>> GOOD MORNING.
I'VE SEEN A NUMBER OF SLIDES UP
THAT SAY NIAID BUT THIS IS A
JOINT CONFERENCE WORKSHOP
SPONSORED BY NIAID, NIA, NIDCR.
AS YOU HEARD, I'M THE ACTING
DIRECTOR OF NIAID.
PEOPLE LOOKING FOR THE SUCCESSOR
FOR DR. FAUCI ARE IN THE ROOM, I
APPRECIATE THAT THEY HAVE BEEN
WORKING RAPIDLY.
THANK YOU.
BY WAY OF BACKGROUND, DO WE HAVE
MY SLIDES?
THE WORKSHOP FOCUS ACCORDING TO
THE INFORMATION I RECEIVED BY
E-MAIL, KNOWLEDGE OF IMMUNE
FUNCTION DURING AGING, AND
IMPROVED METHODS TO DEFINE
IMMUNOLOGIC STATES, DOES THAT
COME UP ON MY SCREEN?
THERE WE GO.
SINGLE CELL TECHNOLOGY FOR
INTERROGATION OF IMMUNE CELLS,
AND MECHANISMS OF IMMUNE AGING
AND CHRONIC DISEASE.
SORRY.
NOT RESPONDING.
CAN I GO BACK?
NOW FORWARD ONE.
OKAY.
SO, YES, THIS IS A JOINT
CONFERENCE, IT REFLECTS MANY
YEARS OF COOPERATION BETWEEN OUR
INSTITUTES GOING BACK TO 2009,
WITH AN RFA FOR REJUVENATING THE
AGED IMMUNE SYSTEM BETWEEN NIAID
AND NIA, AND THEN REPEAT IN 2014
AGAIN NIAID AND NIA, IMMUNITY IN
THE ELDERLY, AND THEN WE WERE
JOINED BY NIDCR WITH IMMUNITY IN
THE ELDERLY IN 2019, AND THEN AN
RFA THAT IS GOING TO COME TO
FRUITION IN 2024 BUT
APPLICATIONS HAVE BEEN SUBMITTED
ALREADY, AGAIN INVOLVING THE
THREE INSTITUTES.
THIS IS THE FUNDING FOR AGING
AND IMMUNITY WHICH SHOWS A
PRETTY ROBUST INVESTMENT OF OVER
$100 MILLION BY ESPECIALLY NIA
BUT ALSO NIAID, SO IN TERMS OF
SOLICITED RESEARCH AND AMOUNT OF
MONEY THAT'S BEEN PUT INTO THIS
AREA, I THINK IT IS CLEAR THAT
THERE'S A SERIOUS COMMITMENT ON
THE PART OF NIH TO THIS ISSUE OF
IMMUNITY IN THE AGING
POPULATION.
NEXT SLIDE.
THEN TO HIGHLIGHT WHAT WE'VE
LEARNED IN COVID THE PARTICULAR
PROBLEMS OF AGING, WHERE THE
HIGHEST AT-RISK GROUP WERE THOSE
OVER 65.
WE ALSO ACCORDING TO THIS
ARTICLE THINK WE'VE LEARNED THAT
YOU CAN IDENTIFY MARKERS THAT
SHOW THERE ARE SOME PEOPLE WHO
ARE TRULY AT RISK AS THEY AGE
AND OTHERS WHO SHOW RESILIENCE.
SO THERE'S LOTS TO LEARN ABOUT
WHAT IS HAPPENING IN THE AGING
IMMUNE SYSTEM.
LET ME CONCLUDE, NEXT SLIDE, BY
JUST THANKING THE ORGANIZING
GROUP WHO PUT IN I KNOW A LOT OF
THOUGHT, A LOT OF EFFORT AND
TIME TO MAKE THIS WORKSHOP
POSSIBLE AND IT'S FUN TO BE BACK
IN PERSON.
THANK YOU VERY MUCH.
>> THANK YOU VERY MUCH.
NOW DR. RICHARD HODES WILL GIVE
REMARKS.
>> TRIGGERED BY THE SLIDES HUGH
WAS SHOWING, 2009 THE TITLE OF
THE SLIDES REFLECTS, IF YOU
WILL, THE LIMITED STATUS OF WHAT
WE UNDERSTOOD OR TALKED ABOUT IN
TERMS OF AGING VERSUS THE IMMUNE
SYSTEM.
BOTH DISCIPLINES WERE MOVING
FORWARD BUT WE HAD A MEETING TO
TRY TO FIND OUT WHY, THAT WAS
THE FOCUS FOR OUR DISCIPLINES.
SINCE THEN IT'S REMARKABLE.
IN THE FIELD OF IMMUNOLOGY MORE
SOPHISTICATED MOLECULAR CELLULAR
PROBES, SAME THING HAPPENING IN
AGING RESEARCH AND CONVERGENCE
HAS BEEN SPECTACULAR SO A LOT OF
WHAT GOES ON IN AGING NOW IS
ATTRIBUTING TO INFLAMMATORY
IMMUNE RESPONSES, AMONG THE
HALLMARKS OF AGINGI
IMMUNOSENESCENCE APPEAR TO BE
DRAMATICALLY OCCURRING IN THE
IMMUNE SYSTEM, EVEN FINDINGS
THAT SUGGEST THE WHOLE ANIMAL
THAT MAY BE THE CHANGES
OCCURRING IN THE IMMUNE SYSTEM,
THOSE WRITE SENTINEL AND CENTRAL
TO THINGS IN THE WHOLE BODY,
IT'S AN EXTRAORDINARY AND
EXCITING TIME, THE CONVERGENCE
REFLECTED IN FUNDING WITH GOOD
SCIENCE BEING PROPOSED, I'M
EXCITED TO BE HERE AS PART OF
THIS COLLABORATION ACROSS THE
THREE INSTITUTES AND SHARE WITH
YOU THE NEXT AGE OF EXCITING
SCIENCE.
THAT'S ALL.
LET IT BEGIN.
>> THANK YOU VERY MUCH, DR.
HODES.
NOW PREETHI CHANDER WILL SPEAK
ON BEHALF OF THE DIRECTOR OF
NIDCR, UNABLE TO BE HERE TODAY.
>> YES, GOOD MORNING.
LIKE MERCY SAID, UNFORTUNATELY
ALREADY RENA D'SOUZA COULDN'T
MAKE IT, I'M THE PROGRAM
OFFICER, I MANAGE BIOLOGY AND
IMMUNOLOGY PROGRAM, GLAD TO BE
PARTICIPATING IN THIS GREAT
WORKSHOP.
SO SINCE WE'RE ONE OF THE FEW
ORGAN-SPECIFIC -- IS THERE A WAY
TO GO BACK?
I WANT YOU TO KEEP IN MIND ABOUT
THE PERIPHERAL TISSUES AS YOU
THINK AND PARTICIPATE IN THE
DISCUSSIONS IN THE NEXT FEW
DAYS.
SO, I COME FROM ORAL HEALTH
PERSPECTIVE, I WANTED TO SAY
THAT AS THE AGING POPULATION OF
65 AND OLDER ARE INCREASING
RAPIDLY, THE UNIQUE THING ABOUT
THIS POPULATION IS THEY ARE BY
FAR THE MOST DIVERSE IN TERMS OF
RACE/ETHNICITY, SOCIOECONOMIC
STATUS, HENCE THE HEALTH AND
FUNCTIONAL STATUS THAT WE'RE
GOING TO SEE.
I WANT TO DRAW YOUR ATTENTION
TODAY TO THE ORAL HEALTH IN
AMERICA REPORT RELEASED IN 2021.
IT INCLUDES INPUT FROM MULTIPLE
CONTRIBUTORS, AND EXAMINES OVER
TWO DECADES OF RESEARCH SINCE
THE LAST U.S. SURGEON GENERAL
REPORT FROM 2000.
IT'S ORGANIZED ACROSS THE
LIFESPAN, CHALLENGES,
OPPORTUNITIES, BUT MOST
IMPORTANTLY ARTICULATES FUTURE
PROVISION AND CALL TO ACTION.
THANK YOU.
ONE OF THE SECTIONS IS
SPECIFICALLY DEDICATED TO ORAL
HEALTH IN OLDER ADULTS.
IF YOU HAVE TIME, TAKE A LOOK.
AS THE POPULATION KEEPS
INCREASING AND THERE ARE
INCREASED EXPECTATIONS OF ORAL
HEALTH QUALITY OF RESEARCH,
THERE ARE MORE OLDER ADULTS
SEEKING DENTAL CARE, THAT'S ORAL
HYGIENE AND WITH THAT INCREASE
IN CHRONIC DISEASES IN THIS
PARTICULAR POPULATION THERE'S
INCREASED NEED TO ADDRESS ORAL
HEALTH IN THE DISABLED OR
CARE-GIVING SETTING.
SO, THE KEY CHALLENGES THAT THIS
POPULATION FACES WITH REGARD TO
ORAL HEALTH IS THAT AS WE GET
OLDER THERE'S ALSO A CHALLENGE
WITH ACCESS TO DENTAL CARE IN
TERMS OF INSURANCE AND WITH THAT
AND INCREASING PROPENSITY OF
SYSTEMIC DISEASE AND CHRONIC
INFLAMMATION AND MEDICATIONS
THAT ARE PRESCRIBED TO THIS
POPULATION THERE'S INCREASED
PROBLEM OF DRY MOUTH IN OLDER
ADULTS, ALSO INCREASE IN
DISEASES THAT HAVE ORAL
MANIFESTATION.
I WANT TO LEAVE WITH YOU A
COUPLE ADVANCES TO KEEP IN MIND
THROUGH THE NEXT TWO DAYS.
SO, THIS IS FROM JONATHAN AHM
WHO ASKED THE QUESTION IS IT
POSSIBLE TO TREAT GUM DISEASE BY
TARGETING AGING?
WHAT HE FOUND IS THAT TREATMENT
WITH RAPAMYCIN IN MICE
REJUVENATES THE ORAL MICROBIOME
TO A MORE YOUTHFUL COMPETITION,
ATTENUATES INFLAMMATIONS,
INCREASES REGENERATION.
ON THE RIGHT IS THE BIG STUDY
THE BUFFALO STUDY LOOKING AT
POST-MENOPAUSAL WOMEN, AND
LOOKED AT CORRELATING
ASSOCIATION OF MICROBIOME WITH
ALVEOLAR BONE LOSS AND
PERIODONTITIS.
THEY FOUND YEARS BEFORE
PERIODONTAL BONE LOSS,
MICROBIOME SHOWS CHANGES, ALSO
DIFFERENCE BETWEEN WOMEN WHO
HAVE USED OR ARE CURRENT USERS
OF HORMONAL THERAPY, THESE ARE
CERTAIN THINGS TO KEEP IN MIND
AND THE LAST ONE I WANT TO LEAVE
YOU WITH IS THIS STUDY THAT'S
DONE OUT OF THE U.K. WHERE THEY
LOOKED AT ORAL HEALTH AND HOW
THAT CAN BE ASSOCIATED WITH
REDUCED MUSCLE STRENGTH AND
COULD BE INDICATOR OF FRAILTY
AND LOSS OF PHYSICAL STRENGTH
LATER IN LIFE.
WITH THAT SAID, I THINK ALL THE
AREAS THAT WE COVER IN THIS
CLASS IN THE NEXT TWO DAYS CAN
ONLY BE ADDRESSED BY HAVING
LONG-TERM VISION IN TERMS OF THE
CONTINUUM OF TRANSLATION WHICH
MANY OF YOU MIGHT BE FAMILIAR
WITH AND THEY CAN ONLY BE
ADDRESSED BY ADDRESSING ALL THE
FINDERS ACROSS THE SPECTRUM.
NIDCR IS EXCITED ABOUT THIS
PARTNERSHIP WITH NIAID AND NIA
AND LOOK FORWARD TO TWO DAYS OF
DISCUSSION.
AND THANK YOU VERY MUCH.
>> THANK YOU VERY MUCH.
AT THIS MOMENT WE'LL THEN GO ON
TO OUR KEYNOTE ADDRESS, GIVEN BY
DR. MARK DAVIS, FROM STANFORD.
AND HE WILL BE SPEAKING ON HUMAN
IMMUNE ORGANIZE TO ANALYZE
VACCINE RESPONSES, AUTOIMMUNITY,
AND AGING.
THANK YOU, MARK.
>> GREAT.
THANKS VERY MUCH, MERCY.
IT'S GREAT TO BE BACK HERE AT
NIH IN AN IN-PERSON MEETING,
WHICH IS SO MUCH MORE
INFORMATION TRANSFER MORE
EASILY.
SO, I'M NOT GOING TO TALK
SPECIFICALLY ABOUT AGING.
WE HAVE SOME DATA, SOME
PROMISING DATA, OF COURSE WE'VE
BEEN DOING COHORTS, AGING THE
THE LONGEST-RUNNING AT 15 YEARS,
THE STANFORD COHORT ON AGING,
BUT I'M NOT GOING TO TALK ABOUT
THAT TODAY.
MAYBE DAVID FURMAN WILL.
I'LL TALK ABOUT SOMETHING
HAPPENING THAT I THINK WILL
TOTALLY CHANGE HOW WE DO HUMAN
IMMUNOLOGY.
AND, YOU KNOW, I THINK HUMAN
IMMUNOLOGY HAS STRUGGLED TO MAKE
PROGRESS, SO MANY CHALLENGES IN
TERMS OF TECHNOLOGIES AND SO
FORTH, MOSTLY DESIGNED AROUND
MICE, ALSO THE FIELD OF
IMMUNOLOGY HAS BEEN HEAVILY
DOMINATED BY INBRED MICE AND
PEOPLE WANT TO KEEP DOING THAT
BUT -- HOW DO I MOVE?
HERE?
NOT ALL BUT SOME OF THE MAJOR
PROBLEMS WE FACE BECAUSE IT'S
ONLY BY ELABORATING THAT WE CAN
START TO THINK ABOUT SOLUTIONS,
AND WHAT WE'VE SEEN REPEATEDLY
OVER THE LAST 15 YEARS OF OUR
WORK IS REALLY WE FIND SOMETHING
INTERESTING IN A HUMAN COHORT OR
THIS POPULATION, AND TO GO ANY
FURTHER WE HAVE TO GO TO MICE TO
GET A KNOCKOUT OR SOMETHING, AND
THIS HAS BEEN THE REALITY.
SO IT MEANS WE CAN NEVER STUDY
HUMAN IMMUNE RESPONSES IF THEY
ARE DIFFERENT IN MICE.
AND WE KNOW THEY ARE DIFFERENT.
THERE'S ABUNDANT EVIDENCE THAT
THERE'S LOTS OF DIFFERENCES IN
AERATION, IF NOTHING ELSE, BUT
THERE COULD BE FUNDAMENTAL
PATHWAYS IN HUMAN IMMUNITY THAT
ARE NOT PRESENT IN MICE.
AND THEN YOU CAN'T ACTUALLY DO
ANYTHING ABOUT THAT.
IT DIES ON THE VINE BECAUSE HOW
DO YOU GO FURTHER?
HUMANIZED MICE HAS BEEN A WORK
IN PROGRESS FOR 30-SOME YEARS,
CAN YOU DO SOME THINGS BUT THEY
DON'T DO A LOT OF THINGS WE
WOULD LOOK THEM TO DO AND YOU'RE
FUNDAMENTALLY TRYING TO BALANCE
THE IMMUNE SYSTEM OF ONE SPECIES
IN THE FRAMEWORK OF ANOTHER, AND
THERE'S ALL KINDS OF ISSUES
THERE.
SO, I THOUGHT WE NEEDED AN
ENTIRELY HUMAN SYSTEM THAT CAN
BE MANIPULATED SO THAT WE CAN
ACTUALLY TEST HYPOTHESES IN THAT
SYSTEM AND NOT HAVE TO ALWAYS
RELY ON MICE BECAUSE MICE ARE
GOING TO BE DIFFERENT.
AND THE OTHER THING THAT'S
DRIVEN US INTO THE ORGANOID
BUSINESS IS -- WE HAVE A LOT OF
EXPERIENCE ASSEMBLING AND
WORKING WITH COHORTS OVER THE
LAST 15 YEARS.
THAT'S BEEN GREAT.
WE'VE BEEN AGING COHORTS, TWIN
COHORTS.
IT'S BEEN A REALLY GOOD WAY TO
KIND OF EXPLORE THE IMMUNE
RESPONSES IN BROAD POPULATIONS
OF SPECIFIC TYPES.
BUT IT TAKES A LONG, LONG TIME.
AND JUST IN TERMS OF RECRUITING
YOUNG PEOPLE, YOU KNOW, ONE OF
THE WORST SITUATIONS I CAN
IMAGINE IS THAT YOU HAVE A
REALLY BRIGHT GRADUATE STUDENT
SITTING IN FRONT OF YOU, A GREAT
REALLY, YOU SAY THAT'S JUST A
GREAT IDEA, FANTASTIC, LET'S
WRITE A GRANT, AND SET UP A
COHORT.
AND IN THREE OR FIVE YEARS WE'LL
ACTUALLY BE ABLE TO TEST THAT
IDEA.
AND THE STUDENT WILL SAY BYE!
SHOW ME THE MICE!
YOU KNOW, IT'S A NON-STARTER FOR
A POSTDOCTORAL STUDENT.
THINK ABOUT THAT.
THINK ABOUT HOW YOU CAN LOSE THE
GREATEST TALENT CROSSING OUR
DESK HERE.
THAT'S NOT COOL.
AND NOW I SHOULD HAVE LEARNED
FROM WHAT -- OH, THERE WE GO.
NEXT.
THIS IS AN AWKWARD SYSTEM.
OKAY.
WHY DO WE THINK WE'LL SEE
DIFFERENCES IN HUMANS IN TERMS
OF FUNDAMENTAL DIFFERENCES?
LOOK AT VACCINE RESPONSES.
WE'VE BEEN VERY LUCKY WITH
SARS-COV-2.
THAT JUST FELL OUT ESPECIALLY
WITH RNA VACCINES, HUGELY
SUCCESSFUL, HUGELY FAST.
THAT AIN'T THE CASE WITH A LOT
OF OTHER VACCINE TRIALS.
WE HAVE REPEATED FAILURES.
AND MOSTLY THE INDUSTRY HAS NOT
INNOVATED FOR THE MOST PART.
THAT'S BIONTECH AND MODERNA
COULD BLOW PAST TRADITIONAL
VACCINE MAKERS LIKE NOBODY'S
BUSINESS.
I HEARD ABOUT RNA VACCINES
CONSULTING FOR NOVARTIS TEN
YEARS AGO, PEOPLE SAID THIS WAS
THE FUTURE, THIS IS HOW WE ADAPT
AND MAKE ALL THE VACCINES IN
THIS ONE ROOM.
NOVARTIS SOLD THE WHOLE VACCINE
UNIT BECAUSE THEY COULD MAKE
MORE MONEY WITH CANCER DRUGS
BASICALLY.
WHY MAKE A DRUG FOR $50 WHEN YOU
CAN MAKE ONE FOR $500?
A NO-BRAINER IF YOU'RE A BEAN
COUNTER.
SO, HERE WE GO.
THIS IS AWKWARD.
THERE OUGHT TO BE A BETTER WAY
TO DO THIS. HERE WE GO, OKAY.
NOW OVERLY SUCCESSFUL HERE.
OKAY.
SO, THIS IS A BIG REASON WHY
WHEN WE FOUND OUT THAT THERE WAS
A FAIRLY ABUNDANT SUPPLY OF
TONSILS BEING WHACKED OUT OF
INNOCENT CHILDREN NEXT DOOR IN
THE PEDIATRIC SURGERY, TONSILS
HAD BILLIONS OF LYMPHOCYTES,
EVEN WAY MORE LYMPHOCYTES THAN
WE GET FROM A SMALL CHILD, LISA
WAGAR DEVELOPED A SIMPLE SYSTEM
ASSOCIATING THE CELLS FROM
TONSILS, AND EITHER FREEZING
THEM DOWN OR JUST CULTURING THEM
IN TRANSWELL PLATE, FIVE OR SIX
MILLION CELLS AT A TIME, AND
THIS TURNS OUT TO WORK WELL FOR
AT LEAST SOME VACCINE RESPONSES.
AND, AGAIN, NOW I HAVE TO --
YEAH, AND WE COULD SEE GERMINAL
CENTERS FORMING IN THE DISH.
WE COULD SEE ANTIBODIES, TREATED
ANTIBODIES WOULD SHOW UP, 7 OR
10 DAYS LATER.
THEY WERE MUTATED, THEY WERE
HIGH AFFINITY.
WE COULD SEE AFFINITY
MATURATION, AND A LOT OF OTHER
STUFF IN THE ORIGINAL PAPER
HERE.
OKAY, GOOD.
GREAT.
AND SO THIS TURNED OUT TO BE A
REALLY ROBUST SYSTEM AND HELPED
US ADDRESS SOME REALLY
INTERESTING THINGS THAT WE HAD
SEEN OVER THE YEARS AND
PARTICULARLY FOR ONE ASPECT OF
THIS IS WE HAD DONE A CELIAC
STUDY IN 2013 WHERE NOT ONLY
WHEN WE INDUCE CELIAC DISEASE IN
VOLUNTEERS ON GLUTEN FREE DIET
BY EATING BREAD WE SAW CD4 CELLS
FOR GLUTEN AND GAMMADELTA CELLS,
SURPRISING, NO ONE EXPECTED
THESE TO BE SHOWING UP.
WHAT WERE THEY AND WHAT ROLE DID
THEY HAVE IN CELIAC DISEASE ?
AND WE MOVED ON TO EAE SYSTEM IN
MICE, AND HERE SALIGRAMA CAME
IN, HAD DONE A THESIS ON EAE, WE
HAVE TO LOOK AT THE BLOOD IN
MICE, THAT'S WHAT WE DID IN
HUMANS, LET'S SEE WHAT HAPPENS.
NO ONE LOOKS AT BLOOD IN MICE,
BUT HE DID.
AND WE SAW BASICALLY THE SAME
THING, THAT DAY 10 AFTER
INDUCTION SAW A SURGE OF CD 4,
CD8, GAMMA CELLS.
A WEEK LATER ANOTHER SURGE IN
THE BLOOD OF THE SAME CELLS,
EVEN A THIRD SURGE.
THIS WAS MIRRORED IN THE NERVOUS
SYSTEM TISSUES OF THESE MICE,
BUT IF YOU LOOK TO THE SPLEEN
AND LYMPH NODES YOU DIDN'T SEE
THIS BECAUSE THERE'S ALSO SO
MUCH ACTIVITY.
SO THE BLOOD EVEN THOUGH WE WERE
CRITICIZED FOR LOOKING AT BLOOD
IN HUMANS, TURNED OUT IF YOU
WANT REALTIME IMMUNE RESPONSES
BLOOD IS ACTUALLY A GREAT PLACE
TO LOOK AT.
THAT'S WHAT'S HAPPENING AT THE
MOMENT.
SPLEEN AND LYMPH NODES THAT
ACCUMULATED WEEKS AND MONTHS AND
YEARS OF PREVIOUS ACTIVITY.
NEXT SLIDE.
AND SO THIS LED TO THE DISCOVERY
OF CD8 REGULATORY T CELLS THAT
WERE BROADLY IMPORTANT, BOTH IN
MICE AND HUMANS, AND THIS IS
WORK THAT CAME OUT LAST YEAR IN
"SCIENCE," JING LI, A POSTDOC IN
THE LAB SHOWED THE EQUIVALENCE
CD8 CELLS, CD4, POSITIVE, 1 OR
2% OF HEALTHY HUMANS IN THE
BLOOD CAN BE 20, 25% IN PEOPLE
WITH ACTIVE LUPUS OR M.S. OR
EVEN CELIAC DISEASE THERE'S
ELEVATION.
NEXT SLIDE.
AND SO RECENTLY WE -- NEXT SLIDE
PLEASE.
RECENTLY WE WANTED TO TEST THIS.
NOW, WE'RE TALKING ABOUT A WHOLE
OTHER AXIS OF TOLERANCE IN THE
IMMUNE SYSTEM DRIVEN BY -- HERE
WE GO.
CD 8 CELLS.
ARE THESE IMPORTANT?
YES.
EVEN IN MICE WE HAVE A
CONDITIONAL KNOCKOUT, TURNED OUT
THAT IF YOU HAVE THIS KNOCKOUT
FOLLOWING INFECTION WITH LCMV
YOU HAVE AUTOIMMUNE SEQUELAE IN
THE MICE, THESE ARE ACTUALLY
ANTIBODY DEPOSITS IN THE KIDNEYS
OF MICE FOLLOWING LCMV
INFECTION, AND THAT WE CAN SEE,
AND THEN IN FLU WE SEE LUNG
INFLAMMATION WHICH WE DON'T SEE
IN MICE, THIS DOESN'T HAPPEN.
THIS SHOWS AUTOIMMUNITY BUT WE
KNOW ABOUT CD 4 TREGS, SO WHAT'S
THE DIVISION OF LABOR?
WELL, WE REPORTED IN THE
"SCIENCE" PAPER, REPORTED IN
COVID WE SEE A LOT OF ACTIVITY
OF CD8 REGULATORY CELLS BUT NOT
CD4 REGULATORY CELLS, WE CAN SEE
DIVISION OF LABOR IN TERMS OF
POSITIVE CD8S BEING MORE
IMPORTANT SUPPRESSING
AUTOIMMUNITY IN INFECTIOUS
DISEASES, WHAT ELSE CAN WE
FIGURE OUT?
THIS IS WHERE WE WENT TO
ORGANOIDS, TONSIL ORGANOIDS.
NEXT SLIDE PLEASE.
SO -- NEXT SLIDE.
AND I THINK THIS IS NOW
TECHNOLOGY THAT'S GOING TO BE
INCREDIBLY POWERFUL IN ORGANIZE
AND FOR HUMAN IMMUNOLOGY
GENERALLY, SPEAKING TO THE IDEA
OF TESTING IN A PURELY HUMAN
SYSTEM.
THIS IS WORK OF A FANTASTIC
GRADUATE STUDENT AND POSTDOC,
WORKING OUT A METHOD FOR DOING
CRISPR KNOCKOUTS IN TONSIL
ORGANOIDS, MAKING USE OF THE
FACT WE GET MULTIPLE ALIQUOTS,
10, 20, 50, FROM THE SAME DONOR,
FREEZE AND THAW WHEN YOU WANT.
TOOK ONE ALIQUOT FROM ONE DONOR,
GOT T CELLS, ELECTROPORATED,
INCUBATED, PUT THEM BACK INTO A
SECOND ALIQUOT DEPLETED T CELLS.
THEN I START THE CULTURE.
AS ADJUVANT PUT IN LIVE
ATTENUATED FLU VACCINE THAT
HELPS EVERYTHING GO BETTER
BASICALLY.
NEXT SLIDE.
AND THESE KNOCKOUTS ARE
EFFICIENT GETTING 90, 95%
DEPLETION, TARGETING THE TWO
PILLARS OF REGULATION HERE, FLOX
B 3 AND GRANZYME B KNOCKS OUT
THE CD 8 FUNCTION.
AND RESULTS ARE COOL.
IF WE STIMULATE CON SILLS
DEPLETED OF FOXP3 AND REGULATORY
T CELLS NOW THE TONSILS WILL
MAKE AUTOANTIBODIES WHICH THEY
WOULDN'T BEFORE, WE USE A
COCKTAIL OF AUTOANTIGENS,
NUCLEAR RNP, HISTONE
DOUBLE-STRANDED DNA, EVERY DAYS
WE'RE GETTING SIGNIFICANT LEVELS
OF A BACKGROUND OF SECRETED
AUTOANTIBODIES.
WE'RE ABLE TO TAKE HEALTHY
TONSIL TISSUE AND CREATE A MODEL
SYSTEM OF AUTOIMMUNITY,
REPRODUCES SOME OF WHAT WE SEE
IN AUTOIMMUNITY, PARTICULARLY
FOXP3 KNOCKOUTS IN MOUSE AND
HUMAN PHENOTYPE IS MASSIVE
AUTOANTIBODY PRODUCTION AND
INFLAMMATION AND EARLY DEATH.
SO IT'S REPRODUCING WHAT WE HAVE
KNOWN.
NEXT SLIDE PLEASE.
AND THEN AS A BONUS, I WAS
IMPRESSED BY THIS PAPER THAT
CAME OUT NOW SEVEN YEARS AGO,
WHICH SHOWED THAT PATIENTS
DEFICIENT IN IN THE AIRE GENE,
IT CONTROLS IN THE THYMUS,
MAKING ANTIBODIES TO SOME
AUTOANTIGEN, INTERFERING WITH T
CELL TOLERANCE COULD RESULT IN
HIGHER AFFINITY ANTIBODIES,
NORMALLY WE SEE NANOMOLAR
AFFINITY ANTIBODIES, PLUS OR
MINUS, TIGHT DISTRIBUTION, FROM
BIOGEN, SO FORTH.
NOT BIOGEN.
WE TOOK A SHOT TO SAY MAYBE
FOXP3, NEXT SLIDE, AND -- NEXT
SLIDE PLEASE.
THERE WE GO.
SURE ENOUGH, LOOKING AT
AFFINITY, THIS IS A STUDY
BASICALLY WE'RE GETTING HIGHER
AFFINITY FLU ANTIBODIES, MUCH
HIGHER THAN NORMALLY SEEN IN
TONSILS, YOU CAN LOOK HERE AT
THE OFF-RATE, WE SEE SOME TONSIL
DONORS MAKING 10 TO 20 TIMES
HIGHER AFFINITY ANTIBODIES,
SLOWER OFF RATE, FOXP3 ARE NOT
ONLY GATE KEEPERS FOR
AUTOANTIGENS BUT ALSO GATE
KEEPERS FOR ANTIBODY AFFINITY IN
GENERAL.
AND PROBABLY BECAUSE HIGHER UP
YOU GO IN AFFINITY, THE MORE
CHANCES OF CROSS-REACTIVITY TO
SOMETHING IMPORTANT THAT YOU'RE
TRYING TO PREVENT.
NEXT SLIDE PLEASE.
BUT THEN WE ALSO -- THE WHOLE
PURPOSE HERE WAS TO LOOK AT THE
RELATIVE ROLE OF THESE DIFFERENT
CD4 AND CD8 CONTROLS OR
CHECKPOINTS, AND SO HERE THE
GRANZYME B KNOCKOUT WHICH KNOCKS
OUT PEER POSITIVE T CELL
FUNCTION, YOU KNOW, WE SEE BOTH
CD4 AND -- SORRY, CD8 AND CD4
AUTOREACTIVE T CELLS THEN COME
UP.
SO NOW WE'RE SIMULATING BOTH
CASES, SIMULATING WITH
AUTOANTIGENS IN IN THE T CELL E
A SELECTION OF CD4 AUTOREACTIVE
THINGS THAT HAVE BEEN DESCRIBED
OR CD 8, THESE ARE RARE CELLS
BUT THEY ARE THERE.
AND THEY ARE JUST BEING
CONTROLLED NORMALLY, BUT SO
WE'RE GETTING A GLIMPSE INTO THE
CONTROL MECHANISM AND SEEING IT
IN A DISH, SO IT'S REALLY
IMPORTANT IN TERMS OF GOING
FURTHER AND LOOKING AT MORE
DETAIL.
NEXT SLIDE PLEASE.
ALL RIGHT.
WHAT ABOUT AGING, MERCY HAS
ASKED?
IN FACT WE'RE IN THE MIDDLE OF
AN INTERESTING PROJECT RUN BY
NATHAN, A POSTDOC IN THE LAB,
AND NOW WE'RE TAKING ADVANTAGE
OF THE LONG TIME SPAN, TONSILS
FROM KIDS AS YOUNG AS 2 YEARS
OLD, AND MORE RECENTLY IT'S NOT
COMMON BUT WE'VE GOT TONSILS
FROM 60 TO 70-YEAR-OLDS, WE WANT
MORE.
A STUDY FIRST STARTING WITH
ANTIBODY TITERS, WE'VE DONE LOTS
OF CONSOLES SIMULATED MOSTLY
WITH LIVE ATTENUATED FLU
VACCINE, GET ANTIBODY RESPONSES
THAT WE MEASURE, PUT THEM
TOGETHER, YOU CAN SEE A CLEAR
CORRELATION WITH AGE.
YOUNGER PEOPLE DOING GREAT,
OLDER PEOPLE DOING LESS AND LESS
GREAT.
SO, THIS MEANS, AGAIN, WE CAN
LOOK AT AGING IN A DISH, TRY TO
FIGURE OUT WHAT'S HAPPENING.
WE'RE STILL IN THE MIDDLE OF
THIS BUT RESULTS ARE ALREADY
STARTING TO BE VERY INTERESTING.
NEXT SLIDE PLEASE.
AND ONE IS JUST LOOKING AT
REPERTOIRE.
AND THIS CORRELATES WITH SOME
THINGS THAT WERE DONE SOME YEARS
BACK, AND WE SEE A DIFFERENCE IN
DIVERSITY OF THE OLDER TONSILS
VERSUS YOUNGER FOLKS, PBMCs,
BRINGING THAT INTO GREATER
RESOLUTION.
MORE IMPORTANTLY, NEXT SLIDE,
GIVES US A PICTURE OF WHAT'S
HAPPENING, WHAT'S DIFFERENT
BETWEEN TONSIL.
TONSIL IS A MUCOSAL ORGAN SO
THERE ARE DIFFERENCES BOTH IN
TERMS OF T CELL SPECIFICITY BUT
ALSO SOME PHENOTYPES.
BUT WHAT'S MOST INTERESTING,
NEXT SLIDE, IS DOING A VOLCANO
PLOT AND JUST SAYING WHAT'S
HEAVILY WEIGHTED IN THE YOUNG
TONSILS VERSUS OLD TONSILS?
AND BASICALLY ASSOCIATED WITH
GERMINAL CENTER FORMATION AND T
CELL -- HELPER T CELL.
THIS IS WHAT'S HAPPENING IN THE
YOUNG TONSILS VERSUS OLD
TONSILS.
SO, THIS MAKES PERFECT SENSE IN
TERMS OF WE KNOW WHAT'S THE
HALLMARK OF AGING FUNCTIONALLY
AND WHAT'S CLINICAL IMPORTANT IS
DECLINE IN ANTIBODY TITER.
SO HERE WE STARTED LOOKING AT
DECLINING ANTIBODY TITERS, AND
NOW WE'RE SEEING A GERMINAL
CENTER T CELL DEFECT, HELPER
CELL DEFECT.
SO THIS MAKES PERFECT SENSE THAT
IF THESE CELLS ARE DEFECTIVE FOR
SOME REASON, WE'LL HAVE TROUBLE
MAKING GOOD ANTIBODY RESPONSES.
SO ANYWAY, WE'RE FOLLOWING THIS
UP AND OF COURSE WE'RE GOING TO
ALSO USE THE CRISPR KNOCKOUT TO
KNOCKOUT SOME OF THE GENES
COMING UP.
WHAT'S ACTUAL OR WHAT'S CAUSAL,
WHAT'S CORRELATION.
NEXT SLIDE.
ANOTHER BIG QUESTION IN
VACCINOLOGY THAT WE'VE BEEN
TACKLING IS SUBTYPE BIAS IN FLU.
SO THIS IS SOMETHING THAT'S BEEN
OBSERVED SINCE THE 1940s IS
THAT PEOPLE HAVE PARTICULAR
PREFERENCES IN TERMS OF WHAT
SUBTYPE OF FLU, SO SUBTYPE IS
ONE TIME H3, B TYPE, MAIN
SUBTYPES THAT GO ON, AND PEOPLE
HAVE A PREFERENCE FOR ONE OR THE
OTHER WHICH MEANS THAT EVEN IF
THEY ARE VACCINATED AS PEOPLE
ARE WITH THE TETRAVALENT FLU
VACCINE, YOU'RE ONLY -- MOSTLY
ONLY GOING TO MAKE A GOOD
RESPONSE AGAINST THE ONE YOU
LIKE, OR THAT YOUR PREFERENCE
IS.
AND SO THAT'S A PROBLEM IF
YOU'RE INFECTED WITH ONE OF THE
OTHER STRAINS.
WE MAKE THIS SELECTION OF
STRAINS BECAUSE THAT'S WHAT'S
CIRCULATING, THAT'S WHAT COULD
INFECT YOU, BUT THIS SUBTYPE
BIAS DEFEATS THE PURPOSE OF
HAVING A MULTI-STRAIN VACCINE.
AND WILL FOR EVERY MULTI-STRAIN.
PNEUMONIA VACCINE IS NOW UP TO
19 STRAINS.
ARE YOU GOING TO BE EQUALLY
PROTECTED AGAINST ALL 19
STRAINS?
ALMOST CERTAINLY NOT BUT THAT'S
WHAT WE KNOW, THAT'S WHAT THE
VACCINE INDUSTRY IS USED TO
DOING, IT'S THE ONLY GAME IN
TOWN.
WE BUY IT.
HAVE TO TAKE YOUR CHANCES.
THAT'S ONE REASON FLU VACCINE
EFFICACY HAS NEVER BEEN THAT
GREAT, NEVER BEEN EVEN CLOSE TO
THE COVID VACCINES WE HAVE NOW.
SO WHAT'S THE BASIS OF IT?
THAT'S WHAT'S INTERESTING IS
THAT SINCE 1960, THE POPULAR
NOTION HAS BEEN THAT IT DEPENDS
ON WHAT FLU STRAIN YOU'RE FIRST
INFECTED WITH OR VACCINATED
WITH.
AND WHAT WAS REALLY BRILLIANT
ABOUT THIS HYPOTHESIS IT WAS
GIVEN THE NAME ORIGINAL ANGENIC,
IF YOU CAN ATTACH THE WORD SIN
TO ANY ANYTHING, YOU'LL
IMMEDIATELY GET A LOT OF
INTEREST AND EXCITEMENT, OF
COURSE.
BUT IS THIS REALLY THE THING?
AND SO THIS IS WORK OF MALIDOSAL
WHO DID FLU AS A Ph.D. AND HAS
DUG IN, IN AMAZING WAY, TAKING
ADVANTAGE OF THE MANY COHORTS.
I CAN'T GO THROUGH EVERYTHING
BUT ONE OF THE MORE RELEVANT
ONES WE HAVE A TWIN COHORT WHERE
WE HAVE SUBSTANTIAL NUMBER OF 78
MONOZYGOTIC TWINS ANALYZED FOR
FLU VACCINE OVER THE YEARS, AND
SO -- NEXT SLIDE.
WE'RE ABLE TO KIND OF LOOK AT
THIS AND -- SORRY, SKIPPING A
SLIDE HERE.
BASICALLY 70-SOME PERCENT OF
MONOZYGOTIC TWINS ARE THE SAME
BIAS, OKAY?
BUT IT DOESN'T CORRELATE WITH
PRIOR EXPOSURE.
THEY HAVE A BIAS THAT THEY SHARE
BUT IT DOESN'T CORRELATE WITH
PRIOR EXPOSURE OR THE YEAR THAT
THEY WERE BORN, BECAUSE THAT'S
BEEN ANOTHER WAY PEOPLE LOOKED
AT THIS.
CERTAIN FLU STRAINS WERE
PREVALENT AT CERTAIN AGE RANGES.
SO POINTED TO A SUBSTANTIAL
COMPONENT OF THIS EFFECT AS
GENETIC, REINFORCED BY OTHER
COLLABORATION WITH MARY STOUT IN
THE IMPRINT COHORT.
THAT'S BEEN GREAT.
SHE HAS JUST A FANTASTIC COHORT
OF YOUNG CHILDREN AND
PARTICULARLY WERE ABLE TO GET 15
SAMPLES FROM 15 KIDS 6 TO 12
MONTHS WHO NEVER HAD A FLU
INFECTION, WE KNOW THIS BECAUSE
IN THIS COHORT EVERY WEEK THE
MOTHER SWABBED THE NOSES OF THE
KIDS AND SENDS IN THE SWABS, AND
THEY ARE ANALYZED FOR FLU
INFECTION.
THIS IS A GROUP OF CHILDREN IN
THIS AGE GROUP WHO NEVER HAD
FLU.
THEY WERE ALL GIVEN A STANDARD
VACCINE, AT 6 MONTHS I BELIEVE.
WE COULD SEE STRAIN BIAS
ALREADY.
SO THIS IS THE FIRST EXPOSURE TO
FLU, AND THEY ARE ALREADY
SHOWING STRAIN BIASES.
OKAY.
MAYBE WE'LL HAVE A MOMENT OF --
OH.
OKAY.
THANK YOU.
SO ANYWAY, THIS IS FURTHER
EVIDENCE THAT FIRST EXPOSURE IS
NOT THE CAUSE OF STRAIN BIAS OR
ISN'T THE ONLY CAUSE.
I THINK IT IS PART OF THE
EQUATION BUT IT DOESN'T SEEM
LIKE IT'S THE MAIN THING.
NEXT SLIDE.
OH.
LET'S SEE IF I CAN DO THIS
MYSELF.
ALL RIGHT.
OKAY, GREAT.
SO, FROM HERE A TERRIFIC LEAP
WAS TAKEN TO WHAT'S REALLY AT
THE HEART OF THIS.
BASICALLY HE COULD SEE A HUGE
GENETIC COMPONENT BUT WHAT WAS
THAT GENETIC COMPONENT?
GENOME IS A BIG THING. WHERE IN
THE GENOME DO YOU LOOK?
AND SO HE LOOKED AT CLASS 2
POLYMORPHISM, HUMANS HAVE A
TERRIFIC AMOUNT OF CLASS II
POLYMORPHISM.
IF YOU USE THE IMMUNE EPITOPE
DATABASE, IN LA JOLLA, YOU CAN
CLEARLY -- YOU FEED IN DIFFERENT
FLU STRAIN SEQUENCES, YOU CAN
SEE A TREMENDOUS HETEROGENEITY
IN HOW CLASS II ALLELES PRESENT
PEPTIDES FOR THOSE STRAINS,
THAT'S WHAT'S SHOWN HERE, FOR
INSTANCE IF YOU HAVE THESE HLA
CLASS II POLYMORPHISMS YOU'LL DO
GREAT WITH H3 STRAINS, DO
TERRIBLE WITH B STRAIN.
SIMILARLY YOU HAVE THESE
ALLELES, YOU'RE GOING TO DO
GREAT WITH THESE STRAINS,
TERRIBLY WITH H3 STRAINS.
THIS EXPLAINS AND IN FACT CAN
PREDICT YOUR STRAIN BIAS.
AND THERE WAS FURTHER WORK, I
DON'T HAVE TIME TO GO OVER IT,
CORRELATING THIS WITH HELPER T
CELLS.
HE MADE PEPTIDES FOR THESE AND
SHOWED THAT YOU GET A
CORRELATION WITH HELPER T CELLS.
WHAT ANY MEANS IS THAT IF YOU
HAVE THESE ALLELES, THEY JUST
DON'T
[AUDIO DISTORTION]
FOR THESE STRAINS.
HELLO?
IT'S WORKING.
WOW!
OKAY.
NOW,
[AUDIO DISTORTION]
THIS IS WHAT ORGANIZE COME IN.
YOU CAN'T DO THIS WITH A MOUSE.
THE MOUSE AS ONE OR TWO ALLELES
CLASS II.
WE REACH FOR OUR SELECTION OF
TONSIL ORGANOIDS.
HE MADE CONSTRUCTING DISPLAYING
SEPARATE MOLECULES FROM EACH FLU
STRAIN, BASICALLY WHAT THE
VACCINE IS, OR HE ALSO MADE
ANOTHER CONSTRUCT WHERE HE MIXED
ALL FOUR FROM DIFFERENT STRAINS.
AND SO THE COCKTAIL, EACH OF THE
CONSTRUCTS WOULD ONLY HIT B
CELLS THAT HAD THESE
SPECIFICITIES ON THEIR
ANTIBODIES, BUT THESE WOULD HIT
ALL THESE CELLS THAT HAD ANY FLU
STRAIN SPECIFICITY AND
FURTHERMORE PRESENT FROM ALL
FOUR OF THE MAJOR STRAINS.
GO BACK ONE SLIDE.
YEAH, SO JUST TO INTRODUCE THIS,
HERE WE HAVE GIVEN INDIVIDUAL
GETTING THE TETRAVALENT AND HAS
A PREFERENCE FOR THREE, YOU CAN
SEE THE NICE ANTIBODY RESPONSE,
CRAPPY RESPONSE TO THE OTHER
THREE STRAINS.
WE USE THE HA COCKTAIL, THAT IS
A SEPARATE CONSTRUCT, BASICALLY
GET THE SAME THING.
GOOD H3 RESPONSE, CRAPPY OTHER.
WE USE CROSS-LINK HA AND WE GIVE
ALL OF THE RESULTS SPECIFIC FOR
ANY STRAIN, FULL COMPLEMENT OF T
CELL HELP, WE KNOW THERE'S A
TREMENDOUS AMOUNT OF T CELLS
SPECIFIC FOR FLU IN TONSILS AND
SPLEENS.
[AUDIO DISTORTION]
STAINED WITH A FLU REAGENT, HA
REAGENT, A LOT OF FLU OVER THE
YEARS, BUILD UP A TREMENDOUS
AMOUNT OF HEALTH.
NEXT SLIDE PLEASE.
THESE ARE INDIVIDUAL RESPONSES
FROM TEN TONSILS.
SOMETHING LIKE SEVEN OF THE TEN
SHOW ANTIBODY RESPONSES BUT
THAT'S GOOD.
SEVEN OUT OF TEN.
I'LL TAKE THAT.
BASICALLY OUGHT THE VACCINES,
COVID VACCINES ARE GOING TO BE
MULTI-STRAIN, MULTI-STRAINS.
ALL THESE OTHER ONES, SO JUST
MIXING TOGETHER, EASY LAZY MAN'S
VACCINE WHERE WE JUST MIX ALL
THE STRAINS TOGETHER, AND HOPING
WE GET GOOD RESPONSE, YOU WILL
GET -- YOU'LL ENCOURAGE MORE
CROSS-REACTIVE RESPONSES, BUT
YOU WON'T -- GENETICS IS A
POWERFUL THING.
I THINK THIS IS HOW WE SHOULD BE
MAKING MULTI-STRAIN VACCINES.
THIS RAISES THE PROSPECT OF CAN
WE HARNESS THIS TREMENDOUS
(INDISCERNIBLE) FOR FLU-SPECIFIC
EPITOPES, HARNESS TO MAKE BETTER
RESPONSES AGAINST OTHER EPITOPES
LIKE HIV, LIKE BIRD FLU, THINGS
THAT WE'RE GETTING CRAPPY
RESPONSES FROM THE GET-GO BUT
ALL THIS ABUNDANT T CELL HELP WE
COULD BOOST ANTIBODY RESPONSE.
THAT'S SOMETHING WE'RE WORKING
ON.
NEXT SLIDE PLEASE.
AND SO THEN WE GET MORE
AMBITIOUS, AND THOUGHT, WELL,
MAYBE WE CAN COMBINE THESE
IMMUNE ORGANOIDS WITH TISSUES
RELEVANT TO IMMUNE CIRCUITRY, SO
FORTH.
ELSA SOLA IS HEAD OF OUR
ORGANOID EFFORT, AND CHEN WANG
IS A DERMATOLOGY IS, I ASKED CAN
YOU GET A PIECE OF SKIN AND
THROW IN THE TONSIL-RELATED
DONOR?
SURE, WHY NOT.
NEXT SLIDE PLEASE.
AND WHAT HAPPENED IS TONSIL
CELLS ATTACKED THE SKIN, SO
BASICALLY A FOREIGN TISSUE COMES
INTO VIEW, T CELLS ARE ON IT, B
CELLS ARE ON IT TOO, IF YOU LOOK
AT T AND B CELLS, EVEN MORE B
CELL INFILTRATION THAN T CELL
INFILTRATION.
NEXT SLIDE.
WE GET THIS INFILTRATION AND THE
TONSILS THEMSELVES START KILLING
THE SKIN, OF COURSE.
AS YOU CAN SEE IN THIS ASSAY IN
RED, ALL EPITHELIAL CELLS ARE
BUSY DYING.
WE CAN INHIBIT WITH CYCLOSPORIN
AND CLASSIC TRANSPLANT REJECTION
DRUGS, SO WE ARE LOOKING FOR ALL
INTENTS AND PURPOSES AT
CLASSICAL SKIN GRAFT REJECTION
AND OLD-TIME IMMUNOLOGY, I
ORIGINALLY READ ABOUT THESE
THINGS HAPPENING IN ANCIENT
TIMES, BUT NEVER THOUGHT I'D BE
WORKING ON IT.
WE WANT TO WORK ON HAPPIER
THINGS OF SYNERGY BETWEEN SKIN
AND IMMUNE ORGANOIDS BUT HOW DO
YOU GET THAT SYSTEM?
HOW DO YOU WORK THAT OUT?
SO, THIS FORCED US INTO THE
ARMS, NEXT SLIDE, OF TRANSPLANT
COMMUNITY BECAUSE IT TURNS OUT
THAT WHEN SURGEONS GO TO HARVEST
ORGANS FROM DONORS, THEY JUST
SCOOP OUT THE WHOLE INNARDS,
THROW THEM IN THE ICE BUCKET AND
HELICOPTER OVER TO WHEREVER THEY
ARE GOING.
AND THE SPLEENS ARE IN THE MIX.
BUT AT THE END OF THE DAY WHEN
THEY ARE PUTTING ORGANS INTO --
VALUABLE ORGANS INTO RECIPIENTS
THEY THROW AWAY THE SPLEEN.
NOBODY WANTS TO TRANSPLANT
SPLEENS.
YOU PROBABLY GET THE WORST
GvHD, YOU THROW THEM AWAY, ONE
SURGEON TOLD ME YOU MAKE DNA, I
WAS THINKING, TENS OF BILLIONS
OF LYMPHOCYTES THAT TELL THE
IMMUNE HISTORY OF THAT
PARTICULAR PERSON, AND WE CAN DO
NOW ALL THESE THINGS WITH.
SO LET'S TALK.
SEND THEM TO US.
SO OVER THE PAST YEAR WE'VE
GOTTEN OVER 30 SPLEENS, EVERY
OTHER WEEK WE GET A SPLEEN.
THEY ARE HUGE.
WE GET UP TO 50 ALIQUOTS OF
MATERIAL WE CAN FREEZE DOWN, YOU
CAN GO BACK TO THE SAME DONOR
OVER AND OVER AGAIN, BUT THE
OTHER GOOD THING IS THE SPLEENS
ARE MUCH MORE DIVERSE THAN
TONSILS.
TONSILS ARE MOSTLY B AND T
CELLS, 99%, BUT SPLEENS ARE 60%
B AND T, LOTS OF DENDRITIC AND
NK CELLS, MORE DIVERSE ORGAN,
BIGGER, MORE ATTRACTIVE.
NEXT SLIDE PLEASE.
AND WE GET BETTER ANTIBODY
RESPONSES, IT'S A QUIETER
ORGAN.
TONSILS ARE FRONT LINE, LOTS OF
STUFF COMING INTO THE MOUTH,
KNOWS YOU'RE TRYING TO MAKE A
RESPONSE.
NEXT SLIDE.
AND ALSO THEY ARE CLEANER.
LOWER BACKGROUND.
AND WE GET BIGGER ANTIBODY
RESPONSES IN SPLEENS VERSUS
TONSILS.
SO THAT'S ALL COOL.
AND BUT WHAT'S REALLY IMPORTANT,
THE REASON WE WENT TO THIS TO
GET SKIN AND LUNG AND OTHER BODY
PARTS FROM THE SAME DONOR AS
WHAT WE'RE MAKING IN THE IMMUNE
JOGGER -- JOGGER -- ORGANOID.
WE HAVE SOLVED A NUMBER OF
PROBLEMS THAT WERE BUGGING US.
ONE IS WE COULD NEVER GET A
YELLOW FEVER VACCINE RESPONSE IN
THE TONSILS.
PROBABLY BECAUSE THERE ARE TOO
FEW DENDRITIC CELLS.
NOW WITH SPLEENS ARE ABLE TO GET
YELLOW FEVER ANTIBODY RESPONSE,
SO FAR JUST IgM BUT THEY ARE
CHARACTERISTIC OF YELLOW FEVER
AND WE HAVE THE PUSH TO CELLS
LONGER TO GET INTO SOME IgG
TERRITORY.
WE NEVER COULD GET RNA VACCINES
TO WORK IN THE TONSILS.
BUT NOW THEY DO WORK IN SPLEENS,
AGAIN PROBABLY CELL DRIVEN.
IF WE DIDN'T GET A RESPONSE, WE
ISOLATED DENDRITIC CELLS FROM
THE SPLEEN, ONE ALIQUOT OF
SPLEEN, HIT THAT DIRECTLY WITH
RNA VACCINE, AND THEN PUT THAT
WITH A SECOND ALIQUOT FROM THE
SAME DONOR.
NOW WE GET A GOOD ANTIBODY
RESPONSE.
SO THESE ARGUMENTS, 20, 30 YEARS
AGO, HEATED ARGUMENTS WITH MY
PROFESSIONAL APC IS MORE
PROFESSIONAL THAN YOURS.
ALL RIGHT, FINE.
DIDN'T HAVE ANYTHING TO DO WITH
ME SO I JUST IGNORED IT BUT NOW
I'M STARTING TO APPRECIATE IT.
THERE WAS SOMETHING TO WHAT
PEOPLE SAID.
OF COURSE EVERYBODY WAS RIGHT.
I THINK THE FLU EXPERIMENT SHOWS
TARGETING B CELLS IS USEFUL FOR
T-CELL RESPONSES.
AND DENDRITIC CELLS ARE REALLY
IMPORTANT FOR SOME FORMS OF
IMMUNITY.
EVERYONE IS RIGHT SO THAT'S
GOOD.
NEXT SLIDE.
I THINK WE'RE ALMOST AT THE END.
SO WE'RE JUST STARTING TO DO
EXPERIMENTS WHERE WE HAVE SKIN
AND SPLEEN FROM THE SAME DONOR
AND WE'RE ABLE TO VACCINATE THE
SKIN AND SEE A RESPONSE IN THE
SPLEEN.
AGAIN YOU DON'T NEED PLUMBING.
YOU CALL IN THE BIOENGINEERS,
THEY ARE GOING TO BUILD A
TREMENDOUSLY BEAUTIFUL
MICROFLUIDIC DEVICE AND ORGANS
ON CHIP, SO FORTH.
WE PUT THINGS IN THE SAME WELL,
AND THEY TALK.
IMMUNE CELLS ARE PRETTY FLEXIBLE
THAT WAY.
WE'RE JUST GETTING A LUNG,
SPECIFICALLY USED FOR TRANSPLANT
SO WE DON'T GET LUNG ALL THE
TIME, BUT WE DO GET LUNG SOME OF
THE TIME.
HERE IN THE NEXT SLIDE WE'VE
BEEN WORKING WITH CALVIN QUO WHO
HAS A LUNG ORGANOID SYSTEM, IT'S
A MORE STANDARD TYPE OF ORGANOID
DRIVEN BY STEM CELLS THAN WHAT
WE'RE DRIVEN WITH IMMUNE CELLS,
BUT ANYWAY IT WORKS.
HE'S ALREADY SHOWN THAT HE CAN
GET SARS-COV-2 IN LUNG AND IN
THIS LATEST PAPER YOU CAN SEE
USING OUR TECHNOLOGY, CAN SEE
SARS-COV-2 SPECIFIC T CELLS IN
THE LUNG, THIS TYPE OF LUNG
ORGANOID HAS SOME OF THE
ENDOGENOUS LYMPHOCYTES IN IT.
WE'RE COUPLING THIS TYPE OF LUNG
ORGANOID WITH A SPLEEN ORGANOID
FROM THE SAME INDIVIDUAL AND
HOPEFULLY WE CAN TEST VACCINES
IN AN ENTIRELY DIFFERENT WAY
NOW, VACCINATE THE SPLEEN, DOES
IT PROTECT FROM THIS OR THAT
VIRUS.
SO NO MICE WILL BE HARMED IN
THESE EXPERIMENTS, I WANT TO
ASSURE PEOPLE OF THAT.
NEXT SLIDE.
OH, OF COURSE WE'RE ALSO VERY
KEENLY INTERESTED, DEVELOPING
THE CASE THAT THERE ARE
HUMAN-SPECIFIC SYSTEMS IN
IMMUNITY, HAVE BEEN PART OF
WHAT'S HOLDING US UP IN THE
VACCINE BUSINESS.
SO, WE BROKE DOWN AND MADE NOW A
MOUSE SPLEEN ORGANOID, AND
STIMULATED WITH ATTENUATED FLU
VACCINE, GET STIMULATION,
ANTIBODIES.
WE'LL BE ABLE TO RUN HUMAN
SPLEENS AND MOUSE SPLEENS SIDE
BY SIDE WITH THE SAME VACCINE,
AND DO SINGLE CELL EVERYTHING TO
SEE ARE THERE DIFFERENT
PATHWAYS, CAN WE IDENTIFY WHOLE
NEW WAYS IN WHICH HUMANS ARE
RESPONDING OR DIFFERENT HUMANS
ARE RESPONDING BECAUSE THAT'S
THE OTHER ADVANTAGE OF AN
ORGANOID, WE'RE SEEING HUMAN
DIVERSITY WHICH MICE ARE
DESIGNED NOT TO HAVE ANY
DIVERSITY, BUT HUMANS, WE'RE
STUCK WITH HUMAN DIVERSITY.
DIFFERENT PHENOTYPES, DIFFERENT
DRUG AND VACCINE RESPONSES.
HOW DO WE GET AT THAT?
THERE ARE OTHER SYSTEMS PEOPLE
HAVE ADVOCATED BUT I WOULD SAY
THIS IS -- GET THOSE SPLEENS, WE
HAVE NOW 33 SPLEENS AND WE'LL
HAVE 100 BY NEXT YEAR.
IT'S A COHORT.
AND YOU'RE GOING TO BE ABLE TO
DO THE SAME ASSAYS, SAME VACCINE
ACROSS SEVERAL COHORTS AND LOOK
AT THIS VARIATION AND TRY TO GET
AT WHAT IS CAUSAL, WHAT IS
ACTUALLY HAPPENING HERE, WHY ARE
PEOPLE LIKE THIS?
I THINK IT'S A WHOLE, YOU KNOW,
NEW ERA OF HUMAN IMMUNOLOGY AND
WE'RE GOING TO LEARN A
TREMENDOUS AMOUNT OVER THE
NEXT -- AT THE END HERE.
NEXT SLIDE PLEASE.
COULD CONCLUDE WE'RE FINDING OUT
ABOUT RELATIVE ROLES OF CD4
VERSUS CD8 REGULATORY CELLS,
ABLE TO ADDRESS SOME
LONGSTANDING ISSUES IN HUMAN
IMMUNOLOGY LIKE AGING, LIKE
STRAIN PREFERENCES IN FLU.
AND JUST THE ABILITY TO
MANIPULATE CELL POPULATIONS AND
GENE EDITING MEANS REALLY FOR
THE FIRST TIME WE CAN TEST
HYPOTHESES AND FIND MECHANISMS
IN ENTIRELY HUMAN SYSTEMS AND
THAT WILL BE THE BASIS OF A NEW
IMMUNOLOGY THAT NOW WE'RE GOING
TO FIND OUT A LOT OF WHAT WE'VE
BEEN MISSING.
AND THEN ALSO RECAPITULATING
IMMUNE NETWORKS, SKIN, THE
TRIPLE PLAY YOU HAVE SKIN AND
SPLEEN AND LUNG FROM THE SAME
DONOR, AND YOU VACCINATE THE
SKIN TO TRIGGER A RESPONSE IN
THE SPLEEN THAT HOPEFULLY IS
THEN PROTECTIVE AGAINST
INFECTION IN THE LUNG.
ALL IN THE SAME.
AND OF COURSE WE'RE ALSO TRAINED
MORE DIRECTLY TO COMPARE HUMAN
AND MICE USING ALL THE FANTASTIC
TECHNOLOGY THAT'S AVAILABLE.
LAST SLIDE.
OF COURSE NONE OF THIS WOULD BE
POSSIBLE WITHOUT SOME REALLY
TALENTED PEOPLE IN THE GROUP AND
COLLABORATORS, I MENTIONED CD
SUPPRESSION KNOCKOUT
EXPERIMENTS, GREAT
COLLABORATORS, MARY, CALVIN,
SCOTT.
LOTS OF PATIENT-FUNDING
AGENCIES, NATIONAL INSTITUTE OF
AGING, NIA, SO THANK YOU.
>> THANKS FOR A GREAT TALK.
WE HAVE TIME FOR QUESTIONS.
PLEASE RAISE YOUR HAND.
SPEAK INTO THE MICROPHONE AND
INTRODUCE YOURSELF AND WHICH
INSTITUTION YOU'RE FROM.
>> MICHELLE, CAMBRIDGE U.K.
I THOUGHT THE FOXP3 KNOCKOUT WAS
COOL AND DATA ON AGING ANTIBODY
AND AFFINITY
[AUDIO DISTORTION]
CURIOUS WHETHER YOU HAVE MORE
CENTERS --
[AUDIO DISTORTION]
>> YEAH.
IT'S INTERESTING.
ONE OF THE TECHNICAL ISSUES WITH
ORGANOIDS IS THEY ARE VERY
SLOPPY, THEY ARE NOT AS WELL
FORMED, OTHER ORGANOIDS ARE
BIOPSIES THAT YOU THEN ARE
CULTURING, DON'T HAVE A LOT OF
STRUCTURE AROUND FALL APART
EASILY.
IT'S A CHALLENGE TO EVEN GET
GERMINAL CENTER PICTURES, WE'RE
LOOKING FOR BETTER WAYS.
MAYBE MULTI-PHOTON MICROSCOPY,
IT WILL BE REALLY GOOD.
SOMEDAY WE HOPE TO HAVE MOVIES
OF GERMINAL CENTERS FORMING AND
CELLS RUNNING RUN.
WE'RE NOT THERE YET.
>> I WAS CURIOUS BECAUSE YOU
DON'T HAVE THE NETWORK THAT
UNDERPINS THE --
>>WE DO.
>> WITH THE SPLEEN ORGANOIDS
YOU GET THE STROMAL CELLS?
>> YEAH, YEAH.
>> DOES IT FORM THE NORMAL
ZONAL STRUCTURES?
AGAIN WE NEED BETTER MICROSCOPY,
TRYING TO WORK THAT OUT.
IT'S A FRONTIER.
IT'S SOMETHING WE WANT TO GET
TO.
[AUDIO DISTORTION]
>> ONE THING WE CAN DO PARTLY
BECAUSE IT IS A DIFFUSE TYPE OF
ORGANOID CAN MANIPULATE CELL
POPULATIONS, AND THAT'S ALMOST
THE EASIEST THING.
SO WE JUST NOTICED IN THE
ORIGINAL PROTOCOL FOR SPLEENS,
WE DID NOT GET STROMAL CELLS,
BUT THEN ONE OF MY STUDENTS
FIGURED THIS OUT AND DEVELOPED A
NEW PROTOCOL SO WE'RE JUST IN
THAT MIX RIGHT NOW.
STAY TUNED.
YES?
>> LIZ KOVAZ, UNIVERSITY OF
COLORADO, INTRIGUED BY THE
CONCEPT OF BEING ABLE TO TAKE
TISSUE FROM YOUNGER AND OLDER
SUBJECTS AND BEING ABLE TO
COMPARE BECAUSE HOW ELSE --
[AUDIO DISTORTION]
BUT I'M CONCERNED WHEN TONSILS
ARE TAKEN OUT OF LITTLE KIDS,
BECAUSE OF INFECTION.
>> THEY ARE ACTUALLY -- KIDS,
LITTLE THROATS.
WE TRY TO USE TONSILS FROM
TONSILLITIS, THEY WERE A MESS,
INFLAMED, YOU COULDN'T REALLY DO
ANY OF THE THINGS WE DO, SO WE
ONLY NOW GET THEM FROM SLEEP
APNEA FOR CHILDREN AND ALL THE
WAY UP.
SO THE WHOLE AGE SPAN IS
AVAILABLE.
THERE'S ANOTHER PROJECT WE'RE
STILL KNOCK QUITE READY FOR
PRIME TIME WHICH IS LOOKING AT
IMMUNE RESPONSES, WHAT'S
DIFFERENT?
I MEAN WE KNOW HISTORICALLY THAT
KIDS UNDER 5 ARE TREMENDOUSLY
SUSCEPTIBLE TO INFECTIOUS
DISEASE, THERE'S HUGE INFANT
MORTALITY FOR THAT REASON BUT
NOW IT'S GONE AWAY BECAUSE OF
VACCINES BUT THAT MEANS THERE'S
A WHOLE MYSTERY THERE JUST
WHAT'S DEFICIENT IN EARLY
CHILDHOOD FROM THE IMMUNE SYSTEM
THAT MAKES THEM SO VULNERABLE.
ONE ANSWER IS T INDEPENDENT
RESPONSES.
IN THE NATURE MEDICINE PAPER WE
HAVE NICE DATA TO SAY CHILDREN
UNDER 5 COULD NOT, IF YOU
DELETED T CELLS, COULD NOT MAKE
AN ANTIBODY RESPONSE TO FLU BUT
OVER 5 COULD.
AND SO IT'S ABOUT T
INDEPENDENTS, SOMEHOW T CELL
INDEPENDENT RESPONSES ONLY
HAPPEN AFTER 5 OR SO YEARS, SO
ANYWAY THERE'S A HUGE AMOUNT TO
DO AND TONSILS ARE A REALLY
PROMISING WAY TO TAKE APART
WHAT'S GOING ON AND MAKE BETTER
VACCINES THOUGH WE ALREADY MAKE
VACCINES FOR KIDS LIKE
PNEUMONIA, THEY HAVE TO HAVE A
PROTEIN COMPONENT OR THEY DON'T
WORK.
SO, AGAIN, BECAUSE T INDEPENDENT
IS OFTEN CARBOHYDRATE SPECIFIC,
AND LIPID.
THERE'S A TREMENDOUS AMOUNT WE
CAN LEARN FROM ORGANOIDS.
YEAH, THEY ARE NOT -- THEY MAY
NOT BE NORMAL.
WE GOT THIS CRITICISM ALL THE
TIME IN OUR EARLY GRANTS.
WELL, THEY ARE NOT NORMAL.
YEAH, WELL, PROBABLY NOT.
BUT THEY WORK.
SO WE'RE GOING WITH IT.
THERE'S SOME THINGS YOU JUST
HAVE TO IGNORE.
I'M SURE NO ONE ELSE HAS THIS.
>> I'LL ASK OTHER QUESTIONS.
BAYLOR COLLEGE OF MEDICINE.
CAN YOU COMMENT ON LOGISTICAL
ISSUES WITH HAVING TISSUES FROM
VARIOUS ACROSS THE BODY AND
IMMUNE CELLS, MATRIGEL, SO ON,
COMMENT ON LOGISTICS TO THINK
ABOUT.
>> THIS IS A HUGE CHALLENGE FOR
ACADEMIC LABS.
IF I WAS IN A COMPANY YOU WOULD
SET UP A WHOLE FACILITY TO DO
THIS.
THAT'S WHAT I'VE DONE IN THE
LAB.
I HAVE SENIOR POSTDOC AND TWO
TECHNICIANS WHO ARE BRINGING IN
TONSILS, PEDIATRIC TONSILS,
ADULT TONSILS FROM ADULT
SURGEONS, NOW WE HAVE THREE
DIFFERENT SCREENS OF TISSUE.
AND OF COURSE IT'S NOT SOMETHING
MOST LABS WANT TO HANDLE BUT IT
WORKS.
AND WE'RE BANKING BASICALLY
PROCESSING, YOU KNOW, MAKING
SINGLE CELL SUSPENSIONS OF
EVERYTHING WHICH TAKES HOURS FOR
EACH EVENT.
AND SO WE'VE GOT A LOT OF WORK
TO DO.
AT THE END OF THE DAY NOW WE
HAVE OVER 400 ALIQUOTS FROM
SPLEENS ALONE.
WE HAVE A FEW HUNDRED FROM
TONSILS.
IT MAKES AVAILABLE TO EVERYONE
IN THE LAB, THEY CAN GET A
FROZEN FILE AND DO AN
EXPERIMENT.
SO I'D LIKE TO SEE THIS IN THE
NATIONAL LEVEL, IN CASE ANYONE
IS LISTENING ON THAT SIDE.
THIS IS -- YOU KNOW, THESE
SPLEENS ARE THIRTY OR FORTY
THOUSAND TRANSPLANTS EVERY YEAR
IN THE U.S., 30,000 OR 40, 40,00
SPLEENS NO ONE WANTS, COULD BE
PART OF A NATIONAL FACILITY THAT
WOULD LOWER ACTIVATION ENERGY
FOR ANYONE THAT WANTS TO DO
HUMAN IMMUNOLOGY BUT IT'S
UNCOMFORTABLE BEING TOO FAR FROM
THE MOUSE ROUTE.
JUST A THOUGHT.
>>ORGANOID CHIP MODELS.
>> THAT'S OUR BIG RIVAL.
>> YEAH.
>> SORT OF.
WE'RE SLIGHTLY AHEAD OF THEM.
I THINK FLOW IS GOOD.
FLOWING MEDIA DEFINITELY IS A
WAY TO KEEP CELLS HEALTHIER BUT
WE SEEM TO BE DOING OKAY WITH
THE TRANSWELL SYSTEM WHERE YOU
BASICALLY HAVE A MEDIA THAT'S
SUPPORTING 12 WELLS WITH
PERMEABLE MEMBRANES.
WE DO CHANGE THE MEDIA.
WE DO FEED THE MEDIA.
THESE ARE NOT SUPER LONG TERM,
TWO WEEKS, TWO WEEKS TO FOUR
WEEKS IS THE LIFETIME OF A
CONSOLE OR SPLEEN ORGANOID.
SO, SO FAR WE HAVEN'T SEEN THE
NEED.
WE HAVE BEEN OF COURSE LOOKING
AT THE LITERATURE FOR ORGAN ON A
CHIP AND I DO THINK FLOW IS
ALWAYS A GOOD THING, IF YOU CAN
WORK IT IN, DISRUPTION.
>> ONE MORE QUESTION.
>> RICHARD HODES, NIA,
DIFFERENCE BETWEEN EPITOPE AND
CROSS-LINKING, TAKE US THROUGH
WHAT ULTIMATELY GIVES THAT
DIFFERENCE.
>> RIGHT.
SO, THE WAY WE THINK IT'S
HAPPENING IS YOU HAVE THIS
CONSTRUCT THAT HAS FOUR
DIFFERENT HA STRAINS ON IT, AND
SO ANY B CELL THAT HAS
ANTIBODIES SPECIFIC FOR ANY OF
THOSE STRAINS AS WELL AS
CROSS-REACTIVE ONES WILL PULL IN
THE WHOLE SELECTION AND PROCESS
AND PRESENT ALL THAT IT CAN,
GIVEN ITS MAKEUP IS.
SO THAT'S A LOT OF HELP.
YOU KNOW, AND I'M ALSO -- WE
DON'T HAVE EXACT NUMBERS BUT
KNOW A TREMENDOUS NUMBER OF B
CELLS ALREADY SPECIFIC FOR FLU,
WE IMAGINE T CELLS AS WELL, SO
BEING ABLE TO MOBILIZE ALL OF
THAT HELP THAT'S THERE SITTING
WAITING SEEMS TO BE ABLE TO
BOOST UP THE OTHER ANTIBODY
RESPONSES TO THE DISFAVORITE
STRAIN.
>> SO THE EFFICIENCY OF CELLS,
ULTIMATELY ANTIBODY RESPONSE --
[AUDIO DISTORTION]
>> ABSOLUTELY.
BUT THERE HAVE BEEN -- THE ONE
THEY SHOWED ME, OTHER PAPERS IN
THE FIELD HAVE DONE EXPERIMENTS
TO SHOW THAT HELP IS LIMITING,
SPECIFICALLY HELP IS LIMITING
FOR ANY PARTICULAR B CELL
RESPONSE SO BY MOBILIZING MORE T
CELL HELP WE'LL PUSH TO THE
LIMIT.
WHAT THAT LIMIT IS, I DON'T
KNOW, WE HAVEN'T HIT IT YET.
WE'VE REALLY HIT IT WITH SOME OF
THESE EXPERIMENTS WE'RE PLANNING
WITH HIV OR BIRD FLU, IT'S GOING
TO DEPEND HOW MANY B CELLS ARE
THERE WITH SPECIFICITY TO WORK
WITH, AND HOW MUCH, YOU KNOW,
GOING TO BE SOME PLATEAU VALUE.
SO INDEPENDENT ON THE FREQUENCY
OF B CELLS WITH BIGGER
SPECIFICITY BUT IT WORKED REALLY
WELL.
>>BASED ON EFFICIENCY PRIMING T
CELLS NOT HAVING MORE B CELLS.
>> RIGHT.
>> WHICH EVER IS LIMITING IN A
GIVEN CIRCUMSTANCE
EFFICIENCY OF THAT APPROACH.
>> ABSOLUTELY.
>> ANY QUESTIONS ONLINE?
THANK YOU SO MUCH.
>> WE'RE GOING TO TAKE SHORT
BREAK BEFORE THE NEXT SESSION,
SO MAYBE 10 OR 12 MINUTES.
MARK, THANK YOU.
THANK YOU FOR B CELL HELP.
WE'LL BE BACK.
>> WE'LL COME BACK AT 10:20.
THE AV PERSON WILL MAKE SOME
ADJUSTMENTS.
AND GRACE HAS AN ANNOUNCEMENT
FOR EVERYBODY AS WELL.
INADEQUATE STEM CELL BIOLOGY,
WORKING WITH MOUSE MODEL, GOOD
SURROGATE TO UNDERSTAND BIOLOGY
OF THE BLOOD SYSTEM.
WITH AGE, WE HAVE AN EXPANSION
OF HEMATOPOIETIC STEM CELL IN
BLACK 57 MICE, OKAY IN OTHERS,
PROGRESSIVELY EXPONENTIAL.
IN THE BEST CHARACTERISTIC IN
TERMS OF DEFICIENCY IS LACK OF
POTENTIAL, YOUNG MICE FAIL TO
RECONSTITUTE TO THE EXTENT TO
YOUNG STEM CELL DO, AND OUTPUT
IS EXTREMELY BIASED, FAIL TO
MAKE.
THE UNDERLYING BASIS OF A LOT OF
AGE-RELATED BLOOD DEFECT,
ACCUMULATION OF HEMATOPOIETIC
STEM CELL IMPAIR REGENERATION
POTENTIAL WHICH PRODUCE A LOT
MORE MYELOID AND PLATELET IN
MICE AND MUCH LESS RED BLOOD
CELL ASSOCIATED WITH DISORDER
I'M NOT GOING TO TALK ABOUT.
LIKE IN EVERY AGING CELL, WE
HAVE THIS BALANCE BETWEEN ALL
RANGE OF REGULATION IN THE CASE
OF THE BONE MARROW NICHE.
I FORGET TO PUT THE SLIDE TO
HIGHLIGHT THIS QUESTION, IF
THERE IS ONE THING I WOULD LIKE
TO SAY THE PROBLEM WE ARE FACING
AT THIS POINT WE HAVE A LOT OF
INDICATION OF INDIVIDUAL
REGULATION, BUT VERY LITTLE
UNDERSTANDING OF HOW THEY FIT
TOGETHER WHAT I WANT TO TELL YOU
IS A TALE OF CHRONIC
INFLAMMATION, CHANGE IN THE
STROMA DRIVING AGE-RELATED
INFLAMMATION HAS IMPACT ON THE
BLOOD SYSTEM AND ITS FUNCTION.
I WANT TO START WITH WORK I'VE
DONE WHEN I WAS AT UCSF TO SHOW
IN THE CONTEXT OF BLACK THE GOAL
OF AGING BIOLOGY HEMATOPOIETIC
STEM CELL FUNCTION, CLASSICAL
SYSTEMIC BLOOD-BORNE
INTERVENTION WHICH HAS SHOWN TO
WORK IN MANY OTHER ORGANS DO NOT
WORK WITH HEMATOPOIETIC STEM
CELL AND YOU HAVE AN EXAMPLE OF
THIS APPROACH, THERE'S
ABSOLUTELY NO CHANGE, PLASMA
TRANSFER TO OLD MICE DOESN'T
CHANGE ABILITY OF STEM CELL OR
LOOKING AT CROSSOVER AND THE
LODGING OF OLD CELL CROSSING TO
YOUNG EXPOSED TO YOUNG BONE
MARROW NICHE DOES HAVE EFFECT,
SHOWN IN GRADIENT OF ONE MONTH
AFTER, FOUR MONTHS AFTER
SEPARATION, LACKS REGENERATIVE
POTENTIAL EXTENDED TO OTHER TYPE
OF INTERVENTION.
AND WE DO NOT SEE AN EFFECT ON
REGENERATIVE HEMATOPOIETIC STEM
CELL, REGENERATION POTENTIAL.
BASICALLY WHAT WE NOTICED, NONE
OF THE SYSTEMIC APPROACH WERE
ABLE TO CHANGE THE LEVEL OF BONE
MARROW INFLAMMATION.
ANOTHER STORY, CAN I GO BACK ONE
SLIDE?
OKAY.
ANOTHER STORY WE DID, AND WE
LOOK AT THE GRADATION OF THE
BONE NARROW NICHE, YOU CAN SEE
IN THE RNAseq ANALYSIS OF THE
YOUNG STROMA, A LOT OF DIVERSITY
HERE, BIG POPULATION OF
ENDOTHELIAL CELL, AND SMALL
POPULATION OF MESENCHYMAL CELL,
WHICH EXPRESS A PARTICULAR
MARKER, LEPTIN RECEPTOR, A
SITUATION IN YOUNG MICE,
ABSOLUTELY NO CHRONIC
INFLAMMATION IN THE YOUNG NICHE.
IN CONTRAST IN OLD NICHE WE SEE
WE HAVE MASSIVE DEGRADATION,
THEY DIE FROM THE PROCESS AND
THIS MASSIVE EXPANSION OF
INFLAMMATORY POPULATION MSC-L,
ESTABLISH CROSS-TALK BETWEEN
DYSFUNCTION DRIVING PRODUCTION
OF THE INFLAMMATORY FACTOR, ACT
ON THE MARROW, LEPTIN RECEPTOR,
BUT MORE IMPORTANTLY THERE'S A
CROSSOVER BETWEEN THE
DYSFUNCTIONAL NICHE AND
DYSFUNCTIONAL AGED BLOOD SYSTEM
WHERE IN RESPONSE TO CHRONIC
INFLAMMATION WE HAVE ACTIVATION,
THE NOTION, ACTIVATION OF STEM
CELLS TO PRODUCE MORE
PROGENITOR.
AWAY IN NORMAL DISTRIBUTION OF
BLOOD CELL, TOWARD
OVEREXPRESSION OF MYELOID CELL
AND I DON'T KNOW IF IT'S BECAUSE
(INDISCERNIBLE).
BASICALLY WHAT WE FOUND AS WELL
IS THAT WE CAN --
>>ROOM 160 IS MUTED.
ROOM 160 IS MUTED.
WE BLOCK SIGNALING CAUSING STEM
CELL TO ACTIVATE AND PRODUCE
BLOOD CELL.
YOU CAN SEE RESULTS HERE IN
YOUNG MICE, TREATMENT WITH
ANAKINRA NO NEGATIVE EFFECT, IN
OLD MICE VERY NASTY MARROW
CONTENT WHEN YOU INDUCE 5FU
CHALLENGE, REGENERATE THE BLOOD
SYSTEM IN SITU, USUALLY IMPROVED
WHEN WE BLOCK SIGNALING.
FOR THE MICE WE USE INTERLEUKIN
1 DEFICIENT MICE AND CAN SEE IN
THE CONTEXT WE ARE VERY MUCH
RECUING INFLAMMATORY NATURE, AGE
BONE MARROW NICHE, NOT RESCUING
THE CHANGING BUT DAMPENING THE
BLUE, THEY ARE BACK TO THIS
ORANGE MSCL 2 SUBSET
NON-INFLAMMATORY GOOD GUY.
AS A CONSEQUENCE, WHEN
TRANSPLANTED COMPARED TO OLD
STEM CELL, OLD STEM CELL FROM
INTERLEUKIN 1 REMAINS IN
ORIGINAL STATE POTENTIAL MUCH
LESS AGING FEATURE IN THE MICE
WHICH LACK INTERLEUKIN 1
SIGNALING OVER THE LIFESPAN.
SO THIS IS KIND OF LIKE THE
MESSAGE OF THE PAPER, REALLY THE
CROSS-TALK BETWEEN AN INFLAMED
NICHE AND REGULATION OF BLOOD
PRODUCTION, ALL WE CAN RESCUE
SOME ASPECT OF AGING, BALANCING
OF BLOOD PRODUCTION BY BLOCKING
INTERLEUKIN 1 SIGNALING.
WHAT I WANT TO TELL YOU NOW IS
THAT YOU CANNOT WELL PLATE ON
AGE-RELATED CHRONIC
INFLAMMATION, AND HAVE DIRECT
EFFECT, ON SOME PROPERTIES WHICH
ARE THE DEREGULATED IN
HEMATOPOIETIC STEM CELL AND
BRING BACK AUTOPHAGY, IN
PARTICULAR USED IN YOUNG STEM
CELL AS KEY STRESS RESPONSE
MECHANISM WHICH PARTICULARLY
QUIESCENCE, A FUNDAMENTAL
PROPERTY FOR STEM CELLS TO BE
ABLE TO ENGRAFT IN TRANSPLANTED
MICE.
AUTOPHAGY, WITH SIGNAL FROM
MITOCHONDRIA, GLYCOLYTIC, THE
BASIS OF YOUNG STEM CELL
REGENERATIVE ACTIVITY.
WHAT WE SEE WITH AGE IN THIS
EXPANDED POPULATION, ACTIVATION
OF AUTOPHAGY IN A SUBSET, AND
THESE WHEN TRANSPLANTED ENGRAFT
MUCH BETTER, WITH ALL THE
HALLMARKS.
SO WE WERE VERY INTERESTED TO
UNDERSTAND THE MECHANISM BEHIND
THAT AND CONNECTION TO CHRONIC
INFLAMMATION.
THIS IS JUST THE MODEL WE USE,
YOUNG AND OLD, AUTOPHAGY
REPORTER MICE, CAN SEPARATE
BASED ON INTENSITY OF THE GFP
SIGNAL WHEN YOU DOWNREGULATE
GPF-LC 3 INTENSITY AND CAN
REGULATE FROM AUTOPHAGY
INACTIVATED OLD STEM CELL
DIFFERENT FROM YOUNG, WHERE WE
TAKE ANYTHING ALONG THE CURVE,
EXACTLY THE SAME FUNCTION, VERY
DIFFERENT.
SO THE ANALYSIS, WE DID
ATAC-SEQ, RNAseq, SINGLE CELL
RNAseq.
I'M NOT GOING TO SHOW ALL OF
THAT.
I WANT TO SHOW YOU THE RESULTS,
DIFFERENCE IN TRANSCRIPTIONAL
NATURE OF AUTOPHAGY ACTIVATED
NON-ACTIVATED OLD STEM CELL AND
WHAT WAS TRACKING WAS STRONG
PROMINENCE FOR INFLAMMATORY
SIGNATURE IN ASSOCIATE WITH
AUTOPHAGY ENGAGEMENT IN THE
QUIESCENT OLD STEM CELL SUBSET.
THAT LED US TO INFLAMMATION AS
AN INDUCER OF AUTOPHAGY, EXPOSED
YOUNG MICE TO ONE INJECTION OF
INTERFERON GAMMA WE HAVE THE
SAME RESULT WITH TNF ALPHA, IN
INTERFERON GAMMA PARTICULARLY
YOU SEE REPRESSION OF AUTOPHAGY
SIGNAL INTENSITY, THAT WHEN THE
CELL ENTERS THE CELL CYCLE
THERE'S MUCH LESS QUIESCENCE,
MUCH MORE CELL IN G1 PHASE, AND
BY 48 HOUR FOLLOWING ONE
CHALLENGE WHEN THE CELL ARE THE
MAX OF THEIR ACTIVATION AND NEED
TO RETURN TO QUIESCENCE, THIS IS
WHEN WE SEE THE DOWN-SHIFT
ENGAGEMENT OF AUTOPHAGY, USING
DEFICIENT MICE WE CAN SHOW WHEN
WE SUPPRESS THIS ABILITY TO
ENGAGE AUTOPHAGY TO REENTER
QUIESCENCE WE KILLED THE STEM
CELL, WHICH WAS AT IN VIVO BY
THE LOSS OF THE STEM CELL
COMPARTMENT, IN VITRO BY
PARTICULARLY LOSS OF EXPANSION
ACTIVITY AND AUTOPHAGY.
IN YOUNG MICE WITH REPEATED
INJECTION OF IL-1, A PERFECT
MODEL TO MIMIC AGING IN A YOUNG
BACKGROUND, 20 DAYS OF DAILY
INJECTION OF IL-1, WE SEE AGAIN
WITH DOWN SHIFT OF GFPL,
PARTICULARLY WHEN WE TEST
TRANSPLANTABILITY WE SEE EXACTLY
WHAT WE'VE SEEN WITH OLD AGE
WHICH IS AUTOPHAGY ENGAGED CELL
ENGRAFT ALMOST LIKE UNCHALLENGED
CELL, OKAY, VERSUS NON-ENGAGED,
ABSOLUTELY DEFECTIVE IN THE
REGENERATION POTENTIAL.
I NEED TO SPEED UP.
THE MECHANISM IS COMPLICATED,
INTERPLAY BETWEEN INFLAMMATION,
NUTRIENT SENSING PATHWAY,
KINASE, SIGNALING, MANAGEMENT OF
BLEW GLUCOSE.
WE SHOW SOC 3 IS DIFFERENTIALLY
EXPRESSED BETWEEN YOUNG AND OLD
STEM CELL, REPRESS PATHWAY,
TRANSPORTER, GLUCOSE RECEPTOR TO
THE SURFACE, EXPRESSION OF
GLUT1, NO CHANGE IN LOSS BETWEEN
YOUNG AND OLD, JUST EXPRESSION
ON THE SURFACE AND UPTAKE,
SUPPRESS IN THOSE CELLS, OLD
CELL, SUPPRESS KINASE, REALLY
LACK OF CORRELATION WHICH
INDICATE CELL WITH HIGHER LEVEL
OF INFLAMMATORY SIGNALING HAS NO
PHOSPHORYLATED FOXO, AND WHEN
THEY DO THAT THEY UNDERGO
METABOLIC ADAPTATION, I'M NOT
SHOWING DATA BUT PARTICULARLY
SHIFT TO LIPID METABOLISM,
BETTER OXIDATION, WHICH IS
ALTERNATIVE WAY TO BE MAINTAINED
IN THIS INFLAMMATORY NICHE,
SURVIVE THE INFLAMMATORY
CHALLENGE.
CAN WE MANIPULATE THIS
INFORMATION TO OLD STEM CELL
FUNCTION AND IMPROVE
REGENERATION POTENTIAL?
YES, WE WENT BACK TO THE LITTER,
REFEEDING, WHEN WE DO RECEIPT IN
SHORT STEM, 24 HOUR FASTING, 24
HOUR REFEEDING WITH FASTING, WE
SEE INDUCTION OF AUTOPHAGY IN
YOUNG MICE AND IN OLD MICE.
WE SEE NOW REVISION BRINGS BACK
TO THE LEVEL WHAT WE EXPECT IN
YOUNG MICE.
BINGO.
WHEN WE TEST ENGRAFTABILITY OF
OLD CELL WE SEE ALMOST NORMAL
REGENERATIVE POTENTIAL, WHICH IS
ABSOLUTELY NOT OBSERVED WHEN WE
JUST FAST AND ACTUALLY HAVE SOME
REBALANCING OF BLOOD
DISTRIBUTION IN THESE
TRANSPLANTED MICE WITH
REAPPEARANCE OF SOME BETTER
OUTPUT.
SO WE KNOW IT'S NOT JUST
AUTOPHAGY ENGAGEMENT BECAUSE WE
DON'T SEE THIS RESCUE.
AND PARTICULARLY WHAT WE'RE
DOING IS WE'RE RESTORING GLUCOSE
METABOLISM EXPRESSION OF GLUT1
AND GLYCOLYTIC METABOLICS, THAT
PARTICULARLY THE MODEL THAT
WE'RE PROPOSING AND HOPEFULLY
YOU WILL BE ABLE TO READ ABOUT
SOON IN THE LITERATURE, AND
PARTICULARLY IT JUST TELL US BY
UNDERSTANDING THE CROSSOVER
BETWEEN NICHE AND DEREGULATION
WE CAN REALLY DESIGN THE
TARGETED INTERVENTION,
HEMATOPOIETIC STEM CELL, BASED
ON WHAT THE CELL ARE
EXPERIENCING IN THEIR OWN NICHE
AND NOT WHAT'S TRENDING WITH
OTHER ORGAN DAMAGE.
I THANK MY LAB, ALL THE PEOPLE
WORKENING ON THIS PROJECT HAVE
BEEN HIGHLIGHTED, AND CARL
MITCHELL IS HERE AND WILL
PRESENT A POSTER TOMORROW IN THE
POSTER SESSION.
IF ANYONE IS INTERESTED WE HAVE
SOME LITERATURE RELATED TO THIS
QUESTION.
THANK YOU.
>> THANK YOU.
EXCELLENT.
WE MAY HAVE TIME FOR ONE
QUESTION SO WE CAN STAY ON TIME
BUT THIS WAS -- YOUR CONNECTION
BETWEEN ALL OF THE METABOLISM
AND EVERYTHING THAT YOU'VE BEEN
DOING.
IN THE BACK, SAY YOUR NAME.
>> FRED HUTCH.
INTRODUCED IN THE MESENCHYMAL
CELLS, ARE THEY DYING,
UNDERGOING APOPTOSIS?
>> ONE SOURCE OF IL-1, OTHER
SOURCES HAVE BEEN ISOLATED BY
OTHER PEOPLE, NO, WE DIDN'T SEE
MACROPHAGE BEING THE MAIN SOURCE
OF IL-1.
WE SAW OSTEOPROGENITOR, ONE
POPULATION SHRINKING WITH AGE,
THIS CELL BECOME EVEN MORE
DYSFUNCTION, ACTIVATED, WE SEE A
LOT OF PRODUCTION OF IL-1 FROM
THIS CELL.
>> ARE THEY DYING OUT?
>>WELL, THE POPULATION IS
COLLAPSING SO I THINK THEY ARE
PROGRESSIVELY DYING, AND IN
DYING CREATING A LOT OF IL-1.
BUT THEY DO NOT HAVE MARKER OF
THAT, WE CAN CULTIVATE, DO
CULTURE WITH OLD, SO THEY WILL
EVENTUALLY DIE BUT BEFORE THAT
THEY ARE PRODUCING A LOT OF
IL-1.
>> THANK YOU SO MUCH.
WE'LL GO TO THE NEXT SPEAKER,
EMILY GOLDBERG FROM UCSF,
TALKING ABOUT INNATE LYMPHOID
CELLS IN AN AGED
MICROENVIRONMENT.
>> HERE WE GO.
I DON'T KNOW IF I'LL BE
CONTROLLING THIS.
EMILY GOLDBERG.
THANKS FOR THE INTRODUCTION.
WHAT I HAVE TODAY IS NOT THE
COMPLETE STORY, BEAUTIFUL STORY
EMANUELLE JUST SHOWED YOU, THIS
IS A LOOK AT WHERE WE'RE GOING.
LET'S SEE IF I CAN MAKE THIS --
I DON'T KNOW WHAT I'M GOING TO
MAKE IT MOVE BUT IT'S GOING.
EVERYONE IN THIS ROOM KNOWS THAT
AGING IS ASSOCIATED WITH A
CHRONIC LOW GRADE INFLAMMATION,
ASSOCIATED WITH MANY AGE-RELATED
DISEASES.
BUT I THINK WHAT IS REALLY
IMPORTANT TO THINK ABOUT IS THAT
THIS AFFECTS BASICALLY EVERY
ORGAN SYSTEM IN THE BODY, RIGHT?
EVERY ORGAN IS SUSCEPTIBLE TO
AGE-RELATED DISEASE, AGE-RELATED
FUNCTIONAL DECLINE, ILLUSTRATED
IN THE PIECHART ON THE BOTTOM
RIGHT, WHERE WE LOOKED AT DATA
THAT WAS EXPLAINING THE CAUSE OF
DEATH IN ELDERLY AND YOU CAN SEE
IT'S IN EVERY ORGAN.
WE HAVE CARDIOVASCULAR DISEASES,
LEADING CAUSE OF DEATH.
CANCERS, METABOLIC DISORDERS,
NEUROLOGICAL DISORDERS,
MUSCULOSKELETAL, A COMPLEX
PROBLEM RATHER THAN TREATING
INDIVIDUAL SYMPTOMS OF
INDIVIDUAL DISEASES, IF WE COULD
INSTEAD UNDERSTAND MECHANISMS
THAT ARE ALLOWING FOR THAT
INFLAMMATION TO ARISE IN THE
FIRST PLACE PERHAPS WE COULD
PREVENT DISEASE, WE COULD A
ALLEVIATE MULTIPLE SYMPTOMS OR
DISEASES SIMULTANEOUSLY.
AND I REALLY LIKE THIS CARTOON
BECAUSE THIS IS SUPPOSED TO
EMPHASIZE THAT EXCESSIVE
ADIPOSITY IS ALSO ASSOCIATED
WITH CHRONIC DISEASES AND
INFLAMMATION.
THIS IS ILLUSTRATED IN THE
CONTEXT OF OBESITY BUT WHAT I
HOPE YOU CAN APPRECIATE IS THAT
ALL THESE DISEASES HERE ARE
BASICALLY ON THE PREVIOUS SLIDE,
RIGHT?
THESE ARE IMMUNE SENESCENCE
DISEASES, INFECTION
SUSCEPTIBILITY, CANCERS, ALL
DISEASES OF AGING.
THERE ARE PEOPLE IN THIS ROOM
TALKING ABOUT THIS FOR A LONG
TIME TOO BUT WE THINK THAT
ADIPOSE TISSUE CAN BE A VERY
IMPORTANT DRIVER OF INFLAMMATION
IN AGING, SOME OF THIS MIGHT
MODEL -- MIGHT BE SIMILAR TO
WHAT WE SEE IN OBESITY, SOME
MIGHT BE AGE-SPECIFIC
MECHANISMS.
AND SO WE ARE IMMUNOLOGISTS,
INTERESTED IN STUDYING HOW THE
IMMUNE SYSTEM CAN HELP CONTROL
INFLAMMATION AND ORGAN
PHYSIOLOGY, AND SO BECAUSE WE'RE
INTERESTED IN ADIPOSE TISSUE WE
WANTED TO STUDY THIS IN THE
ADIPOSE-RESIDENT IMMUNE
COMPARTMENT.
THE WAY WE STUDY THIS IS WE CAN
GIVE AN IV INJECTION OF AN
ANTIBODY THAT WILL BIND ALL
MATURE IMMUNE CELLS IN THE
BLOOD, IT DOESN'T GET A CHANCE
TO GO INTO THE TISSUE.
WE CAN USE THIS TO BASICALLY BE
ABLE TO SEGREGATE CELLS THAT ARE
CIRCULATING IN THE TISSUE OR
NON-CIRCULATING AT THE TIME OF
TISSUE COLLAPSING.
THERE'S A REPRESENTATIVE IMAGE
HERE OF A MOUSE, ALL THE IMMUNE
CELLS IN GREEN, YOU CAN SEE THEY
ARE RESTRICTED IN VAST VASCULAN
RED, ONE TINY PIECE OF FAT FROM
THE ANIMAL.
YOU CAN APPRECIATE IN DENSELY
VASCULARIZED TISSUE LIKE THE
FAT, FOR INSTANCE, HOW MANY
IMMUNE CELLS ARE ACTUALLY IN
CIRCULATION AND PASSIVELY MOVING
THROUGH THE TISSUE AT THE TIME
OF TISSUE COLLECTION BUT HAVE NO
INTEREST OR BEARING ON THE
BIOLOGY OF THAT ORGAN.
WE USE THIS APPROACH TO DO
SINGLE CELL RNA-SEQ TO HAVE AN
UNBIASED AND BROAD VIEW OF WHAT
IMMUNE CELLS ARE THAT ARE IN THE
FAT AND HOW THEY ARE CHANGING
DURING AGING.
WE DID THESE IN THE LAB AND WE
KNEW THERE'S A TON OF IMMUNE
CELLS IN THE FAT.
IF YOU DON'T KNOW ALREADY,
ESSENTIALLY ANY IMMUNE CELLS IN
THE PERIPHERY, YOU CAN FIND IN
SOME FLAVOR IN YOUR FAT TISSUE,
HAS A HUGE IMMUNE COMPARTMENT,
DISPLAYS VERY LARGE CHANGES WITH
AGE.
BASICALLY EVERY IMMUNE CELL
THAT'S PRESENT IN THE FAT IS
CHANGING IN SOME WAY IN AGING,
SOME ARE GOING UP, SOME GOING
DOWN.
WHAT I HAVE TODAY IS A VERY
BRIEF RECAP ON THE --
ESSENTIALLY COMPLETE LOSS OF
IMMUNE CELL SUBSET.
WE PUBLISHED THIS ALREADY BUT
I'M GOING TO USE THIS AS SORT OF
OUR SEGUE TO EXPLAIN HOW WE ARE
CHOOSING WHAT DIRECTIONS WE MOVE
FORWARD IN.
AND SO, YOU KNOW, TO EXPLAIN WHY
WE'RE INTERESTED IN FOLLOWING UP
ON THIS LOSS OF ILC 2 OF AGING,
IT'S BECAUSE WE'VE BEEN GIVEN A
CENTRAL ROLE IN ADIPOSE TISSUE
BIOLOGY, AND SO THEY ARE THOUGHT
TO BE ABLE TO CONTROL ADIPOSE
TISSUE INFLAMMATION WITH
IMPORTANT SEQUENCES ON GLUCOSE
TOLERANCE, INSULIN SENSITIVITY,
BUT CAN ALSO BE IMPORTANT IN
HELPING TO INDICATE ADIPOSE
TISSUE THERMOGENESIS, IN
RESPONSE TO COLD.
IN AGING, BOTH OF THESE PROGRAMS
GET LOST AND DEREGULATED IN
AGING.
SO THIS WAS SHEATHING --
SATISFYING TO SEE A CELL TYPE
THAT CAN CONTROL BOTH IS LOSTING
IN AGING, PERHAPS A VERY SIMPLE
EXPLANATION FOR WHY YOU LOSE
THESE FUNCTIONS OF YOUR ADIPOSE
TISSUE.
SO WE ASKED THE FIRST QUESTION,
COULD WE RESTORE THESE CELLS?
CURE AGING WITH IMMUNE
REJUVENATION.
AND WE CAN DO THAT.
WE GIVE MICE IP INJECTION OF
ILC2 GROWTH FACTOR, IL-33, A
CYTOKINE IN THE IL-1 FAMILY.
THERE WE ARE.
AND WHAT YOU CAN SEE IS IN OLD
MICE GIVEN IL-33 WE CAN EXPAND
ILC2 ROBUSTLY, WHICH WE THOUGHT
WAS PROMISING.
AND WE'VE LOOKED AT LEAST THREE
MONTHS AFTER WE DO INJECTIONS,
ILC2s ARE RETAINED IN THE FAT,
A NICE THERAPEUTIC WINDOW TO
TEST AND ASK THE QUESTION COULD
WE RESTORE THE DYSFUNCTION THAT
SEEMS TO ARISE IN AGED FAT.
OKAY.
SO WE ASKED THIS QUESTION, CAN
WE INCREASE ILC 2 TO RECOVER
LOSS OF FUNCTIONALITY WITH
BENEFITS TO THE ORGANISM AS A
RESULT?
AND SO WHAT I'LL DO FOR THE SAKE
OF TIME IS SKIP EVERYTHING WE
LOOKED AT FOR METABOLIC HEALTH,
NO IMPACT ON GLUCOSE
HOMEOSTASIS, ADIPOSE TISSUE
INFLAMMATION, NOTHING.
INSTEAD WHAT HAPPENS WITH
THERMOGENESIS, CORE BODY
TEMPERATURE, WHAT YOU NEED, ALL
YOU NEED TO KNOW IS THAT ILC
2s HAVE A FEW DIFFERENT WAYS
THAT IT CAN -- THEY CAN INDUCE
THERMOGENESIS EITHER INDIRECTLY,
STIMULATE MACROPHAGE OR
EOSINOPHILS, CAN DO THIS
DIRECTLY THROUGH RELEASE OF
PEPTIDE, ALL OF THIS LEADS TO
THE ACTIVATION OF A PROGRAM
WHERE THEY INCREASE EXPRESSION
OF THIS PROTEIN UCP1, WHAT THIS
DOES IS WHEN YOU'RE BURNING FAT
FOR ENERGY INSTEAD OF GENERATING
ATP YOU GENERATE HEAT, OKAY?
AND WHAT WE WERE SURPRISED TO
FIND IS OLD MICE THAT WERE GIVEN
IL-33 AND EXPANDED ILC2s, HAVE
INCREASED SUSCEPTIBILITY TO COLD
CHALLENGE, FAILING TO UPREGULATE
UCP 1 IN ADIPOSE TISSUE,
SUCCUMBING TO THE COLD
CHALLENGE.
THIS IS WEIRD BECAUSE THE ILC 2
SHOULD NOT BE DOING THIS, SHOULD
HAVE OPPOSITE EFFECT.
WE THOUGHT THIS MEANT SOMETHING
IS WRONG WITH ILC2s PRESENT IN
OLD MICE.
WE DID ADOPTIVE TRANSFER
EXPERIMENT.
WE GOT MICE THAT EXPRESS THE RED
FLUORESCENT PROTEIN, ILC2s ARE
THE ONLY CELLS IN THE FAT
EXPRESSING IL-5 SO WE CAN EXPAND
IN VIVO, WE CAN SORT WITH FLOW
CYTOMETRY AND TRANSFER INTO OLD
MICE, THAT GOT ADULT ILC2s,
NOW PROTECTED FROM THE COLD
CHALLENGE.
INTRODUCTION OF ADULT ILC2 INTO
OLD HOST IS SUFFICIENT TO
PROTECT AGAINST THE COLD
CHALLENGE THAT'S OTHERWISE
LETHAL IN THE OLD MICE.
AND SO WE WANTED TO FIGURE OUT
WHAT IS THE DIFFERENCE IN ILC
2s IN AGING THAT MIGHT BE
UNDERLYING THE SORT OF -- THIS
PROBLEM WHETHER THE OLD ILC2s
ARE HEIGHTENING SUSCEPTIBILITY
TO COLD AND SO WE DID BOTH
RNAseq ON ADULT AND OLD
ILC2s FROM ADIPOSE TISSUE TO
UNDERSTAND THIS, AND AS EXPECTED
WE SAW A LOT OF CHANGES.
WHAT I WANT TO EMPHASIZE IS THE
GENE SIGNATURES BEING ENRICHED
IN THE OLD CELLS ARE ALL SORT OF
DOWNSTREAM ACTIVATION SIGNALS,
LIKE CYTOKINE SIGNALING
PATHWAYS, REFLECTIVE THAT THE
OLD ENVIRONMENT IS STILL
INFORMING AND IMPACTING THESE
CELLS, RIGHT?
SORT OF OUTSIDE-IN SIGNALING
BECOMING DYSREGULATED.
WE HAVE AN IMMUNE CELL INTRINSIC
DEFECT IN OLD ILC2s WE THOUGHT
THIS WAS STILL BEING --
REFLECTIVE STILL OF EXTERNAL
SIGNALS THAT ARE HAVING A
CONSEQUENCE ON THESE CELLS.
AND SO THAT HAS SHAPED A LOT
ABOUT HOW WE'RE THINKING ABOUT
THIS PROBLEM MOVING FORWARD.
WHERE WE STEP BACK AND THINK HOW
DOES AN IMMUNE CELL IN ADIPOSE
TISSUE BECOME DYSREGULATED OVER
THE LIFESPAN?
THEY ARE LONG LIVED, SEATED
EARLY, MAINTAINED THROUGH THE
LIFESPAN.
WE THINK THAT MAKES THEM
SUSCEPTIBLE TO DYSFUNCTIONAL
DYSREGULATION, THREE WAYS COULD
YOU HAVE APPARENT DYSREGULATION
OF THE RESIDENT IMMUNE
COMPARTMENT.
WE KNOW CELLS FROM THE PERIPHERY
ARE INFILTRATING OVER THE
LIFESPAN AND BECOME RESIDENT IN
THE FAT AND EVERY ORGAN, SO THAT
WOULD EFFECTIVELY MAKE THE
RESIDENT COMPARTMENT LOOK
DIFFERENT BECAUSE NEW CELLS ARE
COMING IN, THROUGH UNKNOWN
MECHANISMS.
THESE ARE CELLS ARE MAINTAINED
THROUGH SELF-RENEWAL, THIS COULD
PREDISPOSE TO THE POSSIBILITY OF
ACCUMULATING DEFECTS OVER TIME.
AND THEN BECAUSE THEY LIVE IN
THE TISSUE AND NEVER LEAVE, THEY
ARE GOING TO BE SUSCEPTIBLE TO
AGE-RELATED CHANGES THAT ARISE
IN THE TISSUE.
SO THAT'S GOING TO TELL YOU ONE
OF THE AREAS WE'RE INVESTIGATING
IS HOW WE CAN IDENTIFY SECRETED
FACTORS SPECIFICALLY IN AGED
ENVIRONMENT INFLUENCING IMMUNE
CELLS, NOT ONLY IN THAT TISSUE
BUT PERHAPS SYSTEMICALLY.
WE HAVE A PROBLEM HERE.
WE'RE INTERESTED IN HOW
DIFFERENT CELL TYPES IN FAT ARE
INFLUENCING RESIDENT IMMUNE
CELLS, BUT HOW DO WE DO THAT?
HOW DO WE TAKE BE A OLD ANIMAL,
OLD ORGANISM, WE KNOW A PROTEIN
CAME FROM FAT, IMPORTANT FOR
DOWNSTREAM PHYSIOLOGY WE'RE
INTERESTED IN STUDYING.
WE'VE BEEN THINKING ABOUT THAT
AND SAW A TALK BY MY COLLEAGUE
JOHN LONG AT STANFORD WHERE HE
HAD A BRILLIANT IDEA TO USE
ADENO-ASSOCIATE VIRUSES AS GENE
DELIVERY TOOLS TO EXPRESS
PROMISCUOUS LIGASE, EXPRESSING
THIS NOW SPECIFICALLY IN FAT
TISSUE AND CAN NOW MEASURE
SECRETED PROTEINS FROM FAT IN
VIVO.
THE WAY THIS WORKS IS IF WE HAVE
ADIPOCYTE HERE, USING THE VIRUS
TO EXPRESS ON MEMBRANE, WHAT
HAPPENS IS WE KNOW THERE'S A LOT
OF PROTEINS IN THE BLOOD.
WE'VE ALL MEASURED CYTOKINES IN
THE BLOOD.
NOW IT GETS BIOTINYLATED, WE CAN
ACTIVE PROTEINS THAT CAME FROM
ADIPOCYTES AND IDENTIFY AND ASK
WHAT'S GOING, IN AGING OR STRESS
CONDITIONS.
THE VIRUS HAS A V5 TAG WHICH
WE'RE USING TO CHECK TISSUE
SPECIFICITY.
LIVER LOVES AAVs, IT'S A
MASSIVE PROTEIN SECRETION ORGAN
SO WE MAKE SURE THERE'S
SPECIFICITY AND WE'RE NOT
INTEGRATING INTO THE LIVER, THAT
WOULD SWAMP OUT FAT SECRETION
BASICALLY.
AND THIS WAS WHAT THIS LOOKS
LIKE.
THIS IS -- PROTEINS ARE
BIOTYNLATED, THIS IS THE SILVER
STAIN GEL OF ADULT AND OLD MICE
THAT UNDERWENT THIS TREATMENT.
IF THEY DON'T GET THE AAV, IT'S
A CLEAN SYSTEM, YOU HAVE NO
BIOTYNLATED PROTEINS IN PLASMA,
IT'S REALLY NICE.
THANK YOU.
NOW WE CAN USE THESE SAMPLES AND
SUBMIT THEM FOR MASS SPEC,
IDENTIFY PROTEINS SECRETED.
WHERE ARE WE NOW, THE BIG
QUESTIONS WE THINK WE CAN HELP
ADDRESS IN THESE EXPERIMENTS?
WE CAN ASK HOW DIFFERENT TISSUES
ARE -- WHAT THEY ARE SECRETING,
HOW IT MIGHT CHANGE WITH AGE, IN
RESPONSE TO STRESS LIKE
INFECTION OR DIETARY
MANIPULATION, ASK HOW THESE
SECRETED PROTEINS MIGHT BE
INFLUENCING LOCAL IMMUNE CELLS,
SYSTEMIC IMMUNE RESPONSES,
VACCINATION OR SOMETHING LIKE
THAT, AND WE CAN ASK HOW AGED
FAT IS CONTRIBUTING TO OTHER
INFLAMMATORY DISEASES, HAVE ANY
MODEL OF DISEASE, YOU CAN INDUCE
IN MICE, WE CAN NOW USE THESE
STRATEGIES AND DO THIS IN LOTS
OF TISSUES, I'M SHOWING FAT BUT
WE HAVE TOOLS FOR LOTS OF
ORGANS.
I'LL END WITH ACKNOWLEDGMENTS.
THE IDEAS STARTED DURING MY
POSTDOC'S LAB, AND WE DID
SEQUENCING WITH MAX AND IRINA,
CONTINUING IN MY LAB ARE
PROTEOMICS, HAPPY TO TAKE
QUESTIONS.
>> GREAT.
JUST GREAT.
HERE'S A QUESTION.
>> BAYLOR COLLEGE OF MEDICINE.
TERRIFIC TALK, EMILY.
I NOTICED IN YOUR TRANSCRIPTOMIC
ANALYSIS YOUNG VERSUS OLD YOU
SAW INVOLVEMENT OF RIBOSOMES IN
YOUNG NOT IN OLD.
YOU DISCUSSED EXTRINSIC BUT AS
CELLS ARE AGING MAYBE THEY ARE
LOSING TRANSLATIONAL CAPACITY?
>> YES, WE HAVE AN NIH-FRIENDLY
HYPOTHESIS THAT BOTH CELL
INTRINSIC AN EXTRINSIC ARE AT
PLAY.
I FOCUSED ON ONE, FUN AND OF
INTEREST TO THE COMMUNITY.
WE THINK THERE'S INTRINSIC AS
WELL.
THESE ARE SUPPOSED TO BE MAJOR
CYTOKINE PRODUCERS AND STUFF
LIKE THAT SO WE EXPECT TO SEE
SIGNATURES IN HEALTHY CELLS.
>> AND FOLLOWING UP DO YOU SEE
REDUCED IL-33 SECRETION?
>> IL-33 DOESN'T COME FROM
THESE CELLS BUT FROM STROMAL
CELLS IN THE FAT, NOT SO MUCH
THERE'S LESS BUT WE THINK
BIOAVAILABILITY, YEAH.
>> AND WE HAVE ANOTHER
QUESTION.
>> NORTHWESTERN.
THANKS FOR A GREAT TALK.
QUICK QUESTION.
IF YOU SEE AGE RELATED CHANGES
IN ILCs IN THE FAT, CALORIC
RESTRICTION, ANTI-AGING
INTERVENTION OR RAPAMYCIN OR GLP
AGONIST?
>>WE HAVEN'T DONE ANYTHING
MODERN.
WE'VE DONE CALORIC RESTRICTION.
AS A PIECE OF THE PIE THE ILC2S
ARE RETAINED IN CALORICALLY
RESTRICTED ANIMALS BUT THESE
MICE ARE LYMPHOPENIC, DEPENDS
WHAT'S IMPORTANT, DO YOU NEED
MORE CELLS OR TO BE A BIGGER
REPRESENTATION?
THEY SEEM LIKE THEY ARE
PRESERVED BUT THAT'S AS MUCH
CHARACTERIZATION AS WE DID.
YEAH, THANK YOU.
>> ONE LAST QUESTION.
>>UCSF.
SYMPATHETIC NERVOUS SYSTEM THAT
TISSUE IS INNOVATIVE, I WAS
WONDERING ABOUT LOCAL INFLUENCE.
>> YEAH, SO THERE'S BEEN A
LITTLE BIT OF WORK DONE ON THAT
WITH THESE CELLS IN PARTICULAR,
DAVID ARTIS' LAB LOOKED AT
NEUROIMMUNE INTERACTION, ALL THE
IMMUNE CELLS IN THE FAT ARE
ARRANGED NEAR THE VASCULATURE
WHICH TENDS TO CO-LOCALIZE WITH
THE SYMPATHETIC NERVOUS SYSTEM
SO THERE'S SOMETHING GOING ON
THERE BUT I DON'T KNOW THAT'S
BEEN LOOKED AT CAREFULLY AND WE
DIDN'T REALLY INVESTIGATE IT
DEEPLY IN THIS PROJECT.
I CAN'T REALLY ANSWER.
YEAH, THANKS.
>> MAYBE WE'LL BRING IT UP AT
THE END DURING GAPS OR
SOMETHING.
NEXT SPEAKER IS BERENICE
BENAYOUN, SO SORRY IF I
MISPRONOUNCE THESE BEAUTIFUL
NAMES.
SHE'S TALK FROM USC, TALKING
ABOUT NEUTROPHIL AGING
MECHANISMS, TISSUE PATHOLOGY AND
SEXUAL DIMORPHISM.
>> TODAY I'M GOING TO TELL YOU
ABOUT THE WORK WE'RE DOING ON
NEUTROPHILS WITH AGING.
THIS IS GOING TO BE PAINFUL.
MANY PEOPLE IN THE AGING FIELD
KNOW THERE'S BEEN A
DISPROPORTIONATE AMOUNT OF WORK
IN MALE ANIMALS SPECIFICALLY.
WHEN YOU TALK TO PEOPLE AND ASK
WHAT PUSHED THEM TO FOCUS ON
MALES YOU GET A LOT OF
EXPLANATION LIKE TOO EXPENSIVE
TO DO BOTH SEXES, FEMALE DATA IS
TOO NOISY.
AND MY FAVORITE
[AUDIO DISTORTION]
THAT MEANS WE HAVE A VERY, VERY
LIMITED SORT OF SITUATION,
DIFFERENCE BETWEEN FEMALES AND
MALES IN AGING.
NEXT.
REALLY IMPORTANT BECAUSE IF WE
LOOK AT THE FANTASTIC WORK DONE
BY THE NIH INTERVENTION TESTING
PROGRAM WHAT WE KNOW IS THAT
APPARENTLY -- APPARENTLY PEOPLE
AREN'T HEARING ME?
WHAT WE KNOW IS OF ALL OF THE
INTERVENTIONS THAT HAVE BEEN
SHOWN TO WORK TO IMPROVE HEALTH
AND LIFESPAN IN MICE BASICALLY
THERE'S NOT A SINGLE
INTERVENTION THAT WORKS THE SAME
IN FEMALES AND MALES, BUT
MAJORITY EITHER WORK IN ONLY ONE
SEX OR WORKING MUCH BETTER IN
ONE SEX THAN THE OTHER.
NEXT.
AND WE ALSO KNOW IN HUMANS JUST
FROM OBSERVATIONAL DATA THAT
AGE-RELATED DISEASES SKYROCKET
AFTER MENOPAUSE, REALLY
SUGGESTING THAT SEX IS SOMETHING
WE NEED TO TAKE INTO ACCOUNT FOR
THE STUDY OF AGING.
NEXT.
WHEN WE THINK OF LEVEL OF GENE
REGULATION THIS IS ALL THE MORE
IMPORTANT.
LARGE CONSORTIUM EFFORTS LIKE
NIH ROADMAP SHOW GENE REGULATION
PATTERNS ARE EXTREMELY DIFFERENT
IN MALE AND FEMALE CELLS AND
TISSUE.
NEXT.
AND IN THE IMMUNE COMPARTMENT
ITSELF THIS IS A
WELL-ESTABLISHED FACT THAT
AUTOIMMUNE DISEASE ARE MORE
FREQUENT IN WOMEN, SEPSIS MUCH
WORSE IN MEN, SUGGESTING A HUGE
GAP AND HUGE OPPORTUNITY TO
UNDERSTAND IMPORTANT THINGS
THERE.
NEXT.
AND SO I'M GOING TO SHOW WORK OF
SOME FANTASTIC PEOPLE IN MY LAB,
I'LL INTRODUCE THEM.
RYAN LU, GRAD OPPORTUNITY ON
MIGHT ROW FILLS WITH HELP OF MIN
HOO KIM AND CLAYTON BAKER JOINED
THE LAB TO HELP DO THE WORK.
IN THIS AUDIENCE I'M SURE I
DON'T NEED TO EXPLAIN WHY
NEUTROPHILS ARE SUPER COOL BUT
I'M STILL GOING TO DO IT A
LITTLE BIT.
THEY ARE THE MOST ABUNDANT WHITE
BLOOD CELL IN HUMANS, 50 TO 70%
OF CIRCULATING WHITE BLOOD
CELLS, SHORT-LIVED.
NEXT.
WITH THE MAJORITY OF THEM HAVING
ABOUT 12 HOURS AFTER TERMINAL
DIFFERENTIATION, ALTHOUGH SOME
CAN SURVIVE LONGER IN TISSUES.
AND THEY ARE REALLY IMPORTANT AS
A FIRST LINE OF DEFENSE FOR
INFECTION.
NEXT.
NOTABLY THROUGH A MECHANISM
WHERE THEY CAN EXPEL TO TRAP
PATHOGENS BASICALLY AND HELP
KICK START IMMUNE RESPONSE.
THE PROBLEM IS THOSE
EXTRACELLULAR TRAPS, IF THERE
ARE TOO MANY OR IF THEY ARE FOR
NO GOOD REASON CAN FUEL
INFLAMMATORY DISEASE, A LOT OF
REASONS TO BELIEVE NEUTROPHILS
WILL HAVE IMPORTANT IMPLICATION
IN AGE-RELATED INFLAMMATION.
NEXT.
BECAUSE OF THAT WE DECIDED TO
SEE, OKAY, THERE'S NOT MUCH
KNOWN AS A MATTER OF SEX AND AGE
IN NEUTROPHILS, SO WE'RE GOING
TO TAKE ADVANTAGE OF THE
FANTASTIC RESOURCES AND TRY TO
UNDERSTAND WHAT'S GOING ON BY
USING MULTIOMIC APPROACH.
SO WE'RE USING OBVIOUSLY FEMALE
AND MALES, AND WE'RE LOOKING AT
YOUNG MICE, USING HORMONES
BECAUSE THAT'S WHEN A STRESS
CYCLE IS STABILIZED, THIS
CORRESPONDS TO REAL LIKE
REPRODUCTIVE STABLE ADULTS, AND
20 MONTH OLD ANIMALS, BECAUSE
THERE'S AN EXPLOSION OF 24
MONTHS, MODELING HORMONE DEFECT
SIGNALING.
THERE'S NOT MUCH BLOOD IN THE
MOUSE.
WENT TO THE MOST ABUNDANT SOURCE
OF NEUTROPHILS IN THE BONE
MARROW.
NEXT.
PERFORMED A THREE PRONGED
PROFILING USING TRANSCRIPTOMICS,
METABOLOMICS, LIPIDOMICS.
WE DIDN'T KNOW WHAT TO EXPECT.
BUT WE WERE REALLY IMPRESSED
SEEING -- THAT RESONATES WITH
WHAT I TOLD YOU, BUT THE BIGGEST
SOURCE OF SEPARATION BETWEEN ANY
SAMPLES, THIS IS HERE IN
MULTI-DIMENSIONAL SCALING SPACE,
WAS BETWEEN FEMALES AND MALES
AND NOT REALLY YOUNG AND OLD
SAMPLES.
THIS IS TRANSCRIPTOMIC LEVEL.
NEXT.
AND NEXT ACTUALLY.
BUT WE ALSO SAW A HUGE
SEPARATION BY METABOLOMICS AND
LIPIDOMIC LEVEL, NOT EVEN A
SECONDARY SEPARATION BY AGE
THERE.
NEXT THREE TIMES.
WE CONSISTENTLY SAW GENES AND
GENES REGULATED AS A FUNCTION OF
AGING AND SEX WITH AGE.
IN RNAseq.
BUT ONLY METABOLITES AND LIPIDS
REGULATED AS A FUNCTION.
FOR INTEREST OF TIME I'LL FOCUS
ON THE AGE AND SEX RELATIONSHIP
AND TRANSCRIPTOME.
NEXT.
SO ONE THING I WANT TO SAY
BECAUSE, AGAIN, I KNOW WHEN I'M
TALKING TO IMMUNOLOGISTS THE
ISSUE IS UNDERLYING
HETEROGENEITY, ONE THING WE'VE
BEEN DOING IS OPTIMIZING RNA
SINGLE CELL Seq ON
NEUTROPHILS, A PAIN TO WORK ON
FOR THIS SPECIFIC THING, WE HAD
TO OPTIMIZE PROTOCOL.
BUT THE NICE THING, NEXT AND
NEXT, WE WERE ABLE TO -- THESE
ARE YOUNG ANIMALS, ABLE TO DO
SINGLE CELL RNAseq, IDENTIFY
PRE-DETERMINED SORT OF DEFINED
DIFFERENTIATION IN OUR
POPULATION, RECOMMENDED BY
PROBING, SEEING SEX DIFFERENCE.
WHEN YOU SIGH BIG DIFFERENCES IN
THE BASAL STATE, THE QUESTION
IS, WELL, ARE THEY STILL GOING
TO AGE THE SAME OR ALSO GOING TO
AGE DIFFERENTLY?
AND SO HERE ON THE X-AXIS I'M
SHOWING TO YOU THE RATE OF
CHANGE IN GENE EXPRESSION IN
FEMALE NEUTROPHILS, ON THE
Y-AXIS IN THE MALE NEUTROPHILS.
AND OBVIOUSLY THE CORRELATION IS
NOT PERFECT BUT IT'S PRETTY
GOOD.
SO GOOD THAT THE COMPUTER CAN'T
GIVE US AN ACTUAL P-VALUE
SUGGESTING THAT THERE'S A PRETTY
GOOD CORRELATION BETWEEN THE
TRAJECTORIES OF AGING IN THE
FEMALES, NEXT PLEASE, AND
FEMALES AND MALE NEUTROPHILS.
THAT BEING SAID, IF WE THEN
FOCUS ON THINGS THAT ARE
SIGNIFICANT WITH AGE IN ONE SEX
AND NOT THE OTHER WE SEE HERE IN
THIS SPECIFIC CASE IT'S
DIFFERENT IN OTHER CELL TYPES
WE'VE LOOKED AT.
A LOT MORE AGE-RELATED CHANGES
IN THE MALES THAN THE FEMALES.
BUT IF YOU LOOK AT THEM, IT'S
MORE LIKE THIS SLOPE HAS BEEN
INCREASED SUGGESTING MAYBE AN
ACCELERATION AT TRANSCRIPTIONAL
LEVEL.
AT THAT POINT WE WONDERED WHAT
FUNCTIONS WERE REGULATED AS A
FUNCTION OF AGE AND SEX IN
NEUTROPHILS OMIC LANDSCAPES.
WE PERFORMED -- THERE'S A LOT OF
ANIMATION.
AND SO THESE ARE THE TOP TEN
PATHWAYS UPREGULATED AND
DOWNREGULATED IN THIS CASE WITH
AGE BECAUSE WE HAD A GOOD
CORRELATION BETWEEN SEXES, WE
CAN REGRESS OUT EFFECTS OF SEX
IN THIS CASE.
AND SO THERE'S SOME THINGS
HAPPENING ON THE UPREGULATION
SIDE, NOTHING TOO EXCITING, BUT,
NEXT, WE THOUGHT WHAT WAS REALLY
INTERESTING IS THE PREPONDERANCE
OF CELL CYCLE AND CHROMATIN
RELATED TERMS IN DOWNREGULATED
SIDE OF THINGS.
FOR THOSE WONDERING, WE HAVE
CHECKED NEUTROPHILS, NOT
PROLIFERATING, WE THINK THIS HAS
TO DO WITH ACTUALLY MITOSIS
REGULATION SHOWN TO CAUSE A LOT
OF CELL CYCLE MACHINERY.
NEXT.
WE DO THE SAME ANALYSIS LOOKING
AT WHAT'S GOING ON WITH SEX.
NEXT.
AND YOU CAN SEE ON THE FEMALE
SIDE OF THINGS THERE'S, AGAIN,
ENRICHMENTS, NOTHING TOO
EXCITING.
MIGHT BE INTERFERON GAMMA
SIGNALING WHICH WE HAVE IDEAS
THAT IS.
BUT ON THE MALE SIDE OF THINGS
WE HAVE THIS ENRICHMENT.
NEXT.
FOR CELL CYCLE, AND
CHROMATIN-RELATED GENES.
AND SO AT THIS POINT, NEXT,
NEXT, WE WONDERED WHETHER THOSE
CHANGES WE HAVE SEEN WOULD HAVE
FUNCTIONAL IMPACT.
BECAUSE WE SAW UNIQUE ROLE OF
CHROMATIN AND NEUTROPHILS MIGHT
BE RELATED TO MITOSIS,
UPREGULATED PROTOCOL TO MEASURE.
AND SO THIS IS A CAUTIONARY TALE
BASED ON OMICS, BECAUSE EVEN
THOUGH AT THE TRANSCRIPTIONAL
LEVEL THINGS SEEM TO BE
INTERACTING LINEARLY, WHAT WE
OBSERVED WAS CLEAR INCREASE IN
NETosis CAPACITY OF FEMALES
WITH AGE BUT IN MALE NEUTROPHILS
THERE'S NOT REALLY MUCH GOING ON
THERE.
BUT THAT SHOWS WE HAVE SOME
POTENTIAL IMPACT HERE OF
INTERACTION, EFFECT AND AGE.
NEXT.
AND SO ANYTIME YOU SEE SEX
DIFFERENCES, MY LAB IS
INTERESTED IN GENERAL, YOU
WONDER WHAT DRIVES DIFFERENCES.
NEXT.
AND IF I TAKE YOU BACK TO VERY
LONG TIME AGO IN YOUR BIOLOGY
CLASSES THERE CAN BE TWO THINGS
BASICALLY THAT ARE RELATED TO
SEX DIFFERENCES.
ONE OF THEM, NEXT, BEING GONADAL
HORMONES, FEMALES ARE HIGHER
LEVELS OF ESTROGEN, MALES HIGHER
LEVELS OF ANDROGEN, THOSE ARE
NORMALLY RELATED, FEMALES ARE
GENETICALLY XX, AND MALES ARE
XY.
ALL OF THOSE CAN LEAD TO, NEXT,
REGULATORY DIFFERENCES BECAUSE
SEX HORMONE RECEPTORS, NEXT, CAN
ACT AS TRANSCRIPTION FACTORS AND
HAVE HUGE IMPACT EVEN IN SOMATIC
CELLS.
AND THERE ARE A NUMBER OF REALLY
IMPORTANT CHROMATIN REGULATORS
AND RNA PROCESSING PROTEINS
ENCODED ON X AND Y, AND THAT ARE
NOT EXPRESSED AT THE SAME DOSES
IN FEMALE AND MALE CELLS.
NEXT.
THE REALLY -- BACK.
THE REALLY INTERESTING THING A
LOT OF PEOPLE DON'T KNOW IS THAT
SEX HORMONES HAVE TWO WINDOWS OF
ACTION.
ONE IS IN UTERO DURING
DEVELOPMENT, ONE IS AFTER
PUBERTY.
THOSE ARE CALLEDOAL VERSUS
ACTIVATIONAL EFFECT HORMONES AND
CAN HAVE COMPLETELY OPPOSITE
EFFECTS ON BIOLOGY, EXAMPLE
BEING ESTROGENS IN ALZHEIMER'S,
IN UTERO EXPOSURE INCREASES
LIFETIME RISK VERSUS POST
PUBERTY.
I WAS FAMILIAR WITH A MODEL THAT
COULD BE LEVERAGED, I'M NOT
GOING TO GIVE ALL OF THE REASONS
WHY IT WORKS BUT THERE'S A GENE
FOXL2, MASTER DETERMINATOR OF
OVARIAN FATE.
IN 2009 THEY SHOWED IF YOU LET
THE MICE DEVELOP NORMALLY, DO
THEIR THING, LET THEM BECOME
SEXUALLY MATURE, NEXT, INTUITION
FOXL2, EVERYONE IS NORMALLY
EXCEPT THE MICE, THE FEMALE MICE
THAT LOSE FOXL2 WITHIN TWO
WEEKS, GIVING ACTIVATIONAL
EFFECT, YOU GET A COMPLETE
REORGANIZATION OF OVARIAN
TISSUE.
WILD TYPE IS WHAT YOU EXPECT FOR
A YOUNG HEALTHY TWO TO THREE
MONTH OLD MICE, INDUCED KNOCKOUT
EMERGENCE OF TUBULARRIZED
STRUCTURES, YOU HAVE LEVELS OF
TESTOSTERONE IN MICE AND THIS IS
TWO WEEKS AFTER INDUCTION THAT
ARE NOW BASICALLY ALMOST
IDENTICAL TO THOSE OF THE MALE
LITTERMATES.
THE PROBLEM IS THAT THE LAST
AUTHOR ON THE PAPER WOULD NOT
SHARE THE MOUSE.
DON'T BE LIKE HIM WHEN YOU GROW
UP.
WE HAD TO REGENERATE THEM FROM
SCRATCH.
NEXT.
OKAY.
NEXT, NEXT.
BASICALLY WE'RE ABLE TO
RECAPITULATE HISTOLOGY, CAN SEE
GONAD AL MARKERS, WE SEE
TESTOSTERONE.
NEXT.
AND WE GOT NEUTROPHILS, JUST A
YOUNG COHORT.
IT TAKES TWO YEARS TO GET A
2-YEAR-OLD MOUSE.
NEXT.
WHEN WE DO RNAseq THE FIRST
THING WE SEE, WE CAN REPRODUCE
OUR OWN RESULTS, FEMALE AND MALE
NEUTROPHILS SEPARATE NICELY BUT
NOW THE NEUTROPHILS ISOLATED
FROM SEX REVERSE MICE ARE IN
PURPLE, BASICALLY OVERLAPPING
WITH THE MALE ONES.
NEXT.
AND IF WE COMPARE AGAIN LIKE THE
CHANGE IN GENE EXPRESSION AND
CONTROLS XY VERSUS XX COMPARED
TO KNOCKOUTS VERSUS CONTROLS
THERE'S A NICE CORRELATION.
NEXT.
AND NEXT.
WHEN WE PERFORMED DSC WE CAN SE
UPREGULATION.
SKIP THE NEXT SLIDE BECAUSE OF
TIME.
STARTING TO DO SINGLE CELL ON
THIS.
BASICALLY WE SEE THAT NEUTROPHIL
BIOLOGY IS SEX DIMORPHIC, SHOW
THE ENTIRE SLIDE.
IF YOU'RE INTERESTED ABOUT WHAT
WE'VE ALREADY DONE ON JUST AGING
AND SEX, THIS IS PUBLISHED,
WE'RE INTERESTED IN THOSE
HORMONAL VERSUS GENETIC DRIVERS
OF SEX DIFFERENCES.
NEXT.
AND SO REALLY THAT'S ONE OF THE
BIG CHALLENGES HERE IS
UNDERSTANDING SEX IS NOT JUST AN
ANNOYING CONFOUND, YOU NEED TO
DEAL WITH, BECAUSE NIH ASKED YOU
TO BUT IT'S BIOLOGICALLY
RELEVANT AND IMPORTANT AND WITH
TRANSLATIONAL POTENTIAL WHEN
WE'RE TALKING ABOUT, YOU KNOW,
PERSONALIZED MEDICINE AND THINGS
LIKE THIS.
SO CAN YOU SKIP TO MY
ACKNOWLEDGMENT SLIDE PLEASE.
I WANT TO THANK THE PEOPLE WHO
HAVE DONE THE WORK, FANTASTIC
COLLABORATORS.
AND OBVIOUSLY THE SOURCES OF
FUNDING WITHOUT WHOM WE WOULDN'T
DO THIS WORK.
>> THANK YOU.
THAT WAS JUST GREAT.
USC HAS A REALLY GOOD PERSON IN
YOU.
WE HAVE A COUPLE MINUTES FOR
QUESTIONS.
THERE'S A QUESTION ONLINE.
TO WHAT EXTENT DAWES SEXUAL
DIMORPH NICHE IN RODENTS MIRROR
SEXUAL DIMORPHISM IN HUMANS.
>> CLOSE MOLECULARLY BECAUSE
BROAD EXPRESSION OF SEX HORMONE
RECEPTORS IS RECAPITULATED
PERFECTLY.
AND ALTHOUGH THE EXTENT OF
CHROMATIN INACTIVATION IS NOT
EXACTLY THE SAME A LOT OF
FUNDAMENTAL MECHANISMS ARE GOING
TO BE CONSERVED.
IT'S NOT AS IF PEOPLE ARE
RUSHING TO UNDERSTAND SEX
DIFFERENCES IN HUMANS, WE HAVE
TO START SOMEWHERE.
THAT'S WHERE WE'RE GOING.
>> DO AGED FEMALE MICE
DEMONSTRATE ANESTRUS?
>>YEAH, BASICALLY FEMALE MICE
WILL BECOME ACYCLIC 12 TO 13
MONTHS, THEY DON'T GET
MENOPAUSE.
SEPARATE DIRECTION OF RESEARCH
IN MY LAB, WE'RE DEVELOPING
MODELS OF MENOPAUSE IN MICE SO
WE CAN MODEL THIS PROPERLY.
BUT AGAIN YOU HAVE TO START
SOMEWHERE.
>> GO AHEAD, MARK.
>> OKAY.
IT'S WORKING, GOOD.
THAT'S REALLY INTERESTING.
I WANT TO MENTION THAT IN OUR
KNOCKOUT EXPERIMENTS WITH TONSIL
ORGANOIDS, ESPECIALLY WITH FOXP3
KNOCKOUT, THE TONSILS FROM WOMEN
TEND TO MAKE MUCH HIGHER LEVELS
OF AUTOANTIBODIES, AND ALSO EVEN
IN UNMANIPULATED TONSILS WE SEE
SOME WOMEN HAVE DETECTABLE
LEVELS OF B CELLS SPECIFIC FOR
CLASSICAL AUTOANTIGEN LIKE
DOUBLE-STRANDED DNA AND SO FORTH
AND I WOULD PUT UP LIKE FOR
ORGANOIDS IN TERMS OF SPLEEN
ORGANOIDS PRESERVE SOME
NEUTROPHILS, MOST PBMCs OF
COURSE DO NOT, AND SO DOING
THINGS LIKE HORMONAL TREATMENTS
WOULD BE SUPER EASY IN A DISH OF
THE MOUSE.
>> TERRIFIC.
I WAS WONDERING, I'M WONDERING
IF SEX DIFFERENCES CHANGE WITH
AGE.
>> YEAH, I DIDN'T WANT TO GO
INTO IT, AGE DECLINE IS OBSERVED
WHEN YOU PRIME NEUTROPHILS WITH
TNF ALPHA IN VITRO,
RECAPITULATED IN OUR PAPER BUT
IF YOU DON'T PRIME THEM IN VITRO
BECAUSE THEY ARE TECHNICALLY
ALREADY PRIMED IN VIVO WITH AGE
THERE'S AN INCREASE.
YEAH, THAT'S YOU -- YOU GO INTO
THE MATERIAL METHODS, PRIMED IN
VITRO, CELLS ARE ALREADY EXPOSED
TO MORE TNF ALPHA IN VIVO THAT
WOULD CREATE ISSUES THERE BUT
THERE'S AN INCREASE WHICH MAKES
SENSE WITH INCREASED AGE-RELATED
INFLAMMATION ACTUALLY.
>> EXCELLENT.
IN MICE, THE CYCLE IS SHORT, AND
THESE ARE SHORT-LIVED CELLS.
DO YOU SEE CHANGES THAT ARE
HORMONAL DEPENDENT IN SPECIES
WITH A LONG NEUTROPHIL LIFE
BACKED BY HORMONAL CHANGE?
>>FROM REANALYZING PUBLICLY
AVAILABLE TRANSCRIPTOMIC DATA
THERE ARE HUGE DIFFERENCES IN
TRANSCRIPTOMES, ADULT
NEUTROPHILS FEMALE AND MALE
HUMANS.
THAT'S DEFINITELY THE CASE.
AND JUST EVEN WERE SUPER SHORT
NEUTROPHILS WE HAVE WORK ON
MACROPHAGE, PHENOTYPES CHANGE
QUITE A LOT BASED ON HORMONAL
STATUS.
IT LOOKS LIKE RESPONSE OF THE
CELLS CAN BE SUPER DYNAMIC,
DOESN'T NEED TO LAST 28 DAYS.
>> THANK YOU VERY MUCH.
WE'VE HAD A GREAT SESSION.
IT'S TIME FOR A SHORT BREAK.
AND SO IF WE CAN COME BACK IN 15
MINUTES.
THANK YOU.
HIS REAL TITLE IS IMMUNE AGING
AT SINGLE-CELL RESOLUTION,
PBMCs.
ALL RIGHT.
>> AM I GOING TO HAVE TO SAY
THE WORD "NEXT" MORE IN THIS
CONFERENCE?
OKAY.
[LAUGHTER]
AT LEAST HALF THE AUDIENCE
IMMUNE SYSTEMS SHOULD BE IN THE
CENTER OF THE AGING PHENOTYPE
PERHAPS, FOR MANY PEOPLE BEFORE
US, AND FOR ME THE BIGGEST
CONVINCING ARGUMENT IS ON THE
NEXT SLIDE, THAT SHOWS THE
EXTENSION OF THE LIFE FOR
LONGEVITY HAPPENS DUE TO
DRAMATIC IMPROVEMENTS IN IMMUNE
SCIENCES.
AND SO IF YOU GO NEXT NOW, THREE
SLIDES, YOU'LL SEE THAT THERE
ARE CURRENT CANCER IMMUNOLOGY,
NEURODEGENERATION, I WILL
SPECULATE IMMUNE AGING IS THE
ULTIMATE FRONTIER THAT COMES
NEXT TO IT.
AS MUCH AS IT IS FUNDAMENTAL,
NEXT SLIDE, YOU'LL SEE ALSO IN
THE NEXT, IT'S FOR ALL OF US, A
PERSONAL PROBLEM AS WELL.
SURPRISINGLY ACCURATE PICTURE OF
PREDICTION, MIXTURE OF MY MOM
AND DAD'S IMAGES.
GOING TO SCIENCE, NEXT, WHEN YOU
THINK ABOUT CHARACTERIZING
AGING, BIGGEST ISSUE THAT SOME
OF THE SPEAKERS BEFORE ME TALKED
ABOUT, CHANGES ASSOCIATED WITH
AGING, DUE TO THE LIMITATIONS OF
TECHNOLOGY MOST OF THE -- A LOT
OF STUDIES USED BLOOD TISSUE,
BLOOD PROFILING, NOT INFORMATIVE
ABOUT BIOLOGY INSIDE THE CELLS
OR WITH THE CELL SYSTEMS.
GOING NEXT, NEXT, NEXT, GO TO
SINGLE-CELL RESOLUTION OR
PROFILING TO ISOLATE AND PURIFY
SINGLE POPULATION SUCH AS
BERENICE.
ONE ABOUT THE POSTER THAT'S
UNPUBLISHED, NEXT SLIDE, IRINA
WHO HELPED EMILY AND SHE WILL
PRESENT A POSTER, LONGED AT THE
ISOLATED MONOCYTES BETWEEN YOUNG
AND OLD INDIVIDUALS, AND
COMPREHENSIVELY CHARACTERIZED
DIFFERENCE, MULTIPLE MULTIOMICS
LEVELS.
WHAT IS INTERESTING THEY DO LOOK
VERY IDENTICAL IF YOU TAKE TRULY
HEALTHY OLD INDIVIDUALS, IT WILL
NOT BE EASY BUT MONOCYTES ARE NO
DIFFERENT EXCEPT, NEXT SLIDE,
EXCEPT FOR THE DNA METHYLATION
PROFILE.
SOMETHING IS HAPPENING IN
PURIFIED POPULATION NOT ON
TRANSCRIPTION LEVEL OR CHROMATIN
LEVEL BUT CHANGES IN DNA
METHYLATION.
NEXT.
THIS PAPER CHARACTERIZES
PREVIOUS SLIDE THE DNA
METHYLATION LOCATIONS, NOT THE
INDIVIDUAL CpGs BUT
STRETCHES IN PROMOTERS OR
ENHANCER REGIONS WHICH ARE
CHANGING AND PERHAPS HAVE TO DO
WITH THE CHANGING OF THE
HEMATOPOIETIC STEM CELL,
SOMETHING THAT WE TALKED ABOUT.
SWITCHING GEARS TO THE NEXT
SLIDE, THEN LOOKING AT MONOCYTES
THOUGHT WE'LL USE COMPLEMENTARY
APPROACH, SINGLE CELL TECHNIQUES
TO LOOK AT ALL IMMUNE CELLS THAT
ARE POSSIBLE, IT OF COURSE AS
SOMEBODY WAS SAYING IT'S EASY TO
LOOK AT TISSUES OF MICE, HARD IN
HUMANS, MUCH EASIER IN BLOOD.
NEXT SLIDE.
LOOKED AT THE MICE, SEVERAL
ORGANS IN MICE, NEXT SLIDE.
WHAT HE FOUND SHORT SUMMARY,
PARTICULAR SUBPOPULATION OF
GRANZYME POSITIVE CELLS STRONG
LINEAGE, POPULATION HIGH IN
TYPICAL MARKERS.
IN LIVER, MAJORITY OF CELLS WITH
AGE, SAME TRUE FOR OTHER ORGANS.
WHAT IS INTERESTING, NEXT, IS
THAT THESE ARE THE, IN MICE, THE
CELLS THAT ARE RESPONSIBLE FOR
THE INCREASE.
THE QUESTION, WE CAN CURE THE
MICE AM PRETTY MUCH ANY DISEASE,
WHAT ABOUT HUMANS?
TRANSLATING TO HUMANS, LET'S SEE
THE GRANZYME.
HE SET UP THE PANEL TO LOOK INTO
GRANZYME B, AND WHAT YOU SEE
HERE IS GRANZYME K POSITIVE
CELLS ARE INCREASING WITH AGE
WHILE GRANZYME B POSITIVE ARE
TRENDING BUT NOT REALLY
INCREASING WITH AGE IN THIS
COHORT.
SO YOU CAN SEE ALSO IN THE RIGHT
THESE ARE TWO SUBPOPULATIONS,
GRANZYME K OR GRANZYME B
POSITIVE CELLS.
IF YOU LOOK AT DATA, YOUNG
VERSUS OLD, THEN YOU'LL SEE
THERE ARE FIVE MAJOR POPULATIONS
IN CD8 T CELLS, NAIVE AND THREE
MEMORY AND POPULATIONS DEFINED
BY SINGLE CELL RNA SEQUENCINGS,
CENTRAL MEMORY, TWO CLUSTERS
GRANZYME K AND GRANZYME B
POSITIVE, CENTRAL MEMORY ALSO
ACCUMULATING WITH AGE.
AND NEXT.
SO THE QUESTION FOR HUMANS
TYPICALLY YOU WANT MANY MORE,
WOULD HAVE TO COVER, INURE WE
WANTED FIRST TO SCALE USING
CYTOMETRY, THIS IS THE BROAD
CYTOMETRY STUDY THAT INCLUDED
GRANZYME K AND GRANZYME B AS ONE
OF IMPORTANT PROTEINS.
SO THERE'S ALSO IN THE PAPER A
LITTLE BIT ABOUT COVID.
ONCE WE COLLECTED DATA COVID
HIT, TO CONTINUE THE WORK WE HAD
TO INCLUDE SOME OF THE POPULAR
DISEASE AT THE TIME.
WE GOT DATA.
HERE IS THE MAP SHOWING
POPULATIONS, YOU CAN SEE
SUBPOPULATION POSITIVE IN
GRANZYME K AND MORE OF THE
GRANZYME B, THEY ARE ASSOCIATED
WITH TRANSCRIPTION FACTOR T-BET,
SUGGESTING EPIGENETIC AND
TRANSCRIPTIONALLY DISTINCT
POPULATION.
SLOWLY CLICK THROUGH THE NEXT
FOUR SLIDES YOU CAN SEE HOW
AGING DENSITY FLOW CHANGES OVER
HERE, SO YOU CAN SEE
ACCUMULATION, ONE MORE, THAT
BASICALLY THESE ARE THE THREE
SUBPOPULATIONS THAT ARE REALLY
HEAVILY ACCUMULATED.
NEXT SLIDE.
COVID IS SCREWING UP EVERYTHING,
YES, WE ARE HERE.
YOU CAN SEE STATISTICALLY IF YOU
LOOK AT NOT JUST VISUALLY BUT
WITH PROPER DISTANCE YOU CAN SEE
STATISTICALLY GRANZYME K
POSITIVE ARE ACCUMULATING, SAME
TRUE FOR CENTRAL MEMORIES, NAIVE
GOING DOWN, EMRA NOT
STATISTICALLY GOING UP.
NEXT.
AND WE COVER A LOT OF GROUND,
YOU CAN LOOK IT UP.
NEXT.
THIS IS THE PART OF THE
UNPUBLISHED STORY THAT I'M GOING
TO TELL YOU, AND MARINA HERE,
YOU CAN SEE HER PICTURE, SHE'S
PRESENTING THE POSTER, PLEASE GO
BY AND TALK TO HER ABOUT THE
DETAILS.
AND HAVING SEEN THESE CHANGES IN
OUR DATA WE WERE WONDERING CAN
WE TAKE A LOOK AND IDENTIFY
CHANGES IN BROADER SPEAKING.
AT THIS POINT THERE HAVE BEEN A
LOT IN THE COMMUNITY OF THE
STANDARDIZED DATASET OF THE
HUMAN SINGLE CELL RNA SEQUENCING
ACROSS HEALTHY AGING, WE BELIEVE
WE WILL FILL THIS GAP, WHAT WE
HAVE DONE COLLECTED 166 DONORS
ACROSS 25 TO 85 YEARS OLD,
HEALTHY AGERS, SOME PROFILED
TWICE.
ONE YEAR AFTER FOLLOW-UP, TWO
YEARS FOLLOW-UP.
PERFORMED SINGLE-CELL RNA
SEQUENCING AND SOME OF THE
FINDINGS VALIDATED USING
CYTOMETRY.
NEXT SLIDE.
ONE OF THE QUESTIONS AND ONE OF
THE VERY -- NEXT SLIDE PLEASE.
ONE OF THE IMPORTANT QUESTIONS
IS SELECTION OF THE COHORTS,
VERY DIFFICULT AS SOME PEOPLE
HAVE BEEN MENTIONING, VERY HARD
TO MAINTAIN OR RECRUIT PEOPLE TO
DO THAT BECAUSE COLLECT COHORT
FOR THREE YEARS AND THEN ANOTHER
FOUR YEARS WOULD BE DOING
SCIENCE, BUT IMPORTANT QUESTION
IS WHAT IS THE CRITICAL PART OF
THE LOOKING HUMAN AGING TO HAVE
THE HEALTHY AGING, NOTE SOMEBODY
WHO IS SICK WITH ARTHRITIS,
INFLAMED MONOCYTES, HERE IS THE
BLOOD OF BIOCHEMICAL PROFILES,
TYPICAL AGING, TESTOSTERONE
GOING DOWN, TSH GOING UP, CRP
AND OTHER TRIGLYCERIDES AND SO
ON ARE IDENTICAL BETWEEN THESE
AGES, EXCLUSIVELY VERY HEALTHY
COHORT, SOME PEOPLE TAKING HEART
MEDICATION, NOT ABSOLUTELY
HEALTHY PEOPLE.
NEXT.
WE'VE COLLECTED AND PROFILED 300
SAMPLES, ABOUT 2 MILLION
PBMCs, THE BIGGEST DATASET OUT
THERE, ONE OF THE BIGGEST
CHALLENGES APPROPRIATE
BIOLOGICALLY RELEVANT IN
SUBPOPULATION, CD4 AND CD8
SUBPOPULATIONS, YOU CAN SEE HOW
THESE ARE CHANGING WITH AGE, AND
WHAT I'M GOING TO DO IS GIVE A
LITTLE PRIMER FOR THOSE WHO ARE
INTERESTED TO COME TO MARINA'S
POSTER, NEXT SLIDE, AND TO SAY
THAT WE RECAPITULATE RATIO,
TYPICAL HALLMARKS OF AGING PBMC.
NEXT.
AND THEN CD 4 T CELLS,
ACCUMULATION OF MEMORY CELLS.
AND THIS WAS PARALLEL, NEXT, BY
VERY NICE ACCUMULATION OF
CENTRAL MEMORY THAT WE DISCUSSED
BUT TWO SUBSETS.
YOU CAN SEE ON SINGLE CELL
RNAseq TWO SUBSETS OF CD4
POSITIVE AND NEGATIVE CELLS.
MOST INTRIGUING WAS AMAZING
POPULATION OF CELLS GOING DOWN
WITH AGE.
THIS IS EXTREMELY
COUNTERINTUITIVE.
AND FIRST I DID NOT BELIEVE, I
HARASSED MARINA, SAYING IT'S A
DUPLICATE, MANY AN ARTIFACT, SO
ON, BUT SHE PERSISTED, LOOKED AT
THE OTHER DATA AND SAME
POPULATION EXISTS, NOBODY LOOKED
AT AGE.
PEOPLE JUST IGNORED IT, ALSO
PROBABLY LIKE ME THINKING THIS
IS JUST SOME KIND OF ARTIFACT
BUT AGE BEHAVIOR AND COMPLIANCE
BETWEEN THE DATASETS SERVED
THESE ARE REAL DISTINCT
TRANSCRIPTIONAL SUBPOPULATIONS.
THE REASON WHY I THINK
SEPARATION WITH CELLS IS THEY
ACCUMULATE WITH DIFFERENT PLACE
BUT MOST IMPORTANTLY TCR
POSITIVE CELLS BEAR STRONG
SIGNATURES OF IL-4 AND IL-13
SIGNALING, AND OVERALL
SIGNATURES FOR A MOMENT, PLUG
THEM INTO CD8 CELLS THEY WOULD
BE ENRICHED IN THE TCR4
POPULATION.
ACROSS THE DATASET THEY
ACCUMULATE Th2 AND POSITIVE
CD8 CELLS, TO US THERE IS SOME
SORT OF HEALTHY AGING
ACCUMULATION OF Th2 TYPE 2
MEMORY AXIS, NO TYPE 1, NO TYPE
17, SPECIFICALLY TYPE 2 MEMORY
AXIS.
NEXT.
SO THIS IS A LITTLE BIT OF A
SUMMARY IF YOU LOOK AT THE
DATASETS YOU CAN DEFINE
BIOLOGICALLY MATCHING TO THE
PUBLISHED DATA TRANSCRIPTIONAL
SIGNATURE, 53 SUBPOPULATION, 10
STATISTICALLY SIGNIFICANT
INCLUDING GAMMADELTA 1 T CELLS,
AND IF YOU CAN ADVANCE BY
IMPORTANCE YOU CAN SEE ON THE
VOLCANO PLOT ON THE LEFT THE
CELLS ARE AMONG THE STRONGEST
DECREASING ONES, AND MEMORY
CELLS ARE THE STRONGEST AND MOST
DISTINCT, GRANZYME K CELLS AS
WELL AMONG THE STRONGEST
ACCUMULATING CELLS.
NEXT.
I WANT TO THANK THREE GROUPS OF
PEOPLE, THIS IS NOT THE WHOLE
LAB PICTURE.
I THANK MANY PEOPLE WHO DID THIS
PROCESS, WE HAVE OUR OWN FAMILY
INTERNAL CONTROL FOR ALL OF THE
OPTIMIZATION, THERE'S MY DAD AND
ME GIVING BLOOD FOR MY LAB TO
PLAY WITH IT, AND OF COURSE THE
COLLEAGUES WHO ARE FUN BUT I
LEARNED THIS MORNING THIS
ALCOHOL IS NOT GOOD FOR YOU.
THANK YOU.
[LAUGHTER]
WHAT I WANTED TO POINT OUT WHEN
YOU LOOK AT SINGLE CELL RNAseq
DATASET WHICH WE'VE DON AD
NAUSEAM, YOU FIND MANY IF NOT
ALL INCLUDING HUMAN
IMMUNOLOGISTS USE IS NOT WORKING
FOR CD8 T CELLS, SO THIS IS THE
BIG QUESTION AND NOW THAT WE
HAVE SINGLE CELL RNA SEQUENCING
DATA WE NEED TO FIGURE OUT HOW
TO DO IT PROPERLY.
I THINK IT'S ONE OF THE BIGGEST
QUESTIONS BECAUSE ONCE WE TALK
ABOUT SUBPOPULATIONS WE NEED TO
KNOW HOW WE DO IT THE RIGHT WAY
WHICH FOR ME IS SINGLE CELL
RNAseq WAY OR (INDISCERNIBLE).
>> THANK YOU.
WE HAVE TIME FOR -- YEAH.
>> THANK YOU.
I HAVE A QUESTION ON TYPE 2
EXPANDING IN AGING, ARE THEY
CONTRIBUTING TO INFLAME AGING OR
EXPANDING TO INFLAMMATORY?
>>YEAH, THESE ARE THE
HOMEOSTATIC WHAT WE BELIEVE
INDIVIDUALS, THE INFLAME AGING
IN HUMANS, FOR THAT WE NEED TO
TAKE HEALTHY TISSUES, ESTABLISH
INFLAMMATION IN HUMANS, WHICH IS
DIFFERENT COMPARED TO THE IDEA
THAT WITH AGE AT THE RATE OF
RHEUMATOID ARTHRITIS, FOR
EXAMPLE, IS INCREASING, SO IN
MICE IT'S VERY EASY TO DO.
IN HUMANS I DON'T THINK THERE
HAVE BEEN CONVINCING STUDIES
STATISTICALLY ON A LOT OF
HEALTHY OLD TISSUES FROM HEALTHY
NON-INFLAMED INDIVIDUALS.
BUT TO ANSWER YOUR QUESTION WITH
RESPECT TO ACTIVATION THESE ARE
NOT ACTIVATING CELLS, DO NOT
PRODUCE BIOACTIVELY BUT EVEN IN
YOUNG INDIVIDUALS 5% ALWAYS NICE
PROPORTION.
HOWEVER STUDIES IN GERMANY, FOR
EXAMPLE, AND FINLAND
EPIDEMIOLOGICAL STUDIES WITH AGE
INCREASED WHAT CALLED ATYPICAL
ASTHMA.
WHEN YOU'RE YOUNG IT'S POLLEN,
THIS OR THAT.
PERHAPS THE CONNECTION THERE
COULD BE THESE CELLS ARE
PREDISPOSING, NOT NECESSARILY
CONTRIBUTING TO THE ONGOING, BUT
PREDISPOSING TO EASIER
DEVELOPMENT OF TYPE 2 IMMUNE.
>> UNIVERSITY OF VIRGINIA.
WONDERING IF YOU HAD IDEAS ON,
FIRST, WHAT ARE POTENTIAL SIGNAL
PATHWAYS OR MECHANISMS FOR
DESCRIBING THESE CHANGES OVER
AGING, HAVE YOU TRANSCRIPTIONAL.
AND MORE BIG PICTURE, HEALTHY
AGING POPULATION, DO YOU SEE
THESE PATHWAYS THAT YOU'D FIND
AT BENEFICIAL OR DETRIMENTAL TO
HUMAN HEALTH?
>>OH, YES, THIS IS GREAT
QUESTIONS.
SO I'M NOT SURE WHAT ARE
SPECIFIC MECHANISMS, AND I'M NOT
EVEN SURE HOW TO EXACTLY
ESTABLISH THEM BECAUSE IT'S
PROBABLY CONNECTION BETWEEN
EVOLUTION AND PERIPHERAL TISSUE
CHANGE IN HOMEOSTATIC, SO MY
FEELING IS THAT THESE ARE WHAT
WE'VE SEE IN BLOOD AND THIS IS
REFLECTION OF PERIPHERAL TISSUE
OR PROCESSES.
NOW, SECOND PART BASICALLY
DETRIMENTAL OR PROTECTIVE, I
GUESS WITH IMMUNE SYSTEM IT'S
PROBABLY BOTH.
IT'S ONE MECHANISM THAT'S
REUTILIZED FOR OTHER PURPOSES,
AND IT TRIES TO BASICALLY WHEN
YOU STOP INFLAKS OF THE MAIN
-- STOP INFLUX,
TRIES TO REBALANCE BUT CREATES
OTHER ISSUES, MORE
PHILOSOPHICAL.
>> WONDERFUL TALK, AS ALWAYS.
DID YOU LOOK AT SEX DIFFERENCES?
>>I MEANT TO SAY WE DID.
NO DIFFERENCE, SORRY.
WE WERE HOPING.
IN INITIAL PLAN OF PAPER BEFORE
WE HAD EVEN DATA I RESERVED
DIFFERENCES, LIKE, OH, IT'S VERY
COMMON.
BUT I THINK WE'RE NOT TALKING
ABOUT THE FACT THAT PBMC
POPULATION NOT REALLY MUCH OF
THE SEX DIFFERENCE WITH AGE, A
NUMBER OF OTHER PAPERS TALK
ABOUT IT.
ONE PAPER --
>>SORRY.
QUICKLY, YOUR QUESTION.
YOU'RE NEXT.
>> IF YOU LOOK AT THE
DISTRIBUTION OF USUAL HEALTHY
AGERS, DO YOU HAVE ENOUGH
CLINICAL DATA TO ASK ABOUT
DIFFERENCE?
>>THIS IS THE NEXT STEP
PERHAPS, TO TRANSLATE, IF I
UNDERSTAND CORRECTLY, TRANSLATE
THE QUESTION, SOME OF THE OLDER
PEOPLE LOOK YOUNGER, MORE LIKE
SOME YOUNGER PEOPLE BASED ON
PROPORTIONS OF THE CELLS.
SO SINCE WE HAVE A LOT OF
BIOCHEMISTRY, AND OFTENTIMES
WITH THIS HAPPENING YOU CAN LOOK
YOUNGER IN CD8, SLIGHTLY OLDER
OR THE DIFFERENCE IN CD4
PROPORTION, SO CONNECTION LIKE
WAS PUBLISHED WITH CONNECTION
BETWEEN FATTY ACID AND
MONOCYTES, SO ON, SO WE'RE
HOPEFUL.
>> THANK YOU.
>> NEXT IS SCOTT BOYD, ANTIBODY
REPERTOIRE ACROSS THE LIFESPAN.
>> THANKS FOR THE OPPORTUNITY
TO TALK TODAY.
OKAY.
SO I'M HIGHLIGHTING SOME OF THE
LAB MEMBERS THAT HAVE DONE THE
WORK I'M GOING TO TALK ABOUT,
I'LL MENTION THEM AS WE GO
ALONG, BEGINNING WITH A BIT OF
BACKGROUND.
WE'VE BEEN LOOKING HARD AT
DIFFERENT IMMUNOLOGIC
CONDITIONS, SEEING HOW THEY
CHANGE, WHICH ARE MOST IMPORTANT
FOR FUNCTIONAL RESPONSES.
WE THINK THIS IS AN INFORMATIVE
WAY TO LOOK AT THE B CELL
POPULATIONS BECAUSE THE HUGE
DIVERSITY OF RECEPTORS GIVES US
THE CHANCE TO RESPOND TO ALL
KINDS OF ANTIGENS.
THE SIGNAL OF CLONAL EXPANSIONS
WHEN YOU GET A SPECIFIC RESPONSE
IS A LARGE SIGNAL IN BIOLOGICAL
DATA, IF YOU SEQUENCE RECEPTORS.
YOU CAN TRACK FUNCTIONAL ASPECTS
LIKE AFFINITY MATURATION OF
ACCUMULATION OF SOMATIC MUTATION
THAT LEADS TO INCREASING BINDING
OF ANTIBODIES.
REVIEWING THINGS WITH REGARD TO
SEROLOGICAL RESPONSES, IT'S BEEN
WELL REPORTED IN COHORTS AND
STUDIES THAT OLDER INDIVIDUALS
ARE MORE SUSCEPTIBLE TO
DIFFERENT INFECTIOUS DISEASES,
OFTEN HAVE POORER SEROLOGICAL
RESPONSES.
ON THE LEFT PANEL ELDERLY GIVE
LOWER RESPONSE TO INFLUENZA
VACCINE COMPARED TO YOUNG
PEOPLE.
BUT THE PICTURE IS NOT QUITE AS
SIMPLE AS THAT BECAUSE THERE ARE
OTHER FACTORS THAT CAN AFFECT A
SEROLOGICAL RESPONSE, FOR
EXAMPLE WHAT DEGREE OF
PREEXISTING ANTIBODIES YOU HAD
THAT RECOGNIZED ANTIGENS OR
THOSE SIMILAR IS PARTLY BEHIND
WHAT MAY ACCOUNT FOR ELDERLY
VERSUS YOUNG DIFFERENCES, NOT
THE WHOLE STORY BUT PART OF IT.
LONGITUDINAL DATA GOING BACK TO
EARLIER FLU VACCINE STUDIES, IF
YOU IMMUNIZE REPEATEDLY THE GAP
DECREASES OVER TIME, THE ELDERLY
JUST NEED A HIGHER DOSE OR MORE
ROUNDS OF BOOSTING.
WHICH IS A GOOD THING AND CAN BE
HELPFUL FOR INTERVENTIONS OF
COURSE.
IT'S REALLY IMPORTANT TO KEEP
TRACK OF THOSE POTENTIAL
CONFOUNDERS OF RESPONSES.
SO, WHEN SARS-COV-2 CAME ALONG
THIS GAVE A GREAT OPPORTUNITY TO
STUDY YOUNG AND OLD RESPONSES TO
ANTIGENS WE HADN'T ENCOUNTERED,
THERE'S SOME CROSS-REACTIVITY,
CORONAVIRUS SPIKES AND SO ON,
BUT NOT STRONG ONES.
AND WE ALSO HAD THE OPPORTUNITY
TO LOOK AT RNA VACCINE RESPONSES
IN MUCH BIGGER COHORTS THAN EVER
TESTED BEFORE.
SO THE RESULTS WERE PRETTY
INTRIGUES, FOR EXAMPLE, THE RED
BOX IF YOU LOOKED A RESPONSE TO
SARS-COV-2 SPIKE FROM YOUNGER OR
OLDER INDIVIDUALS WHO GOT THE
REGULAR RNA VACCINE, THERE'S
SOME DECREASE TITER RESPONSE IN
OLDER INDIVIDUALS BUT NOT A HUGE
DIFFERENCE, RELATIVELY MODESTER.
AND THIS IS SOMETHING THAT WOULD
ELIMINATE THE DIFFERENCE OF
PREVIOUS EXPOSURE THAT WE HAVE
IN INFLUENZA STUDIES FOR
EXAMPLE.
SOME OTHER ANALYSIS DONE BY A
DIFFERENT GROUP ON RIGHT-HAND
PANEL SHOWS IF YOU LOOK AT VERY
ELDERLY OVER 80 YEARS OLD YOU
SEE BIGGER DIFFERENCE IN RNA
VACCINE RESPONSE BUT IT'S STILL
NOT LIKE ELDERLY DON'T RESPOND
AT ALL.
THAT WAS A GOOD OPPORTUNITY TO
SAY THERE'S CERTAINLY SOME
IMPAIRMENTS BUT NOT AS SEVERE AS
SOME OF THE LITERATURE MIGHT
SUGGEST.
OTHER THINGS WE LOOKED AT, IF WE
LOOK AT TIME SERIES OF INFECTION
LIKE SARS-COV-2 INFECTION
SEROLOGICAL RESPONSES THESE ARE
PEOPLE THAT HAD COVID, COVID-19,
LOOK AT OLDER INDIVIDUALS AND
YOUNGER ONES, THE SETS THERE,
RESPONSE OF IgG, OF VARIANTS
LISTED OVER A TIME SOURCE HOW
LONG AFTER ONSET, THERE ISN'T
MUCH OF A DIFFERENCE BETWEEN THE
YOUNG AND OLD.
HOWEVER, THAT'S A DIFFERENT
CONFOUNDER, WHICH IS THAT VERY
OFTEN OLDER INDIVIDUALS HAD MORE
SEVERE SARS-COV-2 AND SEVERITY
OF ILLNESS IS ASSOCIATED WITH
HIGHER ANTIBODY RESPONSE.
SO THESE WERE THINGS THEY ARE
ALL DIFFERENT, SHIFTING ASPECTS,
YOU CAN'T ALWAYS FULLY CONTROL
FOR IN STUDIES BUT IMPORTANT FOR
UNDERSTANDING WHAT'S HAPPENING.
SO, IN THINKING WHAT'S CHANGING
IN THE B CELL REPERTOIRES AND
RESPONSES OVER TIME THERE ARE A
FEW THINGS CLEAR IF YOU SEQUENCE
RECEPTOR REPERTOIRES IN PEOPLE
OF DIFFERENT AGES, HEALTHY
INDIVIDUALS ABLE TO PARTICIPATE
IN STUDY, ONGOING ACCUMULATION
OF SOMATIC MUTATION OVER TIME
BEGINNING FROM FIRST MONTHS OF
LIFE THROUGH TO WELL INTO THE
PEOPLE'S 80s, IF YOU LOOK AT
THE TOP ROW IgG SOMATIC
MUTATION CONTINUES TO INCREASE,
MAY PLATEAU IN YOUR 80s OR
90s BUT PEOPLE STILL SEEM TO
BE ABLE TO HAVE INCREASED
ANTIGENIC STIMULATION OF NEW
MUTATIONS THAT ACCUMULATE OVER
TIME.
THAT'S TRUE FOR IgA.
PEOPLE WITH COVID-19 THE LEVEL
OF MUTATION AND CLONES HAS
SHIFTED DOWNWARD, BECAUSE YOU
HAVE A MIXTURE OF NEW RECENTLY
STIMULATED CLONES WHICH HAVE
VERY LITTLE MUTATION MIXED INTO
THE REPERTOIRE.
THIS SHIFTS EVERYTHING DOWN BUT
DOESN'T REALLY CHANGE THE
OVERALL TREND OF MUTATION WITH
AGE.
SO IT'S A BIT HARD TO GET YOUR
HEAD AROUND REPERTOIRES AND
STUDYING IN THE SCALE OF
CLINICAL STUDIES, GROUPS OF
INDIVIDUALS.
SO THIS IS A SORT OF BIG PICTURE
OVERVIEW OF ONE OF THE
LONGITUDINAL COHORTS THAT WAS
STARTED BY MARK'S GROUP AND
CONTINUED IN COLLABORATION WITH
HIS LAB AND MINE OF STUDYING
VACCINE RESPONSES IN ELDERLY
INDIVIDUALS VERSUS YOUNG ADULTS.
EACH OF THOSE BOXES IS THE
RESULTS OF SEQUENCING THE
ANTIBODY HEAVY CHAIN REPERTOIRE,
EACH WAS A PERSON TRACKED
LONGITUDINALLY OVER TIME, EACH
ROW IS A TIME POINT IN THE
MANY-YEAR ANALYSIS, WE HAVE
MULTIPLE YEARS WITH DAY ZERO,
DAY 7, DAY 28 AFTER VACCINATION.
CLONES SEEN THERE ARE DEPICTED
WHERE THE HEAVY CHAIN IS X-AXIS,
CDR 3 IS THE Y-AXIS.
IF YOU FOLLOW INDIVIDUALS THERE
ARE SEVERAL KINDS OF CLONES YOU
CAN PICK OUT, SOME PERSISTENT,
DETECTED AT EVERY TIME POINT,
THERE ARE OTHERS RELATED TO THE
VACCINE RESPONSE SO YOU DON'T
SEE THEM CLONALLY EXPANDED AT
SOMEDAY ZERO BUT SEE THEM AT DAY
7 OR 28 AND OTHERS AT MULTIPLE
YEARS IN RESPONSE TO
VACCINE,OTHERS YOU SEE ONCE AND
NEVER AGAIN.
IF WE LOOK AT THE PERSISTENT
ONES THIS IS SOMETHING WE'RE
USED TO READING ABOUT IN
LITERATURE ABOUT ELDERLY, THEY
WOULD HAVE LARGE EXPANDED CLONES
OF LYMPHOCYTES.
WE SEE THAT, IN THE OLDER
INDIVIDUALS IN THE STUDY.
FOR EXAMPLE THIS IS RANKED IN
ORDER OF AGE, OLDEST INDIVIDUAL
WAS IN THEIR 90s.
YOUNG ADULTS IN THEIR 20s AND
30s.
IF YOU LOOK CLOSELY, YOUNG
INDIVIDUALS ALSO HAVE PERSISTENT
CLONES YOU CAN DETECT EVERY TIME
YOU SEQUENCE THEM, NOT SOLELY
AGE RELATED.
CHARACTERISTICS CHANGE.
THIS IS SHOWING AMOUNT OF
MUTATION IN THE CLONES, PURPLE
MORE HEAVILY MUTATED.
YOUNGER ADULTS PERSIST OVER LONG
TIMES, WE SEE THEM, BUT THEY ARE
NOT HEAVILY MUTATED LIKE THEY
HAVE HAD MULTIPLE ROUNDS EVER
ANTIGEN EXPERIENCE.
IN ELDERLY THEY ARE QUITE
MUTATED USUALLY.
IF WE LOOK AT VACCINE-STIMULATED
CLONES, DAY 7 TIME POINTS, EACH
ROW WITH MORE DOTS IN THEM, YOU
CAN SEE BOTH ELDERLY AND YOUNG
ADULTS ARE HAVING PRETTY
VIGOROUS RESPONSES TO THE
VACCINATION, MOST OF THE PEOPLE
IN THE STUDY BEGAN TO BE FLU
VACCINATED IN 2008, REVACCINATED
EVERY YEAR.
LATER YEARS REPEAT VACCINATIONS
GETTING REDUCES RESPONSES IN
MANY INDIVIDUALS REGARDLESS OF
AGE.
THIS UNDERSCORES NOT A HUGE
IMPAIRMENT OF RESPONSE, RESPOND
WITH LOTS OF CLONES, NOT ALL THE
CLONAL PROCESS, BUT THAT'S
SOMETHING THEY SHARE WITH
YOUNGER ADULTS.
SOMETHING THAT DOES SEEM TO BE
TRUE THEY ARE HAVING A POOR
ABILITY TO GENERATE
PLASMABLASTS, OVERALL GETTING
LOWER TITERS BECAUSE THEY HAVE
FEWER CELLS BUT PER CELL
ANTIBODY PROSECUTION IS NOT THAT
DIFFERENT.
SO WHEN WE LOOK AT PUNITIVE
--
PUTATIVE, IN BOTH YOUNG AND
ELDERLY.
EVERY WITH FLU VACCINES RESPONDS
TO THE CLONES, SOMETHING THE
LITERATURE HAS NOT CAPTURED IN
SENSE OF TECHNOLOGY, SOMETHING
WE'RE TRYING TO ADDRESS.
A FEW OTHER POINTS IF YOU LOOK
FOR RECURRENT VACCINE-STIMULATED
CLONES, THERE'S NOT THAT BIG A
DIFFERENCE.
I WENT INTO THIS WITH
PRE-CONCEPTION MAYBE OLDER
PEOPLE REUSE THE SAME CLONES
OVER AND OVER BUT WE SEE THAT IN
YOUNG PEOPLE AS WELL.
MANY CLONES FOR EXAMPLE
RESPONSIVE TO H1, H-A OR H3,
YOU'LL SEE THEM REPEATEDLY, IT'S
NOT BLACK AND WHITE DIFFERENCE
BETWEEN, YOU KNOW, AND OLD.
WAYS THAT WE AND OTHERS HAVE
BEEN TRYING EXTRACT MAXIMUM
INFORMATION FROM THESE
REPERTOIRES, BY LOOKING FOR
ANTIBODIES WITH HIGHLY SIMILAR
SEQUENCES, BINDING ACTIVITY YOU
KNOW FOR SURE IS A WAY TO
GENERALIZE IF YOU IDENTIFY A
SPECIFIC ANTIBODY AND FIND
OTHERS HIGH OR SIMILAR, WE
LOOKED AT THAT IN THIS PAPER
PUBLISHED A COUPLE YEARS AGO, IN
"SCIENCE" LOOKING FOR
CONVERGENCE OF HEAVY CHAINS.
LOOKING AT YOUNG PEOPLE,
CHILDREN IN EARLY YEARS, CLONAL
EXPANSIONS ARE BIGGER WITH A
MORE PUBLIC REPERTOIRE RESPONSE
TO COMMON EXPOSURE LIKE
CHILDHOOD VACCINES, INFLUENZA.
IN OLDER PEOPLE SEE COMMON
THINGS LIKE INFLUENZA.
THE LOWER PANEL SHOWS DIFFERENT
AGES, PUBLIC CLONOTYPES FOR FLU
OVER AGE RANGE FREQUENCIES DON'T
DIFFER MUCH, A PUBLIC
REPERTOIRE, BUT UNLESS YOU'RE
RECENTLY EXPOSED AS THE CHILDREN
HAD BEEN TO OTHER VACCINES AND
ANTIGENS, NOT TERRIBLY HIGH,
ONLY REPEATED EXPOSURES.
I WANTED TO HIGHLIGHT SOME
CHALLENGES IN HUMAN B CELL
STUDIES, WE'VE HAD LOWER ABILITY
TO ANALYZE ANTIGEN SPECIFIC B
CELLS BECAUSE IT'S QUITE
EXPENSIVE TO CHARACTERIZE IN THE
WAY WE'VE DONE UP TO NOW, SORT
ANTIGEN BINDING B CELLS OR
PLASMABLASTS, MAKING MONOCLONAL
ANTIBODIES, CHARACTERIZE THEM,
AND THAT LIMITS THE NUMBER OF
PEOPLE YOU CAN STUDY, NUMBER OF
CELLS PER PERSON, AND RESULTED
IN MANY PAPERS BASED ON
INDIVIDUALS THAT MAY NOT BE
REPRESENTATIVE FOR ASKING
QUESTIONS THAT WOULD TACKLE TRUE
HUMAN DIVERSITY WE HAVE IN
POPULATIONS.
AND ALSO FOR EACH CELL YOU WANT
TO KNOW BREADTH OF BINDING,
PARTICULARLY IMPORTANT DURING
COVID, ALSO FOR FLU AND OTHER
TOPICS IT'S REALLY IMPORTANT.
AND TO UNDERSTAND IMMUNOLOGIC
IMPRINTING, EVOLUTION OF
RESPONSES OVER TIME AS PEOPLE
ARE EXPOSED TO VARIANTS OF
ANTIGENS WHICH CLONES ARE
RETAINED, WHICH GO INTO MEMORY
COMPARTMENT OR BECOME PLASMA
CELLS IS KEY.
SECOND THING IS IT WOULD BE
IDEAL TO EXTRACT FOR FUNCTIONAL
INFORMATION, WE HAVE SOME
APPROACHES TO THAT.
AS MARK HIGHLIGHTED SO NICELY,
WE NEED TO STUDY OTHER TISSUES
IN THE HUMANS MORE TO UNDERSTAND
WHAT'S OUTSIDE THE BLOOD TO GET
A SENSE OF MEMORY, MARROW,
PLASMA CELLS AND SO ON.
A COUPLE APPROACHES TO ADDRESS
SOME ISSUES, AREA OF SARS-COV-2,
A GREAT OPPORTUNITY TO STUDY
PEOPLE'S RESPONSES TO VARIANTS.
THIS IS THE APPROACH WE'VE BEEN
USING, HELPFUL GOING FORWARD.
AND IT'S THE FOLLOWING.
SO, PEOPLE HAVE BEEN SORTING
ANTIGEN SPECIFIC B CELLS BY
MAKING FLUORESCENTLY LABELED
COMPLEXES, RIGHT?
WITH THE SIMPLE ADDITION OF
HAVING A DNA TAG ATTACHED TO
THE, FOR EXAMPLE, ANTIGEN, THAT
ALLOWS MUCH BIGGER PANELS OF
ANTIGENS THAT YOU CAN ALL
DISTINGUISH IF DO YOU SICKLE
CELL TRANSCRIPTOME SEQUENCING,
THE EXPERIMENTAL DESIGN IS LAID
OUT HERE, A PANEL OF ANTIGENS,
SARS-COV-2 SPIKE, F2 DOMAIN, F2,
RBD, YOU CAN MAKE COMPLEXES WITH
DIFFERENT DNA TAGS ON EACH ONE
AND MIX THEM TOGETHER WITH CELL
THAT CONTAINS B CELLS, ANTIGENS
WILL BIND, IF THE B CELL HAS
REACTIVITY IT WILL BIND TO ALL.
SINGLE CELL TRANSCRIPTOME
SEQUENCING YOU CAN READ GENE
EXPRESSION OF EACH B CELL,
CHAINS, AND TAGS ON ANY OF THE
ANTIGENS OF THE CELL BOUND SO
YOU CAN HAVE A BIG PANEL AND
READ OUT SPECIFICITY AND
BREADTH.
WE'VE APPLIED THAT TO
SARS-COV-2.
12 ANTIGENS, ANOTHER WITH 26,
ENABLING A SCALING OF ANALYZING
A SPECIFIC CELL, YOU CAN FOLLOW
THE TIME COURSE OF RESPONSE TO
INFECTION OR VACCINATION, AND
SEE DIFFERENT PHENOTYPES.
FOR EXAMPLE IN INFECTION A
SUBSET OF MEMORY TYPE B CELLS
WITH ACTIVATION MARKERS YOU
DON'T SEE IN VACCINATED PEOPLE
WITH RNA VACCINES.
HERE IS WHERE WE SEE SPECIFICS.
IN THE UPPER PANEL ON THE UMAP
PLOD, WHICH ANTIGENS THEY BIND,
WHAT PHENOTYPES ARE ON THE UMAP,
FOR EXAMPLE, AND THIS ALLOWS US
TO DO THINGS EQUIVALENT TO
EPISODE MAPPING OR IDENTIFYING
WHAT AMOUNT OF BREADTH OR
CROSS-REACTIVITY B CELLS HAVE.
IF YOU LOOK AT B CELLS THAT BIND
TO RBD WUHAN VERSUS VARIANTS,
FOR INDIVIDUAL B CELLS SOME
VIRUSES ESCAPE BINDING MORE THAN
OTHERS, FOR EXAMPLE BETA HAS
POOR BINDING, OTHERWISE WOULD BE
THE RBD WUHAN, GENERALIZED
ACROSS BIG DATA SETS, THIS SHOWS
FROM INFECTED AND VACCINATED
PEOPLE RESULTS FROM OVER A
THOUSAND B CELLS FROM JUST A
COUPLE EXPERIMENTS, WHERE EACH
ROW IS A CELL, EACH COLUMN IS
ANTIGEN, SPIKE BINDERS, RBD
VARIANTS, YOU GET A READOUT.
SO THAT'S SOMETHING THAT'S GOING
TO BE USEFUL FOR ANALYZING
DIFFERENCES AND OF IN
REPERTOIRES, HOW PEOPLE RESPOND,
EXPOSURES OVER TIME.
AND WE'VE ALSO VALIDATED THE
METHOD BY ALSO MAKING
MONOCLONALS SHOWING BINDING IS
RECAPITULATED WHEN YOU DO
STANDARD EXPRESSIONS.
THAT'S ONE THING.
A SECOND ONE I'LL TOUCH ON
BRIEFLY IS USING MACHINE
LEARNING METHODS TO ANALYZE
IMMUNOGLOBULIN SEQUENCES TO
IDENTIFY ONES SIMILAR BUT NOT
NECESSARILY AT LEVEL OF SEQUENCE
IDENTITY.
BY LOOKING AT SOMEBODY'S OVERALL
REPERTOIRE COMPOSITION, MUTATION
LEVELS YOU HAVE, WHAT SEQUENCE
IDENTITY CLUSTERS WITHIN THE
REPERTOIRE COMPARED TO OTHERS,
USING PROTEIN LANGUAGE MODEL TO
EXTRACT, WE CAN IDENTIFY PEOPLE
IN TERMS OF WHAT INFECTIONS THEY
HAVE HAD OR WHAT EXPOSURES AND
WE THINK THIS WILL BE USEFUL FOR
TRACKING IMMUNOLOGICAL
DEFICIENCY ASSOCIATED WITH AGE.
JUST BRIEFLY IF YOU LOOK AT
DIFFERENT IMMUNOLOGIC DISORDERS
YOU CAN PICK THEM OUT BASED ON
HEAVY CHAIN SEQUENCING ALONE IN
THIS ANALYSIS.
I'LL LEAVE OFF THERE.
AND SAY WE THINK THESE WILL HELP
US GET A BETTER GRIP ON HUMAN
IMMUNE REPERTOIRES AND T CELLS
BY EXTENSION AND UNDERSTAND
DIFFERENCES WITH AGING CLOSING
GAPS IN LITERATURE BASED ON TOO
FEW PEOPLE.
THANK YOU VERY MUCH.
THESE ARE THE GRAD STUDENTS AND
POSTDOCS WHO DID THIS WORK I'VE
HIGHLIGHTED AS WE WENT ALONG,
SPECIFIC BINDING STUFF, KATRINA,
ONEL VEER,
ON -- OLIVER AND BRANDON, AND
MAXIM.
THANKS FOR YOUR ATTENTION.
>> SOME WILL CARRY TO THE
DISCUSSION AT THE END.
GO AHEAD.
>> HI.
SO DID YOU SEE ANY DIFFERENCES
IN THE REPERTOIRES BETWEEN OLDER
AND YOUNGER PEOPLE IN YOUR COVID
DATASETS?
>> YEAH, SO I WOULD SAY SO FAR
IN THE COVID ONES WE HAD WE
HAVEN'T SEEN ANYTHING THAT WAS
ABSOLUTELY SYSTEMATIC, DIFFERENT
BETWEEN OLDER AND YOUNG
IRINDIVIDUALS.
WE DID SEE FEWER CLONES OR FEWER
SPECIFIC CELLS IN THE MOST
ELDERLY WE LOOKED AT BUT OVERALL
MORE SIMILARITIES THAN
DIFFERENCES.
IT'S PROBABLY BECAUSE MOST
PEOPLE START WITH A CLEAN SLATE,
THERE AREN'T THAT MANY
CROSS-REACTIVE TO VIRUSES WE'VE
BEEN EXPOSED TO, T CELL MAY BE
MORE, B CELLS IT'S A SMALL
FRACTION THAT BIND.
>> THANKS.
>> IN THE BACK.
>> I WAS WONDERING IF IN ANY OF
YOUR MACHINE LEARNING MODELS YOU
HAVE HAD THE OPPORTUNITY YET TO
ASK THE QUESTION IF YOU CAN
PREDICT SOMEONE'S RESPONSE BASED
OFF THEIR REPERTOIRE BEFORE
VACCINATION?
>> YEAH, SO WE HAVEN'T DONE
THAT YET.
I THINK THERE'S PROSPECT ONE
COULD DO SO BUT IN TERMS OF
FREQUENCY OF MEMORY CELLS THAT
SHOULD RESPOND TO THAT
PARTICULAR ANTIGEN, IT'S
SOMETHING WE'RE HEADED TOWARDS.
IT'S PROBABLY -- YOU KNOW, WILL
WORK MORE COMBINED WITH OTHER
INFORMATION FROM THE PERSON'S
REPERTOIRE.
I SHOWED BCR DATA, ALSO APPLYING
TO TCRs FROM THE SAME
INDIVIDUALS.
>> EXCELLENT.
WONDERING IF IT'S POSSIBLE TO
IDENTIFY THE B CELL CLONES
PRODUCING AUTOANTIBODIES FOR
INTERFERON AGAINST THE -- IN
COVID, ARE THOSE THE POTENTIAL
DRIVERS OF CHANGES IN THE
ELDERLY?
>> YEAH, I THINK THAT'S A GREAT
EXPERIMENT, USING THOSE AS
SORTING BUT WE HAVEN'T DONE THAT
YET.
I THINK THE FREQUENCY OF SUCH B
CELLS IS PROBABLY NOT TERRIBLY
HIGH, YOU KNOW, SOME OF THE
STUDIES THAT REPORT THEY ARE
PRESENT IN 30 OR 50% OF
INDIVIDUALS MAYBE USING VERY
SENSITIVE ASSAYS, BUT I THINK
THAT'S A VERY FOCUSED TOPIC TO
LOOK AT IN THE ELDERLY, AND WE
EXPECT TO SEE A DIFFERENCE.
>> I THINK WE CAN GO ON IF
THERE ARE NO OTHER QUESTIONS.
KEEP THOSE QUESTIONS FOR THE
NEXT DISCUSSION.
NEXT SPEAKER IS JARROD DUDAKOV.
AND HE'S GOING TO SPEAK ABOUT
AGE-RELATED T CELL FUNCTIONAL
CHANGES.
AND WE'LL HAVE AN ANNOUNCEMENT
ABOUT A PROGRAM AFTER HIS TALK
RELATED TO THIS.
>> THANK YOU.
I'M TRYING SOMETHING DIFFERENT
HERE.
I'M NOT GOING TO TALK MUCH ABOUT
T CELLS BUT WHERE THEY COME FROM
AND HOW THAT CHANGES WITH AGE
AND IMPACT T CELL FUNCTION IN
THE PERIPHERY.
THE TITLE IS REALLY TALKING
ABOUT NEW STORY TOTALLY
UNPUBLISHED, NOW OUT AS
PRE-PRINT, WE'LL TRYING TO
IDENTIFY THE ATYPICAL EPITHELIAL
POPULATION, T CELL DEVELOPMENT
AND REPAIR AS WELL.
AS MARK SAID EARLIER, WE'RE
INTERESTED BECAUSE OF THE BROAD
REPERTOIRE OF CELLS THAT THEY
CAN PRODUCE THAT CAN RECOGNIZE
UNKNOWN ANTIGENS, NEOANTIGENS,
PATHOGENS, THINGS LIKE THAT.
NOW, THERE'S ENORMOUSLY DIVERSE
REPERTOIRE POTENTIAL OF T CELLS,
MOST AUTOREACTIVE, TAKEN CARE OF
IN THE THYMUS THROUGH TOLERANCE
MECHANISMS BUT REALLY THE RESULT
IS THAT THERE'S THE REQUIREMENT
THAT IS SPECIALIZED ORGAN TO
MAKE THIS HAPPEN SO UNLIKE
PRETTY MUCH EVERY OTHER
HEMATOPOIETIC CELL INCLUDING B
CELLS THAT REQUIRE SPRINKLING OF
CYTOKINES IN BONE MARROW T CELLS
REQUIRE THIS SPECIALIZED ROLE.
THE REASON IS BECAUSE OF THE
STROMAL MARKER ENVIRONMENT THAT
SUPPORTS THAT T CELL
DEVELOPMENT.
THIS IS COMPRISED OF THYMIC
EPITHELIAL CELLS, THESE ARE THE
CELLS THAT SUPPORT ALL ASPECTS
OF T CELL DEVELOPMENT, REALLY
CRITICALLY ALSO NEGATIVE
SELECTION STUDIES, EDUCATING T
CELLS AGAINST ANTIGENS.
THIS IS A COMPLICATED SLIDE,
HIGHLIGHTING STROMAL CELL
POPULATIONS, FIBROBLASTS,
ENDOTHELIAL, HEMATOPOIETIC,
DENDRITIC, MACROPHAGES, THINGS
LIKE THAT.
THYMIC FUNCTION IS NOT A STATIC
PROCESS, ONE OF THE EARLIEST
ORGANS TO SHOW SIGNS OF AGE.
YOU CAN SEE THIS IS IN THE HUMAN
TISSUE WHERE EVEN AS EARLY AS
PEDIATRIC PATIENTS YOU START TO
SEE PERIVASCULAR SPACES FORMING,
FATTY ISSUE ACCUMULATING, PAST
50 YOU'VE GOT VERY LITTLE
FUNCTIONAL TISSUE LEFT, SOME BUT
VERY LITTLE FUNCTIONAL TISSUE
LEFT, MOST IS JUST FAT, AT LEAST
IN HUMAN.
IN THE MOUSE IF IT SHRINKS IN
SIZE YOU HAVE LESS FATTY TISSUE
ITSELF.
THIS RESULTS IN A LOSS OF EXPORT
OF NEW NAIVE T CELLS OUT OF THE
PERIPHERY.
THESE ARE A MARKER OF THE T-CELL
RECEPTOR RECOMBINATION EVENTS IN
THE THYMUS, TRECs, CELLS WITH
A REMNANT RECENTLY COMING OUT OF
THE THYMUS.
WHAT DOES THIS MEAN WHEN YOU
TALK ABOUT A NORMAL HEALTHY
INDIVIDUAL?
IN A NORMAL YOUNG PERSON YOU GET
A ROBUST EXPORT OF NEW NAIVE
CELLS COMING OUT, ROBUST
REPERTOIRE OF T CELLS.
IN AN AGED INDIVIDUAL, OLD
INDIVIDUAL, FEWER T CELLS COMING
OUT, HOMEOSTATIC EXPANSION OF
MEMORY CELLS, SAME NUMBER BUT
RATIO OF NAIVE TO MEMORY CELLS
IS RADICALLY REDUCED, MAXIM
INDICATED THAT EARLIER AS WELL.
HOW CAN THIS IMPACT OUR CLINICAL
PATHOLOGY?
TWO ASPECTS HERE, MARK INDICATED
THIS EARLIER, RESPONSES TO FLU
VACCINE, AND OTHER VACCINES
REDUCED WITH AGE.
SOME IS GOING TO BE DEPENDS ON T
CELLS, SOME IS T CELL DEPENDENT.
AND SO THIS REDUCED EXPORT OF
NAIVE T CELLS CAN IMPACT ON
THAT.
AND SOMETHING WE'RE INTERESTED
IN AT THE MOMENT, LESS DIRECT
EVIDENCE BUT A GOOD RATIONALE,
THERE'S A STRONG CORRELATION
BETWEEN RESPONSES TO CHECKPOINT
IMMUNOTHERAPY AND MUTATIONAL
BURDEN OF THE TUMOR ITSELF.
NOW, WHAT THIS SAYS TO ME IS
THAT THERE IS THIS KIND OF STASH
OF ABILITY TO RESPOND,
MUTATIONAL BURDEN IS ONE ASPECT,
BREADTH OF T-CELL RECEPTOR IS
ANOTHER BECAUSE IF YOU -- BOTH
THERAPIES ARE PREDICATED ON THE
FACT THERE'S A T CELL THERE THAT
CAN RECOGNIZE THAT ANTIGEN OR
PATHOGEN OR WHATEVER IT IS.
IF YOU'VE GOT REDUCED NAIVE T
CELLS COMING OUT THE POSSIBILITY
OF HAVING THAT CLONE IS GOING TO
DECLINE AND DECLINE AND DECLINE.
NOW, THE OTHER PROBLEM, IF IT
WANTS TO ADVANCE, IS THE THYMUS
IS EXTREMELY SENSITIVE TO
NEGATIVE STIMULUS, SO ACUTE
DAMAGE.
THERE ARE THREE FORMS OF DAMAGE
HERE THAT I'M HIGHLIGHTING,
IONIZING RADIATION,
CYCLOPHOSPHAMIDE, AND
DEXAMETHASONE GOING DOWN OVER
THE FIRST COUPLE DAYS AFTER THE
INJURY.
THE THING IS THERE'S A
REMARKABLE CAPACITY TO REPAIR
ITSELF.
IF YOU FOLLOW THAT KINETIC
ANALYSIS YOU SEE UPSTREAM IN THE
ABILITY TO REPAIR AND GET ROBUST
CELLULARITY GAIN.
IN THE CORTICOSTEROID MODEL YOU
GET THIS IN THE TISSUE.
WHERE THIS COMES REALLY INTO THE
FORE IS IN LET'S SAY BONE MARROW
TRANSPLANT PARTICULARLY
ALLOGENEIC, YOU CAN TAKE YEARS
TO RECOVER T CELLS AFTER THERAPY
BECAUSE THE WHY YOU GIVE A
TRANSPLANT, YOU WIPE OUT THE
ENTIRE HEMATOPOIETIC SYSTEM AND
REPLACE WITH SOMEBODY ELSE'S, IT
CAN TAKE A LONG TIME TO COME
BACK.
THIS CAN HAVE PROFOUND IMPACT IN
CLINICAL OUTCOMES.
ON THE LEFT IS LOOKING AT T CELL
RECONSTITUTION AFTER BONE MARROW
TRANSPLANT, ALLOGENEIC
TRANSPLANT, DAY 100 CD4 T CELL
RECONSTITUTION, IF YOU STRATIFY,
YOU SEE PROFOUND BETWEEN THE
GROUPS, OVERALL SURVIVAL,
ANYTHING THAT MIGHT BE GOING
WITH THOSE PATIENTS.
ON THE RIGHT THERE'S A FLIP
SLIDE.
THIS IS LOOKING AT THYMIC
FUNCTION AT THE TIME OF
TRANSPLANT, THE NUMBER OF
TRECs BEFORE THE TRANSPLANT
ITSELF, AND AGAIN IF YOU HAVE
PATIENTS WITH HIGH TREC LEVELS,
YOU HAVE A BETTER CLINICAL
OUTCOME THAN LOW TREC LEVELS.
WHAT BOTH SAY IS HAVING THYMUS,
THYMIC FUNCTION, ROBUST THYMIC
FUNCTION, IS GOING TO BE OF
BENEFIT TO OUR TRANSPLANT
OUTCOMES.
PART OF WHY THIS IS IS THAT EVEN
THOUGH IT HAS A REMARKABLE
CAPACITY TO REPAIR ITSELF THAT
DECLINE WITH AGE.
YOU CAN SEE IN THE MODEL ON THE
LEFT IN MOUSE, IT TAKES A LITTLE
BIT LONGER TO COME BACK.
THE RIGHT IS CLINICAL DATA GOING
QUITE A FEW YEARS BACK FROM
CRYSTAL McCALL SHOWING THE
PERIPHERY.
YOU CAN SEE EVEN AFTER ALMOST
TWO YEARS THEY STILL HAVE NOT
RECOVERED THEIR CD4 COUNTS.
TO GO TO SCOTT'S POINT BEFORE,
THIS IS A 23-YEAR-OLD.
THESE EFFECTS, BEFORE ANYONE IS
SAYING YOU WOULD NOT CALL THIS
PERSON AND OLD PERSON, BUT
IMMUNOLOGICALLY THEY ARE
STARTING TO BECOME AN OLD
PERSON, AT LEAST IN SOME SENSE
ANYWAY.
AND WHEN YOU PUT THIS INTO THE
TRANSPLANT CONTEXT, LOOK AT AGE,
THIS COMES TOGETHER, OLDER
PATIENTS DO PERFORM WORSE
OVERALL AFTER TRANSPLANT.
WE'RE INTERESTED OVER THE LAST
COUPLE YEARS UNDERSTANDING WHY
IS IT THAT REGENERATIVE CAPACIY
IS LIMITED WITH AGE, STARTING TO
UNDERSTAND THAT.
WHAT DO YOU DO WHEN YOU DON'T
KNOW WHERE TO START?
GO INTO SINGLE CELL SEQUENCING.
THAT'S WHAT WE DID.
WE WANTED TO FOCUS ON
NON-HEMATOPOIETIC STROMAL CELL
TAKING CD45 NEGATIVE CELLS,
SINGLE CELL SEQUENCING IN YOUNG
AND AGED MICE, AND ALSO ADDING A
DAMAGED STIMULI AS WELL.
WE'VE GOT TOTAL BODY IRRADIATION
LOOKING AT DAY 0, 1, 4, 7.
YOU CAN SEE THIS IS A DOWN
SWING, SIMILARITY, STARTING TO
COME BACK BUT HASN'T PROGRESSED
TOO MUCH.
WHEN WE DO THIS WE GET A BUNCH
OF CELL POPULATIONS.
THREE BIG ONES WE'RE
CONCENTRATING ON ENDOTHELIAL, WE
CAN BREAK DOWN, GET SUBSETS,
FIBROBLAST SUBSETS, I WON'T GO
INTO THOSE TODAY, IN THE
INTEREST OF TIME.
SOMETHING THAT STOOD OUT IS WHEN
WE WERE LOOKING AT EPITHELIAL
CELLS, IN ADDITION TO
HETEROGENEITY THAT'S BEEN
IDENTIFIED OVER THE LAST FEW
YEARS IN THYMIC EPITHELIAL
CELLS, WHAT WE FOUND WERE TWO
ATYPICAL POPULATIONS OF THYMIC
EPITHELIAL CELLS THAT ONLY SEEM
TO BE THERE IN OLD MICE AND NOT
YOUNG MICE.
THAT'S THESE TWO POPULATIONS
OVER HERE, REFERRED TO AS AATEC
1 AND IT.
THEY ONLY START TO EMERGE WITH
AGE.
IF WE LOOK AT WHAT THEY ARE
EXPRESSING, THEY ARE QUITE
ATYPICAL.
THE Y DO NOT EXPRESS MARKERS,
THEY LOSE A LOT OF MARKERS.
IN FACT, IF YOU LOOK AT STANDARD
FLOW CYTOMETRY, THESE ARE
MARKERS, WHAT WE'VE NOTICED,
DISMISSED AS ARTIFACTUAL IS WE
SEE THIS EMERGENCE OF DOUBLE
NEGATIVE POPULATION, WE THINK
THIS IS AATEC 1.
WHEN YOU TALK ABOUT AATEC 2,
EVEN WEIRDER, QUINTESSENTIAL
MARKER OF EPITHELIAL CELLS, DO
NOT SEEM TO EXPRESS.
IF WE RUN GSEA ANALYSIS WE LOSE
ANTIGEN PROCESSING, CORRELATES
WITH THEM LOSING TYPICAL
EPITHELIAL CELL FUNCTION AND
PRESENTATION IS A MAJOR ROLE OF
CELLS, IN THE AATEC 2s THE
HIGHEST ENRICHED PATHWAY WAS
THIS EMT SIGNATURE.
IF WE LOOK AT THAT MORE CLOSELY
AND GAUGE ON THESE -- THIS IS A
LIST OF 9,000 EMT-RELATED GENES,
WE RANK THEM ACCORDING TO
EXPRESSION ACROSS THE CELL
SUBSETS AND FIND THE AATEC 2s
ARE IN THE MIDDLE HERE,
SOMEWHERE IN THE MIDDLE.
IN THE SCATTER PLOT CAN LOOK AT
MARKERS, WE THINK AATEC 2s ARE
AT LEAST PARTIALLY DOWN THE
PHENOTYPE.
WE DON'T THINK THEY HAVE GONE
THE FULL WAY BUT SITTING IN THE
MIDDLE SECTION.
ARE THESE EPITHELIAL CELLS?
WE DID A LINEAGE TRACING
EXPERIMENT WITH OUR
COLLABORATORS AT UNIVERSITY OF
GEORGIA WHO THEY HAD GENERATED A
REPORTER MOUSE UNDER THE CONTROL
OF FOXM 1 PROMOTER, THIS IS
EXPRESSED.
WHEN WE OVERLAY THAT DATASET ON
TOP OF THE LARGER DATASET, IT'S
ONLY A FEW NUMBER OF CELLS AWAY,
A THOUSAND VERSUS 20,000 LARGE
DATASET, YOU CAN SEE WHEN YOU
LOOK AT EXPRESSION, IT'S PRETTY
MUCH ALL OVER OUR DIFFERENT
EPITHELIAL CELLS, INCLUDING
AATEC 2 AND A SMATTERING OF
1s, COMING FROM A POPULATION
BEFOREHAND.
WE TOOK A SIMILAR APPROACH,
COLLABORATORS DOING A SIMILAR
STUDY, THIS TIME INSTEAD OF
STRAIGHT TD TOMATO REPORTER, IN
THIS MOUSE IT IS EXPRESSED, THEY
SWITCH TO GFP.
YOU CAN SEE NEGATIVE POPULATION
GFP POSITIVE CELLS AS WELL AS
POSITIVE POPULATION AND DOUBLE
NEGATIVE AATAC 1 POPULATION.
WE CAN CONFIRM TWO POPULATIONS,
BOTH COME FROM FOXM 1 PRECURSOR.
THE BEAUTY, IT REALLY ALLOWS FOR
HIGH RESOLUTION IMAGING.
THE REASON IS THE CONSTRUCT
LEADS TO NUCLEAR LOCALIZATION.
NOW YOU CAN GET HIGH DIMENSIONAL
HIGH RESOLUTION IMAGING OF
THYMUS AND LOOK AT THINGS
LIKE -- WE CAN LOOK AT THE
CENTRAL MEDULLA REGION, YOU'LL
SEE THIS IN TWO SECONDS HERE
WHERE THE CENTRAL MEDULLA IS
ALMOST ALL CONNECTED, ALL
CONNECTED THROUGHOUT THE
MEDULLA.
A BIT OF A SURPRISE.
LOOK AT AGING MOUSE, FIRSTLY YOU
LOSE THAT AREA, SEE SPINDLES OF
BLUE.
BLUE AREAS ARE HIGH DENSITY
AREAS OF EPITHELIAL CELLS,
CURIOUS BECAUSE YOU DO NOT SEE
THESE IN YOUNG MICE.
LOOKING AT CONFOCAL IMAGES, BLUE
HERE IS GFPs, EPITHELIAL CELLS
THROUGHOUT, DOTS AS YOU DO IN
MEDULLARY AREAS, BUT IN
PERIMEDULLARY SPACE YOU SEE HIGH
DENSITY REGIONS OF EPITHELIAL
CELLS.
AND YOU DON'T SEE THEM IN YOUNG
AT ALL.
WE DO THINK THESE ARE AATECs,
DON'T EXPRESS THE SAME MARKERS.
THEY DON'T SEEM TO EXPRESS THE
SAME THINGS.
INTERESTINGLY, THEY ARE
THYMOCYTE DESERTS, WHEN WE LOOK
AT THESE YOU CANNOT SEE ANY TD
TOMATO CELLS IN THE HIGH DENSITY
REGIONS, AATEC REGIONS.
I'LL SKIP OVER THAT.
SO HOW COULD THIS BE IMPACTING
ON THE RESPONSE TO DAMAGE?
THESE POPULATIONS SEEM TO EMERGE
WITH AGE, SEEM TO BE
NON-PRODUCTIVE, TAKING AWAY
FUNCTIONAL TISSUE REPLACING WITH
NON-FUNCTIONAL TISSUE, HOW DOES
THIS IMPACT ON RESPONSE TO
DAMAGE?
FIRST OF ALL WHEN WE LOOK AT THE
DAMAGE RESPONSE THEY DO
DISAPPEAR AFTER RADIATION.
WE DO KNOW THEY COME BACK.
THIS IS IN DAY 42, YOU CAN SEE
ALL THESE AGER, DAY ZERO, AND
THEY COME BACK.
IF YOU LOOK AT IMAGING THEY COME
BACK IN A MAJOR WAY, THERE'S A
MUCH GREATER PROPORTION OF THE
THYMUS NOW TAKEN OUT BY THIS
AGE-AASSOCIATED AATEC REASON.
WE HAVE PATHWAYS THAT UNDERLINE
ENDOGENOUS REGENERATION, KGF,
FGF 7, IL-22, BNP 4.
ONE THING THAT HAPPENS WITH AGE,
NOW SWINGING TOWARDS TOWARDS THE
SUPPORT OF FIBROBLASTS AND
EPITHELIAL CELLS AS WE LOSE THE
ENDOGENOUS RESPONSE, PRIMARILY
IN FIBROBLASTS, ENDOTHELIAL
CELLS AS WELL, YOU LOSE THAT
INDUCTION OF REGENERATIVE
PROGRAM AFTER DAMAGE.
WHAT PROGRAM THERE IS THERE IS
ACTUALLY STOLEN BY THE
AGE-ASSOCIATED TECs,
INTERACTION MAP LOOKING AT
INTERACTION BETWEEN FIBROBLASTS,
EPITHELIAL CELLS, AGE-ASSOCIATED
TECs ARE HERE, NO SIGNAL IN
YOUNG BUT IN AGED FGS SIGNALING,
BNP SIGNALING GOING TOWARDS AGE
ASSOCIATED, ROARING AWAY FROM
NORMAL TECs, REPLACING THEIR
FUNCTION.
WHAT TO NOW?
I THINK THE PROBLEM WE HAVE AT
THE MOMENT IS BEING ABLE TO
TARGET THE CELLS, YET TO COME UP
WITH A GREAT MARKER, BUT WORKING
ON WAYS TO TARGET PARTICULARLY
AFTER RADIATION.
AND I'VE NOT MENTIONED BUT ONE
OF THE THINGS THAT DRIVES THEIR
EMERGENCE IS SENESCENCE,
FORMATION OF SENESCENT
FIBROBLASTS THAT START TO TURN
ON INFLAME AGING, YOU KNOW,
PHENOTYPE AND THAT SEEMS TO
DRIVE THE DRIVER.
THAT'S WHAT WE THINK IS GOING
ON.
WE'RE STARTING TO WORK ON
WHETHER WE CAN TARGET FOR
REPAIR.
THIS IS A LARGE COLLABORATIVE
EFFORT, PARTICULARLY BETWEEN
MELBOURNE, AND MY GROUP AND
MARCEL AND MEMORIAL
SLOAN-KETTERING.
WITH THAT I'LL TAKE ANY
QUESTIONS.
THANK YOU.
>> GREAT.
I COMMEND YOU AND ALL THE OTHER
SPEAKERS PUTTING THE GAP IN THE
FIELD IN YOUR LAST SLIDE SO
WE'LL HAVE A GREAT DISCUSSION
AFTER WE HAVE SOME QUESTIONS
FROM PEOPLE HERE.
YES, PLEASE, GO RIGHT AHEAD.
>> DID YOU SEE SENESCENT
PROFILING IN THE POPULATION OR
DID YOU NOT?
IT'S HARD TO DETECT.
>> WE'VE TRIED A LITTLE BIT BUT
NOT ABLE TO STATE THE OBVIOUS AT
THE MOMENT.
THEY DO SEEM TO -- WHEN WE LOOK
PATHWAY ANALYSIS THEY UPREGULATE
A LOT OF PATHWAYS THAT YOU
ASSOCIATE WITH INFLAME AGING BUT
NOT P16 OR ANY MARKERS, FIND ANY
ROBUST, THAT'S DEFINITELY THE
THING, YEAH
>>AWESOME.
IT'S GREAT TO SEE THESE DATA, IN
2008 USING CRE OR MODEL YOU CAN
TRANSITION TO PHENOTYPE BUT THE
POINT I WAS TRYING TO UNDERSTAND
WAS ATYPICAL TECs THAT EMERGE
DO THEY EXPRESS CANONICAL
MESENCHYMAL MARKERS?
>> THEY ARE STARTING TO.
THEY ARE MORE OF A PARTIAL,
DON'T TEAM TO HAVE GONE THE FULL
WAY.
I WONDER IN THE HUMAN WHETHER
THEY DO, IN THE MOUSE THEY
DON'T.
I'M NOT SURE BUT THEY DON'T --
THEY DO START TO UPREGULATE.
>> (INAUDIBLE).
>> I'M SORRY?
>> (INAUDIBLE).
>> WE'VE NOT DONE THE FULL LIFE
COURSE ANALYSIS, LET'S SAY AGING
VERSUS TWO MONTH OLD, BUT WE DID
NOTICE -- IT'S HARD TO
OSCILLATE.
>> ALL DATA, IF YOU TAKE THEM
OUT FROM STROMAL, THAT
DETECTS -- NO LONGER DETECTS IN
THE THYMUS, WHEN WE DO SINGLE
CELL ANALYSIS HOW REAL ARE THESE
CELLS AND HAVE WE DONE
ORTHOGONAL VALIDATION?
>> THAT'S WHERE THE IMAGING IS
SO POWERFUL, WHOLE TISSUE
IMAGING APPROACH.
DAN WAS DOING HIS IMAGING, WE
WERE TALKING ABOUT THE SAME
THING, WE STARTED TO FOLLOW THAT
UP.
SO I THINK THERE ARE PROBLEMS
WITH SINGLE CELL DIGESTION
THAT'S GOING TO HAVE AN IMPACT
ON THE TRANSCRIPTOME, BUT I DO
THINK WE'RE ABLE TO VALIDATE IN
SOME OTHER DAYS.
>> ONE MORE QUESTION.
YOU HAD YOUR HAND UP.
>> JESSICA, MAYO CLINIC.
DOES LYMPHOTOXIN CHANGE WITH
AGING?
>> RANK GOES DOWN, IT MIGHT BE
MORE RANK THAN LYMPHOTOXIN, I
THINK, BUT THAT'S SPECULATIVE AT
THE MOMENT.
I DON'T KNOW ABOUT LEVELS.
WE'VE NOT LOOKED AT CELLS IN
EITHER OF THE TWO FACTORS
THEMSELVES.
>> I THOUGHT IT WAS INTERESTING
BECAUSE YOUR AATEC 2 AS BCL-2 1.
>> ONE QUESTION ONLINE.
HERE WE GO.
>> M1/M2, OH, I HAVE NO IDEA.
I MEAN, WE'RE STARTING A
MACROPHAGE PROJECT, IMMUNE CELLS
ARE DIFFERENT IN THE THYMUS,
THERE ARE DIFFERENT MACROPHAGES.
>> WOULD ALL THE SPEAKERS
PLEASE COME TO THE TABLE.
WE'RE GOING TO HAVE OUR GAPS IN
THE FIELD DISCUSSION.
WE HAVE ANOTHER QUESTION, WE PUT
IN THE GAPS.
>> WE HAVE -- THIS QUESTION
CAME IN, ADVOCACY GROUP,
REPRESENTATIVE WOULD LIKE TO
KNOW IF PATIENTS WITH HERPES
WERE CONSIDERED AS A
SUBPOPULATION FOR THE RESEARCH,
ALSO IF THE HYPOTHESIS
CONSIDERED CHRONIC NEUROPATHIC
HERPES INFECTION WOULD BE
CONTRIBUTED TO SOME OF THIS?
>> IT MIGHT BE THAT SOME OF THE
SECTION WOULD BE CONTRIBUTING TO
WHAT IS SUBPOPULATION, EDD AND
HERPES, NONE OF THESE PEOPLE HAD
ACTIVE HERPES MANIFESTATIONS,
BUT OVERALL HEALTH WAS A BIT ON
THE KIND OF THEIR OWN SELF
ASSESSMENT, SOMETIMES THERE WAS
PEOPLE DID NOT -- THEY WERE
REQUIRED -- THE BENEFIT OF
METABOLIC PROFILING, REQUIRED TO
FAST, COLLECT METABOLIC DATA BUT
FOR SOME PEOPLE WE COULD SEE
SPIKES, YOU HAD A DOUGHNUT IN
THE MORNING.
THE SAME DAY A COUPLE PEOPLE
WITH HIGH CYTOKINE, WE KNEW THEY
WERE LYING ABOUT SOMETHING, OR
JUST RECOVERING, BUT MIGHT HAVE
BEEN HERPES BUT WE'VE NOT
(INDISCERNIBLE) THIS LATENT
INFECTION.
>> THIS IS A GAPS IN THE FIELD
DISCUSSION.
WE HAVE A LOT OF GOOD SPEAKERS
WHO HAVE INTRODUCED SOME OF THE
THINGS THAT THEY THOUGHT WERE
GAPS IN THE FIELD.
WE PROBABLY COULD HAVE A WHOLE
OTHER SESSION ON THIS, BUT WE
ONLY HAVE ENOUGH TIME FOR ABOUT
MAYBE TWO MINUTES PER PERSON,
BASICALLY BOTTOM LINE WHAT YOU
THINK WOULD BE A GAP THAT YOU
ARE INTERESTED IN OR YOU THINK
WE SHOULD BE INTERESTED IN, IN
THE FIELD, WITH REGARD TO WHAT
YOU'VE ALREADY SAID OR SOMETHING
THAT YOU WANT TO SAY NEWLY.
IS THERE ANYBODY ELSE THAT HAS
ANY OTHER POINT THEY WOULD LIKE
TO BRING UP THAT, YOU KNOW,
WE'RE GOING TO DISCUSS GAPS IN
THE FIELD, HOPEFULLY THAT WILL
GO ON OVER LUNCH, YOU CAN
DISCUSS OTHER GAPS THAT YOU WANT
TO DISCUSS WITH THE SPEAKERS OR
EACH OTHER.
I GUESS WE'LL START AT THE FIRST
SPEAKER AT THE OTHER END PLEASE.
THANK YOU.
>> CHALLENGING QUESTION.
THANK YOU.
SO ONE GAP FOR ME IS THIS AGING
FEMALE, THE DOMINANCE OF THE
SENESCENT CELL, FITTING THE
STROMA, WE DIDN'T SEE THE
FEATURE.
WE HAVE STILL SECRETED CYTOKINE,
SO BROADER MINDSET UNDERSTANDING
INFLAMMATION TO CONFER RESPONSE,
BEING PRODUCED, BEING AMBIGUATED
IN BIOLOGY AND AGING IN THE
CONTEXT.
>> I TOUCHED ON THIS.
THERE'S A FOCUS, AREAS GOING
FORWARD, RARE CELLS ARE
IMPORTANT LIKE ANTIGEN SPECIFIC
B OR T CELLS, THERE'S NO REASON
THAT STUDIES COULDN'T BE DONE ON
BIGGER COHORTS LOOKING AT THOSE,
SOME CURRENT METHODS, LIKE A
THOUSAND PEOPLE OR SOMETHING
LIKE THAT THAT WOULD BE THE
WITHIN THE SCALE OF THINGS YOU
COULD LOOK AT, THAT'S A
DIRECTION THAT WOULD BE GOOD, IT
MEANS THERE WOULD HAVE TO BE
COHORTS AND GOOD QUALITY
BIOSPECIMENS AND THINGS LIKE
THAT, SOMETHING THAT WOULD BE
VALUABLE AND COULD GIVE MORE
INSIGHT INTO WHAT REALLY CHANGES
IN IMMUNE MEMORY ARE AGE TO THE
VERY EXTREMES OF AGE RANGE AND
ARE DIFFERENT COMORBIDITIES TO
UNDERSTAND WHY SOME PEOPLE HAVE
WORSE IMMUNE RESPONSES TO
SCENARIOS LIKE VACCINATION OR
INFECTIONS THAT MIGHT BE
NECESSARY TO UNDERSTAND WHAT'S
HAPPENING IN PEOPLE.
ONE TOPIC AREA MAYBE.
>> GO AHEAD.
>> TO THE SURPRISE OF NO ONE
SEX DIFFERENCES NEED TO BE
STUDIED MORE AND THEY ARE
IGNORED.
SOME PEOPLE DON'T KNOW ABOUT
LIKE 80% OF PHASE 1 CLINICAL
TRIALS ARE DONE SPECIFICALLY IN
MALES.
AND THEN ONCE THE DRUG HITS THE
MARKET 2/3 OF SEVERE SIDE
EFFECTS ARE REPORTED IN WOMEN.
AND SO I THINK IF WE HAD A
CHANGE IN MENTALITY AND INSTEAD
OF CONSIDERING THAT, YOU KNOW,
OH, THIS HORMONAL CYCLE MAKES
THINGS COMPLICATED WE SHOULD SEX
DIFFERENCES AS AN OPPORTUNITY TO
UNDERSTAND BIOLOGY AND CHEAPLY
AND EASILY BE ABLE TO
PERSONALIZE MEDICINE AND
RESEARCH TO UNDERSTAND
DIFFERENCES IN HETEROGENEITY.
>> I THINK NIH AND THE REST OF
US AGREE WITH YOU.
THANK YOU.
>> I THINK UNDERSTANDING SOME
OF THE ENVIRONMENTAL CHANGES IN
AGING AND CLEARLY DEFINING WHAT
THOSE ARE IS REALLY IMPORTANT
AND MISSING.
WE'RE LOOKING FROM SECRETED
PROTEIN PERSPECTIVE BUT BORROWED
IDEAS FROM TUMOR IMMUNOLOGY, HOW
METABOLIC ENVIRONMENT IS
CONTROLLING ACCESS TO NUTRIENTS
FOR IMMUNE CELLS AND HOW THIS IS
CONTROLLING THEIR ABILITY TO
RESPOND OR PERFORM FUNCTIONS,
AND THAT'S GOING TO BE TRUE FOR
EVERY CELL IN EVERY ORGAN ALL
THESE THINGS ARE CHANGING AND WE
DON'T REPLACING HAVE GRANULAR
VIEW HOW THIS IS HAPPENING OWNED
OVER THE -- OVER THE COURSE OF
THE LIFESPAN.
IT'S AN IMPORTANT PART OF
TARGETING DISEASE MECHANISMS.
>> ABOUT THE SEX STUFF,
ABSOLUTELY RIGHT.
I PRESENTED EVERYTHING TODAY IN
FEMALES, WE'VE DONE A BUNCH IN
MALE, GENERALLY WORSE IN AGING.
IN TERMS OF GAPS, I'M A HAMMER
SO I'LL TALK ABOUT A NAIL.
STROMAL CELLS ARE IGNORED.
WE'RE THINKING THYMIC STROMAL
CELLS ARE IMPACTED BY AGE, MAYBE
HARD OR BARRIER TO OVERCOME
MIGHT BE HARDER, I WAS GOING TO
ASK ABOUT MARK'S TALK, STROMAL
CELLS TOO OFTEN IGNORED.
NOT ALWAYS INTRINSIC TO T CELLS,
THAT SEEMS IMPORTANT TOO.
>> MARK WAS GIVING HIS FINGER
UP AND SO I'D LIKE TO SAY AFTER
WE HAVE YOU SPEAK IF OTHER
PEOPLE WOULD LIKE TO CHIME IN
ABOUT A GAP, YES, RAISE YOUR
HAND.
JUST A SECOND.
GO AHEAD.
ONE MORE.
>> I WANT TO TAKE THE
OPPORTUNITY TO BE PROVOCATIVE,
ON THREE TOPICS.
ONE WITH THE MOUSE, AGING
MODELS, MUCH THAT WE SEE IS FROM
THE OBESITY, VERSUS AGE.
IL-1 EFFECTS IN AGING MOUSE
BECAUSE IT'S OBESE OR AGED?
THAT'S ONE.
THE OTHER IS SENESCENCE.
WHEN PEOPLE REPORT
ANTI-SENESCENT TREATMENT
INHIBITOR OF PCR SIGNALING HOW
MUCH IS SENESCENCE VERSUS IMMUNE
EFFECT FOR ONE, OR ANY OTHER
EFFECT.
AND DISCORDANCE BETWEEN SICKLE
CELL RNA SEQUENCING AND EXISTING
SINCE 1999, GREAT AT THAT TIME
BUT THERE WAS NO SINGLE CELL
RNA-SEQ DATA SO WE NEED TO DO
SOMETHING ABOUT IT.
>> I CAN ADD SOMETHING?
THE MOUSE THING IS REALLY
IMPORTANT BECAUSE ONE THING I'VE
BEEN GRAPPLING WITH, WITH AGED
MICE, PARTICULARLY WITH REGARDS
TO T CELL FUNCTION, THEY ARE NOT
NORMAL, HAVE NOT SEEN ANYTHING,
SPF, DEPENDING ON ANIMAL HOUSE
AND HOW CLEAN IT IS, BUT I THINK
THAT'S GOING TO BE A REAL
PROBLEM FOR US.
THE WORK ABOUT WILD MICE IS
FANTASTIC BUT HAS ITS OWN
LIMITATIONS HOW YOU CAN DO
EXPERIMENTS BUT I THINK THIS IS
A REAL PROBLEM THAT WE NEED TO
ADDRESS THESE SORT OF THINGS.
>> I'D LIKE TO OPEN TO THE
AUDIENCE.
AND REMEMBER THIS IS NOT GOING
TO BE THE ONLY GAPS IN THE FIELD
DISCUSSION.
SO DON'T WORRY, I THINK -- WHO
WAS THE FIRST PERSON?
OKAY.
>> BONE MARROW, THYMUS,
PERIPHERAL, LYMPH NODE
STRUCTURES, ALL HAVE ISSUES WITH
STROMA.
AND I THINK WE'RE WAKING UP TO
THAT PART.
I COULDN'T AGREE MORE WITH THE
LIMITATIONS MAX WAS MAKING, AND
JARROD.
MICROBIOME IS GOING TO BE HUGELY
IMPORTANT, DIFFERENCES WERE
AMPLIFIED WHEN IT COMES TO
THYMUS VERSUS PERIPHERAL,
MAINTENANCE OF AT LEAST HUGELY
IMPACTED BY MICROBIOME, SO IN
DIRTY MICE OR IN CO-HOUSED MICE
THYMUS INVOLUTES AS EARLY AS IN
HUMAN.
SO THEN YOU'VE GOT A DIFFERENT
SHIFT IN PERIPHERAL MAINTENANCE
THAT IS AGAIN A LOT MORE
HUMAN-LIKE BUT IN APPROXIMATING
HUMANS WITH MICE AND STUDYING
THESE THINGS THAT WE HEARD ABOUT
I THINK PUSH THE ENVELOPE IN
HUMANS IS PHENOMENAL.
MAX, WHAT WOULD BE THE BEST WAY
TO FIGURE OUT THE GATING ON
SINGLE CELL, THAT'S ONE OF THE
THINGS THAT I FIND CHALLENGING
AND OF COURSE I DON'T KNOW THAT
--
>>YOU'RE GOING TO HATE ME FOR
THAT.
ONE PERSON IN THE ROOM, SHE
MIGHT HAVE AN ANSWER FOR YOU.
WE CAN TALK AFTERWARDS.
BUT THE WAY -- PRACTICALLY THE
WAY IS TAKE CLUSTERS, LOOK
THROUGH MANY MARKERS AND SEE
THEM ONCE YOU HAVE THE ANSWER,
THEN PULL THEM DOWN AND DO THE
SINGLE CELL SUBPOPULATION AND
SEE IF IT MATCHES.
>> THANKS.
>> I WANT TO DIRECTLY COMMENT
ON A COUPLE POINTS.
I WORK ON AGING AND VACCINE
RESPONSES, MY LAB DOES WORK IN
PARALLEL IN HUMAN AND MICE, TO
WHAT EXTENT WE CAN USE MICE AS A
MODEL.
WE DID AN EXPERIMENT WITH THE
ASTRAZENECA VACCINE JUST BEFORE
THEY WERE RUNNING THE CLINICAL
TRIALS, WE RAN IT IN OUR AGED
MICE, ABOUT 22 MONTHS OLD.
AND I WAS REALLY IMPRESSED AT
LEAST FROM ALL OF THE PARAMETERS
THAT WERE MEASURED.
AGED MICE DID A GOOD JOB
MIMICKING IN HUMANS, FAIRLY
REASONABLE PRE-CLINICAL MODEL.
OBVIOUSLY HUMANS ARE NOT MICE.
IT'S ABOUT UNDERSTANDING THE
STRENGTHS AND WEAKNESSES OF ALL
OF OUR MODELS AND JUST DOING THE
COMPARATIVE ANALYSES.
WE ALSO DID THE EXPERIMENT
STARTED WEIGHING EVERY ONE OF
OUR AGED MICE, BEFORE WE DO ANY
EXPERIMENTS BECAUSE MANY OF YOU
WILL KNOW THERE CAN BE A 30-GRAM
DISPARITY DEPENDING ON THE
STRAIN.
WE SAW NO EFFECT OF WEIGHT ON
VACCINE RESPONSE.
NO CORRELATION, IF YOU JUST DID
A CLASSIC LINEAR, WHICH I WASN'T
EXPECTING BUT THAT WAS WHAT THE
DATA SAID.
>> WAIT, WAIT, WAIT.
>> I WANT TO SAY REASONABLE
KNOWN IN THE COMMUNITY AS FAR AS
B CELL RESPONSE MICE ARE GOOD
MODELS.
>>
[CROSSTALK]
>>MARK, HOLD ON.
PLEASE GIVE YOUR NAME AND WHERE
YOU'RE FROM.
>> HELLO, INDIANA SCHOOL OF
DENTISTRY, A COMMENT ABOUT THE
SEX DIFFERENCES, I AGREE IT'S
REALLY IMPORTANT TOPIC NOW, SO
ABOUT DENTISTY, THERE IS A CLEAR
EVIDENCE PERIODONTITIS IS MORE
RELEVANT IN MALES, AND RECENTLY
IT MAY NOT BE TRUE BECAUSE WOMEN
MAY NOT HAVE ENOUGH TIME TO GO
TO DENTIST BECAUSE THEY ARE BUSY
WITH OTHER THINGS.
>> OKAY.
MARK, YOU'RE NEXT.
THANK YOU.
>> YEAH, WE HAVE TO REMIND
OURSELVES THAT MICE, BLACK OF
MICE, IS AN ARTIFICIAL ORGANISM
IN AN ARTIFICIAL ENVIRONMENT.
MICE LIVE UNDER HEPA FILTERS,
INBREEDING IS BAD IN TERMS OF
FITNESS.
THERE'S A BIG ADVANTAGE TO
ZYGOSITY, LOOKING AT
HETEROZYGOSITY, IMMUNE SYSTEM IS
BIG.
AND I THINK ALSO SOMETHING MORE
RECENTLY THAT THERE'S THOUSANDS
OF GENES INVOLVED IN THE IMMUNE
SYSTEM THAT THERE'S A HUGE
PROPORTION OF GENOME DEVOTED TO
YOUR IMMUNE SYSTEM WORKING WELL,
THERE'S A HUGE GENETIC LOAD ON
IMMUNE SYSTEM WHICH MEANS THAT
INDIVIDUALS ARE GOING TO BE
DEFECTIVE IN MAYBE ALL SORTS OF
GENES, AFFECT THE IMMUNE SYSTEM,
SO THAT COULD EXPLAIN A LOT OF
HETEROGENEITY THAT WE SEE IN
TERMS OF DRUG TREATMENT FOR
CANCER AND AUTOIMMUNITY, FOR
EXAMPLE.
THIS IS REALLY WHAT YOU DON'T
SEE IN MICE, IT'S INDICATING
THAT PROBABLY PEOPLE HAVE
DIFFERENT IMMUNE SYSTEMS.
AND THAT BY STUDYING HUMANS, NOT
JUST BLOOD BUT ALSO ORGANOIDS,
WE'LL GET A SENSE OF THAT, THAT
WE'RE GETTING NO SENSE OF, IN
INBRED MICE AS POWERFUL AS THEY
ARE.
WE KNOW HOW POWERFUL THIS SYSTEM
IS AND ILLUSTRATED ALL THE
THINGS YOU CAN DO WITH THAT, BUT
HUMANS ARE GOING TO BE THE NEXT
LEVEL IN TERMS OF THAT VARIATION
AND PROBABLY WE'LL SEE A LOT
MORE SEX VARIATIONS AND
GEOGRAPHIC, RACIAL, ETHNIC
POPULATIONS DOING DIFFERENT
THINGS JUST BECAUSE SOME PART OF
THE IMMUNE SYSTEM IS NOT WORKING
WELL SO YOU GO TO THE BACKUP
PLAN B, ET CETERA.
>> I THINK WE ALL KNOW THAT YOU
STARTED IN MICE.
WE ALL APPRECIATE THAT HUMANS
AND MICE ARE VERY IMPORTANT TO
THE BEGINNING, MIDDLE, END.
YOU'RE PREACHING TO THE CHOIR.
THERE WAS ANOTHER QUESTION.
YES, ONLINE FROM BEFORE.
>> IT WAS MAX'S QUESTION, MAX'S
COMMENT ON DISENANGLING OBESITY
FROM AGING, HARD TO DO.
>> OKAY.
WE HAVE ONE MORE COMMENT ABOUT
AN OPPORTUNITY I THINK.
>> HELLO.
I AM FROM THE RADIATION MEASURES
PROGRAM AT NIAID, AND I WANTED
TO BRING UP A LITTLE BIT OF
MAYBE SOMETIMES WE COME EMPTY
HANDED BUT I HAVE SOMETHING TO
SHARE WITH YOU ALL.
THIS IS A SEX DIFFERENCES
OPPORTUNITY.
I KEEP HEARING ABOUT THIS.
AND I ACTUALLY PUBLISHED A
REQUEST FOR INFORMATION LAST
YEAR ON UNDERSTANDING THE SEX
DIFFERENCES IN RADIATION
EXPOSURES SO WE ARE A PROGRAM
THAT WAS ESTABLISHED IN 2004,
CONGRESSIONALLY MANDATED, THREE
PILLARS.
ONE IS TO IDENTIFY AND DEVELOP
MEDICAL COUNTERMEASURES FOR
RADIATION EXPOSURE IN A MASS
CASUALTY SITUATION, DEVELOP
DIAGNOSTICS AS WELL AS
RADIONUCLEID MEASURES.
WE GIANT A -- GAINED A LOT OF
INFORMATION.
THIS IS WHAT'S REALLY IMPORTANT.
FROM THAT WE WERE ABLE TO PUT
TOGETHER A REQUEST FOR
APPLICATION, WHICH IS ACTUALLY
ALREADY PUBLIC, IT'S THREE-YEAR
OPPORTUNITY FOR A YEAR 1
COOPERATIVE AGREEMENT AND THEY
ARE GOING TO POST IT UP ON THE
BOARD DURING THE BREAK.
AND SO THIS IS A THREE-YEAR
PROGRAM FOR DIRECT COSTS UP TO
$350,000, COME IN AS A
CONSORTIUM, REALLY GREAT TO HEAR
JARROD, JARROD IS PART OF OUR
PORTFOLIO NOW, HE HAS A UO1 IN
IMMUNE DYSFUNCTION, A LOT OF
GREAT THINGS I HEARD TOGETHER
AND PROGRAM THAT I WANTED TO
HEAR, A MEDICAL COUNTERMEASURE
THAT IMPROVED BLOOD FUNCTION, WE
WANT TO SEE THESE PRODUCTS,
REALLY IMPORTANT IN RADIATION
EXPOSURE.
I HEARD ABOUT COVID-19, AND
THERE ARE A LOT OF SIMILARITIES
BETWEEN COVID-19 AND RADIATION
EXPOSURE.
THERE'S A PUBLICATION OUR GROUP
PUBLISHED, BY CARMEN RIOS.
LASTLY I HEARD ABOUT
INFLAMMATORY PATHWAYS, A LOT OF
GAPS, ONE IS SEX DIFFERENCES, TO
MAKE SURE THERE ARE EQUAL
REPRESENTATION OF MALE VERSUS
FEMALE ANIMAL MODELS AS WELL AS
CELL LINES, ET CETERA.
SO PLEASE APPLY, IF YOU HAVE
QUESTIONS PLEASE LOOK UP THE
RADIATION AND NUCLEAR
COUNTERMEASURES PROGRAM OR LOOK
AT THE RFA.
OR SEE ME.
THANK YOU.
>> THANK YOU.
WE'RE GOING TO LUNCH.
>> ONE QUICK COMMENT.
THERE'S NOBODY TALKING ABOUT
AGING IN CANCER, THAT MAY BE
BECAUSE NCI IS NOT A
CO-ORGANIZER.
THERE'S A HUGE GAP IN THE FIELD,
IT'S LIKE --
>>SOME OF US ARE WORKING ON
THAT.
YOU CAN SPEAK UP.
OR GO TO LUNCH AND WE'LL HIT IT
AT THE NEXT BREAK.
OR THE NEXT ONE.
THANK YOU SO MUCH.
I APPRECIATE THAT.
WHERE ARE WE GOING?
>> THANK YOU VERY MUCH.
>> YOU CAN FOLLOW ME OUTSIDE.
I CAN SHOW YOU WHERE THE CAFE IS
OR GO IN ONE GROUP AFTER THE
OTHER SO ONE GROUP CAN PUT YOUR
ORDER IN, THEN THE SECOND GROUP
COMES.
YOU CAN COME TOGETHER OR COME IN
DIFFERENT GROUPS.
I WILL TAKE YOU THERE.
I WILL GUIDE YOU THERE.
JUST FOLLOW ME.
THANK YOU.
ALL RIGHT, EVERYONE, I THINK
WE'RE ABOUT READY.
EVERYONE LOOKS LIKE THEY'VE COME
IN.
SO I'M HAPPY TO BE CHAIRING THE
SECOND SESSION ON ORGAN-IMMUNE
SYSTEM CROSSTALK.
THANK YOU.
I'M HAPPY TO INTRODUCE OUR FIRST
SPEAKER, GEORGE HAJISHENGALLIS.
HELLO.
CAN YOU HEAR ME?
>>YOU CAN START YOUR SLIDES.
>>I WILL SHARE MY SCREEN.
JUST A SECOND.
>>YES, THAT TOO.
CAN YOU SEE MY SCREEN?
YES, WE GOT IT.
IT THANK YOU.
>>I'M STARTING.
WELL, I WOULD LIKE TO THANK THE
ORGANIZERS FOR THIS INVITATION
AND TO TALK ABOUT OUR WORK ON
THE CHRONIC INFLAMMATORY
DISEASE.
I WILL START WITH PER PERIODONTL
DISEASE --
>>CAN YOU SPEAK LOUDER OR
CLOSER TO YOUR MICROPHONE,
PLEASE?
>>IS THAT BETTER?
>>NOT REALLY.
LET ME SEE WHEN I CAN DO.
UNLESS THE AV PEOPLE CAN MAKE IT
LOUDER FOR US IN THE ROOM.
IS 245 BETTER NOW.
MUCH BETTER.
>>I HAVE SOMETHING APPEARS THAT
IT HAS WORKED.
SO, PERIODONTAL DISEASE IS AN
ORAL INFLAM ARY DISEASE THAT
LEADS TO THE TISSUE THAT
SURROUNDING AND SUPPORT THE
TEETH AND QUITE PREVALENT
DISEASE EVEN IF IT MEANS SEVERE
FORSEVEREFORM IT HAS THE POPULAD
INVOLVES A TREMENDOUS
EXPENDITURE AND VERY IMPORTANTLY
THE INCREASES THE RISK OF
SYSTEMIC INFLAMMATORY DISEASE.
THERE'S AN UP MET NEED FOR
THERAPY IN THIS DISEASE WHICH IS
TREATED THE SAME WAY IT WAS
TREATED 100 YEARS AGO AND IN
THAT REGARD AND WITH THE HELP OF
NIDCR FUNDING MORE THAN 10 YEARS
AND STARTING ORIGINALLY WE HAVE
SHOWN THERE'S TARGET FOR PERRY
RODENTAL DISEASE AND IN OUR WORK
A CLINICAL TRIAL WE HAVE SHOWN
THAT LOCAL TREATMENT OF HUMAN
PATIENTS WITH INHIBITOR CALLED
ME101 SIGNIFICANTLY INHIBITS
PERRY RODENTAL INFLAMMATION AND
PERIODONTAL INFLAMMATION AND OUR
NEXT STEP IS PHASE 3 CRYO AND
HOPING WE CAN BRING AND FOR THE
BENEFIT OF THE HUMAN PERRY
ADOPERIODONTALPATIENT.
WHAT OTHER DISEASES HAVE BEEN
INFLAMMATION AND THE -- TISSUE
MICROENVIRONMENT AND THE VARIOUS
TISSUE AND THE MICROBIOME ALL
CONTRIBUTE TO THE INFLAMMATION.
IN SOME OF OUR REGIONAL WORK, WE
FOCUSED ON THE TISSUE
MICROENVIRONMENT AND WE HAVE
DESCRIBED PROTEINS CALLED
PRODUCED BY TISSUE RESIDENT
CELLS IN SOME OF THE TISSUES
BECAUSE TISSUE PATTERN
EXPRESSION THAT IS NOT HOMO
GENIOUS AND IN THE WE HAVE SHOWN
THAT THE EXPRESSION OF DEL-1 AND
THIS IS WORK FROM MICE BUT OTHER
INDEPENDENT GROUPS IN EUROPE
HAVE SHOWN THE SAME THING IS
SEEN IN HUMAN PATIENTS AND
ANYWAY.
WE HAD A VERY INTERESTING
CORRELATION IN OUR FIRST STUDIES
WE SHOWED THAT THE OLD MICE WHO
HAD VERY LITTLE EXPRESSION OF
DEL-1 THIS DECLINE EXPRESSION
WAS CORRELATED WITH INCREASING
INFLAMMATION AND INCREASE INFILL
STATION AND MORE BONE LOSS.
AND OVER THE YEARS, IN
SUBSEQUENT STUDIES WE WERE ABLE
TO FULLY UNDERSTAND THE
MECHANISTIC BASIS OF THESE.
ORIGINALLY WE KNEW THAT DEL-1
BLOCKS THE INTERACTION BETWEEN
THE NEUTROPHILS AND IN THE CELLS
AND THIS IS PREREQUISITE FOR
NEUTROPHIL OF DEL-1 IS
REGULATING THIS STEP AND
INFLAMMATION.
WE'VE SHOWED THAT DEL-1 PROMOTES
A WASTE DISPOSAL TO GET RID OF
DEAD NUT TREE FILLS AND IT'S FOR
THIS FUNCTION AT LEAST IN
CERTAIN TISSUE AND WE HAVE ALSO
SHOWN THAT DEL-1 REGULATES CELLS
THAT PROMOTES THE STABILITY AND
SUPPRESSIVE ACTIVITY AND IN
RELEVANT WITH BONE LOSS AND
DISORDERS SUCH AS DEL-1 PROMOTES
DIFFERENTIATION BUT SUB CRISIS
OF ACTIVITY SO, IT'S OF USE THAT
SEEMS DEL-1 IS IMPORTANT FROM
YOUR STATIC FUNCTIONS IT'S
DECLINED IN OLD AGE IN BOTH MICE
AND HUMANS IS GOING TO HAVE
REPERCUSSIONS AND WE HAVE SHOWN
BY THE WAYS THIS CONCEPT NOT
ONLY IN PRECLINICAL MODELS OF
PERRY ADPERRYADOPTAL IN MULTIPL.
I DIDN'T HAVE TIME TO SHOW YOU
TODAY IS THAT WE COULD REVERSE
THIS CONDITIONS BY SUPPLYING
DEL-1.
HOWEVER IN OLD AGE, IT MAY BE
MORE PRACTICAL NOT TO REPLENISH
THE MISSING DEL-1 LEVELS BUT TO
FIND A WAY TO STIMULATE DELL 1
EXPRESSION IN OLD AGE.
WE HAVE A HORMONE AT LOW LEVELS
IN OLD AGE AND WE HAVE SHOWN
THAT IN DEL-1 EXPRESSION OLD AGE
BUT MORE RECENTLY, THIS IS VERY
MORE INTERESTING, THE
ANTIBIOTICS PROMOTES GOOD
EXPRESSION OF DEL-1 IN OLD MICE
AND IN FACT THERE ARE MICRO
LIGHTS THAT DO NOT HAVE ACTIVITY
AND THEY'RE GOOD REGULATING
DEL-1 IN OLD AGE IN OLD MICE BUT
THIS IS SOMETHING THAT CAN BE
EASILY TESTED IN HUMANS.
SO, I WOULD LIKE NOW TO FOCUS ON
THE POET HE POETIC SYSTEM AND S
SYSTEM CAN IMPACT FROM PERRY OWE
TONIGHTAL DISEASE AND OTHER
CO-MORBIDITIES.
THEY HAVE THE IMMUNE SYSTEM TO
FORM A MEMORY AND BASED ON THAT,
TO ILLICIT NEW RESPONSES TO
SECONDARY CHALLENGES.
SO THIS IS HOW LET'S SAY A MACRO
PAGE WILL RESPOND BUT IF YOU
ACQUIRE THIS EXPERIENCE WITH A
PREVIOUS INFECTION IT CAN
RESPOND MUCH FASTER AND STRONGER
TO A SECONDARY INSPECTION WHICH
IS NOT THE SAME AS THE ORIGINAL
ONE.
THIS IS THE CLASSICAL MEMORY
WHICH IS SPECIFIC.
SO, THIS IMMUNITY IS SUPPOSED TO
BE PROTECTIVE AND SELECTED
PROTECTING US AGAINST INFECTION
AND THERE ARE STUDIES THAT SHOW
IT PROTECTS AGAINST TUMORS BUT
LIKE EVERYTHING, NOTHING CAN BE
100% PROTECTIVE AND SO HAVING
'EM UNITY IT MAY BE EXCESSIVE
AND INFLAMMATION IN THAT CASE WE
WOULD CALL IT MALL ADAPTIVE
TRAINED IMMUNITY.
SO RECENTLY MY LAB AND
COLLABORATORS HAVE SHOWN THAT IS
THE MACKNESS TICK BASIS THAT CAN
EXPLAIN THE CO MORBID CONNECTION
BETWEEN PERIODONTAL DISEASE.
THE SYSTEMIC INNA MISSION IN
MICE AND HUMANS, THE
INFLAMMATION IS SENT TO THE BONE
MARROW BY THE PROGENITORSES AND
THEY UNDERGO GENETIC ALTERATIONS
AND THEY BECOME TRAINED AND
MYELOID BIAS THAT MEANS THEY
PRODUCE A LOT OF MYELOID CELLS
AND MONOCYTES WHICH THEMSELVES
ARE TRAINED THAT IS HYPER
INFLAMMATORY OF COURSE THEY WILL
NOT STAY IN THE BONE MARROW,
THEY CIRCULATE AND THEY CAN BE
RECRUITED IN TISSUE WHERE
THERE'S AN I AM FEX AND INFECTID
INFLAMMATION AND THEY GO BACK
BUT THEY CAN ALSO BE RECRUITED
IN LET'S SEE IN THE JOINTS AND
WE HAVE SHOWN THAT THESE ALSO
EXACERBATES ARTHRITIS.
SO, THESE ARE HUMAN RELEVANCE
FOR THAT.
WELL, GOING BACK TO IN HUMANS,
WE SEE THAT WHEN PEOPLE WERE
GETTING PERIPHERAL BLOOD
MONOCYTES THESE CELLS WHEN
STIMULATED, HAD BACTERIA OR LPS
THEY WERE PRODUCING HIGH LEVELS
OF INFLAMMATORY CYTOKINES THEN
CELLS FROM NORMAL CONTROLS.
ALSO THIS IS VERY IMPORTANT AND
AT THAT TIME THEY COULD NOT
EXPLAIN THIS OBSERVATION.
EVEN THE BLOOD WAS TAKEN FROM
PATIENTS, THAT WERE TREATED
SUCCESSFULLY AND THEY HAD NO
SIGNS OF PER OWE ADOPTAL PER PEE
ONLY EXPLANATION FOR THAT IS
INFLAMMATORY MEMORY AND EVEN A
GROUP IN BOSTON WITH A CLINICAL
IMAGING STUDY HAVE SHOWN THAT
VERY NICE CORRELATION BETWEEN
PERIODONTAL INFLAMMATION AND
TISSUE ACTIVITY WHICH IMPLIES
THAT THERE IS AN INFLAMMATORY
AND WHAT WE HAVE DESCRIBED IN
OUR PUBLICATION ABOUT THE MOUSE
MODEL.
NOW, TRADE IMMUNITY CAN PERSIST
FOR SEVERAL MONTHS IN MICE.
THERE'S SOME PAPERS IN HUMAN
STATING THIS CAN GO MORE THAN A
YEAR FOR 14 OR 15 MONTHS SO IT'S
QUITE SUSTAINED BUT
NEVERTHELESS, IT'S A REVERSIBLE
STATE OF WEARING SO IS THERE ANY
PATHOLOGICAL CONDITION WHICH IS
ASSOCIATED WITH THE FIX STATE OF
A LOT TERRATIONS SO THIS IS THE
LAST PART OF MY TALK AND IN DEED
IT APPEARS THE DETERMINE SHAPE
IS SUCH A CONDITION AND LET ME
EXPLAIN WHAT SO AS WE BECOME
OLDER, THERE'S A ACCUMULATION OF
CELLS AND OF THESE MUTATIONS ARE
CONFER TO THE AFFECTED CELL AS
SELF-RENEWAL OR PROLIFERATION
ADVANTAGE AND THIS LEADS THE
MUTANT CELLS PRODUCE AND A LARGE
FRACTION OF MUTANT CELLS IN THE
BLOOD AND NOT ONLY THAT BUT
THESE MUTANT CELLS MYELOID CELLS
LIKE ET CETERA, THEY'RE HYPER
INFLAMMATORY AND THE GENES THAT
ARE MORE COMMONLY EFFECTED IS
THESE ARE EPIGENETIC ENZYMES BUT
IT'S A THIRD ASXL1.
AND IT'S PREF LEAPT OF CHIP AND
EFFECTS 10% THAT ARE OLDER THAN
65 YEARS OF AGE.
VERY EPIDEMIOLOGICAL EVIDENCE
WHICH IS CONCLUSIVE THAT CHIP
PROMOTES OR EXACERBATES
CARDIOVASCULAR DISEASE AND THIS
IS EPIDEMIOLOGICAL LEVEL THERE'S
BEEN SEVERAL STUDIES WHICH IS
THE FIRST ONE OR THERE WERE 1 AT
THE SAME TIME BUT THIS IS
SHOWING THAT IN MICE ACCELERATED
THROUGH CELLO SIS IN THAT MODEL
SO THE QUESTION WE ASKED IS THAT
WHETHER KEEP THESE ASSOCIATED
WITH CARDIOVASCULAR DISEASE OR
WHETHER IT CAN PROMOTE TERRY OWE
TONIGHTAL DISEASE IN OLD AGE.
WE STARTED ASKING ASKING THIS
QUESTION AT EPIDEMIOLOGICAL
LEVEL AND WE'VE BEEN
COLLABORATING WITH AN ONGOING
STUDY AND HUMAN DEVICES FROM THE
UNIVERSITY OF NORTH CAROLINA AND
THESE ARE SOME OF OUR INITIAL
DATA THAT I'M REPORTING BRIEFLY
HERE SO WE ANALYZED THE
PARTICIPANTS OF DENTAL STUDY AND
IN THIS STUDY THERE'S NOT ONLY
INFORMATION ABOUT THE STUDIES OF
THESE PATIENTS BUT THERE IS FULL
GENETIC INFORMATION AND THIS
ANALYSIS HAS SHOWN THAT
INDIVIDUALS IN PARTICULARLY
THOSE WITH MUTATIONS IN THE FREE
AGING HAD INCREASES PERIODONTAL
DISEASE AND INFLAMMATION AND
THES ASSOCIATION ASK CORRELATIVE
AND THAT'S WHY WE HAVE THE
CLINICAL MODELS AND HERE I WOULD
LIKE TO SAY THAT THE MOST
MUTATION IN HUMAN THE HOTSPOT
MUTATION IS THE R82H AND THE
EQUIVALENT MUTATION IN MICE IS
R878H WE HAVE THESE MICE AND WE
HAVE THIS MODEL IF MY LAB RIGHT
NOW AND WE'RE USE PARTICULAR TO
ANSWER THESE QUESTIONS.
THE MICE WOULD HAVE 100% MUTANT
CLONES AND IN HUMANS THIS IS NOT
OF COURSE 100% BUT THE CLINICAL
RELEVANCE OF VAF IS 10% OR
AROUND THERE AND SO WE ARE USING
THIS MICE AND TO BONE MARROW
TRANSPLANTATION WE TRANSPLANT A
CLINICAL IRRELEVANT FACTION LIKE
10% TO RECEIVE IN MICE AND WE
FOLLOW WHETHER WE HAVE EXPANSION
OF THE MUTANT CLONES AND WHAT
HAPPENS OF COURSE IN CONTROLS.
AND WE DID THIS A STUDY AND IT'S
UNPUBLISHED DATA RIGHT NOW SO
THE MUTANT CLONES WE'RE
EXPANDING WITH TIME LIKE THE
WHITE TYPE CLONES IN THESE
RECIPIENTS HERE THAT THE
FREQUENCY IN THE PERIPHERAL
BLOOD WAS PRETTY MUCH CONSTANT
AND OF COURSE, THE CASE WE'RE
ALSO EXPANDING IF THE BONE
MARROW AND VERY INTERESTINGLY
AND THIS IS WITHOUT ANY
CONVENTION NOW, THIS IS NOT ANY
MODEL, WE NOTICED THIS MICE THAT
RECEIVED THE 10% MUTANT CLONES,
DEVELOPED MORE NATURALLY BONE
LOSS, NATURAL BONE LOSS THAN THE
CONTROLLERS AND NOT ONLY THAT,
WHEN THE TISSUE WAS ANALYZED FOR
FOR FOR IN FROM MISSION AND IT S
CYTOKINES AND IN MICE AND HUMANS
AND ALSO I OBJECT CREASED
ACTIVITY.
WE HAVE ALSO SUBJECTED THE MICE
THAT WE SEE THE MUTANT CLONES TO
ANTIBODY INDUCED ARTHRITIS AND
THE CONTROLS AND -- HELLO?
AND THE MICE THAT RECEIVED THE
CLONES HAD INCREASED A ALSO
INCREASED AND THIS IS THIS
CORRELATED WITH INCREASES
FILTRATION OF MUTANT MYELOID
CELLS.
VERY VICIOUS CYCLE HERE IN THE
CONTEXT OF I SAID BEFORE,
INCREASES FROM MISSION AND
EXACERBATES AND FROM THIS
CHRONIC DISEASES.
ANOTHER QUESTION OF CLINICAL
SIGNIFICANCE IS WHETHER WE CAN
SCREEN FOR IDENTIFY INDIVIDUALS
WITH INCREASE RISK FOR CLONE INA
FLAM TORI DISEASES AND IF THAT
IS POSSIBLE, CAN WE INTERVENE
WITH PREVENTATIVE TREATMENTS
WHEN WE HAVE IN MINDS IS WHETHER
WE CAN BLOCK THE EXPANSION OF
CLONES AND BLOCK THEM TO HAVE
IMPACT ON CO MORBID CONDITIONS
AND WE'LL GIVE AN EXAMPLE.
THIS IS FROM OUR RECENT STUDY
WHICH WE IMPLICATED IMMUNITY AS
MECHANISTIC BASIS BETWEEN THEM
AND WE HAVE SHOWN WE DIDN'T HAVE
TIME TO SHOW YOU DATA BUT FOR
ANYONE INTERESTED IN THE PAPER
AND SEE IT BUT WE HAVE
IDENTIFIED THAT BETA WAS THE
RESPONSIBLE FOR THE MALL
ADAPTIVE FOR THE OTHER
ALTERATIONS AND ALSO, THIS IS
FROM A DIFFERENT GROUP.
WORKING WITH CHEAP AND
SPECIFICALLY FOR THE TWO DRIVEN
THEY HAVE SHOWN ANYONE BETTER
WILL CYTOKINE THAT WAS DRIVING
THIS FORM OF INHIB (INAUDIBLE).
SO, CAN WE USE L1 BLOCKADES FOR
HOLISTIC TREATMENT OF
INFLAMMATORY CO-MORBIDITY.
WE DON'T KNOW THE ANSWER.
NO ONE HAS DONE THIS STUDY YET
BUT WE CAN GET AND FINISH WITH
THAT I THINK WE CAN GET SOME
INSIGHTS FROM THE TRIAL THAT WAS
I SAID IT'S A HUGE TRIAL BECAUSE
YOU CAN WORK MORE THAN 10,000
PATIENTS AND MIO CARDIAL
INFECTION SO THESE PEOPLE SHOWED
WHAT THESE INVESTIGATORS SHOWED
IS THAT THE TREATMENT RESULTED
IN A USE INCIDENTS OF MAJOR
CARDIOVASCULAR EVENTS BUT
SURPRISINGLY, NOT SURPRISINGLY
BASED ON WHAT WE KNOW NOW, IT
HAS ALSO EXACTED IN THE REDUCE
INCIDENTS OF CO MORBID
CONDITIONS LIKE ARTHRITIS, GATE
AND OSTEOARTHRITIS SO I'M
TEMPTED TO SUGGEST THIS
SUCCESSFUL APPLICATION THE
BLOCKADE IN THE TRIAD COULD IN
PART HAVE RESULTED FROM TRAINED
IMMUNE IN BONE MARROW AND THIS
IS ALSO FROM A RECENT STUDY,
THEY HAVE SHOWN IN THAT STUDY IN
THE TRIAL WAS MORE EFFECTIVE IN
THOSE PATIENTS WHO HAD ALSO
MUTATIONS AND THEY'RE SPECIFIC
REFERRING TO THE TED 2 MUTATIONS
SUGGESTING THAT THE MAJOR
EFFECTOR OF CARDIOVASCULAR
DISEASE TO WITH THAT I WOULD
LIKE TO THANK THE PEOPLE IN MY
LIFE THAT CONTRIBUTED TO THESE
STUDIES AND MORE SPECIFICALLY
WHO PERFORMED MOST OF THE
EXPERIMENTS IN THE STUDIES THAT
I MENTIONED.
OF COURSE WE WOULD NOT BE ABLE
TO DO ALL THE STUDIES WITHOUT
THIS SIGNIFICANCE CONTRIBUTION
FROM OUR COLLABORATORS AND WE
HAVE MANY COLLABORATORS BUT FOR
THE WORK I PRESENTED TODAY I
WOULD LIKE TO THANK THEM AND THE
GROUP FOR THE UNIVERSITY WHO
PARTICIPATED IN ALMOST
EVERYTHING I SAID TODAY BECAUSE
WE'RE COLLABORATING FOR MANY
YEARS IN THE WORK WE WANT
BETWEEN IMMUNITY AND FOR OUR
COLLABORATION AND THE PERSON WHO
PROMOTED THIS CONCEPT OF TRAINED
IMMUNITY AND OF COURSE FOR THE
HEMATOLOGICAL STUDY TO THANK THE
VERY MUCH HUMAN DEVICE OF
UNIVERSITY OF NORTH CAROLINA AND
THE COLLABORATORS FOR THE WEEK
WE'VE DONE FOR MANY YEARS AND
MEN FORWARD TO OF THE INHIBITOR
THAT WAS USED IN THE CLINICAL
TRIAL AND WAS THE P.I. AT
FORESIGHT WHO CONDUCTED THE
CLINICAL STUDY THE PHASE 2 TRIAL
CLINICAL STUDY AND OF COURSE, WE
WOULD NOT BE ABLE TO DO ANYTHING
OF WHAT I PRESENTED TODAY
WITHOUT THE GENEROUS SUPPORT
FROM THE NIH AND PARTICULARLY
FROM THE NIDCI SO THANK YOU VERY
MUCH FOR YOUR ATTENTION.
>>WE'LL TAKE A QUESTION AND
WE'RE GOING TO KEEP MOVING.
>>CAN THEY BE EXAMINED TO SEE
IF THEY'RE RESIST ANTS TO
MUTATION IN DNA 3.
>>CAN YOU REPEAT THE QUESTION,
PLEASE?
>>CAN CENTENARIANS BE EXAMINED
TO SEE IF APPROXIMATE THEY'RE
RESISTANT.
>>THAT'S A GOOD QUESTION.
I DON'T KNOW THE ANSWER.
I DON'T KNOW IF THEY HAVE BEEN
CHECKED AND FOUND TO HAVE LESS
PREVIOUS LENS.
HOWEVER I HAVE TO SAY HERE THAT
BY HAVING CHIP IT DOES NOT MEAN
THESE WILL BE SO HE IS A TIVE
WITH SOME FOREIGN DISEASE LIKE
MALIGNANCY OR SOME OTHER
INFLAMMATORY DISEASE AND THE
THING IS IF YOU HAVE CHIP YOUR
CHANCES FOR THESE DISEASES IS
INCREASING BUT THIS IS A GREAT
QUESTION AND I WILL LOOK AT
LITERATURE AND FIND OUT WHETHER.
BUT IF IT'S NOT BEEN SO FAR IT'S
A GREAT QUESTION TO FOLLOW.
THANK YOU.
>>THANK YOU, GEORGE.
WE'LL MOVE ON TO OUR SECOND
SPEAKER, SCOTT BUDINGER.
>>AM I DOING THIS OR ARE YOU?
>>I CAN?
WHICH WAY DO I CONTROL IT?
PUSHING WE WENT TOO FAR.
OKAY.
ALL RIGHT, SO OUR GROUP IS
UNDERSTANDING WHY AGE IS THE
BIGGEST RISK FACT OR FOR
MORBIDITY AND MORTALITY RELATE
TO PNEUMONIA AND AS EVERYONE IN
THIS ROOM KNOWS, PNEUMONIA IS
THE NUMBER ONE CAUSE OF
INFECTIOUS DISEASE BEFORE THE
PANDEMIC AND THIS AGE RELATED
SUSCEPTIBLE TO PNEUMONIA
SEVERITY WAS EVIDENT DURING THE
FIRST WAVES OF THE PANDEMIC AND
THE SPAIN SHOWING THAT OLDER
INDIVIDUALS IN TERMS OF MOR
TATTI AND OLDER MEN IN
PARTICULAR.
AND SO, I LEAD A PROGRAMME
PROJECT GROUP GRANT FROM A
NUMBER OF VERY TALENTED
INVESTIGATORS THAT ARE ASKING
QUESTIONS WHY ARE OLDER
INDIVIDUALS MORE SUSCEPTIBLE TO
DEVELOPING DEATH FROM PNEUMONIA
AND WHY ARE THEY MORE
SUSCEPTIBLE TO THE WELL
ESTABLISHED BEFORE THE PANDEMIC
ACUTE OR POST SA QUELL A MA
KNOWNIA AND SKELETAL MUSCLE
DYSFUNCTION AND TODAY I WILL
TALK ABOUT TWO OF THOSE STORIES
BRIEF LEASE AND THE EFFECT
ABILITY OF PNEUMONIA AND SOME OF
THE HYPOTHESIS THAT WE HAVE
ABOUT MECHANISMS WE HAVE.
I'LL TELL YOU THE STORY FROM A
SINGLE SELL POPULATION IN THE
TISSUE RESIDENTS AND THIS IS
STARTING HERE WITH MOUSE DATA
AND THIS IS A SUMMARY FROM A
REVIEW ARTICLE IN 2020 AND I'M
MAKING A LOT OF WORK ABOUT THE
FUNCTION OF MACRO PAGES AND
THEY'RE DERIVED FROM THE FETAL
YOKE SACK OR LIVER.
I WANT TO SHOW YOU DATA TODAY
BUT THEY'RE NOT REPLACED BY BONE
MARROW CELLS AND EACH OF THEM IS
CAPABLE OF SELF-RENEWAL SO
THEY'RE OWN STEM CELL AND
IMPORTANT FOR HOMO OWE STATIC
FUNCTION.
EVERYTHING CHANGES DURING
INJURY.
THEY AIR DATE INTO CELLS AND WE
MONETIZE THE MACROPHAGES AT THE
LEVEL OF FOE, THEY ARE VERY
SIMILAR TO TISSUE IN MAKO PAGES
AND IT'S VERY HARD TO
DISTINGUISH THEM BY SURFACE
MARKERS ALONE BUT THEY'RE
FUNCTIONALLY DISTINCT AND
THEY'RE FUNCTIONALLY DISTINCT
BECAUSE YOU USE GENETIC TRAITS
SPECIFICALLY DELETE THOSE
THEY'LL BE IN A MACROPHAGES
LEAVING THE TISSUE CELLS IN FACT
YOU ARE A RATE OF SEVERITY LIKE
FIBROSIS AND THEY
HAVE UNDERGO POP TOE SIS AND
REPOPULATION IN THIS HAPPENS
BOTH BY PROLIFERATION OF TISSUE
RESIDENTS THERE BEFORE THE
INJURY AND SOME OF THESE
MONOCYTE DRIVES PERSIST IN THE
LUNG WHERE THEY'RE SLOWLY SHAPED
INTO CELLS THAT BECOME
FUNCTIONALLY AND
TRANSCRIPTIONALLY INDISTINGUISH
ABLE FROM THEIR TISSUE RESIDENT
COUNTERPARTS AND WHICH KNOW THAT
FROM VIN YANG THAT I'LL TALK
ABOUT LATER.
I'LL START IF THE ACUTE PART IN
THE PNEUMONIA AND TALK ABOUT OUR
WORK IN COVID-19.
AND THIS IS GOING TO BE DATA
THAT'S PRIMARILY DERIVED FROM
HUMAN.
SO, WE HAD BEEN INTERESTED IN
THESE MONOCYTE DRIVE AND TISSUE
RESIDENT MACROPHAGES IN MOUSE
MODELS PRIOR TO THE INCIDENT AND
WE HAVE DEVELOPED A PROGRAMME IN
OUR INTENSIVE CARE UNIT WITH OUR
ICU DIRECTOR CALLED THE
SUCCESSFUL CLINICAL RESPONSE OF
PNEUMONIA THERAPY SYSTEMS
BIOLOGY CENTRE.
THIS PROGRAMME LEVERAGES THE
FACT IN CLINICIANS IN OUR
INTENSIVE CARE UNIT THEY HAVE
THE PRIMARY SIDE OF INFECTION OF
PNEUMONIA OVER THE COURSE OF THE
PATIENT ILLNESS IF THEY'RE INNU
BATED AND ON A VENT A LATER TO
GUIDE.
>> Donald Berwick: THAT THERAPY
FOR THOSE NON CLINICIANS IN THE
ROOM, WHAT THIS IS AWE TAKE A
SMALL SCOPE AND PUT IT THROUGH
THE END OF THE TUBE AND WAGE IT
INTO AIRWAVES AND BACKOUT AND
MOST THAT HAVE IS IN AND GOES TO
THE MICROBIOLOGY LACK WHERE IT'S
CULTURE AND WE GET PATIENTS THAT
COME TO THE RESEARCH LAB AND
THIS IS THE PROCEDURE THAT WE'RE
DOING ON THE LEFT SIDE.
YOU CAN SEE A PATIENT WITH
COVID-19 WHO HAS GROWN IN OUR
INFENCE I HAVE CARE UNITS AND
ALL THE OF THE SAMPLES ARE
SUBJECTED AND WE HAVE A VARIETY
OF DIFFERENT ANALYSIS WE CAN
APPLY FOR THE CELLS AND FLUID
THAT WE OBTAINED "OUR EDMONTON"
WORKFORCE TECHNOLOGY IS SIMPLE
AND WE COMBINE THOSE DATA WITH
WE ATTAINED FROM THE DATA
WAREHOUSE TO DEVELOP MODELS OF
MA KNOWNIA PATHOGENESIS AND THIS
IS A RICH RESOURCE WE HAVE 710
PATIENTS AND A LITTLE OVER 200
WERE CHOSEN AND WE HAD 1500
PATIENTS AND IT CONTINUES TO
RECRUIT AT TWO PATIENTS A WEEK.
SO BECAUSE WE HAVE COLLECTED
DATA FROM 200 PATIENTS PRIOR TO
THE PANDEMIC WE WERE POISE TO
ASK QUESTIONS WHAT DIS TINGE
WISH AS FAR AS A WHAT PNEUMONIA
PATHOGEN.
SO FIRST WE LOOKED AT THE
CLINICAL DIFFERENCES BETWEEN
PATIENTS WITH SARS-CoV-2
COMPARED TO OTHER PNEUMONIA AND
THE RED IS GOING TO BE YOUR
SARS-CoV-2 AND THE GREEN BARS
ARE PATIENTS INTUBATE REQUESTED
OTHER KINDS OF PNEUMONIA AND
THOSE WITH BACTERIAL PATHOGENS
AND THE BLUE ON 9 LEFT WE
THOUGHT THEY HAD MA MOANIA FROM
ANOTHER CONSTRUCT.
YOU WITH SEE THIS IS ALL THE
AIMS ARE SIMILAR AND OLD.
AS WE TALKED ABOUT IN THE FIRST
SLIDES.
THESE PATIENTS ARE SIMILE
ACUTELY ILL.
THERE ARE SEVERAL OTHERS THAT
ARE SIMILAR AND MORTALITY IS
SIMILAR IN THE PATIENTS WITH
SARS-CoV-2.
WHAT IS DIFFERENT AND WHAT IS
REALLY DIFFERENT LENGTH OF STAY.
PATIENTS HAVE DOUBLE THE LENGTH
OF STAY AND TRIPLE VIRAL VI PNEA
THAT'S WHY SARS-CoV-2 IS
DEVASTATING TO THE HEALTH SYSTEM
AND PATIENTS IN THE ICU AND ONE
SHICU BED FOR ONE MONTH.
WE DID MOLECULAR ANALYSIS THAT I
WON'T HAVE TIME TO GO THROUGH
WITH YOU.
IT'S PUBLISHED INCLUDING
SEQUENCING AND FLOATS AND
LOOKING THE HOST RESPONSE AND
LOOKING FOR PACKAGED AS WELL AS
SINGLE CELL WITH CONFIRMATION
WITH SINGLE MOLECULE FISH AND WE
USE THAT TO DEVELOP A MODEL OF
SARS-CoV-2 MA MOANIA AND HOW
IT MIGHT BE DIFFERENT.
ON THE LEFT WE HAVE A SIMPLIFIED
VERSION.
WE HAVE THE TYPE 2 CELL AND WE
HAVE THE SMALL CELLS FOR CORNERS
OF THE SPACE AND YOU HAVE THESE
BIG FLAT CELLS WHERE THE GAS
EXCHANGE RAPS AND YOU HAVE A
TISSUE MACROPHAGE SITTING THERE
IN THE SCHEMATIC AND
IMPORTANTLY, THE TYPE 2 CELLS
ARE THOSE THAT EXPRESS THE H2
RECEPTORS THAT'S IS RECEPTORS
FOR SARS-CoV-2 AND PAULSLY SO
IN THE HUMAN HUNG CELL LESS THAN
1% CHROME TWO AND NO AGING ONE
AND MACROPHAGES DO NOT AS WELL.
WE'RE A PRODUCTIVELY AND ACE TO
EXPRESS TYPE TWO CELLS AND
INCREASING THE CONCENTRATION AND
AND IT'S IN BOTH SOUTH END AND
GAMMA INDUCES THE APOPTOSIS AND
MONO TYPE DRIVE MACROPHAGES AND
THE MACROPHAGES ARE SUSCEPTIBLE
TO SARS-CoV-2 INFECTION SO
AMPLIFIED THAT SIGNALING MOVE
AND MORE IMPORTANTLY DURING THE
PANDEMIC SHOWED THOSE
MACROPHAGES AND CREATING THAT
LONG PROLONGED INFLAMMATORY TIME
FORCE AND WE ARE ACTUALLY VERY
FORTUNATE DURING THE PANDEMIC TO
BE ABLE TO TEST THIS MODEL AND
WITH T CELLS AND MACRO PAGES SO
WE DID A PKPD STUDY WITH A
CLINICAL TRIAL OF A CROSS
CHANNEL INHIBITOR WITH A GROUP
AND THIS WAS USING AGAIN THOSE
SAME ANALYSIS OF LOOKING FOUR
AND A HALF TREATMENT WITH THE
DRUGS AND IN TERMS OF THE
TRANSRIPTOME OF MONOCYTE DRIVE
AND T CELLS REMEMBER THIS IS
DATA FOR THE T CELLS BUT THEY
HAVE A RESPONDING AND SO ON THE
LEFT YOU SEE THE CHANGE WE SEE
BETWEEN DAY ONE AND DAY THREE
AND THE TREATED RESPONSE OF THE
PATIENTS AND WE WERE PLEASE
TODAY SEE THE MULTI CENTRED HAD
PROMISING PHASE 2 TRIALS
FINDINGS WITH A 56% REDUCTION IN
THE COHORT.
SO, THAT WAS THE AND I'M GOING
TO MOVE TO THE CHRONIC DISEASE
AND WE TURNED AGAIN TO MICE
BECAUSE THE QUESTION WE WERE
ASKING IS WHAT IS WRONG WITH OLD
MACK PAGES AND I SHOWED YOU HALL
OF OUR HUMAN DATA AND OUR SICK
PATIENTS ARE ALL OLD PATIENTS
RIGHT SO WE DON'T HAVE YOUNG
PATIENTS AND ANY POWER AND WE
HAD SEVERAL HIGH BOTH SIS ABOUT
WHY IT MIGHT BE TRUE.
ONE HAD CHIMER THAT DEVELOPS
WITH AGING THAT IS LONG MAKE ROW
FAGE POPULATIONS ARE REPLACED BY
CELLS OVER THE LIFESPAN REMEMBER
THEY WERE ONCE INFLAME TORI
MONOCYTE WAS DIFFERENT TO ACCEPT
STIMULI AND ANOTHER POSSIBILITY
WE HAD DIFFERENCES IN
CIRCULATING CELLS OR CIRCULATING
BONE NARROW AND THAT WAS ANOTHER
POSSIBILITY AND STILL ONE WITH
CHANGES IN THE ENVIRONMENT THAT
WERE DRIVING.
WE NEED TO TRANSCRIPTOMIC
APPROACH TO DO AND WE LOOKED AND
FOUND A REPRODUCE ABLE TRANCE
PERFORM I CAN SIGNATURE THAT HAD
INFLUENZA INFECTION AND THE DOWN
REGULATION OF CELL CYCLE GENES
THAT IS IMPORTANT IN THE A
COUPLE AND SOME HAVE A LOT OF IT
QUICKLY HERE AND THE ANSWER IS
NO, NO, NO, ALL THESE QUESTIONS.
IT'S NOT.
SO WE DID A COMPLICATED SECOND
HIT EXPERIMENT WHICH IS NO
DIFFERENT AND IT'S NOT CELL
AUTONOMOUS AND EVERYTHING
REVERTS TO THE AGE OF THE HOST
AND IT'S DRIVEN BY MODELS
ITSELF.
IT WAS CHANGING THE PHENOTYPE OF
THESE OLD MACROPHAGES AND
FIBROSIS AND HUMAN STUDIES USING
LONG EX PLANTS FROM PATIENTS AND
INCLUDING PATIENTS WITH
COVID-19.
WE HAVE THE AT1 CELL LIKE I
SHOWED YOU BEFORE AND WE HAVE
INJURY LIKE SARS-CoV-2 THAT
DAMAGES THAT TYPE 2 CELL AND WE
HAVE THE MONEY SIGHT DRIVER
COMING IN AND INTERACTING WITH
AND CEILING OF THE JOINT AND WE
HAVE WHAT WE FOUND IN THE SINGLE
CELL RNA SEQUENCING DATA IT'S
TYPE TWO CELL AND DIVIDES TO
REPLACE THE TYPE 1 CELL AND CELL
POPULATIONS FORMED AND THESE ARE
THE MAIN THINGS.
I'LL JUST CALL THEM A TRANSITION
CELL SO SHARE FEATURES WITH THE
TYPE ONE AND THE TYPE 2 CELL AND
THEY'RE FOUND IN DISEASE IN MICE
AND HUMANS YOU DON'T FIND THEM
AT ALL IN NORMAL LUNG.
AND WE FOUND THESE CELLS WERE
ACTUALLY PRESENT IN PATIENTS
WITH SARS-CoV-2 AND USING DATA
FROM OUR LUNG TRANSPLANT
PROGRAMME IN PART OF 19 EX
PLANTS AND IT AT THE EXPRESS P16
AND OTHER MARKERS BUT DEFINITIVE
ORGANOID STUDIES AND SHOWS THESE
THEY WILL DURING THE
DIFFERENTIATION OF THE TYPE 2
CELL INTO A TYPE ONE CELL AND
MARKERS AND ONE OF OUR POSTDOCS
NOTED THERE WAS AN ACTIVATION OF
THE EXPRESS RESPONSE THAT
HAPPENED IN THESE CELLS PRIOR TO
THEIR DIFFERENTIATION AND SO HE
GAVE A SMALL INHIBITOR AT UCSF
SO HE SHOWED THAT WAS ABLE TO
DECREASE THE SEVERITY FIBROSIS
AND HE PUT A PINE AND EACH TYPE
CELLS AND THE DECREASE AND THIS
TRANSITIONAL POPULATION AND
SUGGESTING THAT THE ACCELERATED
THESE TYPE TWO CELLS AND TYPE
ONE CELLS AND WHAT WAS REALLY
INTERESTING WITH WHAT HAPPENED
WITH THE MACROPHAGE POPULATION
SO YOU HAVE LYNN YANG SYSTEM AND
SHOWED THERE WAS DECREASE
RECRUITMENT OF MONO TYPE FOR
MACROPHAGES IN THIS MODEL AND IF
WE LOOKED AT THE GENE EXPRESSION
PATTERN WE SAW THOSE MACROPHAGES
WERE MORE MATURE AND EXPRESSING
LESS IMMATURE GENES.
THEY WERE GETTING SIGNALS THEY
NEEDED FROM THE EPITHELIAL TO BE
A MATURE MACROPHAGES SO THIS IS
BOTH A SUMMARY AND DATA SO WHAT
WE'RE THINKING RIGHT NOW IS
WE'RE THINKING THAT DURING THESE
TYPE 2 CELLS AND TYPE 1 CELLS
AND THEY'RE A BIG BLANKETS THAT
FITS OVER THREE, IT'S A BIG
CELL.
YOU HAVE TO MAKE A LOT OF
PROTEIN AND A LOT OF LIPIDS AND
THERE'S DURING AGING, OR IN
CERTAIN GENETIC CONDITIONS THAT
ISR IS PATHOLOGICAL ALLOWING
ACCUMULATION OF THESE CELLS AND
UNDERSTANDING WHY THAT IS A BIG
GAP AND THE SECOND QUESTION IS
WHY DO YOU HAVE THIS RECRUITMENT
OF THESE MONOCYTE MACROPHAGES
WHEN YOU DON'T HAVE THE FULL
DIFFERENTIATION AND JUST ONE
LAST SLIDE SHOWS THAT THIS,
THESE MACROPHAGES IS A SIGNAL
FOR DYSFUNCTIONAL PAIR AND I
WILL SHOW YOU A BRIEF SUMMARY OF
WORK WE'VE DONE IN PATIENTS WITH
POST ACUTE SEE QUELL' SO THESE
ARE SYMPTOMS AND 180 DAYS OR
MORE AFTER THEIR COVID INFECTION
YOU CAN SEE THEY HAVE
ABNORMALITIES ON THE LIFE
CHARACTERIZED WHEN WE DO SINGLE
CELL ARMY SEQUENCING ON SAMPLES
FROM THE PATIENTS WE DETECT
THOSE MACROPHAGES WHICH ARE
CORRELATED WITH THE SEVERITY OF
FIBROSIS.
SO, I WANTED TO THANK ALL THE
PEOPLE THAT DID IT WORK AND IT
TAKES A VILLAGE.
THERE'S A LOT OF PEOPLE
ACKNOWLEDGED HERE AND I TRY TO
ACKNOWLEDGE PEOPLE DURING THE
TALK AND I WANT TO ADDRESS AND
THANK OUR FUNDERS AND THE NIA
AND NIAAD AND THIS WOULDN'T BE
SO POSSIBLE WITHOUT THE
PHILANTHROPY FROM THE INSTITUTE
FOR TRANSLATIONAL TIME.
YOU THANK YOU.
>>REALLY FANTASTIC WORK.
SO WHEN YOU COLLECT THE LAVAGES
DO YOU SEE A LOT OF SHED OF
CELLS.
>>YES, WE SEE SOME.
NOT A LOT.
SO WE DO HAVE SOME TYPE, I
DIDN'T SHOW YOU BUT WE SEE
THE -- WE CAN'T MAKE MUCH OF
THEIR TRANSCRIPT SEEM BECAUSE
THEY'RE DYING AND WE SEE
SARS-CoV-2 IN THERE.
>>BECAUSE I'M THINKING WITH ALL
INCREASED INFLAMMATION AND
INABILITY TO REPAIR THEMSELVES
THE CELLS ARE CHOOSING TO DIE?
>>YES, WE DON'T HAVE CONTROL
FOR THAT SO WE DON'T HAVE
ANYBODY.
WE HAVE A HEAVY BIAS TOWARDS
PEOPLE THAT ARE SICK.
>>YES.
>>SO, THE HOTSPOT FOR COVID-19
BY MULTIPLE DEVICES IS AN CHROME
OWE SOME 3B21.
THE MORPHISM IS SUPPOSED TO BE
INVOLVING DYSFUNCTION SO HOW DO
YOU RECONCILE THAT WORK WITH
YOUR INITIAL ONE?
>>WELL IT GETS BACK TO THE
FIRST QUESTION WE'RE NOT
SAMPLING IT.
AND THERE'S WHAT IT LOOKS LIKE
IS IF WE LOOK AMOUNT STUDIES
THEY'RE LOOKING AT SEVERE
DISEASE AND WE'RE AT POST APP
RIGHT, WE'RE LOOK AT PEOPLE THAT
HAVE SEVERE DISEASE AND IF YOU
HOOK FOR EXAMPLE THE LOSS OF
INTERFERON TYPE ONE AT THE TIME
ARE AT THAT TIME WE'RE SAMPLING
THESE, WE SEE DON'T DETECT HIGH
FORM INTERFERENCE ANYMORE WE'RE
PAST THAT POINT SO THEY HAVE
GOTTEN TO THE POINT WHERE THEY
HAVE SEVERE DISEASES INVOLVING
THE SO I THINK YOU HAVE TO JUST
HAVE A LOT OF THOSE GENETIC
STUDIES BY DEFINITION BECAUSE
THEY'RE LOOKING AT THE WHOLE
POPULATION TO IDENTIFY RISK
FACTORS FOR GETTING TO OUR ICU
AND WHAT ARE THE RISK FACTORS
FOR THEM DYING WHEN WHEN YOU ARE
IN INTENSIVE CARE UNIT.
HOW DO WE INTERRUPT THAT.
>>THANK YOU, SCOTT.
NEXT UP IS DAN YAM TYRRELL.
>>THANK YOU FOR THE
INTRODUCTION.
MY TALK IS GOING TO BE ON AIMING
AND MOSTLY T CELLS AND ALTHOUGH
I TALKED ABOUT THE AGENT LER OWE
CIRRHOSIS AND MOSTLY USING MY ON
HUMAN DATA SPRINKLED INFUL DRIVY
HIGH LEVELS OF LDL CHOLESTEROL
AND IF YOU DON'T RESOLVE THE
CHOLESTEROL, WITH HEARD ATTACK
HEART ATTACK AND STROKE.
I WILL TALK ABOUT VASCULAR
PATHWAYS AND THAT WE'VE FOUND
OUR ACTIVATED WITH AGING.
FOR THIS STUDY WE WERE LOOKING
AT THE VASCULAR IN DISEASE FREE
OLD AND YOUNG MICE.
SO WHAT WE DID WITH IS WE JUST
TOOK THE ATE AORTA FROM YOUNG
AND AGED MICE AND YOUNG IS Y AND
AGED IS A AND LOW FAT DIET AND
DISEASE FREE AND YOUNG AND OLD
MICE AND THREE MONTHS AND 18
MONTHS OF AGE AND LOOKED FOR
SOME OF THESE INFLAMMATORY
PROTEINS THAT WE THINK COULD BE
ACTIVATED BY HIGH DOUGH CON
TREAL DNA AND DYSFUNCTION IN THE
AGING EIGHT OR THE A SO WE SEE
TLR9 MIGHT BE THE EIGHTH AND IL6
ARE ELEVATED WITH AGING.
SO THE NEXT THING THAT WE WERE
CORE COWS ABOUT IS AND I DIDN'T
PUT AN INTRODUCTION TO THIS
PROTEIN BUT THIS EXPRESSION SO
WE SEE THAT EXPRESSION GOES UP
WITH AGE AND THE EIGHT ORDER AND
THIS IS PROTEINS THAT -- THERE'S
SOMETHING CIRCULATE TAG CAN
UPDATE THE CAUSE AND WE FOLLOWED
UP WITH A LITTLE BIT CLEANER OF
AN EXPERIMENT WHERE WE JUST ADD
IL6.
WE HAD ACCESS TO SOME BIOBANK
HUMAN HAIR AND SOME WERE
HEALTHY.
AND SO WE DID A APPROACH JUST TO
LOOK AT AN UNBIASED WAY PROTEINS
AND HOPING THAT IDENTIFY
PATHWAYS WE FOUND.
WE DID A PATHWAY ANALYSIS AND
THESE ARE ANALYSIS PATHWAYS WE
FOUND AND THOSE ARE PUBLISHED
THAT THESE ARE SOME THAT RELATED
THAT WE FOUND TO IN MICE.
SOME OF THE POTH WAYS OF AGING
AND DIFFERENT INFLAMMATORY
RESPONSES AND RESPONSIVE TO THEY
WERE ALL STATISTICALLY
SIGNIFICANT TO VALIDATING WHAT
WE LOOKED AT.
WE HAD AN IDEA SOMETHING WAS
GOING ON IN THE IMMUNE
DEPARTMENT SO I WANT TO TALK
ABOUT OUR MODEL.
THIS IS A MODEL AND THIS IS
POTENTIALLY YOU HAVE TO DO
SOMETHING AND IN MICE AND MICE
NORMALLY HAVE HIGH HDL LEVELS
AND LOW LDL LEVELS SO YOU CAN
SEE A WILD TYPE AS HIGH FAT DIET
AS YOU CAN THINK AND IT WON'T
DEVELOP AGENTER OWE CELLO SIS
AND WHEN YOU DO THAT, THE
DOUBLED.
IF YOU AGE THE MICE THEY DEVELOP
OVER THE COURSE OF 12 MONTHS
EVEN ON A LOW FAT DIET.
THIS WAS PUBLISHED IN 2016 AND
UP REGULATE AND THAT LDL
RECEPTORS TO BE DEGRADED SO WE
DO THE INJECTIONS AND SEE THE
HIGH FAT DIET SO THE YOUNG MICE
AND THE OLD MICE AND HAVE THE
SAME LDL.
ONE DATA WE HAD WHEN WE DID THAT
BACK IN 2016 OR 217, THIS WERE
MORE T CELLS IN THE PLAQUE OF
THE OLD MICE.
THEY WILL BE OUTLINED AND
THEY'RE HARD INFORM SEE AND
THERE'S NOT A LOT OF THEM SO THE
NEXT THING O DO WAS DELETE THE
CELLS.
WE DID THE SAME APPROACH.
WE DID THE INJECTION AND USED
THE WESTERN DIET AND WE TREATED
THE MICE WITH AN ANTI CD8
ANTIBODY WHICH DOWN REGULATES
THE NUMBER OF CIRCULATING T
CELLS OVER THE COURSE OF THE 10
WEEKS AND WE GET 30 PER MOUSE
AND THAT'S QUANTIFIED HERE.
WE DON'T SEE A DIFFERENCE IN A
CHRONIC BUT IN THE OLD MICE WE
SEE A SIGNIFICANT REDUCTION AND
IN THE AREA.
THAT GOT ME WONDERING WHAT WAS
GOING ON.
WHY DID THIS WORK FOR OLD MICE
BUT NOT YOUNG MICE.
AND SO THIS NEXT EXPERIMENT WE
ISOLATED THREE-MONTH-OLD OR
18-MONTH-OLD WILD TYPE DONORS
AND TRANSLATED THEM INTO CDA
KNOCK OUT MICE AND THEY HAVE
CD8T-CELLS AND WE GAVE THEM ONE
MONTH TO RECOVER AND WE DID THE
SAME EXPERIMENT AND WE PULLED
ALL THE SPLEENS AND THE YOUNG
AND OLD DONORS AND THE YOUNG WAS
YOUNG AND OLD WAS OLD.
T CELLS FROM THE YOUNG DONORS
RECEIVED ABOUT 75% CD8T CELLS
VERSUS THE MIGHT WHO RECEIVED
CD8s FROM THE OLD DONORS AND A
LOT MORE CENTRAL MEMORY AND
EFFECTIVE MEMORY CELLS AND A LOT
OF THESE WERE PD1 POSITIVE SO
LIKELY EXHAUSTED.
AND WHEN WE DO THIS EXPERIMENT
WE SEE THE MICE, THE YOUNG MICE,
THAT RECEIVED CD8T CELLS FROM
OLD DONORS HAD TOTAL PLAQUE SIZE
COMPARED TO THE MICE THAT
RECEIVED NO T CELLS OR NO CD8T
CELLS OR THE YOUNG CD8T CELLS.
SO WE DID LIKE MOST PEOPLE,
SINGLE CELL AND THE PLAQUE AND
ENRICHED FOR CD3 IT WILL CELLS
AND MOST OF THE CELLS WE HAVE
ARE T CELLS AND THERE ARE SOME
OTHER CELLS IN THERE AND WHEN
YOU LOOK AT JUST THE CD8 T-CELL
CLUSTERS ONE THING THAT POPPED
OUT WAS THIS GREEN CLUSTER WHICH
YOU REMEMBER FROM THE TALK
EARLIER ARE THESE PD8C CELLS
EFFECTIVE MEMORY CAN AND HIGH
EXPRESSION AND IT'S THE MOST
SPECIFIC GENE FOR THIS CLUSTER
AND WHEN WE LOOKED AT THE
COMPETITION OF CELLS YOU SEE THE
SAME PREPORTIONS YOU MIGHT
EXPECT BUT THE CELLS WE
IDENTIFIED WAS THIS EFFECTER
MEMORY AND IT WAS IN THE PAPER
AND I DON'T KNOWN IT WAS IN THE
PAPER MEMORY CELLS WHEN WE SAW
THESE CELLS IN OUR DATA AND
LOOKING AND LUCKILY WE PUBLISHED
THIS PAPER BEFORE WE STARTED
LOOKING AND IT WAS A VERY GOOD
RESOURCE SHOUT AND SO WE STARTED
LOOKING AT THE INTENSELY AND ONE
THING THAT WE DID THAT WE
CALCULATED THIS COURSE FOR
EXHAUSTION AND THE GENES WE USED
AND BELOW TODAY AND IN ESSENCE
AND THEN SPEND THIS PAPER CAME
OUT IN THE FALL OF LAST YEAR
WITH A SET OF 120 GENES AND
WHICH WE HAVE 112 IN OUR DATASET
AND WE LEFT IT FROM MAYO CORE
AND INTERESTINGLY THE CLUSTER
CELLS AND THE GROUP THEY CAME
FROM WITH THE PRY AND BOTH OF
THESE MARKERS WAS FROM THE AGE
EIGHT OWE A OR PLAQUE AND IT WAS
THE YOUNG BLACK CELLS AND I
DON'T KNOW THAT THESE ARE BASED
ON THE TRANSCRIPT LEVEL DATA
THAT IS SO SOMETHING IS GOING ON
I THINK AND WE NEED TO LOOK MORE
INTO THAT SO WE HAVE CONCLUSIONS
AND THE GAP I CAME UP WITH
ACHI --CONTRIBUTES TO DISEASES D
AGING FREQUENCIES FUNCTION AND
IN DATA FROM MY AND MOST DISEASE
OCCURRING IN AGING AND IT'S
IMPORTANT LESS FOR THIS AUDIENCE
AND IT'S LESS CONVINCING AND I
THINK THAT LEADS INTO THE GAP
AND OPPORTUNITIES SO WE'RE DOING
DISEASE RELATED EXPERIMENTS AND
RESEARCH IN THE CONTEXT OF AGING
AND IF WE HAD ONE WHAT MOST
MOUSE STUDIES DID WE WOULD USE
YOUNG MICE AND WE WOULD NEVER
FOUND THESE MECHANISMS RELATE TO
T ELSE AND SO I THINK THAT THE
OPPORTUNITIES ARE IF YOU ARE
DOING A MODEL AND YOU CAN GET
ACCESS TO STAGE MICE THEN THOSE
ARE USEFUL AND I THINK
EXPERIENCE OF YOUR OWN FROM THE
NIH TO GET THOSE COMPLETION AND
SHARES TISSUE AND ON THE PEOPLE
CAN TAKE ADVANTAGE OF.
IF ANYONE HAS ANY IDEAS, WHEN WE
LOOK AT THE STYLES WE DID THE
DEPRESSION AND THEY'RE NOT VERY
MANY PEOPLE IN THE POCKET CELL
SO WE THINK THERE'S SOMETHING
AND LIVE NODES OR OTHER TYPES OF
IF THEY HAVE ANY IDEA I'M ALL
YEARS.
I TAUNT TO THANK THEM AND IT WAS
UNDER TO PRESENT THIS TALK AND
WOULDN'T FOR PERSONAL REASONS
AND I THANK YOU FOR SUGGESTING
ME FOR THIS AND I'M HAPPY TO
TAKE THIS RESPONSE.
MORGUE APP.
>>DO YOU GET ANY SORT OF
(INAUDIBLE) AROUND THE.
LIKE AGRI GETS OF T AND VASSEL.
>>ONLY IN A VERY MINOR NUMBER
OF CASES.
YOU DON'T KNOW WHAT THE CELLS
ARE BUT I HAVEN'T TRIED TO
FIGURE IT OUT BUT WE'VE DONE
ANOTHER THEY'RE NOT T CELLS BUT
IT ONLY OCCURS WHEN IT'S REALLY
A LESS THAN 1% OF MICE.
>>THANK YOU.
>>SUPER COOL TALK.
I HAVE A QUESTION ABOUT LIKE TH.
IF YOU COULD SUB SORT THOSE OLD
O T CELLS AND TOOK JUST THE
NAIVE ONCE, DO YOU THINK THAT
THEY WOULD LEAD TO NORMAL, THE
YOUNG PLAQUE FORMATION OR DO YOU
THINK IT'S THE COMPOSITION OR
THERE'S SOMETHING INTRINSICALLY
WRONG WITH THE CELLS?
>>YEAH, I DON'T KNOW ANYBODY
KNOWS THAT AND MOST PEOPLE
LOOKING AT THESE MAP, DON'T LOOK
AT AGING SO, YOU COULD PROBABLY
SORT CELLS, I DON'T THINK THAT
THE PROBLEM WITH THE INEXTRA
CELLULAR MARKERS YOU COULD SORT
CELLS FROM YOUNG MICE AND DO THE
SAME THING FROM OLD MICE AND
COMPARE HEAD-TO-HEAD WITH THE
MICE AND THEY HAVE TO COME FROM
THE SPLEEN BECAUSE WE
TRANSFERRED 10 MILLION CELLS BUT
IT'S POSSIBLE.
I THINK, I DON'T HAVE DATA TO
SUPPORT THIS BUT THE CELLS MAY
BE PROTECTIVE WHERE THE MEMORY
CELLS, IT'S IN THE AGED MICE,
MAYBE MORE PRO (INAUDIBLE) WHEN
YOU COMPARE THEM NAIVE YOUNG
VERSUS NAIVE AGE CELLS THERE ARE
DIFFERENCES BUT NOTHING THAT'S A
SMOKING GUN THAT WOULD BE THE
ANSWER.
>>WONDERFUL TALK.
YOU COULD GIVE US ANOTHER TALK
ABOUT YOUR CANINE TO NINE ROO
PATHWAY TO PEOPLE.
YOU MENTIONED ABOUT THE
CIRCULATING FACTORS, RIGHT.
DO YOU THINK AS THESE CELLS ARE
GOING ARE THEY RESPONDING TO
SIGNALS FROM THE TISSUES OR IS
IT JUST A GRADIENT THING IN THE
PERIPHERY WHERE DO YOU THINK THE
SIGNALS AND ORGAN COMMUNICATION
ARE COMING FROM IF.
>>THAT'S A GOOD QUESTION.
I'VE BEEN THINKING A LOT ABOUT
THAT AND THERE'S A STUDY WHERE
THEY DID THE SAME DEPRESSION IN
MICE AND THEY SEE THAT IS
BENEFICIAL AND IT REDUCES PLAQUE
SIZE AND CHANGES CIRCULATING MAN
OWE FACE OF IT AND MOST OF IT IN
THE PLATFORM ARE MACROPHAGES AND
THE COMPARED OF THE YOUNG LDL IN
MICE AND THEY HAVE DIFFERENT
T-CELL SUBSETS AND THAT MOST
YOUNG LDL MICE HAVE NOT A LOT OF
CENTRAL CELLS AND WE HAVE TO DO
ANOTHER EXPERIMENT TO FIND OUT,
I GUESS.
>>THANK YOU.
>>OUR NEXT SPEAKER IS CONNIE
WEYAND.
I'M NOT GOING TO TRY TO TELL
WHAT SHE'S GOING TO TELL US
ABOUT BUT SOMETHING FUN.
>>YOU'LL GET THIS.
>>HE WAS RIGHT.
>>YES, THAT'S WHAT WE ARE GOING
TO TALK ABOUT.
ACTUALLY, THIS IS OUR DISEASE
MODEL.
WE ARE INTERESTED IN AUTOIMMUNE
DISEASE AND THIS IS A PROTO TIP
I CAN AUTOIMMUNE DISEASE AND A
CLASS 2HLA CLASS II ASSOCIATED
DISEASE SO IT'S THE STRONGESTEN
GET I CAN RISK FACTORS AND THESE
PATIENTS ARE CENTERING ENOUGH
THEY BUILD THEM AGAIN RANGE OF
TRANSCRIPTION BE MODIFIED
PROTEIN AND IF YOU GO INTO THIS
LESION FOR THESE PATIENTS THEIR
JOINTS ARE UNDER FIRE.
YOU WILL FIND MICRO LANGUAGE'
AND T CELLS AND OF COURSE FORMER
CELLS.
WE'RE NOT GOING TO TRY TO SEE IF
IT'S A DISEASE OF OLD
INDIVIDUALS, HIGHEST INCIDENTS
IN VICTIMS OVER 07 BUT MUCH MORE
IMPORTANTLY, IF YOU GO INTO
YOUNGER PATIENTS, AND THIS IS AN
OBSERVATION WE MADE A COUPLE OF
YEARS BACK, YOU SEE THAT THESE
PATIENTS AND WHAT WE CALL
PREMATURE AGING, WE MEASURED THE
LINK AND WE MEASURED THE
TELOMERE LENGTH BECAUSE THIS IS
A CLASS ASSOCIATED THE C AND WE
MEASURED THE TELOMERE CELLS THAT
HAVE A NAIVE PHENOTYPE AND YOU
SEE THE PATIENT AT THE AGE OF 30
LOOKED ABOUT 50 SO THERE AN
INTERESTING SHIFT THAT THEY
PREMATURELY AGED AND THE COULD
SURFS BETWEEN US AND ORANGE AND
THE PATIENTS AND BLUE THAT'S
ANOTHER INTERESTING PHENOMENON
MANY AND IT NEEDS EXPLANATION.
ED QUESTION IS WHY DO THESE T
CELLS AGE AND PREMATURELY AGE.
WELL WE HEARD TODAY IT'S NOT
ONLY IMPORTANT WHAT HAPPENED IN
THE CELLS IT'S IMPORTANT WHAT
HAPPENS AROUND THE CELLS.
SO, WE HAVE REALLY GIVEN
ATTENTION TO WHAT HAPPENS AROUND
THE CELLS AND WE HAVE MEASURES
IN THE MICROENVIRONMENT WHAT
KIND OF NUTRIENTS THE CELLS
ENCOUNTER THERE AND I'LL SHOW
YOU THE DATA HERE FOR GLUCOSE
BECAUSE EVERYBODY OF COURSE WAS
PREDICTING THE INFLAMMATORY
CELLS WILL BE EATING GLUCOSE AND
WHILE THEY MIGHT EAT GLUCOSE IF
THEY COULD, I CAN TELL YOU THEY
CAN'T.
BECAUSE THERE IS NO GLUCOSE.
AT LEAST NOT MUCH.
SO, THE GLUCOSE LEVELS IN THESE
SIN OAF Y'ALL TISSUE AND THESE
WERE COLLECTED OUT OF THE DONOR
INDIVIDUAL -- SO MORE TISSUE
HERE DO HAVE LOWER LEVELS BUT
YOU SEE THAT THE UNINFLAMED
TISSUE WHICH WERE SELECTED FROM
PATIENTS WITH SPORTS INJURIES
THAT THESE NOT PATHS ARE VERY
LOW GLUCOSE LEVELS AS WELL SO
HOW DO T-CELLS AIMING IN THESE
PATIENTS AND WHAT DO THEY LIVE
OFF?
THEY SAY REALLY DON'T HAVE A
CHANCE TO EAT GLUCOSE IN THE
SYNOVIAL ENVIRONMENT.
WELL, MANY LEADS TO THIS
ORGANIZE INHE WILL AND I'LL GIVE
YOU AN OVERVIEW ABOUT WHAT WE
HAVE FOUND OVER THE YEARS.
SO, OF A REAL PROBLEM IS THAT
THE MIGHT OWE CON DEGREE AN THE
T CELLS HAVE A PROBLEM WITH DNA
PREPARE AND THEY'RE GETTING A
NUKELY ACE WHICH LEADS TO DNA
LEAKAGE TO INFLAM TOMORROW
ACTIVATION AND SO THE TWO PLANS
UNDERGO WHEN THEY REACH SYNOVIAL
TISSUE AND THE CELLS REVERT BY
SHUTTING DOWN AND THIS LEADS TO
AN INCREASE SIGH TRADE AND AND
HYPER ESCALATION WHICH MAKES THE
CELL VERY MIGRATORY.
THE CELLS DO NOT PRODUCE ENOUGH
ASPERTAME IN THE MITOCHONDRIA
AND THIS IS A CRITICAL
DEFICIENCY.
THIS DISRUPTS ADPD OF VIP AND
LEADS TO THE EXPANSION OF ER
MEMBRANE AND TO INCREASE
PROLIFERATION TRANSPORTATION AND
BIOGEN SIS WHILE YOU MAY ALL
KNOW THAT IN RHUMATOID ARTHRITIS
CNF IS TH TH THE CYTOKINE WHICHT
SO IT'S POSSIBLE FOR THE OVER
PRODUCTION AND THE SHAFTION
GLUCOSE AWAY FROM THE
MITOCHONDRIA INTO THE FOSS EIGHT
AND IT INCREASES IN A NIDPH
LEVEL AND INCREASE FINAL GENESIS
LEADS TO LIPID DROPLET FORMATION
I AM VASE I HAVE MEMBRANE
FORMATION AND TISSUE
INVASIVENESS AND THEY HAVE SAFE
FUNCTION AM TRANSPORT CHAIN
WHICH DECREASES THE PRODUCTION
OF A IT TP AND THIS ACTUALLY IN
OUR HANDS CONNECTS DIRECTLY TO
THE -- AND OPPOSED UPON
ACTIVATION.
SO THIS IS THE NATURAL SUMMARY
AND I'LL JUST SHOW YOU HAVE
WHERE THE MAJOR MOLECULAR
TARGETS ARE BECAUSE WE'RE HERE
TODAY TO TALK ABOUT THE FUTURE.
WHERE WE COULD GO?
HOW CAN WE TAKE IT KNOWLEDGE AND
BRING IT TO THE PATIENT AND
ACTUALLY MAKE THEM BETTER.
SO IF YOU MISH ATP PRODUCTION IN
THE CD4 CELLS OF PATIENTS TO SEE
THAT APP IS SLOWS AND AMP IS
HIGH, BUT YOU ALSO SEE THAT
THERE'S A RANGE OF ATP
PRODUCTION AND SOME CELLS ARE
SLOW AND SOME CELLS ARE AS HIGH
AS 7.
DOES THAT MATTER?
IS THAT IMPORTANT?
HOW MUCH THEY MAKE?
IF YOU RECRUITED A QUICK WORD OF
THAT PATIENTS WE STARTED WITH
MEASURING ATP CELLS AND YOU SEE
THAT THERE'S THAT RANGE IF WE
ACTUALLY CLASSIFY THEM INTO AN
ATPEL SUBJECT AND INTO AN ATP
SUBSET BECAUSE THE ATP NEVER AS
HIGH AS THEFT IN THE YELLOW
CONTROLS AND THEN YOU SEE THAT
WE HAVE ABOUT ATP LOCATIONS AND
ATP IN IMMEDIATE PATIENTS AND
WELL IF YOU MEASURE COMPLEX
ACTIVITY OF THE MITOCHONDRIA WE
SEE THAT ATP PRODUCTION AND IS
EXPECTED CORRELATES VERY WELL
WITH -- THIS IS OUR MODERN
SYSTEM WHERE YOU CRASH AND HUMAN
SYNOVIAL TISSUE INTO A MOUSE
THAT WE HAVE MODIFIED AND WE
ADOPTED THE TRANSFER INTO THAT
NSG MOUSE THE PATIENT AND THEN
WE EXPLAINED THE TISSUE AND DO
TISSUE TRANCE CHROME I CAN AND
DO CLOSE OR WHATEVER YOUR HEART
DESIRES.
SO, IF WE TAKE THE PRODUCES THE
LOWER A-A-T-P OR IN THE
IMMEDIATE AMOUNT OF ATP THAT HAS
A MAJOR IMPACT ON THE INTENSITY
OF THE NIAGARA FALLS THE CELLS
OF THE LOW PATIENT THERE'S LOW
MITOCHONDRIAL TO TEN SHALL WHERE
THE PATIENTS HAVE A POPULATION
OF CELLS THAT STILL HAVE OF
THESE ARE THE TISSUE TRANSCRIPT
OWN AND WITH WHEN THE CELLS A
ARRIVE INTO THE TISSUE, THEY
INDUCE AN INFLAMMATION THAT UP
REGULATE CD163FAP AND IN THE GAM
AND IL6.
WE ARE GO AND LOOK WHICH CELLS
THAT ARE AND BEFORE I SHOW YOU
THAT, I SHOULD EXPLAIN THAT WE
DID ONE EXPERIMENT AND WE TOOK A
HEALTHY T-CELL AND WE INHIBITED
THE COMPLEX 5, THIS WAS WE
TRANSFERRED IT INTO THE MICE AND
WE WONDERED IT'S EFFICIENT TO
INDUCE IT THIS TYPE OF TISSUE
INFORMATION AND THE ANSWER IS
YES, SO IN THE UPPER BLUE YOU
SEE THE CD4 CELLS THAT HAVE A
FUNCTIONAL COMPLEX HIGH AND IN
THE LOWER RED, YOU SEE THE
RESULT FOR THE T CELLS THAT HAVE
AN INHIBITED COMPLEX AND YOU SEE
HERE THAT THE DENSITY OF T CELLS
IN THE TISSUE IS HIGHER IN THE T
CELLS AND THAT THE PRODUCTION OF
IL6 AND THE PLAN IS POSITIVE
THAT ARE HYPO GLASS AND IT'S
MUCH HIGHER AND THE PRODUCTION
IN MICROFAGES IS MUCH HIGHER AND
THAT THE PRODUCTION OF IL6 IN
THE MICRO IS MUCH HIGHER IF ALL
OF WHAT WE DID IS TO BLOCK THE
COMPLEX PIE IN THE CD4 CELLS.
SO, HOW DO WE REPAIR THIS?
HOW DO WE MAKE THIS BETTER?
WELL WE HAVE TO GO TO THE ROOT
MOLECULE.
HERE IS ONE OF THE ROOT
MOLECULES.
WE STARRED WITH THE ANALYSIS OF
CD4 CELLS OF BOTH NAIVE AND AS
WELL AS MEMORY CD4 CELLS COMING
OUT OF OUR ROTATION IN CONTROLS
AND THE PATIENTS ARE IN REST AND
WE ARE IN PURPLE AND ONE OF THE
MOLECULES THAT FELL OUT WAS
MRE11A.
IT DECLINED IN T CELLS WITH H
AND IT IS MUCH MORE PRONOUNCED
IN THE PATIENTS AND MEMORY C
CELLS AND MRE11 IS A ' LACE THAT
FORMS WITH NUCLEASES ATPA
NUCLEAR PLAN AND IT REPAIRS THE
MA DOUBLE TREND AND WE WEPT
LOOKING FOR MRE11 AND SAW THAT
MRE11 IN HEALTHY CELLS IS IN THE
AND IN THE MIO CON DEGREE A AND
OF COURSE THERE'S MRE11 AND IT'S
A NUKELY ACE AND YOU SEE THE RA
CELLS DO LESS MRE22 BOTH IN THE
WHEN YOU COMPARE CONTROLS.
NOT ONLY DOES MITOCHONDRIAL MIGN
DEGREE CONSUMPTION GO DOWN THEY
LEAD MITOCHONDRIAL OUTSIDE OF
THE CELLS AND SO THIS SHOWS
INCLUDES WHAT A HAPPENED WHEN
MRE11 IS KNOCKED DOWN OR WHEN WE
PHARMACOLOGICALLY INHIBIT THIS
OR SPONTANEOUSLY IN THE PATIENT
AND SO WE DO KNOW THAT HAPPENS
IN VIVO HERE WE ARE IN THE LYMPH
NODE.
WE DO KNOW THAT ACTIVATES CHEST
PACE ONE AND ACTUALLY FROM
ACTIVATION AS PART OF THE
PROCESS AND EDITED IN THE
POSITIVE CONTROL.
THIS HAPPENS IN THE LIVE NODE OF
THE PATIENTS AND IT IS A RESULT
OF THOF YOU SEE IT'S PLACED IN E
CD3 POSITIVE CELL.
WE DO KNOW THAT THE RA T-CELL
UTILIZES THESE CYTO PLASTIC AND
AS A RESOURCE TO MIGRATE INTO
THE THE AMOUNT OF MY PROTEIN IS
LOWER IN THE CELLS AND WHAT THIS
LEADS TO IS THEY FAILED TO AMPK
AND YOU ALL KNOW THAT AMPK IS
THE ONE KINASE THAT MAINTAINS
HEALTH OF THE MIGHT OWE CON MIGA
AND YOU SEE HERE THAT IN THE
PATIENT, THE AMPK MOLECULES
PROTEIN IS NOT.
WHAT THIS LEADS TO IS THAT WHEN
YOU GO TO THE LIPOSOME WHERE IT
IT HAS TO TRAVEL TO, THE AMK
AMOUNT IS LOWER AND YOU SEE THAT
ON THE SURFACE M.T.O. R IS STILL
MAINTAINED BECAUSE M.T.O. R AND
MEET ON THE SURFACE OF THE LICE
OWE SEEM WE HAVE CON SPAIN YUS
AND UNIMPOSED ACTIVATION.
OR WHAT HAPPENS IN A HEALTHY
CELL, THE MODIFICATION OF AMPK
TARGETS AMPK TO THE SURFACE
WHERE THERE IT ROSS REGULATES
AND THIS PATHWAY IS DISRUPTED IN
THE RAC4 T-CELL AND AMPK IS NO
LONGER AND IT FAILS TO TRAVEL TO
THE LICE OSEM AND IMPORT ONE
REMAINS UNOPPOSED EX AMPK NEEDS
TO BE PROTECTIVE SO IF THE AMPK
ACTIVATION WE CAN AND REDUCE
TISSUE AND INFLAMMATION.
I'LL BRIEFLY SHOW YOU HOW THE
MITOCHONDRIA TALK TO THE ER HAD
WE STARTED LOOKING AT SIZE OF ER
IN THE RA T CELLS WE SAW THAT
THE RA TELL CELL HAS EXPANSION
OF THE ER AND THE EXPANSION OF
THE ER IS INVERSELY RELATED TO
THE ACTIVITY OF THE MITOCHONDRIA
AND BY PLUCKING MITOCHONDRIA
ACTIVITY WE CAN PAN THE E.R.
MEMBRANE AND IT'S MOSTLY AN
EXPANSION OF THE ROUGH ER AS YOU
SEE HERE WHEN WE PRUNE DOWN THE
E.R. IT'S THE ROUGH E.R. THAT IS
EXPANDED.
WHY IS THE ROUGH E.R. EXPANDED?
THE MITOCHONDRIA IS NOT
PRODUCING ENOUGH AND ENOUGH
ASPER TATE SO IF YOU GO INTO THE
RA T-CELL YOU SEE THAT ASPER
TATE LEVELS ARE REDUCED TO ABOUT
50% AND THIS LEADS TO THE CUTEL
AND TO RESTORE THE NADP POOL AND
IT'S THAT TRUE IS THAT
IMPORTANT?
BECAUSE IF WE GO INTO THE MOUSE
AND THREE THE MOUSE WITH ASPER
TATE YOU SEE THAT WE HAVE A VERY
NICE ANTIINFLAMMATORY EFFECT.
WHY?
BECAUSE THE E.R. ON THE SURFACE
HINDS RYAN OWE TOMES AND DEMANDS
THESE BE BROUGHT AND THERE'S
ENRICH.
FOR THE SO WHEN THE E.R.
MEMBRANE EXPANDS, THERE IS MORE
PRODUCED AND THAT IS SHOWN HERE
AND TD14.
SO, IN A NUTSHELL, MITOCHONDRIA
AND THE ROUGH ER AND THE
LYSOZOME ARE THESE PATIENTS HAVE
BEEN A VERY NICE MODEL AND HOW
IT CAUSES A SCENE.
I THINK I WILL STOP HERE AND
GIVE ME A MINUTE.
I'M ALREADY OVER TIME.
SO LET ME SHOW YOU WHO IS DOING
THE WORK.
THEY HELPED US FIND THESE
PATIENTS AND BECAUSE WE DO NOT
HAVE DONE IT AND IN THE TODAY
IT'S REALLY THREE NIH INSTITUTES
THAT CONTRIBUTE TODAY THIS WORK.
>>THANK YOU, VERY MUCH.
YOU HAVE THE AGE CELLS OR AIM
MISSING SOMETHING?
>>WELL, WE SEE THIS H PHONE OWE
TYPE IN A AND A E CELL AND WE
SEE APPROXIMATE PRONOUNCED
DIFFERENT BETWEEN THE NAIVE
YOUNG AND THE NAIVE OLD AND THE
NAIVE RA CELL AND WITH THE OLD
AND NAIVE AND THE OLD RA BEING
PRETTY SIMILAR TO EACH OTHER.
>>THEY ARE EVEN UNIFIED.
>>YES.
>>BECAUSE WHEN YOU ACTIVATE
THEY DON'T LOSE RA PLUS RIGHT
AWAY.
SO, THEY ARE NOT EYE THIEF AND
THE NEUROLOGICAL SENSE.
>>THAT'S TRUE.
>>THANK YOU.
>>SO IS THE OLD NAIVE CELLS.
IT'S NO LONGER AS NAIVE, RIGHT.
WE CANNOT SEE THAT IN THE
TRANSCRIPT.
YOU HAVE TO LOOK UNDER MEMBRANE
OF THE E.R.
>>THANK YOU.
>>OUR LAST SPEAKER IS DAVID.
>>GOOD AFTERNOON, EVERYBODY,
AND I HOPE YOU STICK AROUND AND
ARE STILL AWAKE.
IT'S BEEN A LONG AFTERNOON.
I'M REALLY PLEASED TO BE HERE
BACK AT THE NIAD AND THANK YOU
FOR PUTTING TOGETHER THIS
AMAZING WORKSHOP AND REALLY
STELLAR AND THEY SEE SO MANY
BASIS EX IT'S GO AHEAD TO BE
BACK AND I'M GOING TO TALK ABOUT
CLINICAL RELEVANCE OF THE CLOCKS
THAT WE'RE BUILDING USING FOR
THE MOST PART HUMAN BEINGS.
SOME OF THE DISCLOSURES ARE
THERE AND I'M GOING TO
SCHOLARSHIP THROUGH THIS TO
COVER THIS SESSION.
24 WAS PUBLISHED IN MARK AND IN
20717 AND PUTTING TOGETHER THE
IDEA THAT IMMUNE LOGICAL HEALTH
IS IMPORTANT FOR OTHER ASPECTS
OF AGING AND NOT JUST UM UNION
AND AGING BUT OTHERS AND ONE
ASPECT OF AGING, THAT IS
PARTICULARLY TO A IMMUNE SIS TO
IS THE AGING AND MANY OF YOU
HAVE SEEN TALKS RELATED TO
CHRONIC INFORMATION AND IT'S
IMPORTANT TO NOTICE THAT THIS
VERY DIFFERENT FROM ACUTE
INFORMATION AND I THINK THAT
THERE'S NO GOOD CONSENSUS AS TO
WHAT REALLY THIS TYPE OF
INFLAMMATORY RESPONSES SO AS
PART OF THE PROJECT THAT WE
STARTED IN 2007, IN WHICH WE
COLLECTED SIM POLLS FROM A
THOUSAND PEOPLE, A FRACTION WERE
PROVIDED BOTH FOR 13 YEARS NOW
AND SECURE THE FUNDING AND NO
NIH AND AND TO CONTINUE THIS
STUDY FOR THE NEXT FIVE YEARS
AND RECENTLY AND WE FOCUS ON
SYSTEMIC INFORMATION BUT REALLY
WE LOOK AT MANY DIFFERENT
ASPECTS OF IMMUNITY AND WE'RE
LOOKING AT A THOUSAND AND THE
THE FIRST STORY WE SUCCESSFULLY
PUT TOGETHER WAS IDENTIFIED
INFLAM OZONE WHICH IS KNOWN FOR
RECOGNIZING BACTERIAL FROM
GELLEN FOUND IN INDIVIDUALS THAT
ARE INFLAMED AND THEY SUFFER
FROM A NUMBER OF CARDIOVASCULAR
CONDITIONS AND THOSE DEATH AND
IN THE FOLLOW-UP LONGITUDINAL
STUDY THAT WE DID IN THAT
FRACTION OF INDIVIDUALS.
MORE UNBIASED, WE BUILD A DEEP
NEURO NETWORK TO CREATE WHAT WE
CALL INFLAMMATORY AGE USING A
THOUSAND INDIVIDUALS IN THE
STUDY AND THE TYPE OF APPROACH
WE DID IS NOT JUST A TYPICAL
DEEP LEARNING APPROACH, IN THIS
CASE WE'RE TRYING TO PREDICT
CHRONOLOGICAL AGE AND AT THE
TIME, IN PARALLEL,
RECONSTRUCTION THE SITE OWE KEEN
DATA AND IT'S CLOSEST TO
INFLAMMATORY AGE AND YOU CAN SEE
THE LOSS FUNCTION THERE AND SO
WHEN WE BUILD A EDGE FLAM TORI
AGE CLOCK WE START LOOKING AT
DIFFERENT MORBIDITIES AND THINGS
LIKE THAT AND IT DID CORRELATEEL
SIGNIFICANTLY WITH MULTI
MORBIDITY AS SHOWN IN THIS FIRST
BLOCK.
WE COULD PREDICT QUALITY IN
INDIVIDUALS OVER 75 YEARS OF AGE
AND THEIR PROTECTS INTERESTED
THIS TYPE OF INFLAMMATORY
RESPONSE AND THIS SHOW HERE,
THIS I'M POINTING WITH MY CURSOR
THAT OVER ALL, INDIVIDUALS WITH
HIGH INFLAMMATORY AGE HAS LOW
RESPONSES TO MULTI EX VIVO SO
THE IMMUNE HEALTH OF THOSE IS
COMPROMISED AND WE DO GENE
EXPRESSION OF INFLAMMATORY AGE
TO GO TO THE PUBLIC DOMAIN AND
ASKED THE QUESTION IS THIS A
CLINICAL OR RELEVANCE IN OTHER
TYPES OF COHORTS AND YES WE CAN
PREDICT MORTALITY IN THE
FRAMING.
SO GOING FORWARD WE WANTED TO
DEVELOP INTERVENTIONS FOR IN
FLAM TORI AGE WE BUILT AN ATLAS
FOR IN FLAM TORI MODULATORS AND
WE TUFTED SOME OF THESE THINGS
WITH A CORPORATE PARTNER IN WE
SHOWED IN THE EXPERIMENTAL GROUP
WE INCREASE INFLAMMATORY AGE AS
WELL AS PROTEIN TAX AND IT'S
TYPICALLY KNOWN AS ASSOCIATED
WITH DRAINAGE SO WE'RE NOW
ANALYZING THE DATA FROM A MUCH
LARGER STUDY ALSO DOUBLE BLINDED
PRACTICE TEAGUE OWE CONTROL IN A
THOUSAND PEOPLE AS PART OF THIS
EFFORTS.
I WANTED TO POINT OUT IT'S
REALLY IMPORTANT SO THIS PAPER
WILL PUBLISH WITH MARK DAVIS AS
WELL AND IN 2019 AND SHOWS THAT
INDIVIDUAL VARIATIONS IF WE WERE
NOT TO SEPARATE INDIVIDUALS
BASED ON THEIR PROJECTORY SO
THERE'S A POPULATION BASE EFFECT
OF AGING THAT WE HAVE OUTLIERS
THAT HAVE DIFFERENT RATES OF
AGING AND THOSE RATES OF EDGING
ARE LARGELY DUE TO THE IMMUNE
SYSTEM BEHAVES AND THIS SECOND
PAPER I'M SHOWING YOU HERE, WE
BUILD CLOCKS.
WE DO LIKE FOR A LIVING.
AND, I'M SHOWING YOU A NEW CLUB
EXTRUDING AND YOU SEE THE
POPULATION TREND AND THE
INDIVIDUAL RATES THAT SHALL
REMARKABLY DIFFERENT AND
DIFFERENT INDIVIDUALS AND THAT
ACTUALLY PREDICTS THE HEART
FAILURE AND AND INJECTION
PROTECTION IN THIS STUDY AND IT
DOES HAVE A CLINICAL IMPORTANCE
AND NOT YET ANOTHER CLOCK AND WE
PUBLISHED LAST YEAR AND
INTERESTING BECAUSE BRAIN AGING
DOES NOT MOSTLY RELATED WITH
AGING AND BUT WE LOOKED AT THE
PARTICULAR WAY THAT CYTOKINE IN
BLOOD BECAUSE IT'S A COMPLETELY
SEPARATE STUDY WE DID IN
COLLABORATION WITH JOEL KRAMER
AT UCSF AND THE AGE EFFECT IS
SHOWN HERE, NOTHING NOVEL HERE,
IT WAS REALLY INTERESTING
BECAUSE WOMEN TEND TO HAVE A
BETTER EXECUTIVE FUNCTION SO
THIS IS SOMETHING I THINK REALLY
NOVEL AND IT WAS START TO BE
PRETTY SIMILAR IN MULTIPLE
STUDIES NOW WE'RE SHOWING THAT
WOMEN ARE DOING BETTER AND IT
HAS AN EFFECT ON A NETWORK OF
BRAIN FUNCTION WHICH IS RELATED
HOW WE GRASP THINGS WE REACH
THINGS WHICH IS THE DEFAULT MODE
NETWORK AND WE THINK OURSELVES
IN THE PAST OR THE FUTURE WE'RE
USING THAT NETWORK AND THAT'S
ASSOCIATED WITH INCREASING
INDIKE LOW SO WE HAVE LOON BEING
LIKE AT AGING IN MICE WE'RE
BUILDING CLOCKS FOR TISSUE AND
BONE, BRAIN, FAT, LUNG AND I
KNOW ALL THIS IS IN MICE AND WE
WERE INTERESTED IN THE BRAIN AND
YOU SEE IN THE SLIDES IS THE
TRANSCRIPT DOME I CAN AGE OF THE
BRAIN AND CORRELATED WITH
CHRONOLOGICAL AGE AND IN THE
RIGHT-HAND SIDE OF THE SLIDE,
YOU CAN SEE THE MICE THESE ARE
MUTATIONS THAT IS A MODEL FOR.
>>Al: DISEASE WITH AMYLOID
ALTERATIONS OR PLAQUES AND YOU
CAN SEE THAT THE MICE HAVE A
MASSIVE OF THE CLOTHE AS
COMPARED TO THE NORMAL MICE AND
WHAT YOU SEE ON THE LEFT-HAND
SIDE IS A CORRELATION WITH AGING
HUMANS AND THE Y IS CORRELATION
WITH AGE IN MICE AND IN THE X
AXIS OF THE MOST SIGNIFICANT
GENES THAT ARE PART OF THIS
BRAIN AGING PLOT AND THEY WERE
TWO MAJOR CONTRIBUTORS TO THIS
CLOCK AND THEY'RE ALL ELEVATED
IN ALL DIFFERENT WITH NORMAL
AGING AND HUMANS.
SO WE THEN WEPT AHEAD AND DID
SOMETHING SIMILAR TO WHAT WE'VE
DONE BEFORE FOR TH THAT CAN REVE
THE SIGNATURES FOR TESTING THEM
IN ORGANIZE AN SYSTEMS.
I'M GOING TO SWITCH GEARS AND
TELL YOU ABOUT A RELATIONSHIP I
HAVE THAT WITH SUZANNE.
SHE USED TO BE AT NASA IN THE
RUMINA AN RESOURCE PROGRAMME IN
HOUSTON AND SHE REACHED OUT TO
ME TWO AND A HALF YEARS AGO AND
SAID YOU ARE RESEARCH IS
IMPORTANT FOR US BECAUSE WE'RE
TRYING TO DEVELOP COUNTER
MEASURES FOR THE STATES RELATED
RISK WHICH SEEMS TO BE
ASSOCIATED WITH AGING.
WE HAVE THIS ACCELERATED AGING
IN ASTRONAUTS AND IT'S
INFLAMMATION OR AGING AND SO
THAT'S STARTED A WHOLE
CONVERSATION WITH SUZIE AND I
REALISED SHE WAS REALLY PASSING
THE TORCH SAYS SHE HAD TERMINAL
CANCER AND I GOT TO KNOW HER
FAMILY AND WE WERE BECAME GOOD
FRIENDS AND SHE PASSED AWAY IN
DECEMBER OF LAST YEAR BUT WE
WERE ASKING THIS QUESTION MANY,
MANY TIMES AS TO THE SAME
QUESTION THAT WAS POSED IN
PRINCETON IN 1969 TO HIS
STUDENTS.
HE ASKED THE QUESTION, IS THE
PLANETARY SURFACE THE RIGHT
PLACE FOR EXPANDING
CIVILIZATION?
AND OBVIOUSLY THE ANSWER IS NO.
WE CREATED AS PART OF THIS
EFFORT THE CONSORTIUM FOR SPACE
HEATHER AND HUMAN LONGEVITY
WHICH INTENDS TO FUND RESEARCH
IN THAT INTERSECTION.
JUST TO GIVE YOU A ACCELERATED
AGING YOU CAN SEE DIFFERENT
PHYSIOLOGICAL MEASUREMENTS AND
COGNITIVE FUNCTION, MUSCLE SIZE
AND MASS AND CARDIOVASCULAR
HEALTH THEY'RE ALL ACCELERATED
IN SPACE AND ON AVERAGE, THERE'S
AN EXCEL RACE OF 34.
FOR EVERY YEAR, SOMEONE SPENT
YOU WOULD AGE SIMILARLY TO A 30
YEARS ON THE GROUND AND THINGS
CAN REVERSE WHEN THEY COME BACK
TO EARTH AND THEY RETURN.
BUT IT'S A PARTICULAR RELEVANCE
THAT WE SEE THIS IMMUNE
DYSFUNCTION SO THERE ARE
REACTIVATION OF VIRUSES AND WE
DO SPACE LIFE AND THERE'S AN
ENHANCED IMPAIRED FUNCTION AND
THERE'S A SHIFT FROM TH1 TO TH2
AND ELEVATED AGING SO WE CREATED
THIS PIPELINE WHERE WE HAVE A
SYSTEM TO MEASURE MICRO GRAVITY
VERSUS SIMULATE MICRO GRAVITY ON
THE GROUPED AND THAT IS A
ROTATING VESSEL DESIGNED BY NASA
AND WE HAVE A SYSTEM IN WHICH WE
AGE AND IMMUNE ORGANOIDS IN THE
ROTATING WALL VESSEL AND THIS
SIMULATED GRAVITY AND YOU CAN
SEE THAT WITH THIS DISCOLORATION
AND MARK DATA HERE AS WELL IN
THE IMMUNE ORGANOIDS WE HAVE
ORGANOIDS AND THEY'RE BEATING
AND THEY'RE LARGELY EFFECTED BY
MICRO GRAVITY AND WE KNOW KNOW
THAT THE CELLS ARE PLAYING A BIG
ROLE IN WE CAN TEST THE NEURO
ORGANOIDS BY LOOKING AT ELECTRO
PHYSIOLOGY AND HOW IT EFFECTED
BY MICRO GRAVITY AND WE ALSO
TEST DIFFERENT SEQUENCING
METHODS AND WE USED SEQUENCING
METHODS TO DO OTHER ASSESSMENTS
AND MOLECULAR ASSESSMENTS AND
WHERE YOU CAN SEE HERE IS AN
INCREASE IN INFLAMMATORY AGE AND
24 HOURS OF SIMULATED MICRO
GRAVITY INCREASES BY 50% SO
WE'RE AGING THESE THINGS AND
WE'RE ADDING COMPOUNDS TO THOSE
CULTURES TO SEE IF WE CAN
REVERSE THOSE.
AND THESE ARE PARTICULARLY
REALLY STRONG EVIDENCE IN
MONOCYTES.
WE USE ALSO SPACE DATA AND MORE
DATA TO SHOW YOU WE SEE
REACTIVATION OF VIRUS AND IN
VITRO AND WE SEE CELLULAR
SENESCENCE AND THIS IS THE MAYO
SCORE AND INCREASE IN MIKE GROW
GRAVITY AND INCREASE IN THE
CLOTHE AND PREDICTED PACE OF
AGING AND A DECREASING NEW
RESPONSE WHEN WE STIMULATE CELLS
AND WE HAVE A REALLY AMAZING
EVIDENCE FROM FE WU WHO IS
SPEARHEADING THIS PROJECT AND HE
CAN REDUCE THE EFFECT OF MICRO
GRAVITY SIGNIFICANTLY AFTER
TREATING THE CELLS WITH THESE
COMPOUNDS.
SO WITH THAT I WOULD LIKE TO
THANK MY MANY COLLABORATORS
AROUND THE U.S. AND FUNDING.
WE DO OTHER THINGS RATHER THAN
SCIENCE AND WE GO SURFING AND
PARTY AND WE GROW WATERMELON.
THANK YOU SO MUCH.
>>THANK YOU, DAVID.
MAYBE I CAN ASK A GENERAL
QUESTION.
I MEAN, THERE ARE SO MANY CLOCKS
IN THE FIELD AS YOU KNOW, AIMING
FIELDS AND EVERYBODY PREDICTS
MORTALITY AND BIOLOGICAL AGE SO
IT'S GREAT TO SEE IT'S A CLOCK
YOU HAVE BASED ON BIOLOGY AND
HOW MUCH OF THIS CORRELATES WITH
THE NEGATIVE OUTCOMES THAT
PEOPLE ARE TALKING ABOUT IN
TERMS OF AGE REVERSAL AND DO YOU
SEE THE THINGS THAT YOU HAVE
DESCRIBED IN THE IMMUNAL CLOCK.
DO OTHER INTERVENTIONS IN MOUSE
WHICH INCREASES LIFESPAN ARE
THEY IMPACTED BY THAT?
>>
>>THAT'S A LOADED QUESTION.
I COULD STAY THAT WE DO SEE
EARLY SIGNS INTERVENTION WHEN
YOU TREAT A GROUP OF INDIVIDUALS
IN THE IH WE ALSO SEE
MODIFICATIONS AT THE PROTEIN
LEVEL AND WHETHER OR NOT THAT
TRANSLATES INTO IMPROVEMENT OF
OUTCOMES, WE HAVE YET TO ANALYZE
THE DATA FROM THE 1,000
INDIVIDUALS THAT WE'RE RUNNING
AND THAT STUDY.
WE HAVEN'T DONE ANY MOUSE
EXPERIMENTS TO TWEAK
INFLAMMATORY AGE OF THIS OTHER
CLOCKS.
BUT THEY'RE ALL GOOD THING.
>>I WAS GOING TO ASK A QUESTION
THAT JUST POPPED UP ON THE CHAT.
WHICH FOR SPACE TRAVEL, WHAT
DOES RADIATION DO TO THIS AND DO
YOU HAVE A RADIATION COMPONENT
IN YOUR ORGANOID CENTRE FUGE IN
CALIFORNIA OR WHERE IT IS?
>>YEAH, SO, IF YOU STAY WITHIN
THE LOWER ORBIT, RADIATION IS
NOT A BIG DEAL.
WE'RE VERY MUCH PARTICULAR.
IF YOU GO ABOVE AND BEYOND TO
THE MOON AND MARS, THERE ARE
HEAVY PARTICLES, SHOWERS OF
PARTICLES THAT WILL BE AFTER AND
SO ON AND WE HAVE WITH NASA AND
WHERE WE'RE SPENDING ORGANOIDS
THROUGH THE NATIONAL LAB TO
SIMULATE THE RADIATION SO WE
HAVE THAT COMPONENT AND IT'S
JUST STARTING.
THE MAIN FOCUS AT THE MOMENT IS
MICRO GRAVITY.
>>IS THERE A DAMAGE RESPONSE A
IMPORTANT PART OF THAT.
>>IT'S EVERYTHING, RIGHT.
AND YOU HAVE DAMAGE RESPONSE.
WE'RE NOW TRYING TO FIND
PREDICTORS OF THE DAMAGE SO WE
HAVE ALL THE BASELINE DATA AND
THEN THE ASSAY WHICH TELLS YOU
WHO RESPONDED WELL AND YOU FIND
PREDICTORS AND TRY TO FIND
MIMICKERS TO BOOST THE DEALINGS
AND RESPONSE.
>>THANK YOU.
DON'T GO ANYWHERE BECAUSE LET'S
GO MY COLLEAGUE WILL TAKE OVER
AND MODERATE GAPS AND THE
DISCUSSION SESSION.
THANK YOU FOR YOUR TIME.
>>THANK YOU.
>>THIS WAS A WONDERFUL AND
ENTERTAINING ORGAN SYSTEM
DISCUSSION.
YOU CAN SIT WHERE YOU WANT.
WITHIN REASON.
AND JUST LIKE BONNIE DID IN HER
SESSION, I'D LIKE TO GO THROUGH
EACH PERSON GIVING THEM TWO
MINUTES OR SO AND WE WILL START
WITH OUR ON-LINE SPEAKER BECAUSE
I HAVE HIM STARING AT ME,
THROUGH THE COMPUTER SCREEN.
YOU CAN'T SEE.
BUT MAYBE YOU WILL GET TO AT
SOME POINT.
SO, GO AHEAD, TWO MINUTES, OF
WHAT YOU THINK ARE THE GAP.
>>YOU ARE MUTED.
HE IS HERE.
HE IS RIGHT THERE.
THERE HE IS.
CAN'T HEAR YOU.
>>WELL, WITH REGARD TO THE WORK
THAT I PRESENTED, LIKE I
SUGGESTED, WE THINK IT IS GOOD
TO TRY TO PREVENT INFLAMMATORY
DISEASES, NOT ONE BY ONE, NOT
EACH ONE DIFFERENTLY, BUT SINCE
THERE ARE SYSTEMIC MECHANISM
THAT CAN PRECIPITATION THE
UNRELATED SYSTEMIC DISEASES LIKE
TRAINED IMMUNITY OR (INAUDIBLE)
POTENTIAL I THINK THAT THE
KNOWLEDGE IS TO IDENTIFY FACTORS
THAT CAN BE COMMON IN THE
PROMOTION OR EXACERBATION OF
THESE DISEASES AND I GAVE SOME
PRELIMINARY EXAMPLES BASED ON
SOME EVIDENCE FROM IN VIVO MODEL
OR FROM HUMAN STUDIES AND ONE
EXAMPLE IS L1 BETA.
WHICH APPEARS TO HAVE SOMETHING
TO DO WITH INDUCTION OF TRAINED
IMMUNITY.
THERE'S PARTICULAR EVIDENCE AND
THERE'S SOME SUGGESTION THAT
HUMAN STUDIES AND IT'S ALSO
CRITICAL CYTOKINE THAT DRIVES AT
LEAST SOME FORMS OF DRIVEN CHIP
SO BY BLOCKING L1 BETA IN PEOPLE
THAT WE ARE IDENTIFIED THAT THEY
WILL BENEFIT, YOU CAN HELP THEM
NOT ONLY TO TREAT THE AGENTER
CIRRHOSIS BUT LINK DISEASE AND
SO ON SO THERE ARE A LOT OF
OTHER THINGS THAT I WOULD SAY AT
THE MORE BASIC LEVEL BUT I THINK
THAT WITH ALL THIS METHODS OF
INVESTIGATE YEAR AFTER YEAR IT'S
TIME NOW TO PROVIDE SOMETHING
FOR THE PATIENT AND I SAY THIS
IS ESPECIALLY FROM MY POINT OF
VIEW, WORKING THE RESEARCH
FIELD, THE PER PER PERRY OWE DOT
HAVE BEEN DOING THIS FOR THE
PAST 100 YEARS THAT'S WHY WE'RE
TRYING TO BRING A TREATMENT, AT
LEAST A LOCAL TREATMENT BASED ON
THE COMPLIMENT SYSTEM IN THE
CLINIC LIKE I SAID, WE'RE AT
PHASE 2A AND WE HOPE TOP GO TO
PHASE 3 BEFORE I RETIRE TO SEE
AT LEAST THE HOST WITH
RECOLLECTION TREATMENT FOR THE
PERIODONTAL PATIENT OTHER THAN
THE MECHANICAL TREATMENT THAT IS
DONE.
THE MECHANICAL DEPARTMENT.
THAT'S ALL I HAVE TO SAY.
>>TERRIFIC.
WE'LL MOVE ON TO OUR NEXT.
WE'LL TALK DOWN THE LINE THERE.
>>SO, I THINK I AGREE
COMPLETELY THAT THE NEXT STEP WE
HAVE TO STAKE TO BRING THIS TO
THE PATIENT AND THE QUESTION IS
HOW CAN WE BRING IT TO THE
PATIENT AND THE PATIENT IN THAT
SENSE ALL OF US.
BECAUSE WE HAVE TO BRING IT TO
THE AGING PROSPER SAY.
WE CAN OF COURSE LEARN FROM
OTHERS THAT HAVE ONE IMMUNO
MODULATORY THERAPY AND THAT IS
PARTICULARLY IN CANCER
IMMUNOLOGY AND THE BIG BREAK
THROUGH CAME WHEN THE CANCER
IMMUNOLOGISTS BEGAN TO MAKE THE
IMMUNE SYSTEM STRONGER AND NOT
WEAKER.
SO WHEN THEY ARE NOT
IMMUNOSUPPRESSED BUT IMMUNO
ENHANCED AND I THINK WE NEED TO
BE VERY THANKFUL TO THEM THAT
THEY SHOWED US THAT THE NEGATIVE
SIGNALS IN THE IMMUNE SYSTEM ARE
PROBABLY MORE IMPORTANT THAN THE
POSITIVE SIGNALS.
BECAUSE THEY CAN'T STOP NEGATIVE
SIGNALS AND UNLEASH THE IMMUNE
SYSTEM.
SO I THINK THAT IS A DIMENSION
AM STEP THAT WE HAVE ALL TAKEN
AND THAT WE HAVE TO BRING TO THE
THERAPY OF OUR PATIENTS.
WE CAN ACTUALLY INDUCE
AUTOIMMUNE DISEASE IN PATIENTS
BY CHECKPOINT INHIBITOR AND WE
DO IT EVERYDAY AND THERE WILL BE
MORE AUTOIMMUNE DIS SIS THAN
SPONTANEOUS DISEASE VERY SOON.
IN TERMS OF MECHANIC AND WE ALSO
HAPPEN TO COME FROM THE MOTHER
SIDE SO THAT MAKES IT VERY
VALUABLE AND I THINK WE COULD BE
VERY MUCH MAKE PROGRESS AND IN
TERMS OF BASIC MECHANISMS I
THINK THE NEXT FRONTIER LIES AND
DNA PREPARE AND WE CAN REPAIR
THE DNA.
TERRIFIC.
>>NEXT, SCOTT.
I'LL FOCUS ON MONO TYPE.
AND THERE I THINK ACTUALLY WE
WENT INTO THIS WITH A STRONG
BIAS THAT WE WERE GOING TO SEE
ECONOMIST CHANGES AND WHAT THEY
HAVE SEEN RIGHT IN MONO TIGHT
AND MICROFAGES WE SAW I SHOWED
YOU SOME OF THE DATA AND WE ALSO
FOUND IN THE MICROGLIA THAT YOU
HAVE THE VERY REPRODUCE ABLE
MICRO DEAL AT YOU COMPLETE AND
IT COMES BACK WITH EX SEE THE
SAME SIGNATURE RIGHT AWAY AND WE
SEE THAT WE HAVE THESE NON SELL
OUT A CON US IN CHANGES INDUCED
BY ININFLUENZA INFECTION WHERE
WE DON'T HAVE INFLUENZA LIKE
SARS-CoV-2 WE DON'T HAVE
DIRECT INFECTION BUT WE SEE
THESE REPRODUCE ABLE CHANGES
THAT ARE REFERRING IN THE
MICROGLIA SO UNDERSTANDING HOW
THOSE CELLS, WHAT THOSE CELLS
ARE RESPOND TO GO IN THE MICRO
ENVIRONMENT THAT IS DRIVING THAT
AND HOW CAN WE SORT OF GO BACK
DOWN THE CHAIN OF CAUSALITY AND
TRYING TO FIGURE OUT WHAT IT IS
IN THE MICROENVIRONMENT INDUCING
THOSE CHANGES AND I THINK IT'S
REALLY GOING TO BE A BIG
CHALLENGE.
>>I THINK PIGGYBACKING ON WHAT
WAS SAID EARLIER WE'VE LEARNED A
LOT FROM T-CELL BIOLOGY FROM
CANCER AND I THINK WE CAN APPLY
A LOT THAT HAVE BUT I KEEP
COMING UP AGAINST THIS UNKNOWN
WHERE WE'RE SITTING AT CHRONIC
DISEASE THAT'S INFLAMMATION IN
THE MICE AND SFF FREE CONDITIONS
WE SEE THIS PCR EXPANSION AND
SUBSET AND WE SEE EXHAUSTED IN
DISEASE TYPE BUT WE DON'T REALLY
KNOW WHAT THE ANTIGEN IS AND
IT'S NOT CLEAR WHETHER THERE IS
A FUNCTIONAL ANTIGEN BUT IT
FEELS LIKE WE'RE AT THIS POINT
AND WE'RE THINKING BEYOND
FOLLOWING THESE INFECTIOUS
DISEASE MODELS AND CANCER MODEL
WHERE WE CAN ADAPT IT TO A
SPECIFIC DISEASE AND IT'S TAKING
THINGS FROM THE PERSPECTIVE OF
TREATING ALL AGING AND YOU CAN
TREAT ALL THE BUT KEEPING IN
MIND THAT MICROENVIRONMENT AND
THERE'S DIFFERENCES AND THE WAY
CELL FUNCTION AND SO, YEAH I
DON'T HAVE ANY CLEAR ANSWERS BUT
LOTS OF QUESTIONS.
>>I SOMEWHAT DISAGREE BUT WORE
READING FOR PRIME TIME AND
TREAT.
THE MORE I LEARN THE MORE
PUZZLED I AM AND THE REASON IS
THERE'S SO MUCH VARIABILITY,
RIGHT.
WHEN WE USE A COHORT HERE, AND
CONTINUE A PLAN FORM WE LEARN
SOMETHING AND IT'S AN ASPECT OF
AGING AND YOU DO SOMETHING
DIFFERENT, AND A DIFFERENT
COHORT AND A DIFFERENT DEM A
GREAT I HAVE AND A DIFFERENT
PLATFORM YOU HAVE A DIFFERENT
ASPECT THAT YOU ARE OPTION IN
THERE AND MAYBE OPPOSING RESULTS
SO I THINK THERE'S A MEAN TO
COORDINATE THE EFFORTS AND HAVE
A MUCH LARGER STUDY SO WE NEED
MORE MONEY.
I THINK THAT'S WHAT WE NEED.
MAYBE PEOPLE THAT WE COULD
FOLLOW BECAUSE VARIABILITY AGAIN
IS SO LARGE THAT YOU ARE JUST
CAPTURING A FEW ASPECTS OF THE
AGING PROCESS IN THIS SENSE.
THE OTHER IMPORTANT ASPECT THAT
I THINK IT'S PRETTY TOUGH TO
DISCUSS IS THAT WHEN WE DEVELOP
BIOMARKERS OF DERIVE BIOMARKERS
CLOCKS THEY OFTEN DISAGREE AND
THERE'S NOT A UNIFIED VERSION OF
IT AND I THINK THE REASON ALSO
COMES DOWN TO THERE ARE FACTSORS
THAT PROMOTE AGING AND FACTORS
THAT ARE BENEFICIAL THAT
INCREASE OR CHANGE WITH AGE AND
WE DON'T KNOW WHAT IS WHAT.
SO THERE'S THE BODY FIGHTING
AGING, RIGHT, AND THEN YOU HAVE
BIOMARKERS OF AGING AND THERE'S
THE AGING PROSPER SAY AND.
>>BEFORE I OPEN IT UP TO
QUESTIONS OR COMMENTS FROM THE
AUDIENCE, ONE THING I'D LIKE TO
BRING UP IS THE TITLE OF THIS
SESSION HAS THE WORD CROSSTALK
AND MULTI OR I GUESS IT'S ORGAN
IMMUNE SO I THINK THINKING ABOUT
WHAT IS GOING ON AGING WISE IN
ONE ORGAN AND HOW IT MIGHT
AFFECT ANOTHER ORGAN I THINK IS
A CRITICAL ELEMENT THAT WE NEED
TO CONTINUE TO EXPLORE AND FOR
THOSE OF YOU WHO ARE DOING
ANIMAL BASED STUDIES, THINK
ABOUT COLLECTING EVERY POSSIBLE
ORGAN YOU CAN THINK OF PUTTING
IT IN A FREEZER AND FINDING A
COLLABORATOR WHO WANTS TO PURSUE
THAT ORGAN BECAUSE IT REALLY
ACCELERATES THE OPPORTUNITY TO
BE ABLE TO SEE IF YOU SEE THE
SAME THING IN DIFFERENT ORGANS.
SCOTT MENTIONED MACROPHAGES AND
LUNG MACROPHAGES SUBSETS AND
MICROGLIA.
LOOKING AT THE GUT-BRAIN
CROSSTALK AND GUT-LUNG BRAIN AND
ANY OF THE OTHER THE HEART IS
IMPORTANT SOMEHOW TOO.
THINKING ABOUT HOW ALL THESE
ORGANS INTERACT BECAUSE WE ARE
ALL AT LEAST PHYSICALLY
CONNECTED WITH OURSELVES AND TO
CONTINUE ALONG THAT CONCEPT.
ALSO, ANOTHER THING THAT WAS
BROUGHT UP BY DANIEL IS TO THINK
ABOUT PEOPLE WHO ARE DOING SOME
OF THESE MODELS IN YOUNG MICE
THAT ARE NOT PARTICULARLY
RELEVANT TO AGING.
LOOKING AT AGENTER OWE SCLEROSIS
IN A 12-YEAR-OLD IS HAPPENING IN
AMERICA BECAUSE OF OUR DIET BUT
IT MAY NOT BE AS POTENT OR THE
SAME AS THE AGENTER OWE
SCLEROSIS OF A SUBJECT.
>>THIS IS AN EXCELLENT POINT
AND IN DATE THE COMMUNICATION
BETWEEN DIFFERENT ORGANS,
BETWEEN LET'S SAY THE BONE
NARROW AND THE TESTING THESE ARE
CRITICAL THINGS AND THIS IS A
RELEVANT WITH THE ESSENTIAL
REDUCTION OF IMMUNE RESPONSE
WITH HOW WE RESPOND TO INFECTION
AND WITH ALL DUE RESPECT TO THE
IN VITRO MODELS WHICH ARE
SOPHISTICATED LIKE THE
ORGANOIDS, HOW DO YOU ADDRESS
COMMUNICATION BETWEEN DIFFERENT
ORGANS WHEN YOU USE ORGANOIDS?
BY PUTTING THEM SIDE BY SIDE?
THIS DOES NOT HAPPEN.
THE CLINICAL SAID YEAH, IF
THEY'RE USED CORRECTLY.
THEY'RE NEEDED 100 IN BIOMEDICAL
RESEARCH AND THE POINT IS IT TO
FIND THE RELEVANT MODELS TO USE
AND REFRESH NO MODEL CAN
CAPITULATE THE HUMAN DISEASE AND
IT CAN BE USED TORR SPECIFIC
HYPOTHESIS AND IF THEY'RE USED
WISELY THEY'RE USED FOR US.
>>THAT'S AN EXCELLENT POINT.
WE HAVE THREE MORE MINUTES.
AND ANYBODY FROM THE AUDIENCE
WANT TO SAY ANYTHING?
YES,.
>>I WANTED TO COMMAND ON THE
TIME SCALE OF THE EXAMINATION
AND I THINK THAT IT'S VERY
IMPORTANT.
THE MAJOR BREAK THROUGH IN ALL
AUTOIMMUNE DISEASES HAS BEEN THE
RECOGNITION THAT BY THE TIME THE
PATIENT COMES TO US, THEY HAVE
BEEN QUOTE SICK FOR 30 OR 40
YEARS.
I THINK THAT IS VERY IMPORTANT.
WE NEED TO START STUDYING AGING
IN THE YOUNG.
>>THANK YOU.
VERY INTERESTING.
I THINK THERE'S A BASIC THING
THAT I DON'T THINK ANYONE HAS
TOUCHED ON WHICH IS THINGS CAN
FALL APART IN SO MANY DIFFERENT
WAYS AND FROM WHAT EXTENT IS
THERE OVER ALL AGING PROGRESSION
DRIVEN BY WHAT?
AND WHAT EXTENT ARE JUST
DIFFERENT ORGAN SYSTEMS BREAKING
DOWN MAYBE BECAUSE OF THE
MUTATIONS?
I THINK IT'S A MIXTURE BUT I
DON'T KNOW AND I THINK YOU HAVE
TO LOOK ALMOST LOOK AT THIS IN
CROSS MICE NOT BLACK SIX MICE
BECAUSE BLACK MICE YOU LOOK AT
ONE GENOTYPE.
HUMANS AND OF COURSE ALSO WORK.
AND THEY AGE IN DIFFERENT WAYS
AND THEY AGE IN DIFFERENT RATES
CLEARLY AND SO THERE'S A LOT OF
CLUES THERE AND I THINK THAT A
LOT OF QUESTIONS THAT ARE
DIFFICULT TO ANSWER BUT I THINK
PEOPLE SHOULD GET AND THINK
ABOUT THEM.
>>I THINK THAT COMES DOWN TO
COLLABORATION.
WE HAVE A COUPLE MORE QUESTIONS.
>>SO I WAS JUST GOING TO ADD TO
WHAT DAVID MENTIONED ABOUT THE
NEED FOR -- I MEAN ALWAYS MORE
FUNDING BUT DIFFERENT FUNDING.
ONE OF THE THINGS THAT WE
PROBABLY CANNOT DO IS MASSIVE
CLINICAL TRIALS.
WE CAN DO SMALL PRAGMATIC WITH A
WHOLE BUNCH OF THINGS THAT AS
LONG AS THEY'RE SAFE AND WE
STUDIED THEM IN DEPTH WITH
EVERYTHING ELSE SO WE SHOULD BE
ABLE TO LEARN A LOT ABOUT THE
VARIABILITY AND WHAT IS NOISE
AND WHAT IS SIGNAL.
>>VERY IMPORTANT.
LAST QUESTION.
>>YES, I WANT TO FORMATION ON
ORGAN AND COMMUNICATION NIA HAS
WRITTEN ON THIS RESEARCH AND WE
SEE A GREAT GAP ON THAT AREA AND
WE PUT AN RECENTLY AND SOME OF
YOU MAY HAVE SEEN THAT AND RFA
ON THE UO1 ON ENTERSER ORGAN
COMMUNICATION DURING AGING AND
WE COULD BE CLOSING BY
JUNE 3rd AND.
>>SO HURRY UP AND WRITE YOUR
APPLICATION.
>>OKAY.
THAT LAST THING.
>>I JUST WANT TO ECHO SOME OF
THE COMMENTS BEFORE.
I MEAN, ONE OF THE THINGS THAT I
THINK IS IMPORTANT THAT WE USE
THE RESOURCES WE HAVE A LITTLE
BIT BETTER AND WE HAVE
ELECTRONIC HEALTH RECORDS NOW IN
ALL OF OUR FEDERAL CENTRES.
THE DATA COMING OUT OF THEM ARE
A MESS AND THEY'RE DIFFICULT TO
USE AND I THINK ORGANIZATION
WE'LL HAVE A BIG EXPERIMENT
WHERE WE PUT PEOPLE AND WE'LL
LOOSE A LOT OF WEIGHT AND SEE
WHAT HAPPENS AND WE'RE GOING TO
MISS IT BECAUSE WE'LL HAVE NO
WAY TO LOOK AT THOSE MEDICAL
RECORDS AND TO SEE WHAT IS GOING
ON AND ALSO MAKES IT DIFFICULT
TO DO WHAT WE'RE DOING WHICH IS
TAKING SAMPLES GENERATED IN
CLINICAL CARE AND INTEGRATING
THEM WITH PATIENTS IS REALLY
IMPORTANT TO UNDERSTAND THE
GENEITY AND THE NIH TO MAKE
COMMENTS AND MAKING ELECTRONIC
HEALTH RECORDS MORE ACCESSIBLE.
>>THAT'S TERRIFIC.
I WILL CLOSE THIS DISCUSSION.
THANK YOU EVERYBODY FOR WHO
SPOKE.
LONG DISTANCE AND LOCALLY.
AS WELL AS QUESTIONS.
ALSO, WE HAVE, WE NEED TO BE
BACK HERE AT 4:40.
SO IT'S TIME FOR THE LAST
SESSION OF THE DAY AND CHRISTINA
CAMEL FROM THE UNIVERSITY OF
MINNESOTA AND I WILL CO-CHAIR.
MY NAME IS MAYA MAREK AND I'M A
PROGRAMME OFFICER AT THE
DIVISION OF NEUROSCIENCE AT NIH.
SO APPROPRIATELY AS OUR BRAINS
ARE SHUTTING DOWN THIS LATE, THE
THIRD SESSION WILL BE ABOUT
NEURO IMMUNE PASS WAYS AND
NEURODEGENERATIVE DISEASES AND I
ALSO WANT TO REMIND THE
PRESENTERS 15 MINUTES.
I WILL TRY TO KEEP YOU IN LINE
WITH SOUND REMINDERS.
13 MINUTES AND THEN TWO MINUTE
AT THE END.
SO CHRISTINA --
>>LET ME GO AHEAD AND INTRODUCE
OUR FIRST SPEAKER IT'S GOING TO
BE SAUL VILLEDA FROM UNIVERSITY
OF CALIFORNIA OF SAN FRANCISCO
WHO WILL TALK TO US ABOUT
SYSTEMIC MECHANISMS OF BRAIN
REJUVENATION.
>>GREAT.
GOOD AFTERNOON, EVERYONE, FIRST
OF ALL THANK YOU FOR THIS
MEETING.
I'VE LEARNED A LOT.
FULL DISCLOSURE I'M A
NEUROSCIENTIST BY TRAINING AND
ONE SPEAKER SAID EVERYTHING
AGING LEADS TO IMMUNOLOGY AND
HERE I AM AT THIS WORKSHOP.
I GOT WITH OH NO, HERE IS THIS.
OKAY, MAYBE.
WELL, BIG PICTURE AND IF NOT I
WILL JUST SAY NEXT 400 TIMES,
WHAT WE ARE INTERESTED LONG TERM
VISION OF THIS IDEA OF REVERSE
ABILITY AND SO NOT JUST HALTING
AGING BUT WAYS WE CAN TAKE AN
ALREADY OLD BRAIN AND SOMEHOW
BRING IT BACK TO YOUTH AND FOR
MY PERSPECTIVE THAT'S ABOUT
FUNCTION.
SO I FOCUS ON -- IT'S OKAY.
LEFT SIDE.
HERE.
THERE WE GO.
OKAY.
FUNCTIONS.
SO, THE WAY WE DEFINE
REJUVENATION IN IN LAB IS CAN WE
REVERSE THAT COGNITIVE DECLINE
WHETHER IT'S BY ENGAGEMENT
MECHANISMS CHANGE IN AGING OR BY
ENGAGING PARALLEL MECHANISMS
WHERE THE END RESULT IS ROSS
TORRATION OF COGNITION.
WE THINK THIS IS IMPORTANT IS
YOU KNOW, AS WE GET OLDER AND
USUALLY THE TOPPINGS AREN'T
RETIREMENT AGE YOU SEE SOME
SIGNS OF COGNITIVE DECLINE.
AND THAT TRAINING IS ASSOCIATED
WELL WITH INCREASE THE RISK OR
NEURODEGENERATIVE DISEASES WHAT
WE THINK ABOUT IS ALZHEIMER'S
AND NOW THE IDEA IS THERE ARE
NORMAL MECHANISMS FOR EXAMPLE
SOMEONE THAT IS 20 DOES NOT HAVE
OVERT PATHOLOGY OF ALZHEIMER'S.
EVEN WITH GENETIC
PREDISPOSITIONS WHICH MEANS WE
CAN LEVERAGE BIOLOGY OF AGING TO
UNDERSTAND WHAT ARE MECHANISMS
THEN THAT CAN MAINTAIN FUNCTION
OR EPIDEMIOLOGY RESTORE
FUNCTIONS.
WHETHER THEY ARE SYSTEMIC OR
BLOOD BASED INTERVENTIONS AND
THE WHOLE IDEA IS BY LEVERAGING
THOSE MECHANISMS WE CAN BRING
BACK THE STATE THAT WE HAVE
EARLIER ON THAT NATURALLY WAS
ABLE TO STAVE OFF THIS DISEASE
AND THAT'S WHAT WE FOCUS ON IN
THE LAB.
WHAT DO I MEAN BY COGNITIVE
DECLINE.
I LOVE THIS EXAMPLE JUST BECAUSE
IT'S A PARKING LOT AND AT LEAST
IN CALIFORNIA WE ALL DRIVE.
I'M TAKING TRAINING HERE AND SO
LET'S PRETEND WE'RE DRIVING AN
ELECTRIC CAR AND YOU COME IN IN
THE MORNING AND YOUR JUST
NATURALLY GOING TO LOOK AT
COMPUTERS IF APPROXIMATE YOU
HAVE THE GOLDEN GATE BRIDGE YOU
CAN GET THE END OF THE DAY NO
PROBLEM YOUR BRAIN IS LIKE YOU
LIKE THAT VIEW SO GO FIND YOUR
CAR NEAR THAT.
AS YOU GET OLDER YOU CAN'T DO
THIS SO WELL ANYMORE.
THAT'S BASICALLY ONE TYPE OF
COGNITIVE DECLINE.
SPACIAL LEARNING AND MEMORY
BECOMES IMPAIRED.
NOT ALL COGNITIVE DECLINED BUT A
VAST MAJORITY OF THEM DO.
WHAT WE DO IS WE THEN USE THIS
BECAUSE IT'S THE SAME TYPE OF I
REMEMBER AMOUNT.
AS ACROSS SPECIES AND WE FOCUS
ON THE MOUSE PODAL AND THEY'RE
GOING IN DIFFERENT DIRECTIONS SO
THEY'RE MAKING ERRORS AND THEY
FIND LIKE AN ELDERLY PERSON WILL
FIND THEIR CAR AND BEHAVIOURAL
TASK TO ASK WHAT'S PROMOTING
DECLINE OR ALREADY OLD ANIMAL
WITH REMOTING RECOVERY OR
IMPROVEMENT.
WE'VE HEARD THIS ON ONE PART OF
THE BRAIN.
A REGULATE OR OF LEARNING IN
MEMORY AND HERE IT'S JUST
HIPPOCAMPUS NOW WHAT IS
INTERESTING IT'S ONE OF THE
FIRST PARTS OF THE BRAIN
IMPACTED BY AGING SO IT'S A
REGION AND THERE'S A SERIES OF
CELLULAR HALLMARKS THAT WE
UNDERSTAND TO CONTRIBUTE TOWARDS
THAT COGNITIVE DECLINE.
FOR EXAMPLE, THINGS LIKE
REGENERATION, STEM CELL FUNCTION
GOES AWAY AND WE KNOW THAT THE
COMMUNICATION BETWEEN THE
NEURONS AND THE DECLINES AND ONE
IS REALLY EMERGING A LOT IS THE
IDEA OF NEUROINFLAMMATION BOTH
WITHIN THE BRAIN AND IT'S GLEIA
OR MICROGLIA AS WELL AS ALSO
INFILTRATING CELLS IN THE
CONFLICT OF DISEASE AND THE
OTHER ONE THAT THERE'S MORE AND
MORE EVIDENCE NOW FOR A REAL KEY
ROLE WOULD BE THE VASCULAR WHERE
WE'LL HEAR ABOUT IN TERMS OF
BLOOD BRAIN BARRIER AS WELL.
TODAY MY LAB LOOKS AT ALL OF
THESE DIFFERENT HALLMARKS AND
TODAY I WANT TO SHARE ON THE
NEUROINFLAMMATION COMMENT WITHIN
THE HIPPOCAMPUS AND THE INTRA
PLAY.
SO I WAS DOING SO WELL FOR SO
LONG.
SO I MENTIONED, IN MY LAB WE
FOCUS ON INTERVENTIONS WHEN WE
FIRST BEGAN IN THE LAB WE
FOCUSED ON CONNECT THE YOUNG AND
OLD ANIMAL AND WE SHOWED THAT
THERE'S AGING FACTORS A LOT OF
IMMUNE FACTORS PROMOTING AIMING
SO WE SAW SAW THE CONVERSE
THERE'S SOMETHING IN YOUNG BLOOD
THAT RESTORES FUNCTION AND WE
SHARED IT IN NEURONS AND ON
REGENERATION ALTHOUGH UP UNTIL
THIS POINT WE DID NOT LOOK INTO
NEURO AND OUGHT WRACK WE'VE BEEN
DOING SO THIS IS NOW ALMOST A
DECADE AGO THAT WE SHARED YOU
REQUEST CORRECT THE PLASMA AND
IT'S MOSTLY DESTROYED OF CELLS
AS WE DISCOVERED NOT COMPLETELY
DESTROYED OF CELLS AND YOU DO
THE BEHAVIOUR AND WHEN YOU COME
BACK A MONTH LATER AFTER THESE
TREATMENTS IN GRAY YOU SEE A
NORMAL OLD ANIMAL RECEIVING OLD
PLASMA THEY'RE ABOUT
TWO-YEARS-OLD AND EQUIVALENT TO
SOMEONE IN THEIR 70s AND WHEN
YOU GIVE THIS OLDER AND LITTER
MATES THIS CASE, OLD ANIMALS AND
YOU GIVE THEM IN RED IT'S A HUGE
SEPARATION WHERE THE ANIMALS ARE
MAKING LESSER OR.
THEY'RE GUIDED DIRECTLY TOWARDS
THAT POPCORN.
SO WE KNOW THAT THERE'S
REVERSION ABILITY AND WE THOUGH
THERE'S SOMETHING IN YOUNG
BLOOD.
AND WE HAVE NOW SPENT A LONG
TIME TRYING TO FIGURE OUT THE
CELLULAR MECHANISMS THAT ARE
PROMOTING THAT RECOVERY THAT
REJUVENATION AND WE HAVE TO GIVE
CREDIT TO A VERY TALENTED
POSTDOC WHO IS REALLY
SPEARHEADED THE RESEARCH THAT
I'M ABOUT TO SHEAR WITH YOU.
SO FIRST THING WE DID IS WENT
BACK AND JUST FOCUSED ON THAT
SORT OF YOUNG AND AGED PLASMA.
THIS IS ABOUT 20 TO 22 MONTHS
OLD VERSUS ABOUT THREE TO FOUR
MONTHS AND WE DIDN'T ASK THIS IS
UNI BELIEVED AND WE ASKED WHAT
BIOLOGICAL PROCESS ARE CHANGING
BASED ON THE CHANGES WE SEE IN
THE SOL YOU ABLE FACTORS IN THE
TOP IT WAS CHANGES IN PLATELETS
AND WE WENT BACK AND THE FIELD
USE AND WE WERE AMONG THE FIRST
THAT DID THIS WE ENDED UPTAKING
PLATE LATE AND OF THE CONTROL,
THE YOUNG PLASMA AS WELL AS THE
AN MEALS RECEIVING THAT AND WE
PHOTOGRAPHIC YOU USED ON THE
QUEEN'S THAT WERE CONSERVED
BETWEEN BOTH AND THERE WERE
ABOUT 200 OUT OF 600 IN CASE
CASE AND WE LOOKED AT THE LIE
LOGICAL PROCESSES ASSOCIATED
WITH THAT WE SAW CENTRAL NERVOUS
SYSTEM DEVELOPMENT INDICATIVE OF
THAT PLASTICITY OR REGENERATION
WHICH WE SHOWN TO BE IMPACTED BY
AND WE SAW THINGS LIKE A LOT OF
CHEMO SIGN 123458ING POP UP AND
WE HAD NOT YET LOOKED INTO
NEUROINFLAMMATION SO IT COULD BE
IT'S YOUNG PLASMA COULD EXTEND
TO THE NEUROINFLAMMATION
HALLMARKS OF AGING SO WE THOUGHT
NEXT WORK AND AGAIN BROADLY JUST
YOUNG PLASMA AS WELL AS THAT
YOUNG FRACTION FIRST WE JUST
LOOKED AT SOME MARKERS THAT
CHANGES AGE AND IT'S TMS AND
TD11B AND SAW A REDUCTION
COMPARED TO THAT OLD ANIMAL AND
AND REDISCUSSION WE RESIDENT AND
MAKE OWE PAGES AND MIKE GLIA
WHICH IS WHEN THESE PEOPLE ON
THE WILL SAY ACTIVATED AND I'M
JUST GOING TO RESPONSE WITH BUT
WITH AGING WE KNOW THERE'S ANNA
ACCUMULATION OF CDC CA HAD WE
TREAT THESE ANIMALS WITH YOUNG
PLASMA OR PLATELET FRACTION SO
WE GOT EXCITED WITH THAT AND MY
LAB WE'D LIKE TO TAKE A
REDUCTION APPROACH AND GO FROM
BIGGER TO SMALLER SO WE FOUND
COMPARE BIAS TO PLASMA AND
PLASMA TO INFRACTION WHAT IS
LEADING TOWARDS THESE
ATTENUATION AND MICRO GLEE OWE
MARKERS AND SO WHAT WE ENDED UP
DOING HERE IS TAKING APPROACH
AND WE DID ADDITIONAL PROTEOMIC
AND WE SAW THE PLATELET FRACTION
WHAT IS HAPPENING BETWEEN THAT
PLATELET FRACTION IN THE END AND
THE TECHNICAL REASONS AND
LIMITATIONS AND IT'S REALLY WE
PULLED A LOT OF ANIMALS INTO ONE
GROUP AND SO I'M ONLY LISTING
ONE FACTORS BUT THIS IS JUST
PULLING A LOT INTO ONE WHERE WE
HAD ONE CHANCE AT IT BASICALLY.
WE SURVEYED THE FACTORIES THAT
WE HAD AND WHAT WAS REALLY
INTERESTING IS THAT THERE'S ONE
FACTOR THAT HAD APPEARED AND
BEEN ASSOCIATED WITH ADDITIONAL
INTERCEPTIONS BUT NO ONE LOOKED
AT IT FUNCTIONALLY AND BOTH
EXERCISING IN YOUNG ANIMALS AND
CXCL4 IT'S ELEVATED IN YOUNG
ANIMALS AND ASSOCIATED WITH
INCREASE NEURO GENESIS IN THE
BRAIN WHEN YOU ACTUALLY REPLACE
450RE 50 OFBLOOD WITH OLD ANIMAE
AN INCREASE IN ASSOCIATED WITH
SOME OF THE IMPROVEMENT THAT'S
THEY SAW ON THAT MODEL SO WE
THOUGHT THIS WAS INTERESTING
IT'S ONE FACTOR THAT APPEARS
ACROSS DIFFERENT INTERVENTIONS
AND WE ARE PERSUADE IT
FUNCTIONALLY.
THE FIRST WE DID IS JUST LET
THAT PLATELET FRACTION AS WELL
AS THE PROBLEM ITSELF AND YOU
CAN SEE THERE'S A DECREASE ON
THE VARIABLE WITH AN AGE RELATED
DECREASE IN OUR PREPARATIONS AND
WE HAVE ACCESS TO HUMAN SAMPLES
SO WE RECRUITED AROUND 20 YOUNG
INDIVIDUALS BETWEEN 22 TO 34 AND
THEN ABOUT 20 OLDER INDIVIDUALS.
ACTUALLY 16 IS THE ACTUAL
NUMBER.
AND AGAIN THIS IS A CASE WE
LOOKED AT PLATELET RICH PLASMA
AND WE SORT OF SAW THIS DECREASE
WITHIN AGAIN THIS PLATELET RICH
PREPARATION THAT WE HAD.
SO FROM THERE WE WANTED GO INTO
THE ONE MARK.
WHAT IS IT WE CAN DO JUST HERE.
WHEN WE SORT OF SYSTEMICALLY
ADMINISTERED IT BEFORE THE INTRA
VENUS INJECTIONS WE LOOK AT THE
READ OUT AND AGAIN SIMILAR TO
PLASMA AND PLATELET FRACTION WE
SEE IT IN TNF AND WE LOOKED AT
IL AND BETA AND AGAIN WE LOOKED
AT THAT CD68 AS A MARKER AT A
SEM YOU LAR LEVEL AND WE SAW
REJECTION SO IT'S JUST INJECTION
THAT IN INNU EIGHTING THEIR I AM
FLEW INDICATION AND WE ISOLATED
THE MICROGLIA FROM ANIMALS THAT
WERE ADMINISTERED AND WE DID RNA
SEQUENCING AND WE LOOKED AT THE
QUEEN'S THAT WERE DECREASED,
FOLLOWING ADMINISTRATION, WE SAW
A LOT OF TNF MEDIATED SIGNALING
PATHWAYS THAT WERE DECREASING
AND IT SEEMED TO BE TARGETING
SOME OF THESE SIGNALING WITHIN
THE MICROGLIA.
THE NEXT QUESTION WHEN YOU THINK
ABOUT THE BRAIN BECAUSE WE HAVE
BLOOD BRAIN BARRIER YOU ARE
GETTING IN FROM THE BLOOD OR
IT'S IMPACTING THE PERIPHERY AND
THE PERIPHERY HAS AN IMPACT ON
THE BRAIN AND WE WANTED TO
PURSUE THAT PARTICULAR IDEA.
SO WE MADE A FORM OF THAT WE
COULD OVER PRESS INTO THE RIVER
THAT HAS A HYBRID TAG THAT WHEN
EXPRESSED, THEY HAVE THE HUMAN
INNES ENTRY ACTION AND WHEN OF
COURSE THEN YOU HAVE TO GO WHAT
IS IT WE WENT AND ASKED WHAT
CHANGING AND WHEN WE LOOKED AT
THE SORT OF FACTORS IN BLOOD
THAT WERE BEING LOWER IN THE PF4
TREAT AND THE CONTROL, WE SAW A
LOT OF THINGS THAT WERE INVOLVED
IN SORT OF INFLAMMATORY
RESPONSES AND WE WERE SEEING A
DECREASE IN FACTORS ASSOCIATED
WITH INFLAMMATION.
SO THAT PROMPTED US TO GET A
LITTLE BIT MORE OF A PERSPECTIVE
ON WHAT IS HAPPENING TO THE
IMMUNE SYSTEM IN THESE ANIMALS
FOLLOWING PM4 ADMINISTRATION WE
DID RNA SEQUENCING WHERE YOU
HAVE CON GRA JAYED WITH NUCLI
OWE TIED SO YOU CAN GET
TRANSCRIPTIONAL CHANGES WITHIN
THE CELL AND DETECT THE SURFACE
INVESTIGATION ON THE SURFACE AS
A NEUROSCIENTIST COMING INTO THE
IMMUNOLOGY RNA AND DO NOT LIKE
MATCH IN THIS PARTICULAR PART OF
THE BODY SO WE JUST HAD TO TAKE
THIS APPROACH.
I IT GIVE YOU HIGHLIGHT WE
LOOKED AT THE EXPRESS IN AND YOU
WILL NOTICE THERE'S THIS AGE
RELATED TRANSPORTATION PROFILE
THAT EMERGING THAT IS IN PART
REVERSE IN THESE TREATED ANIMALS
AND WHEN WE LOOKED AT THE
RELATIVE POPULATIONS AND TO
MACROPHAGES YOU HAVE TWO MINUTES
LEFT?
WE LOOKED AT THE MACROPHAGES YOU
WILL SEE THAT IF YOU LOOK AT THE
LINE ZERO IT IS YOUTHFUL LEVELS
AND INCREASE IN THE MACROPHAGE
POPULATION THAT IS BROUGHT DOWN
CLOSER TO YOUNGER LEVELS AND IF
WE LOOK ALTERNATIVELY, AT T
CELLS WHICH IS WHAT I'M
HIGHLIGHTING HERE YOU HAVE THIS
AGE RELATED TRANSCRIPTIONAL
CHANGES YOU SEE IN PART REVERSE
I WILL HIGHLIGHT THE AGE
ASSOCIATED AND THE POSITIVE AND
THEN A HIGH INCREASE JUST LIKE
WE HEARD ABOUT IN A COUPLE OF
TALKS BEFORE AND THOSE LEVELS
ARE BROUGHT DOWN FOR EXAMPLE IF
YOU LOOKED AT NAIVE DETAILS
THOSE ARE A DECREASE AND THAT
DECREASE IS IN PART AND
FOLLOWING THIS ADMINISTRATION
AND AGAIN SUGGESTING THAT WE'RE
GETTING CLOSER TO A YOUNGER
COMPETITION AND THEY'RE LOOKING
AT REFLECTIVE OF A YOUNGER
CONTINUE AS WELL.
SO JUST BIG PICTURE.
YOU KNOW, A LOT OF WORK THAT HAS
DONE FOR RECONSTITUTION IS THE
OLD AND YOUNG HAVE SHOWN THAT
THE PERIPHERAL IMMUNE SYSTEM CAN
IMPACT COGNITION AND BEAUTIFUL
WORK THAT YOU WILL HEAR ABOUT
MORE TOMORROW AND SHOWED
TARGETING METABOLISM WITHIN THE
AGE CAN IMPROVE COGNITION AND WE
THOUGHT WE HAVE AN INTERVENTION
HERE THAT IS CHANGING
NEUROINFLAMMATION IN THE BRAIN
AND CHANGING I OBJECT FROM
MISSION COULD IT BE THAT
FUNCTIONING IS REFLECTIVE IN
IMPROVED COGNITION.
WE WENT BACK I HAVE TO SPEND
WITH BEHAVIOUR BECAUSE I AM A
NEUROSCIENTIST AND IN BLACK IT'S
AN OLD ANIMAL CREATED WITH
CONTROL AND IN BLUE OLD ANIMAL
TREATED SYSTEMICALLY AND YOU CAN
SEE THE NUMBER OF ERRORS BY THE
NUMBER OF TESTING IS IMPROVED SO
AGAIN, WE KNOW INTERESTED
ADDITIVE MECHANISMS AND IT DOES
NOT ACCOUNT FOR THE BLOOD BUT WE
THINK IT'S ONE QUITE POTENT
FACTOR THAT WE'VE IDENTIFIED.
WITH THAT, WE FOUND AN
INTERESTING ROLE FOR LATE LET'S
AND DIFFERENT INTERVENTIONS AND
EXERCISES DELIVER FACTORS SO
THEY'RE ALL THERE AND SORT OF
BIG QUESTION WHAT ARE THINGS
THAT ARE A GAP I HOPE THE
INTERACT AND COMMUNICATION
BETWEEN NEUROSCIENCE AND
IMMUNOLOGIST GETS BETTER BECAUSE
WE'RE THINKING A LOT ABOUT
MICROGLIA, GLIA, INFILTRATION,
NOT SO MUCH NECESSARILY ABOUT
HOW IS THE PERIPHERAL IMMUNE
SYSTEM HAVING HUGE IMPACTS ON
FUNCTION WITH WITHOUT
NECESSARILY THOSE FACTORS
GETTING IN AND THERE MUST BE
THAT WAY AND WE'RE STILL TO
FIGURE THOSE OUT.
WITH THAT I'LL TAKE THAT.
>>ALL THE ACKNOWLEDGMENTS
FUNDING AND THANK YOU NIH.
>>THANK YOU.
>>SO THE CORRECTED AND WHEN YOU
SUBSTITUTE BLOOD AND TF4 GOES UP
DID YOU THAT THAT?
>>YOU ARE IN A CONVOY AT
BERKELEY AND THE INTERVENTION
SHE'S DONE AS WELL AND THEY DID
PROTEOMIC THEY DID SEE A LOT OF
THINGS GO DOWN AND THINGS
STEPPED UP OF WHICH IT'S ONE OF
AND EXERCISE.
>>HOW DO YOU IMAGINE.
>>THESE ARE INVOLVED IN WOUND
HEALING IT'S LIKE A WOUND
HEALING RESPONSE AN ANDED WE ARE
ENGAGING THOSE MECHANISMS.
>>IN THE LAST SLIDE YOU SHOWED
WHICH YOU SHOWED PREVIOUSLY, WAS
THE 99 DAYS AND HOW LONG TUESDAY
THAT LAST AND IF YOU ADD MORE
PLAS THAT CAN YOU GO LONGER OR
GIVE MORE DETAIL?
>>PEOPLE HAVE DONE IT AND WE'VE
DONE SOME OF IT AND IF YOU
SEPARATE THEM IN TISSUE LIKE
MUSCLE YOU CAN ASSOCIATE SIX
MONTHS LATER AND WE'VE DONE
COGNITION BY THREE MONTHS AND
THERE'S STILL KIND OF A TREND
BUT THE VARIABILITIES IS MUCH
HIGHER IT DOES DECAY.
I DON'T THINK WE'VE BOOSTED THE
FACT BEFORE AND WE'VE DONE IT
WITH LIVER ENZYMES TA WE FOUND
IN EXERCISE AND THAT WE CAN
BOOST OR MAINTAIN THE EFFECT FOR
LONGER.
BUT IT DOES WAIN.
>>THAT WAS GREAT.
I JUST WANTED TO SAY THERE'S
THIS OLD DATA THAT SUGGESTS THAT
IT'S ACTUALLY INCREASE IN THE
CONTEXT OF AGE AND SO IS THIS A
MATTER OF A DIFFERENT
PREPARATION OF PLATELETS OR.
>>THAT'S A GREAT QUESTION.
SO IN A LOT OF, I GET THESE
BECAUSE ACTIVATION AND THERE'S
AN INCREASE NUMBER OF ABOUT WE
LOOKED.
ALL OF THESE INDIVIDUALS THAT WE
GOT ARE HEALTHY SO THEY'RE
EXCLUDEDDED ANYTHING AND THE
WHAT IS IT IN THE PREPARATION
AND WE TRY AND FIGURE OUT WHAT
IS IT AND WHAT ARE WE PUTTING
THAT INTO IT THAT MIGHT HAVE AN
EFFECT AND WHEN WE MEASURED IT
HOWEVER IN WE DID SEE A DECLINE
IN SORT OF THAT PRP LEVELS AS
WELL.
THERE'S EVIDENCE THAT IS SHOWN
THAT IF YOU INCREASE AT LEAST A
CERTAIN LEVELS, WHEN IT'S A
MONEY MER VERSUS A DIMER IT CAN
HAVE NEGATIVE AND POSITIVE
EFFECTS AND THE CREASE IS THE
LOWER LEVEL WHICH HAS BEEN
SHOWING THE LITERATURE TO IMPACT
THINGS LIKE T CELLS AND PREVENT
THAT ACTIVATION O IT'S
CONSISTENT.
I DIDN'T SHOW RECEPTORS STUFF
WEAN DONE ON T-CELL THAT MEDIATE
PART OF IT FOR KINE BUT THAT'S
HOW WE SEE IT.
>>YOU ARE ASKING HOW WE LOOKED
AT CONDITIONS IN WHICH LEVELS
ABOUT DOWN AND WHAT WOULD BE THE
IMPACT OF THAT.
WE'VE DONE THE PLATELET BEFORE
KNOCK OUTS SO WHEN YOU DO THE
KNOCK OUT AT YOUNG AGES,
NOTHING, THERE'S THEY'RE FINE IT
SEEMS LIKE IT'S INVOLVED IN
RESILIENCE OR PROTECTION RATHER
THAN HOMEOSTATIC CONTINUE AND IT
WILL PLAY A ROLE IN THE HUMAN
CONTINUE IF YOU ARE UNDER
HOMEOSTATIC VERSUS WHAT THE
CONDITION.
>>HAVE YOU LOOKED AT PHENOTYPES
DO YOU SEE REDUCED ASSOCIATED
MICROGLIA WITH AGING AND THERE'S
AN IMPLICATION IN AGING YOU CAN
SEE WITH THAT GAIN OR LOSS
FUNCTION?
>>GOOD QUESTION.
LET ME START FIRST WITH T-CELL
BECAUSE IT'S INTERESTING.
WHEN WE LOOKED AT LET'S SAY
INFILTRATION, WE'VE SEEN IT A
LOT ON THE VENTRICLES WHERE
THERE'S CSF SORT OF DEPRESSION
AND YOU COMPLETE THEM AND YOU
START GETTING DOWN TO THE HIM A
CAMPUS WE DON'T SEE THAT THEY'RE
REDUCING IT SO THEY'RE
MAINTAINING IT AND WHEN YOU LOOK
AT THE SEVEN ON THERE LIKE GANG
BUSTERS EVERYWHERE SO THE
MECHANISMS WHICH INFILTRATING IN
AN AREA LIKE THE VENTRICLES
VERSUS A DEEP AREA LIKE THE TIP
A CAMPUS IS DIFFERENT.
WE JUST DID BOTH WITH THESE.
THANK YOU VERY MUCH FOR THAT
PRESENTATION.
I WOULD LIKE TO INTRODUCE THE
NEXT SPEAKER FROM BAYLOR COLLEGE
OF MEDICINE AND WE'LL TAKE ABOUT
THE BRAIN BLOOD BARRIER AND
VASCULAR BETT BEAR YEAR FUNCTIO.
ALL RIGHT.
I WILL CONTINUE WITH THE NEW
THING TO TALK ABOUT THE AGING
AND THE DISEASES OF THE CENTRAL
NERVOUS SYSTEM AND I
SPECIFICALLY RELATED TO THE
COMPLIMENT SIGNALING IN THE
AGING AND ALL THE THEM AND SO,
ALL THE IS THE MOST COMMON FORM
OF THE AIMING RELATED WITH TWO
PATHOLOGICAL PAUL MARK ONE IS
THE EXTRA CELLULAR AND INTRA AND
SINGLE AND DECIDE THOSE
PATHOLOGICAL HALLMARKS, IT'S
KNOWN THAT THE DISEASE IS THE
ACCOMPANIED BY THE HYPER
ACTIVATION ON THE THREE OF THOSE
AND IN PARTICULAR THE EXERCISE
AND THE MICROGLIA THAT IS MARKED
BY THIS GFAP AND RESPECTIVELY
YOU CAN COMPARE TO THE NORMAL
THOSE ASSOCIATED WITH THIS IS
ASSOCIATED WITH INCREASE
PRODUCTION OF OUR CYTOKINES AND
THE RECENT ASSOCIATED STUDY THAT
DEMONSTRATED A IMAGINE ON COP
CONTRIBUTING ROLE OF THOSE
IMMUNE SYSTEMS AND ALSO LOOKING
AT METABOLIC PATHWAYS IN THE
LATE ONSET OF ALZHEIMER'S
DISEASE.
AND FOR EXAMPLE, THE FOR ALLELE
IS A RISK FACTOR FOR DISEASES
AND IT'S EXPRESSED IN EXERCISE
AND IT LIPID AND CHOLESTEROL
METABOLISM.
AND IT'S ANOTHER RESPOND RISK
FACTORS FOR ALZHEIMER'S DISEASE
AND IT IS EXCLUSIVELY EXPRESSED
IN THE MICROGLIA OF THE BRAIN.
AND SO IN ADDITION THE COMPANY
PATHWAY ARE ALSO SEVERAL
COMPANIES HAVE MOLECULES AND
ALSO GENETIC MODIFIERS OF
ALZHEIMER'S DISEASE SUCH AS CR1
AND THE BLUE SO IN PART OF THE
COMPLIMENT IN THE (INAUDIBLE)
THIS AFTERNOON, IT IS IMPORTANT
OF UNITY SYSTEM AND RESPONSIBLE
FOR RECRUITMENT AND CYTO SIS AND
CYTOKINE REGULATION AND THE COL
OOPS ARE EXPRESSED AND
ASSOCIATED WELCOME BACK
ALZHEIMER'S DISEASE AND THE
COMPLIMENT HALFWAY CAN BE
ACTIVATED BY ONE OF THE THREE
TRIGGERS.
AND ON THE COMPLIMENT FACTORS
WHICH UNDERGOES A CASCADE OF
REACTION LEADING TO THE REGION
OF TAX SO TODAY, I'LL BE
FOCUSING ON THE THROUGH AID
BINDING TO THE RECEPTORS AND THE
AMYLOID FOLLOWED BY ATP THAT WE
CAPITULATE THE PATHOLOGY AND THE
OTHER IS THE IN AGING.
SO, WORK IN MY LAB IN THE PAST
THREE YEARS ALSO, MAPPED OUT IN
PRO ACTION PATHWAY AND THAT IS
THE C3 IS EXPRESSING EXERCISE ON
WHERE THE RECEPTORS IS EXPRESSED
IN MICROGLIA FORMING A C3
RECEPTORS MEDIATED EXERCISE
MICROGLIA THIS IS ACTIVATED IN
THE SMALL DOSE AND THAT IS
ASSOCIATED WITH THE GFAP
POSITIVE EXERCISE AND THE
MICROGLIA.
AND LATER ON IT IT HAS SHOWN
THIS NORMALLY HAPPENS IN MOUSE
MODELS BUT IT ALSO HAPPENS IN
HUMANS AND DISEASES AND IT IT
SUCH AS ALZHEIMER'S AND
PARKINSON'S DISEASE.
AND KNOWING THE THREE
EXPRESSIONS MY STUDENTS DECIDED
TO TAKE A CLOSER LOOK OF ITS
CRIMES BETWEEN ACCEPT AND SO
USING THE HUMAN I SAW MOUSE
MODELS AND HERE MICROGLIA IS
MARKED AND BETWEEN REIS SCEPTER
IT'S MARG MARKED BY PURPLE HERD
IT'S SHOWN IN WHITE AND WHAT SHE
FOUND IS THAT THE RECEPTORS IS
ACTUALLY EXPRESSED QUITE HETERO
GENIOUSLY AND IT'S IN THE AREA
SURROUNDING THE AMYLOID WERE IN
THE MICROGLIA THIS IS THE PLUS
MUCH LOWER WITH THE AR
EXPRESSION O SHE DECIDED TO LOOK
THAT AND SHE USED RIGHT
SCEPTER AND WHICH THE RECEPTORS
IS MATCHED BY THE WHEN SHE DID
THIS CLOSE AND WHAT SHE FOUND IS
THAT IN THE WILD TYPE CONDITION
THE POPULATION OF THE C3AR LOW
AND THE MID AND IN THE A IT TC
MICE THIS POPULATION IS SHIFTED
TO C3R HIGH CONSISTENT WITH THE
EXPRESSION IN THE MICROGLIA
SURROUNDING AMYLOID AND SHE
WANTED TO UNDERSTAND WHAT
MOLECULES THAT ARE ASSOCIATED
WITH THIS C3 HIGH POP NATION SHE
SORTED THE MICROGLIA AND THIS
SEQUENCING AND WHAT SHE FOUND
THAT IT HAS PATHWAYS THAT
SPECULATED ASSOCIATED WITH A
HIGH STATE AND IN PARTICULAR IT
WAS ONE PATHWAY AND ALSO THE
LIPID AND IN ALSO SHOWN HERE IN
THE STIGMA AND WE'RE INTERESTED
IN THE PATHWAY BECAUSE AND THAT
PERSISTENT IT'S ASSOCIATED WITH
AND CELLULAR METABOLISM AND
LOWER AND SO THEY WANTED TO
FURTHER GET INTO THE MAG NISM IN
WHICH THE ISOLATED MICROGLIATURE
FROM THE WILD TYPE AND THE MOUSE
OF MICROGLIA AND THE PERFORMANCE
OF HIS ONE EXPRESSION.
JUST LIKE THE I EXPRESSION
ASSOCIATED WITH EXPRESSION AND
NOW IS LEAST TO THE LOWER ONE
EXPRESSION AND THE ASSOCIATED
WITH HIGHER ATP PRODUCTION AND
THE PUT THOSE CELLS INTO THE AND
THE CONDITIONS IN THE WILD TYPE
MICROGLIA IS ASSOCIATED WITH
INTEREST IF EXPRESSION AND
INTERESTINGLY BETWEEN IT'S
RESIST APARTMENT TO HYPOXIA
INDUCED IN ONE EXPRESSION.
THIS IS REFLECTED IN EXPRESSION
IT'S ALSO CAN BE CAPTURED BY ITS
FUNCTION AND USING THE CORE IN
WHICH THE INDUCED HYPOXIA USING
THE SUPPORT AND THE PERFORM THIS
EXPRESSION AND THE RECEIPT
FORATION OF THE MAXIMUM OF THE
CR AND ITS PRODUCTION AND UNDER
ALL THIS CONDITIONS, THE HYPOXY
IS TO REDUCE OCR PRODUCTION AND
HOWEVER IN THE THE MICROGLIA IS
RESISTANT TO THIS OCAR REDUCTION
AND FORMATIONS THAT THE IT'S
HIGH, MICK ROW GLIA IS THE
ASSOCIATED WITH HIGH
PRODUCTIVITY AND IT'S ONE
PATHWAY AND ALSO THE METABOLISM
SO TO DETECT WHETHER THIS AR HAS
ONE ACCESS ALSO REGULATES THE
LIPID METABOLISM MEANT THE
EXAMINED THE LIPID JOBLESS
FORMATION USING THE HIGH POX IS
TREATMENT WHICH LEADS TO THE
LIPID ACCUMULATION IN THE WILD
TYPE CULTURE BUT AGAIN, THE IS
RESIST APARTMENT AND AND ONE
REGULATION.
WHILE IN VIVO, WHAT WE FOUND IS
THAT JUST LIKE WHAT WE SAW IN IN
VIVO IT'S NOW CROSSING THE ON TO
THE ATP ON WHAT SHE FOUND THAT
IN THIS ASSOCIATED THAT THE DO
IT'S OUR EXPRESSION IN THE
MICROGLIA AND THAT NEEDS TO THE
(INAUDIBLE) OF THIS MICROGLIA
SURROUNDING THE BEAT AN AM LLOYD
AND FORMATION AND ALSO THE
HIGHER CYTO SIS OF THE MICRO
GLEE TO THE BETA AM LLOYD SHOWN
BY INCREASE AND SIX TO EIGHT AND
IT MEANS IN HERE WE USE
MICROGLIA FITTING MARKER AND THE
DATA THAT IS BY THE MICROGLIA
AND OVER ALL, THIS INTEREST
UPDATE LEADS TO THE REDUCED BETA
PATHOLOGY AS THE HERE YOU SEE
USING THAT THE ACT AND THE
PROPOFOL SPEAKER TALKS ABOUT THE
BEHAVIOUR AND HERE WE USE THIS
NOVEL OBJECT AND RECOGNITION AND
THAT IS WE LET THE MOUSE TO
RECOGNIZE THIS TWO OBJECTS AND
WHICH THE ONE OBJECT WITH A
DIFFERENT OBJECT AND THE MOUSE
REMEMBERS, THIS OBJECT THEN IT
WILL NATURALLY SPEND MORE TIME
ON THIS NOVEL OBJECT AND THE
MICE THIS IS REDUCED TO THE
LEVEL 50 PERSON HOWEVER IT'S THE
AMOUNT OF MY SHOW ALMOST CLOSE
TO WILD TYPE AND RESPONSE IN
THIS WORKING MEMORY PET SO ALL
AND ALL WE ARE COMING UP WITH
THIS MODEL AND THAT IS THE POPPY
AND IN RESPONSE TO THE AMYLOID
PATHOLOGY AND THE HEIGHTENED GTR
LEADS TO THE OPERATING THOSE ARE
REVERSED LEADING TO THE BETTER
MICRO GLOW A PATH STREAM AND
REDUCE APP MALL PATHOLOGY AND
BEHAVIOUR AND THIS ALZHEIMER'S
MODEL ANOTHER STUDENT NICK
THOMPSON WAS INTERESTED IN
UNDERSTANDING THIS PATHWAY IN
DOING AGING AND SO WHAT NICK
FOUND WAS THAT IT'S NOT ONLY UP
REGULATED IN THE CONDITION IT'S
ACTUALLY UP REMEMBER LATED IN
AGING AND EVEN A AGE OF ABOUT 12
MONTHS THERE'S A CLEAR UP
REGULATION OF THESE THREE AND
THAT IS ASSOCIATED WITH VASCULAR
INFLAMMATION MARKED BY LOCALIZE
WITH THE 31 POSITIVE AND THIS
INCREASE IS BECAUSE WHEN WE LOOK
AT THIS IT BECOMES ON THE
BACKGROUND AND IT IS SO TO EXAM
WHETHER IT'S ASSOCIATED WITH THE
BLOOD BARRIER CHANGES NICK
PROSECUTE FORMED THIS FLOW
CYTOMETRY AND EXAMINED THE
POPULATION OF THOSE CELLS
INCLUDING THE MICROGLIA AND THE
TAKING THE MONOCYTES AND IT'S
DIFFERENT AGES AND THE WORK KEEP
IS THAT THERE'S EIGHT RELATED
INCREASE OF THE EIGHT POSITIVE
HEALING FOR SIDE AND BUT NOT THE
MONOCYTE AND AGAIN THIS INCREASE
IS BECAUSE WHEN YOU LOOK AT THIS
POPULATION THIS INCREASE IS NO
LONGER HAPPENING.
SO THEN HE CHECKED ON THE
VASCULAR MORPHOLOGY USING THIS
OF THE AND THE DIFFERENT AGES
AND WHAT HE FOUND IS THAT THERE
IS SOME VASCULAR CHANGES HELPS
AT MID AGE AND IT GOATS WORSE
AMONG AGES AND THIS CHANGES CAN
BE RESCUED BY USING THE C3R
ANTAGONIST AND ALSO BY GENETIC
KNOCK OFF OF C3R SO THEN NEXT
NICK ASKED WHETHER THIS MORPH
LOGICAL CHANGES WOULD LEAD TO
THE REGION OF THE INTEGRITY SO
TO DO THAT, HE USED IT IN VITRO
AS SAY AND IMAGE HE CULTURE AND
THE PRIMARY HUMOUR VES KULAR
CELLS WITH A EXERCISE AND THE
MEASURED THIS SPIRAL
INTERPRETATION USING THIS CORE
AS SAY AND IT'S A PEER VALUE AND
WE KNOW THAT THIS PEER POSITIVE
CONTROL WITH BARRIER AS EXPECTED
AND SIMILAR, WHEN HE TREATED
THIS VARIOUS SYSTEM THAT ALSO
NEEDS TO DISRUPT THE BARRIER AND
THIS AREA OF DISRUPTION CAN BE
BLOCKED BY TREATING THE CULTURES
WITH THE C3R RECEPTORS AND ALSO
USING THIS SHOWING THAT THE
INTRA CELLULAR IS DOWN STREAM
MEDIATOR OF THE C3A BARRIER
IMPAIRMENT AND THEN THE FURTHER
PAST THE HYPOTHESIS HE PERFORMED
THIS ON THE USES OF LIGHTS WHICH
IS A CAUSE OF INDEPENDENT AND
THAT REGULATES THE DO YOU THE
VASCULAR DISRUPTION.
THIS CAN BE BLOCKED BY SEEKING
THE CELLS WITH RECEPTION AND
HAPPINESS FOR BY WHEN HE LOOKED
AT THOSE THE SAME TREATMENT AS
24 HOURS AND IT'S AND HOWEVER AT
THIS STAGE, AND OUR SIMPLE AND I
MOTIONED ABOUT THE IN MICROGLIA
AND OKAY, OKAY AND I'M ALMOST
DONE SO THE QUESTION IS THIS
AUTONOMOUS OR THIS SO I USED IT
INTO A CONDITIONAL A LEGAL AND
THE SPECIFIC DELETED THE CTR IN
THE CSL AND BASICALLY SO SIMILAR
EFFECT AND SO WITH THAT,
MODELING AND THAT AMOUNTERS THE
FUNCTION LEAD TO GO THE CDHT
CELLS.
IN ALL THE AND IN AGING AND THE
IN FACT THERE'S A PROPOSAL FOR
OF A COMPLIMENT OF POSITIVE
RECEIVE AND THIS IS SUPPORT THE
PREMISE AND AND I WILL I'LL TALK
ABOUT THAT TOMORROW AND I THINK
THERE'S A GAP IN OPPORTUNITIES
DISCUSSION AND I WILL END BY OF
AK KNOWLEDGING THE PEOPLE AND I
WILL LIKE TO GIVE A SPECIAL
SHOUT OUT TO A THAT FOLLOW ME.
THANK YOU.
>>IT'S A COMPLIMENT C3 IS
REALLY COOL AND IT POPS UP
EVERYWHERE IN AGING IN MULTIPLE
PLACES IT GOES UP AND I RECALL
WE HAVE SEEN SEVERAL YEARS AGO
IN GOING UP AND JUST A REGULAR
AGE DATA APART FROM ALZHEIMER'S
MODELS AND IT'S REALLY STRONG
MOLECULES AND HAVE YOU SEEN THE
INHIB TANTS HAVE ANY IMPACT ON
AGING ASSOCIATED DECLINE?
JUST THE C3 INHIBITORS?
ACTUALLY, C3 IS APPROVED.
I DIDN'T KNOW IF IT WAS A BLOOD
BARRIER.
SO ACTUALLY, I'M CONCERNED ABOUT
THE FACT AND I THINK IT'S
PROBABLY USEFUL TO TREAT
PROPERTY PIECES AND FOR WHEN YOT
ROLE IN THE UNITY AND INFECTION
SO I DON'T KNOW IF YOU JUST
BLOCK THE C3 AND WHETHER IT WILL
FIGHT FOR THE OVER ALL IMMUNE
AND WHETHER IT WILL FIGHT IT'S A
CONCERN AND HERE IT'S THE SAME
THING WITH THE SITUATED AND
ANTAGONIST AND THE ANTAGONIST IS
NOT APPROVED BECAUSE IT'S HAVING
ISSUES WITH THE PENETRATION AND
AND AND PROBABLY NOT AND AND
IT'S MINUS AND ANOTHER ANIMAL
AND ANY SORT OF MAINTENANCE AND
AND THAT'S NOT AGE ASSOCIATED
DEGENERATION.
>>WITH LESS FUNCTION OF DECLINE
ANDED WE HAVE BEHAVIOUR AND THE
WAY WE DIDN'T SEE A DEGREE OF
CHANGE BUT WE HAVEN'T HAD VERY
MUCH DETAIL HOWEVER, THEY HAVE
LOOKED AT THE SHOW THAT IS
ACTUALLY RESIST APARTMENT TO AGE
RELATED FUNCTION AND DECLINE.
>>THANK YOU.
>>WE'LL PULL UP THE NEXT
SPEAKER'S SLIDE.
>>THANK YOU.
ALL RIGHT, SO OUR LAST SPEAKER
FOR THE DAY AND THEN WE'LL
ADJOURN FOR THE DAY PICKING UP
THE REMAINDER OF THIS SESSION
TOMORROW.
IT'S GOING TO BE SARAH KNOX FROM
UCSF REVERSING ORGAN AGING IN
THE SALIVARY GLAND.
THANK YOU.
>>LOOK AT THAT.
AMAZING.
RIGHT UP THERE WITH YOU.
SO, IT'S THE AFTERNOON PEOPLE
IT'S GOING ONTO THE EVENING I
FEEL LIKE MY TASTE BUDS ARE
DOING THINGS I DON'T FIND
APPROPRIATE RIGHT NOW BECAUSE MY
SALIVARY GLANDS ARE STILL
WORKING.
I MIGHT HAVE DRY MOUTH BUT MY
SALIVA IS RIGHT THERE AND I HOPE
YOU APPRECIATE YOUR GLANDS
BECAUSE IT'S ONE OF THE MOST
UNDERSTAND STUDIED ORGANS IN
YOUR BODY.
MOST PEOPLE DON'T CARE ABOUT IT
UNTIL THEY LOSE THEM AND THEY
CALL ME.
HOW ABOUT THAT.
I'M NOT EVEN A CLINICIAN BUT
THERE'S NOTHING TO DO AND A
FRIEND OF MINE HAS LOSS OF
SALARY GLANDS CANCER AND HE
CARRIES AROUND A BOTTLE OF MILK.
IF I GIVE YOU A BOTHEL OF MILK
AND SAY THAT'S IT, GOOD LUCK,
YOU WOULD BE LIKE NOT HAPPY WITH
ME SO LET'S EXPLORE THAT AND
WE'RE GOING TO GO INTO THE ROLE
OF AGING HERE.
WE'RE NOT TALKING ABOUT THE
BRAIN PEOPLE, WE'RE OUT OF THE
BRAIN GOING INTO THE NERVOUS
SYSTEM.
SO I STUDY NERVES AND
DEVELOPMENT.
SO WE'VE LEARNED A LOT THERE AND
NERVES AND REGENERATION IT
SOMETHING EXTREMELY VITAL AND OF
COURSE NERVES AND AGING, THAT'S
THE REASON WHY I GOT INTO IT BUT
I DON'T KNOW MUCH ABOUT IT
COMPARED TO YOU GUYS I'M SURE.
I'M NOT GOING TO TALK ABOUT THE
SYSTEM YOU CAN TELL ME WHAT YOUR
THOUGHTS ON THE IMMUNE CELLS.
WE WERE TALKING ABOUT SALIVARY
GLANDS AND THESE ARE DEVELOPING
SALIVARY GLANDS THIS IS ALL DONE
BECAUSE WE WANT TO LOOK AT THE
NERVES AND SEE A NERVE AND THIS
IS A GANG GLEE ON WRAPPED AROUND
THAT GLAND EARLY IN ITS
DEVELOPMENT SO YOU KEEP THE NOSE
ON THAT GRAND AND UNDERGO AND IT
FORMS A BUD LIKE STRUCTURES AND
WE MADE CHANGES AND POSITIVE POS
LAKE OF STEM CELLS IF YOU LOSE
THOSE NERVES, GUESS WHAT, YOU
GET A MOR PHYSICAL AND VEMMENT
AND DEVELOPMENT OF CELL AND LOSS
OF THESE STEM CELLS IF YOU
SIMPLY AND I JUST WANT YOU TO
LOOK AT THE SIMPLY ADD BACK SETS
OF THIS IS COLOURFUL YOU ARE
GOING THROUGH TO RETURN THOSE
CELLS.
NOT ALL THE WAY.
BUT LET'S NOT BE TOO HASTY ABOUT
THAT AND WE'RE
>>THIS IS REALLY GOOD AT COMING
BACK TOGETHER AND HEALING.
WHEN THEY HEAL YOU SEE A LARGE
INCREASE AND GUESS WHAT YOUR
COME BACK AND DO WE HAVE ANY
ANYONE ELSE.
I WANTED TO TELL YOU THAT YOU
CAN DO THIS OUTSIDE THE BODY AND
YOU ARE ONLY GOING TO ON THE
LEFT IS SENSE OF SELLING ON THE
RIGHT-HAND AND IT'S AGO NIST AND
YOU CAN SEE EXTENSIVE
REPOPULATION OF THAT ISSUE SO
THAT'S SIMPLE.
WE ONLY HAVE ONE FACTOR.
THE LAST THING I WILL TELL YOU
ABOUT BEFORE WE GET INTO AGING
IS THIS IMPORTANT PIECE.
SO, IT'S ALL ABOUT GAMMA
RADIATION AND WE TALKED ABOUT
RADIATION TODAY AND YOU HAVE
RADIATION AND THE OPPORTUNITY TO
GET IS HIGH AND WHAT WE DID WAS
ASKED WHETHER WE COULD MAINTAIN
OR REGENERATE THE DELIVERY OF A
OF (INAUDIBLE) AND SO THIS
EXPERIMENT, RADIATION AND AMONG
PLACE WE'RE GOING TO START
TREATMENT AND THIS IS A VERY
LONG TIME BY THE WAY.
HUMANS IS A VERY LONG TIME.
NOW ON THE LEFT-HAND SIDE IS THE
RED, THE RADIATED YOU CAN SEE A
LOT OF RED THERE AND THAT IS
BECAUSE THERE'S NOT MANY CELLS
THERE AND WE TREAT GUESS WHAT WE
GET THE CELLS ARE THERE AND
GLORIOUS FORM AND THEY'RE HIGHLY
FUNCTIONSAL SO THIS IS A GREAT
FUNCTIONS IS ESSENTIAL FOR AWFUL
YOUR ORGANS SO THINK ABOUT THAT
THIS IS ONE TREATMENT RESULT IN
COMPLETE REGENERATION OF
FUNCTION.
AGING, OKAY, AGING GREAT.
BUT WHAT HAPPENS WITH HUMAN
GLANDS AT THE TIME NONE OF US
HERE TODAY AND HERE IS THE
MIDDLE.
THE MID LIFE SOME OF US HERE.
I'M GOING TO SAY ANYBODY OVER
THERE.
MOSTLY WE'RE GOING TO BE AROUND
THE MIDDLE I WOULD SAY.
SO THIS TELLS YOU THAT YOU ARE
LOSING THESE CELLS AND YOU ARE
GETTING AN INCREASE IN FAT SO
YOU KNOW, EMILY CAN YOU HELP ME
WITH THAT IS SO WE DON'T KNOW
WHAT THE FAT IS DOING BUT MICE
DON'T GET FAT IN THEIR ORGANS
BUT SOMETHING WE HAVE TO
CONSIDER.
SO WHEN WE LOOK AT POPULATIONS,
LET'S DO SOME WE DID THAT AND
YOU CAN SEE FROM THE ANALYSIS
IT'S VERY SEPARATE IF YOU LOOK
ACROSS TIME IT'S SEPARATE AND
YOU LOOK ACROSS TIME AND YOU
LOOK AT THE POPULATIONS YOU CAN
SAY THIS DECREASES AT A TIME SO
THAT GOES ALONG WITH THAT DATA.
SO IF WE LOOK AT ONE OF THE MOST
IT IS GOING DOWN AND GUESS WHAT,
WE ALSO LOOK AT HUMAN TISSUE AND
THIS GOES DOWN THERE TOO WITH
AGE SO WE LOOKED AT PEOPLE LESS
THAN 45 YEARS AND OTHER PEOPLE
WHO ARE OVER 65.
IT GOES OFF A CLIFF AND DRAMATIC
REDUCTION AND OBVIOUSLY
PROLIFERATING THESE GILLS IS
GREATLY DIMINISHED.
THE NERVOUS SYSTEM, OKAY, THE
NERVES.
WHAT ARE THE NERVES DOING AT A
TIME.
SO WHEN THEY LOOKED AT TWO
MONTHS AND VERSUS 189 MONTHS WE
SAW A GREAT REDUCTION IN
INNOVATION AND HERE SO WE'RE
LIKE OKAY, WE DIDN'T SEE A
DECREASE AT NINE MONTHS OR 12
MONTHS OKAY SO THE NERVES ARE
STILL PRESENT AND WHAT ARE YOU
ASKING?
YOU ASK ABOUT FUNCTION.
WE ASK ABOUT FUNCTION BY GUESS
WHAT DOING A TWO PCR.
THANK YOU SO MUCH.
WE DID THAT BUT IT'S DOWN AND
IT'S DOWN BY NINE MONTHS AND YOU
STILL HAVE IT PRESENT AND
REDUCING YOUR NEURON FUNCTION.
SO REPLENISHMENT AND TELLING YOU
BY NINE MONTHS OF AGE THE
SUBSTITUTE CELLS ARE RIGHT AT
NOT SO GOOD AT NINE MONTHS YOU
SEE A MASSIVE REDUCTION IN
REPLACEMENT OF THESE CELLS SO
THIS IS THE AGING.
IT WORLD IT'S A THAT DECREASE
FUNCTIONAL INNOVATION SO THESE
TWO THINGS CAN IT WORK TOGETHER.
SO WE'RE JUST GOING TO USE THIS
SAME THING THAT WE TALKED ABOUT
BEFORE, RIGHT.
WE'RE GOING TO ASK IF THE
ACTIVITY TALKING RECEPTORS
ACTIVATION CAN DO SOMETHING
POSITIVE TO THIS AGING
EXPERIENCE OF ALL COMING FROM SO
THIS IS EXPERIMENTS WE DID AND
WE ASKED OKAY CAN WE GET TWO
CELLS BACK BY OVER TIME AND WE
LOOK AT YOUR ON YOUR LEFT AND
YOUR RIGHT AND YOU CAN SAY YES,
CLEARLY THESE CELLS BRING CELLS
ARE EXAMINING BACK SO WHAT THEY
NOTE HERE WE'RE USING LPO IS A
MARKER ACTIVITY AND STEM CELL
POPULATION AND IT'S NOT BRIGHT
IN THE UNTREATED LOOK IT'S
TWO-MONTH-OLD AND 11 TO OLD YOU
CAN SAY THAT AS REDUCTION IN THE
LPO AND YOU GET A REDUCTION
HOWEVER IF YOU COMPLETE WITH AGO
NISM OF 11 ANIMALS AND FOR 30
DAYS, GUESS WHAT, YOU ARE
ACTIVATING AND GETTING YOUR
CELLS BACK SO THAT'S PRETTY
SCHOOL ISN'T IT AND SO OF
COURSE, I JUST WANTED TO POINT
OUT I KNOW WE'RE TALKING ABOUT
IT TODAY I FEEL -- IT'S
11-MONTH-OLD AND WE'RE GOING TO
DO WITH FEMALE IN THE MALE AND
WE'RE GOING TO TREAT THIS FOR 30
DAYS AND WHAT HAPPENS IS THAT
YOU USE THE EX AT THE PRESENT
TIME OF REPLACEMENT AND YOU HAVE
TREATMENT AND GUESS WHAT THIS IS
THE MALES.
THE MALES AND FEMALES DO WELL.
THE MALES DO BETTER.
I HATE IT SAY IT LADIES BUT THAT
IS WHAT WE'RE THINKING.
SOME DAYS THEY'RE 18-MONTH-OLD
AND SO THE OTHER PIECES OF THIS
IS WE FEEL IT'S CELL IDENTITY
AND YOU NOTICE DOWN HERE THERE'S
A PROBLEM, MISSED ONE IS A
MARKER CREATIVE FUNCTION IT'S
DEREGULATED THAT YOU MUST HAVE
IT SO YOU CAN SEE IT'S ON THE
LEFT AND YOU CAN SEE WAY MORE ON
THE RIGHT AND WE'RE ALSO SEEING
THESE PLEASURE WE THINK IT COULD
BE THIS AND THEY CERTAINLY NOT
(INAUDIBLE) OKAY, SO WE ARE
RISKING THE DISEASE STATE AND
THE IDENTITY OR MAYBE A OF
DEGREE SET.
SO, THE LAST BIT ARE ABOUT
REGENERATION OF AGED PEOPLE.
YOU SHOULD ALL BE INTERESTED IN
THIS.
SOME OF YOU ARE.
I'M INTERESTED.
AND WHAT WAS INTERESTING TO US
BECAUSE WE STUDY REGENERATION
AFTER RADIATION, YOUNG LAND HERE
ON THE LEFT RADIATION OF THE
YOUNG AND THE MIDDLE, AND THE
RADIATION AGE ON THE RIGHT OKAY,
THE YOUNG AND RAID IS SIMILAR
AND MAYBE THE NO RADIATION AGE
IS GOING BETTER AND BUT THIS IS
THE STATE OF THINGS AND IF YOU
COME IN AND YOU HAVE RADIATION
AND YOU ARE OVER THE AGE OF 65
WHICH IS BASICALLY A LOT OF
PATIENTS IT COULD BE A PROBLEM
FOR YOU WITH REGENERATION.
I MEAN, THE TISSUE IS GOING TO
BE GENERATION OVER TIME BUT YOU
MIGHT HAVE A WORK.
WHAT WE'RE GOING TO DO HERE IS
WE'RE GOING TO TREAT THESE NOT
EGGS.
THIS IS 11-MONTH-OLD MICE AND
DAY 30 WE'RE GOING TO TREAT THEM
WITH FOR ANOTHER TWO MONTHS.
SO THAT 14 MONTH DAY LOOK AT
THEM AND RADIATION HERE ON YOUR
LEFT AND LOTS OF THE BEAUTIFUL
LOOKING MARK 10 AND IN THE
MIDDLE YOU SEE RADIATION AND
SALINE AND A LOT AND WHEN YOU
SEE IT'S DAMAGE RADIATED ALL
ANIMALS YOU ARE GETTING A RESCUE
OF THE TISSUE AND WHAT YOU ARE
SEEING OVER ON THE FAR-RIGHT, IS
THE NERVES INDUCED SALIVA OUTPUT
SO YOU WANT TO COMPARE THE BLUE
BAR WITH THE RED BAR AND YOU
WILL NOTICE IT KEEPS GOING UP
AND IT'S TRUE AND THIS IS A
SIGNIFICANT RISK YOU ARE SAYING
IT OTHER IS COMPLETELY SIMILAR
TO THE SO I HOPE THAT YOU CAN
THINK ABOUT IMMUNE CELLS IN
THERE.
I CAN TELL YOU RIGHT NOW THAT WE
ACTUALLY SAY AND I'M HAPPY TO BE
TALKING ABOUT IT OVER DINNER, AN
INCREASE IN IMMUNE RELATED GENES
BUT SINCE I DON'T KNOW ABOUT IT
I'M ASKING YOU TO HELP ME WHEN
YOU SEE THAT DATA.
SO, THERE ARE A NUMBER OF
QUESTIONS AND YOU ALL ASKING --
I'M GOING TO TURN INTO ROLL BACK
BECAUSE THEY'RE AMAZING LIVING
FOREVER.
I'M NOT BECAUSE IT LOOKS LIKE
THAT.
SO, YOU PROBABLY ARE THINKING
CHOLINERGIC NERVES AND WOULD
THEY BE INVOLVED IN A PROCESS
LIKE THIS.
CAN IT BE MAINTAINED LONG-TERM?
WE'RE WORKING ON THIS RIGHT NOW.
I CAN TELL YOU WHEN YOU TURN OFF
THE DELIVERY OF AGO NISM IT
HOLDS IT AND NOW HOW LONG CAN IT
HOLD IT WE'VE LOOKED AT TWO
MONTHS, THREE MONTHS, IT LOOKS
GOOD.
WHETHER IT'S GOING TO BE IT I
DOUBT IT BUT WITH GOING INTO
THAT BUT REALLY WHAT ARE WE
GOING TO DO IN HUMANS?
PLEASE COME AND COLLABORATE WITH
THEM AND CONSERVE AND I'M
INTERESTED IN IT YOU SHOULD BE
INTERESTED AND IS IT ONLY
ENOUGH.
MAYBE THEY WITH WRITE ABOUT IT
MAYBE IT'S GOING ON NERVE
COMMUNICATION.
THAT'S IT.
I'M THREE MINUTES OVER.
I HOPE I DIDN'T SPEAK TOO
QUICKLY WITH MY AUSTRALIAN
ACCENT.
AND THERE'S ANOTHER STRAIN.
>>REALLY FASCINATING.
I WAS ROCKED BY HOW SIMILAR IN
MANY DIFFERENT WAYS AND THE
TISSUE AND I HAVE MANY
QUESTIONS, ONE INVOLVING KGF TO
TREAT AND DID YOU HAVE A ROLE IN
THE SALIVARY GLANDS AS WELL BUT
I WAS MORE CURIOUS WHAT TO GET
REGULAR.
>>IF THE SALIVARY GLANDS IF.
>>SO, OVER TIME OR JUST
NATURALLY?
>>JUST NATURALLY.
>>YOU HAVE A BUNCH OF
MACROPHAGES MAKES SENSE AND OVER
TIME YOU GET BOTH WE TALKED
ABOUT THAT AND SO THIS IS MAYBE
12 MONTHS AND ON AND THERE'S
MORE AND MORE ACCUMULATION
THERE.
EARLY ON, YOU KNOW, WE THINK
THAT THERE'S GOING TO BE SOME
LEVEL OF INLOUD AND IT'S VERY
KNOWN AND IT'S BEEN KNOWN FOR
LIKE I DON'T KNOW 50 PLUS YEARS
AND DO WE KNOW WHAT THEY DO THE
ANSWER IS NO.
UNLESS YOU DO.
BUT YEAH, THERE'S AN ASSORTMENT
OF I MEAN, HOW THEY ACT IN AGING
PROCESS AND HOW THEY ACT IN
REGENERATIVE PROCESS, RIGHT.
AND WHETHER YOU CAN ACTIVATE IN
AGE AGING PROCESS WHETHER
THEY'RE AGING OR WHETHER THEY'RE
INVOLVED IN THE REVERSAL OF
AGING.
>>VERY GOOD.
>>THE NERVE HEALING EXPERIMENT
THAT YOU DID WAS IN YOUNG MICE.
DO OLD MICE FEEL THE NERVES?
>>THAT'S A GREAT QUESTION.
WE HAVEN'T DONE IT AND WE
SHOULD.
IT'S ONE OF THE HARDEST
EXPERIMENTS YOU CAN DO AND THE
LIKELIHOOD OF KILLING THE MICE
IS HIGH SO IT WILL BE BETTER.
ON-LINE QUESTIONS?
WHAT ABOUT INCREASING
AVAILABILITY AND YEAH, SO, OKAY,
YOU WANT TO INCREASE A INSCEPTER
ANTAGONIST.
IT'S VEIL ABILITY.
>>YOU THINK SO OKAY, THE
QUESTION IS ABOUT AVAILABILITY.
IT COULD BE A PROBLEM TOO,
RIGHT.
SO I JUST THINK ABOUT OKAY, THE
MAJORITY OF THE ORGANS ARE GOING
TO BE WRAPPED INTENSELY BY THESE
NERVES, RIGHT AND YOU GOT THEM
COVERED AS WELL WHICH WE DON'T
KNOW ABOUT AND IT'S RIGHT AROUND
THAT TISSUE SO IS IT THAT YOU
ARE NOT HAVING CONNECTIONS WITH
THOSE CELLS AND SO THOSE ARE THE
THINGS THAT I THINK ABOUT ALL
THE TIME BECAUSE YOU HAVE TO
HAVE THOSE IN ORDER TO RECEIVE
IT AS IT GETS TAKEN AWAY WITH IN
SECONDS AND MILLEY SECONDS
WHATEVER YOU WANT TO CALL IT SO,
YOU KNOW, YES, THE PRODUCTION
AND THE INTERACTION WITH THE
CELLS, RIGHT, BUT THE THEY ALL
HAVE IT OTHERWISE WE CANNOT SEE
CRATE AND THIS IS INVOLVED
THOUGH IN PROLIFERATION AS WELL
AS REPLENISHMENT, RIGHT.
SO, YES, IT'S A GREAT POINT AND
I THINK THAT MOST OF US THINK
ABOUT THE SIN AS TICK
CONNECTIONS WITH YOU THINK ABOUT
YOUR ORGANS AND THE NEO FILLS
COME IN THERE TOO SO THEY TRAVEL
ON THE NERVOUS SYSTEM YEAST.
CANCER DOES TOO, REALLY BAD.
I STUDIED THAT AS WELL.
ANYTHING ELSE.
>>ONE MORE QUESTION.
>>ANY DATA TO VERIFY THE
AGONIST YOU THINK ANTAGONIST IN
PRO CLINICAL MODELS?
>>YEAH, SO, CLINICAL MODEL.
I SUPPOSE IT'S BECAUSE WE DID
ALL OF OUR STUDIES WHERE WE CAN
JUST ADD THE AGO NIST OUTSIDE OF
THE BODIES AND SO WE TAKE BLOOD,
TISSUE AND WE CAN TRACE THEM.
NOW THE QUESTION COULD BE IF YOU
TAKE THAT TISSUE AND YOU PLACE
IT IN VIVO AND YOU PUT IT AGO
NIST IF THERE DOES IT CAUSE IT
TO PROLIFERATE AND THE ANSWER IS
YES.
SO, IT'S WHETHER YOU CAN BLOCK
IT.
WE HAVEN'T DONE THAT.
IT'S VERY DIFFICULT TO DO IT
BECAUSE YOU NEED YOUR NERVOUS
SYSTEM AND IT'S NOT REALLY A
WHAT SPECIFICALLY DEACTIVATE,
RIGHT.
YOU HAVE TO DEACT EVERYTHING.
DON'T DO THAT BECAUSE IT WON'T
GOOD.
BUT THERE'S A PROBLEM THERE WITH
THAT ASK JUST THE FOOL.
I THINK IT'S THE CENTRAL NERVOUS
SYSTEM BY THE WAY BECAUSE GUESS
WHAT THERE'S NO FALL.