATING WITH THE DISEASE
STRONGLY ON ANY INDIVIDUAL
LEVEL.
A NEW CATEGORY APPRECIATED IS
WILDFIRES.
IT REALLY BECAME PREVALENT AFTER
THE BIG FIRES IN AUSTRALIA WHICH
MADE THE NEWS, THEN THE MOST
RECENT ONES FROM CALIFORNIA,
MAYBE EACH EVEN THE LAST ONES M
THE EASTERN PART OF CANADA
INCREASED RATES OF ATOPIC DERM,
INDUCING IMMEDIATE FLARES IN THE
PEOPLE AS THE PLUME GOES THROUGH
THEIR SOCIETY.
THEN THE LAST CATEGORY IS KIND
OF A HODGEPODGE.
IT WOULD BE THINGS THAT YOU
WOULD DO IN YOUR HOUSE, HOME
RENOVATION BEHAVIOR, WEARING
NYLON, SPANDEX OR POLYESTER CAN
INCREASE YOUR RISK OF DUST,
ENVIRONMENTAL TOBACCO --
SECONDHAND SMOKE.
ONLY IF YOU'RE UNDER 2, THAT
INCLUDES BY THE WAY IN THE WOMB,
SO IF YOU RENOVATE, THE RISK
GOES MUCH HIGHER.
AFTER FOUR YEARS, YOU CAN
BASICALLY DO WHATEVER YOU WANT
TO YOUR HOUSE AND IT'S NOT GOING
TO MAKE A DIFFERENCE.
SO THESE DON'T FEEL VERY WELL
CONNECTED AND IT WOULD BE HARD
TO FIND A THROUGH LINE, PER SE.
BUT WE THINK WE GOT A LITTLE BIT
SMARTER IN THE FIELD IN 2023, WE
HAD FOUR DIFFERENT STUDIES, ONE
OF WHICH WE'RE A COLLABORATOR
WITH.
THEY'RE IN FOUR DIFFERENT CAN
YCOUNTRIES.
ALL OF THEM TOOK SAMPLES OF
BABIES IN THE FIRST WEEK OF
LIFE, THEN THEY FOLLOWED THEM
FROM ANYWHERE FROM 1 TO 4 YEARS
TO SEE WHO WENT ON TO DEVELOP AN
ATOPIC DERMATITIS, AND NOW CAN
WE GO BACK TO OUR SAMPLES AND
SEE WHAT COULD HAVE PREDICTED
WHO WAS GOING TO GET ECZEMA AND
WHO WASN'T.
THEY USED THREE DIFFERENT
METHODS WHICH I DON'T NEED TO
DETAIL BECAUSE ALL OF THEM --
EACH METHOD HAD ITS OWN QUIRKY
FINDING BUT WHEN YOU ADD THEM
ALL TOGETHER, THERE WAS REALLY
ONLY ONE THROUGH LINE, THAT WAS
THESE CLASSES OF LIPIDS OR OILS,
WHATEVER YOU WANT TO CALL THEM
CALLED CERAMIDES, AS WELL AS
SINGLE LIPIDS AND PHOSPHOLIPIDS.
I GUARANTEE IF YOU GO TO YOUR
GROCERY STORE, YOUR DEPARTMENT
STORE, GO DOWN ONE OF THE --
THEY WILL BRAG ABOUT THE FACT
THAT IT HAS CERAMIDES, LIPIDS,
PHOSPHOLIPIDS AND IT WE WILL
COME BACK TO WHETHER THEIR
BRAGGING IS JUSTIFIABLE.
ATOPIC DERM IS AN EARLY LIFE
DEFICIENCY OF THESE SPECIFIC
LIPIDS.
SO SOMETHING IN THE ENVIRONMENT
MIGHT BE INFLUENCING THOSE.
AND THE GOOD NEWS IS FROM A
RESEARCH STANDPOINT, WE ARE NOT
THE ONLY CREATURES THAT SHARE
OUR ENVIRONMENT.
SO WE ALL HAVE MICROBIOME AND I
THINK THE GREATEST DEPICTION OF
WHAT YOU MIGHT THINK OF AS THE
MICROBIOME IS RICHARD SCARRY'S
BUSY TOWN.
THIS IS HOW THE MICROBIOME
RESEARCH KIND OF BUILT ON
ITSELF.
USUALLY IT WAS VERY BROAD
CLASSIFICATIONS LIKE MAMMALS
VERSUS WORMS AND YOU CAN GET
MORE AND MORE AND MORE DETAILED
ALL THE WAY DOWN TO WHAT WE
WOULD CALL STRAIN LEVEL
ANALYSIS, WHERE YOU CAN START TO
HAVE VERY SPECIFIC COMMENTS
ABOUT SPECIFIC ORGANISMS LIVING
ON THE SKIN.
BUT NOW WE HAVE A BETTER
APPRECIATION FOR THE FACT THAT
LIKE IN BUSY TOWN, THEY EACH
HAVE A ROLE.
THEY HAVE A JOB THAT THEY'RE
SUPPOSED TO PLAY.
WE CAN START TO CLASSIFY THEM BY
SAYING WHAT ARE THESE BACTERIA
SUPPOSED TO DO, BECAUSE THE SAME
EXACT SPECIES MIGHT END UP
PLAYING DIFFERENT ROLES BASED ON
THE SKIN VERSUS THE GUT, OR ONE
PERSON -- ONE PERSON MIGHT NOT
NEED VITAMIN K PRODUCTION,
SOMEBODY MIGHT USE SOMETHING
ELSE.
SO WE CAN REALLY START TO PIECE
TOGETHER WHAT THESE BACTERIA ARE
SUPPOSED TO BE DOING AND THESE
OTHER MICROORGANISMS ON THE
SKIN.
SO IN BECOMES INTRIGUING IF YOU
LOOK AT WHERE ON THE BODY YOU
EXPECT SOMEBODY WITH ATOPIC
DERMATITIS TO MANIFEST THEIR
RASH.
YOU CAN KIND OF SEE THIS IS MORE
OR LESS BASED ON AGE WHERE YOU
EXPECT IT.
OVER HERE IS A GRAPH FROM
DR. JULIE SEGRE AND DR. HEIDI
CONGRESS WHE HIGHKONG AND THEY L
OVER THE BODY WHERE DIFFERENT
ORGANISMS WERE LIVING.
AT THE TIME THEY WERE JUST DOING
SPECIES SO THEY ONLY KNEW WHICH
ANIMALS BUT NOT THEIR EXACT
FUNCTIONS.
I'VE COLORED IN ON TO THIS GRAPH
WHERE YOU WOULD EXPECT TO FIND
GRAM-NEGATIVE ORGANISMS, SO WHY
THAT WOULD BE IMPORTANT IS THAT
OF ALL THE ORGANISMS IN THE
MICROBIAL WORLD THAT ARE CAPABLE
OF MAKING CERAMIDES,
SPHINGOLIPIDS AND PHOSPHOLIPIDS,
THE THINGS WE SAID WILL PROTECT
THE KIDS AGAINST ATOPIC
DETERMINE.
ALMOST ALL OF THEM ARE
GRAM-NEGATIVE ORGANISMS AND THE
ONLY ONES THAT ARE GRAM
POSITIVES ARE ALSO RESIDENTS ON
THE SKIN.
SO MOST OF THE BACTERIA LIVING
ON YOUR SKIN ARE MAKING THE
CLASS OF LIPIDS THAT APPEAR TO
PROTECT YOU AGAINST ATOPIC
DERMATITIS.
THE FEW ORGANISMS THAT DON'T
ACTIVELY MAKE CERAMIDES FOR YOU
HELP YOU MAKE MORE CERAMIDES FOR
YOURSELF.
SO THIS IS OUT OF MIKE OTTO'S
GROUP HERE AT NIAID WHERE A
STRAIN OF STAPH -- IT SURE SEEMS
THAT ALL THE BACTERIAS FUNCTION
ON THE GUT SEEMS TO ALIGN WITH
MAKING THESE SPECIFIC LIPID
CLASSES TO PROTECT YOU AGAINST
ATOPIC DERMATITIS.
SO THIS KIND OF GENERATES TWO
QUESTIONS, THE FIRST OF WHICH
WAS ALL RIGHT, COULD WE PUT THE
BACTERIA BACK?
A PERSON WITH ATOPIC DERM LOST
THESE KIND OF BENEFICIAL
ORGANISMS, WHAT WOULD HAPPEN IF
WE PUT THOSE ORGANISMS BACK ON
THE SKIN, COULD WE USE THAT AS A
TREATMENT?
SO FIRST WE HAD TO LEARN HOW TO
GROW GRAM-NEGATIVES FROM THE
SKIN.
I'LL SPARE YOU THE MS. REOF THAT
MISERY OFTHAT ONE.
WE TOOK THIS ORGANISM FROM
PATIENTS WHO WERE HEALTHY --
EXCUSE ME -- VOLUNTEERS WHO WERE
HEALTHY VERSUS PATIENTS WHO HAVE
ATOPIC DETERMINE.
EVEN THOUGH THESE ORGANISMS ARE
REMARKABLY SIMILAR GENETICALLY,
JUST VISUALLY IT WAS OBVIOUS
THAT THESE BACTERIA WERE GOING
TO BE DIFFERENT, YOU COULD SEE
THIS KIND OF MUCOUSY, YOU KNOW,
LIPID-LIKE STRUCTURE VERSUS ONES
THAT ARE A LITTLE MORE
TRADITIONAL FOR BACTERIAL
GROWTH.
WE PUT THOSE INTO DIFFERENT
MODELS TO SEE WHAT WOULD HAPPEN,
AND THE SHORT VERSION IS THE
THEY WHEALTHY VERSION WAS GOOD T
IMPROVING DISEASE IN MICE AND
BARRIER FUNCTION IN MICE AS WELL
AS KILLING OFF SOME OF THE BAD
BACTERIA SO THIS LOOKED LIKE IT
HAD SOME OBVIOUS POTENTIAL
BENEFITS.
THE NEXT QUESTION, OF COURSE,
WAS, DO WE EVEN NEED A LIVE
BACTERIA IF WE'RE GOING TO START
SPRAYING PEOPLE WITH AN ORGANISM
THAT ISN'T REALLY WELL-KNOWN AT
THE TIME, WOULDN'T IT BE BETTER
TO USE SOME KIND OF EXTRACT OR A
DEAD BACTERIA.
AND THE SHORT VERSION IS WE DID
LOTS OF DIFFERENT WAYS AND
NOTHING WORKED.
THIS IS WHAT IT LOOK LIKE WHEN
YOU GIVE A MOUSE ECZEMA ON THE
EAR.
THIS IS WHAT IT LOOKS LIKE WHEN
YOU BASICALLY COMPLETELY TAKE IT
AWAY USING OUR LIVING BACTERIA,
BUT IF YOU KILL THE BACTERIA OR
EXTRACT, THE LIPIDS, DO
WHATEVER, IT DOESN'T CUT IT.
SO IT REALLY DOES SEEM THAT YOU
NEED A LIVING ORGANISM TO PULL
THIS OFF.
AND THEN OF COURSE WE WANT TO
ASK IS IT SAFE.
BECAUSE YOU ARE SPRAYING --
POTENTIALLY SPRAYING THIS ON
CHILDREN WHO HAVE DISRUPTED SKIN
FUNCTION.
SOME OF THAT BACTERIA MIGHT GET
INTO THEIR BLOODSTREAM AND COULD
THAT BE A PROBLEM.
SO WHAT YOU'RE LOOKING AT HERE
IS MOUSE DATA, WHERE WE INJECTED
THE MICE ON PURPOSE WITH LARGE
AMOUNTS OF VARIOUS DIFFERENT
KINDS OF ORGANISMS.
THIS IS THE ONE AT THE TIME WE
WERE PLANNING TO USE.
IT JUST DOESN'T HAVE THE
CAPACITY TO GENERATE AN
INFECTION IN A MOUSE.
YOU CAN COMPARE THAT TO OTHER
HEALTHY ORGANISMS O OF THE SKIN
AND THAT'S NOT TRUE.
BECAUSE THE BACTERIA IS NATURAL
OR NORMAL, THAT IT'S GOING TO
BE -- NOT GOING TO BE ABLE TO
CREATE AN INFECTION BECAUSE
YOU'RE USING IT AT SUCH NATURAL
DOSES THAT WOULD BE A NATURAL
EXPOSURE.
SO WITH ALL THAT, WE GO TO THE
FDA AND SAY WE'D LIKE TO DO OUR
CLINICAL TRIAL BECAUSE OF THE
MOUSE STUDIES, SO THIS IS A
RESULT FROM THE -- WHAT WE CALL
THE OPEN LABEL PHASE.
SO EVERYBODY IN THE STUDY GOT
THE REAL DRUG AND THEY KNEW THAT
THEY WERE GETTING THE REAL DRUG.
WE HAD TWO DIFFERENT DOSING
STRATEGIES.
IT DEPARTMENT SEEM TO MATTER.
PEOPLE USED IT TWICE A WEEK FOR
THREE MONTHS, AND THREE TIMES A
WEEK FOR THE FINAL MONTH.
AND ON AVERAGE, GOT ABOUT 57%
BETTER, BUT THE IMPORTANT PART
WAS YOU REALLY TALKED TO THE
PATIENTS AND YOU ASKED THEM WHAT
ARE YOU LOOKING FOR.
THEY'RE NOT LOOKING FOR ANOTHER
TOPICAL PRODUCT THAT THEY'RE
COMMITTED TO FOR THE REST OF
THEIR LIFE.
WHAT THEY REALLY WANT IS
SOMETHING THEY CAN USE AND STOP
AND GAIN BENEFIT THAT THEY DON'T
HAVE TO COMMIT TO.
SO WE HAD THIS EXTENDED WASHOUT
PERIOD, WE HAD STOPPED THE DRUG
AT 16 WEEKS BUT THEY WERE
FOLLOWED FOR ANOTHER THREE OR
FOUR MONTHS AND THEY CAME BACK
AND YOU COULD SEE THAT THE
TREATMENT PERSISTED UP TO 36
WEEKS OFFICIALLY, THAT WAS THE
FARTHEST THAT WE LOOKED OUT.
YOU CAN COLLECT BACTERIAL SWABS
AND USING GENETIC MARKERS ASK
WHETHER THE BACTERIA THAT WE
SPRAYED ON THEM IS PRESENT ON
THE SKIN.
AND THAT'S WHAT YOU'RE SEEING
HERE, THAT NO ONE CAME IN WITH
OUR SPECIFIC STRAINS OF BACTERIA
WHICH MAINGS SE MAKES SENSE BUTD
OF THE STUDY, EVERYBODY HAD SOME
BACTERIA ON THE SKIN.
THAT'S WHAT I WOULD ANTICIPATE
WOULD BE ABLE TO ALLOW THEM TO
HAVE THE LONG TERM BENEFIT,
BECAUSE THE BACTERIA ARE STILL
THERE DOING WHAT THEY NEED TO
DO, BUT YOU DON'T NEED TO USE
THE MEDICINE FOREVER MORE.
SO THE WAY THIS WORKS, THE NIH
LICENSED IT OUT TO THE PRIVATE
SECTOR, WHO RAN TO THEIR CREDIT
AN OUTPATIENT ECZEMA TRIAL
THROUGH THE HEART OF THE COVID
PANDEMIC.
BUT THERE WERE SOME THINGS THAT
COULD HAVE BEEN DONE BETTER IN
RETROSPECT.
THE FIRST THING IS THAT
EVERYBODY IN THE STUDY WAS
FORCED TO USE A LOTION THAT HAD
CERAMIDES IN IT, WHICH CREATES A
VEHICLE EFFECT, JUST TELLING
SOMEBODY TO USE A CERAMIDE
LOTION TWO OR THREE TIMES A DAY
SHOULD CREATE A BENEFIT ON ITS
OWN, AND THEY HAVE TO ADJUST FOR
THAT IN THE STUDY AND THEY DID
NOT.
BUT THE OTHER THING IS THAT
THERE WAS KIND OF THIS LONG
WASHOUT PERIOD.
THIS IS THE -- THEY STOPPED THE
MEDICINE AT FOUR MONTHS AND THEN
A MONTH LATER, WHICH IS AS FAR
AS THEY LOOKED, WE LOOKED AT 36
WEEKS, LIKE I SAID, THE PEOPLE
WHO WERE TREATED WITH THE REAL
DRUG, THE BENEFITS PERSISTED,
WHEREAS THE PLACEBO EFFECT
STARTED TO WEAR OFF, WHICH IS
WHAT YOU WOULD ANTICIPATE.
SO COULD HAVE BEEN BETTER, SO
WE'RE REDOING THIS TRIAL AND THE
TWO MAJOR CHANGES, NO ONE IS
BEING FORCED TO USE ANY
PARTICULAR LOTION AND WE'RE
GOING TO HAVE A MUCH LONGER
WASHOUT PERIOD UNDER THE
ANTICIPATION THAT EVEN IF YOU
HAVE PLACEBO RESPONSE, IT'S NOT
GOING TO STAY FOR THREE OR FOUR
MONTHS VERSUS THE TREATMENT
WHICH WE EXPECT TO HOLD TIGHT.
SO WE'RE STILL RUNNING THAT.
BUT BECAUSE IT SURE LOOKS LIKE
IT HAS SOME EVIDENCE FOR
EFFICACY AND THE SAFETY LOOKS
FANTASTIC, A FEW PEOPLE WHO --
IT FEELS A LITTLE WEIRD GOING ON
BECAUSE IT'S GOT SUGAR IN THERE
AS THE STABILIZER, BUT THIS IS
WHERE NIH MADE THE DEAL WITH
SKINESA TO SELL IT, SO SOME
PATIENTS ARE ALREADY USING THIS
OVER THE COUNTER AND THIS IS
AVAILABLE.
SO LIKE I SAID, OUR YOUNG MAN
CAME IN AND THIS IS WHAT HE
LOOKS LIKE, YOU KNOW, 8 WEEKS
LATER.
HE WAS ABLE TO SUSTAIN IT,
RETURNED TO CAMPUS, IT WAS
OVERALL DOING WELL AND THEN
NOTICED KIND OF SLIGHT WORSENING
IN HIS NEW DORM ROOM, NOTHING
BACK TO WHERE HE WAS BUT THEN IS
KIND OF ASKING THE QUESTION OF
LIKE, ALL RIGHT, IT WAS WORKING,
NOW IT'S NOT, WHAT DO YOU THINK
IS GOING ON?
AND AGAIN, THIS IS KIND OF THE
BROADER QUESTION NOT JUST WITHIN
AN INDIVIDUAL PATIENT, WHY AM I
FLARING TODAY WHEN I WAS FINE
TOMORROW?
BUT IT'S GREAT THAT THESE
BACTERIA CAN BE USED AS THERAPY,
BUT IT DOESN'T ANSWER IN ANY
WAY, SHAPE OR FORM WHY WE SHOULD
HAVE SUCH A PROBLEM SINCE THE
1970s.
SO TO GET AT THAT, WE STARTED
WITH TWO -- WE STARTED WITH THE
FIRST APPROACH ASKING THE
QUESTION OF LIKE ALL THE TOPICAL
SOAPS AND PRODUCTS AND STUFF
THAT WE USE NOWADAYS THAT HAVE A
THOUSAND INGREDIENTS IN THE
BACK.
LIKE I SAID, YOU CAN GO TO THE
STORE AND FIND ONE THAT BRAGS
THAT IT HAS CERAMIDES BUT THAT'S
NOT THE ONLY THING IT HAS IN
THAT BOTTLE.
SO ONE OF THE FIRST THINGS WE
LOOKED AT IS THE ABILITY OF
DIFFERENT WHAT THEY CALL
EMOLLIENTS OR MOISTURIZERS, THE
DIFFERENT CHEMICAL INGREDIENTS
TO KILL OFF THE GOOD BACTERIA
AND WE DO THIS -- THIS IS THE
SAME PLATE THAT YOU WOULD USE TO
TEST IF A BACTERIA IS RESISTANT
TO PENICILLIN.
SO THIS IS OUR GOOD KIND OF
ROSIMONAS.
YOU CAN SEE IT KILLS IT OFF AND
BLEACHES IT BEYOND THE INITIAL
CORE, AND THIS IS STAPH AUREUS
THAT FOR THE MOST PART SEEMS
PRETTY WELL ADJUSTED TO BEING
ABLE TO SURVIVE IN THE FACE OF
PAIR BINS.
SO WHAT THIS MEANS IS THAT SOME
OF THE PRODUCTS THAT YOU BUY
OVER THE STORE THAT YOU'RE
SLATHERING ON, THOSE
PRESERVATIVES THAT THEY USE IN
THERE ARE MEANT TO KEEP
MICROORGANISMS FROM GROWING AND
IF YOU SLATHER THOSE ON YOUR
SKIN, SOME OF THOSE WILL BE
REALLY GOOD AT KEEPING YOUR
COMMENSAL ORGANISMS FROM GROWING
AND WILL GIVE AN ADVANTAGE OR
DISADVANTAGE TO THE GOOD
BACTERIA OR BAD BACTERIA
DEPENDING ON THE SPECIFIC
INGREDIENTS.
THE OTHER PROBLEM IS THAT SOME
OF THESE MOISTURIZERS CAN
CONTAIN IRRITANTS THEMSELVES, SO
THIS IS FROM ONE STUDY THAT -- A
META-ANALYSIS THAT COLLECTED A
BUNCH OF DIFFERENT STUDIES AND
LOOKED AT WHAT ARE THE RATES OF
DIFFERENT TOPICAL PRODUCTS THAT
PEOPLE ARE STUDYING, HOW MANY OF
THEM HAVE A KNOWN IRRITANT OR
SOMETHING WE KNOW PEOPLE WILL
POTENTIALLY REACT TO.
ONLY 25% HAD NONE.
SO A LARGE PERCENTAGE OF
PRODUCTS ON THE SHELF WILL
EITHER HAVE SOMETHING THAT IS A
KNOWN IRRITANT OR IT WILL HAVE
SOMETHING THAT KILLS OFF YOUR
POTENTIALLY GOOD BACTERIA.
SO THAT BECOMES A LITTLE
PROBLEMATIC IN TERMS OF HOW ARE
PATIENTS SUPPOSED TO DEAL AND
PICK OUT THEIR BEST
MOISTURIZERS.
BUT WE DIDN'T START WITH THAT IN
THE 1970s.
THERE'S ABSOLUTELY NO WAY THAT
THAT COULD CREATE THIS KIND OF
IMPACT ON THE ENTIRETY OF
SOCIETY IN SUCH A SHORT PERIOD
OF TIME SO WE FIGURED IT HAD TO
BE SOMETHING DIFFERENT.
SO WHAT WE DID WAS, WE'RE
LOOKING FOR ECZEMA HOT SPOTS
THAT YOU'VE PROBABLY HEARD FOR
CANCER CLUSTERS OR THINGS THAT
ERIN BROCKOVICH MADE FAMOUS IN
THE MOVIE AND THE BOOK.
SO WHAT WE'RE DOING IS SAYING
WHICH TOWNS HAVE WAY MORE ATOPIC
DERM THAN WE EXPECT ON AVERAGE,
WHICH HAVE WAY LESS, BHU USING
EPA DATABASES, WHICH CHEMICALS
ARE OVERREPRESENTED IN EACH OF
THOSE DIFFERENT ZIP CODES.
TO CUT TO THE CHASE, THESE TWO
CHEMICALS ARE FAR AND AWAY THE
ONES WITH THE STRONGEST
ASSOCIATION WITH DISEASE ON A
POPULATION LEVEL.
WE THEN WANT TO GO BACK AND LOOK
AT THOSE DIFFERENT EPIDEMIOLOGIC
FACTORS THAT I TOLD YOU, LIVING
IN AN INDUSTRIALIZED
ENVIRONMENT, AUTOMOBILE EXHAUST,
AND WE START TO ASK THE
QUESTION, ARE THERE SIGNS THAT
THESE CHEMICALS ALIGN WITH THOSE
EXPOSURES?
SO TDI IS THE NUMBER ONE
ISOCYANATE, SO IN EARNEST ITS
MANUFACTURING BEGAN AROUND 1970.
XYLENE GAME -- MANUFACTURING FOR
IT ALSO KICKS OFF IN THE UNITED
STATES ON OR AROUND 1970 SO
THESE START TO SPRING UP RIGHT
AROUND THESE OUTBREAKS.
PRIOR TO 1970, NOT A SINGLE
AUTOMOBILE ON THE ROAD PRODUCED
EITHER ONE OF THESE CHEMICALS.
IN 1970, WE BEGAN TRANSITIONING
OFF OF LEADED GASOLINE AND ON TO
NON-LEADED GASOLINE.
I WOULD LIKE TO NOTE COMING OFF
LEADED GASOLINE HAS ITS OWN
MASSIVE BENEFITS BUT AN
UNFORTUNATE UNINTEND THE
CONSEQUENCE THAT AFTER THE
CATALYTIC CONVERTER WAS MANDATED
IN 1970 EVERY AUTOMOBILE BECAME
A PRODUCER OF XYLENE AND
ISOCYANATES, THUS POTENTIALLY
EXPLAINING THE CONNECTION WITH
HIGHWAYS.
THE ONLY NATURAL SOURCE OF BOTH
OF THESE CHEMICALS IS WILDFIRES
OR TIMBER WASTE.
SO THAT WAS CONCERNING.
THEN WHEN WE WENT THROUGH TO
START LOOKING, BECAUSE WHEN
THESE CAME UP, I HAD NEVER HEARD
OF THESE CHEMICALS IN OUR
ANALYSIS.
YOU START LOOKING IN WHAT THESE
THINGS ARE FOUND ON, THEY ARE IN
NEW FURNITURE, WALLPAPER GLUE,
SEALANTS AND PAINTS, ALL OF THE
THINGS THAT YOU WOULD USE TO
REMODEL A HOME ALMOST ALL
REQUIRE ONE IF NOT BOTH OF THESE
CHEMICALS.
LOOKING AT THE MECHANISM, I
WON'T BEAT THIS TO DEATH BUT THE
SHORT VERSION IS YOUR BACTERIA
BREATHED NITROGEN, AT LEAST THE
ONES ON THE SKIN, AND THESE
PARTICULAR CHEMICALS CHOKE OFF
THEIR ABILITY TO BREATHE
NITROGEN SO THE WAY THEY GET
AROUND THAT IS THEY STOP MAKING
THESE BENEFICIAL LIPIDS, THEY
TURN OFF THEIR CERAMIDE
PRODUCTION, AND THEY START
SHIFTING THEIR PHYSIOLOGY TO
SOMETHING THAT WILL PROTECT THEM
FROM THESE CHEMICALS BUT COME AT
OUR EXPENSE.
YOU CAN ACTUALLY WATCH THIS
HAPPEN ON THE DOSING, SO IN RED
IS THE AMOUNT OF CERAMIDES THAT
THESE BACTERIA ARE MAKING AND AS
A CRANK UP THE DOSE OF THESE
PARTICULAR CHEMICALS, THIS ONE
IS ISOCYANATE, I CAN TURN OFF
THE BA BACTERIA'S ABILITY TO MAE
THESE PARTICULAR LIPIDS, EVEN IN
LOWER CONCENTRATIONS WHERE THE
BACTERIAL GROWTH IS IMPROVED.
SO THESE BACTERIA HAVE THE
ABILITY TO EAT THESE TOXINS AND
GROW MORE, BUT THEY'RE DOING IT
AT THE EXPENSE OF OUR LIPID
PHYSIOLOGY AND SO TURNING OFF
THESE PARTICULAR PATHWAYS.
SO CONNECTING IT BACK TO THE
REAL WORLD TO SAY ALL RIGHT, IT
LOOKS LIKE THESE THINGS ARE
TURNING OFF THESE LIPIDS, IS
THERE ANYTHING IN THE REAL WORLD
THAT MIGHT BE CONCERNING?
I'LL SHOW YOU TWO THING HERE.
THE FIRST IS GOING BACK TO THAT
CLINICAL TRIAL, SO IF YOU GOT
TREATED, THAT'S THE ONE IN THE
PINK, WITH THE REAL TREATMENT
VERSUS THE BLACK WHICH IS THE
PLACEBO, YOU NOTICE ONCE AGAIN
LIKE I SHOWED YOU BEFORE, THE
PLACEBO WEARS OFF AND THE PINK
ONES HOLD TIGHT.
BUT IF YOU LIVE IN AN AREA WHERE
YOU HAVE MORE THAN AVERAGE
ISOCYANATE EXPOSURE, THE
BACTERIA ACTUALLY WORKED EVEN
BETTER FOR THOSE PEOPLE THAN
PEOPLE WHO LIVE IN BELOW AVERAGE
AREAS.
AND WE ARE FOLLOWING UP ON THIS
IN OUR SUBSEQUENT STUDY MORE
PURPOSEFULLY, BUT THE TAKE-HOME
FROM THIS IN OUR MIND IS THAT IF
YOU LIVE IN AN AREA WHERE YOUR
NATURAL BACTERIA ARE MORE LIKELY
TO BE POISONED OFF BY THESE
CHEMICALS, THEN REPLACING THEM
WITH BETTER BACTERIA IS GOING TO
BE MORE BENEFICIAL TO YOU THAN
IF YOU LIVE IN AN OTHERWISE
PRISTINE ENVIRONMENT.
THE LAST THING WE CAN DO IS TEST
THIS IN THE LAB, SO ALL OF THOSE
DIFFERENT THINGS THAT YOU
BROUGHT IN YOUR HOME, WE CAN
TEST THAT IN THE LAB.
SO HERE'S WHAT HAPPENS WHEN YOU
SPRAY STAPH AUREUS ON TO
DIFFERENT KINDS OF BED SHEETS
MADE OUT OF THESE DIFFERENT
MATERIALS, JUST LET THEM SIT AND
SEE HOW LONG THEY CAN SURVIVE ON
THE BED SHEETS BY THEMSELVES AND
LOOK AT THE GROWTH.
SO YOU CAN SEE COTTON AND BAMBOO
DO NOT SUPPORT THE GROWTH OF
STAPH AUREUS VERY LONG, EVEN
THOUGH THESE OTHER SYNTHETIC FAB
BRIFABRICS DO.
YOU MUTE L MIGHT LOOK AT OUR GOD
BACTERIA AND SAY THIS IS GOOD
NEWS, OF COURSE THE BAD NEWS IS
GROWING ON SPANDEX, NYLON OR
POLYESTER CAUSES THEM TO ONCE
AGAIN SHIFT THEIR PHYSIOLOGY.
SO THEY'LL GROW ON THOSE
FABRICS, BUT THEY WILL STOP
MAKING LIPIDS IN ORDER TO GROW
ON THOSE FABRICS.
AND SO FOR OUR PATIENT, WE KIND
OF GAVE HIM SOME GENERAL ADVICE,
SO IN HIS DORM, HE FOUND OUT HE
HAD A MEMORY FOAM MATTRESS SO HE
SWITCHED TO A LATEX FOAM
MATTRESS.
SHEETS WERE POLYESTER, HE
SWITCHED OVER TO COTTON.
I'M NOT -- I AM AWARE THAT THIS
IS NOT A 0-DOLLAR EVENT SO NOT
EVERYONE IS GOING TO BE ABLE TO
DO THAT.
HE GOT HIMSELF AN AIR FILTER.
WE CAN COME BACK TO THAT IF YOU
WANT.
IT'S HARD TO KNOW EXACTLY WHICH
ONE TO GET, BUT HE SEEMED TO
IMPROVE BACK TO HIS KIND OF
POST-TREATMENT LEVELS FOR WHAT
IT'S WORTH.
SO THESE TWO CHEMICALS ALIGN
WITH ISOCYANATES IN TIME IN
TERMS OF WHEN THEY HIT THE
MARKET SPACE IN TERMS OF WHERE
THEY ARE IN THE COUNTRY AND IN
YOUR HOME.
WE HAVE MECHANISMS THAT IMPLY
THAT BOTH THE INDIVIDUAL IS
HARMED AND THE MICROBIOME, SO
THE REALLY TAKE HOME POINTS FOR
THIS, THERE'S SOMETHING TO BE
HAD ABOUT GENUINE PREVENTION, IF
YOU REALLY WANT TO START TALKING
ABOUT PREVENTING THESE DISEASES
IN KIDS, YOU NEED TO START
PROTECTING THEM FROM THESE
EXPOSURES EARLY IN LIFE BECAUSE
A LOT OF TIMES PREVENTION
STUDIES TALK ABOUT SLATHERING
THEM IN SOME KIND OF MOISTURIZER
OR GIVING THEM A DRUG.
THAT'S NOT REALLY PREVENTION IN
THE WAY THAT WE WOULD THINK
ABOUT IT.
THERE'S IMPLICATIONS FOR
DISPARITIES IN TERMS OF THE
POPULATIONS THAT GET EXPOSED TO
THE MOST AMOUNT OF THESE
PARTICULAR DISORDERS ARE ALSO
THE ONES THAT HAVE THE HIGHEST
RATES OF ATOPIC DERM AND OTHER
ALLERGIC DISEASES SO THAT'S
SOMETHING THAT SHOULDING
FOLLOWED UP ON.
AND THERE'S SOMETHING TO BE HAD
ABOUT OTHER DISEASES.
WE MADE THE MODEL OF TRYING TO
FIND THE ECZEMA HOT SPOTS AND
THEN LOOKING FOR THE CHEMICALS
ASSOCIATED WITH THOSE ECZEMA HOT
SPOTS.
WE'VE SINCE EXPANDED TO MANY
OTHER DISEASES.
I AM JUST SHOWING YOU THE ONES
FOR WATER POLLUTION IN CHILDREN
6 TO 17, AND THIS IS UNPUBLISHED
BUT WE'RE WORKING TOWARDS THIS
AND I'M JUST GOING TO QUICKLY
HIGHLIGHT THE ONES IN YELLOW
HERE ARE BEHAVIORAL
NEURODEVELOPMENTAL DISORDERS.
SO WHEN WE'RE LOOKING AT WHICH
DISEASES HAVE THE STRONGEST
CHEMICAL SIGNAL, WHICH CHEMICALS
MIGHT BE DRIVING OTHER DISEASES
BEYOND ATOPIC DERM, THE
NEUROBEHAVIORAL DISORDERS ARE BY
FAR THE ONES THAT COME UP THE
MOST WITH SOME OF THESE
ENVIRONMENTAL TOXINS.
SO REALLY WHAT SHOULD WE BE
DOING ABOUT THIS?
THE FIRST THING IS TO KIND OF
RECOGNIZE THAT THE DISEASE CAN
BE TREATED BY DRUGS BUT IT
DOESN'T MEAN THE DISEASE IS
CAUSED BY A LACK OF THAT DRUG.
AND I THINK WE ALL INHERENTLY
KNOW THIS BUT IT'S EASY TO GET
VERY EXCITED ABOUT HOW YOU GIVE
A PATIENT A DRUG, THEY GET A LOT
BETTER AND YOU GET EXCITED TO
THINK IF I COULD JUST GIVE THIS
DRUG TO EVERYBODY, THEN WE COULD
MAKE A BIG IMPACT.
AND MAYBE.
BUT I STILL THINK PREVENTION
SHOULD REIGN IF WE HAVE THE
OPTION.
WE HEAR A LOT OH, I WORK ON
MECHANISM, AND I WOULD SAY THAT
MECHANISM DOESN'T START AT THE
SKIN, WE REALLY NEED TO FOCUS ON
THINGS ABOVE THE SKIN AND WE
NEED TO START DEMANDING
SPECIFICITY.
SO I HEAR THIS OH, WELL, INDIA
IS MORE POLLUTED THAN THE UNITED
STATES AND WHY DON'T THEY HAVE
HIGHER RATES?
MY RESPONSE TO THAT IS INDIA IS
DIFFERENT POLLUTED THAN THE
UNITED STATES.
WE CAN'T JUST USE POLLUTION AS A
BLANKET STATEMENT.
LOS ANGELES MAY HAVE MORE TOTAL
POLLUTANTS THAN, SAY, RURAL
KANSAS, BUT IF THE DISEASE
YOU'RE INTERESTED IN IS
AFFILIATED WITH HERBICIDES OR
PESTICIDES THAT ARE MORE LIKELY
TO BE SPRAYED ON FARMS, THEN
KANSAS IS MORE POLLUTED IN THAT
SPECIFIC CONTEXT THAN
LOS ANGELES.
SO ONE OF THE THINGS OUR LAB IS
TRYING TO DO IS COLLECT THIS
DIRECTLY.
SO THIS IS A PUMP THAT VACUUMS
IN AIR THROUGH THIS LITTLE
CASSETTE AND INSIDE THIS
CASSETTE ARE DIFFERENT FILTERS
THAT ARE BUILT TO CATCH
DIFFERENT TYPES OF CHEMICALS,
AND I'LL JUST SHOW YOU THE
TAKEHOME SO WE CAN BRING ONE OF
THESE INTO THE LAB AND DO IT IN
A CONTROLLED ENVIRONMENT WHERE
I'M ONLY RELEASING TWO SPECIFIC
CHEMICALS AND I CAN FIND SIGHLY
AND DIISOCYANATE, SO IN A
CONTROLLED ENVIRONMENT, I CAN
FIND EXACTLY WHAT I PUT.
THIS IS AFTER 24 HOURS.
THIS IS JUST POINTED AT THE
BELTWAY FOR FIVE HOURS.
AND THESE ARE ALL THE CHEMICALS
THAT I CAN START TO FIND AND IF
I GO LONGER, I BET I CAN PULL
OUT ISOCYANATE.
AND THEN I TOOK ONE OF THESE AND
PUT THEM ACTUALLY IN MY KITCHEN,
AND TIP OF THE HAT TO MY WINDOWS
AND DOORS, I GUESS, BECAUSE I'M
KEEPING OUT THE BELTWAY, BUT
THESE ARE ACTUALLY COOKING OILS
THAT I'M PICKING UP.
SO I KNOW I NEED TO BE A LITTLE
LIGHTER ON THE OILS WHEN I'M
COOKING.
BUT WE CAN START TO DO SPECIFIC
COMMENTS ABOUT THE EXACT
CHEMICALS IN A SPECIFIC
ENVIRONMENT AND HOW MUCH OF IT
AND MAYBE START USING THAT
RATHER THAN JUST KIND OF BLANKET
STATEMENTS ABOUT POLLUTION.
SO THE OTHER THING WE NEED TO DO
IS UNDERSTAND -- I'M SEEING THIS
MORE AND MORE NOW IN MICROBIOME
RESEARCH, SOMEBODY SAID OH,
THERE'S A MICROBIOME SIGNATURE
FOR THIS DISEASE OR THAT
DISEASE, AND THAT'S GREAT, BUT
WE'VE GOT TO UNDERSTAND THAT
THESE THINGS KIND OF RUN IN
FAMILIES AND THEY'RE GOING TO
CLUSTER IN THE SAME
ENVIRONMENTS.
SO THIS COMES UP MORE IN TERMS
OF THE PUSHBACK OF PEOPLE WHO
MIGHT SAY THAT OH, YOU KNOW,
ECZEMA IS GENETIC OR THIS
DISEASE IS GENETIC.
AND JUST FROM A MATERNAL
STANDPOINT, JUST FROM ASKING
ABOUT A MOM WHO'S GIVEN BIRTH TO
TWO CHILDREN, THESE ARE ALL THE
THINGS THAT COULD BE DIFFERENT
ABOUT THE HOME THAT YOU BRING
THOSE TWO CHILDREN INTO JUST
FROM -- THAT WOULD BE RELEVANT
TO ATOPIC DERM ALONE.
SO MAYBE MOM GOT ANTIBIOTICS
WITH THE FIRST ONE AND NOT THE
OTHER, OR MAYBE DIET WAS
DIFFERENT OR SMOKING EXPOSURE
WAS DIFFERENT.
SO THESE ARE ALL THINGS WE WOULD
NEED TO KNOW BEFORE WE WOULD
MAKE ASSUMPTIONS ABOUT THE
ENVIRONMENT CHILDREN GROW UP IN.
SO WHEN I HEAR PEOPLE SAY TWO
PEOPLE GROW UP IN THE SAME
ENVIRONMENT BUT ONLY ONE GOT THE
DISEASE SO WOULDN'T IT BE MORE
LIKELY TO BE SOMETHING GENETIC?
AND MY PUSHBACK WOULD BE WHAT DO
YOU MEAN BY THE SAME
ENVIRONMENT?
WHAT METRICS WOULD YOU USE?
ONCE YOU START GOING DOWN THAT
ROAD, YOU REALIZE VERY QUICKLY
THAT THE ENVIRONMENT IS FAR MORE
DYNAMIC THAN WE APPRECIATE.
SOME OF MY HYPOTHESIS HERE, I
DON'T HAVE DATA FOR IT YET, BUT
THE OLDER SIBLING IS THE ONE
THAT GETS THE NICE REMODELED
BEDROOM AND ALL THE OTHER FANCY
NEW EQUIPMENT, AND THE FOURTH
KID IS JUST GETTING WHATEVER THE
FIRST THREE DON'T DESTROY.
SO THEN THE LAST THING IS TO
KIND OF IMPROVE OUR FUTURE
PERFORMANCE SO WE REALLY NEED TO
START TEACHING ENVIRONMENTAL
ASSESSMENTS AND HAVING
CONVERSATIONS WITH OUR PATIENTS
ABOUT HOW TO DO THIS BECAUSE I
CAN ASSURE YOU THEY ARE VERY
INTERESTED IN THINGS THAT THEY
CAN DO EVEN IN ADDITION TO THEIR
MEDICATION.
THEY DON'T HAVE TO NECESSARILY
BE MEDICALLY AVERSE, BUT IN
ADDITION TO IT, WHAT CAN I DO.
SO NADIA SHOBNAM IS A FELLOW IN
THE LAB AND DEVELOPED THIS KIND
OF MNEMONIC, I'LL KIND OF SHOW
YOU ONE PART FOR THE AIR QUALITY
BECAUSE I THINK IT'S COUNTER
INTEU TI. YOCOUNTERINTUITIVE.
YOU MIGHT THINK IF THERE'S BAD
AIR OUTSIDE, I'LL LOCK THE
DOORS, CLOSE THE WINDOWS AND
I'LL BE PROTECTED.
THAT IS TRUE FROM LARGE
PARTICLES AND FROM POLL EN, BUT
IT IS NOT TRUE FROM GASES.
GASES ACTUALLY CONCENTRATE
INSIDE YOUR HOUSE IF YOU SEAL
EVERYTHING UP.
SO HERE WOULD JUST BE ONE THING
THAT PEOPLE COULD DO, CHEAP BOX
FANS, THE KIND OF STUFF YOU
WOULD FIND IN ANY DORM ROOM, YOU
CAN FIND ANY BASIC FILTER, MERV.
THE HIGHER THE NUMBER, THE
STRONGER THE FILTRATION.
YOU GO TOO HIGH, THE FAN MAY NOT
BE ABLE TO HANDLE IT.
BUT WHAT YOU DO IS YOU FIND
WHATEVER PART OF YOUR LIVING
ENVIRONMENT POINTS CLOSEST TO
THE BIGGEST ROAD AND YOU PUT A
FAN THERE AND YOU BLOW OUT.
AND THEN AS BEST YOU CAN ON THE
OTHER SIDE OF THE HOUSE, OTHER
SIDE OF THE APARTMENT OR SOME
OTHER PART OF THE LIVING SPACE,
YOU SET UP A WINDOW WHERE IT
DRAGGING AIR IN THROUGH THE
FILTER, SO THAT WAY YOU'RE NOT
PULLING IN THE SOOT OR THE POLL
ENINTO YOUR HOUSE, BUT YOU'RE
BRINGING IN FILTERED AIR AND
VENTILATING OUT CONTAMINATED
AIR.
JUST TO SHOW YOU SOME OF THE
RESULTS I HAD JUST FOR SETTING
THIS UP IN MY HOME, SO I COULD
TAKE THE TOTAL VOLATILE ORGANIC
COMPOUNDS FROM .041 TO .005,
THESE ARE THE ALDEHYDES DROP, I
CAN GET THE CO2 LEVELS TO DROP
BUT I DO GET A TRACE INCREASE IN
BOTH THE PARTICULATE MATTER
TELLING ME THAT MAYBE THIS
FILTER WASN'T QUITE GOOD ENOUGH
TO PREVENT EVERYTHING FROM GOING
THROUGH, BUT YOU GET THE IDEA.
WHAYOU WANT TO BRING IN FILTERED
AIR AND PUSH OUT THE BAD AIR,
NOT TO SEAL EVERYTHING UP AND
PREVENT AIR FROM COMING THROUGH.
SO WITH THAT, I'LL THANK MY
GROUP HERE FOR EVERYTHING, AND
AGAIN, NADIA AS WELL AS GRACE
HELPED CREATE THIS FIGURE.
IF YOU WANT MORE INFORMATION,
YOU CAN GO TO OUR -- THIS
PUBLICATION WHERE YOU CAN SEE
ALL THE DIFFERENT CHEMICALS,
WHAT THEY'RE DOING AND HOW TO
AVOID IT, AND I SHOWED YOU THE
CITATION FOR MITIGATION, AND
THIS IS OUR FLAG.
SO WITH THAT, I'LL STOP.
THANK YOU.
>> ALL RIGHT.
WELL, YOU KNOW, THIS HAS BEEN
REALLY A SPECTACULAR, EXCITING
PAIR OF PRESENTATIONS, WHICH
HAVE GREAT IMPORTANCE AND
LINKAGE.
AND I THINK WE'VE ALL ENJOYED
AND LEARNED A GREAT DEAL FROM
IT.
THERE ARE A WHOLE HOST OF
QUESTIONS HERE, AND SO I'M GOING
TO GO THROUGH MANY OF THEM,
PROBABLY NOT ALL.
SO LET'S BEGIN HERE.
SO IAN, DO CERAMIDE AND THE
OTHER LIPIDS RELEASED BY THE
ROSAMONA MUCOSA INTERACT WITH
ITCH RECEPTORS?
>> PROBABLY.
THE ONLY ITCH RECEPTOR THAT
WE'VE PLAYED AROUND WITH IS
CALLED TRIP RECEPTORS, SO TRIP
V1, TRPA1, THOSE ARE ITCH TRALT
AND PAIN, WHICH IS A LITTLE
DIFFERENT.
SO WE JOKE WITH DR. HOON, WE
HAVE NOT LOOKED AT THAT, BUT THE
TRIP RECEPTORS ARE LIKELY
INFLUENCED BY THESE LIPIDS, THE
SPECIFIC LIPID RESIDUES HAVE NOT
BEEN GENUINELY ASSESSED.
>> THERE WAS ALSO A QUESTION
ABOUT THE ASSOCIATION WITH
WATER.
WHERE MUCH CONTAMINATION IN
WATER IS PARTICULARLY FROM THE
HORMONAL STANDPOINT IS
ASSOCIATED OR CLAIMED TO BE
ASSOCIATED WITH A WHOLE HOATS OF
DISORDERS, IS THERE AN
ASSOCIATION?
IS IT KNOWN WHETHER THE CHRONIC
ITCH DISORDERS HAVE ANY
EPIDEMIOLOGIC RELATIONSHIP TO
EXPOSURE TO WATER IN NATURE AND
DOES PURIFIED WATER OR THE
FILTERED WATER THAT'S SOLD IN A
SUPERMARKET, SHA DESUPERMARKET,F
THESE LIPID MOLECULES?
>> THERE HAVE BEEN A STUDY OF --
THOSE ARE USELESS FOR ATOPIC
DERM, MAYBE THEY'RE GOOD FOR
SOMETHING ELSE, BUT THE
ASSOCIATIONS FOR PSORIASIS ARE A
LITTLE BIT DIFFERENT, AND
THEY'RE MORE AROUND BARIUM,
WHICH COULD SLIP THROUGH.
IN TERMS OF FILTERED WATER, A
LOT OF THE PROBLEM IS THE
FILTERED WATER COMES IN A BIG
PLASTIC JUG, AND YOU KNOW, ONE
OF OUR PH.D. STUDENTS WAS
LOOKING THROUGH FOR THE
MOLECULES CALLED PFAS, WHICH ARE
HORMONAL DISREGULATORS AND
THEY'RE KNOWN MORE FOR TEFLON
AND THE FOREVER CHEMICALS, AND
YOUR LAB WATER THAT YOU BUY TO
DO YOUR EXPERIMENTS AND HAS
PURIFIED WHAT TERL COMES IN A
PLASTIC JUG AND THAT PLASTIC HAS
DETECTABLE LEVELS OF PFAS.
SO IT IS HARD TO TRULY ELIMINATE
ALL EXPOSURE TO THESE.
>> YOU COMMENTED ABOUT THE USE
OF FILTERS.
SO ONE OF OUR LISTENERS ASKED
ABOUT MEMORY FOAM.
I'M NOT FAMILIAR WITH MEMORY
FOAM, BUT MAYBE YOU CAN
ENLIGHTEN US.
>> SO THE TERM MEMORY FOAM IS
USUALLY JUST USED FOR YOU PUT
YOUR HAND IN AND DOES IT, LIKE,
HOLD ITS SHAPE A LITTLE BIT.
SO THERE IS A LATEX-BASED MEMORY
FOAM WHICH DOES NOT HAVE
ISOCYANATES OR XYLENE OR ANY OF
THE CHEMICALS THAT WE ASSOCIATE
WITH ATOPIC DERM.
I CANNOT ATTEST TO ITS SAFETY
FOR EVERY OUT THERE BUT --
MEMORY FOAM, THE BRAND, AND THE
NAME OR WHATEVER, IF IT IS A
NON-LATEX FOAM MEMORY FOAM, IT
ALMOST CERTAINLY IS MADE OUT OF
THOSE PARTICULAR CHEMICALS, AND,
THEREFORE, GENERATE THESE RISKS
OF EXPOSURE.
SO WHEN YOU OFF-GAS A MATTRESS
AND YOU SEE THAT STINK WHEN YOU
UNSEAL IT, THIS IS PART OF IT.
AND WE DON'T REALLY KNOW HOW
LONG THAT LASTS AND WE'D LIKE TO
TEST THAT IN THE LAB TOO.
BUT LATEX FOAM IS DEVOID OF
THESE CHEMICALS.
NON-LATEX MEMORY FOAM IS MADE
OUT OF THEM.
>> COULD YOU EXPLAIN OR MAYBE
MARK, IT SEEMS LIKE THE WORDS
ATOPIC DERMATITIS AND ECZEMA
SOMETIMES ARE ALMOST USED
INTERCHANGEABLY.
COULD YOU EXPLAIN THAT, PLEASE?
>> ATOPIC DETERMINE IS A DERM IF
ECZEMA.
BUT IT'S OVERWHELMINGLY THE MOST
COMMON FORM OF ECZEMA, SO IF
YOU'RE TALKING TO A PATIENT,
THAT'S PROBABLY WHAT THEY MEAN.
BUT YOU KNOW, THERE'S NOMULAR
ECZEMA, THERE'S OTHER KINDS.
SO IT JUST DEPENDS ON THE
AUDIENCE, WHICH ONE YOU WANT TO
USE, BUT THEY OFTEN USE
INTERCHANGEABLY -- THE
DERMATOLOGISTS GET MORE UPSET
THAN THE ALLERGISTS DO WHEN YOU
USE THEM INTERCHANGEABLY, BUT
ATOPIC DERM IS A SUBTYPE OF
ECZEMA.
>> SO WHAT IS ECZEMA THEN?
>> THAT'S A DEEP QUESTION.
I GUESS IT DEPENDS ON WHICH
SPECIFIC SUBTYPE, I MEAN, I
WOULD SAY IT'S AN UMBRELLA TERM
FOR, YOU KNOW, REDNESS,
IRRITATION, THICK ENING OF THE
SKIN, AND IT JUST KIND OF
DEPENDS ON THE BREAKDOWN.
I'M SURE SOMEBODY HAS A BETTER
ANSWER, BUT I DON'T KNOW.
>> SO MARK, WHAT IS THE ROLE OF
EOSEOSINOPHILIA IN ITCHING IN MY
OF THE PATHOLOGIC SPECIMENS FROM
PEOPLE WITH PARTICULARLY CHRONIC
ITCH, EOSINOPHILS ARE A
SIGNIFICANT POPULATION, AND EVEN
MANY OF THOSE PATIENTS HAVE
CIRCULATING EOSIN FEEL YA.
>> SO I DON'T KNOW SPECIFICALLY,
BUT YEAH, I MEAN, IN THE END,
THEY'RE LIKELY TO BE RELEASING
THE TYPES OF MOLECULES THAT I
TALKED ABOUT THAT ACTIVATE THE
NPPB NEURONS, SO IN THE END,
EOSINOPHILS LIKE MAST CELLS HAVE
GRANULES THEY RELEASE AND
OFTEN -- THEY'RE NOT THE SAME,
BUT THEY'RE VERY SIMILAR.
-- IN GENERAL WILL ACTIVATE
THESE NERVE ENDINGS.
SO HISTAMINE AND SEROTONIN ARE
BOTH MONO -- AN ASSORTMENT OF
OTHER LIPID MOLECULES WILL
ACTIVATE.
INCLUDING THEY RELEASED BY A
WHOLE SET OF DIFFERENT INNATE
IMMUNE CELLS.
>> YOU COMMENTED ABOUT THE
IMPORTANCE OF MAST CELLS IN THE
ACUTE REACTION.
DO THEY PARTICIPATE AT ALL IN
CHRONIC ITCH?
>> SO PEOPLE HAVE LOOKED TIME
AND TIME AGAIN TO TRY TO SHOW A
CONNECTION, BUT TH THERE REALLY
ISN'T A CONNECTION.
THE ONLY EXCEPTION IS URTICARIA,
WHICH IS COMPLETELY DRIVEN BY
MAST CELLS.
BUT THAT'S QUITE A DIFFERENT
SKIN CONDITION.
IT'S CHARACTERIZED BY WHEELS, IT
TENDS TO BE PERIODIC SO IT COMES
AND GOES, SO THERE'S WAXES AND
WANES DEPENDING ON THE CONDITION
OF THE PATIENT.
AND FUNDAMENTALLY IT'S
DIFFERENT, IT'S THROUGH THE MAST
CELLS, SO FOR THOSE PATIENTS,
ANTIHISTAMINES WORK, ABSOLUTELY.
BUT FOR ATOPIC DERMATITIS
PATIENTS, MOSTLY THEY DON'T
WORK.
BUT IT'S VERY OFTEN THE FIRST
THING THAT A DERMATOLOGIST WILL
GIVE YOU.
BECAUSE IT'S THE EASIEST THING
TO GIVE YOU AND BASICALLY RULE
OUT THAT -- IT HELPS WITH THE
DIAGNOSIS I GUESS AND IT CHEAP
AND QUICK.
I SEE IAN SMILING BECAUSE HE'S
AGREEING WITH ME.
HE PROBABLY KNOWS BETTER THAN ME
SINCE HE'S THE PHYSICIAN HERE.
>> IAN, YOU WANT TO COMMENT
ABOUT THAT?
>> I AGREE.
I MEAN, PEOPLE CHASE DOWN
HISTAMINE QUITE A BIT, AND IT
JUST IS COMPLETELY IRRELEVANT IN
THE DISORDER WHICH IS KIND OF
INTRIGUING FROM AN ALLERGY
STANDPOINT BECAUSE THE
HISTAMINES CAN HELP A LOT IN
ALLERGIC RHINITIS, BUT ARE
USELESS IN ATOPIC DERM.
LIKE YOU SAID.
>> WE HAD A QUESTION AS TO
WHETHER YOU THOUGHT BACTERIAL
TREATMENT AS A NASAL SPRAY COULD
HELP IN ALLERGIES.
>> YEAH, WE HAVEN'T -- WE'D WANT
TO KNOW WHAT WE THINK IS
DEFICIENT IN THE BACTERIA IN
NASAL SPRAYS, BUT WE DON'T YET
HAVE ANY REAL GOOD STUDIES WHERE
IT WOULD COLLECT THE BACTERIA IN
THE NOSE OF CHILDREN WHO DON'T
HAVE ALLERGIC DISEASE AND THEN
FOLLOW THEM.
THAT WOULD BE THE BEST STUDY TO
TELL YOU WHAT MIGHT BE MOST
PROMISING.
AND I'VE EVEN THOUGHT ABOUT, YOU
KNOW, COULD YOU USE -- COULD YOU
MA ANYBODY LATE THE GUT MICROBES
TO CREATE PROTECTION AGAINST
FOOD ALLERGY, HAVE A BENEFICIAL
ORGANISM THAT DRESSES UP LIKE A
PEANUT SO TO SPEAK IN A WAY
THAT'S A LITTLE MORE PEACE
OFFERING THAN THE PEANUT ITSELF.
SO YEAH, I THINK BACTERIAL
THERAPIES ARE PROMISING AND
THEY'LL EXPAND OVER THE YEARS.
>> SO DEALING WITH THE QUESTION
OF THE VARIED AND SOMETIMES
SELECTIVE DISTRIBUTION, WE HAVE
A QUESTION AS TO WHETHER IT'S
POSSIBLE THAT THERE'S AN
ASSOCIATION BETWEEN THE
INTRAEPIDERMAL NERVE FIBER
DENSITY AND ANY PARTICULAR
REGION OF THE SKIN.
IS THAT A VARIABLE THAT COULD
AFFECT THE SOMEWHAT CURIOUS
DISTRIBUTION OF MANY OF THESE
DISORDERS?
>> CLEARLY THERE ARE SOME
DIFFERENCES IN INNOVATION, BUT I
THINK WHAT IAN WAS ALSO POINTING
TO IS THE EXPOSURE AS WELL.
I MEAN, CLEARLY YOUR BACK
DOESN'T GET EXPOSED TO MANY
DIFFERENT THINGS APART IN WHEN
YOU UNDRESS, WHEREAS YOUR HANDS
ARE FAR MORE LIKELY TO GET --
PERHAPS HAVE SYMPTOMS AND THEN
THEY'RE COMPLETELY EXPOSED ALL
THE TIME AND OFTEN BECOME
IMMERSED AND COVERED IN VARIOUS
DIFFERENT THINGS DURING THE DAY.
SO WITH THAT, THE THING IS, THE
INNOVATION IS DIFFERENT BUT ALSO
THE EXPOSURE IS DIFFERENT, SO I
THINK IT'S HARD TO REALLY SAY IF
ONE THING IS MORE IMPORTANT THAN
ANOTHER.
I MEAN, ONE THING IS FOR CERT
CERTAIN, THE NERVES THAT I
TALKED ABOUT THAT ARE
INNERVATING THE SKIN, THEY ALSO
INNERVATE, FOR INSTANCE, THE --
CAVITY, OTHER PLACES IN THE
BODY, THEY MAY BE INVOLVED IN
DIFFERENT PROCESSES AND
DIFFERENT PLACES, AND CAUSE
DIFFERENT REACTIONS AS WELL.
SO I THINK THAT'S -- IT IS A
COMPLICATED THING AND ALSO THERE
ARE SOME STUDIES THAT HAVE
PROPOSED A REDUCTION IN THE
NUMBER OF FIBERS IS ASSOCIATED
ACTUALLY WITH INCREASED ITCH.
WHICH IS LARD TO REALLY
UNDERSTAND WHY THAT WOULD BE.
THE PROPOSAL IS THAT THIS IS THE
LEVEL OF THE SPINAL CORD, WHERE
THERE'S -- AND CLEARLY THERE'S A
LOT MORE TO BE UNDERSTOOD ABOUT
HOW THE DIFFERENT NERVES
ACTUALLY INTERACT WITH EACH
OTHER.
SO I MEAN, AS SOMEBODY WHO OFTEN
GETS OR HAS LARGE REACTIONS TO
MOSQUITOES, I KNOW THAT IF, FOR
INSTANCE, I PUT AN ICE CUBE ON
MY HAND AFTER A MOSQUITO BITE, I
DON'T SCRATCH, AND THAT'S A
REALLY EFFECTIVE WAY TO
BASICALLY COUNTER STIMULUS, SO
THE FACT THAT THERE MAY BE THIS
INTERACTION BETWEEN DIFFERENT
NERVE FIBERS IS NOT A WILD IDEA.
>> MARK, YOU MADE THE STATEMENT
THAT ITCH IS FUNDAMENTALLY A
DISEASE OF THE BRAIN.
NOW, THE VARIOUS NEUROLOGIC
CONDITIONS AFFECTING THE BRAIN
OR THE SPINAL CORD INTERFERE OR
PREVENT THE PERCEPTION OF ITCH
BY A PATIENT?
DO PEOPLE WHO HAVE A VOAB ROW
VASCULAR ACCIDENT, HEMIPLEGIA?
>> SO I'M DOING THIS AT THE
MOMENT, SCRATCHING MYSELF,
BECAUSE YOU'LL PROBABLY FIND
THERE'S SOME PEOPLE IN THE
AUDIENCE WHO WILL ACTUALLY BE
FOLLOWING ME.
DOING THAT, AND IT
ACTUALLY BEEN STUDIED IN
MONKEYS, THAT IT'S ACTUALLY A
MIRROR BEHAVIOR.
SO IF YOU HAVE -- IF YOU SHOW A
VIDEO TO MONKEYS OF ANOTHER
MONKEY SCRATCHING, A VERY LARGE
NUMBER OF THEM WILL START
SCRATCHING.
SO THIS TELLS YOU THAT IT IS --
THE BRAIN.
BASICALLY IF YOU THINK OF
SOMETHING VERY ITCHY, IT'S
ACTUALLY PRETTY COMMON THAT YOU
WILL ACTUALLY START SCRATCHING.
SO CLEARLY THERE'S A GREAT DEAL
OF SUPPRESSION FOR ITCHING AND
FOR ALL KIND OF DIFFERENT
REASONS.
SO VERY OFTEN I WILL SCRATCH --
PERHAPS WHEN I'M NEWER VEST,
IT'S JUST SOMETHING THAT YOU DO.
SO FROM THAT EXAMPLE, WHAT I'M
SAYING IS THAT THERE MAY BE
CENTRAL ITCH, WHAT A
NEUROBIOLOGIST WOULD CALL
CENTRAL ITCH, AND THIS IS NOT
UNUSUAL TO THINK ABOUT,
BECAUSE -- AND BECAUSE FOR
INSTANCE, THERE'S NEUROGENIC
PAIN, SO YOU CAN HAVE PATIENTS
THAT HAVE NO SYMPTOM AT ALL,
THEY SEEM TO BE COMPLETELY
RECOVERED AFTER AN INJURY, BUT
THEY STILL HAVE PAIN.
SO IT'S THOUGHT THAT THIS COULD
ALSO OCCUR FOR ITCH AS WELL.
IT'S PROBABLY JUST A LOT LESS
COMMON.
SO ONE OF THE SYMPTOMS OF
SHINGLES, FOR INSTANCE, IS LESS
COMMON BUT SOME PEOPLE ACTUALLY
DEVELOP CHRONIC ITCH AFTER
SHINGLES.
SO THIS IS SOMETHING THAT
BECOMES PERMANENT AND THEY DON'T
GET RID OF IT.
AND THAT'S PURELY NEUROGENIC.
THERE'S NOTHING HAPPENING TO
THEIR SKIN.
THERE'S NO OTHER REASON THAT THE
NERVE FIBERS HAVE BEEN ACTIVATED
AND STAY ACTIVATED.
>> SO IF SOMEONE HAS A
HEMIPLEGIA AND ECZEMA OR ATOPIC
DERMATITIS, DO THEY ITCH IN THE
DEINNERVATED PORTION OF THEIR
BODY?
>> PROBABLY NOT.
I'VE NOT LOOKED INTO THAT, BUT I
WOULD BE SURPRISED IF THEY DID,
BECAUSE YOU NEED TO HAVE THE
CONNECTION.
AND ITCH IS LOCATION-SPECIFIC.
SO THERE'S THE CONNECTIONS INTO
THE CENTRAL NERVOUS SYSTEM ARE
DEFINED, I MEAN, THAT'S WHY YOU
KNOW YOU'VE BEEN -- A MOSQUITO'S
GOT YOUR LEFT HAND RATHER THAN
YOUR RIGHT HAND.
YOU KNOW WHERE THE CRITTERS GOT
YOU.
>> SO IAN, YOU'RE THE CLINICIAN.
DO HEMIPLEGIC PATIENTS ITCH IF
THEY HAVE ATOPIC DERMATITIS?
>> I HAVEN'T STUDIED THAT
DIRECTLY, BUT I AGREE WITH MARK,
I'D SAY NO.
I MEAN, YOU HEAR ABOUT
NEUROPATHIC PAIN SYNDROMES, BUT
I'VE NEVER HEARD ANYBODY SAY
THAT THEY HAVE ITCH.
IF THEY'RE GENUINE, THEY DENER
SERRATED IN THAT AREA, THEY
DON'T HAVE ITCH EITHER.
>> SO MARK, ARE THERE WAYS OF
DIRECTLY INHIBITING MPBB?
>> SO I DIDN'T GO INTO THIS IN
MY TALK.
SO WE TOGETHER WITH
COLLABORATORS IN NCATS ACTUALLY
PERFORMED A HIGH-THROUGHPUT
SCREEN TO TRY AND IDENTIFY
ANTAGONISTS TO THE NPPB
RECEPTOR, THIS IS A RECEPTOR
CALLED N PB1, AND WE'VE
IDENTIFIED ANTAGONISTS AND AT
LEAST IN ANIMAL STUDIES, THEY
WORK.
THEY PREVENT THE ANIMAL
SCRATCHING TO PRURITOGENS.
SO IN THEORY, YES, THAT WOULD BE
A WAY THAT YOU COULD ACTUALLY
PREVENT ITCH.
I MEAN, ONE OF THE REASONS WHY
WE THOUGHT OF THAT AS A
POTENTIAL WAY IS THAT IT WOULD
CIRCUMVENT THE NEED TO DEVELOP
ANTAGONISTS TO INDIVIDUAL
CHEMICALS TO DIFFERENT
RECEPTORS, BECAUSE THIS
TRANSMITTER IS CENTRAL TO
TRANSMISSION OF ALL THE ITCH
SIGNALS.
SO THAT'S SOMETHING THAT'S STILL
UNDER DEVELOPMENT, BECAUSE THE
MOLECULES THAT WE IDENTIFIED,
FIRST OF ALL, ARE NOT HIGH
AFFINITY AND NOT ITCH SPECIFIC
SO WE KNOW THERE CAN BE SOME
EFFECTS ON OTHER RECEPTORS.
>> SO WHAT IS THE PHYSIOLOGIC
PURPOSE IN HAVING ITCH
RECEPTORS?
>> SO YOU'RE ASKING ME TO
SPECULATE NOW, AND I'M HAPPY TO
SPECULATE, BUT SO THE AUDIENCE
UNDERSTANDS, THIS IS NOT KNOWN,
SO THIS IS JUST ME MAKING THINGS
UP.
I MEAN, CLEARLY, I WOULD SAY
ITCH CAN BE THOUGHT OF AS AN
ANTIPARASITIC DEFENSE.
IT'S NOT AN ACCIDENT THAT MOST
OF THE NATURAL PARASITES THAT
TRY TO PREY ON US MAKE US
SCRATCH, AND IF YOU THINK ABOUT
SCRATCHES, WE'RE REMOVING THE
VERY OUTER LAYERS OF THE SKIN,
SO THIS COULD BE QUITE AN
EFFECTIVE WAY TO POTENTIALLY --
FIRST OF ALL WE MOVE THE
PARASITE, BUT THEN WE MOVE
ANYTHING ELSE THAT MIGHT BE IN
THAT TOP LAYER OF THE SKIN.
THE OTHER THING THAT I'LL POINT
OUT IS THAT IT IS THAT VERY TOP
LAYER THAT THE ITCH NEURONS
ACTUALLY INNERVATE, THAT TOP
LAYER IS NOT INNERVATED BY THE
NEURONS THAT ARE INVOLVED IN
DETECTING PAINFUL STIMULI,
THEY'RE MUCH DEEPER, VERY MUCH
MUCH MORE IN THE DERMIS, AND WE
ALL KNOW THAT RECENT WHY WE
OFTEN SCRATCH AND THEN WE STOP
SCRATCHING IS WE'VE ACTUALLY GOT
DOWN TO THAT DEEPER LAYER AND
ITCH IS REPLACED BY PAIN.
AND PAIN EVOLUTIONARILY, WE
WOULD STOP SCRATCHING.
SO THIS COULD BE A MECHANISM FOR
REMOVAL OF EGG TO PARASITES.
>> THERE'S A QUESTION ABOUT
WHETHER -- LET'S SEE.
AS SOMEONE WHO HAS ATOPIC
DERMATITIS AND IS CURRENTLY ON
DUPIXENT, IN MY EXPERIENCE, THE
ITCH IS REALLY FOCUSED ON WHERE
THE NERVES ARE.
ENDS ARE ALWAYS THE WORST, MOST
LIKELY DUE TO ALL THE NERVES IN
THE AREA.
I FIND THAT LOCATIONS WITH FEWER
NERVES ARE SIGNIFICANTLY LESS
ITCHY.
STOMACH, BACK, BUT STILL ITCHY
IF THERE'S AN ALLERGEN
TRIGGERING MY ECZEMA.
WHAT DO YOU THINK ABOUT THAT?
IS THAT A COMMON OBSERVATION?
>> I DON'T KNOW IF PEOPLE PEGGED
TO THE NERVES, BUT CERTAINLY
HAND DISEASES MOST COMMON FOR
ADULTS, BUT THEN AS SHOWN IN THE
PICTURES, IT'S MORE EXTREMITIES
ARE GOING TO BE MORE AFFECTED
THAN YOUR CHEST AND BACK, SO I
DON'T KNOW HOW -- YOU CAN'T
NECESSARILY SORT THOSE APART
DIRECTLY, NERVE CONCENTRATION
VERSUS EXPOSURE OF THOSE
PARTICULAR AREAS, KIND OF LIKE
DR. WIN WAS ALREADY SAYING.
BUT YES, THAT'S A COMMON
PRESENTATION, PARTICULARLY FOR
ADULTS, IS THE HAPPENED.
-- THE HAND.
>> AND I'LL ADD TO WHAT IAN HAS
SAID THAT AS I POINTED OUT, THIS
IS AN ITCH-SCRATCH CYCLE, SO
CLEARLY, YOUR HANDS, YOU HAVE
ACCESS TO, TO SCRATCH.
IF YOU DON'T SCRATCH, IT WILL
PROBABLY CLEAR UP OR BE A LOT
LESS.
AND THAT'S NOT TO SAY THAT IT
EASY TO STOP SCRATCHING, BUT
CLEAR LIE YOU'RE NOT GOING TO BE
SCRATCHING YOUR BACK, ALSO
BECAUSE, SOCIALLY, THAT WOULD BE
SORT OF A STRANGE THING TO BE
DOING, WHEREAS SCRATCHING YOUR
HANDS, YEAH, YOU CAN DO IT UNDER
THE TABLE AND BE -- MAKE THE
ITCH WORSE, INCREASE THE
INFLAMMATION, AND AS I WAS
SAYING, IT'S THE ITCH-SCRATCH
CYCLE.
AND I'VE HEARD FROM SOME
PHYSICIANS, IN REALLY BAD CASES
OF PRURITIS, ONE TREATMENT IS
ACTUALLY TO BUNDLE THE PATIENT
IN BANDAGES, PREVENT THEM FROM
SCRATCHING, AND THIS ACTUALLY IS
VERY EFFECTIVE.
>> WHY NOT JUST WEAR GLOVES OR
SOME SOFT --
>> SO THAT'S EXACTLY WHAT
KIDS -- I THINK -- I'VE HEARD
THAT AT LEAST YOU TRIM THE NAILS
AND YOU PUT SOME LITTLE GLOVES
ON, ON THE KIDS, AND THIS WILL
STOP THEM FROM SCRATCHING
EFFECTIVELY AND PREVENT -- I HAD
NO -- IN RESEARCH ANIMALS, OFTEN
THE VETERINARIAN WILL ACTUALLY
TRIM THE NAILS OF THE ANIMALS
AND THIS WILL ACTUALLY REDUCE
THE AMOUNT OF DAMAGE THAT THE
ANIMALS INFLICT TO THEMSELVES.
SO THIS IS A REAL THING THAT YOU
ACTUALLY STIMULATE MORE
INFLAMMATION IF YOU SCRATCH
MORE, AND THAT'S JUST GOING TO
CAUSE MORE ITCH.
>> IAN, THERE ARE STUDIES ON THE
CHANGE IN THE MICROBIOME WITH
ADVANCING AGE, PARTICULARLY VERY
ADVANCED AGE.
AND DP ARE IS THERE ANY
RELATIONSHIP OR ANY INFORMATION
ON THE ROLE OF LET'S CALL IT
POLLUTION IN THESE OLDER
ADUME --PARTICULARLY IN LIGHT OE
CHANGING PLY MIE MICROBIOME WI?
>> MOST OF THE MICROBIOME
STUDIES I'VE SEEN HAVE SUGGESTED
YOU GET A RAPID CHANGE FROM
BIRTH ALL THE WAY THROUGH AND A
STEADY CHANGE ALL THE WAY TO 26.
AND 26 AND FORWARD, IT TENDS TO
BE FAIRLY STABLE.
SO I HAVEN'T SEEN DRAMATIC
CHANGES WITH AGE.
THE BIGGEST PROBLEM IS MOST OF
THE GUT MICROBIOME STUDIES ARE
GOING TO BE ENTIRELY DEPENDENT
ON DIET, SO YOU START TO GET OF
THE AGE WHERE DIETARY STAGES --
EXPECT TO SEE MICROBIOME
CHANGES.
THERE HAS NOT BEEN VERY MUCH
EVALUATION OF MAYBE THE TERM
WOULD BE FOOD POLLUTION.
OF WHAT DOES -- WHAT DO
PROCESSED INGREDIENTS DO TO THE
MICROBIOME, WHAT CONTAMINANTS DO
TO THE MICRO MICROBIOME.
-- WILL KILL OFF GUT BACTERIA
TOO, IS SOMEWHAT THEY ARE BUILT
TO PREVENT ORGANISMS FROM
GROWING IN WHATEVER PRODUCT YOU
PUT THEM IN.
AND SO WHEN YOU START DRINKING
THESE THROUGH WATER
CONTAMINATION, BECAUSE NOT --
NOT EVERY MUNICIPALITY WILL
FILTER OUT EVERY SINGLE CON TAM
CONTAMINANT.
OR IF THEY'RE INTENTIONALLY PUT
INTO FOODS TO PREVENT MICROBIAL
OVERGROWTH, THEY WILL WIPE THAT
OUT AS WELL.
SO I HAVEN'T SEEN A STRONG
SIGNAL FOR MICROBIOME IN AGING.
IF THERE IS ONE, I WOULD BET THE
OVERWHELMING MAJORITY OF THAT
SIGNAL WILL BE IMMEDIATELY TIED
TO -- AND I DON'T SEE ANYWHERE
NEAR THE RESEARCH THAT WE NEED
FOR WHAT DO DIETARY FACTORS DO
TO THE MICROBIOME AND TO START
TO GET VERY SPECIFIC.
YOU CAN FIND ONES FOR LIKE OH,
PUT SOMEBODY ON AN
ULTRAPROCESSED DIET, KETO DIET
OR VEGAN DIET SO YOU SEE THESE
SWEEPING DIFFERENCES BUT I FEEL
LIKE THE NEXT PHASE IS GOING TO
BE SPECIFIC INGREDIENT AND
SPECIFIC EXPOSURES TO SEE WHAT
HAPPENS.
>> SO IAN, WHAT DO YOU THINK IS
HAPPENING AT AGE 2, 3 OR 4, THAT
CHANGES THE PHENOTYPE WITH
RESPECT TO ATOPIC DERMATITIS?
>> I THINK COMBINING WHAT MARK
IS TALKING ABOUT, MY BIGGEST
WORRY WOULD BE SOME SORT OF
NEUROLOGIC PRIMING.
THIS IS THE TIME FOR
NEURODEVELOPMENT, IMMUNE
DEVELOPMENT, AND YOU FORCE THE
CHILD TO APPROPRIATELY RESPOND
TO A VERY INAPPROPRIATE STIMULUS
OF THESE PARTICULAR TOXINS THAT
THEY'RE GETTING.
AND THAT WILL EVENTUALLY GET
BUILT INTO SYSTEMS OF
PARTICIPATING AND POTENTIALLY
OVERREACTING.
I THINK IT MORE CLEAR FOR ASTHMA
IN THE LUNGS, WHERE CHRONIC
EXPOSURE CREATE A LOT OF
NEUROGENIC RESPONSE IN THE LUNG
AND THE NEXT EXPOSURE WILL
TRIGGER A MORE ROBUST RESPONSE
FROM ANYBODY ELSE, BUT I THINK
YOU ARE TRAINING THE IMMUNE
SYSTEMS AND THE PRIF PAL NERVOUS
SYSTEM TO RESPOND TO THESE
CHEMICALS, AND I THINK THAT THAT
IS A HARD LESSON TO UNLEARN.
OVER THE COURSE.
NOW, ONE OF THE BIGGEST
MYSTERIES IN ECZEMA IS WHY IS IT
THAT IN EVERY SOCIETY ON THE
PLANET, THE VAST MAJORITY OF
CHILDREN WITH ECZEMA WILL
EVENTUALLY OUTGROW IT.
OUTGROWING IT BEING A VERY
POORLY USED TERM, BUT THE SKIN
WILL CLEAR UP AND THEY MIGHT BE
LEFT WITH ALLERGIES AND ASTHMA
AND SO FORTH.
THERE'S NOT REALLY WELL-KNOWN, I
WOULD START TO THEN QUESTION
ABOUT NEUROLOGIC -- WHERE WE
TALKED ABOUT BEFORE, RECEPTOR
CONCENTRATIONS IN DIFFERENT PART
OF THE BODY, WE HAVE ONE STUDY
WHERE WE'RE TRYING TO LOOK AT
THE DIFFERENT NEURORECEPTORS AS
A MOUSE AGES, YOU OBVIOUSLY
CAN'T DO THIS IN HUMANS, BUT
FROM BIRTH ALL THE WAY FORWARD
TO SAY LIKE IS THERE A POINT
WHERE YOU JUST -- YOUR NEWER
LOGIC PRESENTATION CHANGES AS
YOU AGE.
OTHER PEOPLE HAVE JUST
HYPOTHESIZED THE STIN SCIN JUST
GETS THICKER AS YOU GO FROM 2 TO
10 TO 25 AND SO FORTH.
BUT THAT WOULD BE, I THINK
IMMUNOLOGIC AND NEUROLOGIC
TRAINING.
>> WE HAVE THE QUESTION ABOUT
RELATIONSHIP OF MITOCHONDRIA TO
THESE PROCESSES.
I REALIZE THAT'S A PRETTY BIG
TOPIC, BUT IS THERE ANY EVIDENCE
LINKING MITOCHONDRIAL DYNAMICS
OR METABOLISM TO ATOPIC
DETERMINE TIGHT OR IN
RELATIONSHIP TO THE NEURAL
PATHWAYS?
>> I CAN ANSWER FOR ATOPIC DERM.
IT'S BEEN PRETTY EXHAUSTIVELY
EVALUATED -- WE HAVE TOPICAL
STEROID WITHDRAWAL THAT IS OFTEN
CONFUSED FOR ATOPIC DERMATITIS,
SO IT LOOKS A LOT LIKE ATOPIC
DERM.
AND THAT INVOLVES MITOCHONDRIAL
DEFECTS THAT RUN THROUGH THE
COAL NER JIG PCHOLINERGIC PATHW.
BUT FOR YOUR ROUTINE ATOPIC
DERMATITIS PATIENT WALKING
AROUND, THERE HAS NOT BEEN ANY
STRONG SIGNAL IMPLICATING
MITOCHONDRIA IN ANY WAY.
>> LET SEE.
>> LET'S SEE.
WE HAD ANOTHER INTERESTING -- SO
DO EITHER OF YOU SEE A WAY IN
WHICH THESE TWO TYPES OF
RESEARCH THAT EACH OF YOU ARE
DOING CAN BRIDGE OR AFFECT YOUR
BLANS PLANS FOR FUTURE RESEARCHN
COLLABORATIVELY?
ARE THERE THREADS IN BOTH THAT
TEND TO MAYBE INTRODUCE NEW
IDEAS OR DO WE HAVE A WAYS TO GO
YET?
>> I THINK ONE OF THE THINGS
THAT IAN TALKED ABOUT WAS -- AND
I THINK IT WAS BROUGHT UP IN A
QUESTION AS WELL, WAS THE -- SO
WHAT MIGHT BE THE RECEPTORS FOR
THE SETTING OF SOME OF THESE
THINGS UP.
AND CLEARLY NOW WE'RE TO SAY IN
THIS GENOMIC AGE THAT BASICALLY
A LOT OF THIS INFORMATION IS
PUBLICLY AVAILABLE.
SO BASICALLY IAN DOESN'T REALLY
NEED ME.
ALL HE NEEDS IS A COMPUTER AND
SOME DIRECTION OF WHERE TO LOOK.
SO WHICH I THINK IS A GREAT
DEMOCRATIZATION OF SCIENCE.
I THINK THAT'S REALLY A
FANTASTIC THING THAT'S HAPPENED
IN THE LAST 10, 20 YEARS THAT
WE'RE NOW FORCED TO MAKE ALL OUR
DATA AVAILABLE, AND THAT MAKES
IT POSSIBLE -- AS YOU POINTED
OUT AT THE VERY BEGINNING,
SOMETIMES SCIENCE CAN BECOME
SILOED, BUT THIS IS ACTUALLY ONE
OF THE WAYS THAT I THINK THIS
HAS ACTUALLY BEEN BROKEN.
AND ANOTHER ILLUSTRATION OF THAT
IS THAT, FOR INSTANCE, I'M NOT
AN IMMUNOLOGIST, BUT I WAS ABLE
TO ACCESS DATA FROM
IMMUNOLOGISTS AND WHEN I WAS
LOOKING AT -- CELLS EXPRESS
ONCOSTATIN M AND THE PATIENT
GROUPS THAT ARE ALL PUBLICLY
AVAILABLE DATA, WE CAN ACTUALLY
ANALYZE TO SEE WHICH
INTERLEUKINS ARE ACTUALLY
ELEVATED AND SEARCH FOR NEW
POTENTIAL TARGETS.
SO I WOULD BE QUITE HAPPEN TO
POINT IAN IF HE NEEDS ANY HELP
IN THE RIGHT DIRECTION FOR THOSE
THINGS.
AND I THINK THAT'S WONDERFUL,
THAT THAT CAN BE DONE.
>> SO IAN, DO YOU HAVE A --
>> I AGREE, I THINK SEARCHING
FOR DIFFERENT CHEMICALS AND HOW
THEY WOULD ACTIVATE OR INHIBIT
THE RECEPTORS AND THE PROCESSES
THAT MARK TALKED ABOUT AND THEN
I THINK WHEN YOU TALK TO A
PARENT WITH ATOPIC DERM AND YOU
SAY WHAT ARE YOUR NUMBER ONE
CONCERNS, NUMBER ONE THROUGH 10
IS ITCH.
THEY WANT THE RASH TO GET
BETTER, BUT ITCH MAKING THEIR
LIFE MISERABLE IS BY FAR THEIR
NUMBER ONE CONCERN.
AND SO IF THERE ARE NEW
THERAPIES THAT MARK'S GROUP IS
DISCOVERING THAT ARE GOOD AT
BLOCKING THE ITCH PART, EVEN IF
IT DID NOTHING TO THE RASH AND I
AGREE WITH MARK THAT YOU'D BREAK
THE ITCH-SCRATCH CYCLE SO YOU
SHOULD IMPROVE THE RASH ANYWAY,
BUT EVEN JUST BLOCKING THE ITCH,
PATIENTS WOULD TRIP OVER
THEMSELVES TO GO GIVE MARK A
HIGH FIVE.
SO I THINK IT IS A PATIENT
POPULATION THAT IT WOULD BE GOOD
TO VALIDATE SOME OF THE
MECHANISMS THAT HE TALKED ABOUT.
>> I'M ALL FOR THAT.
YOU WANT TO SAY A FEW WORDS,
IAN, ABOUT THE PRURITIS
ASSOCIATED WITH LIVER DISEASE,
LIKE PBC, WHAT'S YOUR VIEW OF
THE MECHANISM THERE?
>> I HAVE NO IDEA.
THAT'S WAY OUTSIDE MY
WHEELHOUSE.
THAT ONE IS FOR MARK.
>> OKAY, I CAN TAKE A STAB AT
THAT.
SO I CAN TALK ABOUT OTHER
PEOPLE'S RESEARCH, IT'S NOT
SOMETHING THAT WE'VE WORKED ON.
THERE HAVE BEEN SOME -- I MEAN,
THERE'S BEEN A FEW PAPERS WHICH
HAVE SUGGESTED THAT ONE OF THE
FAMILIES OF RECEPTORS I TALKED
ABOUT, IN IS THE MAST-RELATED G
PROTEIN RECEPTORS MIGHT BE THE
RECEPTORS FOR SOME OF THE -- SO
THE COMPOUNDS THAT ARE ELEVATED
IN THE BLOOD THAT ARE ASSOCIATED
WITH THOSE LIVER CONDITIONS.
I CAN'T REMEMBER EXACTLY THE
NAMES OF THEM.
I'M BLANKING, I DON'T REMEMBER
EXACTLY WHAT THE CHEMICALS ARE,
BUT THEY ACTIVATE THE MAST
RELATED G PROTEIN -- RECEPTORS.
>> WELL, LISTEN, ON BEHALF OF A
LARGE NUMBER OF PEOPLE WHO ARE
WATCHING THIS PROGRAM AND MANY
MORE WHEN THEY DOWNLOAD IT, I
WANT TO THANK BOTH OF YOU FOR
OPENING OUR EYES TO SOME REALLY
VERY EXCITING DEVELOPMENTS, BOTH
FROM THE STANDPOINT OF THE
NEUROSCIENCE, THE IMMUNOLOGY,
AND THE MICROBIOLOGY.
IT'S GOING TO BE VERY EXCITING
TIMES AHEAD, AND HOPEFULLY FOR
THE BENEFIT OF PEOPLE WHOSE
LIVES ARE MADE MISERABLE BY
PARTICULARLY CHRONIC ITCHING,
THAT HAS A GREAT DEAL OF
INTEREST.
SO THANK YOU VERY, VERY MUCH.
THIS HAS BEEN AN EXCITING
AFTERNOON.
AND I THINK WE HAVE RUN OUT OF
OUR TIME.
SO WE HAVE TO END THIS SESSION.
THANK YOU AGAIN.
>> YOU'RE WELCOME.
AND I THINK WE BOTH ENJOYED IT.
>> YEP.
TAKE CARE.
>> OKAY.