IN THE INTEREST OF TIME, WE
THOUGHT WE'D GO AHEAD AND START.
AND IT'S MY ABSOLUTE PLEASURE TO
BE ABLE TO INTRODUCE I'M
CHRISTINA ABRAHAM FROM THE
NATIONAL INSTITUTE OF DIABETES
AND DIGESTIVE AND KIDNEY
DISEASES AND I'M THRILLED TO BE
ABLE TO INTRODUCE DR. GRIF
RODGERS OR INSTITUTE DIRECTOR
AND HAS BEEN THE INSTITUTE
DIRECTOR SINCE 2007.
SO, NEARLY NOT QUITE BUT NEARLY
ALL OF MY TENURE AT NIDDK HAS
WITHIN UNDER GRIFFIN.
HE'S BEEN VERY SUPPORTIVE OF
TYPE I RESEARCH, DIABETES
RESEARCH IN GENERAL AND THE
HERN.
HE WAS GRACIOUS ENOUGH TO RETURN
AND GIVE US OPENING REMARK SO,
GRIF.
[APPLAUSE]
>>
>> THANKS SO MUCH FOR THE KIND
INTRODUCTION.
GOOD MORNING TO YOU ALL AND ON
BEHALF OF NIDDK I WANT IT
WELCOME TO YOU THE 10th
ANNIVERSARY SYMPOSIUM.
IT'S GREAT TO SEE SO MANY PEOPLE
HERE TO CELEBRATE HERN'S
ACCOMPLISHMENTS AND DISCUSS
EXCITING OPPORTUNITIES IN THE
RESEARCH YOU ALL DO.
I'M HAPPY TO REPORT THAT L.A.
PLANS TO HIGHLIGHT HERN IN AN
UPCOMING ANNUAL REPORT.
THAT WILL BE POSTED ON OUR
WEBSITE LATE JANUARY AS WE'RE
EXTREMELY PROUD OF ALL OF ITS
ACCOMPLISHMENTS.
LET ME FIRST START BY NOTING
NIDDK IS CELEBRATING ITS
ANNIVERSARY THIS YEAR.
THIS YEAR WILL MARK THE 75th
ANNIVERSARY OF THE INSTITUTE AND
AS WE LOOK FORWARD PARTICULARLY
DURING ANY TIME OF TRANSITION, I
CAN ENSURE YOU THAT NIDDK WILL
REMAIN COMMITTED TO SUPPORTING
THE BEST SCIENCE JUST AS WE HAVE
FOR THE LAST 75 YEARS.
WE PLAN TO KEEP A FOCUS ON
SCIENCE, CONTINUE TO ACHIEVE
SIGNIFICANT RESEARCH PROGRESS
THROUGH HERN AND OUR OTHER
EFFORTS AND CONTINUE TRANSLATING
THAT PROGRESS INTO IMPROVING THE
HEALTH OF ALL PEOPLE.
AS WE'RE HERE TO CELEBRATE THE
10th ANNIVERSARY OF HIRN IT'S
PART OF THE NIDDK DIABETES
RESEARCH PORTFOLIO.
THIS SHOWS SEVERAL DIFFERENT
LONG-TERM COLLABORATIVE
CONSORTIA INCLUDING HIRN MADE
POSSIBLE BY THE SPECIAL DIABETES
PROGRAM.
THESE ARE TACKLING ALL STAGES OF
TYPE I FROM EARLY STAGE DISEASE
THROUGH ITS COMPLICATIONS.
AND SOME OF THESE PROGRAMS LIKE
THE TYPE I DIABETES TRIAL NET
AND T TEDDY AND OTHER UNMET
NEEDS.
TYPE I TRIAL NET AND TEDDY HAVE
BEEN GOING ON OR DECADES AND
OTHER AREAS ARE MORE RECENT
INCLUDING THOSE THAT ARE
ADDRESSING UNMET NEEDS IN TYPE I
DIABETES.
SUCH AS NEUROCOGNITIVE
COMPLICATIONS AND CARDIOVASCULAR
DISEASE IN TYPE I DIABETES.
THEY'RE ALL ADDRESSING KEY AREAS
TO ADDRESS PROGRESS IN TYPE I
DIABETES RESEARCH AND IMPROVE
THE LIVES OF INDIVIDUALS WITH
THE DISEASE.
NOW, TODAY'S SYMPOSIA LOOKS BACK
AT HOW IT STARTED.
THE PREDECESSOR OF HIRN WAS BCBC
ANOTHER EXTREMELY SUCCESSFUL
EFFORT.
AS NIDDK WAS LOOKING TO BUILD ON
BCCC'S SUCCESS, THERE WERE A FEW
KEY GOALS THAT WERE SET UP.
FIRST, WAS TO BUILD A RESEARCH
EFFORT THAT WOULD FOCUS ON HUMAN
DISEASE.
AT A TIME WHEN MOST OF OUR
KNOWLEDGE ABOUT WHAT WAS
HAPPENING IN THE PANCREAS, AT
THE TISSUE AND CELLULAR AND
MOLECULAR LEVELS WAS GATHERED
FROM RODENT MODELS OF DIABETES.
SECOND, NIDDK WANTED TO CREATE A
COLLABORATIVE NIMBLE STRUCTURE
THAT ORIGINAL STRUCTURE IS SHOWN
HERE.
WE DECIDED TO ORGANIZE HIRN AS
AN INDIVIDUAL CONSORTIUM WITH
THEIR OWN SCIENTIFIC MISSION.
THIS MODULAR STRUCTURE WOULD
ALLOW COLLABORATIONS WITHIN
THESE CONSORTIUM AND ALLOW IT TO
EVOLVE OVER TIME.
IT WAS SEEN SOME WOULD END AS
RESEARCH GOALS WERE MET AND NEW
CONSORTIA WOULD FORM AS NOVEL
OPPORTUNITIES AROSE.
AND IN ANOTHER KEY GOAL IN
ESTABLISHING HIRN WAS TO BOLSTER
THE INTERACTION BETWEEN BETA
CELL BIOLOGISTS AND
IMMUNOLOGISTS RECOGNIZING THAT
ADDRESSING AUTO IMMUNITY WAS
CRITICAL TO HIRN'S SCIENTIFIC
GOALS OF PROTECTING OR REPLACING
BETA CELLS FROM PEOPLE WITH TYPE
I DIABETES AND IMMUNOLOGISTS
HAVE BEEN CRITICAL CONTRIBUTORS
TO HIRN AS HAVE THE NUMBER OF
MULTI-DISCIPLINARY PARTICIPANTS.
THEY FOUNDED THE CONSORTIUM
SHOWN HERE AND THE ENHANCEMENT
CENTERS THAT COORDINATE NETWORK
OPERATIONS.
IN 2016 HIRN WAS EXPANDED WITH
THE ADDITION OF LARGE DATA
GENERATION PROGRAM CALLED THE
HUMAN PANCREAS PROGRAM OR HPAP
T1D WITH PERFORMING THE DEEP
FUNCTIONAL AND MOLECULAR
PHENOTYPING OF HUMAN PANCREATIC
TISSUES FROM DISEASE DONORS.
AND THE SHARING OF THE RELATED
DATA SETS WITH THE SCIENTIFIC
COMMUNITY WITHOUT ANY STRINGS
ATTACHED.
THIS WAS FOLLOWED IN 2018 BY THE
CREATION OF THE HUMAN PANCREAS
ANALYSIS CONSORTIUM IN 2019 BY
AN EXPANSION OF THE SCOPE OF
HPAP TO PHENOTYPING FROM DONORS
WITH TYPE II DIABETES.
IN 2024 TO TAKE ADVANTAGE OF THE
RAPID DEVELOPMENT OF
COMPUTATIONAL ANALYSIS IN LARGE
DATA SETS AND ARTIFICIAL
INTELLIGENCE TOOLS, THE
KNOWLEDGE BASE KNOWN AS PANC
BASE WAS CREATED TO HELP THE
SCIENTIFIC COMMUNITY TO ACCESS
THE RELEVANT DATA SETS AS WELL
AS A NEW CONSORTIUM ON MODELLING
AUTO IMMUNE DIABETES.
SO AS ENVISIONED FROM THE
OUTSET, HIRN CONTINUES TO EVOLVE
IT EMERGING CONSORTIA AND
BUILDING ON A THE NETWORK'S
TREMENDOUS SUCCESSES AND
CAPITALIZE ON NEW RESEARCH
OPPORTUNITIES.
HIRN'S OUTSTANDING SCIENTIFIC
TALENT ALONG WITH ITS NIMBLE
STRUCTURE HAVE BEEN CRITICAL FOR
THE NETWORKS ACCOMPLISHMENTS.
I'LL MENTION JUST A FEW OF THE
ACCOMPLISHMENTS IT LITERALLY
WOULD TAKE ALL TWO DAYS OF THE
SYMPOSIA TO MENTION ALL SO I'LL
GIVE A FEW EXAMPLES.
HIRN PUBLISHED OVER 1,000 PAPERS
AND PUBLISHED ABOUT 100 NEW
PAPERS EACH YEAR UNDER SCORING
ITS ROBUST SCIENTIFIC
PRODUCTIVITY.
SOME OF THAT PRODUCT IS
HIGHLIGHTED HERE INCLUDING
HIRN'S CONTRIBUTED NEW INSIGHT
INTO THE TYPE I DIABETES DISEASE
PROCESS IDENTIFIED POTENTIAL
THERAPEUTIC TARGETS SOME OF
WHICH HAVE BEEN TARGETS IN
CLINICAL TRIALS, DEVELOPED NEW
MODELS OF TYPE I DIABETES
FACILITATING NOVEL STUDIES OF
DISEASE PATHOPHYSIOLOGY AND
SERVING AS PLATFORMS FOR
PRE-CLINICAL TESTING OF NEW
THERAPIES.
IT'S CREATED RESOURCES THAT ARE
BEING USED BY THE BROADER
SCIENTIFIC COMMUNITY AND MANY
MANY MORE.
ANOTHER IMPORTANT ACCOMPLISHMENT
AND LONG LASTING LEGACY OF HIRN
THE NETWORK DEVELOPED INNOVATIVE
WAYS TO PROMOTE CAREER
DEVELOPMENT WHICH IS A PRIORITY
AREA OF NIDDK'S STRATEGIC PLAN.
AND TO ENGAGE WITH EARLY STAGE
INVESTIGATORS SUCH AS THROUGH
THE EMERGING LEADERS AWARD NEW
INVESTIGATORS AWARD.
GATEWAY AWARDS.
THESE PROGRAMS HAVE ALLOWED
AWARDEES STOW BE EMBEDDED IN THE
RICH INTELLECTUAL ENVIRONMENT OF
HIRN AND IT LEARN FROM AND
COLLABORATE WITH ESTABLISH HIRN
SCIENTISTS.
ADDITIONALLY, HIRN HAS GIVEN
EARLY CAREER SCIENTISTS
OPPORTUNITIES TO TAKE LEADERSHIP
ROLES WHICH GIVES THEM A
VALUABLE MANAGEMENT EXPERIENCE
NEEDED FOR CAREER DEVELOPMENT.
AS ONE EXAMPLE OF HOW HIRN HAS
QUICKLY STEPPED IN TO FILL THE
EARLY STAGE SCIENTISTS THE
EMERGING LEADERS PROGRAM WAS
LAUNCHED DURING COVID WHEN THE
PANDEMIC WAS NEGATIVELY
AFFECTING POSTDOCS READY TO
TRANSITION TO INDEPENDENT
FACULTY POSITIONS BUT EVERYTHING
WAS ON HOLD BECAUSE OF THE
PANDEMIC.
AND HIRN PROVIDING FUNDING TO
SUPPORT THE POSTDOCTORAL
RESEARCHERS DURING THIS TIME OF
UNCERTAINTY UNTIL IT WAS
FEASIBLE FOR THEM TO MOVE TO A
NEW POSITION.
OVER ALL HIRN'S CAREER
DEVELOPMENT EFFORTS HAVE BEEN
HUGELY SUCCESSFUL AND A WIN-WIN
AND HIRN IS HELPING FOSTER
CAREER DEVELOPMENT AND IN TURN
HIRN AND NIDDK ARE WELCOMING
EXTREMELY TALENTED SCIENTISTS TO
THE STUDY OF TYPE I DIABETES
RESEARCH.
I'LL CHOSE BY CONGRATING HIRN
AND YOU WILL OF YOU ON ITS MANY
ACCOMPLISHMENTS AND INVITE TO
YOU VISIT OUR WEBSITE FOR MORE
INFORMATION ON NIDDK'S
ACTIVITIES AND CONNECT WITH US
ON SOCIAL MEDIA.
THANK YOU AND SORRY FOR THE
PROBLEM GETTING THROUGH THE
GATEWAY.
THIS IS A TIME OF TRANSITION
I'LL JUST END IT AT THAT.
>> HERE SEEING MORE PEOPLE
TRICKLING AND IN WE CAN BEGIN
THE PROGRAM FOR GOOD.
NEXT UP IS GOING TO BE SOME
COMMENTS.
I'M HAPPY TO INTRODUCE DR. JOHN
KADDIS A PROFESSOR IN THE DWEPT
OF CANCER AND DIABETES DISCOVERY
SCIENCE AT THE CITY OF HOPE.
JOHN IS A CO-P.I. ON THE HIRN
COORDINATING CENTER WE REFER TO
AS THE RESEARCH ENHANCEMENT
CENTER.
HE'S GOING TO GIVE MORE
BACKGROUND ABOUT HIRN AND WHERE
IT'S COME FROM AND HOPEFULLY
WHERE IT'S GOING.
>> HI, EVERYONE.
AS A PRIMER FOR THE PLENARY
TALKS YOU'LL SEE THIS MORNING
YOU'LL GET A MORE BROADER
PERSPECTIVE OF THE OVERVIEW AND
CHANGES THAT HAVE BEEN HAPPENING
IN TYPE I DIABETES.
SO, I THINK MOST WILL AGREE THE
BETA CELL IS ONE OF THE HARDEST,
IF NOT THE HARDEST WORKING CELL
IN THE BODY IT'S GOT TO MAKE
MILLIONS AND MILLIONS OF HORMONE
MOLECULES AND SYNTHESIZE AND
MAINTAIN AND LOOK AT THE SIGNALS
AARON IT AND HAS TO DO THAT MANY
TIME THROUGHOUT THE DAY.
WHAT COMES INTO KEEN FOCUS IN
THE LAST 10 YEARS IS JUST HOW
VULNERABLE THE BETA CELL IS VERY
EARLY ON IN THE DISEASE AND WHAT
I MEAN HERE IS NOT ONLY THOSE
THAT HAVE A MULTIPLE ANDS BUT AS
MANY AS ONE AUTO ANTIBODY.
WE TEND TO THINK AND STUDY
SOMETIMES OF TYPE I DIABETES AS
A SINGLE CELL DISEASE BUT THAT
IN FACT IS NOT THE DISEASE.
THERE'S LOTS OF HORMONES AND
THERE'S A LARGE CAST OF PLAYERS
SUPPORTING THE BETA CELL AND
OTHER CELLS AROUND THE PANCREAS
AND YOU'RE GOING TO HEAR IN
TALKS TODAY THAT EVEN IF YOU
TAKE OUT ONE MUCH THOSE CAST
MEMBERS YOU CAN SEE DYSFUNCTION
IN THE ISLET AND BETA CELL EARLY
ON IN THE DISEASE PROCESS.
AND JUST LIKE THE BETA CELL
CAN'T WORK ALONE, NEITHER CAN
WE.
SO THE QUESTION IS, HOW DO THESE
DEVELOPMENTS COME ABOUT?
AND SO WHAT I WANT TO DO IS SORT
OF ELABORATE MORE ON WHAT
DR. RODGERS WAS TELLING YOU
ABOUT AND START WITH THE BETA
CELL BIOLOGY CONSORTIUM WHICH
STARTED IN 2001 AND LAST ABOUT
15 YEARS.
WHAT THE BCBC GAVE US IS GAVE US
A LOT OF MICE AND LOTS OF
ANTIBODIES AND FOCUS ON THE BETA
CELL AND FOCUS ON DEVELOPMENTAL
BIOLOGY WHICH WAS GREAT.
THEN SHORTLY AFTER THAT CAME
WHAT IS NOW KNOWN AS THE
INTEGRATED ISLET DISTRIBUTION
PROGRAM AND THAT WAS GIVEN BOTH
THROUGH EARLY EFFORTS THAT SOME
OF YOU HERE STARTED IN THE EARLY
2000 WHEN THERE WAS A FOCUS ON
THE CLINICAL ASPECTS AND
CLINICAL TRANSPLANTATION AND
THIS CAME ABOUT TRUE THE ISLET
CELL RESOURCES CENTER.
THE FIRST SHIPMENT OF HUMAN
ISLETS WENT OUT IN 2004 AND HAVE
BEEN GOING STRONG OVER 20 YEARS.
MOST OF US IN THE FIELD ALSO
KNOW ABOUT THE EFFORTS OF NPOD
WHICH WAS THEN A PRETTY
AMBITIOUS EFFORT TO ESSENTIALLY
MAKE NOT ONLY THE ISLETS
AVAILABLE THAT THE IIDP STARTED
TO GET BUT ALSO TISSUE AND
TISSUE NOT ONLY FROM THE
PANCREAS BUT SURROUNDING TISSUES
AND CELLS AS WELL.
NPOD HAS BEEN GOING FOR ALMOST
20 YEARS AS WELL.
AND THE FOCUS OF TODAY IS HIRN.
AS YOU'VE HEARD DR. RODGERS
POINT OUT THE LATEST PLAYER, THE
NEW KID ON THE BLOCK WHICH IS
THE CARDIOVASCULAR REPOSITORY IN
TYPE 1 DIABETES.
NOW, I KNOW THIS IS AN
INCOMPLETE TIME LINE BUT IT DOES
HELP TO POINT OUT TWO THINGS.
ONE, IT CAN TAKE A DECADE OR
MORE FOR THESE INITIATIVES TO
ACTUALLY BEAR FRUIT.
SO THERE IS A TIME COMPONENT
THERE.
AND IT TAKES CONSISTENT ENGAGED
COMMUNITY AND COLLABORATIVE
EFFORTS IN ORDER TO SEE THE
CHANGE IN CONCEPTS IN THE
PLENARY SESSIONS.
STARTING SOMETHING IS NEVER EASY
AND IT HAD IT OWN SET OF
CHALLENGES LISTED HERE THAT WILL
BE TOUCHED UPON IN THE PLENARY
SESSIONS.
I'VE BRIEFLY GIVEN YOU AN
EXAMPLE IN TERMS OF THE EARLY
PATHOGENIC EVENTS THAT HAPPENED
THROUGHOUT THE DISEASE.
BUT WITH EVERY GOOD CHALLENGE
THERE'S ALSO A SET OF
OPPORTUNITIES AGAIN ALL OF THESE
WILL BE HIGHLIGHTED LATER ON
DURING THE PLENARY SESSIONS BUT
FOR EXAMPLE WE CAN'T TAKE FOR
GRANTED THE FACT WE HAVE HUMAN
PANCREATIC TISSUE, ISLET, ALL
THESE CELLS AND TISSUES
AVAILABLE BECAUSE PEOPLE SPEND
THEIR CAREERS ESSENTIALLY
PROVIDING THIS FOR US AND MOVING
THINGS FORWARD.
SO WITH THAT THE MISSION OF HIRN
WAS AND IS UP HERE WHICH IS TO
UNDERSTAND HOW HUMAN BETA CELLS
ARE LOST IN THE DISEASE AND FIND
INNOVATIVE STRATEGIES TO PROTECT
OR REPLACE FUNCTIONAL BETA CELL
MASS.
WHAT I'LL EMPHASIZE HERE IS ONE
OF THE THINGS THAT WE'RE LOOKING
AT IS EARLY DISEASE DEVELOPMENT
BECAUSE WHAT WE'D LIKE IS TO
PREVENT THE DISEASE FROM
BEGINNING AT ALL.
THE WAY THIS STARTED WAS THROUGH
A GROUP AND EACH ONE OF THESE
BOX HERE AS DR. RODGERS POINTS
OUT REPRESENTS A DIFFERENT
THEME.
EACH ONE OF THESE THEM HAD FROM
FOUR TO SIX GROUPS WORKING
TOGETHER TO MEET SPECIFIC
OBJECTIVE.
THIS IS HOW IT LOOKED BACK IN
2014.
SOME OF YOU WILL HOPEFULLY
RECOGNIZE WHAT IT LOOKS LIKE
TODAY BUT THIS IS ABOUT 10 YEARS
AGO AND AGAIN DOWN THE STREET
WHEN WE STARTED.
FAST FORWARD TO NOT LAST WE'RE
BUT THE END OF THE YEAR BEFORE
THAT IN 2023, THIS WAS OUR LAST
HIRN MEETING.
SO, HOW DO YOU TAKE A BUNCH OF
PEOPLE WORKING INDIVIDUALLY OR
WITHIN THEIR GROUPS AND START
GETTING THEM TO WORK TOGETHER.
THIS IS A DIFFERENT LOOK AT THE
SLIDE DR. RODGERS SHOWED YOU
OUTLINING THE EVOLUTION OF HIRN.
AND I'D LIKE TO GO THROUGH SOME
OF THAT WITH YOU.
AGAIN IN 2014 WE STARTED OFF NOT
BEING CONNECTED WITH ONE ANOTHER
ADVANCING THROUGH IN 2019 TO
WHAT YOU SEE HERE TODAY.
SO LET ME WALK YOU THROUGH THESE
QUICKLY.
FIRST WE HAVE THE COORDINATING
CENTER AND THE BIO INFORMATICS
CENTER MERGING TO 42 HUMAN
RESEARCH CENTER AND I WON'T
COVER THAT THERE'S A POSTER FOR
THAT AND THE HUMAN ANALYSIS
CONSORTIUM AND GIVEN FROM
EFFORTS IN 2016 AS DR. RODGERS
SAID WHEN THERE WAS A
PHENOTYPING OF THE HUMAN
PANCREAS AND MAKING WIDELY
AVAILABLE.
IN THE BREAKOUT SESSIONS IF
YOU'RE INTERESTED ABOUT FINDING
OUT ABOUT THE PANCDB I THINK
THAT SESSION WILL HAPPEN LATER
SO YOU CAN FIND OUT MORE ABOUT
THAT.
AS DR. RODGERS ELUDED TO, HIRN
WAS NEVER DESIGN TO BE A
STAGNANT ORGANIZATION CONTR
CONTRASTING ON THE LATEST NEEDS.
THE CONSORTIUM TARGETING
REGENERATION FOLDED INTO THE
CONSORTIUM ON BETA CELL DEATH
AND SURVIVAL.
LIKEWISE THE CONE SHUM EMERGED
TO THE NEWEST KID ON THE BLOCK
THE CONSORTIUM ON MODELLING AUTO
IMMUNE DISEASE.
SO NEW THEY'LL BE MEETING FOR
THE FIRST TIME THIS MONTH.
LAST BUT NOT LEAST AS YOU HEARD
THE AGAIN AMBITIOUS EFFORTS TO
BRING HUMAN PANCREAS TOGETHER
AND DATA NOT ONLY FROM HIRN,
OUTSIDE OF HIRN AND I'LL
HIGHLIGHT THERE'S A BREAKOUT
SESSION THAT WILL BE HAPPENING
TOMORROW TO ADDRESS THAT.
NOW, EVERY ONE OF THESE
TRANSITIONS WERE PRECEDED BY AN
RFA.
THESE ARE OPEN OPPORTUNITIES
FROM ANYONE IN THE COMMUNITY TO
GET INVOLVED IN HIRN.
SO THE QUESTION IS WITH THIS
INFRASTRUCTURE IN PLACE, WHAT IS
HIRN ACCOMPLISHED AND WHERE IS
IT GOING?
THE PLENARY TALKS ARE GOING TO
ADDRESS THE SCIENCE OF WHERE
HIRN IS PLACED BUT I WANT TO
LOOK AT TWO DIFFERENT OTHER
ACCOMPLISHMENTS AND ONE IS IN
TERMS OF THE COLLABORATION AND
SCIENCE IN TERMS OF WHAT IT HAS
DONE TO THE COMMUNITY.
WHAT YOU'RE LOOKING AT HERE IS
AN ANALYSIS AROUND ABOUT 1,000
PAPERS HIRN PUBLISHED IN THE
LAST DECADE.
THE YELLOW DOTS ARE 300 OR SO
INVESTIGATORS FROM HIRN.
THE GREEN DOTS ARE OVER 4,000
INDIVIDUALS WHO HAVE NO
AFFILIATION FROM HIRN AND THOSE
BLUE LINES ARE 18,000
CONNECTIONS BETWEEN HIRN AND THE
COMMUNITY AROUND IT.
THERE IS ROOM FOR IMPROVEMENT
BUT WHAT I WANT TO POINT OUT IS
THAT OVER THE LAST DECADE HIRN
HAS AFFECTED OR CHANGES IN 12
COUNTRIES IN TERMS OF THESE
COLLABORATIONS.
109 INSTITUTIONS, OVER 800
INVESTIGATORS AND WHAT I MEAN BY
THAT IS THIS COULD BE TRAINEES,
THESE COULD BE POSTDOCS, THESE
COULD BE MPIs.
EVERYONE WHO HAS COME THROUGH
HIRN LABS AND AS I SAID OVER
18,000 CONNECTIONS.
THE SECOND EXAMPLE I WANT TO
HIGHLIGHT ARE THESE CAREER
ADVANCEMENTS.
AND HOW THESE HAPPEN IS ONE OF
TWO WAYS.
FIRST, OPEN ANNOUNCEMENTS FROM
NIH IN WHICH INDIVIDUALS CAN
COME IN THROUGH HIRN.
THE SECOND WAY IS THAT HIRN
ACTUALLY HAS ITS OWN FUNDING
ANNOUNCEMENT AND OWN FUNDING
OPPORTUNITIES AND SO INDIVIDUALS
CAN COME IN HERE AND I'M
HIGHLIGHTING FOR YOU FACULTY
MEMBERS THAT VERY RECENTLY IN
THE LAST FIVE TO SEVEN YEARS
EITHER GOT THEIR FACULTY
APPOINTMENT OR PROMOTED DURING
THE COURSE OF HIRN SO THERE'S A
FEW DIFFERENT FACES HERE, A
NUMBER OF THEM YOU'LL SEE TODAY
AS PART OF THIS PROGRAM.
IT ISN'T ONLY FACULTY POSITIONS,
PEOPLE GO FROM LABS.
THEY GO TO POLICY.
THEY GO TO INDUSTRY.
SO THERE'S A LOT OF DIFFERENT
WAYS THAT HIRN IS AFFECTING
CAREER GROWTH AND PROMOTION IN
THE FIELD.
SO THE OTHER THING I WANT TO
POINT OUT IS THESE OPPORTUNITIES
COME UP PERIODICALLY AND IN THE
BREAKOUT SESSIONS NOT ONLY WILL
YOU SEE A LOT OF THE THINGS THAT
WE'VE BEEN TALKING ABOUT TODAY
BUT ALSO FUNDING OPPORTUNITIES
AND SOME RECENT FUNDING
OPPORTUNITIES THAT WILL BE
COMING UP IN HIRN AS WELL AND
WE'LL BE TALKING ABOUT THAT
DURING THE DAY 2.
SO WITH THAT OVER THE COURSE OF
10 YEARS WE'VE HAD OVER 20
STRATEGIC PARTNERS.
I HIGHLIGHTED SOME OF THOSE
HERE.
I HAVEN'T GOTTEN A CHANCE TO
TALK ABOUT THEM LIKE DK NET
HELPING WITH DATA INFORMATION
AND EXCHANGE AND SUCH AND POINT
OUT THE GENEROUS GIVING OF
FAMILIES THAT GIVE US THEIR
TISSUES AND APPRECIATION ORGANS
FOR US TO STUDY.
I DO WANT TO ACKNOWLEDGE SO
REALLY IN MY LAB WHO CREATE THE
FIGURE AND OTHER DATA THAT
DIDN'T SHOW UP IN THE
PRESENTATION TODAY AND SOME OF
OUR PARTNERS THAT MAKE THE
COFFEE AND THE TEA AND DRINKS SO
KINDLY AVAILABLE TO US.
BUT I WOULD BE REMISS IF I ALSO
NOT ACKNOWLEDGE THE PLANNING
COMMITTEE AS WELL.
THIS IS A GROUP OF PEOPLE THAT
HAVE BEEN MEETING OVER THE LAST
SEVERAL MONTHS, CALLS, E-MAILS,
COMMUNICATION TO BRING THIS
MEETING TOGETHER WITH YOU AND
THEN ALSO I WANT TO POINT OUT TO
YOU JUST TO HIGHLIGHT A FEW
PEOPLE.
RAFAEL AND RODRIGO AND LEO
TERROROOO -- FERERRO AND CHRIS D
ABRAHAM WHO HAVE BEEN GREAT
CONTACTS IN FACILITATING
EVERYTHING ON THE NIH CAMPUS AND
THEN I WILL EMBARRASS NELL Y
BERGER AND FOR THOSE INVOLVED
YOU KNOW THEY FACILITATE A LOT
OF THINGS.
AS I SUSPECT TODAY AS YOU HAVE
QUESTIONS, THESE ARE THE FACES
YOU WANT TO BE LOOKING FOR.
NOW, HIRN IS DIFFERENT IN SOME
WAYS IN THERE IS HEAVY
PROGRAMATIC INVOLVEMENT AND THAT
MAKES SIRN -- HIRN A SUCCESS
AND I WANT TO ACKNOWLEDGE THE
OFFICIALS THAT PARTICIPATE
THREE, FOUR, FIVE TIMES ON THE
CALLS AND BEING ACTIVELY ENGAGED
WITH THE COMMUNITY AND THAT'S
BEEN A REAL HELP AS WELL.
CAREEN WHO I DIDN'T OUT UP BUT
WAS INVOLVED IN OUR COORDINATING
CENTER EFFORT.
I REMEMBER THAT AS WELL.
WITH ALL THAT NOW WE CAN JUMP
INTO THE SCIENCE WHICH I THINK
YOU ALL ARE EXCITED TO HEAR
ABOUT.
THIS IS PROBABLY THE EASIEST
PRESENTATION OR EASIEST
INTRODUCTION I HAVE TO GIVE.
MOST OF US KNOW DR. MARK
ATKINSON AT THE UNIVERSITY OF
FLORIDA, SCHOLAR.
HE PUBLISH CLOSE TO 450 PAPERS
AND HIS LIFE'S PASSION IS
LEARNING ABOUT THE PATHOGENESIS
OF HIS DISEASE AND MANY OF US
KNOW ABOUT HIS HUMANITARIAN
EFFORTS.
40 YEARS HE'S BEEN IN THE FIELD
OF TYPE I DIABETES AND I'VE HAD
THE PRIVILEGE OF WORKING
ALONGSIDE HIM 20 OF THOSE YEARS.
MOST WILL AGREE WHEN WE SAY MARK
IS A GENEROUS MAN IN TERMS OF
HIS TIME AND ENCOURAGING TO THE
YOUNGER FACULTY.
SO WITH THAT I'D LIKE TO
INTRODUCE MARK.
>> IS ALL THAT APPLAUSE IS TO
YOU.
AND THANK YOU EVERYBODY FOR
COMING HERE TODAY.
>> MY GOAL IS TALKING ABOUT THE
SUCCESS STORIES AFFILIATED WITH
THE IN TYPE I DIABETES.
IN SETTING UP THE TALK TODAY AND
WHERE DO WE BEGIN THE STORY WITH
OUR JOURNEY.
LET'S GO BACK ABOUT 100 YEARS TO
WHERE WE KNOW ABOUT THE
PRE-INSULIN ERA.
>> YOU'D HAVE TWO-THIRDS TO 75%
MORTALITY BECAUSE THERE WAS NO
REAL MEANS.
THIS AGAIN, THIS IS THE
PRE-INSULIN AREA TO TREAT.
AND A BIO CHEMIST CAME ALONG
NAMED FRED ALLEN AND HE CAME UP
WITH THE NOVEL CONCEPT YOU HEAR
ABOUT, THE LOW CARBOHYDRATE PLUS
EXERCISE DIET.
FRED TOOK DOGS AND CATS AND DID
PARTIAL PANCREECTOMY AND LOOKED
AT YOUNG PATIENTS WITH DIABETES
AND TALKED ABOUT A MIRACLE
FACILITY YOU CAN SEE ON THE
RIGHT-HAND SIDE THE BUILDING
DR. ALLEN AND THE PATIENTS COME
IN THE MORNING AND SPEND AN HOUR
OR SO RUNNING UP AND DOWN THE
STAIRS AND THEN GIVEN THESE
DIETS NO LOWER THAN 150 CALORIES
AND ABOUT 400 CALORIES A DAY AND
NO MORE THAN 1,000 CALORIES A
DAY.
IT IF KEEP A CERTAIN PERCENTAGE
OF PEOPLE ALIVE BUT THE REAL
BREAKTHROUGH IS WHAT WE
CELEBRATED WITH THE CENTENNIAL
OF THE DISEASE IN CANADA AND
TAKING BOVINE AND PORCINE
PANCREASES AND TAKING THIS AND
ROLLING THIS OUT AND SENDING IT
OVER TO DEVELOP TO DEVELOP THE
PRODUCT OF INSULIN.
AGAIN, MOST OF US HAVE SEEN THIS
PICTURE HERE OF THE CHILD ON THE
LEFT-HAND SIDE AND THEN THE
CHILD AFTER HAVING RECEIVED
INSULIN BUT THE CHILD ON THE
LEFT WAS TREATED WITH THE ALLEN
DIET AND YOU CAN SEE HOW MUCH
BETTER INSULIN IS FOR SOMEBODY
WITH THIS DISEASE.
AGAIN, IN THE TORONTO PAPERS AT
THE TIME THE NOTION WAS THAT
WE'RE ON THE CUSP OF A YOU'RE
FOR DIABETES.
SO THIS IS EARLY, EARLY IN THE
JOURNEY.
THANKFULLY THERE HAS BEEN MANY
MANY MANY ADVANCES SINCE THEN 37
IF YOU LOOK OVER THAT TIME
PERIOD AND I'M NOT GOING TO ALL
THE WAYS THAT THERE ARE BUT FROM
THE WAY WE MEASURE COMPLIANCE TO
MEASURE INSULIN AND DIFFERENT
TYPES OF INSULIN WE HAD AND
AGAIN WE'VE MADE THE DISEASE
MORE MANAGEABLE AND THE
TREATMENT HAS CHANGED
DRAMATICALLY BUT WE DON'T HAVE A
CURE YET.
AND SO I DON'T WANT ANYBODY TO
BE DISCOURAGED.
I HAVE A FRIEND AND JORDAN IF
YOU CAN SWITCH OVER, I HAVE AN
INDIVIDUAL THAT LIVES A COUPLE
HOURS SOUTH OF ME IN ORLANDO,
FLORIDA.
HE WAS DIAGNOSED WITH TYPE I AT
THE AGE OF 6 IN 1957 AND I'VE
ASKED HER TO SHARE HOW THE
JOURNEY HAS BEEN FOR HER AND
MORE IMPORTANTLY HOW RESEARCH
THE TYPE OF RESEARCH YOU DO AS
CHANGED HER LIFE AND SO JORDAN,
PLEASE.
>> HI, I'M BRENDA MARTINEZ.
I'M 74 YEARS OLD AND DIAGNOSED
WITH TYPE I DIABETES IN 1967, I
WAS 6-YEAR-OLD OLD.
MOM WAS GIVEN A STRICT DIET FOR
ME TO FOLLOW AND INSTRUCTIONS
HOW TO ADMINISTER INSULIN.
MOM GAVE ME ONE SHOT PER DAY.
ONCE THE INSULIN WAS IN MY BODY
I HAD TO EAT REGARDLESS OF
APPETITE.
WE FOUND OUT QUICKLY I HAD TO
EAT ON TIME FOR ALL MEALS OR
SUFFER THE RESULTS OF LOW BLOOD
SUGAR.
TO HELP THE DOCTOR DETERMINE
EFFICACY OF THE REGIMENT WE
LOGGED THE RESULTS OF TESTS FOUR
TIMES A DAY.
WHEN I WAS ABOUT 11 I BEGAN TO
TAKE MY OWN SHOTS AND MANAGE
WAYS FOR MY BLOOD SUGAR AND
FOLLOWED THIS FOR AT LEAST 16
YEARS.
THE NEXT GAME CHANGER WAS THE
HOME BLOOD GLUCOSE MONITOR.
FOR THE FIRST TIME I COULD SEE
MY BLOOD SUGAR LEVEL IN REAL
TIME AND COULD ADJUST MY DIET
ACCORDING TO THOSE RESULTS.
1996 BROUGHT TWO WONDERFUL
CHANGES.
RAPID ACTING INSULIN AND INSULIN
PROMPT.
RAPID ACTING INSULIN BEGAN
ACTING MORE QUICKLY THAN THE
OLDER INSULINS DID.
THE INSULIN PUMP FREED ME FROM
HAVING TO EAT FOOD TO MATCH MY
INSULIN.
NOW I COULD TAKE IT TO MATCH
WHAT I ATE WHEN I CHOSE TO EAT.
CONTINUOUS GLUCOSE MONITORS HAVE
BEEN THE BIGGEST GAME CHANGER
YET.
I'M NOT LIMITED TOE CHECK IN
JUST FOUR TIMES A DAY.
NOW I CAN ALWAYS KNOW WHAT MY
BLOOD SUGAR IS.
I'VE TAUGHT CHILDREN FOR 30
YEARS AND IN MY LAST YEAR I HAD
THREE STUDENTS WITH DIABETES.
WE HAD A SPECIAL UNDERSTANDING
ALMOST AN EXCLUSIVE CLUB BECAUSE
WE GOT IT.
ENCOURAGED WITH THE KNOWLEDGE WE
AND SCIENTISTS ARE WORKING TO
NOT ONLY FIND A CURE BUT RAISED
TO MAKE OUR LIVES WITH DIABETES
EASIER IN THE MEANTIME IS
INVALUABLE.
>> MY THANKS AGAIN TO BRENDA.
IT WAS AN AMAZING INTERVIEW WITH
HER AND IT WAS A CUT DOWN
VERSION OF IT BUT IT SHOWS HOW
AGAIN RESEARCH CAN IMPACT THE
LIFE AND IT IT'S TO KNOW GOING
FROM ONE SHOT A DAY INSULIN TO
THIS WHERE WE ARE TODAY IS A BIG
FACTOR.
LET'S NOW SWITCH GEARS JUST A
LITTLE BIT AND WHAT I WANTED TO
DO IS TO SAY, ALL RIGHT, WHETHER
YOU MENTIONED A NUMBER OF THESE
CHANGES, LET'S GO THROUGH THEM
WHAT WE'VE SEEN AND THEN TAKE
SOME OF THEM THAT HAVE IMPACT
WITH HIRN.
I POLLED EXPERTS ACROSS THE
COUNTRY FAR SMARTER THAN ME AND
SAID I HAVE A PILOT LIST AND
WITH A FEW ADDITIONS IT WAS
UNIVERSALLY THOUGHT EVERYBODY
MAY HAVE THEIR OPINIONS.
EVERY ONE OF THESE ADVANCEMENTS
THANKS TO NIDDK AND THEY'RE
CELEBRATING THEIR 75th
ANNIVERSARY AND SOME LIKE THE
INSULIN FORMULATIONS AND THE CGM
BRENDA MEASURED AND MANAGEMENT
TOOLS ARE DIRECTLY IMPACTED BY
WHAT YOU AS HIRN INVESTIGATORS
WILL DO ONE DAY BUT THE BOTTOM
FIVE I THINK ARE MORE DIRECTLY
RELATED AND LET'S SEE HOW WHAT I
WANT TO DO IS GO THROUGH THEM
AND SEE HOW HIRN CAN MAKE A
DIFFERENCE AND IMPACT.
THE FIRST ONE I WANT TO TALK
WITH IS DEFINING DIABETES AS AN
AUTO IMMUNE DISEASE.
ON THE RIGHT SIDE OF THE SCREEN
IS THE THREE DIMENSIONAL VIEW OF
HUMAN INSULINITIS AND IT WAS A
DESCRIPTION FIRST FOUND IN 1903
BY A GERMAN PATHOLOGIST NOTING
SOME PEOPLE WHO HAD THIS FORM OF
DIABETES HAD A WHITE BLOOD CELL
OR CELLULAR INFILTRATE OF IT.
WE NOW KNOW WE HAVE LOSS OF BETA
CELLS AND IN THE OTHER THOUGHT
IS THIS FORMS A FUNDAMENTAL
BASIS FOR TYPE I DIABETES AND
AUTO IMMUNE DISEASE BUT THE
PANCREAS IS NOT A TISSUE YOU CAN
BIOPSY AND SOME GROUPS IT WERE
DIRECTLY RELATED AND WE NEED
GREATER BIOMEDICALS THAT MAY
TELL US WHAT IS GOING ON AT THE
SITE OF THE DESCRIPTIONIVE
PROCESS.
MANY OF THE HIRN GROUPS ARE
WORKING ON THAT.
SO A VERY EFFECTIVE USE OF HIRN.
ANOTHER MAJOR TOP 10 ADVANCE HAS
BEEN IN THE AREA OF GENETICS AND
SEROLOGICAL BIOMARKERS AND
PEOPLE THOUGHT THERE WERE ONE TO
THREE GENES OR LOCI THAT FORM
THE GENETIC BASIS OF TYPE I
DIABETES AND NOW WE KNOW THERE'S
OVER 100 AND THE BIG ONE IS HLA1
HIGHLIGHTED IN BLUE, THE
MOLECULE THAT IS POLY GENIC BY
NATURE AND VARIES BETWEEN US BUT
INDIVIDUALS WITH A FORM OF HLA
FORM THE LARGEST FORM OF
INDIVIDUALS WITH TYPE I DIABETES
AND THERE'S OTHER GENES INVOLVED
IN MANY THINGS FROM BETA CELLS
TO PANCREAS DEVELOPMENT TO
IMMUNE RESPONSE SHOWN HERE THAT
FORM PART OF THESE LOCI AND SO
HIRN HAS A CHANCE TO REALLY GET
INVOLVED HERE AND TRY TO FIND
WHAT IT DOES.
ANOTHER NEW DEVELOPMENT IS TO
TAKE WHEN YOU HAVE SO MANY LOCI
HOW CAN YOU COMBINED THEM TO
MAKE THEM SOMETHING MORE
EFFECTIVE IN TERMS OF AND HAVE
IMPACT AND THAT'S SHOEB HERE 1
>> WITH GENETIC RISK SCORES AND
SEPARATE THOSE WITH TYPE I OR
MONOGENIC DIABETES.
IN THIS STAGE IN DIAGNOSIS HAS
IMPLICATIONS THE RATE PATIENT IS
TREATED WITH WITH THE RIGHT DRUG
AT THE RIGHT TIME.
AND ANOTHER AREA IS ABOUT THE
BENEFITS OF THE SEROLOGICAL
MARKER DISCOVERIES STARTED OUT
IN THE MID TO MID '70s AND
ANTIBODIES AND MANY LISTED HERE
AND THERE'S A WHOLE CONSORTIUM
WITH MANY DIFFERENT SITES
WORKING ON THESE DATA AND OTHERS
LIKE IT, IT WAS FOUND WHEN YOU
FOLLOW RELATIVES AT RISK FOR
TYPE I DIABETES AT ONE TIME AND
IF YOU HAVE ONE ANTIBODY THE
OVER ALL RISK FOR DEVELOPING
TYPE I IN 10 OR 20 YEARS IS
LOWER THAN FOR SOMETHING WITH
THREE AUTO ANTIBODIES AND WE
KNOW SIMILAR FINDINGS OCCUR.
WHAT'S THE BIG DEAL ABOUT MOVING
TO GENERAL POPULATION?
IT'S CURRENTLY ESTIMATED BETWEEN
85% AND 92% OF NEW ONSET CASES
OF DIABETES DON'T OCCUR IN
INDIVIDUAL WITH A FAMILY HISTORY
OF DISEASE.
THAT'S THE GREAT FRONTIER AND
MANY PROGRAMS HAVE BEEN FORMED
AND INTERNATIONAL DATA ON THIS.
BUT THERE ARE NEEDS THERE.
THEY PROVIDE BENEFIT.
IF YOU SCREEN YOU HAVE REDUCED
RISK FOR DKA.
WE CAN IDENTIFY PEOPLE TO BE PUT
IN TRIALS.
BUT THERE ARE NEEDS FOR MORE.
WE NEED BIOMARKERS THAT CAN BE
USED WITH AUTO ANTIBODIES AND WE
NEED TO FIND OUT WHAT TAKES
SOMETHING FROM RISK TO DISEASE
TO DEVELOPMENT AND HIRN STUDIES
HAVE THE OPPORTUNITY TO ADD TO
THAT KNOWLEDGE BASE.
AND ANOTHER ONE AND THIS MAY BE
ONE OF MY FAVORITE ADVANCES IN
THE JOURNEY IS IMPROVED STUDIES
OF THE NATURAL HISTORY OF
DIABETES STARTING IN 1986 AND
THIS IS PROBABLY THE MOST SHOWN
FIGURE AND POWER POINT
PRESENTATIONS IN THE LAST 50
YEARS IS THIS MODEL OF NATURAL
HISTORY STARTING WITH A BETA
CELLS FOR REASONS STILL UNKNOWN
THERE BEGINS A PROCESS OF LOSS
OF BETA CELLS THAT EVENTUALLY
RESULTS IN INSULIN DEPENDENCE.
SOME OF THESE INITIAL THOUGHTS
HAVE UNDER GONE MODIFICATION BUT
SERVED AS AN INCREDIBLE ROAD MAP
FOR GENERATIONS TO UNDERSTAND
THE DISEASE.
FAST FORWARD TO DISEASE AND THE
MODEL ON THE RIGHT SIDE IS
UNDERGOING CHANGES BUT NOW YOU
LEARN A FEW TALKS TODAY ABOUT
STAGES OF TYPE I.
WE TALK ABOUT STAGE I DISEASE
PEOPLE WITH TWO OR MORE
ANTIBODIES AND NO DISCERNIBLE
METABOLIC ABNORMALITIES AND
STAGE II, MULTIPLE ANTIBODIES
AND ASSOCIATED WITH DYSGLYCEMIA
AND STAGE II THE DIAGNOSIS OF
DIABETES AND DESCRIBING
INSULINITIS AND WHEN IT OCCURS
AND AT WHAT STAGE WE DON'T KNOW
WHAT TO CALL IT YET MANY SOME
CALL IT STAGE ZERO OR SOME CALL
IT STAGE .5, THERE ARE BETA CELL
ABNORMALITIES OCCUR BEFORE
PEOPLE DEVELOP MULTIPLE
ANTIBODIES AND THEY'RE
CONTINUING TO PUSH FORWARD IN
STUDIES ON ENVIRONMENTAL AGENT.
-- AGENTS.
THE NEXT THING IS AUTO IMMUNE
THERAPIES.
THIS MAY BE OBVIOUS WITH ALL THE
HIRN PROJECTS THAT HAVE
IMMUNOLOGY IN THEM BUT IT'S NOT
A NEW CONCEPT.
THE FIRST TRIALS BEGAN WITH
CYCLOSPORIN AND THE TOXICITIES
ASSOCIATED WITH IT PRECLUDED ITS
USE BUT WHERE DID IT LEAVE US?
THAT DIDN'T STALL.
IT'S ESTIMATED SINCE
CYCLOSPORINE MANY HAVE
PARTICIPATED IN THE TRIALS.
IT'S BEEN INEFFICIENT AND WE RUN
CLINICAL TRIALS VERY WELL IN
THANKS DUE TO EFFORTS
DR. RODGERS MENTIONED.
THE PROBLEM OF SUCCESS STORIES
HAS BEEN LOW.
THAT CHANGED WITH THIS NTCD3
SHOWN ON THE RIGHT.
THE FIRST IN-CLASS FDA APPROVED
DRUG THAT AS IS SHOWN IN THE
MIDDLE THERE AND IN MATCH
POPULATIONS AT RISK FOR DIABETES
IF YOU ADMINISTER THIS DRUG YOU
HAVE THE POTENTIAL TO DELAY
SYMPTOMATIC ONSET FROM 27 MONTHS
OUT TO THREE YEARS.
EFFORTS ARE GOING ON TO IMPROVE
THAT BUT WE DO HAVE A SUCCESS
STORY NOW.
IT'S FUNNY AFTER ALL THESE YEARS
OF HAVING LIMITED SUCCESS NOW WE
HAVE A LOT OF DRUGS SHOWING
SUCCESS AND THIS ARTICLE WAS
LATE LAST YEAR IN THE LANCET
SHOWING WE NOW HAVE ABOUT 10
DRUGS IMMUNE MODULATORS WITH THE
ABILITY TO PROVIDE BENEFIT BUT
WE STILL DON'T KNOW WHAT CAUSES
TYPE I DIABETES AT A MOLECULAR
LEVEL AND HIRN IS WORKING ON
THAT AND THERE'S OTHER ISSUES
THE COMMUNITY HAS TO WORK ON
INCLUDING HOW TO TREAT WHEN AND
WHAT WITH.
THERE'S TWO MORE AREAS AND MANY
PATIENTS BENEFIT FROM PANCREAS
AND KIDNEY TRANSPLANTATION.
YOU WANT TO TALK ABOUT THE GROUP
IN ST. LOUIS OR THEIR
PREDECESS
PREDECESSORS AND THE GROUP BACK
IN 2004 AND THE FIRST CARTICO
STEROID FREE USE OF ISLETS
SHOWING POSITIVE BENEFIT AND TWO
CAREERS LATER THIS WAS PUT
THROUGH AN INTERNATIONAL
CONSORTIUM TO REPEAT.
WE'VE LEARNED A LOT FROM ISLET
CELL TRANSPLANTATION AND 55
PATIENTS AND 10,000 ORGAN DONORS
THERE'S A MATH PROBLEM.
BUS WHEN YOU TALK ABOUT AL
ALLOGENEIC SETTING AND SHOWING
IS THIS OPTIMAL?
THE LAST BIG DISCOVERY I WANT TO
GO THROUGH BEFORE I CLOSE OUT IS
THAT THE WHOLE PROCESS OF ISLET
ISOLATION AND STUDIES IN ISLET
BIOLOGY AND CELL DEVELOPMENT AND
REPLICATION AND TALKING WITH
AUDREY AND THEY WERE SAYING THE
STEM CELL FIELD WOULD NOT BE
WHERE IT IS WITHOUT THIS AREA OF
ADVANCE.
YOU CAN GO FROM THE RECORDING
CHAMBERS SYSTEM HERE OF 25 YEARS
AGO TO ISOLATE ISLETS.
WE LEARNED HOW TO STUDY ISLETS
THROUGH THESE NOTIONS BUT ISSUES
FROM COST, SCALABILITY, UNKNOWNS
ARE OUT THERE.
SO THE FUTURE AND AGAIN I'M NOT
GOING IN DEEP HERE BECAUSE
YOU'LL HEAR WITH THE NEXT TWO
SPEAKERS A LOT OF THE FUTURE IS
IN STEM CELLS.
IS IS IS CAN CAN
AGE IS ON THE BOTTOM AND OUR
INDICATOR OF MANAGEMENT IS ON
THE OTHER AXIS.
WHAT YOU CAN SEE IS WITH TIME WE
ARE GETTING A LITTLE BIT BETTER
BUT AT THE BOTTOM OUR ADA
TARGETS ARE 7 AND SOME ARE
MEETING IT BUT THE VAST MAJORITY
DON'T MEET AND THERE'S A GAP
BETWEEN MEETING CLINICAL
THERAPEUTIC TARGETS AND WHERE
WARE AND THE REASONS RANK FROM
COST, EDUCATION, DEVICE, TRYING
TO EDUCATE PEOPLE TO USE IT,
REIMBURSEMENT AND ACCESS ISSUES
IF YOU START TO THINK ABOUT
GLOBALLY.
WE NEED TO DO THINGS BETTER
DESPITE EVERYTHING BRENDA SAID
AND SHE'S HAPPY AS CAN BE BUT
THERE'S MORE.
AND THERE'S ALL THE MENTAL
HEALTH CARE ISSUES WE'VE BEEN
AFRAID TO SPEAK OF.
THE FEAR OF COMPLICATIONS AND
LIFESTYLE ISSUES AND MENTAL
HEALTH CARE COSTS AND THE
CHALLENGES BOTH WITHIN THE
FAMILY, WITHIN THE COMMUNITY AND
WITHIN EMPLOYMENT SETTINGS AND
SCHOOL SETTINGS.
AND HERE'S AS LOU PHILLIPSON
TOLD ME ABOUT THIS AND I SAID
WHERE DID YOU HEAR THIS AND I
LOOKED IT UP.
PEOPLE WITH TYPE II DIABETES
TAKE MORE THAN 180 ADDITIONAL
DECISIONS A DAY AND MARK THAT
OUT BY WEEKS, MONTHS, YEARS,
THAT'S A LOT OF THOUGHTS.
IF IT'S LACED WITH THESE
CONCEPTUALIZATIONS, THERE'S A
NEED FOR IMPROVEMENT.
HIRN HELPED CHANGE THIS COURSE
AND MY THOUGHT WAS WHAT HAPPENED
IN THE PAST AND WHAT IS HIRN
POISED TO DO AND WHAT HAS IT
DONE IN ITS 10 YEARS.
THIS ONE WHEN WE TALKED TO
OLIVIER AND THE NUMBER ONE
ACCOMPLISHMENT OF HIRN IS IT
FACILITATED A FOCUS OF IT TYPE I
DIABETES IS A STUDY OF HUMAN
DISEASE AND HUMAN TISSUES.
THE GROUP YOU'VE SEEN WITH ALL
THE REPORTS ARE DOWNLOADABLE AS
PDFs.
THERE'S THE SITE FOR IT SO IF
YOU WANT TO GET REAL IN DEPTH TO
WHAT HIRN'S DONE THE REPORTS ARE
GOOD AS IS THE SPECIAL ISSUE OF
MOLECULAR METABOLISM THAT CAME
OUT.
AND NOT GOING TO SPEND TOO MUCH
TIME HERE BECAUSE JOHN WENT
THROUGH IT BUT ONE THE MAIN
ACHIEVEMENTS OF HIRN IN THE 10
YEARS HAS BEEN TO DEFINE THE
MANY MANY ROLES FOR BETA AND
ISLET CELL DISEASE AND AGAIN
YOU'LL HEAR PEOPLE FROM
RICHARDSON TO KRAUS AND OTHERS
THROUGHOUT THIS TALK BRING UP
SOME OF THESE.
THIS IS A FUNDAMENTAL CHANGE OF
THOUGHT.
AGAIN, FOR MOST OF MY EXISTENCE
THE BETA CELLS WERE FINE WHILE
MAYBE THEY HAD CHALLENGES AND
SOME STRESS BUT THE CHINK OF --
CHUNK WAS ON THE IMMUNE SIDE AND
WE'RE STARTING TO POKE THE BEAR
ON THAT ONE AND SEE WHAT'S
INVOLVED HERE.
ANOTHER THING I THINK TALKING
ABOUT TRANSLATIONAL IS THE WAY
HIRN HAS HELPED DEFINE THE BETA
CELL PROLIFERATION.
TALK ABOUT A BLACK BOX FOR
DECADES.
HOW DO YOU GET A BETA CELL
DESIGN AND WHAT'S THE DIFFERENCE
BETWEEN MOUSE AND HUMAN BETA
CELLS AND HUGE PROGRESS AND HIRN
CAN TAKE PRIDE IN THAT IN IN
VITRO AND IN VIVO MOVING FORWARD
AND DEVELOPING NOVEL SYSTEMS AND
TECHNOLOGIES.
THEY BROUGHT TOGETHER BIO
MEDICAL ENGINEERS AND BIOLOGISTS
AND CELL BIOLOGISTS AND
DEVELOPED SYSTEMS AND SOME LABS
DON'T LOOK LIKE MY LAB IN THE
LOWER LEFT WHERE THERE'S DESIGN
KITS TO DO STUFF AND MAKING
MODULAR DEVICES TO GO FROM A
PANCREAS ON A CHIP AND THE AREA
IN THE PURPLE IS AN ISLET AND
YOU CAN VISUALIZE BETA CELL
KILLING.
AND BOTH SPEAKERS MENTIONED HIRN
AND WE THANK KLAUS AND THE GROUP
THERE FOR MAKING PANCDB SPECIAL.
THEY SAID OPEN ACCESS SHARING
WAS AN IMPORTANT FEATURE AND IT
MADE IT A VERY DIFFERENT
FEATURE.
THE OPPOSING FEATURE OF NPOD AND
THEY GIVE UM SAMPLES AND HOPE
DATA COMES BACK AND HIRN GETS
THE SAMPLES AND ANALYZES THE
DATA AND THE TWO IN TANDEM WORK
TOGETHER INCREDIBLY WELL.
THAT'S IMPORTANT.
THE FINAL THING I THINK HIRN HAS
DONE IS HIT HARD ON THE
INTERFACE OF BETA CELL AND AUTO
IMMUNITY.
WE AGAIN HISTORICALLY WE'VE BEEN
SILOED AS A COMMUNITY.
WE HAVE CLINICAL CONFERENCES AND
CELL BIOLOGY CONFERENCES AND
AUTO IMMUNITY CONFERENCES AND I
THINK WITHIN HIRN IT'S ONE OF
THE RICHEST GROUPS OUT THERE
BECAUSE YOU HAVE IT ALL HERE.
AND YET IT'S GOING TO TAKE THAT
TYPE OF EFFORT IN ORDER TO
FIGURE OUT THESE TYPES OF NEEDS
AND INTERACTION.
SO, HIRN IS POISED TO CHANGE THE
COURSE AND IMPROVE TYPE I
DIABETES MANAGEMENT IN THE
FUTURE.
I FIRMLY BELIEVE THAT.
WHAT I DON'T KNOW IS WHAT BOXES
ARE YOU AS HIRN INVESTIGATORS
GOING TO FILL IN.
WHAT ADVANCES WILL YOU TAKE IN
TERMS OF ADDING ANOTHER COG TO
THIS TURNING.
WITH THAT THANK YOU AND TO NIDDK
AND ALL THE HUNDREDS OF HIRN
INVESTIGATORS AND ORGAN DONORS
AND THEIR FAMILIES WHO MAKE
THESE POSSIBLE AND PATIENTS
THEMSELVES WITH THEIR
WILLINGNESS TO PARTICIPATE AND
RESEARCH IN THE COURSE OF THE
DISEASE.
THANK YOU.
[APPLAUSE]
>> OKAY.
IT'S BREAK TIME BUT WE'RE STILL
GOING TO COME BACK AT 10:20.
WE WERE STILL RUNNING AHEAD OF
SCHEDULE TECHNICALLY.
WE'LL START AT 10:20.
CATCH YOU IN A FEW MINUTES. THANK YOU.
WE'RE GOING TO START THE
SECOND HALF OF THE PLENARY
SESSIONS.
IN THE FIRST HALF, MARK WAS
LOOKING IN THE PAST AND
PROJECTING WHAT WE NEEDED FOR
THE FUTURE BUT WE HAVE AN
EXCITING SET OF TALKS THIS
MORNING WHERE WE'RE GOING TO
EXAMINE IN SOME DETAIL THE
FUTURE AND SO I HAVE THE
PRIVILEGE OF SHARING WITH YOU
OUR FIRST SPEAKER IN THIS
SESSION, DR. HOLGER RUSS WHO IS
AN ASSOCIATE PROFESSOR CAN
ANYBODY HEAR THIS.
SORRY, I GUESS THAT WOULD
EXPLAIN WHY EVERYBODY KEEPS
TALKING.
SO WE ARE GOING TO START THE
SECOND SESSION HEAR SO IF YOU
CAN FIND YOUR -- HERE AND SO IF
YOU CAN FIND YOUR SEAT AND HAVE
T
PRIVILEGE OF INTRODUCING HOLGER
RUSS TO YOU AT THE UNIVERSITY OF
FLORIDA.
HOLGER'S BEEN DOING FANTASTIC
WORK.
LET'S WELCOME HOLGER.
>> THANK YOU, JOHN.
NICE TO SEE FAMILIAR FACES AND
UNFAMILIAR FACES HOPEFULLY WE'LL
GET TO KNOW LATER IN THE
AUDIENCE.
I'M HUMBLED AND IN A SENSE
HONORED TO GIVE THIS
PRESENTATION A NEW DAWN IN TYPE
I DIABETES RESEARCH WITH AUDREY
PARENT ASSOCIATE PROFESSOR AT
UCSF AND I'LL HAND OVER THE
FLOOR LATER TO HER.
I WANT TO START OFF WITH THE
FUNDAMENTALS ABOUT LIKE WHAT
HIRN STANDS FOR AND THIS GOES IN
A WAY AS PROBABLY MANY IN THE
AUDIENCE FOR ME MY CAREER
DEVELOPMENT WENT ALONG AND I'M
PROBABLY A PRODUCT IMPRINTED BY
WHAT HIRN STANDS FOR.
THE KEY MISSION AND I READ THAT
OUT AGAIN, UNDERSTAND HOW HUMAN
BETA CELLS ARE LOST IN TYPE I
DIABETES AND FIND INNOVATIVE
WAYS TO PROTECT OR REPLACE
FUNCTIONAL BETA CELL MASS IN
PEOPLE WITH THE DISEASE.
THERE'S BEEN TREMENDOUS
IMPROVEMENT IN OUR DISEASE
UNDERSTANDING IN THE HUMAN
CONTEXT THROUGH HER.
YET, IS A LOT OF THE
TRANSLATIONAL WORK FROM BEFORE
STILL HAS SUFFERED FROM
TRANSLATION.
I THINK NOW WHAT WE NEED TO
EMPHASIZE WITH THE IMMUNE
MODULATION AND MANY DIFFERENT
APPROACHES THAT WE ACTUALLY
START TO HARVEST THE FRUIT FROM
LOOKING MORE INTO THE DETAILED
MECHANISM OF THE DISEASE.
HOWEVER, WE STILL DON'T
UNDERSTAND THE FUNDAMENTAL
DETAILS OF THE DISEASE
ESPECIALLY IN A STRATIFIED
PERSONALIZED MANNER.
YOU NEED TO UNDERSTAND THE
PROBLEM TO INTELLIGENTLY FIX IT.
WE HAVE THIS STATEMENT DOWN IN
MY MIND MAYBE ON MY HOME PAGE AS
WELL THAT WE NEED DETAILED
UNDERSTANDING MOLECULAR AND
CELLULAR MECHANISMS THAT RESULT
AND TRIGGER THE DISEASE AND ITS
PROGRESSION AND THAT WILL ALLOW
FORWARD PAYMENT TO DEVELOPING
NOVEL BIOMEDICALS AND
INTERVENTION MODALITIES.
SO IN THE LAST COUPLE TALKS WE
HEARD A LOT ABOUT HIRN AND I
WANT TO EMPHASIZE THERE'S THREE
MAIN POINTS.
ONE IS COLLABORATION.
WE'RE ALL DIFFERENT INDIVIDUALS
WITH DIFFERENT VIEW POINTS AND
WE COME TOGETHER TO DISCUSS AND
CHALLENGE EACH OTHER AND MOVE
THE FIELD FORWARD AND THEN THE
OTHER PART IS THE HUMAN DEEP
PHENOTYPING, CHARACTERIZATION OF
DISEASE STAGES COMBINED WITH THE
MODELLING ASPECT AND
REDISTRICTING OF FOCUS WE'RE NOW
FOCUSSING ON THE HUMAN PANCREAS
UNDER STUDIED AREAS OF THE
DISEASE.
HOW'S THAT LOOK IN REAL LIFE?
HPAP AND INDDP HAVE DONE A
TREMENDOUS JOB IN ESTABLISHING
LARGE COLLECTIONS OF PRIMARY
TISSUE.
AND THROUGH DISCOVERY AND
CHARACTERIZATION OF AVAILABLE
TECHNOLOGY WE UNDERSTAND THE
DISEASE IN THE HUMAN CONTEXT
BETTER AND THAT WE CAN SHARE AND
MAKE ACCESSIBLE TO THE
SCIENTIFIC COMMUNITY.
SO PROMOTE INNOVATION BUT AT THE
SAME TIME WE CAN USE THE
KNOWLEDGE AND INTEGRATE IT WITH
DISEASE MODELLING AND DISEASE
MODELLING IS ALWAYS A REDUCTIVE
PROCESS WHERE WE TRY TO BREAK
DOWN THE FUNDAMENTALS AND LOOK
AT A PERSPECTIVE ACTION OF THE
DISEASE.
WE NEED COMPLEMENTARY APPROACHES
TO DO THIS AND THEY BENEFIT FROM
NOVEL TECHNOLOGY DEVELOPMENT
WITH OTHER FIELDS AND OUR FIELD
AS WELL AS NEW SCIENTIFIC
CONCEPT AND AS SUCH BECAUSE MORE
PEOPLE THINK OF THE DISEASE WE
ATTRACT TALENT.
THEN WHAT WE LEARN IN THE
DISEASE MODELLING CONTEXT WHERE
WE CAN MANIPULATE AND USE GENOME
ENGINEERING AND LOOK AT DISTINCT
FEATURES WE CAN NOW RE-INTEGRATE
THIS KNOWLEDGE INTO THE LARGE
DATABASES AND TEST IS WHAT WE
LEARNED IN A REDUCTIVE MODELS
ACTUALLY HOLDING TRUE IN
PATIENTS.
FLIES THERE'S ANOTHER COMPONENT
AND THE SINGLE CELL DEVELOP THE
IS KEY AND APPRECIATE MORE THAN
IMMUNE CELLS ARE CHANGED IN THE
DISEASE ESPECIALLY EARLY ON.
WE WILL HEAR ON ALL THESE POINTS
COMING UP ON DETAIL AND WITH THE
LARGE DATA SETS WE CANNOT JUST
LOOK AT ONE MODALITY BUT USE
MULTI-OMIC AND PLUG AND PLAY
MACHINE LEARNING AND ARTIFICIAL
INTELLIGENCE IN THERE.
WHAT IS ALSO HAPPENING NOW ONCE
THE RESOURCES ARE ESTABLISHED
THE CAN BE UTILIZED IN THE CYCLE
OF RESEARCH AND USE SPATIAL
TRANSCRIPTOMICS WHERE WE LEARN
HOW THE CHANGED CELLS ARE IN
RELATION TO EACH OTHER.
ANOTHER FRONTIER.
OKAY.
SO THIS REDEFINED OUR
UNDERSTANDING OF TYPE I DIABETES
BUT WHAT ARE THE QUESTIONS THAT
REVISED DERIVED FROM THAT?
WE HAVE OXIDATIVE STRESS, ER
STRESS, NEOEPITOPE FORMATION AND
AUTOPHAGY AND PROCESSING IS
CHANGED, SENESCENCE AND HLA IS A
HIGH INFORMATION WHICH PROBABLY
INCREASES IMMUNE GENICITY AND
PLL1 AND HOW CAN WE MODEL THEM
IN THE DISH?
WE CAN USE DIFFERENT APPROACHES.
WE CHANGE METABOLIC DEMAND AND
CYTOKINES AND HEAR ABOUT THE
FINE TUBING IN TALKS AND MIMIC
VIRAL INFECTION AND IN THE
FUTURE WHAT WE SHOULD AIM TO
REALLY ASK OURSELVES, DO WE
MODEL THE DISEASE IN A
PHYSIOLOGICAL RELEVANT MANNER?
DO WE HAVE TO DO BETTER?
AND WE HAVE TO HARBOR ON THIS
POINT BECAUSE WE DON'T WANT TO
GO DOWN THE WRONG RABBIT HOLE.
WE WANT TO BE WITHIN THE REALM
OF WHAT HAPPENS IN A PATIENT
BECAUSE WE MODEL THE DISEASE.
THAT BRINGS OF COURSE THE
QUESTION OF OKAY, I LIST ALL
THESE POTENTIAL OUTCOMES AND
STRESS FACTORS SO WHAT DOES EACH
STRESS FACTOR DO?
WHAT DOES IT CHANGE WITHIN THE
CELLS AND IS THERE SYNERGY
BETWEEN THE DIFFERENT FACTORS?
NOW, WHEN WE DO OUR MANIPULATION
AND LOOK AT THE CELLS WE
SHOULDN'T USE THE FLASHLIGHT
EFFECT AND THIS IS OUR FAVORITE
SPOT WITH THE FLASHLIGHT BUT
FOCUS ON UNBIASSED ANALYSIS
APPROACHES WE CAN SEE THE WHOLE
PICTURE WHICH ALSO LEADS INTO
THAT WE NEED TO EVALUATE UNKNOWN
OR UNDER STATED FACTORS AND
PATHWAYS WITHIN THE DISEASE
PROGRESSION.
THIS TROPE OF KNOWLEDGE WE HAVE
NOW.
SO WHAT IS MISSING FROM THIS
PATH?
LET'S LOOK IN THE AREAS WHERE
NOT EVERYBODY'S LOOKING.
OKAY, THIS IS JUST EXTERNAL
ENVIRONMENTAL STRESS.
HOW DOES THAT RELATE TO GENETIC
RISK.
WE KNOW OVER 100 LOCI ARE HAVING
DIFFERENT RATIOS OF RISK FOR
DEVELOPING THE DISEASE.
SO WE NEED TO UNDERSTAND THE
MODE OF ACTION OF EACH ONE OF
THEM.
WE WANT TO PRIORITIZE HIGHEST
RISK ON AND THEN COMBINE THIS
WITH EXTERNAL STRESS.
YOU CAN APPRECIATE THIS GETS
EXCEEDINGLY COMPLICATED.
I LIKE TO THINK OF IT THAT
DISEASE WITH PHENOTYPIC IMPACT
WAS DISGUISED DISTRIBUTION YOU
CAN HAVE A DIFFERENT PROFILE FOR
EACH LOCI AND WITH OTHER STRESS
FACTORS YOU CAN GET A SHIFT NOT
JUST INTO MORE RISK BUT INTO
LESS RISK WHERE WE ULTIMATELY
LOOK.
OF COURSE WHEN WE NOW GET
INSIGHTS FROM THESE STUDIES THE
MODEL SYSTEMS WE NEED TO VERIFY
THIS AND BLOCK IT BACK INTO
LARGE DATA SETS WHICH PEOPLE
ALREADY DO.
YOU CAN DOWNLOAD THE DATA AND
TEST YOUR HYPOTHESIS AND THIS A
GREAT WAY FORWARD.
BUT THIS IS ONLY THE BETA CELL
AS I TALKED ABOUT.
WHAT ABOUT INTEGRATION OF OTHER
CELL TYPES?
IT WILL BE CRITICAL MOVING
FORWARD TO REALLY HAVE CULTURES
AND INTERACTION MODEL OF CELLS.
CELLS FROM THE PERSPECTIVE NOW
WHEN I STARTED IN THE FIELD
THERE WAS REALLY LIKE SILOS.
SO BETA CELL BIOLOGISTS AND
IMMUNOLOGISTS.
AND WHEN I STARTED I THOUGHT CDs
SUCH AS MUSIC BUT TURNS OUT
THEY'RE SURFACE MARKERS.
SO THEY NEED TO TALK TO EACH
OTHER AND I JUST USE THE TWO
GROUPS AS AN EXAMPLE.
ACTUALLY, WE NEED TO BRING MUCH
MORE PEOPLE AND YOU ARE THE
REPRESENTATIVE OF THE GROUP 67
PEOPLE TOGETHER TO ILLUMINATE
THE BLACK BOX OF TYPE I DIABETES
BETTER.
WE START WITH WHAT WE KNOW BEST
WHICH IS THE T CELL WHICH
UNDOUBTEDLY IS CRITICAL FOR THE
CONSTRUCTION OF BETA CELLS AND
PROBABLY THE BEST STUDIED TODAY.
AND WE HAVE THROUGH STUDIES WE
HAVE A GOOD UNDERSTANDING OF
INFORMATION ON TCR NATURAL GAS
AND ISLETS FROM TYPE I PATIENTS.
SO CAN WE USE THEM TO START TO
EVALUATE HOW GENETIC AND
ENVIRONMENTAL RISK IN THOSE TWO
CELL TYPES WHEN PUT TOGETHER
INTERACT WITH EACH OTHER.
ARE THEY PROTECTIVE OR
ACTIVATING MECHANISMS?
WHAT IS IT DOING IN EACH CONCEPT
AND THE PERMUTATIONS ARE QUITE
LARGE AND IN A PHYSIOLOGICAL
LEVEL.
THERE'S GOOD EXAMPLES OF THIS.
FOR EXAMPLE, WHEN WE LOOK AT
IMMUNE MODULATION IN SENESCENCE
AND HAS BEEN SHOWN TO PROTECT IN
REAL LIFE EXAMPLE HUMAN BETA
CELLS SO IF YOU EXPOSE HUMAN
BETA CELLS WITH PROINFLAMMATORY
ENVIRONMENT THEY UPREGULATE
PDL-1.
IT'S ALSO USED IN CERTAIN
CANCERS.
CANCER PATIENTS WHO RECEIVE
IMMUNE CHECKPOINT INHIBITERS TO
MESS WITH THIS PATHWAY SOME
DEVELOP DIABETES WHICH IS AN
AUTO IMMUNE DIABETES CELL PROVEN
THE BETA CELL HAS THE ABILITY TO
PROTECT ITSELF FROM AUTO
IMMUNITY.
CAN WE IDENTIFY OTHER PATHWAYS?
YOU CAN THINK OF AND THIS A
REDUCTION AREA AND WHAT IS THE
INFLUENCE OF PARACRINE
MECHANISMS AND THE CELL-CELL
CONNECTIVITY AND EXTRA CELLULAR
VESICLES AND WHAT PROTECTS THE
CELLS WHICH IS IN THE DISEASE
PROTECTING IT.
ANOTHER POINT WHICH INTERESTED
IN HEARING ABOUT TOMORROW IS A
LOT OF THE TCRs IN PATIENTS ARE
REACTIVE TO ANTIGENS FOREMOST
INSULIN WHICH IS A KEY ROLE BUT
MANY ARE UNKNOWN.
SO THERE'S A ROLE FOR LOOKING AT
NEOOPEN NEOEPITOPE AND IS THERE
A ROLE FOR UNKNOWN EPITOPES TO
BREAK THE DISEASE AND BREAK T
TOLERA
TOLERANCE.
WE NEED TO GET TO THESE QUES
QUESTIQUESTION
S TO DEFINE THE DISEASE BETTER
AND IT'S MORE COMPLICATED WHEN
YOU LOOK CLOSER AND CAN SUB
DIVIDE BY TRANSCRIPTOMIC
ANALYSIS THERE ARE MANY BETA
CELLS.
THAT'S THE T CELL BUT THERE'S
MANY MORE IMMUNE CELLS I'M NOT
AN EXPERT IN BUT THERE ARE MORE.
WHAT ABOUT THE B CELLS AND
DENDRITIC CELLS BUT OVER ALL
THERE IS MORE CHANGES NOT JUST
IN THE BETA CELL BUT IN THE
PRESENTATION OF HUMAN DIABETES
IN GENERAL.
WE SEE LESS INSULITIS AND YOU
CAN HAVE ONE THAT LOOKS HEALTHY
AND ANOTHER THAT HAS ACTIVE AUTO
IMMUNITY.
WHAT TRIGGERS THE DIFFERENCE?
HOW IS IT IMPORTANT AND HOW DO
THE T CELLS COME TO THE SITE OF
THE AND THE SITE OF ACTION IS
WHERE IT HAPPENS?
THESE ARE THINGS WE NEED TO
REALLY ADDRESS.
I DON'T EVEN KNOW HOW WE CAN GET
AT THE DIFFERENTIAL PROGRESSION
TIME BETWEEN PATIENTS BUT WE
NEED TO START THINKING ABOUT
THIS AND OVER ALL UNDERSTANDING
THE CONTRIBUTION OF IMMUNE CELLS
AND CAN WE DEVELOP BETTER MODELS
TO GET THE IDEA TO MANIPULATE
AND TEST AGAIN IN PRIMARY
TISSUE.
IT TRIGGERS IN A WAY THE CHICKEN
AND EGG QUESTION.
NOW WE HAVE PANCREAS AND IMMUNE
CELLS AND IS IT ALWAYS THE
MECHANISM?
I DON'T THINK IT'S TYPE I BUT
TYPE 100.
YOU HAVE PROBABLY DIFFERENT WAYS
THAT CAB RESULT IN TO THE SAME
OUTCOME DESTRUCTION OF BETA
CELLS.
OKAY.
WHAT ABOUT OTHER CELL TYPES, NOT
THAT I ALREADY RAMBLED ON ABOUT
ENOUGH OF THEM BUT WHAT ABOUT
OTHER ONES WE PREVIOUSLY HAVEN'T
THOUGHT OF?
WE'LL SEE A NICE TALK THAT SHOWS
THAT ALPHA CELLS THAT DON'T
HAVE -- NOT TARGETS BY AUTO
IMMUNITY ARE IMPAIRED EVEN
BEFORE STAGE 1?
WHAT IS THE ROLE?
DO THEY HAVE AN ACTIVE ROLE BY
TRIGGER BETA CELLS IN THE
DISEASE PROGRESSION?
CAN WE LEARN WHY THEY'RE NOT
GETTING DESTROYED?
THESE ARE THINGS TO CONSIDER.
THERE'S MANY MORE CHANGES IN THE
PANCREAS IN GENERAL THAT HAPPEN
EARLY ON.
THERE'S A LOSS OF THE BASAL
MEMBRANE WHICH DIRECTS T CELLS
TO COME IN EARLIER AND
SYMPATHETIC INNERVATION AND THE
TISSUE IS SMALLER.
HOW CAN WE MAKE SENSE OF THIS
AND LEVERAGE THE KNOWLEDGE OVER
THE LAST 10 YEARS HAS EMERGED
FROM HIRN AND THE WIDER TYPE I
RESEARCH SPACE FOR THE BENEFIT
OF PATIENTS.
I PUT UP THE ISENBERG CURVE AND
THERE'S EARLY IMPAIRMENTS IN
MULTIPLE TISSUES AND CELL TYPES.
CAN WE NOW FIND WAYS TO BETTER
PREDICT THE DISEASE?
DOES IT HAVE TO BE IN A PATIENT
SPECIFIC MANNER AND USE IT FOR
DISCOVERY AND ULTIMATELY CAN WE
MODULATE THE CHANGES IN
INDIVIDUAL CELL TYPES OR IN CELL
TYPES TOGETHER TO REALLY PREVENT
THE DISEASE FROM OCCURRING IN
THE FIRST PLACE?
AND THIS IS TO ME AT LEAST A
PRIME EXAMPLE HOW THE FORESIGHT
INVESTING INTO BASIC RESEARCH
AND UNDERSTANDING FUNDAMENTAL
DISEASE MECHANISM IN A HUMAN
CONTEXT IS NOW ALLOWING US AND
WE SEE THE DISEASE MODIFYING
THERAPIES THAT ARE FDA APPROVED
AND MANY MORE AS WE LEARN IN THE
PIPELINE.
I THINK THIS IS THE DIRECT
RESULT.
THIS IS GREAT.
SHOULD WE ONLY FOCUS ON WHAT WE
LEARNED SO FAR OR HOW DO WE PAY
FORWARD MOVING ON?
I DON'T ARGUE WE HAVE A ROAD MAP
BY THE PANCREAS HOW WE DID IN
DEPTH COHORTS AND DO THAT WITH
CELL TYPES ASSOCIATED WITH THE
DISEASE AND THYMUS?
IS THERE A WILL DEFECT IN THE
EDUCATION OF THE REPERTOIRE AND
WHAT IS THE ROLE OF THE LYMPH
NODE FOR THE ACTIVATION OF THE
IMMUNE SYSTEM AND SPLEEN AND
PROBABLY MORE I HAVEN'T THOUGHT
OF MORE.
AND WHEN WE PHENOTYPE WE NEED TO
BE ABLE TO MANIPULATE IT AND
FUNNEL IT BACK TO OUR PRIMARY
TISSUES.
AND I BELIEVE THAT'S HOPEFULLY
NOT 10 YEARS BUT SEVEN WILL
RESULT IN BETTER PREDICTIVE
MEASUREMENT AND READ WHAT TYPE I
DIABETES IS IN THE LARGER
CONTEXT.
WHEN I WAS ON THE PHONE CALL
WITH THE PANELISTS AND THE
PLANNING COMMITTEE, IT'S
ACTUALLY WAS SUGGESTED TO ME
WE'RE NOT GOING IN CIRCLES.
WE'RE ACTUALLY GOING DOWN THE
RABBIT HOLE LIKE ALICE.
WE'RE FALLING DOWN THIS SPIRAL
AND CONTINUOUSLY IMPROVING BY
INTEGRATING NOVEL TECHNOLOGY,
SCIENTIFIC CONCEPTS AND NOW
WE'RE AT THE STAGE WE CAN TAKE
EVEN INSIGHTS FROM HUMAN TRIAL
DATA BECAUSE THE FIRST
INTERVENTIONS AND IDEAS WE HAVE
REALLY MANIFEST IN BENEFIT FOR
THE PATIENT.
WE CAN INTEGRATE THIS INTO OUR
KNOWLEDGE BASE TO MOVE ON DOWN,
SHARE WITH THE SCIENTIFIC
COMMUNITY NOT JUST SHARE BUT
MAKE THE DATA ACCESSIBLE AND
ACCELERATE INNOVATION IN THIS TO
HOPEFULLY FIND A CURE.
SO, IF THIS WAS A BIT MUCH, WHAT
I HOPE YOU CAN TAKE TAKEAWAY
FROM THIS IS TYPE I IS A
COMPLEX, MULTI-FACTORIAL DISEASE
THAT I HOPE YOU APPRECIATE
FUNDAMENTAL DISEASE
UNDERSTANDING IS NEEDED AND
NEEDS TO BE DONE RIGHT.
WE NEED TO EVALUATE TYPE I
ASSOCIATED OR MEDIATING FACTORS
IN A SINGLE BUT MUCH MORE
IMPORTANT NETWORK LEVEL.
THAT WE NEED TO CAPITALIZE OR
CONTINUE CAPITALIZING ON
EXISTING OFFICES AND
INFRASTRUCTURE AND CONTINUE
PAVING THE BASIC RESEARCH FOR
WAR AND HAVE UNBIASSED DIGITAL
ANALYSIS APPROACHES OVER YANG
ANALOG APPROACHES AND WHAT WE
HAVEN'T DONE YET AS A COMMUNITY
FROM MY PERSPECTIVE IS FOCUS ON
INDIVIDUALS THAT ARE PROTECTED.
THOSE INDIVIDUALS THAT HAVE TWO
ALTERED ANTIBODIES BUT NEVER
DEVELOPED THE DISEASE.
HOW IS THAT?
AND CAN WE LEARN FROM THIS?
FOR THE YOUNGER GENERATIONS
QUESTION ESTABLISHED HYPOTHESIS.
GO BACK, READ THE OLD PAPERS.
THINK OF HOW TO USE NEW
TECHNOLOGY TO QUESTION IN MORE
DETAIL THE EXISTING DOGMAS AND
THINK OUTSIDE OF THE BOX BECAUSE
WE NEED STILL A LOT OF
INNOVATION AND THE OTHER TAKE
HOME IS IT TAKES A VILLAGE.
WE NEED TO WORK TOGETHER AND
FOSTER DIALOGUE AND CHALLENGE
EACH OTHER AND SHARE OUR
KNOWLEDGE FREELY AND THAT IS IN
THE SPIRIT OF KEEPING OUR EYES
ON THE PRIZE AND FOSTER THE WORK
BECAUSE I THINK WE'RE ALL
WORKING REALLY HARD FOR THIS AND
MAYBE WE CAN LOOK BACK ON OUR
SUCCESSES IN A LITTLE WHILE.
SO, WITH THIS WHILE THIS WAS ALL
CONCEPTUALLY DRIVEN I WANT TO
HAND THE FLOOR OVER TO AUDREY
PARENT ASSOCIATE PROFESSOR AT
UCSF TO TELL YOU MORE IN ACUTE
OR CONCRETE STEPS HOW THIS CAN
BE FACILITATED.
THANK YOU SO MUCH.
>> HOLGER, THANK YOU, THAT WAS
EXCITING AND SETS THE STAGE FOR
MY PART.
HOW THAT WE HEARD ABOUT OUR
THINKING OF THE DISEASE AND
ESPECIALLY THE EARLY STAGE OF
THE DISEASE IS EVOLVING I WANT
TO DIG INTO HOW TO VALIDATE
THESE IDEAS AND TRANSLATE THE
MECHANISTIC OBSERVATIONS AND
TURN THEM INTO BETTER CLINICAL
OUTCOMES.
I'LL SPEND A LITTLE BIT OF TIME
TALKING ABOUT THE TOOLS AND
MODELS IS INEVITABLE TO VALIDATE
SOME OF THE FINDINGS THAT WERE
GENERATED TO THE CYCLE HOLGER
DESCRIBED AND HOW TO DO THAT
KEEPING AN EYE ON INFORMATION
AND CLOSE WITH SOME DISCUSSION
ABOUT WHAT ARE THE CURRENT
THERAPIES THAT ARE UNDER
EVALUATION IN PATIENTS AND ALSO
TOUCH ON SOME OF THE REMAINING
BARRIERS AND HOW RESEARCH CAN
HELP ADDRESS SOME OF THESE
BARRIERS.
SO WHEN WE THINK ABOUT MODELLING
TYPE I DIABETES ONE OF THE
CHALLENGES IS THE COMPLEXITY OF
THE DISEASE.
THIS IS MY TAKE ON IT.
THERE'S A LOT OF DIFFERENT CELL
TYPES.
IT'S PROBABLY ALREADY MISSING
SOME AND EVOLVING QUITE RAPIDLY
BUT THE POINT I WANTED TO MAKE
IS IT'S COMPLICATED AND WHEN WE
ARE TALKING ABOUT PLATFORMS TO
MODEL WE NEED TO TAKE THIS INTO
ACCOUNT AND FOCUS ON INTEGRATING
THE COMPLICATED INTERACTIONS.
ANOTHER POINT IS WE NEED TO
INTEGRATE AS MUCH AS POSSIBLE
HUMANIZED COMPONENT.
SO THERE ARE A LOT OF CELL TYPE
SPECIFIC DIFFERENCES BETWEEN
SPECIES AND AWAY HEARD ABOUT
MOUSE BETA CELLS NOT BEING
EQUIVALENT TO HUMAN BETA CELLS
AND THERE WERE EXCELLENT MOUSE
BETA CELLS AND HAD NO EFFECT AT
ALL ON HUMAN BETA CELLS AND
MAKES THE CASE FOR STUDYING
HUMAN CELLS AS MUCH POSSIBLE.
WHAT DO WE HAVE AVAILABLE TO
START BUILDING THE COMPLEX
MODELS.
THERE'S A LOT OF THINGS BUT I
WANTED TO HIGHLIGHT TWO AREAS
WHICH I THINK HAVE EVOLVED IN
THE LAST FEW YEARS.
ONE IS ACCESS TO HUMAN DONOR
TISSUE CONTROL AND TYPE I
DIABETES.
THERE'S A LOT OF THINGS
AVAILABLE WHETHER IT'S BLOOD,
STEM CELLS, PANCREAS, THYMUS,
THERE'S A LOT OF THINGS I CAN
USE AND LIMITATIONS OF ALL THESE
THINGS WHEN WE TALK ABOUT HUMAN
DONORS ONE THING IS TO GET THEM
FROM PATIENTS SO YOU CAN WORK
WITH T CELLS THAT WERE PULLED
OUT OF THE PANCREAS FROM THE
TYPE 1 PATIENT.
HOWEVER, THERE'S LIMITATION IN
TERMS OF MATCHING THESE
DIFFERENT CELL TYPES.
WE'VE BEEN TALKING ABOUT LOOKING
AT INTERACTIONS BETWEEN CELLS IF
YOU WANT TO LOOK AT ISLETS AND T
CELLS, ONE OF THE KEY COMPONENT
IS IT THEY NEED TO BE
GENETICALLY MATCHED.
IF THEY DON'T HAVE THE SAME HLAs
YOU'RE NOT GOING TOE LOOK AT
AUTO IMMUNITY BUT TRANSPLANT
REJECTION WHICH IS A DIFFERENT
MECHANISM.
THAT'S ONE OF THE LIMITATION AND
THE VARIABILITY BETWEEN DONORS
IS SOMETHING TO TAKE INTO
ACCOUNT.
SO ANYONE THAT'S WORKED WITH
HUMAN ISLETS KNOWS THERE'S A
WIDE RANGE OF NORMAL WHEN IT
COMES TO THESE ISLETS.
AS AN ALTERNATIVE WE'VE BEEN
PUTTING EFFORT INTO PLURIPOTENT
STEM CELLS AND IT'S SCALABILITY
AND YOU CAN MAKE A TON OF THEM
AND GIVE RISE TO ANY CELL TYPE
IN THE BODY.
FOR EXAMPLE WE ALREADY HAVE
PROTOCOLS TO GENERATE THE
DIFFERENT CELLS AND IT'S A
POWERFUL SYSTEM.
THE MAIN MANAGE IS THEY'LL BE
GENETICALLY IDENTICAL GETTING
RID OF THE HLA MATCHING PROBLEM
AND YOU CAN INTRODUCE WHATEVER
GENETIC MANIPULATION YOU'RE
INTERESTED IN.
HOWEVER, SOMETHING TO KEEP IN
MIND IN GENERAL THEY TEND TO BE
LESS MATURE THAN THEIR PRIMARY
COU
COUNTERPARTS SO SOMETHING TO
KEEP IN MIND.
ONCE YOU IDENTIFY TO THE SOURCE
HOW DO YOU GO GOOD LOOKING AT
THE DIFFERENT INTERACTIONS.
THERE'S A LOT OF IN VITRO
MODELS.
I WANTED TO TALK ABOUT THESE TWO
BECAUSE THEY HIGHLIGHT THE
IMPORTANCE OF LOOKING AT
DIFFERENT CELL TYPES AND HOW
THEY INTERACT AND ONE IS THE
TISSUE IN A CHIP.
A LOT OF THE WORK HAS BEEN
SPEARHEADED BY HIRN
INVESTIGATORS.
SO BASICALLY THE GOAL IS TO
INTEGRATE THE ISLETS INTO
DEVICES AND TRY TO RECREATE AS
MUCH POSSIBLE THEIR
MICROENVIRONMENT WHETHER IT'S
EXTRA CELLULAR MATRIX, VASCU
VASCULARIZATION AND FLOW OF
CELLS WHICH ALLOWS YOU TO GET A
MORE PHYSIOLOGICAL SYSTEM.
YOU CAN USE THAT TO LOOK AT CELL
MIGRATION AND LOOK AT CELL
INTERACTIONS IN A WAY NOT
POSSIBLE WITH STATIC CULTURES.
THE OTHER ONE I WANTED TO
INTRODUCE IS THE LIVING
PANCREATIC SLICES.
THIS IS A LITTLE BIT NEWER
PLATFORM BUT THIS IS BASICALLY
TAKING A FRESH PIECE OF PANCREAS
AND SLICE IT AND PUT THEM INTO
CULTURE.
YOU LOOK AT ISLETS EMBEDDED IN
THEIR NORMAL MICROENVIRONMENT
AND YOU HAVE VASCULARIZATION AND
NEURONS AND DIFFERENT CELL TYPES
STILL PRESENT.
WHEN YOU THINK HOW TO MODEL CELL
TO CELL INTERACTION IT'S A NICE
MODEL.
AND NOT GOING MUCH INTO DETAIL.
THERE'S SOME TALKS LATER IN THE
MEETING TO SHOW YOU REAL LIFE
APPLICATION OF THESE MODELS.
LOOKING FORWARD TO SEEING THEM.
ONE POINT I DID WANT TO MAKE IS
THAT ESPECIALLY FOR THE TISSUE
ON A CHIP PART, THIS IS A REAL
GOOD EXAMPLE OF HOW HIRN HAS
BEEN ABLE TO BRING TOGETHER
EXPERTISE FROM DIFFERENT PEOPLE
IN ORDER TO MAKE TISSUE ON A TIP
TECHNOLOGY YOU NEED BIO
ENGINEERS, YOU NEED VASCULAR
BIOLOGISTS TO ALL WORK TOGETHER.
IT'S A SUCCESS STORY OF THE IDEA
OF BRINGING PEOPLE TOGETHER AND
PROMOTING TEAM SCIENCE.
I'M GOING TO TOUCH ON IN VIVO.
THERE'S ALWAYS TO BE A PLACE FOR
IN VIVO ESPECIALLY IF YOU THINK
OF CLINICAL TRANSLATION.
THERE'S A LOT OF DIFFERENT
OPTIONS AND DEPENDING ON YOUR
QUESTION IT'S WORTH LOOKING INTO
THE DIFFERENT MODELS.
FOR EXAMPLE IF YOU'RE INTERESTED
IN ISLET SURVIVAL AND
IMMUNODEFICIENT MODELS ARE
PERFECTLY FINE.
AS WE MOVE TOWARDS INTERACTION
IMMUNE CELL IMMUNIZED MOUSE
MODELS MAY BE REQUIRED.
I DON'T HAVE TIME TO GO INTO
DETAILS BUT THESE ARE HIGHLY
CUSTOMIZABLE DEPENDING STRAIN
YOU'LL GET DIFFERENT FLAVORS OF
THE IMMUNE SYSTEM.
SO IT'S WORTH DIGGING INTO THE
LIMITATION OF EACH MODEL AND
THINKING THROUGH YOU'RE RESEARCH
QUESTION SO YOU CAN PICK THE
RIGHT MODEL TO ANSWER.
THEN I WANTED TO ALSO HAVE UP
THERE IMMUNOCOMPETENT MODEL AND
NO MOUSE MODEL REPLICATES THE
DISEASE AND PART OF THE
PROCESSES WE WANT TO STUDY.
SO SOMETIMES YOU NEED A WHOLE
IMMUNE SYSTEM.
THERE'S STILL A PLACE FOR MODELS
THAT HAVE BEEN CRITICAL TO GET
US TO THE POINT WHERE WE ARE
NOW.
THERE'S NEW TECHNOLOGIES THAT
CAN BE APPLIED TO THAT AND
INTRODUCE HUMAN GENES THE TRANS
IMMUNE MICE AND REPRODUCE IT AND
TO LOOK AT THE CELL TYPES AND
MODELS FOR PIG AND NON HUMAN
PRIMATES AND WANTED TO HAVE THEM
UP THERE.
ANOTHER PLACE WHERE I THINK THE
COMPLEMENTARY EXPERTISE IS
HIGHLIGHTED IS IN THE DEVELOPED
HUMAN MOUSE MODELS AND IT'S
COMPLICATED AND TAKES A VILLAGE
TO MAKE IT HAPPEN AND HIRN HAS
BEEN GREAT AT SUPPORTING AND
PUTTING RESOURCES BEHIND THE
COMPLICATED PROBLEM.
SO WE HAVE THESE MODELS.
HOW CAN WE ACTUALLY USE THEM TO
ACCELERATE TRANSLATION?
IT'S A COMPLICATED PROBLEM.
AS WE HEARD WE GENERATED ALL
THIS INFORMATION AND HAVE A LOT
OF NEW HYPOTHESIS BUT HOW CAN WE
START TO HAVE THE INFORMATION
AND GET TO THE PATHWAY IS
CRITICAL FOR DISEASE PROGRESSION
AND THE TARGETS LIKELY TO LEAD
TO SUCCESSFUL TRANSLATION?
I THINK THIS IS WHERE THE MODELS
ARE REALLY IMPORTANT.
THEY CAN TAKE US FROM HYPOTHESIS
GENERATING STUDIES TO FUNCTIONAL
STUDIES TO REALLY VALIDATE SOME
OF THESE TARGETS.
YOU CAN MAKE A MUTATION IN YOUR
CELLS AND OVERPRESS IT AND
INTRODUCE ENVIRONMENTAL FACTOR
AND TRESS THE CELLS AND LAYER
FACTORS AND DOES IT AFFECT THEIR
TRANSACTION DOES IT MAKE IT MORE
OR LESS IMMUNOGENIC?
DOES IT CHANGE THE BIOMARKER
YOU'RE INTERESTED IN AND START
TO DIG INTO THE MECHANISM OF
THIS.
YOU CAN DO DRUG SKREEJ --
SCREENING AND IT'S A GOOD WAY TO
START GETTING DATA FOR PRE
CLINICAL TESTING.
THIS IS PROBABLY AN OPPORTUNITY
TO START LOOKING AT COMBINATION
THERAPIES.
I'LL TOUCH OWN THAT LATER BUT
MOST LIKELY WE'LL HAVE TO
COMBINE DIFFERENT STRATEGIES.
IT'S A NOT THAT EASY TO DO IN
PATIENTS SO I THINK THERE'S
OPPORTUNITIES HERE TO GATHER
SOME PROOF OF CONCEPT AND WE'LL
LIKELY HAVE TO GO WITH A
MULTI-PRONGED APPROACH.
A LOT OF DIFFERENT STRATEGIES
ARE BEING DEVELOPED MOST OF THEM
FALL INTO CATEGORIES EITHER THE
TARGET OF THE IMMUNE SYSTEM WE
NEED TO SOLVE THAT ISSUE AND THE
OTHER ARM IS PROTECTING BETA
CELL FUNCTION AND LOOK AT THOSE
TWO THINGS TOGETHER.
THERE'S DIFFERENT OPTIONS BEING
TESTED.
SOME FAILED AND SOME ARE LOOKING
PROMPTING.
THERE'S CELL BASED THERAPIES AND
A LOT OF THEM HAVE THE AIM AIM
TO REBALANCE THE IMMUNE SYSTEM.
4:AND YOU CAN HAVE TOO MUCH
ACTIVITY IN YOUR IMMUNE SYSTEM
AND NOT ENOUGH SUPPRESSION.
WHENEVER THE TREATMENT IS THE
GOAL IS IT TO REBALANCE THIS BY
REDUCING THE ACTIVITY OF THE
IMMUNE SYSTEM OR INCREASING
SUPPRESSION.
YOU CAN DO THAT BY TARGETING A
LOT OF DIFFERENT CELL TYPES AND
IMPROVE SUPPRESSION BY STANDING
TREGS AND TREAT WITH JACK
INHIBITERS.
THERE'S DIFFERENT OPPORTUNITIES
AND YOU CAN DISCUSS THE
DIFFERENT ATTORNEY GENERALS.
MOVING ON TO THE STRATEGIES MORE
FOCUSSED ON BETA CELLS.
AND THINK ABOUT CELL REPLACEMENT
THERAPIES.
I CO WANT TO TALK A BIT ABOUT
CELL REPLACEMENT THERAPIES.
THERE'S A LOT OF EXCITING THINGS
HAPPENING IN THAT SPACE.
I'VE BEEN WORKING IN THE FIELD
MANY YEARS NOW AND THERE'S A
CHANGE IN THE WAY WE THINK ABOUT
THIS.
IT'S EXCITING TIME TO BE WORKING
ON THIS.
I WANTED TO PUT THE FIGURE UP
HERE AND TAKE THIS FROM A ROW
VIEW WHERE THOUGHT LEADERS IN
THE FIELD WITH THE SUPPORTERS
BUILD THE ROAD MAP HOW WE THINK
ABOUT THEY WILL WE PLACEMENT
THERAPY WITH BROAD
IMMUNOEXPRESSION.
THAT WORKS.
THERE'S SOME ISSUES WITH
SCALABILITY AND IMMUNE
EXPRESSION.
THERE STILL NEEDS TO BE
ALTERNATIVES DEVELOPED.
THE FIRST GENERATION IS LIKELY
GOING TO BE STEM CELL DERIVED
ISLETS.
THERE ARE CURRENT CLINICAL
TRIALS AND THE VERTEX TRIAL AND
THERE WAS A PATIENT IN CHINA WHO
GOT TREATED WITH THEIR OWN IPS
DERIVED ISLETS AND TURNED THEM
INTO STEM CELLS AND TRANSPLANT
THEM BACK.
THIS IS EXCITING.
THIS IS DONE UNDER PNEUMO
EXPRES --
IMM
IMMUNOEXPRESSION.
THE NEXT GENERATION WILL REDUCE
IMMUNE GENICITY AND I'M EXCITED
TO SEE WHAT'S GOING TO HAPPEN
THERE.
ONE EXAMPLE IS THE LACK OF
THERAPEUTICS WHETHER IT'S SMALL
MOLECULES OR ANTIBODIES OR SOME
CELL-BASED THERAPIES I THINK WE
CAN DO BETTER IN TERMS OF
INCREASING THE SPECIFICITY.
HOW CAN WE DELIVER THEM TO THE
RIGHT PLACE.
HOW CAN WE GET THEM TO GO
STRAIGHT TO THE BETA CELLS AND
ACTIVATE LOCALLY.
THERE'S OPPORTUNITIES THERE
ESPECIALLY WITH CELL-BASED
THERAPY AND WE'LL HEAR ABOUT
SOME OF THE STRATEGIES LATER
DURING THE MEET.
-- MEETING.
ANOTHER THING I THINK IS REALLY
CHALLENGING WITH IMMUNE
MODULATION THERAPY IS MATCHING
THE RIGHT PATIENT WITH THE RIGHT
AGENT AT THE RIGHT STAGE.
WHEN YOU LOOK AT A PATIENT
POPULATION I PUT THIS FIGURE UP
THERE TO TRY TO ILLUSTRATE THE
POINT.
THIS IS IMPORTANT FOR CLINICAL
TRIAL DESIGN AND WILL BE
IMPORTANT WHEN IT'S TIME TO PICK
AN INTERVENTION FOR A PATIENT.
IF YOU'RE IN A POOL OF PATIENT
YOU PROBABLY HAVE A SET OF
PEOPLE THAT WILL NEVER PROGRESS.
YOU HAVE TO RECRUIT MORE PEOPLE
IN YOUR TRIAL BECAUSE MANY WILL
NOT PROGRESSION TO TYPE I
DIABETES.
THREES A POOL OF RESPONDERS.
THOSE ARE THE ONES YOU WANT TO
FOCUS ON AND THERE ARE PEOPLE
THAT WILL NOT RESPOND.
WHETHER IT'S TOO EARLY IN THE
DISEASE OR TO -- TOO LATE OR THE
WRONG MECHANISM OR DON'T HAVE
ENOUGH BETA CELL FUNCTION
READOUT YOU MAY NOT GET THE
RESULTS YOU'RE LOOKING FOR.
BASICALLY HOW CAN WE UNDERSTAND
BETTER THIS POOL OF PATIENT AND
CAN WE IDENTIFY THEM BETTER IN
EARLY STAGES?
CAN WE TELL MORE EFFICIENTLY WHO
IS MORE LIKELY TO PROGRESS?
TELL RESPONDERS VERSUS
NON-RESPONDERS AND SHOULD WE BE
THINKING ABOUT USING DIFFERENT
OUTCOMES DEPENDING ON THE
INTERVENTIONS OR SHOULD WE BE
LOOKING AT IMMUNOLOGICAL
OUTCOMES INSTEAD OF BETA CELL
FUNCTION?
A LOT OF QUESTIONS.
I DON'T HAVE ANSWERS FOR ALL OF
THEM BUT WANTED TO PUT THEM OUT
THERE.
ONE THING THAT I THINK WE CAN
ALSO DO TO HELP SO HOLGER
TOUCHED ON THIS A LITTLE BIT BUT
I THINK AT THE END OF THE DAY
THE BEST MODEL WE HAVE FOR HUMAN
TYPE I DIABETES ARE THE
PATIENTS.
SO HOW CAN WE USE INFORMATION
THAT'S COMING OUT OF THESE
CLINICAL TRIALS BETTER TO INFORM
OUR DISEASE MODELLING EFFORTS?
SO CAN WE ACTUALLY MAKE A
CONSCIOUS EFFORT AS A GROUP TO
BETTER DESIGN CLINICAL TRIALS SO
THERE'S SAMPLES BEING CONNECTED
SEND BACK TO THE RESEARCHERS TO
GET BETTER INSIGHT HOW OUR DRUG
WORKS IN HUMANS AND MAKE OUR
MODELS BETTER?
LAST POINT I WANTED TO MAKE IS
HOW CAN WE LEARN FROM OTHER
DISEASES?
AND THERE ARE PATIENTS OUT THERE
THAT HAVE DISEASES THAT LOOK A
LOT LIKE TYPE I DIABETES AND
PATIENTS BEING TREATED WITH
CHECKPOINT BLOCKADE DEVELOP
QUICK DIABETES.
CAN WE LEARN FROM THEM?
IS THERE SOMETHING THERE ABOUT
THE INHIBITORY PATHWAYS WE CAN
STUDY?
SAME THING FOR OTHER AUTO IMMUNE
DISEASES?
FOR EXAMPLE THERE'S EXCITING
WORK BEING DONE WITH CAR T CELLS
IN THE CONTEXT OF AUTO IMMUNE
DISEASES AND THEY'RE BEING USED
FOR DISEASES THAT HAVE A LEVY --
HEAVY B CELL LIKE LUPUS AND
MULTIPLE SCLEROSIS BUT THERE'S
EXCITING DATA IN THE AREA.
IS THERE AN OPPORTUNITY TO
TRANSLATE THAT TO TYPE I
DIABETES AND LEARN ABOUT THE
ROLE OF B CELLS IN TYPE I
DIABETES AND TRYING TO KEEP AN
OPEN MIND OF WHAT'S GOING ON IN
OTHER FIELDS.
SO, CONCLUSION I HOPE WITH THE
TALKS THIS MORNING WE'VE
CONVINCED YOU CONTINUED
INVESTMENT IN NETWORKS LIKE HIRN
AND BASIC RESEARCH IS IMPORTANT.
IT ENABLES THE DEVELOPMENT OF
RESOURCES AND TECHNOLOGIES THAT
ARE REALLY CRITICAL TO THE TYPE
I RESEARCH COMMUNITY.
I HOPE YOU GUYS ARE AWARE OF IT
AND TAKE ADVANTAGE IT AND WE
MENTIONED THE BREAKOUT SESSIONS
ABOUT PANC DB AND IF YOU DON'T
KNOW WHERE TO START ATTEND THE
BREAKOUT SESSIONS.
WITHOUT THESE NOVEL INSIGHTS
THAT ARE GAINED FROM THESE NOVEL
STUDIES I HOPE WE GAVE YOU HOW
THEY CAN RESULT IN FASTER
CLINICAL TRANSLATION OF
THERAPIES AND IMPROVE CARE OF
PATIENTS.
OKAY.
I DON'T THINK WE HAVE TIME FOR
DISCUSSION BUT I JUST WANTED TO
MENTION THAT THAT WITH THE TALKS
THIS MORNING WE'VE SHOWN SOME OF
THE PROGRESS.
WE ALSO PUT OUT SOME OF THE
QUESTIONS.
WE'VE RAISED A LOT OF QUESTIONS.
I HOPE IT WILL STIMULATE
DISCUSSIONS FOR THE REST OF THE
MEETING.
PLEASE PARTICIPATE IN POSTER
SESSIONS AND BREAKOUT SESSIONS.
WE WANT TO HEAR FEEDBACK FROM
THE COMMUNITY AND LEARN FROM YOU
GUYS AND GET INPUT HOW WHERE THE
FIELD IS HEADING IN THE NEXT FEW
YEARS.
THANK YOU.
>> OKAY.
EVERYONE.
IT IS NOW LUNCH TIME AND POSTER
SESSION TIME
WE'RE GOING TO GET STARTED.
SO IF YOU'RE OUTSIDE THE MEETING
ROOM AND HEARING THIS, PLEASE
COME ON IN AND FIND A SEAT.
THIS IS THE FIRST OF THREE
SCIENTIFIC SESSIONS THAT WE'VE
PLANNED.
YOU NOTICE THE THEME OF TODAY,
THE TEAM OF THE MEETING, IN
TERMS OF THE TOPIC AREAS, HAVE
BEEN DISCOVERY, ETIOLOGY,
THERAPEUTICS.
AND WE ARE GOING TO START THAT
MISSION WITH DISCOVERY.
I'D LIKE TO ASK OUR MODERATORS
TO COME UP AND KICK OFF THE
DISCUSSION.
KICK OFF THE TALKS, NOT THE
DISCUSSION.
MAYBE BOTH, I GUESS.
>> GOOD AFTERNOON, WELCOME TO
THE FIRST OF THE SESSIONS.
THIS SESSION IS ON EMERGING
APPROACHES AND DISCOVERIES IN
TYPE 1 DIABETES RESEARCH.
I'M ONE OF THE CO-CHAIRS, ROW
ROHIT
KULKARNI FROM JOSLIN DIABETES
CENTER AND MY CO-CHAIR.
>> JUAN ALVAREZ, ASSISTANT
PROFESSOR, UNIVERSITY OF
PENNSYLVANIA.
>> I WANT TO GIVE YOU LOGISTICS
FOR THE SESSION.
FOUR EXCELLENT SPEAKERS ON THIS
VERY, VERY EXCITING TOPIC.
THE SESSION WAS EACH OF THE
SPEAKERS WILL PRESENT FOR 18-20
MINUTES EACH.
WE WON'T HAVE QUESTIONS AT THE
END OF THAT SESSION, BUT AFTER
ALL THE FOUR SPEAKERS HAVE
FINISHED THEIR TALKS, WE'LL
BRING THEM UP FOR THE PANEL
DISCUSSION AND WE'LL HAVE AN
EXTENSIVE PANEL DISCUSSION AT
THE END.
PLEASE KEEP YOUR QUESTIONS NOTED
SO YOU CAN BRING THEM UP DURING
THE DISCUSSION.
WE THOUGHT THAT WAS THE MOST
EFFECTIVE WAY TO DO THAT.
ALSO WANT TO EMPHASIZE TO TURN
OFF YOUR AUDIO ON YOUR
iPHONES, ALSO REQUEST THE
SPEAKERS TO KEEP TO TIME, SO YOU
HAVE 18-20 MINUTES EACH.
SO WITH THAT, I'LL REQUEST MY
CO-CHAIR TO GIVE AN OVERVIEW OF
THE SESSION SO THAT YOU GET AN
IDEA AS TO WHERE THE FOCUS IS
GOING TO BE AND WHAT EACH OF THE
SPEAKERS WILL TALK ABOUT.
AND THEN WE'LL ON TO THE FIRST
SPEAKER.
DR. ALVAREZ.
>> COULD WE MOVE TO THE INTRO
SLIDES.
SO THAT'S CHERIE'S SLIDES.
SESSION 1 IS THE TITLE.
YES, THAT ONE.
ALL RIGHT.
PERFECT.
SO, WELCOME TO THE FIRST SESSION
OF THE MEETING TODAY.
WE'LL HAVE SOME SCIENCE TO
DISCUSS TODAY.
WE'RE ORGANIZED AREN'T THREE
THINGS
FIRST SESSION IS DISCOVERY.
WE'LL HAVE A MICROCOSM AT THE
END.
A QUOTE, PROGRESS IN SCIENCE
DEPENDS ON NEW TECHNIQUES, NEW
DISCOVERIES, NEW IDEAS.
PROBABLY IN THAT ORDER.
ACCORDING TO SIDNEY BRENNER, A
PIONEER IN GENETICS.
SO, GOING WITH TECHNIQUES, OUR
FIRST SPEAKER IS DR. CHERIE
STABLER, PROFESSOR AT UNIVERSITY
OF FLORIDA, TALKING TO US ABOUT
ENGINEERING MICRO PHYSIOLOGY
SYSTEMS.
FOR TEN YEARS HAS SUPPORTED
DEVELOPING BREAKTHROUGH DEVICE
TECHNOLOGIES TO IMPROVE
UNDERSTANDING OF TIE 1 DIABETES,
A GRAND CHALLENGE TO BE TO BUILD
SYSTEMS THAT RECREATE FUNCTIONAL
ISLET NICHE TO TEASE APART
TISSUE TO TISSUE INTERACTION,
TISSUE-ENVIRONMENT INTERACTIONS,
OFFERING ADVANTAGES SUCH AS
PRECISE CONTROL OVER CHEMICAL
ENVIRONMENT, NUTRIENTS, OXYGEN,
SECRETED FACTORS, AND PHYSICAL
PARAMETERS WE'RE NOT USED TO
THINKING ABOUT SUCH AS
MECHANICAL FORCES, SPATIAL
PARAMETERS, ELECTRICAL FEATURES.
AND SO CHERIE WILL TELL US TODAY
HOW MICROPHYSIOLOGICAL SYSTEMS
PUSHING BOUNDARIES OF WHAT IS
POSSIBLE TO MODEL AND BETTER
UNDERSTAND TYPE 1 DIABETES AT
THE BENCH.
SECOND IS ROBERTO MALLONE,
MD/PHD, PROFESSOR AT UNIVERSITY
OF PARIS CITE, DIABETES AS A
DISEASE OF IMMUNE CELLS
CROSS-DOCKING WITH BETA CELLS,
HE HAS INVESTIGATED ROLE OF BETA
CELLS AND DEMISE BY QUESTIONS,
DO BETA CELLS INITIATE T CELL
KILLING, THE NOTION BETA CELLS
MAY PLAY A ROLE IN INITIATING
AUTOIMMUNITY DUE TO STRESS OR
DYSFUNCTION.
SECOND, DO BETA CELLS ENHANCE T
CELL KILLING ITSELF, THE NOTION
THAT THROUGH INTERFERONS THEY
CAN BECOME DETECTABLE PRIOR TO
THE DEVELOPMENT OF ANTIBODIES.
THIRD QUESTION DO BETA CELLS
FINALIZE KILLING THROUGH
SUICIDE, INTRIGUING ROLE THAT
PERHAPS SELF-DETRIMENTAL VERSUS
PROTECTIVE PROCESSES TO FINALIZE
ULTIMATE OUTCOME.
JULIA PANZER REMINDS US TYPE 1
DIABETES IS ALSO A DISEASE OF
THE ALPHA CELL, WHICH IS DEEPLY
ENGAGED IN CROSS-TALK WITH BETA
CELL, PARTICULARLY THROUGH
FAILURE TO RESPOND TO
LIFE-THREATENING HYPOGLYCEMIA.
A KEY MECHANISM, IS THAT
GLUTAMATE RECEPTOR SIGNALING IS
EFFECTIVE IN TYPE 1 DIABETES
PATIENTS, SHE HAS RECENTLY SHOWN
POSITIVE ALLOSTERIC MONOLAYERS
CAN RESCUE THE DEFECT IN VITRO
AND IN VIVO.
AND THEN A TRIP ON A MOST
PROMISING STRATEGY THROUGH
ACTIVATING BETA CELL INHIBITION,
NOW KEY CHALLENGES INCLUDING CAN
WE NOW DELIVER THEM SPECIFICALLY
IN HUMANS, REVERSIVELY AND
SAFELY, CAN WE USE THEM TO
RESTORE BETA CELL MASS THAT IS
FUNCTIONAL SO THEY CAN ALLEVIATE
DIABETES, AND ULTIMATELY CAN THE
NEW CELLS EVADE EXISTENT
AUTOIMMUNE ATTACK PROBLEM.
BRINGING IT BACK TO THE FIRST
SPEAKER I'LL ASK CHERIE TO JOIN
US ON THE STAGE.
[APPLAUSE]
>> OKAY.
THANK YOU FOR THE OPPORTUNITY TO
PRESENT SOME OF THE WORK HERE
TODAY AND GIVE AN OVERVIEW OF MY
MICROPHYSIOLOGICAL SYSTEMS.
AS YOU'VE SEEN THIS MORNING
REALLY JUST DISCUSSING THE
PATHOLOGY OF TYPE 1 DIABETES,
THERE'S A LOT THAT MAY BE KNOWN,
A LOT UNKNOWN.
WE SUSPECT THIS TRANSPORT TO THE
DRAINING LYMPH NODES, AND THEN
THESE ACTIVATED T CELLS THAT
HONE TO THE PANCREAS, DIRECTLY
KILL BETA CELLS.
BUT WE DON'T KNOW WHAT
PRECIPITATES THIS, THE PATHWAYS,
TIMELINES, WE DON'T ACTUALLY
KNOW ANTIGEN SPECIFICITY OR
DIFFERENT TYPES OF ANTIGENS
RELEVANT.
THERE'S A LOT UNKNOWN DESPITE
WHAT IS KNOWN.
AND WHILE MUCH IS UNKNOWN WE DO
KNOW THAT IT IS SPATIALLY
DISTRIBUTED AND MULTI-ORGAN
TISSUE PROCESS.
INVOLVES PANCREAS, VASCULATURE,
LYMPH NODES, AND CELLS THAT PLAY
A ROLE.
IT'S ALSO SOLUBLE GRADIENTS PLAY
KEY ROLES, THE WAYS IN WHICH
CELLS SIGNAL TO EACH OTHER SO
CELLULAR GRADIENTS ARE IMPORTANT
IN DIRECTING CELL RECRUITMENT,
SIGNALING, MANY OTHER THINGS.
WE KNOW THERE'S A UNIQUELY
HUMAN-CENTRIC PATHWAY.
WHAT WE'RE LEARNING FROM THE
MOUSE MAY NOT BE TRANSLATABLE TO
HUMANS, THE SAME FOR ANY OTHER
MODELS THAT WE COLLECT.
WHEN WE THINK ABOUT TOOLS WE'RE
USING TO STUDY TYPE 1 DIABETES,
THESE ARE TOOLS IN A TOOLBOX.
A HAMMER IS EFFECTIVE IN DRIVING
A NAIL, SCREWDRIVER EFFECTIVE IN
TURNING SCREWS, AND YOU WOULDN'T
NECESSARILY BE MAD AT A
SCREWDRIVER FOR NOT BEING
EFFECTIVE AT HAMMERING, RIGHT?
IT'S EFFECTIVE IN WHAT IT DOES.
ALL THESE TOOLS ARE EFFECTIVE.
WE JUST NEED TO UNDERSTAND THEIR
LIMITATIONS.
SO IF WE THINK ABOUT IN VIVO
MODELS, WE HAVE LARGE
PRE-CLINICAL MODELS DOWN TO
SMALL ANIMAL MURINE MODELS,
THESE PROVIDE UNIQUE INSIGHTS.
THEY CAN BE VALUABLE PROVIDING
PHYSIOLOGICAL MICROENVIRONMENT,
WE WITH HUMANIZED CAN USE HUMAN
CELLS AND WE HAVE THIS MODEL
THAT'S PRESENT, BUT THERE ARE
SOME DISADVANTAGES.
EXPENSIVE, REQUIRE EXPERTISE.
TRANSLATION TO HUMANS IS NOT
DIRECT.
A LOT OF LESSONS WE'RE LEARNING
FROM THESE IN VIVO MODELS ARE
NOT DIRECTLY TRANSLATABLE, IT'S
DIFFICULT TO KNOW WHAT'S
TRANSLATABLE AND NOT, MAYBE SOME
FEATURES ARE, OTHERS ARE NOT.
THE OTHER THING THAT IN VIVO WE
HAVE LIMITED TEMPORAL INSIGHT
INTO WHAT'S HAPPENING.
WE CAN'T INVADE THAT PANCREAS
AND ASSESS, INTRAVITAL IMAGING
IS POSSIBLE BUT QUITE LIMITED.
WE HAVE BISTANDARD EVALUATION OF
BLOOD, GLYCEMIC CONTROL, THINGS
LIKE, THAT AUTOANTIBODY MARKERS,
BIOMARKERS, BUT BEING ABLE TO
INTIMATELY EVALUATE HOW CELLS
MIGRATE IS LIMITED.
WE CAN CULTURE, EXPLORE, USE
HUMAN CELLS.
GET CADAVERIC HUMAN TISSUES TO
STUDY DISEASE.
WE HAVE FOR THE CADAVERIC
TISSUES, HIGH HETEROGENEITY,
INTRA AND INTERHETEROGENEITY.
WE CAN'T DETERMINE WHEN A
DONOR -- THE STATE OF THEIR
DISEASE.
WE ALSO HAVE LIMITED ACCESS.
TO THE CELL CULTURE WE CAN GET
CELLS, CELL LINES, STEM CELLS
WHICH ARE VALUABLE, BUT IS THIS
A PHYSIOLOGIC PLATFORM?
WHEN WE PULL THEM OUT OF THE
BODY AND CULTURE ON PLASTIC DISH
THEY DON'T BEHAVE IN WAYS THEY
DO IN VIVO.
S THEY ARE GREAT TOOLS, THEY
HAVE LIMITATIONS.
ONE THING WE'VE IDENTIFIED AS
WELL AS MANY OTHERS, WE WEREN'T
UNIQUE IN THAT, THAT CAN WE
IMPROVE 2D MODELS TO ADDRESS
LIMITATIONS?
THE SYSTEM IS LIMITED, LACK OF
PHYSIOLOGICAL GRADIENTS FORCING
CELLS TOGETHER, TAKE IMMUNE
CELLS, BETA CELLS, BEAUTIFUL
CELLS, WE PUT THEM IN A ROUND
BOTTOM FLASK, FORCING THEM TOE
INTERACT, MESSING UP SIGNALING,
DON'T HAVE CONTROL OF FEATURES.
3D CAN BE BENEFICIAL.
THESE ARE WAYS THEY ARE
INCORPORATING -- DO I HAVE A
LASER?
NO.
OH, INTERESTING.
OKAY.
SO, MANY PEOPLE ARE DEVELOPING
VARIOUS -- THIS IS NOT GOING TO
WORK.
MANY PEOPLE ARE DEVELOPING
DIFFERENT ORGANS, YOU CAN HAVE
DISCRETE THREE DIMENSIONAL
PATTERNS.
YOU CAN HAVE MONOLAYERS,
BARRIERS, YOU CAN HAVE ORGANOIDS
WITHIN THAT SYSTEM.
THIS PROVIDES SIGNIFICANT
ADVANTAGE, ELEVATION OF CLASSIC
2D SYSTEMS.
AND IT WAS RECOGNIZED THROUGH
INVESTMENT IN CONSORTIUM WITH
HUMAN ISLET BIOMEDICS, THE CHIP,
CREATE ISLET PANCREAS OR
DIABETES ON A CHIP.
CELLS INCORPORATING IN SYSTEMS
WE CAN USE CADAVERIC HUMAN SUCH
AS PANCREATIC SLICES, ISOLATED
ISLETS, VALUABLE, BUT WITH
ADVENT OF TECHNOLOGY HAVE
CAPACITY TO INCORPORATE STEM
CELL DERIVED T1D RELEVANT CELLS
TO CREATE ISOGENIC SYSTEMS TO
STUDY IMMUNOLOGIC PATHWAYS IN
THE ABSENCE OF ALLOIMMUNE
RESPONSES.
THEY ARE AVAILABLE, GENE EDITING
CAN LOOK AT RISK ALLELES, WE CAN
GET STEM CELL FROM DIFFERENT
DONORS, EXPLORE DIFFERENT T C
AVATARS.
BEAUTIFUL CELLS ARE AVAILABLE
BUT IF WE PLACE THEM IN IN A
PETRI DISH WE'RE USING OUR
CAPACITY HERE.
WE WANT TO TRANSLATE TO ORGANS
ON A CHIP, AND THREE DIMENSIONAL
THEY ARE MORE ELEVATED.
IN DESIGNING AN ORGAN ON A CHIP
OR DIABETES ON A CHIP WE THINK
ABOUT ENGINEERING DESIGN DRIVEN
BY EXPERIMENTAL QUESTIONS OR
HYPOTHESES, THERE'S MANY TOOLS
TO CREATE BUT THINK ABOUT THE
QUESTIONS YOU WANT TO ASK.
IN TERMS OF CREATING THAT NICHE
WHERE THIS CLUSTER OR, BETA
CLUSTER OR ISLET IS GOING TO GO,
DO YOU WANT IT EMBEDDED IN
EXTRACELLULAR MATRIX, WHAT IS
THE COMPOSITION, WHAT OTHER
CELLS, VASCULAR NETWORK AS
DEVELOP?
WHAT FLOW AND STIMULI, HOW DO
YOU CONTROL MICROENVIRONMENT?
HOW DO WE DELIVER FLUIDS, DRIVE
THAT FLUIDIC FIELD, CONTROL
THAT, DO YOU DO IT THROUGH, SAY,
GRAVITY-DRIVEN FLOW OR
CONTROLLED PUMPS AND SENSORS?
AND THEN ALSO THAT THEN DRIVES
THE OVERALL SPATIAL FEATURES OF
THAT DEVICE.
YOU CAN HAVE SOMETHING AS SIMPLE
AS A MONOLAYER TO THREE
DIMENSIONAL CLUSTERS TO
COMBINATIONS OF THE TWO WITH
DIFFERENT FLOW STREAMS.
AND SO WHILE THERE'S NUMEROUS
MICROPHYSIOLOGICAL SYSTEMS I
COULD TALK ABOUT TODAY IN THE
INTEREST OF TIME I'M JUST GOING
TO FOCUS ON THREE OF THE
PLATFORMS THAT HAVE BEEN
INVESTED IN BY THE CHIP
CONSORTIUM, AND THAT'S LED BY
MICAH SANDERS, STANGER AND OUR
GROUP.
DIFFERENT TOOLS HAVE DIFFERENT
FEATURES, DIFFERENT VALUE.
SO WITH SANDERS GROUP IT'S A
MULTI-DISCIPLINARY TEAM,
IMMUNOLOGY, ENGINEERING,
BIOMATERIALS, STEM CELL WORK,
AND THROUGH THAT WHAT THEY
STARTED FIRST WAS WITH A
VASCULAR NETWORK SYSTEM,
VASCULARIZED MINI ORGAN, THREE
DIMENSIONAL NICHE, LOAD HYDROGEL
AND ENDOTHELIAL TO STROMAL
CELLS, FORMING A VASCULAR
NETWORK IN THE SYSTEM.
IT ALSO HAS INLETS, OUTLETS, YOU
CAN ADD PERFUSION TO THAT.
IT'S A GRAVITY-DRIVEN SYSTEM SO
YOU CAN HAVE THIS PERFUSE
THROUGH THE SYSTEM.
THEN YOU CAN SEE -- OOH, I DO
HAVE A MOUSE -- VASCULAR
NETWORKS THAT ARE FORMED IN THE
SYSTEM.
THEY CAN INCORPORATE ISLETS INTO
THAT SO YOU CAN SEE ISLETS ARE
INTEGRATED INTO THE VASCULAR
NETWORK.
THEY HAVE OBSERVED ISLETS
INCORPORATE INTO VASCULARIZED
INTO MINI ORGANS, BETTER
RETENTION, SEEING ALREADY SOME
BENEFITS OF THAT SYSTEM.
THEY CAN ALSO PERFORM GLUCOSE
STIMULATED INSULIN RELEASE,
ASSESS GSARs IN THAT, THEY
ADDED PBMCs AS
PROOF-OF-CONCEPT, THEY CAN
PERFUSE THROUGH THE SYSTEM,
INTEGRATING INTO VASCULARIZED
NETWORK SHOWN IN GREEN,
ENDOTHELIAL CELLS IN RED.
CIRCLES WHERE ISLETS ARE
PRESENT, THEY MIGRATE INTO THE
REGION, BLOCKED THROUGH MHC
BLOCKER.
YOU CAN ALSO ANALYZE THIS AND
QUANTIFY OVER TIME.
OKAY.
THANK YOU SO MUCH.
OKAY.
YOU CAN SEE THOSE BLOCK THROUGH
AND QUANTIFY OVER TIME SO YOU
CAN GET TEMPORAL ASSESSMENT AND
QUANTIFY WITHIN THE FIELD OF
VIEW WHAT'S HAPPENING IN THE
SYSTEM.
SO I HOPE THIS HIGHLIGHTS AND
SPURS NEW IDEAS.
MY GOAL IS REALLY TO HELP YOU
GUYS SPUR NEW IDEAS OF WHAT
THESE MICROPHYSIOLOGICAL SYSTEMS
CAN DO, WHETHER YOU'RE FROM
ENGINEERING SIDE TO CREATE NEW
ONES OR WANT TO UTILIZE THEM,
WHAT QUESTIONS YOU MAY BE ABLE
TO ASK FROM THAT SYSTEM.
THIS IS THE STANGER GROUP, PENN
CHOP GROUP, MANY PEOPLE ARE
INVOLVED ACROSS MANY SPACES, I'M
FOCUSED ON MICROPHYSIOLOGICAL
BUT THEY DID WORK IN STEM CELL
DEVELOPMENT.
DAN'S CHIP HAS BEEN USED FOR THE
SYSTEM, ORIGINATED FROM A L LUM
PROTOTYPE.
THIS IS THE HYDROGEL WITH
PERFUSED BLOOD VESSELS, USING
SIMILAR FORMATION OF VASCULAR
NETWORKS, THIS IS A BETTER
RESOLUTION.
THIS IS WITHIN THE HYDROGEL AREA
WHERE THE VASCULAR NETWORKS
FORM, THESE ARE PRIMARY CHANNELS
IN GREEN, FLOW THINGS THROUGH,
THROUGH THIS MICROVASCULAR BED.
THEY HAVE BEEN ABLE TO SHOWCASE
THAT THESE ARE COMPETENT LUMENS,
AND INTEGRATE ISLETS IN GREEN,
INTEGRATED INTO THE SYSTEM, ABLE
TO CULTURE THESE ISLETS OVER A
TIME PERIOD.
THIS IS TWO WEEKS.
YOU CAN SEE VASCULAR NETWORK
BECOMES MORE FORMED OVER TIME.
AND WHAT THEY HAVE OBSERVED IS
SIMILAR TO WHAT THE CALIFORNIA
GROUP OBSERVED, IS THAT THESE
PERFUSABLE REVASCULARIZED ISLETS
PERFORM BETTER WITHIN THE SYSTEM
THAN WHEN IN THE EXTRACELLULAR
MATRIX IN TERMS OF RETENTION OF
BETA CELLS AS WELL AS ALPHA
CELLS.
THEY EXPLORE DEGREE OF
VASCULARIZATION, THEY LOOKED AT
HYPERVASCULARIZED OR
NON-VASCULARIZED, HOW THAT
CORRELATES WITH GLUCOSTIMULATED
INSULIN RELEASE.
RELEASE IS MOST IDEAL, TOO
VASCULARIZED CAN AFFECT THE
ISLETS.
THEY HAVE INCORPORATED CAR-T
CELLS, SHOWN HERE IN YELLOW, YOU
CAN SEE THEM MOVING THROUGH THE
VASCULATURE, INTO THE ISLET
ITSELF.
DISCRETE-TIME POINTS COLLECTED
SUPERNATANT, LACKED AT ELEVATION
IN INTERFERON GAMMA, GRANZYME
AND INTERFERON ALPHA,
HIGHLIGHTING CAPACITY TO HAVE
VASCULARIZED NETWORKS
INCORPORATE IMMUNE CELLS AND ASK
QUESTIONS ABOUT EXTRAVISATION.
WE CAN LOOK AT MIGRATION.
WE HAVE AN OPEN PLATFORM AND
HAVE PERFUSION, TRANSPARENT
WHICH ALLOWS FOR TERM POLL IMAGE
OF THE NICHE.
YOU CAN SEE TRACKING OF
APOPTOSIS AND NECROSIS.
WE OBSERVED CELLS PERFORM BETTER
UNDER FLOW THAN STATIC
CONDITIONS, AGAIN VALIDATING
WHAT THE OTHER TWO GROUPS
OBSERVED AS WELL.
WE WERE ABLE TO TEMPORALLY
ADDRESS MURINE ISLETS,
STIMULATED WITH GLUCOSE
CHALLENGE, HOW THE ISLETS CHANGE
OVER TIME, FOR HUMAN AS WELL.
AND YOU CAN ENVISION THIS COULD
BE USED FOR DRUG SCREENING OR
LOOKING AT PERFUSION.
WE INCORPORATED BIOSENSORS,
LOOKED AT CALCIUM IMAGING, WHAT
HAPPENS TO ISLETS WHEN EXPOSED
TO GLUCOSE LIPO TOXIC TREATMENT,
OBSERVED, QUICKLY, SIGNIFICANT
SHIFTS IN CALCIUM SIGNALING,
ELEVATION OF CELL DEATH, BOTH
PRE AND POST STIMULI, AND
CHARACTERIZE WHAT'S HAPPENING IN
THE SYSTEM.
THIS WAS TRANSLATE TO PANCREATIC
SLICES, CONDUCTED SIMILAR WORK
IN TISSUE SLICES, THERE'S VERY
CONTROLLED MICROENVIRONMENTS,
VERY STABLE SYSTEM IN WHICH YOU
CAN THEN DO REPEATED PERFUSION
AND EXAMINATION OF GSIS IN THESE
PANCREATIC SLICES.
WHAT WE'VE ALSO DONE IS EXPLORED
THAT ISLET NICHE ITSELF, SO
INCORPORATING MATRICES THAT
ALLOW SPATIAL PLACEMENT, EXAMINE
THOUSAND T CELLS BEHAVE AND
MIGRATE THROUGH THE SYSTEM.
WHAT WE FOUND IS THAT OUR --
USING DECELLULARIZED PIG
PANCREAS WAS EFFECTING,
PRESERVING THEIR FUNCTION.
WE CAN ALSO INCORPORATE T CELLS
INTO THAT SYSTEM.
AND T CELLS WILL MIGRATE WITHIN
THIS MATRIX IN THREE DIMENSIONAL
MANNER.
WE CAN ACTUALLY CULTURE OVER
EXTENDED TIME PERIODS, DIFFERENT
THAN WHAT WE CAN OBSERVE IN
STATIC SYSTEMS, SO UNDER STATIC
SYSTEMS WHAT WILL HAPPEN AFTER A
FEW HOURS IS ANY CURRENTS WILL
CAUSE THESE CELLS TO MOVE AROUND
RANDOMLY.
WE CAN DIGEST EXTRACELLULAR
MATRIX AND LOOK AT T CELL
PHENOTYPE, IN THIS CASE THAT THE
MATRIX DOES NOT ACTIVATE CELLS,
DOESN'T ALTER PHENOTYPE, DOESN'T
CHANGE VIABILITY BUT SUPPORTS
NATIVE MOTILITY.
CAN USE IMAGE ANALYSIS, TRACK
MATE TO QUANTIFY BEHAVIOR,
GLOBAL ANALYSIS OF THINGS LIKE
TRACK DISPLACEMENT, SPEED TO
LOOK AT HOW T CELLS ARE BEING
ALTERED.
ONE THING WE REALLY ALSO WANT TO
DEVELOP WAS TOOL SET TO ANSWER
DIFFERENT ADDITIONAL QUESTIONS,
TO ALLOW US TO DO DETAILED
ASSESSMENT OF TRAJECTORY
CLASSIFICATION AND
QUANTIFICATION, THIS IS ONE
EXAMPLE IN TERMS OF TRACKING T
CELL MIGRATION OVER TIME, WE CAN
SET TRACKS TO ZERO AND LOOKS AT
PREFERENTIAL MIGRATION, NO
STIMULI OR GRADIENT.
WE CAN CHARACTERIZE HOW BEHAVIOR
CHANGES WITH PHENOTYPE,
STIMULATED VERSUS UNSTIMULATED,
YOU CAN SEE BEHAVIOR SHIFT AS
THEY SEEK COGNATE.
COLLECT THREE DIMENSIONAL IMAGES
AS WELL.
I HOPE YOU CAN APPRECIATE
THROUGH THE TRACKS WHAT WE'RE
OBSERVING IS THIS BEHAVIOR
BECAUSE THEY ARE ACTIVATED
TRYING TO FIND THEIR
COMPLEMENTARY ANTIGEN.
WE CAN EXAMINE AND CLASSIFY
BEHAVIOR SO WE KNOW T CELLS
PRIOR TO STIMULI WILL EXHIBIT
MORE OF A SUBTUSIVE BEHAVIOR,
WHEN ACTIVATED EXHIBIT LEVY
WALK, WITH A GRADIENT WILL
EXHIBIT BALLISTIC MOVEMENT AND
WE CAN CLASSIFY BEHAVIOR.
AND SO WE CAN SEE IN THIS
CLASSIC EXAMPLE OF UNSTIMULATED
VERSUS ACTIVATED T CELLS WHEN
THEY BECOME ACTIVATED THEY
EXHIBIT MORE OF A LEVY WALK
SHIFT FROM UNSTIMULATED TO
STIMULATE WE ISLETS, MURINE, TO
BUILD AND EVALUATE.
WE FOUND THIS IS A NON-ANTIGEN
SPECIFIC SYSTEM, B 6 CTLs, T
CELLS IN GREEN.
HOLD ON.
OKAY.
SO YOU SEE T CELLS SAMPLING,
ACTIVATED TRYING TO FIND
COGNATE, EXPLORING, BUT MOVING
IN AND OUT IN DIRECT CONTRAST TO
WHAT I HOPE TO SHOW.
THERE WE GO.
IN THE ANTIGEN SPECIFIC SYSTEM
ONCE THEY COME INTO INTERACTING
WITH ISLET THEY ACTUALLY SHIFT
MIGRATION BEHAVIOR AND KIND OF
SAMPLE THAT ENVIRONMENT LIKELY
BECAUSE THEY ARE INTERACTED WITH
ANTIGEN.
THIS IS THE HIGH RESOLUTION
IMAGE OF IT.
IT'S NOT GOING TO SHOW.
WE NEED MORE POWER ON THIS
COMPUTER.
NOPE, OKAY.
WELL, YOU CAN SEE THE T CELLS
MIGRATING AROUND.
WE CAN DO IMAGE SEGMENTATION,
ASK QUESTIONS ABOUT SPATIAL
PLACEMENT, SO IN THIS CASE WE
CAN LOOK AT ACCUMULATION, LOOK
AT WITHIN THE ISLET OR OUTSIDE
THE ISLET, AND ACTUALLY
CHARACTERIZE THAT SO LOOKING AT
TOTAL CELL COUNTS, ACCELERATION
ACCUMULATION AS EXPECTED,
OUTSIDE ACTUALLY DEATH BECAUSE
THEY ARE NOT STIMULATED.
WE CAN FURTHER CLASSIFY
BEHAVIOR.
LOOKING AT INSIDE, HOW T CELLS
INTERACT INSIDE VERSUS OUTSIDE.
AND THEN WE CAN CHARACTERIZE
BEHAVIOR LOOKING AT GLOBAL
PARAMETERS AS WELL AS MIGRATION
CHARACTERISTICS, CLASSIFICATION,
SO WE CAN TAKE TRACKS AND SAY
HOW IS IT BEHAVING BEFORE VERSUS
AFTER IT INTERACTS WITH ISLET
AND FOR THIS NON-ANTIGEN
SPECIFIC SYSTEM YOU SEE NO
CHANGE IN BEHAVIOR VERSUS
ANTIGEN SPECIFIC SYSTEM YOU SEE
THE SHIFT DOWN.
ONCE IT INTERACTS WITH ISLET IT
EXHIBITS DECREASES LEVY WALK
BEHAVIOR, EXHIBITS MORE
SUBDIFFUSIVE MIGRATION.
THIS IS LOOKING AT THEM
INTERACTING AND SHIFTING TOWARDS
CELLULAR TOXIC PHENOTYPE.
FIRST 24 HOURS, GREEN IS
APOPTOSIS, SHIFTING NECROSIS, T
CELLS KILLING, BECOMES MORE
EXACERBATED.
OVER THE NEXT 24-48 HOURS WE SEE
ACCELERATED CELL DEATH.
WE CAN QUANTIFY.
YOU CAN SEE NOT MUCH DIFFERENCE
IN THE ANTIGEN VERSUS
NON-ANTIGEN SPECIFIC SYSTEM IN
THE FIRST 24 HOURS BUT THAT
LATTER ONE WE SEE INFLECTION AND
ACTIVATION, I HOPE THIS MAYBE
STIMULATES QUESTIONS ABOUT
IMMUNE THERAPIES, DIFFERENT ONCE
WE CAN SCREEN USING THE SYSTEM.
WE'RE TRANSLATING TO
HUMAN-CENTRIC SYSTEMS.
I'LL HIGHLIGHT ONE WE'VE BEEN
COLLABORATING, BETA CELLS WITH
PPIT CELLS, JUST AN EXAMPLE OF A
CONTROL.
LET ME TRY AGAIN.
T CELLS INTERACTING.
GFP BETA CELLS, RED ARE DEAD
CELLS, VERSUS TREATED.
SIGNIFICANT DIFFERENCES IN
AMOUNT OF CELL DEATH OVER TIME
AND VISUALLY TRACK AND GET
SPATIAL INFORMATION FROM THAT.
WHAT TIME AM I AT NOW?
FIVE MINUTES?
DONE.
OKAY.
FUTURE DIRECTIONS, I'M SORRY
THERE'S NO CLOCK HERE.
I HAVE NO SENSE OF TIME.
FUTURE DIRECTIONS IS SCALE UP
MANUFACTURING, BEING ABLE TO
MODIFY STEM CELL REPERTOIRE, 3D
PRINTING AND LEVERAGING THAT
WOULD BE EXCITING, SPATIAL
DISTRIBUTION, AS WELL AS USING
SPATIAL OMICS INTEGRATE AS WELL
AS 3D PRINTING THE CHIP,
LEVERAGING SHEER EFFECTS, THAT'S
A SPACE WE'VE NOT EXPLORED,
CELLS ARE SENSITIVE TO SHEER, T
CELLS ARE AS WELL.
WE CAN START ASKING QUESTIONS
ABOUT FLOW EFFECT.
MY LAST SLIDE, WE HAVE A UNIQUE
OPPORTUNITY CROSS-VALIDATE USING
ANIMAL MODELS.
SO WHILE MPS ARE USED FOR HUMAN
CELLS, INTERESTING TO USE IN
ANIMAL CELLS AND CROSS-VALIDATE
WITH ANIMAL MODELS, SEE HOW
PREDICTIVE MPS.
WE DON'T KNOW HOW PREDICTIVE
THEY ARE BECAUSE WE STAND STUDY
HUMANS THE WAY WE CAN STUDY
CHIPS OF THE THIS MAY BE
INTERESTING TO VALIDATE THAT.
I'LL ACKNOWLEDGE -- SORRY IF I
WENT OVER TIME.
THANK YOU FOR YOUR ATTENTION.
[APPLAUSE]
>> THANKS VERY MUCH.
NEXT SPEAKER DR. ROBERTO MALONE,
CLINICAL IMMUNOLOGIST IN FRANCE,
ALSO HOLDS SENIOR INVESTIGATOR
POSITION.
I THINK THE CLOCK IS UP.
>> THANK YOU TO THE ORGANIZERS
FOR THE INVITATION.
TODAY I WOULD LIKE TO TELL YOU
ABOUT THE SPATIAL FEAT BETWEEN
BETA CELLS AND INTERFERON ON ONE
SIDE, PARTICULARLY TYPE TYPE I
INTERFERONS, AND CD 8 T CELLS.
THE START OF THE STORY DATES
BACK TO SOME OBSERVATION WE DID
SOME YEARS AGO, WHEN WE STARTED
ISLET REACTIVE CD8 T CELLS,
ISOLATING PBMCs FROM TYPE 1
DIABETES PATIENTS, AND HEALTHY
CONTROLS.
WE MADE SOME SURPRISING
OBSERVATIONS THAT THE FREQUENCY
OF THESE CIRCULATING HIGHLY
REACTIVE CD8 CELLS YOU SEE HERE
REACTIVE TO DIFFERENT PEPTIDES
DERIVED FROM BETA CELL ANTIGENS
WERE ACTUALLY SIMILAR,
IRRESPECTIVE OF DISEASE.
ACQUIRED FREQUENCY RANGE.
AND MOREOVER, THESE CIRCULATING
CD8 T CELLS EXPRESSED A LARGELY
NAIVE PHENOTYPE SUGGESTING THEY
WERE NOT ACTIVELY ENGAGED IN
AUTOIMMUNE PROCESS.
AND THIS WAS KIND OF AN
INCONVENIENT TRUTH BECAUSE
COMPLICATES A BIT THE USE OF T
CELLS CIRCULATING BIOMARKERS,
YET THERE IS ALSO SPACE FOR A
LOT OF OPPORTUNITIES AS I WILL
DEVELOP LATER IN THE TALK.
WHY WAS THIS MISSED BEFORE?
FOR SEVERAL REASONS.
ONE OF THOSE IS THAT WE'RE
LOOKING AT VERY LOW CD8 T CELL
FREQUENCIES, AND SO THE
CENTERING THAT YOU DO IN PBMCs
IS QUITE IMPORTANT.
YOU NEED TO SAMPLE ENOUGH TOTAL
CD8 T CELLS, ENOUGH PBMCs TO
BE ABLE TO CHARACTERIZE IN
RELIABLE WAY THE FREQUENCIES AND
YOU SEE HERE THAT WE OPTIMIZE
OUR TETRAMER HLA CLASS 1
TETRAMER STAINING TO BE ABLE TO
DO SO.
PART OF THE OBSERVATION IN
COLLABORATION WITH PISA, LOOKED
AT THE SAME TYPE OF ISLET
REACTIVE CD8 T CELLS USING HLA
CLASS 1 TETRAMER STAINING THIS
TIME IN SITU, USING FROZEN
TISSUE SECTIONS.
YOU SEE THAT CELLS ARE ENRICHED
IN PANCREAS OF TYPE 1 DIABETIC
PATIENTS AS COMPARED TO CONTROLS
SUGGESTING THAT OVER THE COURSE
OF DISEASE, THESE AUTOIMMUNE T
CELLS ARE NEW FEATURE, NOTABLY
BEING ABLE TO COME TO THE
PANCREAS WHERE WE FIND THEM
ENRICHED.
BASED ON THIS WE PROPOSED THE
IDEA OF UNIVERSAL STATE OF
BENIGN ISLET AUTOIMMUNITY THAT
IS GOING ON IN ALL INDIVIDUALS,
AND THAT EVOLVES TOWARDS
PATHOLOGIC TYPE 1 DIABETES
AUTOIMMUNITY, ONLY IN A FEW OF
THEM, CHARACTERIZED BY THESE
CIRCULATING CD8 T CELLS THAT
LOOK AT LEAST SUPERFICIALLY
SIMILAR.
THEY ARE UNDERLYING HOW IT IS
CRITICAL TO COMPARE WHAT IS
GOING ON IN THE TISSUE, WITH ITS
REFLECTION IN THE BLOOD TO
REALLY UNDERSTAND DISEASE
PATHOGENESIS.
BASED ON THESE OBSERVATIONS WE
STARTED TO ASK WHETHER THERE WAS
KEY DIFFERENCE IN THE BETA CELLS
THAT WAS RESPONSIBLE FOR THESE
SURPRISING OBSERVATIONS.
AND WE FOCUS OUR ATTENTION ON
THE ROLE OF INTERFERONS THAT IS
KNOWN SINCE LONG TIME.
FIRST OF ALL, THESE OBSERVATIONS
THAT DATE BACK TO THE LATE
BOTTAZZO, IN DIABETIC PATIENTS,
PROBABLY RELATED TO THIS TYPE I
INTERFERON SIGNATURE THAT HAS
BEEN DESCRIBED IN A NUMBER OF
PAPERS, AND YOU SEE IT PRECEDES
THE AUTOANTIBODY SEROCONVERSION.
AND INDEED YOU CAN REPRODUCE
THESE IN VITRO WHEN YOU EXPOSE
ISLETS OR BETA CELLS TO
INTERFERONS.
YOU SEE THAT YOU UPREGULATE HLA
CLASS 1 EXPRESSION, AND THESE
RESULTS IN INCREASED
PRESENTATION OF THE PEPTIDES
THAT ARE PRESENT BY THESE HLA
CLASS 1 MOLECULES.
SO THIS WAS FROM OUR PREVIOUS
WORK OF INITIAL CHARACTERIZATION
OF THE PEPTIDE ANTIGENIC PEPTIDE
DISPLAY OF BETA CELLS, UPON
EXPOSURE TO INFLAMMATORY
CYTOKINES, WHAT WE DID NOT
ADDRESS IN THIS WAS THIS DISPLAY
OF ANTIGENIC PEPTIDES CHANGING
UPON EXPOSURE PARTICULARLY TO
INTERFERON ALPHA WHICH IS THE
SIGNATURE TYPE I INTERFERON
CYTOKINE OF TYPE 1 DIABETES.
TO DO SO WE DEVELOPED THIS
WORKFLOW, USING MAINLY BETA CELL
LINES THAT HAVE CARRIED COMMON
HLA CLASS 1 VARIANTS,
PARTICULARLY A2, EXPOSED TO
INTERFERON ALPHA.
THEY WERE ALIVE, PEPTIDE HLA
COMPLEXES IMMUNOPRECIPITATED TO
ALLUDE TO PEPTIDES AND IDENTIFY
MY MASS SPECTROMETRY.
SOME OF THIS WORK I'VE PRESENTED
BEFORE, NOW EXTENDING, NOW THIS
WORK IS IN NATURAL
COMMUNICATION.
SO, THE FIRST OBSERVATION IS
THAT OBSERVED BEFORE WITH
INTERFERON GAMMA, INTERFERON
ALPHA UPREGULATED HLA CLASS 1
EXPRESSION, RESULTED IN
PRESENTATION OF MUCH LARGER
NUMBER OF PEPTIDES SO SUGGESTING
THIS INTERFERON WAS INCREASING
VISIBILITY BY EXPOSING MORE
PEPTIDES.
THE NATURE OF THESE PEPTIDES WAS
ALSO PARTLY CHANGING, AND WE
FOCUSED ON DIFFERENT TYPES OF
PEPTIDES, YOU SEE THOUGH HUER
SOME THAT WE IDENTIFIED AS
POST-TRANSLATIONAL MODIFIED WITH
DIFFERENT CHEMICAL ADDITION THAT
WE COULD IDENTIFY BIOLOGICAL NOT
INDUCED SPURIOUSLY BY THE
ACQUISITION PROCEDURE AND THIS
ONE WE FIND IT PARTICULARLY
INTERESTING BECAUSE YOU SEE IT'S
QUITE BULKY POST-TRANSLATIONAL
MODIFICATION, THREE PEPTIDE, KEY
RESPONSE IN BETA CELLS, PERHAPS
REFLECTING THE OXIDATIVE STRESS
SITUATION OF BETA CELLS UNDER
INFLAMMATORY CONDITIONS.
TOGETHER WITH TEDESIO IDENTIFIED
ALTERNATIVE SPLICING OF
MESSENGER RNA, GIVING RISE TO
NEOEPITOPES, YOU SEE A VARIANT
THAT GIVES RISE TO THIS NEW
PEPTIDE THAT WE'RE STUDYING AS
POTENTIAL NEW ANTIGEN.
THE OTHER OBSERVATION OF THIS
WORK WAS THAT PROTEINS WERE
CONTRIBUTING MORE PEPTIDES TO
DISPLAY OF BETA CELLS WERE
DERIVED FROM INSULIN GRANULES
YOU SEE HERE, ASSOCIATED WITH
GRANULES WITH MIGRATION LIKE KEY
1 ALPHA MAP 1 BETA.
THE MOST REPRESENTED PEPTIDES
OUT OF ALL WAS THESE VERY WELL
KNOWN PPI 1524, YOU SEE THERE'S
SOME LOG OF DIFFERENCE COMPARED
TO ALL OTHER PEPTIDES,
BIOLOGICAL REASON FOR THIS IS
THAT THIS IS THE VERY END OF THE
SIGNAL PEPTIDE SO EVERY TIME
CREATES NEW INSULIN MOLECULE,
THIS FRAGMENT GOES TO FEED THE
HLA PATHWAY, ABUNDANTLY PRESENT.
WE DID CONFIRMATORY EXPERIMENTS
IN ISLETS, VERY INTERESTING
INFORMATION HERE LINKING TO THE
FOLLOWING TALK BY JULIA,
ACTUALLY WHEN YOU LOOK AT THE
ISLETS, MOST REPRESENTED
PROTEIN, AT LEAST EQUALLY
REPRESENTED, AS INSULIN IS
GLUCAGON, SUGGESTING ALPHA CELLS
HAS SAME ANTIGENIC VISIBILITY OF
BETA CELLS BUT FOR SOME REASON
THEY DON'T GET DESTROYED TO THE
SAME EXTENT OF BETA CELLS, SO
THIS NUMBER OF GLUCAGON-DERIVED
PEPTIDES IDENTIFIED MAY
CONSTITUTE USEFUL RESOURCE FOR
FOLLOW-UP STUDIES.
WHY ARE THESE GRANULE PROTEINS
IMPORTANT?
WE THINK IT'S BECAUSE BASED ON
MODEL PROPOSED THESE PROTEINS
MAY ACTUALLY FUNCTION AS
ANTIGENS THAT CAN SENSITIZE
IMMUNE SYSTEM AT DISTANCE BY
BEING CAPTURED BY
ANTIGEN-PRESENTING CELLS AND
PRIMING T CELLS, IDENTIFIED THAT
PEPTIDES DERIVED FROM THESE
GRANULE PROTEINS ARE ACTUALLY
SHARED BY MANY DIFFERENT HLAs,
HLA CLASS 1 IN HUMANS, 2
4, WORK WITH JAMES, AND IN THE
MOUSE COULD DEMONSTRATE T CELLS
RECOGNIZE THESE NOVEL GRANULE
PROTEINS YOU SEE HERE, WHEN YOU
INJECT THEM INTO IMMUNODEFICIENT
MICE THEY CAN ACTUALLY TRANSFER
DISEASE EFFICIENTLY, SIMILAR TO
WHAT IS OBTAINED WITH CD8 T
CELLS.
THE OTHER VERY SURPRISING
OBSERVATION OF THIS WORK IS THAT
THE EXPOSURE OF BETA CELLS TO
INTERFERON ALPHA ACTUALLY
COMPLETELY CHANGED THE
RESTRICTION ELEMENT, HLA CLASS 1
MOLECULE THAT WAS PRESENT IN THE
PEPTIDES IN THE TWO CONDITIONS.
YOU SEE THERE WAS A MAJOR SHIFT
IN PEPTIDES PRESENTED BY THE
SUBFAMILY OF HLA-B.
THIS WAS THROUGH IN TERMS OF
NUMBER OF PEPTIDES, YOU SEE NOT
MUCH DIFFERENCE FOR HLA-A BUT
BIG JUMP FOR B, IN TERMS OF
QUANTITY OF EACH INDIVIDUAL
PEPTIDE.
YOU SEE NO DIFFERENCE FOR HLA-A
BUT MAJOR SHIFT FOR HLA-B AND
SOMETHING INTERMEDIATE FOR
HLA-C.
LOOKING AT WHETHER THIS
CORRESPONDED TO PREFERENTIAL
UPREGULATION OF HLA-B, AND YOU
SEE HERE THAT INDEED THIS WAS
THE CASE USING DIFFERENT
INTERFERONS, THIS IS THE LEVEL
OF GENE EXPRESSION IN BETA CELL
LINE, YOU SEE THERE IS
PREFERENTIAL UPREGULATION OF
HLA-B, IT IS TRUE AT THE PROTEIN
LEVEL BY FLOW CYTOMETRY AND
WESTERN BLOT AND COULD CONFIRM
IN PRIMARY HUMAN ISLETS WITH
SOME HETEROGENEITY BUT STILL
HLA-B WAS LARGELY FAVORED, IT
LOOKED FOR US CELLS THIS
PHENOMENON MORE BIASED TO HLA-C.
ACTUALLY THIS OBSERVATION IS
PRESENT IN DIFFERENT PAPERS,
ALTHOUGH IT WENT PRETTY MUCH
UNNOTICED.
YOU SEE HERE TWO EXAMPLES, THESE
ARE RNAseq STUDIES IN TYPE 1
DIABETES VERSUS NON-DIABETIC
ISLETS, YOU SEE THE EXACT
HIERARCHY WE DESCRIBED IN THE IN
VITRO EXPERIMENT.
AND THESE ARE MORE RECENT WORK
ALSO SHOWING KIND OF THE SAME
PATTERN.
AND MECHANIC IN THIS PARTICULAR
REASON FOR THIS GOES BACK TO
DIFFERENT PAPERS PUBLISHED QUITE
MANY YEARS AGO SHOWING THAT
INTERFERON RESPONSIVE ELEMENT
PRESENT IN HLA-B LOCUS HAS
HIGHER AFFINITY TO REGULATORY
FACTORS 1 AND 2 THAN INTERFERON
RESPONSIVE ELEMENTS OF HLA-A
LOCUS, SO INTERFERON EXPOSURE
FAVORS THESE HLA UPREGULATIONS,
BIAS TOWARDS THIS HLA-B.
THE OTHER QUESTION WE ASKED WAS
WHETHER THE LONGER KNOWN HLA
CLASS 1 HYPER EXPRESSION PRESENT
IN THE ISLETS OF TYPE 1 DIABETES
PATIENTS COULD ALSO REFLECT
MOSTLY HLA-B, AND YOU SEE HERE
IN THESE STAININGS FOR DIFFERENT
ANTIBODIES, DATED FOR
SPECIFICITY, BUT THIS SEEMS TO
BE THE CASE.
THESE ARE REPRESENTATIVE
STAININGS, AND YOU SEE HERE
OVERALL CUMULATIVE DATA SHOWING
THAT HLA-B IS MORE UPREGULATED
IN A, IN BOTH CELLS.
TRANSLATED INTO DIFFERENT
RECOGNITION BY T CELLS WAS THIS
UPREGULATION MOSTLY INVOLVED
HLA-B, YOU COULD EXPECT
RESTRICTED CELLS TO BE MORE
POTENTIATED IN RECOGNITION OF
BETA CELLS EXPOSED TO
INTERFERONS, AND YOU SEE HERE
THE FIRST EXPERIMENT TESTING
THIS USING BOTH HLA-A RESTRICTED
OR HbA-B 4 RESTRICTED,
FLUORESCENT REPORTERS WITH THE
MODEL USING BETA CELLS THAT
EXPRESS INSULIN, CD8 T CELLS
RECOGNIZE INSULIN PEPTIDES, YOU
SEE WHEN YOU EXPOSE THE BETA
CELLS TO INTERFERONS, AND TO
HLA-2 RESTRICTED CD8 CELLS
THERE'S NOT MUCH DIFFERENCE IN
THE TWO CONDITIONS, WHILE YOU
HAVE VERY SIGNIFICANT
UPREGULATION OF THE ACTIVATION
OF THESE CD8 T CELLS, HLA
RESTRICTED WHEN EXPOSED TO
INTERFERON-TREATED BETA CELLS
VERSUS THE BETA CELLS NOT
TREATED, HERE SHOWN IN LIGHT
BLUE.
THIS TRANSLATES INTO AN
INCREASED LINK BY HLA-B
RESTRICTED CELLS, WE'VE DONE
THIS IN THE OTHER EXPERIMENTS
USING REACTIVE MODEL TO CONTROL
AMOUNT OF PEPTIDE PRESENTED IN
EACH CONDITION, AND YOU SEE NO
DIFFERENCE IN BETA CELLS EXPOSED
TO INTERFERON ALPHA, YOU GET THE
SAME CYTOTOXICITY, WHILE IT GETS
SIGNIFICANTLY ENHANCED FOR HLA
RESTRICTED T CELLS.
WE ALSO WENT TO LOOK AT
DIFFERENT CD8 T CELL LINES THAT
SHE HAS GENERATED INFILTRATING T
CELLS WHERE THESE WOULD
RECOGNIZE RESTRICTED PEPTIDES
THAT WE'VE IDENTIFIED, YOU SEE
FIRST USING PEPTIDE DONE BY
CONVOLUTING WITH INDIVIDUAL
PEPTIDES WE FIND A NUMBER OF
HITS, HERE I HIGHLIGHT SOME THAT
HAVE BEEN SHOWN IN AT LEAST TWO
DIFFERENT CELL LINES, WITH SOME
ENVELOPE ANTIGENS IDENTIFIED,
PRESENCE OF RECOGNITION OF SOME
POST-TRANSLATIONALLY MODIFIED
PEPTIDES PARTICULARLY THIS ONE.
PREVIOUS OBSERVATIONS OF LACK OF
DIFFERENCE OF BETWEENS OF THESE
CD8 T CELLS BETWEEN TYPE 1
DIABETIC AND NON-DIABETIC
INDIVIDUALS ALL THIS WORK HAS
BEEN DONE BY FOCUSING ON HLA-A2
RESTRICTED CD8 T CELLS, IN THE
LITERATURE THERE'S BEEN VERY
LITTLE ATTENTION GIVEN TO THE
EPITOPES THAT ARE PRESENTED BY
HLA-B ALLELES.
YOU SEE THE NUMBER OF EPITOPES
THAT ARE KNOWN IN THE LITERATURE
IS EXTREMELY SMALL.
AND NOW WE HAVE SOME HUNDRED
NOVEL CANDIDATES THAT WE CAN
TEST TO SEE WHETHER THEY CAN
PROVIDE BETTER MARKERS OF
SECURITY MARKERS OF TYPE 1
DIABETES AUTOIMMUNITY.
WHY DO WE THINK THIS IS
IMPORTANT?
WELL, BECAUSE MAYBE THIS COULD
BE ANOTHER MECHANISM OF LOSS OF
IMMUNE, YOU SEE THE SITUATION OF
ANTI-ISLET, WITH LOW EXPRESSION
OF HLA-A, NOT HLA-B.
WHEN YOU GET INTERFERON RESPONSE
INCREASING IMMUNE VISIBILITY,
HLA UPREGULATION IS RELATIVELY
MINOR WITH MAJOR UPREGULATION SO
YOU MAY HAVE RECRUITMENT OF
COMPLETELY DISTINCT SET OF CD8 T
CELLS RECOGNIZING DIFFERENT
REPERTOIRE OF ANTIGENIC PEPTIDES
AND SO ON LEFT SIDE THESE
NEGLECTED CD8 T CELLS REPERTOIRE
MAY HAVE VERY IMPORTANT
PATHOGENIC ROLE, AND ON THE
OTHER MAY CONSTITUTE BETTER
BIOMARKERS OF ONGOING
AUTOIMMUNITY.
AND ONE LAST SLIDE TO THANK THE
PEOPLE THAT HAS DONE THE JOB,
THAT'S PARTICULARLY THE JOB OF
PREVIOUS Ph.D. STUDENT IN THE
LAB WITH TWO POSTDOCS IN
COLLABORATION ALSO WITH OUR
SATELLITE LAB IN INDIANAPOLIS,
AND OUR COLLABORATORS, TEAM WORK
THAT HAS BEEN A VERY PLEASANT
JOURNEY WITH DIFFERENT
COLLEAGUES I'VE MENTIONED
THROUGHOUT, IN DENVER, AND MY
NEIGHBOR, AND OF COURSE OUR
SPONSORS, IN PARTICULAR THE
TRUST, AND THANK YOU FOR YOUR
ATTENTION.
>> JULIA PANZER, RIGGS DIABETES
INSTITUTE OF CITY OF HOPE.
>> I'M GOING TO SWITCH GEARS.
WHICH POINTER AM I USING?
AND TALK ABOUT THE ALPHA CELL,
WHICH DESERVES A LITTLE MORE
ATTENTION THAN IT'S GETTING
CURRENTLY.
I'M GOING TO TELL YOU WHY.
BECAUSE SECRETION IS THE MOST
IMPORTANT DEFENSE MECHANISM.
OBVIOUSLY SOMETHING IS GOING
WRONG IN TYPE 1 DIABETES.
THIS IS NOT WORKING.
SO, IF WE LOOK AT GLYCEMIC
PROFILE OF A PATIENT WITH TYPE 1
DIABETES WE CAN SEE ALMOST EVERY
SINGLE DAY THIS PATIENT FACES A
HYPOGLYCEMIC EPISODE WITH SEVERE
CONSEQUENCES.
TO QUOTE, HYPOGLYCEMIA IS THE
LIMITING FACTOR IN MANAGEMENT OF
DIABETES, IF IT WEREN'T FOR
THAT, WE COULD TREAT DIABETES
MORE AGGRESSIVELY BUT ALSO MORE
SAFELY WITH INSULIN THERAPY.
ALSO WE COULD GIVE PATIENTS MORE
PEACE OF MIND BEFORE THEY GO TO
BED.
SO THE QUESTION IS WHERE IS
GOING WRONG WITH THE ALPHA CELL?
SO IF WE LOOK AT THE MORPHOLOGY
YOU CAN SEE TWO PANCREATIC
TISSUE SLICES, ON THE LEFT FROM
HEALTHY INDIVIDUAL, ON THE RIGHT
FROM AN AGE MATCHED DONOR WITH
TYPE 1 DIABETES STAINED FOR BETA
CELLS, FOR INSULIN IN GREEN,
ALPHA CELLS FOR GLUCAGON IN
MAGENTA.
THERE'S A LOSS OF BETA CELLS IN
TYPE 1 DIABETES, ALPHA CELLS
REMAIN, CLUSTERED TOGETHER IN
WHAT WE CAN ASSUME WHERE WERE
ISLETS BEFORE.
THERE'S NOT LOSS OF ALPHA CELLS,
NOT THAT THERE'S A LOSS OF
GLUCAGON A CON PER SE, WHAT IS
THE PROBLEM?
THEY DON'T SEEM TO SECRETE.
YOU CAN SEE HERE FROM HEALTHY
INDIVIDUALS, ON GENE
CORRESPONDING INSULIN TRACE.
THIS IS WHAT WE WOULD EXPECT
FROM AN ALPHA CELL.
THERE'S BASELINE SECRETION, THEN
THERE'S DECREASED GLUCAGON
SECRETION, TWO TO THREE-FOLD
INCREASE ON THE LOW GLUCOSE
LEVELS.
IN TYPE 1 DIABETES THIS
SECRETION IS COMPLETELY ABSENT.
THERE'S NOT ONLY THE LOSS DURING
HYPOGLYCEMIA, THERE'S THE CHANGE
RESPONSE UNDER HIGH GLUCOSE
LEVELS.
THIS IS NOT SIGNIFICANTLY
DIFFERENT IN GLUCAGON CONTENT
COMPARING HEALTHY INDIVIDUALS,
IN EXPLAIN WE CAN EXPLAIN BY
LOSS OF BETA CELLS.
SO THIS BRINGS ME TO THE CURRENT
MODEL THAT WE THINK IS HAPPENING
IN THE ALPHA CELL.
WE THINK THERE ARE TWO STATES.
THE SECRETORY AND INACTIVE
STATE.
SO WE KNOW THAT ALPHA CELLS ARE
ELECTRICALLY EXCITABLE, WORK
WITH FIRING ACTION POTENTIALS,
WHICH ACTIVATE CHANNELS, THIS
LEADS TO CONFLICT IN SECRETION.
THESE ACTION POTENTIAL HAVE TO
REACH A CERTAIN THRESHOLD
BECAUSE ONLY ABOVE THIS
THRESHOLD GLUCAGON SECRETION
OCCURS.
MULTIPLE STUDIES HAVE SHOWN
THESE ACTION POTENTIALS GET
SMALLER OVER TIME WHICH LEADS TO
THE INACTIVATED STATE AND
INACTIVATION OF CHANNELS.
SO WHAT THIS MEANS I'LL SHOW IN
THE SECRETION TRACE.
WHAT WE DID WAS SIMPLE
EXPERIMENT, EXPOSED HUMAN ISLETS
FOR A LONG TIME TO LOW GLUCOSE
CONCENTRATIONS.
THERE'S A RESPONSE WITH
INCREASED GLUCAGON SECRETION,
HOWEVER THIS LASTS FOR 30-60
MINUTES.
AFTER THIS GLUCAGON SECRETION
DECLINES, ALTHOUGH WE'RE STILL
IN ONE MILLIMOLAR GLUCOSE,
DECLINES AND DROPS AS LOW AS THE
LEVELS ARE WITH ACTIVE
INHIBITION DURING HIGH GLUCOSE.
THIS IS SPECIFIC FOR THE ALPHA
CELL BECAUSE THIS BEAUTIFUL
STUDY PERFORMED ON INSULIN
SECRETION SHOWS THAT THERE'S
AFTER THE FIRST RESPONSE OF
INSULIN RELEASE THERE'S A
PLATEAU, THIS LASTS FOR AS LONG
AS YOU STIMULATE THEM WITH HIGH
GLUCOSE.
COMPARED, SECRETION IS NOT
SUSTAINED.
THIS HAS BEEN SHOWN IN VITRO BUT
ALSO IN VIVO WITH HYPOGLYCEMIC
IN HUMAN, YOU CAN SEE, AGAIN,
THERE'S RESPONSE OF ABOUT 60
MINUTES, AFTERWARDS GLUCAGON
SECRETION DROPS, RESPONSE IS
ABSENT IN PATIENTS WITH TYPE 1
DIABETES, ALSO BEEN SHOWN IN
DOGS, ALSO IN RATS.
SO HOW DO WE GET ALPHA CELL BACK
TO SECRETORY STATE?
THIS HAPPENS BY THE WHOLE
ENVIRONMENT OF THE ALPHA CELL,
MEANING BY PARACRINE CELL.
THIS CLOSES THE CYCLE, LEADS TO
REPOLARIZATION, ACTIVE RESET OF
ALPHA CELL, SO IT'S NOT ONLY
IMPORTANT WHAT ACTIVATES THE
ALPHA CELL; IT'S EQUALLY
IMPORTANT WHAT INACTIVATES THE
CELL IN ORDER FOR IT TO
FUNCTION.
SO WE THINK IN TYPE 1 DIABETES
BECAUSE OF THESE CONSTANT
CONDITIONS, THE CELL REMAINS IN
THE INACTIVATED STATE, AND
BECAUSE THERE'S THE LOSS OF
PARACRINE SIGNALS BECAUSE WE
LOSE BETA CELLS IT CANNOT GO
BACK TO SECRETORY STATE.
HYPOTHESIS IS THAT IF WE CAN
REACTIVATE SIGNALS WE CAN
RESTORE ALPHA CELL'S ABILITY TO
RESPONSE TO HYPOGLYCEMIA.
SO, TO PROVE IF THIS IS ACCURATE
WE DID A VERY SIMPLE EXPERIMENT
TO START WITH.
AGAIN, WE EXPOSED HUMAN ISLETS
FOR A LONG TIME TO LOW GLUCOSE,
YOU SEE THE PROFILE, 60-MINUTE
RESPONSE, GLUCAGON SECRETION
DECLINES.
THEN WE THOUGHT WE JUST TRIED TO
RECOVER THIS BY RESETTING ALPHA
CELL BY ADDING A SHORT PERIOD OF
HIGH GLUCOSE AND STARTED WITH
FIVE MINUTES.
AND YOU CAN SEE ON TOP THE
RESPONSE OF INSULIN, YOU CAN
ALSO SEE GLUCAGON SECRETION IS
INHIBITED.
HOWEVER, THE REBOND EXCITATION
DOES NOT EXCEED THE NO RESET.
IF WE INCREASE THIS PERIOD TO 15
MINUTES YOU CAN ACTUALLY SEE THE
REBOUND EXCITATION GOES BACK TO
BASICALLY THE FIRST -- AS HIGH
AS THE FIRST RESPONSE BEFORE.
THIS IS VERY SIMILAR TO 30
MINUTES RESET.
SO BASICALLY IF WE GIVE ALPHA
CELL 15 MINUTE RESET TIME WE CAN
RESTORE ITS CAPACITY AND BRING
IT BACK FROM THE INACTIVATED TO
THE ACTIVATED STATE.
NOW HIGH GLUCOSE CONDITIONS IN
HEALTHY EYE LET WE ACTIVATE ALL
KINDS OF CELLS, RIGHT?
BETA CELL, PROBABLY DELTA CELL,
NEXT QUESTION WAS IS IT A
SPECIFIC PARACRINE SIGNAL
WITHOUT HIGH GLUCOSE CELLS.
WE USED TWO.
AND FOR BOTH OF THESE YOU CAN
SEE -- A LITTLE BLURRY, SORRY.
YOU CAN SEE FOR BOTH OF THEM
THAT IF WE USE THEM IN THE
PRESENCE OF LOW GLUCOSE WE CAN
INACTIVATE GLUCAGON SECRETION,
AND THIS IS ON THE RIGHT
NORMALIZED, YOU CAN SEE WE CAN
INHIBIT BY 50%.
IT ALSO LEADS TO REBOUND
EXCITATION AFTERWARDS.
SO BOTH OF THESE PARACRINE
SIGNALS ARE CAPABLE OF
INHIBITING THE ALPHA CELL.
WE CAN ALSO USE ANTAGONIST
AGAINST SPECIFIC SIGNALS, SO WE
USED ONE SPECIFICALLY AGAINST
THEIR 5HD 1 RESET, SPECIFIC IN
ALPHA CELLS, IF WE GIVE THIS
RECEPTOR ANTAGONIST UNDER LOW
GLUCOSE CONDITIONS WE CAN DOUBLE
GLUCAGON SECRETION WHICH SHOWS
US THAT THESE CELLS ARE ACTUALLY
INHIBITED EVEN IN THE LOW
GLUCOSE CONDITIONS, MAYBE JUST A
SUBSET OF THEM IS INHIBITED.
WHAT YOU CAN ALSO SEE IS THAT
THEY CAN STILL BE INHIBITED
UNDER HIGH GLUCOSE, PROBABLY NOT
ONE OF THESE SIGNALS, PROBABLY
THE NETWORK OF ALL OF THEM THAT
WORKS TOGETHER ON THE ALPHA CELL
TO BRING IT BACK TO ITS STATE.
NOW, DOES CAN WE ACTUALLY
RECOVER GLUCAGON SECRETION BY
REACTIVE WAITING PATHWAYS.
YOU CAN SEE GLUCAGON SECRETION
IS DEFECTIVE IN DONORS WITH TYPE
1 DIABETES.
NEXT, CONTINUES EXACTLY -- AFTER
THE 120 MINUTES, SO WE JUST
CONTINUE WITH THE TRACE, AND
EDIT SEROTONIN OR SOMATOSTATIN
TO THE CELLS, Y-AXIS IS TEN-FOLD
HIGHER, WE GET THIS HUGE
RESPONSE WHILE THEY ARE IN
SEROTONIN OR SOMATOSTATIN, EVEN
AFTERWARDS WHEN THE SIGNALS ARE
GONE WE HAVE SIGNIFICANTLY
INCREASED GLUCAGON SECRETION.
THEY ARE SUPPOSED TO INHIBIT
ALPHA CELL BUT WE GET THIS HUGE
RECOVERY.
SO WE THINK THE ANSWER TO THIS
ARE THE G-PROTEIN GATED
RECTIFYING POTASSIUM CHANNELS,
THE SO ACTIVATE OF THESE
CHANNELS LEADS TO DECREASED
ALPHA CELL EXCITABILITY AND
GLUCAGON INHIBITION.
THESE CHANNELS ARE PRESENT IN
HUMAN ISLETS.
AND ESPECIALLY PRESENT IN HUMAN
ALPHA CELL, BOTH GIRK 1 AND 2.
WHAT HAPPENS IF WE ACTIVATE OR
BLOCK?
AGAIN YOU SEE TYPICAL PROFILE.
NOW WE USE A BLOCKER, TERTIAPIN,
AND AN ACTIVATOR OF THIS.
SO WE ADDED DRUG UNDER BASELINE
CONDITIONS, LEFT IT THERE EVEN
UNDER HIGH GLUCOSE CONDITIONS.
THE CHANNEL BLOCKER LEADS TO A
DOUBLING OF GLUCAGON SECRETION
UNDER BASELINE CONDITIONS, YOU
CAN SEE NO MORE INHIBITION UNDER
HIGH GLUCOSE, EVEN AFTERWARDS
LEADS TO INCREASED GLUCAGON
SECRETION.
ACTIVATOR OF THE CHANNELS LEADS
TO COMPLETE BLOCKAGE OF GLUCAGON
CON SECRETION, SO IT IS
INHIBITED TO LEVELS ALMOST
UNDETECTABLE SO WE CAN ALMOST
COMPLETELY BLOCK GLUCAGON
SECRETION.
THERE'S NO DIFFERENCE IN INSULIN
SECRETION USING EITHER OF THESE,
ACTIVATOR OR CHANNEL BLOCKER.
SECONDLY WANTED TO KNOW WHETHER
WEIR WEEK RECOVER GLUCAGON CON
SECRETION AFTER IN THE ACTIVATED
STATE, IF WE ADD TERTIAPIN-Q WE
CAN RECOVER OVER THOUGH AT ITS
LOWEST POINT.
USING ACTIVATOR CAN FURTHER DO
THIS, ALREADY AT THE LOW POINT
OF 20 MINUTES.
LAST THING WANTED TO CHECK
WHETHER THIS IS SPECIFIC EFFECT
ON SOMATOSTATIN AND SEROTONIN SO
WE ADDED THIS DRUG IN THE
PRESENCE OF SOMATOSTATIN OR
SEROTONIN, YOU CAN SEE
SOMATOSTATIN UNDER LOW GLUCOSE
CONDITIONS, IF WE ADD THIS BEE
TOXIN INCREASE SECRETION AND
THERE'S NO INHIBITION WITH
SOMATOSTATIN SO WE CAN BLOCK
THIS EFFECT ALMOST ENTIRELY SO
HERE I'M SHOWING THE
NORMALIZATION, YOU CAN SEE
SOMATOSTATIN ITSELF IS CAPABLE
OF INHIBITING GLUCAGON SECRETION
BY 75%, COMPLETELY GONE WITH BY
BLOCKING GIRK CHANNELS.
THE AREA UNDER THE CURVE IS
SIGNIFICANTLY DIFFERENT.
SEROTONIN IS CAPABLE OF
INHIBITING GLUCAGON SECRETION,
LESS IF WE BLOCK THE GIRK
CHANNELS.
40% STILL THERE THROUGH
SEROTONIN, SIGNIFICANTLY BLOCKED
BY BLOCKING THE GIRK
CHANNELINGS.
FUTURE PROSPECTIVE WE WANT TO
TEST IN VIVO, HOWEVER WE HAVE TO
FACE MAJOR CHALLENGES BECAUSE SO
FAR ALL THE DATA THAT'S OUT
THERE THAT IS LOOKING AT THE
GIRK CHANNELS IN MICE DOESN'T
REFLECT WHAT WE SEE IN HUMAN,
MIGHT BE DIFFERENTLY EXPRESSED
IN ALPHA CELLS SO THE WAY TO GO
FOR US WOULD BE TO TRANSPLANT
HUMAN ISLETS INTO MICE AND USE
DIFFERENT MODEL SYSTEMS, FOR
EXAMPLE, STZ MOUSE, THE MODEL,
OR LOOK AT NOD MODEL, ULTIMATE
GOAL TO FIND FDA-APPROVED DRUGS
LIKE FOR THE GLUTAMATE STORY AND
REPURPOSE THOSE SO WE CAN USE
THEM ON TISSUES FROM TYPE 1
DIABETIC DONORS AND HOPEFULLY WE
CAN SEE IMPROVEMENT AND RECOVER
GLUCAGON SECRETION, WE HAVE TO
FACE CHALLENGES OF SPECIFICITY
AND ALSO AVAILABILITY OF HUMAN
DONOR ORGANS.
WITH THIS I WOULD LIKE TO
ACKNOWLEDGE MY CURRENT LAB, MY
FORMER MENTOR WHO I STILL
COLLABORATE WITH A LOT, THE
WHOLE TEAM IN GAINESVILLE,
FUNDING AGENCIES, OF COURSE
DONORS AND FAMILIES.
[APPLAUSE]
>> THANK YOU, RIGHT ON TIME SO
WE HAVE A FINAL SPEAKER, MY OWN
LAB WORKS ON THIS, SO IT'S GREAT
TO HAVE PROFESSOR GARCIA-OCANA,
CHAIR OF DEPARTMENT OF MOLECULAR
AND CELLULAR ENDOCRINOLOGY,
RIGGS CENTER.
>> CAN I USE THE MOUSE?
>> FIRST LET ME START BY THANK
YOU FOR YOUR KIND INTRODUCTION,
CONGRATULATIONS TO THE HUMAN
ISLET RESEARCH NETWORK.
AND THANK YOU TO THE ORGANIZERS
TO GIVE A TALK, THANK YOU FOR
THAT.
AND THANK YOU ALSO FOR
OPPORTUNITY TO TALK ABOUT OUR
LATEST STUDIES ON DYRK1A
INHIBITORS, HOW THEY CAN BE USED
IN TYPE 1 DIABETES IN THE
FUTURE.
I'M GOING TO STATE THE OBVIOUS.
THAT IS ACTUALLY THAT DIABETES
RESULTS FROM INSUFFICIENT AMOUNT
OF BETA CELLS, IN TYPE 1
DIABETES, LEADING TO OR
TRIGGERING AUTOIMMUNE RESPONSE.
HOLD ON A SECOND.
THANK YOU.
SO INCREASING EXTRINSIC AND
INTRINSIC, LEADING TO BETA CELL
DEATH, CELL DEMISE, INSULIN
DEFICIENCY.
IT'S IMPORTANT, THESE ARE
STUDIES, DIABETIC PATIENTS MOST
STILL HAVE BETA CELLS IN THERE.
WE'RE THINKING TO STUDIES TO
TREAT TYPE 1 DIABETES, WE THINK
ABOUT MAYBE ONE MORE WE HEARD
JULIA TALKING ABOUT.
BUT INCREASED POTENTIAL USING
BETA CELL REPLACEMENT.
MORE THINGS ON THE MENU, THE
BETTER.
ALSO TO PROTECT THOSE THAT WE'RE
GENERATING, DEFINITELY TO
RECOVER AND MAINTAIN THE BETA
CELL FUNCTION IN THERAPY THAT'S
PRESENT IN THOSE BETA CELLS, AND
WE HAVE AUTOIMMUNITY TO SILENCE
AUTOIMMUNITY, ENHANCE TOLERANCE.
HOW CAN WE -- THERE ARE MULTIPLE
WAYS THAT HAVE BEEN REPORTED
OVER THE YEARS THAT COULD BE
USEFUL TO ENHANCE BETA CELL MASS
AND STRONG WORK, GREAT WORK
BEING LEARNED ON HOW TO CONVERT
STEM CELLS.
WORK TO COMPARE ALPHA CELLS INTO
FOR EXAMPLE BETA CELLS, HOW TO
CONVERT, THINKING ABOUT HOW TO
CONVERT.
WE HAVE BEEN WORKING HOW TO
ENHANCE REPUTATION OF PERSISTING
BETA CELLS WITH IDEA OF
EXPANDING PARTICULAR PRESENT IN
THE PANCREAS.
IT'S BEEN CHALLENGING.
AND IN THE BREAKOUT ROOMS THAT
WE HAD, WE WERE TALKING ABOUT
THE DIFFERENCE BETWEEN MOUSE AND
HUMAN, WORKING ON AGENTS THAT
COULD INCREASE PROLIFERATION,
THAT THEY FAIL OR INDUCE MILD
EFFECTS ON HUMAN BETA CELLS.
AND WE RECENTLY LEARNED IN THE
LAST TEN YEARS THAT ACTUALLY
BETA CELLS, HUMAN BETA CELLS ARE
RECALCITRANT TO PREFERRATION,
DECLINES IN CHILDHOOD GOING TO
ADOLESCENCE WHERE PROLIFERATION
IS LOW AND IN ADULTS VERY LOW.
SO IT'S CHALLENGING TO FIND
AGENTS THAT CAN INCREASE
PROLIFERATION OF HUMAN BETA
CELLS IN VITRO AND OF COURSE
EVEN MORE IN VIVO.
THAT WAS THE CASE UNTIL 2015 IN
WHICH ACTUALLY THE STEWART WITH
THE SCOTT GROUP AND MY OWN
GROUP, ACTUALLY WE FOUND HUGE
WORK DONE BY THE LEADER OF THE
STUDY THROUGH HUNDREDS OF
THOUSANDS OF COMPOUNDS WERE ABLE
TO FIND A FEW THAT COULD
ACTUALLY ENHANCE EXPRESSION IN
BETA CELLS AND THOSE COMPOUNDS
IN PARTICULAR COMPOUND 1 WERE
ABLE TO INCREASE PROLIFERATION
OF HUMAN BETA CELLS IN ISLETS IN
RATS.
THAT WAS NOT THE GOAL.
THE GOAL WAS TO ENHANCE HUMAN
BETA PROLIFERATION, SO WHEN THEY
TESTED DIFFERENT COMPOUNDS, IN
PARTICULARLY COMPOUND NUMBER ONE
FOUND THERE WAS INCREASING
PROLIFERATION SIMILAR TO WHAT I
JUST SHOWED IN TERMS OF
PROLIFERATION IN HUMANS.
AND THIS COMPOUND NUMBER 1 WAS
HARMINE, GOLD STANDARD IN
INDUCING PROLIFERATION, USED
WITH MANY COMBINATIONS TO
ENHANCE PROLIFERATION, MORE
RECENTLY FUNCTION AND SURVIVAL
OF THE CELLS.
PRESENT IN SOME PLANTS AROUND
THE WORLD, AND BECOMING THAT,
MECHANISM WORKS THROUGH
INCUBATION, PHOSPHORYLATION
KINASE.
NOW IN FACT CAN GO.
THAT HAPPENS BECAUSE OF THE
FIRST THAT ELIMINATES THAT
PHOSPHATE, INCREASES PRESENCE OF
NFAT INTO THE NUCLEUS.
IN HUMAN BETA CELLS WE FIND AS
WELL IN VIVO ACTUALLY INDUCTION
OF HARMINE COULD INDUCE
PROLIFERATION IN HUMAN BETA
CELLS.
THE FOLLOWING PUBLICATION IN
2020 FROM A GROUP IN
COLLABORATION WITH GROUPS IN
MOUNT SINAI, WHEN I WAS OVER
THERE.
THAT CAME OUT ACTUALLY STEM FROM
THE FOLLOWING THOUGHT THAT
INHIBIT 1A, NOW PRESENT IN
CYTOPLASM, PHOSPHORYLATED, HOW
CAN YOU ENHANCE ACTIVITY SO YOU
CAN SEND MORE IN FACT TO THE
NUCLEUS, TO ENHANCE
PROLIFERATION OF BETA CELLS.
AND THIS GROUP TESTED MANY
COMPOUNDS THAT COULD ACTUALLY
ENHANCE AND FLUX INTO THE CELL,
THEY FOUND ACTUALLY SOME IN
PARTICULAR WAS COULD INCREASE
CALCIUM, SO WHAT THEY FOUND IN
THIS PAPER IS THAT WHEN THEY
COMBINE GLP-1 THAT HAS NO EFFECT
WITH HARMINE, NOW ENHANCED.
IMPORTANT POINT ACTUALLY.
IT ALLOWS NOW TO HUGE LOWER DOSE
OF HARMINE IN COMBINATION WITH
WOULD PRODUCE SAME EFFECT AS
HIGHER DOSES OF HARMINE, YOU CAN
LOWER THOSE OF A DRUG GENERALLY,
TO LOWER LEVEL, SECONDLY NOW YOU
CAN HAVE SYNERGISTIC EFFECT IN
DOSE THAT HAVE GLP 1 RECEPTORS,
BETTER WAY TO FIND BY CHALLENGE
OR BY I THINK THAT ACTUALLY THE
COMBINATION ENHANCE WITH
SPECIFICITY AND POTENCY OF A
DRUG SPECIFICALLY FOR BETA
CELLS.
IMPORTANT POINT IN THIS PAPER
WAS THAT CELLS WERE RESPONDING
TO COMBINATION, TYPE 2 DIABETES,
DIABETIC CELLS WERE ABLE TO
RESPOND, INCREASING
PROLIFERATION, SO NOT ONLY
NON-DIABETIC BUT ALSO DIABETIC
CELLS WERE RESPONSIVE.
SO WE HAVE THE STUDY, THERE WAS
ALWAYS THIS -- I WOULD SAY
CONCERN OR COMMENT, ACTUALLY,
FROM REVIEWERS OF THE PAPER
SAYING THIS IS FANTASTIC,
BEAUTIFUL STAINING, SHOW ME THE
MONEY THAT I CAN INCREASE THE
ACTUAL HUMAN BETA CELL NUMBER IN
VIVO IN SITUATIONS BASED ON
POSITIONS.
IT TOOK US A FEW YEARS ACTUALLY
THE WORK BY COSTELOT, AND MANY
OTHERS AT MOUNT SINAI IN CAB
LAYINGS WITH STANLEY, AN EXPERT
IN NEUROENDOCRINOLOGY AND
NEUROIMAGING, APPLY TECHNIQUE 3D
IMAGING OF IMMUNOLABEL SOLVENT
HERE, TO ACTUALLY USE THAT
TECHNIQUE FOR STAINING HUMAN
ALLOGRAFT TO SEE IN 3D AND
CALCULATE VOLUME OF SPECIFIC
HUMAN ALLOGRAFTS TRANSPLANTED
INTO MICE.
WITH MICE FOR SEVERAL DAYS WITH
DIFFERENT DRUGS COULD TAKE THOSE
AND MEASURE THE VOLUME AND SEE
WHERE ACTIVE TREATMENTS IN THE
VOLUME OF BETA CELLS THAT WOULD
TELL US THE NUMBER OF CELLS IS
INCREASING AFTER TREATMENT IN
THIS CASE WITH HARMINE.
TRANSLATED HUMAN ISLETS,
EXPERIMENT IN DIABETIC MICE, WE
TREAT THEM WITH HARMINE, LOWER
DOSES BECAUSE AS I MENTIONED
BEFORE THE COMBINATION
SYNERGISTIC, AND TREAT MICE FOR
FOUR WEEKS, EIGHT WEEKS, OR
TWELVE WEEKS ACTUALLY.
AND FOLLOWING AFTER THOSE,
HARVEST THE GRAFT ACTUALLY IN
BOTH AND PERFORM
IMMUNOHISTOCHEMISTRY TO MEASURE
THE VOLUME OF THE HUMAN ISLET
AFTER TREATMENT FOR THREE MONTHS
WITH THE COMBINATION OF DRUGS.
WE FOUND IT WAS MARKEDLY
INCREASED, SO YOU CAN SEE HERE
THAT INCREASE IN HUMAN BETA CELL
VOLUME IN THREE MONTHS,
EXTENDING FOR TREATED MICE.
AND WE SHOW A MILD INCREASE, NOT
SIGNIFICANT, WITH HARMINE ALONE
BECAUSE WE USED A LOWER DOSE, IN
PART.
IMPORTANTLY WE DIDN'T SEE
INCREASE IN THE VOLUME.
MORE STUDIES DONE, THAT PAPER,
MANY DIFFERENT TIME POINTS.
STOPPING TREATMENT AFTER THREE
MONTHS, SEE WHAT WAS THE RESULT,
MANY ASPECTS THERE.
I DON'T WANT TO GO INTO THOSE
BUT I WILL TELL YOU A MECHANISM
BEHIND ALL OF THAT, YOU ARE
THINKING PROBABLY JUST ABOUT
ENHANCING BETA CELL
PROLIFERATION BUT I CAN TELL YOU
THERE'S MORE.
FOR INCREASING THESE HUMAN BETA
CELL MASS IN TREATMENT,
INCREASED PROLIFERATION, FOR THE
SAME TIME, WITH DIFFERENT DRUGS,
OR COMBINATION, WE FOUND
PROLIFERATION WAS 0.3 TO 1%
MAXIMUM HUMAN BETA CELL
PROLIFERATION.
WITH THAT PROLIFERATION IT'S
DIFFICULT TO THINK OF THE
INCREASE, SOMETHING MAYBE ALL
MECHANISMS INVOLVED IN THIS
EFFECT.
IMMEDIATELY WE THOUGHT MAYBE
CELLS ARE BIGGER IN SIZE,
HYPERTROPHY, THIS FACTOR
INCREASES CELL MASS.
AT THREE MONTHS MEASURE, NOT
DIFFERENT AMONG DIFFERENT
GROUPS, SIZE WAS NOT A FACTOR
ACTUALLY INFLUENCING BETA CELL
MASS INDUCED BY HARMINE.
THIS BEAUTIFUL STUDY ACTUALLY,
FOUND AND REPORTED LIKE MONTHS
AGO IN CELL REPORTS MEDICINE, AT
LEAST IN VITRO, OKAY, IN HUMAN,
THIS ENHANCING AMOUNT, ALPHA
CELLS THAT THEY HAVE
PROLIFERATION OF THESE CELLS,
ACTUALLY ALPHA CELLS, YOU CAN
SEE HOW TREATMENT WITH HARMINE
ALONE OR PLUS HGLP ENHANCES THE
CELLS.
YOU CAN SEE THIS, DIFFERENT
MARKERS OF INSULIN.
SO NOW SOME ALPHA CELLS THAT
PERHAPS THEY ARE BECOMING
INSULIN POSITIVE CELLS.
AND TO DO THAT WITH STAINING AS
WELL.
AND FOUND THAT CELLS WERE
PRESENT IN LARGER NUMBER IN
VITRO IN THESE CONDITIONS, SO IT
COULD BE ANOTHER ASPECT, ANOTHER
CELLULAR MECHANISM INVOLVED IN
HUMAN BETA CELLS IN VIVO.
OF COURSE MORE STUDIES ARE
NEEDED, NEED TO EXPAND INTO IN
VIVO SITUATION, THESE ARE EX
VIVO.
DIFFERENT STUDY, MORE WORK TO DO
IN THAT SENSE.
OF COURSE ALSO WE FOUND NOVEL
BETA CELLS PROTECTIVE ACTIONS OF
THE THERAPY, HOW DID WE FIND
THIS?
EVERYTHING I SHOWED BEFORE,
TREATMENT WITH HARMINE
IMMEDIATELY AND WITH
PROLIFERATION.
IF WE WAIT ONE MONTH, ALLOW
ISLETS TO ENGRAFT AND STARTED
TREATMENT.
IN THAT SITUATION WHAT WE FOUND
STILL BETA CELL MASS IN THESE
ANIMALS WASN'T AS LARGE AS WE
FOUND WHEN WE TREAT THE MICE
IMMEDIATELY AFTER
TRANSPLANTATION.
SUGGESTING PERHAPS ADVANTAGE TO
ISLET TO ENGRAFT AND THAT WAY
YOU HAVE MORE MATERIAL TO EXPAND
FROM, HOW YOU GET 6% INCREASE IN
BETA CELL MASS.
WE MEASURE ONE WEEK AFTER
TRANSPLANTATION, EFFECT OF
HARMINE, 50% MORE MASS AT ONE
WEEK ALREADY AFTER THE TREATMENT
WITH THIS DRUG IN THE GRAFT,
BASICALLY SAYING 50% MORE BETA
CELLS FROM THE BEGINNING, AND
TREATMENT, SO EFFECT, PLUS
POTENTIAL CHANGES OF ALPHA CELLS
INTO BETA, SO IT'S A CONTINUUM
OF MANY DIFFERENT, AND FOUND
DECREASED ONE WEEK AFTER
PLANTATION, HARMINE PROTECTS,
INDICATING IT'S A TRULY
PROTECTOR OF BETA CELLS IN VIVO
AND IN VITRO.
SO TAKEHOME MESSAGES FROM THIS
PART OF MY TALK, EVERYTHING HAS
BEEN PUBLISHED, INCREASED HUMAN
BETA CELL IN VIVO IN MICE,
TRANSPLANTED, HOWEVER, DOES NOT
SIGNIFICANTLY INCREASE,
SPECIFICITY.
INCREASING MASS PERSISTS AT
LEAST ONE MONTH AFTER DRUG
WITHDRAWAL.
BASICALLY REMOVE THE DRUG, THE
LEVELS OF THE DRUG,
PROLIFERATION, NO EVIDENCE OF
ABNORMAL PRO LIVATION OF TISSUE
HISTOLOGY, NO POSTURING, FEEDING
OR GROOMING BEHAVIORS OBSERVED
IN MICE WITH THIS COMBINATION,
HAVING SAID THAT THIS IS IN THE
STUDY WE USED ALSO ANOTHER
INHIBITERROR CROSSING THE
BLOOD-BRAIN BARRIER, THAT'S
IMPORTANT, AND ISLET
VASCULARIZATION, IN VIVO,
UNEXPLORED CELLULAR PROCESS
REQUIRED.
PHASE 1 CLINICAL TRIAL HAS BEEN
INCREASINGLY PUBLISHED, ACTUALLY
BY STEWART, SAFE AND TOLERABLE
DOSE OF HARMINE, LEVELS HIGHER
THAN THE LEVELS IN THE HUMAN
PROLIFERATION, JUST IN SAFETY.
WE BELIEVE THE COMBINATION OF
DYRK1A INHIBITORS AND LLP 1R
AGONIST IS REALISTIC APPROACH.
NOW THE PART THAT'S NOT
PUBLISHED.
STUDIES DONE BY LOU BRYANT IN MY
LAB, BASED ON THE PROTECTIVE
EFFECTS WE THOUGHT COULD IT BE
ALSO PROTECTIVE AGAINST
CYTOKINES, IMPORTANT THERAPEUTIC
EFFECTS IN TYPE 1 DIABETES.
THE COMBINATION PROTECTIVE
EFFECT AGAINST CYTOKINES IN IN
VITRO, IN HUMAN ISLETS, COMPARED
WITH INDIVIDUAL DRUGS.
AS WELL PERFORMED SINGLE CELL
RNAseq ANALYSIS, DIFFERENT
DRUG AND DRUG COMBINATIONS, AND
BASICALLY CONFIRMED ACTUALLY IN
BETA CELL CLUSTER THE ACTIVATION
OF CYTOKINE PATHWAYS THAT OCCURS
WITH CYTOKINES IS CONTINUING TO
DIMINISH BY HARMINE, BUT ALSO
IMPORTANTLY APOPTOSIS PATHWAYS
ALSO REDUCED.
CONFIRMING EFFECTS WE SEE.
BUT ACTUALLY LOOKING AT OTHER
GENOTYPES ACTUALLY IMPORTANT FOR
TYPE 1 DIABETES WITH CYTOKINES
OR DIFFERENT DRUGS FOUND
ACTUALLY FOR EXAMPLE THE CXCL 9,
10, 11, NOW TREATMENT WITH
COMBINATION IS REDUCING THESE
LEVELS AS WELL.
THIS WAS FURTHER CONFIRMED BY
CXCL 10 RELEASE IN THE MEDIA
SHOWING LEVELS ARE DECREASED BY
TREATMENT IN THE CYTOKINE
PRESENT.
ALSO IT'S IMPORTANT TO SHOW
ACTUALLY HLA-A, B, AND C GO UP
WITH CYTOKINE TREATMENT, ALSO
ARE REDUCED BY THE TREATMENT
TOGETHER, AND THIS IS ALSO
CONFIRMED BY IMMUNOSTAINING AND
ANALYSIS OF IMMUNOFLUORESCENCE,
TREATMENT WITH DIFFERENT DRUGS,
COMBINATION, SEEING THAT ONE
REDUCED.
ON THE OTHER HAND, WE SAW
INHIBITOR HLA-E ALSO ENHANCED BY
CYTOKINE BY ITSELF OR TOGETHER
AND AGAIN CONFIRMED BY
IMMUNOSTAINING WITH ANTIBODIES
AGAINST HLA.
IN ADDITION, ALSO MEASURED RATIO
WITH CYTOKINES AND FOUND THE
TREATMENT WAS ABLE TO REDUCE
RATIO OF INSULIN, DECREASING PRO
INSULIN SECRETION, MOSTLY
BECAUSE OF PRO INSULIN
SECRETION.
LET'S USE THE NOD MOUSE MODEL
AND NOW TREATMENT AND SEE BY
ITSELF OR COMBINATION, WE COULD
REVERSE TYPE 1 DIABETES IN THESE
MICE.
FROM THAT ACTUALLY WE FIRST TRY
TO INJECT WITH AND PUT IN PUMPS,
ONE OR THE OTHER OR COMBINATION,
NOW THESE MICE, IT'S NOT
MODERATED ACTUALLY, THERE WILL
BE NO CHANCE FOR BETA CELLS TO
BE REGENERATED.
90 TO 100% DIABETIC AT THE END
OF THE STUDY.
WE TREATED MICE FOR THREE DAYS,
WITH LOW DOSE PREVIOUSLY
PUBLISHED, AND THEY TREAT THE
MICE WITH FOLLOWING THOSE THREE
DAYS OF TREATMENT, AND WE FOUND
ACTUALLY ALTHOUGH IMPROVE BLOOD
GLUCOSE LEVELS IN THE MICE,
APPROXIMATELY 40% OF THEM AT
THIS POINT, TREATMENT BY
THEMSELVES DON'T GIVE YOU MUCH
MORE THAN THE 40, 50% OF
IMPROVEMENT.
ONLY WHEN YOU COMBINE FOR THREE
DAYS, YOU PUT PUMPS, YOU SHOW
REACTION OF BLOOD GLUCOSE LEVELS
WITH APPROXIMATELY 85 TO 90% OF
THE MICE REVERSING DIABETES.
SO AT LEAST THE IDEA THE
COMBINATION CAN IMPROVE BLOOD
GLUCOSE LEVELS AND REVERSE
DIABETES IN THE MICE.
WE FOUND THAT PREPARATION WAS
INCREASED AS SUSPECTED OF BETA
CELLS, LEADING TO INCREASE IN
THESE MICE.
THEY IMMUNE LEVEL FOUND CD8 AND
INTERFERON GAMMA CD8S AND CD4
POSITIVE CELLS REDUCED BY THE
TREATMENT. .
WE FOUND INCREASE OF THE
MARKERS, THESE ARE THE MARKERS.
THIS COMBINATION REDUCES HUMAN
BETA CELL IMMUNITY IN
INFLAMMATORY ENVIRONMENT, AND
TOGETHER WITH IMMUNOMODULATORS,
WE LEARNED OF MANY DIFFERENT
IMMUNOMODULATORS USED, OR
TESTED, WITH DYRK1A INHIBITORS,
REVERSE IN MICE, WE THINK THAT
COMBINATION ACTUALLY CAN BE
THERAPEUTIC APPROACH FOR TYPE 1
DIABETES REVERSAL, AND JUST TO
THANK THE MEMBERS OF MY LAB, IN
PARTICULAR BRIAN AND RANDY, WHO
HAVE RUN MANY OF THESE STUDIES,
PREVIEWS, COLLABORATORS AT MOUNT
SINAI, AND THE GROUPS BY ANDY,
DON, AND BOB, AND SARAH, WHO
WORK ON THESE STUDIES WITH ME,
TOGETHER, AND MY NEW PARTNERS
ACTUALLY AT CITY OF HOPE, AND
THE DONORS.
THANK YOU.
[APPLAUSE]
>> THANKS VERY MUCH.
AN EXCITING PROVOCATIVE STUDY
NEAR THE END OF THE STUDY.
ALL FOUR SPEAKERS WILL COME ON
THE PODIUM.
I REQUEST THEM TO COME UP HERE,
SO THAT WE CAN BEGIN A LIVELY
DISCUSSION.
I HOPE YOU HAD ENOUGH COFFEE TO
ENGAGE YOURSELVES FOR THE NEXT
40 OR 45 MINUTES ON A DISCUSSION
FROM EACH OF THE TOPICS,
ENGINEERING, BETA CELLS, T
CELLS, INTERFERONS, AND JULIA
SPOKE ON RESTORING ALPHA CELL
FUNCTION, AND DYRK 1 INHIBITION.
THESE ARE RELEVANT FOR TYPE 1
DIABETES.
I WANT TO INITIATE DISCUSSION
MAKE SURE YOU IDENTIFY
YOURSELVES.
MAYBE WE CAN START ON THE RIGHT
SIDE.
>> HI.
UMass.
I HAVE A QUESTION FOR JULIA AND
ADOLFO.
JULIA, SEEMS TO ME THAT YOU
COULD IN A PATIENT WITH
LONGSTANDING TYPE 1 DIABETES
INFUSE SOMATO SATIN AND
SEROTONIN AND SEE IF CLINICALLY
YOU COULD SEE RECOVERY BECAUSE
THAT COULD BE QUICKLY TRANSLATED
TO PATIENTS WITH INSULIN PUMPS,
EVERY 2 OR 3 HOURS, 15 MINUTES
OF THOSE DRUGS IF YOU SEE A
RECOVERY OF ALPHA CELL FUNCTION.
>> NOT IN VIVO.
>> THEORETICALLY YOU SHOULD SEE
THAT EFFECT BASED ON DATA OR B
TOXIN, ET CETERA.
>> YES, THE PROBLEM IS
AVAILABILITY OF TISSUE.
>> NO, DO IT IN CLINICAL.
>> YEAH, YEAH.
WANTED TO TEST FIRST IN VITRO,
AVAILABILITY IS A PROBLEM.
>> FDA APPROVED DRUGS, SHOULD BE
A DOABLE THING, COULD BE
IMMEDIATELY IMPLEMENTED, TAKE
PATIENTS WITH SEVERE RECURRENT
HYPOGLYCEMIA, IDEAL CANDIDATES
TO PUT EVERY 3 HOURS.
>> BUT WE ALSO HAD GLUTAMATE
STORY, FDA-APPROVED DRUGS BUT
GETTING TO THE CLINIC AND DOING
IT IS NOT AS EASY AS THAT.
>> TRUE.
>> ADOLFO, I THOUGHT YOU SHOWED
AT LEAST ONE OF THE MECHANISMS
WAS ALPHA CELL TO BETA CELL
POSSIBLE TRANSDIFFERENTIATION
BUT YOUR CONCLUSION YOU SAID
THERE WAS NO INCREASE IN ALPHA
CELL NUMBER, AND I THOUGHT YOU
DO SHOW INCREASE.
DID I MISUNDERSTAND?
>> INCREASE IN ALPHA CELL
NUMBER, RIGHT, BECAUSE DOSES IN
VIVO ARE LOWER THAN IN VITRO,
COMMON IN THAT ACTUALLY.
SO WHAT WE THINK IS HAPPENING,
IF THAT'S HAPPENING IN VIVO IS
SMALL IN TERMS OF THE DONORS
WE'RE USING, ACTUALLY GOING TO
MAKE LOW PERCENTAGE OF ALPHA
CELLS BECOME BETA CELLS, WE
DON'T SEE EXPANSION OF THAT
PARTICULAR OPERATION.
>> THANK YOU.
>> UNIVERSITY OF MINNESOTA, I
HAVE ALSO A QUESTION FOR ADOLFO.
BEAUTIFUL WORK.
THE ISSUE IS
TRANSDIFFERENTIATION, HAVE YOU
EVER TRIED TO DELETE TRACING
STUDIES AT ALL?
>> GREAT QUESTION.
I DON'T THINK DOING
DEMONSTRATION IN HUMAN ISLET,
HUMAN BETA CELLS.
>> IN THE MOUSE.
>> IN THE MOUSE, NO, THAT'S
PROBABLY -- ACTUALLY, IN MICE,
COMBINING THEM WITH
DEMONSTRATION MICE WE CAN SEE
BECOMING BETA CELLS IN VIVO IN
MICE, ACTUALLY AFTER TREATMENT
WITH HARMINE.
>> THANK YOU FOR THE SUGGESTION,
IT'S A GREAT SUGGESTION.
WE HAVEN'T MADE PLANS OF DOING
THESE STUDIES IN MICE BUT WE
STARTING WORK WITH STEM CELL
BASED OR STEM CELL DERIVED
ISLETS, BECAUSE THEY ARE EASIER
TO MANIPULATE AND THIS WORK HAS
BEEN INITIATED, HOPEFULLY SOON
I'LL BE ABLE TO REPORT THE
RESULTS.
>> WE'RE WORKING ON CROSSING
GLUCAGON AND AALLELE, WHICH
TAKES TWO YEARS.
>> GREAT FOR COLLABORATION.
>> GO AHEAD.
>> ROBERTO CASTRO, UCSF, FOR THE
OTHER ROBERTO, FOR HLA-B
CO-CULTURES THAT YOU DID, ALL
THE PEPTIDES YOU FOUND, DO THEY
HAVE DIFFERENT AFFINITIES
TOWARDS HLA-B, DO YOU MEASURE IF
THEY BIND STRONGER TO HLA-B, OR
DO YOU THINK IT'S JUST BECAUSE
THERE'S MORE HLA-B?
>> SO, YEAH, THIS WORK HAS BEEN
BASED ON PREDICTION, REVIEW
BASED ON DIFFERENCE OF
PREDICTION SCORES, SO WE CAN
REASONABLY SAY THERE'S A
PRESENTATION BUT WE HAVEN'T
FORMALLY TESTED FOR MOST OF
THESE PEPTIDES WHETHER THEY BIND
TO HLA-B, THIS IS THE WORK THAT
IS ONGOING, WE'RE MAKING
TETRAMERS FOR ALL THESE PEPTIDES
AND SEEING WHERE WE SEE AN
INCREASED FREQUENCY OF HLA-B
RESTRICTED ISLET REACTIVE CD8
CELLS IN TYPE 1 VERSUS NON-DIE
BEATIC DONORS WE DIDN'T SAY
BEFORE FOR AGE RESTRICTED CELLS.
>> LET ME JUMP IN TO THE ENTIRE
PANEL.
I'M SURE ALL OF YOU KNOW ABOUT
THE LOBULAR PATTERN, SO FOR ME,
PRESENTATIONS, STARTING WITH
ROBERTO PERHAPS AND THE OTHERS
AS WELL, HOW IS IT THAT THE
MÉNAGE À TROIS IS NOT WORKING IN
SOME LOBES BUT AFFECTING ONLY
CERTAIN LOBES, AND SAME QUESTION
PERHAPS ALPHA CELLS, YOU THINK
SOME LOBES ARE FUNCTIONING
NORMALLY AND THEN GOING TO
ADOLFO, DO YOU THINK BETA CELL
REGENERATION COULD AFFECT ALL
THE LOBES IN THE ISLETS?
SO LOBULAR PATTERN IS A
HAPPENING ITEM IN TYPE 1, SO HOW
DO YOU ADDRESS THAT PARTICULAR
QUESTION?
>> IF I CAN START WITH A
COMMENT, FIRST FACTOR IN THIS
COULD BE THE SIZE OF THE ISLET,
BECAUSE THE EXPOSURE TO
INTERFERONS COULD BE DIFFERENT.
AND THERE IS DATA, SO YOU
SUPPORT OF THIS POSSIBILITY.
IT'S NOT THE ONLY FACTOR THAT
COULD BE AFFECT.
>> I'LL TALK.
SO I COMPLETELY AGREE WITH YOU.
>> TWO MICROPHONES.
>> COMPLETELY AGREE WITH YOU.
>> I AGREE WITH YOU.
DIFFERENT POPULATIONS INSIDE OF
THE ISLET, NOT THE PROPORTION OF
BETA CELLS IS MAINTAINED
CONSTANTLY IN ALL THE ISLETS,
PROBABLY THERE ARE DIFFERENCES.
SO, MOST LIKELY THE RESPONSE OF
ISLETS, DIFFERENT, EXPLAINING
THAT EXPRESSION OF HLA MAYBE IN
SOME ISLETS, THAN THE OTHER.
>> MAINTAINING CONSTANT NUMBER,
PROPORTION OF CELLS.
>> THAT DOESN'T HAPPEN, RIGHT?
>> YEAH, I THINK IT'S VARIABLE
JUST LIKE STEM CELL.
WE'RE USING WITH A LOT OF
QUALITY CONTROL, CLUSTER TO
CLUSTER THERE'S VARIABILITY, AND
THE QUESTIONS WE DEFINITELY WANT
TO EXPLORE, IF WE HAVE 20 ISLETS
IN FIELD OF VIEW, TRACKING,
RESPONSIVE, CROSS-CORRELATE TO
COMPOSITION, THE NEXT STEP THAT
WE'RE EXPLORING CAN RETRIEVE
THOSE CELLS, CAN WE FIX THEM AND
DO SPATIAL PROTEOMICS AND BE
ABLE TO CROSS-CORRELATE
MIGRATION AND KILLING WE'VE
LEARNED WITH COMPOSITION OF THE
CELLS OR DIFFERENT PHENOTYPES OF
THE T CELLS, BUT I THINK THERE'S
A LOT OF EVIDENCE HETEROGENEITY
IS LINK, AS YOU SAID, RELATED TO
COMPOSITION, COULD BE RELATED TO
FORMATION OF THE PANCREAS, THAT
VARIABILITY FROM TAIL TO HEAD,
MATRIX COMPOSITION, SO MANY
FACTORS MAY LEAD TO THAT, WHICH
IS WHY WE'RE SEEING INCREDIBLE
VARIABILITY.
>> I THINK YOU'RE SHOWING
ORGANOIDS THAT ARE USED, IMMUNE
CELLS, ET CETERA, ANY PLANS FOR
USING ALSO NEURONS?
>> THAT WOULD BE VERY COOL.
MONEY FOR THAT, I GUESS.
>> I HAVE A QUESTION.
HOW DO WE IDENTIFY
NEUROPEPTIDES, HOW IS THAT
IDENTIFIED?
>> THE QUESTION IS WHICH
NEOPEPTIDES WOULD BE RELEVANT IN
PATIENTS?
>> YEAH, IN VITRO DISCOVERY
DATA TO THE IN SITU, HUMAN
PATIENTS, LIKE MANY NEOPEPTIDE
IDENTIFY FROM IN VITRO, WE HAVE
NO IDEA PEPTIDES EXIST IN HUMAN
PATIENTS, WHAT DO WE HAVE TO
CONNECT.
>> YEAH, ABSOLUTELY RIGHT.
SO THESE DATA DEMONSTRATE THAT
THESE PEPTIDES ARE PRESENTED BY
BETA CELLS.
>> YES.
>> IT'S IN VITRO.
SO, NOT NECESSARILY THE SAME IN
VIVO, AND THE FACT THAT THESE
PEPTIDES ARE PRESENTED BY BETA
CELLS DOESN'T NECESSARILY MEAN
THAT THE T CELLS -- WE'VE SHOWN
THIS FOR SOME OF THEM, THANKS TO
USING T CELL LINES, THE
FOLLOW-UP OF THE WORK IS TO LOOK
AT THE T CELL RECOGNITION IN
TYPE 1 DIABETIC PATIENTS OF
THESE PEPTIDES IDENTIFIED,
LOOKING IN THE BLOOD USING
PBMCs, LOOKING ALSO IN LOCAL
TISSUES, USING TISSUE SECTIONS
FROM THE PANCREAS, FROM
PANCREATIC LYMPH NODES, AND THAT
WOULD BE ANOTHER EVIDENCE OF
RELEVANCE IN PATHOGENESIS, YEAH.
>> PLEASE GO AHEAD.
>> LEO FERRERA, MEDICAL
UNIVERSITY OF SOUTH CAROLINA.
TWO RELATED QUESTIONS, DR.
MALONE.
FASCINATING BETA CELLS
SPECIFICALLY UPREGULATE HLAV, I
USED TO WORK ON DIFFERENTIALLY
REGULATION TROPHOBLASTS IN
PREGNANCY, WONDERING QUESTION
ONE, DO YOU HAVE A SENSE OF WHAT
TRANSCRIPTION FACTORS OR
ENHANCERS ELEMENTS ARE INVOLVED?
IS THIS A DRIVING MECHANISM OR
SYMPTOM OF SOMETHING BIGGER,
SAME TRANSCRIPTIONAL NETWORK IS
DOING OTHER THINGS FOR THE BETA
CELLS, REALLY THE ONES IMPORTANT
IN PATHOLOGY.
>> TRANSCRIPTION FACTORS, DATA
IN LITERATURE SUGGESTING THIS
DIFFERENCE IN AFFINITY OF THE
INTERFERON RESPONSIVE ELEMENT IN
THE HLA-B VERSUS HLA-LOCUS, ALSO
LITERATURE SUGGESTING MECHANISM
OF UBIQUITINATION THAT CAN
REGULATE EXPRESSION, I DON'T
THINK THIS IS SOMETHING SPECIFIC
TO BETA CELLS.
IT'S PROBABLY SOMETHING QUITE
GENERAL PHENOMENON OF TISSUES
EXPOSED TO INTERFERONS, ALSO THE
PARADIGM MAY APPLY TO OTHER
AUTOIMMUNE DISEASES, DISPLAYING
INTERFERON TYPE I INTERFERON
SIGNAL THAT IS QUITE COMMON.
IT COULD SERVE IN INFLAMMATORY
CONDITIONS TO DIVERSIFY THE
PEPTIDES THAT HAVE RECOGNIZED,
NOT ONLY MORE PEPTIDES,
POTENTIALLY VIRAL PEPTIDES, ALSO
YOU CHANGE RESTRICTION,
PREVALENT RESTRICTION ELEMENTS.
INCIDENTALLY THERE'S SOME
LITERATURE, FOR EXAMPLE, IN THE
CANCER FIELD SHOWING THAT CANCER
CELLS THAT EVADE IMMUNE
RECOGNITION MORE FORTUNATELY
DOWNREGULATE HLA-B, OTHER THAN
HLA-A, ALSO DATA IN THE
TRANSPLANTATION SETTING SHOWING
THAT HLA-B IS MATCHING, IS
STRONGER PROGNOSTIC FACTOR FOR
ALLOGRAFT REJECTION AS COMPARED
TO HLA-A, MISMATCH, SUGGESTING
THIS COULD BE SOMETHING MORE
GENERAL IN THE AUTOIMMUNE FIELD
THAN IN OTHER DISEASE SETTINGS,
LINKED TO INTERFERON RESPONSES.
>> THANK YOU.
>> MOUNT SINAI SCHOOL OF
MEDICINE IN NEW YORK.
I HAVE A QUESTION TO DR. PANZER.
A FASCINATING TALK.
I HAVE TO ADMIT I HAVEN'T BEEN
THINKING EXTENSIVELY ABOUT ALPHA
CELL MALFUNCTION IN THE CONTEXT
OF TYPE 1, I'VE LEARNED A LOT.
BUT ONE THING I HAVE BEEN AND
ALSO THE REST OF THE FIELD HAS
BEEN THINKING A LOT ABOUT IS
HETEROGENEITY OF CELL TIMES.
SO I WAS JUST THINKING,
WONDERING IF YOU'VE EVER
APPROACHED FROM A HETEROGENEITY
POINT OF VIEW AND TRIED TO
IDENTIFY FUNCTIONAL SUBSETS OF
ALL THE CELLS?
>> YEAH, VERY GOOD POINTS.
EXACTLY WHAT I WROTE IN MY K
AWARD.
SO, I DO SEE A LOT OF
HETEROGENEITY IN ALPHA CELLS.
AND I MEAN IT'S VERY HARD TO
LOOK AT IT IF YOU LOOK AT
SECRETION, YOU LOOK AT WHATEVER
COMES OUT.
WHEN I DID A LOT OF CALCIUM
IMAGING YOU CAN SEE THERE ARE A
LOT OF SUBPOPULATIONS RESPONDING
TO DIFFERENT STIMULI.
I THINK THERE'S SOME CELLS THAT
RESPOND TO GLUCOSE SPECIFICALLY,
SOME GET ACTIVATED, THERE'S SOME
THAT INHIBIT IT.
AND THAT ALL OF THEM HAVE A
COMPLETELY DIFFERENT FUNCTION,
PROBABLY SOME OF THEM ARE
DYSFUNCTIONING IN DIABETES, THE
OTHERS ARE NOT.
IN THIS WHOLE NETWORK DOESN'T
PLAY TOGETHER ANYMORE, THEN
THAT'S WHEN EVERYTHING GETS
MESSED UP.
BUT, YEAH, THEY DEFINITELY --
>> THANK YOU.
>> QUESTION ON THE RIGHT.
>> HE WAS FIRST.
GO AHEAD.
>> GO AHEAD.
>> SORRY.
I ENJOYED ALL THE TALKS BUT THIS
IS SPECIFICALLY FOR DR.
GARCIA-OCANA.
FIRST, IN THE CYTOKINE-TREATED
CELLS LOOKING AT HARMINE, IS THE
PROLIFERATION MARKER THE SAME?
INCREASED PROLIFERATION WITH
HARMINE EXTENDIN, SECONDLY
LOOKING AT PROLIFERATION YOU GET
NEUROEPITOPES, NOW YOU'RE
GETTING EXPRESSION OF NEW
EPITOPES BECAUSE CELLS ARE
PROLIFERATIONS.
>> GREAT QUESTION, GREAT IDEA,
SOMETHING WE SHOULD DO, SINGLE
CELL RNAseq, IF CELLS ARE
RESPONDING, NON-RESPONDING TO
CYTOKINES CHANGING
IMMUNOGENICITY AT THE SAME TIME
THEY ARE -- THERE'S A CYCLE
MACHINERY, WE HAVEN'T DONE THAT.
GREAT POINT.
THANK YOU FOR THE SUGGESTION.
>> CLASS 1 EXPRESSED WHEN
HARMINE CELLS INCREASED, NEW
EPITOPES.
>> EXACTLY WHAT WE HAVE TO DO,
YEAH.
GREAT POINT.
THANK YOU.
>> RUSSELL COCHRANE, MEDICAL
UNIVERSITY OF SOUTH CAROLINA.
MY QUESTION FOR JULIA.
I WANT TO ECHO REFRESHING TO SEE
ALPHA CELLS AND GLUCAGON, YOU
DON'T SEE THAT MUCH.
I WANT TO CLARIFY YOU MADE THE
POINT SEROTONIN, BEFORE,
INHIBITS GLUCAGON SECRETION,
SSRIs LOWER GLYCEMIA, AND MORE
IN PATIENTS USING CORRELATED
PROBABLY TO THE MECHANISM?
>>> POINT, YEAH.
>> THE OTHER POINT WAS I WANTED
TO KNOW FUTURE DIRECTIONS, ARE
YOU GOING DOWN THE ROAD OF USING
TERTIAPIN Q OR MORE WITH
SEROTONIN SENDING.
>> BOTH.
WE WANT TO FIND THE DRUG WE CAN
USE FOR PATIENTS WITH TYPE 1,
IDEALLY DIRECTLY TO THE CLINIC,
AS SUGGESTED, BUT OF COURSE WE
NEED TO FIGURE OUT MORE ABOUT
THE PATHWAY AND THAT IS REALLY
WHAT'S HAPPENING AND HOW EXACTLY
THIS IS HAPPENING.
SO WE ALSO WANT TO LOOK AT
ELECTROPHYSIOLOGY AND ALTHOUGH
WE COULD USE TPX, IT'S A BEE
TOXIN, MAYBE THERE OTHER DRUGS
THAT COULD BE REPURPOSED THAT
ARE MORE SUITABLE.
>> THANK YOU.
>> I HAVE A QUESTION TO JULIA,
ALSO A COMMENT.
WHAT DO YOU THINK IT IS THAT
STARTS OR INITIATES DYSFUNCTION
IN GLUCAGON?
IS IT THE GLYCEMIA OR RECURRENT
HYPOGLYCEMIA?
OLD DAYS WE GIVE INSULIN
INTRAVENOUSLY, OUR EXPERIENCE IF
YOU GAVE IT TO PEOPLE NOT
DIABETIC YET YOU COULD GIVE HIGH
DOSES WITHOUT EVER HAVING
HYPOGLYCEMIC BUT WHEN THEY
DEVELOP STAGE 3 YOU HAD TO GIVE
MUCH LOWER DOSES, IMMEDIATELY
WENT INTO HYPOGLYCEMIA.
LOOKS LIKE A RICH HAPPENING
CLINICALLY, IN THE ALPHA CELL
FUNCTION, AND I WAS JUST CURIOUS
IF YOU HAVE A HYPOTHESIS?
>> YES, VERY HARD-TO-ANSWER
QUESTION BECAUSE SO WE DO SEE,
FOR EXAMPLE, IN THE NOD MOUSE
MODEL BEFORE THEY BECOME
COMPLETELY HYPERGLYCEMIC,
THERE'S LOSS OF ALPHA CELL
FUNCTION.
ALREADY.
BUT THEN ON THE OTHER HAND WE
CAN SEE IN PATIENTS WITH TYPE 1
DIABETES THAT STILL HAVE CERTAIN
AMOUNT OF REMAINING BETA CELLS
THE ALPHA SEEM TO FUNCTION
BETTER THAN THE ONEs WHERE
IT'S COMPLETELY LOST.
I'M NOT SURE WHAT'S HAPPENING
BUT IN SOME CASES WE CAN SEE --
MAYBE THIS IS ALSO LINKED TO
HETEROGENEITY OF ALPHA CELLS,
MAYBE SOMETHING IS HAPPENING IN
A CERTAIN POPULATION BEFORE
THERE'S A COMPLETE LOSS OF BETA
CELLS.
BUT I'M NOT EXACTLY SURE AT THIS
POINT.
>> DO YOU THINK IT COULD BE ALSO
INTERACTION BETWEEN ALPHA CELLS,
BETA CELLS, THAT NOW IS LOST AND
NOW THAT CHANGES IN BETWEEN,
PLAYS A ROLE?
>> ABSOLUTELY, THE MORE WE
KNOW, THE MORE WE GET TO KNOW,
THE MORE WE KNOW THAT ALL OF
THESE CELLS INTERACT WITH EACH
OTHER AND THEY NEED THIS
COMMUNICATION AND I MEAN I HOPE
I CONVINCED YOU THAT
SPECIFICALLY THE ALPHA CELL
NEEDS FEEDBACK FROM ALL OF THESE
CELLS.
IF EVEN ONE CONNECTION IS NOT
THERE THIS LEADS TO DYSFUNCTION
>> MAYBE WE'RE THE ONLY ONES IN
THE ROOM OLD ENOUGH TO REMEMBER,
ROGER UNGER DID A TRIAL IN THE
'60s, INFUSED SOMATOSTATIN IN
PATIENTS WITH TYPE 1 DIABETES,
WAS MORE ABLE TO CONTROL
DIABETES PROBABLY BECAUSE BETA
CELLS ARE ALREADY DEAD, HE WAS
WAKING UP ALPHA CELLS, GOOD
HYPOTHESIS TO TEST, PUBLISHED IN
NEW ENGLAND JOURNAL, ROGER
UNGER, IF YOU WANT TO LOOK FOR
IT.
ROBERTO, IF YOU WENT BACK TO
THERESA CALVO AND MATISSE VON
HARRIS, HLA CLASS 1 DO YOU HAVE
REAGENTS THAT CAN STAIN FOR
HLA-B TO SEE HOW MUCH
UPREGULATION RELATIVE TO A AND C
IN THE HUMAN SAMPLES?
>> SO, THERE IS PART OF THE
WORK WAS TO IDENTIFY HLA-B
ANTIBODIES, REASONABLY SPECIFIC.
AND WE CHARACTERIZE QUITE
EXTENSIVELY A COUPLE OF WHICH
ONE WORKS IN IMMUNOFLUORESCENCE.
IT'S CALLED HC-10, AND IT'S
EPITOPE MAPPING, EXTENSIVELY
CHARACTERIZED, SO SOME
CROSS-ACTIVITY WITH SOME
SPECIFIC HLA-A ALLELES, SO WE
TOOK CARE IN EXCLUDING DONORS
WITH HLA-A ALLELES TO AVOID
POTENTIAL CROSS-REACTIVITY, WITH
THAT LIMITATION CAN BE USED IN
IMMUNO FLUORESCENT STUDIES,
SARAH RICHARDSON HAS DONE THESE,
SHE DOES HLA-B UPREGULATION THAT
IS HIGHER THAN WHAT IS SEEN FOR
HLA-A.
>> I'D LIKE TO THINK EACH OF OF
YOU PLACED AN EASTER EGG, I'LL
START WITH CHERIE, DIFFERENT
IMMUNE CELLS SENSITIVE TO SHEER.
MY QUESTION WAS DO YOU KNOW OF
RELATION BETWEEN SHEER AND
MIGRATION CAPACITY, WHETHER THEY
ARE TARGETING SPECIFIC HLA?
>> STUDIES EXPLORED SIMPLE
SHEER EXPERIMENTS, OBSERVED
ALMOST DOING LIKE A SLINGBACK
MECHANISM, PROPEL THEMSELVES
BACKWARDS, REVERSE TO SHEER AS
OPPOSED TO STATIC EXHIBITING
UNIQUE PHENOMENON, STUDIES
LOOKED AT T CELL ADHESION ON
ENDOTHELIAL CELL LAYERS, WHEN
EXPOSED TO SHEER THEY ALTER
PHENOTYPE, AND THEN WHEN YOU CAN
ADD T CELLS TO THAT YOU SEE
DIFFERENT PHENOMENON IN TERMS OF
ADHESION AND TRANSMIGRATION.
THOSE STUDIES HAVE BEEN QUITE
LIMITED USUALLY MONOLAYERS,
MAYBE THERE'S A LITTLE SPACE
UNDER KNEAD WHERE THEY LOOK AT
MIGRATION, MOST IN TRANSWELLS, A
NEED TO EXPLORE LONG-TERM SHEER
ON T CELLS, RECIRCULATION, WHICH
IS NOT PUBLISHED.
PEOPLE HAVEN'T REALLY SHOWN THAT
SIDE.
THERE'S A LOT WE DON'T KNOW
THAT'S BEEN OBSERVED IN VIVO,
THAT WE NEED TO START
TRANSLATING IN VIVO.
>> DO WE KNOW IF THE ENGINEERED
T CELLS SUCH AS CAR-T CELLS HAVE
THAT PROPERTY OR CAN THE SYSTEM
HELP US?
>> NOT THAT I'M AWARE OF.
>> AND I THINK ADOLFO, YOU SAID
WE KNOW MECHANISM FOR THIS WHICH
WOULD BE PROLIFERATION, HOW
ABOUT MECHANISM FOR PROTECTION
AGAINST STRESS, DO WE HAVE CLUES
ON THAT?
>> YES.
ACTUALLY WE'RE DOING DGs,
ANALYSIS, CYTOKINE TREATMENT,
GENES ARE INVOLVED IN APOPTOSIS,
THEY ARE ACTIVATED BY HARMINE,
STILL HAVE TO BE CONFIRMED
BEFORE I NAME NAMES OF GENES
THAT THEY ARE INVOLVED.
SORRY.
BUT, YEAH.
>> IS THIS ONLY KINASE THAT WE
KNOW.
>> DEFINITELY NOT.
HARMINE.
INHIBITORS INHIBIT OTHER KINASES
AS WELL THAT THEY ARE INVOLVED
IN OTHER PATHWAYS, SOME FROM THE
SAME FAMILY, ACTUALLY, SOME
CRKs, INVOLVED IN
PROLIFERATION, SOME KINASES
INVOLVED IN APOPTOSIS, AND
INFLAMMATION SUCH AS, FOR
EXAMPLE, HEAT KINASES, THE SAME
FAMILY.
WE'RE WORKING ON THAT ASPECT AS
WELL.
IT'S MORE COMPLICATED THAN WE
EXPECTED.
BUT, YEAH, I MEAN THOSE ARE --
KINASES AS WELL TARGETED BY
HARMINE, HARMALOGS.
THINK OF SOMETHING.
COMBINE TO OTHER MOLECULES,
METABOLIZE, WE DON'T KNOW.
A LOT OF THINGS TO STUDY THERE.
>> SO WE STILL HAVE TIME FOR
QUESTIONS, FOLKS.
PLEASE DON'T HESITATE.
I WANT TO TALK TO CHERIE AND
ROBERTO ABOUT ONE FACTOR WHICH
DID COME UP IN DISCUSSIONS, GUT
MICROBIOME.
SO HOW ARE YOU FACTORING IN YOUR
PHYSIOLOGICAL OR
MICROPHYSIOLOGICAL SYSTEMS THE
GUT.
GUT TISSUE IS ALSO AN IMPORTANT
COMPONENT OF THE GUT MICROBIOME,
HOW DOES THAT FIGURE INTO YOUR
MÉNAGE À TROIS?
>> FUN QUESTION.
THERE'S A LOT OF WORK INVESTING
IN CONNECTING DIFFERENT ORGANS.
THERE IS A LOT OF WORK IN TERMS
OF GUT ON A CHIP, EXPLORE
MICROBIOMES, A LOT OF
CONDITIONS, IBS, CROHNS, MODELS
ARE RELEVANT, CAN EXPLORE THE
ROLE OF MICROBIOME ON THAT.
THAT WOULD BE A FASCINATING
STUDY TO REALLY EXPLORE THOSE
TWO CONNECTED, AND SEE
ALTERATIONS OR SEE IF T CELLS
ARE EXPOSED VERSUS CIRCULATING
THROUGH THE PANCREAS ON A CHIP,
HOW THAT ADJUSTS, LOTS OF FUN
THINGS COULD BE DONE.
I DON'T THINK ANYONE IS WORKING
ON THAT JUST YET.
>> TWO DIFFERENT ANGLES, ONE IS
CROSS-ACTIVITY OF THE REACTIVE
CD8 T CELLS, WITH POTENTIAL
PEPTIDES FROM GUT MICROBIOMES
THAT COULD POSSIBLY FAVOR THE
ACTIVATION OF THESE AUTOREACTIVE
T CELLS.
THE OTHER QUESTION IS ABOUT THE
ROLE OF ENTEROVIRUSES, WHICH IS
ANOTHER ACTIVE LINE OF RESEARCH
IN THE LAB, SO WE'VE
CHARACTERIZED A NUMBER OF
COXSACKIE EPITOPES IN BETA CELLS
INFECTED BY THESE VIRUSES, NOW
LOOKING AT WHAT HAPPENS AT THE
LEVEL OF ENTRY SITE IN THE GUT
TO SEE WHETHER THE SAME
PHENOMENON IN THE BETA CELLS
APPLY TO THE GUT AND WHETHER WE
SEE A SIMILAR EXPOSURE OF THE
SAME EPITOPES AND WE'RE ALSO
USING SOME GUT MICROORGANS,
ORGANOIDS, FOR LOOKING MORE
SPECIFICALLY AT INTERACTION OF
DIFFERENT IMMUNE CELLS BECAUSE
WITH VIRUS INFECTION WE DON'T
HAVE THE NATURAL INTERFERON
RESPONSE SO WE WOULD LIKE TO
HAVE A SYSTEM WHERE THIS IS
PRESERVED, THE GUT ORGANS CAN BE
A GOOD STARTING POINT.
>> I HAVE A QUESTION FOR DR.
PANZER.
THE NIH PUT IN A LOT OF FUNDING
ON CROSS-TALK, IN YOUR SYSTEMS
SPECIFICALLY LOOKING ONLY AT
ALPHA CELLS, HOW DO YOU FACTOR
IN EFFECT OF EXOCRINE TISSUE
DURING INITIATION OR
HYPOGLYCEMIA.
>> THE ALPHA CELL IS INFLUENCED
BY A LOT OF FACTORS INCLUDING
NEURONS, THE GUT TOO.
AND I MEAN WE HAVEN'T EVEN
STARTED LOOKING AT ALL OF -- WE
CAN NOW THAT ALSO WE CAN USE THE
SLIDE SYSTEM, WE CAN LOOK AT
EFFECT OF WHATEVER CELLS IN THE
PANCREAS, OBVIOUSLY USE WHATEVER
COMES FROM THE BLOOD VESSELS OR
EVEN THE GUT, BUT WE HAVEN'T
LOOKED INTO THAT YET.
BUT I THINK THERE ARE A LOT OF
FACTORS THAT INFLUENCE THE ALPHA
CELL, OUTSIDE OF THE ISLET
MICROENVIRONMENT.
>> PLEASE, YES.
>> LAST-MINUTE QUESTION ABOUT
THE BETA CELL.
LIKE WHEN YOU TREATED THE MICE
WITH JUST THE COMBINATION
WITHOUT THE CD3 YOU DID NOT SEE
ANY, I WAS THINKING WHEN THE
CELL PROLIFERATES, LIKE WOULDN'T
THAT BE A PROBLEM FOR MAKING
CELLS MORE VULNERABLE TO TYPE 1
DIABETES?
>> GREAT POINT, ACTUALLY, AND
THAT GOES WITH THE QUESTION FROM
SOMEBODY IN THE AUDIENCE BEFORE
ABOUT ACTUALLY THOSE CELLS
PROLIFERATING, THE ONES THAT ARE
CHANGING EXPRESSION OF DIFFERENT
IMMUNOGENETIC MARKERS.
THE ANSWER IS I DON'T KNOW,
THAT'S FOR SURE.
I COULD ANSWER, FOR EXAMPLE,
THAT STILL I THINK WE'RE
THINKING INCREASING
PROLIFERATION DECREASES FINE
CELLS, SO IF INCREASING
PROLIFERATION OF THOSE CELLS
MAYBE ARE MAKING THEM LESS
IMMUNOGENIC, THAT WAY THEY ARE
LESS ATTACKED BY THE IMMUNE
SYSTEM, AND THAT'S WHY WHEN WE
HAVE DISEASE IN THE ENVIRONMENT,
COULD BE, THAT'S SOMETHING WE
NEED TO EXPLORE AS WELL, BUT
IT'S ANOTHER IDEA.
THANK YOU FOR THE QUESTION.
>> A FOLLOW-UP ON THAT, WERE YOU
THINKING OF LESS FUNCTION FOR
REPLICATING BETA CELL, WOULD A
REPLICATING ALPHA CELL ALSO BE
LESS FUNCTIONAL?
AND DO WE HAVE ANY EVIDENCE OF
HYPOGLYCEMIA RISK WITH TREATMENT
OF HARMINE?
>> I DON'T KNOW AT THIS POINT.
>> BOTH OF YOU WORK IN THE SAME
SECTOR, RIGHT?
[LAUGHTER]
>> WE'RE ACTUALLY WORKING ON
THIS.
>> GREAT QUESTION.
IT'S SOMETHING AS WELL WE
HAVEN'T EXAMINED, MAYBE SINGLE
CELL RNAseq OF MARKER FUNCTION
THAT COULD PERHAPS COULD GUIDE
US WHETHER THIS THERAPY COULD
CHANGE ACTUALLY, COULD CHANGE
THE FATE OF THOSE ALPHA CELLS OR
RESPONSE.
>> WE HAVE LOOKED AT BETA CELLS,
WITH HARMINE TREATMENT THERE'S
HIGHER EXPRESSION OF THE BETA
CELL MARKERS, MATURATION CELL
MARKERS, IF YOU WILL, BUT FOR
THE ALPHA CELLS PERHAPS I WAS
TOO FOCUSED ON CYCLING ALPHA,
THEY ARE NOT GAINING AN ALPHA
CELL MARKER EXPRESSION.
THEY DO EXPRESS ALPHA CELL
MARKERS BUT WITHIN THAT CYCLING
THERE'S SUBSETS AS WELL.
ONE OF WHICH LOOKS MORE
ALPHA-LIKE AND ANOTHER ONE WHICH
LOOKS MORE BETA-LIKE.
SO IF YOU LOOK AT OTHER TWO
ALPHA CELL SUBTYPES THAT WE
HAVE, AGAIN I DON'T HAVE THE
INFORMATION OFF THE TOP OF MY
HEAD BUT I DO NOT RECALL SEEING
MORE EXPRESSION OF ALPHA CELL
MARKERS BUT I CAN DOUBLE CHECK.
>> IT'S GOING TO BE TRICKY TO
FIND THESE FEW CELLS BECAUSE
FIRST WE HAVE LESS ALPHA CELLS,
AND THEN THE ONES THAT REALLY
CONVERT OR PROLIFERATE, SO YOU
HAVE TO LOOK AT INDIVIDUAL
CELLS, DO FUNCTIONAL STUDIES ON
CELLULAR LEVEL, AND THEN YOU
NEED TO BE ABLE TO FIND THE
NEEDLE IN THE HAYSTACK, THE ONE
CONVERTING OR PROLIFERATING.
SO I THINK THAT'S CHALLENGING.
BUT NOT IMPOSSIBLE.
>> A QUESTION FOR DR. PANZER.
I KNOW IN A HEALTHY SYSTEM
ADRENALINE IS ALSO SOMETHING
THAT MIGHT STIMULATE THE
SECRETION OF GLUCAGON.
DO YOU KNOW WHETHER THAT'S
MAINTAINED IN DIABETIC PATIENTS?
>> YEAH, GREAT POINT.
IT DOES.
AND IT IS.
>> IS THAT VIA THE SAME PATHWAY
THAT YOU EXPLAINED THAT
SEROTONIN INHIBITS?
AND CAN THIS PATHWAY BE USED IN
TREATMENTING HYPOGLYCEMIC
EPISODES?
>> SO ADRENALINE WORKS
DIFFERENTLY, IT ACTIVATES
GLUCAGON SECRETION, ALSO IS ONE
OF THE MAJOR STEPS AS A DEFENSE
AGAINST HYPOGLYCEMIA.
IF WE LOOK AT TISSUES FROM TYPE
1 DIABETICS, WE SEE THE RESPONSE
TO ADRENALINE IS STILL THERE.
SO, IT'S NOT AFFECTED IN THE
SAME WAY.
>> DO WE KNOW WHY THAT FUNCTION
IS MAINTAINED?
THANK YOU.
>> FOLLOWING UP ON THAT, JULIA,
YOU SAID YOU WANT YOUR PATIENTS
TO SLEEP BETTER AT NIGHT.
AND SO IS THERE PLANS TO STUDY
THE TIMING IN WHICH YOU WOULD
TREAT THE MICE, IN VIVO, WHETHER
YOU APPLY AT NIGHT WHEN THE MOST
FREQUENT HYPOGLYCEMIC EVENTS
WOULD HAPPEN?
>> YEAH, SO, YES, THERE ARE.
THE PROBLEM IS ALSO WHEN WE --
SO LIKE THE SUGGESTION TO YOU,
JUST SEROTONIN, THERE'S A LOT OF
SOMATOSTATIN IN YOUR SYSTEM, BUT
IT'S DIFFERENT AND ALSO HAS
DIFFERENT FUNCTIONS.
SO THE PROBLEM IS WHATEVER WE
GIVE UNTO THE ISLET PER SE MIGHT
NOT WORK IF WE GIVE IT IN VIVO.
SO I THINK THERE'S A LOT MORE
THAT WE HAVE TO FIGURE OUT, AND
THEN OF COURSE WE NEED TO TEST
WHAT EFFECTS THESE DIFFERENT
DRUGS MIGHT HAVE BECAUSE WE ALSO
DON'T WANT THEM TO INFLUENCE
INSULIN SECRETION, BECAUSE THAT
WOULDN'T BE GOOD IN WE FURTHER
INCREASE GLYCEMIA.
YEAH, THERE'S A LOT OF THINGS TO
DO, BUT TIMING IS IMPORTANT TO
LOOK AT AS WELL.
>> GO AHEAD.
>> UNIVERSITY OF PENNSYLVANIA.
A COMMENT, JULIA, RELATED TO THE
ALPHA CELL SECRETION IN VIVO,
ONE THING, REMEMBER, OUR
PATIENTS WITH TYPE 1 DIABETES
DEVELOP HYPOGLYCEMIA WHEN THEY
HAVE A THERAPEUTIC INSULIN
EXCESS, SO RESPONSES OF THE
ALPHA CELL TO EPINEPHRINE IS
INHIBITED IN PRESENCE OF INSULIN
SO WHEN WE LOOK AT ALPHA CELL
RESPONSES, TYPICALLY GLUCAGON
INCREASING, OTHER REGULATORY
HORMONES AMPLIFY, WITH INSULIN
HIGH THEY DON'T HAVE EFFECT ON
INCREASING ALPHA CELL FUNCTION
SO SOMEONE WITH TYPE 1 DIABETES
HAVE HAVE A NORMAL EPINEPHRINE
RESPONSE, NO INCREASE IN
GLUCAGON, THAT'S A REAL
CHALLENGING CONUNDRUM WHEN
MOVING TO TESTING IN THE IN VIVO
SITUATION.
>> GREAT COMMENT.
THANK YOU.
>> MAYBE ONE FINAL POINT.
FANTASTIC PRESENTATIONS FROM
EACH ONE OF YOU.
ALL EXCITING THINGS, BETA CELL
PROLIFERATION, ALWAYS VERY COOL
BECAUSE TRADITIONALLY TYPE 1
DIABETES, THERAPEUTICS HAS
ALWAYS BEEN IMMUNE RELATED,
RIGHT?
LAST 30 OR 40 YEARS.
I THINK THERE'S POTENTIAL
STRENGTH HERE IN TERMS OF
PUSHING THE PROLIFERATION, I
MEAN, DYRK 1 INHIBITION IS ONE,
THERE ARE MULTIPLE FACTORS
COMING OUT, THE CHALLENGE IS TO
PUSH THE PROLIFERATION,
SOMETHING SUPPRESSING IMMUNE
SYSTEM, SO THAT SEEMS TO BE
EXTREMELY EXCITING IN THIS AREA.
IN TERMS OF THE EFFECT OF
DYRK1A, DO YOU KNOW THE
MECHANISM HOW GLP-1 ENHANCES
EFFECT, CREB PHOSPHORYLATION
EVENT, DOES IT LINK WITH DYRK1A
AT ALL.
>> NO, IT'S INVOLVED IN CALCIUM
FLUX, ACTUALLY ACTIVATES CALCIUM
MURINES, HELPING IN FACT GOING
TO THE NUCLEUS, WHILE INHIBITING
1A IN THAT SENSE.
YEAH, I MEAN, THAT WAS THE IDEA.
ANY WAY YOU CAN INCREASE
CALCIUM, THAT WILL ACTUALLY
FAVOR THE CREATION IN INHIBITORY
SITUATION IN WHICH DYRK1A IS
INHIBITED, ENHANCES
PROLIFERATION, THERE ARE MANY
OTHER KINASES THAT MAYBE
PARTICIPATE NOT JUST IN
PROLIFERATION BUT IN SURVIVAL,
PARTICIPATE IN CONVERSION OF
ALPHA CELLS TO BETA CELLS, NOT
AS SIMPLE AS INCREASED
PROLIFERATION THAT WAY.
IT'S MORE COMPLICATED THAT WAY.
>> DO WE KNOW EFFECT ON THE GUT?
THERE'S A LOT OF GLP-1 RECEPTOR
THERE.
>> IT'S IMPORTANT, LET ME SAY
THIS AGAIN.
I SAID IT DURING MY TALK.
THE DISCOVERY THAT ACTUALLY
GLP-1 SYNERGIZE WITH INHIBITOR
IS IMPORTANT BECAUSE IT ALLOWS
ACTUALLY TO FIRST OF ALL REDUCE
THOSE OF HARMINES, THAT IS
ACTING, THAT COULD EXPRESS 1A,
NOW THE DOSE GLP-1 RECEPTOR WILL
HAVE EFFECT PERHAPS HAPPENING IN
THE GUT, PERHAPS BECOME INSULIN,
WE HAVEN'T LOOKED AT THE GUT
THAT WAY.
WE LOOKED TO SEE WHETHER
INCREASING PROLIFERATION,
MICROLESIONS, WE DIDN'T FIND
ANYTHING THAT BUT DIDN'T LOOK AT
INSULIN POSITIVITY.
MAYBE IT'S ANOTHER AREA.
>> THANK YOU SO MUCH.
JOIN ME IN CONGRATULATING EACH
OF THE SPEAKERS FOR A GREAT
TALK.
A LOT OF EXCITEMENT FOR TEN
YEARS.
WE'RE GOING TO TAKE A 15-MINUTE
BREAK AND COME BACK FOR THE
KEYNOTE PRESENTATION, SO PLEASE
MAKE SURE YOU'RE BACK HERE AT
5:00 SHARP.
THANK YOU.
WE'LL START THIS FINAL KEYNOTE
TALK.
I'D LIKE TO INVITE DR. KAESTNER
UP.
>> A GREAT PLEASURE TO INTRODUCE
DR. ANETTE-GABRIELE ZEIGLER.
MOST OF YOU WILL HAVE HEARD
ABOUT HER AMAZING WORK OVER THE
YEARS.
A BIT MORE ABOUT HER HISTORY.
STUDIED MEDICINE IN MUNICH
BEFORE A POSTDOC AT THE JOSLIN
DIABETES CENTER IN BOSTON WITH
GEORGE EISSENBERG, RETURNED BACK
TO MUNICH, FURTHERED HER CAREER,
NOW DIRECTOR OF THE DIABETES
RESEARCH INSTITUTE AT THE
HELMHOLTZ CENTER IN MUNICH,
PROFESSOR AND CHAIR OF DIABETES
AT THE UNIVERSITY OF IMMUNE
DISEASE.
SHE'S RECEIVED MULTIPLE AWARDS
DURING HER CAREER.
SHE RECEIVED MARY TAYLOR MOORE
EXCELLENCE AWARD FROM JDRS,
GEORGE EISSENBERG AWARD FOR TYPE
1 DIABETES PREVENTION, ALSO FROM
GERMAN DIABETES ASSOCIATION,
HIGHEST HONOR IN GERMANY FOR
THAT FIELD.
SHE'S ALSO PRINCIPAL
INVESTIGATOR OF THE TEDDY STUDY,
AND PRINCIPAL INVESTIGATOR OF
THE TRIAL NETWORK, AND SHE ALSO
IS CO-LEADER OF EUROPEAN HORIZON
EFFORT IN THE SAME FIELD.
DR. ZEIGLER PUBLISHED OVER 500
PEER REVIEWED PAPERS, HIGHLY
CITED, A GREAT HONOR TO HAVE HER
AND TELL US ABOUT THE VULNERABLE
PERIOD FOR ISLET AUTOIMMUNITY.
>> THANK YOU VERY MUCH FOR THIS
VERY KIND INTRODUCTION.
OKAY.
YEAH, IT IS REALLY A GREAT HONOR
FOR ME TO BE INVITED TO THIS
MEETING, AND A GREAT MEETING.
THANK YOU SO MUCH FOR HAVING ME
HERE.
HERE ARE MY DISCLOSURES, ONE
OTHER, I'M WORKING MORE ON THE
PERIPHERY, PERIPHERAL BLOOD,
THIS IS WHAT I'M PRESENTING.
SO, MY TALK WILL BE MAINLY ABOUT
THE PERIOD LEADING TO
AUTOIMMUNITY, BUT AT THE END
WILL ALSO BRIEFLY SPEAK ABOUT
PROGRESSION FROM AUTOIMMUNITY TO
CLINICAL DIABETES.
AND I WILL PRESENT THREE
COHORTS, LONGITUDINAL BIRTH
COHORTS, WITH MULTIPLE SAMPLES
FROM BIRTH THROUGHOUT MANY, MANY
YEARS, ONE IS THE FIRST BIRTH
COHORT STUDY I INITIATED IN
GERMANY, EXCLUSIVELY IN FIRST
DEGREE RELATIVES, CHILDREN WITH
FATHER, SIBLING, OR MOTHER WITH
DIABETES.
FROM THE TEDDY STUDY, FOLLOWING
CHILDREN ALSO FROM THE GENERAL
POPULATION, AND SELECTED BY AGE
SUSCEPTIBILITY, AND POINT,
COLLECTED BY GENETIC RISK SCORE,
HIGH GENETIC RISK ALSO INCLUDING
GENERAL POPULATION.
A BIT PARTICULAR, SPEAKING ABOUT
THIS COHORT RECRUITED THROUGHOUT
THE PANDEMIC.
SO THIS IS THE VULNERABLE
PERIOD.
WHAT IS SPECIAL ABOUT
AUTOIMMUNITY?
WE'VE SHOWN FIRST IN THE
BABYDIET STUDY, IT'S NOT
INITIATING THROUGHOUT LIFE AT
THE SAME PACE.
THERE'S A PEAK PERIOD OF ISLET
AUTOIMMUNITY, VERY EARLY IN
LIFE, WHAT YOU SEE HERE IS THE
INCIDENCE OF ISLET
AUTOANTIBODIES, SO THE START,
SEROCONVERSION OF THESE
ANTIBODIES, IN WONDERING IF THIS
IS THE SAME IN THE GENERAL
POPULATION.
IN THE TEDDY STUDY, IT'S REALLY
THE SAME PEAK.
BECAUSE OF THIS PEAK THIS
ACTUALLY ENABLES US TO STUDY
THIS PERIOD BEFORE, AND ALSO ASK
THE QUESTION, WHY THERE IS SUCH
A SUSS SUSCEPTIBLE PERIOD IN
EARLY LIFE.
THIS IS A VERY GOOD AGE TO
DIAGNOSE, AND LASTLY TO DO
PRIMARY PREVENTION STUDIES
BECAUSE WE HAVE A VERY SHORT
READOUT, NAMELY THIS PEAK VERY
EARLY IN LIFE.
SO, THERE IS SOME HETEROGENEITY,
AND I'M JUST GIVING YOU ONE
EXAMPLE.
YOU CAN SEE MALES HAVE EARLIER
AND HIGHER PEAK OF THIS
AUTOIMMUNITY THAN FEMALES.
OTHER FACTORS INFLUENCE THE PEAK
BUT I JUST WANTED TO GIVE ONE
EXAMPLE.
AND I'M ALSO SHOWING YOU THAT IF
ONE LOOKS AT THAT, A BIT OF A
DIFFERENT WAY, NOT AS AN
INCIDENCE CURVE BUT JUST AS THE
RELATIVE RISK TO DEVELOP THIS
ISLET ANTIBODY, THERE ARE
FACTORS LIKE GENETIC FACTORS,
PROBABLY ENVIRONMENTAL FACTORS
THAT HAVE DIFFERENT IMPACT ON
THE RISK DEPENDING ON THE AGE.
YOU SEE HERE THE INCREASE OF
RISK FOR THE INSULIN GENOTYPE IS
TWO-FOLD IN EARLY AGE GROUPS BUT
GOES DOWN BELOW 1, THAT MEANS IF
YOU DEVELOP ANTIBODIES LATER ON,
THIS GENOTYPE, FOR EXAMPLE,
DOESN'T MATTER ANYMORE.
BUT IF YOU DEVELOP IT EARLY, IT
INCREASES THE RISK.
AND THIS IS THE FACT, THE SAME
WITH HLA AND OTHER GENETIC
FACTORS, SO THESE IMPACT MAINLY
FOR EARLY PEAK AUTOIMMUNITY, NOT
SO MUCH LATER ON.
THIS IS WHY I THINK WE HAVE ALSO
TO LOOK AT ENVIRONMENTAL
FACTORS, TRIGGERS, IN A
DIFFERENT WAY AND VERY AGE
DEPENDENT.
SO WHY ARE CHILDREN SO
SUSCEPTIBLE IN THE FIRST YEARS?
BECAUSE YOU ARE VERY MUCH
INTERESTED IN BETA CELLS, AND
JUST STARTING WITH BETA CELL,
WHAT WE DID IN THIS POINT STUDY
FOR SAFETY REASONS, WE MONITORED
GLUCOSE LEVELS IN THE CHILDREN
INTENSIVELY OVER THE FIRST
YEARS, AND WHEN WE LOOKED AT ALL
THE CHILDREN, JUST WITH GENETIC
RISK SCORE, SAW GLUCOSE LEVELS
ARE NOT STABLE OVER FIRST YEARS
OF LIFE.
THEY DECREASE AND THEY INCREASE.
AND THIS KIND OF MIRRORS ALMOST
THE PEAK INCIDENCE OF
AUTOIMMUNITY, IN LIFE.
SO GLUCOSE METABOLISM LIKELY
PANCREATIC ISLETS UNDERGO
SUBSTANTIAL MODIFICATIONS DURING
THE FIRST YEAR OF LIFE, AND THIS
IS A FIRST INDICATION THAT MAYBE
DURING THIS TIME THE BETA CELL
IS VERY ACTIVE, AND MAYBE EVEN
MORE VULNERABLE AND THIS IS WHY
AUTOIMMUNITY HAPPENS DURING THIS
ACTIVITY PHASE.
WHAT WE DID, WE LOOKED AT
FACTORS THAT INFLUENCED THE
DECREASE AND ALSO INCREASE, WE
WERE CUTTING THIS CURVE KIND OF
IN HALF.
YOU SEE AGAIN SEX MATTERS.
SO BOYS HAVE HIGHER LEVELS THAN
GIRLS.
I SHOWED YOU JUST BEFORE THAT
THE PEAK INCIDENCE OF
AUTOIMMUNITY IS SOMEHOW ALSO
DIFFERENT BY SEX.
YOU SEE ALSO INSULIN PHENOTYPE
MATTERS.
IF YOU HAVE THE SUSCEPTIBLE
GENOTYPE, HAVE YOU SOME OF
HIGHER AND STEEPER FALL OF THE
GLUCOSE LEVELS THAN THE OTHERS.
SO THESE FACTORS SEEM TO SOMEHOW
INFLUENCE EARLY GLUCOSE AND BETA
CELL ACTIVITY AS THEY DO
AUTOIMMUNITY.
SO, OF COURSE, WE ALSO LOOKED,
THESE WERE IN ALL CHILDREN, JUST
INDEPENDENT WHETHER THEY
DEVELOPED AUTOIMMUNITY OR NOT.
WE LOOKED AT GLUCOSE LEVELS TO
THE TIME OF SEROCONVERSION.
AND WHAT WAS KIND OF STRIKING TO
US WE COLLECTED PRE-PLANNEDDAL
AND POSTPRANDIAL, THERE WAS
AFTERWARDS RISE IN THIS,
DIFFERENCE OF 15-MILLIGRAM THIS
RISE WAS WITHIN THE NORMAL
GLYCEMIC LEVELS.
THE QUESTION IS DOES THIS
SUGGEST BETA CELL INJURY BEFORE
THE START OF AUTOIMMUNITY?
AND JUST AS A FIRST BRIEF
SUMMARY, BLOOD GLUCOSE
METABOLISM AS I SHOWED INVERSELY
FOLLOWS AUTOIMMUNITY INCIDENCE,
MAY INDICATE PERIOD OF
VULNERABILITY AND ACTIVITY, AND
THIS SUDDEN RISE IN
POST-PARANDIAL MAY BE CONSISTENT
WITH EVENT THAT AFFECTS ISLET
FUNCTION.
WHAT COULD BE SUCH AN EVENT?
WHAT WE ALSO DID, WE STARTED
INTENSIVELY DURING THIS VERY
EARLY PERIOD, EVERYTHING SOMEHOW
RELATED TO INFECTION AND
INFLAMMATION.
AND YOU CAN SEE IN THIS TEDDY
STUDY JUST LOOKING AT
RESPIRATORY INFECTION EPISODES,
THAT ALSO THOSE ARE QUITE
FREQUENT IN THIS VERY EARLY AGE
PERIOD, AND THEY DECLINE, ALSO
SOMEHOW ALMOST MIRRORING
AUTOIMMUNITY INCIDENCE.
WE STUDIED CHILDREN OVER 800
CHILDREN FOR A CD 169 EXPRESSION
ON MONOCYTES.
HERE YOU CAN SEE THAT THERE IS
MUCH MORE INFLAMMATION OF THESE
MONOCYTES EARLY IN AGE, AND THAT
DECREASES OVER TIME.
THIS IS PROBABLY REFLECTING
THESE CHILDREN HAVE MANY MORE
INFECTIONS, AND ARE EXPOSED TO
NEW ENVIRONMENTAL FACTORS, AND
THIS IS WHY THERE IS A LOT OF
INFLAMMATION.
THIS WAS ALREADY SHOWN BY
ROBERTO BEFORE.
WE ALSO SEE INDEED TYPE I
INTERFERON TRANSCRIPTIONAL
SIGNATURE PRECEDES ISLET
AUTOIMMUNITY SEROCONVERSION.
ALSO AN INDICATION THAT THERE
MAY BE INFLAMMATION HAPPENING,
INFECTION HAPPENING, BEFORE THE
AUTOIMMUNITY STARTS.
AND IN FACT WHAT WE DID THAT WE
INCUBATED, THIS IS IN VITRO
DATA, T CELLS WITH THESE
INFLAMED CYCLIC MONOCYTES
COMPARED TO THOSE NEGATIVE.
YOU SEE IN VITRO IN CHILDREN
WITH SUSCEPTIBLE GENOTYPES YOU
SEE MORE REACTIVITY TO INSULIN
FROM CD4 T CELLS UNDER THIS
INFLAMED CONDITION, JUST
INDICATING INFLAMMATION
INFECTION ALSO PROVIDES SOME
PROPENSITY TO AUTOREACTIVITY.
AND THERE'S ALSO SOME DATA FROM
DREY SON STUDDING ANTIGEN
RESPONSIVE EFT CELLS AT THE AGE
OF SIX MONTHS IN CHILDREN, THAT
WERE ALL BEFORE THEY DEVELOPED
AUTOIMMUNITY.
IF YOU COMPARE THOSE WHO DEVELOP
LATER ANTIBODIES TO ANTIBODY
NEGATIVE GROUP, YOU ALSO SEE
HERE THAT THERE IS ACTUALLY A
SIGNATURE OF PRO-INFLAMMATORY
T-CELL RESPONSES.
JUST ALL INDICATING THAT
INFLAMMATION DURING THIS PERIOD
MAY REALLY SOMEHOW MATTER FOR
THE IMMUNE RESPONSE.
SO, AS A SUMMARY INFLAMMATORY
PROCESSES ARE QUITE FREQUENT
EARLY IN LIFE, MAY LEAD TO
INCREASED PROPENSITY FOR
AUTOREACTIVITY, THIS ALREADY
EARLY BETA CELL STRESS OR INJURY
WHICH INCREASES THE LIKELIHOOD
OF AUTOIMMUNITY.
ARE THERE IDENTIFIERS EARLY IN
LIFE?
AND I WILL SPEAK ABOUT MYERS,
BRIEFLY MENTION MATERNAL
DIABETES BECAUSE I THINK IT'S
ALSO VERY RELEVANT FOR THE BETA
CELL.
YOU ALSO KNOW THAT MANY OF THOSE
PROSPECTIVE BIRTH COHORT STUDIES
NOT ONLY BABYDIET AND TEDDY BUT
DIP, DAISY MEDIA, INSURANCE
DATA, FOUND AN ASSOCIATION OF
EARLY MAINLY RESPIRATORY
INFECTIONS, IN PARTICULAR VIRAL
INFECTIONS, ASSOCIATED WITH
INCREASED OF ISLET IMMUNITY.
YOU SEE FROM TEDDY, EARLY
INFECTION, SIX TO NINE MONTHS,
THREE TO SIX MONTHS OR SO,
ASSOCIATED WITH ISLET
AUTOIMMUNITY, SIMILAR THING IN
BABYDIET, BUT NOT
GASTROINTESTINAL INFECTIONS,
THEY WERE RESPIRATORY.
TEDDY DID AMAZING WORK, ONE OF
THE LARGEST SEQUENCING STUDIES
OF VIRUSES IN STOOL SAMPLES,
FURTHER FOUNT ENTEROVIRUS B
POSITIVITY INCREASES SUSCEPTIBLE
TO AUTOIMMUNITY, THE SPECIAL
THING THAT PROLONGED INFECTION
WERE CRITICAL BECAUSE
SIGNIFICANCE ONLY THERE IF
SEVERAL CONSECUTIVE STOOL
SAMPLES WERE FOUND POSITIVE FOR
THE SAME VIRUS, FIRST EVIDENCE
IT IS ENTEROVIRUS, COXSACKIE,
NOT ONLY INFECTION OR UPPER
RESPIRATORY, IT'S ONE VIRUS
CANDIDATE, A DATA IN ISLETS
WHERE YOU FOUND COXSACKIE AS A
POSSIBLE VIRUS IN HISTOLOGY
STUDIES.
WHAT IS ALSO CLEAR THIS IS NOT
SO FREQUENT.
THIS PROLONGED INFECTION WAS
FOUND IN 30% OF THE CASES,
COMPARED TO 5.7% OF CONTROLS.
SO EITHER IT IS NOT FOUND IN
SCHOOL SAMPLES OR THE TIME, BUT
IT'S POSSIBLE, OR MAYBE THERE
ARE ALSO OTHER VIRUSES WHO CAN
HAVE A SIMILAR EFFECT, OR OTHER
JUST INFLAMMATORY CONDITIONS
COULD MAYBE INDUCE AUTOIMMUNITY,
PROBABLY NOT ALL VIRUS.
BUT ALSO THEN ALONG CAME COVID.
AND WE WENT TO SOME NATURAL
EXPERIMENT, WHERE WE COULD LOOK
AT INFECTIONS AND BECAUSE WE DID
THIS CLINICAL TRIAL POINT, WE
HAD TO LOOK AT STUDY AND STUDY
ADVERSE EVENTS INTENSIVELY IN
CHILDREN, 4 TO 9 MONTHS, ET
CETERA, COMPARED TO PRE-PANDEMIC
PERIOD, DURING THE PANDEMIC
PERIOD INFECTIONS AND
RESPIRATORY INFECTIONS WENT
DOWN, IF YOU LOOK AT COXSACKIE
INFECTIONS THEY WERE ALMOST
ZERO.
AFTER THE FIRST YEAR OF
PANDEMIC, LOCKDOWNED RELEASED,
INFECTIONS SAME BACK TO EVEN
SLIGHTLY HIGHER LEVEL THAN
BEFORE.
LOOK AT ISLET AUTOIMMUNITY, THE
BLUE CURVE IS PRE-PANDEMIC, THE
INCIDENCE.
DURING THIS TIME WHERE THESE
INFECTIONS AND COXSACKIE
INFECTIONS WENT DOWN, THE ISLET
ANTIBODY INCIDENTS WERE
ABSOLUTELY IDENTICAL.
AFTERWARDS IT WAS EVEN
INCREASED, SUGGESTING THAT ALSO
IT'S NOT ALL COXSACKIE, AND WE
STARTED IN THIS COHORT ALSO THE
ASSOCIATION WITH COVID
INFECTIONS AND WHAT WE SAW THAT
IN POINT TWO INFECTIONS IN THE
CHILDREN ACTUALLY INCREASED ALSO
THE LIKELIHOOD TO DEVELOP THESE
ANTIBODIES, IF YOU COMPARE ISLET
ANTIBODY INCIDENCE FROM
PRE-PANDEMIC IF A CHILD DID NOT
HAVE A COVID INFECTION, TO THOSE
WHO WERE INFECTED.
SARS INFECTION INCREASED IT
TWO-FOLD.
WHAT WAS ALSO INTERESTING IS
THAT IF THAT INFECTION HAPPENED
BEFORE 18 MONTHS OF LIFE IN THE
CHILDREN, THEN IT WAS ACTUALLY
FIVE-FOLD, WHAT YOU CAN SEE
HERE.
ALSO TEDDY STUDIED SARS-COV-2
INFECTION, DID NOT SEE INCREASE
IN THE TEENAGERS, INDICATING
THAT IT IS PROBABLY DIFFERENT,
THIS ENVIRONMENTAL TRIGGERS, HIT
SOMEONE DURING THIS VULNERABLE
PERIOD OR LATER ON.
SO, ALTOGETHER, THERE ARE MANY
POSSIBILITIES HOW VIRUSES AND
IMMUNE SYSTEM MIGHT DESTROY BETA
CELLS, AND THAT CAN BE OF COURSE
THROUGH DIRECT INFECTION OF BETA
CELL BUT COULD BE ALSO JUST
THROUGH STRESS OF THE BETA CELL
THROUGH INFLAMMATION, AND WE
KNOW THAT THERE IS ACTUALLY
TRANSIENT HYPERGLYCEMIA, NOT SO
UNFREQUENT, DURING INFECTION IN
CHILDREN.
AND ALSO I SHOWED YOU SOME
EVIDENCE THERE'S ACTIVATION OF
AUTOREACTIVITY DURING
INFLAMMATION, AND OF COURSE ALSO
OTHER POSSIBILITIES.
SO WE LOOKED ALSO IN OTHER POINT
COHORT, AND WE LOOKED AT
SARS-COV-2, AND METHYLATION, AND
WE HAD ACTUALLY, THIS IS
UNPUBLISHED DATA, SOME KIND OF
VERY INTERESTING FINDING THAT A
RECENT SARS-COV-2 INFECTION WAS
ASSOCIATED WITH MODULATED
METHYLATION.
AND THE CHANGES THAT WE FOUND
THROUGH THE CHROMOSOMES WERE
MAINLY T ANTI-VIRAL GENES, THAT
IS EXPECTED, YOU -- BUT WHAT WS
INTERESTING WE LOOKED AT
INFLUENZA IN THE CHILDREN AND
FOUND NO CHANGE IN METHYLATION
CPTs.
SO IT SEEMED THAT THERE IS
SOMETHING THAT SARS INFECTION
DOES MUCH MORE THAN OTHERS.
AND WHAT WAS ALSO INTERESTING IS
THAT THERE WAS ONE GENE ADAR,
OTHERS HAVE LOOKED AT ADAR 1
KNOCKOUT MOUSE AND HAVE ACTUALLY
SEEN THAT MIMICS ALMOST EARLY
STAGE TYPE 1 DIABETES PHENOTYPES
WITH MASSIVE INTERFERON
PRODUCTION, AND ALSO ISLET
INFLAMMATION, AND BETAS IN THE
ANIMALS.
INTERESTING THAT SARS INFECTION
SEEMS HERE TO MAKE CHANGES IN
THE METHYLATION ASPECT.
IT ALTERED DNA METHYLATION, TYPE
OF BETA 1 GENES.
SUMMARY HERE, DURING THE
PANDEMIC FEWER CHILDREN -- FEWER
CHILDHOOD INFECTIONS WERE
OBSERVED, INCLUDING COXSACKIE B.
INCIDENCE OF ISLET AUTOIMMUNITY
REMAINED THE SAME FOR THE FIRST
YEAR, HIGHER LATER.
PRESENCE OF SARS ANTIBODIES WERE
ALSO ASSOCIATED WITH RISK OF
ISLET IMMUNITY IN YOUNG
CHILDREN, AND INFECTION IN YOUNG
CHILDREN ASSOCIATED WITH
METHYLATION CHANGES IN TYPE 1
DIE DETECTIVES-RELEVANT GENE
REGIONS.
I WILL MENTION MATERNAL
DIABETES.
AS A SECOND POSSIBLE MODIFIER,
WE KNOW IF A CHILD IS BORN TO A
MOTHER WITH TYPE 1 DIABETES, HER
RISK TO HAVE THIS PEAK IS MUCH
LESS WHEN COMPARED TO A CHILD
FROM A FATHER WITH TYPE 1
DIABETES.
AND THERE ARE MANY, MANY
DISCUSSIONS, WHY THIS IS THE
CASE.
AND I THINK IT IS ALSO OF COURSE
INTERESTING RELATIVE TO THE BETA
CELL, BUT BECAUSE IT COULD BE
THAT THE DIABETES IN THE MOTHER
ALSO MAY LEAD TO SOME INCREASE
IN BETA CELL MASS, SO THERE ARE
A LOT OF PEOPLE I THINK
INTERESTED IN STUDYING THIS.
AND WE IN THIS LOOKED ALSO AT
METHYLATION.
I'M NOT SHOWING THE DATA BECAUSE
IT'S FROM MY COLLEAGUE, NOT YET
PUBLISHED, BUT I JUST CAN ALSO
SAY THAT WE FOUND SOME
SIGNIFICANT GENETIC
MODIFICATIONS, ASSOCIATED WITH
MATERNAL DIABETES AND IN THE
TYPE 1 ASSOCIATED TYPE 1
DIABETES GENES.
AND THAT MAY ALSO SUGGEST THAT
MATERNAL DIABETES SOMEHOW
DECREASES THE DIABETICOGENIC
EFFECT OF SUSCEPTIBLE GENES, A
BIT SIMILAR THAT AFFECTS LIKE
THE SARS-COV-2 INFECTION.
SO, CAN WE TRANSLATE THIS TO
PREVENTION?
WE HAVE ACTUALLY SINCE THE --
OTHER THE LAST TEN YEARS
ESTABLISHED A PREVENTION
PLATFORM IN EUROPE, THIS
PLATFORM IS ACTIVE IN MANY
EUROPEAN COUNTRIES, REALLY TO
TRANSLATE AND TRY TO TEST IN
PRIMARY PREVENTION TRIALS.
TO REDUCE INCIDENCE OF ISLET
IMMUNITY.
IN GPPAD WE IDENTIFY WITH A HIGH
ELEVATED GENETIC RISK BY USING
RISK SCORES LIKE I SAID IN THIS
POINT STUDY, POINT IS ONE OF THE
GPPAD STUDIES, TO PERFORMED
PRIMARY PREVENTION TRIALS, ALSO
TO USE IT TO IDENTIFY KEY EVENTS
AND MECHANISMS IN THE
PATHOGENESIS.
THIS IS JUST THE GPPED TEAM AND
CONSORTIUM, CLINICAL CENTERS
THAT CONTRIBUTED NOT ONLY TO
POINT BUT ALSO TO THE OTHER
STUDIES.
OVER THE LAST TEN YEARS WE HAVE
SCREENED OVER 500,000 NEWBORNS
IN THESE DIFFERENT CLINICAL
SITES BY USING A 47 SNP RISK
SCORE TO IDENTIFY CHILDREN FROM
THE GENERAL POPULATION THAT HAVE
A 25-FOLD INCREASE IN RISK, AND
WE IDENTIFY THOSE WITH A VERY
HIGH RISK.
THIS IS ABOUT 1.2%, OVER 6,000,
ASKED THEM TO PARTICIPATE IN
THESE PRIMARY PREVENTION TRIALS.
WE HAVE ENROLLED OVER 2,000
BABIES IN SUCH TRIALS.
HAVE COMPLETED ENROLLMENT OF TWO
TRIALS, ONE THE ONE I WAS
TALKING ABOUT ALL THE TIME,
PRIMARY INSULIN TRIAL TESTING
WHETHER ANTIGEN THERAPY, ORAL
INSULIN THERAPY, CAN PREVENT OR
REDUCE THE INCIDENCE OF ISLET
AUTOIMMUNITY.
SO IT'S NOT GIVEN TO PEOPLE WITH
ISLET AUTOIMMUNITY, BUT TO
HEALTHY CHILDREN IN ORDER TO
PREVENT IT.
OVER THESE THOUSAND CHILDREN
ENROLLED, WE WILL EXPECT
ACTUALLY THE RESULTS THIS YEAR.
THE SECOND STUDY IS A PROBIOTIC
STUDY CALLED SINT1A, ENROLLMENT
COMPLETE, THE TREATMENT PHASE IS
ALSO OVER ALREADY, JUST ONE
YEAR, TREATED FOR THREE YEARS,
AND PROSPECTIVE END IS 27.
WE JUST INITIATED A NEW TRIAL
CALLED ANTI-VIRAL ACTION AGAINST
TYPE 1 DIABETES AUTOIMMUNITY, A
TRIAL TESTING WHETHER A
VACCINATION AGAINST SARS-COV-2
VERY EARLY IN CHILDREN AGE 6, 7,
9 MONTHS IN REGULAR SCHEME
AGAINST PLACEBO IN THIS VERY,
VERY HIGH RISK CHILDREN CAN
REDUCE ISLET AUTOIMMUNITY.
AND WE HAVE A SECOND PART IN
THIS STUDY, WHERE WE DO VERY
INTENSE INFECTION SURVEILLANCE
BY COLLECTING WEEKLY SALIVA
SAMPLES, AND PCR THOSE SAMPLES
FOR 20 OTHER VIRUSES, TO REALLY
STUDY INTENSIVELY THE
CONTRIBUTION OF VIRAL INFECTIONS
FOR -- DURING THIS VULNERABLE
PERIOD IN THE CHILDREN.
PRIMARY OUTCOME IS ISLET
AUTOIMMUNITY.
WE NEED OVER 2,000 CHILDREN AND
STARTED ENROLLING.
IF YOU'RE INTERESTED, YOU CAN
LOOK AT OUR WEBSITE AND IF YOU
ARE IN EUROPE YOU COULD EVEN
CONTACT US IF YOU'RE INTERESTED
IN PARTICIPATING.
SO, VERY, VERY BRIEFLY, I HAVE A
FEW MORE MINUTES, I WANT ALSO TO
SAY SOMETHING ABOUT PROGRESSION,
FROM AUTOIMMUNITY TO SYMPTOMATIC
DIABETES BECAUSE ALSO HERE I
THINK BETA CELL FUNCTION IS
REALLY A VERY IMPORTANT
PREDICTOR OF PROGRESSION.
SO, YOU KNOW AN THIS WAS
MENTIONED BEFORE, WE HAVE
ACTUALLY IN GERMANY INITIATED A
LARGE GENERAL POPULATION,
SCREENING FOR ISLET
AUTOIMMUNITY, THE PROJECT IS
CALLED FREEDA, SCREENED IN
BAVARIA OVER 200,000
PARTICIPANTS IN THIS AGE RANGE,
AND HAVE IDENTIFIED 560 CHILDREN
WITH MULTIPLE ISLET ANTIBODIES,
AND WE INVITE THEM FOR STAGING.
THE MAJORITY HAS AT THE
BEGINNING STAGE 1, ONLY A FEW
STAGE 2, AND SOME HAVE ALREADY
OVERT DIABETES.
WE ASKED THE QUESTION, CAN WE
SOMEHOW STRATIFY FURTHER WITHIN
THESE STAGES, AND WHAT ARE THE
MARKERS THAT PREDICT
PROGRESSION, AND WE HAD A LOT OF
CHILDREN OF COURSE ALSO GOING
THROUGH THESE STAGES FROM STAGE
1 TO STAGE 2.
SO, I'M STARTING WITH STAGE 1.
WE LOOKED AT MULTIPLE PARAMETERS
IN THE MULTI-VARIABLE ANALYSIS
AT WHAT WE FOUND, IF THE T IS
MISSING, THAT I TOO, IT'S THE
CATEGORY, HIGH, LOW, NEGATIVE,
HBA1C, 90-MINUTE GLUCOSE AFTER
ORAL GLUCOSE THE BEST PREDICTORS
WITHIN THIS STAGE TO PREDICT
PROGRESSION.
AND WHEN WE LOOK AT A TWO-YEAR
RISK IN THE CHILDREN, YOU CAN
SEE IF THIS PROGRESSION SCORE
WAS ABOVE 90th PERCENTILE
CHILDREN HAD A 38% RISK TO
DEVELOP STAGE 3, WHILE IF IT WAS
LOW THEN IT WAS ZERO.
IF YOU JUST TOOK IA2 YOU CAN
ALSO DISCRIMINATE, MUCH LESS
THAN IF YOU INCLUDE MARKERS OF
BETA CELL FUNCTION.
WE ALSO LOOKED WITHIN STAGE 2,
AND WITHIN STAGE 2 WE SOLELY
USED THIS GLYCEMIA MARKERS, USED
HBA1C, FASTING, 120-MINUTE, OR
INTERMEDIATE OGTT LEVELS, JUST
PUBLISHED, WE LOOKED AT VERY
MANY DIFFERENT COMBINATIONS, BUT
I JUST TO SIMPLIFY BECAUSE I
THOUGHT IT IS INTERESTING THAT
IF YOU LOOK, YOU CAN'T COUNT,
MAXIMUM CAN HAVE FOUR, IN YOU
HAVE ONE COMPARED TO TWO
COMPARED TO THREE TWO-YEAR RISK
IS HERE ALMOST THE SAME LIKE IN
STAGE 1 BY THIS PLS BUT THEN
ABOUT TWO, 66%, 80%, COMBINATION
HBA1C PLUS ONE OF THESE
ABNORMALITIES WAS ALSO VERY HIGH
IN RISK.
SO I THINK JUST THE BETA CELL
FUNCTION IN BOTH STAGE 1 AND
STAGE 2 CAN REALLY STRATIFY HOW
QUICKLY SOMEBODY DEVELOPS
DIABETES.
AND I KNOW THAT YOU ARE TALKING
ABOUT THE VITILIGO OF THE BETA
CELL, AND BETA CELLS DO THEY
FUNCTION OR NOT, BUT I THINK
THIS SOMEHOW ALSO INDICATES THAT
REALLY HOW WELL THEY FUNCTION
CORRELATES EXTREMELY WELL WITH
PROGRESSION RATES.
SO, BETA CELL FUNCTION ARE GOOD
PREDICTORS OF THE PHASE.
NOW I HAVE TWO MORE ADVERTISING
SLIDES, I WANTED TO TELL YOU
THAT WE ARE HAVING A EUROPEAN
NETWORK CALLED IDENTIFY WITH 28
PARTNERS, WHERE WE BRING SUCH A
GENERAL POPULATION TO DIFFERENT
COUNTRIES IN EUROPE, WITH
UNIFIED SCREENING, AND ALSO WE
HAVE ESTABLISH A PRE-TYPE 1
DIABETES REGISTRY IN EUROPE,
WHERE WE REGISTER ALL THOSE THAT
CHILDREN THAT ARE ANTIBODY
POSITIVE AND HAVE NOT YET
DEVELOPED DIABETES, TO
FACILITATE TRIALS.
AND WITH THOSE CONSORTIA IN THE
EARLY STAGES AND ALSO IN THE
PROGRESSION STAGES, WE REALLY
COLLABORATE AND OFFER DATA,
OFFER TRIALS, SHARE SAMPLES, AND
OF COURSE WE ARE ALSO INTERESTED
TO PARTICIPATE IN TRIALS AND
COLLABORATE WITH ALL OF YOU.
SO THANK YOU VERY MUCH.
I WOULD LOVE TO ACKNOWLEDGE ALL
THOSE WHO FUNDED MY RESEARCH,
THAT IS VERY MUCH ALSO HELMSLEY
BREAK THROUGH TYPE 1D AND ALSO
THANK YOU TO NIDDK, TO THE
PATIENTS, THE TEAMS THAT WORK IN
THE CONSORTIA.
HERE IS THE TEDDY TEAM, ACTUALLY
THE LAST TEDDY MEETING NEXT
WEEK, AGAIN HERE IN THE STATES,
AFTER SO MANY YEARS OF WORKING
TOGETHER, AND THIS IS MY TEAM
THAT I ACKNOWLEDGED ALREADY ALSO
ON THE SLIDE THROUGHOUT.
THANK YOU SO MUCH FOR YOUR
ATTENTION.
[APPLAUSE]
>> QUESTIONS FOR DR. ZEIGLER,
PLEASE.
GET TO THE MICROPHONE PLEASE.
STATE YOUR NAME AND AFFILIATION.
THANK YOU.
>> DAVID FROM YALE UNIVERSITY.
NICE TALK.
A COMMENT ABOUT YOUR PLAN TO
TEST THE SARS VACCINE FOR
PREVENTING TYPE 1 DIABETES.
THERE WERE SEVERAL CASE REPORTS
OF PEOPLE WHO TOOK THE VACCINE
AND DEVELOPED TYPE 1 DIABETES.
AND WHEN GENOTYPED ALREADY HAD
PREDISPOSITION TO TYPE 1
DIABETES.
INHIBITORS, YOU ACTIVATE IMMUNE
RESPONSE, AND TRIGGER TYPE 1
DIABETES, SO YOU MAY WANT TO BE
CONSCIOUS USING THE VACCINE TO
HAVE THE OPPOSITE EFFECT, WHERE
AUTOIMMUNITY.
>> YEAH, I MEAN, I KNOW THAT
PEOPLE ARE TALKING ABOUT IT.
UNFORTUNATELY, THERE ARE KNOW
PUBLICATIONS, AND ALSO IN THE
DATABASES WE'RE USING BIOTECH
VACCINE, THESE CASES ARE NOT
REGISTERED.
BUT I CAN SAY THAT OF COURSE
THIS IS A CLINICAL TRIAL,
REGISTERED AS A CLINICAL TRIAL,
PLACEBO-CONTROLLED, WITH DSMB,
ALL MONITORING, LOOKING AT THE
SAFETY AND IF THERE'S ANY
WORRYING SIGNAL WE WOULD
IMMEDIATELY OF COURSE STOP THE
TRIAL.
>> THERE ARE A FEW PUBLICATIONS
GENOTYPE, SOME PEOPLE WHO
DEVELOP, QUITE ELDER LY, IN THE
80s, AFTER TAKING THE COVID
VACCINE DEVELOPED TYPE 1
DIABETES, IF YOU GENOTYPE THEM
YOU DO SO MOST OF THEM HAVE HLA
TYPE I INTERFERON RESPONSE, AN
OBSERVATION, GOING INTO YOUR
TRIAL.
>> THANK YOU.
>> THANK YOU, DR. ZEIGLER.
WONDERFUL PRESENTATION.
ABOUT INFLAMMATORY PROCESSES,
YOU WERE COMMENTING ABOUT, COULD
IT BE BECAUSE OF A CHANGE IN THE
DIET OF THE BABIES, MAYBE
RELATED BECAUSE OF THE LACK OF
MODERN MILK OR SOMETHING LIKE
THAT, IS THERE A CO-FOUNDER
VARIABLE THAT YOU CHECK TOO?
>> I DON'T KNOW WHAT YOU MEAN,
THE CHANGE IN GLUCOSE OR I MEAN
OF COURSE AT THE TIME WHEN THE
GLUCOSE LEVELS GLOW DOWN, ALSO
MAYBE MORE ISLET ACTIVITY,
PEOPLE ARE CHANGING FROM DIET
USING ONLY MILK TO SOLID FOOD,
THAT IS ALSO SOMETHING THAT IS
OF COURSE VERY CRITICAL, BUT WE
LOOKED IN TEDDY INTENSIVELY INTO
DIET AND WE DID NOT REALLY FIND
MUCH IN TERMS OF DIET AND
ASSOCIATION WITH ISLET
AUTOIMMUNITY, A LITTLE IN THE
AMOUNT OF PROTEIN USED, BUT
OTHERWISE IT WAS NOT SO MUCH
ASSOCIATION.
>> AND AUTOIMMUNITY THAT THE
MOTHER GIVE TO BABY THROUGH THE
MILK?
>> I DON'T KNOW WHAT THE
QUESTION -- WHAT IS THE
QUESTION?
>> SO, THIS AUTOIMMUNITY FOUND
ON THE PANCREAS, RIGHT, COULD IT
BE BECAUSE OF THE RECENT CHANGE
FROM THE MOTHER'S MILK TO
REGULAR MILK OR FORMULA?
>> I DON'T KNOW.
I MEAN, THERE WAS ONE STUDY
CALLED TRIGGER THAT TESTED
ACTUALLY FORMULA AND HYDROLYZED
FORMULAS, AND ALSO
BREASTFEEDING, AND DID ALSO NOT
SEE REALLY AN EFFECT, BUT OF
COURSE I MEAN WE HAVEN'T REALLY
LOOKED AT THAT OVER TIME TO KNOW
WHETHER CHANGES OF THE LAST 50
YEARS MATTERED IN THAT
DIRECTION.
>> THANK YOU.
>> WEILL CORNELL MEDICINE, THANK
YOU FOR SHARING EXCITING WORK.
I JUST HAVE QUICK QUESTION,
CLARIFICATION, YOU SHOWED SOME
UNPUBLISHED DATA SARS-COV-2
INFECTION CHANGED METHYLATION
STATUS, WANT CLARIFICATION FROM
PBMC OF PATIENT SAMPLES OR IN
VITRO EXPERIMENT OR IF PBMC HAVE
YOU HEARD ANY MAJOR EXPERIMENT
WOULD SEE RESULT?
>> FROM BLOOD DNA TAKEN IN THE
CHILDREN, NOT PBMCs.
>> ARE YOU AWARE OF IN VITRO
EXPERIMENTS?
>> NO, I DON'T KNOW WHETHER IT
WAS SHOWN BEFORE, I DON'T KNOW.
>> THANK YOU.
>> THAT WAS AWESOME,
OUTSTANDING.
THE NUMBER OF PEOPLE YOU
SCREENED IS STAGGERING, RIGHT?
WHEN YOU TALK ABOUT 500,000.
I'D LIKE YOU TO SPECULATE.
WE KNOW MAYBE 30 OR 40% OF
INDIVIDUALS WHO DEVELOP TYPE 1
DIABETES DEVELOP IT OVER THE AGE
OF 30.
SO ARE THERE CONNECTIONS THAT
YOU WOULD LIKE TO MAKE OR
SPECULATIONS, IS THAT -- DO
SIMILAR THINGS HAPPEN IN THAT,
DOES IT INFORM US AT ALL?
WHAT ARE YOUR THOUGHTS.
THANK YOU.
>> DO YOU MEAN WHETHER BOTH
PEOPLE WHO DEVELOP THE DIABETES
AT 30 ARE SIMILAR TO THOSE EARLY
ONES?
>> CORRECT.
IS THERE METABOLIC INSTABILITY
THAT PRECEDES?
YOU KNOW HAVE DATA BUT
SPECULATE.
>> IF YOU LOOK AT PROGRESSION,
RELATIVELY STABLE, NO PEAK,
INCIDENCE OF PROGRESSION, NO
PEAK.
SO IF WE MODEL THIS, THAT
ACTUALLY FROM THOSE WHO DEVELOP
THIS AUTOIMMUNITY VERY EARLY,
THERE IS SUBPOPULATION THAT WILL
PROGRESS TO DIABETES BY 30 YEARS
ONLY, ABOUT 10 OF HUNDRED WILL
ACTUALLY TAKE SOME LONG TIME
UNTIL THEY WILL PROGRESS.
SO I THINK THEY VERY SIMILAR
FEATURES BUT THERE ARE OTHER
AUTOIMMUNITY ARISING THROUGHOUT
LIFE AND WE HAVE PEOPLE WHO
SEROCONVERT 18, 19, 20, THEY
LOOK DIFFERENT.
MY SPECULATION WOULD BE THAT
AUTOIMMUNITY THAT IS INITIATED
LATER IN LIFE HAS PROBABLY OTHER
FEATURES.
AND MAYBE ONE CAN SAY MAY BE A
DIFFERENT ENDOTYPE.
>> CAN I MAKE SURE I UNDERSTOOD?
SOME PEOPLE WHO DEVELOP DIABETES
AT AGE 30, AUTOIMMUNITY MIGHT
HAVE BEEN INITIATED IN THAT
VULNERABLE PERIOD OF LIFE?
>> WE HAVE FROM OUR BABY DIET
STUDY, EIGHT PEOPLE HAVE OVER 25
YEARS FOLLOW-UP WITHOUT
DIABETES, AND STILL ALL MULTIPLE
ANTIBODY POSITIVE AND ACTUALLY
FIVE I THINK HAVE FOUR
ANTIBODIES, THEY HAVE NOT YET
PROGRESSED.
SINCE 25 YEARS HAVE INITIATED IN
THE FIRST TWO YEARS OF LIFE.
AND SO IT HAPPENS, AND I'M STILL
CONVINCED THEY WILL DEVELOP THIS
DISEASE.
THERE'S NO SIGNS THAT THEY WILL
NOT.
AND THEY HAVE NO PROTECTIVE
GENOTYPES, SO ALSO IT WAS
MENTIONED THEY ARE PROTECTED
FOREVER, I THINK THEY WILL
DEVELOP, BUT THEY ARE JUST VERY
SLOW.
AND BUT THERE ARE OTHERS WHO
INITIATE LATER ON, AND WE HAVE
THOSE EXAMPLES IN TEDDY AND ALL
THE STUDIES, THEY ARE MUCH LESS
THAN THE EARLY PEAK, BUT THEY
EXIST.
AND THEY HAVE OFTEN THE SCAD
PHENOTYPE, AND OTHERS, OR HAVE
MORE FREQUENTLY ALSO SIMILAR
ANTIBODIES ONLY.
SO I THINK THEY MAY BE
DIFFERENT.
AND NOT SO THIS INFLAMMATORY
TYPE.
I CAN ALSO SAY THAT WE LOOKED AT
AN ONSET POPULATION IN A
REGISTRY, AND KIND OF
CHARACTERIZED AND CLUSTERED
THEM.
THOSE CHILDREN WHO DEVELOPED
VERY EARLY IN LIFE HAD REALLY
MUCH MORE AUTO-INFLAMMATORY TNF
INTERFERON GAMMA CLUSTERS AND
THE OLDER ONES DIDN'T HAVE THAT.
THEY HAVE HAD EVEN MORE KIND OF
INSULIN RESISTANT SIGNS, A
LITTLE BIT, SO I THINK THERE ARE
OTHER MECHANISMS MAYBE.
THAT'S VERY SPECULATIVE.
>> TWO MORE QUESTIONS.
>> THANK YOU FOR THE EXCELLENT
TALK.
CHRISTY FROM VANDERBILT, CURIOUS
ABOUT IF YOU HAVE THOUGHTS ON
THE RECENT META-ANALYSIS
PUBLISHED IN JAMA PEDIATRICS
THAT SHOWS DAY CARE ATTENDANCE
SEEMS TO BE PROTECTIVE AGAINST
TYPE 1, AND HOW YOU RECONCILE
WITH YOUR QUESTIONSIVE BODY OF
WORK THAT INDICATES EXPOSURE TO
MICROBES WHICH HAPPENS IN DAY
CARE SEEMS TO ACTUALLY BE
CAUSATIVE?
>> THANK YOU VERY MUCH FOR
BRINGING THIS UP.
I THINK IT'S VERY, VERY
IMPORTANT THAT CHILDREN ARE
EXPOSED TO INFECTIONS AND MAYBE
EXPOSED REGULARLY AND EARLY
MAYBE ALSO INFLAMMATORY
RESPONSES MAY BE LESS BECAUSE
THEY LEARN IMMUNE SYSTEM LEARNS
TO COPE WITH INFECTION, BUT THIS
IS ALSO SPECULATION.
AND IT IS MAYBE ALSO REALLY
SPECIFIC INFECTIONS THAT MATTER.
BUT I DON'T KNOW.
>> THANK YOU.
>> BRIAN ZANE, ADAPTIVE
BIOTECHNOLOGIES.
THANK YOU VERY MUCH.
I WAS WONDERING I READ ABOUT HLA
AND THAT THAT CAN CORRELATE WITH
ONSET SO I'VE READ SOMETHING
AROUND DQA BEING SECRETARIED
WITH YOUNGSER ONSET VERSUS DQ 2
ASSOCIATED WITH OLDER ONSET,
PERHAPS PHENOTYPE YOU MENTIONED,
WONDERING DO YOU HAVE HLA TYPING
AND HAVE YOU LOOKED AT THAT?
>> YES, WE HAVE HLA TYPING.
I MEAN, YES, I DIDN'T SHOW THIS,
JUST SHOWED FOR INSULIN SNP BUT,
YES, THE HLA MATTERS FOR MORE
EARLY ONSET.
AND THOSE WHO DEVELOP DIABETES
LATER OFTEN HAVE NOT ALWAYS THE
CLASSICAL HLA GENOTYPES, THEY
ARE MORE DIVERSE AND HAVE ALSO
KIND OF NEUTRAL GENOTYPES, ET
CETERA.
BUT THERE ARE ALSO CHANGES OVER
TIME HAPPENING.
WE COMPARED EARLY COHORTS WITH
LATER COHORTS, AND WE SEE THE
EARLY COHORTS ALTOGETHER HAD
MORE HIGH RISK GENOTYPES, ALSO
WITHIN THE HLA, THAT THE LATER
COHORTS, THERE IS ALSO A SHIFT
THAT THOSE WHO DEVELOPED
DIABETES TODAY HAVE LESS OF THIS
OR HIGH RISK GENOTYPES THAN
THOSE WHO DEVELOP DIABETES 20
YEARS AGO.
SO IT'S KIND OF COMPLEX.
>> THANK YOU.
>> LAST QUESTION.
>> HI.
MOUNT SINAI SCHOOL OF MEDICINE
IN NEW YORK.
THANK YOU VERY MUCH FOR THIS
AMAZING TALK.
AND IMPRESSIVE BODY OF WORK.
MY QUESTION IS ABOUT THE
OBSERVATION THAT YOU MADE ABOUT
DEVELOPING -- CHANCES OF
DEVELOPING TYPE 1D IF YOU HAVE A
MOTHER WITH TYPE 1D VERSUS A
FATHER WITH TYPE 1D AND WHAT
COULD BE POTENTIAL MECHANISMS,
YOU HINTED EPIGENETICS, BROUGHT
TO MIND GENETIC IMPRINTING, IT'S
AN IMPORTANT PROCESS, VARIOUS
ASPECTS OF BIOLOGY AND HUMAN
DEVELOPMENT AND DISEASE, BUT WE
ALSO KNOW FROM KASTNER'S WORK
THAT IMPRINTING ON CHROMOSOME 11
ARE IMPORTANT.
I'M JUST THINKING ALONG THE
LINES OF WHETHER ANY GENES --
WHETHER EPIGENETIC CHANGES THAT
YOU HINTED ON WERE ABOUT
METHYLATION AND ALSO IF WE COULD
LEARN ANYTHING ABOUT THE
IMPRINTED REGIONS ON THE GENOME
AND IF THIS HAS ANYTHING TO DO
WITH DIFFERENCE DEVELOPING TYPE
1D, MANY PEOPLE LOOKED AND
DIDN'T FIND MUCH DIFFERENCE IN
GENES, METHYLATION IS DIFFERENT
STORY.
IF YOU LOOK AT GENES, GENETIC
RISK SCORES, NO DIFFERENCE
REALLY.
IMPRINTING EARLY DAYS WAS LOOKED
AT BUT NOT REALLY FOUND AS
EXPLANATION, THERE WAS ALSO THE
QUESTION, DO CHILDREN OF MOTHERS
DIE MORE FREQUENTLY DURING
ALREADY PREGNANCY AND THAT IS
KIND OF A SELECTION PROCESS THAT
I THINK ALL EVIDENCE IS NOT SO
STRONG FOR EXPLAINING REALLY THE
DIFFERENCE.
>> THANK YOU.
>> LET'S THANK DR. ZEIGLER AND
ALL THE SPEAKERS.
[APPLAUSE]